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This is the first phase II trial in which adding oral leucovorin (LV) to S-1 (SL) significantly prolonged progression-free survival (PFS) when compared with S-1 monotherapy (S) in patients with gemcitabine-refractory advanced pancreatic cancer (PC). The significantly better PFS and disease control rate with SL than with S suggest that the antitumor activity of S-1 is enhanced by LV in advanced PC., Background We evaluated the efficacy and toxicity of adding oral leucovorin (LV) to S-1 when compared with S-1 monotherapy in patients with gemcitabine-refractory pancreatic cancer (PC). Patients and methods Gemcitabine-refractory PC patients were randomly assigned in a 1:1 ratio to receive S-1 at 40, 50, or 60 mg according to body surface area plus LV 25 mg, both given orally twice daily for 1 week, repeated every 2 weeks (SL group), or S-1 monotherapy at the same dose as the SL group for 4 weeks, repeated every 6 weeks (S-1 group). The primary end point was progression-free survival (PFS). Results Among 142 patients enrolled, 140 were eligible for efficacy assessment (SL: n = 69 and S-1: n = 71). PFS was significantly longer in the SL group than in the S-1 group [median PFS, 3.8 versus 2.7 months; hazard ratio (HR), 0.56; 95% confidence interval (CI), 0.37–0.85; P = 0.003]). The disease control rate was significantly higher in the SL group than in the S-1 group (91% versus 72%; P = 0.004). Overall survival (OS) was similar in both groups (median OS, 6.3 versus 6.1 months; HR, 0.82; 95% CI, 0.54–1.22; P = 0.463). After adjusting for patient background factors in a multivariate analysis, OS tended to be better in the SL group (HR, 0.71; 95% CI, 0.47–1.07; P = 0.099). Both treatments were well tolerated, although gastrointestinal toxicities were slightly more severe in the SL group. Conclusion The addition of LV to S-1 significantly improved PFS in patients with gemcitabine-refractory advanced PC, and a phase III trial has been initiated in a similar setting. Clinical trials number Japan Pharmaceutical Information Center: JapicCTI-111554.

An unusual primary adenomatoid tumour arising in the normal liver is described. Hepatectomy was performed, and the patient is alive and free of disease 1 year postsurgery. Grossly, the tumour showed a haemorrhagic cut surface with numerous microcystic structures. Histological examination revealed cystic or angiomatoid spaces of various sizes lined by cuboidal, low-columnar, or flattened epithelioid cells with vacuolated cytoplasm and round to oval nuclei. The epithelioid cells were entirely supported by proliferated capillaries and arteries together with collagenous stroma. Immunohistochemical studies showed that the epithelioid cells were strongly positive for a broad spectrum of cytokeratins (AE1/AE3, CAM5.2, epithelial membrane antigen and cytokeratin 7) and mesothelial markers (calretinin, Wilms' tumour 1 and D2-40). These cells were negative for Hep par-1, carcinoembryonic antigen, neural cell adhesion molecule, CD34, CD31 and HMB45. Atypically, abundant capillaries were observed; however, the cystic proliferation of epithelioid cells with vacuoles and immunohistochemical profile of the epithelioid element were consistent with hepatic adenomatoid tumour.

Background The optimal left ventricle (LV) pacing site for cardiac resynchronization therapy (CRT) has been investigated, but less is known about the optimal site in the right ventricle (RV). The present study examined whether electrical resynchronization guided by electroanatomical mapping (CARTO) results in mechanical resynchronization. Methods and Results The study group included 13 patients indicated for CRT: 10 with nonischemic cardiomyopathy, 2 with ischemic cardiomyopathy and 1 with cardiac sarcoidosis, (mean LV ejection fraction: 32±10%). CARTO of the RV septum was performed to identify the site with the most delayed conduction time during LV pacing. Hemodynamic measurements were performed during conventional biventricular pacing with the RV apex and LV (C-BVP) and during biventricular pacing with the most delayed site of the RV (d-RV) and LV (D-BVP). Lead placement at 15 coronary sinus veins was examined in the 13 patients. During pacing from anterolateral veins (n=2), the d-RV was the RV apex (RVA) in 1 patient and the mid-septum in the other. During pacing from lateral veins (n=9), the d-RV comprised the RVA (n=3), the mid-septum (n=5), and the right ventricular outflow tract (RVOT) (n=1). During pacing from the posterolateral veins (n=3), the d-RV was the RVOT in all cases. In 11 of 15 sites, d-RV differed from conventional RVA. Compared with C-BVP, D-BVP produced a significant improvement in LV dp/dt. Furthermore, RV mid-septum and LV pacing markedly increased LV dp/dt and pulse pressure (PP), but RVOT and LV pacing did not. D-BVP vs C-BVP: %LV dp/dt 30±20 and 15±15%, p

Nonischemic dilated cardiomyopathy (DCM) is associated with a high risk of sudden cardiac death. Signal-averaged electrocardiography (SAECG) is a useful clinical tool for detecting late ventricular potentials (LP). Gap junction alterations have recently been shown to be involved in the pathogenesis of ventricular arrhythmias in DCM; however, the possible relationship between gap junctional connexin43 (C x 43) expression and SAECG has not yet been evaluated. In the present study 16 patients (47+/-13 years) with DCM who had undergone SAECG testing were evaluated. In each patient, the expression of C x 43 proteins was qualitatively and quantitatively determined using immunoconfocal microscopy and right ventricular biopsy specimens. The level of expression of C x 43 protein was defined as the proportion of tissue area occupied by C x 43 (percent tissue area) in each test area. The abundance and distribution of the C x 43 signal was assessed in relation to LP. Late ventricular potentials were positive in 5 patients (LP (+) group) and negative in 11 patients (LP (-) group). The incidence of sustained ventricular tachycardia in the LP (+) group was higher than that in the LP (-) group (80% vs 18%, p=0.04). The percent tissue area of C x 43 in the LP (+) group was significantly lower than that in the LP (-) group (p=0.02). Furthermore, C x 43 protein in the LP (+) group was distributed more heterogeneously than that in the LP (-) group (p=0.001). The heterogeneous expression of C x 43 protein may contribute to impaired ventricular conduction, which may be related to the LP detected on SAECG.

This study examined some of the variables determining the efficiency of lipid peroxidation in egg yolk phosphatidylcholine liposomes and in microsomes exposed to enzymatically-generated superoxide radicals. The initiation of peroxidation required the presence of preformed lipid peroxides and a chelated metal catalyst. Comparison of the relative effectiveness of four iron chelating agents showed that the chelate must bind to the membrane by coulombic attraction between the charged membrane and a chelate carrying an opposite net charge. Of the chelates tested, only the carcinogenic ferric nitrilotriacetate [corrected] (Fe(3+)-NTA) was an effective catalyst of oxidation of all membranes, whether carrying a net charge, or not. We postulate that the unique catalytic capacity of the ferric nitrilotriacetate [corrected] (Fe(3+)-NTA) can be explained by its existence in two forms at neutral pH, each binding to oppositely charged membranes and initiating their peroxidation. This gives the complex the unique ability to bind to any membrane, which may be a factor in its carcinogenicity.

Many authors have reported that Helicobacter pylori (H. pylori) is one of the major causes of gastritis and peptic ulcer. This study was conducted to evaluate the incidence of H. pylori infection and the curative effects of amoxicillin and omeprazole on H. pylori in the remnant stomach.Biopsy specimens were obtained from 70 patients who underwent gastrectomy for gastric cancer. H. pylori was subsequently diagnosed by CLO test and culture of H. pylori. Gastritis was assessed by the scoring of four characteristic pathological parameters. Patients with positive H. pylori were eligible for the eradication study. Amoxicillin, 750 mg per day for 2 weeks, and omeprazole, 20 mg per day for 8 weeks, were administered to them. Endoscopic reexamination was performed 12 weeks after the initiation of treatment.The overall positive rate of H. pylori was 37.1%; 39.6% in Billroth I reconstruction, 0% in Billroth II reconstruction, and 55.6% in pylorus preserving gastrectomy, respectively. The positive H. pylori rate of Billroth II reconstruction was significantly low. However, there was no association of positive rate of H. pylori with time. There was no significant difference of gastritis scores between H. pylori infected patients and non-infected patients. The eradication rate was 70.0%.H. pylori was present in 37.1% of patients who underwent gastrectomy. Gastritis was not significantly severe in H. pylori infected patients. The treatment with amoxicillin and omeprazole was effective for these patients.

Lysophosphatidic acids (LPAs) are known to be normal constituents of mammalian serum, and they mimic some biological effects of the serum. We previously reported that lysophospholipase D (LPLD) was involved in the accumulation of LPAs in incubated rat plasma and serum. In this study we detected, by gas-liquid chromatography, various molecular species of LPA in follicular fluids collected from women programmed for in vitro fertilization. When the follicular fluid was incubated at 37 degrees C for 48 h, persistent increases in the amounts of LPAs were observed concomitant with decreases in the amounts of the corresponding lysophosphatidylcholines (LPCs), although the concentrations of saturated LPCs increased in the first 6 h of incubation. These results suggest that human follicular fluid has LPLD activity, and this was confirmed by experiments with follicular fluids mixed with an exogenous radioactive LPC. The LPLD showed preference for unsaturated over saturated LPCs, similar to plasma LPLD, indicating that it originated from the circulation.

It is not clear whether alimentary hyperglycemia in gastrectomized patients is related with glucose tolerance or not.Glucose tolerance, insulin secretion, and peripheral insulin sensitivity were evaluated in 36 patients who underwent subtotal gastrectomy for gastric cancer using the oral glucose tolerance test (OGTT), the intravenous glucose tolerance test (IVGTT) and the euglycemic hyperinsulinemic glucose clamp technique (Glucose clamp).Patients were categorized into three groups by OGTT; 8 cases were in group I (normal), 19 cases in group II (alimentary hyperglycemia), and 9 cases in group III (glucose intolerance). Both glucose disappearance rate (K value expressed as, %/min) and insulinogenic index as determined by IVGTT were significantly lower in groups II (1.00 +/- 0.24, 0.21 +/- 0.18, respectively) and III (0.90 +/- 0.13, 0.11 +/- 0.14, respectively), compared with group I (1.58 +/- 0.71, 0.35 +/- 0.18, respectively). Peripheral insulin sensitivity as measured by glucose clamp was not decreased in groups II and III.These results suggest that in patients with alimentary hyperglycemia, glucose tolerance was impaired due to a decreased pancreatic sensitivity to blood glucose and not due to insulin resistance.

A case of thoracic empyema after artificial pneumothorax for lung tuberculosis was presented, which extended into the abdominal cavity. 65 years old man, who was operated on for lung tuberculosis about 30 years ago, took the routine physical examination and the abdominal mass was picked up on examination. Echogram and CT showed huge homogeneous mass in the right thorax and the right upper abdominal cavity. The operative finding showed that thoracic empyema extended into the abdominal cavity and formed a huge mass. Decortication and extirpation of thoracic empyema and abdominal mass was performed with a combined partial resection of the lung, diaphragma, and thoracic wall. The histopathology of the abdominal mass showed chronic empyema and hematoma.

We encountered two chemotherapy (CDDP and 5-FU) cases related to mesenteric thrombotic occlusion. Case 1 was a 26 yo male with adrenal carcinoma recurrence. He had been treated by CDDP and 5-FU. Five days after completion of the second course, he suffered from acute abdomen. Laparotomy revealed thrombotic occlusion of the superior mesenteric artery. Most of the small intestine and a part of the ascending colon were necrotic. Case 2 was a 60 yo female with lung and hepatic metastasis from uretal tumor. CDDP based chemotherapy was initiated. Severe abdominal pain and melena occurred one day after completion of the second course of chemotherapy. The inferior mesenteric artery was occluded and the descending colon was necrotic. Recently, a variety of chemotherapy-induced vascular lesions, including thrombotic microangiopathy, myocardial infarction and cerebral infarction, have been reported. CDDP and 5-FU were shown to be related to the acute thrombotic occlusion of the major vessels. Although the incidence is rare, the prognosis is poor. Acute vascular obstruction should be taken into consideration as a possible course of chemotherapy-related complications.

From January, 1978, through December, 1990, surgical treatment for active infective endocarditis was performed in 11 patients. There were 8 men and 3 women who ranged in age from 19 to 54 years with a mean age of 38.8 years. Two patients had ventricular septal defects and 1 patient had rheumatic valve disease. In all patients, the infecting organism was isolated from blood, including streptococcus in 7, staphylococcus in 2, and gram-negative rods in 2. The indication for operation at the active phase was uncontrolled infection in 7 and progressive heart failure in 4. The operation was performed at 7 to 150 days with a mean of 53 days after diagnosis. Operative findings showed vegetations in all cases and perforations of the valve in 6. There were no operative deaths. Perioperative complications developed in 5, whose indication for operation was uncontrolled infection. Complications consisted of 1 prosthetic valve endocarditis, 1 pulmonary suppuration, 1 ruptured mycotic aneurysm of the hepatic artery, 1 ruptured mycotic aneurysm of the popliteal artery, and 1 pyogenic spondylitis. All were successfully treated surgically or with antibiotic therapy. There were no complications in patients whose indication for operation was progressive heart failure. We conclude that the risk of embolism is high in patients undergoing surgery at the active phase of infective endocarditis because of uncontrolled infection; thus, such patients should be carefully monitored for emboli.

To evaluate the effect of surgical treatment for spontaneous pneumothorax, we examined eighty patients who underwent the surgical treatment. Out of these, thirty five patients (53.0%) were the recurrent episode of the disease, since we vigorously chose surgical treatment for the second attack of the disease. Operative complications were observed in 6 cases (7.1%) including 2 cases of lasting air leakage and 1 case of bleeding, pneumonia, wound infection and atelectasis. Postoperative recurrence was not seen. From a viewpoint of prevention of the postoperative recurrence, the surgical treatment is effective and safe method.

Injection of lysophosphatidic acid into anesthetized rats induced immediate hypertension, the effect depending on the structure of the sn-1-acyl moiety of the molecule. A hydroxyl group at the sn-2-position was not necessary, but a wedgeshaped structure was suitable for hypertensive activity. Most lysophospholipids with a chemical group attached to the phosphate portion had only weak hypotensive effects, but the sn-2-acetylated analogs of these depressor lysophospholipids elicited a hypotension at much lower doses. The durations of the hypotensions evoked by the sn-2-acetylated choline phospholipids were longer than those produced by 1-palmitoyl-2-acetoyl-sn-glycerol-3-phosphorylmethanol, ethanol and propanol.

On intravenous injection into cats, lysophosphatidic acid elicited a biphasic change in arterial blood pressure: sharp hypotension followed immediately by hypertension. Respiration was greatly disturbed immediately after injection of lysophosphatidic acid, and remained stimulated for a long period, and the heart rate increased during the period of hypertension. Unsaturated lysophosphatidic acids were more potent in evoking hypertension than saturated ones. The hypotensive activity of 1-palmitoyl-2-0-acetyl-sn-glycero-3-phosphate was about half that of 1-palmitoyl-2-lyso-sn-glycero-3-phosphate (lysophosphatidic acid). Elongation of the acyl chain at the sn-2-position of the glycerol moiety resulted in progressive reduction in the hypotensive activity. Chemically modified analogs with a head group, such as phosphoryl-methanol, ethanol, propanol and choline, had little or no activity. However, sn-2-acetyl-analogs of lyso-phosphatidyl cholines had hypotensive activity. 1-0-Hexadecyl-2-lyso-sn-glycero-3-phosphate, an alkyl-lyso-phosphatidic acid, had much stronger hypotensive activity than the corresponding acyl-lysophosphatidic acid, like its sn-2-0-acetyl analog. These structure-activity relationships of lysophosphatidic acids indicate the existence of their specific binding sites on cardiovascular cells.