Leveraging the neurosurgical operating room for therapeutic development in NeuroOncology.

Glioblastoma (GBM) remains a disease with a dismal prognosis. For all the hope and promise immunotherapies and molecular targeted therapies have shown for systemic malignancies, these treatments have failed to show any promise in GBM. In this context, the paradigm of investigation of therapeutics for this disease itself must be examined and modifications considered. The unique challenge of the presence of blood-brain and blood-tumor barriers (BBB/BTB) raises questions about both the true levels of systemic drug delivery to the affected tissues. Window-of-opportunity (WoO) trials in neuro-oncology allow for proof-of-concept at the start of a classic phase I-II-III clinical trial progression. For therapeutics that do not have the ability to cross the BBB/BTB, direct delivery into tumor and/or tumor-infiltrated brain in the setting of a surgical procedure can provide a novel route of therapeutic access. These approaches permit neurosurgeons to play a greater role in therapeutic development for brain tumors.

Nervus Intermedius Outcomes After Vestibular Schwannoma Surgery and Radiosurgery: A Single-Institution Experience.

OBJECTIVE: Nervus intermedius (NI) dysfunction after the management of vestibular schwannoma (VS) is underreported and is experienced by patients undergoing stereotactic radiosurgery and surgical resection. The aim of this study was to present NI outcomes in a series of patients who underwent all treatment modalities for VS and to review the existing literature. METHODS: We performed a retrospective review of all patients with VS who were treated at our institution between January 1, 2008, and December 31, 2018. Demographic data, tumor size, Koos grade, treatment modality, extent of resection, postoperative facial nerve function, and hearing function were collected. NI outcomes were determined from phone interview using a previously published functional questionnaire. RESULTS: Of 222 patients who were reviewed, 98 patients responded to the questionnaire. Patients were stratified into 3 groups: group 1, 54 patients who underwent radiation; group 2, 27 patients who underwent surgical treatment; group 3, 17 patients who underwent both radiation and surgery. Of patients, 28% presented with preoperative NI dysfunction, most commonly dry eye followed by taste dysfunction and lacrimation dysfunction. Following treatment, 79% of patients experienced NI dysfunction, most commonly dry eye. Statistical differences in dry eye and taste dysfunction were observed when comparing the treatment groups. CONCLUSIONS: NI dysfunction is common following treatment for VS and should be included in pretreatment counseling of patients, as it may impact treatment choice and quality of life. Additional studies are warranted to fully characterize NI dysfunction after treatment.

Hydroxyapatite cement cranioplasty for reconstruction of translabyrinthine approach: aesthetic results, long-term satisfaction, quality of life, and complications.

BACKGROUND: Translabyrinthine approaches (TLAs) for resection of skull base neoplasms are complex with variable reconstruction techniques. Fat grafts in conjunction with hydroxyapatite bone cement techniques have seldom been described in terms of possible superiority to other skull base reconstruction techniques. We sought to determine the impact of this skull base reconstruction technique on clinical outcomes and patient's satisfaction. METHOD: We performed a retrospective analysis of all patients who underwent translabyrinthine approaches for resection of CPA lesions over a 5-year period. Both post-op objective and subjective markers of reconstruction, as well as postoperative complications, were collected and analyzed. RESULTS: Sixty-nine patients were included, 34 underwent reconstruction with hydroxyapatite and fat (rHAC) and 35 with fat alone (rF). rHAC was associated with fewer cranial wound superficial infection/dehiscence (0% vs 14.3%; p = 0.029) and shorter length of stay (mean ± standard deviation) (6.9 ± 7.4 vs 4.4 ± 3.7 days, p = 0.008). Postoperative subjective characterization of rHAC demonstrated improved satisfaction scores (1.38 ± 0.5 vs 1.83 ± 1; p = 0.049) and fewer reports of post-operative irregularities (11.5% vs 37.5%; p = 0.017). CONCLUSION: The use of hydroxyapatite for cranial reconstruction after translabyrinthine approaches has improved patient satisfaction and decreased cranial defects in our small series. Postoperative complications are consistent with other described methods, but with shorter hospital stay, decreased risk of superficial wound dehiscence/infection, and a perceived superiority in preventing percutaneous post-op CSF leaks.

Acute Sigmoid Sinus Compromise Following Skull Base Procedures: Is a "Laissez-Faire" Approach Best?

Objective Venous sinus compromise (VSC) of the sigmoid sinus can manifest as either venous sinus thrombosis, stenosis, or a combination of the two. It may occur following retro and presigmoid craniotomy, even in the absence of overt intraoperative sinus injury. Currently, the optimal management of VSC in the perioperative period is not well established. We report our incidence and management of VSC following skull base surgery around the sigmoid sinus. Patients and Methods A retrospective chart review of all patients undergoing presigmoid, retrosigmoid, or combined approach by the senior author from 2014 to 2019 was performed. Main Outcome Measures Charts were reviewed for patient demographics, surgical details, details of venous sinus compromise, and patient outcomes. Statistical analyses were performed using R 3.6.0 (R Project). Results A 115 surgeries were found with a total of 13 cases of VSC (overall incidence of 11.3%). Nine cases exhibited thrombosis and four stenosis. There were no statistically significant differences between the groups with (group 1) or without (group 2) VSC. Operation on the side of the dominant sinus did not predispose to postoperative VSC. Five patients received antiplatelet medication in the perioperative period. There was no difference in outcomes in the group that did not receive antiplatelet medication versus those who did. Conclusion Acute iatrogenic sigmoid sinus compromise can be managed expectantly. We believe that the treatment for each instance of VSC must be individualized, considering the symptoms of the patient, rather than applying a universal algorithm.

Clinical Features of Pineal Parenchymal Tumors of Intermediate Differentiation (PPTID): A Single-Institution Series.

OBJECTIVE: Pineal parenchymal tumors of intermediate differentiation (PPTID) are rare tumors of the pineal gland. Their treatment is often heterogeneous due to the lack of literature to compile standardized treatments. Although no single institution has large numbers of cases, our experience has been that the clinical course is more varied and complicated than reported. METHODS: We reviewed the clinical data for all patients with pathology found to be consistent with PPTID at our institution between the years 2006 and 2019. RESULTS: Nine patients were identified. At initial diagnosis, all were treated with surgery and 4 of 9 patients underwent gross total resection. Adjuvant radiation therapy to the resection bed was administered in 6 of 9 patients. Mean follow-up time was 95.3 months. Mean progression-free survival was 50.5 months, with a tendency to be longer for male sex and after gross total resection. Seven patients developed a recurrence. Five of 6 known locations of first recurrences had either distant metastases or dissemination of disease. First recurrences were treated with radiation alone in 5 patients, craniospinal radiation with multiagent chemotherapy in 1 patient, and surgery with radiation therapy in 1. At last follow-up, 2 patients had died. CONCLUSIONS: Herein, we report clinical patterns of disease progression and treatment patterns of PPTID. Many patients progressed during the follow-up period. Disseminated disease was the most common presentation at recurrence. Ultimately, given the risk of recurrence and dissemination at recurrence, more aggressive treatment strategies should be considered. Specifically, our series suggests a benefit of adjuvant radiation at initial diagnosis for grade II patients.

Therapeutic Delivery to Central Nervous System.

Therapies for glioblastoma face several physiologic hurdles. The blood-brain barrier (BBB) and blood-brain-tumor barrier (BTB) present impediments to therapeutic delivery of drugs to the central nervous system. Strategies to disrupt or bypass the native BBB are necessary to deliver therapeutic agents. Techniques to bypass the BBB/BTB include implantable controlled-release polymer systems, intracavitary drug delivery, direct injection of viral vectors, and infusion via convection-enhanced delivery. Ideal methods and agents to accomplish the goal providing survival benefit are yet to be determined. Further development of methods to break down or bypass the BBB and BTB is necessary for patients with glioblastoma.

Defining the timing and role of acute postoperative imaging in pituitary adenoma surgery: clinical study.

BACKGROUND: The ideal timing of postoperative imaging after pituitary adenoma surgery has yet to be determined. We reviewed our pituitary database to determine whether timing of routine postoperative imaging has significantly changed patients' clinical course or outcomes. METHODS: Retrospective chart review of patients undergoing resection of pituitary adenoma at our university center between 2012 and 2017 was performed. Timing and indication for postoperative imaging, findings of immediate and delayed postoperative imaging, as well as re-operations and radiosurgery details were recorded. Visual functions such as acuity and visual fields were used as clinical outcome indicators. Statistical analysis was run using Microsoft Excel. RESULTS: Five hundred and nineteen patients were identified; 443 had imaging data in our system and were included in the study. Early (< 90 days) MRIs were obtained in 71 patients and late (≥ 90 days) in 372 patients. We found statistical differences in our demographic groups including larger tumors in the early MRI group (early mean 12.33 cm3, late mean 4.64 cm3, p < 0.001) and higher Knosp grade (p = 0.0006). We found a significant difference in rates of return to the OR (16.9% in the early group and 4.84% in the late group; p < 0.001). There was a significant difference in the rate of residual identified on first postoperative MRI: 52.11% in the early group and 29.57% in the late group (p < 0.001). There was no difference in visual outcomes between the patient cohorts. CONCLUSION: After surgical treatment of pituitary adenoma, MRI obtained before 3 months is associated with higher rates of return to OR but no difference in long-term clinical outcomes. Due to cost efficiency, we argue for a delayed first postoperative MRI. The timing of MRI should also be governed by other factors such as large pituitary macroadenomas or postoperative complications. We recommend a consistent institutional protocol for determining the most cost-effective follow-up of postoperative pituitary patients.

The predictive value of preoperative apparent diffusion coefficient (ADC) for facial nerve outcomes after vestibular schwannoma resection: clinical study.

OBJECT: Diffusion MRI has been used to predict intraoperative consistency of tumors. Apparent diffusion coefficient (ADC) has shown predictive value as an imaging biomarker in many CNS tumors but has not been studied in a large cohort of patients with vestibular schwannoma. In this study, we examine the utility of ADC as a predictive biomarker for intraoperative tumor characteristics and postoperative facial nerve outcome. METHODS: A retrospective review of patients who underwent vestibular schwannoma resection at our institution from 2008 to 2018 yielded 87 patients, of which 72 met inclusion criteria. Operative reports and clinical records were reviewed for clinical data; MRI data were interpreted in a blinded fashion for qualitative and quantitative biomarkers, including tumor ADC. RESULTS: Mean tumor ADC values did not predict intraoperative consistency or adherence (p = 0.63). Adherent tumors were associated with worse facial nerve outcomes (p = 0.003). Regression tree analysis identified 3 ADC categories with statistically different facial nerve outcomes. The categories identified were ADC < 1006.04 × 10-6 mm2/s; ADC 1006.04-1563.93 × 10-6 mm2/s and ADC ≥ 1563.94 × 10-6 mm2/s. Postoperative and final House-Brackmann (HB) scores were significantly higher in the intermediate ADC group (2.3, p = 0.0038). HB outcomes were similar between the group with ADC < 1006.04 × 10-6 mm2/s and ≥ 1563.94 × 10-6 mm2/s (1.3 vs 1.3). CONCLUSIONS: Middle-range preoperative ADC in vestibular schwannoma suggests a less favorable postoperative HB score. Preoperative measurement of ADC in vestibular schwannoma may provide additional information regarding prognostication of facial nerve outcomes.

Retrosigmoid Approach for Vestibular Schwannoma.

Vestibular schwannoma is a benign tumor that affects 3% of the population, but accounts for 85% of tumors occurring at the cerebellopontine angle (CPA). In this case, we present a 48-year-old female with history of cholesteatoma on the right and chronic suppurative otitis media on the left who presented with an 18 month history of bilateral hearing loss, worse on the right. Investigations revealed a right sided vestibular schwannoma measuring 1.6 cm in diameter. Audiogram revealed an AAO-HNS (American Academy of Otolaryngology-Head and Neck Surgery) class C hearing on the right and class B on the left. There are several management options for this size of vestibular schwannoma including observation and radiosurgery. However, preserving cochlear nerve function remains a challenging enterprise. Furthermore, the ideal management that confers the highest chance of hearing preservation remains heavily debated. Given the patient's young age, the goal of hearing preservation and the tumor size/extension into the CPA, surgery was decided through a right retrosigmoid transmeatal approach for tumor resection with intraoperative brain auditory evoked responses monitoring. For hearing preservation, we emphasize few important dissection techniques: tumor debulking from the top first to avoid early manipulation of the cochlear nerve at the bottom of the tumor, sharp dissection from medial to lateral off the vestibular nerve which is kept intact as a tension band to minimize cochlear nerve manipulations, and limit the drilling of the posterolateral wall of the internal auditory canal (IAC) medial to the labyrinth and endolymphatic apparatus. Postoperatively, the patient was discharged home within 2 days, with imaging showing a gross total resection. Follow-up audiogram shows unchanged pure tone thresholds. The link to the Video can be found at: https://youtu.be/Z5ftkpJN5k8 .

Presigmoid Approach to Dumbbell Trigeminal Schwannoma.

This case is a 15-year-old male, presenting with headaches, right face, and arm numbness, and ataxia. MRI (magnetic resonance imaging) revealed a large right sided dumbbell shaped lesion, extending into the middle and posterior fossa with compression of the brainstem consistent with a trigeminal schwannoma. Treatment options here would be a retrosigmoid suprameatal approach or a lateral presigmoid approach. Given the tumor extension into multiple compartments, a presigmoid craniotomy, combining a middle fossa approach with anterior petrosectomy, and retrolabyrinthine approach with posterior petrosectomy were used to maximize the direct access corridor for resection. The petrous apex was already expanded and remodeled by the tumor. Nerve fascicles preservation technique is paramount to the functional preservation of the trigeminal nerve. The extent of resection should be weighed against the anatomical functional integrity of the nerve. Near total resection is considered if that means more nerve preservation. Postoperatively, the patient had a slight (House-Brackman grade II) facial droop, which resolved over days and developed right trigeminal hypesthesia at several weeks. This case is presented to demonstrate a combined petrosectomy technique for resection of lesions extending into both the middle and posterior cranial fossa with near total resection and trigeminal nerve preservation. The link to the video can be found at: https://youtu.be/kA9GyFhL1dg .

Retrosigmoid Approach to the Posterior Fossa Trigeminal Schwannoma.

We present a case of a posterior fossa trigeminal schwannoma in a 31-year-old gentleman. Preoperative symptomatology included headaches and dizziness of 6 months in duration. Trigeminal schwannomas isolated to the posterior fossa, not extending into Meckel's Cave, may be adequately resected via a retrosigmoid approach. Thus, a tailored retrosigmoid approach was planned with navigation assistance. A key point to highlight is the difficult identification and preservation of trigeminal nerve fascicles within the tumor mass. In this operative video we show a nerve preservation technique. By identifying the nerve at the anticipated anatomical location and utilizing sharp dissection, we create a dissection plane from the nerve fascicles. The surgical strategy of near total resection and leaving minimal tumor tissue on the nerve should be pursued in return for anatomical preservation of the nerve. Postoperative course was significant for facial hypoesthesia, abducens partial palsy, and gradual improvement of headaches. The link to the video can be found at: https://youtu.be/JsE1-Eonr0k .

Endoscopic Assisted Retrosigmoid Approach for Cerebellopontine Angle Epidermoid Tumor.

This case is a 20-year-old male, who presented with 1 month of right facial weakness (HB4) and complaints of ipsilateral eye dryness. He was initially treated for Bell's palsy with steroids and antiviral agents, but subsequently developed diplopia with right lateral gaze and underwent an MRI (magnetic resonance imaging). MRI demonstrated a 4.5 cm irregular lesion in the right cerebellopontine angle consistent with an epidermoid cyst. Because the tumor had grown with the development of the central nervous system, it has extended into different compartments, including the tentorial incisura and pineal region. A predefined surgical corridor created by the tumor facilitated access to the majority of the tumor through a retrosigmoid approach. Angled endoscopes (30-degree up and down) provided further visualization of tumor away from the line of sight of the microscope, thus allowing for gross total resection of the lesion. This video also demonstrates a sharp dissection technique necessary for safe removal of adherent tumor from critical neurovascular structures, including the basilar artery and several cranial nerves. The ipsilateral auditory evoked responses (ABRs) showed slight improvement from baseline toward the end of the case. A gross total resection was achieved, as shown by the MRI. The patient remained at his baseline cranial nerve (CN) V, VII, and VIII deficits during the immediate postoperative period. The link to the video can be found at: https://youtu.be/vCq5juJh8hk .

The Effect of Preoperative Direct Ligation of Ethmoidal Arteries on the Perioperative Outcomes of Large Anterior Skull Base Meningiomas Surgery: A Clinical Study.

BACKGROUND: Anterior skull base meningiomas often grow to a large size (≥4 cm) before detection. Their blood supply is mostly provided by the anterior and posterior ethmoidal arteries. Because of their vascularity, intraoperative bleeding can be a challenging prospect that increases the risk of perioperative complications. Preoperative ethmoidal arteries ligation has been used to aid in limiting blood loss. Our objective was to assess the effect of preoperative arterial ligation on the perioperative course of large (≥4 cm) to giant (≥6 cm) anterior skull base meningiomas. METHODS: We retrospectively searched our database for large anterior skull base meningiomas (≥4 cm). We analyzed differences in intraoperative blood loss, operative time, intraoperative transfusion, and hematologic parameters between patients who did not undergo preoperative ethmoidal arteries ligation (Group 1) and those who did (Group 2). RESULTS: Average estimated blood loss (EBL) was 825 mL (Group 1) versus 350 mL (Group 2) (P = 0.42), decrease in hemoglobin was 4 g/dL versus 3.2 g/dL (P = 0.53), decrease in hematocrit was 12.4% versus 9.6% (P = 0.64), and average operative time was 656 minutes versus 598 minutes (P = 0.58). EBL per volume yielded a ratio of 10.6 mL/cm3 versus 4.1 mL/cm3 (P = 0.06). CONCLUSIONS: Ethmoidal arteries ligation may have a benefit in large-to-giant anterior skull base meningiomas surgery. Our results showed a decrease in EBL and lesser decrease in pre- and postoperative hemoglobin and hematocrit levels as compared with cases in which no vascular ligation was performed when corrected for tumor volume.

The Dichotomy of Tumor Exosomes (TEX) in Cancer Immunity: Is It All in the ConTEXt?

Exosomes are virus-sized nanoparticles (30-130 nm) formed intracellularly as intravesicular bodies/intralumenal vesicles within maturing endosomes ("multivesicular bodies", MVBs). If MVBs fuse with the cell's plasma membrane, the interior vesicles may be released extracellularly, and are termed "exosomes". The protein cargo of exosomes consists of cytosolic, membrane, and extracellular proteins, along with membrane-derived lipids, and an extraordinary variety of nucleic acids. As such, exosomes reflect the status and identity of the parent cell, and are considered as tiny cellular surrogates. Because of this closely entwined relationship between exosome content and the source/status of the parental cell, conceivably exosomes could be used as vaccines against various pathologies, as they contain antigens associated with a given disease, e.g., cancer. Tumor-derived exosomes (TEX) have been shown to be potent anticancer vaccines in animal models, driving antigen-specific T and B cell responses, but much recent literature concerning TEX strongly places the vesicles as powerfully immunosuppressive. This dichotomy suggests that the context in which the immune system encounters TEX is critical in determining immune stimulation versus immunosuppression. Here, we review literature on both sides of this immune coin, and suggest that it may be time to revisit the concept of TEX as anticancer vaccines in clinical settings.