Gastrointestinal T cell lymphoma: predominant cytotoxic phenotypes, including alpha/beta, gamma/delta T cell and natural killer cells

Gastrointestinal T cell lymphoma (TCL) is a rare subset of peripheral TCL, presenting with or without cytotoxic phenotype, a history of coeliac disease (CD) and enteropathy. However, CD is rare in Japan. Here, we describe the clinicopathological features of 18 Japanese cases. Lesions were found in the small intestine (n=13), stomach (n=3) and colon (n=2). Seven patients presented with enteropathy but none had a history of CD. Lymphomas appeared as ulceration (n=11), tumour formation (n=6), or polypoid growth (n=1). Histologically (REAL classification), neoplastic lesions were composed of intestinal type T cell lymphoma (ITCL, n=13, including one case with NK type), anaplastic large cell (ALCL, n=2), adult T cell leukaemia/lymphoma (ATLL, n=2), and lymphoblastic type (n=1). Epstein Barr virus infection was detected by EBER-1 in situ hybridization in 6 of 11 cases with ITCL but not in the other types. ALCL expressed CD30. CD56 was expressed in 3 of 11 cases of ITCL but not in other types. Among the 10 examined cases, 8 were alphabeta T cell type [CD2+, CD3+, T cell receptor (TCR)delta-1-, betaF1+], one was gammadelta T cell type [CD2+, CD3+, TCRdelta-1+, betaF1-], and the remaining case expressed natural killer (NK) cell type [CD2+, CD3-, CD56+, TCRdelta-1-, betaF1-]. Among the 8 examined cases, 3 expressed CD103 molecule, which was associated with extrathymic T cells of intraepithelial lymphocytes. All cases except ATLL expressed the cytotoxicity-associated molecule of TIA-1, and 11 of 14 TIA-1 positive cases expressed activated cytotoxic molecules of perforin, granzyme B, and/or Fas ligand. Despite the morphological, genetic and phenotypic heterogeneity, prognosis was poor, and 11 of 13 patients with small intestinal lesions died albeit appropriate treatment, but 3 of 4 patients with gastric or colonic lesions were still alive. The main cause of death was intestinal perforation. The latter might be due to the site specificity of small intestine and tumour cytotoxicity.     

A study on contrast discrimination of CT images

We investigated the range of differences in CT values by which radiologists could distinguish among tissues. The contrast discrimination thresholds and contrast discrimination ratios were determined. The test pattern consisted of a square CT film (12 cm in width and 6 cm in length). The film had a circular reference field and a circular test field. Each field was 1 cm in diameter with the distance between the two center being 6.5 cm. The reference fields were set at 60 or 100 H. U.. The test fields were changed and compared with the reference. The window width (WW) and the window level (WL) were set at 400 and 50 H. U. or 250 and 60 H. U.. The contrast dincrimination thresholds for ten observers ranged from 5.9 to 19.3 H. U., and the contrast discrimination ratios were from 11.5 to 21.3%. The effect of WW on contrast discrimination was analyzed for various WWs ranging from 200 to 1000 H. U.. Changes in WW produced no significant difference under the conditions of this investigation.     

Thoracotomy for a Patient with Stevens-Johnson Syndrome: Report of a Case

(Received for publication on Oct. 24, 1996; accepted on May 12, 1997)     

Clinical reevaluation of aztreonam (AZT) on urinary tract infections

The clinical effectiveness and safety of Aztreonam (AZT) were studied in 55 patients with complicated urinary tract infections. AZT was administered at a dose of 4 g/day for 5 days. The results as evaluated by the UTI criteria were excellent in 8 cases, moderate in 26 and poor in 21. The overall effectiveness rate was 61.8%. Out of 64 strains of bacteria isolated before treatment, 50 strains (78.0%) were eradicated by the treatment. Bacteriological eradication rates for gram negative rods and gram positive cocci were 79.6% and 66.7%, respectively. There were no obvious side effects, except for a temporary elevation of glutamic oxaloacetic transaminase, glutamic pyruvic transaminase alkalinephosphatase, and total bilirubin in some patients. The results indicate that AZT tablets are useful and safe for the treatment of complicated urinary tract infections.     

Aurora-B/AIM-1 kinase activity is involved in Ras-mediated cell transformation

Aurora-B, previously known as AIM-1, is a conserved eukaryotic mitotic protein kinase. In mammals, this kinase plays an essential role in chromosomal segregation processes, including chromosome condensation, alignment, control of spindle checkpoints, chromosome segregation, and cytokinesis. Aurora-B is overexpressed in various cancer cells, suggesting that the kinase activity perturbs chromosomal segregation processes. Its forced overexpression induces chromosomal number instability and progressive tumorigenicity in rodent cells in vitro and in vivo. Nevertheless, based on focus formation in BALB/c 3T3 A31-1-1 cells, Aurora-B is not oncogenic. Here, we show that Aurora-B kinase activity augments Ras-mediated cell transformation. RNA interference with short hairpin RNA inhibits transformation by Ras and its upstream oncogene Src, but not by the downstream oncogene Raf. In addition, the inner centromere protein, which is a passenger protein associated with Aurora-B, has a similar ability to potentiate the activity of oncogenic Ras. These data indicate that elevated Aurora-B activity promotes transformation by oncogenic Ras by enhancing oncogenic signaling and by converting chromosome number-stable cells to aneuploid cells.     

5-aza-2'-deoxycytidine sensitizes hepatoma and pancreatic cancer cell lines

Hepatocellular carcinoma (HCC) and pancreatic cancer are at the forefront of chemotherapy-resistant tumors with poor prognosis. Even with innovative treatment regimens, response rates remain low and the duration of response is short. We examined whether the suppression of DNA methylation was capable of enhancing the sensitivity of hepatoma and pancreatic cancer cell lines to 5-fluorouracil (5-FU). 5-aza-2'-deoxycytidine (5-aza-dC) at 2 microM, a specific DNA methylation inhibitor, did not induce cell death in Huh-7 with or without HCV, HLE, HepG2 and MIA PaCa-2 cells. However, a combination of 5-aza-dC with 5-FU showed a reduction in cell viability and induction of apoptosis in these cell lines to a greater degree than with 5-FU only. These findings underline the fact that DNA methylation plays a key role in conferring chemoresistance to hepatoma and pancreatic cancer, and the combination of DNA methylation inhibitor with chemotherapy could be a novel and highly effective tool for future targeted therapy of chemoresistant tumors.     

Pancreatic and gastric metastases of leiomyosarcoma arising in the left leg

Pancreatic or gastric metastases from other primary malignancies are rare, especially from leiomyosarcoma. We report a case of leiomyosarcoma in the left lower leg with metastases to the pancreas and stomach. A 61-year-old man had liver cirrhosis caused by hepatitis C virus infection and was followed up by his primary physician. Two years before presentation at our hospital, he had undergone surgical resection of leiomyosarcoma in the left lower leg and systemic chemotherapy for multiple metastatic tumors in the lung. On admission, endoscopic examination and computed tomography were performed for a routine checkup to exclude esophageal varices and liver tumor. Although the patient had no specific symptoms, multiple gastric and pancreatic metastases were identified by endoscopy and computed tomography, respectively. In general, metastases to the pancreas and stomach are rare. We discuss the clinical and diagnostic findings of pancreatic and gastric metastases by reviewing previously reported cases.     

Microscopic anatomy of the brain–meningioma interface

We analyzed the relation between meningioma and the brain in 50 surgical cases. So-called capsule formation was seen in 20 meningiomas, of which 13 were categorized as thin and 7 as thick. In 21 meningiomas the arachnoid membrane was intact, and 10 meningiomas had no underlying arachnoid membrane. The other 19 tumors showed partial disruption of the arachnoid membrane. The degree of arachnoid disruption correlated with the tumor grade, perifocal edema, pial blood supply on angiography, and tumor size. The existence of brain invasion correlated with the tumor grade and partially with tumor size. In case of invasive tumor, GFAP-positive cells were found deep in the tumor, usually in contact with blood vessels. The axons in gliotic brain often showed degenerative changes such as ballooning or varicose swelling. Meningiomas were usually demarcated by a basement membrane that was collagen type 4 (Col4)-positive. However, atypical and anaplastic meningiomas usually lacked Col4 staining at the interface. In two benign meningiomas that looked like an invasive growth, Col4 staining was seen above the brain. A pia mater-like structure covered the tumor surface in both cases. We could not demonstrate a relation between the expression of matrix metalloproteinase (MMP)-2 or MMP-9 and arachnoid disruption or brain invasion.     

QT PRODACT: evaluation of the potential of compounds to cause QT interval prolongation by action potential assays using guinea-pig papillary muscles

Certain compounds that prolong QT interval in humans have little or no effect on action-potential (AP) duration used traditionally, but they inhibit rapidly-activated-delayed-rectifier potassium currents (IKr) and/or human ether-a-go-go-related gene (hERG) currents. In this study using isolated guinea-pig papillary muscles, we investigated whether new parameters in AP assays can detect the inhibitory effects of various compounds on IKr and/or hERG currents with high sensitivity. The difference in AP duration between 60% and 30% repolarization, 90% and 60% repolarization, and 90% and 30% repolarization (APD30-60, APD60-90, and APD30-90, respectively) were calculated as the new parameters. All the 15 IKr and/or hERG current inhibitors that have been reported (9 compounds) or not reported (6 compounds) to inhibit calcium currents prolonged APD30-60, APD60-90, and/or APD30-90; and 8 of the 15 inhibitors prolonged APD30-60, APD60-90, and/or APD30-90 more potently than APD90. The APD30-60, APD60-90, and APD30-90 measurements revealed no difference in sensitivity when evaluating the effects of the IKr and/or hERG current inhibitors on the three parameters. On the other hand, compounds with little or no effect on hERG currents had no effect on APD30-60, APD60-90, or APD30-90. Therefore, it is concluded that in AP assays using isolated guinea-pig papillary muscles, APD30-60, APD60-90, and APD30-90 are useful indexes for evaluating the inhibitory effects of compounds including mixed ion-channel blockers on IKr and/or hERG currents.     

Modulation of intestinal transport of 2,4-dinitrophenyl-S-glutathione, a multidrug resistance-associated protein 2 substrate, by bilirubin treatment in rats

The effect of bilirubin treatment on intestinal transport of 2,4-dinitrophenyl-S-glutathione (DNP-SG), a substrate of multidrug resistance-associated protein 2 (MRP2), after application of 1-chloro-2, 4-dinitrobenzene (CDNB), a precursor of DNP-SG, was examined in rat intestine by the in-vitro everted sac, in-situ re-circulating perfusion, and in-situ loop methods. CDNB was taken up rapidly by jejunum and ileum, and the consequent intestinal efflux of DNP-SG, a glutathione conjugated metabolite of CDNB, was significantly higher in jejunum than in ileum in the in-situ and in-vitro studies. Co-administration of bilirubin (100 microM), as well as probenecid (1 mM) or ciclosporin (100 microM), with CDNB decreased the DNP-SG efflux in jejunum significantly, but not in ileum. The suppression of DNP-SG efflux in jejunum was also observed after intravenous administration of bilirubin (85.5 micromol kg-1), in which plasma bilirubin glucuronide levels were approximately 100 microM. In the in-vitro metabolism study, bilirubin exerted no significant effect on CDNB metabolism in the intestinal S9 fraction (supernatant of 9000 g). These results suggested that the diseased states accompanied with hyperbilirubinaemia might have increased the intestinal absorption, or oral bioavailability, of MRP2 substrates by suppressing MRP2 function at the proximal intestinal region.