Citations

Abstract Background The ataxia-telangiectasia mutated (ATM) protein coordinates the cellular response to therapeutic radiation, and ATM inhibitors can potentially enhance the efficacy of radiation in otherwise radiation-resistant tumors. Methods The small molecule ATM kinase inhibitor WSD0628 was specifically designed for enhanced distribution across the blood-brain barrier to more effectively treat glioblastoma (GBM) and brain metastases in combination with radiation therapy (RT). GBM and brain metastasis patient-derived xenograft models were used to understand target inhibition, radiosensitization, inhibition of the DNA damage response, and in vivo efficacy. Results Initial in vitro characterization of WSD0628 demonstrates a high level of selectivity across kinase families, limited aldehyde oxidase liability, and low risk of hERG interactions. Consistent with a central role for ATM in radiation response, WSD0628 blocked radiation-induced signaling and enhanced radiosensitivity in U251 glioma cells and brain tumor PDXs GBM120 and M12. In comparison to control or RT alone in orthotopic PDXs, the combination of WSD0628 with RT markedly prolonged median survival—GBM12 (19, 55, and 408 days, respectively); GBM43 (26, 44, and 143 days, respectively); GBM120 (51, 89, and 231 days, respectively); M12 (17, 39, and 190 days, respectively). Pharmacokinetic and pharmacodynamic testing after treatment in orthotopic GBM43 tumors showed inhibitory levels of WSD0628 and a reduction of γH2AX foci in the combination-treated tumors. Conclusions Collectively, these results suggest a promising role for WSD0628 in combination with RT in brain tumors and provide the rationale for an ongoing Phase 0/1A clinical trial testing this combination in recurrent GBM.

Background We automated subarachnoid hemorrhage volume (SAHV) calculation with artificial intelligence (SAHVAI) and created 3‐dimensional volumetric images (SAHVAI‐3D) using noncontrast head computed tomography data for patients with aneurysmal SAH. We also defined 4‐dimensional SAHVAI (SAHVAI‐4D), representing SAHV over time. We aimed to compare automated SAHVAI values and computational times to manual SAHV measurement methods, explore the potential of imaging biomarkers to identify at‐risk brain regions for delayed cerebral ischemia and explore potential insights in future neurotherapeutic interventions for patient recovery after SAH. Methods A training set of 10 consecutive patients with aneurysmal SAH was used to manually compute SAHV, SAHVAI‐3D, and SAHVAI‐4D, including 92 noncontrast computed tomography scans (182 slices each). The SAHVAI deep learning algorithm generated automated SAHV values in cubic centimeters. A 3‐dimensional SAH brain map was created for each patient for the SAHVAI and manual evaluations. Blood volumetric outputs were analyzed and compared to neurologic outcomes at discharge, including delayed cerebral ischemia events, symptomatic vasospasm, and areas with the thickest SAH blood concentration. Results SAHVAI quantified SAHV in a mean of 6.7 seconds per scan, significantly faster than the manual method, which took >60 minutes per scan (Fisher exact test, P <0.001). SAHVAI demonstrated an accuracy of 99.8%, Dice score of 0.701, false‐positive rate of 0.0005, and negative predictive value of 0.999. The mean absolute error between SAHVAI and manual methods was 5.67 mL. SAHVAI‐3D brain map and total SAHV at admission were inversely associated with Glasgow Coma Scale (R 2 = 0.23, P = 0.017) and directly associated with length of hospital stay (R 2 = 0.175, P = 0.004), especially in regions with dense blood concentration. Conclusion SAHVAI‐3D and SAHVAI‐4D brain mapping techniques represent innovative imaging biomarkers for SAH. These advancements enable rapid evaluation and targeted interventions, potentially improving patient care in SAH management.

Abstract Lineage switch (LS), defined as the immunophenotypic transformation of acute leukemia, has emerged as a mechanism of relapse after antigen-targeted immunotherapy, which is associated with dismal outcomes. Through an international collaborative effort, we identified cases of LS after a host of antigen-targeted therapies (eg, CD19, CD22, CD38, and CD7), described how LS was diagnosed, reviewed treatment approaches, and analyzed overall outcomes for this form of postimmunotherapy relapse. Collectively, 75 cases of LS were evaluated, including 53 (70.7%) cases of B-cell acute lymphoblastic leukemia (B-ALL) transforming to acute myeloid leukemia (AML), 17 (22.7%) cases of B-ALL transforming to mixed phenotypic acute leukemia (MPAL)/acute leukemias of ambiguous lineage (ALAL), and 5 (6.7%) cases of rare LS presentation (ie, T-cell ALL to AML). An additional 10 cases with incomplete changes in immunophenotype, referred to as “lineage drift” were also described. With a primary focus on the 70 cases of LS from B-ALL to AML or MPAL/ALAL, LS emerged at a median of 1.5 months (range, 0-36.5) after immunotherapy, with 81.4% presenting with LS within the first 6 months from the most proximal immunotherapy. Although most involved KMT2A rearrangements (n = 45, 64.3%), other rare cytogenetic and/or molecular alterations were uniquely observed. Treatment outcomes were generally poor, with remission rates of &lt;40%. The median overall survival after LS diagnosis was 4.8 months. Outcomes were similarly poor for those with rare immunophenotypes of LS or lineage drift. This global initiative robustly categorizes lineage changes after immunotherapy and, through enhanced understanding, establishes a foundation for improving outcomes of LS.

Purpose Venetoclax-based treatment for chronic lymphocytic leukemia (CLL) can be a logistically burdensome regimen due to extensive required monitoring of tumor lysis syndrome (TLS). The purpose of this study was to evaluate the feasibility and safety of pharmacist and registered nurse (RN) driven management of venetoclax ramp-up in CLL. Methods This was a prospective, pilot program for patients receiving venetoclax-based therapy for CLL. Patients had nine weekly visits during the first three cycles of therapy, of which five visits were independently performed by a pharmacist or RN. Laboratory tests to evaluate TLS were ordered and monitored independently by the RN in collaboration with clinicians (physician, nurse practitioner, physician assistant). Results Thirty CLL patients, median age 67 years, 73% treated in the frontline setting, started venetoclax between May 2022 and January 2023. After the initial three weeks of obinutuzumab treatment, TLS risk prior to venetoclax initiation had improved to low (93%), medium (3%), and high (3%). There was zero incidence of laboratory or clinical TLS by Howard criteria during the venetoclax ramp-up for all patients. Pharmacist and RNs performed 139 independent visits and monitored 197 sets of TLS labs. Conclusion Use of independent pharmacist and RN visits for toxicity checks and TLS monitoring during weekly venetoclax dose ramp-up did not lead to increased incidence of TLS in patients with CLL. These visits increased both access and efficiency within the CLL clinic. This concept has the potential to be applied in other cancer care settings with a variety of treatment regimens.

Abstract Objectives In an effort to maintain the technical aspects of traditional prosthetic surgical aortic valve replacement (AVR) while reducing invasiveness and facilitate options for concomitant operations, transaxillary lateral mini-thoracotomy endoscopic robotic-assisted aortic valve replacement (RAVR) has been introduced. The present data highlight the contemporary international collaborative experience. METHODS All consecutive patients undergoing standardized RAVR across 10 international sites (1/2020–7/2024) were evaluated using a central database with 1 year follow-up. RESULTS A total of 300 patients were analysed with a median predicted risk of 1.6% with aortic stenosis in 85.7%, nearly half with bicuspid valves. Biological prostheses were implanted in 220 (73.3%) with a median valve size 23 mm, 10% receiving aortic root enlargement, with 17% of all patients undergoing concomitant procedures. Median cross-clamp 120 min with no conversions to sternotomy. Median length of stay was 5 days, 4.3% with prolonged ventilation, 1.7% renal failure, 1.0% stroke and 8.3% required re-thoracotomy for evacuation of haemothorax. There were two 30-day operative mortalities (0.7%). The new permanent pacemaker rate for the full cohort was 2.6%. Of 163 patients with complete 1-year clinical and echocardiographic follow-up, mean aortic valve gradient was 10 mmHg and all but 2 patients (1.2%) had trace to no prosthetic or paravalvular insufficiency. CONCLUSIONS RAVR is safe and effective, providing the reproducible benefits of surgical AVR while affording a less invasive approach that permits the opportunity for concomitant procedures. For low and intermediate risk patients with aortic valve disease, RAVR is a potential reproducible alternative for patients and heart teams.

Background: Severe alcohol-associated hepatitis (sAH) is a well-characterized disease with high short-term mortality. However, there is limited research on those with a “less severe condition” (moderate AH). This study aims to characterize in-depth patients with moderate AH (mAH), including the performance of mortality scoring systems, key prognostic factors, and survival over time. Methods: A multicenter retrospective cohort study (2009–2019) included patients with mAH (MELD score ≤20 at admission). Cox regression and receiver operating characteristic curves with AUC were used for analysis. Results: We included 1845 patients with AH (20 centers, 8 countries) between 2009 and 2019. mAH was defined as a MELD score ≤20 at admission. Twenty-four percent met the criteria for an mAH episode. Patients with mAH tend to be older and have a higher proportion of females, with a median MELD of 17 (15–19), Maddrey discriminant function (mDF) of 33 (22–40), the trajectory of serum bilirubin of 0.83 (0.60–1.21), and neutrophil-to-lymphocyte ratio (NLR) of 5 (2.96–8.60). The primary causes of death in mAH included multiple organ failure (34.1%) and infections (16.6%). The cumulative survival rates at 30, 90, and 180 days were 94.3%, 90.4%, and 88.2%, respectively. In multivariable analysis, age was the only significant predictor of 30-day mortality (HR 1.49, 95% CI: 1.27–1.76, p <0.001). Mortality prediction models showed poor performance, with AUC for MELD (0.671), mDF (0.726), trajectory of serum bilirubin (0.733), and NLR (0.697). Conclusions: Patients with moderate AH exhibited a mortality of 11.8% at 6 months, primarily driven by multiple organ failure and infections. These patients also exhibit a different clinical profile compared to those with sAH. Tailored models and therapeutic strategies are needed to improve long-term outcomes in mAH.

Importance Neoadjuvant systemic therapy (NST) has been associated with pathologic complete response (pCR) in up to 60% of breast cancers (BCs). The findings of this trial question the necessity of surgery. Objective To report preplanned 5-year efficacy outcomes evaluating radiotherapy alone without breast surgery in patients selected with image-guided vacuum assisted biopsy (VAB). Design, Setting, and Participants This single-arm, prospective, phase 2 nonrandomized clinical trial was conducted at 7 US medical centers and included women 40 years or older with cT1-2N0-1M0 ERBB2 -positive (formerly HER2 -positive) or triple-negative invasive BC who showed residual breast lesions after NST of less than 2 cm on imaging. Enrollment was from March 6, 2017, to November 9, 2021. Data analysis was from October to December 2024. Intervention Image-guided VAB of the tumor bed (9G with a minimum of 12 cores) was performed after standard NST. Patients with clinically node-negative disease at diagnosis and no residual cancer in the breast on post-NST VAB underwent whole-breast radiotherapy with a boost without breast or axillary surgery. Patients with initial documented nodal disease and a breast pCR on VAB underwent targeted axillary dissection, while those with residual cancer when undergoing VAB had standard breast and axillary surgery. Patients were monitored with physical examinations and mammography every 6 months. Main Outcome Measures The primary outcome was ipsilateral breast tumor recurrence. Results Fifty patients (median [IQR] age, 62 [55-77] years) were enrolled and underwent post-NST VAB. Twenty-nine (58%) and 21 (42%) patients had ERBB2 -positive and triple-negative invasive BC, respectively. Breast pCR on VAB was identified in 31 patients (62%; 95% CI, 47.2%-75.34%), and axillary pCR was identified among all 8 patients with initial nodal metastases and breast pCR on VAB who underwent targeted axillary dissection. At a median follow-up of 55.4 (IQR, 44.0-63.5) months, the ipsilateral breast tumor recurrence rate was 0%, and disease-free and overall survival rates were 100% for patients without breast surgery. Conclusions and Relevance The results of this nonrandomized clinical trial that reported preplanned 5-year outcomes suggest that omission of breast surgery in select patients after NST may be feasible, with no recurrences seen. More confirmatory studies are necessary before this new approach alters surgical practice. Trial Registration ClinicalTrials.gov Identifier: NCT02945579

Abstract Excessively restrictive inclusion and exclusion criteria in clinical trials are one of many barriers to clinical trial enrollment for patients with myelodysplastic syndromes/neoplasms (MDSs). Many organizations are developing efforts to increase clinical trial eligibility; yet, several recent publications focused on patients with MDS suggest that many patients with this disease may be excluded from clinical trials unnecessarily. Clinical trial eligibility should reflect the phase of the study and risks of the agent being studied. Phase 3 trials should be less restrictive than early-phase trials to represent the real-world population as closely as possible. We hypothesize that many clinical trials, particularly phase 3 trials, have unnecessarily restrictive eligibility criteria. This study aims to evaluate the most common eligibility criteria according to phase of trial and to determine whether criteria correspond with drug safety signals. We identified MDS clinical trials registered on ClinicalTrials.gov from 1 January 2000 to 1 September 2023 and analyzed the eligibility criteria of 191 therapeutic MDS trials. We found that categorical inclusion and exclusion criteria are remarkably similar in representation across trial phases. Additionally, only 13% of trials are concordant with drug safety signals, suggesting that the eligibility criteria are often arbitrary. On behalf of the icMDS (International Consortium for Myelodysplastic Syndromes), an association of international MDS experts, we provide a position statement on restrictive eligibility criteria for MDS clinical trials that should be avoided with the aim of removing barriers to clinical trial enrollment.