Ariel E. Marciscano

LAG3 (CD223) as a cancer immunotherapy target

Despite the impressive impact of CTLA4 and PD1‐PDL1‐targeted cancer immunotherapy, a large proportion of patients with many tumor types fail to respond. Consequently, the focus has shifted to targeting alternative inhibitory receptors (IRs) and suppressive mechanisms within the tumor microenvironment. Lymphocyte activation gene‐3 (LAG3) (CD223) is the third IR to be targeted in the clinic, consequently garnering considerable interest and scrutiny. LAG3 upregulation is required to control overt activation and prevent the onset of autoimmunity. However, persistent antigen exposure in the tumor microenvironment results in sustained LAG3 expression, contributing to a state of exhaustion manifest in impaired proliferation and cytokine production. The exact signaling mechanisms downstream of LAG3 and interplay with other IRs remain largely unknown. However, the striking synergy between LAG3 and PD1 observed in multiple settings, coupled with the contrasting intracellular cytoplasmic domain of LAG3 as compared with other IRs, highlights the potential uniqueness of LAG3. There are now four LAG3‐targeted therapies in the clinic with many more in preclinical development, emphasizing the broad interest in this IR. Given the translational relevance of LAG3 and the heightened interest in the impact of dual LAG3/PD1 targeting in the clinic, the outcome of these trials could serve as a nexus; significantly increasing or dampening enthusiasm for subsequent targets in the cancer immunotherapeutic pipeline.

Stereotactic body radiation therapy in pancreatic cancer: the new frontier.

Pancreatic cancer (PCA) remains a disease with a poor prognosis. The majority of PCA patients are unable to undergo surgical resection, which is the only potentially curative option at this time. A combination of chemotherapy and chemoradiation (CRT) are standard options for patients with locally advanced, unresectable disease, however, local control and patient outcomes remains poor. Stereotactic body radiation therapy (SBRT) is an emerging treatment option for PCA. SBRT delivers potentially ablative doses to the pancreatic tumor plus a small margin over a short period of time. Early studies with single-fraction SBRT demonstrated excellent tumor control with high rates of toxicity. The implementation of SBRT (3–5 doses) has demonstrated promising outcomes with favorable tumor control and toxicity rates. Herein we discuss the evolving role of SBRT in PCA treatment.

Benign meningiomas (WHO Grade I) with atypical histological features: correlation of histopathological features with clinical outcomes

OBJECT World Health Organization (WHO) Grade I (benign) meningiomas with atypical features may behave more aggressively than similarly graded tumors without atypical features. Here, the prognostic significance of atypical features in benign meningiomas was determined. METHODS Data from patients diagnosed with WHO Grade I benign meningiomas per the 2007 WHO criteria and who underwent surgery between 2002 and 2012 were retrospectively reviewed. Patients were stratified by the absence or presence of 1 to 2 atypical features with review of the clinical and histological factors. RESULTS A total of 148 patients met the inclusion criteria (n = 77 with atypia; n = 71 without atypia). The median follow-up duration after pathological diagnosis was 37.5 months. Thirty patients had progression/recurrence (P/R) after initial treatment, and 22 (73%) of 30 patients with P/R had 1-2 atypical features. The presence of atypical features was significantly associated with P/R (p = 0.03) and independent of the MIB-1 labeling index. The 1-year and 5-year actuarial rates of P/R were 9.6% versus 1.4% and 30.8% versus 13.8% fortumors with and without atypical features, respectively. Higher Simpson grade resection (II-IV vs I) was associated with the increased risk of P/R (p < 0.001). Stratification of patients into low-risk (Simpson Grade I), intermediate-risk (Simpson Grade II-IV with no atypical features), and high-risk groups (Simpson Grade II-IV with atypical features) was significantly correlated with increased risk of P/R (p < 0.001). CONCLUSIONS Patients with benign meningiomas with atypical features and those undergoing Simpson Grade II-IV resection are at significantly increased risk of P/R. Patients with these features may benefit from the consideration of additional surgery and/or radiation therapy.

Antiangiogenic Therapies and Extracranial Metastasis in Glioblastoma: A Case Report and Review of the Literature

We present a case report of a patient with glioblastoma multiforme (GBM) complicated by extracranial metastasis (ECM) whose survival of nearly four years surpassed the anticipated life expectancy given numerous negative prognostic factors including EGFRvIII-mutation, unmethylated MGMT promoter status, and ECM. Interestingly, while this patient suffered from locally aggressive disease with multiple intracranial recurrences, the proximal cause of death was progressive extracranial disease and complications related to pulmonary metastases. Herein, we review potential mechanisms of ECM with an emphasis upon glioblastoma molecular and genetic profiles and the potential implications of targeted agents such as bevacizumab.

Incorporating Radiation Oncology into Immunotherapy: Proceedings from the ASTRO-SITC-NCI immunotherapy workshop

Radiotherapy (RT) has been a fundamental component of the anti-cancer armamentarium for over a century. Approximately half of all cancer patients are treated with radiotherapy during their disease course. Over the two past decades, there has been a growing body of preclinical evidence supporting the immunomodulatory effects of radiotherapy, particularly when combined with immunotherapy, but only anecdotal clinical examples existed until recently. The renaissance of immunotherapy and the recent U.S. Food and Drug Administration (FDA) approval of several immune checkpoint inhibitors (ICIs) and other immuno-oncology (IO) agents in multiple cancers provides the opportunity to investigate how localized radiotherapy can induce systemic immune responses. Early clinical experiences have demonstrated feasibility of this approach but additional preclinical and clinical investigation is needed to understand how RT and immunotherapy can be optimally combined.To address questions that are critical to successful incorporation of radiation oncology into immunotherapy, the American Society for Radiation Oncology (ASTRO), the Society for Immunotherapy of Cancer (SITC) and the National Cancer Institute (NCI) organized a collaborative scientific workshop, Incorporating Radiation Oncology into Immunotherapy, that convened on June 15 and 16 of 2017 at the Natcher Building, NIH Campus in Bethesda, Maryland. This report summarizes key data and highlights from each session.

Long-term Treatment Response and Patient Outcomes for Vestibular Schwannoma Patients Treated with Hypofractionated Stereotactic Radiotherapy

Purpose The aim of this study is to evaluate long-term treatment outcome and toxicities among vestibular schwannoma (VS) patients treated with hypofractionated stereotactic radiotherapy (HSRT). Methods 383 patients with unilateral VS treated with HSRT (25 Gy, five fractions) between 1995 and 2007 were retrospectively reviewed. Treatment failure was defined as requiring salvage microsurgery. Posttreatment new/progressive clinical symptoms or increases in baseline tumor volume (BTV) due to treatment effect or progression were noted. Symptom outcomes were reported as baseline and posttreatment ± improvement, respectively. Symptoms were grouped by cranial nerve (CN) VII or CNVIII. Audiometry was assessed baseline and posttreatment hearing. Patients were grouped as having greater than serviceable hearing [Gardner Robertson (GR) score 1–2] or less than non-serviceable hearing (GR score 3–5) by audiometry. Results Median follow-up was 72.0 months. Nine (2.3%) experienced treatment failure. At last follow-up, 74 (19.3%) had new/progressive symptoms and were categorized as radiologic non-responders, whereas 300 (78.3%) had no tumor progression and were grouped as radiologic responders. Average pretreatment BTV for treatment failures, radiologic non-responders, and radiologic responders was 2.11, 0.44, and 1.87 cm3, respectively. Pretreatment CNVII and CNVIII symptoms were present in 9.4 and 93.4% of patients, respectively. Eight (24%) with pre-HSRT CNVII and 37 (10%) with pre-HSRT CNVIII symptoms recovered CN function post-HSRT. Thirty-five (9%) and 36 (9.4%) experienced new CNVII and CNVIII deficit, respectively, after HSRT. Of these, 20 (57%) and 18 (50%) recovered CNVII and CNVIII function, respectively, after HSRT. Evaluable audiograms were available in 199 patients. At baseline and at last follow-up, 65.8 and 36.2% had serviceable hearing, respectively. Fifty-one percent had preservation of serviceable hearing at last follow-up. Conclusion Treatment of VS with HSRT is effective with treatment success in 97.7% and an acceptable toxicity profile. Less than one-third of patients experience any new CNVII or CNVIII deficit posttreatment. Greater than 50% of patients with serviceable hearing at baseline maintained hearing function. Improved methods to differentiate treatment effect and tumor progression are needed.

Effects of perineural invasion on biochemical recurrence and prostate cancer-specific survival in patients treated with definitive external beam radiotherapy

OBJECTIVES Perineural invasion (PNI) has not yet gained universal acceptance as an independent predictor of adverse outcomes for prostate cancer treated with external beam radiotherapy (EBRT). We analyzed the prognostic influence of PNI for a large institutional cohort of prostate cancer patients who underwent EBRT with and without androgen deprivation therapy (ADT). MATERIAL AND METHODS We, retrospectively, reviewed prostate cancer patients treated with EBRT from 1993 to 2007 at our institution. The primary endpoint was biochemical failure-free survival (BFFS), with secondary endpoints of metastasis-free survival (MFS), prostate cancer-specific survival (PCSS), and overall survival (OS). Univariate and multivariable Cox proportional hazards models were constructed for all survival endpoints. Hazard ratios for PNI were analyzed for the entire cohort and for subsets defined by NCCN risk level. Additionally, Kaplan-Meier survival curves were generated for all survival endpoints after stratification by PNI status, with significant differences computed using the log-rank test. RESULTS Of 888 men included for analysis, PNI was present on biopsy specimens in 187 (21.1%). PNI was associated with clinical stage, pretreatment PSA level, biopsy Gleason score, and use of ADT (all P<0.01). Men with PNI experienced significantly inferior 10-year BFFS (40.0% vs. 57.8%, P = 0.002), 10-year MFS (79.7% vs. 89.0%, P = 0.001), and 10-year PCSS (90.9% vs. 95.9%, P = 0.009), but not 10-year OS (67.5% vs. 77.5%, P = 0.07). On multivariate analysis, PNI was independently associated with inferior BFFS (P<0.001), but not MFS, PCSS, or OS. In subset analysis, PNI was associated with inferior BFFS (P = 0.04) for high-risk patients and with both inferior BFFS (P = 0.01) and PCSS (P = 0.05) for low-risk patients. Biochemical failure occurred in 33% of low-risk men with PNI who did not receive ADT compared to 8% for low-risk men with PNI treated with ADT (P = 0.01). CONCLUSION PNI was an independently significant predictor of adverse survival outcomes in this large institutional cohort, particularly for patients with NCCN low-risk disease. PNI should be carefully considered along with other standard prognostic factors when treating these patients with EBRT. Supplementing EBRT with ADT may be beneficial for select low-risk patients with PNI though independent validation with prospective studies is recommended.

Long-term Outcomes With Planned Multistage Reduced Dose Repeat Stereotactic Radiosurgery for Treatment of Inoperable High-Grade Arteriovenous Malformations: An Observational Retrospective Cohort Study.

BACKGROUND There is no consensus regarding the optimal management of inoperable high-grade arteriovenous malformations (AVMs). This long-term study of 42 patients with high-grade AVMs reports obliteration and adverse event (AE) rates using planned multistage repeat stereotactic radiosurgery (SRS). OBJECTIVE To evaluate the efficacy and safety of multistage SRS with treatment of the entire AVM nidus at each treatment session to achieve complete obliteration of high-grade AVMs. METHODS Patients with high-grade Spetzler-Martin (S-M) III-V AVMs treated with at least 2 multistage SRS treatments from 1989 to 2013. Clinical outcomes of obliteration rate, minor/major AEs, and treatment characteristics were collected. RESULTS Forty-two patients met inclusion criteria (n = 26, S-M III; n = 13, S-M IV; n = 3, S-M V) with a median follow-up was 9.5 yr after first SRS. Median number of SRS treatment stages was 2, and median interval between stages was 3.5 yr. Twenty-two patients underwent pre-SRS embolization. Complete AVM obliteration rate was 38%, and the median time to obliteration was 9.7 yr. On multivariate analysis, higher S-M grade was significantly associated ( P = .04) failure to achieve obliteration. Twenty-seven post-SRS AEs were observed, and the post-SRS intracranial hemorrhage rate was 0.027 events per patient year. CONCLUSION Treatment of high-grade AVMs with multistage SRS achieves AVM obliteration in a meaningful proportion of patients with acceptable AE rates. Lower obliteration rates were associated with higher S-M grade and pre-SRS embolization. This approach should be considered with caution, as partial obliteration does not protect from hemorrhage.