Multicentre study of perioperative versus adjuvant chemotherapy for resectable colorectal liver metastases.

Background: It is not known whether perioperative chemotherapy, compared with adjuvant chemotherapy alone, improves disease-free survival (DFS) in patients with upfront resectable colorectal liver metastases (CLM). The aim of this study was to estimate the impact of neoadjuvant 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX) on DFS in patients with upfront resectable CLM. Methods: Consecutive patients who presented with up to five resectable CLM at two Japanese and two French centres in 2008-2015 were included in the study. Both French institutions favoured perioperative FOLFOX, whereas the two Japanese groups systematically preferred upfront surgery plus adjuvant chemotherapy. Inverse probability of treatment weighting (IPTW) and Cox regression multivariable models were used to adjust for confounding. The primary outcome was DFS. Results: Some 300 patients were included: 151 received perioperative chemotherapy and 149 had upfront surgery plus adjuvant chemotherapy. The weighted 3-year DFS rate was 33·5 per cent after perioperative chemotherapy compared with 27·1 per cent after upfront surgery plus adjuvant chemotherapy (hazard ratio (HR) 0·85, 95 per cent c.i. 0·62 to 1·16; P = 0·318). For the subgroup of 165 patients who received adjuvant FOLFOX successfully (for at least 3 months), the adjusted effect of neoadjuvant chemotherapy was not significant (HR 1·19, 0·74 to 1·90; P = 0·476). No significant effect of neoadjuvant chemotherapy was observed in multivariable regression analysis. Conclusion: Compared with adjuvant chemotherapy, perioperative FOLFOX does not improve DFS in patients with resectable CLM, provided adjuvant chemotherapy is given successfully.

Antecedentes: Se desconoce si la quimioterapia perioperatoria en comparación con la quimioterapia adyuvante sola mejora la supervivencia libre de enfermedad (disease­free survival, DFS) en pacientes con metástasis hepáticas de origen colorrectal (colorectal liver metastases, CLM) resecables de inicio. El objetivo de este estudio fue estimar el impacto de la neoadyuvancia con 5­fluorouracilo, leucovorina y oxaliplatino (FOLFOX) sobre la DFS en pacientes con CLM resecables desde el principio. Métodos: Se incluyeron pacientes consecutivos que presentaban hasta cinco CLM resecables en dos centros japoneses y dos centros franceses entre 2008 a 2015. Ambas instituciones francesas favorecían FOLFOX perioperatorio, mientras que los dos grupos japoneses utilizaban sistemáticamente la cirugía de entrada y quimioterapia adyuvante. Se utilizaron la probabilidad inversa del tratamiento ponderado (Inverse Probability of Treatment Weighting, IPTW) y el modelo multivariable de regresión de Cox para ajustar por factores de confusión. El resultado primario fue la DFS. Resultados: Se incluyeron 300 pacientes (grupo de quimioterapia perioperatoria n = 151 y grupo de cirugía de entrada más quimioterapia adyuvante n = 149). La DFS a los 3 años ponderada fue del 33% después de quimioterapia perioperatoria versus 27% tras cirugía de entrada (cociente de riesgos instantáneos, hazard ratio HR: 0,85; i.c. del 95% (0,62­1,16); P = 0,32). Cuando se consideró el subgrupo de pacientes que (n = 165) de manera efectiva (al menos 3 meses) recibieron FOLFOX adyuvante, el efecto ajustado de la quimioterapia neoadyuvante no fue significativo (HR: 1,19 (0,74­1,90); P = 0,48). No se observó un efecto significativo de la quimioterapia neoadyuvante en el análisis de regresión multivariable. Conclusión: En comparación con la quimioterapia adyuvante, el FOLFOX perioperatorio no mejora la DFS en CLM resecables siempre y cuando la quimioterapia adyuvante se administre de forma efectiva.

Evaluation of post-repolarization refractoriness for conduction block in cardiac muscle: studies in an artificial isthmus in the canine right atrium.

Post-repolarization refractoriness (PRR) is an important factor in determining conduction block and is the difference between the effective refractory period (ERP) and the duration of the monophasic action potential (MAPD). In the present study, conduction block in an artificial isthmus in the canine atrium was evaluated and the coupling interval of a premature beat, which caused the block, was defined as the block coupling interval (BCI). The usefulness of this value was also evaluated. Radiofrequency linear ablation was performed on the right atrial surface parallel to the atrioventricular groove in 5 mongrel dogs, and an artificial isthmus (8-10mm wide and 25-30mm long) was created. Fourteen simultaneous unipolar recordings were performed in the isthmus with a resolution of 1.2 mm. Single extra-stimuli with basic drive train were delivered to induce conduction block in the isthmus and when it occurred, the coupling interval at the recording site just proximal to the site of the block was defined as the BCI. At the site of the block, the ERP and MAPD at each drive cycle length were measured. The PRR was calculated using 2 different formulae: (1) [ERP-MAPD], and (2) [BCI-MAPD]. It was found that each value was shortened in accordance with the shortening of the basic drive cycle length. In all basic drive trains, BCI>ERP>MAPD, and [ERP-MAPD] was always shorter than [BCI-MAPD]. In the shorter cycle length of basic drives, the difference between [ERP-MAPD] and [BCI-MAPD] was more prominent. In the artificial isthmus model in the canine atrium, BCI was always longer than the ERP measured at the same site as the block. Because the ERP may not directly reflect the block phenomenon, the electrophysiologic evaluation should use the BCI instead, as in the PRR evaluation.

Selection, enrichment, and culture expansion of murine mesenchymal progenitor cells by retroviral transduction of cycling adherent bone marrow cells.

It has been difficult to characterize murine bone marrow (BM)-derived mesenchymal progenitor cells (MPCs) because of contamination with hematopoietic cells. We took advantage of the rapid proliferation of MPCs after replating to enrich murine MPCs by transfection with a retroviral vector carrying both LacZ and the selective neomycin resistance (neoR) gene. Freshly harvested BM cells from mice were incubated with BAG retroviral vector produced by amphotropic psi-CRIP or ecotropic psi-CRE producer cells for 48 hours and grown in the presence of G418.Cells incubated in psi-CRIP supernatant formed colonies composed of large homogeneous cells that were free of CD45(+) cells, but cells incubated in psi-CRE supernatant did not form stromal cell colonies. In the undifferentiated state, the cells displayed a fibroblast-like phenotype with low alkaline phosphatase activity. However, upon treatment with dexamethasone or 5-azacytidine, the retrovirally transduced cells differentiated into oil-red-O-positive adipocytic cells and osteogenic cells generating von Kossa-positive bone nodules. Osteogenic supplements composed of beta-glycerophosphate, dexamethasone, and ascorbic acid induced an increase in alkaline phosphatase activity and acute osteogenesis associated with early cell detachment. Subcutaneous injection with retrovirally transduced cells into day 1 newborn mice of the same strain produced ectopic calcium depositions surrounded by X-gal(+) cells. Retroviral selection of cycling adherent cells is an effective approach for enrichment of MPCs.

Modulation of picryl chloride-induced contact hypersensitivity reaction in mice by nitric oxide.

We have studied the possible involvement of nitric oxide (NO) in the contact hypersensitivity reaction. A biphasic response of ear swelling was observed at 2 h (early phase) and 24 h (late phase) after application of the antigen to picryl chloride (PC1)-sensitized CBA/J mice. Intravenous injection of NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), at the time of PC1 challenge, inhibited in a concentration-dependent fashion the antigen-induced contact hypersensitivity reaction. Low-dose (1 mg/kg) L-NAME inhibited the early-phase reaction but not the late-phase reaction. High-dose (250 mg/kg) L-NAME inhibited both early- and late-phase reactions. D-NAME (enantiomer of L-NAME) did not inhibit the antigen-induced ear swelling. High-dose (250 mg/kg) L-arginine increased both early and late phase reactions. D-Arginine (enantiomer of L-arginine) did no increase the antigen-induced ear swelling. L-NAME injection, however, did not suppress phenol-induce irritant inflammation. Treatment of mice undergoing PC1-induced contact hypersensitivity reaction with L-NAME reduced the production of interleukin-2 and interferon-gamma by draining lymph node cells. Treatment with L-arginine, on the other hand increased the production of interleukin-2 and interferon-gamma. These results suggest that NO plays a modulating role in contact hypersensitivity reaction.

Dual role of tropomyosin on chemically modified actin filaments from skeletal muscle.

Actin filaments copolymerized with both intact and chemically modified actin monomers restored their sliding activity when they were supplemented with tropomyosin extracted from skeletal muscle. In contrast, the ATPase activation of the copolymers was decreased when supplemented with tropomyosin. The results indicate that tropomyosin along with actin monomers may facilitate sliding activity of the entire actin filament but suppress ATPase activation of intact actin monomers themselves. Accordingly, tropomyosin molecules could be viewed as playing a dual role of both mechanical and chemical regulation of actin monomers.

Protective effects of kampo medicines and baicalin against intestinal toxicity of a new anticancer camptothecin derivative, irinotecan hydrochloride (CPT-11), in rats.

In clinical use, irinotecan hydrochloride (CPT-11; 7-ethyl-10-[4-(piperidino)-1-piperidino]carbonyloxycamptothecin), a novel antitumor agent, causes a relatively high incidence of severe forms of diarrhea. We investigated whether baicalin, an inhibitor of beta-glucuronidase, which deconjugates the glucuronide of the active metabolite of CPT-11, SN-38 (7-ethyl-10-hydorxycamptothecin), and Japanese herbal medicines (Kampo medicines) which contain baicalin can ameliorate CPT-11-induced intestinal toxicity in rats. CPT-11 (60 mg/kg i.v. once daily for 4 consecutive days) induced intestinal toxicity characterized by diarrhea, loss of body weight, anorexia and disruption of intestinal epithelium. Treatment with baicalin (25 mg/kg p.o. twice daily) or Kampo medicines (TJ-14 and TJ-114; 1 g/kg p.o. twice daily) from the day before to 4 or 10 days after the start of CPT-11 administration resulted in significantly decreased weight loss, improved anorexia and delayed onset of diarrheal symptoms. Histological examination revealed that Kampo medicine-treated animals had less damage to the intestinal epithelium and that damage was repaired more rapidly than in control rats. These results suggest that the prophylactic use of Kampo medicines (TJ-14 and TJ-114) may be of value against CPT-11-induced intestinal toxicity.

[General pharmacological study of iodixanol, a new non-ionic isotonic contrast medium].

The general pharmacological study of iodixanol, a non-ionic isotonic contrast medium, was conducted. 1) Iodixanol administered intravenously over a dose range of 320 to 3,200 mgI/kg had little or no effect on the general behavior, spontaneous locomotor activity, hexobarbital sleeping time, pain response, electroshock- or pentylenetetrazol-induced convulsion (mouse), EEG or body temperature (rabbit), gastrointestinal propulsion (mouse) or skeletal muscle contraction (rabbit). Iodixanol had no specific interaction with acetylcholine, histamine, serotonin, nicotin, BaCl2 (ileum), methacholine (trachea), isoprenaline (atrium) or oxytocin (pregnant uterus), nor had any effect on spontaneous contractility (atrium and uterus), or transmural electrostimulation-induced contractility (vas deferens) at concentrations of < or = 3.2 x 10(-3) gI/ml in vitro. Iodixanol had no effect on the cardiovascular system of dog, except that it increased femoral blood flow and respiratory rate at doses of > or = 1,000 mgI/kg. Iodixanol at 3,200 mgI/kg i.v. reduced urine output with a decrease in Na+ and Cl- excretion, whereas at 320 mgI/kg i.v., it slightly increased urine output (rat). 2) Injections of iodixanol into the cerebroventricular (0.96, 9.6 mgI/mouse and 3.2, 32 mgI/rat), left ventricular (1,920, 6,400 mgI/dog) or coronary artery (640, 1,920 mgI/dog) had no conspicuous effect on the central nervous system or the cardiovascular system, respectively. There was no marked difference among iodixanol, iohexol and iopamidol in this respect. Vascular pain during injection into the femoral artery (300-320 mgI/guinea pig) appeared to be less intense with iodixanol, compared with the other contrast media iohexol and iopamidol. These results suggest that intravenous injection of iodixanol is relatively free from pharmacological activity, and effects of iodixanol on the central nervous system (intracerebroventricular injection) and cardiovascular system (intra-left ventricular and -coronary injections) are comparable to those of iohexol and iopamidol. Furthermore, intra-femoral injection of iodixanol has less of a tendency to produce vascular pain than those of iohexol and iopamidol.

Anticancer drug distribution in lymph and blood during adjuvant chemotherapy after surgery for gastric carcinoma. A study with a combined preparation of 1-(2-tetrahydrofuryl)-5-fluorouracil and uracil.

Previously the authors reported that the fat emulsion of 1-(2-tetrahydrofuryl)-5-fluorouracil, tegafur (FT-207), yielded significantly higher concentrations of tegafur in the lymph and plasma compared to tegafur enteric-coated granules (FT-G). However, the emulsification did not improve the metabolic conversion rate of tegafur to 5-fluorouracil (5-FU). A study was performed to assay the plasma and lymphatic concentrations of tegafur, 5-FU, and uracil in seven patients after radical surgery for gastric carcinoma who were given a combined oral preparation of FT-207 and uracil (UFT). Both lymph and plasma 5-FU levels after UFT were 20 times greater than those after FT-G, although FT-207 levels were not different. Patients given UFT showed significantly greater 5-FU and uracil concentrations in the lymph compared with the plasma. The results of this study suggest a potential use of UFT as an adjuvant postoperative chemotherapeutic agent for gastric carcinoma.

N1-(2 tetrahydrofuryl)-5-fluorouracil (FT-207) in the postoperative adjuvant chemotherapy of gastric cancer. Delivery of a fat-emulsified agent to the lymph.

The influence of fat emulsification of N1-(2-tetrahydrofuryl)-5-fluorouracil (FT-207) on lymphatic transport was studied in seven postoperative gastric cancer patients. The water-in-oil-type of emulsion of FT-207 (FT-w/o), the oil-in-water-type emulsion of FT-207 (FT-o/w) and an enteric-coated granule of FT-207 (FT-G) each in 1-g doses, calculated in terms of FT-207, were administered orally. Lymph from a thoracic duct fistula, prepared in advance, and from the blood of a peripheral vein was collected simultaneously along a time course after administration to measure the concentrations of FT-207 and 5-fluorouracil (5-FU). For FT-w/o, FT-207, and 5-FU, concentrations were significantly higher, both in the lymph and in the blood, than those for FT-G and FT-o/w. However, no significant differences in FT-207 and 5-FU concentrations were observed between FT-o/w and FT-G. It was concluded that FT-w/o can be useful as an adjuvant chemotherapeutic drug in the postoperative treatment of gastric cancer.