Initial Management of BRAF V600E-Variant Anaplastic Thyroid Cancer: The FAST Multidisciplinary Group Consensus Statement.

Importance: BRAF/MEK inhibitors revolutionized the treatment of BRAF V600E-variant anaplastic thyroid carcinoma (BRAFv-ATC), offering improved outcomes for patients with this previously incurable disease. Observations: Anaplastic thyroid carcinoma (ATC) accounts for approximately half of thyroid cancer-related deaths. It presents as a rapidly growing tumor that often invades locoregional structures and spreads to distant sites early; therefore, prompt diagnosis, staging, and treatment initiation are of the essence in the treatment of ATC. Although most oncologists will encounter a patient with ATC in their practice, the rarity of this disease makes treatment challenging, particularly because those with BRAFv-ATC no longer have a dismal prognosis. BRAF/MEK kinase inhibitors have transformed the outlook and treatment of BRAFv-ATC. Therefore, molecular profiling to identify these patients is critical. More recently, the addition of immunotherapy to BRAF/MEK inhibitors as well as the use of the neoadjuvant approach were shown to further improve survival outcomes in BRAFv-ATC. Many of these recent advances have not yet been incorporated in the currently available guidelines, allowing for disparities in the treatment of patients with BRAFv-ATC across the US. With the increasing complexity in the management of BRAFv-ATC, this Consensus Statement aims to formulate guiding recommendations from a group of experts to facilitate therapeutic decision-making. Conclusions and Relevance: This Consensus Statement from the FAST (Facilitating Anaplastic Thyroid Cancer Specialized Treatment) group at MD Anderson Cancer Center emphasizes that rapid identification of a BRAF V600E pathogenic variant and timely initiation of sequential therapy are critical to avoid excess morbidity and mortality in patients with BRAFv-ATC. In the past decade, remarkable progress has been made in the treatment of patients with BRAFv-ATC, justifying these new evidence-based recommendations reached through a consensus of experts from a high-volume center.

A Visualization and Radiation Treatment Plan Quality Scoring Method for Triage in a Population-Based Context.

Purpose: Our purpose was to develop a clinically intuitive and easily understandable scoring method using statistical metrics to visually determine the quality of a radiation treatment plan. Methods and Materials: Data from 111 patients with head and neck cancer were used to establish a percentile-based scoring system for treatment plan quality evaluation on both a plan-by-plan and objective-by-objective basis. The percentile scores for each clinical objective and the overall treatment plan score were then visualized using a daisy plot. To validate our scoring method, 6 physicians were recruited to assess 60 plans, each using a scoring table consisting of a 5-point Likert scale (with scores ≥3 considered passing). Spearman correlation analysis was conducted to assess the association between increasing treatment plan percentile rank and physician rating, with Likert scores of 1 and 2 representing clinically unacceptable plans, scores of 3 and 4 representing plans needing minor edits, and a score of 5 representing clinically acceptable plans. Receiver operating characteristic curve analysis was used to assess the scoring system's ability to quantify plan quality. Results: Of the 60 plans scored by the physicians, 8 were deemed as clinically acceptable; these plans had an 89.0th ± 14.5 percentile value using our scoring system. The plans needing minor edits or deemed unacceptable had more variation, with scores falling in the 62.6nd ± 25.1 percentile and 35.6th ± 25.7 percentile, respectively. The estimated Spearman correlation coefficient between the physician score and treatment plan percentile was 0.53 (P < .001), indicating a moderate but statistically significant correlation. Receiver operating characteristic curve analysis demonstrated discernment between acceptable and unacceptable plan quality, with an area under the curve of 0.76. Conclusions: Our scoring system correlates with physician ratings while providing intuitive visual feedback for identifying good treatment plan quality, thereby indicating its utility in the quality assurance process.

How is ceftobiprole used in Canada: the CLEAR study final results.

BACKGROUND: We report the final results of the clinical usage of ceftobiprole in patients in Canada from data in the national CLEAR (Canadian Le adership on Antimicrobial Real-Life Usage) registry. RESEARCH DESIGN AND METHODS: The authors review the final data using the national ethics approved CLEAR study. Thereafter, the literature is surveyed regarding the usage of ceftobiprole to treat patients with infectious diseases via PubMed (up to March 2024). RESULTS: In Canada, ceftobiprole is primarily used as directed therapy to treat a variety of severe infections caused by MRSA. It is primarily used in patients failing previous antimicrobials, is frequently added to daptomycin and/or vancomycin with high microbiological and clinical cure rates, along with an excellent safety profile. Several reports attest to the microbiological/clinical efficacy and safety of ceftobiprole. Ceftobiprole is also reported to be used empirically in select patients with community-acquired bacterial pneumonia (CABP), as well as hospital-acquired bacterial pneumonia (HABP). CONCLUSIONS: In Canada, ceftobiprole is used mostly as directed therapy to treat a variety of severe infections caused by MRSA, in patients failing previous antimicrobials. It is frequently added to, and thus used in combination with daptomycin and/or vancomycin with high microbiological/clinical cure rates, and an excellent safety profile.

Role of Sex, Anxiety, and Resilience in the Association between Adverse Childhood Experiences and Irritable Bowel Syndrome.

BACKGROUND & AIMS: Adverse childhood experiences (ACE) are associated with increased risk of irritable bowel syndrome (IBS), a female-predominant chronic abdominal disorder. Factors contributing to this association have not been well-studied. We compared sex differences in ACE for adults with and without IBS and evaluated the impact of anxiety and resilience on the relationship between ACE and IBS. METHODS: Sex and disease differences in total score and ACE subtypes from the ACE Questionnaire in subjects with IBS and control subjects were assessed. Cross-sectional mediation analysis determined if anxiety (Hospital Anxiety and Depression Scale) and resilience (Connor-Davidson Resilience Scale or Brief Resilience Scale) mediated the relationship between ACE and IBS. RESULTS: Of 798 participants studied, 368 met IBS diagnostic criteria (265 women, 103 men) and 430 were healthy control subjects (277 women, 153 men). Prevalence and number of ACE were higher in IBS versus control subjects (P < .001) but similar between IBS women and men. Household mental illness increased odds of having IBS in women (odds ratio [OR], 1.95; 95% confidence interval [CI], 1.35-2.85; false discovery rate [FDR], 0.002) and men (OR, 2.32; 95% CI, 1.26-4.33; FDR, 0.014). Emotional abuse increased odds of having IBS in women (OR, 1.94; 95% CI, 1.23-3.09; FDR, 0.019) and sexual abuse increased odds of IBS in men (OR, 3.54; 95% CI, 1.35-10.38; FDR, 0.027). Anxiety mediated 54% (P < .001) of ACE's effect on IBS risk and resilience mediated 12%-14% (Connor-Davidson Resilience Scale, P = .008; Brief Resilience Scale, P = .018). CONCLUSIONS: Both men and women with a history of ACE are twice as likely to have IBS than those without an ACE. Anxiety mediated the relationship between ACE and IBS in men and women and resilience mediated this relationship only in women.

Association between time to surgery and hospital mortality in patients with community-acquired limb necrotizing fasciitis: an 11-year multicenter retrospective cohort analysis.

BACKGROUND: Necrotizing fasciitis (NF) is a rare but potentially life-threatening soft tissue infection. The objective of this study was to assess the association between timely surgery within 6 h and hospital mortality in patients with limb NF, and to describe the trends in patients with NF, time to surgery and standardized mortality ratio (SMR) over 11 years. METHODS: This was a multicenter, retrospective cohort study of all intensive care unit patients who had emergency surgery within 24 h of hospitalization for limb NF between April 1, 2008 and March 31, 2019 in Hong Kong. Timely surgery was defined as the first surgical treatment within 6 h of initial hospitalization. Appropriate antibiotics were achieved if the patient was given antibiotic(s) for all documented pathogens prior to or on day of culture results. The primary outcome was hospital mortality. RESULTS: There were 495 patients (median age 62 years, 349 (70.5%) males) with limb NF treated by surgery within 24 h of hospitalization over the 11 years. Appropriate antibiotic(s) were used in 392 (79.2%) patients. There were 181 (36.5%) deaths. Timely surgery was not associated with hospital mortality (Relative Risk 0.89, 95% CI: 0.73 to 1.07) but admission year, advanced age, higher severity of illness, comorbidities, renal replacement therapy, vasopressor use, and type of surgery were significant predictors in the multivariable model. There was an upward trend in NF diagnosis (1.9 cases/year, 95% CI: 0.7 to 3.1; P < 0.01; R2 = 0.60) but there was no downward trend in median time to surgery (-0.2 h/year, 95% CI: -0.4 to 0.1; P = 0.16) or SMR (-0.02/year, 95% CI: -0.06 to 0.01; P = 0.22; R2 = 0.16). CONCLUSIONS: Among patients operated within 24 h, very early surgery within 6-12 h was not associated with survival. Increasing limb NF cases were reported each year but mortality remained high despite a high rate of appropriate antibiotic use and timely surgical intervention.

The multigenerational impact of long QT syndrome: A Gitxsan perspective.

Long QT syndrome (LQTS), a rare cardiac condition that can lead to sudden death, is highly prevalent in First Nations communities of northern British Columbia. In the Gitxsan community of 5500, an estimated 1 in 125 individuals are affected, primarily due to the novel pathogenic variant p.V205M in KCNQ1. Over the past decade, more than 800 Gitxsan individuals received genetic testing and counseling for LQTS through a community-based study. Despite the substantial research characterizing the biological underpinnings of LQTS, there are few studies exploring the lived experiences of families with LQTS, especially those of Indigenous peoples. The goal of this study was to gain a greater understanding of the impact of the genetic confirmation of LQTS in this community, and the impact the condition has on individuals, their families, and the community. A qualitative study was developed in consultation with a local research advisory board and a Talking Circle, a traditional Indigenous format for discussion, was held. Four people who belonged to the same kindred group attended the Talking Circle. This article presents the multigenerational impact that LQTS and genetic diagnosis have through the reflections of one Gitxsan family. LQTS affects identity and family relationships, including those between parents and children, siblings, and even extended family members. Laughter and humor played an important part in coping. The role of family relationships for this Gitxsan family was seen to be critical in managing an LQTS diagnosis. This multigenerational perspective provides key insights into family structure and dynamics which can inform genetic counseling and clinical care. As cultural safety is experienced and therefore defined by the person receiving services, listening to the perspectives and preferences of Indigenous peoples is essential to the delivery of culturally informed care.

Longitudinal prediction of psychosocial functioning outcomes: Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Section-II personality disorders versus alternative model personality dysfunction and traits.

We aimed to determine and compare the longitudinal predictive power of Diagnostic and Statistical Manual of Mental Disorders, fifth edition's (DSM-5) two models of personality disorder (PD) for multiple clinically relevant outcomes. A sample of 600 community-dwelling adults-half recruited by calling randomly selected phone numbers and screening-in for high-risk for personality pathology and half in treatment for mental health problems-completed an extensive battery of self-report and interview measures of personality pathology, clinical symptoms, and psychosocial functioning. Of these, 503 returned for retesting on the same measures an average of 8 months later. We used Time 1 interview data to assess DSM-5 personality pathology, both the Section-II PDs and the alternative (DSM-5) model of personality disorder's (AMPD) Criterion A (impairment) and Criterion B (adaptive-to-maladaptive-range trait domains and facets). We used these measures to predict 20 Time 2 functioning outcomes. Both PD models significantly predicted functioning-outcome variance, albeit modestly-averaging 12.6% and 17.9% (Section-II diagnoses and criterion counts, respectively) and 15.2% and 23.2% (AMPD domains and facets, respectively). Each model significantly augmented the other in hierarchical regressions, but the AMPD domains (6.30%) and facets (8.62%) predicted more incremental variance than the Section-II diagnoses (3.74%) and criterion counts (3.31%), respectively. Borderline PD accounted for just over half of Section II's predictive power, whereas the AMPD's predictive power was more evenly distributed across components. We note the predictive advantages of dimensional models and articulate the theoretical and clinical advantages of the AMPD's separation of personality functioning impairment from how this is manifested in personality traits. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Disease Site Specialization in the Academic Radiation Oncology Workforce: Evidence of Gender Differences.

PURPOSE: Because some stakeholders within medicine seek to diversify and attain greater workforce equity, it is critical to understand gender-based divisions within specialization. Radiation oncology (RO) has one of the smallest proportions of women representation of all specialties, and to our knowledge, no prior studies have investigated gender differences in all the disease site specializations within RO. Thus, we analyzed the relationship between gender and disease site(s) treated in academic RO (ARO). METHODS AND MATERIALS: Faculty gender and disease site(s) treated by faculty from ARO departments were collected via publicly available department websites in January 2020. X2 analyses were conducted to assess differences between the proportions of women faculty treating each disease site. RESULTS: Of 1337 ARO faculty, 408 (30.5%) were identified as women. Breast, gynecology, and pediatrics had the largest proportions of women faculty (all >40%; P < .001). A majority (53%; P < .001) of women ARO faculty treated breast. Genitourinary, thoracic, and head and neck had the smallest proportions of women faculty (all <25%; P < .001). Women ARO faculty were twice as likely to treat breast and gynecologic malignancies compared with men faculty (risk ratio [RR] with 95% CI, 2.01 [1.75-2.50]; P < .001 and RR [95% CI], 2.06 [1.72-2.79]; P <.001, respectively). Men ARO faculty were 3 times more likely to treat genitourinary cancer compared with women faculty (RR [95% CI], 0.40 [0.34-0.48]; P < .001). There was no difference in the mean number of disease sites treated between women and men ARO faculty (2.63 vs 2.53; P = .29). CONCLUSIONS: Gender differences in disease site specialization were observed in ARO. Future research into the drivers of disease site selection should be explored.

Effects of training with a rehabilitation device (Rebless®) on upper limb function in patients with chronic stroke: A randomized controlled trial.

BACKGROUND: Upper limb dysfunction is one of the most common sequelae of stroke and robotic therapy is considered one of the promising methods for upper limb rehabilitation. OBJECTIVE: This study aimed to explore the clinical effectiveness of upper limb training using a rehabilitation robotic device (Rebless®) for patients with stroke. METHODS: In this prospective, unblinded, randomized controlled trial, patients were randomly assigned to receive robotic training (experimental group, n = 15) or conventional therapy (control group, n = 15). Both groups received upper limb training lasting for 30 minutes per session with a total of 10 training sessions within 4 weeks. Motor function, functional evaluation, and spasticity were clinically assessed before and after the training. Cortical activation was measured using functional near-infrared spectroscopy at the 1st and 10th training sessions. RESULTS: The experimental group demonstrated a significant improvement in the Fugl-Meyer assessment-upper extremity score and the modified Ashworth scale grade in elbow flexors. The cortical activity of the unaffected hemisphere significantly decreased after 10 training sessions in the experimental group compared with the control group. CONCLUSIONS: The experimental group showed significant improvement in the Fugl-Meyer assessment-upper extremity score and spasticity of elbow flexors and had significantly decreased cortical activity of the unaffected hemisphere. Training with Rebless® may help patients with chronic stroke in restoring upper limb function and recovering the contralateral predominance of activation in motor function.

Multi-modal segmentation with missing image data for automatic delineation of gross tumor volumes in head and neck cancers.

BACKGROUND: Head and neck (HN) gross tumor volume (GTV) auto-segmentation is challenging due to the morphological complexity and low image contrast of targets. Multi-modality images, including computed tomography (CT) and positron emission tomography (PET), are used in the routine clinic to assist radiation oncologists for accurate GTV delineation. However, the availability of PET imaging may not always be guaranteed. PURPOSE: To develop a deep learning segmentation framework for automated GTV delineation of HN cancers using a combination of PET/CT images, while addressing the challenge of missing PET data. METHODS: Two datasets were included for this study: Dataset I: 524 (training) and 359 (testing) oropharyngeal cancer patients from different institutions with their PET/CT pairs provided by the HECKTOR Challenge; Dataset II: 90 HN patients(testing) from a local institution with their planning CT, PET/CT pairs. To handle potentially missing PET images, a model training strategy named the "Blank Channel" method was implemented. To simulate the absence of a PET image, a blank array with the same dimensions as the CT image was generated to meet the dual-channel input requirement of the deep learning model. During the model training process, the model was randomly presented with either a real PET/CT pair or a blank/CT pair. This allowed the model to learn the relationship between the CT image and the corresponding GTV delineation based on available modalities. As a result, our model had the ability to handle flexible inputs during prediction, making it suitable for cases where PET images are missing. To evaluate the performance of our proposed model, we trained it using training patients from Dataset I and tested it with Dataset II. We compared our model (Model 1) with two other models which were trained for specific modality segmentations: Model 2 trained with only CT images, and Model 3 trained with real PET/CT pairs. The performance of the models was evaluated using quantitative metrics, including Dice similarity coefficient (DSC), mean surface distance (MSD), and 95% Hausdorff Distance (HD95). In addition, we evaluated our Model 1 and Model 3 using the 359 test cases in Dataset I. RESULTS: Our proposed model(Model 1) achieved promising results for GTV auto-segmentation using PET/CT images, with the flexibility of missing PET images. Specifically, when assessed with only CT images in Dataset II, Model 1 achieved DSC of 0.56 ± 0.16, MSD of 3.4 ± 2.1 mm, and HD95 of 13.9 ± 7.6 mm. When the PET images were included, the performance of our model was improved to DSC of 0.62 ± 0.14, MSD of 2.8 ± 1.7 mm, and HD95 of 10.5 ± 6.5 mm. These results are comparable to those achieved by Model 2 and Model 3, illustrating Model 1's effectiveness in utilizing flexible input modalities. Further analysis using the test dataset from Dataset I showed that Model 1 achieved an average DSC of 0.77, surpassing the overall average DSC of 0.72 among all participants in the HECKTOR Challenge. CONCLUSIONS: We successfully refined a multi-modal segmentation tool for accurate GTV delineation for HN cancer. Our method addressed the issue of missing PET images by allowing flexible data input, thereby providing a practical solution for clinical settings where access to PET imaging may be limited.

Association of Lipoprotein(a) with Progression of Coronary Artery Calcification: Retrospective Longitudinal Study.

Background: Atherosclerotic cardiovascular disease (ASCVD) is a major health concern, and lipoprotein(a) (Lp(a)) is an independent risk factor. However, there is limited evidence regarding Lp(a) and the risk of ASCVD in Asian populations. This study aimed to assess the predictive value of changes in coronary artery calcification (CAC) for ASCVD risk associated with Lp(a) level. Methods: Participants (n=2,750) were grouped according to their Lp(a) levels, and the association between Lp(a) and CAC progression was examined. CAC progression was defined as the occurrence of incident CAC or a difference ≥2.5 between the square root (√) of baseline and follow-up coronary artery calcium scores (CACSs) (Δ√transformed CACS). To adjust for differences in follow-up periods, Δ√transformed CACS was divided by the follow- up period (in years). Results: Over an average follow-up of 3.07 years, 18.98% of participants experienced CAC progression. Those with disease progression had notably higher Lp(a) levels. Higher Lp(a) tertiles correlated with increased baseline and follow-up CACS, CAC progression (%), and Δ√transformed CACS. Even after adjustment, higher Lp(a) levels were associated with CAC progression. However, annualized Δ√transformed CACS analysis yielded no significant results. Conclusion: This study demonstrated an association between elevated Lp(a) levels and CAC progression in a general population without ASCVD. However, longer-term follow-up studies are needed to obtain meaningful results regarding CAC progression. Further research is necessary to utilize Lp(a) level as a predictor of cardiovascular disease and to establish clinically relevant thresholds specific to the Korean population.

Investigating family resilience factors for enhancing family adaptation in children with epilepsy.

PURPOSE: To identify and understand the key family resilience factors that contribute to the improved family adaptation of children with epilepsy. METHODS: Parent of children with epilepsy treated in the outpatient unit and general ward at Severance Children's Hospital in Seoul, Korea, completed a structured online questionnaire between April and May 2023. This study examined risk (epilepsy severity, time since diagnosis, parental depression, and perceived stigma) and protective factors (child temperament, epilepsy knowledge, family communication skills, parent's educational level, monthly household income, and social support) of family adaptation based on Patterson's Family Resilience Model. Furthermore, general characteristics such as daily caregiving time, perceived parental health, family type, and primary caregiver role were analyzed. RESULTS: This study included 131 participants with a mean age of 41.79 ± 5.77 years, with children having an average age of 9.19 ± 4.94 years. The regression model was significant, and revealed the impact of communication skills, social support, and primary caregivers other than parents. Moreover, a shorter time since diagnosis has a more positive impact on family adaptation. CONCLUSIONS: To improve family adaptation in children with epilepsy, the focus should be placed on improving communication skills, increasing social support, and providing access to external support services. Furthermore, families expecting longer illness duration require proactive measures to support them. These findings could guide future strategies to enhance adaptation in families with children with epilepsy.

Meta-Analytic Review of Temperamental Correlates of the Five-Factor Model and Hierarchical Taxonomy of Psychopathology Domains.

Background: There is little and heterogeneous knowledge on the links between the temperamental predispositions of psychopathology and the contemporary dimensional models of psychopathology, such as the Hierarchical Taxonomy of Psychopathology (HiTOP) classification system, which can be aligned with the five-factor model (FFM) of personality. This meta-analysis seeks to expand the temperamental theoretical basis of the HiTOP model by incorporating associations of temperament traits of two temperamental theories measured, respectively, by the Temperament and Character Inventory (TCI) and the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego Autoquestionnaire (TEMPS-A) with (a) the FFM's personality domains and (b) HiTOP's five psychopathological spectra. Methods: A systematic search was done on Web of Science, Scopus, PubMed, ProQuest, Cochrane Database, and Google Scholar for all articles published in English from January 1990 to August 2020. Because of heterogeneity in the results of almost 70% of studies, pooled estimates of correlation coefficients were calculated using the random-effects method. Risk of bias (low-quality studies) and publication bias are reported. Results: The pooled correlations obtained from the analysis of 35 studies showed that the temperamental profile associated with each FFM domain and HiTOP spectra is distinct. Specifically, TCI-harm avoidance (HA) and all TEMPS temperaments were more strongly related to neuroticism/internalizing, extraversion/low detachment, and conscientiousness/disinhibition. In contrast, TCI-novelty seeking was more strongly related to both disinhibited/antagonistic externalizing and thought disorder. Conclusions: A large body of research supports maladaptive variants of all FFM domains and some psychopathological spectra of HiTOP related to the abnormal-range temperaments.

Competing Models of Personality Disorder: Relations With Psychosocial Functioning.

The Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5; American Psychiatric Association, 2013), includes 10 categorical personality disorders (PD) in Section II (Section II PD) and a dimensional alternative model of PD (AMPD) in Section III. We compared the two models in explaining concurrent psychosocial functioning levels in psychiatric outpatients and community residents screened as at risk for PD pathology (N = 600). The AMPD's fully dimensional form showed stronger associations with psychosocial difficulties and explained more of their variance compared with the categorical Section II PD. AMPD Criterion A (personality functioning impairment) and Criterion B (pathological traits) incrementally predicted psychosocial functioning about equally with some unique predictions. Finally, AMPD's six categorical PD diagnoses did not show stronger associations with psychosocial functioning than the corresponding Section II PD diagnoses. Findings directly comparing the two models remain important and timely for informing future conceptualizations of PD in the diagnostic system.

Hydrosulfonylation of Alkynes for Stereodivergent Synthesis of Vinyl Sulfones: Synthetic Strategy and Mechanistic Insights.

Direct synthesis of thermodynamically less favorable (Z)-vinyl sulfones presents a notable challenge in organic synthesis. In addition, the development of a stereodivergent synthesis for (E)- and (Z)-vinyl sulfones is crucial but remains elusive. In this study, we present a hydrosulfonylation of aryl-substituted alkynes, achieving a stereodivergent synthesis of (E)- and (Z)-vinyl sulfones by leveraging both thermodynamic and kinetic controls. Notably, the synthesis of challenging (Z)-vinyl sulfones was achieved through a kinetically controlled process without the need for a catalyst. To synthesize (E)-vinyl sulfones, unconventional visible light-mediated isomerization was employed as a means of facilitating the transition to the thermodynamically favored form. The present study encompasses a comprehensive experimental and computational investigation, which provides valuable insights into the reaction mechanism. This investigation reveals two plausible isomerization pathways: a novel double spin-flip mechanism and a hydrogen atom transfer process in the presence of eosin Y. This study not only advances our understanding of isomerization mechanisms beyond conventional energy-transfer routes but also offers a robust and switchable strategy for synthesizing (E)- and (Z)-vinyl sulfones, thereby providing a versatile avenue for the creation of valuable compounds in the fields of organic synthesis and medicinal chemistry.

Melanoma antigens in pediatric medulloblastoma contribute to tumor heterogeneity and species-specificity of group 3 tumors.

Background: Medulloblastoma (MB) is the most malignant childhood brain cancer. Group 3 MB subtype accounts for about 25% of MB diagnoses and is associated with the most unfavorable outcomes. Herein, we report that more than half of group 3 MB tumors express melanoma antigens (MAGEs), which are potential prognostic and therapeutic markers. MAGEs are tumor antigens, expressed in several types of adult cancers and associated with poorer prognosis and therapy resistance; however, their expression in pediatric cancers is mostly unknown. The aim of this study was to determine whether MAGEs are activated in pediatric MB. Methods: To determine MAGE frequency in pediatric MB, we obtained formalin-fixed paraffin-embedded tissue (FFPE) samples of 34 patients, collected between 2008 - 2015, from the Children's Medical Center Dallas pathology archives and applied our validated reverse transcription quantitative PCR (RT-qPCR) assay to measure the relative expression of 23 MAGE cancer-testis antigen genes. To validate our data, we analyzed several published datasets from pediatric MB patients and patient-derived orthotopic xenografts, totaling 860 patients. We then examined how MAGE expression affects the growth and oncogenic potential of medulloblastoma cells by CRISPR-Cas9- and siRNA-mediated gene depletion. Results: Our RT-qPCR analysis suggested that MAGEs were expressed in group 3/4 medulloblastoma. Further mining of bulk and single-cell RNA-sequencing datasets confirmed that 50-75% of group 3 tumors activate a subset of MAGE genes. Depletion of MAGEAs, B2, and Cs alter MB cell survival, viability, and clonogenic growth due to decreased proliferation and increased apoptosis. Conclusions: These results indicate that targeting MAGEs in medulloblastoma may be a potential therapeutic option for group 3 medulloblastomas. Key Points: Several Type I MAGE CTAs are expressed in >60% of group 3 MBs. Type I MAGEs affect MB cell proliferation and apoptosis. MAGEs are potential biomarkers and therapeutic targets for group 3 MBs. Importance of the Study: This study is the first comprehensive analysis of all Type I MAGE CTAs ( MAGEA , -B , and -C subfamily members) in pediatric MBs. Our results show that more than 60% of group 3 MBs express MAGE genes, which are required for the viability and growth of cells in which they are expressed. Collectively, these data provide novel insights into the antigen landscape of pediatric MBs. The activation of MAGE genes in group 3 MBs presents potential stratifying and therapeutic options.

Preoperative rectus femoris muscle ultrasound, its relationship with frailty scores, and the ability to predict recovery after cardiac surgery: a prospective cohort study.

BACKGROUND: Frailty is common in patients undergoing cardiac surgery and is associated with poorer postoperative outcomes. Ultrasound examination of skeletal muscle morphology may serve as an objective assessment tool as lean muscle mass reduction is a key feature of frailty. METHODS: This study investigated the association of ultrasound-derived muscle thickness, cross-sectional area, and echogenicity of the rectus femoris muscle (RFM) with preoperative frailty and predicted subsequent poor recovery after surgery. Eighty-five patients received preoperative RFM ultrasound examination and frailty-related assessments: Clinical Frailty Scale (CFS) and 5-m gait speed test (GST5m). Association of each ultrasound measurement with frailty assessments was examined. Area under receiver-operating characteristic curve (AUROC) was used to assess the discriminative ability of each ultrasound measurement to predict days at home within 30 days of surgery (DAH30). RESULTS: By CFS and GST5m criteria, 13% and 34% respectively of participants were frail. RFM cross-sectional area alone demonstrated moderate predictive association for frailty by CFS criterion (AUROC: 0.76, 95% CI: 0.66-0.85). Specificity improved to 98.7% (95% CI: 93.6%-100.0%) by utilising RFM cross-sectional area as an 'add-on' test to a positive gait speed test, and thus a combined muscle size and function test demonstrated higher predictive performance (positive likelihood ratio: 40.4, 95% CI: 5.3-304.3) for frailty by CFS criterion than either test alone (p < 0.001). The combined 'add-on' test predictive performance for DAH30 (AUROC: 0.90, 95% CI: 0.81-0.95) may also be superior to either CFS or gait speed test alone. CONCLUSIONS: Preoperative RFM ultrasound examination, especially when integrated with the gait speed test, may be useful to identify patients at high risk of frailty and those with poor outcomes after cardiac surgery. TRIAL REGISTRATION: The study was registered on the Chinese Clinical Trials Registry (ChiCTR2000031098) on 22 March 2020.

Nerve Bundle Density and Expression of NGF and IL-1ß Are Intra-Individually Heterogenous in Subtypes of Endometriosis.

Endometriosis is a gynecological disorder associated with local inflammation and neuroproliferation. Increased nerve bundle density has been attributed to increased expression of nerve growth factor (NGF) and interleukin-1ß (IL-1ß). Immunohistochemical analysis was carried out on 12 patients presenting with all three anatomic subtypes of endometriosis (deep, superficial peritoneal, endometrioma) at surgery, with at least two surgically excised subtypes available for analysis. Immunolocalization for nerve bundle density around endometriosis using protein gene product 9.5 (PGP9.5), as well as NGF and IL-1ß histoscores in endometriosis epithelium/stroma, was performed to evaluate differences in scores between lesions and anatomic subtypes per patient. Intra-individual heterogeneity in scores across lesions was assessed using the coefficient of variation (CV). The degree of score variability between subtypes was evaluated using the percentage difference between mean scores from one subtype to another subtype for each marker. PGP9.5 nerve bundle density was heterogenous across multiple subtypes of endometriosis, ranging from 50.0% to 173.2%, where most patients (8/12) showed CV ≥ 100%. The percentage difference in scores showed that PGP9.5 nerve bundle density and NGF and IL-1ß expression were heterogenous between anatomic subtypes within the same patient. Based on these observations of intra-individual heterogeneity, we conclude that markers of neuroproliferation in endometriosis should be stratified by anatomic subtype in future studies of clinical correlation.

Exploration of Patient Retention in Seeking a Second Opinion: A Retrospective Cohort Study.

INTRODUCTION: It is common for cancer patients to seek a second opinion for a variety of reasons. Understanding what drives patients to choose to receive treatment with their second opinion provider may uncover opportunities to improve the second opinion process. Therefore, we sought to identify the patient, disease, and treatment characteristics that were associated with second opinion retention rates in patients seeking a second surgical opinion for breast, colon, and pancreatic cancer. METHODS: We conducted a retrospective cohort study to evaluate patients who sought a second opinion within a large academic health-care system for breast, colon, and pancreatic cancer. Electronic medical records were reviewed for second opinions. Patient demographics and characteristics were collected and compared between the retained group and the nonretained groups. RESULTS: A total of 237 patients obtained second opinions for breast, colorectal, and pancreatic cancer. Patients that were offered a different treatment plan at their second opinion were more likely to be retained for systemic therapy (P = 0.009) for pancreatic cancer and any treatment for colon cancer (P = 0.003). Seeing a radiation oncologist (P = 0.007) or a plastic surgeon (P = 0.02) during the multidisciplinary consultation increased retention rates for breast cancer. CONCLUSIONS: Surgeons can better identify patients that are more likely to be retained after a second opinion by the individual patient characteristics and treatment factors. Understanding the factors that lead to retention for these three cancer types may help physicians provide the best possible resources for most patients presenting for second opinion evaluations.

Whole genome and transcriptome integrated analyses guide clinical care of pediatric poor prognosis cancers.

The role for routine whole genome and transcriptome analysis (WGTA) for poor prognosis pediatric cancers remains undetermined. Here, we characterize somatic mutations, structural rearrangements, copy number variants, gene expression, immuno-profiles and germline cancer predisposition variants in children and adolescents with relapsed, refractory or poor prognosis malignancies who underwent somatic WGTA and matched germline sequencing. Seventy-nine participants with a median age at enrollment of 8.8 y (range 6 months to 21.2 y) are included. Germline pathogenic/likely pathogenic variants are identified in 12% of participants, of which 60% were not known prior. Therapeutically actionable variants are identified by targeted gene report and whole genome in 32% and 62% of participants, respectively, and increase to 96% after integrating transcriptome analyses. Thirty-two molecularly informed therapies are pursued in 28 participants with 54% achieving a clinical benefit rate; objective response or stable disease ≥6 months. Integrated WGTA identifies therapeutically actionable variants in almost all tumors and are directly translatable to clinical care of children with poor prognosis cancers.