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.

Do biologics-naïve patients with rheumatoid arthritis respond better to tocilizumab than patients for whom anti-TNF agents have failed? A retrospective study.

OBJECTIVES: To determine responses to tocilizumab between patients with rheumatoid arthritis (RA) who switched to anti-TNF agents and those who are biologics-naïve. METHODS: This retrospective study investigated 107 patients with RA who were treated with tocilizumab. At baseline, 61 of them had already been treated with anti-TNF agents (switched group; 46 for inefficacy and 15 for adverse events), and 46 were biologics-naïve (naïve group). Treatment responses to tocilizumab at week 12 and 24 were compared between the switched and naïve groups using the disease activity score 28 (DAS28). RESULTS: Forty-two (91.3%) and 50 (82.0%) patients in the naïve and switched groups, respectively, completed 24 weeks of tocilizumab treatment. The DAS28-ESR and DAS28-CRP values (means±SD) at weeks 12 and 24 compared to baseline decreased significantly for the naïve and switched groups. The DAS28-ESR and DAS28-CRP values at weeks 12 and 24 were significantly decreased in the naïve group, compared to the switched group. Disease activity was improved in the naïve patients compared to the switched patients. CONCLUSIONS: Tocilizumab was safe, tolerable, and clinically effective for patients with inadequate responses to anti-TNF therapy and for those who were biologics-naïve, and it was more effective among the latter.

Effect of Sho-saiko-to extract on HGF and TGF-beta levels of intraorgans in liver-injured rats after partial hepatectomy.

To examine the effects of Sho-saiko-to extract on liver regeneration, Sho-saiko-to extract (0.75%, 1.5% or 3%) was administered to 70% partial hepatectomized rats with dimethylnitrosamine-induced liver-injury. S phase cell number, liver retinoid levels, hepatocyte growth factor (HGF) and transforming growth factor-beta (TGF-beta) levels in each intraorgan were measured as indicators of liver regeneration. Three to seven days after hepatectomy, HGF and TGF-beta levels of the liver and spleen of the Sho-saiko-to extract groups were significantly different from the levels of the ordinary food group (P < 0.05-0.1). HGF levels in the Sho-saiko-to extract groups were approximately 1.3-1.8 times higher in the liver and approximately 1.8-2.1 times higher in the spleen compared with the levels found in the ordinary food group. TGF-beta levels in the Sho-saiko-to extract groups were approximately 0.38-0.47 times the level in the liver and 0.58-0.77 times the level in the spleen of the ordinary food group. There was no difference in HGF and TGF-beta levels of the kidney and lung between the Sho-saiko-to extract group and the ordinary food group. There was a significant and positive correlation between HGF level and S phase cell number in the liver (r = 0.826, P < 0.01). There was a significant and negative correlation between TGF-beta level and the retinoid level in the liver (r = -0.696, P < 0.01). In addition, the levels of the active constituents of Sho-saiko-to extract (glycyrrhetic acid, baicalin and baicalein) showed high values in the liver and spleen of partial hepatectomized rats, and increased from the third day after partial hepatectomy. These results show that Sho-saiko-to extract induces liver regeneration by increasing the production of HGF and suppressing the production of TGF-beta in the liver and spleen of partial hepatectomized rats. It was considered that the increase in the Sho-saiko-to extract active constituent levels in the liver and spleen greatly influences this action.

Effects of Sho-saiko-to extract on liver fibrosis in relation to the changes in hydroxyproline and retinoid levels of the liver in rats.

To examine the effects of Sho-saiko-to extract on liver fibrosis, the drug was administered to rats with dimethylnitrosamine-induced liver-injury at various doses. Hydroxyproline and retinoid levels in the liver were measured as indicators of liver function. In liver-injured rats, the hydroxyproline level in the liver (957+/- 154nmol g(-1)) was about 4.16-times that found in normal liver (230+/-11 nmol g(-1)), but administration of Sho-saiko-to extract (0.75%, 1.5% or 3%) reduced the hydroxyproline level significantly (554+/-58, 356+/-51, 374+/-66nmol g(-1), P<0.01). Single administration of the active constituents of Sho-saiko-to extract, glycyrrhizin, baicalin or baicalein, decreased the hydroxyproline level significantly compared with the ordinary food group (P < 0.05), but the decrease was smaller compared with the Sho-saiko-to extract group. The liver retinoid level was higher in the Sho-saiko-to extract group than the ordinary food group and the value increased dose-dependently. A significant negative correlation, r=-0.814 (P<0.001) was detected between the hydroxyproline level and retinoid level in the liver of liver-injured rats. Significant negative correlations, r =-0.728 (P < 0.001) and r= -0.873 (P < 0.001), were also detected between the liver hydroxyproline level and the liver concentrations of the active constituents (glycyrretic acid, baicalin and baicalein) in the liver-injured rats. From these findings, it was considered that the liver concentrations of hydroxyproline and retinoid as well as the active constituents were involved in the improvement of liver fibrosis in the liver-injured rats administered Sho-saiko-to extract. Administration of Sho-saiko-to extract inhibited collagen production while an increase in retinoid level inhibited activation of Ito cells leading to inhibition and prevention of liver fibrosis.

Effects of sho-saiko-to extract on fibrosis and regeneration of the liver in rats.

Sho-saiko-to, one of the most widely used Chinese herbal preparations, has long been used for the treatment of chronic liver diseases. We have investigated its effect in retarding the process of liver fibrosis and accelerating liver regeneration, especially its effect on Ito cells that are thought to be deeply involved with liver fibrosis. Sho-saiko-to extract and its active constituents were orally administered to rats with dimethylnitrosamine-induced liver-injury. After treatment with sho-saiko-to extract hepatic function improved, histopathological results confirmed repair of liver tissue, and retinoid levels increased. On the other hand, when active constituents of sho-saiko-to extract were administered alone, liver retinoid levels remained low, implying that interaction among active constituents of the extract was suppressing Ito cell activation. When sho-saiko-to extract was administered to 70% hepatectomized normal and liver-injured rats, liver weight, the number of S-phase-cells and retinoid levels increased with time. However, these changes were different for normal and liver-injured rats, suggesting that the site of action of sho-saiko-to extract in regenerating liver is different for normal and liver-injured rats. These results show that sho-saiko-to extract was useful for suppressing the activation of Ito cells.

[Properties of glycyrrhizin in Kampo extracts including licorice root and changes in the blood concentration of glycyrrhetic acid after oral administration of Kampo extracts].

We investigated in vitro the properties of glycyrrhizin (GL), such as dissolution, absorption and resolution, using a Sho-Seiryu-To extract, a Sho-Saiko-To extract, both including a licorice root, and licorice extract. The dissolution of GL differed with the pH of the solvent. The absorption (partition coefficient) of GL decreased with an increase in pH, and increased in the presence of other active constituents, such as baicalin, baicalein, and ephedrine. In the case of the Sho-Saiko-To extract, the conversion from GL to glycyrrhetic acid (GA) by beta-glucuronidase originated from E. coli occurred slowly. It was also suppressed by adding baicalin. We determined in vivo the pharmacokinetics of GA after oral administration of Kampo extracts in healthy volunteers. In each Kampo extract, the time of administration had no influence on the mean maximum blood concentration (Cmax) and the area under the blood concentration-time curve (AUC). Tmax was delayed in the case of the administration after meal (p < 0.05).

Fluoride profiles in different sites of approximal surfaces of second primary molars after topical application of acidulated phosphate fluoride gel in vivo.

Thirty-four (17 paired) extracted second primary molars were obtained from 17 individuals (9 boys and 8 girls) aged from 9 yr 2 months to 12 yr 7 months. A tooth on one side was extracted as a control, and an acidulated phosphate fluoride (APF) gel was then applied to the paired contralateral second primary molar. Three months later, the experimental tooth was extracted. Nine sites were assayed by a microsampling technique from small areas of the approximal enamel surface. The fluoride and phosphorus concentrations were determined by a fluoride electrode and by colorimetric procedure, respectively. Fluoride concentrations were higher in the teeth treated with the APF gel than in the control teeth. The highest fluoride uptake was observed in the central area of the approximal surfaces. Deeper areas (> 10 microns) had a marked uptake of fluoride as compared with surface areas (< 3 microns). It was concluded that the APF gel application increased the fluoride levels of approximal tooth surfaces, particularly the mid-central site, of second primary molars, even at 3 months after application.

The origin of common laboratory mice.

The house mouse is one of the model organisms in genetics and more than 400 inbred strains have been established. However, many of the strains are related and their ancestry can be traced back to European fancy mice inbred in the 1920s. Recent molecular studies corroborate the early historical records that assert that Japanese fancy mice were introduced into European stocks and thus contributed to the development of "old" inbred strains. Consequently, many inbred strains have genomic DNA derived from more than one subspecies of Mus musculus. The subspecific hybrid origin of common inbred strains has important bearings on the interpretation of genetic data, and the limitations that history imposes upon the currently available strains make it necessary to establish new inbred strains representing specific wild populations.

Influence of time of administration of a Shosaiko-to extract granule on blood concentration of its active constituents.

Using a Shosaiko-to extract granule, we investigated the effects of the timing of administration (orally, before and after a meal) on the plasma concentration of its active constituents, glycyrrhizin (GL), baicalin, baicalein and glycyrrhizic acid (GA), a metabolite of GL. The pattern of plasma concentration change of GL differed between the two times of administration, and followed a two-phase pattern when the granules were taken before meals. There was no difference neither in the area under the plasma concentration-time curve (AUC) between the two periods, nor AUC itself. GA showed no difference in plasma concentration pattern, nor was baicalin detected in the plasma following administration by either method. The plasma concentration pattern of baicalein differed between the two timings but followed that of the two-phase pattern in each case. The plasma concentration pattern of active constituents of Shosaiko-to extract granule varied with the time of administration, but there was no significant difference in the maximum plasma concentration or AUC of active constituents depending on the administration. We concluded that the present clinical timing of administration of Shosaiko-to should be determined on the basis of patient compliance and other relevant factors.

Differential stability of host mRNAs in Friend erythroleukemia cells infected with herpes simplex virus type 1.

The consequences of herpes simplex virus type 1 infection on cellular macromolecules were investigated in Friend erythroleukemia cells. The patterns of protein synthesis, examined by polyacrylamide gel electrophoresis, demonstrated that by 4 h postinfection the synthesis of many host proteins, with the exception of histones, was inhibited. Examination of the steady-state level of histone H3 mRNA by molecular hybridization of total RNA to a cloned mouse histone H3 complementary DNA probe demonstrated that the ratio of histone H3 mRNA to total RNA remained unchanged for the first 4 h postinfection. In contrast, the steady-state levels of globin and actin mRNAs decreased progressively at early intervals postinfection. Studies on RNA synthesis in isolated nuclei demonstrated that the transcription of the histone H3 gene was inhibited to approximately the same extent as that of actin gene. We concluded that the stabilization of preexisting histone H3 mRNA was responsible for the persistence of H3 mRNA and histone protein synthesis in herpes simplex virus type 1-infected Friend erythroleukemia cells. The possible mechanisms influencing the differential stability of host mRNAs during the course of productive infection with herpes simplex virus type 1 are discussed.