Benralizumab for PDGFRA-Negative Hypereosinophilic Syndrome.

BACKGROUND: Hypereosinophilic syndrome is a group of diseases defined by marked eosinophilia in blood or tissue and eosinophil-related clinical manifestations. Benralizumab is a monoclonal antibody against interleukin-5 receptor α, which is expressed on human eosinophils. METHODS: In this randomized, double-blind, placebo-controlled, phase 2 trial, we administered a series of three monthly subcutaneous injections of either benralizumab (at a dose of 30 mg) or placebo in 20 symptomatic patients who had PDGFRA-negative hypereosinophilic syndrome and an absolute eosinophil count of at least 1000 cells per cubic millimeter; all the patients were receiving stable therapy (drugs or dietary changes) for this disease. This regimen was followed by an open-label phase, during which the patient's background therapy could be tapered as tolerated, and an extension phase. The primary end point of the randomized phase was a reduction of at least 50% in the absolute eosinophil count at week 12. RESULTS: During the randomized phase, the primary end point occurred in more patients in the benralizumab group than in the placebo group (9 of 10 patients [90%] vs. 3 of 10 patients [30%], P = 0.02). During the open-label phase, clinical and hematologic responses were observed in 17 of 19 patients (89%) and were sustained for 48 weeks in 14 of 19 patients (74%); in the latter group, in 9 of 14 patients (64%), background therapies could be tapered. Bone marrow and tissue eosinophilia were also suppressed with benralizumab therapy. The most common drug-related adverse events, headache and an elevated lactate dehydrogenase level, occurred in 32% of the patients after the first dose of benralizumab and resolved within 48 hours in all patients. Other adverse events occurred with similar frequency in the two groups. Of the many potential predictors of response that were examined, only clinical disease subtype appeared to be associated with the initial response or relapse. CONCLUSIONS: In this small phase 2 trial, patients with PDGFRA-negative hypereosinophilic syndrome who received benralizumab for 12 weeks had lower absolute eosinophil counts than those who received placebo. During the open-label phase, clinical and hematologic responses were sustained for 48 weeks in 74% of the patients. Adverse events did not limit treatment. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov numbers, NCT00001406 and NCT02130882.).

Adenoma miss rates associated with a 3-minute versus 6-minute colonoscopy withdrawal time: a prospective, randomized trial.

BACKGROUND AND AIMS: The 6-minute withdrawal time for colonoscopy, widely considered the standard of care, is controversial. The skill and technique of endoscopists may be as important as, or more important than, withdrawal time for adenoma detection. It is unclear whether a shorter withdrawal time with good technique yields an acceptable lesion detection rate. Our objective was to evaluate a 3-minute versus a 6-minute withdrawal time by using segmental tandem colonoscopy. METHODS: We performed a prospective, randomized trial by using 4 expert endoscopists. Patients were randomized to a 3-minute or a 6-minute initial withdrawal, each followed by a tandem second 6-minute withdrawal. All polyps were removed. The primary outcomes were adenoma miss rates (AMRs), adenomas per colonoscopy (APC) rates, and adenoma detection rates (ADRs). RESULTS: A total of 99 and 101 patients were enrolled in the 3-minute and 6-minute withdrawal groups, respectively. The AMR was significantly higher in the 3-minute withdrawal group (48.0% vs 22.9%; P = .0001). After controlling for endoscopist, patient age and/or sex, Boston Bowel Preparation Scale score, and size and/or location and/or morphology of adenoma, the AMR remained significantly higher in the 3-minute withdrawal group (odds ratio, 2.78; 95% confidence interval, 1.35-5.15; P = .0001). The ADR was similar between both groups (39.2% vs 40.6%; P = .84). However, the mean APC rate was significantly lower in the 3-minute withdrawal group (0.55 vs 0.80; P = .0001). CONCLUSIONS: The AMR was significantly higher, and the APC rate was significantly lower in the 3-minute withdrawal group versus the 6-minute withdrawal group. Despite expert technique, a shorter withdrawal time is associated with an unacceptably high AMR and low APC rate. (Clinical trial registration number: NCT01802008.).

The Association Between Helicobacter pylori Infection and Nonalcoholic Fatty Liver Disease.

PURPOSE OF REVIEW: Helicobacter pylori (HP) infection is known to be a significant risk factor in the development of certain gastric conditions, such as ulcers, gastritis, and malignancy. Recently, however, the systemic effect of HP infection on other organ systems has come to be appreciated. In this review, we will explore the association between HP infection and nonalcoholic fatty liver disease (NAFLD), the hepatic component of metabolic syndrome. RECENT FINDINGS: The possible association between HP infection and NAFLD initially stemmed from the isolation of HP bacteria in the livers of patients with NAFLD. Although there have been conflicting results, several subsequent clinical trials have demonstrated a higher rate of fatty liver and NASH in HP-positive patients compared to HP-negative patients; in addition, small trials examining the effect of HP eradication have shown improvement in markers of NAFLD activity, further supporting a link between these two conditions. The pathophysiology behind the possible association between HP infection and NAFLD has yet to be fully elucidated; several possible mechanisms include induction of a pro-inflammatory state that shifts the body toward a more lipogenic profile, and a hormonal shift that favors progression toward insulin resistance and fibrosis. The association between HP infection and NAFLD has been demonstrated in several clinical trials, including small trials evaluating the effect of HP eradication on NAFLD. Future studies examining the pathophysiology behind this association are the next step in characterizing the relationship between these two conditions.

Self-Reported Questionnaire Detects Family History of Cancer in a Pancreatic Cancer Screening Program.

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer death; approximately 5-10% of PDAC is hereditary. Self-administered health history questionnaires (HHQs) may provide a low-cost method to detail family history (FH) of malignancy. Pancreas Center patients were asked to enroll in a registry; 149 with PDAC completed a HHQ which included FH data. Patients with FH of PDAC, or concern for inherited PDAC syndrome, were separately evaluated in a Prevention Program and additionally met with a genetic counselor (GC) to assess PDAC risk (n = 61). FH obtained through GC and HHQ were compared using Wilcoxon signed-rank sum and generalized linear mixed models with Poisson distribution. Agreement between GC and HHQ risk-assessment was assessed using kappa (κ) statistic. In the Prevention Program, HHQ was as precise in detecting FH of cancer as the GC (all p > 0.05). GC and HHQ demonstrated substantial agreement in risk-stratification of the Prevention Program cohort (κ = 0.73, 95% CI 0.59-0.87.) The sensitivity of the HHQ to detect a patient at elevated risk (i.e., moderate- or high-risk) of PDAC, compared to GC, was 82.9% (95% CI 67.3-92.3%) with a specificity of 95% (95% CI 73.1-99.7%). However, seven patients who were classified as average-risk by the HHQ were found to be at an elevated-risk of PDAC by the GC. In the PDAC cohort, 30/149 (20.1%) reported at least one first-degree relative (FDR) with PDAC. The limited sensitivity of the HHQ to detect patients at elevated risk of PDAC in the Prevention Program cohort suggests that a GC adds value in risk-assessment in this population. The HHQ may offer an opportunity to identify high-risk patients in a PDAC population.

BRCA1 and BRCA2 germline mutations are frequently demonstrated in both high-risk pancreatic cancer screening and pancreatic cancer cohorts.

BACKGROUND: Approximately 10% of pancreatic ductal adenocarcinoma (PDAC) is due to a genetic predisposition, including the breast and ovarian cancer syndrome germline mutations BRCA1 and BRCA2. Knowledge of specific genetic mutations predisposing to PDAC may enable risk stratification, early detection, and the development of effective screening and surveillance programs. In the current study, the authors attempted to determine the diagnostic yield of testing for BRCA1/2 germline mutations in a PDAC screening cohort and a PDAC cohort referred for genetic testing. METHODS: Patients in a high-risk PDAC prevention and genetics program or those with a personal history of PDAC who were referred for genetic evaluation underwent testing for BRCA1/2 germline mutations. Clinical BRCA1/2 genetic testing included testing for the 3 Ashkenazi Jewish founder mutations or BRCA1/2 comprehensive testing. RESULTS: A total of 37 patients without PDAC underwent BRCA1/2 testing at the study institution. Genetic testing identified 7 patients who were BRCA1/2 carriers for a yield of 18.9%. Six patients carried Ashkenazi Jewish founder mutations (3 with BRCA1 and 3 with BRCA2), and 1 patient was found to have a BRCA2 mutation on comprehensive testing. Thirty-two patients with PDAC underwent BRCA1/2 genetic testing. Five patients had Ashkenazi Jewish founder mutations (2 with BRCA1 and 3 with BRCA2), and 2 patients were found to have BRCA2 mutations on comprehensive testing. The diagnostic yield was 7 of 32 patients (21.9%). CONCLUSIONS: BRCA1/2 testing is useful in PDAC risk stratification and alters risk assignment and screening recommendations for mutation-positive patients and their families. Clinical BRCA1/2 testing should be considered in patients of Ashkenazi Jewish descent with a personal history or family history of PDAC, even in the absence of a family history of breast and ovarian cancer.

Optical biopsy of sessile serrated adenomas: do these lesions resemble hyperplastic polyps under narrow-band imaging?

BACKGROUND: Serrated colorectal lesions include hyperplastic polyps (HPs) and sessile serrated adenomas (SSAs). Optical biopsy could misclassify SSAs as unimportant if they resemble HPs. OBJECTIVE: To explore the narrow-band imaging (NBI) features of SSAs. We hypothesized that SSAs resemble HPs under NBI. DESIGN: Retrospective analysis of data from our prospective study of NBI in routine practice. SETTING: Single specialty group. PATIENTS: Patients undergoing colonoscopy. INTERVENTION: Colonoscopy. MAIN OUTCOME MEASUREMENTS: Polyp histology prediction by community gastroenterologists. Features of SSAs versus HPs and adenomas by using the Narrow-Band Imaging International Colorectal Endoscopic (NICE) Classification. RESULTS: Among 2388 lesions, 141 were diagnosed on pathology as SSAs, 465 as HPs, and 1546 as adenomas. Each individual NICE feature of HPs was found in 38% to 42% of SSAs, 66% to 67% of HPs, and 15% to 20% of adenomas (P < .001 for each). Each individual NICE feature of adenomas was found in 57% to 62% of SSAs, 33% to 34% of HPs, and 80% to 84% of adenomas (P < .001 for each). Compared with HPs, SSAs were less likely (odds ratio [OR] 0.74; 95% confidence interval [CI], 0.69-0.79) and adenomas were even less likely (OR 0.62; 95% CI, 0.59-0.64) to have all 3 NICE features of HPs. SSAs >5 mm were more likely than smaller SSAs to have all 3 NICE features of adenomas. SSA location did not predict NBI features. Analyses restricted to high-confidence lesions showed similar results. LIMITATIONS: The endoscopists were not NBI experts. CONCLUSION: Community gastroenterologists observed a profile of NICE features among SSAs that was intermediate to the profiles observed for HPs and adenomas. These results require confirmation by NBI experts.

Efficacy and tolerability of colonoscopies in overweight and obese patients: Results from a national database on gastrointestinal endoscopic outcomes.

Background and study aims Gastroenterologists are encountering a rising number of obese patients requiring colonoscopy. Existing literature regarding colonoscopy outcomes in this population is scant and conflicting. We analyzed a nationwide cohort of patients to identify the effects of body mass index (BMI) on colonoscopy success, efficacy, and tolerability. Patients and methods The Clinical Outcomes Research Initiative (CORI) endoscopic database was queried for all colonoscopies in adults between 2008-2014. Patients were stratified into four cohorts based on BMI classification for comparison. Multivariable analysis was performed to identify the effect of BMI on procedure outcome, efficacy and tolerability. Results Of 41,401 procedures, 27,696 met study inclusion criteria. Of these, 49.4 % were performed for colorectal cancer screening, most commonly under anesthesia directed sedation. Patient discomfort was the reason for an incomplete colonoscopy in 18.7 % of all cases, and more frequent among the overweight and obese cohorts. An inadequate bowel preparation was most common in the class III obesity cohort. Compared to the normal BMI group, a BMI ≥ 30 and < 40 kg/m 2 was associated with an increased odds of an incomplete colonoscopy ( P  = 0.001for overweight, P  = 0.0004 for class I/II obesity), longer procedure ( P  < 0.05 for all) and poorer tolerance ( P  < 0.0001 for class I/II obesity, P  = 0.016 for class III obesity). Anesthesia-administered sedation was more commonly used than endoscopist directed sedation amongst the obese cohort compared with the normal BMI cohort ( P  < 0.0001). Conclusions Endoscopists should consider the increased odds of incomplete colonoscopy, longer procedures, and poorer tolerance when performing colonoscopy in obese patients to improve clinical management and procedural outcome.

Benralizumab Completely Depletes Gastrointestinal Tissue Eosinophils and Improves Symptoms in Eosinophilic Gastrointestinal Disease.

BACKGROUND: Previous studies of targeted eosinophil biologics in eosinophilic esophagitis have yielded mixed results. Possible explanations include incomplete eosinophil depletion with anticytokine (anti-IL-5) treatments and/or irreversible fibrotic tissue changes contributing to symptomatology. OBJECTIVE: To characterize the therapeutic effect of eosinophil depletion in patients with hypereosinophilic syndrome with varied eosinophilic gastrointestinal (GI) disorders. METHODS: Hematologic, histologic, endoscopic, and clinical symptoms for a subset (n = 7) of hypereosinophilic syndrome patients with GI tissue eosinophilia enrolled in a phase 2 clinical trial of benralizumab (anti-IL-5RA) were assessed before and after treatment (NCT02130882). RESULTS: Blood and GI tissue eosinophils were completely depleted in all segments of the GI tract, and all patients reported improved GI symptoms, in some cases as early as after the first monthly dose. Some patients had recurrent symptomatic flares without recurrent peripheral or tissue eosinophilia, in most cases after prolonged symptomatic remission and in the setting of liberalization of dietary restrictions and/or tapering of background therapy. Although eosinophil-associated histologic changes improved in all segments, epithelial changes persisted in the esophagus and stomach in patients with recurrent disease flares even after 1 year of treatment. Serum tryptase and GI mast cells were generally unchanged with treatment, and increases were not associated with disease flares. Serum levels of IL-4 and IL-5 increased with benralizumab treatment (both P < .05). CONCLUSIONS: Benralizumab treatment completely depleted blood and GI tissue eosinophilia in patients with eosinophilic GI disorders, but clinical response, while encouraging, was heterogeneous. Residual symptoms in some patients may reflect persistent epithelial changes in the upper GI tract.

Identifying who best tolerates moderate sedation: Results from a national database of gastrointestinal endoscopic outcomes.

BACKGROUND: With increasing volume and cost of gastrointestinal endoscopic procedures, the proper selection of patients for moderate sedation becomes increasingly relevant. The current literature lacks consistent findings that allow for appropriate selection of patients for moderate sedation. AIM: To analyze a nationwide registry of patients to identify patient and procedural factors associated with lower sedation requirements for endoscopy. METHODS: The Clinical Outcomes Research Initiative National Endoscopic Database was queried to assess adult patients undergoing moderate sedation for esophagogastroduodenoscopy (EGD) and colonoscopy from 2008 to 2014. Patients were stratified into two groups [low dose (LD) and high dose sedation] based on sedation requirements. Anthropometric, procedural, and anesthesia data were compared, and multivariable analysis was performed to identify factors associated with LD sedation. RESULTS: Of the 371102 patients included in the study, 63137 where stratified into the LD sedation group and 307965 were in the high dose group. Moderate sedation was managed primarily by endoscopists (50%) and anesthesia providers (47%). Patients undergoing EGDs and procedures performed in the inpatient setting, in ambulatory surgery centers, intensive care units or hospital wards, required less sedation than colonoscopies, outpatient procedures and procedures done in endoscopy suites, respectively (P < 0.0001 for all). On multivariable analysis, factors predictive of tolerance with lower sedation requirements for EGDs and colonoscopies were female gender, age ≥ 50, non-White race, Hispanic descent, body mass index ≤ 25 kg/m2, and higher American Society of Anesthesia Class (P < 0.0001 for all). CONCLUSION: Clinicians should consider these patient profiles in determining which patients will better tolerate moderate sedation vs those better suited for alternative sedation methods.

Single-Organ and Multisystem Hypereosinophilic Syndrome Patients with Gastrointestinal Manifestations Share Common Characteristics.

BACKGROUND: Eosinophilic gastrointestinal diseases (EGIDs) are defined by marked eosinophilia in the gastrointestinal (GI) tract resulting in a wide variety of GI symptoms. When accompanied by blood hypereosinophilia (HE; absolute eosinophil count ≥1500/mm3), EGID can occur as an isolated GI disorder (hypereosinophilic syndrome [HES]/EGID overlap) or as part of a multisystem hypereosinophilic syndrome (Multisystem HES). OBJECTIVE: To describe the GI disease of patients categorized as those with HES/EGID overlap versus those with Multisystem HES. METHODS: Consecutively enrolled patients on a natural history protocol to study eosinophilia with biopsy-proven EGID involving the esophagus, stomach, small-bowel, and/or colon were evaluated for clinical, histopathologic, and endoscopic features by retrospective chart review. RESULTS: Among the 56 patients with EGID and HE, 34 were categorized as HES/EGID overlap and 22 as Multisystem HES. Demographics, GI symptoms, and associated comorbidities were similar between the 2 groups. Multisegment GI eosinophilia was present in 20 of 30 (67%) patients who underwent tissue sampling of all 4 GI segments. Tissue eosinophilia in all 4 GI segments was found in 5 of 30 (17%) patients. Dietary therapy was more common in patients with HES/EGID overlap (65% vs 23%, P = .0028). Patients with Multisystem HES were more likely to receive glucocorticoids (100% vs 79%, P = .0349) and nonglucocorticoid systemic therapies (77% vs 38%, P = .0061). One-third (8 of 22) of patients with Multisystem HES presented with isolated GI symptoms before developing extraintestinal manifestations at a median of 1 year (range, 0.25-15 years). CONCLUSION: There are striking clinical similarities between patients with Multisystem HES and those with HES/EGID overlap, despite differing treatment approaches. Moreover, Multisystem HES can present with isolated GI involvement. Larger prospective studies are needed to confirm these findings.

Absence of pancreatic intraepithelial neoplasia predicts poor survival after resection of pancreatic cancer.

OBJECTIVES: Pancreatic intraepithelial neoplasia (PanIN), thought to represent the dominant precursor of pancreatic adenocarcinoma (PDAC), is often found synchronously adjacent to resected PDAC tumors. However, its prognostic significance on outcome after PDAC resection is unknown. METHODS: A total of 342 patients who underwent resection for PDAC between 2005 and 2010 at a single institution were identified and stratified according to highest grade of PanIN demonstrated surrounding the tumor. Clinical and pathologic characteristics of each patient and tissue were recorded and analyzed. The primary outcome was length of survival after resection. RESULTS: An absence of PanIN lesions was identified in 32 patients (9%), low grade PanIN without synchronous high grade lesions was identified in 52 patients (15%), and high grade PanIN was found in 258 patients (75%). Median survival were 12.8 months for the non-PanIN group, 26.3 months for the low-grade PanIN group, and 23.8 months for the high-grade PanIN groups (P = 0.043). In multivariable analysis, absence of PanIN was independently associated with poor survival (P = 0.002). CONCLUSIONS: The patients who demonstrate an absence of PanIN in the pancreatic tissue adjacent to the resected PDAC tumor have shorter postresection survival compared with those who demonstrate a PanIN lesion.

High prevalence of BRCA1 and BRCA2 germline mutations with loss of heterozygosity in a series of resected pancreatic adenocarcinoma and other neoplastic lesions.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is associated with the breast ovarian cancer syndrome (BRCA1/BRCA2) mutations. It is unknown if this association is causal. EXPERIMENTAL DESIGN: This is a single-site study of patients who underwent surgical pancreatic tumor resection and self-identified as Ashkenazi Jewish. DNA from normal pancreatic tissue was genotyped for the three Ashkenazi Jewish BRCA1/2 founder mutations BRCA1 185delAG, BRCA1 5382insC, and BRCA2 6174delT, and loss of heterozygosity (LOH) was determined by sequencing DNA from microdissected tumor. When additional tumor tissue was available, p53 immunohistochemistry (IHC) was conducted. RESULTS: Thirty-seven patients underwent surgery for PDAC, seven for intraductal papillary mucinous neoplasm (IPMN), and 19 for other diseases. A high prevalence of BRCA1/2 mutations was found in the surgical cohort (12/63; 19.0%; P < 0.001), PDAC cohort (8/37; 21.6%; P < 0.001), and IPMN cohort (2/7; 28.6%; P = .01) compared with published control mutation frequency. A high prevalence of BRCA1 185delAG (8.1%; P < 0.001) and BRCA2 6174delT (10.8%; P < 0.001) in Ashkenazi Jewish patients with PDAC was shown. BRCA1/2 LOH was found in 2 of 4 BRCA1-associated PDACs and 3 of 4 BRCA2-associated PDACs. Positive p53 IHC was found in 5 of 8 BRCA1/2 PDACs. CONCLUSIONS: We show a high prevalence of BRCA1/2 mutations with LOH in an Ashkenazi Jewish cohort of surgically resected PDAC and neoplastic lesions, suggesting that these germline mutations are causal in selected individuals.

Review of the safety and efficacy of ustekinumab.

Ustekinumab is a subcutaneously and intravenously administered fully human monoclonal immunoglobulin (IgG1) antibody targeting the interleukin (IL)-12/23 shared P40 subunit. The pivotal role of IL-12/23 inflammatory-mediated pathways is increasingly recognized in a plethora of immune-mediated inflammatory disorders including Crohn's disease, psoriasis, and multiple sclerosis. In a randomized controlled trial of ustekinumab in moderate-to-severe Crohn's disease, clinical response was achieved most notably in infliximab-experienced primary and secondary nonresponders and suboptimal responders.