Increased ghrelin signaling prolongs survival in mouse models of human aging through activation of sirtuin1.

Caloric restriction (CR) is known to retard aging and delay functional decline as well as the onset of diseases in most organisms. Ghrelin is secreted from the stomach in response to CR and regulates energy metabolism. We hypothesized that in CR ghrelin has a role in protecting aging-related diseases. We examined the physiological mechanisms underlying the ghrelin system during the aging process in three mouse strains with different genetic and biochemical backgrounds as animal models of accelerated or normal human aging. The elevated plasma ghrelin concentration was observed in both klotho-deficient and senescence-accelerated mouse prone/8 (SAMP8) mice. Ghrelin treatment failed to stimulate appetite and prolong survival in klotho-deficient mice, suggesting the existence of ghrelin resistance in the process of aging. However, ghrelin antagonist hastened death and ghrelin signaling potentiators rikkunshito and atractylodin ameliorated several age-related diseases with decreased microglial activation in the brain and prolonged survival in klotho-deficient, SAMP8 and aged ICR mice. In vitro experiments, the elevated sirtuin1 (SIRT1) activity and protein expression through the cAMP-CREB pathway was observed after ghrelin and ghrelin potentiator treatment in ghrelin receptor 1a-expressing cells and human umbilical vein endothelial cells. Furthermore, rikkunshito increased hypothalamic SIRT1 activity and SIRT1 protein expression of the heart in the all three mouse models of aging. Pericarditis, myocardial calcification and atrophy of myocardial and muscle fiber were improved by treatment with rikkunshito. Ghrelin signaling may represent one of the mechanisms activated by CR, and potentiating ghrelin signaling may be useful to extend health and lifespan.

Human equilibrative nucleoside transporter 1 and Notch3 can predict gemcitabine effects in patients with unresectable pancreatic cancer.

BACKGROUND: Pancreatic ductal carcinoma (PDC) is one of the most lethal human carcinomas. Expression patterns of some genes may predict gemcitabine (GEM) treatment efficacy. We examined predictive indicators of survival in GEM-treated patients by quantifying the expression of several genes in pre-treatment endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) samples from patients with PDC. METHODS: The expressions of human equilibrative nucleoside transporter 1 (hENT1), deoxycitidine kinase, ribonucleoside reductase 1, ribonucleoside reductase 2 and Notch3 in EUS-FNA tissue samples from 71 patients with unresectable PDC were quantified using real-time reverse transcription-polymerase chain reactions and examined for correlations with GEM sensitivity. RESULTS: The log-rank test detected no significant differences in overall survival between GEM-treated patients with low and high mRNA levels of all genes examined. However, low Notch3 mRNA expression was significantly associated with longer overall survival in a multivariate analysis for survival (P=0.0094). High hENT1 expression level was significantly associated with a longer time to progression (P=0.039). Interaction tests for GEM administration and hENT1 or Notch3 mRNA expression were statistically significant (P=0.0054 and 0.0047, respectively). CONCLUSION: hENT1 and Notch3 mRNA expressions in EUS-FNA specimens were the key predictive biomarkers of GEM effect and GEM sensitivity in patients with unresectable PDC.

Retrospective analysis of an efficient peripheral blood stem cell collection and the relation between infused cell dose and clinical outcome in patients with malignant lymphoma and multiple myeloma.

INTRODUCTION: Etoposide (VP16) is a drug used not only for the treatment of lymphoma but also for the collection of peripheral blood stem cells (PBSCs). We analysed the efficacy and adverse effects of collecting PBSCs and the relation between the infused cell dose and the clinical outcome in lymphoid malignancies. METHOD: Investigating 30 patients with non-Hodgkin's lymphoma, one patient with Hodgkin's lymphoma, and five patients with multiple myeloma, we compared the effects of several doses of etoposide with those of CHOP or CHOP-like treatments or salvage treatments. We also analysed the relation between the amount of CD34(+) cells collected (above or below 5.0 × 10(6) /kg/day) and prognosis of these patients. RESULTS: We found the collected cell count to be highest in patients treated with 500 mg/m(2) of VP16 and lowest in those not treated with VP16 (P = 0.0073). A CD34(+) cell count above 100/µL on the collection day indicates that the target amount of CD34(+) cells (4.0 × 10(6) /kg) can be readily obtained and was reached most rapidly by the patients who had received 500 mg/m(2) of VP16 (P = 0.01). The longer duration of neutropenia in those patients (P = 0.000006) resulted in longer antibiotic treatment (P = 0.0052). Both progression-free survival (PFS) and overall survival (OS) were better for the patients who yielded more than 5.0 × 10(6) CD34(+) cells/kg/day (P = 0.087 for PFS and P < 0.033 for OS). CONCLUSION: We show here that 3 days of VP16 at 500 mg/m(2) was useful for the collection of PBSCs and that patients who yielded more than 5.0 × 10(6) CD34(+) cells/kg/day survived longer than those who yielded less.

Clinical impact of cycling the administration of antibiotics for febrile neutropenia in Japanese patients with hematological malignancy.

Despite the availability of newer classes of antibiotics, infection with multi-drug-resistant bacteria is a serious problem. To suppress the appearance of multi-drug-resistant bacteria and to avoid severe infection derived from febrile neutropenia (FN), we conducted cycling the administration of antibiotics for FN in patients with hematological malignancy. The treatment protocol consisted of the administration of four antibiotics each for 3 months in 1 year. The above regimen was repeated for 4 years. A total of 193 patients were registered in the protocol. The mean duration of the administration of cycling antibiotics was 5.9 days (range: 1-16 days). The frequency of FN before the study and during the study was unchanged until the third year, but decreased significantly in the fourth year. The frequency of detection of multi-drug-resistant bacteria in the first year was the same as that before the study was started, but dramatically decreased after the second year. Bacteriological treatment success rates were similar in each trimester and each year. The effective rate was not statistically different in each trimester and each year. We conclude that cycling the administration of antibiotics in patients with FN is useful for suppressing the appearance of multi-drug-resistant bacteria and for obtaining excellent clinical efficacy.

Efficacy of folinic acid in preventing oral mucositis in allogeneic hematopoietic stem cell transplant patients receiving MTX as prophylaxis for GVHD.

As the safety of folinic acid administration and its efficacy for reducing the toxicity of MTX remain controversial, we assessed the effect of folinic acid administration after MTX treatment for GVHD prophylaxis on the incidence of oral mucositis and acute GVHD. We retrospectively analyzed data for 118 patients who had undergone allogeneic hematopoietic SCT and had received MTX for GVHD prophylaxis. Multivariate analysis showed that systemic folinic acid administration significantly reduced the incidence of severe oral mucositis (odds ratio (OR)=0.13, 95% confidence interval (CI) 0.04-0.73, P=0.014). There was also a tendency for a lower incidence of severe oral mucositis in patients who received folinic acid mouthwash (OR=0.39, 95%CI 0.15-1.00, P=0.051). No significant difference was observed in the incidence of acute GVHD between patients who received systemic folinic acid administration and those who did not (P=0.88). Systemic folinic acid administration and mouthwash appear to be useful for reducing the incidence of severe oral mucositis in patients who have received allogeneic hematopoietic SCT using MTX as GVHD prophylaxis.

DNA vaccination targeting macrophage migration inhibitory factor prevents murine experimental colitis.

Previous studies have shown that neutralization of macrophage migration inhibitory factor (MIF) by anti-MIF antibody reduces intestinal inflammation in mice. In this study we tested whether or not anti-MIF autoantibody induced by DNA vaccine targeting MIF protects mice against experimental colitis. Mice were administered a MIF-deoxyribonucleic acid (DNA) vaccine by introducing oligonucleotides encoding helper T epitope into the cDNA sequence of murine MIF by in vivo electroporation. Preventive effects of this method against dextran sulphate sodium-induced (DSS) colitis were evaluated. Mice administered with MIF-DNA vaccine raised values of autoantibody significantly. The clinical and histological findings of colitis induced by 3·0% DSS solution were ameliorated significantly in mice treated with MIF-DNA vaccine compared with saline or pCAGGS-treated mice given DSS. Myeloperoxidase activity, infiltration of F4/80-positive staining cells and the levels of proinflammatory cytokines were suppressed in the colon of MIF-DNA vaccine treated mice compared with saline or pCAGGS-treated mice exposed to DSS. Our results suggest that immunization with helper T epitope DNA-vaccine targeting MIF may be a useful approach for the treatment of colitis including inflammatory bowel diseases.

Increased risk of bacterial infection after engraftment in patients treated with allogeneic bone marrow transplantation following reduced-intensity conditioning regimen.

Although bacterial infection is a major cause of death even after reduced-intensity conditioning (RIC) for allogeneic stem cell transplantation (SCT), little is known about the epidemiology and risk factors. The incidence of bacterial infection in 43 patients who received allogeneic bone marrow transplantation (BMT) using a RIC regimen was compared with that in 68 patients who received BMT using a myeloablative conditioning regimen, and risk factors for bacterial infection were identified. Before engraftment, incidences of febrile neutropenia (FN) and documented infections (DI) were significantly decreased in RIC patients (FN: 59.5% vs. 89.6%, P<0.01, DI: 4.8% vs. 17.9%, P<0.01). However, incidence of bacterial infection was significantly increased in RIC patients in the post-engraftment phase (53.8% vs. 11.1%, log-rank, P<0.01). Blood stream was the most frequent focus of infection in both groups. In multivariate analysis, RIC and acute graft-versus-host disease were revealed to be significant risk factors for bacterial infection in this phase. In summary, risk of bacterial infection after engraftment was significantly higher in RIC patients, although infection was decreased before engraftment, and we need to develop a RIC-specific strategy against bacterial infection after RIC SCT.

Endoscopic retrograde cholangiography versus peroral cholangioscopy to evaluate intraepithelial tumor spread in biliary cancer.

BACKGROUND AND STUDY AIMS: Localized-type bile duct carcinoma (LBDC) is often accompanied by extensive intraepithelial tumor spread (ITS) of 2 cm or more, which makes radical resection more difficult. This retrospective case review compares the diagnostic accuracy of endoscopic retrograde cholangiography (ERC) and peroral cholangioscopy (POCS) to detect ITS beyond the visible LBDC. PATIENTS AND METHODS: Forty-four consecutive patients with LBDC diagnosed between April 2004 and October 2008 who underwent radical resection with histopathological analysis were included in this study. Extensive ITS was found histopathologically in one-third of the cases (32 %). The outcome parameters were the presence or absence of extensive ITS and the extent of extensive ITS proximal and distal to the main tumor. RESULTS: In six cases it was not possible to pass the cholangioscope through the tumor sites. ERC correctly identified the presence of extensive ITS in 11/14 cases and did not yield any false-positive results. The three cases in which ERC was negative were all correctly identified by POCS plus biopsy since the cholangioscope could be passed in all three cases. The extent of extensive ITS was correctly diagnosed by ERC alone, ERC with POCS, and ERC with POCS plus mapping biopsy in 22 %, 77 %, and 100 % of cases, respectively. CONCLUSIONS: The presence of extensive ITS was correctly detected in 80 % of cases by ERC alone. POCS with mapping biopsy provided perfect diagnostic accuracy not only of the presence or absence but also of the extent of extensive ITS. However, POCS has the limitation that the cholangioscope cannot be passed through the tumor sites in approximately 15 % of cases.

Effects of preoperative administration of omeprazole on bleeding after endoscopic submucosal dissection: a prospective randomized controlled trial.

BACKGROUND AND AIMS: The effectiveness of preoperative administration of proton pump inhibitors (PPIs) for the prevention of bleeding after endoscopic submucosal dissection (ESD) is unclear. Our aim was to evaluate the benefit of starting PPI treatment 1 day before ESD to prevent bleeding after the procedure. PATIENTS AND METHODS: This was a prospective randomized controlled trial. Data for 155 patients who underwent ESD (preoperative administration group: N = 81; postoperative administration group: N = 74) were analyzed. All patients received standard ESD using an insulation-tipped knife. Patients in the preoperative group were administered omeprazole from the day before ESD, and patients in the postoperative group received omeprazole after ESD. Follow-up endoscopy was performed on day 1, day 7, and day 28. Intragastric pH was measured from samples of gastric juice. The primary endpoint of this study was major bleeding related to ESD, and the secondary endpoint was minor bleeding. RESULTS: Major bleeding occurred in one patient from the postoperative group who had hematemesis. Minor bleeding occurred on day 1 in six patients from the preoperative group and five patients from the postoperative group (7.7 % vs. 7.4 %). There was no significant difference between major and minor bleeding ratios in the two groups. Intragastric pH at ESD in the postoperative group was lower than that in the preoperative group ( P < 0.05). CONCLUSIONS: Preoperative administration of omeprazole offers no additional benefit over postoperative administration alone in the prevention of bleeding after ESD among elderly Japanese people.

Long-term outcome after endoscopic resection in patients with hypopharyngeal carcinoma invading the subepithelium: a case series.

Patients with early stage hypopharyngeal carcinoma can be treated with endoscopic resection. However, strict indication for endoscopic resection in cases of hypopharyngeal carcinoma is unclear. In this paper, we evaluated the long-term outcome after endoscopic resection in patients with hypopharyngeal carcinoma invading the subepithelium. Among 16 patients with hypopharyngeal carcinoma who underwent endoscopic resection, eight patients who were histologically confirmed to have tumors with shallow invasion of the subepithelium were studied. Depth of tumor invasion in the subepithelium in those patients ranged from 300 to 720 microm (mean +/- SD, 490 +/- 140 microm). During a median follow-up period of 40 months, none of the eight patients had local recurrence or metastasis. Kaplan-Meier estimates of relapse-free survival rates at 5 years in the eight patients were 100 %. The results of this study suggest that hypopharyngeal carcinoma with slight invasion to the subepithelium can be successfully treated by endoscopic resection.

Serum macrophage migration inhibitory factor (MIF) levels after allogeneic hematopoietic stem cell transplantation.

Macrophage migration inhibitory factor (MIF) may play an important role in the pathogenesis of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT), as MIF plays an important role to regulate the production of tumor necrosis factor-alpha (TNF-alpha), one of the inflammatory cytokines which induces and exacerbates aGVHD. We examined the association between serum MIF levels and aGVHD vs. chronic GVHD (cGVHD) in allo-SCT patients in this study. We found a significant increase in the peak serum MIF (14.46 ng +/- 1.47 ng/ml) at onset in patients that developed aGVHD (n = 23, P = 0.009). We also found that mean serum MIF levels in patients who developed extensive type cGVHD within 6 months (12.58 +/- 2.18 ng/ml, n = 13) were significantly higher than MIF levels before allo-HSCT (7.86 +/- 1.17 ng/ml, n = 19, P = 0.04). Therefore, we speculated that serum MIF levels increase during the active phase of both aGVHD and cGVHD.

Multiple osteolytic bone lesions with high serum levels of interleukin-6 and CCL chemokines in a patient with adult T cell leukemia.

A 37-year-old woman was diagnosed as having chronic adult T-cell leukemia (ATL) of the skin by a skin biopsy and human T-cell leukemia virus type-1 serology at our hospital in August 1992. The skin lesions of ATL were improved by treatment with psoralen ultraviolet ray A. She complained of severe pain in her bilateral forearms, hands and ankles, and X-ray examination in July 1999 revealed multiple punched-out lesions of the extremities. Serum levels of parathyroid hormone-related peptide, interleukin-1beta (IL-1beta), tumor necrosis factor-alpha and total serum receptor activator of nuclear factor kappaB ligand were not elevated. However, serum levels of IL-6, CCL2 monocyte chemoattractant protein-1 (MCP-1), CCL3 [macrophage inflammatory protein-1alpha (MIP-1alpha)] and CCL4 (MIP-1beta) were markedly elevated. Here, we have discussed the possible mechanism underlying the onset of the osteolytic lesions.