Citations

INTRODUCTION: Studies have shown that dysplasia in Barrett's esophagus (BE) has a predilection for the right hemisphere. There is limited information on the longitudinal distribution. The aim was to determine both the longitudinal and circumferential distributions of dysplasia and early neoplasia from 3 prospective studies. METHODS: This is a pooled analysis from 3 prospective studies of patients with treatment-naive BE. Both circumferential and longitudinal locations (for BE segments greater than 1 cm) of dysplastic and early neoplastic lesions were recorded. RESULTS: A total of 177 dysplastic and early neoplastic lesions from 91 patients were included in the pooled analysis; of which 59.3% (n = 105) were seen on high-definition white light endoscopy, 29.4% (n = 52) on advanced imaging, and 11.2% (n = 20) with random biopsies. The average Prague score was C3M5. Of 157 lesions within BE segments greater than 1 cm, 49 (34.8%) lesions were in the proximal half, whereas 92 lesions (65.2%) were in the distal half ( P < 0.001). The right hemisphere of the esophagus contained 55% (86/157) of the total lesions compared with 45% (71/157) for the left hemisphere ( P = 0.02). This was because of the presence of high-grade dysplasia being concentrated in the right hemisphere compared with the left hemisphere (60% vs 40%, P = 0.002). DISCUSSION: In this pooled analysis of prospective studies, both low-grade dysplasia and high-grade dysplasia are more frequently found in the distal half of the Barrett's segment. This study confirms that the right hemisphere is a hot spot for high-grade dysplasia. Careful attention to these locations is important during surveillance endoscopy.

Abstract Wnt signaling is a major driver of stemness and chemoresistance in ovarian cancer, yet the genetic drivers that stimulate its expression remain largely unknown. Unlike other cancers, mutations in the Wnt pathway are not reported in high-grade serous ovarian cancer (HGSOC). Hence, a key challenge that must be addressed to develop effective targeted therapies is to identify nonmutational drivers of Wnt activation. Using an miRNA sensor-based approach, we have identified miR-181a as a novel driver of Wnt/β-catenin signaling. miR-181ahigh primary HGSOC cells exhibited increased Wnt/β-catenin signaling, which was associated with increased stem-cell frequency and platinum resistance. Consistent with these findings, inhibition of β-catenin decreased stem-like properties in miR-181ahigh cell populations and downregulated miR-181a. The Wnt inhibitor SFRP4 was identified as a novel target of miR-181a. Overall, our results demonstrate that miR-181a is a nonmutational activator of Wnt signaling that drives stemness and chemoresistance in HGSOC, suggesting that the miR–181a–SFRP4 axis can be evaluated as a novel biomarker for β-catenin–targeted therapy in this disease. Significance: These results demonstrate that miR-181a is an activator of Wnt signaling that drives stemness and chemoresistance in HGSOC and may be targeted therapeutically in recurrent disease.

INTRODUCTION: Systemic sclerosis or scleroderma (SSc) is a chronic autoimmune disease that renders the esophagus prone to significant gastroesophageal reflux due to impaired esophageal clearance and reduced lower esophageal sphincter pressure. The reported prevalence of Barrett's esophagus (BE) in women with SSc varies from 2% to 37% and is derived from older studies with small sample sizes. We aimed to assess the prevalence of BE in a large cohort of women with SSc. METHODS: Women with SSc referred from the Mayo Clinic Arizona Rheumatology Clinic who completed esophagogastroduodenoscopy between 2002 and 2020 were included. Demographic and high-resolution manometry data were evaluated. The diagnosis of scleroderma was confirmed by an expert rheumatologist. The BE diagnosis was confirmed by an expert gastrointestinal pathologist. RESULTS: There were 235 women with SSc who underwent EGD. High-resolution manometry (HRM) was completed in 172 patients. Women with SSc with BE were significantly more likely to have scleroderma esophagus (absent contractility with hypotensive lower esophageal sphincter) on HRM than women with SSc without BE ( P = 0.018). There were 30 patients with SSc (12.8%) with histologically proven BE. Dysplasia was found in 13 (43.3%): 4 with indefinite, 7 with low grade, and 2 with adenocarcinoma. The incidence of any dysplasia was 5.3% per year (0.9% per year for adenocarcinoma). DISCUSSION: This the largest study on prevalence of BE in women with SSc, yielding a prevalence of 12.8%. Women with SSc with BE were significantly more likely to have absent contractility with hypotensive lower esophageal sphincter findings on HRM. The high prevalence and incidence of dysplasia found suggest that women with SSc should be included in the screening recommendations for BE.

Richter's syndrome (RS) arising from chronic lymphocytic leukemia (CLL) is a striking example of an aggressive malignant histology that emerges from indolent cancer. A major barrier to disease control in CLL, RS is associated with poor clinical outcomes and limited survival. The genetic basis of RS is poorly understood and its relationship to antecedent CLL remains incompletely characterized. Notable challenges to the genomic study of RS includes those of sample acquisition, the distinction between true tumor events rather than sequence artifacts in archival fixed tissue, and the limitations of available computational techniques for deconvoluting admixtures of CLL and RS DNA within the same biopsy specimen. To address these challenges and characterize the genetic profile of RS, we performed whole-exome sequencing (WES) on samples collected from 42 patients with RS of diffuse large B cell lymphoma (DLBCL) histology. For this genomic characterization, samples from 37 patients were analyzed as 'trios' (matched germline, CLL and RS tissue DNA) and those from 5 as 'duos' (matched CLL and RS DNA). CLL diagnosis preceeded RS diagnosis by a median of 60.6 months (range 0.1-234.5). The median number of prior CLL-directed therapies was 2 (range 0-10). 8 patients had no prior CLL-directed therapy, while 9 were exposed to novel agents. The median time from most proximal CLL sampling to RS was 2.7 months (range: 82.2 months pre- to 3.8 months post RS diagnosis). Critical analytic innovations applied to this dataset included addressing contamination of CLL DNA in the germline sample (through the tool DeTIN) and generating the ability to discriminate between clones arising from RS or from CLL, even while both histologies were commonly co-existing within originating biopsies (via the tool PhylogicNDT). From this discovery cohort of 42 cases, 36 (86%) revealed RS and CLL to be clonally-related based on WES analysis, with a distinct RS clone emerging from an existing CLL subclone. Of the 6 (14%) cases determined to be clonally unrelated by WES, 4 had been previously examined by IGHV sequencing; only 1 of 4 was categorized as clonally unrelated, likely due to CLL and RS admixture. RS displayed mutational signatures reflecting aging (CpG), canonical AID, and non-canonical AID processes. Through deconvoluting clonal composition using PhylogicNDT in related sample trios (n=31), we established several notable differences compared to antecedent CLL. First, RS clones presented higher rates of additional mutations than the ancestral CLL clones from which they developed (2.47 vs. 0.86 Mut/Mb, p&lt;0.0001). Second, the frequency of CLL-associated driver mutations in the RS clones was altered:TP53 mutation (n=21, 50%), NOTCH1 mutation (n=17, 40%) NFKBIE (n=5, 12%), EGR2 (n=6, 14%), XPO1 (n=5, 12%), and RPS15 (n=3, 7%). Third, the clonal transition to RS was marked by a diversity of additional driver mutations and particularly increased copy number variants (CNVs). RS biopsies had recurrent arm level events, including del(17p) in 44%, del(4p) in 27%, del(4q) in 27%, del(9p) in 22%, del(17q) in 22% and del(9q) in 20% (Q&lt;0.05, GISTIC). The top focal alterations in RS biopsies, as identified by tool GISTIC included (Q value &lt;= 0.05): amp(7q21.2) - CDK6,amp(8q24.3) - RECQL4, amp(13q31.3) - ERCC5, amp(19p13.3), amp(19q13.42), del(8p12), del(17p13.1) - TP53, del(13q14.3), del(7q35), and del(16q12.2). Finally, whole genome doubling was observed in 6 cases upon transition to RS. To further investigate RS and CLL clonal evolution at high resolution, we performed single-cell RNA-sequencing (10x Genomics), on biopsies at the time of RS diagnosis in 5 individuals with clonally related transformation. Data analysis and clustering was conducted using Seurat(v3) with doublet removal (DoubletFinder). We identified CNV in single-cell transcriptomes that matched the WES copy-number profiles of individual subclones of the RS and CLL populations and thus linked subclones identified by WES to single-cell expression clusters and states, revealing CLL, RS and intermediate evolutionary cell states. In conclusion, we identify that RS arises from CLL subclones through distinct mutational trajectories. Further molecular subclassification of RS, including genetic characterization of additional cases, and linking mutational data with clinical outcomes is ongoing and has potential to alter clinical classification and prognostication of RS. Disclosures Guieze: abbvie: Honoraria, Other: advisory board, travel funds; janssen cilag: Honoraria, Other: advisory board, travel funds; roche: Other: travle funds; gilead: Honoraria, Other: travel funds; astrazanecka: Honoraria, Other: advisory board. Leshchiner:PACT Pharma, Inc.: Consultancy. Tausch:Roche: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding. Davids:Genentech: Consultancy, Research Funding; Janssen: Consultancy; Gilead Sciences: Consultancy; Novartis: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; Surface Oncology: Research Funding; AbbVie: Consultancy; Adaptive Biotechnologies: Consultancy; Merck: Consultancy; Pharmacyclics: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; Syros Pharmaceuticals: Consultancy; Sunesis: Consultancy; Zentalis: Consultancy; AstraZeneca: Consultancy, Research Funding; Ascentage Pharma: Consultancy, Research Funding; Eli Lilly: Consultancy; Research to Practice: Honoraria; Celgene: Consultancy; BeiGene: Consultancy; Bristol Myers Squibb: Research Funding. Elagina:AbbVie: Current Employment. Jain:TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Pfizer: Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fate Therapeutics: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Cellectis: Research Funding; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Aprea Therapeutics: Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kipps:Oncternal Therapeutics, Inc.: Other: Cirmtuzumab was developed by Thomas J. Kipps in the Thomas J. Kipps laboratory and licensed by the University of California to Oncternal Therapeutics, Inc., which provided stock options and research funding to the Thomas J. Kipps laboratory, Research Funding; Celgene: Honoraria, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; VelosBio: Research Funding; Pharmacyclics/ AbbVie, Breast Cancer Research Foundation, MD Anderson Cancer Center, Oncternal Therapeutics, Inc., Specialized Center of Research (SCOR) - The Leukemia and Lymphoma Society (LLS), California Institute for Regenerative Medicine (CIRM): Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ascerta/AstraZeneca, Celgene, Genentech/F. Hoffmann-La Roche, Gilead, Janssen, Loxo Oncology, Octernal Therapeutics, Pharmacyclics/AbbVie, TG Therapeutics, VelosBio, and Verastem: Membership on an entity's Board of Directors or advisory committees. Broséus:Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Gilead: Honoraria. Kay:MEI Pharma: Research Funding; Cytomx: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno Theraputics: Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Agios Pharma: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; Morpho-sys: Membership on an entity's Board of Directors or advisory committees. Purroy:AstraZenica: Current Employment. Utro:IBM: Current Employment. Rhrissorrakrai:IBM: Current Employment. Levovitz:IBM: Current Employment. Parikh:GlaxoSmithKline: Honoraria; Pharmacyclics: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; MorphoSys: Research Funding; TG Therapeutics: Research Funding; Merck: Research Funding; AbbVie: Honoraria, Research Funding; Ascentage Pharma: Research Funding; Genentech: Honoraria; Verastem Oncology: Honoraria. Brown:Abbvie, Acerta, AstraZeneca, Beigene, Invectys, Juno/Celgene, Kite, Morphosys, Novartis, Octapharma, Pharmacyclics, Sunesis, TG Therapeutics, Verastem: Consultancy; Gilead, Loxo, Sun, Verastem: Research Funding; Janssen, Teva: Speakers Bureau. Parida:IBM: Current Employment. Neuberg:Madrigak Pharmaceuticals: Current equity holder in publicly-traded company; Pharmacyclics: Research Funding; Celgene: Research Funding. Stilgenbauer:Novartis: Consultancy, Honoraria, Other, Research Funding; Mundipharma: Consultancy, Honoraria, Other, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Other: travel support, Research Funding; Genentech: Consultancy, Honoraria, Other: travel support, Research Funding; Genzyme: Consultancy, Honoraria, Other: travel support, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Other: travel support, Research Funding; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding; Amgen: Consultancy, Honoraria, Other: travel support, Research Funding; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding. Getz:Scorpion Therapeutics: Consultancy, Current equity holder in publicly-traded company, Other: Founder; IBM: Research Funding; Pharmacyclics: Research Funding; Broad Institute: Patents & Royalties: MuTect, ABSOLUTE, MutSig, MSMuTect, MSMutSig, POLYSOLVER and TensorQTL. Wu:Pharmacyclics: Research Funding; BionTech: Current equity holder in publicly-traded company.

ObjectiveTo validate the Martini nomogram predicting the decline in estimated glomerular filtration rate after robotic‐assisted partial nephrectomy.MethodsEstimated glomerular filtration rate of 406 patients from a single surgeon series was calculated before robotic‐assisted partial nephrectomy and at postoperative intervals. To determine the risk group, we calculated the total score and corresponding risk of significant estimated glomerular filtration rate reduction at 15 months using the Martini nomogram. The primary outcome was a reduction in estimated glomerular filtration rate of ≥25% from preoperative levels between 1 and 12 months after surgery.ResultsThe median length of follow up for this study was 12 months (interquartile range 6–12 months). Overall, 134 (33%) patients were in the low‐, 143 (35%) in the intermediate‐, 119 (29%) in the high‐ and 10 (2%) in the very high‐risk groups. The Kaplan–Meier estimates for the probability of significant estimated glomerular filtration rate reduction by 12 months after robotic‐assisted partial nephrectomy was 12.9% in the low‐risk group, 24.0% in the intermediate‐risk group, 49.7% in the high‐risk group and 40.0% in the very high‐risk group. Harrell’s C‐index for discriminating between those with and without a significant reduction in estimated glomerular filtration rate 1–12 months after robotic‐assisted partial nephrectomy was 0.73 (95% confidence interval 0.68–0.78).ConclusionsThe risk groups proposed by the Martini nomogram are accurate in predicting those at higher risk for a >25% decline in postoperative estimated glomerular filtration rate after robotic‐assisted partial nephrectomy at 12 months.

AbstractFirst‐degree relatives of patients diagnosed with schizophrenia (SZ‐FDRs) show similar patterns of brain abnormalities and cognitive alterations to patients, albeit with smaller effect sizes. First‐degree relatives of patients diagnosed with bipolar disorder (BD‐FDRs) show divergent patterns; on average, intracranial volume is larger compared to controls, and findings on cognitive alterations in BD‐FDRs are inconsistent. Here, we performed a meta‐analysis of global and regional brain measures (cortical and subcortical), current IQ, and educational attainment in 5,795 individuals (1,103 SZ‐FDRs, 867 BD‐FDRs, 2,190 controls, 942 schizophrenia patients, 693 bipolar patients) from 36 schizophrenia and/or bipolar disorder family cohorts, with standardized methods. Compared to controls, SZ‐FDRs showed a pattern of widespread thinner cortex, while BD‐FDRs had widespread larger cortical surface area. IQ was lower in SZ‐FDRs (d = −0.42,p = 3 × 10−5), with weak evidence of IQ reductions among BD‐FDRs (d = −0.23,p = .045). Both relative groups had similar educational attainment compared to controls. When adjusting for IQ or educational attainment, the group‐effects on brain measures changed, albeit modestly. Changes were in the expected direction, with less pronounced brain abnormalities in SZ‐FDRs and more pronounced effects in BD‐FDRs. To conclude, SZ‐FDRs and BD‐FDRs show a differential pattern of structural brain abnormalities. In contrast, both had lower IQ scores and similar school achievements compared to controls. Given that brain differences between SZ‐FDRs and BD‐FDRs remain after adjusting for IQ or educational attainment, we suggest that differential brain developmental processes underlying predisposition for schizophrenia or bipolar disorder are likely independent of general cognitive impairment.

Introduction: A number of clinical and radiological predictors of either stone impaction or ureteral stone passage (SP) have been proposed. We aimed at identifying the key predictors of successful SP by using readily available CT-based tools/measurements. Methods: Patients presenting to the emergency department from February 2017 to February 2018 with an acute unilateral ureteral stone confirmed on non-contrast CT and managed conservatively were followed for SP. Patients with renal impairment, sepsis or requiring emergent intervention were excluded. Patients were followed at 1 month to confirm SP (stone collection/repeat imaging) or failure of passage. The CT variables analyzed included: Stone factors [location, size, volume, HU density (HUD)], impaction factors [ureteral HUD above and below the stone, maximal ureteral wall thickness (UWT) at the stone site, contralateral UWT, and ureteral diameter above and below the stone]. Binary logistic regression analysis was performed to identify predictors of SP. Results: Forty-nine patients met study inclusion criteria, of whom 32 (65.3%) passed the stone without further intervention. Patients with successful passage were more likely to have smaller, lower volume and less dense stones located in the distal ureter ( p < 0.01). Lower ureteral HUD below the stone, lower maximal UWT, and lower ureteral diameter above the stone were associated with successful passage ( p < 0.01). On multivariable logistic regression analysis, only maximal UWT at the stone site was a significant independent predictor of SP outcome ( p = 0.01). Youden's criterion identified 2.3 mm as the optimal UWT cut-off point, which will accurately predict SP with 82.4% sensitivity and 87.5% specificity. Conclusions: Maximal UWT at the stone site was the most significant predictor of successful passage in acute unilateral ureteral stones, with an optimal cut-off point of 2.3 mm. Further prospective studies are needed to accurately predict spontaneous SP.

Surgical innovation and multidisciplinary management have allowed children born with univentricular physiology congenital heart disease to survive into adulthood. An estimated global population of 70 000 patients have undergone the Fontan procedure and are alive today, most of whom are <25 years of age. Several unexpected consequences of the Fontan circulation include Fontan-associated liver disease. Surveillance biopsies have demonstrated that virtually 100% of these patients develop clinically silent fibrosis by adolescence. As they mature, there are increasing reports of combined heart-liver transplantation resulting from advanced liver disease, including bridging fibrosis, cirrhosis, and hepatocellular carcinoma, in this population. In the absence of a transplantation option, these young patients face a poor quality of life and overall survival. Acknowledging that there are no consensus guidelines for diagnosing and monitoring Fontan-associated liver disease or when to consider heart transplantation versus combined heart-liver transplantation in these patients, a multidisciplinary working group reviewed the literature surrounding Fontan-associated liver disease, with a specific focus on considerations for transplantation.