Cumulative effects of chromosome aberrations and sister chromatid exchanges in rat liver induced in vivo by heterocyclic amines

Cumulative effects of chromosome aberrations and sister chromatidexchanges (SCEs) were studied in hepatocytes of F344 rats exposedin vivo to 2-amino-3-methylimidazo[4,5-fIquinoline (IQ) at dosesof 12.5,25 or 50 mg/kg body wt/day or 2-nitro-3-methylimidazo[4,5-f quinoline (nitro-IQ) at doses of 12.5, 25 or 50 mg/kg bodywt/day. Hepatocytes were isolated 24 h after 1, 7,14 or 28 repeateddoses (once a day) by gastric intubation and allowed to proliferatein Williams' medium E supplemented with epidermal growth factor.Cells were fixed after a culture period of 48 h. Multiple treatmentwith IQ or nitro-IQ induced significant chromosome aberrationstime- and dose-dependently, the maximum frequency of chromosomeaberrations in metaphase cells being 39 and 33% respectively,while that in controls was 1.1%. Single treatment with IQ ornitro-IQ induced significant SCEs dose-dependently, the maximumfrequency being 0.83 and 0.79 per chromosome respectively, whilethe control value was 0.51. Multiple treatment with nitro-IQinduced significant SCEs to a plateau level of 0.90 per chromosome.Cytogenetic damage in the liver by IQ was greater than thatby nitro-IQ. These results show that this assay of chromosomeaberrations and SCEs in rat liver in vivo without partial hepatectomyor mitogen treatment in vivo is a sensitive method for evaluatingthe cumulative tumor-initiating activities of carcinogenic heterocyclicamines at low doses and should be useful for the detection ofunknown hepatocarcinogens.     

Proton Beam Therapy for Patients with Esophageal Carcinoma

Fifteen patients with esophageal carcinoma (superficial, sixcases; advanced, nine cases) were treated with 250 MeV protonbeam irradiation with or without external x-ray irradiation(12 MV linear accelerator) from October, 1985, to May, 1991.Eleven patients were initially treated with x-ray at doses of16.2-50.4 (mean 42.5) Gy, followed by proton beam at doses of30.0-52.9 (mean 37.6) Gy. The other four patients were treatedwith proton beam alone at total doses of 75.0-88.5 (mean 81.4)Gy. The mean total dose for the 15 patients was 80.4 Gy. Asa result, the primary tumor lesions of all 15 patients disappearedand complete responses were obtained. Approximately four tofive months later, nine of the 15 patients developed esophagealulcer formations at the circumferences of their primary lesions.The ulcerations were healed, however, by conservative management.There was no evidence of local recurrence throughout the observationson six cases of superficial carcinoma. Among nine advanced carcinomapatients, three relapsed into esophageal carcinoma. Recurrenceswere observed eight, 16 and 44 months, respectively, after thetreatment. Ten of the 15 patients died, but eight died of otherdiseases. Three of four cases at autopsy did not show any cancercells in irradiated primary lesions. Four of the 15 patientslived for over five years. The results suggest that a high doseof irradiation delivered by a well-defined proton field couldresult in improved local control and long-term survival in esophagealcarcinoma without undue risk of injury to primary and adjacentorgans.     

Inhibition of 1,2-Dimethylhydrazine-induced Oxidative DNA Damage by Green Tea Extract in Rat

Following subcutaneous injection of 1,2-dimethylhydrazine (DMH), which is carcinogenic to rat colon and liver, to Sprague-Dawley rats, a significant increase of 8-hydroxydeoxyguanosine (8-OHdG) was observed in the DNA of colonic mucosa and liver. The 8-OHdG formation reached the maximal level at about 24 h after the DMH injection. On the other hand, no increase of 8-OHdG was observed in the DNA of the kidney. Drinking green tea extract (GTE) for ten days prior to the DMH injection significantly inhibited the formation of 8-OHdG in the colon. These findings demonstrate that DMH causes oxidative damage to the DNA of its target organ, and that GTE protects colonic mucosa from this oxidative damage.     

Detection of Homing, Proliferation, and Infiltration Sites of Adult T Cell Leukemia Cells in Severe Combined Immunodeficiency Mice Using Radiometric Techniques

To clarify the mechanism of in vivo proliferation of adult T cell leukemia (ATL) cells, we examined the organ distribution of ATL-43T cell line cells derived from original leukemic cells in severe combined immunodeficiency (SCID) mice using radiometric techniques. First, we injected ¹¹¹In-oxine-labeled ATL-43T cells into SCID and CB17 mice. On day 6, significant accumulation of radioactivity was found in the spleen and thymus of SCID mice (33.3±9.4 and 10.0±3.6 % injected dose/g of tissue [%ID/g], respectively) in comparison with that in CB17 mice (19.1±2.5 and 3.7±0.9 %ID/g, respectively). Next, we injected radiolabeled anti-Tac monoclonal antibody (MoAb) recognizing human interleukin-2 receptor (IL-2R) α chain or isotype-matched control MoAb RPC5 in SCID mice bearing ATL-43T cells 4 weeks after cell inoculation. The amounts of radioactivity found in the spleen and thymus of SCID mice injected with ¹²⁵I-labeled anti-Tac MoAb (22.5±6.9 and 22.8±9.6 %ID/g, respectively) were significantly higher than those in the corresponding organs of SCID mice injected with ¹²⁵I-labeled RPC5 MoAb (12.0±5.1 and 7.5±4.6 %ID/g, respectively). Similar results were obtained with ¹¹¹In-labeled anti-Tac MoAb. These results were consistent with the histological findings of SCID mice bearing ATL-43T cells, indicating that ATL-43T cells infiltrated preferentially into the lymphoid organs, such as the spleen and thymus, and proliferated there. Thus, the radiometric techniques employed in this study were very useful to evaluate the proliferation sites of ATL-43T cells in SCID mice. Furthermore, this murine model could give us an opportunity to test the feasibility of therapeutic application of radiolabeled anti-Tac MoAb.     

p53 Mutation in B-Cell Lymphoid Neoplasms with Reference to Oncogene Rearrangements Associated with Chromosomal Translocations

We investigated mutations of the p53 tumor suppressor gene in B-cell lymphoid neoplasms with reference to oncogene rearrangements associated with specific chromosomal translocations. These included 15 patients with a BCL1/PRAD1 gene rearrangement and/or PRAD1 overexpression, 45 with a BCL2 rearrangement, 2 with a BCL3 rearrangement, 24 with a BCL6 rearrangement, and 6 with both BCL2 and BCL6 rearrangements. Thirty-six patients lacked detectable oncogene rearrangements. Genomic DNA was isolated from involved tissues or leukemic cells obtained at diagnosis and/or at relapse, and established cell lines. Polymerase chain reaction-mediated single-strand conformation polymorphism analysis and direct sequencing were performed to analyze abnormalities of the p53 gene. We detected p53 gene alterations in 18 of 128 patients, representing 21 of the total 151 materials analyzed. In the total of 66 patients with an oncogene rearrangement studied at diagnosis, only one had a mutation; however, 6 of 37 patients studied at relapse showed p53 mutations. Sequential analysis revealed that the p53 mutation was closely associated with transformation from follicular lymphoma to large cell lymphoma, exclusively in BCL2 -positive lymphoma cases. Two of 13 mutations observed in oncogene rearrangement-positive cases and cell lines were transitions at CpG dinucleotides. In contrast, the relationship between p53 mutations and clinical behavior in oncogene rearrangement-negative cases was variable; 5 patients including one with indolent follicular lymphoma were positive for p53 mutation at initial presentation, and 2 of the 5 showed prolonged disease-free survival. Our findings suggest that p53 alteration exhibits diverse functions in the development and progression of B-cell tumors related to the presence or absence of oncogene rearrangement, and that chemotherapy-related influences may be involved in the occurrence of progression-associated p53 mutations.     

Coronary aneurysms in Kawasaki disease: Follow-up observation by two-dimensional echocardiography

Summary The development and regression of the coronary aneurysms in Kawasaki disease was studied with serial two-dimensional echocardiographic (2D echo) examinations. The diameter of the aneurysms at the proximal portions of the left coronary artery was measured on the 2D echo images in ten patients with Kawasaki disease, in whom left coronary aneurysms were found at the acute stage of the illness, and followed by 2D echo for longer than eight months. It was found that coronary aneurysms usually developed during the second week of the illness, reached maximal size at 3–8 weeks, and regressed gradually thereafter. Small aneurysms disappeared in several months, and those of intermediate size regressed in one to two years. Large aneurysms may remain for many years. Mural thrombi within the aneurysms were detected with 2D echo in three patients. They decreased in echodensity and eventually disappeared echographically.     

Malignant fibrous histiocytoma of the uterus

A primary, malignant pleomorphic giant cell tumor of the uterus was studied by light and electron microscopy. The tumor was characterized by spindle cells, plump epithelioid cells, pleomorphic giant cells, osteoclast-like giant cells, and foamy xanthomatous cells. Histochemically, tumor cells did not show either myogenic or epithelial characteristics. Immunohistochemically, tumor cells were devoid of evidence of desmin, cytokeratin, myoglobin, and lysozyme (muramidase), but vimentin was weakly positive, and alpha 1-antichymotrypsin was weakly positive in the cytoplasm of pleomorphic giant cells. Ultrastructurally, tumor cells did not show either myogenic or epithelial features, but they resembled a variant of malignant fibrous histiocytoma. The present case was classified as a storiform-pleomorphic and giant cell type of malignant fibrous histiocytoma of the soft tissues. The uterus is considered to be an additional possible site of malignant fibrous histiocytoma.     

Diagnosis of esophageal cancer using positron emission tomography

Fluorodeoxyglucose positron emission tomography (FDG-PET) is more accurate than computed tomography (CT) for evaluating lymph node metastases and for N staging, but less accurate than combined CT and endoscopic ultrasonography (EUS). Lymph nodes located adjacent to the primary lesion tend to be false negatives. We consider that combined FDG-PET and EUS is the most accurate for the detection of lymph node metastasis in esophageal cancer. FDG-PET is also more accurate than CT for detecting distant metastases and improves the detection of stage IV disease compared with the conventional staging modalities. For the diagnosis of recurrence except for perianastomotic recurrence, FDG-PET provides additional information and is more sensitive than conventional work-ups. FDGPET is a valuable tool for the noninvasive assessment of tumor response after neoadjuvant therapy. 11C-methionine (MET) is another tracer for PET that can be used to assess the metabolism of amino acids, since MET accumulates in esophageal malignant tumors. Choline-PET is more accurate than FDG-PET for the detection of mediastinal lymph node metastases.     

Functional Mediastinal Parathyroid Cyst: Report of a Case

We report herein a rare case of a functional mediastinal parathyroid cyst. A mediastinal tumor was detected by a chest X-ray film and subsequent computed tomography (CT) scan in a 68-year-old woman who was asymptomatic. Biochemical examination revealed that her serum calcium and intact-parathyroid hormone (i-PTH) levels were above the normal range. The findings of chest CT and magnetic resonance imaging suggested a cystic mass. The mass, which adhered tightly to its surrounding structures, was resected through a median sternotomy. The patient had an uneventful postoperative course, and her serum calcium and i-PTH levels rapidly returned to within the normal range. Received: March 21, 2001 / Accepted: September 11, 2001