Results from a first-in-human phase I safety trial to evaluate the use of a vascularized pericranial/temporoparietal fascial flap to line the resection cavity following resection of newly diagnosed glioblastoma.

PURPOSE: The efficacy of systemic therapies for glioblastoma (GBM) remains limited due to the constraints of systemic toxicity and blood-brain barrier (BBB) permeability. Temporoparietal fascial flaps (TPFFs) and vascularized peri cranial flaps (PCF) are not restricted by the blood-brain barrier (BBB), as they derive their vascular supply from branches of the external carotid artery. Transposition of a vascularized TPFF or PCF along a GBM resection cavity may bring autologous tissue not restricted by the BBB in close vicinity to the tumor bed microenvironment, permit ingrowth of vascular channels fed by the external circulation, and offer a mechanism of bypassing the BBB. In addition, circulating immune cells in the vascularized flap may have better access to tumor-associated antigens (TAA) within the tumor microenvironment. We conducted a first-in-human Phase I trial assessing the safety of lining the resection cavity with autologous TPFF/PCF of newly diagnosed patients with GBM. METHODS: 12 patients underwent safe, maximal surgical resection of newly diagnosed GBMs, followed by lining of the resection cavity with a pedicled, autologous TPFF or PCF. Safety was assessed by monitoring adverse events. Secondary analysis of efficacy was examined as the proportion of patients experiencing progression-free disease (PFS) as indicated by response assessment in neuro-oncology (RANO) criteria and overall survival (OS). The study was powered to determine whether a Phase II study was warranted based on these early results. For this analysis, subjects who were alive and had not progressed as of the date of the last follow-up were considered censored and all living patients who were alive as of the date of last follow-up were considered censored for overall survival. For simplicity, we assumed that a 70% PFS rate at 6 months would be considered an encouraging response and would make an argument for further investigation of the procedure. RESULTS: Median age of included patients was 57 years (range 46-69 years). All patients were Isocitrate dehydrogenase (IDH) wildtype. Average tumor volume was 56.6 cm3 (range 14-145 cm3). Resection was qualified as gross total resection (GTR) of all of the enhancing diseases in all patients. Grade III or above adverse events were encountered in 3 patients. No Grade IV or V serious adverse events occurred in the immediate post-operative period including seizure, infection, stroke, or tumor growing along the flap. Disease progression at the site of the original tumor was identified in only 4 (33%) patients (median 23 months, range 8-25 months), 3 of whom underwent re-operation. Histopathological analyses of those implanted flaps and tumor bed biopsy at repeat surgery demonstrated robust immune infiltrates within the transplanted flap. Importantly, no patient demonstrated evidence of tumor infiltration into the implanted flap. At the time of this manuscript preparation, only 4/12 (33%) of patients have died. Based on the statistical considerations above and including all 12 patients 10/12 (83.3%) had 6-month PFS. The median PFS was 9.10 months, and the OS was 17.6 months. 4/12 (33%) of patients have been alive for more than two years and our longest surviving patient currently is alive at 60 months. CONCLUSIONS: This pilot study suggests that insertion of pedicled autologous TPFF/PCF along a GBM resection cavity is safe and feasible. Based on the encouraging response rate in 6-month PFS and OS, larger phase II studies are warranted to assess and reproduce safety, feasibility, and efficacy. TRIAL REGISTRATION NUMBER AND DATE OF REGISTRATION FOR PROSPECTIVELY REGISTERED TRIALS: ClinicalTrials.gov ID NCT03630289, dated: 08/02/2018.

First in-human intrathecal delivery of bevacizumab for leptomeningeal spread from recurrent glioblastoma: rationale for a dose escalation trial.

PURPOSE: To outline the dose rationale for the first in-human intrathecal delivery of bevacizumab for LMS of GBM. METHODS: A 19-year-old female patient presented to Lenox Hill Hospital following thalamic GBM recurrence. She subsequently underwent two infusions of intra-arterial BEV (NCT01269853) and experienced a period of relative disease stability until progression in 2022. One month later, MRI disclosed diffuse enhancement representative of LMS of GBM. The patient subsequently underwent five cycles of IT BEV in mid-2022 (IND 162119). Doses of 25 mg, 37.5 mg, 50 mg, 50 mg, and 37.8 mg were delivered at two-week intervals between doses 1-4. The final 37.8 mg dose was given one day following her fourth dose, given that the patient was to be discharged, traveled several hours to our center, and was tolerating therapy well. Dosage was decreased due to the short interval between the final two treatments. Shortly after IT BEV completion, she received a third dose of IA BEV. RESULTS: Our patient did not show any signs of serious adverse effects or dose limiting toxicities following any of the treatments. It is difficult to determine PFS due to the rapid progression associated with LMS of GBM and rapid timeframe of treatment. CONCLUSION: LMS continues to be a devastating progression in many types of cancer, including GBM, and novel ways to deliver therapeutics may offer patients symptomatic and therapeutic benefits.

Cranial transposition and revascularization of autologous omentum: a novel surgical technique for resection of recurrent glioblastoma multiforme.

Glioblastoma multiforme (GBM) patients continue to suffer a poor prognosis. The blood brain barrier (BBB) comprises one of the obstacles for therapy, creating a barrier that decreases the bioavailability of chemotherapeutic agents in the central nervous system. Previously, a vascularized temporoparietal fascial scalp flap (TPFF) lining the resection cavity was introduced in a trial conducted in our institution, in newly-diagnosed GBM patients in an attempt to bypass the BBB after initial resection. In this paper, we report on a new technique to bypass the BBB after re-resection and potentially to allow tumor antigens to be surveilled by the immune system. The study aims to assess the feasibility of performing a cranial transposition and revascularization of autologous omentum after re-resection of GBM. Laparoscopically harvested omental free flap was transposed to the resection cavity by a team consisting of neurosurgeons, otolaryngologists, and general surgeons. This was done as part of a single center, single arm, open-label, phase I study. Autologous abdominal omental tissue was harvested laparoscopically on its vascularized pedicle in 2 patients, transposed as a free flap, revascularized using external carotid artery, and carefully laid into the tumor resection cavity. Patients did well postoperatively returning to baseline activities. Graft viability was confirmed by cerebral angiogram. Omental cranial transposition of a laparoscopically harvested, vascularized flap, into the cavity of re-resected GBM patients is feasible and safe in the short term. Further studies are needed to ascertain whether such technique can improve progression free survival and overall survival in these patients.

Repeated superselective intraarterial bevacizumab after blood brain barrier disruption for newly diagnosed glioblastoma: a phase I/II clinical trial.

PURPOSE: Pre-clinical evidence suggests bevacizumab (BV) depletes the GBM peri-vascular cancer-stem cell niche. This phase I/II study assesses the safety and efficacy of repeated doses of superselective intra-arterial cerebral infusion (SIACI) of BV after blood-brain barrier disruption (BBBD). METHODS: Date of surgery was day 0. Evaluated patients received repeated SIACI bevacizumab (15 mg/kg) with BBBD at days 30 ± 7, 120 ± 7, and 210 ± 7 along with 6 weeks of standard chemoradiation. Response assessment in neuro-oncology criteria and the Kaplan-Meier product-limit method was used to evaluate progression free and overall survival (PFS and OS, respectively). RESULTS: Twenty-three patients with a median age of 60.5 years (SD = 12.6; 24.7-78.3) were included. Isocitrate dehydrogenase mutation was found in 1/23 (4%) patients. MGMT status was available for 11/23 patients (7 unmethylated; 3 methylated; 1 inconclusive). Median tumor volume was 24.0 cm3 (SD = 31.1, 1.7-48.3 cm3). Median PFS was 11.5 months (95% CI 7.7-25.9) with 6, 12, 24 and 60 month PFS estimated to be 91.3% (95% CI 69.5-97.8), 47.4% (26.3-65.9), 32.5% (14.4-52.2) and 5.4% (0.4-21.8), respectively. Median OS was 23.1 months (95% CI 12.2-36.9) with 12, 24, and 36 month OS as 77.3% (95% CI 53.6-89.9), 45.0% (22.3-65.3) and 32.1% (12.5-53.8), respectively. CONCLUSIONS: Repeated dosing of IA BV after BBBD offers an encouraging outcome in terms of PFS and OS. Phase III trials are warranted to determine whether repeated IA BV combined with Stupp protocol is superior to Stupp protocol alone for newly diagnosed GBM.

Correction to: Super selective intra­arterial cerebral infusion of modern chemotherapeutics after blood-brain barrier disruption: where are we now, and where we are going.

The name of author Jason A. Ellis was missing in the intial online publication, and there was a typo in the sixth author's first name. The original article has been corrected.

Super selective intra-arterial cerebral infusion of modern chemotherapeutics after blood-brain barrier disruption: where are we now, and where we are going.

INTRODUCTION: Intra-arterial (IA) delivery of therapeutic agents across the blood-brain barrier (BBB) is an evolving strategy which enables the distribution of high concentration therapeutics through a targeted vascular territory, while potentially limiting systemic toxicity. Studies have demonstrated IA methods to be safe and efficacious for a variety of therapeutics. However, further characterization of the clinical efficacy of IA therapy for the treatment of brain tumors and refinement of its potential applications are necessary. METHODS: We have reviewed the preclinical and clinical evidence supporting superselective intraarterial cerebral infusion (SSIACI) with BBB disruption for the treatment of brain tumors. In addition, we review ongoing clinical trials expanding the applicability and investigating the efficacy of IA therapy for the treatment of brain tumors. RESULTS: Trends in recent studies have embraced the use of SSIACI and less neurotoxic chemotherapies. The majority of trials continue to use mannitol as the preferred method of hyperosmolar BBB disruption. Recent preclinical and preliminary human investigations into the IA delivery of Bevacizumab have demonstrated its safety and efficacy as an anti-tumor agent both alone and in combination with chemotherapy. CONCLUSION: IA drug delivery may significantly affect the way treatments are delivered to patients with brain tumors, and in particular GBM. With refinement and standardization of the techniques of IA drug delivery, improved drug selection and formulations, and the development of methods to minimize treatment-related neurological injury, IA therapy may offer significant benefits for the treatment of brain tumors.

Superselective intraarterial cerebral infusion of cetuximab with blood brain barrier disruption combined with Stupp Protocol for newly diagnosed glioblastoma.

OBJECTIVE: We describe the first case of a novel treatment for a newly diagnosed glioblastoma (GBM) using superselective intraarterial cerebral infusion (SIACI) of cetuximab after osmotic disruption of the blood-brain barrier (BBB) with mannitol. A 51year-old female underwent craniotomy for removal of a right frontal GBM. Pathology confirmed EGFR amplification, and she underwent three treatments of SIACI of cetuximab to the tumor site. The first treatment was given within a week of starting standard of care chemoradiation (Stupp protocol), which is a combination of radiation treatment (2 Gy per/ day x 30 days, total of 60 Gy) and oral temozolomide (75 mg/m2). The second and third SIACI of cetuximab were administered 3 and 6 months later, while the patient continued on maintenance temozolomide. Post-radiation changes on MRI were stable, and there were no signs of recurrence at 4 and 6 months post-resection. Herein, we detail the technical aspects of this novel treatment paradigm and suggest that SIACI of cetuximab after BBB disruption using mannitol, combined with the standard of care chemoradiation therapy, may be an effective treatment method for newly diagnosed EGFR amplified glioblastoma.

Durability of single dose intra-arterial bevacizumab after blood/brain barrier disruption for recurrent glioblastoma.

BACKGROUND: Bevacizumab (BV) has been used to treat recurrent glioblastoma with a progression free survival of approximately 3-3.5 months. Typically, it is administered intravenously every 2-3 weeks at dosages ranging from 5-15 mg/kg. Serious side effects include GI tract perforations, hematologic disorders, intracranial hemorrhage, and malignant hypertension. We hypothesized that selective intracranial intra-arterial infusion (SIACI) of BV following blood/brain barrier disruption (BBBD) with mannitol may allow for reduced dosage, lower toxicity, and equivalent or superior progression free survival (PFS). METHODS: Sixteen patients (8 males & 8 females) with a mean age of 55 years (range 27-68), KPS>70, and recurrent glioblastoma were enrolled. All patients underwent super-selective catheterization and were given a single intra-arterial dose of 15 mg/kg BV following osmotic blood/brain barrier disruption with mannitol to the arteries supplying the tumor. The patients had no additional treatment following that initial SIACI mannitol and BV until they met criteria for progression. PFS was assessed using modified Response Assessment in Neuro-Oncology (RANO) criteria. RESULTS: Median progression free survival from only one dose of SIACI mannitol and BV was 3.9 months. Side effects included seizure in 2 patients, and headache in 1 patient. Seizures were well controlled with medications, and there were no serious toxicities. There were no endovascular-related complications. CONCLUSION: SIACI of mannitol and BV at 15mg/kg allows for similar or better PFS compared to biweekly treatments of IV BV at 10mg/kg. The dosage required is lower and side effects were minimal and well tolerated. Future larger trials are warranted to assess whether repeated less frequent IA mannitol and BV may be superior to biweekly IV administration as a monotherapy.

Superselective intraarterial cerebral infusion of cetuximab after osmotic blood/brain barrier disruption for recurrent malignant glioma: phase I study.

Objective To establish a maximum tolerated dose of superselective intraarterial cerebral infusion (SIACI) of Cetuximab after osmotic disruption of the blood-brain barrier (BBB) with mannitol, and examine safety of the procedure in patients with recurrent malignant glioma. Methods A total of 15 patients with recurrent malignant glioma were included in the current study. The starting dose of Cetuximab was 100 mg/m(2) and dose escalation was done to 250 mg/m(2). All patients were observed for 28 days post-infusion for any side effects. Results There was no dose-limiting toxicity from a single dose of SIACI of Cetuximab up to 250 mg/m(2) after osmotic BBB disruption with mannitol. A tolerable rash was seen in 2 patients, anaphylaxis in 1 patient, isolated seizure in 1 patient, and seizure and cerebral edema in 1 patient. Discussion SIACI of mannitol followed by Cetuximab (up to 250 mg/m(2)) for recurrent malignant glioma is safe and well tolerated. A Phase I/II trial is currently underway to determine the efficacy of SIACI of cetuximab in patients with high-grade glioma.

Vascularized Temporoparietal Fascial Flap: A Novel Surgical Technique to Bypass the Blood-Brain Barrier in Glioblastoma.

BACKGROUND: The major difficulty in treating glioblastoma stems from the intrinsic privileged nature of the brain. This complicates therapy, as many traditionally potent chemotherapeutics cannot access their target sites in the brain. Several techniques have been investigated to overcome this barrier and facilitate drug delivery. However, these techniques have inherent shortcomings related to the delivery system, the drug itself, or its bioactivity. Periosteal flaps and temporoparietal fascial flaps (TPFFs) are widely used options because they have predictable vasculature and a wide rotational arc. These flaps are not restricted by the blood-brain barrier, as they derive their vascular supply from branches of the external carotid artery, which can be readily identified with Doppler ultrasound. We hypothesized that transposition of a vascularized TPFF to the walls of a resected tumor surgical cavity may bring autologous tissue not restricted by the blood-brain barrier in close vicinity of the resected tumor bed microenvironment. This offers a nonselective, long-lasting gateway to target the residual tumor cells nesting in the brain adjacent to the tumor. CASE DESCRIPTION: A 47-year-old, right-handed woman with newly diagnosed multifocal glioblastoma underwent excision of the tumor and TPFF placement. This illustrative case report represents the first case of the use of this novel surgical technique with radiologic follow-up. CONCLUSIONS: The blood-brain barrier is identified as a major barrier for effective drug delivery in glioblastoma. This study demonstrates the feasibility of the TPFF technique to bypass this barrier and help facilitate the goal of improving drug delivery.

Update on glioma biotechnology.

Neuro-oncological research is at the forefront of the rising cancer therapy market, as evidenced by its growing revenue and the multitude of clinical trials investigating innovative treatment approaches. The Feinstein Institute for Medical Research, in conjunction with the Department of Neurosurgery at Lenox Hill Hospital and the Zucker School of Medicine at Hofstra / Northwell, sponsored The Brain Tumor Biotech Summit in New York City in June 2019. The aim of the Summit was to provide a forum that encourages collaboration between cancer specialists, biotechnology and pharmaceutical industry leaders, and the investment community in order to promote innovation and advance emerging therapies for brain tumors. Areas highlighted during the Summit included immunotherapy, precision medicine, and novel applications and experimental treatments such as receptor targeting, methods for improved drug delivery, and innovative intraoperative techniques and technologies. This review synthesizes the recent breakthroughs in brain tumor research as presented at The Brain Tumor Biotech Summit.

Rechallenging Recurrent Glioblastoma with Intra-Arterial Bevacizumab with Blood Brain-Barrier Disruption Results in Radiographic Response.

BACKGROUND: High-dose bevacizumab delivered via super selective intra-arterial cerebral infusion (SIACI) is one promising clinical trial combination for patients with glioblastoma (GBM). Although both continuous intravenous and intra-arterial administration of bevacizumab, and rechallenge with intravenous bevacizumab, have demonstrated improved survival, this is the first description of rechallenging GBM with SIACI of bevacizumab. CASE DESCRIPTION: We report a case of a 43-year-old woman with recurrent GBM who had received treatment from 3 clinical trials, including a rechallenge with SIACI of bevacizumab. First, she enrolled into a phase I/II trial for patients newly diagnosed with GBM (NCT01811498) and received 3 doses of SIACI bevacizumab over 180 days in addition to standard of care chemotherapy and radiation. Following progression, as indicated on her magnetic resonance imaging scan, she consented for a separate clinical trial for her disease and received 2 cycles of temozolomide with an investigational agent. The patient was removed from the study on tumor progression. Subsequently, she was rechallenged with SIACI of bevacizumab via a third clinical trial (NCT01269853) and then completed 3 intravenous infusions. After completing the third trial, her magnetic resonance imaging scan demonstrated improvement based on Response Assessment In Neuro-Oncology criteria. CONCLUSIONS: This is the first report to highlight the effect of rechallenging a patient with SIACI of bevacizumab following disease progression after initial bevacizumab treatment and subsequent alternate clinical trial failure. There is a need to conduct further clinical trials to evaluate the benefits of rechallenge with SIACI versus intravenous bevacizumab for GBM and further explore theories of bevacizumab resistance.

Microglia enhance manganese chloride-induced dopaminergic neurodegeneration: role of free radical generation.

Exposure to elevated levels of manganese has been shown to cause neuronal damage in the midbrain and the development of Parkinsonian symptoms. Activation of microglia and release of neurotoxic factors in particular free radicals are known to contribute to neurodegeneration. We have recently reported that manganese chloride (MnCl(2)) stimulates microglia to produce reactive oxygen species (ROS). The aim of this study is to determine the role of microglia in the MnCl(2)-induced degeneration of dopaminergic (DA) neurons that are particularly vulnerable to oxidative insult. MnCl(2) (10-300 microM; 7 days) was markedly more effective in damaging DA neurons in the rat mesencephalic neuron-glia cultures than the neuron-enriched (microglia-depleted) cultures. In addition, the microglia-enhanced MnCl(2) toxicity was found to be preferential to DA neurons. The microglial enhancement of DA neurotoxicity was further supported by the observation that replenishment of microglia to the neuron-enriched cultures significantly increased the susceptibility of DA neurons to the MnCl(2)-induced damage. Analysis of the temporal relationship between microglial activation and DA neurodegeneration revealed that MnCl(2)-stimulated microglial activation preceded DA neurodegeneration. Mechanistically, MnCl(2) (10-300 microM) stimulated a concentration- and time-dependent robust production of ROS and moderate production of nitric oxide but no detectable release of tumor necrosis factor-alpha and interleukin-1beta. Application of free radical scavengers including superoxide dismutase/catalase, glutathione, N-acetyl cysteine and an inhibitor of nitric oxide biosynthesis significantly protected DA neurons against the MnCl(2)-induced degeneration. These results demonstrate that microglial activation and the production of reactive nitrogen and oxygen free radicals promote the MnCl(2)-induced DA neurodegeneration.