Over‐expression of BACH2 is related to ongoing somatic hypermutation of the immunoglobulin heavy chain gene variable region of de novo diffuse large B‐cell lymphoma

The basic region–leucine zipper (bZip) factor BTB, CNC homology 2 (BACH2) is known to have important roles in class switch recombination and somatic hypermutation (SHM) of the immunoglobulin (Ig) gene. In this study, we investigated the relationship between the expression of BACH2 and the status of SHM of the Ig heavy chain gene variable region (IgHV) for SHM in diffuse large B‐cell lymphoma (DLBCL). We examined 20 cases of DLBCL, 13 of which were germinal center B‐cell (GCB) DLBCL and 7 were non‐GCB DLBCL. Seven cases were negative, 6 were positive (cytoplasmic expression) and 7 were strongly positive (both nuclear and cytoplasmic expression) for BACH2. Confirmed mutation (CM) was identified in 8 cases and the CM index (number of confirmed mutations per 10 subclones) was distributed from 0 to 5. A CM index of 7 strongly positive (over‐expression) cases with BACH2 were distributed from 0 to 5, and that of 7 negative and 6 positive cases were distributed from 0 to 1. Over‐expression of BACH2 was statistically related to CM index (P = 0.008). In conclusion, over‐expression of BACH2 is critical for ongoing SHM of IgHV in DLBCL, and our data suggest that BACH2 may play an essential role for SHM of the Ig gene in B‐cell lymphoma.     

Beneficial Effect of Partial Portal Decompression Using the Inferior Mesenteric Vein for Intractable Gastroesophageal Variceal Bleeding in Patients With Liver Cirrhosis

BACKGROUND: Use of the inferior mesenteric vein (IMV) for partial portal decompression has not been recommended as a first-line option for intractable gastroesophageal variceal bleeding because of the thin diameter of the vein. Although these indications remain relevant, few reports have compared partial portal decompression using the IMV with other therapies. We propose that partial portal decompression using the IMV is a useful alternative treatment for intractable variceal bleeding. METHODS: We performed partial portal decompression using the IMV in eight patients with intractable variceal bleeding that had been uncontrolled using medical and endoscopic therapies. All patients were classified into Child's class B or C. The surgical data, morbidity, and mortality were assessed. RESULTS: Mean portal venous pressure significantly decreased from 26.9 +/- 2.0 mmHg before the surgery to 19.8 +/- 3.9 mmHg after the surgery. The operative mortality rate was 0%. The mean duration of hospital stay was 25.5 +/- 13.3 days. Although one patient experienced recurrent bleeding, shunt patency was well maintained in all patients during the follow-up period (mean 28.9 +/- 14.1 months). Six patients are still alive and well without ascites or hepatic encephalopathy. Two of the Child's class C patients who underwent emergency shunt died owing to hepatic decompensation. CONCLUSION: Partial portal decompression using the IMV can be a safe, effective way to treat intractable variceal bleeding in patients with liver cirrhosis. However, use of the shunt procedure may have the most survival benefits for cirrhotic patients with preserved liver function.     

Hepatic resection for liver metastases from carcinomas of the distal bile duct and of the papilla of Vater

Purpose  

Hepatectomy for liver metastasis from carcinomas of the distal bile duct (BDC) and of the papilla of Vater (PVC) has not been studied in detail. The purpose of this study is to analyze risk factors of liver metastasis and to evaluate outcome of hepatectomy for liver metastasis.     

Gastric carcinosarcoma presenting as a huge epigastric mass

Gastric carcinosarcoma often presents with an elevated lesion or increased thickness of the stomach wall. Histological diagnosis is achieved using conventional hematoxylin and eosin staining to confirm the coexistence of both epithelial and mesenchymal elements. We report a case of gastric carcinosarcoma presenting as a large mass in the epigastric region. Specimens obtained by endoscopic biopsy and surgical excision showed diffuse proliferation of atypical cells in sheet formation. No mucus production or glandular structures were apparent, but immunoreactivity for both epithelial and mesenchymal markers was noted. These findings led to a definitive diagnosis of gastric carcinosarcoma. Immunohistochemical analysis is useful for the early diagnosis and treatment of gastric carcinosarcoma.     

Multiple Repeat Resections of Intra- and Extrahepatic Recurrencesin Patients Undergoing Initial Hepatectomy for Colorectal CarcinomaMetastases

Recent evidence suggests that single repeat metastasectomy may provide survival benefits for selected patients experiencing hepatic or pulmonary recurrences following initial hepatectomy for colorectal carcinoma metastases. The aim of this retrospective study was to clarify the efficacy of multiple repeat resections of intra- and extrahepatic recurrences following initial hepatectomy. A total of 100 patients underwent curative partial hepatectomy as the initial procedure for colorectal carcinoma metastases. Tumor relapse after initial hepatectomy was seen in 72 patients, of whom 28 underwent 45 repeat metastasectomies of various sites: 18 patients underwent a single repeat metastasectomy, and 10 underwent multiple repeat metastasectomies. The overall survival rate at 5 years after initial hepatectomy was 36.6%, while the 5-year survival rate after repeat metastasectomy in the 28 patients was 43.6%. The outcome of initial hepatectomy was comparable with that of repeat metastasectomy (p = 0.6924). Among the 28 patients undergoing repeat metastasectomy, the outcome of resection of intrahepatic recurrences in 11 patients was comparable with the outcome of resection of extrahepatic recurrences in 17 patients(p = 0.3926). The outcome of multiple repeat metastasectomies compared favorably with single repeat metastasectomy(p = 0.1803). Multivariate analysis(p < 0.0001) showed that repeat metastasectomy was the strongest prognostic factor. In conclusion, both single and multiple repeat resections of intra- and extrahepatic recurrences after initial hepatectomy are efficacious in colorectal carcinoma patients.Repeat resection should be considered for any resectable recurrences after hepatectomy.     

Effect of grapefruit pulp on the pharmacokinetics of the dihydropyridine calcium antagonists nifedipine and nisoldipine

The effect of the intake of 200 g of grapefruit pulp (corresponding to one grapefruit) on the pharmacokinetics of the calcium antagonists nifedipine (NF) and nisoldipine (NS) were investigated in 8 healthy Japanese male volunteers. A crossover design was used for the study: group I did not ingest any grapefruit (control group); group II ingested grapefruit 1 h after drug administration; and group III ingested grapefruit 1 h before drug administration. The intake of grapefruit pulp increased the plasma concentrations of both NF and NS, an effect that has previously been reported with grapefruit juice. The increase was most marked when grapefruit was eaten before drug administration. For both NF and NS, subjects who ingested grapefruit 1 h before drug administration exhibited a greater Cmax and AUC0-24 than did subjects in the control group. For NF, the Cmax was 1.4 times higher and the AUC0-24 1.3 times larger in group III than in group I. For NS, the Cmax was 1.5 times higher and the AUC0-24 1.3 times larger in group III than in group I. The increase in the AUC0-24 was significant for both drugs (p < 0.05). The finding that the ratios of Cmax and AUC0-24 for unchanged drug and metabolites did not vary greatly among the three groups for either drug suggests that the increase in serum concentration produced by grapefruit intake may be due to other factors than an inhibitory effect on drug metabolism. Also, the increases in Cmax and AUC0-24 of NS produced by grapefruit intake were smaller than those produced by grapefruit juice intake, indicating that grapefruit pulp and juice have different effects on the pharmacokinetics.     

Protective effect of a new nonpeptidyl mimetic of SOD,M40401, against focal cerebral ischemia in the rat

We tested the neuroprotective effects of M40401, a new, low molecular weight (511.4 Da) maganese superoxide dismutase mimetic, against 90 min of middle cerebral artery occlusion (MCAO) in male Wistar rats. Animals received a single injection of vehicle (n=8), 1 mg/kg (n=6), or 3 mg/kg (n=7) 30 min before MCAO. Total lesion volume was reduced only in the group receiving 3 mg/kg M40401 (163.5+/-18.7 versus 43.4+/-7.0 mm(3), for vehicle and M40401, respectively; P<0.05), with almost complete reduction of lesion volume in the cortex but little protection in the basal ganglia. Neurological score was also improved in this group. The dose of 1 mg/kg M40401 had smaller and inconsistent effects on lesion parameters. Administration of a single dose of 3 mg/kg M40401 at 60 min of MCAO or at the end of MCAO (90 min) failed to significantly reduce lesion volume. A single dose of M40401 plus prolonged infusion into the post-MCAO period also failed to decrease lesion volume significantly. These data indicate that M40401 protects cerebral tissue from ischemic insult when administered before MCAO, probably by limiting damage mediated by detrimental actions of superoxide anion.     

A novel approach for the detection of proteolytically activated transglutaminase 1 in epidermis using cleavage site-directed antibodies

It has been suggested that transglutaminase 1 is proteolytically activated upon the terminal differentiation of the keratinocyte, but the mechanisms are not well understood. We have established two mouse hybridoma cell lines producing monoclonal antibodies that specifically detect proteolytically cleaved transglutaminase 1. One detects the amino-terminus of the fragment produced by cleavage between Arginine 93 and Glycine 94, and the other detects the amino-terminus of the fragment produced by cleavage between Arginine 573 and Glycine 574. Using these two antibodies, immunohistochemical analyses of the epidermis revealed that the cleavages of the transglutaminase 1 protein occur early in the terminal differentiation of keratinocytes in the basal layer of the epidermis, that the cleavage between Arginine 573 and Glycine 574 (producing the 574G fragment) precedes the cleavage between Arginine 93 and Glycine 94 (producing the 94G fragment), that the 94G fragment is localized to the plasma membrane of keratinocytes and has cross-linking activity, whereas the 574G fragment is dispersed in the cytosol and does not have detectable levels of activity on in situ transglutaminase assay, and that 1-alpha-25-dihydroxycholecalciferol or all-trans retinoic acid treatment and ultraviolet B exposure disturb the localization of the transglutaminase 1 fragments with changes in the morphology of differentiating keratinocytes. All these results demonstrate that the antibodies generated in this work are useful to dissect the mechanism by which transglutaminase 1 is activated, and would provide us with novel insights into the biogenesis of the epidermis.