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May 2021 – ICYMI
Gastroenterology
February 2021
Worldwide burden of, risk factors for, and trends in pancreatic cancer
Huang J et al. Gastroenterology. 2021 Mar 1;160(4):744-54. doi: 10.1053/j.gastro.2020.10.007.
Fibrates for Itch (FITCH) in fibrosing cholangiopathies: A double-blind, randomized, placebo-controlled trial
de Vries E et al. Gastroenterology. 2021 Mar 1;160(4):734-43.e6. doi: 10.1053/j.gastro.2020.10.001.
March 2021
How to integrate a medical ethics curriculum into gastroenterology fellowships
Rao VL et al. Gastroenterology. 2021 Mar 1;160(4):1003-6. https://doi.org/10.1053/j.gastro.2021.01.211.
Colonoscopist performance and colorectal cancer risk after adenoma removal to stratify surveillance: two nationwide observational studies
Wieszczy P et al. Gastroenterology. 2021 Mar 1;160(4):1067-74. doi: 10.1053/j.gastro.2020.10.009.
Pregnancy and neonatal outcomes after fetal exposure to biologics and thiopurines among women with inflammatory bowel disease
Mahadevan U et al. Gastroenterology. 2021 Mar 1;160(4):1131-9. doi: 10.1053/j.gastro.2020.11.038.
April 2021
AGA Clinical Practice Guidelines on intragastric balloons in the management of obesity
Muniraj T et al. Gastroenterology. 2021 Apr 1;160(5):1799-808. doi: 10.1053/j.gastro.2021.03.003.
How to strategically build your network for early career gastroenterologists
Gaidos JKJ et al. Gastroenterology. 2021 Apr 1;160(5):1461-6. doi: 10.1053/j.gastro.2021.01.025.
The microbiota-gut-brain axis: From motility to mood
Margolis KG et al. Gastroenterology. 2021 Apr 1;160(5):1486-501. doi: 10.1053/j.gastro.2020.10.066.
The association of histologic and noninvasive tests with adverse clinical and patient-reported outcomes in patients with advanced fibrosis due to nonalcoholic steatohepatitis
Younossi ZM et al. Gastroenterology. 2021 Apr 1;160(5):1608-19. doi: 10.1053/j.gastro.2020.12.003.
Clinical Gastroenterology and Hepatology
February 2021
Management of chronic abdominal distension and bloating
Lacy BE et al. Clin Gastroenterol Hepatol. 2021 Feb 1;19(2):219-31. doi: 10.1016/j.cgh.2020.03.056.
Prevalence of gastric intestinal metaplasia in a multiethnic US veterans population
Nguyen TH et al. Clin Gastroenterol Hepatol. 2021 Feb 1;19(2):269-76. doi: 10.1016/j.cgh.2020.03.015.
Rome IV functional gastrointestinal disorders and health impairment in subjects with hypermobility spectrum disorders or hypermobile Ehlers-Danlos syndrome
Lam CY et al. Clin Gastroenterol Hepatol. 2021 Feb 1;19(2):277-87. doi: 10.1016/j.cgh.2020.02.034.
Factors that affect adequacy of colon cleansing for colonoscopy in hospitalized patients
Fucci L et al. Clin Gastroenterol Hepatol. 2021 Feb 1;19(2):339-48. doi: org/10.1016/j.cgh.2020.02.055.
March 2021
Real-world gluten exposure in patients with celiac disease on gluten-free diets, determined from gliadin immunogenic peptides in urine and fecal samples
Stefanolo JP et al. Clin Gastroenterol Hepatol. 2021 Mar 1;19(3):484-91. doi: 10.1016/j.cgh.2020.03.038.
Factors associated with response to anorectal biofeedback therapy in patients with fecal incontinence
Mazor Y et al. Clin Gastroenterol Hepatol. 2021 Mar 1;19(3):492-502. doi: 10.1016/j.cgh.2020.03.050.
April 2021
Long-term outcome of gastric per-oral endoscopic pyloromyotomy in treatment of gastroparesis
Abdelfatah MM et al. Clin Gastroenterol Hepatol. 2021 Apr 1;19(4):816-24. doi: 10.1016/j.cgh.2020.05.039.
What gastroenterologists should know about COVID-19 vaccines
Rolak S et al. Clin Gastroenterol Hepatol. 2021 Apr 1;19(4):657-61. doi: 10.1016/j.cgh.2021.01.001.
No benefit of concomitant immunomodulator therapy on efficacy of biologics that are not tumor necrosis factor antagonists in patients with inflammatory bowel diseases: A meta-analysis
Yzet C et al. Clin Gastroenterol Hepatol. 2021 Apr 1;19(4):668-78. doi: 10.1016/j.cgh.2020.06.071.
Patient safety reporting in GI: All hands on deck
Wall A and Kothari D. Clin Gastroenterol Hepatol. 2021 Apr 1;19(4):626-32. doi: 10.1016/j.cgh.2020.11.007.
Techniques and Innovations in Gastrointestinal Endoscopy
Barriers and pitfalls for artificial intelligence in gastroenterology: Ethical and regulatory issues
Ahmad OF et al. Tech Innov Gastrointest Endosc. 2020 Apr 1;22(2):80-4. doi: 10.1016/j.tgie.2019.150636.
Development of a scoring system to predict a positive diagnosis on video capsule endoscopy for suspected small bowel bleeding
Marya NB et al. Tech Innov Gastrointest Endosc. 2020 Oct 1;22(4):178-84. doi: 10.1016/j.tige.2020.06.001.
Training for Advanced Endoscopic Imaging in Gastrointestinal Diseases
Hoogenboom SA et al. Tech Innov Gastrointest Endosc. 2021 Jan 1;23(1):99-106. doi: 10.1016/j.tige.2020.09.001.
Chromoendoscopy techniques in imaging of colorectal polyps and cancer: Overview and practical applications for detection and characterization.
Rivero-Sanchez L et al. Tech Innov Gastrointest Endosc. 2021 Jan 1;23(1):30-41. doi: 10.1016/j.tige.2020.10.006.
Gastroenterology
February 2021
Worldwide burden of, risk factors for, and trends in pancreatic cancer
Huang J et al. Gastroenterology. 2021 Mar 1;160(4):744-54. doi: 10.1053/j.gastro.2020.10.007.
Fibrates for Itch (FITCH) in fibrosing cholangiopathies: A double-blind, randomized, placebo-controlled trial
de Vries E et al. Gastroenterology. 2021 Mar 1;160(4):734-43.e6. doi: 10.1053/j.gastro.2020.10.001.
March 2021
How to integrate a medical ethics curriculum into gastroenterology fellowships
Rao VL et al. Gastroenterology. 2021 Mar 1;160(4):1003-6. https://doi.org/10.1053/j.gastro.2021.01.211.
Colonoscopist performance and colorectal cancer risk after adenoma removal to stratify surveillance: two nationwide observational studies
Wieszczy P et al. Gastroenterology. 2021 Mar 1;160(4):1067-74. doi: 10.1053/j.gastro.2020.10.009.
Pregnancy and neonatal outcomes after fetal exposure to biologics and thiopurines among women with inflammatory bowel disease
Mahadevan U et al. Gastroenterology. 2021 Mar 1;160(4):1131-9. doi: 10.1053/j.gastro.2020.11.038.
April 2021
AGA Clinical Practice Guidelines on intragastric balloons in the management of obesity
Muniraj T et al. Gastroenterology. 2021 Apr 1;160(5):1799-808. doi: 10.1053/j.gastro.2021.03.003.
How to strategically build your network for early career gastroenterologists
Gaidos JKJ et al. Gastroenterology. 2021 Apr 1;160(5):1461-6. doi: 10.1053/j.gastro.2021.01.025.
The microbiota-gut-brain axis: From motility to mood
Margolis KG et al. Gastroenterology. 2021 Apr 1;160(5):1486-501. doi: 10.1053/j.gastro.2020.10.066.
The association of histologic and noninvasive tests with adverse clinical and patient-reported outcomes in patients with advanced fibrosis due to nonalcoholic steatohepatitis
Younossi ZM et al. Gastroenterology. 2021 Apr 1;160(5):1608-19. doi: 10.1053/j.gastro.2020.12.003.
Clinical Gastroenterology and Hepatology
February 2021
Management of chronic abdominal distension and bloating
Lacy BE et al. Clin Gastroenterol Hepatol. 2021 Feb 1;19(2):219-31. doi: 10.1016/j.cgh.2020.03.056.
Prevalence of gastric intestinal metaplasia in a multiethnic US veterans population
Nguyen TH et al. Clin Gastroenterol Hepatol. 2021 Feb 1;19(2):269-76. doi: 10.1016/j.cgh.2020.03.015.
Rome IV functional gastrointestinal disorders and health impairment in subjects with hypermobility spectrum disorders or hypermobile Ehlers-Danlos syndrome
Lam CY et al. Clin Gastroenterol Hepatol. 2021 Feb 1;19(2):277-87. doi: 10.1016/j.cgh.2020.02.034.
Factors that affect adequacy of colon cleansing for colonoscopy in hospitalized patients
Fucci L et al. Clin Gastroenterol Hepatol. 2021 Feb 1;19(2):339-48. doi: org/10.1016/j.cgh.2020.02.055.
March 2021
Real-world gluten exposure in patients with celiac disease on gluten-free diets, determined from gliadin immunogenic peptides in urine and fecal samples
Stefanolo JP et al. Clin Gastroenterol Hepatol. 2021 Mar 1;19(3):484-91. doi: 10.1016/j.cgh.2020.03.038.
Factors associated with response to anorectal biofeedback therapy in patients with fecal incontinence
Mazor Y et al. Clin Gastroenterol Hepatol. 2021 Mar 1;19(3):492-502. doi: 10.1016/j.cgh.2020.03.050.
April 2021
Long-term outcome of gastric per-oral endoscopic pyloromyotomy in treatment of gastroparesis
Abdelfatah MM et al. Clin Gastroenterol Hepatol. 2021 Apr 1;19(4):816-24. doi: 10.1016/j.cgh.2020.05.039.
What gastroenterologists should know about COVID-19 vaccines
Rolak S et al. Clin Gastroenterol Hepatol. 2021 Apr 1;19(4):657-61. doi: 10.1016/j.cgh.2021.01.001.
No benefit of concomitant immunomodulator therapy on efficacy of biologics that are not tumor necrosis factor antagonists in patients with inflammatory bowel diseases: A meta-analysis
Yzet C et al. Clin Gastroenterol Hepatol. 2021 Apr 1;19(4):668-78. doi: 10.1016/j.cgh.2020.06.071.
Patient safety reporting in GI: All hands on deck
Wall A and Kothari D. Clin Gastroenterol Hepatol. 2021 Apr 1;19(4):626-32. doi: 10.1016/j.cgh.2020.11.007.
Techniques and Innovations in Gastrointestinal Endoscopy
Barriers and pitfalls for artificial intelligence in gastroenterology: Ethical and regulatory issues
Ahmad OF et al. Tech Innov Gastrointest Endosc. 2020 Apr 1;22(2):80-4. doi: 10.1016/j.tgie.2019.150636.
Development of a scoring system to predict a positive diagnosis on video capsule endoscopy for suspected small bowel bleeding
Marya NB et al. Tech Innov Gastrointest Endosc. 2020 Oct 1;22(4):178-84. doi: 10.1016/j.tige.2020.06.001.
Training for Advanced Endoscopic Imaging in Gastrointestinal Diseases
Hoogenboom SA et al. Tech Innov Gastrointest Endosc. 2021 Jan 1;23(1):99-106. doi: 10.1016/j.tige.2020.09.001.
Chromoendoscopy techniques in imaging of colorectal polyps and cancer: Overview and practical applications for detection and characterization.
Rivero-Sanchez L et al. Tech Innov Gastrointest Endosc. 2021 Jan 1;23(1):30-41. doi: 10.1016/j.tige.2020.10.006.
Gastroenterology
February 2021
Worldwide burden of, risk factors for, and trends in pancreatic cancer
Huang J et al. Gastroenterology. 2021 Mar 1;160(4):744-54. doi: 10.1053/j.gastro.2020.10.007.
Fibrates for Itch (FITCH) in fibrosing cholangiopathies: A double-blind, randomized, placebo-controlled trial
de Vries E et al. Gastroenterology. 2021 Mar 1;160(4):734-43.e6. doi: 10.1053/j.gastro.2020.10.001.
March 2021
How to integrate a medical ethics curriculum into gastroenterology fellowships
Rao VL et al. Gastroenterology. 2021 Mar 1;160(4):1003-6. https://doi.org/10.1053/j.gastro.2021.01.211.
Colonoscopist performance and colorectal cancer risk after adenoma removal to stratify surveillance: two nationwide observational studies
Wieszczy P et al. Gastroenterology. 2021 Mar 1;160(4):1067-74. doi: 10.1053/j.gastro.2020.10.009.
Pregnancy and neonatal outcomes after fetal exposure to biologics and thiopurines among women with inflammatory bowel disease
Mahadevan U et al. Gastroenterology. 2021 Mar 1;160(4):1131-9. doi: 10.1053/j.gastro.2020.11.038.
April 2021
AGA Clinical Practice Guidelines on intragastric balloons in the management of obesity
Muniraj T et al. Gastroenterology. 2021 Apr 1;160(5):1799-808. doi: 10.1053/j.gastro.2021.03.003.
How to strategically build your network for early career gastroenterologists
Gaidos JKJ et al. Gastroenterology. 2021 Apr 1;160(5):1461-6. doi: 10.1053/j.gastro.2021.01.025.
The microbiota-gut-brain axis: From motility to mood
Margolis KG et al. Gastroenterology. 2021 Apr 1;160(5):1486-501. doi: 10.1053/j.gastro.2020.10.066.
The association of histologic and noninvasive tests with adverse clinical and patient-reported outcomes in patients with advanced fibrosis due to nonalcoholic steatohepatitis
Younossi ZM et al. Gastroenterology. 2021 Apr 1;160(5):1608-19. doi: 10.1053/j.gastro.2020.12.003.
Clinical Gastroenterology and Hepatology
February 2021
Management of chronic abdominal distension and bloating
Lacy BE et al. Clin Gastroenterol Hepatol. 2021 Feb 1;19(2):219-31. doi: 10.1016/j.cgh.2020.03.056.
Prevalence of gastric intestinal metaplasia in a multiethnic US veterans population
Nguyen TH et al. Clin Gastroenterol Hepatol. 2021 Feb 1;19(2):269-76. doi: 10.1016/j.cgh.2020.03.015.
Rome IV functional gastrointestinal disorders and health impairment in subjects with hypermobility spectrum disorders or hypermobile Ehlers-Danlos syndrome
Lam CY et al. Clin Gastroenterol Hepatol. 2021 Feb 1;19(2):277-87. doi: 10.1016/j.cgh.2020.02.034.
Factors that affect adequacy of colon cleansing for colonoscopy in hospitalized patients
Fucci L et al. Clin Gastroenterol Hepatol. 2021 Feb 1;19(2):339-48. doi: org/10.1016/j.cgh.2020.02.055.
March 2021
Real-world gluten exposure in patients with celiac disease on gluten-free diets, determined from gliadin immunogenic peptides in urine and fecal samples
Stefanolo JP et al. Clin Gastroenterol Hepatol. 2021 Mar 1;19(3):484-91. doi: 10.1016/j.cgh.2020.03.038.
Factors associated with response to anorectal biofeedback therapy in patients with fecal incontinence
Mazor Y et al. Clin Gastroenterol Hepatol. 2021 Mar 1;19(3):492-502. doi: 10.1016/j.cgh.2020.03.050.
April 2021
Long-term outcome of gastric per-oral endoscopic pyloromyotomy in treatment of gastroparesis
Abdelfatah MM et al. Clin Gastroenterol Hepatol. 2021 Apr 1;19(4):816-24. doi: 10.1016/j.cgh.2020.05.039.
What gastroenterologists should know about COVID-19 vaccines
Rolak S et al. Clin Gastroenterol Hepatol. 2021 Apr 1;19(4):657-61. doi: 10.1016/j.cgh.2021.01.001.
No benefit of concomitant immunomodulator therapy on efficacy of biologics that are not tumor necrosis factor antagonists in patients with inflammatory bowel diseases: A meta-analysis
Yzet C et al. Clin Gastroenterol Hepatol. 2021 Apr 1;19(4):668-78. doi: 10.1016/j.cgh.2020.06.071.
Patient safety reporting in GI: All hands on deck
Wall A and Kothari D. Clin Gastroenterol Hepatol. 2021 Apr 1;19(4):626-32. doi: 10.1016/j.cgh.2020.11.007.
Techniques and Innovations in Gastrointestinal Endoscopy
Barriers and pitfalls for artificial intelligence in gastroenterology: Ethical and regulatory issues
Ahmad OF et al. Tech Innov Gastrointest Endosc. 2020 Apr 1;22(2):80-4. doi: 10.1016/j.tgie.2019.150636.
Development of a scoring system to predict a positive diagnosis on video capsule endoscopy for suspected small bowel bleeding
Marya NB et al. Tech Innov Gastrointest Endosc. 2020 Oct 1;22(4):178-84. doi: 10.1016/j.tige.2020.06.001.
Training for Advanced Endoscopic Imaging in Gastrointestinal Diseases
Hoogenboom SA et al. Tech Innov Gastrointest Endosc. 2021 Jan 1;23(1):99-106. doi: 10.1016/j.tige.2020.09.001.
Chromoendoscopy techniques in imaging of colorectal polyps and cancer: Overview and practical applications for detection and characterization.
Rivero-Sanchez L et al. Tech Innov Gastrointest Endosc. 2021 Jan 1;23(1):30-41. doi: 10.1016/j.tige.2020.10.006.
Study aims to enhance understanding of ‘tremendously understudied’ prurigo nodularis
compared with age-matched controls, as well those with atopic dermatitis and psoriasis.
Those are key findings from a retrospective analysis of claims data that was published online April 3, 2021, in the Journal of Investigative Dermatology.
“Prurigo nodularis is a tremendously understudied inflammatory skin disease,” one of the study’s cosenior authors, Shawn G. Kwatra, MD, of the department of dermatology, Johns Hopkins University, Baltimore, said in an interview. “Prurigo nodularis patients have uncontrolled itch, which leads to reduced quality of life, and the association with many disease comorbidities. We focused on better understanding in this work the unique comorbidities of prurigo nodularis, compared to other inflammatory skin diseases.”
For the study, Dr. Kwatra, cosenior author Yevgeniy R. Semenov, MD, of the department of dermatology, Massachusetts General Hospital, Boston, and colleagues evaluated nationally representative, private insurance claims data from October 2015 to December 2019 to identify prurigo nodularis (PN) patients, who were defined as individuals with two or more medical claims for PN using ICD-10-CM codes. For comparison with patients with inflammatory skin diseases, they used the same claims data to identify patients with atopic dermatitis (AD) and psoriasis as well as to select controls who were age and gender matched to PN patients. Next, they quantified the overall comorbidity burden with the Charlson Comorbidity Index (CCI).
In 2016, the claims database included 2,658 patients with PN, 21,482 patients with AD, 21,073 patients with psoriasis, and 13,290 controls. The number of patients in each category rose each subsequent year, so that by the end of 2019 there were 9,426 patients with PN, 70,298 patients with AD, 59,509 patients with psoriasis, and 47,130 controls. Between 2016 and 2019 the mean age of PN patients increased from 57.5 to 59.8 years and the percent of male patients rose from 44.5% to 46.5%.
Between 2016 and 2019, the overall PN prevalence rates rose from 18 per 100,000 to 58 per 100,000, while the PN prevalence rates among adults increased from 22 per 100,000 to 70 per 100,000, and the rates among children rose grew from 2 per 100,000 to 7 per 100,000. “Our report shows an estimated disease prevalence of around 335,000 cases of PN in the United States,” said Dr. Kwatra, who was among a group of researchers to recently report on systemic Th22-polarized inflammation in PN patients.
The researchers also found that patients with PN had the highest mean CCI in both 2016 and 2019. In 2016, their mean CCI was 1.53, compared with 0.98 among controls, 0.53 among those with AD, and 1.16 among those with psoriasis. In 2019, the mean CCI had increased in all groups of patients, to 2.32 among those with PN, 1.57 among controls, 0.75 among those with AD patients, and 1.71 among those with psoriasis.
The top five medical specialties who cared for PN patients, defined as the estimated number of visits per year per patient, were internal medicine (2.01 visits), dermatology (1.87 visits), family practice (1.60 visits), cardiology or cardiovascular disease (0.85 visits), and orthopedics or orthopedic surgery (0.49 visits).
“If you encounter a patient with prurigo nodularis, it’s important to perform a screening for chronic kidney disease, diabetes, and liver disease,” Dr. Kwatra said. “These comorbidities along with emerging studies on circulating blood biomarkers suggest prurigo nodularis is a systemic inflammatory disorder; thus systemic agents are needed for most patients as part of multimodal therapy in prurigo nodularis.”
The researchers acknowledged certain limitations of the study, including its retrospective design and the identification of patients with PN with the ICD-10-CM code, which require further validation. “Furthermore, the increase in annual prevalence estimates for PN, AD, and psoriasis observed in the study could also be a result of increasing coding of these diagnoses in the claims data along with rising awareness by the medical profession,” they wrote.
Dr. Kwatra disclosed that he is an advisory board member/consultant for AbbVie, Galderma, Incyte, Pfizer, Regeneron, and Kiniksa Pharmaceuticals, and has received grant funding from Galderma, Pfizer, and Kiniksa. He has also received a Dermatology Foundation Medical Dermatology Career Development Award, a research grant from the Skin of Color Society, and is supported by the National Institutes of Health. One coauthor has been funded by NIH grants.
compared with age-matched controls, as well those with atopic dermatitis and psoriasis.
Those are key findings from a retrospective analysis of claims data that was published online April 3, 2021, in the Journal of Investigative Dermatology.
“Prurigo nodularis is a tremendously understudied inflammatory skin disease,” one of the study’s cosenior authors, Shawn G. Kwatra, MD, of the department of dermatology, Johns Hopkins University, Baltimore, said in an interview. “Prurigo nodularis patients have uncontrolled itch, which leads to reduced quality of life, and the association with many disease comorbidities. We focused on better understanding in this work the unique comorbidities of prurigo nodularis, compared to other inflammatory skin diseases.”
For the study, Dr. Kwatra, cosenior author Yevgeniy R. Semenov, MD, of the department of dermatology, Massachusetts General Hospital, Boston, and colleagues evaluated nationally representative, private insurance claims data from October 2015 to December 2019 to identify prurigo nodularis (PN) patients, who were defined as individuals with two or more medical claims for PN using ICD-10-CM codes. For comparison with patients with inflammatory skin diseases, they used the same claims data to identify patients with atopic dermatitis (AD) and psoriasis as well as to select controls who were age and gender matched to PN patients. Next, they quantified the overall comorbidity burden with the Charlson Comorbidity Index (CCI).
In 2016, the claims database included 2,658 patients with PN, 21,482 patients with AD, 21,073 patients with psoriasis, and 13,290 controls. The number of patients in each category rose each subsequent year, so that by the end of 2019 there were 9,426 patients with PN, 70,298 patients with AD, 59,509 patients with psoriasis, and 47,130 controls. Between 2016 and 2019 the mean age of PN patients increased from 57.5 to 59.8 years and the percent of male patients rose from 44.5% to 46.5%.
Between 2016 and 2019, the overall PN prevalence rates rose from 18 per 100,000 to 58 per 100,000, while the PN prevalence rates among adults increased from 22 per 100,000 to 70 per 100,000, and the rates among children rose grew from 2 per 100,000 to 7 per 100,000. “Our report shows an estimated disease prevalence of around 335,000 cases of PN in the United States,” said Dr. Kwatra, who was among a group of researchers to recently report on systemic Th22-polarized inflammation in PN patients.
The researchers also found that patients with PN had the highest mean CCI in both 2016 and 2019. In 2016, their mean CCI was 1.53, compared with 0.98 among controls, 0.53 among those with AD, and 1.16 among those with psoriasis. In 2019, the mean CCI had increased in all groups of patients, to 2.32 among those with PN, 1.57 among controls, 0.75 among those with AD patients, and 1.71 among those with psoriasis.
The top five medical specialties who cared for PN patients, defined as the estimated number of visits per year per patient, were internal medicine (2.01 visits), dermatology (1.87 visits), family practice (1.60 visits), cardiology or cardiovascular disease (0.85 visits), and orthopedics or orthopedic surgery (0.49 visits).
“If you encounter a patient with prurigo nodularis, it’s important to perform a screening for chronic kidney disease, diabetes, and liver disease,” Dr. Kwatra said. “These comorbidities along with emerging studies on circulating blood biomarkers suggest prurigo nodularis is a systemic inflammatory disorder; thus systemic agents are needed for most patients as part of multimodal therapy in prurigo nodularis.”
The researchers acknowledged certain limitations of the study, including its retrospective design and the identification of patients with PN with the ICD-10-CM code, which require further validation. “Furthermore, the increase in annual prevalence estimates for PN, AD, and psoriasis observed in the study could also be a result of increasing coding of these diagnoses in the claims data along with rising awareness by the medical profession,” they wrote.
Dr. Kwatra disclosed that he is an advisory board member/consultant for AbbVie, Galderma, Incyte, Pfizer, Regeneron, and Kiniksa Pharmaceuticals, and has received grant funding from Galderma, Pfizer, and Kiniksa. He has also received a Dermatology Foundation Medical Dermatology Career Development Award, a research grant from the Skin of Color Society, and is supported by the National Institutes of Health. One coauthor has been funded by NIH grants.
compared with age-matched controls, as well those with atopic dermatitis and psoriasis.
Those are key findings from a retrospective analysis of claims data that was published online April 3, 2021, in the Journal of Investigative Dermatology.
“Prurigo nodularis is a tremendously understudied inflammatory skin disease,” one of the study’s cosenior authors, Shawn G. Kwatra, MD, of the department of dermatology, Johns Hopkins University, Baltimore, said in an interview. “Prurigo nodularis patients have uncontrolled itch, which leads to reduced quality of life, and the association with many disease comorbidities. We focused on better understanding in this work the unique comorbidities of prurigo nodularis, compared to other inflammatory skin diseases.”
For the study, Dr. Kwatra, cosenior author Yevgeniy R. Semenov, MD, of the department of dermatology, Massachusetts General Hospital, Boston, and colleagues evaluated nationally representative, private insurance claims data from October 2015 to December 2019 to identify prurigo nodularis (PN) patients, who were defined as individuals with two or more medical claims for PN using ICD-10-CM codes. For comparison with patients with inflammatory skin diseases, they used the same claims data to identify patients with atopic dermatitis (AD) and psoriasis as well as to select controls who were age and gender matched to PN patients. Next, they quantified the overall comorbidity burden with the Charlson Comorbidity Index (CCI).
In 2016, the claims database included 2,658 patients with PN, 21,482 patients with AD, 21,073 patients with psoriasis, and 13,290 controls. The number of patients in each category rose each subsequent year, so that by the end of 2019 there were 9,426 patients with PN, 70,298 patients with AD, 59,509 patients with psoriasis, and 47,130 controls. Between 2016 and 2019 the mean age of PN patients increased from 57.5 to 59.8 years and the percent of male patients rose from 44.5% to 46.5%.
Between 2016 and 2019, the overall PN prevalence rates rose from 18 per 100,000 to 58 per 100,000, while the PN prevalence rates among adults increased from 22 per 100,000 to 70 per 100,000, and the rates among children rose grew from 2 per 100,000 to 7 per 100,000. “Our report shows an estimated disease prevalence of around 335,000 cases of PN in the United States,” said Dr. Kwatra, who was among a group of researchers to recently report on systemic Th22-polarized inflammation in PN patients.
The researchers also found that patients with PN had the highest mean CCI in both 2016 and 2019. In 2016, their mean CCI was 1.53, compared with 0.98 among controls, 0.53 among those with AD, and 1.16 among those with psoriasis. In 2019, the mean CCI had increased in all groups of patients, to 2.32 among those with PN, 1.57 among controls, 0.75 among those with AD patients, and 1.71 among those with psoriasis.
The top five medical specialties who cared for PN patients, defined as the estimated number of visits per year per patient, were internal medicine (2.01 visits), dermatology (1.87 visits), family practice (1.60 visits), cardiology or cardiovascular disease (0.85 visits), and orthopedics or orthopedic surgery (0.49 visits).
“If you encounter a patient with prurigo nodularis, it’s important to perform a screening for chronic kidney disease, diabetes, and liver disease,” Dr. Kwatra said. “These comorbidities along with emerging studies on circulating blood biomarkers suggest prurigo nodularis is a systemic inflammatory disorder; thus systemic agents are needed for most patients as part of multimodal therapy in prurigo nodularis.”
The researchers acknowledged certain limitations of the study, including its retrospective design and the identification of patients with PN with the ICD-10-CM code, which require further validation. “Furthermore, the increase in annual prevalence estimates for PN, AD, and psoriasis observed in the study could also be a result of increasing coding of these diagnoses in the claims data along with rising awareness by the medical profession,” they wrote.
Dr. Kwatra disclosed that he is an advisory board member/consultant for AbbVie, Galderma, Incyte, Pfizer, Regeneron, and Kiniksa Pharmaceuticals, and has received grant funding from Galderma, Pfizer, and Kiniksa. He has also received a Dermatology Foundation Medical Dermatology Career Development Award, a research grant from the Skin of Color Society, and is supported by the National Institutes of Health. One coauthor has been funded by NIH grants.
FROM THE JOURNAL OF INVESTIGATIVE DERMATOLOGY
Phage-targeting PCR test picks up early Lyme disease
An investigational polymerase chain reaction (PCR) test that detects the presence of a viral gene in Lyme disease–causing bacteria can distinguish between early and late infection, according to the results of a study that the authors described as “systematic and comprehensive.”
“The current way of diagnosing Lyme disease is struggling to reflect the ‘true’ incidence of Lyme disease,” study investigator Jinyu Shan, PhD, said in an interview. Although there are tests for Lyme disease approved by the Food and Drug Administration, they are based on the development of antibodies in the blood, and the problem is that antibodies might not develop until several weeks after an infection.
Diagnosis therefore still relies heavily on the clinician’s experience. There are often telltale signs – such as a “bullseye” skin rash or having been to an area known to be infested with ticks that carry Lyme disease – but this might not always be the case.
For the new test, “we’re not targeting bacteria. We’re targeting bacteriophages,” said Dr. Shan, a research fellow in the department of genetics and genome biology at the University of Leicester (England).
Fortunately, there’s high correlation between the presence of the terL gene and the presence of Borrelia burgdorferi, the spirochete that causes Lyme disease. “If you find the bacteriophages, the bacteria are there,” said Dr. Shan.
“Importantly, there are 10 times more bacteriophages, compared with the bacteria, so you have a lot more targets,” he added.
In an evaluation of a total of 312 samples (156 whole blood and 156 serum samples), significantly fewer copies of the terL gene were found in samples from people with early Lyme disease than in those with late Lyme disease, whereas the fewest copies of terL were seen in healthy volunteers.
Most pathogenic bacteria carry viral DNA either as multiple complete or partial prophages, Dr. Shan explained. Knowing the prophage sequences means that quantitative PCR primers and probes can be designed and used to detect the presence of the associated bacteria.
Although the novel test still needs evaluation in a clinical trial, it could represent a “step-change” in the detection of Lyme disease, Dr. Shan and associates suggested in their report published in Frontiers in Microbiology.
Early treatment is key to the prevention of longer-term consequences of Lyme disease. Clinicians familiar with the treatment of Lyme disease might choose to initiate antibiotic treatment without a positive lab test. However, the lack of a test that can pick out people with Lyme disease in the first few weeks of infection means that many people are not diagnosed or treated early enough.
The new phage-based PCR test Dr. Shan and associates have developed could change all that. With only 0.3 mL of blood being needed, it can potentially be developed as a simple point-of-care test, but that’s a long way off.
At this stage, the research is very much a “proof of concept,” Dr. Shan said. One of the things he plans to try to work out next is whether the test can distinguish between active and dormant disease, which is a “big question” in the diagnosis of Lyme disease.
“Bacteriophages can only be sustained by actively growing bacteria,” explained Dr. Shan, so there is a chance that if they are present in a substantive amount the disease is active, and if they are not – or are in very low numbers – then the disease is dormant. The cutoff value, however, “is not trivial to establish, but we are working toward it,” added Dr. Shan.
Over the past 2 years, Dr. Shan and associates have been working with the Belgian-based diagnostics company, R.E.D Laboratories, to see how the test will fare in a real-world environment. This relationship is providing useful information to add to their bid to perform a clinical trial for which they are now seeking additional sponsorship.
“The lack of an early and effective diagnosis of Lyme disease remains a major cause of misdiagnosis and long-term patient suffering,” commented Rosie Milsom, charity manager for Caudwell LymeCo Charity in the United Kingdom.
It could be a game changer if the test passes the necessary clinical trial testing and validation stages, noted Ms. Milsom, who was not involved in the research.
“Not only would the test help to establish the level or length of infection,” she said, “but it could also act as a way to test after treatment to see if the infection levels are decreasing.” If levels are still high, “you would know more treatment is needed.
The research is being funded by the charity Phelix Research and Development with support from the University of Leicester and the Dutch-based Lyme Fund, Lymefonds. Dr. Shan is named as coinventor of the phage-targeting PCR test, alongside Martha R.J. Clokie, professor of microbiology at the University of Leicester and the senior author of the study. Dr. Shan is chief scientific officer for Phelix Research and Development. Ms. Clokie and other coauthors hold key positions within the medical research charity.
A version of this article first appeared on Medscape.com.
An investigational polymerase chain reaction (PCR) test that detects the presence of a viral gene in Lyme disease–causing bacteria can distinguish between early and late infection, according to the results of a study that the authors described as “systematic and comprehensive.”
“The current way of diagnosing Lyme disease is struggling to reflect the ‘true’ incidence of Lyme disease,” study investigator Jinyu Shan, PhD, said in an interview. Although there are tests for Lyme disease approved by the Food and Drug Administration, they are based on the development of antibodies in the blood, and the problem is that antibodies might not develop until several weeks after an infection.
Diagnosis therefore still relies heavily on the clinician’s experience. There are often telltale signs – such as a “bullseye” skin rash or having been to an area known to be infested with ticks that carry Lyme disease – but this might not always be the case.
For the new test, “we’re not targeting bacteria. We’re targeting bacteriophages,” said Dr. Shan, a research fellow in the department of genetics and genome biology at the University of Leicester (England).
Fortunately, there’s high correlation between the presence of the terL gene and the presence of Borrelia burgdorferi, the spirochete that causes Lyme disease. “If you find the bacteriophages, the bacteria are there,” said Dr. Shan.
“Importantly, there are 10 times more bacteriophages, compared with the bacteria, so you have a lot more targets,” he added.
In an evaluation of a total of 312 samples (156 whole blood and 156 serum samples), significantly fewer copies of the terL gene were found in samples from people with early Lyme disease than in those with late Lyme disease, whereas the fewest copies of terL were seen in healthy volunteers.
Most pathogenic bacteria carry viral DNA either as multiple complete or partial prophages, Dr. Shan explained. Knowing the prophage sequences means that quantitative PCR primers and probes can be designed and used to detect the presence of the associated bacteria.
Although the novel test still needs evaluation in a clinical trial, it could represent a “step-change” in the detection of Lyme disease, Dr. Shan and associates suggested in their report published in Frontiers in Microbiology.
Early treatment is key to the prevention of longer-term consequences of Lyme disease. Clinicians familiar with the treatment of Lyme disease might choose to initiate antibiotic treatment without a positive lab test. However, the lack of a test that can pick out people with Lyme disease in the first few weeks of infection means that many people are not diagnosed or treated early enough.
The new phage-based PCR test Dr. Shan and associates have developed could change all that. With only 0.3 mL of blood being needed, it can potentially be developed as a simple point-of-care test, but that’s a long way off.
At this stage, the research is very much a “proof of concept,” Dr. Shan said. One of the things he plans to try to work out next is whether the test can distinguish between active and dormant disease, which is a “big question” in the diagnosis of Lyme disease.
“Bacteriophages can only be sustained by actively growing bacteria,” explained Dr. Shan, so there is a chance that if they are present in a substantive amount the disease is active, and if they are not – or are in very low numbers – then the disease is dormant. The cutoff value, however, “is not trivial to establish, but we are working toward it,” added Dr. Shan.
Over the past 2 years, Dr. Shan and associates have been working with the Belgian-based diagnostics company, R.E.D Laboratories, to see how the test will fare in a real-world environment. This relationship is providing useful information to add to their bid to perform a clinical trial for which they are now seeking additional sponsorship.
“The lack of an early and effective diagnosis of Lyme disease remains a major cause of misdiagnosis and long-term patient suffering,” commented Rosie Milsom, charity manager for Caudwell LymeCo Charity in the United Kingdom.
It could be a game changer if the test passes the necessary clinical trial testing and validation stages, noted Ms. Milsom, who was not involved in the research.
“Not only would the test help to establish the level or length of infection,” she said, “but it could also act as a way to test after treatment to see if the infection levels are decreasing.” If levels are still high, “you would know more treatment is needed.
The research is being funded by the charity Phelix Research and Development with support from the University of Leicester and the Dutch-based Lyme Fund, Lymefonds. Dr. Shan is named as coinventor of the phage-targeting PCR test, alongside Martha R.J. Clokie, professor of microbiology at the University of Leicester and the senior author of the study. Dr. Shan is chief scientific officer for Phelix Research and Development. Ms. Clokie and other coauthors hold key positions within the medical research charity.
A version of this article first appeared on Medscape.com.
An investigational polymerase chain reaction (PCR) test that detects the presence of a viral gene in Lyme disease–causing bacteria can distinguish between early and late infection, according to the results of a study that the authors described as “systematic and comprehensive.”
“The current way of diagnosing Lyme disease is struggling to reflect the ‘true’ incidence of Lyme disease,” study investigator Jinyu Shan, PhD, said in an interview. Although there are tests for Lyme disease approved by the Food and Drug Administration, they are based on the development of antibodies in the blood, and the problem is that antibodies might not develop until several weeks after an infection.
Diagnosis therefore still relies heavily on the clinician’s experience. There are often telltale signs – such as a “bullseye” skin rash or having been to an area known to be infested with ticks that carry Lyme disease – but this might not always be the case.
For the new test, “we’re not targeting bacteria. We’re targeting bacteriophages,” said Dr. Shan, a research fellow in the department of genetics and genome biology at the University of Leicester (England).
Fortunately, there’s high correlation between the presence of the terL gene and the presence of Borrelia burgdorferi, the spirochete that causes Lyme disease. “If you find the bacteriophages, the bacteria are there,” said Dr. Shan.
“Importantly, there are 10 times more bacteriophages, compared with the bacteria, so you have a lot more targets,” he added.
In an evaluation of a total of 312 samples (156 whole blood and 156 serum samples), significantly fewer copies of the terL gene were found in samples from people with early Lyme disease than in those with late Lyme disease, whereas the fewest copies of terL were seen in healthy volunteers.
Most pathogenic bacteria carry viral DNA either as multiple complete or partial prophages, Dr. Shan explained. Knowing the prophage sequences means that quantitative PCR primers and probes can be designed and used to detect the presence of the associated bacteria.
Although the novel test still needs evaluation in a clinical trial, it could represent a “step-change” in the detection of Lyme disease, Dr. Shan and associates suggested in their report published in Frontiers in Microbiology.
Early treatment is key to the prevention of longer-term consequences of Lyme disease. Clinicians familiar with the treatment of Lyme disease might choose to initiate antibiotic treatment without a positive lab test. However, the lack of a test that can pick out people with Lyme disease in the first few weeks of infection means that many people are not diagnosed or treated early enough.
The new phage-based PCR test Dr. Shan and associates have developed could change all that. With only 0.3 mL of blood being needed, it can potentially be developed as a simple point-of-care test, but that’s a long way off.
At this stage, the research is very much a “proof of concept,” Dr. Shan said. One of the things he plans to try to work out next is whether the test can distinguish between active and dormant disease, which is a “big question” in the diagnosis of Lyme disease.
“Bacteriophages can only be sustained by actively growing bacteria,” explained Dr. Shan, so there is a chance that if they are present in a substantive amount the disease is active, and if they are not – or are in very low numbers – then the disease is dormant. The cutoff value, however, “is not trivial to establish, but we are working toward it,” added Dr. Shan.
Over the past 2 years, Dr. Shan and associates have been working with the Belgian-based diagnostics company, R.E.D Laboratories, to see how the test will fare in a real-world environment. This relationship is providing useful information to add to their bid to perform a clinical trial for which they are now seeking additional sponsorship.
“The lack of an early and effective diagnosis of Lyme disease remains a major cause of misdiagnosis and long-term patient suffering,” commented Rosie Milsom, charity manager for Caudwell LymeCo Charity in the United Kingdom.
It could be a game changer if the test passes the necessary clinical trial testing and validation stages, noted Ms. Milsom, who was not involved in the research.
“Not only would the test help to establish the level or length of infection,” she said, “but it could also act as a way to test after treatment to see if the infection levels are decreasing.” If levels are still high, “you would know more treatment is needed.
The research is being funded by the charity Phelix Research and Development with support from the University of Leicester and the Dutch-based Lyme Fund, Lymefonds. Dr. Shan is named as coinventor of the phage-targeting PCR test, alongside Martha R.J. Clokie, professor of microbiology at the University of Leicester and the senior author of the study. Dr. Shan is chief scientific officer for Phelix Research and Development. Ms. Clokie and other coauthors hold key positions within the medical research charity.
A version of this article first appeared on Medscape.com.
Making a difference
Hospitalists engaging in advocacy efforts
Hospitalists around the country are devoting large portions of their spare time to a wide range of advocacy efforts. From health policy to caring for the unhoused population to diversity and equity to advocating for fellow hospitalists, these physicians are passionate about their causes and determined to make a difference.
Championing the unhoused
Sarah Stella, MD, FHM, a hospitalist at Denver Health, was initially drawn there because of the population the hospital serves, which includes a high concentration of people experiencing homelessness. As she cared for her patients, Dr. Stella, who is also associate professor of hospital medicine at the University of Colorado, increasingly felt the desire to help prevent the negative downstream outcomes the hospital sees.
To understand the experiences of the unhoused outside the hospital, Dr. Stella started talking to her patients and people in community-based organizations that serve this population. “I learned a ton,” she said. “Homelessness feels like such an intractable, hopeless thing, but the more I talked to people, the more opportunities I saw to work toward something better.”
This led to a pilot grant to work with the Colorado Coalition for the Homeless to set up a community advisory panel. “My goal was to better understand their experiences and to develop a shared vision for how we collectively can do better,” said Dr. Stella. Eventually, she also received a grant from the University of Colorado, and multiple opportunities have sprung up ever since.
For the past several years, Dr. Stella has worked with Denver Health leadership to improve care for the homeless. “Right now, I’m working with a community team on developing an idea to provide peer support from people with a shared lived experience for people who are experiencing homelessness when they’re hospitalized. That’s really where my passion has been in working on the partnership,” she said.
Her advocacy role has been beneficial in her work as a hospitalist, particularly when COVID began. Dr. Stella again partnered with the Colorado Coalition for the Homeless to start a joint task force. “Everyone on our task force is motivated by this powerful desire to improve the health and lives of this community and that’s one of the silver linings in this pandemic for me,” said Dr. Stella.
Advocacy work has also increased Dr. Stella’s knowledge of what community support options are available for the unhoused. This allows her to educate her patients about their options and how to access them.
While she has colleagues who are able to compartmentalize their work, “I absolutely could not be a hospitalist without being an advocate,” Dr. Stella said. “For me, it has been a protective strategy in terms of burnout because I have to feel like I’m working to advocate for better policies and more appropriate resources to address the gaps that I’m seeing.”
Dr. Stella believes that physicians have a special credibility to advocate, tell stories, and use data to back their stories up. “We have to realize that we have this power, and we have it so we can empower others,” she said. “The people I’ve seen in my community who are working so hard to help people who are experiencing homelessness are the heroes. Understanding that and giving power to those people through our voice and our well-respected place in society drives me.”
Strengthening diversity, equity, and inclusion
In September 2020, Michael Bryant, MD, became the inaugural vice chair of Diversity, Equity, and Inclusion for the department of pediatrics at Children’s Hospital Los Angeles, where he is also the division head of pediatric hospital medicine. “I was motivated to apply for this position because I wanted to be an agent for change to eliminate the institutional racism, social injustice, and marginalization that continues to threaten the lives and well-beings of so many Americans,” Dr. Bryant said.
Between the pandemic, the economic decline it has created, and the divisive political landscape, people of color have been especially affected. “These are poignant examples of the ever-widening divide and disenfranchisement many Americans feel,” said Dr. Bryant. “Gandhi said, ‘Be the change that you want to see,’ and that is what I want to model.”
At work, advocacy for diversity, equality, and inclusion is an innate part of everything he does. From the new physicians he recruits to the candidates he considers for leadership positions, Dr. Bryant strives “to have a workforce that mirrors the diversity of the patients we humbly care for and serve.”
Advocacy is intrinsic to Dr. Bryant’s worldview, in his quest to understand and accept each individual’s uniqueness, his desire “to embrace cultural humility,” his recognition that “our differences enhance us instead of diminishing us,” and his willingness to engage in difficult conversations.
“Advocacy means that I acknowledge that intent does not equal impact and that I must accept that what I do and what I say may have unintended consequences,” he said. “When that happens, I must resist becoming defensive and instead be willing to listen and learn.”
Dr. Bryant is proud of his accomplishments and enjoys his advocacy work. In his workplace, there are few African Americans in leadership roles. This means that he is in high demand when it comes to making sure there’s representation during various processes such as hiring and vetting, a disparity known as the “minority tax.”
“I am thankful for the opportunities, but it does take a toll at times,” Dr. Bryant said, which is yet another reason why he is a proponent of increasing diversity and inclusion. “This allows us to build the resource pool as these needs arise and minimizes the toll of the ‘minority tax’ on any single person or small group of individuals.”
This summer, physicians from Dr. Bryant’s hospital participated in the national “White Coats for Black Lives” effort. He found it to be “an incredibly moving event” that hundreds of his colleagues participated in.
Dr. Bryant’s advice for hospitalists who want to get involved in advocacy efforts is to check out the movie “John Lewis: Good Trouble.” “He was a champion of human rights and fought for these rights until his death,” Dr. Bryant said. “He is a true American hero and a wonderful example.”
Bolstering health care change
Since his residency, Joshua Lenchus, DO, FACP, SFHM, has developed an ever-increasing interest in legislative advocacy, particularly health policy. Getting involved in this arena requires an understanding of civics and government that goes beyond just the basics. “My desire to affect change in my own profession really served as the catalyst to get involved,” said Dr. Lenchus, the regional chief medical officer at Broward Health Medical Center in Fort Lauderdale, Fla. “What better way to do that than by combining what we do on a daily basis in the practice of medicine with this new understanding of how laws are passed and promulgated?”
Dr. Lenchus has been involved with both state and national medical organizations and has served on public policy committees as a member and as a chair. “The charge of these committees is to monitor and navigate position statements and policies that will drive the entire organization,” he said. This means becoming knowledgeable enough about a topic to be able to talk about it eloquently and adding supporting personal or professional illustrations that reinforce the position to lawmakers.
He finds his advocacy efforts “incredibly rewarding” because they contribute to his endeavors “to help my colleagues practice medicine in a safe, efficient, and productive manner.” For instance, some of the organizations Dr. Lenchus was involved with helped make changes to the Affordable Care Act that ended up in its final version, as well as changes after it passed. “There are tangible things that advocacy enables us to do in our daily practice,” he said.
When something his organizations have advocated for does not pass, they know they need to try a different outlet. “You can’t win every fight,” he said. “Every time you go and comment on an issue, you have to understand that you’re there to do your best, and to the extent that the people you’re talking to are willing to listen to what you have to say, that’s where I think you can make the most impact.” When changes he has helped fight for do pass, “it really is amazing that you can tell your colleagues about your role in achieving meaningful change in the profession.”
Dr. Lenchus acknowledges that advocacy “can be all-consuming at times. We have to understand our limits.” That said, he thinks not engaging in advocacy could increase stress and potential burnout. “I think being involved in advocacy efforts really helps people conduct meaningful work and educates them about what it means not just to them, but to the rest of the medical profession and the patients that we serve,” he said.
For hospitalists who are interested in health policy advocacy, there are many ways to get involved, Dr. Lenchus said. You could join an organization (many organized medical societies have public policy committees), participate in advocacy activities, work on a political campaign, or even run for office yourself. “Ultimately, education and some level of involvement really will make the difference in who navigates our future as hospitalists,” he said.
Questioning co-management practices
Though he says he’s in the minority, Hardik Vora, MD, SFHM, medical director for hospital medicine at Riverside Regional Medical Center in Newport News, Va., believes that co-management is going to “make or break hospital medicine. It’s going to have a huge impact on our specialty.”
In the roughly 25-year history of hospital medicine, it has evolved from admitting and caring for patients of primary care physicians to patients of specialists and, more recently, surgical patients. “Now there are (hospital medicine) programs across the country that are pretty much admitting everything,” said Dr. Vora.
As a recruiter for the Riverside Health System for the past eight years, “I have not met a single resident who is trained to do what we’re doing in hospital medicine, because you’re admitting surgical patients all the time and you have primary attending responsibility,” Dr. Vora said. “I see that as a cause of a significant amount of stress because now you’re responsible for something that you don’t have adequate training for.”
In the co-management discussion, Dr. Vora notes that people often bring up the research that shows that the practice has improved surgeon satisfaction. “What bothers me is that…you need to add one more question – how does it affect your hospitalists? And I bet the answer to that question is ‘it has a terrible effect.’”
The expectations surrounding hospitalists these days is a big concern in terms of burnout, Dr. Vora said. “We talk a lot about the drivers of burnout, whether it’s schedule or COVID,” he said. The biggest issue when it comes to burnout, as he sees it, is not COVID; it’s when hospitalists are performing tasks that make them feel they aren’t adding value. “I think that’s a huge topic in hospital medicine right now.”
Dr. Vora believes there should be more discussion and awareness of the potential pitfalls. “Hospitalists should get involved in co-management where they are adding value and certainly not take up the attending responsibility where they’re not adding value and it’s out of the scope of their training and expertise,” he said. “Preventing scope creep and burnout from co-management are some of the key issues I’m really passionate about.”
Dr. Vora said it is important to set realistic goals and remember that it takes time to make change when it comes to advocacy. “You still have to operate within whatever environment is given to you and then you can make change from within,” he said.
His enthusiasm for co-management awareness has led to creating a co-management forum through SHM in his local Hampton Roads chapter. He was also a panelist for an SHM webinar in February 2021 in which the panelists debated co-management.
“I think we really need to look at this as a specialty. Are we going in the right direction?” Dr. Vora asked. “We need to come together as a specialty and make a decision, which is going to be hard because there are competing financial interests and various practice models.”
Improving patient care
Working as a hospitalist at University Medical Center, a safety net hospital in New Orleans, Celeste Newby, MD, PhD, sees plenty of patients who are underinsured or not insured at all. “A lot of my interest in health policy stems from that,” she said.
During her residency, which she finished in 2015, Louisiana became a Medicaid expansion state. This impressed upon Dr. Newby how much Medicaid improved the lives of patients who had previously been uninsured. “We saw procedures getting done that had been put on hold because of financial concerns or medicines that were now affordable that weren’t before,” she said. “It really did make a difference.”
When repeated attempts to repeal the Affordable Care Act began, “it was a call to do health policy work for me personally that just hadn’t come up in the past,” said Dr. Newby, who is also assistant professor of medicine at Tulane University in New Orleans. “I personally found that the best way to do (advocacy work) was to go through medical societies because there is a much stronger voice when you have more people saying the same thing,” she said.
Dr. Newby sits on the Council of Legislation for the Louisiana State Medical Society and participates in the Leadership and Health Policy (LEAHP) Program through the Society of General Internal Medicine.
The LEAHP Program has been instrumental in expanding Dr. Newby’s knowledge of how health policy is made and the mechanisms behind it. It has also taught her “how we can either advise, guide, leverage, or advocate for things that we think would be important for change and moving the country in the right direction in terms of health care.”
Another reason involvement in medical societies is helpful is because, as a busy clinician, it is impossible to keep up with everything. “Working with medical societies, you have people who are more directly involved in the legislature and can give you quicker notice about things that are coming up that are going to be important to you or your co-workers or your patients,” Dr. Newby said.
Dr. Newby feels her advocacy work is an outlet for stress and “a way to work at more of a macro level on problems that I see with my individual patients. It’s a nice compliment.” At the hospital, she can only help one person at a time, but with her advocacy efforts, there’s potential to make changes for many.
“Advocacy now is such a large umbrella that encompasses so many different projects at all kinds of levels,” Dr. Newby said. She suggests looking around your community to see where the needs lie. If you’re passionate about a certain topic or population, see what you can do to help advocate for change there.
Hospitalists engaging in advocacy efforts
Hospitalists engaging in advocacy efforts
Hospitalists around the country are devoting large portions of their spare time to a wide range of advocacy efforts. From health policy to caring for the unhoused population to diversity and equity to advocating for fellow hospitalists, these physicians are passionate about their causes and determined to make a difference.
Championing the unhoused
Sarah Stella, MD, FHM, a hospitalist at Denver Health, was initially drawn there because of the population the hospital serves, which includes a high concentration of people experiencing homelessness. As she cared for her patients, Dr. Stella, who is also associate professor of hospital medicine at the University of Colorado, increasingly felt the desire to help prevent the negative downstream outcomes the hospital sees.
To understand the experiences of the unhoused outside the hospital, Dr. Stella started talking to her patients and people in community-based organizations that serve this population. “I learned a ton,” she said. “Homelessness feels like such an intractable, hopeless thing, but the more I talked to people, the more opportunities I saw to work toward something better.”
This led to a pilot grant to work with the Colorado Coalition for the Homeless to set up a community advisory panel. “My goal was to better understand their experiences and to develop a shared vision for how we collectively can do better,” said Dr. Stella. Eventually, she also received a grant from the University of Colorado, and multiple opportunities have sprung up ever since.
For the past several years, Dr. Stella has worked with Denver Health leadership to improve care for the homeless. “Right now, I’m working with a community team on developing an idea to provide peer support from people with a shared lived experience for people who are experiencing homelessness when they’re hospitalized. That’s really where my passion has been in working on the partnership,” she said.
Her advocacy role has been beneficial in her work as a hospitalist, particularly when COVID began. Dr. Stella again partnered with the Colorado Coalition for the Homeless to start a joint task force. “Everyone on our task force is motivated by this powerful desire to improve the health and lives of this community and that’s one of the silver linings in this pandemic for me,” said Dr. Stella.
Advocacy work has also increased Dr. Stella’s knowledge of what community support options are available for the unhoused. This allows her to educate her patients about their options and how to access them.
While she has colleagues who are able to compartmentalize their work, “I absolutely could not be a hospitalist without being an advocate,” Dr. Stella said. “For me, it has been a protective strategy in terms of burnout because I have to feel like I’m working to advocate for better policies and more appropriate resources to address the gaps that I’m seeing.”
Dr. Stella believes that physicians have a special credibility to advocate, tell stories, and use data to back their stories up. “We have to realize that we have this power, and we have it so we can empower others,” she said. “The people I’ve seen in my community who are working so hard to help people who are experiencing homelessness are the heroes. Understanding that and giving power to those people through our voice and our well-respected place in society drives me.”
Strengthening diversity, equity, and inclusion
In September 2020, Michael Bryant, MD, became the inaugural vice chair of Diversity, Equity, and Inclusion for the department of pediatrics at Children’s Hospital Los Angeles, where he is also the division head of pediatric hospital medicine. “I was motivated to apply for this position because I wanted to be an agent for change to eliminate the institutional racism, social injustice, and marginalization that continues to threaten the lives and well-beings of so many Americans,” Dr. Bryant said.
Between the pandemic, the economic decline it has created, and the divisive political landscape, people of color have been especially affected. “These are poignant examples of the ever-widening divide and disenfranchisement many Americans feel,” said Dr. Bryant. “Gandhi said, ‘Be the change that you want to see,’ and that is what I want to model.”
At work, advocacy for diversity, equality, and inclusion is an innate part of everything he does. From the new physicians he recruits to the candidates he considers for leadership positions, Dr. Bryant strives “to have a workforce that mirrors the diversity of the patients we humbly care for and serve.”
Advocacy is intrinsic to Dr. Bryant’s worldview, in his quest to understand and accept each individual’s uniqueness, his desire “to embrace cultural humility,” his recognition that “our differences enhance us instead of diminishing us,” and his willingness to engage in difficult conversations.
“Advocacy means that I acknowledge that intent does not equal impact and that I must accept that what I do and what I say may have unintended consequences,” he said. “When that happens, I must resist becoming defensive and instead be willing to listen and learn.”
Dr. Bryant is proud of his accomplishments and enjoys his advocacy work. In his workplace, there are few African Americans in leadership roles. This means that he is in high demand when it comes to making sure there’s representation during various processes such as hiring and vetting, a disparity known as the “minority tax.”
“I am thankful for the opportunities, but it does take a toll at times,” Dr. Bryant said, which is yet another reason why he is a proponent of increasing diversity and inclusion. “This allows us to build the resource pool as these needs arise and minimizes the toll of the ‘minority tax’ on any single person or small group of individuals.”
This summer, physicians from Dr. Bryant’s hospital participated in the national “White Coats for Black Lives” effort. He found it to be “an incredibly moving event” that hundreds of his colleagues participated in.
Dr. Bryant’s advice for hospitalists who want to get involved in advocacy efforts is to check out the movie “John Lewis: Good Trouble.” “He was a champion of human rights and fought for these rights until his death,” Dr. Bryant said. “He is a true American hero and a wonderful example.”
Bolstering health care change
Since his residency, Joshua Lenchus, DO, FACP, SFHM, has developed an ever-increasing interest in legislative advocacy, particularly health policy. Getting involved in this arena requires an understanding of civics and government that goes beyond just the basics. “My desire to affect change in my own profession really served as the catalyst to get involved,” said Dr. Lenchus, the regional chief medical officer at Broward Health Medical Center in Fort Lauderdale, Fla. “What better way to do that than by combining what we do on a daily basis in the practice of medicine with this new understanding of how laws are passed and promulgated?”
Dr. Lenchus has been involved with both state and national medical organizations and has served on public policy committees as a member and as a chair. “The charge of these committees is to monitor and navigate position statements and policies that will drive the entire organization,” he said. This means becoming knowledgeable enough about a topic to be able to talk about it eloquently and adding supporting personal or professional illustrations that reinforce the position to lawmakers.
He finds his advocacy efforts “incredibly rewarding” because they contribute to his endeavors “to help my colleagues practice medicine in a safe, efficient, and productive manner.” For instance, some of the organizations Dr. Lenchus was involved with helped make changes to the Affordable Care Act that ended up in its final version, as well as changes after it passed. “There are tangible things that advocacy enables us to do in our daily practice,” he said.
When something his organizations have advocated for does not pass, they know they need to try a different outlet. “You can’t win every fight,” he said. “Every time you go and comment on an issue, you have to understand that you’re there to do your best, and to the extent that the people you’re talking to are willing to listen to what you have to say, that’s where I think you can make the most impact.” When changes he has helped fight for do pass, “it really is amazing that you can tell your colleagues about your role in achieving meaningful change in the profession.”
Dr. Lenchus acknowledges that advocacy “can be all-consuming at times. We have to understand our limits.” That said, he thinks not engaging in advocacy could increase stress and potential burnout. “I think being involved in advocacy efforts really helps people conduct meaningful work and educates them about what it means not just to them, but to the rest of the medical profession and the patients that we serve,” he said.
For hospitalists who are interested in health policy advocacy, there are many ways to get involved, Dr. Lenchus said. You could join an organization (many organized medical societies have public policy committees), participate in advocacy activities, work on a political campaign, or even run for office yourself. “Ultimately, education and some level of involvement really will make the difference in who navigates our future as hospitalists,” he said.
Questioning co-management practices
Though he says he’s in the minority, Hardik Vora, MD, SFHM, medical director for hospital medicine at Riverside Regional Medical Center in Newport News, Va., believes that co-management is going to “make or break hospital medicine. It’s going to have a huge impact on our specialty.”
In the roughly 25-year history of hospital medicine, it has evolved from admitting and caring for patients of primary care physicians to patients of specialists and, more recently, surgical patients. “Now there are (hospital medicine) programs across the country that are pretty much admitting everything,” said Dr. Vora.
As a recruiter for the Riverside Health System for the past eight years, “I have not met a single resident who is trained to do what we’re doing in hospital medicine, because you’re admitting surgical patients all the time and you have primary attending responsibility,” Dr. Vora said. “I see that as a cause of a significant amount of stress because now you’re responsible for something that you don’t have adequate training for.”
In the co-management discussion, Dr. Vora notes that people often bring up the research that shows that the practice has improved surgeon satisfaction. “What bothers me is that…you need to add one more question – how does it affect your hospitalists? And I bet the answer to that question is ‘it has a terrible effect.’”
The expectations surrounding hospitalists these days is a big concern in terms of burnout, Dr. Vora said. “We talk a lot about the drivers of burnout, whether it’s schedule or COVID,” he said. The biggest issue when it comes to burnout, as he sees it, is not COVID; it’s when hospitalists are performing tasks that make them feel they aren’t adding value. “I think that’s a huge topic in hospital medicine right now.”
Dr. Vora believes there should be more discussion and awareness of the potential pitfalls. “Hospitalists should get involved in co-management where they are adding value and certainly not take up the attending responsibility where they’re not adding value and it’s out of the scope of their training and expertise,” he said. “Preventing scope creep and burnout from co-management are some of the key issues I’m really passionate about.”
Dr. Vora said it is important to set realistic goals and remember that it takes time to make change when it comes to advocacy. “You still have to operate within whatever environment is given to you and then you can make change from within,” he said.
His enthusiasm for co-management awareness has led to creating a co-management forum through SHM in his local Hampton Roads chapter. He was also a panelist for an SHM webinar in February 2021 in which the panelists debated co-management.
“I think we really need to look at this as a specialty. Are we going in the right direction?” Dr. Vora asked. “We need to come together as a specialty and make a decision, which is going to be hard because there are competing financial interests and various practice models.”
Improving patient care
Working as a hospitalist at University Medical Center, a safety net hospital in New Orleans, Celeste Newby, MD, PhD, sees plenty of patients who are underinsured or not insured at all. “A lot of my interest in health policy stems from that,” she said.
During her residency, which she finished in 2015, Louisiana became a Medicaid expansion state. This impressed upon Dr. Newby how much Medicaid improved the lives of patients who had previously been uninsured. “We saw procedures getting done that had been put on hold because of financial concerns or medicines that were now affordable that weren’t before,” she said. “It really did make a difference.”
When repeated attempts to repeal the Affordable Care Act began, “it was a call to do health policy work for me personally that just hadn’t come up in the past,” said Dr. Newby, who is also assistant professor of medicine at Tulane University in New Orleans. “I personally found that the best way to do (advocacy work) was to go through medical societies because there is a much stronger voice when you have more people saying the same thing,” she said.
Dr. Newby sits on the Council of Legislation for the Louisiana State Medical Society and participates in the Leadership and Health Policy (LEAHP) Program through the Society of General Internal Medicine.
The LEAHP Program has been instrumental in expanding Dr. Newby’s knowledge of how health policy is made and the mechanisms behind it. It has also taught her “how we can either advise, guide, leverage, or advocate for things that we think would be important for change and moving the country in the right direction in terms of health care.”
Another reason involvement in medical societies is helpful is because, as a busy clinician, it is impossible to keep up with everything. “Working with medical societies, you have people who are more directly involved in the legislature and can give you quicker notice about things that are coming up that are going to be important to you or your co-workers or your patients,” Dr. Newby said.
Dr. Newby feels her advocacy work is an outlet for stress and “a way to work at more of a macro level on problems that I see with my individual patients. It’s a nice compliment.” At the hospital, she can only help one person at a time, but with her advocacy efforts, there’s potential to make changes for many.
“Advocacy now is such a large umbrella that encompasses so many different projects at all kinds of levels,” Dr. Newby said. She suggests looking around your community to see where the needs lie. If you’re passionate about a certain topic or population, see what you can do to help advocate for change there.
Hospitalists around the country are devoting large portions of their spare time to a wide range of advocacy efforts. From health policy to caring for the unhoused population to diversity and equity to advocating for fellow hospitalists, these physicians are passionate about their causes and determined to make a difference.
Championing the unhoused
Sarah Stella, MD, FHM, a hospitalist at Denver Health, was initially drawn there because of the population the hospital serves, which includes a high concentration of people experiencing homelessness. As she cared for her patients, Dr. Stella, who is also associate professor of hospital medicine at the University of Colorado, increasingly felt the desire to help prevent the negative downstream outcomes the hospital sees.
To understand the experiences of the unhoused outside the hospital, Dr. Stella started talking to her patients and people in community-based organizations that serve this population. “I learned a ton,” she said. “Homelessness feels like such an intractable, hopeless thing, but the more I talked to people, the more opportunities I saw to work toward something better.”
This led to a pilot grant to work with the Colorado Coalition for the Homeless to set up a community advisory panel. “My goal was to better understand their experiences and to develop a shared vision for how we collectively can do better,” said Dr. Stella. Eventually, she also received a grant from the University of Colorado, and multiple opportunities have sprung up ever since.
For the past several years, Dr. Stella has worked with Denver Health leadership to improve care for the homeless. “Right now, I’m working with a community team on developing an idea to provide peer support from people with a shared lived experience for people who are experiencing homelessness when they’re hospitalized. That’s really where my passion has been in working on the partnership,” she said.
Her advocacy role has been beneficial in her work as a hospitalist, particularly when COVID began. Dr. Stella again partnered with the Colorado Coalition for the Homeless to start a joint task force. “Everyone on our task force is motivated by this powerful desire to improve the health and lives of this community and that’s one of the silver linings in this pandemic for me,” said Dr. Stella.
Advocacy work has also increased Dr. Stella’s knowledge of what community support options are available for the unhoused. This allows her to educate her patients about their options and how to access them.
While she has colleagues who are able to compartmentalize their work, “I absolutely could not be a hospitalist without being an advocate,” Dr. Stella said. “For me, it has been a protective strategy in terms of burnout because I have to feel like I’m working to advocate for better policies and more appropriate resources to address the gaps that I’m seeing.”
Dr. Stella believes that physicians have a special credibility to advocate, tell stories, and use data to back their stories up. “We have to realize that we have this power, and we have it so we can empower others,” she said. “The people I’ve seen in my community who are working so hard to help people who are experiencing homelessness are the heroes. Understanding that and giving power to those people through our voice and our well-respected place in society drives me.”
Strengthening diversity, equity, and inclusion
In September 2020, Michael Bryant, MD, became the inaugural vice chair of Diversity, Equity, and Inclusion for the department of pediatrics at Children’s Hospital Los Angeles, where he is also the division head of pediatric hospital medicine. “I was motivated to apply for this position because I wanted to be an agent for change to eliminate the institutional racism, social injustice, and marginalization that continues to threaten the lives and well-beings of so many Americans,” Dr. Bryant said.
Between the pandemic, the economic decline it has created, and the divisive political landscape, people of color have been especially affected. “These are poignant examples of the ever-widening divide and disenfranchisement many Americans feel,” said Dr. Bryant. “Gandhi said, ‘Be the change that you want to see,’ and that is what I want to model.”
At work, advocacy for diversity, equality, and inclusion is an innate part of everything he does. From the new physicians he recruits to the candidates he considers for leadership positions, Dr. Bryant strives “to have a workforce that mirrors the diversity of the patients we humbly care for and serve.”
Advocacy is intrinsic to Dr. Bryant’s worldview, in his quest to understand and accept each individual’s uniqueness, his desire “to embrace cultural humility,” his recognition that “our differences enhance us instead of diminishing us,” and his willingness to engage in difficult conversations.
“Advocacy means that I acknowledge that intent does not equal impact and that I must accept that what I do and what I say may have unintended consequences,” he said. “When that happens, I must resist becoming defensive and instead be willing to listen and learn.”
Dr. Bryant is proud of his accomplishments and enjoys his advocacy work. In his workplace, there are few African Americans in leadership roles. This means that he is in high demand when it comes to making sure there’s representation during various processes such as hiring and vetting, a disparity known as the “minority tax.”
“I am thankful for the opportunities, but it does take a toll at times,” Dr. Bryant said, which is yet another reason why he is a proponent of increasing diversity and inclusion. “This allows us to build the resource pool as these needs arise and minimizes the toll of the ‘minority tax’ on any single person or small group of individuals.”
This summer, physicians from Dr. Bryant’s hospital participated in the national “White Coats for Black Lives” effort. He found it to be “an incredibly moving event” that hundreds of his colleagues participated in.
Dr. Bryant’s advice for hospitalists who want to get involved in advocacy efforts is to check out the movie “John Lewis: Good Trouble.” “He was a champion of human rights and fought for these rights until his death,” Dr. Bryant said. “He is a true American hero and a wonderful example.”
Bolstering health care change
Since his residency, Joshua Lenchus, DO, FACP, SFHM, has developed an ever-increasing interest in legislative advocacy, particularly health policy. Getting involved in this arena requires an understanding of civics and government that goes beyond just the basics. “My desire to affect change in my own profession really served as the catalyst to get involved,” said Dr. Lenchus, the regional chief medical officer at Broward Health Medical Center in Fort Lauderdale, Fla. “What better way to do that than by combining what we do on a daily basis in the practice of medicine with this new understanding of how laws are passed and promulgated?”
Dr. Lenchus has been involved with both state and national medical organizations and has served on public policy committees as a member and as a chair. “The charge of these committees is to monitor and navigate position statements and policies that will drive the entire organization,” he said. This means becoming knowledgeable enough about a topic to be able to talk about it eloquently and adding supporting personal or professional illustrations that reinforce the position to lawmakers.
He finds his advocacy efforts “incredibly rewarding” because they contribute to his endeavors “to help my colleagues practice medicine in a safe, efficient, and productive manner.” For instance, some of the organizations Dr. Lenchus was involved with helped make changes to the Affordable Care Act that ended up in its final version, as well as changes after it passed. “There are tangible things that advocacy enables us to do in our daily practice,” he said.
When something his organizations have advocated for does not pass, they know they need to try a different outlet. “You can’t win every fight,” he said. “Every time you go and comment on an issue, you have to understand that you’re there to do your best, and to the extent that the people you’re talking to are willing to listen to what you have to say, that’s where I think you can make the most impact.” When changes he has helped fight for do pass, “it really is amazing that you can tell your colleagues about your role in achieving meaningful change in the profession.”
Dr. Lenchus acknowledges that advocacy “can be all-consuming at times. We have to understand our limits.” That said, he thinks not engaging in advocacy could increase stress and potential burnout. “I think being involved in advocacy efforts really helps people conduct meaningful work and educates them about what it means not just to them, but to the rest of the medical profession and the patients that we serve,” he said.
For hospitalists who are interested in health policy advocacy, there are many ways to get involved, Dr. Lenchus said. You could join an organization (many organized medical societies have public policy committees), participate in advocacy activities, work on a political campaign, or even run for office yourself. “Ultimately, education and some level of involvement really will make the difference in who navigates our future as hospitalists,” he said.
Questioning co-management practices
Though he says he’s in the minority, Hardik Vora, MD, SFHM, medical director for hospital medicine at Riverside Regional Medical Center in Newport News, Va., believes that co-management is going to “make or break hospital medicine. It’s going to have a huge impact on our specialty.”
In the roughly 25-year history of hospital medicine, it has evolved from admitting and caring for patients of primary care physicians to patients of specialists and, more recently, surgical patients. “Now there are (hospital medicine) programs across the country that are pretty much admitting everything,” said Dr. Vora.
As a recruiter for the Riverside Health System for the past eight years, “I have not met a single resident who is trained to do what we’re doing in hospital medicine, because you’re admitting surgical patients all the time and you have primary attending responsibility,” Dr. Vora said. “I see that as a cause of a significant amount of stress because now you’re responsible for something that you don’t have adequate training for.”
In the co-management discussion, Dr. Vora notes that people often bring up the research that shows that the practice has improved surgeon satisfaction. “What bothers me is that…you need to add one more question – how does it affect your hospitalists? And I bet the answer to that question is ‘it has a terrible effect.’”
The expectations surrounding hospitalists these days is a big concern in terms of burnout, Dr. Vora said. “We talk a lot about the drivers of burnout, whether it’s schedule or COVID,” he said. The biggest issue when it comes to burnout, as he sees it, is not COVID; it’s when hospitalists are performing tasks that make them feel they aren’t adding value. “I think that’s a huge topic in hospital medicine right now.”
Dr. Vora believes there should be more discussion and awareness of the potential pitfalls. “Hospitalists should get involved in co-management where they are adding value and certainly not take up the attending responsibility where they’re not adding value and it’s out of the scope of their training and expertise,” he said. “Preventing scope creep and burnout from co-management are some of the key issues I’m really passionate about.”
Dr. Vora said it is important to set realistic goals and remember that it takes time to make change when it comes to advocacy. “You still have to operate within whatever environment is given to you and then you can make change from within,” he said.
His enthusiasm for co-management awareness has led to creating a co-management forum through SHM in his local Hampton Roads chapter. He was also a panelist for an SHM webinar in February 2021 in which the panelists debated co-management.
“I think we really need to look at this as a specialty. Are we going in the right direction?” Dr. Vora asked. “We need to come together as a specialty and make a decision, which is going to be hard because there are competing financial interests and various practice models.”
Improving patient care
Working as a hospitalist at University Medical Center, a safety net hospital in New Orleans, Celeste Newby, MD, PhD, sees plenty of patients who are underinsured or not insured at all. “A lot of my interest in health policy stems from that,” she said.
During her residency, which she finished in 2015, Louisiana became a Medicaid expansion state. This impressed upon Dr. Newby how much Medicaid improved the lives of patients who had previously been uninsured. “We saw procedures getting done that had been put on hold because of financial concerns or medicines that were now affordable that weren’t before,” she said. “It really did make a difference.”
When repeated attempts to repeal the Affordable Care Act began, “it was a call to do health policy work for me personally that just hadn’t come up in the past,” said Dr. Newby, who is also assistant professor of medicine at Tulane University in New Orleans. “I personally found that the best way to do (advocacy work) was to go through medical societies because there is a much stronger voice when you have more people saying the same thing,” she said.
Dr. Newby sits on the Council of Legislation for the Louisiana State Medical Society and participates in the Leadership and Health Policy (LEAHP) Program through the Society of General Internal Medicine.
The LEAHP Program has been instrumental in expanding Dr. Newby’s knowledge of how health policy is made and the mechanisms behind it. It has also taught her “how we can either advise, guide, leverage, or advocate for things that we think would be important for change and moving the country in the right direction in terms of health care.”
Another reason involvement in medical societies is helpful is because, as a busy clinician, it is impossible to keep up with everything. “Working with medical societies, you have people who are more directly involved in the legislature and can give you quicker notice about things that are coming up that are going to be important to you or your co-workers or your patients,” Dr. Newby said.
Dr. Newby feels her advocacy work is an outlet for stress and “a way to work at more of a macro level on problems that I see with my individual patients. It’s a nice compliment.” At the hospital, she can only help one person at a time, but with her advocacy efforts, there’s potential to make changes for many.
“Advocacy now is such a large umbrella that encompasses so many different projects at all kinds of levels,” Dr. Newby said. She suggests looking around your community to see where the needs lie. If you’re passionate about a certain topic or population, see what you can do to help advocate for change there.
Microbiota-directed therapy may improve growth rate in malnourished children
according to new research.
Moderate acute malnutrition affects more than 30 million children worldwide, according to the Food and Nutrition Bulletin. The World Health Organization defines the condition by a weight-for-height measurement that is 2 or 3 standard deviations below the international standard.
A 2014 study published in Nature has shown that malnourishment is associated with defects in children’s gut microbiota, including having microbial communities that are immature and younger than those of their healthy counterparts. Microbiota immaturity also correlates with stunted growth.
The authors of new study, which was published in the New England Journal of Medicine on April 7, 2021, wrote that nutritional interventions and treatments, such as therapeutic calorie-dense foods, have limited effectiveness because they don’t restore growth or fully address repairing the gut microbiome.
“This work supports the notion that healthy growth of children is linked to healthy development of their gut microbiota,” study author Jeffrey Gordon, MD, director of the Edison Family Center for Genome Sciences & Systems Biology at Washington University, St. Louis, said in an interview. “This, in turn, indicates that we need to have a more encompassing view of human developmental biology – one that considers both our ‘human’ and ‘microbial’ parts.”
The study establishes the impact of microbiota repair on a child’s growth rate, which may have implications on policies related to complementary feeding practices, Dr. Gorden noted.
Better outcomes seen with microbiota-directed complementary food prototype
For the research, 123 children with moderate acute malnutrition aged between 12 and 18 months were randomly assigned to receive a microbiota-directed complementary food prototype (MDCF-2) or ready-to-use supplementary food (RUSF). The supplementation was given to the kids twice daily for 3 months, followed by 1 month of monitoring. They looked at the weekly rate of change in the weight-for-length z score, weight-for-age z score, mid-upper-arm circumference, length-for-age z score, medical complication, gut microbiota, and blood samples in the group to determine the effectiveness of each food intervention therapy.
They found that, of the 118 children who completed the study, those in the MDCF-2 group had better outcomes than those in the RUSF group based on greater weekly growth in z scores, indicating faster growth rates. For those in the MDCF-2 group, the mean weekly change in weight-for-length z score was 0.021, compared to the RUSF group’s 0.010. When it came to weight-for-age z score, the mean weekly change was 0.017 in the MDCF-2 group and 0.010 in the RUSF group. The mean weekly changes in the mid-upper-arm circumference and length-for-age z scores were similar in both groups.
When examining blood samples of the cohort, researchers noted that 714 proteins were significantly altered after 3-month MDCF-2 supplementation, compared with 82 proteins having shown significant alterations in the RUSF group.
Overall, the findings show that repairing gut microbiota was accompanied by improved weight gain and marked changes in circulating levels of protein biomarkers and mediators of numerous aspects of healthy growth.
Results need to be verified on a larger scale
Tim Joos, MD, who was not part of the study, said it is surprising that MDCF-2 was better at promoting growth than existing nutritional supplements.
“The study suggests that remedying malnutrition requires more than just ensuring adequate calorie and nutrient intake,” Dr. Joos, a pediatrician at NeighborCare Health in Seattle, noted in an interview. “It is a small study and needs to be verified on a larger scale and in more diverse locations and pediatric ages (outside of the 12- to 18-month-old cohort studied).”
Wendy S. Garrett, MD, PhD, who also didn’t participate in the study, wrote in an accompanying editorial that overarching questions remain concerning the long-lasting effects of the intervention on children’s growth trajectory and cognitive development. She also said that the study “provides an abundance of fascinating microbiome profile data, plasma protein correlates, and metadata to sift through.”
Dr. Gordon and colleagues said the findings underscore the broad effects gut microbiota has on human biology and they hope this will open the door to better definitions of wellness for infants/children.
Dr. Garrett is the Irene Heinz Given Professor of Immunology and Infectious Diseases in the departments of immunology and infectious diseases and of molecular metabolism at the Harvard School of Public Health, Boston, and she has no disclosures. Dr. Gordon is the recipient of a Thought Leader award from Agilent Technologies. Dr. Joos disclosed no relevant financial relationships.
according to new research.
Moderate acute malnutrition affects more than 30 million children worldwide, according to the Food and Nutrition Bulletin. The World Health Organization defines the condition by a weight-for-height measurement that is 2 or 3 standard deviations below the international standard.
A 2014 study published in Nature has shown that malnourishment is associated with defects in children’s gut microbiota, including having microbial communities that are immature and younger than those of their healthy counterparts. Microbiota immaturity also correlates with stunted growth.
The authors of new study, which was published in the New England Journal of Medicine on April 7, 2021, wrote that nutritional interventions and treatments, such as therapeutic calorie-dense foods, have limited effectiveness because they don’t restore growth or fully address repairing the gut microbiome.
“This work supports the notion that healthy growth of children is linked to healthy development of their gut microbiota,” study author Jeffrey Gordon, MD, director of the Edison Family Center for Genome Sciences & Systems Biology at Washington University, St. Louis, said in an interview. “This, in turn, indicates that we need to have a more encompassing view of human developmental biology – one that considers both our ‘human’ and ‘microbial’ parts.”
The study establishes the impact of microbiota repair on a child’s growth rate, which may have implications on policies related to complementary feeding practices, Dr. Gorden noted.
Better outcomes seen with microbiota-directed complementary food prototype
For the research, 123 children with moderate acute malnutrition aged between 12 and 18 months were randomly assigned to receive a microbiota-directed complementary food prototype (MDCF-2) or ready-to-use supplementary food (RUSF). The supplementation was given to the kids twice daily for 3 months, followed by 1 month of monitoring. They looked at the weekly rate of change in the weight-for-length z score, weight-for-age z score, mid-upper-arm circumference, length-for-age z score, medical complication, gut microbiota, and blood samples in the group to determine the effectiveness of each food intervention therapy.
They found that, of the 118 children who completed the study, those in the MDCF-2 group had better outcomes than those in the RUSF group based on greater weekly growth in z scores, indicating faster growth rates. For those in the MDCF-2 group, the mean weekly change in weight-for-length z score was 0.021, compared to the RUSF group’s 0.010. When it came to weight-for-age z score, the mean weekly change was 0.017 in the MDCF-2 group and 0.010 in the RUSF group. The mean weekly changes in the mid-upper-arm circumference and length-for-age z scores were similar in both groups.
When examining blood samples of the cohort, researchers noted that 714 proteins were significantly altered after 3-month MDCF-2 supplementation, compared with 82 proteins having shown significant alterations in the RUSF group.
Overall, the findings show that repairing gut microbiota was accompanied by improved weight gain and marked changes in circulating levels of protein biomarkers and mediators of numerous aspects of healthy growth.
Results need to be verified on a larger scale
Tim Joos, MD, who was not part of the study, said it is surprising that MDCF-2 was better at promoting growth than existing nutritional supplements.
“The study suggests that remedying malnutrition requires more than just ensuring adequate calorie and nutrient intake,” Dr. Joos, a pediatrician at NeighborCare Health in Seattle, noted in an interview. “It is a small study and needs to be verified on a larger scale and in more diverse locations and pediatric ages (outside of the 12- to 18-month-old cohort studied).”
Wendy S. Garrett, MD, PhD, who also didn’t participate in the study, wrote in an accompanying editorial that overarching questions remain concerning the long-lasting effects of the intervention on children’s growth trajectory and cognitive development. She also said that the study “provides an abundance of fascinating microbiome profile data, plasma protein correlates, and metadata to sift through.”
Dr. Gordon and colleagues said the findings underscore the broad effects gut microbiota has on human biology and they hope this will open the door to better definitions of wellness for infants/children.
Dr. Garrett is the Irene Heinz Given Professor of Immunology and Infectious Diseases in the departments of immunology and infectious diseases and of molecular metabolism at the Harvard School of Public Health, Boston, and she has no disclosures. Dr. Gordon is the recipient of a Thought Leader award from Agilent Technologies. Dr. Joos disclosed no relevant financial relationships.
according to new research.
Moderate acute malnutrition affects more than 30 million children worldwide, according to the Food and Nutrition Bulletin. The World Health Organization defines the condition by a weight-for-height measurement that is 2 or 3 standard deviations below the international standard.
A 2014 study published in Nature has shown that malnourishment is associated with defects in children’s gut microbiota, including having microbial communities that are immature and younger than those of their healthy counterparts. Microbiota immaturity also correlates with stunted growth.
The authors of new study, which was published in the New England Journal of Medicine on April 7, 2021, wrote that nutritional interventions and treatments, such as therapeutic calorie-dense foods, have limited effectiveness because they don’t restore growth or fully address repairing the gut microbiome.
“This work supports the notion that healthy growth of children is linked to healthy development of their gut microbiota,” study author Jeffrey Gordon, MD, director of the Edison Family Center for Genome Sciences & Systems Biology at Washington University, St. Louis, said in an interview. “This, in turn, indicates that we need to have a more encompassing view of human developmental biology – one that considers both our ‘human’ and ‘microbial’ parts.”
The study establishes the impact of microbiota repair on a child’s growth rate, which may have implications on policies related to complementary feeding practices, Dr. Gorden noted.
Better outcomes seen with microbiota-directed complementary food prototype
For the research, 123 children with moderate acute malnutrition aged between 12 and 18 months were randomly assigned to receive a microbiota-directed complementary food prototype (MDCF-2) or ready-to-use supplementary food (RUSF). The supplementation was given to the kids twice daily for 3 months, followed by 1 month of monitoring. They looked at the weekly rate of change in the weight-for-length z score, weight-for-age z score, mid-upper-arm circumference, length-for-age z score, medical complication, gut microbiota, and blood samples in the group to determine the effectiveness of each food intervention therapy.
They found that, of the 118 children who completed the study, those in the MDCF-2 group had better outcomes than those in the RUSF group based on greater weekly growth in z scores, indicating faster growth rates. For those in the MDCF-2 group, the mean weekly change in weight-for-length z score was 0.021, compared to the RUSF group’s 0.010. When it came to weight-for-age z score, the mean weekly change was 0.017 in the MDCF-2 group and 0.010 in the RUSF group. The mean weekly changes in the mid-upper-arm circumference and length-for-age z scores were similar in both groups.
When examining blood samples of the cohort, researchers noted that 714 proteins were significantly altered after 3-month MDCF-2 supplementation, compared with 82 proteins having shown significant alterations in the RUSF group.
Overall, the findings show that repairing gut microbiota was accompanied by improved weight gain and marked changes in circulating levels of protein biomarkers and mediators of numerous aspects of healthy growth.
Results need to be verified on a larger scale
Tim Joos, MD, who was not part of the study, said it is surprising that MDCF-2 was better at promoting growth than existing nutritional supplements.
“The study suggests that remedying malnutrition requires more than just ensuring adequate calorie and nutrient intake,” Dr. Joos, a pediatrician at NeighborCare Health in Seattle, noted in an interview. “It is a small study and needs to be verified on a larger scale and in more diverse locations and pediatric ages (outside of the 12- to 18-month-old cohort studied).”
Wendy S. Garrett, MD, PhD, who also didn’t participate in the study, wrote in an accompanying editorial that overarching questions remain concerning the long-lasting effects of the intervention on children’s growth trajectory and cognitive development. She also said that the study “provides an abundance of fascinating microbiome profile data, plasma protein correlates, and metadata to sift through.”
Dr. Gordon and colleagues said the findings underscore the broad effects gut microbiota has on human biology and they hope this will open the door to better definitions of wellness for infants/children.
Dr. Garrett is the Irene Heinz Given Professor of Immunology and Infectious Diseases in the departments of immunology and infectious diseases and of molecular metabolism at the Harvard School of Public Health, Boston, and she has no disclosures. Dr. Gordon is the recipient of a Thought Leader award from Agilent Technologies. Dr. Joos disclosed no relevant financial relationships.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
2021 Update on sequencing in prenatal genetics
Prenatal diagnosis has expanded from identification of aneuploidy to include copy number variants detected on microarray (such as 22q11 deletion syndrome) and now single-gene disorders identified by targeted or exome and genome sequencing. How and when different sequencing tests should be used clinically are questions faced by every provider engaged in modern prenatal diagnosis.
In this Update, we highlight new clinical insights into prenatal sequencing and explore how information gained from sequencing may help us understand some of the unanswered questions in obstetrics.
What is the yield of a RASopathy gene panel with specific prenatal findings?
Scott A, Di Giosaffatte N, Pinna V, et al. When to test fetuses for RASopathies? Proposition from a systematic analysis of 352 multicenter cases and a postnatal cohort. Genet Med. Published online February 10, 2021. doi:10.1038/s41436-020-01093-7.
RASopathies, a group of genetic conditions caused by mutations in the RAS/mitogen-activated protein kinase (RAS-MAPK) pathway, are common, occurring in 1:1,000 to 1:2,500 live births. RASopathies are much more common than 22q11 deletion syndrome, or DiGeorge syndrome, which occurs in 1.4:10,000 live births.1
RASopathy disorders include Noonan syndrome, Noonan syndrome with multiple lentigines, Costello syndrome, cardiofaciocutaneous syndrome, and Noonan-like syndrome with loose anagen hair. These are autosomal dominant disorders caused by a pathogenic variant (or mutation) in 1 of more than 20 genes in the RAS-MAPK signaling pathway in the body. Clinical features include congenital anomalies of the kidney and urinary tract, lymphatic anomalies, congenital heart disease (CHD), hypertrophic cardiomyopathy (HCM), postnatal growth disorders, neurodevelopmental disorders, and more rarely hematologic malignancies. Prenatal clues include an increased nuchal translucency (NT), CHD, cystic hygroma, lymphatic anomalies, anomalies of the kidney and urinary tract, hydrops, and HCM.
Cohort of pregnancies that received a RASopathy panel
Scott and colleagues sought to clarify the utility of testing for RASopathies with a prenatal gene panel. They conducted a multicenter retrospective cohort study with cases from 2 hospitals in Italy and Canada; data were collected between 2012 and 2019.
Eligible fetuses were those referred to the prenatal genetics clinic because of an increased NT, increased nuchal fold (NF), hydrops, ascites, thoracic effusions, chylothorax, other lymphatic anomalies, CHD, or HCM with a nondiagnostic (negative) microarray or karyotype. All eligible cases had RASopathy molecular testing in the prenatal or neonatal period.
Among the 352 referrals to clinic, 50 cases of a RASopathy disorder were diagnosed. Additionally, to complement this cohort over the same time period, 25 postnatal diagnoses were made after retrospective review performed to ascertain additional prenatal findings. The size of the testing panel ranged from 9 to 20 genes, which were sent to clinical laboratories that performed sequencing based on standard protocols.
Study outcomes
Overall, 14% of fetuses with an indication for testing had a pathogenic or likely pathogenic variant (diagnostic) on panel testing among 11 genes (notably, all presented results are after excluding copy number variants and aneuploidy). Fetuses with only 1 ultrasonography finding were much less likely to have a positive result than those with more than 1 ultrasonography finding, 3% versus 18%. The highest diagnostic yields were for HCM at 69%; thoracic effusions and ascites, 41%; persistent hydrops, 39%; cystic hygroma combined with another suggestive ultrasonography finding, 28%; CHD, 23%; and persistent cystic hygroma, 21%. Five fetuses were affected with CHD and HCM, and 44% had an intrauterine fetal demise.
Importance of NT size. An isolated increased NT had a diagnostic yield of 1% overall (1/90); however, the size of the NT mattered. Seventeen fetuses had an NT between 3 and 3.5 mm and none of these had diagnostic sequencing, whereas 26% with an NT greater than 6 mm had a diagnostic result (11/43). An increased NF had a diagnostic yield of 25%.
Other findings. Of fetuses with a cystic hygroma, 16% had a pathogenic or likely pathogenic variant, and when these persisted into the second trimester or were associated with other anomalies, the percentages increased to 21% and 28%, respectively. Of prenatal patients, 20.6% had variants of uncertain significance, and 12% of the pathogenic and likely pathogenic variants were inherited, which is less than previously reported series. Additionally, 48% of the postnatal RASopathy diagnosis group did not have an ultrasonography finding on record review.
Continue to: Study strengths and limitations...
Study strengths and limitations
This study presents a large cohort of prenatal and neonatal patients tested for RASopathies at 2 international centers with very granular and clinically useful data about ultrasonography findings and yield of panel testing. Prenatal care providers, geneticists, and computational biologists may find this study of great interest and take away useful information and ideas due to the authors’ presentation and details.
The number of genes tested changed over the inclusion time period, but this is an inescapable reality of retrospective clinical research in an advancing field. The authors presented the prenatal and postnatal diagnoses ultrasonography findings separately and together. Given the different nature of cohort ascertainment, we prefer to consider these groups separately and have presented the data for the prenatal group.
Prenatal sequencing panels and exome sequencing are detecting disorders with important implications for prenatal care. If your practice is not testing for RASopathies in prenatal patients with concerning ultrasonography features, you are missing cases. In this study, the most concerning ultrasonography features (more than 20% diagnosis) were HCM, thoracic effusions and ascites, persistent hydrops, cystic hygroma combined with another suggestive ultrasonography finding, CHD, and persistent cystic hygroma. Isolated ultrasonography findings or findings that resolved had a lower diagnostic yield, and an isolated enlarged NT had a 1% diagnostic yield, with most cases having an NT larger than 6 mm.
For pretest counseling, in this study 20% of patients had a variant of uncertain significance, and preparing patients for this possibility is crucial. Most variants of uncertain significance are reclassified to benign when more information is available. Providers can consider sending parental samples concurrently with the fetal sample to help obtain useful information quickly, although the possibility of an inherited pathogenic variant still exists (12% in this study).
Prenatal diagnosis gives your patients the opportunity to learn about the disorder, plan for treatment and delivery location, and establish their care team before birth or consider pregnancy termination.
Sequencing provides insights into twin pregnancies
Jonsson H, Magnusdottir E, Eggertsson HP, et al. Differences between germline genomes of monozygotic twins. Nat Genet. 2021;53:27-34. doi:10.1038/s41588 -020-00755-1.
You have a monozygotic twin pair with an anomaly and intend to do diagnostic testing for prenatal diagnosis. The question always arises: Do you sample both twins or just one? Surely, they are genetically identical? A wise mentor once instilled a valuable lesson: Monozygotic twins are more likely to have an anomaly. Their existence is already out of the realm of normal. Finally, we now have an engaging and interesting answer to this and other fascinating embryology questions through the work of Jonsson and colleagues.
Study eligibility criteria and treatment protocol
The authors enrolled 381 twin pairs and 2 monozygotic triplets and compared genome sequencing of different tissues (cheek cells and blood). They went further to assess what other tissues might share the genetic change. To do this, they sequenced the children and the partners of 181 of the pairs. Presumably, if a twin and their offspring shared a genetic change that was not present in the spouse or twin, this genetic change must be present in the oocytes or sperm of the parent twin. The goal of sequencing multiple tissue sources in each twin was to help determine when the genetic change occurred in embryonic development.
Study outcomes
The authors found that 15% of twins had mutations that were absent in the other twin. Because of the extent of tissues that had the genetic change, the authors asserted that these changes must have occurred very early in embryonic development (even from one cell after twinning) for the changes to be near-constitutional (among sampled tissues).
An average of 14 genetic differences were found between twin pairs that developed after twinning. However, the number of differences varied. For example, 39 pairs of twins differed by more than 100 changes, and 38 did not differ at all. Differences between twins were more likely in blood samples than in cheek swabs, suggesting that some differences were due to acquired genetic changes in hematologic cell lines, or clonal hematopoiesis.
The authors also looked at what percentage of sequenced DNA contained the variants (or mutations) and found that many of these DNA differences were present at high amounts in sequencing reads. This suggests that the DNA changes happened very early after twinning in about one-third of pairs. Additionally, if one twin had a near-constitutional change, in 42% of pairs the other twin had a different near-constitutional change. Among the triplets, 2 of a triplet pair shared more genetic similarity and were likely descendent from a single split cell and the third likely was formed from a different set of cells.
By examining the offspring of twins, Jonsson and colleagues found that there were 2.6 early embryonic mutations, and this did not differ when blood or buccal DNA was compared. The rate of transmission of a variant to offspring was proportional to the variant allele frequency (proportion of alternate alleles) in the blood or buccal cells. This is an important counseling point when considering patients with mosaic genetic disorders and counseling about the likelihood of inheritance or transmission to future offspring. If the rate of mosaicism was higher in blood or buccal cells, the likelihood of transmission was higher. Additionally, the mutations did not differ by sex, and there was no relationship to whether the chromosome was maternally or paternally inherited.
Continue to: Study strengths and limitations...
Study strengths and limitations
The authors did not have access to information about chorionicity of the monozygotic twin pairs. Consequently, they were unable to correlate chorionicity with the degree of noted genetic difference between the monozygotic twin pairs. Additionally, although the authors were thoughtful in their utilization of offspring and spouses to infer germline genomic content, the study had a limited number of tissues sampled, which could reduce the applicability. However, the sample size, clinically accessible tissue sampling, and thoughtful analysis used in this study make it an interesting and relevant contribution to reproductive medicine and evolutionary biology.
We all accumulate changes to our DNA throughout life. The study by Jonsson and colleagues illustrates that for many, this accumulation of genetic changes starts very early in gestation. In the early zygote, the authors observed roughly 1 mutation per cell division prior to the point of twinning. In the realm of prenatal diagnosis, one should consider that monochorionic twins with different phenotypes (that is, an ultrasonography anomaly in 1 of the twin pair) could represent a genetic change rather than an environmental difference. This genetic change may not be shared by the other twin despite originating from the same primordial cell line. The genetic changes that the authors investigated were detected on genome sequencing, which is much more comprehensive than the exome sequencing that is increasingly utilized in rare disease diagnosis. The clinical utility of this observation in prenatal diagnosis has yet to be proven, but this study provides preliminary data that 15% of monozygotic twins have genetic differences and may warrant individualized testing.
The genetic landscape of the placenta
Coorens TH, Oliver TR, Sanghvi R, et al. Inherent mosaicism and extensive mutation of human placentas. Nature. Published online March 10, 2021. doi:10.1038/ s41586-021-03345-1.
Confined placental mosaicism (CPM) is a phenomenon in which the genetics of the placenta are different from those of the fetus. Historically, this phenomenon has been described in 1% to 2% of pregnancies based on karyotype data obtained from chorionic villus sampling. Some studies have demonstrated adverse pregnancy outcomes in the setting of CPM, thought to be secondary to aneuploid cells in the placenta leading to insufficiency or dysfunction.
Although our sophistication and level of detail in prenatal genetic testing has rapidly expanded to include information about copy number variants and singlenucleotide changes, their contribution to CPM has been understudied. Coorens and colleagues recently published a landmark study that describes a surprisingly high rate of mosaicism for these smaller genetic changes.
A cohort study of placentas
The authors performed whole genome sequencing on placental samples obtained from 37 term pregnancies. Umbilical cord tissue and maternal blood also were collected and served as controls for fetal and maternal genetic profiles, respectively.
In a subgroup of 5 placentas, lasercapture microscopy was used to separate placental cells of different origins, including trophoblastic cells, mesenchymal core cells, and cells originating from the inner cell mass. To investigate variation within different geographic regions of a single placenta, these cell lines were derived multiple times from each quadrant of the 5 placentas.
Placental biopsies revealed “bottlenecks” of genetic differentiation
Genome sequencing was used uniquely in this study to help delineate the phylogeny of placental cells by tracking somatic mutations both in different geographic locations of each placenta and between different cells of origin within 1 placenta.
The authors concluded that bottlenecks of differentiation in placental development led to unique genetic signatures in every bulk placental sample studied. Their findings led them to describe the placenta as a “patchwork” of independent genetic units resulting from clonal expansion at different stages of embryonic development.
Early insights into human placental cells
This study provides fascinating insight into the surprisingly high rates of copy number variants and single-gene changes that exist, in mosaic form, within human placentas. The authors distinguish the placenta from other human organs (such as the colon, endometrium, liver, and skin) in which many fewer genetic changes exist. In fact, they suggest parallels between the “mutational signature” of the placenta with rapidly dividing neoplastic cells.
As one of the first investigations into the variation and complexity of genetic changes within the placenta, this study was not designed to draw conclusions regarding the clinical impact of the numerous genetic changes described. Further studies will elucidate the potential contribution of genetically mosaic placentas to common adverse obstetric outcomes. ●
With a new appreciation for the smaller genetic alterations that exist within placental tissue, it appears that the rate of CPM has been vastly underestimated. We know that aneuploid placental cells increase the risk of adverse pregnancy outcomes and we may learn more about the contribution of copy number variants and single-nucleotide changes to preeclampsia, growth restriction, and pregnancy loss. Furthermore, as the applications of cell-free fetal DNA (cffDNA) in genetic screening continue to expand, we must exercise caution in assuming that copy number variants or single-nucleotide changes detected by cffDNA reflect those of the developing fetus.
- Roberts AE, Allanson JE, Tartaglia M, et al. Noonan syndrome. Lancet. 2013;381:333-342. doi:10.1016/S0140-6736(12)61023-X.
Rebecca Reimers, MD
Dr. Reimers is a Clinical Fellow, Maternal-Fetal Medicine and Clinical Genetics, Division of Maternal-Fetal Medicine, Brigham and Women’s Hospital and Boston Children’s Hospital, Boston, Massachusetts.
Stephanie Guseh, MD
Dr. Guseh is a Clinical Instructor, Maternal-Fetal Medicine and Clinical Genetics, Division of Maternal-Fetal Medicine, Brigham and Women’s Hospital.
The authors report no financial relationships relevant to this article.
Rebecca Reimers, MD
Dr. Reimers is a Clinical Fellow, Maternal-Fetal Medicine and Clinical Genetics, Division of Maternal-Fetal Medicine, Brigham and Women’s Hospital and Boston Children’s Hospital, Boston, Massachusetts.
Stephanie Guseh, MD
Dr. Guseh is a Clinical Instructor, Maternal-Fetal Medicine and Clinical Genetics, Division of Maternal-Fetal Medicine, Brigham and Women’s Hospital.
The authors report no financial relationships relevant to this article.
Rebecca Reimers, MD
Dr. Reimers is a Clinical Fellow, Maternal-Fetal Medicine and Clinical Genetics, Division of Maternal-Fetal Medicine, Brigham and Women’s Hospital and Boston Children’s Hospital, Boston, Massachusetts.
Stephanie Guseh, MD
Dr. Guseh is a Clinical Instructor, Maternal-Fetal Medicine and Clinical Genetics, Division of Maternal-Fetal Medicine, Brigham and Women’s Hospital.
The authors report no financial relationships relevant to this article.
Prenatal diagnosis has expanded from identification of aneuploidy to include copy number variants detected on microarray (such as 22q11 deletion syndrome) and now single-gene disorders identified by targeted or exome and genome sequencing. How and when different sequencing tests should be used clinically are questions faced by every provider engaged in modern prenatal diagnosis.
In this Update, we highlight new clinical insights into prenatal sequencing and explore how information gained from sequencing may help us understand some of the unanswered questions in obstetrics.
What is the yield of a RASopathy gene panel with specific prenatal findings?
Scott A, Di Giosaffatte N, Pinna V, et al. When to test fetuses for RASopathies? Proposition from a systematic analysis of 352 multicenter cases and a postnatal cohort. Genet Med. Published online February 10, 2021. doi:10.1038/s41436-020-01093-7.
RASopathies, a group of genetic conditions caused by mutations in the RAS/mitogen-activated protein kinase (RAS-MAPK) pathway, are common, occurring in 1:1,000 to 1:2,500 live births. RASopathies are much more common than 22q11 deletion syndrome, or DiGeorge syndrome, which occurs in 1.4:10,000 live births.1
RASopathy disorders include Noonan syndrome, Noonan syndrome with multiple lentigines, Costello syndrome, cardiofaciocutaneous syndrome, and Noonan-like syndrome with loose anagen hair. These are autosomal dominant disorders caused by a pathogenic variant (or mutation) in 1 of more than 20 genes in the RAS-MAPK signaling pathway in the body. Clinical features include congenital anomalies of the kidney and urinary tract, lymphatic anomalies, congenital heart disease (CHD), hypertrophic cardiomyopathy (HCM), postnatal growth disorders, neurodevelopmental disorders, and more rarely hematologic malignancies. Prenatal clues include an increased nuchal translucency (NT), CHD, cystic hygroma, lymphatic anomalies, anomalies of the kidney and urinary tract, hydrops, and HCM.
Cohort of pregnancies that received a RASopathy panel
Scott and colleagues sought to clarify the utility of testing for RASopathies with a prenatal gene panel. They conducted a multicenter retrospective cohort study with cases from 2 hospitals in Italy and Canada; data were collected between 2012 and 2019.
Eligible fetuses were those referred to the prenatal genetics clinic because of an increased NT, increased nuchal fold (NF), hydrops, ascites, thoracic effusions, chylothorax, other lymphatic anomalies, CHD, or HCM with a nondiagnostic (negative) microarray or karyotype. All eligible cases had RASopathy molecular testing in the prenatal or neonatal period.
Among the 352 referrals to clinic, 50 cases of a RASopathy disorder were diagnosed. Additionally, to complement this cohort over the same time period, 25 postnatal diagnoses were made after retrospective review performed to ascertain additional prenatal findings. The size of the testing panel ranged from 9 to 20 genes, which were sent to clinical laboratories that performed sequencing based on standard protocols.
Study outcomes
Overall, 14% of fetuses with an indication for testing had a pathogenic or likely pathogenic variant (diagnostic) on panel testing among 11 genes (notably, all presented results are after excluding copy number variants and aneuploidy). Fetuses with only 1 ultrasonography finding were much less likely to have a positive result than those with more than 1 ultrasonography finding, 3% versus 18%. The highest diagnostic yields were for HCM at 69%; thoracic effusions and ascites, 41%; persistent hydrops, 39%; cystic hygroma combined with another suggestive ultrasonography finding, 28%; CHD, 23%; and persistent cystic hygroma, 21%. Five fetuses were affected with CHD and HCM, and 44% had an intrauterine fetal demise.
Importance of NT size. An isolated increased NT had a diagnostic yield of 1% overall (1/90); however, the size of the NT mattered. Seventeen fetuses had an NT between 3 and 3.5 mm and none of these had diagnostic sequencing, whereas 26% with an NT greater than 6 mm had a diagnostic result (11/43). An increased NF had a diagnostic yield of 25%.
Other findings. Of fetuses with a cystic hygroma, 16% had a pathogenic or likely pathogenic variant, and when these persisted into the second trimester or were associated with other anomalies, the percentages increased to 21% and 28%, respectively. Of prenatal patients, 20.6% had variants of uncertain significance, and 12% of the pathogenic and likely pathogenic variants were inherited, which is less than previously reported series. Additionally, 48% of the postnatal RASopathy diagnosis group did not have an ultrasonography finding on record review.
Continue to: Study strengths and limitations...
Study strengths and limitations
This study presents a large cohort of prenatal and neonatal patients tested for RASopathies at 2 international centers with very granular and clinically useful data about ultrasonography findings and yield of panel testing. Prenatal care providers, geneticists, and computational biologists may find this study of great interest and take away useful information and ideas due to the authors’ presentation and details.
The number of genes tested changed over the inclusion time period, but this is an inescapable reality of retrospective clinical research in an advancing field. The authors presented the prenatal and postnatal diagnoses ultrasonography findings separately and together. Given the different nature of cohort ascertainment, we prefer to consider these groups separately and have presented the data for the prenatal group.
Prenatal sequencing panels and exome sequencing are detecting disorders with important implications for prenatal care. If your practice is not testing for RASopathies in prenatal patients with concerning ultrasonography features, you are missing cases. In this study, the most concerning ultrasonography features (more than 20% diagnosis) were HCM, thoracic effusions and ascites, persistent hydrops, cystic hygroma combined with another suggestive ultrasonography finding, CHD, and persistent cystic hygroma. Isolated ultrasonography findings or findings that resolved had a lower diagnostic yield, and an isolated enlarged NT had a 1% diagnostic yield, with most cases having an NT larger than 6 mm.
For pretest counseling, in this study 20% of patients had a variant of uncertain significance, and preparing patients for this possibility is crucial. Most variants of uncertain significance are reclassified to benign when more information is available. Providers can consider sending parental samples concurrently with the fetal sample to help obtain useful information quickly, although the possibility of an inherited pathogenic variant still exists (12% in this study).
Prenatal diagnosis gives your patients the opportunity to learn about the disorder, plan for treatment and delivery location, and establish their care team before birth or consider pregnancy termination.
Sequencing provides insights into twin pregnancies
Jonsson H, Magnusdottir E, Eggertsson HP, et al. Differences between germline genomes of monozygotic twins. Nat Genet. 2021;53:27-34. doi:10.1038/s41588 -020-00755-1.
You have a monozygotic twin pair with an anomaly and intend to do diagnostic testing for prenatal diagnosis. The question always arises: Do you sample both twins or just one? Surely, they are genetically identical? A wise mentor once instilled a valuable lesson: Monozygotic twins are more likely to have an anomaly. Their existence is already out of the realm of normal. Finally, we now have an engaging and interesting answer to this and other fascinating embryology questions through the work of Jonsson and colleagues.
Study eligibility criteria and treatment protocol
The authors enrolled 381 twin pairs and 2 monozygotic triplets and compared genome sequencing of different tissues (cheek cells and blood). They went further to assess what other tissues might share the genetic change. To do this, they sequenced the children and the partners of 181 of the pairs. Presumably, if a twin and their offspring shared a genetic change that was not present in the spouse or twin, this genetic change must be present in the oocytes or sperm of the parent twin. The goal of sequencing multiple tissue sources in each twin was to help determine when the genetic change occurred in embryonic development.
Study outcomes
The authors found that 15% of twins had mutations that were absent in the other twin. Because of the extent of tissues that had the genetic change, the authors asserted that these changes must have occurred very early in embryonic development (even from one cell after twinning) for the changes to be near-constitutional (among sampled tissues).
An average of 14 genetic differences were found between twin pairs that developed after twinning. However, the number of differences varied. For example, 39 pairs of twins differed by more than 100 changes, and 38 did not differ at all. Differences between twins were more likely in blood samples than in cheek swabs, suggesting that some differences were due to acquired genetic changes in hematologic cell lines, or clonal hematopoiesis.
The authors also looked at what percentage of sequenced DNA contained the variants (or mutations) and found that many of these DNA differences were present at high amounts in sequencing reads. This suggests that the DNA changes happened very early after twinning in about one-third of pairs. Additionally, if one twin had a near-constitutional change, in 42% of pairs the other twin had a different near-constitutional change. Among the triplets, 2 of a triplet pair shared more genetic similarity and were likely descendent from a single split cell and the third likely was formed from a different set of cells.
By examining the offspring of twins, Jonsson and colleagues found that there were 2.6 early embryonic mutations, and this did not differ when blood or buccal DNA was compared. The rate of transmission of a variant to offspring was proportional to the variant allele frequency (proportion of alternate alleles) in the blood or buccal cells. This is an important counseling point when considering patients with mosaic genetic disorders and counseling about the likelihood of inheritance or transmission to future offspring. If the rate of mosaicism was higher in blood or buccal cells, the likelihood of transmission was higher. Additionally, the mutations did not differ by sex, and there was no relationship to whether the chromosome was maternally or paternally inherited.
Continue to: Study strengths and limitations...
Study strengths and limitations
The authors did not have access to information about chorionicity of the monozygotic twin pairs. Consequently, they were unable to correlate chorionicity with the degree of noted genetic difference between the monozygotic twin pairs. Additionally, although the authors were thoughtful in their utilization of offspring and spouses to infer germline genomic content, the study had a limited number of tissues sampled, which could reduce the applicability. However, the sample size, clinically accessible tissue sampling, and thoughtful analysis used in this study make it an interesting and relevant contribution to reproductive medicine and evolutionary biology.
We all accumulate changes to our DNA throughout life. The study by Jonsson and colleagues illustrates that for many, this accumulation of genetic changes starts very early in gestation. In the early zygote, the authors observed roughly 1 mutation per cell division prior to the point of twinning. In the realm of prenatal diagnosis, one should consider that monochorionic twins with different phenotypes (that is, an ultrasonography anomaly in 1 of the twin pair) could represent a genetic change rather than an environmental difference. This genetic change may not be shared by the other twin despite originating from the same primordial cell line. The genetic changes that the authors investigated were detected on genome sequencing, which is much more comprehensive than the exome sequencing that is increasingly utilized in rare disease diagnosis. The clinical utility of this observation in prenatal diagnosis has yet to be proven, but this study provides preliminary data that 15% of monozygotic twins have genetic differences and may warrant individualized testing.
The genetic landscape of the placenta
Coorens TH, Oliver TR, Sanghvi R, et al. Inherent mosaicism and extensive mutation of human placentas. Nature. Published online March 10, 2021. doi:10.1038/ s41586-021-03345-1.
Confined placental mosaicism (CPM) is a phenomenon in which the genetics of the placenta are different from those of the fetus. Historically, this phenomenon has been described in 1% to 2% of pregnancies based on karyotype data obtained from chorionic villus sampling. Some studies have demonstrated adverse pregnancy outcomes in the setting of CPM, thought to be secondary to aneuploid cells in the placenta leading to insufficiency or dysfunction.
Although our sophistication and level of detail in prenatal genetic testing has rapidly expanded to include information about copy number variants and singlenucleotide changes, their contribution to CPM has been understudied. Coorens and colleagues recently published a landmark study that describes a surprisingly high rate of mosaicism for these smaller genetic changes.
A cohort study of placentas
The authors performed whole genome sequencing on placental samples obtained from 37 term pregnancies. Umbilical cord tissue and maternal blood also were collected and served as controls for fetal and maternal genetic profiles, respectively.
In a subgroup of 5 placentas, lasercapture microscopy was used to separate placental cells of different origins, including trophoblastic cells, mesenchymal core cells, and cells originating from the inner cell mass. To investigate variation within different geographic regions of a single placenta, these cell lines were derived multiple times from each quadrant of the 5 placentas.
Placental biopsies revealed “bottlenecks” of genetic differentiation
Genome sequencing was used uniquely in this study to help delineate the phylogeny of placental cells by tracking somatic mutations both in different geographic locations of each placenta and between different cells of origin within 1 placenta.
The authors concluded that bottlenecks of differentiation in placental development led to unique genetic signatures in every bulk placental sample studied. Their findings led them to describe the placenta as a “patchwork” of independent genetic units resulting from clonal expansion at different stages of embryonic development.
Early insights into human placental cells
This study provides fascinating insight into the surprisingly high rates of copy number variants and single-gene changes that exist, in mosaic form, within human placentas. The authors distinguish the placenta from other human organs (such as the colon, endometrium, liver, and skin) in which many fewer genetic changes exist. In fact, they suggest parallels between the “mutational signature” of the placenta with rapidly dividing neoplastic cells.
As one of the first investigations into the variation and complexity of genetic changes within the placenta, this study was not designed to draw conclusions regarding the clinical impact of the numerous genetic changes described. Further studies will elucidate the potential contribution of genetically mosaic placentas to common adverse obstetric outcomes. ●
With a new appreciation for the smaller genetic alterations that exist within placental tissue, it appears that the rate of CPM has been vastly underestimated. We know that aneuploid placental cells increase the risk of adverse pregnancy outcomes and we may learn more about the contribution of copy number variants and single-nucleotide changes to preeclampsia, growth restriction, and pregnancy loss. Furthermore, as the applications of cell-free fetal DNA (cffDNA) in genetic screening continue to expand, we must exercise caution in assuming that copy number variants or single-nucleotide changes detected by cffDNA reflect those of the developing fetus.
Prenatal diagnosis has expanded from identification of aneuploidy to include copy number variants detected on microarray (such as 22q11 deletion syndrome) and now single-gene disorders identified by targeted or exome and genome sequencing. How and when different sequencing tests should be used clinically are questions faced by every provider engaged in modern prenatal diagnosis.
In this Update, we highlight new clinical insights into prenatal sequencing and explore how information gained from sequencing may help us understand some of the unanswered questions in obstetrics.
What is the yield of a RASopathy gene panel with specific prenatal findings?
Scott A, Di Giosaffatte N, Pinna V, et al. When to test fetuses for RASopathies? Proposition from a systematic analysis of 352 multicenter cases and a postnatal cohort. Genet Med. Published online February 10, 2021. doi:10.1038/s41436-020-01093-7.
RASopathies, a group of genetic conditions caused by mutations in the RAS/mitogen-activated protein kinase (RAS-MAPK) pathway, are common, occurring in 1:1,000 to 1:2,500 live births. RASopathies are much more common than 22q11 deletion syndrome, or DiGeorge syndrome, which occurs in 1.4:10,000 live births.1
RASopathy disorders include Noonan syndrome, Noonan syndrome with multiple lentigines, Costello syndrome, cardiofaciocutaneous syndrome, and Noonan-like syndrome with loose anagen hair. These are autosomal dominant disorders caused by a pathogenic variant (or mutation) in 1 of more than 20 genes in the RAS-MAPK signaling pathway in the body. Clinical features include congenital anomalies of the kidney and urinary tract, lymphatic anomalies, congenital heart disease (CHD), hypertrophic cardiomyopathy (HCM), postnatal growth disorders, neurodevelopmental disorders, and more rarely hematologic malignancies. Prenatal clues include an increased nuchal translucency (NT), CHD, cystic hygroma, lymphatic anomalies, anomalies of the kidney and urinary tract, hydrops, and HCM.
Cohort of pregnancies that received a RASopathy panel
Scott and colleagues sought to clarify the utility of testing for RASopathies with a prenatal gene panel. They conducted a multicenter retrospective cohort study with cases from 2 hospitals in Italy and Canada; data were collected between 2012 and 2019.
Eligible fetuses were those referred to the prenatal genetics clinic because of an increased NT, increased nuchal fold (NF), hydrops, ascites, thoracic effusions, chylothorax, other lymphatic anomalies, CHD, or HCM with a nondiagnostic (negative) microarray or karyotype. All eligible cases had RASopathy molecular testing in the prenatal or neonatal period.
Among the 352 referrals to clinic, 50 cases of a RASopathy disorder were diagnosed. Additionally, to complement this cohort over the same time period, 25 postnatal diagnoses were made after retrospective review performed to ascertain additional prenatal findings. The size of the testing panel ranged from 9 to 20 genes, which were sent to clinical laboratories that performed sequencing based on standard protocols.
Study outcomes
Overall, 14% of fetuses with an indication for testing had a pathogenic or likely pathogenic variant (diagnostic) on panel testing among 11 genes (notably, all presented results are after excluding copy number variants and aneuploidy). Fetuses with only 1 ultrasonography finding were much less likely to have a positive result than those with more than 1 ultrasonography finding, 3% versus 18%. The highest diagnostic yields were for HCM at 69%; thoracic effusions and ascites, 41%; persistent hydrops, 39%; cystic hygroma combined with another suggestive ultrasonography finding, 28%; CHD, 23%; and persistent cystic hygroma, 21%. Five fetuses were affected with CHD and HCM, and 44% had an intrauterine fetal demise.
Importance of NT size. An isolated increased NT had a diagnostic yield of 1% overall (1/90); however, the size of the NT mattered. Seventeen fetuses had an NT between 3 and 3.5 mm and none of these had diagnostic sequencing, whereas 26% with an NT greater than 6 mm had a diagnostic result (11/43). An increased NF had a diagnostic yield of 25%.
Other findings. Of fetuses with a cystic hygroma, 16% had a pathogenic or likely pathogenic variant, and when these persisted into the second trimester or were associated with other anomalies, the percentages increased to 21% and 28%, respectively. Of prenatal patients, 20.6% had variants of uncertain significance, and 12% of the pathogenic and likely pathogenic variants were inherited, which is less than previously reported series. Additionally, 48% of the postnatal RASopathy diagnosis group did not have an ultrasonography finding on record review.
Continue to: Study strengths and limitations...
Study strengths and limitations
This study presents a large cohort of prenatal and neonatal patients tested for RASopathies at 2 international centers with very granular and clinically useful data about ultrasonography findings and yield of panel testing. Prenatal care providers, geneticists, and computational biologists may find this study of great interest and take away useful information and ideas due to the authors’ presentation and details.
The number of genes tested changed over the inclusion time period, but this is an inescapable reality of retrospective clinical research in an advancing field. The authors presented the prenatal and postnatal diagnoses ultrasonography findings separately and together. Given the different nature of cohort ascertainment, we prefer to consider these groups separately and have presented the data for the prenatal group.
Prenatal sequencing panels and exome sequencing are detecting disorders with important implications for prenatal care. If your practice is not testing for RASopathies in prenatal patients with concerning ultrasonography features, you are missing cases. In this study, the most concerning ultrasonography features (more than 20% diagnosis) were HCM, thoracic effusions and ascites, persistent hydrops, cystic hygroma combined with another suggestive ultrasonography finding, CHD, and persistent cystic hygroma. Isolated ultrasonography findings or findings that resolved had a lower diagnostic yield, and an isolated enlarged NT had a 1% diagnostic yield, with most cases having an NT larger than 6 mm.
For pretest counseling, in this study 20% of patients had a variant of uncertain significance, and preparing patients for this possibility is crucial. Most variants of uncertain significance are reclassified to benign when more information is available. Providers can consider sending parental samples concurrently with the fetal sample to help obtain useful information quickly, although the possibility of an inherited pathogenic variant still exists (12% in this study).
Prenatal diagnosis gives your patients the opportunity to learn about the disorder, plan for treatment and delivery location, and establish their care team before birth or consider pregnancy termination.
Sequencing provides insights into twin pregnancies
Jonsson H, Magnusdottir E, Eggertsson HP, et al. Differences between germline genomes of monozygotic twins. Nat Genet. 2021;53:27-34. doi:10.1038/s41588 -020-00755-1.
You have a monozygotic twin pair with an anomaly and intend to do diagnostic testing for prenatal diagnosis. The question always arises: Do you sample both twins or just one? Surely, they are genetically identical? A wise mentor once instilled a valuable lesson: Monozygotic twins are more likely to have an anomaly. Their existence is already out of the realm of normal. Finally, we now have an engaging and interesting answer to this and other fascinating embryology questions through the work of Jonsson and colleagues.
Study eligibility criteria and treatment protocol
The authors enrolled 381 twin pairs and 2 monozygotic triplets and compared genome sequencing of different tissues (cheek cells and blood). They went further to assess what other tissues might share the genetic change. To do this, they sequenced the children and the partners of 181 of the pairs. Presumably, if a twin and their offspring shared a genetic change that was not present in the spouse or twin, this genetic change must be present in the oocytes or sperm of the parent twin. The goal of sequencing multiple tissue sources in each twin was to help determine when the genetic change occurred in embryonic development.
Study outcomes
The authors found that 15% of twins had mutations that were absent in the other twin. Because of the extent of tissues that had the genetic change, the authors asserted that these changes must have occurred very early in embryonic development (even from one cell after twinning) for the changes to be near-constitutional (among sampled tissues).
An average of 14 genetic differences were found between twin pairs that developed after twinning. However, the number of differences varied. For example, 39 pairs of twins differed by more than 100 changes, and 38 did not differ at all. Differences between twins were more likely in blood samples than in cheek swabs, suggesting that some differences were due to acquired genetic changes in hematologic cell lines, or clonal hematopoiesis.
The authors also looked at what percentage of sequenced DNA contained the variants (or mutations) and found that many of these DNA differences were present at high amounts in sequencing reads. This suggests that the DNA changes happened very early after twinning in about one-third of pairs. Additionally, if one twin had a near-constitutional change, in 42% of pairs the other twin had a different near-constitutional change. Among the triplets, 2 of a triplet pair shared more genetic similarity and were likely descendent from a single split cell and the third likely was formed from a different set of cells.
By examining the offspring of twins, Jonsson and colleagues found that there were 2.6 early embryonic mutations, and this did not differ when blood or buccal DNA was compared. The rate of transmission of a variant to offspring was proportional to the variant allele frequency (proportion of alternate alleles) in the blood or buccal cells. This is an important counseling point when considering patients with mosaic genetic disorders and counseling about the likelihood of inheritance or transmission to future offspring. If the rate of mosaicism was higher in blood or buccal cells, the likelihood of transmission was higher. Additionally, the mutations did not differ by sex, and there was no relationship to whether the chromosome was maternally or paternally inherited.
Continue to: Study strengths and limitations...
Study strengths and limitations
The authors did not have access to information about chorionicity of the monozygotic twin pairs. Consequently, they were unable to correlate chorionicity with the degree of noted genetic difference between the monozygotic twin pairs. Additionally, although the authors were thoughtful in their utilization of offspring and spouses to infer germline genomic content, the study had a limited number of tissues sampled, which could reduce the applicability. However, the sample size, clinically accessible tissue sampling, and thoughtful analysis used in this study make it an interesting and relevant contribution to reproductive medicine and evolutionary biology.
We all accumulate changes to our DNA throughout life. The study by Jonsson and colleagues illustrates that for many, this accumulation of genetic changes starts very early in gestation. In the early zygote, the authors observed roughly 1 mutation per cell division prior to the point of twinning. In the realm of prenatal diagnosis, one should consider that monochorionic twins with different phenotypes (that is, an ultrasonography anomaly in 1 of the twin pair) could represent a genetic change rather than an environmental difference. This genetic change may not be shared by the other twin despite originating from the same primordial cell line. The genetic changes that the authors investigated were detected on genome sequencing, which is much more comprehensive than the exome sequencing that is increasingly utilized in rare disease diagnosis. The clinical utility of this observation in prenatal diagnosis has yet to be proven, but this study provides preliminary data that 15% of monozygotic twins have genetic differences and may warrant individualized testing.
The genetic landscape of the placenta
Coorens TH, Oliver TR, Sanghvi R, et al. Inherent mosaicism and extensive mutation of human placentas. Nature. Published online March 10, 2021. doi:10.1038/ s41586-021-03345-1.
Confined placental mosaicism (CPM) is a phenomenon in which the genetics of the placenta are different from those of the fetus. Historically, this phenomenon has been described in 1% to 2% of pregnancies based on karyotype data obtained from chorionic villus sampling. Some studies have demonstrated adverse pregnancy outcomes in the setting of CPM, thought to be secondary to aneuploid cells in the placenta leading to insufficiency or dysfunction.
Although our sophistication and level of detail in prenatal genetic testing has rapidly expanded to include information about copy number variants and singlenucleotide changes, their contribution to CPM has been understudied. Coorens and colleagues recently published a landmark study that describes a surprisingly high rate of mosaicism for these smaller genetic changes.
A cohort study of placentas
The authors performed whole genome sequencing on placental samples obtained from 37 term pregnancies. Umbilical cord tissue and maternal blood also were collected and served as controls for fetal and maternal genetic profiles, respectively.
In a subgroup of 5 placentas, lasercapture microscopy was used to separate placental cells of different origins, including trophoblastic cells, mesenchymal core cells, and cells originating from the inner cell mass. To investigate variation within different geographic regions of a single placenta, these cell lines were derived multiple times from each quadrant of the 5 placentas.
Placental biopsies revealed “bottlenecks” of genetic differentiation
Genome sequencing was used uniquely in this study to help delineate the phylogeny of placental cells by tracking somatic mutations both in different geographic locations of each placenta and between different cells of origin within 1 placenta.
The authors concluded that bottlenecks of differentiation in placental development led to unique genetic signatures in every bulk placental sample studied. Their findings led them to describe the placenta as a “patchwork” of independent genetic units resulting from clonal expansion at different stages of embryonic development.
Early insights into human placental cells
This study provides fascinating insight into the surprisingly high rates of copy number variants and single-gene changes that exist, in mosaic form, within human placentas. The authors distinguish the placenta from other human organs (such as the colon, endometrium, liver, and skin) in which many fewer genetic changes exist. In fact, they suggest parallels between the “mutational signature” of the placenta with rapidly dividing neoplastic cells.
As one of the first investigations into the variation and complexity of genetic changes within the placenta, this study was not designed to draw conclusions regarding the clinical impact of the numerous genetic changes described. Further studies will elucidate the potential contribution of genetically mosaic placentas to common adverse obstetric outcomes. ●
With a new appreciation for the smaller genetic alterations that exist within placental tissue, it appears that the rate of CPM has been vastly underestimated. We know that aneuploid placental cells increase the risk of adverse pregnancy outcomes and we may learn more about the contribution of copy number variants and single-nucleotide changes to preeclampsia, growth restriction, and pregnancy loss. Furthermore, as the applications of cell-free fetal DNA (cffDNA) in genetic screening continue to expand, we must exercise caution in assuming that copy number variants or single-nucleotide changes detected by cffDNA reflect those of the developing fetus.
- Roberts AE, Allanson JE, Tartaglia M, et al. Noonan syndrome. Lancet. 2013;381:333-342. doi:10.1016/S0140-6736(12)61023-X.
- Roberts AE, Allanson JE, Tartaglia M, et al. Noonan syndrome. Lancet. 2013;381:333-342. doi:10.1016/S0140-6736(12)61023-X.
The interplay between staffing and scheduling
Top five findings from the 2020 SoHM
The biennial State of Hospital Medicine (SoHM) Report was released in fall 2020, reflecting surveys collected just as the pandemic was ramping up. Thus, a COVID Addendum of results was collected and published a few months later. What did these reports tell us about existing and developing trends in staffing and scheduling?
Here is a top five list of findings for hospital medicine programs (HMGs) serving adults only. These are just highlights; for further detail, visit the SHM website to learn more and purchase your copy. The information in the SoHM is extraordinarily helpful in planning for your group’s future staffing and scheduling needs.
5. Average group size has increased
Andrew White, MD, SFHM, associate professor of medicine at the University of Washington, Seattle, provided a deep-dive discussion on the increase of group sizes in the March 2021 issue of The Hospitalist. Group size has impacted the way a hospitalist group schedules, when reviewing correlating scheduling survey responses.
Group size can have a direct correlation to scheduling methodology. The number of employed/contracted physician hospitalists in individual groups is up about 25%. Alongside the increase in physician hospitalists is an increase in both nurse practitioners (NPs) and physician assistants (PAs) in adult hospitalist groups, with the largest growth in PAs. In fact, in 2020, the average number of NPs and PAs per hospitalist group is approaching similar numbers.
In 2020, more than half of all programs reported not having a backup call system. One could speculate that the larger group size has allowed adult hospitalist groups better ability to staff upper fluctuations in daily volume. This could have resulted in day-to-day scheduling ease and flexibility.
4. Shift-type is shifting
In scheduling adult hospitalist groups, fewer groups reported dedicated nocturnists and more groups reported dedicated day admitters.
Just above a third of all adult hospitalist programs report having dedicated day admitter shifts, and the presence of nocturnists is at a 6-year low. One speculation that could be made is that hospitalists are making more of an effort to ensure that more admissions are done during the day and not held over for nighttime. This would be consistent with the strong pressure for hospitals to decrease door-to-floor admission times. However, the presence of nocturnists increases steadily with group size. Ninety-four percent of HMGs with 30-49 physician FTEs and 98% of groups with 50 or more physician FTEs reported using dedicated nocturnists.
3. COVID-19 impacts hospitalist workflows
It’s not hard to imagine that COVID-19 has affected all hospitalist groups: adult, pediatric, and adult/pediatric groups. COVID-19 has affected all lives – at home and at work – across the world. More than 80% of all adult hospitalist groups report having implemented changes (beyond dedicated COVID-19 teams) in workflows and/or how work is allocated among its providers. And nearly 20% report that this is likely a permanent change.
2. Schedules have been disrupted by COVID-19
More than half of adult hospitalist groups report having their schedules disrupted by COVID-19. The top two disruptors are loss of staff time due to exposure quarantine, and lost provider time due to COVID-19 illness. All the while, adult hospitalist groups have been taking care of more and more hospitalized patients.
While some groups have not made any changes in scheduling due to COVID-19, many have. Nearly 60% of all groups have increased scheduling flexibility or changed their scheduling model. For about 11% of all groups, this change is likely to be permanent.
1. COVID-19 has changed scheduling methodologies – perhaps for the long-term
Three out of four adult hospitalist groups have created new COVID-19 dedicated teams each day. This has likely had one of the most impacts.
Unit-based assignment reported in the 2020 SoHM was already up from the 2018 SoHM Report (42.7% vs 36%). Now, in addition to nocturnists, day admitter, rounder roles, and unit-based assignments, hospital medicine groups must also incorporate COVID-19 teams into daily scheduling considerations. One in five groups report this change may likely be a permanent addition to the hospitalist schedule. Wow.
As we think forward to the 2022 SoHM, staffing and scheduling of adult hospital medicine group will be a key topic of the survey. How does COVID-19 change hospital medicine groups in the medium and long term? One thing is for sure – hospital medicine groups are resilient and have proven to be creative in ensuring our hospitalized patients are well cared for.
Post your thoughts and questions for your peer network on the SHM Online Community: HMX. Let’s keep the conversation going on how we can help each other create sustainable staffing and scheduling models that are continuously adapting to our peripandemic environment.
Ms. Trask is national vice president of the Hospital Medicine Service Line at Catholic Health Initiatives in Englewood, Colo.
Top five findings from the 2020 SoHM
Top five findings from the 2020 SoHM
The biennial State of Hospital Medicine (SoHM) Report was released in fall 2020, reflecting surveys collected just as the pandemic was ramping up. Thus, a COVID Addendum of results was collected and published a few months later. What did these reports tell us about existing and developing trends in staffing and scheduling?
Here is a top five list of findings for hospital medicine programs (HMGs) serving adults only. These are just highlights; for further detail, visit the SHM website to learn more and purchase your copy. The information in the SoHM is extraordinarily helpful in planning for your group’s future staffing and scheduling needs.
5. Average group size has increased
Andrew White, MD, SFHM, associate professor of medicine at the University of Washington, Seattle, provided a deep-dive discussion on the increase of group sizes in the March 2021 issue of The Hospitalist. Group size has impacted the way a hospitalist group schedules, when reviewing correlating scheduling survey responses.
Group size can have a direct correlation to scheduling methodology. The number of employed/contracted physician hospitalists in individual groups is up about 25%. Alongside the increase in physician hospitalists is an increase in both nurse practitioners (NPs) and physician assistants (PAs) in adult hospitalist groups, with the largest growth in PAs. In fact, in 2020, the average number of NPs and PAs per hospitalist group is approaching similar numbers.
In 2020, more than half of all programs reported not having a backup call system. One could speculate that the larger group size has allowed adult hospitalist groups better ability to staff upper fluctuations in daily volume. This could have resulted in day-to-day scheduling ease and flexibility.
4. Shift-type is shifting
In scheduling adult hospitalist groups, fewer groups reported dedicated nocturnists and more groups reported dedicated day admitters.
Just above a third of all adult hospitalist programs report having dedicated day admitter shifts, and the presence of nocturnists is at a 6-year low. One speculation that could be made is that hospitalists are making more of an effort to ensure that more admissions are done during the day and not held over for nighttime. This would be consistent with the strong pressure for hospitals to decrease door-to-floor admission times. However, the presence of nocturnists increases steadily with group size. Ninety-four percent of HMGs with 30-49 physician FTEs and 98% of groups with 50 or more physician FTEs reported using dedicated nocturnists.
3. COVID-19 impacts hospitalist workflows
It’s not hard to imagine that COVID-19 has affected all hospitalist groups: adult, pediatric, and adult/pediatric groups. COVID-19 has affected all lives – at home and at work – across the world. More than 80% of all adult hospitalist groups report having implemented changes (beyond dedicated COVID-19 teams) in workflows and/or how work is allocated among its providers. And nearly 20% report that this is likely a permanent change.
2. Schedules have been disrupted by COVID-19
More than half of adult hospitalist groups report having their schedules disrupted by COVID-19. The top two disruptors are loss of staff time due to exposure quarantine, and lost provider time due to COVID-19 illness. All the while, adult hospitalist groups have been taking care of more and more hospitalized patients.
While some groups have not made any changes in scheduling due to COVID-19, many have. Nearly 60% of all groups have increased scheduling flexibility or changed their scheduling model. For about 11% of all groups, this change is likely to be permanent.
1. COVID-19 has changed scheduling methodologies – perhaps for the long-term
Three out of four adult hospitalist groups have created new COVID-19 dedicated teams each day. This has likely had one of the most impacts.
Unit-based assignment reported in the 2020 SoHM was already up from the 2018 SoHM Report (42.7% vs 36%). Now, in addition to nocturnists, day admitter, rounder roles, and unit-based assignments, hospital medicine groups must also incorporate COVID-19 teams into daily scheduling considerations. One in five groups report this change may likely be a permanent addition to the hospitalist schedule. Wow.
As we think forward to the 2022 SoHM, staffing and scheduling of adult hospital medicine group will be a key topic of the survey. How does COVID-19 change hospital medicine groups in the medium and long term? One thing is for sure – hospital medicine groups are resilient and have proven to be creative in ensuring our hospitalized patients are well cared for.
Post your thoughts and questions for your peer network on the SHM Online Community: HMX. Let’s keep the conversation going on how we can help each other create sustainable staffing and scheduling models that are continuously adapting to our peripandemic environment.
Ms. Trask is national vice president of the Hospital Medicine Service Line at Catholic Health Initiatives in Englewood, Colo.
The biennial State of Hospital Medicine (SoHM) Report was released in fall 2020, reflecting surveys collected just as the pandemic was ramping up. Thus, a COVID Addendum of results was collected and published a few months later. What did these reports tell us about existing and developing trends in staffing and scheduling?
Here is a top five list of findings for hospital medicine programs (HMGs) serving adults only. These are just highlights; for further detail, visit the SHM website to learn more and purchase your copy. The information in the SoHM is extraordinarily helpful in planning for your group’s future staffing and scheduling needs.
5. Average group size has increased
Andrew White, MD, SFHM, associate professor of medicine at the University of Washington, Seattle, provided a deep-dive discussion on the increase of group sizes in the March 2021 issue of The Hospitalist. Group size has impacted the way a hospitalist group schedules, when reviewing correlating scheduling survey responses.
Group size can have a direct correlation to scheduling methodology. The number of employed/contracted physician hospitalists in individual groups is up about 25%. Alongside the increase in physician hospitalists is an increase in both nurse practitioners (NPs) and physician assistants (PAs) in adult hospitalist groups, with the largest growth in PAs. In fact, in 2020, the average number of NPs and PAs per hospitalist group is approaching similar numbers.
In 2020, more than half of all programs reported not having a backup call system. One could speculate that the larger group size has allowed adult hospitalist groups better ability to staff upper fluctuations in daily volume. This could have resulted in day-to-day scheduling ease and flexibility.
4. Shift-type is shifting
In scheduling adult hospitalist groups, fewer groups reported dedicated nocturnists and more groups reported dedicated day admitters.
Just above a third of all adult hospitalist programs report having dedicated day admitter shifts, and the presence of nocturnists is at a 6-year low. One speculation that could be made is that hospitalists are making more of an effort to ensure that more admissions are done during the day and not held over for nighttime. This would be consistent with the strong pressure for hospitals to decrease door-to-floor admission times. However, the presence of nocturnists increases steadily with group size. Ninety-four percent of HMGs with 30-49 physician FTEs and 98% of groups with 50 or more physician FTEs reported using dedicated nocturnists.
3. COVID-19 impacts hospitalist workflows
It’s not hard to imagine that COVID-19 has affected all hospitalist groups: adult, pediatric, and adult/pediatric groups. COVID-19 has affected all lives – at home and at work – across the world. More than 80% of all adult hospitalist groups report having implemented changes (beyond dedicated COVID-19 teams) in workflows and/or how work is allocated among its providers. And nearly 20% report that this is likely a permanent change.
2. Schedules have been disrupted by COVID-19
More than half of adult hospitalist groups report having their schedules disrupted by COVID-19. The top two disruptors are loss of staff time due to exposure quarantine, and lost provider time due to COVID-19 illness. All the while, adult hospitalist groups have been taking care of more and more hospitalized patients.
While some groups have not made any changes in scheduling due to COVID-19, many have. Nearly 60% of all groups have increased scheduling flexibility or changed their scheduling model. For about 11% of all groups, this change is likely to be permanent.
1. COVID-19 has changed scheduling methodologies – perhaps for the long-term
Three out of four adult hospitalist groups have created new COVID-19 dedicated teams each day. This has likely had one of the most impacts.
Unit-based assignment reported in the 2020 SoHM was already up from the 2018 SoHM Report (42.7% vs 36%). Now, in addition to nocturnists, day admitter, rounder roles, and unit-based assignments, hospital medicine groups must also incorporate COVID-19 teams into daily scheduling considerations. One in five groups report this change may likely be a permanent addition to the hospitalist schedule. Wow.
As we think forward to the 2022 SoHM, staffing and scheduling of adult hospital medicine group will be a key topic of the survey. How does COVID-19 change hospital medicine groups in the medium and long term? One thing is for sure – hospital medicine groups are resilient and have proven to be creative in ensuring our hospitalized patients are well cared for.
Post your thoughts and questions for your peer network on the SHM Online Community: HMX. Let’s keep the conversation going on how we can help each other create sustainable staffing and scheduling models that are continuously adapting to our peripandemic environment.
Ms. Trask is national vice president of the Hospital Medicine Service Line at Catholic Health Initiatives in Englewood, Colo.
How physicians can provide better care to transgender patients
People who identify as transgender experience many health disparities, in addition to lack of access to quality care. The most commonly cited barrier is the lack of providers who are knowledgeable about transgender health care, according to past surveys.
Even those who do seek care often have unpleasant experiences. A 2015 survey conducted by the National Center for Transgender Equality found that 33% of those who saw a health care provider reported at least one unfavorable experience related to being transgender, such as being verbally harassed or refused treatment because of their gender identity. In fact, 23% of those surveyed say they did not seek health care they needed in the past year because of fear of being mistreated as a transgender person.
This interview has been edited for length and clarity.
Question: Surveys have shown that many people who identify as transgender will seek only transition care, not primary or preventive care. Why is that?
Dr. Brandt: My answer is multifactorial. Transgender patients do seek primary care – just not as readily. There’s a lot of misconceptions about health care needs for the LGBT community in general. For example, lesbian or bisexual women may be not as well informed about the need for Pap smears compared with their heterosexual counterparts. These misconceptions are further exacerbated in the transgender community.
The fact that a lot of patients seek only transition-related care, but not preventive services, such as primary care and gynecologic care, is also related to fears of discrimination and lack of education of providers. These patients are afraid when they walk into an office that they will be misgendered or their physician won’t be familiar with their health care needs.
What can clinics and clinicians do to create a safe and welcoming environment?
Dr. Brandt: It starts with educating office staff about terminology and gender identities.
A key feature of our EHR is the sexual orientation and gender identity platform, which asks questions about a patient’s gender identity, sexual orientation, sex assigned at birth, and organ inventory. These data are then found in the patient information tab and are just as relevant as their insurance status, age, and date of birth.
There are many ways a doctor’s office can signal to patients that they are inclusive. They can hang LGBTQ-friendly flags or symbols or a sign saying, “We have an anti-discrimination policy” in the waiting room. A welcoming environment can also be achieved by revising patient questionnaires or forms so that they aren’t gender-specific or binary.
Given that the patient may have limited contact with a primary care clinician, how do you prioritize what you address during the visit?
Dr. Brandt: Similar to cisgender patients, it depends initially on the age of the patient and the reason for the visit. The priorities of an otherwise healthy transgender patient in their 20s are going to be largely the same as for a cisgender patient of the same age. As patients age in the primary care world, you’re addressing more issues, such as colorectal screening, lipid disorders, and mammograms, and that doesn’t change. For the most part, the problems that you address should be specific for that age group.
It becomes more complicated when you add in factors such as hormone therapy and whether patients have had any type of gender-affirming surgery. Those things can change the usual recommendations for screening or risk assessment. We try to figure out what routine health maintenance and cancer screening a patient needs based on age and risk factors, in addition to hormone status and surgical state.
Do you think that many physicians are educated about the care of underserved populations such as transgender patients?
Dr. Brandt: Yes and no. We are definitely getting better at it. For example, the American College of Obstetricians and Gynecologists published a committee opinion highlighting transgender care. So organizations are starting to prioritize these populations and recognize that they are, in fact, underserved and they have special health care needs.
However, the knowledge gaps are still pretty big. I get calls daily from providers asking questions about how to manage patients on hormones, or how to examine a patient who has undergone a vaginoplasty. I hear a lot of horror stories from transgender patients who had their hormones stopped for absurd and medically misinformed reasons.
But I definitely think it’s getting better and it’s being addressed at all levels – the medical school level, the residency level, and the attending level. It just takes time to inform people and for people to get used to the health care needs of these patients.
What should physicians keep in mind when treating patients who identify as transgender?
Dr. Brandt: First and foremost, understanding the terminology and the difference between gender identity, sex, and sexual orientation. Being familiar with that language and being able to speak that language very comfortably and not being awkward about it is a really important thing for primary care physicians and indeed any physician who treats transgender patients.
Physicians should also be aware that any underserved population has higher rates of mental health issues, such as depression and anxiety. Obviously, that goes along with being underserved and the stigma and the disparities that exist for these patients. Having providers educate themselves about what those disparities are and how they impact a patient’s daily life and health is paramount to knowing how to treat patients.
What are your top health concerns for these patients and how do you address them?
Dr. Brandt: I think mental health and safety is probably the number one for me. About 41% of transgender adults have attempted suicide. That number is roughly 51% in transgender youth. That is an astonishing number. These patients have much higher rates of domestic violence, intimate partner violence, and sexual assault, especially trans women and trans women of color. So understanding those statistics is huge.
Obesity, smoking, and substance abuse are my next three. Again, those are things that should be addressed at any visit, regardless of the gender identity or sexual orientation of the patient, but those rates are particularly high in this population.
Fertility and long-term care for patients should be addressed. Many patients who identify as transgender are told they can’t have a family. As a primary care physician, you may see a patient before they are seen by an ob.gyn. or surgeon. Talking about what a patient’s long-term life goals are with fertility and family planning, and what that looks like for them, is a big thing for me. Other providers may not feel that’s a concern, but I believe it should be discussed before initiation of hormone therapy, which can significantly impact fertility in some patients.
Are there nuances to the physical examination that primary care physicians should be aware of when dealing with transmasculine patients vs. transfeminine patients?
Dr. Brandt: Absolutely. And this interview can’t cover the scope of those nuances. An example that comes to mind is the genital exam. For transgender women who have undergone a vaginoplasty, the pelvic exam can be very affirming. Whereas for transgender men, a gynecologic exam can significantly exacerbate dysphoria and there are ways to conduct the exam to limit this discomfort and avoid creating a traumatic experience for the patient. It’s important to be aware that the genital exam, or any type of genitourinary exam, can be either affirming or not affirming.
Sexually transmitted infections are up in the general population, and the trans population is at even higher risk. What should physicians think about when they assess this risk?
Dr. Brandt: It’s really important for primary care clinicians and for gynecologists to learn to be comfortable talking about sexual practices, because what people do behind closed doors is really a key to how to counsel patients about safe sex.
People are well aware of the need to have safe sex. However, depending on the type of sex that you’re having, what body parts go where, what is truly safe can vary and people may not know, for example, to wear a condom when sex toys are involved or that a transgender male on testosterone can become pregnant during penile-vaginal intercourse. Providers really should be very educated on the array of sexual practices that people have and how to counsel them about those. They should know how to ask patients the gender identity of their sexual partners, the sexual orientation of their partners, and what parts go where during sex.
Providers should also talk to patients about PrEP [pre-exposure prophylaxis], whether they identify as cisgender or transgender. My trans patients tend to be a lot more educated about PrEP than other patients. It’s something that many of the residents, even in a standard gynecologic clinic, for example, don’t talk to cisgender patients about because of the stigma surrounding HIV. Many providers still think that the only people who are at risk for HIV are men who have sex with men. And while those rates are higher in some populations, depending on sexual practices, those aren’t the only patients who qualify for PrEP.
Overall, in order to counsel patients about STIs and safe sexual practices, providers should learn to be comfortable talking about sex.
Do you have any strategies on how to make the appointment more successful in addressing those issues?
Dr. Brandt: Bedside manner is a hard thing to teach, and comfort in talking about sex, gender identity, and sexual orientation can vary – but there are a lot of continuing medical education courses that physicians can utilize through the World Professional Association for Transgender Health.
If providers start to notice an influx of patients who identify as transgender or if they want to start seeing transgender patients, it’s really important for them to have that training before they start interacting with patients. In all of medicine, we sort of learn as we go, but this patient population has been subjected to discrimination, violence, error, and misgendering. They have dealt with providers who didn’t understand their health care needs. While this field is evolving, knowing how to appropriately address a patient (using their correct name, pronouns, etc.) is an absolute must.
That needs to be part of a provider’s routine vernacular and not something that they sort of stumble through. You can scare a patient away as soon as they walk into the office with an uneducated front desk staff and things that are seen in the office. Seeking out those educational tools, being aware of your own deficits as a provider and the educational needs of your office, and addressing those needs is really key.
A version of this article first appeared on Medscape.com.
People who identify as transgender experience many health disparities, in addition to lack of access to quality care. The most commonly cited barrier is the lack of providers who are knowledgeable about transgender health care, according to past surveys.
Even those who do seek care often have unpleasant experiences. A 2015 survey conducted by the National Center for Transgender Equality found that 33% of those who saw a health care provider reported at least one unfavorable experience related to being transgender, such as being verbally harassed or refused treatment because of their gender identity. In fact, 23% of those surveyed say they did not seek health care they needed in the past year because of fear of being mistreated as a transgender person.
This interview has been edited for length and clarity.
Question: Surveys have shown that many people who identify as transgender will seek only transition care, not primary or preventive care. Why is that?
Dr. Brandt: My answer is multifactorial. Transgender patients do seek primary care – just not as readily. There’s a lot of misconceptions about health care needs for the LGBT community in general. For example, lesbian or bisexual women may be not as well informed about the need for Pap smears compared with their heterosexual counterparts. These misconceptions are further exacerbated in the transgender community.
The fact that a lot of patients seek only transition-related care, but not preventive services, such as primary care and gynecologic care, is also related to fears of discrimination and lack of education of providers. These patients are afraid when they walk into an office that they will be misgendered or their physician won’t be familiar with their health care needs.
What can clinics and clinicians do to create a safe and welcoming environment?
Dr. Brandt: It starts with educating office staff about terminology and gender identities.
A key feature of our EHR is the sexual orientation and gender identity platform, which asks questions about a patient’s gender identity, sexual orientation, sex assigned at birth, and organ inventory. These data are then found in the patient information tab and are just as relevant as their insurance status, age, and date of birth.
There are many ways a doctor’s office can signal to patients that they are inclusive. They can hang LGBTQ-friendly flags or symbols or a sign saying, “We have an anti-discrimination policy” in the waiting room. A welcoming environment can also be achieved by revising patient questionnaires or forms so that they aren’t gender-specific or binary.
Given that the patient may have limited contact with a primary care clinician, how do you prioritize what you address during the visit?
Dr. Brandt: Similar to cisgender patients, it depends initially on the age of the patient and the reason for the visit. The priorities of an otherwise healthy transgender patient in their 20s are going to be largely the same as for a cisgender patient of the same age. As patients age in the primary care world, you’re addressing more issues, such as colorectal screening, lipid disorders, and mammograms, and that doesn’t change. For the most part, the problems that you address should be specific for that age group.
It becomes more complicated when you add in factors such as hormone therapy and whether patients have had any type of gender-affirming surgery. Those things can change the usual recommendations for screening or risk assessment. We try to figure out what routine health maintenance and cancer screening a patient needs based on age and risk factors, in addition to hormone status and surgical state.
Do you think that many physicians are educated about the care of underserved populations such as transgender patients?
Dr. Brandt: Yes and no. We are definitely getting better at it. For example, the American College of Obstetricians and Gynecologists published a committee opinion highlighting transgender care. So organizations are starting to prioritize these populations and recognize that they are, in fact, underserved and they have special health care needs.
However, the knowledge gaps are still pretty big. I get calls daily from providers asking questions about how to manage patients on hormones, or how to examine a patient who has undergone a vaginoplasty. I hear a lot of horror stories from transgender patients who had their hormones stopped for absurd and medically misinformed reasons.
But I definitely think it’s getting better and it’s being addressed at all levels – the medical school level, the residency level, and the attending level. It just takes time to inform people and for people to get used to the health care needs of these patients.
What should physicians keep in mind when treating patients who identify as transgender?
Dr. Brandt: First and foremost, understanding the terminology and the difference between gender identity, sex, and sexual orientation. Being familiar with that language and being able to speak that language very comfortably and not being awkward about it is a really important thing for primary care physicians and indeed any physician who treats transgender patients.
Physicians should also be aware that any underserved population has higher rates of mental health issues, such as depression and anxiety. Obviously, that goes along with being underserved and the stigma and the disparities that exist for these patients. Having providers educate themselves about what those disparities are and how they impact a patient’s daily life and health is paramount to knowing how to treat patients.
What are your top health concerns for these patients and how do you address them?
Dr. Brandt: I think mental health and safety is probably the number one for me. About 41% of transgender adults have attempted suicide. That number is roughly 51% in transgender youth. That is an astonishing number. These patients have much higher rates of domestic violence, intimate partner violence, and sexual assault, especially trans women and trans women of color. So understanding those statistics is huge.
Obesity, smoking, and substance abuse are my next three. Again, those are things that should be addressed at any visit, regardless of the gender identity or sexual orientation of the patient, but those rates are particularly high in this population.
Fertility and long-term care for patients should be addressed. Many patients who identify as transgender are told they can’t have a family. As a primary care physician, you may see a patient before they are seen by an ob.gyn. or surgeon. Talking about what a patient’s long-term life goals are with fertility and family planning, and what that looks like for them, is a big thing for me. Other providers may not feel that’s a concern, but I believe it should be discussed before initiation of hormone therapy, which can significantly impact fertility in some patients.
Are there nuances to the physical examination that primary care physicians should be aware of when dealing with transmasculine patients vs. transfeminine patients?
Dr. Brandt: Absolutely. And this interview can’t cover the scope of those nuances. An example that comes to mind is the genital exam. For transgender women who have undergone a vaginoplasty, the pelvic exam can be very affirming. Whereas for transgender men, a gynecologic exam can significantly exacerbate dysphoria and there are ways to conduct the exam to limit this discomfort and avoid creating a traumatic experience for the patient. It’s important to be aware that the genital exam, or any type of genitourinary exam, can be either affirming or not affirming.
Sexually transmitted infections are up in the general population, and the trans population is at even higher risk. What should physicians think about when they assess this risk?
Dr. Brandt: It’s really important for primary care clinicians and for gynecologists to learn to be comfortable talking about sexual practices, because what people do behind closed doors is really a key to how to counsel patients about safe sex.
People are well aware of the need to have safe sex. However, depending on the type of sex that you’re having, what body parts go where, what is truly safe can vary and people may not know, for example, to wear a condom when sex toys are involved or that a transgender male on testosterone can become pregnant during penile-vaginal intercourse. Providers really should be very educated on the array of sexual practices that people have and how to counsel them about those. They should know how to ask patients the gender identity of their sexual partners, the sexual orientation of their partners, and what parts go where during sex.
Providers should also talk to patients about PrEP [pre-exposure prophylaxis], whether they identify as cisgender or transgender. My trans patients tend to be a lot more educated about PrEP than other patients. It’s something that many of the residents, even in a standard gynecologic clinic, for example, don’t talk to cisgender patients about because of the stigma surrounding HIV. Many providers still think that the only people who are at risk for HIV are men who have sex with men. And while those rates are higher in some populations, depending on sexual practices, those aren’t the only patients who qualify for PrEP.
Overall, in order to counsel patients about STIs and safe sexual practices, providers should learn to be comfortable talking about sex.
Do you have any strategies on how to make the appointment more successful in addressing those issues?
Dr. Brandt: Bedside manner is a hard thing to teach, and comfort in talking about sex, gender identity, and sexual orientation can vary – but there are a lot of continuing medical education courses that physicians can utilize through the World Professional Association for Transgender Health.
If providers start to notice an influx of patients who identify as transgender or if they want to start seeing transgender patients, it’s really important for them to have that training before they start interacting with patients. In all of medicine, we sort of learn as we go, but this patient population has been subjected to discrimination, violence, error, and misgendering. They have dealt with providers who didn’t understand their health care needs. While this field is evolving, knowing how to appropriately address a patient (using their correct name, pronouns, etc.) is an absolute must.
That needs to be part of a provider’s routine vernacular and not something that they sort of stumble through. You can scare a patient away as soon as they walk into the office with an uneducated front desk staff and things that are seen in the office. Seeking out those educational tools, being aware of your own deficits as a provider and the educational needs of your office, and addressing those needs is really key.
A version of this article first appeared on Medscape.com.
People who identify as transgender experience many health disparities, in addition to lack of access to quality care. The most commonly cited barrier is the lack of providers who are knowledgeable about transgender health care, according to past surveys.
Even those who do seek care often have unpleasant experiences. A 2015 survey conducted by the National Center for Transgender Equality found that 33% of those who saw a health care provider reported at least one unfavorable experience related to being transgender, such as being verbally harassed or refused treatment because of their gender identity. In fact, 23% of those surveyed say they did not seek health care they needed in the past year because of fear of being mistreated as a transgender person.
This interview has been edited for length and clarity.
Question: Surveys have shown that many people who identify as transgender will seek only transition care, not primary or preventive care. Why is that?
Dr. Brandt: My answer is multifactorial. Transgender patients do seek primary care – just not as readily. There’s a lot of misconceptions about health care needs for the LGBT community in general. For example, lesbian or bisexual women may be not as well informed about the need for Pap smears compared with their heterosexual counterparts. These misconceptions are further exacerbated in the transgender community.
The fact that a lot of patients seek only transition-related care, but not preventive services, such as primary care and gynecologic care, is also related to fears of discrimination and lack of education of providers. These patients are afraid when they walk into an office that they will be misgendered or their physician won’t be familiar with their health care needs.
What can clinics and clinicians do to create a safe and welcoming environment?
Dr. Brandt: It starts with educating office staff about terminology and gender identities.
A key feature of our EHR is the sexual orientation and gender identity platform, which asks questions about a patient’s gender identity, sexual orientation, sex assigned at birth, and organ inventory. These data are then found in the patient information tab and are just as relevant as their insurance status, age, and date of birth.
There are many ways a doctor’s office can signal to patients that they are inclusive. They can hang LGBTQ-friendly flags or symbols or a sign saying, “We have an anti-discrimination policy” in the waiting room. A welcoming environment can also be achieved by revising patient questionnaires or forms so that they aren’t gender-specific or binary.
Given that the patient may have limited contact with a primary care clinician, how do you prioritize what you address during the visit?
Dr. Brandt: Similar to cisgender patients, it depends initially on the age of the patient and the reason for the visit. The priorities of an otherwise healthy transgender patient in their 20s are going to be largely the same as for a cisgender patient of the same age. As patients age in the primary care world, you’re addressing more issues, such as colorectal screening, lipid disorders, and mammograms, and that doesn’t change. For the most part, the problems that you address should be specific for that age group.
It becomes more complicated when you add in factors such as hormone therapy and whether patients have had any type of gender-affirming surgery. Those things can change the usual recommendations for screening or risk assessment. We try to figure out what routine health maintenance and cancer screening a patient needs based on age and risk factors, in addition to hormone status and surgical state.
Do you think that many physicians are educated about the care of underserved populations such as transgender patients?
Dr. Brandt: Yes and no. We are definitely getting better at it. For example, the American College of Obstetricians and Gynecologists published a committee opinion highlighting transgender care. So organizations are starting to prioritize these populations and recognize that they are, in fact, underserved and they have special health care needs.
However, the knowledge gaps are still pretty big. I get calls daily from providers asking questions about how to manage patients on hormones, or how to examine a patient who has undergone a vaginoplasty. I hear a lot of horror stories from transgender patients who had their hormones stopped for absurd and medically misinformed reasons.
But I definitely think it’s getting better and it’s being addressed at all levels – the medical school level, the residency level, and the attending level. It just takes time to inform people and for people to get used to the health care needs of these patients.
What should physicians keep in mind when treating patients who identify as transgender?
Dr. Brandt: First and foremost, understanding the terminology and the difference between gender identity, sex, and sexual orientation. Being familiar with that language and being able to speak that language very comfortably and not being awkward about it is a really important thing for primary care physicians and indeed any physician who treats transgender patients.
Physicians should also be aware that any underserved population has higher rates of mental health issues, such as depression and anxiety. Obviously, that goes along with being underserved and the stigma and the disparities that exist for these patients. Having providers educate themselves about what those disparities are and how they impact a patient’s daily life and health is paramount to knowing how to treat patients.
What are your top health concerns for these patients and how do you address them?
Dr. Brandt: I think mental health and safety is probably the number one for me. About 41% of transgender adults have attempted suicide. That number is roughly 51% in transgender youth. That is an astonishing number. These patients have much higher rates of domestic violence, intimate partner violence, and sexual assault, especially trans women and trans women of color. So understanding those statistics is huge.
Obesity, smoking, and substance abuse are my next three. Again, those are things that should be addressed at any visit, regardless of the gender identity or sexual orientation of the patient, but those rates are particularly high in this population.
Fertility and long-term care for patients should be addressed. Many patients who identify as transgender are told they can’t have a family. As a primary care physician, you may see a patient before they are seen by an ob.gyn. or surgeon. Talking about what a patient’s long-term life goals are with fertility and family planning, and what that looks like for them, is a big thing for me. Other providers may not feel that’s a concern, but I believe it should be discussed before initiation of hormone therapy, which can significantly impact fertility in some patients.
Are there nuances to the physical examination that primary care physicians should be aware of when dealing with transmasculine patients vs. transfeminine patients?
Dr. Brandt: Absolutely. And this interview can’t cover the scope of those nuances. An example that comes to mind is the genital exam. For transgender women who have undergone a vaginoplasty, the pelvic exam can be very affirming. Whereas for transgender men, a gynecologic exam can significantly exacerbate dysphoria and there are ways to conduct the exam to limit this discomfort and avoid creating a traumatic experience for the patient. It’s important to be aware that the genital exam, or any type of genitourinary exam, can be either affirming or not affirming.
Sexually transmitted infections are up in the general population, and the trans population is at even higher risk. What should physicians think about when they assess this risk?
Dr. Brandt: It’s really important for primary care clinicians and for gynecologists to learn to be comfortable talking about sexual practices, because what people do behind closed doors is really a key to how to counsel patients about safe sex.
People are well aware of the need to have safe sex. However, depending on the type of sex that you’re having, what body parts go where, what is truly safe can vary and people may not know, for example, to wear a condom when sex toys are involved or that a transgender male on testosterone can become pregnant during penile-vaginal intercourse. Providers really should be very educated on the array of sexual practices that people have and how to counsel them about those. They should know how to ask patients the gender identity of their sexual partners, the sexual orientation of their partners, and what parts go where during sex.
Providers should also talk to patients about PrEP [pre-exposure prophylaxis], whether they identify as cisgender or transgender. My trans patients tend to be a lot more educated about PrEP than other patients. It’s something that many of the residents, even in a standard gynecologic clinic, for example, don’t talk to cisgender patients about because of the stigma surrounding HIV. Many providers still think that the only people who are at risk for HIV are men who have sex with men. And while those rates are higher in some populations, depending on sexual practices, those aren’t the only patients who qualify for PrEP.
Overall, in order to counsel patients about STIs and safe sexual practices, providers should learn to be comfortable talking about sex.
Do you have any strategies on how to make the appointment more successful in addressing those issues?
Dr. Brandt: Bedside manner is a hard thing to teach, and comfort in talking about sex, gender identity, and sexual orientation can vary – but there are a lot of continuing medical education courses that physicians can utilize through the World Professional Association for Transgender Health.
If providers start to notice an influx of patients who identify as transgender or if they want to start seeing transgender patients, it’s really important for them to have that training before they start interacting with patients. In all of medicine, we sort of learn as we go, but this patient population has been subjected to discrimination, violence, error, and misgendering. They have dealt with providers who didn’t understand their health care needs. While this field is evolving, knowing how to appropriately address a patient (using their correct name, pronouns, etc.) is an absolute must.
That needs to be part of a provider’s routine vernacular and not something that they sort of stumble through. You can scare a patient away as soon as they walk into the office with an uneducated front desk staff and things that are seen in the office. Seeking out those educational tools, being aware of your own deficits as a provider and the educational needs of your office, and addressing those needs is really key.
A version of this article first appeared on Medscape.com.
Steroid-refractory pneumonitis from ICIs: Experience at major centers
Pneumonitis is an uncommon and potentially life-threatening complication of immune checkpoint inhibitor (ICI) therapy. A fraction of patients with ICI-related pneumonitis fail to respond to initial therapy with high-dose systemic steroids.
The recently published experiences at two major cancer centers shed light on the outcomes from treatment and can provide some advice to clinicians for dealing with affected patients.
The Johns Hopkins experience
Because ICI-related pneumonitis typically improves within 48-72 hours of steroid therapy, at Johns Hopkins University, Baltimore, steroid-refractory pneumonitis is defined as pneumonitis that demonstrates no clinical improvement after high-dose corticosteroids for 2-14 days. If the immune toxicity–specialized, multidisciplinary management team implements additional immunosuppressive therapy, that is regarded as confirmatory evidence.
Aanika Balaji, a medical student at Johns Hopkins University, and colleagues retrospectively summarized the clinical course of 12 patients with ICI-related pneumonitis between 2011 and 2020. Clinical improvement with subsequent treatment was evidenced by reduction in either level of care or oxygen requirements.
Three-quarters of the patients were current or former smokers, and the same proportion had lung cancer. Most patients (91.6%) had received chemotherapy, 58.3% had prior chest radiotherapy, and 58.3% had achieved partial response or stable disease with an ICI.
Steroid-refractory ICI-related pneumonitis developed between 40 and 127 days (median, 85 days) after the first dose of ICI therapy. Subsequent immunosuppressive management included IVIg, infliximab, or the combination, in addition to ICU-level supportive care.
Among the seven patients who received IVIg alone, two patients (29%) achieved clinical improvement and hospital discharge. The remainder died.
The two patients treated with infliximab and the three patients treated with sequential IVIg and infliximab died. All deaths were attributed to ICI-related pneumonitis or infectious complications.
Overall, clinically relevant findings were:
- Steroid-refractory ICI-related pneumonitis was seen in 18.5% of patients referred for multidisciplinary care.
- Steroid-refractory ICI-related pneumonitis occurred at a median of 85 days into a patient’s ICI treatment.
- Some patients improved clinically after IVIg therapy, but mortality was high overall.
- Infliximab therapy, alone or in combination with IVIg, was ineffective.
The Memorial Sloan Kettering experience
Jason Beattie, MD, of Memorial Sloan Kettering Cancer Center, New York, and colleagues performed a retrospective study of patients who had pneumonitis after ICI therapy and/or received immune modulator therapy after corticosteroids in the setting of ICI cancer treatment.
Manual record review was performed to exclude cases of pneumonitis from other causes. The period reviewed was roughly contemporaneous with the Johns Hopkins series.
Patients with ICI-related pneumonitis were divided into “steroid refractory” (i.e., no response to high-dose corticosteroids) or “steroid resistant” (i.e., initial response, followed by worsening) categories.
The researchers identified 26 patients with ICI-related pneumonitis, all of whom had advanced malignancy (8 lung cancer, 4 malignant melanoma, 4 renal cell cancer, and 10 “other” cancers).
A majority of patients (85%) were current or former smokers, 73% had received ICI monotherapy, 35% had received prior chest radiation at a median interval of 4.9 months prior to pneumonitis onset, and 27% had preexisting pulmonary disease.
Twelve patients (46%) had steroid-refractory ICI-related pneumonitis, and 14 (54%) had steroid-resistant ICI-related pneumonitis.
The two groups differed in time to pneumonitis onset (a median of 68 days in the refractory group and 182 days in the resistant group) and time to immune modulator therapy after beginning steroids (median 7 days and 2.9 months, respectively). In the steroid-refractory cases, pneumonitis was more severe.
In addition to corticosteroids, most patients received infliximab monotherapy or infliximab with mycophenolate mofetil. In contrast to the Johns Hopkins series, IVIg was not used in the Memorial Sloan Kettering cases.
Outcomes from immune modulators were graded based on clinical evidence (progress notes, oxygen requirements, level of care, radiologic information, etc.) of resolution of pneumonitis on imaging at least 8 weeks after cessation of steroids and immune modulator therapy, durable improvement for at least 8 weeks after immune modulator therapy, transient improvement followed by pneumonitis relapse or inadequate follow-up because of death or hospice referral, or no improvement.
Ten patients (38%) had durable improvement of ICI-related pneumonitis, of whom three (12%) had complete resolution. Two of the patients with complete resolution had steroid-refractory pneumonitis, both of whom had received infliximab followed by mycophenolate mofetil.
Among the seven patients with durable improvement, four remained alive on immune modulators. Time to resolution of pneumonitis was protracted, ranging from 2.3 months to 8.4 months in the steroid-refractory patients.
Durable response was less common with steroid-refractory (25%) than steroid-resistant (50%) disease, with a significant difference in 90-day survival of 25% and 71%, respectively.
Among the 13 (50%) patients with transient improvement in ICI-related pneumonitis, 8 ultimately died, either because of recurrent ICI-related pneumonitis or infection. All three patients with no improvement from immune modulators died.
The 90-day all-cause mortality was 50%, with durable pneumonitis improvement and freedom from severe infectious complications occurring in only about a third of patients.
Lessons for clinicians
The National Comprehensive Cancer Network, the Society for Immunotherapy of Cancer, and the European Society of Medical Oncology have all published guidelines and recommendations for immunosuppression for steroid-refractory adverse events from ICIs.
Unfortunately, there is little experience with steroid-unresponsive ICI-related pneumonitis. The ideal sequence, dose, and duration of additional immune modulator therapy for ICI-related pneumonitis are unclear and may differ from the approaches to other immune-related toxicities.
This is important because, as suggested in an editorial by Margaret Gatti-Mays, MD, and James L. Gulley, MD, PhD, it is likely that ICI-related pneumonitis will be seen more in routine practice than in clinical trial populations. In addition, across all tumor types, ICI-related pneumonitis is the most common cause of ICI-associated death from toxicity.
The retrospective studies from Johns Hopkins and Memorial Sloan Kettering constitute the largest published experience with ICI-related pneumonitis and yield important clinical insights.
Uniform definitions of potentially important patient subgroups (e.g., steroid refractory vs. steroid resistant) are needed. The steroid-refractory and steroid-resistant subgroups have distinctly different clinical features and outcomes. Uniformity in the subgroup definitions would be a useful starting point from both clinical and research perspectives.
Preferred treatment choices need to be tested systematically in multi-institutional studies. Any potential impact of treatment for ICI-related pneumonitis on antitumor immune control should be identified.
Endpoints of interest need to be defined and measured prospectively. All-cause mortality after 90 days is important, but, as the authors of both reviews noted, there are vitally important narratives and differences in functionality that are completely concealed by restricting the focus to mortality.
Potential causal relationships with antecedent exposure to tobacco, radiation, intrathoracic tumor burden, or other factors need to be defined.
Clinicians need predictive biomarkers for ICI-related pneumonitis (e.g., in peripheral blood, pulmonary function testing, or bronchoscopy specimens). At-risk patients may benefit from early intervention.
The limitations of single-institution record reviews in guiding real-world patient management notwithstanding, these reviews illustrate the value of registries and prospective studies to guide the path forward. Taking these next steps will ensure for our patients that the success of immune-targeted therapy against their cancer never becomes a Pyrrhic victory.
The Johns Hopkins investigators and the editorialists reported having no disclosures. The Memorial Sloan Kettering investigators disclosed relationships with Targeted Oncology, Merck, Array BioPharma, Novartis, and many other companies.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
Pneumonitis is an uncommon and potentially life-threatening complication of immune checkpoint inhibitor (ICI) therapy. A fraction of patients with ICI-related pneumonitis fail to respond to initial therapy with high-dose systemic steroids.
The recently published experiences at two major cancer centers shed light on the outcomes from treatment and can provide some advice to clinicians for dealing with affected patients.
The Johns Hopkins experience
Because ICI-related pneumonitis typically improves within 48-72 hours of steroid therapy, at Johns Hopkins University, Baltimore, steroid-refractory pneumonitis is defined as pneumonitis that demonstrates no clinical improvement after high-dose corticosteroids for 2-14 days. If the immune toxicity–specialized, multidisciplinary management team implements additional immunosuppressive therapy, that is regarded as confirmatory evidence.
Aanika Balaji, a medical student at Johns Hopkins University, and colleagues retrospectively summarized the clinical course of 12 patients with ICI-related pneumonitis between 2011 and 2020. Clinical improvement with subsequent treatment was evidenced by reduction in either level of care or oxygen requirements.
Three-quarters of the patients were current or former smokers, and the same proportion had lung cancer. Most patients (91.6%) had received chemotherapy, 58.3% had prior chest radiotherapy, and 58.3% had achieved partial response or stable disease with an ICI.
Steroid-refractory ICI-related pneumonitis developed between 40 and 127 days (median, 85 days) after the first dose of ICI therapy. Subsequent immunosuppressive management included IVIg, infliximab, or the combination, in addition to ICU-level supportive care.
Among the seven patients who received IVIg alone, two patients (29%) achieved clinical improvement and hospital discharge. The remainder died.
The two patients treated with infliximab and the three patients treated with sequential IVIg and infliximab died. All deaths were attributed to ICI-related pneumonitis or infectious complications.
Overall, clinically relevant findings were:
- Steroid-refractory ICI-related pneumonitis was seen in 18.5% of patients referred for multidisciplinary care.
- Steroid-refractory ICI-related pneumonitis occurred at a median of 85 days into a patient’s ICI treatment.
- Some patients improved clinically after IVIg therapy, but mortality was high overall.
- Infliximab therapy, alone or in combination with IVIg, was ineffective.
The Memorial Sloan Kettering experience
Jason Beattie, MD, of Memorial Sloan Kettering Cancer Center, New York, and colleagues performed a retrospective study of patients who had pneumonitis after ICI therapy and/or received immune modulator therapy after corticosteroids in the setting of ICI cancer treatment.
Manual record review was performed to exclude cases of pneumonitis from other causes. The period reviewed was roughly contemporaneous with the Johns Hopkins series.
Patients with ICI-related pneumonitis were divided into “steroid refractory” (i.e., no response to high-dose corticosteroids) or “steroid resistant” (i.e., initial response, followed by worsening) categories.
The researchers identified 26 patients with ICI-related pneumonitis, all of whom had advanced malignancy (8 lung cancer, 4 malignant melanoma, 4 renal cell cancer, and 10 “other” cancers).
A majority of patients (85%) were current or former smokers, 73% had received ICI monotherapy, 35% had received prior chest radiation at a median interval of 4.9 months prior to pneumonitis onset, and 27% had preexisting pulmonary disease.
Twelve patients (46%) had steroid-refractory ICI-related pneumonitis, and 14 (54%) had steroid-resistant ICI-related pneumonitis.
The two groups differed in time to pneumonitis onset (a median of 68 days in the refractory group and 182 days in the resistant group) and time to immune modulator therapy after beginning steroids (median 7 days and 2.9 months, respectively). In the steroid-refractory cases, pneumonitis was more severe.
In addition to corticosteroids, most patients received infliximab monotherapy or infliximab with mycophenolate mofetil. In contrast to the Johns Hopkins series, IVIg was not used in the Memorial Sloan Kettering cases.
Outcomes from immune modulators were graded based on clinical evidence (progress notes, oxygen requirements, level of care, radiologic information, etc.) of resolution of pneumonitis on imaging at least 8 weeks after cessation of steroids and immune modulator therapy, durable improvement for at least 8 weeks after immune modulator therapy, transient improvement followed by pneumonitis relapse or inadequate follow-up because of death or hospice referral, or no improvement.
Ten patients (38%) had durable improvement of ICI-related pneumonitis, of whom three (12%) had complete resolution. Two of the patients with complete resolution had steroid-refractory pneumonitis, both of whom had received infliximab followed by mycophenolate mofetil.
Among the seven patients with durable improvement, four remained alive on immune modulators. Time to resolution of pneumonitis was protracted, ranging from 2.3 months to 8.4 months in the steroid-refractory patients.
Durable response was less common with steroid-refractory (25%) than steroid-resistant (50%) disease, with a significant difference in 90-day survival of 25% and 71%, respectively.
Among the 13 (50%) patients with transient improvement in ICI-related pneumonitis, 8 ultimately died, either because of recurrent ICI-related pneumonitis or infection. All three patients with no improvement from immune modulators died.
The 90-day all-cause mortality was 50%, with durable pneumonitis improvement and freedom from severe infectious complications occurring in only about a third of patients.
Lessons for clinicians
The National Comprehensive Cancer Network, the Society for Immunotherapy of Cancer, and the European Society of Medical Oncology have all published guidelines and recommendations for immunosuppression for steroid-refractory adverse events from ICIs.
Unfortunately, there is little experience with steroid-unresponsive ICI-related pneumonitis. The ideal sequence, dose, and duration of additional immune modulator therapy for ICI-related pneumonitis are unclear and may differ from the approaches to other immune-related toxicities.
This is important because, as suggested in an editorial by Margaret Gatti-Mays, MD, and James L. Gulley, MD, PhD, it is likely that ICI-related pneumonitis will be seen more in routine practice than in clinical trial populations. In addition, across all tumor types, ICI-related pneumonitis is the most common cause of ICI-associated death from toxicity.
The retrospective studies from Johns Hopkins and Memorial Sloan Kettering constitute the largest published experience with ICI-related pneumonitis and yield important clinical insights.
Uniform definitions of potentially important patient subgroups (e.g., steroid refractory vs. steroid resistant) are needed. The steroid-refractory and steroid-resistant subgroups have distinctly different clinical features and outcomes. Uniformity in the subgroup definitions would be a useful starting point from both clinical and research perspectives.
Preferred treatment choices need to be tested systematically in multi-institutional studies. Any potential impact of treatment for ICI-related pneumonitis on antitumor immune control should be identified.
Endpoints of interest need to be defined and measured prospectively. All-cause mortality after 90 days is important, but, as the authors of both reviews noted, there are vitally important narratives and differences in functionality that are completely concealed by restricting the focus to mortality.
Potential causal relationships with antecedent exposure to tobacco, radiation, intrathoracic tumor burden, or other factors need to be defined.
Clinicians need predictive biomarkers for ICI-related pneumonitis (e.g., in peripheral blood, pulmonary function testing, or bronchoscopy specimens). At-risk patients may benefit from early intervention.
The limitations of single-institution record reviews in guiding real-world patient management notwithstanding, these reviews illustrate the value of registries and prospective studies to guide the path forward. Taking these next steps will ensure for our patients that the success of immune-targeted therapy against their cancer never becomes a Pyrrhic victory.
The Johns Hopkins investigators and the editorialists reported having no disclosures. The Memorial Sloan Kettering investigators disclosed relationships with Targeted Oncology, Merck, Array BioPharma, Novartis, and many other companies.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
Pneumonitis is an uncommon and potentially life-threatening complication of immune checkpoint inhibitor (ICI) therapy. A fraction of patients with ICI-related pneumonitis fail to respond to initial therapy with high-dose systemic steroids.
The recently published experiences at two major cancer centers shed light on the outcomes from treatment and can provide some advice to clinicians for dealing with affected patients.
The Johns Hopkins experience
Because ICI-related pneumonitis typically improves within 48-72 hours of steroid therapy, at Johns Hopkins University, Baltimore, steroid-refractory pneumonitis is defined as pneumonitis that demonstrates no clinical improvement after high-dose corticosteroids for 2-14 days. If the immune toxicity–specialized, multidisciplinary management team implements additional immunosuppressive therapy, that is regarded as confirmatory evidence.
Aanika Balaji, a medical student at Johns Hopkins University, and colleagues retrospectively summarized the clinical course of 12 patients with ICI-related pneumonitis between 2011 and 2020. Clinical improvement with subsequent treatment was evidenced by reduction in either level of care or oxygen requirements.
Three-quarters of the patients were current or former smokers, and the same proportion had lung cancer. Most patients (91.6%) had received chemotherapy, 58.3% had prior chest radiotherapy, and 58.3% had achieved partial response or stable disease with an ICI.
Steroid-refractory ICI-related pneumonitis developed between 40 and 127 days (median, 85 days) after the first dose of ICI therapy. Subsequent immunosuppressive management included IVIg, infliximab, or the combination, in addition to ICU-level supportive care.
Among the seven patients who received IVIg alone, two patients (29%) achieved clinical improvement and hospital discharge. The remainder died.
The two patients treated with infliximab and the three patients treated with sequential IVIg and infliximab died. All deaths were attributed to ICI-related pneumonitis or infectious complications.
Overall, clinically relevant findings were:
- Steroid-refractory ICI-related pneumonitis was seen in 18.5% of patients referred for multidisciplinary care.
- Steroid-refractory ICI-related pneumonitis occurred at a median of 85 days into a patient’s ICI treatment.
- Some patients improved clinically after IVIg therapy, but mortality was high overall.
- Infliximab therapy, alone or in combination with IVIg, was ineffective.
The Memorial Sloan Kettering experience
Jason Beattie, MD, of Memorial Sloan Kettering Cancer Center, New York, and colleagues performed a retrospective study of patients who had pneumonitis after ICI therapy and/or received immune modulator therapy after corticosteroids in the setting of ICI cancer treatment.
Manual record review was performed to exclude cases of pneumonitis from other causes. The period reviewed was roughly contemporaneous with the Johns Hopkins series.
Patients with ICI-related pneumonitis were divided into “steroid refractory” (i.e., no response to high-dose corticosteroids) or “steroid resistant” (i.e., initial response, followed by worsening) categories.
The researchers identified 26 patients with ICI-related pneumonitis, all of whom had advanced malignancy (8 lung cancer, 4 malignant melanoma, 4 renal cell cancer, and 10 “other” cancers).
A majority of patients (85%) were current or former smokers, 73% had received ICI monotherapy, 35% had received prior chest radiation at a median interval of 4.9 months prior to pneumonitis onset, and 27% had preexisting pulmonary disease.
Twelve patients (46%) had steroid-refractory ICI-related pneumonitis, and 14 (54%) had steroid-resistant ICI-related pneumonitis.
The two groups differed in time to pneumonitis onset (a median of 68 days in the refractory group and 182 days in the resistant group) and time to immune modulator therapy after beginning steroids (median 7 days and 2.9 months, respectively). In the steroid-refractory cases, pneumonitis was more severe.
In addition to corticosteroids, most patients received infliximab monotherapy or infliximab with mycophenolate mofetil. In contrast to the Johns Hopkins series, IVIg was not used in the Memorial Sloan Kettering cases.
Outcomes from immune modulators were graded based on clinical evidence (progress notes, oxygen requirements, level of care, radiologic information, etc.) of resolution of pneumonitis on imaging at least 8 weeks after cessation of steroids and immune modulator therapy, durable improvement for at least 8 weeks after immune modulator therapy, transient improvement followed by pneumonitis relapse or inadequate follow-up because of death or hospice referral, or no improvement.
Ten patients (38%) had durable improvement of ICI-related pneumonitis, of whom three (12%) had complete resolution. Two of the patients with complete resolution had steroid-refractory pneumonitis, both of whom had received infliximab followed by mycophenolate mofetil.
Among the seven patients with durable improvement, four remained alive on immune modulators. Time to resolution of pneumonitis was protracted, ranging from 2.3 months to 8.4 months in the steroid-refractory patients.
Durable response was less common with steroid-refractory (25%) than steroid-resistant (50%) disease, with a significant difference in 90-day survival of 25% and 71%, respectively.
Among the 13 (50%) patients with transient improvement in ICI-related pneumonitis, 8 ultimately died, either because of recurrent ICI-related pneumonitis or infection. All three patients with no improvement from immune modulators died.
The 90-day all-cause mortality was 50%, with durable pneumonitis improvement and freedom from severe infectious complications occurring in only about a third of patients.
Lessons for clinicians
The National Comprehensive Cancer Network, the Society for Immunotherapy of Cancer, and the European Society of Medical Oncology have all published guidelines and recommendations for immunosuppression for steroid-refractory adverse events from ICIs.
Unfortunately, there is little experience with steroid-unresponsive ICI-related pneumonitis. The ideal sequence, dose, and duration of additional immune modulator therapy for ICI-related pneumonitis are unclear and may differ from the approaches to other immune-related toxicities.
This is important because, as suggested in an editorial by Margaret Gatti-Mays, MD, and James L. Gulley, MD, PhD, it is likely that ICI-related pneumonitis will be seen more in routine practice than in clinical trial populations. In addition, across all tumor types, ICI-related pneumonitis is the most common cause of ICI-associated death from toxicity.
The retrospective studies from Johns Hopkins and Memorial Sloan Kettering constitute the largest published experience with ICI-related pneumonitis and yield important clinical insights.
Uniform definitions of potentially important patient subgroups (e.g., steroid refractory vs. steroid resistant) are needed. The steroid-refractory and steroid-resistant subgroups have distinctly different clinical features and outcomes. Uniformity in the subgroup definitions would be a useful starting point from both clinical and research perspectives.
Preferred treatment choices need to be tested systematically in multi-institutional studies. Any potential impact of treatment for ICI-related pneumonitis on antitumor immune control should be identified.
Endpoints of interest need to be defined and measured prospectively. All-cause mortality after 90 days is important, but, as the authors of both reviews noted, there are vitally important narratives and differences in functionality that are completely concealed by restricting the focus to mortality.
Potential causal relationships with antecedent exposure to tobacco, radiation, intrathoracic tumor burden, or other factors need to be defined.
Clinicians need predictive biomarkers for ICI-related pneumonitis (e.g., in peripheral blood, pulmonary function testing, or bronchoscopy specimens). At-risk patients may benefit from early intervention.
The limitations of single-institution record reviews in guiding real-world patient management notwithstanding, these reviews illustrate the value of registries and prospective studies to guide the path forward. Taking these next steps will ensure for our patients that the success of immune-targeted therapy against their cancer never becomes a Pyrrhic victory.
The Johns Hopkins investigators and the editorialists reported having no disclosures. The Memorial Sloan Kettering investigators disclosed relationships with Targeted Oncology, Merck, Array BioPharma, Novartis, and many other companies.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
Bariatric surgery may cut cancer in obesity with liver disease
In a large cohort of insured working adults with severe obesity and nonalcoholic fatty liver disease (NAFLD), the rate of incident cancer was lower during a 10-month median follow-up period among those who underwent bariatric surgery. The rate was especially lower with regard to obesity-related cancers. The risk reduction was greater among patients with cirrhosis.
Among almost 100,000 patients with severe obesity (body mass index >40 kg/m2) and NAFLD, those who underwent bariatric surgery had an 18% and 35% lower risk of developing any cancer or obesity-related cancer, respectively.
Bariatric surgery was associated with a significantly lower risk of being diagnosed with colorectal, pancreatic, endometrial, and thyroid cancer, as well as hepatocellular carcinoma and multiple myeloma (all obesity-related cancers). The findings are from an observational study by Vinod K. Rustgi, MD, MBA, and colleagues, which was published online March 17, 2021, in Gastroenterology.
It was not surprising that bariatric surgery is effective in reducing the malignancy rate among patients with cirrhosis, the researchers wrote, because the surgery results in long-term weight loss, resolution of nonalcoholic steatohepatitis (NASH), and regression of fibrosis.
“Cirrhosis can happen from fatty liver disease or NASH,” Dr. Rustgi, a hepatologist at Robert Wood Johnson Medical School, New Brunswick, N.J., explained to this news organization. “It’s becoming the fastest growing indication for liver transplant, but also the reason for increased rates of hepatocellular carcinoma.”
Current treatment for patients with obesity and fatty liver disease begins with lifestyle changes to lose weight, he continued. “As people lose 10% of their weight, they actually start to see regression of fibrosis in the liver that is correlated with [lower rates of] malignancy outcomes and other deleterious outcomes.” But long-lasting weight loss is extremely difficult to achieve.
Future studies “may identify new targets and treatments, such as antidiabetic-, satiety-, or GLP-1-based medications, for chemoprevention in NAFLD/NASH,” the investigators suggested. However, pharmaceutical agents will likely be very expensive when they eventually get marketed, Dr. Rustgi observed.
Although “bariatric surgery is a more aggressive approach than lifestyle modifications, surgery may provide additional benefits, such as improved quality of life and decreased long-term health care costs,” he and his coauthors concluded.
Rising rates of fatty liver disease, obesity
An estimated 30% of the population of the United States has NAFLD, the most common chronic liver disease, the researchers noted in their article. The prevalence of NAFLD increased 2.8-fold in the United States between 2003 and 2011, in parallel with increasing obesity.
NAFLD is more common among male patients with obesity and diabetes and Hispanic patients; “70% of [patients with diabetes] may have fatty liver disease, according to certain surveys,” Dr. Rustgi noted.
Cancer is the second greatest cause of mortality among patients with obesity and NAFLD, he continued, after cardiovascular disease. Cancer mortality is higher than mortality from liver disease.
Obesity-related cancers include adenocarcinoma of the esophagus, cancers of the breast (in postmenopausal women), colon, rectum, endometrium (corpus uterus), gallbladder, gastric cardia, kidney (renal cell), liver, ovary, pancreas, and thyroid, as well as meningioma and multiple myeloma, according to a 2016 report from the International Agency for Research on Cancer working group.
Obesity-related cancer accounted for 40% of all cancer in the United States in 2014 – 55% of cancers in women, and 24% of cancers in men, according to a study published in Morbidity and Mortality Weekly Report in 2017, as previously reported by this news organization.
Several studies, including one presented at Obesity Week in 2019 and later published, have shown that bariatric surgery is linked with a lower risk for cancer in general populations.
One meta-analysis reported that NAFLD is an independent risk factor for cholangiocarcinoma and colorectal, breast, gastric, pancreatic, prostate, and esophageal cancers. In another study, NAFLD was associated with a twofold increased risk for hepatocellular carcinoma and uterine, stomach, pancreatic, and colon cancers, Dr. Rustgi and colleagues noted.
Until now, the impact of bariatric surgery on the risk for cancer among patients with obesity and NAFLD was unknown.
Does bariatric surgery curb cancer risk in liver disease?
The researchers examined insurance claims data from the national MarketScan database from Jan. 1, 2007, to Dec. 31, 2017, for patients aged 18-64 years who had health insurance from 350 employers and 100 insurers. They identified 98,090 patients with severe obesity who were newly diagnosed with NAFLD during 2008-2017.
Roughly a third of the cohort (33,435 patients) underwent bariatric surgery. From 2008 to 2017, laparoscopic sleeve gastrectomies increased from 4% of bariatric procedures to 68% of all surgeries. Laparoscopic adjustable gastric band and laparoscopic Roux-en-Y gastric bypass procedures fell from 35% to less than 1% and from 49% to 28%, respectively.
Patients who underwent bariatric surgery were younger (mean age, 44 vs. 46 years), were more likely to be women (74% vs. 62%), and were less likely to have a history of smoking (6% vs. 10%).
During a mean follow-up of 22 months (and a median follow-up of 10 months), there were 911 incident cases of obesity-related cancers. These included cancer of the colon (116 cases), rectum (15), breast (in postmenopausal women; 131), kidney (120), esophagus (16), gastric cardia (8), gallbladder (4), pancreas (44), ovaries (74), endometrium (135), and thyroid (143), as well as hepatocellular carcinoma (49), multiple myeloma (50), and meningioma (6). There were 1,912 incident cases of other cancers, such as brain and lung cancers and leukemia.
A total of 258 patients who underwent bariatric surgery developed an obesity-related cancer (an incidence of 3.83 per 1,000 person-years), compared with 653 patients who did not have bariatric surgery (an incidence of 5.63 per 1,000 person-years).
The researchers noted that study limitations include the fact that it was restricted to privately insured individuals aged 18-64 years with severe obesity. In addition, “the short median follow-up may underestimate the full effect of bariatric surgery on cancer risk,” they wrote.
The authors disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In a large cohort of insured working adults with severe obesity and nonalcoholic fatty liver disease (NAFLD), the rate of incident cancer was lower during a 10-month median follow-up period among those who underwent bariatric surgery. The rate was especially lower with regard to obesity-related cancers. The risk reduction was greater among patients with cirrhosis.
Among almost 100,000 patients with severe obesity (body mass index >40 kg/m2) and NAFLD, those who underwent bariatric surgery had an 18% and 35% lower risk of developing any cancer or obesity-related cancer, respectively.
Bariatric surgery was associated with a significantly lower risk of being diagnosed with colorectal, pancreatic, endometrial, and thyroid cancer, as well as hepatocellular carcinoma and multiple myeloma (all obesity-related cancers). The findings are from an observational study by Vinod K. Rustgi, MD, MBA, and colleagues, which was published online March 17, 2021, in Gastroenterology.
It was not surprising that bariatric surgery is effective in reducing the malignancy rate among patients with cirrhosis, the researchers wrote, because the surgery results in long-term weight loss, resolution of nonalcoholic steatohepatitis (NASH), and regression of fibrosis.
“Cirrhosis can happen from fatty liver disease or NASH,” Dr. Rustgi, a hepatologist at Robert Wood Johnson Medical School, New Brunswick, N.J., explained to this news organization. “It’s becoming the fastest growing indication for liver transplant, but also the reason for increased rates of hepatocellular carcinoma.”
Current treatment for patients with obesity and fatty liver disease begins with lifestyle changes to lose weight, he continued. “As people lose 10% of their weight, they actually start to see regression of fibrosis in the liver that is correlated with [lower rates of] malignancy outcomes and other deleterious outcomes.” But long-lasting weight loss is extremely difficult to achieve.
Future studies “may identify new targets and treatments, such as antidiabetic-, satiety-, or GLP-1-based medications, for chemoprevention in NAFLD/NASH,” the investigators suggested. However, pharmaceutical agents will likely be very expensive when they eventually get marketed, Dr. Rustgi observed.
Although “bariatric surgery is a more aggressive approach than lifestyle modifications, surgery may provide additional benefits, such as improved quality of life and decreased long-term health care costs,” he and his coauthors concluded.
Rising rates of fatty liver disease, obesity
An estimated 30% of the population of the United States has NAFLD, the most common chronic liver disease, the researchers noted in their article. The prevalence of NAFLD increased 2.8-fold in the United States between 2003 and 2011, in parallel with increasing obesity.
NAFLD is more common among male patients with obesity and diabetes and Hispanic patients; “70% of [patients with diabetes] may have fatty liver disease, according to certain surveys,” Dr. Rustgi noted.
Cancer is the second greatest cause of mortality among patients with obesity and NAFLD, he continued, after cardiovascular disease. Cancer mortality is higher than mortality from liver disease.
Obesity-related cancers include adenocarcinoma of the esophagus, cancers of the breast (in postmenopausal women), colon, rectum, endometrium (corpus uterus), gallbladder, gastric cardia, kidney (renal cell), liver, ovary, pancreas, and thyroid, as well as meningioma and multiple myeloma, according to a 2016 report from the International Agency for Research on Cancer working group.
Obesity-related cancer accounted for 40% of all cancer in the United States in 2014 – 55% of cancers in women, and 24% of cancers in men, according to a study published in Morbidity and Mortality Weekly Report in 2017, as previously reported by this news organization.
Several studies, including one presented at Obesity Week in 2019 and later published, have shown that bariatric surgery is linked with a lower risk for cancer in general populations.
One meta-analysis reported that NAFLD is an independent risk factor for cholangiocarcinoma and colorectal, breast, gastric, pancreatic, prostate, and esophageal cancers. In another study, NAFLD was associated with a twofold increased risk for hepatocellular carcinoma and uterine, stomach, pancreatic, and colon cancers, Dr. Rustgi and colleagues noted.
Until now, the impact of bariatric surgery on the risk for cancer among patients with obesity and NAFLD was unknown.
Does bariatric surgery curb cancer risk in liver disease?
The researchers examined insurance claims data from the national MarketScan database from Jan. 1, 2007, to Dec. 31, 2017, for patients aged 18-64 years who had health insurance from 350 employers and 100 insurers. They identified 98,090 patients with severe obesity who were newly diagnosed with NAFLD during 2008-2017.
Roughly a third of the cohort (33,435 patients) underwent bariatric surgery. From 2008 to 2017, laparoscopic sleeve gastrectomies increased from 4% of bariatric procedures to 68% of all surgeries. Laparoscopic adjustable gastric band and laparoscopic Roux-en-Y gastric bypass procedures fell from 35% to less than 1% and from 49% to 28%, respectively.
Patients who underwent bariatric surgery were younger (mean age, 44 vs. 46 years), were more likely to be women (74% vs. 62%), and were less likely to have a history of smoking (6% vs. 10%).
During a mean follow-up of 22 months (and a median follow-up of 10 months), there were 911 incident cases of obesity-related cancers. These included cancer of the colon (116 cases), rectum (15), breast (in postmenopausal women; 131), kidney (120), esophagus (16), gastric cardia (8), gallbladder (4), pancreas (44), ovaries (74), endometrium (135), and thyroid (143), as well as hepatocellular carcinoma (49), multiple myeloma (50), and meningioma (6). There were 1,912 incident cases of other cancers, such as brain and lung cancers and leukemia.
A total of 258 patients who underwent bariatric surgery developed an obesity-related cancer (an incidence of 3.83 per 1,000 person-years), compared with 653 patients who did not have bariatric surgery (an incidence of 5.63 per 1,000 person-years).
The researchers noted that study limitations include the fact that it was restricted to privately insured individuals aged 18-64 years with severe obesity. In addition, “the short median follow-up may underestimate the full effect of bariatric surgery on cancer risk,” they wrote.
The authors disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
In a large cohort of insured working adults with severe obesity and nonalcoholic fatty liver disease (NAFLD), the rate of incident cancer was lower during a 10-month median follow-up period among those who underwent bariatric surgery. The rate was especially lower with regard to obesity-related cancers. The risk reduction was greater among patients with cirrhosis.
Among almost 100,000 patients with severe obesity (body mass index >40 kg/m2) and NAFLD, those who underwent bariatric surgery had an 18% and 35% lower risk of developing any cancer or obesity-related cancer, respectively.
Bariatric surgery was associated with a significantly lower risk of being diagnosed with colorectal, pancreatic, endometrial, and thyroid cancer, as well as hepatocellular carcinoma and multiple myeloma (all obesity-related cancers). The findings are from an observational study by Vinod K. Rustgi, MD, MBA, and colleagues, which was published online March 17, 2021, in Gastroenterology.
It was not surprising that bariatric surgery is effective in reducing the malignancy rate among patients with cirrhosis, the researchers wrote, because the surgery results in long-term weight loss, resolution of nonalcoholic steatohepatitis (NASH), and regression of fibrosis.
“Cirrhosis can happen from fatty liver disease or NASH,” Dr. Rustgi, a hepatologist at Robert Wood Johnson Medical School, New Brunswick, N.J., explained to this news organization. “It’s becoming the fastest growing indication for liver transplant, but also the reason for increased rates of hepatocellular carcinoma.”
Current treatment for patients with obesity and fatty liver disease begins with lifestyle changes to lose weight, he continued. “As people lose 10% of their weight, they actually start to see regression of fibrosis in the liver that is correlated with [lower rates of] malignancy outcomes and other deleterious outcomes.” But long-lasting weight loss is extremely difficult to achieve.
Future studies “may identify new targets and treatments, such as antidiabetic-, satiety-, or GLP-1-based medications, for chemoprevention in NAFLD/NASH,” the investigators suggested. However, pharmaceutical agents will likely be very expensive when they eventually get marketed, Dr. Rustgi observed.
Although “bariatric surgery is a more aggressive approach than lifestyle modifications, surgery may provide additional benefits, such as improved quality of life and decreased long-term health care costs,” he and his coauthors concluded.
Rising rates of fatty liver disease, obesity
An estimated 30% of the population of the United States has NAFLD, the most common chronic liver disease, the researchers noted in their article. The prevalence of NAFLD increased 2.8-fold in the United States between 2003 and 2011, in parallel with increasing obesity.
NAFLD is more common among male patients with obesity and diabetes and Hispanic patients; “70% of [patients with diabetes] may have fatty liver disease, according to certain surveys,” Dr. Rustgi noted.
Cancer is the second greatest cause of mortality among patients with obesity and NAFLD, he continued, after cardiovascular disease. Cancer mortality is higher than mortality from liver disease.
Obesity-related cancers include adenocarcinoma of the esophagus, cancers of the breast (in postmenopausal women), colon, rectum, endometrium (corpus uterus), gallbladder, gastric cardia, kidney (renal cell), liver, ovary, pancreas, and thyroid, as well as meningioma and multiple myeloma, according to a 2016 report from the International Agency for Research on Cancer working group.
Obesity-related cancer accounted for 40% of all cancer in the United States in 2014 – 55% of cancers in women, and 24% of cancers in men, according to a study published in Morbidity and Mortality Weekly Report in 2017, as previously reported by this news organization.
Several studies, including one presented at Obesity Week in 2019 and later published, have shown that bariatric surgery is linked with a lower risk for cancer in general populations.
One meta-analysis reported that NAFLD is an independent risk factor for cholangiocarcinoma and colorectal, breast, gastric, pancreatic, prostate, and esophageal cancers. In another study, NAFLD was associated with a twofold increased risk for hepatocellular carcinoma and uterine, stomach, pancreatic, and colon cancers, Dr. Rustgi and colleagues noted.
Until now, the impact of bariatric surgery on the risk for cancer among patients with obesity and NAFLD was unknown.
Does bariatric surgery curb cancer risk in liver disease?
The researchers examined insurance claims data from the national MarketScan database from Jan. 1, 2007, to Dec. 31, 2017, for patients aged 18-64 years who had health insurance from 350 employers and 100 insurers. They identified 98,090 patients with severe obesity who were newly diagnosed with NAFLD during 2008-2017.
Roughly a third of the cohort (33,435 patients) underwent bariatric surgery. From 2008 to 2017, laparoscopic sleeve gastrectomies increased from 4% of bariatric procedures to 68% of all surgeries. Laparoscopic adjustable gastric band and laparoscopic Roux-en-Y gastric bypass procedures fell from 35% to less than 1% and from 49% to 28%, respectively.
Patients who underwent bariatric surgery were younger (mean age, 44 vs. 46 years), were more likely to be women (74% vs. 62%), and were less likely to have a history of smoking (6% vs. 10%).
During a mean follow-up of 22 months (and a median follow-up of 10 months), there were 911 incident cases of obesity-related cancers. These included cancer of the colon (116 cases), rectum (15), breast (in postmenopausal women; 131), kidney (120), esophagus (16), gastric cardia (8), gallbladder (4), pancreas (44), ovaries (74), endometrium (135), and thyroid (143), as well as hepatocellular carcinoma (49), multiple myeloma (50), and meningioma (6). There were 1,912 incident cases of other cancers, such as brain and lung cancers and leukemia.
A total of 258 patients who underwent bariatric surgery developed an obesity-related cancer (an incidence of 3.83 per 1,000 person-years), compared with 653 patients who did not have bariatric surgery (an incidence of 5.63 per 1,000 person-years).
The researchers noted that study limitations include the fact that it was restricted to privately insured individuals aged 18-64 years with severe obesity. In addition, “the short median follow-up may underestimate the full effect of bariatric surgery on cancer risk,” they wrote.
The authors disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.