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BACKGROUND: Venous thromboembolism (VTE), encompassing both deep vein thrombosis (DVT) and pulmonary embolism (PE), is a leading cause of morbidity and mortality worldwide. METHODS: GARFIELD-VTE is a prospective, non-interventional observational study of real-world treatment practices. We aimed to capture the 36-month clinical outcomes of 10,679 patients with objectively confirmed VTE enrolled between May 2014 and January 2017 from 415 sites in 28 countries. FINDINGS: A total of 6582 (61.6 %) patients had DVT alone, 4097 (38.4 %) had PE ± DVT. At baseline, 98.1 % of patients received anticoagulation (AC) with or without other modalities of therapy. The proportion of patients on AC therapy decreased over time: 87.6 % at 3 months, 73.0 % at 6 months, 54.2 % at 12 months and 42.0 % at 36 months. At 12-months follow-up, the incidences (95 % confidence interval [CI]) of all-cause mortality, recurrent VTE and major bleeding were 6.5 (7.0-8.1), 5.4 (4.9-5.9) and 2.7 (2.4-3.0) per 100 person-years, respectively. At 36-months, these decreased to 4.4 (4.2-4.7), 3.5 (3.2-2.7) and 1.4 (1.3-1.6) per 100 person-years, respectively. Over 36-months, the rate of all-cause mortality and major bleeds were highest in patients treated with parenteral therapy (PAR) versus oral anti-coagulants (OAC) and no OAC, and the rate of recurrent VTE was highest in patients on no OAC versus those on PAR and OAC. The most frequent cause of death after 36-month follow-up was cancer (n = 565, 48.6 %), followed by cardiac (n = 94, 8.1 %), and VTE (n = 38, 3.2 %). Most recurrent VTE events were DVT alone (n = 564, 63.3 %), with the remainder PE, (n = 236, 27.3 %), or PE in combination with DVT (n = 63, 7.3 %). INTERPRETATION: GARFIELD-VTE provides a global perspective of anticoagulation patterns and highlights the accumulation of events within the first 12 months after diagnosis. These findings may help identify treatment gaps for subsequent interventions to improve patient outcomes in this patient population. ispartof: THROMBOSIS RESEARCH vol:222 pages:31-39 ispartof: location:United States status: published

Background: Fulminant myocarditis presentation (FMP) is a rare and severe presentation of myocarditis. The natural history of FMP and its clinical features associated with poor outcomes are incompletely understood because there is a lack of generalizable evidence. Methods: This multicenter retrospective cohort study included patients hospitalized with histologically proven myocarditis who underwent catecholamine or mechanical support from 235 cardiovascular training hospitals across Japan between April 2012 and March 2017. Clinical features and the prognostic predictors of death or heart transplantation within 90 days on the basis of clinical and pathologic findings were determined using the Kaplan-Meier method, log-rank test, and Cox regression analysis. Results: This study included 344 patients with histologically proven FMP (median age, 54 years; 40% female). The median follow-up was 600 days (interquartile range, 36 to 1599 days) and the cumulative risk of death or heart transplantation at 90 days was 29% (n=98). Results from multivariable Cox regression analysis showed that older age, nonsinus rhythm, low left ventricular wall motion ( Conclusions: The results from analyses of data from this multicenter registry demonstrated that patients with FMP are at a higher risk of death or heart transplantation in real-world settings. These observations inform which clinical and pathologic findings may be useful for prognostication in FMP. Registration: URL: https://www.umin.ac.jp/ctr ; Unique identifier: UMIN000039763.

Objective In an extremely aging society, it is beneficial to reconsider the value of medical treatment for extremely elderly patients. We therefore focused on the efficacy of statin therapy in extremely elderly patients. This study investigated the efficacy of statins for secondary prevention in patients over 75 years old. Methods This prospective multicenter registry included 1,676 consecutive extremely elderly patients with coronary artery disease who underwent successful percutaneous coronary intervention (PCI). The patients were followed up clinically for up to three years or until the occurrence of major adverse cardiac events (MACEs), defined as a composite of all-cause death and non-fatal myocardial infarction. Using propensity score methodology to eliminate selection bias, in a 1:1 matching ratio, we selected 466 pairs of patients for the analysis. Results During the median follow-up period of 25 months, MACEs occurred in 176 patients. The Kaplan-Meier analysis showed that statin treatment correlated with a lower probability of initial MACE occurrences within 30 days compared with no statin treatment (log-rank test, p0.001). According to a landmark analysis at day 30, statin treatment still showed consistent effectiveness for reducing MACE occurrence during the follow up period (p=0.04). A multivariable Cox hazard analysis showed that statin therapy significantly reduced MACE occurrence (hazard ratio 0.55 [0.40-0.75], p0.001). In the stratification analysis, statin therapy was especially beneficial in patients without symptomatic heart failure. Conclusion Statins were effective in preventing MACEs in extremely elderly patients after PCI.

The statin use in patients on hemodialysis remains controversial, and no beneficial effects of statin on the reduction of adverse cardiovascular events have been reported in these patients. This study used stratification analysis to examine the clinical factors in patients on hemodialysis who could benefit from statin for secondary prevention. This prospective multicenter study included 234 consecutive patients on hemodialysis with coronary artery disease who underwent successful reperfusion therapy with percutaneous coronary intervention. The patients were followed up for up to 3 years or until the occurrence of major adverse cardiac events (MACEs; defined as a composite of all-cause death and nonfatal myocardial infarction). Inverse probability of treatment weighting adjustment was used to remove the selection bias. During the median follow-up period of 30 months, MACEs occurred in 55 patients. Patients with MACEs had significantly lower statin therapy (P0.001). Multivariable Cox proportional hazards analysis showed that the patients on statins had a significantly reduced rate of MACE occurrence [adjusted hazard ratio 0.30 (0.11-0.81), P = 0.02]. The stratification analysis of outcomes according to the presence of clinical factors showed that beneficial effects of statin were associated with man, elderly, lower body mass index, lower abdominal circumference, hypertension, diabetes, higher C-reactive protein, symptomatic heart failure, lower left ventricular function, nonacute coronary syndrome, and shorter stent length. Statin was effective for the prevention of MACEs in patients on hemodialysis who underwent percutaneous coronary intervention. We identified specific clinical factors affecting statin effectiveness for secondary prevention.

A 66-year-old Japanese woman developed pulseless electrical activity following an acute pulmonary embolism and was treated with thrombolytic therapy. She remained hemodynamically unstable and therefore underwent extracorporeal membrane oxygenation (ECMO). While receiving treatment with ECMO, blood clots induced by endobronchial hemorrhage caused tracheobronchial airway obstruction, leading to ventilatory defect. Furthermore, her cardiac function improved, resulting in cerebral hypoxemia progression. Therefore, the blood clots were removed with a Fogarty balloon catheter and endobronchial urokinase administration, resulting in improvement in her respiratory condition. Finally, ECMO was decannulated, and the patient was discharged from our hospital without difficulties in her activities of daily living.

Iatrogenic left main coronary artery (LMCA) dissection is a complication inadvertently caused by the interventional cardiologist and can have significant consequences. A 38-year-old man presented to hospital with non-ST-elevation myocardial infarction. Coronary angiography (CAG) revealed an obstructed proximal left circumflex artery (LCx) that was successfully treated with revascularization using a drug-eluting stent (DES). However, CAG after recanalization of the LCx demonstrated a spiral dissection of the left coronary artery from the mid-LMCA to the left anterior descending (LAD) artery and LCx. The dissection was classified as National Heart, Lung and Blood Institute type D in LAD and type F in LCx. Immediate exclusion stenting of the dissection flap by another DES and thrombolysis in myocardial infarction 3 flow were achieved in the LAD and LCx. The patient achieved hemodynamic stability with improvement in symptoms, despite residual dissection in the LAD. We, therefore, preferred careful observation over revascularization. The false lumen remained visible with a double-barrel appearance in the LAD on 6-month follow-up CAG, which disappeared at the 2-year follow-up. We report a rare case of a large double-barrel dissection that spontaneously occluded over time without any aggressive interventions.

Chemoradiotherapy (CRT) is a treatment option for esophageal squamous cell carcinoma (ESCC) and prognosis of patients achieved complete response is good. However, we cannot predict the outcome of the CRT before treatment. In previous single center study, RNA expression analysis using biopsy samples of 274 ESCC patients before CRT identified endogenous subtype classification. E type (high expression of squamous epithelial markers) showed good prognosis and M2 type (high expression of mesenchymal markers) did poor prognosis. We conducted a prospective multicenter study to confirm the association between molecular subtyping and outcome of CRT. From January 2015 to July 2016, we prospectively recruited 226 patients from 10 hospitals in Japan. This study was approved by the institutional review board at each hospital, and we obtained written informed consent from all patients (UMIN000016141). Biopsy samples were obtained before treatment, and molecular subtyping was performed. Treatment was selected by each physician. Clinical outcome of the patients treated by CRT was investigated according to the molecular subtype. Among 226 patients, two patients withdrew the content. We could identify the subtype classification in all 224 patients. Fifty-seven patients (25.4%) were classified to E type and 56 (25.0%) to M2 type. In 224 patients, 97 received treatment include CRT (77: CRT alone, 16: induction chemotherapy followed by CRT, 4: CRT followed by surgery). The proportion of patients alive at 5 years was 48.8% (95% CI 28.0-66.7%) in E type, and 29.8% (95% CI 12.4-49.6%) in M2 type. The patients in E type showed better prognosis although it was not significant statistically (HR 0.5; 95% CI 0.23-1.09; p = 0.08). This prospective multicenter study could show the usefulness of molecular subtyping of ESCC to predict the outcome of CRT.

The relationship between low body mass index (BMI) and prognostic factors for patients with coronary artery disease, commonly observed in elderly individuals in Japan, is important. Few studies have evaluated the prognosis for patients with low BMI after percutaneous coronary intervention (PCI). Using a multivariable-adjusted model and data from a prospective cohort registry, we analyzed the risk associated with low BMI for patients after PCI.This prospective, multicenter registry included 5965 consecutive patients with coronary artery disease who underwent successful PCI. The patients were followed-up clinically for up to 3 years or until the occurrence of major adverse cardiac events. The primary endpoint was all-cause death and nonfatal myocardial infarction composite.Primary events occurred in 639 (10.7%) patients during the follow-up period. A risk analysis of the primary endpoint adjusted for the multivariable model showed a significant increase in risk for elderly individuals, underweight individuals [HR 1.43 (95% confidence interval (CI), 1.10-1.85), P＜0.001], those with diabetes mellitus (DM), peripheral artery disease, low left ventricular ejection fraction or acute coronary syndrome (ACS), and smokers. A stratified adjusted risk analysis based on BMI levels showed that the risk associated with underweight status was significantly pronounced for male patients, those aged 60-74 years, and those with DM or ACS.Underweight patients with several risk factors significantly increased risk after PCI. Furthermore, the risk associated with low BMI was significantly more pronounced for men, individuals aged 60-74 years, and patients with DM or ACS.

Nivolumab is useful for the treatment of unresectable/recurrent gastric cancer as third-line or later chemotherapy. However, the factors that predict the efficacy of nivolumab monotherapy remain unclear.We retrospectively studied the predictive factors of response in 59 consecutive patients treated with nivolumab as third-line or later chemotherapy for unresectable/recurrent gastric cancer at our hospital from October 2017 to May 2020.The median follow-up was 5.9 months. The study included 45 men and 14 women (median age: 71 years). We observed that 7 patients had an Eastern Cooperative Oncology Group performance status of 0 and 52 patients had a performance status of 1-2. Forty-three patients were treated with third-line therapy, seven with fourth-line therapy, and three with fifth-line therapy. The response rate to nivolumab was 6.7% and disease control rate was 35.5%. There were 19 (32.2%) immune-related adverse events for all grades and 9 (15.2%) for grades 3 and 4. Progression-free survival was 1.90 months, and overall survival was 6.30 months. Patients with immune-related adverse events had significantly longer overall survival than those without immune-related adverse events. Multivariate analysis showed that the occurrence of immune-related adverse events and a ratio for neutrophil-to-lymphocyte ratio after 8 weeks of nivolumab treatment to the baseline neutrophil-to-lymphocyte ratio before treatment of ≤ 1.5 were independent prognostic factors for overall survival.Occurrence of immune-related adverse events and changes in neutrophil-to-lymphocyte ratio during nivolumab treatment may help predict the therapeutic efficacy of nivolumab monotherapy for unresectable or recurrent gastric cancer.

Tachycardia-induced cardiomyopathy (TIC) is a potentially reversible cardiomyopathy caused by tachyarrhythmia. For atrial flutter (AFL) -induced TIC, a rhythm control strategy, such as catheter ablation, has been recommended. However, the efficacy of rate control has remained unclear due to the difficulty of achieving control using arrhythmic medications.We prospectively assessed 47 symptomatic heart failure (HF) patients with left ventricular ejection fraction (LVEF) < 50% and suspected persistent AFL-induced TIC. Patients were divided into the rhythm control strategy (n = 22; treatment with catheter ablation or electrical cardioversion) and rate control strategy (n = 25; treatment with bisoprolol) groups. The latter was further divided into the strict rate control strategy (average heart rate < 80 bpm) and lenient rate control strategy (average heart rate < 110 bpm) subgroups. The primary outcome was left ventricular (LV) function recovery, which was defined as an increase in LVEF ≥ 20% or to a value of ≥ 55% after 6 months.In the rhythm control strategy group, more patients achieved LV function recovery after 6 months (95.2% versus 60.9%, P = 0.010). The cumulative incidence of worsening HF events was significantly higher in the rate control strategy group than in the rhythm control strategy group (hazard ratio, 4.66; 95% confidence interval, 1.01-21.57). The subgroup study revealed the advantage of the strict rate control strategy for achieving LV function recovery (83.3% versus 36.4%, P = 0.036).The rate control strategy was significantly inferior to the rhythm control strategy for the LV function recovery in TIC patients with persistent AFL. Our findings suggest that the strict rate control strategy should be aimed if the rhythm control strategy cannot be performed.

It is still unclear whether optimal medical therapy (OMT) after percutaneous coronary intervention (PCI) has beneficial effects on long-term clinical outcomes in patients aged ≥80 years with coronary artery disease (CAD).This study analyzed the time to the first major adverse clinical event including death or nonfatal myocardial infarction (MI), for up to 3 years after PCI using multicenter registry data. Data for 1056 patients aged80 years successfully treated with PCI were included in the analysis. OMT was defined as a combination of antiplatelet drug, statin, beta-blocker, and angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker.In total, 204 (19%) patients in this study received OMT and 852 (81%) received sub-OMT. During a median follow-up of 725 days, adverse clinical events occurred in 183 patients (death, n=177; nonfatal MI, n=6). Kaplan-Meier analysis showed that patients who received OMT had a lower probability of adverse clinical events than those who received sub-OMT (p0.01, log-rank test). Propensity score matching yielded 202 patient-pairs treated with OMT or sub-OMT, in whom 64 adverse clinical events (death, n=56, nonfatal MI, n=4) occurred during follow-up. OMT remained significant in the reduction of the risk of adverse clinical events in a multivariate Cox proportional hazards model (hazard ratio 0.44; 95% confidence interval 0.26-0.75; p=0.003).OMT after PCI was associated with significantly fewer adverse clinical events, including all-cause death and nonfatal MI, in patients aged ≥ 80 years with CAD. OMT might be safe and effective for these very elderly patients.

The purpose of this study is to evaluate the long-term survival outcomes of KDOG1001 trial after a minimum follow-up of 3 years. Patients with bulky N2 lymph nodes, linitis plastica (type 4), or large ulcero-invasive-type tumors (type 3) received up to four 28-day cycles of DCS neoadjuvant chemotherapy (docetaxel at 40 mg/m2, cisplatin at 60 mg/m2 on day 1, and S-1 at 40 mg/m2 twice daily for 2 weeks) followed by gastrectomy with D2 lymphadenectomy plus adjuvant S-1 therapy for 1 year. The final preplanned analysis of long-term outcomes including overall survival and relapse-free survival was conducted after minimum follow-up of 3 years. This trial is registered with the University Hospital Medical Information Network Clinical Trials Registry, number UMIN 000003642, and has been completed. From May 2010 through January 2017, 40 patients were enrolled. All included patients underwent neoadjuvant chemotherapy with DCS followed by gastrectomy with D2 lymphadenectomy, and 32 (80%) completed adjuvant S-1 therapy for 1 year. After a median follow-up for surviving patients of 68 months at the last follow-up in January 2020, 3-year overall survival rate was 77.5% (95% confidence interval 62.1–87.9%), while 3-year relapse-free survival rate was 62.5% (95% confidence interval 46.8–76.0%). Neoadjuvant chemotherapy with 4 cycles of DCS followed by D2 gastrectomy plus adjuvant S-1 was associated with relatively good long-term oncologic outcomes for patients with the high-risk gastric cancer.

A 76-year-old man had a diagnosis of double primary cancers consisting of poorly differentiated esophageal squamous cell carcinoma (ESCC) invading the submucosa and poorly differentiated gastric adenocarcinoma (GAC) invading the submucosa. The clinical stage of both ESCC and GAC was T1N0M0 stage I. The tumor diameter of ESCC and GAC was 20 mm and 25 mm, respectively. We performed chemoradiotherapy for ESCC. Chemotherapy consisted of nedaplatin in an intravenous dose of 90 mg/m2 on day 1 and 5-fluorouracil in an intravenous dose of 800 mg/m2 on days 1–5, repeated every 4 weeks for two cycles. Radiotherapy consisted of 50.4 Gy in 28 fractions for ESCC. GAC was down-staged after chemoradiotherapy for ESCC and was treated by endoscopic submucosal dissection (ESD). The tumor was histopathologically confirmed to be down-staged to intramucosal cancer with a diameter of 18 mm and no evidence of lymphovascular invasion and ulceration. Multiple metastasis occurred in the stomach, the small intestine and the colorectum after ESD. ESD is not a curative treatment even if chemotherapy is effective for poorly differentiated GAC invading the submucosa. Multiple gastrointestinal metastasis may be a unique recurrence pattern after ESD for such a lesion.

The optimal dose of each drug used in the docetaxel, oxaliplatin, and S-1 (DOS) chemotherapy remains to be clarified for the Japanese population. The purpose of this study was to determine a recommended dose for a combination neoadjuvant DOS chemotherapy for Japanese patients with locally advanced adenocarcinoma of the esophagogastric junction (AEG). Patients with cT3 or more advanced AEG without distant metastasis were eligible for this study. The planned dosages of docetaxel (mg/m2, day 1), oxaliplatin (mg/m2, day 1), and S-1 (mg/day, days 1–14) were: 50/100/80–120 at level 1, and 60/100/80–120 at level 2, respectively. The treatment cycle was repeated every 3 weeks, and patients were assessed for response to the treatment after 2 and 3 cycles. This study was registered in the UMIN Clinical Trial Registry (UMIN 000022210). We enrolled 12 patients with locally advanced AEG in this study. At dose level 1, one of the six patients experienced dose-limiting toxicity (DLT) of grade 3 diarrhea and grade 3 febrile neutropenia. Two of the next six patients also experienced DLT of need for more than 2-week delay of the start of the second cycle due to adverse events at dose level 2. Based on these results, level 2 was considered the recommended dose for this regimen. Recommended doses of docetaxel (mg/m2), oxaliplatin (mg/m2), and S-1 (mg/day) were 60/100/80–120. This chemotherapy scheme showed good preliminary efficacy with acceptable toxicity warranting a further phase II trial to investigate the efficacy of this regimen.

BACKGROUND The slow-flow/no-reflow phenomenon and impaired ST segment resolution (STR) following primary percutaneous coronary intervention (PCI) in ST-elevation myocardial infarction (STEMI) predict unfavorable prognosis and are characterized by obstruction of the coronary microvascular. Several predictors of slow-flow/no-reflow have been revealed, but few studies have investigated predictors of slow-flow/no-reflow and STR exclusively in acute myocardial infarction patients with initial Thrombolysis in Myocardial Infarction (TIMI) Grade 0.Methods and Results:In all, 279 STEMI patients with initial TIMI Grade 0 were enrolled in the study. Slow-flow/no-reflow was defined as TIMI Grade

Early gastric cancer (EGC) with metachronous lesions developing on scars after endoscopic submucosal dissection (ESD) is extremely rare and hard to treat. We evaluated whether DNA methylation of the cancer-specific methylation gene, cysteine dioxygenase type 1 (CDO1), would predict such lesions. CDO1 methylation (TaqMeth) values were compared between 11 patients with metachronous lesions developing on scars after ESD (M group) identified from 2,055 patients (0.5%) and 33 patients with EGC with no confirmed evidence of metachronous lesions at > 3 years after ESD (solitary [S] group). To assess Helicobacter pylori influence, 11 H. pylori-negative EGC patients (N group) were also analyzed. Each ESD specimen was measured at the tumor (T) and 4-points separated tumor-adjacent noncancerous mucosa (TAM). TaqMeth values for T were significantly higher than TAM (S + M) (P = 0.0019) and TAM (N) (P P CDO1 hypermethylation similar to T (P = 0.5713). Additionally, TaqMeth values for TAM (S) were significantly higher than TAM (N) (P CDO1 hypermethylation promisingly predicted EGC with metachronous lesions developing on scars after ESD.

Standard treatment for resectable small cell neuroendocrine carcinoma of the esophagus (SCNEC-E) remains to be established. We retrospectively studied 7 consecutive patients with resectable SCNEC-E who received definitive chemoradiotherapy (dCRT) to evaluate the safety and efficacy. Treatment consisted of two courses of chemotherapy with cisplatin (80 mg/m2 on day 1) and etoposide (100 mg/m2 on days 1–3) or carboplatin (AUC 5 on day 1) and etoposide (80 mg/m2 on days 1–3) given every 4 weeks during dCRT. The total radiation dose was 50.4 Gy (28 fractions). The clinical stage was IA in 1 patient, IB in 2 patients, IIA in 3 patients, and IIB in 1 patient. Definitive CRT was completed in all patients. The median overall treatment time of radiotherapy was 44 days. The chemotherapy regimen included in dCRT was cisplatin and etoposide in 3 patients and carboplatin and etoposide in 4 patients. Acute adverse events of grade 3 or 4 were neutropenia 100%, thrombocytopenia 43%, febrile neutropenia 43%, and nausea 14%. There were no late grade 3 or 4 adverse events. The median survival time was 32 months. The complete response rate was 100%. The recurrence rate was 43%. The median survival of the 4 patients without recurrence was 56 months. Definitive CRT with cisplatin and etoposide or carboplatin and etoposide is a feasible treatment for the resectable SCNEC-E, and long-term survival can be achieved in some patients.

Painful left bundle branch block (LBBB) syndrome is a rare disease that presents as simultaneous chest pain and transient LBBB without myocardial ischemia. We diagnosed a 72-year-old Japanese man with painful LBBB syndrome complicated by iron-overload cardiomyopathy. Phlebotomy was initially performed to improve myocardial iron deposition and conductive disturbance. Ironically, his chest pain was fully improved by the completion of incessant LBBB and walk-through phenomenon. However, this case demonstrates a clinically significant therapeutic strategy for cardiomyopathy-induced painful LBBB syndrome. Due to the lack of treatment guidelines, individualized treatment is required for each case of painful LBBB.

Background: In diabetes mellitus-related cardiomyopathy (DMCMP), hyperglycemia causes endothelial dysfunction, fibrosis, and myocardial injury, which result in left ventricular (LV) dysfunction. Treatment with sodium–glucose co-transporter 2 inhibitor (SGLT2i) reduces the risk of exacerbation of heart failure (HF). The beneficial effects of SGLT2i on HF depend not only on indirect actions such as osmotic diuresis but also direct actions on the myocardium leading to improvements in LV function. However, it remains unclear whether SGLT2i treatment is equally effective in any phase of DMCMP. The aim of this observational study was to compare the efficacy of SGLT2i treatment on LV dysfunction between early and advanced DMCMP.Methods: Thirty-five symptomatic non-ischemic HF patients with LV ejection fraction (EF) greater than 40% and type 2 diabetes mellitus (T2DM) treated with administration of empagliflozin (10 mg/day) were enrolled. According to the myocardial extracellular volume fraction (ECV), a reliable marker of cardiac fibrosis quantified by cardiac magnetic resonance, the patients were divided into the early DMCMP group (n = 16, ECV ≤ 30%) and advanced DMCMP group (n = 19, ECV > 30%) and followed-up prospectively. Echocardiography was performed at baseline and after 12 months. LV systolic function assessed as LV global longitudinal strain (GLS) and diastolic function assessed as the ratio of early diastolic mitral inflow velocity to early diastolic mitral annular velocity (E/e’) were compared.Results: ECV was strongly correlated with T2DM duration (r2 = 0.65, p < 0.001). At baseline, both groups had similar backgrounds (LVGLS: 7.9 ± 2.4% vs. 6.7 ± 3.0%, p = 0.207, and E/e’: 13.2 ± 6.1 cm/s vs. 12.6 ± 3.8 cm/s, p = 0.694). After 12 months, the early DMCMP group showed greater improvement in LVGLS (ΔLVGLS: 4.6 ± 1.5% vs. 1.6 ± 3.3%, p = 0.003) and E/e’ (ΔE/e’: -3.4 ± 5.5 cm/s vs. -0.1 ± 3.5 cm/s, p = 0.043) than in the advanced DMCMP group.Conclusion: The positive effects of empagliflozin on LV dysfunction were more remarkable in DMCMP with mild cardiac fibrosis than with advanced fibrosis. Early intervention of SGLT2i for DMCMP is preferable.

Background Diabetes mellitus-related cardiomyopathy (DMCMP), defined as left ventricular (LV) dysfunction caused by hyperglycemia in the absence of coronary artery disease, leads to heart failure (HF). Previous studies have shown that treatment with sodium-glucose co-transporter 2 inhibitor (SGLT2i) reduces the risk of exacerbation of HF. The beneficial effects of SGLT2i on HF depend not only on indirect actions such as osmotic diuresis but also on direct actions on the myocardium, leading to improvements in LV function. However, it remains unclear whether SGLT2i treatment is equally effective in any phase of DMCMP. The aim of this observational study was to compare the efficacy of SGLT2i treatment on LV dysfunction between early and advanced DMCMP. Methods Thirty-five symptomatic non-ischemic HF patients with LV ejection fraction > 40% and type 2 diabetes mellitus (T2DM) treated with empagliflozin (EMPA group) and 20 controls treated without SGLT2i were enrolled. According to the myocardial extracellular volume fraction (ECV), a reliable marker of cardiac fibrosis quantified by cardiac magnetic resonance, the EMPA group was further divided into early DMCMP (n = 16, ECV ≤ 30%) and advanced DMCMP (n = 19, ECV > 30%) groups and followed up prospectively. Echocardiography was performed at baseline and after 12 months. LV function assessed as LV global longitudinal strain (LVGLS) and the ratio of early diastolic mitral inflow velocity to early diastolic mitral annular velocity (E/e′) were compared. Results ECV was strongly correlated with T2DM duration (r2 = 0.65, p p = 0.005, and 4.6 ± 1.5% (early DMCMP) vs. 1.6 ± 3.3% (advanced DMCMP), p = 0.003) and E/e′ (ΔE/e′: − 1.5 ± 4.7 vs. − 0.3 ± 3.0, p = 0.253, and − 3.4 ± 5.5 vs. − 0.1 ± 3.5, p = 0.043). Conclusions The positive effects of empagliflozin on LV dysfunction were more remarkable in early than in advanced DMCMP. Early intervention of SGLT2i for DMCMP may be preferable.

Background The effectiveness of endoscopic treatment for superficial esophageal squamous cell carcinoma in the elderly is unclear. Methods We retrospectively studied efficacy and safety of endoscopic submucosal dissection for superficial esophageal squamous cell carcinoma in 358 patients at our hospital from July 2005 to December 2018. Patients were divided into elderly (≥75 years) and young (≤74 years) groups. Efficacy was evaluated based on overall survival and disease-specific survival, whereas safety was investigated based on the frequency of endoscopic submucosal dissection-related adverse events. Results The median observation period was 50 months. The elderly group comprised 111 patients, and young group comprised 247 patients. In the elderly and young groups, 76 (68.5%) and 159 (64.4%) underwent curative resection (P = 0.450), 8 (7.2%) and 34 (13.8%) underwent non-curative resection plus additional treatment and 12 (10.8%) and 15 (6.0%) underwent follow-up, respectively. The frequency of additional treatment for non-curative resection was significantly lower in the elderly group (P = 0.023). The 3-year overall survival of the elderly and young groups was 85.6 and 94.1%, respectively (P = 0.003). The 3-year disease-specific survival of the elderly and young groups was 98.4 and 98.5% (P = 0.682), respectively. The frequency of endoscopic submucosal dissection-related adverse events did not differ significantly between the groups (P = 0.581). The Charlson Comorbidity Index ≥2 was an independent prognostic factor for survival in the elderly group (P = 0.010; hazard ratio, 5.570; 95% confidence interval, 1.519–20.421). Conclusions Endoscopic submucosal dissection for superficial esophageal squamous cell carcinoma in elderly patients is as safe as that for young patients. The evaluation of Charlson Comorbidity Index was considered to help estimate the prognosis of elderly patients.

Background/aims Endoscopic resection is the standard treatment for superficial esophageal squamous-cell neoplasia (SESCN). However, we encounter patients in whom endoscopic resection is difficult to perform. We retrospectively studied the usefulness of argon plasma coagulation (APC) in patients with SESCN. Materials and methods The study comprised 45 patients with SESCN (81 lesions) who underwent APC in our hospital from March 1999 through August 2016. Clinicopathological characteristics, treatment time, the presence or absence of metastasis and recurrence, adverse events, and outcomes were studied. Results The median follow-up was 40 months. The median age was 70 years. The tumor diameter was 10 mm or longer in 48 lesions and less than 10 mm in 33 lesions. The median treatment time was 22 minutes. The reasons for selecting APC were as follows: technical difficulty caused by the presence of metachronous multiple lesions in the radiation field after chemoradiotherapy or close proximity to the ulcer scar remaining after endoscopic treatment in 49 lesions (60.4%), and the presence of underlying diseases in 26 lesions (32.0%). Adverse events occurred in 2 patients (4.4%) who had hypoxemia due to over-sedation. Two lesions (2.5%) recurred locally but could be locally controlled by additional APC. No patient had metastasis or recurrence or died of esophageal neoplasia. The 3-year overall survival rate was 87.0%, and the 3-year recurrence-free survival rate was 97.2%. Conclusion APC can be a useful treatment option for SESCN in patients with a limited life expectancy, poor performance status, or technical difficulty in resection of superficial neoplasms.

Background An exploratory study was designed to evaluate the efficacy of granulocyte colony stimulating factor support for chemotherapy consisting of docetaxel, cisplatin and 5-fluorouracil chemotherapy in patients with oesophageal cancer. Methods The inclusion criteria were as follows: (1) oesophageal squamous cell carcinoma, (2) a schedule to receive three courses of induction chemotherapy (docetaxel 75 mg/m2 day 1, cisplatin 75 mg/m2 day 1, 5-fluorouracil 750 mg/m2 days 1–5, every 3 weeks), (3) stage IB-III, (4) 20–75 years old, (5) 0–1 performance status, (6) preserved organ functions and (7) written informed consent. The endpoints were to evaluate the efficacy of granulocyte colony stimulating factor support including secondary prophylactic usage for docetaxel, cisplatin and 5-fluorouracil chemotherapy. Patients who previously had ‘febrile neutropenia’, or ‘Grade 3 or 4 infection accompanied by grade 3 or 4 neutropenia’ prophylactically received granulocyte colony stimulating factor support from day 7. Results A total of 91 patients were included in the analysis. Granulocyte colony stimulating factor support was given to 81.3%. The incidence of grade 4 neutropenia and febrile neutropenia were 81.3 and 32.9%, respectively. The dose of anticancer agents was reduced in 48.4%. There were no treatment-related deaths. The relative dose intensity of docetaxel, cisplatin and 5-fluorouracil were 92.7 ± 9.8%, 86.0 ± 15.6% and 91.8 ± 10.0%, respectively. In the secondary prophylactic granulocyte colony stimulating factor support group, the neutrophil count significantly increased between day 7 and day 13 as compared with the non-prophylactic granulocyte colony stimulating factor support group (P Conclusions Granulocyte colony stimulating factor support including secondary prophylactic usage may be feasible for maintaining the intensity of docetaxel, cisplatin and 5-fluorouracil chemotherapy in patients with oesophageal cancer.

Hemorrhagic myocardial infarction (HMI) is a complication associated with percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI). We carried out a successful PCI for a 59-year old Japanese man presenting with chest pain due to AMI over 5 h. The onset to balloon time was 363 min. The next morning, he suffered cardiogenic shock, even with an auxiliary circulating device, which eventually resulted in death. An autopsy revealed extensive HMI. The necrotic myocardium showed not only coagulation necrosis but also contraction band necrosis which suggests myocardial injury due to late reperfusion. Although the intramyocardial hemorrhage was confined to the necrotic area, it was beyond the perfusion area of the culprit artery. Here, we describe a case of death with severe HMI. HMI can be a serious complication and worsen prognosis.

This randomized study was designed to evaluate the clinical effect of an elemental diet during chemotherapy in patients with esophageal cancer. The inclusion criteria were as follows: (1) esophageal squamous cell carcinoma, (2) stage IB-IV, (3) schedule to receive docetaxel, cisplatin, and 5-fluorouracil (DCF chemotherapy), (4) 20–80 years old, (5) performance status of 0–2, (6) oral intake ability, and (7) written informed consent. Patients were divided into two groups: the elemental supplementary group and the non-supplementary group. Patients received ELENTAL® (160 g/day) orally 9 weeks after the start of chemotherapy. Primary endpoint was the incidence of grade 2 or higher gastrointestinal toxicity according to the Common Terminology Criteria for Adverse Events, version 4.0. Secondary endpoints were the incidence of all adverse events and the evaluation of nutritional status. Thirty-six patients in the elemental supplementary group and 35 patients in the non-supplementary group were included in the analysis. The incidence of grade 2 or higher gastrointestinal toxicity and all grade 3 or 4 adverse events did not differ significantly between the groups. In the elemental supplementary group, the body weight (p = 0.057), muscle mass (p = 0.056), and blood levels of transferrin (p = 0.009), total amino acids (p = 0.019), and essential amino acids (p = 0.006) tended to be maintained after chemotherapy. Nutritional support provided by an amino acid-rich elemental diet was ineffective for reducing the incidence of adverse events caused by DCF chemotherapy in patients with esophageal cancer.

Endoscopic submucosal dissection (ESD) has been performed in a high proportion of patients with superficial esophageal squamous-cell carcinoma. Endoscopic aspiration mucosectomy (EAM) is a more straightforward technique that is easier to perform. We retrospectively evaluated the safety and efficacy of EAM and ESD to clarify the advantages and disadvantages of each procedure. A total of 374 patients (423 lesions) who underwent endoscopic resection were retrospectively studied. The following variables were evaluated (1) procedure time and adverse events as safety, and (2) en bloc complete resection rate, local recurrence rate, lymph node recurrence rate, overall survival rate, and cause-specific survival rate as efficacy. EAM was performed in 134 patients (149 lesions), and ESD was performed in 240 patients (274 lesions). The procedure times of EAM and ESD were 31.0 ± 22.4 and 85.7 ± 46.5 min (p

In this study, a waveplate using surface plasmons in a silver (Ag) wire grid structure is designed and fabricated. Simulation results confirmed a phase difference at a grating period of 360 nm, a duty ratio of 0.7, and an Ag thickness of 30 nm.

Purpose This study was designed to retrospectively analyze the safety and efficacy of chemoradiation therapy with nedaplatin and 5-fluorouracil in elderly patients with esophageal squamous cell carcinoma. Methods and materials Eligible patients were aged 76 years or older, had a histopathologic diagnosis of esophageal squamous cell carcinoma, and were treated at the Kitasato University Hospital between January 2010 and March 2016. Chemotherapy consisted of nedaplatin in an intravenous dose of 90 mg/m2 on day 1 and 5-fluorouracil in an intravenous dose of 800 mg/m2 on days 1 to 5, repeated every 4 weeks for 2 cycles. Radiation therapy consisted of 50.4 Gy in 28 fractions for thoracic tumors and 61.2 Gy for cervical tumors. Results Twenty-five patients were studied. Patient characteristics were as follows: median age 79 years (range, 76-85 years), clinical stage I/II/III/IV (7/8/8/2, respectively), and surgically resectable/unresectable (17/8, respectively). The completion rates of radiation therapy and chemoradiation therapy were 100% and 84%, respectively. Grade ≥3 acute toxicities included neutropenia (76%), leukopenia (72%), thrombocytopenia (32%), anemia (28%), anorexia (32%), oral mucositis (20%), febrile neutropenia (12%), and esophagitis (8%). Grade ≥3 late toxicities included esophageal stenosis (12%) and pleural effusion (4%). The complete response rate was 64%. In the median follow-up period of 18.9 months, the 1-year overall survival rate was 68%. Conclusions Definitive chemoradiation therapy with nedaplatin and 5-fluorouracil may be a feasible treatment option for elderly patients with esophageal squamous cell carcinoma.

Treatment strategies for superficial esophageal squamous cell carcinoma (S-ESCC) are determined mainly on the basis of the depth of invasion. We retrospectively studied the accuracy of the depth of tumor invasion, comprehensively assessed using the Japan Esophageal Society (JES) classification. The study group comprised 256 patients who underwent narrow band imaging (NBI) magnifying endoscopy, and endoscopic submucosal dissection for S-ESCC. The depth of invasion of S-ESCC was classified into three groups: EP/LPM, MM/SM1, and SM2. The following variables were studied retrospectively: (1) the diagnostic accuracy of non-magnifying white-light endoscopy, (2) the diagnostic accuracy of type B vessels, (3) the diagnostic accuracy of avascular area (AVA), (4) the diagnostic accuracy of the JES classification, and (5) the diagnostic accuracy of comprehensive diagnosis. The depth of invasion was assessed by white-light non-magnifying endoscopy, followed by NBI magnifying endoscopy. The positive predictive value (PPV) of white-light non-magnifying endoscopy was 86% for EP/LPM, 53% MM/SM1, and 74% for SM2. The PPV of the diagnosis of type B vessels was 93% for EP/LPM, 62% for MM/SM1, and 74% for SM2. The PPV of the AVA diagnosis was 73% for EP/LPM, 89% for MM/SM1, and 100% for SM2. The PPV of diagnosis according to the JES classification was 93% for EP/LPM, 65% for MM/SM1, and 77% for SM2. The PPV of the comprehensive diagnosis was 94% for EP/LPM, 63%, for MM/SM1, and 75% for SM2. The additional use of NBI magnifying endoscopy can enhance the diagnostic accuracy of the depth of invasion in patients with S-ESCC.

Few studies have classified risk factors according to the onset time of bleeding after endoscopic submucosal dissection (post-ESD bleeding). We studied 1767 consecutive lesions in patients who underwent ESD for early gastric cancer from December 2006 through June 2016. Patients who had a remnant stomach or who had undergone reconstruction with a gastric tube were excluded. Post-ESD bleeding was classified into acute bleeding (0–5 days after ESD) and delayed bleeding (6 or more days after ESD), and the risk factors for each type of bleeding were compared. Post-ESD bleeding occurred in 150 (8.5%) of 1767 lesions. Bleeding was acute in 129 lesions (7.3%) and delayed in 21 (1.2%). Acute post-ESD bleeding was frequently associated with lesions located in the distal stomach, expanded indications or non-indicated lesions, a specimen diameter of ≥40 mm, and antithrombotic therapy. Delayed post-ESD bleeding was often associated with lesions located in the proximal stomach, hemodialysis, and antithrombotic therapy. Among 334 lesions in patients who received antithrombotic therapy, post-ESD bleeding occurred in 47 lesions (14.1%). Independent risk factors for post-ESD bleeding were a specimen diameter of ≥40 mm and treatment with 2 or more antithrombotic agents. Acute post-ESD bleeding and delayed post-ESD bleeding were associated with different clinical characteristics. Antithrombotic therapy is a risk factor for post-ESD bleeding in both the acute and delayed phases.

This study was designed to validate a health-risk appraisal (HRA) model for identifying Japanese men in specialized hospitals who were at high risk for esophageal cancer on the basis of their past and present facial flushing reactions after drinking alcohol, drinking and smoking status, and intake of vegetables and fruit. We prospectively studied men 50 years or older with no history of head and neck cancer or esophageal cancer who presented at Kitasato University Hospital to undergo endoscopic examination from January 2011 to March 2013. The subjects responded to an HRA questionnaire before examination. Among the 164 patients enrolled, 157 were eligible for analysis. The median HRA score was 3 in patients aged 70–90 years and 6 in those aged 50 to 69 years. Early esophageal cancer was diagnosed on endoscopic examination in 3 subjects (1.9%, 3/157). Among 70 patients 70–90 years of age, 18 (25.7%, 18/70) had an HRA score of 7 or higher, and early esophageal cancer was detected in 2 (11.1%, 2/18) of these patients. Early esophageal cancer was not detected in 87 patients 50–69 years of age. Early esophageal cancer was detected in a 70-year-old patient with an HRA score of 2 who had no history of drinking alcohol or smoking. Our results suggest that an HRA questionnaire is useful for identifying persons 70 years or older who are at high risk for alcohol-related esophageal cancer in specialized hospitals.

Background Parenteral anticoagulants and vitamin K antagonists (VKAs) have constituted the cornerstone of venous thromboembolism (VTE) treatment. Meanwhile, direct oral anticoagulants (DOACs) provide physicians with an alternative. The Global Anticoagulant Registry in the FIELD (GARFIELD)-VTE observes real-world treatment practices. Objectives Describe initial anticoagulation (AC) treatment patterns in VTE patients who received parenteral AC, VKAs, and/or DOACs within ±30 days of diagnosis. Methods VTE patients were categorized into parenteral AC only, parenteral AC with transition to VKA, VKA only, parenteral AC with transition to DOAC, and DOAC only. Results A total of 9647 patients were initiated on AC treatment alone. 4781 (49.6%) patients received DOACs ± parenteral ACs; 3187 (33.0%), VKA ± parenteral ACs; and 1679 (17.4%) parenteral ACs alone. Rivaroxaban was the most frequently used DOAC (79.4%). DOACs were more frequently used in North America/Australia (58.1%), Europe (52.2%), and Asia (47.6%) than in Latin America (29.7%) and the Middle East/South Africa (32.5%). In patients with suspected VTE, most received parenteral AC monotherapy (67.7%). Patients with deep vein thrombosis were more likely to receive DOACs alone than those with pulmonary embolism with or without deep vein thrombosis (36.2% vs 25.9%). Active cancer patients received parenteral AC alone (58.9%), with 25.5% receiving DOAC ± parenteral AC and 12.8% parenteral AC and VKA. A total of 46.5% of pregnant patients received parenteral AC monotherapy, 34.0% were treated with VKA ± parenteral AC, and 19.5% received a DOAC (± parenteral AC). Conclusion AC treatment patterns vary by patient population, geographic region and site of VTE. Guidelines for AC therapy are not always adhered to.

Purpose Promoter DNA methylation of various genes has been associated with metachronous gastric cancer (MGC). The cancer-specific methylation gene, cysteine dioxygenase type 1 (CDO1), has been implicated in the occurrence of residual gastric cancer. We evaluated whether DNA methylation of CDO1 could be a predictive biomarker of MGC using specimens of MGC developing on scars after endoscopic submucosal dissection (ESD). Materials and Methods CDO1 methylation values (TaqMeth values) were compared between 33 patients with early gastric cancer (EGC) with no confirmed metachronous lesions at >3 years after ESD (non-MGC: nMGC group) and 11 patients with MGC developing on scars after ESD (MGCSE groups: EGC at the first ESD [MGCSE-1 group], EGC at the second ESD for treating MGC developing on scars after ESD [MGCSE-2 group]). Each EGC specimen was measured at five locations (at tumor [T] and the 4-point tumor-adjacent noncancerous mucosa [TAM]). Results In the nMGC group, the TaqMeth values for T were significantly higher than that for TAM (P=0.0006). In the MGCSE groups, TAM (MGCSE-1) exhibited significantly higher TaqMeth values than TAM (nMGC) (P

4521 Background: In the phase 2, open-label, KDOG1001 (UMIN000003642) study, neoadjuvant chemotherapy (NAC) with docetaxel, cisplatin, and S-1 (DCS), followed by gastrectomy with D2 lymph node dissection for high-risk advanced gastric cancer showed feasibility of DCS therapy with an enough R0 resection rate of 90%. Here we present long-term results after a minimum follow-up of 3 years. Methods: Patients with bulky node metastasis (bulky N), linitis plastica (type 4), or large ulcero-invasive-type tumors (type 3) received up to four 28-day cycles of DCS neoadjuvant chemotherapy (docetaxel at 40 mg/m2, cisplatin at 60 mg/m2 on day 1, and S-1 at 40 mg/m2 twice daily for 2 weeks) followed by gastrectomy with D2 lymphadenectomy. This analysis presents the final preplanned assessment of outcomes after 3 years. Primary endpoint was R0 resection rate. Secondary endpoints included overall survival (OS), progression free survival (PFS), completion rate of the protocol treatment, and pathological response rate (pRR) of DCS NAC. Results: Of 40 patients enrolled from May 2010 through January 2017, 7 (17.5%) had bulky N, 18 (45.0%) had type 4, and 16 (40%) had large type 3 with 1 (2.5%) having both large type 3 and bulky N2. All included patients underwent preoperative DCS chemotherapy followed by surgery with D2 lymphadenectomy with 32 (80%) completed postoperative S-1 therapy for 1 year. After a median follow-up for surviving patients of 67 mo (range, 36 mo to 110 mo) at the last follow-up in January 2020, 3-year OS was 78% [95% confidence interval (CI) 62–88%], while 3-year PFS was 63% (95% CI 47–76%). Completion rate of the protocol treatment was 62.5% (25/40) with pRR of 57.5% (23/40). In bulky N2, 3-y OS was 86% and 3-y PFS was 71% with pRR of 100%. In type 4, 3-y OS was 67% and 3-y PFS was 50% with pRR of 44%. In large type 3, 3-y OS was 88% and 3-y PFS was 75% with pRR of 56%. Patients with type 4 had significantly worse OS and PFS than those with the other types [HR 7.20 (95% CI 2.23–32.21) and HR 3.00 (95% CI 1.21–8.19)]. Conclusions: Preoperative chemotherapy with up to four cycles of DCS followed by gastrectomy plus adjuvant S-1 therapy is a promising treatment strategy for patients with bulky node metastasis, type 4 and large type 3 gastric cancers. For type 4 cancer, further improvement of treatment strategy is needed. Clinical trial information: 000003642 .

The prognosis of patients with gastric cancer with bulky node metastasis, linitis plastica (type 4), or large ulcero-invasive-type tumors (type 3) remains poor. We conducted a phase II study to evaluate the safety and efficacy of neoadjuvant chemotherapy with docetaxel, cisplatin, and S-1 (DCS) for establishing a new treatment modality that improves prognosis. Patients received up to four 28-day cycles of DCS therapy (docetaxel at 40 mg/m2, cisplatin at 60 mg/m2 on day 1, and S-1 at 40 mg/m2 twice daily for 2 weeks) followed by gastrectomy with D2 nodal dissection. S-1 chemotherapy was administered for 1 year after surgical resection. The primary endpoint was the percentage of complete resections of the primary tumor with clear margins (R0 resection). The planned sample size was 40; this was calculated based on an expected R0 rate of 85% and a threshold R0 rate of 65%, with a one-sided alpha of 5% and a power of 90%. Between 2010 and 2017, 40 patients were enrolled. The R0 resection rate was 90%. The most common grade 3 or 4 adverse events during DCS therapy were leukocytopenia (27.5%), neutropenia (55.0%), and hyponatremia (22.5%). The most common grade 3 or 4 surgical morbidity was pancreatic fistula (12.5%); mortality was 0%. The pathological response rate was 57.5% with a grade 3 histological response rate of 8%. Neoadjuvant chemotherapy with DCS was feasible and showed a sufficient R0 resection rate. A future study with a sufficient follow-up period should confirm survival outcomes.

Background A triple chemotherapeutic regimen including docetaxel, oxaliplatin, and S-1 (DOS) for a neoadjuvant setting has a promising efficacy for locally advanced adenocarcinoma of the esophagogastric junction (AEG). However, the optimal dose of each drug in Japanese population remained to be clarified. The aim of this phase I study is to determine a recommended dose for a triweekly combination neoadjuvant DOS chemotherapy for patients with locally advanced AEG. Methods Patients with cT3 or more advanced AEG without distant metastasis were eligible for this study. The planned dosages of docetaxel (mg/m2, day 1), oxaliplatin (mg/m2, day 1), and S-1 (mg/day, days 1–14) were 50/100/80–120 at level 1, and 60/100/80–120 at level 2. The treatment cycle was repeated every 3 weeks, and patients were assessed for response to the treatment after 2 and 3 cycles. This study was registered with UMIN Clinical Trial Registry (UMIN 000022210). Results Twelve patients with locally advanced AEG were enrolled in this study. At dose level 1, one of six patients experienced dose-limiting toxicity (DLT) of grade 3 febrile neutropenia. At dose level 2, two of the next six patients experienced the same DLT of need for withdrawal of chemotherapy due to serious adverse events. Based on these results, level 2 was considered the recommended dose for this regimen. Total or proximal gastrectomy plus lower esophagectomy, or subtotal esophagectomy was performed in all the 12 patients with the R0 resection rate of 92% (11/12). Histological response evaluation based on the classification defined by Japanese Gastric Cancer Association revealed four patients with grade 1a, two with grade 1b, three with grade 2, and three with Grade 3. Conclusions Recommended doses for a neoadjuvant DOS chemotherapy regimen for locally advanced AEG were determined as Docetaxel: 60 mg/m2, Oxaliplatin: 100 mg/m2 on day 1, S-1: 1.5m2, 120 mg twice a day on days 1–14. DOS chemotherapy showed good preliminary efficacy with acceptable toxicity in this study warranting a further phase II trial to investigate the efficacy of the DOS regimen. Clinical trial identification UMIN 000022210. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

In Table 1, the second item in the right-hand column "Extra-indication" should be changed to "Out of indication". The correct version of Table 1 is displayed.

Objective To evaluate the clinical outcomes in patients with cancer of an unknown primary site (CUP), who were treated by gastrointestinal oncologists. Methods We retrospectively studied 29 patients with CUP who were presented at the Department of Gastroenterology, Kitasato University Hospital from October 2005 to October 2013, and were treated by the gastrointestinal oncologists. The patients were divided into two groups, namely chemotherapy group and symptomatic therapy group, and the clinical characteristics and survival times were compared. The clinical course was studied according to the histologic type (adenocarcinoma or non-adenocarcinoma), prognostic subset (favorable or unfavorable), and the presence or absence of chemotherapy. Results The chemotherapy group comprised 19 patients, and the symptomatic therapy group comprised 10 patients. The median survival time was 11 months in the chemotherapy group and 3 months in the symptomatic therapy group. Twenty-two patients had adenocarcinoma, and 7 had non-adenocarcinoma. Of the 22 patients with adenocarcinoma, 2 belonged to the favorable prognostic subset and received chemotherapy. One of these patients died of cancer at 47 months, and the other was alive and disease free at 58 months. Among the 20 patients with adenocarcinoma in the unfavorable prognostic subset, 16 received chemotherapy and had a median survival of 16 months. Seven (44%) of these patients survived for at least 21 months, and 3 patients who could receive 3 or more regimens survived for at least 46 months. Conclusion It might be appropriate for gastrointestinal oncologists to treat CUP on the basis of clinical experience, depending on the situation.

78 Background: We encounter some cases of early gastric cancer treated by endoscopic submucosal dissection (ESD) that are out of the indication criteria after pathologic diagnosis. These cases require additional treatments because of a risk of lymph node metastasis in Japanese Classification. So further prediction factors associated with lymph node metastasis is expected. We are focusing on poorly differentiated adenocarcinomas in early gastric cancer that we treated by ESD and used these tissues to characterize their gene expression profiles related to canceration, invasion or conversion for metastasis. Methods: We examined two cases of intramucosal carcinoma and three of submucosal infiltrating carcinoma histologically diagnosed as poorly differentiated adenocarcinoma after ESD. Those samples are separated five adjacent normal tissues (N), five tumor tissues in mucosal layer (M) and three tumor tissues in submucosal layer (SM) in total 13 lesions. Formalin-fixed, paraffin-embedded tissues were dissected by the laser-captured microdissection technique and were analyzed for targeted 158 gene expressions using a quantitative real-time polymerase chain reaction (PCR) using commercial PCR plate (profile PCR array of genes related to cancer stem cells and epithelial mesenchymal transition). Results: Among genes that elevated in the cancer tissues (M or SM) against the normal tissues, five gene expressions (DKK1, TIMP1, THY1, FN1, COL1A2) were tended to much higher in the submucosal layer compared to the mucosal layer (N < M < SM). When we compared tumor gene expressions in depth of M, three gene expressions (FZD7, ZEB 2, CD 44) are higher in the tumors with submucosal invasion compared to within mucosal layer. Conclusions: Poorly differentiated adenocarcinoma of stomach had high expression level in cancer-related genes even if it was intramucosal tumor. Some of these genes tended to increase as its depth of invasion and the presence of invasion of the SM. It suggested that the biopsy specimen could be a prediction factor of invasion from the surface of gastric cancer, but additional specimens and analysis are necessary to prove these findings.

Conformational characteristics of poly(trimethylene sulfide) (PTMS) have been investigated by a rotational isomeric state analysis of ab initio molecular orbital calculations and 1H and 13C NMR exp...

AIM: To evaluate the dose-limiting toxicities (DLTs) and determine the maximum-tolerated dose (MTD) and recommended dose (RD) of combination chemotherapy with gemcitabine, cisplatin and S-1 which is an oral fluoropyrimidine pro-drug in patients with advanced biliary tract cancer. METHODS: Patients with histologically or cytologically confirmed unresectable or recurrent biliary tract cancer were enrolled. The planned dose levels of gemcitabine (mg/m2), cisplatin (mg/m2), and S-1 (mg/m2 per day) were as follows: level -1, 800/20/60; level 0, 800/25/60; level 1, 1000/25/60; and level 2, 1000/25/80. In each cycle, gemcitabine and cisplatin were administered intravenously on days 1 and 15, and S-1 was administered orally twice daily on days 1 to 7 and days 15 to 21, every 4 wk. RESULTS: Twelve patients were enrolled, and level 0 was chosen as the starting dose. None of the first three patients had DLTs at level 0, and the dose was escalated to level 1. One of six patients had DLTs (grade 4 febrile neutropenia, leucopenia, and neutropenia; grade 3 thrombocytopenia) at level 1. We then proceeded to level 2. None of three patients had DLTs during the first cycle. Although the MTD was not determined, level 2 was designated at the RD for a subsequent phase II study. CONCLUSION: The RD was defined as gemcitabine 1000 mg/m2 (days 1, 15), cisplatin 25 mg/m2 (days 1, 15), and S-1 80 mg/m2 per day (days 1-7, 15-21), every 4 weeks. A phase II study is planned to evaluate the effectiveness of combination chemotherapy with gemcitabine, cisplatin, and S-1 in advanced biliary tract cancer.

Salivary duct carcinoma (SDC) is an uncommon, high-grade tumor. We present 8 cases of sarcomatoid SDC, which has been defined recently as a rare variant of SDC. The 8 patients (5 men, 3 women) had a mean age of 63.6 years. Histologically, all tumors were characterized by a biphasic neoplasm composed of both SDC and sarcomatoid elements. In 3 cases, sarcomatoid components showed osteosarcomatous heterologous differentiation. A residual pleomorphic adenoma was detected in 5 tumors. The sarcomatoid component showed focal immunoreactivity for cytokeratin in 4 cases and epithelial membrane antigen in all 8 cases. Diffuse p53 immunostaining was detected in 3 cases, and it was coexpressed in both components. Our observations support the histogenetic theory of a common origin of the carcinomatous and sarcomatoid populations. Of the 13 patients, including our 8, reported to have sarcomatoid SDC arising in a major salivary gland and for whom long-term follow-up data were available, 7 have died of disease (mean survival, 15.6 months). These results indicate that sarcomatoid SDC is a highly aggressive tumor, similar to conventional SDC.

背景:卵巣の輪状細管を伴う性索腫瘍 (Sex cord tumor with annular tubules (SCTAT)) の1例において免疫染色および捺印細胞診を行ったので報告する.症例:63歳女性. 2経妊, 2経産にて自覚症状はなく, 健康診断の腹部エコー検査で下腹部腫瘤を指摘された. Peutz-Jeghers症候群の徴候はない. 右卵巣摘出手術が施行され, 9×7×6cmの多房性嚢胞がみられ, 一部に充実性肥厚部を認めた. 肥厚部からのスタンプ標本では多数の腫瘍細胞が採取され, 乳頭状ないし腺腔様構造がみられた. 腫瘍細胞は淡明な胞体内に多糖類と考えられるPAS陽性の穎粒を有していた. 腫瘍の一部には腸管上皮に類似する異所性成分が認められ, 胞体内にAlcianblueに染まる粘液を有しCEAとCAI9-9が陽性であった. 他の大部分の上皮成分ではAFPが陽性であった.結論:異所性成分の存在やAFPの陽性所見はSertoli-Leydigcelltumorlこは高頻度に認められるため, 本症例はSertoli-Leydig cell tumorの性格を有するSCTATと考えられた.

A 41-year-old man was admitted because of syncope. The electrocardiogram showed torsade de pointes (Tdp) with no long QT interval and the coupling interval of the initial beat of Tdp was 240 ms. Heterogeneity of ventricular refractoriness was observed together with shortness of the effective refractory period measured at the right ventricular inflow site where the paced QRS morphology was the same as that of the initial beat of Tdp. Verapamil could suppress frequent ventricular premature complexes with a short coupling interval, which lead to Tdp. Polymorphic ventricular tachycardia was induced by triple ventricular extrastimuli. A pure potassium channel blocker was successful in inhibiting polymorphic ventricular tachycardia inducibility by prolongation of refractoriness. These results suggested that triggered ventricular premature complexes may be represent the initiating mechanism, whereas the shortness of local refractory period and heterogeneity of ventricular refractoriness may play a role in the development and the maintenance of the Tdp.

The purpose of this study was to assess the presence and location of impaired myocardial sympathetic innervation by using 123I metaiodobenzylguanidine (123I MIBG) in 15 patients with coronary vasospasm induced by intracoronary acetylcholine. The results were compared with those using thallium-201 (Tl-201). We also examined 14 patients with severe coronary stenosis (>90%) and 8 control subjects without significant coronary stenosis (