Lu, Victor M.

On this episode of Tumor Talk, Dr. Randy D'Amico and Dr. Jason Sheehan discuss the racial disparities in pediatric malignant glioma management with University of Miami/Jackson Health System Neurosurgical Resident, Dr. Victor Lu, Pediatric Neurosurgeon and Medical Director of Neuro-Oncology Surgical Services at Nicklaus Children's Hospital, Dr. Toba Niazi, and Neurologic Surgery Residency at the Mayo Clinic School of Graduate Medical Education, Dr. Cody Nesvick.

Abstract Background H3K27M-mutant diffuse midline glioma (DMG) is a lethal brain tumor that usually occurs in children. Despite advances in our understanding of its underlying biology, efficacious therapies are severely lacking. Methods We screened a library of drugs either FDA-approved or in clinical trial using a library of patient-derived H3K27M-mutant DMG cell lines with cell viability as the outcome. Results were validated for clinical relevance and mechanistic importance using patient specimens from biopsy and autopsy, patient-derived cell lines, inhibition by gene knockdown and small molecule inhibitors, and patient-derived xenografts. Results Kinase inhibitors were highly toxic to H3K27M-mutant DMG cells. Within this class, STAT3 inhibitors demonstrated robust cytotoxic activity in vitro. Mechanistic analyses revealed one form of activated STAT3, phospho-tyrosine- 705 STAT3 (pSTAT3), was selectively upregulated in H3K27M-mutant cell lines and clinical specimens. STAT3 inhibition by CRISPR/Cas9 knockout, shRNA or small molecule inhibition reduced cell viability in vitro, and partially restored expression of the polycomb repressive mark H3K27me3, which is classically lost in H3K27M-mutant DMG. Putative STAT3-regulated genes were enriched in an H3K27M-knockout DMG cell line, indicating relative gain of STAT3 signaling in K27M-mutant cells. Treatment of patient-derived intracranial xenografts with WP1066, a STAT3 pathway inhibitor currently in clinical use for pediatric brain tumors, resulted in stasis of tumor growth, and increased overall survival. Finally, pSTAT3(Y705) was detected in circulating plasma extracellular vesicles of patients with H3K27M-mutant DMG. Conclusions STAT3 is a biologically relevant therapeutic target in H3K27M-mutant DMG. STAT3 inhibition should be considered in future clinical trials.

Abstract BACKGROUND Malignant peripheral nerve sheath tumors (MPNST) are rare tumors found throughout the body, with their clinical course in children still to be completely understood. Correspondingly, this study aimed to determine survival outcomes and specific clinical predictors of survival in this demographic from a large national database. METHODS All MPNST patients aged ≤18 year in the U.S. National Cancer Database (NCDB) between 2005-2016 were retrospectively reviewed. Data were summarized and overall survival (OS) was modeled using Kaplan-Meier and Cox regression analyses. RESULTS A total of 251 pediatric MPNST cases were identified. Overall, mean age at diagnosis was 13.1 years (range, 1-18) with there being 132 (53%) females and 119 (47%) males. There were 84 (33%) MPNSTs located in extremities, 127 (51%) less than 1cm in size, and 22 (9%) have metastasis at diagnosis. In terms of treatment, surgery was pursued in 187 (74%) patients, chemotherapy in 116 (46%) patients, and radiation therapy in 129 (61%) patients. Five-year overall survival was estimated to be 52% (95% CI, 45-59%), and with median survival of 64 months (range, 36-136). Multivariate regression revealed older age (HR 1.10, P< 0.01), with metastases at time of diagnosis (HR 2.14, P=0.01), and biopsy only (HR 2.98, P< 0.01) all significantly and independently predicted shorter overall survival. Chemotherapy and radiation therapy were not statistically significant. CONCLUSIONS Pediatric MPNSTs are rare malignant entities, and only approximately half of patients will survive to five years. There remains a clear survival benefit in pursuing maximal safe resection in these patients. As such, judicious workup with meticulous surgical resection by an expert team should then be considered the standard of care for these tumors in children.

Abstract BACKGROUND Diffuse leptomeningeal glioneuronal tumor (DLGNT), also known as oligodendrogliomatosis, is a rare neuro-oncologic condition along the neuraxis that remains poorly understood in children. We sought to describe our institutional experience and quantitively summarize the clinical survival and prognostic features of DLGNT in the pediatric population across the contemporary literature. METHODS We report four institutional cases of pediatric DLGNT diagnosed between 2000-2020 based on retrospective review of our records, and performed a comprehensive literature search for published cases from 2000 onwards to create an integrated cohort for analysis. Kaplan-Meier estimations, Fisher’s exact test, and logistic regression were utilized to interrogate the data. RESULTS Our overall integrated cohort consisted of 54 pediatric DLGNT patients, with 19 (35%) female and 35 (65%) male patients diagnosed at an average age of 6.4 years (range, 1.3-17 years) by means of surgical biopsy. Chemotherapy was used in 45 cases (83%), and mean follow-up time of 54 months (range, 3-204). Across the entire cohort, overall survival 1 month after diagnosis was 96% (95% CI 86-99%), and by 10 years was 69% (95% CI 49-82%). On multivariate analysis of complete data, chemotherapy treatment (HR=0.23, P=0.04) was statistically predictive of longer overall survival. When including limited data, longer duration of symptoms by presentation (HR=1.03, P=0.03) was statistically predictive of shorter overall survival. CONCLUSIONS This is the first quantitative study of pediatric DLGNT clinical course. More than 2-out-of-3 pediatric DLGNT patients survive beyond one decade. Chemotherapy is statistically associated with longer survival in DLGNT pediatric patients and should form the core of any treatment regimen in this setting. Early detection by means of judicious imaging and surgical biopsy for tissue diagnosis can lead to earlier treatment and likely superior outcomes.

OBJECTIVE Meralgia paresthetica is caused by entrapment of the lateral femoral cutaneous nerve (LFCN) and often presents with pain. Multiple treatment options targeting the LFCN can be pursued to treat the pain should conservative measures fail, with the most common options being injection, neurolysis, and neurectomy. However, their efficacy in causing pain relief and their clinical outcomes have yet to be directly compared. The aim of this study was to interrogate the contemporary literature and quantitatively define how these options compare. METHODS The electronic databases Ovid Embase, PubMed, SCOPUS, and the Cochrane Library were interrogated from inception to May 2020 following the PRISMA guidelines. Candidate articles were screened against prespecified criteria. Outcome data were abstracted and pooled by random-effects meta-analysis of proportions. RESULTS There were 25 articles that satisfied all criteria, reporting outcomes for a total of 670 meralgia paresthetica patients, with 78 (12%) treated by injection, 496 (74%) by neurolysis, and 96 (14%) by neurectomy. The incidence of complete pain relief was 85% (95% CI 71%–96%) after neurectomy, 63% (95% CI 56%–71%) after neurolysis, and 22% (95% CI 13%–33%) after injection, which were all statistically different (p < 0.01). The incidence of revision procedures was 12% (95% CI 4%–22%) after neurolysis and 0% (95% CI 0%–2%) after neurectomy, which were significantly lower than 81% (95% CI 64%–94%) after injection (p < 0.01). The incidences of treatment complications were statistically comparable across all three treatments, ranging from 0% to 5% (p = 0.34). CONCLUSIONS There are multiple treatment options to target pain in meralgia paresthetica. The incidence of complete pain relief appears to be the greatest among the 3 interventions after neurectomy, accompanied by the lowest incidence of revision procedures. These findings should help inform patient preference and expectations. Greater exploration of the anatomical rationale for incomplete pain relief after surgical intervention will assist in optimizing further surgical treatment for meralgia paresthetica.

OBJECTIVE Intracranial facial nerve schwannomas (FNS) requiring treatment are frequently recommended for surgery or stereotactic radiosurgery (SRS). The objective of this study was to compare facial nerve function outcomes between these two interventions for FNS via a systematic review and meta-analysis. METHODS A search of the Ovid EMBASE, PubMed, SCOPUS, and Cochrane databases from inception to July 2019 was conducted following PRISMA guidelines. Articles were screened against prespecified criteria. Facial nerve outcomes were classified as improved, stabilized, or worsened by last follow-up. Incidence was pooled by random-effects meta-analysis of proportions. RESULTS Thirty-three articles with a pooled cohort of 519 patients with FNS satisfied all criteria. Twenty-five articles described operative outcomes in 407 (78%) patients; 10 articles reported SRS outcomes in 112 (22%). In the surgical cohort, facial nerve function improved in 23% (95% CI 15%–32%), stabilized in 41% (95% CI 32%–50%), and worsened in 30% (95% CI 21%–40%). In the SRS cohort, facial nerve function was improved in 20% (95% CI 9%–34%), stable in 66% (95% CI 54%–78%), and worsened in 9% (95% CI 3%–16%). Compared with SRS, microsurgery was associated with a significantly lower incidence of stable facial nerve function (p < 0.01) and a significantly higher incidence of worsened facial nerve function (p < 0.01). Tumor progression and complication rates were comparable. Outcome certainty assessments were very low to moderate for all parameters. CONCLUSIONS Unfavorable facial nerve function outcomes are associated with surgical treatment of intracranial FNS, whereas stable facial nerve function outcomes are associated with SRS. Therefore, SRS should be recommended to patients with FNS who require treatment, and surgery should be reserved for patients with another indication, such as decompression of the brainstem. Further study is required to definitively optimize and validate management strategies for these rare skull base tumors.

OBJECTIVE Pediatric Chiari I malformation decompression is a common neurosurgical procedure. Liposomal bupivacaine (LB) is a novel formulation that can have an impact on postoperative recovery for particular procedures, but its potential role in pediatric neurosurgery is largely unexplored. The authors sought to describe and assess their initial experience with LB in pediatric Chiari I malformation decompression to better define its potential role as an analgesic agent in a procedure for which the postoperative course is often remarkably painful. METHODS A retrospective review of all pediatric Chiari procedures performed at the authors’ institution between 2018 and 2020 was conducted. Patients were divided into those who were treated with a single intraoperative dose of LB (LB group) and those who were not (control group). Comparisons of total opioid use and pain control were made using chi-square and Wilcoxon rank-sum tests. RESULTS A total of 18 patients were identified, 9 (50%) in the LB group and 9 (50%) in the control group. Overall, there were 13 (72%) female and 5 (28%) male patients with a mean age of 15.9 years. No surgical complications were observed over a mean length of stay of 2.7 days. Within the first 24 hours after surgery, the LB group had significantly lower total opioid use than the control group (17.5 vs 47.9 morphine milligram equivalents, respectively; p = 0.03) as well as lower mean pain scores reported by patients using a 10-point visual analog scale (3.6 vs 5.5 for the LB vs control groups, p = 0.04). However, from the first 24 postoperative hours to discharge, total opioid use (p = 0.51) and mean pain scores (p = 0.09) were statistically comparable between the two groups. There were 2/9 (22%) LB patients versus 0/9 (0%) control patients who did not require opioid analgesia at any point during hospitalization. CONCLUSIONS The use of a single intraoperative dose of LB in pediatric Chiari I malformation surgery appears to be safe and has the potential to reduce pain scores and opioid use when administered during the first 24 postoperative hours. From that time period to discharge, however, there may be no significant difference in total opioid use or pain scores.