Independent Institutional Review Board Research Articles

Chemotherapy effects on mitochondrial function in adipose tissue in oesophageal and gastroesophageal junction adenocarcinomas with or without associated cachexia: protocol for a prospective, comparative observational study (ChiFMeOE)

IntroductionCachexia is strongly associated with digestive cancers, particularly oesogastric cancer. Mitochondria in adipose tissue are involved in the regulation of metabolism and physiopathology of cancer cachexia in animal studies. Chemotherapeutic...

S572 A Pilot Study for Precision Nutrition in Irritable Bowel Syndrome: In-Vitro Stimulation of Pro-and Anti-inflammatory Cytokine Release

Introduction: Inflammation plays a role in the pathogenesis of irritable bowel syndrome (IBS). Foods can trigger and exacerbate IBS flare-ups and symptoms. Diet-induced inflammation is characterized by the release of cytokines as a common feature. The lack of evidence regarding which diet is ideal for IBS underlined the need for personalized and more precise dietary treatment options. The objective of this study was to determine in-vitro the degree of blood inflammatory cytokines release in response to food antigens exposure in subjects with IBS. Methods: Blood samples were collected at Oxford Biomedical Technologies, Inc. from 12 subjects diagnosed with IBS. Whole blood was diluted with buffered physiologic saline, and then an aliquot was pipetted into eight reaction wells, each containing a single food extract. Following a predetermined incubation period at 37°C, all specimens were stored at -20°C until cytokine analysis were performed. Cytokines [interleukin-8 (IL) and IL-10)] reactivity to food antigens challenge was evaluated using Bio-Plex 200 System (Bio-Rad, CA). The IBS-Severity Scoring System (IBS-SSS) was used to measure the severity and intensity of symptoms. The questionnaire scores range from 0 to 500, with cutoffs rated as mild (75-175), moderate (175-300), and severe ( >300). The study received approval from an independent Institutional Review Board (IRB), and all statistical analyses were performed using SPSS version 27.0 (IBM Corp., NY). Results: Mean age was 52.2±17.5 years, 10 (83%) were female and had a BMI of 26.2±5.7 kg/m2. According to IBS-SSS scores, 8 (67%) of the subjects had moderate symptoms, whereas 4 (33%) had severe symptoms. We found statistically significant differences in IL-8 and IL-10 concentrations (pg/mL) release pre- vs. post-antigen exposure to broccoli [(2.17±0.75, P=0.016)]; corn [(1.25±0.44, P=0.018) and (-0.21±0.09, P=0.041)]; milk [(1.40±0.48, P=0.017); egg [(1.17±0.48, P=0.034)]; navy bean [(0.83±0.30, P=0.019) and (-0.14±0.01, P=.004)]; orange [(2.19±1.04, P=0.063)]; tomato [(2.77±1.15, P=0.038) and (-0.26±0.13; P=0.073)]; and wheat [(0.90±0.36, P=0.033) and (-0.27±0.08, P=0.011)] respectively. Conclusion: The findings from this study generate much-needed data to aid the understanding of non-physiological inflammatory responses to foods which can optimize targeted dietary therapy for IBS. Further work is needed to develop a diagnostic assay that could be used to create a precise and personalized diet for clinical practice.

O-10: SICKLE CELL HEALTH AWARENESS, PERSPECTIVES AND EXPERIENCES (SHAPE) SURVEY: FINDINGS ON THE BURDEN OF SICKLE CELL DISEASE AND UNMET NEEDS AS REPORTED BY PATIENTS AND CAREGIVERS

Purpose: Sickle cell disease (SCD) has a substantial emotional and physical burden on patients and their caregivers. Research on the impact of SCD on patient and caregiver quality of life (QOL) is limited, including on the health inequalities faced by different groups around the world. The limitations in research underscore the need for greater understanding of the challenges of living with SCD in different communities. The SHAPE survey aims to broaden the understanding of the global impact of SCD on patients living with the condition, on caregivers caring for those living with the condition, and on healthcare professionals (HCPs) who treat SCD. Materials and methods: The SHAPE survey comprised online, quantitative surveys of patients, caregivers, and HCPs conducted in 10 countries: France, Germany, UK, US, Canada, Brazil, Saudi Arabia, United Arab Emirates, Bahrain, and Oman (patients only). The surveys required participants to answer a range of closed-ended questions about their circumstances and experiences in order to build a robust and reliable dataset on which descriptive statistics were performed. This analysis focuses on findings from the patient and caregiver survey portion of the study. Patients were included if they were diagnosed with SCD by an HCP and were aged ≥12 years. Caregivers were included if they were caring for someone diagnosed with SCD and were aged ≥18 years. Informed consent was obtained from all participants, and all identifiable information was kept private and secure. The study protocol was reviewed and approved by an independent institutional review board. Results: A total of 919 patients and 207 caregivers completed the survey. The mean patient age was 32.3 years, and most patients and caregivers were female. Nearly all patients stated that reducing the risk of long-term complications, such as organ damage (93%) and hemolytic anemia (84%), was important to them (Figure). Caregivers felt that most areas of their lives—particularly their ability to attend and succeed at school or work (56%) and their own overall wellbeing (53%) and mental health (52%)—were impacted by caring for someone with SCD. The symptom experienced by patients with SCD that most impacted caregivers’ lives was fatigue/tiredness (49%), and 54% of caregivers reported a notable impact on their earning potential. Those caring for patients aged <18 years were more likely to have their ability to attend and succeed at school or work impacted than those caring for patients aged ≥18 years (61% vs 38%, respectively). A total of 46% of patients and 33% of caregivers reported that emergency room (ER) HCPs did not believe patients about their symptoms, and 48% of patients felt they were treated as a drug seeker by ER HCPs. Similarly, 54% of patients and 40% of caregivers reported ER HCPs provided poor care due to their lack of knowledge about SCD. Conclusion: The experience of a global group of patients with SCD shows that what most impacted caregivers’ lives was fatigue/tiredness and loss of earnings and this provides insight on the broad impacts of SCD and highlights areas that need greater support or improvement.Figure. Percentage of Patients or Caregivers Who Agreed With or Endorsed the Following Statements I. ODAME declares a conflict of interest: Consultancy, Expert: Novartis, Novo Nordisk, Global Blood Therapeutics F. COSTA declares a conflict of interest: Consultancy, Expert: Novartis;GBT B. INUSA declares a conflict of interest: Consultancy, Expert: Novartis Ltd Global therapeutics Vertex Agios Invitation to national or international congresses: European Hematology Association Sickle cell disease association of America Mumbai international haematology National blood transfusion Society Nigeria Patent or product inventor: none Research support/Scientific studies: Horizon 2020 ARISE (African Reserach and Innovative Initiative for Sickle cell education) Paget foundation Trainings, Teaching: academy for sickle cell and thalassaemia (ASCAT) W. JASTANIAH declares a conflict of interest: Consultancy, Expert: Novartis, Amgen, Servier Research support/Scientific studies: Novartis, Amgen

Study Protocol: Effectiveness of the Lifestyle Eating and Performance (LEAP) Program for the Treatment of Irritable Bowel Syndrome (IBS)

Abstract Objectives Cytokine levels may be an important factor in the metabolic pathways of irritable bowel syndrome (IBS) pathophysiology. Current therapies for IBS are often ineffective, underlining the need for alternative treatment options. Studies on personalized dietary approaches for the treatment of IBS are scarce. We plan to evaluate the effectiveness of the Lifestyle Eating and Performance (LEAP) program to improve cytokines levels, gastrointestinal symptoms, and quality of life with three months of treatment in individuals with IBS. Methods We will conduct a prospective single-arm study (NCT05178017), including 60 adults (age 18–75 years) with diagnosis of IBS. The study received approval from an independent Institutional Review Board (IRB). In-person and virtual sessions will be conducted at baseline and follow-up visits (day 15, 30, 45, 60, and 90). Intervention: A trained dietitian will administer the virtual counseling sessions. The LEAP program is a multiphase tailored eating plan that is methodically prepared for individuals with IBS. Foods for each phase are selected based on the degree of Leukocyte Activation Assay-MRT (LAA-MRT®) immune reactivity and clinical response, starting with the least immune reactive foods, and subsequently foods will be added in a nutritionally balanced manner. Outcome Assessments: Gastrointestinal symptoms [IBS-Symptom Severity Scale (IBS-SSS), IBS-Adequate Relief (IBS-AR), IBS-Global Improvement Scale (IBS-GIS), and Global Symptom Survey (GSS)]; quality of life [IBS-36 Quality of Life]; anthropometrics and vital signs [body mass index (BMI), waist and hip circumferences, and blood pressure)]; dietary intake [Walter Willett's food frequency questionnaire (Harvard University) and food symptom diary]. Oxford Biomedical Technologies, a CLIA-certified laboratory, will perform the LAA-MRT® and cytokine analysis from collected venous blood. LAA-MRT® will be conducted using Sony EC 800 Dual-Mode Flow Cytometry Systems. Cytokine panel will include (IL-1β, IL-6, IL-8, IL-10, IL-12, IL-17, and TNF-α) and analyzed using a Bio-Plex 200 System (Bio-Rad). Results N/A (protocol abstract) Conclusions This study will generate evidence and clinical relevance of diet-induced inflammation that could explain changes in biomarkers for IBS and improved treatment outcomes. Funding Sources Oxford Biomedical Technologies.

Translating Clinical Research to Clinical Care in Nephrology: A Qualitative Study of Nephrology Clinicians

Rationale & ObjectiveThe translation of clinical research to practice has been the subject of intense scrutiny in the efforts to identify ways to improve the uptake of findings that can enhance patient care.Study DesignThis study evaluated the experience of nephrology health care providers who manage patients with autosomal dominant polycystic kidney disease (ADPKD) to identify promoters and barriers to the translation of research results into clinical practice. We used inductive thematic analysis to evaluate the experience, attitudes, and beliefs of physicians in the evaluation and translation of research findings into clinical practice for the care of patients with ADPKD.Setting & ParticipantsParticipants in a continuing education activity on ADPKD volunteered for semistructured interviews exploring their experience translating new knowledge into care for patients with ADPKD. An independent institutional review board (Solutions IRB) found the study to be exempt as an educational survey.Analytical ApproachTranscripts were coded and excerpted, and emergent themes and relationships were identified through an analysis performed using Dedoose software. Particular attention was paid to characterizing the facilitators and barriers to research translation at different levels of the health care environment.ResultsTextual interpretation of data from 13 interviews showed that while well-established barriers to research translation are prevalent among health care providers managing patients with ADPKD, these clinicians also face unique challenges. Principal among these is the burden of interpreting the clinical research literature given the lack of official guidelines.LimitationsThis study did not explore the translation of all levels of research, such as basic science and animal studies, and it was limited to the translation of knowledge from clinical studies. The number of participants was limited but was found to be sufficient for saturation.ConclusionsWe identified factors that may either enhance or impede research translation for nephrology health care providers. These observations may help in the design of continuing education interventions to promote innovation.

Glaucomanet: A Deep-Learning Algorithm for the Diagnosis of Primary Open-Angle Glaucoma from Fundus Photographs

Background: Primary open-angle glaucoma (POAG) is one of the leading causes of irreversible blindness in the United States and worldwide. Although deep learning methods have been proposed to diagnose POAG, it remains challenging to develop a robust and explainable algorithm to facilitate the downstream diagnostic tasks automatically. Methods: We proposed a deep learning model, GlaucomaNet, with joint fusion to identify POAG from fundus photographs. GlaucomaNet consists of two neural networks to simulate the human grading process: one performing preliminary grading and the other detailed grading. An ensemble of network architectures further improved diagnostic accuracy. GlaucomaNet was evaluated on two independent datasets. The performance was measured by AUC, accuracy, precision, sensitivity, specificity, and F1-score. Findings: GlaucomaNet was trained and evaluated on two datasets: 37,339 fundus photographs from the Ocular Hypertension Treatment Study (OHTS), and 4,855 fundus photographs from the Large-scale Attention-based Glaucoma (LAG) dataset. GlaucomaNet achieved superior performance to six state-of-the-art neural networks on OHTS, with accuracy of 0.930 (standard deviation, 0.010), F1-score of 0.490 (0.033), and AUC of 0.904 (0.014). It also outperformed the baselines on the LAG dataset. Interpretations: GlaucomaNet demonstrated high accuracy with increased transparency in POAG diagnosis. It is also applicable for two well-known challenges: image data diversity and POAG only due to visual fields abnormalities. These results highlight the potential of deep learning to assist and enhance clinical POAG diagnosis. GlaucomaNet is publicly available on https://github.com/bionlplab/GlaucomaNet. Funding: This project was supported by the National Library of Medicine (4R00LM013001), the National Eye Institute, the National Center on Minority Health and Health Disparities (EY09341, EY09307) at NIH, Horncrest Foundation, the Department of Ophthalmology and Visual Sciences at Washington University, the NIH Vision Core Grant (P30EY02687), Merck Research Laboratories, Pfizer, Inc., White House Station, New Jersey, and unrestricted grants from Research to Prevent Blindness, Inc., New York, NY. Declaration of Interest: Ethical Approval: The first dataset is obtained from the Ocular Hypertension Treatment Study (OHTS). The OHTS comes from 22 centers in the United States. The study protocol was approved by an independent Institutional Review Board at each clinical center

A Randomized Controlled Pilot Study: Combined 595-nm Pulsed Dye Laser Treatment and Oxymetazoline Hydrochloride Topical Cream Superior to Oxymetazoline Hydrochloride Cream for Erythematotelangiectatic Rosacea.

Background and ObjectivesWe evaluated if oxymetazoline therapy combined with 595‐nm pulsed dye laser (PDL) will be more beneficial than topical oxymetazoline alone for the improvement of erythematotelangiectatic rosacea.Study Design/Materials and MethodsThis was a randomized, controlled, prospective clinical trial approved by an independent Institutional Review Board, which enrolled 34 patients with moderate to severe clinical erythema (CEA) into a two‐arm study of PDL with concomitant oxymetazoline cream (Arm 1) and oxymetazoline cream alone (Arm 2). Patients in Arm 1 were treated with 3 monthly laser sessions, which were started after 1 month of topical oxymetazoline cream. Thirty subjects continued with the study, and 25 subjects (Arm 1: 14, Arm 2: 11) completed the 6‐month follow‐up. With photographic comparison to baseline images, efficacy endpoints were based on clinical on‐site grading by both the investigator and the patient, using the grading tools for CEA, Global Aesthetic Improvement (GAI) assessment, vessel size improvement, and subject self‐assessment. These scales were assessed at baseline and/or at each clinical follow‐up at 1, 2, 3, and 6 months. Subject satisfaction as well as post‐treatment immediate response and treatment‐associated pain scores were also evaluated.ResultsStatistically significant improvement in CEA was seen in both arms at the 1‐, 2‐, and 3‐month post‐baseline visits (P < 0.01). Only Arm 1 presented statistically significant improvement in CEA (P < 0.001) at 6 months post baseline with a mean score of 1.6 (almost clear‐mild) compared with 3.2 at baseline. Arm 1 showed significantly greater mean vessel size improvement at 3 months (P < 0.01) and 6 months (P < 0.05) post baseline compared to Arm 2. Significantly greater improvement (P < 0.05) in the investigator GAI score was reported at the 2‐ and 6‐month follow‐ups compared with Arm 2. Subject GAI scores showed statistically significant greater improvement in Arm 1 compared with Arm 2 at both the 3‐ and 6‐month follow‐ups (P < 0.01). There were no complications or long‐term effects associated with PDL or topical oxymetazoline treatments.ConclusionThe prospective trial verifies a safe, enhanced clinical outcome with the combination of PDL therapy and topical oxymetazoline for the treatment of erythematotelangiectatic rosacea patients. Lasers Surg. Med. © 2021 The Authors. Lasers in Surgery and Medicine published by Wiley Periodicals LLC.

Effectiveness of a Tailored Dietary Program in Subjects With Fibromyalgia

ObjectivesWe examined the effects of the Lifestyle Eating and Performance (LEAP) program to alleviate fibromyalgia-related symptoms. MethodsThe retrospective study included de-identified data of 33 subjects with fibromyalgia. Dietitians used the in-vitro Leukocyte Activation Assay-MRT (LAA-MRT) blood test results to develop the tailored LEAP program for each subject. The LAA-MRT measures white blood cells reactivity to scale the degree of an adverse immune response to 150 food and food-chemical antigens. The LEAP program is based on the principles of the oligoantigenic dietary approach which is built in a nutritionally balanced manner and takes into consideration the subject’s eating habits. Body Mass Index (BMI) was calculated as weight in kg/height in m2. A symptom survey was used to evaluate the severity and frequency of 13 domains of symptoms associated with fibromyalgia. The survey was quantified on a scale of 0 - 4 with a range score from 0 to 248 points. Descriptive statistics and linear mixed models were performed using SPSS version 25. The study received approval from an independent Institutional Review Board (IRB). ResultsSubjects’ age was 47.7 ± 12.4 years, BMI of 27.9 ± 3.8 kg/m2 and 29 (88%) were female. The follow-up time seen by the dietitian was 76.0 ± 60.7 days. Linear mixed models indicated a significant reduction in overall mean (standard error) scores of fibromyalgia symptoms pre- versus post-intervention (98.3 ± 5.7 vs. 54.2 ± 6.3, P < 0.001) and for each of the 13 domains [constitutional (12.9 ± 0.8 vs. 7.0 ± 0.8, P < 0.001); emotional/mental (12.9 ± 1.0 vs. 7.5 ± 1.0, P = 0.001); head/ears (6.7 ± 0.8 vs. 4.3 ± 0.6, P = 0.018); skin (3.5 ± 0.6 vs. 1.9 ± 0.3, P = 0.030); nasal/sinus (9.3 ± 0.7 vs. 5.6 ± 0.8, P = 0.002); mouth/throat (4.7 ± 0.7 vs. 2.2 ± 0.3, P = 0.004); lungs (3.4 ± 0.7 vs. 1.5 ± 0.4, P = 0.026); eyes (6.2 ± 0.6 vs. 3.9 ± 0.6, P = 0.009); genitourinary (2.2 ± 0.3 vs. 1.1 ± 0.2, P = 0.017); musculoskeletal (12.5 ± 0.7 vs. 8.1 ± 1.0, P = 0.001); cardiovascular (1.7 ± 0.3 vs. 0.9 ± 0.2, P = 0.046); digestive (15.3 ± 1.2 vs. 7.6 ± 1.2, P < 0.001); and weight management (6.8 ± 0.7 vs. 2.4 ± 0.5, P < 0.001)]. ConclusionsThis study showed the beneficial improvements in fibromyalgia symptoms by the LEAP program and the potential as a tailored dietary option in the clinical management of fibromyalgia. Funding SourcesOxford Biomedical Technologies, Inc.

Tailored Dietary Approach for Individuals With Migraine

ObjectivesWe examined the therapeutic potential of the Lifestyle Eating and Performance (LEAP) program to improve global symptom scores for frequency and severity in individuals with migraine. MethodsThe retrospective study analyzed de-identified data from individuals (n = 40) suffering from migraine counseled by dietitians in private practices. The LEAP program is based on the oligoantigenic diet principles and is built on selecting less immune reactive foods and chemicals from the Leukocyte Activation Assay-MRT (LAA-MRT) blood results. The LAA-MRT was conducted using Flow Cytometry Systems to characterize and quantify the volumetric change in each white blood cells population after being challenged and incubated with 150 food and chemical antigens. BMI was calculated as weight in kg/height in m2. A global symptom survey was used to evaluate the frequency and severity of 13 domains of symptoms. The survey was quantified on a scale of 0 - 4, ranging from 0 to 248 points, with a higher score signifying a less desirable health state. Descriptive statistics and linear mixed models were performed using the SPSS V25.0. The study received approval from an independent Institutional Review Board (IRB). ResultsThirty-five (87.5%) were female, had a mean age 42.1 ± 11.3 years, and a BMI of 28.2 ± 7.3 kg/m2. The average follow-up time seen by the dietitians was 82.3 ± 71.0 days. Linear mixed models showed a significant decrease in mean (standard error) overall global symptom scores pre- versus post-intervention (72.1 ± 4.5 vs. 31.5 ± 4.5, P < 0.001) and for each of the 13 domains [constitutional (10.1 ± 0.7 vs. 4.9 ± 0.6, P < 0.001); emotional/mental (9.5 ± 0.8 vs. 4.7 ± 0.7, P < 0.001); head/ears (5.2 ± 0.5 vs. 2.1 ± 0.3, P < 0.001); skin (2.9 ± 0.4 vs. 1.4 ± 0.3, P = 0.002); nasal/sinus (6.4 ± 0.8 vs. 2.5 ± 0.4, P < 0.001); mouth/throat (3.2 ± 0.5 vs. 1.1 ± 0.3, P < 0.001); lungs (1.9 ± 0.4 vs. 0.8 ± 0.2, P = 0.020); eyes (4.3 ± 0.5 vs. 1.9 ± 0.4, P < 0.001); genitourinary (1.3 ± 0.3 vs. 0.6 ± 0.1, P = 0.013); musculoskeletal (8.0 ± 0.8 vs. 3.9 ± 0.6, P < 0.001); cardiovascular (1.1 ± 0.7 vs. 0.4 ± 0.1, P < 0.001); digestive (12.4 ± 1.2 vs. 5.3 ± .9, P < 0.001); and weight management (5.5 ± 0.7 vs. 1.8 ± 0.3, P < 0.001)]. ConclusionsThe findings from this study highlight the role of LEAP program as a tailored dietary approach that alleviated overall symptoms in individuals with migraine. Funding SourcesOxford Biomedical Technologies, Inc.

60 A retroperitoneal approach to endometriosis excision: Surgical outcomes & 7-year follow-up

The objective of this mixed method retrospective study was to investigate the outcomes for women up to 7 years after undergoing laparoscopic surgery using a retroperitoneal approach to isolate and lateralize the ureters and excise endometriosis. The 2-part design included a case series of 350 patients who underwent laparoscopic surgical excision at a GYN-only ambulatory surgery center between October 2013 and September 2020; and a voluntary survey of the same patient population administered via email in September 2020 to evaluate symptom relief and triangulate reoperation rate. Surgeries were identified by procedural code and confirmed via operative notes during the medical chart review process. Patient characteristics and operative outcomes were analyzed using descriptive statistics. IntegReview IRB, an independent institutional review board, deemed both the retrospective review and patient survey exempt from informed consent (IRB #CIGC-001; IRB #CIGC-3206). A total of 350 patients with Stage III and IV were included in the case series. The mean age of participants was 33 ± 7.8 years. Intraoperative complication rate was 2.6%; postoperative 2.3%. More than one-third (34.6%) of patients had at least 1 previous surgical procedure for endometriosis, ranging from 1 to 10 procedures. The majority (77.8%) of intraoperative complications occurred in this group. The cumulative reoperation rate for pelvic pain associated with recurring endometriosis was 3.1%. Preliminary results of the patient survey administered to the same population up to 7 years after surgery support a low reoperation rate. Future studies should aim to collect detailed quality of life measures using prospective standardized survey instruments in order to collect baseline data. Endometriotic implants should be thoroughly excised for optimal surgical outcomes.1,2 However, pelvic pathology of endometriosis and adhesions from previous surgeries may distort normal anatomy and limit the ability to visualize pelvic landmarks, impeding the use of blunt dissection.3 Dissection of the retroperitoneum enables skilled surgeons to identify critical structures, preventing unintentional injury to ureters and retroperitoneal pelvic vessels. Entering the retroperitoneum also facilitates complete excision of endometriosis resulting in a low reoperation rate.

Imatinib Therapy for Patients with Recent-Onset Type 1 Diabetes: A Randomised Blinded Phase 2 Trial

Background: Type 1 diabetes results from autoimmune-mediated destruction of beta cells. The tyrosine kinase inhibitor imatinib may impact relevant immunologic and metabolic pathways, and preclinical studies show that it reverses and prevents diabetes. Our goal was to evaluate the safety and efficacy of imatinib in preserving beta cell function in subjects with recent-onset type 1 diabetes. Methods: We conducted a phase 2, randomised, placebo-controlled, blinded clinical trial. Patients with recent-onset type 1 diabetes, aged 18-45 years, and with peak C-peptide ≥ 0.2 nmoles/L on mixed meal tolerance test (MMTT) were enrolled from 9 sites in the USA and Australia. Participants were randomly assigned 2:1 to receive either 400 mg imatinib or matching placebo for 26 weeks, respectively, using a computer-generated blocked randomisation scheme stratified by study site. The primary endpoint was the change in 2-hour area under the curve (AUC) C-peptide response to MMTT from baseline to 12 months, with further observation out to 24 months. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01781975. Findings: Patients were screened and enrolled into the trial between February 12, 2014 and May 19, 2016. 45 patients were assigned to imatinib, 22 to placebo. The study met its primary endpoint: the 12-mo C-peptide AUC mean was 0·583 (95% CI: 0·519, 0·650) nmoles/L in the imatinib group versus 0·489 (95% CI: 0·403, 0·579) nmoles/L for the placebo group, adjusted for baseline C-peptide, age, and gender (p = 0·048, 1-tail test). In secondary analyses, compared to the placebo group, imatinib-treated subjects required less exogenous insulin and trended towards lower HbA 1c , with higher beta cell glucose sensitivity, lower proinsulin/C-peptide ratios, improved insulin sensitivity, and higher serum adiponectin levels. No significant changes were noted in autoantibody titers and immune cell phenotyping. Interpretation: A 26-wk course of imatinib preserves beta cell function at 12 months in adults with recent onset type 1 diabetes. Although no overt effects on immune responses were detected, imatinib may have novel metabolic effects on both beta cell function and insulin sensitivity. Trial Registration: This study is registered with ClinicalTrials.gov, number NCT01781975. Funding: Juvenile Research Diabetes Foundation Declaration of Interests: SG has served on advisory boards for Avotres, Provention Bio, and Tolerion, and participated in clinical trials with Intrexon, Janssen, Provention Bio, and Tolerion. JB has consulted for Vertex Pharmaceuticals, Inc, and participated in clinical trials for Avotres, Caladrius, Janssen, and Tolerion. PG has served on advisory boards for Caladrius, Bristol Myers Squibb, and Lilly, received grant support from Caladrius, Novo Nordisk and Pfizer, and is co-founder and chief medica officer for ImmunoMolecular Therapeutics, Inc. RM has a patent application for DNA methylation in inflammatory disease. SW reports serving on advisory boards for Boehringer Ingelheim Pharmaceuticals, Inc. and Medtronic, and a DSMB for the National Institutes of Health. All other authors report no potential conflicts of interest. Ethics Approval Statement: This phase 2, randomised, placebo-controlled, double-blinded clinical trial was conducted according to the Declaration of Helsinki and in accordance with good clinical practice guidelines, performed under an investigational new drug application (IND 117644) and was approved by independent institutional review boards at each participating center.

Deep Learning-Assisted Diagnosis of Liver Tumors Using Non-Contrast Magnetic Resonance Imaging: A Multi-Center Study

Background: Contrast-enhanced MRI is the best imaging modality for liver tumor detection and differential diagnosis. However, it is long scan times required and has the contrast agent-associated risks. This study aims to develop and validate a deep convolutional neural network for initial diagnosis of liver tumors based on non-contrast MRI. Methods: In total, 50418 images in enhanced MRI from 1959 patients with liver tumor in three center were enrolled. T2-weighted imaging, diffusion-weighted imaging (DWI), and multiphasic T1-weighted imaging provided input for Inception-ResNet V2 through transfer learning to generate four models for three-way classification. The models was then validated on the independent internal and two external datasets consisting of 5172 and 2916,1338 images, respectively. The diagnostic performance of non-contrast models(T2, T2+DWI) for distinguishing malignancy from benign tumors at-patient level were further evaluated in three validation sets. Findings: Non-contrast models demonstrated similar performance for classifying liver tumors to benign, primary malignant and metastatic tumors, compared with two models based on multi-sequence or enhanced images. In the independent internal cohort, the areas under the receiver operating characteristic curves of T2+DWI model reached 0.91(95% CI,0.888–0.932), 0.873(95% CI,0.848-0.899), and 0.876 (95% CI, 0.840-0.911) for three categories, respectively. At patient-level, the sensitivities of malignant tumors gained from non-contrast models reached 98.1%, 85.7%, 87.5% respectively in three validation sets, while all specificities were almost greater than 70%. Interpretation: This study demonstrates that based on non-contrast MRI, deep learning algorithm can correctly classify liver tumors into benign, primary malignant and metastatic tumors at image-level, and distinguish malignancy from benign with high sensitivity at patient-level, potentially reducing the number of enhanced testing to avoid side effects and financial costs. Funding Statement: This work was supported by grants from National Natural Science Foundation of China (81827804 to X.C.). Declaration of Interests: None. Ethics Approval Statement: This study was approved by the independent institutional review boards of three hospitals and performed according to the Helsinki declaration. The requirement for written informed consent was exempted because of the retrospective nature of this study.

41: Laparoscopic retroperitoneal hysterectomy with uterine artery ligation in morbidly obese patients at a freestanding ambulatory surgery center

To compare the outcomes of laparoscopic retroperitoneal hysterectomy (LRH) in morbidly obese patients (BMI ≥ 40 k/m2) versus non-obese patients (BMI < 30 k/m2) and obese patients (BMI ≥ 30 and < 40 k/m2) at a freestanding ambulatory surgery center. A retrospective comparative analysis was performed of 1,679 women, age 18 years or older, non-pregnant, who underwent LRH by one of two laparoscopic gynecologic surgical specialists at a freestanding ambulatory surgery center serving the Washington, DC area, between October 2013 and January 2019. The study was deemed exempt from informed consent according to 45 CFR 46.101(b) by IntegReview IRB, an independent institutional review board. LRH performed via retroperitoneal dissection, uterine artery ligation at the origin at the anterior branch of the internal iliac artery, vaginal uterine extraction, and transvaginal cuff closure. No power morcellation used. Postoperative complications graded using the Clavien-Dindo Classification system. The only statistically significant differences in surgical outcomes were higher mean operative time and estimated blood loss (EBL) in the obese groups, however these differences were not clinically meaningful (3-4 minutes and 25-31 mL, respectively). There was no difference in intraoperative complication rates across BMI categories. The postoperative complication rates were lower in the in the morbidly obese group compared to the non-obese group. There were a total of 2 postoperative hospital transfers out of the 1,679 patients (Table 1, Figure 1). Laparoscopic retroperitoneal hysterectomy can be performed safely in a freestanding ambulatory surgery setting, with low rate of complications and hospital transfers, and no significant difference in surgical outcomes in morbidly obese patients.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

KEYNOTE-204: A Multicentre, Randomised, Open-Label, Phase 3 Study of Pembrolizumab &lt;i&gt;versus&lt;/i&gt; Brentuximab Vedotin in Relapsed or Refractory Classical Hodgkin Lymphoma

Background: Programmed death 1 blockade via pembrolizumab monotherapy has demonstrated favourable anti-tumor activity and toxicity in patients with relapsed/refractory classical Hodgkin lymphoma (cHL). KEYNOTE-204 (NCT02684292) was a randomised, international, open-label, phase 3 study of pembrolizumab versus brentuximab vedotin for relapsed/refractory cHL. Here, we present the interim efficacy and safety analyses. Methods: Patients aged ≥18 years ineligible for autologous stem cell transplant (ASCT) or who had relapsed post-ASCT with measurable disease and Eastern Cooperative Oncology Group performance status of 0 or 1 were enrolled. Brentuximab vedotin-naive and -exposed patients were eligible. Patients were randomised 1:1 to pembrolizumab 200 mg IV every 3 weeks (q3w) or brentuximab vedotin 1.8 mg/kg IV q3w. The primary endpoint, assessed in the intent-to-treat population, was progression-free survival (PFS) by blinded independent central review per International Working Group 2007 criteria including clinical and imaging data after autologous or allogeneic stem cell transplant. Findings: One hundred fifty-one patients were randomised to pembrolizumab and 153 to brentuximab vedotin. After a median time from randomisation to the data cutoff of 25·7 (IQR 9·6) months, median PFS was 13·2 months for pembrolizumab versus 8·3 months for brentuximab vedotin (HR for disease progression or survival: 0·65 [95% CI 0·48-0·88; p=0·00271]). Grade 3-5 treatment-related adverse events (TRAEs) were experienced by 19·6% of patients with pembrolizumab and 25·0% with brentuximab vedotin; serious TRAEs occurred in 16·2% and 10·5% of patients, respectively. One treatment-related death due to pneumonia occurred in the pembrolizumab arm. Interpretation: Pembrolizumab was superior to brentuximab vedotin and demonstrated statistically significant and clinically meaningful improvement in PFS, with safety consistent with previous reports. These data support pembrolizumab as the preferred treatment option for patients with relapsed/refractory cHL who have relapsed post-ASCT or are ineligible for ASCT. Trial Registration: This study is registered with ClinicalTrials.gov (NCT02684292). Funding: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA) Declaration of Interests: John Kuruvilla: Honoraria: AbbVie, Bristol-Myers Squibb, Amgen, AstraZeneca, Celgene, Gilead Sciences, Janssen, Karyopharm Therapeutics, Merck, Novartis, Roche, Seattle Genetics; Consultancy/Advisory: AbbVie, Bristol-Myers Squibb, Gilead Sciences, Karyopharm Therapeutics, Merck, Roche/Genentech, Seattle Genetics; Research funding: Janssen, Roche Radhakrishnan Ramchandren: Consultancy/Advisory: Seattle Genetics, Sandoz-Novartis, Pharmacyclics/Janssen, Bristol-Myers Squibb; Research funding: Merck, Seattle Genetics, Janssen, Genentech Armando Santoro: Consultancy/Advisory: Bristol-Myers Squibb, Servier, Gilead Sciences, Pfizer, Eisai, Bayer, MSD, Sanofi, ArQule; Speaker Bureau: Takeda, Roche, AbbVie, Amgen, Celgene, AstraZeneca, ArQule, Lilly, Sandoz, Novartis, Bristol-Myers Squibb, Servier, Gilead Sciences, Pfizer, Eisai, Bayer, Merck Ewa Paszkiewicz-Kozik: Travel, Accommodations, Expenses: Roche, Takeda, Celgene Robin Gasiorowski: Honoraria: Merck, Takeda, Novartis, AbbVie Nathalie A. Johnson: Honoraria: Roche/Genentech, Merck; Consultancy/Advisory: Roche/Genentech, Merck, Bristol-Myers Squibb, AbbVie; Research funding: AbbVie Laura Maria Fogliatto: No conflicts to disclose Iara Goncalves: Consultancy/Advisory: Janssen; Speaker Bureau: Janssen; Research funding: Janssen, Takeda, Amgen, Bayer, Novartis, Merck, Bayer, Celgene, Glaxo, Bristol-Myers Squibb Jose S. R. de Oliveira: No conflicts to disclose Valeria Buccheri: Consultancy/Advisory: AstraZeneca; Travel, Accommodations, Expenses: AbbVie, Takeda: Research funding: Merck, Roche, Seattle Genetics, Takeda Guilherme Fleury Perini: Honoraria: Janssen, Takeda; Speaker Bureau: AbbVie, Janssen Neta Goldschmidt: No conflicts to disclose Iryna Kriachok: Consultancy/Advisory: Takeda, Janssen; Expert Testimony: Takeda, Janssen; Travel, Accommodations Expenses: Takeda, Merck, AbbVie, Roche; Research funding: Janssen, Bayer, Karyopharm, Merck, Acerta, AbbVie, Debiopharm Michael Dickinson: Honoraria: Merck, Roche, Takeda, Celgene, Novartis; Consultancy/Advisory: Merck, Roche, Takeda, Celgene, Novartis; Speaker Bureau: Merck, Roche, Takeda, Celgene, Novartis; Research funding: Merck, Roche, Takeda, Celgene, Novartis; Mieczyslaw Komarnicki: No conflicts to disclose Andrew McDonald: No conflicts to disclose Muhit Ozcan: Research funding: Merck, Bayer, Roche, Janssen, Celgene, Takeda, Archigen, Novartis, AbbVie; Honoraria: Roche, Takeda, AbbVie, Amgen, Bristol-Myers Squibb Naohiro Sekiguchi: Research funding (institution): Ono, A2 Healthcare, Astellas, Janssen, Merck Sharp & Dohme, Otsuka, Pfizer, PPD-SNBL, Sumitomo Dainippon, Daiichi Sankyo, BristolMyers Squibb Ying Zhu: Employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA Akash Nahar: Employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA Patricia Marinello: Employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and stockholder of Merck & Co., Inc., Kenilworth, NJ, USA; and has received travel expenses from Merck & Co., Inc. Pier Luigi Zinzani: Speakers’ bureaus for Verastem, Celltrion, Gilead, Janssen-Cilag, BristolMyers Squibb, Servier, Sandoz, Merck, Immune Design, Celgene, Portola, Roche, EUSA Pharma, Kyowa Kirin, and Sanofi; Advisory boards: Verastem, Celltrion, Gilead, Janssen-Cilag, Bristol-Myers Squibb, Servier, Merck & Co., Inc., Immune Design, Celgene, Portola, Roche, EUSA Pharma, Kyowa Kirin, and Sanofi; Consultant: Verastem, Merck, EUSA Pharma, and Sanofi. Ethics Approval Statement: The study was approved by the independent institutional review boards for each study site and conducted in accordance with the International Conference on Harmonization Guidelines for Good Clinical Practice and the Declaration of Helsinki.

Prospective exploration of the effect of adiposity and associated microbial factors on healing and progression of diabetic foot ulcers in Tanzania: study protocol of a longitudinal cohort study

BackgroundDiabetic foot ulcers (DFUs) are associated with high morbidity and mortality in low-income countries. This coexists with an increasing prevalence of obesity which has been reported to alter antimicrobial susceptibility...

Abstract LB-073: Generation of novel single cell-derived engineered master pluripotent cell line as a renewable source for off-the-shelf TCR-less CAR T cells in support of first-of-kind clinical trial

Abstract Adoptive transfer of autologous T cells expressing chimeric antigen receptor (CAR) has shown great promise in the treatment of blood malignancies. Challenges for the application of current CAR T cell therapies to broader and more diverse patient populations include inherent variability, cost of manufacture, and the requirement for precise genetic engineering to generate a highly homogenous and consistent CAR T cell product. We have previously reported pre-clinical data supporting the development of FT819, a first-of-kind off-the-shelf CAR T cell product candidate. FT819 is generated from a renewable clonal master human induced pluripotent stem cell (hiPSC) line derived from a single cell engineered to contain bi-allelic disruption of the T cell receptor (TCR) and a novel CD19 CAR targeted into the T cell receptor α constant (TRAC) locus to provide antigen specificity and enhanced efficacy while eliminating the possibility of graft versus host disease. For the manufacture of a clinical-grade FT819 clonal master hiPSC line, we sourced peripheral blood mononuclear cells from a fully consented and eligible donor with protocol overseen by an independent Institutional Review Board. Sourced T cells were enriched (&amp;gt;98%) through positive selection for TCRαβ, and cryopreserved cells were confirmed to have stable genome by karyotyping. Using our proprietary non-integrating cellular reprogramming platform, αβ T cells were reprogrammed into hiPSCs. Concurrently with the reprogramming process, reprogrammed cells received nuclease and donor template to mediate targeting of CD19 CAR into the TRAC locus with bi-allelic knockout of the TCR. To generate clonal lines, engineered cells were sorted by flow cytometry for various markers and single cells were seeded into individual wells of feeder-free 96-well plates. hiPSC clones were screened for bi-allelic integration of CAR into the TRAC locus by amplifying the genomic DNA flanking the homologous recombination site and confirmed by a SNP phasing assay. Clones were further screened for random integration of donor template by quantitative PCR (qPCR), and the CAR copy number was confirmed by droplet digital PCR. Out of 545 hiPSC clones screened, 27 clones (5%) had bi-allelic TRAC targeting with no detectable random integration. Maintenance of pluripotency was confirmed in 19 out of the 27 engineered hiPSC clones (70%). Seventeen clones were further tested and were confirmed to be footprint-free of transgenic reprogramming factors. Of the 18 clones tested for genomic stability, 12 clones had normal karyotypes (67%). Validated, TRAC-targeted hiPSC clones were cryopreserved (~150 vials per clone) and are currently being assessed for off-target editing, differentiation propensity into highly-functional T cells, genomic stability, clone identity, sterility and lack of mycoplasma detection. In summary, using our novel iPSC technology platform for reprogramming, single cell engineering and multiplex high-throughput screening of hiPSCs, we have generated clinical-grade clonal master hiPSC lines in support of our first-of-kind clinical trials evaluating FT819 allogenic off-the-shelf hiPSC-derived TCR-less TRAC-CAR19 T cells for the treatment of blood malignancies. Citation Format: Ramzey Abujarour, Yi-Shin Lai, Mochtar Pribadi, Tom Lee, Megan Robinson, Chelsea Ruller, Sjoukje Van der Stegen, Xiuyan Wang, Jolanta Stefanski, Juan Zhen, Jason Dinella, Greg Bonello, Janel Huffman, Helen Chu, Raedun Clarke, Alec Witty, Amanda Medcalf, Jaeger Davis, Stacey Moreno, Pieter Lindenbergh, Isabelle Riviere, Michel Sadelain, Bahram Valamehr. Generation of novel single cell-derived engineered master pluripotent cell line as a renewable source for off-the-shelf TCR-less CAR T cells in support of first-of-kind clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-073.

Using Real-Time Artificial Intelligence to Detect Upper Gastrointestinal Cancer by Endoscopy

Background: Upper gastrointestinal (UGI) cancers (including esophageal cancer, gastric cancer, etc.) are the most common cancers worldwide. Detection at early stage is the key for increasing the overall survival. Artificial intelligence (AI) using deep learning algorithms have made remarkable progress in medical imaging. Here we constructed a Gastrointestinal Artificial Intelligence Diagnostic System (GRAIDS) to improve the diagnostic accuracy of upper gastrointestinal (UGI) cancer by analyzing imaging data from clinical endoscopies. Methods: A multi-institutional, diagnostic study from six hospitals of different tiers across China was initiated. We included a total of 1,036,496 endoscopy images from 84,424 individuals to develop and validate the GRAIDS. We evaluated the performance of the GRAIDS using an internal validation set and a prospective validation set from a national hospital and five external validation sets from primary care hospitals. We also compared the diagnostic performance of the GRAIDS with that of endoscopists with three degrees of expertise (expert, competent, and trainee). Findings: The diagnostic accuracy in identifying UGI cancer was 0.955 in the internal validation set and 0.927 in the prospective set, and ranged from 0.915 to 0.977 in the five external validation sets. Compared with the expert endoscopists, the GRAIDS achieved a comparable sensitivity to experts (0.942 versus 0.945; P=0.692) and a superior sensitivity to competent (0.858, P<0.001) and trainee endoscopists (0.722, P<0.001). Interpretation: The GRAIDS achieved high diagnostic accuracy in detecting UGI cancer, with a sensitivity comparable to experts and was superior to nonexpert endoscopists. This system could support nonexpert endoscopists from primary basic hospitals by improving their diagnostic accuracy to the level of the experts, thus providing an opportunity for community-based hospitals to improve their effectiveness in UGI cancer diagnosis. Funding Statement: This research was supported by the National Key R&D Program of China (2018YFC1313300), the Natural Science Foundation of Guangdong Province (2017A030313485, 2014A030312015), the Science and Technology Program of Guangdong (2015B020232008), the Science and Technology Program of Guangzhou (201508020250, 201604020003, 2019B020227002). Declaration of Interests: No competing interests are declared. Ethics Approval Statement: This study was approved by all the relevant independent institutional review boards (IRB) and was performed according to the Helsinki declaration.

The role of biostatistics in institutional review boards

Research in humans is associated with risks. These risks are only justifiable if an independent institutional review board (IRB) has evaluated the planned research in terms of scientific integrity. Only scientifically sound research can be considered ethical. Abiostatistician should be amember of the IRB to assure adequate evaluation of fundamental topics like design, sample size estimation, and statistical analysis of the study.This paper presents core biostatistical concepts following the current guidelines of the International Council of Harmonization (ICHE6 and ICHE9). We discuss important pitfalls based on examples from published clinical trials. Furthermore, we discuss new concepts like estimands and their relevance for biostatisticians working in IRBs. Finally, we discuss the role of biostatisticians in IRBs and present thoughts on the way they should be trained.

Off the RAC

Off the RAC

Strengthening research capacity through the medical education partnership initiative: the Mozambique experience

BackgroundSince Mozambique’s independence, the major emphasis of its higher educational institutions has been on didactic education. Because of fiscal and human resource constraints, basic and applied research activities have been relatively modest in scope, and priorities have often been set primarily by external collaborators. These factors have compromised the scope and the relevance of locally conducted research and have limited the impact of Mozambique’s universities as major catalysts for national development.Case descriptionWe developed a multi-institutional partnership to undertake a comprehensive analysis of the research environment at Mozambique’s major public universities to identify factors that have served as barriers to the development of a robust research enterprise. Based on this analysis, we developed a multifaceted plan to reduce the impact of these barriers and to enhance research capacity within Mozambique.InterventionsOn the basis of our needs assessment, we have implemented a number of major initiatives within participating institutions to facilitate basic and applied research activities. These have included specialized training programmes, a reorganization of the research administration infrastructure, the development of multiple collaborative research projects that have emphasized local research priorities and a substantial investment in bioinformatics. We have established a research support centre that provides grant development and management services to Mozambique’s public universities and have developed an independent Institutional Review Board for the review of research involving human research subjects. Multiple research projects involving both communicable and non-communicable diseases have been developed and substantial external research support has been obtained to undertake these projects. A sizable investment in biomedical informatics has enhanced both connectivity and access to digital reference material. Active engagement with relevant entities within the Government of Mozambique has aligned institutional development with national priorities.ConclusionsAlthough multiple challenges remain, over the past 3 years significant progress has been made towards establishing conditions within which a broad range of basic, translational and clinical and public health research can be undertaken. Ongoing development of this research enterprise will enhance capacity to address critical locally relevant research questions and will leverage resources to accelerate the development of Mozambique’s national universities.