Citations

Abstract Medulloblastoma (MB) is one of the most prevalent malignant brain tumors in children, with tremendous cognitive and neuroendocrine disability among survivors. Group 3 (G3) MBs have poor overall survival at < 50%, higher frequency of metastasis, and no targeted therapies. Amplification of MYC and activation of TGFβ signaling are frequent in G3MB. Remarkably, some tumors have no reported mutations, suggesting roles for epigenetic mechanisms in driving disease. We have generated novel humanized models for G3MB by transducing neuroepithelial stem cells (NESC) derived from human induced pluripotent stem (iPSC) cells with TGFβ effectors alone and/or in combination with MYC, prioritizing combinations observed in patients. We determined that both MYC and TGFβ effectors drove tumor formation in vivo with the combination driving more aggressive tumors and higher frequency of metastasis. NESC-derived tumors clustered with human G3/G4MB, indicating our models recapitulated human disease. To decipher mechanisms of resistance, we integrated CUT&RUN for MYC genomic localization and histone PTMs with RNA-sequencing and discovered MYC-bound neural developmental genes repressed in MYC and TGFβR1-driven lines. Further interrogation identified JARID1B, a MYC binding partner, as a regulator of many of these repressed neural genes. We postulate that deregulation of MYC and context-specific targeting to the chromatin template culminates in transcriptional alterations that promote aggressive G3MB. To further investigating therapeutic vulnerabilities, we have performed a in vivo whole genome CRISPRi screen to reveal important drivers of malignancy, one of the first of it’s kind in brain tumors. We are functionally validating key candidate sgRNAs that were differentially significant in primary tumors and may also have key roles in driving metastasis. Excitingly, many sgRNAs identified from the screen were chromatin modifiers and may be important co-factors of MYC-mediated regulation on the epigenome. Collectively, our studies provide a critical framework for understanding mechanisms of resistance and the epigenetic landscape of MYC- and TGFβ-driven MB.

Leptomeningeal disease (LMD) is a devastating complication of metastatic melanoma, affecting up to 15% of patients with central nervous system involvement. Despite advances in systemic therapy, LMD carries poor prognosis. Patients with LMD are often excluded from clinical trials. Contemporary real-world data on prognostic factors and treatment outcomes in melanoma LMD are limited. We conducted a retrospective cohort study of patients diagnosed with leptomeningeal metastasis from melanoma between 1 January 2018 and 31 December 2025, across Mayo Clinic sites. LMD diagnosis was made by magnetic resonance imaging showing leptomeningeal enhancement and confirmation from cerebrospinal fluid cytology and clinical presentation. Demographic, clinical, treatment, and outcome data were collected. Overall survival (OS) from LMD diagnosis was the primary endpoint. Forty-four patients were identified (median age: 60.0 years, range: 30.5–82.7). Before diagnosis of LMD, systemic therapy for metastatic disease was given to 91% of patients. BRAF mutations were present in 65.9%. After LMD diagnosis, 88.6% were treated for LMD. Median OS was 2.96 months (95% confidence interval: 1.39–4.53). Poor Eastern Cooperative Oncology Group performance status was independently associated with worse OS (hazard ratio: 2.10, P = 0.036). Any treatment for LMD (hazard ratio: 0.16, P = 0.005) was associated with improved OS. Melanoma-related LMD remains rapidly fatal. Studies of novel treatments are needed to improve outcomes for patients with this diagnosis.

ABSTRACT Background In pediatric kidney transplant recipients, native nephrectomy is sometimes performed to manage conditions such as polyuria, nephrotic syndrome, and recurrent infections. To minimize surgical morbidity, our center adopted a technique from the adult transplant program involving ligation of native ureters at the time of transplantation as an alternative to native nephrectomy in selected patients. Methods This retrospective study describes our center's experience with pediatric patients who underwent ureteral ligation at transplantation between December 2008 and December 2022. Patient selection was based on clinical judgment rather than predefined criteria. Results Sixteen patients underwent ureteral ligation, with polyuria (12/16) and proteinuria associated with focal segmental glomerulosclerosis (4/16) as the primary indications. Ligation was unilateral in 5 patients and bilateral in 11. The average follow‐up was 5.7 years. No operative complications directly attributable to ureteral ligation were observed, including native kidney pyelonephritis or need for reoperation. Although post‐transplant imaging often revealed hydronephrosis of the native kidneys, it had no clinical consequences. Late postoperative hypertension occurred in 31% of the ligation group compared to 47% of controls without ligation, while new‐onset hypertension was more common in the ligation group (18.8% vs. 5.1%). Pain scores postoperatively were comparable between groups. Conclusions This technical report suggests that native ureteral ligation at pediatric kidney transplantation is feasible in selected patients but represents an empirical, non‐standard‐of‐care approach. Prospective comparative studies are needed to refine patient selection and assess long‐term outcomes.

ABSTRACT Introduction/Aims In severe ulnar neuropathy at the elbow (UNE), occasionally surgeons will employ an end‐to‐side (ETS) nerve transfer of the anterior interosseous nerve (AIN) motor branch of pronator quadratus (PQ) to the ulnar motor component distally (AIN ETS). We used an ultrasound (US)‐guided near‐nerve monopolar needle stimulation of the AIN to determine the specific contribution of the transferred PQ motor branch to the ulnar‐innervated hand intrinsic muscles following AIN ETS in patients with UNE. Methods After inserting the monopolar needle under US guidance, direct stimulation of the AIN was performed while recording from the abductor digiti minimi (ADM), first dorsal interosseous (FDI), and flexor pollicis longus (FPL). The presence or absence of a compound muscle action potential (CMAP) was noted from each muscle. Results The technique was used in two patients with chronic UNE, one with a cubital tunnel decompression and AIN ETS and the other with a decompression alone. In the patient with decompression and AIN ETS, direct stimulation of the AIN revealed a low amplitude CMAP recorded from the FDI and FPL, suggesting AIN axonal contribution to FDI in the setting of prior AIN ETS. In the patient with decompression alone, near‐nerve stimulation generated an expected CMAP in the FPL but no response in the hand intrinsics. Discussion This study may demonstrate the utility of US‐guided near‐nerve monopolar needle AIN stimulation and suggests that it is a reliable technique to isolate the AIN contribution to hand intrinsic reinnervation following AIN ETS.