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Abstract Endometrial cancer (EC) has four molecular subtypes with strong prognostic value and therapeutic implications. The most common subtype (NSMP; No Specific Molecular Profile) is assigned after exclusion of the defining features of the other three molecular subtypes and includes patients with heterogeneous clinical outcomes. In this study, we employ artificial intelligence (AI)-powered histopathology image analysis to differentiate between p53abn and NSMP EC subtypes and consequently identify a sub-group of NSMP EC patients that has markedly inferior progression-free and disease-specific survival (termed ‘p53abn-like NSMP’), in a discovery cohort of 368 patients and two independent validation cohorts of 290 and 614 from other centers. Shallow whole genome sequencing reveals a higher burden of copy number abnormalities in the ‘p53abn-like NSMP’ group compared to NSMP, suggesting that this group is biologically distinct compared to other NSMP ECs. Our work demonstrates the power of AI to detect prognostically different and otherwise unrecognizable subsets of EC where conventional and standard molecular or pathologic criteria fall short, refining image-based tumor classification. This study’s findings are applicable exclusively to females.

Abstract Endometrial carcinoma (EC) is the most common gynecological malignancy and fibroblast growth factor receptor 2 (FGFR2) is a frequently dysregulated receptor tyrosine kinase. FGFR2b and FGFR2c are the two main splice isoforms of FGFR2 and are normally localized in epithelial and mesenchymal cells, respectively. Previously, we demonstrated that FGFR2c mRNA expression was associated with aggressive tumor characteristics, shorter progression‐free survival (PFS), and disease‐specific survival (DSS) in endometrioid ECs (EECs). The objectives of this study were to investigate the spatial expression of FGFR2b in normal and hyperplasia with and without atypia of human endometrium and to assess the prognostic significance of FGFR2b expression in EC. FGFR2b and FGFR2c mRNA expression was evaluated in normal (proliferative [n = 10], secretory [n = 15], and atrophic [n = 10] endometrium), hyperplasia with and without atypia (n = 19) as well as two patient cohorts of EC samples (discovery [n = 78] and Vancouver [n = 460]) using isoform‐specific BaseScope RNA in situ hybridization assays. Tumors were categorized based on FGFR2 isoform expression (one, both, or neither) and categories were correlated with clinicopathologic markers, molecular subtypes, and clinical outcomes. The FGFR2b splice isoform was exclusively expressed in the epithelial compartment of normal endometrium and hyperplasia without atypia. We observed FGFR2c expression at the basalis layer of glands in 33% (3/9) of hyperplasia with atypia. In patients with EEC, FGFR2b+/FGFR2c− expression was found in 48% of the discovery cohort and 35% of the validation Vancouver cohort. In univariate analyses, tumors with FGFR2b+/FGFR2c− expression had longer PFS (hazard ratio [HR] 0.265; 95% CI 0.145–0.423; log‐rank p

Abstract Background To drive translational medicine, modern day biobanks need to integrate with other sources of data (clinical, genomics) to support novel data-intensive research. Currently, vast amounts of research and clinical data remain in silos, held and managed by individual researchers, operating under different standards and governance structures; a framework that impedes sharing and effective use of data. In this article, we describe the journey of British Columbia’s Gynecological Cancer Research Program (OVCARE) in moving a traditional tumour biobank, outcomes unit, and a collection of data silos, into an integrated data commons to support data standardization and resource sharing under collaborative governance, as a means of providing the gynecologic cancer research community in British Columbia access to tissue samples and associated clinical and molecular data from thousands of patients. Results Through several engagements with stakeholders from various research institutions within our research community, we identified priorities and assessed infrastructure needs required to optimize and support data collections, storage and sharing, under three main research domains: (1) biospecimen collections, (2) molecular and genomics data, and (3) clinical data. We further built a governance model and a resource portal to implement protocols and standard operating procedures for seamless collections, management and governance of interoperable data, making genomic, and clinical data available to the broader research community. Conclusions Proper infrastructures for data collection, sharing and governance is a translational research imperative. We have consolidated our data holdings into a data commons, along with standardized operating procedures to meet research and ethics requirements of the gynecologic cancer community in British Columbia. The developed infrastructure brings together, diverse data, computing frameworks, as well as tools and applications for managing, analyzing, and sharing data. Our data commons bridges data access gaps and barriers to precision medicine and approaches for diagnostics, treatment and prevention of gynecological cancers, by providing access to large datasets required for data-intensive science.

Abstract Ovarian carcinoma histotypes are distinct diseases with variable clinical outcomes and response to treatment. There is a need for new subtype‐specific treatment modalities, especially for women with widespread and chemo‐resistant disease. Stimulator of interferon genes (STING) is a part of the cGAS–STING pathway that mediates innate immune defence against infectious DNA‐containing pathogens and also detects tumour‐derived DNA and generates intrinsic antitumour immunity. The STING signalling pathway is suppressed by several mechanisms in a variety of malignant diseases and, in some cancers that may be a requirement for cellular transformation. The aim of this study was to use immunohistochemistry to evaluate STING protein expression across normal tissue, paratubal and ovarian cysts, and ovarian tumour histotypes including ovarian carcinomas. Herein, we show that the fallopian tube ciliated cells express STING protein, whereas the secretory cells are negative. STING expression differs among ovarian cancer histotypes; low‐grade serous ovarian carcinomas and serous borderline tumours have uniform high STING expression, while high‐grade serous and endometrioid carcinomas have heterogeneous expression, and clear cell and mucinous carcinomas show low expression. As low‐grade serous carcinomas are known to be genomically stable and typically lack a prominent host immune response, the consistently high STING expression is unexpected. High STING expression may reflect pathway activation or histogenesis and the mechanisms may be different in different ovarian carcinoma histotypes. Further studies are needed to determine whether the STING signalling pathway is active and whether these tumours would be candidates for therapeutic interventions that trigger innate immunity activation.

ObjectivesPsychoeducation, motivational interviewing, cognitive remediation training, and social skills training have been found to be effective interventions for patients with schizophrenia spectrum disorders. However, their efficacy on psychosocial functioning when provided in combination remains unclear, compared with all types of control conditions. It would also be meaningful to explore the differences of efficacy in patients with first-episode psychosis (FEP) and those with longer term of illness.MethodologyThe present review followed the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Full-text English journal articles of randomized controlled trials published in the past decade in the databases of PubMed, CINAHL Complete, Embase, and PsycINFO were searched. Included studies were all randomized controlled trials (RCTs) with participants diagnosed with schizophrenia spectrum disorders. The included studies should test combined interventions with at least two components from: psychoeducation, motivational interviewing, cognitive remediation training, and social skills training and incorporate assessment of psychosocial functioning at least at baseline and post-intervention.ResultsSeven studies were included for systematic review, and six of them were eligible for meta-analysis. Five out of the seven studies reported effects on psychosocial functioning that favored combined interventions over any type of control condition. A significant pooled effect was derived from the six studies, SMD = 1.03, 95% CI [0.06, 2.00], Z = 2.09, p = 0.04, I2 = 96%. However, the pool effect became insignificant when synthesizing five of the studies with non-FEP patients as participants and four of the studies testing relative effects of combined interventions compared with stand-alone interventions/interventions with one less component. None of the included studies adopted motivational interviewing and only one of the studies worked with FEP patients.ConclusionPsychoeducation, cognitive remediation training, and social skills training in combination can effectively enhance psychosocial functioning of patients with schizophrenia spectrum disorders. It is warranted to conduct more RCTs to test the effects of different specific combinations of the above interventions on psychosocial functioning, especially in FEP patients.

Abstract Early relapse after platinum chemotherapy in epithelial ovarian cancer (EOC) portends poor survival. A‐priori identification of platinum resistance is therefore crucial to improve on standard first‐line carboplatin–paclitaxel treatment. The DNA repair pathway homologous recombination (HR) repairs platinum‐induced damage, and the HR recombinase RAD51 is overexpressed in cancer. We therefore designed a REMARK‐compliant study of pre‐treatment RAD51 expression in EOC, using fluorescent quantitative immunohistochemistry (qIHC) to overcome challenges in quantitation of protein expression in situ. In a discovery cohort (n = 284), RAD51‐High tumours had shorter progression‐free and overall survival compared to RAD51‐Low cases in univariate and multivariate analyses. The association of RAD51 with relapse/survival was validated in a carboplatin monotherapy SCOTROC4 clinical trial cohort (n = 264) and was predominantly noted in HR‐proficient cancers (Myriad HRDscore

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the novel coronavirus responsible for the COVID-19 pandemic. The viral protein of SARS-CoV-2, spike protein (SP), mediates entry into host cells, contributing to pathogenesis of COVID-19. Prostate cancer is the most common cancer among men in the United States. Inducible T-cell costimulator ligand (ICOSL) and intercellular cell adhesion molecule 2 (ICAM-2) are expressed in cancer cells and their roles in cancer growth remain controversial. It is unknown if SP can affect the expression of ICAM-2 or ICOSL in prostate cancer. This study investigated the effects of SARS-CoV-2 SP on the expression of ICAM-2 and ICOSL and the time-dependent effect of SP on growth and survival of prostate cancer cells. Methods: The effect of SARS-CoV-2 SP on the survival of a widely-used prostate cancer cell line, LNCaP, was assessed using clonogenic cell survival assay and quick cell proliferation assay. Reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC) were performed to investigate the expression of ICAM-2 and ICOSL. The survival of an additional prostate cancer cell line, PC-3, was also evaluated by clonogenic survival assay. Results: After 3 days, a significant decrease in the percentage of colonies in LNCaP cells treated with SP was found, which was paralleled by a decrease in optical density (OD) value in LNCaP cells in the presence of SP. A significant decrease in the percentage of colonies treated with SP was also found in PC-3 cells evaluated by clonogenic survival assay. In addition, the mRNA expression of ICAM-2 was lower, whereas the mRNA expression of ICOSL was higher in SP-treated LNCaP cells. This was supported by protein expressions for ICAM-2 and ICOSL evaluated with IHC. Conclusions: In LNCaP cells, SARS-CoV-2 SP downregulates the expression of ICAM-2 but upregulates the expression of ICOSL. SARS-CoV-2 SP inhibits growth of prostate cancer cells in a time-dependent manner. Further studies are needed to fully address the roles of ICAM-2 and ICOSL in the inhibition prostate cancer growth by SARS-CoV-2 SP.

Preclinical studies suggest that some effects of conventional chemotherapy, and in particular, gemcitabine, are mediated through enhanced antitumor immune responses. The objective of this study was to use material from a randomized clinical trial to evaluate whether patients with preexisting immune infiltrates responded better to treatment with gemcitabine + docetaxel (GD) compared to docetaxel alone. Formalin fixed, paraffin-embedded breast cancer tissues from SBG0102 phase 3 trial patients randomly assigned to treatment with GD or docetaxel were used. Immunohistochemical staining for CD8, FOXP3, LAG3, PD-1, PD-L1 and CD163 was performed. Tumor infiltrating lymphocytes (TILs) and tumor associated macrophages were evaluated. Prespecified statistical analyses were performed in a formal prospective-retrospective design. Time to progression was primary endpoint and overall survival secondary endpoint. Correlations between biomarker status and endpoints were evaluated using the Kaplan–Meier method and Cox proportional hazards models. Biomarker data was obtained for 237 patients. There was no difference in treatment effect according to biomarker status for the whole cohort. In planned subgroup analysis by PAM50 subtype, in non-luminal (basal-like and HER2E) breast cancers FOXP3 was a significant predictor of treatment effect with GD compared to docetaxel, with a HR of 0.22 (0.09–0.52) for tumors with low FOXP3 compared to HR 0.92 (0.47–1.80) for high FOXP3 TILs (Pinteraction = 0.01). Immune biomarkers were not predictive of added benefit of gemcitabine in a cohort of mixed breast cancer subtypes. However, in non-luminal breast cancers, patients with low FOXP3+ TILs may have significant benefit from added gemcitabine.

Unravelling the link between somatic mutation and prognosis in estrogen positive (ER+) breast cancer requires the use of long-term follow-up data. Here, combining archival formalin-fixed paraffin embedded tissue and targeted sequencing in three cohorts of ER+ breast cancer, the authors find associations with clinical outcome for NF1 frame-shift nonsense mutations, PIK3R1 mutation, and DDR1 mutations.

Tumor-infiltrating lymphocytes (TILs) are predominantly present in breast cancer patients with estrogen receptor negative tumors, among whom increasing levels correlate with favorable outcomes. Nevertheless, currently available immune checkpoint inhibitors appear to benefit only a small number of women with breast cancer. Upregulation of additional immune checkpoint markers is one mechanism of resistance to current inhibitors that might be amenable to targeting with newer agents. T-cell Immunoglobulin and Mucin domain-containing molecule 3 (TIM-3) is an immune checkpoint receptor that is an emerging target for cancer immunotherapy. We investigated TIM-3 immunohistochemical expression in 3,992 breast cancer specimens assembled into tissue microarrays, linked to detailed outcome, clinico-pathological parameters and biomarkers including CD8, PD-1, PD-L1 and LAG-3. We scored and reported absolute counts for TIM-3+ intra-epithelial and stromal TILs (iTILs and sTILs), and find that breast cancer patients with TIM-3+ iTILs (≥ 1) represent a minority of cases (11%), with a predilection for basal-like breast cancers (among which 28% had TIM-3+ iTILs). TIM-3+ sTILs (≥ 2) represented 20% of cases and included more non-basal cases. The presence of TIM-3+ iTILs highly correlates with hematoxylin and eosin-stained stromal TILs and with other immune checkpoint markers (PD-1+ iTILs, LAG-3+ iTILs and PD-L1+ tumors). In prognostic analyses, early breast cancer patients with TIM-3+ iTILs have significantly improved breast cancer-specific survival whereas TIM-3+ sTILs did not reach statistical significance. In multivariate analyses, the presence of TIM-3+ iTILs is an independent favorable prognostic factor in the whole cohort as well as among ER negative patients. Our study supports TIM-3 as a target for breast cancer immunotherapy.

Background: Survival and hospitalization are critically important outcomes considered when choosing between intensive hemodialysis (HD), conventional HD, and peritoneal dialysis (PD). However, the comparative effectiveness of these modalities is unclear. Objective: We had the following aims: (1) to compare the association of mortality and hospitalization in patients undergoing intensive HD, compared with conventional HD or PD and (2) to appraise the methodological quality of the supporting evidence. Data Sources: MEDLINE, Embase, ISI Web of Science, CENTRAL, and nephrology conference abstracts. Study Eligibility, Participants, and Interventions: We included cohort studies with comparator arm, and randomized controlled trials (RCTs) with >50% of adult patients (≥18 years) comparing any form of intensive HD (>4 sessions/wk or >5.5 h/session) with any form of chronic dialysis (PD, HD ≤4 sessions/wk or ≤5.5 h/session), that reported at least 1 predefined outcome (mortality or hospitalization). Methods: We used the GRADE approach to systematic reviews and quality appraisal. Two reviewers screened citations and full-text articles, and extracted study-level data independently, with discrepancies resolved by consensus. We pooled effect estimates of randomized and observational studies separately using generic inverse variance with random effects models, and used fixed-effects models when only 2 studies were available for pooling. Predefined subgroups for the intensive HD cohorts were classified by nocturnal versus short daily HD and home versus in-center HD. Results: Twenty-three studies with a total of 70 506 patients were included. Of the observational studies, compared with PD, intensive HD had a significantly lower mortality risk (hazard ratio [HR]: 0.67; 95% confidence interval [CI]: 0.53-0.84; I 2 = 91%). Compared with conventional HD, home nocturnal (HR: 0.46; 95% CI: 0.38-0.55; I 2 = 0%), in-center nocturnal (HR: 0.73; 95% CI: 0.60-0.90; I 2 = 57%) and home short daily (HR: 0.54; 95% CI: 0.31-0.95; I 2 = 82%) intensive regimens had lower mortality. Of the 2 RCTs assessing mortality, in-center short daily HD had lower mortality (HR: 0.54; 95% CI: 0.31-0.93), while home nocturnal HD had higher mortality (HR: 3.88; 95% CI: 1.27-11.79) in long-term observational follow-up. Hospitalization days per patient-year (mean difference: –1.98; 95% CI: –2.37 to −1.59; I 2 = 6%) were lower in nocturnal compared with conventional HD. Quality of evidence was similarly low or very low in RCTs (due to imprecision) and observational studies (due to residual confounding and selection bias). Limitations: The overall quality of evidence was low or very low for critical outcomes. Outcomes such as quality of life, transplantation, and vascular access outcomes were not included in our review. Conclusions: Intensive HD regimens may be associated with reduced mortality and hospitalization compared with conventional HD or PD. As the quality of supporting evidence is low, patients who place a high value on survival must be adequately advised and counseled of risks and benefits when choosing intensive dialysis. Practice guidelines that promote shared decision-making are likely to be helpful.

The original version of this Article contained errors in the depiction of confidence intervals in the NF1 BCSS data illustrated in Figure 3b. These have now been corrected in both the PDF and HTML versions of the Article. The incorrect version of Figure 3b is presented in the associated Author Correction.

A major weakness in many high-throughput genomic studies is the lack of consideration of a clinical environment where one patient at a time must be evaluated. We examined generalizable and platform-specific sources of variation from NanoString gene expression data on both ovarian cancer and Hodgkin lymphoma patients. A reference-based strategy, applicable to single-patient molecular testing is proposed for batch effect correction. The proposed protocol improved performance in an established Hodgkin lymphoma classifier, reducing batch-to-batch misclassification while retaining accuracy and precision. We suggest this strategy may facilitate development of NanoString and similar molecular assays by accelerating prospective validation and clinical uptake of relevant diagnostics.

BACKGROUND: Although it has long been appreciated that ovarian carcinoma subtypes (serous, clear cell, endometrioid, and mucinous) are associated with different natural histories, most ovarian carcinoma biomarker studies and current treatment protocols for women with this disease are not subtype specific. With the emergence of high-throughput molecular techniques, distinct pathogenetic pathways have been identified in these subtypes. We examined variation in biomarker expression rates between subtypes, and how this influences correlations between biomarker expression and stage at diagnosis or prognosis. METHODS AND FINDINGS: In this retrospective study we assessed the protein expression of 21 candidate tissue-based biomarkers (CA125, CRABP-II, EpCam, ER, F-Spondin, HE4, IGF2, K-Cadherin, Ki-67, KISS1, Matriptase, Mesothelin, MIF, MMP7, p21, p53, PAX8, PR, SLPI, TROP2, WT1) in a population-based cohort of 500 ovarian carcinomas that was collected over the period from 1984 to 2000. The expression of 20 of the 21 biomarkers differs significantly between subtypes, but does not vary across stage within each subtype. Survival analyses show that nine of the 21 biomarkers are prognostic indicators in the entire cohort but when analyzed by subtype only three remain prognostic indicators in the high-grade serous and none in the clear cell subtype. For example, tumor proliferation, as assessed by Ki-67 staining, varies markedly between different subtypes and is an unfavourable prognostic marker in the entire cohort (risk ratio [RR] 1.7, 95% confidence interval [CI] 1.2%-2.4%) but is not of prognostic significance within any subtype. Prognostic associations can even show an inverse correlation within the entire cohort, when compared to a specific subtype. For example, WT1 is more frequently expressed in high-grade serous carcinomas, an aggressive subtype, and is an unfavourable prognostic marker within the entire cohort of ovarian carcinomas (RR 1.7, 95% CI 1.2%-2.3%), but is a favourable prognostic marker within the high-grade serous subtype (RR 0.5, 95% CI 0.3%-0.8%). CONCLUSIONS: The association of biomarker expression with survival varies substantially between subtypes, and can easily be overlooked in whole cohort analyses. To avoid this effect, each subtype within a cohort should be analyzed discretely. Ovarian carcinoma subtypes are different diseases, and these differences should be reflected in clinical research study design and ultimately in the management of ovarian carcinoma.

Abstract: There is currently great interest in reuse of digital learning resources, from single items to multi-task activities, to whole units or programmes of study. Associated with this interest is the ongoing development of tools to enable such resources to be placed in or recovered from repositories, to facilitate searching for them and their instantiation on different learning platforms. Many of these tools are highly technical, in terms of both technology and terminology, and they are the province of learning technologists and computer scientists, rather than teachers. Concentration on such tools begs the question as to whether teachers and learners will truly benefit from reuse of learning resources. This paper describes the re-purposing of a learning activity created in a university in the US for use in two UK universities. The case study approach facilitates comparison of the technical and content issues that were addressed and resolved. The authors formulate and explore a proposition about the validity of an 'object based' approach to learning resources and conclude with a plea for better tools for teachers.Interactive demonstrations: The learning activities are available at www.dialogplus.soton.ac.uk/aig/index.html.