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Lateral pelvic lymph node dissection for rectal cancer is challenging due to the complexity of the pelvic wall anatomy, and incomplete lateral pelvic lymph node dissection may result in local recurrence in the lateral pelvis. Although 3-dimensional printed organ models are useful for understanding spatial anatomy, it is currently unclear whether they improve surgical outcomes.We aimed to assess whether the surgical effectiveness of lateral pelvic lymph node dissection is increased by the use of individualized 3-dimensional printed pelvic models.This was a retrospective study using a propensity matching analysis.This study was conducted at a university hospital in Japan.In total, 115 patients comprising 184 pelvic sides (right, 85 sides; left, 99 sides) who underwent lateral pelvic lymph node dissection for colorectal adenocarcinoma between January 2012 and December 2019 were enrolled.We compared surgical outcomes using 3-dimensional printed pelvic models with control outcomes.The primary outcome was the number of harvested lateral pelvic lymph nodes on 1 pelvic side after the propensity matching analysis.After matching, 35 pelvic sides each were allocated to the 3-dimensional model and control groups, and no significant differences were observed in patient characteristics between the 2 groups. The number of harvested lateral pelvic lymph nodes was significantly higher in the 3-dimensional model group (median, 9; range, 3-16) than in the control group (median, 6; range, 0-22; p = 0.047).This was a retrospective study using propensity score matching. However, historical backgrounds were not matched, and the majority of lateral pelvic lymph node dissection procedures in the 3-dimensional model group were recently performed. This limitation may have influenced surgical outcomes.The present study demonstrated that, by referring to individualized 3-dimensional printed pelvic models, colorectal surgeons harvested a larger number of lateral pelvic lymph nodes during lateral pelvic lymph node dissection. This result suggests that 3-dimensional printed models help surgeons to complete more detailed procedures. See Video Abstract at http://links.lww.com/DCR/B776.ANTECEDENTES:La disección lateral de los ganglios linfáticos de la pelvis en el cáncer de recto es un desafío debido a la complejidad de la anatomía de la pared pélvica; la disección incompleta de las mismas puede resultar en una recidiva local en dicha zona. Aunque la impresión tridimensional de modelos de órganos es útil para comprender la estructura anatómica espacial, actualmente no está claro si mejoran los resultados quirúrgicos.OBJETIVO:Nuestro objetivo fue evaluar si la efectividad quirúrgica de la disección de los ganglios linfáticos laterales de la pelvis aumenta mediante el uso individualizado de modelos pélvicos impresos en 3D.DISEÑO:Este fue un estudio retrospectivo que utilizó un análisis de coincidencia de propensión.AJUSTE:Este estudio se realizó en un hospital universitario de Japón.PACIENTES:En total, se enrolaron 115 pacientes que comprendían 184 lados pélvicos (85 de lado derecho; 99 de lado izquierdo) que fueron sometidas a disección lateral de ganglios linfáticos de la pelvis por adenocarcinoma colorrectal entre enero de 2012 y diciembre de 2019.INTERVENCIONES:Comparamos los resultados quirúrgicos mediante modelos pélvicos tridimensionales impresos con los resultados de control.PRINCIPALES MEDIDAS DE RESULTADO:El resultado primario fue el número de ganglios linfáticos laterales pélvicos extraídos en un lado pélvico después del análisis de coincidencia de propensión.RESULTADOS:Después del emparejamiento, se asignaron 35 lados pélvicos cada uno, tanto al modelo tridimensional como al grupo de control; no se observaron diferencias significativas con respecto a las características de los pacientes entre los dos grupos. El número de ganglios linfáticos pélvicos laterales extraídos fue significativamente mayor en el grupo del modelo tridimensional (mediana, 9; rango 3-16) que en el grupo de control (mediana, 6; rango, 0-22) (p = 0.047).LIMITACIONES:Este fue un estudio retrospectivo que utilizó el emparejamiento por puntuación de propensión. Sin embargo, antecedentes históricos no fueron encontrados y la mayoría de los procedimientos de disección de los ganglios linfáticos laterales pélvicos en el grupo del modelo tridimensional se realizaron recientemente. Esta limitación pudo haber influido en los resultados quirúrgicos.CONCLUSIONES:El presente estudio demostró que al referirse a modelos pélvicos individualizados impresos en 3D, los cirujanos colorrectales recolectaron un mayor número de ganglios linfáticos laterales de la pelvis durante la disección lateral. Este resultado sugiere que los modelos tridimensionales impresos ayudan a los cirujanos a completar procedimientos más detallados. Consulte Video Resumen en http://links.lww.com/DCR/B776.

This study aimed to investigate the effect of sarcopenia on the prognosis of advanced lower rectal cancer patients receiving neoadjuvant chemoradiotherapy (CRT). Sarcopenia has been recognized as an adverse factor for surgical outcomes in several malignancies. However, the impact of preoperative sarcopenia on rectal cancer patients receiving CRT is still unknown. This retrospective study included cT3-T4 anyN M0 lower rectal cancer patients who underwent CRT followed by R0 resection at our institution between October 2003 and December 2016. CRT consisted of 5-fluorouracil-based oral chemotherapy and long course radiation (50.4 Gy/28 fr). The psoas muscle area at the third lumbar vertebra level was evaluated by computed tomography before and after CRT, and was adjusted by the square of the height to obtain the psoas muscle mass index (PMI). Sarcopenia was defined as the sex-specific lowest quartile of the PMI. We assessed the association between pre- and post-CRT sarcopenia and postoperative prognosis. Among 234 patients, 55 and 179 patients were categorized as sarcopenia and non-sarcopenia patients, respectively. Although post-CRT sarcopenia correlated with residual tumor size, it had no association with other pathological features. The median follow-up period was 72.9 months, and the 5-year DFS and OS were 67.0% and 85.8%, respectively. Multivariate analysis showed that post-CRT sarcopenia was independently associated with poor DFS (HR: 1.76; P = 0.036), OS (HR: 2.01; P = 0.049), and recurrence in the liver (HR: 3.01; P = 0.025). Sarcopenia is a poor prognostic indicator in lower advanced rectal cancer patients treated with CRT.

This study aimed to investigate the relationship between working overtime and psychological stress reactions among school teachers. It also evaluated the interaction of overtime work types (on weekdays, on holidays, and bringing work home) and task content (educational, peripheral and both). This cross-sectional study was conducted on Japanese elementary and junior high school teachers. Primary outcome was psychological stress reactions measured with the Brief Job Stress Questionnaire. Participants were asked how long they work overtime on weekdays, holidays, and at home. Participants were also asked whether they engaged in educational tasks and/or peripheral tasks during that overtime work. Multiple linear regression analyses were applied and 6,135 participants were included in the analyses after imputing missing data. Working hours of all three types were significantly correlated with higher psychological stress reactions. Moreover, engaging in both educational and peripheral tasks showed higher psychological stress reactions than in only educational tasks when working overtime on weekdays and holidays. In conclusion, reducing overtime work regardless of work types is crucial for mitigating psychological stress reactions for teachers. It might also be possible to manage the psychological stress reactions by splitting the role of task contents, when working overtime on weekdays and holidays at school.

Summary Background Systemic sclerosis is a connective tissue disease characterised by multiorgan fibrosis with an autoimmune background and poor prognosis. Although a few drugs have shown some efficacy in treating the disease, there remains a great unmet medical need. We aimed to investigate the efficacy and safety of rituximab in patients with systemic sclerosis. Methods We did a double-blind, investigator-initiated, randomised, placebo-controlled trial at four hospitals in Japan. Patients aged 20–79 years, who fulfilled the 2013 American College of Rheumatology and European League Against Rheumatism classification criteria for systemic sclerosis, with a modified Rodnan Skin Score (mRSS) of 10 or greater, and an expected survival of at least 6 months were randomly assigned (1:1) to receive intravenous rituximab (375 mg/m2) or placebo once per week for 4 weeks. Patients and investigators were masked to treatment allocation. The primary endpoint was the absolute change in mRSS 24 weeks after initiation of study treatment, measured in all patients who received at least one dose of study treatment and had one endpoint assessment. This study is registered with ClinicalTrials.gov, NCT04274257, and UMIN-CTR, UMIN000030139. Findings Between Nov 28, 2017, and Nov 6, 2018, 80 individuals were screened and 56 (70%) were enrolled and randomly assigned; 51 (91%) were women and five (9%) were men. 27 (96%) of 28 patients in the rituximab group and 22 (79%) of 28 patients in the placebo group received at least one dose of their allocated treatment and completed 24 weeks of follow-up. The absolute change in mRSS 24 weeks after initiation of study treatment was lower in the rituximab group than in the placebo group (−6·30 in the rituximab group vs 2·14 in the placebo group; difference −8·44 [95% CI −11·00 to −5·88]; p Interpretation Rituximab appears to be an effective and safe treatment for systemic sclerosis. Although this study has some limitations, this is the first clinical trial to show efficacy of rituximab with skin sclerosis as the primary endpoint. Funding Japan Agency for Medical Research and Development (AMED), Zenyaku Kogyo. Translation For the Japanese translation of the abstract see Supplementary Materials section.

We aimed to determine whether puncture sites for blood sampling and topical disinfectants are associated with rates of contaminated blood cultures in the emergency department (ED) of a single institution. This single-center, prospective observational study of 249 consecutive patients aged ≥ 20 years proceeded in the ED of a university hospital in Japan during 6 months. Pairs of blood samples were collected for aerobic and anaerobic culture from all patients in the ED. Physicians selected puncture sites and topical disinfectants according to their personal preference. We found 50 (20.1%) patients with potentially contaminated blood cultures. Fifty-six (22.5%) patients were true bacteremia and 143 (57.4%) patients were true negatives. Multivariate analysis associated more frequent contamination when puncture sites were disinfected with povidone-iodine than with alcohol/chlorhexidine (adjusted risk difference, 12.9%; 95% confidence interval [CI] 8.8–16.9; P P P = 0.013). Rates of contaminated blood cultures were significantly higher when blood was collected from femoral sites and when povidone-iodine was the topical antiseptic.

Aim Clinical staging is vital for selecting appropriate candidates and designing neoadjuvant treatment strategies for advanced tumors. The aim of this review was to evaluate diagnostic abilities of clinical TNM staging for gastrointestinal, gastrointestinal cancers. Methods We conducted a systematic review of recent publications to evaluate the accuracy of diagnostic modalities on gastrointestinal cancers. A systematic literature search was performed in PubMed/MEDLINE using the keywords “TNM staging,” “T4 staging,” “distant metastases,” “esophageal cancer,” “gastric cancer,” and “colorectal cancer,” and the search terms used in Cochrane Reviews between January 2005 to July 2020. Articles focusing on preoperative diagnosis of: (a) depth of invasion; (b) lymph node metastases; and (c) distant metastases were selected. Results After a full‐text search, a final set of 55 studies (17 esophageal cancer studies, 26 gastric cancer studies, and 12 colorectal cancer studies) were used to evaluate the accuracy of clinical TNM staging. Positron emission tomography–computed tomography (PET‐CT) and/or magnetic resonance imaging (MRI) were the best modalities to assess distant metastases. Fat and fiber mode of CT may be useful for T4 staging of esophageal cancer, CT was a partially reliable modality for lymph node staging in gastric cancer, and CT combined with MRI was the most reliable modality for liver metastases from colorectal cancer. Conclusion The most reliable diagnostic modality differed among gastrointestinal cancers depending on the type of cancer. Therefore, we propose diagnostic algorithms for clinical staging for each type of cancer., We conducted a systematic review of recent publications to evaluate the accuracy of diagnostic modalities on gastrointestinal cancers. Such systematic review on all three cancer types—esophageal cancer, gastric cancer, colorectal cancer—cannot be found in recent publications on PubMed. We believe that this review may be fundamental information to design clinical studies related to neoadjuvant therapy for gastrointestinal cancers.

Background The aim of this study was to evaluate the efficacy and safety of first-line chemotherapy with re-introduction of oxaliplatin (OX) more than 6 months after adjuvant chemotherapy including OX. Methods Stage II/III colon cancer patients with neuropathies of grade ≤ 1 who relapsed more than 6 months after adjuvant chemotherapy including OX were considered eligible. Eligible patients were treated with 5-fluorouracil, l-leucovorin and OX plus molecularly targeted agents or capecitabine and OX plus bevacizumab (BV) or S-1 and OX plus BV. The primary endpoint was the progression-free survival (PFS), and the secondary endpoints were the overall survival (OS), response rate (RR) and toxicity. Results A total of 50 patients were enrolled between September 2013 and May 2019. Twelve patients received 5-fluorouracil, l-leucovorin and OX (FOLFOX) plus BV, 21 patients received capecitabine and OX plus BV, 10 patients received S-1 and OX plus BV and 7 patients received FOLFOX plus cetuximab or panitumumab. The median PFS was 11.5 months (95% confidence interval [CI] 8.3–16.0), the median OS was 45.4 months (95% CI 37.4–NA), and the RR was 56.0% (95% CI 42.3–68.8). Adverse events of grade ≥ 3 that occurred in ≥ 5% of cases were neutropenia in 6 patients (12%), peripheral sensory neuropathy in 5 patients (10%), diarrhea in 4 patients (8%), hypertension in 4 patients (8%), anorexia in 3 patients (6%) and allergic reactions in 3 patients (6%). Conclusions First-line chemotherapy with re-introduction of OX more than 6 months after adjuvant chemotherapy including OX can be used safely with expected efficacy for relapsed colon cancer patients.

Background Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a mitochondrial fatty acid oxidation disorder that causes episodic attacks, such as general fatigue, hypotonia, myalgia, and rhabdomyolysis accompanied by lack of energy. As yet, there are no preventative drugs for these VLCADD-associated metabolic attacks. Patients and methods We conducted an open-label, non-randomized, multi-center study into the effects of bezafibrate on five patients with VLCADD. Bezafibrate was administered for 4 years, and we analyzed the number of myopathic attacks requiring hospitalization and treatment infusions. Results The number of myopathic attacks requiring infusions of 24 h or longer significantly decreased during the study period. The patients’ ability to conduct everyday activities was also improved by the treatment. Conclusion Our findings show the potential long-term efficacy of bezafibrate in preventing myopathic attacks for patients with VLCADD.

INTRODUCTION We aimed to investigate the effect of recent short-term weight gain on the incidence of nonalcoholic fatty liver disease (NAFLD) in nonobese (body mass index < 25 kg/m) participants. METHODS This retrospective cohort study included nonobese individuals who participated in an annual health checkup between 2008 and 2018 in Tokyo, Japan. We estimated the multivariable adjusted hazard ratio for the development of NAFLD diagnosed via ultrasound after a 3-kg unit gain in weight measured at a 2-year landmark time point postbaseline. Multivariable adjustments included weight change from the age of 20 and other relevant confounding factors. Sensitivity analyses using additional landmark time points at 1, 3, 4, and 5 years postbaseline and time-dependent Cox proportional hazards regressions were performed. RESULTS Among the 27,064 nonobese participants (142,699 person years of follow-up), 2,895 were diagnosed with NAFLD. Approximately 90% of the patients with NAFLD maintained their nonobese status before disease diagnosis. The adjusted hazard ratio for the development of NAFLD (for a 3-kg unit of weight gain) at the 2-year landmark time point postbaseline was 1.60 (95% confidence interval, 1.46-1.76) in nonobese men and 1.66 (95% confidence interval, 1.51-1.83) in nonobese women. This association was maintained in the sensitivity analyses. DISCUSSION Recent short-term weight gain is an independent risk factor for NAFLD development in nonobese men and women. Clinicians should be mindful of the association between weight gain and NAFLD onset, even in the nonobese population.

Aims A sodium glucose cotransporter 2 (SGLT2) inhibitor was recently found to reduce heart failure hospitalization in the EMPA‐REG OUTCOME trial. We have hypothesized that autonomic nerve activity may be modulated by SGLT2 inhibition. The current study aims to investigate the impact of empagliflozin on sympathetic and parasympathetic nerve activity in patients with type 2 diabetes mellitus. Methods and results This ongoing study is a prospective, randomized, open‐label, multicentre investigation of 134 patients with type 2 diabetes mellitus. The patients are randomly allocated to receive either empagliflozin or sitagliptin with the treatment goal of the Japan Diabetes Society guidelines. Ambulatory electrocardiographic monitoring is performed at the baseline and at 12 and 24 weeks of treatment. Analyses of heart rate variability are conducted using the MemCalc method, which is a combination of the maximum entropy method for spectral analysis and the non‐linear least squares method for square analysis. The primary endpoint is the change in the low‐frequency (0.04–0.15 Hz)/high‐frequency (0.15–0.4 Hz) ratio from baseline to 24 weeks. Conclusions This investigation on the effect of EMPagliflozin on cardiac sYmpathetic and parasympathetic neRve activity in JapanEse pAtieNts with type 2 diabetes (EMPYREAN study) offers an important opportunity to understand the impact of SGLT2 inhibition on autonomic nerve activity in patients with type 2 diabetes.

Advanced low rectal cancer has a non-negligible risk of lateral pelvic lymph node (LPLN) metastasis (LPLNM) and lateral local recurrence (LR) after neoadjuvant (chemo)radiotherapy and total mesorectal excision. LPLN dissection (LPLND) reduces LR but increases postoperative complications and sexual/urinary dysfunction. The aim of this study was to develop a new radiomics-based prediction model for LPLNM in patients with rectal cancer. A total of 247 patients with rectal cancer and enlarged LPLNs treated by (chemo)radiotherapy and LPLND were enrolled in this retrospective, multicenter study. LPLN radiomic features were extracted from pretreatment portal venous-phase computed tomography images. A radiomics score of LPLN was constructed based on the least absolute shrinkage and selection operator regression in a primary cohort of 175 patients. Model performance was assessed in terms of discrimination, calibration, and decision curve analysis, and was externally validated in 72 patients. The radiomics score showed significantly better discrimination compared with pretreatment short-axis diameter measurements in both the primary (area under the curve [AUC] 0.91 vs. 0.83, p = 0.0015) and validation (AUC 0.90 vs. 0.80, p = 0.0298) cohorts. Decision curve analysis also indicated the superiority of the radiomics score. In a subanalysis of patients with a short-axis diameter ≥ 7 mm, the radiomics nomogram, incorporating the radiomics score and LPLN shrinkage to ≤ 4 mm, had better discrimination compared with a model incorporating only LPLN shrinkage in both cohorts. Radiomics-based prediction modeling provides individualized risk estimation of LPLNM in rectal cancer patients treated with (chemo)radiotherapy, and outperforms measurements of pretreatment LPLN diameter.

Outlet obstruction is defined as bowel obstruction at the stoma opening. The aim of this study was to evaluate the risk factors for outlet obstruction in patients with rectal cancer who underwent laparoscopic surgery and diverting ileostomy. Among consecutive patients who underwent laparoscopic curative resection for primary rectal cancer between 2013 and 2015, 261 patients with diverting ileostomy were included in the analysis. The thickness of the abdominal wall, including the thickness of the rectus abdominis muscle, was measured using preoperative computed tomography. The clinicopathological factors were compared between the patients with and without outlet obstruction. Fourteen (5.4%) patients were diagnosed with outlet obstruction, but reoperation was not required. The rectus abdominis muscle was significantly thicker in male patients with outlet obstruction compared to those without outlet obstruction, but not in females. In a multivariate analysis, a rectus abdominis muscle thickness of 10 mm or more was determined to be an independent risk factor for outlet obstruction (odds ratio, 7.0482; p = 0.0061). The thickness of the rectus abdominis muscle may be used to predict the occurrence of outlet obstruction in male patients with rectal cancer who undergo laparoscopic surgery and diverting ileostomy.

Edge restenosis has still been reported after second-generation drug-eluting stent (DES) implantation. It was more likely attributable to post-procedural angiographic results than to the patient’s background. The aim of this study was to develop and internally validate a prediction model for restenosis in proximal edge after 2nd-generation DES stent implantation using angiographic data. Data were obtained from several post-marketing surveillance (PMS) studies of the cobalt–chromium everolimus-eluting stent (CoCr-EES) and platinum–chromium everolimus-eluting stent (PtCr-EES), second-generation DES, in Japan. Angiographic analysis was conducted at baseline and after 8 or 12 months. We focused on the proximal edge of angiographic analysis. The main outcome was restenosis defined as ≥ 50% diameter stenosis at follow-up. The predictive performance of the prediction model based on multivariable logistic regression was assessed in terms of discrimination and calibration, which were internally validated by the bootstrap method. We also performed decision curve analysis to assess threshold of predicted probability of restenosis at which additional intervention was considered. Among 2053 lesions in 1860 patients, restenosis rates in proximal edge was 2.8%. The final model was constructed with % post-procedural diameter stenosis (DS) and post-procedural reference diameter (RD) as strong predictors for edge restenosis. Discrimination and calibration were satisfactory with optimism-corrected C-statistics 0.75. Predicted probability between 0.03 and 0.24 was preferable threshold for restenosis treatments. Our prediction model can be used to obtain valid prediction for restenosis in proximal edge, assisting to know complete stent coverage of lesion.

The prognostic value of classifying the degree of metastatic lymph node regression grade after neoadjuvant chemoradiotherapy remains unclear. The aim was to assess the prognostic value of lymph node regression grade in patients with rectal cancer treated with chemoradiotherapy.We reviewed a total of 421 patients with rectal cancer who underwent neoadjuvant long-course chemoradiotherapy. All lymph nodes were examined retrospectively for evidence of response to chemoradiotherapy, and lymph node regression grade was scored as lymph node regression grade 0 (normal lymph node), lymph node regression grade 1 (100% fibrosis), lymph node regression grade 2 ( 25% cancer cells), lymph node regression grade 3 (25%-50% cancer cells), lymph node regression grade 4 (50%-75% cancer cells), and lymph node regression grade 5 (75% cancer cells). The prognostic importance of lymph node regression grade was evaluated.Among 301 ypN0 patients, 27 patients were scored as lymph node regression grade 1. The 5-year recurrence-free survival and local recurrence rates in lymph node regression grade 1 patients were similar to those in lymph node regression grade 0 patients (96.3% versus 88.1% in recurrence-free survival and 0% versus 2.7% in local recurrence); however, among 120 ypN+ (lymph node regression grade 2-5) patients, the 5-year recurrence-free survival and local recurrence rates were poor regardless of the lymph node regression grade score (38.1%-61.1% in recurrence-free survival and 8.4%-14.0% in local recurrence). In the multivariate analysis, an intensified regimen using systemic chemotherapy was independently associated with more lymph node regression grade 1 (P.001; odds ratio, 6.06; 95% confidence interval, 2.33-16.20) among patients with lymph node regressions grade 1 through 5. Furthermore, in the multivariate analysis, ypT3-4 (hazard ratio, 7.82; 95% confidence interval, 2.80-27.32; P.001), lymph node regression grade 1 (hazard ratio, 0.048; 95% confidence interval, 0.002-0.27; P.001), the number of retrieved lymph nodes12 (hazard ratio, 5.48; 95% confidence interval, 1.48-16.38; P = .014), and no perioperative chemotherapy (hazard ratio, 3.01; 95% confidence interval, 1.53-5.68; P = .002) were independent predictors of recurrence-free survival.Complete lymph node regression after chemoradiotherapy is a strong prognostic factor in rectal cancer.

The prognosis of patients with type 4 scirrhous gastric cancer remains poor due to a high risk of peritoneal metastasis. We have previously developed combined chemotherapy regimens of intraperitoneal (IP) paclitaxel (PTX) and systemic chemotherapy, and promising clinical efficacy was reported in gastric cancer with peritoneal metastasis. Herein, a randomized, phase III study is proposed to verify the efficacy of IP PTX to prevent peritoneal recurrence. Gastric cancer patients with type 4 tumors and without apparent distant metastasis, including peritoneal metastasis, will be randomized for standard systemic chemotherapy or combined IP and systemic chemotherapy based on peritoneal lavage cytology findings. Those with negative peritoneal cytology will receive radical gastrectomy and adjuvant chemotherapy of S-1 plus docetaxel (control arm), or S-1 plus intravenous and IP PTX (experimental arm). Those with positive peritoneal cytology will receive three courses of S-1 plus oxaliplatin (control arm), or S-1 plus oxaliplatin and IP PTX (experimental arm). Subsequently, they undergo gastrectomy and receive postoperative chemotherapy of S-1 plus docetaxel (control arm), or S-1 plus intravenous and IP PTX (experimental arm). The primary endpoint is disease free survival after a 3-year follow-up period. Secondary endpoints are overall survival, survival without peritoneal metastasis, safety, completion rate, curative resection rate, and histological response of preoperative chemotherapy. A total of 300 patients are to be enrolled.

According to the current international guidelines, high-risk patients diagnosed with pathological T1 (pT1) colorectal cancer (CRC) who underwent complete local resection but may have risk of developing lymph node metastasis (LNM) are recommended additional intestinal resection with lymph node dissection. However, around 90% of the patients without LNM are exposed to the risk of being overtreated due to the insufficient pathological criteria for risk stratification of LNM. Circulating tumor DNA (ctDNA) is a noninvasive biomarker for molecular residual disease and relapse detection after treatments including surgical and endoscopic resection of solid tumors. The CIRCULATE-Japan project includes a large-scale patient-screening registry of the GALAXY study to track ctDNA status of patients with stage II to IV or recurrent CRC that can be completely resected. Based on the CIRCULATE-Japan platform, we launched DENEB, a new prospective study, within the GALAXY study for patients with pT1 CRC who underwent complete local resection and were scheduled for additional intestinal resection with lymph node dissection based on the standard pathologic risk stratification criteria for LNM. The aim of this study is to explore the ability of predicting LNM using ctDNA analysis compared with the standard pathological criteria. The ctDNA assay will build new evidence to establish a noninvasive personalized diagnosis in patients, which will facilitate tailored/optimal treatment strategies for CRC patients.

Objective Associations between hospital treatment volume and survival outcomes for women with 3 types of gynecologic malignancies, and the trends and contributing factors for high-volume centers were examined. Methods The Japan Society of Obstetrics and Gynecology tumor registry databased retrospective study examined 206,845 women with 80,741, 73,647, and 52,457 of endometrial, cervical, and ovarian tumor, respectively, who underwent primary treatment in Japan between 2004 and 2015. Associations between the annual treatment volume and overall survival (OS) for each tumor type were examined using a multivariable Cox proportional hazards model with restricted cubic splines. Institutions were categorized into 3 groups (low-, moderate-, and high-volume centers) based on hazard risks. Results Hazard ratio (HR) for OS each the 3 tumors decreased with hospital treatment volume. The cut-off points of treatment volume were defined for high- (≥50, ≥51, and ≥27), moderate- (20–49, 20–50, and 17–26), and low-volume centers (≤19, ≤19, and ≤16) by cases/year for endometrial, cervical, and ovarian tumors, respectively. Multivariate analysis revealed younger age, rare tumor histology, and initial surgical management as contributing factors for women at high-volume centers (all, p, Synopsis For women with gynecologic malignancy, hospital treatment volume had an impact on survival outcome. The practice pattern shifted with scattering of patients and treatments at high-volume centers were decreasing. High-volume centers in Japan were associated with improved overall survival of gynecologic malignancies.

The benefit of rituximab (RTX) for systemic sclerosis-associated interstitial lung disease (SSc-ILD) has been shown in previous clinical trials. However, predictors of RTX efficacy have not been clarified. We investigated whether B-cell responsiveness to RTX is related to therapeutic effect. Ten SSc-ILD patients treated with RTX in an independent clinical trial (Japan Registry of Clinical Trials, jRCTs031180373) were included in this analysis. Peripheral B-cell counts were examined retrospectively before RTX administration (baseline) and at 2, 4, 12, and 24 weeks after the first RTX administration, along with percent-predicted forced vital capacity (%FVC) before and 24 weeks after RTX treatment. Relative to baseline, the percentage of residual peripheral blood B cells at 2 weeks after RTX was negatively correlated with the %FVC improvement at the 24-week assessment (r = -0.41, p = 0.04). In the subgroup with less than 5% B-cell persistence at week 2, %FVC at the 24-week assessment was significantly improved compared to baseline (p = 0.02). In another subgroup with more than 5% residual B cells, %FVC was not significantly different after 24 weeks compared to baseline (p = 0.41). In conclusion, the removal rate of B cells after 2 weeks of RTX treatment may be a useful surrogate marker of subsequent SSc-ILD improvement.

ObjectivesThe aim of this study is to determine whether the ‘programmed’ infliximab (IFX) treatment strategy (for which the dose of IFX was adjusted based on the baseline serum tumour necrosis factor α (TNF-α)) is beneficial to induction of clinical remission after 54 weeks and sustained discontinuation of IFX for 1 year.MethodsIn this multicentre randomised trial, patients with IFX-naïve rheumatoid arthritis with inadequate response to methotrexate were randomised to two groups; patients in programmed treatment group received 3 mg/kg IFX until week 6 and after 14 weeks the dose of IFX was adjusted based on the baseline levels of serum TNF-α until week 54; patients in the standard treatment group received 3 mg/kg of IFX. Patients who achieved a simplified disease activity index (SDAI) ≤3.3 at week 54 discontinued IFX. The primary endpoint was the proportion of patients who sustained discontinuation of IFX at week 106.ResultsA total of 337 patients were randomised. At week 54, 39.4% (67/170) in the programmed group and 32.3% (54/167) in the standard group attained remission (SDAI ≤3.3). At week 106, the 1-year sustained discontinuation rate was not significantly different between two groups; the programmed group 23.5% (40/170) and the standard group 21.6% (36/167), respectively (2.2% difference, 95% CI −6.6% to 11.0%; p=0.631). Baseline SDAI ConclusionProgrammed treatment strategy did not statistically increase the sustained remission rate after 1 year discontinuation of IFX treatment.

Edge restenosis has gained attention as a main cause of restenosis after first-generation drug-eluting stent (DES) implantation. The aim of this study was to assess the incidence of edge restenosis and identify the predictors of edge restenosis after second-generation DES implantation. Data were obtained from several postmarketing surveillance (PMS) studies on a cobalt-chromium everolimus-eluting stent (CoCr-EES; Xience V/PROMUS, Xience Prime, Xience Prime SV, and Xience Expedition SV), a second-generation DES, in Japan. Angiographic analysis was conducted at the baseline and after eight months on the following subsegments: in-stent region, proximal edge, and distal edge. Restenosis was defined as ≥ 50% diameter stenosis (DS) at follow-up. We used multivariate logistic regression (with lesions as a random effect) to compare the instances of restenosis between the proximal and the distal edges. Univariate and multivariate analyses of the risk factors for restenosis were performed for each subsegment. We analyzed 1,966 lesions in 1,687 patients. The restenosis rates at the in-stent region, proximal edge, and distal edge were 4.4%, 3.0%, and 1.1%, respectively. The risk of restenosis at the distal edge was significantly lower than that at the proximal edge, when adjusted for 13 variables. The predictors of restenosis were postprocedural % diameter stenosis (%DS), postprocedural reference diameter, ≥ 45° bending, stent overlap at the proximal edge, and postprocedural %DS at the distal edge. Our analysis of eight-month angiographic outcomes from CoCr-EES PMS demonstrated that postprocedural %DS is a major predictor of edge restenosis. Edge restenosis is more likely attributable to postprocedural angiographic results than to the patient's background.

Purpose Adjuvant FOLFOX therapy is an established standard-of-care for resected colon cancer. Peripheral sensory neuropathy (PSN) is regarded as the major toxicity issue related to FOLFOX therapy. There have been a few reports on the recovery status from PSN thereafter. JOIN trial investigated the tolerability and efficacy of adjuvant modified FOLFOX6 (mFOLFOX6) in Japanese patients with stage II/III colon cancer. Methods Twelve cycles of mFOLFOX6 were given to patients with stage II/III curatively resected colon cancer. Treatment outcomes, including disease-free survival (DFS), relapse-free survival (RFS), overall survival (OS), and recovery status of PSN during 3-year follow-up, were investigated. Results Of the 882 patients enrolled from 2010 to 2012, 864 were eligible for the efficacy analyses. Three-year DFS, RFS, and OS were favorable in 92.1, 92.8, and 97.4% of stage II patients; 76.4, 77.9, and 93.8% of stage IIIA/B; and 61.6, 62.7, and 85.9% of stage IIIC, respectively. The cumulative incidence of PSN during treatment was 47.8% in grade 1 (G1), 30.3% in G2, and 5.8% in G3. For those with G3 PSN during treatment, there was gradual recovery in 1.1% of patients at 12 months after enrollment, 0.5% at 24 months, and 0.2% at 36 months. However, G1 or G2 residual PSN after 3 years was observed in 21.0% (18.7%, G1; 2.3%, G2). Conclusions Adjuvant mFOLFOX6 therapy was effective and well tolerated in patients with stage II/III colon cancer. Most patients recovered from G3 PSN related to oxaliplatin, but approximately 20% of patients had G1 or G2 PSN at 3-year follow-up.

Background Fluorouracil (5-FU), leucovorin (LV) and oxaliplatin (FOLFOX) plus panitumumab therapy is a commonly used first-line chemotherapy for metastatic colorectal cancer (mCRC). However, the long-term administration of oxaliplatin is associated with peripheral neuropathy (PN). We investigated whether the planned discontinuation of oxaliplatin after FOLFOX plus panitumumab therapy can maintain efficacy and reduce PN incidence. Patients and methods Chemotherapy-naive patients with RAS wild-type mCRC, aged ≥20 years, were enrolled and received six cycles of modified FOLFOX6 (mFOLFOX6) plus panitumumab as induction therapy. Patients who completed induction therapy without progression were randomised to mFOLFOX6 plus panitumumab (group A) or to 5-FU/LV plus panitumumab (group B). The primary end-point was the progression-free survival (PFS) rate at 9 months after randomisation. The secondary end-points were PFS, overall survival (OS), time to treatment failure (TTF), response rate (RR) and safety. Results In total, 164 patients were enrolled; of whom, 113 patients were then randomised (group A, n = 56; group B, n = 57). The median follow-up after randomisation was 19.6 months. The PFS rates at 9 months and median PFS were 46.4% (80% confidence interval [CI], 38.1–54.9) and 9.1 months (95% CI, 8.6–11.1) in group A, compared with 47.4% (80% CI, 39.1–55.8) and 9.3 months (95% CI, 6.0–13.0) in group B, respectively. RR, OS and TTF were also similar in both groups. Grade ≥2 PN incidence was lower in group B (9.3%) than in group A (35.7%). Conclusion Planned discontinuation of oxaliplatin after six cycles of mFOLFOX6 plus panitumumab is a potential treatment option in patients with mCRC, achieving similar efficacy while reducing oxaliplatin-associated PN compared with mFOLFOX6 plus panitumumab. Trial registration number NCT02337946

Early detection of postoperative recurrence is beneficial for patients with cancer; however, optimal surveillance remains an issue. To optimize the follow-up plan, the estimation of an individual patient's risk of recurrence is indispensable.This study aimed to establish a statistical model for predicting the risk of organ-specific recurrence after curative resection of colon cancer.This was a retrospective cohort study at a tertiary referral hospital.This study included 1720 patients with colon cancer treated at the University of Tokyo Hospital between 1997 and 2015. Data were retrospectively retrieved from patient medical charts. The risk score was developed using a competing risk model in a derivation cohort (973 patients treated in 1997-2009) and then validated in a validation cohort (747 patients treated in 2010-2015).Patients who underwent curative resection for stage I to III colon cancer were included.The prediction of the incidence of postoperative liver and lung metastasis of colon cancer was measured.The factors selected for the prediction model for liver metastasis included differentiation, T category, venous invasion, N category, and preoperative CEA level. The model for lung metastasis included sex, lymphatic invasion, venous invasion, N category, preoperative CEA level, and malignant bowel obstruction. During external validation, the area under the curve at 60 months was 0.78 (95% CI, 0.71-0.84) for liver metastasis and 0.72 (95% CI, 0.64-0.81) for lung metastasis.The generalizability of the model to different healthcare settings remains to be elucidated.We developed a prediction model to estimate the risk of recurrence in the liver and lung after curative resection of colon cancer, which demonstrated good discrimination ability in the external validation cohort. Our model can aid clinicians and patients in customizing postoperative surveillance according to an individual patient's risk of organ-specific recurrence. See Video Abstract at http://links.lww.com/DCR/A977. DESARROLLO Y VALIDACIÓN DE UN MODELO DE PREDICCIÓN PARA RECURRENCIAS ESPECÍFICAS DESPUÉS DE RESECCIÓN CURATIVA DE UN CÁNCER DE COLON: La detección temprana de una recidiva postoperatoria es beneficiosa para los pacientes afectados de cáncer. Sin embargo, la mejor vigilancia sigue siendo un problema. Para optimizar el plan de seguimiento, la estimación del riesgo individual de recurrencia de un paciente es indispensable.Establecer un modelo estadístico para predecir el riesgo de recurrencia en un organo específico luego de la resección curativa de un cáncer de colon. DISEÑO:: Estudio retrospectivo de cohortes en un hospital de referencia terciaria.Este estudio incluyó 1720 pacientes con cáncer de colon tratados en el Hospital de la Universidad de Tokio entre 1997 y 2015. Los datos se recuperaron retrospectivamente de las historias clinicas de los pacientes. La puntuación de riesgo fué desarrollada utilizando un modelo de riesgo competitivo en cohortes de derivación (973 pacientes tratados en 1997-2009) y luego se lo validó en cohortes de validación (747 pacientes tratados en 2010-2015).Todos aquellos casos que se sometieron a una resección curativa de cáncer de colon en estadio I-III RESULTADOS PRINCIPLES:: La predicción de la incidencia de metástasis hepáticas y pulmonares postoperatorias del cáncer de colon.Los factores seleccionados para el modelo de predicción de metástasis hepáticas incluyeron diferenciación tumoral, categoría T, invasión venosa, categoría N y nivel de antígeno carcinoembrionario preoperatorio. El modelo de predicción de metástasis pulmonar incluyó el sexo del paciente, la invasión linfática, la invasión venosa, la categoría N, el nivel de antígeno carcinoembrionario preoperatorio y la obstrucción intestinal maligna. Durante la validación externa, el área inferior de la curva a 60 meses fue de 0,78 (intervalo de confianza del 95%: 0,71 a 0,84) para las metástasis hepáticas y de 0,72 (intervalo de confianza del 95%: 0,64 a 0,81) para las metástasis pulmonares.La generalización del presente modelo a diferentes entornos de atención en salud aún no ha podido ser dilucidado.Desarrollamos un modelo de predicción para estimar el riesgo de recurrencia en el hígado y el pulmón después de resección curativa de cáncer de colon, éste modelo demostró una buena capacidad de discriminación en las cohortes de validación externa. El modelo puede ayudar a médicos y pacientes a personalizar la vigilancia postoperatoria de acuerdo con el riesgo individual de recurrencia específica en un órgano específico. Vea el Resumen del Video en http://links.lww.com/DCR/A977.

Background There is a lack of large studies focusing on the prognostic significance of lateral lymph node (LLN) metastasis following LLN dissection (LLND) in rectal cancer. The aim of this study was to evaluate the prognostic impact of LLN metastases on survival of patients with advanced low rectal cancer. Methods Consecutive patients with locally advanced, but not metastatic, extraperitoneal rectal cancer treated with neoadjuvant (chemo)radiotherapy plus total mesorectal excision between 2004 and 2015 were included in the study. LLND was performed when pretreatment imaging documented enlarged LLNs (7 mm or greater in size). Localization of nodal metastases and long‐term outcomes were analysed. Kaplan–Meier analysis was used to compare the survival of patients with ypN0 disease with that of patients with mesorectal ypN+/LLN− status and patients with positive LLNs. The Cox proportional hazards model was used to evaluate predictors of disease‐free survival (DFS) and local recurrence. Results A total of 613 patients were included in the study; LLND was performed in 212 patients (34·6 per cent) and 57 (9·3 per cent) had LLN metastasis. Patients with LLN metastasis had improved DFS and local recurrence cumulative incidence rates compared with patients with mesorectal ypN2+/LLN− disease (DFS: P = 0·014; local recurrence: P = 0·006). Although the DFS rate of patients with LLN metastasis was worse than that of patients with ypN0 disease (P, The prognostic significance of residual lateral lymph node metastasis following neoadjuvant (chemo)radiotherapy and lateral lymph node dissection in patients with advanced low rectal cancer remains unknown. This study shows that residual lateral lymph node metastasis after (chemo)radiotherapy can be considered an intermediate‐risk disease, similar to residual mesorectal ypN1 disease. Lateral nod dissection and rectal cancer

Background/Aims A risk-based approach to clinical research may include a central statistical assessment of data quality. We investigated the operating characteristics of unsupervised statistical monitoring aimed at detecting atypical data in multicenter experiments. The approach is premised on the assumption that, save for random fluctuations and natural variations, data coming from all centers should be comparable and statistically consistent. Unsupervised statistical monitoring consists of performing as many statistical tests as possible on all trial data, in order to detect centers whose data are inconsistent with data from other centers. Methods We conducted simulations using data from a large multicenter trial conducted in Japan for patients with advanced gastric cancer. The actual trial data were contaminated in computer simulations for varying percentages of centers, percentages of patients modified within each center and numbers and types of modified variables. The unsupervised statistical monitoring software was run by a blinded team on the contaminated data sets, with the purpose of detecting the centers with contaminated data. The operating characteristics (sensitivity, specificity and Youden’s J-index) were calculated for three detection methods: one using the p-values of individual statistical tests after adjustment for multiplicity, one using a summary of all p-values for a given center, called the Data Inconsistency Score, and one using both of these methods. Results The operating characteristics of the three methods were satisfactory in situations of data contamination likely to occur in practice, specifically when a single or a few centers were contaminated. As expected, the sensitivity increased for increasing proportions of patients and increasing numbers of variables contaminated. The three methods showed a specificity better than 93% in all scenarios of contamination. The method based on the Data Inconsistency Score and individual p-values adjusted for multiplicity generally had slightly higher sensitivity at the expense of a slightly lower specificity. Conclusions The use of brute force (a computer-intensive approach that generates large numbers of statistical tests) is an effective way to check data quality in multicenter clinical trials. It can provide a cost-effective complement to other data-management and monitoring techniques.

Chemotherapy‐induced nausea and vomiting are common adverse effects associated with the use of cytotoxic chemotherapy drugs. This article evaluates differences in complete response rates and other antiemetic outcomes in dexamethasone‐spacing regimens., Background. A dexamethasone‐sparing regimen consisting of palonosetron plus 1‐day dexamethasone for the prevention of chemotherapy‐induced nausea and vomiting (CINV) has been studied previously. Here, we evaluate the noninferiority of the dexamethasone‐sparing regimen in overall antiemetic control using a meta‐analysis based on individual patient data (IPD). Materials and Methods. We conducted a systematic review for randomized trials reporting CINV outcomes for the comparison of palonosetron plus 1‐day dexamethasone (d1 arm) versus the same regimen followed by dexamethasone on days 2–3 after chemotherapy (d3 arm) in chemotherapy‐naïve adult patients undergoing either moderately emetogenic chemotherapy (MEC) or anthracycline plus cyclophosphamide (AC)‐containing chemotherapy. PubMed and MEDLINE were searched electronically. A manual search was also conducted. The primary endpoint was complete response (CR; no emesis and no rescue medication) in the overall 5‐day study period. The noninferiority margin was set at −8.0% (d1 arm−d3 arm). Results. Five studies (n = 1,194) were eligible for analysis and all IPD was collected. In the overall study period, the d1 arm showed noninferiority to the d3 arm for CR as well as complete control (pooled risk difference in CR rate − 1.5%, 95% confidence interval [CI] −7.1 to 4.0%, I2 = 0%; in complete control rate − 2.4%, 95% CI −7.7 to 2.9%, I2 = 0%). There was no significant interaction between dexamethasone regimen and risk factors (type of chemotherapy, sex, age, and alcohol consumption). Conclusion. This IPD meta‐analysis indicates that the dexamethasone‐sparing regimen is not associated with a significant loss in overall antiemetic control in patients undergoing MEC or AC‐containing chemotherapy, irrespective of known risk factors for CINV. Implications for Practice. Although dexamethasone in combination with other antiemetic agents has been used to prevent chemotherapy‐induced nausea and vomiting (CINV), it is of clinical importance to minimize total dose of dexamethasone in patients undergoing multiple cycles of emetogenic chemotherapy. This individual‐patient‐data meta‐analysis from five randomized controlled trials (1,194 patients) demonstrated a noninferiority of the dexamethasone‐sparing regimen for complete response and complete control of CINV. The outcomes were comparable across patients with different characteristics. These findings thus help physicians minimize use of the steroid and further reduce the burden of dexamethasone‐related side effects in patients undergoing multiple consecutive courses of emetogenic chemotherapy.

Objective To evaluate the efficacy and safety of perampanel in patients with sporadic amyotrophic lateral sclerosis (SALS). Methods This randomized, double-blind, placebo-controlled, multicenter, phase 2 clinical study was conducted at 12 sites. Patients with probable or definite ALS as defined by revised El Escorial criteria were enrolled. Sixty-six patients were randomly assigned (1:1:1) to receive placebo, 4 mg perampanel, or 8 mg perampanel daily for 48 weeks. Adverse events (AEs) were recorded throughout the trial period. The primary efficacy outcome was the change in Amyotrophic Lateral Sclerosis Rating Scale-Revised (ALSFRS-R) score after 48 weeks of treatment. Results One patient withdrew before starting the treatment. Of 65 patients included, 18 of 22 patients randomized to placebo (82%), 14 of 22 patients randomized to 4 mg perampanel (64%), and 7 of 21 patients randomized to 8 mg perampanel (33%) completed the trial. There was a significant difference in the change of ALSFRS-R scores [− 8.4 (95% CI − 13.9 to − 2.9); p = 0.015] between the placebo and the perampanel 8 mg group, primarily due to worsening of the bulbar subscore in the perampanel 8 mg group. Serious AEs were more frequent in the perampanel 8 mg group than in the placebo group (p = 0.0483). Conclusions Perampanel was associated with a significant decline in ALSFRS-R score and was linked to worsening of the bulbar subscore in the 8 mg group.

Background and objectives: The net treatment effect ( increment ) is a new method to assess the treatment benefit that combines multiple time-to-event, binary and continuous endpoints according to a pre-specified sequence. It represents the net probability for a random patient treated in the experimental arm to have a better overall outcome than a random patient from the control arm does. We aimed at characterizing the impact of follow-up on increment estimated from both time-to-event and binary toxicity endpoints, in randomized controlled trials (RCTs) of irinotecan-based regimen in advanced/metastatic gastric cancer (AGC).Study design: Three RCTs are reanalysed. The net treatment effect using from one to three outcomes (i.e. overall survival, time to progression and toxicity in this order) and the hazard ratio (HR) were estimated after various cut-off dates and compared to the values obtained after complete follow-up were reported. Results: In all three RCTs (897 patients), the irinotecan-based regimen was superior to the non-irinotecan containing regimen in terms of HR and increment . This superiority was lower when the net treatment effect also accounted for toxicity. The HR was slightly less influenced by an incomplete follow-up than increment was, but correction proposed by Pe & acute;ron to account for censored observations showed quite robust results.Conclusions: The net treatment effect using Pe & acute;ron's correction can be used in case of interim analyses or high censoring rates. In addition to relative measures such as the hazard ratio, it provides a simple mean to evaluate the net treatment effect with and without toxicity outcomes. This work was partially funded by a French governmental grant from the Programme Hospitalier pour la Recherche Clinique (PHRC). The funder had no involvement neither in the data collection, design, analysis nor interpretation of the data. We are strongly indebted to the F ́ed ́eration Francophone de Canc ́erologie Digestive (FFCD) Group, the Gastrointestinal Oncology Study Group of the Japan Clinical Oncology Group and Sanofi for providing individual patients data to the GASTRIC collaboration. The trials’ sponsors were not involved in the design, the analysis and interpretation of this contribution. We thank the GASTRIC collaboration for giving access to their data collection

Background We aimed to assess the safety and efficacy of combination treatment with panitumumab plus trifluridine/tipiracil (FTD/TPI) in patients with wild-type RAS metastatic colorectal cancer (mCRC) who were refractory/intolerant to standard therapies other than anti-epidermal growth factor receptor therapy. Methods APOLLON was an open-label, multicentre, phase 1/2 trial. In the phase 1 part, 3 + 3 de-escalation design was used to investigate the recommended phase 2 dose (RP2D); all patients in the phase 2 part received the RP2D. The primary endpoint was investigator-assessed progression-free survival (PFS) rate at 6 months. Secondary endpoints included PFS, overall survival (OS), overall response rate (ORR), disease control rate (DCR), time to treatment failure (TTF), and safety. Results Fifty-six patients were enrolled (phase 1, n = 7; phase 2, n = 49) at 25 Japanese centres. No dose-limiting toxicities were observed in patients receiving panitumumab (6 mg/kg every 2 weeks) plus FTD/TPI (35 mg/m2 twice daily; days 1–5 and 8–12 in a 28-day cycle), which became RP2D. PFS rate at 6 months was 33.3% (90% confidence interval [CI] 22.8–45.3). Median PFS, OS, ORR, DCR, and TTF were 5.8 months (95% CI 4.5–6.5), 14.1 months (95% CI 12.2–19.3), 37.0% (95% CI 24.3–51.3), 81.5% (95% CI 68.6–90.8), and 5.8 months (95% CI 4.29–6.21), respectively. Neutrophil count decreased (47.3%) was the most common Grade 3/4 treatment-emergent adverse event. No treatment-related deaths occurred. Conclusion Panitumumab plus FTD/TPI exhibited favourable anti-tumour activity with a manageable safety profile and may be a therapeutic option for pre-treated mCRC patients.

Background Although the efficacy of trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) against metastatic colorectal cancer (mCRC) has been demonstrated, little is known about its effectiveness upon disease stratification by RAS mutations. In this phase II study, we investigated the efficacy and safety profiles of FTD/TPI in mCRC according to RAS mutation status. Patients and methods Eligible patients were mCRC refractory or intolerant to all standard therapies other than FTD/TPI and regorafenib. Patients received 4-week cycles of treatment with FTD/TPI (35 mg/m2, twice daily, days 1-5 and 8-12) and bevacizumab (5 mg/kg, days 1 and 15). The primary endpoint was disease control rate (DCR). The null hypothesis of DCR in both RAS wild-type (WT) and mutant (MUT) cohorts was 44%, assuming a one-sided significance level of 5.0%. The necessary sample size was estimated to be 49 patients (target sample size: 50 patients) for each cohort. Results Between January and September 2018, 102 patients were enrolled, and 97 patients fulfilled the eligibility criteria (48 in the RAS WT cohort and 49 in the RAS MUT cohort). DCRs in the RAS WT and MUT cohort were 66.7% [90% confidence interval (CI), 53.9%-77.8%, P = 0.0013] and 55.1% (90% CI, 42.4%-67.3%, P = 0.0780), respectively. The median progression-free survival (PFS) and overall survival (OS) were 3.8 and 9.3 months, respectively, in the RAS WT cohort and 3.5 and 8.4 months, respectively, in the RAS MUT cohort. The most common grade 3 or higher adverse event in both cohorts was neutropenia (46% in the RAS WT cohort and 62% in the RAS MUT cohort), without unexpected safety signals. Conclusions FTD/TPI plus bevacizumab showed promising activity with an acceptable safety profile for pretreated mCRC, regardless of RAS mutation status, although the efficacy outcomes tended to be better in RAS WT., Highlights • We investigated the efficacy and safety of FTD/TPI in mCRC according to RAS mutation status. • DCRs in the RAS WT and MUT cohorts were 66.7% and 55.1%, respectively. • PFS and OS did not differ significantly according to RAS mutation status. • The most common adverse event (grade 3 or higher) in both cohorts was neutropenia. • FTD/TPI plus BEV treatment showed promising activity for pretreated mCRC, regardless of RAS mutation status.

Background First-line treatment with FOLFOXIRI plus bevacizumab (BEV) is highly effective and regarded as one of the standards-of-care for patients with metastatic colorectal cancer (mCRC), despite the high incidence of neutropenia and diarrhea as side effects. AXEPT, an Asian phase III study, showed that modified CAPIRI+BEV [capecitabine (CAP: 1600 mg/m2), irinotecan (IRI: 200 mg/m2), and BEV (7.5 mg/m2)] was non-inferior to FOLFIRI+BEV as a second-line therapy for mCRC patients and was associated with a lower incidence of hematologic toxicities. Thus, a reduced dose of the CAP and IRI regimen in combination with oxaliplatin (OX) and BEV (CAPOXIRI+BEV) may be more feasible than FOLFOXIRI+BEV, without compromising efficacy. Methods QUATTRO-II is an open-label, multicenter, randomized phase II study. In Step 1, the recommended doses of OX and IRI will be investigated as a safety lead-in. In Step 2, patients will be randomized to the recommended dose of either CAPOXIRI+BEV or FOLFOXIRI+BEV. Induction triplet chemotherapy plus BEV treatments will be administered for up to 4 months followed by fluoropyrimidine plus BEV maintenance. The primary endpoint is progression-free survival (PFS). The similarity in PFS between the two arms will be evaluated by observing whether the point estimate of hazard ratio (HR) for PFS falls between 0.80 and 1.25. Ensuring a 70% probability that the observed HR will be “0.8 Discussion Considering the lower incidence of hematologic toxicities with modified CAPIRI+BEV than with FOLFIRI+BEV, CAPOXIRI+BEV may be a promising treatment option if sufficient efficacy and lower hematologic toxicities are indicated in this study. Additionally, a lower incidence of peripheral sensory neuropathy (PSN) reported following CAPEOX treatment compared to that after FOLFOX in ACHIEVE, an adjuvant phase III trial, suggest that CAPOXIRI+BEV can mitigate OX-induced PSN. Trial registration Clinicaltrials.gov NCT04097444. Registered September 20, 2019, https://clinicaltrials.gov/ct2/show/study/NCT04097444/ Japan Registry of Clinical Trials jRCTs041190072. Registered October 9, 2019.

Background The indications for general anesthesia (GA) in obstetric settings, which are determined in consideration of maternal and fetal outcome, could be affected by local patterns of clinical practice grounded in unique situations and circumstances that vary among medical institutions. Although the use of GA for cesarean delivery has become less common with more frequent adoption of neuraxial anesthesia, GA was previously chosen for pregnancy with placenta previa at our institution in case of unexpected massive hemorrhage. However, the situation has been gradually changing since formation of a team dedicated to obstetric anesthesia practice. Here, we report the results of a review of all cesarean deliveries performed under GA, and assess the impact of our newly launched team on trends in clinical obstetric anesthesia practice at our institution. Methods Our original database for obstetric GA during the period of 2010 to 2019 was analyzed. The medical records of all parturients who received GA for cesarean delivery were reviewed to collect detailed information. Interrupted time series analysis was used to evaluate the impact of the launch of our obstetric anesthesia team. Results As recently as 2014, more than 10% of cesarean deliveries were performed under GA, with placenta previa accounting for the main indication in elective and emergent cases. Our obstetric anesthesia team was formed in 2015 to serve as a communication bridge between the department of anesthesiology and the department of obstetrics. Since then, there has been a steady decline in the percentage of cesarean deliveries performed under GA, decreasing to a low of less than 5% in the latest 2 years. Interrupted time series analysis revealed a significant reduction in obstetric GA after 2015 (P = 0.04), which was associated with decreased use of GA for pregnancy with placenta previa. On the other hand, every year has seen a number of urgent cesarean deliveries requiring GA. Conclusions There has been a trend towards fewer obstetric GA since 2015. The optimized use of GA for cesarean delivery was made possible mainly through strengthened partnerships between anesthesiologists and obstetricians with the support of our obstetric anesthesia team.

Lessons Learned A biweekly TAS-102 plus BEV schedule in patients with heavily pretreated mCRC showed equivalent efficacy with less toxicity compared with the current schedule of TAS-102 plus BEV combination. Biweekly TAS-102 plus BEV combination could reduce unnecessary dose reduction of TAS-102, maintain higher doses, and possibly be effective even in cases without chemotherapy-induced neutropenia (CIN). The prespecified subgroup analysis of this study showed an obvious association between CIN within the first two cycles and prognosis of biweekly TAS-102 plus BEV. Background TAS-102 (trifluridine/tipiracil) plus bevacizumab (BEV) combination therapy has shown promising activity in patients with metastatic colorectal cancer (mCRC). However, the previously reported dose and schedule for the TAS-102 (70 mg/m2/day on days 1–5 and 8–12, every 4 weeks) plus BEV (5 mg/kg on day 1, every 2 weeks) regimen is complicated by severe hematological toxicities and difficult administration schedules. Here, we evaluated the efficacy and safety of a more convenient biweekly TAS-102 plus BEV combination. Methods Patients with mCRC who were refractory or intolerant to standard chemotherapies were enrolled. Patients received biweekly TAS-102 (twice daily on days 1–5, every 2 weeks) with BEV (5mg/kg on day 1, every 2 weeks). The primary endpoint was progression-free survival rate at 16 weeks (16-w PFS rate). Results From October 2017 to January 2018, 46 patients were enrolled. The recommended phase II dose was determined to be TAS-102 (70 mg/m2/day). Of the 44 eligible patients, the 16-w PFS rate was 40.9% (95% confidence interval, 26.3%–56.8%), and the null hypothesis was rejected (p < .0001). Median progression-free survival (PFS) and overall survival were 4.29 months and 10.86 months, respectively. Disease control rate was 59.1%. Common grade 3 or higher adverse events were hypertension (40.9%), neutropenia (15.9%), and leucopenia (15.9%). Conclusion Biweekly TAS-102 plus BEV showed promising antitumor activity with safety.

Systemic sclerosis (SSc) is an autoimmune disease that causes fibrosis and vasculopathy of the skin and internal organs against a background of autoimmune abnormalities. In recent years, the importance of the interleukin (IL)-17 family for inflammatory diseases has received much attention, but autoimmune diseases have not yet been fully explored. As for SSc, there is also no unified perspective on the involvement of the IL-17 family in its development, and few studies have been conducted linking IL-17F and IL-17E particularly to the disease severity. In the present study, we examined the correlation between serum IL-17F and IL-17E levels and disease severity in SSc patients. Moreover, the expression of the receptors for these cytokines, IL-17RB and IL-17RC, in skin tissues obtained by skin biopsy was examined by immunohistochemistry. Both cytokines were significantly elevated in the sera of patients with diffuse cutaneous SSc patients compared with healthy controls. Serum IL-17F levels correlated with modified Rodnan total skin thickness score, a semiquantitative measure of skin sclerosis, percent predicted forced vital capacity, percent predicted carbon monoxide lung diffusion capacity and serum levels of Krebs von den Lungen-6 and surfactant protein-D, serological markers of interstitial lung disease. Serum IL-17E levels were significantly correlated with percent predicted forced vital capacity and serum Krebs von den Lungen-6 levels. Serum levels of IL-17F and IL-17E also correlated with the prevalence of digital ulcers, and serum IL-17F levels were associated with elevated right ventricle systolic pressure values. In addition, IL-17RC and IL-17RB expression was increased in the skin tissues of diffuse cutaneous SSc patients. These results suggested that IL-17F and IL-17E could be involved in fibrosis and vasculopathy in SSc through their respective receptors in the affected organ tissues.

Zinc intake is recommended for zinc deficiency. In clinical practice, polaprezinc has been used as a zinc replacement therapy for zinc deficiency. However, the efficacy of polaprezinc has not been established. To confirm the efficacy on zinc deficiency of polaprezinc and provide additional information on an appropriate regimen, we conducted a systematic review using individual patient data (IPD). We searched PubMed, the Japanese database Ichushi, and the database owned by the marketing authorization holder of polaprezinc. Randomized placebo-controlled trials that reported the serum zinc concentration were eligible. The mean difference of the change from baseline in serum zinc concentration was estimated using a fixed-effects model. The linear dose–response relationship and the subgroup effects were also assessed. Out of 54 unique randomized clinical trials (RCTs), four studies met the eligibility criteria, and we could access IPD for all of them. All three doses of polaprezinc (75 mg, 150 mg, and 300 mg) and the placebo group were examined. The dose-combined overall polaprezinc increased the change from baseline by a mean of 9.08 µg/dL (95% confidence interval: 5.46, 12.70; heterogeneity: I 2 = 0.61%) compared to the placebo. A significant dose–response relationship was confirmed (p < 0.001). Baseline serum zinc concentration was considered an effect modifier in polaprezinc 300 mg. All doses of polaprezinc were tolerable, but a dose–response relationship with adverse events (AEs) was observed in gastrointestinal disorders. The dose of 300 mg may be useful among patients with baseline serum zinc concentration of less than 70 µg/dL, and 150 mg for 70 µg/dL or more.

Albumin has an oxidized form, known as non-mercaptalbumin (HNA), which reflects systemic oxidative stress. The association between serum HNA levels and diabetic complications are yet to be reported. In this cross-sectional study, we investigated 164 diabetic subjects to assess the correlation between HNA% (the proportion in the total albumin) and various clinical parameters. HNA% was significantly associated with the severity of multiple complications including neuropathy (23.3 ± 4.1% vs 26.2 ± 5.1%) and nephropathy (24.1 ± 3.9%, 24.6 ± 4.2%, 28.5 ± 6.1%, 31.3 ± 5.7%, 37.8 ± 2.9%, stage 1/2/3/4/5, respectively). These findings highlight the universal importance of oxidative stress, indicating HNA% potential as a versatile marker of the severity of diabetic complications., Highlights • Albumin has an oxidized form, known as non-mercaptalbumin (HNA), which reflects systemic oxidative stress. • This is the first report indicating that HNA% is significantly associated with severity of multiple diabetes complications. • HNA% may serve as a universal marker representing status of systemic complications in patients with diabetes.

Background: A sodium glucose cotransporter 2 (SGLT2) inhibitor was recently found to reduce heart failure hospitalization in the EMPA-REG OUTCOMES trial. We have hypothesized that autonomic nerve activity may be modulated by SGLT2 inhibition. The current study aims to investigate the impact of empagliflozin on sympathetic and parasympathetic nerve activity in patients with type 2 diabetes mellitus.Methods: This ongoing study is a prospective, randomized, open-label, multicenter investigation of 134 patients with type 2 diabetes mellitus. The patients are randomly allocated to receive either empagliflozin or sitagliptin with the treatment goal of the Japan Diabetes Society guidelines. Ambulatory electrocardiographic monitoring is performed at the baseline and at 12 and 24 weeks of treatment. Analyses of heart rate variability are performed using the MemCalc method, which is a combination of the maximum entropy method for spectral analysis and the non-linear least squares method for square analysis. The primary endpoint is the change in the low frequency (LF; 0.04-0.15 Hz) / high frequency (HF; 0.15-0.4 Hz) ratio from baseline to 24 weeks.Discussion: This investigation on the effect of EMPagliflozin on cardiac sYmpathetic and parasympathetic neRve activity in JapanEse pAtieNts with type 2 diabetes (EMPYREAN study) offers an important opportunity to understand the impact of SGLT2 inhibition on autonomic nerve activity in patients with type 2 diabetes.Trial Registration: UMIN Clinical Trials Registry identifier UMIN000029194. Registered 19 September 2017, https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000033375

Systemic sclerosis (SSc) is an autoimmune disorder characterized by vascular damage and excessive fibrosis. SSc-associated interstitial lung disease (ILD) is a leading cause of death in SSc. Several studies have shown the efficacy of rituximab (RTX) in SSc-ILD, but no study has examined the relation between RTX reactivity and change of serum marker levels. In this study we examined the relation between change of serum surfactant protein-D (SP-D) levels and change of percentage forced vital capacity (FVC) in 11 SSc-ILD patients with anti-topoisomerase I antibody treated by RTX. Serum SP-D levels were significantly decreased compared with baseline at 2 weeks after first RTX infusion in good responders (P = 0.04), while not in poor responders (P = 0.77). Moreover, ΔSP-D at 2 weeks negatively correlated with Δ%FVC at 24 weeks (P = 0.001). In conclusion, we suggested that the rapid decrease of SP-D levels may be a predictive marker of RTX effect against SSc-ILD.

Surgery for gastric cancer should be performed as soon as possible after diagnosis. However, sometimes the waiting time for surgery tends to be longer. The relation between the waiting time for surgery and survival in patients with gastric cancer remains to be fully investigated. This retrospective, single-center cohort study evaluated patients with gastric cancer who underwent curative surgery from 2006 through 2012 at Kanagawa Cancer Center in Japan. Patients who received neoadjuvant chemotherapy were excluded. The waiting time for surgery was defined as the time between the first visit and surgery. We investigated whether the waiting time for surgery has a linear negative impact on outcomes by using a Cox regression model with clinical prognostic factors. In total, 801 patients were eligible. The median waiting time was 45 days (range 10–269 days). The restricted cubic spline regression curve showed that the adjusted time-specific hazard ratios of waiting times did not indicate a linear negative trend on survival between 20 and 100 days (p = 0.759). In the Cox model with a quartile of waiting times, waiting times in the 32–44-day group, 43–62-day group, and ≥63 day groups were not associated with poorer overall survival as compared with the ≤31 day group (HR: 1.01, 95% CI 0.63–1.60, p = 0.984, HR: 1.17, 95% CI 0.70–1.94, p = 0.550, HR: 1.06, 95% CI 0.60–1.88, p = 0.831, respectively). There was no negative relation between the waiting time for surgery (within 100 days) and survival in patients with gastric cancer.

Background: Perampanel, a non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor antagonist, arrested disease progression in a sporadic ALS (SALS) mouse model, suggesting its potential use in humans. Methods: This multicentre, double-blind, randomised, placebo-controlled, phase 2 study was conducted at 12 sites in Japan. Patients with probable or definite ALS as defined by revised El Escorial criteria were enrolled. Using a computerised interactive system with the following minimization factors: change in ALSFRS-R score during the observation period, sex, age, and the use of riluzole or edaravone, patients were randomly assigned in a 1:1:1 ratio to receive placebo, 4 mg perampanel daily, or 8 mg perampanel daily. The primary efficacy outcome was the change in ALSFRS-R scores after 48 weeks of treatment. All patients in the intention-to-treat population were analysed. Patients and investigators were masked to treatment assignment. Findings: Between April 2017 and January 2020, 65 patients were randomised to perampanel 4 mg (n=22), 8 mg (n=21), or placebo groups (n=22). There was a significant difference (−8·4 [95% confidence interval −13·9–−2·9]; p=0·015) between the placebo and the perampanel 8 mg group, primarily due to worsening of the bulbar subscore in the perampanel 8 mg group. Serious adverse events were significantly more frequent in the perampanel 8 mg group than in the placebo group (p=0·0483). The most common event was dysphagia requiring gastrostomy in two (9·1%) of 22 patients treated with placebo, four (18·2%) of 22 patients treated with 4 mg of perampanel, and six (28·6%) of 21 patients treated with 8 mg of perampanel. Interpretation: Perampanel did not prevent an overall decline of ALSFRS-R score and was linked to worsening of bulbar subscore in the 8 mg group. Trial Registration: This trial is registered with ClinicalTrials.gov, # NCT03019419. Funding: This study received funding from the Japan Agency for Medical Research and Development. Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: This study was approved by the institutional review board at each study site. Written informed consent was obtained from the patients.

Coexistence of anti-topoisomerase (topo) I antibody (Ab) and anti-U1 ribonucleoprotein (RNP) Ab is occasionally observed among patients with systemic sclerosis (SSc). To clarify the clinical significance of anti-U1 RNP Ab in patients with anti-topo I Ab-positive SSc, we conducted a retrospective review of SSc patients initially arrived at our clinic since April 2011 until March 2020. Serum levels of anti-topo I Ab were examined by enzyme-linked immunosorbent assay, and anti-topo I Ab-positive patients were recruited into the study. Serum anti-U1 RNP Ab positivity was explored by chemiluminescent enzyme immunoassay. In total, 92 patients were enrolled into our study. Of these, 11 cases were anti-U1 RNP Ab-positive (anti-U1RNP+) and 81 patients were anti-U1 RNP Ab-negative (anti-U1RNP-). Age of SSc onset was significantly lower in anti-U1RNP+ group than in anti-U1RNP- group (median [25-75th percentiles], 26.8 [20.3-39.6] vs 45.1 [31.5-56.8] years, P < 0.01). Additionally, serum levels of anti-topo I Ab were significantly higher among anti-U1RNP+ patients compared to the others (166 [124-195] vs 135 [104-174] U/mL, P < 0.05). Moreover, concurrence of systemic lupus erythematosus and Sjogren’s syndrome was more common in anti-U1RNP+ group than in anti-U1RNP- group (45.5% vs 1.2%, P < 0.001; 54.5% vs 12.3%, P < 0.01). In conclusion, anti-U1 RNP Ab is associated with early disease onset, reduced vital capacity of the lung, and concurrence of systemic lupus erythematosus and Sjogren’s syndrome among SSc patients with anti-topo I Ab.

Objective During the Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial, patients with hypertension who received amlodipine had similar cardiovascular risks as those who received candesartan. We conducted a post-trial study, the Candesartan Antihypertensive Survival Evaluation in Japan 10-year follow-up (CASE-J 10). This study aimed to confirm the long-term cardiovascular effects of candesartan and amlodipine. Methods Case report forms were sent to CASE-J investigators who agreed to participate in the CASE-J 10. All the available information was retrospectively collected. The primary endpoint was a time-to-first event for a composite of cerebrovascular, cardiac, renal, and vascular events, and sudden death. Secondary endpoints included new-onset diabetes (NOD), cardiovascular mortality, and all-cause mortality. For each endpoint, treatment effect was compared on an intention-to-treat basis, according to previous randomization categories. Results A total of 1313 patients' data have been updated. The 10-year Kaplan-Meier rates of the primary endpoint were 14.7% for candesartan and 14.8% for amlodipine. After adjusting for baseline characteristics, the rates for the primary endpoint were similar between the two treatments (hazards ratioadj = 0.99, 95% CI 0.82-1.20). Candesartan had a lower Kaplan-Meier rate of NOD than amlodipine (8.3 vs. 11.1%), and when adjusted for clinical factors, candesartan remained an independent predictor for NOD prevention (hazard ratioadj = 0.71, 95% CI 0.52-0.98). Conclusion With more than 28 385 patient-years follow-up, we demonstrated that candesartan and amlodipine were comparable in reducing cardiovascular events in patients with high-risk hypertension. Additionally, our results may support candesartan's superiority in reducing NOD incidence compared with amlodipine even after the long-term follow-up.

We would like to thank Berkhout et al for their comments on the absence of an association between serum TNF concentrations and treatment response to infliximab in our paper.1 First, reliability of the obtained results on the serum levels of TNF in the study should be firmly confirmed, because the quality control of the assessments was stringently managed by the laboratory company who assessed …

Background The expiratory time constant (RCEXP), which is defined as the product of airway resistance and lung compliance, enable us to assess the mechanical properties of the respiratory system in mechanically ventilated patients. Although RCEXP could also be applied to spontaneously breathing patients, little is known about RCEXP calculated from the maximal expiratory flow-volume (MEFV) curve. The aim of our study was to determine the reference value for RCEXP, as well as to investigate the association between RCEXP and other respiratory function parameters, including the forced expiratory volume in 1 s (FEV1)/ forced vital capacity (FVC) ratio, maximal mid-expiratory flow rate (MMF), maximal expiratory flow at 50 and 25% of FVC (MEF50 and MEF25, respectively), ratio of MEF50 to MEF25 (MEF50/MEF25). Methods Spirometric parameters were extracted from the records of patients aged 15 years or older who underwent pulmonary function testing as a routine preoperative examination before non-cardiac surgery at the University of Tokyo Hospital. RCEXP was calculated in each patient from the slope of the descending limb of the MEFV curve using two points corresponding to MEF50 and MEF25. Airway obstruction was defined as an FEV1/FVC and FEV1 below the statistically lower limit of normal. Results We retrospectively analyzed 777 spirometry records, and 62 patients were deemed to have airway obstruction according to Japanese spirometric reference values. The cut-off value for RCEXP was 0.601 s with an area under the receiver operating characteristic curve of 0.934 (95% confidence interval = 0.898–0.970). RCEXP was strongly associated with FEV1/FVC, and was moderately associated with MMF and MEF50. However, RCEXP was less associated with MEF25 and MEF50/MEF25. Conclusions Our findings suggest that an RCEXP of longer than approximately 0.6 s can be linked to the presence of airway obstruction. Application of the concept of RCEXP to spontaneously breathing subjects was feasible, using our simple calculation method.

The clinical effectiveness of four neuraminidase inhibitors (NAIs) (oseltamivir, zanamivir, laninamivir, and peramivir) for children aged 0 months to 18 years with influenza A and B were investigated in the 2014-2015 to 2016-2017 influenza seasons in Japan. A total of 1207 patients (747 with influenza A and 460 with influenza B) were enrolled. The Cox proportional-hazards model using all of the patients showed that the duration of fever after administration of the first dose of the NAI was shorter in older patients (hazard ratio = 1.06 per 1 year of age, p < 0.001) and that the duration of fever after administration of the first dose of the NAI was shorter in patients with influenza A infection than in patients with influenza B infection (hazard ratio = 2.21, p < 0.001). A logistic regression model showed that the number of biphasic fever episodes was 2.99-times greater for influenza B-infected patients than for influenza A-infected patients (p < 0.001). The number of biphasic fever episodes in influenza A-or B-infected patients aged 0-4 years was 2.89-times greater than that in patients aged 10-18 years (p = 0.010), and the number of episodes in influenza A-or B-infected patients aged 5-9 years was 2.13times greater than that in patients aged 10-18 years (p = 0.012).