Predicting non-muscle invasive bladder cancer outcomes using artificial intelligence: a systematic review using APPRAISE-AI.

Accurate prediction of recurrence and progression in non-muscle invasive bladder cancer (NMIBC) is essential to inform management and eligibility for clinical trials. Despite substantial interest in developing artificial intelligence (AI) applications in NMIBC, their clinical readiness remains unclear. This systematic review aimed to critically appraise AI studies predicting NMIBC outcomes, and to identify common methodological and reporting pitfalls. MEDLINE, EMBASE, Web of Science, and Scopus were searched from inception to February 5th, 2024 for AI studies predicting NMIBC recurrence or progression. APPRAISE-AI was used to assess methodological and reporting quality of these studies. Performance between AI and non-AI approaches included within these studies were compared. A total of 15 studies (five on recurrence, four on progression, and six on both) were included. All studies were retrospective, with a median follow-up of 71 months (IQR 32-93) and median cohort size of 125 (IQR 93-309). Most studies were low quality, with only one classified as high quality. While AI models generally outperformed non-AI approaches with respect to accuracy, c-index, sensitivity, and specificity, this margin of benefit varied with study quality (median absolute performance difference was 10 for low, 22 for moderate, and 4 for high quality studies). Common pitfalls included dataset limitations, heterogeneous outcome definitions, methodological flaws, suboptimal model evaluation, and reproducibility issues. Recommendations to address these challenges are proposed. These findings emphasise the need for collaborative efforts between urological and AI communities paired with rigorous methodologies to develop higher quality models, enabling AI to reach its potential in enhancing NMIBC care.

'Spin' in urology non-randomised studies comparing therapeutic interventions: a temporal analysis.

OBJECTIVE: To determine the prevalence of 'spin' (i.e., reporting practices that distort the interpretation of results by positively reflecting negative findings or downplaying potential harms) strategies and level of spin in urological observational studies and whether the use of spin has changed over time. MATERIALS AND METHODS: MEDLINE and Embase were searched to identify observational studies comparing therapeutic interventions in the top five urology journals and major urological subspecialty journals, published between 2000 and 2001, 2010 and 2011, and 2020 and 2021. RESULTS: A total of 235 studies were included. Spin was identified in 81% of studies, with a median of two strategies per study. The most commonly used strategies were inadequate implication for clinical practice (30%), causal language or causal claim (29%), and use of linguistic spin (29%). Moderate to high levels of spin were found in 55% of conclusions. From 2000 to 2020, the average number of strategies used has significantly decreased each decade (H = 27.459, P < 0.001), and the median level of spin in conclusions was significantly lower in studies published in the 2020s and 2010s than in the 2000s (H = 11.649, P = 0.003). CONCLUSIONS: Our results suggest that 81% of urological observational studies comparing therapeutic interventions contained spin. Over the past two decades, the use of spin has significantly declined, but this remains an area for improvement, with 70% of included studies published in the 2020s employing spin. Medical writing should scrupulously avoid words or phrases that are not supported by data in the manuscript.

An Updated Systematic Review and Meta-Analysis on the Technical, Oncologic, and Safety Outcomes of Microwave Ablation in Patients with Renal Cell Carcinoma.

Introduction: Percutaneous microwave ablation (MWA) has emerged as a new energy modality for percutaneous renal tumor ablation with potential advantages over radiofrequency and cryoablation. The goal of our study was to determine MWA outcomes for suspicious renal masses, with a subset analysis for biopsy-proven renal cell carcinoma (RCC) and larger (T1b) tumors. Methods: Studies reporting outcomes of MWA for RCC were identified. Random-effects models with inverse-variance weighting were used to pool outcomes, including technical success rate (TSR), technical efficacy rate (TER), local recurrence rate (LRR), cancer-specific survival rate (CSSR), overall survival rate (OSR), and complications. Results: Among 914 studies captured, 27 studies with 1584 patients (1683 malignant renal tumors) were included. The pooled TSR and TER were 99.6% (95% confidence interval [CI], 98.0%-100%) and 96.2% (95% CI, 93.8%-98.2%). The pooled LRR was 3.2% (95% CI, 1.9%-4.7%). At 1, 3, and 5 years, the pooled CSSRs were 100% (95% CI, 99.4%-100%), 100% (95% CI, 98.4%-100%), and 97.7% (95% CI, 94.5%-99.7%), while pooled OSRs were 99.0% (95% CI, 97.5%-99.9%), 96.0% (95% CI, 93.1%-98.3%), and 88.1% (95% CI, 80.3%-94.2%). The pooled minor and major complication rates were 10.3% (95% CI, 7.1%-13.9%) and 1.0% (95% CI, 0.3%-2.1%). In 204 patients with 208 T1b tumors, the pooled TSR and TER were 100% (95% CI, 96.6%-100%) and 85.2% (95% CI, 71.0%-95.8%). The pooled LRR was 4.2% (95% CI, 0.9%-8.9%). At 1, 3, and 5 years, the pooled CSSRs were 98.2% (95% CI, 88.7%-100%), 97.2% (95% CI, 78.5%-100%), and 98.1% (95% CI, 72.3%-100%). At 1 and 3 years, the pooled OSRs were 94.3% (95% CI, 85.7%-99.6%) and 89.3% (95% CI, 68.7%-100%). The pooled minor and major complication rates were 14.8% (95% CI, 7.4%-23.8%) and 2.6% (95% CI, 0%-7.8%). Conclusions: MWA demonstrated favorable short- to intermediate-term oncologic outcomes with low complication rates, including in the T1b subset, with moderate quality of data and heterogeneity of assessed outcomes. This supports MWA as a safe and effective treatment for RCC and a potential viable option for larger tumors.

Existing trends and applications of artificial intelligence in urothelial cancer A scoping review.

INTRODUCTION: The use of artificial intelligence (AI) in urology is gaining significant traction. While previous reviews of AI applications in urology exist, there have been few attempts to synthesize existing literature on urothelial cancer (UC). METHODS: Comprehensive searches based on the concepts of "AI" and "urothelial cancer" were conducted in MEDLINE , EMBASE , Web of Science, and Scopus. Study selection and data abstraction were conducted by two independent reviewers. Two independent raters assessed study quality in a random sample of 25 studies with the prediction model risk of bias assessment tool (PROBAST) and the standardized reporting of machine learning applications in urology (STREAM-URO) framework. RESULTS: From a database search of 4581 studies, 227 were included. By area of research, 33% focused on image analysis, 26% on genomics, 16% on radiomics, and 15% on clinicopathology. Thematic content analysis identified qualitative trends in AI models employed and variables for feature extraction. Only 19% of studies compared performance of AI models to non-AI methods. All selected studies demonstrated high risk of bias for analysis and overall concern with Cohen's kappa (k)=0.68. Selected studies met 66% of STREAM-URO items, with k=0.76. CONCLUSIONS: The use of AI in UC is a topic of increasing importance; however, there is a need for improved standardized reporting, as evidenced by the high risk of bias and low methodologic quality identified in the included studies.

"Spin" in Observational Studies in Deep Inferior Epigastric Perforator Flap Breast Reconstruction: A Systematic Review.

The deep inferior epigastric artery perforator (DIEP) flap is widely used in autologous breast reconstruction. However, the technique relies heavily on nonrandomized observational research, which has been found to have high risk of bias. "Spin" can be used to inappropriately present study findings to exaggerate benefits or minimize harms. The primary objective was to assess the prevalence of spin in nonrandomized observational studies on DIEP reconstruction. The secondary objectives were to determine the prevalence of each spin category and strategy. Methods: MEDLINE and Embase databases were searched from January 1, 2015, to November 15, 2022. Spin was assessed in abstracts and full-texts of included studies according to criteria proposed by Lazarus et al. Results: There were 77 studies included for review. The overall prevalence of spin was 87.0%. Studies used a median of two spin strategies (interquartile range: 1-3). The most common strategies identified were causal language or claims (n = 41/77, 53.2%), inadequate extrapolation to larger population, intervention, or outcome (n = 27/77, 35.1%), inadequate implication for clinical practice (n = 25/77, 32.5%), use of linguistic spin (n = 22/77, 28.6%), and no consideration of the limitations (n = 21/77, 27.3%). There were no significant associations between selected study characteristics and the presence of spin. Conclusions: The prevalence of spin is high in nonrandomized observational studies on DIEP reconstruction. Causal language or claims are the most common strategy. Investigators, reviewers, and readers should familiarize themselves with spin strategies to avoid misinterpretation of research in DIEP reconstruction.

"Spin" in Plastic Surgery Randomized Controlled Trials with Statistically Nonsignificant Primary Outcomes: A Systematic Review.

BACKGROUND: "Spin" refers to a manipulation of language that implies benefit for an intervention when none may exist. Randomized controlled trials (RCTs) in other fields have been demonstrated to employ spin, which can mislead clinicians to use ineffective or unsafe interventions. This study's objective was to determine the strategies, severity, and extent of spin in plastic surgery RCTs with nonsignificant primary outcomes. METHODS: A literature search of the top 15 plastic surgery journals using MEDLINE was performed (2000 through 2020). Parallel 1:1 RCTs with a clearly identified primary outcome showing statistically nonsignificant results ( P > 0.05) were included. Screening, data extraction, and spin analysis were performed by two independent reviewers. The spin analysis was then independently assessed in duplicate by two plastic surgery residents with graduate-level training in clinical epidemiology. RESULTS: From 3497 studies identified, 92 RCTs were included in this study. Spin strategies were identified in 78 RCTs (85%), including 64 abstracts (70%) and 77 main texts (84%). Severity of spin was rated moderate or high in 43 abstract conclusions (47%) and 42 main text conclusions (46%). The most identified spin strategy in the abstract was claiming equivalence for statistically nonsignificant results (26%); in the main text, focusing on another objective (24%). CONCLUSIONS: This study suggests that 85% of statistically nonsignificant RCTs in plastic surgery employ spin. Readers of plastic surgery research should be aware of strategies, whether intentional or unintentional, used to manipulate language in reports of statistically nonsignificant RCTs when applying research findings to clinical practice.

Assessing "Spin" in Urology Randomized Controlled Trials With Statistically Nonsignificant Primary Outcomes.

PURPOSE: "Spin" refers to a form of language manipulation that positively reflects negative findings or downplays potential harms. Spin has been reported in randomized controlled trials of other surgical specialties, which can lead to the recommendation of subpar or ineffective treatments. The goal of this study was to characterize spin strategies and severity in statistically nonsignificant urology randomized controlled trials. MATERIALS AND METHODS: A comprehensive search of MEDLINE and Embase for the top 5 urology journals, major urology subspecialty journals, and high-impact nonurology journals from 2019 to 2021 was conducted. Statistically nonsignificant randomized controlled trials with a defined primary outcome were included. Screening, data extraction, and spin assessment were performed in duplicate by 2 independent reviewers. RESULTS: From the database search of 4,339 studies, 46 trials were included for analysis. Spin was identified in 35 studies (76%), with the majority of abstracts (n = 26, 57%) and main texts (n = 35, 76%) containing some level of spin. "Obscuring the statistical nonsignificance of the primary outcome and focusing on statistically significant secondary results" was the most frequently used strategy in abstracts, while "other" strategies not previously defined were the most commonly used strategies in main texts. Moderate or high spin severity was identified in 21 (46%) abstract and 22 (48%) main text conclusions. CONCLUSIONS: Overall, our results suggest that 76% of statistically nonsignificant urology randomized controlled trials contained some level of spin. Readers and writers should be aware of common spin strategies when interpreting nonsignificant results and critically appraise the significance of results when making decisions for clinical practice.

The risk of bias of non-randomized observational studies in deep inferior epigastric perforator flap breast reconstruction: A systematic review using ROBINS-I.

INTRODUCTION: The deep inferior epigastric perforator (DIEP) flap is regarded as the gold standard for autologous breast reconstruction. However, due to difficulty designing and conducting randomized controlled trials in surgical interventions, the majority of literature on DIEP flap breast reconstructions are observational studies. As such, it is pivotal that these studies are performed with high internal validity. METHODS: A literature search was performed using MEDLINE, Embase, and CENTRAL from January 1, 2015 to October 23, 2021. Studies identified as observational studies about DIEP breast reconstruction and published in a journal with a Web of Science impact factor above 1.0 were included. Screening and risk of bias (RoB) assessment using the ROBINS-I tool were performed independently and in duplicate by two authors. RESULTS: From 12,371 studies, 66 observational studies were included. The majority were found at RoB, with 11 at moderate, 26 at serious, and 6 at critical RoB. Only two studies had low RoB. The bias most commonly arose due to Domain 1 (confounding variables), Domain 3 (classification of interventions), and Domain 6 (measurement of outcomes). CONCLUSIONS: In this review, we demonstrate the high RoB of observational studies evaluating DIEP breast reconstruction, which may jeopardize the validity of findings. We recommend that authors consult the ROBINS-I tool not only when assessing observational studies for systematic reviews but also when designing or conducting these studies. In our study, we present additional considerations for each domain to provide researchers with guidance on assessing and conducting surgical observational studies.

Evaluating Breast Reconstruction Reviews Using A Measurement Tool to Assess Systematic Reviews (AMSTAR).

BACKGROUND: Breast reconstruction is an important aspect in breast cancer treatment. METHODS: A comprehensive search of MEDLINE, Embase, and the Cochrane Library of Systematic Reviews was performed. Systematic reviews and meta-analyses that focused on breast reconstruction and were published between 2000 and 2020 were included. Quality assessment was performed using A Measurement Tool to Assess Systematic Reviews (AMSTAR). Study characteristics were extracted, including journal and impact factor, year of publication, country affiliation, reporting adherence to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, number of citations, and number of studies included. RESULTS: The average AMSTAR score was moderate (5.32). There was a significant increase in AMSTAR score (P < 0.01) and number of studies (P < 0.01) over time. There were no significant correlations between AMSTAR score and impact factor (P = 0.038), and AMSTAR score and number of citations (P = 0.52), but there was a significant association between AMSTAR score and number of studies (P = 0.013). Studies that adhered to the PRISMA statement had a higher AMSTAR score on average (P < 0.01). CONCLUSIONS: Systematic reviews and meta-analyses about breast reconstruction had, on average, a moderate AMSTAR score. The number of studies and methodological quality have increased over time. Study characteristics including adherence to PRISMA guidelines are associated with improved methodological quality. Further improvements in specific AMSTAR domains would improve the overall methodological quality.

Evaluating the Quality of Systematic Reviews and Meta-Analyses About Breast Augmentation Using AMSTAR.

BACKGROUND: Breast augmentation is one of the most commonly performed cosmetic surgeries worldwide. Therefore, it is imperative to have evidence with high methodological quality to guide clinical decision making. OBJECTIVES: To evaluate the methodological quality of the systematic reviews (SRs) focused on breast augmentation. METHODS: A comprehensive search of MEDLINE, Embase, and the Cochrane Library of Systematic Reviews was performed. SRs that have a particular focus on breast augmentation and were published in the top 15 plastic and reconstructive surgery journals were included. Quality assessment was performed using a measurement tool to assess systematic reviews (AMSTAR). Study characteristics were extracted including journal and impact factor, year of publication, country affiliation of the corresponding author, reporting adherence to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, number of citations, and number of studies included. RESULTS: Among the 22 studies included for analysis, the mean AMSTAR score was moderate (5.55), with no SR achieving good quality (AMSTAR score of ≥9). There were no significant associations between AMSTAR score and journal impact factor, number of citations, year of publication, or number of included studies. Studies that reported adherence to PRISMA guidelines on average scored higher on the AMSTAR tool (P = 0.03). CONCLUSIONS: The methodological quality of reviews about breast augmentation was found to be moderate, with no significant increase in studies or quality over time. Adherence to PRISMA guidelines and increased appraisal of SRs about breast augmentation using methodological assessment tools would further strengthen methodological quality and confidence in study findings.

An International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of CASQ2-Catecholaminergic Polymorphic Ventricular Tachycardia.

BACKGROUND: Genetic variants in calsequestrin-2 (CASQ2) cause an autosomal recessive form of catecholaminergic polymorphic ventricular tachycardia (CPVT), although isolated reports have identified arrhythmic phenotypes among heterozygotes. Improved insight into the inheritance patterns, arrhythmic risks, and molecular mechanisms of CASQ2-CPVT was sought through an international multicenter collaboration. METHODS: Genotype-phenotype segregation in CASQ2-CPVT families was assessed, and the impact of genotype on arrhythmic risk was evaluated using Cox regression models. Putative dominant CASQ2 missense variants and the established recessive CASQ2-p.R33Q variant were evaluated using oligomerization assays and their locations mapped to a recent CASQ2 filament structure. RESULTS: A total of 112 individuals, including 36 CPVT probands (24 homozygotes/compound heterozygotes and 12 heterozygotes) and 76 family members possessing at least 1 presumed pathogenic CASQ2 variant, were identified. Among CASQ2 homozygotes and compound heterozygotes, clinical penetrance was 97.1% and 26 of 34 (76.5%) individuals had experienced a potentially fatal arrhythmic event with a median age of onset of 7 years (95% CI, 6-11). Fifty-one of 66 CASQ2 heterozygous family members had undergone clinical evaluation, and 17 of 51 (33.3%) met diagnostic criteria for CPVT. Relative to CASQ2 heterozygotes, CASQ2 homozygote/compound heterozygote genotype status in probands was associated with a 3.2-fold (95% CI, 1.3-8.0; P=0.013) increased hazard of a composite of cardiac syncope, aborted cardiac arrest, and sudden cardiac death, but a 38.8-fold (95% CI, 5.6-269.1; P<0.001) increased hazard in genotype-positive family members. In vitro turbidity assays revealed that p.R33Q and all 6 candidate dominant CASQ2 missense variants evaluated exhibited filamentation defects, but only p.R33Q convincingly failed to dimerize. Structural analysis revealed that 3 of these 6 putative dominant negative missense variants localized to an electronegative pocket considered critical for back-to-back binding of dimers. CONCLUSIONS: This international multicenter study of CASQ2-CPVT redefines its heritability and confirms that pathogenic heterozygous CASQ2 variants may manifest with a CPVT phenotype, indicating a need to clinically screen these individuals. A dominant mode of inheritance appears intrinsic to certain missense variants because of their location and function within the CASQ2 filament structure.

Bioorthogonal Tetrazine Carbamate Cleavage by Highly Reactive trans-Cyclooctene.

The high rate of the 'click-to-release' reaction between an allylic substituted trans-cyclooctene linker and a tetrazine activator has enabled exceptional control over chemical and biological processes. Here we report the development of a new bioorthogonal cleavage reaction based on trans-cyclooctene and tetrazine, which allows the use of highly reactive trans-cyclooctenes, leading to 3 orders of magnitude higher click rates compared to the parent reaction, and 4 to 6 orders higher than other cleavage reactions. In this new pyridazine elimination mechanism, wherein the roles are reversed, a trans-cyclooctene activator reacts with a tetrazine linker that is substituted with a methylene-linked carbamate, leading to a 1,4-elimination of the carbamate and liberation of a secondary amine. Through a series of mechanistic studies, we identified the 2,5-dihydropyridazine tautomer as the releasing species and found factors that govern its formation and subsequent fragmentation. The bioorthogonal utility was demonstrated by the selective cleavage of a tetrazine-linked antibody-drug conjugate by trans-cyclooctenes, affording efficient drug liberation in plasma and cell culture. Finally, the parent and the new reaction were compared at low concentration, showing that the use of a highly reactive trans-cyclooctene as the activator leads to a complete cycloaddition reaction with the antibody-drug conjugate in seconds vs hours for the parent system. Although the subsequent release from the IEDDA adduct is slower, we believe that this new reaction may allow markedly reduced click-to-release reagent doses in vitro and in vivo and could expand the application scope to conditions wherein the trans-cyclooctene has limited stability.

Author Correction: Chemically triggered drug release from an antibody-drug conjugate leads to potent antitumour activity in mice.

The original version of this Article omitted the following from the Acknowledgements: 'This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs, through the Breast Cancer Research Program under Award No. W81XWH-15-1-0692. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the Department of Defense'. This error has now been corrected in the PDF and HTML versions of the Article.

Impact of LUTS on urine volume in stone formers The impact of lower urinary tract symptomatology on urine volumes in stone formers.

INTRODUCTION: We aimed to determine if there is a correlation between International Prostate Symptom scores (IPSS) and 24-hour urine collection volumes, as patients experiencing lower urinary tract symptoms (LUTS) may have impaired ability to increase fluid intake for stone prevention. METHODS: We conducted a single-centre, retrospective review was performed of stone-formers presenting from 2014-2016. Inclusion criteria were completion of an IPSS questionnaire and a 24-hour urine collection. Exclusion criteria included symptomatic stone or urinary tract infection at time of IPSS completion, inadequate 24-hour collection, or incomplete IPSS questionnaire. RESULTS: A total of 131 patients met inclusion criteria. Stratification by IPSS severity into mild (0-7), moderate (8-19), and severe (20-35) yielded groups of n=96, 28, and 7, respectively. Linear regression modelling did not reveal a correlation between IPSS score and volume (p=0.10). When compared to those with adequate urine volumes (>2 L/day, n=65), low-volume patients (<1 L/day, n=10) had a significantly higher total IPSS (11.7 vs. 6.1; p=0.036). These groups showed significant differences in their responses to questions about incomplete emptying (p=0.031), intermittency (p=0.011), and stranguria (p=0.0020), with higher scores noted in the low urine output group. CONCLUSIONS: This study is the first to examine the correlation between IPSS and 24-hour urine volume. Though our data does not show a linear relationship between urine output and IPSS, those with lower urine volumes appear to have worse self-reported voiding symptoms when compared to those with adequate volumes (>2 L/day) for stone prevention. The overall number of patients in our study is relatively small, which may account for the lack of a relationship between IPSS and 24-hour urine volumes.

Chemically triggered drug release from an antibody-drug conjugate leads to potent antitumour activity in mice.

Current antibody-drug conjugates (ADCs) target internalising receptors on cancer cells leading to intracellular drug release. Typically, only a subset of patients with solid tumours has sufficient expression of such a receptor, while there are suitable non-internalising receptors and stroma targets. Here, we demonstrate potent therapy in murine tumour models using a non-internalising ADC that releases its drugs upon a click reaction with a chemical activator, which is administered in a second step. This was enabled by the development of a diabody-based ADC with a high tumour uptake and very low retention in healthy tissues, allowing systemic administration of the activator 2 days later, leading to efficient and selective activation throughout the tumour. In contrast, the analogous ADC comprising the protease-cleavable linker used in the FDA approved ADC Adcetris is not effective in these tumour models. This first-in-class ADC holds promise for a broader applicability of ADCs across patient populations.

H3B-6527 Is a Potent and Selective Inhibitor of FGFR4 in FGF19-Driven Hepatocellular Carcinoma.

Activation of the fibroblast growth factor receptor FGFR4 by FGF19 drives hepatocellular carcinoma (HCC), a disease with few, if any, effective treatment options. While a number of pan-FGFR inhibitors are being clinically evaluated, their application to FGF19-driven HCC may be limited by dose-limiting toxicities mediated by FGFR1-3 receptors. To evade the potential limitations of pan-FGFR inhibitors, we generated H3B-6527, a highly selective covalent FGFR4 inhibitor, through structure-guided drug design. Studies in a panel of 40 HCC cell lines and 30 HCC PDX models showed that FGF19 expression is a predictive biomarker for H3B-6527 response. Moreover, coadministration of the CDK4/6 inhibitor palbociclib in combination with H3B-6527 could effectively trigger tumor regression in a xenograft model of HCC. Overall, our results offer preclinical proof of concept for H3B-6527 as a candidate therapeutic agent for HCC cases that exhibit increased expression of FGF19. Cancer Res; 77(24); 6999-7013. ©2017 AACR.

Loss of function JAK1 mutations occur at high frequency in cancers with microsatellite instability and are suggestive of immune evasion.

Immune evasion is a well-recognized hallmark of cancer and recent studies with immunotherapy agents have suggested that tumors with increased numbers of neoantigens elicit greater immune responses. We hypothesized that the immune system presents a common selective pressure on high mutation burden tumors and therefore immune evasion mutations would be enriched in high mutation burden tumors. The JAK family of kinases is required for the signaling of a host of immune modulators in tumor, stromal, and immune cells. Therefore, we analyzed alterations in this family for the hypothesized signature of an immune evasion mutation. Here, we searched a database of 61,704 unique solid tumors for alterations in the JAK family kinases (JAK1/2/3, TYK2). We used The Cancer Genome Atlas and Cancer Cell Line Encyclopedia data to confirm and extend our findings by analyzing gene expression patterns. Recurrent frameshift mutations in JAK1 were associated with high mutation burden and microsatellite instability. These mutations occurred in multiple tumor types including endometrial, colorectal, stomach, and prostate carcinomas. Analyzing gene expression signatures in endometrial and stomach adenocarcinomas revealed that tumors with a JAK1 frameshift exhibited reduced expression of interferon response signatures and multiple anti-tumor immune signatures. Importantly, endometrial cancer cell lines exhibited similar gene expression changes that were expected to be tumor cell intrinsic (e.g. interferon response) but not those expected to be tumor cell extrinsic (e.g. NK cells). From these data, we derive two primary conclusions: 1) JAK1 frameshifts are loss of function alterations that represent a potential pan-cancer adaptation to immune responses against tumors with microsatellite instability; 2) The mechanism by which JAK1 loss of function contributes to tumor immune evasion is likely associated with loss of the JAK1-mediated interferon response.

Gastric Band Removal in Revisional Bariatric Surgery, One-Step Versus Two-Step: a Systematic Review and Meta-analysis.

We aimed to systematically review the literature comparing the safety of one-step versus two-step revisional bariatric surgery from laparoscopic adjustable gastric banding (LAGB) to Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG). There is debate on the safety of removing the gastric band and performing revisional surgery immediately or in a delayed, two-step fashion due to potential higher complications in one-step revisions. A systematic and comprehensive search of the literature was conducted. Included studies directly compared one-step and two-step revisional surgery. Eleven studies were included with 1370 patients. Meta-analysis found comparable rates of complications, morbidity, and mortality between one-step and two-step revisions for both RYGB and SG groups. This suggests that immediate or delayed revisional bariatric surgeries are both safe options for LAGB revisions.

Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms.

Although targeted therapies are initially effective, resistance inevitably emerges. Several methods, such as genetic analysis of resistant clinical specimens, have been applied to uncover these resistance mechanisms to facilitate follow-up care. Although these approaches have led to clinically relevant discoveries, difficulties in attaining the relevant patient material or in deconvoluting the genomic data collected from these specimens have severely hampered the path towards a cure. To this end, we here describe a tool for expeditious discovery that may guide improvement in first-line therapies and alternative clinical management strategies. By coupling preclinical in vitro or in vivo drug selection with next-generation sequencing, it is possible to identify genomic structural variations and/or gene expression alterations that may serve as functional drivers of resistance. This approach facilitates the spontaneous emergence of alterations, enhancing the probability that these mechanisms may be observed in the patients. In this protocol we provide guidelines to maximize the potential for uncovering single nucleotide variants that drive resistance using adherent lines.