Faculty Bibliography

BACKGROUND:Brain metastases (BM) have long been considered a terminal diagnosis with management mainly aimed at palliation and little hope for extended survival. Use of brain stereotactic radiosurgery (SRS) and/or resection, in addition to novel systemic therapies, has enabled improvements in overall and progression-free (PFS) survival. OBJECTIVE:To explore the possibility of extended survival in patients with non-small-cell lung cancer (NSCLC) BM in the current era. METHODS:During the years 2008 to 2020, 606 patients with NSCLC underwent their first Gamma Knife SRS for BM at our institution with point-of-care data collection. We reviewed clinical, molecular, imaging, and treatment parameters to explore the relationship of such factors with survival. RESULTS:The median overall survival was 17 months (95% CI, 13-40). Predictors of increased survival in a multivariable analysis included age <65 years (P < .001), KPS ≥80 (P < .001), absence of extracranial metastases (P < .001), fewer BM at first SRS (≤3, P = .003), and targeted therapy (P = .005), whereas chemotherapy alone was associated with shorter survival (P = .04). In a subgroup of patients managed before 2016 (n = 264), 38 (14%) were long-term survivors (≥5 years), of which 16% required no active cancer treatment (systemic or brain) for ≥3 years by the end of their follow-up. CONCLUSION/CONCLUSIONS:Long-term survival in patients with brain metastases from NSCLC is feasible in the current era of SRS when combined with the use of effective targeted therapeutics. Of those living ≥5 years, the chance for living with stable disease without the need for active treatment for ≥3 years was 16%.

BACKGROUND/UNASSIGNED:Central nervous system (CNS) cancer is the 10th leading cause of cancer-associated deaths for adults, but the leading cause in pediatric patients and young adults. The variety and complexity of histologic subtypes can lead to diagnostic errors. DNA methylation is an epigenetic modification that provides a tumor type-specific signature that can be used for diagnosis. METHODS/UNASSIGNED:We performed a prospective study using DNA methylation analysis as a primary diagnostic method for 1921 brain tumors. All tumors received a pathology diagnosis and profiling by whole genome DNA methylation, followed by next-generation DNA and RNA sequencing. Results were stratified by concordance between DNA methylation and histopathology, establishing diagnostic utility. RESULTS/UNASSIGNED:Of the 1602 cases with a World Health Organization histologic diagnosis, DNA methylation identified a diagnostic mismatch in 225 cases (14%), 78 cases (5%) did not classify with any class, and in an additional 110 (7%) cases DNA methylation confirmed the diagnosis and provided prognostic information. Of 319 cases carrying 195 different descriptive histologic diagnoses, DNA methylation provided a definitive diagnosis in 273 (86%) cases, separated them into 55 methylation classes, and changed the grading in 58 (18%) cases. CONCLUSIONS/UNASSIGNED:DNA methylation analysis is a robust method to diagnose primary CNS tumors, improving diagnostic accuracy, decreasing diagnostic errors and inconclusive diagnoses, and providing prognostic subclassification. This study provides a framework for inclusion of DNA methylation profiling as a primary molecular diagnostic test into professional guidelines for CNS tumors. The benefits include increased diagnostic accuracy, improved patient management, and refinements in clinical trial design.

OBJECTIVE:Maximal safe resection is the goal of surgical treatment for high-grade glioma (HGG). Deep-seated hemispheric gliomas present a surgical challenge due to safety concerns and previously were often considered inoperable. The authors hypothesized that use of tubular retractors would allow resection of deep-seated gliomas with an acceptable safety profile. The purpose of this study was to describe surgical outcomes and survival data after resection of deep-seated HGG with stereotactically placed tubular retractors, as well as to discuss the technical advances that enable such procedures. METHODS:This is a retrospective review of 20 consecutive patients who underwent 22 resections of deep-seated hemispheric HGG with the Viewsite Brain Access System by a single surgeon. Patient demographics, survival, tumor characteristics, extent of resection (EOR), and neurological outcomes were recorded. Cannulation trajectories and planned resection volumes depended on the relative location of white matter tracts extracted from diffusion tractography. The surgical plans were designed on the Brainlab system and preoperatively visualized on the Surgical Theater virtual reality SNAP platform. Volumetric assessment of EOR was obtained on the Brainlab platform and confirmed by a board-certified neuroradiologist. RESULTS:Twenty adult patients (18 with IDH-wild-type glioblastomas and 2 with IDH-mutant grade IV astrocytomas) and 22 surgeries were included in the study. The cohort included both newly diagnosed (n = 17; 77%) and recurrent (n = 5; 23%) tumors. Most tumors (64%) abutted the ventricular system. The average preoperative and postoperative tumor volumes measured 33.1 ± 5.3 cm3 and 15.2 ± 5.1 cm3, respectively. The median EOR was 93%. Surgical complications included 2 patients (10%) who developed entrapment of the temporal horn, necessitating placement of a ventriculoperitoneal shunt; 1 patient (5%) who suffered a wound infection and pulmonary embolus; and 1 patient (5%) who developed pneumonia. In 2 cases (9%) patients developed new permanent visual field deficits, and in 5 cases (23%) patients experienced worsening of preoperative deficits. Preoperative neurological or cognitive deficits remained the same in 9 cases (41%) and improved in 7 (32%). The median overall survival was 14.4 months in all patients (n = 20) and in the newly diagnosed IDH-wild-type glioblastoma group (n = 16). CONCLUSIONS:Deep-seated HGGs, which are surgically challenging and frequently considered inoperable, are amenable to resection through tubular retractors, with an acceptable safety profile. Such cytoreductive surgery may allow these patients to experience an overall survival comparable to those with more superficial tumors.

BACKGROUND: While most meningiomas are considered benign tumors, a subset of these tumors are characterized by a more aggressive clinical course and require multimodal treatment. Beyond surgical and radiotherapeutic options, there are no effective medical treatments available. Somatostatin receptor 2 (SSTR2) is expressed by the majority of meningiomas. 177Lu-DOTATATE is a SSTR2-targeting radionuclide that has been successful in neuroendocrine tumors. Here we report the results of the interim analysis of an ongoing clinical trial (NCT03971461) that is evaluating the effect of 177Lu-DOTATATE in treating progressive intracranial meningiomas.
METHOD(S): In this Simon two-stage design phase II study, adults with advanced intracranial meningiomas received 177Lu-DOTATATE 7.4 GBq (200 mCi) every eight weeks for four doses. 68Ga-DOTATATE PET-MRI was performed before and at the end of treatment. The primary endpoint was progression-free survival at 6 months (PFS-6). Correlative studies evaluated the association of PFS-6, objective response rate, progression-free survival, overall survival with radiographic tumor measurements, 68Ga-DOTATATE uptake on PET-MRI, SSTR2 expression in tumor, and meningioma methylation subclass.
RESULT(S): Fourteen patients (F = 11, M = 3) with progressive meningiomas (WHO I = 3, II = 10, III = 1) have been enrolled. Median age was 63.1 (range 49-78) years. All patients previously underwent tumor resection and at least one course of radiation. Treatment with 177Lu-DOTATATE was well tolerated, no treatment-limiting toxicities were observed. Six of 14 patients (42%) achieved PFS-6. Radiographically, all six patients had achieved Stable Disease. A functional alteration of tumoral SSTR2 expression by 68Ga-DOTATATE PET-MR imaging was observed in three patients.
CONCLUSION(S): Treatment with SSTR2- targeting 177Lu-DOTATATE is well tolerated. In this interim analysis, six of 14 patients achieved PFS-6. This exceeds the predefined threshold to continue to stage two of this study. This clinical trial is now open to patient enrollment at two study sites in the US

BACKGROUND:Endoscopic endonasal approach (EEA) procedures are inherently contaminated due to direct access through the nasopharyngeal mucosa. The reported rate of postoperative meningitis in EEA procedures is 0.7%-3%. A variety of methods exist to minimize the risk of meningitis with antibiotic prophylaxis, although their value is not completely understood. This study investigated whether there is a difference in rates of postoperative meningitis based on Staphylococcus aureus colonization and use of preoperative antibiotic prophylaxis. METHODS:All adult patients who underwent EEA resection at our institution from 2013 to 2021 were retrospectively reviewed. Patients with preoperative cerebrospinal fluid infections were excluded. Data including recent preoperative infections, preoperative colonization status, antibiotic administration, and postoperative outcomes were recorded for each patient. RESULTS:Of 483 patients identified (mean age, 51 years; range, 18-90 years; 274 [56.7%] female), 80 (16.6%) had a positive preoperative methicillin-resistant Staphylococcus aureus (MRSA)/methicillin-sensitive Staphylococcus aureus (MSSA) screening swab. Twenty-one (26.3%) colonized patients were treated with preoperative decolonizing antibiotics. Within 30 days of surgery, 13 (2.7%) patients developed culture-positive meningitis. There was no significant difference in meningitis rates based on MRSA/MSSA colonization status. Among colonized patients, there was no significant difference in rates of MRSA/MSSA meningitis based on preoperative antibiotic decolonization. CONCLUSIONS:Postoperative rates of meningitis after EEA surgery were not significantly changed based on MRSA/MSSA colonization status of the patient or preoperative decolonization. The utility of preoperative testing of MRSA/MSSA status and antibiotics for decolonization to prevent postoperative meningitis should be further investigated.

BACKGROUND:For patients with vestibular schwannoma (VS), stereotactic radiosurgery (SRS) has proven effective in controlling tumor growth while hearing preservation remains a key goal. OBJECTIVE:To evaluate hearing outcomes in the modern era of cochlear dose restriction. METHODS:During the years 2013 to 2018, 353 patients underwent Gamma knife surgery for VS at our institution. We followed 175 patients with pre-SRS serviceable hearing (Gardner-Robertson Score, GR 1 and 2). Volumetric and dosimetry data were collected, including biological effective dose, integral doses of total and intracanalicular tumor components, and hearing outcomes. RESULTS:The mean age was 56 years, 74 patients (42%) had a baseline GR of 2, and the mean cochlear dose was 3.5 Gy. The time to serviceable hearing loss (GR 3-4) was 38 months (95% CI 26-46), with 77% and 62% hearing preservation in the first and second years, respectively. Patients optimal for best hearing outcomes were younger than 58 years with a baseline GR of 1, free canal space ≥0.041 cc (diameter of 4.5 mm), and mean cochlear dose <3.1 Gy. For such patients, hearing preservation rates were 92% by 12 months and 81% by 2 years, staying stable for >5 years post-SRS, significantly higher than the rest of the population. CONCLUSION/CONCLUSIONS:Hearing preservation after SRS for patients with VS with serviceable hearing is correlated to the specific baseline GR score (1 or 2), age, cochlear dose, and biological effective dose. Increased tumor-free canal space correlates with better outcomes. The most durable hearing preservation correlates with factors commonly associated with smaller tumors away from the cochlea.

BACKGROUND:Previous studies comparing hearing outcomes in patients managed with stereotactic radiosurgery (SRS) and a watch-and-wait strategy were limited by small sample sizes that prevented controlling for potential confounders, including initial hearing status, tumor size, and age. OBJECTIVE:To compare hearing outcomes for patients with vestibular schwannomas (VS) managed with observation and SRS while controlling for confounders with propensity score matching. METHODS:Propensity score matching was used to compare 198 patients with unilateral VS with initial serviceable hearing (99 treated with SRS and 99 managed with observation alone) and 116 with initial class A hearing (58 managed with SRS and 58 with observation), matched by initial hearing status, tumor volume, age, and sex. Kaplan-Meier survival methods were used to compare risk of losing class A and serviceable hearing. RESULTS:Between patients with VS managed with SRS or observation alone, there was no significant difference in loss of class A hearing (median time 27.2 months, 95% CI 16.8-43.4, and 29.2 months, 95% CI 20.4-62.5, P = .88) or serviceable hearing (median time 37.7 months, 95% CI 25.7-58.4, and 48.8 months, 95% CI 38.4-86.3, P = .18). For SRS patients, increasing mean cochlear dose was not related to loss of class A hearing (hazard ratio 1.3, P = .17) but was associated with increasing risk of serviceable hearing loss (hazard ratio of 1.5 per increase in Gy, P = .017). CONCLUSION/CONCLUSIONS:When controlling for potential confounders, there was no significant difference in loss of class A or serviceable hearing between patients managed with SRS or with observation alone.