In vivo vulnerabilities to GPX4 and HDAC inhibitors in drug-persistent versus drug-resistant BRAFV600E lung adenocarcinoma.

The current targeted therapy for BRAFV600E-mutant lung cancer consists of a dual blockade of RAF/MEK kinases often combining dabrafenib/trametinib (D/T). This regimen extends survival when compared to single-agent treatments, but disease progression is unavoidable. By using whole-genome CRISPR screening and RNA sequencing, we characterize the vulnerabilities of both persister and D/T-resistant cellular models. Oxidative stress together with concomitant induction of antioxidant responses is boosted by D/T treatment. However, the nature of the oxidative damage, the choice of redox detoxification systems, and the resulting therapeutic vulnerabilities display stage-specific differences. Persister cells suffer from lipid peroxidation and are sensitive to ferroptosis upon GPX4 inhibition in vivo. Biomarkers of lipid peroxidation are detected in clinical samples following D/T treatment. Acquired alterations leading to mitogen-activated protein kinase (MAPK) reactivation enhance cystine transport to boost GPX4-independent antioxidant responses. Similarly to BRAFV600E-mutant melanoma, histone deacetylase (HDAC) inhibitors decrease D/T-resistant cell viability and extend therapeutic response in vivo.

Transcriptional phenocopies of deleterious KEAP1 mutations correlate with survival outcomes in lung cancer treated with immunotherapy.

PURPOSE: Co-occurring mutations in KEAP1 and STK11KRAS have emerged as determinants of survival outcomes in non-small cell lung cancer (NSCLC) patients treated with immunotherapy. However, these mutational contexts identify a fraction of non-responders to immune checkpoint inhibitors. We hypothesized that KEAP1 wild-type tumors recapitulate the transcriptional footprint of KEAP1 mutations, and that this KEAPness phenotype can determine immune responsiveness with higher precision compared to mutation-based models. EXPERIMENTAL DESIGN: The TCGA was used to infer the KEAPness phenotype and explore its immunological correlates at the pan-cancer level. The association between KEAPness and survival outcomes was tested in two independent cohorts of advanced NSCLC patients treated with immunotherapy and profiled by RNA-Seq (SU2C n=153; OAK/POPLAR n=439). The NSCLC TRACERx421 multi-region sequencing study (tumor regions n=947) was used to investigate evolutionary trajectories. RESULTS: KEAPness-dominant tumors represented 50% of all NSCLCs and were associated with shorter progression-free survival (PFS) and overall survival (OS) compared to KEAPness-free cases in independent cohorts of NSCLC patients treated with immunotherapy (SU2C PFS P=0.042, OS P=0.008; OAK/POPLAR PFS P=0.0014, OS P<0.001). Patients with KEAPness tumors had survival outcomes comparable to those with KEAP1-mutant tumors. In the TRACERx421, KEAPness exhibited limited transcriptional intratumoral heterogeneity and immune exclusion, resembling the KEAP1-mutant disease. This phenotypic state occurred across genetically divergent tumors, exhibiting shared and private cancer genes under positive selection when compared to KEAP1-mutant tumors. CONCLUSIONS: We identified a KEAPness phenotype across evolutionary divergent tumors. KEAPness outperforms mutation-based classifiers as a biomarker of inferior survival outcomes in NSCLC patients treated with immunotherapy.

90-Day Emergency Department Utilization and Readmission Rate After Full-Endoscopic Spine Surgery: A Multicenter, Retrospective Analysis of 821 Patients.

BACKGROUND AND OBJECTIVES: Emergency department (ED) utilization and readmission rates after spine surgery are common quality of care measures. Limited data exist on the evaluation of quality indicators after full-endoscopic spine surgery (FESS). The objective of this study was to detect rates, causes, and risk factors for unplanned postoperative clinic utilization after FESS. METHODS: This retrospective multicenter analysis assessed ED utilization and clinic readmission rates after FESS performed between 01/2014 and 04/2023 for degenerative spinal pathologies. Outcome measures were ED utilizations, hospital readmissions, and revision surgeries within 90 days postsurgery. RESULTS: Our cohort includes 821 patients averaging 59 years of age, who underwent FESS. Most procedures targeted the lumbar or sacral spine (85.75%) while a small fraction involved the cervical spine (10.11%). The most common procedures were lumbar unilateral laminotomies for bilateral decompression (40.56%) and lumbar transforaminal discectomies (25.58%). Within 90 days postsurgery, 8.0% of patients revisited the ED for surgical complications. A total of 2.2% of patients were readmitted to a hospital of which 1.9% required revision surgery. Primary reasons for ED visits and clinic readmissions were postoperative pain exacerbation, transient neurogenic bladder dysfunction, and recurrent disk herniations. Our multivariate regression analysis revealed that female patients had a significantly higher likelihood of using the ED (P = .046; odds ratio: 1.77, 95% CI 1.01-3.1 5.69% vs 10.33%). Factors such as age, American Society of Anesthesiologists class, body mass index, comorbidities, and spanned spinal levels did not significantly predict postoperative ED utilization. CONCLUSION: This analysis demonstrates the safety of FESS, as evidenced by acceptable rates of ED utilization, clinic readmission, and revision surgery. Future studies are needed to further elucidate the safety profile of FESS in comparison with traditional spinal procedures.

Minimally Invasive Surgery for Colorectal Cancer: Benchmarking Uptake for a Regional Improvement Programme.

BACKGROUND: The uptake of minimally invasive surgery (MIS) for patients with colorectal cancer has progressed at differing rates, both across countries, and within countries. This study aimed to investigate uptake for a regional colorectal cancer improvement programme in England. METHOD: We calculated the proportion of patients receiving elective laparoscopic and robot-assisted surgery amongst those diagnosed with colorectal cancer over 3 time periods (2007-2011, 2012-2016 and 2017-2021) in hospitals participating in the Yorkshire Cancer Research Bowel Cancer Improvement Programme (YCR BCIP). These were benchmarked against national rates. Regression analysis and funnel plots were used to develop a data driven approach for analysing trends in the use of MIS at hospitals in the programme. RESULTS: In England, resections performed by MIS increased from 34.9% to 72.9% for colon cancer and from 28.8% to 72.5% for rectal cancer. Robot-assisted surgery increased from 0.1% to 2.7% for colon cancer and from 0.2% to 7.9% for rectal cancer. Wide variation in the uptake of MIS was observed at a hospital level. Detailed analysis of the YCR BCIP region identified a decreasing number of surgical departments, since the start of the programme, as potential outliers for MIS when compared to the English national average. CONCLUSION: Wide variation in use of MIS for colorectal cancer exists within the English National Health Service and a data-driven approach can help identify outlying hospitals. Addressing some of the challenges behind the uptake of MIS, such as ensuring adequate provision of surgical training and equipment, could help increase its use.

PARP inhibitor therapy in patients with IDH1 mutated cholangiocarcinoma.

BACKGROUND: Isocitrate dehydrogenase 1 (IDH1) missense mutations occur at a frequency of 10%-15% in intrahepatic cholangiocarcinoma (iCCA). IDH1 mutations result in accumulation of (R)-2-hydroxyglutarate, an oncometabolite that leads to DNA hypermethylation and impairment of homologous recombination (HR). Impairment of HR results in a "BRCAness" phenotype which may confer sensitivity to poly(ADP ribose) polymerase (PARP) inhibition. METHODS: We conducted a retrospective cohort review to identify patients with advanced, IDH1 mutated iCCA treated with a PARP inhibitor (PARPi) at the University of Michigan between 2018 and 2023. Patients are described with respect to prior lines of therapy, response to platinum-based chemotherapy, and progression-free survival (PFS) and overall survival (OS) from the time of PARPi initiation. RESULTS: Between 2018 and 2023 we identified 40 patients with IDH1 mutated iCCA of which 6 patients were treated with a PARPi as monotherapy or in combination with an ATR inhibitor or anti-PD-1 immune checkpoint inhibitor. Majority of patients (n = 5) carried an IDH1 R132C mutation per tissue-based next generation sequencing. All patients had previously received at least one line of cisplatin-based systemic therapy for advanced disease prior to treatment with PARPi. PFS and OS from time of PARPi initiation ranged from 1.4 to 18.5 months and 2.8 to 42.4 months, respectively. Best response on PARPi therapy included 2 partial responses. CONCLUSION: This is the first case series to describe PARPi treatment in IDH1 mutated iCCA. Results underscore the limitation of PARPi monotherapy, potentially support combined PARPi therapies, and highlight a need for effective treatment options for patients with IDH1 mutated iCCA.

The Risk of Medication-Related Osteonecrosis of the Jaw in Children: Guidance for Antiresorptive Use in Pediatric Patients.

BACKGROUND: Antiresorptive targeted cancer therapies, such as denosumab and bisphosphonates, are used in adults, but their application in pediatric cancer is more recent. Side effects such as osteonecrosis of the jaw (ONJ) observed in adults have curtailed use of these medications in the pediatric population. PURPOSE: This study assesses the frequency of ONJ, other side effects, and the indications for use of denosumab versus bisphosphonates in pediatric subjects. STUDY DESIGN, SETTING, SAMPLE: A retrospective cohort study of pediatric subjects who underwent bisphosphonate or denosumab therapy at our institution from 2007-2023 was conducted. Subjects aged ≥ 18 years at therapy initiation were excluded. INDEPENDENT VARIABLE: The independent variable was antiresorptive therapy divided into 2 groups, treatment with intravenous bisphosphonates or denosumab. MAIN OUTCOME VARIABLE(S): Primary outcomes were development of bisphosphonate-related and denosumab-related ONJ. Secondary outcomes included additional side effects. COVARIATES: ONJ risk factors, subject demographics, indications for use, timing, duration, and cumulative dose of antiresorptive therapy were abstracted. ANALYSES: Univariate and bivariate statistics were computed to describe the sample and measure associations between antiresorptive therapy and outcomes. P values < .05 conferred statistical significance. RESULTS: The sample was composed of 178 subjects with a mean age of 11.7 ± 6.1 years. There were 14 (7.9%) and 164 (92.1%) subjects treated with denosumab and bisphosphonate therapies, respectively. There were 0 cases of ONJ across all subjects. The most common indication for treatment was adjuvant targeted therapy for aggressive tumors and malignancy (39.3%) followed by osteoporosis (14.6%). Subjects treated with denosumab had higher frequencies of hypercalcemia and severe bone pain than subjects treated with bisphosphonates, 28.6% versus 1.2% (P < .001) and 14.3% versus 0.00% (P < .001), respectively. CONCLUSION AND RELEVANCE: While invasive dental procedures are ideally performed before antiresorptive treatment, our data suggest that bisphosphonates may be used safely in the pediatric population with low concern for ONJ. Our data also demonstrated bisphosphonates may have a more tolerable side effect profile than denosumab. If the perceived benefits are similar, we recommend using bisphosphonates as first-line therapy in children while reserving denosumab for refractory cases. Future studies will help determine long-term side effects and differences in efficacies of these medications.

Mechanisms of action behind the protective effects of proactive esophageal cooling during radiofrequency catheter ablation in the left atrium.

Proactive esophageal cooling for the purpose of reducing the likelihood of ablation-related esophageal injury resulting from radiofrequency (RF) cardiac ablation procedures is increasingly being used and has been Food and Drug Administration cleared as a protective strategy during left atrial RF ablation for the treatment of atrial fibrillation. In this review, we examine the evidence supporting the use of proactive esophageal cooling and the potential mechanisms of action that reduce the likelihood of atrioesophageal fistula (AEF) formation. Although the pathophysiology behind AEF formation after thermal injury from RF ablation is not well studied, a robust literature on fistula formation in other conditions (eg, Crohn disease, cancer, and trauma) exists and the relationship to AEF formation is investigated in this review. Likewise, we examine the abundant data in the surgical literature on burn and thermal injury progression as well as the acute and chronic mitigating effects of cooling. We discuss the relationship of these data and maladaptive healing mechanisms to the well-recognized postablation pathophysiological effects after RF ablation. Finally, we review additional important considerations such as patient selection, clinical workflow, and implementation strategies for proactive esophageal cooling.

Custom Endoprosthesis-Assisted Pediatric Microsurgical Jaw Reconstruction.

Surgical treatment of pediatric maxillary and mandibular tumors can cause significant postresection disfigurement, mastication, and speech dysfunction. The need to restore form and function without compromising growth at the recipient and donor sites poses a particular reconstructive dilemma. This study evaluates outcomes of the custom endoprosthesis (CE) compared with noncustom reconstruction (NCR) and introduces an algorithm using CE to optimize available soft tissue reconstructive options. An Institutional Review Board-approved retrospective review of all patients undergoing maxillary or mandibular reconstruction between 2016 and 2022 was completed. The independent variable of interest was CE utilization. Primary outcomes of interest included hardware failure/removal or exposure, major complications, and revision surgeries. Covariates of interest included patient demographics, medical comorbidities, tumor size, and pathologic diagnosis. Statistical analyses including independent t test, χ2 analyses, and univariate/multivariate logistic regression were performed using RStudio version 4.2.1. Fifty-one patients (37 mandible and 14 maxilla) underwent CE or NCR. Of patients, 37% (n = 19) received CE. Of patients who underwent mandibular reconstruction, there were significantly lower rates of hardware exposure (14.3% versus 47.8%, P = 0.018), failure (7.1% versus 43.5%, P = 0.048), major complications (28.6% versus 78.2%, P = 0.008), and revisions (11.1% versus 50.0%, P = 0.002) in the CE cohort compared with the NCR cohort. The rates of hardware failure, exposure, major complications, and revisions did not significantly differ in maxillary reconstructions, however, CE successfully reconstructed significantly larger defects (179.5 versus 74.6 cm3, P = 0.020) than NCRs. Deviating from NCR, the authors propose an algorithm considering anatomical location, extent of resection, and patient age for soft tissue selection. This algorithm yielded improved mandibular reconstructive outcomes and no increase in complications rate in maxillary reconstruction despite larger resection defects. Furthermore, the authors' initial findings demonstrate that CE is a safe option for pediatric maxillary and mandibular reconstruction that may, in addition, facilitate improved form and function.

A Nationwide Analysis of the Impact of Cardiopulmonary Anomalies on Cleft Palate Surgical Outcomes.

OBJECTIVE: To increase awareness and improve perioperative care of patients with cleft palate (CP) and coexisting cardiopulmonary anomalies. DESIGN: Retrospective cohort. SETTING: Multi-center. PATIENTS/PARTICIPANTS: Patients who underwent surgical repair of CP between 2012-2020 identified in the American College of Surgeons National Surgical Quality Improvement Program Pediatric Data File. Chi-squared analysis and Student's t-test were implemented to make associations between congenital heart disease (CHD) and congenital pulmonary disease (CPD) and postoperative complications. Multiple logistic regression was performed to identify associations between CP and CHD/CPD while controlling for age, gender, and ASA class. C2 values were used to assess the logistic regressions, with a significance level of 0.05 indicating statistical significance. MAIN OUTCOMES MEASURES: Length of stay (LOS), perioperative complications (readmission, reoperation, reintubation, wound dehiscence, cerebrovascular accidents, and mortality). RESULTS: 9 96 181 patients were identified in the database, 17 786 of whom were determined to have CP, of whom 16.0% had congenital heart defects (CHD) and 13.2% had congenital pulmonary defects (CPD). Patients with CHD and CPD were at a significantly greater risk of increased LOS and all but one operative complication rate (wound dehiscence) relative to patients with CP without a history of CHD and CPD. CONCLUSION: This study suggests that congenital cardiopulmonary disease is associated with increased adverse outcomes in the setting of CP repair. Thus, heightened clinical suspicion for coexisting congenital anomalies in the presence of CP should prompt referring providers to perform a comprehensive and multidisciplinary evaluation to ensure cardiopulmonary optimization prior to surgical intervention.

Mechanistic patterns and clinical implications of oncogenic tyrosine kinase fusions in human cancers.

Tyrosine kinase (TK) fusions are frequently found in cancers, either as initiating events or as a mechanism of resistance to targeted therapy. Partner genes and exons in most TK fusions are followed typical recurrent patterns, but the underlying mechanisms and clinical implications of these patterns are poorly understood. By developing Functionally Active Chromosomal Translocation Sequencing (FACTS), we discover that typical TK fusions involving ALK, ROS1, RET and NTRK1 are selected from pools of chromosomal rearrangements by two major determinants: active transcription of the fusion partner genes and protein stability. In contrast, atypical TK fusions that are rarely seen in patients showed reduced protein stability, decreased downstream oncogenic signaling, and were less responsive to inhibition. Consistently, patients with atypical TK fusions were associated with a reduced response to TKI therapies. Our findings highlight the principles of oncogenic TK fusion formation and selection in cancers, with clinical implications for guiding targeted therapy.

"The ban is there, but it is not there": perceptions of cigarette users and tobacco vendors regarding ban on the sale of loose cigarettes in India.

Introduction: Banning the sales of loose cigarettes is recommended by Article 16 of the World Health Organization - Framework Convention on Tobacco Control. This study aims to understand the perceptions of cigarette users and tobacco vendors regarding such a ban. Methods: Using a systematic recruitment and interview protocol, we interviewed cigarette users (n = 28) and tobacco vendors (n = 28) from two Indian cities where sales of loose cigarettes were banned (Mumbai) or not banned (Delhi). Separate semi-structured interview guides were used for users and vendors. Interview questions focused on reasons for purchasing loose cigarettes, preference for buying and selling loose vs. packs, thoughts on the necessity of banning loose cigarettes, and the perceived impact of the policy ban for vendors and cigarette users. We performed thematic analysis and used NVivo for organizing transcript coding. Results: The main reasons users cited for purchasing loose cigarettes were financial constraints, social restrictions (fear of getting caught), and limiting cigarette consumption. In Mumbai, awareness of the existing ban was poor among both users and vendors. Those who were aware did not think the policy had been implemented. Users thought that loose cigarettes promoted smoking initiation and prevented them from quitting. Both users and vendors reported that a ban on loose cigarettes would reduce cigarette consumption and promote quit attempts as it would not be possible for everyone to purchase packs because of financial and social reasons. Conclusion: Users in both cities reported easy access to and widespread availability of loose cigarettes. Low awareness of the ban in Mumbai suggested inadequate enforcement. A country-wide ban on the sale of loose cigarettes could be highly effective in preventing smoking initiation and promoting quitting.

Additional impact of genetic ancestry over race/ethnicity to prevalence of KRAS mutations and allele-specific subtypes in non-small cell lung cancer.

The KRAS mutation is the most common oncogenic driver in patients with non-small cell lung cancer (NSCLC). However, a detailed understanding of how self-reported race and/or ethnicity (SIRE), genetically inferred ancestry (GIA), and their interaction affect KRAS mutation is largely unknown. Here, we investigated the associations between SIRE, quantitative GIA, and KRAS mutation and its allele-specific subtypes in a multi-ethnic cohort of 3,918 patients from the Boston Lung Cancer Survival cohort and the Chinese OrigiMed cohort with an independent validation cohort of 1,450 patients with NSCLC. This comprehensive analysis included detailed covariates such as age at diagnosis, sex, clinical stage, cancer histology, and smoking status. We report that SIRE is significantly associated with KRAS mutations, modified by sex, with SIRE-Asian patients showing lower rates of KRAS mutation, transversion substitution, and the allele-specific subtype KRASG12C compared to SIRE-White patients after adjusting for potential confounders. Moreover, GIA was found to correlate with KRAS mutations, where patients with a higher proportion of European ancestry had an increased risk of KRAS mutations, especially more transition substitutions and KRASG12D. Notably, among SIRE-White patients, an increase in European ancestry was linked to a higher likelihood of KRAS mutations, whereas an increase in admixed American ancestry was associated with a reduced likelihood, suggesting that quantitative GIA offers additional information beyond SIRE. The association of SIRE, GIA, and their interplay with KRAS driver mutations in NSCLC highlights the importance of incorporating both into population-based cancer research, aiming to refine clinical decision-making processes and mitigate health disparities.

Risk of Lung Cancer in Peripheral Pulmonary Nodules.

PURPOSE: To determine the risk of lung cancer and inter-observer agreement for small pulmonary nodules either touching or near the pleura. METHODS: Nodules were derived from two cohorts: patients from the National Lung Screening Trial with a solid nodule measuring 6-9.5 mm; and patients with incidental pulmonary nodules in our healthcare system with a solid nodule measuring 1-8 mm. Only the dominant nodule was evaluated for each patient. All malignant nodules as well as a random sample of 200 benign nodules from each cohort were included. Two fellowship-trained thoracic radiologists independently reviewed each case to record nodule morphology (compatible with lymph node or not) and nodule location (pleural-based, septal connection to the pleura, or neither). One radiologist measured the distance to the pleura. RESULTS: After exclusion criteria were applied, a total of 434 nodules were included, of which 45 were lung cancers. Considering all pleural-based nodules with lymph node morphology as benign, 0-7% of cancers were misclassified as benign, specificity 33%, and κ = 0.69. Considering subpleural nodules and those with septal connection to the pleura, 7-11% of cancers were misclassified (p = 0.16-0.25 versus pleural-based), specificity 40-52% (p < .0001), and κ = 0.60. Considering nodules with lymph node morphology ≤ 2 mm from the pleura, 2-7% of cancers were misclassified (p = 1 versus pleural-based), specificity 41-36% (p < .0001), and κ = 0.78. CONCLUSION: Considering nodules with lymph node morphology with septal connection, or those ≤ 2 mm from the pleura, as benign does not lead to significant misclassification of lung cancers as benign.

Mixed Reality Navigation in Hip Fusion Conversion: A Novel Utilization of Advanced Technology: A Case Report.

CASE: A 32-year-old woman with a history of hip fusion presented with significant lower back, hip, and knee pain as well as severely limited hip mobility and function. Single-stage fusion takedown and conversion to total hip arthroplasty (THA) was performed using augmented reality navigation. At 1 year, the patient was pain free with improved function. This study is the first to report the technique and outcomes of surgical fusion conversion to THA, using mixed reality navigation. CONCLUSION: Mixed reality navigation in complex conversion THA can be useful for identifying the patient's true acetabulum and for patient-specific acetabular component placement to maximize outcomes.

Revised Diagnosis From Histiocytic Neoplasm to Optic Chiasm Glioblastoma After Genetic Analysis.

ABSTRACT: A 46-year-old man presented with left eye blurring. Automated visual field testing showed an incongruous right hemianopia, with sparing of the lower temporal quadrant in the right eye. MRI revealed foci of gadolinium enhancement in the optic chiasm and optic tracts. Serologic testing (including myelin oligodendrocyte glycoprotein and neuromyelitis optica antibodies) and cerebrospinal fluid analysis were negative. Whole-body PET/CT scan found no malignancy. Biopsy of the optic chiasm revealed a moderately cellular neoplasm composed of atypical, discohesive cells with enlarged nuclei, prominent eosinophilic nucleoli, and abundant vacuolated cytoplasm. Immunohistochemical stains for CD68 and S100 were positive, whereas those for GFAP, OLIG2, SOX10, and multiple others were negative, supporting a diagnosis of histiocytic neoplasm. Five weeks later, results became available from next-generation sequencing targeting the coding regions of hundreds of malignancy-associated genes and select introns. Alterations associated with histiocytic neoplasms (i.e. BRAF and MAP2K1 mutations) were absent. However, there was a nonsense mutation in the PTEN gene, a hotspot mutation in the TERT gene promotor, and focal amplifications of the CDK4 and MDM2 genes. Additionally, there was chromosome 6q loss, 7 gain, and 10q loss. Based on these findings, the diagnosis was revised to glioblastoma, IDH-wildtype, CNS WHO grade 4. The patient began treatment with temozolomide while continuing radiation therapy. This case illustrates how next-generation sequencing can at times provide more accurate diagnostic information than standard tissue histopathology.

Mutation and cell state compatibility is required and targetable in Ph+ acute lymphoblastic leukemia minimal residual disease.

Efforts to cure BCR::ABL1 B cell acute lymphoblastic leukemia (Ph+ ALL) solely through inhibition of ABL1 kinase activity have thus far been insufficient despite the availability of tyrosine kinase inhibitors (TKIs) with broad activity against resistance mutants. The mechanisms that drive persistence within minimal residual disease (MRD) remain poorly understood and therefore untargeted. Utilizing 13 patient-derived xenograft (PDX) models and clinical trial specimens of Ph+ ALL, we examined how genetic and transcriptional features co-evolve to drive progression during prolonged TKI response. Our work reveals a landscape of cooperative mutational and transcriptional escape mechanisms that differ from those causing resistance to first generation TKIs. By analyzing MRD during remission, we show that the same resistance mutation can either increase or decrease cellular fitness depending on transcriptional state. We further demonstrate that directly targeting transcriptional state-associated vulnerabilities at MRD can overcome BCR::ABL1 independence, suggesting a new paradigm for rationally eradicating MRD prior to relapse. Finally, we illustrate how cell mass measurements of leukemia cells can be used to rapidly monitor dominant transcriptional features of Ph+ ALL to help rationally guide therapeutic selection from low-input samples.

A National Analysis of Craniosynostosis Demographic and Surgical Trends Over a 10-Year Period.

The pathogenesis of craniosynostosis, characterized by the premature fusion of calvarial sutures, is multifaceted and often the result of an amalgamation of contributing factors. The current study seeks examine the possible contributors to craniosynostosis development and its surgical trends over time. A multicenter/national retrospective cohort study was conducted of patients who underwent surgical repair of craniosynostosis (n=11,279) between 2012 and 2021 identified in the American College of Surgeons National Surgical Quality Improvement Program Pediatric Data File. Main outcome measures included risk factors and trends relating to surgical repair of craniosynostosis. Nationwide reports of craniosynostosis in the NSQIP-P database have increased between 2012 and 2021 by 195%. The prevalence of craniosynostosis per overall cases has remained between 1.0% and 1.3%. There were predominantly more White male patients in the craniosynostosis cohort (P<0.001). Craniosynostosis patients had significantly greater birth weights, gestational ages, and were less likely to be premature (P<0.05). Linear regression demonstrated that operative time, anesthesia time, and length of stay significantly decreased over the study period (P<0.001). This national data analysis highlights trends in craniosynostosis repair indicating potential improvements in safety and patient outcomes over time. While these findings offer insights for health care professionals, caution is warranted in extrapolating beyond the data's scope. Future research should focus on diverse patient populations, compare outcomes across institutions, and employ prospective study designs to enhance the evidence base for craniosynostosis management. These efforts will help refine diagnostic and treatment strategies, potentially leading to better outcomes for patients.

Body Composition in Advanced Non-Small Cell Lung Cancer Treated With Immunotherapy.

Importance: The association between body composition (BC) and cancer outcomes is complex and incompletely understood. Previous research in non-small-cell lung cancer (NSCLC) has been limited to small, single-institution studies and yielded promising, albeit heterogeneous, results. Objectives: To evaluate the association of BC with oncologic outcomes in patients receiving immunotherapy for advanced or metastatic NSCLC. Design, Setting, and Participants: This comprehensive multicohort analysis included clinical data from cohorts receiving treatment at the Dana-Farber Brigham Cancer Center (DFBCC) who received immunotherapy given alone or in combination with chemotherapy and prospectively collected data from the phase 1/2 Study 1108 and the chemotherapy arm of the phase 3 MYSTIC trial. Baseline and follow-up computed tomography (CT) scans were collected and analyzed using deep neural networks for automatic L3 slice selection and body compartment segmentation (skeletal muscle [SM], subcutaneous adipose tissue [SAT], and visceral adipose tissue). Outcomes were compared based on baseline BC measures or their change at the first follow-up scan. The data were analyzed between July 2022 and April 2023. Main Outcomes and Measures: Hazard ratios (HRs) for the association of BC measurements with overall survival (OS) and progression-free survival (PFS). Results: A total of 1791 patients (878 women [49%]) with NSCLC were analyzed, of whom 487 (27.2%) received chemoimmunotherapy at DFBCC (DFBCC-CIO), 825 (46.1%) received ICI monotherapy at DFBCC (DFBCC-IO), 222 (12.4%) were treated with durvalumab monotherapy on Study 1108, and 257 (14.3%) were treated with chemotherapy on MYSTIC; median (IQR) ages were 65 (58-74), 66 (57-71), 65 (26-87), and 63 (30-84) years, respectively. A loss in SM mass, as indicated by a change in the L3 SM area, was associated with worse oncologic outcome across patient groups (HR, 0.59 [95% CI, 0.43-0.81] and 0.61 [95% CI, 0.47-0.79] for OS and PFS, respectively, in DFBCC-CIO; HR, 0.74 [95% CI, 0.60-0.91] for OS in DFBCC-IO; HR, 0.46 [95% CI, 0.33-0.64] and 0.47 [95% CI, 0.34-0.64] for OS and PFS, respectively, in Study 1108; HR, 0.76 [95% CI, 0.61-0.96] for PFS in the MYSTIC trial). This association was most prominent among male patients, with a nonsignificant association among female patients in the MYSTIC trial and DFBCC-CIO cohorts on Kaplan-Meier analysis. An increase of more than 5% in SAT density, as quantified by the average CT attenuation in Hounsfield units of the SAT compartment, was associated with poorer OS in 3 patient cohorts (HR, 0.61 [95% CI, 0.43-0.86] for DFBCC-CIO; HR, 0.62 [95% CI, 0.49-0.79] for DFBCC-IO; and HR, 0.56 [95% CI, 0.40-0.77] for Study 1108). The change in SAT density was also associated with PFS for DFBCC-CIO (HR, 0.73; 95% CI, 0.54-0.97). This was primarily observed in female patients on Kaplan-Meier analysis. Conclusions and Relevance: The results of this multicohort study suggest that loss in SM mass during systemic therapy for NSCLC is a marker of poor outcomes, especially in male patients. SAT density changes are also associated with prognosis, particularly in female patients. Automated CT-derived BC measurements should be considered in determining NSCLC prognosis.