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Background: Hepatocellular carcinoma has high recurrence rates after surgery; however, there are no approved standard-of-care neoadjuvant or adjuvant therapies. Immunotherapy has been shown to improve survival in advanced hepatocellular carcinoma; we therefore aimed to evaluate the safety and tolerability of perioperative immunotherapy in resectable hepatocellular carcinoma. Methods: In this single-centre, randomised, open-label, phase 2 trial, patients with resectable hepatocellular carcinoma were randomly assigned (1:1) to receive 240 mg of nivolumab intravenously every 2 weeks (for up to three doses before surgery at 6 weeks) followed in the adjuvant phase by 480 mg of nivolumab intravenously every 4 weeks for 2 years, or 240 mg of nivolumab intravenously every 2 weeks (for up to three doses before surgery) plus one dose of 1 mg/kg of ipilimumab intravenously concurrently with the first preoperative dose of nivolumab, followed in the adjuvant phase by 480 mg of nivolumab intravenously every 4 weeks for up to 2 years plus 1 mg/kg of ipilimumab intravenously every 6 weeks for up to four cycles. Patients were randomly assigned to the treatment groups by use of block randomisation with a random block size. The primary endpoint was the safety and tolerability of nivolumab with or without ipilimumab. Secondary endpoints were the proportion of patients with an overall response, time to progression, and progression-free survival. This trial is registered with ClinicalTrials.gov (NCT03222076) and is completed. Findings: Between Oct 30, 2017, and Dec 3, 2019, 30 patients were enrolled and 27 were randomly assigned: 13 to nivolumab and 14 to nivolumab plus ipilimumab. Grade 3–4 adverse events were higher with nivolumab plus ipilimumab (six [43%] of 14 patients) than with nivolumab alone (three [23%] of 13). The most common treatment-related adverse events of any grade were increased alanine aminotransferase (three [23%] of 13 patients on nivolumab vs seven [50%] of 14 patients on nivolumab plus ipilimumab) and increased aspartate aminotransferase (three [23%] vs seven [50%]). No patients in either group had their surgery delayed due to grade 3 or worse adverse events. Seven of 27 patients had surgical cancellations, but none was due to treatment-related adverse events. Estimated median progression-free survival was 9·4 months (95% CI 1·47–not estimable [NE]) with nivolumab and 19·53 months (2·33–NE) with nivolumab plus ipilimumab (hazard ratio [HR] 0·99, 95% CI 0·31–2·54); median time to progression was 9·4 months (95% CI 1·47–NE) in the nivolumab group and 19·53 months (2·33–NE) in the nivolumab plus ipilimumab group (HR 0·89, 95% CI 0·31–2·54). In an exploratory analysis, three (23%) of 13 patients had an overall response with nivolumab monotherapy, versus none with nivolumab plus ipilimumab. Three (33%) of nine patients had a major pathological response (ie, ≥70% necrosis in the resected tumour area) with nivolumab monotherapy compared with three (27%) of 11 with nivolumab plus ipilimumab. Interpretation: Perioperative nivolumab alone and nivolumab plus ipilimumab appears to be safe and feasible in patients with resectable hepatocellular carcinoma. Our findings support further studies of immunotherapy in the perioperative setting in hepatocellular carcinoma. Funding: Bristol Myers Squibb and the US National Institutes of Health.

To identify new susceptibility loci to lung cancer among diverse populations, we performed cross-ancestry genome-wide association studies in European, East Asian and African populations and discovered five loci that have not been previously reported. We replicated 26 signals and identified 10 new lead associations from previously reported loci. Rare-variant associations tended to be specific to populations, but even common-variant associations influencing smoking behavior, such as those with CHRNA5 and CYP2A6, showed population specificity. Fine-mapping and expression quantitative trait locus colocalization nominated several candidate variants and susceptibility genes such as IRF4 and FUBP1. DNA damage assays of prioritized genes in lung fibroblasts indicated that a subset of these genes, including the pleiotropic gene IRF4, potentially exert effects by promoting endogenous DNA damage.

Purpose: Increasing tumor-infiltrating lymphocytes (TIL) is associated with higher rates of pathologic complete response (pCR) to neoadjuvant therapy (NAT) in patients with triple-negative breast cancer (TNBC). However, the presence of TILs does not consistently predict pCR, therefore, the current study was undertaken to more fully characterize the immune cell response and its association with pCR. Experimental Design: We obtained pretreatment core-needle biopsies from 105 patients with stage I–III TNBC enrolled in ARTEMIS (NCT02276443) who received NAT from Oct 22, 2015 through July 24, 2018. The tumor-immune microenvironment was comprehensively profiled by performing T-cell receptor (TCR) sequencing, programmed death-ligand 1 (PD-L1) IHC, multiplex immunofluorescence, and RNA sequencing on pretreatment tumor samples. The primary endpoint was pathologic response to NAT. Results: The pCR rate was 40% (42/105). Higher TCR clonality (median = 0.2 vs. 0.1, P = 0.03), PD-L1 positivity (OR: 2.91, P = 0.020), higher CD3+:CD68+ ratio (median = 14.70 vs. 8.20, P = 0.0128), and closer spatial proximity of T cells to tumor cells (median = 19.26 vs. 21.94 μm, P = 0.0169) were associated with pCR. In a multivariable model, closer spatial proximity of T cells to tumor cells and PD-L1 expression enhanced prediction of pCR when considered in conjunction with clinical stage. Conclusions: In patients receiving NAT for TNBC, deep immune profiling through detailed phenotypic characterization and spatial analysis can improve prediction of pCR in patients receiving NAT for TNBC when considered with traditional clinical parameters.

Purpose:Metaplastic breast cancer (MpBC) is a rare subtype of breast cancer that is commonly triple-negative and poorly responsive to neoadjuvant therapy in retrospective studies.Experimental Design:To better define clinical outcomes and correlates of response, we analyzed the rate of pathologic complete response (pCR) to neoadjuvant therapy, survival outcomes, and genomic and transcriptomic profiles of the pretreatment tumors in a prospective clinical trial (NCT02276443). A total of 211 patients with triple-negative breast cancer (TNBC), including 39 with MpBC, received doxorubicin-cyclophosphamide–based neoadjuvant therapy.Results:Although not meeting the threshold for statistical significance, patients with MpBCs were less likely to experience a pCR (23% vs. 40%; P = 0.07), had shorter event-free survival (29.4 vs. 32.2 months, P = 0.15), metastasis-free survival (30.3 vs. 32.4 months, P = 0.22); and overall survival (32.6 vs. 34.3 months, P = 0.21). This heterogeneity is mirrored in the molecular profiling. Mutations in PI3KCA (23% vs. 9%, P = 0.07) and its pathway (41% vs. 18%, P = 0.02) were frequently observed and enriched in MpBCs. The gene expression profiles of each histologically defined subtype were distinguishable and characterized by distinctive gene signatures. Among nonmetaplastic (non-Mp) TNBCs, 10% possessed a metaplastic-like gene expression signature and had pCR rates and survival outcomes similar to MpBC.Conclusions:Further investigations will determine if metaplastic-like tumors should be treated more similarly to MpBC in the clinic. The 23% pCR rate in this study suggests that patients with MpBC should be considered for NAT. To improve this rate, a pathway analysis predicted enrichment of histone deacetylase (HDAC) and RTK/MAPK pathways in MpBC, which may serve as new targetable vulnerabilities.

Autologous chimeric antigen receptor (CAR) T cell therapies targeting CD19 have high efficacy in large B cell lymphomas (LBCLs), but long-term remissions are observed in less than half of patients, and treatment-associated adverse events, such as immune effector cell-associated neurotoxicity syndrome (ICANS), are a clinical challenge. We performed single-cell RNA sequencing with capture-based cell identification on autologous axicabtagene ciloleucel (axi-cel) anti-CD19 CAR T cell infusion products to identify transcriptomic features associated with efficacy and toxicity in 24 patients with LBCL. Patients who achieved a complete response by positron emission tomography/computed tomography at their 3-month follow-up had three-fold higher frequencies of CD8 T cells expressing memory signatures than patients with partial response or progressive disease. Molecular response measured by cell-free DNA sequencing at day 7 after infusion was significantly associated with clinical response (P = 0.008), and a signature of CD8 T cell exhaustion was associated (q = 2.8 × 10−149) with a poor molecular response. Furthermore, a rare cell population with monocyte-like transcriptional features was associated (P = 0.0002) with high-grade ICANS. Our results suggest that heterogeneity in the cellular and molecular features of CAR T cell infusion products contributes to variation in efficacy and toxicity after axi-cel therapy in LBCL, and that day 7 molecular response might serve as an early predictor of CAR T cell efficacy. Single-cell transcriptomics reveals that the heterogeneity of anti-CD19 CAR T cell infusion products contributes to variability in clinical response, early molecular response and development of immune effector cell-associated neurotoxicity syndrome in patients with large B cell lymphomas.

Folate receptor alpha (FRα) has been reported to be expressed in up to 80% of triple-negative breast cancers (TNBC) with limited expression in normal tissues, making it a promising therapeutic target. Mirvetuximab soravtansine (mirvetuximab-s) is an antibody drug conjugate which has shown promise in the treatment of FRα-positive solid tumors in early phase clinical trials. Herein, are the results of the first prospective phase II trial evaluating mirvetuximab-s in metastatic TNBC. Patients with advanced, FRα-positive TNBC were enrolled on this study. Mirvetuximab-s was administered at a dose of 6.0 mg/kg every 3 weeks. 96 patients with advanced TNBC consented for screening. FRα staining was performed on tumor tissue obtained from 80 patients. The rate of FRα positivity by immunohistochemistry was 10.0% (8/80). Two patients were treated on study, with best overall responses of stable disease in one and progressive disease in the other. Adverse events were consistent with earlier studies. The study was terminated early due to the low rate of FRα positivity in the screened patient population and lack of disease response in the two patients treated. The observed rate of FRα positivity was considerably lower than previously reported and none of the patients had a partial or complete response. Treatment with mirvetuximab-s should only be further explored in TNBC if an alternate biomarker strategy is developed for patient selection on the basis of additional preclinical data.

Arsenic (As) exposure adversely affects neurodevelopment in children. Accumulation of misfolded proteins in cells exposed to As leads to endoplasmic reticulum (ER) stress response, which, if not relieved, results in cell death. Despite the potential role of ER stress for As-induced neurotoxicity, the underlying mechanisms remain poorly understood. Here we aimed to investigate the roles of microRNA(miR)-124, a novel ER stress suppressor, in As-induced ER stress response and cytotoxicity in neural cells. We further aimed to link these in vitro findings to neurodevelopmental outcomes in children who were exposed to As. Using Quantitative RT-PCR and Cyquant assay, we showed that miR-124 protects against As-induced cytotoxicity in neural cells with concomitant suppression of As-induced ER stress. In addition, As-induced cytotoxicity was exacerbated in miR-124 knockout cells generated by CRISPR-based gene editing compared scramble control. Furthermore, we identified two miR-124 SNPs rs67543816 (p = 0.0003) and rs35418153 (p = 0.0004) that are significantly associated with a mental composite score calculated from the Bayley Scales of Infant Development III in Bangladesh children. Our study reveals As-induced ER stress as a crucial mechanism underlying the toxic effects of As on neural cell function and neurodevelopment and identifies miR-124 as a potential preventative and therapeutic target against detrimental effects of As exposure in children.

Attempts to identify and prioritize functional DNA elements in coding and non-coding regions, particularly through use of in silico functional annotation data, continue to increase in popularity. However, specific functional roles can vary widely from one variant to another, making it challenging to summarize different aspects of variant function with a one-dimensional rating. Here we propose multi-dimensional annotation-class integrative estimation (MACIE), an unsupervised multivariate mixed-model framework capable of integrating annotations of diverse origin to assess multi-dimensional functional roles for both coding and non-coding variants. Unlike existing one-dimensional scoring methods, MACIE views variant functionality as a composite attribute encompassing multiple characteristics and estimates the joint posterior functional probabilities of each genomic position. This estimate offers more comprehensive and interpretable information in the presence of multiple aspects of functionality. Applied to a variety of independent coding and non-coding datasets, MACIE demonstrates powerful and robust performance in discriminating between functional and non-functional variants. We also show an application of MACIE to fine-mapping and heritability enrichment analysis by using the lipids GWAS summary statistics data from the European Network for Genetic and Genomic Epidemiology Consortium.

Conditioning chemotherapy (CCT) has been shown to be essential for optimal efficacy of chimeric antigen receptor (CAR) T-cell therapy. Here, we determined whether the change in absolute lymphocyte count, referred to as delta lymphocyte index (DLIx), may serve as a surrogate marker for pharmacodynamic effects of CCT and whether it associated with germline genetic variants in patients with large B-cell lymphoma (LBCL). One-hundred and seventy-one patients were included, of which 86 (50%) received bridging therapy post-leukapheresis. Median DLIx was 0.5 × 10(9)/L (range, 0.01–2.75 X 10(9)/L) and was significantly higher in patients who achieved complete response (p=0.04). On multivariate analysis, low DLIx was associated only with use of bridging therapy (odds ratio 0.4, 95% CI 0.2–0.8, p=0.007). Low DLIx was independently associated with shorter progression-free (p=0.02) and overall survival (p=0.02). DLIx was associated with genetic variations related to drug metabolism and macrophage biology such as ABCB1, MISP and CPVL. The impact of CCT on lymphocyte count is affected by use of bridging therapy but change in lymphocyte count is independently associated with efficacy. Studies aimed at investigating macrophage biology in this setting may suggest strategies to increase the efficacy of CCT and improve outcomes.

Differences by sex in lung cancer incidence and mortality have been reported which cannot be fully explained by sex differences in smoking behavior, implying existence of genetic and molecular basis for sex disparity in lung cancer development. However, the information about sex dimorphism in lung cancer risk is quite limited despite the great success in lung cancer association studies. By adopting a stringent two-stage analysis strategy, we performed a genome-wide gene–sex interaction analysis using genotypes from a lung cancer cohort including ~ 47 000 individuals with European ancestry. Three low-frequency variants (minor allele frequency

Large-scale whole-genome sequencing studies have enabled analysis of noncoding rare variants’ (RVs) associations with complex human traits. Variant set analysis is a powerful approach to study RV association, and a key component of it is constructing RV sets for analysis. However, existing methods have limited ability to define analysis units in the noncoding genome. Furthermore, there is a lack of robust pipelines for comprehensive and scalable noncoding RV association analysis. Here we propose a computationally-efficient noncoding RV association-detection framework that uses STAAR (variant-set test for association using annotation information) to group noncoding variants in gene-centric analysis based on functional categories. We also propose SCANG (scan the genome)-STAAR, which uses dynamic window sizes and incorporates multiple functional annotations, in a non-gene-centric analysis. We furthermore develop STAARpipeline to perform flexible noncoding RV association analysis, including gene-centric analysis as well as fixed-window-based and dynamic-window-based non-gene-centric analysis. We apply STAARpipeline to identify noncoding RV sets associated with four quantitative lipid traits in 21,015 discovery samples from the Trans-Omics for Precision Medicine (TOPMed) program and replicate several noncoding RV associations in an additional 9,123 TOPMed samples.

Objective: The alternations of mtDNA may play an important role in the molecular pathogenesis and process of Pelvic Organ Prolapse (POP) formation in both pre-menopausal and post-menopausal women. The aim of the present study is to analyze the association between the mitochondrial biogenesis gene and development of POP in the uterosacral ligaments (UL) of pre-menopausal women. Materials and methods: Seventy one pre-menopausal women, all below 52 years of age, were enrolled in this study. UL biopsies were obtained from uterine specimens taken from 33 women with POP (n = 33, study group) and 38 myoma patients without POP (n = 38, control group). Quantitative Real-Time PCR was performed to measure mitochondrial DNA (mtDNA) copy number and mtDNA4977. Western blotting and immunohistochemistry were used to assess the protein expression of PGC-1α, TFAM, NRF-1 and NRF-2. Statistical analysis was performed using SPSS statistical software and the Mann–Whitney U test, and the continuous variables were analyzed using the Student's t-test in demographic data. Results: There were no significant differences in the patient demographics between the two groups (p > 0.05). The mtDNA copy number in the UL of pre-menopausal patients with prolapse was significantly higher than that in the no prolapse group (p = 0.008). There were no significant differences between the mtDNA4977 of the POP and non-POP groups, but a significantly higher expression of PGC-1α in the POP group compared to the non-POP group (1.59 ± 1.30 v.s. 0.66 ± 0.53; p = 0.036). The expression of TFAM in the POP group was higher than in the non-POP group). There was no significant difference in the TFAM(p = 0.377), NRF-1 and NRF-2 expression between the POP and non-POP groups (p = 0.647; p = 0.682). Conclusions: Changes in the PGC-1α and mtDNA copy number may play a role in the development of Pelvic Organ Prolapse in pre-menopausal patients. Keywords: Pre-menopause, Pelvic organ prolapse(POP), Gene expression, Mitochondrial DNA (mtDNA), Molecular pathogenesis

Chimeric antigen receptor T-cell (CAR-T) therapy has transformed treatment paradigms for relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) in children and younger adults. We performed a systematic review to investigate the published literature on efficacy and toxicity of CAR-T therapy in adults with r/r B-ALL. We searched MEDLINE, Embase, and the Cochrane Library for prospective interventional studies and included published studies of ≥5 patients with median age at enrollment of ≥18 years. Risk of bias was assessed with a modified Institute of Health Economics tool. A total of 2566 records were assessed; 16 studies involving 489 patients were included in the final analysis. The mean complete remission (CR) rate was 81% and the measurable residual disease (MRD)–negative remission rate was 81% at 4 weeks after CAR-T infusion. With median follow-up across studies of 24 months, the cumulative 12-month probabilities of progression-free survival (PFS) and overall survival (OS) were 37% (95% CI, 26-48) and 57% (95% CI, 49-65), respectively. Relapse occurred in 40.3% of cases; target antigen was retained in 73.2% of relapses. Across studies, any grade of cytokine release syndrome (CRS) occurred in 82% of patients (95% CI, 61-95) and grade 3 or higher CRS in 27% (95% CI, 18-36). Neurotoxicity of any grade occurred in 34% of patients (95% CI, 24-47) and grade 3 or higher in 14% (95% CI, 1-25). In summary, CAR-T therapy achieves high early remission rates in adults with r/r B-ALL and represents a significant improvement over traditional salvage chemotherapy. Relapses are common and durable response remains a challenge.

White adipose tissue (WAT) is an essential regulator of energy storage and systemic metabolic homeostasis. Regulatory networks consisting of immune and structural cells are necessary to maintain WAT metabolism, which can become impaired during obesity in mammals. Using single-cell transcriptomics and flow cytometry, we unveil a large-scale comprehensive cellular census of the stromal vascular fraction (SVF) of healthy lean and obese human WAT. We report novel subsets and developmental trajectories of adipose-resident innate lymphoid cells (ILCs), dendritic cells (DCs) and monocyte-derived macrophage populations that accumulate in obese WAT. Analysis of cell-cell ligand receptor interactions and obesity-enriched signaling pathways revealed a switch from immunoregulatory mechanisms in lean WAT to inflammatory networks in obese WAT. These results provide a detailed and unbiased cellular landscape of homeostatic and inflammatory circuits in healthy human WAT.

Non-surgical skills involving hand–eye coordination and bimanual dexterity may have a transferable impact on the acquisition of ureteroscopy skills. In this study, we aim to investigate the predictors of initial flexible ureteroscopy skills among novice trainees. This was a prospective study involving students with no prior ureteroscopy exposure. Non-surgical parameters were assessed with a detailed survey, including demographics, video game, and musical history. Musical ability was objectively evaluated with the mini-Profile of Music Perception Skills test. Ureteroscopic performance was evaluated using a Boston Scientific© flexible ureteroscope on a bench model. Each participant completed diagnostic ureteroscopy and stone extraction. Outcomes included both speed and quality of performance, based on an Objective Structured Assessment of Technical Skills rubric. A total of 28 pre-clerkship medical students and 10 urology residents were included. Age and musical background were not associated with ureteroscopic aptitude. Those with video game history tended to perform ureteroscopy tasks faster with a higher OSATS score, although no statistical significance was reached. Male gender was associated with faster task completion with statistically higher OSATS score independent of video game activities (p = 0.011), however, the absolute score difference was small. Among novice trainees, musical and video game experience was not predictive of ureteroscopy skills. Male gender was associated with slightly faster and higher ureteroscopy technique scores, however, the differences are small and unlikely to represent clinical significance. Nevertheless, the use of ureteroscopy trainer provides useful insights and should be adopted in training programs as a marker of skills progression.

This cohort study assesses the utility of restricted mean survival time as a method for quantifying time to nursing home placement among patients with dementia.

Clinical trial results have recently demonstrated that inhibiting inflammation by targeting the interleukin-1β pathway can offer a significant reduction in lung cancer incidence and mortality, highlighting a pressing and unmet need to understand the benefits of inflammation-focused lung cancer therapies at the genetic level. While numerous genome-wide association studies (GWAS) have explored the genetic etiology of lung cancer, there remains a large gap between the type of information that may be gleaned from an association study and the depth of understanding necessary to explain and drive translational findings. Thus, in this study we jointly model and integrate extensive multiomics data sources, utilizing a total of 40 genome-wide functional annotations that augment previously published results from the International Lung Cancer Consortium (ILCCO) GWAS, to prioritize and characterize single nucleotide polymorphisms (SNPs) that increase risk of squamous cell lung cancer through the inflammatory and immune responses. Our work bridges the gap between correlative analysis and translational follow-up research, refining GWAS association measures in an interpretable and systematic manner. In particular, reanalysis of the ILCCO data highlights the impact of highly associated SNPs from nuclear factor-κB signaling pathway genes as well as major histocompatibility complex mediated variation in immune responses. One consequence of prioritizing likely functional SNPs is the pruning of variants that might be selected for follow-up work by over an order of magnitude, from potentially tens of thousands to hundreds. The strategies we introduce provide informative and interpretable approaches for incorporating extensive genome-wide annotation data in analysis of genetic association studies.

Immune checkpoint therapy (ICT) provides substantial clinical benefits to cancer patients, but a large proportion of cancers do not respond to ICT. To date, the genomic underpinnings of primary resistance to ICT remain elusive. Here, we performed immunogenomic analysis of data from TCGA and clinical trials of anti-PD-1/PD-L1 therapy, with a particular focus on homozygous deletion of 9p21.3 (9p21 loss), one of the most frequent genomic defects occurring in ~13% of all cancers. We demonstrate that 9p21 loss confers “cold” tumor-immune phenotypes, characterized by reduced abundance of tumor-infiltrating leukocytes (TILs), particularly, T/B/NK cells, altered spatial TILs patterns, diminished immune cell trafficking/activation, decreased rate of PD-L1 positivity, along with activation of immunosuppressive signaling. Notably, patients with 9p21 loss exhibited significantly lower response rates to ICT and worse outcomes, which were corroborated in eight ICT trials of >1,000 patients. Further, 9p21 loss synergizes with PD-L1/TMB for patient stratification. A “response score” was derived by incorporating 9p21 loss, PD-L1 expression and TMB levels in pre-treatment tumors, which outperforms PD-L1, TMB, and their combination in identifying patients with high likelihood of achieving sustained response from otherwise non-responders. Moreover, we describe potential druggable targets in 9p21-loss tumors, which could be exploited to design rational therapeutic interventions., The molecular mechanisms of resistance to immune checkpoint therapy remain elusive. Here, the authors perform immunogenomic analysis of TCGA data and data from clinical trials for antiPD-1/PD-L1 therapy and highlight the association of 9p21 loss with a cold tumor microenvironment and resistance to therapy.

Objective Small bowel adenocarcinoma (SBA) is a rare malignancy with limited evidence regarding outcomes after curative resection of localised disease. We aimed to evaluate presentation and prognostic factors affecting overall survival (OS), relapse-free survival (RFS) and recurrence of SBA. Methods Consecutive patients with completely resected localised SBA (1979–2019) were retrospectively reviewed for presentation, patient and tumour characteristics, perioperative treatment, recurrence, outcomes, and prognostic factors. Results Among 257 total patients, median age was 58 years. Primary location was in the duodenum, jejunum and ileum in 52%, 29%, and 19% of patients, respectively. Median OS was 57.5 months and median follow-up was 40 months. In multivariate analysis, lymph node involvement, lymphovascular invasion, histologic grade and race were independent predictors of RFS, while race, stage and histologic grade were independent predictors of OS. No significant difference in OS or RFS was seen when evaluating the role of perioperative treatment. Median time to diagnosis from first medical evaluation was 31 days and did not change over time. Overall recurrence rate was 56%. Recurrence rate was higher in ileal (77%), than duodenal (54%) and jejunal (65%) SBA (p=0.01). Recurrence presented most commonly as distant metastasis (71%). Proficient mismatch repair was associated with decreased risk of locoregional recurrence (LR) but increased risk of distant recurrence (DR) when compared with deficient mismatch repair (dMMR) in univariate analysis. Conclusions Despite advances in diagnostic modalities, this study did not show any improvement in earlier diagnosis of SBA over the course of the past three decades. The predominant pattern of disease recurrence was distant across all SBA locations, but dMMR status demonstrated a robust predilection for LR as opposed to DR. Perioperative treatment did not improve outcomes; however, a lower stage disease was seen in patients that received neoadjuvant therapy, suggesting further exploration of this approach.

Corticosteroids are used to treat the acute complications of chimeric antigen receptor (CAR) T-cell therapy. Strati et al examine the impact of corticosteroids on patient outcomes following CAR T-cell therapy for large B-cell lymphoma. Use of higher doses of steroids is associated with shorter progression-free survival at 10 months and decreased overall survival., Key Points Higher cumulative dose of corticosteroids is associated with early progression after CAR-T therapy in large B-cell lymphoma.Higher cumulative dose and prolonged, early corticosteroid use is associated with shorter overall survival after CAR-T therapy., Visual Abstract, Corticosteroids are commonly used for the management of severe toxicities associated with chimeric antigen receptor (CAR) T-cell therapy. However, it remains unclear whether their dose, duration, and timing may affect clinical efficacy. Here, we determined the impact of corticosteroids on clinical outcomes in patients with relapsed or refractory large B-cell lymphoma treated with standard of care anti-CD19 CAR T-cell therapy. Among 100 patients evaluated, 60 (60%) received corticosteroids for management of CAR T-cell therapy–associated toxicities. The median cumulative dexamethasone-equivalent dose was 186 mg (range, 8-1803) and the median duration of corticosteroid treatment was 9 days (range, 1-30). Corticosteroid treatment was started between days 0 and 7 in 45 (75%) patients and beyond day 7 in 15 (25%). After a median follow-up of 10 months (95% confidence interval, 8-12 months), use of higher cumulative dose of corticosteroids was associated with significantly shorter progression-free survival. More importantly, higher cumulative dose of corticosteroids, and prolonged and early use after CAR T-cell infusion were associated with significantly shorter overall survival. These results suggest that corticosteroids should be used at the lowest dose and for the shortest duration and their initiation should be delayed whenever clinically feasible while managing CAR T-cell therapy–associated toxicities.

In a comparative oncology study with progression-free or overall survival as the endpoint, the primary or key secondary analysis is routinely stratified by patients’ baseline characteristics when evaluating the treatment difference. The validity of a conventional strategy such as a stratified HR analysis depends on stringent model assumptions that are unlikely to be met in practice, especially in immunotherapy studies. Thus, the resulting summary is generally neither valid nor interpretable. This article discusses issues with conventional stratified analyses and presents alternatives using data from KEYNOTE-189, a recent immunotherapy trial for treating patients with metastatic, non-squamous, non-small-cell lung cancer.

Background Metastatic small bowel adenocarcinoma (SBA) has a poor prognosis. Due to its rarity, high-quality data are lacking to guide treatment. This retrospective analysis was conducted to help characterize the treatment options for patients with metastatic SBA while providing clinically meaningful prognostic information. Patients and methods In total, 437 patients who initially presented with or developed metastatic SBA between September 1977 and September 2019 were identified from the MD Anderson Tumor Registry. Clinical data were collected from review of the medical record. Overall response rates (ORR), time to progression (TTP), and overall survival (OS) were assessed across various treatments and treatment lines. Results The median OS from diagnosis of metastatic disease was 15.9 months [95% confidence interval (CI): 14.3-17.9]. Seventy-five patients (17.1%) underwent metastasectomy, which was associated with a median OS of 34.5 versus 17.1 months among patients who received chemotherapy alone (P < 0.001). Fluoropyrimidine plus platinum (n = 164) was the most common first-line chemotherapy, associated with an ORR of 59% and TTP of 8.1 months. Irinotecan with 5-FU (n = 101) was the most common second-line therapy associated with an ORR of 31% and TTP of 4.0 months. Twenty-two patients received immunotherapy; 5 of 6 patients with deficient mismatch repair (dMMR) responded, while 0 of 16 with proficient mismatch repair (pMMR) responded. Taxane-based chemotherapy was given to 34 patients with an ORR of 21% and a median TTP of 2.4 months. Among 11 patients who received anti-epidermal-growth-factor-receptor (EGFR) monotherapy, the best response was stable disease (SD) in 1 patient. Conclusions In well-selected patients with SBA, metastasectomy appears to be associated with improved OS. This improvement was seen across metastasectomy sites, including liver, lung and peritoneal. Anti-programmed cell death protein 1 (PD-1) based immunotherapy was active for dMMR SBA but not pMMR SBA. While taxane-based chemotherapy demonstrates therapeutic activity, the activity of anti-EGFR therapy was limited., Highlights • Metastasectomy for well-selected metastatic SBA patients was associated with improved OS. • Anti-PD1-based immunotherapy was active for dMMR SBA but not pMMR SBA. • Taxane-based chemotherapy demonstrated clinical activity in refractory SBA. • Anti-EGFR therapy demonstrated minimal activity in SBA.

BACKGROUND: A recent analysis of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial-Lipid-Lowering Trial (ALLHAT-LLT) yielded inconclusive results regarding the use of pravastatin for primary prevention of coronary heart disease (CHD) in older adults. Restricted mean survival time (RMST), which summarizes treatment effect in terms of the event-free time in a fixed time period, may be more useful than hazard ratios for communication of treatment effect with older patients. DESIGN: Secondary analysis of the ALLHAT-LLT trial. SETTING: Ambulatory setting. PARTICIPANTS: 2,867 adults ≥65 years (mean age, 71 years; 49% female) free of cardiovascular disease. INTERVENTION: Pravastatin 40mg daily (n=1,467) vs usual care (n=1,400). MEASUREMENTS: We estimated the difference in RMSTs (95% confidence interval [CI]) for total and CHD-free survival between pravastatin and usual care groups over the 6-year trial period. We also used parametric survival models to estimate the RMST differences projected over 10 years. RESULTS: Over 6 years, patients treated with pravastatin lived, on average, 33.7 fewer days than usual-care patients (RMST: 2008.1 vs 2041.8 days; RMST difference, −33.7 days; 95% CI, −67.0 to −0.5; p=0.047). Pravastatin-treated patients lived, on average, 18.7 more days free of CHD over 6 years than usual-care patients, but this difference was not statistically significant (RMST: 2088.1 vs 2069.4 days; RMST difference, 18.7 days; 95% CI, −10.4 to 47.8; p=0.209). The 10-year projection showed that pravastatin-treated patients would live 108.1 fewer days (95% CI, −204.5 to −14.1; p=0.028) than usual-care patients, although treated patients would gain 77.9 days (95% CI, 3.8 to 159.6; p=0.046) of CHD-free survival. CONCLUSION: RMST provides an intuitive and explicit way to express the effect of pravastatin therapy on CHD-free and overall survival in older adults free of cardiovascular disease. This measure allows a more personalized interpretation of the benefits and risks of a medical intervention for decision-making.

It is believed that genetic factors play a large role in the development of many cognitive and neurological processes; however, epidemiological evidence for the genetic basis of childhood neurodevelopment is very limited. Identification of the genetic polymorphisms associated with early-stage neurodevelopment will help elucidate biological mechanisms involved in neuro-behavior and provide a better understanding of the developing brain. To search for such variants, we performed a genome-wide association study (GWAS) for infant mental and motor ability at two years of age with mothers and children recruited from cohorts in Bangladesh and Mexico. Infant ability was assessed using mental and motor composite scores calculated with country-specific versions of the Bayley Scales of Infant Development. A missense variant (rs1055153) located in the gene WWTR1 reached genome-wide significance in association with mental composite score (meta-analysis effect size of minor allele βmeta = −6.04; 95% CI: −8.13 to −3.94; P = 1.56×10−8). Infants carrying the minor allele reported substantially lower cognitive scores in both cohorts, and this variant is predicted to be in the top 0.3% of most deleterious substitutions in the human genome. Fine mapping and region-based association testing provided additional suggestive evidence that both WWTR1 and a second gene, LRP1B, were associated with infant cognitive ability. Comparisons with recently conducted GWAS in intelligence and educational attainment indicate that our phenotypes do not possess a high genetic correlation with either adolescent or adult cognitive traits, suggesting that infant neurological assessments should be treated as an independent outcome of interest. Additional functional studies and replication efforts in other cohorts may help uncover new biological pathways and genetic architectures that are crucial to the developing brain.

A common complementary strategy in Genome-Wide Association Studies (GWAS) is to perform Gene Set Analysis (GSA), which tests for the association between one phenotype of interest and an entire set of Single Nucleotide Polymorphisms (SNPs) residing in selected genes. While there exist many tools for performing GSA, popular methods often include a number of ad-hoc steps that are difficult to justify statistically, provide complicated interpretations based on permutation inference, and demonstrate poor operating characteristics. Additionally, the lack of gold standard gene set lists can produce misleading results and create difficulties in comparing analyses even across the same phenotype. We introduce the Generalized Berk-Jones (GBJ) statistic for GSA, a permutation-free parametric framework that offers asymptotic power guarantees in certain set-based testing settings. To adjust for confounding introduced by different gene set lists, we further develop a GBJ step-down inference technique that can discriminate between gene sets driven to significance by single genes and those demonstrating group-level effects. We compare GBJ to popular alternatives through simulation and re-analysis of summary statistics from a large breast cancer GWAS, and we show how GBJ can increase power by incorporating information from multiple signals in the same gene. In addition, we illustrate how breast cancer pathway analysis can be confounded by the frequency of FGFR2 in pathway lists. Our approach is further validated on two other datasets of summary statistics generated from GWAS of height and schizophrenia., Author summary Researchers are frequently interested in the association between a biologically related set of genes—for example, a particular immune response pathway—and a complex phenotype. Such associations are often explored by applying various gene set analysis methods to genotype data from genome-wide association studies. However, many common methods are ad-hoc in nature and possess unknown statistical operating characteristics; reviews of existing procedures often show poor Type I error and power. We propose conducting gene set analysis with a class of tests that possesses both rigorous statistical motivation and excellent performance in application. Comparisons with popular alternatives including GSEA and MAGMA show a substantial increase in power. In addition, we introduce a novel step-down inference procedure that mitigates the confounding introduced by different gene set databases. For example, this procedure identifies that a seemingly strong association between breast cancer and Ear Morphogenesis is actually an association between breast cancer and just one single gene in the Ear Morphogenesis pathway. Use of the step-down procedure can improve reproducibility and result in much more interpretable findings when performing gene set analysis.

Objective The study aimed to explore the changes in mitochondrial DNA (mtDNA) copy number, collagen, and matrix metalloproteinase (MMPs) expression with pelvic organ prolapse (POP) in the uterosacral ligaments of premenopausal women. Materials and methods A group of 56 premenopausal women, all younger than 52 years of age, were enrolled in this study. Uterosacral ligament (UL) biopsies were obtained from uterine specimens taken from 22 women with POP ( n = 22, study group) and 34 myoma patients without POP ( n = 34, control group) during abdominal or vaginal hysterectomy. Quantitative real-time polymerase chain reaction (Q-PCR) and immunohistochemistry analysis were applied in the present study. Results The rate of high body mass index (BMI) (> 24 kg/m 2 ) women was significantly higher in the POP group (81.8% vs. 35.3%, p = 0.001 *), and the BMI of the POP women was higher than that of the nonPOP women ( p = 0.029 *). The mtDNA copy number ( p = 0.001 *), collagen III alpha 1 (COL3α1) expression ( p = 0.025 *), and MMP2 expression ( p = 0.047 *) were significantly higher in the POP group when compared with the nonPOP group. The high BMI women had a higher mtDNA copy number ( p = 0.002 *), COL3α1 ( p = 0.028 *) gene expressions compared with the standard BMI women. Conclusion In the premenopausal state, higher BMI may be a stronger associate factor than vaginal birth for the development of POP. The higher mtDNA copy number, COL3α1, and MMP2 gene expressions are highly associated with POP in the UL of premenopausal women.

Motivation Cancer genomics studies frequently aim to identify genes that are differentially expressed between clinically distinct patient subgroups, generally by testing single genes one at a time. However, the results of any individual transcriptomic study are often not fully reproducible. A particular challenge impeding statistical analysis is the difficulty of distinguishing between differential expression comprising part of the genomic disease etiology and that induced by downstream effects. More robust analytical approaches that are well-powered to detect potentially causative genes, are less prone to discovering spurious associations, and can deliver reproducible findings across different studies are needed. Results We propose a set-based procedure for testing of differential expression and show that this set-based approach can produce more robust results by aggregating information across multiple, correlated genomic markers. Specifically, we adapt the Generalized Berk–Jones statistic to test for the transcription factors that may contribute to the progression of estrogen receptor positive breast cancer. We demonstrate the ability of our method to produce reproducible findings by applying the same analysis to 21 publicly available datasets, producing a similar list of significant transcription factors across most studies. Our Generalized Berk–Jones approach produces results that show improved consistency over three set-based testing algorithms: Generalized Higher Criticism, Gene Set Analysis and Gene Set Enrichment Analysis. Availability and implementation Data are in the MetaGxBreast R package. Code is available at github.com/ryanrsun/gaynor_sun_GBJ_breast_cancer. Supplementary information Supplementary data are available at Bioinformatics online.

Complex interplay between genetic and environmental factors characterizes the etiology of many diseases. Modeling gene-environment (GxE) interactions is often challenged by the unknown functional form of the environment term in the true data-generating mechanism. We study the impact of misspecification of the environmental exposure effect on inference for the GxE interaction term in linear and logistic regression models. We first examine the asymptotic bias of the GxE interaction regression coefficient, allowing for confounders as well as arbitrary misspecification of the exposure and confounder effects. For linear regression, we show that under gene-environment independence and some confounder-dependent conditions, when the environment effect is misspecified, the regression coefficient of the GxE interaction can be unbiased. However, inference on the GxE interaction is still often incorrect. In logistic regression, we show that the regression coefficient is generally biased if the genetic factor is associated with the outcome directly or indirectly. Further, we show that the standard robust sandwich variance estimator for the GxE interaction does not perform well in practical GxE studies, and we provide an alternative testing procedure that has better finite sample properties.

Background Neurodevelopment is a complex process involving both genetic and environmental factors. Prenatal exposure to lead (Pb) has been associated with lower performance on neurodevelopmental tests. Adverse neurodevelopmental outcomes are more frequent and/or more severe when toxic exposures interact with genetic susceptibility. Methods To explore possible loci associated with increased susceptibility to prenatal Pb exposure, we performed a genome-wide gene-environment interaction study (GWIS) in young children from Mexico (n = 390) and Bangladesh (n = 497). Prenatal Pb exposure was estimated by cord blood Pb concentration. Neurodevelopment was assessed using the Bayley Scales of Infant Development. Results We identified a locus on chromosome 8, containing UNC5D, and demonstrated evidence of its genome-wide significance with mental composite scores (rs9642758, p meta = 4.35 × 10−6). Within this locus, the joint effects of two independent single nucleotide polymorphisms (SNPs, rs9642758 and rs10503970) had a p-value of 4.38 × 10−9 for mental composite scores. Correlating GWIS results with in vitro transcriptomic profiles identified one common gene, SLC1A5, which is involved in synaptic function, neuronal development, and excitotoxicity. Further analysis revealed interconnected interactions that formed a large network of 52 genes enriched with oxidative stress genes and neurodevelopmental genes. Conclusions Our findings suggest that certain genetic polymorphisms within/near genes relevant to neurodevelopment might modify the toxic effects of Pb exposure via oxidative stress. Electronic supplementary material The online version of this article (doi:10.1186/s12940-017-0288-3) contains supplementary material, which is available to authorized users.

In this retrospective study, a comparison is made of the clinical efficacy of two stress urinary incontinence treatment apparatuses, a single-incision sling and a transobturator sling. Eighty-five (single-incision n = 43, transobturator n = 42) consecutive patients were included in this study. Clinical outcomes were assessed by the cough stress test (CST), the pad test, the Impact Questionnaire-Short Form (IIQ-7), the Urogenital Distress Inventory six-item questionnaire (UDI-6), the Sexual Questionnaire-SF (PIS-Q), the pain score, and the postoperative changes in urodynamic parameters. A comparison of the 1-year follow-up data is presented. Three months post-surgery, 81.8% of the single-incision sling group and 74.4% of the transobturator sling group had a negative cough test and a dry pad test. One year after surgery, significantly decreasing UDI-6, IIQ-7, and increasing PIS-Q scores were observed in both groups, while the complication rates remained similar. Postoperatively, the single-incision sling group seems to show a greater improvement in UDI-6 score, require less operation time, and experience less blood loss, less postoperative pain, and a smaller decrease in maximal urethral closure pressure (MUCP). These results suggest that the single-incision sling and the transobturator sling are equally as effective and safe for the treatment of stress incontinence, as evaluated during the 1-year follow-up. The insertion of a single-incision sling seems to be less painful than that of a conventional sling. One year after surgery, the MUCP and mean flow rate of the transobturator sling group had significantly decreased compared with that of the single-incision sling group.

Objective: To ascertain whether low preoperational maximal urethral closure pressure (MUCP) affects the outcomes of single incision sling (SIS) procedures and changes MUCP values postsurgery. Material and methods: There were 112 (MUCP ≥ 40 cmH2O, n = 88; MUCP

Promising recent investigations have shown that breast malignancies exhibit restricted diffusion on diffusion-weighted imaging (DWI) and may be distinguished from normal tissue and benign lesions in the breast based on differences in apparent diffusion coefficient (ADC) values. In this study, we assessed the influence of intravoxel fat signal on breast diffusion measures by comparing ADC values obtained using a diffusion-weighted single shot fast spin echo sequence with and without fat suppression. The influence of breast density on ADC measures was also evaluated. ADC values were calculated for both tumor and normal fibroglandular tissue in a group of twenty-one women with diagnosed breast cancer. There were systematic underestimations of ADC for both tumor and normal breast tissue due to intravoxel contribution from fat signal on non-fat-suppressed DWI. This ADC underestimation was more pronounced for normal tissue values (mean difference = 40%) than for tumors (mean difference = 27%, p