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The intratumoral heterogeneity (ITH) of the tumor microenvironment (TME) has yet to be addressed in esophageal squamous cell carcinoma (ESCC). Here, we studied the ITH of CD8 and PD-L1 status in ESCC, and examined the potential of the tumor surface for representing the TME. Sixty-seven surgically resected clinical Stage II ESCC specimens were analyzed. The CD8 cell density, PD-L1 tumor proportion score (TPS) and combined positive score (CPS) were calculated in three (superficial, middle and deep) areas of each specimen. ITH was quantified by distance-standardized coefficient variations of the three values. The CD8 and PD-L1 status of each area was dichotomized, and tumor surface capabilities for predicting the entire tumor status were estimated. Variables were compared according to the presence of neoadjuvant chemotherapy (NAC). The ITH, especially PD-L1 heterogeneity, differed markedly among specimens. The concordance rates of CD8 and PD-L1 (CPS and TPS) status among the three different areas were 71.6%, 74.6% and 73.1%, respectively. The sensitivity and the specificity of the tumor surface for predicting the CD8 status of the whole tumor were high, especially in the NAC- group (both 1.0). The tumor surface also showed high capabilities for representing the whole PD-L1 status, while yielding moderate positive predictive values (0.70). The ITH degrees and predictive capabilities did not differ according to NAC. Taken together, the ITH of CD8 and PD-L1 differed among ESCC specimens, while not being markedly affected by NAC. The use of a biopsy specimen from the tumor surface might be feasible for TME evaluation.

Frailty was associated with delayed extubation on protocol‐based weaning from mechanical ventilation., Aim Frailty has been shown to be associated with prolonged mechanical ventilation (MV). However, due to limited physiological data, it has been unclear how frailty affects weaning from MV in septic patients subjected to a specific weaning protocol. Methods This was a single‐center retrospective cohort study. The study included patients with sepsis on MV who underwent protocol‐based weaning between August 2015 and December 2018. Frailty was defined as a Clinical Frailty Scale score 4 or more. The association between frailty and weaning was evaluated. Results Ninety‐nine eligible patients were identified and categorized as frail (n = 67) or not frail (n = 32). The duration of MV was significantly longer in the frail group (8 days versus 5 days, P

BACKGROUND In postoperative patients with breast cancer, the combination of an anthracycline and cyclophosphamide (AC) followed by a taxane is a standard regimen. In the current study, the authors examined whether AC could be safely omitted, and compared the effectiveness of paclitaxel versus docetaxel. METHODS Female postoperative patients with axillary lymph node‐positive breast cancer were eligible for enrollment in this phase 3, open‐label, randomized controlled trial at 84 centers in Japan. Patients were randomized to 4 cycles of doxorubicin at a dose of 60 mg/m2 and cyclophosphamide at a dose of 600 mg/m2 (AC) followed by 4 cycles of paclitaxel at a dose of 175 mg/m2 (ACpT) or AC followed by 4 cycles of docetaxel at a dose of 75 mg/m2 (ACdT), or 8 cycles of paclitaxel (PTx) or docetaxel (DTx) every 3 weeks. The primary endpoint was disease‐free survival (DFS). Secondary endpoints included overall survival adverse events. The authors adopted a 2 × 2 factorial design to examine the AC containing‐regimens (ACpT and ACdT) versus the AC free‐regimens (PTx and DTx), and the paclitaxel‐containing regimens (ACpT and PTx) versus the docetaxel‐containing regimens (ACdT and DTx). RESULTS Of 1060 patients, 1049 were treated and included in the intention‐to‐treat population. The DFS results did not demonstrate noninferiority between the AC‐containing and the AC‐free regimens (hazard ratio [HR], 1.19; 95% confidence interval [95% CI], 0.982‐1.448 [P noninferiority = .30]). Better outcomes were noted in patients treated with the docetaxel‐containing regimens compared with the paclitaxel‐containing regimens with respect to DFS (HR, 0.72; 95% CI, 0.589‐0.875 [P = .0008]) and overall survival (HR, 0.75; 95% CI, 0.574‐0.980 [P = .035]). Neutropenia, nausea, and vomiting were found to occur more often in the AC‐containing arms, whereas the incidence of edema was greater in the docetaxel‐containing treatment arms. CONCLUSIONS Noninferiority in DFS was not demonstrated between the AC‐containing and AC‐free regimens. Compared with a similar regimen of paclitaxel, docetaxel appeared to increase the DFS. Cancer 2017;123:759–68. © 2016 American Cancer Society., In postoperative patients with breast cancer, the combination of an anthracycline and cyclophosphamide followed by a taxane is a standard regimen. The results of the current phase 3 study demonstrate that noninferiority in disease‐free survival is not shown between regimens containing the combination of doxorubicin plus cyclophosphamide and those that do not, and that compared with a similar regimen of paclitaxel, docetaxel increased disease‐free survival.

Progression of anemia in patients with chronic kidney disease (CKD) is associated with an increased risk of death and hospitalization. It is not sufficiently clear whether treating renal anemia with recombinant human erythropoietin (rHuEPO) has a beneficial effect on early survival after hemodialysis (HD) initiation in patients with CKD. The study was an open-label multicenter retrospective cohort study to evaluate the relationship between rHuEPO treatment and early survival after HD initiation in patients with CKD. Predialysis patients with CKD were divided into two groups: an rHuEPO-treated group (rHuEPO group) and a non-treatment group. The primary endpoint was all-cause mortality in the year after HD initiation. A total of 3261 patients were enrolled (2275 in the rHuEPO group and 986 in the non-treatment group). One-year survival was 95.36% in the rHuEPO group and 90.36% in the non-treatment group. The survival rate was significantly higher in the rHuEPO group (P < 0.0001). The results of multivariate analysis confirmed that predialysis treatment with rHuEPO is a predictor for reduced mortality risk (hazard ratio = 0.61, 95% confidence interval: 0.42-0.87, P = 0.006). Risk for the composite event of death/hospitalization was also lower in the rHuEPO group (hazard ratio = 0.88, 95% confidence interval: 0.78-0.98, P = 0.026). The results of this study suggest that treatment with rHuEPO can decrease early mortality risk after initiation of HD in patients with CKD. A prospective study is needed to further investigate early survival after HD initiation.

Objectives To evaluate the prognostic significance of the pretreatment neutrophil-to-lymphocyte ratio in patients with metastatic urothelial carcinoma who underwent salvage chemotherapy. Methods We reviewed 200 metastatic urothelial carcinoma patients who received salvage chemotherapy at our five affiliate institutions between 2003 and 2011. The associations of pretreatment clinicopathological factors, including neutrophil-to-lymphocyte ratio, with cancer-specific survival and overall survival from the start of chemotherapy were assessed. Cox proportional hazards model was used for multivariate analysis. Results A total of 15 cases with missing data were excluded. Among the remaining 185 patients, 157 died during follow up, with a median survival of 13.0 months. Multivariate analysis showed that the pretreatment neutrophil-to-lymphocyte ratio ≥3, Eastern Cooperative Oncology Group performance status ≥2 and liver metastasis were independent poor prognostic factors, both for cancer-specific survival and overall survival. A prognostic model predicting overall survival was constructed based on the number of these three variables (0, 1 and ≥ 2). The classified patients showed significantly different overall survival (each P

Although erythropoiesis-stimulating agents (ESAs) are effective at treating anemia, the association between hemoglobin (Hb) levels and survival is still unclear, especially for the incident Japanese hemodialysis (HD) population. The Japan Erythropoietin Treatment (JET) Study is an open multi-center, prospective, observational study designed to evaluate the relationship between the maintenance of Hb levels and new HD patient prognosis after the first administration of epoetin beta. Landmark analyses were performed to examine the relationship between Hb levels at 6 months and survival. Among a total of 10,310 patients, 6631 completed the initial 6 months of epoetin beta treatment (induction phase) and were followed up for a further 2.5 years (maintenance phase). Three-year survival rate of patients with

The effect of recombinant human erythropoietin (rHuEPO) treatment on the progression of chronic kidney disease (CKD) has not been fully evaluated in Japan. We therefore retrospectively evaluated this in a sub-cohort of a prospective multicenter study to investigate optimal hemoglobin (Hb) level of CKD patients on hemodialysis (HD) treated with rHuEPO; Japan Erythropoietin Treatment Study for Target Hb and Survival (JET study). Effect of rHuEPO treatment during predialysis period to delay initiation of HD was retrospectively assessed in 2434 patients from the JET study comparing groups with and without rHuEPO treatment. The assessment was done by Cox proportional hazards regression analysis and inverse probability-weighted (IPW) analysis to adjust for time-dependent confounders. The weights used in the IPW analysis were calculated using a logistic model that included baseline confounders and time-dependent variables. During the predialysis period, 71.7% (1746 patients) were treated with rHuEPO (mean Hb level of 8.7 g/dL at initiation of rHuEPO treatment). Covariates significantly associated with initiation of rHuEPO treatment were Hb level, serum creatinine level, age, diabetes, cardiac insufficiency, and hypertension. The adjusted hazard ratio for time until HD initiation under rHuEPO treatment was 0.272 (95% CI, 0.223-0.331; P < 0.001) in the Cox analysis and 0.63 (95% CI, 0.53-0.76; P < 0.0001) in the IPW analysis. This retrospective study suggests that rHuEPO treatment during the predialysis period has preventive effects on the progression of CKD although further prospective investigation on the efficacy is needed.

Erythropoiesis‐stimulating agents (ESA) reduce the need for transfusions and improve the quality of life in patients receiving chemotherapy, but several clinical trials have suggested that ESA might have a negative impact on survival. To evaluate the efficacy and safety of ESA, epoetin beta and darbepoetin alfa, including their impact on overall survival and thromboembolic events, we conducted an individual data‐based meta‐analysis of three randomized, placebo‐controlled trials studying Japanese patients with chemotherapy‐induced anemia. All trials were conducted in compliance with Good Clinical Practice. A total of 511 patients with solid tumor or lymphoma (epoetin beta or darbepoetin alfa, n = 273; placebo, n = 238) were included. The ESA significantly reduced the risk of transfusion (relative risk, 0.47; 95% confidence interval, 0.29–0.76). No significant effect of the ESA on overall survival was observed (unadjusted hazard ratio, 1.00; 95% confidence interval, 0.75–1.34). A prespecified subgroup analysis showed no strong interaction between the baseline hemoglobin concentration and the effect of ESA on overall survival. Among the ESA‐treated patients, the highest hemoglobin achieved during the treatment period in each patient had no impact on mortality. No increase in thromboembolic events was observed in the ESA‐treated patients (0.7% vs 1.7% placebo). The ESA reduced the risk of transfusion without a negative impact on the survival of patients with chemotherapy‐induced anemia.

Aim: This study aimed to clarify the factors affecting the outcome of induction of labor (IOL) in a Japanese population and to develop a prediction model to assess the probability of emergent cesarean section (CS). Material and Methods: By reviewing the medical records of 1029 women who underwent IOL, we compared the emergent CS rate during IOL among subgroups divided by parity and pre-labor risk, such as fetal anomaly and maternal complication. We created a prediction model to predict the CS rate during IOL focusing on 392 cases of nulliparous women with premature rupture of membrane (PROM). Six factors, including Bishop score (BS), gestational age, maternal body mass index (BMI), maternal height (MH) and birth weight (BW) were extracted and multivariable logistic regression analysis followed by cross-validation test were performed. Results: The emergent CS rate was remarkably higher in the nulliparous group than in the multiparous group (17.6% vs 2.0%). In the nulliparous group, the high-risk group demonstrated a higher CS rate than the low-risk group (33.8% vs 15.6%). Multivariate analysis on nulliparous low-risk cases with PROM demonstrated significant odds ratios for emergent CS in BS, MH and BW. Cross-validation test selected these three factors as the best combination of parameters. The prediction formula was determined as follows: probability of CS (%) = (odds/1 + odds) ∗ 100, odds = eX and X = 8.18 + 1.23 ∗ BW (kg) − 7.74 ∗ MH (m) − 0.253 ∗ BS. Conclusion: This study is the first to provide a prediction formula targeting an Asian population. Our model, which is specialized for nulliparous low-risk women could enable obstetricians to inform patients of the precise prospect of IOL outcome.