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Can reversing T-cell exhaustion benefit in B-cell lymphoma relapse?
Durable remissions have been obtained in around 30%-40% of relapsed/refractory large B-cell lymphomas (BCL) through the use of CD19-directed chimeric antigen receptor-modified T-cell (CAR T-cell) therapy. However, T cell exhaustion and/or an immunosuppressive tumor environment may contribute to CAR T cell failure and BCL relapse.
To counter this failure, researchers assessed the use PD1 blockade with pembrolizumab after CD19-directed CAR T-cell therapy. Such treatment appeared safe and was able to achieve clinical responses in some patients with B-cell lymphomas refractory to or relapsed after CAR T-cell therapy, according to the results of a small study (NCT02650999) reported in Blood.
Success for some
Twelve patients with BCL who were either refractory to (nine patients) or relapsed after (three patients) CD19-directed CAR T-cell therapy were treated with pembrolizumab at 200 mg IV every 3 weeks, according to Elise A. Chong, MD, of the University of Pennsylvania, Philadelphia, and colleagues.
Overall, 3 of the 12 patients showed a response after pembrolizumab: One complete response; two partial responses. In addition, 1 patient had stable disease; thus, 4 of the 12 patients showed clinical benefit, according to the researchers. After pembrolizumab, these four patients with clinical benefit showed an increase in the percentage of CAR T cells as assessed by mass cytometry, and three out of the four also showed increases in CAR19 transgene levels as determined by qPCR. In addition, immune profiling using mass cytometry revealed increased CAR T-cell activation and proliferation and less T-cell exhaustion in these clinical responders.
In terms of safety, pembrolizumab appeared to be well tolerated and the only ≥ grade 3 adverse events related to pembrolizumab were neutropenia in three patients, the researchers added.
Looking forward
“Although patient numbers are small, these data suggest potential differences in the biology of CAR T cells or in the overall immune landscape of responders and nonresponders that influence the clinical efficacy of PD-1 blockade administered in this setting. Future work aimed at improving immune health after CAR T-cell infusion, as well as work aimed at decreasing CD8+ CAR T-cell exhaustion in CAR T-cell products, may serve as potential platforms for enhancing the efficacy of immune checkpoint blockade in patients treated with CAR T cells,” the researchers concluded.
The study was sponsored by the Abramson Cancer Center of the University of Pennsylvania. The authors reported serving on advisory boards and receiving research funding from a variety of pharmaceutical and biotechnology companies.
Durable remissions have been obtained in around 30%-40% of relapsed/refractory large B-cell lymphomas (BCL) through the use of CD19-directed chimeric antigen receptor-modified T-cell (CAR T-cell) therapy. However, T cell exhaustion and/or an immunosuppressive tumor environment may contribute to CAR T cell failure and BCL relapse.
To counter this failure, researchers assessed the use PD1 blockade with pembrolizumab after CD19-directed CAR T-cell therapy. Such treatment appeared safe and was able to achieve clinical responses in some patients with B-cell lymphomas refractory to or relapsed after CAR T-cell therapy, according to the results of a small study (NCT02650999) reported in Blood.
Success for some
Twelve patients with BCL who were either refractory to (nine patients) or relapsed after (three patients) CD19-directed CAR T-cell therapy were treated with pembrolizumab at 200 mg IV every 3 weeks, according to Elise A. Chong, MD, of the University of Pennsylvania, Philadelphia, and colleagues.
Overall, 3 of the 12 patients showed a response after pembrolizumab: One complete response; two partial responses. In addition, 1 patient had stable disease; thus, 4 of the 12 patients showed clinical benefit, according to the researchers. After pembrolizumab, these four patients with clinical benefit showed an increase in the percentage of CAR T cells as assessed by mass cytometry, and three out of the four also showed increases in CAR19 transgene levels as determined by qPCR. In addition, immune profiling using mass cytometry revealed increased CAR T-cell activation and proliferation and less T-cell exhaustion in these clinical responders.
In terms of safety, pembrolizumab appeared to be well tolerated and the only ≥ grade 3 adverse events related to pembrolizumab were neutropenia in three patients, the researchers added.
Looking forward
“Although patient numbers are small, these data suggest potential differences in the biology of CAR T cells or in the overall immune landscape of responders and nonresponders that influence the clinical efficacy of PD-1 blockade administered in this setting. Future work aimed at improving immune health after CAR T-cell infusion, as well as work aimed at decreasing CD8+ CAR T-cell exhaustion in CAR T-cell products, may serve as potential platforms for enhancing the efficacy of immune checkpoint blockade in patients treated with CAR T cells,” the researchers concluded.
The study was sponsored by the Abramson Cancer Center of the University of Pennsylvania. The authors reported serving on advisory boards and receiving research funding from a variety of pharmaceutical and biotechnology companies.
Durable remissions have been obtained in around 30%-40% of relapsed/refractory large B-cell lymphomas (BCL) through the use of CD19-directed chimeric antigen receptor-modified T-cell (CAR T-cell) therapy. However, T cell exhaustion and/or an immunosuppressive tumor environment may contribute to CAR T cell failure and BCL relapse.
To counter this failure, researchers assessed the use PD1 blockade with pembrolizumab after CD19-directed CAR T-cell therapy. Such treatment appeared safe and was able to achieve clinical responses in some patients with B-cell lymphomas refractory to or relapsed after CAR T-cell therapy, according to the results of a small study (NCT02650999) reported in Blood.
Success for some
Twelve patients with BCL who were either refractory to (nine patients) or relapsed after (three patients) CD19-directed CAR T-cell therapy were treated with pembrolizumab at 200 mg IV every 3 weeks, according to Elise A. Chong, MD, of the University of Pennsylvania, Philadelphia, and colleagues.
Overall, 3 of the 12 patients showed a response after pembrolizumab: One complete response; two partial responses. In addition, 1 patient had stable disease; thus, 4 of the 12 patients showed clinical benefit, according to the researchers. After pembrolizumab, these four patients with clinical benefit showed an increase in the percentage of CAR T cells as assessed by mass cytometry, and three out of the four also showed increases in CAR19 transgene levels as determined by qPCR. In addition, immune profiling using mass cytometry revealed increased CAR T-cell activation and proliferation and less T-cell exhaustion in these clinical responders.
In terms of safety, pembrolizumab appeared to be well tolerated and the only ≥ grade 3 adverse events related to pembrolizumab were neutropenia in three patients, the researchers added.
Looking forward
“Although patient numbers are small, these data suggest potential differences in the biology of CAR T cells or in the overall immune landscape of responders and nonresponders that influence the clinical efficacy of PD-1 blockade administered in this setting. Future work aimed at improving immune health after CAR T-cell infusion, as well as work aimed at decreasing CD8+ CAR T-cell exhaustion in CAR T-cell products, may serve as potential platforms for enhancing the efficacy of immune checkpoint blockade in patients treated with CAR T cells,” the researchers concluded.
The study was sponsored by the Abramson Cancer Center of the University of Pennsylvania. The authors reported serving on advisory boards and receiving research funding from a variety of pharmaceutical and biotechnology companies.
FROM BLOOD
Gluten-free diet may reduce cancer risk in celiac disease
Overall cancer risk is slightly increased in patients older than 40 years within their first year of a celiac disease diagnosis, but the risk drops within a year of diagnosis, shows a Swedish study of 47,000 people with celiac disease.
“Celiac disease is associated with an increased risk of types of cancer, and we believe that this is due to the longstanding inflammation that is induced by gluten,” said first author Benjamin Lebwohl, MD, director of clinical research at the Columbia University Celiac Disease Center in New York.
Writing in Clinical Gastroenterology and Hepatology, the authors explained that most studies investigating cancer risk in patients with celiac disease were done before both the widespread use of serologic testing for celiac disease and access to gluten-free food was widely available. Earlier studies linked celiac disease to gastrointestinal malignancies, such as small intestinal adenocarcinoma, and lymphomas.
A prior analysis of this Swedish cohort found that the risk of small intestinal adenocarcinoma, while low, continued for up to 10 years after diagnosis with celiac disease. In the study, which was published in Gastroenterology, the authors found the risks of small-bowel adenocarcinoma and adenomas were significantly increased in people with celiac disease, compared with those without this disease.
“We have known from prior studies that people with celiac disease are at increased risk of developing certain cancers, but there has been limited study of this risk in celiac disease in the 21st century, where there is increased recognition (leading to more prompt diagnosis) and increased access to gluten-free food options (which may allow for more effective treatment),” said Dr. Lebwohl, who is also the director of quality improvement in the division of digestive and liver diseases at Columbia University. “We aimed to determine whether there is still an increased risk of cancer in this modern era, and we found that there still is an increased risk, but this increase is small and that it diminishes beyond the first year after the diagnosis of celiac disease.”
This nationwide cohort study in Sweden included 47,241 patients with celiac disease (62% female; mean age, 24 years), of which 64% were diagnosed since 2000. Each patient was age and sex matched to up to five controls. After a median follow-up of 11.5 years, a 1.11-fold increased risk of cancer overall was found in patients with celiac disease, compared with controls. The respective incidences of cancer were 6.5 and 5.7 per 1,000 person-years, and most of the excess risk was caused by gastrointestinal and hematologic cancer.
The overall risk of cancer was increased in the first year after celiac disease diagnosis (HR, 2.47; 95% CI, 2.22-2.74) but not afterwards (HR, 1.01; 95% CI, 0.97-1.05).
“It appears that the increased risk of cancer in people with celiac disease decreased over time, and this may be related to the beneficial effect of the gluten-free diet in the long term,” Dr. Lebwohl said.
The authors suggest that cancer risk, followed by a decline to no risk, may alternatively be due to the increased monitoring and medical examinations among patients with celiac disease. Also, symptoms of cancer, such as weight loss, may lead to broad testing that identifies celiac disease, the authors wrote.
For cancer subtypes, the strongest association between celiac disease and cancer was found for hematologic, lymphoproliferative and gastrointestinal cancers. Among gastrointestinal cancer subtypes, elevated risks were found for hepatobiliary and pancreatic cancer, but not for gastric or colorectal cancer. The cancer risk in celiac disease decreased in breast and lung cancer, which the authors suggested may be attributed to lower body mass index and smoking rates, respectively, observed in individuals with celiac disease.
Certain cancer types persist after 1 year
Although there was no overall cancer risk for more than 1 year after celiac disease diagnosis, the risks of hematologic and lymphoproliferative cancers persisted. While the increased risk of gastrointestinal cancers collectively was no longer significant beyond 1 year after celiac disease diagnosis, the risk persisted for hepatobiliary and pancreatic cancer.
“We found that the risk of gastrointestinal cancers is increased in people with celiac disease, compared to the general population, but these risks vary according to the cancer type,” Dr. Lebwohl said. “For instance, the risk of pancreatic cancer is increased in people with celiac disease, compared to the general population, while the risk of colon cancer in people with celiac disease is not increased, compared to the general population.
“But pancreatic cancer is far less common than colon cancer. We found that pancreatic cancer occurs in 1 in 5,000 people with celiac disease per year, whereas colorectal cancer occurred in 1 in 1,400 people per year. Taken all together, the risk of any gastrointestinal cancer was around 1 in 700 per year among people with celiac disease,” Dr. Lebwohl said.
The overall cancer risk was highest in patients diagnosed with celiac disease after age 60 and was not increased in those diagnosed with celiac disease before age 40. The authors noted that, in recent years, there has been a pronounced increase in the diagnosis of celiac disease in people aged over 60, an age group with a higher risk of developing severe outcomes related to refractory celiac disease. The cancer risk was similar among patients diagnosed with celiac disease before or after 2000.
Since this is an observational study, causality cannot be proven, and the authors suggested that the findings may not be applicable to settings outside of the relatively homogeneous ethnic population of Sweden.
Carol E. Semrad, MD, professor of medicine and director of clinical research in the Celiac Center at the University of Chicago Medicine, said: “This is an observational study and therefore cannot answer whether celiac disease is the cause of cancer or merely an association.” She added that “it is unknown why the risk for some cancers is higher in celiac disease.
“This paper argues against delayed diagnosis and low detection rate to explain the increase in cancer risk as those diagnosed with celiac disease prior to 2000 had the same cancer risk as those diagnosed after 2000 when diagnostic testing, earlier diagnosis, and access to a gluten-free diet were better,” Dr. Semrad said.
Link to mortality data
The authors said increased cancer risk being restricted to the first year of diagnosis is consistent with prior celiac disease studies of morbidity and mortality.
A study published in 2019 in United European Gastroenterology looked at mortality risk in 602 patients with celiac disease from Lothian, Scotland, identified between 1979 and 1983 and followed up from 1970 to 2016. All-cause mortality was 43% higher than in the general population, mainly from hematologic malignancies, and this risk was greatest during the first few years of diagnosis.
An analysis of cause-specific mortality in the Swedish cohort, published in 2020 in JAMA, found that celiac disease was associated with a small but statistically significant increased mortality risk. After a median follow-up of 12.5 years of 49,829 patients with celiac disease, the mortality rate was 9.7 and 8.6 deaths per 1000 person-years, compared with the general population, respectively. Individuals with celiac disease were at increased risk of death from cancer, cardiovascular disease and respiratory disease. The overall mortality risk was greatest in the first year after diagnosis with celiac disease, after which the risk diminished with the establishment of the gluten-free diet but remained modestly elevated in the long term.
However, a Finnish population-based study, published in the American Journal of Gastroenterology, found no increase in overall mortality in patients with celiac disease. The study included 12,803 adults diagnosed with celiac disease between 2005 and 2014. Participants were followed for an average of 7.7 years and mortality from all malignancies, gastrointestinal tract malignancies or cardiovascular diseases were not increased among patients with celiac disease, compared with the general population. Mortality from lymphoproliferative diseases was increased in patients with celiac disease but was lower than previously reported.
Dr. Lebwohl and colleagues noted that the incidences of cancer types vary by the age and geographical region of the study population, as does the diagnosis of celiac disease, which may explain why increased risk for cancer or cancer related-mortality in patients with celiac disease has not always been reported.
Dr Ludvigsson coordinates a study on behalf of the Swedish IBD quality register. This study has received funding from Janssen. The remaining authors disclosed no conflicts.
Overall cancer risk is slightly increased in patients older than 40 years within their first year of a celiac disease diagnosis, but the risk drops within a year of diagnosis, shows a Swedish study of 47,000 people with celiac disease.
“Celiac disease is associated with an increased risk of types of cancer, and we believe that this is due to the longstanding inflammation that is induced by gluten,” said first author Benjamin Lebwohl, MD, director of clinical research at the Columbia University Celiac Disease Center in New York.
Writing in Clinical Gastroenterology and Hepatology, the authors explained that most studies investigating cancer risk in patients with celiac disease were done before both the widespread use of serologic testing for celiac disease and access to gluten-free food was widely available. Earlier studies linked celiac disease to gastrointestinal malignancies, such as small intestinal adenocarcinoma, and lymphomas.
A prior analysis of this Swedish cohort found that the risk of small intestinal adenocarcinoma, while low, continued for up to 10 years after diagnosis with celiac disease. In the study, which was published in Gastroenterology, the authors found the risks of small-bowel adenocarcinoma and adenomas were significantly increased in people with celiac disease, compared with those without this disease.
“We have known from prior studies that people with celiac disease are at increased risk of developing certain cancers, but there has been limited study of this risk in celiac disease in the 21st century, where there is increased recognition (leading to more prompt diagnosis) and increased access to gluten-free food options (which may allow for more effective treatment),” said Dr. Lebwohl, who is also the director of quality improvement in the division of digestive and liver diseases at Columbia University. “We aimed to determine whether there is still an increased risk of cancer in this modern era, and we found that there still is an increased risk, but this increase is small and that it diminishes beyond the first year after the diagnosis of celiac disease.”
This nationwide cohort study in Sweden included 47,241 patients with celiac disease (62% female; mean age, 24 years), of which 64% were diagnosed since 2000. Each patient was age and sex matched to up to five controls. After a median follow-up of 11.5 years, a 1.11-fold increased risk of cancer overall was found in patients with celiac disease, compared with controls. The respective incidences of cancer were 6.5 and 5.7 per 1,000 person-years, and most of the excess risk was caused by gastrointestinal and hematologic cancer.
The overall risk of cancer was increased in the first year after celiac disease diagnosis (HR, 2.47; 95% CI, 2.22-2.74) but not afterwards (HR, 1.01; 95% CI, 0.97-1.05).
“It appears that the increased risk of cancer in people with celiac disease decreased over time, and this may be related to the beneficial effect of the gluten-free diet in the long term,” Dr. Lebwohl said.
The authors suggest that cancer risk, followed by a decline to no risk, may alternatively be due to the increased monitoring and medical examinations among patients with celiac disease. Also, symptoms of cancer, such as weight loss, may lead to broad testing that identifies celiac disease, the authors wrote.
For cancer subtypes, the strongest association between celiac disease and cancer was found for hematologic, lymphoproliferative and gastrointestinal cancers. Among gastrointestinal cancer subtypes, elevated risks were found for hepatobiliary and pancreatic cancer, but not for gastric or colorectal cancer. The cancer risk in celiac disease decreased in breast and lung cancer, which the authors suggested may be attributed to lower body mass index and smoking rates, respectively, observed in individuals with celiac disease.
Certain cancer types persist after 1 year
Although there was no overall cancer risk for more than 1 year after celiac disease diagnosis, the risks of hematologic and lymphoproliferative cancers persisted. While the increased risk of gastrointestinal cancers collectively was no longer significant beyond 1 year after celiac disease diagnosis, the risk persisted for hepatobiliary and pancreatic cancer.
“We found that the risk of gastrointestinal cancers is increased in people with celiac disease, compared to the general population, but these risks vary according to the cancer type,” Dr. Lebwohl said. “For instance, the risk of pancreatic cancer is increased in people with celiac disease, compared to the general population, while the risk of colon cancer in people with celiac disease is not increased, compared to the general population.
“But pancreatic cancer is far less common than colon cancer. We found that pancreatic cancer occurs in 1 in 5,000 people with celiac disease per year, whereas colorectal cancer occurred in 1 in 1,400 people per year. Taken all together, the risk of any gastrointestinal cancer was around 1 in 700 per year among people with celiac disease,” Dr. Lebwohl said.
The overall cancer risk was highest in patients diagnosed with celiac disease after age 60 and was not increased in those diagnosed with celiac disease before age 40. The authors noted that, in recent years, there has been a pronounced increase in the diagnosis of celiac disease in people aged over 60, an age group with a higher risk of developing severe outcomes related to refractory celiac disease. The cancer risk was similar among patients diagnosed with celiac disease before or after 2000.
Since this is an observational study, causality cannot be proven, and the authors suggested that the findings may not be applicable to settings outside of the relatively homogeneous ethnic population of Sweden.
Carol E. Semrad, MD, professor of medicine and director of clinical research in the Celiac Center at the University of Chicago Medicine, said: “This is an observational study and therefore cannot answer whether celiac disease is the cause of cancer or merely an association.” She added that “it is unknown why the risk for some cancers is higher in celiac disease.
“This paper argues against delayed diagnosis and low detection rate to explain the increase in cancer risk as those diagnosed with celiac disease prior to 2000 had the same cancer risk as those diagnosed after 2000 when diagnostic testing, earlier diagnosis, and access to a gluten-free diet were better,” Dr. Semrad said.
Link to mortality data
The authors said increased cancer risk being restricted to the first year of diagnosis is consistent with prior celiac disease studies of morbidity and mortality.
A study published in 2019 in United European Gastroenterology looked at mortality risk in 602 patients with celiac disease from Lothian, Scotland, identified between 1979 and 1983 and followed up from 1970 to 2016. All-cause mortality was 43% higher than in the general population, mainly from hematologic malignancies, and this risk was greatest during the first few years of diagnosis.
An analysis of cause-specific mortality in the Swedish cohort, published in 2020 in JAMA, found that celiac disease was associated with a small but statistically significant increased mortality risk. After a median follow-up of 12.5 years of 49,829 patients with celiac disease, the mortality rate was 9.7 and 8.6 deaths per 1000 person-years, compared with the general population, respectively. Individuals with celiac disease were at increased risk of death from cancer, cardiovascular disease and respiratory disease. The overall mortality risk was greatest in the first year after diagnosis with celiac disease, after which the risk diminished with the establishment of the gluten-free diet but remained modestly elevated in the long term.
However, a Finnish population-based study, published in the American Journal of Gastroenterology, found no increase in overall mortality in patients with celiac disease. The study included 12,803 adults diagnosed with celiac disease between 2005 and 2014. Participants were followed for an average of 7.7 years and mortality from all malignancies, gastrointestinal tract malignancies or cardiovascular diseases were not increased among patients with celiac disease, compared with the general population. Mortality from lymphoproliferative diseases was increased in patients with celiac disease but was lower than previously reported.
Dr. Lebwohl and colleagues noted that the incidences of cancer types vary by the age and geographical region of the study population, as does the diagnosis of celiac disease, which may explain why increased risk for cancer or cancer related-mortality in patients with celiac disease has not always been reported.
Dr Ludvigsson coordinates a study on behalf of the Swedish IBD quality register. This study has received funding from Janssen. The remaining authors disclosed no conflicts.
Overall cancer risk is slightly increased in patients older than 40 years within their first year of a celiac disease diagnosis, but the risk drops within a year of diagnosis, shows a Swedish study of 47,000 people with celiac disease.
“Celiac disease is associated with an increased risk of types of cancer, and we believe that this is due to the longstanding inflammation that is induced by gluten,” said first author Benjamin Lebwohl, MD, director of clinical research at the Columbia University Celiac Disease Center in New York.
Writing in Clinical Gastroenterology and Hepatology, the authors explained that most studies investigating cancer risk in patients with celiac disease were done before both the widespread use of serologic testing for celiac disease and access to gluten-free food was widely available. Earlier studies linked celiac disease to gastrointestinal malignancies, such as small intestinal adenocarcinoma, and lymphomas.
A prior analysis of this Swedish cohort found that the risk of small intestinal adenocarcinoma, while low, continued for up to 10 years after diagnosis with celiac disease. In the study, which was published in Gastroenterology, the authors found the risks of small-bowel adenocarcinoma and adenomas were significantly increased in people with celiac disease, compared with those without this disease.
“We have known from prior studies that people with celiac disease are at increased risk of developing certain cancers, but there has been limited study of this risk in celiac disease in the 21st century, where there is increased recognition (leading to more prompt diagnosis) and increased access to gluten-free food options (which may allow for more effective treatment),” said Dr. Lebwohl, who is also the director of quality improvement in the division of digestive and liver diseases at Columbia University. “We aimed to determine whether there is still an increased risk of cancer in this modern era, and we found that there still is an increased risk, but this increase is small and that it diminishes beyond the first year after the diagnosis of celiac disease.”
This nationwide cohort study in Sweden included 47,241 patients with celiac disease (62% female; mean age, 24 years), of which 64% were diagnosed since 2000. Each patient was age and sex matched to up to five controls. After a median follow-up of 11.5 years, a 1.11-fold increased risk of cancer overall was found in patients with celiac disease, compared with controls. The respective incidences of cancer were 6.5 and 5.7 per 1,000 person-years, and most of the excess risk was caused by gastrointestinal and hematologic cancer.
The overall risk of cancer was increased in the first year after celiac disease diagnosis (HR, 2.47; 95% CI, 2.22-2.74) but not afterwards (HR, 1.01; 95% CI, 0.97-1.05).
“It appears that the increased risk of cancer in people with celiac disease decreased over time, and this may be related to the beneficial effect of the gluten-free diet in the long term,” Dr. Lebwohl said.
The authors suggest that cancer risk, followed by a decline to no risk, may alternatively be due to the increased monitoring and medical examinations among patients with celiac disease. Also, symptoms of cancer, such as weight loss, may lead to broad testing that identifies celiac disease, the authors wrote.
For cancer subtypes, the strongest association between celiac disease and cancer was found for hematologic, lymphoproliferative and gastrointestinal cancers. Among gastrointestinal cancer subtypes, elevated risks were found for hepatobiliary and pancreatic cancer, but not for gastric or colorectal cancer. The cancer risk in celiac disease decreased in breast and lung cancer, which the authors suggested may be attributed to lower body mass index and smoking rates, respectively, observed in individuals with celiac disease.
Certain cancer types persist after 1 year
Although there was no overall cancer risk for more than 1 year after celiac disease diagnosis, the risks of hematologic and lymphoproliferative cancers persisted. While the increased risk of gastrointestinal cancers collectively was no longer significant beyond 1 year after celiac disease diagnosis, the risk persisted for hepatobiliary and pancreatic cancer.
“We found that the risk of gastrointestinal cancers is increased in people with celiac disease, compared to the general population, but these risks vary according to the cancer type,” Dr. Lebwohl said. “For instance, the risk of pancreatic cancer is increased in people with celiac disease, compared to the general population, while the risk of colon cancer in people with celiac disease is not increased, compared to the general population.
“But pancreatic cancer is far less common than colon cancer. We found that pancreatic cancer occurs in 1 in 5,000 people with celiac disease per year, whereas colorectal cancer occurred in 1 in 1,400 people per year. Taken all together, the risk of any gastrointestinal cancer was around 1 in 700 per year among people with celiac disease,” Dr. Lebwohl said.
The overall cancer risk was highest in patients diagnosed with celiac disease after age 60 and was not increased in those diagnosed with celiac disease before age 40. The authors noted that, in recent years, there has been a pronounced increase in the diagnosis of celiac disease in people aged over 60, an age group with a higher risk of developing severe outcomes related to refractory celiac disease. The cancer risk was similar among patients diagnosed with celiac disease before or after 2000.
Since this is an observational study, causality cannot be proven, and the authors suggested that the findings may not be applicable to settings outside of the relatively homogeneous ethnic population of Sweden.
Carol E. Semrad, MD, professor of medicine and director of clinical research in the Celiac Center at the University of Chicago Medicine, said: “This is an observational study and therefore cannot answer whether celiac disease is the cause of cancer or merely an association.” She added that “it is unknown why the risk for some cancers is higher in celiac disease.
“This paper argues against delayed diagnosis and low detection rate to explain the increase in cancer risk as those diagnosed with celiac disease prior to 2000 had the same cancer risk as those diagnosed after 2000 when diagnostic testing, earlier diagnosis, and access to a gluten-free diet were better,” Dr. Semrad said.
Link to mortality data
The authors said increased cancer risk being restricted to the first year of diagnosis is consistent with prior celiac disease studies of morbidity and mortality.
A study published in 2019 in United European Gastroenterology looked at mortality risk in 602 patients with celiac disease from Lothian, Scotland, identified between 1979 and 1983 and followed up from 1970 to 2016. All-cause mortality was 43% higher than in the general population, mainly from hematologic malignancies, and this risk was greatest during the first few years of diagnosis.
An analysis of cause-specific mortality in the Swedish cohort, published in 2020 in JAMA, found that celiac disease was associated with a small but statistically significant increased mortality risk. After a median follow-up of 12.5 years of 49,829 patients with celiac disease, the mortality rate was 9.7 and 8.6 deaths per 1000 person-years, compared with the general population, respectively. Individuals with celiac disease were at increased risk of death from cancer, cardiovascular disease and respiratory disease. The overall mortality risk was greatest in the first year after diagnosis with celiac disease, after which the risk diminished with the establishment of the gluten-free diet but remained modestly elevated in the long term.
However, a Finnish population-based study, published in the American Journal of Gastroenterology, found no increase in overall mortality in patients with celiac disease. The study included 12,803 adults diagnosed with celiac disease between 2005 and 2014. Participants were followed for an average of 7.7 years and mortality from all malignancies, gastrointestinal tract malignancies or cardiovascular diseases were not increased among patients with celiac disease, compared with the general population. Mortality from lymphoproliferative diseases was increased in patients with celiac disease but was lower than previously reported.
Dr. Lebwohl and colleagues noted that the incidences of cancer types vary by the age and geographical region of the study population, as does the diagnosis of celiac disease, which may explain why increased risk for cancer or cancer related-mortality in patients with celiac disease has not always been reported.
Dr Ludvigsson coordinates a study on behalf of the Swedish IBD quality register. This study has received funding from Janssen. The remaining authors disclosed no conflicts.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Data supporting cannabis for childhood epilepsy remain scarce
, according to two leading experts.
In a recent invited review article, Martin Kirkpatrick, MD, of the University of Dundee (Scotland), and Finbar O’Callaghan, MD, PhD, of University College London suggested that childhood epilepsy may be easy terrain for commercial interests to break ground, and from there, build their presence.
“Children with epilepsy are at risk of being used as the ‘Trojan horse’ for the cannabis industry,” Dr. Kirkpatrick and Dr. O’Callaghan wrote in Developmental Medicine & Child Neurology.
They noted that some of the first publicized success stories involving cannabis oil for epilepsy coincided with the rise of the medicinal and recreational cannabis markets, which will constitute an estimated 55-billion-dollar industry by 2027.
“Pediatric neurologists, imbued with the need to practice evidence-based medicine and wary of prescribing unlicensed medicines that had inadequate safety data, suddenly found themselves at odds with an array of vested interests and, most unfortunately, with the families of patients who were keen to try anything that would alleviate the effects of their child’s seizures,” the investigators wrote.
According to the review, fundamental questions about cannabis remain unanswered, including concerns about safety with long-term use, and the medicinal value of various plant components, such as myrcene, a terpene that gives cannabis its characteristic smell.
“A widely discussed issue is whether the terpenes add any therapeutic benefit, contributing to the so-called entourage effect of ‘whole-plant’ medicines,” the investigators wrote. “The concept is that all the constituents of the plant together create ‘the sum of all the parts that leads to the magic or power of cannabis.’ Although commonly referred to, there is little or no robust evidence to support the entourage effect as a credible clinical concept.”
Clinical evidence for treatment of pediatric epilepsy is also lacking, according to Dr. Kirkpatrick and Dr. O’Callaghan.
“Unfortunately, apart from the studies of pure cannabidiol (CBD) in Lennox–Gastaut and Dravet syndromes and tuberous sclerosis complex, level I evidence in the field of CBMPs and refractory epilepsy is lacking,” they wrote.
While other experts have pointed out that lower-level evidence – such as patient-reported outcomes and observational data – have previously been sufficient for drug licensing, Dr. Kirkpatrick and Dr. O’Callaghan noted that such exceptions “almost always” involve conditions without any effective treatments, or drugs that are undeniably effective.
“This is not the scenario with CBMPs,” they wrote, referring to current clinical data as “low-level” evidence “suggesting … possible efficacy.”
They highlighted concerns about placebo effect with open-label epilepsy studies, citing a randomized controlled trial for Dravet syndrome, in which 27% of patients given placebo had a 50% reduction in seizure frequency.
“We need carefully designed, good-quality CBMP studies that produce results on which we can rely,” Dr. Kirkpatrick and Dr. O’Callaghan concluded. “We can then work with families to choose the best treatments for children and young people with epilepsy. We owe this to them.”
A therapy of last resort
Jerzy P. Szaflarski, MD, PhD, of the University of Alabama at Birmingham, agreed that data are lacking for the use of CBMPs with patients who have epilepsy and other neurologic conditions; however, he also suggested that Dr. Kirkpatrick and Dr. O’Callaghan did not provide adequate real-world clinical context.
“Medical cannabis is not used as a first-, second-, or third-line therapy,” Dr. Szaflarski said. “It’s mostly used as a last resort in the sense that patients have already failed multiple other therapies.” In that respect, patients and parents are desperate to try anything that might work. “We have medical cannabis, and our patients want to try it, and at the point when multiple therapies have failed, it’s a reasonable option.”
While Dr. Szaflarski agreed that more high-quality clinical trials are needed, he also noted the practical challenges involved in such trials, largely because of variations in cannabis plants.
“The content of the cannabis plant changes depending on the day that it’s collected and the exposure to sun and how much water it has and what’s in the soil and many other things,” Dr. Szaflarski said. “It’s hard to get a very good, standardized product, and that’s why there needs to be a good-quality product delivered by the industry, which I have not seen thus far.”
For this reason, Dr. Szaflarski steers parents and patients away from over-the-counter CBMPs and toward Epidiolex, the only FDA-approved form of CBD.
“There is evidence that Epidiolex works,” he said. “I don’t know whether the products that are sold in a local cannabis store have the same high purity as Epidiolex. I tell [parents] that we should try Epidiolex first because it’s the one that is approved. But if it doesn’t work, we can go in that [other] direction.”
For those going the commercial route, Dr. Szaflarski advised close attention to product ingredients, to ensure that CBMPs are “devoid of any impurities, pesticides, fungicides, and other products that could be potentially dangerous.”
Parents considering CBMPs for their children also need to weigh concerns about long-term neurological safety, he added, noting that, on one hand, commercial products lack data, while on the other, epilepsy itself may cause harm.
“They need to consider the potential effects [of CBMPs] on their child’s brain and development versus … the effects of seizures on the brain,” Dr. Szaflarski said.
Dr. Kirkpatrick and Dr. O’Callaghan disclosed an application for a National Institute for Health Research–funded randomized controlled trial on CBMPs and joint authorship of British Paediatric Neurology Association Guidance on the use of CBMPs in children and young people with epilepsy. Dr. Szaflarski disclosed a relationship with Greenwich Biosciences and several other cannabis companies.
, according to two leading experts.
In a recent invited review article, Martin Kirkpatrick, MD, of the University of Dundee (Scotland), and Finbar O’Callaghan, MD, PhD, of University College London suggested that childhood epilepsy may be easy terrain for commercial interests to break ground, and from there, build their presence.
“Children with epilepsy are at risk of being used as the ‘Trojan horse’ for the cannabis industry,” Dr. Kirkpatrick and Dr. O’Callaghan wrote in Developmental Medicine & Child Neurology.
They noted that some of the first publicized success stories involving cannabis oil for epilepsy coincided with the rise of the medicinal and recreational cannabis markets, which will constitute an estimated 55-billion-dollar industry by 2027.
“Pediatric neurologists, imbued with the need to practice evidence-based medicine and wary of prescribing unlicensed medicines that had inadequate safety data, suddenly found themselves at odds with an array of vested interests and, most unfortunately, with the families of patients who were keen to try anything that would alleviate the effects of their child’s seizures,” the investigators wrote.
According to the review, fundamental questions about cannabis remain unanswered, including concerns about safety with long-term use, and the medicinal value of various plant components, such as myrcene, a terpene that gives cannabis its characteristic smell.
“A widely discussed issue is whether the terpenes add any therapeutic benefit, contributing to the so-called entourage effect of ‘whole-plant’ medicines,” the investigators wrote. “The concept is that all the constituents of the plant together create ‘the sum of all the parts that leads to the magic or power of cannabis.’ Although commonly referred to, there is little or no robust evidence to support the entourage effect as a credible clinical concept.”
Clinical evidence for treatment of pediatric epilepsy is also lacking, according to Dr. Kirkpatrick and Dr. O’Callaghan.
“Unfortunately, apart from the studies of pure cannabidiol (CBD) in Lennox–Gastaut and Dravet syndromes and tuberous sclerosis complex, level I evidence in the field of CBMPs and refractory epilepsy is lacking,” they wrote.
While other experts have pointed out that lower-level evidence – such as patient-reported outcomes and observational data – have previously been sufficient for drug licensing, Dr. Kirkpatrick and Dr. O’Callaghan noted that such exceptions “almost always” involve conditions without any effective treatments, or drugs that are undeniably effective.
“This is not the scenario with CBMPs,” they wrote, referring to current clinical data as “low-level” evidence “suggesting … possible efficacy.”
They highlighted concerns about placebo effect with open-label epilepsy studies, citing a randomized controlled trial for Dravet syndrome, in which 27% of patients given placebo had a 50% reduction in seizure frequency.
“We need carefully designed, good-quality CBMP studies that produce results on which we can rely,” Dr. Kirkpatrick and Dr. O’Callaghan concluded. “We can then work with families to choose the best treatments for children and young people with epilepsy. We owe this to them.”
A therapy of last resort
Jerzy P. Szaflarski, MD, PhD, of the University of Alabama at Birmingham, agreed that data are lacking for the use of CBMPs with patients who have epilepsy and other neurologic conditions; however, he also suggested that Dr. Kirkpatrick and Dr. O’Callaghan did not provide adequate real-world clinical context.
“Medical cannabis is not used as a first-, second-, or third-line therapy,” Dr. Szaflarski said. “It’s mostly used as a last resort in the sense that patients have already failed multiple other therapies.” In that respect, patients and parents are desperate to try anything that might work. “We have medical cannabis, and our patients want to try it, and at the point when multiple therapies have failed, it’s a reasonable option.”
While Dr. Szaflarski agreed that more high-quality clinical trials are needed, he also noted the practical challenges involved in such trials, largely because of variations in cannabis plants.
“The content of the cannabis plant changes depending on the day that it’s collected and the exposure to sun and how much water it has and what’s in the soil and many other things,” Dr. Szaflarski said. “It’s hard to get a very good, standardized product, and that’s why there needs to be a good-quality product delivered by the industry, which I have not seen thus far.”
For this reason, Dr. Szaflarski steers parents and patients away from over-the-counter CBMPs and toward Epidiolex, the only FDA-approved form of CBD.
“There is evidence that Epidiolex works,” he said. “I don’t know whether the products that are sold in a local cannabis store have the same high purity as Epidiolex. I tell [parents] that we should try Epidiolex first because it’s the one that is approved. But if it doesn’t work, we can go in that [other] direction.”
For those going the commercial route, Dr. Szaflarski advised close attention to product ingredients, to ensure that CBMPs are “devoid of any impurities, pesticides, fungicides, and other products that could be potentially dangerous.”
Parents considering CBMPs for their children also need to weigh concerns about long-term neurological safety, he added, noting that, on one hand, commercial products lack data, while on the other, epilepsy itself may cause harm.
“They need to consider the potential effects [of CBMPs] on their child’s brain and development versus … the effects of seizures on the brain,” Dr. Szaflarski said.
Dr. Kirkpatrick and Dr. O’Callaghan disclosed an application for a National Institute for Health Research–funded randomized controlled trial on CBMPs and joint authorship of British Paediatric Neurology Association Guidance on the use of CBMPs in children and young people with epilepsy. Dr. Szaflarski disclosed a relationship with Greenwich Biosciences and several other cannabis companies.
, according to two leading experts.
In a recent invited review article, Martin Kirkpatrick, MD, of the University of Dundee (Scotland), and Finbar O’Callaghan, MD, PhD, of University College London suggested that childhood epilepsy may be easy terrain for commercial interests to break ground, and from there, build their presence.
“Children with epilepsy are at risk of being used as the ‘Trojan horse’ for the cannabis industry,” Dr. Kirkpatrick and Dr. O’Callaghan wrote in Developmental Medicine & Child Neurology.
They noted that some of the first publicized success stories involving cannabis oil for epilepsy coincided with the rise of the medicinal and recreational cannabis markets, which will constitute an estimated 55-billion-dollar industry by 2027.
“Pediatric neurologists, imbued with the need to practice evidence-based medicine and wary of prescribing unlicensed medicines that had inadequate safety data, suddenly found themselves at odds with an array of vested interests and, most unfortunately, with the families of patients who were keen to try anything that would alleviate the effects of their child’s seizures,” the investigators wrote.
According to the review, fundamental questions about cannabis remain unanswered, including concerns about safety with long-term use, and the medicinal value of various plant components, such as myrcene, a terpene that gives cannabis its characteristic smell.
“A widely discussed issue is whether the terpenes add any therapeutic benefit, contributing to the so-called entourage effect of ‘whole-plant’ medicines,” the investigators wrote. “The concept is that all the constituents of the plant together create ‘the sum of all the parts that leads to the magic or power of cannabis.’ Although commonly referred to, there is little or no robust evidence to support the entourage effect as a credible clinical concept.”
Clinical evidence for treatment of pediatric epilepsy is also lacking, according to Dr. Kirkpatrick and Dr. O’Callaghan.
“Unfortunately, apart from the studies of pure cannabidiol (CBD) in Lennox–Gastaut and Dravet syndromes and tuberous sclerosis complex, level I evidence in the field of CBMPs and refractory epilepsy is lacking,” they wrote.
While other experts have pointed out that lower-level evidence – such as patient-reported outcomes and observational data – have previously been sufficient for drug licensing, Dr. Kirkpatrick and Dr. O’Callaghan noted that such exceptions “almost always” involve conditions without any effective treatments, or drugs that are undeniably effective.
“This is not the scenario with CBMPs,” they wrote, referring to current clinical data as “low-level” evidence “suggesting … possible efficacy.”
They highlighted concerns about placebo effect with open-label epilepsy studies, citing a randomized controlled trial for Dravet syndrome, in which 27% of patients given placebo had a 50% reduction in seizure frequency.
“We need carefully designed, good-quality CBMP studies that produce results on which we can rely,” Dr. Kirkpatrick and Dr. O’Callaghan concluded. “We can then work with families to choose the best treatments for children and young people with epilepsy. We owe this to them.”
A therapy of last resort
Jerzy P. Szaflarski, MD, PhD, of the University of Alabama at Birmingham, agreed that data are lacking for the use of CBMPs with patients who have epilepsy and other neurologic conditions; however, he also suggested that Dr. Kirkpatrick and Dr. O’Callaghan did not provide adequate real-world clinical context.
“Medical cannabis is not used as a first-, second-, or third-line therapy,” Dr. Szaflarski said. “It’s mostly used as a last resort in the sense that patients have already failed multiple other therapies.” In that respect, patients and parents are desperate to try anything that might work. “We have medical cannabis, and our patients want to try it, and at the point when multiple therapies have failed, it’s a reasonable option.”
While Dr. Szaflarski agreed that more high-quality clinical trials are needed, he also noted the practical challenges involved in such trials, largely because of variations in cannabis plants.
“The content of the cannabis plant changes depending on the day that it’s collected and the exposure to sun and how much water it has and what’s in the soil and many other things,” Dr. Szaflarski said. “It’s hard to get a very good, standardized product, and that’s why there needs to be a good-quality product delivered by the industry, which I have not seen thus far.”
For this reason, Dr. Szaflarski steers parents and patients away from over-the-counter CBMPs and toward Epidiolex, the only FDA-approved form of CBD.
“There is evidence that Epidiolex works,” he said. “I don’t know whether the products that are sold in a local cannabis store have the same high purity as Epidiolex. I tell [parents] that we should try Epidiolex first because it’s the one that is approved. But if it doesn’t work, we can go in that [other] direction.”
For those going the commercial route, Dr. Szaflarski advised close attention to product ingredients, to ensure that CBMPs are “devoid of any impurities, pesticides, fungicides, and other products that could be potentially dangerous.”
Parents considering CBMPs for their children also need to weigh concerns about long-term neurological safety, he added, noting that, on one hand, commercial products lack data, while on the other, epilepsy itself may cause harm.
“They need to consider the potential effects [of CBMPs] on their child’s brain and development versus … the effects of seizures on the brain,” Dr. Szaflarski said.
Dr. Kirkpatrick and Dr. O’Callaghan disclosed an application for a National Institute for Health Research–funded randomized controlled trial on CBMPs and joint authorship of British Paediatric Neurology Association Guidance on the use of CBMPs in children and young people with epilepsy. Dr. Szaflarski disclosed a relationship with Greenwich Biosciences and several other cannabis companies.
FROM DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY
Concordance of DNA Repair Gene Mutations in Paired Primary Prostate Cancer Samples and Metastatic Tissue or Cell-free DNA
Importance
DNA damage response repair (DDR) gene mutations represent actionable alterations that can guide precision medicine strategies in men with advanced prostate cancer (PC). However, acquisition of contemporary tissue samples for molecular testing can be a barrier to deploying precision medicine approaches. We hypothesized that DDR alterations represent truncal events in PC and that primary tissue would reflect mutations found in cell-free circulating tumor (ctDNA) and/or metastatic tissue. OBJECTIVE: To assess concordance in DDR gene alterations between primary PC and metastases or ctDNA specimens.
Methods
Patients were included if a DDR pathway mutation was detected in metastatic tissue or ctDNA and primary tissue sequencing was available for comparison. Sequencing data from three cohorts were analyzed: (1) FoundationOne; (2) University of Washington (UW-OncoPlex or SU2C/PCF International Dream Team sequencing pipelines); and (3) University of Washington rapid autopsy series. Only pathogenic somatic mutations were included and we required 30 days between primary tumor tissue and ctDNA/ metastatic tissue acquisition. Clonal hematopoiesis of indeterminant potential (CHIP) and germline events were adjudicated by an expert molecular pathologist and excluded. DDR gene mutations detected in primary prostate tissue matched with metastatic tissue and/or ctDNA findings.
Results
Paired primary and ctDNA/metastatic samples were sequenced from 72 individuals with known DDR alterations. After excluding ctDNA studies where only CHIP and/or germline events (N=21) were observed, 51 subjects remained and were included in the final analysis. The median time from acquisition of primary tissue to acquisition of ctDNA or tumor tissue was 55 months (range: 5-193 months). Concordance in DDR gene mutation status across samples was 84% (95% CI: 71-92%). Rates of concordance between metastatic-primary and ctDNAprimary pairs were similar when CHIP cases were excluded. BRCA2 reversion mutations associated with resistance to PARP inhibitors and platinum chemotherapy were detected in ctDNA from two subjects.
Discussion
Primary prostate tissue accurately reflected the mutational status of actionable DDR genes in metastatic tissue, consistent with DDR alterations being truncal in most cases. After excluding likely CHIP events, ctDNA profiling accurately captured these DDR mutations, while also detecting reversion alterations that may suggest resistance mechanisms.
Importance
DNA damage response repair (DDR) gene mutations represent actionable alterations that can guide precision medicine strategies in men with advanced prostate cancer (PC). However, acquisition of contemporary tissue samples for molecular testing can be a barrier to deploying precision medicine approaches. We hypothesized that DDR alterations represent truncal events in PC and that primary tissue would reflect mutations found in cell-free circulating tumor (ctDNA) and/or metastatic tissue. OBJECTIVE: To assess concordance in DDR gene alterations between primary PC and metastases or ctDNA specimens.
Methods
Patients were included if a DDR pathway mutation was detected in metastatic tissue or ctDNA and primary tissue sequencing was available for comparison. Sequencing data from three cohorts were analyzed: (1) FoundationOne; (2) University of Washington (UW-OncoPlex or SU2C/PCF International Dream Team sequencing pipelines); and (3) University of Washington rapid autopsy series. Only pathogenic somatic mutations were included and we required 30 days between primary tumor tissue and ctDNA/ metastatic tissue acquisition. Clonal hematopoiesis of indeterminant potential (CHIP) and germline events were adjudicated by an expert molecular pathologist and excluded. DDR gene mutations detected in primary prostate tissue matched with metastatic tissue and/or ctDNA findings.
Results
Paired primary and ctDNA/metastatic samples were sequenced from 72 individuals with known DDR alterations. After excluding ctDNA studies where only CHIP and/or germline events (N=21) were observed, 51 subjects remained and were included in the final analysis. The median time from acquisition of primary tissue to acquisition of ctDNA or tumor tissue was 55 months (range: 5-193 months). Concordance in DDR gene mutation status across samples was 84% (95% CI: 71-92%). Rates of concordance between metastatic-primary and ctDNAprimary pairs were similar when CHIP cases were excluded. BRCA2 reversion mutations associated with resistance to PARP inhibitors and platinum chemotherapy were detected in ctDNA from two subjects.
Discussion
Primary prostate tissue accurately reflected the mutational status of actionable DDR genes in metastatic tissue, consistent with DDR alterations being truncal in most cases. After excluding likely CHIP events, ctDNA profiling accurately captured these DDR mutations, while also detecting reversion alterations that may suggest resistance mechanisms.
Importance
DNA damage response repair (DDR) gene mutations represent actionable alterations that can guide precision medicine strategies in men with advanced prostate cancer (PC). However, acquisition of contemporary tissue samples for molecular testing can be a barrier to deploying precision medicine approaches. We hypothesized that DDR alterations represent truncal events in PC and that primary tissue would reflect mutations found in cell-free circulating tumor (ctDNA) and/or metastatic tissue. OBJECTIVE: To assess concordance in DDR gene alterations between primary PC and metastases or ctDNA specimens.
Methods
Patients were included if a DDR pathway mutation was detected in metastatic tissue or ctDNA and primary tissue sequencing was available for comparison. Sequencing data from three cohorts were analyzed: (1) FoundationOne; (2) University of Washington (UW-OncoPlex or SU2C/PCF International Dream Team sequencing pipelines); and (3) University of Washington rapid autopsy series. Only pathogenic somatic mutations were included and we required 30 days between primary tumor tissue and ctDNA/ metastatic tissue acquisition. Clonal hematopoiesis of indeterminant potential (CHIP) and germline events were adjudicated by an expert molecular pathologist and excluded. DDR gene mutations detected in primary prostate tissue matched with metastatic tissue and/or ctDNA findings.
Results
Paired primary and ctDNA/metastatic samples were sequenced from 72 individuals with known DDR alterations. After excluding ctDNA studies where only CHIP and/or germline events (N=21) were observed, 51 subjects remained and were included in the final analysis. The median time from acquisition of primary tissue to acquisition of ctDNA or tumor tissue was 55 months (range: 5-193 months). Concordance in DDR gene mutation status across samples was 84% (95% CI: 71-92%). Rates of concordance between metastatic-primary and ctDNAprimary pairs were similar when CHIP cases were excluded. BRCA2 reversion mutations associated with resistance to PARP inhibitors and platinum chemotherapy were detected in ctDNA from two subjects.
Discussion
Primary prostate tissue accurately reflected the mutational status of actionable DDR genes in metastatic tissue, consistent with DDR alterations being truncal in most cases. After excluding likely CHIP events, ctDNA profiling accurately captured these DDR mutations, while also detecting reversion alterations that may suggest resistance mechanisms.
Prevalence and Management of Veterans with Advanced Solid Tumors Harboring NTRK Gene Rearrangements
Background
Oncogenic fusions within Neurotrophic Tyrosine Receptor Kinase (NTRK) 1, 2, or 3 drive constitutive hyperproliferative activity of (TRK) A, B, and C, respectively. Two TRK inhibitors have been approved for patients with advanced solid tumors bearing oncogenic fusions in NTRK1-3. We sought to describe the prevalence of NTRK fusions and rearrangements and to evaluate treatment outcomes among veterans treated with TRK inhibitors.
Methods
Patients with NTRK1-3 gene fusions or rearrangements were identified from the VA National Precision Oncology Program (NPOP) database. Separately, patients with orders for larotrectinib or entrectinib were identified from the Corporate Data Warehouse (CDW) and associated patient demographics and vital status were obtained. The prevalence of NTRK1-3 gene fusions and rearrangements was computed for all patients who had testing within NPOP. For patients who received either larotrectinib or entrectinib, duration of drug use, tumor response, reasons for drug discontinuation and toxicities were abstracted from medical records. For patients not treated with either drug, medical records were used to identify the reason for no drug use.
Results
Among 14,515 samples sequenced through NPOP (11,714 tissue DNA ,176 tissue DNA/RNA and 2625 liquid biopsy DNA tests), 14 (0.096%) had NTRK1-3 gene fusions or rearrangements (6 canonical fusions, 2 non-canonical fusions and 6 non-fusion gene rearrangements). Two patients tested outside of NPOP had canonical fusions. Among the 16 patients, 5 had prostate, 4 lung, 2 thyroid, 2 sarcoma, 1 bladder, 1 gastric, and 1 colorectal cancer. Twelve patients had metastatic disease, and 4 had early-stage disease. Eight patients were prescribed a TRK inhibitor (larotrectinib 5, entrectinib 3). Median duration of treatment was 59 (29 – 88) days. No responses were observed in the 7 evaluable patients. One patient developed neurotoxicity requiring temporary cessation of larotrectinib, and one patient treated with entrectinib developed volume overload requiring hospitalization leading to drug discontinuation.
Conclusion
Among veterans tested in NPOP, oncogenic NTRK fusions and rearrangements are very uncommon, and no patient had a response to treatment with a TRK inhibitor. Reconsideration of NTRK1-3 testing methodology and recommendations is warranted.
Background
Oncogenic fusions within Neurotrophic Tyrosine Receptor Kinase (NTRK) 1, 2, or 3 drive constitutive hyperproliferative activity of (TRK) A, B, and C, respectively. Two TRK inhibitors have been approved for patients with advanced solid tumors bearing oncogenic fusions in NTRK1-3. We sought to describe the prevalence of NTRK fusions and rearrangements and to evaluate treatment outcomes among veterans treated with TRK inhibitors.
Methods
Patients with NTRK1-3 gene fusions or rearrangements were identified from the VA National Precision Oncology Program (NPOP) database. Separately, patients with orders for larotrectinib or entrectinib were identified from the Corporate Data Warehouse (CDW) and associated patient demographics and vital status were obtained. The prevalence of NTRK1-3 gene fusions and rearrangements was computed for all patients who had testing within NPOP. For patients who received either larotrectinib or entrectinib, duration of drug use, tumor response, reasons for drug discontinuation and toxicities were abstracted from medical records. For patients not treated with either drug, medical records were used to identify the reason for no drug use.
Results
Among 14,515 samples sequenced through NPOP (11,714 tissue DNA ,176 tissue DNA/RNA and 2625 liquid biopsy DNA tests), 14 (0.096%) had NTRK1-3 gene fusions or rearrangements (6 canonical fusions, 2 non-canonical fusions and 6 non-fusion gene rearrangements). Two patients tested outside of NPOP had canonical fusions. Among the 16 patients, 5 had prostate, 4 lung, 2 thyroid, 2 sarcoma, 1 bladder, 1 gastric, and 1 colorectal cancer. Twelve patients had metastatic disease, and 4 had early-stage disease. Eight patients were prescribed a TRK inhibitor (larotrectinib 5, entrectinib 3). Median duration of treatment was 59 (29 – 88) days. No responses were observed in the 7 evaluable patients. One patient developed neurotoxicity requiring temporary cessation of larotrectinib, and one patient treated with entrectinib developed volume overload requiring hospitalization leading to drug discontinuation.
Conclusion
Among veterans tested in NPOP, oncogenic NTRK fusions and rearrangements are very uncommon, and no patient had a response to treatment with a TRK inhibitor. Reconsideration of NTRK1-3 testing methodology and recommendations is warranted.
Background
Oncogenic fusions within Neurotrophic Tyrosine Receptor Kinase (NTRK) 1, 2, or 3 drive constitutive hyperproliferative activity of (TRK) A, B, and C, respectively. Two TRK inhibitors have been approved for patients with advanced solid tumors bearing oncogenic fusions in NTRK1-3. We sought to describe the prevalence of NTRK fusions and rearrangements and to evaluate treatment outcomes among veterans treated with TRK inhibitors.
Methods
Patients with NTRK1-3 gene fusions or rearrangements were identified from the VA National Precision Oncology Program (NPOP) database. Separately, patients with orders for larotrectinib or entrectinib were identified from the Corporate Data Warehouse (CDW) and associated patient demographics and vital status were obtained. The prevalence of NTRK1-3 gene fusions and rearrangements was computed for all patients who had testing within NPOP. For patients who received either larotrectinib or entrectinib, duration of drug use, tumor response, reasons for drug discontinuation and toxicities were abstracted from medical records. For patients not treated with either drug, medical records were used to identify the reason for no drug use.
Results
Among 14,515 samples sequenced through NPOP (11,714 tissue DNA ,176 tissue DNA/RNA and 2625 liquid biopsy DNA tests), 14 (0.096%) had NTRK1-3 gene fusions or rearrangements (6 canonical fusions, 2 non-canonical fusions and 6 non-fusion gene rearrangements). Two patients tested outside of NPOP had canonical fusions. Among the 16 patients, 5 had prostate, 4 lung, 2 thyroid, 2 sarcoma, 1 bladder, 1 gastric, and 1 colorectal cancer. Twelve patients had metastatic disease, and 4 had early-stage disease. Eight patients were prescribed a TRK inhibitor (larotrectinib 5, entrectinib 3). Median duration of treatment was 59 (29 – 88) days. No responses were observed in the 7 evaluable patients. One patient developed neurotoxicity requiring temporary cessation of larotrectinib, and one patient treated with entrectinib developed volume overload requiring hospitalization leading to drug discontinuation.
Conclusion
Among veterans tested in NPOP, oncogenic NTRK fusions and rearrangements are very uncommon, and no patient had a response to treatment with a TRK inhibitor. Reconsideration of NTRK1-3 testing methodology and recommendations is warranted.
ITP after COVID-19 Vaccination at the Salisbury VA Healthcare System: Case Studies
Background
An association between vaccines and the rare development of immune thrombocytopenic purpura (ITP) has been reported in the literature. More recently, there have been a few case reports published describing patients developing ITP shortly after COVID- 19 vaccination, but this has not been reported specifically in the Veteran population. The SVAHCS has three cases of Veterans diagnosed with new or relapsed ITP within two months of receiving the second COVID-19 vaccine (all Pfizer brand). The treatment(s) and current outcome for each patient is summarized below.
Case Reports
Case 1 is a 78-year-old male Veteran who received his second COVID-19 vaccine on 2/10/21. Patient was diagnosed with ITP 4/27/21, hospitalized multiple times and treated with pulse dexamethasone, prednisone taper, rituximab IV weekly and romiplostim injections. Currently, patient has a thrombocytosis and romiplostim injections are on hold. Case 2 is a 90-yearold male Veteran who received his second COVID-19 vaccine on 3/16/21. Patient was diagnosed on 5/3/21 and treated with pulse dexamethasone, prednisone taper and rituximab IV weekly. Platelet count is currently normal. Case 3 is a 75-year-old male Veteran who received his second COVID-19 vaccine on 2/1/21. He has a history of ITP diagnosed 12/12/14 that has been well controlled with weekly romiplostim injections until 4/9/21. Patient was hospitalized and treated with pulse dexamethasone and prednisone taper. Upon discharge, therapy was changed from romiplostim to fostamatinib. Currently, platelet count recovered and is stable.
Conclusions
The two Veterans with de novo ITP exhibited resistant disease and had prolonged treatment courses, taking approximately a month to recover their platelet counts. In contrast, the Veteran with relapsed ITP exhibited a faster recovery period of approximately two weeks. In the safety trials conducted for the Pfizer COVID-19 vaccine, participants received vaccination or placebo and had a follow-up for an average of two months which may explain why ITP was not reported as a possible association until after marketing. After treating the above cases, the SVAHCS plans to use thrombopoietin receptor agonists (TPO-RAs) earlier in the treatment of ITP that may be associated with the COVID-19 vaccine as this has recently been recommended in case reports from the general population.
Background
An association between vaccines and the rare development of immune thrombocytopenic purpura (ITP) has been reported in the literature. More recently, there have been a few case reports published describing patients developing ITP shortly after COVID- 19 vaccination, but this has not been reported specifically in the Veteran population. The SVAHCS has three cases of Veterans diagnosed with new or relapsed ITP within two months of receiving the second COVID-19 vaccine (all Pfizer brand). The treatment(s) and current outcome for each patient is summarized below.
Case Reports
Case 1 is a 78-year-old male Veteran who received his second COVID-19 vaccine on 2/10/21. Patient was diagnosed with ITP 4/27/21, hospitalized multiple times and treated with pulse dexamethasone, prednisone taper, rituximab IV weekly and romiplostim injections. Currently, patient has a thrombocytosis and romiplostim injections are on hold. Case 2 is a 90-yearold male Veteran who received his second COVID-19 vaccine on 3/16/21. Patient was diagnosed on 5/3/21 and treated with pulse dexamethasone, prednisone taper and rituximab IV weekly. Platelet count is currently normal. Case 3 is a 75-year-old male Veteran who received his second COVID-19 vaccine on 2/1/21. He has a history of ITP diagnosed 12/12/14 that has been well controlled with weekly romiplostim injections until 4/9/21. Patient was hospitalized and treated with pulse dexamethasone and prednisone taper. Upon discharge, therapy was changed from romiplostim to fostamatinib. Currently, platelet count recovered and is stable.
Conclusions
The two Veterans with de novo ITP exhibited resistant disease and had prolonged treatment courses, taking approximately a month to recover their platelet counts. In contrast, the Veteran with relapsed ITP exhibited a faster recovery period of approximately two weeks. In the safety trials conducted for the Pfizer COVID-19 vaccine, participants received vaccination or placebo and had a follow-up for an average of two months which may explain why ITP was not reported as a possible association until after marketing. After treating the above cases, the SVAHCS plans to use thrombopoietin receptor agonists (TPO-RAs) earlier in the treatment of ITP that may be associated with the COVID-19 vaccine as this has recently been recommended in case reports from the general population.
Background
An association between vaccines and the rare development of immune thrombocytopenic purpura (ITP) has been reported in the literature. More recently, there have been a few case reports published describing patients developing ITP shortly after COVID- 19 vaccination, but this has not been reported specifically in the Veteran population. The SVAHCS has three cases of Veterans diagnosed with new or relapsed ITP within two months of receiving the second COVID-19 vaccine (all Pfizer brand). The treatment(s) and current outcome for each patient is summarized below.
Case Reports
Case 1 is a 78-year-old male Veteran who received his second COVID-19 vaccine on 2/10/21. Patient was diagnosed with ITP 4/27/21, hospitalized multiple times and treated with pulse dexamethasone, prednisone taper, rituximab IV weekly and romiplostim injections. Currently, patient has a thrombocytosis and romiplostim injections are on hold. Case 2 is a 90-yearold male Veteran who received his second COVID-19 vaccine on 3/16/21. Patient was diagnosed on 5/3/21 and treated with pulse dexamethasone, prednisone taper and rituximab IV weekly. Platelet count is currently normal. Case 3 is a 75-year-old male Veteran who received his second COVID-19 vaccine on 2/1/21. He has a history of ITP diagnosed 12/12/14 that has been well controlled with weekly romiplostim injections until 4/9/21. Patient was hospitalized and treated with pulse dexamethasone and prednisone taper. Upon discharge, therapy was changed from romiplostim to fostamatinib. Currently, platelet count recovered and is stable.
Conclusions
The two Veterans with de novo ITP exhibited resistant disease and had prolonged treatment courses, taking approximately a month to recover their platelet counts. In contrast, the Veteran with relapsed ITP exhibited a faster recovery period of approximately two weeks. In the safety trials conducted for the Pfizer COVID-19 vaccine, participants received vaccination or placebo and had a follow-up for an average of two months which may explain why ITP was not reported as a possible association until after marketing. After treating the above cases, the SVAHCS plans to use thrombopoietin receptor agonists (TPO-RAs) earlier in the treatment of ITP that may be associated with the COVID-19 vaccine as this has recently been recommended in case reports from the general population.
Evans’ Syndrome in Undiagnosed Small Lymphocytic Lymphoma: Case Report and Literature Review
Background
Evans’ syndrome is a rare entity characterized by concomitant or sequential multilineage cytopenia particularly autoimmune hemolytic anemia, ITP and very rarely autoimmune neutropenia. Although more common in young adults, it can occur in elderly usually associated with malignancies like CLL.
Case Report
A 74 years old Veteran presented with complaints of fatigue and worsening dyspnea on exertion. His physical exam was unremarkable except jaundice. His labs were significant for macrocytic anemia with Hemoglobin of 7.4g/dl compared to 11.7g/dl 6 months prior, MCV 106.9 fL, LDH 809U/L, indirect bilirubin 4.1mg/dl, absolute reticulocyte 0.16M/uL, Haptoglobin <15mg/dl and Positive DAT. Platelets were mildly decreased at 111K/ul. No lymphocytosis was noted. Initially, the hemolysis was thought to be cephalosporin- related given that the patient had taken cephalexin recently for cellulitis. As part of the workup for anemia, the patient underwent EGD and colonoscopy which was initially unrevealing. However, random biopsies from the descending colon and terminal ileum returned with a small lymphocytic infiltrate consistent with SLL/CLL. Cytogenetics showed trisomy-12 which is associated with intermediate prognosis for CLL. PET scan done subsequently revealed only a reactive marrow and an enlarged 15.8cm non-hypermetabolic spleen. This veteran having anemia, positive DAT, thrombocytopenia, and splenomegaly got diagnosed with Evans’s syndrome. This syndrome was the initial manifestation of his underlying CLL. We started the patient on a prednisone taper for 4 weeks to which anemia and thrombocytopenia barely responded, ultimately Rituximab 375mg/m2 x4 weekly doses was started which led to complete resolution of anemia and thrombocytopenia. We closely followed the patient and monitored CBC and hemolytic markers. The patient relapsed in two years which was subsequently managed with another course of Rituximab 375mg/m2 x4 weekly doses.
Conclusions
This case report aims to call attention to this relatively rare entity which is difficult to treat and often associated with frequent relapses. Though rare, physicians should maintain high suspicion for this syndrome in patients with multi-lineage cytopenia which are usually not even responding well to the common treatment for cytopenia. Furthermore, there is room for improvement in Evans’ syndrome management since mortality remains higher in these patients than in those with isolated autoimmuce cytopenias.
Background
Evans’ syndrome is a rare entity characterized by concomitant or sequential multilineage cytopenia particularly autoimmune hemolytic anemia, ITP and very rarely autoimmune neutropenia. Although more common in young adults, it can occur in elderly usually associated with malignancies like CLL.
Case Report
A 74 years old Veteran presented with complaints of fatigue and worsening dyspnea on exertion. His physical exam was unremarkable except jaundice. His labs were significant for macrocytic anemia with Hemoglobin of 7.4g/dl compared to 11.7g/dl 6 months prior, MCV 106.9 fL, LDH 809U/L, indirect bilirubin 4.1mg/dl, absolute reticulocyte 0.16M/uL, Haptoglobin <15mg/dl and Positive DAT. Platelets were mildly decreased at 111K/ul. No lymphocytosis was noted. Initially, the hemolysis was thought to be cephalosporin- related given that the patient had taken cephalexin recently for cellulitis. As part of the workup for anemia, the patient underwent EGD and colonoscopy which was initially unrevealing. However, random biopsies from the descending colon and terminal ileum returned with a small lymphocytic infiltrate consistent with SLL/CLL. Cytogenetics showed trisomy-12 which is associated with intermediate prognosis for CLL. PET scan done subsequently revealed only a reactive marrow and an enlarged 15.8cm non-hypermetabolic spleen. This veteran having anemia, positive DAT, thrombocytopenia, and splenomegaly got diagnosed with Evans’s syndrome. This syndrome was the initial manifestation of his underlying CLL. We started the patient on a prednisone taper for 4 weeks to which anemia and thrombocytopenia barely responded, ultimately Rituximab 375mg/m2 x4 weekly doses was started which led to complete resolution of anemia and thrombocytopenia. We closely followed the patient and monitored CBC and hemolytic markers. The patient relapsed in two years which was subsequently managed with another course of Rituximab 375mg/m2 x4 weekly doses.
Conclusions
This case report aims to call attention to this relatively rare entity which is difficult to treat and often associated with frequent relapses. Though rare, physicians should maintain high suspicion for this syndrome in patients with multi-lineage cytopenia which are usually not even responding well to the common treatment for cytopenia. Furthermore, there is room for improvement in Evans’ syndrome management since mortality remains higher in these patients than in those with isolated autoimmuce cytopenias.
Background
Evans’ syndrome is a rare entity characterized by concomitant or sequential multilineage cytopenia particularly autoimmune hemolytic anemia, ITP and very rarely autoimmune neutropenia. Although more common in young adults, it can occur in elderly usually associated with malignancies like CLL.
Case Report
A 74 years old Veteran presented with complaints of fatigue and worsening dyspnea on exertion. His physical exam was unremarkable except jaundice. His labs were significant for macrocytic anemia with Hemoglobin of 7.4g/dl compared to 11.7g/dl 6 months prior, MCV 106.9 fL, LDH 809U/L, indirect bilirubin 4.1mg/dl, absolute reticulocyte 0.16M/uL, Haptoglobin <15mg/dl and Positive DAT. Platelets were mildly decreased at 111K/ul. No lymphocytosis was noted. Initially, the hemolysis was thought to be cephalosporin- related given that the patient had taken cephalexin recently for cellulitis. As part of the workup for anemia, the patient underwent EGD and colonoscopy which was initially unrevealing. However, random biopsies from the descending colon and terminal ileum returned with a small lymphocytic infiltrate consistent with SLL/CLL. Cytogenetics showed trisomy-12 which is associated with intermediate prognosis for CLL. PET scan done subsequently revealed only a reactive marrow and an enlarged 15.8cm non-hypermetabolic spleen. This veteran having anemia, positive DAT, thrombocytopenia, and splenomegaly got diagnosed with Evans’s syndrome. This syndrome was the initial manifestation of his underlying CLL. We started the patient on a prednisone taper for 4 weeks to which anemia and thrombocytopenia barely responded, ultimately Rituximab 375mg/m2 x4 weekly doses was started which led to complete resolution of anemia and thrombocytopenia. We closely followed the patient and monitored CBC and hemolytic markers. The patient relapsed in two years which was subsequently managed with another course of Rituximab 375mg/m2 x4 weekly doses.
Conclusions
This case report aims to call attention to this relatively rare entity which is difficult to treat and often associated with frequent relapses. Though rare, physicians should maintain high suspicion for this syndrome in patients with multi-lineage cytopenia which are usually not even responding well to the common treatment for cytopenia. Furthermore, there is room for improvement in Evans’ syndrome management since mortality remains higher in these patients than in those with isolated autoimmuce cytopenias.
Factors Associated with Survival and Epidemiology of Gastrointestinal Neuroendocrine Tumors in the US Department of Veteran Affairs
Introduction
Rectal carcinoid tumors are rare but the second most common carcinoid in the gastrointestinal tract. They are usually found incidentally during endoscopic or rectal examination. They do not often produce carcinoid syndrome like manifestations although they may manifest as rectal bleeding. Rectal carcinoid patients also have a higher morbidity for other cancers such as stomach, small intestine, or secondary lung cancer.
Methods
We retrospectively explored factors associated with survival in Veterans with rectal carcinoid tumors over a ten-year period from 2007-2017 using the National Veterans Affairs Cancer Cube Registry using specific histological ICD-03 coding. We identified 1110 cases of rectal carcinoid. Chi-squared tests were used for statistical analysis.
Results
Regarding age distribution in our cohort, there were 2.61% of patients ages 40-50 group, 14.0% in the 50-60 age group, 41.5% in the 60-70 age group, and 40.7% above ages 70. There was a higher proportion of rectal cancer in stage 1 compared to other stages (86.3%). The majority of diagnoses occur after age 50 (89.8%). A higher proportion of rectal carcinoid was identified in the 60-70 years category compared to <60 and >70 years old. In the general VA population, there are 80.2% White and 12.8% Black patients. We found a higher proportion of rectal carcinoid in Black patients (47.8%) over White patients (42.8%, p=0.02), which differs significantly from the racial makeup of the VA population (12.8% Black vs 80.3% White). Looking at survival time based on diagnosis, it is notable that 82.7% of individuals survive longer than 5 years when the diagnosis is made in ages 50-60 when compared to 68.7% when the diagnosis is made between ages 60-70 (p<0.001).
Conclusions
Our data is consistent with the SEER data in that the incidence and prevalence of rectal carcinoid are higher in Black patients compared to White patients. Further analysis into reasons for this racial disparity may prove beneficial to our understanding of this malignancy in the Veteran population. Further research is needed to determine whether diagnosis at a younger age offers a survival advantage in rectal carcinoid.
Introduction
Rectal carcinoid tumors are rare but the second most common carcinoid in the gastrointestinal tract. They are usually found incidentally during endoscopic or rectal examination. They do not often produce carcinoid syndrome like manifestations although they may manifest as rectal bleeding. Rectal carcinoid patients also have a higher morbidity for other cancers such as stomach, small intestine, or secondary lung cancer.
Methods
We retrospectively explored factors associated with survival in Veterans with rectal carcinoid tumors over a ten-year period from 2007-2017 using the National Veterans Affairs Cancer Cube Registry using specific histological ICD-03 coding. We identified 1110 cases of rectal carcinoid. Chi-squared tests were used for statistical analysis.
Results
Regarding age distribution in our cohort, there were 2.61% of patients ages 40-50 group, 14.0% in the 50-60 age group, 41.5% in the 60-70 age group, and 40.7% above ages 70. There was a higher proportion of rectal cancer in stage 1 compared to other stages (86.3%). The majority of diagnoses occur after age 50 (89.8%). A higher proportion of rectal carcinoid was identified in the 60-70 years category compared to <60 and >70 years old. In the general VA population, there are 80.2% White and 12.8% Black patients. We found a higher proportion of rectal carcinoid in Black patients (47.8%) over White patients (42.8%, p=0.02), which differs significantly from the racial makeup of the VA population (12.8% Black vs 80.3% White). Looking at survival time based on diagnosis, it is notable that 82.7% of individuals survive longer than 5 years when the diagnosis is made in ages 50-60 when compared to 68.7% when the diagnosis is made between ages 60-70 (p<0.001).
Conclusions
Our data is consistent with the SEER data in that the incidence and prevalence of rectal carcinoid are higher in Black patients compared to White patients. Further analysis into reasons for this racial disparity may prove beneficial to our understanding of this malignancy in the Veteran population. Further research is needed to determine whether diagnosis at a younger age offers a survival advantage in rectal carcinoid.
Introduction
Rectal carcinoid tumors are rare but the second most common carcinoid in the gastrointestinal tract. They are usually found incidentally during endoscopic or rectal examination. They do not often produce carcinoid syndrome like manifestations although they may manifest as rectal bleeding. Rectal carcinoid patients also have a higher morbidity for other cancers such as stomach, small intestine, or secondary lung cancer.
Methods
We retrospectively explored factors associated with survival in Veterans with rectal carcinoid tumors over a ten-year period from 2007-2017 using the National Veterans Affairs Cancer Cube Registry using specific histological ICD-03 coding. We identified 1110 cases of rectal carcinoid. Chi-squared tests were used for statistical analysis.
Results
Regarding age distribution in our cohort, there were 2.61% of patients ages 40-50 group, 14.0% in the 50-60 age group, 41.5% in the 60-70 age group, and 40.7% above ages 70. There was a higher proportion of rectal cancer in stage 1 compared to other stages (86.3%). The majority of diagnoses occur after age 50 (89.8%). A higher proportion of rectal carcinoid was identified in the 60-70 years category compared to <60 and >70 years old. In the general VA population, there are 80.2% White and 12.8% Black patients. We found a higher proportion of rectal carcinoid in Black patients (47.8%) over White patients (42.8%, p=0.02), which differs significantly from the racial makeup of the VA population (12.8% Black vs 80.3% White). Looking at survival time based on diagnosis, it is notable that 82.7% of individuals survive longer than 5 years when the diagnosis is made in ages 50-60 when compared to 68.7% when the diagnosis is made between ages 60-70 (p<0.001).
Conclusions
Our data is consistent with the SEER data in that the incidence and prevalence of rectal carcinoid are higher in Black patients compared to White patients. Further analysis into reasons for this racial disparity may prove beneficial to our understanding of this malignancy in the Veteran population. Further research is needed to determine whether diagnosis at a younger age offers a survival advantage in rectal carcinoid.
Development of Debilitating Neuropathy After Two Cycles of Pembrolizumab
Case Report
73-year-old white male presented with large right shoulder soft tissue mass (17x5 cm) near the scapula, and was subsequently sent for surgical resection by his primary care. Pathology showed nodular melanoma with positive margin, lymphovascular invasion and neurotropism present with high mitosis. PET-CT scan showed positive uptake in axillary and supraclavicular lymph nodes as well as uptake in the left proximal tibia. Biopsy of the bone was also positive for melanoma. Molecular study showed BRAF mutation at L597, high tumor mutation burden (24 mutations/Mb), and PD-L1 positive in 60% of tumor cells and PD-1 was positive in immune cells, but not in tumor cells. One other distinct feature of this clinical presentation was the abundance of macrophages (CD68+) in the tumor microenvironment. Patient was initiated therapy with pembrolizumab. However, three weeks after his second cycle, he was admitted to hospital due to severe weakness in both upper extremities and pain at night. He also experienced a new onset of polyarthralgia in both hands, unable to play musical instruments. He was started on steroid treatment and showed significant improvement. Once steroid was tapered off, the sensation of pain substantially decreased but persisted. EMG showed right median motor neuropathy and left median sensory neuropathy. Blood test detected ANA positive, and as TSH was high, levothyroxine was initiated.
Outcome
His PET-CT scan showed improvement after only two cycles of treatment and has remained stable for over ten months without any treatment (patient elected to stop pembrolizumab treatment due to frequent traveling). We have performed a more detailed study of the macrophages in his tumor sample and interestingly, the majority of macrophages were type-1 (CD 80+), with some, type-2 macrophages (CD163+). It is known that type-1 macrophages are pro-inflammatory and have antitumor effect, while type-2 macrophages have opposite effect and often promote tumor growth and metastasis. This could explain the side effect and long duration of response despite only two cycles of pembrolizumab treatment. Characteristics of macrophages in melanoma tumor samples may be an important parameter to predict side effect and tumor response beyond PD1 or PD-L1 expression.
Case Report
73-year-old white male presented with large right shoulder soft tissue mass (17x5 cm) near the scapula, and was subsequently sent for surgical resection by his primary care. Pathology showed nodular melanoma with positive margin, lymphovascular invasion and neurotropism present with high mitosis. PET-CT scan showed positive uptake in axillary and supraclavicular lymph nodes as well as uptake in the left proximal tibia. Biopsy of the bone was also positive for melanoma. Molecular study showed BRAF mutation at L597, high tumor mutation burden (24 mutations/Mb), and PD-L1 positive in 60% of tumor cells and PD-1 was positive in immune cells, but not in tumor cells. One other distinct feature of this clinical presentation was the abundance of macrophages (CD68+) in the tumor microenvironment. Patient was initiated therapy with pembrolizumab. However, three weeks after his second cycle, he was admitted to hospital due to severe weakness in both upper extremities and pain at night. He also experienced a new onset of polyarthralgia in both hands, unable to play musical instruments. He was started on steroid treatment and showed significant improvement. Once steroid was tapered off, the sensation of pain substantially decreased but persisted. EMG showed right median motor neuropathy and left median sensory neuropathy. Blood test detected ANA positive, and as TSH was high, levothyroxine was initiated.
Outcome
His PET-CT scan showed improvement after only two cycles of treatment and has remained stable for over ten months without any treatment (patient elected to stop pembrolizumab treatment due to frequent traveling). We have performed a more detailed study of the macrophages in his tumor sample and interestingly, the majority of macrophages were type-1 (CD 80+), with some, type-2 macrophages (CD163+). It is known that type-1 macrophages are pro-inflammatory and have antitumor effect, while type-2 macrophages have opposite effect and often promote tumor growth and metastasis. This could explain the side effect and long duration of response despite only two cycles of pembrolizumab treatment. Characteristics of macrophages in melanoma tumor samples may be an important parameter to predict side effect and tumor response beyond PD1 or PD-L1 expression.
Case Report
73-year-old white male presented with large right shoulder soft tissue mass (17x5 cm) near the scapula, and was subsequently sent for surgical resection by his primary care. Pathology showed nodular melanoma with positive margin, lymphovascular invasion and neurotropism present with high mitosis. PET-CT scan showed positive uptake in axillary and supraclavicular lymph nodes as well as uptake in the left proximal tibia. Biopsy of the bone was also positive for melanoma. Molecular study showed BRAF mutation at L597, high tumor mutation burden (24 mutations/Mb), and PD-L1 positive in 60% of tumor cells and PD-1 was positive in immune cells, but not in tumor cells. One other distinct feature of this clinical presentation was the abundance of macrophages (CD68+) in the tumor microenvironment. Patient was initiated therapy with pembrolizumab. However, three weeks after his second cycle, he was admitted to hospital due to severe weakness in both upper extremities and pain at night. He also experienced a new onset of polyarthralgia in both hands, unable to play musical instruments. He was started on steroid treatment and showed significant improvement. Once steroid was tapered off, the sensation of pain substantially decreased but persisted. EMG showed right median motor neuropathy and left median sensory neuropathy. Blood test detected ANA positive, and as TSH was high, levothyroxine was initiated.
Outcome
His PET-CT scan showed improvement after only two cycles of treatment and has remained stable for over ten months without any treatment (patient elected to stop pembrolizumab treatment due to frequent traveling). We have performed a more detailed study of the macrophages in his tumor sample and interestingly, the majority of macrophages were type-1 (CD 80+), with some, type-2 macrophages (CD163+). It is known that type-1 macrophages are pro-inflammatory and have antitumor effect, while type-2 macrophages have opposite effect and often promote tumor growth and metastasis. This could explain the side effect and long duration of response despite only two cycles of pembrolizumab treatment. Characteristics of macrophages in melanoma tumor samples may be an important parameter to predict side effect and tumor response beyond PD1 or PD-L1 expression.
Double Hit: Epstein-Barr Virus Causing Infectious Mononucleosis Followed by Hemolytic Uremic Syndrome
Introduction
Epstein-Barr virus (EBV) is a herpes virus that commonly causes infectious mononucleosis (IM) and linked to different hematological conditions. Here we present a case of EBV-triggered Hemolytic Uremic Syndrome (HUS) with pulmonary involvement.
Case Presentation
A 20-year-old male presented with fever, thrombocytopenia, and splenomegaly. Acute EBV serology was positive. Creatinine and hemoglobin were normal. He was diagnosed with IM. platelet count improved within 3 weeks. 4 weeks later, he returned with severe hemoptysis. Hgb 6.8g/dL, platelet 133,000/uL, lactate dehydrogenase 969u/L, creatinine 21mg/dL, and schistocytes on peripheral smear. Chest computed tomography showed bilateral opacities consistent with diffuse alveolar hemorrhage (DAH). Emergent hemodialysis and plasmapheresis were started. Infectious work up was negative. Autoimmune work up was also negative (anti-neutrophil cytoplasmic, anti-basement membrane antibodies, ANA). Aadamts13 activity was 62% (normal ~66%) ruling out thrombotic thrombocytopenic purpura (TTP). Kidney biopsy revealed thrombotic microangiopathic process. The patient was eventually diagnosed with HUS and treated with Eculizumab. 4 months later his renal function has partially recovered and no longer needs hemodialysis.
Discussion
HUS is a rare entity that is known to be triggered by different underlying pathologies. However, its link to EBV remains unclear. Literature review has revealed only two cases of EBV-triggered HUS, even though almost 90-95% of adults are EBV-seropositive. What unique about our case is the patient initially presented with documented IM, and HUS happened a month later. This raises the theory that HUS could be a sequela of the infection, rather than an effect of acute viral phase and this is the first case to report such correlation. The other unique thing is pulmonary involvement in HUS. With consultation with pulmonary service, we believe our patient had DAH based on clinical and radiographic findings. To our knowledge this is the first case to show this association.
Conclusion
EBV is a common virus with high seropositivity among world’s population. Its link to HUS remains unclear and needs more investigation. Providers should recognize HUS as a complication of EBV infection, either in the acute phase or as a sequela. Adolescents are at higher risk for such complication since IM is common in this population.
Introduction
Epstein-Barr virus (EBV) is a herpes virus that commonly causes infectious mononucleosis (IM) and linked to different hematological conditions. Here we present a case of EBV-triggered Hemolytic Uremic Syndrome (HUS) with pulmonary involvement.
Case Presentation
A 20-year-old male presented with fever, thrombocytopenia, and splenomegaly. Acute EBV serology was positive. Creatinine and hemoglobin were normal. He was diagnosed with IM. platelet count improved within 3 weeks. 4 weeks later, he returned with severe hemoptysis. Hgb 6.8g/dL, platelet 133,000/uL, lactate dehydrogenase 969u/L, creatinine 21mg/dL, and schistocytes on peripheral smear. Chest computed tomography showed bilateral opacities consistent with diffuse alveolar hemorrhage (DAH). Emergent hemodialysis and plasmapheresis were started. Infectious work up was negative. Autoimmune work up was also negative (anti-neutrophil cytoplasmic, anti-basement membrane antibodies, ANA). Aadamts13 activity was 62% (normal ~66%) ruling out thrombotic thrombocytopenic purpura (TTP). Kidney biopsy revealed thrombotic microangiopathic process. The patient was eventually diagnosed with HUS and treated with Eculizumab. 4 months later his renal function has partially recovered and no longer needs hemodialysis.
Discussion
HUS is a rare entity that is known to be triggered by different underlying pathologies. However, its link to EBV remains unclear. Literature review has revealed only two cases of EBV-triggered HUS, even though almost 90-95% of adults are EBV-seropositive. What unique about our case is the patient initially presented with documented IM, and HUS happened a month later. This raises the theory that HUS could be a sequela of the infection, rather than an effect of acute viral phase and this is the first case to report such correlation. The other unique thing is pulmonary involvement in HUS. With consultation with pulmonary service, we believe our patient had DAH based on clinical and radiographic findings. To our knowledge this is the first case to show this association.
Conclusion
EBV is a common virus with high seropositivity among world’s population. Its link to HUS remains unclear and needs more investigation. Providers should recognize HUS as a complication of EBV infection, either in the acute phase or as a sequela. Adolescents are at higher risk for such complication since IM is common in this population.
Introduction
Epstein-Barr virus (EBV) is a herpes virus that commonly causes infectious mononucleosis (IM) and linked to different hematological conditions. Here we present a case of EBV-triggered Hemolytic Uremic Syndrome (HUS) with pulmonary involvement.
Case Presentation
A 20-year-old male presented with fever, thrombocytopenia, and splenomegaly. Acute EBV serology was positive. Creatinine and hemoglobin were normal. He was diagnosed with IM. platelet count improved within 3 weeks. 4 weeks later, he returned with severe hemoptysis. Hgb 6.8g/dL, platelet 133,000/uL, lactate dehydrogenase 969u/L, creatinine 21mg/dL, and schistocytes on peripheral smear. Chest computed tomography showed bilateral opacities consistent with diffuse alveolar hemorrhage (DAH). Emergent hemodialysis and plasmapheresis were started. Infectious work up was negative. Autoimmune work up was also negative (anti-neutrophil cytoplasmic, anti-basement membrane antibodies, ANA). Aadamts13 activity was 62% (normal ~66%) ruling out thrombotic thrombocytopenic purpura (TTP). Kidney biopsy revealed thrombotic microangiopathic process. The patient was eventually diagnosed with HUS and treated with Eculizumab. 4 months later his renal function has partially recovered and no longer needs hemodialysis.
Discussion
HUS is a rare entity that is known to be triggered by different underlying pathologies. However, its link to EBV remains unclear. Literature review has revealed only two cases of EBV-triggered HUS, even though almost 90-95% of adults are EBV-seropositive. What unique about our case is the patient initially presented with documented IM, and HUS happened a month later. This raises the theory that HUS could be a sequela of the infection, rather than an effect of acute viral phase and this is the first case to report such correlation. The other unique thing is pulmonary involvement in HUS. With consultation with pulmonary service, we believe our patient had DAH based on clinical and radiographic findings. To our knowledge this is the first case to show this association.
Conclusion
EBV is a common virus with high seropositivity among world’s population. Its link to HUS remains unclear and needs more investigation. Providers should recognize HUS as a complication of EBV infection, either in the acute phase or as a sequela. Adolescents are at higher risk for such complication since IM is common in this population.