Nicholas F. Marko

Extent of Resection of Glioblastoma Revisited: Personalized Survival Modeling Facilitates More Accurate Survival Prediction and Supports a Maximum-Safe-Resection Approach to Surgery

PURPOSE Approximately 12,000 glioblastomas are diagnosed annually in the United States. The median survival rate for this disease is 12 months, but individual survival rates can vary with patient-specific factors, including extent of surgical resection (EOR). The goal of our investigation is to develop a reliable strategy for personalized survival prediction and for quantifying the relationship between survival, EOR, and adjuvant chemoradiotherapy. PATIENTS AND METHODS We used accelerated failure time (AFT) modeling using data from 721 newly diagnosed patients with glioblastoma (from 1993 to 2010) to model the factors affecting individualized survival after surgical resection, and we used the model to construct probabilistic, patient-specific tools for survival prediction. We validated this model with independent data from 109 patients from a second institution. RESULTS AFT modeling using age, Karnofsky performance score, EOR, and adjuvant chemoradiotherapy produced a continuous, nonlinear, multivariable survival model for glioblastoma. The median personalized predictive error was 4.37 months, representing a more than 20% improvement over current methods. Subsequent model-based calculations yield patient-specific predictions of the incremental effects of EOR and adjuvant therapy on survival. CONCLUSION Nonlinear, multivariable AFT modeling outperforms current methods for estimating individual survival after glioblastoma resection. The model produces personalized survival curves and quantifies the relationship between variables modulating patient-specific survival. This approach provides comprehensive, personalized, probabilistic, and clinically relevant information regarding the anticipated course of disease, the overall prognosis, and the patient-specific influence of EOR and adjuvant chemoradiotherapy. The continuous, nonlinear relationship identified between expected median survival and EOR argues against a surgical management strategy based on rigid EOR thresholds and instead provides the first explicit evidence supporting a maximum safe resection approach to glioblastoma surgery.

Cerebral radiation necrosis: A review of the pathobiology, diagnosis and management considerations

Radiation therapy forms one of the building blocks of the multi-disciplinary management of patients with brain tumors. Improved survival following radiation therapy may come with a cost, including the potential complication of radiation necrosis. Radiation necrosis impacts the quality of life in cancer survivors, and it is essential to detect and effectively treat this entity as early as possible. Significant progress in neuro-radiology and molecular pathology facilitate more straightforward diagnosis and characterization of cerebral radiation necrosis. Several therapeutic interventions, both medical and surgical, may halt the progression of radiation necrosis and diminish or abrogate its clinical manifestations, but there are still no definitive guidelines to follow explicitly that guide treatment of radiation necrosis. We discuss the pathobiology, clinical features, diagnosis, available treatment modalities, and outcomes in the management of patients with intracranial radiation necrosis that follows radiation used to treat brain tumors.

The Role of Observational Investigations in Comparative Effectiveness Research

INTRODUCTION Comparative effectiveness research (CER) seeks to inform clinical decisions between alternate treatment strategies using data that reflects real patient populations and real-world clinical scenarios for the purpose of improving patient outcomes. There are multiple clinical situations where the unique characteristics of observational investigations can inform medical decision-making within the CER paradigm. Accordingly, it is critical for clinicians to appreciate the strengths and limitations of observational research, particularly as they apply to CER. METHODS This review focuses on the role of observational research in CER. We discuss the concept of evidence hierarchies as they relate to observational research and CER, review the scope and nature of observational research, present the rationale for its inclusion in CER investigations, discuss potential sources of bias in observational investigations as well as strategies used to compensate for these biases, and discuss a framework to implement observational research in CER. CONCLUSIONS The CER paradigm recognizes the limitations of hierarchical models of evidence and favors application of a strength-of-evidence model. In this model, observational research fills gaps in randomized clinical trial data and is particularly valuable to investigate effectiveness, harms, prognosis, and infrequent outcomes as well as in circumstances where randomization is not possible and in studies of many surgical populations. Observational investigations must be designed with careful consideration of potential sources of bias and must incorporate strategies to control such bias prospectively, and their results must be reported in a uniform and transparent fashion. When these conditions can be achieved, observational research represents a valuable and critical component of modern CER.

Does metabolic radiolabeling stimulate the stress response? Gene expression profiling reveals differential cellular responses to internal beta vs. external gamma radiation

DNA microarray analyses were used to investigate the effect of cell‐incorporated 35S‐methionine on human colorectal carcinoma cells. This β‐radiation‐induced gene expression profile was compared with that induced by external γ‐radiation. The extent of DNA fragmentation was used as a biomarker to determine the external γ dose that was bioequivalent to that received by cells incubated in medium containing 35S‐methionine. Studies showed that 35S‐methionine at 100 µCi/mL induced a much more robust transcriptional response than γ‐radiation (2000 cGy) when evaluated 2 h after the labeling or irradiation period. The cellular response to internal β‐radiation was greater not only with respect to the number of genes induced, but also with respect to the level of gene induction. Not surprisingly, the induced genes overlapped with the set of γ‐responsive genes. However, a distinct β‐gene induction profile that included a large number of cell adhesion proteins was also observed. Taken together, these studies demonstrate that metabolic incorporation of a low energy β‐emitter, such as 35S‐methionine, can globally influence a diverse set of cellular activities that can, in turn, affect the outcome of many experiments by altering the cell cycle, metabolic, signaling, or redox status (set point) of the cell. Additional studies of the mechanism of β‐induced proliferation arrest and cell death and of the significance of its differential gene induction/repression profile in comparison to pulsed γ‐irradiation may lead to new insights into the ways in which ionizing radiation can interact with cells.—Marko, N. F., Dieffenbach, P. B., Yan, G., Ceryak, S., Howell, R. W., McCaffrey, T. A., Hu, V. W. Does metabolic radiolabeling stimulate the stress response? Gene expression profiling reveals differential cellular responses to internal beta vs. external gamma radiation. FASEB J. 17, 1470–1486 (2003)

Comparative effectiveness review of treatment options for pituitary microadenomas in acromegaly

OBJECT Acromegaly, a syndrome of excess growth hormone (GH) secretion typically caused by a GH-secreting pituitary adenoma, reduces life expectancy by approximately 10 years when left untreated. Treatment of acromegaly involves combinations of one or more discrete therapeutic modalities to achieve biochemical control. Unfortunately, data capable of informing decisions among alternate management strategies are presently lacking. METHODS The authors performed a comparative effectiveness research (CER) review integrating efficacy, cost, and quality of life (QOL) analysis for treatment strategies comprising various combinations of surgery, radiotherapy, stereotactic radiosurgery, and pharmacotherapy in patients with acromegaly caused by a pituitary microadenoma. A management decision tree was used to identify 5 treatment strategies, each with up to 4 potential treatment steps. Efficacy was assessed using recent literature reports of biochemical control rates for each modality. Cost estimations were derived from wholesale drug prices and from the Healthcare Cost and Utility Project. Quality of life data were obtained from studies utilizing the Acromegaly Quality of Life Questionnaire. RESULTS Individual treatment modalities were analyzed and ranked in each of 3 domains: highest rate of success, lowest cost, and highest QOL, and these scores were combined to facilitate comparison of overall effectiveness of each of the management strategies. These aggregate effectiveness scores were used to compare the 5 strategies from the decision tree, and a novel strategy was also proposed. CONCLUSIONS The choice of management strategy must be individualized for each patient with acromegaly. This CER analysis provides a comprehensive framework to inform clinical decisions among alternate management strategies in patients with GH-secreting pituitary microadenomas.

A Robust Method for the Amplification of RNA in the Sense Orientation

BackgroundSmall quantities of RNA (1–4 μg total RNA) available from biological samples frequently require a single round of amplification prior to analysis, but current amplification strategies have limitations that may restrict their usefulness in downstream genomic applications. The Eberwine amplification method has been extensively validated but is limited by its ability to produce only antisense RNA. Alternatives lack extensive validation and are often confounded by problems with bias or yield attributable to their greater biological and technical complexity.ResultsTo overcome these limitations, we have developed a straightforward and robust protocol for amplification of RNA in the sense orientation. This protocol is based upon Eberwines method but incorporates elements of more recent amplification techniques while avoiding their complexities. Our technique yields greater than 100-fold amplification, generates long transcript, and produces mRNA that is well suited for use with microarray applications. Microarrays performed with RNA amplified using this protocol demonstrate minimal amplification bias and high reproducibility.ConclusionThe protocol we describe here is readily adaptable for the production of sense or antisense, labeled or unlabeled RNA from intact or partially-degraded prokaryotic or eukaryotic total RNA. The method outperforms several commercial RNA amplification kits and can be used in conjunction with a variety of microarray platforms, such as cDNA arrays, oligonucleotide arrays, and Affymetrix GeneChip™ arrays.

Hyperosmolar Therapy for Intracranial Hypertension

The use of hyperosmolar agents for intracranial hypertension was introduced in the early 20th century and remains a mainstay of therapy for patients with cerebral edema. Both animal and human studies have demonstrated the efficacy of two hyperosmolar agents, mannitol and hypertonic saline, in reducing intracranial pressure via volume redistribution, plasma expansion, rheologic modifications, and anti-inflammatory effects. However, because of physician and institutional variation in therapeutic practices, lack of standardized protocols for initiation and administration of therapy, patient heterogeneity, and a paucity of randomized controlled trials have yielded little Class I evidence on which clinical decisions can be based, most current evidence regarding the use of hyperosmolar therapy is derived from retrospective analyses (Class III) and case series (Class IV). In this review, we summarize the available evidence regarding the use of hyperosmolar therapy with mannitol or hypertonic saline for the medical management of intracranial hypertension and present a comprehensive discussion of the evidence associated with various theoretical and practical concerns related to initiation, dosage, and monitoring of therapy.

Stereotactic radiosurgery as single-modality treatment of incidentally identified renal cell carcinoma brain metastases.

BACKGROUND Initial staging evaluation of patients with renal cell carcinoma (RCC) has led increasingly to the diagnosis of brain metastases in patients who are otherwise neurologically asymptomatic. We present our experience treating patients with incidentally identified brain metastases with initial stereotactic radiosurgery (SRS) monotherapy and compare outcomes with those of patients treated at our institution with other strategies and with those reported in the literature. METHODS We conducted a retrospective outcomes analysis in patients with incidentally identified RCC brain metastasis treated with initial SRS monotherapy. Our radiation oncology and tumor databases were reviewed, identifying 80 patients treated between 1990 and 2006. RESULTS We found 19 patients with asymptomatic, incidentally identified brain metastasis (KPS, 90-100) treated with SRS monotherapy within 60 days of diagnosis. Stereotactic radiosurgery was performed at a mean of 17.8 days from diagnosis to an average of 3.1 lesions (range, 3-11; mean lesion volume, 1.72 cm(3); mean total volume, 4.53 cm(3)). The mean prescription was 21.3 Gy delivered to the mean 59.97% isodose line. The mean survival for these patients was 21.5 months (median, 12.6 months) and was not statistically different from survival in similar patients treated with other therapeutic modalities. Local control was achieved in 95% of patients; distant central nervous system progression occurred in 79% of patients at a mean of 450 days. CONCLUSIONS We demonstrate that patients with incidentally identified RCC brain metastases treated with initial SRS monotherapy achieved a survival rate comparable with that of patients managed with standard therapeutic modalities. Our findings suggest that SRS alone is an attractive therapeutic option for patients with incidentally identified brain metastases from RCC.

Role of Gamma Knife surgery in patients with 5 or more brain metastases

OBJECT The authors evaluated overall survival and factors predicting outcome in patients with ≥ 5 brain metastases who were treated with Gamma Knife surgery (GKS). METHODS Medical records from patients with ≥ 5 brain metastases treated with GKS between 1997 and 2010 at the Cleveland Clinic Gamma Knife Center were retrospectively reviewed. Patient demographics, tumor characteristics, treatment-related factors, and outcome data were evaluated. RESULTS One hundred seventy patients were identified, with a median age of 58 years. The female/male ratio was 1.2:1. Gamma Knife surgery was used as an upfront treatment in 35% of patients and as salvage treatment in 65% of patients with multiple brain metastases. The median overall survival after GKS was 6.7 months (95% CI 5.5-8.1). At the time of GKS, 128 patients (75%) had concurrent extracranial metastases, and in 69 patients (41%) multiple extracranial sites were involved. Ninety-two patients (54%) had a history of whole-brain radiation therapy, and 158 patients (93%) had a Karnofsky Performance Scale (KPS) score ≥ 70. The median total intracranial disease volume was 3.2 cm(3) (range 0.2-37.2 cm(3)). A total intracranial tumor volume ≥ 10 cm(3) was observed in 32 patients (19%). Lower KPS score at the time of treatment (p < 0.0001), patient age > 60 years (p = 0.004), multiple extracranial metastases (p = 0.0001), and greater intracranial burden of disease (p = 0.03) were prognostic factors for poor outcome in the univariate and multivariate analyses. CONCLUSIONS In this study, GKS was safe and effective for upfront and salvage treatment in patients with ≥ 5 brain metastases. Gamma Knife surgery should be considered as an additional treatment modality for these patients, especially in the subset of patients with favorable prognostic factors.

Radiotherapy: Neurocognitive considerations in the treatment of brain metastases

The results of a randomized, controlled trial investigating the neurocognitive effects of stereotactic radiosurgery (SRS), with or without whole-brain radiation therapy (WBRT), to treat brain metastases demonstrated a significant reduction in learning and memory, associated with the addition of WBRT to SRS. the results indicate that SRS monotherapy is an effective and safe initial management strategy for brain metastases.