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Introduction: High-grade endometrial stromal sarcoma (HG-ESS) is a rare and aggressive malignant neoplasm that has a poor prognosis and accounts for 0.2% of uterine malignancies. There is a lack of available information on HG-ESS due to its high case fatality rate. Due to the poor prognosis associated with HG-ESS, it is important to diagnose HG-ESS in its early stages. Case Report: In this case report, we describe the case of a 63-year-old postmenopausal woman who presented with a pelvic mass and postmenopausal bleeding. The patient’s past history included a fibroid for which the patient underwent a successful uterine fibroid embolization. The patient underwent a pelvic ultrasound and an endometrial biopsy prior to gynecological consult. Both were inconclusive and led to an initial diagnosis of a uterine fibroid. After a gynecological consult and an additional biopsy, pathological examination revealed high-grade neoplastic cells that expressed strong and diffuse nuclear BCL1/Cyclin D1. The pattern of diffuse cyclin D1 expression and negative CD10 was suggestive of the YWHAE-rearranged subtype of HG-ESS. The combined morphologic and immunophenotypic features were consistent with a high-grade endometrial stromal sarcoma with fluorescence in situ hybridization (FISH) positivity for YWHAE gene rearrangement and FISH negativity for BCOR gene rearrangement. The patient underwent a robotic-assisted modified radical hysterectomy, radical pelvic tumor resection, bilateral salpingo-oophorectomy, sentinel pelvic lymph node dissections, and an appendectomy. The resulting surgical pathologic diagnosis was HG-ESS stage 1. Currently, no adjuvant therapy is recommended given negative margins with stage 1 status. Conclusion: High-grade endometrial stromal sarcoma is a rare clinical entity in postmenopausal women which is initially misdiagnosed but should be included in the differential diagnosis of necrotic masses.

Disasters (e.g., natural catastrophes, pandemics/epidemics, mass violence events, and human/technological errors) are becoming increasingly common due to factors such as growing population density and accelerated climate change. Exposure to any type of disaster is damaging for both individuals and organizations. Disasters deprive individuals of their livelihoods, alter how employees perform their work, and harm individual well-being. For organizations, disasters compromise functioning and profitability, often resulting in organizational failure. As a result, there is growing interest in research linking disaster events to the workplace. Based on an analysis of 260 disaster articles, we offer a comprehensive, systematic, interdisciplinary review of the disaster literature with organizational implications. Employing a resource-based perspective, embedded within an ecological systems framework, we suggest that disaster exposure depletes (or prompts investment of) individual, team, and organizational resources and subsequently impacts organizational outcomes. This theoretical framework can be used to identify the critical research gaps that exist in the literature and offers a promising agenda for future research.

An equitable approach by the American College of Medical Genetics and Genomics (ACMG) has recently recommended carrier screening for genes associated with moderate to severe autosomal recessive conditions with a carrier frequency of ≥1/200 in the Genome Aggregation Database exomes (gnomADv2.0.2). We analyzed carrier frequencies in gnomADv3.1.1 genomes representing diverse populations. ClinVar data on 35 996 pathogenic/likely pathogenic variants in 419 genes were used to estimate the gnomAD frequency of heterozygous carriers. We found that ninety-two genes had a carrier frequency of ≥1/200, of which 63 were shared between v3.1.1 and v2.0.2 and 29 were new in v3.1.1. Addition of new populations (Amish, Finnish and Middle Eastern) increased the number of new genes with a carrier frequency of ≥1/200 to 71. Changes in carrier frequencies were attributed to new gnomAD populations, different sample sizes, new ClinVar data, and technical differences between exomes and genomes. This study highlights the dynamic changes in carrier frequencies due to new datasets from diverse populations and provides updated carrier frequencies based on the combined data from 184 352 genomes and exomes in gnomAD. We recommend a periodic review for inclusion of new population data to update carrier screening panels in the future.

Research on the impact of supplementing additional dietary choline to modern, large-frame broiler chickens is limited, and current choline recommendations are outdated. The objective of this study was to determine the effect of additional dietary choline chloride supplementation on growth performance and carcass characteristics of modern broilers reared to 32 days of age. Corn and soybean meal-based diets were formulated to contain an additional 0, 400, 800, 1200, 1600, or 2000 mg of choline chloride per kg of feed above the choline present in the basal diet ingredients. As-hatched Ross 708 × Yield Plus broiler chicks (n = 2160; 30 birds per pen; 44 ± 0.2 g initial BW) were randomly allotted to the experimental diets, reared for 31 days, and processed at day 32. Growth performance, carcass yield, and breast myopathy incidence were not impacted by supplemental choline. However, abdominal fat pad weight tended to diminish with increasing dietary choline, and drumstick yield was reduced in birds fed over 800 mg per kg of feed. These results indicate feeding additional choline does not impact growth performance but may result in changes in carcass characteristics of modern, high-yielding broilers reared for 32 days.

Carrier screening began 50 years ago with screening for conditions that have a high prevalence in defined racial/ethnic groups (e.g., Tay–Sachs disease in the Ashkenazi Jewish population; sickle cell disease in Black individuals). Cystic fibrosis was the first medical condition for which panethnic screening was recommended, followed by spinal muscular atrophy. Next-generation sequencing allows low cost and high throughput identification of sequence variants across many genes simultaneously. Since the phrase “expanded carrier screening” is nonspecific, there is a need to define carrier screening processes in a way that will allow equitable opportunity for patients to learn their reproductive risks using next-generation sequencing technology. An improved understanding of this risk allows patients to make informed reproductive decisions. Reproductive decision making is the established metric for clinical utility of population-based carrier screening. Furthermore, standardization of the screening approach will facilitate testing consistency. This practice resource reviews the current status of carrier screening, provides answers to some of the emerging questions, and recommends a consistent and equitable approach for offering carrier screening to all individuals during pregnancy or preconception.

We offer consensus recommendations for the antepartum management of the uterus transplant pregnancy based on our experience at 3 US centers. Patient access to accurate information is important to manage expectations and make informed decisions. Unique aspects of medical management include monitoring tacrolimus levels and performing cervical biopsies for rejection. Low-dose aspirin for preeclampsia is routinely used. Vigilant screening for gestational diabetes and preeclampsia allows for the prompt diagnosis and treatment of these common complications. We aim to deliver patients at 37 to 38 weeks by cesarean section. Shared decision making dominates whether to consider future pregnancies and timing of hysterectomy.

Counseling the uterus transplant patient requires an enhanced knowledge of unique genetic challenges that include an understanding of the spectrum of Mayer-Rokitansky-Küster-Hauser syndrome. Patients should understand their options for genetic screening and testing including preimplantation genetic testing for aneuploidy, genetic screening, and diagnostic testing. This patient population is potentially at risk for fetal anomalies due to the increased susceptibility to infections, such as cytomegalovirus. There are management strategies to minimize this risk. The risk of teratogenicity from mycophenolate is eliminated by a washout period before embryo transfer.

Objective Doppler velocimetry of the uterine and umbilical arteries is used to predict preeclampsia and monitor fetal outcomes. There have been no reports of Doppler velocimetry indices in pregnancies conceived after uterus transplantation, which differ from traditional pregnancies because of different uterine vascular inflow and outflow and exposure to immunosuppressive agents. We sought to examine whether Doppler indices can be used to predict embryo transfer success after uterus transplantation and whether Doppler indices across pregnancy predict fetal growth restriction. Study Design This was a single-center cohort observational study of 14 uterus transplant recipients who underwent embryo transfer. Of these, 12 women successfully delivered 14 babies. Five Doppler investigations were performed within the cohort: (1) prepregnancy; (2) uterine artery assessment across pregnancy; (3) umbilical artery assessment across pregnancy; (4) successive pregnancies; and (5) fetal growth. Results Prepregnancy uterine artery Doppler indices did not correlate with successful implantation after embryo transfer. Uterine artery Doppler indices in uterus transplant recipients decreased across pregnancy as described in pregnancies without uterus transplantation. The umbilical artery systolic/diastolic velocity ratio was lower at all weeks of gestation after uterus transplantation compared with values described in pregnancies without uterus transplantation. In those women who delivered two successive babies after uterus transplant, umbilical artery Doppler indices were significantly lower during the second pregnancy. There was always forward flow throughout diastole in the umbilical arteries, and no babies experienced fetal growth restriction. Conclusion In our study, uterus transplantation was not associated with abnormal blood flow indices in either the uterine or umbilical arteries. Although Doppler indices were not predictive of embryo transfer success, they supported the expectation that pregnancies after uterus transplantation at our center result in normally grown babies. Key Points

To analyze the effect on biochemical recurrence (BCR) of omitting PLND in subsequently upgraded/upstaged patients (pNx regret). Using nomograms, patients with low to intermediate-risk prostate cancer can be selected to omit a pelvic lymph node dissection (PLND) at the time of a radical prostatectomy (RP). However, some patients will experience upgraded pathology and/or stage.We searched a prospectively maintained single institution/multi-surgeon cohort of patients treated by RP and5-year follow-up. From 2006-2012, 1026 (521 pNx and 505 pN0/1) eligible patients with biopsy Gleason Score ≤3+4 and cT1c-cT2 undergoing RARP were included in the study.Gleason upgrading from ≤3+4 to3+4 and/or pT3-4 occurred in 17% of pNx and 32% of pN0/N1 (p0.001). BCR occurred in 5% of the pNx, and 7% of the PLND group. Five-year BCR free survival was higher in the pNx group (94.7% vs. 91%, P = .048). BCR occurred in 3% in the non-pNx regret and 18% in the pNx regret patients. However, with propensity score matching with pNx regret and pN0/N1 patients, 5-year BCR free survival rates were similar (81% vs 77%, P = .466).Low to favorable intermediate-risk patients who PLND was omitted and experienced upgrading or upstaging (pNx regret), have a higher predicted BCR. However, when matched to a similar cohort with pN0/N1, the BCR did not differ. Omission of a PLND does not appear to alter the rates of BCR compared to PLND inclusion.

Venous thromboembolic events (VTEs) are a major cause of morbidity following abdominopelvic oncologic surgery. Enoxaparin, a subcutaneous injectable low molecular weight heparin, is commonly used for extended-duration VTE prophylaxis (EP), but has been associated with noncompliance. Newer direct oral anticoagulants have not been prospectively studied in the urologic oncology post-discharge setting. We aimed to improve compliance with EP following abdominopelvic oncologic surgery and secondarily test the hypothesis that apixaban is noninferior to enoxaparin for EP.A single-center prospective quality improvement study measuring patient compliance and safety with EP was conducted between August 10, 2020 and September 21, 2021. Baseline data were continuously collected for 6 months, followed by a uniform departmental change from enoxaparin to apixaban. The duration of data collection was determinedA total of 161 patients were discharged with enoxaparin (baseline period) and 154 with apixaban (intervention period). Safety events occurred in 3.1% vs 0% of patients receiving enoxaparin and apixaban, respectively. The absolute risk difference of 3.1% (95% CI: 0.043%-5.8%) met the prespecified noninferiority threshold (p=0.028 for apixaban superiority). Compliance events occurred in 33.5% of enoxaparin patients and 14.3% of apixaban patients (p=0.0001).There were fewer compliance events using apixaban for EP than enoxaparin after urologic oncology surgery. Regarding safety, apixaban is noninferior to enoxaparin and may in fact have fewer associated major complications.

Background VTX002 is an oral selective sphingosine 1-phosphate-1 receptor (S1P1R) modulator in clinical development for treatment of ulcerative colitis (UC). Single and multiple doses of a spray-dried dispersion (SDD) oral suspension of VTX002 were well-tolerated up to 45 mg in a phase 1 study in healthy participants and were accompanied by dose proportional reductions in lymphocyte counts, an expected pharmacodynamic outcome of treatment.1 A separate phase 1 study compared the pharmacokinetics (PK) and pharmacodynamics of the SDD oral suspension and a tablet formulation of VTX002. Methods Healthy adult participants (N=12) were randomised (4 per dose group) in an open-label 3-way crossover study to receive single oral doses of 5 mg or 20 mg VTX002 tablets, or 20 mg VTX002 SDD suspension followed by at least a 1-week washout between each dose as shown in Fig. 1. Study assessments included: VTX002 plasma concentrations, PK parameters, change from baseline in absolute lymphocyte count (ALC), and adverse events (AE). Results A total of 10 participants completed the study. Mean plasma VTX002 concentrations were greatest with a single oral dose of 20 mg VTX002 SDD suspension (Fig. 2). The geometric mean peak (Cmax) and total (AUCinf) exposure to VTX002 were lower with the 5 mg (dose normalized to 20 mg tablet) and 20 mg VTX002 tablets compared to the 20 mg VTX002 SDD suspension (Table 1). Geometric mean ratios for the tablet and SDD formulations of VTX002 are shown in Table 2. Maximum percent (SD) reduction in ALC from baseline was greatest for the 20 mg VTX002 SDD suspension and was observed at 6 hours post-dose both for the SDD suspension and the 20 mg VTX002 tablet (59.9% [11.0%] and 51.6% [9.4%], respectively). The maximum percent reduction in ALC from baseline for the 5 mg VTX002 tablet was 22.4% (9.2%) which occurred 2 hours post-dose. A total of 23 AEs were reported; of which 19 were considered mild, and 4 were moderate. Conclusion All doses and formulations of VTX002 were well-tolerated and associated with ALC reductions. Data from this relative bioavailability study was used to convert the results from the prior phase 1 multiple ascending dose study performed with VTX002 SDD suspension to AUC equivalent tablet doses and enable tablet dose selection for phase 2. A phase 2 study of VTX002 tablets for treatment of UC is underway (ClinicalTrials.gov Identifier:NCT05156125). 1Luo A, et al. 2020 Gastroenterology. 2020;158(6):S1188.

Therapeutic gene manipulation has been at the forefront of popular scientific discussion and basic and clinical research for decades. Basic and clinical research applications of CRISPR-Cas9-based technologies and ongoing clinical trials in this area have demonstrated the potential of genome editing to cure human disease. Evaluation of research and clinical trials in gene therapy reveals a concentration of activity in prostate cancer research and practice. Multiple aspects of prostate cancer care - including anatomical considerations that enable direct tumour injections and sampling, the availability of preclinical immune-competent models and the delineation of tumour-related antigens that might provide targets for an induced immune system - make gene therapy an appealing treatment option for this common malignancy. Vaccine-based therapies that induce an immune response and new technologies exploiting CRISPR-Cas9-assisted approaches, including chimeric antigen receptor (CAR) T cell therapies, are very promising and are currently under investigation both in the laboratory and in the clinic. Although laboratory and preclinical advances have, thus far, not led to oncologically relevant outcomes in the clinic, future studies offer great promise for gene therapy to become established in prostate cancer care.

Both transperineal and transrectal ultrasound (TRUS)-guided systematic biopsy are accepted methods to diagnose prostate cancer (PCa). However, systematic sampling misses up to 47% of tumors 0.5 mL or larger and under-represents the tumor grade in 38% of cases [1,2]. These shortcomings result in underestimated risk and repeat prostate biopsies.

PURPOSE: To report long term follow-up of the efficacy of subtotal prostate ablation using a “hockey-stick” template, including oncologic control and quality of life (QoL) impact. METHODS: We performed a prospective controlled trial to evaluate the efficacy of subtotal prostate ablation in selected men with baseline and confirmatory biopsy showing grade group (GG) 1–2 prostate cancer. “Hockey-stick” cryoablation that included the ipsilateral hemi-gland and contralateral anterior prostate was performed. Prostate biopsies and QOL queries were performed at 6, 18 and 36 months following regional ablation, and follow-up was updated to include subsequent clinic visits. RESULTS: Between August 2009 and January 2012, 72 men were screened for eligibility and 47 opted to undergo confirmatory biopsy. Of these, 23 were deemed eligible and treated with regional cryoablation. Median age was 64 years. Median follow-up was 74 months. A single patient had

Objective To describe aggregated pregnancy outcomes after uterus transplantation from a single, experienced center. Methods This prospective study reports on live births among 20 women who received a uterus transplant from 2016 to 2019 at Baylor University Medical Center at Dallas. These live births occurred between November 2017 and September 2020. The main measures were live birth, maternal complications, and fetal and newborn outcomes. Results There were six graft failures (four surgical complications and two with poor perfusion postoperatively). Of the 14 technically successful transplants, at least one live birth occurred in 11 patients. Thus far, the live birth rate per attempted transplant is 55%, and the live-birth rate per technically successful transplant is 79%. Ten uteri were from nondirected living donors and one uterus was from a deceased donor. In vitro fertilization was performed to achieve pregnancy. Ten recipients delivered one neonate, and one recipient delivered two neonates. One organ rejection episode was detected during pregnancy and was resolved with steroids. The median birth weight was 2,890 g (range 1,770-3,140 g [median 68th percentile]). Maternal weight gain was higher than Institute of Medicine recommendations. Maternal medical complications were observed in five recipients (elevated creatinine level, gestational diabetes, gestational hypertension [n=2], and preeclampsia). In five recipients, maternal medical or obstetric complications led to an unplanned preterm delivery (elevated creatinine level, preeclampsia; preterm labor [n=3]). The median gestational age at delivery was 36 6/7 weeks (range 30 6/7-38 weeks). All neonates were liveborn, with Apgar scores of 8 or higher at 5 minutes. Conclusion Over the first 3 years, our program experienced a live-birth rate per attempted transplant of 55% and a live-birth rate per technically successful transplant of 79%. In our experience, uterus transplantation resulted in a third-trimester live birth in all cases in which pregnancies reached 20 weeks of gestation. Maternal medical and obstetric complications can occur; however, these were manageable by applying principles of generally accepted obstetric practice. Clinical trial registration ClinicalTrials.gov, NCT02656550.

Background High-risk (HR) prostate cancer (PCa) is a heterogeneous disease leading to difficulties in designing appropriate inclusion criteria for clinical trials. Objective To describe clinical predictors of organ-confined disease in HR or very-high-risk (VHR) PCa patients staged with multiparametric magnetic resonance imaging with endorectal coil (mp-MRI-ER). Design, setting, and participants We reviewed 366 HR/VHR PCa patients who had preoperative mp-MRI-ER, and underwent radical prostatectomy and extended pelvic lymph node dissection between 2006 and 2015. Intervention Radical prostatectomy with preoperative mp-MRI-ER. Outcome measurements and statistical analysis We used multivariable logistic regression modeling to assess for associations with ≤ pT2N0 stage and multivariable cox modeling to assess for associations with biochemical failure. Results and limitations Of 366 patients, 132 had ≤ pT2N0 disease. For the entire cohort, negative staging mp-MRI-ER (odds ratio [OR] 1.73, 95% confidence interval [CI] 1.06–2.83, p = 0.03), lower prostate-specific antigen (PSA; OR 0.98, 95% CI 0.97–1.00, p = 0.02), and fewer cores of Gleason ≥8 cancer (OR 0.86, 95% CI 0.79–0.93, p = 0.0002) were associated with ≤pT2N0 disease. In HR patients only, negative mp-MRI-ER (OR 3.41, 95% CI 1.73–6.72, p = 0.0004) and fewer than four cores of Gleason ≥8 disease (OR 3.38, 95% CI 1.20–9.56, p = 0.02) were still associated with ≤pT2N0 disease. Lack of non–organ-confined disease on MRI was associated with superior biochemical recurrence-free survival (p = 0.02). Limitations of this study include lack of a central review or quality control of the MRI reporting. Conclusions In HR PCa, negative staging mp-MRI-ER, fewer positive cores of Gleason >8, and lower PSA were significant predictors of pathologic organ-confined disease. Improved prediction of organ-confined disease in HR patients may allow for their inclusion into studies evaluating treatments from which they would otherwise be excluded based solely on their HR status. Patient summary In patients with high-risk prostate cancer, prostate magnetic resonance imaging along with other clinical parameters may help determine which patients are likely to have disease confined to the prostate and thus be eligible for clinical trials that they otherwise might be excluded from based on their high-risk status alone.

Evidence suggests that visceral fat quantity may be associated with post-prostatectomy outcomes and risk of prostate cancer related death. We evaluated whether increased fat volume, normalized to prostate size, is associated with decreased risk of disease progression.Patients enrolled on a prospective active surveillance trial for at least 6 months who had magnetic resonance imaging within 2 years of enrollment were eligible. The surveillance protocol included a standardized followup regimen consisting of biennial prostate specific antigen and examination and yearly biopsy. Clinicopathological characteristics were collected at baseline. Three fat measurements were taken using prostate magnetic resonance imaging, including subcutaneous, linear periprostatic (pubic symphysis to prostate) and volumetrically defined periprostatic. Progression was defined as increase in Gleason grade group. Multivariable Cox proportional hazards models were used to evaluate fat volumes normalized by prostate size (stratified into tertiles).A total of 175 patients were included in the study. Average age was 62.5 years (SD 7.4) and average prostate specific antigen was 5.4 ng/dl (SD 3.9). Median followup was 42 months (IQR 18-60) and 50 patients (28.6%) had progression. Compared to the lowest tertile, the highest tertile of volumetric periprostatic fat measurement (HR 2.63, 95% CI 1.23-5.60, p=0.01) and linear periprostatic fat measurement (HR 2.30, 95% CI 1.01-5.22, p=0.05) were associated with worsened progression-free survival, while subcutaneous fat measurement (p=0.97) was not. Importantly, the model did not substantively change when accounting for patient body mass index and other factors.Increased periprostatic fat volume, normalized to prostate size, may be associated with shortened progression-free survival in men with prostate cancer on active surveillance.

Coffee intake may lower prostate cancer risk and progression, but postdiagnosis outcomes by caffeine metabolism genotype are not well characterized.To evaluate associations between coffee intake, caffeine metabolism genotype, and survival in a large, multicenter study of men with prostate cancer.Data from The PRACTICAL Consortium database for 5727 men with prostate cancer from seven US, Australian, and European studies were included. The cases included had data available for the CYP1A2 -163CA rs762551 single-nucleotide variant associated with caffeine metabolism, coffee intake, and6 mo of follow-up.Multivariable-adjusted Cox proportional hazards models across pooled patient-level data were used to compare the effect of coffee intake (categorized as low [reference], high, or none/very low) in relation to overall survival (OS) and prostate cancer-specific survival (PCSS), with stratified analyses conducted by clinical disease risk and genotype.High coffee intake appeared to be associated with longer PCSS (hazard ratio [HR] 0.85, 95% confidence interval [CI] 0.68-1.08; p = 0.18) and OS (HR 0.90, 95% CI 0.77-1.07; p = 0.24), although results were not statistically significant. In the group with clinically localized disease, high coffee intake was associated with longer PCSS (HR 0.66, 95% CI 0.44-0.98; p = 0.040), with comparable results for the group with advanced disease (HR 0.92, 95% CI 0.69-1.23; p = 0.6). High coffee intake was associated with longer PCSS among men with the CYP1A2 AA (HR 0.67, 95% CI 0.49-0.93; p = 0.017) but not the AC/CC genotype (p = 0.8); an interaction was detected (p = 0.042). No associations with OS were observed in subgroup analyses (p 0.05). Limitations include the nominal statistical significance and residual confounding.Coffee intake was associated with longer PCSS among men with a CYP1A2 -163AA (*1F/*1F) genotype, a finding that will require further replication.It is likely that coffee intake is associated with longer prostate cancer-specific survival in certain groups, but more research is needed to fully understand which men may benefit and why.

Pathogenic variants in the CFTR gene are causative of classic cystic fibrosis (CF) as well as some nonclassic CF phenotypes. In 2001, CF became the first target of pan-ethnic universal carrier screening by molecular methods. The American College of Medical Genetics and Genomics (ACMG) recommended a core panel of 23 disease-causing variants as the minimal set to be included in pan-ethnic carrier screening of individuals with no family history of the disease, and these variants were usually assessed using targeted methods. The original recommendation also left open the option for laboratories to offer expanded CFTR variant panels; however, at the time, expanded CFTR variant panels were met with some controversy on the basis of the available technologies and the limited phenotypic knowledge of rare variants. Both of those aspects have now evolved, prompting this update of the ACMG technical standards for CFTR variant testing.