Effects of Cyclooxygenase on the Urothelium of the Urinary Bladder of Mice Exposed to Pelvic Radiation.

OBJECTIVE: To determine the role of cyclooxygenase (COX) expression in the urothelium of the urinary bladder during radiation injury caused by pelvic radiotherapy for cancer therapy. STUDY DESIGN: Twenty-four male Swiss Albino mice were separated into 4 groups. The first group was the control group (Group 1) and the second, third, and fourth groups were euthanized after 24 hours (Group 2), 48 hours (Group 3), and 7 days (Group 4), respectively. A single-fractioned 10 Gy of ionizing radiation was applied to all mice's pelvic zone with Co-60. Bladders were removed completely from the pelvic region. Histochemical analysis using hematoxylin and eosin and immunohistochemical analysis using anti-COX-1 and COX-2 antibodies were performed on tissue samples. The immunoreactivities of the urinary bladder were quantified using H-score measurement, and statistical comparison was performed. RESULTS: In the immunohistochemical examination the COX-1 immunoreactivities were found to be higher in the urothelium of the bladder in the radiation exposed groups than in the normal control group (group 1) (p < 0.005). Additionally, high immunoreactivity of COX-2 molecule was established in groups 2, 3, and 4 of radiation groups as compared to group 1 (p < 0.005) in examination of the urothelium. COX-1 and COX-2 immunoreactivities in the submucosa were detected higher in group 4 than in the other groups (p < 0.005). CONCLUSION: COX-1 and COX-2 expressions in the urothelium and subepithelium of the urinary bladder were investigated in mice during the acute radiation response. The expression of COX-1 and COX-2 in the urothelium seems to prevent bladder damage from radiation, supplying differentiation and restoration of the urothelium.

Influence of Radiation Exposure During Radiotherapy. Evidence for the Increase of Versican and Heparin-Binding EGF-like Growth Factor Concentrations.

OBJECTIVE: To investigate the reaction of versican and heparin-binding EGF-like growth factor (HB-EGF) molecule concentrations to acute radiation exposure in normal bladder and rectal tissue samples in order to gain more insight into the effects of cancer radiotherapy. STUDY DESIGN: Four groups with 6 male adult Swiss Albino mice per group were investigated. The mice bladder and rectum tissue samples were subjected to a 10-Gy single-dose radiation exposure in the pelvic region with a Co-60 teletherapy device and investigated 1, 2, and 7 days after radiation exposure, with 1 reference group which was not exposed to radiation. RESULTS: In the immunohistochemical examination of the tissue samples with anti-versican and anti-HB-EGF primary antibodies was observed a statistically significant increase 7 days after radiation exposure. CONCLUSION: The observed increase of versican and HB-EGF concentrations in the normal tissue matrix after radiation exposure may play a role in the side effects of radiotherapy.

An Experimental Study of Radiation Effect on Normal Tissue: Analysis of HIF-1α, VEGF, eIF2, TIA-1, and TSP-1 Expression.

OBJECTIVE: This study investigated whether or not the stress and hypoxia, which are the effects of radiation on normal vascular endothelium, leading to the release of HIF-1α, VEGF, eIF2, TIA-1, and TSP-1 were related and the possibility of them stimulating angiogenesis. MATERIALS AND METHODS: Twenty-four male Swiss Albino mice were separated into 4 groups. The first group was the control group (Group 1), and the second, third, and fourth groups were euthanized after 24 h (Group 2), 48 h (Group 3), and 7 days (Group 4), respectively. A single-fractioned 10 Gy of ionizing radiation was applied to all mice's pelvic zone with Co-60. Bladders were removed completely from the pelvic region. Immunohistochemistry and light microscopy were used to investigate whether there would be an increase or not in the angiogenesis pathway by using the HIF-1α, VEGF, eIF2, TIA-1, and TSP-1 antibodies. RESULTS: The HIF-1α antibody showed strong staining in Group 3, while the staining intensity was less in other groups. VEGF showed weak staining in Groups 1 and 4, while moderate staining in Group 2 and strong staining in Group 3 was observed. eIF2 showed strong staining in Groups 1 and 4. Groups 2 and 3 were stained weakly. In the present study, staining with TSP-1 was very strong in the samples belonging to Group 1, while other groups showed very weak staining. CONCLUSION: When normal tissue was exposed to radiation, the positively effective factors (HIF-1, VEGF, eIF2, and TIA-1) on the angiogenesis pathway were increased while the negative factor (TSP-1) was decreased. Radiation may initiate physiological angiogenesis in the normal tissue and accelerate healing in the damaged normal tissue. CONFLICT OF INTEREST: None declared.

Chromosomal aberrations induced by radiotherapy in lymphocytes from patients with lung cancer.

In this study we tried to define incidence and types of chromosomal aberrations (CAs) caused by radiotherapy (RT) in circulating lymphocytes from patients with lung cancer. For this purpose, we used cumulative dose-effect relationship, and correlate these data with statistical parameters. CAs were evaluated in terms of chromosome break, dicentric, ring and chromosome gap. Abnormal metaphase number (AMN) was also calculated Chromosome studies were carried out in peripheral blood lymphocytes of 20 cancer patients receiving RT. Patients were treated with 10 Gy of gamma (gamma) radiation during five wk(s). In all patients, a significant increase in AMN and frequency of CAs (e.g. chromosome break, dicentric, ring and chromosome gap) observed during the RTdepend on cumulative radiation dose when compared to before RT, and this increase was statistically significant (p<0. 05). The highest CAs frequency was observed at the end of fifth wk. Among the CAs, chromosome breaks have a high incidence. But no CAs and abnormal metaphase was observed in lymphocytes before RT. The present study showed that RT possess a significant effect in increasing of CAs and chromosome break, dicentric, ring and chromosome gap are very sensitive and useful biomarkers in the study of this effect. In other words, these CAs may be used as possible fingerprints of RT.

Ghrelin may reduce radiation-induced mucositis and anorexia in head-neck cancer.

Body weight loss is common in cancer patients, and is often associated with poor prognosis, it greatly impairs quality of life (QOL). Radiation therapy (RT) is used in head and neck cancers (HNC) either as a primary treatment or as an adjuvant therapy to surgery. Patients with HNC are most susceptible to malnutrition especially due to anorexia, which is aggravated by RT. Multiple pro-inflammatory cytokines, such as interleukin-6 (IL-6), interleukin-1beta (IL-1beta), interferon (IFN)-gamma and tumor necrosis factor-alpha(TNF-alpha), have been all associated with the development of both anorexia and oral mucositis. Radiation-induced mucositis occurs in almost all patients, who are treated for HNC, it could also cause weight loss. Ghrelin is a novel 28-amino acid peptide, which up-regulates body weight through appetite control, increase food intake, down-regulate energy expenditure and induces adiposity. Furthermore, ghrelin inhibits pro-inflammatory cytokines such as IL-1alpha, IL-1beta, TNF-alpha which may cause oral mucositis and aneroxia, which are the results of weight loss. Thus weight loss during RT is an early indicator of nutritional decline, we propose that recombinant ghrelin used prophylactically could be useful as an appetite stimulant; and preventive of mucositis because of its anti-inflammatory effect, it might help patients maintain weight over the course of curative RT of the HNC and can improve specific aspects of QOL. This issue warrants further studies.

Prevalence of Factor V 1691 G-A (Leiden) and prothrombin G20210A polymorphisms and the risk of venous thrombosis among cancer patients.

AIMS: Cancer patients have an increased risk for thromboembolism (TE). Factor V 1691 G-A(Leiden) (FVL) and prothrombin (PT) G20210A mutation are common inherited risk factor for TE. The aim of the study is to evaluate the prevalence of FVL and PT G20210A polymorphism in cancer patients with and without TE as compared to patients with TE without malignancy and healthy control. MATERIALS AND METHODS: We have studied 43 cancer patients who developed TE during cancer treatment (group 1); 81 cancer patients without TE (group 2); 100 patients with TE without malignancy (group 3); 100 healthy control (group 4). FVL and PT G20210A polymorphisms were determined by the method of polymerase chain reaction-based DNA analysis. RESULTS: The prevalence of FVL was significantly greater in cancer patients with TE (13 of 43, 30.2%) compared with other groups: 3.7% in group 2; 18% in group 3; 8% in group 4 (P < 0.0001). There was no significant difference in the prevalence of PT G20210A among the groups (P > 0.05). CONCLUSIONS: The study suggested that cancer patients with TE should be evaluated for FVL but PT G20210A was not contributing factor to the development of TE during cancer therapy.

Cases of glioblastoma multiforme metastasizing to spinal cord.

Cases of glioblastoma multiforme (GBM) metastasizing to the leptomeninx or the intramedullary spine are quite rare and prognoses are relatively poor. We present three cases of GBM with spinal metastasis, one of which also had leptomeningeal dissemination. Three patients with GBM were admitted to our clinic for postoperative radiotherapy after surgery. Leptomeningeal metastasis and dissemination were diagnosed with magnetic resonance imaging. Radiotherapy provided only temporary relief from pain with small improvement in neurological deficit but no survival advantage.

Carnosine may reduce lung injury caused by radiation therapy.

Ionising radiation is known one of the most effective tools in the therapy of cancer but in many thoracic cancers, the total prescribed dose of radiation that can be safely administered to the target volume is limited by the risk of complications arising in the normal lung tissue. One of the major reasons for cellular injury after radiation is the formation of reactive oxygen species (ROS). Radiation pneumonitis is an acute phase side-effect which generally subsides after a few weeks and is followed by a chronic phase characterized by inflammation and fibrosis, that can develop months or years after irradiation. Carnosine is a dipeptide composed by the amino acids beta-histidine and l-alanine. The exact biological role of carnosine is not totally understood, but several studies have demonstrated that it possesses strong and specific antioxidant properties, protects against radiation damage,and promotes wound healing. The antioxidant mechanism of carnosine is attributed to its chelating effect against metal ions, superoxide dismutase (SOD)-like activity, ROS and free radicals scavenging ability . Either its antioxidant or anti-inflammatuar properties, we propose that carnosine ameliorates irradiation-induced lung injury. Thus, supplementing cancer patients to whom applied radiation therapy with carnosine, may provide an alleviation of the symptoms due to radiation-induced lung injury. This issue warrants further studies.

Mid-course thoracic radiotherapy with cisplatin-etoposide chemotherapy in limited-stage small-cell lung cancer.

Combination chemoradiotherapy is a standard treatment for limited-stage small-cell lung cancer (LSSCLC). However, there is still controversery about the optimal timing of thoracic radiotherapy (TRT). In this study, the outcome of 70 patients who had received TRT at a dose of median 50 Gy (range, 46-60 Gy) with a second or third cycle of chemotherapy (CHT) either concurrently (n=41) or sequentially (n=29) were analyzed retrospectively. All patients were administered a median of five cycles (range, four to six cycles) cisplatin plus etoposide (EP) CHT. Prophylactic cranial radiotherapy was delivered to 30 (43%) patients. The median follow-up for all patients was 15 mo (range, 6-60 mo). The median overall survival was 19 mo in the concurrent arm vs 15 mo in the sequential arm. The 2-yr local control, disease-free survival, and overall survival rates were 60%, 19%, and 36%, respectively. The most common toxicity was esophagitis. However, there were no grade 3-4 esophagitis in either arm. Grade 3-4 hematologic toxicity, on the other hand, appeared significantly more in the concurrent arm (p < 0.001). Mid-course of once-daily TRT at a moderate total dose with CHT failed to show any improvement in survival. Additionally, there were no differences between concurrent and sequential CHT with TRT. However, acceptable toxicity rates support the use of once-daily fractionation to higher total dose of TRT.

Treatment outcome of nasal and paranasal sinus carcinoma.

PURPOSE: Most authors recommend aggressive management for sinonasal carcinoma treatment. In an attempt to determine the optimal treatment, we assessed the treatment results of our patients with nasal cavity and paranasal sinus carcinoma. MATERIALS AND METHODS: From January 1980 to December 2001, 40 patients with malignant tumours of the nasal cavity and the paranasal sinuses were treated. The median follow-up was 6 years. Thirty-two patients had tumours originating from the maxillary sinus. Thirteen patients had T1-T2 (32.5%) tumours and 27 patients had T3-T4 (67.5%) tumours. The treatment method was surgery plus radiotherapy in 24 patients (60%) and radiotherapy alone in 16 patients (40%). RESULTS: The 5-year overall survival rate was 61%, whereas it was 65% for T1-T2 disease and 56% for T3-T4 disease. The 5-year local control rate was 58%, whereas it was 75% and 50% (p = .219) for T1-T2 and T3-T4 disease, respectively. In multivariate analysis; localization (p = .016), adjuvant radiotherapy (p = .040), local control (p = .05), and gender (p = .013 for female) were statistically significant factors. CONCLUSION: The prognosis for patients with tumours of the sinonasal area is dependent on localization, tumour stage, and treatment modality. Because the most common site of treatment failure is the primary site, efforts to maximize local control should be undertaken.

In vivo study to evaluate the protective effects of amifostine on radiation-induced damage of testis tissue.

OBJECTIVE: To investigate the early protective effects of amifostine against radiation-induced damage on rat testis tissue. METHODS: Eighty adult male Wistar rats were randomized to 4 groups: Saline solution was given to group A for control, 200 mg/kg amifostine (WR-2721) to group B, a single fraction of 6 Gy local irradiation to testes in group C and 200 mg/kg amifostine 15-30 min before 6 Gy testicular irradiation to group D. Animals were sacrificed 3 weeks after treatment and their testes were removed for macroscopic, microscopic and ultrastructural histopathological examination. RESULTS: The weights, widths and lengths of testes in the last 3 groups had decreased significantly when compared with the control group, but the decrease in widths after irradiation was found to be significantly less only in the amifostine plus radiation group. There was a significant reduction of testis weights in relation to the individual body weights in the irradiated testes compared with the other groups (p < 0.005), while there was no significant change of testis weight/total body weight ratio in amifostine plus irradiation group. Spermatogonium A and primary spermatocyte counts were also less in the treatment groups, and primary spermatocyte numbers were significantly higher in amifostine plus radiation group when compared with radiation alone group (p < 0.005). Pretreatment with amifostine reduced the decrease of primary spermatocyte counts by a factor of 1.28. Electron microscopic analysis did not show any cytotoxic effect of amifostine alone, and furthermore, ultrastructural findings were normal with the addition of amifostine prior to irradiation, though there was damage in the radiation exposure group. CONCLUSION: Amifostine when given alone by itself appears to cause adverse alterations in testis tissue; however, it has a radioprotective effect on spermiogenetic cells when used prior to radiation.

Intraluminal brachytherapy with metallic stenting in the palliative treatment of malignant obstruction of the bile duct.

PURPOSE: To describe the outcome of intraluminal high-dose-rate (HDR) brachytherapy with metallic stenting in patients with obstructing extrahepatic cholangiocarcinoma. MATERIALS AND METHODS: Eight patients with inoperable and/or unresectable extrahepatic bile duct carcinomas were treated with intraluminal brachytherapy (ILBT) followed by self-expandable metallic stent placement. Following percutaneous transhepatic drainage, ILBT was delivered by an HDR-Ir-192 source using the Micro-Selectron afterloading device. Two treatments were planned one week apart, with each treatment consisting of a single 10 Gy fraction. Biliary patency and palliative effect were assessed by serial labs (including bilirubin/alkaline phosphatase), symptomatic improvement, and/or cholangiography. RESULTS: All eight patients tolerated the first application of ILBT well, and five of them completed two-intraluminal treatments. Six of eight had satisfactory control of jaundice until death. Pain relief was observed in four of five (80%) and pruritus in six of seven (86%) patients experiencing such symptoms. The mean and median times of stent patency were 6.9 and 5 months (range, 4-14), respectively. Gastrointestinal bleeding and/or cholangitis occurred in three patients. CONCLUSION: HDR ILBT with metallic stenting for patients with obstructive jaundice from extrahepatic bile duct carcinoma appears to be feasible and associated with acceptable toxicity. These treatments may lead to an improved quality of life in these patients.

The myeloprotective effect of medroxyprogesterone acetate in an irradiated animal model.

BACKGROUND: In this study we evaluated the effect of medroxyprogesterone acetate (MPA) and its major ingredients on protection of the hematopoietic organs against radiation damage. METHOD: One group of mice was given saline as placebo and the other groups were given MPA. Mice were injected with MPA (10 mg/kg) or saline 10 days before or after a single 8 Gy whole body cobalt irradiation. On day 14 the mice were sacrificed and their bone marrow transplanted to recipient mice. Ten days after the transplantation, spleen colony formation was investigated in mice. RESULTS: Administration of MPA with irradiation increased the formation of the spleen colony. Statistically significant enhancement of the spleen colony formation was found in mice treated with MPA repeatedly, as compared with those treated with placebo (P < 0.001). No significant difference in Spleen Colony Forming Unit (CFU-S) numbers was observed between pre-and post-radiotherapy administration of MPA (P = 0.216). CONCLUSION: It is an important observation that no significant difference was observed in CFU-S numbers between pre- and post-irradiation administration of MPA.

High dose rate endobronchial brachytherapy effectively palliates symptoms due to inoperable lung cancer.

BACKGROUND: Intraluminal brachytherapy has become an established treatment for major airway occlusion by relapsed or persistent inoperable endobronchial tumors. The aim of this study was to compare the palliation improvement pre- and post-radiotherapy. METHODS: The study group was 95 patients with the diagnosis of inoperable lung cancer who were eligible for HDR brachytherapy. Fiber-optic bronchoscopy was performed and the level and degree of endobronchial obstruction were estimated in terms of bronchial obstruction index. Endobronchial irradiation was delivered using remote HDR afterloading brachytherapy with iridium-192. Brachytherapy was delivered at weeks 1, 2 and 3 at 7.5 Gy per fraction or at weeks 1 and 2 at 10 Gy per fraction. All patients were evaluated at the beginning and at the third month of therapy. Using Speiser's symptomatic scoring criteria, the severity of symptoms (dyspnea, cough, hemoptysis and postobstructive pneumonia) was weighted. Bronchoscopic findings at the initial evaluation and at the third month were also scored. Surviving patients were followed up for a minimum of 3 months with a mean of 7.5 +/- 5.35 months (median: 6 months). RESULTS: All the symptoms and bronchial obstruction improved significantly after brachytherapy (P < 0.05). The most responding symptoms were dyspnea and hemoptysis. The factors determining the complete response were evaluated; age, staging, histological type, lesion localization and previous history of radiotherapy did not seem to determine the complete response (P > 0.05). CONCLUSIONS: All the symptoms and bronchial obstruction index seemed to improve after brachytherapy. However, it is difficult to predict the response before the therapy.