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Importance Bilateral vocal cord paralysis is a challenging problem to manage in adults, and a known complication of thyroid surgery which is more common in resource-limited settings. Posterior graft laryngotracheal reconstruction is a management option that has not been studied in this population or setting. Objective To report the surgical outcomes of posterior graft laryngotracheal reconstruction for bilateral vocal cord paralysis in a resource-limited setting, and to evaluate the efficacy of a hybrid system for teaching this technique in Kenya. Design Retrospective cohort study. Setting Tertiary public referral hospital, Eldoret, Kenya Participants Adults >18 years with tracheostomy dependence secondary to bilateral vocal cord paralysis after thyroid surgery or other iatrogenesis. The hybrid training program included Kenyan surgeons and surgical trainees. Intervention or Exposures Posterior graft laryngotracheal reconstruction and hybrid training system included didactic lectures, simulation-based training, case discussion and planning, and live cases. Main Outcomes Measures One-year airway outcomes measured by achievement of tracheostomy decannulation, and self-reported surgeon knowledge and skill acquisition. Results Ten patients met criteria and were included in the analysis, with mean age 42 years (range 30-62 years) and had been tracheostomy dependent for an average of 6 years (range 1-12 years). Seven (70%) had open reconstruction, and 3 (30%) had endoscopic reconstruction. All were decannulated and remained tracheostomy-free at 1 year. Three surgeons and 7 trainees participated in the hybrid teaching methods. All reported increased comfort in laryngotracheal reconstruction, with all 3 surgeons reporting comfort performing the surgeries independently. Conclusion Posterior graft laryngotracheal reconstruction shows promise as a potential method of treating bilateral vocal cord paralysis and achieving decannulation in a resource-limited setting. Relevance The methods reported in this study lend themselves to replication and expansion to other similar settings. The authors plan to replicate this work in other centers in East Africa.

The NCCN Guidelines for Survivorship include screening, evaluation, and treatment recommendations for common physical and psychosocial problems resulting from adult-onset cancer and its treatment and provide a framework for coordination of survivorship care. They also include recommendations to help cancer survivors enhance their wellness and maintain a healthy lifestyle. These NCCN Guidelines Insights summarize the panel’s current recommendations and recent updates regarding physical activity, nutrition, and weight management for cancer survivors.

10035 Background: Ewing sarcoma (EwS) is a rare malignancy of children, adolescents and young adults for which outcomes have progressively improved through intensification of conventional chemotherapy, including interval compression of cycles. Prior cooperative group reports of relapsed EwS included patients treated less intensively and with fewer treatment options at relapse. Here, we report overall survival (OS) and prognostic factors post-first recurrence in patients with EwS treated with frontline interval-compressed chemotherapy. Methods: We included patients treated on the last three phase 3 COG EwS studies treated with interval compressed chemotherapy, which accrued from 2001-2019. Patients with initially localized disease (L-EwS) were treated on AEWS0031 arm B and AEWS1031. Patients with initially metastatic disease (M-EwS) were treated on AEWS1221. The primary outcome was OS from first relapse. Demographic and clinical data from original diagnosis and from relapse were analyzed as potential prognostic factors. Kaplan-Meier survival curves were constructed and groups compared with log-rank tests. Results: 366 patients experienced disease recurrence as first event and were included in this analysis (AEWS0031 arm B, n = 69, AEWS1031, n = 115, for a total of 184 with L-EwS; AEWS1221, n = 182, all with M-EwS). Median age at relapse was 16 years. Median time from initial enrollment to first relapse was 1.52 years and was shorter for patients with M-EwS (Kruskall-Wallis, p < 0.001). First relapses were isolated local, isolated distant, and combined in 24%, 70%, and 6.4% of patients, respectively. Metastatic stage at initial diagnosis was associated with increased risk of post-first recurrence OS event (p < 0.0001). Two-year OS post-first recurrence (OS 2y ) was 25.6% for patients with M-EwS and 48.5% for patients with L-EwS. Time to first recurrence was also a predictor of post-recurrence survival (p < 0.0001): patients with initial L-EwS and relapse < 2 years from diagnosis had OS 2y of 31.4% vs. 70.8% for later relapses. Patients with initial M-EwS and relapse < 2 years from diagnosis had OS 2y of 18.9% vs. 71.2%. Patients with combined relapses had higher risk of post-relapse death compared to other patterns of failure (p = 0.003), an effect that was largely driven by the one seen in patients with initial L-EwS. Conclusions: Overall survival of patients with first recurrent EwS after having received modern era therapy with interval compressed chemotherapy on recent COG trials remains poor, particularly for M-EwS, early relapse and combined relapses. These data will inform the design of trials for this relapsed population and provide critical data to help counsel patients about goals of care at first relapse.

10032 Background: Identifying clinical and biological factors associated with outcomes in localized Ewing sarcoma (ES) will enable risk-stratified clinical trials with the goal of improved outcomes for high-risk patients and decreased treatment toxicity for low-risk patients. The specific aims of this analysis in localized ES patients were 1) to classify extraosseous (EO) primary tumors with subdivisions into deep (viscera, glands, body cavities, muscle, nerves) and superficial (cutaneous and subcutaneous) sites, and 2) to understand the relationship between baseline clinical factors (age, sex, primary tumor site, size (maximum dimension and volume)) and event-free survival (EFS). Methods: The analytic cohort included ES patients treated with ICC on AEWS0031 and AEWS1031. Primary tumor sites were defined as pelvic, non-pelvic, and EO (deep vs. superficial). Post-enrollment EFS was the primary endpoint. Univariate analyses used the Kaplan–Meier method (logrank test). Multivariable analyses used Cox proportional hazards models. To assess the impact of tumor volume as a continuous variable, a subgroup analysis was conducted using AEWS1031 only, as tumor volumes were collected prospectively on this study. Visual exploration of effects of continuous variables on EFS event hazard used restricted cubic splines with 3 knots. Tests were performed at the 5% level. Results: AEWS0031 (n = 628) and AEWS1031 Regimen B (n = 283) yielded 911 patients. In univariate analyses, difference in risk of EFS event was observed between tumor sites ( P = 0.03). EO tumors had the highest estimated EFS compared to pelvic and non-pelvic (5 year EFS 84.7% vs. 72.4% and 75.9%). Superficial EO appeared to be a very low-risk group, albeit interpretations are limited by the small group size and singular event (one second malignant neoplasm among 15 patients). In multivariable analysis of the combined cohort, sex, race, and ethnicity were not prognostic. EO tumors may be associated with decreased hazard compared with non-pelvic bone primaries (HR 0.58, P = 0.07), and tumors ≥200 mL with increased hazard (HR 1.56, P < 0.01). In the subgroup analysis, tumor volume and age were prognostic and in visualizations age was non-linearly related to the hazard of EFS event, increasing until approximately 15 years. Tumor volume was non-linearly related to the hazard of EFS event and increased until approximately 400 mL. Conclusions: Patients with ES and primary tumors ≥200 mL continue to be at higher risk of an EFS event when treated with ICC, and EO tumors may be lower risk compared with other sites. Risk of an event appears to remain constant in ES patients ≥15 years or with primary tumors ≥400 mL. These findings should be validated in prospective trials and tumor biology integrated with clinical factors to improve risk stratification for localized ES.

Abstract Infection is increasingly recognized as a significant cause of morbidity and mortality in patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) receiving CD19 chimeric antigen receptor (CAR) T-cell therapy. The current study analyzed the natural history, risk factors, and outcomes of infection in 3350 patients with R/R LBCL receiving commercial CD19 CAR T-cell therapy (n = 2804 axicabtagene ciloleucel [axi-cel], n = 546 tisagenlecleucel) from December 2017 to June 2022. Infection developed in 834 patients (24.9%) within 100 days after infusion, resulting in an infection density of 0.43 per 100 patient days and a 100-day cumulative incidence of 22%. Bacterial, viral, and fungal infections were recorded in 527 (15.7%), 374 (11.2%), and 108 patients (3.2%), respectively, with corresponding infection densities of 0.23, 0.15, and 0.04 per 100 patient days. After a 24-month median follow-up, 1482 patients (44%) had died, with infection as the primary cause in 173 cases (12%). The 100-day infection-related mortality (IRM) was 1.6% (95% confidence interval, 1.2-2.0). Patients with a Karnofsky performance score of ≤80, infection history before CAR T-cell therapy, axi-cel therapy, severe cytokine release syndrome (grade ≥3), and severe immune effector cell–associated neurotoxicity syndrome (grade ≥3) had increased infection risk. Infections within 100 days were an independent risk factor for inferior overall survival beyond day 100 after CD19 CAR T-cell therapy. In conclusion, study results show a significant incidence of infection and IRM in patients with R/R LBCL treated with CD19 CAR T-cell therapy. Furthermore, results identify patients at a heightened risk of infection, offering insights to guide potential interventions aimed at mitigating infection and improving patient outcomes after CAR T-cell therapy.

TPS5130 Background: Patients with prostate cancer and deleterious HRRa have poorer prognosis but derive benefit from poly (ADP-ribose) polymerase (PARP) inhibition. However, prevalence of HRRa and response to PARP inhibition are less well defined in racial/ethnic minorities. We designed the HARMONY trial to evaluate the efficacy of N/AA/P in HL and NHB patients with mHSPC and deleterious HRRa. Methods: This multicenter, open label, phase II study is open through the Hoosier Cancer Research Network in the United States. The trial enrolls patients who self-identify as HL or NHB and have mHSPC with HRRa including BRCA 1/2, BRIP1, CHEK2, FANCA, PALB2, RAD51B, and/or RAD54L. Eligible patients will have hormone sensitive, treatment naïve or minimally treated prostate cancer (i.e., bicalutamide ≤ 45 days, androgen deprivation therapy [ADT] ± AA plus P ≤ 45 days allowed). Prostate cancer variants, other therapy in mHSPC setting, or symptomatic brain metastases are exclusionary. Enrolled patients will receive 24 weeks (w) of ADT plus N/AA dual action tablet (DAT) plus P, followed by an adaptive approach based on prostate specific antigen (PSA) response. Subjects in Arm A (PSA > 4.0 ng/mL at 24 w) can continue ADT/N/AA/P for max 2 years or stop N and escalate therapy to ADT/AA/P plus 6 cycles of docetaxel followed by standard of care (SOC) therapy. Subjects in Arm B (PSA ≤ 4.0 ng/mL at 24 w) will continue ADT/N/AA/P for a total of 12 months. At 12 months in Arm B, subjects with PSA ≥ 0.2 ng/mL will continue ADT/N/AA/P for max 2 years, and subjects achieving PSA < 0.2 ng/mL have the option to continue ADT/N/AA/P for max 2 years or discontinue all therapy with the option to start SOC treatment at disease progression. PSA decline to < 0.2 ng/mL at 24w (primary endpoint) will be evaluated for each racial/ethnicity group against a historic rate of 50%. Thirty patients per racial/ethnic cohort will give 80% power at 0.1 significance to determine noninferiority with a no-inferiority margin of 0.185. Estimating 5% drop out, 64 patients will be enrolled (n=32 HL and n=32 NHB). Key secondary/exploratory endpoints include PSA reduction ≥ 90%, overall response rate, PSA/radiographic progression free survival, overall survival, time to subsequent anti-cancer therapy, quality of life and safety. Key genomic correlatives will be evaluated. ClinicalTrials.gov: NCT06392841. Study support of drug and funding: Janssen Scientific Affairs LLC. Clinical trial information: NCT06392841 .

7540 Background: The combination of a proteasome inhibitor (PI) with lenalidomide (R) and dex (d) has been a common initial therapy for newly diagnosed myeloma (NDMM). We designed a randomized phase 3 trial to examine if carfilzomib (K), a next generation PI, improved progression free survival (PFS) compared with bortezomib (V) when either is combined with Rd for initial treatment of NDMM. Initial analysis at a median follow up of 15.3 months (mos) showed comparable PFS for both triplets. We present the long-term results of the trial with ~70 months median follow up. Methods: Patients (Pts) with NDMM, were randomized 1:1 to receive VRd or KRd for 36 weeks followed by a 2 nd randomization (1:1) to indefinite versus 2 yrs of R maintenance. Pts without del17p, t(14;16), t(14;20), plasma cell leukemia or high-risk GEP70 profile, were enrolled. VRd arm included V 1.3 mg/m 2 on days(d) 1, 4, 8, and 11 (d1, 8 for cycles 9-12), R 25 mg d1-14, and d 20 mg d1, 2, 4, 5, 8, 9, 11, 12 of a 3-week (wk) cycle for 12 cycles, while pts in the KRd arm received K 36 mg/m 2 d1, 2, 8, 9, 15, 16 with R 25 mg daily on d1-21 and d 40 mg wkly, in 4 wk cycles for 9 cycles. Maintenance used 15 mg R d1-21 q4 wks. Results: The study accrued 1087 pts (VRd=542, KRd=545). Median age was 65y; baseline characteristics including intent to transplant were similar across the arms. Median induction duration (mos; IQR) was 7.2 (3.4-8.9) and 8.4 (5.1-9.1) for VRd and KRd, respectively; 59.8% in VRd and 45.3% in KRd did not proceed to Step 2. Median PFS (mos) was VRd=41.9 and KRd=44.6; HR = 0.89 (0.76-1.04). Toxicity data, PFS sensitivity analyses and OS probabilities are as in the table. Conclusions: In this randomized trial, with median follow up of nearly 6 years, KRd and VRd had comparable PFS and OS in an intent to treat analysis. While similar numbers proceeded to SCT in the 2 arms, more did so during induction in the VRd arm while more patients in the KRd arm went to SCT later. VRd remains a standard triplet induction regimen in standard and intermediate risk NDMM, and a suitable backbone for 4 drug combinations. Clinical trial information: NCT01863550 . N (%) VRd(n=527) KRd(n=526) SCT anytime 186 (34.3) 183 (33.6) SCT without Step 2 registration 146 112 Median Time to SCT (mos; range) 7.7 (3.5-83.9) 10.6 (3.7-70.6) Grade 3-4 Treatment-Related Toxicity 315 (59.8) 344 (65.4) Grade 5 Treatment-Related Toxicity 2 (0.4) 9 (1.7) Grade 5 All Events 11 (2.1) 20 (3.8) Survival outcomes HR Median (95% CI) Median (95% CI) PFS Primary: PD or death within 3 months of last evaluation as events 0.89(0.76-1.04) 41.9(35.7, 50.3) 44.6(38.2, 51.9) PFS Sensitivity: All deaths as events, 0.87(0.75-1.02) 39.5(34.9, 46.0) 42.8(37.4, 49.7) PFS Sensitivity: Censor at alternate Rx 0.83(0.69-0.99) 35.0(31.3, 42.6) 38.7(34.7, 49.0) PFS Sensitivity: Event at alternate Rx 0.84(0.73-0.97) 18.0(14.2, 23.0) 24.4(20.9, 27.9) Overall survival 0.92(0.75-1.12) 119(100, NE) 118(103-NE)

AbstractPatients with resectable Ewing sarcoma (ES) in select sites, such as the pelvis or chest wall, have a higher risk of positive microscopic margins following surgery. AEWS1031 was the first North American/Australasia ES cooperative group trial allowing standardized preoperative radiotherapy, intended to minimize the morbidity of combined modality local tumor control as well as improve the likelihood of clear surgical margins. In this study, we found that the use of low‐dose preoperative radiation to a smaller target volume resulted in a high rate of R0 resection. The robust pathologic response rate strengthens existing evidence illustrating the radiosensitivity of Ewing sarcoma.

AbstractINTRODUCTIONThis study investigated the role of the ubiquitin–proteasome system (UPS) in dominantly inherited Alzheimer's disease (DIAD) by examining cerebrospinal fluid (CSF) levels of UPS proteins.METHODThe SOMAscan assay was used to detect changes in UPS proteins in mutation carriers (MCs) relative to disease progression; imaging and CSF biomarkers of amyloid, tau, and neurodegeneration measures; and Clinical Dementia Rating scale.RESULTSSubtle increases in specific ubiquitin enzymes were detected in MCs up to two decades before symptom onset, with more pronounced elevations in UPS‐activating enzymes near symptom onset. Significant correlations were found between UPS proteins and Alzheimer's disease (AD) biomarkers, especially between autophagy markers and late‐stage tau biomarkers, microglia, and axonal degeneration.DISCUSSIONThe rise in UPS proteins alongside tau‐related markers suggests UPS involvement in tau neurofibrillary tangles. Elevated CSF UPS proteins in DIAD MCs may serve as indicators of disease progression, and may support the UPS as a therapeutic target in AD.Highlights This study investigates the ubiquitin‐proteasome system (UPS) in Dominantly Inherited Alzheimer's Disease (DIAD), highlighting early molecular changes linked to disease progression. Using SOMAscan proteomics, we identified significant UPS protein alterations in cerebrospinal fluid of mutation carriers, notably up to 20 years before clinical symptom onset. Correlations between UPS protein levels and Alzheimer's biomarkers, particularly tau and neurodegeneration markers, suggest a strong association between UPS dysregulation and tau pathology in DIAD. Dynamic UPS changes align with A/T biological staging: UPS proteins were shown to increase across Aβ/tau (A/T) groups, with largest increases in the A+/T+ group, reinforcing their role in late‐stage tau pathology and disease progression. These findings underscore the potential of UPS proteins as early biomarkers for Alzheimer's disease progression and as novel therapeutic targets, especially in tau‐pathology‐driven neurodegeneration. This work contributes to understanding AD pathogenesis, by emphasizing the importance of protein quality control systems and by offering avenues for future biomarker discovery and therapeutic development in Alzheimer's disease.

The NCCN Guidelines for Multiple Myeloma (MM) provide recommendations for diagnosis, initial workup, treatment, follow-up, and supportive care for patients with MM. These NCCN Guidelines Insights highlight the important updates and changes specific to systemic therapy for patients with newly diagnosed as well as previously treated MM included in Version 1.2025 of the NCCN Guidelines for MM.