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Surgery indicates higher survival with adrenal cortical carcinoma
CHICAGO –
These findings, uncovered using the largest cancer registry in the United States, will help give physicians insight into what the best course of action is for treating their patients, according to presenters.
“Surgical resection of the primary tumor improved survival in all stages of disease, whereas adjuvant therapy with chemotherapy or radiation improved overall survival only in stage IVpatients,” said Sri Harsha Tella, MD, endocrinologist at the University of South Carolina, Columbia. “These results may help the prognostication of patients in treatment decision making.”
Investigators conducted a retrospective study of 3,185 pathologically confirmed cases of ACC, registered into the National Cancer Database between 2004 and 2015.
Patients were mostly women with an average age of 55 years old and private insurance, with a nearly even split of patients with stage I-III (26%) and stage IV ACC (24%). Nearly three-quarters of those studied chose to have surgery, of which 31% chose open resection.
Patients with stage I-III ACC had a significant median survival rate of 63 months, compared with those who did not have surgery who had an average survival of 8 months.
In patients with stage IV ACC, surgery lengthened overall survival to 19 months, compared with 6 months for those without surgery, according to Dr. Tella and fellow investigators.
While surgery did have a greater positive effect on patients’ live spans across all stages, the impact of chemotherapy and radiation was significant only among stage IV patients who had complete surgery.
Those in the stage IV group who were given post-surgery adjuvant chemotherapy were likely to live an average of nearly 9 more months than did those who did not have chemotherapy after radiation (22 vs. 13), while those given radiation therapy saw an increase in survival by 19 months (29 vs. 10). These increases did not affect stage I-III patients, who had a similar rate of survival regardless of additional therapies after their surgery (24 vs. 25 months).
One possible explanation for why additional therapy made little difference in survival for stage I-III patients is that, given that the tumors did not spread as widely, the surgical procedures were likely to be more effective at removing most of the disease, according to Dr. Tella.
“One of the possibilities is that surgeons were able to get the whole mass out,” Dr. Tella hypothesized in response to a question from attendees. “On the other hand, patients with stage IV ACC may be more likely to have more presence of metastases and so would benefit more greatly from the removal of the primary tumor and then also additional therapy.”
Investigators noted that because of the structure of the registry, they were unable to determine the initiation and duration of chemotherapy, as well as doses of radiation therapy received by the patient.
A more robust database and future stage-specific, prospective clinical trials are needed in order to better understand these findings, Dr. Tella said.
The investigators reported no relevant financial disclosures.
ezimmerman@frontlinemedcom.com
SOURCE: Tella SH et al. Endo 2018.
CHICAGO –
These findings, uncovered using the largest cancer registry in the United States, will help give physicians insight into what the best course of action is for treating their patients, according to presenters.
“Surgical resection of the primary tumor improved survival in all stages of disease, whereas adjuvant therapy with chemotherapy or radiation improved overall survival only in stage IVpatients,” said Sri Harsha Tella, MD, endocrinologist at the University of South Carolina, Columbia. “These results may help the prognostication of patients in treatment decision making.”
Investigators conducted a retrospective study of 3,185 pathologically confirmed cases of ACC, registered into the National Cancer Database between 2004 and 2015.
Patients were mostly women with an average age of 55 years old and private insurance, with a nearly even split of patients with stage I-III (26%) and stage IV ACC (24%). Nearly three-quarters of those studied chose to have surgery, of which 31% chose open resection.
Patients with stage I-III ACC had a significant median survival rate of 63 months, compared with those who did not have surgery who had an average survival of 8 months.
In patients with stage IV ACC, surgery lengthened overall survival to 19 months, compared with 6 months for those without surgery, according to Dr. Tella and fellow investigators.
While surgery did have a greater positive effect on patients’ live spans across all stages, the impact of chemotherapy and radiation was significant only among stage IV patients who had complete surgery.
Those in the stage IV group who were given post-surgery adjuvant chemotherapy were likely to live an average of nearly 9 more months than did those who did not have chemotherapy after radiation (22 vs. 13), while those given radiation therapy saw an increase in survival by 19 months (29 vs. 10). These increases did not affect stage I-III patients, who had a similar rate of survival regardless of additional therapies after their surgery (24 vs. 25 months).
One possible explanation for why additional therapy made little difference in survival for stage I-III patients is that, given that the tumors did not spread as widely, the surgical procedures were likely to be more effective at removing most of the disease, according to Dr. Tella.
“One of the possibilities is that surgeons were able to get the whole mass out,” Dr. Tella hypothesized in response to a question from attendees. “On the other hand, patients with stage IV ACC may be more likely to have more presence of metastases and so would benefit more greatly from the removal of the primary tumor and then also additional therapy.”
Investigators noted that because of the structure of the registry, they were unable to determine the initiation and duration of chemotherapy, as well as doses of radiation therapy received by the patient.
A more robust database and future stage-specific, prospective clinical trials are needed in order to better understand these findings, Dr. Tella said.
The investigators reported no relevant financial disclosures.
ezimmerman@frontlinemedcom.com
SOURCE: Tella SH et al. Endo 2018.
CHICAGO –
These findings, uncovered using the largest cancer registry in the United States, will help give physicians insight into what the best course of action is for treating their patients, according to presenters.
“Surgical resection of the primary tumor improved survival in all stages of disease, whereas adjuvant therapy with chemotherapy or radiation improved overall survival only in stage IVpatients,” said Sri Harsha Tella, MD, endocrinologist at the University of South Carolina, Columbia. “These results may help the prognostication of patients in treatment decision making.”
Investigators conducted a retrospective study of 3,185 pathologically confirmed cases of ACC, registered into the National Cancer Database between 2004 and 2015.
Patients were mostly women with an average age of 55 years old and private insurance, with a nearly even split of patients with stage I-III (26%) and stage IV ACC (24%). Nearly three-quarters of those studied chose to have surgery, of which 31% chose open resection.
Patients with stage I-III ACC had a significant median survival rate of 63 months, compared with those who did not have surgery who had an average survival of 8 months.
In patients with stage IV ACC, surgery lengthened overall survival to 19 months, compared with 6 months for those without surgery, according to Dr. Tella and fellow investigators.
While surgery did have a greater positive effect on patients’ live spans across all stages, the impact of chemotherapy and radiation was significant only among stage IV patients who had complete surgery.
Those in the stage IV group who were given post-surgery adjuvant chemotherapy were likely to live an average of nearly 9 more months than did those who did not have chemotherapy after radiation (22 vs. 13), while those given radiation therapy saw an increase in survival by 19 months (29 vs. 10). These increases did not affect stage I-III patients, who had a similar rate of survival regardless of additional therapies after their surgery (24 vs. 25 months).
One possible explanation for why additional therapy made little difference in survival for stage I-III patients is that, given that the tumors did not spread as widely, the surgical procedures were likely to be more effective at removing most of the disease, according to Dr. Tella.
“One of the possibilities is that surgeons were able to get the whole mass out,” Dr. Tella hypothesized in response to a question from attendees. “On the other hand, patients with stage IV ACC may be more likely to have more presence of metastases and so would benefit more greatly from the removal of the primary tumor and then also additional therapy.”
Investigators noted that because of the structure of the registry, they were unable to determine the initiation and duration of chemotherapy, as well as doses of radiation therapy received by the patient.
A more robust database and future stage-specific, prospective clinical trials are needed in order to better understand these findings, Dr. Tella said.
The investigators reported no relevant financial disclosures.
ezimmerman@frontlinemedcom.com
SOURCE: Tella SH et al. Endo 2018.
REPORTING FROM ENDO 2018
Key clinical point: Patients who undergo surgical resection at all stages are more likely to survive.
Major finding: Patients stage I-III who underwent surgery survived over nearly 8 times longer than non-surgery patients (63 vs. 8 months [P less than .001]).
Study details: Retrospective study of 3,185 adrenal cortical carcinoma cases entered into the National Cancer Database between 2004 and 2015.
Disclosures: The presenter reported no relevant financial disclosures.
Source: Tella SH et al. Endo 2018.
Study: Natpara slightly boosts health-related QoL in hypoparathyroidism
A new industry-funded analysis suggests that recombinant human parathyroid hormone, an extraordinarily expensive treatment for hypoparathyroidism, produces slight improvement in some health-related quality of life (HRQoL) domains.
While researchers didn’t find any statistically significant between-group differences vs. a placebo, the study lead author said the positive findings about within-group differences reflect her experiences with some patients. “They’re telling me they feel much better, and they don’t have emergency room visits,” endocrinologist Tamara J. Vokes, MD, of the University of Chicago, said in an interview.
And, she said, as reflected in the findings, she’s seen that those with the lowest HRQoL levels at baseline especially show signs of improvement.
The treatment, known as rhPTH(1-84) or Natpara, was approved by the Food and Drug Administration as a treatment for hypoparathyroidism in 2015. The FDA stated that the drug “is only for people who do not respond well to treatment with calcium and active forms of vitamin D alone, because it may increase the possible risk of bone cancer, known as osteosarcoma.”
Pharmacies list the drug as costing $9,500-$9,900 per month with a coupon or discount. According to the new study, research has shown that quality of life is often impaired in patients who have tried the traditional hypoparathyroidism treatments of calcium supplements and vitamin D. Dr. Vokes and her colleagues aimed to expand upon previous studies of HRQoL that did not reach conclusions or failed to include controls.
They examined findings of a previous multinational, randomized, placebo-controlled study of 122 adults with hypoparathyroidism. Average age was 48 years, and roughly 80% of the patients were women.
After their serum calcium levels were adjusted through medication, the patients were randomly assigned to placebo (n = 39) or rhPTH(1-84) (n = 83, starting dose of 50 mg/d that could be raised to 100 mg/d).
The study, which appears in the Journal of Clinical Endocrinology and Metabolism, analyzes the changes in HRQoL from baseline to 24 weeks per the 36-Item Short-Form Health Survey (SF-36).
The researchers found no significant between-group differences. However, those who took the drug did see statistically significant improvements in 4 of 10 domains: physical component summary score (P = .004), body pain (P = .05), general health (P = .05), and vitality (P less than .001). The changes were small, with the vitality score improving the most, from a mean SF-36 score of 49.5 to 53.
In some cases, she said, she’s seen QoL improve in patients whom she normally wouldn’t consider candidates for the medication. “I would have not have recommended PTH for them, but they insisted on taking it, and they report feeling better.”
This may be a placebo effect, she said. Even so, “if someone doesn’t feel well, it’s worth it at least to try to use PTH and see whether they improve.”
She added that lack of well-being is a preexisting condition for some hypoparathyroidism patients. “I’ve seen quite a number of them who have what we call premorbid personality disorder. They didn’t feel well and weren’t happy, and when you get hypoparathyroidism, you’re more unwell and unhappy.”
With medication, however, “you’re a bit less unhappy but you’re still miserable,” she said.
Carol Greenlee, MD, an endocrinologist in Grand Junction, Colo., said in an interview that she saw a patient in a clinical study who had experienced a marked improvement in QoL. However, she said, “it will be the cost of the PTH that is the burden.”
For her part, Dr. Vokes cautioned that it’s important to take special care with patients taking Natpara. “You can’t just give this injection and say, ‘Goodbye, you will be better.’ It requires following certain protocol, frequent monitoring of the blood levels. Be sure the patient has access to the lab, and insurance that covers the test.”
Dr. Greenlee reported no relevant disclosures. The study was funded by Shire Human Genetic Therapies, and the initial clinical trial was funded by NPS Pharmaceuticals, a wholly owned indirect subsidiary. Dr. Vokes reported consulting for Shire and serving as an investigator for the initial clinical trial. Other study authors reported serving as clinical investigators and/or consulting for Shire, and three authors are employees of Shire.
SOURCE: Vokes, TJ et al. J Clin Endocrinol Metab. 2018 Feb 1;103(2):722-31
A new industry-funded analysis suggests that recombinant human parathyroid hormone, an extraordinarily expensive treatment for hypoparathyroidism, produces slight improvement in some health-related quality of life (HRQoL) domains.
While researchers didn’t find any statistically significant between-group differences vs. a placebo, the study lead author said the positive findings about within-group differences reflect her experiences with some patients. “They’re telling me they feel much better, and they don’t have emergency room visits,” endocrinologist Tamara J. Vokes, MD, of the University of Chicago, said in an interview.
And, she said, as reflected in the findings, she’s seen that those with the lowest HRQoL levels at baseline especially show signs of improvement.
The treatment, known as rhPTH(1-84) or Natpara, was approved by the Food and Drug Administration as a treatment for hypoparathyroidism in 2015. The FDA stated that the drug “is only for people who do not respond well to treatment with calcium and active forms of vitamin D alone, because it may increase the possible risk of bone cancer, known as osteosarcoma.”
Pharmacies list the drug as costing $9,500-$9,900 per month with a coupon or discount. According to the new study, research has shown that quality of life is often impaired in patients who have tried the traditional hypoparathyroidism treatments of calcium supplements and vitamin D. Dr. Vokes and her colleagues aimed to expand upon previous studies of HRQoL that did not reach conclusions or failed to include controls.
They examined findings of a previous multinational, randomized, placebo-controlled study of 122 adults with hypoparathyroidism. Average age was 48 years, and roughly 80% of the patients were women.
After their serum calcium levels were adjusted through medication, the patients were randomly assigned to placebo (n = 39) or rhPTH(1-84) (n = 83, starting dose of 50 mg/d that could be raised to 100 mg/d).
The study, which appears in the Journal of Clinical Endocrinology and Metabolism, analyzes the changes in HRQoL from baseline to 24 weeks per the 36-Item Short-Form Health Survey (SF-36).
The researchers found no significant between-group differences. However, those who took the drug did see statistically significant improvements in 4 of 10 domains: physical component summary score (P = .004), body pain (P = .05), general health (P = .05), and vitality (P less than .001). The changes were small, with the vitality score improving the most, from a mean SF-36 score of 49.5 to 53.
In some cases, she said, she’s seen QoL improve in patients whom she normally wouldn’t consider candidates for the medication. “I would have not have recommended PTH for them, but they insisted on taking it, and they report feeling better.”
This may be a placebo effect, she said. Even so, “if someone doesn’t feel well, it’s worth it at least to try to use PTH and see whether they improve.”
She added that lack of well-being is a preexisting condition for some hypoparathyroidism patients. “I’ve seen quite a number of them who have what we call premorbid personality disorder. They didn’t feel well and weren’t happy, and when you get hypoparathyroidism, you’re more unwell and unhappy.”
With medication, however, “you’re a bit less unhappy but you’re still miserable,” she said.
Carol Greenlee, MD, an endocrinologist in Grand Junction, Colo., said in an interview that she saw a patient in a clinical study who had experienced a marked improvement in QoL. However, she said, “it will be the cost of the PTH that is the burden.”
For her part, Dr. Vokes cautioned that it’s important to take special care with patients taking Natpara. “You can’t just give this injection and say, ‘Goodbye, you will be better.’ It requires following certain protocol, frequent monitoring of the blood levels. Be sure the patient has access to the lab, and insurance that covers the test.”
Dr. Greenlee reported no relevant disclosures. The study was funded by Shire Human Genetic Therapies, and the initial clinical trial was funded by NPS Pharmaceuticals, a wholly owned indirect subsidiary. Dr. Vokes reported consulting for Shire and serving as an investigator for the initial clinical trial. Other study authors reported serving as clinical investigators and/or consulting for Shire, and three authors are employees of Shire.
SOURCE: Vokes, TJ et al. J Clin Endocrinol Metab. 2018 Feb 1;103(2):722-31
A new industry-funded analysis suggests that recombinant human parathyroid hormone, an extraordinarily expensive treatment for hypoparathyroidism, produces slight improvement in some health-related quality of life (HRQoL) domains.
While researchers didn’t find any statistically significant between-group differences vs. a placebo, the study lead author said the positive findings about within-group differences reflect her experiences with some patients. “They’re telling me they feel much better, and they don’t have emergency room visits,” endocrinologist Tamara J. Vokes, MD, of the University of Chicago, said in an interview.
And, she said, as reflected in the findings, she’s seen that those with the lowest HRQoL levels at baseline especially show signs of improvement.
The treatment, known as rhPTH(1-84) or Natpara, was approved by the Food and Drug Administration as a treatment for hypoparathyroidism in 2015. The FDA stated that the drug “is only for people who do not respond well to treatment with calcium and active forms of vitamin D alone, because it may increase the possible risk of bone cancer, known as osteosarcoma.”
Pharmacies list the drug as costing $9,500-$9,900 per month with a coupon or discount. According to the new study, research has shown that quality of life is often impaired in patients who have tried the traditional hypoparathyroidism treatments of calcium supplements and vitamin D. Dr. Vokes and her colleagues aimed to expand upon previous studies of HRQoL that did not reach conclusions or failed to include controls.
They examined findings of a previous multinational, randomized, placebo-controlled study of 122 adults with hypoparathyroidism. Average age was 48 years, and roughly 80% of the patients were women.
After their serum calcium levels were adjusted through medication, the patients were randomly assigned to placebo (n = 39) or rhPTH(1-84) (n = 83, starting dose of 50 mg/d that could be raised to 100 mg/d).
The study, which appears in the Journal of Clinical Endocrinology and Metabolism, analyzes the changes in HRQoL from baseline to 24 weeks per the 36-Item Short-Form Health Survey (SF-36).
The researchers found no significant between-group differences. However, those who took the drug did see statistically significant improvements in 4 of 10 domains: physical component summary score (P = .004), body pain (P = .05), general health (P = .05), and vitality (P less than .001). The changes were small, with the vitality score improving the most, from a mean SF-36 score of 49.5 to 53.
In some cases, she said, she’s seen QoL improve in patients whom she normally wouldn’t consider candidates for the medication. “I would have not have recommended PTH for them, but they insisted on taking it, and they report feeling better.”
This may be a placebo effect, she said. Even so, “if someone doesn’t feel well, it’s worth it at least to try to use PTH and see whether they improve.”
She added that lack of well-being is a preexisting condition for some hypoparathyroidism patients. “I’ve seen quite a number of them who have what we call premorbid personality disorder. They didn’t feel well and weren’t happy, and when you get hypoparathyroidism, you’re more unwell and unhappy.”
With medication, however, “you’re a bit less unhappy but you’re still miserable,” she said.
Carol Greenlee, MD, an endocrinologist in Grand Junction, Colo., said in an interview that she saw a patient in a clinical study who had experienced a marked improvement in QoL. However, she said, “it will be the cost of the PTH that is the burden.”
For her part, Dr. Vokes cautioned that it’s important to take special care with patients taking Natpara. “You can’t just give this injection and say, ‘Goodbye, you will be better.’ It requires following certain protocol, frequent monitoring of the blood levels. Be sure the patient has access to the lab, and insurance that covers the test.”
Dr. Greenlee reported no relevant disclosures. The study was funded by Shire Human Genetic Therapies, and the initial clinical trial was funded by NPS Pharmaceuticals, a wholly owned indirect subsidiary. Dr. Vokes reported consulting for Shire and serving as an investigator for the initial clinical trial. Other study authors reported serving as clinical investigators and/or consulting for Shire, and three authors are employees of Shire.
SOURCE: Vokes, TJ et al. J Clin Endocrinol Metab. 2018 Feb 1;103(2):722-31
FROM THE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM
Key clinical point: Health-related quality of life (HRQoL) may improve slightly in patients on recombinant human parathyroid hormone for hypoparathyroidism.
Major finding: In 4 of 10 SF-36 domains, HRQoL improved in within-group analysis. There was no statistically significant improvement vs. placebo.
Study details: A 24-week analysis of previous drug vs. placebo clinical trial of 122 adults with hypoparathyroidism.
Disclosures: Shire Human Genetic Therapies funded the study, and the initial clinical trial was funded by NPS Pharmaceuticals, a wholly owned indirect subsidiary. The researchers reported various relationships to Shire, including employment.
Source: Vokes TJ et al. J Clin Endocrinol Metab. 2018 Feb 1;103(2):722-31.
PCOS may influence the diversity of the gut microbiome
according to a study from the Journal of Clinical Endocrinology and Metabolism.
“This study demonstrated that Caucasian women diagnosed with PCOS using the Rotterdam criteria had a reduction in overall species richness [alpha diversity] of the gut microbiome, compared to healthy women, and changes in the composition of the microbial community [beta diversity]” wrote Pedro J. Torres and his associates. “Interestingly, our study found that the biodiversity of the microbiome strongly correlated with hyperandrogenism.”
Dr. Torres of the University of California, San Diego, and his colleagues recruited 163 women at the University of Poznan (Poland) and conducted analysis on fecal samples to determine the effects of PCOS on the gut microbiome. Each woman underwent a battery of tests to determine whether she had PCOS or polycystic ovarian morphology (PCOM). Ovarian morphology was determined from a transvaginal ultrasound evaluation. The women were assessed for body mass index and hirsutism. Blood samples were taken to test for hormonal abnormalities common with PCOS and metabolic issues, like type 2 diabetes mellitus and glucose tolerance. Fecal samples were taken to analyze the gut microbiota of each study participant; analysis of the fecal samples generated gut microbial diversity profiles for each of the 163 women. Analysis of the samples was conducted at the University of California, San Diego.
Of the subjects, 48 were healthy, 42 had PCOM, and 73 were diagnosed with PCOS. The researches noted that, compared with healthy women and those with PCOM, women with PCOS had higher levels of serum total and free testosterone, as well as higher rates of hirsutism and fewer menses per year. These women also had higher levels of serum luteinizing hormone and increased ratios of luteinizing hormone to follicle stimulating hormone.
The DNA analysis of fecal samples yielded 481 sequence variants from the fecal swabs. Women with PCOS were found to have lower alpha diversity in their gut microbiome, as evidenced by abundance (P = .04) and Faith’s phylogenetic diveristy (P = .02). The luteinizing hormone to follicle stimulating hormone ratio also appeared to affect the alpha diversity of women with PCOS, as seen in observed sequence variants and Faith’s phylogenetic diversity (P = .08).
Beta diversity analysis, or the biodiversity between samples, revealed that hyperandrogenism could be a primary driver of changes in the gut microbiome. Using permutational multivariate analysis of variance, researchers determined that hyperandrogenism significantly affected beta diversity (P = .0009).
Androgens may help affect the gut microbiome in important ways, and changes in the gut microbiome may influence how the pathology of PCOS develops, according to Mr. Torres and his colleagues; however, more studies should be conducted to determine the effects of androgens on the gut microbiome.
“If hyperandrogenism drives the microbial composition of the gut, it would be interesting to determine if treatment of PCOS with androgen antagonists or oral contraceptives results in recovery of the gut microbiome and improvement of the PCOS metabolic phenotype” wrote Mr. Torres and his colleagues. “Moreover, it would be informative to determine whether the gut microbiome of women diagnosed with PCOS using the criteria of oligomenorrhea and polycystic ovaries is distinct from that of women diagnosed with the other subtypes of PCOS that include hyperandrogenism.”
The authors had no relevant financial disclosures to report.
SOURCE: Torres PJ et al. J Clin Endocrinol Metab. 2018 Jan 23. doi: 10.1210/jc.2017-02153.
Polycystic ovarian syndrome (PCOS) can manifest itself in many ways, but this study reveals that it can directly affect the metabolism of those who have the disorder.
“We’re still early days in studying this, but this study suggests that one of the clinical characteristics of these women with this disorder – their elevated testosterone – is correlated with changes in the gut microbiome,” Varykina G. Thackray, PhD, of the department of reproductive medicine and the center for reproductive science and medicine at the University of California, San Diego, said in an interview. “That means that these women are in a different group than other people with metabolic disorders, and it potentially gives us a way to think of new therapies that might be helpful for this specific group of women.”
When asked whether fecal transplants may be a potential therapy to help treat the metabolic issues associated with PCOS, Dr. Thackray stated that she did not believe a lot of women would use that as a therapy because of the “ick” factor. She stated the goal is to identify some beneficial bacteria that could be taken as a probiotic to help restore the gut microbiome.
Unfortunately, researchers still do not understand what causes PCOS. Some studies suggest that there are environmental and genetic factors, but there is nothing definitive. Dr. Thackray stated that getting more funding and conducting more research are the best ways to understand and combat this disorder.
Dr. Thackray is an associate professor of reproductive medicine at the University of California, San Diego.
Polycystic ovarian syndrome (PCOS) can manifest itself in many ways, but this study reveals that it can directly affect the metabolism of those who have the disorder.
“We’re still early days in studying this, but this study suggests that one of the clinical characteristics of these women with this disorder – their elevated testosterone – is correlated with changes in the gut microbiome,” Varykina G. Thackray, PhD, of the department of reproductive medicine and the center for reproductive science and medicine at the University of California, San Diego, said in an interview. “That means that these women are in a different group than other people with metabolic disorders, and it potentially gives us a way to think of new therapies that might be helpful for this specific group of women.”
When asked whether fecal transplants may be a potential therapy to help treat the metabolic issues associated with PCOS, Dr. Thackray stated that she did not believe a lot of women would use that as a therapy because of the “ick” factor. She stated the goal is to identify some beneficial bacteria that could be taken as a probiotic to help restore the gut microbiome.
Unfortunately, researchers still do not understand what causes PCOS. Some studies suggest that there are environmental and genetic factors, but there is nothing definitive. Dr. Thackray stated that getting more funding and conducting more research are the best ways to understand and combat this disorder.
Dr. Thackray is an associate professor of reproductive medicine at the University of California, San Diego.
Polycystic ovarian syndrome (PCOS) can manifest itself in many ways, but this study reveals that it can directly affect the metabolism of those who have the disorder.
“We’re still early days in studying this, but this study suggests that one of the clinical characteristics of these women with this disorder – their elevated testosterone – is correlated with changes in the gut microbiome,” Varykina G. Thackray, PhD, of the department of reproductive medicine and the center for reproductive science and medicine at the University of California, San Diego, said in an interview. “That means that these women are in a different group than other people with metabolic disorders, and it potentially gives us a way to think of new therapies that might be helpful for this specific group of women.”
When asked whether fecal transplants may be a potential therapy to help treat the metabolic issues associated with PCOS, Dr. Thackray stated that she did not believe a lot of women would use that as a therapy because of the “ick” factor. She stated the goal is to identify some beneficial bacteria that could be taken as a probiotic to help restore the gut microbiome.
Unfortunately, researchers still do not understand what causes PCOS. Some studies suggest that there are environmental and genetic factors, but there is nothing definitive. Dr. Thackray stated that getting more funding and conducting more research are the best ways to understand and combat this disorder.
Dr. Thackray is an associate professor of reproductive medicine at the University of California, San Diego.
according to a study from the Journal of Clinical Endocrinology and Metabolism.
“This study demonstrated that Caucasian women diagnosed with PCOS using the Rotterdam criteria had a reduction in overall species richness [alpha diversity] of the gut microbiome, compared to healthy women, and changes in the composition of the microbial community [beta diversity]” wrote Pedro J. Torres and his associates. “Interestingly, our study found that the biodiversity of the microbiome strongly correlated with hyperandrogenism.”
Dr. Torres of the University of California, San Diego, and his colleagues recruited 163 women at the University of Poznan (Poland) and conducted analysis on fecal samples to determine the effects of PCOS on the gut microbiome. Each woman underwent a battery of tests to determine whether she had PCOS or polycystic ovarian morphology (PCOM). Ovarian morphology was determined from a transvaginal ultrasound evaluation. The women were assessed for body mass index and hirsutism. Blood samples were taken to test for hormonal abnormalities common with PCOS and metabolic issues, like type 2 diabetes mellitus and glucose tolerance. Fecal samples were taken to analyze the gut microbiota of each study participant; analysis of the fecal samples generated gut microbial diversity profiles for each of the 163 women. Analysis of the samples was conducted at the University of California, San Diego.
Of the subjects, 48 were healthy, 42 had PCOM, and 73 were diagnosed with PCOS. The researches noted that, compared with healthy women and those with PCOM, women with PCOS had higher levels of serum total and free testosterone, as well as higher rates of hirsutism and fewer menses per year. These women also had higher levels of serum luteinizing hormone and increased ratios of luteinizing hormone to follicle stimulating hormone.
The DNA analysis of fecal samples yielded 481 sequence variants from the fecal swabs. Women with PCOS were found to have lower alpha diversity in their gut microbiome, as evidenced by abundance (P = .04) and Faith’s phylogenetic diveristy (P = .02). The luteinizing hormone to follicle stimulating hormone ratio also appeared to affect the alpha diversity of women with PCOS, as seen in observed sequence variants and Faith’s phylogenetic diversity (P = .08).
Beta diversity analysis, or the biodiversity between samples, revealed that hyperandrogenism could be a primary driver of changes in the gut microbiome. Using permutational multivariate analysis of variance, researchers determined that hyperandrogenism significantly affected beta diversity (P = .0009).
Androgens may help affect the gut microbiome in important ways, and changes in the gut microbiome may influence how the pathology of PCOS develops, according to Mr. Torres and his colleagues; however, more studies should be conducted to determine the effects of androgens on the gut microbiome.
“If hyperandrogenism drives the microbial composition of the gut, it would be interesting to determine if treatment of PCOS with androgen antagonists or oral contraceptives results in recovery of the gut microbiome and improvement of the PCOS metabolic phenotype” wrote Mr. Torres and his colleagues. “Moreover, it would be informative to determine whether the gut microbiome of women diagnosed with PCOS using the criteria of oligomenorrhea and polycystic ovaries is distinct from that of women diagnosed with the other subtypes of PCOS that include hyperandrogenism.”
The authors had no relevant financial disclosures to report.
SOURCE: Torres PJ et al. J Clin Endocrinol Metab. 2018 Jan 23. doi: 10.1210/jc.2017-02153.
according to a study from the Journal of Clinical Endocrinology and Metabolism.
“This study demonstrated that Caucasian women diagnosed with PCOS using the Rotterdam criteria had a reduction in overall species richness [alpha diversity] of the gut microbiome, compared to healthy women, and changes in the composition of the microbial community [beta diversity]” wrote Pedro J. Torres and his associates. “Interestingly, our study found that the biodiversity of the microbiome strongly correlated with hyperandrogenism.”
Dr. Torres of the University of California, San Diego, and his colleagues recruited 163 women at the University of Poznan (Poland) and conducted analysis on fecal samples to determine the effects of PCOS on the gut microbiome. Each woman underwent a battery of tests to determine whether she had PCOS or polycystic ovarian morphology (PCOM). Ovarian morphology was determined from a transvaginal ultrasound evaluation. The women were assessed for body mass index and hirsutism. Blood samples were taken to test for hormonal abnormalities common with PCOS and metabolic issues, like type 2 diabetes mellitus and glucose tolerance. Fecal samples were taken to analyze the gut microbiota of each study participant; analysis of the fecal samples generated gut microbial diversity profiles for each of the 163 women. Analysis of the samples was conducted at the University of California, San Diego.
Of the subjects, 48 were healthy, 42 had PCOM, and 73 were diagnosed with PCOS. The researches noted that, compared with healthy women and those with PCOM, women with PCOS had higher levels of serum total and free testosterone, as well as higher rates of hirsutism and fewer menses per year. These women also had higher levels of serum luteinizing hormone and increased ratios of luteinizing hormone to follicle stimulating hormone.
The DNA analysis of fecal samples yielded 481 sequence variants from the fecal swabs. Women with PCOS were found to have lower alpha diversity in their gut microbiome, as evidenced by abundance (P = .04) and Faith’s phylogenetic diveristy (P = .02). The luteinizing hormone to follicle stimulating hormone ratio also appeared to affect the alpha diversity of women with PCOS, as seen in observed sequence variants and Faith’s phylogenetic diversity (P = .08).
Beta diversity analysis, or the biodiversity between samples, revealed that hyperandrogenism could be a primary driver of changes in the gut microbiome. Using permutational multivariate analysis of variance, researchers determined that hyperandrogenism significantly affected beta diversity (P = .0009).
Androgens may help affect the gut microbiome in important ways, and changes in the gut microbiome may influence how the pathology of PCOS develops, according to Mr. Torres and his colleagues; however, more studies should be conducted to determine the effects of androgens on the gut microbiome.
“If hyperandrogenism drives the microbial composition of the gut, it would be interesting to determine if treatment of PCOS with androgen antagonists or oral contraceptives results in recovery of the gut microbiome and improvement of the PCOS metabolic phenotype” wrote Mr. Torres and his colleagues. “Moreover, it would be informative to determine whether the gut microbiome of women diagnosed with PCOS using the criteria of oligomenorrhea and polycystic ovaries is distinct from that of women diagnosed with the other subtypes of PCOS that include hyperandrogenism.”
The authors had no relevant financial disclosures to report.
SOURCE: Torres PJ et al. J Clin Endocrinol Metab. 2018 Jan 23. doi: 10.1210/jc.2017-02153.
FROM THE JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM
Key clinical point: Hyperandrogenism may have an effect on the gut microbiome of women with PCOS.
Major finding: Lower bacterial diversity was observed in women with PCOS, compared with healthy women
Study details: Researchers recruited 163 women diagnosed with PCOS. Blood and fecal samples were collected, and ovaries were imaged using ultrasound.
Disclosures: The authors had no relevant financial disclosures to report.
Source: Torres PJ et al. J Clin Endocrinol Metab. 2018 Jan 23. doi: 10.1210/jc.2017-02153.
Iodine deficiency linked to delay in pregnancy
Iodine deficiency could lead to significant delays in becoming pregnant, according to data from a prospective cohort study published online in Human Reproduction.
Researchers followed 501 couples that were discontinuing contraception to become pregnant, for 12 months, with the woman’s iodine levels measured at the time of enrollment.
This negative impact on fecundity remained even after researchers controlled for hypo/hyperthyroidism and adjusted for body mass index and cotinine as an indicator of smoking status.
“The significant delay in time to pregnancy in that group raises serious concerns given the high prevalence of iodine deficiency in women of childbearing age,” wrote James L. Mills, MD, of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, and his coauthors. Previous research has found that around one-third of American women of childbearing age have urinary iodine concentrations below 100 mcg/L, and iodine deficiency may be present in more than two-thirds of British schoolgirls.
“Although it seems incongruous that deficiency would be common in a population with high sodium intake, the likely explanation is that most sodium in the diet comes from processed food, and it appears that most salt in processed food is not iodized,” they wrote.
Women with iodine-creatinine ratios in the 50-99 mcg/g range – categorized as mildly deficient – had a smaller but nonsignificant increase in time to pregnancy, compared with women with ratios above 100 mcg/g.
Iodine deficiency is known to have effects on thyroid function, and hypothyroidism in particular is associated with infertility, the authors wrote.
“Low thyroid hormone concentrations are associated with thyrotropin-releasing hormone elevations that stimulate prolactin, which in turn interferes with GnRH pulsatility,” they wrote. “They also cause decreased granulosa cell steroid production and alterations in androgen and estrogen concentrations.”
The researchers selected couples that had recently stopped using contraception to rule out individuals with long-term fertility problems. They also used sensitive HCG pregnancy tests, and the women kept daily journals so that the time to pregnancy could be calculated accurately.
However, they did note that iodine levels were measured only at enrollment and may have varied over the course of the study. They also did not measure thyroid levels during the study.
The study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. No conflicts of interest were declared.
SOURCE: Mills JL et al. Hum Reprod. 2018 Jan 11. doi: 10.1093/humrep/dex379.
Iodine deficiency could lead to significant delays in becoming pregnant, according to data from a prospective cohort study published online in Human Reproduction.
Researchers followed 501 couples that were discontinuing contraception to become pregnant, for 12 months, with the woman’s iodine levels measured at the time of enrollment.
This negative impact on fecundity remained even after researchers controlled for hypo/hyperthyroidism and adjusted for body mass index and cotinine as an indicator of smoking status.
“The significant delay in time to pregnancy in that group raises serious concerns given the high prevalence of iodine deficiency in women of childbearing age,” wrote James L. Mills, MD, of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, and his coauthors. Previous research has found that around one-third of American women of childbearing age have urinary iodine concentrations below 100 mcg/L, and iodine deficiency may be present in more than two-thirds of British schoolgirls.
“Although it seems incongruous that deficiency would be common in a population with high sodium intake, the likely explanation is that most sodium in the diet comes from processed food, and it appears that most salt in processed food is not iodized,” they wrote.
Women with iodine-creatinine ratios in the 50-99 mcg/g range – categorized as mildly deficient – had a smaller but nonsignificant increase in time to pregnancy, compared with women with ratios above 100 mcg/g.
Iodine deficiency is known to have effects on thyroid function, and hypothyroidism in particular is associated with infertility, the authors wrote.
“Low thyroid hormone concentrations are associated with thyrotropin-releasing hormone elevations that stimulate prolactin, which in turn interferes with GnRH pulsatility,” they wrote. “They also cause decreased granulosa cell steroid production and alterations in androgen and estrogen concentrations.”
The researchers selected couples that had recently stopped using contraception to rule out individuals with long-term fertility problems. They also used sensitive HCG pregnancy tests, and the women kept daily journals so that the time to pregnancy could be calculated accurately.
However, they did note that iodine levels were measured only at enrollment and may have varied over the course of the study. They also did not measure thyroid levels during the study.
The study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. No conflicts of interest were declared.
SOURCE: Mills JL et al. Hum Reprod. 2018 Jan 11. doi: 10.1093/humrep/dex379.
Iodine deficiency could lead to significant delays in becoming pregnant, according to data from a prospective cohort study published online in Human Reproduction.
Researchers followed 501 couples that were discontinuing contraception to become pregnant, for 12 months, with the woman’s iodine levels measured at the time of enrollment.
This negative impact on fecundity remained even after researchers controlled for hypo/hyperthyroidism and adjusted for body mass index and cotinine as an indicator of smoking status.
“The significant delay in time to pregnancy in that group raises serious concerns given the high prevalence of iodine deficiency in women of childbearing age,” wrote James L. Mills, MD, of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, and his coauthors. Previous research has found that around one-third of American women of childbearing age have urinary iodine concentrations below 100 mcg/L, and iodine deficiency may be present in more than two-thirds of British schoolgirls.
“Although it seems incongruous that deficiency would be common in a population with high sodium intake, the likely explanation is that most sodium in the diet comes from processed food, and it appears that most salt in processed food is not iodized,” they wrote.
Women with iodine-creatinine ratios in the 50-99 mcg/g range – categorized as mildly deficient – had a smaller but nonsignificant increase in time to pregnancy, compared with women with ratios above 100 mcg/g.
Iodine deficiency is known to have effects on thyroid function, and hypothyroidism in particular is associated with infertility, the authors wrote.
“Low thyroid hormone concentrations are associated with thyrotropin-releasing hormone elevations that stimulate prolactin, which in turn interferes with GnRH pulsatility,” they wrote. “They also cause decreased granulosa cell steroid production and alterations in androgen and estrogen concentrations.”
The researchers selected couples that had recently stopped using contraception to rule out individuals with long-term fertility problems. They also used sensitive HCG pregnancy tests, and the women kept daily journals so that the time to pregnancy could be calculated accurately.
However, they did note that iodine levels were measured only at enrollment and may have varied over the course of the study. They also did not measure thyroid levels during the study.
The study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. No conflicts of interest were declared.
SOURCE: Mills JL et al. Hum Reprod. 2018 Jan 11. doi: 10.1093/humrep/dex379.
FROM HUMAN REPRODUCTION
Key clinical point: Women with moderate to severe iodine deficiency could experience significant delays in time to achieving pregnancy.
Major finding: Women with iodine levels in the moderate to severe range showed a 44% lower odds ratio of becoming pregnant in any one cycle, compared with women with levels in the normal range.
Data source: Population-based prospective cohort study in 501 couples.
Disclosures: The study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. No conflicts of interest were declared.
Source: Hum Reprod. 2018 Jan. doi: 10.1093/humrep/dex379.
New and improved classifiers may sharpen thyroid nodule diagnosis
VICTORIA, B.C. – Several new and improved molecular classifiers show good performance for preoperatively assessing the nature of thyroid nodules, including histologic subsets that continue to pose diagnostic challenges, according to a trio of studies reported at the annual meeting of the American Thyroid Association.
ThyroSeq v3 classifier
In a prospective, blinded, multi-institutional study, investigators validated the ThyroSeq v3 genomic classifier, which uses next-generation sequencing to test for mutations, fusions, gene expression alterations, and copy number variations in 112 genes.
The validation cohort consisted of 234 patients from 10 centers who had thyroid nodules with Bethesda III to V cytology and known surgical outcome, with central pathology review, and successful molecular testing. In total, they had 257 fine needle aspiration samples.
Of the 247 samples from nodules having Bethesda III or IV cytology – those of greatest interest – 28% were cancer or noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), reported senior author Yuri Nikiforov, MD, PhD, professor of pathology and director of the division of molecular & genomic pathology at the University of Pittsburgh Medical Center. “Both cancer and NIFTP are surgical diseases, so we felt they belong in one group,” he noted.
Among the Bethesda III or IV samples, ThyroSeq v3 had a sensitivity of 94%, a specificity of 82%, a positive predictive value of 66%, and a negative predictive value of 97%. Additional analyses showed that the test would still have a negative predictive value of 95% or better up to a cancer/NIFTP prevalence of 44%.
All five false-negative cases in the entire study cohort were intrathyroidal nodules of low stage and without aggressive histology.
Of the 33 false-positive cases, 68% were diagnosed on pathology as Hurthle cell or follicular adenomas, 10% were initially diagnosed by local pathologists as cancer or NIFTP, and 94% harbored clonal oncogenic molecular alterations.
“So, these are not actually hyperplasia; these are true tumors. Probably at least some of them would have the potential to progress,” said Dr. Nikiforov. “I believe that this so-called false-positive rate may not be really false positive. This is a rate of detection of precancerous tumors, not hyperplasia, that still may require surgical excision.”
In this study, “we found very high sensitivity and negative predictive value of ThyroSeq v3, with robust negative predictive value in populations with different disease prevalence,” he concluded. “Robust performance was achieved in many thyroid cancer types, including Hurthle cell cancer.”
All study patients underwent surgery, so it is not clear how the classifier would perform in the context of surveillance, he acknowledged. But the 97% negative predictive value gives confidence for patients having a negative result.
“Those patients very likely can be observed – not necessarily dismissed from medical surveillance, but observed – and could probably avoid surgery,” he said. “If patients have a positive test, it will depend on the type of mutation, because some of them confer a high risk and others confer low risk. So, there may be a spectrum of management based on combination of clinical parameters and molecular testing. But those are more likely to be surgical candidates.”
“This is a study that is desperately needed in this field,” session attendee Bryan McIver, MD, PhD, an endocrinologist and deputy physician-in-chief at the Moffitt Cancer Center in Tampa, said in an interview. “These are very challenging studies to do, because the marketing of these molecular tests has run ahead of a lot of the clinical studies. 
“It’s very hard in the United States, at least, to find patients who are truly naive to molecular testing whom you can take to the operating room,” he explained. “And if you can’t take patients with a negative molecular test to the operating room, then you can’t actually calculate the true sensitivity and specificity of the test, and the whole evaluation of the test starts to become skewed.”
According to Dr. McIver, this study is noteworthy in that it largely fulfills four key criteria: There were no post hoc sample exclusions after unblinding of data, both pathology evaluation and decision to operate were blinded to classifier results, and patients were generally unselected, with little to no prior molecular testing.
“So, we actually have a proper high-quality validation study now available for this new test, the ThyroSeq v3,” he noted. “That sets the bar where it needed to be set a long time ago, and I can’t begin to tell you how excited I am to finally have a test that passed that bar. The fact that it shows a negative predictive value of 97% in this clinical study and a positive predictive value in the mid-60% range means that there is a potential for a clinical utility there that is backed by solid science. In this field, that’s almost unique.”
Afirma GSC with Hurthle classifiers
In a second study, investigators led by Quan-Yang Duh, MD, professor of surgery, division of general surgery, and chief, section of endocrine surgery, University of California, San Francisco, developed and validated a pair of classifiers to enhance performance of the Afirma platform among Hurthle cell specimens.
“The Hurthle cell lesions tend to give us trouble,” Dr. Duh said. On molecular analysis, those that are malignant seldom harbor mutations that would aid diagnosis, whereas those that are benign are usually classified as suspicious by the original Afirma Gene Expression Classifier (GEC).
“The specific group that is causing trouble are those that are Hurthle cell but not neoplasm, because they are the ones that give you the false positives,” Dr. Duh said. Therefore, it makes sense to stratify lesions on both of these factors, and then subject that specific subset to a more stringent threshold. 
The investigators developed two classifiers that work with the Afirma core Genomic Sequencing Classifier (GSC), which uses RNA sequencing and machine learning algorithms.
The first classifier uses differential expression of 1,408 genes to determine whether a sample contains Hurthle cells. The second classifier, applied only to lesions containing Hurthle cells, uses differential expression of 2,041 genes and assesses loss of heterozygosity – which is prevalent in Hurthle cell neoplasms – to determine whether a Hurthle cell lesion is a neoplasm.
The ensemble model then makes a final classification, using a higher threshold for suspicious lesions determined to be Hurthle cell but not neoplasm, and a normal threshold for all the rest.
The investigators validated the Afirma GSC with the two classifiers in blinded fashion using 186 thyroid lesion samples having Bethesda III or IV cytology that had been part of the overall multicenter validation of the original Afirma GEC (N Engl J Med. 2012 Aug 23;367[8]:705-15).
Among the 26 Hurthle cell lesions, specificity for identifying benign lesions improved from 11.8% with the original Afirma GEC to 58.8% with the Afirma GSC and new classifiers. That was an absolute gain of 47% (P = .012), Dr. Duh reported. Sensitivity for identifying cancer was 88.9%.
There were also smaller absolute gains in specificity of 18% among all lesions in the cohort (P = .0028) and 14% among non-Hurthle lesions (P = .028).
“The new GSC test has significantly improved specificity in the patients with Bethesda III and IV specimens with Hurthle cells, and this may reduce unnecessary diagnostic surgery,” said Dr. Duh. “Basically, there are fewer false positives and more patients who can be called benign in the Hurthle cell group who would not need an operation.”
Further validation is needed, he acknowledged. “For a while, I wouldn’t send my Hurthle cell aspirate patients for Afirma, because I knew it was going to come back suspicious. I think I will start to do it now, but we need to see what the answers look like” with additional validation.
Afirma GSC with medullary thyroid cancer classifier
In a third study, investigators developed and validated a classifier for medullary thyroid cancer to be used with the Afirma GSC. They were led by Gregory Randolph, MD, professor of otolaryngology and the Claire and John Bertucci Endowed Chair in Thyroid Surgical Oncology at Harvard Medical School, and division chief of the general and thyroid/parathyroid endocrine surgical divisions at the Massachusetts Eye and Ear Infirmary, Boston.
Better preoperative identification of this cancer is key for several reasons, he maintained.
Establishing the diagnosis from needle biopsy is challenging, because some features overlap with those of other thyroid lesions, according to Dr. Randolph. In about a third of patients with medullary thyroid cancer brought to the operating room, the diagnosis is unknown at the time, and that often results in inadequate initial surgery.
The investigators developed a medullary thyroid cancer classifier cassette that assesses differential expression of 108 genes. They then performed blinded, independent validation in a cohort of 211 fine-needle aspiration samples from thyroid nodules: 21 medullary thyroid cancers and 190 other benign and malignant neoplasms.
Results showed that the Afirma GSC with the medullary thyroid cancer classifier had sensitivity of 100% and specificity of 100%, reported Dr. Randolph.
“The Afirma GSC medullary thyroid cancer testing cassette, within the larger GSC system, uses RNA sequencing and advanced machine learning to improve the diagnostic detection of medullary thyroid cancer, which currently misses approximately a third of medullary thyroid cancer patients,” he said.
Session attendees wondered which patients are appropriate candidates and how much the test will cost.
“We have to have a discussion about that, because the missed medullaries are, frankly, widely distributed – they can be in any of the Bethesda categories, basically,” Dr. Randolph said. “So, there are cytopathologic mistakes made uniformly, including in the suspicious and frankly malignant Bethesda categories. In terms of cost, this is embedded in the GSC classifier; so, if you order that test, you will obtain this medullary cassette.”
Actual sensitivity of the classifier may ultimately be less than 100% with use in larger samples, he acknowledged. “I think a greater number of validation tests is absolutely in order. I imagine this classifier may not be perfect, but it is way better than the third we miss with just cytopathology.”
Dr. Nikiforov disclosed that he is owner of an IP for ThyroSeq, and that his laboratory has a contract to offer the test commercially. Dr. Duh disclosed that he had no relevant conflicts of interest. Dr. Randolph disclosed that he had no relevant conflicts of interest.
VICTORIA, B.C. – Several new and improved molecular classifiers show good performance for preoperatively assessing the nature of thyroid nodules, including histologic subsets that continue to pose diagnostic challenges, according to a trio of studies reported at the annual meeting of the American Thyroid Association.
ThyroSeq v3 classifier
In a prospective, blinded, multi-institutional study, investigators validated the ThyroSeq v3 genomic classifier, which uses next-generation sequencing to test for mutations, fusions, gene expression alterations, and copy number variations in 112 genes.
The validation cohort consisted of 234 patients from 10 centers who had thyroid nodules with Bethesda III to V cytology and known surgical outcome, with central pathology review, and successful molecular testing. In total, they had 257 fine needle aspiration samples.
Of the 247 samples from nodules having Bethesda III or IV cytology – those of greatest interest – 28% were cancer or noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), reported senior author Yuri Nikiforov, MD, PhD, professor of pathology and director of the division of molecular & genomic pathology at the University of Pittsburgh Medical Center. “Both cancer and NIFTP are surgical diseases, so we felt they belong in one group,” he noted.
Among the Bethesda III or IV samples, ThyroSeq v3 had a sensitivity of 94%, a specificity of 82%, a positive predictive value of 66%, and a negative predictive value of 97%. Additional analyses showed that the test would still have a negative predictive value of 95% or better up to a cancer/NIFTP prevalence of 44%.
All five false-negative cases in the entire study cohort were intrathyroidal nodules of low stage and without aggressive histology.
Of the 33 false-positive cases, 68% were diagnosed on pathology as Hurthle cell or follicular adenomas, 10% were initially diagnosed by local pathologists as cancer or NIFTP, and 94% harbored clonal oncogenic molecular alterations.
“So, these are not actually hyperplasia; these are true tumors. Probably at least some of them would have the potential to progress,” said Dr. Nikiforov. “I believe that this so-called false-positive rate may not be really false positive. This is a rate of detection of precancerous tumors, not hyperplasia, that still may require surgical excision.”
In this study, “we found very high sensitivity and negative predictive value of ThyroSeq v3, with robust negative predictive value in populations with different disease prevalence,” he concluded. “Robust performance was achieved in many thyroid cancer types, including Hurthle cell cancer.”
All study patients underwent surgery, so it is not clear how the classifier would perform in the context of surveillance, he acknowledged. But the 97% negative predictive value gives confidence for patients having a negative result.
“Those patients very likely can be observed – not necessarily dismissed from medical surveillance, but observed – and could probably avoid surgery,” he said. “If patients have a positive test, it will depend on the type of mutation, because some of them confer a high risk and others confer low risk. So, there may be a spectrum of management based on combination of clinical parameters and molecular testing. But those are more likely to be surgical candidates.”
“This is a study that is desperately needed in this field,” session attendee Bryan McIver, MD, PhD, an endocrinologist and deputy physician-in-chief at the Moffitt Cancer Center in Tampa, said in an interview. “These are very challenging studies to do, because the marketing of these molecular tests has run ahead of a lot of the clinical studies.
“It’s very hard in the United States, at least, to find patients who are truly naive to molecular testing whom you can take to the operating room,” he explained. “And if you can’t take patients with a negative molecular test to the operating room, then you can’t actually calculate the true sensitivity and specificity of the test, and the whole evaluation of the test starts to become skewed.”
According to Dr. McIver, this study is noteworthy in that it largely fulfills four key criteria: There were no post hoc sample exclusions after unblinding of data, both pathology evaluation and decision to operate were blinded to classifier results, and patients were generally unselected, with little to no prior molecular testing.
“So, we actually have a proper high-quality validation study now available for this new test, the ThyroSeq v3,” he noted. “That sets the bar where it needed to be set a long time ago, and I can’t begin to tell you how excited I am to finally have a test that passed that bar. The fact that it shows a negative predictive value of 97% in this clinical study and a positive predictive value in the mid-60% range means that there is a potential for a clinical utility there that is backed by solid science. In this field, that’s almost unique.”
Afirma GSC with Hurthle classifiers
In a second study, investigators led by Quan-Yang Duh, MD, professor of surgery, division of general surgery, and chief, section of endocrine surgery, University of California, San Francisco, developed and validated a pair of classifiers to enhance performance of the Afirma platform among Hurthle cell specimens.
“The Hurthle cell lesions tend to give us trouble,” Dr. Duh said. On molecular analysis, those that are malignant seldom harbor mutations that would aid diagnosis, whereas those that are benign are usually classified as suspicious by the original Afirma Gene Expression Classifier (GEC).
“The specific group that is causing trouble are those that are Hurthle cell but not neoplasm, because they are the ones that give you the false positives,” Dr. Duh said. Therefore, it makes sense to stratify lesions on both of these factors, and then subject that specific subset to a more stringent threshold.
The investigators developed two classifiers that work with the Afirma core Genomic Sequencing Classifier (GSC), which uses RNA sequencing and machine learning algorithms.
The first classifier uses differential expression of 1,408 genes to determine whether a sample contains Hurthle cells. The second classifier, applied only to lesions containing Hurthle cells, uses differential expression of 2,041 genes and assesses loss of heterozygosity – which is prevalent in Hurthle cell neoplasms – to determine whether a Hurthle cell lesion is a neoplasm.
The ensemble model then makes a final classification, using a higher threshold for suspicious lesions determined to be Hurthle cell but not neoplasm, and a normal threshold for all the rest.
The investigators validated the Afirma GSC with the two classifiers in blinded fashion using 186 thyroid lesion samples having Bethesda III or IV cytology that had been part of the overall multicenter validation of the original Afirma GEC (N Engl J Med. 2012 Aug 23;367[8]:705-15).
Among the 26 Hurthle cell lesions, specificity for identifying benign lesions improved from 11.8% with the original Afirma GEC to 58.8% with the Afirma GSC and new classifiers. That was an absolute gain of 47% (P = .012), Dr. Duh reported. Sensitivity for identifying cancer was 88.9%.
There were also smaller absolute gains in specificity of 18% among all lesions in the cohort (P = .0028) and 14% among non-Hurthle lesions (P = .028).
“The new GSC test has significantly improved specificity in the patients with Bethesda III and IV specimens with Hurthle cells, and this may reduce unnecessary diagnostic surgery,” said Dr. Duh. “Basically, there are fewer false positives and more patients who can be called benign in the Hurthle cell group who would not need an operation.”
Further validation is needed, he acknowledged. “For a while, I wouldn’t send my Hurthle cell aspirate patients for Afirma, because I knew it was going to come back suspicious. I think I will start to do it now, but we need to see what the answers look like” with additional validation.
Afirma GSC with medullary thyroid cancer classifier
In a third study, investigators developed and validated a classifier for medullary thyroid cancer to be used with the Afirma GSC. They were led by Gregory Randolph, MD, professor of otolaryngology and the Claire and John Bertucci Endowed Chair in Thyroid Surgical Oncology at Harvard Medical School, and division chief of the general and thyroid/parathyroid endocrine surgical divisions at the Massachusetts Eye and Ear Infirmary, Boston.
Better preoperative identification of this cancer is key for several reasons, he maintained.
Establishing the diagnosis from needle biopsy is challenging, because some features overlap with those of other thyroid lesions, according to Dr. Randolph. In about a third of patients with medullary thyroid cancer brought to the operating room, the diagnosis is unknown at the time, and that often results in inadequate initial surgery.
The investigators developed a medullary thyroid cancer classifier cassette that assesses differential expression of 108 genes. They then performed blinded, independent validation in a cohort of 211 fine-needle aspiration samples from thyroid nodules: 21 medullary thyroid cancers and 190 other benign and malignant neoplasms.
Results showed that the Afirma GSC with the medullary thyroid cancer classifier had sensitivity of 100% and specificity of 100%, reported Dr. Randolph.
“The Afirma GSC medullary thyroid cancer testing cassette, within the larger GSC system, uses RNA sequencing and advanced machine learning to improve the diagnostic detection of medullary thyroid cancer, which currently misses approximately a third of medullary thyroid cancer patients,” he said.
Session attendees wondered which patients are appropriate candidates and how much the test will cost.
“We have to have a discussion about that, because the missed medullaries are, frankly, widely distributed – they can be in any of the Bethesda categories, basically,” Dr. Randolph said. “So, there are cytopathologic mistakes made uniformly, including in the suspicious and frankly malignant Bethesda categories. In terms of cost, this is embedded in the GSC classifier; so, if you order that test, you will obtain this medullary cassette.”
Actual sensitivity of the classifier may ultimately be less than 100% with use in larger samples, he acknowledged. “I think a greater number of validation tests is absolutely in order. I imagine this classifier may not be perfect, but it is way better than the third we miss with just cytopathology.”
Dr. Nikiforov disclosed that he is owner of an IP for ThyroSeq, and that his laboratory has a contract to offer the test commercially. Dr. Duh disclosed that he had no relevant conflicts of interest. Dr. Randolph disclosed that he had no relevant conflicts of interest.
VICTORIA, B.C. – Several new and improved molecular classifiers show good performance for preoperatively assessing the nature of thyroid nodules, including histologic subsets that continue to pose diagnostic challenges, according to a trio of studies reported at the annual meeting of the American Thyroid Association.
ThyroSeq v3 classifier
In a prospective, blinded, multi-institutional study, investigators validated the ThyroSeq v3 genomic classifier, which uses next-generation sequencing to test for mutations, fusions, gene expression alterations, and copy number variations in 112 genes.
The validation cohort consisted of 234 patients from 10 centers who had thyroid nodules with Bethesda III to V cytology and known surgical outcome, with central pathology review, and successful molecular testing. In total, they had 257 fine needle aspiration samples.
Of the 247 samples from nodules having Bethesda III or IV cytology – those of greatest interest – 28% were cancer or noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), reported senior author Yuri Nikiforov, MD, PhD, professor of pathology and director of the division of molecular & genomic pathology at the University of Pittsburgh Medical Center. “Both cancer and NIFTP are surgical diseases, so we felt they belong in one group,” he noted.
Among the Bethesda III or IV samples, ThyroSeq v3 had a sensitivity of 94%, a specificity of 82%, a positive predictive value of 66%, and a negative predictive value of 97%. Additional analyses showed that the test would still have a negative predictive value of 95% or better up to a cancer/NIFTP prevalence of 44%.
All five false-negative cases in the entire study cohort were intrathyroidal nodules of low stage and without aggressive histology.
Of the 33 false-positive cases, 68% were diagnosed on pathology as Hurthle cell or follicular adenomas, 10% were initially diagnosed by local pathologists as cancer or NIFTP, and 94% harbored clonal oncogenic molecular alterations.
“So, these are not actually hyperplasia; these are true tumors. Probably at least some of them would have the potential to progress,” said Dr. Nikiforov. “I believe that this so-called false-positive rate may not be really false positive. This is a rate of detection of precancerous tumors, not hyperplasia, that still may require surgical excision.”
In this study, “we found very high sensitivity and negative predictive value of ThyroSeq v3, with robust negative predictive value in populations with different disease prevalence,” he concluded. “Robust performance was achieved in many thyroid cancer types, including Hurthle cell cancer.”
All study patients underwent surgery, so it is not clear how the classifier would perform in the context of surveillance, he acknowledged. But the 97% negative predictive value gives confidence for patients having a negative result.
“Those patients very likely can be observed – not necessarily dismissed from medical surveillance, but observed – and could probably avoid surgery,” he said. “If patients have a positive test, it will depend on the type of mutation, because some of them confer a high risk and others confer low risk. So, there may be a spectrum of management based on combination of clinical parameters and molecular testing. But those are more likely to be surgical candidates.”
“This is a study that is desperately needed in this field,” session attendee Bryan McIver, MD, PhD, an endocrinologist and deputy physician-in-chief at the Moffitt Cancer Center in Tampa, said in an interview. “These are very challenging studies to do, because the marketing of these molecular tests has run ahead of a lot of the clinical studies.
“It’s very hard in the United States, at least, to find patients who are truly naive to molecular testing whom you can take to the operating room,” he explained. “And if you can’t take patients with a negative molecular test to the operating room, then you can’t actually calculate the true sensitivity and specificity of the test, and the whole evaluation of the test starts to become skewed.”
According to Dr. McIver, this study is noteworthy in that it largely fulfills four key criteria: There were no post hoc sample exclusions after unblinding of data, both pathology evaluation and decision to operate were blinded to classifier results, and patients were generally unselected, with little to no prior molecular testing.
“So, we actually have a proper high-quality validation study now available for this new test, the ThyroSeq v3,” he noted. “That sets the bar where it needed to be set a long time ago, and I can’t begin to tell you how excited I am to finally have a test that passed that bar. The fact that it shows a negative predictive value of 97% in this clinical study and a positive predictive value in the mid-60% range means that there is a potential for a clinical utility there that is backed by solid science. In this field, that’s almost unique.”
Afirma GSC with Hurthle classifiers
In a second study, investigators led by Quan-Yang Duh, MD, professor of surgery, division of general surgery, and chief, section of endocrine surgery, University of California, San Francisco, developed and validated a pair of classifiers to enhance performance of the Afirma platform among Hurthle cell specimens.
“The Hurthle cell lesions tend to give us trouble,” Dr. Duh said. On molecular analysis, those that are malignant seldom harbor mutations that would aid diagnosis, whereas those that are benign are usually classified as suspicious by the original Afirma Gene Expression Classifier (GEC).
“The specific group that is causing trouble are those that are Hurthle cell but not neoplasm, because they are the ones that give you the false positives,” Dr. Duh said. Therefore, it makes sense to stratify lesions on both of these factors, and then subject that specific subset to a more stringent threshold.
The investigators developed two classifiers that work with the Afirma core Genomic Sequencing Classifier (GSC), which uses RNA sequencing and machine learning algorithms.
The first classifier uses differential expression of 1,408 genes to determine whether a sample contains Hurthle cells. The second classifier, applied only to lesions containing Hurthle cells, uses differential expression of 2,041 genes and assesses loss of heterozygosity – which is prevalent in Hurthle cell neoplasms – to determine whether a Hurthle cell lesion is a neoplasm.
The ensemble model then makes a final classification, using a higher threshold for suspicious lesions determined to be Hurthle cell but not neoplasm, and a normal threshold for all the rest.
The investigators validated the Afirma GSC with the two classifiers in blinded fashion using 186 thyroid lesion samples having Bethesda III or IV cytology that had been part of the overall multicenter validation of the original Afirma GEC (N Engl J Med. 2012 Aug 23;367[8]:705-15).
Among the 26 Hurthle cell lesions, specificity for identifying benign lesions improved from 11.8% with the original Afirma GEC to 58.8% with the Afirma GSC and new classifiers. That was an absolute gain of 47% (P = .012), Dr. Duh reported. Sensitivity for identifying cancer was 88.9%.
There were also smaller absolute gains in specificity of 18% among all lesions in the cohort (P = .0028) and 14% among non-Hurthle lesions (P = .028).
“The new GSC test has significantly improved specificity in the patients with Bethesda III and IV specimens with Hurthle cells, and this may reduce unnecessary diagnostic surgery,” said Dr. Duh. “Basically, there are fewer false positives and more patients who can be called benign in the Hurthle cell group who would not need an operation.”
Further validation is needed, he acknowledged. “For a while, I wouldn’t send my Hurthle cell aspirate patients for Afirma, because I knew it was going to come back suspicious. I think I will start to do it now, but we need to see what the answers look like” with additional validation.
Afirma GSC with medullary thyroid cancer classifier
In a third study, investigators developed and validated a classifier for medullary thyroid cancer to be used with the Afirma GSC. They were led by Gregory Randolph, MD, professor of otolaryngology and the Claire and John Bertucci Endowed Chair in Thyroid Surgical Oncology at Harvard Medical School, and division chief of the general and thyroid/parathyroid endocrine surgical divisions at the Massachusetts Eye and Ear Infirmary, Boston.
Better preoperative identification of this cancer is key for several reasons, he maintained.
Establishing the diagnosis from needle biopsy is challenging, because some features overlap with those of other thyroid lesions, according to Dr. Randolph. In about a third of patients with medullary thyroid cancer brought to the operating room, the diagnosis is unknown at the time, and that often results in inadequate initial surgery.
The investigators developed a medullary thyroid cancer classifier cassette that assesses differential expression of 108 genes. They then performed blinded, independent validation in a cohort of 211 fine-needle aspiration samples from thyroid nodules: 21 medullary thyroid cancers and 190 other benign and malignant neoplasms.
Results showed that the Afirma GSC with the medullary thyroid cancer classifier had sensitivity of 100% and specificity of 100%, reported Dr. Randolph.
“The Afirma GSC medullary thyroid cancer testing cassette, within the larger GSC system, uses RNA sequencing and advanced machine learning to improve the diagnostic detection of medullary thyroid cancer, which currently misses approximately a third of medullary thyroid cancer patients,” he said.
Session attendees wondered which patients are appropriate candidates and how much the test will cost.
“We have to have a discussion about that, because the missed medullaries are, frankly, widely distributed – they can be in any of the Bethesda categories, basically,” Dr. Randolph said. “So, there are cytopathologic mistakes made uniformly, including in the suspicious and frankly malignant Bethesda categories. In terms of cost, this is embedded in the GSC classifier; so, if you order that test, you will obtain this medullary cassette.”
Actual sensitivity of the classifier may ultimately be less than 100% with use in larger samples, he acknowledged. “I think a greater number of validation tests is absolutely in order. I imagine this classifier may not be perfect, but it is way better than the third we miss with just cytopathology.”
Dr. Nikiforov disclosed that he is owner of an IP for ThyroSeq, and that his laboratory has a contract to offer the test commercially. Dr. Duh disclosed that he had no relevant conflicts of interest. Dr. Randolph disclosed that he had no relevant conflicts of interest.
AT ATA 2017
Key clinical point:
Major finding: ThyroSeq v3 had a negative predictive value of 97%. Specificity was an absolute 47% greater for Afirma GSC with Hurthle-specific classifiers than for Afirma GEC. The Afirma GSC with a medullary thyroid cancer classifier had 100% sensitivity and specificity.
Data source: Validation studies of the ThyroSeq v3 classifier (257 samples), the Afirma GSC with Hurthle-specific classifiers (186 samples), and the Afirma GSC with a medullary thyroid cancer classifier (211 samples).
Disclosures: Dr. Nikiforov disclosed that he is owner of an IP for ThyroSeq, and that his laboratory has a contract to offer the test commercially. Dr. Duh disclosed that he had no relevant conflicts of interest. Dr. Randolph disclosed that he had no relevant conflicts of interest.
Potential postthyroidectomy quality improvement metrics arise from study
of U.S. hospitals, suggesting to the authors that these measures could be used for quality improvement metrics.
In the study, published Nov. 29 in JAMA Surgery, hospitals with significantly lower rates of hypocalcemia were more likely to conduct postoperative parathyroid hormone level measurement as well as to prescribe vitamin D, calcium supplements, or both. Hospitals with lower RLN injury rates more frequently used energy devices and intraoperative nerve monitoring.
“Causation cannot be proven by this, but the confidence that these practice parameters are important is high,” senior author Bruce Hall, MD, PhD, vice president and chief quality officer at BJC Healthcare, and professor of surgery at Washington University, St. Louis, said in an interview. Dr. Hall is consulting director for the American College of Surgeon’s National Surgical Quality Improvement Program (NSQIP), which provided data for the analysis (JAMA Surg. 2017 Nov 29. doi: 10.1001/jamasurg.2017.4593).
The researchers examined data from 14,540 patients who underwent thyroidectomies at 98 hospitals between Jan. 1, 2013, and Dec. 31, 2015. These included 13,242 operations at 96 hospitals with complete hypocalcemia data, 13,144 operations at 95 hospitals with complete RLN data, and 13,197 operations at 95 hospitals with complete hematoma data. The primary outcome was the 30-day incidence of hypocalcemia, RLN, and hematoma. The researchers also measured 30-day mortality, surgical site infections, and hospital readmissions.
A total of 3.3% of patients experienced clinically severe hypocalcemia (0.6% after partial thyroidectomy, 4.7% after total or subtotal thyroidectomy). Another 5.7% experienced RLN (4.2% after partial, 6.6% after total or subtotal). Hematoma occurred in 1.3% of cases, but there were no significant variations in rates of hematoma across participating institutions.
For hypocalcemia and RLN injury, there were hospital outliers both on the low end of complication rates and on the high end of complication rates, defined by odds ratios with 95% confidence ratios that were greater than 1 for high outliers, or lower than 1 for low outliers. There were no outliers with respect to hematoma, suggesting that it may not be a useful barometer of hospital performance.
With respect to hypocalcemia rates, four hospitals were low outliers, and seven were high. Eight hospitals were low outliers with respect to RLN injury, and 14 were high outliers.
In the analysis of postoperative hypocalcemia, both low and high outliers measured postoperative calcium with similar frequency (68.4% vs. 71.0%; P =.09). However, high performance outliers were more likely to prescribe postoperative calcium, vitamin D, or both (76.6% vs. 66.8%; P less than .001).
Among RLN outliers, intraoperative nerve monitoring was more common in the top performing hospitals (55.7% vs. 37.7%; P less than .001), as was the use of energy devices (69.1% vs. 55.2%; P less than .001).
There was one high outlier when it came to surgical site infections, and one high and one low outlier with respect to morbidity outcomes. There were no hospital readmission outliers.
No source of funding was disclosed. Dr. Liu and Dr. Hall reported having no financial disclosures.
of U.S. hospitals, suggesting to the authors that these measures could be used for quality improvement metrics.
In the study, published Nov. 29 in JAMA Surgery, hospitals with significantly lower rates of hypocalcemia were more likely to conduct postoperative parathyroid hormone level measurement as well as to prescribe vitamin D, calcium supplements, or both. Hospitals with lower RLN injury rates more frequently used energy devices and intraoperative nerve monitoring.
“Causation cannot be proven by this, but the confidence that these practice parameters are important is high,” senior author Bruce Hall, MD, PhD, vice president and chief quality officer at BJC Healthcare, and professor of surgery at Washington University, St. Louis, said in an interview. Dr. Hall is consulting director for the American College of Surgeon’s National Surgical Quality Improvement Program (NSQIP), which provided data for the analysis (JAMA Surg. 2017 Nov 29. doi: 10.1001/jamasurg.2017.4593).
The researchers examined data from 14,540 patients who underwent thyroidectomies at 98 hospitals between Jan. 1, 2013, and Dec. 31, 2015. These included 13,242 operations at 96 hospitals with complete hypocalcemia data, 13,144 operations at 95 hospitals with complete RLN data, and 13,197 operations at 95 hospitals with complete hematoma data. The primary outcome was the 30-day incidence of hypocalcemia, RLN, and hematoma. The researchers also measured 30-day mortality, surgical site infections, and hospital readmissions.
A total of 3.3% of patients experienced clinically severe hypocalcemia (0.6% after partial thyroidectomy, 4.7% after total or subtotal thyroidectomy). Another 5.7% experienced RLN (4.2% after partial, 6.6% after total or subtotal). Hematoma occurred in 1.3% of cases, but there were no significant variations in rates of hematoma across participating institutions.
For hypocalcemia and RLN injury, there were hospital outliers both on the low end of complication rates and on the high end of complication rates, defined by odds ratios with 95% confidence ratios that were greater than 1 for high outliers, or lower than 1 for low outliers. There were no outliers with respect to hematoma, suggesting that it may not be a useful barometer of hospital performance.
With respect to hypocalcemia rates, four hospitals were low outliers, and seven were high. Eight hospitals were low outliers with respect to RLN injury, and 14 were high outliers.
In the analysis of postoperative hypocalcemia, both low and high outliers measured postoperative calcium with similar frequency (68.4% vs. 71.0%; P =.09). However, high performance outliers were more likely to prescribe postoperative calcium, vitamin D, or both (76.6% vs. 66.8%; P less than .001).
Among RLN outliers, intraoperative nerve monitoring was more common in the top performing hospitals (55.7% vs. 37.7%; P less than .001), as was the use of energy devices (69.1% vs. 55.2%; P less than .001).
There was one high outlier when it came to surgical site infections, and one high and one low outlier with respect to morbidity outcomes. There were no hospital readmission outliers.
No source of funding was disclosed. Dr. Liu and Dr. Hall reported having no financial disclosures.
of U.S. hospitals, suggesting to the authors that these measures could be used for quality improvement metrics.
In the study, published Nov. 29 in JAMA Surgery, hospitals with significantly lower rates of hypocalcemia were more likely to conduct postoperative parathyroid hormone level measurement as well as to prescribe vitamin D, calcium supplements, or both. Hospitals with lower RLN injury rates more frequently used energy devices and intraoperative nerve monitoring.
“Causation cannot be proven by this, but the confidence that these practice parameters are important is high,” senior author Bruce Hall, MD, PhD, vice president and chief quality officer at BJC Healthcare, and professor of surgery at Washington University, St. Louis, said in an interview. Dr. Hall is consulting director for the American College of Surgeon’s National Surgical Quality Improvement Program (NSQIP), which provided data for the analysis (JAMA Surg. 2017 Nov 29. doi: 10.1001/jamasurg.2017.4593).
The researchers examined data from 14,540 patients who underwent thyroidectomies at 98 hospitals between Jan. 1, 2013, and Dec. 31, 2015. These included 13,242 operations at 96 hospitals with complete hypocalcemia data, 13,144 operations at 95 hospitals with complete RLN data, and 13,197 operations at 95 hospitals with complete hematoma data. The primary outcome was the 30-day incidence of hypocalcemia, RLN, and hematoma. The researchers also measured 30-day mortality, surgical site infections, and hospital readmissions.
A total of 3.3% of patients experienced clinically severe hypocalcemia (0.6% after partial thyroidectomy, 4.7% after total or subtotal thyroidectomy). Another 5.7% experienced RLN (4.2% after partial, 6.6% after total or subtotal). Hematoma occurred in 1.3% of cases, but there were no significant variations in rates of hematoma across participating institutions.
For hypocalcemia and RLN injury, there were hospital outliers both on the low end of complication rates and on the high end of complication rates, defined by odds ratios with 95% confidence ratios that were greater than 1 for high outliers, or lower than 1 for low outliers. There were no outliers with respect to hematoma, suggesting that it may not be a useful barometer of hospital performance.
With respect to hypocalcemia rates, four hospitals were low outliers, and seven were high. Eight hospitals were low outliers with respect to RLN injury, and 14 were high outliers.
In the analysis of postoperative hypocalcemia, both low and high outliers measured postoperative calcium with similar frequency (68.4% vs. 71.0%; P =.09). However, high performance outliers were more likely to prescribe postoperative calcium, vitamin D, or both (76.6% vs. 66.8%; P less than .001).
Among RLN outliers, intraoperative nerve monitoring was more common in the top performing hospitals (55.7% vs. 37.7%; P less than .001), as was the use of energy devices (69.1% vs. 55.2%; P less than .001).
There was one high outlier when it came to surgical site infections, and one high and one low outlier with respect to morbidity outcomes. There were no hospital readmission outliers.
No source of funding was disclosed. Dr. Liu and Dr. Hall reported having no financial disclosures.
FROM JAMA SURGERY
Key clinical point: Prescription of postoperative calcium, vitamin D, or both, and greater use of intraoperative nerve monitoring may lead to fewer adverse events after thyroidectomy.
Major finding: Both low and high outliers on 30-day rates of postoperative hypocalcemia measured postoperative calcium with similar frequency (68.4% vs. 71.0%; P =.09). However, high performance outliers were more likely to prescribe postoperative calcium, vitamin D, or both (76.6% vs. 66.8%; P less than .001).
Data source: Retrospective analysis of 14,540 patients at 98 hospitals in the American College of Surgeon’s National Surgical Quality Improvement Program.
Disclosures: No source of funding was disclosed. Dr. Liu and Dr. Hall reported having no financial disclosures.
Cancer patients with TKI-induced hypothyroidism had better survival rates
VICTORIA, B.C. – When it comes to the adverse effects of tyrosine kinase inhibitors (TKIs), hypothyroidism appears to have a bright side, according to a retrospective cohort study among patients with nonthyroid cancers.
While taking one of these targeted agents, roughly a quarter of patients became overtly hypothyroid, an adverse effect that appears to be due in part to immune destruction. Risk was higher for women and earlier in therapy.
Relative to counterparts who remained euthyroid, overtly hypothyroid patients were 44% less likely to die after other factors were taken into account.
Hypothyroidism may reflect changes in immune activation, Dr. Angell proposed. “Additional studies may be helpful, both prospectively looking at the clinical importance of this finding [of survival benefit], and also potentially mechanistically, to understand the relationship between hypothyroidism and survival in these patients.”
“This is an innovative study that looked at an interesting clinical question,” observed session cochair Angela M. Leung, MD, of the University of California, Los Angeles, and an endocrinologist at both UCLA and the VA Greater Los Angeles Healthcare System.
Thyroid dysfunction is a well-known, common side effect of TKI therapy, Dr. Angell noted. “The possible mechanisms that have been suggested for this are direct toxicity on the thyroid gland, destructive thyroiditis, increased thyroid hormone clearance, and vascular endothelial growth factor (VEGF) inhibition, among others.”
Some previous research has suggested a possible survival benefit of TKI-induced hypothyroidism. But “there are limitations in our understanding of hypothyroidism in this setting, including the timing of onset, what risk factors there may be, and the effect of additional clinical variables on the survival effect seen,” Dr. Angell pointed out.
He and his coinvestigators studied 538 adult patients with nonthyroid cancers (mostly stage III or IV) who received a first TKI during 2000-2013 and were followed up through 2017. They excluded those who had preexisting thyroid disease or were on thyroid-related medications.
During TKI therapy, 26.7% of patients developed overt hypothyroidism, and another 13.2% developed subclinical hypothyroidism.
“For a given drug, patients were less likely to develop hypothyroidism when they were given it subsequent to another TKI, as opposed to it being the initial TKI,” Dr. Angell reported. But median time to onset of hypothyroidism was about 2.5 months, regardless.
Cumulative months of all TKI exposure during cancer treatment were not significantly associated with development of hypothyroidism.
In a multivariate analysis, patients were significantly more likely to develop hypothyroidism if they were female (odds ratio, 1.99) and significantly less likely if they had a longer total time on treatment (OR, 0.98) or received a non-TKI VEGF inhibitor (OR, 0.43). Age, race, and cumulative TKI exposure did not influence the outcome.
In a second multivariate analysis, patients’ risk of death was significantly lower if they developed overt hypothyroidism (hazard ratio, 0.56; P less than .0001), but not if they developed subclinical hypothyroidism (HR, 0.79; P = .1655).
Treatment of hypothyroidism did not appear to influence survival, according to Dr. Angell. However, “there wasn’t a specific decision on who was treated, how they were treated, [or] when they were treated,” he said. “So, it is difficult within this cohort to look specifically at which cutoff would be ideal” for initiating treatment.
Similarly, thyroid function testing was not standardized in this retrospectively identified cohort, so it was not possible to determine how long patients were hypothyroid and whether that had an impact, according to Dr. Angell.
Dr. Angell had no relevant conflicts of interest.
VICTORIA, B.C. – When it comes to the adverse effects of tyrosine kinase inhibitors (TKIs), hypothyroidism appears to have a bright side, according to a retrospective cohort study among patients with nonthyroid cancers.
While taking one of these targeted agents, roughly a quarter of patients became overtly hypothyroid, an adverse effect that appears to be due in part to immune destruction. Risk was higher for women and earlier in therapy.
Relative to counterparts who remained euthyroid, overtly hypothyroid patients were 44% less likely to die after other factors were taken into account.
Hypothyroidism may reflect changes in immune activation, Dr. Angell proposed. “Additional studies may be helpful, both prospectively looking at the clinical importance of this finding [of survival benefit], and also potentially mechanistically, to understand the relationship between hypothyroidism and survival in these patients.”
“This is an innovative study that looked at an interesting clinical question,” observed session cochair Angela M. Leung, MD, of the University of California, Los Angeles, and an endocrinologist at both UCLA and the VA Greater Los Angeles Healthcare System.
Thyroid dysfunction is a well-known, common side effect of TKI therapy, Dr. Angell noted. “The possible mechanisms that have been suggested for this are direct toxicity on the thyroid gland, destructive thyroiditis, increased thyroid hormone clearance, and vascular endothelial growth factor (VEGF) inhibition, among others.”
Some previous research has suggested a possible survival benefit of TKI-induced hypothyroidism. But “there are limitations in our understanding of hypothyroidism in this setting, including the timing of onset, what risk factors there may be, and the effect of additional clinical variables on the survival effect seen,” Dr. Angell pointed out.
He and his coinvestigators studied 538 adult patients with nonthyroid cancers (mostly stage III or IV) who received a first TKI during 2000-2013 and were followed up through 2017. They excluded those who had preexisting thyroid disease or were on thyroid-related medications.
During TKI therapy, 26.7% of patients developed overt hypothyroidism, and another 13.2% developed subclinical hypothyroidism.
“For a given drug, patients were less likely to develop hypothyroidism when they were given it subsequent to another TKI, as opposed to it being the initial TKI,” Dr. Angell reported. But median time to onset of hypothyroidism was about 2.5 months, regardless.
Cumulative months of all TKI exposure during cancer treatment were not significantly associated with development of hypothyroidism.
In a multivariate analysis, patients were significantly more likely to develop hypothyroidism if they were female (odds ratio, 1.99) and significantly less likely if they had a longer total time on treatment (OR, 0.98) or received a non-TKI VEGF inhibitor (OR, 0.43). Age, race, and cumulative TKI exposure did not influence the outcome.
In a second multivariate analysis, patients’ risk of death was significantly lower if they developed overt hypothyroidism (hazard ratio, 0.56; P less than .0001), but not if they developed subclinical hypothyroidism (HR, 0.79; P = .1655).
Treatment of hypothyroidism did not appear to influence survival, according to Dr. Angell. However, “there wasn’t a specific decision on who was treated, how they were treated, [or] when they were treated,” he said. “So, it is difficult within this cohort to look specifically at which cutoff would be ideal” for initiating treatment.
Similarly, thyroid function testing was not standardized in this retrospectively identified cohort, so it was not possible to determine how long patients were hypothyroid and whether that had an impact, according to Dr. Angell.
Dr. Angell had no relevant conflicts of interest.
VICTORIA, B.C. – When it comes to the adverse effects of tyrosine kinase inhibitors (TKIs), hypothyroidism appears to have a bright side, according to a retrospective cohort study among patients with nonthyroid cancers.
While taking one of these targeted agents, roughly a quarter of patients became overtly hypothyroid, an adverse effect that appears to be due in part to immune destruction. Risk was higher for women and earlier in therapy.
Relative to counterparts who remained euthyroid, overtly hypothyroid patients were 44% less likely to die after other factors were taken into account.
Hypothyroidism may reflect changes in immune activation, Dr. Angell proposed. “Additional studies may be helpful, both prospectively looking at the clinical importance of this finding [of survival benefit], and also potentially mechanistically, to understand the relationship between hypothyroidism and survival in these patients.”
“This is an innovative study that looked at an interesting clinical question,” observed session cochair Angela M. Leung, MD, of the University of California, Los Angeles, and an endocrinologist at both UCLA and the VA Greater Los Angeles Healthcare System.
Thyroid dysfunction is a well-known, common side effect of TKI therapy, Dr. Angell noted. “The possible mechanisms that have been suggested for this are direct toxicity on the thyroid gland, destructive thyroiditis, increased thyroid hormone clearance, and vascular endothelial growth factor (VEGF) inhibition, among others.”
Some previous research has suggested a possible survival benefit of TKI-induced hypothyroidism. But “there are limitations in our understanding of hypothyroidism in this setting, including the timing of onset, what risk factors there may be, and the effect of additional clinical variables on the survival effect seen,” Dr. Angell pointed out.
He and his coinvestigators studied 538 adult patients with nonthyroid cancers (mostly stage III or IV) who received a first TKI during 2000-2013 and were followed up through 2017. They excluded those who had preexisting thyroid disease or were on thyroid-related medications.
During TKI therapy, 26.7% of patients developed overt hypothyroidism, and another 13.2% developed subclinical hypothyroidism.
“For a given drug, patients were less likely to develop hypothyroidism when they were given it subsequent to another TKI, as opposed to it being the initial TKI,” Dr. Angell reported. But median time to onset of hypothyroidism was about 2.5 months, regardless.
Cumulative months of all TKI exposure during cancer treatment were not significantly associated with development of hypothyroidism.
In a multivariate analysis, patients were significantly more likely to develop hypothyroidism if they were female (odds ratio, 1.99) and significantly less likely if they had a longer total time on treatment (OR, 0.98) or received a non-TKI VEGF inhibitor (OR, 0.43). Age, race, and cumulative TKI exposure did not influence the outcome.
In a second multivariate analysis, patients’ risk of death was significantly lower if they developed overt hypothyroidism (hazard ratio, 0.56; P less than .0001), but not if they developed subclinical hypothyroidism (HR, 0.79; P = .1655).
Treatment of hypothyroidism did not appear to influence survival, according to Dr. Angell. However, “there wasn’t a specific decision on who was treated, how they were treated, [or] when they were treated,” he said. “So, it is difficult within this cohort to look specifically at which cutoff would be ideal” for initiating treatment.
Similarly, thyroid function testing was not standardized in this retrospectively identified cohort, so it was not possible to determine how long patients were hypothyroid and whether that had an impact, according to Dr. Angell.
Dr. Angell had no relevant conflicts of interest.
AT ATA 2017
Key clinical point:
Major finding: Relative to peers who remained euthyroid, patients who developed overt hypothyroidism had a reduced risk of death (HR, 0.56; P less than .0001).
Data source: A retrospective cohort study of 538 adult patients with mainly advanced nonthyroid cancers treated with a tyrosine kinase inhibitor.
Disclosures: Dr. Angell had no relevant conflicts of interest.
Most hyperparathyroidism cases can be considered cured after surgery
SCOTTSDALE, ARIZ. – Patients with hyperparathyroidism and single-gland disease can be considered cured if their intraoperative parathyroid hormone (PTH) level drops by 50% or more, or to normal or near-normal levels (15-65 pg/mL), and don’t require immediate follow-up for lab work, according to a retrospective review of patients who underwent parathyroidectomy at Mayo Clinic, Rochester, Minn.
These findings applied only to patients in the study whose preoperative sestamibi scans were concordant with intraoperative findings. Single-gland disease represented about 85% of cases, Melanie L. Lyden, MD, reported at the annual meeting of the Western Surgical Association.
Her team conducted a retrospective analysis of 214 patients who underwent parathyroidectomy at Mayo Clinic, Rochester, between January 2012 and March 2014. The investigators excluded patients with a history of multiple endocrine neoplasia syndrome, as well as patients with secondary or tertiary hyperparathyroidism. All patients received instructions at discharge for completing calcium testing, as well as a follow-up letter and phone call.
The overall cure rate at 6 months was 94% (202 cured, 12 not cured). In 205 of 214 cases (96%), the patients had an intraoperative drop in PTH level by 50% to normal or near-normal levels, and were therefore considered cured immediately.
The cured and not cured rate groups had no significant differences in age, gland weight, or preoperative PTH levels. Final intraoperative PTH levels were lower in patients who were cured (37 pg/mL vs. 55 pg/mL, P = .008), and the percentage decrease in PTH was greater (69% vs. 43%, P less than .0001).
A subgroup analysis found that concordant sestamibi imaging, single adenoma pathology, and an intraoperative cure combined to correlate with a 6-month cure rate of 97%.
In addition to identifying cures early, the findings suggest that patients whose PTH levels don’t drop adequately during surgery, and those with multiglandular disease should be aggressively targeted for follow-up – an important concern because many patients fail to complete calcium testing. “We were very aggressive in terms of follow-up recommendations, a follow-up letter, and a follow-up phone call, and still close to 30% of them we were not able to get to come in and get their blood checked,” said Dr. Lyden.
The study received no external funding. Dr. Lyden reported having no relevant financial disclosures.
SCOTTSDALE, ARIZ. – Patients with hyperparathyroidism and single-gland disease can be considered cured if their intraoperative parathyroid hormone (PTH) level drops by 50% or more, or to normal or near-normal levels (15-65 pg/mL), and don’t require immediate follow-up for lab work, according to a retrospective review of patients who underwent parathyroidectomy at Mayo Clinic, Rochester, Minn.
These findings applied only to patients in the study whose preoperative sestamibi scans were concordant with intraoperative findings. Single-gland disease represented about 85% of cases, Melanie L. Lyden, MD, reported at the annual meeting of the Western Surgical Association.
Her team conducted a retrospective analysis of 214 patients who underwent parathyroidectomy at Mayo Clinic, Rochester, between January 2012 and March 2014. The investigators excluded patients with a history of multiple endocrine neoplasia syndrome, as well as patients with secondary or tertiary hyperparathyroidism. All patients received instructions at discharge for completing calcium testing, as well as a follow-up letter and phone call.
The overall cure rate at 6 months was 94% (202 cured, 12 not cured). In 205 of 214 cases (96%), the patients had an intraoperative drop in PTH level by 50% to normal or near-normal levels, and were therefore considered cured immediately.
The cured and not cured rate groups had no significant differences in age, gland weight, or preoperative PTH levels. Final intraoperative PTH levels were lower in patients who were cured (37 pg/mL vs. 55 pg/mL, P = .008), and the percentage decrease in PTH was greater (69% vs. 43%, P less than .0001).
A subgroup analysis found that concordant sestamibi imaging, single adenoma pathology, and an intraoperative cure combined to correlate with a 6-month cure rate of 97%.
In addition to identifying cures early, the findings suggest that patients whose PTH levels don’t drop adequately during surgery, and those with multiglandular disease should be aggressively targeted for follow-up – an important concern because many patients fail to complete calcium testing. “We were very aggressive in terms of follow-up recommendations, a follow-up letter, and a follow-up phone call, and still close to 30% of them we were not able to get to come in and get their blood checked,” said Dr. Lyden.
The study received no external funding. Dr. Lyden reported having no relevant financial disclosures.
SCOTTSDALE, ARIZ. – Patients with hyperparathyroidism and single-gland disease can be considered cured if their intraoperative parathyroid hormone (PTH) level drops by 50% or more, or to normal or near-normal levels (15-65 pg/mL), and don’t require immediate follow-up for lab work, according to a retrospective review of patients who underwent parathyroidectomy at Mayo Clinic, Rochester, Minn.
These findings applied only to patients in the study whose preoperative sestamibi scans were concordant with intraoperative findings. Single-gland disease represented about 85% of cases, Melanie L. Lyden, MD, reported at the annual meeting of the Western Surgical Association.
Her team conducted a retrospective analysis of 214 patients who underwent parathyroidectomy at Mayo Clinic, Rochester, between January 2012 and March 2014. The investigators excluded patients with a history of multiple endocrine neoplasia syndrome, as well as patients with secondary or tertiary hyperparathyroidism. All patients received instructions at discharge for completing calcium testing, as well as a follow-up letter and phone call.
The overall cure rate at 6 months was 94% (202 cured, 12 not cured). In 205 of 214 cases (96%), the patients had an intraoperative drop in PTH level by 50% to normal or near-normal levels, and were therefore considered cured immediately.
The cured and not cured rate groups had no significant differences in age, gland weight, or preoperative PTH levels. Final intraoperative PTH levels were lower in patients who were cured (37 pg/mL vs. 55 pg/mL, P = .008), and the percentage decrease in PTH was greater (69% vs. 43%, P less than .0001).
A subgroup analysis found that concordant sestamibi imaging, single adenoma pathology, and an intraoperative cure combined to correlate with a 6-month cure rate of 97%.
In addition to identifying cures early, the findings suggest that patients whose PTH levels don’t drop adequately during surgery, and those with multiglandular disease should be aggressively targeted for follow-up – an important concern because many patients fail to complete calcium testing. “We were very aggressive in terms of follow-up recommendations, a follow-up letter, and a follow-up phone call, and still close to 30% of them we were not able to get to come in and get their blood checked,” said Dr. Lyden.
The study received no external funding. Dr. Lyden reported having no relevant financial disclosures.
AT WSA 2017
Key clinical point: The vast majority of cures could be identified during surgery, reducing the need for costly follow-up to monitor calcium levels.
Major finding: Concordant sestamibi imaging, single adenoma pathology, and an intraoperative cure combined to correlate with a 6-month cure rate of 97%.
Data source: A retrospective analysis of 214 patients at a single center.
Disclosures: The study received no external funding. Dr. Lyden reported having no relevant financial disclosures.
Pediatric thyroid nodules: Experienced radiologists best ultrasound risk stratification
VICTORIA, B.C. – Ultrasound risk criteria for adults are no match for the training, skill, and gut instinct of an experienced radiologist when evaluating pediatric thyroid nodules, results of a retrospective cohort study reported at the annual meeting of the American Thyroid Association suggest.
“In 2015, the ATA commissioned a pediatric task force that developed valuable guidelines specific to our pediatric patients. These guidelines recommend performing an FNA [fine-needle aspiration biopsy] in any nodule with a concerning clinical history or a concerning ultrasound feature,” commented first author Ana L. Creo, MD, a pediatric endocrinology fellow at the Mayo Clinic in Rochester, Minn.
She and her colleagues analyzed findings from diagnostic ultrasound in 112 patients aged under 21 years who had 145 thyroid nodules that were ultimately assessed histologically or cytologically.
Results showed that the radiologists’ overall impression and the ATA risk-stratification system for adults had the same high sensitivity, picking up 9 out of 10 malignant cases, she reported. But the radiologists’ overall impression had much higher specificity, correctly classifying 8 out of 10 benign cases, versus about 5 out of 10 for the risk stratification.
“These findings may have implications in trying to avoid unnecessary FNAs, particularly in our population,” Dr. Creo summarized. “Our million dollar question is trying to get in the heads of the radiologists to figure out what really goes into that overall impression. And if we can apply a specific score to that, I think that would be most clinically useful.”
“Based upon these results, further work is needed to determine the usefulness of the adult ATA ultrasound risk stratification in children, moving towards an ultrasound-based stratification system specific to our pediatric patients,” she concluded.
One session cochair, Catherine A. Dinauer, MD, a pediatric endocrinologist and clinician at the Yale Pediatric Thyroid Center, New Haven, Conn., commented, “It seems as though we’re pretty good at picking up which nodules are malignant, but I still feel like so many of the nodules that are benign are suspicious by ultrasound. Trying to tease out what is it about those benign ones may allow us to figure out in which ones we could avoid biopsy. That’s where we see we are not that good at it.”
Nodule attributes that might help in this regard include subtypes of microcalcifications, irregular margins, and position of the nodule in the gland relative to the skin, she proposed.
The other session cochair, Yaron Tomer, MD, chair of the department of medicine and the Anita and Jack Saltz Chair in Diabetes Research at the Montefiore Medical Center, New York, stressed knowing one’s radiologist and questioned the generalizability of the findings.
“You have to know your own radiologist well and how well you can trust them. Probably, the investigators chose some of the top radiologists in their institution and maybe even in the nation, so we have to be careful as to whether this applies to places that don’t have access to such great radiologists,” he commented. “But I think even if the guidelines are not perfect, they are the best we have right now.”
Study details
The investigators studied pediatric patients (mean age, 15.5 years) with thyroid nodules who underwent initial ultrasound at the Mayo Clinic during 1996-2015, had at least a year of follow-up, and for whom histology or cytology results were available. Those with a known genetic tumor syndrome or a history of radiation exposure were excluded.
Two blinded radiologists assessed nodule ultrasound features using the Thyroid Imaging and Reporting Data System (TIRADS) (J Am Coll Radiol. 2015;12[12 Pt A]:1272-9) and then rendered their overall impression: malignant, indeterminate, or benign.
Next, an independent reviewer assigned each nodule an ATA adult risk category (Thyroid. 2016;26:1-133): high, intermediate, low, or very low suspicion.
Finally, both measures were compared against the reference standard of the nodule’s histology or cytology results.
Ultimately, 34% of the patients had malignant nodules, Dr. Creo reported. “This is likely quite a bit elevated from the true prevalence due to our intentional study design requiring follow-up, likely excluding some patients with benign nodules,” she commented.
Patients with benign and malignant nodules did not differ significantly on any of a variety of sociodemographic and clinical factors, such as family history and mode of detection.
For comparison of sensitivity, the investigators combined the ATA risk categories of high and intermediate suspicion and combined the overall radiologists’ impression of malignant and indeterminate. “We felt this best answered the practical clinical question of how many malignant nodules would be missed if FNA was not performed, assuming FNA would typically be performed if the ATA risk stratification was high or intermediate or if the radiologist’s overall impression was malignant or indeterminate,” Dr. Creo explained.
Results here showed that the ATA risk stratification and the radiologists’ overall impression had the same high sensitivity of 90%.
For comparison of specificity, the investigators compared the ATA risk category of high suspicion with the radiologists’ overall impression of malignant.
Results showed that the overall impression had specificity of 80%, whereas the risk category had a specificity of only about 52%. Findings were similar when analyses instead used ATA high suspicion and intermediate suspicion combined.
“The key ultrasound characteristics that drove the diagnosis included having a solid component, calcifications, irregular margins, and hypoechogenicity – all similar to those seen in pediatric studies and similar to those in adult studies as well,” Dr. Creo noted.
Compared with benign nodules, malignant nodules significantly more often had a greater than 75% solid component (84% vs. 64%; P = .01), contained calcifications (60% vs. 18%; P less than .0001), had irregular margins (70% vs. 46%; P = .0073), and were hypoechogenic (74% vs. 51%; P = .0073). Notably, size and presence of halo did not differ significantly.
“Our study adds to previous work in that it had a relatively large pediatric sample size, used strict inclusion criteria with at least a year of follow-up to increase the validity of the diagnosis, and had precise definitions of the ultrasound features,” concluded Dr. Creo, who disclosed that she had no relevant conflicts of interest.
At the same time, the study had limitations, such as its use of a referral population, likely loss to follow-up of some patients with benign nodules, and possible clustering effect. “Lastly, we had the benefit of extremely experienced pediatric radiologists, and their overall diagnostic accuracy may not universally apply across all radiologists,” she said.
VICTORIA, B.C. – Ultrasound risk criteria for adults are no match for the training, skill, and gut instinct of an experienced radiologist when evaluating pediatric thyroid nodules, results of a retrospective cohort study reported at the annual meeting of the American Thyroid Association suggest.
“In 2015, the ATA commissioned a pediatric task force that developed valuable guidelines specific to our pediatric patients. These guidelines recommend performing an FNA [fine-needle aspiration biopsy] in any nodule with a concerning clinical history or a concerning ultrasound feature,” commented first author Ana L. Creo, MD, a pediatric endocrinology fellow at the Mayo Clinic in Rochester, Minn.
She and her colleagues analyzed findings from diagnostic ultrasound in 112 patients aged under 21 years who had 145 thyroid nodules that were ultimately assessed histologically or cytologically.
Results showed that the radiologists’ overall impression and the ATA risk-stratification system for adults had the same high sensitivity, picking up 9 out of 10 malignant cases, she reported. But the radiologists’ overall impression had much higher specificity, correctly classifying 8 out of 10 benign cases, versus about 5 out of 10 for the risk stratification.
“These findings may have implications in trying to avoid unnecessary FNAs, particularly in our population,” Dr. Creo summarized. “Our million dollar question is trying to get in the heads of the radiologists to figure out what really goes into that overall impression. And if we can apply a specific score to that, I think that would be most clinically useful.”
“Based upon these results, further work is needed to determine the usefulness of the adult ATA ultrasound risk stratification in children, moving towards an ultrasound-based stratification system specific to our pediatric patients,” she concluded.
One session cochair, Catherine A. Dinauer, MD, a pediatric endocrinologist and clinician at the Yale Pediatric Thyroid Center, New Haven, Conn., commented, “It seems as though we’re pretty good at picking up which nodules are malignant, but I still feel like so many of the nodules that are benign are suspicious by ultrasound. Trying to tease out what is it about those benign ones may allow us to figure out in which ones we could avoid biopsy. That’s where we see we are not that good at it.”
Nodule attributes that might help in this regard include subtypes of microcalcifications, irregular margins, and position of the nodule in the gland relative to the skin, she proposed.
The other session cochair, Yaron Tomer, MD, chair of the department of medicine and the Anita and Jack Saltz Chair in Diabetes Research at the Montefiore Medical Center, New York, stressed knowing one’s radiologist and questioned the generalizability of the findings.
“You have to know your own radiologist well and how well you can trust them. Probably, the investigators chose some of the top radiologists in their institution and maybe even in the nation, so we have to be careful as to whether this applies to places that don’t have access to such great radiologists,” he commented. “But I think even if the guidelines are not perfect, they are the best we have right now.”
Study details
The investigators studied pediatric patients (mean age, 15.5 years) with thyroid nodules who underwent initial ultrasound at the Mayo Clinic during 1996-2015, had at least a year of follow-up, and for whom histology or cytology results were available. Those with a known genetic tumor syndrome or a history of radiation exposure were excluded.
Two blinded radiologists assessed nodule ultrasound features using the Thyroid Imaging and Reporting Data System (TIRADS) (J Am Coll Radiol. 2015;12[12 Pt A]:1272-9) and then rendered their overall impression: malignant, indeterminate, or benign.
Next, an independent reviewer assigned each nodule an ATA adult risk category (Thyroid. 2016;26:1-133): high, intermediate, low, or very low suspicion.
Finally, both measures were compared against the reference standard of the nodule’s histology or cytology results.
Ultimately, 34% of the patients had malignant nodules, Dr. Creo reported. “This is likely quite a bit elevated from the true prevalence due to our intentional study design requiring follow-up, likely excluding some patients with benign nodules,” she commented.
Patients with benign and malignant nodules did not differ significantly on any of a variety of sociodemographic and clinical factors, such as family history and mode of detection.
For comparison of sensitivity, the investigators combined the ATA risk categories of high and intermediate suspicion and combined the overall radiologists’ impression of malignant and indeterminate. “We felt this best answered the practical clinical question of how many malignant nodules would be missed if FNA was not performed, assuming FNA would typically be performed if the ATA risk stratification was high or intermediate or if the radiologist’s overall impression was malignant or indeterminate,” Dr. Creo explained.
Results here showed that the ATA risk stratification and the radiologists’ overall impression had the same high sensitivity of 90%.
For comparison of specificity, the investigators compared the ATA risk category of high suspicion with the radiologists’ overall impression of malignant.
Results showed that the overall impression had specificity of 80%, whereas the risk category had a specificity of only about 52%. Findings were similar when analyses instead used ATA high suspicion and intermediate suspicion combined.
“The key ultrasound characteristics that drove the diagnosis included having a solid component, calcifications, irregular margins, and hypoechogenicity – all similar to those seen in pediatric studies and similar to those in adult studies as well,” Dr. Creo noted.
Compared with benign nodules, malignant nodules significantly more often had a greater than 75% solid component (84% vs. 64%; P = .01), contained calcifications (60% vs. 18%; P less than .0001), had irregular margins (70% vs. 46%; P = .0073), and were hypoechogenic (74% vs. 51%; P = .0073). Notably, size and presence of halo did not differ significantly.
“Our study adds to previous work in that it had a relatively large pediatric sample size, used strict inclusion criteria with at least a year of follow-up to increase the validity of the diagnosis, and had precise definitions of the ultrasound features,” concluded Dr. Creo, who disclosed that she had no relevant conflicts of interest.
At the same time, the study had limitations, such as its use of a referral population, likely loss to follow-up of some patients with benign nodules, and possible clustering effect. “Lastly, we had the benefit of extremely experienced pediatric radiologists, and their overall diagnostic accuracy may not universally apply across all radiologists,” she said.
VICTORIA, B.C. – Ultrasound risk criteria for adults are no match for the training, skill, and gut instinct of an experienced radiologist when evaluating pediatric thyroid nodules, results of a retrospective cohort study reported at the annual meeting of the American Thyroid Association suggest.
“In 2015, the ATA commissioned a pediatric task force that developed valuable guidelines specific to our pediatric patients. These guidelines recommend performing an FNA [fine-needle aspiration biopsy] in any nodule with a concerning clinical history or a concerning ultrasound feature,” commented first author Ana L. Creo, MD, a pediatric endocrinology fellow at the Mayo Clinic in Rochester, Minn.
She and her colleagues analyzed findings from diagnostic ultrasound in 112 patients aged under 21 years who had 145 thyroid nodules that were ultimately assessed histologically or cytologically.
Results showed that the radiologists’ overall impression and the ATA risk-stratification system for adults had the same high sensitivity, picking up 9 out of 10 malignant cases, she reported. But the radiologists’ overall impression had much higher specificity, correctly classifying 8 out of 10 benign cases, versus about 5 out of 10 for the risk stratification.
“These findings may have implications in trying to avoid unnecessary FNAs, particularly in our population,” Dr. Creo summarized. “Our million dollar question is trying to get in the heads of the radiologists to figure out what really goes into that overall impression. And if we can apply a specific score to that, I think that would be most clinically useful.”
“Based upon these results, further work is needed to determine the usefulness of the adult ATA ultrasound risk stratification in children, moving towards an ultrasound-based stratification system specific to our pediatric patients,” she concluded.
One session cochair, Catherine A. Dinauer, MD, a pediatric endocrinologist and clinician at the Yale Pediatric Thyroid Center, New Haven, Conn., commented, “It seems as though we’re pretty good at picking up which nodules are malignant, but I still feel like so many of the nodules that are benign are suspicious by ultrasound. Trying to tease out what is it about those benign ones may allow us to figure out in which ones we could avoid biopsy. That’s where we see we are not that good at it.”
Nodule attributes that might help in this regard include subtypes of microcalcifications, irregular margins, and position of the nodule in the gland relative to the skin, she proposed.
The other session cochair, Yaron Tomer, MD, chair of the department of medicine and the Anita and Jack Saltz Chair in Diabetes Research at the Montefiore Medical Center, New York, stressed knowing one’s radiologist and questioned the generalizability of the findings.
“You have to know your own radiologist well and how well you can trust them. Probably, the investigators chose some of the top radiologists in their institution and maybe even in the nation, so we have to be careful as to whether this applies to places that don’t have access to such great radiologists,” he commented. “But I think even if the guidelines are not perfect, they are the best we have right now.”
Study details
The investigators studied pediatric patients (mean age, 15.5 years) with thyroid nodules who underwent initial ultrasound at the Mayo Clinic during 1996-2015, had at least a year of follow-up, and for whom histology or cytology results were available. Those with a known genetic tumor syndrome or a history of radiation exposure were excluded.
Two blinded radiologists assessed nodule ultrasound features using the Thyroid Imaging and Reporting Data System (TIRADS) (J Am Coll Radiol. 2015;12[12 Pt A]:1272-9) and then rendered their overall impression: malignant, indeterminate, or benign.
Next, an independent reviewer assigned each nodule an ATA adult risk category (Thyroid. 2016;26:1-133): high, intermediate, low, or very low suspicion.
Finally, both measures were compared against the reference standard of the nodule’s histology or cytology results.
Ultimately, 34% of the patients had malignant nodules, Dr. Creo reported. “This is likely quite a bit elevated from the true prevalence due to our intentional study design requiring follow-up, likely excluding some patients with benign nodules,” she commented.
Patients with benign and malignant nodules did not differ significantly on any of a variety of sociodemographic and clinical factors, such as family history and mode of detection.
For comparison of sensitivity, the investigators combined the ATA risk categories of high and intermediate suspicion and combined the overall radiologists’ impression of malignant and indeterminate. “We felt this best answered the practical clinical question of how many malignant nodules would be missed if FNA was not performed, assuming FNA would typically be performed if the ATA risk stratification was high or intermediate or if the radiologist’s overall impression was malignant or indeterminate,” Dr. Creo explained.
Results here showed that the ATA risk stratification and the radiologists’ overall impression had the same high sensitivity of 90%.
For comparison of specificity, the investigators compared the ATA risk category of high suspicion with the radiologists’ overall impression of malignant.
Results showed that the overall impression had specificity of 80%, whereas the risk category had a specificity of only about 52%. Findings were similar when analyses instead used ATA high suspicion and intermediate suspicion combined.
“The key ultrasound characteristics that drove the diagnosis included having a solid component, calcifications, irregular margins, and hypoechogenicity – all similar to those seen in pediatric studies and similar to those in adult studies as well,” Dr. Creo noted.
Compared with benign nodules, malignant nodules significantly more often had a greater than 75% solid component (84% vs. 64%; P = .01), contained calcifications (60% vs. 18%; P less than .0001), had irregular margins (70% vs. 46%; P = .0073), and were hypoechogenic (74% vs. 51%; P = .0073). Notably, size and presence of halo did not differ significantly.
“Our study adds to previous work in that it had a relatively large pediatric sample size, used strict inclusion criteria with at least a year of follow-up to increase the validity of the diagnosis, and had precise definitions of the ultrasound features,” concluded Dr. Creo, who disclosed that she had no relevant conflicts of interest.
At the same time, the study had limitations, such as its use of a referral population, likely loss to follow-up of some patients with benign nodules, and possible clustering effect. “Lastly, we had the benefit of extremely experienced pediatric radiologists, and their overall diagnostic accuracy may not universally apply across all radiologists,” she said.
AT ATA 2017
Key clinical point:
Major finding: Radiologists’ overall impression and ATA risk stratification had the same good sensitivity (90% for each), but the former had higher specificity (80% vs. 52%).
Data source: A retrospective cohort study of 112 patients younger than 21 who had 145 thyroid nodules.
Disclosures: Dr. Creo disclosed that she had no relevant conflicts of interest.
Location matters when it comes to thyroidectomy rates
Thyroidectomy rates differ widely across the United States, according to a cross-sectional analysis of Medicare beneficiaries, but researchers aren’t sure what’s driving the variation.
There was a 6.2-fold difference in thyroidectomy rates across U.S. hospital referral regions in 2014, ranging from 22 to 139 per 100,000 Medicare beneficiaries. The national average was 60 procedures per 100,000 Medicare beneficiaries, David O. Francis, MD, of the University of Wisconsin, Madison, and his coauthors, reported (JAMA Otolaryngol Head Neck Surg. 2017 Oct 12. doi: 10.1001/jamaoto.2017.1746).
The researchers conducted a cross-sectional analysis of 15,888 Medicare beneficiaries aged 65 years and older who underwent a thyroidectomy in 2014. Of the thyroidectomies performed, 7,056 were partial and 8,382 were total thyroidectomies. They compared the frequency of partial and total thyroidectomies to total prostatectomy rates (high variation) and hospitalizations for hip fractures (low variation).
The stark variation in thyroidectomy outpaced those in hip fracture hospitalization (2.2-fold variation) and radical prostatectomy (5.6-fold variation) across U.S. hospital referral regions.
Higher rates of thyroidectomy were seen in Southern, Central, and certain urban regions of the United States.
But the variation in rates did not correlate with health care availability, socioeconomic status, or the availability of surgeons. This suggests that variation is caused by something other than disease burden. The researchers speculated that the “variability in thyroid surgery rates in areas with similar access to surgical services largely relates to local beliefs and practice patterns.”
The researchers also noted that the findings, which are based on Medicare data, may not be generalizable to young patients who account for more than half of all thyroidectomies performed in the United States.
The study was funded by the Department of Veterans Affairs and the Dartmouth Institute for Health Policy & Clinical Practice, with salary support from the National Institutes of Health. The researchers reported having no relevant conflicts of interest.
Thyroidectomy rates differ widely across the United States, according to a cross-sectional analysis of Medicare beneficiaries, but researchers aren’t sure what’s driving the variation.
There was a 6.2-fold difference in thyroidectomy rates across U.S. hospital referral regions in 2014, ranging from 22 to 139 per 100,000 Medicare beneficiaries. The national average was 60 procedures per 100,000 Medicare beneficiaries, David O. Francis, MD, of the University of Wisconsin, Madison, and his coauthors, reported (JAMA Otolaryngol Head Neck Surg. 2017 Oct 12. doi: 10.1001/jamaoto.2017.1746).
The researchers conducted a cross-sectional analysis of 15,888 Medicare beneficiaries aged 65 years and older who underwent a thyroidectomy in 2014. Of the thyroidectomies performed, 7,056 were partial and 8,382 were total thyroidectomies. They compared the frequency of partial and total thyroidectomies to total prostatectomy rates (high variation) and hospitalizations for hip fractures (low variation).
The stark variation in thyroidectomy outpaced those in hip fracture hospitalization (2.2-fold variation) and radical prostatectomy (5.6-fold variation) across U.S. hospital referral regions.
Higher rates of thyroidectomy were seen in Southern, Central, and certain urban regions of the United States.
But the variation in rates did not correlate with health care availability, socioeconomic status, or the availability of surgeons. This suggests that variation is caused by something other than disease burden. The researchers speculated that the “variability in thyroid surgery rates in areas with similar access to surgical services largely relates to local beliefs and practice patterns.”
The researchers also noted that the findings, which are based on Medicare data, may not be generalizable to young patients who account for more than half of all thyroidectomies performed in the United States.
The study was funded by the Department of Veterans Affairs and the Dartmouth Institute for Health Policy & Clinical Practice, with salary support from the National Institutes of Health. The researchers reported having no relevant conflicts of interest.
Thyroidectomy rates differ widely across the United States, according to a cross-sectional analysis of Medicare beneficiaries, but researchers aren’t sure what’s driving the variation.
There was a 6.2-fold difference in thyroidectomy rates across U.S. hospital referral regions in 2014, ranging from 22 to 139 per 100,000 Medicare beneficiaries. The national average was 60 procedures per 100,000 Medicare beneficiaries, David O. Francis, MD, of the University of Wisconsin, Madison, and his coauthors, reported (JAMA Otolaryngol Head Neck Surg. 2017 Oct 12. doi: 10.1001/jamaoto.2017.1746).
The researchers conducted a cross-sectional analysis of 15,888 Medicare beneficiaries aged 65 years and older who underwent a thyroidectomy in 2014. Of the thyroidectomies performed, 7,056 were partial and 8,382 were total thyroidectomies. They compared the frequency of partial and total thyroidectomies to total prostatectomy rates (high variation) and hospitalizations for hip fractures (low variation).
The stark variation in thyroidectomy outpaced those in hip fracture hospitalization (2.2-fold variation) and radical prostatectomy (5.6-fold variation) across U.S. hospital referral regions.
Higher rates of thyroidectomy were seen in Southern, Central, and certain urban regions of the United States.
But the variation in rates did not correlate with health care availability, socioeconomic status, or the availability of surgeons. This suggests that variation is caused by something other than disease burden. The researchers speculated that the “variability in thyroid surgery rates in areas with similar access to surgical services largely relates to local beliefs and practice patterns.”
The researchers also noted that the findings, which are based on Medicare data, may not be generalizable to young patients who account for more than half of all thyroidectomies performed in the United States.
The study was funded by the Department of Veterans Affairs and the Dartmouth Institute for Health Policy & Clinical Practice, with salary support from the National Institutes of Health. The researchers reported having no relevant conflicts of interest.
FROM JAMA OTOLARYNGOLOGY–HEAD & NECK SURGERY
Key clinical point:
Major finding: Thyroidectomy rates vary 6.2-fold across U.S. hospital referral regions.
Data source: A cross-sectional analysis of Medicare data for 15,888 patients in 2014.
Disclosures: This study was funded by the Department of Veterans Affairs and the Dartmouth Institute for Health Policy & Clinical Practice, with salary support from the National Institutes of Health. The researchers reported having no relevant conflicts of interest.