Shorook Na'ara

Mechanisms of cancer dissemination along nerves

The local extension of cancer cells along nerves is a frequent clinical finding for various tumours. Traditionally, nerve invasion was assumed to occur via the path of least resistance; however, recent animal models and human studies have revealed that cancer cells have an innate ability to actively migrate along axons in a mechanism called neural tracking. The tendency of cancer cells to track along nerves is supported by various cell types in the perineural niche that secrete multiple growth factors and chemokines. We propose that the perineural niche should be considered part of the tumour microenvironment, describe the molecular cues that facilitate neural tracking and suggest methods for its inhibition.

Improving the rate of negative margins after surgery for oral cavity squamous cell carcinoma: A prospective randomized controlled study.

A positive margin is among the most significant factors that affects the outcome in head and neck squamous cell carcinoma (SCC). The purpose of this study was to compare the negative margin rates between 2 methods of intraoperative margin assessment in patients with oral cavity SCC.

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.

Perineural Spread in Noncutaneous Head and Neck Cancer: New Insights into an Old Problem.

Head and neck malignancies have the propensity to invade nerves. Perineural tumor invasion is common, with some series reporting rates of 30 to 100%. Squamous cell carcinoma and adenoid cystic carcinoma are the most commonly involved tumors. The most commonly involved nerves are the trigeminal (cranial nerve [CN] V) and facial (CN VII) and their branches. Neural spread away from a tumor is encountered less often and usually causes specific symptoms such as pain, muscle weakness, and atrophy, depending on the involved nerves. While clinical symptoms and physical examination may suggest the presence of neural invasion, specific imaging modalities such as fat-suppressed T1-weighted magnetic resonance images, should be utilized to identify perineural tumor spread in its early phases. Perineural tumor spread should be considered and addressed in the treatment planning of patients with head and neck or skull base cancers as it can influence the extent of surgery, and the dosage and fields of radiation therapy. In the current review, we discuss the clinical course of perineural tumor spread and its therapeutic implications.

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.

Plasmacytoma of the Skull Base: A Meta-Analysis.

Objective Extramedullary plasmacytomas are rare tumors. In the current study we aim to characterize its clinical course at the skull base and define the most appropriate therapeutic protocol. Methods We conducted a meta-analysis of articles in the English language that included data on the treatment and outcome of plasmacytoma of the base of skull. Results The study cohort consisted of 47 patients. The tumor originated from the clivus and sphenoclival region in 28 patients (59.5%), the nasopharynx in 10 patients (21.2%), the petrous apex in 5 patients (10.6%), and the orbital roof in 4 patients (8.5%). The chief complaints at presentation included recurrent epistaxis and cranial nerve palsy, according to the site of tumor. Twenty-two patients (46.8%) had surgical treatment; 25 (53.2%) received radiation therapy. Adjuvant therapy was administered in 11 cases (50%) with concurrent multiple myeloma. The 2-year and 5-year overall survival rates were 78% and 59%, respectively. Clear margin resection was achieved in a similar proportion of patients who underwent endoscopic surgery and open surgery (p = 0.83). A multivariate analysis of outcome showed a similar survival rate of patients treated surgically or with radiotherapy. Conclusions The mainstay of treatment for plasmacytoma is based on radiation therapy, but when total resection is feasible, endoscopic resection is a valid option.

The role of adjuvant treatment in early-stage oral cavity squamous cell carcinoma: An international collaborative study: Treatment of Early Squamous Cell Carcinoma

Up to half of patients with oral cavity squamous cell carcinoma (OCSCC) have stage I to II disease. When adequate resection is attained, no further treatment is needed; however, re‐resection or radiotherapy may be indicated for patients with positive or close margins. This multicenter study evaluated the outcomes and role of adjuvant treatment in patients with stage I to II OCSCC.

Defining the surgical margins of adenoid cystic carcinoma and their impact on outcome: An international collaborative study.

The mainstay of treatment in adenoid cystic carcinoma (ACC) of the head and neck is surgical resection with negative margins. The purpose of this study was to define the margin status that associates with survival outcomes of ACC of the head and neck.

Contemporary Management of Recurrent Nodal Disease in Differentiated Thyroid Carcinoma

Differentiated thyroid carcinoma (DTC) comprises over 90% of thyroid tumors and includes papillary and follicular carcinomas. Patients with DTC have an excellent prognosis, with a 10-year survival rate of over 90%. However, the risk of recurrent tumor ranges between 5% and 30% within 10 years of the initial diagnosis. Cervical lymph node disease accounts for the majority of recurrences and in most cases is detected during follow-up by ultrasound or elevated levels of serum thyroglobulin. Recurrent disease is accompanied by increased morbidity. The mainstay of treatment of nodal recurrence is surgical management. We provide an overview of the literature addressing surgical management of recurrent or persistent lymph node disease in patients with DTC.

Post-translational Regulation of Radioactive Iodine Therapy Response in Papillary Thyroid Carcinoma

Background Radioactive iodine (RAI) is the mainstay of treatment for differentiated thyroid carcinoma (DTC). Nevertheless, the mechanism of RAI resistance that occurs in many patients with DTC remains unknown. We aimed to elucidate the role of post-translational regulation of radioiodine uptake. Methods We analyzed the expression pattern of the ribosomal glycosylphosphatidylinositol transamidase (GPIT) complex in freshly excised tumors from 10 patients with DTC. We used functional RAI uptake assays to assess the role of GPIT in iodine uptake both in vivo and in vitro. The effects of MEK inhibition on the GPIT subunit PIGU and the sodium iodide symporter (NIS) were assessed in three DTC cell lines and in four human DTC biopsies. We used a multivariable logistic regression model to study the role of PIGU in the response to RAI treatment in advanced DTC. All statistical tests were two-sided. Results Expression profiling of different GPIT complex subunits revealed statistically significantly lower expression of PIGU in papillary carcinomas than in matched normal thyroid tissue (P < .001). Expression of PIGU in the K1 human papillary carcinoma cell line resulted in a robust increase in NIS glycosylation and trafficking to the cell membrane, accompanied by a robust increase in I125 uptake both in vitro (465 200 ± 56 343 vs 1236 ± 156 counts per million, P < .001) and in vivo (128 945 ± 28 556 vs 7963 ± 192 counts per million, P < .001, n = 5 mice per group). Treatment with the MEK inhibitors U0126 and PD302 rescued PIGU expression. Finally, the PIGU expression levels in tumors of 18 patients with recurrent DTC were associated with a biochemical response to RAI treatment (hazard ratio = 8.06, 95% confidence interval = 3.72 to 12.3, P = .001). Conclusions We showed that downregulation of PIGU in DTC determines NIS function and RAI avidity. This represents a novel mechanism for RAI resistance.