Increased stomach cancer risk following radiotherapy for testicular cancer.

BACKGROUND: Abdominal radiotherapy for testicular cancer (TC) increases risk for second stomach cancer, although data on the radiation dose-response relationship are sparse. METHODS: In a cohort of 22,269 5-year TC survivors diagnosed during 1959-1987, doses to stomach subsites were estimated for 92 patients who developed stomach cancer and 180 matched controls. Chemotherapy details were recorded. Odds ratios (ORs) were estimated using logistic regression. RESULTS: Cumulative incidence of second primary stomach cancer was 1.45% at 30 years after TC diagnosis. The TC survivors who received radiotherapy (87 (95%) cases, 151 (84%) controls) had a 5.9-fold (95% confidence interval (CI) 1.7-20.7) increased risk of stomach cancer. Risk increased with increasing stomach dose (P-trend<0.001), with an OR of 20.5 (3.7-114.3) for ⩾50.0 Gy compared with <10 Gy. Radiation-related risks remained elevated ⩾20 years after exposure (P<0.001). Risk after any chemotherapy was not elevated (OR=1.1; 95% CI 0.5-2.5; 14 cases and 23 controls). CONCLUSIONS: Radiotherapy for TC involving parts of the stomach increased gastric cancer risk for several decades, with the highest risks after stomach doses of ⩾30 Gy. Clinicians should be aware of these excesses when previously irradiated TC survivors present with gastrointestinal symptoms and when any radiotherapy is considered in newly diagnosed TC patients.

Pancreatic cancer risk after treatment of Hodgkin lymphoma.

BACKGROUND: Although elevated risks of pancreatic cancer have been observed in long-term survivors of Hodgkin lymphoma (HL), no prior study has assessed the risk of second pancreatic cancer in relation to radiation dose and specific chemotherapeutic agents. PATIENTS AND METHODS: We conducted an international case-control study within a cohort of 19 882 HL survivors diagnosed from 1953 to 2003 including 36 cases and 70 matched controls. RESULTS: Median ages at HL and pancreatic cancer diagnoses were 47 and 60.5 years, respectively; median time to pancreatic cancer was 19 years. Pancreatic cancer risk increased with increasing radiation dose to the pancreatic tumor location (Ptrend = 0.005) and increasing number of alkylating agent (AA)-containing cycles of chemotherapy (Ptrend = 0.008). The odds ratio (OR) for patients treated with both subdiaphragmatic radiation (≥10 Gy) and ≥6 AA-containing chemotherapy cycles (13 cases, 6 controls) compared with patients with neither treatment was 17.9 (95% confidence interval 3.5-158). The joint effect of these two treatments was significantly greater than additive (P = 0.041) and nonsignificantly greater than multiplicative (P = 0.29). Especially high risks were observed among patients receiving ≥8400 mg/m(2) of procarbazine with nitrogen mustard or ≥3900 mg/m(2) of cyclophosphamide. CONCLUSION: Our study demonstrates for the first time that both radiotherapy and chemotherapy substantially increase pancreatic cancer risks among HL survivors treated in the past. These findings extend the range of nonhematologic cancers associated with chemotherapy and add to the evidence that the combination of radiotherapy and chemotherapy can lead to especially large risks.

Risk of treatment-related esophageal cancer among breast cancer survivors.

BACKGROUND: Radiotherapy for breast cancer may expose the esophagus to ionizing radiation, but no study has evaluated esophageal cancer risk after breast cancer associated with radiation dose or systemic therapy use. DESIGN: Nested case-control study of esophageal cancer among 289 748 ≥5-year survivors of female breast cancer from five population-based cancer registries (252 cases, 488 individually matched controls), with individualized radiation dosimetry and information abstracted from medical records. RESULTS: The largest contributors to esophageal radiation exposure were supraclavicular and internal mammary chain treatments. Esophageal cancer risk increased with increasing radiation dose to the esophageal tumor location (P(trend )< 0.001), with doses of ≥35 Gy associated with an odds ratio (OR) of 8.3 [95% confidence interval (CI) 2.7-28]. Patients with hormonal therapy ≤5 years preceding esophageal cancer diagnosis had lower risk (OR = 0.4, 95% CI 0.2-0.8). Based on few cases, alkylating agent chemotherapy did not appear to affect risk. Our data were consistent with a multiplicative effect of radiation and other esophageal cancer risk factors (e.g. smoking). CONCLUSIONS: Esophageal cancer is a radiation dose-related complication of radiotherapy for breast cancer, but absolute risk is low. At higher esophageal doses, the risk warrants consideration in radiotherapy risk assessment and long-term follow-up.

Surgical management of radiation-associated cutaneous breast angiosarcoma.

The purpose of this study was to investigate the surgical management of radiation-associated cutaneous breast angiosarcoma with an emphasis on surgical margins and choice of reconstruction. Nine cases of angiosarcoma were identified in patients earlier treated with radiotherapy for breast cancer. Breast angiosarcoma was diagnosed a median of 5.25 years following radiotherapy. Median age at diagnosis was 60 years. Surgical treatment consisted of radical mastectomy (four cases), simple mastectomy (two cases) and wide local excision (three cases). Defect reconstruction involved three latissimus dorsi flap reconstructions and four skin grafts. Clear histological margins were achieved in all cases. Median follow-up was 81 months. Six patients were alive and disease-free at the end of the study period. Aggressive surgical resection with wide margins is essential to reduce local recurrence and improve survival.

Ipsilateral breast recurrence after breast conserving surgery in patients with small (≤ 2cm) breast cancer treated with modern adjuvant therapies.

BACKGROUND: Modern multimodality treatment greatly influences the rate and the predictive factors for ipsilateral cancer recurrence (IBR) after breast conserving surgery. MATERIAL AND METHODS: The study is based on 1297 patients with pT1 breast cancer and treated with breast conserving surgery in February 2001-August 2005. The median duration of follow-up was 57 months. RESULTS: IBR occurred in 27 (2.1%) patients. It was located in the quadrant of prior breast resection in 17 (63%) cases. The median time to an IBR was 41 months (range, 6-78) regardless of whether the recurrence was located in the same or in another quadrant. Omission of radiotherapy was associated with a higher IBR incidence, HR 10,344 (95% CI 1904-56,184; p=0.007). The IBRs occurred particularly often, in 27% of the 11 patients who refused radiotherapy. Patients diagnosed with ER+ cancer had a lower risk of IBR when compared with those with ER-/HER2+ cancer, HR 0.215 (95% CI 0.049-0.935; p=0.040). CONCLUSIONS: The risk of IBR was low during the first 5 years after breast resection among patients with pT1 breast cancer and treated with modern surgical and adjuvant therapies. The majority IBRs still occur at or close to the prior resection site underlining the importance of local therapies. Omission of radiotherapy was the most significant risk factor for IBR.

The prevalence of and risk factors for four or more metastatic axillary lymph nodes in breast cancer patients undergoing sentinel node biopsy.

BACKGROUND: Our aim was to investigate the prevalence of and risk factors for having four or more positive axillary lymph nodes among breast cancer patients undergoing sentinel node (SN) biopsy. PATIENTS AND METHODS: Between February 2005 and July 2007, 1,062 breast cancer patients with the clinical tumour size not larger than 3 cm underwent SN biopsy and axillary clearance (AC), when SN was positive. These patients were identified in a prospectively collected database. RESULTS: Four or more positive axillary nodes were detected in 68 patients representing 6% of the entire study population and 16% of the 436 node positive cases. Features regarded as predictive for a very low risk included (1) T1a or T1b tumours, (2) grade I tumours, (3) tumours with a favourable subtype, that is mucinous, tubular or medullary breast cancer, (4) no nodal macrometastases and (5) SN ratio lower than 0.5. CONCLUSIONS: Only few patients with T1a-b tumours or grade 1 tumours, as well as those with minimal involvement of the sentinel nodes have four or more positive axillary lymph nodes. However, these risk factors can be definitely assessed only after surgery, decreasing their value in the clinical decision making.

Comparative toxicological study on the hepatic safety of entacapone and tolcapone in the rat.

Entacapone and tolcapone are novel COMT (catechol-O-methyltransferase) inhibitors indicated for the adjunctive treatment of Parkinson's disease (PD) in combination with levodopa. The marketing authorisation of tolcapone was suspended in the European Union (EU) in 1998 mainly due to severe abnormal hepatic reactions. This fact raised concern about the safety of COMT inhibitors in the treatment of parkinsonian patients. In order to investigate whether these COMT inhibitors exhibit different effects on the liver comparative toxicological studies were performed in the rat. Short term toxicological studies in rats at high oral doses of entacapone and tolcapone (200, 400 or 600mg/kg daily) were carried out. Tolcapone (400 mg/kg/day or 600 mg/kg/day) increased mortality after only one week treatment and induced signs of toxicity such as a rise in body temperature, stimulation of respiration and rapid onset of rigor mortis after death. Entacapone did not show any adverse effects at the tested dose levels. In the histopathological examination liver cell necrosis was observed in the tolcapone (400 and 600mg/kg/day) treated rats, but it revealed no treatment related signs of toxicity in entacapone-treated rats. We conclude that the toxicological profile of the two COMT inhibitors, entacapone and tolcapone, differ from each other, tolcapone--unlike entacapone--showed hepatotoxicity.

Perturbation of artificial and biological membranes by organic compounds of aliphatic, alicyclic and aromatic structure.

Aliphatic, alicyclic and aromatic hydrocarbons interact with biological membranes. Until now little has been known about their mode of interaction with the membrane bilayer and membrane integral proteins with toxic effects to cells. The lipid theory hypothesis explains the toxic effects by the organic solvent-induced disorder in the lipid bilayer, which indirectly affects the function of membrane-embedded proteins. The extent of bilayer perturbations is ascribed to the solvent accumulation in the bilayer, which is related only to the lipophilicity of the molecule, independent of the chemical structure. In this study the fluidizing effects of aliphatic, alicyclic and aromatic hydrocarbons were compared. Membrane fluidity changes were estimated from the pyrene excimer formation, using pyrene and pyrene derivatives to label specifically the localization of solvent molecules in the transverse plane of the bilayer. Liposomal, microsomal and synaptosomal membrane preparations were evaluated because proteins and cholesterol, as natural membrane components, increase the bilayer order and reduce the organic solvent membrane/buffer partition. In the concentration range investigated, only the aromatic solvents disorder the lipid bilayer, with the greatest perturbation in the centre of the bilayer. These results are related to structural properties of the organic solvents investigated.

Effects of selected organic solvents on the astrocyte membrane ATPase in vitro.

1. The present study deals with astrocyte cultures as a model for studying the membrane-mediated central nervous system-depressing effect of organic solvents. 2. The primary astrocyte cultures were prepared from neonatal rat cerebella. The cells were cultured in modified essential medium. The astrocyte membranes isolated from the cultures were exposed to solvents in incubation mixture at different dose levels (3, 6 and 9 mmol/L) for 1 h. The physiologically important integral proteins Na+, K(+)-ATPase and Mg(2+)-ATPase were studied. 3. The aromatic hydrocarbons (benzene, toluene, styrene, xylene and ethylbenzene) inhibited the ATPase activities according to their lipid solubilities. n-Hexane and cyclohexane clearly had less effect than aromatic hydrocarbons, despite their greater lipid solubilities. 4. Astrocytes were shown to be sensitive targets to the effects of organic solvents, measured as the inhibition of the integral enzymes Na+, K(+)-ATPase and Mg(2+)-ATPase.

Astrocyte membrane Na+, K(+)-ATPase and Mg(2+)-ATPase as targets of organic solvent impact.

Astrocytes serve to maintain the proper homeostatic environment for neurons. In these regulations, the astrocyte membrane ATPase plays an important role. In the present study, the astrocyte were cultured in the modified Minimum Essential Medium (MEM), and the isolated cell membranes were exposed to solvents at different concentrations (3, 6 and 9 mM) for one hour. The activities of the membrane-bound Na+, K(+)-ATPase and Mg(2+)-ATPase were determined after exposure to aromatic, alicyclic and aliphatic hydrocarbons. Aromatic hydrocarbons decreased the enzyme activities dose-dependently according to their lipid solubilities. The slight enzyme-inhibiting effect of aliphatic and alicyclic hydrocarbons was not dependent on the lipophilicity of these solvents. Their molecular structure may have determined the solvent impact. In the present study, the activity of ouabain sensitive Na+, K(+)-ATPase in astrocytes was only 20-15% of the total ATPase activity, and in neurons 45-55%. The enzyme inhibition caused by organic solvents may disturb the homeostatic regulatory functions of astrocytes and thus have a toxic effect on the CNS.