A Polymorphism rs6726395 in Nrf2 Contributes to the Development of Emphysema-Associated Age in Smokers Without COPD.

INTRODUCTION: Several studies have reported that single nucleotide polymorphisms (SNPs) in the gene encoding NF-E2-related factor 2 (Nrf2) contribute to airflow limitations in smokers without COPD. Although small airway lesions and emphysema contribute cooperatively to airflow limitation, the relationship between Nrf2 SNPs and the development of emphysema in smokers without COPD is not well understood. METHODS: Healthy subjects who underwent an annual health checkup with computed tomography (CT) of the chest at Osaka City University Hospital were prospectively recruited. The percentage of low-attenuation area (%LAA) on chest CT was quantified, and correlations between %LAA, Nrf2 SNP [rs6726395 (G/A)] genotypes, and clinical characteristics were examined. RESULTS: A total of 245 subjects without COPD [non-/light-smoker: 153 (62.4%) and smoker: 92 (37.6%)] were enrolled. The %LAA in the upper lung field was higher than that in the lower lung field (p < 0.001). The %LAA in smokers was significantly higher than that in non-/light-smokers (p = 0.021). The %LAA showed significant but weak correlation with age in all subjects (r = 0.141, p = 0.028). Divided by genotype, the %LAA of the upper lung field was significantly correlated with age in smokers with genotype GG (wild type) (r = 0.333, p = 0.022), but was not significantly correlated with age in smokers with genotype AG/AA. These correlations were not observed in non-/light smokers. CONCLUSION: A polymorphism rs6726395 in Nrf2 can contribute to the development of emphysema-associated aging in smokers. The Nrf2 SNP may be a predictive factor for smoking-induced emphysema, and genotyping of Nrf2 SNP may serve as biomarker for emphysema prevention.

Efficacy and Safety of High-Dose Mizoribine Combined With Cyclosporine, Basiliximab, and Corticosteroids in Renal Transplantation: A Japanese Multicenter Study.

Mizoribine (MZR) is an immunosuppressive agent that exhibits a less potent immunosuppressive effect at doses up to 3 mg/kg/d. We investigated whether high-dose MZR is effective and safe for renal transplant patients in conjunction with cyclosporine (CsA), basiliximab, and corticosteroids. Ninety Japanese renal transplant patients were administered MZR (6 mg/kg/d), CsA (7 mg/kg/d), prednisolone (maintenance dose, 10 mg/d), and basiliximab (20 mg/body). They were compared with a control group of 81 renal transplant patients who received mycophenolate mofetil (MMF; 1500 mg/d), CsA, prednisolone, and basiliximab. The 2-year patient and graft survival rates were 98.9% and 97.8% in the MZR group and 98.8% and 97.5% in the MMF group, respectively. The rejection rate within 2 years after transplantation was 21.1% in the MZR group and 16.0% in the MMF group; the difference was nonsignificant. None of the MZR group developed cytomegalovirus (CMV) disease, whereas 12.3% of the MMF group contracted CMV (P < .0001). CMV viremia developed in 28.9% of the MZR group vs 46.9% of the MMF group (P < .0001); their peak antigen levels were 20.4 ± 44.1 and 252.8 ± 527.0 (P < .01). Furthermore, the incidence of gastrointestinal disorder, hyperlipidemia, and blood disorder was significantly lower in the MZR group than in the MMF group. The combination of high-dose MZR with CsA, basiliximab, and corticosteroids not only provides satisfactory immunosuppression but is also associated with a low incidence of CMV infection and gastrointestinal and blood disorders.

Excellent results with high-dose mizoribine combined with cyclosporine, corticosteroid, and basiliximab in renal transplant recipients: multicenter study in Japan.

We performed a multicenter study in Japan to assess the efficacy and safety of immunosuppressive therapy with high-dose mizoribine (MZR; 6 mg/kg) combined with basiliximab (Bas), cyclosporine (CyA), and a corticosteroid in 90 patients. MZR was adjusted to maintain a target trough level of 1 to 2 µg/mL. CyA was started at 7 mg/kg to maintain blood levels in the target therapeutic range of 200 ng/mL (trough [C0]), 1200 ng/mL (2-hour post-dose [C2]), and 6000 ng·h/mL (area under the curve(0-9)). Bas (20 mg/body weight) was administered on the day of transplantation and on postoperative day 4. Rejection was diagnosed by episode and protocol biopsies. Cytomegalovirus (CMV) antigenemia (direct immunological staining of leukocytes using peroxidase-labeled monoclonal antibody [C7-HRP]) levels were measured every 2 weeks for 6 months. At 12 months, all patients and grafts were surviving except for one death from infection: the 1-year patient and graft survival rate was 98.9%. The acute rejection rate was 21.1%. The mean serum creatinine level at 1 year was 1.51 ± 0.61 mg/dL. The incidence of CMV disease was 0% with 28.9%, CMV antigenemia and 5.6%, ganoyclovir treatment. The incidence of BK virus disease was 2.2%. The mean serum uric acid level was 7.15 ± 1.79 mg/dL at 1 month and 7.06 ± 1.78 mg/dL at 3 months. We observed that a high-dose MZR regimen in combination with CyA, Bas, and corticosteroid was safe and effective to reduce the frequency of CMV and BK virus-related events in renal transplant recipients.

Current status of organ transplantation in Japan.

To overcome severe donor shortage, Japanese doctors over the years have developed innovative strategies to maximize organs transplanted per brain death donor and expanded the donor pool using living donors. They also used living and marginal organs and drastically improved living donor lung, liver, pancreas and kidney transplantations. Moreover, they initiated ABO blood type incompatible liver transplantation advancements and succeeded in overcoming the blood type barrier in kidney and liver transplantations. Similar efforts are underway for pancreas transplantation. Furthermore, Japanese doctors have developed a nonaggressive step to achieve immunosuppression following organ transplantation by carefully monitoring donor-specific hyporesponsiveness and infectious immunostatus. However, the institution of amendments to allocation systems and the intensification of efforts to decrease living donor morbidity and to increase the number of brain death donors have remained important issues needing attention. Overall, the strategies Japan has adopted to overcome donor shortage can provide useful insights on how to increase organ transplantations.

Histologic studies of islets of Langerhans in transplanted pancreata from marginal donors in Japan.

The serious shortage of brain-dead donors leads to the use of pancreata from marginal donors, including cardiac death in Japan. We studied the islet histology of pancreas graft biopsies to investigate the adequacy of using pancreata from marginal donors. Pancreas allograft biopsy was performed originally to diagnose acute rejection (Drachenberg grade I-III) at a mean of 6 months after transplantation. The percentage of beta cells showing oxidative DNA changes, replication, and apoptosis was investigated in 7 recipients of simultaneous pancreas-kidney transplantations with good graft function from marginal donors. Their causes of death were cerebrovascular with donor ages >44 years (n = 3), cardiac (n = 2), and cerebrovascular (n = 2). The percentage of beta cells per islet in the transplanted pancreas (71.9 +/- 3.3%) did not correlate with glycemic control or insulin secretion, but did correlated inversely with donor age (r = -0.81; P < .05). Oxidative DNA changes as revealed by 8-hydroxy-2'-deoxyguanosine (8-OHdG) staining were diffusely present in islet cells as well as in the exocrine cells of the transplanted pancreas. The percentage of 8-OHdG-positive cells per pancreas (71.8 +/- 4.5%) did not correlate with glycemic levels, insulin secretion, donor age, or ischemic time. There were no Ki67-positive replicating cells or terminal deoxynucleotide transferase-mediated dUTP nick-end labeling-positive apoptotic islet cells. Transplanted pancreata from marginal donors showed preserved beta cells and function despite diffuse oxidative changes.

Evaluation of inosin-5'-monophosphate dehydrogenase activity during maintenance therapy with tacrolimus.

OBJECTIVES: The aim of this study was to identify a target range for inosin-5'-monophosphate dehydrogenase (IMPDH) activity in maintenance therapy with tacrolimus (TCL), and to apply the measurement of IMPDH activity to the therapeutic drug monitoring for mycophenolate mofetil (MMF). METHODS: Eleven patients with renal transplants and 10 healthy volunteers were investigated. All patients were treated with a combination of TCL, steroid and MMF for 2 months after transplantation, and were in stable and good condition. IMPDH activity was determined indirectly by measuring xanthosine 5'-monophophate in cell lysates supplemented with IMP and beta-nicotine adenine dinucleotide using an high-performance liquid chromatography (HPLC) method. RESULTS: The within-run reproducibility of the assay was excellent, with relative standard deviation (RSD) values of 0.41-4.08%. The mean differences between the spiked concentrations of xanthosine 5'-monophophate and their real values (mean relative errors; MREs) were within a range of 2.66-8.89%, showing good accuracy. The interday RSD values were 1.51-6.12% and MREs ranged from 2.10% to 8.89%. Cell lysates showed a 5-6 nmol/L IC(50) mycophenolic acid (MPA) concentration. TCL, cyclosporine and prednisolone did not affect IMPDH activity. The peak MPA concentration was achieved at 1 h after dosing. IMPDH activity decreased to 75% and 67% at 1 and 2 h after dosing respectively. Therefore, the inhibition rates of MPA against IMPDH activity may be adequate at 25-40% in TCL maintenance therapy. CONCLUSION: Inosin-5'-monophosphate dehydrogenase activity in cell lysates could be reliably determined by HPLC. A 25-40% inhibition of IMPDH activity may be an appropriate range for preventing rejection with MPF but this requires further validation using larger studies with harder outcomes such as rejection episodes.

A case of recurrent type 1 diabetes mellitus with insulitis of transplanted pancreas in simultaneous pancreas-kidney transplantation from cardiac death donor.

AIMS/HYPOTHESIS: A 41-year-old woman undergoing simultaneous pancreas-kidney transplantation from an HLA-mismatched cardiac death donor abruptly developed overt hyperglycaemia under standard immunosuppressive therapy at 48 months after transplantation. Unexpectedly, we found insulitis in the transplanted pancreas and characterised the insulitis. METHODS: Pancreas graft biopsies were performed 3 years before and after the development of hyperglycaemia and the specimens were examined histologically. RESULTS: Insulitis was absent in the first biopsy, although oxidative DNA changes revealed by 8-hydroxy-2'-deoxyguanosine (8-OHdG) staining were diffusely present both in islet cells and exocrine cells. No Ki67-positive proliferating cells were seen in the islets. Anti-glutamic acid decarboxylase antibody was undetectable 6 months earlier but increased to 6.3 U/l at the development of hyperglycaemia. The level of anti-insulinoma-associated protein 2 antibody was 18.5 U/l. Insulin secretion was severely suppressed and insulin therapy was resumed. In the second biopsy, although acute allograft rejection was minimal, insulin-positive beta cells were markedly reduced, and glucagon-positive alpha cells predominated. CD3-positive T lymphocytes, CD8-positive cytotoxic T lymphocytes and CD68-positive macrophages infiltrated around and into islets. The infiltrating cells expressed Fas ligand as well as granzyme B. More than 80% of islets were affected by insulitis. 8-OHdG-positive cells were also present in islets and exocrine tissue. The percentage of Ki67-positive cells in total islet cells was 1.5%. There were no TUNEL-positive apoptotic cells in the islet cells. CONCLUSIONS/INTERPRETATION: The histological features of insulitis in transplanted pancreas were consistent with common type 1 diabetes mellitus, but the clinical course of the recurrence appeared to be more rapid.

Availability of pancreatic allograft biopsies via a laparotomy.

OBJECTIVE: The aim of this study was to evaluate the availability of a pancreatic allograft biopsy via a laparotpmy. PATIENTS AND METHODS: From September 2004 to November 2007, 17 pancreas transplantations were performed: 15 simultaneous pancreas and kidney transplantations (SPK), 1 pancreas transplant alone (PTA), and one pancreas after kidney transplantation (PAK). Thirteen pancreatic allograft biopsies were obtained via an open laparotomy. This study evaluated the complications associated with this procedure, the rate of obtaining an adequate sample, and the relationship between biopsy-proven rejections and laboratory markers. In SPK cases we evaluated the synchronization between pancreas and kidney rejection. The pancreatic samples were diagnosed according to the Drachenberg classification. RESULTS: No complications resulted from the procedure. The rate of obtaining adequate samples was 84.6%. Pancreas rejection correlated with elevation of the laboratory markers in 71.4%. Simultaneous pancreas and kidney rejection occurred in 62.5%, only kidney in 25%, and only pancreas in 12.5%. CONCLUSION: A pancreas graft biopsy was absolutely imperative to improve the outcome in PTA, and even in SPK cases. A pancreatic allograft biopsy via a laparotomy was a safe, necessary and easy procedure to obtain an accurate diagnosis of rejection among pancreas transplantation patients.

Present status of pancreas transplantation in Japan--donation predominantly from marginal donors and modified surgical technique: report of Japan pancreas transplantation registry.

In Japan, organ donation has been still limited because of the strict donor criteria. The aim of this study was to show the effectiveness of pancreas transplantation (PTx) by analyzing the outcomes even under poor donor conditions. Thirty-six cases of PTx (32 simultaneous pancreas and kidney transplantations [SPK], 4 pancreas after kidney transplantations) performed during the last 8 years were examined especially for donor characteristics. Mean donor age of 41.4 +/- 11.9 years was considerably older compared with that in the United States and Europe; donors aged over 40 years comprised 67% of the total. According to the criteria described by Kapur, 29 cases (81%) in our series would be considered marginal. Thus, to increase blood supply into the pancreatic head, the gastroduodenal artery (GDA) was anastomosed using donor artery to common hepatic artery or iliac Y graft. These procedures were performed in 16 of the 24 cases in which there was liver procurement. Eventually, 34 cases (94%) preserved GDA continuity. Mean total cold ischemic time of pancreatic grafts was 12 hours 15 minutes. Of 214 registrants, 17 patients on the waiting list for SPK died of diabetic complications. To date, patient survival remains 100% with a mean follow-up period of 33 months. Pancreas graft survivals at 1, 3, and 5 years posttransplantation were 92%, 80%, and 80%, respectively. In contrast, kidney survivals were 91%, 91%, and 91%, respectively. The integrity of the pancreas head and duodenum by preservation of the GDA continuity might have decreased the risk associated with the marginal donors.

Estimation of the area under the curve for mycophenolic acid in adult renal transplant patients with concomitant tacrolimus using a limited sampling strategy.

OBJECTIVES: The aim of this study was to develop a limited sampling strategy (LSS) for monitoring the use of mycophenolic acid (MPA) in maintenance therapy with tacrolimus (TCL) in renal transplant patients. METHODS: Eighteen adult patients receiving a first transplant were investigated. All patients were treated with a combination of TCL, steroid and mycophenolate mofetil (MMF). Besides the predose trough concentration (C(0)), whole blood samples were taken for measurement of the MPA concentration at 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 h for a 14-point 12-h pharmacokinetic (PK) profile. Using stepwise linear regression analysis, an abbreviated area under the concentration time curve (AUC) was calculated using all 14, and any combination of sampling points to give an estimating equation with up to three predictors. RESULTS: The equation derived from C(2), C(7) and C(12,) for AUC estimation: AUC = (2.05 x C(2)) + (8.51 xC(7)) + (2.29 x C(12)) + 4.24. was found to be optimal. Using this formula, there was an excellent correlation between the estimated 3-point AUC and AUC(0-12 h). To assess the agreement between the abbreviated methods and the full PK profile, we plotted the average AUC of the abbreviated estimates and the full PK profile. This Bland-Altman analysis indicated good agreement to within +/-2 SD and a prediction variability of 7.56 microg x h/mL. CONCLUSION: Our proposed three-sampling-point estimate of AUCs is clinically acceptable. However, the sampling times are inconvenient for outpatients, and is recommended only for monitoring MMF treatment of inpatients with suspected toxicity or at high risk of organ rejection.

Persistent hyperparathyroidism in renal allograft recipients: vitamin D receptor, calcium-sensing receptor, and apoptosis.

The phenotypic changes in parathyroid cells after successful renal transplantation remain to be elucidated. We compared 10 diffuse and 11 nodular hyperplastic parathyroid glands from five renal allograft recipients with persistent hyperparathyroidism, with five diffuse and 13 nodular hyperplasia from seven uremic patients on hemodialysis, and 13 normal glands. Comparisons included expressions of both vitamin D receptor (VDR) and calcium-sensing receptor (CaSR), proliferative activity (Ki67), and apoptosis (TUNEL). Immunoreactivity was assessed semiquantitatively and expressed as labeling index. The area/cell was also measured to assess cellular hypertrophy. The labeling indexes of VDR (587+/-71; mean+/-s.e.m.) and CaSR (45.0+/-2.8) in recipients' diffuse hyperplasia were significantly higher than those in uremic diffuse hyperplasia (224+/-44, 29.3+/-2.3, respectively) (P<0.01, each). However, these expressions remained low in recipients' nodular hyperplasia (42+/-8, 11.8+/-1.4, respectively). Ki67 labeling index in recipients' nodular hyperplasia (7+/-1) was significantly smaller than in uremic patients (24+/-6, P<0.01). TUNEL labeling index in recipients' diffuse hyperplasia (30+/-5) was the highest among the groups. The cell volume tended to be smaller in both patterns of hyperplasia in allograft recipients compared with uremic patients. Our results suggest that the phenotypic change in parathyroid cells after renal transplantation depends on the pattern of hyperplasia, where it is normalized only in diffuse hyperplastic glands in which the number of cells also regresses with significant induction of apoptosis.

Long-term results of tacrolimus therapy for renal transplantation in patients with diabetic nephropathy in Japan.

In Japan, the number of kidney transplants for the patients with diabetic nephropathy is limited because of an extreme organ shortage and poor patient and graft survival rates. We analyzed the 5-year outcomes in kidney transplant recipients treated with tacrolimus with (group 1; n = 53) and without a diagnosis of diabetic nephropathy (group 2; n = 1432). We also investigated outcomes in patients who received simultaneous pancreas and kidney transplants since 2000 (group 3; n = 15). Patients in group 1 were older than those in group 2, with a shorter duration of pretransplant dialysis (P = .0001). Five-year patient survival rates in groups 1 and 2 were 89.7% and 97.9%, respectively (P = .13), and 5-year graft survival rates were 89.6% and 94.8%, respectively (P = .44). The incidence of acute rejection within 3 months of transplantation was 28.3% in group 1 and 29.2% in group 2 (P = .98). Tacrolimus-based induction therapy was used in 13 of the 15 group 3 cases. Both kidney and pancreas grafts are surviving to date in all but one of the group 3 patients; one patient had the pancreas removed due to venous thrombosis at 7 days. It was concluded that tacrolimus-based therapy resulted in excellent 5-year outcomes in patients who had kidney transplantation because of diabetic nephropathy, despite the higher risks associated with this condition. Tacrolimus was also beneficial in association with simultaneous pancreas and kidney transplantation. These data encourage us to perform kidney transplantation in patients with diabetic nephropathy.

Characteristics of pancreas transplantation currently performed in japan.

The Pancreas Transplantation (tx) Program under the Japanese Organ Transplant Act was started in 2000. PTx is indicated for type 1 diabetic patients on hemodialysis therapy. As of April 2003 93 patients are listed as candidates. Ten cases of PTx with enteric or bladder-drained technique were performed during the last 3 years as well as nine SPK and one PAK. Of 10 cases, nine recipients are insulin-free with HbA1c values ranging from 4.4% to 5.7%, although exogenous insulin was required in six cases temporarily, namely for a median 63 days (12 to 225 days). One case was lost due to pancreatic graft thrombosis. All 10 kidney grafts are functioning. Based on the experiences with 14 cases of pancreas tx using non-heart-beating (NHB) donors, we defined the criteria of NHB donor as: age younger than 40 years and cessation of respiratory support. One case of SPK with graft of NHB donor was done, and the recipient is off insulin. Pancreas and kidney are allocated for SPK if the recipient shares at least one HLA-DR antigen. Marginal donors were defined as higher mean donor age, median 37 (range 18 to 58 years); mean 38 +/- 12 years), and no death cause of by trauma. The revascularization of gastroduodenal artery to the pancreatic graft was performed in eight cases to minimize the risk of ischemic injury to the pancreatic graft and technical failure in cases of marginal donor.

Pancreas-kidney transplantation in Japan: impact of cyclosporine on the development of immunosuppressive therapy.

The number of pancreas transplants reached 16,043 worldwide in October 2001, with 1800 performed in 2000. Since the introduction of cyclosporine (CyA) in 1979, a regimen consisting of CyA, azathioprine, and steroids has been shown to improve long-term survival of clinical transplants. In Japan, the first simultaneous pancreas-kidney transplantation was performed in 1984, using organs from a brain-dead donor. This procedure was followed by 14 pancreas transplantations from cardiac arrest donors. All cases utilized a CyA-based regimen with antilymphocyte globulin or OKT3 induction. Six of the 15 recipients required less insulin postoperatively. Under a new transplant law enforced in 1997, 10 pancreas/pancreas-kidney transplantations were performed in patients diagnosed with end-stage renal failure due to diabetes mellitus type 1. In 1 patient, the graft failed due to venous thrombosis, but the other 9 recipients achieved an increased quality of life without the need for insulin or for dialysis. Pancreas transplantation represents an effective treatment worldwide and in Japan, due to the availability of CyA or tacrolimus in combination with other agents such as antilymphocyte globulin, OKT3, or mycophenolate mofetil. This investigation presents the results of pancreas-kidney transplantation in Japan, in comparison with those worldwide, and describes a recent case in Japan.

The combined use of prostaglandin I2 analogue (OP-2507) and thromboxane A2 synthetase inhibitor (OKY-046) strongly inhibits atherosclerosis of aortic allografts in rats.

BACKGROUND: Atherosclerosis is the main lesion in allografts undergoing chronic rejection. We investigated the effect of OP-2507 (prostaglandin I2 analogue) and OKY-046 (thromboxane A2 synthetase inhibitor) on graft atherosclerosis morphologically and the production of eicosanoids in grafts in a rat aortic allograft model. METHODS: Abdominal aortic allografts of Lewis (RT-1(l)) rats were transplanted orthotopically into fully major histocompatibility complex mismatched Wistar King A/Qdj (RT-1(u)) rats that were subcutaneously administered OP-2507 (0.1 mg/kg/d) or OKY-046 (125 mg/kg/d), or both, with an osmotic pump. Four, 8, or 12 weeks later, the grafts were harvested and examined histologically, and the concentration of eicosanoids in the grafts were analyzed. RESULTS: Lewis aortic allografts in Wistar King A recipients with no treatment displayed atherosclerosis, which involved gradual intimal thickening and medial thinning with continuous inflammation in adventitia. Neither OP-2507 nor OKY-046 treatment affected the intensity of adventitial inflammation. Although inhibition of medial thinning or a decrease in medial nuclear density was not observed, OKY-046 administration alone significantly inhibited an increase in intimal thickness. OP-2507 administration alone significantly inhibited a decrease in medial nuclear density and intimal thickening. Combined treatment with OP-2507 and OKY-046 further decreased the alteration of media and intima. The ratio of thromboxane B2 and 6-keto-prostaglandin F(1alpha) in the grafts was significantly reduced by OKY-046 but not by OP-2507 alone. CONCLUSIONS: We have demonstrated that atherosclerosis in aortic allografts is inhibited by the continuous administration of either OP-2507 or OKY-046, and a combination of both agents strongly increases this inhibitory effect. Amelioration of balance in eicosanoid production in the grafts by the use of thromboxane A2 synthetase inhibitor and the simultaneous usage of stable prostaglandin I2 analogue may be a strategy for preventing atherosclerosis that results from chronic rejection.

Intraductal papillary-mucinous tumor of the pancreas: assessing the grade of malignancy from natural history.

Intraductal papillary-mucinous tumor of the pancreas is a spectrum of conditions ranging from benign to malignant, and very few papers have referred to the natural history of this disease. In this communication the indicators of malignancy were examined from a viewpoint of natural history. Follow-up computed tomographies (CTs) more than 6 months after the diagnosis were reviewed in 17 Japanese patients with intraductal papillary-mucinous tumor of the pancreas. They were divided into two groups by the presence or absence of morphological progressive changes by the follow-up CTs, and the clinicopathological features were compared between the two groups to examine possible malignant indicators. The 17 patients consisted of seven patients in the no-change group and ten in the progressive group. The distribution of the patients was not different with regard to age; gender; or presence or absence of pancreatitis, diabetes mellitus, or unique findings of the ampulla of Vater between the two groups. The dilatation of the main pancreatic duct (> or = 3 mm) was more frequent in the progressive group: (eight of ten patients; 80%) than in the no-change group (two of seven patients; 29%) (P = 0.03). Six (86%) of the seven tumors in the no-change group were located in the branch duct, whereas five (50%) of the ten in the progressive group were situated in the main pancreatic duct. Histopathologic diagnoses of the resected specimens of the four in the no-change group examined were intraductal papillary-mucinous adenoma in three and adenoma with moderate dysplasia in one, whereas the diagnoses in the six in the progressive group examined were adenoma in two, adenoma with moderate dysplasia in two, and carcinoma (invasive) in two. The patients with intraductal papillary-mucinous tumor of the pancreas with a dilatation of the main pancreatic duct at the time of diagnosis should be followed up more carefully than those without dilatation. Once progressive morphological changes are detected by the follow-up CTs surgical resection should be considered because of possible malignancy.

Effect of FR167653 on pancreatic ischemia-reperfusion injury in dogs.

BACKGROUND: The role of inflammatory cytokines is still unclear in ischemia-reperfusion injury of the pancreas. We investigated the effect of FR167653 (FR), a newly developed compound that is a potent suppressor of interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha on ischemia-reperfusion injury of the isolated pancreatic tail in dogs. METHODS: The tail of the pancreas was subjected to ischemia for 90 minutes. During occlusion of the vascular inflow, the head of the pancreas was removed. A control group (n = 14) and an FR treatment group (n = 11) were evaluated for survival rate, tissue blood flow, arterial oxygen pressure (Pao(2)), serum amylase and lipase levels, glucose and insulin, liver enzymes, creatinine, IL-1beta mRNA in the peripheral blood, and histopathology. RESULTS: Six of the 14 control animals and 2 of the 11 FR-treated animals died. The FR treatment group showed lower amylase (P=.037) and lipase (P =.030) levels, lower IL-1beta mRNA expression (P =.033), and less pancreatic tissue damage (P =.041) than did the control group, but there was no remarkable change in endocrine function (P =.422). Pao(2) during the acute phase in the FR treatment group was maintained (P=.009), but pulmonary tissue was damaged. Results of biochemical and histologic examinations of the liver and kidneys were unremarkable. CONCLUSIONS: FR ameliorates ischemia-reperfusion injury of the pancreas and reduces the production of inflammatory cytokines that may contribute to secondary damage to distant organs.

Role of surgery for gallbladder carcinoma with special reference to lymph node metastasis and stage using western and Japanese classification systems.

The role of radical resection in the treatment of gallbladder carcinoma was examined with special reference to lymph node metastasis using two classifications: one proposed by the American Joint Committee on Cancer (AJCC) and the other by the Japanese Society of Biliary Surgery (JSBS). Histologic evaluations for the depth of tumor invasion (T), lymph node metastasis (N), stage, and follow-up for a mean period of 38 months (range 4-185 months) were completed in 52 patients with gallbladder carcinoma who underwent surgical resection from 1982 to 1997. The definition of T was similar in the two classifications. The extent of nodal involvement (N, AJCC; n, JSBS), stage, and survival were examined. In the absence of lymph node metastasis, the 5-year survival rate reached 71%. The 5-year survival rate in patients with involved nodes confined to the hepatoduodenal ligament, posterosuperior pancreaticoduodenal region, or along the common hepatic artery (N1 and part of N2 by AJCC; nl and n2 by JSBS) approximated 28%. In contrast, postoperative survival was poor in the presence of more extensive nodal involvement (rest of N2 by AJCC; n3 and n4 by JSBS), with no 2-year survivors. The definition of stage I was the same in both classifications, and all patients in this stage are alive. The 5-year survival rates in stages II and III by the AJCC were 70.7% and 22.4%, respectively, and those by JSBS 61.9% and 23.1%, respectively. Thus the survival rates in stages I to III were essentially similar irrespective of the staging system. Stage IV showed significantly worse survival than stage III by the JSBS classification. In contrast, the differentiation of stage IV from III by the AJCC was not significant because of the better survival in stage IV that contained any T with nodal involvement in the posterosuperior pancreaticoduodenal region and along the common hepatic artery. Radical resection should be considered for patients with stage I to III disease defined by either classification and applied to the tumor invasion up to T3 with nodal involvement confined to the hepatoduodenal ligament, posterosuperior pancreaticoduodenal region, and along the common hepatic artery. The role of radical surgery seems to be limited in patients with more extensive tumor invasion or lymph node metastasis.

The role of percutaneous transhepatic abscess drainage for liver abscess.

To evaluate the efficacy of percutaneous transhepatic abscess drainage (PTAD) as an initial choice of treatment for liver abscess, the medical records of 28 patients with liver abscess were retrospectively analyzed. The patients were predominantly men (23 of 28) with a mean age of 59 years (range, 19-86 years). Their chief complaints were fever (86%), right hypochondralgia (32%), and jaundice (11%). Fifteen of the 28 patients (54%) had hepatobiliary and pancreatic carcinoma, and 31% had postoperative liver abscess. PTAD was performed in 23 patients and surgical drainage in 5. The overall success rate for PTAD was 83%. The success rate for PTAD for patients with multiple abscesses was 83% (5 of 6), compared with a success rate of 82% (14 of 17) for patients with solitary abscess. The prognostic factors for survival were cancer and sepsis and the mortality rate for patients with cancer was 40% (6 of 15) while the mortality rate for patients with sepsis was 56% (5 of 9). As a complication of drainage, 1 patient (4%) in the PTAD group had pleural abscess due to the transpleural puncture. Our findings support the use of PTAD as the primary treatment for liver abscess, as it is safe and effective irrespective of the number of abscesses and the patient's condition.

Pancreatic carcinoma: < or = 2 cm versus > 2 cm in size.

BACKGROUND: Despite recent progress in diagnosis and therapy, the clinical course of patients with pancreatic carcinoma remains dismal. There have been several approaches to improve the clinical course of patients with pancreatic carcinoma, namely: (i) detection of small pancreatic carcinoma; (ii) radical resection with retroperitoneal clearance and portal vein resection; (iii) multidisciplinary therapy including chemoradiation; and so forth. METHODS: In this series, eight Japanese patients with small pancreatic carcinoma measuring less than 2 cm in diameter (including two with non-invasive carcinoma and one with minimally invasive carcinoma) and 53 with larger pancreatic carcinoma were reviewed to find the diagnostic and therapeutic clues to improve the clinical course of patients with pancreatic carcinoma. RESULTS: Lymphatic (ly) and perineural (pn) permeation was significantly more frequent and extensive in the 53 patients with large pancreatic carcinoma than in the eight with small pancreatic carcinoma (ly 0/1/2/3:3/24/18/8 versus 5/2/1/0, P = 0.0284; pn 011/2/3:4/29/14/6 versus 3/2/3/0, P = 0.0491). The surgical margin was affected by malignant cells in 18 (34%) of the 53 patients with large carcinoma but none (0%) of the eight with small carcinoma (P = 0.0004). The comprehensive stage was significantly earlier in the eight with small carcinoma than in the 53 with large carcinoma (comprehensive stage I/II/II/IV:4/0/3/1 versus 0/3/26/24, P < 0.0001). Comprehensive curability of the eight small carcinoma cases was significantly higher than that of the 53 large carcinoma cases (comprehensive curability A/B/C:5/3/0 versus 9/5/39; P = 0.0003). 1-year and 3-year cumulative survival rates of the eight patients with small carcinoma were 100% and 82%, whereas those of the 53 with large carcinoma were 51% and 17%, respectively (P = 0.0207). However, the eight small carcinoma cases already showed frequent invasion to the vascular (v), lymphatic (ly) and perineural (pn) structure [v(+): 3/8, ly(+): 5/8, pn(+):5 /8] and lymph node metastasis (n) [n(+): 3/8]. Out of the eight small pancreatic carcinomas, one minimally invasive carcinoma and two non-invasive carcinomas showed no vascular, lymphatic or perineural invasion or lymph node metastasis. All the three patients have been doing well 19, 32 and 44 months after the operation. The diagnostic clues in the three patients were dilatation of the main pancreatic duct in one and of the branch duct in the other two. CONCLUSIONS: These findings suggest that surgical resection frequently cures patients with small pancreatic carcinoma but more effective adjuvant therapy should be developed to control lymphatic permeation, venous invasion or perineural infiltration in surgical resection of large pancreatic carcinoma. The supreme goal is to detect non-invasive or minimally invasive pancreatic carcinoma with a dilatation of the main or branch pancreatic duct as a diagnostic aid.