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Fluorouracil monotherapy, instead of the FOLFOX or FOLFIRI regimen, is administered to patients intolerant to oxaliplatin or irinotecan because of their adverse effects. A prospective clinical trial was designed to evaluate the efficacy and safety of fluorouracil monotherapy combined with panitumumab administered to patients with KRAS wild-type (WT) metastatic colorectal cancer (mCRC) intolerant to oxaliplatin and irinotecan. Screening for potential serum biomarkers to predict early therapeutic responses was conducted. This single-arm, open-label multicenter phase II trial recruited patients with KRAS WT mCRC from 16 institutes between January 2012 and October 2014. Panitumumab (6 mg/kg) was intravenously administered every 2 weeks, combined with fluorouracil monotherapy, in 2-week cycles. The primary objective was overall response rate, and secondary endpoints included disease-control rate, progression-free survival, overall survival, toxicity, and blood-test data. Forty patients (male, 65.0%; median age, 74 years; colon cancer, 72.5%) met eligibility criteria and received 7 cycles (median) of fluorouracil chemotherapy combined with panitumumab. There were no treatment-related deaths. Median time to treatment failure was 3.2 months. 23 (57.5%) patients experienced at least one adverse effect ≥ grade 3. The response rate was 10.0% (95% confidence interval 2.8–23.7%). Median progression-free survival and overall survival were 4.3 and 11.3 months, respectively. Total lactase dehydrogenase (LDH) levels and those of LDH-4 and LDH-5, quickly changed with disease reduction or progression. Fluorouracil monotherapy combined with panitumumab was safely administered to patients with KRAS WT mCRC intolerant to oxaliplatin and irinotecan. Serum LDH levels may predict early responses.

The synergistic effect of combining immune checkpoint inhibitors with radiotherapy was reported recently, but there are few studies on programmed cell death-ligand 1 (PD-L1) expression in rectal cancer treated by preoperative chemoradiotherapy (CRT). The aim of the present study was to investigate the PD-L1 expression status before and after CRT and its association with clinicopathological characteristics and recurrence in rectal cancer.Immunostainings of PD-L1 and CD8 were performed in 287 patients with rectal cancer treated by CRT. PD-L1 expression on the tumour cells (tPD-L1) and on the stromal immune cells (iPD-L1) was evaluated before and after CRT. CD8+ cell density in tumour area (tCD8+) before CRT and in the stromal area (sCD8+) before and after CRT was also evaluated.High tPD-L1 expression was observed in only three patients (1.0%). High iPD-L1 expression significantly increased from 31.7% before CRT to 49.2% after CRT (P 0.0001). The increase in high iPD-L1 expression after CRT was only observed in patients with tumour regression grades 1 and 2. High iPD-L1 expression was associated with high tCD8+ cell density before CRT (P 0.0001) and sCD8+ cell density after CRT (P 0.0001). High tCD8+ cell density before CRT was associated with better disease-free survival (DFS) (P = 0.0331), but its improved effect on DFS could be observed in patients with high iPD-L1 expression (P = 0.0081), not in patients with low iPD-L1 expression (P = 0.516).The present study demonstrated the significant correlations between iPD-L1 expression and CD8+ cell density both before and after CRT.

BACKGROUND: Most previous reports to analyze risk factors for peritoneal recurrence in patients with colon cancer have been observational studies of a population-based cohort. OBJECTIVE: This study aimed to determine the risk factors for peritoneal recurrence in patients with stage II to III colon cancer who underwent curative resection. DESIGN: This was a pooled analysis using a combined database obtained from 3 large phase III randomized trials (N = 3714). SETTINGS: Individual patient data were collected from the Japanese Foundation for Multidisciplinary Treatment of Cancer clinical trials 7, 15, and 33, which evaluated the benefits of postoperative 5-fluorouracil–based adjuvant therapies in patients with locally advanced colorectal cancer. PATIENTS: We included patients who had stage II to III colon cancer and underwent curative resection with over D2 lymph node dissection. MAIN OUTCOME MEASURES: Main outcomes measured were risk factors for peritoneal recurrence without other organ metastasis after curative surgery. RESULTS: Peritoneal recurrence occurred in 2.3% (86/3714) of all patients undergoing curative resection. Mean duration from operation to peritoneal recurrence was 17.0 ± 10.3 months. Of these patients with peritoneal recurrence, 29 patients (34%) had recurrence in ≥1 other organ. Multivariate analysis showed that age (≥60 y: HR = 0.531; p = 0.0182), pathological T4 (HR = 3.802; p < 0.0001), lymph node involvement (HR = 3.491; p = 0.0002), and lymphadenectomy (D2: HR = 1.801; p = 0.0356) were independent predictors of peritoneal recurrence. The overall survival was lower in patients who developed peritoneal recurrence than in those with other recurrence (HR = 1.594; p = 0.002). LIMITATIONS: The regimens of adjuvant chemotherapy were limited to oral 5-fluorouracil. CONCLUSIONS: Our findings clarified the risk factors for peritoneal recurrence in patients who underwent curative resection for colon cancer. See Video Abstract at http://links.lww.com/DCR/A609.

The vasoactive-inotropic score (VIS) is a scale showing the amount of vasoactive and inotropic support. Recently, it was suggested that the VIS after cardiac surgery predicts morbidity and mortality in infants. The purpose of this study was to evaluate the VIS at the end of surgery as a predictor of morbidity and mortality in adult cardiac surgery. A retrospective cohort study of 129 adult cardiac surgery patients was performed at a university hospital. The primary outcome was termed “poor outcome”, which was a composite of morbidity and mortality. The secondary outcomes were the duration of intensive care unit (ICU) stay and time to first extubation. Multivariate logistic regression analysis was performed to evaluate the association between the VIS and poor outcomes. A proportional hazards model was used to evaluate the duration of the ICU stay and time to first extubation. After adjusting for the EuroSCORE, preoperative ejection fraction, and bypass time, a high VIS at the end of surgery was associated with a poor outcome with an adjusted odds ratio of 4.87 (95% confidence interval 1.51–18.94; p = 0.007). After controlling for the EuroSCORE and bypass time, patients with a high VIS experienced longer ICU stay (hazard ratio 1.62; 95% confidence interval 1.10–2.39; p = 0.015) and needed longer ventilation (hazard ration 1.87; 95% confidence interval 1.28–2.74, p = 0.001). The amount of cardiovascular support at the end of cardiac surgery may predict morbidity and mortality in adults.

Background Individual patient data (IPD) meta-analysis is considered to be a gold standard when the results of several randomized trials are combined. Recent initiatives on sharing IPD from clinical trials offer unprecedented opportunities for using such data in IPD meta-analyses. Methods First, we discuss the evidence generated and the benefits obtained by a long-established prospective IPD meta-analysis in early breast cancer. Next, we discuss a data-sharing system that has been adopted by several pharmaceutical sponsors. We review a number of retrospective IPD meta-analyses that have already been proposed using this data-sharing system. Finally, we discuss the role of data sharing in IPD meta-analysis in the future. Results Treatment effects can be more reliably estimated in both types of IPD meta-analyses than with summary statistics extracted from published papers. Specifically, with rich covariate information available on each patient, prognostic and predictive factors can be identified or confirmed. Also, when several endpoints are available, surrogate endpoints can be assessed statistically. Conclusions Although there are difficulties in conducting, analyzing, and interpreting retrospective IPD meta-analysis utilizing the currently available data-sharing systems, data sharing will play an important role in IPD meta-analysis in the future.

There is concern that vitamin D deficiency is prevalent among children in Japan as well as worldwide. We conducted a nationwide epidemiologic survey of symptomatic vitamin D deficiency to observe its incidence rate among Japanese children. A questionnaire inquiring the number of new patients with vitamin D deficiency rickets and/or hypocalcemia for 3 years was sent to 855 randomly selected hospitals with a pediatrics department in Japan. In this survey, we found that 250 children were diagnosed with symptomatic vitamin D deficiency. The estimated number of patients with symptomatic vitamin D deficiency per year was 183 (95% confidence interval (CI): 145-222). The overall annual incidence rate among children under 15 years of age was 1.1 per 100,000 population (95% CI: 0.9-1.4). The second survey has provided detailed information on 89 patients with symptomatic vitamin D deficiency under 5 years of age in hospitals in the current research group. The nationwide and second surveys estimated the overall annual incidence rate of symptomatic vitamin D deficiency in children under 5 years of age to be 3.5 (2.7-4.2) per 100,000 population. The second survey revealed 83% had bowed legs, 88% had exclusive breastfeeding, 49% had a restricted and/or unbalanced diet and 31% had insufficient sun exposure among the 89 patients. This is the first nationwide survey on definitive clinical vitamin D deficiency in children in Japan. Elucidating the frequency and characteristics of symptomatic vitamin D deficiency among children is useful to develop preventative public health strategies.

Background: Oxaliplatin and capecitabine (CapeOX) combined with cetuximab is rarely used to treat advanced and metastatic colorectal cancer (mCRC). The present study aimed to clarify the clinical benefits of this treatment regimen when used as a first-line therapy in patients with expanded RAS/BRAF/PIK3CA wild-type mCRC, using the data and tumor specimens from two previously published Phase II clinical trials. Methods: The gene mutation status and clinical data of 102 patients with KRAS wild-type mCRC, who received either of CapeOX + cetuximab or FOLFOX + cetuximab, were analyzed. The primary endpoint was response rate (RR) of CapeOX + cetuximab treatment in patients with extended RAS/BRAF/PIK3CA wild-type mCRC. RR comparisons and maximum tumor size changes between different treatment regimens and gene mutation status were set as key secondary endpoints. Results: We identified 88 patients with extended RAS/BRAF/PIK3CA wild-type mCRC. Those treated with CapeOX + cetuximab (n = 52) had a 61.5% RR (95% CI, 47.0-74.7%), while those treated with FOLFOX + cetuximab (n = 36) had a 66.7% RR (95% CI, 49.0-81.4%). Patients with any mutation (n = 14) had a 42.9% RR (95% CI, 17.1-71.1%). There were no significant differences between these three groups (P = 0.298). The disease control rate was 86.5% (95% CI, 74.2-94.4%) in the CapeOX + cetuximab group, and 88.9% (95% CI, 73.9-96.9%) in the FOLFOX + cetuximab group. Maximum tumor size changes were largest in patients with wild-type mCRC treated with FOLFOX + cetuximab followed by patients with wild-type mCRC treated with CapeOX + cetuximab, and then by those with any mutation (-63.2%, -52.6%, and -27.3%, respectively; P = 0.035). Conclusions: Patients with RAS/BRAF/PIK3CA wild-type mCRC had a sufficient RR following first-line treatment with CapeOX + cetuximab. These results suggest that this combination therapy should be considered as a treatment option for patients with advanced mCRC.

Objectives: To examine the effect of hospital treatment volume on overall survival outcomes with gynecologic malignancies in Japan. Methods: This society-based retrospective study in Japan included women with gynecologic malignancies who diagnosed from 2004-2015. The association between the annual hospital treatment volume (aHTV) and overall survival (OS) was examined per tumor type using a multivariable Cox proportional hazards model with restricted cubic splines. Institutions were categorized into 3 groups based on fractional proportions: High- (1-10 percentile), moderate- (11-50 percentile), and low- (51-100 percentile) volume centers. Results: A total of 206,845 women (Endometrial cancer n=80,741, cervical cancer n=73,647, and ovarian cancer n=52,457) at 431 hospitals were identified. There were 43 high-volume centers (34.6%, 40.5%, 31.5% of cases for endometrial, cervical, and ovarian cancer, respectively), 186 moderate-volume centers (50.3%, 49.8%, and 50.7% of cases), and 202 low-volume centers (15.1%, 9.8%, and 17.8% of cases) in the study sample. Among high-volume centers, the median annual hospital treatment volume were 52 (interquartile range (IQR), 44-71), 59 (IQR 50-80), and 34 (IQR 29-41) cases for endometrial, cervical, and ovarian cancer. Women treated at high-volume centers were younger, more likely to have rare tumor histology and to have undergone surgical management (P Download : Download high-res image (123KB) Download : Download full-size image Conclusions: High-volume centers were associated with a higher likelihood of improved overall survival outcome in women with gynecologic malignancies in Japan. Centralization of cancer treatment may improve survival outcomes.

Background We conducted a randomized phase III trial comparing tegafur/uracil (UFT) and Polysaccharide-K (PSK) to surgery alone in curatively resected stage II rectal cancer patients. Methods Patients were randomly assigned to receive either UFT and PSK or surgery alone in a 1:1 ratio with a minimization method to balance the treatment allocation. The primary end point of this study was the disease-free survival (DFS). The secondary end point was the overall survival (OS). Results From October 2011 to February 2013, 111 patients were registered from 62 institutions. The study was prematurely closed due to poor accrual after reaching 20% of its goal. The patients’ characteristics were similar between the UFT and PSK group and the surgery-alone group. The DFS rate was 76.0% at 3 years and 65.1% at 5 years in the UFT and PSK arm and 84.0% at 3 years and 77.2% at 5 years in the surgery-alone arm. The DFS was slightly worse in the UFT + PSK arm than in the surgery-alone arm, but the difference did not reach statistical significance (log rank p = 0.102). The OS rate was 100% at 3 years and 97.9% at 5 years in the UFT + PSK arm, while that was 100% at 3 years and 93.4% at 5 years in the surgery-alone arm. The OS was similar in the UFT + PSK arm and surgery-alone arm (p = 0.533). Conclusion The present study suggests that UFT and PSK are not attractive candidates to advance to the next phase III study because the DFS was slightly worse in the UFT and PSK arm than in the surgery-alone arm.

Objectives We conducted a phase-II study to evaluate the efficacy and safety of dasatinib in patients newly diagnosed with chronic-phase chronic myeloid leukaemia (CML-CP) in Japan (IMIDAS PART 2 study). Methods Seventy-nine patients were administered 100 mg dasatinib once daily. We examined pre-treatment and post-treatment influences of various factors. The BCR-ABL1 international scale (IS), halving time (HT), and reduction rate of BCR-ABL1 transcript within the initial 1 or 3 months of therapy (RR-BCR-ABL11m,3m) were the post-treatment factors investigated to predict the molecular response. Results The estimated major molecular response (MMR), molecular response 4.0 (MR4.0), and molecular response 4.5 (MR4.5) rates were 77.2%, 49.4%, and 35.4%, respectively, at 12 months. Grade 3/4 non-haematologic adverse events were infrequent. Multivariate analysis showed that age >65 years was significantly correlated with MR4.0 and MR4.5 (deep molecular response: DMR) at 12 months. All post-treatment factors at 3 months predicted DMR by univariate analysis. However, RR-BCR-ABL13m was the only significant landmark for predicting DMR by multivariate analysis. Conclusions Primary treatment of CML-CP with dasatinib enabled early achievement of MMR and DMR, particularly in elderly patients, with high safety. Furthermore, RR-BCR-ABL13m was found to be a more useful predictor of DMR than HT-BCR-ABL1 and BCR-ABL1 IS. This article is protected by copyright. All rights reserved.

Background Stage IV colorectal cancer encompasses various clinical conditions. The differences in prognosis after surgery between different metastatic organs have not been fully investigated. Objective This study aimed to assess prognostic significance in peritoneal metastasis in R0 resected stage IV colorectal cancer. Design We conducted a multicenter retrospective study of patients with R0 resected stage IV colorectal cancer; they were categorized into 3 groups according to the number and location of metastatic organs, including single-organ metastasis in the peritoneum, single-organ metastasis at sites except the peritoneum, and multiple-organ metastases. Settings This study used data accumulated by the Japanese Study Group for Postoperative Follow-Up of Colorectal Cancer. Patients A total of 1133 patients with R0 resected stage IV colorectal cancer were registered retrospectively between 1997 and 2007 in 20 referral hospitals. Main outcome measures Cancer-specific survival rates between the groups were measured. Results The median cancer-specific survival of the single-organ metastasis in the peritoneum group was considerably shorter than that of the single-organ metastasis at a site other than the peritoneum group and was almost comparable to that of the multiple-organ metastases group (3.41 years, 6.20 years, and 2.99 years). In a multivariate analysis of cancer-specific survival, peritoneal dissemination was confirmed as an independent prognostic factor of survival. The median postrecurrence survival of single-organ metastasis in the peritoneum group was considerably shorter than that of the single-organ metastasis at a site other than the peritoneum group. Approximately half of the patients who experienced recurrence of single-organ metastasis in the peritoneum experienced peritoneal recurrence. Limitations This was a retrospective, population-based study that requires a prospective design to validate its conclusions. Conclusions Peritoneal metastasis of colorectal cancer frequently recurred in the peritoneum even after R0 resection. The cancer-specific survival of the single-organ metastasis in the peritoneum group was as poor as that of the multiple-organ metastases group. See Video Abstract at http://links.lww.com/DCR/A398.

This study assessed the impact of postoperative complications on the colorectal cancer survival and recurrence after curative surgery using pooled individual patients’ data from three large phase III randomized trials. In total, 5530 patients were included in this study. The patients were classified as those with postoperative complications (C group) and those without postoperative complications (NC group). The risk factors for the overall survival (OS) and the disease‐free survival (DFS) were analyzed. Postoperative complications were found in 861 (15.6%) of the 5530 patients. The OS and DFS rates at 5 years after surgery were 68.9% and 74.8%, respectively, in the C group and 75.8% and 82.2%, respectively, in the NC group, values that were significantly different between the two groups (P

Laparoscopy-assisted distal gastrectomy (LADG) for gastric cancer may prevent the loss of body weight and lean body mass resulting from reduced surgical stress in comparison to open distal gastrectomy (ODG). A multicenter phase III trial conducted by the Japan Clinical Oncology Group (JCOG0912 trial) was performed to confirm the non-inferiority of LADG to ODG for stage I gastric cancer in terms of relapse-free survival. This study was performed as a single-institution exploratory analysis using the data of the patients from our hospital who were enrolled in the JCOG0912 phase III trial. Body weight and lean body mass were evaluated using a bioelectrical impedance analyzer within 1 week before and at 1 week, 1 month, and 3 months after surgery. One-hundred six patients were randomized to undergo ODG (54 patients) or LADG (51 patients). Body weight loss at 1 week, 1 month, and 3 months was −3.0%, −4.9%, and −5.4%, respectively, in the ODG group and −2.7%, −4.3%, and −5.7%, respectively, in the LADG group; the differences were not statistically significant (p = 0.330, 0.166, and 0.656, respectively). Lean body mass loss at 1 week, 1 month, and 3 months was −2.8%, −4.1%, and −2.3%, respectively, in the ODG group and −2.7%, −2.9%, and −3.0%, respectively, in the LADG group; the differences were not statistically significant (p = 0.610, 0.413, and 0.925, respectively). The laparoscopic approach did not attenuate the loss of body weight and lean body mass in comparison to patients who underwent open distal gastrectomy for gastric cancer.

Purpose The impact of postoperative complications on survival after radical surgery for esophageal, gastric, and colorectal cancers remains controversial. We conducted a systematic review of recent publications to examine the effect of postoperative complications on oncological outcome. Methods A literature search of PubMed/MEDLINE was performed using the keywords “esophageal cancer,” “gastric cancer,” and “colorectal cancer,” obtaining 27 reports published online up until the end of April 2016. Articles focusing on (i) postoperative morbidity and oncological outcome; and (ii) body mass index (BMI), postoperative morbidity, and oncological outcome, were selected. Univariate and multivariate analyses (Cox proportional hazards model) were performed. Results Patients with postoperative complications had significantly poorer long-term survival than those without complications. Complications were associated with impaired oncological outcomes. The hazard ratios for overall survival were 1.67 (95% confidence interval [CI], 1.31-2.12), 1.59 (95% CI, 1.13-2.24), and 1.55 (95% CI, 1.28-1.87) in esophageal, gastric, and colorectal cancers, respectively. High BMI was associated with postoperative morbidity rate but not with poor oncological outcome. Low BMI was significantly associated with inferior oncological outcome. Conclusions Complications after radical surgery for esophageal, gastric, and colorectal cancers are associated with patient prognosis. Avoiding such complications might improve the outcomes.

Background: Advantages of neoadjuvant chemotherapy combined with monoclonal antibodies for treating patients with resectable colorectal cancer liver metastasis (CLM) have not been established. The purpose of this study was to evaluate the efficacy and safety of oxaliplatin-based regimen (FOLFOX or XELOX) plus monoclonal antibodies (cetuximab or bevacizumab) treatment in patients with resectable CLM. Methods: A single-arm, open-label, multicenter, phase II trial was conducted for patients aged ≥ 20 years with resectable and untreated CLM. Patients received preoperative FOLFOX (6 cycles) or XELOX (4 cycles). Cetuximab or bevacizumab was administered to patients with wild-type or mutated KRAS codons 12 and 13, respectively. The primary endpoint was progression-free survival (PFS). Results: Between January 2010 and June 2012, 47 patients were enrolled from 12 institutions. Wild-type or mutant KRAS sequences were examined in 32 and 15 patients, respectively. Twenty-one (45 %) patients experienced Grades 3/4 adverse events, and 55 % of all patients responded to therapy. The sizes of tumors of patients in the wild-type KRAS group were significantly reduced compared with those of the mutant KRAS group. The overall rates of liver resection and postoperative morbidity were 83 and 14 %, respectively, and the median PFS was 15.6 months. The median PFS times of the KRAS wild-type and mutant groups were 22.5 months and 10.5 months, respectively. Conclusions: Neoadjuvant therapy using FOLFOX/XELOX combined with monoclonal antibodies did not improve PFS, although it was administered safely and had less adverse effects after liver resection.

To establish the safety of laparoscopic-assisted colorectal resection for colorectal cancer in elderly patients aged ≥80 years. Data were obtained from a chart review of patients who underwent colorectal cancer resection between 2009 and 2014 in Kochi Medical School. The effect of patient age on the extent of lymph node dissection and operative safety was assessed by comparing the short-term results of elderly patients with those of younger patients after propensity score matching. Of a total of 506 patients with colorectal cancer, 398 underwent laparoscopic surgery and 23% of these patients were aged ≥80 years old. The elderly patients tended to have poorer general condition and larger tumors, although no significant differences were found in tumor invasion, lymph node metastasis, or synchronous distant metastasis between the groups. After adjustment for preoperative factors, we noted that the elderly patients tended to undergo less aggressive surgical resection (P = 0.01). Further analysis after including surgical factors for propensity score matching revealed a similar rate of complications in the two groups (24 vs. 25%, respectively; P = 0.85), and similar postoperative death rates and length of postoperative hospital stay. The findings of the present study demonstrate that laparoscopic surgery for colorectal cancer should not be avoided based on simply the age of the patient.

The current version (ver. 7.3) of the popular quantitative coronary analysis system QAngio XA (Medis Medical Imaging System BV, Leiden, the Netherlands) is widely used without evaluating the agreement between the current and older versions in relation to a change of algorithms. The purpose of this study was to assess the equivalence of averages between QAngio XA versions 7.3 and 6.0. Based on the calculated sample size, angiographic images of 100 patients who underwent percutaneous coronary intervention of a single target lesion were randomly selected from two published studies (OUCH-TL: 154 lesions; OUCH-PRO: 160 lesions). The primary endpoint was the minimum lumen diameter (MLD), and the secondary endpoints were the reference diameter (RefD) and length of the stenotic lesion (LL). Two independent analysts measured the same frame using both previous and current versions of QAngio XA. Version-order for each lesion was randomly determined per coronary locations targeted. Data were analysed by using a mixed model that includes random lesion effects and fixed rater effects and reading-order effects. A Bland-Altman plot of parameters showed no large differences between the versions. Differences in parameters were estimated by the mixed model, and the 95% confidence interval of the MLD, RefD, and LL estimates was from -0.045 to -0.0001 mm, from -0.040 to 0.006 mm, and from -1.08 to 0.46 mm, respectively, compared with the predefined non-inferiority margin of ±0.2 mm. Measurements of MLD and RefD using QAngio XA showed no major systematic differences between versions.

Background: The feasibility and efficacy of adjuvant hepatic arterial infusion (HAI) in preventing the development of liver metastases in patients with advanced colon carcinoma have not been validated. The aim of this randomized controlled study was to compare the feasibility of HAI and the protective effect against liver metastasis after curative resection to those of systemic chemotherapy. Methods: Between July 2000 and June 2003, 91 patients were enrolled. Patients were randomly assigned to receive 5-fluorouracil (5-FU) via continuous venous infusion (CVI) or intra-hepatic arterial weekly high-dose 5-FU (WHF). The primary endpoint was overall survival (OS). Results: In the WHF group, the cumulative failure rate of hepatic arterial catheterization was 16.7% at 6 months. The occurrence of grade 3 adverse events was comparable between the groups. The 5-year OS rates were 59.0% in the CVI group and 34.9% in the WHF group (P = 0.164). CVI tended to show a protective effect against liver metastasis regarding the 5-year liver-specific cumulative recurrence rate: CVI, 45.0% vs. WHF, 68.3%; P = 0.037). Conclusion: HAI therapy has a certain protective effect against liver metastasis after curative resection in patients with colorectal cancer. However, this therapy did not contribute to any marked improvement in their overall survival.

Purpose: Reliable risk estimates of recurrence are necessary to establish optimal postoperative surveillance strategies. The purpose of the present study was to clarify changes in the hazard rate (HR) for tumor recurrence over time in Japanese patients with colon cancer. Methods: Data for 3984 patients from three clinical trials evaluating the benefit of adjuvant chemotherapy for colon cancer were analyzed. Estimated HRs were plotted over time for the entire cohort, as well as for node-positive and node-negative patients separately. The changes in risk were further analyzed according to eight clinical variables, and factors predictive of early (3 years) recurrence were explored using Cox's regression analysis. Results: In node-positive patients, there was a prominent HR peak 0.6 years after surgery, whereas HR remained at consistently low levels in node-negative patients. In node-positive patients, HR decreased steadily until 3 years, after which the decline in HR plateaued. Those with T4 tumors had a prominent HR peak around 1 year, including node-negative patients. The HR for T1/T2 Stage III colon cancers showed a similar pattern as that for T1-T3 node-negative colon cancers. Cox regression analysis revealed that a lack of adjuvant chemotherapy, positive node status, T3/T4 factors, and male gender predict early recurrence, whereas patients with lymph node metastasis, T4 tumors, and a lesser extent of lymph node removal have a higher risk of recurrence 3-4 years after surgery (P

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.

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.

Network meta-analysis has been gaining prominence as an evidence synthesis method that enables the comprehensive synthesis and simultaneous comparison of multiple treatments. In many network meta-analyses, some of the constituent studies may have markedly different characteristics from the others, and may be influential enough to change the overall results. The inclusion of these "outlying" studies might lead to biases, yielding misleading results. In this article, we propose effective methods for detecting outlying and influential studies in a frequentist framework. In particular, we propose suitable influence measures for network meta-analysis models that involve missing outcomes and adjust the degree of freedoms appropriately. We propose three influential measures by a leave-one-trial-out cross-validation scheme: (1) comparison-specific studentized residual, (2) relative change measure for covariance matrix of the comparative effectiveness parameters, (3) relative change measure for heterogeneity covariance matrix. We also propose (4) a model-based approach using a likelihood ratio statistic by a mean-shifted outlier detection model. We illustrate the effectiveness of the proposed methods via applications to a network meta-analysis of antihypertensive drugs. Using the four proposed methods, we could detect three potential influential trials involving an obvious outlier that was retracted because of data falsifications. We also demonstrate that the overall results of comparative efficacy estimates and the ranking of drugs were altered by omitting these three influential studies.

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.

This study compared the efficacy of two different methods for lymph node (LN) searching after colorectal cancer surgery: the fat dissolution and the conventional manual method. For the fat dissolution method, we used a commercially available solution of collagenase and lipase (FD group). The primary endpoint was the number of identified LNs in the FD group compared to an historical control (control group) after adjusting by propensity score matching. Using 37 matched patients from each group, we identified 20.6 ± 7.2 LNs using the fat dissolution method compared to 13.5 ± 5.9 using the conventional method (t test, P

Background Lateral pelvic lymph node dissection for rectal cancer is a difficult technique due to the complex pelvic anatomy involved. Three-dimensional (3D) organ models have been introduced as education tools to study anatomy in some fields. In this study, we educated the participants about pelvic anatomy using a 3D model, and evaluated learning efficiency, comparing the outcomes with those using a traditional textbook. Study Design This study was a randomized, controlled, single-center trial conducted between July 2018 and July 2019. A total of 102 participants (34 medical students, 34 residents, and 34 surgeons) were enrolled. Participants were randomly assigned to the 3D model group or the textbook group. First, they completed a short test to confirm their basic knowledge before further education. After collocated education, they completed the same short test again and another long test to evaluate their learning outcomes. Results Before education, there was no significant difference in the short test scores between the 3D model group and the textbook group. After education, the short and long test scores of the 3D model group were significantly higher than those of the textbook group for students (short test; p = 0.05, long test; p = 0.03), residents (short test; p = 0.05, long test; p = 0.002), and surgeons (short test; p = 0.009, long test; p Conclusions Using a 3D pelvic model is superior to using a textbook when learning pelvic anatomy required for lateral pelvic lymph node dissection.

Treatment outcomes for chronic myeloid leukemia (CML) have dramatically improved with the development of tyrosine kinase inhibitors (TKI). However, due to the improved prognosis for CML, problems have arisen from long-term administration of TKI. The present study sought to verify whether more patients could achieve treatment-free remission (TFR) after stopping the administration of dasatinib using dasatinib as frontline treatment. Treatment-naive chronic phase CML cases were treated with dasatinib as frontline treatment. Dasatinib treatment was stopped for 26 patients who achieved deep molecular response (DMR) within 24 months and were able to maintain DMR for an additional 2 years. Ten patients (38.5%) achieved DMR maintenance after 12 months. Recurrence was confirmed in 16 patients, and the median recurrence-free survival time was 5.1 months. The cumulative DMR rates at six and 12 months after restarting treatment were 84.6% and 100%, respectively. The results of this study demonstrated that the DMR maintenance rate after 12 months was 38.5%, which was not significantly different from previous TKI stop trials. The 2-year dasatinib administration period after reaching DMR did not contribute to improve TFR rates. These results suggest that the type of TKI is not associated with better TFR rates.

Intervention for higher-risk participants of health checkups especially with diabetes has been started in Japan to prevent renal replacement therapy (RRT) initiation, but evidence about RRT initiation risk among checkup participants has been scarce. To estimate the incidence by risk factors, we conducted a retrospective cohort study using medical claims and checkup data of a community-based insurance scheme in Japan. Beneficiaries who participated in the checkup in 2012-2013 were included and followed up for about five years. We estimated the incidence of RRT initiation by the subject characteristics, followed by investigation for risk factors in bivariate analyses and multivariable regression analyses with Bayesian prior probability distributions. As a result, among 49,252 participants, 37 initiated dialysis (0.21/1,000 person-years); no kidney transplantation was performed during the period. Baseline estimated glomerular filtration rate was strongly associated with dialysis initiation. No dialysis was initiated among those without baseline hypertension; cumulative incidence by hypertension status was significantly different (p < 0.001). Diabetes was significantly associated with dialysis initiation in bivariate analysis, but the association was not significant in multivariable regression analysis [reference: no diabetes; incidence rate ratio (IRR) for diabetes without medication, 3.30 (95% credible interval, 0.48-15.56); IRR for diabetes with medication, 1.69 (95% credible interval, 0.68-3.47)]. In conclusion, potential risk factors for RRT initiation include male sex, comorbid hypertension, and current smoking status, in addition to advanced chronic kidney disease, proteinuria, and diabetes. New initiatives should consider these factors to increase the efficacy of the programs at the population level.

Among numerous systemic inflammatory biomarkers, it remains unclear which is the most prognostic for patients with stage II/III colon cancer. We aimed to compare the prognostic significance of systemic inflammatory biomarkers among patients with stage II/III colon cancer. We included 1303 patients with stage II/III colon cancer who underwent potentially curative resection from July 2004 to December 2013. Sixteen systemic inflammatory biomarkers—derived from combinations of neutrophils, lymphocytes, monocytes, platelets, C-reactive protein (CRP), and albumin—were compared to identify the biomarker most associated with overall survival (OS) and disease-free survival (DFS) using receiver operating characteristic (ROC) curve analysis. Nine inflammatory biomarkers were predictive for OS, among which lymphocyte-to-CRP ratio (LCR), CRP-to-albumin ratio (CAR), neutrophil × CRP, monocyte × CRP, and platelet × CRP were also predictive for DFS. Among these five inflammatory biomarkers, the area under the curve (AUC) value was highest (0.630) for LCR, being significantly higher than that for neutrophil × CRP (P = 0.010), monocyte × CRP (P = 0.007), or platelet × CRP (P = 0.010) for OS. When the prognostic impact of LCR and CAR were analyzed by multivariate analysis, only LCR was an independent predictor of both OS [hazard ratio (HR), 1.77; 95% confidence interval (CI), 1.23–2.60; P = 0.002] and DFS (HR, 1.29; 95% CI, 1.00–1.66; P = 0.048). LCR may be the most useful predictive factor for OS and DFS in patients with stage II or III colon cancer.

Background Previous studies have shown the relationship between higher skin thickness score and the existence of organ involvements in systemic sclerosis (SSc). Here, we firstly investigated the correlation between skin thickness score and quantitative measurements of each organ involvement in Japanese patients with SSc. Methods All Japanese SSc patients hospitalized to our clinic for initial evaluation of SSc were selected. Skin thickness was evaluated by modified Rodnan total skin thickness score (mRSS). Relationship between mRSS and prevalence or incidence of organ involvements was examined by logistic analyses. Correlation between mRSS and quantitative measurements of organ involvements was examined by correlation analyses and regression analyses. Results We recruited 198 patients into our study. The mean disease duration was 7.3 years with the mean follow-up duration of 3.2 years. Multivariate logistic regression analyses revealed that higher mRSS is related to higher prevalence of interstitial lung disease (P

Our aim was to determine the accuracy of ultrasound (US) examination-based testicular torsion diagnosis in adult patients with acute scrotal pain. A comprehensive electronic search was performed using internet retrieval systems up to 5 August 2018 in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The quality of eligible studies was assessed using Quality Assessment for Studies of Diagnostic Accuracy (QUADAS-2). The diagnostic value of ultrasound in patients with testicular torsion was evaluated using pooled estimates of sensitivity, specificity, likelihood ratio, and diagnostic odds ratio, as well as the summary receiver operating characteristics curve. Twenty-six studies with 2116 patients were included in the study. Overall diagnostic sensitivity was 0.86 [95% confidence interval (CI) 0.79–0.91] and specificity was 0.95 (95% CI: 0.92–0.97). Subgroup analysis of prospective studies showed pooled sensitivity of ultrasound for testicular torsion was 0.94 (95% CI 0.83–0.98), and pooled specificity was 0.98 (95% CI 0.94–1.00). Recent studies after 2010 showed diagnostic sensitivity of 0.95 (95% CI 0.84–0.99) and specificity of 0.98 (95% CI 0.93–0.99). This meta-analysis demonstrated that ultrasound represents an effective imaging modality for diagnosing testicular torsion in adult patients with acute scrotal pain.

Systemic sclerosis (SSc) is a multisystem fibrotic disorder with autoimmune background. Accumulating evidence has highlighted the importance of T helper (Th) 2 cells in the pathogenesis of SSc and its complications. Because thymus and activation-regulated chemokine (TARC) is a potent chemoattractant for Th2 cells, we measured serum TARC levels in SSc patients and analyzed their correlation with interstitial lung disease (ILD), a major complication of SSc. Serum TARC levels were significantly elevated in patients with SSc, especially in those with the diffuse subtype, compared with healthy controls. In particular, dcSSc patients with SSc-associated ILD (SSc-ILD) showed higher TARC levels than those without SSc-ILD. However, there was no significant correlation between serum TARC levels and pulmonary function in SSc patients. Serum TARC levels did not correlate with serum levels of interleukin-13, an important Th2 cytokine, either. Furthermore, in the longitudinal study, serum TARC levels did not predict the onset or progression of SSc-ILD in patients with SSc. These results were in contrast with those of KL-6 and surfactant protein D, which correlated well with the onset, severity, and progression of SSc-ILD. Overall, these results suggest that serum TARC levels are not suitable for monitoring the disease activity of SSc-ILD.

Background: Ultrasound training is an essential part of residency programs during emergency medicine rotations for first-year trainees (postgraduate year 1). The Focused Assessment with Sonography for Trauma examination used to assess for internal bleeding in trauma patients is one of the essential skills postgraduate year 1 residents must acquire during the emergency medicine rotation. Method: A prospective, longitudinal, observational study of postgraduate year 1 residents during a 2-month long emergency medicine rotation conducted from 1 April 2019 to 31 May 2021. The primary outcome was the mean difference between the hands-on Focused Assessment with Sonography for Trauma examination scores of the first week of the emergency medicine rotation and the same hands-on Focused Assessment with Sonography for Trauma examination scores of the last week of the emergency medicine rotation. All postgraduate year 1 residents had open access to the ultrasound machine to practice examining on other postgraduate year 1 residents or could use it on real patients under supervision of emergency medicine physicians. Result: A total of 91 postgraduate year 1 residents (65 male and 26 female) were recruited and submitted to the hands-on Focused Assessment with Sonography for Trauma test in both the first and last weeks of the rotation. The mean test score for the postgraduate year 1 residents in the first week was 7.81 (standard deviation = 2.11). The mean test score in the last week was 16.17 (standard deviation = 2.60). The primary outcome of this study was the score difference between the first and last weeks (mean = 8.35, 95% confidence interval = 7.73 to 8.94, p Conclusion: Hands-on practical Focused Assessment with Sonography for Trauma training for postgraduate year 1 residents during emergency medicine rotations significantly improved their Focused Assessment with Sonography for Trauma test scores.

Background & AimsA random biopsy is recommended for surveillance of ulcerative colitis (UC)-associated colorectal cancer. However, a targeted biopsy might be more effective. We conducted a randomized controlled trial to compare rates of neoplasia detection by targeted vs random biopsies in patients with UC.MethodsWe performed a study of 246 patients with UC for 7 years or more, seen at 52 institutions in Japan from October 1, 2008 through December 31, 2010. Patients were randomly assigned to the random group (4 random biopsies collected every 10 cm in addition to targeted biopsies, n = 122) or the target group (biopsies collected from locations of suspected neoplasia, n = 124). The primary end point was the number of neoplastic lesions detected in a single surveillance colonoscopy. We estimated the ratio and difference in the mean number of neoplastic lesions between the groups. We also evaluated the non-inferiority between the groups as an exploratory study. A non-inferiority margin of 0.65 (0.13 of 0.20) was considered for the ratio of the mean number of neoplastic lesions between groups.ResultsThe mean number of biopsies found to contain neoplastic tissue per colonoscopy was 0.211 (24 of 114) in the target group and 0.168 (18 of 107) in the random group (ratio of 1.251; 95% confidence interval, 0.679–2.306). The lower limit was above the non-inferiority margin of 0.65. Neoplasias were detected in 11.4% of patients in the target group and 9.3% of patients in the random group (P = .617). Larger numbers of biopsy samples per colonoscopy were collected in the random group (34.8 vs 3.1 in the target group; P < .001), and the total examination time was longer (41.7 vs 26.6 minutes in the target group; P

Background Despite the comparable clinical benefit of XELOX (capecitabine with oxaliplatin) and FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin), the value of XELOX treatment in combination with cetuximab for metastatic colorectal cancer (mCRC) remains largely unknown. Patients and Methods In this clinical trial we evaluated the efficacy and safety of weekly/biweekly cetuximab administration combined with biweekly XELOX in patients with previously untreated v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) wild type mCRC. The primary end point was response rate (RR) with confirmation, and the secondary end points included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), dose intensity, and the safety of the protocol treatment. Results Forty patients who fulfilled the inclusion criteria participated in this study. The median treatment cycle number was 8 and the median dose intensities were 218 mg/m2/wk for cetuximab, 34 mg/m2/wk for oxaliplatin, and 821 mg/m2/d for capecitabine. One patient showed complete response and partial response was observed in 19 patients, giving an overall RR of 50% (95% confidence interval [CI], 33.8%-66.2%). Stable disease was obtained in 13 patients, resulting in a DCR of 82.5% (95% CI, 67.2%-92.7%). The PFS was 6.5 months (95% CI, 3.5-9.6 months), and the OS was 24.3 months (95% CI, 14.9-33.7 months). The safety profile revealed the common Grade 3/4 adverse events to be acneiform eruption (12.5%), peripheral neuropathy (7.5%), and elevated alanine transaminase levels (7.5%). Grade 3/4 thrombocytopenia and neutropenia occurred only in 5.0% and 2.5% of the patients, respectively. Grade 1 hand-foot syndrome (HFS) was not uncommon (20%), whereas Grade 2/3 HFS occurred in only 3 patients (7.5%). No deaths were reported within 30 days of the last dose. Conclusion Cetuximab with XELOX showed a confirmed overall RR of 50%, which was within the previously reported range of RR. The safety profile showed an acceptable rate and severity of adverse events. In light of the several advantages of XELOX, including convenience and the reported cost-saving aspects, further study of this combination therapy is warranted.

Purpose: Dose adjustment of 5-fluorouracil (FU) based on pharmacokinetic monitoring has been shown to reduce toxicities and increase efficacy compared with dosing based on body surface area in patients with metastatic colorectal cancer (mCRC). We evaluated the efficacy and safety of pharmacokinetic dose adjustment of FU in a modified FOLFOX7 (mFOLFOX7) plus bevacizumab regimen in Japanese patients with previously untreated mCRC. Methods: This single-arm, multicenter phase II trial enrolled 48 patients with mCRC. Treatment consisted of 5 mg/kg intravenous bevacizumab followed by mFOLFOX7 (oxaliplatin 85 mg/m2 on day 1, infused leucovorin 200 mg/m2, followed by a 2400 mg/m2 infusion of FU for 46 h starting on day 1), repeated every 2 weeks. FU concentrations were measured by immunoassay between 18 and 36 h after the start of continuous FU infusion, and the FU dose was then adjusted if required in subsequent cycles. The primary endpoint was response rate. Results: The median initial area under the concentration–time curve for FU was 23 mg h/L. Twenty-nine patients (60%) achieved the target concentration at the first cycle, and all 48 achieved it within the fourth cycle. The overall frequency of grade 3/4 adverse effects was 38%, with no significant difference between patients who did and not require dose adjustments. The overall response rate was 48% (95% confidence intervals = 34–62%). The median progression-free and overall survival rates were 11.3 and 24.1 months, respectively. Conclusions: Pharmacokinetic dose adjustment of FU in mFOLFOX7 plus bevacizumab can optimize FU concentrations promptly and is safe in Japanese patients with mCRC.

Purpose This study investigated the efficacy and safety of cetuximab-based treatment in patients with chemotherapy-resistant refractory mCRC with KRAS G13D mutation. Patients and methods An assessment of the efficacy and safety of cetuximab-based treatment was performed in an observation-enriched randomized controlled study comparing the cetuximab alone group (Cet group) and the combination of cetuximab and irinotecan group (CetI group) for KRAS G13D-mutated mCRC in Japan. In this study, the patients received a biweekly (500 mg/m2 on day 1) or weekly (250 mg/m2) intravenous infusion of cetuximab in Cet group, or a biweekly (500 mg/m2 on day 1) or weekly (250 mg/m2) intravenous infusion of cetuximab followed by irinotecan (150 mg/m2) in CetI group. Propensity score adjustment was used to achieve balance in the observational arm. Results Data from a total of 29 patients (10 in Cet group, 19 in CetI group) were analyzed. Crude median progression-free survival time was 2.9 months in the Cet group and 2.5 months in the CetI group. Crude disease control rates were 55.6% in the Cet group and 47.4% in the CetI group. After a median follow-up of 43 months, the crude median overall survival was 8.0 months in the Cet group and 7.6 months in the CetI group. Cetuximab-based treatment did not markedly increase any characteristic toxicity and was generally well tolerated. Propensity score analyses adjusted for performance status and number of metastases showed comparable results with the crude results. Conclusion Cetuximab-based treatment seemed to benefit patients with chemotherapy-resistant, refractory KRAS G13D-mutated mCRC. Our results might support the administration of cetuximab-based treatment for KRAS-mutant mCRC and would be able to provide treatment flexibility in this setting.

BACKGROUND AND AIM Prophylactic clipping has been widely used to prevent post-procedural bleeding in colon polypctomy. However, its efficiency has not been confirmed and there is no consensus on the usefulness of prophylactic clipping. The aim of the present study was to evaluate the preventive effect of prophylactic clipping on post-polypectomy bleeding. METHODS A multicenter randomized controlled study was conducted from January 2012 to July 2013 in Japan. Patients who had polyps

Recently, macrolide-resistant (MR) Mycoplasma pneumonia appeared, and prevalence of macrolide resistance among M. pneumoniae infections varies by country. However, reports on regional differences in the prevalence of MR M. pneumonia within a country are scarce. In this study, 617 nasopharyngeal swab samples were collected from 617 pediatric patients, and DNA of M. pneumoniae was identified in 95 samples. In 51 of the 95 M. pneumonia positive samples, we detected the presence of mutation A2063G mutation (conferring macrolide resistance) in the 23S rRNA gene. The overall macrolide resistance rate was 53.7%, but there were regional differences: 0.0% in Muroran, 5.3% in Asahikawa, 55.3% in Sapporo, and 100.0% in Kushiro. Statistically significant pairwise differences in the prevalence of MR M. pneumoniae were observed among these cities except for the pair of Muroran and Asahikawa. After exclusion (in order to avoid the influence of macrolides) of patients who were prescribed macrolides before collection of nasopharyngeal swab samples, statistically significant differences persisted: 0.0% in Muroran, 5.6% in Asahikawa, 38.5% in Sapporo, and 100.0% in Kushiro.

e16506 Background: In 2013, the GASTRIC (Global Advanced/Adjuvant Stomach Tumor Research through International Collaboration) evaluated the surrogacy of PFS based on IPD of 4,069 patients from 20 randomized trials of AGC. Treatment effects on PFS and on OS were only moderately correlated, and we could not validate PFS as a surrogate endpoint for OS. More recent trials, with refined inclusion criteria and higher standards for evaluating progression, may allow for a more accurate estimate of the correlation. The 2nd round of the GASTRIC sought to re-evaluate the surrogacy of PFS for OS in AGC. Methods: The GASTRIC database was updated with trials published after 2010 which used RECIST (Response Evaluation Criteria in Solid Tumors). Since the proportional hazards assumption was questionable for PFS, we primarily used mean-time ratio as a treatment effect measure, estimated by using the log-logistic model. Using the meta-analytic approach, correlations between PFS and OS at the individual level (Rindiv), and between treatment effects on PFS and on OS at the trial level (Rtrial), were estimated using Spearman’s rank-correlation and estimation-error-adjusted regression, respectively. Surrogate threshold effect was estimated as well. Results: We analyzed 10,912 patient data (1st round 4,069 patients from 20 trials and 2nd round 6,843 patients from 17 trials). Overall, moderate correlations were found at the individual level (Rindiv = 0.75, 95%CI = 0.75 to 0.76 in Hougaard copula) and at the trial level (Rtrial = 0.77, 95%CI = 0.32 to 1.00), respectively. Surrogate threshold effect was equal to 1.29, i.e., observing 29% increase in mean PFS time would predict a significant increase of the OS time. In the subgroup of patients with measurable disease in the 2nd round dataset (4,866 patients), Rtrial was higher and equal to 0.93 (95%CI = 0.70 to 1.00), with STE equal to 1.21. These results were same for 1st and 2nd line trials. Conclusions: The meta-analysis indicates a strong correlation between treatment effects (expressed as log-mean-ratios) on PFS and OS in patients with measurable disease.

Background & Aims Patients with Crohn’s disease (CD) can require multiple intestinal operations. We examined time trends and risk factors for reoperation in patients with CD who underwent intestinal surgery, focusing on the effects of post-operative medical treatments. Methods We performed a retrospective analysis of 1871 patients with CD who underwent initial intestinal resection at 10 tertiary care institutions in Japan, with initial operative date after May 1982. We collected data on background characteristics of all patients, including Montreal Classification, smoking status, and medical therapy after surgery (tumor necrosis factor antagonists [anti-TNF agents] or immunomodulators). The primary outcome was requirement for first reoperation. Rate of reoperation was estimated using the Kaplan-Meier method, and risk factors for reoperation were identified using the Cox regression model. Results The overall cumulative 5- and 10-year reoperation rates were 23.4% and 48.0%, respectively. Multivariable analysis revealed that patients who underwent the initial operation after May 2002 had a significantly lower rate of reoperation than patients who were operated on before April 2002 (hazard ratio [HR], 0.72; 95% CI, 0.61–0.86). Preoperative smoking (HR 1.40; 95% CI, 1.18–1.68), perianal disease (HR, 1.50; 95% CI, 1.27–1.77), and ileocolic type of CD (HR, 1.42; 95% CI, 1.20–1.69) were significant risk factors for reoperation. Post-operative use of immunomodulators (HR, 0.60; 95% CI, 0.44–0.81) and anti-TNF therapy (HR, 0.71; 95% CI, 0.57–0.88) significantly reduced the risk. Anti-TNF was effective in the bio-naive subgroup. Conclusions The rate of reoperation in patients with CD significantly decreased after May 2002. Post-operative use of anti-TNF agents might reduce the reoperation rate for bio-naive patients with CD.

121 Background: We have conducted the multicenter, phase Ib/II study to assess the activity and safety of biweekly Trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) combination for pts with metastatic colorectal cancer (mCRC) who were refractory or intolerant to standard therapies, and the primary endpoint of investigator assessed progression-free survival rate at 16 weeks (16w-PFS) was met [Kotaka M, ASCO-GI 2018]. We show longer follow-up data from this prospective study. Methods: Patients with unresectable mCRC; refractory or intolerant to standard chemotherapies were enrolled. Phase Ib part is designed to determine the recommended phase II dose (RP2D), and the treatment was determined as biweekly FTD/TPI (70mg/m2/day on day 1-5, every 2 weeks) with BEV (5mg/kg, every 2 weeks). The primary endpoint in phase II part was a 16w-PFS with a hypothesis of 15% considered unacceptable and 38.7% deemed promising. Given a one-sided α of 0.025 and statistical power of 90%, a minimum of 40 pts were required for phase II part. This trial registered in University Hospital Medical Information Network, number UMIN000029198. Results: From October 2017 to January 2018, totally 46 pts were enrolled. Nine patients (20.5 %) received regorafenib before enrollment. Of the 44 eligible pts, 16w-PFS rate was 40.9 %. With a median follow up of 15.36 months (range, 2.79-16.93), median PFS was 4.29 months (95% CI: 2.54 to 5.83), median TTF was 4.16 months (95% CI: 2.39 to 5.82), and median OS was 10.86 months (95% CI:8.32 to 13.68), respectively. Disease control rate was 59.1 % (95%CI: 43.3 to 73.7 %). Patients received the study treatment for a median of 6.5 cycles (range, 1 to 24). The median relative dose intensity of FTD/TPI and BEV was 80.9% (range: 44.0 to 100%), 81.5% (range: 50.0 to 100%), respectively. Common grade 3 or higher adverse events were hypertension (40.9%), neutropenia (11.4 %) and leucopenia (11.4 %). Conclusions: An update analysis confirmed that biweekly FTD/TPI plus BEV showed promising anti-tumor effect with acceptable less toxicities, and might be one of the treatment options for patients with heavily treated mCRC. Clinical trial information: UMIN000029198.

TPS267 Background: The first-line FOLFOXIRI with Bevacizumab (BEV) is highly effective and regarded as one of standard-of-care treatments in patients (pts) with metastatic colorectal cancer (mCRC) despite a high incidence of adverse events (AEs) such as neutropenia and diarrhea. The AXEPT, Asian Phase III study showed CAPIRI+BEV [Capecitabine (CAP: 1600 mg/m2), Irinotecan (IRI: 200 mg/m2) and BEV (7.5 mg/m2)] q3wk was non-inferior to FOLFIRI+BEV in pts with the second-line mCRC, with a lower incidence hematologic toxicity favoring CAPIRI+BEV over FOLFIRI+BEV. Based on these, a reduced dose of 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. Key eligibility criteria are as follows; age ≥20 years, ECOG performance status (PS) 0-1 (≥71 years age: PS 0), adequate organ function, and UGT1A1 single-heterozygous (UGT1A1*1/*6 or *1/*28) or wild-type (*1/*1) genotype. Pts are randomized to either the recommended dose of CAPOXIRI+BEV or FOLFOXIRI+BEV (OX: 85 mg/m2, IRI: 165 mg/m2, l-leucovorin: 200 mg/m2, 5-FU: 3200 mg/m2), with the strata of RAS/ BRAF status, previous adjuvant OX, tumor sidedness, and UGT1A1 status. Induction triplet chemotherapy plus BEV treatments are administered for up to 4 months followed by fluoropyrimidine plus BEV maintenance. The recommended dose of CAPOXIRI+BEV will be determined as a safety-lead-in before moving forward to the phase II main part. The primary endpoint is progression-free survival (PFS). The similarity of PFS between the two arms is evaluated by observing whether the point estimate of hazard ratio (HR) for PFS falls in between 0.80 and 1.25. Ensuring 70% probability that the observed HR will be “0.8

Predicting tumor response prior to starting anti-epidermal growth factor receptor (EGFR) antibody therapy would benefit patients with advanced/metastatic colorectal cancer (mCRC). The present study investigated the association between efficacy of cetuximab treatment and gene polymorphisms of fragment C γ receptor (FcγR) 2A, FcγR3A and EGFR in patients with extended RAS/BRAF wild-type mCRC. Clinical data and specimens were obtained from 90 patients who participated in either of two clinical studies evaluating the first-line, cetuximab plus oxaliplatin-based treatment. It was hypothesized that polymorphisms H/H of FcγR2A, V/V of FcγR3A, K/K of EGFR and