Person: Hamada, Tsuyoshi
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Hamada
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Tsuyoshi
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Hamada, Tsuyoshi
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Publication Fusobacterium nucleatum in Colorectal Carcinoma Tissue According to Tumor Location(Nature Publishing Group, 2016) Mima, Kosuke; Cao, Yin; Chan, Andrew; Qian, Zhi Rong; Nowak, Jonathan; Masugi, Yohei; Shi, Yan; Song, Mingyang; da Silva, Annacarolina; Gu, Mancang; Li, Wanwan; Hamada, Tsuyoshi; Kosumi, Keisuke; Hanyuda, Akiko; Liu, Li; Kostic, Aleksandar; Giannakis, Marios; Bullman, Susan; Brennan, Caitlin; Milner, Danny; Baba, Hideo; Garraway, Levi; Meyerhardt, Jeffrey; Garrett, Wendy; Huttenhower, Curtis; Meyerson, Matthew; Giovannucci, Edward; Fuchs, Charles; Nakashima, Reiko; Ogino, ShujiObjectives: Evidence suggests a possible role of Fusobacterium nucleatum in colorectal carcinogenesis, especially in right-sided proximal colorectum. Considering a change in bowel contents and microbiome from proximal to distal colorectal segments, we hypothesized that the proportion of colorectal carcinoma enriched with F. nucleatum might gradually increase along the bowel subsites from rectum to cecum. Methods: A retrospective, cross-sectional analysis was conducted on 1,102 colon and rectal carcinomas in molecular pathological epidemiology databases of the Nurses’ Health Study and the Health Professionals Follow-up Study. We measured the amount of F. nucleatum DNA in colorectal tumor tissue using a quantitative PCR assay and equally dichotomized F. nucleatum-positive cases (high vs. low). We used multivariable logistic regression analysis to examine the relationship of a bowel subsite variable (rectum, rectosigmoid junction, sigmoid colon, descending colon, splenic flexure, transverse colon, hepatic flexure, ascending colon, and cecum) with the amount of F. nucleatum. Results: The proportion of F. nucleatum-high colorectal cancers gradually increased from rectal cancers (2.5% 4/157) to cecal cancers (11% 19/178), with a statistically significant linear trend along all subsites (P<0.0001) and little evidence of non-linearity. The proportion of F. nucleatum-low cancers was higher in rectal, ascending colon, and cecal cancers than in cancers of middle segments. Conclusions: The proportion of F. nucleatum-high colorectal cancers gradually increases from rectum to cecum. Our data support the colorectal continuum model that reflects pathogenic influences of the gut microbiota on neoplastic and immune cells and challenges the prevailing two-colon (proximal vs. distal) dichotomy paradigm.Publication Tumor LINE-1 methylation level and colorectal cancer location in relation to patient survival(Impact Journals LLC, 2016) Mima, Kosuke; Nowak, Jonathan; Qian, Zhi Rong; Cao, Yin; Song, Mingyang; Masugi, Yohei; Shi, Yan; da Silva, Annacarolina; Gu, Mancang; Li, Wanwan; Hamada, Tsuyoshi; Zhang, Xuehong; Wu, Kana; Meyerhardt, Jeffrey; Baba, Hideo; Giovannucci, Edward; Chan, Andrew; Fuchs, Charles; Ogino, Shuji; Nakashima, ReikoColorectal tumors arise with genomic and epigenomic alterations through interactions between neoplastic cells, immune cells, and microbiota that vary along the proximal to distal axis of colorectum. Long interspersed nucleotide element-1 (LINE-1) hypomethylation in colorectal cancer has been associated with worse clinical outcome. Utilizing 1,317 colon and rectal carcinoma cases in two U.S.-nationwide prospective cohort studies, we examined patient survival according to LINE-1 methylation level stratified by tumor location. Cox proportional hazards model was used to assess a statistical interaction between LINE-1 methylation level and tumor location in colorectal cancer-specific mortality analysis, controlling for potential confounders including microsatellite instability, CpG island methylator phenotype, and KRAS, BRAF, and PIK3CA mutations. A statistically significant interaction was found between LINE-1 methylation level and tumor location in colorectal cancer-specific mortality analysis (Pinteraction = 0.011). The association of LINE-1 hypomethylation with higher colorectal cancer-specific mortality was stronger in proximal colon cancers (multivariable hazard ratio [HR], 1.66; 95% confidence interval [CI], 1.21 to 2.28) than in distal colon cancers (multivariable HR, 1.18; 95% CI, 0.81 to 1.72) or rectal cancers (multivariable HR, 0.87; 95% CI, 0.57 to 1.34). Our data suggest the interactive effect of LINE-1 methylation level and colorectal cancer location on clinical outcome.Publication PIK3CA mutation and colorectal cancer precision medicine(Impact Journals LLC, 2017) Hamada, Tsuyoshi; Nowak, Jonathan; Ogino, ShujiPublication Biomarker correlation network in colorectal carcinoma by tumor anatomic location(BioMed Central, 2017) Nakashima, Reiko; Glass, Kimberly; Mima, Kosuke; Hamada, Tsuyoshi; Nowak, Jonathan; Qian, Zhi Rong; Kraft, Phillip; Giovannucci, Edward; Fuchs, Charles; Chan, Andrew; Quackenbush, John; Ogino, Shuji; Onnela, Jukka-PekkaBackground: Colorectal carcinoma evolves through a multitude of molecular events including somatic mutations, epigenetic alterations, and aberrant protein expression, influenced by host immune reactions. One way to interrogate the complex carcinogenic process and interactions between aberrant events is to model a biomarker correlation network. Such a network analysis integrates multidimensional tumor biomarker data to identify key molecular events and pathways that are central to an underlying biological process. Due to embryological, physiological, and microbial differences, proximal and distal colorectal cancers have distinct sets of molecular pathological signatures. Given these differences, we hypothesized that a biomarker correlation network might vary by tumor location. Results: We performed network analyses of 54 biomarkers, including major mutational events, microsatellite instability (MSI), epigenetic features, protein expression status, and immune reactions using data from 1380 colorectal cancer cases: 690 cases with proximal colon cancer and 690 cases with distal colorectal cancer matched by age and sex. Edges were defined by statistically significant correlations between biomarkers using Spearman correlation analyses. We found that the proximal colon cancer network formed a denser network (total number of edges, n = 173) than the distal colorectal cancer network (n = 95) (P < 0.0001 in permutation tests). The value of the average clustering coefficient was 0.50 in the proximal colon cancer network and 0.30 in the distal colorectal cancer network, indicating the greater clustering tendency of the proximal colon cancer network. In particular, MSI was a key hub, highly connected with other biomarkers in proximal colon cancer, but not in distal colorectal cancer. Among patients with non-MSI-high cancer, BRAF mutation status emerged as a distinct marker with higher connectivity in the network of proximal colon cancer, but not in distal colorectal cancer. Conclusion: In proximal colon cancer, tumor biomarkers tended to be correlated with each other, and MSI and BRAF mutation functioned as key molecular characteristics during the carcinogenesis. Our findings highlight the importance of considering multiple correlated pathways for therapeutic targets especially in proximal colon cancer. Electronic supplementary material The online version of this article (doi:10.1186/s12859-017-1718-5) contains supplementary material, which is available to authorized users.Publication Aspirin exerts high anti-cancer activity in PIK3CA-mutant colon cancer cells(Impact Journals LLC, 2017) Gu, Mancang; Nakashima, Reiko; Chen, Yang; Li, Wanwan; Shi, Yan; Masugi, Yohei; Hamada, Tsuyoshi; Kosumi, Keisuke; Liu, Li; da Silva, Annacarolina; Nowak, Jonathan; Twombly, Tyler; Du, Chunxia; Koh, Hideo; Li, Wenbin; Meyerhardt, Jeffrey; Wolpin, Brian M.; Giannakis, Marios; Aguirre, Andrew; Bass, Adam; Drew, David; Chan, Andrew; Fuchs, Charles S.; Qian, Zhi Rong; Ogino, ShujiEvidence suggests that nonsteroidal anti-inflammatory drug aspirin (acetylsalicylic acid) may improve patient survival in PIK3CA-mutant colorectal carcinoma, but not in PIK3CA-wild-type carcinoma. However, whether aspirin directly influences the viability of PIK3CA-mutant colon cancer cells is poorly understood. We conducted in vitro experiments to test our hypothesis that the anti-proliferative activity of aspirin might be stronger for PIK3CA-mutant colon cancer cells than for PIK3CA-wild-type colon cancer cells. We measured the anti-proliferative effect of aspirin at physiologic concentrations in seven PIK3CA-mutant and six PIK3CA-wild-type human colon cancer cell lines. After exposure to aspirin, the apoptotic index and cell cycle phase of colon cancer cells were assessed. In addition, the effect of aspirin was examined in parental SW48 cells and SW48 cell clones with individual knock-in PIK3CA mutations of either c.3140A>G (p.H1047R) or c.1633G>A (p.E545K). Aspirin induced greater dose-dependent loss of cell viability in PIK3CA-mutant cells than in PIK3CA-wild-type cells after treatment for 48 and 72 hours. Aspirin treatment also led to higher proportions of apoptotic cells and G0/G1 phase arrest in PIK3CA-mutant cells than in PIK3CA-wild-type cells. Aspirin treatment of isogenic SW48 cells carrying a PIK3CA mutation, either c.3140A>G (p.H1047R) or c.1633G>A (p. E545K), resulted in a more significant loss of cell viability compared to wild-type controls. Our findings indicate that aspirin causes cell cycle arrest, induces apoptosis, and leads to loss of cell viability more profoundly in PIK3CA-mutated colon cancer cells than in PIK3CA-wild-type colon cancer cells. These findings support the use of aspirin to treat patients with PIK3CA-mutant colon cancer.Publication Multicenter retrospective and comparative study of 5-minute versus 15-second endoscopic papillary balloon dilation for removal of bile duct stones(© Georg Thieme Verlag KG, 2017) Hakuta, Ryunosuke; Hamada, Tsuyoshi; Nakai, Yousuke; Isayama, Hiroyuki; Kogure, Hirofumi; Mizuno, Suguru; Naminatsu, Takahara; Yagioka, Hiroshi; Togawa, Osamu; Matsubara, Saburo; Ito, Yukiko; Yamamoto, Natsuyo; Tsujino, Takeshi; Koike, KazuhikoBackground and study aims Endoscopic papillary balloon dilation (EPBD) is a method of bile duct stone removal that has a better long-term outcome but a high risk of post-ERCP pancreatitis (PEP). Recent studies have suggested that 5-minute EPBD can reduce the incidence of PEP. This study aimed to examine the safety and effectiveness of longer duration EPBD compared with shorter duration EPBD (5 minutes vs. 15 seconds after disappearance of the waist of a dilation catheter). Patients and methods Patients without a history of endoscopic sphincterotomy or EPBD who underwent EPBD to remove bile duct stones were selected retrospectively from five centers. The incidence of PEP, other early adverse events, and outcomes of EPBD were compared between the groups. A multivariable analysis of risk factors for PEP was performed. Results: A total of 607 patients (157 and 450 in the 5-minute and 15-second EPBD groups, respectively) were included. There were no statistically significant differences between the groups in terms of the incidence of PEP (8.3 % and 8.9 % in the 5-minute and 15-second EPBD groups, respectively; P = 0.871) and the incidence of overall early adverse events ( P = 0.999). Although 5-minute EPBD elongated the procedure time (45 vs. 37 minutes, P < 0.001), it increased the rate of complete stone removal during a single session ( P < 0.001) and decreased the use of lithotripsy ( P < 0.001). Conclusions: Compared with 15-second EPBD, 5-minute EPBD did not reduce the incidence of PEP.Publication Aspirin in the era of immunotherapy(Impact Journals LLC, 2017) Hamada, Tsuyoshi; Giannakis, Marios; Ogino, ShujiPublication Integration of pharmacology, molecular pathology, and population data science to support precision gastrointestinal oncology(2017) Ogino, Shuji; Jhun, Iny; Mata, Douglas; Soong, Thing Rinda; Hamada, Tsuyoshi; Liu, Li; Nakashima, Reiko; Giannakis, Marios; Cao, Yin; Manson, JoAnn; Nowak, Jonathan; Chan, AndrewPrecision medicine has a goal of customizing disease prevention and treatment strategies. Under the precision medicine paradigm, each patient has unique pathologic processes resulting from cellular genomic, epigenomic, proteomic, and metabolomic alterations, which are influenced by pharmacological, environmental, microbial, dietary, and lifestyle factors. Hence, to realize the promise of precision medicine, multi-level research methods that can comprehensively analyze many of these variables are needed. In order to address this gap, the integrative field of molecular pathology and population data science (i.e., molecular pathological epidemiology) has been developed to enable such multi-level analyses, especially in gastrointestinal cancer research. Further integration of pharmacology can improve our understanding of drug effects, and inform decision-making of drug use at both the individual and population levels. Such integrative research demonstrated potential benefits of aspirin in colorectal carcinoma with PIK3CA mutations, providing the basis for new clinical trials. Evidence also suggests that HPGD (15-PDGH) expression levels in normal colon and the germline rs6983267 polymorphism that relates to tumor CTNNB1 (β-catenin)/WNT signaling status may predict the efficacy of aspirin for cancer chemoprevention. As immune checkpoint blockade targeting the CD274 (PD-L1)/PDCD1 (PD-1) pathway for microsatellite instability-high (or mismatch repair-deficient) metastatic gastrointestinal or other tumors has become standard of care, potential modifying effects of dietary, lifestyle, microbial, and environmental factors on immunotherapy need to be studied to further optimize treatment strategies. With its broad applicability, our integrative approach can provide insights into the interactive role of medications, exposures, and molecular pathology, and guide the development of precision medicine.Publication Groove Pancreatitis: Endoscopic Treatment via the Minor Papilla and Duct of Santorini Morphology(Editorial Office of Gut and Liver, 2018) Chantarojanasiri, Tanyaporn; Isayama, Hiroyuki; Nakai, Yousuke; Matsubara, Saburo; Yamamoto, Natsuyo; Takahara, Naminatsu; Mizuno, Suguru; Hamada, Tsuyoshi; Kogure, Hirofumi; Koike, KazuhikoBackground/Aims Groove pancreatitis (GP) is an uncommon disease involving the pancreaticoduodenal area. Possible pathogenesis includes obstructive pancreatitis in the duct of Santorini and impaired communication with the duct of Wirsung, minor papilla stenosis, and leakage causing inflammation. Limited data regarding endoscopic treatment have been published. Methods: Seven patients with GP receiving endoscopic treatment were reviewed. The morphology of the pancreatic duct was evaluated by a pancreatogram. Endoscopic dilation of the minor papilla and drainage of the duct of Santorini were performed. Results: There were two pancreatic divisum cases, one ansa pancreatica case and four impaired connections between the duct of Santorini and the main pancreatic duct. Three to 31 sessions of endoscopy, with 2 to 24 sessions of transpapillary stenting and dilation, were performed. Interventions through the minor papilla were successfully performed in six of seven cases. The pancreatic stenting duration ranged from 2 to 87 months. Five patients with evidence of chronic pancreatitis (CP) tended to receive more endoscopic interventions than did the two patients without CP (2–24 vs 2, respectively) for GP and other complications associated with CP. Conclusions: Disconnection or impairment of communication between the ducts of Santorini and Wirsung was observed in all cases of GP. No surgery was required, and endoscopic minor papilla dilation and drainage of the duct of Santorini were feasible for the treatment of GP.