Journal of Neurosurgery
Michael S. Dirks, John A. Butman, H. Jeffrey Kim, Tianxia Wu, Keaton Morgan, Anne P. Tran, Russell R. Lonser and Ashok R. Asthagiri
Neurofibromatosis Type 2 (NF2) is a heritable tumor predisposition syndrome that leads to the development of multiple intracranial tumors, including meningiomas and schwannomas. Because the natural history of these tumors has not been determined, their optimal management has not been established. To define the natural history of NF2-associated intracranial tumors and to optimize management strategies, the authors evaluated long-term clinical and radiographic data in patients with NF2.
Consecutive NF2 patients with a minimum of 4 years of serial clinical and MRI follow-up were analyzed.
Seventeen patients, 9 males and 8 females, were included in this analysis (mean follow-up 9.5 ± 4.8 years, range 4.0–20.7 years). The mean age at initial evaluation was 33.2 ± 15.5 years (range 12.3–57.6 years). Patients harbored 182 intracranial neoplasms, 164 of which were assessable for growth rate analysis (18 vestibular schwannomas [VSs], 11 nonvestibular cranial nerve [CN] schwannomas, and 135 meningiomas) and 152 of which were assessable for growth pattern analysis (15 VSs, 9 nonvestibular CN schwannomas, and 128 meningiomas). New tumors developed in patients over the course of the imaging follow-up: 66 meningiomas, 2 VSs, and 2 nonvestibular CN schwannomas. Overall, 45 tumors (29.6%) exhibited linear growth, 17 tumors (11.2%) exhibited exponential growth, and 90 tumors (59.2%) displayed a saltatory growth pattern characterized by alternating periods of growth and quiescence (mean quiescent period 2.3 ± 2.1 years, range 0.4–11.7 years). Further, the saltatory pattern was the most frequently identified growth pattern for each tumor type: meningiomas 60.9%, VSs 46.7%, and nonvestibular schwannoma 55.6%. A younger age at the onset of NF2-related symptoms (p = 0.01) and female sex (p = 0.05) were associated with an increased growth rate in meningiomas. The identification of saltatory growth in meningiomas increased with the duration of follow-up (p = 0.01).
Neurofibromatosis Type 2–associated intracranial tumors most frequently demonstrated a saltatory growth pattern. Because new tumors can develop in NF2 patients over their lifetime and because radiographic progression and symptom formation are unpredictable, resection may be best reserved for symptom-producing tumors. Moreover, establishing the efficacy of nonsurgical therapeutic interventions must be based on long-term follow-up (several years).
Matthew J. Shepard, Alejandro Bugarini, Nancy A. Edwards, Jie Lu, Qi Zhang, Tianxia Wu, Zhengping Zhuang and Prashant Chittiboina
Von Hippel-Lindau disease (VHL) is a tumor predisposition syndrome characterized by CNS hemangioblastomas (HBs) and clear cell renal cell carcinomas (RCCs) due to hypoxia-inducible factor activation (pseudohypoxia). Because of the lack of effective medical therapies for VHL, HBs and RCCs account for significant morbidity and mortality, ultimately necessitating numerous neurological and renal surgeries. Propranolol is an FDA-approved pan-beta adrenergic antagonist with antitumor effects against infantile hemangiomas (IHs) and possibly VHL HBs. Here, the authors investigated the antitumor efficacy of propranolol against pseudohypoxia-driven VHL-HBs and VHL-RCCs.
Patient-derived VHL-associated HBs (VHL-HBs) or 786-O-VHL
−/− RCC cells were treated with clinically relevant concentrations of propranolol in vitro and assessed with viability assays, flow cytometry, quantitative real-time polymerase chain reaction, and western blotting. In vivo confirmation of propranolol antitumor activity was confirmed in athymic nude mice bearing 786-O xenograft tumors. Lastly, patients enrolled in a VHL natural history study (NCT00005902) were analyzed for incidental propranolol intake. Propranolol activity against VHL-HBs was assessed retrospectively with volumetric HB growth kinetic analysis.
Propranolol decreased HB and RCC viability in vitro with IC50 (half maximal inhibitory concentration) values of 50 µM and 200 µM, respectively. Similar to prior reports in infantile hemangiomas, propranolol induced apoptosis and paradoxically increased VEGF-A mRNA expression in patient-derived VHL-HBs and 786-O cells. While intracellular VEGF protein levels were not affected by propranolol treatment, propranolol decreased HIF expression in 786-O cells (7.6-fold reduction, p < 0.005). Propranolol attenuated tumor progression compared with control (33% volume reduction at 7 days, p < 0.005) in 786-O xenografted tumor-bearing mice. Three patients (harboring 25 growing CNS HBs) started propranolol therapy during the longitudinal VHL-HB study. HBs in these patients tended to grow slower (median growth rate 27.1 mm3/year vs 13.3 mm3/year) during propranolol treatment (p < 0.0004).
Propranolol decreases VHL-HB and VHL-related RCC viability in vitro likely by modulation of VEGF expression and by inducing apoptosis. Propranolol abrogates 786-O xenograft tumor progression in vivo, and retrospective clinical data suggest that propranolol curtails HB growth. These results suggest that propranolol may play a role in the treatment of VHL-related tumors.
Russell R. Lonser, John A. Butman, Kristin Huntoon, Ashok R. Asthagiri, Tianxia Wu, Kamran D. Bakhtian, Emily Y. Chew, Zhengping Zhuang, W. Marston Linehan and Edward H. Oldfield
The tumors most frequently associated with von Hippel-Lindau (VHL) disease are hemangioblastomas. While they are associated with significant neurological impairment and mortality, their natural history and optimal management have not been fully defined.
Patients with VHL were enrolled in a prospective study designed to define the natural history of CNS hemangioblastomas. In the present analysis, serial imaging, laboratory, genetic, and clinical data were evaluated in those with at least 2 years of follow-up data.
At study entrance 225 patients (111 males, 114 females) harbored 1921 CNS hemangioblastomas in the supratentorial compartment (21 tumors [1%]), cerebellum (865 [45%]), brainstem (129 [7%]), spinal cord (689 [36%]), cauda equina (212 [11%]), and nerve roots (5 [0.3%]; follow-up 15,819 hemangioblastoma-years). Increased tumor burden was associated with partial deletions in the VHL gene (p = 0.005) and male sex (p = 0.002). Hemangioblastoma development (median 0.3 new tumors/year) was associated with younger age (p < 0.0001) and more tumors at study entrance (p < 0.0001). While 1278 hemangioblastomas (51%) did not grow, 1227 hemangioblastomas (49%) grew in a saltatory (886 [72%]), linear (76 [6%]), or exponential (264 [22%]) pattern. Faster tumor growth was associated with male sex (p = 0.001), symptomatic tumors (p < 0.0001), and tumors associated with cysts (p < 0.0001). Location-dependent tumor size was the primary predictor of eventual symptom formation (159 symptomatic tumors [6.3%]; area under the curve > 0.9).
Central nervous system hemangioblastoma burden in VHL is associated with partial germline deletions and male sex. Unpredictable growth of hemangioblastomas compromises assessment of nonsurgical therapies. The judicious treatment of symptom-producing hemangioblastomas, while avoiding unnecessary treatment of asymptomatic tumors that may not progress, can provide clinical stability. Clinical trial registration no.: NCT00005902 (ClinicalTrials.gov).
Kristin Huntoon, Tianxia Wu, J. Bradley Elder, John A. Butman, Emily Y. Chew, W. Marston Linehan, Edward H. Oldfield and Russell R. Lonser
Peritumoral cysts are frequently associated with CNS hemangioblastomas and often underlie neurological morbidity and mortality. To determine their natural history and clinical impact, the authors prospectively analyzed hemangioblastoma-associated peritumoral cysts in patients with von Hippel-Lindau (VHL) disease.
Patients with VHL disease who had 2 or more years of follow-up and who were enrolled in a prospective study at the National Institutes of Health were included. Serial prospectively acquired laboratory, genetic, imaging, and clinical data were analyzed.
One hundred thirty-two patients (of 225 in the VHL study with at least 2 years of follow-up) had peritumoral cysts that were followed for more than 2 years (total of 292 CNS peritumoral cysts). The mean age at study entrance was 37.4 ± 13.1 years ([mean ± SD], median 37.9, range 12.3–65.1 years). The mean follow-up was 7.0 ± 1.7 years (median 7.3, range 2.1–9.0 years). Over the study period, 121 of the 292 peritumoral cysts (41.4%) became symptomatic. Development of new cysts was associated with a larger number cysts at study enrollment (p = 0.002) and younger age (p < 0.0001). Cyst growth rate was associated with anatomical location (cerebellum cysts grew faster than spine and brainstem cysts; p = 0.0002 and p = 0.0008), younger age (< 35 years of age; p = 0.0006), and development of new neurological symptoms (p < 0.0001). Cyst size at symptom production depended on anatomical location (p < 0.0001; largest to smallest were found, successively, in the cerebellum, spinal cord, and brainstem). The most common location for peritumoral cysts was the cerebellum (184 cysts [63%]; p < 0.0001).
Peritumoral cysts frequently underlie symptom formation that requires surgical intervention in patients with VHL disease. Development of new cysts was associated with a larger number of cysts at study enrollment and younger age. Total peritumoral cyst burden was associated with germline partial deletion of the VHL gene.
Raymund L. Yong, Tianxia Wu, Nino Mihatov, Michael J. Shen, M. Anthony Brown, Kareem A. Zaghloul, Grace E. Park and John K. Park
Maximal safe tumor resection is part of the standard of care for patients with newly diagnosed glioblastoma. The role of reoperation in the care of patients with recurrent glioblastoma is less clear, and less than a quarter of patients undergo a second surgery. Previous studies have identified preoperative variables associated with the improved survival of patients following reoperation, and guidelines for the selection of patients for reoperation have been devised and validated. In this study, the authors analyzed the relative survival benefit of maximal safe tumor removal in a series of patients with recurrent glioblastoma who all underwent reoperation.
In this longitudinal study, the clinical and radiological data of 97 consecutive patients who underwent reoperation for recurrent glioblastoma were prospectively collected. Multiple regression analyses and Kaplan-Meier plotting were performed to identify pre- and postoperative clinical and radiological variables associated with increased survival following reoperation.
The median postoperative survival of all patients following reoperation was 12.4 months (95% confidence interval [CI] 9.0–15.6 months). Multiple Cox regression analysis revealed that patients with large (> 3 cm3) residual tumors following reoperation had significantly decreased survival relative to those with residual tumors that were small (> 0–3 cm3; hazard ratio [HR] = 3.10, 95% CI 1.69–5.70; p < 0.001) or radiologically absent (0 cm3; HR = 5.82, 95% CI 2.98–11.37; p < 0.001). Large residual tumors had faster rates of subsequent regrowth than small (odds ratio [OR] = 4.22, 95% CI 1.19–14.97; p = 0.026) or radiologically absent (OR = 11.00, 95% CI 2.79–43.43; p = 0.001) residual tumors, and a faster regrowth rate was significantly associated with decreased survival (HR = 4.01, 95% CI 2.26–7.14; p < 0.001).
The overall survival of patients with recurrent glioblastoma who underwent reoperations increased with decreasing postoperative residual tumor volumes. For patients meeting prognostic criteria for reoperation, the surgical goal should be to minimize residual tumor volume to maximize overall survival. Clinical trial registration no.: NCT00060541 (ClinicalTrials.gov).