Jennifer Shepphird

Acute myeloid leukemia (AML) consists of at least 11 disease classes that represent distinct paths in the evolution of AML and have prognostic implications, based on an analysis of somatic driver mutations in 1,540 patients.

In total, 5,234 driver mutations were identified in 76 genes or regions, with 96% of patients having at least one mutation and 86% having two or more mutations. However, nearly one-half of the cohort did not fall into one of the molecular groups defined by the World Health Organization in 2008.

“The characterization of many new leukemia genes, multiple driver mutations per patient, and complex co-mutation patterns prompted us to reevaluate genomic classification of AML from the beginning,” wrote Elli Papaemmanuil, Ph.D., a molecular geneticist at Memorial Sloan Kettering, New York, and of the Cancer Genome Project, Wellcome Trust Sanger Institute, and her colleagues (N Engl J Med. 2016 Jun 9; 374:2209-21).

The team developed a Bayesian statistical model to define 11 mutually exclusive subtypes based on patterns of co-mutations. The schema unambiguously classified 1,236 of 1,540 patients (80%) into a single subgroup and 56 (4%) into two or more groups. A subset of patients (166, 11%) remained unclassified, possibly due to mutations in genes not sequenced in the study.

NPM1-mutated AML was the largest class (27% of the cohort), followed by the chromatin-spliceosome group (18% of the cohort) that included mutations in genes regulating RNA splicing (SRSF2, SF3B1, U2AF1, and ZRSR2), chromatin (ASXL1, STAG2, BCOR, MLL^PTD, EZH2, and PHF6), or transcription (RUNX1). Another subgroup consisted of mutations in TP53, as well as complex karyotype alterations, cytogenetically visible copy-number alterations (aneuploidies), or a combination. While broader than previous classifications, such as “monosomal karyotype AML” and “complex karyotype AML,” this group emerged from correlated chromosomal abnormalities and was mutually exclusive of other class-defining lesions. In general, patients in this group were older and had fewer RAS pathway mutations.

The groups had considerable differences in clinical presentation and overall survival, according to the report. The TP53-aneuploidy subgroup had poor outcomes, as previously described. Patients in the chromatin-spliceosome group had lower rates of response to induction chemotherapy, higher relapse rates, and poorer long-term outcomes, compared with other groups. Most of these patients (84%) would be classified as intermediate risk under current guidelines, but the characteristics were more similar to those of subgroups with adverse outcomes.

Overall survival was correlated with the number of driver mutations, and deleterious affects of mutations often were found to be additive. In some cases, complex gene interactions accounted for variation in outcomes, suggesting the clinical effect of some driver mutations may depend on the occurrence of co-mutations in a wider genomic context.

Acute myeloid leukemia (AML) consists of at least 11 disease classes that represent distinct paths in the evolution of AML and have prognostic implications, based on an analysis of somatic driver mutations in 1,540 patients.

In total, 5,234 driver mutations were identified in 76 genes or regions, with 96% of patients having at least one mutation and 86% having two or more mutations. However, nearly one-half of the cohort did not fall into one of the molecular groups defined by the World Health Organization in 2008.

“The characterization of many new leukemia genes, multiple driver mutations per patient, and complex co-mutation patterns prompted us to reevaluate genomic classification of AML from the beginning,” wrote Elli Papaemmanuil, Ph.D., a molecular geneticist at Memorial Sloan Kettering, New York, and of the Cancer Genome Project, Wellcome Trust Sanger Institute, and her colleagues (N Engl J Med. 2016 Jun 9; 374:2209-21).

The team developed a Bayesian statistical model to define 11 mutually exclusive subtypes based on patterns of co-mutations. The schema unambiguously classified 1,236 of 1,540 patients (80%) into a single subgroup and 56 (4%) into two or more groups. A subset of patients (166, 11%) remained unclassified, possibly due to mutations in genes not sequenced in the study.

NPM1-mutated AML was the largest class (27% of the cohort), followed by the chromatin-spliceosome group (18% of the cohort) that included mutations in genes regulating RNA splicing (SRSF2, SF3B1, U2AF1, and ZRSR2), chromatin (ASXL1, STAG2, BCOR, MLL^PTD, EZH2, and PHF6), or transcription (RUNX1). Another subgroup consisted of mutations in TP53, as well as complex karyotype alterations, cytogenetically visible copy-number alterations (aneuploidies), or a combination. While broader than previous classifications, such as “monosomal karyotype AML” and “complex karyotype AML,” this group emerged from correlated chromosomal abnormalities and was mutually exclusive of other class-defining lesions. In general, patients in this group were older and had fewer RAS pathway mutations.

The groups had considerable differences in clinical presentation and overall survival, according to the report. The TP53-aneuploidy subgroup had poor outcomes, as previously described. Patients in the chromatin-spliceosome group had lower rates of response to induction chemotherapy, higher relapse rates, and poorer long-term outcomes, compared with other groups. Most of these patients (84%) would be classified as intermediate risk under current guidelines, but the characteristics were more similar to those of subgroups with adverse outcomes.

Overall survival was correlated with the number of driver mutations, and deleterious affects of mutations often were found to be additive. In some cases, complex gene interactions accounted for variation in outcomes, suggesting the clinical effect of some driver mutations may depend on the occurrence of co-mutations in a wider genomic context.

Acute myeloid leukemia (AML) consists of at least 11 disease classes that represent distinct paths in the evolution of AML and have prognostic implications, based on an analysis of somatic driver mutations in 1,540 patients.

In total, 5,234 driver mutations were identified in 76 genes or regions, with 96% of patients having at least one mutation and 86% having two or more mutations. However, nearly one-half of the cohort did not fall into one of the molecular groups defined by the World Health Organization in 2008.

“The characterization of many new leukemia genes, multiple driver mutations per patient, and complex co-mutation patterns prompted us to reevaluate genomic classification of AML from the beginning,” wrote Elli Papaemmanuil, Ph.D., a molecular geneticist at Memorial Sloan Kettering, New York, and of the Cancer Genome Project, Wellcome Trust Sanger Institute, and her colleagues (N Engl J Med. 2016 Jun 9; 374:2209-21).

The team developed a Bayesian statistical model to define 11 mutually exclusive subtypes based on patterns of co-mutations. The schema unambiguously classified 1,236 of 1,540 patients (80%) into a single subgroup and 56 (4%) into two or more groups. A subset of patients (166, 11%) remained unclassified, possibly due to mutations in genes not sequenced in the study.

NPM1-mutated AML was the largest class (27% of the cohort), followed by the chromatin-spliceosome group (18% of the cohort) that included mutations in genes regulating RNA splicing (SRSF2, SF3B1, U2AF1, and ZRSR2), chromatin (ASXL1, STAG2, BCOR, MLL^PTD, EZH2, and PHF6), or transcription (RUNX1). Another subgroup consisted of mutations in TP53, as well as complex karyotype alterations, cytogenetically visible copy-number alterations (aneuploidies), or a combination. While broader than previous classifications, such as “monosomal karyotype AML” and “complex karyotype AML,” this group emerged from correlated chromosomal abnormalities and was mutually exclusive of other class-defining lesions. In general, patients in this group were older and had fewer RAS pathway mutations.

The groups had considerable differences in clinical presentation and overall survival, according to the report. The TP53-aneuploidy subgroup had poor outcomes, as previously described. Patients in the chromatin-spliceosome group had lower rates of response to induction chemotherapy, higher relapse rates, and poorer long-term outcomes, compared with other groups. Most of these patients (84%) would be classified as intermediate risk under current guidelines, but the characteristics were more similar to those of subgroups with adverse outcomes.

Overall survival was correlated with the number of driver mutations, and deleterious affects of mutations often were found to be additive. In some cases, complex gene interactions accounted for variation in outcomes, suggesting the clinical effect of some driver mutations may depend on the occurrence of co-mutations in a wider genomic context.

The oral immunotherapy tasquinimod improved radiographic progression-free survival (rPFS) in men with metastatic castration-resistant prostate cancer (mCRPC), but the drug failed to improve overall survival (OS), according to results from a large, multinational phase III trial.

©alexdans/Thinkstock

Median rPFS was 7.0 months (95% CI, 5.8-8.2 months) for the tasquinimod group and 4.4 months (95% CI, 3.5-5.5 months) for placebo (HR, 0.64; 95% CI, 0.54-0.75; P less than .001). However, median OS was similar for the two groups: 21.3 months (19.5-23.0) for tasquinimod and 24.0 months (21.4-26.9) for placebo (HR, 1.10; 95% CI, 0.94 to 1.28; P = .25). At a median follow-up of 30 months, 96% of patients had discontinued treatment, most commonly because of progression (radiographic and symptomatic) and adverse events (J Clin Oncol. 2016 June 13. doi: 10.1200/JCO.2016.66.9697).

The 36% reduced risk of progression with tasquinimod versus placebo confirmed the phase II trial results, but the significant rPFS benefit did not translate to improved OS. The authors note that among one of several explanations for the lack of OS benefit is the availability of effective salvage therapies, many of which were not available during the phase II study.

“The current availability of such agents (e.g., abiraterone and enzalutamide) may have had an impact on the course of disease because patients in the placebo group gained access before those in the tasquinimod group on account of their earlier withdrawal from study treatment. Indeed, posttreatment use of abiraterone and enzalutamide was more common among patients in the placebo group,” wrote Dr. Cora Sternberg, chair of the department of medical oncology at San Camillo Forlanini Hospital, Italy, and colleagues.

The randomized, double-blind, placebo-controlled phase III study enrolled 1,245 patients from 241 sites in 37 countries. Patients with prostate adenocarcinoma with evidence of bone metastasis who had not received cytotoxic chemotherapy for 2 years were randomly assigned 2:1 to receive tasquinimod (n = 832) or placebo (n = 413).

Radiographic- and PSA-based secondary outcomes favored tasquinimod over placebo. By contrast, symptomatically assessed outcomes, such as time to symptomatic progression, time to opiate use, and deterioration of QoL, favored placebo. A greater proportion of the tasquinimod group discontinued treatment because of adverse events (17.7% vs. 10.2%), mainly decreased appetite, fatigue, asthenia, or nausea.

Tasquinimod affects the tumor microenvironment to counteract tumor growth. Preclinical evidence suggests it has an inhibitory effect on myeloid-derived suppressive cells and M2-polarized tumor-associated macrophages. Identification of immunologic biomarkers may help patient selection and determination of a rational combination strategy, according to the authors. Due to the lack of OS benefit, further clinical development of tasquinimod in this patient population was not pursued.

Dr. Sternberg reported having financial ties to Pfizer, Novartis, Janssen Pharmaceuticals, Sanofi, GlaxoSmithKline, Bristol-Myers Squibb, Bayer HealthCare Pharmaceuticals, Astellas Pharma, Eisai, Exelixis, Medivation, Active Biotech, and Genentech. Several of her coauthors reported ties to industry sources.

The oral immunotherapy tasquinimod improved radiographic progression-free survival (rPFS) in men with metastatic castration-resistant prostate cancer (mCRPC), but the drug failed to improve overall survival (OS), according to results from a large, multinational phase III trial.

©alexdans/Thinkstock

Median rPFS was 7.0 months (95% CI, 5.8-8.2 months) for the tasquinimod group and 4.4 months (95% CI, 3.5-5.5 months) for placebo (HR, 0.64; 95% CI, 0.54-0.75; P less than .001). However, median OS was similar for the two groups: 21.3 months (19.5-23.0) for tasquinimod and 24.0 months (21.4-26.9) for placebo (HR, 1.10; 95% CI, 0.94 to 1.28; P = .25). At a median follow-up of 30 months, 96% of patients had discontinued treatment, most commonly because of progression (radiographic and symptomatic) and adverse events (J Clin Oncol. 2016 June 13. doi: 10.1200/JCO.2016.66.9697).

The 36% reduced risk of progression with tasquinimod versus placebo confirmed the phase II trial results, but the significant rPFS benefit did not translate to improved OS. The authors note that among one of several explanations for the lack of OS benefit is the availability of effective salvage therapies, many of which were not available during the phase II study.

“The current availability of such agents (e.g., abiraterone and enzalutamide) may have had an impact on the course of disease because patients in the placebo group gained access before those in the tasquinimod group on account of their earlier withdrawal from study treatment. Indeed, posttreatment use of abiraterone and enzalutamide was more common among patients in the placebo group,” wrote Dr. Cora Sternberg, chair of the department of medical oncology at San Camillo Forlanini Hospital, Italy, and colleagues.

The randomized, double-blind, placebo-controlled phase III study enrolled 1,245 patients from 241 sites in 37 countries. Patients with prostate adenocarcinoma with evidence of bone metastasis who had not received cytotoxic chemotherapy for 2 years were randomly assigned 2:1 to receive tasquinimod (n = 832) or placebo (n = 413).

Radiographic- and PSA-based secondary outcomes favored tasquinimod over placebo. By contrast, symptomatically assessed outcomes, such as time to symptomatic progression, time to opiate use, and deterioration of QoL, favored placebo. A greater proportion of the tasquinimod group discontinued treatment because of adverse events (17.7% vs. 10.2%), mainly decreased appetite, fatigue, asthenia, or nausea.

Tasquinimod affects the tumor microenvironment to counteract tumor growth. Preclinical evidence suggests it has an inhibitory effect on myeloid-derived suppressive cells and M2-polarized tumor-associated macrophages. Identification of immunologic biomarkers may help patient selection and determination of a rational combination strategy, according to the authors. Due to the lack of OS benefit, further clinical development of tasquinimod in this patient population was not pursued.

Dr. Sternberg reported having financial ties to Pfizer, Novartis, Janssen Pharmaceuticals, Sanofi, GlaxoSmithKline, Bristol-Myers Squibb, Bayer HealthCare Pharmaceuticals, Astellas Pharma, Eisai, Exelixis, Medivation, Active Biotech, and Genentech. Several of her coauthors reported ties to industry sources.

The oral immunotherapy tasquinimod improved radiographic progression-free survival (rPFS) in men with metastatic castration-resistant prostate cancer (mCRPC), but the drug failed to improve overall survival (OS), according to results from a large, multinational phase III trial.

©alexdans/Thinkstock

Median rPFS was 7.0 months (95% CI, 5.8-8.2 months) for the tasquinimod group and 4.4 months (95% CI, 3.5-5.5 months) for placebo (HR, 0.64; 95% CI, 0.54-0.75; P less than .001). However, median OS was similar for the two groups: 21.3 months (19.5-23.0) for tasquinimod and 24.0 months (21.4-26.9) for placebo (HR, 1.10; 95% CI, 0.94 to 1.28; P = .25). At a median follow-up of 30 months, 96% of patients had discontinued treatment, most commonly because of progression (radiographic and symptomatic) and adverse events (J Clin Oncol. 2016 June 13. doi: 10.1200/JCO.2016.66.9697).

The 36% reduced risk of progression with tasquinimod versus placebo confirmed the phase II trial results, but the significant rPFS benefit did not translate to improved OS. The authors note that among one of several explanations for the lack of OS benefit is the availability of effective salvage therapies, many of which were not available during the phase II study.

“The current availability of such agents (e.g., abiraterone and enzalutamide) may have had an impact on the course of disease because patients in the placebo group gained access before those in the tasquinimod group on account of their earlier withdrawal from study treatment. Indeed, posttreatment use of abiraterone and enzalutamide was more common among patients in the placebo group,” wrote Dr. Cora Sternberg, chair of the department of medical oncology at San Camillo Forlanini Hospital, Italy, and colleagues.

The randomized, double-blind, placebo-controlled phase III study enrolled 1,245 patients from 241 sites in 37 countries. Patients with prostate adenocarcinoma with evidence of bone metastasis who had not received cytotoxic chemotherapy for 2 years were randomly assigned 2:1 to receive tasquinimod (n = 832) or placebo (n = 413).

Radiographic- and PSA-based secondary outcomes favored tasquinimod over placebo. By contrast, symptomatically assessed outcomes, such as time to symptomatic progression, time to opiate use, and deterioration of QoL, favored placebo. A greater proportion of the tasquinimod group discontinued treatment because of adverse events (17.7% vs. 10.2%), mainly decreased appetite, fatigue, asthenia, or nausea.

Tasquinimod affects the tumor microenvironment to counteract tumor growth. Preclinical evidence suggests it has an inhibitory effect on myeloid-derived suppressive cells and M2-polarized tumor-associated macrophages. Identification of immunologic biomarkers may help patient selection and determination of a rational combination strategy, according to the authors. Due to the lack of OS benefit, further clinical development of tasquinimod in this patient population was not pursued.

Dr. Sternberg reported having financial ties to Pfizer, Novartis, Janssen Pharmaceuticals, Sanofi, GlaxoSmithKline, Bristol-Myers Squibb, Bayer HealthCare Pharmaceuticals, Astellas Pharma, Eisai, Exelixis, Medivation, Active Biotech, and Genentech. Several of her coauthors reported ties to industry sources.

A single, baseline prostate-specific antigen (PSA) level measured at midlife predicted risk of lethal prostate cancer over a 30-year follow-up, according to a nested, case-control study among men who participated in the Physicians’ Health Study.

PSA levels at the 90th percentile and above, compared with levels at the median and lower, were associated with increased risk of lethal prostate cancer (PCa) across all age groups: for men aged 40-49 years, the odds ratio was 8.7 (95% confidence interval, 1.0-78.2), for 50-54 years, 12.6 (1.4-110.4), and for 55-59 years, 6.9 (2.5-19.1). PSA levels above the median were associated with increased risk of all PCa: odds ratios were 7.3 (95% CI, 2.4-21.8) for 40-49 years, 7.6 (3.4-17.2) for 50-54 years, and 10.1 (5.2-19.6) for 55-59 years.

“These data identify subgroups of men, on the basis of their PSA levels at a given age, with widely divergent lifetime risk of PCa death, who therefore could benefit from screening intervals tailored to their actual magnitude of risk,” wrote Dr. Mark Preston of Brigham and Women’s Hospital, Boston, and colleagues (J Clin Oncol. 2016 Jun 13. doi: 10.1200/JCO.2016.66.7527).

The investigators noted that one of seven men with PSA greater than 2.1 mg/mL at 55-59 years and one of 12 men with PSA greater than 2.1 ng/mL at 50-54 years died as a result of PCa within 30 years.

“These findings do not necessarily imply that prostate biopsy or definitive treatment is immediately required in younger men with higher PSA levels at baseline, because this could lead to overdiagnosis, but only that they undergo more intensive PSA screening to enable earlier identification of cancer and potential cure while still possible,” the investigators wrote.

As a subset of the Physicians’ Health Study, a randomized, placebo-controlled trial of aspirin and beta-carotene, 14,916 men aged 40-84 years provided a blood sample during 1982-1984. Total PSA was determined from stored specimens, and self-reported incident PCa cases from 1982 to 2012 were confirmed through medical records.

In answer to the question of whether a low PSA level at 40-49 years might safely exempt men from further screening, results showed that for PSA levels below the 25th percentile, cumulative incidence of lethal PCa at 30 years was 0.37% (0.05-1.70) for men 40-44 years and 0.97% (0.30-2.49) for men 45-49 years. Because a small risk remains even with an exceptionally low first measure, another PSA test during the lifetime of men 40-49 is prudent, according to the researchers. At age 60 years, men with PSA below the median are unlikely to develop lethal PCa, based on the analysis.

[email protected]

A single, baseline prostate-specific antigen (PSA) level measured at midlife predicted risk of lethal prostate cancer over a 30-year follow-up, according to a nested, case-control study among men who participated in the Physicians’ Health Study.

PSA levels at the 90th percentile and above, compared with levels at the median and lower, were associated with increased risk of lethal prostate cancer (PCa) across all age groups: for men aged 40-49 years, the odds ratio was 8.7 (95% confidence interval, 1.0-78.2), for 50-54 years, 12.6 (1.4-110.4), and for 55-59 years, 6.9 (2.5-19.1). PSA levels above the median were associated with increased risk of all PCa: odds ratios were 7.3 (95% CI, 2.4-21.8) for 40-49 years, 7.6 (3.4-17.2) for 50-54 years, and 10.1 (5.2-19.6) for 55-59 years.

“These data identify subgroups of men, on the basis of their PSA levels at a given age, with widely divergent lifetime risk of PCa death, who therefore could benefit from screening intervals tailored to their actual magnitude of risk,” wrote Dr. Mark Preston of Brigham and Women’s Hospital, Boston, and colleagues (J Clin Oncol. 2016 Jun 13. doi: 10.1200/JCO.2016.66.7527).

The investigators noted that one of seven men with PSA greater than 2.1 mg/mL at 55-59 years and one of 12 men with PSA greater than 2.1 ng/mL at 50-54 years died as a result of PCa within 30 years.

“These findings do not necessarily imply that prostate biopsy or definitive treatment is immediately required in younger men with higher PSA levels at baseline, because this could lead to overdiagnosis, but only that they undergo more intensive PSA screening to enable earlier identification of cancer and potential cure while still possible,” the investigators wrote.

As a subset of the Physicians’ Health Study, a randomized, placebo-controlled trial of aspirin and beta-carotene, 14,916 men aged 40-84 years provided a blood sample during 1982-1984. Total PSA was determined from stored specimens, and self-reported incident PCa cases from 1982 to 2012 were confirmed through medical records.

In answer to the question of whether a low PSA level at 40-49 years might safely exempt men from further screening, results showed that for PSA levels below the 25th percentile, cumulative incidence of lethal PCa at 30 years was 0.37% (0.05-1.70) for men 40-44 years and 0.97% (0.30-2.49) for men 45-49 years. Because a small risk remains even with an exceptionally low first measure, another PSA test during the lifetime of men 40-49 is prudent, according to the researchers. At age 60 years, men with PSA below the median are unlikely to develop lethal PCa, based on the analysis.

[email protected]

A single, baseline prostate-specific antigen (PSA) level measured at midlife predicted risk of lethal prostate cancer over a 30-year follow-up, according to a nested, case-control study among men who participated in the Physicians’ Health Study.

PSA levels at the 90th percentile and above, compared with levels at the median and lower, were associated with increased risk of lethal prostate cancer (PCa) across all age groups: for men aged 40-49 years, the odds ratio was 8.7 (95% confidence interval, 1.0-78.2), for 50-54 years, 12.6 (1.4-110.4), and for 55-59 years, 6.9 (2.5-19.1). PSA levels above the median were associated with increased risk of all PCa: odds ratios were 7.3 (95% CI, 2.4-21.8) for 40-49 years, 7.6 (3.4-17.2) for 50-54 years, and 10.1 (5.2-19.6) for 55-59 years.

“These data identify subgroups of men, on the basis of their PSA levels at a given age, with widely divergent lifetime risk of PCa death, who therefore could benefit from screening intervals tailored to their actual magnitude of risk,” wrote Dr. Mark Preston of Brigham and Women’s Hospital, Boston, and colleagues (J Clin Oncol. 2016 Jun 13. doi: 10.1200/JCO.2016.66.7527).

The investigators noted that one of seven men with PSA greater than 2.1 mg/mL at 55-59 years and one of 12 men with PSA greater than 2.1 ng/mL at 50-54 years died as a result of PCa within 30 years.

“These findings do not necessarily imply that prostate biopsy or definitive treatment is immediately required in younger men with higher PSA levels at baseline, because this could lead to overdiagnosis, but only that they undergo more intensive PSA screening to enable earlier identification of cancer and potential cure while still possible,” the investigators wrote.

As a subset of the Physicians’ Health Study, a randomized, placebo-controlled trial of aspirin and beta-carotene, 14,916 men aged 40-84 years provided a blood sample during 1982-1984. Total PSA was determined from stored specimens, and self-reported incident PCa cases from 1982 to 2012 were confirmed through medical records.

In answer to the question of whether a low PSA level at 40-49 years might safely exempt men from further screening, results showed that for PSA levels below the 25th percentile, cumulative incidence of lethal PCa at 30 years was 0.37% (0.05-1.70) for men 40-44 years and 0.97% (0.30-2.49) for men 45-49 years. Because a small risk remains even with an exceptionally low first measure, another PSA test during the lifetime of men 40-49 is prudent, according to the researchers. At age 60 years, men with PSA below the median are unlikely to develop lethal PCa, based on the analysis.

[email protected]

Patients with severe hemophilia A treated with plasma-derived factor VIII, as compared with recombinant factor VIII, had a lower risk of developing neutralizing antibodies, based on a recent report from the randomized SIPPET trial published in the New England Journal of Medicine.

In a second study, also published in the journal, prophylactic treatment with the bispecific antibody emicizumab decreased bleeding in patients with or without neutralizing antibodies.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

Of 125 patients with severe hemophilia A who were treated with plasma-derived factor VIII with von Willebrand factor, 29 (23.2%) developed inhibitors, compared with 47 of 126 patients (37.3%) treated with recombinant factor VIII. In the plasma-derived group, 20 (16.0%) had high-titer inhibitors compared with 30 (23.8%) in the recombinant group. Cox regression models showed an 87% higher rate of inhibitor development with recombinant factor VIII (hazard ratio, 1.87; 95% confidence interval, 1.17-2.96). For development of high-titer inhibitors, the HR was 1.69 (95% CI, 0.96-2.98).

Previous observational studies have suggested greater immunogenicity of recombinant vs. plasm-derived factor VIII, but the results remained inconclusive. Meta-analyses of studies have been hindered by differences in design, enrollment criteria, definition of hemophilia A, sample size, method of inhibitor detection, and intervals of follow-up testing, according to Dr. Flora Peyvandi of the IRCCS Maggiore Hospital, University of Milan and colleagues. “Our trial was specifically designed to compare the immunogenicity of factor VIII products. As a result of randomization, the main risk factors for inhibitor development were evenly distributed between the two factor VIII classes,” they wrote, adding, “The finding that native factor VIII products from human plasma are less immunogenic than those engineered by recombinant DNA technology in animal cell lines has the potential to affect treatment strategies and open new investigations to better understand the mechanisms of the immunogenicity of various factor VIII preparations.” (N Engl J Med. 2016 May 25. doi: 10.1200/JCO.2015.64.0730).

The Survey of Inhibitors in Plasma-Product Exposed Toddlers (SIPPET) clinical trial randomized 251 patients with severe hemophilia A who received infusions of plasma-derived or recombinant factor VIII. The investigators found no association between risk of inhibitor development and race, intensity of treatment, or age at first treatment.

The second study, a 12-week dose-escalation trial of emicizumab, included 18 patients with severe hemophilia A, aged 12-59 years. Patients were assigned to one of three cohorts and received a once-weekly subcutaneous dose of 0.3, 1, or 3 mg per kilogram of body weight. During prophylactic emicizumab treatment, median annualized bleeding rates decreased from 32.5 (range, 8.1-77.1) to 4.4 (0.0-59.5) in cohort 1, from 18.3 (range, 10.1-38.6) to 0.0 (range, 0.0-4.3) in cohort 2, and from 15.2 (range, 0.0-32.5) to 0.0 (range, 0.0-4.2) in cohort 3. The annualized bleeding rate decreased regardless of factor VIII inhibitor status. Of 11 patients with factor VIII inhibitors, 8 (73%) had no bleeding episodes; 5 of 7 patients without factor VIII inhibitors (71%) had no bleeding episodes.

“This study showed that once-weekly subcutaneous administration of emicizumab as prophylaxis is safe and has the potential to reduce or prevent bleeding episodes in patients who have severe hemophilia A with or without factor VIII inhibitors,” wrote Dr. Midori Shima of Nara Medical University, Kashihara, Japan, and colleagues (N. Engl J Med. 2016 May 25. doi: 10.1056/NEJMoa1511769).

Emicizumab had an acceptable safety profile. In total, 43 adverse events were reported in 15 of 18 patients. All were mild, except two moderate events – an upper respiratory tract infection and a headache. Events thought to be treatment related included malaise, injection-site erythema, injection-site rash, diarrhea, increased C-reactive protein level, and increased blood creatine kinase level.

Dr. Peyvandi and coauthors disclosed consulting, advising, research funding and other relationships with several industry sources, including Grifols, Kedrion, and LFB. Dr. Shima and coauthors disclosed consulting, advising, research funding and other relationships with several industry sources, including Chugai Pharmaceuticals, which supported the study.

Patients with severe hemophilia A treated with plasma-derived factor VIII, as compared with recombinant factor VIII, had a lower risk of developing neutralizing antibodies, based on a recent report from the randomized SIPPET trial published in the New England Journal of Medicine.

In a second study, also published in the journal, prophylactic treatment with the bispecific antibody emicizumab decreased bleeding in patients with or without neutralizing antibodies.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

Of 125 patients with severe hemophilia A who were treated with plasma-derived factor VIII with von Willebrand factor, 29 (23.2%) developed inhibitors, compared with 47 of 126 patients (37.3%) treated with recombinant factor VIII. In the plasma-derived group, 20 (16.0%) had high-titer inhibitors compared with 30 (23.8%) in the recombinant group. Cox regression models showed an 87% higher rate of inhibitor development with recombinant factor VIII (hazard ratio, 1.87; 95% confidence interval, 1.17-2.96). For development of high-titer inhibitors, the HR was 1.69 (95% CI, 0.96-2.98).

Previous observational studies have suggested greater immunogenicity of recombinant vs. plasm-derived factor VIII, but the results remained inconclusive. Meta-analyses of studies have been hindered by differences in design, enrollment criteria, definition of hemophilia A, sample size, method of inhibitor detection, and intervals of follow-up testing, according to Dr. Flora Peyvandi of the IRCCS Maggiore Hospital, University of Milan and colleagues. “Our trial was specifically designed to compare the immunogenicity of factor VIII products. As a result of randomization, the main risk factors for inhibitor development were evenly distributed between the two factor VIII classes,” they wrote, adding, “The finding that native factor VIII products from human plasma are less immunogenic than those engineered by recombinant DNA technology in animal cell lines has the potential to affect treatment strategies and open new investigations to better understand the mechanisms of the immunogenicity of various factor VIII preparations.” (N Engl J Med. 2016 May 25. doi: 10.1200/JCO.2015.64.0730).

The Survey of Inhibitors in Plasma-Product Exposed Toddlers (SIPPET) clinical trial randomized 251 patients with severe hemophilia A who received infusions of plasma-derived or recombinant factor VIII. The investigators found no association between risk of inhibitor development and race, intensity of treatment, or age at first treatment.

The second study, a 12-week dose-escalation trial of emicizumab, included 18 patients with severe hemophilia A, aged 12-59 years. Patients were assigned to one of three cohorts and received a once-weekly subcutaneous dose of 0.3, 1, or 3 mg per kilogram of body weight. During prophylactic emicizumab treatment, median annualized bleeding rates decreased from 32.5 (range, 8.1-77.1) to 4.4 (0.0-59.5) in cohort 1, from 18.3 (range, 10.1-38.6) to 0.0 (range, 0.0-4.3) in cohort 2, and from 15.2 (range, 0.0-32.5) to 0.0 (range, 0.0-4.2) in cohort 3. The annualized bleeding rate decreased regardless of factor VIII inhibitor status. Of 11 patients with factor VIII inhibitors, 8 (73%) had no bleeding episodes; 5 of 7 patients without factor VIII inhibitors (71%) had no bleeding episodes.

“This study showed that once-weekly subcutaneous administration of emicizumab as prophylaxis is safe and has the potential to reduce or prevent bleeding episodes in patients who have severe hemophilia A with or without factor VIII inhibitors,” wrote Dr. Midori Shima of Nara Medical University, Kashihara, Japan, and colleagues (N. Engl J Med. 2016 May 25. doi: 10.1056/NEJMoa1511769).

Emicizumab had an acceptable safety profile. In total, 43 adverse events were reported in 15 of 18 patients. All were mild, except two moderate events – an upper respiratory tract infection and a headache. Events thought to be treatment related included malaise, injection-site erythema, injection-site rash, diarrhea, increased C-reactive protein level, and increased blood creatine kinase level.

Dr. Peyvandi and coauthors disclosed consulting, advising, research funding and other relationships with several industry sources, including Grifols, Kedrion, and LFB. Dr. Shima and coauthors disclosed consulting, advising, research funding and other relationships with several industry sources, including Chugai Pharmaceuticals, which supported the study.

Patients with severe hemophilia A treated with plasma-derived factor VIII, as compared with recombinant factor VIII, had a lower risk of developing neutralizing antibodies, based on a recent report from the randomized SIPPET trial published in the New England Journal of Medicine.

In a second study, also published in the journal, prophylactic treatment with the bispecific antibody emicizumab decreased bleeding in patients with or without neutralizing antibodies.

Crystal/Wikimedia Commons/Creative Commons Attribution 2.0

Of 125 patients with severe hemophilia A who were treated with plasma-derived factor VIII with von Willebrand factor, 29 (23.2%) developed inhibitors, compared with 47 of 126 patients (37.3%) treated with recombinant factor VIII. In the plasma-derived group, 20 (16.0%) had high-titer inhibitors compared with 30 (23.8%) in the recombinant group. Cox regression models showed an 87% higher rate of inhibitor development with recombinant factor VIII (hazard ratio, 1.87; 95% confidence interval, 1.17-2.96). For development of high-titer inhibitors, the HR was 1.69 (95% CI, 0.96-2.98).

Previous observational studies have suggested greater immunogenicity of recombinant vs. plasm-derived factor VIII, but the results remained inconclusive. Meta-analyses of studies have been hindered by differences in design, enrollment criteria, definition of hemophilia A, sample size, method of inhibitor detection, and intervals of follow-up testing, according to Dr. Flora Peyvandi of the IRCCS Maggiore Hospital, University of Milan and colleagues. “Our trial was specifically designed to compare the immunogenicity of factor VIII products. As a result of randomization, the main risk factors for inhibitor development were evenly distributed between the two factor VIII classes,” they wrote, adding, “The finding that native factor VIII products from human plasma are less immunogenic than those engineered by recombinant DNA technology in animal cell lines has the potential to affect treatment strategies and open new investigations to better understand the mechanisms of the immunogenicity of various factor VIII preparations.” (N Engl J Med. 2016 May 25. doi: 10.1200/JCO.2015.64.0730).

The Survey of Inhibitors in Plasma-Product Exposed Toddlers (SIPPET) clinical trial randomized 251 patients with severe hemophilia A who received infusions of plasma-derived or recombinant factor VIII. The investigators found no association between risk of inhibitor development and race, intensity of treatment, or age at first treatment.

The second study, a 12-week dose-escalation trial of emicizumab, included 18 patients with severe hemophilia A, aged 12-59 years. Patients were assigned to one of three cohorts and received a once-weekly subcutaneous dose of 0.3, 1, or 3 mg per kilogram of body weight. During prophylactic emicizumab treatment, median annualized bleeding rates decreased from 32.5 (range, 8.1-77.1) to 4.4 (0.0-59.5) in cohort 1, from 18.3 (range, 10.1-38.6) to 0.0 (range, 0.0-4.3) in cohort 2, and from 15.2 (range, 0.0-32.5) to 0.0 (range, 0.0-4.2) in cohort 3. The annualized bleeding rate decreased regardless of factor VIII inhibitor status. Of 11 patients with factor VIII inhibitors, 8 (73%) had no bleeding episodes; 5 of 7 patients without factor VIII inhibitors (71%) had no bleeding episodes.

“This study showed that once-weekly subcutaneous administration of emicizumab as prophylaxis is safe and has the potential to reduce or prevent bleeding episodes in patients who have severe hemophilia A with or without factor VIII inhibitors,” wrote Dr. Midori Shima of Nara Medical University, Kashihara, Japan, and colleagues (N. Engl J Med. 2016 May 25. doi: 10.1056/NEJMoa1511769).

Emicizumab had an acceptable safety profile. In total, 43 adverse events were reported in 15 of 18 patients. All were mild, except two moderate events – an upper respiratory tract infection and a headache. Events thought to be treatment related included malaise, injection-site erythema, injection-site rash, diarrhea, increased C-reactive protein level, and increased blood creatine kinase level.

Dr. Peyvandi and coauthors disclosed consulting, advising, research funding and other relationships with several industry sources, including Grifols, Kedrion, and LFB. Dr. Shima and coauthors disclosed consulting, advising, research funding and other relationships with several industry sources, including Chugai Pharmaceuticals, which supported the study.

Using checklists and electronic decision support in an inpatient liver unit, quality improvement (QI) care protocols reduced 30-day readmissions of patients with cirrhosis by 40%, due mostly to a drop in readmissions for hepatic encephalopathy (HE) according to a report published in the May issue of Clinical Gastroenterology and Hepatology.

For patients initially admitted for overt HE, the 30-day readmission rate was 26.0% (27 of 104), compared with 48.9% (66 of 135) before implementation of QI. The proportion of total readmissions due to HE after QI was 9.6% (14 of 146), compared with 40.7% (79 of 194) before QI. In addition, length of stay for HE patients was significantly reduced (–1.34 days; 95% confidence interval, –2.38 to –0.32; P = .01). There were no significant changes in 90-day mortality.

Source: American Gastroenterological Association

“Our study advances the current literature on QI for patients with cirrhosis by presenting an inexpensive, easy to implement, and generalizable approach,” wrote Dr. Elliot Tapper of Beth Israel Deaconess Medical Center, Boston, and his colleagues. Previous studies have addressed readmission interventions among patients with cirrhosis, but the protocols required costly infrastructure, expertise, and institutional commitments. The current study supports the value of standard checklists and education, according to the investigators, “showing that outcomes improve further when checklist items are hard-wired into the ordering system.” (Clin Gastroenterol Hepatol. 2016 Apr 7. doi: 10.1016/j.cgh.2015.08.041).

The QI initiative encompassed several aspects of care. All HE patients were designated to receive rifaximin, and their lactulose dosing was adjusted to mental status using the Richmond Agitation and Sedation Scale. For patients with spontaneous bacterial peritonitis (SBP), timely administration of the correct dose of antibiotics and albumin was promoted, as were prophylactic measures for all patients, such as variceal hemorrhage prophylaxis and subcutaneous heparin for the prevention of venous thrombosis.

The three-part program entailed a run-in phase for preliminary checklist troubleshooting, a hand-held checklist phase, including the HE protocol, SBP treatment, and prophylactic measures, and a final electronic phase in which checklist items were incorporated into the hospital’s electronic provider order entry system using mandatory preset doses and linked medications.

Individual protocol items were demonstrated to affect the readmission rate. Rifaximin use for HE patients rose from 78.1% to 96.3%, and use of rifaximin was associated with lower adjusted odds of 30-day readmission (OR, 0.39; 95% CI, 0.16-0.87; P = .02). The dose/frequency of lactulose for HE patients increased, and patients who had 6 or more cups of lactulose on the day of their readmission had significantly lower adjusted length of stay (–2.36 days; 95% CI, –3.40 to –1.31; P less than .0001). Patients taking SBP prophylaxis had lower readmission rates (OR, 0.51; 95% CI, 0.31-0.83; P = .007).

The prospective study from 2011 to 2013 evaluated patients with cirrhosis who were admitted to the liver unit of Beth Israel Deaconess Medical Center, Boston. Patients were diagnosed with cirrhosis caused by hepatitis C (44.9%), alcoholic liver disease (34%), hepatitis B (5.4%), and biliary cirrhosis (1.8%). In total, 824 unique patients were admitted 1,720 times; 485 (58.9%) were admitted once, 268 (32.5%) were admitted 2-4 times, and 71 (8.6%) were admitted 5 or more times. The median length of stay for all patients was 4.0 days (interquartile range, 2.0-8.0).

Dr. Tapper and his coauthors reported having no disclosures.

Using checklists and electronic decision support in an inpatient liver unit, quality improvement (QI) care protocols reduced 30-day readmissions of patients with cirrhosis by 40%, due mostly to a drop in readmissions for hepatic encephalopathy (HE) according to a report published in the May issue of Clinical Gastroenterology and Hepatology.

For patients initially admitted for overt HE, the 30-day readmission rate was 26.0% (27 of 104), compared with 48.9% (66 of 135) before implementation of QI. The proportion of total readmissions due to HE after QI was 9.6% (14 of 146), compared with 40.7% (79 of 194) before QI. In addition, length of stay for HE patients was significantly reduced (–1.34 days; 95% confidence interval, –2.38 to –0.32; P = .01). There were no significant changes in 90-day mortality.

Source: American Gastroenterological Association

“Our study advances the current literature on QI for patients with cirrhosis by presenting an inexpensive, easy to implement, and generalizable approach,” wrote Dr. Elliot Tapper of Beth Israel Deaconess Medical Center, Boston, and his colleagues. Previous studies have addressed readmission interventions among patients with cirrhosis, but the protocols required costly infrastructure, expertise, and institutional commitments. The current study supports the value of standard checklists and education, according to the investigators, “showing that outcomes improve further when checklist items are hard-wired into the ordering system.” (Clin Gastroenterol Hepatol. 2016 Apr 7. doi: 10.1016/j.cgh.2015.08.041).

The QI initiative encompassed several aspects of care. All HE patients were designated to receive rifaximin, and their lactulose dosing was adjusted to mental status using the Richmond Agitation and Sedation Scale. For patients with spontaneous bacterial peritonitis (SBP), timely administration of the correct dose of antibiotics and albumin was promoted, as were prophylactic measures for all patients, such as variceal hemorrhage prophylaxis and subcutaneous heparin for the prevention of venous thrombosis.

The three-part program entailed a run-in phase for preliminary checklist troubleshooting, a hand-held checklist phase, including the HE protocol, SBP treatment, and prophylactic measures, and a final electronic phase in which checklist items were incorporated into the hospital’s electronic provider order entry system using mandatory preset doses and linked medications.

Individual protocol items were demonstrated to affect the readmission rate. Rifaximin use for HE patients rose from 78.1% to 96.3%, and use of rifaximin was associated with lower adjusted odds of 30-day readmission (OR, 0.39; 95% CI, 0.16-0.87; P = .02). The dose/frequency of lactulose for HE patients increased, and patients who had 6 or more cups of lactulose on the day of their readmission had significantly lower adjusted length of stay (–2.36 days; 95% CI, –3.40 to –1.31; P less than .0001). Patients taking SBP prophylaxis had lower readmission rates (OR, 0.51; 95% CI, 0.31-0.83; P = .007).

The prospective study from 2011 to 2013 evaluated patients with cirrhosis who were admitted to the liver unit of Beth Israel Deaconess Medical Center, Boston. Patients were diagnosed with cirrhosis caused by hepatitis C (44.9%), alcoholic liver disease (34%), hepatitis B (5.4%), and biliary cirrhosis (1.8%). In total, 824 unique patients were admitted 1,720 times; 485 (58.9%) were admitted once, 268 (32.5%) were admitted 2-4 times, and 71 (8.6%) were admitted 5 or more times. The median length of stay for all patients was 4.0 days (interquartile range, 2.0-8.0).

Dr. Tapper and his coauthors reported having no disclosures.

Using checklists and electronic decision support in an inpatient liver unit, quality improvement (QI) care protocols reduced 30-day readmissions of patients with cirrhosis by 40%, due mostly to a drop in readmissions for hepatic encephalopathy (HE) according to a report published in the May issue of Clinical Gastroenterology and Hepatology.

For patients initially admitted for overt HE, the 30-day readmission rate was 26.0% (27 of 104), compared with 48.9% (66 of 135) before implementation of QI. The proportion of total readmissions due to HE after QI was 9.6% (14 of 146), compared with 40.7% (79 of 194) before QI. In addition, length of stay for HE patients was significantly reduced (–1.34 days; 95% confidence interval, –2.38 to –0.32; P = .01). There were no significant changes in 90-day mortality.

Source: American Gastroenterological Association

“Our study advances the current literature on QI for patients with cirrhosis by presenting an inexpensive, easy to implement, and generalizable approach,” wrote Dr. Elliot Tapper of Beth Israel Deaconess Medical Center, Boston, and his colleagues. Previous studies have addressed readmission interventions among patients with cirrhosis, but the protocols required costly infrastructure, expertise, and institutional commitments. The current study supports the value of standard checklists and education, according to the investigators, “showing that outcomes improve further when checklist items are hard-wired into the ordering system.” (Clin Gastroenterol Hepatol. 2016 Apr 7. doi: 10.1016/j.cgh.2015.08.041).

The QI initiative encompassed several aspects of care. All HE patients were designated to receive rifaximin, and their lactulose dosing was adjusted to mental status using the Richmond Agitation and Sedation Scale. For patients with spontaneous bacterial peritonitis (SBP), timely administration of the correct dose of antibiotics and albumin was promoted, as were prophylactic measures for all patients, such as variceal hemorrhage prophylaxis and subcutaneous heparin for the prevention of venous thrombosis.

The three-part program entailed a run-in phase for preliminary checklist troubleshooting, a hand-held checklist phase, including the HE protocol, SBP treatment, and prophylactic measures, and a final electronic phase in which checklist items were incorporated into the hospital’s electronic provider order entry system using mandatory preset doses and linked medications.

Individual protocol items were demonstrated to affect the readmission rate. Rifaximin use for HE patients rose from 78.1% to 96.3%, and use of rifaximin was associated with lower adjusted odds of 30-day readmission (OR, 0.39; 95% CI, 0.16-0.87; P = .02). The dose/frequency of lactulose for HE patients increased, and patients who had 6 or more cups of lactulose on the day of their readmission had significantly lower adjusted length of stay (–2.36 days; 95% CI, –3.40 to –1.31; P less than .0001). Patients taking SBP prophylaxis had lower readmission rates (OR, 0.51; 95% CI, 0.31-0.83; P = .007).

The prospective study from 2011 to 2013 evaluated patients with cirrhosis who were admitted to the liver unit of Beth Israel Deaconess Medical Center, Boston. Patients were diagnosed with cirrhosis caused by hepatitis C (44.9%), alcoholic liver disease (34%), hepatitis B (5.4%), and biliary cirrhosis (1.8%). In total, 824 unique patients were admitted 1,720 times; 485 (58.9%) were admitted once, 268 (32.5%) were admitted 2-4 times, and 71 (8.6%) were admitted 5 or more times. The median length of stay for all patients was 4.0 days (interquartile range, 2.0-8.0).

Dr. Tapper and his coauthors reported having no disclosures.

Among a large cohort of patients referred for endoscopy for suspected celiac disease as well as all upper gastrointestinal symptoms, a single additional D1 biopsy specimen from any site significantly increased the diagnostic yield for celiac disease, according to researchers.

Of 1,378 patients who had D2 and D1 biopsy specimens taken, 268 were newly diagnosed with celiac disease, and 26 had villous atrophy confined to D1, defined as ultrashort celiac disease (USCD). Compared with a standard D2 biopsy, an additional D1 biopsy increased the diagnostic yield by 9.7% (P less than .0001). Among the 26 diagnosed with USCD, 7 had normal D2 biopsy specimens, and 4 others had negative tests for endomysial antibodies (EMAs), totaling 11 patients for whom celiac disease would have been missed in the absence of a D1 biopsy.

“The addition of a D1 biopsy specimen to diagnose celiac disease may reduce the known delay in diagnosis that many patients with celiac disease experience. This may allow earlier institution of a gluten-free diet, potentially prevent nutritional deficiencies, and reduce the symptomatic burden of celiac disease,” wrote Dr. Peter Mooney of Royal Hallamshire Hospital, Sheffield, England, and his colleagues. (Gastroenterology 2016 April 7. doi: 10.1053/j-gastro.2016.01.029).

The prospective study recruited 1,378 consecutive patients referred to a single teaching hospital for endoscopy from 2008 to 2014. In total, 268 were newly diagnosed with celiac disease, and 26 were diagnosed with USCD.

To investigate the optimal site for targeted D1 sampling, 171 patients underwent quadrantic D1 biopsy, 61 of whom were diagnosed with celiac disease. Biopsy specimens from any topographical area resulted in high sensitivity, a fact that increases the feasibility of a D1 biopsy policy, since no specific target area is required, according to the researchers. Nonceliac abnormalities such as peptic duodenitis or gastric heterotopia have been suggested to impede interpretation of D1 biopsies, but these were rare in the study and did not interfere with the analysis.

USCD may be an early form of conventional celiac disease, an idea supported by the findings. Compared with patients diagnosed with conventional celiac disease, patients diagnosed with USCD were younger and had a much lower rate of diarrhea, which by decision-tree analysis was the single factor discriminating between the two groups. Compared with healthy controls, individuals with conventional celiac disease, but not USCD, were more likely to present with anemia, diarrhea, a family history of celiac disease, lethargy, and osteoporosis. Patients with USCD and conventional disease had similar rates of IgA tissue transglutaminase antibodies (tTG), but USCD patients had lower titers (P less than .001). The USCD group also had fewer ferritin and folate deficiencies.

The researchers suggested that clinical phenotypic differences may be due to minimal loss of absorptive capacity associated with a short segment of villous atrophy. Given the younger average age at diagnosis of USCD and lower tTG titers, USCD may represent an early stage of celiac disease, resulting in fewer nutritional deficiencies observed because of a shorter lead time to diagnosis.

Although USCD patients had a milder clinical phenotype, which has raised concerns that a strict gluten-free diet may be unnecessary, follow-up data demonstrated that a gluten-free diet produced improvement in symptoms and a significant decrease in the tTG titer. These results may indicate that the immune cascade was switched off, according to the researchers, and that early diagnosis may present a unique opportunity to prevent further micronutrient deficiency.

Dr. Mooney and his coauthors reported having no relevant financial disclosures.

Among a large cohort of patients referred for endoscopy for suspected celiac disease as well as all upper gastrointestinal symptoms, a single additional D1 biopsy specimen from any site significantly increased the diagnostic yield for celiac disease, according to researchers.

Of 1,378 patients who had D2 and D1 biopsy specimens taken, 268 were newly diagnosed with celiac disease, and 26 had villous atrophy confined to D1, defined as ultrashort celiac disease (USCD). Compared with a standard D2 biopsy, an additional D1 biopsy increased the diagnostic yield by 9.7% (P less than .0001). Among the 26 diagnosed with USCD, 7 had normal D2 biopsy specimens, and 4 others had negative tests for endomysial antibodies (EMAs), totaling 11 patients for whom celiac disease would have been missed in the absence of a D1 biopsy.

“The addition of a D1 biopsy specimen to diagnose celiac disease may reduce the known delay in diagnosis that many patients with celiac disease experience. This may allow earlier institution of a gluten-free diet, potentially prevent nutritional deficiencies, and reduce the symptomatic burden of celiac disease,” wrote Dr. Peter Mooney of Royal Hallamshire Hospital, Sheffield, England, and his colleagues. (Gastroenterology 2016 April 7. doi: 10.1053/j-gastro.2016.01.029).

The prospective study recruited 1,378 consecutive patients referred to a single teaching hospital for endoscopy from 2008 to 2014. In total, 268 were newly diagnosed with celiac disease, and 26 were diagnosed with USCD.

To investigate the optimal site for targeted D1 sampling, 171 patients underwent quadrantic D1 biopsy, 61 of whom were diagnosed with celiac disease. Biopsy specimens from any topographical area resulted in high sensitivity, a fact that increases the feasibility of a D1 biopsy policy, since no specific target area is required, according to the researchers. Nonceliac abnormalities such as peptic duodenitis or gastric heterotopia have been suggested to impede interpretation of D1 biopsies, but these were rare in the study and did not interfere with the analysis.

USCD may be an early form of conventional celiac disease, an idea supported by the findings. Compared with patients diagnosed with conventional celiac disease, patients diagnosed with USCD were younger and had a much lower rate of diarrhea, which by decision-tree analysis was the single factor discriminating between the two groups. Compared with healthy controls, individuals with conventional celiac disease, but not USCD, were more likely to present with anemia, diarrhea, a family history of celiac disease, lethargy, and osteoporosis. Patients with USCD and conventional disease had similar rates of IgA tissue transglutaminase antibodies (tTG), but USCD patients had lower titers (P less than .001). The USCD group also had fewer ferritin and folate deficiencies.

The researchers suggested that clinical phenotypic differences may be due to minimal loss of absorptive capacity associated with a short segment of villous atrophy. Given the younger average age at diagnosis of USCD and lower tTG titers, USCD may represent an early stage of celiac disease, resulting in fewer nutritional deficiencies observed because of a shorter lead time to diagnosis.

Although USCD patients had a milder clinical phenotype, which has raised concerns that a strict gluten-free diet may be unnecessary, follow-up data demonstrated that a gluten-free diet produced improvement in symptoms and a significant decrease in the tTG titer. These results may indicate that the immune cascade was switched off, according to the researchers, and that early diagnosis may present a unique opportunity to prevent further micronutrient deficiency.

Dr. Mooney and his coauthors reported having no relevant financial disclosures.

Among a large cohort of patients referred for endoscopy for suspected celiac disease as well as all upper gastrointestinal symptoms, a single additional D1 biopsy specimen from any site significantly increased the diagnostic yield for celiac disease, according to researchers.

Of 1,378 patients who had D2 and D1 biopsy specimens taken, 268 were newly diagnosed with celiac disease, and 26 had villous atrophy confined to D1, defined as ultrashort celiac disease (USCD). Compared with a standard D2 biopsy, an additional D1 biopsy increased the diagnostic yield by 9.7% (P less than .0001). Among the 26 diagnosed with USCD, 7 had normal D2 biopsy specimens, and 4 others had negative tests for endomysial antibodies (EMAs), totaling 11 patients for whom celiac disease would have been missed in the absence of a D1 biopsy.

“The addition of a D1 biopsy specimen to diagnose celiac disease may reduce the known delay in diagnosis that many patients with celiac disease experience. This may allow earlier institution of a gluten-free diet, potentially prevent nutritional deficiencies, and reduce the symptomatic burden of celiac disease,” wrote Dr. Peter Mooney of Royal Hallamshire Hospital, Sheffield, England, and his colleagues. (Gastroenterology 2016 April 7. doi: 10.1053/j-gastro.2016.01.029).

The prospective study recruited 1,378 consecutive patients referred to a single teaching hospital for endoscopy from 2008 to 2014. In total, 268 were newly diagnosed with celiac disease, and 26 were diagnosed with USCD.

To investigate the optimal site for targeted D1 sampling, 171 patients underwent quadrantic D1 biopsy, 61 of whom were diagnosed with celiac disease. Biopsy specimens from any topographical area resulted in high sensitivity, a fact that increases the feasibility of a D1 biopsy policy, since no specific target area is required, according to the researchers. Nonceliac abnormalities such as peptic duodenitis or gastric heterotopia have been suggested to impede interpretation of D1 biopsies, but these were rare in the study and did not interfere with the analysis.

USCD may be an early form of conventional celiac disease, an idea supported by the findings. Compared with patients diagnosed with conventional celiac disease, patients diagnosed with USCD were younger and had a much lower rate of diarrhea, which by decision-tree analysis was the single factor discriminating between the two groups. Compared with healthy controls, individuals with conventional celiac disease, but not USCD, were more likely to present with anemia, diarrhea, a family history of celiac disease, lethargy, and osteoporosis. Patients with USCD and conventional disease had similar rates of IgA tissue transglutaminase antibodies (tTG), but USCD patients had lower titers (P less than .001). The USCD group also had fewer ferritin and folate deficiencies.

The researchers suggested that clinical phenotypic differences may be due to minimal loss of absorptive capacity associated with a short segment of villous atrophy. Given the younger average age at diagnosis of USCD and lower tTG titers, USCD may represent an early stage of celiac disease, resulting in fewer nutritional deficiencies observed because of a shorter lead time to diagnosis.

Although USCD patients had a milder clinical phenotype, which has raised concerns that a strict gluten-free diet may be unnecessary, follow-up data demonstrated that a gluten-free diet produced improvement in symptoms and a significant decrease in the tTG titer. These results may indicate that the immune cascade was switched off, according to the researchers, and that early diagnosis may present a unique opportunity to prevent further micronutrient deficiency.

Dr. Mooney and his coauthors reported having no relevant financial disclosures.

Although black patients with colon cancer received significantly less treatment than white patients, particularly for late stage disease, much of the overall survival disparity between black and white patients was explained by tumor presentation at diagnosis rather than treatment differences, according to an analysis of SEER data.

Among demographically matched black and white patients, the 5-year survival difference was 8.3% (P less than .0001). Presentation match reduced the difference to 5.0% (P less than .0001), which accounted for 39.8% of the overall disparity. Additional matching by treatment reduced the difference only slightly to 4.9% (P less than .0001), which accounted for 1.2% of the overall disparity. Black patients had lower rates for most treatments, including surgery, than presentation-matched white patients (88.5% vs. 91.4%), and these differences were most pronounced at advanced stages. For example, significant differences between black and white patients in the use of chemotherapy was observed for stage III (53.1% vs. 64.2%; P less than .0001) and stage IV (56.1% vs. 63.3%; P = .001).

Courtesy Wikimedia Commons/Nephron/Creative Commons License

“Our results indicate that tumor presentation, including tumor stage, is indeed one of the most important factors contributing to the racial disparity in colon cancer survival. We observed that, after controlling for demographic factors, black patients in comparison with white patients had a significantly higher proportion of stage IV and lower proportions of stages I and II disease. Adequately matching on tumor presentation variables (e.g., stage, grade, size, and comorbidity) significantly reduced survival disparities,” wrote Dr. Yinzhi Lai of the Department of Medical Oncology at Sidney Kimmel Cancer Center, Philadelphia, and colleagues (Gastroenterology. 2016 Apr 4. doi: 10.1053/j.gastro.2016.01.030).

Treatment differences in advanced-stage patients, compared with early-stage patients, explained a higher proportion of the demographic-matched survival disparity. For example, in stage II patients, treatment match resulted in modest reductions in 2-, 3-, and 5-year survival rate disparities (2.7%-2.8%, 4.1%-3.6%, and 4.6%-4.0%, respectively); by contrast, in stage III patients, treatment match resulted in more substantial reductions in 2-, 3-, and 5-year survival rate disparities (4.5%-2.2%, 3.1%-2.0%, and 4.3%-2.8%, respectively). A similar effect was observed in patients with stage IV disease. The results suggest that, “to control survival disparity, more efforts may need to be tailored to minimize treatment disparities (especially chemotherapy use) in patients with advanced-stage disease,” the investigators wrote.

The retrospective data analysis used patient information from 68,141 patients (6,190 black, 61,951 white) aged 66 years and older with colon cancer identified from the National Cancer Institute SEER-Medicare database. Using a novel minimum distance matching strategy, investigators drew from the pool of white patients to match three distinct comparison cohorts to the same 6,190 black patients. Close matches between black and white patients bypassed the need for model-based analysis.

The primary matching analysis was limited by the inability to control for substantial differences in socioeconomic status, marital status, and urban/rural residence. A subcohort analysis of 2,000 matched black and white patients showed that when socioeconomic status was added to the demographic match, survival differences were reduced, indicating the important role of socioeconomic status on racial survival disparities.

Significantly better survival was observed in all patients who were diagnosed in 2004 or later, the year the Food and Drug Administration approved the important chemotherapy medicines oxaliplatin and bevacizumab. Separating the cohorts into those who were diagnosed before and after 2004 revealed that the racial survival disparity was lower in the more recent group, indicating a favorable impact of oxaliplatin and/or bevacizumab in reducing the survival disparity.

Although black patients with colon cancer received significantly less treatment than white patients, particularly for late stage disease, much of the overall survival disparity between black and white patients was explained by tumor presentation at diagnosis rather than treatment differences, according to an analysis of SEER data.

Among demographically matched black and white patients, the 5-year survival difference was 8.3% (P less than .0001). Presentation match reduced the difference to 5.0% (P less than .0001), which accounted for 39.8% of the overall disparity. Additional matching by treatment reduced the difference only slightly to 4.9% (P less than .0001), which accounted for 1.2% of the overall disparity. Black patients had lower rates for most treatments, including surgery, than presentation-matched white patients (88.5% vs. 91.4%), and these differences were most pronounced at advanced stages. For example, significant differences between black and white patients in the use of chemotherapy was observed for stage III (53.1% vs. 64.2%; P less than .0001) and stage IV (56.1% vs. 63.3%; P = .001).

Courtesy Wikimedia Commons/Nephron/Creative Commons License

“Our results indicate that tumor presentation, including tumor stage, is indeed one of the most important factors contributing to the racial disparity in colon cancer survival. We observed that, after controlling for demographic factors, black patients in comparison with white patients had a significantly higher proportion of stage IV and lower proportions of stages I and II disease. Adequately matching on tumor presentation variables (e.g., stage, grade, size, and comorbidity) significantly reduced survival disparities,” wrote Dr. Yinzhi Lai of the Department of Medical Oncology at Sidney Kimmel Cancer Center, Philadelphia, and colleagues (Gastroenterology. 2016 Apr 4. doi: 10.1053/j.gastro.2016.01.030).

Treatment differences in advanced-stage patients, compared with early-stage patients, explained a higher proportion of the demographic-matched survival disparity. For example, in stage II patients, treatment match resulted in modest reductions in 2-, 3-, and 5-year survival rate disparities (2.7%-2.8%, 4.1%-3.6%, and 4.6%-4.0%, respectively); by contrast, in stage III patients, treatment match resulted in more substantial reductions in 2-, 3-, and 5-year survival rate disparities (4.5%-2.2%, 3.1%-2.0%, and 4.3%-2.8%, respectively). A similar effect was observed in patients with stage IV disease. The results suggest that, “to control survival disparity, more efforts may need to be tailored to minimize treatment disparities (especially chemotherapy use) in patients with advanced-stage disease,” the investigators wrote.

The retrospective data analysis used patient information from 68,141 patients (6,190 black, 61,951 white) aged 66 years and older with colon cancer identified from the National Cancer Institute SEER-Medicare database. Using a novel minimum distance matching strategy, investigators drew from the pool of white patients to match three distinct comparison cohorts to the same 6,190 black patients. Close matches between black and white patients bypassed the need for model-based analysis.

The primary matching analysis was limited by the inability to control for substantial differences in socioeconomic status, marital status, and urban/rural residence. A subcohort analysis of 2,000 matched black and white patients showed that when socioeconomic status was added to the demographic match, survival differences were reduced, indicating the important role of socioeconomic status on racial survival disparities.

Significantly better survival was observed in all patients who were diagnosed in 2004 or later, the year the Food and Drug Administration approved the important chemotherapy medicines oxaliplatin and bevacizumab. Separating the cohorts into those who were diagnosed before and after 2004 revealed that the racial survival disparity was lower in the more recent group, indicating a favorable impact of oxaliplatin and/or bevacizumab in reducing the survival disparity.

Although black patients with colon cancer received significantly less treatment than white patients, particularly for late stage disease, much of the overall survival disparity between black and white patients was explained by tumor presentation at diagnosis rather than treatment differences, according to an analysis of SEER data.

Among demographically matched black and white patients, the 5-year survival difference was 8.3% (P less than .0001). Presentation match reduced the difference to 5.0% (P less than .0001), which accounted for 39.8% of the overall disparity. Additional matching by treatment reduced the difference only slightly to 4.9% (P less than .0001), which accounted for 1.2% of the overall disparity. Black patients had lower rates for most treatments, including surgery, than presentation-matched white patients (88.5% vs. 91.4%), and these differences were most pronounced at advanced stages. For example, significant differences between black and white patients in the use of chemotherapy was observed for stage III (53.1% vs. 64.2%; P less than .0001) and stage IV (56.1% vs. 63.3%; P = .001).

Courtesy Wikimedia Commons/Nephron/Creative Commons License

“Our results indicate that tumor presentation, including tumor stage, is indeed one of the most important factors contributing to the racial disparity in colon cancer survival. We observed that, after controlling for demographic factors, black patients in comparison with white patients had a significantly higher proportion of stage IV and lower proportions of stages I and II disease. Adequately matching on tumor presentation variables (e.g., stage, grade, size, and comorbidity) significantly reduced survival disparities,” wrote Dr. Yinzhi Lai of the Department of Medical Oncology at Sidney Kimmel Cancer Center, Philadelphia, and colleagues (Gastroenterology. 2016 Apr 4. doi: 10.1053/j.gastro.2016.01.030).

Treatment differences in advanced-stage patients, compared with early-stage patients, explained a higher proportion of the demographic-matched survival disparity. For example, in stage II patients, treatment match resulted in modest reductions in 2-, 3-, and 5-year survival rate disparities (2.7%-2.8%, 4.1%-3.6%, and 4.6%-4.0%, respectively); by contrast, in stage III patients, treatment match resulted in more substantial reductions in 2-, 3-, and 5-year survival rate disparities (4.5%-2.2%, 3.1%-2.0%, and 4.3%-2.8%, respectively). A similar effect was observed in patients with stage IV disease. The results suggest that, “to control survival disparity, more efforts may need to be tailored to minimize treatment disparities (especially chemotherapy use) in patients with advanced-stage disease,” the investigators wrote.

The retrospective data analysis used patient information from 68,141 patients (6,190 black, 61,951 white) aged 66 years and older with colon cancer identified from the National Cancer Institute SEER-Medicare database. Using a novel minimum distance matching strategy, investigators drew from the pool of white patients to match three distinct comparison cohorts to the same 6,190 black patients. Close matches between black and white patients bypassed the need for model-based analysis.

The primary matching analysis was limited by the inability to control for substantial differences in socioeconomic status, marital status, and urban/rural residence. A subcohort analysis of 2,000 matched black and white patients showed that when socioeconomic status was added to the demographic match, survival differences were reduced, indicating the important role of socioeconomic status on racial survival disparities.

Significantly better survival was observed in all patients who were diagnosed in 2004 or later, the year the Food and Drug Administration approved the important chemotherapy medicines oxaliplatin and bevacizumab. Separating the cohorts into those who were diagnosed before and after 2004 revealed that the racial survival disparity was lower in the more recent group, indicating a favorable impact of oxaliplatin and/or bevacizumab in reducing the survival disparity.

Surveillance of CDNK2A mutation carriers detected most pancreatic ductal carcinoma in situ (PDAC) at a resectable stage, while the surveillance benefit was lower for those with familial prostate cancer.

Among 178 CDKN2A mutation carriers, PDAC was detected in 13 (7.3%), 9 of whom underwent surgery. Compared with previously reported rates of 15%-20% for symptomatic PDAC, this 70% resection rate represents a substantial increase. The 5-year survival rate of 24% for screen-detected PDAC was higher than 4%-7% reported for symptomatic sporadic PDAC. Among individuals with familial prostate cancer (FPC), 13 of 214 individuals (6.1%) underwent surgery, but with a higher proportion of precursor lesions detected, just four high-risk lesions (1.9% of screened FPC patients) were removed.

Whether surveillance improved prognosis for FPC families was difficult to determine, according to the investigators. The yield of PDAC was low at 0.9%, as was the yield of relevant precursor lesions (grade 3 PanIN and high-grade IPMN) at 1.9%.

“However, if surgical removal of multifocal grade 2 PanIN and multifocal BD-IPMNs is regarded as beneficial, the diagnostic yield increases to 3.7% (eight of 214 patients), and surveillance of FPC might also be considered effective,” wrote Dr. Hans Vasen, professor in the department of gastroenterology and hepatology at the Leiden University Medical Center, the Netherlands, and colleagues. “The value of surveillance of FPC is still not clear, and the main effect seems to be prevention of PDAC by removal of” precursor lesions, they added (J Clin Oncol. 2016 Apr 25. doi: 10.1200/JCO.2015.64.0730).

The retrospective evaluation of an ongoing prospective follow-up study included 411 high-risk individuals: 178 with CDKN2A mutations, 214 with familial pancreatic cancer, and 19 with BRCA1/2 or PALB2 mutations. The study was conducted at three expert centers in Marburg, Germany; Leiden, the Netherlands; and Madrid.

In the BRCA1/2 and PALB2 mutation cohort, one individual (3.8%) with a BRCA2 mutation developed PDAC and underwent surgery; 17 months after the surgery this patient died of liver metastasis. Two others underwent surgery for cystic lesions and are in good health at 10 and 21 months after surgery.

In the cohort of CDKN2A mutation carriers, the mean age at the start of surveillance was 56 years (range, 37-75) and the mean follow-up time was 53 months (range, 0-169): in total, 866 MRIs and 106 endoscopic ultrasounds were conducted. In the FPC group, the mean age was 48 years (range, 27-81), and the mean follow up was 2.8 years (range, 0-10.8): 618 MRIs and 402 endoscopic ultrasounds were conducted. Among BRCA1/2 and PALB2 mutation carriers, the mean age was 52.6 years (range, 25-70), and the mean follow up was 32.7 months (range, 1-119).

Surveillance of CDNK2A mutation carriers detected most pancreatic ductal carcinoma in situ (PDAC) at a resectable stage, while the surveillance benefit was lower for those with familial prostate cancer.

Among 178 CDKN2A mutation carriers, PDAC was detected in 13 (7.3%), 9 of whom underwent surgery. Compared with previously reported rates of 15%-20% for symptomatic PDAC, this 70% resection rate represents a substantial increase. The 5-year survival rate of 24% for screen-detected PDAC was higher than 4%-7% reported for symptomatic sporadic PDAC. Among individuals with familial prostate cancer (FPC), 13 of 214 individuals (6.1%) underwent surgery, but with a higher proportion of precursor lesions detected, just four high-risk lesions (1.9% of screened FPC patients) were removed.

Whether surveillance improved prognosis for FPC families was difficult to determine, according to the investigators. The yield of PDAC was low at 0.9%, as was the yield of relevant precursor lesions (grade 3 PanIN and high-grade IPMN) at 1.9%.

“However, if surgical removal of multifocal grade 2 PanIN and multifocal BD-IPMNs is regarded as beneficial, the diagnostic yield increases to 3.7% (eight of 214 patients), and surveillance of FPC might also be considered effective,” wrote Dr. Hans Vasen, professor in the department of gastroenterology and hepatology at the Leiden University Medical Center, the Netherlands, and colleagues. “The value of surveillance of FPC is still not clear, and the main effect seems to be prevention of PDAC by removal of” precursor lesions, they added (J Clin Oncol. 2016 Apr 25. doi: 10.1200/JCO.2015.64.0730).

The retrospective evaluation of an ongoing prospective follow-up study included 411 high-risk individuals: 178 with CDKN2A mutations, 214 with familial pancreatic cancer, and 19 with BRCA1/2 or PALB2 mutations. The study was conducted at three expert centers in Marburg, Germany; Leiden, the Netherlands; and Madrid.

In the BRCA1/2 and PALB2 mutation cohort, one individual (3.8%) with a BRCA2 mutation developed PDAC and underwent surgery; 17 months after the surgery this patient died of liver metastasis. Two others underwent surgery for cystic lesions and are in good health at 10 and 21 months after surgery.

In the cohort of CDKN2A mutation carriers, the mean age at the start of surveillance was 56 years (range, 37-75) and the mean follow-up time was 53 months (range, 0-169): in total, 866 MRIs and 106 endoscopic ultrasounds were conducted. In the FPC group, the mean age was 48 years (range, 27-81), and the mean follow up was 2.8 years (range, 0-10.8): 618 MRIs and 402 endoscopic ultrasounds were conducted. Among BRCA1/2 and PALB2 mutation carriers, the mean age was 52.6 years (range, 25-70), and the mean follow up was 32.7 months (range, 1-119).

Surveillance of CDNK2A mutation carriers detected most pancreatic ductal carcinoma in situ (PDAC) at a resectable stage, while the surveillance benefit was lower for those with familial prostate cancer.

Among 178 CDKN2A mutation carriers, PDAC was detected in 13 (7.3%), 9 of whom underwent surgery. Compared with previously reported rates of 15%-20% for symptomatic PDAC, this 70% resection rate represents a substantial increase. The 5-year survival rate of 24% for screen-detected PDAC was higher than 4%-7% reported for symptomatic sporadic PDAC. Among individuals with familial prostate cancer (FPC), 13 of 214 individuals (6.1%) underwent surgery, but with a higher proportion of precursor lesions detected, just four high-risk lesions (1.9% of screened FPC patients) were removed.

Whether surveillance improved prognosis for FPC families was difficult to determine, according to the investigators. The yield of PDAC was low at 0.9%, as was the yield of relevant precursor lesions (grade 3 PanIN and high-grade IPMN) at 1.9%.

“However, if surgical removal of multifocal grade 2 PanIN and multifocal BD-IPMNs is regarded as beneficial, the diagnostic yield increases to 3.7% (eight of 214 patients), and surveillance of FPC might also be considered effective,” wrote Dr. Hans Vasen, professor in the department of gastroenterology and hepatology at the Leiden University Medical Center, the Netherlands, and colleagues. “The value of surveillance of FPC is still not clear, and the main effect seems to be prevention of PDAC by removal of” precursor lesions, they added (J Clin Oncol. 2016 Apr 25. doi: 10.1200/JCO.2015.64.0730).

The retrospective evaluation of an ongoing prospective follow-up study included 411 high-risk individuals: 178 with CDKN2A mutations, 214 with familial pancreatic cancer, and 19 with BRCA1/2 or PALB2 mutations. The study was conducted at three expert centers in Marburg, Germany; Leiden, the Netherlands; and Madrid.

In the BRCA1/2 and PALB2 mutation cohort, one individual (3.8%) with a BRCA2 mutation developed PDAC and underwent surgery; 17 months after the surgery this patient died of liver metastasis. Two others underwent surgery for cystic lesions and are in good health at 10 and 21 months after surgery.

In the cohort of CDKN2A mutation carriers, the mean age at the start of surveillance was 56 years (range, 37-75) and the mean follow-up time was 53 months (range, 0-169): in total, 866 MRIs and 106 endoscopic ultrasounds were conducted. In the FPC group, the mean age was 48 years (range, 27-81), and the mean follow up was 2.8 years (range, 0-10.8): 618 MRIs and 402 endoscopic ultrasounds were conducted. Among BRCA1/2 and PALB2 mutation carriers, the mean age was 52.6 years (range, 25-70), and the mean follow up was 32.7 months (range, 1-119).