RET,a targetable driver of pancreatic adenocarcinoma

Pancreatic ductal adenocarcinoma (PDA) remains a deadly disease, affecting about 40,000 individuals in the United States annually. We aimed to characterize the role of RET as a co-driver of pancreas tumorigenesis. To assess the role of RET as a co-driver of PDA, we generated a novel triple mutant transgenic mouse based on the cre-activated p53^R172H gene and a constitutively active RET ^M919T mutant (PRC). Survival analysis was performed using Kaplan–Meier analysis. Study of human PDA specimens and Pdx-1-Cre/Kras^G12D /p53^R172H (KPC) mice revealed that RET is upregulated during pancreas tumorigenesis, from inception through precursor lesions, to invasive cancer. We demonstrated that activation of RET is capable of inducing invasive pancreatic carcinomas in the background of the P53 inactivation mutation. Compared to KPC mice, PRC animals had distinct phenotypes, including longer latency to tumor progression, longer survival, and the presence of multiple macrometastases. Enhanced activation of the MAPK pathway was observed as early as the PanIN 2 stage. Sequencing of the exonic regions of KRAS in PRC-derived PDA cells revealed no evidence of KRAS mutations. RET can be an essential co-driver of pancreatic tumorigenesis in conjugation with KRAS activity. These data suggest that RET may be a potential target in the treatment of PDA.     

Treatment and Outcome of Patients with Skull Base Chordoma: A Meta-analysis

Objective Chordoma is a locally aggressive tumor. The aim of this study was to assess the efficacy of different surgical approaches and adjuvant radiation modalities used to treat these patients. Design Meta-analysis. Main Outcome Measures Overall survival (OS), disease-specific survival (DSS), and progression-free survival (PFS). Results The 5-year OS and PFS rates of the whole cohort (n = 467) were 86% and 65.7%, respectively. The 5-year DSS for patients who underwent open surgery and endoscopic surgery was 45% and 49%, respectively (p = 0.8); PFS was 94% and 79%, respectively (p = 0.11). The 5-year OS of patients treated with surgery followed by adjuvant radiotherapy was 90% compared with 70% of those treated by surgery alone (p = 0.24). Patients undergoing partial resection without adjuvant radiotherapy had a 5-year OS of 41% and a DSS of 45%, significantly lower than in the total-resection group (p = 0.0002 and p = 0.01, respectively). The complication rates were similar in the open and endoscopic groups. Conclusions Patients undergoing total resection have the best outcome; adjuvant radiation therapy improves the survival of patients undergoing partial resection. In view of the advantages of minimally invasive techniques, endoscopic surgery appears an appropriate surgical approach for this disease.     

Paracrine regulation of glioma cells invasion by astrocytes is mediated by glial‐derived neurotrophic factor

It was suggested that the brain microenvironment plays a role in glioma progression. Here we investigate the mechanism by which astrocytes which are abundant in glioma tumors, promote cancer cell invasion. In this study, we evaluated the effects of astrocytes on glioma biology both in vitro and in vivo and determined the downstream paracrine effect of glial‐derived neurotrophic factor (GDNF) on tumor invasion. Astrocytes‐conditioned media (ACM) significantly increased human and murine glioma cells migration compared to controls. This effect was inhibited when the activity of GDNF on glioma cells was blocked by RET‐Fc chimera or anti‐GDNF Ab and by small interfering RNA directed against GDNF expression by astrocytes. Glioma cells incubated with ACM led to time dependent phosphorylation of the GDNF receptor, RET and downstream activation of AKT. Tumor migration and GDNF‐RET‐AKT activation was inhibited by the RET small‐molecule inhibitor pyrazolopyrimidine‐1 (PP1) and by the AKT inhibitor LY294002. Finally, blocking of RET by PP1 or knockout of the RET coreceptor GFRα1 in glioma cells reduced the size of brain tumors in immunocompetent mice. We suggest a mechanism by which astrocytes attracted to the glioma tumors facilitate brain invasion by secretion of GDNF and activation of RET/GFRα1 receptors expressed by the cancer cells.     

Contemporary Treatment Approaches to Sinonasal Mucosal Melanoma

Sinonasal mucosal melanoma (SNMM) is a rare oncological entity that comprises most head and neck mucosal melanomas. SNMM has distinctive genetic background, different from cutaneous melanoma. Survival outcomes among SNMM patients are poor; while there is no clear consensus on the optimal management of SNMM, the primary treatment modality is generally considered to be wide surgical excision, and radiation therapy (RT) is often used in the postoperative adjuvant setting to improve locoregional control. Systemic therapies have demonstrated little or no survival benefit, and most SNMM patients die of distant metastatic disease. Owing to the rarity of the disease, the literature describing treatment approaches for SNMM is lacking and largely limited to isolated case reports and retrospective series. Here, we describe contemporary diagnostic and therapeutic approaches to SNMM based on the most recent molecular and outcome data.     

Outcome of Patients Undergoing Salvage Surgery for Recurrent Nasopharyngeal Carcinoma: A Meta-analysis

Background

The common treatment of primary patients with nasopharyngeal carcinoma is chemotherapy and radiotherapy. Surgery is reserved as salvage procedure for recurrent or persistent disease. Nevertheless, information on the outcome of these patients and the role of adjuvant reirradiation treatment is scarce.

Methods

We conducted a meta-analysis to identify prognostic factors associated with outcomes of patients with recurrent nasopharyngeal carcinoma treated by salvage surgery.

Results

The study group consisted of 779 patients from 17 published studies who met the inclusion criteria. The primary tumor classification at recurrence was T1–2 in 83 % of patients and T3–4 in 16.6 %. Regional lymph node metastases were present in 88 patients. The 5-year overall survival and local recurrence-free survival rates of the entire cohort were 51.2 and 63.4 %, respectively, with a distant metastases rate of 11.3 %. The 5-year overall survival was 63 % in patients receiving surgery and adjuvant radiotherapy compared to 39 % in patients receiving surgery alone (P = 0.05). Independent predictors of outcome on multivariate analysis were sex, N classification, surgical approach (endoscopic vs. open), adjuvant treatment, and margin status. Both endoscopic surgery and reirradiation were independent predictors of improved survival.

Conclusions

More than half of the patients with recurrent disease can be salvaged by surgery. Margins status, and N and T classification are significant predictors of outcome. Multivariate analysis revealed that endoscopic surgery offers better outcome than open surgery for T3/4 disease in selected patients, and adjuvant reirradiation offers an additional survival advantage over surgery alone.