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Objective This study was undertaken to describe a novel biomarker of germ cell tumor and associated paraneoplastic neurological syndrome (PNS). Methods Archival sera from patients with germ cell tumor–associated PNS were evaluated. We identified a common autoantigen in a human testicular cancer cell line (TCam‐2) by Western blot and mass spectrometry. Its identity was confirmed by recombinant‐protein Western blot, enzyme‐linked immunosorbent assay (ELISA), and cell‐based assay. Autoantibody specificity was confirmed by analyzing assorted control sera/cerebrospinal fluid. Results Leucine zipper 4 (LUZP4)–immunoglobulin G (IgG) was detected in 28 patients' sera, 26 of whom (93%) were men. The median age at neurological symptom onset was 45 years (range = 28–84). Median titer (ELISA) was 1:300 (1:50 to >1:6,400, normal value < 1:50). Coexistent kelchlike protein 11–IgG was identified in 18 cases (64%). The most common presenting phenotype was rhombencephalitis (17/28, 61%). Other presentations included limbic encephalitis (n = 5, 18%), seizures and/or encephalitis (n = 2, 7%), and motor neuronopathy/polyradiculopathy (n = 4, 14%). The most common malignancy among cancer‐evaluated PNS patients was seminoma (21/27, 78%). Nine of the 21 seminomas detected by whole‐body fluorodeoxyglucose positron emission tomography scan (43%) were extratesticular. Both female patients had ovarian teratoma. Regressed testicular germ cell tumors were found in 4 patients. Exposure of T‐cell–dendritic‐cell cocultures from chronic immunosuppression‐naïve LUZP4‐IgG–seropositive patients to recombinant LUZP4 protein evoked a marked increase in CD69 expression on both CD4+ and CD8+ T cells when compared to vehicle‐exposed and healthy control cultures. Interpretation LUZP4‐IgG represents a novel serological biomarker of PNS and has high predictive value for germ cell tumors. The demonstrated antigen‐specific T‐cell responses support a CD8+ T‐cell–mediated cytotoxic paraneoplastic and antitumor potential. ANN NEUROL 2021;89:1001–1010

Given the dearth of established safe and effective interventions to respond to COVID-19, there is an urgent ethical imperative to conduct meaningful clinical research. The good news is that interventions to be tested are not in short supply. Unfortunately, the human and material resources needed to conduct these trials are finite. It is essential that trials be robust and meet enrollment targets and that lower-quality studies not be permitted to displace higher-quality studies, delaying answers to critical questions. Yet, with few exceptions, existing research review bodies and processes are not designed to ensure these conditions are satisfied. To meet this challenge, we offer guidance for research institutions about how to ethically consolidate and prioritize COVID-19 clinical trials, while recognizing that consolidation and prioritization should also take place upstream (among manufacturers and funders) and at a higher level (e.g. nationally). In our proposed three-stage process, trials must first meet threshold criteria. Those that do are evaluated in a second stage to determine whether the institution has sufficient capacity to support all proposed trials. If it does not, the third stage entails evaluating studies against two additional sets of comparative prioritization criteria: those specific to the study and those that aim to advance diversification of an institution’s research portfolio. To implement these criteria fairly, we propose that research institutions form COVID-19 research prioritization committees. We briefly discuss some important attributes of these committees, drawing on the authors’ experiences at our respective institutions. Although we focus on clinical trials of COVID-19 therapeutics, our guidance should prove useful for other kinds of COVID-19 research, as well as non-pandemic research, which can raise similar challenges due to the scarcity of research resources.

Abstract Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): Mayo Clinic Foundation Background Left atrial (LA) volume is linked to outcome in degenerative mitral regurgitation (DMR) but does not encompass LA function assessment. Thus, we ought to determine the prognostic role of left atrial coupling-index (LACI), as left atrial volume-index (LAVI) by Tissue-Doppler-Imaging a’ (TDI-a’), in a large cohort of DMR. Methods All consecutive 4792 patients (61 ± 16 years, 48% women) with isolated degenerative mitral valve disease diagnosed at Mayo Clinic 2003-2011, comprehensively characterized, in whom LAVI and TDI-a’ in sinus rhythm was prospectively measured in routine practice, was enrolled and their long-term survival analyzed. Results LACI (5.8 ± 3.7–T1 &lt; 3.8; T2 3.8-6.3; T3 &gt; 6.3) was significantly higher through different DMR grades (no, mild, moderate, severe DMR: 3.77 ± 2.26, 5.08 ± 2.95, 6.54 ± 3.74 and 7.84 ±4.29 respectively; p &lt; 0.0001). Independent determinants of LA dysfunction assessed by LACI were age, E/e’, left-ventricle (LV) end-systolic-diameter, mitral-regurgitation (MR) grade, and LV ejection-fraction (all P ≤ 0.0001). LACI &gt; 6 was independently associated with dyspnea, edema, more severe functional tricuspid-regurgitation and elevated pulmonary artery pressure, irrespective of age, sex, Charlson-comorbidity-index, ventricular function and MR severity. Total follow-up was 7.03 ± 3.0 years, during which 1146 (24%) underwent mitral-valve surgery (94% repair-6% replacement) and 880 (18%) died, 780 under medical treatment and 100 after surgery. Overall survival throughout follow-up (10-year 76 ± 1%) was strongly associated with LACI (88 ± 1% vs. 78 ± 1% and 62 ± 2% for LACI &lt;3.8, 3.8-6.3 and ≥6.3, P &lt; 0.0001) even adjusting comprehensively, including for DMR severity (adjusted-hazard-ratio 1.23[1.07-1.43] for LACI &gt; 5.79, P = 0.005). Mortality under medical management was profoundly affected by LACI (adjusted-hazard-ratio 1.11[1.05-1.18] per 3 unit increment; 1.35[1.15-1.58] for LACI &gt; 5.79 vs. ≤5.79, both P = 0.0002). Survival improved after mitral surgery (time-dependent adjusted-hazard-ratio 0.40[0.28-0.65], P &lt; 0.0001) but remained humbly linked to LACI (10-year 93 ± 3% vs. 90 ± 2% and 80 ± 3% for LACI tertiles, P = 0.0008). Most importantly, LACI provided incremental prognostic information over LAVI and other conventional determinants of survival (P &lt; 0.0001) with Net-reclassification-improvement vs. LAVI of 0.21 ± 0.02, P &lt; 0.0001. Conclusion LA function assessed by LACI in routine practice, by conventional echocardiographic measurements, displays incremental and independent link to excess-mortality, considerable under medical management and partially alleviated by mitral surgery. Thus, LACI is a simple tool of crucial interest in DMR risk-stratification. Abstract Figure. LACI in DMR

The NCCN Guidelines for Prostate Cancer address staging and risk assessment after a prostate cancer diagnosis and include management options for localized, regional, and metastatic disease. Recommendations for disease monitoring and treatment of recurrent disease are also included. The NCCN Prostate Cancer Panel meets annually to reevaluate and update their recommendations based on new clinical data and input from within NCCN Member Institutions and from external entities. This article summarizes the panel’s discussions for the 2021 update of the guidelines with regard to systemic therapy for metastatic castration-resistant prostate cancer.

ABSTRACT Background With pathway‐specific trials in PD associated with variants in the glucocerebrosidase gene (PD GBA ) under way, we need markers that confirm the impact of genetic variants in patient‐derived biofluids in order to allow patient stratification merely based on genetics and that might serve as biochemical read‐out for target engagement. Objective To explore GBA‐pathway‐specific biomarker profiles cross‐sectionally (TUEPAC‐MIGAP, PPMI) and longitudinally (PPMI). Methods We measured enzyme activity of the lysosomal glucocerebrosidase, CSF levels of glucosylceramides (upstream substrate of glucocerebrosidase), CSF levels of ceramides (downstream product of glucocerebrosidase), lactosylceramides, sphingosines, sphingomyelin (by‐products) and CSF levels of total α‐synuclein in PD GBA patients compared to PD GBA_wildtype patients. Results Cross‐sectionally in both cohorts and longitudinally in PPMI: (1) glucocerebrosidase activity was significantly lower in PD GBA compared to PD GBA_wildtype . (2) CSF levels of upstream substrates (glucosylceramides species) were higher in PD GBA compared to PD GBA_wildtype . (3) CSF levels of total α‐synuclein were lower in PD GBA compared to PD GBA_wildtype . All of these findings were most pronounced in PD GBA with severe mutations (PD GBA_severe ). Cross‐sectionally in TUEPAC‐MIGAP and longitudinally in PPMI, CSF levels of downstream‐products (ceramides) were higher in PD GBA_severe . Cross‐sectionally in TUEPAC‐MIGAP by‐products sphinganine and sphingosine‐1‐phosphate and longitudinally in PPMI species of by‐products lactosylceramides and sphingomyelin were higher in PD GBA_severe . Interpretation These findings confirm that GBA mutations have a relevant functional impact on biomarker profiles in patients. Bridging the gap between genetics and biochemical profiles now allows patient stratification for clinical trials merely based on mutation status. Importantly, all findings were most prominent in PD GBA with severe variants. © 2021 International Parkinson and Movement Disorder Society

Introduction: The NHLBI National MDS Study (NCT02775383) is a prospective cohort study conducted at 92 community hospitals and 29 academic centers. It enrolls patients undergoing work up for suspected MDS to understand the genetic, epigenetic, and biological factors associated with the initiation and progression of the disease. Previously untreated, cytopenic participants undergo both local and centralized pathology review and are assigned a diagnosis, including MDS, MDS/MPN, AML with blasts &lt; 30%, and "Other". Emerging data suggests that Next Generation Sequencing (NGS), along with cytogenetics and clinical variables, may improve MDS diagnostic precision. Given that our study relies on central review (with additional tertiary pathology review used to adjudicate disagreements), we examined whether targeted gene sequencing data could be used to increase the agreement between local and central pathologic diagnosis of MDS vs. Other. Methods: Peripheral blood and bone marrow (BM) biopsy specimens from cytopenic patients, along with clinical history, CBC, and other results including karyotyping, FISH and pathology reports from local pathologists were reviewed by central pathologists. The updated 2016 WHO classifications were used to diagnose MDS. Targeted exon sequencing of 96 genes was performed using BM specimens. A subset of 648 individuals that were classified as MDS (n=212) or Other (n=436, including 90 CCUS and 89 individuals with other cancers) by pathology assessments were selected. A mean coverage of 1,317X was achieved and variants had a minimum variant allele frequency (VAF) of 2% (except FLT3). Variants for 596 subjects were manually reviewed to retain likely disease-causing variants to build a binary classifier (MDS vs. Other) using the maximum VAF per gene as input (Figure 1). Subjects diagnosed with MDS or Other by both central and local pathology were used for training, validation, and testing, and were considered "gold standard" (GS) cases (n=546). These subjects were split into 4 random groups with equal proportions of MDS cases. 75% of the GS cases were used to train and validate lasso-regularized logistic regression models using 3-fold cross validation. ROC curve analysis was carried out using the remaining 25% of GS cases (Test Set 1) on the best model to identify an optimal probability cut off point for classifying subjects as MDS. Model performance was then tested on 50 subjects for which the central and local pathology diagnosis disagreed (Test Set 2), as well as on 52 additional subjects irrespective of agreement (Test Set 3). Results : The best performing logistic regression model retained 7 genes as most informative in a discriminating diagnosis of MDS from Other based on their VAFs, in order of impact: TP53, SF3B1, U2AF1, ASXL1, TET2,STAG2, and SRSF2. We used this model to assign probabilities for each of the subjects in Test Set 1 and to estimate the performance using ROC analysis (Figure 1), resulting in a high area under the curve (AUC) of 0.89. We chose a probability cut-off of ≥0.17, being associated with a high percentage of correct classification of MDS with a sensitivity and specificity of 0.90 and 0.81, respectively. Among the cohort of 50 subjects with a discordant local and central pathology diagnosis (Test Set 2), the classifier accurately reassigned 37 subjects (accuracy = 74%) from the local to the central pathology. The blinded tertiary pathology reviewer agreed with central in all Test Set 2 cases. This included 24/34 MDS cases that had been labeled as Other by local pathology (positive predictive value [PPV]=0.89). 3/16 final pathology-classified Other cases were mis-classified as MDS by the local pathologist (negative predictive value [NPV] = 0.57). Next, we assessed the ability of the model to predict MDS vs. Other for 52 additional independent subjects using the third pathologist's diagnosis to break any ties (Test Set 3). The classifier correctly predicted 15/21 MDS cases (PPV=0.83) and misclassified 6/31 Others as MDS (NPV=0.82). The overall accuracy was 83%. Conclusions: We identified that VAFs for 7 genes can correctly re-classify subjects as either MDS or Other in 74% of cases that were misclassified between local and central pathology review. Further assessment on an independent cohort showed an accuracy of 83% of the model. Taken together, these data suggest that complementing pathology reviews with targeted sequencing of 7 genes could improve MDS diagnosis. Disclosures Lindsley: MedImmune: Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Bluebird Bio: Consultancy; Takeda Pharmaceuticals: Consultancy. Bejar:Aptose Biosciences: Current Employment; AbbVie/Genentech: Honoraria; Astex/Otsuka: Honoraria; Takeda: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria; Forty-Seven/Gilead: Honoraria; Genoptix/NeoGenomics: Honoraria. DeZern:MEI: Consultancy; Astex: Research Funding; Abbvie: Consultancy; Celgene: Consultancy, Honoraria. Foran:H3Biosciences: Research Funding; Aptose: Research Funding; Kura Oncology: Research Funding; Trillium: Research Funding; Takeda: Research Funding; Revolution Medicine: Consultancy; Xencor: Research Funding; Agios: Honoraria, Research Funding; Aprea: Research Funding; Actinium: Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Research Funding. Gore:Abbvie: Consultancy, Honoraria, Research Funding. Komrokji:Acceleron: Honoraria; Incyte: Honoraria; Abbvie: Honoraria; Agios: Speakers Bureau; BMS: Honoraria, Speakers Bureau; Jazz: Honoraria, Speakers Bureau; Geron: Honoraria; Novartis: Honoraria. Maciejewski:Alexion, BMS: Speakers Bureau; Novartis, Roche: Consultancy, Honoraria. Padron:Novartis: Honoraria; BMS: Research Funding; Incyte: Research Funding; Kura: Research Funding. Starczynowski:Captor Therapeutics: Consultancy; Tolero Therapeutics: Research Funding; Kurome Therapeutics: Consultancy, Current equity holder in private company, Research Funding. Sekeres:BMS: Consultancy; Takeda/Millenium: Consultancy; Pfizer: Consultancy.

Abstract Magnetic resonance enterography (MRE) is a well-established imaging technique that is commonly used for evaluating a variety of bowel diseases, most commonly inflammatory bowel disease which is increasing in prevalence. Inflammatory bowel disease is composed of 2 related, but distinct disease entities: Crohn disease (CD) and ulcerative colitis. In ulcerative colitis, inflammation is generally limited to the mucosa and invariably involves the rectum, and often the more proximal colon. CD is typified by transmural inflammation with skip lesions occurring anywhere from the mouth to anus, but characteristically involves the terminal ileum. The transmural involvement of CD may lead to debilitating ulceration and, ultimately, development of sinus tracts, which can be associated with abscesses and fistulae as extraenteric manifestations of the disease. Because much of the small bowel and extraenteric disease cannot be adequately assessed with conventional endoscopy, imaging plays a crucial role in initial diagnosis and follow-up. MRE does not use ionizing radiation which is important for these patients, many of which present earlier in life and may require multiple imaging examinations. In this article, we review the clinical indications, patient preparation, and optimal technique for MRE. We also discuss the role and proper selection of intravenous gadolinium-based contrast material, oral contrast material, and antiperistaltic agents, including pediatric considerations. Finally, we review the recommended and optional pulse sequence selection, including discussion of a “time-efficient” protocol, reviewing their utility, advantages, and limitations. Our hope is to aid the radiologist seeking to develop a robust MRE imaging program for the evaluation of bowel disease.

Abstract Advanced molecular and pathophysiologic characterization of primary central nervous system lymphoma (PCNSL) has revealed insights into promising targeted therapeutic approaches. Medical imaging plays a fundamental role in PCNSL diagnosis, staging, and response assessment. Institutional imaging variation and inconsistent clinical trial reporting diminishes the reliability and reproducibility of clinical response assessment. In this context, we aimed to: (1) critically review the use of advanced positron emission tomography (PET) and magnetic resonance imaging (MRI) in the setting of PCNSL; (2) provide results from an international survey of clinical sites describing the current practices for routine and advanced imaging, and (3) provide biologically based recommendations from the International PCNSL Collaborative Group (IPCG) on adaptation of standardized imaging practices. The IPCG provides PET and MRI consensus recommendations built upon previous recommendations for standardized brain tumor imaging protocols (BTIP) in primary and metastatic disease. A biologically integrated approach is provided to addresses the unique challenges associated with the imaging assessment of PCNSL. Detailed imaging parameters facilitate the adoption of these recommendations by researchers and clinicians. To enhance clinical feasibility, we have developed both “ideal” and “minimum standard” protocols at 3T and 1.5T MR systems that will facilitate widespread adoption.

AbstractBackgroundSex‐based differences in transcatheter aortic valve replacement (TAVR) outcomes have been previously documented. However, whether these differences persist with contemporary third generation transcatheter heart valves (THVs) is unknown.MethodsWe utilized Vizient's clinical database/resource manager (CDB/RM™) to identify patients who underwent TAVR between January 1, 2018 and March 31, 2020 to compare in‐hospital outcomes between males and females. The primary endpoint was in‐hospital mortality. Secondary endpoints included key in‐hospital complications, length of stay, discharge disposition, and cost. Unadjusted, propensity‐score matched and risk‐adjusted analyses of outcomes were performed.ResultsDuring the study period, 44,280 patients (24,842 males, 19,438 females) underwent TAVR. The primary endpoint of in‐hospital mortality was higher in females than in males (1.6 vs. 1.1% p < .001) in unadjusted analysis and persisted following propensity matching (1.6 vs. 0.9%, p < .001) and multivariable logistic regression with various risk‐adjustment models. In the most comprehensive model adjusting for age, race, and clinical comorbidities, female sex was associated with 34% greater odds of in‐hospital death (95% CI 20–50%, p < .001). Unadjusted and risk‐adjusted rates of post‐TAVR stroke, vascular complication, and blood transfusion were higher in females. Moreover, females demonstrated longer hospitalizations, higher costs and reduced rates of independent discharge home.ConclusionSex‐based differences in TAVR in‐hospital outcomes persist in contemporary practice with third generation transcatheter heart valves. Further research is needed to assess the reasons for these observed disparities and to identify effective mitigation strategies.