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Oncometabolites, such as D/L-2-hydroxyglutarate (2HG), have directly been implicated in carcinogenesis; however, the underlying molecular mechanisms remain poorly understood. Here, we showed that the levels of the L-enantiomer of 2HG (L2HG) were specifically increased in colorectal cancer (CRC) tissues and cell lines compared with the D-enantiomer of 2HG (D2HG). In addition, L2HG increased the expression of ATF4 and its target genes by activating the mTOR pathway, which subsequently provided amino acids and improved the survival of CRC cells under serum deprivation. Downregulating the expression of L-2-hydroxyglutarate dehydrogenase (L2HGDH) and oxoglutarate dehydrogenase (OGDH) increased L2HG levels in CRC, thereby activating mTOR-ATF4 signaling. Furthermore, L2HGDH overexpression reduced L2HG-mediated mTOR-ATF4 signaling under hypoxia, whereas L2HGDH knockdown promoted tumor growth and amino acid metabolism in vivo. Together, these results indicate that L2HG ameliorates nutritional stress by activating the mTOR-ATF4 axis and thus could be a potential therapeutic target for CRC.

Pancreatic adenosquamous carcinoma (PASC) is a rare variant of pancreatic ductal adenocarcinoma (PDAC). The usual treatment for metastatic or recurrent PASC is systemic chemotherapy in accordance with the PDAC treatment strategy. This study aimed to investigate the efficacy of chemotherapy, especially the benefit of recent combination therapies, in patients with metastatic or recurrent PASC.We conducted a multicenter retrospective analysis of 116 patients with metastatic or recurrent PASC treated with first-line chemotherapy between April 2001 and December 2017 at 24 Japanese institutions.Combination chemotherapies included gemcitabine + nab-paclitaxel (GnP, n = 28), fluorouracil/leucovorin + irinotecan + oxaliplatin (FFX, n = 10), gemcitabine + S-1 (GS, n = 10), and others (n = 9). Monotherapies included gemcitabine (n = 51) and S-1 (n = 8). The median overall survival (OS) was 6.5, 7.3, and 4.3 months for the whole cohort, the combination therapy group, and the monotherapy group, respectively. Multivariate analysis indicated that combination therapy showed a better trend in OS than monotherapy (hazard ratio = 0.68; 95% confidence interval, 0.38-1.20). GnP or FFX were selected in 58.7% of patients after FFX was approved in Japan, and revealed a median OS, median progression-free survival, and objective response rate of 7.3 months, 2.8 months, and 26.9% in GnP and 7.2 months, 2.3 months, and 20.0% in FFX respectively.This study suggests that combination therapy may be more effective than monotherapy. GnP and FFX showed similar and clinically meaningful efficacy for patients with metastatic or recurrent PASC.

Medication is a major determinant of human gut microbiome structure, and its overuse increases the risks of morbidity and mortality. However, effects of certain commonly prescribed drugs and multiple medications on the gut microbiome are still underinvestigated.We performed shotgun metagenomic analysis of fecal samples from 4198 individuals in the Japanese 4D (Disease, Drug, Diet, Daily life) microbiome project. A total of 759 drugs were profiled, and other metadata, such as anthropometrics, lifestyles, diets, physical activities, and diseases, were prospectively collected. Second fecal samples were collected from 243 individuals to assess the effects of drug initiation and discontinuation on the microbiome.We found that numerous drugs across different treatment categories influence the microbiome; more than 70% of the drugs we profiled had not been examined before. Individuals exposed to multiple drugs, polypharmacy, showed distinct gut microbiome structures harboring significantly more abundant upper gastrointestinal species and several nosocomial pathobionts due to additive drug effects. Polypharmacy was also associated with microbial functions, including the reduction of short-chain fatty acid metabolism and increased bacterial stress responses. Even nonantibiotic drugs were significantly correlated with an increased antimicrobial resistance potential through polypharmacy. Notably, a 2-time points dataset revealed the alteration and recovery of the microbiome in response to drug initiation and cessation, corroborating the observed drug-microbe associations in the cross-sectional cohort.Our large-scale metagenomics unravels extensive and disruptive impacts of individual and multiple drug exposures on the human gut microbiome, providing a drug-microbe catalog as a basis for a deeper understanding of the role of the microbiome in drug efficacy and toxicity.

Metastasis is responsible for the majority of deaths of patients with cancer. However, mechanisms governing metastasis in colorectal cancer remain largely unknown. Here we investigated how colorectal cancer cells acquire metastatic potential using a novel mouse model of colorectal cancer that spontaneously develops liver metastasis, generated by introducing sporadic mutations of Ctnnb1, Kras, Trp53, and Smad4 (CKPS) genes. Proteomic analyses revealed elevated expression of colorectal cancer stem cell markers ALCAM (CD166) and PROM1 (CD133) in colorectal cancer cells from the metastatic model compared with those from a nonmetastatic model. Spleen-to-liver metastasis assays using colorectal cancer cells derived from the CKPS model (CKPS cells) demonstrated the functional importance of ALCAM and PROM1 in initiating metastasis. Genetic and pharmacologic analyses using CKPS cells in 2D and spheroid culture revealed that expression of ALCAM and PROM1 is regulated positively and negatively by the cAMP/PKA/CREB and TGFβ/SMAD4 pathways, respectively. Consistently, phospho-CREB was expressed in both primary and metastatic lesions of CKPS mice and patients with colorectal cancer, and knockout of CREB in CKPS cells reduced their spheroid-forming and metastasis-initiating abilities. Treatment with a CREB inhibitor potentiated the effect of irinotecan in suppressing liver metastasis by CKPS cells. These results reveal the essential roles of ALCAM and PROM1, as well as their upstream regulators, the cAMP/PKA/CREB and TGFβ/SMAD4 pathways, in maintaining the stemness and metastatic potential of colorectal cancer cells and indicate that CREB inhibition may be a potential therapeutic strategy against metastatic colorectal cancer. Significance: This study identifies signaling pathways essential for maintaining the stemness and metastatic potential of colorectal cancer cells and proposes CREB as a therapeutic target in metastatic colorectal cancer.

To identify gut and oral metagenomic signatures that accurately predict pancreatic ductal carcinoma (PDAC) and to validate these signatures in independent cohorts.We conducted a multinational study and performed shotgun metagenomic analysis of fecal and salivary samples collected from patients with treatment-naïve PDAC and non-PDAC controls in Japan, Spain, and Germany. Taxonomic and functional profiles of the microbiomes were characterized, and metagenomic classifiers to predict PDAC were constructed and validated in external datasets.Comparative metagenomics revealed dysbiosis of both the gut and oral microbiomes and identified 30 gut and 18 oral species significantly associated with PDAC in the Japanese cohort. These microbial signatures achieved high area under the curve values of 0.78 to 0.82. The prediction model trained on the Japanese gut microbiome also had high predictive ability in Spanish and German cohorts, with respective area under the curve values of 0.74 and 0.83, validating its high confidence and versatility for PDAC prediction. Significant enrichments of Streptococcus and Veillonella spp and a depletion of Faecalibacterium prausnitzii were common gut signatures for PDAC in all the 3 cohorts. Prospective follow-up data revealed that patients with certain gut and oral microbial species were at higher risk of PDAC-related mortality. Finally, 58 bacteriophages that could infect microbial species consistently enriched in patients with PDAC across the 3 countries were identified.Metagenomics targeting the gut and oral microbiomes can provide a powerful source of biomarkers for identifying individuals with PDAC and their prognoses. The identification of shared gut microbial signatures for PDAC in Asian and European cohorts indicates the presence of robust and global gut microbial biomarkers.

Supplementary Data from The cAMP/PKA/CREB and TGFβ/SMAD4 Pathways Regulate Stemness and Metastatic Potential in Colorectal Cancer Cells

Metastasis is responsible for the majority of deaths of patients with cancer. However, mechanisms governing metastasis in colorectal cancer remain largely unknown. Here we investigated how colorectal cancer cells acquire metastatic potential using a novel mouse model of colorectal cancer that spontaneously develops liver metastasis, generated by introducing sporadic mutations of Ctnnb1, Kras, Trp53, and Smad4 (CKPS) genes. Proteomic analyses revealed elevated expression of colorectal cancer stem cell markers ALCAM (CD166) and PROM1 (CD133) in colorectal cancer cells from the metastatic model compared with those from a nonmetastatic model. Spleen-to-liver metastasis assays using colorectal cancer cells derived from the CKPS model (CKPS cells) demonstrated the functional importance of ALCAM and PROM1 in initiating metastasis. Genetic and pharmacologic analyses using CKPS cells in 2D and spheroid culture revealed that expression of ALCAM and PROM1 is regulated positively and negatively by the cAMP/PKA/CREB and TGFβ/SMAD4 pathways, respectively. Consistently, phospho-CREB was expressed in both primary and metastatic lesions of CKPS mice and patients with colorectal cancer, and knockout of CREB in CKPS cells reduced their spheroid-forming and metastasis-initiating abilities. Treatment with a CREB inhibitor potentiated the effect of irinotecan in suppressing liver metastasis by CKPS cells. These results reveal the essential roles of ALCAM and PROM1, as well as their upstream regulators, the cAMP/PKA/CREB and TGFβ/SMAD4 pathways, in maintaining the stemness and metastatic potential of colorectal cancer cells and indicate that CREB inhibition may be a potential therapeutic strategy against metastatic colorectal cancer.Significance:This study identifies signaling pathways essential for maintaining the stemness and metastatic potential of colorectal cancer cells and proposes CREB as a therapeutic target in metastatic colorectal cancer.

Comprehensive cancer genome profiling (CGP) has been nationally reimbursed in Japan since June 2019. Less than 10% of the patients have been reported to undergo recommended treatment. Todai OncoPanel (TOP) is a dual DNA-RNA panel as well as a paired tumor-normal matched test. Two hundred patients underwent Todai OncoPanel as part of Advanced Medical Care B with approval by the Ministry of Health, Labour and Welfare between September 2018 and December 2019. Tests were performed in patients with cancers without standard treatment or when patients had already undergone standard treatment. Data from DNA and RNA panels were analyzed in 198 and 191 patients, respectively. The percentage of patients who were given therapeutic or diagnostic recommendations was 61% (120/198). One hundred and four samples (53%) harbored gene alterations that were detected with the DNA panel and had potential treatment implications, and 14 samples (7%) had a high tumor mutational burden. Twenty-two samples (11.1%) harbored 30 fusion transcripts or MET exon 14 skipping that were detected by the RNA panel. Of those thirty transcripts, six had treatment implications and four had diagnostic implications. Thirteen patients (7%) were found to have pathogenic or likely pathogenic germline variants and genetic counseling was recommended. Overall, 12 patients (6%) received recommended treatment. In summary, patients benefited from both TOP DNA and RNA panels while following the same indication as the approved CGP tests. (UMIN000033647).

Capecitabine plus oxaliplatin, CAPOX, therapy is one of the standardized options for adjuvant chemotherapy for colorectal cancer, but the efficacy and the safety of CAPOX in elderly patients are unclear. In this study, we investigated the relative dose intensity (RDI) and reasons for dose reduction in patients over the age of 70 (elderly group) (n = 12) and those under the age of 70 (non-elderly group) (n = 24) receiving adjuvant CAPOX therapy for colorectal cancer. The median RDIs were 71.1% in the elderly group and 67.9% in the non-elderly group for oxaliplatin (p = 0.416), and 81.6% and 86.4% for capecitabine (p = 0.166), respectively. The rate of peripheral neuropathy which was the reason for dose reduction of oxaliplatin was approximately 4.5-fold higher in the non-elderly group than in the elderly group. In addition, hematologic toxicity was the most common reason for dose reduction at 50.0% in the elderly group. The results of this study suggested that a similar therapeutic intensity can be maintained in elderly patients relative to non-elderly patients by appropriate dose reduction and discontinuation of drug treatments. Elderly patients are more susceptible to hematologic toxicity than to peripheral neuropathy.

The prognosis of glioblastoma remains poor despite intensive research efforts. Glioblastoma stem cells (GSCs) contribute to tumorigenesis, invasive capacity, and therapy resistance. Leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5), a stem cell marker, is involved in the maintenance of GSCs, although the properties of Lgr5-positive GSCs remain unclear. Here, the Sleeping-Beauty transposon-induced glioblastoma model was used in Lgr5-GFP knock-in mice identify GFP-positive cells in neurosphere cultures from mouse glioblastoma tissues. Global gene expression analysis showed that Gli2 was highly expressed in GFP-positive GSCs. Gli2 knockdown using lentiviral-mediated shRNA downregulated Hedgehog-related and Wnt signaling pathway-related genes, including Lgr5; suppressed tumor cell proliferation and invasion capacity; and induced apoptosis. Pharmacological Gli inhibition with GANT61 suppressed tumor cell proliferation. Silencing Gli2 suppressed the tumorigenicity of GSCs in an orthotopic transplantation model in vivo. These findings suggest that Gli2 affects the Hedgehog and Wnt pathways and plays an important role in GSC maintenance, suggesting Gli2 as a therapeutic target for glioblastoma treatment.

Objectives The aim of this multicenter retrospective study was to identify the optimal chemotherapeutic regimen for advanced pancreatic acinar cell carcinoma (PACC). Methods Fifty-eight patients with histopathologically confirmed advanced PACC who had received chemotherapy between 1996 and 2013 were enrolled. The clinical characteristics of the patients and the treatment efficacy data were collected from the medical records at 16 Japanese institutions, using standardized data collection instrument. Results The most commonly selected treatment regimens were gemcitabine-, fluoropyrimidine-, platinum-, and irinotecan-containing regimens. The overall response rate in the patients who received first-line chemotherapy were 7% and 38%, respectively, and the median overall survival was 13.2 months. When the data for all the treatment lines were aggregated, the response rates to gemcitabine-, fluoropyrimidine-, platinum-, and irinotecan-containing regimens were 7%, 18%, 40%, and 29%, respectively. The overall survival tended to be better in patients who had received a platinum-containing regimen (hazard ratio, 0.50; 95% confidence interval, 0.23-1.11; P = 0.08) or irinotecan-containing regimen (hazard ratio, 0.42; 95% confidence interval, 0.15-1.19; P = 0.09) at least once in the treatment course as compared with those who had not. Conclusions Our findings suggested that platinum- and irinotecan-containing regimens exhibited some potential efficacy in patients with advanced PACC.

Background/objectives Pancreatic neuroendocrine carcinoma (PanNEC)-G3 often presents along with genetic abnormalities such as KRAS, RB1, and TP53 mutations. However, the association between these genetic findings and response to chemotherapy and prognosis has not been clarified. This study aimed to clarify the clinicopathological features of PanNEC-G3. Methods We performed a subgroup analysis of the Japanese PanNEN-G3 study (multicenter, retrospective study), which revealed that Rb loss and KRAS mutation were predictors of the response to platinum-based regimen in PanNEN-G3. We re-classified WHO grades of PanNENs using the 2017 WHO classification and then analyzed the clinicopathological features and prognostic factors in 49 patients with PanNEC-G3. Results The rates of Rb loss and KRAS mutation in PanNEC-G3 were 54.5% and 48.7%, respectively. Patients with Rb loss and/or KRAS mutation showed a higher response rate to first-line platinum-based regimen than those without Rb loss or KRAS mutation (object response rate 70.0% vs 33.3%, odds ratio 9.22; 95% CI 1.26–67.3, P = 0.029), but tended to have shorter overall survival rates than those without Rb loss or KRAS mutation (median 239 vs 473 days, hazard ratio 2.11; 95% CI 0.92–4.86, P = 0.077). Conclusions Patients with PanNEC-G3 have varied clinical outcomes for platinum-based regimen. When grouped based on Rb loss and KRAS mutation, there seemed to be two groups with distinct prognoses and responses to the platinum-based regimen. PanNEC-G3 could, therefore, be classified into two distinct groups based on immunohistochemical and genetic findings.

We investigate interrelationships between gut microbes, metabolites, and cytokines that characterize COVID-19 and its complications, and we validate the results with follow-up, a Japanese Disease, Drug, Diet, Daily Life microbiome cohort, and non-Japanese data sets.We performed shotgun metagenomic sequencing and metabolomics on stools and cytokine measurements on plasma from 112 hospitalized patients with SARS-CoV-2 infection and 112 non-COVID-19 control individuals matched by important confounders.Multiple correlations were found between COVID-19-related microbes (eg, oral microbes and short-chain fatty acid producers) and gut metabolites (eg, branched-chain and aromatic amino acids, short-chain fatty acids, carbohydrates, neurotransmitters, and vitamin B6). Both were also linked to inflammatory cytokine dynamics (eg, interferon γ, interferon λ3, interleukin 6, CXCL-9, and CXCL-10). Such interrelationships were detected highly in severe disease and pneumonia; moderately in the high D-dimer level, kidney dysfunction, and liver dysfunction groups; but rarely in the diarrhea group. We confirmed concordances of altered metabolites (eg, branched-chain amino acids, spermidine, putrescine, and vitamin B6) in COVID-19 with their corresponding microbial functional genes. Results in microbial and metabolomic alterations with severe disease from the cross-sectional data set were partly concordant with those from the follow-up data set. Microbial signatures for COVID-19 were distinct from diabetes, inflammatory bowel disease, and proton-pump inhibitors but overlapping for rheumatoid arthritis. Random forest classifier models using microbiomes can highly predict COVID-19 and severe disease. The microbial signatures for COVID-19 showed moderate concordance between Hong Kong and Japan.Multiomics analysis revealed multiple gut microbe-metabolite-cytokine interrelationships in COVID-19 and COVID-19related complications but few in gastrointestinal complications, suggesting microbiota-mediated immune responses distinct between the organ sites. Our results underscore the existence of a gut-lung axis in COVID-19.

Background Gemcitabine plus nab-paclitaxel (GnP) has been a standard treatment for unresectable pancreatic cancer (uPC); however, the current treatment status and usefulness in older adults with uPC remain unclear. Therefore, we aimed to investigate the patient background and compare the efficacy and safety of GnP versus other treatments in older adults with uPC. Patients and Methods In this prospective observational study, we enrolled 233 eligible patients aged ≥76 years with pathologically proven, clinically uPC, and no history of chemotherapy from 55 Japanese centers during September 2018-September 2019. The main endpoints were overall survival (OS), progression-free survival (PFS), and safety. Geriatric assessments were performed upon registration and after 3 months. To adjust for confounders, we conducted propensity score-matched analyses. Results GnP, gemcitabine alone (Gem), best supportive care, and other therapies were administered to 116, 72, 16, and 29 patients, respectively. In the propensity score-matched analysis, 42 patients each were selected from the GnP and Gem groups. The median OS was longer in the GnP group than in the Gem group (12.2 vs. 9.4 months; hazard ratio [HR], 0.65; 95% CI, 0.37-1.13). The median PFS was significantly longer in the GnP group than in the Gem group (9.2 vs. 3.7 months; HR, 0.38; 95% CI, 0.23-0.64). The incidence of severe adverse events was higher with GnP than with Gem; however, the difference was not significant. Conclusion GnP is more efficacious than Gem in patients aged ≥76 years with uPC despite demonstrating a higher incidence of severe adverse events.

547 Background: Early tumor shrinkage (ETS) has been reported as a prognostic predictor of chemotherapy for colorectal cancer. However, few studies have examined the potential of ETS in chemotherapy for pancreatic cancer. Herein, we evaluated whether ETS could be a prognostic predictor in patients treated with modified FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) or GnP (gemcitabine plus nab-paclitaxel) for locally advanced pancreatic cancer (LAPC), as an exploratory analysis of JCOG1407, a randomized phase II selection design trial comparing modified FOLFIRINOX and GnP for LAPC. Methods: Of 126 patients enrolled in JCOG1407, 112 with measurable lesions were included in this exploratory analysis. ETS was defined as a ≥ 20% reduction in tumor diameter compared with baseline at the initial imaging assessment 6–10 weeks after initiating chemotherapy. Patients were divided into two cohorts based on their ETS status as described above: the ETS cohort that achieved ETS and the non-ETS cohort that failed to achieve ETS. The impact of ETS on overall survival (OS) was compared using multivariable Cox regression analysis in (ⅰ) the modified FOLFIRINOX group, (ⅱ) the GnP group, and (ⅲ) the overall population. Results: Herein, we included 55 patients in the modified FOLFIRINOX group and 57 in the GnP group. Notably, 14 (25.5%) and 24 (42.1%) patients achieved ETS in the modified FOLFIRINOX and GnP groups, respectively. In the modified FOLFIRINOX group, the median OS in the ETS and non-ETS cohorts was 2.5 and 1.7 years, respectively; the adjusted hazard ratio (HR) of the ETS to the non-ETS cohort for OS was 0.37 (95% confidence interval [CI], 0.15-0.93). In the GnP group, the median OS in the ETS and non-ETS cohorts was 2.0 and 1.7 years, respectively; the adjusted HR of the ETS to the non-ETS cohort for OS was 0.51 (95% CI, 0.26-1.01). In the overall population, the median OS in the ETS and non-ETS cohorts was 2.3 and 1.7 years, respectively; the adjusted HR of the ETS to the non-ETS cohort for OS was 0.45 (95% CI, 0.27-0.75). Conclusions: We noted a trend toward increased survival in patients who achieved ETS, suggesting that ETS may be a prognostic predictor in patients with LAPC treated with modified FOLFIRINOX or GnP.

Definitive chemoradiation (dCRT) is the mainstay treatment for cStage IVa esophageal squamous cell carcinoma (ESCC) with good performance status (PS), according to standard practice guidelines. Salvage surgery may incur operation complications and risk of mortality. According to the esophageal cancer practice guidelines outlined by the Japan Esophageal Society, when a tumor is residual and recurrent, chemotherapy and palliative symptomatic treatment is continued. However, salvage operation has been selected as a therapeutic option for recurrent or residual tumors after dCRT. There is weak evidence for not recommending surgery for cStage IVa ESCC exhibiting residual disease following dCRT. It has been reported that during salvage surgery the only prognostic factor that is thought to be performed is complete resection (R0), but at the same time, salvage esophagectomy increases the incidence of postoperative complications and mortality. The phase II chemoselection study by Yokota T et al. in Japan showed that multidisciplinary treatment initiated by induction therapy, in which docetaxel is added to cisplatin and 5-fluorouracil, resulted in a good prognosis in the short term. In this review, we discuss the surgical strategy and future of unresectable clinical T4 (cT4) ESCC.

Background: Platinum-containing regimens are widely used as first-line chemotherapy for unresectable pancreatic neuroendocrine carcinoma (NEC), but second-line chemotherapies have yet to be established. Objectives: We evaluated the safety and efficacy of everolimus in patients with pancreatic NEC refractory or intolerant to platinum-containing chemotherapy. Methods: This study was a prospective, multicenter, phase II trial in patients with pancreatic NEC after platinum-containing chemotherapy. Everolimus treatment was continued until disease progression or intolerable toxicity was observed. The primary endpoint was progression-free survival (PFS). Results: Participants comprised 25 patients. Median age was 63 years, median PFS was 1.2 months (95% confidence interval [CI] 0.9–3.1 months), median overall survival was 7.5 months (95% CI 3.1–13.5 months), overall response rate was 0%, and disease control rate was 39.1%. Common grade 3/4 adverse events were hyperglycemia (20%), thrombocytopenia (16%), and anemia (16%). Conclusion: The efficacy of everolimus was limited in patients with unresectable pancreatic NEC.

Chylothorax is the accumulation of lipid pleural effusion. Few reports have described chylothorax caused by gastric cancer. A 45-year-old woman presented with progressive lymphedema and bilateral chylothorax. Although repetitive thoracentesis was performed to relieve her dyspnea, swelling of her axillary lymph nodes became significant. Positron emission tomography/computed tomography demonstrated the accumulation of 18F-fluorodeoxyglucose in these nodes, and a lymph node biopsy showed signet ring cell carcinoma. The primary site was a 0-IIc type lesion in the gastric body that was only detected by upper gastrointestinal endoscopy. The patient was diagnosed with advanced gastric cancer 3.5 months after presentation for chylothorax.

A multicenter phase 2 trial analysed chemoselection with docetaxel plus 5-fluorouracil and cisplatin (DCF) induction chemotherapy (ICT) and subsequent conversion surgery (CS) for locally advanced unresectable esophageal cancer. This study presents updated 3-year analyses to further characterize the impact of DCF-ICT followed by CS. Esophageal cancer patients with clinical T4 disease, unresectable supraclavicular lymph node metastasis, or both were eligible for this study. The treatment starts with DCF-ICT, followed by CS if the cancer is resectable, or by concurrent chemoradiation if it is not resectable. This updated analysis presents 3-year overall survival (OS), 3-year progression-free survival (PFS), and pattern of relapse. The median follow-up period for the patients surviving without death was 39.3 months. The estimated 1-year OS was 66.7%, and the lower limit of the 80% confidence interval (CI) was 54.6%. The estimated 3-year OS was 46.6% (95% CI 34.2–63.5%). The OS for the patients who underwent R0 resection (n = 19) was significantly longer than for those who did not (3-year OS: 71.4% vs. 30.1%). The estimated 1-year PFS was 50.6%, and the 3-year PFS was 39.6%. The PFS for R0 was significantly longer than for non-R0 (3-year PFS: 61.3% vs 25.0%). Recurrence or progression at the primary site was observed in 31% of the non-R0 group. The rate of distant metastasis did not differ significantly between the non-R0 and R0 groups (21% vs 16%). Long-term follow-up evaluation confirmed that DCF chemoselection aimed at CS is feasible and promising in terms of survival for patients with locally advanced esophageal cancer.

Iodothyronine deiodinase 2 (DIO2) converts the prohormone thyroxine (T4) to bioactive T3 in peripheral tissues and thereby regulates local thyroid hormone (TH) levels. Although epidemiologic studies suggest the contribution of TH to the progression of colorectal cancer (CRC), the role of DIO2 in CRC remains elusive. Here we show that Dio2 is highly expressed in intestinal polyps of Apc Δ716 mice, a mouse model of familial adenomatous polyposis and early stage sporadic CRC. Laser capture microdissection and in situ hybridization analysis show almost exclusive expression of Dio2 in the stroma of Apc Δ716 polyps in the proximity of the COX‐2‐positive areas. Treatment with iopanoic acid, a deiodinase inhibitor, or chemical thyroidectomy suppresses tumor formation in Apc Δ716 mice, accompanied by reduced tumor cell proliferation and angiogenesis. Dio2 expression in Apc Δ716 polyps is strongly suppressed by treatment with the COX‐2 inhibitor meloxicam. Analysis of The Cancer Genome Atlas data shows upregulation of DIO2 in CRC clinical samples and a close association of its expression pattern with the stromal component, consistently with almost exclusive expression of DIO2 in the stroma of human CRC as revealed by in situ hybridization. These results indicate essential roles of stromal DIO2 and thyroid hormone signaling in promoting the growth of intestinal tumors.

Fibroblast growth factor receptor 2 (FGFR2) rearrangement is expected to be a novel therapeutic target in advanced/recurrent biliary tract cancer (BTC). However, efficient detection and the exact frequency of FGFR2 rearrangements among patients with advanced/recurrent BTC have not been determined, and the clinical characteristics of FGFR2 rearrangement-positive patients have not been fully elucidated. We aimed to determine the frequency of FGFR2 rearrangement-positive patients among those with advanced/recurrent BTC and elucidate their clinicopathological characteristics. Paraffin-embedded tumor samples from formalin-fixed surgical or biopsy specimens of patients with advanced/recurrent BTC were analyzed for positivity of FGFR2 rearrangement by fluorescent in situ hybridization (FISH). RNA sequencing was performed on samples from all FISH-positive and part of FISH-negative patients. A total of 445 patients were enrolled. FISH was performed on 423 patients (272 patients with intrahepatic cholangiocarcinoma (ICC), 83 patients with perihilar cholangiocarcinoma (PCC), and 68 patients with other BTC). Twenty-one patients with ICC and four patients with PCC were diagnosed as FGFR2-FISH positive. Twenty-three of the 25 FISH-positive patients (20 ICC and 3 PCC) were recognized as FGFR2 rearrangement positive by targeted RNA sequencing. Younger age (≤ 65 years; p = 0.018) and HCV Ab- and/or HBs Ag-positivity (p = 0.037) were significantly associated with the presence of FGFR2 rearrangement (logistic regression). FGFR2 rearrangement was identified in ICC and PCC patients, and was associated with younger age and history of hepatitis viral infection.

Global Observing Satellite for Greenhouse gases and Water cycle (GOSAT-GW) is a polar-orbiting satellite carrying two mission instruments, Total Anthropogenic and Natural emissions mapping SpectrOmeter-3 (TANSO-3) and Advanced Microwave Scanning Radiometer 3 (AMSR3). TANSO-3 is developed by Ministry of the Environment for the follow-on mission of Greenhouse-gas Observation Satellite 2 (GOSAT-2) launched in 2018. AMSR3 is developed by Japan Aerospace Exploration Agency (JAXA) for the Global Change Observation Mission-Water (GCOM-W) follow-on mission to keep continuity of the passive microwave observation. GCOM-W had completed its nominal mission of five years in 2017 and has transferred to extended operation phase. Continuous observation by the onboard instrument, AMSR2 and early launch of a follow-on instrument are now strongly required both in science community and in operational fields. Specifications of the AMSR3 is almost equivalent to AMSR2. The characteristics and performances of existing 16 frequency channels are secured by making use of heritage design, meanwhile three high frequency channels (166 GHz, 183±3 GHz and 183±7 GHz) and 10-GHz channels with improved Noise Equivalent Delta Temperature (NEDT) will be added for observation of solid precipitation and humidity and improvement in measurement accuracy of sea surface temperature. These additional channels will enhance data utilization in wide fields such as meteorology, polar research and fishery. To produce long-term continuous data record by succeeding to GCOM-W is also one of the most important targets for studies on global climate change. Development of GOSAT-GW and AMSR3 had been officially approved in December 2019 and moved into Phase-B. An overview and current status of the mission and AMSR3 are given in this paper.

INTRODUCTION: Monitoring trends in diving-related injuries enables implementation of effective safety measures. Divers Alert Network Japan (DAN Japan) membership includes insurance covering recreational diving-related injuries and fatalities. Use of claim data provides both a known denominator and demographic data about injured members. METHODS: The study analysed 325 insurance claims reported to DAN Japan from 2010 to 2014. Four fatalities were excluded, leaving 321 claims for analysis. Claimants were divided into three age groups: young adults (< 40 years); middle-aged (40–59 years) and older adults (≥ 60 years). The total injury claims rate (ICR), decompression illness (DCI) rate (DCR) and trauma rate (TCR) were calculated. Differences between the sexes within each age group were analysed. RESULTS: The total number of DAN Japan member-years in the period was 80,617, with a mean age of 45 years. Claims were made by 153 males and 168 females with a mean and median age of 46 years. Trauma was the most frequent reason for a claim (113 cases, 35%), followed by DCI (109 cases, 34%). The ICR (per 10(4) member-years) was 39.8 (95% confidence interval 35.5 to 44.2) and the TCR was 14.0 (11.4 to 16.6). For every age group, the ICR and TCR were significantly higher for females than males. The DCR was 13.5 (11.0 to 16.1) and did not significantly differ between the sexes. CONCLUSIONS: The incidence of trauma-related diving injuries exceeds that of claims related to DCI. Females appear to have a higher risk of injury than the general diving population.

Background UGT1A1 *28 and *6 polymorphism is associated with reduced enzyme activity and severe toxicities of irinotecan, especially in patients with homozygous or heterozygous for UGT1A1*28 or *6 polymorphism for both UGT1A1*28 and *6 (double-variant-type of UGT1A1 polymorphism, UGT1A1-DV). FOLFIRINOX is one of the standard treatments for metastatic pancreatic cancer (PC). The optimal dose of irinotecan as a component of the FOLFIRINOX has not been established yet for patients with UGT1A1-DV. Patients and methods Advanced PC patients with UGT1A1-DV who had received at least one cycle of FOLFIRINOX from December 2013 to March 2016 were collected retrospectively conducted at multicenter in Japan. We evaluated the patient characteristics, efficacy and safety of FOLFIRINOX and investigate the optimal initial dose of irinotecan in Japanese advanced PC patients with UGT1A1-DV. Results A total of 31 patients were enrolled. Grade 4 neutropenia was seen more frequently (67%; 4/6) in patients who had received irinotecan at an initial dose of ≥ 150 mg/m2 than in those who had received the drug at an initial dose of ≤ 120 mg/m2 (20%; 5/24). The response rate (RR) and progression-free survival (PFS) in patients given irinotecan of ≤ 120 mg/m2 were 21.4% and 8.1 months, respectively, which were consistent with previous report for patients without UGT1A1-DV. Conclusion Based on our findings, we recommend that in Japanese advanced PC patients with UGT1A1- DV treated with FOLFIRINOX, irinotecan be administered at an initial dose of ≤ 120 mg/m2.

Sorafenib is a multi-kinase inhibitor for treatment of advanced hepatocellular carcinoma (HCC). Beyond its clinical benefit against advanced HCC, the efficacy and safety of sorafenib chemotherapy are critical concerns. In this study, we addressed the lipid profiles associated with the efficacy and safety of sorafenib chemotherapy. Plasma samples from HCC patients before sorafenib chemotherapy (N = 44) were collected and subjected to lipidomic analysis. We measured the levels of 176 lipids belonging to 8 classes of phosphoglycerolipids, 2 classes of sphingolipids, 3 classes of neutral lipids, and 4 other classes of lipids. To characterize lipids associated with efficacy, we compared the responder group (N = 21; partial response and stable disease) with non-responder group (N = 22; progressive disease). To characterize lipids associated with hand-foot skin reaction (HFSR), we compared the susceptible group (N = 12; grade 2 and 3) with non-susceptible group (N = 32; grade 0 and 1). The levels of 8 lipids, including phosphatidylcholine (PC)[34:2], PC[34:3]a, PC[35:2], PC[36:4]a, PC[34:3e], acylcarnitine (Car)[18:0], cholesterol ester[20:2], and diacylglycerol (DG)[34:2], were significantly lower in the responder group, and 6 out of 8 these lipids contained FA(18:2). In addition, the levels of 7 lipids (Car[12:0], Car[18:0], Car[18:1], Car[20:1] and fatty acid amides (FAA[16:0], FAA[18:0], and FAA[18:1]b)) were significantly lower in the group susceptible to HFSR. Our comprehensive lipidomics study using samples from sorafenib-treated patients with HCC revealed that significant differences in the lipid profiles of pre-treatment plasma were associated with sorafenib efficacy and sorafenib-induced HFSR. Validation using another set of patient plasma samples and elucidating the molecular basis of these changes will lead to better treatment with sorafenib chemotherapy.

A combination of S-1 and cisplatin is recognized as one of the standard first-line chemotherapy regimens for patients with advanced gastric cancer. However, demographic analyses of pivotal phase III studies have showed that only a minority of treated patients were aged 76 years or older. The purpose of this phase II study was to evaluate the safety and efficacy of combination therapy with S-1 and cisplatin in elderly patients with chemotherapy-naive advanced gastric cancer. Patients aged 76 years or older received S-1 40 mg/m2 orally twice daily for 21 days and cisplatin 60 mg/m2 intravenously infused at day 8 of each 35-day cycle. Dose modification was performed according to creatinine clearance. The primary endpoint was overall survival (OS). Secondary endpoints included response rate, progression-free survival (PFS), time to treatment failure (TTF), and adverse events. A total of 40 patients were enrolled. Median OS was 12.3 months, PFS was 7.8 months, and TTF was 4.3 months. The response rate was 54%. The most common grade 3–4 adverse events were anorexia (25%), neutropenia (23%), hyponatremia (20%), anemia (18%), and febrile neutropenia (8%). No treatment-related death occurred. Combination chemotherapy with S-1 and cisplatin is an effective and well-tolerated regimen for elderly patients with advanced gastric cancer when the dose is adjusted according to renal function.

Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) is frequently activated in cancers and can be counteracted with the clinical mTORC1 inhibitors everolimus and temsirolimus. Although mTORC1 and dual mTORC1/2 inhibitors are currently under development to treat various malignancies, the emergence of drug resistance has proven to be a major complication. Using the cis-Apc/Smad4 mouse model of locally invasive intestinal adenocarcinoma, we show that administration of everolimus or the dual mTORC1/2 inhibitor AZD8055 significantly reduces the growth of intestinal tumors. In contrast, although everolimus treatment at earlier phase of tumor progression delayed invasion of the tumors, both inhibitors exhibited little effect on blocking invasion of the tumors when administered later in their progression. Biochemical and immunohistochemical analyses revealed that treatment of cis-Apc/Smad4 mice with everolimus or AZD8055 induced marked increases in epidermal growth factor receptor (EGFR) and MEK/ERK signaling in tumor epithelial and stromal cells, respectively. Notably, co-administration of AZD8055 and the EGFR inhibitor erlotinib or the MEK inhibitor trametinib was sufficient to suppress tumor invasion in cis-Apc/Smad4 mice. These data indicate that mTOR inhibitor resistance in invasive intestinal tumors involves feedback signaling from both cancer epithelial and stromal cells, highlighting the role of tumor microenvironment in drug resistance, and support that simultaneous inhibition of mTOR and EGFR or MEK may be more effective in treating colon cancer.

OBJECTIVE Due to the occurrence of severe adverse drug reactions to regorafenib, a drug used in cancer therapy, the identification of a predictive marker(s) is needed to increase the therapeutic applicability of this compound. We therefore investigated whether polymorphisms in the ABCG2 and SLCO1B genes are associated with adverse drug reactions to regorafenib. METHODS For these analyses, 37 Japanese cancer patients were treated with regorafenib, genotyped for polymorphisms in ABCG2 and SLCO1B, and evaluated for drug-related adverse drug reactions. RESULTS There was no association between the ABCG2 421C>A variant and adverse drug reactions to regorafenib. After treatment, the incidences of increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) as well as increased total bilirubin (grade ≥ 2) were 8%, 4%, and 12%, and 42%, 25%, and 25% among SLCO1B1*1b carriers and non-carriers, respectively. There were no significant associations between elevated ALT and bilirubin and the SLCO1B1*1b allele. However, there were significantly lower incidences of increased AST (8% vs. 42%) and anemia (16% vs. 50%) in SLCO1B1*1b carriers than in non-carriers. CONCLUSIONS The absence of SLCO1B1*1b allele appears to be associated with the development of adverse drug reactions to regorafenib; however, further studies involving larger test groups and other populations are needed to confirm these findings. .

Cachexia is considered as a complex metabolic disease accompanied by systemic inflammation. However, we still do not understand the essential nature of the metabolic disorder associated with cachexia or the precise molecular mechanisms that drive cachexia. This reviewsummarizes the current knowledge on the pathogenesis of cancer cachexia obtained mainly from mouse models with emphasis on the findings that could reach the bedside in the future. Basic studies using animal models of cancer cachexia indicate that mediators such as pro-inflammatory cytokines and members of TGF-b superfamily disturb the cross-talks among metabolism-related organs including skeletal muscle, adipose tissue, liver, and CNS and thereby induce the collapse of metabolic homeostasis. The inhibitors of these mediators are currently under development for the treatment of cancer cachexia. Skeletal muscle atrophy is a key feature of cancer cachexia and is induced by enhanced proteolysis via ubiquitin-proteasome system and autophagy-lysosome system, as well as by decreased protein synthesis and increased fatty acid oxidation. Adipose tissue atrophy due to excessive lipolysis is another common feature of cancer cachexia, and the involvement of the browning of white adipose tissue and of the increased energy expenditure associated with the futile cycle of lipolysis/lipogenesis is suggested. The liver of cachectic tumor-bearing mice shows increased gluconeogenesis which leads to energy expenditure via futile cycle, and also develops steatosis due to decreased triglyceride usage. In the CNS, inflammation in the hypothalamus induces anorexia and excessive peripheral energy expenditure. Cachectic animals also showresistance to the appetite-promoting effects of ghrelin. We hope that cancer cachexia will gain better awareness in the near future, leading to the growth and progress of the research field, and that the elucidation of its pathogenesis will contribute to the development of novel preventive/therapeutics strategies.

4123 Background: Gemcitabine plus nab-paclitaxel (GN) demonstrated a significant improvement of OS over gemcitabine alone (G) in the MPACT trial for metastatic pancreatic cancer. However, since patients aged 75 years or older was less than 10% in the trial, data for the efficacy and safety of GN in that population have been limited. Methods: We prospectively enrolled patients who were 76 years or older if they had pathologically proven, clinically unresectable pancreatic cancer and no prior history of chemotherapy. Treatment regimen was based on physicians' choice. The primary endpoint was OS and secondary endpoints included PFS, objective response, and safety. Geriatric assessments including G8, IADL, CCI and Mini-COG were performed at the time of registration and 3 months after. To adjust confounding factors in the comparison of GN and G, propensity score-matched analyses were performed. Results: We enrolled 233 eligible patients from 55 centers in Japan between September 2018 and September 2019. GN, G, other therapy, and BSC were administered to 116, 72, 29 and 16 patients, respectively. With propensity scores adjusted for age, sex, clinical stage, ECOG PS, CA19-9, and neutrophil-lymphocyte ratio, 42 patients each in GN and G were compared. Patients characteristics in the matched pair were well-balanced; median age, 79/79 years; ECOG PS 0, 43/36%; stage IV, 69%/64%. With a median follow-up of 14.8 months and 50 observed deaths, OS in GN showed a longer tendency than that in G: 12.2 vs. 9.4 months in median with a hazard ratio (HR) of 0.65 (95% CI, 0.37-1.13; p= 0.120). PFS in GN was significantly longer than that in G: 9.2 vs. 3.7 months in median with a HR of 0.38 (95% CI, 0.23-0.64; p= 0.0002). The objective response rates were 29% and 11% ( p= 0.082), and the disease control rates were 81% and 61% ( p= 0.088), respectively. Decline of G8 scores at 3 months was observed in 35% and 28% of patients in GN and G, respectively ( p= 0.610), and that in IADL scores was observed in 61% and 37%, respectively ( p = 0.194). GN had higher incidence of adverse events than G though all were not statistically significant: grade 4 neutropenia (23%/8%); grade 3-4 malaise (13%/8%), fatigue (15 %/10%), peripheral sensory neuropathy (5%/0%). The incidence of the other adverse events was comparable between GN and G: grade 4 leucopenia (3%/5%) and thrombocytopenia (0%/3%); grade 3-4 nausea (3%/5%), vomit (3%/5%) and febrile neutropenia (0%/0%). Treatment discontinuation due to adverse events was more often in GN than G (39%/14%). Conclusions: Our data suggests GN is more efficacious than G even in patients aged 76 years or older, although GN have higher incidence of grade 3-4 adverse events and tends to decrease geriatric assessment scores. Clinical trial information: UMIN000034265.

Background: The standard treatment for locally advanced unresectable squamous cell carcinoma (SCC) of the oesophagus is chemoradiation with cisplatin and 5-fluorouracil (CF-RT). This multicentre phase II trial assessed the safety and efficacy of chemoselection with docetaxel plus cisplatin and 5-fluorouracil (DCF) induction chemotherapy (ICT) and subsequent conversion surgery (CS) for initially unresectable locally advanced SCC of the oesophagus. Methods: Patients with clinical T4 and/or unresectable supraclavicular lymph node metastasis were eligible. Treatment started with three cycles of DCF-ICT, followed by CS if resectable, or by CF-RT if unresectable. The resectability was re-evaluated at 30–40 Gy of CF-RT, followed by CS if resectable, or by completion of 60 Gy of CF-RT. If resectable after CF-RT, CS was performed. The primary end point was 1-year overall survival (OS). Results: From April 2013 to July 2014, 48 patients were enrolled. CS was performed in 41.7% (n=20), including DCF-CS (n=18), DCF-CF-RT40Gy-CS (n=1), and DCF-CF-RT60Gy-CS (n=1). R0 resection was confirmed in 19 patients (39.6%). Grade ⩾3 postoperative complications included one event each of recurrent laryngeal nerve palsy, lung infection, wound infection, pulmonary fistula, and dysphagia; but no serious postoperative complications were observed in patients undergoing CS. Clinical complete response after CF-RT was confirmed in 4 patients (8.3%). The estimated 1-year OS was 67.9% and lower limit of 80% confidence interval was 59.7%. There was one treatment-related death in patient receiving DCF-CF-RT60Gy. Conclusions: Chemoselection with DCF-ICT followed by CS as a multidisciplinary treatment strategy showed promising signs of tolerability and efficacy in patients with locally advanced unresectable SCC of the oesophagus.

Background/Aim: We evaluated the efficacy of vonoprazan (VPZ), a novel potassium-competitive acid blocker, in patients with proton pump inhibitor (PPI)-refractory gastroesophageal reflux disease (GERD), exhibiting continued pathological esophageal acid exposure (EAE). Methods: Despite ≥8 weeks of appropriate PPI therapy, patients with ­persistent reflux symptoms and pathological EAE times (EAETs ≥4%) were invited to switch to VPZ treatment. After an 8-week-course of once-daily VPZ (20 mg), multichannel intraluminal impedance-pH (MII-pH) monitoring was repeated to compare gastric acid exposure times (GAETs), EAETs, and other reflux parameters relative to the baseline values. Before each MII-pH study, reflux symptom severities were scored using the Gastrointestinal Symptom Rating Scale; erosive esophagitis and fasting plasma gastrin levels were also assessed. Results: From among the 124 patients undergoing MII-pH monitoring, 13 patients (median age, 69 years; females, 64%) were monitored at baseline (while on PPI therapy) and after VPZ therapy. The median GAET associated with VPZ treatment (23.8%) was less than that for PPI treatment (41.1%; p = 0.01), including both daytime and nighttime measurements. VPZ therapy resulted in better median EAET values (4.5%) than did PPI therapy (10.6%) during the 24-h monitoring period (p = 0.055). EAE normalization was achieved in 46% of VPZ-treated patients and was associated with complete gastric acid suppression (p = 0.005). After switching to VPZ, reflux symptoms (p < 0.01) and erosive esophagitis (p = 0.01) improved. Conclusion: In patients with PPI-refractory GERD, VPZ provides more potent gastric acid suppression, more effective EAE control, enhanced symptom improvement, and better esophagitis healing than PPIs.

Background Epithelioid hemangioendothelioma is an exceedingly rare sarcoma often occurring as an indolent angiocentric vascular tumor at various anatomic sites. Few reports have evaluated large case series of epithelioid hemangioendothelioma. Methods We conducted a retrospective analysis of the clinical data of 42 consecutive patients with epithelioid hemangioendothelioma who were pathologically diagnosed between 1990 and 2014 at 13 Japanese tertiary hospitals. We analyzed their clinical characteristics, tumor features and prognostic factors. Results The study included 22 men and 20 women, with a median age of 54 (range, 18–78) years. Pain was the most common symptom, occurring in 15 (68%) of the 22 symptomatic patients. The median maximum tumor diameter was 4.0 (range, 1.0–12.8) cm. The most commonly involved organs were the liver (81%), lungs (57%), and bones (12%). The overall survival rates were 79.5% at 1 year and 72.0% at 5 years. Substantially better survival was observed in asymptomatic patients than in symptomatic patients (P = 0.03), and better survival was also ovserved in patients with Ki-67 index ≤10% than in those with Ki-67 index > 10% (P = 0.04). By multivariate analysis, tumor size > 3.0 cm was associated with decreased survival (P = 0.049, hazard ratio 13.33). Conclusions This study showed the clinical characteristics of Japanese patients with epithelioid hemangioendothelioma. Tumor size > 3.0 cm is an independent indicator of a poor prognosis in epithelioid hemangioendothelioma. The presence of symptoms at the time of diagnosis and high Ki-67 index implied poor survival.

The role of surgery in pancreatic neuroendocrine neoplasm grade 3 (pNEN-G3) treatment remains unclear. We aimed to clarify the role of surgery for pNEN-G3, which has recently been reclassified as pancreatic neuroendocrine tumor-G3 (pNET-G3) and pancreatic neuroendocrine carcinoma-G3 (pNEC-G3), with and without metastases, respectively. We analyzed a subgroup of patients from the Japanese pancreatic NEC study, a Japanese multicenter case-series study of pNEN-G3. Pathologists subclassified 67 patients as having pNET-G3 or pNEC-G3 based on morphological features. We compared the overall survival (OS) rates among patients who were grouped according to whether they had undergone tumor-targeted surgery for tumors without (SwoM) or with (SwM) metastases, or non-surgical procedures (NS). Data from 21 patients with pNET-G3 (SwoM, n = 6; SwM, n = 5; NS, n = 10) and 46 patients with pNEC-G3 (SwoM, n = 8; SwM, n = 5; NS, n = 33) were analyzed. OS of patients with pNET-G3 was significantly longer after SwoM and SwM than with NS (p = 0.018 and p = 0.022). In contrast, OS did not significantly differ between either SwoM or SwM and NS (p = 0.093 and p = 0.489) among patients with pNEC-G3. The role of surgery should be considered separately for pNET-G3 and pNEC-G3. Although SwoM and SwM can be considered for pNET-G3, caution is advised before considering SwM and SwoM for pNEC-G3.

Background: Decompression sickness (DCS) is a rare condition that is often difficult to diagnose in deep-sea divers. Because of this, prevention and early diagnosis are important. In this case-control study, we examined the risk and preventive factors associated with DCS. Methods: Our original questionnaire survey was conducted among 269 recreational divers in Okinawa. Divers who were diagnosed with DCS by a physician (n = 94) were compared with healthy recreational divers (n = 175). The questionnaire consisted of 30 items and included a dive profile. Odds ratios and multiple logistic regression analysis were used to estimate the relative risk of DCS. Results: Logistic regression analysis revealed the following risk factors for DCS: a past history of DCS, drinking alcohol the evening before diving, indicating decompression stops, cold exposure after the dive, and maximum depth. Preventive factors included hydration before the dive, deep stops, safety stops and using nitrox gas. The results were reliable according to the Hosmer-Lemeshow and omnibus tests. Conclusion: We identified certain risk factors, together with their relative risks, for DCS. These risk factors may facilitate prevention of DCS among Okinawa divers.