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OBJECTIVES Although the impact of surgery in glioblastoma (GBM) is well-established, there is insufficient data to determine how surgical resection affects overall survival (OS). The impact of other GBM genomic alterations on EOR-induced survival remains poorly understood. Here, we leverage a large cohort of GBM patients with genomic data to establish the impact of genomic alterations on resection-dependent overall survival in GBM. METHODS 537 IDH WT GBMs from UPMC were analyzed using Glioseq next generation sequencing panel. Using molecular profiles derived from Glioseq data, semi-supervised Monte Carlo reference-based consensus clustering was used to define 5 distinct groups. Cox Proportional Hazards models were used to identify predictors of OS within molecular groups. RESULTS Clustering of 537 IDH wild-type GBM identified 5 distinct groups: 1: TERT mutated/MGMT methylated/EGFR mutated or gain; 2: TERT mutated /MGMT methylated/p53 mutated; 3: TERT WT; 4: TERT mutated/MGMT methylated/CDKN2A loss; 5: TERT mutated/MGMT unmethylated. Thresholds in postoperative residual contrast enhancing volume (rCEV) and residual non-contrast enhancing volume (rNCEV) were identified which marked significant differences in median overall survival (MOS) between molecular groups in rCEV -Group 1: 11.7cc, Group 2: 14.4cc, Group 3: 1.1cc, Group 4: 0.1cc, and Group 5 1.1cc. Sex, age, KPS >70, temozolomide, and radiation along with thresholded rCEV and rNCEV were used in multivariate Cox analyses. Groups demonstrated distinct predictors of OS: radiation only in Group 1 tumors, low rCEV in Group 2 tumors, younger age, temodar, low CEV, and KPS >70 in Group 3 tumors, female sex, younger age, radiation, KPS >70 low rCEV in Group 4 tumors, and KPS >70, temodar, and low rCEV in Group 5 tumors. CONCLUSIONS Clustering results suggest that there are clinically distinct molecular groups of IDH wild-type glioblastomas. Age, sex, KPS >70, temozolomide treatment, radiation therapy, and EOR have varying affects on these molecular groups.

Benchmarks are important to measure and aid in improve outcomes for surgical procedures. However, best achievable results that have been validated internationally for transsphenoidal surgery are not available. Therefore, we aimed to establish robust, standardized outcome benchmarks for transsphenoidal surgery of pituitary adenomas. A total of 2862 transsphenoidal tumor resections from 12 high-volume centers in 4 continents were analyzed. Patients were risk stratified and the median values of each center’s outcomes were established. The outcome benchmark was defined as the 75th percentile of all median values for a particular outcome as defined by Staiger et al. Out of 2862 patients, 1201 (41.9%) defined the benchmark cohort. The proportion of benchmark cases contributing to the final cohort ranged across centers between 22.1% to 59.7%. Within the benchmark cases, 928 (73.3%) patients underwent microscopic (MTS) and 263 (21.9%) patients endoscopic endonasal resection (EES). The overall postoperative complication rate was 18.9% with an in-hospital mortality between 0.0-0.8%. Benchmark cutoffs were ≤ 3.3% for reoperation rate, ≤ 4.6% for cerebrospinal fluid leak requiring intervention, and ≤ 15.3% for transient diabetes insipidus. At 6 months follow-up, benchmark cutoffs were calculated as follows: readmission rate: ≤ 7.1%, new hypopituitarism ≤ 15.5%, new neurological deficit ≤ 1.2%, tumor remnant ≤ 25.5%. This analysis defines benchmark values for transsphenoidal resection of pituitary adenomas targeting morbidity, mortality, surgical and tumor-related outcomes. The benchmark cutoffs can be used to assess different centers, patients’ populations, and novel surgical techniques.

INTRODUCTION Preoperative stereotactic radiosurgery (SRS) is an emerging therapeutic strategy for treatment of brain metastasis requiring surgical resection. Prior reports have been highly-controlled, excluding very large brain metastases. Here, we report a prospectively-collected preoperative series reflective of a real-world neurosurgical patient cohort, with a particular focus on resumption of immunotherapy. METHODS Our series included Nf27 prospective preoperative compared to concurrently collected Nf37 postoperative patients. Demographic, SRS volumes/dose, pre/postoperative immunotherapy, and clinical outcomes were collected. Subsequent univariate comparisons between groups were performed. RESULTS Pre/postoperative tumor volumes (19.1 [range: 2.4-65.1] vs. 12.5 [3.6-80.3]cc, p=0.20); local tumor control at 1 year (77.6% vs. 71.4%, p=0.616); overall survival (1.0 [0.8-2.2] vs. 1.3 [0.7-NR] years, p=0.8) were comparable between groups. Rates of LMD (3.7% vs. 8.0%, p=0.39) and subsequent WBRT (8.0% vs. 16.2%, p=0.46) were not statistically different. OR time (168 vs. 173 min, p=0.64), estimated blood loss (133 vs. 180 mL, p=0.31), and wound infections (1 vs. 1, p=1.00) were not significantly different.An ostensible advantage to preoperative SRS is that steroids may be weaned more quickly to allow resumption of immunotherapy. Median steroid taper length was significantly shorter (8 vs. 21.5 days, p=0.007), and median daily Dexamethasone dose at 1 week post-op was significantly lower in the preoperative group (1 vs. 7mg d, p=0.007). All preoperative patients eligible for resumption of immunotherapy (Nf5) resumed treatment within 6 weeks. Conversely, only 2/6 in postoperative patients resumed treatment within 6 weeks, (p=0.07), while 4 failed to resume immunotherapy altogether. In patients initiating immunotherapy after OR/SRS, time to initiation was non-significantly lower in the preoperative group (52[38-84] vs.163[108-208] days, p=0.06). CONCLUSIONS Preoperative SRS is safe and provides comparable local tumor control rate even in large tumors ( >20cc). In patients requiring resumption of immunotherapy, preoperative SRS may provide a faster pathway towards resumption of systemic therapy.

Although patients with localized and regional kidney tumors have a high survival rate, incidence of mortality significantly increases for patients with metastatic disease. It is imperative to decipher the molecular mechanisms of kidney tumor migration and invasion in order to develop effective therapies for patients with advanced cancer. Rap1, a small GTPase protein, has been implicated in cancer cell growth and invasion. Here, we profile migratory and invasive properties of commonly used renal cell carcinoma (RCC) cell lines and correlate that with expression and function of the Rap inactivator Rap1GAP. We report that levels of Rap1GAP inversely correlate with invasion but not migration. We also report that forced over-expression of Rap1GAP decreases invasion of RCC cells but does not impact their rate of proliferation. Low expression levels of Rap1GAP in RCC cells are due, at least in part, to promoter hypermethylation. Rescued expression of Rap1GAP with a demethylating drug, decitabine (5-azadC), decreases the RCC SN12C cell invasion of collagen, fibronectin, and Matrigel matrices. RCC cell lines express distinct levels of cell adhesion proteins and the forced over-expression of Rap1GAP attenuated levels of both cadherins and integrins that are known to regulate the cancer cells invasion. These results demonstrate that targeted restoration of Rap1GAP expression may serve as a potential therapeutic approach to reduce metastasis of kidney cancers.