Ari J. Kane

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.

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.

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.

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.

Hearing preservation rates after microsurgical resection of vestibular schwannoma

Preservation of hearing is a major goal of surgery for patients with vestibular schwannoma (VS). We performed an analysis of the published literature on hearing outcome after microsurgery for VS. Our objective was to provide a comprehensive and unbiased description of published results. We completed a comprehensive search of the English language literature, most recently in October 2009, and identified a total of 62 studies publishing disaggregated hearing outcome data of patients undergoing microsurgical resection of VS. Inclusion criteria for articles were: (i) hearing preservation rates were reported specifically for VS; (ii) hearing status was reported using the American Association of Otolaryngology-Head and Neck Surgery (AAO-HNS) or Gardner-Robertson (GR) classification; and (iii) initial tumor size was documented. We performed a multivariate step-wise logistic regression based on the results of univariate analysis, to determine factors which significantly impacted rates of hearing preservation in these patients. Of these, 49 articles involving 998 patients presented disaggregated data regarding the outcomes of individual patients, and were included in our analysis, with an over-all hearing preservation rate of 52%. In total, 286 patients underwent surgery by the middle cranial fossa (MCF) approach, and 702 patients underwent surgery via the retrosigmoid (RS) approach. The follow-up in these series ranged from 6months to 7years. Rates of hearing preservation in general declined with increasing age and tumor size. Patients undergoing surgery via the MCF had better hearing outcomes on univariate analysis than those undergoing the RS approach (63% vs. 47%, p<0.0001). Multivariate analysis found that tumor size >1.5cm (odds ratio [OR] 2.81, 95% confidence interval [CI]=1.59-4.95, p<0.001), and the RS approach (OR 4.15, 95% CI=1.97-8.77, p<0.001) were independent significant risk factors for loss of serviceable hearing during VS surgery. Use of the MCF demonstrates superior hearing outcomes to the RS approach, even after correcting for the effect of the increased size of tumors addressed by the RS approach.

Extent of resection and the long-term durability of vestibular schwannoma surgery.

OBJECT With limited studies available, the correlation between the extent of resection and tumor recurrence in vestibular schwannomas (VSs) has not been definitively established. In this prospective study, the authors evaluated 772 patients who underwent microsurgical resection of VSs to analyze the association between total tumor resection and the tumor recurrence rate. METHODS The authors selected all cases from a prospectively collected database of patients who underwent microsurgical resection as their initial treatment for a histopathologically confirmed VS. Recurrence-free survival was analyzed using Kaplan-Meier analysis. The authors studied the impact of possible confounders such as patient age and tumor size using stepwise Cox regression to calculate the proportional hazard ratio of recurrence while controlling for other cofounding variables. RESULTS The authors analyzed data obtained in 571, 89, and 112 patients in whom gross-total, near-total, and subtotal resections, respectively, were performed. A gross-total resection was achieved in 74% of the patients, and the overall recurrence rate in these patients 8.8%. There was no significant relation between the extent of resection and the rate of tumor recurrence (p = 0.58). As expected, the extent of resection was highly correlated with patient age, tumor size, and surgical approach (p < 0.0001). Using Cox regression, the authors found that the approach used did not significantly affect tumor control when the extent of resection was controlled for. CONCLUSIONS While complete tumor removal is ideal, the results presented here suggest that there is no significant relationship between the extent of resection and tumor recurrence.

Postoperative seizures following the resection of convexity meningiomas: are prophylactic anticonvulsants indicated? Clinical article.

OBJECT Seizures in the perioperative period are a well-recognized clinical entity in the setting of brain tumor surgery. At present, the suitability of antiepileptic prophylaxis in patients following brain tumor surgery is unclear, especially in those without prior seizures. Given the paucity of tumor-type and site-specific data, the authors evaluated the incidence of postoperative seizures in patients with convexity meningiomas and no prior seizures. METHODS The authors identified 180 patients with no preoperative history of seizures who underwent resection of a convexity meningioma. Some patients received antiepileptic prophylaxis for 7 days postoperatively while others did not, based on the practice patterns of different attendings. The rates of clinically evident seizures in the first 3-4 weeks after surgery were compared. RESULTS Patients who received antiepilepsy drugs (129 patients) did not significantly differ from those who did not (51 patients) in terms of age, sex, WHO tumor grade, extent of resection, rate of previous cranial surgery or radiation therapies, or use of preoperative embolization. There was a single new postoperative seizure in the entire cohort, yielding a new seizure rate of 1.9% in patients not on antiepileptic prophylaxis compared with 0% in patients on antiepileptics (p = not significant). CONCLUSIONS While it is thought that the routine use of prophylactic antiepileptics may prevent new seizures in patients undergoing surgery for a convexity meningioma, the rate of new seizures in untreated patients is probably very low. Data in this study call into question whether the cost and side effects of these medications are worth the small benefit their administration may confer.

The long-term postsurgical prognosis of patients with pineoblastoma.

For this report, the authors comprehensively summarized the existing literature on patients with pineoblastoma and identified the variables and treatments that had an impact patient on outcomes.