Citations

Abstract We evaluated outcomes by management type for patients with stage IA nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) in the Global NLPHL One Working Group retrospective database of 2243 patients with stages I to IV disease diagnosed from 1992 to 2021 at 38 international institutions. A total of 779 patients had stage IA disease with median age of 35 years (range, 3-89) and median follow-up of 6.1 years. The 6-year progression-free survival (PFS) and overall survival were 86.3% and 97.7%, respectively. Outcomes were analyzed for the 2 groups: complete resection and unresected disease. Patients with a complete resection and observation alone (n = 99) had a 6-year PFS of 65.5% vs 90.5% for those who received radiotherapy (RT) (n = 53). Patients with unresected disease (n = 627; 80.5%) had a 6-year PFS of 62.0% for rituximab alone (n = 31), 89.6% for RT alone (n = 325), 76.8% for ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) alone (n = 40), and 94.3% for ABVD plus RT (n = 130). A total of 127 patients relapsed (16.3%), of which 25 (19.7%) had transformation. Our analysis suggests the following: (1) RT improves the PFS in patients with completely resected disease; (2) rituximab or ABVD alone does not appear to achieve a durable response; and (3) chemotherapy was not observed to add additional PFS benefit when used in combination with RT. Thus, for stage IA NLPHL, RT alone is likely sufficient for definitive treatment.

Introduction Trigeminal neuralgia is a debilitating facial pain condition characterized by recurrent, electric shock-like episodes within the trigeminal nerve distribution. While first-line treatment involves pharmacologic therapy, treatment options are limited for patients who are refractory or poor surgical candidates. Case Presentation We present a 75-year-old female with long-standing idiopathic trigeminal neuralgia refractory to combination anticonvulsant therapy and nerve block, with notable medication-related side effects. Management and Outcomes The patient underwent percutaneous cryoneurolysis targeting the maxillary (V2) and mandibular (V3) divisions of the trigeminal nerve under fluoroscopic guidance. She experienced immediate pain reduction and complete symptom resolution at a one-month follow-up with no complications. Conclusion This case highlights percutaneous cryoneurolysis as a minimally invasive treatment option for selected patients with refractory trigeminal neuralgia who are not candidates for open surgical intervention.

Background Psychiatric disorders are increasingly contributing to global disability. Despite advances in conservative management, the prevalence of treatment-resistant cases remains high. Meanwhile, neurosurgery for psychiatric disorders (NPD) remains underused, largely due to strict regulations and historical concerns, particularly those related to neuropsychological side effects (NPSE). Objective To address this issue, we conducted a systematic review with meta-analysis to compare NPSE associated with radiofrequency ablative NPD to those observed in neuro-oncological, neurovascular and epilepsy surgeries. Methods PubMed, Embase and LILACS databases were searched in April 2024 for articles published in English/Spanish from 1990 to 2022, following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Results A total of 48 articles with 2678 participants were included. The frequency of transient and permanent NPSE in the NPD group ranged from 0.94% to 11.50% and 0.94% to 2.03%, respectively, comparable to the other surgical groups (epilepsy: 0.31–11.70%; vascular: 0.52–22.90%; oncology: 0.94–17.60% for transient NPSE; epilepsy: 0.31–12%; vascular: 0.40–1.96% and oncology: 0.84–1.48% for permanent NPSE). Regarding permanent NPSE, arguably the most critical consideration, the NPD group showed better outcomes in memory, language and social cognition than the epilepsy group, but worse outcomes in executive and perceptual-motor functions. Compared with the vascular group, the NPD group had better executive function but worse complex attention. Finally, the NPD group had fewer permanent deficits than the oncology group in executive function, complex attention and perceptual-motor domains, although language performance was lower. Conclusions Contemporary NPD apparently carries a similar risk of NPSE as other conventional neurosurgical procedures, challenging misconceptions and this unjustified barrier to its broader use.

Abstract Breast and ovarian cancers are major causes of cancer mortality in women with frequent relapse after curative intent treatment, underscoring the need for novel therapeutics. To this end, we identified CTPS1 as an essential gene in multiple breast and ovarian cancer models, including those resistant to chemotherapy and PARP inhibitors. CTPS1 and CTPS2 are responsible for de novo synthesis of cytidine triphosphate (CTP) which is required for DNA/RNA polymerization, phospholipid synthesis and protein glycosylation. We found CTPS1 to be the predominant isoform expressed in cancer cells, with significantly higher levels in advanced and resistant disease models compared to normal tissue, benign lesions and treatment naïve cancers. Using CTPS1 siRNAs and CTPS1-dTAG (degradation tag) cell lines, we discovered that depletion of CTPS1 induces S-phase cell cycle arrest followed by apoptosis. Leveraging a first-in-class, highly selective, and orally bioavailable CTPS1 inhibitor (STP938) developed by Step Pharma, we identified nanomolar IC50 values across a panel of cell lines, both in 2D and 3D culture systems, and potent anti-neoplastic activity ex vivo and in vivo using patient-derived xenograft (PDX) models. STP938 also synergized with standard-of-care chemotherapy agents and PARP inhibitors, including in therapy-resistant models. Given the essentiality of CTP for biosynthetic processes, we performed bulk and single cell RNA-seq, total and phospho-proteomics, metabolomics, and lipidomic strategies to examine changes induced by acute and chronic STP938 exposure. This revealed that cancer cells are able to overcome pharmacologic CTPS1 inhibition by rewiring of pyrimidine and purine synthesis pathways, upregulation of the pentose phosphate pathway, and extensive remodeling of lipid synthesis pathways including shifts in PC/PE content, increased lysophospholipid production, and altered mitochondrial lipid composition (decreased cardiolipin and increased PG). To identify genetic drivers of STP938 resistance and synthetic lethal vulnerabilities, we performed a genome-wide CRISPR knockout screen together with a PRISM drug sensitivity screen. Genes regulating dNTP biosynthesis, S-phase progression, and RNA processing were identified as primary escape mechanisms, while DHODH inhibitors, purine and nucleoside analogs, and mitosis modifiers were implicated as synthetic lethal opportunities. Notably, we discovered that 25% of ovarian tumors lack CTPS2 protein expression, suggesting near complete reliance on CTPS1 for survival. Thus, a Phase 1a/b clinical trial of STP938 (NCT06297525) has been initiated, including an expansion cohort for patients with CTPS2-null ovarian tumors. These laboratory discoveries and ongoing clinical efforts aim to enable broader uptake of this novel therapeutic approach to improve long-term outcomes in patients with CTPS1-dependent disease. Citation Format: Xiyin Wang, Michael Emch, Lauren Voll, Rebecca Epp, Esther Rodman, Noa Odell, Hannah Smith, Nicole Pearson, Xiaonan Hou, Matthew Goetz, Scott Kaufmann, S. John Weroha, Phillip Beer, John Hawse. CTPS1 as a metabolic vulnerability and novel therapeutic target in breast and ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4560.

Abstract Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal human malignancies due to its silent clinical onset, rapid progression, and limited responsiveness to current treatment options. These features underscore the urgent need for early detection strategies and for new molecular targets that can be exploited therapeutically. Epithelial Cell Transforming Sequence 2 (ECT2) is a Rho family guanine nucleotide exchange factor that was originally identified as an oncoprotein and later shown to regulate cytokinesis. In this study, we examined the clinical relevance of ECT2 expression in PDAC and determined its functional contribution to transformed growth and tumorigenicity. Our analyses revealed that ECT2 expression increases at the earliest stages of PDAC development, remains persistently elevated during disease progression, and associates with reduced overall patient survival. Furthermore, a substantial fraction of ECT2 is aberrantly localized to the cytoplasm of PDAC cells. Functional studies demonstrated that depletion of ECT2 suppresses three-dimensional growth, invasive behavior, and tumor formation in vivo, while having little impact on PDAC cell cytokinesis. Mechanistically, we found that ECT2 is required for activation of Rac1 and RhoA and downstream MEK/ERK and ROCK signaling, respectively. Consistent with these results, analyses of PDAC patient datasets revealed a strong positive association between ECT2 expression and Rho GTPase as well as MEK/ERK and ROCK pathway signatures. Together, our data identify ECT2 as an early driver of PDAC transformation and highlight it as a promising therapeutic target. Citation Format: Dania Al-Qasrawi, Nayya N. Murray, Ryan A. Argo, Alicia K. Fleming Martinez, Prita Pandya, Anaya Y. Clarke, Kayla C. Winter, Murli Krishna, Peter Storz, Nicole R. Murray, Verline Justilien, . The Rho-GEF ECT2 links Rho GTPases to MEK/ERK pathway activation in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5993.

Abstract Approximately 288,000 men are diagnosed with prostate cancer (PCa) in the United States each year, with cases expected to double by 2040. While metastatic PCa can be treated with androgen deprivation therapy (ADT) and AR pathway inhibitors (ARPI), it inevitably develops into treatment resistant, lethal disease. The most common ARPI resistance mechanism in PCa is the expression of AR splice variant AR-V7 that lacks the ligand binding domain and is constitutively active. Patients with PCa expressing AR-V7 experience inferior overall survival. Speckle-type POZ protein (SPOP) is an adaptor protein of the Cullin3-based E3 ubiquitin ligase that facilitates both degradative and non-degradative polyubiquitination of targets such as AR. Loss-of-function SPOP mutations occur in approximately 10-15% of prostate cancers, and SPOP-mutant PCa is a unique subtype that has been shown to be exquisitely sensitive to ADT and ARPI treatment. This sensitivity is mediated in part by increased androgen availability via upregulation of hydroxysteroid 17-beta dehydrogenase 4 (HSD17B4) and related steroid synthesis pathways, reduced AR degradation, and enhanced AR cofactor activity. The remarkable efficacy of ARPI in ADT-resistant SPOP-mutant prostate cancer is not well understood. We hypothesized a novel mechanism by which wild-type SPOP promotes AR-V7-mediated resistance to ARPI in PCa. This mechanism may explain the exceptional ARPI sensitivity of SPOP-mutant PCa, distinct from its susceptibility to ADT. We further proposed that clinical SPOP inhibition may broaden this enhanced ARPI susceptibility to the 85-90% of PCa expressing wild-type SPOP. Our results show that SPOP drives ARPI resistance in prostate cancer that can be reversed by SPOP inhibitor. Bulk RNA sequencing showed that SPOP inhibitor targets spliceosome machinery and more importantly, abrogated AR-V7 expression both at transcriptional and protein level. Further investigation revealed that wild-type SPOP ubiquitinates spliceosome regulator SFPQ, promoting AR-V7 alternative splicing and ARPI resistance. While SPOP loss is pathogenic in PCa, leveraging the weakness conferred by SPOP mutation in the 85% of patients with SPOP-wild type provides an innovative strategy to sensitize ARPI resistant disease to standard of care treatment and save lives. Citation Format: Joanina K. Gicobi, Susanna M. Gregory, Nicole A. Becker, Elizabeth A. Bering, Jacob J. Orme.. SPOP drives AR-V7-mediated ARPI resistance in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3904.

Background: Tranexamic acid (TXA) is widely used in craniosynostosis surgery to reduce blood loss. Although the efficacy of TXA administration has been documented in the literature, dosing in the perioperative setting is variable and without a standard protocol. The purpose of this study is to determine the efficacy of continuing TXA postoperatively for patients undergoing suturectomy for metopic or unicoronal synostosis. Methods: We conducted a retrospective cohort study evaluating the use of postoperative TXA infusion in patients undergoing suturectomy for metopic and unicoronal craniosynostosis. All patients received a TXA bolus of 10 mg/kg at the time of surgical prep, followed by a TXA infusion at 5 mg/kg/hour during the procedure. Patients undergoing suturectomy for metopic or unicoronal synostosis in 2020 to 2021 received postoperative TXA infusion at 5 mg/kg/hour for the first 4 hours after surgery. Following a protocol change in anemia management at the institution in 2022, patients undergoing this surgery in 2022 did not receive a postoperative TXA infusion. Chart review was performed, and mean hemoglobin values were compared between patients who received postoperative TXA and those who did not, with analyses stratified by suture involvement to determine the impact of the protocol change. Results: Twenty-eight patients met the inclusion criteria: 14 patients received postoperative TXA, and 14 patients did not. Both groups included 8 patients undergoing metopic suturectomy and 6 patients undergoing unicoronal suturectomy. For patients who underwent metopic suturectomy and received postoperative TXA, the mean preoperative hemoglobin was 11.4 g/dL, and on postoperative day 1 (POD1) was 8.1 g/dL. For patients who underwent metopic suturectomy and did not receive postoperative TXA, the mean preoperative hemoglobin was 11 g/dL and on POD1 was 9.2 g/dL ( P =0.27). The differences in mean preoperative and postoperative hemoglobin were not statistically significant between the 2 cohorts, P =0.15 and P =0.20, respectively. For patients who underwent unicoronal suturectomy and received postoperative TXA, the mean preoperative hemoglobin was 12 g/dL, and on POD1 was 8.7 g/dL. For patients who underwent unicoronal suturectomy and did not receive postoperative TXA, the mean preoperative hemoglobin was 11.4 g/dL and on POD1 was 9.1 g/dL ( P =0.36). The mean preoperative and postoperative hemoglobin were not statistically different between the 2 cohorts, P =0.42 and P =0.92, respectively. Hospital length of stay averaged 1 day across both cohorts. No patient received a postoperative blood transfusion. Conclusion: In patients undergoing suturectomy for metopic or unicoronal craniosynostosis, postoperative TXA infusion made no significant difference in postoperative hemoglobin levels, length of stay, or postoperative transfusion. Discontinuing postoperative TXA could potentially decrease monitoring needs and lower hospital costs.

PURPOSE Artificial intelligence (AI) has been rapidly evolving in medicine. While there are existing data about the perceptions and concerns of health care workers regarding AI, those of the hematology and oncology (HemOnc) workforce remain unknown. We assessed opinions of physicians (faculty and fellows), advanced practice providers (APPs), and nurses in HemOnc on integrating AI in medical education (MedEd) and clinical practice (CP). METHODS Group-specific electronic surveys were developed. The HemOnc workforce from the three Mayo Clinic sites was invited to participate. Participation was anonymous, with data collection between November 7, 2024, and January 20, 2025. Results were reported as proportions, with 95% binomial CI when appropriate. RESULTS A total of 344 participants responded, 118 physicians (77 faculty, 41 fellows), 49 APPs, and 177 nurses. Most had used AI although less than half felt very or moderately knowledgeable about it. A total of 95% of fellows, 97% of faculty physicians, 96% of APP, and 92% of nurses believe that AI will be integrated in MedEd. A total of 94% of physicians and 88% of nonphysicians believe that this integration would be beneficial. In CP, 98% of fellows, 96% of faculty physicians, 100% of APPs, and 92% of nurses believe in AI's integration. However, 51% of physicians and 68% of nonphysicians had some concerns, including technology time, medical costs, and burnout. Nonetheless, 85% of fellows, 94% of faculty physicians, 98% of APPs, and 86% of nurses would embrace AI. CONCLUSION The majority of this single health system HemOnc's workforce endorsed AI integration into MedEd and CP but highlighted relevant concerns. Proper education, effective partnership among all stakeholders, and well-organized integration are essential for optimizing AI's incorporation into HemOnc's MedEd and CP and ensuring that it fully supports the mission of providing high-quality patient care.