Citations

Abstract Background: The lack of consensus on whether bilateral oophorectomy impacts risk of developing breast cancer among BRCA1 mutation carriers might be attributed to various biases, specifically, cancer-induced testing bias due to inclusion of prevalent cases. We conducted two complementary matched case–control analyses to evaluate the association of oophorectomy and BRCA1 breast cancer. Methods: A research questionnaire was administered every two years to collect information on exposures and disease. In the first analysis, we limited the study to prevalent breast cancer cases (diagnosed prior to study entry; n = 2,962) who were matched to controls on year of birth and country of residence (n = 4,358). In the second approach, we limited to 330 incident cases (diagnosed in the follow-up period) and 1,548 matched controls. Conditional logistic regression was used to estimate the adjusted odds ratios (OR) and 95% confidence intervals (CI) of invasive breast cancer. Results: In the first approach, there was a significant inverse association between oophorectomy and the risk of developing breast cancer [OR = 0.43; 95% confidence interval (CI), 0.34–0.55; P < 00001]. In the second approach, there was no association between oophorectomy and risk (OR = 1.21; 95% CI, 0.87–1.70; P = 0.26). Conclusions: The inclusion of women with a personal history of breast cancer prior to ascertainment likely impacts upon the association of oophorectomy and BRCA1 breast cancer risk. Impact: Oophorectomy is unlikely a determinant of breast cancer risk in BRCA1 mutation carriers but should be offered at age 35 to reduce the risk of ovarian and fallopian tube cancer.

ABSTRACT Introduction Peyronie's Disease (PD) is a well described pathology affecting up to 5-10% of men. The presence and extent of penile calcifications is an important determinant in disease management. Calcifications have a variety of clinical presentations ranging from microcalcifications to calcified plaques. Calcified plaques were excluded from past Xiaflex clinical trials. Calcified plaques may necessitate plaque excision and grafting (E&G) sometimes combined with inflatable penile prosthesis (IPP) placement, which is more complex than plaque incision and grafting. Peyronie's Disease guidelines recommend color duplex Doppler ultrasound (CDDU) primarily to rule out Erectile Dysfunction. PD pathology such as corporal septal involvement, multifocal calcifications, and circumferential corporal calcification can be difficult to assess on penile ultrasound (PUS) due to acoustic shadowing and device limitations. We describe a series of patients in whom non-contrast CT scan was used to further define calcified or complicated pathology. Objective To describe the role of non-contrast CT scan of the penis for anatomic evaluation and surgical planning in patients with complicated calcified Peyronie's disease. Methods 23 male patients with a diagnosis of PD were evaluated by a single surgeon at a single academic institution between 2017 and 2021. All patients underwent color doppler ultrasound (CDDU) examination with artificial erection via intracavernosal alprostadil injection and were evaluated based on erectile function, plaque dimension, hourglass deformity, plaque septal involvement, and suspected calcification status. Patients with CDDU examination concerning for significant calcification or complexity proceeded to non-contrast CT scan for calcific confirmation and for 3-dimensional evaluation of their PD plaque prior to surgical discussion. Complexity was defined as concern for multifocal calcified plaques (>2), partial/complete circumferential corpus cavernosum involvement, or septal involvement. Results All 23 patients had concerning findings on initial examination for calcified plaque. 9 of 23 (39.1%) patients had exam findings of an hourglass deformity. On CT evaluation, calcification was confirmed in 22 of 23 patients (95.7%). Plaque dimensions on CT scan ranged from 0.4 × 0.2 × 0.5 cm to 4.0 × 2.0 × 1.7 cm. Many of these measurements were approximations due to circumferential calcified plaque. This classic “gull-wing” appearance (Figure 1) was noted in 6 of 23 (26%) patients. 12 of 23 (52.2%) of patients had septal involvement on CT (Figure 2). 8 of 23 patients (34.8%) had significant multifocal disease (Figure 3). 8 of 23 patients (34.8%) decided to proceed with surgical correction via E&G (n = 3), IPP with E&G (n =1), or via IPP with manual remodeling via the Wilson technique (n = 4). Conclusions Non-contrast penile CT scan for evaluation of calcified Peyronie's disease allows for increased accuracy of surgical planning especially when evaluating for multifocal disease, circumferential plaque and/or septal involvement. These elements are critical in being able to provide accurate surgical recommendations and post operative discussions. Disclosure No

Abstract Objective: To analyze operating room (OR) efficiency by evaluating fixed and variable OR times for open (OPN) and robotic-assisted partial nephrectomies (RAPN).Methods: We analyzed consecutive OPN and RAPN performed by one surgeon over a 24-month period. All patients were placed in the lateral decubitus position and secured with a beanbag regardless of approach. Fixed (nonprocedural) OR times were prospectively collected and defined as: in room to anesthesia release time (IRAT), anesthesia release to cut time (ARCT), and close to wheels out time (CTWO). Variable OR time was procedural cut to close time (CTCT). Comparison of fixed and variable OR time points between OPN and RAPN were performed using the Wilcoxon rank sum test. Results: 146 RAPN and 31 OPN were evaluated from 2019-2020. Median IRAT was similar for RAPN versus OPN [20 min (IQR: 16-25) vs. 20 min (IQR: 16-26), P=0.57]. Median ARCT was longer for RAPN than it was for OPN [40 min (IQR: 36-46) vs. 34 min (IQR: 30-39), P<0.001]. Median CTWO was similar for OPN (12 min, IQR: 9-14) and RAPN (11 min, IQR: 7-15) (P=0.89). Median CTCT was longer for RAPN (202 min, IQR: 170-236) compared to OPN (164 min, IQR: 154-184) (P<0.001).Conclusions: In a single surgeon partial nephrectomy series with the same patient positioning, utilization of robotic technology was associated with longer surgeon operating time as well as less efficient fixed OR times, specifically ARCT.

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

Aim: To compare the efficacy of two popular weight loss approaches on weight loss, body composition, and markers of health in sedentary obese women. Methods: In total, 51 sedentary women (age 34.5 ± 7.7 yrs.; weight 90.0 ± 14.5 kg; BMI 34.0 ± 5.1 kg/m2; 46.5 ± 7.0% fat) were matched and randomized to participate in the Weight Watchers® Momentum™ (WW) or Curves® (CV) Fitness and Weight Management program for 16 weeks. Participants in the WW group (n = 27) were provided a point-based diet program, received weekly progress checks and counseling, and were encouraged to exercise. Participants in the CV group (n = 24) followed a menu-based higher protein/low-fat diet (1200 kcal/d) for 1 week; 1500 kcal/d diet for 3 weeks; and 2000–2500 kcals/d for 2 weeks that was repeated three times (except the last segment) while participating in a supervised circuit-style resistance training program (3 d/wk). A general linear model (GLM) with repeated measures was used to analyze data and are presented as mean changes from baseline (mean [UL, LL]). Results: Supervised CV training resulted in greater amounts of vigorous and total physical activity. After 16 weeks, both groups lost weight (WW −6.1 [−7.8, −4.6], CV −4.9 [−6.2, −3.2] kg, p = 0.264). Participants in the CV group observed greater reductions in fat mass (WW −2.9 [−6.7, −0.2], CV −6.4 [−9.2, −3.6] kg, p = 0.081) and increases in lean mass (WW −2.5 [−4.3, −0.7], CV 1.3 [−0.6, 3.2] kg, p = 0.005) resulting in more favorable changes in percent body fat (WW −1.4 [−4.1, 1.2], CV −4.7 [−7.5, −1.8]%, p = 0.098). Both groups observed improvements in peak aerobic capacity and muscular endurance, although bench press lifting volume was greater in the CV group. Those in the CV group experienced a greater increase in HDLc and reduction in the CHL–HDLc ratio and triglycerides. Conclusion: Both interventions promoted weight loss and improvements in fitness and markers of health. The CV program, which included supervised resistance training and higher protein diet menus, promoted greater fat loss, increases in lean mass, and improvements in percent body fat and blood lipids. Trial Registration: clinicaltrials.gov, #NCT04372771, registered retrospectively 1 May 2020.

Introduction: Bortezomib has been reported to favourably impact the outcomes of t(4;14) and del(17p) in multiple myeloma (MM), but its impact on gain 1q (+1q) is unknown. Methods: To address this, 250 patients treated with bortezomib-based induction were analysed. All myeloma samples had fluorescence in situ hybridization (FISH) performed on CD138-sorted bone marrow aspirate, and plasma cells were analysed using DNA probes specific for the following chromosomal aberrations: del(13q14), del(17p), t(14;16), t(4;14), and +1q. Presence of +1q was defined as the presence of at least three copies of 1q21 at the cut off level of 20% of bone marrow plasma cells. Results: +1q identified in 167 (66.8%) and associated with t(4;14) and high lactate dehydrogenase (LDH). +1q was not associated with response rate but shorter event-free survival (EFS) (median EFS 35 vs 55 months, p = 0.05) and overall survival (OS) (median OS 74 vs 168 months, p = 0.00025). Copy number and clone size did not impact survival. Multivariate analysis showed +1q was an independent adverse factor for OS together with International Staging System (ISS)3, high LDH, del(17p) and t(4;14). When a risk score of 1 was assigned to each independent adverse factor, OS was shortened incrementally by a risk score from 0 to 4. Post-relapse/progression survival was inferior in those with +1q (median 60 vs 118 months, p = 0.000316). Autologous stem cell transplantation (ASCT) improved OS for those with +1q (median OS 96 vs 49 months, p = 0.000069). Conclusion: +1q is an adverse factor for OS in MM uniformly treated with bortezomib-based induction but was partially mitigated by ASCT. A risk scoring system comprising +1q, LDH, high-risk FISH, and ISS is a potential tool for risk stratification in MM.

AbstractProsthetic valve endocarditis (PVE) remains a serious condition with a high mortality rate. Precise identification of the PVE-associated pathogen/s and their virulence is essential for successful therapy and patient survival. The commonly described PVE-associated pathogens are staphylococci, streptococci, and enterococci, with Staphylococcus aureus being the most frequently diagnosed species. Furthermore, multi-drug resistance pathogens are increasing in prevalence and continue to pose new challenges mandating a personalized approach. Blood cultures in combination with echocardiography are the most common methods to diagnose PVE, often being the only indication, it exists. In many cases, the diagnostic strategy recommended in the clinical guidelines does not identify the precise microbial agent, and frequently, false-negative blood cultures are reported. Despite the fact that blood culture findings are not always a good indicator of the actual PVE agent in the valve tissue, only a minority of re-operated prostheses are subjected to microbiological diagnostic evaluation. In this review, we focus on the diversity and the complete spectrum of PVE-associated bacterial, fungal, and viral pathogens in blood and prosthetic heart valve, their possible virulence potential, and their challenges in making a microbial diagnosis. We are curious to understand if the unacceptable high mortality of PVE is associated with the high number of negative microbial findings in connection with a possible PVE. Herein, we discuss the possibilities and limits of the diagnostic methods conventionally used and make recommendations for enhanced pathogen identification. We also show possible virulence factors of the most common PVE-associated pathogens and their clinical effects. Based on blood culture, molecular biological diagnostics, and specific valve examination, better derivations for the antibiotic therapy as well as possible preventive intervention can be established in the future.

PURPOSE Antitumor activity in preclinical models and a phase I study of patients with dedifferentiated liposarcoma (DD-LPS) was observed with selinexor. We evaluated the clinical benefit of selinexor in patients with previously treated DD-LPS whose sarcoma progressed on approved agents. METHODS SEAL was a phase II-III, multicenter, randomized, double-blind, placebo-controlled study. Patients age 12 years or older with advanced DD-LPS who had received two-five lines of therapy were randomly assigned (2:1) to selinexor (60 mg) or placebo twice weekly in 6-week cycles (crossover permitted). The primary end point was progression-free survival (PFS). Patients who received at least one dose of study treatment were included for safety analysis (ClinicalTrials.gov identifier: NCT02606461 ). RESULTS Two hundred eighty-five patients were enrolled (selinexor, n = 188; placebo, n = 97). PFS was significantly longer with selinexor versus placebo: hazard ratio (HR) 0.70 (95% CI, 0.52 to 0.95; one-sided P = .011; medians 2.8 v 2.1 months), as was time to next treatment: HR 0.50 (95% CI, 0.37 to 0.66; one-sided P < .0001; medians 5.8 v 3.2 months). With crossover, no difference was observed in overall survival. The most common treatment-emergent adverse events of any grade versus grade 3 or 4 with selinexor were nausea (151 [80.7%] v 11 [5.9]), decreased appetite (113 [60.4%] v 14 [7.5%]), and fatigue (96 [51.3%] v 12 [6.4%]). Four (2.1%) and three (3.1%) patients died in the selinexor and placebo arms, respectively. Exploratory RNA sequencing analysis identified that the absence of CALB1 expression was associated with longer PFS with selinexor compared with placebo (median 6.9 v 2.2 months; HR, 0.19; P = .001). CONCLUSION Patients with advanced, refractory DD-LPS showed improved PFS and time to next treatment with selinexor compared with placebo. Supportive care and dose reductions mitigated side effects of selinexor. Prospective validation of CALB1 expression as a predictive biomarker for selinexor in DD-LPS is warranted.