Yoshiyuki Yamaguchi

Randomized phase III trial of treatment duration for oral uracil and tegafur plus leucovorin as adjuvant chemotherapy for patients with stage IIB/III colon cancer: final results of JFMC33-0502

While adjuvant chemotherapy is preferable for colon cancer, treatment duration is controversial. This phase III trial is investigated optimal duration of adjuvant chemotherapy for Stage IIB/III colon cancer. Eighteen-month treatment with UFT/LV did not improve DFS compared with 6-month UFT/LV treatment. This study suggests that 6 months treatment duration is enough for Stage IIB/III colon cancer.

Contrasting Effects of the Cytotoxic Anticancer Drug Gemcitabine and the EGFR Tyrosine Kinase Inhibitor Gefitinib on NK Cell-Mediated Cytotoxicity via Regulation of NKG2D Ligand in Non-Small-Cell Lung Cancer Cells

Introduction Several cytotoxic anticancer drugs inhibit DNA replication and/or mitosis, while EGFR tyrosine kinase inhibitors inactivate EGFR signalling in cancer cell. Both types of anticancer drugs improve the overall survival of the patients with non-small-cell lung cancer (NSCLC), although tumors often become refractory to this treatment. Despite several mechanisms by which the tumors become resistant having been described the effect of these compounds on anti-tumor immunity remains largely unknown. Methods This study examines the effect of the cytotoxic drug Gemcitabine and the EGFR tyrosine kinase inhibitor Gefitinib on the expression of NK group 2 member D (NKG2D) ligands as well as the sensitivity of NSCLC cells to the NK-mediated lysis. Results We demonstrate that Gemcitabine treatment leads to an enhanced expression, while Gefitinib downregulated the expression of molecules that act as key ligands for the activating receptor NKG2D and promote NK cell-mediated recognition and cytolysis. Gemcitabine activated ATM and ATM- and Rad-3-related protein kinase (ATR) pathways. The Gemcitabine-induced phosphorylation of ATM as well as the upregulation of the NKG2D ligand expression could be blocked by an ATM-ATR inhibitor. In contrast, Gefitinib attenuated NKG2D ligand expression. Silencing EGFR using siRNA or addition of the PI3K inhibitor resulted in downregulation of NKG2D ligands. The observations suggest that the EGFR/PI3K pathway also regulates the expression of NKG2D ligands. Additionally, we showed that both ATM-ATR and EGFR regulate MICA/B via miR20a. Conclusion In keeping with the effect on NKG2D expression, Gemcitabine enhanced NK cell-mediated cytotoxicity while Gefitinib attenuated NK cell killing in NSCLC cells.

Regulating surgical oncotaxis to improve the outcomes in cancer patients

Excessive surgical stress and postoperative complications cause a storm of perioperative cytokine release, which has been shown to enhance tumor metastasis in experimental models. We have named this phenomenon “surgical oncotaxis”. The mechanisms that underpin this process are thought to be excessive corticosteroid secretion, coagulopathy in the peripheral vasculature, immune suppression and excessive production of reactive oxygen species. Nuclear factor-kappa B (NFkB) activation plays a key role in these mechanisms. Minimally invasive surgical techniques should be used, and postoperative complications should be avoided whenever possible to lessen the impact of surgical oncotaxis. Furthermore, there may be a role for a small preoperative dose of corticosteroid or the use of free radical scavengers in the perioperative period. Recently, there has been a great deal of interest in omega-3 fatty acid, because it regulates NFkB activation. The use of multimodal treatments that regulate surgical oncotaxis may be as important as chemotherapy for determining the outcome of patients with cancer undergoing surgery.

Protocol of a randomised phase III clinical trial of sequential capecitabine or 5-fluorouracil plus bevacizumab (Cape/5-FU-Bmab) to capecitabine or 5-fluorouracil plus oxaliplatin plus bevacizumab (CapeOX/mFOLFOX6-Bmab) versus combination CapeOX/mFOLFOX6-Bmab in advanced colorectal cancer: the C-cubed (C3) study

Introduction Results from several randomised trials suggest that the sequential use of cytotoxic agents in patients with metastatic colorectal cancer (mCRC) has the potential to improve overall survival compared with combination chemotherapy. This study is designed to investigate whether sequential treatment with bevacizumab-based first-line treatment with oxaliplatin is superior to combination treatment of mCRC. Methods and analysis The C-cubed (C3) study is a two-arm, multicentre, open-label, randomised phase III trial in Japan comparing the efficacy and safety of sequential capecitabine or 5-fluorouracil plus bevacizumab (Cape/5-FU-Bmab) with escalation to capecitabine or 5-fluorouracil plus oxaliplatin plus bevacizumab (CapeOX/mFOLFOX6-Bmab) versus combination CapeOX/mFOLFOX6-Bmab as the first-line treatment of mCRC. In the sequential arm (Arm A: oxaliplatin ‘wait-and-go’), treatment escalation from Cape/5-FU-Bmab to CapeOX/mFOLFOX6-Bmab is recommended in the case of progressive disease. In the combination arm (Arm B: oxaliplatin ‘stop-and-go’), de-escalation from CapeOX/mFOLFOX6-Bmab to Cape/5-FU-Bmab is possible after 12 weeks of treatment. Re-escalation to CapeOX/mFOLFOX6-Bmab after progressive disease is considered only for patients who received de-escalation of oxaliplatin after 12 weeks of treatment not caused by oxaliplatin-associated toxicity. A target sample size of 304 evaluable patients is considered sufficient to validate an expected HR for time to failure of strategy of the sequential approach ‘wait-and-go’ compared to the combination approach ‘stop-and go’ with 80% power and 2-sided 5% α in case of a true HR<0.69. Ethics and dissemination This study is conducted according to the standards of Good Clinical Practice and in compliance with the Declaration of Helsinki 2013 and local regulations, and has been submitted and approved by the Ethical Committee of the Non-Profit Organization MINS Institutional Review Board. The protocol and the trial results, even inconclusive, will be presented at international oncology congresses and published in peer-reviewed journals. Trial registration number UMIN000015405, Pre-results.

Guidance for peptide vaccines for the treatment of cancer

Recent progress in fundamental understanding of tumor immunology has opened a new avenue of cancer vaccines. Currently, the development of new cancer vaccines is a global topic and has attracted attention as one of the most important issues in Japan. There is an urgent need for the development of guidance for cancer vaccine clinical studies in order to lead to drug development. Peptide vaccines characteristically have the effect of indirectly acting against cancer through the immune system – a mechanism of action that clearly differs from anticancer drugs that exert a direct effect. Thus, the clinical development of cancer peptide vaccines should be planned and implemented based on the mechanism of action, which differs significantly from conventional anticancer drug research. The Japanese Society for Biological Therapy has created and published Guidance for peptide vaccines for the treatment of cancer as part of its mission and responsibilities towards cancer peptide vaccine development, which is now pursued globally. We welcome comments from regulators and business people as well as researchers in this area.

Current status of immunotherapy against gastrointestinal cancers and its biomarkers: Perspective for precision immunotherapy

Immunotherapy has shown encouraging results for some types of tumor. Although enormous efforts have been made toward the development of specific immunotherapeutic strategies against gastrointestinal cancers, such as adoptive T‐cell transfer, peptide vaccines, or dendritic cell vaccines, the efficacy of immunotherapies prior to the introduction of immune checkpoint inhibitors was not substantial. This article reviews immunotherapy for gastrointestinal malignancies, including cell therapy, peptide vaccine, and immune checkpoint inhibitors, and attempts to resolve the immunosuppressive conditions surrounding the tumor microenvironment, and to construct novel combination immunotherapies beyond immune checkpoint inhibitors.

Clinical outcomes of women with ovarian metastases of colorectal cancer treated with oophorectomy with respect to their somatic mutation profiles

We clarified the clinical prevalence of ovarian metastases from colorectal cancers (CRCs) in 296 female patients with CRC and evaluated clinical outcomes with relation to their mutational profiles, such as BRAF/KRAS mutation and microsatellite instability (MSI) status. The female CRCs were categorised into three subsets: CRCs with ovarian metastases [6.4% (n = 19), 5-year overall survival (OS) = 24.7%], CRCs with extra-ovarian metastases only [32.4% (n = 96), 5-year OS = 34.5%] and CRCs without any recurrence or metastasis [61.2% (n = 181), 5-year OS = 91.3%]. All patients with ovarian metastases underwent oophorectomy; of these, 9 who received preoperative chemotherapy had measurable metastases to extra-ovarian sites and the ovaries. Although 5 of 9 (56%) achieved partial response or complete response at extra-ovarian sites, no patient archived objective response at ovarian sites. Regarding the mutation profiles, in CRCs with extra-ovarian metastases only, the median survival time (MST) after initial treatments to progression to stage IV or recurrence was 13 [95% confidence interval (CI): 7–16 months] in BRAF-mutant and 34 months (95% CI: 22–58 months) in BRAF wild-type (P = 0.0033). Although ovarian metastases demonstrated poor response to systemic chemotherapy in CRCs with ovarian metastases, the MST after initial treatments to progression to stage IV or recurrence was 22 (95% CI: 21–25 months) in BRAF-mutant and 38 months (95% CI: 24–42 months) in BRAF wild-type (P = 0.0398). The outcomes of patients with ovarian metastases could be improved by oophorectomy regardless of their mutation profiles.

Heterogeneity of Epigenetic and Epithelial Mesenchymal Transition Marks in Hepatocellular Carcinoma with Keratin 19 Proficiency

Objective: Keratin 19 (K19) expression is a potential predictor of poor prognosis in patients with hepatocellular carcinoma (HCC). To clarify the feature of K19-proficient HCC, we traced epigenetic footprints in cultured cells and clinical materials. Patients and Methods: In vitro, KRT19 promoter methylation was analyzed and 5-aza-2’-deoxycytidine with trichostatin A (TSA) treatment was performed. Among 564 surgically resected HCCs, the clinicopathological relevance of K19-proficent HCCs was performed in comparison with hepatocytic (HepPar-1 and arginase-1), epithelial-mesenchymal transition (E-cadherin and vimentin), biliary differentiation-associated (K7 and NOTCH-1) markers, and epigenetic markers (KRT19 promoter/long interspersed nucleotide element-1 [LINE-1] methylation status). Results: KRT19 promoter methylation was clearly associated with K19 deficiency and 5-aza-2’-deoxycytidine with TSA treatment-stimulated K19 re-expression, implicating DNA methylation as a potential epigenetic process for K19 expression. After excluding HCCs with recurrence, TNM stage as IIIB or greater, preoperative therapy, transplantation, and combined hepatocellular cholangiocarcinoma, we assessed 125 of 564 HCC cases. In this cohort, K19 expression was found in 29 HCCs (23.2%) and corresponded with poor survival following surgery (p = 0.025) and extrahepatic recurrence-free survival (p = 0.017). Compared with K19-deficient HCCs, lower KRT19 promoter methylation level was observed in K19-proficient HCCs (p < 0.0001). Conversely, HCC with genome-wide LINE-1 hypermethylation was frequently observed in K19-proficient HCCs (p = 0.0079). Additionally, K19 proficiency was associated with K7 proficiency (p = 0.043), and reduced E-cadherin and HepPar-1 expression (p = 0.043 and p < 0.0001, respectively). Conclusions: K19-proficient HCC exhibited poor prognosis owing to extrahepatic recurrence, with molecular signatures differing from those in conventional cancer stem cells, providing novel insights of the heterogeneity underlying tumor development.

Overview of Current Cancer Immunotherapy

Immunotherapy has been investigated worldwide as the fourth cancer treatment modality, following the standard modalities of surgery, chemotherapy, and radiotherapy. Recently, the significant progress in our fundamental understanding of tumor immunology and the recent clinical advances in cancer immunotherapy trials have opened new avenues of cancer immunotherapy. At last, cancer immunotherapy has come of age, now. There is no longer any doubt that the immune system does work in tumor eradication. In this chapter, the progress made in cancer immunotherapy during the past half-century and the many types of cancer immunotherapy are summarized. A brief review of important nomenclature in tumor immunology is also provided, which may further facilitate the reader’s understanding of the later chapters. Moreover, a future perspective for cancer immunotherapy development is discussed. Finally, I would say now that one lymphocyte, one dendritic cell, one antigen, and one drug can change the cancer treatment, immunotherapy, together.

Abstract 1757: The new molecular target therapy of Hsp90 inhibition in esophageal squamous cell carcinoma

Heat shock protein 90 (HSP90) has numerous cellular functions, including promotion of proper protein folding, and stabilizes a number of oncogenic proteins, many of which are overexpressed in cancers. The objective of this study is to evaluate an antitumor effect of HSP90 inhibitor, AUY922, in esophageal squamous cell carcinoma(ESCC) cell lines. ESCC cell lines were treated with AUY922 to examine the effect on proliferation assay, apoptosis assay, Western blotting, and chemotaxis assay. AUY922 inhibited cell proliferation in ESCC cells in a dose- and time-dependent manner. Growth inhibitory effect of AUY922 for ESCC cells was higher than CDDP. With flowcytometry and immunostaining, we showed that AUY922 induced apoptosis in ESCC cells and inhibited chemotaxis of ESCC cells. These antitumor effects of AUY922 were due to inhibition of cell proliferation through suppression of phosphorylation of the client proteins. The HSP90 inhibitor is useful as an antitumor drug in ESCC by inhibiting proliferation of ESCC cells through novel mechanism. Citation Format: Masahiro Yamamura, Tsutomu Nohno, Akira Yamauchi, Naoki Katase, Makoto Okawaki, Akira Sawaki, Hideo Matsumoto, Toshihiro Hirai, Yoshiyuki Yamaguchi. The new molecular target therapy of Hsp90 inhibition in esophageal squamous cell carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1757. doi:10.1158/1538-7445.AM2015-1757