The endoscopic evaluation of gastritis,gastric remnant residue,and the incidence of secondary cancer after pylorus-preserving and transverse gastrectomies

Background Pylorus-preserving gastrectomy (PPG) and transverse gastrectomy (TrG) have been accepted as function-preserving procedures for node-negative early gastric cancer. It is believed that a better quality of life is guaranteed after PPG or TrG compared to that after distal subtotal gastrectomy (DSG) with Billroth type-I reconstruction. However, objective evaluations of the gastric remnant following gastrectomy have not been widely reported, and the real advantages and disadvantages of PPG or TrG over DSG remain unclear. Moreover, the risk of secondary cancer after PPG or TrG is uncertain.Methods Between 1991 and 2000, 834 DSGs were carried out in our institute for preoperatively diagnosed patients with early gastric cancer. The degree of residual gastritis and the amount of diet residue in the gastric remnant were evaluated by annual gastrointestinal endoscopic investigations prospectively for 72 patients after PPG, 95 patients after TrG, and 60 patients after DSG. These analyses were performed using the RGB classification (residue, gastritis, bile). The incidence of disease greater than or equal to grade 2 was calculated, and the time trends of the incidence for each procedure were also studied for 3 years after gastrectomy. In addition, secondary cancer cases in the gastric remnant mucosa were checked for each procedure during this period, and the incidence of secondary cancer after each operation was calculated.Results The incidence of gastritis, of grade 2 or more, found in the gastric remnant was significantly lower after PPG (1.4%) and TrG (2.1%) than after DSG (43.3%). However, the incidence of moderate or greater residue in the gastric remnant, grade 2 or more, was significantly higher after PPG (45.8%) and TrG (40.0%) than after DSG (11.7%). The analysis of time trends of gastritis and diet residue reflected the significant advantage or disadvantage for each procedure 1 year after surgery. The analysis also included these factors without consideration of elapsed time following surgery. Two patients after PPG (2.8%) and three patients after TrG (3.2%) developed secondary cancer in the gastric remnant. No DSG-treated patient showed new cancer genesis in the remaining stomach.Conclusion PPG and TrG have the advantage over DSG in preventing postoperative gastritis in the gastric remnant. On the other hand, moderate or greater diet residue in the gastric remnant is more common after PPG or TrG than after DSG. For the risk of carcinogenesis in the remnant gastric mucosa, we could not conclude that there was any apparent difference between these range-limited gastrectomies and conventional DSG. Further study is necessary to determine the significant advantages and disadvantages of using PPG or TrG.     

Critical role of the p400/mDomino chromatin-remodeling ATPase in embryonic hematopoiesis

The SWI2/SNF2 family ATPase, p400/mDomino, is a core subunit of a large chromatin-remodeling complex, and is currently suggested to play a unique function in histone variant exchange, a process by which chromatin structure is altered. Here, we investigated the role of p400/mDomino in mammalian development by generating mutant mice with a targeted deletion of the N-terminal domain of p400/mDomino (referred to as mDom(DeltaN/DeltaN)). The mDom(DeltaN/DeltaN) mice died on embryonic day 11.5 (E11.5), and displayed an anemic appearance and slight deformity of the neural tube. DNA microarray and quantitative RT-PCR analyses revealed that all of the embryonic globin genes and a globin chaperone gene were poorly expressed in the mDom(DeltaN/DeltaN) embryo and yolk sac on E8.5, indicating that primitive erythropoiesis was impaired. A hematopoietic colony assay indicated that the hematopoietic activity of the yolk sac was significantly blocked in the mutant mice. We also found that the expression of a limited set of Hox genes, including Hoxa7, Hoxa9 and Hoxb9, was drastically enhanced in the mDom(DeltaN/DeltaN) yolk sacs. These results suggest that p400/mDomino plays a critical role in embryonic hematopoiesis by regulating the expression of developmentally essential genes such as those in the Hox gene cluster.     

Oral administration of the extract from Hatakeshimeji (Lyophyllum decastes sing.) mushroom inhibits the development of atopic dermatitis-like skin lesions in NC/Nga mice

We examined whether the extract from Hatakeshimeji (Lyophyllum decastes, LD) mushrooms suppresses the development of atopic dermatitis (AD)-like skin lesions induced by repeated application of picryl chloride (PiCl) in NC/Nga mice. Oral administration of LD extract to NC/Nga mice inhibited the development of AD-like skin lesions based on lower total skin severity scores and serum immunoglobulin E (IgE) levels. Splenic lymphocytes were stimulated with the T cell mitogen concanavalin A, and secretion of a Th1 cytokine (IFN-gamma) and a Th2 cytokine (IL-4) was determined by ELISA. IFN-gamma production was not inhibited by treatment with LD extract. On the other hand, IL-4 production was significantly decreased by treatment with LD extract. These results suggest that LD extract exerts anti-allergic actions by suppressing the serum IgE and Th2-type immune responses.     

Differential alteration of cardiotonic effects of EMD 57033 and β-adrenoceptor agonists in volume-overload rabbit ventricular myocytes

Background: We investigated the effects of EMD 57033, a prototype Ca²⁺ sensitizer, and β-adrenoceptor agonists in ventricular myocytes isolated from the volume-overload (V-O) heart failure model of the rabbit. Methods and Results: V-O cardiac hypertrophy was induced in rabbits by the formation of an arterio-venous shunt between the carotid artery and jugular vein 12 to 15 weeks after the operation. Ventricular myocytes were enzymically isolated from normal and V-O rabbit hearts. The myocyte was loaded with a fluorescence Ca²⁺ dye, indo-1, and Ca²⁺ transients, and cell lengths were measured simultaneously. V-O myocytes were significantly larger than control myocytes. Duration of Ca²⁺ transients and cell shortening was significantly longer in the V-O myocytes than in control myocytes. Effects of cardiotonic interventions, including EMD 57033, isoproterenol, and dobutamine, on Ca²⁺ transients and cell shortening in V-O myocytes were compared with those in control rabbit myocytes. Isoproterenol and dobutamine increased the systolic cell shortening and peak Ca²⁺ transients and abbreviated the duration of cell shortening and Ca²⁺ transients. These responses were markedly attenuated in V-O myocytes. By contrast, the response of cell shortening to EMD 57033 was unaltered, and the Ca²⁺ sensitizing effect of EMD 57033 was rather enhanced in V-O myocytes. Conclusion: Our results indicate that the effectiveness of Ca²⁺ sensitizers is maintained in the V-O rabbit hypertrophy and heart failure model in contrast to the blunted response to β-adrenoceptor agonists, which provides an insight on therapeutic strategy with Ca²⁺ sensitizers for the treatment of contractile dysfunction in congestive heart failure.     

Modified ProMACE-MOPP hybrid regimen with moderate-dose methotrexate for patients with primary CNS lymphoma

The object of this study was to assess the estimation of 2- and 5-year overall survival and tumor response and the frequency and severity of treatment morbidity with a modified ProMACE-MOPP hybrid protocol in patients with primary CNS lymphoma (PCNSL). Thirty-two immunocompetent patients were treated with a regimen of pirarubicin, cyclophosphamide, etoposide, vincristine, and methotrexate (500 mg/m(2)) administered in 21-day cycles. Intraventricular 10 mg of methotrexate was given for eight cycles once a week. Patients received 20 Gy of whole brain radiotherapy after three cycles of chemotherapy. A single cycle of chemotherapy was repeated every 4 months for 2 years. Older patients (aged >60) received a reduced dose of chemotherapeutic agents. Eighteen patients were followed up with neuroimaging and neuropsychological assessments for evidence of CNS toxicity. Sixteen patients completed the regimen as planned. The response rate was 87.5% after the initial chemoradiotherapy. The cumulative survival and progression-free survival rates at 5 years were 56 and 31%, respectively. The median survival time was 68 months. The median progression-free survival time was 39 months. Toxicity included grade 3 or 4 leukopenia in 33% of the cycles administered. There were eight grade 3 or 4 pulmonary toxicities. There were three deaths during chemotherapy: one as a result of sepsis and two of pneumonitis. Three patients (25%) experienced delayed neurologic toxicity while on the complete regimen. Maintaining the dose of methotrexate while adding chemotherapeutic agents improved disease control and overall survival in patients with PCNSL, but early toxicity and delayed neurotoxicity are still a risk of this approach.     

TMEM16F is required for phosphatidylserine exposure and microparticle release in activated mouse platelets

Phosphatidylserine (PtdSer) exposure on the surface of activated platelets requires the action of a phospholipid scramblase(s), and serves as a scaffold for the assembly of the tenase and prothrombinase complexes involved in blood coagulation. Here, we found that the activation of mouse platelets with thrombin/collagen or Ca²⁺ ionophore at 20 °C induces PtdSer exposure without compromising plasma membrane integrity. Among five transmembrane protein 16 (TMEM16) members that support Ca²⁺-dependent phospholipid scrambling, TMEM16F was the only one that showed high expression in mouse platelets. Platelets from platelet-specific TMEM16F-deficient mice exhibited defects in activation-induced PtdSer exposure and microparticle shedding, although α-granule and dense granule release remained intact. The rate of tissue factor-induced thrombin generation by TMEM16F-deficient platelets was severely reduced, whereas thrombin-induced clot retraction was unaffected. The imaging of laser-induced thrombus formation in whole animals showed that PtdSer exposure on aggregated platelets was TMEM16F-dependent in vivo. The phenotypes of the platelet-specific TMEM16F-null mice resemble those of patients with Scott syndrome, a mild bleeding disorder, indicating that these mice may provide a useful model for human Scott syndrome.Phospholipids are asymmetrically distributed between the inner and outer leaflets of plasma membranes as a result of the activity of flippase(s), which specifically translocates phosphatidylserine (PtdSer) and phosphatidylethanolamine from the outer to the inner leaflet of plasma membranes (1). PtdSer is preferentially exposed on the cell surface during certain physiological processes. During apoptosis, cell-surface PtdSer functions as an “eat me” signal to induce engulfment by phagocytic cells, and, during platelet activation, it serves as a scaffold for the activation of clotting factors. Exposed PtdSer is also implicated in pathological processes and may promote the retention of Ca²⁺ oxalate in kidneys, leading to kidney stone formation (2).PtdSer exposure is accomplished by the inactivation of flippase(s), along with the activation of scramblases (3). We recently identified two protein families (TMEM16 and Xkr) that support phospholipid scrambling (4–6). The TMEM16 family consists of 10 members with 10 transmembrane regions, and TMEM16C, 16D, 16F, 16G, and 16J support the Ca²⁺-dependent scrambling of phospholipids. Scott syndrome is a mild bleeding disorder caused by a defect in platelet procoagulant activity (7, 8). Platelets, red blood cells, and EBV-transformed B cells from patients with Scott syndrome exhibit defective PtdSer exposure following platelet activation or treatment with Ca²⁺ ionophore (9–11). We and others reported that patients with Scott syndrome carry null mutations in the TMEM16F gene (6, 12).The fetal thymocyte cell lines established from TMEM16F^−/− mouse embryos exhibit defective PtdSer exposure upon treatment with Ca²⁺ ionophore (5), reminiscent of the EBV-transformed B-cell lines from patients with Scott syndrome. In contrast, Yang et al. (13) reported that TMEM16F-deficient mouse platelets exhibit only a mild defect in Ca²⁺ionophore–induced PtdSer exposure and tissue factor-induced thrombin generation. Furthermore, in contrast to a human patient with Scott syndrome (14) and dogs with a similar hereditary syndrome (15), neither of which exhibits apparent bleeding-time defects, TMEM16F^−/− mice exhibit a prolonged bleeding time—twice that of WT mice (13).To address the apparent discrepancies between TMEM16F^−/− mouse phenotypes and the clinical presentation of patients with Scott syndrome, and to examine the role of platelet-expressed TMEM16F in blood clotting, we generated a platelet-specific TMEM16F deletion in mice. Our in vitro and in vivo analyses of thrombus formation induced by TMEM16F-null platelets suggested a role for TMEM16F in activation-induced PtdSer exposure, and supported the model in which Ca²⁺-induced PtdSer exposure is involved in the generation of thrombin and fibrin, but not clot retraction (16, 17). Mice with the platelet-specific deletion of TMEM16F exhibited a phenotype similar to that of human patients with Scott syndrome, and may provide a useful model for this human disease.     

Effects of marker for hepatic fibrosis and viral status on recurrence after resection of hepatitis B virus-related hepatocellular carcinoma

BACKGROUND/AIMS: We investigated the relationship between the serum concentration of type IV collagen 7s domain (7s collagen) and viral status and the effects of these factors on recurrence after resection of hepatitis B virus-related hepatocellular carcinoma. METHODOLOGY: Serum concentration of 7s collagen was measured in 39 patients who underwent liver resection for hepatitis B virus-related hepatocellular carcinoma. The clinicopathologic findings and tumor-free survival rate were compared between patients with a low serum concentration of 7s collagen (< 7.0 ng/mL, group 1) and those with a high serum concentration of 7s collagen (> or = 7.0 ng/mL, group 2). RESULTS: Aspartate aminotransferase activity and the proportion of patients with a high viral load and cirrhosis were significantly higher in group 2 than in group 1. The tumor-free survival rate was significantly lower in group 2 than in group 1 (P = 0.0050). The survival rate was significantly lower in patients with a high viral load than in patients with a low viral load (P = 0.0006). CONCLUSIONS: A high serum concentration of 7s collagen was closely related with a high viral load of hepatitis B virus. A high serum concentration of 7s collagen and a high viral load of hepatitis B virus are risk factors for recurrence after resection of hepatitis B virus-related hepatocellular carcinoma.     

Gardner''s Syndrome Associated with Carcinoma of the Duodenal Bulb: Report of a Case

A 49-year-old woman with Gardner's syndrome, who underwent total proctocolectomy in 1982, was found to have a cancer of the duodenal bulb. Subsequently, resection of the stomach and duodenal bulb was performed in 1983. The surgical specimen showed an ulcerating tumor in the duodenal bulb which was a moderately differentiated adenocarcinoma histologically. Multiple adenomas were present in the gastric antrum and the duodenum. Duodenal cancer so far reported has been mostly confined to the periampullary region, and cancer of the duodenal bulb associated with familial polyposis coli has not been reported.