Bevacizumab plus Irinotecan,Fluorouracil,and Leucovorin for Metastatic Colorectal Cancer

結腸癌術後の早期離床・早期経口摂取に関するProspective Randomized Trial

Chemotherapy is the main strategy for the treatment of cancer. However, the main problem limiting the success of chemotherapy is the development of multidrug resistance. The resistance can be intrinsic or acquired. The resistance phenotype is associated with the tumor cells that gain a cross-resistance to a large range of drugs that are structurally and functionally different. Multidrug resistance arises via many unrelated mechanisms, such as overexpression of energy-dependent efflux proteins, decrease in uptake of the agents, increase or alteration in drug targets, modification of cell cycle checkpoints, inactivation of the agents, compartmentalization of the agents, inhibition of apoptosis and aberrant bioactive sphingolipid metabolism. Exact elucidation of resistance mechanisms and molecular and biochemical approaches to overcome multidrug resistance have been a major goal in cancer research. This review comprises the mechanisms guiding multidrug resistance in cancer chemotherapy and also touches on approaches for reversing the resistance.

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Molecular mechanisms of drug resistance and its reversal in cancer

Dendritic cell-derived exosomes elicit tumor regression in autochthonous hepatocellular carcinoma mouse models

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.28549

Tumor-derived exosomes elicit tumor suppression in murine hepatocellular carcinoma models and humans in vitro.

Hepatocellular carcinoma (HCC) is one of the most common malignancies, with an increasing incidence. With advances in surgical techniques and instrumentation and the development of molecular-target drugs, a number of potentially curative treatments have become available. Management of HCC patients depends on the stage of their tumor. Liver resection remains the first choice for very early-stage HCC, but it is being challenged by local ablative therapy. For early-stage HCC that meet the Milan criteria, liver transplantation still offers a better outcome; however, local ablative therapy can be a substitute when transplantation is not feasible. Local ablation is also used as a bridging therapy toward liver transplantation. HCC recurrence is the main obstacle to successful treatment, and there is currently no effective means of preventing or treating HCC recurrence. Transarterial therapy is considered suitable for intermediate-stage HCC, while sorafenib is recommended for advanced-stage HCC. This stage-based approach to therapy not only provides acceptable outcomes but also improves the quality of life of HCC patients. Because of the complexity of HCC, therapeutic approaches must be adapted according to the characteristics of each individual patient. This review discusses the current standards and trends in the treatment of HCC.

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Treatment of hepatocellular carcinoma: a systematic review.

Everolimus is an orally administrated mammalian target of rapamycin (mTOR) inhibitor Several large-scale randomized controlled trials (RCTs) have demonstrated the survival benefits of everolimus at the dose of 10 mg/day for solid cancers Furthermore, mTOR-inhibitor-based immunosuppression is associated with survival benefits for patients with hepatocellular carcinoma (HCC) who have received liver transplantation However, a low rate of tumor reduction and some adverse events have been pointed out This review summarizes the antitumor effects and adverse events of everolimus and evaluates its possible application in advanced HCC For the meta-analysis of adverse events, we used the RCTs for solid cancers The odds ratios of adverse events were calculated using the Peto method Manypreclinical studies demonstrated that everolimus had antitumor effects such as antiproliferation and antiangiogenesis However, some differences in the effects were observed among in vivo animal studies for HCC treatment Meanwhile, clinical studies demonstrated that the response rate of single-agent everolimus was low, though survival benefits could be expected The meta-analysis revealed the odds ratios (95% confidence interval [CI]) of stomatitis: 542 [431–673], hyperglycemia: 322 [237–439], anemia: 334 [237–467], pneumonitis: 602 [395–916], aspartate aminotransferase levels: 222 [137–362], and serum alanine aminotransferase levels: 294 [172–502], respectively Everolimus at the dose of 10 mg/day significantly increased the risk of the adverse events In order to enable its application to the standard conventional therapies of HCC, further studies are required to enhance the antitumor effects and manage the adverse events of everolimus

https://www.onlinelibrary.wiley.com/doi/pdf/10.1002/cam4.150

Therapeutic potential and adverse events of everolimus for treatment of hepatocellular carcinoma – systematic review and meta‐analysis

Hepatocellular carcinoma (HCC) exhibits strong intrinsic and acquired drug resistance which is the main obstacle to chemotherapy. Overexpression of ATP binding cassette (ABC) proteins correlates with activation of mitogen activated protein kinase (MAPK) pathway in HCC. Here, we systematically investigated the inhibition of MAPK pathway and its role in regulating HCC cell growth as well as ABC proteins MRP1 and MRP3 expression. The Raf1 kinase inhibitor (GW5074) and different MEK inhibitors (U0126 and AZD6244) were used to treat HCC cells to identify their effects on HCC cell growth and ABC proteins expression in vitro. Cell viability tests were performed after the treatment of MAPK pathway inhibitors and in combination with gemcitabine or doxorubicin. Western blot was applied to assess the changes of MAPK pathway and protein expression of MRP1 and MRP3. Flow cytometry was used to measure intracellular doxorubicin accumulation after the treatment of MEK inhibitors. Both Raf1 inhibitor (GW5074) and MEK inhibitors (U0126 and AZD6244) suppressed HCC cell growth in a dose dependent manner. Pre-treatment of MEK inhibitor U0126 or AZD6244 sensitized HCC cells to gemcitabine or doxorubicin based chemotherapy. Raf1 inhibitor GW5074 had no effect on MRP1 and MRP3 protein expression. Treatment of gemcitabine or doxorubicin activated phosphorylated ERK and induced the upregulation of MRP1 and MRP3. MEK inhibitors U0126 and AZD6244 deactivated phosphorylated ERK, decreased endogenous MRP1 expression, reversed gemcitabine or doxorubicin induced MRP1 and MRP3 upregulation, and increased the intracellular doxorubicin accumulation. This study provides evidence that MEK inhibitors sensitize HCC cells to chemotherapy by increasing intracellular chemodrug accumulation. MEK inhibirors U0126 and AZD6244 reduced MRP1 as well as MRP3 expression, and may contribute partially to the sensitization. The combination of MEK inhibitor and conventional chemotherapy may offer new therapeutic option for the treatment of resistant HCC.

/pdf/mek-inhibition-induced-downregulation-of-mrp1-and-mrp3-dql07qka6g.pdf

MEK inhibition induced downregulation of MRP1 and MRP3 expression in experimental hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a highly vascularized tumor with limited susceptibility to chemotherapy. Modern targeted therapies are aimed at specific properties of this neoplasm. Glycine is a simple non-essential amino acid with potential antiangiogenic effects. In this study, the amino acid’s effect on angiogenic signaling in an in vitro model of HCC was evaluated. HepG2 and Huh7 cells were treated with glycine-free DMEM supplemented with 0, 0.01, 0.1, 1.0, 2.0, 5.0 and 10 mM glycine. The direct effects of glycine on the viability of HCC cells were monitored using MTT assay. To detect angiogenic signaling, mRNA and protein levels of vascular endothelial growth factor (VEGF-A) were measured using RT-PCR and Western Blot assays. To determine whether or not glycine receptors (GlyR) played a significant role, the specific antagonist, strychnine, was used as a direct inhibitor. Western Blotting was performed to show the presence of GlyR. While there was no direct pro- or antiproliferative effect of either glycine or strychnine in both cell lines, glycine was shown to significantly decrease VEGF-A expression on mRNA and protein level up to 63 % in both cell lines. This effect was blunted by the presence of strychnine. GlyR was also identified in both cell lines. Glycine decreases GlyR-dependent, VEGF-A-mediated, angiogenic signaling in human HCC and thus might be a promising additive to chemotherapy treatment strategies for highly vascularized tumors.

Glycine inhibits angiogenic signaling in human hepatocellular carcinoma cells

Pancreatic surgery, especially pancreaticoduodenectomy, requires the resection and reconstruction of multiple organs which is a technical challenge. Fine surgical techniques are warranted to reach the R0 resection and reduce morbidity and mortality. However, due to the complicated anatomy and surgical procedure, the postoperative complication of pancreatic resection remains high. Thus, current techniques for pancreatic surgery still need to be optimized to increase the resectability and decrease the postoperative complication. This article intends to provide an overview of techniques for pancreatic surgery.

/pdf/review-of-techniques-for-pancreatic-surgery-59up7uym39.pdf

Shibo Lin

Papers

Treatment of hepatocellular carcinoma: a systematic review.

Therapeutic potential and adverse events of everolimus for treatment of hepatocellular carcinoma – systematic review and meta‐analysis

MEK inhibition induced downregulation of MRP1 and MRP3 expression in experimental hepatocellular carcinoma

Glycine inhibits angiogenic signaling in human hepatocellular carcinoma cells

Review of Techniques for Pancreatic Surgery