A phase II trial of low-dose gemcitabine and radiation alternated to cisplatin and 5-fluorouracil: an active and manageable regimen for stage IV squamous cell carcinoma of the head and neck.

BACKGROUND: The addition of gemcitabine may be a reasonable way to enhance the activity of the alternating cisplatin/5-fluorouracil and radiation regimen considered the referring approach for patients with advanced squamous cell carcinoma (SCC) of the head and neck at the National Institute for Cancer Research of Genoa. METHODS: Three courses of cisplatin, 20mg/m(2)/day and 5-fluorouracil, 200mg/m(2)/day, days 1-5 (weeks 1, 4, and 7) alternated to 3 courses of radiotherapy at standard fractionation (weeks 2-3, 5-6, 8-9) up to 60Gy, and gemcitabine, 50mg/m(2) on monday of each week of radiation, were administered to 47 patients with stage IV (42 patients) or relapsed after surgery (5 patients), SCC of the oral cavity, pharynx or larynx. RESULTS: Eighty-five percent of the patients completed the planned treatment. Main grade 3-4 acute toxicities were: mucositis (40%), neutropenia (26%) and thrombocytopenia (30%). Twenty-seven patients reached a complete response (57%). Seven partial responders were rendered disease-free by surgery (final complete response rate: 72%). At a median follow-up of 37 months, 3-year overall survival, progression-free survival and loco-regional control are 50%, 43% and 54%, respectively. CONCLUSIONS: The addition of gemcitabine at low dose to our referring alternating regimen is feasible and very active. It may improve the long-term outcomes despite an acceptable increase of acute mucoseal toxicity.

Clinical applications of autologous cryoplatelet gel for the reconstruction of the maxillary sinus. A new approach for the treatment of chronic oro-sinusal fistula.

The authors report their clinical experience regarding an original method of surgical repair of oro-sinusal communications. From September 1999 to December 2003, 13 patients (7 male and 6 female patients; mean age: 52 years, range: 24-68 years) underwent surgical repair of an oro-antral fistula by means of cryoplatelet gel: in three patients, it was mixed with bioglass granules; in two, it was mixed with Bioss; in three, it was mixed with particulate bone extracted by means of a bone grafter from the oral cavity close to the operative site, with addition of demineralised bovine bone; in three, it was used together with porose hydroxyapatite, and in two patients the cryoplatelet gel was used only. No postoperative complication was reported; primary wound healing was achieved within seven to nine days. A bony orthopantoscintigraphy was performed a few months following the operative procedure, showing an active osteogenic process. In eight patients, a CT was performed after 8 to 12 months from the operation, showing a normal pneumatization with reconstruction of the floor of the maxillary sinus. Although preliminary, these findings seem to suggest that the use of bioengineered materials coupled with growth factors and osteoprogenitor cells may represent a valuable alternative to autologous bone transplantation for the reconstruction of the maxillary sinus.

Comparison of DNA adduct levels in nasal mucosa, lymphocytes and bronchial mucosa of cigarette smokers and interaction with metabolic gene polymorphisms.

The recent introduction of biomarkers in population studies of lung cancer has improved the traditional epidemiological approach, especially in the detection of high risk groups. Many inhalable carcinogens form DNA adducts, an initial event in lung carcinogenesis, and therefore the identification of easily accessible sources of DNA for population studies is considered a leading priority in the field. In this study we compared the frequency of DNA adducts in samples from nasal brushing, bronchial biopsy and peripheral blood lymphocytes (PBL) in a group of 55 subjects, both smokers and non-smokers, undergoing bronchoscopy for diagnostic purposes. Polymorphisms in the CYP1A1, GSTM1 and GSTT1 genes were also evaluated. The level of DNA adducts measured by (32)P-labelling assay in nasal mucosa (10(8) relative adduct level, mean +/- SD 1.10 +/- 0.66) was higher than in bronchial mucosa (0.82 +/- 0.36) and in PBL (0.54 +/- 0.39, P < 0.01). DNA adducts measured in nasal mucosa and in PBL were correlated with those in bronchial mucosa (P < 0.01 and P < 0.05, respectively). DNA adducts in smokers were significantly increased in both nasal mucosa and PBL, with a significant dose-response linear trend (P < 0.05). No significant effect on DNA adduction of the genetic polymorphisms investigated was found. Nasal mucosa brushing proved to be a suitable procedure for the (32)P-labelling assay and its use in population studies should be further explored.

13-cis retinoic acid in head and neck cancer chemoprevention: results of a randomized trial from the Italian Head and Neck Chemoprevention Study Group.

Patients with squamous cell carcinoma of the head and neck (HNSCC) after being treated radically remain at high risk for both recurrent and second primary tumours. 13-cis retinoic acid (13-cRA) was demonstrated to reverse pre-malignant lesions of the oral cavity and to reduce the incidence of second primary tumours in patients treated radically for HNSCC. Synergism between retinoids and interferon in tumoural cell lines have been demonstrated. Based on these data, the Italian Head and Neck Chemoprevention Study Group started a randomized chemoprevention study in patients radically treated for stage III and IV HNSCC. From February 1992 to January 1996, 267 patients were randomized: 126 were allocated to the control group, 126 were randomized to receive 13-cRA at a dose of 0.5 mg/kg per day per os and 15 patients have been assigned to the group of 13-cRA plus interferon alpha2a (IFN-alpha2a) at a dose of 3,000,000 UI 3 times a week (randomization in this arm interrupted due to administrative financial problems). The mean follow-up was 39 months. The 5-year actuarial survival was 58.9% for patients of the 13-cRA group and 57.2% for those of the control group (P=0.94). Among evaluable patients, disease progression was observed in 45 of 123 patients (36.6%) of the 13-cRA group and in 42 of 124 (33.9%) of the control group. The 5-year actuarial relapse-free survival was 48.9% for the 13-cRA group and 55.6% for the control group (P=0.62). Adverse effects, mostly of grade I were reported in 69.4% of treated patients (haematologic disorders, mucositis, conjunctivitis, cutaneous toxicity, hypertriglyceridemia and hypercholesterolemia). Only 5 patients (4.1%) reported grade III-IV toxicity. Low-dose of 13-cRA given for 1 year is ineffective as chemoprevention in patients with radically treated HNSCC.

beta-carotene supplementation in patients radically treated for stage I-II head and neck cancer: results of a randomized trial.

This study was aimed at evaluating the efficacy of beta-carotene in improving survival (S) and in disease-free survival (DFS) and reducing the incidence of second primary tumors (SPT) in patients with a radically treated stage I-II squamous head and neck tumors. Eligible patients were randomly allocated to receive beta-carotene (n=104) or no treatment (n=110). beta-carotene was administered at the dose of 75 mg/day for 3-month cycles within one month intercycle intervals for a 3-year period. The 3-year compliance to the beta-carotene was 68.7%. Only eight patients reported drug-related toxicity (7.8%). The median follow-up of all patients was 59 months. The median follow-up was 61 months (range 1-116 months) in the beta-carotene and 58 months (1-123 months) in the control group. The 10-year DFS was 75.7% for the patients in the beta-carotene and 74.3% for those in the control group (P=0.56). The 10-year S was 85.9% in the beta-carotene group and 80.9% in the control group (P=0.20). beta-carotene supplementation had no significant effect on the incidence of second primary tumors (RR=0.99; 95% C.I. 0.28-3.44). A statistically non-significant 40% reduction in the risk of death among subjects assigned to the beta-carotene compared to the controls was observed (RR=0.60; 95% C.I. 0.26-1.38). No increase in the death from cardiovascular diseases was observed among patients treated with beta-carotene. Our results might support the hypothesis that an adequate beta-carotene treatment could be potentially associated with a decreased risk of death in these patients.

Expansion of natural killer cells in patients with head and neck cancer: detection of "noninhibitory" (activating) killer Ig-like receptors on circulating natural killer cells.

BACKGROUND: In a group of patients with head and neck cancers (H&NC), the expansion of the population of CD3-,CD16+ natural killer (NK) cells in the peripheral blood was studied. METHODS: Cytofluorimetric analysis of the expression of killer Ig-like receptors (KIR, namely p58.1, p58.2, p58.3, p70, and p140) and CD94-NKG2a was performed. Cytolytic activities were studied using 51Cr release assay. T and NK cell cloning was performed using limiting dilution culture conditions. Cytokine production was analyzed using commercial enzyme immunoassays. RESULTS: Phenotypic analysis showed that the expanded populations were heterogeneous. Even in the presence of a large number of circulating NK cells, "nonspecific" cytolytic capacities were heavily reduced, whereas cytolytic capacity related to T cells was virtually normal. Unlike NK cell clones derived from healthy donors, most NK cells derived from H&NC patients expressed surface "activating" NK cell receptors (KAR) for HLA, detected by use of a redirected cytolytic assay. Analysis of the CD4+ subpopulation at the clonal level demonstrated that they had a severe proliferative defect. CONCLUSION: These experimental data indicated that H&NC patients have a polyclonal expansion of functionally deficient NK cells expressing KAR. In addition, the proliferative capacity of patients' "helper" cells was strongly inhibited, thus accounting for a severe impairment of cytolytic activity of the expanded NK cells.

Micronuclei and p53 accumulation in preneoplastic and malignant lesions of the head and neck.

No single biomarker can predict the risk for malignant transformation of precancerous lesions of the head and neck. Micronucleus frequency, nuclear p53 accumulation and mitotic index were determined in proliferating basal cells using paraffin-embedded specimens from normal, dysplastic and malignant tissues. p53 accumulation was detected by immunohistochemistry using pAb 1081 and pAb 240 antibodies. Micronuclei were scored in the same cell population and classified for the presence/ absence of p53 accumulation in the main nucleus. Fifty-three carcinomas and 15 precancerous lesions were studied. Both micronuclei and p53 accumulation were found in precancerous lesions, suggesting that they are early events in head and neck squamous cell carcinoma progression. The two biomarkers were not related to each other: indeed, micronucleus frequency was higher in p53-negative than in p53-positive cells. Three patients with precancerous lesions later developed carcinomas; all three cases showed high frequencies of both micronuclei and cells accumulating p53 protein.