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Preclinical efficacy of ribavirin in SHH and group 3 medulloblastoma

Sakibul Huq, Nivedha V. Kannapadi, Joshua Casaos, Tarik Lott, Raphael Felder, Riccardo Serra, Noah L. Gorelick, Miguel A. Ruiz-Cardozo, Andy S. Ding, Arba Cecia, Ravi Medikonda, Jeff Ehresman, Henry Brem, Nicolas Skuli, and Betty M. Tyler

OBJECTIVE

Medulloblastoma, the most common pediatric brain malignancy, has Sonic Hedgehog (SHH) and group 3 (Myc driven) subtypes that are associated with the activity of eukaryotic initiation factor 4E (eIF4E), a critical mediator of translation, and enhancer of zeste homolog 2 (EZH2), a histone methyltransferase and master regulator of transcription. Recent drug repurposing efforts in multiple solid and hematologic malignancies have demonstrated that eIF4E and EZH2 are both pharmacologically inhibited by the FDA-approved antiviral drug ribavirin. Given the molecular overlap between medulloblastoma biology and known ribavirin activity, the authors investigated the preclinical efficacy of repurposing ribavirin as a targeted therapeutic in cell and animal models of medulloblastoma.

METHODS

Multiple in vitro assays were performed using human ONS-76 (a primitive SHH model) and D425 (an aggressive group 3 model) cells. The impacts of ribavirin on cellular growth, death, migration, and invasion were quantified using proliferation and Cell Counting Kit-8 (CCK-8) assays, flow cytometry with annexin V (AnnV) staining, scratch wound assays, and Matrigel invasion chambers, respectively. Survival following daily ribavirin treatment (100 mg/kg) was assessed in vivo in immunodeficient mice intracranially implanted with D425 cells.

RESULTS

Compared to controls, ribavirin treatment led to a significant reduction in medulloblastoma cell growth (ONS-76 proliferation assay, p = 0.0001; D425 CCK-8 assay, p < 0.0001) and a significant increase in cell death (flow cytometry for AnnV, ONS-76, p = 0.0010; D425, p = 0.0284). In ONS-76 cells, compared to controls, ribavirin significantly decreased cell migration and invasion (Matrigel invasion chamber assay, p = 0.0012). In vivo, ribavirin significantly extended survival in an aggressive group 3 medulloblastoma mouse model compared to vehicle-treated controls (p = 0.0004).

CONCLUSIONS

The authors demonstrate that ribavirin, a clinically used drug known to inhibit eIF4E and EZH2, has significant antitumor effects in multiple preclinical models of medulloblastoma, including an aggressive group 3 animal model. Ribavirin may represent a promising targeted therapeutic in medulloblastoma.

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Letter to the Editor. The Frazier Scholar Program at Penn Neurosurgery: an adaptable model for nurturing early interest in neurosurgery for current and aspiring medical students

Donald K. Detchou, Gregory Glauser, Ryan Dimentberg, Eileen Maloney Wilensky, Daniel Yoshor, and Neil R. Malhotra

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The safety and efficacy of dexamethasone in the perioperative management of glioma patients

Ravi Medikonda, Kisha Patel, Christina Jackson, Laura Saleh, Siddhartha Srivastava, James Feghali, Aditya Mohan, Ayush Pant, Christopher M. Jackson, Jon Weingart, Debraj Mukherjee, Chetan Bettegowda, Gary L. Gallia, Henry Brem, and Michael Lim

OBJECTIVE

In this single-institution retrospective cohort study, the authors evaluated the effect of dexamethasone on postoperative complications and overall survival in patients with glioma undergoing resection.

METHODS

A total of 435 patients who underwent resection of a primary glioma were included in this retrospective cohort study. The inclusion criterion was all patients who underwent resection of a primary glioma at a tertiary medical center between 2014 and 2019.

RESULTS

The use of both pre- and postoperative dexamethasone demonstrated a trend toward the development of postoperative wound infections (3% vs 0% in single use or no use, p = 0.082). No association was detected between dexamethasone use and the development of new-onset hyperglycemia (p = 0.149). On multivariable Cox proportional hazards analysis, dexamethasone use was associated with a greater hazard of death (overall p = 0.017); this effect was most pronounced for preoperative (only) dexamethasone use (hazard ratio 3.0, p = 0.062).

CONCLUSIONS

Combined pre- and postoperative dexamethasone use may increase the risk of postoperative wound infection, and dexamethasone use, specifically preoperative use, may negatively impact survival. These findings highlight the potential for serious negative consequences with dexamethasone use.

Free access

Letter to the Editor. Puerto Rico medical schools: neurosurgery residents matched during the 2014–2020 period

Orlando De Jesus and Aixa de Jesús Espinosa

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Predictors of surgical site infection in glioblastoma patients undergoing craniotomy for tumor resection

Sumil K. Nair, David Botros, Sachiv Chakravarti, Yuncong Mao, Esther Wu, Brian Lu, Sophie Liu, Mazin Elshareif, Christopher M. Jackson, Gary L. Gallia, Chetan Bettegowda, Jon Weingart, Henry Brem, and Debraj Mukherjee

OBJECTIVE

Surgical site infections (SSIs) burden patients and healthcare systems, often requiring additional intervention. The objective of this study was to identify the relationship between preoperative predictors inclusive of scalp incision type and postoperative SSI following glioblastoma resection.

METHODS

The authors retrospectively reviewed cases of glioblastoma resection performed at their institution from December 2006 to December 2019 and noted preoperative demographic and clinical presentations, excluding patients missing these data. Preoperative nutritional indices were available for a subset of cases. Scalp incisions were categorized as linear/curvilinear, reverse question mark, trapdoor, or frontotemporal. Patients were dichotomized by SSI incidence. Multivariable logistic regression was used to determine predictors of SSI.

RESULTS

A total of 911 cases of glioblastoma resection were identified, 30 (3.3%) of which demonstrated postoperative SSI. There were no significant differences in preoperative malnutrition or number of surgeries between SSI and non-SSI cases. The SSI cases had a significantly lower preoperative Karnofsky Performance Status (KPS) than the non-SSI cases (63.0 vs 75.1, p < 0.0001), were more likely to have prior radiation history (43.3% vs 26.4%, p = 0.042), and were more likely to have received steroids both preoperatively and postoperatively (83.3% vs 54.5%, p = 0.002). Linear/curvilinear incisions were more common in non-SSI than in SSI cases (56.9% vs 30.0%, p = 0.004). Trapdoor scalp incisions were more frequent in SSI than non-SSI cases (43.3% vs 24.2%, p = 0.012). On multivariable analysis, a lower preoperative KPS (OR 1.04, 95% CI 1.02–1.06), a trapdoor scalp incision (OR 3.34, 95% CI 1.37–8.49), and combined preoperative and postoperative steroid administration (OR 3.52, 95% CI 1.41–10.7) were independently associated with an elevated risk of postoperative SSI.

CONCLUSIONS

The study findings indicated that SSI risk following craniotomy for glioblastoma resection may be elevated in patients with a low preoperative KPS, a trapdoor scalp incision during surgery, and steroid treatment both preoperatively and postoperatively. These data may help guide future operative decision-making for these patients.

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A thermal gel depot for local delivery of paclitaxel to treat experimental brain tumors in rats

Laboratory investigation

Betty Tyler, Kirk D. Fowers, Khan W. Li, Violette Renard Recinos, Justin M. Caplan, Alia Hdeib, Rachel Grossman, Luca Basaldella, Kimon Bekelis, Gustavo Pradilla, Federico Legnani, and Henry Brem

Object

Paclitaxel, a cellular proliferation inhibitor/radiation sensitizer, while effective against gliomas in vitro, has poor CNS penetration and dose-limiting toxicities when administered systemically. OncoGel (paclitaxel in Re-Gel) provides controlled local paclitaxel release when placed into the CNS. The authors evaluated the safety and efficacy of OncoGel in rats with intracranial 9L gliosarcoma.

Methods

Safety studies included intracranial delivery of increasing volumes of ReGel and OncoGel containing 1.5 (OncoGel 1.5) or 6.3 (OncoGel 6.3) mg/ml paclitaxel. An in vivo radiolabeled biodistribution study was performed in 18 Fischer-344 rats to determine intracerebral distribution. Efficacy studies compared overall survival for controls, ReGel only, radiation therapy only, OncoGel 6.3, or OncoGel 6.3 in combination with radiation therapy. ReGel and OncoGel 6.3 were delivered either simultaneously with tumor implantation (Day 0) or 5 days later (Day 5). Radiation therapy was given on Day 5.

Results

Control and ReGel animals died of tumor within 17 days. Survival significantly increased in the Onco-Gel 6.3 group on Day 0 (median 31 days; p = 0.0001), in the OncoGel 6.3 group on Day 5 (median 17 days; p = 0.02), and in the radiation therapy–only group (median 26 days; p = 0.0001) compared with controls. Animals receiving both OncoGel and radiation therapy had the longest median survival: 83 days in the group with radiation therapy combined with OncoGel 6.3 on Day 0, and 32 days in the group combined with OncoGel 6.3 on Day 5 (p = 0.0001 vs controls). After 120 days, 37.5% of the animals in the OncoGel Day 0 group, 37.5% of animals in the OncoGel 6.3 Day 0 in combination with radiation therapy group, and 12.5% of the animals in the OncoGel 6.3 on Day 5 in combination with radiation therapy group were alive. In the biodistribution study, measurable radioactivity was observed throughout the ipsilateral hemisphere up to 3 weeks after the OncoGel injection, with the most radioactivity detected 3 hours after injection. The highest dose of radioactivity observed in the contralateral hemisphere was at the Day 3 time point.

Conclusions

OncoGel containing 6.3 mg/ml of paclitaxel is safe for intracranial injection in rats and effective when administered on Day 0. When combined with radiation therapy, the combination was more effective than either therapy alone and should be studied clinically for the treatment of malignant glioma.

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Local delivery of angiogenesis-inhibitor minocycline combined with radiotherapy and oral temozolomide chemotherapy in 9L glioma

Laboratory investigation

Hansen Bow, Lee S. Hwang, Noam Schildhaus, Joanna Xing, Luke Murray, Quinn Salditch, Xiaobu Ye, Yonggang Zhang, Jon Weingart, Henry Brem, and Betty Tyler

Object

Over the past several years, there has been increasing interest in combining angiogenesis inhibitors with radiotherapy and temozolomide chemotherapy in the treatment of glioblastoma. Although the US FDA approved bevacizumab for the treatment of glioblastoma in 2009, the European Medicines Agency rejected its use due to its questionable impact on patient survival. One factor contributing to the failure of angiogenesis inhibitors to increase overall patient survival may be their inability to cross the blood-brain barrier. Here the authors examined in a 9L glioma model whether intracranial polymer-based delivery of the angiogenesis inhibitor minocycline potentiates the effects of both radiotherapy and temozolomide chemotherapy in increasing median survival. The authors also investigated whether the relative timing of minocycline polymer implantation with respect to radiotherapy affects the efficacy of radiotherapy.

Methods

Minocycline was incorporated into the biodegradable polymer polyanhydride poly(1,3-bis-[p-carboxyphenoxy propane]-co-[sebacic anhydride]) (CPP:SA) at a ratio of 50:50 by weight. Female Fischer 344 rats were implanted with 9L glioma on Day 0. The minocycline polymer was then implanted on either Day 3 or Day 5 posttumor implantation. Cohorts of rats were exposed to 20 Gy focal radiation on Day 5 or were administered oral temozolomide (50 mg/kg daily) on Days 5–9.

Results

Both minocycline polymer implantations on Days 3 and 5 increased survival from 14 days to 19 days (p < 0.001 vs control). Treatment with a combination of both minocycline polymer and radiotherapy on Day 5 resulted in a 139% increase in median survival compared with treatment with radiotherapy alone (p < 0.005). There was not a statistically significant difference in median survival between the group that received minocycline implanted on the same day as radiotherapy and the group that received minocycline polymer 2 days prior to radiotherapy. Lastly, treatment with a combination of minocycline polymer with oral temozolomide resulted in a 38% extension of median survival compared with treatment of oral temozolomide alone (p < 0.001).

Conclusions

These results show that minocycline delivered locally potentiates the effects of both radiotherapy and oral temozolomide in increasing median survival in a rodent glioma model. More generally, these results suggest that traditional therapy in combination with local, as opposed to systemic, delivery of angiogenesis inhibitors may be able to increase median survival for patients with glioblastoma.

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Reduction of cerebrospinal fluid rhinorrhea after vestibular schwannoma surgery by reconstruction of the drilled porus acusticus with hydroxyapatite bone cement

Clinton J. Baird, Alia Hdeib, Ian Suk, Howard W. Francis, Michael J. Holliday, Rafael J. Tamargo, Henry Brem, and Donlin M. Long

Object

Cerebrospinal fluid (CSF) rhinorrhea remains a significant cause of morbidity after resection of vestibular schwannomas (VSs), with rates of rhinorrhea after this procedure reported to range between 0 and 27%. The authors investigated whether reconstruction of the drilled posterior wall of the porus acusticus with hydroxyapatite cement (HAC) would decrease the incidence of postoperative CSF rhinorrhea.

Methods

A prospective observational study of 130 consecutive patients who underwent surgery for reconstruction of the posterior wall of the drilled porus acusticus with HAC was conducted between October 2002 and September 2005. All patients underwent a retrosigmoid transmeatal approach for VS resection and were followed up to document cases of CSF rhinorrhea, incisional CSF leak, meningitis, or rhinorrhea-associated meningitis. A cohort of 150 patients with VSs who were treated with the same surgical approach but without HAC reconstruction served as a control group.

Results

The authors found that HAC reconstruction of the porus acusticus wall significantly reduced the rate of postoperative CSF rhinorrhea in their patients. In the patients treated with HAC, rhinorrhea developed in only three patients (2.3%) compared with 18 patients (12%) in the control group. This was a statistically significant finding (p = 0.002, odds ratio = 5.8).

Conclusions

The use of HAC in the reconstruction of the drilled posterior wall of the porus acusticus, occluding exposed air cells, greatly reduces the risk of CSF rhinorrhea.

Free access

Targeting of cyclin-dependent kinases in atypical teratoid rhabdoid tumors with multikinase inhibitor TG02

Andy S. Ding, Sakibul Huq, Joshua Casaos, Divyaansh Raj, Manuel Morales, Tianna Zhao, Timothy Kim, Siddhartha Srivastava, Ayush Pant, Riccardo Serra, Noah L. Gorelick, Henry Brem, and Betty Tyler

OBJECTIVE

Atypical teratoid rhabdoid tumors (ATRTs) are aggressive pediatric brain tumors with no current standard of care and an estimated median patient survival of 12 to 18 months. Previous genetic analyses have implicated cyclin D1 and enhancer of zeste homolog 2 (EZH2), a histone methyltransferase that is implicated in many cancers, as key drivers of tumorigenicity in ATRTs. Since the effects of EZH2 and cyclin D1 are facilitated by a host of cyclin-dependent kinases (CDKs), the authors sought to investigate the potential therapeutic effects of targeting CDKs in ATRTs with the multi–CDK inhibitor, TG02.

METHODS

Human ATRT cell lines BT12, BT37, CHLA05, and CHLA06 were selected for investigation. The effects of TG02 on cell viability, proliferation, clonogenicity, and apoptosis were assessed via Cell Counting Kit-8 assays, cell counting, clonogenic assays, and flow cytometry, respectively. Similar methods were used to determine the effects of TG02 combined with radiation therapy (RT) or cisplatin. Synergism indices for TG02-cisplatin combination therapy were calculated using CompuSyn software.

RESULTS

TG02 was observed to significantly impair ATRT cell growth in vitro by limiting cell proliferation and clonogenicity, and by inducing apoptosis. TG02 inhibited ATRT cell proliferation and decreased cell viability in a dose-dependent manner with nanomolar half maximal effective concentration (EC50) values (BT12, 207.0 nM; BT37, 127.8 nM; CHLA05, 29.7 nM; CHLA06, 18.7 nM). TG02 (150 nM) dramatically increased the proportion of apoptotic ATRT cells 72 hours posttreatment (TG02 8.50% vs control 1.52% apoptotic cells in BT12, p < 0.0001; TG02 70.07% vs control 15.36%, p < 0.0001). Combination therapy studies revealed that TG02 acted as a potent radiosensitizer in ATRT cells (BT12 surviving fraction, RT 51.2% vs RT + TG02 21.7%). Finally, CompuSyn analysis demonstrated that TG02 acted synergistically with cisplatin against ATRT cells at virtually all therapeutic doses. These findings were consistent in cell lines that cover all three molecular subgroups of ATRTs.

CONCLUSIONS

The results of this investigation have established that TG02 is an effective therapeutic against ATRTs in vitro. Given the lack of standard therapy for ATRTs, these findings help fill an unmet need and support further study of TG02 as a potential therapeutic option for patients with this deadly disease.

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Clinical features and surgical outcomes of intracranial and spinal cord subependymomas

Jordina Rincon-Torroella, Maureen Rakovec, Adham M Khalafallah, Ann Liu, Anya Bettegowda, Carmen Kut, Fausto J. Rodriguez, Jon Weingart, Mark Luciano, Alessandro Olivi, George I. Jallo, Henry Brem, Debraj Mukherjee, Michael Lim, and Chetan Bettegowda

OBJECTIVE

Subependymomas are low-grade ependymal tumors whose clinical characteristics, radiographic features, and postsurgical outcomes are incompletely characterized due to their rarity. The authors present an institutional case series and a systematic literature review to achieve a better understanding of subependymomas.

METHODS

Adult patients with histologically confirmed subependymoma or mixed subependymoma-ependymoma surgically treated at a tertiary hospital between 1992 and 2020 were identified. A systematic literature review of the PubMed, Embase, Web of Science, and Google Scholar databases from inception until December 4, 2020, was conducted according to PRISMA guidelines. Data extracted from both groups included demographics, radiographic features, tumor characteristics, management, and follow-up variables.

RESULTS

Forty-eight unique patients with subependymoma were identified by chart review; of these patients, 8 (16.7%) had mixed subependymoma-ependymoma tumors. The median age at diagnosis was 49 years (IQR 19.8 years), and 26 patients (54.2%) were male. Forty-two patients (87.5%) had intracranial subependymomas, and 6 (12.5%) had spinal tumors. The most common presentation was headache (n = 20, 41.7%), although a significant number of tumors were diagnosed incidentally (n = 16, 33.3%). Among the 42 patients with intracranial tumors, 15 (35.7%) had hydrocephalus, and the most common surgical strategy was a suboccipital approach with or without C1 laminectomy (n = 26, 61.9%). Gross-total resection (GTR) was achieved in 33 cases (68.7%), and 2 patients underwent adjuvant radiotherapy. Most patients had no major postsurgical complications (n = 34, 70.8%), and only 1 (2.1%) had recurrence after GTR. Of 2036 reports initially identified in the systematic review, 39 were eligible for inclusion, comprising 477 patients. Of 462 patients for whom tumor location was reported, 406 (87.9%) were intracranial, with the lateral ventricle as the most common location (n = 214, 46.3%). Spinal subependymomas occurred in 53 patients (11.5%), with 3 cases (0.6%) in multiple locations. Similar to the case series at the authors’ institution, headache was the most common presenting symptom (n = 231, 54.0%) among the 428 patients whose presentation was reported. Twenty-seven patients (6.3%) were diagnosed incidentally, and 36 cases (8.4%) were found at autopsy. Extent of resection was reported for 350 patients, and GTR was achieved in 250 (71.4%). Fifteen of 337 patients (4.5%) had recurrence or progression.

CONCLUSIONS

The authors’ case series and literature review demonstrate that patients with subependymoma are well managed with resection and generally have a favorable prognosis.