Martin J. Rutkowski

Gliomas Promote Immunosuppression through Induction of B7-H1 Expression in Tumor-Associated Macrophages

Purpose: Gliomas are known to induce local and systemic immunosuppression, inhibiting T-cell–mediated cytotoxic responses to tumor growth. Tumor-associated macrophages are a significant component of the immune infiltrate in gliomas and may express immunosuppressive surface ligands, such as B7-H1. Experimental Design: Tumor and peripheral blood samples from patients with glioblastoma (GBM) were analyzed by flow cytometry to evaluate the expression of B7-H1 in circulating and tumor-infiltrating macrophages. Human monocytes from healthy patients were stimulated with conditioned media from glioma cells to evaluate B7-H1 expression. Production of interleukin (IL)-10 by stimulated monocytes was measured by ELISA, and stimulation with IL-10 alone was evaluated for the ability to induce B7-H1 expression. The effect of inhibiting IL-10 and its receptor on glioma-induced B7-H1 expression in monocytes was evaluated. Results: Circulating monocytes in patients with GBM had significantly increased expression of B7-H1 compared with healthy control patients. Tumor-associated macrophages from matched GBM tissue had even greater B7-H1 expression. Treatment of normal monocytes with glioma-conditioned media could significantly increase B7-H1 expression. Stimulation of monocytes with conditioned media resulted in substantial production of IL-10 and upregulation of the IL-10 receptor. Stimulation of monocytes with IL-10 alone could significantly increase B7-H1 expression, sufficient to induce T-cell apoptosis when cocultured with stimulated monocytes. Inhibition of IL-10 and the IL-10 receptor could knock down the effect of glioma media on B7-H1 by more than 50%. Conclusions: Gliomas can upregulate B7-H1 expression in circulating monocytes and tumor-infiltrative macrophages through modulation of autocrine/paracrine IL-10 signaling, resulting in an immunosuppressive phenotype. Clin Cancer Res; 19(12); 3165–75. ©2013 AACR.

Cancer and the Complement Cascade

Despite significant research on the role of inflammation and immunosurveillance in the immunologic microenvironment of tumors, little attention has been given to the oncogenic capabilities of the complement cascade. The recent finding that complement may contribute to tumor growth suggests an insidious relationship between complement and cancer, especially in light of evidence that complement facilitates cellular proliferation and regeneration. We address the hypothesis that complement proteins promote carcinogenesis and suggest mechanisms by which complement can drive the fundamental features of cancer. Evidence shows that this diverse family of innate immune proteins facilitates dysregulation of mitogenic signaling pathways, sustained cellular proliferation, angiogenesis, insensitivity to apoptosis, invasion and migration, and escape from immunosurveillance. Given that the traditionally held functions for the complement system include innate immunity and cancer defense, our review suggests a new way of thinking about the role of complement proteins in neoplasia. Mol Cancer Res; 8(11); 1453–65. ©2010 AACR.

The relevance of Simpson Grade I and II resection in modern neurosurgical treatment of World Health Organization Grade I meningiomas

OBJECT In 1957, Simpson published a seminal paper defining the risk factors for recurrence following surgical treatment of intracranial meningiomas. Given that Simpsons study was published more than 50 years ago, preceding image guidance technology and MR imaging, the authors reviewed their own experience with surgical treatment of Grade I meningiomas to determine if Simpsons grading scale is still relevant to modern neurosurgical practice. METHODS From this cohort, the authors evaluated all patients undergoing craniotomy for resection of a histologically proven WHO Grade I meningioma as their initial therapy. Clinical information was retrospectively reconstructed using patient medical records and radiological data. Recurrence analysis was performed using the Kaplan-Meier method. RESULTS The 5-year recurrence/progression-free survival for all patients receiving a Simpson Grade I, II, III, or IV resection was 95, 85, 88, and 81%, respectively (p = not significant, log-rank test). Kaplan-Meier analysis revealed no significant difference in recurrence-free survival between patients receiving a Simpson Grade I, II, III, or IV resection. Analysis limited to meningiomas arising from the skull base (excluding the cavernous sinus) similarly found no significant benefit to Simpson Grade I or II resection, and the survival curves were nearly superimposed. CONCLUSIONS In this study of a cohort of patients undergoing surgery for WHO Grade I meningiomas, the authors demonstrate that the benefit of more aggressive attempts to resect the tumor with dura and underlying bone was negligible compared with simply removing the entire tumor, or even leaving small amounts of tumor attached to critical structures. The authors believe that these data reflect an evolution in the nature of meningioma surgery over the past 2 decades, and bring into question the relevance of using Simpsons grading system as the sole predictor of recurrence.

Craniopharyngioma: a comparison of tumor control with various treatment strategies.

OBJECT Craniopharyngiomas have a propensity to recur after resection, potentially causing death through their aggressive local behavior in their critical site of origin. Recent data suggest that subtotal resection (STR) followed by adjuvant radiotherapy (XRT) may be an appealing substitute for gross-total resection (GTR), providing similar rates of tumor control without the morbidity associated with aggressive resection. Here, the authors summarize the published literature regarding rates of tumor control with various treatment modalities for craniopharyngiomas. METHODS The authors performed a comprehensive search of the English language literature to identify studies publishing outcome data on patients undergoing surgery for craniopharyngioma. Rates of progression-free survival (PFS) and overall survival (OS) were determined through Kaplan-Meier analysis. RESULTS There were 442 patients who underwent tumor resection. Among these patients, GTR was achieved in 256 cases (58%), STR in 101 cases (23%), and STR+XRT in 85 cases (19%). The 2- and 5-year PFS rates for the GTR group versus the STR+XRT group were 88 versus 91%, and 67 versus 69%, respectively. The 5- and 10-year OS rates for the GTR group versus the STR+XRT group were 98 versus 99%, and 98 versus 95%, respectively. There was no significant difference in PFS (log-rank test) or OS with GTR (log-rank test). CONCLUSIONS Given the relative rarity of craniopharyngioma, this study provides estimates of outcome for a variety of treatment combinations, as not all treatments are an option for all patients with these tumors.

The complement cascade as a mediator of tissue growth and regeneration.

Recent evidence has demonstrated that the complement cascade is involved in a variety of physiologic and pathophysiologic processes in addition to its role as an immune effector. Research in a variety of organ systems has shown that complement proteins are direct participants in maintenance of cellular turnover, healing, proliferation and regeneration. As a physiologic housekeeper, complement proteins maintain tissue integrity in the absence of inflammation by disposing of cellular debris and waste, a process critical to the prevention of autoimmune disease. Developmentally, complement proteins influence pathways including hematopoietic stem cell engraftment, bone growth, and angiogenesis. They also provide a potent stimulus for cellular proliferation including regeneration of the limb and eye in animal models, and liver proliferation following injury. Here, we describe the complement cascade as a mediator of tissue growth and regeneration.

Anatomic location is a risk factor for atypical and malignant meningiomas.

Grade II and III meningiomas have higher rates of tumor recurrence than grade I meningiomas after surgery and/or external irradiation. As the utility of noninvasive treatments for brain tumors increases, it is becoming increasingly important to assess the likelihood that a tumor is not benign before treatment initiation. Hence, the authors have reviewed a large series of their patients to determine risk factors for higher‐grade pathology, with particular interest paid to tumor location.

Intracranial hemangiopericytoma: Clinical experience and treatment considerations in a modern series of 40 adult patients

Intracranial hemangiopericytoma (HPC) is a malignant meningothelial tumor. Because of its rarity, few guidelines exist for optimal management.

Predictors of mortality following treatment of intracranial hemangiopericytoma

OBJECT Intracranial hemangiopericytoma (HPC) is a rare and malignant extraaxial tumor with a high proclivity toward recurrence and metastasis. Given this lesions rarity, little information exists on prognostic factors influencing mortality rates following treatment with surgery or radiation or both. A systematic review of the published literature was performed to ascertain predictors of death following treatment for intracranial HPC. METHODS The authors identified 563 patients with intracranial HPC in the published literature, 277 of whom had information on the duration of follow-up. Statistical analysis of survival was performed using Kaplan-Meier and Cox regression analysis. RESULTS Hemangiopericytoma was diagnosed in 246 males and 204 females, ranging in age from 1 month to 80 years. Among patients treated for HPC, overall median survival was 13 years, with 1-, 5-, 10-, and 20-year survival rates of 95%, 82%, 60%, and 23%, respectively. Gross-total resection alone (105 patients) was associated with superior survival rates overall, with a median survival of 13 years, whereas subtotal resection alone (23 patients) resulted in a median survival of 9.75 years. Subtotal resection plus adjuvant radiotherapy led to a median survival of 6 years. Gross-total resection was associated with a superior survival benefit to patients regardless of the addition or absence of radiation, and patients receiving > 50 Gy of radiation had worse survival outcomes (median survival 4 vs 18.6 years, p < 0.01, log-rank test). Patients with tumors of the posterior fossa had a median survival of 10.75 versus 15.6 years for those with non-posterior fossa tumors (p < 0.05, log-rank test). CONCLUSIONS Treatment with gross-total resection provides the greatest survival advantage and should be pursued aggressively as an initial therapy. The addition of postoperative adjuvant radiation does not seem to confer a survival benefit.

Treatment decision making based on the published natural history and growth rate of small meningiomas

OBJECT Definitive data allowing clinicians to predict which meningioma patients will fail to respond to conservative management are lacking. To address this need, the authors systematically reviewed the published literature regarding the natural history of small, untreated meningiomas. METHODS The authors performed a systematic review of the existing literature on untreated meningiomas that were followed with serial MR imaging. They summarize the published linear rates of tumor growth, and the risk factors for development of new or worsened symptoms during follow-up by using a stratified chi-square test. RESULTS The search methods identified 22 published studies reporting on 675 patients with untreated meningiomas followed by serial MR imaging. Linear growth rates varied significantly: no growth was the most common rate, although reports of more aggressive tumors noted growth rates of up to a 93% linear increase in size per year. The authors found that few patients with initial tumor diameters < 2 cm went on to develop new or worsened symptoms over a median follow-up period of 4.6 years. Patients with initial tumor diameters of 2-2.5 cm demonstrated a marked difference in the rate of symptom progression if their tumors grew > 10% per year, compared with those tumors growing ≤ 10% per year (42% vs 0%; p < 0.001, chi-square test). Patients with tumors between > 2.5 and 3 cm in initial size went on to develop new or worsened symptoms 17% of the time. CONCLUSIONS This systematic review of the literature regarding the clinical behavior of untreated meningiomas suggests that most meningiomas ≤ 2.5 cm in diameter do not proceed to cause symptoms in the approximately 5-year period following their discovery. Those that do cause symptoms can usually be predicted with close radiographic follow-up. Based on these findings, the authors suggest the importance of observation in the early course of treatment for small asymptomatic meningiomas, especially those with an initial diameter < 2 cm.

Posttreatment prognosis of patients with esthesioneuroblastoma.

OBJECT There is no Class I evidence to guide the appropriate management of esthesioneuroblastoma (EN). Most data currently guiding treatment come from small- or modest-sized series gathered at individual centers that have concluded that surgery with radiotherapy is the preferred treatment. In this study, the authors summarize the published literature on treatment outcomes in patients with EN. The objective was to ascertain what variables predict prognosis in these patients and to determine the relative effect of different therapies. METHODS The authors identified 205 published studies containing treatment outcomes for surgery, radiotherapy, chemotherapy, or multimodal treatment. Using Kaplan-Meier analysis, the survival of patients who received surgery was compared with that in those who received surgery and radiotherapy. Additionally, Kadish staging was compared with low- and high-grade Hyams criteria to assess for subgroup prognostic significance in survival differences. RESULTS Nine hundred fifty-six patients met the inclusion criteria, with a median follow-up time of 3 years. Kaplan-Meier analysis demonstrated no difference in survival between patients who underwent surgery alone and those who underwent surgery plus radiotherapy at 5 years (78 vs 75%) or 10 years (67 vs 61%, respectively) (p = 0.3). Univariate analysis demonstrated worse survival in cases involving Kadish Grade C tumors, Hyams Grade 3 and 4 tumors, and in patients older than 65 years of age. Multivariate analysis demonstrated that Hyams Grade 3 and 4 lesions carried significant risk (proportional hazard = 4.83, p < 0.001) with 5- and 10-year survival of 47 and 31%. CONCLUSIONS A biopsy should always be obtained in cases suspected of EN because histology is a strong prognostic indicator and will help guide appropriate treatment. Unimodal surgery and combined surgery/radiotherapy appear to be of equivalent efficacy with respect to survival in patients with EN. Chemotherapy should be considered in high-grade EN.