Accelerated hypofractionated radiation for elderly or frail patients with a newly diagnosed glioblastoma: A pooled analysis of patient-level data from 4 prospective trials.

BACKGROUND: The standard of care for elderly or frail patients with glioblastoma (GBM) is 40 Gy in 15 fractions of radiotherapy. However, this regimen has a lower biological effective dose (BED) compared with the Stupp regimen of 60 Gy in 30 fractions. It is hypothesized that accelerated hypofractionated radiation of 52.5 Gy in 15 fractions (BED equivalent to Stupp) is safe and efficacious. METHODS: Elderly or frail patients with GBM treated with 52.5 Gy in 15 fractions were pooled from 3 phase 1/2 studies and a prospective observational study. Overall survival (OS) and progression-free survival (PFS) were defined time elapsing between surgery/biopsy and death from any cause or progression of disease. RESULTS: Sixty-two newly diagnosed patients were eligible for this pooled analysis of individual patient data. The majority (66%) had a Karnofsky performance status (KPS) score <70. The median age was 73 years. The median OS and PFS were 10.3 and 6.9 months, respectively. Patients with KPS scores ≥70 and <70 had a median OS of 15.3 and 9.5 months, respectively. Concurrent chemotherapy was an independent prognostic factor for improved PFS and OS. Grade 3 neurologic toxicity was seen in 2 patients (3.2%). There was no grade 4/5 toxicity. CONCLUSIONS: This is the only analysis of elderly/frail patients with GBM prospectively treated with a hypofractionated radiation regimen that is isoeffective to the Stupp regimen. Treatment was well tolerated and demonstrated excellent OS and PFS compared with historical studies. This regimen gives the elderly/frail population an alternative to regimens with a lower BED. Randomized trials are needed to validate these results.

Dose-escalated accelerated hypofractionation for elderly or frail patients with a newly diagnosed glioblastoma.

BACKGROUND: The standard of care for elderly glioblastoma patients is 40 Gy in 15 fraction radiotherapy with temozolomide (TMZ). However, this regimen has a lower biologic equivalent dose (BED) compared to the Stupp regimen of 60 Gy in 30 fractions. We hypothesize that accelerated hypofractionated radiation of 52.5 Gy in 15 fractions (BED equivalent to Stupp) will have superior survival compared to 40 Gy in 15 fractions. METHODS: Elderly patients (≥ 65 years old) who received hypofractionated radiation with TMZ from 2010 to 2020 were included in this analysis. Overall survival (OS) and progression free survival were defined as the time elapsed between surgery/biopsy and death from any cause or progression. Baseline characteristics were compared between patients who received 40 and 52.5 Gy. Univariable and multivariable analyses were performed. RESULTS: Sixty-six newly diagnosed patients were eligible for analysis. Thirty-nine patients were treated with 40 Gy in 15 fractions while twenty-seven were treated with 52.5 Gy in 15 fractions. Patients had no significant differences in age, sex, methylation status, or performance status. OS was superior in the 52.5 Gy group (14.1 months) when compared to the 40 Gy group (7.9 months, p = 0.011). Isoeffective dosing to 52.5 Gy was shown to be an independent prognostic factor for improved OS on multivariable analysis. CONCLUSIONS: Isoeffective dosing to 52.5 Gy in 15 fractions was associated with superior OS compared to standard of care 40 Gy in 15 fractions. These hypothesis generating data support accelerated hypofractionation in future prospective trials.

The Effects of Patient Positioning on the Outcome During Posterior Cranial Fossa and Pineal Region Surgery.

Background: Surgery on posterior cranial fossa (PCF) and pineal region (PR) carries the risks of intraoperative trauma to the brainstem structures, blood loss, venous air embolism (VAE), cardiovascular instability, and other complications. Success in surgery, among other factors, depends on selecting the optimal patient position. Our objective was to find associations between patient positioning, incidence of intraoperative complications, neurological recovery, and the extent of surgery. Methods: This observational study was conducted in two medical centers: The Ohio State University Wexner Medical Center (USA) and The Burdenko Neurosurgical Institute (Russian Federation). Patients were distributed in two groups based on the surgical position: sitting position (SP) or horizontal position (HP). The inclusion criteria were adult patients with space-occupying or vascular lesions requiring an open PCF or PR surgery. Perioperative variables were recorded and summarized using descriptive statistics. The post-treatment survival, functional outcome, and patient satisfaction were assessed at 3 months. Results: A total of 109 patients were included in the study: 53 in SP and 56 in HP. A higher proportion of patients in the HP patients had >300 mL intraoperative blood loss compared to the SP group (32 vs. 13%; p = 0.0250). Intraoperative VAE was diagnosed in 40% of SP patients vs. 0% in the HP group (p < 0.0001). However, trans-esophageal echocardiographic (TEE) monitoring was more common in the SP group. Intraoperative hypotension was documented in 28% of SP patients compared to 9% in HP group (p = 0.0126). A higher proportion of SP patients experienced a new neurological symptom compared to the HP group (49 vs. 29%; p = 0.0281). The extent of tumor resection, postoperative 3-months survival, functional outcome, and patient satisfaction were not different in the groups. Conclusions: The SP was associated with, less intraoperative bleeding, increased intraoperative hypotension, VAE, and postoperative neurological deficit. More HP patients experienced macroglossia and increased blood loss. At 3 months, there was no difference of parameters between the two groups. Clinical Trial Registration: ClinicalTrials.gov: registration number NCT03364283.

Surgical management of craniopharyngiomas in adult patients: a systematic review and consensus statement on behalf of the EANS skull base section.

BACKGROUND AND OBJECTIVE: Craniopharyngiomas are locally aggressive neuroepithelial tumors infiltrating nearby critical neurovascular structures. The majority of published surgical series deal with childhood-onset craniopharyngiomas, while the optimal surgical management for adult-onset tumors remains unclear. The aim of this paper is to summarize the main principles defining the surgical strategy for the management of craniopharyngiomas in adult patients through an extensive systematic literature review in order to formulate a series of recommendations. MATERIAL AND METHODS: The MEDLINE database was systematically reviewed (January 1970-February 2019) to identify pertinent articles dealing with the surgical management of adult-onset craniopharyngiomas. A summary of literature evidence was proposed after discussion within the EANS skull base section. RESULTS: The EANS task force formulated 13 recommendations and 4 suggestions. Treatment of these patients should be performed in tertiary referral centers. The endonasal approach is presently recommended for midline craniopharyngiomas because of the improved GTR and superior endocrinological and visual outcomes. The rate of CSF leak has strongly diminished with the use of the multilayer reconstruction technique. Transcranial approaches are recommended for tumors presenting lateral extensions or purely intraventricular. Independent of the technique, a maximal but hypothalamic-sparing resection should be performed to limit the occurrence of postoperative hypothalamic syndromes and metabolic complications. Similar principles should also be applied for tumor recurrences. Radiotherapy or intracystic agents are alternative treatments when no further surgery is possible. A multidisciplinary long-term follow-up is necessary.

The Role of Decompressive Craniectomy in the Context of Severe Traumatic Brain Injury: Summary of Results and Analysis of the Confidence Level of Conclusions From Systematic Reviews and Meta-Analyses.

Introduction: Traumatic brain injury (TBI) is a global epidemic. The incidence of TBI in low and middle-income countries (LMICs) is three times greater than in high-income countries (HICs). Decompressive craniectomy (DC) is a surgical procedure to reduce intracranial pressure (ICP) and prevent secondary injury. Multiple comparative studies, and several randomized controlled trials (RCTs) have been conducted to investigate the influence of DC for patients with severe TBI on outcomes such as mortality, ICP, neurological outcomes, and intensive care unit (ICU) and hospital length of stay. The results of these studies are inconsistent. Systematic reviews and meta-analyses have been conducted in an effort to aggregate the data from the individual studies, and perhaps derive reliable conclusions. The purpose of this project was to conduct a review of the reviews about the effectiveness of DC to improve outcomes. Methods: We conducted a systematic search of the literature to identify reviews and meta-analyses that met our pre-determined criteria. We used the AMSTAR 2 instrument to assess the quality of each of the included reviews, and determine the level of confidence. Results: Of 973 citations from the original search, five publications were included in our review. Four of them included meta-analyses. For mortality, three reviews found a positive effect of DC compared to medical management and two found no significant difference between groups. The four reviews that measured neurological outcome found no benefit of DC. The two reviews that assessed ICP both found DC to be beneficial in reducing ICP. DC demonstrated a significant reduction in ICU length of stay in the one study that measured it, and a significant reduction in hospital length of stay in the two studies that measured it. According to the AMSTAR 2 criteria, the five reviews ranged in levels of confidence from low to critically low. Conclusion: Systematic reviews and meta-analyses are important approaches for aggregating information from multiple studies. Clinicians rely of these methods for concise interpretation of scientific literature. Standards for quality of systematic reviews and meta-analyses have been established to support the quality of the reviews being produced. In the case of DC, more attention must be paid to quality standards, in the generation of both individual studies and reviews.

Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines on Treatment Options for Adults With Multiple Metastatic Brain Tumors.

TARGET POPULATION: These recommendations apply to adult patients newly diagnosed with multiple (more than 1) brain metastases. QUESTION 1: In what circumstances should whole brain radiation therapy be recommended to improve tumor control and survival in patients with multiple brain metastases? RECOMMENDATION: Level 2: It is recommended that whole brain radiation therapy can be added to stereotactic radiosurgery to improve local and distant control keeping in mind the potential for worsened neurocognitive outcomes and that there is unlikely to be a significant impact on overall survival. QUESTION 2: In what circumstances should stereotactic radiosurgery be recommended to improve tumor control and survival in patients with multiple brain metastases? RECOMMENDATIONS: Level 1: In patients with 2 to 3 brain metastases not amenable to surgery, the addition of stereotactic radiosurgery to whole brain radiation therapy is not recommended to improve survival beyond that obtained with whole brain radiation therapy alone. Level 3: The use of stereotactic radiosurgery alone is recommended to improve median overall survival for patients with more than 4 metastases having a cumulative volume < 7 cc. QUESTION 3: In what circumstances should surgery be recommended to improve tumor control and survival in patients with multiple brain metastases? RECOMMENDATION: Level 3: In patients with multiple brain metastases, tumor resection is recommended in patients with lesions inducing symptoms from mass effect that can be reached without inducing new neurological deficit and who have control of their cancer outside the nervous system.The full guideline can be found at https://www.cns.org/guidelines/guidelines-treatment-adults-metastatic-brain-tumors/chapter_6.

Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines on the Role of Surgery in the Management of Adults With Metastatic Brain Tumors.

Please see the full-text version of this guideline https://www.cns.org/guidelines/guidelines-treatment-adults-metastatic-brain-tumors/chapter_2) for the target population of each recommendation listed below. SURGERY FOR METASTATIC BRAIN TUMORS AT NEW DIAGNOSIS QUESTION: Should patients with newly diagnosed metastatic brain tumors undergo surgery, stereotactic radiosurgery (SRS), or whole brain radiotherapy (WBRT)? RECOMMENDATIONS: Level 1: Surgery + WBRT is recommended as first-line treatment in patients with single brain metastases with favorable performance status and limited extracranial disease to extend overall survival, median survival, and local control. Level 3: Surgery plus SRS is recommended to provide survival benefit in patients with metastatic brain tumors Level 3: Multimodal treatments including either surgery + WBRT + SRS boost or surgery + WBRT are recommended as alternatives to WBRT + SRS in terms of providing overall survival and local control benefits. SURGERY AND RADIATION FOR METASTATIC BRAIN TUMORS QUESTION: Should patients with newly diagnosed metastatic brain tumors undergo surgical resection followed by WBRT, SRS, or another combination of these modalities? RECOMMENDATIONS: Level 1: Surgery + WBRT is recommended as superior treatment to WBRT alone in patients with single brain metastases. Level 3: Surgery + SRS is recommended as an alternative to treatment with SRS alone to benefit overall survival. Level 3: It is recommended that SRS alone be considered equivalent to surgery + WBRT. SURGERY FOR RECURRENT METASTATIC BRAIN TUMORS QUESTION: Should patients with recurrent metastatic brain tumors undergo surgical resection? RECOMMENDATIONS: Level 3: Craniotomy is recommended as a treatment for intracranial recurrence after initial surgery or SRS. SURGICAL TECHNIQUE AND RECURRENCE QUESTION A: Does the surgical technique (en bloc resection or piecemeal resection) affect recurrence? RECOMMENDATION: Level 3: En bloc tumor resection, as opposed to piecemeal resection, is recommended to decrease the risk of postoperative leptomeningeal disease when resecting single brain metastases. QUESTION B: Does the extent of surgical resection (gross total resection or subtotal resection) affect recurrence? RECOMMENDATION: Level 3: Gross total resection is recommended over subtotal resection in recursive partitioning analysis class I patients to improve overall survival and prolong time to recurrence. The full guideline can be found at https://www.cns.org/guidelines/guidelines-treatment-adults-metastatic-brain-tumors/chapter_2.

Fabrication and characterization of implantable flushable electrodes for electric field-mediated drug delivery in a brain tissue-mimic agarose gel.

Every forty minutes, one person dies in the USA due to glioblastoma multiforme; a deadly form of brain cancer with an average five-year survival rate less than 3%. The current standard of care for treatment involves surgical resection of the accessible tumor followed by radiation therapy and concomitant chemotherapy. Despite their potency, delivering chemotherapeutic agents to the brain is limited by the highly selective blood-brain barrier, which prevents molecules >500 Da from reaching the brain. Other techniques, such as convection-enhanced delivery, controlled release by drug-loaded wafers or intracerebroventricular infusion have limited clinical utility due to unpredictable targeting and volume of drug distribution. We introduce a novel drug delivery technique that can use direct current electric fields to deliver charged chemotherapeutics to the site of brain parenchyma after tumor resection. We fabricate and characterize an implantable drug delivery system using flushable electrodes to deliver the charged chemotherapeutic or doxorubicin (+1) in a brain tissue-mimic agarose gel (0.2% w/v) model by electrophoresis. The optimized capillary-embedded electrode system exhibited a sustained movement of charged doxorubicin through nearly 3.5 mm in four hours, a distance for achieving effective intratumoral concentrations.

Quantitative evaluation of different far lateral approaches to the cranio-vertebral junction using the microscope and the endoscope: a cadaveric study using a tumor model.

BACKGROUND: Several far lateral approaches have been proposed to deal with cranio-vertebral junction (CVJ) tumors including the basic, transcondylar, and supracondylar far lateral approaches (B-FLA, T-FLA, and S-FLA). However, the indications on when to use one versus the other are not well systematized yet. Our purpose is to evaluate in an experimental cadaveric setting which approach is best suited to remove tumors of different sizes. METHODS: We implanted at the CVJ, using a transoral approach, tumor models of different sizes (five 1-cm3 and five 3-cm3 tumors) in ten embalmed cadaveric heads. The artificial tumors were exposed via the three approaches using endoscopic-assisted microneurosurgical technique and neuronavigation. The skull base area exposed and the maneuverability linked to each approach were evaluated using neuronavigation. RESULTS: In 1-cm3 tumors, the T-FLA and the S-FLA exposed a significantly larger skull base area than the B-FLA both using the microscope and the endoscope (P < 0.05); the T-FLA executed with the microscope provided wider vertical and horizontal maneuverability than the B-FLA (P = 0.030 and 0.017, respectively); the S-FLA executed with the endoscope provided wider vertical maneuverability than the T-FLA (P = 0.031). The S-FLA executed using the microscope and the endoscope provided wider vertical maneuverability than the B-FLA both in 1 and 3-cm3 tumors (P < 0.05). CONCLUSIONS: In 1-cm3 tumors, the S-FLA and the T-FLA expose a wider skull base area than the B-FLA. In larger tumors, the exposure is similar for all three approaches. Use of the endoscope in an assistive mode may further increase the surgical exposure and maneuverability.

NCCN Guidelines Insights: Central Nervous System Cancers, Version 1.2017.

For many years, the diagnosis and classification of gliomas have been based on histology. Although studies including large populations of patients demonstrated the prognostic value of histologic phenotype, variability in outcomes within histologic groups limited the utility of this system. Nonetheless, histology was the only proven and widely accessible tool available at the time, thus it was used for clinical trial entry criteria, and therefore determined the recommended treatment options. Research to identify molecular changes that underlie glioma progression has led to the discovery of molecular features that have greater diagnostic and prognostic value than histology. Analyses of these molecular markers across populations from randomized clinical trials have shown that some of these markers are also predictive of response to specific types of treatment, which has prompted significant changes to the recommended treatment options for grade III (anaplastic) gliomas.

The Changing Health Care Landscape and Implications of Organizational Ethics on Modern Medical Practice.

INTRODUCTION: Medicine is rapidly changing, both in the level of collective medical knowledge and in how it is being delivered. The increased presence of administrators in hospitals helps to facilitate these changes and ease administrative workloads on physicians; however, tensions sometimes form between physicians and administrators. ANALYSIS: This situation is based on perceptions from both sides that physicians obstruct cost-saving measures and administrators put profits before patients. In reality, increasing patient populations and changes in health care are necessitating action by hospitals to prevent excessive spending as health care systems become larger and more difficult to manage. Recognizing the cause of changes in health care, which do not always originate with physicians and administrators, along with implementing changes in hospitals such as increased physician leadership, could help to ease tensions and promote a more collaborative atmosphere. Ethically, there is a need to preserve physician autonomy, which is a tenet of medical professionalism, and a need to rein in spending costs and ensure that patients receive the best possible care. CONCLUSION: Physicians and administrators both need to have a well-developed personal ethic to achieve these goals. Physicians need be allowed to retain relative autonomy over their practices as they support and participate in administrator-led efforts toward distributive justice.

Ethical clinical translation of stem cell interventions for neurologic disease.

The application of stem cell transplants in clinical practice has increased in frequency in recent years. Many of the stem cell transplants in neurologic diseases, including stroke, Parkinson disease, spinal cord injury, and demyelinating diseases, are unproven-they have not been tested in prospective, controlled clinical trials and have not become accepted therapies. Stem cell transplant procedures currently being carried out have therapeutic aims, but are frequently experimental and unregulated, and could potentially put patients at risk. In some cases, patients undergoing such operations are not included in a clinical trial, and do not provide genuinely informed consent. For these reasons and others, some current stem cell interventions for neurologic diseases are ethically dubious and could jeopardize progress in the field. We provide discussion points for the evaluation of new stem cell interventions for neurologic disease, based primarily on the new Guidelines for Stem Cell Research and Clinical Translation released by the International Society for Stem Cell Research in May 2016. Important considerations in the ethical translation of stem cells to clinical practice include regulatory oversight, conflicts of interest, data sharing, the nature of investigation (e.g., within vs outside of a clinical trial), informed consent, risk-benefit ratios, the therapeutic misconception, and patient vulnerability. To help guide the translation of stem cells from the laboratory into the neurosurgical clinic in an ethically sound manner, we present an ethical discussion of these major issues at stake in the field of stem cell clinical research for neurologic disease.

Is less always better? Keyhole and standard subtemporal approaches: evaluation of temporal lobe retraction and surgical volume with and without zygomatic osteotomy in a cadaveric model.

OBJECTIVE The subtemporal approach is one of the surgical routes used to reach the interpeduncular fossa. Keyhole subtemporal approaches and zygomatic arch osteotomy have been proposed in an effort to decrease the amount of temporal lobe retraction. However, the effects of these modified subtemporal approaches on temporal lobe retraction have never been objectively validated. METHODS A keyhole and a classic subtemporal craniotomy were executed in 4 fresh-frozen silicone-injected cadaver heads. The target was defined as the area bordered by the superior cerebellar artery, the anterior clinoid process, supraclinoid internal carotid artery, and the posterior cerebral artery. Once the target was fully visualized, the authors evaluated the amount of temporal lobe retraction by measuring the distance between the base of the middle fossa and the temporal lobe. In addition, the volume of the surgical and anatomical corridors was assessed as well as the surgical maneuverability using navigation and 3D moldings. The same evaluation was conducted after a zygomatic osteotomy was added to the two approaches. RESULTS Temporal lobe retraction was the same in the two approaches evaluated while the surgical corridor and the maneuverability were all greater in the classic subtemporal approach. CONCLUSIONS The zygomatic arch osteotomy facilitates the maneuverability and the surgical volume in both approaches, but the temporal lobe retraction benefit is confined to the lateral part of the middle fossa skull base and does not result in the retraction necessary to expose the selected target.

Properties and Storage Methods of the Stratathane ST-504-Based Neurosurgical Tumor Model: Comprehensive Analysis.

BACKGROUND: Constrains on neurosurgical residents' work hours demand innovative teaching models to complement the traditional "in the operating room" model. Stratathane ST-504 (Strata-Tech, Inc., Des Moines, Iowa, USA) has been proposed as a useful artificial neurosurgical tumor model. The consistency, dissectability, and radio-opacity of this model strongly depend on its preparation and storage. However, little work has addressed the interplay of these properties. Hence our study was undertaken to explore the properties of ST-504, its preparation, and storage and how these interactions affect its radio-opacity and consistency. METHODS: Tumor mixture was prepared by mixing 4.5 mL of water, 1.5 mL of computed tomography contrast medium, 2 mL of ST-504, and 0.5 mg turmeric powder. The tumor mixture was either allowed to solidify, yielding solid tumor blocks, or injected into an anatomic specimen to create a tumor model. Both tumor blocks and tumor model were stored at different temperature, under different storage conditions and for different time. Their volumes, computed tomography appearance, and consistency were evaluated. RESULTS: The tumor blocks stored in water or ethanol absorbed fluid, resulting in enlargement and associated decrease in radiodensity and consistency. The same results were displayed by the tumor implanted in cadaveric specimen. CONCLUSION: For any given ratio of ST-504/water, the time sequence after polymer solidification and the storage method determine the computed tomography appearance and consistency of the tumor block/model. When taking these properties into consideration, ST-504-based artificial tumor models can be customized for different dissection practices, from more solid (meningioma-like) to less solid (schwannoma-like) models.