Inactivation of the putative suppressor gene DOK1 by promoter hypermethylation in primary human cancers.

The DOK1 gene is a putative tumour suppressor gene located on the human chromosome 2p13 which is frequently rearranged in leukaemia and other human tumours. We previously reported that the DOK1 gene can be mutated and its expression down-regulated in human malignancies. However, the mechanism underlying DOK1 silencing remains largely unknown. We show here that unscheduled silencing of DOK1 expression through aberrant hypermethylation is a frequent event in a variety of human malignancies. DOK1 was found to be silenced in nine head and neck cancer (HNC) cell lines studied and DOK1 CpG hypermethylation correlated with loss of gene expression in these cells. DOK1 expression could be restored via demethylating treatment using 5-aza-2'deoxycytidine. In addition, transduction of cancer cell lines with DOK1 impaired their proliferation, consistent with the critical role of epigenetic silencing of DOK1 in the development and maintenance of malignant cells. We further observed that DOK1 hypermethylation occurs frequently in a variety of primary human neoplasm including solid tumours (93% in HNC, 81% in lung cancer) and haematopoietic malignancy (64% in Burkitt's lymphoma). Control blood samples and exfoliated mouth epithelial cells from healthy individuals showed a low level of DOK1 methylation, suggesting that DOK1 hypermethylation is a tumour specific event. Finally, an inverse correlation was observed between the level of DOK1 gene methylation and its expression in tumour and adjacent non tumour tissues. Thus, hypermethylation of DOK1 is a potentially critical event in human carcinogenesis, and may be a potential cancer biomarker and an attractive target for epigenetic-based therapy.

Classification of GLOSSECTOMIES: Proposal for tongue cancer resections.

BACKGROUND: Surgery of tongue tumors includes different procedures ranging from mucosal resection to complex combined resection. Numerous terms have been used to describe such procedures, but there is no consensus between the terminology and the extent of resection. METHODS AND RESULTS: We searched the medical literature and found a lack of published information. We undertook to describe a new classification of surgical procedures for tongue tumor resection. We based it upon the surgical anatomy of the tongue and the spread of the cancer. We posited that there were five major types of glossectomy embracing all the methods of tongue cancer resection. This classification was reviewed and endorsed by an international team of experts. CONCLUSION: We propose a more precise classification than that currently in practice, thereby bringing clarity and consistency to the terminology, facilitating shared communication between surgeons, comparison between published research, and ultimately improving surgical practice and patient care.

Total glossectomy with preservation of the larynx: oncological and functional results.

Our aim was to analyse the overall and disease-free survival (DFS), time to recovery of oral feeding, and morbidity, in a consecutive series of patients who had total glossectomy with preservation of the larynx for advanced cancer of the tongue at the European institute of Oncology (Milan). From June 2002 to April 2011, 37 patients who were treated for advanced cancer of the tongue had total glossectomy, bilateral neck dissection, and preservation of the larynx. Various flaps were used for reconstruction. Overall and disease-free survival were assessed from the day of operation to the latest outpatient examination. Postoperative morbidity and rehabilitation of feeding were also assessed. Six patients had major complications, four of whom had a second operation for necrosis of the flap. Actuarial five-year overall survival (OS) and disease-free survival were 54% and 47%. Twenty-four patients (65%) were operated on as their first treatment, and had 79% five-year overall survival and 61% 5-year disease-free survival. Twenty-six patients were eventually able to feed orally postoperatively. Although this retrospective study include a limited number of patients, the results support the validity of total glossectomy as a safe procedure for advanced cancer of the tongue. Pretreated patient were previously treated with surgery, radiotherapy or chemoradiotherapy with curative purposes. Nevertheless, the long period required for recovery of oral feeding indicates that total glossectomy should be reserved for highly motivated patients.

Compartmental tongue surgery: Long term oncologic results in the treatment of tongue cancer.

Compartmental tongue surgery (CTS) is a surgical technique that removes the compartments (anatomo-functional units) containing the primary tumor, eliminating the disease and potential muscular, vascular, glandular and lymphatic pathways of spread and recurrence. Compartment boundaries are defined as each hemi-tongue bounded by the lingual septum, the stylohyoid ligament and muscle, and the mylohyoid muscle. In this non-randomized retrospective study we evaluated the oncologic efficacy of CTS in patients with squamous cell carcinoma (SCCA) of the tongue treated from 1995 to 2008. We evaluated 193 patients with primary, previously untreated cT2-4a, cN0, cN+, M0 SCCA with no contraindication to anesthesia and able to give informed consent. Fifty patients treated between October 1995 and July 1999 received standard surgery (resection margin >1cm); 143 patients treated between July 1999 and January 2008 received CTS. Study endpoints were: 5-year local disease-free, locoregional disease-free and overall survival. After 5years, local disease control was achieved in 88.4% of CTS patients (16.8% improvement on standard surgery); locoregional disease control in 83.5% (24.4% improvement) and overall survival was 70.7% (27.3% improvement). The markedly improved outcomes in CTS patients, compared to those treated by standard surgery, suggest CTS as an important new approach in the surgical management of tongue cancer.

Composite reconstruction in advanced cancer of the mouth floor: autogenous frozen-thawed mandibular bone and free flaps.

Mandibular symphyseal resection requires composite reconstructions, often with unsatisfactory morphofunctional results. Seven patients with advanced squamous cell carcinoma of the floor of the mouth underwent block resection with immediate reconstruction, using the removed mandible treated with liquid nitrogen and covered with a free forearm flap. In all cases, the resection was radical and no major postoperative complications occurred. Two patients died in 6 months for distant metastases and regional recurrence. In the other 5 patients, no local recurrence occurred at a mean follow-up of 52 months (36-70). Immediate cosmetic and functional results were good. Of the 5 patients, 4 had late complications requiring further surgery. This technique of bone reimplantation produces no donor site morbidity, perfect immediate morphological result, and is of low cost. The free forearm flap is effective in sealing the oral cavity, though further clinical and experimental studies are necessary to reduce late local complications.

Phase II trial of vinorelbine, cisplatin and continuous infusion of 5-fluorouracil followed by hyperfractionated radiotherapy in locally advanced head and neck cancer.

OBJECTIVE: We undertook a prospective phase II study to assess the feasibility and activity of a new induction chemotherapy regimen followed by hyperfractionated irradiation in locally advanced squamous cell head and neck cancer. METHODS: 25 patients with locally advanced head and neck cancer were treated with 4 cycles of vinorelbine (20 mg i.v. day 1, 3), cisplatin (60 mg/m(2) i.v. day 1) and 5-fluorouracil (200 mg/m(2) continuous i.v. infusion day 1-21) (ViFuP regimen) followed by bifractionated radiotherapy (bidRT) up to 74.4 Gy in 62 fractions of 1.2 Gy twice daily. RESULTS: Chemotherapy was well tolerated, 6 patients developed grade 3 and one patient grade 4 neutropenia. Response to chemotherapy was observed in 19 patients (76%) including three complete responses and 16 partial responses. Planned bidRT was completed in 25 patients and all but one received planned bidRT dose without interruptions. Radiotherapy was well tolerated, mucositis was the most common side effect (grade 3-12 patients, grade 4-1 patient). At evaluation after the completion of bidRT, 13 patients had complete response (52%), 7 partial response (28%), 2 stable disease and 3 tumor progression. At the median follow-up of 18.2 months, 11 patients were alive and free of disease, and 14 patients had died (12 of tumor). Late xerostomy was observed in all but one 3-month survivors. Late mandibular necrosis was seen in 1 patient. CONCLUSIONS: bidRT preceded by ViFuP seems a feasible and active combination in locally advanced head and neck cancer. Good patient compliance did not compromise the delivery of planned dose of bidRT. However, short median duration of response (14.6 months) and moderate median overall survival (18.7 months) indicate the need for more intensive therapeutic strategies. On the basis of these results, modifications of our treatment schedule (shortening the overall treatment time by reduction of chemotherapy cycles and the use of chemotherapy concomitantly with irradiation) are planned for the future study.