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This article discusses the lack of diversity in terms of sexual and gender minority identities among orthopaedic professionals in the United States. It highlights the low representation of sexual and gender minority orthopaedic surgeons and the need for efforts to recruit more diverse professionals in the field. The article emphasizes the importance of creating a welcoming and inclusive environment within orthopaedics and promoting cultural competency. It also suggests strategies such as starting early in medical education to make orthopaedics a welcoming specialty and fostering support for faculty of diverse backgrounds. [Extracted from the article]

Orthopaedic surgery research increasingly utilizes statistical models to adjust for confounding, provide additional precision, and describe complex relationships. Traditionally, a statistical model is termed "multivariable" if it examines the relationship between multiple independent variables (e.g., covariables). The term "multivariate" is used to describe statistical models with multiple dependent variables (e.g., outcomes). The precise use of statistical terminology is important for study appraisal and reproducibility. The term "multivariate" is frequently used incorrectly in the orthopaedic literature to describe statistical models with a single dependent variable. In our analysis, we found that the term "multivariate" was used frequently, and in >90% of cases, the term was used to describe models that contain only a single dependent variable. Consistent with our perception, the terms "multivariable" and "multivariate" are not used with optimal precision. Below, we discuss the impact of the misuse of statistical terminology and present suggestions for improving statistical reporting. [ABSTRACT FROM AUTHOR]

Background: End-stage knee osteoarthritis (OA) is a highly debilitating disease for which total knee arthroplasty (TKA) serves as an effective treatment option. Although a genetic component to OA in general has been described, evaluation of the genetic contribution to end-stage OA of the knee is limited. To this end, we present a genome-wide association study involving patients undergoing TKA for primary knee OA to characterize the genetic features of severe disease on a population level.Methods: Individuals with the diagnosis of knee OA who underwent primary TKA were identified in the U.K. Biobank using administrative codes. The U.K. Biobank is a data repository containing prospectively collected clinical and genomic data for >500,000 patients. A genome-wide association analysis was performed using the REGENIE software package. Logistic regression was also used to compare the total genetic risk between subgroups stratified by age and body mass index (BMI).Results: A total of 16,032 patients with end-stage knee OA who underwent primary TKA were identified. Seven genetic loci were found to be significantly associated with end-stage knee OA. The odds ratio (OR) for developing end-stage knee OA attributable to genetics was 1.12 (95% confidence interval [CI], 1.10 to 1.14), which was lower than the OR associated with BMI (OR = 1.81; 95% CI, 1.78 to 1.83) and age (OR = 2.38; 95% CI, 2.32 to 2.45). The magnitude of the OR for developing end-stage knee OA attributable to genetics was greater in patients <60 years old than in patients ≥60 years old (p = 0.002).Conclusions: This population-level genome-wide association study of end-stage knee OA treated with primary TKA was notable for identifying multiple significant genetic variants. These loci involve genes responsible for cartilage development, cartilage homeostasis, cell signaling, and metabolism. Age and BMI appear to have a greater impact on the risk of developing end-stage disease compared with genetic factors. The genetic contribution to the development of severe disease is greater in younger patients.Level Of Evidence: Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence. [ABSTRACT FROM AUTHOR]

Aims: SMARCB1 (INI‐1)‐deficient vulvar neoplasms comprise a group of rare tumours that include epithelioid sarcoma (ES), myoepithelial carcinoma (MEC), the recently described myoepithelioma‐like tumour of the vulvar region (MELTVR), and sarcomas that are difficult to classify. It has been suggested that so‐called vulvar yolk sac tumours (YST) may represent morphologic variants of SMARCB1‐deficient tumours; thus, we investigated the immunoreactivity of germ cell markers in SMARCB1‐deficient vulvar neoplasms. Methods and results: Ten SMARCB1‐deficient vulvar neoplasms were stained with germ cell tumour markers (SALL4, glypican‐3, OCT3/4, and AFP) and re‐reviewed for morphologic features. The tumours occurred in adult females (median age 41 years) and included ES (n = 7), MELTVR (n = 2), and MEC (n = 1). All cases showed loss of SMARCB1 expression. Four cases (40%) were focally positive for SALL4 in areas with morphology of typical‐appearing ES. One of these cases also showed focal staining for OCT3/4. One ES showed a transition from typical‐appearing ES to YST‐like morphology, with diffuse expression of SALL4 and glypican‐3, and focal expression of AFP, in these latter areas. All other tested cases were negative for AFP. Conclusion: Our study reveals that SALL4, glypican‐3, and OCT3/4 are positive in a subset of SMARCB1‐deficient vulvar neoplasms, which may pose a diagnostic challenge and result in consideration of a germ cell tumour. We also highlight a case with transition from ES to YST‐like morphology, lending further support that YSTs of the vulva are somatically derived SMARCB1‐deficient neoplasms and do not represent true germ‐cell neoplasia. [ABSTRACT FROM AUTHOR]

Background: As the value of patient-reported outcomes becomes increasingly recognized, minimum clinically important difference (MCID) thresholds have seen greater use in shoulder arthroplasty. However, MCIDs are unique to certain populations, and variation in the modes of calculation in this field may be of concern. With the growing utilization of MCIDs within the field and value-based care models, a detailed appraisal of the appropriateness of MCID use in the literature is necessary and has not been systematically reviewed.Questions/purposes: We performed a systematic review of MCID quantification in existing studies on shoulder arthroplasty to answer the following questions: (1) What is the range of values reported for the MCID in commonly used shoulder arthroplasty patient-reported outcome measures (PROMs)? (2) What percentage of studies use previously existing MCIDs versus calculating a new MCID? (3) What techniques for calculating the MCID were used in studies where a new MCID was calculated?Methods: The Embase, PubMed, and Ovid/MEDLINE databases were queried from December 2008 through December 2020 for total shoulder arthroplasty and reverse total shoulder arthroplasty articles reporting an MCID value for various PROMs. Two reviewers (DAK, MAM) independently screened articles for eligibility, specifically identifying articles that reported MCID values for PROMs after shoulder arthroplasty, and extracted data for analysis. Each study was classified into two categories: those referencing a previously defined MCID and those using a newly calculated MCID. Methods for determining the MCID for each study and the variability of reported MCIDs for each PROM were recorded. The number of patients, age, gender, BMI, length of follow-up, surgical indications, and surgical type were extracted for each article. Forty-three articles (16,408 patients) with a mean (range) follow-up of 20 months (0.75 to 68) met the inclusion criteria. The median (range) BMI of patients was 29.3 kg/m2 (28.0 to 32.2 kg/m2), and the median (range) age was 68 years (53 to 84). There were 17 unique PROMs with MCID values. Of the 112 MCIDs reported, the most common PROMs with MCIDs were the American Shoulder and Elbow Surgeons (ASES) (23% [26 of 112]), the Simple Shoulder Test (SST) (17% [19 of 112]), and the Constant (15% [17 of 112]).Results: The ranges of MCID values for each PROM varied widely (ASES: 6.3 to 29.5; SST: 1.4 to 4.0; Constant: -0.3 to 12.8). Fifty-six percent (24 of 43) of studies used previously established MCIDs, with 46% (11 of 24) citing one study. Forty-four percent (19 of 43) of studies established new MCIDs, and the most common technique was anchor-based (37% [7 of 19]), followed by distribution (21% [4 of 19]).Conclusion: There is substantial inconsistency and variability in the quantification and reporting of MCID values in shoulder arthroplasty studies. Many shoulder arthroplasty studies apply previously published MCID values with variable ranges of follow-up rather than calculating population-specific thresholds. The use of previously calculated MCIDs may be acceptable in specific situations; however, investigators should select an anchor-based MCID calculated from a patient population as similar as possible to their own. This practice is preferable to the use of distribution-approach MCID methods. Alternatively, authors may consider using substantial clinical benefit or patient-acceptable symptom state to assess outcomes after shoulder arthroplasty.Clinical Relevance: Although MCIDs may provide a useful effect-size based alternative to the traditional p value, care must be taken to use an MCID that is appropriate for the particular patient population being studied. [ABSTRACT FROM AUTHOR]

Graph: Figure 2 Adjusted hazard ratios for primary venous thromboembolism for common medications and non-cancer illnesses. (C) Shows 10-year event rates for venous thromboembolism, stratified by both the clinical score and genetic score. [Extracted from the article]

Both clinical and genetic factors drive the risk of venous thromboembolism. However, whether clinically recorded risk factors and genetic variants can be combined into a clinically applicable predictive score remains unknown. Using Cox proportional-hazard models, we analyzed the association of risk factors with the likelihood of venous thromboembolism in U.K. Biobank, a large prospective cohort. We then created a polygenic risk score of 36 single nucleotide polymorphisms and a clinical score determined by age, sex, body mass index, previous cancer diagnosis, smoking status, and fracture in the last 5 years. Participants were at significantly increased risk of venous thromboembolism if they were at high clinical risk (subhazard ratio, 4.37 [95% CI, 3.85–4.97]) or high genetic risk (subhazard ratio, 3.02 [95% CI, 2.63–3.47]) relative to participants at low clinical or genetic risk, respectively. The combined model, consisting of clinical and genetic components, was significantly better than either the clinical or the genetic model alone (P < 0.001). Participants at high risk in the combined score had nearly an eightfold increased risk of venous thromboembolism relative to participants at low risk (subhazard ratio, 7.51 [95% CI, 6.28–8.98]). This risk score can be used to guide decisions regarding venous thromboembolism prophylaxis, although external validation is needed. [ABSTRACT FROM AUTHOR]

Background: We sought to investigate the relationship between the time from an anterior cruciate ligament (ACL) tear to the surgical procedure and meniscal tears in the pediatric and adolescent population.Methods: Patients who were ≤18 years of age and had undergone an ACL reconstruction from 2006 to 2018 were identified in a retrospective, multicenter cohort. The primary outcomes were arthroscopically confirmed medial meniscal or lateral meniscal tears specifically and, in general, if any meniscal tear was present (medial and/or lateral). A multivariable Poisson regression model was used to determine whether the time from the injury to the surgical procedure was a risk factor for subsequent meniscal injury, after controlling for sex, age, and body mass index (BMI). Multivariable Poisson regression was also used to characterize associations of age, sex, and BMI with meniscal injury.Results: In this study, 546 patients with a mean age (and standard deviation) of 15.3 ± 1.6 years were identified. For each week that the surgical procedure was delayed, there was a 2% increased risk of a medial meniscal tear (adjusted relative risk [ARR], 1.02 [95% confidence interval (CI), 1.01 to 1.03]). The weekly increase in risk of a medial meniscal injury was significant for male patients (ARR, 1.03 [95% CI, 1.01 to 1.05]), but not for female patients (ARR, 1.00 [95% CI, 0.97 to 1.04]), even though the effect modification was not significant (p = 0.24). Obese male patients had a 77.9% increased risk of medial meniscal tear for each 10-week delay (p < 0.001). The use of crutches was associated with a decreased risk of medial meniscal tears (ARR, 0.47 [95% CI, 0.34 to 0.64]).Conclusions: In pediatric and adolescent patients, the risk of meniscal injury is substantial after an ACL tear. A delay from the injury to the surgical procedure was associated with a 3% weekly increased risk of medial meniscal injury for male patients, but not for female patients. The increased risk of medial meniscal injury with delays to the surgical procedure was particularly high for obese male patients.Level Of Evidence: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence. [ABSTRACT FROM AUTHOR]

Background: Coronavirus disease 2019 (Covid-19) has rapidly infected millions of people worldwide. Recent studies suggest that racial minorities and patients with comorbidities are at higher risk of Covid-19. In this study, we analyzed the effects of clinical, regional, and genetic factors on Covid-19 positive status. Methods: The UK Biobank is a longitudinal cohort study that recruited participants from 2006 to 2010 from throughout the United Kingdom. Covid-19 test results were provided to UK Biobank starting on March 16, 2020. The main outcome measure in this study was Covid-19 positive status, determined by the presence of any positive test for a single individual. Clinical risk factors were derived from UK Biobank at baseline, and regional risk factors were imputed using census features local to each participant's home zone. We used robust adjusted Poisson regression with clustering by testing laboratory to estimate relative risk. Blood types were derived using genetic variants rs8176719 and rs8176746, and genomewide tests of association were conducted using logistic-Firth hybrid regression. Results: This prospective cohort study included 397,064 UK Biobank participants, of whom 968 tested positive for Covid-19. The unadjusted relative risk of Covid-19 for Black participants was 3.66 (95% CI 2.83–4.74), compared to White participants. Adjusting for Townsend deprivation index alone reduced the relative risk to 2.44 (95% CI 1.86–3.20). Comorbidities that significantly increased Covid-19 risk included chronic obstructive pulmonary disease (adjusted relative risk [ARR] 1.64, 95% CI 1.18–2.27), ischemic heart disease (ARR 1.48, 95% CI 1.16–1.89), and depression (ARR 1.32, 95% CI 1.03–1.70). There was some evidence that angiotensin converting enzyme inhibitors (ARR 1.48, 95% CI 1.13–1.93) were associated with increased risk of Covid-19. Each standard deviation increase in the number of total individuals living in a participant's locality was associated with increased risk of Covid-19 (ARR 1.14, 95% CI 1.08–1.20). Analyses of genetically inferred blood types confirmed that participants with type A blood had increased odds of Covid-19 compared to participants with type O blood (odds ratio [OR] 1.16, 95% CI 1.01–1.33). A meta-analysis of genomewide association studies across ancestry groups did not reveal any significant loci. Study limitations include confounding by indication, bias due to limited information on early Covid-19 test results, and inability to accurately gauge disease severity. Conclusions: When assessing the association of Black race with Covid-19, adjusting for deprivation reduced the relative risk of Covid-19 by 33%. In the context of sociological research, these findings suggest that discrimination in the labor market may play a role in the high relative risk of Covid-19 for Black individuals. In this study, we also confirmed the association of blood type A with Covid-19, among other clinical and regional factors. [ABSTRACT FROM AUTHOR]

Background: Hemorrhage is a leading cause of death after trauma and childbirth. In response to severe hemorrhage, bleeding patients often receive transfusions of red blood cells, plasma, platelets, or other blood components. We examined risk factors for transfusion in acute severe bleeding in two trials of over 20,000 patients to better understand factors associated with transfusion likelihood. Study design and methods: We conducted a cohort analysis of data from the CRASH-2 and WOMAN trials, two multinational trials that recruited patients with traumatic and postpartum hemorrhage, respectively. For each trial, we examined the effect of 10 factors on blood transfusion likelihood. Univariate and multivariate Poisson regressions were used to analyze the relationship between risk factors and blood transfusion. Results: Of the 20,207 traumatic hemorrhage patients, 10,232 (51%) received blood components. Of the 20,060 women with postpartum hemorrhage, 10,958 (55%) received blood components. For patients who suffered from traumatic hemorrhage, those greater than three hours from injury to hospitalization were more likely to be transfused (ARR 1.37; 95% CI, 1.20–1.56). Postpartum hemorrhage patients had an increased likelihood of transfusion if they gave birth outside the hospital (ARR 1.30; 95% CI 1.22–1.39), gave birth more than three hours before hospitalization (ARR 1.09; 95% CI 1.01–1.17), had a Caesarean section (ARR 1.16; 95% CI 1.08–1.25), and if they had any identifiable causes of hemorrhage other than uterine atony. Conclusion: Several risk factors are associated with an increased likelihood of transfusion in traumatic and postpartum hemorrhage patients. Altering modifiable factors, by reducing time from injury or childbirth to hospitalization, for example, might be able to reduce transfusions and their complications. Trial registration: CRASH-2 is registered as ISRCTN86750102, ClinicalTrials.gov NCT00375258 and South African Clinical Trial Register DOH-27–0607–1919. WOMAN is registered as ISRCTN76912190, ClinicalTrials.gov NCT00872469, PACTR201007000192283, and EudraCT number 2008-008441-38. [ABSTRACT FROM AUTHOR]

Fluctuation-based fluorescence correlation techniques are widely used to study dynamics of fluorophore labeled biomolecules in cells. Semiconductor quantum dots (QDs) have been developed as bright and photostable fluorescent probes for various biological applications. However, the fluorescence intermittency of QDs, commonly referred to as “blinking”, is believed to complicate quantitative correlation spectroscopy measurements of transport properties, as it is an additional source of fluctuations that contribute on a wide range of time scales. The QD blinking fluctuations obey power-law distributions so there is no single characteristic fluctuation time for this phenomenon. Consequently, it is highly challenging to separate fluorescence blinking fluctuations from those due to transport dynamics. Here, we quantify the bias introduced by QD blinking in transport measurements made using fluctuation methods. Using computer simulated image time series of diffusing point emitters with set “on” and “off” time emission characteristics, we show that blinking results in a systematic overestimation of the diffusion coefficients measured with correlation analysis when a simple diffusion model is used to fit the time correlation decays. The relative error depends on the inherent blinking power-law statistics, the sampling rate relative to the characteristic diffusion time and blinking times, and the total number of images in the time series. This systematic error can be significant; moreover, it can often go unnoticed in common transport model fits of experimental data. We propose an alternative fitting model that incorporates blinking and improves the accuracy of the recovered diffusion coefficients. We also show how to completely eliminate the bias by applying k-space image correlation spectroscopy, which completely separates the diffusion and blinking dynamics, and allows the simultaneous recovery of accurate diffusion coefficients and QD blinking probability distribution function exponents. [ABSTRACT FROM AUTHOR]

Since the realisation that most "ovarian" high-grade serous carcinomas (HGSC) arise from precancers and early cancers in the fallopian tube fimbria, much work has been devoted during the past two decades to the spectrum of tubal I TP53 i mutant lesions. Since the introduction of the SEE-FIM protocol for examining fallopian tubes more than 10 years ago and the concomitant increase in prophylactic and opportunistic salpingectomies, fallopian tubes are routinely undergoing far more scrutiny by pathologists than previously. A candidate precursor to pelvic serous cancer (p53 signature) and its prevalence in ovaries and fallopian tubes from women with BRCA mutations. [Extracted from the article]

A 42-year-old woman with a germline BRCA2 mutation and recurrent low-grade endometrioid endometrial adenocarcinoma experienced clinical and radiographic response to the poly (ADP ribose) polymerase (PARP) inhibitor, olaparib. Molecular and treatment factors are discussed. [ABSTRACT FROM AUTHOR]

The prognosis of patients following surgery for gastric cancer is often poor and is estimated using traditional clinicopathological parameters, which can be inaccurate predictors of future survival. Kallikreins are a group of serine proteases, which are differentially expressed in many human tumors and are being investigated as potential cancer biomarkers. This study assessed the prognostic utility of human tissue kallikrein-like peptidases 6 and 10 (KLK6 and KLK10) and correlated their expression with histopathological and clinical parameters in gastric cancer. We constructed a gastric tumor tissue microarray from 113 gastrectomy specimens and quantified KLK6 and KLK10 expression using immunohistochemistry. To overcome the problem of inter-observer variability and subjectivity in immunohistochemistry interpretation, a whole-slide scanned image of the tissue microarray was analyzed using an automated algorithm to quantify staining intensity. KLK6 expression was positively correlated with nodal involvement (p = 0.002) and was predictive of advanced-stage disease (p < 0.05). Kaplan-Meier survival curves revealed that tumors expressing high levels of KLK6 were significantly associated with significantly lower overall survival (p = 0.04). KLK10 overexpression was also a predictor of advanced-stage disease (p < 0.01), but was not significantly correlated with lymph node involvement or survival period. Our results show the potential ability of KLK6 as a prognostic marker for gastric cancer. [ABSTRACT FROM AUTHOR]

Background: Identifying genetic risk factors for spinal disorders may lead to knowledge regarding underlying molecular mechanisms and the development of new treatments. Methods: Cases of lumbar spondylolisthesis, spinal stenosis, degenerative disc disease, and pseudarthrosis after spinal fusion were identified from the UK Biobank. Controls were patients without the diagnosis. Whole-genome regressions were used to test for genetic variants potentially implicated in the occurrence of each phenotype. External validation was performed in FinnGen. Results: A total of 389,413 participants were identified from the UK Biobank. A locus on chromosome 2 spanning GFPT1, NFU1, AAK1, and LOC124906020 was implicated in lumbar spondylolisthesis. Two loci on chromosomes 2 and 12 spanning genes GFPT1, NFU1, and PDE3A were implicated in spinal stenosis. Three loci on chromosomes 6, 10, and 15 spanning genes CHST3, LOC102723493, and SMAD3 were implicated in degenerative disc disease. Finally, 2 novel loci on chromosomes 5 and 9, with the latter corresponding to the LOC105376270 gene, were implicated in pseudarthrosis. Some of these variants associated with spinal stenosis and degenerative disc disease were also replicated in FinnGen. Conclusions: This study revealed nucleotide variations in select genetic loci that were potentially implicated in 4 different spinal pathologies, providing potential insights into the pathological mechanisms. Level of Evidence: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. [ABSTRACT FROM AUTHOR]

PURPOSE: The multicenter, open-label, randomized phase 2 NCI-9944 study (NCT02595892) demonstrated that addition of ATR inhibitor (ATRi) berzosertib to gemcitabine increased progression-free survival (PFS) compared to gemcitabine alone (hazard ratio [HR]=0.57, one-sided log-rank P =.044, which met the one-sided significance level of 0.1 used for sample size calculation). METHODS: We report here the final overall survival (OS) analysis and biomarker correlations (ATM expression by immunohistochemistry, mutational signature 3 and a genomic biomarker of replication stress) along with post-hoc exploratory analyses to adjust for crossover from gemcitabine to gemcitabine/berzosertib. RESULTS: At the data cutoff of January 27, 2023 (>30 months of additional follow-up from the primary analysis), median OS was 59.4 weeks with gemcitabine/berzosertib versus 43.0 weeks with gemcitabine alone (HR 0.79, 90% CI 0.52 to 1.2, one-sided log-rank P =.18). An OS benefit with addition of berzosertib to gemcitabine was suggested in patients stratified into the platinum-free interval ≤3 months (N = 26) subgroup (HR, 0.48, 90% CI 0.22 to 1.01, one-sided log-rank P =.04) and in patients with ATM-negative/low (N = 24) tumors (HR, 0.50, 90% CI 0.23 to 1.08, one-sided log-rank P =.06). CONCLUSION: The results of this follow-up analysis continue to support the promise of combined gemcitabine/ATRi therapy in platinum resistant ovarian cancer, an active area of investigation with several ongoing clinical trials. Final OS and biomarker analysis support the promise of gemcitabine with ATR inhibitor therapy in platinum resistant ovarian cancer [ABSTRACT FROM AUTHOR]

Aims: STK11 adnexal tumour is a rare, recently described malignant neoplasm that is associated with Peutz–Jeghers syndrome. [Correction added on 3 October 2024, after first online publication: 'ST11' in preceding sentence has been corrected to 'STK11' in this version.] It predominantly originates from the para‐adnexal soft tissues and often shows secondary involvement of the fallopian tube and ovary. STK11 adnexal tumours have a broad differential diagnosis due to their variable morphology and non‐specific immunoprofile, and diagnostic confirmation currently requires sequencing to identify an STK11 mutation. We investigate the diagnostic utility of STK11 (LKB1) immunohistochemistry (IHC) in a cohort of STK11 adnexal tumours and morphological mimics. Methods and results: IHC for STK11 was performed on 122 tumours, including 17 STK11 adnexal tumours and 105 morphological mimics (10 female adnexal tumours of Wolffian origin, 22 adult granulosa cell tumours, 10 juvenile granulosa cell tumours, four Sertoli–Leydig cell tumours, two Leydig cell tumours, one Sertoli cell tumour, one steroid cell tumour, four extra‐ovarian sex cord‐stromal tumours, 16 ovarian endometrioid carcinomas, eight tubo‐ovarian high‐grade serous carcinomas, five ovarian mesonephric‐like adenocarcinomas, 14 ovarian carcinosarcomas, five peritoneal malignant mesotheliomas, two pelvic plexiform leiomyomata and one ovarian solid pseudopapillary tumour). All STK11 adnexal tumours showed complete loss of cytoplasmic staining for STK11. All other tumour types showed retained cytoplasmic staining, except for one endometrioid carcinoma with mucinous differentiation which showed complete loss of STK11 expression and a high‐grade serous carcinoma with subclonal loss. Conclusions: STK11 is a highly sensitive and specific immunohistochemical marker for distinguishing STK11 adnexal tumour from its histological mimics, and can obviate the need for confirmatory molecular studies in the appropriate morphological context. [ABSTRACT FROM AUTHOR]

Aims: Areas of gland crowding that do not fulfil diagnostic criteria of endometrioid intra‐epithelial neoplasia (EIN) are often encountered in endometrial biopsies. In this study, we document the prevalence of neoplastic outcome in patients with these subdiagnostic lesions (SL) and assess the utility of morphological features and a three‐marker immunohistochemistry panel (PAX2, PTEN, beta‐catenin) to predict outcome. Methods and results: Of 430 women with SL on endometrial sampling at Brigham and Women's Hospital between 2001 and 2021 with available follow‐up biopsy, 72 (17%) had a neoplastic outcome (EIN or endometrioid carcinoma). Multilayered epithelium and mitoses in SL were statistically associated with a neoplastic outcome. Abnormal three‐marker staining was observed in 93% (53 of 57) of SL with neoplastic outcome and 60% (37 of 62) of a control group with benign outcome. Among the 72 patients with neoplastic outcome, EIN/carcinoma tissue was available in 33; of these, 30 (91%) showed abnormal staining for one or more markers. Remarkably, in 84% of these cases the EIN/carcinoma had the aberrant expression seen in the preceding SL. Based on a prevalence of 17%, the positive and negative predictive values of abnormal staining in one or more markers were 24 and 97%, respectively. Conclusions: The presence of SL warrants clinical surveillance and repeat sampling because it is followed by endometrioid neoplasia in a significant subset of patients. Normal three‐marker staining identifies women with a very low risk of neoplastic outcome. Conversely, abnormal staining is frequent in SL with benign outcome leading to poor specificity and positive predictive value. [ABSTRACT FROM AUTHOR]

Aims: Areas of gland crowding that do not fulfil diagnostic criteria of endometrioid intra‐epithelial neoplasia (EIN) are often encountered in endometrial biopsies. In this study, we document the prevalence of neoplastic outcome in patients with these subdiagnostic lesions (SL) and assess the utility of morphological features and a three‐marker immunohistochemistry panel (PAX2, PTEN, beta‐catenin) to predict outcome. Methods and results: Of 430 women with SL on endometrial sampling at Brigham and Women's Hospital between 2001 and 2021 with available follow‐up biopsy, 72 (17%) had a neoplastic outcome (EIN or endometrioid carcinoma). Multilayered epithelium and mitoses in SL were statistically associated with a neoplastic outcome. Abnormal three‐marker staining was observed in 93% (53 of 57) of SL with neoplastic outcome and 60% (37 of 62) of a control group with benign outcome. Among the 72 patients with neoplastic outcome, EIN/carcinoma tissue was available in 33; of these, 30 (91%) showed abnormal staining for one or more markers. Remarkably, in 84% of these cases the EIN/carcinoma had the aberrant expression seen in the preceding SL. Based on a prevalence of 17%, the positive and negative predictive values of abnormal staining in one or more markers were 24 and 97%, respectively. Conclusions: The presence of SL warrants clinical surveillance and repeat sampling because it is followed by endometrioid neoplasia in a significant subset of patients. Normal three‐marker staining identifies women with a very low risk of neoplastic outcome. Conversely, abnormal staining is frequent in SL with benign outcome leading to poor specificity and positive predictive value. [ABSTRACT FROM AUTHOR]

Beginning with the discovery of the BRCA-associated ovarian cancer susceptibility genes and subsequent detailed examination of risk-reducing salpingo-oophorectomy (RRSO) specimens, a new paradigm of ovarian carcinogenesis has unfolded with attention to the distal fallopian tube. The primary focus has been an early cancer or neoplasm in the fallopian tube which is seen in virtually all incidentally discovered high-grade serous cancers in asymptomatic women. This high-frequency of tubal involvement in early serous neoplasm (usually in the form of serous tubal intraepithelial carcinoma—STIC) has galvanized attention to this organ as a primary source of this disease. However, an enduring mystery has been the relatively low frequency of STIC in the fallopian tubes of women with advanced malignancy. This paradox, a high frequency of tubal involvement early on and a low frequency of involvement later in the disease process, has spurred interest in other potential sources, such as the ovarian surface epithelium or cortical inclusions and the secondary Mullerian system. However, because essentially all high-grade serous carcinomas are linked by TP53 mutations, and because fallopian tubes frequently contain early serous proliferations (ESPs) with these mutations, attention has turned to the possibility that the nonmalignant but TP53 mutated tubal epithelium could be responsible for an eventual malignancy. Recent data have shown evidence of a lineage continuity between ESPs and concurrent serous carcinomas prompting the concept of "precursor escape". This creates a second component of the paradigm by which cells from early precursors are shed from the tube and undergo subsequent malignant transformation, emerging suddenly as widespread intraperitoneal malignancy. This dualistic model thus provides a unique pathway by which the future outcome (wide spread high-grade serous carcinomas—HGSC) is ultimately explained by going back in time to an early serous proliferation. This paradigm also brings the peritoneal cavity into focus, raising new questions about the potential co-variables or exposures that might facilitate the occasional malignant transformation of an ESP in the peritoneal cavity or on the peritoneal surface. [ABSTRACT FROM AUTHOR]

SCCOHT: PATHOGENESIS AND HISTORICAL TREATMENT SCCOHT is a rare, aggressive malignancy primarily affecting young women; mean age at diagnosis is 24 years.[3] Tumors are large, averaging 15.7 cm,[4] and hypercalcemia is present in approximately 65% of patients. SCCOHT is typified by genomic stability, with a low tumor mutational burden and few chromosomal abnormalities.[13],[14] Despite this, these tumors have immunogenic microenvironments with strong PD-L1 expression and increased tumor-infiltrating lymphocytes (TILs).[15] Given the rarity of this malignancy, treatment beyond cytoreductive surgery is heterogeneous and unstandardized. MOLECULAR TUMOR BOARD CASE DISCUSSION AND PERSPECTIVES ON MATCHED THERAPIES To our knowledge, this is the first report of this I SMARCA4 i germline mutation in SCCOHT[11],[21] and the first report of treatment with either ponatinib or combination CDK4/6 inhibition and immune checkpoint blockade (ICB) in SCCOHT. Ann Oncol 29:viii576-viii595, 2018 36 Soldi R, Ghosh Halder T, Weston A, et al: The novel reversible LSD1 inhibitor SP-2577 promotes anti-tumor immunity in SWItch/Sucrose-NonFermentable (SWI/SNF) complex mutated ovarian cancer [Internet]. bioRxiv 2020.01.10.902528, 2020 37 Sheng W, LaFleur MW, Nguyen TH, et al: LSD1 Ablation stimulates anti-tumor immunity and enables checkpoint blockade. [Extracted from the article]

PURPOSE: The multicenter, open-label, randomized phase 2 NCI-9944 study (NCT02595892) demonstrated that addition of ATR inhibitor (ATRi) berzosertib to gemcitabine increased progression-free survival (PFS) compared to gemcitabine alone (hazard ratio [HR]=0.57, one-sided log-rank P =.044, which met the one-sided significance level of 0.1 used for sample size calculation). METHODS: We report here the final overall survival (OS) analysis and biomarker correlations (ATM expression by immunohistochemistry, mutational signature 3 and a genomic biomarker of replication stress) along with post-hoc exploratory analyses to adjust for crossover from gemcitabine to gemcitabine/berzosertib. RESULTS: At the data cutoff of January 27, 2023 (>30 months of additional follow-up from the primary analysis), median OS was 59.4 weeks with gemcitabine/berzosertib versus 43.0 weeks with gemcitabine alone (HR 0.79, 90% CI 0.52 to 1.2, one-sided log-rank P =.18). An OS benefit with addition of berzosertib to gemcitabine was suggested in patients stratified into the platinum-free interval ≤3 months (N = 26) subgroup (HR, 0.48, 90% CI 0.22 to 1.01, one-sided log-rank P =.04) and in patients with ATM-negative/low (N = 24) tumors (HR, 0.50, 90% CI 0.23 to 1.08, one-sided log-rank P =.06). CONCLUSION: The results of this follow-up analysis continue to support the promise of combined gemcitabine/ATRi therapy in platinum resistant ovarian cancer, an active area of investigation with several ongoing clinical trials. Final OS and biomarker analysis support the promise of gemcitabine with ATR inhibitor therapy in platinum resistant ovarian cancer [ABSTRACT FROM AUTHOR]

Detecting early cancer through liquid biopsy is challenging due to the lack of specific biomarkers for early lesions and potentially low levels of these markers. The current study systematically develops an extracellular‐vesicle (EV)‐based test for early detection, specifically focusing on high‐grade serous ovarian carcinoma (HGSOC). The marker selection is based on emerging insights into HGSOC pathogenesis, notably that it arises from precursor lesions within the fallopian tube. This work thus establishes murine fallopian tube (mFT) cells with oncogenic mutations and performs proteomic analyses on mFT‐derived EVs. The identified markers are then evaluated with an orthotopic HGSOC animal model. In serially‐drawn blood of tumor‐bearing mice, mFT‐EV markers increase with tumor initiation, supporting their potential use in early cancer detection. A pilot clinical study (n = 51) further narrows EV markers to five candidates, EpCAM, CD24, VCAN, HE4, and TNC. The combined expression of these markers distinguishes HGSOC from non‐cancer with 89% sensitivity and 93% specificity. The same markers are also effective in classifying three groups (non‐cancer, early‐stage HGSOC, and late‐stage HGSOC). The developed approach, for the first time inaugurated in fallopian tube‐derived EVs, could be a minimally invasive tool to monitor women at high risk of ovarian cancer for timely intervention. [ABSTRACT FROM AUTHOR]

We have recently shown that the small proton chemical shift difference in 2-methyl-1-(methyl-d)piperidine supports a long-lived nuclear spin state. To identify additional candidate molecules with CH2D groups exhibiting accessible long-lived states, and to investigate the factors governing the magnitude of the shift differences, we report a computational and experimental investigation of methyl rotational equilibria and proton chemical shifts in a variety of 2-substituted 1-(methyl-d)piperidines. The polarity and size of the 2-substituent affect the 1,2-stereoisomeric relationship, and consequently, the strength of the rotational asymmetry within the CH2D group. Nonpolar and large 2-substituents prefer the equatorial position, and relatively large shift differences (i.e., > 13 ppb) are observed. Polar and small substituents, however, increasingly prefer the axial position, and medium to small shift differences (i.e., 0 to 9 ppb) are observed. In addition, the diastereotopic CH2D proton chemical shift difference for tricarbonyl(1-chloro-2-deuteriomethylbenzene) chromium(0) was computed, showing that reasonable predictions of these small shift differences can be extended to more complex, organometallic species. [ABSTRACT FROM AUTHOR]

Background: Adhesive capsulitis of the shoulder involves loss of passive range of motion with associated pain and can develop spontaneously, with no obvious injury or inciting event. The pathomechanism of this disorder remains to be elucidated, but known risk factors for adhesive capsulitis include diabetes, female sex, and thyroid dysfunction. Additionally, transcriptional profiling and pedigree analyses have suggested a role for genetics. Identification of elements of genetic risk for adhesive capsulitis using population-based techniques can provide the basis for guiding both the personalized treatment of patients based on their genetic profiles and the development of new treatments by identification of the pathomechanism.Methods: A genome-wide association study (GWAS) was conducted using the U.K. Biobank (a collection of approximately 500,000 patients with genetic data and associated ICD-10 [International Classification of Diseases, 10th Revision] codes), comparing 2,142 patients with the ICD-10 code for adhesive capsulitis (M750) to those without. Separate GWASs were conducted controlling for 2 of the known risk factors of adhesive capsulitis-hypothyroidism and diabetes. Logistic regression analysis was conducted controlling for factors including sex, thyroid dysfunction, diabetes, shoulder dislocation, smoking, and genetics.Results: Three loci of significance were identified: rs34315830 (in WNT7B; odds ratio [OR] = 1.28; 95% confidence interval [CI], 1.22 to 1.39), rs2965196 (in MAU2; OR = 1.67; 95% CI, 1.39 to 2.00), and rs1912256 (in POU1F1; OR = 1.22; 95% CI, 1.14 to 1.31). These loci retained significance when controlling for thyroid dysfunction and diabetes. The OR for total genetic risk was 5.81 (95% CI, 4.08 to 8.31), compared with 1.70 (95% CI, 1.18 to 2.36) for hypothyroidism and 4.23 (95% CI, 2.32 to 7.05) for diabetes.Conclusions: The total genetic risk associated with adhesive capsulitis was significant and similar to the risks associated with hypothyroidism and diabetes. Identification of WNT7B, POU1F1, and MAU2 implicates the Wnt pathway and cell proliferation response in the pathomechanism of adhesive capsulitis.Level Of Evidence: Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence. [ABSTRACT FROM AUTHOR]

Aberrant expression of viral-like repeat elements is a common feature of epithelial cancers, and the substantial diversity of repeat species provides a distinct view of the cancer transcriptome. Repeatome profiling across ovarian, pancreatic, and colorectal cell lines identifies distinct clustering independent of tissue origin that is seen with coding gene analysis. Deeper analysis of ovarian cancer cell lines demonstrated that human satellite II (HSATII) satellite repeat expression was highly associated with epithelial-mesenchymal transition (EMT) and anticorrelated with IFN-response genes indicative of a more aggressive phenotype. SATII expression - and its correlation with EMT and anticorrelation with IFN-response genes - was also found in ovarian cancer RNA-Seq data and was associated with significantly shorter survival in a second independent cohort of patients with ovarian cancer. Repeat RNAs were enriched in tumor-derived extracellular vesicles capable of stimulating monocyte-derived macrophages, demonstrating a mechanism that alters the tumor microenvironment with these viral-like sequences. Targeting of HSATII with antisense locked nucleic acids stimulated IFN response and induced MHC I expression in ovarian cancer cell lines, highlighting a potential strategy of modulating the repeatome to reestablish antitumor cell immune surveillance. [ABSTRACT FROM AUTHOR]

Aims: Most vulvar squamous cell carcinomas are human papillomavirus (HPV)‐associated or TP53‐mutant. A third category of HPV‐independent TP53‐wild‐type lesions is uncommon and not fully understood. Differentiated exophytic vulvar intraepithelial lesion (DEVIL) has been characterised as a precursor of this latter category. The reproducibility of the diagnosis of DEVIL and its distinction from lesions with overlapping morphology has not been studied. Our aim was to establish the interobserver agreement in the diagnosis of DEVIL and its distinction from neoplastic and reactive conditions of the vulva on haematoxylin and eosin evaluation. Methods and results: A set of 35 slides was evaluated by eight reviewers (two trainees and six practising gynaecological pathologists). The set included DEVIL, condyloma, established vulvar precursors [high‐grade squamous intraepithelial lesion (HSIL) and differentiated vulvar intraepithelial neoplasia (dVIN)] with superimposed acanthosis or verruciform growth, lichen simplex chronicus (LSC), and psoriasis. Kappa (κ) values were calculated. Overall, interobserver agreement was moderate (κ = 0.56), improving to substantial (κ = 0.7) when evaluation was performed by practising pathologists. Agreement was strong for the diagnosis of HSIL (κ = 0.88), and substantial for the diagnosis of DEVIL (κ = 0.61), condyloma (κ = 0.79), and LSC (κ = 0.72). Agreement was moderate for the diagnosis of dVIN (κ = 0.59) and psoriasis (κ = 0.53). Perfect agreement (6/6) among practising pathologists was observed in 43% of cases, and majority agreement (5/6 or 4/6) was observed in 48% of cases. Conclusions: Reproducibility in the diagnosis of verruciform vulvar lesions, including the novel DEVIL, is acceptable overall. Reproducibility is higher for well‐known lesions such as HSIL and condyloma than for more challenging diagnoses such as DEVIL, dVIN, and psoriasis. Agreement is higher among practising gynaecological pathologists, suggesting that training and experience improve reproducibility. Our findings support the inclusion of DEVIL as a diagnostic entity in the classification of vulvar squamous lesions. [ABSTRACT FROM AUTHOR]

We report the development and characterization of a method, named reversible association with motor proteins (RAMP), for manipulation of organelle positioning within the cytoplasm. RAMP consists of coexpressing in cultured cells (i) an organellar protein fused to the streptavidin-binding peptide (SBP) and (ii) motor, neck, and coiled-coil domains from a plus-end–directed or minus-end–directed kinesin fused to streptavidin. The SBP–streptavidin interaction drives accumulation of organelles at the plus or minus end of microtubules, respectively. Importantly, competition of the streptavidin–SBP interaction by the addition of biotin to the culture medium rapidly dissociates the motor construct from the organelle, allowing restoration of normal patterns of organelle transport and distribution. A distinctive feature of this method is that organelles initially accumulate at either end of the microtubule network in the initial state and are subsequently released from this accumulation, allowing analyses of the movement of a synchronized population of organelles by endogenous motors. [ABSTRACT FROM AUTHOR]

Inaugurating High-Throughput Profiling of Extracellular Vesicles for Earlier Ovarian Cancer Detection (Adv. Sci. 27/2023) This biological insight offers a novel opportunity to detect early ovarian cancer by assessing circulating extracellular vesicles specific to the fallopian tube. B Early Cancer Message from the Source b Most high-grade serous ovarian cancers originate from the precursor lesions in the fallopian tube. [Extracted from the article]

Cell migration is regulated in part by the connection between the substratum and the actin cytoskeleton. However, the very large number of proteins involved in this linkage and their complex network of interactions make it difficult to assess their role in cell migration. We apply a novel image analysis tool, spatio-temporal image correlation spectroscopy (STICS), to quantify the directed movements of adhesion-related proteins and actin in protrusions of migrating cells. The STICS technique reveals protein dynamics even when protein densities are very low or very high, and works in the presence of large, static molecular complexes. Detailed protein velocity maps for actin and the adhesion-related proteins α-actinin, α5-integrin, talin, paxillin, vinculin and focal adhesion kinase are presented. The data show that there are differences in the efficiency of the linkage between integrin and actin among different cell types and on the same cell type grown on different substrate densities. We identify potential mechanisms that regulate efficiency of the linkage, or clutch, and identify two likely points of disconnect, one at the integrin and the other at α-actinin or actin. The data suggests that the efficiency of the linkage increases as actin and adhesions become more organized showing the importance of factors that regulate the efficiency in adhesion signaling and dynamics. [ABSTRACT FROM AUTHOR]