Current evidence of irinotecan combination chemotherapy with TS-1 in patients with advanced colorectal cancer

A combination of irinotecan (CPT-11) with continuous intravenous infusions of (infusional) 5-fluorouracil (5-FU) and Leucovorin (LV) is one of the standard treatments for advanced colorectal cancer patients. However, recent concerns about safety and convenience have prompted the development of new oral fluoropyrimidine derivatives and improved regimens. TS-1, the oral fluoropyrimidine widely used in the treatment for gastric cancer, was approved for advanced colorectal cancer. Recently, several phase I/II studies assessed the efficacy and safety of combined treatment with TS-1 plus CPT-11 in patients with advanced colorectal cancer. These results showed that TS-1 plus CPT-11 was very effective. Toxicity was generally mild and manageable on an outpatient basis. Current evidence showed that a combination of CPT-11 plus TS-1 was more convenient and easier to administer than a combination of CPT-11 plus infusional 5-FU and LV. It is essential to prove that the combination of TS-1 plus CPT-11 can replace the combination of infusional 5-FU and LV plus CPT-11 without negatively affecting efficacy and toxicity.     

The current evidence of S-1 and irinotecan hydrochloride combination chemotherapy with tri-weekly schedule

A combination therapy of irinotecan hydrochloride (CPT-11) with continuous intravenous infusions of (infusional) 5-fluorouracil (5-FU) and Leucovorin (LV) is often used to treat advanced colorectal cancer. However, recent concerns on safety and convenience have prompted the development of new oral fluoropyrimidine derivatives which improved regimens. Yamada et al conducted a phase I study to assess the maximum tolerated dose and recommended dose of S-1 combined with CPT-11. The study recommended that 150 mg/m2 of CPT-11 be given on day 1 and 80 mg/m2 of S-1 daily on days 1 to 14 every 3 weeks. Recently, several phase I/II studies assessed the efficacy and safety of the combined therapy with S-1 and CPT-11 in patients with advanced colorectal cancer. Some of the studies which were ongoing assessed a tri-weekly schedule regimen. Our results showed that S-1 plus CPT-11 was very effective, with a response rate of 63% and PFS of 8 months. Toxicity was generally mild and manageable on an outpatient basis. The current evidence showed that a combination of S-1 and CPT-11 was more convenient and easier to administer than a combination of CPT-11 plus infusional 5-FU and LV. It will be essential to prove that the combination of S-1 plus CPT-11 can replace the combination of infusional 5-FU and LV plus CPT-11 without negatively affecting efficacy and toxicity.     

Performance of polysulfone membrane dialyzers and dialysate flow pattern

Background It is important to observe the flow pattern of dialysate when evaluating dialyzer function and developing the most appropriate design. We investigated dialysate flow through two polysulfone membrane dialyzers (TS-UL [Toray Medical] and APS-S [Asahi Medical]) by computed tomography (CT), with barium sulfate as the contrast medium. We also performed a clinical comparison of these two dialyzers. Methods For the in vitro experiment, after confirming the steady-state flow of mock blood (xanthan gum solution; 200 ml/min) and dialysate (500 ml/min), fresh dialysate, containing 5% (w/v) barium sulfate was perfused, and longitudinal CT scans of the dialyzer were obtained. Then the concentration of barium sulfate was measured (in Hounsfield units) in three fixed regions of interest. For the in vivo experiment, 12 patients on stable hemodialysis who had been using the APS-S for more than 1 month were switched to the TS-UL for 1 month and changes in various parameters were assessed. Results The distribution of dialysate was homogeneous on CT scans of the TS-UL, but not on scans of the APS-S. The dialysate concentration curves for the three regions of interest were similar with the TS-UL, but not with the APS-S. Clearance of urea nitrogen and albumin loss were both significantly higher with the TS-UL than with the APS-S. The decrease in alpha 1-microglobulin was larger with the TS-UL than with the APS-S, but not significantly. Conclusions Clearance of substances over a wide range of molecular weights was higher with the TS-UL than with the APS-S, and differences in the design of the dialysate compartment may have been involved in this feature.     

Prolonged nitric oxide inhalation fails to regress hypoxic vascular remodeling in rat lung

STUDY OBJECTIVE: The purpose of present study was to investigate whether long-term nitric oxide (NO) inhalation during the recovery in air might improve the regression of chronic hypoxic pulmonary hypertension (PH) and vascular changes. MATERIALS AND METHODS: The rats were exposed to 10 ppm of NO in air for 10 days (n = 12) and 30 days (n = 4), or 40 ppm of NO in air for 10 days (n = 6) and 30 days (n = 12) following 10 days of hypobaric hypoxia (380 mm Hg, 10% oxygen). For each NO group, air control rats following hypoxic exposure were studied at the same time (n = 13, 11, 9, and 11, respectively). Normal air rats (n = 6) without hypoxic exposure and rats (n = 7) following 10 days of hypoxic exposure were used as normal and chronic hypoxic control groups, respectively. Muscularization of normally nonmuscular peripheral arteries and medial hypertrophy of normally muscular arteries were assessed by light microscopy. An additional 16 rats were used to investigate the recovery of pulmonary artery pressure with (n = 8) and without NO inhalation (n = 8) after 10 days of hypobaric hypoxia. RESULTS: Long-term hypoxia-induced PH, right ventricular hypertrophy (RVH), and hypertensive pulmonary vascular changes, each of which regressed partly after recovery in room air. There were no differences among rats with and without NO during each recovery period in RVH, medial wall thickness of muscular artery, and the percentages of muscularized arteries at the alveolar wall and duct levels. Continuous inhaled 40 ppm NO decreased pulmonary artery pressure from 40.1 +/- 1.1 to 29.9 +/- 3.8 mm Hg (mean +/- SE) [n = 8], which was not different in the rats without NO inhalation (n = 8). Urine nitrate level was higher in rats that had inhaled NO. CONCLUSION: Continuous NO inhalation showed no effect on regression of pulmonary vascular remodeling in chronic hypoxic PH after returning to room air.     

Reducing bacterial contamination inside fluid catch bag in 25-gauge vitrectomy by use of 0.25 % povidone-iodine ocular surface irrigation

To examine the bacterial detection rate in infusion fluid collected inside the fluid catch bag during 25-gauge (25G) vitrectomy when the ocular surface was irrigated with infusion fluid or 0.25 % povidone-iodine. Two groups using different fluids for ocular surface irrigation during 25G vitrectomy were studied. Fifty-five consecutive eyes received ocular surface irrigation with infusion fluid (IF group) and 52 consecutive eyes with 0.25 % povidone-iodine (PI group). Samples of ocular surface fluid were collected at the beginning of surgery and samples of infusion fluid inside the fluid catch bag were collected at the end of surgery for bacteriological cultures. At the beginning of surgery, the bacterial detection rates in ocular surface fluid samples were 5.8 % (3 of 52 eyes) in the IF group and 7.7 % (4 of 52 eyes) in the PI group, with no significant difference (P = 0.6955). At the end of surgery, the bacterial detection rates in infusion fluid collected inside the fluid catch bag were 23.1 % (12 of 52 eyes) in the IF group and 3.8 % (2 of 52 eyes) in the PI group, with a significant difference (P = 0.0041). No endophthalmitis occurred in either group. These results demonstrate the risk of bacterial contamination when surgical instruments fall accidentally into the fluid catch bag during conventional 25G vitrectomy. Irrigating the ocular surface with 0.25 % povidone-iodine instead of infusion fluid significantly reduces the bacterial contamination rate in the fluid catch bag.     

Outcome of transarterial chemoembolization monotherapy, and in combination with percutaneous ethanol injection, or radiofrequency ablation therapy for hepatocellular carcinoma

Aim:  Hepatocellular carcinoma (HCC) is one of the most commonly occurring malignances worldwide. Curative therapies such as resection, percutaneous ethanol injection (PEI) and radiofrequency ablation (RFA) have been applied to patients with early-stage HCC. Patients with more advanced cancers require local or systemic therapies. We present the results of our retrospective review conducted to evaluate whether transarterial chemoembolization (TACE) alone and combined TACE with percutaneous ablation for HCC exhibited superior efficacy to palliative treatment.
Methods:  The effects of TACE and of the combined therapies (TACE + PEI or TACE + RFA) on the long-term survival rates were evaluated in 268 untreated HCC patients by various statistical analyses.
Results:  The cumulative survival rates in the TACE alone group were significantly superior to those in the palliative treatment group. Further, the cumulative survival rates in the combined TACE + PEI/RFA group were significantly superior to those in the TACE alone group. When the comparison among the groups was restricted to patients with two or three tumors fulfilling the Milan criteria, significantly greater prolongation of survival was observed in the combined TACE + PEI/RFA group than in the PEI/RFA alone group.
Conclusions:  The aforementioned treatment modalities yielded greater improvements of the survival rate and survival duration as compared to palliative treatment in HCC patients. Furthermore, in terms of the effect on the survival period, combined TACE + PEI/RFA therapy was more effective than TACE monotherapy, and also more effective than PEI or RFA monotherapy in cases with multiple tumors fulfilling the Milan criteria.     

Functional analysis of LAT3 in prostate cancer: Its downstream target and relationship with androgen receptor

L-type amino acid transporter 3 (LAT3, SLC43A1) is abundantly expressed in prostate cancer (PC) and is thought to play an essential role in PC progression through the cellular uptake of essential amino acids. Here, we analyzed the expression, function, and downstream target of LAT3 in PC. LAT3 was highly expressed in PC cells expressing androgen receptor (AR), and its expression was increased by dihydrotestosterone treatment and decreased by bicalutamide treatment. In chromatin immunoprecipitation sequencing of AR, binding of AR to the SLC43A1 region was increased by dihydrotestosterone stimulation. Knockdown of LAT3 inhibited cell proliferation, migration, and invasion, and the phosphorylation of p70S6K and 4EBP-1. Separase (ESPL1) was identified as a downstream target of LAT3 by RNA sequencing analysis. In addition, immunostaining of prostatectomy specimens was performed. In the multivariate analysis, high expression of LAT3 was an independent prognostic factor for recurrence-free survival (hazard ratio: 3.24; P = .0018). High LAT3 expression was correlated with the pathological T stage and a high International Society of Urological Pathology grade. In summary, our results suggest that LAT3 plays an important role in the progression of PC.