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.     

Autotransplantation of frozen-thawed ovarian tissue in a young woman: ultrastructure and viability of grafted tissue

This is the first report of the presence of ultrastructurally normal primordial and primary follicles, 13 months after autotransplantation of frozen-thawed human ovarian tissue. The stroma contained numerous viable and ultrastructurally normal blood vessels but showed poor cellular density.     

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.     

Menstrual and reproductive factors and risk of non-fatal acute myocardial infarction in Italy

OBJECTIVE: We analyzed the relation between factors related to endogenous female hormones and the risk of acute myocardial infarction (AMI). STUDY DESIGN: We used a combined dataset from three Italian case-control studies, including 609 women with non-fatal AMI and 1106 controls hospitalized for acute conditions. RESULTS: The odds ratios (OR) of AMI were 1.36 (95% confidence intervals, CI 0.95-1.96) in women with an irregular menstrual pattern compared to a regular one, and 1.45 (95% CI 1.07-1.97) in parae compared to nulliparae, without linear trend in risk with number of children. No relation was found with menopausal status, age at menarche and menopause, abortion, and age at first and last birth. Compared to women without abortions the OR was 0.84 (95% CI 0.60-1.18) for >1 abortion; compared to women without spontaneous or induced abortion, the ORs were 0.92 (95% CI 0.62-1.38) for >1 spontaneous and 0.63 (95% CI 0.36-1.08) for >1 induced abortion. The association of parity and irregular menstrual cycles was stronger in pre-/peri-menopausal women and in current smokers. Compared to nonsmokers with regular menstrual cycle, the OR was 5.98 (95% CI 3.38-10.56) for smokers with irregular one, and compared to nonsmokers nulliparae the OR for smokers parae was 4.77 (95% CI 3.12-7.29). CONCLUSIONS: Irregular menstrual cycles and parity were related to increased AMI risk, mainly among pre-/peri-menopausal women and among smokers.