Jobin K. Varughese

Conservative Management of Vestibular Schwannoma—A Prospective Cohort Study: Treatment, Symptoms, and Quality of Life

BACKGROUND One hundred ninety-three patients with sporadic unilateral vestibular schwannoma given conservative management were enrolled in a prospective study. OBJECTIVE To evaluate the efficacy of conservative management and to determine the effect of an initial conservative management on the quality of life (QOL) and severity of audio vestibular symptoms. METHODS The patients underwent magnetic resonance imaging scans, clinical examination, and QOL assessment by 2 validated questionnaires, the Short Form-36 (SF-36) and Glasgow Benefit Inventory (GBI). Using regression analysis of clustered data, we analyzed possible associations between tumor growth and symptoms and tested whether our earlier finding that vertigo is associated with reduced QOL could be verified. RESULTS The median follow-up time was 43 months (range, 9-115 months; SD, 21.48 months). Results are based on 703 clinical controls and 642 (SF-36) and 638 (GBI) questionnaires. Seven patients were lost to follow-up. Approximately 40% of patients were in need of treatment during follow-up. We found a statistically significant association between tinnitus and vertigo and tumor growth. Vertigo was found to significantly reduce QOL. There was a significant drop in the Social Function subscales of both SF-36 and GBI, possibly attributable to progressive hearing loss. Otherwise, there was no overall trend toward any change in QOL during the observation period. In addition, QOL seemed to be little affected by treatment. CONCLUSION There was a small but statistically significant improvement in vestibular complaints and no change in the occurrence of tinnitus. Except for hearing loss caused by surgery, treatment did not affect symptoms or QOL significantly. Growth was associated with the occurrence of tinnitus and balance problems.

Conservative management or gamma knife radiosurgery for vestibular schwannoma: tumor growth, symptoms, and quality of life.

BACKGROUND There are few reports about the course of vestibular schwannoma (VS) patients following gamma knife radiosurgery (GKRS) compared with the course following conservative management (CM). In this study, we present prospectively collected data of 237 patients with unilateral VS extending outside the internal acoustic canal who received either GKRS (113) or CM (124). OBJECTIVE The aim was to measure the effect of GKRS compared with the natural course on tumor growth rate and hearing loss. Secondary end points were postinclusion additional treatment, quality of life (QoL), and symptom development. METHODS The patients underwent magnetic resonance imaging scans, clinical examination, and QoL assessment by SF-36 questionnaire. Statistics were performed by using Spearman correlation coefficient, Kaplan-Meier plot, Poisson regression model, mixed linear regression models, and mixed logistic regression models. RESULTS Mean follow-up time was 55.0 months (26.1 standard deviation, range 10-132). Thirteen patients were lost to follow-up. Serviceable hearing was lost in 54 of 71 (76%) (CM) and 34 of 53 (64%) (GKRS) patients during the study period (not significant, log-rank test). There was a significant reduction in tumor volume over time in the GKRS group. The need for treatment following initial GKRS or CM differed at highly significant levels (log-rank test, P < .001). Symptom and QoL development did not differ significantly between the groups. CONCLUSION In VS patients, GKRS reduces the tumor growth rate and thereby the incidence rate of new treatment about tenfold. Hearing is lost at similar rates in both groups. Symptoms and QoL seem not to be significantly affected by GKRS.

Growth of untreated vestibular schwannoma: a prospective study.

OBJECT Small vestibular schwannomas (VSs) are often conservatively managed and treated only upon growth. Growth is usually reported in mm/year, but describing the growth of a 3D structure by a single diameter has been questioned. As a result, VS growth dynamics should be further investigated. In addition, baseline clinical parameters that could predict growth would be helpful. In this prospective study the authors aimed to describe growth dynamics in a cohort of conservatively managed VSs. They also compared different growth models and evaluated the ability of baseline parameters to predict future growth. METHODS Between 2000 and 2006, 178 consecutive patients with unilateral de novo small-sized VSs identified among the Norwegian population of 4.8 million persons were referred to a tertiary care center and were included in a study protocol of conservative management. Tumor size was defined by MR imaging-based volume estimates and was recorded along with clinical data at regular visits. Mixed-effects models were used to analyze the relationships between observations. Three growth models were compared using statistical diagnostic tests: a mm/year-based model, a cm(3)/year-based model, and a volume doubling time (VDT)-based model. A receiver operating characteristic curve analysis was used to determine a cutoff for the VDT-based model for distinguishing growing and nongrowing tumors. RESULTS A mean growth rate corresponding to a VDT of 4.40 years (95% CI 3.49-5.95) was found. Other growth models in this study revealed mean growth rates of 0.66 mm/year (95% CI 0.47-0.86) and 0.19 cm(3)/year (95% CI 0.12-0.26). Volume doubling time was found to be the most realistic growth model. All baseline variables had p values > 0.09 for predicting growth. CONCLUSIONS Based on the actual measurements, VDT was the most correct way to describe VS growth. The authors found that a cutoff of 5.22 years provided the best value to distinguish growing from nongrowing tumors. None of the investigated baseline predictors were usable as predictors of growth.

Analysis of vestibular schwannoma size in multiple dimensions: a comparative cohort study of different measurement techniques

Clin. Otolaryngol. 2010, 35, 97–103

Gamma Knife Treatment of Growing Vestibular Schwannoma in Norway: A Prospective Study

PURPOSE Gamma Knife radiosurgery (GKRS) has been increasingly used in the treatment of vestibular schwannoma (VS). Very few studies relate tumor control and post-treatment growth rates to pretreatment growth rates. METHODS AND MATERIALS We prospectively included 45 consecutive VS patients who were initially treated conservatively and then received GKRS between 2000 and 2007 because of demonstrated tumor growth. Pretreatment and post-treatment tumor volumes were estimated. Patients underwent audiograms, reported their symptoms, and responded to the Short Form General Health Survey (SF-36) questionnaire on each visit. RESULTS Volume doubling times before and after treatment were 1.36 years (95% confidence intervals, 1.14-1.68) and -13.1 years (95% confidence intervals, -111.0 to -6.94), respectively. Tumor control, defined as a post-GKRS growth rate ≤ 0, was achieved in 71.1% of patients, with highest odds for tumor control among older patients and those with larger tumors. The 5-year retreatment-free survival rate was 93.9% (95% confidence intervals, 76.5-98.5). None of the clinical endpoints investigated showed statistically significant changes after GKRS, but improvement was seen in a few SF-36 parameters. CONCLUSIONS GKRS alters the natural course of the tumor by reducing growth. Mathematic models yield poorer tumor control rates than those found by clinical assessment. Symptoms were unaffected by treatment, but quality of life was improved.

In Vitro Treatment of Melanoma Brain Metastasis by Simultaneously Targeting the MAPK and PI3K Signaling Pathways

Malignant melanoma is the most lethal form of skin cancer, with a high propensity to metastasize to the brain. More than 60% of melanomas have the BRAFV600E mutation, which activates the mitogen-activated protein kinase (MAPK) pathway [1]. In addition, increased PI3K (phosphoinositide 3-kinase) pathway activity has been demonstrated, through the loss of activity of the tumor suppressor gene, PTEN [2]. Here, we treated two melanoma brain metastasis cell lines, H1_DL2, harboring a BRAFV600E mutation and PTEN loss, and H3, harboring WT (wild-type) BRAF and PTEN loss, with the MAPK (BRAF) inhibitor vemurafenib and the PI3K pathway associated mTOR inhibitor temsirolimus. Combined use of the drugs inhibited tumor cell growth and proliferation in vitro in H1_DL2 cells, compared to single drug treatment. Treatment was less effective in the H3 cells. Furthermore, a strong inhibitory effect on the viability of H1_DL2 cells, when grown as 3D multicellular spheroids, was seen. The treatment inhibited the expression of pERK1/2 and reduced the expression of pAKT and p-mTOR in H1_DL2 cells, confirming that the MAPK and PI3K pathways were inhibited after drug treatment. Microarray experiments followed by principal component analysis (PCA) mapping showed distinct gene clustering after treatment, and cell cycle checkpoint regulators were affected. Global gene analysis indicated that functions related to cell survival and invasion were influenced by combined treatment. In conclusion, we demonstrate for the first time that combined therapy with vemurafenib and temsirolimus is effective on melanoma brain metastasis cells in vitro. The presented results highlight the potential of combined treatment to overcome treatment resistance that may develop after vemurafenib treatment of melanomas.

Thioridazine inhibits autophagy and sensitizes glioblastoma cells to temozolomide: Thioridazine blocks autophagy in glioblastoma cells

Glioblastoma multiforme (GBM) has a poor prognosis with an overall survival of 14–15 months after surgery, radiation and chemotherapy using temozolomide (TMZ). A major problem is that the tumors acquire resistance to therapy. In an effort to improve the therapeutic efficacy of TMZ, we performed a genome‐wide RNA interference (RNAi) synthetic lethality screen to establish a functional gene signature for TMZ sensitivity in human GBM cells. We then queried the Connectivity Map database to search for drugs that would induce corresponding changes in gene expression. By this approach we identified several potential pharmacological sensitizers to TMZ, where the most potent drug was the established antipsychotic agent Thioridazine, which significantly improved TMZ sensitivity while not demonstrating any significant toxicity alone. Mechanistically, we show that the specific chemosensitizing effect of Thioridazine is mediated by impairing autophagy, thereby preventing adaptive metabolic alterations associated with TMZ resistance. Moreover, we demonstrate that Thioridazine inhibits late‐stage autophagy by impairing fusion between autophagosomes and lysosomes. Finally, Thioridazine in combination with TMZ significantly inhibits brain tumor growth in vivo, demonstrating the potential clinical benefits of compounds targeting the autophagy‐lysosome pathway. Our study emphasizes the feasibility of exploiting drug repurposing for the design of novel therapeutic strategies for GBM.

Abstract 4036: Drug repurposing to treat melanoma brain metastases

Despite recent therapeutic advances in the management of patients with metastatic melanoma, brain metastases remain an intractable problem. It has proven difficult to identify and target single genes or pathways critical to brain metastasis formation. In this work we set out to explore a more global and preventive treatment approach to melanoma brain metastases within an established xenograft model of human melanoma. Mice were injected intracardially under ultrasound guidance and followed for six weeks with whole-body BLI and brain MRI. Tumor-bearing brains, adrenals, ovaries, and femurs were harvested and enzymatically dissociated before three tumor cell samples from each organ were flow-sorted and subjected to RNA sequencing. We developed a combined workflow of several independent computational and statistical analyses based on differential expression, and defined a brain metastasis gene signature of 54 upregulated and 54 downregulated genes. We then queried the Connectivity Map database using our 108-gene signature for candidate drugs, i.e. drugs that induce an opposite gene expression profile in various cancer cell lines. Three of the top ten drugs, already in use for other clinical conditions, showed significant efficacy in monolayer proliferation assays and colony forming assays with two brain-tropic melanoma cell lines and one brain-tropic lung cancer cell line. To examine these results in vivo, we used a highly standardized and predictive model system with automated MRI-based quantification of nanoparticle-labeled cells in the mouse brain following intracardiac injection of human melanoma cells. Treatment was started shortly after verification of comparable tumor cell exposure in the mouse brains and animals were monitored with whole-body BLI and brain MRI. Preliminary results showed promising therapeutic effects with respect to brain metastatic burden and survival, as well as acceptable toxicity profiles. We are currently validating these results on a larger scale in vivo, in other models, as well as applying systems biology and network modeling approaches to explore the fundamental mechanisms of action. Together, our results demonstrate a previously unrecognized potential for drug repurposing in the treatment of patients at risk of developing melanoma brain metastases or with clinically occult micrometastatic disease. Finding new uses for old drugs can greatly expedite translation to clinical practice; thus, further investigations are warranted to determine the safety, tolerability, and efficacy of these therapies. Citation Format: Terje Sundstrom, Jobin K. Varughese, Francisco Azuaje, Kjell Petersen, Clifford G. Tepper, Elizabeth Ingham, Lisa Even, Sarah Tam, Kai Ove Skaftnesmo, Morten Lund-Johansen, Rolf Bjerkvig, Katherine W. Ferrara, Frits A. Thorsen. Drug repurposing to treat melanoma brain metastases. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4036. doi:10.1158/1538-7445.AM2014-4036