Tumor mutational burden assessment and standardized bioinformatics approach using custom NGS panels in clinical routine.

BACKGROUND: High tumor mutational burden (TMB) was reported to predict the efficacy of immune checkpoint inhibitors (ICIs). Pembrolizumab, an anti-PD-1, received FDA-approval for the treatment of unresectable/metastatic tumors with high TMB as determined by the FoundationOne®CDx test. It remains to be determined how TMB can also be calculated using other tests. RESULTS: FFPE/frozen tumor samples from various origins were sequenced in the frame of the Institut Curie (IC) Molecular Tumor Board using an in-house next-generation sequencing (NGS) panel. A TMB calculation method was developed at IC (IC algorithm) and compared to the FoundationOne® (FO) algorithm. Using IC algorithm, an optimal 10% variant allele frequency (VAF) cut-off was established for TMB evaluation on FFPE samples, compared to 5% on frozen samples. The median TMB score for MSS/POLE WT tumors was 8.8 mut/Mb versus 45 mut/Mb for MSI/POLE-mutated tumors. When focusing on MSS/POLE WT tumor samples, the highest median TMB scores were observed in lymphoma, lung, endometrial, and cervical cancers. After biological manual curation of these cases, 21% of them could be reclassified as MSI/POLE tumors and considered as "true TMB high." Higher TMB values were obtained using FO algorithm on FFPE samples compared to IC algorithm (40 mut/Mb [10-3927] versus 8.2 mut/Mb [2.5-897], p < 0.001). CONCLUSIONS: We herein propose a TMB calculation method and a bioinformatics tool that is customizable to different NGS panels and sample types. We were not able to retrieve TMB values from FO algorithm using our own algorithm and NGS panel.

Diffuse Midline H3K27-Altered Gliomas in the Spinal Cord: A Systematic Review.

PURPOSE: To systematically review the clinical features, management, and outcomes of diffuse midline H3K27-altered gliomas of the spinal cord (DMG-SCs). METHODS: PubMed, Ovid EMBASE, Scopus, and Web of Science were searched from database inception to 23 September 2023 for histologically confirmed cases of DMG-SC. Patient demographics, tumor characteristics, management information, and survival outcomes were extracted and analyzed. RESULTS: A total of 279 patients from 39 studies were collected. Patients were mostly male (61%), with an average age of 32 years. Patients were treated with surgery, radiotherapy, and chemotherapy combined (31%) or surgery only (24%), and extent of resection was most often subtotal (38%). Temozolomide was the most common chemotherapeutic agent (81%). Radiation therapy was delivered with mean dose of 47 Gy in 23 fractions. At mean follow-up time of 21 months, 13% of patients were alive. Average median overall survival was 24 months (range of 13 to 40 months) with a median progression-free survival of 14 months. Historical WHO grades of 2 or 3 appeared to exhibit a longer average median overall survival time than that of grade 4 DMG-SCs (32 vs. 23 months, p = 0.009). CONCLUSIONS: Outcomes for DMG-SCs are poor overall but appear to be favorable compared to intracranial DMGs. Despite the recent WHO 2021 grade 4 classification for all DMGs, given the differences in overall survival reported based on historical grading systems, future studies on DMG-SCs are needed to further define if DMG-SCs may represent a heterogeneous group of tumors with different prognoses.

A Case of Digital Papillary Carcinoma Arising on the Toe in a Young Female.

Syringocystadenoma papilliferum is a rare benign adnexal hamartoma that is often associated with the nevus sebaceous of Jadassohn. It usually presents on the scalp and malignant transformation is rare. Here we present a case of digital papillary carcinoma on the toe of a teenage girl. The lesion recurred after two prior excisions without biopsy. The biopsy was read as a syringocystadenoma papilliferum with concerns for aggressive digital papillary adenocarcinoma, highlighting the importance of biopsy with excisions of neoplasms of unknown etiology.

Carvedilol increases seizure resistance in a mouse model of SCN8A-derived epilepsy.

Patients with mutations that alter the function of the sodium channel SCN8A present with a range of clinical features, including mild to severe seizures, developmental delay, intellectual disability, autism, feeding dysfunction, motor impairment, and hypotonia. In an effort to identify compounds that could be potentially beneficial in SCN8A-associated epilepsy, Atkin et al. conducted an in vitro screen which resulted in the identification of 90 compounds that effectively reduced sodium influx into the cells expressing the human SCN8A R1872Q mutation. The top compounds that emerged from this screen included amitriptyline, carvedilol, and nilvadipine. In the current study, we evaluated the ability of these three compounds to increase resistance to 6 Hz or pentylenetetrazole (PTZ)-induced seizures in wild-type CF1 mice and in a mouse line expressing the human SCN8A R1620L mutation. We also evaluated the effects of fenfluramine administration, which was recently associated with a 60%-90% decrease in seizure frequency in three patients with SCN8A-associated epilepsy. While amitriptyline, carvedilol, and fenfluramine provided robust protection against induced seizures in CF1 mice, only carvedilol was able to significantly increase resistance to 6 Hz- and PTZ-induced seizures in RL/+ mutants. These results provide support for further evaluation of carvedilol as a potential treatment for patients with SCN8A mutations.

The effects of aftercare/resettlement services on crime and violence in children and youth: A systematic review.

Background: High rates of youth re-offending indicate that young custody-leavers face challenges when reintegrating into their communities. Aftercare and resettlement programs can occur pre-, during, and post-release and generally provide multiple forms of support services to address youths' transitional needs. Objectives: The present review examines (1) the impact of youth aftercare/resettlement programs on crime-related outcomes, (2) how treatment effect is moderated by participant, program, and study characteristics, (3) whether some types of interventions are more effective than others, (4) barriers/facilitators to effective program implementation, (5) the theory of change underlying resettlement interventions, and (6) available research on intervention cost. Search Methods: A comprehensive set of keywords and synonyms was combined in a Boolean search across 26 electronic databases. Multiple gray literature sources were also searched, including 23 journals, 4 meeting archives, 11 organization websites, 3 open access journal websites, and the CVs of 8 well-known researchers in the field. The search was completed in January 2023. Selection Criteria: For objectives 1-3, studies were included if they utilized a randomized controlled design or quasi-experimental comparison group design in which participants were matched on at least some baseline variables and included at least one quantitative individual-measure of crime. For objective 4, included studies presented process evaluations of aftercare/reentry programs, clearly stated their research goals, and used qualitative methods in an appropriate way to answer the stated research question. For objectives 5 and 6, no specific methods were required; any study meeting the criteria for objectives 1-4 which presented findings on theory of change or cost data were included. For all outcomes, only studies conducted in a westernized country, and published after 1991 in English, French, or German were considered. Data Collection and Analysis: Two coders conducted primary data extraction for the included studies. Data were entered into a Microsoft Excel database. After data extraction, the two coders validated the coding by cross-checking the database with each research report. Discrepancies between coders were discussed until consensus was reached. Where consensus could not be reached, a third coder was consulted. Study risk of bias was addressed using the ROBINS-I (Sterne et al., 2016), ROB-2 (Higgins et al., 2019), and the critical appraisal skills programme (CASP, 2018). Objectives 1-3 were addressed by synthesizing quantitative outcomes from rigorous impact evaluations of aftercare interventions using random effects models and meta-regression. Thematic and narrative analysis was conducted to address objectives 4-6. Results: The search resulted in 15 impact studies, representing 4,718 participants across 21 program sites, and 35 effect sizes. The 21 impact evaluations were rated as having either low/moderate bias (k = 11) or serious bias (k = 10). The synthesis of 15 impact studies found no significant effects for arrest (k = 14; OR = 1.044, 95% prediction interval [0.527, 2.075], t = 0.335) or incarceration (k = 8, OR = 0.806, 95% prediction interval [2.203, 1.433], t = -1.674). A significant pooled effect was found for conviction (k = 13, OR = 1.209, 95% prediction interval [1.000, 1.462], t = 2.256), but results were highly sensitive to the inclusion of specific studies. No meaningful pattern of results emerged in moderator analyses with respect to study, sample, program component, or program delivery characteristics. The 19 process studies were rated as either high quality (k = 12) or moderate quality (k = 7). Thematic synthesis of the process evaluations revealed 15 themes related to the strengths/challenges of program implementation. The assessment of program cost (k = 7) determined a lack of data within the literature, preventing any summative analysis. Authors' Conclusions: Current evidence is promising with respect to conviction outcomes but overall does not find that aftercare/resettlement interventions have a reliably positive impact on crime-related outcomes for young people who have offended. High variability across outcomes and reported data resulted in small sample sizes per outcome and limited moderator analyses. Multiple challenges for program implementation exist; additional rigorous research is sorely needed to further investigate the nuances of the program effects.

Improving Radial EBUS Signal with Creation of False Airway to Target Lesion During Electromagnetic Navigational Bronchoscopy: A Case Series.

Navigational bronchoscopy is increasingly used to target peripheral pulmonary nodules using electromagnetic navigational platforms (ENB), fluoroscopic navigation, or robotic-assisted bronchoscopy. The selection of equipment largely depends on the availability of technology, expertise, and the characteristics of the nodule and patient. Radial EBUS (r-EBUS) is often combined with these techniques for real-time confirmation of the nodule location. A bronchus sign is considered to have a higher diagnostic yield when biopsy tools can directly reach the nodule. We describe a case series of creating a false airway into the nodule when an eccentric r-EBUS signal is seen to subsequently obtain a concentric signal.

Enabling successful change in a high-demand working environment: a case study in a health care organization.

PURPOSE: The anticipation of organizational change and the transition process often creates uncertainty for employees and can lead to stress and anxiety. It is therefore essential for all organizations, especially those that operate in high-demand working environments, to support the well-being of staff throughout the change process. DESIGN/METHODOLOGY/APPROACH: Research on how employees respond to the organizational change of relocating to a new work space is limited. To fill this gap in the research, we present a case study examining the well-being of clinical and health care employees before and after a disruptive change: relocation in workplace facilities. In addition, factors that enabled successful change in this high-stress, high-demand working environment were investigated. Interviews were conducted with 20 participants before the relocation and 11 participants after relocation. Following an inductive approach, data were analyzed using thematic analysis to identify key themes. FINDINGS: Our findings suggest that a supportive team, inclusive leadership and a psychologically safe environment, may buffer negative employee well-being outcomes during disruptive organizational change. ORIGINALITY/VALUE: This research contributes to the literature on successful organizational change in health care by highlighting the resources which support well-being throughout the change process and enabling the successful transition to a new facility.

Retropubic Versus Transobturator Midurethral Slings at Time of Colpocleisis.

IMPORTANCE: This study aimed to evaluate if there is a difference between outcomes when retropubic or transobturator midurethral sling surgery is performed at the time of colpocleisis. OBJECTIVES: The purpose of this study was to compare the surgical outcomes of the retropubic midurethral sling (RP-MUS) versus the transobturator midurethral sling (TO-MUS) in women who underwent concomitant colpocleisis, specifically 2-year MUS failure and 1-year lower urinary tract symptoms (LUTSs). A secondary aim was to identify factors associated with these surgical outcomes. STUDY DESIGN: All cases of concomitant MUS and colpocleisis within a closed, integrated health care delivery system were reviewed between April 1, 2010, and March 31, 2020. Postoperative MUS failure was defined as (1) postoperative stress urinary incontinence symptoms and/or (2) additional anti-incontinence surgery. Postoperative LUTSs were defined as (1) MUS lysis and/or (2) overactive bladder requiring management with a new treatment. RESULTS: Of the 558 women included, 454 (81%) received RP-MUS and 104 (19%) received TO-MUS. Cohort demographics were similar. Neither MUS failure (7% RP-MUS and 9% TO-MUS, P = 0.450) nor LUTSs (7% RP-MUS and 12% TO-MUS, P = 0.171) were significantly different between RP-MUS and TO-MUS. In multivariable analysis, age was found to be significantly associated with LUTSs (odds ratio 0.29, 95% confidence interval 0.09-0.93, P = 0.038 among 70-74-year-olds; odds ratio 0.28, 95% confidence interval 0.09-0.83, P = 0.022 among 75-79-year-olds). CONCLUSIONS: At the time of colpocleisis, both RP-MUS and TO-MUS were highly successful and associated with a low incidence of LUTSs, including MUS lysis. The findings of this large study support RP-MUS and TO-MUS as similarly effective anti-incontinence options at time of colpocleisis.

Predictors of operative management in diabetic foot ulcers.

BACKGROUND & AIMS: Surgery plays a key role in the management of complicated diabetic foot disease (DFD). Currently, indications for medical versus surgical management are poorly defined. Prompt identification of patients who require surgery may reduce morbidities and length of hospital stay. This study aims to analyse factors in DFD that necessitate early surgical interventions. METHODS: All patients admitted under a multi-disciplinary diabetic foot team in a tertiary institution over 2 years were included in a retrospective case-control study comparing patients who received medical management and patients who received surgical management. Logistic regression was performed to identify factors associated with surgical management of diabetic foot complications. RESULTS: Three hundred and forty patients were included. 49% of patients required surgical management. Toe ulceration, elevated C-reactive protein (CRP), and the presence of osteomyelitis were associated with surgical management. Multivariate analysis calculated an odds ratio (OR) of 1.01 for CRP (p < 0.001), OR 2.19 (p < 0.019) favouring surgical management for forefoot ulcers, and OR 2.2 (p < 0.019) if osteomyelitis was present. CONCLUSIONS: Patients with elevated CRP levels, a forefoot diabetic ulcer and established osteomyelitis were more likely to undergo surgical management. Prompt recognition of these patients has the potential benefit of earlier decision making in definitive surgical interventions.

COVID-19 Vaccine Acceptance, Hesitancy, and Uptake in People with Diabetes in Australia.

Background: This study explored vaccination hesitancy, diabetes-specific COVID-19 vaccination concerns, and whether they predicted vaccination uptake in people with diabetes. Methods: Quantitative, cross-sectional, and predictive approaches were used. An online survey was conducted with people with diabetes attending four Australian health services, using convenience sampling (n = 842). The survey data collected included clinico-demographic characteristics, COVID-19 vaccine hesitancy, and attitudes around COVID-19 vaccine confidence and complacency. Clinico-demographic characteristics that predicted vaccination status, vaccine hesitancy, and vaccine-related attitudes were identified using regression analyses. Results: Most participants received at least one COVID-19 vaccine dose. Younger age and type 1 diabetes were associated with lower vaccination status, and they were partially mediated through higher vaccine hesitancy. Younger age and English as a dominant language were associated with higher negative attitudes towards speed of vaccine development. Conclusions: Despite an overall high vaccination rate, general and diabetes-specific COVID-19 vaccine concerns are a barrier to uptake for some people with diabetes, particularly in those who are younger or have type 1 diabetes. A detailed understanding of concerns for particular subgroups can help tailor information to increase vaccine acceptance, particularly in the context of requiring booster doses.

The role for endobronchial biopsy in the era of endobronchial ultrasound guided transbronchial needle aspiration for the diagnosis of sarcoidosis: a single center experience.

BACKGROUND AND AIM: Endobronchial biopsy (EBBX) has been reported to increase diagnostic yield for pulmonary sarcoidosis. The purpose of this study is to investigate the diagnostic yield for EBBX following endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA). METHODS: We identified a cohort of patients in the University of Minnesota Sarcoidosis Registry who had EBBx and EBUS-TBNA as part of workup for abnormal chest imaging. Data regarding demographics, biopsy approach and technique were recorded. RESULTS: Our cohort included 37 patients (53.24±9.5, Male, 22±0.57; 3.8% were African American). In these patients who had EBBX, EBUS-TBNA was performed in 100% of patients and TBBX was performed in 2 patients (5%). EBBX was positive in 9 patients (24%) and EBUS-TBNA was positive in 34 patients (92%). TBBX was diagnostic in one of two patients. EBBX was the only diagnostic tissue in 3 of the 37 patients (8%).  Conclusion: The diagnostic yield of EBBX is lower than previously reported, with only 8% of EBBXs demonstrating granulomatous inflammation. However, instrumentation used for obtaining EBBX as well as the presence of visible lesions does influence the diagnostic yield. Studies with adequate power are needed before implementing changes in clinical practice.  When performed alongside EBUS-TBNA, EBBX did not significantly add to the diagnostic yield in sarcoidosis unless visible lesions were observed.

Findings from the 2019 nationally representative oral health survey for adults in Singapore.

OBJECTIVES: The aim of this study was to present key findings from the 2019 national adult oral health survey in Singapore (NAOHS). METHODS: A multi-stage stratified sampling method was used to recruit participants for a representative national adult oral health survey. A total of 12 212 households were randomly selected from the National Database on Dwellings in Singapore. Within each household eligible persons aged ≥65 years were automatically invited to participate while a Kish selection method was used to invite those between 21 and 64 years old. The survey comprised a face-to-face interview questionnaire and a clinical examination which recorded details of tooth loss, DMFT, DMFS and prevalence of periodontal disease according to the CPITN and the US CDC-AAP classifications. Weighted analysis was performed to adjust for oversampling, non-response and post-stratification. Multivariate regression with backward stepwise selection was carried out to identify predictors of chronic periodontal disease and untreated dental caries. RESULTS: Six hundred and sixty-three participants completed both the questionnaires and the clinical examination. The prevalence of edentulousness was 2.7%. Of participants, 34.8% presented with untreated dental caries with a higher proportion found in those who were aged ≥60 years, of Malay ethnicity, living in 1-2-room public housing and who only visited the dentist when there was a problem. Mean DMFS and DMFT indices were 24.7 and 7.9 respectively. Based on the CDC-AAP classification, the prevalence of moderate-severe chronic periodontitis was 56.9% and increased with age, with a higher proportion in males. Participants with untreated dental caries were more likely to have moderate or severe periodontal disease. CONCLUSIONS: Survey findings showed high prevalence of dental caries and periodontal disease, at 34.8% and 77.6% respectively. A clear socio-economic gradient in the distribution of tooth loss, untreated dental caries and moderate-to-severe periodontitis was observed.

Metastatic renal cell carcinoma with occult primary: a multicenter prospective cohort.

Metastatic carcinoma of presumed renal origin (rCUP) has recently emerged as a new entity within the heterogeneous entity of Cancers of Unknown Primary (CUP) but their biological features and optimal therapeutic management remain unknown. We report the molecular characteristics and clinical outcome of a series of 25 rCUP prospectively identified within the French National Multidisciplinary Tumor Board for CUP. This cohort strongly suggests that rCUP share similarities with common RCC subtypes and benefit from renal-tailored systemic treatment. This study highlights the importance of integrating clinical and molecular data for optimal diagnosis and management of CUP.