Use of E mu-PIM-1 transgenic mice short-term in vivo carcinogenicity testing: lymphoma induction by benzo[a]pyrene, but not by TPA

E mu-pim-1 transgenic mice are predisposed to develop lymphomas. Due to their low spontaneous tumour incidence and their increased sensitivity towards the lymphomagen ethylnitrosourea these mice may present an interesting model for short-term carcinogenicity testing. Here, we report on the further exploration of this transgenic mouse model with two additional carcinogens known to have, among others, the lymphohaematopoietic system as target, i.e. benzo[a]pyrene (B[a]P) and 12-O-tetradecanoylphorbol-13-acetate (TPA). B[a]P, given three times a week (by gavage) for 13 weeks at 4.3, 13 or 39 mg/kg body weight, resulted in a dose-related increase in lymphomas up to a 90% incidence in E(mu)-pim-1 mice during the observation period of 40 weeks. B[a]P also induced tumours of the forestomach within this observation period, though at a lower incidence and apparently equally effective in wildtype and transgenic mice. TPA, on the other hand, was unable to induce lymphomas (or tumours in any other organ) in either transgenic or wildtype animals within the observation period of 44 weeks, when applied dermally at the maximum tolerated dose of 3 microg/mouse, twice a week for 35 weeks. Molecular analysis showed that B[a]P-induced lymphomas in transgenic mice were of T-cell origin, 80% of which had elevated levels of c-myc expression. None of the lymphomas had increased N-myc expression and mutation analysis of the ras-gene family revealed a K-ras mutation in only one out of eight tumours investigated. Also, none of the lymphomas showed aberrant expression of p53 as determined by immunohistochemistry. It is concluded that the E mu-pim-1 mouse model will not be very suitable for short-term carcinogenicity testing in general: only genotoxic chemicals that have the lymphohaematopoietic system as target for carcinogenesis in wild- type mice, appear to be efficiently identified.      

Second Primary Cancers Following Non-Hodgkin's Lymphoma in Japan: Increased Risk of Hepatocellular Carcinoma

We evaluated the risk of development of second primary cancers, with particular reference to subsequent hepatocellular carcinoma (HCC), in 592 patients diagnosed as non-Hodgkin's lymphoma (NHL), at Osaka Medical Center for Cancer and Cardiovascular Diseases. During 1978–1994, 2,163 person-years of observation were accrued, and 27 of the patients developed a second primary cancer, yielding an observed-to-expected ratio (O/E) of 1.53 [95% confidence interval (CI) = 1.01–2.23]. Significant excess risk was noted for primary liver cancer (PLC; O/E=4.36, 95% CI=1.99–8.28; O =9) and non-lymphocytic leukemia (O/E=26.17, 95% CI=5.26–76.46; O=3). The excess risk of PLC was relatively constant within the first 10 years after the NHL diagnosis. Patients who received chemotherapy as the NHL treatment had a significantly increased risk of PLC (O/E=5.91, 95% CI =2.70–11.23; O=9). Their clinical reports indicated that all nine patients with PLC were diagnosed as HCC, and eight of them had clinical and/or histologic evidence of cirrhosis at the time of HCC diagnosis. None of the nine patients had a history of blood transfusion between the first NHL treatment and the diagnosis of HCC. These findings suggested that Japanese NHL patients might have an increased risk of developing HCC, and they indicated the importance of medical surveillance for liver malignancies, as well as subsequent leukemias. Possible explanations for the excess risk of subsequent HCC are discussed.     

A case of locally advanced rectal carcinoma with liver metastasis treated with a combination of CRT, HAI, and systemic chemotherapy

A 55-year-old man with locally advanced rectal carcinoma and liver metastasis was treated with a combination of chemo-radiotherapy (5-FU suppository 100 mg/day and 63 Gy of RT), hepatic arterial infusion chemotherapy (5-FU 1,000 mg/3 h, biweekly), and systemic chemotherapy (5'-DFUR 800 mg/day + cimetidine 800 mg/day). His rectal tumor was reduced and his symptoms such as pain and bleeding had markedly decreased. The river metastasis did not change during the entire course. HAI and administration of 5-FU suppository, 5'-DFUR, and cimetidine were continued. As of 18 months after the onset of the combination therapy, NC has been maintained, and the general condition of the patient is favorable.     

Radial and lumbar bone mineral density after wrist synovectomy in rheumatoid arthritis

Bone mineral density (BMD) of both radii and lumbar vertebrae was measured by single-photon absorptiometry and dual X-ray absorptiometry, respectively, before and 2.1–4.8 years after a unilateral wrist synovectomy in 10 patients with rheumatoid arthritis. Radial BMD on the operated side significantly increased after synovectomy, while that on the non-operated side did not change. Lumbar BMD significantly decreased after the operation. The grip strength of the operated side increased significantly after synovectomy, while there were no changes in the grip strength on the non-operated side. These findings suggest that wrist synovectomy results in pain relief and improves use, thereby increasing the BMD of the operated radius.     

Radiotherapy for uterine cervical cancer: results of the 1995-1997 patterns of care process survey in Japan

OBJECTIVE: The aim of this study is to establish Japanese national practice patterns for uterine cervical cancer patients who received radiotherapy without surgery. METHODS: The Japanese Patterns of Care Study (JPCS) conducted a national survey of 73 institutions using two-stage cluster sampling, and collected specific information on 591 patients with uterine cervical cancer treated by radiotherapy without planned surgery between 1995 and 1997. RESULTS: The median age of the patients was 70 years. Karnofsky performance status (KPS) was >/=90 for 37%. Most patients (95%) had histology of squamous cell carcinoma. Ten percent were stage I, 29% stage II, 48% stage III and 13% stage IVA. Photon beams of 10-14 MV were the most used for external beam radiotherapy (EBRT). The beam energy utilized varied significantly by institution strata. Midline block was used in approximately 70% of institutions. Intracavitary brachytherapy (ICBT) was performed in 77%. Institution strata correlated significantly with the ICBT application. The majority of patients (89%) were treated with high-dose-rate (HDR) ICBT. The median single point A dose of HDR-ICBT was 600 cGy. The median summated point A dose from EBRT and HDR-ICBT was 5800 cGy (range: 1196-8600). The median overall treatment time including ICBT was 49 days. Twenty-four percent of the patients received chemotherapy. Concurrent chemoradiation was performed in 5%. CONCLUSIONS: The JPCS established the Japanese national practice patterns of care for uterine cervical cancer patients treated with radiotherapy without planned surgery between 1995 and 1997. This survey demonstrated that the institutional strata significantly affected several practice patterns.     

Patterns of care study in Japan

BACKGROUND: The Patterns of Care Study (PCS), started in the 1970's, is a well-known study used for clinical quality assurance (QA) in radiation oncology in the United States. PCS has been introduced in Japan since 1996. METHODS: Three national PCS surveys have been performed by means of external audit to evaluate patterns of care for the patients with carcinoma of any of esophagus and cervix treated with radiation between 1992 and 1994, for those with carcinoma of any of esophagus, cervix, breast, lung and prostate between 1995 and 1997, and for those with any of the five disease sites between 1999 and 2001. In the first PCS, feasibility of the study was confirmed. In the second PCS, two-stage cluster sampling of institutions and patients was performed and national averages for the survey items were calculated as QA measures. In the third PCS, additional imaging data were collected. The Japan/USA PCS workshops were held at San Francisco in 2001 and at Tokyo in 2003. RESULTS: Significant variations in process and structure were observed according to institutional stratification. In academic institutions, external beam energy > or =6 MV for deep-seated tumors of esophagus, lung, prostate and cervix, and brachytherapy for those of cervix and esophagus were used more frequently. There was an average of less than one full-time equivalent radiation oncologist in most non-academic institutions. These variations influenced the outcomes. There were also significant differences between USA and Japan in various aspects, e.g. a difference in radiation dose of 20% for uterine cervix cancer patients. It is higher in the USA. The number of new cancer patients requiring radiation is increasing steeply (120,000 in 2000 and 170,000 in 2005). Based on PCS data, structural guidelines were published and distributed throughout Japan. CONCLUSION: PCS is useful for establishing the clinical QA for radiation oncology as well as other specialties through detailed monitoring and evaluation of their structures, processes and outcomes.     

Clinical outcome after cardiac operations in patients with cirrhosis

BACKGROUND: To evaluate the clinical outcome after cardiac operations in patients with cirrhosis, a retrospective study was undertaken. METHODS: Between 1989 and 2003, 18 patients with cirrhosis who underwent cardiac operations were identified. Their preoperative status and postoperative clinical results were assessed. RESULTS: Ten patients were classified as having Child-Pugh class A cirrhosis, 7 as having class B cirrhosis, and 1 as having class C cirrhosis. Fifteen of 18 patients underwent cardiac surgery using cardiopulmonary bypass, and the remaining 3 patients with class B cirrhosis received coronary artery bypass grafting without cardiopulmonary bypass. In patients undergoing cardiopulmonary bypass, 60% of those with class A cirrhosis and 100% of those with class B cirrhosis and class C cirrhosis had postoperative major complications, including infection, respiratory failure, renal failure, bleeding, and gastrointestinal disorder. One of 3 patients (33%) with class B cirrhosis undergoing coronary artery bypass grafting without cardiopulmonary bypass had major complications. The overall postoperative mortality rate was 17%. Hospital mortality of patients with class A cirrhosis, class B cirrhosis, and class C cirrhosis undergoing cardiopulmonary bypass was 0%, 50%, and 100%, respectively. None of 3 patients with class B cirrhosis undergoing coronary artery bypass grafting without cardiopulmonary bypass died in this study. CONCLUSIONS: Although the incidence of major complications was high, patients with Child-Pugh class A cirrhosis tolerated cardiac surgery satisfactorily. Patients with more advanced cirrhosis, however, may not be suitable for elective cardiac operations with cardiopulmonary bypass. Although our results are not conclusive, coronary artery bypass grafting without cardiopulmonary bypass can be an alternative therapeutic strategy for patients with advanced cirrhosis requiring surgical revascularization.     

Engineered FGF-2 expression induces glandular epithelial hyperplasia in the murine prostatic dorsal lobe

OBJECTIVE: It is known that androgens and stromal-epithelial interactions are required for the formation and growth of the prostate. FGF-2 is overexpressed in prostatic stromal cells in benign prostatic hypertrophy (BPH)/prostate cancer. This supports the paracrine/autocrine growth of prostatic epithelial/stromal cells in the pathogenesis of BPH and invasive prostate cancer. METHODS: We established transgenic mice expressing FGF-2 under the control of a short rat probasin promotor. FGF-2 transgenic founder mice expressing FGF-2 in the prostate were infertile. Thus, male founder mice were sacrificed for histological analysis. RESULTS: FGF-2 was expressed in epithelial cells in glands of the dorsal, lateral, and ventral prostatic lobes of two FGF-2 transgenic founder mice, but not in the anterior lobe of transgenic mice or in any lobe of non-transgenic control littermates. Acinar epithelial glands in dorsal prostatic lobes of FGF-2 transgenic mice expressing FGF-2 were more dense and showed simple papillary hyperplasia of epithelial cells compared with those of control littermate mice. Glandular and luminal enlargement without epithelial growth was observed in the ventral lobe of FGF-2 transgenic mice compared with the controls. CONCLUSION: In conclusion, FGF-2 transgenic mice under the control of rat probasin promoter showed simple epithelial hyperplasia in glands of the prostatic dorsal lobe and glandular enlargement without epithelial growth in the prostatic ventral lobe.