Citations

ABSTRACT Bispecific T cell engagers (BTEs) induce MHC‐independent cytotoxicity by bridging T cells to tumor cells via binding a T cell–activating receptor and a tumor‐associated antigen. BTEs have proven effective in hematologic malignancies and some solid tumors, yet their potential in glioblastoma (GBM) is largely unexplored. We developed a fully humanized BTE (hBTE) targeting interleukin‐13 receptor alpha 2 (IL13RA2), a tumor‐associated antigen widely expressed in GBM and associated with poor prognosis. In vitro, hBTE activated T cells and induced antigen‐dependent cytokine release and cytotoxicity against IL13RA2‐positive GBM cells. In vivo, hBTE showed robust target‐specific activity and markedly prolonged survival in primary and recurrent GBM xenograft models, without detectable off‐target local or systemic toxicity. Beyond GBM, hBTE also exhibited antitumor activity in IL13RA2‐expressing solid tumors, demonstrating selective tumor accumulation and therapeutic efficacy in models of breast cancer brain metastases and extracranial lung cancer. This work highlights the therapeutic potential of BTEs in IL13RA2‐expressing tumors and establishes a strong preclinical rationale for advancing hBTE therapy toward clinical translation in GBM and other tumors.

Purpose To assess the ability of artificial intelligence (AI) to identify common sports‐related pathologies using radiologic imaging and to compare ChatGPT 4.0 with 2 competitors, Grok 2 and Claude 3.5 Sonnet. Methods ChatGPT 4.0, Grok 2, and Claude 3.5 Sonnet were used. Five common orthopaedic sports pathologies were chosen: anterior cruciate ligament tears, posterior cruciate ligament tears, meniscal tears, chondral pathologies, and rotator cuff tears. Fifty images representing each pathology were collected from a radiologic imaging database when possible, which included radiographic images, computed tomography, and magnetic resonance imaging. Normal images were collected that corresponded to each diagnostic category. Receiver operator characteristic curves and area under the curve values were calculated to assess the accuracy of each AI platform. Results ChatGPT 4.0, Grok 2, and Claude 3.5 Sonnet accurately identified the pathology in 23.6%, 15.7%, and 17.1% of diseased images, respectively. ChatGPT and Grok were most accurate at identifying meniscus pathologies (ChatGPT: 48%, Grok: 42%), whereas Claude Sonnet was most accurate at identifying anterior cruciate ligament pathologies (30%). The area under the curve for ChatGPT, Grok, and Claude Sonnet was 0.21, 0.16, and 0.15, respectively (ChatGPT 4.0 vs Grok 2, P = .30; ChatGPT 4.0 vs Claude 3.5 Sonnet, P = .24; Grok 2 vs Claude 3.5 Sonnet, P > .99). There were no differences in performance between the 3 platforms overall or within any of the diagnostic categories. Conclusions ChatGPT 4.0, Grok 2, and Claude 3.5 Sonnet correctly identified the pathology in less than 25% of images of common sports‐related pathologies and showed area under the curve values well below 0.5, indicating poor accuracy. Based on these findings, we do not recommend the current use of these generative AI models for image‐based diagnosis in orthopaedics. Clinical Relevance As the use of AI becomes more popular within the general public, it becomes increasingly important to make aware the capabilities and limitations of popular AI platforms in regard to their current image‐based diagnostic capabilities.

ABSTRACT As interest in the use of cannabinoids for supportive care in pediatric cancers grows, there are emerging concerns about potential interactions with antineoplastic agents. This review provides an overview of potential drug–drug interactions between cannabinoids and 25 antineoplastic agents commonly used in pediatric hematology/oncology. Antineoplastic agents were stratified into low, medium, or high interaction risk based on the potential impact of cannabinoids on metabolic and/or pharmacodynamic pathways. The antineoplastic agents identified as high risk for interactions with cannabinoids included cyclophosphamide, doxorubicin, etoposide, ifosfamide, irinotecan, vinblastine, and vincristine. Key mechanisms of interaction include inhibition of cytochrome P450 enzymes and UDP‐glucuronosyltransferases and modulation of drug transporters such as P‐glycoprotein and breast cancer resistance protein. There is emerging evidence of a synergistic effect between cannabinoids and antineoplastic agents such as temozolomide, vinblastine, vinorelbine, and irinotecan. Pediatric patients exhibit developmental differences in drug metabolism and transporter expression, yet most pharmacokinetic data on cannabinoids are extrapolated from adult studies. There is a lack of pediatric‐specific safety, efficacy, and dosing data that underscores the need for age‐appropriate studies to ensure safe and effective integration of cannabinoids in pediatric cancer care.

Advances in oncology drug development are driving the emergence of novel therapies, challenging traditional dose-efficacy assumptions in dose-finding oncology trials. Traditional trial designs aim to identify a maximum tolerated dose (MTD) by assessing patients’ dose-limiting toxicities (DLTs) – adopting traditional dose-efficacy paradigms that efficacy increases with treatment dose. With these new therapies in mind, emphasis should shift toward methodological advancements in trial designs aimed at identifying optimal doses, rather than solely determining MTDs. Incorporating patient-reported outcomes (PROs) within dose-finding oncology trials is increasingly recommended to better understand treatments’ tolerability profiles, especially given the extended tolerability assessment windows for novel immunotherapies and targeted therapies. This article introduces PRO-ADD ( P atient- R eported O utcomes A ided D ose-optimisation D esign), a modular trial design framework for dose-optimisation. We leverage this framework to optimise dosage with respect to three key outcomes – clinician-assessed DLTs, PROs and preliminary efficacy. PRO-ADD performs well at identifying the optimal dose (both efficacious and tolerable) – successfully identifying the most tolerable effective dose and avoiding escalation to larger, safe doses offering no additional efficacy benefit. As the field evolves, patient-centric dose-finding approaches incorporating PROs are crucial in advancing our understanding of treatment tolerability, and in turn, shaping the future landscape of dose-finding oncology trials.

Abstract Cerebellopontine angle (CPA) tumors, including vestibular schwannomas (VS), often require microsurgical resection. These are typically surgical procedures performed by co-surgeons, and some controversy and confusion exist regarding use of common procedural terminology (CPT) codes for billing, given the American Medical Association (AMA) describes two distinct coding sets for such cases. This investigation endeavored to: (1) Comprehensively review all surgical coding options; (2) instruct on application; and (3) explore contemporary coding trends among surgeons. A multi-disciplinary task force (otologist/neurotologists and neurosurgeons) performed direct correspondence with various surgical societies, private consultancies, and the AMA. Survey instruments were distributed to active surgeons. Investigational period: 2022 to 2025. Survey instruments distributed at the 2023 American Neurotology Society (ANS) Fall Meeting. ANS, American Academy of Otolaryngology (AAO-HNSF), and the North American Skull Base Society (NASBS) representatives. Usage rate for CPT code sets (percentage of responders). Two CPT coding systems are currently accepted for surgical management of CPA tumors. The traditional/legacy codes (Indicator-2) allow use of co-surgery modifiers (-62). The newer approach/resection codes (skull base codes; Indicator-1) restrict modifier use. The history, application, and controversies surrounding the codes are detailed herein. About 40% of surgeons reported use of the traditional codes, while 45 to 49% use the skull base codes. Response rate was 31% of the active ANS membership in 2023. The AMA recognizes two CPT code sets for surgical management of CPA tumors. Both are appropriate, if properly applied. Contemporary surgeons likely utilize the sets in equal proportions.

ABSTRACT Background and Objectives NCCN guidelines recommend right hemicolectomy (RHC) for appendiceal neuroendocrine tumors (aNETs) > 2 cm and observation for < 1 cm. However, optimal surgical management of 1–2 cm tumors remains controversial. This study compared long‐term survival and recurrence between patients undergoing RHC versus appendectomy (APY) for 1–2 cm aNETs. Methods Patients with pathologically confirmed 1–2 cm aNETs treated at three Mayo Clinic sites (1972–2024) were included. Primary outcomes were recurrence and all‐cause mortality after resection. Associations with lymph node (LN) metastasis were assessed in patients with lymphadenectomy. Results Sixty‐five patients were identified: 29 (45%) underwent APY, 35 (54%) RHC, and one ileocecectomy. Median age at diagnosis was 39 years; 71% were female and 94% white. LN positivity was 15.2% for tumors with nodes examined. Tumor size > 1.5 cm, stage T3/T4, and lymphovascular invasion were not associated with nodal metastasis. No survival differences were observed between APY and RHC. LN positivity did not impact survival. No recurrences occurred during a median follow‐up of 6.25 years (IQR 2.44–12.63). Conclusions Among patients with 1–2 cm aNETs, RHC conferred no survival benefit over APY. Absence of recurrence and the limited prognostic value of nodal disease suggest APY alone may suffice for this population.

Background There is growing evidence suggesting a bidirectional relationship between fibromyalgia and migraine. The aim of this work was to study the impact of fibromyalgia on the frequency and severity of migraine headache attacks and the psychological burden in patients with comorbid migraine and fibromyalgia. Methods This cross-sectional comparative study was conducted on 114 patients with comorbid migraine and fibromyalgia and 270 patients with migraine only. All included patients were subjected to a comprehensive assessment of headache through face-to-face interview and assessment of the psychological state using the Depression, Anxiety and Stress Scale-12 (DASS-12). Patients with fibromyalgia were requested to answer the Revised Fibromyalgia Impact Questionnaire (FIQR). Results Patients with comorbid migraine and fibromyalgia had significantly higher monthly migraine days (MMD), headache impact test-6 (HIT-6), and DASS-12 total scores than patients with migraine only ( p -value &lt; 0.001, 0.009, and &lt; 0.001, respectively). There was a statistically significant positive correlation between the FIQR total score and DASS-12 total score ( p -values = 0.001). Additionally, statistically significant positive correlations were found between the FIQR total score and both the MMD and HIT-6 total scores ( p -values = 0.002 and 0.008, respectively). There were also statistically significant positive correlations between the DASS-12 total score and both the MMD and HIT-6 total scores ( p -values = 0.006, 0.027, respectively). Conclusion Fibromyalgia is an aggravating comorbid condition with migraine that is associated with a higher frequency and severity of migraine headache attacks, in addition to increasing the psychological burden.

ABSTRACT Although Doxorubicin (Dox) is an effective anticancer drug, it can cause severe cardiotoxicity. While several mechanisms have been proposed to explain Dox‐induced cardiomyopathy (DIC), strategies to prevent it remain limited. In previous research on isolated cardiomyocytes, we identified that Empagliflozin (EMPA), an antidiabetic drug, mitigated Dox‐induced ER stress and apoptosis. In this in vivo study using rats, we further investigated EMPA's potential in preventing and treating DIC. Rats administered a cumulative dose of 15 mg/kg Dox exhibited significant cardiovascular damage, including left ventricular cavity dilation, decreased left ventricular ejection fraction (LVEF), ER dilation, mitochondrial defects and vacuole formation. These structural changes were linked to the activation of ER‐stress pathways (PERK, IRE1 and ATF6) and upregulation of apoptotic proteins initiated by ER stress. When EMPA (10 mg/kg/day) was administered either prophylactically or concurrently with Dox, it significantly attenuated adverse LV remodelling and preserved LVEF. Additionally, EMPA prevented ER stress and subsequent apoptosis in the myocardium of the Dox + EMPA‐treated group. These findings suggest that EMPA offers cardioprotective benefits in DIC, likely through the inhibition of ER‐stress‐induced myocardial injury.