Citations

SummaryBackgroundNeoplasia detection rate, the proportion of Barrett's oesophagus patients with high‐grade dysplasia or oesophageal adenocarcinoma detected at index surveillance endoscopy has been proposed as a quality metric. However, the correlation between neoplasia detection rate and a clinically relevant outcome like post‐endoscopy Barrett's neoplasia remains unknown. Post‐endoscopy Barrett's neoplasia refers to the rate of high‐grade dysplasia or oesophageal adenocarcinoma on repeat endoscopy within one year of an index screening examination revealing non‐dysplastic Barrett's oesophagus or low‐grade dysplasia.AimTo assess correlation between neoplasia detection rate and post‐endoscopy Barrett's neoplasia.MethodsWe performed a systematic search of multiple databases from date of inception to June 2021 to identify cohort studies reporting both neoplasia detection rate and post‐endoscopy Barrett's neoplasia. Data from each study were pooled using a random effects model, and their correlation assessed using meta‐regression. Heterogeneity was assessed and a priori planned subgroup analyses were conducted.ResultsTen studies with 27 894 patients with Barrett's oesophagus were included. The pooled neoplasia detection rate and post‐endoscopy Barrett's neoplasia were 5.0% (95% CI: 3.4%‐7.1%, I2 = 97%) and 19.6% (95% CI: 10.1%‐34.7%, I2 = 96%), respectively. Meta‐regression revealed a statistically significant inverse relationship between the two variables (coefficient −3.50, 95% CI: −4.63 to −2.37, P < 0.01). With every 1% increase of neoplasia detection rate, post‐endoscopy Barrett's neoplasia decreased by 3.50%. Heterogeneity was high despite adjusting for study quality and performing several subgroup analyses.ConclusionWe observed a statistically significant inverse correlation between neoplasia detection rate and post‐endoscopy Barrett's neoplasia. Additional studies are needed to further validate this correlation.

Abstract Richter's transformation (RT) is a clinically challenging and aggressive transformation of CLL (Chronic lymphocytic leukemia) to lymphoma. Immune-checkpoint therapy has improved outcomes in selective lymphoma types. Nearly 40% of RT patients respond to anti-PD1, while the underlying CLL do not show any response, and 10% of CLL patients progress post-anti-PD1 treatment. Previous studies mostly focused on T-cell responses elicited by anti-PD1, however, intrinsic changes in CLL and RT B-cells induced by the treatment remains elusive. We hypothesized that pre-existing active transcriptional circuitry and distinct B-cell subsets in the CLL and RT B-cells may determine the response to anti-PD1 treatment. Peripheral blood mononuclear cells (PBMCs) from 3 patients who received pembrolizumab(anti-PD1) as a single agent. Samples were obtained at baseline and 3 months post-treatment initiation. Among these patients, 2 are progressors while 1 is a responder. We performed single-cell RNAseq (10X Genomics) on B-cells enriched from PBMCs derived from 3 samples (1 Responder: RS2, 2 progressors: CLL14 and CLL17) before and after treatment using chromium single cell 3' gene expression library. A total of ~10000 cells were captured with an average detection of 1000 genes/sample. To delineate the transcriptional changes upon the anti-PD1 treatment, we first integrated the single-cell data from 6 samples (before and after Pembro) and performed unsupervised clustering analysis using UMAP (Uniform Manifold Approximation and projection). We identified 8 different clusters based on highly expressed marker genes. Cluster 2(C2) was increased in the responder as compared to the progressors post-pem treatment. To determine the activated pathways in each cluster, we performed gene-set enrichment analysis (GSEA) using the Enrichr method. This analysis revealed upregulation of distinct pathways related to IFNG/MYC(C1), IFNG(C2), ER stress(C3), B-cell dependent T cell activation related pathway(C4), MYC targets/TNFα(C5,6,7) indicating intra-tumor transcriptional heterogeneity. To decipher the intratumor cell differentiation changes, we performed pseudotime trajectory analysis using Monocle 2 coupled with B cell developmental stage markers. We identified 7 different states, with distinct changes of state in responder sample RS2 (State 4,5, 6, and 7 were increased in RS2 post-treatment) while CLL samples(progressors) did not have distinct changes. Integration with B cell development revealed that aggressive B cells with CD38 expression were highly induced upon anti-PD1 in responder RS2 while regulatory (CD1d) and memory B cells (CD27) remained the same, suggesting PD1 induced intrinsic changes contributing to the disease response. We identified distinct transcriptional states in B cells within responders and progressors which may govern the intra-tumor and inter-tumor heterogeneity to the anti-PD1 response. Citation Format: Prajish Sundaram Iyer, Lu Yang, Yang Zhi Zhang, Hyo Jin Kim, Charla Secreto, Sutapa Sinha, Neil Kay, Stephen Ansell, Wei Ding, Lili Wang. Tumor intrinsic changes determine immune-checkpoint response in Richter's transformation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1612.

Background: It remains unclear if asthma is a risk factor associated with worse outcomes among patients with coronavirus disease 2019 (COVID-19). Methods: We performed a comprehensive database search for studies published from January 1, 2019, to October 2, 2020. We included studies that evaluated outcomes among patients with COVID-19 and underlying asthma. Outcomes of interest included the need for hospitalization, length of hospitalization, intensive care unit (ICU) admission, and death. The meta-analysis was conducted by using random-effects methodology. Results: A total of 389 studies were identified through data base searches. After abstract and full-text screening, 16 observational studies with 92,275 patients were included in the analysis. Of the 16 studies, 15 were retrospective and 1 was a prospective cohort study. The average age was 39.6 years, with 48% female patients. Six of the studies included pediatric patients, and one of these studies only evaluated pediatric patients. One study only evaluated pregnant patients. Among patients with COVID-19, the presence of asthma was not associated with any significant increase in risk of hospitalization (odds ratio [OR] 1.46 [95% confidence interval {CI}, 0.29-7.28]), length of hospitalization (1.59 days [‐0.55 to 3.74]), ICU admission (OR 1.65 [95% CI, 0.56-4.17]), or death (OR 0.73 [95% CI, 0.38-1.40]). The overall risk of bias of the included studies was high. Conclusion: Among the patients with COVID-19, asthma did not seem to significantly increase the risk of hospitalization, length of hospitalization, ICU admission, or death.

INTRODUCTION: Minimally invasive tests for Barrett's esophagus (BE) detection have raised the prospect of broader nonreflux-based testing. Cost-effectiveness studies have largely studied men aged 50 years with chronic gastroesophageal reflux disease (GERD) symptoms. We evaluated the comparative cost effectiveness of BE screening tests in GERD-based and GERD-independent testing scenarios. METHODS: Markov modeling was performed in 3 scenarios in 50 years old individuals: (i) White men with chronic GERD (GERD-based); (ii) GERD-independent (all races, men and women), BE prevalence 1.6%; and (iii) GERD-independent, BE prevalence 5%. The simulation compared multiple screening strategies with no screening: sedated endoscopy (sEGD), transnasal endoscopy, swallowable esophageal cell collection devices with biomarkers, and exhaled volatile organic compounds. A hypothetical cohort of 500,000 individuals followed for 40 years using a willingness to pay threshold of $100,000 per quality-adjusted life year (QALY) was simulated. Incremental cost-effectiveness ratios (ICERs) comparing each strategy with no screening and comparing screening strategies with each other were calculated. RESULTS: In both GERD-independent scenarios, most non-sEGD BE screening tests were cost effective. Swallowable esophageal cell collection devices with biomarkers were cost effective (<$35,000/QALY) and were the optimal screening tests in all scenarios. Exhaled volatile organic compounds had the highest ICERs in all scenarios. ICERs were low (<$25,000/QALY) for all tests in the GERD-based scenario, and all non-sEGD tests dominated no screening. ICERs were sensitive to BE prevalence and test costs. DISCUSSION: Minimally invasive nonendoscopic tests may make GERD-independent BE screening cost effective. Participation rates for these strategies need to be studied.

The Genitourinary Pathology Society (GUPS) undertook a critical review of the recent advances in bladder cancer focusing on important topics of high interest for the practicing surgical pathologist and urologist. This review represents the second of 2 manuscripts ensuing from this effort. Herein, we address the effective reporting of bladder cancer, focusing particularly on newly published data since the last 2016 World Health Organization (WHO) classification. In addition, this review focuses on the importance of reporting bladder cancer with divergent differentiation and variant (subtypes of urothelial carcinoma) histologies and the potential impact on patient care. We provide new recommendations for reporting pT1 staging in diagnostic pathology. Furthermore, we explore molecular evolution and classification, emphasizing aspects that impact the understanding of important concepts relevant to reporting and management of patients.

The Genitourinary Pathology Society (GUPS) undertook a critical review of the recent advances in bladder neoplasia with a focus on issues relevant to the practicing surgical pathologist for the understanding and effective reporting of bladder cancer, emphasizing particularly on the newly accumulated evidence post-2016 World Health Organization (WHO) classification. The work is presented in 2 manuscripts. Here, in the first, we revisit the nomenclature and classification system used for grading flat and papillary urothelial lesions centering on clinical relevance, and on dilemmas related to application in routine reporting. As patients of noninvasive bladder cancer frequently undergo cystoscopy and biopsy in their typically prolonged clinical course and for surveillance of disease, we discuss morphologies presented in these scenarios which may not have readily applicable diagnostic terms in the WHO classification. The topic of inverted patterns in urothelial neoplasia, particularly when prominent or exclusive, and beyond inverted papilloma has not been addressed formally in the WHO classification. Herein we provide a through review and suggest guidelines for when and how to report such lesions. In promulgating these GUPS recommendations, we aim to provide clarity on the clinical application of these not so uncommon diagnostically challenging situations encountered in routine practice, while also importantly advocating consistent terminology which would inform future work.

Introduction Visceral obesity is associated with GERD and, traditionally, it has been assumed that visceral fat predisposes to GERD primarily by increasing intra‐abdominal pressure. However, transmission electron microscopy (TEM) of esophageal biopsies from obese individuals without GERD exhibit dilated intercellular spaces (DIS) and, in earlier studies, we found that substances secreted by mature adipocytes in visceral fat from obese patients impair esophageal epithelial barrier function, induce DIS and reduce transepithelial resistance (TER). There is a fat pad at the gastroesophageal junction (GEJ) that is in intimate contact with the distal esophagus. We now explore whether whole GEJ fat tissue of obese individuals secretes substances that impair esophageal barrier function. Methods We obtained GEJ fat from 3 obese (BMI 46, 60, 74) and 3 non‐obese (BMI 24, 26, 27) patients having foregut surgery. Human esophageal squamous cells were seeded into transwells and grown to confluence for 3 days. On day 4, cells were raised to an air‐liquid interface (ALI) to allow for differentiation, stratification, and esophageal barrier formation. ALI cultures were exposed to conditioned media (CM) from GEJ fat or to control medium beginning at day 4. TER was measured on days 4, 6, and 8 using the EVOM2 Epithelial Volt/Ohm Meter. On day 8, ALI cultures were stained with H&E and Ki‐67 and imaged; barrier permeability was assessed by a biotinylation reagent applied to the ALI surface. TEM of ALIs and of esophageal biopsies from 2 non‐obese and 2 obese patients without GERD were assessed. Results CM from all 3 obese patients significantly reduced TER on days 6 and 8; CM from 2 non‐obese patients did not reduce TER whereas CM from 1 non‐obese patient induced a slight reduction in TER at day 8 (Table 1). Marked DIS were found only in ALI cultures grown with CM from obese patients. In ALIs grown with CM from non‐obese patients, the biotinylation reagent stopped at the superficial layers of esophageal cells. In contrast, the biotinylation reagent diffused through all cell layers in ALIs grown with obese patient CM. Increases in basaloid cells and in Ki‐67 were found in ALIs grown with obese patient CM. TEMs of ALIs grown with non‐obese patient CM demonstrated well‐oriented cell‐cell junctions similar to TEMs of non‐obese patient esophageal biopsies. In contrast, ALIs grown with obese patient CM demonstrated cell‐cell junctional structures that were disorganized, aggregated, and floating within the DIS, similar in appearance to TEMs of the obese patients’ esophageal biopsies. Conclusion Substances produced by GEJ fat of obese patients impair esophageal epithelial barrier integrity, cause basal cell hyperplasia and DIS, and disrupt intercellular connections. These findings in ALI cultures recapitulate abnormalities seen by TEM in esophageal biopsies of obese patients.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant hereditary disorder that results in arteriovenous malformations (AVMs) in the nose, mucocutaneous surfaces and visceral organs, including lung, brain, liver, bowel and rarely spinal cord. We describe a case of a young child with HHT who presented with acute paraparesis due to acute thrombosis of a spinal perimedullary arteriovenous fistula. Patient underwent coil embolization of spinal arteriovenous shunt with resolution of clinical symptoms. This case highlights the possibility of catastrophic complications in young children with HHT, the potential preventive role of screening for spinal AVMs in HHT and the importance of timely intervention.