Standardized intraoperative 5-ALA photodynamic therapy for newly diagnosed glioblastoma patients: a preliminary analysis of the INDYGO clinical trial.

Glioblastoma (GBM) is the most aggressive malignant primary brain tumor. The unfavorable prognosis despite maximal therapy relates to high propensity for recurrence. Thus, overall survival (OS) is quite limited and local failure remains the fundamental problem. Here, we present a safety and feasibility trial after treating GBM intraoperatively by photodynamic therapy (PDT) after 5-aminolevulinic acid (5-ALA) administration and maximal resection. Ten patients with newly diagnosed GBM were enrolled and treated between May 2017 and June 2018. The standardized therapeutic approach included maximal resection (near total or gross total tumor resection (GTR)) guided by 5-ALA fluorescence-guided surgery (FGS), followed by intraoperative PDT. Postoperatively, patients underwent adjuvant therapy (Stupp protocol). Follow-up included clinical examinations and brain MR imaging was performed every 3 months until tumor progression and/or death. There were no unacceptable or unexpected toxicities or serious adverse effects. At the time of the interim analysis, the actuarial 12-months progression-free survival (PFS) rate was 60% (median 17.1 months), and the actuarial 12-months OS rate was 80% (median 23.1 months). This trial assessed the feasibility and the safety of intraoperative 5-ALA PDT as a novel approach for treating GBM after maximal tumor resection. The current standard of care remains microsurgical resection whenever feasible, followed by adjuvant therapy (Stupp protocol). We postulate that PDT delivered immediately after resection as an add-on therapy of this primary brain cancer is safe and may help to decrease the recurrence risk by targeting residual tumor cells in the resection cavity. Trial registration NCT number: NCT03048240. EudraCT number: 2016-002706-39

Caroticoclinoid Bar: A Systematic Review and Meta-Analysis of Its Prevalence and Potential Implications in Cerebrovascular and Skull Base Surgery

Background: The presence of a caroticoclinoid bar (CCB) has been implicated in both transcranial and endonasal surgery. Its morphology reflects differences in the microsurgical anatomy of the parasellar area and its manipulation during anterior or middle clinoidectomy can result in internal carotid artery injury. Although adjustment of the surgical technique according to the CCB anatomic variants is required for safe surgical access to the paraclinoid region, a review indicated the lack of a systematic assortment of reported data regarding the prevalence of the CCB. Thus, our objective was to systematically review and document the prevalence of the CCB and its anatomic variations. Methods: Three databases were systematically reviewed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement through August 2018 to identify relevant studies. Results: A total of 27 reports (7521 subjects or specimens, 14,449 sides) were included in the present meta-analysis. The overall pooled prevalence of the CCB was 32.6% (95% confidence interval [CI], 26.6%–38.8%) when measured in the subjects or specimens and 23.6% (95% CI, 19.7%–27.6%) when measured in each side. The overall prevalence of the CCB reported from imaging studies was 23.1% (95% CI, 8.9%–41.4%) for the subjects/specimens and 18.7% (95% CI, 12.6%–25.7%) for each side. The presence of the CCB was slightly more prevalent (P = 0.050) on the right side. Conclusions: Our results showed a considerable prevalence of the CCB, with lower prevalence rates found among imaging studies. Although meticulous preoperative investigation is mandatory, surgeons treating patients with parasellar pathologic entities should always be vigilant regarding the CCB. © 2019 Elsevier Inc

Intraoperative fluorescence diagnosis in the brain: a systematic review and suggestions for future standards on reporting diagnostic accuracy and clinical utility

Background Surgery for gliomas is often confounded by difficulties in distinguishing tumor from surrounding normal brain. For better discrimination, intraoperative optical imaging methods using fluorescent dyes are currently being explored. Understandably, such methods require the demonstration of a high degree of diagnostic accuracy and clinical benefit. Currently, clinical utility is determined by tissue biopsies which are correlated to optical signals, and quantified using measures such as sensitivity, specificity, positive predictive values, and negative predictive values. In addition, surgical outcomes, such as extent of resection rates and/or survival (progression-free survival (PFS) and overall survival (OS)) have been measured. These assessments, however, potentially involve multiple biases and confounders, which have to be minimized to ensure reproducibility, generalizability and comparability of test results. Test should aim at having a high internal and external validity. The objective of this article is to analyze how diagnostic accuracy and outcomes are utilized in available studies describing intraoperative imaging and furthermore, to derive recommendations for reliable and reproducible evaluations. Methods A review of the literature was performed for assessing the use of measures of diagnostic accuracy and outcomes of intraoperative optical imaging methods. From these data, we derive recommendations for designing and reporting future studies. Results Available literature indicates that potential confounders and biases for reporting the diagnostic accuracy and usefulness of intraoperative optical imaging methods are seldom accounted for. Furthermore, methods for bias reduction are rarely used nor reported. Conclusions Detailed, transparent, and uniform reporting on diagnostic accuracy of intraoperative imaging methods is necessary. In the absence of such reporting, studies will not be comparable or reproducible. Future studies should consider some of the recommendations given here

Review of clinical trials in intraoperative molecular imaging during cancer surgery

Most solid cancers are treated by surgical resections to reduce the burden of disease. Surgeons often face the challenge of detecting small areas of residual neoplasm after resection or finding small primary tumors for the initial resection. Intraoperative molecular imaging (IMI) is an emerging technology with the potential to dramatically improve cancer surgery operations by allowing surgeons to better visualize areas of neoplasm using fluorescence imaging. Over the last two years, two molecular optical contrast agents received U.S. Food and Drug Administration approval, and several more drugs are now on the horizon. Thus a conference was organized at the University of Pennsylvania to bring together oncologic surgeons from different specialties to discuss the current clinical status of IMI trials with a specific focus on phase 2 and phase 3 studies. In addition, phase 1 and experimental trials were also discussed briefly, to highlight other novel techniques. Our review summarizes the discussions from the conference and delves into the types of cancers discussed, different contrast agents in human trials, and the clinical value being studied. (C) The Authors. Published by SPIE under a Creative Commons Attribution 4.0 Unported License.Surgical oncolog

Dissecting the default mode network: Direct structural evidence on the morphology and axonal connectivity of the fifth component of the cingulum bundle

OBJECTIVE Although a growing body of data support the functional connectivity between the precuneus and the medial temporal lobe during states of resting consciousness as well as during a diverse array of higher-order functions, direct structural evidence on this subcortical circuitry is scarce. Here, the authors investigate the very existence, anatomical consistency, morphology, and spatial relationships of the cingulum bundle V (CB-V), a fiber tract that has been reported to reside close to the inferior arm of the cingulum (CingI). METHODS Fifteen normal, formalin-fixed cerebral hemispheres from adults were treated with Klingler's method and subsequently investigated through the fiber microdissection technique in a medial to lateral direction. RESULTS A distinct group of fibers is invariably identified in the subcortical territory of the posteromedial cortex, connecting the precuneus and the medial temporal lobe. This tract follows the trajectory of the parietooccipital sulcus in a close spatial relationship with the CingI and the sledge runner fasciculus. It extends inferiorly to the parahippocampal place area and retrosplenial complex area, followed by a lateral curve to terminate toward the fusiform face area (Brodmann area [BA] 37) and lateral piriform area (BA35). Taking into account the aforementioned subcortical architecture, the CB-V allegedly participates as a major subcortical stream within the default mode network, possibly subserving the transfer of multimodal cues relevant to visuospatial, facial, and mnemonic information to the precuneal hub. Although robust clinical evidence on the functional role of this stream is lacking, the modern neurosurgeon should be aware of this tract when manipulating cerebral areas en route to lesions residing in or around the ventricular trigone. CONCLUSIONS Through the fiber microdissection technique, the authors were able to provide original, direct structural evidence on the existence, morphology, axonal connectivity, and correlative anatomy of what proved to be a discrete white matter pathway, previously described as the CB-V, connecting the precuneus and medial temporal lobe. © 2021 American Association of Neurological Surgeons. All rights reserved

Optimizing Whole Brain Radiation Therapy Dose and Fractionation: Results From a Prospective Phase 3 Trial (NCCTG N107C [Alliance]/CEC.3)

Purpose: Whole brain radiation therapy (WBRT) remains a commonly used cancer treatment, although controversy exists regarding the optimal dose/fractionation to optimize intracranial tumor control and minimize resultant cognitive deficits. Methods and Materials: NCCTG N107C [Alliance]/CEC.3 randomized 194 patients with brain metastases to either stereotactic radiosurgery alone or WBRT after surgical resection. Among the 92 patients receiving WBRT, sites predetermined the dose/fractionation that would be used for all patients treated at that site (either 30 Gy in 10 fractions or 37.5 Gy in 15 fractions). Analyses were performed using Kaplan-Meier estimates, log rank tests, and Fisher's exact tests. Results: Among 92 patients treated with surgical resection and adjuvant WBRT, 49 were treated with 30 Gy in 10 fractions (53%), and 43 were treated with 37.5 Gy in 15 fractions (47%). Baseline characteristics, including cognitive testing, were well balanced between groups with the exception of primary tumor type (lung cancer histology was more frequent with protracted WBRT: 72% vs 45%, P =.01), and 93% of patients completed the full course of WBRT. A more protracted WBRT dose regimen (37.5 Gy in 15 fractions) did not significantly affect time to cognitive failure (hazard ratio [HR], 0.9; 95% confidence interval [CI], 0.6-1.39; P =.66), surgical bed control (HR, 0.52 [95% CI, 0.22-1.25], P =.14), intracranial tumor control (HR, 0.56 [95% CI, 0.28-1.12], P =.09), or overall survival (HR, 0.72 [95% CI, 0.45-1.16], P =.18). Although there was no reported radionecrosis, there is a statistically significant increase in the risk of at least 1 grade 653 adverse event with 37.5 Gy in 15 fractions versus 30 Gy in 10 fractions (54% vs 31%, respectively, P =.03). Conclusions: This post hoc analysis does not demonstrate that protracted WBRT courses reduce the risk of cognitive deficit, improve tumor control in the hypoxic surgical cavity, or otherwise improve the therapeutic ratio. Adverse events were significantly higher with the lengthened course of WBRT. For patients with brain metastases where WBRT is recommended, shorter course hypofractionated regimens remain the current standard of care

Proposed definition of competencies for surgical neuro-oncology training

Objective: The aim of this work is to define competencies and entrustable professional activities (EPAs) to be imparted within the framework of surgical neuro-oncological residency and fellowship training as well as the education of medical students. Improved and specific training in surgical neuro-oncology promotes neuro-oncological expertise, quality of surgical neuro-oncological treatment and may also contribute to further development of neuro-oncological techniques and treatment protocols. Specific curricula for a surgical neuro-oncologic education have not yet been established. Methods: We used a consensus-building approach to propose skills, competencies and EPAs to be imparted within the framework of surgical neuro-oncological training. We developed competencies and EPAs suitable for training in surgical neuro-oncology. Result: In total, 70 competencies and 8 EPAs for training in surgical neuro-oncology were proposed. EPAs were defined for the management of the deteriorating patient, the management of patients with the diagnosis of a brain tumour, tumour-based resections, function-based surgical resections of brain tumours, the postoperative management of patients, the collaboration as a member of an interdisciplinary and/or -professional team and finally for the care of palliative and dying patients and their families. Conclusions and Relevance: The present work should subsequently initiate a discussion about the proposed competencies and EPAs and, together with the following discussion, contribute to the creation of new training concepts in surgical neuro-oncology. © 2021, The Author(s)