Proton Therapy Outcomes for Head and Neck Cutaneous Melanoma: Proton Collaborative Group Analysis.

Purpose: Reports of proton beam therapy (PBT) utilization for cutaneous melanoma of the head and neck (HN) region is virtually non-existent. This study reports on the efficacy and acute toxicities of PBT for primary HN cutaneous melanoma. Materials and Methods: We queried the prospectively collected, multi-institutional Proton Collaborative Group registry for all consecutive patients with HN cutaneous melanoma receiving PBT from May 2010 to December 2019. Kaplan-Meier methods were used to estimate overall survival (OS), progression free survival (PFS), and local regional recurrence free survival (LRFS). Toxicity was reported per CTCAE version 4.0. Results: A total of 8 patients were identified with a median age of 69 (range, 37-88). All patients (100%) underwent surgery followed with postoperative PBT. There were 3 patients (37.5%) with T3 or T4 disease and 4 (50%) with N2 or N3 disease. The median radiation dose was 46 GyRBE (range, 27-70) and median dose per fraction was 2.4 GyRBE (range, 2.0-6.0) with the most common dose fractionation being 44 or 48 GyRBE in 20 fractions (n = 4). At a median follow-up of 40.1 months (range, 1.6-62.4) the 1 and 3 year OS rates were 85.7% and 35.7%, respectively. The median PFS was 25.40 months (95% CI, 2.53-58.70) while PFS at 1 year and 3 years was 85.7% and 35.7%, respectively. LRFS was 100% at 1 year and 85.7% at 3 years. Five of the 8 patients developed distant metastases, of which 3 received immunotherapy. Acute G2+ and G3+ toxicities occurred in 5 of 8 patients and 2 of 8 patients, respectively. G3 toxicities included radiation dermatitis (n = 1) and immunotherapy-related rash (n = 1). No G4+ toxicities were reported. Conclusion: Single modality PBT for HN melanomas in the definitive setting provides effective and durable local control rates with tolerable acute toxicity. Distant failure remains the primary pattern of failure.

Optimal surgical timing and radiotherapy dose for trimodality therapy in locally advanced non-small cell lung cancer.

PURPOSE/OBJECTIVES: Data are conflicting on the effects of time interval from neoadjuvant chemoradiation (NCRT) to surgery for locally advanced non-small-cell lung cancer (LA-NSCLC). This study investigated the impact of surgical timing after NCRT and radiation dose on postoperative mortality and overall survival (OS). MATERIALS AND METHODS: Using the National Cancer Database, we identified 3489 LA-NSCLC patients treated with NCRT and surgery. Multivariate Cox proportional hazards analysis (MVA) was used to examine the effects of surgery >7 weeks from NCRT completion on OS. Propensity score (PS)-matched survival analysis for surgery ≤7 and >7 weeks was performed. Postoperative mortality was assessed. RESULTS: Median OS for surgery ≤7 weeks and >7 weeks after NCRT were 56.9 versus 45.6 months (hazard ratio, HR 1.18 [1.07-1.30]; p < 0.001). Surgery >7 weeks correlated with decreased OS on MVA (HR 1.15 [1.04-1.27]; p = 0.009) and PS matching (HR 1.16 [1.049-1.29]; p = 0.004). Time as a continuous variable correlated with OS on MVA (HR 1.003 [1.001-1.006]; p = 0.0056) and PS matching (HR 1.004 [1.001-1.006]; p = 0.004). Among 2902 lobectomy patients, the mortality rate for surgery ≤66 days was 5.2% versus 8.1% for >66 days (MVA HR 1.59 [1.02-2.49]; p = 0.04). Higher neoadjuvant radiotherapy dose correlated with surgery >7 weeks and lobectomy >66 days on MVA. CONCLUSIONS: Increased interval >7 weeks from NCRT to surgery for LA-NSCLC is correlated with worse OS and lobectomy ≤66 days correlated with improved OS. Surgery ≤7weeks may improve tumor control, whereas higher mortality for surgery >66 days may relate to late NCRT manifestations. Neoadjuvant doses of 44-50.4 Gy may minimize risks of radiation-induced lung injury and surgical complications and facilitate surgery within the optimal 7-week interval.

Treatment interruptions affect biochemical failure rates in prostate cancer patients treated with proton beam therapy: Report from the multi-institutional proton collaborative group registry.

INTRODUCTION: To date, no studies examining the effect of treatment interruptions (TI) with proton beam therapy (PBT) have been published. The goal of our study was to determine the predictors of TI amongst patients with prostate cancer (PCa) treated with PBT and to determine whether TI are associated with biochemical failure (BF). We hypothesized that any correlation between TI and biochemical control would be more pronounced in high risk groups. METHODS: Data for 4278 patients with PCa was obtained from the prospectively collected Proton Collaborative Group (PCG) data registry. Univariate and multivariate logistic regression analysis (MVA) was used to model possible predictors of BF. A subset analysis was performed for high risk patients treated with ADT and PBT. Finally, propensity score (PS) analysis was performed to account for any indication bias caused by lack of randomization. RESULTS: Total treatment duration (OR, 1.05 [1.04-1.06]; p < 0.001) increased the likelihood of TI on MVA. TI did not have a statistically significant correlation with BF (OR, 1.44 [0.86-2.39]; p = 0.162) amongst PS matched patients. However, on subset analyses of high risk group patients with PS matching, there was a trend towards worse BF in patients with TI (OR 3.85; 95%CI (0.96-15.44); p = 0.057). CONCLUSION: In the first analysis of its kind, the results suggest that TI in high risk PCa patients treated with PBT and ADT have worse BF rates. Interventions such as increased patient education, proper maintenance of proton facilities, and decreasing total treatment duration with alternative fractionation schedules may help avoid the unintended negative effects on tumor control due to TI. However, future analyses on a larger patient population is needed.

Neoadjuvant chemotherapy improves survival compared with concurrent chemoradiation alone in nasopharyngeal carcinoma patients with N3 disease.

BACKGROUND: Neoadjuvant chemotherapy (NAC) trials in endemic regions of nasopharyngeal carcinoma (NPC) found improved survival, but studies are lacking in nonendemic regions. We assessed whether adding NAC to concurrent chemoradiation (CRT) improves overall survival (OS), especially in high-risk nonendemic patients. METHODS: Definitively treated NPC patients (n = 5424) from the National Cancer Database were analyzed for predictors of NAC and NAC effects on OS with multivariate Cox proportional hazards analysis (multivariate analysis [MVA]). Propensity score matched (1:2) survival analysis of NAC (n = 968) and CRT alone (n = 1914) was also performed. Effects on OS were stratified by risk group. RESULTS: On MVA, NAC-improved OS among the total cohort (hazard ratio [HR] 0.89, P = .049), particularly among stratified keratinizing histology (HR 0.82, P = .015) and N3 disease (HR 0.73, P = .046). Among propensity matched patients, NAC improved OS in patients with N3 disease (n = 336; HR 0.71, P = .046). CONCLUSIONS: NAC may improve OS among nonendemic NPC patients at higher risk of distant micrometastases, particularly N3 disease and those with unfavorable histology.

Frequency of symptomatic vertebral body compression fractures requiring intervention following single-fraction stereotactic radiosurgery for spinal metastases.

OBJECTIVE The purpose of this study was to determine the rate of symptomatic vertebral body compression fractures (VCFs) requiring kyphoplasty or surgery in patients treated with 24-Gy single-fraction stereotactic radiosurgery (SRS). METHODS This retrospective analysis included all patients who had been treated with 24-Gy, single-fraction, image-guided intensity-modulated radiation therapy for histologically confirmed solid tumor metastases over an 8-year period (2005-2013) at Memorial Sloan Kettering Cancer Center. Charts and imaging studies were reviewed for post-SRS kyphoplasty or surgery for mechanical instability. A Spinal Instability Neoplastic Score (SINS) was calculated for each patient both at the time of SRS and at the time of intervention for VCF. RESULTS Three hundred twenty-three patients who had undergone single-fraction SRS between C-1 and L-5 were included in this analysis. The cumulative incidence of VCF 5 years after SRS was 7.2% (95% CI 4.1-10.2), whereas that of death following SRS at the same time point was 82.5% (95% CI 77.5-87.4). Twenty-six patients with 36 SRS-treated levels progressed to symptomatic VCF requiring treatment with kyphoplasty (6 patients), surgery (10 patients), or both (10 patients). The median time to symptomatic VCF was 13 months. Seven patients developed VCF at 11 levels adjacent to the SRS-treated level. Fractured levels had no evidence of tumor progression. The median SINS changed from 6.5 at SRS (interquartile range [IQR] 4.3-8.8) to 11.5 at stabilization (IQR 9-13). In patients without prior stabilization at the level of SRS, there was an association between the SINS and the time to fracture. CONCLUSIONS Five years after ablative single-fraction SRS to spinal lesions, the cumulative incidence of symptomatic VCF at the treated level without tumor recurrence was 7.2%. Higher SINSs at the time of SRS correlated with earlier fractures.

Kinase Regulation of Human MHC Class I Molecule Expression on Cancer Cells.

The major histocompatibility complex I (MHC-1) presents antigenic peptides to tumor-specific CD8+ T cells. The regulation of MHC-I by kinases is largely unstudied, even though many patients with cancer are receiving therapeutic kinase inhibitors. Regulators of cell-surface HLA amounts were discovered using a pooled human kinome shRNA interference-based approach. Hits scoring highly were subsequently validated by additional RNAi and pharmacologic inhibitors. MAP2K1 (MEK), EGFR, and RET were validated as negative regulators of MHC-I expression and antigen presentation machinery in multiple cancer types, acting through an ERK output-dependent mechanism; the pathways responsible for increased MHC-I upon kinase inhibition were mapped. Activated MAPK signaling in mouse tumors in vivo suppressed components of MHC-I and the antigen presentation machinery. Pharmacologic inhibition of MAPK signaling also led to improved peptide/MHC target recognition and killing by T cells and TCR-mimic antibodies. Druggable kinases may thus serve as immediately applicable targets for modulating immunotherapy for many diseases. Cancer Immunol Res; 4(11); 936-47. ©2016 AACR.

von Willebrand factor genetic variant associated with hematoma expansion after intracerebral hemorrhage.

BACKGROUND: Hematoma expansion, the leading cause of neurologic deterioration after intracerebral hemorrhage (ICH), remains one of the few modifiable risk factors for poor outcome. In the present study, we explored whether common genetic variants within the hemostasis pathway were related to hematoma expansion during the acute period after ICH. METHODS: Patients with spontaneous ICH who were admitted to the institutional Neuro-ICU between 2009 and 2011 were enrolled in the study, and clinical data were collected prospectively. Hematoma size was measured in patients admitted on or before postbleed day 2. Baseline models for hematoma growth were constructed using backwards stepwise logistic regression. Genotyping of single-nucleotide polymorphisms for 13 genes involved in hemostasis was performed, and the results were individually included in the above baseline models to test for independent association of hematoma expansion. RESULTS: During the study period, 82 patients were enrolled in the study and had complete data. The mean age was 65.9 ± 14.9 years, and 38% were female. Only von Willebrand factor was associated with absolute and relative hematoma growth in univariate analysis (P < .001 and P = .007, respectively); von Willebrand factor genotype was independently predictive of relative hematoma growth but only approached significance for absolute hematoma growth (P = .002 and P = .097, respectively). CONCLUSIONS: Our genomic analysis of various hemostatic factors identified von Willebrand factor as a potential predictor of hematoma expansion in patients with ICH. The identification of von Willebrand factor single-nucleotide polymorphisms may allow us to better identify patients who are at risk for hematoma enlargement and will benefit the most from treatment. The relationship of von Willebrand factor with regard to hematoma enlargement in a larger population warrants further study.

The role of STAT3 activation in modulating the immune microenvironment of GBM.

Glioblastoma multiforme (GBM) modulates the immune system to engance its malignant potential. Signal transducer and activator of transcription 3 (STAT3) activation is a regulatory node in modulating the immune microenvironment in several human tumors, including GBM. To investigate whether STAT3 inhibition might enhance anti-tumor responses, we inhibited STAT3 signaling using small interfering RNA against STAT3. We tested the human GBM cell lines U87, U251, and HS683, which are known to constitutively express high levels of phospho-STAT3. STAT3 inhibition resulted in enhanced expression of several pro-inflammatory cytokines and chemokines and supernatants from STAT3-silenced human GBM cell lines increased lipopolysaccharide-induced dendritic cell activation in vitro. We obtained comparable results when STAT3 activity was suppressed with specific small molecule inhibitors. Our results support the hypothesis that activated STAT3 contributes to the immunosuppressive microenvironment in GBM and support previous studies implicating STAT3 as a potential target for immunotherapy.

Immunologic consequences of signal transducers and activators of transcription 3 activation in human squamous cell carcinoma.

Paracrine cross-talk between tumor cells and immune cells within the tumor microenvironment underlies local mechanisms of immune evasion. Signal transducer and activator of transcription 3 (STAT3), which is constitutively activated in diverse cancer types, is a key regulator of cytokine and chemokine expression in murine tumors, resulting in suppression of both innate and adaptive antitumor immunity. However, the immunologic effects of STAT3 activation in human cancers have not been studied in detail. To investigate how STAT3 activity in human head and neck squamous cell carcinoma (HNSCC) might alter the tumor microenvironment to enable immune escape, we used small interfering RNA and small-molecule inhibitors to suppress STAT3 activity. STAT3 inhibition in multiple primary and established human squamous carcinoma lines resulted in enhanced expression and secretion of both proinflammatory cytokines and chemokines. Although conditioned medium containing supernatants from human HNSCC inhibited lipopolysaccharide-induced dendritic cell activation in vitro, supernatants from STAT3-silenced tumor cells reversed this immune evasion mechanism. Moreover, supernatants from STAT3-silenced tumor cells were able to stimulate the migratory behavior of lymphocytes from human peripheral blood in vitro. These results show the importance of STAT3 activation in regulating the immunomodulatory mediators by human tumors and further validate STAT3 as a promising target for therapeutic intervention.

Mechanisms of local immunoresistance in glioma.

Even though the central nervous system (CNS) was conventionally defined as "immunologically privileged", new discoveries have demonstrated the role of the immune system in neurologic disease and illness, including gliomas. Brain tumor immunotherapy is an exciting and revived area of research, in which neurosurgeons have taken a major position. Despite the ability to induce a tumor-specific systemic immune response, the challenge to effectively eradicate intracranial gliomas remains mainly because of tumor-induced immunoresistance. This article gives an overview of the immunologic responses that occur in the CNS and their potential role in brain tumors. The main cellular and molecular mechanisms that mediate tumor escape from natural immune surveillance are also covered in this article. Glioma cells have been shown to diminish the expression of danger signals necessary for immune activation and to increase the concentration of immunosuppressive factors in the tumor microenvironment, which results in T-cell anergy or apoptosis. Finally, the authors discuss most of the over-expressed oncogenic signaling pathways that cause tumor tolerance.

Immunotherapy combined with chemotherapy in the treatment of tumors.

This article provides a broad overview of the data, including laboratory and clinical studies, currently available on the combination of immunotherapy and chemotherapy for treating cancer. The various forms of immunotherapy combined with chemotherapy include monoclonal antibodies, adoptive lymphocyte transfer, or active specific immunotherapy, such as tumor proteins, irradiated tumor cells, tumor cell lysates, dendritic cells pulsed with peptides or lysates, or tumor antigens expressed in plasmids or viral vectors. This discussion is not limited to malignant brain tumors, because many of the studies have been conducted on various cancer types, thereby providing a comprehensive perspective that may encourage further studies that combine chemotherapy and immunotherapy for treating brain tumors.

Paclitaxel: a review of adverse toxicities and novel delivery strategies.

Better known as Taxol (Bristol-Myers Squibb), paclitaxel is the first member of the taxane family to be used in cancer chemotherapy. The taxanes exert their cytotoxic effect by arresting mitosis through microtubule stabilization, resulting in cellular apoptosis. The use of paclitaxel as a chemotherapeutic agent has become a broadly accepted option in the treatment of patients with ovarian, breast and non-small cell lung cancers, malignant brain tumors, and a variety of other solid tumors. However, significant toxicities, such as myelosuppression and peripheral neuropathy, limit the effectiveness of paclitaxel-based treatment regimens. This review addresses the toxicities associated with paclitaxel treatment and describes existing and future strategies of paclitaxel administration directed at limiting these toxicities.