Decrease of Serum IGF-I following Transsphenoidal Pituitary Surgery for Acromegaly.

BACKGROUND: In the immediate postoperative period following resection of growth hormone (GH)-secreting pituitary tumors, serum concentrations of GH have limited ability to predict remission of acromegaly. Since many actions of GH actions are mediated by insulin-like growth factor-1 (IGF-I), we aimed to determine the rates of fall of IGF-I during 72 h after surgical resection of pituitary tumors. METHODS: We studied patients who were undergoing pituitary surgery for acromegaly. IGF-I was measured by LC-MS and GH by immunoassay. Remission was defined by the combination of serum GH <0.4 ng/mL during oral glucose tolerance testing performed 8 weeks after the surgical procedure and normal IGF-I at ≥8 weeks. RESULTS: During the first 72 h after surgery, the mean (SD) rate of decline of IGF-I was 185 (61) ng/mL per 24 h in those who achieved remission (n = 23), with a mean (SD) apparent half-life of 55 (19) h. IGF-I had decreased to <65% of the preoperative IGF-I on postoperative day 2 in 20 of 23 remission patients (87%) vs none of 5 patients who did not achieve remission. GH was <2.7 ng/mL on day 2 in 21 of 23 remission patients (91%), but in none of the nonremission patients. The combination of IGF-I and GH on day 2 separated the remission and nonremission groups of patients. CONCLUSIONS: Rapid decline of serum IGF-I during the immediate postoperative period warrants further study as an analytically independent adjunct to GH measurement for early prediction of biochemical remission of acromegaly.

Surgical management of Cushing's disease.

BACKGROUND: Transsphenoidal selective adenomectomy is the first-line treatment for Cushing's disease. At experienced centers, early remission rates after transsphenoidal surgery range from 65 to 98%, however disease relapse frequently occurs with rates ranging from 2 to 35% at long-term follow up. METHODS: This article discusses recently reported studies on the surgical outcomes from transsphenoidal surgery for Cushing's disease. CONCLUSIONS: One of the keys to a successful long-term surgical outcome is meticulous dissection using the adenoma's pseudocapsule as a surgical plane for complete resection. MRI-negative and invasive ACTH-secreting adenomas pose particular challenges for pituitary surgeons.

VHL-deficient vasculogenesis in hemangioblastoma.

Hemangioblasts are capable of differentiation into vascular structures and blood. Patients with von Hippel-Lindau (VHL) disease develop hemangioblastomas which are composed of VHL-deficient tumor cells with protracted hemangioblastic differentiation potential. In a subset of these tumors, hemangioblastic differentiation is characterized by different stages of red blood cell formation. It has remained controversial, however, whether VHL-deficient hemangioblastic cells are similarly capable of differentiating into vascular cells and functioning vascular structures in vivo. By histologic, immunohistologic and microdissection-based genetic analysis of 60 VHL disease-associated hemangioblastomas, we re-examined the controversial question whether VHL-deficient neoplastic hemangioblastic cells are capable of vascular differentiation (vasculogenesis). In most tumors (n=47), there was no evidence of either vasculogenesis or hematopoiesis; tumor cells were either scattered between reactive angiogenetic vascular structures or arranged in solid clusters. A subset of tumors (n=13), however, revealed vaculogenetic structures that were composed of cuboidal or flat cells and frequently contained red blood cell precursors or mature red blood cells. Microdissection-based deletion analysis of epithelial cells confirmed them to be VHL-deficient tumor cells. Immunohistochemistry for CD31 was consistently negative in these structures, and no evidence could be obtained for connectivity with reactive vasculature. We demonstrate that hemangioblastic differentiation capacity of VHL-deficient hemangioblastic cells includes not only erythropoiesis, but also differentiation into primitive vasculogenetic structures. Tumor cells, however, do not appear to have the potential of terminal differentiation into mature and functional vascular structures.

Nervous system involvement in von Hippel-Lindau disease: pathology and mechanisms.

Patients with von Hippel-Lindau disease carry a germline mutation of the Von Hippel-Lindau (VHL) tumor-suppressor gene. We discuss the molecular consequences of loss of VHL gene function and their impact on the nervous system. Dysfunction of the VHL protein causes accumulation and activation of hypoxia inducible factor (HIF) which can be demonstrated in earliest stages of tumorigenesis and is followed by expression of VEGF, erythropoietin, nitric oxide synthase and glucose transporter 1 in VHL-deficient tumor cells. HIF-independent functions of VHL, epigenetic inactivation of VHL, pVHL proteostasis, and links between loss of VHL function and developmental arrest are also described. A most intriguing feature in VHL disease is the occurrence of primary hemangioblastic tumors in the nervous system, the origin of which has not yet been entirely clarified, and current hypotheses are discussed. Endolymphatic sac tumors may extend into the brain, but originally arise from proliferation of endolymphatic duct/sac epithelium; the exact nature of the proliferating epithelial cell, however, also has remained unclear, as well as the question why tumors almost consistently develop in the intraosseous portion of the endolymphatic sac/duct only. The epitheloid clear cell morphology of both advanced hemangioblastoma and renal clear cell carcinoma can make the differential diagnosis challenging, recent developments in immunohistochemical differentiation are discussed. Finally, metastasis to brain may not only be caused by renal carcinoma, but may derive from VHL disease-associated pheochromocytoma/paraganglioma, or pancreatic neuroendocrine tumor.

Developmentally arrested structures preceding cerebellar tumors in von Hippel-Lindau disease.

There is increasing evidence that suggests that knockout of tumor-suppressor gene function causes developmental arrest and protraction of cellular differentiation. In the peripheral nervous system of patients with the tumor-suppressor gene disorder, von Hippel-Lindau disease, we have demonstrated developmentally arrested structural elements composed of hemangioblast progenitor cells. Some developmentally arrested structural elements progress to a frank tumor, hemangioblastoma. However, in von Hippel-Lindau disease, hemangioblastomas are frequently observed in the cerebellum, suggesting an origin in the central nervous system. We performed a structural and topographic analysis of cerebellar tissues obtained from von Hippel-Lindau disease patients to identify and characterize developmentally arrested structural elements in the central nervous system. We examined the entire cerebella of five tumor-free von Hippel-Lindau disease patients and of three non-von Hippel-Lindau disease controls. In all, 9 cerebellar developmentally arrested structural elements were detected and topographically mapped in 385 blocks of von Hippel-Lindau disease cerebella. No developmentally arrested structural elements were seen in 214 blocks from control cerebella. Developmentally arrested structural elements are composed of poorly differentiated cells that express hypoxia-inducible factor (HIF)2α, but not HIF1α or brachyury, and preferentially involve the molecular layer of the dorsum cerebelli. For the first time, we identify and characterize developmentally arrested structural elements in the central nervous system of von Hippel-Lindau patients. We provide evidence that developmentally arrested structural elements in the cerebellum are composed of developmentally arrested hemangioblast progenitor cells in the molecular layer of the dorsum cerebelli.

Intrathecal gene therapy for treatment of leptomeningeal carcinomatosis.

Leptomeningeal carcinomatosis occurs occasionally in patients with solid malignancies and carries a poor prognosis despite treatment with systemic chemotherapy and/or radiotherapy. We describe the case of a 43 year old man who presented with leptomeningeal carcinomatosis secondary to malignant melanoma. The patient received intraventricular delivery of NIH3T3 producer cells expressing the thymidine kinase (HSV-Tk1) gene via a retroviral vector followed by intravenous ganciclovir. He experienced abrupt and severe meningeal irritation and hyperpyrexia immediately after injection of the producer cells into the ventricular CSF. Vector producer cells (VPC) survived and were detected by NeoR marker gene expression in the CSF for a week, until a single dose of ganciclovir (GCV) was followed by a decline in the copy number of the NeoR marker gene to undetectable levels over 24 h. This decline upon introduction of ganciclovir suggests effective distribution of ganciclovir to producer cells bearing the HSV-Tk gene. The patient survived 9 months after treatment. Side-effects from the treatment included acute hyperpyrexia which was short-lived and medically manageable.

Surgical management of Cushing's disease: a personal perspective.

One of the rewards of studying Cushing's disease is that the understanding of the stages of these tumors provides insight into what happens during the evolution of all types of pituitary tumors. The evolution of the development of the pseudocapsule at the margin of small adenomas begins to occur at about 2 to 3 mm in diameter, the minimum size at which we can identify them during surgical exploration. Certain advantages derive from removal of pituitary adenomas using the histological pseudocapsule as a surgical capsule and as a defined tissue plane. Other unresolved issues need our focus over the next few years. Surgical success would be enhanced if we had more accurate ways of localizing the very smallest tumors, either before or during surgery, in patients with Cushing's disease and negative MRI. We also need better therapies for tumors that invade the cavernous sinus, and we need to understand the biological basis of invasion in patients who have truly invasive tumors. Finally, it would be rewarding to understand the molecular basis of the relative resistance to negative cortisol feedback characterizing these tumors and why it is linked to tumor formation. We still have much to do.

A change in pituitary magnetic resonance imaging protocol detects ACTH-secreting tumours in patients with previously negative results.

OBJECTIVE: While detection of pituitary tumours with magnetic resonance imaging (MRI) may reduce diagnostic costs and improve surgical outcomes for patients with Cushing's disease, the optimal T1-weighted spin-echo (SE) MRI protocol remains unknown. We hypothesized that specific MR scanning parameters influence detection of corticotropinomas. DESIGN AND PATIENTS: Between December 1997 and November 2004, 21 of 84 consecutive patients with Cushing's disease had a falsely negative initial pituitary MRI study and a lesion identified subsequently at the National Institutes of Health Clinical Center. This study retrospectively reviewed and compared technical parameters used for the two pituitary T1-weighted SE MRIs in 18 patients with available scans. MEASUREMENTS: Repetition time (TR)/echo times (TE), field of view (FOV), matrix size, magnetic field strength, slice thickness, use of gadolinium contrast and the time interval between studies were recorded. RESULTS: The MRI interscan interval was 5.4 +/- 1.1 months. All scans used gadolinium, matrix sizes were similar and nearly all had 3-mm thick slices. Parameters that differed between the NIH- and externally performed scans were: TR (400 ms vs. 492 +/- 19 ms, P = 0.0002); TE (10.3 +/- 0.5 vs. 17.2 +/- 1.2 ms, P = 0.0003); FOV (12 x 12 cm vs.17 +/- 0.6 x 18 +/- 0.7 cm, P < 0.0001). Immunohistochemistry of tumours resected at transsphenoidal surgery confirmed all to be corticotropinomas. CONCLUSIONS: Not all 'T1-weighted SE' scans are equally accurate. MRI technique, particularly FOV and TR/TE value, influences results. We recommend that endocrinologists consider pituitary MRI parameters when interpreting the results.

Novel anti-filamin-A antibody detects a secreted variant of filamin-A in plasma from patients with breast carcinoma and high-grade astrocytoma.

Identification of tumor-derived proteins in the circulation may allow for early detection of cancer and evaluation of therapeutic responses. To identify circulating tumor-derived proteins, mice were immunized with concentrated culture medium conditioned by human breast cancer cells. Antibodies generated by hybridomas were screened against conditioned media from both normal epithelial cells and tumor cells. Antibody selectively reacting with tumor cell-conditioned media was further characterized. This led to the development of a monoclonal antibody (Alper-p280) that reacts with a newly identified 280-kDa secreted variant of human filamin-A. Circulating filamin-A was detected in patient plasma samples using Alper-p280 in an ELISA assay. Human plasma samples from 134 patients with brain, breast, or ovarian cancer, 15 patients with active arthritis, and 76 healthy controls were analyzed. Filamin-A protein levels in human cell lines and tissues were analyzed by western blotting, immunohistochemistry, and electron and confocal microscopy. Circulating filamin-A was detected in the plasma of 109 of 143 patients with breast cancer and primary brain tumors. Plasma levels of filamin-A showed 89.5% sensitivity (95% confidence interval [CI] = 0.67% to 0.99%) and 97.8% specificity (95% CI = 0.88% to 0.99%) for glioblastoma at a cut-off of 21.0 ng/mL. Plasma levels of filamin-A (>36.0 ng/mL) had 96.7% sensitivity (95% CI = 0.80% to 0.99%) and 67.8% specificity (95% CI = 0.54% to 0.79%) for metastatic breast cancer. Filamin-A levels were increased in malignant breast or brain tissues, but not in normal control tissues. Filamin-A localized to lysosomes in MDA.MB.231 breast cancer cells, but not in normal human mammary epithelial cells, suggesting that filamin-A may undergo cancer-specific processing. Plasma filamin-A appears to be a specific and sensitive marker for patients with high-grade astrocytoma or metastatic breast cancer. Additional novel cancer biomarkers have been identified and are being developed alongside Alper-p280 for use in diagnosis of breast carcinoma and high-grade astrocytoma, and for use in the evaluation of therapeutic responses.

Pituitary stalk hemangioblastomas in von Hippel-Lindau disease.

OBJECT: Pituitary stalk hemangioblastomas are rare, and information on them is limited to a small number of case reports. To gain insight into the incidence, clinical effects, and management of pituitary stalk hemangioblastomas, the authors analyzed a series of patients with von Hippel-Lindau (VHL) disease. METHODS: Patients with VHL disease who were enrolled in a prospective National Institutes of Health natural history study were included. Clinical, imaging, and laboratory findings were analyzed. RESULTS: Two hundred fifty patients were included in the study (120 male and 130 female patients). In 8 patients (3%), 8 pituitary stalk hemangioblastomas were identified on MR imaging. This anatomical location was the most common supratentorial site for these lesions; 29% of all supratentorial hemangioblastomas were found there. The mean (+/- standard deviation) pituitary stalk hemangioblastoma volume was 0.5 +/- 0.9 cm(3) (range 0.08-2.8 cm(3)). Results of endocrine laboratory profiles were normal in all patients. All patients remained asymptomatic and none required treatment during the follow-up period (mean duration 41.4 +/- 14.4 months). CONCLUSIONS: The pituitary stalk is the most common site for the development of supratentorial hemangioblastomas in patients with VHL disease. Pituitary stalk hemangioblastomas often remain asymptomatic and do not require treatment. These findings indicate that pituitary stalk hemangioblastomas in patients with VHL disease may be managed with observation and that surgery for them can be reserved until associated signs or symptoms occur.

Outcome of using the histological pseudocapsule as a surgical capsule in Cushing disease.

OBJECT: Many patients with Cushing disease still have active or recurrent disease after pituitary surgery. The histological pseudocapsule of a pituitary adenoma is a layer of compressed normal anterior lobe that surrounds the adenoma and can be used during surgery to identify and guide removal of the tumor. In this study the authors examined the results of using the pseudocapsule as a surgical capsule in the resection of adenomas in patients with Cushing disease. METHODS: The authors reviewed a prospective database of data obtained in patients with Cushing disease who underwent surgery. The analysis included all cases in which a lesion was identified during surgery and in which the lesion was believed to be confined to the pituitary gland in patients with Cushing disease between January 1990 and March 2007. Since the objective was to determine the success of using the pseudocapsule as a surgical capsule, patients with invasive tumors and patients in whom no lesion was identified during surgery-challenging cases for surgical success-were excluded from analysis. RESULTS: In 261 patients an encapsulated adenoma was identified at surgery. Tumor was visible on MR imaging in 135 patients (52%); in 126 patients (48%) MR imaging detected no tumor. The range of tumor size overlapped considerably in the groups with positive and negative MR imaging results, indicating that in addition to size other features of the adenoma influence the results of MR imaging. In 252 patients hypercortisolism resolved after the first operation, whereas in 9 patients (3 with positive MR imaging and 6 with negative MR imaging) early reoperation was required. Hypercortisolism resolved in all 261 patients (256 with hypocortisolism and 5 with eucortisolism) before hospital discharge. Forty-six patients (18%) had postoperative electrolyte abnormalities (30 with hyponatremia and 16 with diabetes insipidus), but only 2 patients required treatment at discharge. The mean clinical follow-up duration was 84 months (range 12-215 months). Six patients (2%) had recurrence of hypercortisolism, all of whom were treated successfully with reoperation. CONCLUSIONS: Because of their small size, adenomas can be challenging to identify in patients with Cushing disease. Use of the histological pseudocapsule of an adenoma allows accurate identification of the tumor and helps guide its complete excision. With this approach the overall remission rate is high and the rate of complications is low.

Introduction: Spinal vascular malformations.

From the earliest observations of spinal vascular malformations, successful management has been challenging. Initially the challenges were diagnosing, understanding, and treating these lesions. They were originally considered all to be the same, or at least to be a single general type, of disease. With the introduction of selective spinal arteriography in the 1960s and more recently with the introduction and widespread use of MR imaging, the initial challenge of diagnosing spinal vascular malformations was overcome, and significant progress has been made in understanding their anatomy as well as the pathophysiology that underlies the myelopathy commonly associated with them. The anatomical features defined by selective arteriography and the observations permitted with the operating microscope ultimately led to distinctions between the major categories of the vascular lesions affecting the spinal cord; these distinctions were based on the lesions' anatomy, epidemiology, and the mechanism of spinal cord injury.

Origin of Syrinx Fluid in Syringomyelia: A Physiological Study.

BACKGROUND: The origin of syrinx fluid is controversial. OBJECTIVE: To elucidate the mechanisms of syringomyelia associated with cerebrospinal fluid pathway obstruction and with intramedullary tumors, contrast transport from the spinal subarachnoid space (SAS) to syrinx was evaluated in syringomyelia patients. METHODS: We prospectively studied patients with syringomyelia: 22 with Chiari I malformation and 16 with SAS obstruction-related syringomyelia before and 1 wk after surgery, and 9 with tumor-related syringomyelia before surgery only. Computed tomography-myelography quantified dye transport into the syrinx before and 0.5, 2, 4, 6, 8, 10, and 22 h after contrast injection by measuring contrast density in Hounsfield units (HU). RESULTS: Before surgery, more contrast passed into the syrinx in Chiari I malformation-related syringomyelia and spinal obstruction-related syringomyelia than in tumor-related syringomyelia, as measured by (1) maximum syrinx HU, (2) area under the syrinx concentration-time curve (HU AUC), (3) ratio of syrinx HU to subarachnoid cerebrospinal fluid (CSF; SAS) HU, and (4) AUC syrinx/AUC SAS. More contrast (AUC) accumulated in the syrinx and subarachnoid space before than after surgery. CONCLUSION: Transparenchymal bulk flow of CSF from the subarachnoid space to syrinx occurs in Chiari I malformation-related syringomyelia and spinal obstruction-related syringomyelia. Before surgery, more subarachnoid contrast entered syringes associated with CSF pathway obstruction than with tumor, consistent with syrinx fluid originating from the subarachnoid space in Chiari I malformation and spinal obstruction-related syringomyelia and not from the subarachnoid space in tumor-related syringomyelia. Decompressive surgery opened subarachnoid CSF pathways and reduced contrast entry into syringes associated with CSF pathway obstruction.

Nitrite infusion in humans and nonhuman primates: endocrine effects, pharmacokinetics, and tolerance formation.

BACKGROUND: The recent discovery that nitrite is an intrinsic vasodilator and signaling molecule at near-physiological concentrations has raised the possibility that nitrite contributes to hypoxic vasodilation and to the bioactivity of nitroglycerin and mediates the cardiovascular protective effects of nitrate in the Mediterranean diet. However, important questions of potency, kinetics, mechanism of action, and possible induction of tolerance remain unanswered. METHODS AND RESULTS: In the present study, we performed biochemical, physiological, and pharmacological studies using nitrite infusion protocols in 20 normal human volunteers and in nonhuman primates to answer these questions, and we specifically tested 3 proposed mechanisms of bioactivation: reduction to nitric oxide by xanthine oxidoreductase, nonenzymatic disproportionation, and reduction by deoxyhemoglobin. We found that (1) nitrite is a relatively potent and fast vasodilator at near-physiological concentrations; (2) nitrite functions as an endocrine reservoir of nitric oxide, producing remote vasodilation during first-pass perfusion of the opposite limb; (3) nitrite is reduced to nitric oxide by intravascular reactions with hemoglobin and with intravascular reductants (ie, ascorbate); (4) inhibition of xanthine oxidoreductase with oxypurinol does not inhibit nitrite-dependent vasodilation but potentiates it; and (5) nitrite does not induce tolerance as observed with the organic nitrates. CONCLUSIONS: We propose that nitrite functions as a physiological regulator of vascular function and endocrine nitric oxide homeostasis and suggest that it is an active metabolite of the organic nitrates that can be used therapeutically to bypass enzymatic tolerance.

Nitrite does not provide additional protection to thrombolysis in a rat model of stroke with delayed reperfusion.

An adjuvant therapy to prolong the therapeutic window for stroke patients is urgently needed. This randomized, blinded, placebo-controlled study investigated adjuvant intravenous sodium nitrite with recombinant tissue plasminogen activator (rtPA) in middle cerebral artery occlusion (MCAO) with 6 and 2 h of ischemia followed by reperfusion in Sprague-Dawley rats (n=59). Quantitative diffusion, T(1)-, T(2)-weighted, and semiquantitative perfusion imaging were performed before and after reperfusion and at 48 h after ischemia to determine the spatiotemporal evolution of stroke. After 48 h animals were killed and examined to evaluate infarct size and evidence of hemorrhagic transformation. Factor VIII immunostaining was performed to assess vessel morphology. Nitrite treatment (6 h group: 37.5 micromol for more than 90 mins; 2 h group: 26.25 and 1.75 micromol for more than 60 mins) did not reduce infarct volume 48 h after MCAO compared with saline-treated placebo groups after 6 or 2 h of MCAO. Stroke progression from baseline to 48 h, based on the apparent diffusion coefficient and relative cerebral blood flow deficits before and after reperfusion and T(2)-weighted hyperintensity at 48 h, did not differ between treated and control animals. These results suggest that nitrite is not a protective adjuvant therapy to delayed rtPA administration after ischemic stroke in rats.

Identification of a novel proliferation-related protein, WHSC1 4a, in human gliomas.

Dynamic changes in the expression of multiple genes appear to be common features that distinguish transformed cells from their normal counterparts. We compared the proteomic profiles of four glioblastoma multiforme (GBM) tissue samples and four normal brain cortex samples to examine the molecular basis of gliomagenesis. Trypsin-digested protein samples were separated by capillary isoelectric focusing with nano-reversed-phase liquid chromatography and were profiled by mass spectrometric sequencing. Wolf-Hirschhorn syndrome candidate 1 (WHSC1), along with 103 other proteins, was found only in the GBM proteomes. Western blot and immunohistochemistry verified our proteomic findings and demonstrated that 30-kDa WHSC1 expression increases with ascending tumor proliferation activity. RNA interference could suppress glioma cell growth by blocking WHSC1 expression. Our novel findings encourage the application of proteomic techniques in cancer research.

Sublabial-endonasal approach to the sella turcica.

In this paper the authors describe the sublabial-endonasal-transsphenoidal approach to the sella turcica, a modification that combines elements of the sublabial-submucosal-transseptal approach and the endonasal approach. It provides a midline, or near midline, trajectory, wide exposure of the sella, and secure speculum placement on the osseous edge of the pyriform aperture, while avoiding dissection of the nasal mucosa, and it can be used for microscopic and endoscopic surgery.

Surgical management of cerebellar hemangioblastomas in patients with von Hippel-Lindau disease.

OBJECT: Despite the frequency of cerebellar hemangioblastomas in von Hippel-Lindau (VHL) disease, their optimum contemporary management has not been defined, and is made complex because of the multiple, progressive, and protean nature of the tumors found in patients with this disorder. To examine modern management and outcomes of cerebellar hemangioblastomas in VHL disease, the authors reviewed findings in patients with this disease who underwent resection of cerebellar hemangioblastomas. METHODS: Consecutive patients with VHL disease who underwent surgery for cerebellar hemangioblastoma(s) at the National Institutes of Health were included. Eighty consecutive patients (44 female and 36 male patients) underwent 126 operations for removal of 164 cerebellar hemangioblastomas (age at surgery 37.8+/-10.3 years, follow-up duration 96.0+/-60.3 months). Serial clinical examinations, imaging studies, and operative records were analyzed. RESULTS: Symptoms and signs included headache (94 operations; 75%), ataxia (55%), dysmetria (29%), and hydrocephalus (28%). Although the primary objective of surgery was resection of the hemangioblastoma considered responsible for symptoms (136 of the hemangioblastomas [83%]), 28 additional hemangioblastomas (17%) were removed during the same surgeries. Tumors associated with symptoms were larger (diameter 1.8+/-1.9 cm; volume 2.8+/-3.4 cm3; p<0.05) and more likely to be associated with peritumoral edema or peritumoral cysts (100% associated with edema and/or cyst; p<0.05) than asymptomatic tumors (diameter 1.1+/-0.9 cm; volume 0.7+/-0.4 cm3; 18%). More tumors were located in the posterior (74%) compared with the anterior (26%) half of the cerebellum (p<0.05). Three months after resection, symptom improvement/stabilization had occurred following 124 of the operations (98%). Preoperative hydrocephalus resolved after tumor removal in 33 cases (94%) and did not require cerebrospinal fluid diversion. Long-term imaging follow-up (61.5+/-15.0 months) revealed no recurrences. CONCLUSIONS: Symptoms and signs caused by cerebellar hemangioblastomas in VHL disease are associated with edema and peritumoral cyst formation/propagation and are treated safely and effectively with resection. Cerebrospinal fluid diversion is rarely necessary after complete tumor removal in patients with preoperative hydrocephalus. Cerebellar hemangioblastomas are preferentially distributed in the posterior half of the cerebellum, as they are in the brainstem and spinal cord. Tumor recurrence is avoided by meticulous extracapsular resection.