ACTN4 copy number increase as a predictive biomarker for chemoradiotherapy of locally advanced pancreatic cancer.

BACKGROUND: Several clinical trials have compared chemotherapy alone and chemoradiotherapy (CRT) for locally advanced pancreatic cancer (LAPC) treatment. However, predictive biomarkers for optimal therapy of LAPC remain to be identified.We retrospectively estimated amplification of the ACTN4 gene to determine its usefulness as a predictive biomarker for LAPC. METHODS: The copy number of ACTN4 in 91 biopsy specimens of LAPC before treatment was evaluated using fluorescence in situ hybridisation (FISH). RESULTS: There were no statistically significant differences in overall survival (OS) or progression-free survival (PFS) of LAPC between patients treated with chemotherapy alone or with CRT. In a subgroup analysis of patients treated with CRT, patients with a copy number increase (CNI) of ACTN4 had a worse prognosis of OS than those with a normal copy number (NCN) of ACTN4 (P=0.0005, log-rank test). However, OS in the subgroup treated with chemotherapy alone was not significantly different between patients with a CNI and a NCN of ACTN4. In the patients with a NCN of ACTN4, the median survival time of PFS in CRT-treated patients was longer than that of patients treated with chemotherapy alone (P=0.049). CONCLUSIONS: The copy number of ACTN4 is a predictive biomarker for CRT of LAPC.

Strategies for management of bile duct injury during laparoscopic cholecystectomy.

We encountered 10 patients with bile duct injuries during laparoscopic cholecystectomy. Their causes were electrocautery in 2 patients, misjudgment in 2, mechanical injury in 3, aberrant bile duct in 2, and weakness of the bile duct wall in one. The sites of injury were cystic duct in 4 patients, common bile duct in 2, aberrant bile duct in 2, common hepatic duct in one, and common bile duct plus right hepatic duct in one. Treatments for the injuries discovered intraoperatively consisted of T-tube drainage above in 2 patients, re-ligation of the cystic duct in one, ligation of an aberrant bile duct in one, simple suture and T-tube in one, and choledochojejunostomy in one. In the remaining 4 patients discovered postoperatively, 2 were conservatively treated by endoscopic retrograde biliary drainage. The duration of hospitalization was 9-12 days in the 4 patients with simple suture or ligation, 10-21 days in 2 cases of bile drainage, and 34-43 days in 3 with T-tube drainage. The patient with choledochojejunostomy suffered repeated cholangitis, resulting in hepatic abscess with hospitalization for 6 months. Since laparoscopic surgery should be minimally invasive, meticulous attention is necessary before and during surgery to avoid bile duct injury.

[Efficacy of combination chemotherapy with mitoxantrone, vincristine, doxifluridine and prednisolone for recurrence of breast cancer].

We treated fifteen patients with recurrent breast cancer by a combination of mitoxantrone (8 mg/m i.v., day 1), vincristine (1.2 mg/m i.v., day 1), doxifluridine (800 mg/body po, everyday) and prednisolone (30 mg/body po, day 1-7). Cycles were repeated every 3 weeks and all patients received more than 2 cycles. A response to treatment was observed in 9 of 15 evaluable patients (60.0%) with 4 complete remissions and 5 partial remissions. Eight patients were previously exposed to anthracyclines. In 5 of 7 cases with no previous chemotherapy, treatment was effective, and in 4 of 8 cases previous chemotherapy was effective. The toxicity was primarily leucopenia (86.7%), and 9 patients received G-CSF therapy. Other toxicities (alopecia, neurologic and general fatigue) were mild. Two patients with heart failure were recognized and treated with other therapy. This chemotherapy is effective for the treatment of recurrent breast cancer.

[Two patients with far advanced gastric cancer responding to combination chemotherapy with 5-FU and CDDP].

Combination chemotherapy with 5-FU and CDDP was given to two patients with far advanced gastric cancer. One patient was associated with metastases of lung, liver, pancreas and Virchow and periaortic lymph nodes, and the other was associated with metastases of periaortic lymph nodes and malignant ascitis. The regimen consisted of 5-FU 1,000 mg/m2 (day 1-5, continuous infusion) and CDDP 100 mg/m2 (day 3, 1 hr drip infusion). The interval was from the 6th to the 21st day. The response to chemotherapy showed shrinking of primary gastric lesions and metastases of liver, pancreas and periaortic lymph nodes, and disappearance of Virchow lymph nodes and malignant ascitis. Adverse reactions were thrombocytopenia (Grade 4), leukocytopenia (Grade 3), stomatitis (Grade 1, 3), vomiting (Grade 1, 2) and peripheral neuropathy (Grade 3). This therapy is thought to be effective against far advanced gastric cancer.

Effect of the combination of antiplatelet agents in man: combination of aspirin, trapidil, ticlopidine and dipyridamole.

An in vitro study of how platelet aggregation would be inhibited by the combination of aspirin or ticlopidine irreversibly inhibitory to platelet aggregation and trapidil or dipyridamole reversibly inhibitory, was carried out. The measured 50% inhibition concentrations indicated that aspirin was most inhibitory to collagen-induced platelet aggregation, followed by trapidil, ticlopidine and dipyridamole in decreasing sequence of inhibition. The combination of either aspirin or ticlopidine with trapidil inhibited platelet aggregation more intensely than the combination of either agent with dipyridamole. Thus, in clinical use of aspirin or ticlopidine, it may be expected that the lower dosage of aspirin or ticlopidine with lower frequencies of side effects inhibits platelet aggregation effectively with the combination of trapidil rather than dipyridamole.

Effect of nicergoline on platelet aggregation, plasma viscosity and erythrocyte deformability in geriatric patients with cerebral infarction. Preliminary report.

The effects of nicergoline (Sermion) on platelet aggregation, plasma viscosity and erythrocyte deformability were evaluated in 11 geriatric patients with cerebral infarction, 2 men and 9 women (ages 61-78, mean age 71.6). Nicergoline was given orally at a dose of 5 mg 3 times daily after meals for 8 weeks. Hematological variables were determined twice prior to the administration and at 4 and 8 weeks after the administration. The platelet aggregation in vitro was determined by the turbidimetric method and the level of circulating platelet aggregates was determined according to the method of Wu-Hoak. Erythrocyte deformability was determined according to the method based on the examination of passing erythrocytes through a filter containing pores smaller than the undeformed cells. Collagen-, arachidonic acid- and PAF-induced platelet aggregation was decreased after nicergoline administration. Erythrocyte deformability was increased and plasma viscosity was also decreased after the administration. Thus the improvement of platelet aggregation, plasma viscosity and erythrocyte deformability in cerebral infarction may prevent disturbing blood flow and may contribute to prevention of formation and progression of thrombosis and atherosclerosis in geriatric patients with cerebral infarction.

Effects of carvedilol on common carotid arterial flow, peripheral hemodynamics, and hemorheologic variables in hypertension.

The effects of a beta-blocker, carvedilol, on peripheral hemodynamics and hemorheologic parameters were evaluated in 11 geriatric patients with essential hypertension [3 men and 8 women aged 62-79 years (mean, 68.6 years)]. Carvedilol was given orally after breakfast at a dose of 10 or 20 mg daily for 8 weeks. Peripheral hemodynamics, the common carotid arterial flow, and hemorheologic parameters were determined twice prior to administration and after 4 and 8 weeks of carvedilol treatment. The common carotid arterial flow was determined using the pulsed Doppler method. Peripheral hemodynamics were assessed by venous occlusion plethysmography. The hemorheologic parameters assessed include erythrocyte aggregation, erythrocyte deformability, plasma viscosity, whole-blood hematocrit, and platelet function tests. Erythrocyte aggregation was measured using an Erythrocyte Aggregometer MA-1 (Myrenne, USA), taking a high shear rate of 600 s-1 and a low shear rate of 3 s-1 as the indices. Statistical comparisons of values before and after carvedilol administration were made using the paired Student's t-test. Systolic and diastolic blood pressure were decreased by carvedilol. The common carotid arterial flow was increased, and peripheral hemodynamics were improved by carvedilol. Erythrocyte aggregation (measured at both a high and a low shear rate) and plasma viscosity were decreased, erythrocyte deformability was increased, and levels of circulating platelet aggregates were also improved by carvedilol. This improvement of hemorheologic variables may contribute to prevention of the initiation and progression of thrombosis and atherosclerosis in geriatric patients with essential hypertension.

Effect of flunarizine on volume flow of the common carotid artery, peripheral hemodynamics, erythrocyte deformability and platelet function.

The Ca2+ antagonist flunarizine (Flunarl) was administered to 14 patients (4 men and 10 women, 70.9 +/- 2.5 years old, mean +/- S.E.), suffering from cerebral atherosclerosis. The dose was 10 mg/day given for 8 weeks and the following results were obtained. The volume flow of the common carotid artery was increased in the 4th week after the administration, and this increase was maintained until the 8th week. Flunarizine caused improvement of peripheral hemodynamics, induced inhibition of platelet aggregation and improvement erythrocyte deformability. These results indicate that the Ca2+ entry blocker flunarizine improves cerebral and peripheral hemodynamics including microcirculation by inhibiting platelet aggregation and erythrocyte deformability.

The anti-platelet effect of niceritrol in patients with arteriosclerosis and the relationship of the lipid-lowering effect to the anti-platelet effect.

A hypolipidemic agent, pentaerythritol tetranicotinate (niceritrol) yields nicotinic acid upon hydrolysis in vivo, but niceritrol is hardly soluble in distilled water, so that the effects of nicotinic acid on platelet aggregation in vitro were studied. Nicotinic acid inhibited in vitro platelet aggregation induced by ADP, collagen and adrenaline. Twenty patients (61.4 +/- 2.4 years (mean +/- S.E.)) with ischemic heart disease, cerebral infarction, transient cerebral ischemic attack and hypercholesterolemia were given niceritrol orally at 750 mg per day for 8 weeks. Significant decreases in ADP-, collagen- and adrenaline-induced platelet aggregation were observed at 4 and 8 weeks after niceritrol treatment. There was a significant correlation between the rates of changes in platelet aggregation and those in plasma total cholesterol or plasma LDL-cholesterol before treatment and 8 weeks following treatment. The results indicate that niceritrol has inhibitory effects on platelet aggregation not only caused by its direct action on platelet but mediated by its secondary action due to decrease in blood lipids.

Effect of eicosapentaenoic acid on the platelet aggregation and composition of fatty acid in man. A double blind study.

Twelve volunteers (mean age, 60.7 +/- 4.2 years) were treated with placebo for the first week and then given partially purified eicosapentaenoic acid (EPA, 67% purity) at 2 g per day for 4 weeks. Significant decreases in ADP-, collagen- and adrenalin-induced platelet aggregation were observed at 2 and 4 weeks after EPA treatment, together with an increase in the plasma ratio of EPA to arachidonic acid and in platelet phospholipids. It was concluded that the administration of partially purified EPA was effective in decreasing platelet aggregation, possibly by changing the platelet ratio of EPA to arachidonic acid.