Pharmacokinetic study of the oral fluorouracil antitumor agent S‐1 in patients with impaired renal function

Although dose reduction of S‐1 is recommended for patients with impaired renal function, dose modification for such patients has not been prospectively evaluated. The aim of the present study was to investigate the pharmacokinetic parameters of 5‐fluorouracil, 5‐chloro‐2,4 dihydroxypyridine and oteracil potassium, and to review the recommended dose modification of S‐1 in patients with renal impairment. We classified patients receiving S‐1 into 4 groups according to their renal function, as measured using the Japanese estimated glomerular filtration rate (eGFR) equation. The daily S‐1 dose was adjusted based on the patient's eGFR and body surface area. Blood samples were collected for pharmacokinetic analysis. A total of 33 patients were enrolled and classified into 4 groups as follows: 10 patients in cohort 1 (eGFR ≥ 80 mL/min/1.73 m²), 10 patients in cohort 2 (eGFR = 50‐79 mL/min/1.73 m²), 10 patients in cohort 3 (eGFR = 30‐49 mL/min/1.73 m²), and 3 patients in cohort 4 (eGFR < 30 mL/min/1.73 m²). Those in cohorts 3 and 4 treated with an adjusted dose of S‐1 showed a similar area under the curve for 5‐fluorouracil (941.9 ± 275.6 and 1043.5 ± 224.8 ng/mL, respectively) compared with cohort 2 (1034.9 ± 414.3 ng/mL). Notably, while there was a statistically significant difference between cohort 1 (689.6 ± 208.8 ng/mL) and 2 (P = 0.0474) treated with an equal dose of S‐1, there was no significant difference observed in the toxicity profiles of the cohorts. In conclusion, dose adjustment of S‐1 in patients with impaired renal function using eGFR is appropriate and safe.     

Quality of life after single-incision laparoscopic cholecystectomy: A randomized,clinical trial

Background

Controversy continues as to whether single-incision laparoscopic cholecystectomy, with the somewhat larger incision at the umbilicus, may lead to a worse postoperative quality of life and more pain compared with the more classic 4-port laparoscopic cholecystectomy. The aim of this study was to compare single-incision and 4-port laparoscopic cholecystectomy from the perspective of quality of life.

Feasibility and mid- to long-term results of endovascular treatment for portal vein thrombosis after living-donor liver transplantation

PURPOSEWe aimed to evaluate mid- to long-term results of endovascular treatment for portal vein thrombosis (PVT) after living-donor liver transplantation (LDLT).METHODSThirty cases (14 males, 16 females; age range, 0.67–65 years) who underwent endovascular treatment including thrombolysis, angioplasty, stent placement, and/or collateral embolization for PVT after LDLT from 2001 to 2017 were retrospectively reviewed. Clinical and procedural data were collected and analyzed regarding the patency of the PVT site at the last follow-up date (PVT-free persistency) using Log-rank test. Results were considered statistically significant at p < 0.05.RESULTSMedian follow-up was 120 months. The technical success rate was 80% (n=24). Patency rates at 1 week and 1, 3, 6, 12, 36, and 60 months were 73%, 59%, 55%, 51%, 51%, 51%, and 51% for primary patency and 80%, 70%, 66%, 66%, 66%, 61%, and 61% for assisted patency after secondary endovascular treatment. PVT-free persistency rates regarding the subgroups were as follows: children under 12 years vs. adults, 50% vs. 68% (p = 0.42); acute vs. nonacute, 76% vs. 46% (p = 0.10); localized vs. extensive, 90% vs. 50% (p = 0.035); transileocolic approach vs. percutaneous-transhepatic approach, 71% vs. 54% (p = 0.39); and thrombolysis-based treatment vs. non-thrombolysis-based treatment, 71% vs. 44% (p = 0.12), respectively. Among technically successful cases, PVT-free persistency rate was 94% for those with hepatopetal flow in the peripheral portal vein vs. 17% for those without hepatopetal flow (p < 0.001). The only major complication occurring was pleural hemorrhage (n=1). Minor complications (i.e., fever) occurred in 18 patients (60%).CONCLUSIONIn conclusion, mid- to long-term portal patency following endovascular treatment was approximately 50%–60% in PVT patients after LDLT. PVT site patency over three months after the first endovascular treatment, localized PVT, and hepatopetal flow in the peripheral portal vein were identified as key prognostic factors for mid- to long-term portal patency.

Portal vein thrombosis (PVT) is a vascular complication of living-donor liver transplantation (LDLT), with an estimated incidence of up to 4% (1, 2). The risk of vascular complications, including PVT, is higher in LDLT compared with conventional deceased-donor liver transplantation, because of the smaller vessels, insufficient vessel length for reconstruction, neointimal proliferation, and higher risk of twisting and kinking of the vascular pedicle (3) due to smaller graft size than in deceased-donor liver transplantation. PVT after LDLT can lead to graft failure and the need for retransplantation or death (2), making immediate treatment crucial.Endovascular-based treatment is one option for treating PVT. The utility of target-focused thrombolysis, balloon angioplasty, and stent placement to restore portal flow has been reported previously (4–10). However, the efficacy of endovascular treatment after LDLT has only been presented in some case reports (11, 12) and the mid- to long-term outcomes remain unclear.The purpose of this study was to evaluate the technical success, feasibility, and mid- to long-term results of endovascular treatment for PVT after LDLT in our institution.     

A case report: Severe bone marrow suppression caused by 6-mercaptopurin in Crohn's disease patient]

A 23-year-old man was admitted for treatment of acute exacerbation of ileitis and perianal abscess caused by Crohn's disease. After incision and drainage of the abscess, coupled with antibiotic therapy, 6-mercaptopurine (6-MP) was commenced. His white blood cell (WBC) count on day 12 after initiation of 6-MP was not decreased. However, on day 24 he was re-admitted because of severe myelosuppression (WBC: 300/microl), which was complicated by the recurrence of the perianal abscess. Myelosuppression was prolonged and required the administration of granulocyte colony stimulating factor (G-CSF). G-CSF was continued for 17 days to achieve recovery of his WBC count to a normal level.     

Induced tolerance to ischemia in gerbil hippocampal neurons

Brief ischemia induced tolerance to subsequent ischemia in the hippocampal neurons. Male Mongolian gerbils were subjected to 2 min of ischemia in an awake condition. This ischemic insult only rarely produced neuronal damage in the gerbil brain. One day (n = 9), 2 days (n = 9), or 4 days (n = 10) following the first brief ischemia, the animals (double-ischemia group) were subjected to the second ischemia for 5 min. The single-ischemia group received a sham procedure instead of the first ischemia and was identically subjected to the second ischemia 1 day (n = 9), 2 days (n = 10), and 4 days (n = 13) following the sham procedure. One week following the second ischemia, all gerbils were perfusion fixed and the neuronal density in the hippocampal CA1 sector was measured. In double-ischemia groups, the neuronal density per 1-mm length of the pyramidal cell layer was 103.4 +/- 93.1 (SD) in the 1-day subgroup, 125.6 +/- 64.2 in the 2-day subgroup, and 176.2 +/- 93.7 in the 4-day subgroup, while the density in normal gerbils was 254.7 +/- 18.6. The average neuronal density in the single-ischemia group was much lower than that in the double-ischemia group (whole control group: 10.9 +/- 27.4). Immunostaining using monoclonal antibody raised against 70-kDa heat-shock protein revealed an increase in 70-kDa heat-shock protein in the CA1 area following 2 min of ischemia. Very brief ischemia induces heat-shock proteins and, presumably, thereby renders neurons more tolerant to subsequent metabolic stress.     

Hepatic conversion of 1-(tetrahydro-2-furanyl)-5-fluorouracil into 5-fluorouracil in patients with hepatocellular carcinoma

The pharmacokinetics of 1-(tetrahydro-2-furanyl)-5-fluorouracil (FT) and its conversion into 5-fluorouracil (FUra) in liver tissue were studied in ten patients with hepatocellular carcinoma (HCC). The plasma concentration of FT after its intravenous injection (dosage: 800 mg) was computerfitted to a bi-exponential function (C = Ae-alpha t + Be-beta t), indicating a two-compartment disposition. The pharmacokinetic parameters did not significantly differ between the five patients with, and the five without cirrhosis of the liver. The plasma concentrations of FUra likewise showed no significant difference between the two groups. The rates of FT degradation in the liver tissue homogenate were similar for four of the patients with cirrhosis (0.10 +/- 0.05 mumol/g liver protein/30 min) and four of those without it (0.13 +/- 0.05). The rates of cytochrome P-450-dependent FUra formation in the microsomal fraction of liver tissue from two patients (1.1 and 1.3 nmol/mg microsomal protein/30 min) were dramatically reduced to less than half of those of two control subjects (2.4 and 2.7). The estimated rates of FUra formation in the soluble fraction (105,000 X g supernatant fraction) from the two patients (0.1 and 0.13 nmol/mg protein/30 min) were almost identical to those from the controls (0.12 and 0.14), suggesting that the rate in the soluble fraction from HCC patients may not be as strongly affected as the rate in the microsomal fraction.(ABSTRACT TRUNCATED AT 250 WORDS)