Involvement of mitochondrial DNA sequence variations and respiratory activity in late complications following radiotherapy.

PURPOSE: Mitochondria and ionizing radiation overlap in a number of features; for instance, both generate harmful reactive oxygen species, and that radiation can induce cell death through the intermediary of mitochondria. Because a number of genetic variations in nuclear genes are frequently associated with response to cancer treatment, the aim of this case-control study was to test the hypothesis that mitochondrial DNA (mtDNA) genetic variations can contribute to patient-to-patient variability in normal tissue response to radiotherapy. EXPERIMENTAL DESIGN: Thirty-two nasopharyngeal carcinomas patients treated with definitive radiotherapy were included. The grade (G) of s.c. and deep tissue fibrosis was scored according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer grading system. Coding and RNA mtDNA (between 611 and 15,978 bp) were sequenced, and genetic variations were scored. Mitochondrial respiratory activity was measured by resazurin reduction assay. RESULTS: Data showed a significantly (P = 0.003) higher number of nonsynonymous genetic variations in the radiosensitive (G(2)-G(3); 16 patients) as compared with the control (G(0)-G(1); 16 patients) groups. The nonsynonymous A10398G variation in the ND3 gene was significantly associated with fibrotic reaction (P = 0.01). The radiosensitive patients had a 7-fold (95% confidence interval, 1.16-51.65) higher risk of developing moderate to severe fibrosis (G(2)-G(3)) following radiotherapy. This was significantly correlated with lower mitochondrial respiratory activity (P = 0.001). CONCLUSION: Mitochondria contribute to radiation sensitivity, and genetic variations can be associated with late reactions to radiotherapy. Predictive markers of radiosensitivity should take into account mtDNA genetic variations in addition to variations in nuclear genes.

Maxillary sinus carcinoma. Natural history and outcome.

OBJECTIVE: To assess natural history, treatment outcome and pattern of relapse in patients with maxillary sinus carcinoma. METHODS: A review was conducted of the medical records of all adult patients with maxillary sinus carcinoma, who were treated at King Faisal Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia, between January 1990 and December 1999. A total of 60 patients were identified for analysis, 36 men and 24 women; the median age was 58-years (range 23-95). Major presenting symptoms were facial swelling 55%, facial pain 50%, and nasal obstruction 43.4%, with a median duration of 5-months (range 1-24). Histology was squamous cell carcinoma in 71.7% and adenoid cystic in 16.7%. They were restaged according to American Joint Committee on Cancer classification 1997 as II, III and IV in 1, 10 and 49. Thirty patients received treatment with curative intent (surgery in 4 patients, radiotherapy in 2, and combined modality in 24), 6 patients refused treatment and 24 were treated palliatively. RESULTS: With a median follow up of 50-months (range 2-128) in surviving patients treated with a curative intent, 12/30 failed locally, 4/30 in the regional neck nodes and 2/30 had systemic relapse. The actuarial 5-year overall survival (OS), relapse free survival (RFS) and local control rate (LC) were 55%, 39% and 51%. Treatment modality was the only significant prognostic factor for outcome, with 5 year OS, RFS and LC of 72%, 49% and 61%, for combined modality using surgery followed by radiotherapy compared to 0% for single approach (p=0.0003, p=0.0052 and p=0.0098) CONCLUSION: This study indicates that the majority of our patients presented with advanced disease, resulting in poor outcome to conventional treatment modalities. Efforts should be directed to minimize the delay in diagnosis at the primary care level. Combined modality treatment should be offered to all patients with locally advanced disease. New approaches such as neoadjuvant or concurrent chemoradiotherapy with or without surgery need to be considered and evaluated in prospective studies.

Predictors of outcome after radical cystectomy for bladder cancer in saudi patients; single institution experience.

AIM OF THE STUDY: To evaluate different prognostic factors that may affect disease-specific survival in patients with bladder cancer following radical cystectomy. METHODS: Between July 1975 and December 2000, 229 patients underwent radical cystectomy and urinary diversion for bladder cancer in King Faisal Specialist Hospital and Research Center (KFSH & RC), Riyadh, Saudi Arabia. 175 patients had available records for review. Retrospective chart review was done. Demographic, clinical and pathological variables which may affect disease specific survival in bladder cancer patients were pooled. Univariate and multivariate analyses were done with disease specific survival as an end point. RESULTS: Our patients were 140 males (80%) and 35 females (20%). Their mean age was 54 years (range: 21-90 years). The median follow-up period was 1.5 years (range: one month-19 years). Five-year disease specific survival was 44%. On univariate analysis, patients' age, lymph node status, pathological staging and presence of hydronephrosis were significant predictors of disease specific survival. However, only lymph node status (p<0.0001), pathological staging (p=0.0411) & presence of hydronephrosis (p=0.0264) were significant predictors of disease specific survival in multivariate analysis. CONCLUSION: Pathological stage, lymph node status and upper obstructive uropathy are significant prognostic factors in bladder cancer patients after radical cystectomy. These factors may help to define bladder cancer patient groups who require further therapy or enrollment in controlled trials to investigate additional therapy.