R.L. Bakst

GFRα1 released by nerves enhances cancer cell perineural invasion through GDNF-RET signaling

Significance In this study, we identify nerve-released glial cell line-derived neurotrophic factor (GDNF) family receptor (GFR)α1 as a key factor that enhances perineural invasion (PNI) through GDNF-Ret proto-oncogene (RET) signaling. We demonstrate that GFRα1 is released from nerves in a soluble form and cooperates with secreted GDNF to activate cancer cell surface RET, activating downstream signaling, cancer cell migration, and PNI. These findings advance our understanding of the molecular mechanisms of PNI and define the specific cancer cell requirements necessary for PNI to occur. This work promotes the concept that a ligand and receptor both released by the microenvironment may cooperate together to facilitate cancer invasion. These findings highlight the key participatory role that the nerve microenvironment plays in enabling cancer perineural invasion. The ability of cancer cells to invade along nerves is associated with aggressive disease and diminished patient survival rates. Perineural invasion (PNI) may be mediated by nerve secretion of glial cell line-derived neurotrophic factor (GDNF) attracting cancer cell migration through activation of cell surface Ret proto-oncogene (RET) receptors. GDNF family receptor (GFR)α1 acts as coreceptor with RET, with both required for response to GDNF. We demonstrate that GFRα1 released by nerves enhances PNI, even in the absence of cancer cell GFRα1 expression. Cancer cell migration toward GDNF, RET phosphorylation, and MAPK pathway activity are increased with exposure to soluble GFRα1 in a dose-dependent fashion. Dorsal root ganglia (DRG) release soluble GFRα1, which potentiates RET activation and cancer cell migration. In vitro DRG coculture assays of PNI show diminished PNI with DRG from GFRα1+/− mice compared with GFRα1+/+ mice. An in vivo murine model of PNI demonstrates that cancer cells lacking GFRα1 maintain an ability to invade nerves and impair nerve function, whereas those lacking RET lose this ability. A tissue microarray of human pancreatic ductal adenocarcinomas demonstrates wide variance of cancer cell GFRα1 expression, suggesting an alternate source of GFRα1 in PNI. These findings collectively demonstrate that GFRα1 released by nerves enhances PNI through GDNF-RET signaling and that GFRα1 expression by cancer cells enhances but is not required for PNI. These results advance a mechanistic understanding of PNI and implicate the nerve itself as a key facilitator of this adverse cancer cell behavior.

Mucosal Melanoma of the Head and Neck: A Systematic Review of the Literature

Primary mucosal melanoma of the head and neck (MMHN) comprises approximately 1% of all malignant melanomas. It presents more commonly in an elderly population and has no significant gender predominance. Given its rarity, most evidence of the causes, behavior, and treatment approaches for MMHN originates from isolated case reports and retrospective series. Between 1945 and 2011, at least 1951 cases of MMHN have been reported in the literature. Despite numerous technological developments in surgery and radiation therapy, as well as advances in systemic modalities, MMHN is an aggressive malignancy with a very poor prognosis. Complete surgical excision with clear margins remains the primary treatment modality. Adjuvant postoperative radiation therapy may improve locoregional control but does not appear to affect survival. Definitive particle radiation therapy promises to provide high rates of local control for nonoperable patients. Recent molecular evidence suggests that proto-oncogene KIT aberrations in a subset of mucosal melanomas may represent a potential diagnostic value and serve as a therapeutic target for tyrosine kinase inhibitors in an adjuvant setting for patients with advanced MMHN.

The chemokine (CCL2-CCR2) signaling axis mediates perineural invasion.

Perineural invasion is a form of cancer progression where cancer cells invade along nerves. This behavior is associated with poor clinical outcomes; therefore, it is critical to identify novel ligand–receptor interactions between nerves and cancer cells that support the process of perineural invasion. A proteomic profiler chemokine array was used to screen for nerve-derived factors secreted from tissue explants of dorsal root ganglion (DRG), and CCL2 was identified as a lead candidate. Prostate cancer cell line expression of CCR2, the receptor to CCL2, correlated closely with MAPK and Akt pathway activity and cell migration towards CCL2 and DRG. In vitro nerve and cancer coculture invasion assays of perineural invasion demonstrated that cancer cell CCR2 expression facilitates perineural invasion. Perineural invasion is significantly diminished in coculture assays when using DRG harvested from CCL2−/− knockout mice as compared with control CCL2+/+ mice, indicating that CCR2 is required for perineural invasion in this murine model of perineural invasion. Furthermore, 20 of 21 (95%) patient specimens of prostate adenocarcinoma with perineural invasion exhibited CCR2 expression by immunohistochemistry, while just 3 of 13 (23%) lacking perineural invasion expressed CCR2. In summary, nerve-released CCL2 supports prostate cancer migration and perineural invasion though CCR2-mediated signaling. Implications: These results reveal CCL2–CCR2 signaling as a key ligand–receptor mechanism that mediates cancer cell communication with nerves during perineural invasion and highlight a potential future therapeutic target. Mol Cancer Res; 13(2); 380–90. ©2014 AACR.

Tolerability, Toxicity, and Temporal Implications of Transoral Robotic Surgery (TORS) on Adjuvant Radiation Therapy in Carcinoma of the Head and Neck

Objectives: Overall treatment package time (from surgery to radiotherapy [RT] completion) > 100 days can portend poor outcomes in head and neck cancer. Faster postoperative recovery seen with transoral robotic surgery may decrease treatment duration and toxicity for adjuvant RT and chemoradiation. Methods: We retrospectively reviewed all patients treated with transoral robotic surgery (n = 124) and adjuvant RT and chemoradiation (n = 33) at our institution for head and neck cancer from April 2007 to December 2011 to determine treatment duration, acute toxicity, and long-term percutaneous gastric tube rates. Results: The median overall treatment time was 86 days and from surgery to RT start was 41 days; median RT duration was 44 days. No wound breakdown or infection occurred during or after RT. Two-year actuarial locoregional control, distant metastasis–free survival, and overall survival rates were 93%, 96%, and 97%, respectively. Conclusions: Adjuvant RT after transoral robotic surgery for head and neck cancer can be completed safely and in a timely fashion. Longer follow-up and a larger cohort will be needed to determine if this regimen is more effective than traditional surgery followed by adjuvant RT.

Intracoronary brachytherapy for in-stent restenosis of drug-eluting stents

Purpose Given the limited salvage options for in-stent restenosis (ISR) of drug-eluting stents (DES), our high-volume cardiac catheterization laboratory has been performing intracoronary brachytherapy (ICBT) in patients with recurrent ISR of DES. This study analyzes their baseline characteristics and assesses the safety/toxicity of ICBT in this high-risk population. Methods and materials A retrospective analysis of patients treated with ICBT between September 2012 and December 2014 was performed. Patients with ISR twice in a single location were eligible. Procedural complications included vessel dissection, perforation, tamponade, slow/absent blood flow, and vessel closure. Postprocedural events included myocardial infarction, coronary artery bypass graft, congestive heart failure, stroke, bleeding, thrombosis, embolism, dissection, dialysis, or death occurring within 72 hours. A control group of patients with 2 episodes of ISR at 1 location who underwent percutaneous coronary intervention without ICBT was identified. Unpaired t tests and χ2 tests were used to compare the groups. Results There were 134 (78%) patients in the ICBT group with 141 treated lesions and 37 (22%) patients in the control group. There was a high prevalence of hyperlipidemia (>95%), hypertension (>95%), and diabetes (>50%) in both groups. The groups were well-balanced with respect to age, sex, and pre-existing medical conditions, with the exception of previous coronary artery bypass graft being more common the ICBT group. Procedural complication rates were low in the control and ICBT groups (0% vs 4.5%, P = .190). Postprocedural event rates were low (<5%) in both groups. Readmission rate at 30 days was 3.7% in the ICBT group and 5.4% in the control group (P = .649). Conclusions This is the largest recent known series looking at ICBT for recurrent ISR of DES. ICBT is a safe treatment option with similarly low rates (<5%) of procedural and postprocedural complications compared with percutaneous coronary intervention alone. This study establishes the safety of ICBT in a high-risk patient cohort.

Human Papilloma Virus Positive Oropharyngeal Squamous Cell Carcinoma in the Elderly

BACKGROUND/AIMnElderly patients with HPV+ oropharyngeal cancer (OPC) represent an understudied cohort of the HPV epidemic. We aimed to investigate the clinical presentation, treatment tolerability and outcomes in patients ≥65 years old with HPV+ OPC.nnnPATIENTS AND METHODSnWe identified all patients aged 65 and older treated at our Institution with HPV+ OPC and analyzed patient demographics, disease characteristics, treatment modalities, toxicities, treatment failures, and survival. Charlson comorbidity index was calculated for each patient.nnnRESULTSn43 patients were identified with a mean age of median age was 70.0 (range 65-86). The mean Charlson comorbidity index score for the cohort was 5.2. In total, 72.1% of patients received what was considered standard-of-care based on stage and pathological features. Nine point three percent of patients required RT-related treatment breaks with the majority being women (75%). Three-year actuarial overall survival was 85.5% (95% CI: 71.4%-100%) and 3-year disease-free survival was 67.3% (95% CI: 49.7-91.0%).nnnCONCLUSIONnThis study presented one of the largest series to date evaluating HPV-related OPC in patients ≥65. Elderly individuals with HPV+ OPC have favorable overall survival with high treatment tolerability independent of Charlson co-morbidity score. Elderly patients should be considered for stage-appropriate care with omission of specific therapies based on absolute contraindications and patient preference, but not assumptions regarding tolerability.

Prognostic significance of Kadish staging in esthesioneuroblastoma: An analysis of the National Cancer Database

Given the rarity of esthesioneuroblastoma, it is difficult to validate a staging system. The purpose of this study was to investigate the utility of the Kadish staging system in esthesioneuroblastoma using the National Cancer Database (NCDB).