Does waiting for surgery matter? How time from diagnostic MRI to resection affects outcomes in newly diagnosed glioblastoma.

OBJECTIVE: Maximal safe resection is the standard of care for patients presenting with lesions concerning for glioblastoma (GBM) on magnetic resonance imaging (MRI). Currently, there is no consensus on surgical urgency for patients with an excellent performance status, which complicates patient counseling and may increase patient anxiety. This study aims to assess the impact of time to surgery (TTS) on clinical and survival outcomes in patients with GBM. METHODS: This is a retrospective study of 145 consecutive patients with newly diagnosed IDH-wild-type GBM who underwent initial resection at the University of California, San Francisco, between 2014 and 2016. Patients were grouped according to the time from diagnostic MRI to surgery (i.e., TTS): ≤ 7, > 7-21, and > 21 days. Contrast-enhancing tumor volumes (CETVs) were measured using software. Initial CETV (CETV1) and preoperative CETV (CETV2) were used to evaluate tumor growth represented as percent change (ΔCETV) and specific growth rate (SPGR; % growth/day). Overall survival (OS) and progression-free survival (PFS) were measured from the date of resection and were analyzed using the Kaplan-Meier method and Cox regression analyses. RESULTS: Of the 145 patients (median TTS 10 days), 56 (39%), 53 (37%), and 36 (25%) underwent surgery ≤ 7, > 7-21, and > 21 days from initial imaging, respectively. Median OS and PFS among the study cohort were 15.5 and 10.3 months, respectively, and did not differ among the TTS groups (p = 0.81 and 0.17, respectively). Median CETV1 was 35.9, 15.7, and 10.2 cm3 across the TTS groups, respectively (p < 0.001). Preoperative biopsy and presenting to an outside hospital emergency department were associated with an average 12.79-day increase and 9.09-day decrease in TTS, respectively. Distance from the treating facility (median 57.19 miles) did not affect TTS. In the growth cohort, TTS was associated with an average 2.21% increase in ΔCETV per day; however, there was no effect of TTS on SPGR, Karnofsky Performance Status (KPS), postoperative deficits, survival, discharge location, or hospital length of stay. Subgroup analyses did not identify any high-risk groups for which a shorter TTS may be beneficial. CONCLUSIONS: An increased TTS for patients with imaging concerning for GBM did not impact clinical outcomes, and while there was a significant association with ΔCETV, SPGR remained unaffected. However, SPGR was associated with a worse preoperative KPS, which highlights the importance of tumor growth speed over TTS. Therefore, while it is ill advised to wait an unnecessarily long time after initial imaging studies, these patients do not require urgent/emergency surgery and can seek tertiary care opinions and/or arrange for additional preoperative support/resources. Future studies are needed to explore subgroups for whom TTS may impact clinical outcomes.

Exoscope Efficacy and Feasibility in Pediatric Spinal Neurosurgery: A Single-Institution Cohort Case Series.

BACKGROUND: The exoscope has emerged as an efficacious microscope in adult spinal neurosurgery providing improved operative field visibility and surgeon ergonomics. However, outcome data and feasibility are underrepresented in the pediatric literature. We present the largest case series aimed at assessing operative and clinical outcomes in pediatric patients undergoing various exoscope-assisted spinal surgeries. METHODS: A retrospective review was conducted on all consecutive pediatric (age <18 years) spinal surgeries performed with the use of an exoscope by 3 senior surgeons at a single institution from 2020-2023. Demographics and clinical and operative outcomes were reviewed and analyzed. RESULTS: Ninety-six exoscope-assisted pediatric spine surgeries were performed on 89 unique patients, 41 (42.7%) of which were male. The mean age at surgery was 12 (±5.3) years. Spinal cord detethering (55.8%) was the most common procedure performed. The overall mean operative time for all procedures was 155 (±86) minutes, and the mean estimated blood loss was 18 (±41) mL. The mean length of stay was 5.4 (±6.5) days. There were 14 (14.6%) patients with complications in this cohort. At final follow-up, 64 (83.1%) of symptomatic patients reported neurologic symptom improvement. CONCLUSIONS: Using the exoscope in a variety of pediatric spinal surgeries resulted in an acceptable average operative time, estimated blood loss, length of stay, and rate of neurologic symptom improvement. The exoscope appears to be an efficacious option for pediatric neurosurgical spinal procedures.

Posterior-based resection of spinal meningiomas: an institutional experience of 141 patients with an average of 28 months of follow-up.

OBJECTIVE: Spinal meningiomas pose unique challenges based on the location of their dural attachment. However, there is a paucity of literature investigating the role of dural attachment location on outcomes after posterior-based approach for spinal meningioma resection. The aim of this study was to investigate any differences in outcomes between dural attachment location subgroups in spinal meningioma patients who underwent posterior-based resection. METHODS: This was a single-institution review of patients who underwent resection of a spinal meningioma from 1997 to 2017. Surgical, oncological, and neurological outcomes were compared between patients with varying dural attachments. Multivariate analysis was utilized. RESULTS: A total of 141 patients were identified. The mean age was 62 years, and 110 women were included. The sites of dural attachments were as follows: 16 (11.3%) dorsal, 31 (22.0%) dorsolateral, 17 (12.1%) lateral, 40 (28.4%) ventral, and 37 (26.2%) ventrolateral. Most meningiomas were WHO grade I (92.2%) and in the thoracic spine (61.0%). All patients underwent a posterior approach for tumor resection. There were no differences between subgroups in terms of largest diameter of tumor resected (p = 0.201), gross-total resection (GTR) or subtotal resection (p = 0.362), Simpson grade of resection, perioperative complications (p = 0.116), long-term neurological deficit (p = 0.100), or postoperative radiation therapy (p = 0.971). Cervical spine location was associated with reduced incidence of GTR (OR 0.271, 95% CI 0.108-0.684, p = 0.006) on multivariate analysis. The overall incidence of recurrence/progression was 4.6%, with no difference (p = 0.800) between subgroups. Similarly, the average length of follow-up was 28.1 months, with no difference between subgroups (p = 0.413). CONCLUSIONS: Posterior-based approaches for resection of spinal meningiomas are safe and effective, regardless of dural attachment location, with similar surgical, oncological, and neurological outcomes. Comparison of long-term recurrence rates between dural attachment subgroups is required.

Rib fixation for flail chest physiology and the facilitation of safe prone spinal surgery: illustrative case.

BACKGROUND: Spine fractures are frequently associated with additional injuries in the trauma setting, with chest wall trauma being particularly common. Limited literature exists on the management of flail chest physiology with concurrent unstable spinal injury. The authors present a case in which flail chest physiology precluded safe prone surgery and after rib fixation the patient tolerated spinal fixation without further issue. OBSERVATIONS: Flail chest physiology can cause cardiovascular decompensation in the prone position. Stabilization of the chest wall addresses this instability allowing for safe prone spinal surgery. LESSONS: Chest wall fixation should be considered in select cases of flail chest physiology prior to stabilization of the spinal column in the prone position. Further research is necessary to identify patients that are at highest risk to not tolerate prone surgery.

Correlation between tumor volume and serum prolactin and its effect on surgical outcomes in a cohort of 219 prolactinoma patients.

OBJECTIVE: Prolactinoma is the most common pituitary adenoma and can be managed medically or surgically. The authors assessed the correlation between tumor volume and prolactin level and its effect on surgical outcomes. METHODS: The authors reviewed 219 patients who underwent transsphenoidal prolactinoma resection at a single institution from 2012 to 2019. Outcomes were compared between patients with and without biochemical remission. Tumor volumes were quantified with BrainLab Smartbrush. Correlation analysis and linear regression were used to examine the association between tumor volume and serum prolactin level. Volume-adjusted prolactin level was defined as serum prolactin level divided by tumor volume. The authors utilized receiver operating characteristic (ROC) curve analysis to determine the thresholds for predicting biochemical remission status. RESULTS: The mean tumor volume was 5.66 cm3, and the mean preoperative prolactin level was 752.3 µg/L. Men had larger prolactinomas than women (mean volume 11.32 vs 2.54 cm3; p < 0.001), and women had a greater volume-adjusted prolactin level (mean 412.5 vs 175.9 µg/L/cm3, p < 0.001). In total, 66.7% of surgical patients achieved biochemical remission 6 weeks after surgery, whereas a similar cohort of medically treated patients during the same time frame demonstrated a 69.4% remission rate. Pearson correlation and linear regression analysis revealed a strong association between preoperative tumor volume and prolactin levels, with an increase in serum prolactin level of 101.31 µg/L per 1-cm3 increase in tumor volume (p < 0.001). This held true for men (R = 0.601, p < 0.001) and women (R = 0.935, p < 0.001), with women demonstrating a greater increase in prolactin level per 1-cm3 increase in volume (185.70 vs 79.77 µg/L, p < 0.001). Patients who achieved remission exhibited a 66.08-µg/L increase in preoperative prolactin level per 1 cm3 of preoperative tumor volume (p < 0.001), which was less than the 111.46-µg/L increase per 1 cm3 in patients without remission (p < 0.001). Patients who failed to achieve remission had residual tumors with a 77.77-µg/L increase in prolactin per 1 cm3 of remaining tumor volume after resection (p < 0.001). ROC curve analysis revealed significant thresholds that optimally predicted lack of postoperative remission on the basis of preoperative prolactin and tumor volume. These thresholds were rendered nonsignificant in patients with documented Knosp grade ≥ 3. CONCLUSIONS: Although the authors found a correlation between prolactinoma volume and serum prolactin level, patients without remission had a greater increase in serum prolactin level per increase in preoperative tumor volume than those who achieved remission, suggesting unique tumor composition. The authors also identified prolactin and tumor volume thresholds that optimally predicted biochemical remission status. The authors hope that their results can be used to identify prolactinomas for which surgery could achieve remission as an alternative to medical management.

Identifying risk factors for postoperative diabetes insipidus in more than 2500 patients undergoing transsphenoidal surgery: a single-institution experience.

OBJECTIVE: Diabetes insipidus (DI) following transsphenoidal surgery can adversely impact quality of life and be difficult to manage. This study sought to characterize pre- and perioperative risk factors that may predispose patients to DI after pituitary surgery. METHODS: A retrospective review of patients treated at a single institution from 2007 to 2019 was conducted. DI was defined as postoperative sodium > 145 mEq/L and urine output > 300 ml/hr and/or postoperative desmopressin (ddAVP) use. DI was further characterized as transient or permanent. Uni- and multivariate analyses were performed to determine variables associated with postoperative DI. RESULTS: The authors identified 2529 patients who underwent transsphenoidal surgery at their institution. Overall, DI was observed in 270 (10.7%) of the 2529 patients, with 114 (4.5%) having permanent DI and 156 (6.2%) with transient symptoms. By pathology type, DI occurred in 31 (46.3%) of 67 craniopharyngiomas, 10 (14.3%) of 70 apoplexies, 46 (14.3%) of 322 Rathke's cleft cysts, 77 (7.7%) of 1004 nonfunctioning pituitary adenomas (NFPAs), and 62 (7.6%) of 811 functioning pituitary adenomas (FPAs). Final lesion pathology significantly affected DI rates (p < 0.001). Multivariate analysis across pathologies showed that younger age (odds ratio [OR] 0.97, p < 0.001), intraoperative CSF encounter (OR 2.74, p < 0.001), craniopharyngioma diagnosis (OR 8.22, p = 0.007), and postoperative hyponatremia (OR 1.50, p = 0.049) increased the risk of DI. Because surgery for each pathology created specific risk factors for DI, the analysis was then limited to the 1815 pituitary adenomas (PAs) in the series, comprising 1004 NFPAs and 811 FPAs. For PAs, younger age (PA: OR 0.97, p < 0.001; NFPA: OR 0.97, p < 0.001; FPA: OR 0.97, p = 0.028) and intraoperative CSF encounter (PA: OR 2.99, p < 0.001; NFPA: OR 2.93, p < 0.001; FPA: OR 3.06, p < 0.001) increased DI rates in multivariate analysis. Among all PAs, patients with DI experienced peak sodium levels later than those without DI (postoperative day 11 vs 2). Increasing tumor diameter increased the risk of DI in FPAs (OR 1.52, p = 0.008), but not in NFPAs (p = 0.564). CONCLUSIONS: In more than 2500 patients treated at a single institution, intraoperative CSF encounter, craniopharyngioma diagnosis, and young age all increased the risk of postoperative DI. Patients with postoperative hyponatremia exhibited higher rates of DI, suggesting possible bi- or triphasic patterns to DI. Greater vigilance should be maintained in patients meeting these criteria following transsphenoidal surgery to ensure early recognition and treatment of DI.

Resection of supplementary motor area gliomas: revisiting supplementary motor syndrome and the role of the frontal aslant tract.

OBJECTIVE: The supplementary motor area (SMA) is an eloquent region that is frequently a site for glioma, or the region is included in the resection trajectory to deeper lesions. Although the clinical relevance of SMA syndrome has been well described, it is still difficult to predict who will become symptomatic. The object of this study was to define which patients with SMA gliomas would go on to develop a postoperative SMA syndrome. METHODS: The University of California, San Francisco, tumor registry was searched for patients who, between 2010 and 2019, had undergone resection for newly diagnosed supratentorial diffuse glioma (WHO grades II-IV) performed by the senior author and who had at least 3 months of follow-up. Pre- and postoperative MRI studies were reviewed to confirm the tumor was located in the SMA region, and the extent of SMA resection was determined by volumetric assessment. Patient, tumor, and outcome data were collected retrospectively from documents available in the electronic medical record. Tumors were registered to a standard brain atlas to create a frequency heatmap of tumor volumes and resection cavities. RESULTS: During the study period, 56 patients (64.3% male, 35.7% female) underwent resection of a newly diagnosed glioma in the SMA region. Postoperatively, 60.7% developed an SMA syndrome. Although the volume of tumor within the SMA region did not correlate with the development of SMA syndrome, patients with the syndrome had larger resection cavities in the SMA region (25.4% vs 14.2% SMA resection, p = 0.039). The size of the resection cavity in the SMA region did not correlate with the severity of the SMA syndrome. Patients who developed the syndrome had cavities that were located more posteriorly in the SMA region and in the cingulate gyrus. When the frontal aslant tract (FAT) was preserved, 50% of patients developed the SMA syndrome postoperatively, whereas 100% of the patients with disruption of the FAT during surgery developed the SMA syndrome (p = 0.06). Patients with SMA syndrome had longer lengths of stay (5.6 vs 4.1 days, p = 0.027) and were more likely to be discharged to a rehabilitation facility (41.9% vs 0%, p < 0.001). There was no difference in overall survival for newly diagnosed glioblastoma patients with SMA syndrome compared to those without SMA syndrome (1.6 vs 3.0 years, p = 0.33). CONCLUSIONS: For patients with SMA glioma, more extensive resections and resections involving the posterior SMA region and posterior cingulate gyrus increased the likelihood of a postoperative SMA syndrome. Although SMA syndrome occurred in all cases in which the FAT was resected, FAT preservation does not reliably avoid SMA syndrome postoperatively.

Socioeconomic predictors of case presentations and outcomes in 225 nonfunctional pituitary adenoma resections.

OBJECTIVE: Clinical presentations and outcomes of nonfunctional pituitary adenoma (NFPA) resections can vary widely, and very little prior research has analyzed this variance through a socioeconomic lens. This study sought to determine whether socioeconomic status (SES) influences NFPA presentations and postoperative outcomes, as these associations could aid physicians in understanding case prognoses and complications. METHODS: The authors retrospectively analyzed 225 NFPA resections from 2012 to 2019 at their institution. Race, ethnicity, insurance status, estimated income, and having a primary care provider (PCP) were collected as 5 markers of SES. These markers were correlated with presenting tumor burden, presenting symptoms, surgical outcomes, and long-term clinical outcomes. RESULTS: All 5 examined SES markers influenced variance in patient presentation or outcome. Insurance status's effects on patient presentations disappeared when examining only patients with PCPs. Having a PCP was associated with significantly smaller tumor size at diagnosis (effect size = 0.404, p < 0.0001). After surgery, patients with PCPs had shorter postoperative hospital lengths of stay (p = 0.043) and lower rates of readmission within 30 days of discharge (OR 0.256, p = 0.047). Despite continuing follow-up for longer durations (p = 0.0004), patients with PCPs also had lower rates of tumor recurrence (p < 0.0001). Higher estimated income was similarly associated with longer follow-up (p = 0.002) and lower rates of tumor recurrence (p = 0.013). Among patients with PCPs, income was not associated with recurrence. CONCLUSIONS: This study found that while all 5 variables (race, ethnicity, insurance, PCP status, and estimated income) affected NFPA presentations and outcomes, having a PCP was the single most important of these socioeconomic factors, impacting hospital lengths of stay, readmission rates, follow-up adherence, and tumor recurrence. Having a PCP even protected low-income patients from experiencing increased rates of tumor recurrence. These protective findings suggest that addressing socioeconomic disparities may lead to better NFPA presentations and outcomes.

Geographic landscape of foreign medical graduates in US neurosurgery training programs from 2007 to 2017.

OBJECTIVE: Although foreign medical graduates (FMGs) have been essential to the US physician workforce, the increasing competitiveness has made it progressively challenging for FMGs to match in US neurosurgery programs. We describe geographic origins and characteristics associated with successful match into US neurosurgery training programs. METHODS: Retrospective review of AANS membership data (2007-2017). Scopus was used to collect bibliometrics. RESULTS: From 2009 neurosurgical residents, 165 (8.2%) were FMGs. Most were male (n = 148; 89.6%) with a median age of 34.0 years. Top six feeder countries (TFC) included India (13.9%; n = 23), Lebanon and Pakistan (9.1%; n = 15), Caribbean Region (7.2%; n = 12), Mexico (6.67%; n = 11), and Greece (3.6%; n = 6). Compared to FMGs from non-top feeder countries (NTFC), TFC FMGs had higher H-indices (2 vs 4, p = 0.049), greater number of publications (2 vs 5, p = 0.04), were more likely to have an MBBS/MBBCh (n = 38 vs n = 17, p = 0.03), and had twice as many candidates from major feeder medical schools that successfully matched into a US neurosurgery program (n = 43 vs NTFC = 20, p < 0.001). NTFC FMGs were almost 3-times more likely to match at an affiliated neurosurgery program (8 vs TFC = 3, p = 0.03), while TFC FMGs were 1.5-times more likely to match at an NIH Top-40 program (33 vs NTFC = 21, p = 0.03). CONCLUSIONS: TFC graduates have higher bibliometrics, frequently come from major feeder schools, and have greater match success at a broader selection of programs and NIH top-40 programs. Future studies characterizing FMG country and medical school origins may enable foreign students to geographically target institutions of interest and could allow US programs to better evaluate foreign training environments.

Plurihormonal PIT-1-Positive Pituitary Adenomas: A Systematic Review and Single-Center Series.

OBJECTIVE: The 2017 World Health Organization classification of pituitary adenomas identified the plurihormonal PIT-1-positive (PP1) adenoma as a distinct subtype. The reported data suggest that PP1 adenomas encompass the former class of silent subtype 3 (SS3) adenomas and might have an aggressive phenotype. In the present study, we summarized the current clinical data on PP1 and SS3 adenomas and compared the reported data with the data from a single institutional cohort. METHODS: Medline and Google Scholar were searched from 1990 to 2020 for clinical series of PP1 and SS3 adenomas in accordance with the PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines. Studies were included if they had reported pituitary pathology as PP1 or SS3 adenomas and had reported the clinical outcomes after surgical intervention. To better define the PP1 phenotype compared with non-PP1 adenomas, we also reviewed the adenomas treated surgically at our institution from 2012 to 2019. RESULTS: Of all the tumors reported in the studies as PP1 or SS3, 99% were macroadenomas and 18% were giant adenomas (>4 cm). Of the reported patients, 31.8% had received radiotherapy, and 22.9% had undergone multiple surgeries for their pituitary tumor. In our single-center experience, 20 patients had an adenoma that met the criteria for a PP1 adenoma. Compared with the 1146 non-PP1 tumors, the PP1 tumors did not show statistically significant differences in the extent of resection, size, number of previous surgeries, future reoperations, rate of radiotherapy, p53 staining, or MIB-1 labeling index. CONCLUSIONS: The findings from the present large, single-center study comparing PP1 and non-PP1 adenomas do not suggest that PP1 tumors are more aggressive. Further work is warranted to identify the pathologic subtypes of pituitary adenomas that are consistently more clinically aggressive.

The Role of Cancer-Associated Fibroblasts in Tumor Progression.

In the era of genomic medicine, cancer treatment has become more personalized as novel therapeutic targets and pathways are identified. Research over the past decade has shown the increasing importance of how the tumor microenvironment (TME) and the extracellular matrix (ECM), which is a major structural component of the TME, regulate oncogenic functions including tumor progression, metastasis, angiogenesis, therapy resistance, and immune cell modulation, amongst others. Within the TME, cancer-associated fibroblasts (CAFs) have been identified in several systemic cancers as critical regulators of the malignant cancer phenotype. This review of the literature comprehensively profiles the roles of CAFs implicated in gastrointestinal, endocrine, head and neck, skin, genitourinary, lung, and breast cancers. The ubiquitous presence of CAFs highlights their significance as modulators of cancer progression and has led to the subsequent characterization of potential therapeutic targets, which may help advance the cancer treatment paradigm to determine the next generation of cancer therapy. The aim of this review is to provide a detailed overview of the key roles that CAFs play in the scope of systemic disease, the mechanisms by which they enhance protumoral effects, and the primary CAF-related markers that may offer potential targets for novel therapeutics.

Effects of ventricular entry on patient outcome during glioblastoma resection.

OBJECTIVE: Tumor proximity to the ventricle and ventricular entry (VE) during surgery have both been associated with worse prognoses; however, the interaction between these two factors is poorly understood. Given the benefit of maximal tumor resection, it is imperative for surgical planning and technique to know if VE has negative consequences for patient survival and tumor dissemination. METHODS: The University of California, San Francisco tumor registry was searched for patients with newly diagnosed and recurrent supratentorial glioblastoma (GBM) who underwent resection by the senior author between 2013 and 2018. Tumor location with respect to the subventricular zone (SVZ), size, and extent of resection were assessed using pre- and postoperative imaging. VE was determined by postoperative imaging and/or the operative report. RESULTS: In this 200-patient cohort of newly diagnosed and recurrent GBM, 26.5% of patients had VE during resection. Patients with VE were more likely to have preexisting subependymal disease (41.5% vs 15.0%, p < 0.001). Comparing patients with VE to those without VE, there was no difference in the rates of postoperative hydrocephalus (1.9% vs 4.8%, p = 0.36), ventriculoperitoneal shunting (0% vs 3.4%, p = 0.17), pseudomeningoceles (7.5% vs 5.4%, p = 0.58), or subdural hematomas (11.3% vs 3.4%, p = 0.07). Importantly, rates of subsequent leptomeningeal disease (7.5% vs 10.2%, p = 0.57) and distant parenchymal recurrence (17.0% vs 23.1%, p = 0.35) were not different between the groups. Newly diagnosed patients with tumors contacting the SVZ (type I or II) had worse survival than patients with tumors that did not contact the SVZ (type III or IV) (1.27 vs 1.84 years, p = 0.014, HR 1.8, 95% CI 1.08-3.03), but VE was not associated with worse survival in these patients with high-risk SVZ type I and II tumors (1.15 vs 1.68 years, p = 0.151, HR 0.59, 95% CI 0.26-1.34). CONCLUSIONS: VE was well tolerated, with postoperative complications being rare events. There was no increase in leptomeningeal spread or distant parenchymal recurrence in patients with VE. Finally, although survival was worse for patients with preoperative subependymal disease, VE did not change survival for patients with tumors contacting the ventricle. Therefore, VE during GBM resection is not associated with adverse patient outcomes and should be used by surgeons to enhance extent of resection.■ CLASSIFICATION OF EVIDENCE Type of question: therapeutic; study design: retrospective cohort; evidence: class II.

Evaluating the Clinical Utility and Cost of Imaging Strategies in Adults with Newly Diagnosed Primary Intradural Spinal Tumors.

OBJECTIVE: In patients with new primary intradural spinal tumors, the best screening strategy for additional central nervous system (CNS) lesions is unclear. The goal of this study was to document the rate of additional CNS tumors in these patients. METHODS: Adults with primary intradural spinal tumors were retrospectively reviewed. Imaging strategy at diagnosis was classified as focused spine (cervical, thoracic, or lumbar), total spine, or complete neuraxis (brain and total spine). Tumor pathology, genetic syndromes, and presence of additional CNS lesions at diagnosis or follow-up were collected. RESULTS: The study comprised 319 patients with mean age of 51 years and mean follow-up of 41 months. In 151 patients with focused spine imaging, 3 (2.0%) were found to have new lesions with 2 (1.4%) requiring treatment. In 35 patients with total spine imaging, there were no additional lesions. In 133 patients with complete neuraxis imaging, 4 (3.0%) were found to have new lesions with 2 (1.5%) requiring treatment. There was no difference in the identification of new lesions (P = 0.542) or new lesions requiring treatment (P = 0.772) across imaging strategies. Among patients without genetic syndromes, rates of new lesions requiring treatment were 1.4% for focused spine, 0% for total spine, and 2.2% for complete neuraxis (P = 0.683). There were no cases of delayed identification causing risk to life or neurological function. Complete neuraxis imaging carried an increased charge of $4420 per patient. CONCLUSIONS: Among patients without an underlying genetic syndrome, the likelihood of identifying additional CNS lesions requiring treatment is low. In appropriate cases, focused spine imaging may be a more cost-effective strategy.

Clinical characteristics and outcomes in elderly patients undergoing transsphenoidal surgery for nonfunctioning pituitary adenoma.

OBJECTIVE: Life expectancy has increased over the past century, causing a shift in the demographic distribution toward older age groups. Elderly patients comprise up to 14% of all patients with pituitary tumors, with most lesions being nonfunctioning pituitary adenomas (NFPAs). Here, the authors evaluated demographics, outcomes, and postoperative complications between nonelderly adult and elderly NFPA patients. METHODS: A retrospective review of 908 patients undergoing transsphenoidal surgery (TSS) for NFPA at a single institution from 2007 to 2019 was conducted. Clinical and surgical outcomes and postoperative complications were compared between nonelderly adult (age ≥ 18 and ≤ 65 years) and elderly patients (age > 65 years). RESULTS: There were 614 and 294 patients in the nonelderly and elderly groups, respectively. Both groups were similar in sex (57.3% vs 60.5% males; p = 0.4), tumor size (2.56 vs 2.46 cm; p = 0.2), and cavernous sinus invasion (35.8% vs 33.7%; p = 0.6). Regarding postoperative outcomes, length of stay (1 vs 2 days; p = 0.5), extent of resection (59.8% vs 64.8% gross-total resection; p = 0.2), CSF leak requiring surgical revision (4.3% vs 1.4%; p = 0.06), 30-day readmission (8.1% vs 7.3%; p = 0.7), infection (3.1% vs 2.0%; p = 0.5), and new hypopituitarism (13.9% vs 12.0%; p = 0.3) were similar between both groups. Elderly patients were less likely to receive adjuvant radiation (8.7% vs 16.3%; p = 0.009), undergo future reoperation (3.8% vs 9.5%; p = 0.003), and experience postoperative diabetes insipidus (DI) (3.7% vs 9.4%; p = 0.002), and more likely to have postoperative hyponatremia (26.7% vs 16.4%; p < 0.001) and new cranial nerve deficit (1.9% vs 0.0%; p = 0.01). Subanalysis of elderly patients showed that patients with higher Charlson Comorbidity Index scores had comparable outcomes other than higher DI rates (8.1% vs 0.0%; p = 0.006). Elderly patients' postoperative sodium peaked and troughed on postoperative day 3 (POD3) (mean 138.7 mEq/L) and POD9 (mean 130.8 mEq/L), respectively, compared with nonelderly patients (peak POD2: mean 139.9 mEq/L; trough POD8: mean 131.3 mEq/L). CONCLUSIONS: The authors' analysis revealed that TSS for NFPA in elderly patients is safe with low complication rates. In this cohort, more elderly patients experienced postoperative hyponatremia, while more nonelderly patients experienced postoperative DI. These findings, combined with the observation of higher DI in patients with more comorbidities and elderly patients experiencing later peaks and troughs in serum sodium, suggest age-related differences in sodium regulation after NFPA resection. The authors hope that their results will help guide discussions with elderly patients regarding risks and outcomes of TSS.

Surgical management of incidentally discovered low-grade gliomas.

OBJECTIVE: Although most patients with low-grade glioma (LGG) present after a seizure, a small proportion is diagnosed after neuroimaging is performed for a sign or symptom unrelated to the tumor. While these tumors invariably grow, some surgeons argue for a watchful waiting approach. Here, the authors report on their experience in the surgical treatment of patients with incidental LGG (iLGG) and describe the neurological outcomes, survival, and complications. METHODS: Relevant cases were identified from a prospective registry of patients undergoing glioma resection at the University of California, San Francisco, between 1997 and 2019. Cases were considered iLGG when the lesion was noted on imaging performed for a reason unrelated to the tumor. Demographic, clinical, pathological, and imaging data were extracted from the electronic medical record. Tumor volumes, growth, and extent of resection were calculated from pre- and postoperative volumetric FLAIR sequences. RESULTS: One hundred thirteen of 657 (17.2%) first-time resections for LGG were for incidental lesions. The most common reasons for the discovery of an iLGG were headaches (without mass effect, 34.5%) or trauma (16.8%). Incidental tumors were no different from symptomatic lesions in terms of laterality or location, but they were significantly smaller (22.5 vs 57.5 cm3, p < 0.0001). There was no difference in diagnosis between patients with iLGG and those with symptomatic LGG (sLGG), incorporating both molecular and pathological data. The median preoperative observation time for iLGG was 3.1 months (range 1 month-12 years), and there was a median growth rate of 3.9 cm3/year. Complete resection of the FLAIR abnormality was achieved in 57% of patients with incidental lesions but only 23.8% of symptomatic lesions (p < 0.001), and the residual volumes were smaller for iLGGs (2.9 vs 13.5 cm3, p < 0.0001). Overall survival was significantly longer for patients with incidental tumors (median survival not reached for patients with iLGG vs 14.6 years for those with sLGG, p < 0.0001). There was a 4.4% rate of neurological deficits at 6 months. CONCLUSIONS: The authors present the largest cohort of iLGGs. Patient age, tumor location, and molecular genetics were not different between iLGGs and sLGGs. Incidental tumors were smaller, a greater extent of resection could be achieved, and overall survival was improved compared to those for patients with sLGG. Operative morbidity and rates of neurological deficit were acceptably low; thus, the authors advocate upfront surgical intervention aimed at maximal safe resection for these incidentally discovered lesions.

Higher cytolytic score correlates with an immunosuppressive tumor microenvironment and reduced survival in glioblastoma.

Cytolytic score (CYT), calculated from mRNA expression levels of granzyme and perforin, positively correlates with CD8+ T cell infiltration/activity in a variety of cancers. Unlike other cancers, higher CYT has been associated with worse prognosis in glioblastoma (GBM). To address this discrepancy, we sought to investigate the relationship between CYT and immune checkpoint gene score (ICGscore), as well as their correlation with patient survival and tumor immune cell infiltration. Clinical and RNA-sequencing data for patients with newly diagnosed GBM were obtained from The Cancer Genome Atlas. Maximally-selected rank statistics was used to dichotomize subgroups. CIBERSORT was used to estimate abudence of immune cell-types. Spearman correlation was used to characterize the relationship between CYT and ICGscore. Kaplan-Meier curves were generated for survival analysis. Overall, 28/151 patients had high CYT. High CYT was associated with a mesenchymal subtype (p < 0.001) and worse survival (7.45 vs. 12.2 months, p < 0.001). There were no differences in patient demographics, IDH/MGMT mutation status, or treatment. On subgroup analysis, patients with high CYT/ICGscore had significantly increased CD8+ infiltration (p < 0.001), as expected, and worse survival (HR 0.445, p < 0.01). Furthermore, CYT strongly correlated with ICGscore (RS = 0.675, p < 0.001). The high CYT/ICGscore subgroup was associated with greater infiltration of M2 macrophages (p = 0.011) and neutrophils (p = 0.055). Our study highlights a multidimensional immunosuppressive GBM microenvironment in patients with higher CYT and potentially identifies patients with high CYT/ICGscore as a subgroup that may particularly benefit from multi-faceted immunotherapies, given their already elevated tumor CD8+ T cell levels.

Clinical characteristics and outcomes of null-cell versus silent gonadotroph adenomas in a series of 1166 pituitary adenomas from a single institution.

OBJECTIVE: Nonfunctioning pituitary adenomas present without biochemical or clinical signs of hormone excess and are the second most common type of pituitary adenomas. The 2017 WHO classification scheme of pituitary adenomas differentiates null-cell adenomas (NCAs) and silent gonadotroph adenomas (SGAs). The present study sought to highlight the differences in patient characteristics and clinical outcomes between NCAs and SGAs. METHODS: The records of 1166 patients who underwent transsphenoidal surgery for pituitary adenoma between 2012 and 2019 at a single institution were retrospectively reviewed. Patient demographics and clinical outcomes were collected. RESULTS: Of the overall pituitary adenoma cohort, 12.8% (n = 149) were SGAs and 9.2% (n = 107) NCAs. NCAs were significantly more common in female patients than SGAs (61.7% vs 26.8%, p < 0.001). There were no differences in patient demographics, initial tumor size, or perioperative and short-term clinical outcomes. There was no significant difference in the amount of follow-up between patients with NCAs and those with SGAs (33.8 months vs 29.1 months, p = 0.237). Patients with NCAs had significantly higher recurrence (p = 0.021), adjuvant radiation therapy usage (p = 0.002), and postoperative diabetes insipidus (p = 0.028). NCA pathology was independently associated with tumor recurrence (HR 3.64, 95% CI 1.07-12.30; p = 0.038), as were cavernous sinus invasion (HR 3.97, 95% CI 1.04-15.14; p = 0.043) and anteroposterior dimension of the tumor (HR 2.23, 95% CI 1.09-4.59; p = 0.030). CONCLUSIONS: This study supports the definition of NCAs and SGAs as separate subgroups of nonfunctioning pituitary adenomas, and it highlights significant differences in long-term clinical outcomes, including tumor recurrence and the associated need for adjuvant radiation therapy, as well as postoperative diabetes insipidus. The authors also provide insight into independent risk factors for these outcomes in the adenoma population studied, providing clinicians with additional predictors of patient outcomes. Follow-up studies will hopefully uncover mechanisms of biological aggressiveness in NCAs and associated molecular targets.

Clonal ZEB1-Driven Mesenchymal Transition Promotes Targetable Oncologic Antiangiogenic Therapy Resistance.

Glioblastoma (GBM) responses to bevacizumab are invariably transient with acquired resistance. We profiled paired patient specimens and bevacizumab-resistant xenograft models pre- and post-resistance toward the primary goal of identifying regulators whose targeting could prolong the therapeutic window, and the secondary goal of identifying biomarkers of therapeutic window closure. Bevacizumab-resistant patient specimens and xenografts exhibited decreased vessel density and increased hypoxia versus pre-resistance, suggesting that resistance occurs despite effective therapeutic devascularization. Microarray analysis revealed upregulated mesenchymal genes in resistant tumors correlating with bevacizumab treatment duration and causing three changes enabling resistant tumor growth in hypoxia. First, perivascular invasiveness along remaining blood vessels, which co-opts vessels in a VEGF-independent and neoangiogenesis-independent manner, was upregulated in novel biomimetic 3D bioengineered platforms modeling the bevacizumab-resistant microenvironment. Second, tumor-initiating stem cells housed in the perivascular niche close to remaining blood vessels were enriched. Third, metabolic reprogramming assessed through real-time bioenergetic measurement and metabolomics upregulated glycolysis and suppressed oxidative phosphorylation. Single-cell sequencing of bevacizumab-resistant patient GBMs confirmed upregulated mesenchymal genes, particularly glycoprotein YKL-40 and transcription factor ZEB1, in later clones, implicating these changes as treatment-induced. Serum YKL-40 was elevated in bevacizumab-resistant versus bevacizumab-naïve patients. CRISPR and pharmacologic targeting of ZEB1 with honokiol reversed the mesenchymal gene expression and associated stem cell, invasion, and metabolic changes defining resistance. Honokiol caused greater cell death in bevacizumab-resistant than bevacizumab-responsive tumor cells, with surviving cells losing mesenchymal morphology. Employing YKL-40 as a resistance biomarker and ZEB1 as a target to prevent resistance could fulfill the promise of antiangiogenic therapy. SIGNIFICANCE: Bevacizumab resistance in GBM is associated with mesenchymal/glycolytic shifts involving YKL-40 and ZEB1. Targeting ZEB1 reduces bevacizumab-resistant GBM phenotypes. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/7/1498/F1.large.jpg.