Will Pass

Aluminum ingested in small amounts causes visceral hypersensitivity in rats, suggesting that dietary levels of aluminum may trigger irritable bowel syndrome (IBS) in humans, according to a study published in Cellular and Molecular Gastroenterology and Hepatology.

Rats given oral aluminum exhibited dose-dependent visceral pain along with activation of proteinase-activated receptor-2 (PAR2) and mast cell degranulation, a combination of events that mirror clinical signs and molecular mechanisms of IBS in humans, reported lead author, Nicolas Esquerre, PhD, of Lille Inflammation Research International Center at Université Lille in France, and his colleagues. The study contributes to ongoing research surrounding causes and mechanisms of IBS, which may vary among patients because of disease subsets. These findings suggest that some patients with IBS may benefit from dietary aluminum restriction or chelation therapy.

“[T]he question of the initial trigger [of IBS] still remains unresolved,” the investigators wrote. “A more precise link between food and IBS has been demonstrated for gluten and other wheat proteins, lactose, and nickel, highlighting particular subsets of IBS patients now diagnosed as nonceliac gluten/wheat sensitivity, lactose intolerance, and nickel-allergic contact mucositis,” they added. “Here, we evaluated the effect of aluminum, a common contaminant of food and water, on abdominal pain.”

Aluminum may enter the diet as a food additive, or it may contaminate foods grown in aluminum-rich soil. Other sources of oral exposure include packaging and kitchenware. A previous study showed that most Americans ingest 0.01-1.4 mg/kg of aluminum daily, and 5% ingest 1.58 mg/kg daily (i.e., 95 mg per day for a 60-kg person).

Based on these statistics, rats in the present study received oral aluminum citrate (AlCi) corresponding with three doses of aluminum: 0.5 mg/kg, 1.5 mg/kg, or 3.0 mg/kg. Treatment continued for 30 days, with colorectal distension (CRD) measured on days 2, 4, 8, 15, and 30.

Results showed a dose-dependent relationship between aluminum ingestion and visceral hypersensitivity. Within 2 days, rats receiving 3.0 mg/kg of aluminum exhibited a significantly lower pain threshold, and within 8 days, rats receiving 0.5 mg/kg and 1.5 mg/kg also showed increased visceral hypersensitivity.

After 1 month of treatment, rats receiving 1.5 mg/kg per day demonstrated a 30% increase in pain compared with control animals. In the same group, visceral hypersensitivity began to wane 7 days after cessation of treatment; 4 more weeks were needed to return to baseline. When treatment was restarted, visceral hypersensitivity occurred within 2 days, compared with 8 days upon initial administration. These findings are particularly relevant to some people, as the 1.5-mg/kg dose corresponds with the daily amount of aluminum ingested by 5% of Americans. Similar patterns of response and sensitization were observed in rats ingesting 0.5 mg/kg and 3.0 mg/kg. Female rats were more sensitive to aluminum than were male rats, a sex pattern that mimics human IBS.

Further testing showed that rats treated with zinc citrate (ZnCi) did not exhibit changes to pain threshold, thereby excluding citrate as an aggravating factor. Rat models of noninflammatory and inflammatory colonic hypersensitivity (butyrate enema or intrathecal injection of 25%-50% ethanol in combination with 2,4,6-trinitrobenzenesulfonic acid, respectively) had visceral hypersensitivity similar to that of rats in the 1.5-mg/kg AlCi group.

Testing of colonic tissue from AlCi-treated rats did not reveal inflammatory changes according to a variety of qualifiers, including histology, myeloperoxidase activity, mRNA expression of several inflammatory cytokines, or infiltration of eosinophils or macrophages. Noninflammatory effects of aluminum, however, were found. For instance, treated rats had lower serotonin levels in enteroendocrine cells.

“Enteroendocrine cells are specialized epithelial cells that respond to luminal stimuli by releasing various biologically active compounds,” the investigators wrote. “They regulate several physiological and homeostatic functions of the gastrointestinal tract, such as postprandial secretion, motility, immune responses, and sensory functions. A reduced number of enteroendocrine cells has been observed in the duodenum, ileum, and colon of some patients with IBS.”

SOURCE: Esquerre N et al. Cell Mol Gastroenterol Hepatol. 2019 Sep 20. doi: 10.1016/j.jcmgh.2018.09.012.

Aluminum ingested in small amounts causes visceral hypersensitivity in rats, suggesting that dietary levels of aluminum may trigger irritable bowel syndrome (IBS) in humans, according to a study published in Cellular and Molecular Gastroenterology and Hepatology.

Rats given oral aluminum exhibited dose-dependent visceral pain along with activation of proteinase-activated receptor-2 (PAR2) and mast cell degranulation, a combination of events that mirror clinical signs and molecular mechanisms of IBS in humans, reported lead author, Nicolas Esquerre, PhD, of Lille Inflammation Research International Center at Université Lille in France, and his colleagues. The study contributes to ongoing research surrounding causes and mechanisms of IBS, which may vary among patients because of disease subsets. These findings suggest that some patients with IBS may benefit from dietary aluminum restriction or chelation therapy.

“[T]he question of the initial trigger [of IBS] still remains unresolved,” the investigators wrote. “A more precise link between food and IBS has been demonstrated for gluten and other wheat proteins, lactose, and nickel, highlighting particular subsets of IBS patients now diagnosed as nonceliac gluten/wheat sensitivity, lactose intolerance, and nickel-allergic contact mucositis,” they added. “Here, we evaluated the effect of aluminum, a common contaminant of food and water, on abdominal pain.”

Aluminum may enter the diet as a food additive, or it may contaminate foods grown in aluminum-rich soil. Other sources of oral exposure include packaging and kitchenware. A previous study showed that most Americans ingest 0.01-1.4 mg/kg of aluminum daily, and 5% ingest 1.58 mg/kg daily (i.e., 95 mg per day for a 60-kg person).

Based on these statistics, rats in the present study received oral aluminum citrate (AlCi) corresponding with three doses of aluminum: 0.5 mg/kg, 1.5 mg/kg, or 3.0 mg/kg. Treatment continued for 30 days, with colorectal distension (CRD) measured on days 2, 4, 8, 15, and 30.

Results showed a dose-dependent relationship between aluminum ingestion and visceral hypersensitivity. Within 2 days, rats receiving 3.0 mg/kg of aluminum exhibited a significantly lower pain threshold, and within 8 days, rats receiving 0.5 mg/kg and 1.5 mg/kg also showed increased visceral hypersensitivity.

After 1 month of treatment, rats receiving 1.5 mg/kg per day demonstrated a 30% increase in pain compared with control animals. In the same group, visceral hypersensitivity began to wane 7 days after cessation of treatment; 4 more weeks were needed to return to baseline. When treatment was restarted, visceral hypersensitivity occurred within 2 days, compared with 8 days upon initial administration. These findings are particularly relevant to some people, as the 1.5-mg/kg dose corresponds with the daily amount of aluminum ingested by 5% of Americans. Similar patterns of response and sensitization were observed in rats ingesting 0.5 mg/kg and 3.0 mg/kg. Female rats were more sensitive to aluminum than were male rats, a sex pattern that mimics human IBS.

Further testing showed that rats treated with zinc citrate (ZnCi) did not exhibit changes to pain threshold, thereby excluding citrate as an aggravating factor. Rat models of noninflammatory and inflammatory colonic hypersensitivity (butyrate enema or intrathecal injection of 25%-50% ethanol in combination with 2,4,6-trinitrobenzenesulfonic acid, respectively) had visceral hypersensitivity similar to that of rats in the 1.5-mg/kg AlCi group.

Testing of colonic tissue from AlCi-treated rats did not reveal inflammatory changes according to a variety of qualifiers, including histology, myeloperoxidase activity, mRNA expression of several inflammatory cytokines, or infiltration of eosinophils or macrophages. Noninflammatory effects of aluminum, however, were found. For instance, treated rats had lower serotonin levels in enteroendocrine cells.

“Enteroendocrine cells are specialized epithelial cells that respond to luminal stimuli by releasing various biologically active compounds,” the investigators wrote. “They regulate several physiological and homeostatic functions of the gastrointestinal tract, such as postprandial secretion, motility, immune responses, and sensory functions. A reduced number of enteroendocrine cells has been observed in the duodenum, ileum, and colon of some patients with IBS.”

SOURCE: Esquerre N et al. Cell Mol Gastroenterol Hepatol. 2019 Sep 20. doi: 10.1016/j.jcmgh.2018.09.012.

Aluminum ingested in small amounts causes visceral hypersensitivity in rats, suggesting that dietary levels of aluminum may trigger irritable bowel syndrome (IBS) in humans, according to a study published in Cellular and Molecular Gastroenterology and Hepatology.

Rats given oral aluminum exhibited dose-dependent visceral pain along with activation of proteinase-activated receptor-2 (PAR2) and mast cell degranulation, a combination of events that mirror clinical signs and molecular mechanisms of IBS in humans, reported lead author, Nicolas Esquerre, PhD, of Lille Inflammation Research International Center at Université Lille in France, and his colleagues. The study contributes to ongoing research surrounding causes and mechanisms of IBS, which may vary among patients because of disease subsets. These findings suggest that some patients with IBS may benefit from dietary aluminum restriction or chelation therapy.

“[T]he question of the initial trigger [of IBS] still remains unresolved,” the investigators wrote. “A more precise link between food and IBS has been demonstrated for gluten and other wheat proteins, lactose, and nickel, highlighting particular subsets of IBS patients now diagnosed as nonceliac gluten/wheat sensitivity, lactose intolerance, and nickel-allergic contact mucositis,” they added. “Here, we evaluated the effect of aluminum, a common contaminant of food and water, on abdominal pain.”

Aluminum may enter the diet as a food additive, or it may contaminate foods grown in aluminum-rich soil. Other sources of oral exposure include packaging and kitchenware. A previous study showed that most Americans ingest 0.01-1.4 mg/kg of aluminum daily, and 5% ingest 1.58 mg/kg daily (i.e., 95 mg per day for a 60-kg person).

Based on these statistics, rats in the present study received oral aluminum citrate (AlCi) corresponding with three doses of aluminum: 0.5 mg/kg, 1.5 mg/kg, or 3.0 mg/kg. Treatment continued for 30 days, with colorectal distension (CRD) measured on days 2, 4, 8, 15, and 30.

Results showed a dose-dependent relationship between aluminum ingestion and visceral hypersensitivity. Within 2 days, rats receiving 3.0 mg/kg of aluminum exhibited a significantly lower pain threshold, and within 8 days, rats receiving 0.5 mg/kg and 1.5 mg/kg also showed increased visceral hypersensitivity.

After 1 month of treatment, rats receiving 1.5 mg/kg per day demonstrated a 30% increase in pain compared with control animals. In the same group, visceral hypersensitivity began to wane 7 days after cessation of treatment; 4 more weeks were needed to return to baseline. When treatment was restarted, visceral hypersensitivity occurred within 2 days, compared with 8 days upon initial administration. These findings are particularly relevant to some people, as the 1.5-mg/kg dose corresponds with the daily amount of aluminum ingested by 5% of Americans. Similar patterns of response and sensitization were observed in rats ingesting 0.5 mg/kg and 3.0 mg/kg. Female rats were more sensitive to aluminum than were male rats, a sex pattern that mimics human IBS.

Further testing showed that rats treated with zinc citrate (ZnCi) did not exhibit changes to pain threshold, thereby excluding citrate as an aggravating factor. Rat models of noninflammatory and inflammatory colonic hypersensitivity (butyrate enema or intrathecal injection of 25%-50% ethanol in combination with 2,4,6-trinitrobenzenesulfonic acid, respectively) had visceral hypersensitivity similar to that of rats in the 1.5-mg/kg AlCi group.

Testing of colonic tissue from AlCi-treated rats did not reveal inflammatory changes according to a variety of qualifiers, including histology, myeloperoxidase activity, mRNA expression of several inflammatory cytokines, or infiltration of eosinophils or macrophages. Noninflammatory effects of aluminum, however, were found. For instance, treated rats had lower serotonin levels in enteroendocrine cells.

“Enteroendocrine cells are specialized epithelial cells that respond to luminal stimuli by releasing various biologically active compounds,” the investigators wrote. “They regulate several physiological and homeostatic functions of the gastrointestinal tract, such as postprandial secretion, motility, immune responses, and sensory functions. A reduced number of enteroendocrine cells has been observed in the duodenum, ileum, and colon of some patients with IBS.”

SOURCE: Esquerre N et al. Cell Mol Gastroenterol Hepatol. 2019 Sep 20. doi: 10.1016/j.jcmgh.2018.09.012.

Young women with HPV-16/-18 are significantly more likely to develop high-grade cervical intraepithelial neoplasia (CIN), compared with young women who do not have HPV-16/-18, and therefore require close monitoring, according to a 9-year study of more than 500 women.

Specific strain of HPV had less effect on risk in women aged 30 years or older, compared with younger women, reported lead author Maria Fröberg, MD, PhD, of Karolinska University Hospital and Institute in Stockholm and her colleagues.

“With today’s introduction of HPV primary screening into several organized screening programs and with many triage algorithms available, further research is needed to ensure safe follow-up management and prevent the unnecessary treatment of transient positive HPV findings associated with regressive high-grade CIN,” the investigators wrote in Cancer.

To better understand risk associated with HPV, the investigators drew from a database of 9,464 Swedish women who were cytologically negative for cervical intraepithelial lesions or malignancy (NILM) at baseline during 2005-2007. These baseline-negative women were followed for 9 years; during this time, 96 women developed histologically confirmed, high-grade CIN (CIN2, CIN3, cervical cancer, or adenocarcinoma in situ [AIS]). For each case, five age-matched women were selected who did not develop high-grade CIN to make a control cohort of 480 women.

Approximately half of the cases had CIN2 (45.8%), and half had CIN3 or worse histopathology (CIN3+, 54.2%). HPV-16/-18 was more often associated with CIN3+, compared with CIN2 (Pearson x2, 6.12; P less than .02 [2-sided]). Women with high-grade CIN were significantly more likely to have HPV of any strain, compared with controls (odds ratio, 6.78). Women aged younger than 30 years who had HPV-16/-18 at baseline were far more likely to develop high-grade CIN (OR, 9.44) but showed less impact from other strains of HPV (OR, 2.24). In contrast, women aged 30 years or older showed similar increases in high-grade CIN risk when comparing HPV-16/-18 with other strains (OR, 8.16 vs. 9.04).

“These latter findings suggest that genotyping for HPV-16/-18 might be useful for risk stratification among younger women,” the investigators suggested, noting that “further prospective study on this topic is warranted.”

The study was funded by the Swedish Cancer Foundation, the Stockholm County Council, the Swedish Research Council, and the King Gustaf V Jubilee Fund, and the Karolinska Institute. During the study, one investigator received grants from VALGENT and the 7th Framework Programme of DG Research and Innovation (European Commission).

SOURCE: Fröberg M et al. Cancer. 2018 Dec 10. doi: 10.1002/cncr.31788.

Young women with HPV-16/-18 are significantly more likely to develop high-grade cervical intraepithelial neoplasia (CIN), compared with young women who do not have HPV-16/-18, and therefore require close monitoring, according to a 9-year study of more than 500 women.

Specific strain of HPV had less effect on risk in women aged 30 years or older, compared with younger women, reported lead author Maria Fröberg, MD, PhD, of Karolinska University Hospital and Institute in Stockholm and her colleagues.

“With today’s introduction of HPV primary screening into several organized screening programs and with many triage algorithms available, further research is needed to ensure safe follow-up management and prevent the unnecessary treatment of transient positive HPV findings associated with regressive high-grade CIN,” the investigators wrote in Cancer.

To better understand risk associated with HPV, the investigators drew from a database of 9,464 Swedish women who were cytologically negative for cervical intraepithelial lesions or malignancy (NILM) at baseline during 2005-2007. These baseline-negative women were followed for 9 years; during this time, 96 women developed histologically confirmed, high-grade CIN (CIN2, CIN3, cervical cancer, or adenocarcinoma in situ [AIS]). For each case, five age-matched women were selected who did not develop high-grade CIN to make a control cohort of 480 women.

Approximately half of the cases had CIN2 (45.8%), and half had CIN3 or worse histopathology (CIN3+, 54.2%). HPV-16/-18 was more often associated with CIN3+, compared with CIN2 (Pearson x2, 6.12; P less than .02 [2-sided]). Women with high-grade CIN were significantly more likely to have HPV of any strain, compared with controls (odds ratio, 6.78). Women aged younger than 30 years who had HPV-16/-18 at baseline were far more likely to develop high-grade CIN (OR, 9.44) but showed less impact from other strains of HPV (OR, 2.24). In contrast, women aged 30 years or older showed similar increases in high-grade CIN risk when comparing HPV-16/-18 with other strains (OR, 8.16 vs. 9.04).

“These latter findings suggest that genotyping for HPV-16/-18 might be useful for risk stratification among younger women,” the investigators suggested, noting that “further prospective study on this topic is warranted.”

The study was funded by the Swedish Cancer Foundation, the Stockholm County Council, the Swedish Research Council, and the King Gustaf V Jubilee Fund, and the Karolinska Institute. During the study, one investigator received grants from VALGENT and the 7th Framework Programme of DG Research and Innovation (European Commission).

SOURCE: Fröberg M et al. Cancer. 2018 Dec 10. doi: 10.1002/cncr.31788.

Young women with HPV-16/-18 are significantly more likely to develop high-grade cervical intraepithelial neoplasia (CIN), compared with young women who do not have HPV-16/-18, and therefore require close monitoring, according to a 9-year study of more than 500 women.

Specific strain of HPV had less effect on risk in women aged 30 years or older, compared with younger women, reported lead author Maria Fröberg, MD, PhD, of Karolinska University Hospital and Institute in Stockholm and her colleagues.

“With today’s introduction of HPV primary screening into several organized screening programs and with many triage algorithms available, further research is needed to ensure safe follow-up management and prevent the unnecessary treatment of transient positive HPV findings associated with regressive high-grade CIN,” the investigators wrote in Cancer.

To better understand risk associated with HPV, the investigators drew from a database of 9,464 Swedish women who were cytologically negative for cervical intraepithelial lesions or malignancy (NILM) at baseline during 2005-2007. These baseline-negative women were followed for 9 years; during this time, 96 women developed histologically confirmed, high-grade CIN (CIN2, CIN3, cervical cancer, or adenocarcinoma in situ [AIS]). For each case, five age-matched women were selected who did not develop high-grade CIN to make a control cohort of 480 women.

Approximately half of the cases had CIN2 (45.8%), and half had CIN3 or worse histopathology (CIN3+, 54.2%). HPV-16/-18 was more often associated with CIN3+, compared with CIN2 (Pearson x2, 6.12; P less than .02 [2-sided]). Women with high-grade CIN were significantly more likely to have HPV of any strain, compared with controls (odds ratio, 6.78). Women aged younger than 30 years who had HPV-16/-18 at baseline were far more likely to develop high-grade CIN (OR, 9.44) but showed less impact from other strains of HPV (OR, 2.24). In contrast, women aged 30 years or older showed similar increases in high-grade CIN risk when comparing HPV-16/-18 with other strains (OR, 8.16 vs. 9.04).

“These latter findings suggest that genotyping for HPV-16/-18 might be useful for risk stratification among younger women,” the investigators suggested, noting that “further prospective study on this topic is warranted.”

The study was funded by the Swedish Cancer Foundation, the Stockholm County Council, the Swedish Research Council, and the King Gustaf V Jubilee Fund, and the Karolinska Institute. During the study, one investigator received grants from VALGENT and the 7th Framework Programme of DG Research and Innovation (European Commission).

SOURCE: Fröberg M et al. Cancer. 2018 Dec 10. doi: 10.1002/cncr.31788.

Serum biomarkers may enable a noninvasive method of detecting advanced hepatic fibrosis in patients with nonalcoholic fatty liver disease (NAFLD), according to results from a recent study.

Nephron/Wikimedia/Creative Commons License

An algorithm created by the investigators distinguished NAFLD patients with advanced liver fibrosis from those with mild to moderate fibrosis, reported lead author Rohit Loomba, MD, of the University of California at San Diego and his colleagues.

“Liver biopsy is currently the gold standard for diagnosing NASH [nonalcoholic steatohepatitis] and staging liver fibrosis,” the investigators wrote in Clinical Gastroenterology and Hepatology. “However, it is a costly and invasive procedure with an all-cause mortality risk of approximately 0.2%. Liver biopsy typically samples only 1/50,000th of the organ, and it is liable to sampling error with an error rate of 25% for diagnosis of hepatic fibrosis.”

Existing serum-based tests are reliable for diagnosing nonfibrotic NAFLD, but they may misdiagnosis patients with advanced fibrosis. Although imaging-based techniques may provide better diagnostic accuracy, some are available only for subgroups of patients, while others come with a high financial burden. Diagnostic shortcomings may have a major effect on patient outcomes, particularly when risk groups are considered.

“Fibrosis stages F3 and F4 (advanced fibrosis) are primary predictors of liver-related morbidity and mortality, with 11%-22% of NASH patients reported to have advanced fibrosis,” the investigators noted.

The investigators therefore aimed to distinguish such high-risk NAFLD patients from those with mild or moderate liver fibrosis. Three biomarkers were included: hyaluronic acid (HA), TIMP metallopeptidase inhibitor 1 (TIMP-1), and alpha₂-macroglobulin (A2M). Each biomarker has documented associations with liver fibrosis. For instance, higher A2M concentrations inhibit fibrinolysis, HA is associated with excessive extracellular matrix and fibrotic tissue, and TIMP-1 is a known liver fibrosis marker and inhibitor of extracellular matrix degradation. The relative strengths of each in detecting advanced liver fibrosis was determined through an algorithm.

The investigators relied on archived serum samples from Duke University, Durham, N.C., (n = 792) and University of California at San Diego (n = 244) that were collected within 11 days of liver biopsy. Biopsies were performed with 15- to 16-gauge needles using at least eight portal tracts, and these samples were used to diagnose NAFLD. Patients with alcoholic liver disease or hepatitis C virus were excluded.

Algorithm training was based on serum measurements from 396 patients treated at Duke University. Samples were divided into mild to moderate (F0-F2) or advanced (F3-F4) fibrosis and split into 10 subsets. The logical regression model was trained on nine subsets and tested on the 10th, with iterations 10 times through this sequence until all 10 samples were tested. This process was repeated 10,000 times. Using the median coefficients from 100,000 logistical regression models, the samples were scored using the algorithm from 0 to 100, with higher numbers representing more advanced fibrosis, and the relative weights of each biomarker measurement were determined.

A noninferiority protocol was used to validate the algorithm, through which the area under the receiver operating characteristic (AUROC) curve was calculated. The AUROC curve of the validation samples was 0.856, with 0.5 being the score for a random algorithm. The algorithm correctly classified 90.0% of F0 cases, 75.0% of F1 cases, 53.8% of F2 cases, 77.4% of F3 cases, and 94.4% of F4 cases. The sensitivity was 79.7% and the specificity was 75.7%.

The algorithm was superior to Fibrosis-4 (FIB-4) and NAFLD Fibrosis Score (NFS) in two validation cohorts. In a combination of validation cohorts, the algorithm correctly identified 79.5% of F3-F4 patients, compared with rates of 25.8% and 28.0% from FIB-4 and NFS, respectively. The investigators noted that the algorithm was unaffected by sex or age. In contrast, FIB-4 is biased toward females, and both FIB-4 and NFS are less accurate with patients aged 35 years or younger.

“Performance of the training and validation sets was robust and well matched, enabling the reliable differentiation of NAFLD patients with and without advanced fibrosis,” the investigators concluded.

The study was supported by Prometheus Laboratories. Authors not employed by Prometheus Laboratories were employed by Duke University or the University of California, San Diego; each institution received funding from Prometheus Laboratories.

SOURCE: Loomba R et al. Clin Gastroenterol Hepatol. 2018 Nov 15. doi: 10.1016/j.cgh.2018.11.004.

Serum biomarkers may enable a noninvasive method of detecting advanced hepatic fibrosis in patients with nonalcoholic fatty liver disease (NAFLD), according to results from a recent study.

Nephron/Wikimedia/Creative Commons License

An algorithm created by the investigators distinguished NAFLD patients with advanced liver fibrosis from those with mild to moderate fibrosis, reported lead author Rohit Loomba, MD, of the University of California at San Diego and his colleagues.

“Liver biopsy is currently the gold standard for diagnosing NASH [nonalcoholic steatohepatitis] and staging liver fibrosis,” the investigators wrote in Clinical Gastroenterology and Hepatology. “However, it is a costly and invasive procedure with an all-cause mortality risk of approximately 0.2%. Liver biopsy typically samples only 1/50,000th of the organ, and it is liable to sampling error with an error rate of 25% for diagnosis of hepatic fibrosis.”

Existing serum-based tests are reliable for diagnosing nonfibrotic NAFLD, but they may misdiagnosis patients with advanced fibrosis. Although imaging-based techniques may provide better diagnostic accuracy, some are available only for subgroups of patients, while others come with a high financial burden. Diagnostic shortcomings may have a major effect on patient outcomes, particularly when risk groups are considered.

“Fibrosis stages F3 and F4 (advanced fibrosis) are primary predictors of liver-related morbidity and mortality, with 11%-22% of NASH patients reported to have advanced fibrosis,” the investigators noted.

The investigators therefore aimed to distinguish such high-risk NAFLD patients from those with mild or moderate liver fibrosis. Three biomarkers were included: hyaluronic acid (HA), TIMP metallopeptidase inhibitor 1 (TIMP-1), and alpha₂-macroglobulin (A2M). Each biomarker has documented associations with liver fibrosis. For instance, higher A2M concentrations inhibit fibrinolysis, HA is associated with excessive extracellular matrix and fibrotic tissue, and TIMP-1 is a known liver fibrosis marker and inhibitor of extracellular matrix degradation. The relative strengths of each in detecting advanced liver fibrosis was determined through an algorithm.

The investigators relied on archived serum samples from Duke University, Durham, N.C., (n = 792) and University of California at San Diego (n = 244) that were collected within 11 days of liver biopsy. Biopsies were performed with 15- to 16-gauge needles using at least eight portal tracts, and these samples were used to diagnose NAFLD. Patients with alcoholic liver disease or hepatitis C virus were excluded.

Algorithm training was based on serum measurements from 396 patients treated at Duke University. Samples were divided into mild to moderate (F0-F2) or advanced (F3-F4) fibrosis and split into 10 subsets. The logical regression model was trained on nine subsets and tested on the 10th, with iterations 10 times through this sequence until all 10 samples were tested. This process was repeated 10,000 times. Using the median coefficients from 100,000 logistical regression models, the samples were scored using the algorithm from 0 to 100, with higher numbers representing more advanced fibrosis, and the relative weights of each biomarker measurement were determined.

A noninferiority protocol was used to validate the algorithm, through which the area under the receiver operating characteristic (AUROC) curve was calculated. The AUROC curve of the validation samples was 0.856, with 0.5 being the score for a random algorithm. The algorithm correctly classified 90.0% of F0 cases, 75.0% of F1 cases, 53.8% of F2 cases, 77.4% of F3 cases, and 94.4% of F4 cases. The sensitivity was 79.7% and the specificity was 75.7%.

The algorithm was superior to Fibrosis-4 (FIB-4) and NAFLD Fibrosis Score (NFS) in two validation cohorts. In a combination of validation cohorts, the algorithm correctly identified 79.5% of F3-F4 patients, compared with rates of 25.8% and 28.0% from FIB-4 and NFS, respectively. The investigators noted that the algorithm was unaffected by sex or age. In contrast, FIB-4 is biased toward females, and both FIB-4 and NFS are less accurate with patients aged 35 years or younger.

“Performance of the training and validation sets was robust and well matched, enabling the reliable differentiation of NAFLD patients with and without advanced fibrosis,” the investigators concluded.

The study was supported by Prometheus Laboratories. Authors not employed by Prometheus Laboratories were employed by Duke University or the University of California, San Diego; each institution received funding from Prometheus Laboratories.

SOURCE: Loomba R et al. Clin Gastroenterol Hepatol. 2018 Nov 15. doi: 10.1016/j.cgh.2018.11.004.

Serum biomarkers may enable a noninvasive method of detecting advanced hepatic fibrosis in patients with nonalcoholic fatty liver disease (NAFLD), according to results from a recent study.

Nephron/Wikimedia/Creative Commons License

An algorithm created by the investigators distinguished NAFLD patients with advanced liver fibrosis from those with mild to moderate fibrosis, reported lead author Rohit Loomba, MD, of the University of California at San Diego and his colleagues.

“Liver biopsy is currently the gold standard for diagnosing NASH [nonalcoholic steatohepatitis] and staging liver fibrosis,” the investigators wrote in Clinical Gastroenterology and Hepatology. “However, it is a costly and invasive procedure with an all-cause mortality risk of approximately 0.2%. Liver biopsy typically samples only 1/50,000th of the organ, and it is liable to sampling error with an error rate of 25% for diagnosis of hepatic fibrosis.”

Existing serum-based tests are reliable for diagnosing nonfibrotic NAFLD, but they may misdiagnosis patients with advanced fibrosis. Although imaging-based techniques may provide better diagnostic accuracy, some are available only for subgroups of patients, while others come with a high financial burden. Diagnostic shortcomings may have a major effect on patient outcomes, particularly when risk groups are considered.

“Fibrosis stages F3 and F4 (advanced fibrosis) are primary predictors of liver-related morbidity and mortality, with 11%-22% of NASH patients reported to have advanced fibrosis,” the investigators noted.

The investigators therefore aimed to distinguish such high-risk NAFLD patients from those with mild or moderate liver fibrosis. Three biomarkers were included: hyaluronic acid (HA), TIMP metallopeptidase inhibitor 1 (TIMP-1), and alpha₂-macroglobulin (A2M). Each biomarker has documented associations with liver fibrosis. For instance, higher A2M concentrations inhibit fibrinolysis, HA is associated with excessive extracellular matrix and fibrotic tissue, and TIMP-1 is a known liver fibrosis marker and inhibitor of extracellular matrix degradation. The relative strengths of each in detecting advanced liver fibrosis was determined through an algorithm.

The investigators relied on archived serum samples from Duke University, Durham, N.C., (n = 792) and University of California at San Diego (n = 244) that were collected within 11 days of liver biopsy. Biopsies were performed with 15- to 16-gauge needles using at least eight portal tracts, and these samples were used to diagnose NAFLD. Patients with alcoholic liver disease or hepatitis C virus were excluded.

Algorithm training was based on serum measurements from 396 patients treated at Duke University. Samples were divided into mild to moderate (F0-F2) or advanced (F3-F4) fibrosis and split into 10 subsets. The logical regression model was trained on nine subsets and tested on the 10th, with iterations 10 times through this sequence until all 10 samples were tested. This process was repeated 10,000 times. Using the median coefficients from 100,000 logistical regression models, the samples were scored using the algorithm from 0 to 100, with higher numbers representing more advanced fibrosis, and the relative weights of each biomarker measurement were determined.

A noninferiority protocol was used to validate the algorithm, through which the area under the receiver operating characteristic (AUROC) curve was calculated. The AUROC curve of the validation samples was 0.856, with 0.5 being the score for a random algorithm. The algorithm correctly classified 90.0% of F0 cases, 75.0% of F1 cases, 53.8% of F2 cases, 77.4% of F3 cases, and 94.4% of F4 cases. The sensitivity was 79.7% and the specificity was 75.7%.

The algorithm was superior to Fibrosis-4 (FIB-4) and NAFLD Fibrosis Score (NFS) in two validation cohorts. In a combination of validation cohorts, the algorithm correctly identified 79.5% of F3-F4 patients, compared with rates of 25.8% and 28.0% from FIB-4 and NFS, respectively. The investigators noted that the algorithm was unaffected by sex or age. In contrast, FIB-4 is biased toward females, and both FIB-4 and NFS are less accurate with patients aged 35 years or younger.

“Performance of the training and validation sets was robust and well matched, enabling the reliable differentiation of NAFLD patients with and without advanced fibrosis,” the investigators concluded.

The study was supported by Prometheus Laboratories. Authors not employed by Prometheus Laboratories were employed by Duke University or the University of California, San Diego; each institution received funding from Prometheus Laboratories.

SOURCE: Loomba R et al. Clin Gastroenterol Hepatol. 2018 Nov 15. doi: 10.1016/j.cgh.2018.11.004.

Single neurons in the human medial frontal cortex appear to be involved in the signaling of self-monitored errors, and this activity can be tracked through a scalp EEG pattern called error-related negativity, according to findings from experiments carried out during intracranial EEG recordings of candidates for surgical treatment of epilepsy.

Epifantsev/Thinkstock

“Our results suggest that coordinated neural activity can serve as a substrate for information routing that enables the performance-monitoring system to communicate the need for behavioral control to other brain regions, including those that maintain flexible goal information, such as the lateral prefrontal cortex and the frontal polar cortex,” first author Zhongzheng Fu, a PhD student at the California Institute of Technology in Pasadena, Calif., and Cedars-Sinai Medical Center, Los Angeles, and his colleagues reported in Neuron.

The findings offer insights that could lead to treatments for conditions in which the important executive function task of error self-monitoring is unbalanced, such as obsessive-compulsive disorder and schizophrenia, the authors noted in a press release.

“We discovered that the activity of error neurons correlates with the size of the ERN [error-related negativity],” Mr. Fu said. “This identifies the brain area that causes the ERN and helps explain what it signifies. This new insight might allow doctors to use the ERN as a standard tool to diagnose mental diseases and monitor responses to treatment.”

Error neuron firing and intracranial ERN occurred first in pre-supplementary motor area (pre-SMA), then in the dorsal anterior cingulate cortex (dACC) about 50 ms later, with significant correlations between firing and intracranial ERN in both locations. In dACC, this activity, with error-integrating neuron responses, correlated with magnitude of post-error slowing (PES).

Previous research suggested a link between “the detection of self-generated errors, as reflected in the ERN, with changes in cognitive control, as exhibited behaviorally in PES,” the investigators wrote. “However, several electroencephalogram (EEG) studies have failed to find a significant relationship between PES and ERN.”

The present study involved intracranial EEG of 29 candidates for surgical treatment of epilepsy and scalp EEG of 12 control participants, with each modality measuring activity in the frontal cortex. Both cohorts performed a rapid version of the color-word Stroop task, in which the words “red,” “green,” or “blue” were printed either in corresponding or noncorresponding colors of red, green, or blue. Subjects were presented various color-word combinations while being asked to click one of three buttons indicating the color of the word as quickly as possible. The investigators monitored neuronal activity throughout, discarding responses that were too slow.

As found in previous trials, the subjects demonstrated the “Stroop effect,” which refers to a slower response when word and color are incongruent (224.9 ms difference; P less than .001). As anticipated, correct responses following correct responses were faster than were correct responses following erroneous responses, which defines PES.

In the intracranial EEG group, the investigators isolated 1,171 neurons, of which 618 were located in dACC and 553 in pre-SMA. Using a Poisson regression model and correlations with erroneous responses, the investigators identified 99 “type I” error neurons in dACC and 118 in pre-SMA, based on higher frequency of firing during erroneous responses than during correct responses. At a single-cell level, error neuron mean spike rates were highest when intracranial ERN amplitude was greatest, such that error neuron firing in dACC and pre-SMA had maximal likelihood ratios of 7.9 (P = .01) and 15.1 (P less than .001), respectively. The strength of correlation between intracranial ERN and error neuron firing rate was directly related to PES magnitude exclusively in the dACC (maximum likelihood ratio of 13.9; P = .015). In post-error trials, faster error-integrating neuron firing rates in dACC predicted greater PES (maximal likelihood ratio of 18.3; P less than .001).

The study was funded by the National Institutes of Health, the McKnight Endowment for Neuroscience, and the National Science Foundation. The authors declared no conflicts of interest.

SOURCE: Fu Z et al. Neuron. 2018 Dec 4. doi: 10.1016/j.neuron.2018.11.016

Single neurons in the human medial frontal cortex appear to be involved in the signaling of self-monitored errors, and this activity can be tracked through a scalp EEG pattern called error-related negativity, according to findings from experiments carried out during intracranial EEG recordings of candidates for surgical treatment of epilepsy.

Epifantsev/Thinkstock

“Our results suggest that coordinated neural activity can serve as a substrate for information routing that enables the performance-monitoring system to communicate the need for behavioral control to other brain regions, including those that maintain flexible goal information, such as the lateral prefrontal cortex and the frontal polar cortex,” first author Zhongzheng Fu, a PhD student at the California Institute of Technology in Pasadena, Calif., and Cedars-Sinai Medical Center, Los Angeles, and his colleagues reported in Neuron.

The findings offer insights that could lead to treatments for conditions in which the important executive function task of error self-monitoring is unbalanced, such as obsessive-compulsive disorder and schizophrenia, the authors noted in a press release.

“We discovered that the activity of error neurons correlates with the size of the ERN [error-related negativity],” Mr. Fu said. “This identifies the brain area that causes the ERN and helps explain what it signifies. This new insight might allow doctors to use the ERN as a standard tool to diagnose mental diseases and monitor responses to treatment.”

Error neuron firing and intracranial ERN occurred first in pre-supplementary motor area (pre-SMA), then in the dorsal anterior cingulate cortex (dACC) about 50 ms later, with significant correlations between firing and intracranial ERN in both locations. In dACC, this activity, with error-integrating neuron responses, correlated with magnitude of post-error slowing (PES).

Previous research suggested a link between “the detection of self-generated errors, as reflected in the ERN, with changes in cognitive control, as exhibited behaviorally in PES,” the investigators wrote. “However, several electroencephalogram (EEG) studies have failed to find a significant relationship between PES and ERN.”

The present study involved intracranial EEG of 29 candidates for surgical treatment of epilepsy and scalp EEG of 12 control participants, with each modality measuring activity in the frontal cortex. Both cohorts performed a rapid version of the color-word Stroop task, in which the words “red,” “green,” or “blue” were printed either in corresponding or noncorresponding colors of red, green, or blue. Subjects were presented various color-word combinations while being asked to click one of three buttons indicating the color of the word as quickly as possible. The investigators monitored neuronal activity throughout, discarding responses that were too slow.

As found in previous trials, the subjects demonstrated the “Stroop effect,” which refers to a slower response when word and color are incongruent (224.9 ms difference; P less than .001). As anticipated, correct responses following correct responses were faster than were correct responses following erroneous responses, which defines PES.

In the intracranial EEG group, the investigators isolated 1,171 neurons, of which 618 were located in dACC and 553 in pre-SMA. Using a Poisson regression model and correlations with erroneous responses, the investigators identified 99 “type I” error neurons in dACC and 118 in pre-SMA, based on higher frequency of firing during erroneous responses than during correct responses. At a single-cell level, error neuron mean spike rates were highest when intracranial ERN amplitude was greatest, such that error neuron firing in dACC and pre-SMA had maximal likelihood ratios of 7.9 (P = .01) and 15.1 (P less than .001), respectively. The strength of correlation between intracranial ERN and error neuron firing rate was directly related to PES magnitude exclusively in the dACC (maximum likelihood ratio of 13.9; P = .015). In post-error trials, faster error-integrating neuron firing rates in dACC predicted greater PES (maximal likelihood ratio of 18.3; P less than .001).

The study was funded by the National Institutes of Health, the McKnight Endowment for Neuroscience, and the National Science Foundation. The authors declared no conflicts of interest.

SOURCE: Fu Z et al. Neuron. 2018 Dec 4. doi: 10.1016/j.neuron.2018.11.016

Single neurons in the human medial frontal cortex appear to be involved in the signaling of self-monitored errors, and this activity can be tracked through a scalp EEG pattern called error-related negativity, according to findings from experiments carried out during intracranial EEG recordings of candidates for surgical treatment of epilepsy.

Epifantsev/Thinkstock

“Our results suggest that coordinated neural activity can serve as a substrate for information routing that enables the performance-monitoring system to communicate the need for behavioral control to other brain regions, including those that maintain flexible goal information, such as the lateral prefrontal cortex and the frontal polar cortex,” first author Zhongzheng Fu, a PhD student at the California Institute of Technology in Pasadena, Calif., and Cedars-Sinai Medical Center, Los Angeles, and his colleagues reported in Neuron.

The findings offer insights that could lead to treatments for conditions in which the important executive function task of error self-monitoring is unbalanced, such as obsessive-compulsive disorder and schizophrenia, the authors noted in a press release.

“We discovered that the activity of error neurons correlates with the size of the ERN [error-related negativity],” Mr. Fu said. “This identifies the brain area that causes the ERN and helps explain what it signifies. This new insight might allow doctors to use the ERN as a standard tool to diagnose mental diseases and monitor responses to treatment.”

Error neuron firing and intracranial ERN occurred first in pre-supplementary motor area (pre-SMA), then in the dorsal anterior cingulate cortex (dACC) about 50 ms later, with significant correlations between firing and intracranial ERN in both locations. In dACC, this activity, with error-integrating neuron responses, correlated with magnitude of post-error slowing (PES).

Previous research suggested a link between “the detection of self-generated errors, as reflected in the ERN, with changes in cognitive control, as exhibited behaviorally in PES,” the investigators wrote. “However, several electroencephalogram (EEG) studies have failed to find a significant relationship between PES and ERN.”

The present study involved intracranial EEG of 29 candidates for surgical treatment of epilepsy and scalp EEG of 12 control participants, with each modality measuring activity in the frontal cortex. Both cohorts performed a rapid version of the color-word Stroop task, in which the words “red,” “green,” or “blue” were printed either in corresponding or noncorresponding colors of red, green, or blue. Subjects were presented various color-word combinations while being asked to click one of three buttons indicating the color of the word as quickly as possible. The investigators monitored neuronal activity throughout, discarding responses that were too slow.

As found in previous trials, the subjects demonstrated the “Stroop effect,” which refers to a slower response when word and color are incongruent (224.9 ms difference; P less than .001). As anticipated, correct responses following correct responses were faster than were correct responses following erroneous responses, which defines PES.

In the intracranial EEG group, the investigators isolated 1,171 neurons, of which 618 were located in dACC and 553 in pre-SMA. Using a Poisson regression model and correlations with erroneous responses, the investigators identified 99 “type I” error neurons in dACC and 118 in pre-SMA, based on higher frequency of firing during erroneous responses than during correct responses. At a single-cell level, error neuron mean spike rates were highest when intracranial ERN amplitude was greatest, such that error neuron firing in dACC and pre-SMA had maximal likelihood ratios of 7.9 (P = .01) and 15.1 (P less than .001), respectively. The strength of correlation between intracranial ERN and error neuron firing rate was directly related to PES magnitude exclusively in the dACC (maximum likelihood ratio of 13.9; P = .015). In post-error trials, faster error-integrating neuron firing rates in dACC predicted greater PES (maximal likelihood ratio of 18.3; P less than .001).

The study was funded by the National Institutes of Health, the McKnight Endowment for Neuroscience, and the National Science Foundation. The authors declared no conflicts of interest.

SOURCE: Fu Z et al. Neuron. 2018 Dec 4. doi: 10.1016/j.neuron.2018.11.016

IgA vasculitis, also called Henoch-Schönlein purpura, increases risks for hypertension and chronic kidney disease (CKD), according to a retrospective study of more than 13,000 patients with IgAV.

In patients with adult-onset IgA vasculitis (IgAV), mortality risk is also increased, reported first author Alexander Tracy and his colleagues at the University of Birmingham (England).

“Long-term health outcomes of adult-onset IgAV are not well characterized,” the investigators wrote in Annals of Rheumatic Disease. “Most evidence regarding complications of IgAV in adults derives from case reports and case series; there is need for controlled epidemiological studies to address this question.”

The retrospective study compared 2,828 patients with adult-onset IgAV and 10,405 patients with childhood-onset IgAV against sex- and age-matched controls. Patients diagnosed at age 16 years or older were classified as having adult-onset disease. The investigators drew their data from The Health Improvement Network database, which includes 3.6 million active patients from more than 675 general practices in the United Kingdom. Patients in the present study were diagnosed with IgAV between 2005 and 2016. After diagnosis, participant follow-up continued until any of the following occurred: outcome event, patient left practice, death, the practice stopped contributing data, or the study ended. Primary outcomes for adult-onset patients were venous thromboembolism (VTE), ischemic heart disease, hypertension, stage 3-5 CKD, stroke/transient ischemic attack, and all-cause mortality. Primary outcomes for patients with childhood-onset disease were limited to CKD, hypertension, and VTE.

The incidence of childhood-onset IgAV was 27.22 per 100,000 person-years, whereas adult-onset disease was much less common at 2.20 per 100,000 person-years. Mean age at onset of childhood IgAV was 6.68 years. The adult-onset group had a mean age at diagnosis of 38.1 years.


Compared with controls, all patients with IgAV, regardless of onset age, had increased risks of hypertension (adult-onset adjusted hazard ratio, 1.42; P less than .001; childhood-onset aHR, 1.52; P less than .001) and CKD (adult-onset aHR, 1.54; P less than .001; childhood-onset aHR, 1.89; P = .01). Patients with adult-onset IgAV showed increased risk of death, compared with controls (aHR, 1.27; P = .006). No associations were found between IgAV and stroke/transient ischemic attack, VTE, or ischemic heart disease.

“These findings emphasize the importance of blood pressure and renal function monitoring in patients with IgAV,” the investigators concluded. “Our data also suggest that IgAV should not be considered a ‘single-hit’ disease, but that clinicians should monitor for long-term sequelae. Further research is required to clarify the cause of hypertension in patients with IgAV, and to investigate whether such patients suffer from additional long-term sequelae than that are currently unrecognized.”

The investigators reported no funding sources or conflicts or interest.

SOURCE: Tracy A et al. Ann Rheum Dis. 2018 Nov 28. doi: 10.1136/annrheumdis-2018-214142.

IgA vasculitis, also called Henoch-Schönlein purpura, increases risks for hypertension and chronic kidney disease (CKD), according to a retrospective study of more than 13,000 patients with IgAV.

In patients with adult-onset IgA vasculitis (IgAV), mortality risk is also increased, reported first author Alexander Tracy and his colleagues at the University of Birmingham (England).

“Long-term health outcomes of adult-onset IgAV are not well characterized,” the investigators wrote in Annals of Rheumatic Disease. “Most evidence regarding complications of IgAV in adults derives from case reports and case series; there is need for controlled epidemiological studies to address this question.”

The retrospective study compared 2,828 patients with adult-onset IgAV and 10,405 patients with childhood-onset IgAV against sex- and age-matched controls. Patients diagnosed at age 16 years or older were classified as having adult-onset disease. The investigators drew their data from The Health Improvement Network database, which includes 3.6 million active patients from more than 675 general practices in the United Kingdom. Patients in the present study were diagnosed with IgAV between 2005 and 2016. After diagnosis, participant follow-up continued until any of the following occurred: outcome event, patient left practice, death, the practice stopped contributing data, or the study ended. Primary outcomes for adult-onset patients were venous thromboembolism (VTE), ischemic heart disease, hypertension, stage 3-5 CKD, stroke/transient ischemic attack, and all-cause mortality. Primary outcomes for patients with childhood-onset disease were limited to CKD, hypertension, and VTE.

The incidence of childhood-onset IgAV was 27.22 per 100,000 person-years, whereas adult-onset disease was much less common at 2.20 per 100,000 person-years. Mean age at onset of childhood IgAV was 6.68 years. The adult-onset group had a mean age at diagnosis of 38.1 years.


Compared with controls, all patients with IgAV, regardless of onset age, had increased risks of hypertension (adult-onset adjusted hazard ratio, 1.42; P less than .001; childhood-onset aHR, 1.52; P less than .001) and CKD (adult-onset aHR, 1.54; P less than .001; childhood-onset aHR, 1.89; P = .01). Patients with adult-onset IgAV showed increased risk of death, compared with controls (aHR, 1.27; P = .006). No associations were found between IgAV and stroke/transient ischemic attack, VTE, or ischemic heart disease.

“These findings emphasize the importance of blood pressure and renal function monitoring in patients with IgAV,” the investigators concluded. “Our data also suggest that IgAV should not be considered a ‘single-hit’ disease, but that clinicians should monitor for long-term sequelae. Further research is required to clarify the cause of hypertension in patients with IgAV, and to investigate whether such patients suffer from additional long-term sequelae than that are currently unrecognized.”

The investigators reported no funding sources or conflicts or interest.

SOURCE: Tracy A et al. Ann Rheum Dis. 2018 Nov 28. doi: 10.1136/annrheumdis-2018-214142.

IgA vasculitis, also called Henoch-Schönlein purpura, increases risks for hypertension and chronic kidney disease (CKD), according to a retrospective study of more than 13,000 patients with IgAV.

In patients with adult-onset IgA vasculitis (IgAV), mortality risk is also increased, reported first author Alexander Tracy and his colleagues at the University of Birmingham (England).

“Long-term health outcomes of adult-onset IgAV are not well characterized,” the investigators wrote in Annals of Rheumatic Disease. “Most evidence regarding complications of IgAV in adults derives from case reports and case series; there is need for controlled epidemiological studies to address this question.”

The retrospective study compared 2,828 patients with adult-onset IgAV and 10,405 patients with childhood-onset IgAV against sex- and age-matched controls. Patients diagnosed at age 16 years or older were classified as having adult-onset disease. The investigators drew their data from The Health Improvement Network database, which includes 3.6 million active patients from more than 675 general practices in the United Kingdom. Patients in the present study were diagnosed with IgAV between 2005 and 2016. After diagnosis, participant follow-up continued until any of the following occurred: outcome event, patient left practice, death, the practice stopped contributing data, or the study ended. Primary outcomes for adult-onset patients were venous thromboembolism (VTE), ischemic heart disease, hypertension, stage 3-5 CKD, stroke/transient ischemic attack, and all-cause mortality. Primary outcomes for patients with childhood-onset disease were limited to CKD, hypertension, and VTE.

The incidence of childhood-onset IgAV was 27.22 per 100,000 person-years, whereas adult-onset disease was much less common at 2.20 per 100,000 person-years. Mean age at onset of childhood IgAV was 6.68 years. The adult-onset group had a mean age at diagnosis of 38.1 years.


Compared with controls, all patients with IgAV, regardless of onset age, had increased risks of hypertension (adult-onset adjusted hazard ratio, 1.42; P less than .001; childhood-onset aHR, 1.52; P less than .001) and CKD (adult-onset aHR, 1.54; P less than .001; childhood-onset aHR, 1.89; P = .01). Patients with adult-onset IgAV showed increased risk of death, compared with controls (aHR, 1.27; P = .006). No associations were found between IgAV and stroke/transient ischemic attack, VTE, or ischemic heart disease.

“These findings emphasize the importance of blood pressure and renal function monitoring in patients with IgAV,” the investigators concluded. “Our data also suggest that IgAV should not be considered a ‘single-hit’ disease, but that clinicians should monitor for long-term sequelae. Further research is required to clarify the cause of hypertension in patients with IgAV, and to investigate whether such patients suffer from additional long-term sequelae than that are currently unrecognized.”

The investigators reported no funding sources or conflicts or interest.

SOURCE: Tracy A et al. Ann Rheum Dis. 2018 Nov 28. doi: 10.1136/annrheumdis-2018-214142.

Telomere maintenance mechanisms, RAS mutations, and p53 mutations can be used to mechanistically classify clinical phenotypes of neuroblastoma, according to investigators.

Genomic analysis of neuroblastomas showed that the aforementioned markers were strongly associated with outcome and other disease characteristics, reported Sandra Ackermann, MD, of the department of experimental pediatric oncology at the University Children’s Hospital of Cologne (Germany), and her colleagues.

Although previous studies have shown relationships between genetic alterations and behavior of neuroblastomas, “to date, these genomic data have not produced a coherent model of pathogenesis that can explain the extremely divergent clinical phenotypes of neuroblastoma,” the investigators wrote in Science.

The present study involved genomic sequencing of 416 pretreatment neuroblastomas, with tests for telomere maintenance mechanisms, RAS-pathway mutations, and p53-pathway mutations.

Based on existing data, the investigators first devised a panel based on 17 genes related to the RAS pathway (11 genes included ALK) and 6 related to the p53 pathway. In 198 cases, 28 tested positive for RAS- or p53-pathway abnormalities (17.8%). Positivity was more common in high-risk tumors than non–high-risk tumors (21.3% vs. 13.3%; P = .048), and in both risk groups, positivity was associated with poor outcome (hazard ratio, 2.056; P = .001).

However, because clinical courses varied widely among non–high-risk patients with RAS/p53 mutations, the investigators recognized that a piece of the puzzle was missing. They hypothesized that telomere maintenance mechanisms could also be playing a role. Following several intervening experiments, the investigators devised telomere maintenance mechanism testing, defined by MYCN amplification or TERT rearrangements, elevated TERT expression if negative for these abnormalities, or presence of ALT-associated promyelocytic leukemia nuclear bodies. Subsequent testing revealed that positivity for these parameters was associated with a HR of 5.184 (P less than .001), thereby confirming that telomere maintenance mechanisms could independently predict survival.

“Together, our findings demonstrate that the divergent clinical phenotypes of human neuroblastoma are driven by molecular alterations affecting telomere maintenance and RAS or p53 pathways, suggesting a mechanistic classification of this malignancy,” the authors concluded.

The proposed classification scheme also includes associations with other genetic features (tumor cell ploidy, segmental copy number alterations, MYCN/TERT/ATRX alterations, and gene expression favorability) and clinical characteristics (stage of disease and age at diagnosis).

The study was funded by the German Cancer Aid, the German Ministry of Science and Education, the MYC-NET, the Deutsche Forschungsgemeinschaft, the Berlin Institute of Health, the European Union, and others. One coauthor reported financial relationships with Biogazelle and pxlence, and another reported consulting fees from NEO New Oncology.

SOURCE: Ackermann S et al. Science. 2018 Dec 7. doi: 10.1126/science.aat6768.

Telomere maintenance mechanisms, RAS mutations, and p53 mutations can be used to mechanistically classify clinical phenotypes of neuroblastoma, according to investigators.

Genomic analysis of neuroblastomas showed that the aforementioned markers were strongly associated with outcome and other disease characteristics, reported Sandra Ackermann, MD, of the department of experimental pediatric oncology at the University Children’s Hospital of Cologne (Germany), and her colleagues.

Although previous studies have shown relationships between genetic alterations and behavior of neuroblastomas, “to date, these genomic data have not produced a coherent model of pathogenesis that can explain the extremely divergent clinical phenotypes of neuroblastoma,” the investigators wrote in Science.

The present study involved genomic sequencing of 416 pretreatment neuroblastomas, with tests for telomere maintenance mechanisms, RAS-pathway mutations, and p53-pathway mutations.

Based on existing data, the investigators first devised a panel based on 17 genes related to the RAS pathway (11 genes included ALK) and 6 related to the p53 pathway. In 198 cases, 28 tested positive for RAS- or p53-pathway abnormalities (17.8%). Positivity was more common in high-risk tumors than non–high-risk tumors (21.3% vs. 13.3%; P = .048), and in both risk groups, positivity was associated with poor outcome (hazard ratio, 2.056; P = .001).

However, because clinical courses varied widely among non–high-risk patients with RAS/p53 mutations, the investigators recognized that a piece of the puzzle was missing. They hypothesized that telomere maintenance mechanisms could also be playing a role. Following several intervening experiments, the investigators devised telomere maintenance mechanism testing, defined by MYCN amplification or TERT rearrangements, elevated TERT expression if negative for these abnormalities, or presence of ALT-associated promyelocytic leukemia nuclear bodies. Subsequent testing revealed that positivity for these parameters was associated with a HR of 5.184 (P less than .001), thereby confirming that telomere maintenance mechanisms could independently predict survival.

“Together, our findings demonstrate that the divergent clinical phenotypes of human neuroblastoma are driven by molecular alterations affecting telomere maintenance and RAS or p53 pathways, suggesting a mechanistic classification of this malignancy,” the authors concluded.

The proposed classification scheme also includes associations with other genetic features (tumor cell ploidy, segmental copy number alterations, MYCN/TERT/ATRX alterations, and gene expression favorability) and clinical characteristics (stage of disease and age at diagnosis).

The study was funded by the German Cancer Aid, the German Ministry of Science and Education, the MYC-NET, the Deutsche Forschungsgemeinschaft, the Berlin Institute of Health, the European Union, and others. One coauthor reported financial relationships with Biogazelle and pxlence, and another reported consulting fees from NEO New Oncology.

SOURCE: Ackermann S et al. Science. 2018 Dec 7. doi: 10.1126/science.aat6768.

Telomere maintenance mechanisms, RAS mutations, and p53 mutations can be used to mechanistically classify clinical phenotypes of neuroblastoma, according to investigators.

Genomic analysis of neuroblastomas showed that the aforementioned markers were strongly associated with outcome and other disease characteristics, reported Sandra Ackermann, MD, of the department of experimental pediatric oncology at the University Children’s Hospital of Cologne (Germany), and her colleagues.

Although previous studies have shown relationships between genetic alterations and behavior of neuroblastomas, “to date, these genomic data have not produced a coherent model of pathogenesis that can explain the extremely divergent clinical phenotypes of neuroblastoma,” the investigators wrote in Science.

The present study involved genomic sequencing of 416 pretreatment neuroblastomas, with tests for telomere maintenance mechanisms, RAS-pathway mutations, and p53-pathway mutations.

Based on existing data, the investigators first devised a panel based on 17 genes related to the RAS pathway (11 genes included ALK) and 6 related to the p53 pathway. In 198 cases, 28 tested positive for RAS- or p53-pathway abnormalities (17.8%). Positivity was more common in high-risk tumors than non–high-risk tumors (21.3% vs. 13.3%; P = .048), and in both risk groups, positivity was associated with poor outcome (hazard ratio, 2.056; P = .001).

However, because clinical courses varied widely among non–high-risk patients with RAS/p53 mutations, the investigators recognized that a piece of the puzzle was missing. They hypothesized that telomere maintenance mechanisms could also be playing a role. Following several intervening experiments, the investigators devised telomere maintenance mechanism testing, defined by MYCN amplification or TERT rearrangements, elevated TERT expression if negative for these abnormalities, or presence of ALT-associated promyelocytic leukemia nuclear bodies. Subsequent testing revealed that positivity for these parameters was associated with a HR of 5.184 (P less than .001), thereby confirming that telomere maintenance mechanisms could independently predict survival.

“Together, our findings demonstrate that the divergent clinical phenotypes of human neuroblastoma are driven by molecular alterations affecting telomere maintenance and RAS or p53 pathways, suggesting a mechanistic classification of this malignancy,” the authors concluded.

The proposed classification scheme also includes associations with other genetic features (tumor cell ploidy, segmental copy number alterations, MYCN/TERT/ATRX alterations, and gene expression favorability) and clinical characteristics (stage of disease and age at diagnosis).

The study was funded by the German Cancer Aid, the German Ministry of Science and Education, the MYC-NET, the Deutsche Forschungsgemeinschaft, the Berlin Institute of Health, the European Union, and others. One coauthor reported financial relationships with Biogazelle and pxlence, and another reported consulting fees from NEO New Oncology.

SOURCE: Ackermann S et al. Science. 2018 Dec 7. doi: 10.1126/science.aat6768.

Recent research on the genetic basis of renal cell carcinoma has expanded and improved treatment options; however, personalized medicine is still largely unavailable, so future efforts should aim to link genetic knowledge with prognosis and treatment selection, according to the authors of a recent review article.

The article, written by Christopher D’Avella, MD, of the Fox Chase Cancer Center in Philadelphia, and his colleagues provides an overview of renal cell carcinoma (RCC) mutations and associated therapies, with updates of ongoing trials and a look at future directions.

“The expansion of treatment options for patients with advanced RCC over the past 15 years is a testament to enhanced understanding of the genetics and genomics of RCC and the ability to apply this knowledge to drug development,” the authors wrote in Urologic Oncology. “However, much work remains to be done as there are still no validated biomarkers to select patient treatment, and in only rare cases, the knowledge of particular mutations in RCC can lead to rational treatment selection.”

RCC accounts for approximately 80%-85% of renal tumors. About three out of four RCC patients have clear cell disease, of which about 30% develop metastases and need systemic therapy. The authors pointed out that vascular endothelial growth factor tyrosine kinase inhibitors (TKIs) have been standard first-line care for these patients since the mid-2000s, based on improved molecular understanding. Still, responses to TKIs are limited and patients eventually develop resistance. Several agents are in development to overcome this obstacle, including inhibitors of hypoxia inducible factor, which have recently shown promise. Among biomarkers for ccRCC, PBRM1 mutations may be associated with susceptibility to checkpoint inhibitors, and TSC1 could predict response to mTOR (mammalian target of rapamycin) inhibition.

Along with clear cell RCC, the review article addressed topics in papillary and sarcomatoid subtypes.

Patients with papillary RCC often have MET mutations, and ongoing research is focused on associated targeted therapies. For example, savolitinib is a highly selective MET inhibitor that has shown promise in this patient subgroup.

Sarcomatoid features remain characteristic of large and aggressive tumors. Unfortunately, treatment options are currently limited in this area. Recent studies suggest that TP53 and NF2 mutations are associated with sarcomatoid differentiation.

“Future studies should explore linking genetics to prognosis, resistance to targeted therapies, and the identification of future therapeutic targets,” the authors concluded.

SOURCE: D’Avella C et al. Urol Oncol. 2018 Nov 23. doi: 10.1016/j.urolonc.2018.10.027.

Recent research on the genetic basis of renal cell carcinoma has expanded and improved treatment options; however, personalized medicine is still largely unavailable, so future efforts should aim to link genetic knowledge with prognosis and treatment selection, according to the authors of a recent review article.

The article, written by Christopher D’Avella, MD, of the Fox Chase Cancer Center in Philadelphia, and his colleagues provides an overview of renal cell carcinoma (RCC) mutations and associated therapies, with updates of ongoing trials and a look at future directions.

“The expansion of treatment options for patients with advanced RCC over the past 15 years is a testament to enhanced understanding of the genetics and genomics of RCC and the ability to apply this knowledge to drug development,” the authors wrote in Urologic Oncology. “However, much work remains to be done as there are still no validated biomarkers to select patient treatment, and in only rare cases, the knowledge of particular mutations in RCC can lead to rational treatment selection.”

RCC accounts for approximately 80%-85% of renal tumors. About three out of four RCC patients have clear cell disease, of which about 30% develop metastases and need systemic therapy. The authors pointed out that vascular endothelial growth factor tyrosine kinase inhibitors (TKIs) have been standard first-line care for these patients since the mid-2000s, based on improved molecular understanding. Still, responses to TKIs are limited and patients eventually develop resistance. Several agents are in development to overcome this obstacle, including inhibitors of hypoxia inducible factor, which have recently shown promise. Among biomarkers for ccRCC, PBRM1 mutations may be associated with susceptibility to checkpoint inhibitors, and TSC1 could predict response to mTOR (mammalian target of rapamycin) inhibition.

Along with clear cell RCC, the review article addressed topics in papillary and sarcomatoid subtypes.

Patients with papillary RCC often have MET mutations, and ongoing research is focused on associated targeted therapies. For example, savolitinib is a highly selective MET inhibitor that has shown promise in this patient subgroup.

Sarcomatoid features remain characteristic of large and aggressive tumors. Unfortunately, treatment options are currently limited in this area. Recent studies suggest that TP53 and NF2 mutations are associated with sarcomatoid differentiation.

“Future studies should explore linking genetics to prognosis, resistance to targeted therapies, and the identification of future therapeutic targets,” the authors concluded.

SOURCE: D’Avella C et al. Urol Oncol. 2018 Nov 23. doi: 10.1016/j.urolonc.2018.10.027.

Recent research on the genetic basis of renal cell carcinoma has expanded and improved treatment options; however, personalized medicine is still largely unavailable, so future efforts should aim to link genetic knowledge with prognosis and treatment selection, according to the authors of a recent review article.

The article, written by Christopher D’Avella, MD, of the Fox Chase Cancer Center in Philadelphia, and his colleagues provides an overview of renal cell carcinoma (RCC) mutations and associated therapies, with updates of ongoing trials and a look at future directions.

“The expansion of treatment options for patients with advanced RCC over the past 15 years is a testament to enhanced understanding of the genetics and genomics of RCC and the ability to apply this knowledge to drug development,” the authors wrote in Urologic Oncology. “However, much work remains to be done as there are still no validated biomarkers to select patient treatment, and in only rare cases, the knowledge of particular mutations in RCC can lead to rational treatment selection.”

RCC accounts for approximately 80%-85% of renal tumors. About three out of four RCC patients have clear cell disease, of which about 30% develop metastases and need systemic therapy. The authors pointed out that vascular endothelial growth factor tyrosine kinase inhibitors (TKIs) have been standard first-line care for these patients since the mid-2000s, based on improved molecular understanding. Still, responses to TKIs are limited and patients eventually develop resistance. Several agents are in development to overcome this obstacle, including inhibitors of hypoxia inducible factor, which have recently shown promise. Among biomarkers for ccRCC, PBRM1 mutations may be associated with susceptibility to checkpoint inhibitors, and TSC1 could predict response to mTOR (mammalian target of rapamycin) inhibition.

Along with clear cell RCC, the review article addressed topics in papillary and sarcomatoid subtypes.

Patients with papillary RCC often have MET mutations, and ongoing research is focused on associated targeted therapies. For example, savolitinib is a highly selective MET inhibitor that has shown promise in this patient subgroup.

Sarcomatoid features remain characteristic of large and aggressive tumors. Unfortunately, treatment options are currently limited in this area. Recent studies suggest that TP53 and NF2 mutations are associated with sarcomatoid differentiation.

“Future studies should explore linking genetics to prognosis, resistance to targeted therapies, and the identification of future therapeutic targets,” the authors concluded.

SOURCE: D’Avella C et al. Urol Oncol. 2018 Nov 23. doi: 10.1016/j.urolonc.2018.10.027.

Human telomerase reverse transcriptase (hTERT) protein expression is associated with clear cell renal carcinoma (ccRCC) tumor aggressiveness and disease-specific survival (DSS), according to investigators.

Associations between hTERT expression and clinicopathologic features and outcomes were less robust or nonexistent in papillary and chromophobe subtypes, reported Leili Saeednejad Zanjani, MD, of the Oncopathology Research Center at Iran University of Medical Sciences in Tehran, and colleagues.

“Evidence shows that telomerase is expressed in 85% of malignancies, and the level of its activity is higher in advanced and metastatic tumors,” the authors wrote in Pathology.

“A number of clinical studies have been performed to evaluate the association between telomerase activity and clinicopathological parameters in renal cancer showing that telomerase activity level correlates with progression of RCC,” Dr. Zanjani and associates wrote. As none of these specifically evaluated hTERT protein expression, the investigators conducted a study to learn more.

The investigators analyzed hTERT expression level in 176 cases of RCC, requiring that each tumor had three core biopsies because of concerns of heterogeneity. The population consisted of 113 clear cell, 12 type I papillary, 20 type II papillary, and 31 chromophobe subtypes. Patient and clinicopathologic features were compared with survival and hTERT expression. Median follow-up time was 42 months.

Correlations between hTERT expression and disease characteristics were pronounced in cases of ccRCC, compared with other subtypes. In ccRCC, hTERT expression was significantly associated with tumor stage, nucleolar grade, tumor size, microvascular invasion, lymph node invasion, renal pelvis involvement, renal sinus fat involvement, Gerota fascia invasion, and distant metastasis. Survival analysis showed that DSS of ccRCC patients with high hTERT expression was 58 months, compared with 68 months for those with low hTERT expression (P =.012). Other parameters associated with survival were nucleolar grade, tumor stage, and tumor size.

For type I and II papillary subtypes, associations were found between hTERT expression and tumor stage and distant metastasis. In contrast, chromophobe RCC revealed no such relationships. No associations were found between hTERT expression and survival in any of these three latter subtypes, for slightly different reasons; no patients with type I disease died of renal cancer, disallowing creation of a Kaplan-Meier survival curve, whereas type II and chromophobe survival curves revealed insignificant relationships with hTERT expression. Along the same lines, no clinicopathologic characteristics of these subtypes were tied with survival.

“From these findings we are able to conclude that hTERT protein expression may be a novel prognostic indicator of worse outcome in tumor biopsies of patients with ccRCC, if follow up time is more prolonged,” the authors wrote. They noted that “telomerase is an attractive and ideal target for therapy due to overexpression in the majority of malignancies and low or nonexpression in most somatic cells.”

The study was funded by the Iran National Science Foundation. The authors declared no conflicts of interest.
 

SOURCE: Zanjani LS et al. Pathology. 2018 Nov 19. doi: 10.1016/j.pathol.2018.08.019.

Human telomerase reverse transcriptase (hTERT) protein expression is associated with clear cell renal carcinoma (ccRCC) tumor aggressiveness and disease-specific survival (DSS), according to investigators.

Associations between hTERT expression and clinicopathologic features and outcomes were less robust or nonexistent in papillary and chromophobe subtypes, reported Leili Saeednejad Zanjani, MD, of the Oncopathology Research Center at Iran University of Medical Sciences in Tehran, and colleagues.

“Evidence shows that telomerase is expressed in 85% of malignancies, and the level of its activity is higher in advanced and metastatic tumors,” the authors wrote in Pathology.

“A number of clinical studies have been performed to evaluate the association between telomerase activity and clinicopathological parameters in renal cancer showing that telomerase activity level correlates with progression of RCC,” Dr. Zanjani and associates wrote. As none of these specifically evaluated hTERT protein expression, the investigators conducted a study to learn more.

The investigators analyzed hTERT expression level in 176 cases of RCC, requiring that each tumor had three core biopsies because of concerns of heterogeneity. The population consisted of 113 clear cell, 12 type I papillary, 20 type II papillary, and 31 chromophobe subtypes. Patient and clinicopathologic features were compared with survival and hTERT expression. Median follow-up time was 42 months.

Correlations between hTERT expression and disease characteristics were pronounced in cases of ccRCC, compared with other subtypes. In ccRCC, hTERT expression was significantly associated with tumor stage, nucleolar grade, tumor size, microvascular invasion, lymph node invasion, renal pelvis involvement, renal sinus fat involvement, Gerota fascia invasion, and distant metastasis. Survival analysis showed that DSS of ccRCC patients with high hTERT expression was 58 months, compared with 68 months for those with low hTERT expression (P =.012). Other parameters associated with survival were nucleolar grade, tumor stage, and tumor size.

For type I and II papillary subtypes, associations were found between hTERT expression and tumor stage and distant metastasis. In contrast, chromophobe RCC revealed no such relationships. No associations were found between hTERT expression and survival in any of these three latter subtypes, for slightly different reasons; no patients with type I disease died of renal cancer, disallowing creation of a Kaplan-Meier survival curve, whereas type II and chromophobe survival curves revealed insignificant relationships with hTERT expression. Along the same lines, no clinicopathologic characteristics of these subtypes were tied with survival.

“From these findings we are able to conclude that hTERT protein expression may be a novel prognostic indicator of worse outcome in tumor biopsies of patients with ccRCC, if follow up time is more prolonged,” the authors wrote. They noted that “telomerase is an attractive and ideal target for therapy due to overexpression in the majority of malignancies and low or nonexpression in most somatic cells.”

The study was funded by the Iran National Science Foundation. The authors declared no conflicts of interest.
 

SOURCE: Zanjani LS et al. Pathology. 2018 Nov 19. doi: 10.1016/j.pathol.2018.08.019.

Human telomerase reverse transcriptase (hTERT) protein expression is associated with clear cell renal carcinoma (ccRCC) tumor aggressiveness and disease-specific survival (DSS), according to investigators.

Associations between hTERT expression and clinicopathologic features and outcomes were less robust or nonexistent in papillary and chromophobe subtypes, reported Leili Saeednejad Zanjani, MD, of the Oncopathology Research Center at Iran University of Medical Sciences in Tehran, and colleagues.

“Evidence shows that telomerase is expressed in 85% of malignancies, and the level of its activity is higher in advanced and metastatic tumors,” the authors wrote in Pathology.

“A number of clinical studies have been performed to evaluate the association between telomerase activity and clinicopathological parameters in renal cancer showing that telomerase activity level correlates with progression of RCC,” Dr. Zanjani and associates wrote. As none of these specifically evaluated hTERT protein expression, the investigators conducted a study to learn more.

The investigators analyzed hTERT expression level in 176 cases of RCC, requiring that each tumor had three core biopsies because of concerns of heterogeneity. The population consisted of 113 clear cell, 12 type I papillary, 20 type II papillary, and 31 chromophobe subtypes. Patient and clinicopathologic features were compared with survival and hTERT expression. Median follow-up time was 42 months.

Correlations between hTERT expression and disease characteristics were pronounced in cases of ccRCC, compared with other subtypes. In ccRCC, hTERT expression was significantly associated with tumor stage, nucleolar grade, tumor size, microvascular invasion, lymph node invasion, renal pelvis involvement, renal sinus fat involvement, Gerota fascia invasion, and distant metastasis. Survival analysis showed that DSS of ccRCC patients with high hTERT expression was 58 months, compared with 68 months for those with low hTERT expression (P =.012). Other parameters associated with survival were nucleolar grade, tumor stage, and tumor size.

For type I and II papillary subtypes, associations were found between hTERT expression and tumor stage and distant metastasis. In contrast, chromophobe RCC revealed no such relationships. No associations were found between hTERT expression and survival in any of these three latter subtypes, for slightly different reasons; no patients with type I disease died of renal cancer, disallowing creation of a Kaplan-Meier survival curve, whereas type II and chromophobe survival curves revealed insignificant relationships with hTERT expression. Along the same lines, no clinicopathologic characteristics of these subtypes were tied with survival.

“From these findings we are able to conclude that hTERT protein expression may be a novel prognostic indicator of worse outcome in tumor biopsies of patients with ccRCC, if follow up time is more prolonged,” the authors wrote. They noted that “telomerase is an attractive and ideal target for therapy due to overexpression in the majority of malignancies and low or nonexpression in most somatic cells.”

The study was funded by the Iran National Science Foundation. The authors declared no conflicts of interest.
 

SOURCE: Zanjani LS et al. Pathology. 2018 Nov 19. doi: 10.1016/j.pathol.2018.08.019.

Older patients with ccRCC may respond better than younger patients to phosphoinositide 3-kinase (PI3K) or checkpoint inhibition because of age-related changes in gene expression, according to investigators.

This possibility was raised by in silico results from a broader study of gene expression patterns in clear cell renal carcinoma (ccRCC) and normal kidney tissues, reported lead author, Lara Feulner, MD, of the department of human genetics at McGill University and Genome Quebec Innovation Centre in Montreal.

“Several factors could contribute to the interindividual diversity among cancer patients,” the investigators wrote in a report published in Urologic Oncology.

“Their disease course could be affected not only by cell-intrinsic factors, but also by age-related changes impacting the vasculature, immune system and stroma. Little is known in this regard about ccRCC, a disease which affects adults across a wide age spectrum. Whether and how aging and comorbidities such as atherosclerosis may affect the biology and therapy of ccRCC has scarcely been considered,” they wrote.

The investigators explored this territory by analyzing datasets from The Cancer Genome Atlas (TCGA) and the Cancer Genomics of the Kidney (CAGEKID) program of the International Cancer Genome Consortium. Using regression, pathway enrichment, and connectivity mapping analyses, they were able to determine associations between age and gene expression, cellular processes, and drug treatment responses, respectively.

The investigators reported that age-related gene expression patterns occurred commonly in both normal and tumor tissues. Associations were reproducible between TCGA and CAGEKID datasets for both classes of tissue (tumor samples, R equal to 0.416, P less than 2.2 x 10-16; normal samples, R equal to 0.403, P less than 2.2 x 10-16). Out of the top 1,000 age-associated genes in tumor samples from each dataset, 383 were commonly downregulated with age and 294 were commonly upregulated with age in both datasets (P less than 2.2 x 10-16).

Among cellular pathways, the investigators found opposite age-relationship patterns. For example, normal tissues upregulated extracellular matrix and cell adhesion pathways with age, whereas tumor tissues downregulated the same pathways. Similar patterns of opposition were found in metabolism and oxidation pathways. Other age-related patterns were noted in some immune pathways, such as upregulation of toll-like receptor and tumor necrosis factor 2 noncanonical NF-kappa-B signaling in tumors, which became more common with age. A closer look showed that upregulation of tumor necrosis factor signaling was more common in female patients, who also downregulated Notch pathways more often than men.

Analysis of treatment responses showed possible relationships with age-dependent gene expression and immunotherapy. Specifically, of 532 genes tied to programmed cell death protein 1 (PD-1) resistance, 69 were among the 383 genes downregulated in older patients with ccRCC (P less than 2.2 x 10-16; 4.05 fold-enrichment), suggesting that older patients may respond better to anti-PD-1 therapy than younger patients. Similarly, connectivity map analysis showed that age-dependent gene expression may improve candidacy of older ccRCC patients for PI3K inhibition.

“We now have evidence that there are notable differences in tumor-associated pathway regulation between younger and older ccRCC patients, which may be therapeutically actionable,” the authors concluded.

The study was funded by the Cancer Research Society operation grant, a Canadian Cancer Society Research Institute Innovation-to-Impact grant, and a Canadian Institutes of Health Research Foundation grant. The authors reported no conflicts of interest.

SOURCE: Feulner et al. Urol Onc. 2018 Nov 23. doi: 10.1016/j.urolonc.2018.11.006.

Older patients with ccRCC may respond better than younger patients to phosphoinositide 3-kinase (PI3K) or checkpoint inhibition because of age-related changes in gene expression, according to investigators.

This possibility was raised by in silico results from a broader study of gene expression patterns in clear cell renal carcinoma (ccRCC) and normal kidney tissues, reported lead author, Lara Feulner, MD, of the department of human genetics at McGill University and Genome Quebec Innovation Centre in Montreal.

“Several factors could contribute to the interindividual diversity among cancer patients,” the investigators wrote in a report published in Urologic Oncology.

“Their disease course could be affected not only by cell-intrinsic factors, but also by age-related changes impacting the vasculature, immune system and stroma. Little is known in this regard about ccRCC, a disease which affects adults across a wide age spectrum. Whether and how aging and comorbidities such as atherosclerosis may affect the biology and therapy of ccRCC has scarcely been considered,” they wrote.

The investigators explored this territory by analyzing datasets from The Cancer Genome Atlas (TCGA) and the Cancer Genomics of the Kidney (CAGEKID) program of the International Cancer Genome Consortium. Using regression, pathway enrichment, and connectivity mapping analyses, they were able to determine associations between age and gene expression, cellular processes, and drug treatment responses, respectively.

The investigators reported that age-related gene expression patterns occurred commonly in both normal and tumor tissues. Associations were reproducible between TCGA and CAGEKID datasets for both classes of tissue (tumor samples, R equal to 0.416, P less than 2.2 x 10-16; normal samples, R equal to 0.403, P less than 2.2 x 10-16). Out of the top 1,000 age-associated genes in tumor samples from each dataset, 383 were commonly downregulated with age and 294 were commonly upregulated with age in both datasets (P less than 2.2 x 10-16).

Among cellular pathways, the investigators found opposite age-relationship patterns. For example, normal tissues upregulated extracellular matrix and cell adhesion pathways with age, whereas tumor tissues downregulated the same pathways. Similar patterns of opposition were found in metabolism and oxidation pathways. Other age-related patterns were noted in some immune pathways, such as upregulation of toll-like receptor and tumor necrosis factor 2 noncanonical NF-kappa-B signaling in tumors, which became more common with age. A closer look showed that upregulation of tumor necrosis factor signaling was more common in female patients, who also downregulated Notch pathways more often than men.

Analysis of treatment responses showed possible relationships with age-dependent gene expression and immunotherapy. Specifically, of 532 genes tied to programmed cell death protein 1 (PD-1) resistance, 69 were among the 383 genes downregulated in older patients with ccRCC (P less than 2.2 x 10-16; 4.05 fold-enrichment), suggesting that older patients may respond better to anti-PD-1 therapy than younger patients. Similarly, connectivity map analysis showed that age-dependent gene expression may improve candidacy of older ccRCC patients for PI3K inhibition.

“We now have evidence that there are notable differences in tumor-associated pathway regulation between younger and older ccRCC patients, which may be therapeutically actionable,” the authors concluded.

The study was funded by the Cancer Research Society operation grant, a Canadian Cancer Society Research Institute Innovation-to-Impact grant, and a Canadian Institutes of Health Research Foundation grant. The authors reported no conflicts of interest.

SOURCE: Feulner et al. Urol Onc. 2018 Nov 23. doi: 10.1016/j.urolonc.2018.11.006.

Older patients with ccRCC may respond better than younger patients to phosphoinositide 3-kinase (PI3K) or checkpoint inhibition because of age-related changes in gene expression, according to investigators.

This possibility was raised by in silico results from a broader study of gene expression patterns in clear cell renal carcinoma (ccRCC) and normal kidney tissues, reported lead author, Lara Feulner, MD, of the department of human genetics at McGill University and Genome Quebec Innovation Centre in Montreal.

“Several factors could contribute to the interindividual diversity among cancer patients,” the investigators wrote in a report published in Urologic Oncology.

“Their disease course could be affected not only by cell-intrinsic factors, but also by age-related changes impacting the vasculature, immune system and stroma. Little is known in this regard about ccRCC, a disease which affects adults across a wide age spectrum. Whether and how aging and comorbidities such as atherosclerosis may affect the biology and therapy of ccRCC has scarcely been considered,” they wrote.

The investigators explored this territory by analyzing datasets from The Cancer Genome Atlas (TCGA) and the Cancer Genomics of the Kidney (CAGEKID) program of the International Cancer Genome Consortium. Using regression, pathway enrichment, and connectivity mapping analyses, they were able to determine associations between age and gene expression, cellular processes, and drug treatment responses, respectively.

The investigators reported that age-related gene expression patterns occurred commonly in both normal and tumor tissues. Associations were reproducible between TCGA and CAGEKID datasets for both classes of tissue (tumor samples, R equal to 0.416, P less than 2.2 x 10-16; normal samples, R equal to 0.403, P less than 2.2 x 10-16). Out of the top 1,000 age-associated genes in tumor samples from each dataset, 383 were commonly downregulated with age and 294 were commonly upregulated with age in both datasets (P less than 2.2 x 10-16).

Among cellular pathways, the investigators found opposite age-relationship patterns. For example, normal tissues upregulated extracellular matrix and cell adhesion pathways with age, whereas tumor tissues downregulated the same pathways. Similar patterns of opposition were found in metabolism and oxidation pathways. Other age-related patterns were noted in some immune pathways, such as upregulation of toll-like receptor and tumor necrosis factor 2 noncanonical NF-kappa-B signaling in tumors, which became more common with age. A closer look showed that upregulation of tumor necrosis factor signaling was more common in female patients, who also downregulated Notch pathways more often than men.

Analysis of treatment responses showed possible relationships with age-dependent gene expression and immunotherapy. Specifically, of 532 genes tied to programmed cell death protein 1 (PD-1) resistance, 69 were among the 383 genes downregulated in older patients with ccRCC (P less than 2.2 x 10-16; 4.05 fold-enrichment), suggesting that older patients may respond better to anti-PD-1 therapy than younger patients. Similarly, connectivity map analysis showed that age-dependent gene expression may improve candidacy of older ccRCC patients for PI3K inhibition.

“We now have evidence that there are notable differences in tumor-associated pathway regulation between younger and older ccRCC patients, which may be therapeutically actionable,” the authors concluded.

The study was funded by the Cancer Research Society operation grant, a Canadian Cancer Society Research Institute Innovation-to-Impact grant, and a Canadian Institutes of Health Research Foundation grant. The authors reported no conflicts of interest.

SOURCE: Feulner et al. Urol Onc. 2018 Nov 23. doi: 10.1016/j.urolonc.2018.11.006.

Photo by Chad McNeeley

A retrospective study suggests elderly patients with non-Hodgkin lymphoma (NHL) are more likely to die, but not relapse, within a year of allogeneic hematopoietic stem cell transplant (allo-HSCT).

The rate of non-relapse mortality (NRM) at 1 year was significantly higher for elderly patients than for middle-aged or young patients.

However, the 3-year rate of relapse was similar across the age groups.

Charalampia Kyriakou, MD, PhD, of University College London in the U.K., and her colleagues reported these findings in Biology of Blood and Marrow Transplantation.

The investigators analyzed 3,919 patients with NHL who underwent allo-HSCT between 2003 and 2013.

The patients had follicular lymphoma (n=1,461), diffuse large B-cell lymphoma (n=1,192), mantle cell lymphoma (n=823), and peripheral T-cell lymphoma (n=443).

At the time of transplant, about 85% of patients were chemo-sensitive, with the remainder being chemo-refractory.

Results

The investigators compared outcomes in patients assigned to three age groups—young (18-50), middle-aged (51-65), and elderly (66-77).

NRM at 1 year was 13% for young patients, 20% for middle-aged patients, and 33% for elderly patients (P<0.001).

Overall survival at 3 years was 60% in young patients, 54% in middle-aged patients, and 38% in the elderly (P<0.001).

In contrast to these significant associations between age and survival, the rate of relapse at 3 years remained relatively consistent—30% in young patients, 31% in middle-aged patients, and 28% in elderly patients (P=0.355).

The increased risk of NRM in elderly patients could not be fully explained by comorbidities, although these were more common in the elderly.

After analyzing information from a subset of patients, the investigators concluded that “the presence of comorbidities is a significant risk factor for NRM and survival, but this does not fully explain the outcome disadvantages in our [elderly] group.”

Therefore, age remains an independent risk factor.

The investigators did not report conflicts of interest.

Photo by Chad McNeeley

A retrospective study suggests elderly patients with non-Hodgkin lymphoma (NHL) are more likely to die, but not relapse, within a year of allogeneic hematopoietic stem cell transplant (allo-HSCT).

The rate of non-relapse mortality (NRM) at 1 year was significantly higher for elderly patients than for middle-aged or young patients.

However, the 3-year rate of relapse was similar across the age groups.

Charalampia Kyriakou, MD, PhD, of University College London in the U.K., and her colleagues reported these findings in Biology of Blood and Marrow Transplantation.

The investigators analyzed 3,919 patients with NHL who underwent allo-HSCT between 2003 and 2013.

The patients had follicular lymphoma (n=1,461), diffuse large B-cell lymphoma (n=1,192), mantle cell lymphoma (n=823), and peripheral T-cell lymphoma (n=443).

At the time of transplant, about 85% of patients were chemo-sensitive, with the remainder being chemo-refractory.

Results

The investigators compared outcomes in patients assigned to three age groups—young (18-50), middle-aged (51-65), and elderly (66-77).

NRM at 1 year was 13% for young patients, 20% for middle-aged patients, and 33% for elderly patients (P<0.001).

Overall survival at 3 years was 60% in young patients, 54% in middle-aged patients, and 38% in the elderly (P<0.001).

In contrast to these significant associations between age and survival, the rate of relapse at 3 years remained relatively consistent—30% in young patients, 31% in middle-aged patients, and 28% in elderly patients (P=0.355).

The increased risk of NRM in elderly patients could not be fully explained by comorbidities, although these were more common in the elderly.

After analyzing information from a subset of patients, the investigators concluded that “the presence of comorbidities is a significant risk factor for NRM and survival, but this does not fully explain the outcome disadvantages in our [elderly] group.”

Therefore, age remains an independent risk factor.

The investigators did not report conflicts of interest.

Photo by Chad McNeeley

A retrospective study suggests elderly patients with non-Hodgkin lymphoma (NHL) are more likely to die, but not relapse, within a year of allogeneic hematopoietic stem cell transplant (allo-HSCT).

The rate of non-relapse mortality (NRM) at 1 year was significantly higher for elderly patients than for middle-aged or young patients.

However, the 3-year rate of relapse was similar across the age groups.

Charalampia Kyriakou, MD, PhD, of University College London in the U.K., and her colleagues reported these findings in Biology of Blood and Marrow Transplantation.

The investigators analyzed 3,919 patients with NHL who underwent allo-HSCT between 2003 and 2013.

The patients had follicular lymphoma (n=1,461), diffuse large B-cell lymphoma (n=1,192), mantle cell lymphoma (n=823), and peripheral T-cell lymphoma (n=443).

At the time of transplant, about 85% of patients were chemo-sensitive, with the remainder being chemo-refractory.

Results

The investigators compared outcomes in patients assigned to three age groups—young (18-50), middle-aged (51-65), and elderly (66-77).

NRM at 1 year was 13% for young patients, 20% for middle-aged patients, and 33% for elderly patients (P<0.001).

Overall survival at 3 years was 60% in young patients, 54% in middle-aged patients, and 38% in the elderly (P<0.001).

In contrast to these significant associations between age and survival, the rate of relapse at 3 years remained relatively consistent—30% in young patients, 31% in middle-aged patients, and 28% in elderly patients (P=0.355).

The increased risk of NRM in elderly patients could not be fully explained by comorbidities, although these were more common in the elderly.

After analyzing information from a subset of patients, the investigators concluded that “the presence of comorbidities is a significant risk factor for NRM and survival, but this does not fully explain the outcome disadvantages in our [elderly] group.”

Therefore, age remains an independent risk factor.

The investigators did not report conflicts of interest.