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Duchenne muscular dystrophy (DMD) is the most severe and frequent form of muscular dystrophy. The mdx mouse is one of the most widely used experimental models to understand aspects of the biology of dystrophic skeletal muscles and the mechanisms of DMD. Oxidative stress and apoptosis are present in early stages of the disease in mdx mice. The high production of reactive oxygen species (ROS) causes activation of apoptotic death regulatory proteins due to DNA damage and breakdown of nuclear and mitochondrial membranes. The quadriceps (QUA) muscle of the mdx mouse is a good tool to study oxidative events. Previous studies have demonstrated that cilostazol exerts an anti-oxidant effect by decreasing the production of reactive oxygen species (ROS). The present study aimed to evaluate the ability of cilostazol to modulate oxidative stress and apoptosis in the QUA muscle of mdx mice. Fourteen-day-old mdx mice received cilostazol or saline for 14 days. C57BL/10 mice were used as a control. In the QUA muscle of mdx mice, cilostazol treatment decreased ROS production (-74%), the number of lipofuscin granules (-47%), lipid peroxidation (-11%), and the number of apoptotic cells (-66%). Thus cilostazol showed anti-oxidant and anti-apoptotic action in the QUA muscle of mdx mice., (© 2022 Company of the International Journal of Experimental Pathology (CIJEP).)

There is strong cross-talk between abnormal intracellular calcium concentration, high levels of reactive oxygen species (ROS) and an exacerbated inflammatory process in the dystrophic muscles of mdx mice, the experimental model of Duchenne muscular dystrophy (DMD). In this study, we investigated effects of Idebenone, a potent anti-oxidant, on oxidative stress markers, the anti-oxidant defence system, intracellular calcium concentrations and the inflammatory process in primary dystrophic muscle cells from mdx mice. Dystrophic muscle cells were treated with Idebenone (0.05 μM) for 24 h. The untreated mdx muscle cells were used as controls. The MTT assay showed that Idebenone did not have a cytotoxic effect on the dystrophic muscle cells. The Idebenone treatment was able to reduce the levels of oxidative stress markers, such as H 2 O 2 and 4-HNE, as well as decreasing intracellular calcium influx in the dystrophic muscle cells. Regarding Idebenone effects on the anti-oxidant defence system, an up-regulation of catalase levels, glutathione reductase (GR), glutathione peroxidase (GPx) and superoxide dismutase (SOD) activity was observed in the dystrophic muscle cells. In addition, the Idebenone treatment was also associated with reduction in inflammatory molecules, such as nuclear factor kappa-B (NF-κB) and tumour necrosis factor (TNF) in mdx muscle cells. These outcomes supported the use of Idebenone as a protective agent against oxidative stress and related signalling mechanisms involved in dystrophinopathies, such as DMD., (© 2022 Company of the International Journal of Experimental Pathology (CIJEP).)

Oxidative stress is a critical element in relationship to the pathophysiology of Duchenne muscular dystrophy (DMD). In the mice the diaphragm (DIA) is most resembles the dystrophic human pathology. In this study we have evaluated the consequences of a synthetic antioxidant (tempol) on oxidative stress parameters in the DIA muscle of mdx mice. The mdx mice were separated into two groups: mdx, the control group receiving intraperitoneal (i.p.) injections of saline solution (100 µL), and mdxT, the treated group receiving i.p. injections of tempol (100 mg/kg). The tempol-treated group showed reduced oxidative stress markers, decreasing the dihydroethidium reaction (DHE) area; autofluorescent lipofuscin granules; and 4-hydroxynonenal (4-HNE)-protein adduct levels. DIA muscle of mdx mice. At the same time, the manganese-superoxide dismutase 2 (SOD2) levels were increased in the tempol-treated group. In addition, the tempol-treated group showed reduced levels of glutathione-disulphide reductase (GSR), glutathione peroxidase 1 (GPx1) and catalase (CAT) in immunoblots. The tempol-treated group has also shown lower relative gene expression of SOD1, CAT and GPx than the non-treated group. Our data demonstrated that tempol treatment reduced oxidant parameters and increased anti-oxidant SOD2 levels in the DIA muscle of mdx mice, which may contribute to the normalization of the redox homeostasis of dystrophic muscles., (© 2020 Company of the International Journal of Experimental Pathology (CIJEP).)

Background: The role of low doses of cisplatin and concomitant postoperative radiotherapy in high risk head and neck squamous cell carcinoma has not yet been defined., Methods: Patients treated with definitive surgery, who had histological evidence of involvement of more than 2 lymph nodes, extracapsular extension of disease, perineural and/or intravascular invasion, involved or close surgical margins, received postoperative radiotherapy plus 75 mg/m(2) of cisplatin every 3 weeks during the radiotherapy cycle. The primary endpoints were to evaluate treatment compliance and overall, cause-specific, and disease-free survival., Results: A total of 142 patients were enrolled. With a median follow-up of 40 months, 5-year overall survival was 68%, cause-specific survival 78% and disease-free survival 82%. At multivariate analysis surgical margins status and extracapsular lymph node invasion were the only statistically significant prognostic factors. Fifty-three percent of the patients developed severe mucositis and 14% hematologic toxicity of grade 3. The 3 planned concomitant chemotherapy cycles were delivered to 48% of the patients., Conclusions: Postoperative radiotherapy and concomitant low-dose cisplatin was an effective treatment in high risk head and neck patients. The total toxicity observed was lower compared with that reported with higher doses of cisplatin, although the delivery of all the 3 planned chemotherapy cycles was challenging. The distant failure rate was high, which was an unsatisfactory result., ((c) 2009 American Cancer Society.)

Background: Radiotherapy (RT) has a remarkable success rate in the treatment of patients with glottic carcinoma. The objectives of the current study were to assess the results in a group of consecutive patients with comparable characteristics who were treated with RT (6-megavolt photon linear accelerator) and to determine the prognostic factors that may influence local control in patients with early-stage glottic carcinoma. The impact on local control of tobacco smoking and second primary malignancies also was investigated., Methods: Four hundred ten patients with T1-T2 squamous cell carcinoma of the glottis who were treated between 1986 and 2001 were analyzed retrospectively with regard to local control and overall survival. Potential prognostic factors for local control were evaluated with univariate and multivariate models. The impact of technologic advances also was evaluated., Results: The 5-year and 10-year overall survival rates were 83% and 63.5%, respectively. The overall 10-year local control rate for patients with T1-T2 glottic carcinoma was 89%. The median time to recurrence was 7 months. Univariate analysis showed that tumor category, tumor size, macroscopic appearance of the lesion, RT fraction size, persistent edema, year of RT treatment, unchanged dysphonia, and surgical option all had a significant influence on local control; whereas multivariate analysis showed that only persistent dysphonia and year of RT treatment were significantly associated with increased local control. A 22.2% rate of second primary malignancies was reported: second primary tumors were the major cause of death in the patients studied. Only 2 patients died of laryngeal carcinoma; 304 patients were alive with their disease in complete remission, 1 patient was alive with recurrent laryngeal carcinoma after undergoing salvage surgery, and 103 patients died of either intercurrent disease or a second primary tumor., Conclusions: The use of a 6-megavolt photon linear accelerator achieved a high rate of local control in patients with T1-T2 glottic carcinoma. Dysphonia and the year of RT treatment were the most important prognostically significant factors for patient outcome. The occurrence of a second primary tumor was the most frequent cause of death, especially among patients who did not stop smoking after a diagnosis of glottic carcinoma., (Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11575)

Background: During the last 20 years, survival rates of head and neck carcinoma patients in the United States and Europe have plateaued. To determine the factors that can reduce mortality rates, we examined changes in clinical presentation and survival rates across 24 years of treatment of head and neck carcinoma patients., Methods: A retrospective study of patients with head and neck carcinoma was conducted from January 1, 1975, to December 31, 1998. We identified 2143 eligible patients with squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, and larynx. Changes in gender, clinical stage, and therapy were evaluated separately for each site of cancer across five consecutive periods. Probability of dying and overall survival rates were estimated. Odds ratios (ORs) and hazard ratios were calculated., Results: An increase in T1 versus T2 or higher stage carcinoma was more probable for the oral cavity and larynx (OR = 4.1 and 3.0, respectively) in the last versus the earliest period. An increase in radical treatments was more probable for carcinomas of the oral cavity, oropharynx, hypopharynx, and larynx (10.2, 34.8, 12.5, and 2.1-fold, respectively) in the last versus the earliest period. A decreasing trend of probability of dying from the first head and neck carcinoma during the 1970s versus the 1990s was found. The overall survival rates at 5 years was 32% in 1975-1978 versus 51% in 1989-1993., Conclusions: In contrast with survival rates in the United States and Europe, our findings show a significant increase in overall survival rates during the last 20 years. This increase is attributable to changes in diagnostic-therapeutic approaches and to early consultation with a physician for symptoms arising in the head and neck region., (Copyright 2002 American Cancer Society.)

Background: Patients with advanced, inoperable head and neck cancers have cure rates of approximately 10-15%. In these patients, concomitant chemoradiotherapy seems to improve local control and survival. 5-Fluorouracil (5-FU) administered by continuous infusion and cisplatin plus concomitant conventional radiation therapy may be promising in treating advanced, inoperable head and neck cancers., Methods: Forty-five evaluable patients with primary nonmetastatic, inoperable head and neck cancers were treated. From January 1987 to April 1988, the patients were treated with cisplatin plus radiation therapy (Group 1) and from May 1988 to November 1990, they were treated with the same combination plus 5-FU, given in continuous infusion (Group 2). Clinical and pathologic responses were assessed after radiation therapy was completed. Patients who relapsed underwent salvage surgery, if possible. The disease free and overall survival rates of the patients were evaluated., Results: The overall response rate (complete and partial response) was 93%, 60% of which comprised complete remissions. Despite the high response rates obtained in the two groups, the time to progression for complete responses and the median survival time were unsatisfactory (13 [Group 1] and 10 months [Group 2] and 17 [Group 1] and 16 months [Group 2], respectively). The toxicity rate from the two treatments was not relevant. A Grade II mucositis, according to the World Health Organization, was found in 25 patients, and the treatment was interrupted for 7-10 days in 5., Conclusions: In this study, despite an improvement in the number of complete responses, the chemotherapeutic regimen with or without 5-FU did not prolong the overall patient survival significantly.

Between June 1980 and December 1983, 111 patients with inoperable epidermoid bronchogenic carcinoma (limited disease) were entered into a randomized trial comparing radiotherapy alone versus radiotherapy and combination chemotherapy with cyclophosphamide, Adriamycin (doxorubicin), methotrexate, and procarbazine. Thirty-five of 62 (56.4%) patients treated with 4500 rad in 15 fractions in 3 weeks and 19 of 49 (38.8%) patients treated with the same radiation treatment and chemotherapy had an objective response. The difference in response rate was not significant (P = 0.900). Median time to progression was 5.9 and 7.02 months, respectively, for the radiation treatment and the combined treatment. Median survival was 11.74 and 10.03 months, respectively, without statistically significant differences between the two groups of patients. The toxicity was acceptable and no treatment-related death occurred in either treatment schedule. In this study no significant superiority of combined radiotherapy and chemotherapy treatment over radiation therapy alone was evidenced. Whether different chemotherapy regimens may prove more effective in this context should be clarified by further studies.