Combination therapy of bevacizumab with either S-1 and irinotecan or mFOLFOX6/CapeOX as first-line treatment of metastatic colorectal cancer (TRICOLORE): Exploratory analysis of RAS status and primary tumour location in a randomised, open-label, phase III, non-inferiority trial.

AIM: The TRICOLORE trial previously demonstrated that S-1 and irinotecan plus bevacizumab was non-inferior, based on progression-free survival (PFS), to 5-fluorouracil, leucovorin and oxaliplatin (mFOLFOX6)/capecitabine and oxaliplatin (CapeOX) plus bevacizumab as first-line chemotherapy for metastatic colorectal cancer (mCRC). Overall survival (OS) data were immature at the time of the primary analysis. METHODS: In total, 487 patients from 53 institutions with previously untreated mCRC were randomly assigned (1:1) to receive either mFOLFOX6/CapeOX plus bevacizumab (control group) or S-1 and irinotecan plus bevacizumab (experimental group; 3- or 4-week regimen). The final OS data were analysed from follow-up data collected until 30th September 2017. RESULTS: With a median follow-up period of 48.7 months, median survival times were 32.6 and 34.3 months (hazard ratio [HR]: 0.89, 95% confidence interval [CI]: 0.72-1.10, P = 0.293) and median PFS durations were 10.8 and 14.0 months in the control and experimental groups, respectively (HR: 0.86, 95% CI: 0.71-1.04, P < 0.0001 for non-inferiority). In patients with left-sided RAS wild-type tumours, median PFS durations were 11.4 and 16.9 months in the control and experimental groups, respectively (HR: 0.68, 95% CI: 0.48-0.96, P = 0.028). CONCLUSION: S-1 and irinotecan plus bevacizumab resulted in comparable OS and non-inferior PFS with that of mFOLFOX6/CapeOX plus bevacizumab treatment as first-line chemotherapy for patients with mCRC. We recommend the use of S-1 and irinotecan plus bevacizumab as a standard first-line regimen independent of tumour sidedness or RAS status in mCRC. TRIAL REGISTRATION: UMIN-CTR: 000007834.

Cdc42 has important roles in postnatal angiogenesis and vasculature formation.

Cdc42, a Rho family low molecular weight G protein, has important roles in various cell functions, including cytoskeletal rearrangement, cell adhesion and cell proliferation and differentiation. To investigate the involvement of Cdc42 in the activities of vascular endothelial cells, we generated Cdc42 conditional knockout mice in which Cdc42 was time -specifically deficient in vascular endothelial cells (Cdc42 â€‹fl/fl; VE-Cad CreERT: Cdc42 cKO). When the Cdc42 gene was deleted after birth, Cdc42 cKO mice were smaller than the control mice, and died between postnatal day 8 (P8) and P10. Necropsy findings confirmed that these mice had various pathological aberrances in the vessels of most organs, such as blood flow congestion and blood cell invasion. Electron microscopic observations also revealed that capillary endothelial cells were detached from the basement membrane as well as phagocytosis of dead endothelial cells induced by macrophages. Moreover, vascular sprouting from aortic rings induced by VEGF-A was diminished in samples from the Cdc42 cKO mice because of an endothelial cell proliferation defect. These results suggest that Cdc42 in vascular endothelial cells has important roles in blood vessel formation after birth.

Osteoblastic differentiation of bone marrow mesenchymal stem cells in uremic rats.

Severe secondary hyperparathyroidism (SHPT) represents a high turnover bone disease, osteitis fibrosa, but the pathogenesis of osteitis fibrosa remains to be fully elucidated. We examined the characteristics of the differentiation of bone marrow mesenchymal stem cells (BMSCs) into osteoblasts in uremic rats. We bred 5/6 nephrectomized (Nx) rats with a high phosphorus (P) diet to induce SHPT (Nx + HP), or Nx (Nx + ND) and normal rats (Nc + ND) fed a standard diet (ND). After 8 weeks, BMSCs were isolated from the femur and serum were analyzed. BMSCs underwent flow cytometric examination for the expression patterns of cell surface markers (CD90+, CD29+, CD45-, and CD31-). Serum creatinine (Cre) levels were significantly elevated in the Nx + NP rats compared with the Nc + NP rats. Cre levels in the Nx + HP rats were levels to those in the Nx + ND rats. Serum P and PTH levels were significantly elevated in the Nx + HP rats compared with the Nx + ND rats. Bone morphometrical analysis showed increases in both osteoid volume and eroded surfaces in the Nx + HP but not in the Nx + ND rats. The populations of harvested BMSCs were similar between all three groups. Alp, Runx2, Pth1r and Cyclin D1 mRNA expression in the BMSCs from the Nx + ND rats were significantly suppressed compared with those isolated from the Nc + ND groups. Alizarin red staining tended to be similar to the expression of these mRNA. These results suggest that the BMSCs differentiation into osteoblasts was disturbed in the uremic rats.

Cdc42 regulates cranial suture morphogenesis and ossification.

Cdc42 (cell division cycle 42) is ubiquitously expressed small GTPases belonging to the Rho family of proteins. Previously, we generated limb bud mesenchyme-specific Cdc42 inactivated mice (Cdc42 conditional knockout mice; Cdc42 fl/fl; Prx1-Cre), which showed short limbs and cranial bone deformities, though the mechanism related to the cranium phenotype was unclear. In the present study, we investigated the role of Cdc42 in cranial bone development. Our results showed that loss of Cdc42 caused a defect of intramembranous ossification in cranial bone tissues which is related to decreased expressions of cranial suture morphogenesis genes, including Indian hedgehog (Ihh) and bone morphogenetic proteins (BMPs). These findings demonstrate that Cdc42 plays a crucial role in cranial osteogenesis, and is controlled by Ihh- and BMP-mediated signaling during cranium development.

Nephronectin Expression is Inhibited by Inorganic Phosphate in Osteoblasts.

Nephronectin (Npnt), an extracellular matrix protein, is known to be a ligand of integrin α8ß1, and it has also been known to play critical roles as various organs. In the present study, elevated extracellular inorganic phosphate (Pi) strongly inhibited the expression of Npnt in MC3T3-E1 cells, while the existence of extracellular calcium (Ca) was indispensable for its effect. Furthermore, Pi-induced inhibition of Npnt gene expression was recovered by inhibitors of both sodium-dependent Pi transporter (Pit) and fibroblast growth factor receptors (Fgfrs). These results demonstrated that Npnt gene expression is regulated by extracellular Pi via Pit and Fgfrs.

FGF-2 suppresses expression of nephronectin via JNK and PI3K pathways.

Nephronectin (Npnt), an extracellular matrix protein, is a ligand for integrin α8ß1 and is involved in the development of various organs, such as the kidneys, bones, liver, and muscles. Previously, we found that Npnt expression was inhibited by various cytokines including transforming growth factor-ß (Tgf-ß) and oncostatin M (Osm). Fibroblast growth factor (Fgf)-2, otherwise known as basic Fgf, also plays important roles in skeletal development and postnatal osteogenesis. In this study, Npnt expression was found to be suppressed by Fgf-2 in MC3T3-E1 cells, an osteoblast-like cell line, in a dose- and time-dependent manners. Furthermore, Fgf-2-mediated Npnt mRNA suppression was shown to involve the Jun N-terminal kinase (JNK) and phosphoinositide-3 kinase (PI3K) pathways. Together, our results suggest that FGF-2 suppresses Npnt gene expression via JNK and PI3K pathways.

Cooperation of Rho family proteins Rac1 and Cdc42 in cartilage development and calcified tissue formation.

Rac1 and Cdc42, Rho family low molecular weight G proteins, are intracellular signaling factors that transmit various information from outside to inside cells. Primarily, they are known to control various biological activities mediated by actin cytoskeleton reorganization, such as cell proliferation, differentiation, and apoptosis. In order to investigate the functions of Rac1 and Cdc42 in bone formation, we prepared cartilage-specific double conditional knockout mice, Rac1fl/fl; Cdc42fl/fl; Col2-Cre (Rac1: Cdc42 dcKO mice), which died just after birth, similar to Cdc42fl/fl; Col2-Cre mice (Cdc42 cKO mice). Our findings showed that the long tubule bone in Rac1: Cdc42 dcKO mice was shorter than that in Rac1fl/fl; Col2-Cre mice (Rac1 cKO mice) and Cdc42 cKO mice. Abnormal skeleton formation was also observed and disordered columnar formation in the growth plate of the Rac1: Cdc42 dcKO mice was more severe as compared to the Rac1 cKO and Cdc42 cKO mice. Together, these results suggest that Rac1 and Cdc42 have cooperating roles in regulation of bone development.

IL-1ß suppresses nephronectin expression in osteoblasts via ERK1/2 and JNK.

Nephronectin (Npnt), an extracellular matrix protein, is considered to play critical roles in development of various tissues and their functions. In basic science experiments, we found that interleukin-1ß (IL-1ß), well known to have an important role in inflammatory response, inhibited Npnt gene expression in MC3T3-E1 cells, a mouse osteoblastic cell line. The purpose of this study was to investigate mechanisms that govern the regulation of Npnt gene expression by IL-1ß in osteoblasts.

[5-FU/l-LV therapy is useful for hemodialysis patients with advanced gastric cancer].

A 71-year-old man receiving maintenance dialysis because of diabetic nephropathy presented with hematemesis at another hospital in January 2008. A gastrointestinal endoscopy demonstrated a II a-like lesion in the angle of the stomach, and he was admitted to our hospital. A diagnosis of gastric adenocarcinoma (cT2N2M0, Stage IIIA) was made. An operation could not be performed because of the high risk, so combination chemotherapy with 5-FU and l-LV was initiated. After 3 courses of treatment, the size of the primary tumor was markedly reduced. After 6 courses, the primary lesion had changed to a scar, and an endoscopic biopsy revealed no cancer cells. His performance status did not deteriorate, and no serious adverse events occurred during the course of treatment. Chemotherapy was continued because the overall response was SD. 5-FU/l-LV therapy should be considered as a safe and useful treatment for a hemodialysis patient with advanced gastric cancer.

A new laser ablation system for quantitative analysis of solid samples with ICP-MS.

The laser ablation (LA) method is an effective technique for quantitative analysis. In the present work, a new LA system was developed for the high-sensitivity analysis of metal materials using inductively coupled plasma mass spectrometry (ICP-MS). This system consists of a high-frequency Q-switched laser and 2 scanning mirrors for scanning the ablation spot in an adequately large area of the specimen without vacant spaces. The influence of elemental fractionation (non-stoichiometric generation of vapor species) can be eliminated by repetitive irradiation of this pattern on the same area. Particles generated with an average laser power of 0.6 W with the developed LA system gave intensity and stability substantially similar to that of a 500 microg/ml solution steel sample in solution ICP-MS. The analytical performance of the developed LA-ICP-MS was compared with that of a solution ICP-MS using NIST steel SRMs. The performance of the newly-developed system is comparable to that of conventional solution ICP-MS in both accuracy and precision. The correlation coefficients between the contents and the intensity ratios to Fe were over 0.99 for most elements. The relative standard deviation (RSD) obtained by LA-ICP-MS revealed that this system can analyze iron samples with good precision. The results of ultra trace level analysis of high-purity iron showed that developed LA-ICP-MS is capable of analyzing ppm concentration levels with a 20 - 30 ppb level standard deviation. The detection limit was on the order of 10 ppb for most elements.

[Hypersensitivity reactions to cancer chemotherapeutic agents].

Although hypersensitivity reactions to the anticancer drug are rare, since the reactions occasionally are clinical problems enough, that measure is important. The backgrounds (the etiologic mechanisms, the frequency, and etc) differ by each, therefore the knowledge for each medicine is required for measures including prediction and the prevention. This paper reviews the sensitivity reactions of various anticancer drugs (especially, paclitaxel, cisplatin and carboplatin) also including the molecular targeting drugs (trastuzumab, rituximab).

Clinical and genetic characteristics of Japanese Burkitt lymphomas with or without leukemic presentation.

To clarify the clinical and genetic features of Burkitt lymphoma with or without leukemic presentation, we have conducted clinical, cytogenetic, and genetic studies. Of 40 Japanese patients with Burkitt lymphoma examined by cytogenetic and/or fluorescence in situ hybridization analysis or Southern blot analysis using MYC probes, 35 patients had t(8;14) translocations, and 5 had t(8;22). Breakpoints were located far upstream of MYC in 4 (12%) of 33 tumors with t(8;14), and Epstein-Barr virus infection was found in 3 (8%) of 40 tumors. These findings are similar to those reported for non-Japanese patients with the sporadic form of Burkitt lymphoma. Clinical and genetic characteristic were compared for 30 patients presenting with lymphoma and 10 presenting with leukemia. The overall survival was shorter in aggressively treated leukemia patients than in aggressively treated lymphoma patients (P = .003); however, the incidence rates of TP53 mutation, p16INK4a deletion, and p15INK4b deletion that were found in 6 (15%) of 40,3 (9%) of 35, and 2 (6%) of 35 tumors, respectively, were similar between the 2 subtypes. Thus, the present study has shown the different prognoses for the 2 subtypes of Burkitt lymphoma but has failed to clarify the genetic backgrounds that may explain the different outcomes.

[Mucositis].

Mucositis is a significant dose-limiting factor associated with cancer chemotherapy and radiotherapy. For exact management, an early diagnosis and precise evaluation are surely required. A basis of the prevention and care of stomatitis is maintaining cleanliness and moisture in the mouth. The medical treatment plans of oral mucositis are a measure against infection, and prevention against symptoms, and are restoration of a tissue damage, and treatment to sharp pain. However, there is no still established prevention method. As for the present condition, in the clinical practice, there are many portions depending on experiential knowledge. In this paper, it outlined including Empiric therapy about measures of oral mucositis.