Adenoviruses historically have been one of the main vectors used in human gene therapy. To date, the majority of brain tumor trials of these vectors have used replication-defective viruses. The relative lack of success obtained with replication-defective vectors has prompted a search for new and improved therapies. In this context, oncolytic (conditionally replicative) adenoviruses, which selectively bind and replicate only in tumor cells, have gained increasing importance. These adenoviruses, once they are rendered conditionally replicative by transductional and transcriptional modifications, offer significant promise for patients with malignant glioma. In this review, the authors discuss the genetic approaches to adenoviral modification and their applications in the field of neurooncology.
Adam M. Sonabend, Ilya V. Ulasov, Yu Han and Maciej S. Lesniak
Víctor A. Arrieta, Fabio Iwamoto, Rimas V. Lukas, Sean Sachdev, Raul Rabadan and Adam M. Sonabend
Adam M. Sonabend, Brad E. Zacharia, Hannah Goldstein, Samuel S. Bruce, Dawn Hershman, Alfred I. Neugut and Jeffrey N. Bruce
Central nervous system (CNS) hemangiopericytomas are relatively uncommon and unique among CNS tumors as they can originate from or develop metastases outside of the CNS. Significant difference of opinion exists in the management of these lesions, as current treatment paradigms are based on limited clinical experience and single-institution series. Given these limitations and the absence of prospective clinical trials within the literature, nationwide registries have the potential to provide unique insight into the efficacy of various therapies.
The authors queried the Surveillance Epidemiology and End Results (SEER) database to investigate the clinical behavior and prognostic factors for hemangiopericytomas originating within the CNS during the years 2000–2009. The SEER survival data were adjusted for demographic factors including age, sex, and race. Univariate and multivariate analyses were performed to identify characteristics associated with overall survival.
The authors identified 227 patients with a diagnosis of CNS hemangiopericytoma. The median length of follow-up was 34 months (interquartile range 11–63 months). Median survival was not reached, but the 5-year survival rate was 83%. Univariate analysis showed that age and radiation therapy were significantly associated with survival. Moreover, young age and supratentorial location were significantly associated with survival on multivariate analysis. Most importantly, multivariate analysis using the Cox proportional hazards model showed a statistically significant survival benefit for patients treated with gross-total resection (GTR) in combination with adjuvant radiation treatment (HR 0.31 [95% CI 0.01–0.95], p = 0.04), an effect not appreciated with GTR alone.
The authors describe the epidemiology of CNS hemangiopericytomas in a large, national cancer database, evaluating the effectiveness of various treatment paradigms used in clinical practice. In this study, an overall survival benefit was found when GTR was accomplished and combined with radiation therapy. This finding has not been appreciated in previous series of patients with CNS hemangiopericytoma and warrants future investigations into the role of upfront adjuvant radiation therapy.
Bryan A. Lieber, Geoffrey Appelboom, Blake E. Taylor, Franklin D. Lowy, Eliza M. Bruce, Adam M. Sonabend, Christopher Kellner, E. Sander Connolly Jr. and Jeffrey N. Bruce
Preoperative corticosteroids and chemotherapy are frequently prescribed for patients undergoing cranial neurosurgery but may pose a risk of postoperative infection. Postoperative surgical-site infections (SSIs) have significant morbidity and mortality, dramatically increase the length and cost of hospitalization, and are a major cause of 30-day readmission. In patients undergoing cranial neurosurgery, there is a lack of data on the role of patient-specific risk factors in the development of SSIs. The authors of this study sought to determine whether chemotherapy and prolonged steroid use before surgery increase the risk of an SSI at postoperative Day 30.
Using the national prospectively collected American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database for 2006–2012, the authors calculated the rates of superficial, deep-incisional, and organ-space SSIs at postoperative Day 30 for neurosurgery patients who had undergone chemotherapy or had significant steroid use within 30 days before undergoing cranial surgery. Trauma patients, patients younger than 18 years, and patients with a preoperative infection were excluded. Univariate analysis was performed for 25 variables considered risk factors for superficial and organ-space SSIs. To identify independent predictors of SSIs, the authors then conducted a multivariate analysis in which they controlled for duration of operation, wound class, white blood cell count, and other potential confounders that were significant on the univariate analysis.
A total of 8215 patients who had undergone cranial surgery were identified. There were 158 SSIs at 30 days (frequency 1.92%), of which 52 were superficial, 27 were deep-incisional, and 79 were organ-space infections. Preoperative chemotherapy was an independent predictor of organ-space SSIs in the multivariate model (OR 5.20, 95% CI 2.33–11.62, p < 0.0001), as was corticosteroid use (OR 1.86, 95% CI 1.03–3.37, p = 0.04), but neither was a predictor of superficial or deep-incisional SSIs. Other independent predictors of organ-space SSIs were longer duration of operation (OR 1.16), wound class of ≥ 2 (clean-contaminated and further contaminated) (OR 3.17), and morbid obesity (body mass index ≥ 40 kg/m2) (OR 3.05). Among superficial SSIs, wound class of 3 (contaminated) (OR 6.89), operative duration (OR 1.13), and infratentorial surgical approach (OR 2.20) were predictors.
Preoperative chemotherapy and corticosteroid use are independent predictors of organ-space SSIs, even when data are controlled for leukopenia. This indicates that the disease process in organ-space SSIs may differ from that in superficial SSIs. In effect, this study provides one of the largest analyses of risk factors for SSIs after cranial surgery. The results suggest that, in certain circumstances, modulation of preoperative chemotherapy or steroid regimens may reduce the risk of organ-space SSIs and should be considered in the preoperative care of this population. Future studies are needed to determine optimal timing and dosing of these medications.
Andrew L. A. Garton, Connor J. Kinslow, Ali I. Rae, Amol Mehta, Susan C. Pannullo, Rajiv S. Magge, Rohan Ramakrishna, Guy M. McKhann, Michael B. Sisti, Jeffrey N. Bruce, Peter Canoll, Simon K. Cheng, Adam M. Sonabend and Tony J. C. Wang
Genomic analysis in neurooncology has underscored the importance of understanding the patterns of survival in different molecular subtypes within gliomas and their responses to treatment. In particular, diffuse gliomas are now principally characterized by their mutation status (IDH1 and 1p/19q codeletion), yet there remains a paucity of information regarding the prognostic value of molecular markers and extent of resection (EOR) on survival. Furthermore, given the modern emphasis on molecular rather than histological diagnosis, it is important to examine the effect of maximal resection on survival in all gliomas with 1p/q19 codeletions, as these will now be classified as oligodendrogliomas under the new WHO guidelines.
The objectives of the present study were twofold: 1) to assess the association between EOR and survival for patients with oligodendrogliomas in the National Cancer Database (NCDB), which includes information on mutation status, and 2) to demonstrate the same effect for all patients with 1p/19q codeleted gliomas in the NCDB.
The NCDB was queried for all cases of oligodendroglioma between 2004 and 2014, with follow-up dates through 2016. The authors found 2514 cases of histologically confirmed oligodendrogliomas for the final analysis of the effect of EOR on survival. Upon further query, 1067 1p/19q-codeleted tumors were identified in the NCDB. Patients who received subtotal resection (STR) or gross-total resection (GTR) were compared to those who received no tumor debulking surgery. Univariable and multivariable analyses of both overall survival and cause-specific survival were performed.
EOR was associated with increased overall survival for both histologically confirmed oligodendrogliomas and all 1p/19q-codeleted–defined tumors (p < 0.001 and p = 0.002, respectively). Tumor grade, location, and size covaried predictably with EOR. When evaluating tumors by each classification system for predictors of overall survival, facility setting, age, comorbidity index, grade, location, chemotherapy, and radiation therapy were all shown to be significantly associated with overall survival. STR and GTR were independent predictors of improved survival in historically classified oligodendrogliomas (HR 0.83, p = 0.18; HR 0.69, p = 0.01, respectively) and in 1p/19q-codeleted tumors (HR 0.49, p < 0.01; HR 0.43, p < 0.01, respectively).
By using the NCDB, the authors have demonstrated a side-by-side comparison of the survival benefits of greater EOR in 1p/19q-codeleted gliomas.
John H. Sampson, Shivanand P. Lad, James E. Herndon II, Robert M. Starke and Douglas Kondziolka
Randy S. D’Amico, Justin A. Neira, Jonathan Yun, Nikita G. Alexiades, Matei Banu, Zachary K. Englander, Benjamin C. Kennedy, Timothy H. Ung, Robert J. Rothrock, Alexander Romanov, Xiaotao Guo, Binsheng Zhao, Adam M. Sonabend, Peter Canoll and Jeffrey N. Bruce
Intracerebral convection-enhanced delivery (CED) has been limited to short durations due to a reliance on externalized catheters. Preclinical studies investigating topotecan (TPT) CED for glioma have suggested that prolonged infusion improves survival. Internalized pump-catheter systems may facilitate chronic infusion. The authors describe the safety and utility of long-term TPT CED in a porcine model and correlation of drug distribution through coinfusion of gadolinium.
Fully internalized CED pump-catheter systems were implanted in 12 pigs. Infusion algorithms featuring variable infusion schedules, flow rates, and concentrations of a mixture of TPT and gadolinium were characterized over increasing intervals from 4 to 32 days. Therapy distribution was measured using gadolinium signal on MRI as a surrogate. A 9-point neurobehavioral scale (NBS) was used to identify side effects.
All animals tolerated infusion without serious adverse events. The average NBS score was 8.99. The average maximum volume of distribution (Vdmax) in chronically infused animals was 11.30 mL and represented 32.73% of the ipsilateral cerebral hemispheric volume. Vdmax was achieved early during infusions and remained relatively stable despite a slight decline as the infusion reached steady state. Novel tissue TPT concentrations measured by liquid chromatography mass spectroscopy correlated with gadolinium signal intensity on MRI (p = 0.0078).
Prolonged TPT-gadolinium CED via an internalized system is safe and well tolerated and can achieve a large Vdmax, as well as maintain a stable Vd for up to 32 days. Gadolinium provides an identifiable surrogate for measuring drug distribution. Extended CED is potentially a broadly applicable and safe therapeutic option in select patients.