Citations

Abstract The treatment patterns and clinical outcomes for patients experiencing progression of disease (POD) following CD19-directed chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory (R/R) mantle cell lymphoma (MCL) are undefined. We identified all patients who received CD19-directed CAR T-cell therapy for R/R MCL therapy across 15 international centers, and studied those experiencing POD post–CAR T-cell therapy in detail. We extracted clinical/treatment/pathologic variables, and associated these features with survival outcomes. In total, 384 patients received CAR T-cell therapy, and 135 (35%) experienced POD. POD occurred at a median of 6 months following CAR T-cell therapy infusion, and most (64%) patients with POD had complete response as best response to CAR T-cell therapy. Tumor features at POD included blastoid/pleomorphic morphology in 29 of 78 (37%) patients, and TP53 mutation in 21 of 41 (51%) patients. Following POD, 17 patients received no further therapy, 13 underwent local therapy, and 105 received systemic therapy. The most common first-line systemic therapies were chemo(immuno)therapy (22 patients; overall response rate [ORR], 40%), pirtobrutinib (17 patients; ORR, 36%), and bispecific antibodies (13 patients; ORR, 67%). Among patients experiencing POD, the median progression-free survival and overall survival (OS) were 2.5 months and 5.4 months, respectively, from POD. Lack of response to CAR T-cell therapy and short time from CAR T-cell therapy infusion to POD (<3 vs 3-6 vs >6 months), among other factors, were associated with inferior OS after POD. In conclusion, we confirm the challenging prognosis for patients experiencing POD following CD19 CAR T-cell therapy for R/R MCL, and establish a benchmark for future investigations in this patient population.

Abstract Background Proton therapy offers precise tumor targeting while minimizing damage to surrounding healthy tissue, making it especially valuable for treating tumors near critical organs and in pediatric patients. However, its success depends on accurate beam delivery, requiring rigorous quality assurance (QA) to maintain treatment precision and effectiveness. Purpose This study aims to standardize the measurement of key aspects of proton therapy delivery, such as gantry and couch isocentricity, spot position accuracy, and spot size consistency. The goal is to enhance the delivery accuracy of proton therapy across various clinical settings, improving patient outcomes. Methods The QA framework uses the Octopoint phantom, Gafchromic film, and spot position monitor (SPM) log data to evaluate proton beam isocentricity, spot position, and spot size. The Octopoint phantom, made from acrylic, was used with Gafchromic films at various gantry and couch angles to measure isocentricity. MATLAB tools were used to analyze spot positions, and SPM logs provided verification. Sensitivity tests were conducted to assess the system's response to intentional shifts and errors, ensuring alignment with clinical QA standards. Results The Octopoint phantom's stepwise two‐dimensional (2D) fitting process, validated against film‐measured dose profiles, accurately identified beam and ball bearing (BB) centroid locations. Isocentricity tests conducted over 8 months across four gantries demonstrated consistent beam‐to‐BB radial offsets. The phantom showed excellent repeatability, with a maximum standard deviation of 0.1 mm across various couch‐gantry combinations. Sensitivity testing across all axes revealed a strong alignment between intended shifts and measured values. Over the course of a year, film measurements tracked spot position and size consistency, with deviations remaining within acceptable clinical limits. Comparisons with SPM data further confirmed the system's reliability in maintaining beam accuracy across different gantry angles and energy levels. Conclusions This study presents a reliable QA framework for ensuring precision in proton therapy delivery. By combining the Octopoint phantom, Gafchromic film analysis, and SPM log file evaluation, we effectively measured isocentricity, spot position accuracy, and spot size stability. The framework demonstrated adaptability across various clinical QA tasks, enhancing the accuracy and safety of proton therapy treatments.

Objective: To establish benchmark cutoffs for robotic liver resection (R-LR), encompassing both major and minor resections, and to determine the impact of patient selection on outcomes. Background: R-LR is a key advancement in minimally invasive liver surgery but lacks standardized benchmarks, especially for minor resections. While guidelines endorse R-LR, its role in optimizing outcomes remains unclear. This study establishes the first benchmarks for R-LR, enabling comparisons across surgical modalities and refining patient selection. Methods: This retrospective, multicenter study analyzed consecutive adult patients undergoing R-LR at 30 international centers (2020–2023). Benchmark centers had an annual case volume of ≥15 R-LR. Benchmark criteria included ASA ≤2, no major comorbidities, no prior liver resections, and Child-Pugh A status. Benchmark cutoffs for 14 key outcomes were set at the 50th and 75th percentiles of median values across benchmark centers. Multivariable logistic regression identified predictors of textbook outcomes. Results: Eighteen high-volume centers contributed 4028 cases with 2632 (65.3%) meeting benchmark criteria. Malignancy was the indication in 29.6%, most commonly hepatocellular carcinoma followed by colorectal liver metastases. Major liver resection was performed in 42.6%. The distribution of Iwate difficulty scores was low (25.4%), intermediate (53.9%), advanced (15.9%), and expert (4.9%). Benchmark cutoffs were established for minor and major resection, and stratified by Iwate low (0-3), intermediate (4-6) and high (7-12): Open conversion (≤6.5% minor, ≤10.5% major), major complications within 90 days (≤5.2% minor, ≤16.7% major), R1 resection (≤9.2% minor, ≤6.7% major). Benchmark cases performed at low-volume centers were able to achieve outcomes within the corresponding benchmark cutoffs. In fact, patient selection reflected by the proportion of benchmark patients, rather than case volume, was associated with textbook outcomes. Conclusions: This study defines R-LR benchmarks, emphasizing patient selection over center volume for optimal outcomes. Benchmark cutoffs guide training and support the expansion of R-LR.

Abstract Background In 2021, the American Academy of Physical Medicine and Rehabilitation established the Multi‐Disciplinary Post‐Acute Sequelae of SARS‐CoV‐2 Infection Collaborative to provide guidance from established Long COVID clinics for the evaluation and management of Long COVID. The collaborative previously published eight Long COVID consensus guidance statements using a primarily symptom‐based approach. However, Long COVID symptoms most often do not occur in isolation. Aims This compendium aims to equip clinicians with an efficient, up‐to‐date clinical resource for evaluating and managing adults experiencing Long COVID symptoms. The primary intended audience includes physiatrists, primary care physicians, and other clinicians who provide first‐line assessment and management of Long COVID symptoms, especially in settings where subspecialty care is not readily available. This compendium provides a holistic framework for assessment and management, symptom‐specific considerations, and updates on prevalence, health equity, disability considerations, pathophysiology, and emerging evidence regarding treatments under investigation. Because Long COVID closely resembles other infection‐associated chronic conditions (IACCs) such as myalgic encephalomyelitis/chronic fatigue syndrome, the guidance in this compendium may also be helpful for clinicians managing these related conditions. Methods Guidance in this compendium was developed by the collaborative's established modified Delphi approach. The collaborative is a multidisciplinary group whose members include physiatrists, primary care physicians, pulmonologists, cardiologists, psychiatrists, neuropsychologists, neurologists, occupational therapists, physical therapists, speech and language pathologists, patients, and government representatives. Over 40 Long COVID centers are represented in the collaborative. Results Long COVID is defined by the National Academies of Sciences, Engineering, and Medicine as “an IACC that occurs after SARS‐CoV‐2 infection and is present for at least 3 months as a continuous, relapsing and remitting, or progressive disease state that affects one or more organ systems.” The current global prevalence of Long COVID is estimated to be 6%. Higher prevalence has been identified among female gender, certain racial and ethnic groups, and individuals who live in nonurban areas. However, anyone can develop Long COVID after being infected with the SARS‐CoV‐2 virus. Long COVID can present as a wide variety of symptom clusters. The most common symptoms include exaggerated fatigue and diminished energy windows, postexertional malaise (PEM)/postexertional symptom exacerbation (PESE), cognitive impairment (brain fog), dysautonomia, pain/myalgias, and smell and taste alterations. Holistic assessment should include a traditional history, physical examination, and additional diagnostic testing, as indicated. A positive COVID‐19 test during acute SARS‐CoV‐2 infection is not required to diagnose Long COVID, and currently, there is no single laboratory finding that is definitively diagnostic for confirming or ruling out the diagnosis of Long COVID. A basic laboratory assessment is recommended for all patients with possible Long COVID, and consideration for additional labs and diagnostic procedures is guided by the patient's specific symptoms. Current management strategies focus on symptom‐based supportive care. Critical considerations include energy conservation strategies and addressing comorbidities and modifiable risk factors. Additionally, (1) it is essential to validate the patient's experience and provide reassurance that their symptoms are being taken seriously because many patients have had their symptoms dismissed by loved ones and clinicians; (2) physical activity recommendations must be carefully tailored to the patient's current activity tolerance because overly intense activity can trigger PEM/PESE and worsened muscle damage; and (3) treatment recommendations should be delivered with humility because there are many persistent unknowns related to Long COVID. To date, there are limited data to guide medication management specifically in the context of Long COVID. As such, medication use generally follows standard practice regarding indications and dosing, with extra attention to prioritize (1) patient preference via shared decision‐making and (2) cautious use of medications that may improve some symptoms (eg, cognitive/attention impairment) but may worsen other symptoms (eg, PEM/PESE). Numerous clinical trials are investigating additional treatments. The return‐to‐work process for individuals with Long COVID can be challenging because symptoms can fluctuate, vary in nature, affect multiple functional areas (eg, physical and cognitive), and often manifest as an “invisible disability” that may not be readily acknowledged by employers or coworkers. Clinicians can help patients return to work by identifying suitable workplace accommodations and resources, providing necessary documentation, and recommending occupational or vocational therapy when needed. If these efforts are unsuccessful and work significantly worsens Long COVID symptoms or impedes recovery, applying for disability may be warranted. Long COVID is recognized as a potential disability under the Americans with Disabilities Act. Conclusion To contribute to the overall health and well‐being for all patients, Long COVID care should be delivered in a holistic manner that acknowledges challenges faced by the patient and uncertainties in the field. For more detailed information on assessment and management of specific Long COVID symptoms, readers can reference the collaborative's symptom‐specific consensus guidance statements.

Abstract Castleman disease (CD) describes a group of rare lymphoproliferative disorders that exhibit a wide range of symptomatology and degree of lymphadenopathy, particularly across the 2 forms of CD with unknown etiology, unicentric CD (UCD), and human herpesvirus-8–negative/idiopathic multicentric CD (iMCD). Whereas UCD cases typically present with localized lymphadenopathy and mild symptoms, iMCD involves multicentric lymphadenopathy and cytokine storm–driven symptoms with 3 recognized clinical phenotypes. Increasingly, there are anecdotal reports of cases that do not fit into this framework, but these cases have not been systematically described. Herein, we use the ACCELERATE natural history registry to characterize the spectrum of CD based on disease features, symptomatology, and severity. Our results characterize a cohort of 179 CD cases, which were reviewed and confirmed by an expert panel of clinicians and hematopathologists. We show that patients with CD present on a continuous spectrum of clinical phenotypes, and we describe oligocentric CD (OligoCD), an intermediate phenotype that does not fit the criteria for UCD or iMCD. These cases tend to have “oligocentric” lymphadenopathy (median [interquartile range] regions of lymphadenopathy, 3.0 [2.0-4.0]) in a regional pattern and exhibit a mild clinical phenotype that is more similar to UCD than iMCD. We also show that patients with OligoCD are inconsistently categorized as UCD vs iMCD, highlighting the need for this characterization. Future data collected through ACCELERATE may further elucidate the natural history and risk profile of these patients.

Background: CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy is an established treatment with high efficacy in treating relapsed or refractory (R/R) mantle cell lymphoma (MCL). However, with CAR-T therapy, refractory disease occurs and a continuous pattern of relapse over time has been observed. Limited data exist about post-CAR-T progression of disease (POD) management and outcomes in MCL. Such data would meaningfully inform practice and set a critical benchmark for future studies in the post-CAR-T setting. We characterized treatment patterns and outcomes for pts with POD after CD19 CAR-T therapy for R/R MCL. Methods: We queried institutional databases to identify pts with R/R MCL who received CD19-directed CAR-T therapy. Treatment may have occurred as standard-of-care or in a clinical trial. We performed chart review to extract variables and categorized therapies by mechanism(s) of action. We used descriptive statistics to characterize patient/disease characteristics and treatment patterns, the reverse Kaplan-Meier method to calculate follow-up, the Kaplan-Meier method to calculate survival, and Cox proportional hazards to associate clinical and disease features with survival outcomes. Results: Across 9 sites, we identified 306 pts who received CD19 CAR-T for R/R MCL, of which 104 (34%) experienced POD and were investigated in detail: pts with POD were mostly men (73%), had a median age of 67 yrs (range 36-86) at infusion, and had received a median of 3 lines of therapy pre-leukapheresis, including a BTK inhibitor (BTKi) in 97% of patients; 36% of BTKi-exposed patients had BTKi-unresponsive disease. High-risk tumor features were common pre-CAR-T: 47/68 (69%) with a TP53 mutation, 66/93 (71%) with Ki67 ≥50%, and 47/102 (46%) with blastoid/pleomorphic MCL. Most pts (75%) received bridging therapy. Pts received brexucabtagene autoleucel (88%) or lisocabtagene maraleucel (12%). Regarding best CAR-T response for pts with POD, 71% had a complete response (CR), 13% partial response (PR), and 15% had no response. The median time from CAR-T infusion to POD was 6 months (IQR 3-12). At time of POD, high-risk MCL features were again common: 55% blastoid/pleomorphic, 42/56 (75%) Ki67 ≥50%, 51/83 (61%) MIPIb high-risk, and 21/35 (60%) TP53-mutated MCL. Among 69 pts with CD19 assessed on a post-POD biopsy, 8 (12%) had CD19-negative disease. 30% of pts had an ECOG performance status of ≥2 at time of POD. After POD occurred, 15 pts received no anti-lymphoma therapy (Tx), 11 pts underwent excision or radiation, and 78 pts received systemic therapy. The most commonly used first-line systemic Tx post-CAR-T progression included: pirtobrutinib in 13 pts [overall response rate (ORR) 31%], chemoimmunotherapy in 12 pts (ORR 25%), venetoclax in 10 patients (ORR 20%), bispecific antibodies (BsAb) in 10 pts (ORR 60%), and small molecule combinations (at least 2 of BTK inhibitor, BCL2 inhibitor, and lenalidomide) in 8 patients with ORR 50%. The ORR to all first systemic Tx post-POD was 42%. The median follow-up from POD is 15.2 months among survivors. The median progression-free and overall survival (OS) from time of POD were 2.3 (95% CI 1.9-3.4) and 5.4 months (95% CI 4.5-9.4), respectively, and 1-year OS rate was 33%. TP53 mutations predicted inferior OS (HR 2.83, 95% CI 1.08-7.43, P = 0.026) as did age ≥65 years at time of POD (HR 1.83, 95% CI 1.07-3.15, P = 0.023), MIPIb high-risk (HR 3.56, 95% CI 1.08-11.7, P = 0.042), and non-response to CAR-T (HR 3.55, 95% CI 1.93-6.53, P < 0.001). Discussion: Our data, the largest reported cohort of pts with POD post-CAR-T with R/R MCL, confirm the poor prognosis in this patient population, with a median OS of 5.4 months. BsAbs showed promise with an overall response rate of 60%. The presence of a TP53 mutation significantly predicted inferior OS, corroborating the prognostic importance of this finding in the post-CAR-T context. Data from pts treated at additional sites and updated analyses will be presented at the meeting.

Introduction Emerging evidence suggests that responses to CPI in Hodgkin lymphoma (HL) may be adversely affected by the reductions in microbiome diversity associated with concomitant antibiotic (abx) exposure. Given the increasingly key role that CPI-based regimens (CPI+) appear to have on improving post-ASCT outcomes, we evaluated the potential impact of abx exposure on CPI+ efficacy and post-ASCT outcomes in RRHL patients treated with CPI+ prior to ASCT. Methods This retrospective study of RRHL patients at 11 US academic centers included patients ≥18 who received CPI+ between 1/2012-12/2022. Patient/disease characteristics, treatment histories, outcomes, and abx exposure (2 weeks prior to and 30 days after CPI+) were collected by participating sites and analyzed centrally. Primary and key secondary objectives were overall response rate (ORR) to CPI+ by Lugano criteria, and PFS/overall survival (OS) by abx exposure. PFS/OS were estimated by Kaplan-Meier and compared by log-rank tests. Univariate and multivariate regression models evaluated the impact of abx exposure on ORR/complete response rate (CR)/PFS/OS. Results 237 patients with median follow-up of 3.20 and 2.73 years from CPI+ initiation and ASCT, respectively, were evaluated. At diagnosis: median age 30.6 (range 7.8 - 71.7) years, female (53.6%), nodular sclerosing (75.1%), and stages I-IIB/bulky and III/IV (73.4%). 1L regimens were ABVD/ABVD-like (75.5%), brentuximab vedotin (BV)+AVD (15.2%), and other (9.3%). 65.8% received 6 cycles of chemotherapy, and 10.5% received 1L radiation. End of 1L responses were CR (39.7%), partial response (PR; 13.1%), refractory disease (37.6%), and unknown (8.0%). Median time to first relapse from diagnosis was 0.95 (range 0.15 - 22.2) years. All patients underwent ASCT after 1 (58.2%), 2 (22.8%), or 3+ (19.0%) lines of salvage. CPI+ was given as 1st (65.8%), 2nd (21.5%), or 3rd+ (12.5%) salvage therapy. CPI+ included BV-nivolumab (44.3%) + ipilimumab (7.2%), pembrolizumab, gemcitabine, vinorelbine, and liposomal doxorubicin (P-GVD; 24.5%), and CPI-monotherapy (20.2%). ORR to CPI+ was 88.0% (CR 68.4%) in all lines; as 1st salvage ORR was 91.7% (CR 76.3%). 75.1% of patients underwent ASCT in CR (PR 19.4%) increasing to 91.1% CR after ASCT. At 3-years, PFS was 88.0% (95% CI: 83.5% - 92.8%) and OS was 94.8% (95% CI: 91.3% - 98.3%) for the full cohort. Overall, 46.8% patients were abx exposed during CPI+, 22.8% fluoroquinolone/beta-lactams (BL) prophylaxis (ppx) and 38.8% abx [BL 29.5%, carbapenems (CB) 12.2%, vancomycin (VM) 19.8%, anti-pseudomonas (PA) 24.9%, anti-MRSA (SA) 22.4%, anti-anaerobe (AN) 16.5%] for suspected/documented infection. Use of ppx, BL, CB, VM, PA, SA were significantly higher with CP1+ as 2nd+ vs 1st salvage. At 3-years, PFS (87.0% vs 88.4%, p=0.91) and OS (92.5% vs 95.8%, p=0.47) were similar for abx exposed vs naïve patients, respectively. On univariate analysis, line of salvage and CPI+ regimen (Cytotoxic vs Monotherapy) were associated with ORR/CR, while overall abx exposure was not associated with inferior ORR (OR 0.62; p=0.24), CR (OR 0.85, p=0.56), PFS (HR 0.95, p=0.91), or OS (HR 1.58, p=0.47). When adjusted for line of salvage and CPI+ regimen, exposure to BL, CB, VM, PS, SA, or AN, abx indication (ppx vs treatment), duration of abx exposure (<7 vs ≥7 days) by class were all not associated with ORR/CR or PFS/OS. Conclusion In this large cohort abx exposure does not appear to adversely affect ORR/CR to CPI+ or PFS/OS following ASCT, when adjusted for line of CPI+ salvage and CPI+ regimen. Our findings may be related the high proportion of patients (79.8%) receiving CPI-combinations compared to CPI monotherapy (20.2%), whereas in previous series all patients received CPI without cytotoxic agents. This observation could be related to intrinsic antimicrobial activities of some cytotoxic agents (e.g. gemcitabine and doxorubicin) that may overshadow impact from concomitant abx exposure. Alternatively, the lack of effect could be related to the inherent fitness of patients with RRHL who undergo ASCT, compared to those treated with CPI+ following ASCT or those with solid tumors receiving where abx exposure may indicate an overall sicker/higher-risk population. Overall, our findings demonstrate that combination of CPI with BV or chemotherapy may overcome any adverse impact of abx on the efficacy of CPI+ prior to ASCT.

Introduction: Pembrolizumab Gemcitabine Vinorelbine and Liposomal Doxorubicin (P-GVD) has become a commonly employed regimen for the treatment of relapsed or refractory classical Hodgkin lymphoma (CHL), often preceding autologous stem cell transplant in patients with good response. The utilization of P-GVD is based on a 38-evaluable patient prospective trial (Moskowitz et al. JCO 2021). There remains minimal data regarding the efficacy of this regimen in a larger, real-world cohort. Methods:Patients with CHL who received P-GVD at 9 United States centers were retrospectively evaluated to estimate efficacy and safety, with a focus on the second line use of this regimen. Demographic and clinical data were extracted from medical records. Responses reflected Lugano criteria per local investigator assessment. Study objectives were overall response rates (ORR), complete response rates (CRR), progression free survival (PFS), overall survival (OS), and safety. PFS and OS were estimated by Kaplan-Meier. Results: Patients and Treatment: We identified 65 CHL patients who received P-GVD between July 2019 and June 2024, including 43 who were treated in the second line. Enrolled patients included a median age of 31 years (range 17-69 years), 36.9% (24) females, 75.4% (49) nodular sclerosing subtype, and 60% (39) stage III-IV at diagnosis. Patients included 64.6% (42) White and non-Hispanic, 15.4% (10) Hispanic or White and Hispanic, 10.8% (7) Black, 3.1% (2) Asian/Pacific Islander, 3.1% (2) other, and 3.1% (2) unknown. The median number of prior regimens was 1 (range 0-12); these included 3.1% (2) who had prior checkpoint inhibitor (CPI), 50.8% (33) who had prior brentuximab vedotin (BV), and 3.1% (2) who had prior transplant. Patients with primary refractory disease [no initial complete response (CR)] comprised 58.5% (38), and 35.4% (23) had relapse within 1 year of completing initial therapy. The median number of cycles received was 3 (range 1-5). Treatment in a community practice setting was noted for 21.5% (14) patients. Efficacy: At a median follow up of 17.7 months, ORR and CRR after P-GVD were 95% (62/65) and 74% (48/65), respectively. This increased to 95% ORR and 81% CRR when limited to 43 patients who were treated 2nd line. Responses by line included: 1st [n=1; 100% ORR and CRR]; 3rd [n=15; 100% ORR, 73.3% CRR], 4th [n=3; 100% ORR, 33.3% CRR], 5th [n=2; 100% ORR, 0% CRR], and 13th [n=1; SD]. CRR in BV- and CPI-exposed patients were 60.6% and 50%, respectively. Ninety one percent (39) of 2nd line treated patients proceeded to autologous transplant, as well as all 3 patients > age 60. Among 41 response-evaluable second-line patients, CR was achieved in 94% (30/32) who received 2 or 3 cycles of P-GVD, and 56% (5/9) who received 4 cycles of P-GVD. For the entire cohort at 12 and 24 months after starting P-GVD, PFS was 95% (95% CI: 89-100%), 91% (95% CI: 83-100%) and OS was 98% (95% CI: 94-100%), 94% (95% CI: 86-100%), respectively. Ninety five percent (41) of 2nd line transplanted patients remain alive and in remission at a median of 18.5 months (range 3.5-38.7 months). In the primary refractory subset, PFS and OS at 24 months were 91% and 97%, respectively. For the cohort with 2 or more prior lines of therapy, PFS and OS at 24 months were 91% and 94%, respectively. Safety: Immune-related adverse events (IRAEs) were reported in 20% (13) of patients, of which grade 3 IRAEs per NCCN criteria version 1.2024 comprised 38.5%; all others were grades 1-2. Non-IRAE grade 3-4 toxicities per CTCAE version 5.0 were reported in 22% (14) patients. Of 29 patients evaluable for treatment-related interruptions, 7% (2) had therapy discontinued, and 34% (10) had holds, dose reductions, and/or delays. No deaths were attributed to P-GVD treatment. Conclusions:This retrospective study confirms the utility of P-GVD in treating relapsed/refractory CHL in a real-world population. Though fewer CRs and higher rates of grade 3 adverse events were observed, the vast majority of patients were able to proceed to transplant, and outcomes to date are highly encouraging.

Abstract Ataxia Telangiectasia–mutated (ATM) inhibitors are being developed as radiosensitizers to improve the antitumor effects of radiotherapy, but ATM inhibition can also radiosensitize normal tissues. Therefore, understanding the elevated risk of normal tissue toxicities is critical for radiosensitizer development. This study focused on modeling the relationship between acute mucosal toxicity, radiation dose, fractionation schedule, and radiosensitizer exposure. The ATM inhibitor WSD0628 was combined with single or fractionated doses of radiation delivered to the oral cavity or esophagus of Friend Leukemia virus B (FVB) mice. The potentiation by WSD0628 was quantified by a sensitizer enhancement ratio (SER), which describes the changes in radiation tolerance for radiation combined with WSD0628 relative to radiation-only regimens. WSD0628 profoundly enhanced radiation-induced acute oral and esophageal toxicities. For oral mucosal toxicity, the enhancement by WSD0628 with 3 fractions of radiation resulted in an SER ranging from 1.3 (0.25 mg/kg) to 3.1 (7.5 mg/kg). For the 7.5 mg/kg combination, the SER increased with increasing number of fractions from 2.2 (1 fraction) to 4.3 (7 fractions) for oral toxicity and from 2.2 (1 fraction) to 3.6 (3 fractions) for esophageal toxicity, which reflects a loss of the normal tissue sparing benefit of fractionated radiation. These findings were used to develop a modified biologically effective dose model to determine alternative radiation schedules with or without WSD0628 that result in similar levels of toxicity. Successful radiosensitizer dose escalation to a maximally effective therapeutic dose will require careful deliberation of tumor site and reduction of radiation dose volume limits for organs at risk.

Objective Epilepsy surgery is vital in managing of children with drug-resistant epilepsy. Noninvasive and invasive testing modalities allow for evaluation and treatment of children with drug-resistant epilepsy. Evidence-based algorithms for this process do not exist. This study examines expert response to a vignette of pediatric nonlesional epilepsy to assess associations in evaluation and treatment choices. Methods We analyzed annual report data and an epilepsy practice survey reported in 2020 from 135 pediatric epilepsy center directors in the United States. Characteristics of centers along with noninvasive and invasive testing and surgical treatment strategies were collected. Multivariable logistic regression modeling was performed. Results The response rate was 100% with 135 responses included in the analyses. Most used noninvasive testing modalities included Neuropsychology evaluation (90%), interictal brain fluorodeoxyglucose-positron emission tomography (85%), and functional magnetic resonance imaging (MRI) (72%) with nearly half obtaining genetic testing. Choosing functional MRI was associated with stereo electroencephalography (EEG) ( P = .025) and selecting Wada with subdural grid/strips ( P = .038). Directors from pediatric-only centers were more likely to choose stereo EEG as opposed to combined centers ( P = .042). Laser interstitial thermal therapy was almost 7 times as likely to be chosen as a treatment modality compared with open resection in dedicated pediatric centers (OR 6.96, P = .002). Significance In a vignette of nonlesional childhood drug-resistant epilepsy, epilepsy center directors’ patterns of noninvasive testing, invasive testing, and treatment were examined. Management choices were associated with pediatric versus combined pediatric/adult center characteristics. Expert opinions demonstrated equipoise in evaluation and management of children with drug-resistant epilepsy and the need for evidence-based management strategies.