Citations

Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States, with less than half of patients living >5 years following diagnosis. The NCCN Guidelines for Ovarian Cancer provide recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with ovarian, fallopian tube, and primary peritoneal cancers. These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines, including revised guidance on alternative chemotherapy regimens for patients with advanced age and/or comorbidities, a new algorithm for recurrent low-grade serous carcinoma based on developing research and novel therapeutic agents, and updated language regarding tumor molecular analysis applications in ovarian cancer.

Importance In patients with severe aortic valve stenosis at intermediate surgical risk, transcatheter aortic valve replacement (TAVR) with a self-expanding supra-annular valve was noninferior to surgery for all-cause mortality or disabling stroke at 2 years. Comparisons of longer-term clinical and hemodynamic outcomes in these patients are limited. Objective To report prespecified secondary 5-year outcomes from the Symptomatic Aortic Stenosis in Intermediate Risk Subjects Who Need Aortic Valve Replacement (SURTAVI) randomized clinical trial. Design, Setting, and Participants SURTAVI is a prospective randomized, unblinded clinical trial. Randomization was stratified by investigational site and need for revascularization determined by the local heart teams. Patients with severe aortic valve stenosis deemed to be at intermediate risk of 30-day surgical mortality were enrolled at 87 centers from June 19, 2012, to June 30, 2016, in Europe and North America. Analysis took place between August and October 2021. Intervention Patients were randomized to TAVR with a self-expanding, supra-annular transcatheter or a surgical bioprosthesis. Main Outcomes and Measures The prespecified secondary end points of death or disabling stroke and other adverse events and hemodynamic findings at 5 years. An independent clinical event committee adjudicated all serious adverse events and an independent echocardiographic core laboratory evaluated all echocardiograms at 5 years. Results A total of 1660 individuals underwent an attempted TAVR (n = 864) or surgical (n = 796) procedure. The mean (SD) age was 79.8 (6.2) years, 724 (43.6%) were female, and the mean (SD) Society of Thoracic Surgery Predicted Risk of Mortality score was 4.5% (1.6%). At 5 years, the rates of death or disabling stroke were similar (TAVR, 31.3% vs surgery, 30.8%; hazard ratio, 1.02 [95% CI, 0.85-1.22]; P = .85). Transprosthetic gradients remained lower (mean [SD], 8.6 [5.5] mm Hg vs 11.2 [6.0] mm Hg; P < .001) and aortic valve areas were higher (mean [SD], 2.2 [0.7] cm 2 vs 1.8 [0.6] cm 2 ; P < .001) with TAVR vs surgery. More patients had moderate/severe paravalvular leak with TAVR than surgery (11 [3.0%] vs 2 [0.7%]; risk difference, 2.37% [95% CI, 0.17%- 4.85%]; P = .05). New pacemaker implantation rates were higher for TAVR than surgery at 5 years (289 [39.1%] vs 94 [15.1%]; hazard ratio, 3.30 [95% CI, 2.61-4.17]; log-rank P < .001), as were valve reintervention rates (27 [3.5%] vs 11 [1.9%]; hazard ratio, 2.21 [95% CI, 1.10-4.45]; log-rank P = .02), although between 2 and 5 years only 6 patients who underwent TAVR and 7 who underwent surgery required a reintervention. Conclusions and Relevance Among intermediate-risk patients with symptomatic severe aortic stenosis, major clinical outcomes at 5 years were similar for TAVR and surgery. TAVR was associated with superior hemodynamic valve performance but also with more paravalvular leak and valve reinterventions.

AbstractThe Pulmonary Vascular Research Institute GoDeep meta‐registry is a collaboration of pulmonary hypertension (PH) reference centers across the globe. Merging worldwide PH data in a central meta‐registry to allow advanced analysis of the heterogeneity of PH and its groups/subgroups on a worldwide geographical, ethnical, and etiological landscape (ClinTrial. gov NCT05329714). Retrospective and prospective PH patient data (diagnosis based on catheterization; individuals with exclusion of PH are included as a comparator group) are mapped to a common clinical parameter set of more than 350 items, anonymized and electronically exported to a central server. Use and access is decided by the GoDeep steering board, where each center has one vote. As of April 2022, GoDeep comprised 15,742 individuals with 1.9 million data points from eight PH centers. Geographic distribution comprises 3990 enrollees (25%) from America and 11,752 (75%) from Europe. Eighty‐nine perecent were diagnosed with PH and 11% were classified as not PH and provided a comparator group. The retrospective observation period is an average of 3.5 years (standard error of the mean 0.04), with 1159 PH patients followed for over 10 years. Pulmonary arterial hypertension represents the largest PH group (42.6%), followed by Group 2 (21.7%), Group 3 (17.3%), Group 4 (15.2%), and Group 5 (3.3%). The age distribution spans several decades, with patients 60 years or older comprising 60%. The majority of patients met an intermediate risk profile upon diagnosis. Data entry from a further six centers is ongoing, and negotiations with >10 centers worldwide have commenced. Using electronic interface‐based automated retrospective and prospective data transfer, GoDeep aims to provide in‐depth epidemiological and etiological understanding of PH and its various groups/subgroups on a global scale, offering insights for improved management.

Abstract Somatic mutations in UBA1 cause vacuoles, E1 ubiquitin-activating enzyme, X-linked, autoinflammatory somatic (VEXAS) syndrome, an adult-onset inflammatory disease with an overlap of hematologic manifestations. VEXAS syndrome is characterized by a high mortality rate and significant clinical heterogeneity. We sought to determine independent predictors of survival in VEXAS and to understand the mechanistic basis for these factors. We analyzed 83 patients with somatic pathogenic variants in UBA1 at p.Met41 (p.Met41Leu/Thr/Val), the start codon for translation of the cytoplasmic isoform of UBA1 (UBA1b). Patients with the p.Met41Val genotype were most likely to have an undifferentiated inflammatory syndrome. Multivariate analysis showed ear chondritis was associated with increased survival, whereas transfusion dependence and the p.Met41Val variant were independently associated with decreased survival. Using in vitro models and patient-derived cells, we demonstrate that p.Met41Val variant supports less UBA1b translation than either p.Met41Leu or p.Met41Thr, providing a molecular rationale for decreased survival. In addition, we show that these 3 canonical VEXAS variants produce more UBA1b than any of the 6 other possible single-nucleotide variants within this codon. Finally, we report a patient, clinically diagnosed with VEXAS syndrome, with 2 novel mutations in UBA1 occurring in cis on the same allele. One mutation (c.121 A>T; p.Met41Leu) caused severely reduced translation of UBA1b in a reporter assay, but coexpression with the second mutation (c.119 G>C; p.Gly40Ala) rescued UBA1b levels to those of canonical mutations. We conclude that regulation of residual UBA1b translation is fundamental to the pathogenesis of VEXAS syndrome and contributes to disease prognosis.

Abstract Atypical teratoid/rhabdoid tumor (AT/RT) is a malignant central nervous system tumor predominantly affecting infants. Mutations of SMARCB1 or (rarely) SMARCA4 causing loss of nuclear SMARCB1 or SMARCA4 protein expression are characteristic features, but further recurrent genetic alterations are lacking. Most AT/RTs occur de novo, but secondary AT/RTs arising in other central nervous system tumors have been reported. Malignant gliomas, IDH-wildtype, arising in patients with Li-Fraumeni syndrome typically show somatic mutations of TP53 as well as complex copy number alterations, but little is known about loss of SMARCB1 or SMARCA4 protein expression in this context. Here we report two children, in whom malignant supratentorial brain tumors with SMARCB1-deficiency, complex copy number alterations and somatic TP53 mutations lead to the discovery of pathogenic/likely pathogenic TP53 variants in the germ line. Screening of the molecularneuropathology.org data set for cases with similar genetic and epigenetic alterations yielded another case with SMARCA4-deficiency in a young adult with Li-Fraumeni syndrome. In conclusion, SMARCB1- or SMARCA4-deficient malignant brain tumors with complex copy number alterations and somatic TP53 mutations in children and young adults may represent the first clinical manifestation of Li-Fraumeni syndrome and should prompt genetic counseling and investigation for TP53 germline status.

Atypical teratoid/rhabdoid tumor (AT/RT) is a malignant central nervous system tumor predominantly affecting infants. Mutations of SMARCB1 or (rarely) SMARCA4 causing loss of nuclear SMARCB1 or SMARCA4 protein expression are characteristic features, but further recurrent genetic alterations are lacking. Most AT/RTs occur de novo, but secondary AT/RTs arising from other central nervous system tumors have been reported. Malignant gliomas, IDH wild-type, arising in patients with Li-Fraumeni syndrome typically show somatic mutations of TP53 as well as complex copy number alterations, but little is known about the loss of SMARCB1 or SMARCA4 protein expression in this context. Here, we report 2 children in whom malignant supratentorial brain tumors with SMARCB1 deficiency, complex copy number alterations, and somatic TP53 mutations lead to the discovery of pathogenic/likely pathogenic TP53 variants in the germline. Screening of the molecularneuropathology.org dataset for cases with similar genetic and epigenetic alterations yielded another case with SMARCA4 deficiency in a young adult with Li-Fraumeni syndrome. In conclusion, SMARCB1-deficient or SMARCA4-deficient malignant brain tumors with complex copy number alterations and somatic TP53 mutations in children and young adults may represent the first clinical manifestation of Li-Fraumeni syndrome and should prompt genetic counseling and investigation for TP53 germline status.

ABSTRACT Background The second consensus criteria for the diagnosis of multiple system atrophy (MSA) are widely recognized as the reference standard for clinical research, but lack sensitivity to diagnose the disease at early stages. Objective To develop novel Movement Disorder Society (MDS) criteria for MSA diagnosis using an evidence‐based and consensus‐based methodology. Methods We identified shortcomings of the second consensus criteria for MSA diagnosis and conducted a systematic literature review to answer predefined questions on clinical presentation and diagnostic tools relevant for MSA diagnosis. The criteria were developed and later optimized using two Delphi rounds within the MSA Criteria Revision Task Force, a survey for MDS membership, and a virtual Consensus Conference. Results The criteria for neuropathologically established MSA remain unchanged. For a clinical MSA diagnosis a new category of clinically established MSA is introduced, aiming for maximum specificity with acceptable sensitivity. A category of clinically probable MSA is defined to enhance sensitivity while maintaining specificity. A research category of possible prodromal MSA is designed to capture patients in the earliest stages when symptoms and signs are present, but do not meet the threshold for clinically established or clinically probable MSA. Brain magnetic resonance imaging markers suggestive of MSA are required for the diagnosis of clinically established MSA. The number of research biomarkers that support all clinical diagnostic categories will likely grow. Conclusions This set of MDS MSA diagnostic criteria aims at improving the diagnostic accuracy, particularly in early disease stages. It requires validation in a prospective clinical and a clinicopathological study. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Neurodevelopmental disorders are associated with metabolic pathway imbalances; however, most metabolic measurements are made peripherally, leaving central metabolic disturbances under-investigated. Cerebrospinal fluid obtained intraoperatively from children with autism spectrum disorder (ASD, n = 34), developmental delays (DD, n = 20), and those without known DD/ASD (n = 34) was analyzed using large-scale targeted mass spectrometry. Eighteen also had epilepsy (EPI). Metabolites significantly related to ASD, DD and EPI were identified by linear models and entered into metabolite–metabolite network pathway analysis. Common disrupted pathways were analyzed for each group of interest. Central metabolites most involved in metabolic pathways were L-cysteine, adenine, and dodecanoic acid for ASD; nicotinamide adenine dinucleotide phosphate, L-aspartic acid, and glycine for EPI; and adenosine triphosphate, L-glutamine, ornithine, L-arginine, L-lysine, citrulline, and L-homoserine for DD. Amino acid and energy metabolism pathways were most disrupted in all disorders, but the source of the disruption was different for each disorder. Disruption in vitamin and one-carbon metabolism was associated with DD and EPI, lipid pathway disruption was associated with EPI and redox metabolism disruption was related to ASD. Two microbiome metabolites were also detected in the CSF: shikimic and cis-cis-muconic acid. Overall, this study provides increased insight into unique metabolic disruptions in distinct but overlapping neurodevelopmental disorders.

Background: Optimum management of carotid stenosis, both symptomatic (sx) and asymptomatic (asx), remains controversial despite clinical trials evaluating Carotid Endarterectomy (CEA) and Carotid Stenting (CAS). Objective: We compared attitudes in management of carotid stenosis between experts in Europe (EU), and North America (NA). Methods: From April 2011 to July 2012, a 3-round, email-Delphi survey was sent to members of the European Stroke Organisation (n=390) and to a list of NA stroke neurologists developed at the University of Texas at Houston Stroke Program (n=289). Those completing the survey were shown all responses broken down by EU/NA after each of the first 2 survey rounds. Continent specific consensus was defined a priori to be > 80% agreement. Results: 100 (15%, of which 73% EU) participated in all 3-Delphi rounds, 19% of all EU vs 9% NA (χ2=11.62, p=0.0007): 76% male; 69% treating between 1-8 new cases of carotid stenosis per month. In the final round, EU reached consensus in 7/11 statements (3 reached in phase-I), while NA did in 4/11 (1 reached in phase-I).Ninety-percent of EU vs 70% of NA (χ2=8.09, p=0.017) disagreed that CAS and CEA are equivalent treatments for sx carotid stenosis, and stated that CEA is superior. There remains a significant difference between EU and NA when considering ipsilateral stroke and death < 30 days as primary outcome (χ2=12.18, p=0.007). Sixty-nine-percent of NA agreed that there is a stronger indication for CAS over CEA in patients < 65 years for sx carotid stenosis whereas 55% of EU (χ2=11.39, p=0.023) disagreed with the statement. When asked how likely they would recommend CEA for an asx carotid stenosis, 81% of EU and 80% of NA said ‘sometimes’. When asked how likely they would recommend CAS for an asx carotid stenosis, 62% of NA said ‘sometimes’ vs 60% of EU said ‘never’(χ2=3.54, p=0.06). Conclusion: There are several clear differences in attitudes regarding the management of carotid stenosis between EU and NA: EU has a stronger attitude towards superiority of CEA while in NA there is more equipoise between the two treatments. Areas of lack of consensus may provide direction for future clinical trials.

Background Combining immunotherapy and antiangiogenic agents is a promising treatment strategy in endometrial cancer. To date, no biomarkers for response have been identified and data on post-immunotherapy progression are lacking. We explored the combination of a checkpoint inhibitor (nivolumab) and an antiangiogenic agent (cabozantinib) in immunotherapy-naïve endometrial cancer and in patients whose disease progressed on previous immunotherapy with baseline biopsy for immune profiling. Patients and methods In this phase II trial (ClinicalTrials.gov NCT03367741, registered December 11, 2017), women with recurrent endometrial cancer were randomized 2:1 to nivolumab with cabozantinib (Arm A) or nivolumab alone (Arm B). The primary endpoint was Response Evaluation Criteria in Solid Tumors-defined progression-free survival (PFS). Patients with carcinosarcoma or prior immune checkpoint inhibitor received combination treatment (Arm C). Baseline biopsy and serial peripheral blood mononuclear cell (PBMC) samples were analyzed and associations between patient outcome and immune data from cytometry by time of flight (CyTOF) and PBMCs were explored. Results Median PFS was 5.3 (90% CI 3.5 to 9.2) months in Arm A (n=36) and 1.9 (90% CI 1.6 to 3.4) months in Arm B (n=18) (HR=0.59, 90% CI 0.35 to 0.98; log-rank p=0.09, meeting the prespecified statistical significance criteria). The most common treatment-related adverse events in Arm A were diarrhea (50%) and elevated liver enzymes (aspartate aminotransferase 47%, alanine aminotransferase 42%). In-depth baseline CyTOF analysis across treatment arms (n=40) identified 35 immune-cell subsets. Among immunotherapy-pretreated patients in Arm C, non-progressors had significantly higher proportions of activated tissue-resident (CD103+CD69+) ɣδ T cells than progressors (adjusted p=0.009). Conclusions Adding cabozantinib to nivolumab significantly improved outcomes in heavily pretreated endometrial cancer. A subgroup of immunotherapy-pretreated patients identified by baseline immune profile and potentially benefiting from combination with antiangiogenics requires further investigation.