Mustafa Aziz Hatiboglu

Impact of intraoperative high-field magnetic resonance imaging guidance on glioma surgery: a prospective volumetric analysis.

OBJECTIVETo determine the impact of intraoperative magnetic resonance imaging (iMRI) on the decision to proceed with additional glioma resection during surgery and to maximize extent of resection (EOR). METHODSPatients who underwent craniotomy for glioma resection with high-field iMRI guidance were prospectively evaluated between September 2006 and August 2007. Volumetric analysis and EOR were assessed with iMRI, using postcontrast T1-weighted images for tumors showing contrast enhancement and T2-weighted images for nonenhancing tumors. RESULTSForty-six patients underwent resection using iMRI guidance, with iMRI being used to evaluate the EOR in 44 patients and for reregistration in 2 patients. Surgery was terminated after iMRI in 23 patients (52%) because gross total resection was achieved or because of residual tumor infiltration in an eloquent brain region. Twenty-one patients (47%) underwent additional resection of residual tumor after iMRI. For enhancing gliomas, the median EOR increased significantly from 84% (range, 59%–97%) to 99% (range, 85%–100%) with additional tumor removal after iMRI (P < 0.001). For nonenhancing gliomas, the median EOR increased (from 63% to 80%) with additional tumor removal after iMRI, but not significantly, owing to the small sample size (7 patients). Overall, the EOR increased from 76% (range, 35%–97%) to 96% (range, 48%–100%) (P < 0.001). Gross total resection was achieved after additional tumor removal after iMRI in 15 of 21 patients (71%). Overall, 29 patients (65%) experienced gross total resection, and in 15 (52%), this was achieved with the contribution of iMRI. CONCLUSIONHigh-field iMRI is a safe and reliable technique, and its use optimizes the extent of glioma resection.

Glioma-Associated Cytomegalovirus Mediates Subversion of the Monocyte Lineage to a Tumor Propagating Phenotype

Purpose: Cytomegalovirus (CMV) has been ubiquitously detected within high-grade gliomas, but its role in gliomagenesis has not been fully elicited. Experimental Design: Glioblastoma multiforme (GBM) tumors were analyzed by flow cytometry to determine CMV antigen expression within various glioma-associated immune populations. The glioma cancer stem cell (gCSC) CMV interleukin (IL)-10 production was determined by ELISA. Human monocytes were stimulated with recombinant CMV IL-10 and levels of expression of p-STAT3, VEGF (vascular endothelial growth factor), TGF-β, viral IE1, and pp65 were determined by flow cytometry. The influence of CMV IL-10–treated monocytes on gCSC biology was ascertained by functional assays. Results: CMV showed a tropism for macrophages (MΦ)/microglia and CD133+ gCSCs within GBMs. The gCSCs produce CMV IL-10, which induces human monocytes (the precursor to the central nervous system MΦs/microglia) to assume an M2 immunosuppressive phenotype (as manifested by downmodulation of the major histocompatibility complex and costimulatory molecules) while upregulating immunoinhibitory B7-H1. CMV IL-10 also induces expression of viral IE1, a modulator of viral replication and transcription in the monocytes. Finally, the CMV IL-10–treated monocytes produced angiogenic VEGF, immunosuppressive TGF-β, and enhanced migration of gCSCs. Conclusions: CMV triggers a feedforward mechanism of gliomagenesis by inducing tumor-supportive monocytes. Clin Cancer Res; 17(14); 4642–9. ©2011 AACR.

Factors influencing the risk of local recurrence after resection of a single brain metastasis

OBJECT Local recurrence (LR) of a resected brain metastasis occurs in up to 46% of patients. Postoperative whole-brain radiation therapy (WBRT) reduces that incidence. To isolate factors associated with the risk of LR after resection, the authors only studied patients who did not receive adjuvant radiotherapy. METHODS The authors reviewed data from 570 cases involving patients who had undergone resection of a previously untreated single brain metastasis at The University of Texas M. D. Anderson Cancer Center between 1993 and 2006 without receiving postoperative WBRT. All tumors were measured preoperatively on MR images. The resection method (en bloc resection [EBR] or piecemeal resection [PMR]) was noted at the time of surgery. Predictors of LR were assessed using the Cox proportional hazards model. RESULTS The median patient age was 58 years, 55% were male, and 88% had a Karnofsky Performance Scale Score > or = 80. The most common primary cancers were those of the lung (28%), skin (melanoma, 21%), kidney (19%), and breast (11%). Piecemeal resection was performed in 201 patients (35%) and EBR in 369 (65%). Local recurrence developed in 84 patients (15%). The histological type of the primary cancer did not significantly predict LR; however, 7 of 22 patients with sarcoma developed LR (p = 0.16). The authors identified 2 variables that increased the risk of LR. Undergoing PMR carried a significantly higher LR risk than EBR (crude hazard ratio [HR] 1.7, 95% CI 1.1-2.6, p = 0.03). Tumors exceeding the median volume (9.7 cm(3)) had a significantly higher LR risk than those that were < 9.7 cm(3) (crude HR 1.7; 95% CI 1.1-2.6; p = 0.02). In the multivariate analysis, small tumors removed by EBR had a significantly lower LR risk. CONCLUSIONS The LR risk of a single brain metastasis is influenced by biological factors (such as tumor volume) and treatments (such as the resection method). Early administration of postoperative WBRT may be particularly warranted when such negative tumor-related prognostic factors are noted or when treatment-related ones such as PMR are unavoidable.

Comparative risk of leptomeningeal dissemination of cancer after surgery or stereotactic radiosurgery for a single supratentorial solid tumor metastasis

OBJECTIVETo test the hypothesis that differential risks of developing leptomeningeal disease (LMD) exist in patients having a single supratentorial brain metastasis resected via a piecemeal or en bloc approach or treated with stereotactic radiosurgery (SRS). METHODSBetween 1993 and 2006, 827 patients with a supratentorial brain metastasis underwent resection or SRS at The University of Texas M.D. Anderson Cancer Center. The primary outcome was the incidence of LMD. RESULTSResection was performed piecemeal in 191 patients and en bloc in 351 patients; 285 patients received SRS. LMD occurred in 33 patients, 29 in the resection group and 4 in the SRS group. Risk of LMD was significantly higher with piecemeal tumor resection than with other procedures (SRS: hazard ratio [HR] for piecemeal, 5.8; 95% confidence interval [CI], 1.9–17.2; P = 0.002; en bloc, HR for piecemeal, 2.7; 95% CI, 1.3–5.6; P = 0.009). The difference between piecemeal and en bloc was particularly pronounced in patients with a melanoma primary (HR, 8.4; 95% CI, 1.8–39.2; P = 0.007). The risk of LMD was not significantly different between en bloc resection and SRS (HR for en bloc, 2.1; 95% CI, 0.7–6.4; P = 0.21). Similar results were obtained when comparing effects of SRS and both resection approaches after limiting the sample to patients with tumors in a specific volume range. CONCLUSIONPiecemeal resection of a supratentorial brain metastasis carries a higher risk of LMD than en bloc resection or SRS. Further assessment of the role of the 2 surgical resection approaches and SRS in a controlled prospective setting with large numbers of patients is warranted.

Outcomes and prognostic factors for patients with brainstem metastases undergoing stereotactic radiosurgery.

BACKGROUND:Treatment of tumors metastatic to the brainstem with stereotactic radiosurgery (SRS) has not been widely studied. OBJECTIVE:To identify the effects of SRS on patients with brainstem metastases by assessing duration of local progression-free survival (LPFS) and overall survival. METHODS:We retrospectively reviewed clinical data collected from 60 patients undergoing linear accelerator-based SRS for tumors metastatic to the brainstem between August 1994 and December 2007. The LPFS and overall survival were calculated with the Kaplan-Meier method. Prognostic factors were evaluated with the log-rank test and Cox proportional hazards model. RESULTS:The median age of patients was 61 years (range, 39-85 years); the median treated lesion volume was 1.0 mL (range, 0.1-8.7 mL); and the median SRS dose was 15 Gy (range, 8-18 Gy). The median overall survival interval after SRS was 4 months (95% confidence interval, 3.4-4.9 months); crude local tumor control was 76%; and median LPFS was 5.7 months (95% confidence interval, 3.0-8.4 months). Shorter overall survival was associated with a pretreatment tumor volume ≥4 mL (P < .001) and male sex (P = .03). Shorter LPFS was associated with a pretreatment tumor volume ≥4 mL (P = .008), a melanoma primary tumor (P = .002), and the presence of necrosis in pre-SRS magnetic resonance imaging (P = .04). A Basic Score for Brain Metastases of 2 to 3 vs 1 (P = .007) and a Score Index for Radiosurgery >5 (P = .003) were significantly associated with longer survival. Twelve patients (20%) developed SRS-related complications. CONCLUSION:Stereotactic radiosurgery provides noninvasive treatment and favorable local tumor control for patients with brainstem metastases.

The role of surgical resection in patients with brain metastases

Brain metastasis is a devastating complication of systemic malignancy that affects a considerable number of cancer patients. The appearance of brain metastases is often considered to be a sign of poor prognosis; in patients with brain metastases poor survival time has been reported in the literature. Therefore, treatment of these brain lesions in cancer patients is important for quality of life, providing local tumour control, preventing death from neurological causes, and improving survival, although potentially only in a minority of patients. Surgical resection of brain metastases has been the cornerstone treatment in select patients. Careful patient selection, the use of appropriate surgical techniques, and surgical adjuncts are the major determinants of favourable outcome in patients undergoing resection of brain metastases. In this review, we explain the role of surgical resection in the treatment of patients with brain metastases with consideration of patient selection, surgical techniques and the use of intraoperative adjuncts.

Factors affecting survival in 267 consecutive patients undergoing surgery for spinal metastasis from renal cell carcinoma.

OBJECT Renal cell carcinoma (RCC) frequently metastasizes to the spine, and the prognosis can be quite variable. Surgical removal of the tumor with spinal reconstruction has been a mainstay of palliative treatment. The ability to predict prognosis is valuable when determining the role and magnitude of surgical intervention in cancer patients. To better identify factors affecting survival in patients undergoing surgery for spinal metastasis from RCC, the authors undertook a retrospective analysis of a large patient cohort at a tertiary care cancer center. METHODS Relevant clinical data on a consecutive series of patients who had undergone surgery for spinal metastasis of RCC between 1993 and 2007 at The University of Texas MD Anderson Cancer Center were retrospectively reviewed. Demographic data, histopathological grade of primary tumor, timing of spinal surgery relative to diagnosis, treatment history prior to surgery, neurological status, and systemic disease burden were analyzed to determine the impact of these factors on survival outcome. RESULTS The authors identified 267 patients who met the study criteria. Five-year overall survival (OS) after spine tumor resection was 7.8%, with a median OS of 11.3 months (95% CI 9.5-13.0 months). Patients with Fuhrman Grade 4 RCC had a median OS of 6.1 months (95% CI 3.5-8.7 months), which was significantly lower than the 14.3 months (95% CI 9.1-19.4 months) observed in patients with Fuhrman Grade 3 or less RCC (p < 0.001). Patients with preoperative neurological deficits had a median survival of 5.9 months (95% CI 4.1-7.7 months), which was significantly lower than the 13.5 months (95% CI 10.4-16.6 months) observed in patients with a normal neurological examination (p < 0.001). Patients whose spine was the only site of metastasis had a median OS of 19 months (95% CI 9.8-28.2 months) after surgery, significantly longer than the 9.7 months (95% CI 8.1-11.3 months) observed in patients with additional extraspinal metastasis sites (p < 0.001). Patients with nonprogressing extraspinal metastasis (no metastasis, stable, or concurrent) had a median survival of 20.6 months (95% CI 15.1-26.1 months), compared with 5.6 months (95% CI 4.4-6.8 months) in patients with progressing metastasis (p < 0.001). CONCLUSIONS The authors identified several factors influencing survival after spine surgery for metastatic spinal RCC, including grade of the original nephrectomy specimen, activity of the systemic disease, and neurological status at the time of surgery. These clinical features may help to identify patients who may benefit from aggressive surgical intervention.

The tumor microenvironment expression of p-STAT3 influences the efficacy of cyclophosphamide with WP1066 in murine melanoma models

Melanoma is a common and deadly tumor that upon metastasis to the central nervous system (CNS) has median survival duration of less than 5 months. Activation of the signal transducer and activator of transcription 3 (STAT3) has been identified as a key mediator that drives the fundamental components of melanoma. We hypothesized that WP1066, a novel inhibitor of STAT3 signaling, would enhance the antitumor activity of cyclophosphamide (CTX) against melanoma, including disease within the CNS. The mechanisms of efficacy were investigated by tumor‐ and immune‐mediated cytotoxic assays, in vivo evaluation of the reduction of regulatory T cells (Tregs) and by determining intratumoral p‐STAT3 expression by immunohistochemistry. Combinational therapy of WP1066, with both metronomic and cytotoxic dosing of CTX, was investigated in a model system of systemic and intracerebral melanoma in syngeneic mice. Inhibition of p‐STAT3 by WP1066 was enhanced with CTX in a dose‐dependent manner. However, in mice with intracerebral melanoma, the greatest therapeutic benefit was seen in animals treated with cytotoxic CTX dosing and WP1066, whose median survival time was 120 days, an increase of 375%, with 57% long‐term survivors. This treatment efficacy correlated with p‐STAT3 expression levels within the tumor microenvironment. The efficacy of the combination of cytotoxic dosing of CTX with WP1066 is attributed to the direct tumor cytotoxic effects of the agents and has the greatest therapeutic potential for the treatment of CNS melanoma.

Utilization of Intraoperative Motor Mapping in Glioma Surgery with High-Field Intraoperative Magnetic Resonance Imaging

Background/Aims: The main goal of glioma surgery is to maximize tumor resection while minimizing neurologic injury. The use of high-field intraoperative magnetic resonance imaging (iMRI) and intraoperative cortical mapping (IOM) together enable the surgeon to increase the extent of tumor resection (EOR) and preserve the neurological function. However, there is insufficient evidence to validate the use of IOM with high-field iMRI. Methods: To study the safety and utility of IOM in a high-field (1.5 T) iMRI suite, we retrospectively studied 38 patients with glioma who underwent surgery with IOM in the iMRI suite. Results: We were able to use IOM in the iMRI suite without any adverse side effects or difficulty. Median EOR was 97%. A new or worsening motor deficit occurred in 14 (37%) patients immediately after the surgery, with 3 (8%) patients exhibiting persistent deficit at 6 months. Conclusion: Our findings suggest that IOM can be successfully used in a high-field MRI environment and can help minimize postoperative motor deficit with a higher EOR.

Abscess formation within invasive pituitary adenoma

Pituitary abscess secondary to an adenoma is rare. To date, only 19 cases have been reported. This is the first report of a patient who presented with bilateral total ophthalmoplegia. A 59-year-old male patient presented with headache, nausea, vomiting, decreasing visual acuity, diplopia and bilateral ophthalmoplegia with ptosis. Magnetic resonance imaging was suggestive of a pituitary abscess with adenoma. Transphenoidal surgery was performed and, during debulking of the tumour, the abscess was seen and excised. After the operation, the patient received antibiotic therapy and his neurological condition improved. Pituitary abscess with adenoma is a serious condition that has a high mortality rate. Therefore, early diagnosis and surgical intervention with antibiotic therapy are necessary.