Molecular diagnostic alterations in squamous cell carcinoma of the head and neck and potential diagnostic applications

Head and neck squamous cell carcinoma (HNSCC) is a common malignancy that continues to be difficult to treat and cure. In many organ systems and tumor types, there have been significant advances in the understanding of the molecular basis for tumorigenesis, disease progression and genetic implications for therapeutics. Although tumorigenesis pathways and the molecular etiologies of HNSCC have been extensively studied, there are still very few diagnostic clinical applications used in practice today. This review discusses current clinically applicable molecular markers, including viral detection of Epstein–Barr virus and human papillomavirus, and molecular targets that are used in diagnosis and management of HNSCC. The common oncogenes EGFR, RAS, CCND1, BRAF, and PIK3CA and tumor suppressor genes p53, CDKN2A and NOTCH are discussed for their associations with HNSCC. Discussion of markers with potential future applications is also included, with a focus on molecular alterations associated with targeted therapy resistance.     

Neck dissection: past, present and future?

With the exception of distant metastasis, the presence of cervical lymph node metastasis is the single most adverse independent prognostic factor in head and neck squamous cell carcinoma. Surgical removal of metastatic cervical lymph nodes had been attempted during the late nineteenth century, with varying techniques and poor results. A systematic approach to en bloc removal of cervical lymph node disease, described in detail by Jawdyński at the end of the nineteenth century and popularized and illustrated by Crile in the early twentieth century, provided consistent and more effective treatment and forms the basis of our current techniques. The concepts of radical neck dissection, employed extensively by Martin, were followed with almost religious consistency by most head and neck surgeons until the late twentieth century, when the principles of 'functional' neck dissection, developed by Suárez and popularized by Bocca, Gavilán, Ballantyne, Byers and others, led to the acceptance of modified radical neck dissection as treatment for lymph node disease in various stages. More recently, selective neck dissection, involving removal of nodes confined to the levels at greatest risk of metastasis from primary tumours at various sites, has become accepted practice for elective and, in some instances, therapeutic treatment of the neck. In the future, sentinel lymph node biopsy and the use of molecular pathological analyses may be employed to predict the presence of occult cervical disease, thus directing therapy to patients at greatest risk and sparing those without regional metastasis.     

Paraneoplastic syndromes in patients with laryngeal neuroendocrine carcinomas: clinical manifestations and prognostic significance

Paraneoplastic syndromes are associated with a variety of malignant neoplasms and are systemic and non-metastatic manifestations that develop in a minority of cancer patients. This review examines all published cases of paraneoplastic syndromes associated with neuroendocrine carcinomas of the larynx. There are a total of ten patients reported with paraneoplastic syndromes associated with laryngeal neuroendocrine carcinomas in the literature. Of these, nine died and the tenth is alive with liver metastases. There were five cases of small-cell neuroendocrine carcinoma, four cases of moderately differentiated neuroendocrine carcinoma, and one case of well-differentiated neuroendocrine carcinoma associated with paraneoplastic syndromes. As these syndromes have significant clinical relevance, physicians should be aware of the possible presence of paraneoplastic syndromes in the diagnostic process of patients with neuroendocrine carcinoma of the larynx.     

A fluorescent curcumin-based Zn(II)-complex reactivates mutant (R175H and R273H) p53 in cancer cells

Background

Mutations of the p53 oncosuppressor gene are amongst the most frequent aberration seen in human cancer. Some mutant (mt) p53 proteins are prone to loss of Zn(II) ion that is bound to the wild-type (wt) core, promoting protein aggregation and therefore unfolding. Misfolded p53 protein conformation impairs wtp53-DNA binding and transactivation activities, favouring tumor growth and resistance to antitumor therapies. Screening studies, devoted to identify small molecules that reactivate mtp53, represent therefore an attractive anti-cancer therapeutic strategy. Here we tested a novel fluorescent curcumin-based Zn(II)-complex (Zn-curc) to evaluate its effect on mtp53 reactivation in cancer cells.

Methods

P53 protein conformation was examined after Zn-curc treatment by immunoprecipitation and immunofluorescence assays, using conformation-specific antibodies. The mtp53 reactivation was evaluated by chromatin-immunoprecipitation (ChIP) and semi-quantitative RT-PCR analyses of wild-type p53 target genes. The intratumoral Zn-curc localization was evaluated by immunofluorescence analysis of glioblastoma tissues of an ortothopic mice model.

Results

The Zn-curc complex induced conformational change in p53-R175H and -R273H mutant proteins, two of the most common p53 mutations. Zn-curc treatment restored wtp53-DNA binding and transactivation functions and induced apoptotic cell death. In vivo studies showed that the Zn-curc complex reached glioblastoma tissues of an ortothopic mice model, highlighting its ability to crossed the blood-tumor barrier.

Conclusions

Our results demonstrate that Zn-curc complex may reactivate specific mtp53 proteins and that may cross the blood-tumor barrier, becoming a promising compound for the development of drugs to halt tumor growth.     

Feasibility and safety of vaginal myomectomy: a prospective pilot study

STUDY OBJECTIVE: Classic myomectomy was performed via laparotomy. More recently, laparoscopic myomectomy has become a valuable treatment option. Vaginal myomectomy is a surgical procedure that has recently been evaluated. However, few trials have been reported in past literature. The aim of this study was to evaluate feasibility and complication rate of patients submitted to vaginal myomectomy. DESIGN: Prospective study with review of literature (Canadian Task Force classification II-2). SETTING: Department of Obstetrics and Gynecology, S. Filippo Neri Hospital of Rome, Italy. PATIENTS: Consecutive patients with symptomatic myomas who refused hysterectomy. INTERVENTIONS: After preoperative assessment, patients were submitted to vaginal myomectomy using posterior colpotomy. MEASUREMENTS AND MAIN RESULTS: Operative time, perioperative complications, and hospital stay were prospectively recorded. Follow-up examinations were performed at 1 and 12 months postoperatively. Data on possible symptoms, fertility, and pregnancy outcome during follow-up periods were recorded. Myomectomy was completed vaginally in 17 (94%) of 18 patients. Mean operating time was 48 +/- 22 minutes; mean operative blood loss and hospital stay were 210 +/- 350 mL and 3.5 +/- 2.4 days, respectively. Only 2 (11%) patients required blood transfusion. Three patients have conceived spontaneously. CONCLUSION: Vaginal myomectomy is a feasible and safe surgical procedure, with low morbidity and short hospital stay, and could represent a valid alternative to open or laparoscopic myomectomy in selected cases.     

The Effect of a 2-Year Intervention Consisting of Diet,Physical Exercise,Cognitive Training,and Monitoring of Vascular Risk on Chronic Morbidity—the FINGER Randomized Controlled Trial

Objective

To verify whether a multidomain intervention lowers the risk of developing new chronic diseases in older adults.

Grape seed extract suppresses MDA-MB231 breast cancer cell migration and invasion

Background and aim

Breast cancer remains a leading cause of mortality among women. In metastasis, cascade migration of cancer cells and invasion of extracellular matrix (ECM) represent critical steps. Urokinase-type plasminogen activator (uPA), as well as metalloproteinases MMP-2 and MMP-9, strongly contribute to ECM remodelling, thus becoming associated with tumour migration and invasion. In addition, the high expression of cytoskeletal (CSK) proteins, as fascin, has been correlated with clinically aggressive metastatic tumours, and CSK proteins are thought to affect the migration of cancer cells. Consumption of fruits and vegetables, characterized by high procyanidin content, has been associated to a reduced mortality for breast cancer. Therefore, we investigated the biological effect of grape seed extract (GSE) on the highly metastatic MDA-MB231 breast cancer cell line, focusing on studying GSE ability in inhibiting two main metastatic processes, i.e., cell migration and invasion.

Methods

After MDA-MB231 breast cancer cells stimulated with GSE migration and invasion were evaluated by means of trans-well assays and uPA as well as MMPs activity was detected by gelatin zymography. Fascin, β-catenin and nuclear factor-κB (NF-κB) expression were determined using western blot technique. β-Catenin localization was observed by confocal microscopy.

Results

We observed that high concentrations of GSE inhibited cell proliferation and apoptosis. Conversely, low GSE concentration decreased cell migration and invasion, likely by hampering β-catenin expression and localization, fascin and NF-κB expression, as well as by decreasing the activity of uPA, MMP-2 and MMP-9.

Conclusions

These results make GSE a powerful candidate for developing preventive agents against cancer metastasis.