Citations

Background: Residency programs have developed monetary initiatives for students underrepresented in medicine (URiM). Our team sought to provide a centralized resource for URiM students seeking plastic surgery subinternships with funded opportunities. Methods: A cross sectional analysis of URiM scholarships offered by US integrated plastic surgery programs (n = 91) between July and September 2023. The study used residency program web domains. Investigators collected information on the monetary value of scholarship, eligibility criteria, and required application documents. Inferential analyses were conducted to investigate whether programs’ geographic region or Doximity ranking played a role in likelihood of scholarship existence. Results: The study found that approximately 52.7% (n = 48) of programs have in place monetary support for underrepresented visiting medical students (eg, stipend or reimbursement). The average monetary support was $1670. A univariate test demonstrated that programs with lower rankings in both reputation and research were less likely to have a scholarship available than higher ranking programs (P = 0.002; P = 0.02, respectively). Programs located in the Midwest regions were 3.5 times more likely to have a diversity scholarship available (P = 0.034). In our multivariate analysis, reputation ranking and geographic region remained significant. A Pearson chi square test showed the greatest proportions of scholarships among geographically similar programs to be in the Midwest (70%), however, not statistically significant. Conclusions: This study provides a centralized resource for URiM students interested in completing away rotations. Further investigation into development of these scholarship opportunities would be of much benefit and could guide other programs in the funding their own diversity scholarships.

Introduction: The Mindfulness-Based Stress Reduction (MBSR) Program for breast cancer survivors (BCS) is designed to enhance cognitive training through formal and informal meditational practices. This randomized clinical trial (RCT) aimed to evaluate if BCS assigned to either the MBSR(BC), Breast Cancer Education Support (BCES), or Usual Care (UC) regimens experienced greater improvements at 6, 12, and 26 weeks on objective and subjective cognitive performance. Methods: BCS ( n = 212) randomized to a three-group RCT: MBSR(BC) ( n = 91), BCES ( n = 90), or UC ( n = 31) were assessed on cognitive performance and symptoms at baseline, 6, 12, and 26 weeks. Linear mixed models were fit to evaluate the effects of the MBSR(BC) program, hypothesizing ordered effect improvements: (MBSR[BC] highest, BCES intermediate, UC lowest) along with baseline characteristics evaluated as moderators. Results: Of the BCS (mean age of 57), 73% were White, and non-Hispanic, and 77% received both chemotherapy (CT) and radiation. Cognitive performance improved in all groups. Although there were no statistically significant between-group differences in cognitive outcomes, significant symptom reductions occurred for the MBSR(BC) group ( p = 0.003). Within-group effect size analysis at 26 weeks showed substantial improvements in all three groups (effect sizes >0.50) in subjective impairments and quality of life (effect size >0.50) and objective measures of cognitive performance. MBSR(BC) showed the largest within-group effect size in the reduction of fatigue (effect size = 0.81). Effect sizes occurred in the hypothesized direction for 10 of the 18 outcomes. Discussion: Although the MBSR(BC) program did not show significant differences in cognitive performance compared with BCES and UC, all groups improved and reductions in fatigue were beneficial for MBSR(BC). Results suggest that cognitive performance may improve after CT over time considering one’s natural history. Furthermore, BCS enrolled in RCTs may be more motivated to improve their health status (NCT02786797).

ImportancePatients with chronic migraine and medication overuse headaches (CM-MOH) represent a particularly burdened subpopulation. This trial provides first, to our knowledge, American Academy of Neurology class I evidence for a preventive therapy in CM-MOH.ObjectiveTo assess erenumab efficacy and safety in patients with nonopioid CM-MOH.Design, Settings, and ParticipantsThis randomized, double-blind, parallel-group, placebo-controlled trial took place at 67 centers in North America, Europe, and Australia from October 7, 2019, to November 2, 2022. This report reflects the primary analysis conducted in January 2023, using a database snapshot from December 1, 2022, which contains the complete dataset of the double-blind treatment period (DBTP). Participants included adults with CM-MOH who had 1 or more preventive treatment failure(s). There were 992 participants screened and 620 participants enrolled (584 in nonopioid cohort and 36 in opioid cohort)InterventionsErenumab, 70 mg, 140 mg, or placebo, once monthly for 24 weeks.Main Outcomes and MeasuresThe primary end point was MOH remission at month 6. Secondary end points included change from baseline in mean monthly acute headache medication days (AHMD) at month 6 and sustained MOH remission throughout the DBTP. Safety end points were adverse events and changes in vital signs.ResultsThe primary analysis population included 584 participants in the nonopioid-treated cohort with a mean age of 44 years and 482 participants were female (82.5%). Baseline demographics and disease characteristics were balanced across groups. At month 6, 134 participants in the erenumab, 140 mg group (69.1%) (odds ratio [OR], 2.01; 95% CI, 1.33-3.05; P < .001 vs placebo) and 117 in the erenumab, 70 mg group (60.3%) (OR, 1.37; 95% CI, 0.92-2.05; P = .13 vs placebo) achieved MOH remission vs 102 participants in the placebo group (52.6%). AHMD use was also reduced in the erenumab groups vs placebo. Least squares mean (standard error) change from baseline in average monthly AHMD was –9.4 (0.4) days in the erenumab, 140 mg group (difference from placebo, –2.7; 95% CI, –3.9 to –1.6; P < .001) and –7.8 (0.4) days in the erenumab, 70 mg group (difference from placebo, –1.2; 95% CI, –2.4 to –0.1; P = .03), vs –6.6 (0.4) days in the placebo group. MOH remission throughout the DBTP was sustained in 119 participants (61.3%,) 96 participants (49.5%), and 73 participants (37.6%) in the erenumab, 140 mg, 70 mg, and placebo groups, respectively. Adverse events were consistent with the known safety profile of erenumab. Treatment-emergent adverse events incidence in the combined erenumab group was 66.8% (259 participants; constipation 15.2% (59 participants) and COVID-19 13.9% (54 participants) were most common.Conclusions and RelevanceIn this study, monthly, 140 mg, erenumab injections safely and effectively achieved MOH remission in patients with nonopioid CM-MOH within 6 months.Trial RegistrationClinicalTrials.gov Identifier: NCT03971071

Abstract Objective Limb girdle muscular dystrophies (LGMDs) are a group of genetically heterogeneous autosomal conditions with some degree of phenotypic homogeneity. LGMD is defined as having onset >2 years of age with progressive proximal weakness, elevated serum creatine kinase levels and dystrophic features on muscle biopsy. Advances in massively parallel sequencing have led to a surge in genes linked to LGMD. Methods The ClinGen Muscular Dystrophies and Myopathies gene curation expert panel (MDM GCEP, formerly Limb Girdle Muscular Dystrophy GCEP) convened to evaluate the strength of evidence supporting gene–disease relationships (GDR) using the ClinGen gene–disease clinical validity framework to evaluate 31 genes implicated in LGMD. Results The GDR was exclusively LGMD for 17 genes, whereas an additional 14 genes were related to a broader phenotype encompassing congenital weakness. Four genes ( CAPN3 , COL6A1 , COL6A2 , and COL6A3 ) were split into two separate disease entities, based on each displaying both dominant and recessive inheritance patterns, resulting in curation of 35 GDRs. Of these, 30 (86%) were classified as definitive, 4 (11%) as moderate, and 1 (3%) as limited. Two genes, POMGNT1 and DAG1 , though definitively related to myopathy, currently have insufficient evidence to support a relationship specifically with LGMD. Interpretation The expert‐reviewed assertions on the clinical validity of genes implicated in LGMDs form an invaluable resource for clinicians and molecular geneticists. We encourage the global neuromuscular community to publish case‐level data that help clarify disputed or novel LGMD associations.

Abstract Aims The extravascular implantable cardioverter-defibrillator (EV ICD) has been shown to be safe and effective for patients at risk of sudden cardiac death, but little is known about EV ICD lead removal in humans. This analysis aimed to characterize the EV ICD lead removal experience thus far. Methods and results This was a retrospective analysis of lead removals from the EV ICD Pilot, Pivotal, and Continued Access Studies. Patients with a successful EV ICD implant who underwent lead removal were included. The main objective was lead removal success. Ancillary objectives included characterizing technique used, procedure complications, and reimplantation status. An EV ICD system was successfully implanted in 347 patients across the 3 studies (25.9% female; 53.4 ± 13.3 years; left ventricular ejection fraction: 39.7 ± 15.9). Of these patients, 29 (8.4%) underwent lead removal with a mean lead dwell time of 12.6 ± 14.3 months (0.2–58.4). The main reason for lead removal was lead dislodgement (n = 9, 31.0%). Lead removal was successful in 27/29 (93.1%) cases [100% (19/19) success rate <1 year and 80% (8/10) success rate >1 year post-implant]. Simple traction was used in 22/26 (84.6%) and extraction tools in 4/26 (15.4%) successful cases where technique was known. No complications were reported for any of the removal procedures. All 11 EV ICD reimplant attempts were successful. Conclusion Complete removal of the EV ICD lead was successful in 93.1% of cases, and simple traction was sufficient in most instances. Based on these results, lead removal from the substernal space was safe and achievable up to 3 years post-implant.

Dysregulated actin cytoskeleton gives rise to aberrant cell motility and metastatic spread of tumor cells. This study evaluates the effect of overexpression of wild-type versus functional mutants of MRTF-A on migration and invasion of breast cancer (BC) cells. Our studies indicate that SRF's interaction is critical for MRTF-A-induced promotion of both two-dimensional and three-dimensional cell migration, while the SAP-domain function is important selectively for three-dimensional cell migration. Increased MRTF-A activity is associated with more effective membrane protrusion, a phenotype that is attributed predominantly to SRF's interaction with MRTF. We demonstrate formin-family protein mDia2 as an important mediator of MRTF-stimulated actin polymerization at the leading edge and cell migration. Multiplexed quantitative immunohistochemistry and transcriptome analyses of clinical BC specimens further demonstrate a positive correlation between nuclear localization of MRTF with malignant traits of cancer cells and enrichment of MRTF–SRF gene signature in pair-matched distant metastases versus primary tumors. In conclusion, this study establishes a novel mechanism of MRTF-dependent regulation of cell migration and provides evidence for the association between MRTF activity and increased malignancy in human BC, justifying future development of specific small molecule inhibitors of the MRTF-SRF transcriptional complex as potential therapeutic agents in BC.

AbstractEndometriosis is a complex gynecologic disorder characterized primarily by symptoms of pelvic pain, infertility, and altered quality of life. National and international guidelines highlight the diagnostic difficulties and lack of conclusive diagnostic tools for endometriosis. Furthermore, guidelines are becoming questionable at an increasingly rapid rate as new diagnostic techniques emerge. This work aims to provide a knowledge synthesis of the relevance of various diagnostic tools and to assess areas of improvement of conventional algorithms. MEDLINE and Cochrane Library databases were searched from January 2021 to December 2023 using relevant key words. Articles evaluating the diagnostic relevance and performance of various tools were included and independently reviewed by the authors for eligibility. Included studies were assessed using the GRADE and QUADAS‐2 tools. Of the 4204 retrieved articles, 26 were included. While anamnesis and clinical examination do contribute to diagnostic accuracy, their level of evidence and impact on the diagnostic process remains limited. Although imaging techniques are recommended to investigate endometriosis, ultrasonography remains highly operator dependent. Magnetic resonance imaging appears to exhibit higher sensitivities than ultrasound. However, concerns persist with regards to the terminology, anatomical definition of lesions, and accuracies of both ultrasound and magnetic resonance imaging. Recently, several biological markers have been studied and cumulative evidence supports the contribution of noncoding RNAs to the diagnosis of endometriosis. Marginal improvements have been suggested for anamnesis, clinical examination, and imaging examinations. Conversely, some biomarkers, including the saliva microRNA signature for endometriosis, have emerged as diagnostic tools which inspire reflection on the revision of conventional diagnostic algorithms.

74 Background: We identified computed tomography (CT)-derived radiomic features predictive of tumor progression within three months, then examined their ability to prognosticate overall survival (OS) along with clinical features in pancreatic cancer. We evaluated these features in patients with unresected pancreatic cancer who underwent stereotactic body radiation therapy (SBRT) in sequence with chemotherapy, but not surgery. Methods: In this retrospective study, we examined a cohort of 101 patients with stage II-III pancreatic cancer who underwent SBRT with sequential chemotherapy at a single institution (Stanford Health Care) between 1999-2020. From their pre-SBRT contrast-enhanced CT images with segmented tumors, delineating regions-of-interest, we extracted 900 radiomic (quantitative pixel-level imaging characteristic) features. In the first phase, we identified radiomic features that predicted rapid tumor progression within three months following SBRT. We divided the dataset into a training set (n = 53) for model development and a test set (n = 48) for evaluation. Using logistic regression with the Least Absolute Shrinkage and Selection Operator algorithm for feature selection and classification, we built a binary prediction model on the training set to identify patients at risk of progression within three months of SBRT. To fine-tune parameters, we performed five-fold cross-validation (CV) on the training set, repeating each set of parameters five times. We assessed model performance on the test set using the area under the curve (AUC). We selected the model with the best AUC, generating the predictive radiomic feature set. In the second phase, we conducted univariate and multivariate Cox regression analyses to assess the relationship between OS and individual clinical variables (age, sex, stage, vessel involvement, tumor location, performance status, body mass index, biological equivalent dose of radiation) and the radiomic feature set as high versus low risk. Results: Our cohort consisted of 48 men (mean age, 70 years ± 11 [SD]) and 53 women (mean age, 67 years ± 13 [SD]). From the first phase, 32 textural features comprised the radiomic feature set that best predicted rapid tumor progression, with mean AUCs of 0.852 (CV, n=53) and 0.814 (test, n=48). In the univariate Cox model, only the radiomic feature set was predictive of OS (hazard ratio, HR, 1.724, p=0.011). In the multivariate Cox model, radiomic features and age were significant predictors of OS, with HR of 1.819 (p=0.007) and 1.024 (p=0.024), respectively. Conclusions: CT-derived radiomic features predict rapid tumor progression following SBRT, confer nearly a twofold increase in mortality risk, and, along with patient age, enhance the identification of patients with stage II-III pancreatic cancer with poor OS. [Table: see text]

56 Background: We sought to identify the clinical determinants of overall survival (OS) in patients diagnosed with stage II-III pancreatic cancer not undergoing surgery. We curated a relatively homogenous cohort of patients who did not undergo surgical resection, but instead underwent chemotherapy in sequence with stereotactic body radiation therapy (SBRT) to examine the features that differentiated those with poor OS. Methods: In a retrospective study, we examined a cohort of 259 patients with stage II-III pancreatic cancer who underwent chemotherapy in sequence with SBRT without surgery at a single institution (Stanford Health Care). We conducted both univariate and multivariate Cox regression analyses to assess the relationships between OS and individual clinical and tumoral variables, including: age, sex, stage, Karnofsky performance status (KPS), body mass index, vessel involvement, tumor location, and biological equivalent dose [BED] of SBRT as potential determinants. Results: The study cohort consisted of 136 men (52.5%) and 123 women (47.5%) with a median age of 69 (range 38-94). Tumor histology was predominantly ductal adenocarcinoma (n=249, 96.1%), with tumor sites of involvement spanning: uncinate (n=35, 13.5%), head (n=160, 61.8%), body (n=59, 22.8%), and tail (n=5,1.9%). More patients had stage III (n=171, 66%) than stage II (n=88, 34%) disease, and their tumor resectability by NCCN criteria were rated as: unresectable (n=145, 56%), borderline (n=28, 10.8%), resectable (n=11, 4.2%), or unrecorded (n=75, 29%). Tumor progression was observed in local (n=71, 27.4%), regional (n=29, 11.2%), and distant (n=150, 57.9%) sites during the median follow up period of 17 months (range 15-18 months) from diagnosis and 12 months (10-13 months) from SBRT. Death (n=213, 82.2%) during this period was more common than survival (n=46, 17.8%). In univariate analyses, clinical features impacting OS included: KPS (hazard ratio [HR] 0.14, p=0.007); male sex (HR 1.44, p=0.01), pancreatic head tumors (HR 1.44, p=0.011), BED (HR 1.33, p=0.035), and age (HR 1.013, p=0.044). In the multivariate analysis, which incorporated only features significant in the univariate analyses, tumor location at the pancreatic head (HR 1.412, p=0.021) and male sex (HR 1.360, p=0.03) conferred the highest risks for poor OS, with BED bordering on significance (p=0.059) (Table). Conclusions: Among patients with stage II-III pancreatic cancer who underwent chemotherapy in sequence with SBRT, but not surgery, the most significant clinical determinants of poor OS were location of the tumor in the pancreatic head and male sex. Prioritizing additional disease monitoring and alternative therapies for this subset of patients at higher risk of poor survival may be warranted. [Table: see text]

2053 Background: Current methods for glioma treatment response assessment are limited. This study aimed to assess the technical and clinical feasibility of molecular profiling using intracranial CSF from patients with gliomas during their disease course. Methods: Adults with gliomas were recruited for longitudinal intracranial CSF collection using 1) Ommaya reservoirs, from which CSF would be sampled on at least two separate occasions, or 2) CSF collection from other clinically indicated CSF access devices, such as ventriculoperitoneal (VP) shunts. Patients were followed until their last visit or present time for ongoing participants. For this initial cfDNA feasibility study, CSF was collected from Ommaya reservoirs in four patients and from an existing VP shunt in one patient. cfDNA was then extracted and analyzed using two sequencing platforms, PredicineCARE for cancer variant profiling and PredicineSCORE for low-pass whole genome sequencing (LP-WGS). This analysis generated genomic aberration profiles and genome-wide copy number burden (CNB) score. Results: Five patients (2 females, 3 males; median age: 40 years, range 32-64 years) underwent longitudinal intracranial CSF collection via Ommaya reservoirs (n=4) or VP shunt (n=1). In total, thirty-five CSF samples were obtained (median volume: 3.80 mL; 0.5-5 mL), with 30 samples (85.7%) yielding sufficient cfDNA for variant profiling and LP-WGS. Our initial findings suggest that tumor fraction increased by 6.28x and 2.87x with radiographic progression in two patients. Tumor fraction decreased by 0.08x and 0.04x in two patients with paired immediate pre-versus-post chemoradiation samples. Despite ongoing pseudoprogression in one patient, tumor fraction decreased to unmeasurable levels from a post-resection baseline of 0.26. Patient-specific tumor-associated variant allelic frequencies (VAFs), including TP53, PTEN, TERT, and CDKN2A/B, decreased within individual patients after resection and chemoradiation. In two patients with isocitrate dehydrogenase (IDH) mutant gliomas, decreasing IDH1 VAF after resection correlated with decreased CSF D-2-hydroxyglutarate (D-2-HG) levels (0.64x and 0.62x, respectively, for the first patient, and 0.01x and 0.07x for the other patient). Both CSF IDH1 VAF and CSF D-2-HG increased in the patient who had radiographic progression (2.56x and 9.21x, respectively). Moreover, CNB decreased below the limit of quantification during treatment and increased above the limit at progression. Conclusions: Longitudinal CSF cfDNA can feasibly be obtained via CSF access devices in patients with gliomas during their disease course. Ongoing studies will evaluate hypotheses generated in this case series regarding how longitudinal CSF cfDNA could be utilized to sensitively detect changes in disease burden. Clinical trial information: NCT04692337 ; NCT04692324 .