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Surgeons strongly influenced chances of contralateral prophylactic mastectomy
Surgeons, not clinical factors, accounted for 20% of variation in rates of contralateral prophylactic mastectomy (CPM), according to the results of a large survey study.
Only 4% of patients elected CPM when their surgeons were among those who least favored it overall and most preferred breast-conserving treatment, according to Steven J. Katz, MD, MPH, of the University of Michigan, Ann Arbor, and his associates. But 34% of patients chose CPM when their surgeons least favored BCT and were most willing to perform CPM, the researchers found. “Attending surgeons exert strong influence on the likelihood of receipt of CPM after diagnosis of breast cancer,” highlighting “the need to help surgeons address this growing clinical conundrum in the examination room,” they wrote (JAMA Surg. 2017 Sep 13. doi: 10.1001/jamasurg.2017.3415).
Rates of CPM have risen markedly in the United States although it has not been shown to confer a survival advantage for average-risk women. To examine how surgeons themselves affected rates of CPM, the investigators sent surveys to 7,810 women treated for stage 0 to II breast cancer from 2013 to 2015 and included in the Surveillance, Epidemiology, and End Results (SEER) registries of Georgia and Los Angeles County. (Among the 7,810 women, 507 were ineligible.) The researchers also surveyed 488 attending surgeons of these patients.
Response rates were high – 70% among patients (5,080 of 7,303) and 77% (377 of 488) among surgeons, the investigators reported. The average age of the patients was 62 years; 28% had an elevated risk of second primary cancer, and 16% underwent CPM. Patients whose surgeons’ rates of CPM exceeded the mean by at least one standard deviation had nearly threefold greater odds of undergoing CPM themselves (odds ratio, 2.8; 95% confidence interval, 2.1-3.4) regardless of age, date of diagnosis, BRCA mutation status, or risk of second primary cancer.
“One quarter of the surgeon influence was explained by attending attitudes about initial recommendations for surgery and responses to patient requests for CPM,” the researchers wrote. Additional predictors of CPM included elevated risk of second primary breast cancer, BRCA mutation, and younger age.
“We observed a range of reasons why a surgeon would be willing to perform CPM if asked: give peace of mind, yield better cosmetic outcomes, avoid conflict with patient, reduce need for surveillance, improve long-term quality of life, reduce recurrence of invasive disease, avoid losing patient to another surgeon, or improve survival (in order of endorsement),” the researchers wrote. “Our findings reinforce the need to address better ways to communicate with patients with regard to their beliefs about the benefits of more extensive surgery and their reactions to the management plan including surgeon training and deployment of decision aids.”
The National Cancer Institute provided funding. The researchers reported having no conflicts of interest.
Patients who are provided education tools regarding the decision between [breast conserving therapy] and mastectomy are more likely to opt for BCT. However, this discussion is arduous and time consuming. We offer decision-making autonomy to patients, but, in creating that autonomy, we have resigned to overtreatment, motivated by the desire to avoid creating conflict in our relationship with the patient.
How do we overcome this hurdle? Consensus statements reinforce that contralateral prophylactic mastectomy should be discouraged in average-risk patients, but it is time to move beyond consensus statements and create communication tools that guide the surgeon and patient through a stepwise informed discussion. We are participating in a multi-institutional randomized trial to develop such an aid, and we believe this will effect real change in the way surgeons counsel patients. The goal is to standardize the methods and information patients receive to ensure that their decisions are based on facts, not fear.
Julie A. Margenthaler, MD, and Amy E. Cyr, MD, are in the department of surgery, Washington University, St. Louis. They reported no conflicts of interest. These comments are from their editorial (JAMA Surg. 2017 Sep 13. doi: 10.1001/jamasurg.2017.3435).
Patients who are provided education tools regarding the decision between [breast conserving therapy] and mastectomy are more likely to opt for BCT. However, this discussion is arduous and time consuming. We offer decision-making autonomy to patients, but, in creating that autonomy, we have resigned to overtreatment, motivated by the desire to avoid creating conflict in our relationship with the patient.
How do we overcome this hurdle? Consensus statements reinforce that contralateral prophylactic mastectomy should be discouraged in average-risk patients, but it is time to move beyond consensus statements and create communication tools that guide the surgeon and patient through a stepwise informed discussion. We are participating in a multi-institutional randomized trial to develop such an aid, and we believe this will effect real change in the way surgeons counsel patients. The goal is to standardize the methods and information patients receive to ensure that their decisions are based on facts, not fear.
Julie A. Margenthaler, MD, and Amy E. Cyr, MD, are in the department of surgery, Washington University, St. Louis. They reported no conflicts of interest. These comments are from their editorial (JAMA Surg. 2017 Sep 13. doi: 10.1001/jamasurg.2017.3435).
Patients who are provided education tools regarding the decision between [breast conserving therapy] and mastectomy are more likely to opt for BCT. However, this discussion is arduous and time consuming. We offer decision-making autonomy to patients, but, in creating that autonomy, we have resigned to overtreatment, motivated by the desire to avoid creating conflict in our relationship with the patient.
How do we overcome this hurdle? Consensus statements reinforce that contralateral prophylactic mastectomy should be discouraged in average-risk patients, but it is time to move beyond consensus statements and create communication tools that guide the surgeon and patient through a stepwise informed discussion. We are participating in a multi-institutional randomized trial to develop such an aid, and we believe this will effect real change in the way surgeons counsel patients. The goal is to standardize the methods and information patients receive to ensure that their decisions are based on facts, not fear.
Julie A. Margenthaler, MD, and Amy E. Cyr, MD, are in the department of surgery, Washington University, St. Louis. They reported no conflicts of interest. These comments are from their editorial (JAMA Surg. 2017 Sep 13. doi: 10.1001/jamasurg.2017.3435).
Surgeons, not clinical factors, accounted for 20% of variation in rates of contralateral prophylactic mastectomy (CPM), according to the results of a large survey study.
Only 4% of patients elected CPM when their surgeons were among those who least favored it overall and most preferred breast-conserving treatment, according to Steven J. Katz, MD, MPH, of the University of Michigan, Ann Arbor, and his associates. But 34% of patients chose CPM when their surgeons least favored BCT and were most willing to perform CPM, the researchers found. “Attending surgeons exert strong influence on the likelihood of receipt of CPM after diagnosis of breast cancer,” highlighting “the need to help surgeons address this growing clinical conundrum in the examination room,” they wrote (JAMA Surg. 2017 Sep 13. doi: 10.1001/jamasurg.2017.3415).
Rates of CPM have risen markedly in the United States although it has not been shown to confer a survival advantage for average-risk women. To examine how surgeons themselves affected rates of CPM, the investigators sent surveys to 7,810 women treated for stage 0 to II breast cancer from 2013 to 2015 and included in the Surveillance, Epidemiology, and End Results (SEER) registries of Georgia and Los Angeles County. (Among the 7,810 women, 507 were ineligible.) The researchers also surveyed 488 attending surgeons of these patients.
Response rates were high – 70% among patients (5,080 of 7,303) and 77% (377 of 488) among surgeons, the investigators reported. The average age of the patients was 62 years; 28% had an elevated risk of second primary cancer, and 16% underwent CPM. Patients whose surgeons’ rates of CPM exceeded the mean by at least one standard deviation had nearly threefold greater odds of undergoing CPM themselves (odds ratio, 2.8; 95% confidence interval, 2.1-3.4) regardless of age, date of diagnosis, BRCA mutation status, or risk of second primary cancer.
“One quarter of the surgeon influence was explained by attending attitudes about initial recommendations for surgery and responses to patient requests for CPM,” the researchers wrote. Additional predictors of CPM included elevated risk of second primary breast cancer, BRCA mutation, and younger age.
“We observed a range of reasons why a surgeon would be willing to perform CPM if asked: give peace of mind, yield better cosmetic outcomes, avoid conflict with patient, reduce need for surveillance, improve long-term quality of life, reduce recurrence of invasive disease, avoid losing patient to another surgeon, or improve survival (in order of endorsement),” the researchers wrote. “Our findings reinforce the need to address better ways to communicate with patients with regard to their beliefs about the benefits of more extensive surgery and their reactions to the management plan including surgeon training and deployment of decision aids.”
The National Cancer Institute provided funding. The researchers reported having no conflicts of interest.
Surgeons, not clinical factors, accounted for 20% of variation in rates of contralateral prophylactic mastectomy (CPM), according to the results of a large survey study.
Only 4% of patients elected CPM when their surgeons were among those who least favored it overall and most preferred breast-conserving treatment, according to Steven J. Katz, MD, MPH, of the University of Michigan, Ann Arbor, and his associates. But 34% of patients chose CPM when their surgeons least favored BCT and were most willing to perform CPM, the researchers found. “Attending surgeons exert strong influence on the likelihood of receipt of CPM after diagnosis of breast cancer,” highlighting “the need to help surgeons address this growing clinical conundrum in the examination room,” they wrote (JAMA Surg. 2017 Sep 13. doi: 10.1001/jamasurg.2017.3415).
Rates of CPM have risen markedly in the United States although it has not been shown to confer a survival advantage for average-risk women. To examine how surgeons themselves affected rates of CPM, the investigators sent surveys to 7,810 women treated for stage 0 to II breast cancer from 2013 to 2015 and included in the Surveillance, Epidemiology, and End Results (SEER) registries of Georgia and Los Angeles County. (Among the 7,810 women, 507 were ineligible.) The researchers also surveyed 488 attending surgeons of these patients.
Response rates were high – 70% among patients (5,080 of 7,303) and 77% (377 of 488) among surgeons, the investigators reported. The average age of the patients was 62 years; 28% had an elevated risk of second primary cancer, and 16% underwent CPM. Patients whose surgeons’ rates of CPM exceeded the mean by at least one standard deviation had nearly threefold greater odds of undergoing CPM themselves (odds ratio, 2.8; 95% confidence interval, 2.1-3.4) regardless of age, date of diagnosis, BRCA mutation status, or risk of second primary cancer.
“One quarter of the surgeon influence was explained by attending attitudes about initial recommendations for surgery and responses to patient requests for CPM,” the researchers wrote. Additional predictors of CPM included elevated risk of second primary breast cancer, BRCA mutation, and younger age.
“We observed a range of reasons why a surgeon would be willing to perform CPM if asked: give peace of mind, yield better cosmetic outcomes, avoid conflict with patient, reduce need for surveillance, improve long-term quality of life, reduce recurrence of invasive disease, avoid losing patient to another surgeon, or improve survival (in order of endorsement),” the researchers wrote. “Our findings reinforce the need to address better ways to communicate with patients with regard to their beliefs about the benefits of more extensive surgery and their reactions to the management plan including surgeon training and deployment of decision aids.”
The National Cancer Institute provided funding. The researchers reported having no conflicts of interest.
FROM JAMA SURGERY
Key clinical point: Attending surgeons explained 20% of variation in rates of contralateral prophylactic mastectomy.
Major finding: Only 4% of patients elected CPM when their surgeons were among those who least favored it and most preferred breast-conserving treatment (BCT). However, 34% of patients chose CPM when their surgeons least favored initial BCT and were most willing to perform CPM.
Data source: Surveys of 5,080 patients with stage 0-II breast cancer and 339 attending surgeons.
Disclosures: The National Cancer Institute provided funding. The researchers reported having no conflicts of interest.
CB-5083 showed significant activity against B-ALL
A first-in-class oral inhibitor of valosin-containing protein (VCP) p97 showed significant activity against human B acute lymphoblastic leukemia (B-ALL) cells, including those with the most common fusion genes seen in pediatric and adult B-ALL, researchers reported.
The drug, dubbed CB-5083 (Cleave Biosciences), induces cell death by causing endoplasmic reticulum stress, to which B-ALL cells are “distinctly vulnerable,” wrote Gabriele Gugliotta, MD, PhD, of Cedars-Sinai Medical Center in Los Angeles, Calif., and her coinvestigators. In their study, CB-5083 significantly reduced the viability of 10 B-ALL cell lines tested, and did so at blood concentrations that caused no significant toxicities in mice. Human B-ALL cells also showed no signs of upfront drug resistance, the researchers wrote in Neoplasia.
CB-5083 received an FDA orphan drug designation in 2015 for treating multiple myeloma, and also has shown activity against solid tumors. In the study, exposing BALL1 and OP1 B-ALL cell lines to CB-5083 triggered “early and strong” apoptosis, along with a “robust” cleavage of PARP, the researchers reported (Neoplasia. 2017 Aug 24. doi: 10.1016/j.neo.2017.08.001). http://www.neoplasia.com/article/S1476-5586(17)30258-0/fulltext
The drug also reduced the viability of human B-ALL cells without genes for GRP78, GRP94, or XBP1, suggesting that CB-5083 does not require the presence of these proteins to work, the investigators said. Deficiency of X-box binding protein 1 (XBP1) predicted greater sensitivity to CB-5083, which might mean that XBP1 splicing counteracts drug activity by mitigating endoplasmic reticulum stress, they added. “Finally, vincristine was synergistic with CB-5083 in both BALL1 and OP1 [cell lines],” they wrote. “In summary, the targeting of p97 with CB-5083 is a novel promising therapeutic approach that should be further evaluated in B-ALL.”
The investigators acknowledged support from the Melamed family, Reuben Yeroushalmi, National Research Foundation Singapore, Singapore Ministry of Education, Leukemia Lymphoma Society of America, and University of Bologna, Italy. They did not report having conflicts of interest.
A first-in-class oral inhibitor of valosin-containing protein (VCP) p97 showed significant activity against human B acute lymphoblastic leukemia (B-ALL) cells, including those with the most common fusion genes seen in pediatric and adult B-ALL, researchers reported.
The drug, dubbed CB-5083 (Cleave Biosciences), induces cell death by causing endoplasmic reticulum stress, to which B-ALL cells are “distinctly vulnerable,” wrote Gabriele Gugliotta, MD, PhD, of Cedars-Sinai Medical Center in Los Angeles, Calif., and her coinvestigators. In their study, CB-5083 significantly reduced the viability of 10 B-ALL cell lines tested, and did so at blood concentrations that caused no significant toxicities in mice. Human B-ALL cells also showed no signs of upfront drug resistance, the researchers wrote in Neoplasia.
CB-5083 received an FDA orphan drug designation in 2015 for treating multiple myeloma, and also has shown activity against solid tumors. In the study, exposing BALL1 and OP1 B-ALL cell lines to CB-5083 triggered “early and strong” apoptosis, along with a “robust” cleavage of PARP, the researchers reported (Neoplasia. 2017 Aug 24. doi: 10.1016/j.neo.2017.08.001). http://www.neoplasia.com/article/S1476-5586(17)30258-0/fulltext
The drug also reduced the viability of human B-ALL cells without genes for GRP78, GRP94, or XBP1, suggesting that CB-5083 does not require the presence of these proteins to work, the investigators said. Deficiency of X-box binding protein 1 (XBP1) predicted greater sensitivity to CB-5083, which might mean that XBP1 splicing counteracts drug activity by mitigating endoplasmic reticulum stress, they added. “Finally, vincristine was synergistic with CB-5083 in both BALL1 and OP1 [cell lines],” they wrote. “In summary, the targeting of p97 with CB-5083 is a novel promising therapeutic approach that should be further evaluated in B-ALL.”
The investigators acknowledged support from the Melamed family, Reuben Yeroushalmi, National Research Foundation Singapore, Singapore Ministry of Education, Leukemia Lymphoma Society of America, and University of Bologna, Italy. They did not report having conflicts of interest.
A first-in-class oral inhibitor of valosin-containing protein (VCP) p97 showed significant activity against human B acute lymphoblastic leukemia (B-ALL) cells, including those with the most common fusion genes seen in pediatric and adult B-ALL, researchers reported.
The drug, dubbed CB-5083 (Cleave Biosciences), induces cell death by causing endoplasmic reticulum stress, to which B-ALL cells are “distinctly vulnerable,” wrote Gabriele Gugliotta, MD, PhD, of Cedars-Sinai Medical Center in Los Angeles, Calif., and her coinvestigators. In their study, CB-5083 significantly reduced the viability of 10 B-ALL cell lines tested, and did so at blood concentrations that caused no significant toxicities in mice. Human B-ALL cells also showed no signs of upfront drug resistance, the researchers wrote in Neoplasia.
CB-5083 received an FDA orphan drug designation in 2015 for treating multiple myeloma, and also has shown activity against solid tumors. In the study, exposing BALL1 and OP1 B-ALL cell lines to CB-5083 triggered “early and strong” apoptosis, along with a “robust” cleavage of PARP, the researchers reported (Neoplasia. 2017 Aug 24. doi: 10.1016/j.neo.2017.08.001). http://www.neoplasia.com/article/S1476-5586(17)30258-0/fulltext
The drug also reduced the viability of human B-ALL cells without genes for GRP78, GRP94, or XBP1, suggesting that CB-5083 does not require the presence of these proteins to work, the investigators said. Deficiency of X-box binding protein 1 (XBP1) predicted greater sensitivity to CB-5083, which might mean that XBP1 splicing counteracts drug activity by mitigating endoplasmic reticulum stress, they added. “Finally, vincristine was synergistic with CB-5083 in both BALL1 and OP1 [cell lines],” they wrote. “In summary, the targeting of p97 with CB-5083 is a novel promising therapeutic approach that should be further evaluated in B-ALL.”
The investigators acknowledged support from the Melamed family, Reuben Yeroushalmi, National Research Foundation Singapore, Singapore Ministry of Education, Leukemia Lymphoma Society of America, and University of Bologna, Italy. They did not report having conflicts of interest.
FROM NEOPLASIA
Key clinical point: A novel oral inhibitor of valosin-containing protein (VCP) p97 showed significant activity against human B acute lymphoblastic leukemia (B-ALL) cells.
Major finding: After exposure, BALL1 and OP1 cell lines showed early and strong indicators of apoptosis and robust cleavage of PARP.
Data source: In vitro studies of human B-ALL cells and in vivo studies in mice.
Disclosures: The investigators acknowledged support from the Melamed family, Reuben Yeroushalmi, National Research Foundation Singapore, Singapore Ministry of Education, Leukemia Lymphoma Society of America, and University of Bologna, Italy. They did not report having conflicts of interest.
Half of young men at-risk for HIV maintained protective PrEP levels with monthly visits
Up to 54% of adolescent men who had sex with men maintained tenofovir disphosphate levels consistent with a high degree of anti-HIV protection while attending monthly clinic visits, but this proportion fell as low as 17% after they switched to quarterly visits, according to the results of a first-of-its-kind 48-week, prospective, multicenter trial.
The Adolescent Medicine Trials Network for HIV/AIDS Interventions (Project PrEPare) evaluated the safety, tolerability, and acceptability of tenofovir disoproxil fumarate and emtricitabine among 78 HIV-negative MSM aged 15-17 years who had condomless anal intercourse with a male of positive or unknown HIV status, had multiple male sex partners, or had other high-risk sexual behaviors or sexually transmitted infections within the previous 6 months. Participants averaged 16.5 years old age, 33% were of mixed race or ethnicity, 29% were African American, 21% were white Hispanic, 14% were white, and 3% were Asian or Pacific Islander. They received one cognitive-behavioral risk-reduction session before starting PrEP and were paid $50-$75 to attend follow-up visits every month for 3 months and then quarterly after that.
While attending monthly visits, between 47% and 54% of participants maintained highly protective levels of tenofovir disphosphate (above 700 fmol/punch, based on dried blood spot tests), but this proportion fell as low as 17% after participants switched to quarterly visits. At week 48, the HIV seroconversion rate was 6.4 per 100 person-years (95% confidence interval, 1.3-8.7), underscoring the need to offer PrEP and behavioral support to this population, the researchers emphasized. “The waning adherence, especially with quarterly visits, demonstrates that more time, attention, and resources may need to be allocated to adolescents who are seeking prevention services,” they wrote. “We need to better understand the barriers to adherence and develop more effective ways to enhance adherence for youth who are clinically prescribed PrEP.”
Gilead Sciences provided the study drugs and helped fund the study. The study was supported by grants from the National Institute of Child Health and Human Development, the National Institutes on Drug Abuse and Mental Health, and the Adolescent Medicine Trials Network for HIV/AIDS Interventions. Dr. Hosek had no disclosures. Two coinvestigators disclosed research support and contract work fees from Gilead.
As an adolescent medicine specialist who cares for youth living with and at risk for HIV, I am excited to see data that will help young men at risk for HIV to access and use emtricitabine/tenofovir disoproxil fumarate as pre-exposure prophylaxis (PrEP) in their daily lives.
In the United States, the rates of HIV acquisition are highest among adolescent young men who have sex with men (MSM), and data suggest that 40% of young black MSM will acquire HIV by age 40 years unless prevention efforts improve. Clinician barriers to caring for sexual minority men, combined with young men’s having to feel comfortable disclosing their sexual orientation and sexual history to receive counseling about emtricitabine/tenofovir disoproxil fumarate, will mean we will also need to address the institutional, social, and historical factors in medical settings to effectively increase access to PrEP; otherwise, it may further contribute to the HIV inequity among this population.
Clinicians, public health practitioners, and researchers who aim to improve adolescent access to PrEP will need not only to focus on the developmental and cognitive needs of adolescents but also to address the social contexts of stigma, minority stress, and sexual identity that intersect to affect adherence. This work suggests that adolescents may require more frequent visits than is currently recommended by national guidelines and suggests a need for multiple team members to address structural barriers to accessing PrEP, assist with youths’ interpretation of HIV risk, and support self-efficacy to swallow and adhere to medications.
Renata Arrington-Sanders, MD, MPH, ScM, is at the division of general pediatrics and adolescent medicine, Johns Hopkins University, Baltimore. She reported having no conflicts of interest. These comments are from her editorial (JAMA Ped. 2017 Sep 5. doi: 10.1001/jamapediatrics.2017.2397).
As an adolescent medicine specialist who cares for youth living with and at risk for HIV, I am excited to see data that will help young men at risk for HIV to access and use emtricitabine/tenofovir disoproxil fumarate as pre-exposure prophylaxis (PrEP) in their daily lives.
In the United States, the rates of HIV acquisition are highest among adolescent young men who have sex with men (MSM), and data suggest that 40% of young black MSM will acquire HIV by age 40 years unless prevention efforts improve. Clinician barriers to caring for sexual minority men, combined with young men’s having to feel comfortable disclosing their sexual orientation and sexual history to receive counseling about emtricitabine/tenofovir disoproxil fumarate, will mean we will also need to address the institutional, social, and historical factors in medical settings to effectively increase access to PrEP; otherwise, it may further contribute to the HIV inequity among this population.
Clinicians, public health practitioners, and researchers who aim to improve adolescent access to PrEP will need not only to focus on the developmental and cognitive needs of adolescents but also to address the social contexts of stigma, minority stress, and sexual identity that intersect to affect adherence. This work suggests that adolescents may require more frequent visits than is currently recommended by national guidelines and suggests a need for multiple team members to address structural barriers to accessing PrEP, assist with youths’ interpretation of HIV risk, and support self-efficacy to swallow and adhere to medications.
Renata Arrington-Sanders, MD, MPH, ScM, is at the division of general pediatrics and adolescent medicine, Johns Hopkins University, Baltimore. She reported having no conflicts of interest. These comments are from her editorial (JAMA Ped. 2017 Sep 5. doi: 10.1001/jamapediatrics.2017.2397).
As an adolescent medicine specialist who cares for youth living with and at risk for HIV, I am excited to see data that will help young men at risk for HIV to access and use emtricitabine/tenofovir disoproxil fumarate as pre-exposure prophylaxis (PrEP) in their daily lives.
In the United States, the rates of HIV acquisition are highest among adolescent young men who have sex with men (MSM), and data suggest that 40% of young black MSM will acquire HIV by age 40 years unless prevention efforts improve. Clinician barriers to caring for sexual minority men, combined with young men’s having to feel comfortable disclosing their sexual orientation and sexual history to receive counseling about emtricitabine/tenofovir disoproxil fumarate, will mean we will also need to address the institutional, social, and historical factors in medical settings to effectively increase access to PrEP; otherwise, it may further contribute to the HIV inequity among this population.
Clinicians, public health practitioners, and researchers who aim to improve adolescent access to PrEP will need not only to focus on the developmental and cognitive needs of adolescents but also to address the social contexts of stigma, minority stress, and sexual identity that intersect to affect adherence. This work suggests that adolescents may require more frequent visits than is currently recommended by national guidelines and suggests a need for multiple team members to address structural barriers to accessing PrEP, assist with youths’ interpretation of HIV risk, and support self-efficacy to swallow and adhere to medications.
Renata Arrington-Sanders, MD, MPH, ScM, is at the division of general pediatrics and adolescent medicine, Johns Hopkins University, Baltimore. She reported having no conflicts of interest. These comments are from her editorial (JAMA Ped. 2017 Sep 5. doi: 10.1001/jamapediatrics.2017.2397).
Up to 54% of adolescent men who had sex with men maintained tenofovir disphosphate levels consistent with a high degree of anti-HIV protection while attending monthly clinic visits, but this proportion fell as low as 17% after they switched to quarterly visits, according to the results of a first-of-its-kind 48-week, prospective, multicenter trial.
The Adolescent Medicine Trials Network for HIV/AIDS Interventions (Project PrEPare) evaluated the safety, tolerability, and acceptability of tenofovir disoproxil fumarate and emtricitabine among 78 HIV-negative MSM aged 15-17 years who had condomless anal intercourse with a male of positive or unknown HIV status, had multiple male sex partners, or had other high-risk sexual behaviors or sexually transmitted infections within the previous 6 months. Participants averaged 16.5 years old age, 33% were of mixed race or ethnicity, 29% were African American, 21% were white Hispanic, 14% were white, and 3% were Asian or Pacific Islander. They received one cognitive-behavioral risk-reduction session before starting PrEP and were paid $50-$75 to attend follow-up visits every month for 3 months and then quarterly after that.
While attending monthly visits, between 47% and 54% of participants maintained highly protective levels of tenofovir disphosphate (above 700 fmol/punch, based on dried blood spot tests), but this proportion fell as low as 17% after participants switched to quarterly visits. At week 48, the HIV seroconversion rate was 6.4 per 100 person-years (95% confidence interval, 1.3-8.7), underscoring the need to offer PrEP and behavioral support to this population, the researchers emphasized. “The waning adherence, especially with quarterly visits, demonstrates that more time, attention, and resources may need to be allocated to adolescents who are seeking prevention services,” they wrote. “We need to better understand the barriers to adherence and develop more effective ways to enhance adherence for youth who are clinically prescribed PrEP.”
Gilead Sciences provided the study drugs and helped fund the study. The study was supported by grants from the National Institute of Child Health and Human Development, the National Institutes on Drug Abuse and Mental Health, and the Adolescent Medicine Trials Network for HIV/AIDS Interventions. Dr. Hosek had no disclosures. Two coinvestigators disclosed research support and contract work fees from Gilead.
Up to 54% of adolescent men who had sex with men maintained tenofovir disphosphate levels consistent with a high degree of anti-HIV protection while attending monthly clinic visits, but this proportion fell as low as 17% after they switched to quarterly visits, according to the results of a first-of-its-kind 48-week, prospective, multicenter trial.
The Adolescent Medicine Trials Network for HIV/AIDS Interventions (Project PrEPare) evaluated the safety, tolerability, and acceptability of tenofovir disoproxil fumarate and emtricitabine among 78 HIV-negative MSM aged 15-17 years who had condomless anal intercourse with a male of positive or unknown HIV status, had multiple male sex partners, or had other high-risk sexual behaviors or sexually transmitted infections within the previous 6 months. Participants averaged 16.5 years old age, 33% were of mixed race or ethnicity, 29% were African American, 21% were white Hispanic, 14% were white, and 3% were Asian or Pacific Islander. They received one cognitive-behavioral risk-reduction session before starting PrEP and were paid $50-$75 to attend follow-up visits every month for 3 months and then quarterly after that.
While attending monthly visits, between 47% and 54% of participants maintained highly protective levels of tenofovir disphosphate (above 700 fmol/punch, based on dried blood spot tests), but this proportion fell as low as 17% after participants switched to quarterly visits. At week 48, the HIV seroconversion rate was 6.4 per 100 person-years (95% confidence interval, 1.3-8.7), underscoring the need to offer PrEP and behavioral support to this population, the researchers emphasized. “The waning adherence, especially with quarterly visits, demonstrates that more time, attention, and resources may need to be allocated to adolescents who are seeking prevention services,” they wrote. “We need to better understand the barriers to adherence and develop more effective ways to enhance adherence for youth who are clinically prescribed PrEP.”
Gilead Sciences provided the study drugs and helped fund the study. The study was supported by grants from the National Institute of Child Health and Human Development, the National Institutes on Drug Abuse and Mental Health, and the Adolescent Medicine Trials Network for HIV/AIDS Interventions. Dr. Hosek had no disclosures. Two coinvestigators disclosed research support and contract work fees from Gilead.
FROM JAMA PEDIATRICS
Key clinical point: With monthly clinic visits, about half of adolescent men who had sex with men were able to maintain highly protective blood levels of pre-exposure prophylaxis.
Major finding: Up to 54% of participants maintained tenofovir disphosphate levels above 700 fmol/punch when they attended monthly visits, but as few as 17% did so after switching to quarterly visits.
Data source: A multicenter, open-label clinical trial of 78 high-risk men who had sex with men aged 15-17 years.
Disclosures: Gilead Sciences provided the study drugs and helped fund the study. The study was supported by grants from the National Institute of Child Health and Human Development, the National Institutes on Drug Abuse and Mental Health, and the Adolescent Medicine Trials Network for HIV/AIDS Interventions. Dr. Hosek had no disclosures. Two coinvestigators disclosed research support and contract work fees from Gilead.
POEM found safe, effective for treating achalasia after failed Heller myotomy
Peroral endoscopic myotomy (POEM) safely and effectively treated achalasia in patients with persistent symptoms after Heller myotomy, according to the results of a retrospective study of 180 patients treated at 13 centers worldwide.
Rates of clinical success were 81% among patients who had previously undergone Heller myotomy and 94% among those who had not (P = .01), reported Saowanee Ngamruengphong, MD, of Johns Hopkins Medical Center, Baltimore, with her associates. The groups did not significantly differ in terms of rates of adverse events (8% and 13%, respectively), postprocedural symptomatic reflux (30% and 32%), or reflux esophagitis (44% and 52%). “Although the rate of clinical success in patients with prior Heller myotomy is lower than in those without [it], the safety profile of POEM is comparable,” they wrote in the October issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2017.01.031).
Heller myotomy achieves a long-term symptomatic response in about 90% of patients with achalasia and has a complication rate of only about 5%, according to Dr. Ngamruengphong and her associates. When this surgery does not successfully resolve symptoms, patients historically have chosen between repeating it or undergoing pneumatic dilation. However, POEM posted high success rates in several small, single-center case series. Thus, the researchers analyzed data on 180 adults with achalasia whose Eckardt scores were at least 3 and who underwent POEM at 13 tertiary care centers in Australia, France, Hong Kong, India, Italy, Japan, the United Kingdom, and the United States during 2009-2015.
POEM was a technical success for 98% for the group of patients who previously had undergone Heller myotomy and for 100% for those who had not, the researchers reported. In the univariate analysis, predictors of clinical failure included prior Heller myotomy (odds ratio, 3.6; 95% confidence interval, 1.3-10.4; P = .02) and prior pneumatic dilation (OR, 2.9; 95% CI, 1.2-7.4; P = .02). In the multivariable analysis, prior Heller myotomy significantly increased the chances of clinical failure (adjusted OR, 3.0; 95% confidence interval, 1.0-8.9; P = .04) after accounting for prior pneumatic dilation and baseline Eckardt score. Prior pneumatic dilation reached borderline significance (adjusted OR, 2.6; 95% CI, 0.99-7.0; P = .05). Clinical failure was not associated with age, sex, achalasia subtypes, previous therapy, baseline Eckardt score, length of myotomy, orientation of myotomy, or extent of lower esophageal sphincter myotomy.
“Previous studies have reported that the success rates of pneumatic dilation in patients who failed prior Heller myotomy ranged between 50% and 89%,” the researchers said. However, success is often short-lived, with up to 45% of patients needing another procedure within 2 years, putting them at risk of “potentially serious adverse events, such as esophageal perforation or aspiration,” they added.
Repeat surgical myotomy is reportedly successful in 73%-89% of cases; however, itis technically challenging because of adhesions and fibrosis from the previous surgery and is associated with a high risk of gastrointestinal perforation.
Clinicians should carefully investigate the reasons a Heller myotomy failed in order to elect a course of action, the researchers emphasized. “For instance, for patients with symptom relapse or failure to respond to surgical myotomy as a result of incomplete myotomy or myotomy fibrosis, POEM is likely to be effective,” they said. “On the other hand, when the cause of persistent symptoms after surgical myotomy is tight fundoplication, a redo fundoplication should be recommended.”
Dr. Ngamruengphong had no disclosures. Three coinvestigators disclosed consulting relationships with Boston Scientific, Medtronic, Sandhill Scientific, Erbe, and Cosmo Pharmaceuticals.
Peroral endoscopic myotomy (POEM) safely and effectively treated achalasia in patients with persistent symptoms after Heller myotomy, according to the results of a retrospective study of 180 patients treated at 13 centers worldwide.
Rates of clinical success were 81% among patients who had previously undergone Heller myotomy and 94% among those who had not (P = .01), reported Saowanee Ngamruengphong, MD, of Johns Hopkins Medical Center, Baltimore, with her associates. The groups did not significantly differ in terms of rates of adverse events (8% and 13%, respectively), postprocedural symptomatic reflux (30% and 32%), or reflux esophagitis (44% and 52%). “Although the rate of clinical success in patients with prior Heller myotomy is lower than in those without [it], the safety profile of POEM is comparable,” they wrote in the October issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2017.01.031).
Heller myotomy achieves a long-term symptomatic response in about 90% of patients with achalasia and has a complication rate of only about 5%, according to Dr. Ngamruengphong and her associates. When this surgery does not successfully resolve symptoms, patients historically have chosen between repeating it or undergoing pneumatic dilation. However, POEM posted high success rates in several small, single-center case series. Thus, the researchers analyzed data on 180 adults with achalasia whose Eckardt scores were at least 3 and who underwent POEM at 13 tertiary care centers in Australia, France, Hong Kong, India, Italy, Japan, the United Kingdom, and the United States during 2009-2015.
POEM was a technical success for 98% for the group of patients who previously had undergone Heller myotomy and for 100% for those who had not, the researchers reported. In the univariate analysis, predictors of clinical failure included prior Heller myotomy (odds ratio, 3.6; 95% confidence interval, 1.3-10.4; P = .02) and prior pneumatic dilation (OR, 2.9; 95% CI, 1.2-7.4; P = .02). In the multivariable analysis, prior Heller myotomy significantly increased the chances of clinical failure (adjusted OR, 3.0; 95% confidence interval, 1.0-8.9; P = .04) after accounting for prior pneumatic dilation and baseline Eckardt score. Prior pneumatic dilation reached borderline significance (adjusted OR, 2.6; 95% CI, 0.99-7.0; P = .05). Clinical failure was not associated with age, sex, achalasia subtypes, previous therapy, baseline Eckardt score, length of myotomy, orientation of myotomy, or extent of lower esophageal sphincter myotomy.
“Previous studies have reported that the success rates of pneumatic dilation in patients who failed prior Heller myotomy ranged between 50% and 89%,” the researchers said. However, success is often short-lived, with up to 45% of patients needing another procedure within 2 years, putting them at risk of “potentially serious adverse events, such as esophageal perforation or aspiration,” they added.
Repeat surgical myotomy is reportedly successful in 73%-89% of cases; however, itis technically challenging because of adhesions and fibrosis from the previous surgery and is associated with a high risk of gastrointestinal perforation.
Clinicians should carefully investigate the reasons a Heller myotomy failed in order to elect a course of action, the researchers emphasized. “For instance, for patients with symptom relapse or failure to respond to surgical myotomy as a result of incomplete myotomy or myotomy fibrosis, POEM is likely to be effective,” they said. “On the other hand, when the cause of persistent symptoms after surgical myotomy is tight fundoplication, a redo fundoplication should be recommended.”
Dr. Ngamruengphong had no disclosures. Three coinvestigators disclosed consulting relationships with Boston Scientific, Medtronic, Sandhill Scientific, Erbe, and Cosmo Pharmaceuticals.
Peroral endoscopic myotomy (POEM) safely and effectively treated achalasia in patients with persistent symptoms after Heller myotomy, according to the results of a retrospective study of 180 patients treated at 13 centers worldwide.
Rates of clinical success were 81% among patients who had previously undergone Heller myotomy and 94% among those who had not (P = .01), reported Saowanee Ngamruengphong, MD, of Johns Hopkins Medical Center, Baltimore, with her associates. The groups did not significantly differ in terms of rates of adverse events (8% and 13%, respectively), postprocedural symptomatic reflux (30% and 32%), or reflux esophagitis (44% and 52%). “Although the rate of clinical success in patients with prior Heller myotomy is lower than in those without [it], the safety profile of POEM is comparable,” they wrote in the October issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2017.01.031).
Heller myotomy achieves a long-term symptomatic response in about 90% of patients with achalasia and has a complication rate of only about 5%, according to Dr. Ngamruengphong and her associates. When this surgery does not successfully resolve symptoms, patients historically have chosen between repeating it or undergoing pneumatic dilation. However, POEM posted high success rates in several small, single-center case series. Thus, the researchers analyzed data on 180 adults with achalasia whose Eckardt scores were at least 3 and who underwent POEM at 13 tertiary care centers in Australia, France, Hong Kong, India, Italy, Japan, the United Kingdom, and the United States during 2009-2015.
POEM was a technical success for 98% for the group of patients who previously had undergone Heller myotomy and for 100% for those who had not, the researchers reported. In the univariate analysis, predictors of clinical failure included prior Heller myotomy (odds ratio, 3.6; 95% confidence interval, 1.3-10.4; P = .02) and prior pneumatic dilation (OR, 2.9; 95% CI, 1.2-7.4; P = .02). In the multivariable analysis, prior Heller myotomy significantly increased the chances of clinical failure (adjusted OR, 3.0; 95% confidence interval, 1.0-8.9; P = .04) after accounting for prior pneumatic dilation and baseline Eckardt score. Prior pneumatic dilation reached borderline significance (adjusted OR, 2.6; 95% CI, 0.99-7.0; P = .05). Clinical failure was not associated with age, sex, achalasia subtypes, previous therapy, baseline Eckardt score, length of myotomy, orientation of myotomy, or extent of lower esophageal sphincter myotomy.
“Previous studies have reported that the success rates of pneumatic dilation in patients who failed prior Heller myotomy ranged between 50% and 89%,” the researchers said. However, success is often short-lived, with up to 45% of patients needing another procedure within 2 years, putting them at risk of “potentially serious adverse events, such as esophageal perforation or aspiration,” they added.
Repeat surgical myotomy is reportedly successful in 73%-89% of cases; however, itis technically challenging because of adhesions and fibrosis from the previous surgery and is associated with a high risk of gastrointestinal perforation.
Clinicians should carefully investigate the reasons a Heller myotomy failed in order to elect a course of action, the researchers emphasized. “For instance, for patients with symptom relapse or failure to respond to surgical myotomy as a result of incomplete myotomy or myotomy fibrosis, POEM is likely to be effective,” they said. “On the other hand, when the cause of persistent symptoms after surgical myotomy is tight fundoplication, a redo fundoplication should be recommended.”
Dr. Ngamruengphong had no disclosures. Three coinvestigators disclosed consulting relationships with Boston Scientific, Medtronic, Sandhill Scientific, Erbe, and Cosmo Pharmaceuticals.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Key clinical point:
Major finding: Rates of clinical success were 81% when patients had previously undergone Heller myotomy and 94% when they had not (P = .01). Rates of adverse events (8% and 13%, respectively), as well as rates of postprocedural symptomatic reflux (30% and 32%) and reflux esophagitis (44% and 52%), were similar between groups.
Data source: A multicenter retrospective study of 180 patients with achalasia, half of whom had symptoms despite prior Heller myotomy.
Disclosures: Dr. Ngamruengphong had no disclosures. Three coinvestigators disclosed consulting relationships with Boston Scientific, Medtronic, Sandhill Scientific, Erbe, and Cosmo Pharmaceuticals.
Study linked H2 receptor antagonists, but not PPIs, to dementia
A large prospective study of middle-aged and older women found no convincing evidence that using proton pump inhibitors increased their risk of dementia, investigators reported.
However, using H2 receptor antagonists for at least 9 years was associated with a slight decrease in scores of learning and working memory (mean decrease, –0.2; 95% confidence interval, –0.3 to –0.08; P less than .001), Paul Lochhead, MBChB, PhD, and his associates wrote in the October issue of Gastroenterology (doi: 10.1053/j.gastro.2017.06.061). “Since our primary hypothesis related to PPI [proton pump inhibitor] use, our findings for [H2 receptor antagonists] should be interpreted with caution,” they said.
Source: American Gastroenterological Association
In a recent German study of a medical claims database, use of PPIs was associated with a 44% increase in the likelihood of incident dementia (JAMA Neurol. 2016;73:410-6). “The existence of a causal mechanism linking PPI use to dementia is suggested by observations from cellular and animal models of Alzheimer’s disease, where PPI exposure appears to influence amyloid-beta metabolism,” Dr. Lochhead and his associates wrote. “However, other preclinical data on PPIs and Alzheimer’s disease are conflicting.” Noting that cognitive function predicts dementia later in life, they analyzed prospective data on medications and other potential risk factors from 13,864 participants in the Nurses’ Health Study II who had completed Cogstate, a computerized, self-administered neuropsychological battery.
Study participants averaged 61 years old when they underwent cognitive testing, ranging in age from 50 to 70 years. Users of PPIs tended to be older, had more comorbidities, were less physically active, had higher body mass indexes, had less education, and ate a lower-quality diet than women who did not use PPIs. After adjusting for such confounders, using PPIs for 9-14 years was associated with a modest decrease in scores for psychomotor speed and attention (mean score difference, compared with never users, –0.06; 95% CI, –0.11 to 0.00; P = .03). “For comparison, in multivariable models, a 1-year increase in age was associated with mean score decreases of 0.03 for psychomotor speed and attention, 0.02 for learning and working memory, and 0.03 for overall cognition,” the researchers wrote.
Next, they examined links between use of H2 receptor antagonists and cognitive scores among 10,778 study participants who had used PPIs for 2 years or less. Use of H2 receptor antagonists for 9-14 years predicted poorer scores on learning, working memory, and overall cognition, even after controlling for potential confounders (P less than or equal to .002). “The magnitudes of mean score differences were larger than those observed in the analysis of PPI use, particularly for learning and working memory,” the researchers noted. Additionally, PPI use did not predict lower cognitive scores among individuals who had never used H2 receptor antagonists.
On the other hand, using PPIs for 9-14 years was associated with the equivalent of about 2 years of age-related cognitive decline, and controlling for exposure to H2 receptor antagonists weakened even this modest effect, the investigators said. Users and nonusers of PPIs tend to differ on many measures, and analyses of claims data, such as the German study above, are less able to account for these potential confounders, they noted. “Nonjudicious PPI prescribing is especially frequent among the elderly and those with cognitive impairment,” they added. “Therefore, elderly individuals who have frequent contact with health providers are at increased risk of both PPI prescription and dementia diagnosis. This bias may not be completely mitigated by adjustment for comorbidities or polypharmacy.”
The findings regarding H2 receptor antagonists reflect those of three smaller cohort studies, and these medications are known to cause central nervous system effects in the elderly, including delirium, the researchers said. Ranitidine and cimetidine have anticholinergic effects that also could “pose a risk for adverse cognitive effects with long-term use.”
Dr. Lochhead reported having no conflicts. Two coinvestigators disclosed ties to Bayer Healthcare, Pfizer, Aralez Pharmaceuticals, AbbVie, Samsung Bioepis, and Takeda.
Numerous possible PPI-related adverse events have been reported within the past few years; some resultant media attention has caused anxiety for patients. Dementia is a dreaded diagnosis. Therefore, initial reports that PPI treatment might be associated with an increased risk of dementia attracted considerable media attention, much of which was unbalanced and uninformed. There is no obvious biological rationale for such an association, and the risks reported initially were of small magnitude (for example, hazard ratios of approximately 1.4). However, patients cannot reliably assess levels of risk from media coverage that often veers toward sensationalism.
The study by Lochhead et al. is a welcome contribution to the topic of PPI safety. Using the Nurses’ Health Study II database, the investigators measured cognitive function in a large group of female PPI users and nonusers. Unsurprisingly, PPI users were older and sicker than nonusers. There were quantitatively small changes in some measures of cognitive function among PPI users. However, learning and working memory scores, which are more predictive of Alzheimer’s-type cognitive decline, were unaffected by PPI use.
For those prescribers with residual concerns about any association between PPIs and dementia, these prospectively collected data on cognitive function should provide further reassurance. It is appropriate that this study should have been highlighted in GI & Hepatology News, but since it lacks the potential sensationalism of studies that report a putative association, we should not expect it to be discussed on the TV evening news anytime soon!
Colin W. Howden, MD, AGAF, is chief of gastroenterology at University of Tennessee Health Science Center, Memphis. He has been a consultant, investigator, and/or speaker for all PPI manufacturers at some time. He is currently a consultant for Takeda, Aralez, and Pfizer Consumer Health.
Numerous possible PPI-related adverse events have been reported within the past few years; some resultant media attention has caused anxiety for patients. Dementia is a dreaded diagnosis. Therefore, initial reports that PPI treatment might be associated with an increased risk of dementia attracted considerable media attention, much of which was unbalanced and uninformed. There is no obvious biological rationale for such an association, and the risks reported initially were of small magnitude (for example, hazard ratios of approximately 1.4). However, patients cannot reliably assess levels of risk from media coverage that often veers toward sensationalism.
The study by Lochhead et al. is a welcome contribution to the topic of PPI safety. Using the Nurses’ Health Study II database, the investigators measured cognitive function in a large group of female PPI users and nonusers. Unsurprisingly, PPI users were older and sicker than nonusers. There were quantitatively small changes in some measures of cognitive function among PPI users. However, learning and working memory scores, which are more predictive of Alzheimer’s-type cognitive decline, were unaffected by PPI use.
For those prescribers with residual concerns about any association between PPIs and dementia, these prospectively collected data on cognitive function should provide further reassurance. It is appropriate that this study should have been highlighted in GI & Hepatology News, but since it lacks the potential sensationalism of studies that report a putative association, we should not expect it to be discussed on the TV evening news anytime soon!
Colin W. Howden, MD, AGAF, is chief of gastroenterology at University of Tennessee Health Science Center, Memphis. He has been a consultant, investigator, and/or speaker for all PPI manufacturers at some time. He is currently a consultant for Takeda, Aralez, and Pfizer Consumer Health.
Numerous possible PPI-related adverse events have been reported within the past few years; some resultant media attention has caused anxiety for patients. Dementia is a dreaded diagnosis. Therefore, initial reports that PPI treatment might be associated with an increased risk of dementia attracted considerable media attention, much of which was unbalanced and uninformed. There is no obvious biological rationale for such an association, and the risks reported initially were of small magnitude (for example, hazard ratios of approximately 1.4). However, patients cannot reliably assess levels of risk from media coverage that often veers toward sensationalism.
The study by Lochhead et al. is a welcome contribution to the topic of PPI safety. Using the Nurses’ Health Study II database, the investigators measured cognitive function in a large group of female PPI users and nonusers. Unsurprisingly, PPI users were older and sicker than nonusers. There were quantitatively small changes in some measures of cognitive function among PPI users. However, learning and working memory scores, which are more predictive of Alzheimer’s-type cognitive decline, were unaffected by PPI use.
For those prescribers with residual concerns about any association between PPIs and dementia, these prospectively collected data on cognitive function should provide further reassurance. It is appropriate that this study should have been highlighted in GI & Hepatology News, but since it lacks the potential sensationalism of studies that report a putative association, we should not expect it to be discussed on the TV evening news anytime soon!
Colin W. Howden, MD, AGAF, is chief of gastroenterology at University of Tennessee Health Science Center, Memphis. He has been a consultant, investigator, and/or speaker for all PPI manufacturers at some time. He is currently a consultant for Takeda, Aralez, and Pfizer Consumer Health.
A large prospective study of middle-aged and older women found no convincing evidence that using proton pump inhibitors increased their risk of dementia, investigators reported.
However, using H2 receptor antagonists for at least 9 years was associated with a slight decrease in scores of learning and working memory (mean decrease, –0.2; 95% confidence interval, –0.3 to –0.08; P less than .001), Paul Lochhead, MBChB, PhD, and his associates wrote in the October issue of Gastroenterology (doi: 10.1053/j.gastro.2017.06.061). “Since our primary hypothesis related to PPI [proton pump inhibitor] use, our findings for [H2 receptor antagonists] should be interpreted with caution,” they said.
Source: American Gastroenterological Association
In a recent German study of a medical claims database, use of PPIs was associated with a 44% increase in the likelihood of incident dementia (JAMA Neurol. 2016;73:410-6). “The existence of a causal mechanism linking PPI use to dementia is suggested by observations from cellular and animal models of Alzheimer’s disease, where PPI exposure appears to influence amyloid-beta metabolism,” Dr. Lochhead and his associates wrote. “However, other preclinical data on PPIs and Alzheimer’s disease are conflicting.” Noting that cognitive function predicts dementia later in life, they analyzed prospective data on medications and other potential risk factors from 13,864 participants in the Nurses’ Health Study II who had completed Cogstate, a computerized, self-administered neuropsychological battery.
Study participants averaged 61 years old when they underwent cognitive testing, ranging in age from 50 to 70 years. Users of PPIs tended to be older, had more comorbidities, were less physically active, had higher body mass indexes, had less education, and ate a lower-quality diet than women who did not use PPIs. After adjusting for such confounders, using PPIs for 9-14 years was associated with a modest decrease in scores for psychomotor speed and attention (mean score difference, compared with never users, –0.06; 95% CI, –0.11 to 0.00; P = .03). “For comparison, in multivariable models, a 1-year increase in age was associated with mean score decreases of 0.03 for psychomotor speed and attention, 0.02 for learning and working memory, and 0.03 for overall cognition,” the researchers wrote.
Next, they examined links between use of H2 receptor antagonists and cognitive scores among 10,778 study participants who had used PPIs for 2 years or less. Use of H2 receptor antagonists for 9-14 years predicted poorer scores on learning, working memory, and overall cognition, even after controlling for potential confounders (P less than or equal to .002). “The magnitudes of mean score differences were larger than those observed in the analysis of PPI use, particularly for learning and working memory,” the researchers noted. Additionally, PPI use did not predict lower cognitive scores among individuals who had never used H2 receptor antagonists.
On the other hand, using PPIs for 9-14 years was associated with the equivalent of about 2 years of age-related cognitive decline, and controlling for exposure to H2 receptor antagonists weakened even this modest effect, the investigators said. Users and nonusers of PPIs tend to differ on many measures, and analyses of claims data, such as the German study above, are less able to account for these potential confounders, they noted. “Nonjudicious PPI prescribing is especially frequent among the elderly and those with cognitive impairment,” they added. “Therefore, elderly individuals who have frequent contact with health providers are at increased risk of both PPI prescription and dementia diagnosis. This bias may not be completely mitigated by adjustment for comorbidities or polypharmacy.”
The findings regarding H2 receptor antagonists reflect those of three smaller cohort studies, and these medications are known to cause central nervous system effects in the elderly, including delirium, the researchers said. Ranitidine and cimetidine have anticholinergic effects that also could “pose a risk for adverse cognitive effects with long-term use.”
Dr. Lochhead reported having no conflicts. Two coinvestigators disclosed ties to Bayer Healthcare, Pfizer, Aralez Pharmaceuticals, AbbVie, Samsung Bioepis, and Takeda.
A large prospective study of middle-aged and older women found no convincing evidence that using proton pump inhibitors increased their risk of dementia, investigators reported.
However, using H2 receptor antagonists for at least 9 years was associated with a slight decrease in scores of learning and working memory (mean decrease, –0.2; 95% confidence interval, –0.3 to –0.08; P less than .001), Paul Lochhead, MBChB, PhD, and his associates wrote in the October issue of Gastroenterology (doi: 10.1053/j.gastro.2017.06.061). “Since our primary hypothesis related to PPI [proton pump inhibitor] use, our findings for [H2 receptor antagonists] should be interpreted with caution,” they said.
Source: American Gastroenterological Association
In a recent German study of a medical claims database, use of PPIs was associated with a 44% increase in the likelihood of incident dementia (JAMA Neurol. 2016;73:410-6). “The existence of a causal mechanism linking PPI use to dementia is suggested by observations from cellular and animal models of Alzheimer’s disease, where PPI exposure appears to influence amyloid-beta metabolism,” Dr. Lochhead and his associates wrote. “However, other preclinical data on PPIs and Alzheimer’s disease are conflicting.” Noting that cognitive function predicts dementia later in life, they analyzed prospective data on medications and other potential risk factors from 13,864 participants in the Nurses’ Health Study II who had completed Cogstate, a computerized, self-administered neuropsychological battery.
Study participants averaged 61 years old when they underwent cognitive testing, ranging in age from 50 to 70 years. Users of PPIs tended to be older, had more comorbidities, were less physically active, had higher body mass indexes, had less education, and ate a lower-quality diet than women who did not use PPIs. After adjusting for such confounders, using PPIs for 9-14 years was associated with a modest decrease in scores for psychomotor speed and attention (mean score difference, compared with never users, –0.06; 95% CI, –0.11 to 0.00; P = .03). “For comparison, in multivariable models, a 1-year increase in age was associated with mean score decreases of 0.03 for psychomotor speed and attention, 0.02 for learning and working memory, and 0.03 for overall cognition,” the researchers wrote.
Next, they examined links between use of H2 receptor antagonists and cognitive scores among 10,778 study participants who had used PPIs for 2 years or less. Use of H2 receptor antagonists for 9-14 years predicted poorer scores on learning, working memory, and overall cognition, even after controlling for potential confounders (P less than or equal to .002). “The magnitudes of mean score differences were larger than those observed in the analysis of PPI use, particularly for learning and working memory,” the researchers noted. Additionally, PPI use did not predict lower cognitive scores among individuals who had never used H2 receptor antagonists.
On the other hand, using PPIs for 9-14 years was associated with the equivalent of about 2 years of age-related cognitive decline, and controlling for exposure to H2 receptor antagonists weakened even this modest effect, the investigators said. Users and nonusers of PPIs tend to differ on many measures, and analyses of claims data, such as the German study above, are less able to account for these potential confounders, they noted. “Nonjudicious PPI prescribing is especially frequent among the elderly and those with cognitive impairment,” they added. “Therefore, elderly individuals who have frequent contact with health providers are at increased risk of both PPI prescription and dementia diagnosis. This bias may not be completely mitigated by adjustment for comorbidities or polypharmacy.”
The findings regarding H2 receptor antagonists reflect those of three smaller cohort studies, and these medications are known to cause central nervous system effects in the elderly, including delirium, the researchers said. Ranitidine and cimetidine have anticholinergic effects that also could “pose a risk for adverse cognitive effects with long-term use.”
Dr. Lochhead reported having no conflicts. Two coinvestigators disclosed ties to Bayer Healthcare, Pfizer, Aralez Pharmaceuticals, AbbVie, Samsung Bioepis, and Takeda.
FROM GASTROENTEROLOGY
Key clinical point: A large prospective cohort study linked long-term use of H2 receptor antagonists, but not PPIs, to dementia.
Major finding: Use of PPIs did not significantly predict incident dementia in the adjusted analysis. However, using H2 receptor antagonists for at least 9 years was associated with a slight decrease in scores of learning and working memory (mean decrease, –0.2; P less than .001).
Data source: A population-based cohort study of 13,864 middle-aged and older women.
Disclosures: Dr. Lochhead reported having no conflicts. Two coinvestigators disclosed ties to Bayer Healthcare, Pfizer, Aralez Pharmaceuticals, AbbVie, Samsung Bioepis, and Takeda.
Statin use cuts risks in compensated cirrhosis
For patients with compensated cirrhosis, statin therapy was associated with about a 46% decrease in the risk of hepatic decompensation and mortality and with a 27% drop in the risk of portal hypertension and variceal bleeding, according to moderate-quality evidence from a systematic review and meta-analysis of 13 studies.
Low-quality data also suggested that statins might help protect against the progression of noncirrhotic chronic liver disease, said Rebecca G. Kim of the University of California at San Diego and her associates. “Large, pragmatic randomized controlled trials in patients with compensated cirrhosis are required to confirm these observations,” they wrote in the October issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2017.04.039).
Prior studies have reported mixed findings on how statin therapy affects chronic liver disease. For their review, Ms. Kim and her associates searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, Cochrane Database and Systematic Reviews, Scopus, Web of Science, and PubMed for randomized controlled trials or cohort studies published through March 25, 2017. They identified 10 cohort studies and three randomized controlled trials of adults with fibrosis without cirrhosis, compensated cirrhosis, or decompensated cirrhosis that evaluated statin exposure and reported associations between exposure and outcomes related to cirrhosis. They excluded case-control studies, cross-sectional studies, and studies that focused only on the relationship between statin use and the risk of hepatocellular carcinoma.
The resulting data set included 121,058 patients with chronic liver diseases, of whom 85% had chronic hepatitis C virus infection. A total of 46% of patients were exposed to statins, which appeared to reduce their risk of hepatic decompensation, variceal bleeding, and mortality. Among 87 such patients in five studies, statin use was associated with a 46% decrease in the risk of hepatic decompensation and death, with risk ratios of 0.54 (95% confidence intervals, 0.46-0.62 and 0.47-0.61, respectively). Statin use also was associated with a 27% lower risk of variceal bleeding or progression of portal hypertension, based on an analysis of 110 events in 236 patients from three trials (RR, 0.73; 95% CI, 0.59-0.91). Finally, statin use also was associated with a 58% lower risk of fibrosis progression or cirrhosis in patients with noncirrhotic chronic liver disease, but the 95% CIs for the risk estimate did not reach statistical significance (0.16-1.11).
Source: American Gastroenterological Association
Most studies lacked data on dose and duration of statin exposure, the researchers said. However, four cohort studies reported dose-dependent effects that were most pronounced after more than a year of treatment. “Similarly, several different types of statins were studied, and observed effects were assumed to be class-specific effects,” the reviewers wrote. “However, it is possible that lipophilic and lipophobic statins may have differential efficacy in decreasing fibrosis progression.”
Together, these findings support prior studies suggesting that statin therapy is safe and can potentially reduce the risk of hepatocellular carcinoma in this patient population, they concluded. Statins “may potentially improve patient-relevant outcomes in patients with chronic liver diseases and improve survival without significant additional costs.”
The reviewers acknowledged the American Gastroenterological Association Foundation, a T. Franklin Williams Scholarship Award, the National Institutes of Health, and the National Library of Medicine. They reported having no relevant conflicts of interest.
This story was updated on 9/13/2017.
The main mechanism in the development of cirrhosis in patients with chronic liver disease (CLD) is increased hepatic fibrogenesis. The initial consequence of cirrhosis is portal hypertension, which is the main driver of decompensation (defined as the presence of ascites, variceal hemorrhage, or encephalopathy). 
Statins are widely used for reducing cholesterol levels and cardiovascular risk. However, statins ameliorate endothelial dysfunction and have additional antifibrotic, anti-inflammatory, and antithrombotic properties, all of them of potential benefit in preventing progression of CLD/cirrhosis. In fact, statins have been shown to reduce portal pressure in cirrhosis.
In a meta-analysis of 13 studies, Kim et al. demonstrated that statin use is associated with a 58% lower risk of developing cirrhosis/fibrosis progression in patients with CLD (not statistically significant), while in patients with compensated cirrhosis of any etiology, statin use was associated with a statistically significant 46% lower risk of developing decompensation and death.
Most studies in the meta-analysis were observational/retrospective. Although the authors jointly analyzed three randomized controlled trials, only one of the trials looked at clinical outcomes. This important double-blind, placebo-controlled study in patients with recent variceal hemorrhage showed a significantly lower mortality in patients randomized to simvastatin.
Therefore, although the evidence is not yet sufficient to recommend the widespread use of statins in patients with CLD/cirrhosis, providers should not avoid using statins in patients with CLD/cirrhosis who otherwise need them. In fact, they should actively look for indications that would justify their use.
Guadalupe Garcia-Tsao, MD, is professor of medicine at Yale University, chief of digestive diseases at the VA-CT Healthcare System, and director of the clinical core of the Yale Liver Center, New Haven, Conn. She had no conflicts of interest.
The main mechanism in the development of cirrhosis in patients with chronic liver disease (CLD) is increased hepatic fibrogenesis. The initial consequence of cirrhosis is portal hypertension, which is the main driver of decompensation (defined as the presence of ascites, variceal hemorrhage, or encephalopathy).
Statins are widely used for reducing cholesterol levels and cardiovascular risk. However, statins ameliorate endothelial dysfunction and have additional antifibrotic, anti-inflammatory, and antithrombotic properties, all of them of potential benefit in preventing progression of CLD/cirrhosis. In fact, statins have been shown to reduce portal pressure in cirrhosis.
In a meta-analysis of 13 studies, Kim et al. demonstrated that statin use is associated with a 58% lower risk of developing cirrhosis/fibrosis progression in patients with CLD (not statistically significant), while in patients with compensated cirrhosis of any etiology, statin use was associated with a statistically significant 46% lower risk of developing decompensation and death.
Most studies in the meta-analysis were observational/retrospective. Although the authors jointly analyzed three randomized controlled trials, only one of the trials looked at clinical outcomes. This important double-blind, placebo-controlled study in patients with recent variceal hemorrhage showed a significantly lower mortality in patients randomized to simvastatin.
Therefore, although the evidence is not yet sufficient to recommend the widespread use of statins in patients with CLD/cirrhosis, providers should not avoid using statins in patients with CLD/cirrhosis who otherwise need them. In fact, they should actively look for indications that would justify their use.
Guadalupe Garcia-Tsao, MD, is professor of medicine at Yale University, chief of digestive diseases at the VA-CT Healthcare System, and director of the clinical core of the Yale Liver Center, New Haven, Conn. She had no conflicts of interest.
The main mechanism in the development of cirrhosis in patients with chronic liver disease (CLD) is increased hepatic fibrogenesis. The initial consequence of cirrhosis is portal hypertension, which is the main driver of decompensation (defined as the presence of ascites, variceal hemorrhage, or encephalopathy).
Statins are widely used for reducing cholesterol levels and cardiovascular risk. However, statins ameliorate endothelial dysfunction and have additional antifibrotic, anti-inflammatory, and antithrombotic properties, all of them of potential benefit in preventing progression of CLD/cirrhosis. In fact, statins have been shown to reduce portal pressure in cirrhosis.
In a meta-analysis of 13 studies, Kim et al. demonstrated that statin use is associated with a 58% lower risk of developing cirrhosis/fibrosis progression in patients with CLD (not statistically significant), while in patients with compensated cirrhosis of any etiology, statin use was associated with a statistically significant 46% lower risk of developing decompensation and death.
Most studies in the meta-analysis were observational/retrospective. Although the authors jointly analyzed three randomized controlled trials, only one of the trials looked at clinical outcomes. This important double-blind, placebo-controlled study in patients with recent variceal hemorrhage showed a significantly lower mortality in patients randomized to simvastatin.
Therefore, although the evidence is not yet sufficient to recommend the widespread use of statins in patients with CLD/cirrhosis, providers should not avoid using statins in patients with CLD/cirrhosis who otherwise need them. In fact, they should actively look for indications that would justify their use.
Guadalupe Garcia-Tsao, MD, is professor of medicine at Yale University, chief of digestive diseases at the VA-CT Healthcare System, and director of the clinical core of the Yale Liver Center, New Haven, Conn. She had no conflicts of interest.
For patients with compensated cirrhosis, statin therapy was associated with about a 46% decrease in the risk of hepatic decompensation and mortality and with a 27% drop in the risk of portal hypertension and variceal bleeding, according to moderate-quality evidence from a systematic review and meta-analysis of 13 studies.
Low-quality data also suggested that statins might help protect against the progression of noncirrhotic chronic liver disease, said Rebecca G. Kim of the University of California at San Diego and her associates. “Large, pragmatic randomized controlled trials in patients with compensated cirrhosis are required to confirm these observations,” they wrote in the October issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2017.04.039).
Prior studies have reported mixed findings on how statin therapy affects chronic liver disease. For their review, Ms. Kim and her associates searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, Cochrane Database and Systematic Reviews, Scopus, Web of Science, and PubMed for randomized controlled trials or cohort studies published through March 25, 2017. They identified 10 cohort studies and three randomized controlled trials of adults with fibrosis without cirrhosis, compensated cirrhosis, or decompensated cirrhosis that evaluated statin exposure and reported associations between exposure and outcomes related to cirrhosis. They excluded case-control studies, cross-sectional studies, and studies that focused only on the relationship between statin use and the risk of hepatocellular carcinoma.
The resulting data set included 121,058 patients with chronic liver diseases, of whom 85% had chronic hepatitis C virus infection. A total of 46% of patients were exposed to statins, which appeared to reduce their risk of hepatic decompensation, variceal bleeding, and mortality. Among 87 such patients in five studies, statin use was associated with a 46% decrease in the risk of hepatic decompensation and death, with risk ratios of 0.54 (95% confidence intervals, 0.46-0.62 and 0.47-0.61, respectively). Statin use also was associated with a 27% lower risk of variceal bleeding or progression of portal hypertension, based on an analysis of 110 events in 236 patients from three trials (RR, 0.73; 95% CI, 0.59-0.91). Finally, statin use also was associated with a 58% lower risk of fibrosis progression or cirrhosis in patients with noncirrhotic chronic liver disease, but the 95% CIs for the risk estimate did not reach statistical significance (0.16-1.11).
Source: American Gastroenterological Association
Most studies lacked data on dose and duration of statin exposure, the researchers said. However, four cohort studies reported dose-dependent effects that were most pronounced after more than a year of treatment. “Similarly, several different types of statins were studied, and observed effects were assumed to be class-specific effects,” the reviewers wrote. “However, it is possible that lipophilic and lipophobic statins may have differential efficacy in decreasing fibrosis progression.”
Together, these findings support prior studies suggesting that statin therapy is safe and can potentially reduce the risk of hepatocellular carcinoma in this patient population, they concluded. Statins “may potentially improve patient-relevant outcomes in patients with chronic liver diseases and improve survival without significant additional costs.”
The reviewers acknowledged the American Gastroenterological Association Foundation, a T. Franklin Williams Scholarship Award, the National Institutes of Health, and the National Library of Medicine. They reported having no relevant conflicts of interest.
This story was updated on 9/13/2017.
For patients with compensated cirrhosis, statin therapy was associated with about a 46% decrease in the risk of hepatic decompensation and mortality and with a 27% drop in the risk of portal hypertension and variceal bleeding, according to moderate-quality evidence from a systematic review and meta-analysis of 13 studies.
Low-quality data also suggested that statins might help protect against the progression of noncirrhotic chronic liver disease, said Rebecca G. Kim of the University of California at San Diego and her associates. “Large, pragmatic randomized controlled trials in patients with compensated cirrhosis are required to confirm these observations,” they wrote in the October issue of Clinical Gastroenterology and Hepatology (doi: 10.1016/j.cgh.2017.04.039).
Prior studies have reported mixed findings on how statin therapy affects chronic liver disease. For their review, Ms. Kim and her associates searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, Cochrane Database and Systematic Reviews, Scopus, Web of Science, and PubMed for randomized controlled trials or cohort studies published through March 25, 2017. They identified 10 cohort studies and three randomized controlled trials of adults with fibrosis without cirrhosis, compensated cirrhosis, or decompensated cirrhosis that evaluated statin exposure and reported associations between exposure and outcomes related to cirrhosis. They excluded case-control studies, cross-sectional studies, and studies that focused only on the relationship between statin use and the risk of hepatocellular carcinoma.
The resulting data set included 121,058 patients with chronic liver diseases, of whom 85% had chronic hepatitis C virus infection. A total of 46% of patients were exposed to statins, which appeared to reduce their risk of hepatic decompensation, variceal bleeding, and mortality. Among 87 such patients in five studies, statin use was associated with a 46% decrease in the risk of hepatic decompensation and death, with risk ratios of 0.54 (95% confidence intervals, 0.46-0.62 and 0.47-0.61, respectively). Statin use also was associated with a 27% lower risk of variceal bleeding or progression of portal hypertension, based on an analysis of 110 events in 236 patients from three trials (RR, 0.73; 95% CI, 0.59-0.91). Finally, statin use also was associated with a 58% lower risk of fibrosis progression or cirrhosis in patients with noncirrhotic chronic liver disease, but the 95% CIs for the risk estimate did not reach statistical significance (0.16-1.11).
Source: American Gastroenterological Association
Most studies lacked data on dose and duration of statin exposure, the researchers said. However, four cohort studies reported dose-dependent effects that were most pronounced after more than a year of treatment. “Similarly, several different types of statins were studied, and observed effects were assumed to be class-specific effects,” the reviewers wrote. “However, it is possible that lipophilic and lipophobic statins may have differential efficacy in decreasing fibrosis progression.”
Together, these findings support prior studies suggesting that statin therapy is safe and can potentially reduce the risk of hepatocellular carcinoma in this patient population, they concluded. Statins “may potentially improve patient-relevant outcomes in patients with chronic liver diseases and improve survival without significant additional costs.”
The reviewers acknowledged the American Gastroenterological Association Foundation, a T. Franklin Williams Scholarship Award, the National Institutes of Health, and the National Library of Medicine. They reported having no relevant conflicts of interest.
This story was updated on 9/13/2017.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Key clinical point: Statin therapy was associated with a significantly lower risk of hepatic decompensation and death in patients with compensated cirrhosis.
Major finding: Statin therapy was associated with a 46% decrease in the risk of both hepatic decompensation and mortality (risk ratios, 0.54) and with a 27% drop in the risk of portal hypertension and variceal bleeding (RR, 0.73).
Data source: A systematic review and meta-analysis of 10 cohort studies and three randomized controlled trials (121,058 patients).
Disclosures: The reviewers acknowledged the American Gastroenterological Association Foundation, a T. Franklin Williams Scholarship Award, the National Institutes of Health, and the National Library of Medicine. They reported having no relevant conflicts of interest.
Enhanced disinfection of duodenoscopes did not reduce contamination
Duodenoscopes had similar rates of contamination after double high-level disinfection, standard high-level disinfection, or standard high-level disinfection followed by ethylene oxide gas sterilization, a randomized, prospective study of 516 bacterial cultures of 18 duodenoscopes showed.
“Our results do not support the routine use of double high-level disinfection or ethylene oxide sterilization for duodenoscope reprocessing,” wrote Graham M. Snyder, MD, of Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, and his associates. They stopped the study after 3 months because none of the duodenoscopes cultured multidrug-resistant organisms, the primary endpoint. “[We] found that in the nonoutbreak setting, duodenoscope contamination by multidrug-resistant organisms is extremely uncommon,” they wrote in the October issue of Gastroenterology (doi: 10.1053/j.gastro.2017.06.052). However, 16% of duodenoscopes cultured at least one colony-forming unit (CFU) after either standard high-level or double high-level disinfection, and 23% of duodenoscopes produced at least one CFU despite standard high-level disinfection followed by ethylene gas sterilization (P = .2), the investigators reported.
Outbreaks of carbapenem-resistant Enterobacteriaceae infections have been traced to duodenoscopes, even though they were reprocessed according to manufacturer instructions. In 2015, the Food and Drug Administration responded by warning that the design of duodenoscopes might preclude effective cleaning. Reasons for residual contamination remain uncertain, but biofilms, which are notoriously resistant to standard disinfection methods, might be a culprit, Dr. Snyder and his associates noted. Accordingly, some experts have suggested repeating the reprocessing cycle or adding ethylene oxide sterilization, but these measures are costly, time intensive, and not widely available. Furthermore, their efficacy “has never been systematically studied in a nonoutbreak setting,” the researchers wrote.
In response, they studied 516 cultures of elevator mechanisms and working channels from 18 reprocessed duodenoscopes (Olympus, model TJF-Q180). Immediately after use, each duodenoscope was manually wiped with enzymatic solution (EmPower), and then was manually reprocessed within an hour before undergoing automated reprocessing (System 83 Plus 9) with ortho-phthalaldehyde disinfectant (MetriCide OPA Plus) followed by ethanol flush. One-third of the duodenoscopes were randomly assigned to undergo double high-level disinfection with two automated reprocessing cycles, and another third underwent standard high-level disinfection followed by ethylene oxide gas sterilization (Steri-Vac sterilizer/aerator). All instruments were stored by hanging them vertically in an unventilated cabinet.
Multidrug-resistant organisms were cultured from 3% of rectal swabs and duodenal aspirates, but not from any of the cultures of duodenoscopes. Therefore, the study was stopped for futility. The enhanced disinfection methods failed to prevent contamination, compared with standard high-level disinfection, the researchers noted. Ten or more CFUs grew in 2% of duodenoscopes that underwent standard high-level disinfection, 4% of those that underwent double high-level disinfection, and 4% of those that underwent high-level disinfection followed by ethylene oxide sterilization (P = .4).
“There is no consensus on what parts of the standard high-level disinfection process should be repeated,” the investigators wrote. “It is uncertain if the addition of a second cycle of manual reprocessing might have improved the effectiveness of double high-level disinfection.”
Funders included the American Society for Gastrointestinal Endoscopy and Beth Israel Deaconess Medical Center. The investigators reported having no conflicts of interest.
Duodenoscopes had similar rates of contamination after double high-level disinfection, standard high-level disinfection, or standard high-level disinfection followed by ethylene oxide gas sterilization, a randomized, prospective study of 516 bacterial cultures of 18 duodenoscopes showed.
“Our results do not support the routine use of double high-level disinfection or ethylene oxide sterilization for duodenoscope reprocessing,” wrote Graham M. Snyder, MD, of Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, and his associates. They stopped the study after 3 months because none of the duodenoscopes cultured multidrug-resistant organisms, the primary endpoint. “[We] found that in the nonoutbreak setting, duodenoscope contamination by multidrug-resistant organisms is extremely uncommon,” they wrote in the October issue of Gastroenterology (doi: 10.1053/j.gastro.2017.06.052). However, 16% of duodenoscopes cultured at least one colony-forming unit (CFU) after either standard high-level or double high-level disinfection, and 23% of duodenoscopes produced at least one CFU despite standard high-level disinfection followed by ethylene gas sterilization (P = .2), the investigators reported.
Outbreaks of carbapenem-resistant Enterobacteriaceae infections have been traced to duodenoscopes, even though they were reprocessed according to manufacturer instructions. In 2015, the Food and Drug Administration responded by warning that the design of duodenoscopes might preclude effective cleaning. Reasons for residual contamination remain uncertain, but biofilms, which are notoriously resistant to standard disinfection methods, might be a culprit, Dr. Snyder and his associates noted. Accordingly, some experts have suggested repeating the reprocessing cycle or adding ethylene oxide sterilization, but these measures are costly, time intensive, and not widely available. Furthermore, their efficacy “has never been systematically studied in a nonoutbreak setting,” the researchers wrote.
In response, they studied 516 cultures of elevator mechanisms and working channels from 18 reprocessed duodenoscopes (Olympus, model TJF-Q180). Immediately after use, each duodenoscope was manually wiped with enzymatic solution (EmPower), and then was manually reprocessed within an hour before undergoing automated reprocessing (System 83 Plus 9) with ortho-phthalaldehyde disinfectant (MetriCide OPA Plus) followed by ethanol flush. One-third of the duodenoscopes were randomly assigned to undergo double high-level disinfection with two automated reprocessing cycles, and another third underwent standard high-level disinfection followed by ethylene oxide gas sterilization (Steri-Vac sterilizer/aerator). All instruments were stored by hanging them vertically in an unventilated cabinet.
Multidrug-resistant organisms were cultured from 3% of rectal swabs and duodenal aspirates, but not from any of the cultures of duodenoscopes. Therefore, the study was stopped for futility. The enhanced disinfection methods failed to prevent contamination, compared with standard high-level disinfection, the researchers noted. Ten or more CFUs grew in 2% of duodenoscopes that underwent standard high-level disinfection, 4% of those that underwent double high-level disinfection, and 4% of those that underwent high-level disinfection followed by ethylene oxide sterilization (P = .4).
“There is no consensus on what parts of the standard high-level disinfection process should be repeated,” the investigators wrote. “It is uncertain if the addition of a second cycle of manual reprocessing might have improved the effectiveness of double high-level disinfection.”
Funders included the American Society for Gastrointestinal Endoscopy and Beth Israel Deaconess Medical Center. The investigators reported having no conflicts of interest.
Duodenoscopes had similar rates of contamination after double high-level disinfection, standard high-level disinfection, or standard high-level disinfection followed by ethylene oxide gas sterilization, a randomized, prospective study of 516 bacterial cultures of 18 duodenoscopes showed.
“Our results do not support the routine use of double high-level disinfection or ethylene oxide sterilization for duodenoscope reprocessing,” wrote Graham M. Snyder, MD, of Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, and his associates. They stopped the study after 3 months because none of the duodenoscopes cultured multidrug-resistant organisms, the primary endpoint. “[We] found that in the nonoutbreak setting, duodenoscope contamination by multidrug-resistant organisms is extremely uncommon,” they wrote in the October issue of Gastroenterology (doi: 10.1053/j.gastro.2017.06.052). However, 16% of duodenoscopes cultured at least one colony-forming unit (CFU) after either standard high-level or double high-level disinfection, and 23% of duodenoscopes produced at least one CFU despite standard high-level disinfection followed by ethylene gas sterilization (P = .2), the investigators reported.
Outbreaks of carbapenem-resistant Enterobacteriaceae infections have been traced to duodenoscopes, even though they were reprocessed according to manufacturer instructions. In 2015, the Food and Drug Administration responded by warning that the design of duodenoscopes might preclude effective cleaning. Reasons for residual contamination remain uncertain, but biofilms, which are notoriously resistant to standard disinfection methods, might be a culprit, Dr. Snyder and his associates noted. Accordingly, some experts have suggested repeating the reprocessing cycle or adding ethylene oxide sterilization, but these measures are costly, time intensive, and not widely available. Furthermore, their efficacy “has never been systematically studied in a nonoutbreak setting,” the researchers wrote.
In response, they studied 516 cultures of elevator mechanisms and working channels from 18 reprocessed duodenoscopes (Olympus, model TJF-Q180). Immediately after use, each duodenoscope was manually wiped with enzymatic solution (EmPower), and then was manually reprocessed within an hour before undergoing automated reprocessing (System 83 Plus 9) with ortho-phthalaldehyde disinfectant (MetriCide OPA Plus) followed by ethanol flush. One-third of the duodenoscopes were randomly assigned to undergo double high-level disinfection with two automated reprocessing cycles, and another third underwent standard high-level disinfection followed by ethylene oxide gas sterilization (Steri-Vac sterilizer/aerator). All instruments were stored by hanging them vertically in an unventilated cabinet.
Multidrug-resistant organisms were cultured from 3% of rectal swabs and duodenal aspirates, but not from any of the cultures of duodenoscopes. Therefore, the study was stopped for futility. The enhanced disinfection methods failed to prevent contamination, compared with standard high-level disinfection, the researchers noted. Ten or more CFUs grew in 2% of duodenoscopes that underwent standard high-level disinfection, 4% of those that underwent double high-level disinfection, and 4% of those that underwent high-level disinfection followed by ethylene oxide sterilization (P = .4).
“There is no consensus on what parts of the standard high-level disinfection process should be repeated,” the investigators wrote. “It is uncertain if the addition of a second cycle of manual reprocessing might have improved the effectiveness of double high-level disinfection.”
Funders included the American Society for Gastrointestinal Endoscopy and Beth Israel Deaconess Medical Center. The investigators reported having no conflicts of interest.
FROM GASTROENTEROLOGY
Key clinical point: Enhanced disinfection of duodenoscopes did not provide additional protection against contamination.
Major finding: No cultures were positive for multidrug-resistant organisms, but 16% of duodenoscopes had at least one colony-forming unit despite standard high-level disinfection or double high-level disinfection. Standard high-level disinfection followed by ethylene oxide gas failed to sterilize 23% of duodenoscopes (P = .2).
Data source: A single-center, prospective randomized study of 516 cultures of 18 duodenoscopes.
Disclosures: Funders included the American Society for Gastrointestinal Endoscopy and Beth Israel Deaconess Medical Center. The investigators reported having no conflicts of interest.
Pembrolizumab, nivolumab linked to 3% rate of neurologic events
Three percent of patients developed immune-related adverse neurologic events within 12 months of receiving nivolumab or pembrolizumab, according to the results of a single-center retrospective study.
These syndromes included myopathy, axonal thoracolumbar polyradiculopathy, severe demyelinating length-dependent peripheral neuropathy with axonal loss, a facial diplegic variant of Guillain-Barré syndrome, asymmetric vasculitic neuropathy, cerebellar ataxia with dysarthria, autoimmune retinopathy, bilateral internuclear ophthalmoplegia, and headache, reported Justin C. Kao, MD, of Mayo Clinic, Rochester, Minn., and his coinvestigators. Most patients improved after stopping treatment and starting corticosteroids, but one patient developed necrotizing myopathy and died after withdrawal of ventilator support.
Nivolumab and pembrolizumab, which inhibit the programmed death–1 (PD-1) receptor, are approved for treating metastatic melanoma, non–small-cell lung cancer, renal cell carcinoma, Hodgkin lymphoma, head and neck cancers, and urothelial carcinoma. In response to a surge in reports of neurologic events associated with anti–PD-1 therapy, the investigators searched the Mayo Clinic pharmacy database and identified 347 patients treated with pembrolizumab or nivolumab between 2014 and 2016. Ten patients (2.9%) developed neurologic complications within 12 months of anti–PD-1 exposure, including eight men and two women. The median age was 71 years. None of their neurologic symptoms could be directly attributed to other treatments or to metastatic disease. Most had mild to moderate disability, with modified Rankin Scale (mRS) scores of 2, and symptom severity peaked between 1 day and more than 3 months after starting anti–PD-1 treatment (JAMA Neurol. 2017 Sep 5. doi: 10.1001/jamaneurol.2017.1912).
Stopping anti–PD-1 treatment and starting high-dose corticosteroids led to substantial neurologic improvements (mRS scores, 0-3), except in the case of fatal necrotizing myopathy, the researchers said. That patient, who was receiving pembrolizumab for stage 4 melanoma, developed extraocular, bulbar, and proximal limb girdle weakness that worsened over a period of 3 weeks and did not respond to prednisone (80 mg daily) or to three sessions of plasmapheresis.
If a patient on anti–PD-1 therapy develops neurologic symptoms, clinicians should promptly stop treatment and pursue a full work-up, including electrodiagnostic studies and consideration of muscle or nerve biopsy to clarify underlying pathophysiologic mechanisms, the researchers said. “If the clinical examination demonstrates severe clinical deficits at onset or worsens despite medication discontinuation, additional immune suppressant treatment should be considered,” they said. They recommended prednisone (1 mg/kg) with a taper over a 1-month period. Intravenous immunoglobulin therapy or plasma exchange may be warranted if patients continue to worsen, they said.
The investigators did not report external funding sources. Mr. Kao had no disclosures. Two coinvestigators disclosed ties to the American Association of Neuromuscular & Electrodiagnostic Medicine, the American Academy of Neurology, the Continuum: Lifelong Learning in Neurology, Ionis Pharmaceuticals, Alnylam, and Oxford University Press. The remaining coinvestigators reported having no conflicts of interest.
Neurologic symptoms have been and continue to be one of the most common reasons for admission to a cancer center. Neurotoxic chemotherapy, direct invasion of cancer, and other neurologic complications of treatment contribute to the substantial cross talk between oncologists and neurologists. Over the past 5 years, oncology has witnessed an explosion of new immunotherapeutics that are revolutionizing drug development and patient care in oncology today. In contrast to traditional chemotherapy, which targets rapidly dividing cancer cells and can lead to adverse effects in other organs with rapid cell turnover, immunotherapies target and activate the immune system, potentially leading to a wide range of inflammatory and immune-mediated adverse events, including those in the nervous system.
Only 5 of the 10 patients described by Kao et al. experienced nonneurologic immune-related adverse events, suggesting that neurologic complications may be the only defining symptom of an immune-related reaction. Consultation calls from the cancer center are all too familiar for neurologists, and this pattern appears likely to persist in the era of immunotherapy. The horizon of new checkpoint targets continues to expand, and combination therapies are beginning to emerge. Neurologists and oncologists need to be aware of the important checkpoints ahead in patient care.
Roy E. Strowd III, MD, is with the section on hematology and oncology, department of neurology and internal medicine, Wake Forest University, Winston-Salem, N.C. He reported having no conflicts of interest. These comments are excerpted from his editorial (JAMA Neurol. 2017 Sep 5. doi: 10.1001/jamaneurol.2017.1916).
Neurologic symptoms have been and continue to be one of the most common reasons for admission to a cancer center. Neurotoxic chemotherapy, direct invasion of cancer, and other neurologic complications of treatment contribute to the substantial cross talk between oncologists and neurologists. Over the past 5 years, oncology has witnessed an explosion of new immunotherapeutics that are revolutionizing drug development and patient care in oncology today. In contrast to traditional chemotherapy, which targets rapidly dividing cancer cells and can lead to adverse effects in other organs with rapid cell turnover, immunotherapies target and activate the immune system, potentially leading to a wide range of inflammatory and immune-mediated adverse events, including those in the nervous system.
Only 5 of the 10 patients described by Kao et al. experienced nonneurologic immune-related adverse events, suggesting that neurologic complications may be the only defining symptom of an immune-related reaction. Consultation calls from the cancer center are all too familiar for neurologists, and this pattern appears likely to persist in the era of immunotherapy. The horizon of new checkpoint targets continues to expand, and combination therapies are beginning to emerge. Neurologists and oncologists need to be aware of the important checkpoints ahead in patient care.
Roy E. Strowd III, MD, is with the section on hematology and oncology, department of neurology and internal medicine, Wake Forest University, Winston-Salem, N.C. He reported having no conflicts of interest. These comments are excerpted from his editorial (JAMA Neurol. 2017 Sep 5. doi: 10.1001/jamaneurol.2017.1916).
Neurologic symptoms have been and continue to be one of the most common reasons for admission to a cancer center. Neurotoxic chemotherapy, direct invasion of cancer, and other neurologic complications of treatment contribute to the substantial cross talk between oncologists and neurologists. Over the past 5 years, oncology has witnessed an explosion of new immunotherapeutics that are revolutionizing drug development and patient care in oncology today. In contrast to traditional chemotherapy, which targets rapidly dividing cancer cells and can lead to adverse effects in other organs with rapid cell turnover, immunotherapies target and activate the immune system, potentially leading to a wide range of inflammatory and immune-mediated adverse events, including those in the nervous system.
Only 5 of the 10 patients described by Kao et al. experienced nonneurologic immune-related adverse events, suggesting that neurologic complications may be the only defining symptom of an immune-related reaction. Consultation calls from the cancer center are all too familiar for neurologists, and this pattern appears likely to persist in the era of immunotherapy. The horizon of new checkpoint targets continues to expand, and combination therapies are beginning to emerge. Neurologists and oncologists need to be aware of the important checkpoints ahead in patient care.
Roy E. Strowd III, MD, is with the section on hematology and oncology, department of neurology and internal medicine, Wake Forest University, Winston-Salem, N.C. He reported having no conflicts of interest. These comments are excerpted from his editorial (JAMA Neurol. 2017 Sep 5. doi: 10.1001/jamaneurol.2017.1916).
Three percent of patients developed immune-related adverse neurologic events within 12 months of receiving nivolumab or pembrolizumab, according to the results of a single-center retrospective study.
These syndromes included myopathy, axonal thoracolumbar polyradiculopathy, severe demyelinating length-dependent peripheral neuropathy with axonal loss, a facial diplegic variant of Guillain-Barré syndrome, asymmetric vasculitic neuropathy, cerebellar ataxia with dysarthria, autoimmune retinopathy, bilateral internuclear ophthalmoplegia, and headache, reported Justin C. Kao, MD, of Mayo Clinic, Rochester, Minn., and his coinvestigators. Most patients improved after stopping treatment and starting corticosteroids, but one patient developed necrotizing myopathy and died after withdrawal of ventilator support.
Nivolumab and pembrolizumab, which inhibit the programmed death–1 (PD-1) receptor, are approved for treating metastatic melanoma, non–small-cell lung cancer, renal cell carcinoma, Hodgkin lymphoma, head and neck cancers, and urothelial carcinoma. In response to a surge in reports of neurologic events associated with anti–PD-1 therapy, the investigators searched the Mayo Clinic pharmacy database and identified 347 patients treated with pembrolizumab or nivolumab between 2014 and 2016. Ten patients (2.9%) developed neurologic complications within 12 months of anti–PD-1 exposure, including eight men and two women. The median age was 71 years. None of their neurologic symptoms could be directly attributed to other treatments or to metastatic disease. Most had mild to moderate disability, with modified Rankin Scale (mRS) scores of 2, and symptom severity peaked between 1 day and more than 3 months after starting anti–PD-1 treatment (JAMA Neurol. 2017 Sep 5. doi: 10.1001/jamaneurol.2017.1912).
Stopping anti–PD-1 treatment and starting high-dose corticosteroids led to substantial neurologic improvements (mRS scores, 0-3), except in the case of fatal necrotizing myopathy, the researchers said. That patient, who was receiving pembrolizumab for stage 4 melanoma, developed extraocular, bulbar, and proximal limb girdle weakness that worsened over a period of 3 weeks and did not respond to prednisone (80 mg daily) or to three sessions of plasmapheresis.
If a patient on anti–PD-1 therapy develops neurologic symptoms, clinicians should promptly stop treatment and pursue a full work-up, including electrodiagnostic studies and consideration of muscle or nerve biopsy to clarify underlying pathophysiologic mechanisms, the researchers said. “If the clinical examination demonstrates severe clinical deficits at onset or worsens despite medication discontinuation, additional immune suppressant treatment should be considered,” they said. They recommended prednisone (1 mg/kg) with a taper over a 1-month period. Intravenous immunoglobulin therapy or plasma exchange may be warranted if patients continue to worsen, they said.
The investigators did not report external funding sources. Mr. Kao had no disclosures. Two coinvestigators disclosed ties to the American Association of Neuromuscular & Electrodiagnostic Medicine, the American Academy of Neurology, the Continuum: Lifelong Learning in Neurology, Ionis Pharmaceuticals, Alnylam, and Oxford University Press. The remaining coinvestigators reported having no conflicts of interest.
Three percent of patients developed immune-related adverse neurologic events within 12 months of receiving nivolumab or pembrolizumab, according to the results of a single-center retrospective study.
These syndromes included myopathy, axonal thoracolumbar polyradiculopathy, severe demyelinating length-dependent peripheral neuropathy with axonal loss, a facial diplegic variant of Guillain-Barré syndrome, asymmetric vasculitic neuropathy, cerebellar ataxia with dysarthria, autoimmune retinopathy, bilateral internuclear ophthalmoplegia, and headache, reported Justin C. Kao, MD, of Mayo Clinic, Rochester, Minn., and his coinvestigators. Most patients improved after stopping treatment and starting corticosteroids, but one patient developed necrotizing myopathy and died after withdrawal of ventilator support.
Nivolumab and pembrolizumab, which inhibit the programmed death–1 (PD-1) receptor, are approved for treating metastatic melanoma, non–small-cell lung cancer, renal cell carcinoma, Hodgkin lymphoma, head and neck cancers, and urothelial carcinoma. In response to a surge in reports of neurologic events associated with anti–PD-1 therapy, the investigators searched the Mayo Clinic pharmacy database and identified 347 patients treated with pembrolizumab or nivolumab between 2014 and 2016. Ten patients (2.9%) developed neurologic complications within 12 months of anti–PD-1 exposure, including eight men and two women. The median age was 71 years. None of their neurologic symptoms could be directly attributed to other treatments or to metastatic disease. Most had mild to moderate disability, with modified Rankin Scale (mRS) scores of 2, and symptom severity peaked between 1 day and more than 3 months after starting anti–PD-1 treatment (JAMA Neurol. 2017 Sep 5. doi: 10.1001/jamaneurol.2017.1912).
Stopping anti–PD-1 treatment and starting high-dose corticosteroids led to substantial neurologic improvements (mRS scores, 0-3), except in the case of fatal necrotizing myopathy, the researchers said. That patient, who was receiving pembrolizumab for stage 4 melanoma, developed extraocular, bulbar, and proximal limb girdle weakness that worsened over a period of 3 weeks and did not respond to prednisone (80 mg daily) or to three sessions of plasmapheresis.
If a patient on anti–PD-1 therapy develops neurologic symptoms, clinicians should promptly stop treatment and pursue a full work-up, including electrodiagnostic studies and consideration of muscle or nerve biopsy to clarify underlying pathophysiologic mechanisms, the researchers said. “If the clinical examination demonstrates severe clinical deficits at onset or worsens despite medication discontinuation, additional immune suppressant treatment should be considered,” they said. They recommended prednisone (1 mg/kg) with a taper over a 1-month period. Intravenous immunoglobulin therapy or plasma exchange may be warranted if patients continue to worsen, they said.
The investigators did not report external funding sources. Mr. Kao had no disclosures. Two coinvestigators disclosed ties to the American Association of Neuromuscular & Electrodiagnostic Medicine, the American Academy of Neurology, the Continuum: Lifelong Learning in Neurology, Ionis Pharmaceuticals, Alnylam, and Oxford University Press. The remaining coinvestigators reported having no conflicts of interest.
FROM JAMA NEUROLOGY
Key clinical point: Watch for immune-related adverse effects of nivolumab and pembrolizumab.
Major finding: Ten of 347 patients (2.9%) developed subacute neurologic immune-related adverse events, typically neuromuscular syndromes.
Data source: A single-center, retrospective cohort study of 347 patients who received pembrolizumab or nivolumab for metastatic melanoma or solid tumors.
Disclosures: The investigators did not report external funding sources. Mr. Kao had no disclosures. Two coinvestigators disclosed ties to the American Association of Neuromuscular & Electrodiagnostic Medicine, the American Academy of Neurology, the Continuum: Lifelong Learning in Neurology, Ionis Pharmaceuticals, Alnylam, and Oxford University Press. The remaining coinvestigators reported having no conflicts of interest.
In California, medical vaccine exemptions tripled after personal belief exemption ban
The proportion of California kindergartners with medical exemptions from vaccination tripled after the state eliminated personal belief exemptions, a study has shown.
Furthermore, California counties that previously had the highest rates of personal belief exemptions now have the highest rates of medical exemptions, Paul L. Delamater, PhD, of the University of North Carolina at Chapel Hill, and his associates reported in a research letter in JAMA. Such trends undermine California Senate Bill 277, will “limit [the law’s] long-term benefits, if sustained,” and could lead to outbreaks of vaccine-preventable diseases in the near future, the researchers warned.
Beginning in fall 2016, SB 277 prohibited unvaccinated kindergartners from matriculating at a public or private school in California without a medical exemption from vaccination, having eliminated the personal belief exemption from the state’s school-entry vaccine requirements. But the new law also gave physicians broader discretion to grant the medical exemptions, prompting concerns that “vaccine-hesitant” parents might successfully obtain medical exemptions in lieu of personal belief exemptions. To explore that possibility, the researchers analyzed data from the California state health department on kindergarten enrollment, vaccination, and vaccination exemptions. These data covered about 95% of California kindergartners, Dr. Delamater and his associates noted (JAMA. 2017;318[9]:863-4).
At the county level, rates of medical exemptions strongly correlated with historic rates of personal belief exemptions (P less than .001). Thus, counties with the highest historic rates of personal belief exemptions had the largest increases in rates of medical exemptions in 2016, that is, a change of between –1.00% and 3.38% of kindergartners. Furthermore, vaccination rates among all elementary school-aged children in California are even lower because SB 277 permitted children who previously entered kindergarten with personal belief exemptions to continue attending school without receiving vaccines until seventh grade. “Because the largest increases in [medical exemption] percentage occurred in regions with high past–[personal belief exemption] use, portions of California may remain susceptible to vaccine-preventable disease outbreaks in the near future,” Dr. Delamater and his associates concluded.
The investigators reported having no conflicts of interest.
The proportion of California kindergartners with medical exemptions from vaccination tripled after the state eliminated personal belief exemptions, a study has shown.
Furthermore, California counties that previously had the highest rates of personal belief exemptions now have the highest rates of medical exemptions, Paul L. Delamater, PhD, of the University of North Carolina at Chapel Hill, and his associates reported in a research letter in JAMA. Such trends undermine California Senate Bill 277, will “limit [the law’s] long-term benefits, if sustained,” and could lead to outbreaks of vaccine-preventable diseases in the near future, the researchers warned.
Beginning in fall 2016, SB 277 prohibited unvaccinated kindergartners from matriculating at a public or private school in California without a medical exemption from vaccination, having eliminated the personal belief exemption from the state’s school-entry vaccine requirements. But the new law also gave physicians broader discretion to grant the medical exemptions, prompting concerns that “vaccine-hesitant” parents might successfully obtain medical exemptions in lieu of personal belief exemptions. To explore that possibility, the researchers analyzed data from the California state health department on kindergarten enrollment, vaccination, and vaccination exemptions. These data covered about 95% of California kindergartners, Dr. Delamater and his associates noted (JAMA. 2017;318[9]:863-4).
At the county level, rates of medical exemptions strongly correlated with historic rates of personal belief exemptions (P less than .001). Thus, counties with the highest historic rates of personal belief exemptions had the largest increases in rates of medical exemptions in 2016, that is, a change of between –1.00% and 3.38% of kindergartners. Furthermore, vaccination rates among all elementary school-aged children in California are even lower because SB 277 permitted children who previously entered kindergarten with personal belief exemptions to continue attending school without receiving vaccines until seventh grade. “Because the largest increases in [medical exemption] percentage occurred in regions with high past–[personal belief exemption] use, portions of California may remain susceptible to vaccine-preventable disease outbreaks in the near future,” Dr. Delamater and his associates concluded.
The investigators reported having no conflicts of interest.
The proportion of California kindergartners with medical exemptions from vaccination tripled after the state eliminated personal belief exemptions, a study has shown.
Furthermore, California counties that previously had the highest rates of personal belief exemptions now have the highest rates of medical exemptions, Paul L. Delamater, PhD, of the University of North Carolina at Chapel Hill, and his associates reported in a research letter in JAMA. Such trends undermine California Senate Bill 277, will “limit [the law’s] long-term benefits, if sustained,” and could lead to outbreaks of vaccine-preventable diseases in the near future, the researchers warned.
Beginning in fall 2016, SB 277 prohibited unvaccinated kindergartners from matriculating at a public or private school in California without a medical exemption from vaccination, having eliminated the personal belief exemption from the state’s school-entry vaccine requirements. But the new law also gave physicians broader discretion to grant the medical exemptions, prompting concerns that “vaccine-hesitant” parents might successfully obtain medical exemptions in lieu of personal belief exemptions. To explore that possibility, the researchers analyzed data from the California state health department on kindergarten enrollment, vaccination, and vaccination exemptions. These data covered about 95% of California kindergartners, Dr. Delamater and his associates noted (JAMA. 2017;318[9]:863-4).
At the county level, rates of medical exemptions strongly correlated with historic rates of personal belief exemptions (P less than .001). Thus, counties with the highest historic rates of personal belief exemptions had the largest increases in rates of medical exemptions in 2016, that is, a change of between –1.00% and 3.38% of kindergartners. Furthermore, vaccination rates among all elementary school-aged children in California are even lower because SB 277 permitted children who previously entered kindergarten with personal belief exemptions to continue attending school without receiving vaccines until seventh grade. “Because the largest increases in [medical exemption] percentage occurred in regions with high past–[personal belief exemption] use, portions of California may remain susceptible to vaccine-preventable disease outbreaks in the near future,” Dr. Delamater and his associates concluded.
The investigators reported having no conflicts of interest.
FROM JAMA
Key clinical point:
Major finding: In 2016, 0.51% of California kindergartners had medical exemptions, a threefold rise from 2015.
Data source: An analysis of reportable state health department data from 2001 to 2016.
Disclosures: The investigators reported having no conflicts of interest.
Pembrolizumab showed ‘promising’ antitumor activity in small-cell lung cancer
One patient died of treatment-related mesenteric ischemia, reported Patrick A. Ott, MD, of Dana-Farber Cancer Institute in Boston, and his associates. Nonetheless, with an objective response rate of 33% and a median duration of response of 19 months, the checkpoint inhibitor “demonstrated a favorable safety profile and promising durable clinical activity,” they concluded.
Study participants received pembrolizumab (10 mg/kg) every 2 weeks for 24 months or until disease progression or intolerable toxicity occurred. After a median follow-up of 9.8 months (range, 0.5-24 months), one patient (4%) had a complete response, and seven (29%) had partial responses. The median onset of response was 2 months, and responses lasted from 3.6 to 20 months, Dr. Ott and his associates reported (J Clin Oncol. 2017 Aug 16. doi: 10.1200/JCO.2017.72.5069). Two-thirds of patients developed treatment-related adverse events, most often arthralgia, asthenia, rash, diarrhea, and fatigue. Two patients developed grade 3 or worse treatment-related adverse events, including a 65-year-old man with small cell lung cancer and liver metastasis who developed grade 3 bilirubin elevation, and a 58-year-old woman with a history of sleeve gastrectomy who developed grade 3 asthenia, grade 5 colitis, and intestinal ischemia.
The patient who died had received 10 cycles of pembrolizumab, was hospitalized with abdominal pain, nausea, and vomiting, and was discharged home with a diagnosis of food intolerance, the researchers reported. She received an 11th cycle of pembrolizumab and was readmitted with abdominal pain. A rectal biopsy showed chronic colitis. She received systemic corticosteroids and was discharged, was admitted to a different hospital several weeks later with diffuse abdominal pain and septic shock, and subsequently died. “Mesenteric ischemia resulted in death,” the researchers wrote. “The cause of the colitis and intestinal ischemia was reported as probably related to pembrolizumab.”
Pembrolizumab (Keytruda) is a programmed death receptor–1 blocking antibody approved for treating non–small cell lung cancer, head and neck squamous cell cancer, classical Hodgkin lymphoma, urothelial carcinoma, and microsatellite instability–high cancer or mismatch repair deficient solid tumors. Treatment with the checkpoint inhibitor led to grade 5 treatment-related adverse events in other trials. Most recently, in July 2017, the Food and Drug Administration placed clinical holds on phase 1 and phase 3 studies of pembrolizumab for treating multiple myeloma after more patients died in the pembrolizumab arms than did in the comparison arms. Pembrolizumab also recently came up short in a phase 3 trial of patients with head and neck cancer, although it has kept its FDA label for this indication. Multiple trials of pembrolizumab for small cell lung cancer are recruiting or ongoing.
Merck funded the study. Dr. Ott disclosed research funding from Merck and several other pharmaceutical companies, and advisory or consulting relationships with several companies, excluding Merck.
One patient died of treatment-related mesenteric ischemia, reported Patrick A. Ott, MD, of Dana-Farber Cancer Institute in Boston, and his associates. Nonetheless, with an objective response rate of 33% and a median duration of response of 19 months, the checkpoint inhibitor “demonstrated a favorable safety profile and promising durable clinical activity,” they concluded.
Study participants received pembrolizumab (10 mg/kg) every 2 weeks for 24 months or until disease progression or intolerable toxicity occurred. After a median follow-up of 9.8 months (range, 0.5-24 months), one patient (4%) had a complete response, and seven (29%) had partial responses. The median onset of response was 2 months, and responses lasted from 3.6 to 20 months, Dr. Ott and his associates reported (J Clin Oncol. 2017 Aug 16. doi: 10.1200/JCO.2017.72.5069). Two-thirds of patients developed treatment-related adverse events, most often arthralgia, asthenia, rash, diarrhea, and fatigue. Two patients developed grade 3 or worse treatment-related adverse events, including a 65-year-old man with small cell lung cancer and liver metastasis who developed grade 3 bilirubin elevation, and a 58-year-old woman with a history of sleeve gastrectomy who developed grade 3 asthenia, grade 5 colitis, and intestinal ischemia.
The patient who died had received 10 cycles of pembrolizumab, was hospitalized with abdominal pain, nausea, and vomiting, and was discharged home with a diagnosis of food intolerance, the researchers reported. She received an 11th cycle of pembrolizumab and was readmitted with abdominal pain. A rectal biopsy showed chronic colitis. She received systemic corticosteroids and was discharged, was admitted to a different hospital several weeks later with diffuse abdominal pain and septic shock, and subsequently died. “Mesenteric ischemia resulted in death,” the researchers wrote. “The cause of the colitis and intestinal ischemia was reported as probably related to pembrolizumab.”
Pembrolizumab (Keytruda) is a programmed death receptor–1 blocking antibody approved for treating non–small cell lung cancer, head and neck squamous cell cancer, classical Hodgkin lymphoma, urothelial carcinoma, and microsatellite instability–high cancer or mismatch repair deficient solid tumors. Treatment with the checkpoint inhibitor led to grade 5 treatment-related adverse events in other trials. Most recently, in July 2017, the Food and Drug Administration placed clinical holds on phase 1 and phase 3 studies of pembrolizumab for treating multiple myeloma after more patients died in the pembrolizumab arms than did in the comparison arms. Pembrolizumab also recently came up short in a phase 3 trial of patients with head and neck cancer, although it has kept its FDA label for this indication. Multiple trials of pembrolizumab for small cell lung cancer are recruiting or ongoing.
Merck funded the study. Dr. Ott disclosed research funding from Merck and several other pharmaceutical companies, and advisory or consulting relationships with several companies, excluding Merck.
One patient died of treatment-related mesenteric ischemia, reported Patrick A. Ott, MD, of Dana-Farber Cancer Institute in Boston, and his associates. Nonetheless, with an objective response rate of 33% and a median duration of response of 19 months, the checkpoint inhibitor “demonstrated a favorable safety profile and promising durable clinical activity,” they concluded.
Study participants received pembrolizumab (10 mg/kg) every 2 weeks for 24 months or until disease progression or intolerable toxicity occurred. After a median follow-up of 9.8 months (range, 0.5-24 months), one patient (4%) had a complete response, and seven (29%) had partial responses. The median onset of response was 2 months, and responses lasted from 3.6 to 20 months, Dr. Ott and his associates reported (J Clin Oncol. 2017 Aug 16. doi: 10.1200/JCO.2017.72.5069). Two-thirds of patients developed treatment-related adverse events, most often arthralgia, asthenia, rash, diarrhea, and fatigue. Two patients developed grade 3 or worse treatment-related adverse events, including a 65-year-old man with small cell lung cancer and liver metastasis who developed grade 3 bilirubin elevation, and a 58-year-old woman with a history of sleeve gastrectomy who developed grade 3 asthenia, grade 5 colitis, and intestinal ischemia.
The patient who died had received 10 cycles of pembrolizumab, was hospitalized with abdominal pain, nausea, and vomiting, and was discharged home with a diagnosis of food intolerance, the researchers reported. She received an 11th cycle of pembrolizumab and was readmitted with abdominal pain. A rectal biopsy showed chronic colitis. She received systemic corticosteroids and was discharged, was admitted to a different hospital several weeks later with diffuse abdominal pain and septic shock, and subsequently died. “Mesenteric ischemia resulted in death,” the researchers wrote. “The cause of the colitis and intestinal ischemia was reported as probably related to pembrolizumab.”
Pembrolizumab (Keytruda) is a programmed death receptor–1 blocking antibody approved for treating non–small cell lung cancer, head and neck squamous cell cancer, classical Hodgkin lymphoma, urothelial carcinoma, and microsatellite instability–high cancer or mismatch repair deficient solid tumors. Treatment with the checkpoint inhibitor led to grade 5 treatment-related adverse events in other trials. Most recently, in July 2017, the Food and Drug Administration placed clinical holds on phase 1 and phase 3 studies of pembrolizumab for treating multiple myeloma after more patients died in the pembrolizumab arms than did in the comparison arms. Pembrolizumab also recently came up short in a phase 3 trial of patients with head and neck cancer, although it has kept its FDA label for this indication. Multiple trials of pembrolizumab for small cell lung cancer are recruiting or ongoing.
Merck funded the study. Dr. Ott disclosed research funding from Merck and several other pharmaceutical companies, and advisory or consulting relationships with several companies, excluding Merck.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: Pembrolizumab showed antitumor activity and was usually safe for treating extensive-stage small cell lung cancer.
Major finding: The objective response rate was 33%. Two patients developed grade 3 or worse treatment-related adverse events, which included fatal mesenteric ischemia and colitis.
Data source: A phase 1b open-label trial of 24 patients with PD-L1–positive extensive-stage small cell lung cancer.
Disclosures: Merck funded the study. Dr. Ott disclosed research funding from Merck and several other pharmaceutical companies, and advisory or consulting relationships with several companies, excluding Merck.