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ImportanceRetrieval strategies for children, adolescents, and young adults with relapsed classic Hodgkin lymphoma (cHL) aim to maintain efficacy while minimizing long-term toxic effects. Children, adolescents, and young adults with low-risk, relapsed cHL may benefit from replacing high-dose chemotherapy and autologous stem cell transplant with less intensive involved-site radiotherapy (ISRT).ObjectiveTo evaluate a risk-stratified, response-adapted, transplant-free approach for treatment of children, adolescents, and young adults with low-risk relapsed cHL with nivolumab plus brentuximab vedotin (BV) followed by BV plus bendamustine for patients with suboptimal response and ISRT (30.0 to 30.6 Gy).Design, Setting, and ParticipantsCheckMate 744 (R1 cohort) was a phase 2, nonrandomized, single-arm study enrolling children, adolescents, and young adults aged 5 to 30 years with low-risk cHL between September 25, 2017, and December 16, 2020, across the US, Canada, and Europe. Data were analyzed from September 2017 to November 2022.ExposuresPatients received 4 cycles of nivolumab plus BV induction; patients with complete metabolic response (CMR) received an additional 2 cycles of nivolumab plus BV while patients with suboptimal response received 2 cycles of BV plus bendamustine intensification. Patients with CMR after induction or intensification received ISRT consolidation.Main Outcomes and MeasuresPrespecified coprimary end points were CMR rate (Lugano 2014 classification) any time before ISRT and 3-year event-free survival (EFS) rate, per blinded independent central review (BICR).ResultsOf 28 included patients treated in the low-risk cohort, 18 (64%) were female, and the median (range) age was 17 (6-27) years. At a median (range) follow-up of 31.9 (2.2-55.3) months, CMR per BICR any time before ISRT was 93% (26 of 28; 90% CI, 79.2-98.7; objective response rate [ORR], 100%), and 23 of 28 (82%) achieved CMR per BICR after 4 cycles of nivolumab plus BV (ORR, 96.4%). Kaplan-Meier estimates of EFS and progression-free survival rates at 3 years were 87% (3 of 18; 90% CI, 69.5-94.7) and 95% (1 of 18; 90% CI, 76.7-99.0), respectively. During induction, 22 patients (79%) had treatment-related adverse events, including 7 with grade 3 or 4 adverse events, 2 with anemia, 1 with neutropenia, and 6 with immune-mediated adverse events. Serious adverse events leading to discontinuation occurred in 2 patients.Conclusions and RelevanceThis nonrandomized clinical trial found that for children, adolescents, and young adults with low-risk, relapsed cHL, a transplant-free, risk-adapted, response-based approach with nivolumab plus BV and ISRT offered high CMR rates and high 3-year EFS rate, with a safety profile consistent with that of each agent used.Trial RegistrationClinicalTrials.gov Identifier: NCT02927769

Abstract Patients with relapsed/refractory diffuse large B-cell lymphoma progressing after chimeric antigen receptor T-cell (CAR-T) therapy have dismal outcomes. The prespecified post–CAR-T expansion cohort of the ELM-1 study investigated the efficacy and safety of odronextamab, a CD20×CD3 bispecific antibody, in patients with disease progression after CAR-Ts. Sixty patients received IV odronextamab weekly for 4 cycles followed by maintenance until progression. The primary end point was objective response rate (ORR) by independent central review. The median number of prior lines of therapy was 3 (range, 2-9), 71.7% were refractory to CAR-Ts, and 48.3% relapsed within 90 days of CAR-T therapy. After a median follow-up of 16.2 months, ORR and complete response (CR) rate were 48.3% and 31.7%, respectively. Responses were similar across prior CAR-T products and time to relapse on CAR-T therapy. Median duration of response was 14.8 months and median duration of CR was not reached. Median progression-free survival and overall survival were 4.8 and 10.2 months, respectively. The most common treatment-emergent adverse event was cytokine release syndrome (48.3%; no grade ≥3 events). No cases of immune effector cell–associated neurotoxicity syndrome were reported. Grade ≥3 infections occurred in 12 patients (20.0%), 2 of which were COVID-19. Odronextamab monotherapy demonstrated encouraging efficacy and generally manageable safety, supporting its potential as an off-the-shelf option for patients after CAR-T therapy. This trial was registered at www.clinicaltrials.gov as #NCT02290951.

OBJECTIVE The objective of this study was to compare a multiple pelvic screw fixation strategy (dual bilateral 4 pelvic screw fixation [4PvS]) with the use of single bilateral 2 pelvic screw fixation (2PvS), with the aim of addressing lumbosacral junction stability. METHODS This analysis is a single-center, retrospective review of ASD patients treated between 2015 and 2021. All patients had a minimum 2-year follow-up and spinal fusion to the sacrum without sacroiliac fusion and met at least one radiographic and procedural criterion: pelvic incidence–lumbar lordosis ≥ 20°, T1 pelvic angle ≥ 20°, sagittal vertical axis ≥ 7.5 cm, scoliosis ≥ 50°, three-column osteotomy, or spinal fusion of ≥ 8 levels. Two sacropelvic fixation methods were compared: 4PvS versus 2PvS. Primary outcomes included spinal implant-related reoperation and screw breakage, while secondary outcomes included reoperation for symptomatic pelvic screws, screw loosening or bending, L5–S1 pseudarthrosis, and patient-reported outcomes. Propensity score matching and inverse probability of treatment weighting (IPTW) were used to minimize selection bias and estimate causal treatment effects. Clinical outcomes were assessed using conditional multivariable logistic regression. RESULTS In this study of 406 patients (67.98% female, mean age 64.48 years), 349 patients (85.96%) received 2PvS and 57 (14.04%) received 4PvS. Age (OR 1.081, 95% CI 1.027–1.145) and total number of osteotomies (OR 1.180, 95% CI 1.048–1.355) emerged as independent predictors of receiving the 4PvS technique. In unmatched cohorts (n = 406), 2-year implant-related reoperation rates (p = 0.1896) and pelvic screw breakage rates (p = 0.2498) were not significantly different between groups. However, in the 4:1 propensity score–matched cohort, the 2-year reoperation rate (10.53% for 2PvS vs 3.51% for 4PvS; OR 3.27, 95% CI 1.10–9.74 [p = 0.0312]) and the pelvic screw breakage rate (9.21% for 2PvS vs 3.51% for 4PvS; OR 2.87, 95% CI 1.08–7.63 [p = 0.0349]) were significantly higher among the 2PvS groups. The IPTW analysis confirmed these findings, with reoperation rates of 10.45% for 2PvS and 1.18% for 4PvS (p = 0.0244) and pelvic screw breakage rates of 8.72% and 1.18%, respectively (p = 0.0477). A safety assessment revealed comparable operative times and intra- and perioperative complications between the two techniques. CONCLUSIONS Patients who underwent 4PvS demonstrated significantly lower 2-year implant-related reoperation and pelvic screw breakage rates compared with 2PvS, with no differences in intraoperative or perioperative complications.

Abstract Background Temozolomide (TMZ) treatment has demonstrated a variable impact on glioma prognosis. This study examines associations of survival with DNA repair gene germline polymorphisms among glioma patients who did and did not have TMZ treatment. Identifying genetic markers which sensitize tumor cells to TMZ could personalize therapy and improve outcomes. Methods We evaluated TMZ-related survival associations of pathogenic germline SNPs and genetically predicted transcript levels within 34 DNA repair genes among 1504 glioma patients from the University of California San Francisco Adult Glioma Study (UCSF AGS) and Mayo Clinic, whose diagnoses spanned pre- and post-TMZ eras within the major known glioma prognostic molecular subtypes. Results Among those who received TMZ, 5 SNPs were associated with overall survival, but not in those who did not receive TMZ. Only rs2308321-G, in MGMT, was associated with decreased survival (hazard ratio = 1.21, P = .019) for all glioma subtypes. Rs73191162-T (near UNG), rs13076508-C (near PARP3), rs7840433-A (near NEIL2), and rs3130618-A (near MSH5) were only associated with survival and TMZ treatment for certain subtypes, suggesting subtype-specific germline chemosensitization. Genetically predicted elevated expression of PNKP, compared to normal brain expression, was associated with markedly poor survival in TMZ-treated patients with isocitrate dehydrogenase (IDH)-mutant and 1p/19q non-codeleted gliomas (P = .015), with a median difference of over 70 months in overall survival times. Similarly, NEIL2 and TDG expressions were associated with altered TMZ-related survival only among certain subtypes. Conclusions Functional germline alterations within DNA repair genes were associated with TMZ sensitivity, measured by overall survival among adults with glioma. These variants should be evaluated in prospective analyses and functional studies.

Abstract Background A passive dosimeter framework for the measurement of dose in carbon ion beams has yet to be characterized or implemented for regular use. Purpose This work determined the dose calculation correction factors for absorbed dose in thermoluminescent dosimeters (TLDs) in a therapeutic carbon ion beam. TLD could be a useful tool for remote audits, particularly in the context of clinical trials as new protocols are developed for carbon ion radiotherapy. Methods TLD‐100 were irradiated in a carbon ion beam at the Centro Nazionale di Adroterapia Oncologica (CNAO) in Pavia, Italy. The dose correction factors for linearity, fading, and beam quality were characterized. Fading was characterized from 5 to 100 days post‐irradiation. For linearity, the TLDs were irradiated to absorbed doses ranging from 1 to 15 Gy in both the entrance of a high‐energy pristine carbon ion peak and the center of a 2 cm spread‐out Bragg peak. For beam quality, the TLD was irradiated to the same absorbed dose (3 Gy) in several pristine carbon ion Bragg peaks, as well as in several spread‐out Bragg peaks. Each correction factor was calculated and compared to photon correction factors. The correction factors were also compared between high and low dose‐averaged linear energy transfer (LET D ) in the carbon ion beams. The absorbed dose was compared between ion chamber and TLD‐100 in the several tissue substitute phantom materials, applying the carbon ion TLD correction factors. Results There was no statistically significant difference in the TLD fading correction factor between photons, low LET D carbon ion beams, or high LET D carbon ion beams. The TLD linearity correction factor did differ between photons, low LET D carbon ions, and high LET D carbon ions. The beam quality correction factor was large and changed linearly with LET D . The overall uncertainty of the carbon ion absorbed dose calculation was 3.9% at the one‐sigma level, driven largely by a 3.5% uncertainty in the beam quality correction. TLD measurements were within 1.2% of ion chamber measurements in the phantom material for polyethylene, solid water (Gammex and Sun Nuclear), acrylic, blue water, and techtron HPV. TLD measurements in balsa wood were within 3.0% and cork was 6.6% low compared to ion chamber. Conclusion TLD‐100 can be used for passive dosimetry in a therapeutic carbon ion beam. Importantly, the linearity and beam quality correction factors are both different from photon therapy, and dependent on LET D of the carbon ion beam. This opens the possibility of TLD use for carbon ion output audits, phantom audits, and in vivo dose measurements, but may be subject to more complicated management and slightly larger uncertainties than are achieved in photon beams.

ABSTRACT Introduction Lack of social support negatively impacts medical trainees' wellness. Programmes to educate medical trainees and their support persons (SPs) have been developed to improve resident wellness, but implementation of these programmes at other institutions remains unclear. We aimed to demonstrate the feasibility of implementing the Family Anesthesia Experience (FAX) programme across multiple institutions and to assess the programme's utility. Methods FAX includes didactics on wellness, burnout, substance use disorder and institutional resources; a panel of senior residents and their SPs; and small‐group simulations of airway management, common procedures and a high‐fidelity intraoperative code. We assessed the programme qualitatively using semistructured interviews of 20 first year anaesthesiology residents and 20 SPs. Data analysis was performed via a content analysis approach. Results Twelve anaesthesiology programmes of varying size and geographic locations implemented FAX with minor adaptations. Minimal direct costs were incurred for the virtual programme. Participants enjoyed the event overall. Content analysis showed that FAX improved SPs' understanding of residency and communication between SPs and residents, had minimal impact on SPs' stress, reduced residents' interpersonal stress with SPs and modified perceptions on wellness and burnout. We developed a conceptual model in which we propose SPs' understanding and empathy for their residents would improve through FAX, which may improve communication with and support for residents. Conclusion We demonstrated that FAX can be implemented at varying anaesthesiology residency programmes. Family‐oriented educational events like FAX may be an effective approach to improve SPs' understanding of a resident's role, thereby increasing social support for residents.

Case: A 67-year-old woman sustained a periprosthetic tibial tubercle avulsion fracture with extensor mechanism disruption. She underwent open reduction internal fixation (ORIF) with orthogonal mini-fragment plates applied in a tension band fashion with patellar tendon suture augmentation. Radiographs, range of motion, and patient-reported outcomes were completed over 1 year. Conclusion: Isolated periprosthetic tibial tubercle fractures with disruption of the extensor mechanism can be treated with ORIF using orthogonal tension band plating. At 1-year follow-up, the surgical technique described in this report yielded radiographic union, clinical restoration of preinjury motion, and excellent patient-reported outcomes.

ABSTRACTBackgroundThe self‐expanding, supra‐annular Evolut valve is an established platform for Transcatheter Aortic Valve Implantation (TAVI). Evolut PRO introduced an outer sealing wrap to mitigate paravalvular leakage. We evaluated the 3‐year clinical outcomes and valve performance of the Evolut PRO in standard clinical practice for severe aortic stenosis (AS) patients at intermediate or higher risk for surgery.MethodsThe FORWARD PRO prospective, single‐arm, multicentre, post‐market clinical study enrolled 638 patients with native aortic valve stenosis or failed surgical bioprosthetic aortic valve undergoing TAVI, at intermediate or high risk, with the Evolut PRO valve. Clinical and serial echocardiographic outcomes were followed‐up for 3 years.ResultsTAVI using Evolut PRO was attempted in 629 AS patients (implanted in 97%) (mean age 81.7 years; STS PROM score, 4.7%). At 3 years all‐cause mortality was 25.0%, disabling stroke 6.5% (all‐cause mortality or disabling stroke, 28.5%) and rate of new permanent pacemaker implantation 24.7%. Excellent valve haemodynamics were maintained (mean gradient 8.8 ± 4.7 mm Hg; mean effective orifice area 2.0 ± 0.5 cm2) at 3 years. In a paired analysis of patients with ≥ mild paravalvular leakage (PVL) at discharge, more than two‐thirds demonstrated improved PVL at 3 years. Patients with ≥ mild PVL at discharge had higher median total calcium volume than those with no/trace PVL (p < 0.001).ConclusionsIn clinical practice TAVI with the Evolut PRO valve is associated with favorable clinical outcomes and excellent haemodynamic performance out to 3 years. The observation of improvements in PVL over time warrants further research.

OBJECTIVE The floor of the third ventricle and the interpeduncular and prepontine regions represent challenging surgical targets. The expanded endoscopic endonasal approach (EEA) with pituitary gland (PG) transposition has been proposed to provide direct access to these anatomical regions. Through the years, different endoscopic PG transposition techniques have been studied and presented. The goal of this study was to compare the techniques, relevant anatomy, and surgical exposure of extradural, intradural, and interdural PG transposition techniques. METHODS Six formalin-fixed, latex-injected cadaveric head specimens were used to perform the EEA with extradural, unilateral interdural, and unilateral intradural PG transpositions. The interpeduncular and prepontine regions and the neurovascular structures located within these cisterns were carefully exposed and analyzed. The maximal cranial, caudal, and lateral accessible points within the surgical field were identified for each approach. Consequently, the relative craniocaudal and horizontal surgical axes were measured to quantify the extent of accessibility of each approach. RESULTS The extradural PG transposition technique provided the largest horizontal extensions and bilateral access to structures within the interpeduncular and prepontine regions; the mean horizontal axis was 17.9 (range 13.9–20.4) mm. The unilateral interdural PG transposition provided wider vertical exposure, with a mean craniocaudal axis of 16.2 (range 13.0–20.9) mm. In this approach, the surgical field was extended cranially above the ipsilateral mammillary body (MB). The unilateral intradural PG transposition provided a similar surgical exposure to the interdural approach, with a mean craniocaudal axis of 14.7 (range 12.9–15.8) mm. The approach required significant manipulation of the PG after opening both periosteal and meningeal dura layers. CONCLUSIONS The extradural PG transposition is indicated for lesions of the upper clivus region that extend bilaterally and do not have a cranial extension beyond the MBs. The inter- and intradural PG transpositions are beneficial for unilateral lesions that extend cranially to the MBs. Both techniques require coagulation of the ipsilateral inferior hypophyseal artery. The intradural technique requires more manipulation of the PG, while the interdural technique requires opening and access to the cavernous sinus. If needed, the intra- and interdural techniques can also be performed bilaterally.