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Background. The aim of the study was to investigate how the expression of tumor markers p21, p27, p53, cyclin D1, EGFR, Ki-67, and CD31 influenced the outcome of advanced inoperable oropharyngeal carcinoma patients, treated with concomitant radiochemotherapy.

Purpose: The long term results and patterns of failure in patients with squamous cell head and neck carcinoma (SCHNC) treated in a prospective randomized trial in which concomitant postoperative radiochemotherapy with Mitomycin C and Bleomycin (CRT) was compared with radiotherapy only (RT), were analyzed., Patients and Methods: Between March 1997 and December 2001, 114 eligible patients with Stage III or IV SCHNC were randomized. Primary surgical treatment was performed with curative intent in all patients. Patients in both groups were postoperatively irradiated to the total dose of 56-70 Gy. Chemotherapy included Mitomycin C 15 mg/m2 after 10 Gy and 5 mg of Bleomycin twice weekly during irradiation. Median follow-up was 76 months (48-103 months)., Results: At 5 years in the RT and CRT arms, the locoregional control was 65% and 88% (p = 0.026), disease-free survival 33% and 53% (p = 0.035), and overall survival 37% and 55% (p = 0.091) respectively. Patients who benefited from chemotherapy were those with high-risk factors. The probability of distant metastases was 22% in RT and 20% in CRT arm (p = 0.913), of grade III or higher late toxicity 19% in RT and 26% in CRT arm (p = 0.52) and of thyroid dysfunction 36% in RT and 56% in CRT arm (p = 0.24). The probability to develop a second primary malignancy (SPM) was 34% in the RT and 8% in the CRT arm (p = 0.023). One third of deaths were due to infection, but there was no difference between the 2 groups., Conclusion: With concomitant radiochemotherapy, locoregional control and disease free survival were significantly improved. Second primary malignancies in the CRT arm compared to RT arm were significantly less frequent. The high probability of post treatment hypothyroidism in both arms warrants regular laboratory evaluation.

Background: Verrucous carcinoma (VC) is a low-grade variant of squamous cell carcinoma. The involvement of the temporal bone and maxillary antrum is very rare., Patients and Methods: The clinicopathologic features of 2 such tumors are reported, and the pertinent literature is reviewed., Results: In the 2 patients, the diagnostic procedure was complicated due to initial inconclusive histology. Both were treated with concomitant radiochemotherapy. They were free of disease for 5.8 and 11 years after diagnosis. An additional 15 cases of VC of the temporal bone and 10 cases of maxillary antrum tumors have been reported in the literature. In 10 patients, multiple biopsies were required, and in 7 patients, a definitive histological diagnosis was not obtained before surgery. The disease reappeared in 8 out of 15 patients treated solely with surgery. Only 2 of them were salvaged by reoperation. Radiochemotherapy only (without any surgery) was successfully used in 4 patients., Conclusions: VC of the temporal bone or maxillary antrum is an extremely rare tumor. For reliable histological diagnosis, multiple biopsies of deep and ample tissue samples are mandatory. Surgery is a mainstay of therapy; however, radiochemotherapy also represents a viable treatment option with curative potential.

Nasopharyngeal carcinoma (NPC) is a malignancy closely associated with Epstein-Barr virus (EBV). It is prevalent among the Chinese of Southern China, whereas outside China, the position seems to be different. The aim of this study was to determine the distribution of EBV genotypes in the patients with NPC in Slovenia, which is a nonendemic area. Detection of EBV was undertaken by testing the throat washes, sera, peripheral blood lymphocytes (PBLs), and biopsies of primary tumors of 48 patients with NPC in Slovenia. The sera of 20 patients with serologically confirmed primary EBV infection served as a control clinical material. The analysis of genotypes was carried out on three regions of EBV genome; BamHI WYH, BamHI I, and BamHI F, using the polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). The results show that, in Slovenia, the predominant combination of EBV genotypes based on the differences in the three genomic regions is ADF. This combination was found in 56 out of 103 different EBV positive clinical samples (throat washes, sera, PBLs, and tumor biopsies) of patients with NPC and in 15 out of 17 sera of patients with primary EBV infection. Very low number of genotypes C and f were detected, in spite of the fact that these two genotypes were considered to be associated with the development and/or maintenance of NPC in Southern China. Genotype f was found in only two tumor biopsies; in all other clinical samples (throat washes, sera and PBLs), genotype F was detected. Genotype C was proven in 31/103 clinical samples, with the highest percentage in tumor biopsies (37.5%). As in the NPC patients from other countries (Alaska is an exception), genotype A was predominant and was detected in 86/103 clinical samples. Genotype B was found in 15 clinical samples of patients with NPC and in 3 the two genotypes A and B were found. In comparison to China, these results show different EBV genotypes distribution. It seems that the genetic disposition of human population is an important factor that may contribute to different susceptibility for specific EBV genotypes., (2006 Wiley-Liss, Inc.)

Objective: To explore whether the combined radiochemotherapy with Vinblastine, Methotrexate, and Bleomycin could be an effective alternative treatment to surgery in verrucous carcinoma (VC) of the head and neck., Methods: Combined radiochemotherapy was used in 12 patients with previously untreated VC. They were irradiated to equivalent tumor dose of 44-70 Gy (median, 56 Gy) and had > or = 2 courses of concomitant chemotherapy. Chemotherapy regimen consisted of prolonged intravenous infusions of Vinblastine 2 mg (day 1); Methotrexate 50 mg (day 2); Bleomycin 15 mg (days 2 and 3), and repetition at 2-3 week intervals., Results: Eleven of 12 patients were cured of VC, and one died of purulent meningitis associated with intracranial extension of VC from the oral cavity. Of 11 patients cured of VC, eight had advanced tumors. The median follow-up of cured patients was 3.6 years (range, 1.4-13.6 years). All the patients developed mucositis of grade > or = 3, whereas no serious late side-effects were recorded., Conclusions: Combined radiochemotherapy with Vinblastine, Methotrexate, and Bleomycine is highly effective in the treatment of VC of the head and neck. It could be successfully used in the patients with inoperable VC or as an alternative to surgery., (2005 Wiley-Liss, Inc.)

Patients with inoperable head and neck tumors were treated concomitantly with radiochemotherapy with mitomycin C and bleomycin in our prospective randomized clinical trial (1991- 1993). For the subgroup of patients with oropharyngeal carcinoma the results with radiochemotherapy were significantly superior to irradiation alone. Such scheme of treatment was then adopted as standard method. Here we present the long-term results and dose- response relationships in patients with inoperable oropharyngeal carcinoma treated by the same radiochemotherapy scheme till 1997. Ninety-five patients with stage III and IV inoperable oropharyngeal squamous cell carcinoma were treated with curative intent, concomitantly with supra-voltage irradiation 2 Gy/day 5 times weekly to 60-73 Gy, bleomycin 5 mg 2 times weekly and. one application of mitomycin C 15 mg/m(2) after 10 Gy. Logistic dose- response curve was calculated. Median follow-up was 85 months. The loco-regional control, disease- free survival and overall survival at 5 years were 55%, 51% and 32% (95% CI: 44-67%, 41-62%, 22-42%), respectively. The probability of new primary malignancy at 5 years was 23%. In multivariate analysis performance status, biological equivalent dose, dose of bleomycin, and stage were identified as independent prognostic factors for loco-regional control, disease-free, and overall survival. Th gamma-value of dose response curve was 2.86. The outcome of the disease was directly proportional to intensity of irradiation and chemotherapy. It appears that in our concomitant radiochemotherapy MiC increased radioresponsiveness of the tumor by its effect on hypoxic fraction.

Purpose: In a prospective randomized clinical study, simultaneous postoperative application of irradiation (RT), mitomycin C, and bleomycin was tested in a group of patients with operable advanced head-and-neck carcinoma. It was expected that the planned combined postoperative therapy would reduce the number of locoregional recurrences and prolong survival., Methods and Materials: A total of 114 eligible patients with Stage III or IV squamous cell head-and-neck carcinoma were randomized to receive postoperative RT alone (Group 1) or RT combined with simultaneous mitomycin C and bleomycin (Group 2). Patients were stratified according to the stage and site of the primary tumor and the presence or absence of high-risk prognostic factors. Primary surgical treatment was performed with curative intent in all patients. Patients in both groups were postoperatively irradiated to the total dose of 56-70 Gy. Chemotherapy included mitomycin C 15 mg/m(2) after 10 Gy and 5 mg of bleomycin twice a week during RT to the planned total dose of 70 mg., Results: At 2 years, patients in the radiochemotherapy group had better locoregional control (86%) than those in the RT alone group (69%; p = 0.037). Disease-free survival and overall survival was also better in the radiochemotherapy group compared with the RT-alone group (76% vs. 60%, p = 0.099; and 74% vs. 64%, p = 0.036, respectively). Patients who benefited from chemotherapy were those with high-risk factors., Conclusion: The results of the present study indicate that concomitant postoperative radiochemotherapy with mitomycin C and bleomycin improves locoregional control and survival in patients with advanced head-and-neck carcinoma. The patients who benefited from chemotherapy were those with high-risk factors.

Purpose: To review the histories of extramedullary plasmacytoma patients diagnosed in Slovenia between 1969 and 1999, to determine the relationship between radiotherapy (XRT) dose and local tumor control, and to clarify the role of elective nodal XRT and the prognostic value of Bartl's histologic grading criteria (originally devised for multiple myeloma [MM])., Methods and Materials: The database of the Cancer Registry of Slovenia was used for the identification of patients. The inclusion criteria were as follows: bone marrow biopsy showing less than 10% plasma cells, normal skeletal survey, and immunohistochemically determined tumor monoclonality. Simulation/portal films were reviewed to assess the extent of elective nodal XRT., Results: Twenty-six patients with 31 tumors fulfilled the inclusion criteria. In 4 patients, nine metachronously appearing solitary tumors were diagnosed. The head-and-neck region and other body sites were the sites of origin of primary tumors in 84% and 16% of patients, respectively, whereas in the two regions, regional disease was seen in 15% and 60% of patients, respectively. Therapy was as follows: XRT, 12 patients; surgery and postoperative XRT, 15 patients; and surgery, 4 patients. Ultimate local and regional control rates were 90% and 97%, respectively, and MM developed in 2 (8%) patients. The 10-year disease-specific and overall survival rates were 87% and 61%, respectively. The analysis of the dose-effect relationship showed that more conservative treatment is justified: for macroscopic disease, 40-50 Gy (2 Gy/day), adjusted to the bulk of disease; for microscopic disease, 36-40 Gy; after R0 surgery, no XRT is required, but close observation is needed. No attempts should be made to treat uninvolved nodal regions. Using Bartl's histologic grading criteria, trends were detected in patients with higher tumor grades: regional lymph node involvement (p = 0.04) and shorter disease-specific survival (p = 0.08)., Conclusions: Extramedullary plasmacytoma is a highly curable disease when XRT is used with or without previous surgery. The rate of conversion to MM is low. Moderate-dose XRT using limited fields is recommended. The prognostic value of Bartl's grading system needs further evaluation.

Objective: The purpose of the present study was to investigate the influence of parasympathomimetic pilocarpine and anticholinergic biperiden on salivation, pH value, and calcium, phosphate, and bicarbonate concentrations in saliva in patients irradiated for malignant tumors of the head and neck region., Study Design: Sixty-nine patients were randomly assigned into 3 groups. Group A consisted of patients receiving pilocarpine, group B of those who were receiving biperiden during radiotherapy and pilocarpine for 6 weeks after its completion, and group C comprised patients receiving neither of the mentioned drugs. The quantity of secreted unstimulated saliva, its pH value, as well as calcium, phosphate, and bicarbonate concentrations in saliva were measured before the beginning of radiotherapy, after 30 Gy of irradiation, at completed irradiation, and 3, 6, and 12 months after completion of radiotherapy., Results: Saliva secretion was found to be the least affected in the group of patients receiving biperiden throughout the course of radiotherapy. One year after completion of therapy, the quantity of secreted saliva could only be measured in the patients receiving biperiden during radiotherapy; it amounted to 16% of the average initial quantity of saliva secreted before the beginning of irradiation. In all 3 groups of patients, mean pH value decreased during radiotherapy and started to increase again after completion of irradiation. In group B the decrease in pH value after radiotherapy was statistically significantly smaller than that in group C (P =.01). During and after irradiation, calcium concentration was increased in all 3 groups of patients. Phosphate concentration decreased during radiotherapy in all 3 groups. In group B it started to increase again 3 months after completion of radiotherapy. Bicarbonate concentration showed a slight increase during radiotherapy and started to decrease again after completion of irradiation., Conclusion: The results of our study indicate that the inhibition of saliva secretion during radiotherapy and its stimulation after completion of treatment can contribute not only to some preservation of the quantity of saliva but also to at least partial preservation of its quality in terms of pH value and calcium, phosphate, and bicarbonate concentrations.

We report a case of a 35-year-old man who died of a brain infarct 20 months after radiotherapy for carcinoma of the tonsil with metastases to the cervical lymph nodes. Histology revealed mild atherosclerosis, necrotizing vasculitis, and occlusive thrombosis of the internal carotid artery. Significant changes were observed in the vasa vasorum: swelling and detachment of the endothelium, subendothelial oedema, hyaline change, fibrinoid necrosis of the vessel walls with mononuclear cellular infiltration, accompanied by focal haemorrhages and chronic inflammation in the periadventitial soft tissue. We believe that these changes of the vasa vasorum and necrotizing vasculitis are causally related and that vasculitis represents focal ischaemic necroses with inflammatory reaction. Our findings support the hypothesis, based on experimental studies, that injury to the vasa vasorum is an important mechanism in the development of radiation-induced vasculopathy of large arteries. They also suggest an evolution of the injury to the vasa vasorum and periadventitial tissue from the early lesions described in our patient, to late stages resulting in dense periadventitial fibrosis as reported previously. We suggest that injury to the vasa vasorum and the consequent ischaemic lesions of the arterial wall are morphological features distinguishing radiation-induced arterial injury from spontaneous atherosclerosis.

Sixty-one patients with locally advanced squamous cell carcinomas of oral cavity and oropharynx were treated with chemotherapy, intravenously applied, in addition to radiation and/or surgery. An attempt was made to synchronize the tumor cell population by application of low doses of Vinblastine and the subsequent chemotherapy was based on the uptake of 99m-Tc --labelled Bleomycin in the tumor as an indication of synchronization. Increased number of mitoses in aspiration biopsy specimens and shift in the DNA distribution pattern on DNA histograms were taken as indicative of synchronization. A 50--100% regression of the tumor was achieved in 19 out of 38 patients with residual or recurrent tumors. The results were better in those patients, who received chemotherapy based on individual Tc-Bleomycin uptake curves. In 23 patients with previously untreated T3 tumors of oral cavity and oropharynx the results were somewhat better, but there was not statistically significant improvement on attempts with synchronization in this small series. There were no serious complications connected with chemotherapy.