Citations

AbstractAimTo identify the appropriate methods of synovial fluid (SF) specimen storage, manipulation and handling for crystal associated arthritides (CAA) diagnosis.MethodA systematic literature review was conducted using 5 medical databases to identify diagnostic studies assessing SF specimen handling for calcium pyrophosphate (CPP) and monosodium urate (MSU) crystals identification. All included studies were rated for quality using the Quality Assessment of Diagnostic Accuracy Studies 2.ResultsFifteen studies, including 2 non‐English language manuscripts, were included. Eight studies examined both types of crystals, while 3 studies examined CPP and 4 studies examined MSU crystals only. Overall, MSU crystals were more stable over time compared to CPP crystals. MSU stability was generally independent of time, preservative and temperature. CPP crystals deteriorated with time and were more stable if refrigerated. Ethylenediaminetetraacetic acid (EDTA) was a suitable preservative. Re‐examining an initially negative SF sample at 24 hours facilitated detection of additional cases. Very few studies had an overall low risk of bias and applicability.ConclusionMonosodium urate crystals remain stable over time independent of storage time, temperature and preservative. CPP crystals are mostly stable for 24‐48 hours but can deteriorate with time. Overall, SF crystal examination should ideally be done within 24‐48 hours. They may be stored at room temperature without any preservative. Otherwise, refrigeration (4°C/39°F) and EDTA preservation is reasonable. Stored SF re‐examination, at 24 hours, helps identify a small number of additional MSU and CPP cases. Centrifugation techniques allow better and easier crystal identification, particularly CPP. Most studies were of unclear or low quality.

Crystal-storing histiocytosis (CSH) is an uncommon condition in which histiocytes accumulate a crystalline matter within their cytoplasm. Generally, those crystals are composed of either monoclonal or polyclonal immunoglobulin chains, which have a strong association with an underlying lymphoproliferative or plasma cell disorder (LP-PCD). Rarely, CSH has been reported as local or generalized manifestation of a variety of benign disorders. These cases are associated with crystals composed of nonimmunoglobulin substances. We are reporting an exceptional case of a local colonic CSH with Charcot–Leyden crystals. This patient underwent a screening colonoscopy that detected some polyps. The biopsy reported tubular adenomas, with a markedly dense, transmural inflammatory infiltrates, which were predominantly composed of eosinophils and crystal-storing histiocytes containing Charcot–Leyden crystals. The patient had a negative workup for LP-PCD and autoimmune conditions, including a normal skeletal survey and bone marrow aspirate/biopsy. The only positive laboratory workup was an elevated absolute eosinophil count and a positive IgG anti-Strongyloides antibody. Giving those findings, this parasitic infection is the most likely etiology of the CSH in our patient. Although there was an initial negative evaluation for LP-PCD, close monitoring of patients with either immunoglobulin or nonimmunoglobulin CSH is recommended.

Abstract Purpose: The safety and preliminary efficacy of MEDI1873, an agonistic IgG1 fusion protein targeting glucocorticoid-induced TNF receptor–related protein (GITR), were evaluated in an open-label, first-in-human, phase I, dose escalation study in previously treated patients with advanced solid tumors. Patients and Methods: Two single-patient cohorts at 1.5 and 3 mg i.v. were followed by 3+3 dose escalation in six cohorts at 7.5, 25, 75, 250, 500, and 750 mg, all every 2 weeks, for up to 52 weeks. Primary endpoints were safety and tolerability, dose-limiting toxicities (DLT), and MTD. Secondary endpoints included antitumor activity, pharmacokinetics, immunogenicity, and pharmacodynamics. Results: Forty patients received MEDI1873. Three experienced DLTs: grade 3 worsening tumor pain (250 mg); grade 3 nausea, vomiting, and headache (500 mg); and grade 3 non-ST segment elevation myocardial infarction (750 mg). An MTD was not reached and treatment was well tolerated up to 500 mg. Most common treatment-related adverse events were headache (25%), infusion-related reaction (17.5%), and decreased appetite (17.5%). MEDI1873 exposure was dose proportional. Antidrug–antibody incidence was low. MEDI1873 increased peripheral CD4+ effector memory T-cell proliferation as well as cytokines associated with effector T-cell activation at dose levels ≥75 mg. The best response was stable disease (SD) in 17 patients (42.5%), including 1 unconfirmed partial response. Eight patients (20.0%) had SD ≥24 weeks. Conclusions: MEDI1873 showed acceptable safety up to 500 mg i.v. every 2 weeks with pharmacodynamics activity, and prolonged SD in some patients. However, further development is not planned because of lack of demonstrated tumor response.

Abstract Despite progress of immune checkpoint therapies, many cases of non-small cell lung cancer (NSCLC) are refractory or acquire resistance to current therapies. Antibody blockade of semaphorin 4D (SEMA4D, CD100) can overcome resistance mechanisms of immune exclusion and myeloid suppression. Importantly, combinations of anti-SEMA4D with various immunotherapies enhanced T cell infiltration and activity, leading to durable tumor regression in preclinical models. Pepinemab (VX15/2503) is a first-in-class humanized monoclonal antibody targeting SEMA4D. The CLASSICAL-Lung clinical trial tests the combination of pepinemab with avelumab to couple immune activation via checkpoint inhibition with beneficial modifications of the tumor immune microenvironment via pepinemab. Here, we present interim results of the Phase 2 portion of the CLASSICAL-Lung study. This phase 1b/2, open label, single arm, first-in-human combination study is designed to evaluate the safety, tolerability and efficacy of pepinemab in combination with avelumab in 62 subjects with advanced stage (IIIB/IV) NSCLC, including immunotherapy-naïve (ION) patients and patients whose tumors progressed during or following immunotherapy (IOF). Dose escalation was successfully completed, presented previously, and no concerning safety signals have been identified to date. Among 29 evaluable IOF patients, 2 experienced confirmed partial response (PR) with 66% and 52% tumor reduction following acquired resistance to prior treatment with pembrolizumab, 15 additional patients experienced stable disease (SD), and at least 7 patients had durable clinical benefit of ≥ 23 weeks. Among 21 evaluable ION patients, 5 experienced PR, and 3 patients had clinical benefit ≥ 1 year. The disease control rate was 81%. Analysis of pre- and on-treatment biopsies demonstrated increased CD8+ T cell density correlating with response, with reduction or elimination of tumor in 10/11 biopsies from subjects with PR or SD. It was notable that 79% of patients who experienced PR or SD were reported to have tumors with negative or low PD-L1 expression. Enrollment is complete and this interim analysis suggest the combination of pepinemab plus avelumab is well tolerated and shows initial clinical signals of antitumor activity. Updated clinical response data, as well as additional immunophenotyping of both inflammatory and suppressive myeloid cells will be presented. Citation Format: Jonathan W. Goldman, Terrence L. Fisher, Elizabeth Evans, John E. Leonard, Desa Rae Pastore, Crystal Mallow, Ernest Smith, Andreas Schröeder, Kevin Chin, Michael Shafique, Thaddeus Beck, Megan A. Baumgart, Ramaswamy Govindan, Nashat Gabrail, Rachel E. Sanborn, Alexander I. Spira, Nagashree Seetharamu, Yanyan Lou, Aaron S. Mansfield, Maurice Zauderer. Interim results from CLASSICAL-Lung, phase 1b/2 study of pepinemab (VX15/2503) in combination with avelumab in advanced NSCLC [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 CT191.

The NCCN Guidelines for Survivorship provide screening, evaluation, and treatment recommendations for consequences of adult-onset cancer and its treatment, with the goal of helping healthcare professionals who work with survivors, including those in primary care. The guidelines also provide recommendations to help clinicians promote physical activity, weight management, and proper immunizations in survivors and facilitate care coordination to ensure that all of the survivors’ needs are addressed. These NCCN Guidelines Insights summarize additions and changes made to the guidelines in 2020 regarding cardiovascular disease risk assessment and screening for subsequent primary malignancies.

INTRODUCTION: Esophageal dysmotility including features of achalasia may develop because of bariatric surgery. However, the prevalence of these complications is unknown. We sought to define the prevalence of dysphagia and major esophageal motility disorders including achalasia after bariatric surgery through a large retrospective database review. METHODS: Patients with a history of laparoscopic sleeve gastrectomy or Roux-en-Y gastric bypass who underwent a diagnostic high-resolution impedance manometry (HRIM) either before or after bariatric surgery across 3 large tertiary referral sites from June 2012 through February 2019 were identified from a procedural database. HRIM studies were interpreted per the Chicago classification v3.0 by a blinded investigator (K.R.). Demographic/clinical features were collected. In addition, patients who underwent bariatric surgery from January 2014 to April 2015 were contacted and administered a validated symptom assessment survey to gauge the overall prevalence of dysphagia in a postbariatric population. RESULTS: A total of 137 patients were identified, including 97 who underwent HRIM after bariatric surgery (laparoscopic sleeve gastrectomy [n = 39, 40.1%]; Roux-en-Y gastric bypass [n = 58, 59.8%]) at a median of 5.84 years (interquartile range 2.1–12.5) postoperatively and 40 preoperative bariatric surgery candidates with medically complicated obesity. A manometric pattern consistent with achalasia was identified in 7 (7.2%) postsurgical patients compared with none in the preoperative group ( P = 0.08). We further identified a separate achalasia-like pattern defined by aperistalsis and increased intragastric pressure (postobesity surgery esophageal dysfunction [POSED]) in 5 (5.2%) postsurgical patients vs none found preoperatively ( P = 0.14). Achalasia or POSED was associated with postbariatric surgery (12.4% vs 0%, P = 0.02). Increasing time since surgery was independently associated with the development of achalasia (median 12.5 vs 5.8 years, P = 0.02), POSED (median 15.0 vs 5.8 years, P = 0.02) and major motility disorders (6.6 vs 4.9 years, P = 0.01). Furthermore, among 271 postbariatric surgery patients contacted for symptom assessment via survey, the prevalence of dysphagia was 13.7% at a mean 3.9 years after surgery. DISCUSSION: Postoperative dysphagia is a common long-term complication of bariatric surgery. This is potentially the consequence of a time-dependent association with the development of postoperative esophageal dysmotility, particularly achalasia and POSED. Consequently, esophageal dysmotility may be an important under-recognized complication of bariatric surgery.

Abstract Background Median overall survival is 12 to 15 months in patients with metastatic adrenal cortical carcinoma (ACC). Etoposide, doxorubicin, and cisplatin with or without the adrenolytic agent mitotane is considered the best first-line approach in this context, but has limited activity and no curative potential; additional salvage therapeutic options are needed. Methods Fifteen total patients with recurrent/metastatic ACC were treated with single-agent multikinase inhibitors (MKI) (n = 8), single-agent PD-1 inhibition (n = 8), or cytotoxic chemotherapy plus PD-1 inhibition (n = 4) at our institution as later-line systemic therapies in efforts to palliate disease and attempt to achieve a therapeutic response when not otherwise possible using standard approaches. Results Two of 8 patients (25%) treated with single-agent MKI achieved a partial response (PR), including 1 PR lasting 23.5 months. Another 3 patients (38%) had stable disease (SD); median progression-free survival (PFS) with single-agent MKI was 6.4 months (95% confidence interval [CI] 0.8—not reached). On the other hand, 2 of 12 patients (17%) treated with PD-1 inhibitors (either alone or in combination with cytotoxic chemotherapy) attained SD or better, with 1 patient (8%) achieving a PR; median PFS was 1.4 months (95% CI 0.6-2.7). Conclusions Our single-institution experience suggests that select ACC patients respond to late-line MKI or checkpoint inhibition despite resistance to cytotoxic agents. These treatments may be attractive to ACC patients with limited other therapeutic options. The use of MKI and immunotherapy in ACC warrants prospective investigation emphasizing parallel correlative studies to identify biomarkers that predict for response.

AbstractCOVID-19 was declared a global pandemic by the WHO and has affected millions of patients around the world. COVID-19 disproportionately affects persons with endocrine conditions, thus putting them at an increased risk for severe disease. We discuss the mechanisms that place persons with endocrine conditions at an additional risk for severe COVID-19 and review the evidence. We also suggest precautions and management of endocrine conditions in the setting of global curfews being imposed and offer practical tips for uninterrupted endocrine care.