Citations

Abstract Our group has demonstrated that combinations of epigenetic modifiers produce potent synergy in pre-clinical models of PTCL, and has confirmed this data in early phase clinical studies. We showed that the combination of romidepsin and hypomethylating agents, decitabine or azacytidine, uniquely induces the expression of genes, including cancer testis antigens, gamma interferon and endogenous retrovirus. We are conducting a phase 1 study of pembrolizumab combined with pralatrexate alone (Arm A), with pralatrexate + decitabine (Arm B), or decitabine alone (Arm C) in patients with peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma. In addition, we are conducting a Phase 1/2A study of durvalumab combined with oral 5-azacitidine + romidepsin (Arm A), pralatrexate + romidepsin (Arm B), romidepsin (Arm C), or oral 5-azacitidine (Arm D) in patients with PTCL. Patient characteristics are listed in Table 1. We have treated a total of 12 patients across the 2 trials and 4 different Arms including pralatrexate plus pembrolizumab (3 patients), pralatrexate, decitabine and pembrolizumab (3 patients), decitabine and pembrolizumab (3 patients) and azacytidine, romidepsin and durvalumab (3 patients). Twelve patients out of 12 received at least one dose of drug and were evaluable for toxicity. There was a dose limiting toxicity (DLT) for each arm including prolonged grade 3 thrombocytopenia, febrile neutropenia, grade 3 hyponatremia and rash, and cytokine release syndrome, respectively. There were no treatment-related deaths. Eight patients out of 12 are evaluable for response at the time of this analysis. Three out of 8 patients achieved a complete remission, 3 out of 8 patients had a partial remission, and 2 out of 8 patients experienced progression of disease. Interestingly, all of the responses were seen in the triple combination of pralatrexate, decitabine, pembrolizumab and azacytidine, romidepsin and durvalumab. These preliminary clinical data suggest that the addition of immune-checkpoint inhibitors on an epigenetic backbone is safe and demonstrates encouraging responses in patient with PTCL and CTCL. These trials are registered at www.clinicaltrials.gov (NCT03240211, NCT03161223). Patient characteristics (n=12)Median age (range)68 (26-77)Sex, n (%) Male Female6 (50) 6 (50)Race, n (%)White/Non-Hispanic White/Hispanic Black Asian Unknown5 (42) 1 (8) 3 (25) 1 (8) 2 (17)Histology, n (%) PTCL, NOS AITL Mycosis Fungoides PTCL, NOS TFH ATLL Sezary Syndrome ALCL, ALK+2 (17) 2 (17) 2 (17) 1 (8) 1 (8) 1 (8) 1 (8)Stage at diagnosis IB II III IV Unknown1 (8) 2 (17) 3 (25) 4 (33) 2 (17)Median number of prior therapies (range) **2 unknown3 (0-5) Citation Format: Enrica Marchi, Helen Ma, Francesca Montanari, Ahmed Sawas, Jennifer K. Lue, Changchun Deng, Kareema T. Whitfield, Sandra Klein, Matthew V. Matthew, Freedy J. Loffredo, Luigi Scotto, Hyejung Lee, Hye A. Kim, Alice T. Jacobs, Aishling M. Rada, Karen A. Khan, Salvia Salvia, John Lister, Nora N. Benanni, Mark A. Francescone, Pier Luigi Zinzani, Wonseog Kim, Owen A. O'Connor. The integration of PD1 blockade with epigenetic therapy is highly active and safe in heavily treated patients with T-cell lymphoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT160.

Background: Representation trends of women, older adults, and ethnic/racial minorities in randomized controlled trials (RCTs) of atrial fibrillation (AF) are uncertain. Methods: We systematically reviewed 134 AF related RCTs (phase II and III) encompassing 149,162 participants using Medline and ClinicalTrials.gov through April 2019 to determine representation trends of women, older patients (≥ 75 years), and ethnic/racial minorities. Weighted data on the prevalence of AF from epidemiological studies were used to compare the representation of the studied groups of interest in AF RCTs to their expected burden of the disease. Results: Only 18.7% of the RCTs reported proportion of older patients, and 12.7% RCTs reported ethnic/racial minorities. In RCTs, proportions of women, Hispanics, Blacks, American Indian/Alaskan patients, Asians, native Hawaiian/Pacific Islanders and non-Whites were 35.2%, 11.9%, 1.2%, 0.2%, 14.2%, 0.05%, and 19.5%, respectively. The corresponding proportions in general population were 35.1%, 5.2%, 5.7%, 0.2%, 2.4%, 0.1%, and 22.5%, respectively. The weighted mean age (SD) across the trials was 65.3 (3.2) years which was less than the corresponding weighted mean age of 71.1 (4.5) years in the comparative epidemiological data. Conclusion: The reporting of older patients and ethnic/racial minorities was poor in RCTs of AF. The representation of women and American Indian/Alaskan natives matched their expected population share of disease burden. Hispanics and Asians were over-represented and Blacks, native Hawaiian/Pacific Islanders and non-Whites were under-represented in RCTs of AF. In nearly all studied RCTs, the reporting of racial demographics did not start until later part of last decade.

AbstractThe functional lumen imaging probe (FLIP) is a diagnostic tool that utilizes impedance planimetry to allow the assessment of luminal diameter and distensibility. It has been used primarily in esophageal diseases, in particular, in the assessment of achalasia, esophagogastric junction outflow obstruction, and eosinophilic esophagitis (EoE). The usage and publications have increased over the past decade and it is now an essential tool in the armamentarium of the esophagologist. Indications are emerging outside of the esophagus, in particular with regard to gastroparesis. Our paper will review the history of FLIP, optimal current usage, data for key esophageal disorders (including achalasia, reflux, and EoE), data for nonesophageal disorders, and our sense as to whether FLIP is ready for prime time, as well as gaps in evidence and suggestions for future research.

8106 Background: Bcl-2 family proteins are expressed in SCLC and are associated with chemotherapy resistance. AT-101 is an oral, pan Bcl-2 family protein inhibitor (Bcl-2, Bcl-XL, Mcl-1, and Bcl-w) and potent inducer of proapoptotic proteins. AT-101 has demonstrated activity in SCLC models, including those that express Mcl-1 and are resistant to other Bcl-2 inhibitors. The P1 portion of the study was previously reported. Methods: Pts ≥18 years of age, PS 0–1, with relapsed or refractory SCLC after first line chemotherapy with measurable disease per RECIST were eligible. Pts were stratified into 2 cohorts; cohort A ≥ 60 days and cohort B < 60 days relapse from prior chemotherapy and treated with T 1.25 mg/m2 daily and AT-101 40 mgs daily on days 1–5, q21 along with the use of myeloid growth factors. Adverse Events (AEs) were graded by the NCI CTCAE v. 3.0. Efficacy assessments (RECIST) were performed every 6-weeks. A 2-stage design was used with power/alpha of 80%/0.05 to detect a RR of > 25% and > 5%, in cohort A and B respectively. Results: 36 pts enrolled: ages 41–76; cohort A/B 23/13. The PR/SD/PD/NE rates were 17%/70%/9%/4% and 8%/54%/23%/15%, in cohorts A/B respectively. The median times to progression (TTP) were 18 and 13 weeks, respectively. The most common (>20 %) AEs (all grades): anemia (64%); neutropenia (53%); nausea (47%); fatigue (44%); thrombocytopenia (42%); dyspnoea (25%); and vomiting (22%). Most common Grade 3/4 related events (>5%): neutropenia (31%); thrombocytopenia (25%); anemia (14%); and asthenia (6%). No ileus was reported. Conclusions: AT-101 can be safely combined with T. The observed toxicities were consistent with the known rates of G4 cytopenias of T alone. The response rates observed did not meet the criteria for additional enrolment; however, many patients had a best response of SD and the median TTP in both cohorts was favorable compared to historical controls. Additional trials of AT-101 in SCLC are ongoing. [Table: see text]

Abstract ObjectiveThis study aims to determine the role of personal protective measures in the prevention of COVID-19 spread among the physicians working at different health facilities in Bangladesh.MethodsThis hospital-based cross-sectional comparative was conducted from May to June 2020. A total of 98 COVID-19 positive physicians and 92 COVID-19 negative physicians (physicians having no symptoms of COVID-19 or tested negative), were enrolled. The questionnaire was adapted from a tool developed by the World Health Organization (WHO) for risk assessment and management of exposure of health care workers in the context of COVID-19. Data was collected from the respondents online using google forms.ResultsThere was no significant difference in baseline information between COVID-19 positive and COVID-19 negative physicians. The physicians, who were unaware of direct participation in COVID-19 patient care, had higher odds of being COVID-19 positive (OR= 4.018; CI: 1.532-10.535). Also, the physicians, who were unaware of the COVID-19 status while performing aerosol generated procedure (AGP), had a higher chance of being COVID-19 positive, had a higher chance of being COVID-19 positive (OR= 2.522; CI: 1.020-6.233). Using face shields/goggles (OR=0.437; CI:0.228-0.837), regular decontamination of the patient’s surroundings (OR=0.392; CI:0.176-0.873) while usual take care of patients and use of N95 masks while performing AGP (OR=0.372; CI:0.159-0.873) had protective roles against COVID-19 among the physicians. The physicians who had reused the medical gown had two times more chance of being tested positive for COVID-19 than those who had not reused it (OR= 2.3; CI:1.251-4.259).ConclusionThe use of face shield/goggles and N95 masks and decontamination of the patient’s surroundings may give protection against COVID-19. Also, reusing medical gown should be avoided as much as possible.

Background While there is a long history of measuring death and disability from injuries, modern research methods must account for the wide spectrum of disability that can occur in an injury, and must provide estimates with sufficient demographic, geographical and temporal detail to be useful for policy makers. The Global Burden of Disease (GBD) 2017 study used methods to provide highly detailed estimates of global injury burden that meet these criteria. Methods In this study, we report and discuss the methods used in GBD 2017 for injury morbidity and mortality burden estimation. In summary, these methods included estimating cause-specific mortality for every cause of injury, and then estimating incidence for every cause of injury. Non-fatal disability for each cause is then calculated based on the probabilities of suffering from different types of bodily injury experienced. Results GBD 2017 produced morbidity and mortality estimates for 38 causes of injury. Estimates were produced in terms of incidence, prevalence, years lived with disability, cause-specific mortality, years of life lost and disability-adjusted life-years for a 28-year period for 22 age groups, 195 countries and both sexes. Conclusions GBD 2017 demonstrated a complex and sophisticated series of analytical steps using the largest known database of morbidity and mortality data on injuries. GBD 2017 results should be used to help inform injury prevention policy making and resource allocation. We also identify important avenues for improving injury burden estimation in the future.

Temporal inference from laboratory testing results and triangulation with clinical outcomes extracted from unstructured electronic health record (EHR) provider notes is integral to advancing precision medicine. Here, we studied 246 SARS-CoV-2 PCR-positive (COVID pos ) patients and propensity-matched 2460 SARS-CoV-2 PCR-negative (COVID neg ) patients subjected to around 700,000 lab tests cumulatively across 194 assays. Compared to COVID neg patients at the time of diagnostic testing, COVID pos patients tended to have higher plasma fibrinogen levels and lower platelet counts. However, as the infection evolves, COVID pos patients distinctively show declining fibrinogen, increasing platelet counts, and lower white blood cell counts. Augmented curation of EHRs suggests that only a minority of COVID pos patients develop thromboembolism, and rarely, disseminated intravascular coagulopathy (DIC), with patients generally not displaying platelet reductions typical of consumptive coagulopathies. These temporal trends provide fine-grained resolution into COVID-19 associated coagulopathy (CAC) and set the stage for personalizing thromboprophylaxis.

Background and AimsColorectal cancer (CRC) is the third most common cause of cancer worldwide. Studies have shown a strong association between screening colonoscopy and a reduced risk of death from colorectal cancers. The incidence of poor bowel preparation has been reported in up to 25% cases. We conducted a systematic review and comprehensive meta‐analysis to evaluate the effect of patient education using multimedia platforms on adenoma detection rate and adequacy of bowel preparation.MethodsMultiple databases were searched through May 2020 for studies that reported the efficacy of multimedia education (smartphone app and online audio‐visual aids) in improving quality of bowel preparation and its effect on adenoma detection rate (ADR). Meta‐analysis was performed to determine whether multimedia based patient education (MM) helps improve ADR and bowel preparation quality as compared to controls (CT).ResultsWe included 13 randomized controlled trials with a total of 3754 patients. Eight studies reported outcomes on ADR and 12 reported on adequacy of bowel preparation. Overall ADR was higher in patients receiving multimedia based education as compared to CT (risk ratio (RR) 1.25, confidence interval (CI) 1.01–1.56, P = 0.04). A higher proportion of patients receiving multimedia based education achieved adequate bowel preparation (RR 1.2, CI 1.1–1.3, P = 0.001). In patients with mean age over 50 years, ADR was better in MM cohort as compared to controls (RR 1.3, CI 1.1–1.6, P = 0.001).ConclusionPre‐colonoscopy patient education using multimedia based platforms seems to improve ADR and the adequacy of bowel preparation.

Study Design. Retrospective analysis of prospectively collected registry data. Objective. To develop and validate prediction models for 12-month patient-reported outcomes of disability, pain, and myelopathy in patients undergoing elective cervical spine surgery. Summary of Background Data. Predictive models have the potential to be utilized preoperatively to set expectations, adjust modifiable characteristics, and provide a patient-centered model of care. Methods. This study was conducted using data from the cervical module of the Quality Outcomes Database. The outcomes of interest were disability (Neck Disability Index:), pain (Numeric Rating Scale), and modified Japanese Orthopaedic Association score for myelopathy. Multivariable proportional odds ordinal regression models were developed for patients with cervical radiculopathy and myelopathy. Patient demographic, clinical, and surgical covariates as well as baseline patient-reported outcomes scores were included in all models. The models were internally validated using bootstrap resampling to estimate the likely performance on a new sample of patients. Results. Four thousand nine hundred eighty-eight patients underwent surgery for radiculopathy and 2641 patients for myelopathy. The most important predictor of poor postoperative outcomes at 12-months was the baseline Neck Disability Index score for patients with radiculopathy and modified Japanese Orthopaedic Association score for patients with myelopathy. In addition, symptom duration, workers’ compensation, age, employment, and ambulatory and smoking status had a statistically significant impact on all outcomes (P < 0.001). Clinical and surgical variables contributed very little to predictive models, with posterior approach being associated with higher odds of having worse 12-month outcome scores in both the radiculopathy and myelopathy cohorts (P < 0.001). The full models overall discriminative performance ranged from 0.654 to 0.725. Conclusions. These predictive models provide individualized risk-adjusted estimates of 12-month disability, pain, and myelopathy outcomes for patients undergoing spine surgery for degenerative cervical disease. Predictive models have the potential to be used as a shared decision-making tool for evidence-based preoperative counselling. Level of Evidence: 2.