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Adenocarcinoma of the endometrium (also known as endometrial cancer, or more broadly as uterine cancer or carcinoma of the uterine corpus) is the most common malignancy of the female genital tract in the United States. It is estimated that 65,950 new uterine cancer cases will have occurred in 2022, with 12,550 deaths resulting from the disease. Endometrial carcinoma includes pure endometrioid cancer and carcinomas with high-risk endometrial histology (including uterine serous carcinoma, clear cell carcinoma, carcinosarcoma [also known as malignant mixed Müllerian tumor], and undifferentiated/dedifferentiated carcinoma). Stromal or mesenchymal sarcomas are uncommon subtypes accounting for approximately 3% of all uterine cancers. This selection from the NCCN Guidelines for Uterine Neoplasms focuses on the diagnosis, staging, and management of pure endometrioid carcinoma. The complete version of the NCCN Guidelines for Uterine Neoplasms is available online at NCCN.org .

ImportanceA safe and effective treatment for recurrent Clostridioides difficile infection (CDI) is urgently needed. Antibiotics kill toxin-producing bacteria but do not repair the disrupted microbiome, which promotes spore germination and infection recurrence.ObjectivesTo evaluate the safety and rate of CDI recurrence after administration of investigational microbiome therapeutic SER-109 through 24 weeks.Design, Setting, and ParticipantsThis phase 3, single-arm, open-label trial (ECOSPOR IV) was conducted at 72 US and Canadian outpatient sites from October 2017 to April 2022. Adults aged 18 years or older with recurrent CDI were enrolled in 2 cohorts: (1) rollover patients from the ECOSPOR III trial who had CDI recurrence diagnosed by toxin enzyme immunoassay (EIA) and (2) patients with at least 1 CDI recurrence (diagnosed by polymerase chain reaction [PCR] or toxin EIA), inclusive of their acute infection at study entry.InterventionsSER-109 given orally as 4 capsules daily for 3 days following symptom resolution after antibiotic treatment for CDI.Main Outcomes and MeasuresThe main outcomes were safety, measured as the rate of treatment-emergent adverse events (TEAEs) in all patients receiving any amount of SER-109, and cumulative rates of recurrent CDI (toxin-positive diarrhea requiring treatment) through week 24 in the intent-to-treat population.ResultsOf 351 patients screened, 263 were enrolled (180 [68.4%] female; mean [SD] age, 64.0 [15.7] years); 29 were in cohort 1 and 234 in cohort 2. Seventy-seven patients (29.3%) were enrolled with their first CDI recurrence. Overall, 141 patients (53.6%) had TEAEs, which were mostly mild to moderate and gastrointestinal. There were 8 deaths (3.0%) and 33 patients (12.5%) with serious TEAEs; none were considered treatment related by the investigators. Overall, 23 patients (8.7%; 95% CI, 5.6%-12.8%) had recurrent CDI at week 8 (4 of 29 [13.8%; 95% CI, 3.9%-31.7%] in cohort 1 and 19 of 234 [8.1%; 95% CI, 5.0%-12.4%] in cohort 2), and recurrent CDI rates remained low through 24 weeks (36 patients [13.7%; 95% CI, 9.8%-18.4%]). At week 8, recurrent CDI rates in patients with a first recurrence were similarly low (5 of 77 [6.5%; 95% CI, 2.1%-14.5%]) as in patients with 2 or more recurrences (18 of 186 [9.7%; 95% CI, 5.8%-14.9%]). Analyses by select baseline characteristics showed consistently low recurrent CDI rates in patients younger than 65 years vs 65 years or older (5 of 126 [4.0%; 95% CI, 1.3%-9.0%] vs 18 of 137 [13.1%; 95% CI, 8.0%-20.0%]) and patients enrolled based on positive PCR results (3 of 69 [4.3%; 95% CI, 0.9%-12.2%]) vs those with positive toxin EIA results (20 of 192 [10.4%; 95% CI, 6.5%-15.6%]).Conclusions and RelevanceIn this trial, oral SER-109 was well tolerated in a patient population with recurrent CDI and prevalent comorbidities. The rate of recurrent CDI was low regardless of the number of prior recurrences, demographics, or diagnostic approach, supporting the beneficial impact of SER-109 for patients with CDI.Trial RegistrationClinicalTrials.gov identifier: NCT03183141

PURPOSE Brexucabtagene autoleucel (brexu-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory mantle cell lymphoma (MCL). This therapy was approved on the basis of the single-arm phase II ZUMA-2 trial, which showed best overall and complete response rates of 91% and 68%, respectively. We report clinical outcomes with brexu-cel in the standard-of-care setting for the approved indication. PATIENTS AND METHODS Patients who underwent leukapheresis between August 1, 2020 and December 31, 2021, at 16 US institutions, with an intent to manufacture commercial brexu-cel for relapsed/refractory MCL, were included. Patient data were collected for analyses of responses, outcomes, and toxicities as per standard guidelines. RESULTS Of 189 patients who underwent leukapheresis, 168 (89%) received brexu-cel infusion. Of leukapheresed patients, 79% would not have met ZUMA-2 eligibility criteria. Best overall and complete response rates were 90% and 82%, respectively. At a median follow-up of 14.3 months after infusion, the estimates for 6- and 12-month progression-free survival (PFS) were 69% (95% CI, 61 to 75) and 59% (95% CI, 51 to 66), respectively. The nonrelapse mortality was 9.1% at 1 year, primarily because of infections. Grade 3 or higher cytokine release syndrome and neurotoxicity occurred in 8% and 32%, respectively. In univariable analysis, high-risk simplified MCL international prognostic index, high Ki-67, TP53 aberration, complex karyotype, and blastoid/pleomorphic variant were associated with shorter PFS after brexu-cel infusion. Patients with recent bendamustine exposure (within 24 months before leukapheresis) had shorter PFS and overall survival after leukapheresis in intention-to-treat univariable analysis. CONCLUSION In the standard-of-care setting, the efficacy and toxicity of brexu-cel were consistent with those reported in the ZUMA-2 trial. Tumor-intrinsic features of MCL, and possibly recent bendamustine exposure, may be associated with inferior efficacy outcomes.

This article addresses the issue of patient sleep during hospitalization, which the Society of Anesthesia and Sleep Medicine believes merits wider consideration by health authorities than it has received to date. Adequate sleep is fundamental to health and well-being, and insufficiencies in its duration, quality, or timing have adverse effects that are acutely evident. These include cardiovascular dysfunction, impaired ventilatory function, cognitive impairment, increased pain perception, psychomotor disturbance (including increased fall risk), psychological disturbance (including anxiety and depression), metabolic dysfunction (including increased insulin resistance and catabolic propensity), and immune dysfunction and proinflammatory effects (increasing infection risk and pain generation). All these changes negatively impact health status and are counterproductive to recovery from illness and operation. Hospitalization challenges sleep in a variety of ways. These challenges include environmental factors such as noise, bright light, and overnight awakenings for observations, interventions, and transfers; physiological factors such as pain, dyspnea, bowel or urinary dysfunction, or discomfort from therapeutic devices; psychological factors such as stress and anxiety; care-related factors including medications or medication withdrawal; and preexisting sleep disorders that may not be recognized or adequately managed. Many of these challenges appear readily addressable. The key to doing so is to give sleep greater priority, with attention directed at ensuring that patients’ sleep needs are recognized and met, both within the hospital and beyond. Requirements include staff education, creation of protocols to enhance the prospect of sleep needs being addressed, and improvement in hospital design to mitigate environmental disturbances. Hospitals and health care providers have a duty to provide, to the greatest extent possible, appropriate preconditions for healing. Accumulating evidence suggests that these preconditions include adequate patient sleep duration and quality. The Society of Anesthesia and Sleep Medicine calls for systematic changes in the approach of hospital leadership and staff to this issue. Measures required include incorporation of optimization of patient sleep into the objectives of perioperative and general patient care guidelines. These steps should be complemented by further research into the impact of hospitalization on sleep, the effects of poor sleep on health outcomes after hospitalization, and assessment of interventions to improve it.

Background: Meniscal and chondral damage is common in the patient undergoing revision anterior cruciate ligament (ACL) reconstruction. Purpose: To determine if meniscal and/or articular cartilage pathology at the time of revision ACL surgery significantly influences a patient’s outcome at 6-year follow-up. Study Design: Cohort study; Level of evidence, 3. Methods: Patients undergoing revision ACL reconstruction were prospectively enrolled between 2006 and 2011. Data collection included baseline demographics, surgical technique, pathology, treatment, and scores from 4 validated patient-reported outcome instruments: International Knee Documentation Committee (IKDC), Knee injury and Osteoarthritis Outcome Score (KOOS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Marx Activity Rating Scale. Patients were followed up at 6 years and asked to complete the identical set of outcome instruments. Regression analysis assessed the meniscal and articular cartilage pathology risk factors for clinical outcomes 6 years after revision ACL reconstruction. Results: An overall 1234 patients were enrolled (716 males, 58%; median age, 26 years). Surgeons reported the pathology at the time of revision surgery in the medial meniscus (45%), lateral meniscus (36%), medial femoral condyle (43%), lateral femoral condyle (29%), medial tibial plateau (11%), lateral tibial plateau (17%), patella (30%), and trochlea (21%). Six-year follow-up was obtained on 79% of the sample (980/1234). Meniscal pathology and articular cartilage pathology (medial femoral condyle, lateral femoral condyle, lateral tibial plateau, trochlea, and patella) were significant drivers of poorer patient-reported outcomes at 6 years (IKDC, KOOS, WOMAC, and Marx). The most consistent factors driving outcomes were having a medial meniscal excision (either before or at the time of revision surgery) and patellofemoral articular cartilage pathology. Six-year Marx activity levels were negatively affected by having either a repair/excision of the medial meniscus (odds ratio range, 1.45-1.72; P≤ .04) or grade 3-4 patellar chondrosis (odds ratio, 1.72; P = .04). Meniscal pathology occurring before the index revision surgery negatively affected scores on all KOOS subscales except for sports/recreation ( P < .05). Articular cartilage pathology significantly impaired all KOOS subscale scores ( P < .05). Lower baseline outcome scores, higher body mass index, being a smoker, and incurring subsequent surgery all significantly increased the odds of reporting poorer clinical outcomes at 6 years. Conclusion: Meniscal and chondral pathology at the time of revision ACL reconstruction has continued significant detrimental effects on patient-reported outcomes at 6 years after revision surgery.

Heart failure (HF) is a chronic, debilitating condition associated with significant morbidity, mortality, and socioeconomic burden. Patients with end-stage HF (ESHF) who are not a candidate for advanced therapies will continue to progress despite standard medical therapy. Thus, the focus of care shifts from prolonging life to controlling symptoms and improving quality of life through palliative care ( PC). Because the condition and prognosis of HF patients evolve and can rapidly deteriorate, it is imperative to begin the discussion on end-of-life (EOL) issues early during HF management. These include the completion of an advance directive, do-not-resuscitate orders, and policies on device therapy and discontinuation as part of advance care planning (ACP). ESHF patients who do not have indications for advanced therapies or those who wish not to have a left ventricular assist device (LVAD) or heart transplant (HT) often experience high symptom burden despite adequate medical management. The proper identification and assessment of symptoms such as pain, dyspnea, nausea, depression, and anxiety are essential to the management of ESHF and may be underdiagnosed and undertreated. Psychological support and spiritual care are also crucial to improving the quality of life during EOL. Caregivers of ESHF patients must also be provided supportive care to prevent compassion fatigue and improve resilience in patient care. In this narrative review, we compare the international guidelines and provide an overview of end-of-life and palliative care for patients with ESHF.

ABSTRACT Fibrodysplasia ossificans progressiva (FOP) is an ultra‐rare, severely disabling genetic disorder of progressive heterotopic ossification (HO). The single‐arm, open‐label, phase 3 MOVE trial (NCT03312634) assessed efficacy and safety of palovarotene, a selective retinoic acid receptor gamma agonist, in patients with FOP. Findings were compared with FOP natural history study (NHS; NCT02322255) participants untreated beyond standard of care. Patients aged ≥4 years received palovarotene once daily (chronic: 5 mg; flare‐up: 20 mg for 4 weeks, then 10 mg for ≥8 weeks; weight‐adjusted if skeletally immature). The primary endpoint was annualized change in new HO volume versus NHS participants (by low‐dose whole‐body computed tomography [WBCT]), analyzed using a Bayesian compound Poisson model (BcPM) with square‐root transformation. Twelve‐month interim analyses met futility criteria; dosing was paused. An independent Data Monitoring Committee recommended trial continuation. Post hoc 18‐month interim analyses utilized BcPM with square‐root transformation and HO data collapsed to equalize MOVE and NHS visit schedules, BcPM without transformation, and weighted linear mixed‐effects (wLME) models, alongside prespecified analysis. Safety was assessed throughout. Eighteen‐month interim analyses included 97 MOVE and 101 NHS individuals with post‐baseline WBCT. BcPM analyses without transformation showed 99.4% probability of any reduction in new HO with palovarotene versus NHS participants (with transformation: 65.4%). Mean annualized new HO volume was 60% lower in MOVE versus the NHS. wLME results were similar (54% reduction fitted; nominal p = 0.039). All palovarotene‐treated patients reported ≥1 adverse event (AE); 97.0% reported ≥1 retinoid‐associated AE; 29.3% reported ≥1 serious AE, including premature physeal closure (PPC)/epiphyseal disorder in 21/57 (36.8%) patients aged <14 years. Post hoc computational analyses using WBCT showed decreased vertebral bone mineral density, content, and strength, and increased vertebral fracture risk in palovarotene‐treated patients. Thus, post hoc analyses showed evidence for efficacy of palovarotene in reducing new HO in FOP, but high risk of PPC in skeletally immature patients. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

AbstractBackgroundProgressive supranuclear palsy (PSP) is a neurodegenerative disorder characterized by cell‐type‐specific tau lesions in neurons and glia. Using bulk brain RNAseq, we previously identified PSP‐associated genes and co‐expression networks that are enriched with cell‐type marker genes. We extended our work to identify cell‐type‐specific expression perturbations in PSP using a systems approach and in vivo validations in a model system.MethodSingle‐nucleus RNAseq (snRNAseq) was performed using 33 frozen brain temporal cortex (TCX) samples from PSP and control brains. After quality control (QC), integration, and clustering of nuclei, each cluster was annotated for its cell type. We identified differentially expressed genes (DEG) in PSP and further investigated them using an independent bulk RNAseq dataset comprising 408 PSP and control TCX samples for replication and assessing co‐expression patterns. Top DEGs were identified and then validated using external bulk RNAseq datasets from a tau transgenic mouse model. Further, the ability of the validated DEGs to rescue tau‐mediated cellular toxicity was evaluated in a tau transgenic Drosophila model.ResultAfter QC, 30 clusters comprised of 27,284 nuclei were obtained, encompassing two neuronal and six glial cell types. DEGs of each cluster revealed cell‐type‐specific PSP associations. Notably, many of the up‐regulated DEGs in the astroglial clusters were members of the bulk RNAseq co‐expression modules that were also up‐regulated in PSP and enriched with astrocytic markers. There were also consistent findings for the up‐regulated DEGs in the endothelial and microglial clusters, and for down‐regulated DEGs in the oligodendroglial clusters. Subsequently, we prioritized 240 DEGs with congruent cell‐type‐specific perturbations in snRNAseq and bulk RNAseq and validated 29 of those using transgenic mouse model data. Lastly, a significant number of the up‐regulated glial genes, when knocked down in a tau transgenic Drosophila model, led to reduced tau‐mediated cellular toxicity, suggesting novel potential therapeutic avenues.ConclusionPSP brains demonstrated robust cell‐type‐specific gene expression perturbations in the glial cells populations that were validated across different datasets. Importantly, inhibiting the up‐regulated expression perturbations rescued tau‐mediated toxicity in a Drosophila model. Our findings highlight the cell‐type‐specific transcriptome changes in PSP and provide potential therapeutic options for primary tauopathies.

AbstractBackgroundInter‐cellular communication within the gliovascular unit (GVU) is critical for cerebral blood flow regulation, maintenance of the blood‐brain‐barrier (BBB) properties, and brain energy metabolism. Although numerous cell biology studies demonstrate the role of the GVU for BBB breakdown in Alzheimer’s disease (AD), the precise molecular changes contributing to its pathophysiology are unclear.MethodWe performed single nucleus RNA sequencing (snRNAseq) of temporal cortex tissue in 24 AD and control brains to understand the transcriptional changes in the cells of GVU. We acquired the snRNAseq profile of 79,751 total brain cells that comprise 6,541 astrocytes and 2,210 vascular cells. The latter formed three distinct vascular clusters characterized as activated pericytes, endothelia and resting pericytes. We identified differentially expressed genes (DEGs) and their enriched pathways in these clusters and detected the most transcriptional changes within activated pericytes. Using our data and a knowledge‐based predictive algorithm, we discovered and prioritized molecular interactions between vascular and astrocyte clusters, the main cell types of the GVU of the BBB.ResultsVascular targets predicted to interact with astrocytic ligands have biological functions in signalling, angiogenesis, amyloid ß metabolism and cytoskeletal structure. Top astrocytic and vascular interacting molecules include both novel and known AD risk genes such as APOE, APP and ECE1. We validated gene expression changes using qPCR. We are in the process of evaluating these gene expression changes in antemortem blood from AD and control participants.ConclusionOur findings provide valuable information into the transcriptional changes in predicted vascular‐astrocytic partners at the GVU, highlighting insights into the molecular mechanisms of BBB breakdown in AD.