Mira A. Patel

Combination therapy with anti-PD-1, anti-TIM-3, and focal radiation results in regression of murine gliomas

Purpose: Checkpoint molecules like programmed death-1 (PD-1) and T-cell immunoglobulin mucin-3 (TIM-3) are negative immune regulators that may be upregulated in the setting of glioblastoma multiforme. Combined PD-1 blockade and stereotactic radiosurgery (SRS) have been shown to improve antitumor immunity and produce long-term survivors in a murine glioma model. However, tumor-infiltrating lymphocytes (TIL) can express multiple checkpoints, and expression of ≥2 checkpoints corresponds to a more exhausted T-cell phenotype. We investigate TIM-3 expression in a glioma model and the antitumor efficacy of TIM-3 blockade alone and in combination with anti-PD-1 and SRS. Experimental Design: C57BL/6 mice were implanted with murine glioma cell line GL261-luc2 and randomized into 8 treatment arms: (i) control, (ii) SRS, (iii) anti-PD-1 antibody, (iv) anti-TIM-3 antibody, (v) anti-PD-1 + SRS, (vi) anti-TIM-3 + SRS, (vii) anti-PD-1 + anti-TIM-3, and (viii) anti-PD-1 + anti-TIM-3 + SRS. Survival and immune activation were assessed. Results: Dual therapy with anti-TIM-3 antibody + SRS or anti-TIM-3 + anti-PD-1 improved survival compared with anti-TIM-3 antibody alone. Triple therapy resulted in 100% overall survival (P < 0.05), a significant improvement compared with other arms. Long-term survivors demonstrated increased immune cell infiltration and activity and immune memory. Finally, positive staining for TIM-3 was detected in 7 of 8 human GBM samples. Conclusions: This is the first preclinical investigation on the effects of dual PD-1 and TIM-3 blockade with radiation. We also demonstrate the presence of TIM-3 in human glioblastoma multiforme and provide preclinical evidence for a novel treatment combination that can potentially result in long-term glioma survival and constitutes a novel immunotherapeutic strategy for the treatment of glioblastoma multiforme. Clin Cancer Res; 23(1); 124–36. ©2016 AACR.

STAT3 Activation in Glioblastoma: Biochemical and Therapeutic Implications

Signal transducer and activator of transcription 3 (STAT3) is a potent regulator of gliomagenesis through its induction of angiogenesis, host immunosuppression, and tumor invasion. Gain of function mutations result in constitutive activation of STAT3 in glioma cells, making STAT3 an attractive target for inhibition in cancer therapy. Nevertheless, some studies show that STAT3 also participates in terminal differentiation and apoptosis of various cell lines and in glioma with phosphatase and tensin homolog (PTEN)-deficient genetic backgrounds. In light of these findings, the utility of STAT3 as a prognostic indicator and as a target of drug therapies will be contingent on a more nuanced understanding of its pro- and anti-tumorigenic effects.

The Future of Glioblastoma Therapy: Synergism of Standard of Care and Immunotherapy

The current standard of care for glioblastoma (GBM) is maximal surgical resection with adjuvant radiotherapy and temozolomide (TMZ). As the 5-year survival with GBM remains at a dismal <10%, novel therapies are needed. Immunotherapies such as the dendritic cell (DC) vaccine, heat shock protein vaccines, and epidermal growth factor receptor (EGFRvIII) vaccines have shown encouraging results in clinical trials, and have demonstrated synergistic effects with conventional therapeutics resulting in ongoing phase III trials. Chemoradiation has been shown to have synergistic effects when used in combination with immunotherapy. Cytotoxic ionizing radiation is known to trigger pro-inflammatory signaling cascades and immune activation secondary to cell death, which can then be exploited by immunotherapies. The future of GBM therapeutics will involve finding the place for immunotherapy in the current treatment regimen with a focus on developing strategies. Here, we review current GBM therapy and the evidence for combination of immune checkpoint inhibitors, DC and peptide vaccines with the current standard of care.

Pituitary adenomas: historical perspective, surgical management and future directions

Pituitary adenomas are among the most common central nervous system tumors. They represent a diverse group of neoplasms that may or may not secrete hormones based on their cell of origin. Epidemiologic studies have documented the incidence of pituitary adenomas within the general population to be as high as 16.7%. A growing body of work has helped to elucidate the pathogenesis of these tumors. Each subtype has been shown to demonstrate unique cellular changes potentially leading to tumorigenesis. Surgical advancements over several decades have included microsurgery and the employment of the endoscope for surgical resection. These advancements increase the likelihood of gross-total resection and have resulted in decreased patient morbidity.

Immune Checkpoint Modulators: An Emerging Antiglioma Armamentarium

Immune checkpoints have come to the forefront of cancer therapies as a powerful and promising strategy to stimulate antitumor T cell activity. Results from recent preclinical and clinical studies demonstrate how checkpoint inhibition can be utilized to prevent tumor immune evasion and both local and systemic immune suppression. This review encompasses the key immune checkpoints that have been found to play a role in tumorigenesis and, more specifically, gliomagenesis. The review will provide an overview of the existing preclinical and clinical data, antitumor efficacy, and clinical applications for each checkpoint with respect to GBM, as well as a summary of combination therapies with chemotherapy and radiation.

Clinical outcomes after ventriculoatrial shunting for idiopathic normal pressure hydrocephalus

INTRODUCTION Idiopathic normal pressure hydrocephalus (iNPH) is a neurological disorder that classically presents with a triad of progressive gait impairment, urinary incontinence, and cognitive deterioration. Treatment predominantly involves ventriculoperitoneal (VP) shunting, but one alternative is ventriculoatrial (VA) shunting. This study sought to describe and evaluate the clinical outcomes of patients with iNPH primarily treated with VA shunting. MATERIALS AND METHODS A retrospective review of patients with iNPH who were treated with VA shunting at a single institution, from 2003 to 2013, was performed. RESULTS 58 patients with iNPH underwent primary VA shunting at a median age of 74 (IQR: 70-80) years. The most common comorbidities included hypertension (n=39, 67%) and diabetes mellitus (n=11, 19%). Median duration of symptoms prior to VA shunting was 24 (IQR: 12-36) months. All patients had gait impairment, 52 (90%) had cognitive decline, and 43 (74%) had urinary incontinence. Forty-three (74%) patients had all three symptoms. At a median last follow-up of 16 (IQR: 7-26) months, median iNPH score improved from 6 to 3 (p<0.0001), mini mental status exam (MMSE) tended to increase from 26 to 29 (p=0.082), timed up-and-go (TUG) improved from 18 to 13s (p<0.0001), and Tinetti score improved from 19 to 25 (p<0.0001) after VA shunting. 78% of patients had improvement in at least one of their symptoms with 66% of patients having improvement in gait, 53% having improvement in their cognition, and 52% having improved urinary incontinence. A total of 21 patients (36%) had improvement in all 3 symptoms. CONCLUSIONS There were significant improvements in functional outcomes as evaluated via the iNPH score, TUG, and Tinetti score, while improvement in MMSE trended toward significance. Patients also had improvement of clinical symptoms related to gait, urinary function and cognition. These results suggest that VA shunting can be an effective primary treatment alternative to VP shunting for iNPH.

Concepts of immunotherapy for glioma.

Immunotherapy is coming to the fore as a viable anti-cancer treatment modality, even in poorly immunogenic cancers such as glioblastoma (GBM). Accumulating evidence suggests that the central nervous system may not be impervious to tumor-specific immune cells and could be an adequate substrate for immunologic anti-cancer therapies. Recent advances in antigen-specific cancer vaccines and checkpoint blockade in GBM provide promise for future immunotherapy in glioma. As anti-GBM immunotherapeutics enter clinical trials, it is important to understand the interactions, if any, between immune-based treatment modalities and the current standard of care for GBM involving chemoradiation and steroid therapy. Current data suggests that chemoradiation may not preclude the success of immunotherapeutics, as their effects may be synergistic. The future of therapy for GBM lies in the power of combination modalities, involving immunotherapy and the current standard of care.

Tobacco Smoke Exposure and Eustachian Tube Disorders in US Children and Adolescents

Objectives To describe the association between active, environmental tobacco smoke (ETS) exposure and the prevalence of eustachian tube dysfunction (ETD) in the U.S. pediatric population. Study Design Cross-sectional. Setting U.S. representative demographic and audiometric data from the National Health and Nutrition Examination Survey (NHANES);2005–2010. Subjects and Methods The study consisted of 2,977 children aged 12–19 years. ETD was defined as middle ear pressure <100mm H20. ETS was defined as non-active smoking in individuals with serum cotinine over the limit of detection (≥0.015 ng/mL) and <10 ng/mL(N = 1559). Results The prevalence of ETD was 6.1%. After multivariate adjustment for age, sex, body mass index, education level, ethnicity, or having a cold, sinus problem or earache during the last 24 hours, compared to unexposed children, the odds ratios (95% confidence interval) of ETD for those exposed to ETS ages 12–15 in the first, second and third tertile of cotinine concentrations were, respectively, 1.38 (0.53–3.60), 0.99 (0.53–3.60) and 2.67 (1.12–6.34). Similarly, the odds ratios (95% confidence interval) of ETD for those exposed to ETS ages 16–19 in the first, second and third tertile of cotinine concentrations were, respectively, 1.28 (0.48–3.41), 0.99 (0.40–2.48) and 2.86 (1.19–6.88). Conclusion These data suggest that children and adolescents exposed to high concentrations of ETS may have an increased prevalence of ETD.

Alzheimer’s disease pathology and shunt surgery outcome in normal pressure hydrocephalus

We aimed to determine whether presence of AD neuropathology predicted cognitive, gait and balance measures in patients with idiopathic normal pressure hydrocephalus (iNPH) after shunt surgery. This is a prospective study of gait and balance measured by Timed Up and Go (TUG) and Tinetti tests, and cognitive function measured by Mini Mental Status Exam (MMSE), before and after shunt surgery in participants 65 years and older with iNPH at the Johns Hopkins University. Random effects models were used and adjusted for confounders. 88 participants were included in the analysis with a median (IQR) time of 104 (57–213) days between surgery and follow-up. 23 (25%) participants had neuritic plaques present (NP+) and were significantly older [76.4 (6.0) years], but were otherwise similar in all demographics and outcome measures, when compared to the group without neuritic plaques (NP-). NP- and NP+ participants equally improved on measures of TUG (β = -3.27, 95% CI -6.24, -0.30, p = 0.03; β = -2.37, 95% CI -3.90, -0.86, p = 0.02, respectively), Tinetti-total (β = 1.95, 95% CI 1.11, 2.78, p<0.001; β = 1.72, 95% CI 0.90, 2.53, p<0.001, respectively), -balance (β = 0.81, 95% CI 0.23, 1.38, p = 0.006; β = 0.87, 95% CI 0.40, 1.34, p<0.001, respectively) and -gait (β = 1.03, 95% CI 0.61, 1.45, p<0.001; β = 0.84, 95% CI 0.16, 1.53, p = 0.02, respectively), while neither NP- nor NP+ showed significant improvement on MMSE (β = 0.10, 95% CI -0.27, 0.46, p = 0.61, β = 0.41, 95% CI -0.27, 1.09, p = 0.24, respectively). In summary, 26% of participants with iNPH had coexisting AD pathology, which does not significantly influence the clinical response to shunt surgery.

Arterial fenestrations and their association with cerebral aneurysms

Fenestrations of intracranial arteries and associated aneurysms are rare. The significance of these fenestrations in relation to aneurysms remains unclear. We present four patients with fenestration-associated aneurysms and a comprehensive review of associations with aneurysms and other vascular lesions. A PubMed search of the literature was conducted from 1970-2012 reporting cases of intracranial aneurysms associated with arterial fenestration or duplications. Data were collected on patient presentation, sex, age, aneurysm and fenestration location, aneurysm treatment, and presence of other vascular lesions. We performed a retrospective review of four patients with intracranial fenestrations associated with aneurysms at our institution from 2012-2013. There were 59 cases of fenestrations and associated aneurysms in the literature. Aneurysms were reported as either arising from (n=50) or adjacent to but distinct from (n=13) fenestrations. The most common single fenestration location was at the basilar artery (n=23, 36.5%); however the majority of fenestrations were in the carotid circulation (n=34, 54.0%). The majority of patients with aneurysms and fenestrations at all locations except those at the anterior communicating artery (70.5%) presented with subarachnoid hemorrhage. Patients with aneurysms arising from a fenestration or adjacent to a fenestration presented with an additional intracranial vascular lesion in 38% and 31% of cases, respectively. The majority of all aneurysms were treated with microsurgical clipping. Aneurysms associated with cerebral arterial fenestrations are most commonly discovered after subarachnoid hemorrhage and are most often located in the carotid circulation. A high index of suspicion must be maintained for an associated vascular lesion if an intracranial fenestration is discovered.