Citations

Background Challenges in predicting which neoantigens mediate tumor rejection limit the efficacy of neoantigen vaccines to treat cancers, especially for cancers with a high mutational burden like cutaneous squamous cell carcinoma (cSCC). Only a small portion of neoantigens prioritized by current methods elicit effective T cell responses, demonstrating the critical need for improved criteria for the prediction of tumor-rejecting neoantigens. Methods Publicly available human cSCC datasets were used to assess the frequency of shared mutations between patients. A transplantable ultraviolet light-induced mouse model of cSCC was generated. The mutational signature and driver mutations in the mouse model were compared with human tumors. Neoantigens were prioritized in the mouse model, and tumor-rejecting neoantigens were identified through (enzyme-linked immunosorbent spot (ELISpot) and in vivo prophylactic vaccination. Binding of the neoantigens and corresponding wild-type peptides to major histocompatibility complex (MHC) class I was determined. Structural modeling of peptide:MHC complexes was performed to assess for changes in structural characteristics of the neoantigens relative to the wild-type peptides. Results A minority of human cSCC tumors shared neoantigens. The mouse cSCC model recapitulated the mutational signature and driver mutations found in human disease and was constrained by CD8 T cells. Two MHC class I neoantigens were identified in the mouse model that constrained cSCC growth. One tumor-rejecting neoantigen exhibited improved MHC binding, and the other had increased solvent accessibility of the mutated residue, compared with wild-type. Across known neoantigens that do not impact MHC binding, increased exposure of the mutated residue distinguished tumor-rejecting from non-immunogenic neoantigens. Conclusions Given the paucity of shared mutations, this work supports the need for personalized neoantigen vaccines in cSCC. To facilitate further discovery, we provide a clinically relevant mouse cSCC model with two defined neoantigens that mediate tumor rejection. Structural changes in the exposure of features that promote T cell receptor recognition defined tumor-rejecting neoantigens. Incorporation of structural modeling to predict changes in T cell receptor accessibility is anticipated to improve the selection of neoantigens for inclusion in personalized cancer vaccines.

Objective: To evaluate whether effects of oral hormone therapy (HT) on risks of venous and arterial vascular events differ by baseline statin or aspirin use. Methods: We performed time-to-event analysis using data from the Women’s Health Initiative menopausal HT randomized trials to assess risk of thrombotic events. Women were randomized to oral conjugated equine estrogens (CEEs) alone or placebo among women with prior hysterectomy (n = 10,739), and CEE with medroxyprogesterone acetate (MPA) or placebo among women with an intact uterus (n = 16,608), stratified by baseline personal use of statins and aspirin. We evaluated risk of prespecified, adjudicated thrombotic events, including coronary heart disease, stroke, venous thromboembolism, and/or composite major adverse cardiovascular events, at 2 and 5 years. Results: Baseline statin use (n = 827 in CEE-alone trial; n = 1,115 in CEE+MPA trial) or aspirin use (n = 2,212; n = 3,431) was limited. At 5-year follow-up, coronary heart disease risk for CEE-alone versus placebo was hazard ratio (HR) = 0.81 (95% CI: 0.44-1.49) in statin users, similar to nonusers, HR = 1.07 (95% CI: 0.82-1.40). For CEE+MPA, there was also no difference by statin use, HR = 1.02 (95% CI: 0.55-1.89) and HR = 1.47 (95% CI: 1.13-1.90), respectively. Neither statin nor aspirin exposure significantly modified effects of HT on any arterial or venous thrombotic outcome at 2 or 5 years. Conclusions: In this secondary randomized clinical trial analysis, neither statins nor aspirin significantly modified effects of oral HT on key arterial or venous thrombotic outcomes at 2 or 5 years. Results, however, may be underpowered given low baseline exposure prevalence for both statins and aspirin.

Background: Chronic hamstring tears can result in challenging surgical repairs. Allografts may be used to augment the repair; however, there is limited clinical evidence supporting their use. Purposes: To (1) evaluate clinical outcomes of patients who underwent proximal hamstring repair with allograft augmentation or interposition and (2) compare them to matched controls who underwent primary hamstring repair. Study Design: Cohort study; Level of evidence, 3. Methods: A total of 117 patients who underwent proximal hamstring repair were included, consisting of 19 allograft augmentations, 20 allograft interpositions, and 78 primary repairs. Allograft cohorts were propensity-matched with those who underwent primary repair in a 1 to 2 ratio. Clinical outcomes were obtained at the final follow-up. Data were extracted using continuous variables, with normality reported as mean values ± standard deviation, and non-normality reported as median values with interquartile ranges (IQR). Results: The median follow-up of the augmentation cohort was 1.9 [IQR, 0.8-3.9] years, while it was 3.2 [IQR, 1.6-5.1] years ( P = .182) for the primary repair cohort. The mean follow-up for the interposition cohort was 3.5 ± 2.4 years, while it was 4.2 ± 2.5 years for the primary repair cohort ( P = .227). Forty-two percent of the augmentation cohort had undergone previous surgery, compared with 5% of the interposition cohort. The time from injury to surgery for the augmentation and primary repair cohorts was 6.4 and 1.3 months, respectively ( P < .001). For the interposition and primary repair cohorts, the durations were 17.8 and 1 months, respectively ( P < .001). Clinical outcomes, including the Tegner Activity Scale (3 vs 3), pain with activity (47.4% vs 23.7%), and muscle spasms (36.8% vs 26.3%), did not show significant differences between the augmentation and primary repair cohorts. The augmentation cohort had a significantly worse Lower Extremity Functional Scale (LEFS) score (64 vs 75; P < .001) and were more likely to experience pain with sitting (52.6% vs 21.1%; P = .034) than the primary repair cohort. There was no significant difference in clinical outcomes between the interposition and primary repair cohorts (LEFS: 69 vs 75.5, Tegner Activity Scale: 4 vs 4; pain with sitting: 26.3% vs 27.5%; pain with activity: 42.1% vs 30%; muscle spasms: 26.3% vs 30%). Revision rates were similar between cohorts ( P ≥ .255). Conclusion: Proximal hamstring repair for chronic tears with allograft augmentation or interposition is a reproducible procedure that results in satisfactory, yet poorer clinical outcomes compared with patients who underwent primary hamstring repair. These procedures should be considered in symptomatic patients with chronic tears that are not amenable to primary repair.

BACKGROUND: Pelvic exenteration is the treatment of choice for selected patients with locally advanced primary and recurrent rectal cancer. Involvement of major pelvic neurovascular structures and bone was historically considered a contraindication due to unacceptably high rates of morbidity and low R0 resection rates. OBJECTIVE: To compare the outcomes of these “high-complexity” exenterative resections to those of “conventional” pelvic exenteration. DESIGN: International multicenter retrospective cohort study. SETTINGS: Sixteen specialized exenteration centers. PATIENTS: Those who underwent total pelvic exenteration for locally advanced primary and recurrent rectal cancer between 2018 and 2023 at participating centers. MAIN OUTCOME MEASURES: Perioperative resource utilization, morbidity, mortality, and R0 resection rates were reported. RESULTS: Seven hundred sixty-three patients underwent total pelvic exenteration, of whom 478 (63%) and 285 (37%) required conventional and high-complexity procedures, respectively. High-complexity pelvic exenteration was associated with longer operating time (600 vs 480 minutes, p < 0.001 for locally advanced primary rectal cancer, 623 vs 480 minutes, p < 0.001 for locally recurrent rectal cancer), intensive care stay (2 vs 1 day, p < 0.001 and 3 vs 1 day, p < 0.001), hospital stay (19 vs 15 days, p = 0.008 and 23 vs 15 days, p < 0.001), and higher blood loss (2000 vs 1236 mL, p < 0.001 and 3000 vs 1600 mL, p < 0.001). Morbidity and mortality outcomes and R0 resection rates were similar between the groups. LIMITATIONS: Generalizability of findings outside of expert units. CONCLUSIONS: High-complexity pelvic exenteration for the treatment of rectal cancer is associated with similar morbidity, mortality, and R0 resection rates, but it has a significantly higher operative time, blood loss, and hospital resource utilization compared to conventional pelvic exenteration. In high-volume, specialized centers, these techniques are considered the standard of care for appropriately selected patients with tumors that involve major pelvic bone or neurovascular structures. See Video Abstract . EXENTERACIÓN PÉLVICA TOTAL CONVENCIONAL FRENTE A EXENTERACIÓN PÉLVICA TOTAL DE ALTA COMPLEJIDAD PARA EL CÁNCER RECTAL LOCALMENTE AVANZADO Y LOCALMENTE RECURRENTE: UN ESTUDIO MULTICÉNTRICO INTERNACIONAL ANTECEDENTES: La exenteración pélvica es el tratamiento de elección para determinados pacientes con cáncer rectal primario y recurrente localmente avanzado. La afectación de las principales estructuras neurovasculares y óseas pélvicas se consideraba históricamente una contraindicación debido a las tasas inaceptablemente altas de morbilidad y a las bajas tasas de resección R0. OBJETIVO: Comparar los resultados de estas resecciones exenteración «de alta complejidad» con los de la exenteración pélvica «convencional». DISEÑO: Estudio de cohorte retrospectivo multicéntrico internacional. ENTORNOS: Dieciséis centros especializados en exenteración. PACIENTES: Aquellos que se sometieron a una exenteración pélvica total por cáncer rectal primario y recurrente localmente avanzado entre 2018 y 2023 en los centros participantes. PRINCIPALES MEDIDAS DE RESULTADOS: Se informaron la utilización de recursos perioperatorios, la morbilidad, la mortalidad y las tasas de resección R0. RESULTADOS: 763 pacientes se sometieron a una exenteración pélvica total, de los cuales 478 (63 %) y 285 pacientes (37 %) requirieron procedimientos convencionales y de alta complejidad, respectivamente. La exenteración pélvica de alta complejidad se asoció con un tiempo quirúrgico más prolongado (600 frente a 480 minutos, p < 0,001 para el cáncer rectal primario localmente avanzado, 623 frente a 480 minutos, p < 0,001 para el cáncer rectal localmente recurrente), estancia en cuidados intensivos (2 frente a 1 día, p < 0,001 y 3 frente a 1 día, p < 0,001), estancia hospitalaria (19 frente a 15 días, p = 0,008 y 23 frente a 15 días, p < 0,001) y mayor pérdida de sangre (2000 frente a 1236 ml, p < 0,001 y 3000 frente a 1600 ml, p < 0,001). Los resultados de morbilidad y mortalidad, así como las tasas de resección R0, fueron similares entre los grupos. LIMITACIONES: Generalización de los resultados fuera de las unidades especializadas CONCLUSIONES: La exenteración pélvica de alta complejidad para el tratamiento del cáncer de recto se asocia con tasas similares de morbilidad, mortalidad y resección R0, pero con un tiempo quirúrgico, una pérdida de sangre y una utilización de recursos hospitalarios significativamente mayores en comparación con la exenteración pélvica convencional. En centros especializados con un gran volumen de casos, estas técnicas se consideran el tratamiento estándar para pacientes adecuadamente seleccionados con tumores que afectan a los huesos pélvicos principales o a las estructuras neurovasculares. ( AI-generated translation )

Background: Femoroacetabular impingement (FAI) is a common cause of hip pain in female athletes. There are limited data on midterm outcomes for female athletes undergoing hip arthroscopic surgery. Purpose: To evaluate return-to-sport rates and clinical outcomes in female athletes with FAI after primary hip arthroscopic surgery with labral repair and femoral osteochondroplasty. Study Design: Case series; Level of evidence, 4. Methods: A retrospective analysis of a single institution’s database was performed to identify female athletes who underwent primary hip arthroscopic surgery with labral repair and femoral osteochondroplasty from July 2011 to October 2019 with a minimum 5-year follow-up. Preoperative radiographs were evaluated for the lateral center-edge angle, Tonnis angle, Tonnis grade, and alpha angle. Patient-reported outcome measure (PROM) scores, including those for the modified Harris Hip Score, Hip Outcome Score, Tegner Activity Scale, and visual analog scale for pain, as well as patient satisfaction with surgery were analyzed postoperatively. Results: A total of 63 hips (27 left, 36 right) in 56 female patients (mean age, 21.6 ± 8.0 years; mean body mass index, 24.7 ± 4.8 kg/m 2 ) were included and followed for a mean of 8.4 ± 2.1 years (range, 5.0-13.2 years). Preoperatively, patients participated in basketball (n = 18), dance (n = 21), hockey (n = 8), and soccer (n = 12). Of the 56 patients, 41 attempted to return to sport. There were 28 (68%) female athletes who successfully returned to their preoperative sport. Of the total cohort, 21 (38%) patients cited non–hip-related factors for discontinuing their sport. All postoperative PROM scores improved significantly compared with preoperatively ( P ≤ .002) for patients with available preoperative data. Those who returned to sport had significantly improved Hip Outcome Score values compared with those who did not return to sport ( P ≤ .010). Conclusion: Female athletes who underwent primary hip arthroscopic surgery for FAI had significant improvements in PROM scores and moderate return-to-sport rates at a minimum 5-year follow-up. Most athletes discontinued sports because of non–hip-related factors, although hip-related issues were also cited. Our analysis highlights the need for thorough perioperative counseling and establishing appropriate patient expectations for female athletes before hip arthroscopic surgery.

Abstract Rationale Critically ill lung cancer patients are a growing, high-risk population. However, prognostic tools to guide intensive care unit (ICU) decision-making are limited. Objectives To identify oncologic and critical illness factors associated with 90-day mortality following ICU admission in patients with lung cancer. Methods We conducted a retrospective cohort study of lung cancer patients admitted to the ICU across Mayo Clinic Health System between 2018 and 2024. The primary outcome was 90-day mortality. Two complementary Cox proportional hazards models were developed: a focused model including cancer-specific variables (stage, time since diagnosis, time since last systemic therapy, prior thoracotomy, Eastern Cooperative Oncology Group [ECOG] performance status prior to admission, body mass index, cause of critical illness, code status at admission) and a full model that added broader clinical factors (age and Sequential Organ Failure Assessment [SOFA] score). We also evaluated discharge disposition and transitions in code status. Results Among 528 patients, 90-day mortality was 58.7%. In the focused model (C-index 0.67), independent predictors of mortality included late-stage disease, cancer-specific reason for ICU admission, limitations in resuscitation orders, and ECOG &gt;1. In the full model (C-index 0.95), only age and SOFA score remained significant. Among early-stage patients, recent targeted or combination therapy was associated with higher mortality, though this association may reflect underlying disease characteristics or treatment selection rather than direct treatment effects. Patients who changed code status during admission had high mortality (83%) and a low rate of discharge home (11%). Conclusion Lung cancer patients admitted to ICU experience high short-term mortality, with outcomes shaped by both oncologic status and the severity of acute illness. A dual-model approach suggests a risk hierarchy: Cancer-specific factors inform baseline mortality risk with an ICU admission, but age and physiologic derangement are the dominant drivers of survival once critical illness develops. These findings support dynamic, multidisciplinary prognostication and underscore the need to integrate oncology and critical care expertise in ICU decision-making.

Abstract INTRODUCTION Increased white matter hyperintensity (WMH) volume is a common but non‐specific finding in AD. This study investigates the effect of baseline WMH volume and APO E ε4 on magnetic resonance imaging (MRI)‐visible hemorrhagic lesion emergence. METHODS We included A4 participants with 0/1 hemorrhagic lesion at baseline and >1 post‐baseline MRI. We examined age, sex, amyloid, WMH, APOE ε4, and cardiovascular risk as predictors of whether people would accrue ≥2 hemorrhagic lesions by their last MRI. RESULTS Among 1097 individuals with 0/1 baseline lesion, 120 had at least two hemorrhagic lesions on their last MRI. Elevated baseline WMH (odds ratio [OR] = 2.3, p = 0.002) and APOE ɛ4/ɛ4 (OR = 4.8, p < 0.001) independently predicted membership to this group. Both hetero‐ and homozygous APOE ɛ4 carriers with low WMH volume had a low risk of accumulating hemorrhagic lesions. DISCUSSION These results support the independent consideration of WMH and APOE ɛ4 in the natural history of hemorrhagic lesion accumulation and suggest that individuals with low WMH volume have a low short‐term risk, irrespective of APOE genotype. Trial Registration : NCT02008357 Highlights Elevated baseline white matter lesion volume is related to the risk of ARIA‐H emergence. The effects of white matter lesion volume and APOE ɛ4 on ARIA‐H are independent. APOE ɛ4 carriers with low white matter lesion volume had a low risk of ARIA‐H emergence.

Background: Arthrofibrosis is seen in 1.7% to 38% of patients after anterior cruciate ligament reconstruction (ACLR) and has been associated with worse postoperative patient-reported outcomes. There are limited data regarding the optimal time to intervene in cases of arthrofibrosis after ACLR. Purpose: To assess if timing of arthrofibrosis treatment after ACLR affects final knee range of motion (ROM) and to help establish guidelines with regard to timing of intervention for arthrofibrosis after ACLR. Study Design: Cohort study; Level of evidence, 3. Methods: Databases were retrospectively screened at 2 high-volume practices for patients who underwent lysis of adhesions (LOA; Current Procedural Terminology [CPT] 29884 and 29875) with or without manipulation under anesthesia (CPT 27570) after ACLR (CPT 29888). Clinical ROM assessments were collected at multiple time points. Patients were grouped into cohorts based on timing of LOA. Comparative analysis was performed to assess for relationships between ROM and timing of intervention. Results: Seventy-nine patients underwent LOA after ACLR: 25 patients who had a time from ACLR to LOA <3 months, 23 patients between 3 and 6 months, and 31 patients >6 months. Earlier LOA was associated with greater total loss of motion before LOA. The final total arc of motion was 132.7°, 133.7°, and 131.8° for patients who had a time from ACLR to LOA <3 months, between 3 and 6 months, and >6 months, respectively. There were no significant differences among groups in final flexion ( P = .8), extension ( P = .746), or total arc of motion ( P = .781). Linear regression modeling did not identify time from ACLR to LOA as a predictive variable ( P = .982) in final ROM. Conclusion: This study failed to demonstrate a linear relationship between the timing of LOA and final ROM. Regardless of the time to intervention, ROM improved significantly; however, patients with more severe arthrofibrosis underwent LOA at earlier time points.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Hematopoietic Cell Transplantation (HCT) provide expert, multidisciplinary recommendations for autologous and allogeneic HCT based on current evidence. The NCCN Guidelines focus on pretransplant recipient evaluation, hematopoietic cell mobilization, conditioning, and the diagnosis and management of graft-versus-host disease (GVHD), a common complication of allogeneic HCT that is associated with significant morbidity. This selection from the NCCN Guidelines for HCT focuses on the diagnosis, workup, and management of acute and chronic GVHD, as well as important supportive care considerations.

Background: Optimized surgical fixation and meniscal stabilization during rehabilitation increase healing success. However, the latest generation of all-inside devices has not yet been biomechanically compared with inside-out suture tape (IO-ST) repair. Hypothesis: (1) The contact area of a suture anchor (SA) would compensate for a meniscal defect better than polyether ether ketone anchors (PA); (2) adjustable tensioning for all-inside meniscal repair fixation would result in higher initial load than IO-ST repair; and (3) stiffer constructs would decrease secondary displacement. Study Design: Controlled laboratory study. Methods: This study investigates human menisci (N = 39) via microscopic imaging and a biomechanical testing protocol. For the imaging protocol, needles of an all-inside SA or PA device and an IO-ST device were inserted after staining to measure the iatrogenic defect created by the needle insertion (n = 20) and the length, width, and meniscus contact area of deployed all-inside anchors (n = 6). For biomechanical testing, menisci with longitudinal bucket handle tears were prepared, and single stitches were repaired (each n = 9). After suture tensioning (50 N) and fixation, initial load, initial stiffness, and relief displacement were measured. Constructs underwent cyclic loading between 2 and 20 N, with 10,000 cycles (0.75 Hz), and stiffness and displacement were measured. Ultimate stiffness and load-to-failure were analyzed at 3.15 mm/sec. Results: All-inside needles created greater iatrogenic meniscal defects ( P < .001) than IO-ST repair. While PAs were longer ( P < .001), SAs were wider with a greater meniscal contact area (both P < .001). IO-ST repair resulted in the lowest initial load ( P < .001) and relief displacement ( P < .001), whereas SA repair resulted in a higher initial load ( P < .007) and stiffness ( P < .023) than PA repair. The overall stiffer SA fixation ( P < 001) significantly reduced cyclic displacement compared with other repairs ( P < .044). The PA group failed due to an anchor fracture at a significantly lower load (84.3 ± 10.7 N; P < .001) than the IO-ST (136.4 ± 10.5 N) and the SA repair (122.1 ± 17.5 N), with a suture-based failure mode. The ultimate stiffness of SA constructs was higher ( P < .045) than that of other repairs. Conclusion: While all-inside devices showed improved primary stability, the IO-ST construct demonstrated the highest load-to-failure. In a human cadaveric model, meniscal repair with a more compact and conforming SA was stiffer and reduced cyclic displacement compared with PA and IO-ST repair. Clinical Relevance: All-inside SA repair improved primary stability. Future clinical series will define the overall significance of healing rates.