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.

Expression of claudins 7 and 18 in pancreatic ductal adenocarcinoma: association with features of differentiation.

AIM: This study was undertaken to evaluate the expression of claudins 7 and 18 in pancreatic ductal adenocarcinoma. METHODS AND RESULTS: Material tested included 111 operated samples and 47 additional biopsy samples consisting of 26 cases of pancreatitis, 3 cases of pancreatic intraepithelial neoplasia and 18 ductal adenocarcinomas. Samples were stained with antibodies to claudins 7 and 18 and analysed for membranous and cytoplasmic expression. Membrane bound claudin 7 and 18 expression was detected in 62 of 105 (59%) and 78 of 111 (70%) cases, respectively. Membrane bound claudin 7 and 18 were associated with large or intermediate neoplastic ducts (p=0.01, p=0.002, respectively). Well differentiated pancreatic adenocarcinomas displayed more cases with membrane bound claudin 7 or 18 immunopositivity (p=0.003, p=0.03, respectively). All pancreatic intraepithelial neoplasias studied expressed membrane bound claudin 18. Membrane bound claudin 7 or 18 positivity was not associated with survival (p=0.17, p=0.98). In the biopsy cases membrane bound claudin 18 had 100% specificity and 51% sensitivity for a tumour marker. CONCLUSION: Claudin 7 and 18 expression is related to gland size of neoplastic cells and is especially found in tumours with intermediate and large ducts and well differentiated tumours. Membrane bound claudin 18, when present, is a useful marker for diagnosis of pancreatic cancer. Claudins 7 and 18 were not associated with patient survival or spread of tumours.

Spontaneous porphyria of the Long-evans cinnamon rat: an animal model of Wilson's disease.

To confirm and extend our previous microspectrophotometric observations of 30-week-old male Long-Evans Cinnamon (LEC) rats, an animal model of human Wilson's disease, we analyzed the porphyrin patterns of the organs, urine, and plasma of LEC rats. Abnormal accumulation of porphyrins, especially highly carboxylated porphyrins (uro- and heptaporphyrin), in the kidneys and liver was seen in male and female LEC rats aged 30 weeks and also in 10-week-old rats, before the onset of spontaneous hepatic dysfunction. Accumulation of copper and iron in the kidneys was not observed in the 10-week-old rats. Massive accumulation of porphyrins was observed only in the kidneys of the 30-week-old male LEC rat, indicating that this symptom is related to sex and age. Renal accumulation of porphyrins was reflected in the rate of urinary porphyrin excretion. Hepatic accumulation of porphyrins appeared to be independent of sex and age. These results indicate that neither renal nor hepatic porphyrin accumulation is the result of renal deposition of metals or of spontaneous hepatic dysfunction and that porphyrinuria in the LEC rat is closely related to the renal accumulation of porphyrins. In contrast to these organs, a reduction in the porphyrin levels was observed in the brain of the LEC rat. This was independent of sex and age. The present work stresses the existence of an abnormal heme metabolism in the LEC rat, and thus, the necessity to study the heme metabolism in human Wilson's disease is strongly suggested.

Abnormal accumulation of porphyrin derivatives in the kidneys of Long-Evans Cinnamon rats, as evidenced by microspectrophotometry.

In the study described here we have revealed an abnormal accumulation of porphyrin derivatives in the kidneys of Long-Evans Cinnamon (LEC) rats, an animal model for human Wilson's disease. In addition, we have confirmed that the derivatives emitted red-orange light in renal sections under UV excitation. This renal red-orange emission has previously been identified as luminescence from cuprous metallothioneins [Cu(I)-MTs], which also accumulate in both the kidneys and liver of LEC rats. In this study, we measured the emission spectra of the luminescence in the kidneys using microspectrophotometry. The spectra of the renal red-orange emission resembled those of porphyrin derivatives rather than those of Cu(I)-MTs. We then extracted these derivatives from the kidneys. An abundance of porphyrin derivatives was established. A significant increase in the levels of the derivatives in the liver and urine of the LEC rats was also confirmed. These results provide evidence of a heme-metabolism abnormality in LEC rats.

[Effectiveness of surgical repair of mitral regurgitation concomitant with dilated cardiomyopathy].

Dilated cardiomyopathy (DCM) is often accompanied by severe mitral regurgitation (MR) which deteriorates the clinical course. Mitral reconstruction for severe MR may improve the symptoms and prognosis. Five patients with DCM and one patient with dilated phase of hypertrophic cardiomyopathy underwent mitral reconstruction for severe MR (4 males, 2 females, mean age 50 +/- 17 years) from 1983 to 1995. Their New York Heart Association (NYHA) functional class and findings of echocardiography and cardiac catheterization were compared before and after surgery. Five patients underwent annuloplasty and one patient underwent mechanical valve replacement. There was no operative or in-hospital death. NYHA class improved from 3.2 to 1.8 (p < 0.05). The degree of MR was reduced from 3.5 to 1.2 (p < 0.05), and left ventricular end-diastolic pressure decreased from 18 +/- 7 to 13 +/- 8 mmHg (p < 0.05). Left ventricular fractional shortening, ejection fraction and cardiac index (2.4 +/- 0.4 to 2.7 +/- 1.1 l/min/m2) did not change significantly. Two patients died within one year due to exacerbation of congestive heart failure (2.5 month later) or sudden death (6 months later). Three patients died at 21 months, 5 and 8 years after the operation (renal insufficiency, heart failure, sudden death, respectively). Mitral reconstruction improved the symptoms in patients with DCM and severe MR in the short term. However, 5 of 6 patients died in the intermediate or long-term. Mitral reconstruction may be a therapeutic option for early outcome in patients with refractory congestive heart failure due to DCM and severe MR.

Autopsy findings of Addison's disease caused by systemic cytomegalovirus infection in a patient with acquired immunodeficiency syndrome.

We previously reported a case of Addison's disease associated with acquired immunodeficiency syndrome (AIDS) (Endocr J, 41:13, 1994). A 46-year-old man with hemophilia B and AIDS was diagnosed as Addison's disease. The positive cytomegalovirus (CMV) antigen in urine suggested that CMV adrenalitis may have caused the adrenal insufficiency. Despite treatment with ganciclovir, the patient died one year later. Autopsy findings revealed that the typical inclusions of CMV were seen in the lung, adrenal glands (both cortex and medulla) and small intestine. Here, we describe the subsequent clinical course and postmortem findings of this case.

[Cardiac surgery in chronic dialysis patients: usefulness of continuous ambulatory peritoneal dialysis (CAPD)].

Eleven chronic dialysis patients underwent cardiac surgery in the past six years. Six of these cases had coronary artery disease, three had valvular heart disease and the other two had congenital heart disease. Of those 11 patients, 5 cases were successfully maintained on CAPD in the pre- and post-operative period. The remaining 6 patients were treated with hemodialysis before the operation and received intermittent peritoneal dialysis or hemodialysis following cardiac surgery. Intraoperative hemodialysis was carried out in 9 cases under cardiopulmonary bypass. There was one early death of low cardiac output syndrome, and two patients died of brain hemorrhage in the late post-operative period. Both of the latter two had hypertension and were maintained on hemodialysis under anticoagulant therapy. The other 8 are doing well and 5 of them are on CAPD. These results suggest that the procedure without anti-coagulation and/or CAPD should be chosen for the cardiac operation of chronic dialysis patients with hypertension.