John L. Villano

Epidemiologic and Molecular Prognostic Review of Glioblastoma

Glioblastoma multiforme (GBM) is the most common and aggressive primary central nervous system malignancy with a median survival of 15 months. The average incidence rate of GBM is 3.19/100,000 population, and the median age of diagnosis is 64 years. Incidence is higher in men and individuals of white race and non-Hispanic ethnicity. Many genetic and environmental factors have been studied in GBM, but the majority are sporadic, and no risk factor accounting for a large proportion of GBMs has been identified. However, several favorable clinical prognostic factors are identified, including younger age at diagnosis, cerebellar location, high performance status, and maximal tumor resection. GBMs comprise of primary and secondary subtypes, which evolve through different genetic pathways, affect patients at different ages, and have differences in outcomes. We report the current epidemiology of GBM with new data from the Central Brain Tumor Registry of the United States 2006 to 2010 as well as demonstrate and discuss trends in incidence and survival. We also provide a concise review on molecular markers in GBM that have helped distinguish biologically similar subtypes of GBM and have prognostic and predictive value. Cancer Epidemiol Biomarkers Prev; 23(10); 1985–96. ©2014 AACR.

Age, gender, and racial differences in incidence and survival in primary CNS lymphoma

Background:Primary central nervous system lymphoma (PCNSL) is a rare subtype of extranodal non-Hodgkin lymphoma that accounts for ∼4% of newly diagnosed central nervous system (CNS) tumours. The objective of this study was to analyse the epidemiology, incidence, and outcome of these rare tumours.Methods:Primary brain and CNS lymphoma cases were identified from the Surveillance, Epidemiology, and End Results (SEER) research data sets for the years 1980–2008 for analysis of trends in incidence and survival. SEER*Stat v. 7.0.4 software was used to analyse the data.Results:The overall incidence rate of PCNSL was 0.47 per 100 000 person-years. The incidence was significantly higher in males compared with females, blacks aged 0–49 years at diagnosis compared with whites, and whites aged 50 years and older at diagnosis compared with blacks. After a significant decline in incidence between 1995 and 1999, incidence rates rose slightly; those aged 75+ years at diagnosis had the most dramatic increase in incidence rates over time. Five-year survival rates were significantly higher in whites compared with blacks aged 0–49 years at diagnosis, but was primarily driven by white women aged 0–49 years.Conclusion:There is an increase in incidence of PCNSL in the elderly, and elderly blacks have lower incidence compared with white population. Survival remains poor and is negatively dominated by factors associated with HIV infection and advanced age.

Toward determining the lifetime occurrence of metastatic brain tumors estimated from 2007 United States cancer incidence data

Few population estimates of brain metastasis in the United States are available, prompting this study. Our objective was to estimate the expected number of metastatic brain tumors that would subsequently develop among incident cancer cases for 1 diagnosis year in the United States. Incidence proportions for primary cancer sites known to develop brain metastasis were applied to United States cancer incidence data for 2007 that were retrieved from accessible data sets through Centers for Disease Control and Prevention (CDC Wonder) and Surveillance, Epidemiology, and End Results (SEER) Program Web sites. Incidence proportions were identified for cancer sites, reflecting 80% of all cancers. It was conservatively estimated that almost 70 000 new brain metastases would occur over the remaining lifetime of individuals who received a diagnosis in 2007 of primary invasive cancer in the United States. That is, 6% of newly diagnosed cases of cancer during 2007 would be expected to develop brain metastasis as a progression of their original cancer diagnosis; the most frequent sites for metastases being lung and bronchus and breast cancers. The estimated numbers of brain metastasis will be expected to be higher among white individuals, female individuals, and older age groups. Changing patterns in the occurrence of primary cancers, trends in populations at risk, effectiveness of treatments on survival, and access to those treatments will influence the extent of brain tumor metastasis at the population level. These findings provide insight on the patterns of brain tumor metastasis and the future burden of this condition in the United States.

Clinical Practice Experience With NovoTTF-100A™ System for Glioblastoma: The Patient Registry Dataset (PRiDe)

Recurrent glioblastoma multiforme (GBM) is a highly aggressive cancer with poor prognosis, and an overall survival of 6 to 7 months with optimal therapies. The NovoTTF-100A™ System is a novel antimitotic cancer therapy recently approved for the treatment of recurrent GBM, based on phase III (EF-11) trial results. The Patient Registry Dataset (PRiDe) is a post-marketing registry of all recurrent GBM patients who received NovoTTF Therapy in a real-world, clinical practice setting in the United States between 2011 and 2013. Data were collected from all adult patients with recurrent GBM who began commercial NovoTTF Therapy in the United States between October 2011 and November 2013. All patients provided written consent before treatment was started. Overall survival (OS) curves were constructed for PRiDe using the Kaplan-Meier method. Median OS in PRiDe was compared for patients stratified by average daily compliance (≥75% v<75% per day) and other prognostic variables. Adverse events were also evaluated. Data from 457 recurrent GBM patients who received NovoTTF Therapy in 91 US cancer centers were analyzed. More patients in PRiDe than the EF-11 trial received NovoTTF Therapy for first recurrence (33% v 9%) and had received prior bevacizumab therapy (55.1% v 19%). Median OS was significantly longer with NovoTTF Therapy in clinical practice (PRiDe data set) than in the EF-11 trial (9.6 v 6.6 months; HR, 0.66; 95% CI, 0.05 to 0.86, P = .0003). One- and 2-year OS rates were more than double for NovoTTF Therapy patients in PRiDe than in the EF-11 trial (1-year: 44% v 20%; 2-year: 30% v 9%). First and second versus third and subsequent recurrences, high Karnofsky performance status (KPS), and no prior bevacizumab use were favorable prognostic factors. No unexpected adverse events were detected in PRiDe. As in the EF-11 trial, the most frequent adverse events were mild to moderate skin reactions associated with application of the NovoTTF Therapy transducer arrays. Results from PRiDe, together with those previously reported in the EF-11 trial, indicate that NovoTTF Therapy offers clinical benefit to patients with recurrent GBM. NovoTTF Therapy has high patient tolerability and favorable safety profile in the real-world, clinical practice setting.

Quantitative Sodium MR Imaging and Sodium Bioscales for the Management of Brain Tumors

Treatment of high-grade primary brain tumors is based on experience from multicenter trials. However, the prognosis has changed little in 3 decades. This suggests that there is a fundamental oversight in treatment. This article provides an imaging perspective of how regional responses of primary brain tumors may be examined to guide a flexible treatment plan. Sodium imaging provides a measurement of cell density that can be used to measure regional cell kill. Such a bioscales of regionally and temporally sensitive biologic-based parameters may be helpful to guide tumor treatment. These suggestions are speculative and still being examined, but are presented to challenge the medical community to be receptive to changes in the standard of care when that standard continues to fail.

Characterization and Management of Dermatologic Adverse Events With the NovoTTF-100A System, a Novel Anti-mitotic Electric Field Device for the Treatment of Recurrent Glioblastoma

The NovoTTF-100A System (NovoTTF™ Therapy, Novocure Inc.) is a device that delivers alternating electric fields (TTFields) to tumor cells and interferes with mitosis. It is approved for use as monotherapy for the treatment of recurrent glioblastoma (rGB). TTFields are delivered through insulated transducer arrays applied onto the shaved scalp and connected to a battery-operated field generator. The occurrence of dermatologic adverse events (dAEs) is primarily due to the continuous contact between the array-related components and the scalp for periods of 3-4 days (together with other risk factors). These dAEs may include allergic and irritant dermatitis, mechanical lesions, ulcers, and skin infection. The incidence of dAEs in the phase III trial (n = 116) was 16% (2% grade 2, 0% grade 3/4); the post-marketing surveillance program (n = 570) revealed 156 (21.8%) dAEs with some patients reporting more than one event. Prophylactic strategies for dAEs include proper shaving and cleansing of the scalp and array relocation. Treatment-based strategies are AE-specific and include topical or oral antibiotics, topical corticosteroids, and isolation of affected skin areas from adhesives and pressure. The addition of skin care strategies to the NovoTTF-100A System use will maximize adherence to therapy while maintaining quality of life, all of which contribute to the therapeutic benefit of NovoTTF Therapy in rGB.

Response assessment of novoTTF-100A versus best physician’s choice chemotherapy in recurrent glioblastoma.

The NovoTTF‐100A device emits frequency‐tuned alternating electric fields that interfere with tumor cell mitosis. In phase III trial for recurrent glioblastomas, NovoTTF‐100A was shown to have equivalent efficacy and less toxicity when compared to Best Physicians Choice (BPC) chemotherapy. We analyzed the characteristics of responders and nonresponders in both cohorts to determine the characteristics of response and potential predictive factors. Tumor response and progression were determined by Macdonald criteria. Time to response, response duration, progression‐free survival (PFS) ± Simon–Makuch correction, overall survival (OS), prognostic factors, and relative hazard rates were compared between responders and nonresponders. Median response duration was 7.3 versus 5.6 months for NovoTTF‐100A and BPC chemotherapy, respectively (P = 0.0009). Five of 14 NovoTTF‐100A responders but none of seven BPC responders had prior low‐grade histology. Mean cumulative dexamethasone dose was 35.9 mg for responders versus 485.6 mg for nonresponders in the NovoTTF‐100A cohort (P < 0.0001). Hazard analysis showed delayed tumor progression in responders compared to nonresponders. Simon–Makuch‐adjusted PFS was longer in responders than in nonresponders treated with NovoTTF‐100A (P = 0.0007) or BPC chemotherapy (P = 0.0222). Median OS was longer for responders than nonresponders treated with NovoTTF‐100A (P < 0.0001) and BPC chemotherapy (P = 0.0235). Pearson analysis showed strong correlation between response and OS in NovoTTF‐100A (P = 0.0002) but not in BPC cohort (P = 0.2900). Our results indicate that the response characteristics favor NovoTTF‐100A and data on prior low‐grade histology and dexamethasone suggest potential genetic and epigenetic determinants of NovoTTF‐100A response.

Defined Populations of Bone Marrow Derived Mesenchymal Stem and Endothelial Progenitor Cells for Bladder Regeneration

PURPOSE Autologous sources of bone marrow mesenchymal stem cells and endothelial progenitor cells are attractive alternatives to cells currently used for bladder tissue regeneration. To evaluate the potential use of these cells we determined whether mesenchymal stem cells have contractile protein profiles and physiological functions similar to those of normal bladder smooth muscle cells, and determined the angiogenic potential of endothelial progenitor cells. MATERIALS AND METHODS Mesenchymal stem cells and smooth muscle cells (Lonza, Gaithersburg, Maryland) underwent proliferation and Western blot analyses. Immunofluorescence imaging was performed using antibodies against smooth muscle cell epitopes. Contractility was assessed by intracellular Ca(2+) release assays and confocal microscopy after carbachol stimulation. Endothelial progenitor cells were evaluated using a chicken chorioallantoic membrane model to determine neo-angiogenic potential. RESULTS Western blot and immunofluorescence data showed that mesenchymal stem cells endogenously expressed known smooth muscle cell contractile proteins at levels similar to those of smooth muscle cells. Ca(2+) release assays revealed that smooth muscle cells and mesenchymal stem cells responded to carbachol treatment with a mean +/- SD of 8.6 +/- 2.5 and 5.8 +/- 0.8 RFU, respectively, which was statistically indistinguishable. Proliferation trends of mesenchymal stem cells and control smooth muscle cells were also similar. Chorioallantoic membrane assay showed the growth of vasculature derived from endothelial progenitor cells. CONCLUSIONS Data demonstrate that mesenchymal stem cells and smooth muscle cells express the same contractile proteins and can function similarly in vitro. Endothelial progenitor cells also have the ability to form vasculature in an in vivo chorioallantoic membrane model. These findings provide evidence that mesenchymal stem cells and endothelial progenitor cells have characteristics that may be applicable for bladder tissue regeneration.

Epidemiology of meningiomas post‐Public Law 107‐206: The Benign Brain Tumor Cancer Registries Amendment Act

The current analysis follows the implementation of Public Law 107‐260, the Benign Brain Tumor Cancer Registries Amendment Act, which mandated the collection of nonmalignant brain tumors.

Post Hoc analyses of intention-to-treat population in phase III comparison of NovoTTF-100A™ system versus best physician's choice chemotherapy.

We performed a treatment-based analysis of data from the pivotal phase III trial of the NovoTTF-100A System™ versus best physicians choice (BPC) chemotherapy in patients with recurrent glioblastoma multiforme (GBM), with particular focus on efficacy in patients using NovoTTF Therapy as intended. Median overall survival (OS) was compared for recurrent GBM patients receiving at least one full cycle of treatment with NovoTTF-100A System or BPC chemotherapy (modified intention-to-treat [mITT] population) in the recently reported phase III trial. The relationship between NovoTTF-100A System compliance and OS was evaluated in the ITT population. Kaplan-Meier analyses examined treatment-related differences in OS for various patient subgroups. Median OS was significantly higher in patients receiving≥1 course of NovoTTF Therapy versus BPC (7.7 v 5.9 months; hazard ratio, 0.69; 95% confidence interval [CI], 0.52-0.91; P = .0093). Median OS was also significantly higher in patients receiving NovoTTF Therapy with a maximal monthly compliance rate≥75% (≥18 hours daily) versus those with a<75% compliance rate (7.7 v 4.5 months; P = .042), and Kaplan-Meier analysis demonstrated a significant trend for improved median OS with higher compliance (P = .039). Additional post hoc analysis showed significantly higher median OS with NovoTTF Therapy than with BPC for patients with prior low-grade glioma, tumor size≥18 cm(2), Karnofsky performance status≥80, and those who had previously failed bevacizumab therapy. When used as intended in mITT patients with recurrent GBM, NovoTTF Therapy provides an OS benefit compared with chemotherapy in patients with recurrent GBM. This contrasts with the equivalent efficacy reported previously based on analysis of all randomized ITT subjects, including many who did not receive a full cycle of treatment. Higher NovoTTF Therapy compliance corresponds with greater survival benefit in the present study.