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Colorectal cancer: New observations, new implications
The incidence and mortality of colorectal cancer (CRC) have declined by 3% per year over the past 10-15 years – a remarkable achievement. The decline in incidence has been dramatic for individuals over age 50 years, who are targeted by screening. However, the reduction in CRC risk does not apply to all populations in the United States. New epidemiologic trends and observations point to patient demographics and regional variation as potential risk factors. While such observations provide what I call “blurry snapshots,” they may well have important implications for our approach to screening and prevention.
What are the reasons? There are several personal and environmental factors that could be contributing. Obesity and metabolic syndrome are risk factors for CRC and have been more commonly developing in childhood over the past 40 years. Alteration of the microbiome could also potentially predispose one to developing CRC. The use of antibiotics in childhood was more common for some of these younger generations than it was for the preceding generations, and antibiotics have been introduced into the food industry to fatten animals. The introduction of food chemicals could also either alter the microbiome and/or promote inflammation, which could lead to neoplasia. Exposure to more ambient radiation may be another risk factor.
These hypotheses are biologically plausible – but untested. Nevertheless, this observational trend does have implications for clinicians. First, studies have shown that up to 20% of CRCs before age 50 years are associated with germline mutations, while others are associated with a family history of CRC. Therefore, it is important to capture and update family history. In addition, there is evidence that individuals aged 40-49 years with rectal bleeding have a higher risk of advanced adenomas, so our threshold for performing diagnostic colonoscopy should be lowered. African Americans also have a higher risk of CRC at a younger age than do other racial groups and might benefit from early screening at age 45 years. Notably, recent recommendations from the American Cancer Society call for consideration of screening everyone at age 45 years.
There is substantial state-to-state and county-to-county variation in the incidence and mortality of CRC. While some of this variation can be explained by racial variation, smoking, obesity, and social determinants of health, there are “hot-spots” that may defy easy explanation. There has been very little research about environmental factors (air, water, and ambient radiation). Two regions at particularly high risk are the Mississippi Delta region and Appalachia – areas where water pollution could be a factor. The substantial county-to-county variation within these high-risk areas points to a potential environmental culprit, but further research is needed.
For the GI community, there are several implications to be found in these changing demographics and risks. For one, we may need to consider expanding our risk concepts to include not only genetic and personal risk factors but also environmental factors. To mitigate risk, providers and public health officials may need to then target these high-risk areas for more intensive screening efforts.
Dr. Lieberman is a professor of medicine and chief of gastroenterology and hepatology at Oregon Health and Science University in Portland. He has no conflicts of interest. Dr. Lieberman made his comments during the AGA Institute Presidential Plenary at the Annual Digestive Disease Week.
The incidence and mortality of colorectal cancer (CRC) have declined by 3% per year over the past 10-15 years – a remarkable achievement. The decline in incidence has been dramatic for individuals over age 50 years, who are targeted by screening. However, the reduction in CRC risk does not apply to all populations in the United States. New epidemiologic trends and observations point to patient demographics and regional variation as potential risk factors. While such observations provide what I call “blurry snapshots,” they may well have important implications for our approach to screening and prevention.
What are the reasons? There are several personal and environmental factors that could be contributing. Obesity and metabolic syndrome are risk factors for CRC and have been more commonly developing in childhood over the past 40 years. Alteration of the microbiome could also potentially predispose one to developing CRC. The use of antibiotics in childhood was more common for some of these younger generations than it was for the preceding generations, and antibiotics have been introduced into the food industry to fatten animals. The introduction of food chemicals could also either alter the microbiome and/or promote inflammation, which could lead to neoplasia. Exposure to more ambient radiation may be another risk factor.
These hypotheses are biologically plausible – but untested. Nevertheless, this observational trend does have implications for clinicians. First, studies have shown that up to 20% of CRCs before age 50 years are associated with germline mutations, while others are associated with a family history of CRC. Therefore, it is important to capture and update family history. In addition, there is evidence that individuals aged 40-49 years with rectal bleeding have a higher risk of advanced adenomas, so our threshold for performing diagnostic colonoscopy should be lowered. African Americans also have a higher risk of CRC at a younger age than do other racial groups and might benefit from early screening at age 45 years. Notably, recent recommendations from the American Cancer Society call for consideration of screening everyone at age 45 years.
There is substantial state-to-state and county-to-county variation in the incidence and mortality of CRC. While some of this variation can be explained by racial variation, smoking, obesity, and social determinants of health, there are “hot-spots” that may defy easy explanation. There has been very little research about environmental factors (air, water, and ambient radiation). Two regions at particularly high risk are the Mississippi Delta region and Appalachia – areas where water pollution could be a factor. The substantial county-to-county variation within these high-risk areas points to a potential environmental culprit, but further research is needed.
For the GI community, there are several implications to be found in these changing demographics and risks. For one, we may need to consider expanding our risk concepts to include not only genetic and personal risk factors but also environmental factors. To mitigate risk, providers and public health officials may need to then target these high-risk areas for more intensive screening efforts.
Dr. Lieberman is a professor of medicine and chief of gastroenterology and hepatology at Oregon Health and Science University in Portland. He has no conflicts of interest. Dr. Lieberman made his comments during the AGA Institute Presidential Plenary at the Annual Digestive Disease Week.
The incidence and mortality of colorectal cancer (CRC) have declined by 3% per year over the past 10-15 years – a remarkable achievement. The decline in incidence has been dramatic for individuals over age 50 years, who are targeted by screening. However, the reduction in CRC risk does not apply to all populations in the United States. New epidemiologic trends and observations point to patient demographics and regional variation as potential risk factors. While such observations provide what I call “blurry snapshots,” they may well have important implications for our approach to screening and prevention.
What are the reasons? There are several personal and environmental factors that could be contributing. Obesity and metabolic syndrome are risk factors for CRC and have been more commonly developing in childhood over the past 40 years. Alteration of the microbiome could also potentially predispose one to developing CRC. The use of antibiotics in childhood was more common for some of these younger generations than it was for the preceding generations, and antibiotics have been introduced into the food industry to fatten animals. The introduction of food chemicals could also either alter the microbiome and/or promote inflammation, which could lead to neoplasia. Exposure to more ambient radiation may be another risk factor.
These hypotheses are biologically plausible – but untested. Nevertheless, this observational trend does have implications for clinicians. First, studies have shown that up to 20% of CRCs before age 50 years are associated with germline mutations, while others are associated with a family history of CRC. Therefore, it is important to capture and update family history. In addition, there is evidence that individuals aged 40-49 years with rectal bleeding have a higher risk of advanced adenomas, so our threshold for performing diagnostic colonoscopy should be lowered. African Americans also have a higher risk of CRC at a younger age than do other racial groups and might benefit from early screening at age 45 years. Notably, recent recommendations from the American Cancer Society call for consideration of screening everyone at age 45 years.
There is substantial state-to-state and county-to-county variation in the incidence and mortality of CRC. While some of this variation can be explained by racial variation, smoking, obesity, and social determinants of health, there are “hot-spots” that may defy easy explanation. There has been very little research about environmental factors (air, water, and ambient radiation). Two regions at particularly high risk are the Mississippi Delta region and Appalachia – areas where water pollution could be a factor. The substantial county-to-county variation within these high-risk areas points to a potential environmental culprit, but further research is needed.
For the GI community, there are several implications to be found in these changing demographics and risks. For one, we may need to consider expanding our risk concepts to include not only genetic and personal risk factors but also environmental factors. To mitigate risk, providers and public health officials may need to then target these high-risk areas for more intensive screening efforts.
Dr. Lieberman is a professor of medicine and chief of gastroenterology and hepatology at Oregon Health and Science University in Portland. He has no conflicts of interest. Dr. Lieberman made his comments during the AGA Institute Presidential Plenary at the Annual Digestive Disease Week.
In Ghana, SCD research is meeting patients on home turf
WASHINGTON – Sometimes, the hardest part of solving a problem is figuring out how to work around misaligned resources, and so it has been with sickle cell disease research.
“From my point of view, what I call the geographical disparity in sickle cell disease research can be explained by the fact that the majority of affected individuals are living in the East, and the overwhelming majority of the research takes place in the West,” said Solomon Ofori-Acquah, PhD. He and three physician collaborators from Ghana shared their roadmap to conducting clinical trials in West Africa during an “East Meets West” session of the annual symposium of the Foundation for Sickle Cell Disease Research.
In Ghana, not far from where scientists now believe the hemoglobin sickling mutation originated, fully 2% of newborns have SCD; this translates into 16,000 new cases per year in a population of just 28 million, compared with the 2,000 new SCD cases seen annually in the entire United States. And access even to proven therapies can be limited; historically, little to no clinical drug development work has been conducted in this part of the world.
In the United States, half of the SCD trials that were withdrawn or terminated listed recruitment and retention of study participants as a factor in the study’s discontinuation, said Amma Owusu-Ansah, MD. “I see what we are doing as a very feasible solution to the problem of inadequate accrual to studies in the U.S.,” said Dr. Owusu-Ansah, a hematologist at the University of Pittsburgh’s Center for Translational and International Hematology (CTIH), where she serves as clinical director.
From the African perspective, hosting clinical trials – and building a robust infrastructure to do so – may help alleviate the delay in translation of disease-modifying therapies for SCD to Africa, where most people with the disease live, she said.
An existing example of resource sharing is the Human Heredity & Health in Africa (H3Africa) initiative, said Dr. Ofori-Acquah, who directs the CTIH and also holds an appointment at the University of Ghana. The project, funded by the National Institutes of Health and the Wellcome Trust, “aims to facilitate a contemporary research approach to the study of genomics and environmental determinants of common diseases with the goal of improving the health of African populations,” according to the H3Africa website. Within this framework of 40 research centers conducting genomics research and biobanking, several discrete projects aim to expand knowledge of sickle cell disease.
“All of these networks are going to study thousands of patients,” said Dr. Ofori-Acquah. “I see the H3 as a mechanism to accelerate genomics research in sickle cell disease.”
“We created a research team and built capacity for future work…. Ghana, and Africa, are capable of conducting clinical trials to global standards and producing quality data,” she said.
The story of one clinical trial is illustrative of the challenges and strengths of the multinational approach.
The phase 1b trial of a novel treatment for sickle cell disease, NVX-508, began with an initial hurdle of lack of access to emergency care at the study site, said Dr. Owusu-Ansah, a study investigator. Her first reaction, she said, was, “Well, we can’t do this, because we don’t have access to a big staff and emergency facilities.”
But after consulting with colleagues, she realized a shift in mindset was needed: “Rather than focus on what we don’t have, what do we actually have available? We have relationships we have built with institutions,” including the oldest SCD clinic in Ghana, the Ghana Institute of Clinical Genetics (GICG). This facility sits next door to a hospital with 24-hour care, Korle Bu Teaching Hospital (KBTH), a major tertiary care and referral center.
Open since 1974, the KBTH-allied GICG provides comprehensive outpatient health care to teens and adult with SCD. Currently, more than 25,000 SCD patients are registered at GICG; about half have the HbSS genotype, and another 40% have the HbSC genotype, said Yvonne Dei-Adomakoh, MD. Dr. Dei-Adomakoh of the University of Ghana is an investigator for an upcoming phase 3 trial to test voxelotor against placebo in SCD.
The GICG is working hard to become a site where clinical trials, as well as research and development, are embedded into clinic functions. In this way, not only will research be advanced for all those with SCD, but advances will be more easily incorporated into clinical care, said Dr. Dei-Adomakoh.
Dr. Owusu-Ansah noted that the facility offers a pharmacy, a laboratory, exam rooms, and information technology and medical record resources. Importantly, GICG is already staffed with physicians and allied health personnel with SCD expertise.
The University of Ghana campus is home to one of Africa’s leading biomedical research facilities, a sophisticated 11,000-square-foot laboratory that can perform testing ranging from polymerase chain reactions to DNA sequencing to genotyping and flow cytometry; it also houses a laboratory animal facility. This laboratory, the Noguchi Memorial Institute for Medical Research, also offers administrative, scientific, and research support, and houses an institutional review board.
The problem of the Noguchi laboratory site’s distance from the 24-hour support of KBTH has been solved by arranging to have an ambulance with paramedics available on site during the clinical trials.
Some other challenges the investigators discovered highlighted less-obvious infrastructure deficits; keeping a refrigerated chain of custody for biological samples, for example, can be difficult. In preparation for the trials, much basic laboratory and clinical equipment has been updated.
Conducting a U.S.-registered clinical trial in Ghana doesn’t obviate the need to meet that country’s considerable regulatory hurdles, said Dr. Owusu-Ansah. Requirements include a full regulatory submission to, and physical inspection by, Ghana’s FDA. Ghana also requires that the principal investigator must live in Ghana for the duration of the trial and that key study personnel complete Ghanaian good clinical practices training, she said.
The University of Pittsburgh is a U.S. partner in the NVX-508 study, and it was non-negotiable for that institution that a clinical trial monitor visit the African study sites. The institution’s institutional review board was sensitive to the importance of protecting vulnerable populations, and needed to hear complete plans for risk assessment, data protection, and compensation for Ghanaian study participants, Dr. Owusu-Ansah said.
But, in a turn of events typical of the ups and downs of drug development, the phase 1 trial had passed most of the administrative hurdles when in July the drug’s sponsor, NuvOx Pharma, suspended the NVX-508 trial to focus on other areas. For now, the trial registration has been withdrawn on clinicaltrials.gov and the new drug application is inactive. But Dr. Owusu-Ansah said study preparations could resume in the future, if the drug is made available to investigators.
Dr. Owusu-Ansah reported that she has received salary support from NuvOx Pharma. Dr. Segbefia reported that she has received support from Daiichi-Sankyo and Eli Lilly and Company.
WASHINGTON – Sometimes, the hardest part of solving a problem is figuring out how to work around misaligned resources, and so it has been with sickle cell disease research.
“From my point of view, what I call the geographical disparity in sickle cell disease research can be explained by the fact that the majority of affected individuals are living in the East, and the overwhelming majority of the research takes place in the West,” said Solomon Ofori-Acquah, PhD. He and three physician collaborators from Ghana shared their roadmap to conducting clinical trials in West Africa during an “East Meets West” session of the annual symposium of the Foundation for Sickle Cell Disease Research.
In Ghana, not far from where scientists now believe the hemoglobin sickling mutation originated, fully 2% of newborns have SCD; this translates into 16,000 new cases per year in a population of just 28 million, compared with the 2,000 new SCD cases seen annually in the entire United States. And access even to proven therapies can be limited; historically, little to no clinical drug development work has been conducted in this part of the world.
In the United States, half of the SCD trials that were withdrawn or terminated listed recruitment and retention of study participants as a factor in the study’s discontinuation, said Amma Owusu-Ansah, MD. “I see what we are doing as a very feasible solution to the problem of inadequate accrual to studies in the U.S.,” said Dr. Owusu-Ansah, a hematologist at the University of Pittsburgh’s Center for Translational and International Hematology (CTIH), where she serves as clinical director.
From the African perspective, hosting clinical trials – and building a robust infrastructure to do so – may help alleviate the delay in translation of disease-modifying therapies for SCD to Africa, where most people with the disease live, she said.
An existing example of resource sharing is the Human Heredity & Health in Africa (H3Africa) initiative, said Dr. Ofori-Acquah, who directs the CTIH and also holds an appointment at the University of Ghana. The project, funded by the National Institutes of Health and the Wellcome Trust, “aims to facilitate a contemporary research approach to the study of genomics and environmental determinants of common diseases with the goal of improving the health of African populations,” according to the H3Africa website. Within this framework of 40 research centers conducting genomics research and biobanking, several discrete projects aim to expand knowledge of sickle cell disease.
“All of these networks are going to study thousands of patients,” said Dr. Ofori-Acquah. “I see the H3 as a mechanism to accelerate genomics research in sickle cell disease.”
“We created a research team and built capacity for future work…. Ghana, and Africa, are capable of conducting clinical trials to global standards and producing quality data,” she said.
The story of one clinical trial is illustrative of the challenges and strengths of the multinational approach.
The phase 1b trial of a novel treatment for sickle cell disease, NVX-508, began with an initial hurdle of lack of access to emergency care at the study site, said Dr. Owusu-Ansah, a study investigator. Her first reaction, she said, was, “Well, we can’t do this, because we don’t have access to a big staff and emergency facilities.”
But after consulting with colleagues, she realized a shift in mindset was needed: “Rather than focus on what we don’t have, what do we actually have available? We have relationships we have built with institutions,” including the oldest SCD clinic in Ghana, the Ghana Institute of Clinical Genetics (GICG). This facility sits next door to a hospital with 24-hour care, Korle Bu Teaching Hospital (KBTH), a major tertiary care and referral center.
Open since 1974, the KBTH-allied GICG provides comprehensive outpatient health care to teens and adult with SCD. Currently, more than 25,000 SCD patients are registered at GICG; about half have the HbSS genotype, and another 40% have the HbSC genotype, said Yvonne Dei-Adomakoh, MD. Dr. Dei-Adomakoh of the University of Ghana is an investigator for an upcoming phase 3 trial to test voxelotor against placebo in SCD.
The GICG is working hard to become a site where clinical trials, as well as research and development, are embedded into clinic functions. In this way, not only will research be advanced for all those with SCD, but advances will be more easily incorporated into clinical care, said Dr. Dei-Adomakoh.
Dr. Owusu-Ansah noted that the facility offers a pharmacy, a laboratory, exam rooms, and information technology and medical record resources. Importantly, GICG is already staffed with physicians and allied health personnel with SCD expertise.
The University of Ghana campus is home to one of Africa’s leading biomedical research facilities, a sophisticated 11,000-square-foot laboratory that can perform testing ranging from polymerase chain reactions to DNA sequencing to genotyping and flow cytometry; it also houses a laboratory animal facility. This laboratory, the Noguchi Memorial Institute for Medical Research, also offers administrative, scientific, and research support, and houses an institutional review board.
The problem of the Noguchi laboratory site’s distance from the 24-hour support of KBTH has been solved by arranging to have an ambulance with paramedics available on site during the clinical trials.
Some other challenges the investigators discovered highlighted less-obvious infrastructure deficits; keeping a refrigerated chain of custody for biological samples, for example, can be difficult. In preparation for the trials, much basic laboratory and clinical equipment has been updated.
Conducting a U.S.-registered clinical trial in Ghana doesn’t obviate the need to meet that country’s considerable regulatory hurdles, said Dr. Owusu-Ansah. Requirements include a full regulatory submission to, and physical inspection by, Ghana’s FDA. Ghana also requires that the principal investigator must live in Ghana for the duration of the trial and that key study personnel complete Ghanaian good clinical practices training, she said.
The University of Pittsburgh is a U.S. partner in the NVX-508 study, and it was non-negotiable for that institution that a clinical trial monitor visit the African study sites. The institution’s institutional review board was sensitive to the importance of protecting vulnerable populations, and needed to hear complete plans for risk assessment, data protection, and compensation for Ghanaian study participants, Dr. Owusu-Ansah said.
But, in a turn of events typical of the ups and downs of drug development, the phase 1 trial had passed most of the administrative hurdles when in July the drug’s sponsor, NuvOx Pharma, suspended the NVX-508 trial to focus on other areas. For now, the trial registration has been withdrawn on clinicaltrials.gov and the new drug application is inactive. But Dr. Owusu-Ansah said study preparations could resume in the future, if the drug is made available to investigators.
Dr. Owusu-Ansah reported that she has received salary support from NuvOx Pharma. Dr. Segbefia reported that she has received support from Daiichi-Sankyo and Eli Lilly and Company.
WASHINGTON – Sometimes, the hardest part of solving a problem is figuring out how to work around misaligned resources, and so it has been with sickle cell disease research.
“From my point of view, what I call the geographical disparity in sickle cell disease research can be explained by the fact that the majority of affected individuals are living in the East, and the overwhelming majority of the research takes place in the West,” said Solomon Ofori-Acquah, PhD. He and three physician collaborators from Ghana shared their roadmap to conducting clinical trials in West Africa during an “East Meets West” session of the annual symposium of the Foundation for Sickle Cell Disease Research.
In Ghana, not far from where scientists now believe the hemoglobin sickling mutation originated, fully 2% of newborns have SCD; this translates into 16,000 new cases per year in a population of just 28 million, compared with the 2,000 new SCD cases seen annually in the entire United States. And access even to proven therapies can be limited; historically, little to no clinical drug development work has been conducted in this part of the world.
In the United States, half of the SCD trials that were withdrawn or terminated listed recruitment and retention of study participants as a factor in the study’s discontinuation, said Amma Owusu-Ansah, MD. “I see what we are doing as a very feasible solution to the problem of inadequate accrual to studies in the U.S.,” said Dr. Owusu-Ansah, a hematologist at the University of Pittsburgh’s Center for Translational and International Hematology (CTIH), where she serves as clinical director.
From the African perspective, hosting clinical trials – and building a robust infrastructure to do so – may help alleviate the delay in translation of disease-modifying therapies for SCD to Africa, where most people with the disease live, she said.
An existing example of resource sharing is the Human Heredity & Health in Africa (H3Africa) initiative, said Dr. Ofori-Acquah, who directs the CTIH and also holds an appointment at the University of Ghana. The project, funded by the National Institutes of Health and the Wellcome Trust, “aims to facilitate a contemporary research approach to the study of genomics and environmental determinants of common diseases with the goal of improving the health of African populations,” according to the H3Africa website. Within this framework of 40 research centers conducting genomics research and biobanking, several discrete projects aim to expand knowledge of sickle cell disease.
“All of these networks are going to study thousands of patients,” said Dr. Ofori-Acquah. “I see the H3 as a mechanism to accelerate genomics research in sickle cell disease.”
“We created a research team and built capacity for future work…. Ghana, and Africa, are capable of conducting clinical trials to global standards and producing quality data,” she said.
The story of one clinical trial is illustrative of the challenges and strengths of the multinational approach.
The phase 1b trial of a novel treatment for sickle cell disease, NVX-508, began with an initial hurdle of lack of access to emergency care at the study site, said Dr. Owusu-Ansah, a study investigator. Her first reaction, she said, was, “Well, we can’t do this, because we don’t have access to a big staff and emergency facilities.”
But after consulting with colleagues, she realized a shift in mindset was needed: “Rather than focus on what we don’t have, what do we actually have available? We have relationships we have built with institutions,” including the oldest SCD clinic in Ghana, the Ghana Institute of Clinical Genetics (GICG). This facility sits next door to a hospital with 24-hour care, Korle Bu Teaching Hospital (KBTH), a major tertiary care and referral center.
Open since 1974, the KBTH-allied GICG provides comprehensive outpatient health care to teens and adult with SCD. Currently, more than 25,000 SCD patients are registered at GICG; about half have the HbSS genotype, and another 40% have the HbSC genotype, said Yvonne Dei-Adomakoh, MD. Dr. Dei-Adomakoh of the University of Ghana is an investigator for an upcoming phase 3 trial to test voxelotor against placebo in SCD.
The GICG is working hard to become a site where clinical trials, as well as research and development, are embedded into clinic functions. In this way, not only will research be advanced for all those with SCD, but advances will be more easily incorporated into clinical care, said Dr. Dei-Adomakoh.
Dr. Owusu-Ansah noted that the facility offers a pharmacy, a laboratory, exam rooms, and information technology and medical record resources. Importantly, GICG is already staffed with physicians and allied health personnel with SCD expertise.
The University of Ghana campus is home to one of Africa’s leading biomedical research facilities, a sophisticated 11,000-square-foot laboratory that can perform testing ranging from polymerase chain reactions to DNA sequencing to genotyping and flow cytometry; it also houses a laboratory animal facility. This laboratory, the Noguchi Memorial Institute for Medical Research, also offers administrative, scientific, and research support, and houses an institutional review board.
The problem of the Noguchi laboratory site’s distance from the 24-hour support of KBTH has been solved by arranging to have an ambulance with paramedics available on site during the clinical trials.
Some other challenges the investigators discovered highlighted less-obvious infrastructure deficits; keeping a refrigerated chain of custody for biological samples, for example, can be difficult. In preparation for the trials, much basic laboratory and clinical equipment has been updated.
Conducting a U.S.-registered clinical trial in Ghana doesn’t obviate the need to meet that country’s considerable regulatory hurdles, said Dr. Owusu-Ansah. Requirements include a full regulatory submission to, and physical inspection by, Ghana’s FDA. Ghana also requires that the principal investigator must live in Ghana for the duration of the trial and that key study personnel complete Ghanaian good clinical practices training, she said.
The University of Pittsburgh is a U.S. partner in the NVX-508 study, and it was non-negotiable for that institution that a clinical trial monitor visit the African study sites. The institution’s institutional review board was sensitive to the importance of protecting vulnerable populations, and needed to hear complete plans for risk assessment, data protection, and compensation for Ghanaian study participants, Dr. Owusu-Ansah said.
But, in a turn of events typical of the ups and downs of drug development, the phase 1 trial had passed most of the administrative hurdles when in July the drug’s sponsor, NuvOx Pharma, suspended the NVX-508 trial to focus on other areas. For now, the trial registration has been withdrawn on clinicaltrials.gov and the new drug application is inactive. But Dr. Owusu-Ansah said study preparations could resume in the future, if the drug is made available to investigators.
Dr. Owusu-Ansah reported that she has received salary support from NuvOx Pharma. Dr. Segbefia reported that she has received support from Daiichi-Sankyo and Eli Lilly and Company.
EXPERT ANALYSIS FROM FSCDR 2018
Former Smokers Motivate Quitters
In 2012, the CDC launched the “Tips from Former Smokers” campaign. It was memorable and emotionally forceful—one woman who had oral and throat cancer delivered her ad through an artificial voicebox—but did it have an impact on actual quitting rates?
No study had been done to assess the campaign’s combined, multiyear impact until CDC researchers looked at sustained (6 month) cigarette abstinence during the first 4 years of the campaign (2012-2015).
They found that the Tips campaign led to about 9.15 million total quit attempts. Based on an assumed 5.7% abstinence rate for people attempting to quit, this amounts to approximately 522,000 sustained quits.
The researchers say their findings indicate that the comprehensive approach combining evidence-based messages with the promotion of cessation resources was highly successful. Their finding of more than half-million sustained quits underscores the critical role of national tobacco education campaigns as a “counterpoint” to the substantial pro-tobacco advertising and promotion.
In 2012, the CDC launched the “Tips from Former Smokers” campaign. It was memorable and emotionally forceful—one woman who had oral and throat cancer delivered her ad through an artificial voicebox—but did it have an impact on actual quitting rates?
No study had been done to assess the campaign’s combined, multiyear impact until CDC researchers looked at sustained (6 month) cigarette abstinence during the first 4 years of the campaign (2012-2015).
They found that the Tips campaign led to about 9.15 million total quit attempts. Based on an assumed 5.7% abstinence rate for people attempting to quit, this amounts to approximately 522,000 sustained quits.
The researchers say their findings indicate that the comprehensive approach combining evidence-based messages with the promotion of cessation resources was highly successful. Their finding of more than half-million sustained quits underscores the critical role of national tobacco education campaigns as a “counterpoint” to the substantial pro-tobacco advertising and promotion.
In 2012, the CDC launched the “Tips from Former Smokers” campaign. It was memorable and emotionally forceful—one woman who had oral and throat cancer delivered her ad through an artificial voicebox—but did it have an impact on actual quitting rates?
No study had been done to assess the campaign’s combined, multiyear impact until CDC researchers looked at sustained (6 month) cigarette abstinence during the first 4 years of the campaign (2012-2015).
They found that the Tips campaign led to about 9.15 million total quit attempts. Based on an assumed 5.7% abstinence rate for people attempting to quit, this amounts to approximately 522,000 sustained quits.
The researchers say their findings indicate that the comprehensive approach combining evidence-based messages with the promotion of cessation resources was highly successful. Their finding of more than half-million sustained quits underscores the critical role of national tobacco education campaigns as a “counterpoint” to the substantial pro-tobacco advertising and promotion.
Hematology and Oncology Federal Health Data Trends (FULL)
Cancer research is a high priority for the DoD and especially for the VA. Researchers in both agencies played an important role in the early stages of the Cancer Moonshot. As part of this initiative, the VA, DoD, and National Cancer Institute joined forces in the Applied Proteogenomics Organizational Learning and Outcomes (APOLLO) project to develop a system to quickly identify unique targets and pathways of cancer for better interventions.
The VA also will provide access to the Million Veteran Program database, and > 20 years of electronic health records data for analysis using the U.S. Department of Energy’s advanced computer systems. The enhanced computational infrastructure provided by the departments will facilitate new studies of cancer genomics. The research will begin with prostate cancer, and it is hoped that the project will help researchers distinguish between those prostate cancers that require aggressive management and the more benign cancers that are less likely to progress.
According to the latest VA budget, its researchers are conducting a broad array of research on cancers common in the veteran population, including prostate, lung, colorectal, bladder, kidney, pancreatic, skin, esophageal, and femalespecific cancers (such as breast and cervical cancer), as well as lymphomas and melanomas. For example, one study is focused on improving palliative care for patients with advanced cancer, and another will enroll 50,000 veterans to compare colorectal cancer screening strategies.
Click here to read the digital edition.
Cancer research is a high priority for the DoD and especially for the VA. Researchers in both agencies played an important role in the early stages of the Cancer Moonshot. As part of this initiative, the VA, DoD, and National Cancer Institute joined forces in the Applied Proteogenomics Organizational Learning and Outcomes (APOLLO) project to develop a system to quickly identify unique targets and pathways of cancer for better interventions.
The VA also will provide access to the Million Veteran Program database, and > 20 years of electronic health records data for analysis using the U.S. Department of Energy’s advanced computer systems. The enhanced computational infrastructure provided by the departments will facilitate new studies of cancer genomics. The research will begin with prostate cancer, and it is hoped that the project will help researchers distinguish between those prostate cancers that require aggressive management and the more benign cancers that are less likely to progress.
According to the latest VA budget, its researchers are conducting a broad array of research on cancers common in the veteran population, including prostate, lung, colorectal, bladder, kidney, pancreatic, skin, esophageal, and femalespecific cancers (such as breast and cervical cancer), as well as lymphomas and melanomas. For example, one study is focused on improving palliative care for patients with advanced cancer, and another will enroll 50,000 veterans to compare colorectal cancer screening strategies.
Click here to read the digital edition.
Cancer research is a high priority for the DoD and especially for the VA. Researchers in both agencies played an important role in the early stages of the Cancer Moonshot. As part of this initiative, the VA, DoD, and National Cancer Institute joined forces in the Applied Proteogenomics Organizational Learning and Outcomes (APOLLO) project to develop a system to quickly identify unique targets and pathways of cancer for better interventions.
The VA also will provide access to the Million Veteran Program database, and > 20 years of electronic health records data for analysis using the U.S. Department of Energy’s advanced computer systems. The enhanced computational infrastructure provided by the departments will facilitate new studies of cancer genomics. The research will begin with prostate cancer, and it is hoped that the project will help researchers distinguish between those prostate cancers that require aggressive management and the more benign cancers that are less likely to progress.
According to the latest VA budget, its researchers are conducting a broad array of research on cancers common in the veteran population, including prostate, lung, colorectal, bladder, kidney, pancreatic, skin, esophageal, and femalespecific cancers (such as breast and cervical cancer), as well as lymphomas and melanomas. For example, one study is focused on improving palliative care for patients with advanced cancer, and another will enroll 50,000 veterans to compare colorectal cancer screening strategies.
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FDA approves Nivestym, second biosimilar to Neupogen
Nivestym (filgrastim-aafi), a biosimilar to Neupogen (filgrastim) was approved July 20 by the Food and Drug Administration, according to a statement provided by the agency. Nivestym is the second biosimilar to Neupogen to be approved in the United States.
- Patients with cancer receiving myelosuppressive chemotherapy.
- Patients with acute myeloid leukemia receiving induction or consolidation chemotherapy.
- Patients with cancer undergoing bone marrow transplantation.
- Patients undergoing autologous peripheral blood progenitor cell collection and therapy.
- Patients with severe chronic neutropenia.
According to a press release from Pfizer, the manufacturer of the biosimilar, Nivestym is expected to be available in the United States at a significant discount to the current wholesale acquisition cost of Neupogen, which is not inclusive of discounts to payers, providers, distributors, and other purchasing organizations.
The FDA statement notes that a biosimilar is approved based on a showing that it is highly similar to an already approved biologic product, known as a reference product. The biosimilar also must be shown to have no clinically meaningful differences in terms of safety and effectiveness from the reference product. Only minor differences in clinically inactive components are allowable in biosimilar products.
Prescribing information is available here.
Nivestym (filgrastim-aafi), a biosimilar to Neupogen (filgrastim) was approved July 20 by the Food and Drug Administration, according to a statement provided by the agency. Nivestym is the second biosimilar to Neupogen to be approved in the United States.
- Patients with cancer receiving myelosuppressive chemotherapy.
- Patients with acute myeloid leukemia receiving induction or consolidation chemotherapy.
- Patients with cancer undergoing bone marrow transplantation.
- Patients undergoing autologous peripheral blood progenitor cell collection and therapy.
- Patients with severe chronic neutropenia.
According to a press release from Pfizer, the manufacturer of the biosimilar, Nivestym is expected to be available in the United States at a significant discount to the current wholesale acquisition cost of Neupogen, which is not inclusive of discounts to payers, providers, distributors, and other purchasing organizations.
The FDA statement notes that a biosimilar is approved based on a showing that it is highly similar to an already approved biologic product, known as a reference product. The biosimilar also must be shown to have no clinically meaningful differences in terms of safety and effectiveness from the reference product. Only minor differences in clinically inactive components are allowable in biosimilar products.
Prescribing information is available here.
Nivestym (filgrastim-aafi), a biosimilar to Neupogen (filgrastim) was approved July 20 by the Food and Drug Administration, according to a statement provided by the agency. Nivestym is the second biosimilar to Neupogen to be approved in the United States.
- Patients with cancer receiving myelosuppressive chemotherapy.
- Patients with acute myeloid leukemia receiving induction or consolidation chemotherapy.
- Patients with cancer undergoing bone marrow transplantation.
- Patients undergoing autologous peripheral blood progenitor cell collection and therapy.
- Patients with severe chronic neutropenia.
According to a press release from Pfizer, the manufacturer of the biosimilar, Nivestym is expected to be available in the United States at a significant discount to the current wholesale acquisition cost of Neupogen, which is not inclusive of discounts to payers, providers, distributors, and other purchasing organizations.
The FDA statement notes that a biosimilar is approved based on a showing that it is highly similar to an already approved biologic product, known as a reference product. The biosimilar also must be shown to have no clinically meaningful differences in terms of safety and effectiveness from the reference product. Only minor differences in clinically inactive components are allowable in biosimilar products.
Prescribing information is available here.
FDA approves IDH1 inhibitor for relapsed/refractory AML
The Food and Drug Administration has approved ivosidenib (Tibsovo) as the first treatment of adult patients with relapsed/refractory acute myeloid leukemia (AML) and an isocitrate dehydrogenase-1 (IDH1) mutation.
More specifically, the oral treatment has been approved for patients whose mutations have been identified by the Abbott RealTime IDH1 assay, a companion diagnostic test.
The approval was based on results from a phase 1, open-label, single-arm, multicenter, dose-escalation and expansion trial of adult patients in this AML population. The primary end point was combined complete remission and complete remission with partial hematologic improvement; this combined rate was 32.8%, and the median duration of this remission was 8.2 months.
The most serious adverse events included differentiation syndrome, QTc prolongation, and Guillain-Barré syndrome. Other adverse reactions included fatigue, leukocytosis, arthralgia, diarrhea, dyspnea, edema, and constipation.
Ivosidenib is marketed as Tibsovo by Agios Pharmaceuticals. The RealTime IDH1 Assay is marketed by Abbott Laboratories.
The Food and Drug Administration has approved ivosidenib (Tibsovo) as the first treatment of adult patients with relapsed/refractory acute myeloid leukemia (AML) and an isocitrate dehydrogenase-1 (IDH1) mutation.
More specifically, the oral treatment has been approved for patients whose mutations have been identified by the Abbott RealTime IDH1 assay, a companion diagnostic test.
The approval was based on results from a phase 1, open-label, single-arm, multicenter, dose-escalation and expansion trial of adult patients in this AML population. The primary end point was combined complete remission and complete remission with partial hematologic improvement; this combined rate was 32.8%, and the median duration of this remission was 8.2 months.
The most serious adverse events included differentiation syndrome, QTc prolongation, and Guillain-Barré syndrome. Other adverse reactions included fatigue, leukocytosis, arthralgia, diarrhea, dyspnea, edema, and constipation.
Ivosidenib is marketed as Tibsovo by Agios Pharmaceuticals. The RealTime IDH1 Assay is marketed by Abbott Laboratories.
The Food and Drug Administration has approved ivosidenib (Tibsovo) as the first treatment of adult patients with relapsed/refractory acute myeloid leukemia (AML) and an isocitrate dehydrogenase-1 (IDH1) mutation.
More specifically, the oral treatment has been approved for patients whose mutations have been identified by the Abbott RealTime IDH1 assay, a companion diagnostic test.
The approval was based on results from a phase 1, open-label, single-arm, multicenter, dose-escalation and expansion trial of adult patients in this AML population. The primary end point was combined complete remission and complete remission with partial hematologic improvement; this combined rate was 32.8%, and the median duration of this remission was 8.2 months.
The most serious adverse events included differentiation syndrome, QTc prolongation, and Guillain-Barré syndrome. Other adverse reactions included fatigue, leukocytosis, arthralgia, diarrhea, dyspnea, edema, and constipation.
Ivosidenib is marketed as Tibsovo by Agios Pharmaceuticals. The RealTime IDH1 Assay is marketed by Abbott Laboratories.
Phase 3 results shed light on L-glutamine use in SCD
Children and adults with sickle cell disease who received L-glutamine alone or with hydroxyurea had a median number of pain episodes that was 25% lower than those who received placebo, according to newly published results from the phase 3 trial that led to the agent’s approval in 2017.
The median number of hospitalizations was 33% lower among individuals receiving L-glutamine than it was among those receiving placebo, in results reported by investigators led by Yutaka Niihara, MD, of the University of California, Los Angeles, and Emmaus Medical.
Blood test results showed persistent elevation of mean corpuscular volume, indicating adherence to hydroxyurea therapy and suggesting that the effect of L-glutamine might be additive, Dr. Niihara and his coauthors wrote in the New England Journal of Medicine.
“L-glutamine thus provides an alternative therapy for those who decline treatment with hydroxyurea or who may have unacceptable side effects from hydroxyurea, as well as an additive therapy to lower the incidence of pain crises for those who may have suboptimal response to hydroxyurea,” they wrote.
The multicenter, randomized, placebo-controlled, double-blind, phase 3 trial by Dr. Niihara and his colleagues included 230 children and adults with sickle cell anemia or sickle-beta0-thalassemia and two or more pain crises in the previous year.
Participants at 31 sites across the United States were randomized to receive L-glutamine powder (n = 152) or placebo (n = 78) orally twice weekly for 48 weeks, followed by a 3-week tapering period. Two-thirds received concomitant hydroxyurea during the trial.
Participants were contacted by telephone weekly during the study to encourage adherence.
A total of 156 individuals completed the study, including 97 of 152 (63.8%) in the L-glutamine arm and 59 of 78 (75.6%) in the placebo arm. The most common reasons for discontinuation were withdrawal of consent, nonadherence, or reasons classified as “other,” according to investigators.
The primary end point was the number of pain crises through week 48 of the trial. A median of 3.0 pain crises occurred in the L-glutamine group, compared with 4.0 in the placebo group (P = .005). Additionally, the median number of hospitalizations was 2.0 for the L-glutamine group versus 3.0 for the placebo group (P = .005).
Nausea, arm or leg pain, and back pain all had an incidence in the L-glutamine group that was 5% higher than in the placebo group, investigators reported.
Based on these results, the Food and Drug administration approved oral L-glutamine powder to reduce the acute complications of sickle cell disease in patients 5 years of age and older in July 2017.
The reasons for study withdrawal were similar in the L-glutamine and placebo groups, despite the higher withdrawal rate in the L-glutamine group, investigators said in a discussion of their results. “Recruitment and retention in a year-long study is difficult in an already burdened population,” they wrote.
The overall noncompletion rate was 32%, similar to the 35% rate seen in a recent multicenter trial of crizanlizumab in patients with sickle cell disease, they added.
Dr. Niihara is the founder and CEO of Emmaus Medical, which sponsored the trial. Other coauthors also reported disclosures related to Emmaus Medical and other companies.
SOURCE: Niihara Y et al. N Engl J Med. 2018 Jul 19;379(3):226-35.
Results of this phase 3 trial were “much awaited” and illustrate the efficacy of L-glutamine in reducing the number of acute vasoocclusive episodes in patients with sickle cell disease.
However, as with any new breakthrough in medicine, there are now compelling questions that need to be answered, Caterina P. Minniti, MD, said in an accompanying editorial.
How to handle cost is one such question. One year of treatment with pharmaceutical-grade L-glutamine carries an estimated cost of $40,515 versus $1,700 for a year of hydroxyurea, but whether the price tag will hinder prescribing of the newer agent has yet to be seen, according to Dr. Minniti.
“This agent certainly has been slow to enter the market because prescribing L-glutamine for patients requires many steps, which may dissuade busy practitioners from actively prescribing it,” she said.
Another question is whether it should be used alongside hydroxyurea, as was done in two-thirds of patients in the present trial. Concomitant use is possible and “most likely advantageous” given that L-glutamine has a different toxicity profile and putatively different mechanism of action from hydroxyurea, Dr. Minniti said.
Who should receive L-glutamine is another important question. Dr. Minniti said that, based on previous trial data, caution may be warranted in giving L-glutamine to patients with significant renal and hepatic dysfunction, but she added that its role could be broad.
“In the absence of specific guidelines, I believe that L-glutamine may be prescribed to persons older than 5 years of age who have any sickle genotype and continue to have episodes of acute disease exacerbations despite appropriate use of hydroxyurea or to those who cannot or do not use hydroxyurea,” she said in the editorial.
Caterina P. Minniti, MD, is with the division of hematology at Montefiore Medical Center at Einstein College of Medicine, New York. These comments are excerpted from her accompanying editorial ( N Engl J Med. 2018;379:292-4 ). Dr. Minniti reported disclosures related to Global Blood Therapeutics and Bayer, along with a patent pending for a topical sodium nitrite formulation.
Results of this phase 3 trial were “much awaited” and illustrate the efficacy of L-glutamine in reducing the number of acute vasoocclusive episodes in patients with sickle cell disease.
However, as with any new breakthrough in medicine, there are now compelling questions that need to be answered, Caterina P. Minniti, MD, said in an accompanying editorial.
How to handle cost is one such question. One year of treatment with pharmaceutical-grade L-glutamine carries an estimated cost of $40,515 versus $1,700 for a year of hydroxyurea, but whether the price tag will hinder prescribing of the newer agent has yet to be seen, according to Dr. Minniti.
“This agent certainly has been slow to enter the market because prescribing L-glutamine for patients requires many steps, which may dissuade busy practitioners from actively prescribing it,” she said.
Another question is whether it should be used alongside hydroxyurea, as was done in two-thirds of patients in the present trial. Concomitant use is possible and “most likely advantageous” given that L-glutamine has a different toxicity profile and putatively different mechanism of action from hydroxyurea, Dr. Minniti said.
Who should receive L-glutamine is another important question. Dr. Minniti said that, based on previous trial data, caution may be warranted in giving L-glutamine to patients with significant renal and hepatic dysfunction, but she added that its role could be broad.
“In the absence of specific guidelines, I believe that L-glutamine may be prescribed to persons older than 5 years of age who have any sickle genotype and continue to have episodes of acute disease exacerbations despite appropriate use of hydroxyurea or to those who cannot or do not use hydroxyurea,” she said in the editorial.
Caterina P. Minniti, MD, is with the division of hematology at Montefiore Medical Center at Einstein College of Medicine, New York. These comments are excerpted from her accompanying editorial ( N Engl J Med. 2018;379:292-4 ). Dr. Minniti reported disclosures related to Global Blood Therapeutics and Bayer, along with a patent pending for a topical sodium nitrite formulation.
Results of this phase 3 trial were “much awaited” and illustrate the efficacy of L-glutamine in reducing the number of acute vasoocclusive episodes in patients with sickle cell disease.
However, as with any new breakthrough in medicine, there are now compelling questions that need to be answered, Caterina P. Minniti, MD, said in an accompanying editorial.
How to handle cost is one such question. One year of treatment with pharmaceutical-grade L-glutamine carries an estimated cost of $40,515 versus $1,700 for a year of hydroxyurea, but whether the price tag will hinder prescribing of the newer agent has yet to be seen, according to Dr. Minniti.
“This agent certainly has been slow to enter the market because prescribing L-glutamine for patients requires many steps, which may dissuade busy practitioners from actively prescribing it,” she said.
Another question is whether it should be used alongside hydroxyurea, as was done in two-thirds of patients in the present trial. Concomitant use is possible and “most likely advantageous” given that L-glutamine has a different toxicity profile and putatively different mechanism of action from hydroxyurea, Dr. Minniti said.
Who should receive L-glutamine is another important question. Dr. Minniti said that, based on previous trial data, caution may be warranted in giving L-glutamine to patients with significant renal and hepatic dysfunction, but she added that its role could be broad.
“In the absence of specific guidelines, I believe that L-glutamine may be prescribed to persons older than 5 years of age who have any sickle genotype and continue to have episodes of acute disease exacerbations despite appropriate use of hydroxyurea or to those who cannot or do not use hydroxyurea,” she said in the editorial.
Caterina P. Minniti, MD, is with the division of hematology at Montefiore Medical Center at Einstein College of Medicine, New York. These comments are excerpted from her accompanying editorial ( N Engl J Med. 2018;379:292-4 ). Dr. Minniti reported disclosures related to Global Blood Therapeutics and Bayer, along with a patent pending for a topical sodium nitrite formulation.
Children and adults with sickle cell disease who received L-glutamine alone or with hydroxyurea had a median number of pain episodes that was 25% lower than those who received placebo, according to newly published results from the phase 3 trial that led to the agent’s approval in 2017.
The median number of hospitalizations was 33% lower among individuals receiving L-glutamine than it was among those receiving placebo, in results reported by investigators led by Yutaka Niihara, MD, of the University of California, Los Angeles, and Emmaus Medical.
Blood test results showed persistent elevation of mean corpuscular volume, indicating adherence to hydroxyurea therapy and suggesting that the effect of L-glutamine might be additive, Dr. Niihara and his coauthors wrote in the New England Journal of Medicine.
“L-glutamine thus provides an alternative therapy for those who decline treatment with hydroxyurea or who may have unacceptable side effects from hydroxyurea, as well as an additive therapy to lower the incidence of pain crises for those who may have suboptimal response to hydroxyurea,” they wrote.
The multicenter, randomized, placebo-controlled, double-blind, phase 3 trial by Dr. Niihara and his colleagues included 230 children and adults with sickle cell anemia or sickle-beta0-thalassemia and two or more pain crises in the previous year.
Participants at 31 sites across the United States were randomized to receive L-glutamine powder (n = 152) or placebo (n = 78) orally twice weekly for 48 weeks, followed by a 3-week tapering period. Two-thirds received concomitant hydroxyurea during the trial.
Participants were contacted by telephone weekly during the study to encourage adherence.
A total of 156 individuals completed the study, including 97 of 152 (63.8%) in the L-glutamine arm and 59 of 78 (75.6%) in the placebo arm. The most common reasons for discontinuation were withdrawal of consent, nonadherence, or reasons classified as “other,” according to investigators.
The primary end point was the number of pain crises through week 48 of the trial. A median of 3.0 pain crises occurred in the L-glutamine group, compared with 4.0 in the placebo group (P = .005). Additionally, the median number of hospitalizations was 2.0 for the L-glutamine group versus 3.0 for the placebo group (P = .005).
Nausea, arm or leg pain, and back pain all had an incidence in the L-glutamine group that was 5% higher than in the placebo group, investigators reported.
Based on these results, the Food and Drug administration approved oral L-glutamine powder to reduce the acute complications of sickle cell disease in patients 5 years of age and older in July 2017.
The reasons for study withdrawal were similar in the L-glutamine and placebo groups, despite the higher withdrawal rate in the L-glutamine group, investigators said in a discussion of their results. “Recruitment and retention in a year-long study is difficult in an already burdened population,” they wrote.
The overall noncompletion rate was 32%, similar to the 35% rate seen in a recent multicenter trial of crizanlizumab in patients with sickle cell disease, they added.
Dr. Niihara is the founder and CEO of Emmaus Medical, which sponsored the trial. Other coauthors also reported disclosures related to Emmaus Medical and other companies.
SOURCE: Niihara Y et al. N Engl J Med. 2018 Jul 19;379(3):226-35.
Children and adults with sickle cell disease who received L-glutamine alone or with hydroxyurea had a median number of pain episodes that was 25% lower than those who received placebo, according to newly published results from the phase 3 trial that led to the agent’s approval in 2017.
The median number of hospitalizations was 33% lower among individuals receiving L-glutamine than it was among those receiving placebo, in results reported by investigators led by Yutaka Niihara, MD, of the University of California, Los Angeles, and Emmaus Medical.
Blood test results showed persistent elevation of mean corpuscular volume, indicating adherence to hydroxyurea therapy and suggesting that the effect of L-glutamine might be additive, Dr. Niihara and his coauthors wrote in the New England Journal of Medicine.
“L-glutamine thus provides an alternative therapy for those who decline treatment with hydroxyurea or who may have unacceptable side effects from hydroxyurea, as well as an additive therapy to lower the incidence of pain crises for those who may have suboptimal response to hydroxyurea,” they wrote.
The multicenter, randomized, placebo-controlled, double-blind, phase 3 trial by Dr. Niihara and his colleagues included 230 children and adults with sickle cell anemia or sickle-beta0-thalassemia and two or more pain crises in the previous year.
Participants at 31 sites across the United States were randomized to receive L-glutamine powder (n = 152) or placebo (n = 78) orally twice weekly for 48 weeks, followed by a 3-week tapering period. Two-thirds received concomitant hydroxyurea during the trial.
Participants were contacted by telephone weekly during the study to encourage adherence.
A total of 156 individuals completed the study, including 97 of 152 (63.8%) in the L-glutamine arm and 59 of 78 (75.6%) in the placebo arm. The most common reasons for discontinuation were withdrawal of consent, nonadherence, or reasons classified as “other,” according to investigators.
The primary end point was the number of pain crises through week 48 of the trial. A median of 3.0 pain crises occurred in the L-glutamine group, compared with 4.0 in the placebo group (P = .005). Additionally, the median number of hospitalizations was 2.0 for the L-glutamine group versus 3.0 for the placebo group (P = .005).
Nausea, arm or leg pain, and back pain all had an incidence in the L-glutamine group that was 5% higher than in the placebo group, investigators reported.
Based on these results, the Food and Drug administration approved oral L-glutamine powder to reduce the acute complications of sickle cell disease in patients 5 years of age and older in July 2017.
The reasons for study withdrawal were similar in the L-glutamine and placebo groups, despite the higher withdrawal rate in the L-glutamine group, investigators said in a discussion of their results. “Recruitment and retention in a year-long study is difficult in an already burdened population,” they wrote.
The overall noncompletion rate was 32%, similar to the 35% rate seen in a recent multicenter trial of crizanlizumab in patients with sickle cell disease, they added.
Dr. Niihara is the founder and CEO of Emmaus Medical, which sponsored the trial. Other coauthors also reported disclosures related to Emmaus Medical and other companies.
SOURCE: Niihara Y et al. N Engl J Med. 2018 Jul 19;379(3):226-35.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point:
Major finding: The median number of pain crises was 3.0 in the L-glutamine group, compared with 4.0 in the placebo group (P = .005).
Study details: A multicenter, randomized, placebo-controlled, double-blind, phase 3 trial including 230 chidren and adults with sickle cell anemia or sickle-beta0-thalassemia and two or more pain crises in the previous year.
Disclosures: Dr. Niihara is the founder and CEO of Emmaus Medical, which sponsored the trial. Other coauthors also reported disclosures related to Emmaus Medical and other companies. Source: Niihara Y et al. N Engl J Med. 2018 Jul 19;379(3):226-35.
For men with SCD and priapism, hypoxia may prompt RBC adhesion
WASHINGTON – For male patients with sickle cell disease, priapism can be more than just painful and embarrassing. The prolonged erections prompted by vasoocclusive events in the penis may lead to irreversible impotence, but little is known about risk factors for priapism, which remains a difficult-to-treat complication of the disease.
In males with HbSS sickle cell disease (SCD) and priapism, RBC adhesion is increased in hypoxic conditions, according to preliminary findings from work using a newly developed biochip that mimics microvascular conditions in SCD. This significant level of adhesion prompted by hypoxia was not seen in men who did not have priapism, according to study coauthor Erina Quinn, a research assistant in hematology and oncology at Case Western Reserve University, Cleveland, who presented the results at the annual meeting of the Foundation for Sickle Cell Disease Research.
When hemoglobin desaturation occurs, polymerization can be increased, leading to increased end-organ damage, Ms. Quinn said. The biochip is “an effort to measure cellular adhesion in a clinically meaningful way.” The tool can detect hemoglobin phenotype, differentiating among HbSS, HbSbeta+, and HbSC. It can also measure the degree of hemolysis and RBC deformability.
The biochip “mimics postcapillary flow conditions in microchannels,” Ms. Quinn said. The device forces blood samples through microchannels that are at the diameter of smaller venules, approximately 50 mcm, and at a physiological flow rate ranging from 1-13 mm/sec. The microfluidic channels are coated with laminin, a subendothelial matrix protein implicated in RBC adhesion. A second microfluidic biochip mimics hypoxic conditions.
The study enrolled 26 men with the HbSS genotype, 14 of whom reported priapism, and assessed RBC adhesion in blood samples run though both the SCD-modeled biochip and the hypoxia biochip. Investigators also assessed contemporaneous in vivo hemoglobin desaturation, and looked for associations with the in vitro biochip findings.
Of the 26 participants, 16 also had either nocturnal or exertional hemoglobin desaturation. In addition, 10 participants had both priapism and desaturations. These data were collected by retrospective chart review and patient survey.
Patients with priapism were a mean age of 34 years, compared with a mean age of 29 years for the other participants, a nonsignificant difference. There were no significant differences in mean hemoglobin or bilirubin levels, or in reticulocyte counts, between the two groups.
However, white blood count, absolute neutrophil count, and lactate dehydrogenase levels were significantly higher for men with priapism (P = .022, .037, and .008, respectively). Ferritin levels were higher as well, at a mean 2,433 (plus or minus 2,234) mcg/L for those with priapism, compared with a mean 269 (plus or minus 3,015) mcg/L for those without priapism (P = .031).
When absolute reticulocyte count was mapped against lactate dehydrogenase levels to create a measure of degree of hemolysis, “individuals with priapism had a more hemolytic lab profile,” said Ms. Quinn (P = .0186).
Though 10 of 14 men with priapism had hemoglobin desaturation, compared with 5 of 12 who did not have priapism, the difference was not statistically significant.
When the researchers compared microchip analysis of RBC adhesion, though, they found marked differences in RBC adhesion in hypoxic versus nonhypoxic conditions. Significantly more RBCs were adherent under hypoxic conditions – in the hypoxic biochip – for the patients with priapism than for patients without priapism (mean, 529 vs. 3,268 adherent cells; P = .016).
Though numbers were small, RBCs from patients with reported priapism and hemoglobin desaturation in vivo showed increased hypoxia enhanced adhesion in vitro (P = .013), Ms. Quinn said. These was no significant difference between adhesion in normoxic and hypoxic conditions for the patients without priapism.
Future directions of work with the biochip include prospective identification of desaturation events and better characterization of nocturnal symptoms, Ms. Quinn said. The investigators also plan to see whether treatment with supplemental oxygen affects RBC adhesion.
The research was supported by the National Institutes of Health, the Doris Duke Charitable Foundation, and the National Science Foundation. Two coauthors have filed an international patent for the biochip technology.
WASHINGTON – For male patients with sickle cell disease, priapism can be more than just painful and embarrassing. The prolonged erections prompted by vasoocclusive events in the penis may lead to irreversible impotence, but little is known about risk factors for priapism, which remains a difficult-to-treat complication of the disease.
In males with HbSS sickle cell disease (SCD) and priapism, RBC adhesion is increased in hypoxic conditions, according to preliminary findings from work using a newly developed biochip that mimics microvascular conditions in SCD. This significant level of adhesion prompted by hypoxia was not seen in men who did not have priapism, according to study coauthor Erina Quinn, a research assistant in hematology and oncology at Case Western Reserve University, Cleveland, who presented the results at the annual meeting of the Foundation for Sickle Cell Disease Research.
When hemoglobin desaturation occurs, polymerization can be increased, leading to increased end-organ damage, Ms. Quinn said. The biochip is “an effort to measure cellular adhesion in a clinically meaningful way.” The tool can detect hemoglobin phenotype, differentiating among HbSS, HbSbeta+, and HbSC. It can also measure the degree of hemolysis and RBC deformability.
The biochip “mimics postcapillary flow conditions in microchannels,” Ms. Quinn said. The device forces blood samples through microchannels that are at the diameter of smaller venules, approximately 50 mcm, and at a physiological flow rate ranging from 1-13 mm/sec. The microfluidic channels are coated with laminin, a subendothelial matrix protein implicated in RBC adhesion. A second microfluidic biochip mimics hypoxic conditions.
The study enrolled 26 men with the HbSS genotype, 14 of whom reported priapism, and assessed RBC adhesion in blood samples run though both the SCD-modeled biochip and the hypoxia biochip. Investigators also assessed contemporaneous in vivo hemoglobin desaturation, and looked for associations with the in vitro biochip findings.
Of the 26 participants, 16 also had either nocturnal or exertional hemoglobin desaturation. In addition, 10 participants had both priapism and desaturations. These data were collected by retrospective chart review and patient survey.
Patients with priapism were a mean age of 34 years, compared with a mean age of 29 years for the other participants, a nonsignificant difference. There were no significant differences in mean hemoglobin or bilirubin levels, or in reticulocyte counts, between the two groups.
However, white blood count, absolute neutrophil count, and lactate dehydrogenase levels were significantly higher for men with priapism (P = .022, .037, and .008, respectively). Ferritin levels were higher as well, at a mean 2,433 (plus or minus 2,234) mcg/L for those with priapism, compared with a mean 269 (plus or minus 3,015) mcg/L for those without priapism (P = .031).
When absolute reticulocyte count was mapped against lactate dehydrogenase levels to create a measure of degree of hemolysis, “individuals with priapism had a more hemolytic lab profile,” said Ms. Quinn (P = .0186).
Though 10 of 14 men with priapism had hemoglobin desaturation, compared with 5 of 12 who did not have priapism, the difference was not statistically significant.
When the researchers compared microchip analysis of RBC adhesion, though, they found marked differences in RBC adhesion in hypoxic versus nonhypoxic conditions. Significantly more RBCs were adherent under hypoxic conditions – in the hypoxic biochip – for the patients with priapism than for patients without priapism (mean, 529 vs. 3,268 adherent cells; P = .016).
Though numbers were small, RBCs from patients with reported priapism and hemoglobin desaturation in vivo showed increased hypoxia enhanced adhesion in vitro (P = .013), Ms. Quinn said. These was no significant difference between adhesion in normoxic and hypoxic conditions for the patients without priapism.
Future directions of work with the biochip include prospective identification of desaturation events and better characterization of nocturnal symptoms, Ms. Quinn said. The investigators also plan to see whether treatment with supplemental oxygen affects RBC adhesion.
The research was supported by the National Institutes of Health, the Doris Duke Charitable Foundation, and the National Science Foundation. Two coauthors have filed an international patent for the biochip technology.
WASHINGTON – For male patients with sickle cell disease, priapism can be more than just painful and embarrassing. The prolonged erections prompted by vasoocclusive events in the penis may lead to irreversible impotence, but little is known about risk factors for priapism, which remains a difficult-to-treat complication of the disease.
In males with HbSS sickle cell disease (SCD) and priapism, RBC adhesion is increased in hypoxic conditions, according to preliminary findings from work using a newly developed biochip that mimics microvascular conditions in SCD. This significant level of adhesion prompted by hypoxia was not seen in men who did not have priapism, according to study coauthor Erina Quinn, a research assistant in hematology and oncology at Case Western Reserve University, Cleveland, who presented the results at the annual meeting of the Foundation for Sickle Cell Disease Research.
When hemoglobin desaturation occurs, polymerization can be increased, leading to increased end-organ damage, Ms. Quinn said. The biochip is “an effort to measure cellular adhesion in a clinically meaningful way.” The tool can detect hemoglobin phenotype, differentiating among HbSS, HbSbeta+, and HbSC. It can also measure the degree of hemolysis and RBC deformability.
The biochip “mimics postcapillary flow conditions in microchannels,” Ms. Quinn said. The device forces blood samples through microchannels that are at the diameter of smaller venules, approximately 50 mcm, and at a physiological flow rate ranging from 1-13 mm/sec. The microfluidic channels are coated with laminin, a subendothelial matrix protein implicated in RBC adhesion. A second microfluidic biochip mimics hypoxic conditions.
The study enrolled 26 men with the HbSS genotype, 14 of whom reported priapism, and assessed RBC adhesion in blood samples run though both the SCD-modeled biochip and the hypoxia biochip. Investigators also assessed contemporaneous in vivo hemoglobin desaturation, and looked for associations with the in vitro biochip findings.
Of the 26 participants, 16 also had either nocturnal or exertional hemoglobin desaturation. In addition, 10 participants had both priapism and desaturations. These data were collected by retrospective chart review and patient survey.
Patients with priapism were a mean age of 34 years, compared with a mean age of 29 years for the other participants, a nonsignificant difference. There were no significant differences in mean hemoglobin or bilirubin levels, or in reticulocyte counts, between the two groups.
However, white blood count, absolute neutrophil count, and lactate dehydrogenase levels were significantly higher for men with priapism (P = .022, .037, and .008, respectively). Ferritin levels were higher as well, at a mean 2,433 (plus or minus 2,234) mcg/L for those with priapism, compared with a mean 269 (plus or minus 3,015) mcg/L for those without priapism (P = .031).
When absolute reticulocyte count was mapped against lactate dehydrogenase levels to create a measure of degree of hemolysis, “individuals with priapism had a more hemolytic lab profile,” said Ms. Quinn (P = .0186).
Though 10 of 14 men with priapism had hemoglobin desaturation, compared with 5 of 12 who did not have priapism, the difference was not statistically significant.
When the researchers compared microchip analysis of RBC adhesion, though, they found marked differences in RBC adhesion in hypoxic versus nonhypoxic conditions. Significantly more RBCs were adherent under hypoxic conditions – in the hypoxic biochip – for the patients with priapism than for patients without priapism (mean, 529 vs. 3,268 adherent cells; P = .016).
Though numbers were small, RBCs from patients with reported priapism and hemoglobin desaturation in vivo showed increased hypoxia enhanced adhesion in vitro (P = .013), Ms. Quinn said. These was no significant difference between adhesion in normoxic and hypoxic conditions for the patients without priapism.
Future directions of work with the biochip include prospective identification of desaturation events and better characterization of nocturnal symptoms, Ms. Quinn said. The investigators also plan to see whether treatment with supplemental oxygen affects RBC adhesion.
The research was supported by the National Institutes of Health, the Doris Duke Charitable Foundation, and the National Science Foundation. Two coauthors have filed an international patent for the biochip technology.
REPORTING FROM FSCDR 2018
Key clinical point: RBC adhesion was increased, but only in hypoxia, for men with sickle cell disease and priapism.
Major finding: Men who had desaturations and priapism had significantly higher RBC adhesion than those without priapism (P = .013).
Study details: An in vitro and in vivo study of 26 men with HbSS sickle cell disease, with and without priapism.
Disclosures: The study was funded by the National Institutes of Health, the Doris Duke Charitable Foundation, and the National Science Foundation. Two coauthors have filed an international patent for the biochip technology.
Pfizer launches phase 3 gene therapy study in hemophilia B
Pfizer has begun early work on a phase 3 study of an investigational gene therapy to treat hemophilia B.
Pfizer, along with Spark Therapeutics, launched a phase 3 lead-in study at multiple centers to evaluate the efficacy and safety of current factor IX prophylaxis replacement therapy in the usual care setting. The efficacy data from the lead-in study will become the within-subject control group for patients who enroll in the next part of the
Fidanacogene elaparvovec is a vector containing a bioengineered adeno-associated virus capsid and a high-activity human coagulation factor IX gene. In an ongoing phase 1/2 trial of fidanacogene elaparvovec, all 15 participants with hemophilia B were able to discontinue routine infusion of factor IX concentrates without serious adverse events, according to data released by Pfizer and Spark Therapeutics in May 2018.
Pfizer has begun early work on a phase 3 study of an investigational gene therapy to treat hemophilia B.
Pfizer, along with Spark Therapeutics, launched a phase 3 lead-in study at multiple centers to evaluate the efficacy and safety of current factor IX prophylaxis replacement therapy in the usual care setting. The efficacy data from the lead-in study will become the within-subject control group for patients who enroll in the next part of the
Fidanacogene elaparvovec is a vector containing a bioengineered adeno-associated virus capsid and a high-activity human coagulation factor IX gene. In an ongoing phase 1/2 trial of fidanacogene elaparvovec, all 15 participants with hemophilia B were able to discontinue routine infusion of factor IX concentrates without serious adverse events, according to data released by Pfizer and Spark Therapeutics in May 2018.
Pfizer has begun early work on a phase 3 study of an investigational gene therapy to treat hemophilia B.
Pfizer, along with Spark Therapeutics, launched a phase 3 lead-in study at multiple centers to evaluate the efficacy and safety of current factor IX prophylaxis replacement therapy in the usual care setting. The efficacy data from the lead-in study will become the within-subject control group for patients who enroll in the next part of the
Fidanacogene elaparvovec is a vector containing a bioengineered adeno-associated virus capsid and a high-activity human coagulation factor IX gene. In an ongoing phase 1/2 trial of fidanacogene elaparvovec, all 15 participants with hemophilia B were able to discontinue routine infusion of factor IX concentrates without serious adverse events, according to data released by Pfizer and Spark Therapeutics in May 2018.
Are We Beating Cancer—Finally?
Cancer death rates continue to decline in the US in all major racial and ethnic groups, according to the National Cancer Institute’s (NCI) latest Annual Report to the Nation on the Status of Cancer. The data are an “encouraging indicator of progress” in cancer research, says NCI Director Ned Sharpless, MD. “It’s clear that interventions are having an impact.”
Overall incidence, or rates of new cancers, dropped by 1.8% in men and 1.4% in women from 1999 to 2015. Between 2011 and 2015, death rates dropped for 11 of the 18 most common cancer types in men and 14 of the 20 most common types in women. The researchers say the “significant declines” also hold “significant differences” in rate by sex, race, and ethnicity. For example, black men and white women had the highest incidence rates, and black men and black women had the highest death rates.
However, over the same period, death rates for cancers of the liver, pancreas, and brain and nervous system rose in both men and women. Death rates for cancer of the uterus rose (the researchers say obesity is thought to be a contributing factor) and death rates for cancers of the oral cavity and pharynx and soft tissue increased in men, perhaps associated with human papillomavirus infection.
In a companion study, when researchers explored prostate cancer trends in more detail they found overall prostate cancer incidence rates declined an average of 6.5% each year between 2007 and 2014, from 163 new cases per 100,000 men to 104 new cases. Still, after a 2-decade steady decline, rates leveled off. Incidence of distant disease rose from 7.8 new cases per 100,000 to 9.2, but there was no increase in the rates of cases with aggressive histologic grade.
Interestingly, the researchers also report a decline in recent prostate-specific antigen screening between 2010 and 2013 national surveys. “The increase in late-stage disease and the flattening of the mortality trended occurred contemporaneously with the observed decrease in PSA screening,” said Serban Negoita, MD, DrPH, of NCI’s Surveillance Research Program. However, while “suggestive,” Negoita adds, their observation does not demonstrate causality: many factors contribute to incidence and mortality, such as improvements in staging and treating cancer.
Cancer death rates continue to decline in the US in all major racial and ethnic groups, according to the National Cancer Institute’s (NCI) latest Annual Report to the Nation on the Status of Cancer. The data are an “encouraging indicator of progress” in cancer research, says NCI Director Ned Sharpless, MD. “It’s clear that interventions are having an impact.”
Overall incidence, or rates of new cancers, dropped by 1.8% in men and 1.4% in women from 1999 to 2015. Between 2011 and 2015, death rates dropped for 11 of the 18 most common cancer types in men and 14 of the 20 most common types in women. The researchers say the “significant declines” also hold “significant differences” in rate by sex, race, and ethnicity. For example, black men and white women had the highest incidence rates, and black men and black women had the highest death rates.
However, over the same period, death rates for cancers of the liver, pancreas, and brain and nervous system rose in both men and women. Death rates for cancer of the uterus rose (the researchers say obesity is thought to be a contributing factor) and death rates for cancers of the oral cavity and pharynx and soft tissue increased in men, perhaps associated with human papillomavirus infection.
In a companion study, when researchers explored prostate cancer trends in more detail they found overall prostate cancer incidence rates declined an average of 6.5% each year between 2007 and 2014, from 163 new cases per 100,000 men to 104 new cases. Still, after a 2-decade steady decline, rates leveled off. Incidence of distant disease rose from 7.8 new cases per 100,000 to 9.2, but there was no increase in the rates of cases with aggressive histologic grade.
Interestingly, the researchers also report a decline in recent prostate-specific antigen screening between 2010 and 2013 national surveys. “The increase in late-stage disease and the flattening of the mortality trended occurred contemporaneously with the observed decrease in PSA screening,” said Serban Negoita, MD, DrPH, of NCI’s Surveillance Research Program. However, while “suggestive,” Negoita adds, their observation does not demonstrate causality: many factors contribute to incidence and mortality, such as improvements in staging and treating cancer.
Cancer death rates continue to decline in the US in all major racial and ethnic groups, according to the National Cancer Institute’s (NCI) latest Annual Report to the Nation on the Status of Cancer. The data are an “encouraging indicator of progress” in cancer research, says NCI Director Ned Sharpless, MD. “It’s clear that interventions are having an impact.”
Overall incidence, or rates of new cancers, dropped by 1.8% in men and 1.4% in women from 1999 to 2015. Between 2011 and 2015, death rates dropped for 11 of the 18 most common cancer types in men and 14 of the 20 most common types in women. The researchers say the “significant declines” also hold “significant differences” in rate by sex, race, and ethnicity. For example, black men and white women had the highest incidence rates, and black men and black women had the highest death rates.
However, over the same period, death rates for cancers of the liver, pancreas, and brain and nervous system rose in both men and women. Death rates for cancer of the uterus rose (the researchers say obesity is thought to be a contributing factor) and death rates for cancers of the oral cavity and pharynx and soft tissue increased in men, perhaps associated with human papillomavirus infection.
In a companion study, when researchers explored prostate cancer trends in more detail they found overall prostate cancer incidence rates declined an average of 6.5% each year between 2007 and 2014, from 163 new cases per 100,000 men to 104 new cases. Still, after a 2-decade steady decline, rates leveled off. Incidence of distant disease rose from 7.8 new cases per 100,000 to 9.2, but there was no increase in the rates of cases with aggressive histologic grade.
Interestingly, the researchers also report a decline in recent prostate-specific antigen screening between 2010 and 2013 national surveys. “The increase in late-stage disease and the flattening of the mortality trended occurred contemporaneously with the observed decrease in PSA screening,” said Serban Negoita, MD, DrPH, of NCI’s Surveillance Research Program. However, while “suggestive,” Negoita adds, their observation does not demonstrate causality: many factors contribute to incidence and mortality, such as improvements in staging and treating cancer.