Sperm DNA integrity in testicular cancer patients.

BACKGROUND: We evaluated the impact of testicular germ cell cancer (TGCC), its treatment and length of follow-up on sperm DNA integrity. METHODS: In 96 TGCC patients, semen was collected at specific intervals until 5 years after treatment. Sperm DNA integrity was assessed by the sperm chromatin structure assay (SCSA, n = 193) and by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL, n = 159) assay. Results were expressed as DNA fragmentation index (DFI). Controls comprised of 278 military conscripts. RESULTS: Post-surgery testicular cancer (TC) patients did not differ from controls. Compared with pretreatment values, radiotherapy induced a transient increase in SCSA(DFI) (medians: 12 versus 19%; P = 0.03), normalizing after 3-5 years. One year or more after therapy, 5/13 (38%) of normozoospermic, irradiated patients had SCSA(DFI) >27% compared with 7% of normozoospermic controls (P = 0.002). More than two cycles of chemotherapy decreased DFI 3-5 years post-therapy (median SCSA(DFI): 12 versus 9.1%, P = 0.02; median TUNEL(DFI): 11 versus 7.5%, P = 0.03). CONCLUSION: Irradiation increases sperm DNA damage 1-2 years after treatment, and 38% of irradiated patients with normozoospermia had high (>27%) DNA damage, which may affect the sperm-fertilizing ability. TC per se is not associated with an increase of DFI, and DFI is reduced by three or more cycles of chemotherapy.

Impact of therapy and androgen receptor polymorphism on sperm concentration in men treated for testicular germ cell cancer: a longitudinal study.

BACKGROUND: Testicular cancer (TC) patients have a high survival rate, and the question of post-therapy recovery of sperm production and its dependence on genetic predisposition is of major interest. METHODS: Ejaculates were obtained from 112 TC patients at one or more of the following time points: post-orchidectomy, or 6, 12, 24, 36 and 60 months post-therapy. The lengths of the androgen receptor (AR) function modulating CAG and GGN repeats in leukocyte DNA were also analysed. RESULTS: No significant decrease in sperm concentration was seen in men who received 1-2 cycles of adjuvant chemotherapy (ACT). Radiotherapy (RT) or more than two cycles of chemotherapy (HCT) caused an initial decline in sperm concentration, which returned to pre-treatment levels 2-5 years after therapy. In the HCT group, sperm concentration 12-24 months post-treatment (T(12-24)) was inversely correlated with CAG length (rho = -0.72, P = 0.03). The type of treatment, but not the concentration at T(0), was an independent predictor of sperm concentration at T(6) (P < 0.0005) and T(12-24) (P = 0.004). CONCLUSION: ACT did not induce a significant decline in sperm concentration. After HCT and RT, a significant reduction of sperm concentration was observed, recovering to pre-treatment levels 2-5 years post-treatment. In HCT-treated patients, the AR CAG length influenced the recovery of spermatogenesis.

A Swedish study of chemoradiation in squamous cell carcinoma of the esophagus.

This multicenter study describes the development of a chemoradiation protocol for the treatment of non-metastatic squamous cell carcinoma of the esophagus. Eighty patients were treated with three courses of chemotherapy (cisplatinum and 5-fluorouracil) with concomitant radiotherapy (40 Gy) during the last two courses of chemotherapy. Esophagectomy was performed, when feasible. If no operation was performed, patients were planned to receive a target dose of 64 Gy. Toxicity was mainly attributable to hematological impairment and led to two adjustments of the treatment protocol (addition of filgrastim and lowering of the 5-fluorouracil dose). These changes made it possible to administer the planned treatment in a gradually higher proportion of patients (13/23 [57%] before changes of treatment compared with 30/36 [83%] after changes). Treatment-related mortality was 3.75% (3 patients, associated with leucopenic septicemia after chemotherapy). Fifty-four patients were resected. No per- or postoperative mortality was encountered. The complete response (pathological CR) rate in operated patients was 46% (27/59 patients) after chemoradiation. In the whole series the CR rate (including clinical CR for non-resected patients) was 44%. With a minimum follow-up of 37 months, the 3-year survival for the whole group was 31% compared with 57% for the CR patients. Total 5-year survival thus far (July 1999) is 26%.

Antithrombotic treatment in protection against thrombogenic effects of 5-fluorouracil on vascular endothelium: a scanning microscopy evaluation.

Cardiotoxicity is a serious side effect of treatment of malignant diseases with 5-fluorouracil (5-FU). The underlying pathophysiologic mechanism remains unclear but clinical data suggest that the endothelium of coronary arteries may be involved. Experimental studies indicate that the endothelium is especially susceptible to 5-FU and support the hypothesis that a thrombogenic effect of 5-FU, secondary to its direct toxic effect on the endothelium, is one of the pathophysiologic mechanisms behind 5-FU-induced cardiotoxicity. In the present study we evaluate the role of antithrombotic treatment with dalteparin as protection against the thrombogenic effect of 5-FU on the vascular endothelium in a rabbit model. The effects on the vascular endothelium of 5-FU, dalteparin, and the combination of these two substances were evaluated with scanning electron microscopy 1, 3, 7, 14, and 30 days after treatment and compared with a control group. Very severe damage to the endothelium was seen in 5-FU-treated animals, often leading to intima disruption and denudation of underlying structures, with accompanying platelet accumulation and fibrin formation. The most extensive damage was observed on Day 3 after treatment. The cytotoxic effect of 5-FU was partly reversible. The combination of 5-FU and dalteparin gave lower scores on Day 3 because of less evidence of thrombotic events. However, the reversibility of the endothelial damage was poorer in this group, as well as in the group that received dalteparin alone. The findings support the hypothesis that antithrombotic treatment with dalteparin can protect against the thrombogenic effect of 5-FU, secondary to its direct toxic effect on the vascular endothelium. However, the study indicates that dalteparin per se has a toxic effect on the endothelium that is different from that of 5-FU.

No serious late cardiac effects after adjuvant radiotherapy following mastectomy in premenopausal women with early breast cancer.

PURPOSE: To assess cardiac mortality, coronary artery disease, myocardial dysfunction, and valvular heart disease in women younger than 65 years of age, at least 10 years after adjuvant radiotherapy following mastectomy in early breast cancer. METHODS AND MATERIALS: Ninety women (45-64 years old) with Stage II breast cancer without relapse, included in the South Sweden Breast Cancer Trial (premenopausal arm), with or without adjuvant postoperative radiotherapy +/- cyclophosphamide were examined with myocardial scintigraphy and echocardiography/Doppler, 10-17 years after radiotherapy. Thirty-four patients had been irradiated for left-sided tumors, 33 for right-sided tumors, and 23 patients had not been treated with radiotherapy. The radiotherapy (conventional roentgen, electron beams, and high-energy photon beams combined, in each patient) included the chest wall and the regional lymph nodes, with a specified target dose of 38-48 Gy, administered in daily fractions of 1.9-2.4 Gy, 5 days/week. RESULTS: No cardiac deaths were found among the original 275 patients randomized to adjuvant therapy. In the 90 patients examined, abnormal findings were recorded for ECG (14 patients), exercise test (5 patients), myocardial scintigraphy (6 patients), thickening of valve cusps (14 patients), and mild valvular regurgitation (20 patients). All patients had normal systolic function. Diastolic dysfunction was observed in 6 patients (abnormal relaxation in 4 patients and restrictive filling abnormality in 2 patients). Although no significant differences were found between the 3 study groups, there was a tendency to more abnormal findings after radiotherapy. CONCLUSION: Women younger than 50 years of age at the time of adjuvant radiotherapy following mastectomy in early breast cancer, had no serious cardiac sequelae 13 years (median) later, despite partly old-fashioned radiation techniques.

Malignant dysphagia: palliation with esophageal stents--long-term results in 100 patients.

PURPOSE: To evaluate the long-term palliative effect of self-expanding nitinol esophageal stents in patients with malignant dysphagia. MATERIALS AND METHODS: One hundred patients with severe dysphagia secondary to malignant esophageal strictures were treated with self-expanding nitinol stents. The strictures were caused by squamous carcinoma (n = 43), adenocarcinoma (n = 28), anastomotic tumor recurrence (n = 14), and mediastinal tumor (n = 15). RESULTS: One hundred six stents were successfully positioned in 100 patients. Attempts to insert a second, coaxial stent were unsuccessful in two patients; a second stent was placed incorrectly in another patient. Statistically significant (P < .001) reduction of dysphagia was noted after expansion of the stents. Complications consisted of incomplete expansion secondary to stent twisting (n = 4), stent migration (n = 4), tumor ingrowth (n = 17), tumor overgrowth (n = 3), food impaction (n = 5), fracture of stent wires (n = 2), benign strictures at stent edges (n = 2), tumor bleeding (n = 3), and esophagorespiratory fistula (n = 5). The primary patency rate was 75% (77 of 102 stents); the secondary patency rate was 94% (96 of 102 stents). The survival time (mean, 6.2 months; range, 0.1-47 months) varied with the diagnosis. CONCLUSION: Placement of self-expanding nitinol stents is safe and has a good long-term palliative effect on dysphagia in patients with malignant esophageal strictures.

The influence of 5-fluorouracil and methotrexate on vascular endothelium. An experimental study using endothelial cells in the culture.

BACKGROUND: Cardiotoxicity still remains an unexplained toxic manifestation of 5-fluorouracil (5-FU). Clinical and experimental data suggest that endothelium of coronary arteries could be involved in the pathophysiological mechanisms of the syndrome. In order to further explain 5-FU induced cardiotoxicity, we investigated the influence of this drug on endothelial cells (EC) in a cell culture model. MATERIALS AND METHODS: The influence of 5-FU on EC, with respect to DNA synthesis, cell death and release of prostacyclin by endothelial cells (EC) was studied. For comparison, we tested methotrexate (MTX), an antimetabolite without cardiotoxic properties, in the same way. Human endothelial cell lines (HEC) and bovine endothelial cells (BEC) were incubated with increasing concentrations of 5-FU and MTX for 48 hours. (3H)thymidine incorporation, total cellular protein, loss of (3H)thymidine from prelabelled cells and 6-keto-prostaglandin F1 were measured. RESULTS: DNA synthesis decreased significantly in both HEC and BEC, and the release of prostacyclin by BEC increased significantly when incubated with 5-FU. This effect was not seen with MTX. CONCLUSION: The results indicate specific susceptibility of benign EC to 5-FU. Such susceptibility was confirmed by the release of prostacyclin by the BEC, indicating leakage secondary to EC injury.

Palliation of dysphagia in patients with malignant esophageal strictures. Comparison of results of radiotherapy, chemotherapy and esophageal stent treatment.

Dysphagia is the earliest and the most common symptom of malignant disease in the esophagus. The palliative effects on dysphagia of radiotherapy (RT) and chemotherapy (CT) were evaluated retrospectively and compared with the effect of the self-expanding stent, evaluated in the prospective study. After completion of treatment, 78 (56%) of 140 patients treated with RT; 31 (49%) of 63 patients treated with CT; and 53 (81%) of 66 patients treated with stent insertion were free from dysphagia. Stent treatment has a good and prompt effect on dysphagia and can be recommended for palliation of patients with malignant esophageal strictures.

The appearance of endothelium in small arteries after treatment with 5-fluorouracil. An electron microscopic study of late effects in rabbits.

Cardiotoxicity is an unexplained toxic manifestation of 5-fluorouracil (5-FU). Its possible mechanism could be a direct cytotoxic effect on the vascular endothelium. We have tested this hypothesis in an experimental study in rabbits, using scanning and transmission electron microscopic evaluation of endothelium in small arteries (the central artery of the ear). The perfusion fixation method at physiological pressure and temperature was used. Both local and systemic effects of 5-FU on endothelium were studied 1, 3, 7, 14 and 30 days after in vivo treatment with 5-FU. Fifteen rabbits were used and five additional animals served as controls. The following parameters were evaluated: vessel wall and endothelial cell contraction, cell oedema, cytolysis, occurrence of denuded areas, platelet adhesion/aggregation and fibrin formation. For the description of each parameter, a scale of negative points (0.0-3.0) was used. We found severe cell damage with accompanying thrombus formation. The findings support the hypothesis that the thrombogenic effect of 5-FU, secondary to its direct cytotoxic effect on endothelium, is the pathophysiological mechanism behind 5-FU cardiotoxicity.

The influence of 5-fluorouracil on the endothelium in small arteries. An electron microscopic study in rabbits.

5-Fluorouracil (5-FU) is a widely used antineoplastic agent. 5-FU induced cardiotoxicity is a still relatively unknown side-effect of this drug. This phenomenon could be due to a direct cytotoxic effect on the endothelial cells. We tested this hypothesis in an experimental study in rabbits, by scanning or transmission electron microscopic evaluation of endothelium in small arteries (the central artery of the ear) after in vivo treatment with 5-FU. Both local and systemic effects of 5-FU on endothelium were studied 15, 30, 60 and 120 minutes after intra-arterial or intraperitoneal treatment. Perfusion fixation at physiological pressure and temperature was used in order to minimize damage to the endothelium during the preparation procedure. Eighteen rabbits weighing 2.5-3.0 kg were used, and 6 animals served as controls. The following parameters were evaluated: vessel wall and endothelial cell contraction, cell edema, cytolysis, occurrence of denuded areas, platelet adhesion/aggregation and fibrin formation. For the description of each parameter a scale of negative points was used. Irreversible cell damage was observed in 5-FU treated animals: disruption of the endothelial sheet and patchy exposure of the subendothelium, sometimes as a focus for thrombus formation. Our findings support the hypothesis that the thrombogenic effect of 5-FU secondary to its direct cytotoxic effect on endothelium might be one of the pathophysiological mechanisms behind 5-FU induced cardiotoxicity.

Changes of blood viscosity in patients treated with 5-fluorouracil--a link to cardiotoxicity?

Cardiotoxicity is a serious but relatively unknown side-effect of treatment with 5-fluorouracil (5-FU). The underlying mechanism of 5-FU cardiotoxicity has not been defined. The aim of the present study was to determine whether hemorheological factors might in part explain 5-FU cardiotoxicity. Changes of blood and plasma viscosity, fibrinogen and hematocrit were studied in 11 patients treated by 5-FU. The study showed a decrease in blood and plasma viscosity during treatment with 5-FU, probably caused by a decrease of plasma fibrinogen. Reversible cardiotoxic effects were demonstrated in four patients.

Acute and delayed effects of radiotherapy in patients with oesophageal squamous cell carcinoma treated with chemotherapy, surgery and pre- and postoperative radiotherapy.

Among 73 patients with oesophageal squamous cell carcinoma treated with chemotherapy (cisplatin + 5-fluorouracil), surgery and pre- and postoperative radiotherapy, the 1-year survival rate was 68% and the 5-year rate 26%. The treatment was well tolerated, though there were 11 cases of pericardial or pleural effusion, in all of which the effusion was benign and could be successfully treated with pleural aspiration and/or pleurodesis, pericardiocentesis, or in one case pericardectomy.

Scanning electron microscopy of human esophageal mucosa in patients with carcinoma of the esophagus.

Specimens taken at surgery from 15 patients with carcinoma of the esophagus were examined with scanning electron microscopy. Nine patients were treated with chemotherapy (cisplatin + 5-fluorouracil), surgery and radiotherapy; one received preoperative radiotherapy only; and the remaining five primary surgery only. Scanning electron microscopy was performed on specimens of both tumor tissue and the mucosa at least 5 cm from the tumor. In adjacent non-tumor tissue, damage due to treatment was observed in the form of changes in microridges and increased cell loss. In tumor tissue, the degree of damage was correlated to tumor response to treatment. For patients with no residual tumor after treatment, the ultrastructure was normalized with a low tumor score, while for patients with residual tumor, the score was high.

Response of the esophageal epithelium to concomitant cis-dichlorodiammineplatinum(II) and radiation treatment. An electron microscopic study in rabbits.

The rabbit esophageal mucosa was irradiated with daily fractions of 2 Gy up to an accumulated dose of 20 Gy (total dose 2, 6, 10. 16 or 20 Gy). Fifteen to forty-five minutes before the start of each irradiation 0.3 mg Cis-dichlorodiammineplatinum (cis-DDP, cisplatinum) was given by intraperitoneal injection to each rabbit. Examinations were carried out 1-10 days after each fractionation schedule, when specimens were taken for morphological investigations. Scanning electron microscope (SEM) examination showed a gradual development of damage with cell loss and structural disarrangement of the microridges and whorls on the surface. However, with further treatment the esophageal mucosa exposed to cis-DDP and radiation normalized faster and more complete compared to the esophageal part exposed to cis-DDP alone. The difference may depend on an accelerated proliferation in the part of the trachea that is exposed to a combined treatment.