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ImportanceThe optimal radiotherapy technique for unresectable locally advanced non–small cell lung cancer (NSCLC) is controversial, so evaluating long-term prospective outcomes of intensity-modulated radiotherapy (IMRT) is important.ObjectiveTo compare long-term prospective outcomes of patients receiving IMRT and 3-dimensional conformal radiotherapy (3D-CRT) with concurrent carboplatin/paclitaxel for locally advanced NSCLC.Design, Setting, and ParticipantsA secondary analysis of a prospective phase 3 randomized clinical trial NRG Oncology–RTOG 0617 assessed 483 patients receiving chemoradiotherapy (3D-CRT vs IMRT) for locally advanced NSCLC based on stratification.Main Outcomes and MeasuresLong-term outcomes were analyzed, including overall survival (OS), progression-free survival (PFS), time to local failure, development of second cancers, and severe grade 3 or higher adverse events (AEs) per Common Terminology Criteria for Adverse Events, version 3. The percentage of an organ volume (V) receiving a specified amount of radiation in units of Gy is reported as V(radiation dose).ResultsOf 483 patients (median [IQR] age, 64 [57-70] years; 194 [40.2%] female), 228 (47.2%) received IMRT, and 255 (52.8%) received 3D-CRT (median [IQR] follow-up, 5.2 [4.8-6.0] years). IMRT was associated with a 2-fold reduction in grade 3 or higher pneumonitis AEs compared with 3D-CRT (8 [3.5%] vs 21 [8.2%]; P = .03). On univariate analysis, heart V20, V40, and V60 were associated with worse OS (hazard ratios, 1.06 [95% CI, 1.04-1.09]; 1.09 [95% CI, 1.05-1.13]; 1.16 [95% CI, 1.09-1.24], respectively; all P < .001). IMRT significantly reduced heart V40 compared to 3D-CRT (16.5% vs 20.5%; P < .001). Heart V40 (<20%) had better OS than V40 (≥20%) (median [IQR], 2.5 [2.1-3.1] years vs 1.7 [1.5-2.0] years; P < .001). On multivariable analysis, heart V40 (≥20%), was associated with worse OS (hazard ratio, 1.34 [95% CI, 1.06-1.70]; P = .01), whereas lung V5 and age had no association with OS. Patients receiving IMRT and 3D-CRT had similar rates of developing secondary cancers (15 [6.6%] vs 14 [5.5%]) with long-term follow-up.Conclusions and RelevanceThese findings support the standard use of IMRT for locally advanced NSCLC. IMRT should aim to minimize lung V20 and heart V20 to V60, rather than constraining low-dose radiation bath. Lung V5 and age were not associated with survival and should not be considered a contraindication for chemoradiotherapy.Trial RegistrationClinicalTrials.gov Identifier: NCT00533949

Abstract Background Tumor microenvironment (TME) characteristics including tumor stroma ratio (TSR), tumor budding (TB), and tumor-infiltrating lymphocytes (TILs) were examined in resected gastric cancer. These TME features have been shown to indicate metastatic potential in colon cancer, and intestinal-type gastric cancer (IGC) has pathological similarities with that malignancy. Methods TSR, TB, and TILs were quantified in routine histological sections from 493 patients with IGC who underwent radical resection at 2 university hospitals in China from 2010 to 2016. TME variables were dichotomized as follows: TSR (50%), TILs (median), TB per international guidelines (4 buds/0.785mm2), and platelet-lymphocyte ratio (PLR) per survival ROC. Association of TME features with patient clinicopathological characteristics, time-to-recurrence (TTR), and cancer-specific-survival (CSS) were examined using univariate and multivariate analysis, including a relative contribution analysis by Cox regression. Results Patients whose tumors showed high TSR or high TB or low TILs were each significantly associated with increased T and N stage, higher histological grade, and poorer TTR and CSS at 5 years. Only TSR and N stage were independently associated with TTR and CSS after adjustment for covariates. PLR was only independently associated with TTR after adjustment for covariates. Among the variables examined, only TSR was significantly associated with both TTR (HR 1.72, 95% CI, 1.14-2.60, P = .01) and CSS (HR 1.62, 95% CI, 1.05-2.51, P = .03) multivariately. Relative contribution to TTR revealed that the top 3 contributors were N stage (45.1%), TSR (22.5%), and PLR (12.9%), while the top 3 contributors to CSS were N stage (59.9%), TSR (14.7%), and PLR (10.9%). Conclusions Among the examined TME features, TSR was the most robust for prognostication and was significantly associated with both TTR and CSS. Furthermore, the relative contribution of TSR to patient TTR and CSS was second only to nodal status.

Abstract BACKGROUND Primary intracranial germ cell tumors (GCTs) are rare heterogeneous tumors; germinoma accounts for two-thirds of cases. While neoadjuvant chemotherapy followed by response-based reduced radiotherapy dose and field is the established approach for managing localized CNS germinomas, controversy persists regarding the treatment of primary metastatic disease. Additionally, limited research exists on the utilization of neoadjuvant chemotherapy in primary metastatic germinoma. METHODS A retrospective multi-institutional analysis was conducted to assess overall survival (OS) and event-free survival (EFS) among patients diagnosed with metastatic germinoma who were treated with various modalities. RESULTS We identified 88 patients, including 63 males and 25 females. The median age at presentation was 13.5 years. All patients, who had undergone both brain and spine MRIs, had their diagnoses confirmed through a biopsy, positive CSF cytology, and/or positive CSF tumor markers at presentation. Primary Tumor location was pineal (n=37), suprasellar (n=27), bifocal (n=14) and others (n=9). Eight patients underwent subtotal resection. Craniospinal irradiation (CSI; 21-24 Gy) was administered to 71 patients (81%), while eight patients (9%) received whole ventricular irradiation (WVI; 23.4-30 Gy). Whole brain radiation was given to four patients (5%; 24 Gy), and two patients (2%) had unknown fields. Boosts to primary and/or metastatic sites were administered in all but seven patients. Notably, thirty patients (34%) received CSI without neoadjuvant chemotherapy. At the end of therapy, 69 patients had complete response, 10 partial response and the response was unknown in six. Three patients did not receive irradiation, all died of disease progression. The median follow-up was 64 months (range 6-159 months), yielding an OS of 96.6%. Ongoing multi-institutional data collection and analysis will be presented at the meeting. CONCLUSION Our study is one of the largest studies to date in metastatic germinoma and may provide insight into the role of neoadjuvant chemotherapy with lower CSI doses.

Objectives Primary human papillomavirus (HPV) testing by clinician-collection is endorsed by U.S. guideline organizations for cervical cancer screening, but uptake remains low and insights into patients’ understanding are limited. This study aims to primarily address patient awareness of primary HPV screening by clinician-collection and acceptance of primary HPV screening by clinician- and self-collection, and secondarily assess factors associated with awareness and acceptance. Setting Primary care practices affiliated with an academic medical center. Methods A cross-sectional survey study of screening-eligible women aged 30–65 years was conducted to assess awareness and acceptability of primary HPV screening. We analyzed bivariate associations of respondent characteristics with awareness of primary HPV screening by clinician-collection, willingness to have clinician- or self-collected primary HPV testing, and reasons for self-collection preference. Results Respondents (n = 351; response rate = 23.4%) reported cervical cancer screening adherence of 82.8% but awareness of clinician-collected primary HPV as an option was low (18.9%) and only associated with HPV testing with recent screening ( p = 0.003). After reviewing a description of primary HPV screening, willingness for clinician-collected (81.8%) or home self-collected (76.1%) HPV testing was high, if recommended by a provider. Acceptability of clinician-collected HPV testing was associated with higher income ( p = 0.009) and for self-collection was associated with higher income ( p = 0.002) and higher education ( p = 0.02). Higher education was associated with reporting self-collection as easier than clinic-collection ( p = 0.02). Women expected self-collection to be more convenient (94%), less embarrassing (85%), easier (85%), and less painful (81%) than clinician-collection. Conclusions Educational interventions are needed to address low awareness about the current clinician-collected primary HPV screening option and to prepare for anticipated federal licensure of self-collection kits. Informing women about self-collection allows them to recognize benefits which could address screening barriers.

Chimeric antigen receptor (CAR) T cell immunotherapy for the treatment of neurological autoimmune diseases is promising, but CAR T cell kinetics and immune alterations after treatment are poorly understood. Here, we performed single-cell multi-omics sequencing of paired cerebrospinal fluid (CSF) and blood samples from patients with neuromyelitis optica spectrum disorder (NMOSD) treated with anti–B cell maturation antigen (BCMA) CAR T cells. Proliferating cytotoxic-like CD8 + CAR T cell clones were identified as the main effectors in autoimmunity. Anti-BCMA CAR T cells with enhanced features of chemotaxis efficiently crossed the blood-CSF barrier, eliminated plasmablasts and plasma cells in the CSF, and suppressed neuroinflammation. The CD44-expressing early memory phenotype in infusion products was potentially associated with CAR T cell persistence in autoimmunity. Moreover, CAR T cells from patients with NMOSD displayed distinctive features of suppressed cytotoxicity compared with those from hematological malignancies. Thus, we provide mechanistic insights into CAR T cell function in patients with neurological autoimmune disease.

Study Design: Retrospective observational study of consecutive patients Objective: The purpose of the study was to evaluate VBQ as a predictor of interbody subsidence and to determine threshold values that portend increased risk of subsidence. Summary of Background Data: Many risk factors have been reported for the subsidence of interbody cages in anterior cervical discectomy and fusion (ACDF). MRI Vertebral Bone Quality (VQB) is a relatively new radiographic parameter that can be easily obtained from preoperative MRI and has been shown to correlate with measurements of bone density such as DXA and CT Hounsfield Units. Methods: All patients who underwent 1- to 3-level ACDF using titanium interbodies with anterior plating between the years 2018 and 2020 at our tertiary referral center were included. Subsidence measurements were performed by 2 independent reviewers on CT scans obtained 6 months postoperatively. VBQ was measured on pre-operative sagittal T1 MRI by 2 independent reviewers, and values were averaged. Results: Eight-five fusion levels in 44 patients were included in the study. There were 32 levels (38%) with moderate subsidence and 12 levels with severe subsidence (14%). The average VBQ score in those patients with severe subsidence was significantly higher than those without subsidence (3.80 vs. 2.40, P<0.01). A threshold value of 3.2 was determined to be optimal for predicting subsidence (AUC=0.99) and had a sensitivity of 100% and a specificity of 94.1% in predicting subsidence. Conclusions: VBQ strongly correlates with the subsidence of interbody grafts after ACDF. A threshold VBQ score value of 3.2 has excellent sensitivity and specificity for predicting subsidence. Spine surgeons can use VBQ as a readily available screening tool to identify patients at higher risk for subsidence. Level of Evidence: Level—IV

AbstractBackgroundMany patients with quiescent inflammatory bowel disease (IBD) suffer from irritable bowel syndrome (IBS)‐like symptoms. Although these symptoms cause significant reductions in quality of life, evidence‐based treatments are lacking as risk factors and pathophysiology of these symptoms are not clearly defined. We aimed to identify risk factors for development of IBS‐like symptoms in IBD patients with quiescent disease.MethodsWe performed a single‐center retrospective cohort study of adults with IBD from 2015 to 2021. Quiescent IBD was defined by a fecal calprotectin level <250 μg/g of stool or endoscopic evidence of quiescent disease. Cox regression was performed to identify variables that were independently associated with the incident development of IBS‐like symptoms in IBD patients.Key ResultsA total of 368 IBD patients were included for analysis, including 278 patients with UC and 88 with Crohn's disease. 15.5% of quiescent IBD patients developed IBS symptoms, with an incidence rate of (95% CI 48.0–82.0) 63.3 per 1000 person‐years. In the multivariate model, mood disorders (including anxiety and depression) and Crohn's disease were associated with increased risk for developing IBS symptoms. Male sex and higher iron levels conferred lower risk for developing IBS symptoms. Results from the multivariable model were similar in sensitivity analysis with quiescent IBD defined by fecal calprotectin level <150 mcg/g.Conclusions & InferencesMood disorder and Crohn's disease were positively associated with IBS‐like symptoms in quiescent IBD, whereas male sex and iron levels were protective. Our results were robust to different fecal calprotectin levels, arguing against inflammation as a mechanism for IBS‐like symptoms. This data suggests noninflammatory mechanisms may be important in the pathogenesis of IBS‐like symptoms in quiescent IBD. Future work may address whether modifying these risk factors may alter disease course.

Implantable cardioverter-defibrillator (ICD) therapy in children and congenital heart disease (CHD) patients is hampered by poor long-term lead survival. Lead extraction is technically difficult and carries substantial morbidity. Manufacturers developed distinct strategies for this issue: thinner lead bodies or a Gore ePTFE coil coating. Both design changes were thought to improve ease of lead removal, but have not been directly compared in children or adults. The purpose of this study was to assess thin and ePTFE-coated ICD lead survival in pediatric and CHD pts. Methods: The Pediatric Lead Extractability and Survival Evaluation (PLEASE) Study began as a Phase IV multicenter open-label prospective study [ NCT00335036 ], facilitated by the Pediatric & Congenital EP Society. Initially designed as a randomized study, it changed to a parallel assignment registry when 1 lead had an advisory due to high incidence of failure, prompting concern about continued clinical equipoise. Pediatric and CHD pts who underwent ICD lead implant from 2005-2010 were eligible. The end date was NCDR ICD Registry v2.0 release (includes pediatric & lead data). 23 centers participated; each site obtained IRB approval. De-identified data was sent to the PI center for verification and statistical analyses. Results: A total of 982 ICD pts (357 VVI, 558 DDD, 67 CRT-D) entered the PLEASE study, incl. 423 pts (43%) with CHD. Mean age at implant = 18.3 ± 9.9 yrs. Thin (< 7Fr) ICD leads accounted for 51%, 23% were ePTFE-coated, 26% neither thin nor coated. There were 113 ICD lead failures (11.5%) at a mean lead-age of 2.2 ± 1.7 yrs, causing shocks in 55 pts. Failure occurred in 21% of thin leads vs 3.5% of ePTFE leads (p<0.01). Extraction was performed on 142 (14.5%) leads overall; 21% of thin leads (incl. extraction of 29 functioning leads due to recall) vs. 4.4% of ePTFE leads (p<0.01). There were 7 major extraction complications (4.9%), but no procedural mortality. Among thin leads, 90/270 (33.3%) of recalled leads failed vs 15/229 (6.6%) non-recalled thin leads. Conclusions: This Phase IV study demonstrates that ICD leads in children and CHD pts have suboptimal performance overall. Thinner leads were much more likely to fail and/or be extracted compared with ePTFE leads, chiefly driven by one lead type.

AbstractThis study aimed to compare the clinically established autologous extrasynovial tendon graft to a newly developed tissue‐engineered allograft (Eng‐allograft) in terms of functional outcomes following flexor tendon reconstruction in a canine model. The second and fifth flexor digitorum profundus (FDP) tendons from 16 dogs were transected and repaired in Zone II. After 6 weeks of cage activity, the repaired tendons were intentionally ruptured, creating a clinically relevant model for reconstruction. The re‐ruptured FDP tendons were then reconstructed using either the clinically standard autologous extrasynovial tendon graft or the Eng‐allograft, which had been revitalized with autologous bone marrow‐derived mesenchymal stem cells (BMSCs) and synovialized using carbodiimide derivatized synovial fluid (cd‐SYN). Following 12 weeks of postoperative rehabilitation, the functional outcomes of the surgical digits were evaluated. The Eng‐allograft group exhibited improved digital function, including lower digit work of flexion and reduced adhesion status, while maintaining similar tendon gliding resistance compared to the autograft group. However, the failure load of both the distal and proximal host/graft conjunctions in the Eng‐allograft group was significantly lower than that of the autograft group with higher graft rupture at the host−graft junction. In conclusion, the decellularized allogenic intrasynovial tendon, when revitalized BMSCs and synovialized with cd‐SYN, demonstrates positive effects on digital function improvement and adhesion reduction. However, the healing at both proximal and distal graft/host junctions is far lower than the autograft. Further research is needed to enhance the healing capacity of allograft conjunctions, aiming to achieve a comparable level of healing seen with autografts.

PURPOSE The multicenter, open-label, randomized phase 2 NCI-9944 study ( NCT02595892 ) demonstrated that addition of ATR inhibitor (ATRi) berzosertib to gemcitabine increased progression-free survival (PFS) compared to gemcitabine alone (hazard ratio [HR]=0.57, one-sided log-rank P = .044, which met the one-sided significance level of 0.1 used for sample size calculation). METHODS We report here the final overall survival (OS) analysis and biomarker correlations (ATM expression by immunohistochemistry, mutational signature 3 and a genomic biomarker of replication stress) along with post-hoc exploratory analyses to adjust for crossover from gemcitabine to gemcitabine/berzosertib. RESULTS At the data cutoff of January 27, 2023 (>30 months of additional follow-up from the primary analysis), median OS was 59.4 weeks with gemcitabine/berzosertib versus 43.0 weeks with gemcitabine alone (HR 0.79, 90% CI 0.52 to 1.2, one-sided log-rank P = .18). An OS benefit with addition of berzosertib to gemcitabine was suggested in patients stratified into the platinum-free interval ≤3 months (N = 26) subgroup (HR, 0.48, 90% CI 0.22 to 1.01, one-sided log-rank P =.04) and in patients with ATM-negative/low (N = 24) tumors (HR, 0.50, 90% CI 0.23 to 1.08, one-sided log-rank P = .06). CONCLUSION The results of this follow-up analysis continue to support the promise of combined gemcitabine/ATRi therapy in platinum resistant ovarian cancer, an active area of investigation with several ongoing clinical trials.