Yasuhiro Shimada

Background VEGFR-2 has a role in gastric cancer pathogenesis and progression. We assessed whether ramucirumab, a monoclonal antibody VEGFR-2 antagonist, in combination with paclitaxel would increase overall survival in patients previously treated for advanced gastric cancer compared with placebo plus paclitaxel. Methods This randomised, placebo-controlled, double-blind, phase 3 trial was done at 170 centres in 27 countries in North and South America, Europe, Asia, and Australia. Patients aged 18 years or older with advanced gastric or gastro-oesophageal junction adenocarcinoma and disease progression on or within 4 months after first-line chemotherapy (platinum plus fluoropyrimidine with or without an anthracycline) were randomly assigned with a centralised interactive voice or web-response system in a 1:1 ratio to receive ramucirumab 8 mg/kg or placebo intravenously on days 1 and 15, plus paclitaxel 80 mg/m2 intravenously on days 1, 8, and 15 of a 28-day cycle. A permuted block randomisation, stratified by geographic region, time to progression on first-line therapy, and disease measurability, was used. The primary endpoint was overall survival. Efficacy analysis was by intention to treat, and safety analysis included all patients who received at least one treatment with study drug. This trial is registered with ClinicalTrials.gov, number NCT01170663, and has been completed; patients who are still receiving treatment are in the extension phase. Findings Between Dec 23, 2010, and Sept 23, 2012, 665 patients were randomly assigned to treatment—330 to ramucirumab plus paclitaxel and 335 to placebo plus paclitaxel. Overall survival was significantly longer in the ramucirumab plus paclitaxel group than in the placebo plus paclitaxel group (median 9·6 months [95% CI 8·5–10·8] vs 7·4 months [95% CI 6·3–8·4], hazard ratio 0·807 [95% CI 0·678–0·962]; p=0·017). Grade 3 or higher adverse events that occurred in more than 5% of patients in the ramucirumab plus paclitaxel group versus placebo plus paclitaxel included neutropenia (133 [41%] of 327 vs 62 [19%] of 329), leucopenia (57 [17%] vs 22 [7%]), hypertension (46 [14%] vs eight [2%]), fatigue (39 [12%] vs 18 [5%]), anaemia (30 [9%] vs 34 [10%]), and abdominal pain (20 [6%] vs 11 [3%]). The incidence of grade 3 or higher febrile neutropenia was low in both groups (ten [3%] vs eight [2%]). Interpretation The combination of ramucirumab with paclitaxel significantly increases overall survival compared with placebo plus paclitaxel, and could be regarded as a new standard second-line treatment for patients with advanced gastric cancer. Funding Eli Lilly and Company.

Japanese mortality due to colorectal cancer is on the rise, surpassing 49,000 in 2015. Many new treatment methods have been developed during recent decades. The Japanese Society for Cancer of the Colon and Rectum Guidelines 2016 for the treatment of colorectal cancer (JSCCR Guidelines 2016) were prepared to show standard treatment strategies for colorectal cancer, to eliminate disparities among institutions in terms of treatment, to eliminate unnecessary treatment and insufficient treatment, and to deepen mutual understanding between health-care professionals and patients by making these Guidelines available to the general public. These Guidelines were prepared by consensus reached by the JSCCR Guideline Committee, based on a careful review of the evidence retrieved by literature searches, and in view of the medical health insurance system and actual clinical practice settings in Japan. Therefore, these Guidelines can be used as a tool for treating colorectal cancer in actual clinical practice settings. More specifically, they can be used as a guide to obtaining informed consent from patients and choosing the method of treatment for each patient. As a result of the discussions held by the Guideline Committee, controversial issues were selected as Clinical Questions, and recommendations were made. Each recommendation is accompanied by a classification of the evidence and a classification of recommendation categories based on the consensus reached by the Guideline Committee members. Here we present the English version of the JSCCR Guidelines 2016.

Abstract The number of deaths from colorectal cancer in Japan continues to increase. Colorectal cancer deaths exceeded 50,000 in 2016. In the 2019 edition, revision of all aspects of treatments was performed, with corrections and additions made based on knowledge acquired since the 2016 version (drug therapy) and the 2014 version (other treatments). The Japanese Society for Cancer of the Colon and Rectum guidelines 2019 for the treatment of colorectal cancer (JSCCR guidelines 2019) have been prepared to show standard treatment strategies for colorectal cancer, to eliminate disparities among institutions in terms of treatment, to eliminate unnecessary treatment and insufficient treatment and to deepen mutual understanding between healthcare professionals and patients by making these guidelines available to the general public. These guidelines have been prepared by consensuses reached by the JSCCR Guideline Committee, based on a careful review of the evidence retrieved by literature searches and in view of the medical health insurance system and actual clinical practice settings in Japan. Therefore, these guidelines can be used as a tool for treating colorectal cancer in actual clinical practice settings. More specifically, they can be used as a guide to obtaining informed consent from patients and choosing the method of treatment for each patient. Controversial issues were selected as clinical questions, and recommendations were made. Each recommendation is accompanied by a classification of the evidence and a classification of recommendation categories based on the consensus reached by the Guideline Committee members. Here, we present the English version of the JSCCR guidelines 2019.

Early clinical trials conducted primarily in Japan have shown that TAS-102, an oral agent that combines trifluridine and tipiracil hydrochloride, was effective in the treatment of refractory colorectal cancer. We conducted a phase 3 trial to further assess the efficacy and safety of TAS-102 in a global population of such patients.In this double-blind study, we randomly assigned 800 patients, in a 2:1 ratio, to receive TAS-102 or placebo. The primary end point was overall survival.The median overall survival improved from 5.3 months with placebo to 7.1 months with TAS-102, and the hazard ratio for death in the TAS-102 group versus the placebo group was 0.68 (95% confidence interval [CI], 0.58 to 0.81; P<0.001). The most frequently observed clinically significant adverse events associated with TAS-102 were neutropenia, which occurred in 38% of those treated, and leukopenia, which occurred in 21%; 4% of the patients who received TAS-102 had febrile neutropenia, and one death related to TAS-102 was reported. The median time to worsening performance status (a change in Eastern Cooperative Oncology Group performance status [on a scale of 0 to 5, with 0 indicating no symptoms and higher numbers indicating increasing degrees of disability] from 0 or 1 to 2 or more) was 5.7 months with TAS-102 versus 4.0 months with placebo (hazard ratio, 0.66; 95% CI, 0.56 to 0.78; P<0.001).In patients with refractory colorectal cancer, TAS-102, as compared with placebo, was associated with a significant improvement in overall survival. (Funded by Taiho Oncology-Taiho Pharmaceutical; RECOURSE ClinicalTrials.gov number, NCT01607957.).

Background Effective systemic therapies for patients with advanced, progressive neuroendocrine tumours of the lung or gastrointestinal tract are scarce. We aimed to assess the efficacy and safety of everolimus compared with placebo in this patient population. Methods In the randomised, double-blind, placebo-controlled, phase 3 RADIANT-4 trial, adult patients (aged ≥18 years) with advanced, progressive, well-differentiated, non-functional neuroendocrine tumours of lung or gastrointestinal origin were enrolled from 97 centres in 25 countries worldwide. Eligible patients were randomly assigned in a 2:1 ratio by an interactive voice response system to receive everolimus 10 mg per day orally or identical placebo, both with supportive care. Patients were stratified by tumour origin, performance status, and previous somatostatin analogue treatment. Patients, investigators, and the study sponsor were masked to treatment assignment. The primary endpoint was progression-free survival assessed by central radiology review, analysed by intention to treat. Overall survival was a key secondary endpoint. This trial is registered with ClinicalTrials.gov, number NCT01524783. Findings Between April 3, 2012, and Aug 23, 2013, a total of 302 patients were enrolled, of whom 205 were allocated to everolimus 10 mg per day and 97 to placebo. Median progression-free survival was 11·0 months (95% CI 9·2–13·3) in the everolimus group and 3·9 months (3·6–7·4) in the placebo group. Everolimus was associated with a 52% reduction in the estimated risk of progression or death (hazard ratio [HR] 0·48 [95% CI 0·35–0·67], p<0·00001). Although not statistically significant, the results of the first pre-planned interim overall survival analysis indicated that everolimus might be associated with a reduction in the risk of death (HR 0·64 [95% CI 0·40–1·05], one-sided p=0·037, whereas the boundary for statistical significance was 0·0002). Grade 3 or 4 drug-related adverse events were infrequent and included stomatitis (in 18 [9%] of 202 patients in the everolimus group vs 0 of 98 in the placebo group), diarrhoea (15 [7%] vs 2 [2%]), infections (14 [7%] vs 0), anaemia (8 [4%] vs 1 [1%]), fatigue (7 [3%] vs 1 [1%]), and hyperglycaemia (7 [3%] vs 0). Interpretation Treatment with everolimus was associated with significant improvement in progression-free survival in patients with progressive lung or gastrointestinal neuroendocrine tumours. The safety findings were consistent with the known side-effect profile of everolimus. Everolimus is the first targeted agent to show robust anti-tumour activity with acceptable tolerability across a broad range of neuroendocrine tumours, including those arising from the pancreas, lung, and gastrointestinal tract. Funding Novartis Pharmaceuticals Corporation.

To date, no anatomic or biomechanical studies have been conducted to clarify what size of a Hill-Sachs lesion needs to be treated. Nine fresh-frozen cadaveric shoulders were tested in a custom device. With the arm in maximum external rotation, horizontal extension, and 0 degrees, 30 degrees, and 60 degrees of abduction, the location of the entire rim of the glenoid was marked on the humeral head using a Kirschner wire. The distance from the contact area to the footprint of the rotator cuff with the arm in 60 degrees of abduction was measured by a digital caliper. With an increase in arm elevation, the glenoid contact shifted from the inferomedial to the superolateral portion of the posterior aspect of the humeral head, creating a zone of contact (glenoid track). The medial margin of the glenoid track was located 18.4 +/- 2.5 mm medial from the footprint, which was equivalent to 84% +/- 14% of the glenoid width. A Hill-Sachs lesion has a risk of engagement and dislocation if it extends medially over the medial margin of the glenoid track.

NK911 is a novel supramolecular nanocarrier designed for the enhanced delivery of doxorubicin (DXR) and is one of the successful polymer micelle systems to exhibit an efficient accumulation in solid tumours in mice. The purpose of this study was to define the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLTs) of NK911 and to evaluate its pharmacokinetic profile in man. NK911 was given intravenously to patients with solid tumours every 3 weeks using an infusion pump at a rate of 10 mg DXR equivalent min(-1). The starting dose was 6 mg DXR equivalent m(-2), and the dose was escalated according to the accelerated titration method. A total of 23 patients participated in this study. Neutropenia was the predominant haematological toxicity, and grade 3 or 4 neutropenia was observed at doses of 50 and 67 mg m(-2). Common nonhaematological toxicities were mild alopecia, stomatitis, and anorexia. In the dose identification part of the study, DLTs were observed at a dose of 67 mg m(-2) (grade 4 neutropenia lasting more than 5 days). Thus, this dosage level was determined to be the MTD. Infusion-related reactions were not observed in any cases. The C(5 min) and area under the concentration curve parameters of NK911 exhibited dose-dependent characteristics. Among the 23 patients, a partial response was obtained in one patient with metastatic pancreatic cancer. NK911 was well tolerated and produced only moderate nausea and vomiting at myelosuppressive dosages. The recommended phase II dose was determined to be 50 mg m(-2) every 3 weeks.

Abstract Colorectal cancer is a major cause of death in Japan, where it accounts for the largest number of deaths from malignant neoplasms among women and the third largest number among men. Many new methods of treatment have been developed during recent decades. The Japanese Society for Cancer of the Colon and Rectum Guidelines 2014 for treatment of colorectal cancer (JSCCR Guidelines 2014) have been prepared as standard treatment strategies for colorectal cancer, to eliminate treatment disparities among institutions, to eliminate unnecessary treatment and insufficient treatment, and to deepen mutual understanding among health-care professionals and patients by making these guidelines available to the general public. These guidelines have been prepared as a result of consensuses reached by the JSCCR Guideline Committee on the basis of careful review of evidence retrieved by literature searches and taking into consideration the medical health insurance system and actual clinical practice in Japan. They can, therefore, be used as a guide for treating colorectal cancer in clinical practice. More specifically, they can be used as a guide to obtaining informed consent from patients and choosing the method of treatment for each patient. As a result of the discussions of the Guideline Committee, controversial issues were selected as clinical questions, and recommendations were made. Each recommendation is accompanied by a classification of the evidence and a classification of recommendation categories, on the basis of consensus reached by Guideline Committee members. Here we present the English version of the JSCCR Guidelines 2014.

Purpose: To compare fluorouracil (FU) alone with FU plus cisplatin (FP) and with uracil and tegafur plus mitomycin (UFTM) for patients with advanced gastric cancer in a prospective, randomized, controlled trial. Patients and Methods: A total of 280 patients with advanced gastric cancer were randomly allocated and analyzed for survival, response, and toxicity. The survival curves were compared between groups by log-rank test on an intent-to-treat basis. Results: At the interim analysis, the UFTM arm showed a significantly inferior survival with higher incidences of hematologic toxic effects than did control arm FU alone, and the registration to UFTM was terminated. Both investigational regimens, FP and UFTM, had a significantly higher incidence of hematologic toxic effects than FU alone, although the effects were manageable. The overall response rates of the FU-alone, FP, and UFTM arms were 11%, 34%, and 9%, respectively. The median progression-free survival was 1.9 months with FU alone, 3.9 months with FP, and 2.4 months with UFTM, respectively. Although FP demonstrated a higher response rate (P &lt; .001) and longer progression-free survival than did FU alone (P &lt; .001), no differences in overall survival were observed between the arms. The median survival times and 1-year survival rates were 7.1 months and 28% with FU, 7.3 months and 29% with FP, and 6.0 months and 16% with UFTM, respectively. Conclusion: Neither investigational regimen, FP nor UFTM, showed a survival advantage as compared with FU alone. FU alone will remain a reference arm in our future trial for advanced gastric cancer.

This phase I study was designed to examine the maximum tolerated dose (MTD), the dose-limiting toxicities (DLTs), the recommended dose (RD) for phase II, and the pharmacokinetics of NK105, a new polymeric micelle carrier system for paclitaxel (PTX). NK105 was administered as a 1-h intravenous infusion every 3 weeks, without antiallergic premedication. The starting dose was 10 mg m(-2), and the dose was escalated according to the accelerated titration method. Nineteen patients were recruited. The tumour types treated included pancreatic (n=11), bile duct (n=5), gastric (n=2), and colonic (n=1) cancers. Neutropenia was the most common haematological toxicity. A grade 3 fever developed in one patient given 180 mg m(-2). No other grades 3 or 4 nonhaematological toxicities, including neuropathy, was observed during the entire study period. DLTs occurred in two patients given 180 mg m(-2) (grade 4 neutropenia lasting for more than 5 days). Thus, this dose was designated as the MTD. Grade 2 hypersensitivity reactions developed in only one patient given 180 mg m(-2). A partial response was observed in one patient with pancreatic cancer. The maximum concentration (C(max)) and area under the concentration (AUC) of NK105 were dose dependent. The plasma AUC of NK105 at 150 mg m(-2) was approximately 15-fold higher than that of the conventional PTX formulation. NK105 was well tolerated, and the RD for the phase II study was determined to be 150 mg m(-2) every 3 weeks. The results of this phase I study warrant further clinical evaluation.

Background Studies done in Asia have shown that a regimen of S-1 plus oxaliplatin (SOX) has promising efficacy and safety in patients with metastatic colorectal cancer. We aimed to establish whether SOX plus bevacizumab is non-inferior to mFOLFOX6 (modified regimen of leucovorin, fluorouracil, and oxaliplatin) plus bevacizumab as first-line chemotherapy for metastatic colorectal cancer. Methods We undertook an open-label, non-inferiority, randomised phase 3 trial in 82 sites in Japan. We enrolled individuals aged 20–80 years who had metastatic colorectal cancer, had an Eastern Cooperative Oncology Group performance status of 0 or 1, had assessable lesions, had received no previous chemotherapy or radiotherapy, could take drugs orally, and had adequate organ function. Eligible patients were randomly assigned (1:1) to receive either mFOLFOX6 plus bevacizumab (on day 1 of each 2-week cycle, 5 mg/kg intravenous infusion of bevacizumab and a simultaneous intravenous infusion of 85 mg/m2 oxaliplatin, 200 mg/m2 l-leucovorin, 400 mg/m2 bolus fluorouracil, and 2400 mg/m2 infusional fluorouracil) or SOX plus bevacizumab (on day 1 of each 3-week cycle, 7·5 mg/kg intravenous infusion of bevacizumab and 130 mg/m2 intravenous infusion of oxaliplatin; assigned dose of S-1 twice a day from after dinner on day 1 to after breakfast on day 15, followed by 7-day break). Randomisation was done centrally with the minimisation method, with stratification by institution and whether postoperative adjuvant chemotherapy had been given. Participants, investigators, and data analysts were not masked to treatment assignment. The primary endpoint was progression-free survival (PFS), which was defined as the interval between enrolment and progressive disease (≥20% increase in sum of longest dimensions of target lesions from baseline, or appearance of new lesions) or death, whichever came first. The primary analysis was done by modified intention to treat. This trial is registered with the Japan Pharmaceutical Information Center, number JapicCTI-090699. Findings Between Feb 1, 2009, and March 31, 2011, 512 patients underwent randomisation. 256 patients assigned to receive SOX plus bevacizumab and 255 assigned to receive mFOLFOX6 plus bevacizumab were included in the primary analysis. Median PFS was 11·5 months (95% CI 10·7–13·2) in the group assigned to mFOLFOX6 plus bevacizumab and 11·7 months (10·7–12·9) in the group assigned to SOX plus bevacizumab (HR 1·04, 95% CI 0·86–1·27; less than non-inferiority margin of 1·33, pnon-inferiority=0·014). The most common haematological adverse events of grade 3 or higher were leucopenia (21 [8%] of 249 patients given mFOLFOX6 plus bevacizumab included in safety analysis vs six [2%] of 250 given SOX plus bevacizumab; p=0·0029) and neutropenia (84 [34%] vs 22 [9%]; p<0·0001). Grade 3 or higher anorexia (13 [5%] vs three [1%]; p=0·019) and diarrhoea (23 [9%] vs seven [3%]; p=0·0040) were significantly more common in patients given SOX plus bevacizumab than in those given mFOLFOX6 plus bevacizumab. We recorded seven treatment-related deaths (three in the group given mFOLFOX6 plus bevacizumab; four in that given SOX plus bevacizumab). Interpretation SOX plus bevacizumab is non-inferior to mFOLFOX6 plus bevacizumab with respect to PFS as first-line treatment for metastatic colorectal cancer, and could become standard treatment in Asian populations. Funding Taiho.

Background Although benefits of laparoscopic surgery compared with open surgery have been suggested, the long-term survival of patients undergoing laparoscopic surgery for colon cancer requiring Japanese D3 dissection remains unclear. We did a randomised controlled trial to establish non-inferiority of laparoscopic surgery to open surgery. Methods We did an open-label, multi-institutional, randomised, two-arm phase 3 trial in 30 hospitals in Japan. Patients aged 20–75 years who had histologically proven colon cancer; tumours located in the caecum or ascending, sigmoid, or rectosigmoid colon; T3 or deeper lesions without involvement of other organs, node stages N0–2, and metastasis stage M0; and tumour size of 8 cm or smaller were included. Only accredited surgeons did surgery as an operator or instructor. Patients were randomly assigned (1:1) preoperatively to undergo D3 resection either by an open route or a laparoscopic route, via phone call or fax to the Japan Clinical Oncology Group (JCOG) Data Center. Randomisation used a minimisation method with a biased-coin assignment according to tumour location (caecum, ascending vs sigmoid, rectosigmoid) and institution. The primary endpoint was overall survival and was analysed by intention to treat. The non-inferiority margin for the hazard ratio (HR) was set at 1·366. This study is registered with UMIN Clinical Trials Registry, number C000000105, and ClinicalTrials.gov, number NCT00147134. Findings Between Oct 1, 2004, and March 27, 2009, 1057 patients were randomly assigned to either open surgery (n=528) or laparoscopic surgery (n=529). 5-year overall survival was 90·4% (95% CI 87·5–92·6) for open surgery and 91·8% (89·1–93·8) for laparoscopic surgery. Laparoscopic D3 surgery was not non-inferior to open surgery for overall survival (HR 1·06, 90% CI 0·79–1·41; pnon-inferiority=0·073). 65 (13%) patients in the open surgery group and 53 (10%) patients in the laparoscopic surgery group had grade 2–4 adverse events. Grade 2–4 adverse events included diarrhoea (15 [3%] in the open surgery group vs 14 [3%] in the laparoscopic surgery group), paralytic ileus (six [1%] vs nine [2%]), and small intestine bowel obstruction (16 [3%] vs 11 [2%]). Two treatment-related deaths occurred in the open surgery group: one patient died 7 days after surgery (probably due to myocardial infarction), and one patient died from febrile neutropenia, pneumonia, diarrhoea, and gastrointestinal haemorrhage during postoperative chemotherapy. Interpretation Laparoscopic D3 surgery was not non-inferior to open D3 surgery in terms of overall survival for patients with stage II or III colon cancer. However, because overall survival in both groups was similar and better than expected, laparoscopic D3 surgery could be an acceptable treatment option for patients with stage II or III colon cancer. Funding National Cancer Center Research and Development Fund, Grant-in-Aid for Cancer Research, and Health and Labour Sciences Research Grant for Clinical Cancer Research from the Ministry of Health, Labour and Welfare of Japan.

Guidelines recommend measuring preoperative carcinoembryonic antigen (CEA) in patients with colon cancer. Although persistently elevated CEA after surgery has been associated with increased risk for metastatic disease, prognostic significance of elevated preoperative CEA that normalized after resection is unknown.To investigate whether patients with elevated preoperative CEA that normalizes after colon cancer resection have a higher risk of recurrence than patients with normal preoperative CEA.This retrospective cohort analysis was conducted at a comprehensive cancer center. Consecutive patients with colon cancer who underwent curative resection for stage I to III colon adenocarcinoma at the center from January 2007 to December 2014 were identified.Patients were grouped into 3 cohorts: normal preoperative CEA, elevated preoperative but normalized postoperative CEA, and elevated preoperative and postoperative CEA.Three-year recurrence-free survival (RFS) and hazard function curves over time were analyzed.A total of 1027 patients (461 [50.4%] male; median [IQR] age, 64 [53-75] years) were identified. Patients with normal preoperative CEA had 7.4% higher 3-year RFS (n = 715 [89.7%]) than the combined cohorts with elevated preoperative CEA (n = 312 [82.3%]) (P = .01) but had RFS similar to that of patients with normalized postoperative CEA (n = 142 [87.9%]) (P = .86). Patients with elevated postoperative CEA had 14.9% lower RFS (n = 57 [74.5%]) than the combined cohorts with normal postoperative CEA (n = 857 [89.4%]) (P = .001). The hazard function of recurrence for elevated postoperative CEA peaked earlier than for the other cohorts. Multivariate analyses confirmed that elevated postoperative CEA (hazard ratio [HR], 2.0; 95% CI, 1.1-3.5), but not normalized postoperative CEA (HR, 0.77; 95% CI, 0.45-1.30), was independently associated with shorter RFS.Elevated preoperative CEA that normalizes after resection is not an indicator of poor prognosis. Routine measurement of postoperative, rather than preoperative, CEA is warranted. Patients with elevated postoperative CEA are at increased risk for recurrence, especially within the first 12 months after surgery.

When collecting large amounts of neuroimaging data associated with psychiatric disorders, images must be acquired from multiple sites because of the limited capacity of a single site. However, site differences represent a barrier when acquiring multisite neuroimaging data. We utilized a traveling-subject dataset in conjunction with a multisite, multidisorder dataset to demonstrate that site differences are composed of biological sampling bias and engineering measurement bias. The effects on resting-state functional MRI connectivity based on pairwise correlations because of both bias types were greater than or equal to psychiatric disorder differences. Furthermore, our findings indicated that each site can sample only from a subpopulation of participants. This result suggests that it is essential to collect large amounts of neuroimaging data from as many sites as possible to appropriately estimate the distribution of the grand population. Finally, we developed a novel harmonization method that removed only the measurement bias by using a traveling-subject dataset and achieved the reduction of the measurement bias by 29% and improvement of the signal-to-noise ratios by 40%. Our results provide fundamental knowledge regarding site effects, which is important for future research using multisite, multidisorder resting-state functional MRI data.

It remains controversial whether primary tumor resection (PTR) before chemotherapy improves survival in patients with colorectal cancer (CRC) with asymptomatic primary tumor and synchronous unresectable metastases.This randomized phase III study investigated the superiority of PTR followed by chemotherapy versus chemotherapy alone in relation to overall survival (OS) in patients with unresectable stage IV asymptomatic CRC and three or fewer unresectable metastatic diseases confined to the liver, lungs, distant lymph nodes, or peritoneum. Chemotherapy regimens of either mFOLFOX6 plus bevacizumab or CapeOX plus bevacizumab were decided before study entry. The primary end point was OS, which was analyzed by intention-to-treat.Between June 2012 and September 2019, a total of 165 patients were randomly assigned to either chemotherapy alone (84 patients) or PTR plus chemotherapy (81 patients). When the first interim analysis was performed in September 2019 with 50% (114/227) of the expected events observed among 160 patients at the data cutoff date of June 5, 2019, the Data and Safety Monitoring Committee recommended early termination of the trial because of futility. With a median follow-up of 22.0 months, median OS was 25.9 months (95% CI, 19.9 to 31.5) in the PTR plus chemotherapy arm and 26.7 (95% CI, 21.9 to 32.5) in the chemotherapy-alone arm (hazard ratio, 1.10; 95% CI, 0.76 to 1.59; one-sided P = .69). Three postoperative deaths occurred in the PTR plus chemotherapy arm.Given that PTR followed by chemotherapy showed no survival benefit over chemotherapy alone, PTR should no longer be considered a standard of care for patients with CRC with asymptomatic primary tumors and synchronous unresectable metastases.

Adjuvant chemotherapy after hepatectomy is controversial in liver-only metastatic colorectal cancer (CRC). We conducted a randomized controlled trial to examine if adjuvant modified infusional fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) is superior to hepatectomy alone for liver-only metastasis from CRC.In this phase II or III trial (JCOG0603), patients age 20-75 years with confirmed CRC and an unlimited number of liver metastatic lesions were randomly assigned to hepatectomy alone or 12 courses of adjuvant mFOLFOX6 after hepatectomy. The primary end point of phase III was disease-free survival (DFS) in intention-to-treat analysis.Between March 2007 and January 2019, 300 patients were randomly assigned to hepatectomy alone (149 patients) or hepatectomy followed by chemotherapy (151 patients). At the third interim analysis of phase III with median follow-up of 53.6 months, the trial was terminated early according to the protocol because DFS was significantly longer in patients treated with hepatectomy followed by chemotherapy. With median follow-up of 59.2 months, the updated 5-year DFS was 38.7% (95% CI, 30.4 to 46.8) for hepatectomy alone compared with 49.8% (95% CI, 41.0 to 58.0) for chemotherapy (hazard ratio, 0.67; 95% CI, 0.50 to 0.92; one-sided P = .006). However, the updated 5-year overall survival (OS) was 83.1% (95% CI, 74.9 to 88.9) with hepatectomy alone and 71.2% (95% CI, 61.7 to 78.8) with hepatectomy followed by chemotherapy. In the chemotherapy arm, the most common grade 3 or higher severe adverse event was neutropenia (50% of patients), followed by sensory neuropathy (10%) and allergic reaction (4%). One patient died of unknown cause after three courses of mFOLFOX6 administration.DFS did not correlate with OS for liver-only metastatic CRC. Adjuvant chemotherapy with mFOLFOX6 improves DFS among patients treated with hepatectomy for CRC liver metastasis. It remains unclear whether chemotherapy improves OS.

PURPOSE: A phase II study of a combination chemotherapy regimen of cisplatin (CDDP) and irinotecan (CPT-11) was conducted to assess its efficacy and feasibility in patients with metastatic gastric cancer. PATIENTS AND METHODS: Eligibility criteria included the following: (1) histologically proven gastric cancer with measurable metastatic lesions, (2) performance status of 2 or less, (3) age of 75 years or younger, (4) one or no prior chemotherapy regimens, (5) adequate bone marrow, liver, renal, and cardiac functions, and (6) written informed consent. The treatment consisted of CPT-11 (70 mg/m 2 ) on day 1 and day 15 and CDDP (80 mg/m 2 ) on day 1, repeated every 4 weeks. RESULTS: Forty-four patients were entered onto the study. The overall response rate was 48% (21 of 44 patients, 95% confidence interval [CI], 33% to 63%) and included one complete remission (2%). The response rate of the patients who had not received prior chemotherapy was 59% (17 of 29 patients, 95% CI, 39% to 77%). The median survival time was 272 days for all patients and 322 days for the 29 patients who had not received prior chemotherapy. Grade 4 neutropenia was observed in 25 patients (57%), and grade 3 or 4 diarrhea was observed in nine patients (20%). Other adverse reactions were mild. No treatment-related deaths occurred. CONCLUSION: This combination chemotherapy regimen is active and well tolerated. It may be an appropriate regimen for future phase III trials.

MCC-465 is an immunoliposome-encapsulated doxorubicin (DXR). The liposome is tagged with polyethylene glycol (PEG) and the F(ab')2 fragment of human monoclonal antibody GAH, which positively reacts to >90% of cancerous stomach tissues, but negatively to all normal tissues. In preclinical studies, MCC-465 showed superior cytotoxic activity against several human stomach cancer cells compared with DXR or DXR-incorporated PEG liposomes. The main purpose of this trial was to define the maximum tolerated dose (MTD), dose limiting toxicity (DLT), recommended phase II dose and pharmacokinetics (PK) of MCC-465.Patients with metastatic or recurrent stomach cancer were eligible for entry. The initial dose was 6.5 mg/m2. MCC-465 was administered as a 1-h infusion every 3 weeks and the treatment continued for up to six cycles.Twenty-three patients received a total of 62 cycles at the 6.5-45.5 mg/m2 dose level. DLTs were myelosuppression and appetite loss at the 45.5 mg/m2 dose level. Other toxicities were mild. Neither palmar-plantar erythrodysesthesia nor cardiotoxicity was observed. Acute reactions related to infusion were observed commonly in 16 patients over the entire dose range. While no antitumor response was observed, stable disease (SD) was observed in 10 out of 18 evaluable patients. The pharmacokinetic study showed a similar AUC and Cmax to Doxil.MCC-465 was well tolerated. The recommended dose for a phase II study of MCC-465, for a 3-week schedule, is considered to be 32.5 mg/m2 in an equivalent amount of DXR.

The influence of bone mineral density on the stability of transpedicle screwing was studied in the human cadaveric lumber vertebrae. The pull-out force correlated with bone mineral density. The tilting moment (load needed to tilt the screw 4$$ cranially at the screw-plate junction) and the cut-up force (load needed to tip the end plate up by the screw) correlated with bore mineral density, A correlation was also found between the maximum insertion torque of the screw and bone mineral density. The maximum insertion torque correlated with the pull-out force, the tilting moment, and the cut-up force. In the cyclic tiling lest (200 cycles), the mean value of the tilting moment at the 200th cycles was 67.4 $$ 6.1%, compared with the first cycle. The results suggest that preoperative measurement of BMD is necessary far transpedicle screwing in osteoporotic cases, and that the cyclic tilting motion decrease its mechanical stability. The authors have also concluded that the maximum insertion torque could predict the mechanical stability.

Fluorouracil and folinic acid with either oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) are widely used as first-line or second-line chemotherapy for metastatic colorectal cancer. However, infusional fluorouracil-based regimens, requiring continuous infusion and implantation of an intravenous port system, are inconvenient. We therefore planned an open-label randomised controlled trial to verify the non-inferiority of irinotecan plus oral S-1 (a combination of tegafur, 5-chloro-2,4-dihydroxypyridine, and potassium oxonate; IRIS) to FOLFIRI as second-line chemotherapy for metastatic colorectal cancer.Between Jan 30, 2006, and Jan 29, 2008, 426 patients with metastatic colorectal cancer needing second-line chemotherapy from 40 institutions in Japan were randomly assigned by a computer-based minimisation method to receive either FOLFIRI (n=213) or IRIS (n=213). In the FOLFIRI group, patients received folinic acid (200 mg/m(2)) and irinotecan (150 mg/m(2)) and then a bolus injection of fluorouracil (400 mg/m(2)) on day 1 and a continuous infusion of fluorouracil (2400 mg/m(2)) over 46 h, repeated every 2 weeks. In the IRIS group, patients received irinotecan (125 mg/m(2)) on days 1 and 15 and S-1 (40-60 mg according to body surface area) twice daily for 2 weeks, repeated every 4 weeks. The primary endpoint was progression-free survival, with a non-inferiority margin of 1.333. Statistical analysis was on the basis of initially randomised participants. This study is registered with ClinicalTrials.gov, number NCT00284258.All randomised patients were included in the primary analysis. After a median follow-up of 12.9 months (IQR 11.5-18.2), median progression-free survival was 5.1 months in the FOLFIRI group and 5.8 months in the IRIS group (hazard ratio 1.077, 95% CI 0.879-1.319, non-inferiority test p=0.039). The most common grade three or four adverse drug reactions were neutropenia (110 [52.1%] of 211 patients in the FOLFIRI group and 76 [36.2%] of 210 patients in the IRIS group; p=0.0012), leucopenia (33 [15.6%] in the FOLFIRI group and 38 [18.1%] in the IRIS group; p=0.5178), and diarrhoea (ten [4.7%] in the FOLFIRI group and 43 [20.5%] in the IRIS group; p<0.0001). One treatment-related death from hypotension due to shock was reported in the FOLFIRI group within 28 days after the end of treatment; no treatment-related deaths were reported in the IRIS group.Progression-free survival with IRIS is not inferior to that with FOLFIRI in patients receiving second-line chemotherapy for metastatic colorectal cancer. Treatment with IRIS could be an additional therapeutic option for second-line chemotherapy in metastatic colorectal cancer.Taiho Pharmaceutical Co Ltd and Daiichi Sankyo Co Ltd.

Adipocytokines are adipocyte-secreted hormones associated with some malignancies such as colorectal, breast, and prostate cancer. We hypothesized that changes in the levels of adipocytokines may indicate the carcinogenesis and progression of colorectal cancer and adenoma, and investigated the association of the blood levels of several adipocytokines through a case-control study. Blood levels of adiponectin, leptin, resistin, visfatin, and C-peptide at diagnosis were measured in 115 colorectal cancer patients and 115 age-, sex-, and body mass index-matched controls. The same analysis was performed in 72 colorectal adenoma patients and 72 controls. Logistic regression models were used for estimating odds ratios and 95% confidence intervals, and one-way anova was performed to determine the prevalence of each variable between two or more groups. Resistin and visfatin levels in cancer patients were significantly higher than those of controls on multivariate analysis (P = 0.03 and P < 0.01, respectively). Stage progression significantly correlated with resistin and visfatin levels (P < 0.01 for both). The adiponectin level in adenoma patients was significantly lower than that of controls on multivariate analysis (P = 0.04). Its level was inversely correlated with the number of adenoma (P = 0.02), but not correlated with the size of adenoma. Resistin and visfatin may be good biomarkers of colorectal malignant potential and stage progression. Adiponectin level may be a good biomarker of colorectal adenoma.

Background The contact pressure and contact area at the tendon-bone interface after the most commonly used rotator cuff repair methods have not been investigated. Hypothesis There are no significant differences among the transosseous, the single-row suture anchor, and the double-row suture anchor techniques in terms of contact pressure, contact area, and pressure patterns at the tendon-bone interface. Study Design Controlled laboratory study. Methods After creating a full-thickness supraspinatus tendon tear in 10 cadaveric shoulder specimens, we inserted pressure-sensitive film between the tendon stump and the bone, and we repaired the tear by (1) transosseous, (2) single-row suture anchor, and (3) double-row suture anchor techniques. Results The contact area of the double-row technique was 42% greater than that of the transosseous technique (P &lt;. 0001) and 60% greater than that of the single-row technique. The contact area of the transosseous technique was 31% greater than that of the single-row technique (P =. 0015). The average pressures of the single-row and double-row techniques were 18% (P =. 014) and 16% (P =. 03) greater, respectively, than that of the transosseous technique, but there was no significant difference between the single-row and double-row techniques (P =. 915). Conclusions The double-row technique produced the greatest contact area and the second-highest contact pressure, whereas the single-row technique created the highest contact pressure and the least contact area. The transosseous technique produced the second-greatest contact area and the least contact pressure. Clinical Relevance The double-row suture anchor technique and the transosseous technique may provide a better environment for tendon healing.

Review of the clinical and radiologic records of patients who underwent one-level posterior lumbar interbody fusion (PLIF) at L4-L5.To determine whether adjacent intervertebral disc degeneration after PLIF affects the clinical results, and whether preoperative caudal disc (L5-S1) degeneration affects postoperative clinical results.There is little reliable information in the literature regarding clinical results and adjacent disc degeneration after PLIF.Forty-five patients who underwent L4-L5 PLIF for spondylolisthesis with more than 5 years of postoperative observation were included in this study. PLIF was performed in conjunction with posterior instrumentation. The posterior lumbar intervertebral grafting was performed using both autograft and a ceramic spacer. Intervertebral disc heights at L2-L3, L3-L4, and L5-S1 were measured before and after surgery. The patients were divided into two groups based on the presence or absence of the preoperative L5-S1 narrowing. Correlation between clinical status evaluated by the recovery rate of the Japanese Orthopedic Association (JOA) score and disc heights were determined.All intervertebral disc heights adjacent to the fusion decreased after surgery (P < 0.05). However, no significant correlation was seen between clinical results estimated by the recovery rate and postoperative disc narrowing. There was also no significant difference in clinical results between patients with or without preoperative L5-S1 narrowing.There is no evidence from the results that postoperative narrowing of the adjacent disc and preoperative narrowing of the L5-S1 disc affects the clinical outcome of L4-L5 PLIF.

Journal Article Toxicity Grading Criteria of the Japan Clinical Oncology Group Get access Kensei Tobinai, Kensei Tobinai 1Departments of Medical Oncology, National Cancer Center HospitalTokyo For reprints and all correspondence: Kensei Tobinai, Department of Medical Oncology, National Cancer Center Hospital, 1-1, Tsukiji 5-chome, Chuo-ku, Tokyo 104 Search for other works by this author on: Oxford Academic PubMed Google Scholar Akio Kohno, Akio Kohno 1Departments of Medical Oncology, National Cancer Center HospitalTokyo Search for other works by this author on: Oxford Academic PubMed Google Scholar Yasuhiro Shimada, Yasuhiro Shimada 1Departments of Medical Oncology, National Cancer Center HospitalTokyo Search for other works by this author on: Oxford Academic PubMed Google Scholar Toru Watanabe, Toru Watanabe 1Departments of Medical Oncology, National Cancer Center HospitalTokyo Search for other works by this author on: Oxford Academic PubMed Google Scholar Tomohide Tamura, Tomohide Tamura 1Departments of Medical Oncology, National Cancer Center HospitalTokyo Search for other works by this author on: Oxford Academic PubMed Google Scholar Kunihiko Takeyama, Kunihiko Takeyama 1Departments of Medical Oncology, National Cancer Center HospitalTokyo Search for other works by this author on: Oxford Academic PubMed Google Scholar Masaru Narabayashi, Masaru Narabayashi 1Departments of Medical Oncology, National Cancer Center HospitalTokyo Search for other works by this author on: Oxford Academic PubMed Google Scholar Takashi Fukutomi, Takashi Fukutomi 2Departments of Surgery, National Cancer Center HospitalTokyo Search for other works by this author on: Oxford Academic PubMed Google Scholar Haruhiko Kondo, Haruhiko Kondo 2Departments of Surgery, National Cancer Center HospitalTokyo Search for other works by this author on: Oxford Academic PubMed Google Scholar Masanori Shimoyama, Masanori Shimoyama 1Departments of Medical Oncology, National Cancer Center HospitalTokyo Search for other works by this author on: Oxford Academic PubMed Google Scholar ... Show more Keiichi Suemasu, Keiichi Suemasu 2Departments of Surgery, National Cancer Center HospitalTokyo Search for other works by this author on: Oxford Academic PubMed Google Scholar Members of the Clinical Trial Review Committee of the Japan Clinical Oncology Group Members of the Clinical Trial Review Committee of the Japan Clinical Oncology Group Search for other works by this author on: Oxford Academic PubMed Google Scholar Japanese Journal of Clinical Oncology, Volume 23, Issue 4, August 1993, Pages 250–257, https://doi.org/10.1093/oxfordjournals.jjco.a039642 Published: 01 August 1993 Article history Received: 03 March 1993 Accepted: 07 July 1993 Published: 01 August 1993

Frequency of FGFR2 amplification, its clinicopathological features, and the results of high-throughput screening assays in a large cohort of gastric clinical samples remain largely unclear.Drug sensitivity to a fibroblast growth factor receptor (FGFR) inhibitor was evaluated in vitro. The gene amplification of the FGFRs in formalin-fixed, paraffin-embedded (FFPE) gastric cancer tissues was determined by a real-time PCR-based copy number assay and fluorescence in situ hybridisation (FISH).FGFR2 amplification confers hypersensitivity to FGFR inhibitor in gastric cancer cell lines. The copy number assay revealed that 4.1% (11 out of 267) of the gastric cancers harboured FGFR2 amplification. No amplification of the three other family members (FGFR1, 3 and 4) was detected. A FISH analysis was performed on 7 cases among 11 FGFR2-amplified cases and showed that 6 of these 7 cases were highly amplified, while the remaining 1 had a relatively low grade of amplification. Although the difference was not significant, patients with FGFR2 amplification tended to exhibit a shorter overall survival period.FGFR2 amplification was observed in 4.1% of gastric cancers and our established PCR-based copy number assay could be a powerful tool for detecting FGFR2 amplification using FFPE samples. Our results strongly encourage the development of FGFR-targeted therapy for gastric cancers with FGFR2 amplification.

Growth factors are known to appear during wound healing. We hypothesized that growth factors would also appear during the healing process of a rotator cuff tear. We determined the expression of various growth factors during healing of acute rotator cuff tears in the rabbit. We made a full-thickness defect in the supraspinatus tendon of 27 Japanese white rabbits. The shoulders were harvested on days 1, 3, 5, 7, 9, 11, 14, 21, and 28 postoperatively (n = 3 at each time point). We assessed the expression of basic fibroblast growth factor, insulin-like growth factor 1, platelet-derived growth factor, and transforming growth factor beta. Basic fibroblast growth factor appeared with its peak on days 7 and 9, insulin-like growth factor 1 appeared with its peak on day 5, platelet-derived growth factor appeared with a mild expression between days 7 and 14, and transforming growth factor beta appeared with constant mild expression throughout the observation period. It is likely that each of these growth factors plays a role in the early phase of healing of the supraspinatus tendon in rabbits.

Abstract Purpose: We conducted a first-in-human phase I study to determine the dose-limiting toxicity (DLT), evaluate the pharmacokinetic profile, and document any antitumor activity of NK012, a novel SN-38–incorporating micellar nanoparticle. Experimental Design: Patients with solid tumors refractory to standard therapy, or for which no standard therapy is available, were enrolled. NK012 was administered as a 30-minute infusion every 3 weeks. The starting dose was 2 mg/m2 as SN-38 equivalent, and an accelerated titration schedule was used. Pharmacokinetic analysis was conducted in cycles 1 and 2. Results: Twenty-four patients were enrolled in the study. No UGT1A1*28 homozygous patients were enrolled. Predominant toxicity was neutropenia. Nonhematologic toxicity, especially diarrhea, was mostly grade 1 or 2 during study treatments. Two of nine patients had DLT during cycle 1 at the 28 mg/m2 dose level. DLTs were mostly neutropenia or a related event. Polymer-bound SN-38 (NK012) and SN-38 released from NK012 were slowly eliminated from the plasma, with a terminal-phase half-life of approximately 140 and 210 hours, respectively. Systemic exposure to both polymer-bound SN-38 and SN-38 increased in proportion to the dose. A refractory esophageal cancer patient and a lung carcinoid tumor patient had an objective response and continued the study treatment for 5 and 12 months, respectively. Conclusions: NK012 was well tolerated and showed antitumor activity including partial responses and several occurrences of prolonged stable disease across a variety of advanced refractory cancers. Phase II studies are ongoing. Clin Cancer Res; 16(20); 5058–66. ©2010 AACR.

Next generation sequencing (NGS) has been an invaluable tool to put genomic sequencing into clinical practice. The incorporation of clinically relevant target sequences into NGS-based gene panel tests has generated practical diagnostic tools that enable individualized cancer-patient care. The clinical utility of gene panel testing includes investigation of the genetic basis for an individual's response to therapy, such as signaling pathways associated with a response to specific therapies, microsatellite instability and a hypermutated phenotype, and deficiency in the DNA double-strand break repair pathway. In this review, we describe the concept of precision cancer medicine using target sequences in gene panel tests as well as the importance of the control of sample quality in routine NGS-based genomic testing. We describe geographic and ethnic differences in cancer genomes, and discuss issues that need to be addressed in the future based on our experiences in Japan.

Neuroendocrine tumors (NETs) occur in various primary sites, but rarely in the stomach. NETs are classified into three types, carcinoids, malignant carcinoids and poorly differentiated neuroendocrine carcinomas (PNECs), whose clinical behavior is different. Currently, clinical outcomes and standard chemotherapy for NETs of the stomach remain unclear.We conducted a retrospective review of histopathologically confirmed NETs of the stomach at our hospital between January 2000 and August 2006.Thirty-seven NETs were identified. Fifteen patients had carcinoids while 22 had PNECs. Among the carcinoid patients, 7 underwent endoscopic mucosal resection and 5 had gastrectomy as first-line treatment. Three patients were observed without intervention. All patients were alive after an average follow-up period of 27 months. Among the 22 PNEC patients, 3 had no metastasis, 11 had regional lymph node metastasis, and 8 had distant metastasis. Eight of 14 patients relapsed at a median of 177 days (range 120-1459 days) after curative surgery. Twelve patients with metastatic or recurrent disease received palliative cisplatin plus irinotecan chemotherapy. The response rate was 75%, the median progression-free survival time was 212 days, and median survival time was 679 days.Gastric PNEC patients with distant metastasis had poor outcomes. Regimens containing cisplatin plus irinotecan produced a good response in gastric PNEC.

NSABP C-06 demonstrated the non-inferiority of oral adjuvant uracil and tegafur plus leucovorin (UFT/LV) to weekly fluorouracil and folinate (5-FU/LV) with respect to disease-free survival (DFS) for stage II/III colon cancer. This is the first report of JCOG0205, which compared UFT/LV to standard 5-FU/levofolinate (l-LV) for stage III colorectal cancer patients who have undergone Japanese D2/D3 lymph node dissection.Patients were randomised to three courses of 5-FU/l-LV (5-FU 500 mg/m(2), l-LV 250 mg/m(2) on days 1, 8, 15, 22, 29, 36 every 8 weeks) or five courses of UFT/LV (UFT 300 mg m(-2)day(-1), LV 75 mg/day on days 1-28 every 5 weeks). The primary end-point was DFS. The sample size was 1100 determined with one-sided alpha of 0.05, power of 0.78 and non-inferiority margin of hazard ratio of 1.27. This trial is registered with UMIN-CTR (C000000193).Between February 2003 and November 2006, 1,101 patients (1092 eligible patients) were randomised to 5-FU/l-LV (n=550) or UFT/LV (n=551). Median age: 61 years, colon/rectum: 67%/33%, number of positive nodes ⩽3/>3: 73%/27%, stage IIIa/IIIb: 75%/25%. The hazard ratio of DFS was 1.02 (91.3% confidence interval, 0.84-1.23), demonstrating the non-inferiority of UFT/LV (P=0.0236). Five-year overall survival (87.5%) was higher than that in NSABP C-06 (69.6%). Grade 3/4 toxicities were 8.4% neutropenia in 5-FU/l-LV and 8.7% alanine aminotransferase elevation in UFT/LV, respectively. The incidences of diarrhoea (9.6% versus 8.5%) and anorexia (4.0% versus 3.7%) were similar between the two arms. No treatment-related deaths were reported.Adjuvant UFT/LV is non-inferior to standard 5-FU/l-LV with respect to DFS. UFT/LV should be an oral treatment option for patients with stage III colon cancer who have undergone Japanese D2/D3 lymph node dissection.

This study compared the efficacy of regorafenib and trifluridine/tipiracil (TFTD) in patients with metastatic colorectal cancer (mCRC) who are refractory to standard chemotherapy, because despite their clinical approval, it still remains unclear which of these two drugs should be used as initial treatment.The clinical data of patients with mCRC who were treated with regorafenib or TFTD and those of drug-naive patients, between June 2014 and September 2015, were retrospectively collected from 24 institutions in Japan. Overall survival (OS) was evaluated using the Cox's proportional hazard models based on propensity score adjustment for baseline characteristics.A total of 550 patients (223 patients in the regorafenib group and 327 patients in the TFTD group) met all criteria. The median OS was 7.9 months (95% confidence interval [CI], 6.8-9.2) in the regorafenib group and 7.4 months (95% CI, 6.6-8.3) in the TFTD group. The propensity score adjusted analysis showed that OS was similar between the two groups (adjusted hazard ratio [HR], 0.96; 95% CI, 0.78-1.18). In the subgroup analysis, a significant interaction with age was observed. Regorafenib showed favorable survival in patients aged <65 years (HR, 1.29; 95% CI, 0.98-1.69), whereas TFTD was favored in patients aged ≥65 years (HR, 0.78; 95% CI, 0.59-1.03).No significant difference in OS between regorafenib and TFTD was observed in patients with mCRC. Although the choice of the drug by age might affect survival, a clearly predictive biomarker to distinguish the two drugs should be identified in further studies.Previous studies of patients with metastatic colorectal cancer refractory to standard chemotherapy had demonstrated that both regorafenib and trifluridine/tipiracil could result in increased overall survival compared with placebo, but there are no head-to-head trials. This large, multicenter, observational study retrospectively compared the efficacy of regorafenib and trifluridine/tipiracil in 550 patients with metastatic colorectal cancer refractory to standard chemotherapy who had access to both drugs. Although no difference in overall survival was found between the two drugs in adjusted analysis using propensity score, regorafenib showed favorable survival in patients aged <65 years, whereas trifluridine/tipiracil was favored in patients aged ≥65 years in the subgroup analysis.

Machine learning classifiers for psychiatric disorders using resting-state functional magnetic resonance imaging (rs-fMRI) have recently attracted attention as a method for directly examining relationships between neural circuits and psychiatric disorders. To develop accurate and generalizable classifiers, we compiled a large-scale, multi-site, multi-disorder neuroimaging database. The database comprises resting-state fMRI and structural images of the brain from 993 patients and 1,421 healthy individuals, as well as demographic information such as age, sex, and clinical rating scales. To harmonize the multi-site data, nine healthy participants ("traveling subjects") visited the sites from which the above datasets were obtained and underwent neuroimaging with 12 scanners. All participants consented to having their data shared and analyzed at multiple medical and research institutions participating in the project, and 706 patients and 1,122 healthy individuals consented to having their data disclosed. Finally, we have published four datasets: 1) the SRPBS Multi-disorder Connectivity Dataset 2), the SRPBS Multi-disorder MRI Dataset (restricted), 3) the SRPBS Multi-disorder MRI Dataset (unrestricted), and 4) the SRPBS Traveling Subject MRI Dataset.

The role of vertical larynx movement in vocal frequency (F0) change has attracted the attention of many researchers. Recently, Hirai, Honda, Fujimoto, and Shimada (1994) proposed a mechanism of F0 control by vertical larynx movement based on the measurement of magnetic resonance images (MRI). In F0 changes, the larynx moves vertically along the cervical spine, which displays anterior convexity (lordosis) at the level of the larynx. Therefore, the vertical larynx movement results in the rotation of the cricoid cartilage and vocal fold tension changes. The present study reexamines the above mechanism based on a qualitative analysis of midsagittal MRI data using three male subjects with evident cervical lordosis. Tracings of the jaw, hyoid bone, laryngeal cartilage, and cervical spine were compared in high and low F0 ranges. In the high F0 range, the hyoid bone moved horizontally while the larynx height remained relatively constant. In the low F0 range, the entire larynx moved vertically, and the cricoid cartilage rotated along the cervical lordosis. These results indicate that the vertical movement of the larynx comprises an effective F0 lowering mechanism, and suggest that the human morphologies of low larynx position and spinal curvature contribute to voluntary use of the vocal function.

The autonomic nervous system is an important neural control system for maintaining cardiovascular stability in humans. Analysis of heart rate variations may provide important clinical information on the influence of anesthesia on the autonomic nervous system and the central nervous system. Therefore, the effects of 1.0, 1.5, and 2.0 minimum alveolar concentrations of isoflurane anesthesia on beat-to-beat heart rate variations were studied in ten patients (ASA Physical Status 1). Spectral analysis was used to determine the intensity of the variations. For each power spectrum, the frequency components were identified as follows: 1) the parasympathetically mediated respiratory component (0.15-0.4 Hz) and 2) both parasympathetically and sympathetically mediated components (0.04-0.15 Hz). The latter was subdivided into the low-frequency component (0.04-0.09 Hz) of vasomotor origin and the mid-frequency component (0.09-0.15 Hz) of baroreceptor origin. Marked reductions in the power of heart rate variations, at all frequencies, were found during isoflurane anesthesia, indicating isoflurane decreased total autonomic nervous system activity. Isoflurane decreased the high-frequency and mid-frequency components in a concentration-dependent manner. The low-frequency component increased transiently at 1.5 minimum alveolar concentrations concomitant with the burst suppression in the electroencephalogram. The ratio of mid-frequency to high-frequency components did not change significantly during isoflurane anesthesia compared with the awake period. These frequency characteristics of heart rate variations during isoflurane anesthesia suggest there are dose-related decreases in autonomic nervous system activity in both the vagus and the cardiac sympathetic nerves.

A dose-escalation study of irinotecan hydrochloride (CPT-11) combined with fixed-dose cisplatin was conducted to determine the maximum-tolerated dose (MTD), dose-limiting toxicities, and objective response rate in patients with advanced gastric cancer.Twenty-four patients with or without prior chemotherapy were enrolled. All patients were assessable for toxicities and response. On day 1, CPT-11 was administered as a 90-minute intravenous (I.V.) infusion, which was followed 2 hours later by a 120-minute I.V. infusion of cisplatin 80 mg/m2. CPT-11 alone at the same dose was administered again on day 15. The treatment was repeated every 4 weeks until disease progression was observed. The initial dose of CPT-11 was 60 mg/m2, and was escalated in increments of 10 mg/m2 until severe or life-threatening toxicity was observed.The MTD of this combination was CPT-11 80 mg/m2. At this dose level, 16.7% of patients (two of 12) had leukopenia of less than 1,000/microL, 66.7% (eight of 12) had neutropenia of less than 500/microL, and 16.7% (two of 12) had severe diarrhea of grade 4 during the first course. The dose-limiting toxicity was neutropenia. Ten patients achieved a partial response (PR), and the overall response rate was 41.7% among 24 patients (95% confidence interval, 21.9% to 61.4%).The recommended dose and schedule is CPT-11 70 mg/m2 on days 1 and 15 and cisplatin 80 mg/m2 on day 1 every 4 weeks. This combination of CPT-11 and cisplatin, considered to be active against advanced gastric cancer with acceptable toxicity, should be further assessed in a phase II study.

Background Ketamine potentiates intravenous or epidural morphine analgesia. The authors hypothesized that very-low-dose ketamine infusion reduces acute and long-term postthoracotomy pain. Methods Forty-nine patients scheduled to undergo open thoracotomy were randomly assigned to receive one of two anesthesia regimens: continuous epidural infusion of ropivacaine and morphine, along with intravenous infusion of ketamine (0.05 mg . kg(-1) . h(-1) [approximately 3 mg/h], ketamine group, n = 24) or placebo (saline, control group, n = 25). Epidural analgesia was continued for 2 days after surgery, and infusion of ketamine or placebo was continued for 3 days. Pain was assessed at 6, 12, 24, and 48 h after surgery. Patients were asked about their pain, abnormal sensation on the wound, and inconvenience in daily life at 7 days and 1, 3, and 6 months after surgery. Results The visual analog scale scores for pain at rest and on coughing 24 and 48 h after thoracotomy were lower in the ketamine group than in the control group (pain at rest, 9 +/- 11 vs. 25 +/- 20 and 9 +/- 11 vs. 18 +/- 13; pain on coughing, 26 +/- 16 vs. 50 +/- 17 and 30 +/- 18 vs. 43 +/- 18, mean +/- SD; P = 0.002 and P = 0.01, P &amp;lt; 0.0001 and P = 0.02, respectively). The numerical rating scale scores for baseline pain 1 and 3 months after thoracotomy were significantly lower in the ketamine group (0.5 [0-4] vs. 2 [0-5] and 0 [0-5] vs. 1.5 [0-6], median [range], respectively; P = 0.02). Three months after surgery, a higher number of control patients were taking pain medication (2 vs. 9; P = 0.03). Conclusions Very-low-dose ketamine (0.05 mg . kg(-1) . h(-1)) potentiated morphine-ropivacaine analgesia and reduced postthoracotomy pain.

The majority of gastrointestinal stromal tumors (GIST) can be cured by surgery alone, but relapse occurs in 20% to 40% of cases. GISTs are considered to invariably arise through gain of function KIT or PDGFA mutation of the interstitial cells of Cajal (ICC). However, the genetic basis of the malignant progression of GISTs are poorly understood.The expression levels of 54,613 probe sets in 32 surgical samples of untreated GISTs of the stomach and small intestine were analyzed with oligonucleotide microarrays. The representative GeneChip data were validated by real-time reverse transcriptase polymerase chain reaction and immunohistochemistry.Unbiased hierarchical clustering consistently separated the 32 cases of GIST into two major classes according to tumor site. The two major classes were further separated into novel subclasses, which were significantly correlated with various pathological prognostic parameters, the frequency of metastasis (P < .05), and clinical outcome. Immunohistochemical analysis of 152 independent patients with gastric GISTs revealed that the expression of dipeptidyl peptidase IV (T-cell activation antigen CD26) protein was significantly associated with poorer overall and disease-free survival (P < .00001).CD26 appears to be a reliable biomarker of malignant GISTs of the stomach. The postoperative recurrence rate of CD26-negative cases was as low as 2.0% (two of 102). Therefore, postoperative follow-up of such patients might be made less intensive. CD26 may play an important role in the malignant progression of gastric GISTs and serve as a therapeutic target.

Plasma lipid peroxide measured as thiobarbituric acid reactive substances (TBARS) and alpha-tocopherol levels in 24 critically ill patients were compared with those of control subjects. The mean plasma alpha-tocopherol level was significantly lower and the mean TBARS level was significantly higher in critically ill patients. Eight ICU patients developed disseminated intravascular coagulation (DIC); the mean TBARS level during DIC was significantly above the mean pre-DIC level. These results indicate that lipid peroxidation may contribute to the development of DIC in critically ill patients.

The purpose of this study was to evaluate the feasibility and efficacy of 3-hour infusional paclitaxel for the treatment of advanced gastric cancer with measurable metastatic diseases. Eligibility criteria included no more than one regimen of prior chemotherapy. Paclitaxel was administered as an intravenous infusion over 3 hours at a dose of 210 mg/m2 every 3 weeks. Premedication of dexamethazone, ranitidine, and diphenhydramine were given to all patients. Sixteen patients were registered in the study. One patient did not receive paclitaxel because of gastrointestinal bleeding before the initiation of drug's administration. Thirteen of the 15 patients had a prior history of chemotherapy. Although 10 patients (67%) developed grade 4 neutropenia, no serious infections occurred during the study. Nonhematologic toxicities were generally mild. Three (20%) patients who showed evidences of resistance to the previous intensive regimen achieved a partial response. In conclusion, a 3-hour infusion of paclitaxel is a safe and promising treatment for advanced gastric cancer. Paclitaxel appears to be non-cross resistant to other agents that are commonly used for gastric cancer. A largescale phase II study is now underway.

Expression levels of insulin-like growth factor type 1 receptor (IGF-IR), epidermal growth factor receptor (EGFR), and HER2 expressions have been linked to clinical outcomes in several solid tumors. However, the clinical significance of these biomarkers in gastric cancer (GC) remains unclear. This study was designed to delineate the clinical implications of these three biomarkers in GC.The study group comprised 87 patients who underwent gastrectomy at National Cancer Center Hospital and subsequently received chemotherapy for recurrent or residual tumors. Using immunohistochemical techniques, we analyzed the expressions of IGF-IR, EGFR, and HER2 on formalin-fixed paraffin-embedded specimens of surgically removed primary tumors.IGF-IR expression (defined as >10% membranous staining) was found in 67 tumors (77%), EGFR expression in 55 (63%), and HER2 expression in 16 (18%). Positive coexpression of IGF-IR and EGFR was found in 48 tumors (55%), that of IGF-IR and HER2 in 16 (18%), and that of EGFR and HER2 in 13 (15%). Multivariate survival analysis showed that IGF-IR-positive expression [hazard ratio (HR) 2.14, 95% confidence interval (95% CI) 1.20-3.82; P = 0.01], performance status 1 or 2 (HR 1.83, 95% CI 1.15-2.91; P = 0.01), and diffuse type tumors (HR 1.71; 95% CI 1.08-2.70; P = 0.02) were significant predictors of poor survival.IGF-IR expression in surgical GC specimens, poor performance status, and diffuse type tumors are significant predictors of poor outcomes in patients with GC. Our data suggest that anti-IGF-IR strategies may prove valuable in such patients.

Using laser-captured microdissection and a real-time RT–PCR assay, we quantitatively evaluated mRNA levels of the following biomarkers in paraffin-embedded gastric cancer (GC) specimens obtained by surgical resection or biopsy: excision repair cross-complementing gene 1 (ERCC1), dihydropyrimidine dehydrogenase (DPD), methylenetetrahydrofolate reductase (MTHFR), epidermal growth factor receptor (EGFR), and five other biomarkers related to anticancer drug sensitivity. The study group comprised 140 patients who received first-line chemotherapy for advanced GC. All cancer specimens were obtained before chemotherapy. In patients who received first-line S-1 monotherapy (69 patients), low MTHFR expression correlated with a higher response rate (low: 44.9% vs high: 6.3%; P=0.006). In patients given first-line cisplatin-based regimens (combined with S-1 or irinotecan) (43 patients), low ERCC1 correlated with a higher response rate (low: 55.6% vs high: 18.8%; P=0.008). Multivariate survival analysis of all patients demonstrated that high ERCC1 (hazard ratio (HR): 2.38 (95% CI: 1.55–3.67)), high DPD (HR: 2.04 (1.37–3.02)), low EGFR (HR: 0.34 (0.20–0.56)), and an elevated serum alkaline phosphatase level (HR: 1.00 (1.001–1.002)) were significant predictors of poor survival. Our results suggest that these biomarkers are useful predictors of clinical outcomes in patients with advanced GC.

Intermittent administration of human parathyroid hormone (hPTH) has an anabolic effect on bone in animals and humans and is expected to be a potent agent for the treatment of osteoporosis. However, little is known about the effects of hPTH on cancellous bone healing after cancellous bone fractures or osteotomies. We evaluated whether hPTH enhanced bone union at the site of cancellous bone osteotomy and further elucidated the possible mechanisms of hPTH effects on cancellous bone healing. After a bilateral ovariectomy (OVX) or sham operation in mature female rats, cancellous bone osteotomy was performed on the right proximal tibia. After once-a-week administration of hPTH (1-34) (100 microg/kg) or its vehicle for 4 weeks, bilateral tibiae including osteotomy and non-osteotomy sites were harvested. Along with conventional bone histomorphometry, cancellous bone union at the osteotomy site and the rate of proliferating cells immunostained with proliferating cell nuclear antigen (PCNA) and adipocytes in the surrounding bone marrow were evaluated. hPTH increased cancellous bone volume by stimulating bone formation in both normal and OVX rats and suppressed adipocyte volume (p<0.05). The percentage of PCNA-positive cells at the osteotomy site after PTH treatment was 2- to 3-fold higher than that of vehicle treatment controls both in sham-operated and OVX rats (p<0.05). The magnitude of increase in the percentage of PCNA-positive cells after PTH treatment at the osteotomy site was two times higher than that at the non-osteotomy site. Furthermore, PTH treatment increased cancellous bone union after osteotomy both in sham-operated and OVX rats (p<0.05). These results suggest that hPTH enhances cancellous bone healing at the site of osteotomy with, at least in part, a local regulating action that increases osteoblastogenesis and decreases adipocytogenesis at and around the osteotomy.

We aimed to develop prognostic biomarkers for gastrointestinal stromal tumors (GIST) using a proteomic approach.We examined the proteomic profile of GISTs using two-dimensional difference gel electrophoresis. The prognostic performance of biomarker candidates was examined using a large-scale sample set and specific antibodies.We identified 43 protein spots whose intensity was statistically different between GISTs with good and poor prognosis. Mass spectrometric protein identification showed that the 43 spots corresponded to 25 distinct gene products. Eight of the 43 spots derived from pfetin, a potassium channel protein, and four of the eight pfetin spots had a high discriminative power between the two groups. Western blotting and real-time PCR showed that pfetin expression and tumor metastasis were inversely related. The prognostic performance of pfetin was also examined by immunohistochemistry on 210 GIST cases. The 5-year metastasis-free survival rate was 93.9% and 36.2% for patients with pfetin-positive and pfetin-negative tumors, respectively (P < 0.0001). Univariate and multivariate analyses revealed that pfetin expression was a powerful prognostic factor among the clinicopathologic variables examined, including risk classification and c-kit- or platelet-derived growth factor receptor A mutation status.These results establish pfetin as a powerful prognostic marker for GISTs and may provide novel therapeutic strategies to prevent metastasis of GIST.

The study aimed to determine the value of a novel site-specific grading system based on quantifying poorly differentiated clusters (PDC; Grade(PDC)) in colorectal cancer (CRC). A multicenter pathologic review involving 12 institutions was performed on 3243 CRC cases (stage I, 583; II, 1331; III, 1329). Cancer clusters of ≥5 cancer cells and lacking a gland-like structure (PDCs) were counted under a ×20 objective lens in a field containing the maximum clusters. Tumors with <5, 5 to 9, and ≥10 PDCs were classified as grades G1, G2, and G3, respectively. According to Grade(PDC), 1594, 1005, and 644 tumors were classified as G1, G2, and G3 and had 5-year recurrence-free survival rates of 91.6%, 75.4%, and 59.6%, respectively (P<0.0001). Multivariate analysis showed that Grade exerted an influence on prognostic outcome independently of TNM staging; approximately 20% and 46% of stage I and II patients, respectively, were selected by Grade(PDC) as a population whose survival estimate was comparable to or even worse than that of stage III patients. Grade(PDC) surpassed TNM staging in the ability to stratify patients by recurrence-free survival (Akaike information criterion, 2915.6 vs. 2994.0) and had a higher prognostic value than American Joint Committee on Cancer (AJCC) grading (Grade(AJCC)) at all stages. Regarding judgment reproducibility of grading tumors, weighted κ among the 12 institutions was 0.40 for Grade(AJCC) and 0.52 for Grade(PDC). Grade(PDC) has a robust prognostic power and promises to be of sufficient clinical value to merit implementation as a site-specific grading system in CRC.

We evaluated the safety and efficacy of ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients previously treated for advanced gastric or gastroesophageal junction adenocarcinoma in Japanese and Western subgroups from the RAINBOW trial. Patients received ramucirumab at 8 mg/kg or placebo (days 1 and 15) plus paclitaxel at 80 mg/m2 (days 1, 8, and 15 of a 28-day cycle). End points were compared between treatment arms within Japanese (N = 140) and Western (N = 398) populations. The incidence of adverse events of grade 3 or higher was higher for ramucirumab plus paclitaxel in both populations (Japanese population, 83.8 % vs 52.1 %; Western population, 79.1 % vs 61.9 %). Neutropenia was the commonest adverse event of grade 3 or higher, with a higher incidence for ramucirumab plus paclitaxel (Japanese population, 66.2 % vs 25.4 %; Western population, 32.1 % vs 14.7 %). The incidence of febrile neutropenia was low and was similar between treatment arms in both populations. The overall survival hazard ratio was 0.88 (95 % confidence interval, 0.60–1.28) in the Japanese population and 0.73 (95 % confidence interval, 0.58–0.91) in the Western population. The progression-free survival hazard ratio was 0.50 (95 % confidence interval, 0.35–0.73) in the Japanese population and 0.63 (95 % confidence interval, 0.51–0.79) in the Western population. The objective response rate was higher for ramucirumab plus paclitaxel in both populations (Japanese population, 41.2 % vs 19.4 %; Western population, 26.8 % vs 13.0 %), as was the 6-month survival rate (Japanese population, 94.1 % vs 71.4 %; Western population, 66.0 % vs 49.0 %). Safety profiles of the ramucirumab plus paclitaxel arm were similar between populations, though there was a higher incidence of neutropenia in Japanese patients. Progression-free survival and objective response rate improvements were observed for ramucirumab plus paclitaxel in both populations. NCT01170663

There has been no phase III study of comparing the efficacy of first- and second-generation 5-HT3 receptor antagonists in the triplet regimen with dexamethasone and aprepitant for preventing chemotherapy-induced nausea and vomiting after highly emetogenic chemotherapy (HEC).Patients with a malignant solid tumor who would receive HEC containing 50 mg/m(2) or more cisplatin were randomly assigned to either palonosetron (0.75 mg) arm (Arm P) or granisetron (1 mg) arm (Arm G), on day 1, both arms with dexamethasone (12 mg on day 1 and 8 mg on days 2-4) and aprepitant (125 mg on day 1 and 80 mg on days 2-3). The primary end point was complete response (CR; no vomiting/retching and no rescue medication) at the 0-120 h period and secondary end points included complete control (CC; no vomiting/retching, no rescue medication, and no more than mild nausea) and total control (TC; no vomiting/retching, no rescue medication, and no nausea).Between July 2011 and June 2012, 842 patients were enrolled. Of 827 evaluable, 272 of 414 patients (65.7%) in Arm P had a CR at the 0-120 h period when compared with 244 of 413 (59.1%) in Arm G (P = 0.0539). Both arms had the same CR rate of 91.8% at the acute (0-24 h) period, while at the delayed (24-120 h) period, Arm P had a significantly higher CR rate than Arm G (67.2% versus 59.1%; P = 0.0142). In secondary end points, Arm P had significantly higher rates than Arm G at the 0-120 h period (CC rate: 63.8% versus 55.9%, P = 0.0234; TC rate: 47.6% versus 40.7%, P = 0.0369) and delayed periods (CC rate: 65.2% versus 55.9%, P = 0.0053; TC rate: 48.6% versus 41.4%, P = 0.0369).The present study did not show the superiority of palonosetron when compared with granisetron in the triplet regimen regarding the primary end point.UMIN000004863.

Comprehensive genomic sequencing (CGS) has the potential to revolutionize precision medicine for cancer patients across the globe. However, to date large-scale genomic sequencing of cancer patients has been limited to Western populations. In order to understand possible ethnic and geographic differences and to explore the broader application of CGS to other populations, we sequenced a panel of 415 important cancer genes to characterize clinically actionable genomic driver events in 201 Japanese patients with colorectal cancer (CRC).Using next-generation sequencing methods, we examined all exons of 415 known cancer genes in Japanese CRC patients (n = 201) and evaluated for concordance among independent data obtained from US patients with CRC (n = 108) and from The Cancer Genome Atlas-CRC whole exome sequencing (WES) database (n = 224). Mutation data from non-hypermutated Japanese CRC patients were extracted and clustered by gene mutation patterns. Two different sets of genes from the 415-gene panel were used for clustering: 61 genes with frequent alteration in CRC and 26 genes that are clinically actionable in CRC.The 415-gene panel is able to identify all of the critical mutations in tumor samples as well as WES, including identifying hypermutated tumors. Although the overall mutation spectrum of the Japanese patients is similar to that of the Western population, we found significant differences in the frequencies of mutations in ERBB2 and BRAF. We show that the 415-gene panel identifies a number of clinically actionable mutations in KRAS, NRAS, and BRAF that are not detected by hot-spot testing. We also discovered that 26% of cases have mutations in genes involved in DNA double-strand break repair pathway. Unsupervised clustering revealed that a panel of 26 genes can be used to classify the patients into eight different categories, each of which can optimally be treated with a particular combination therapy.Use of a panel of 415 genes can reliably identify all of the critical mutations in CRC patients and this information of CGS can be used to determine the most optimal treatment for patients of all ethnicities.

Case-control study.To evaluate clinical and radiological results of transforaminal lumbar interbody fusion (TLIF) performed with cortical bone trajectory (CBT) pedicle screw insertion with those of TLIF using 'conventional' or percutaneous pedicle screw insertion.CBT is a new trajectory for pedicle screw insertion in the lumbar spine; clinical and radiological results of TLIF using pedicle screws inserted with CBT are unclear.In total, 26 patients (11 males, 15 females) were enrolled in this retrospective study and divided into three groups: TLIF with pedicle screw insertion by conventional minimally invasive methods via the Wiltse approach (M-TLIF, n=10), TLIF with percutaneous pedicle screw insertion (P-TLIF, n=6), and TLIF with pedicle screw insertion with CBT (CBT-TLIF, n=10). Surgical results and preand postoperative radiological findings were evaluated and compared.Intraoperative blood loss was significantly less with CBT-TLIF (p=0.03) than with M-TLIF. Postoperative lordotic angles did not differ significantly among the three groups. Complete fusions were obtained in 10 of 12 levels (83%) with M-TLIF, in seven levels (100%) with P-TLIF, and in 10 of 11 levels (91%) with CBT-TLIF. On postoperative computed tomography, correct positioning was seen in 84.1% of M-TLIF screws, 88.5% of P-TLIF screws, and 90% of CBT-TLIF screws.CBT-TLIF resulted in less blood loss and a shorter operative duration than M-TLIF or P-TLIF. Postoperative rates of bone union, maintenance of lordotic angles, and accuracy of pedicle screw positions were similar among the three groups.

The Japanese Society for Spine Surgery and Related Research (JSSR) previously carried out two nationwide surveys in 1994 and 2001 on complications from spine and spinal cord surgery. More than 10 years have now elapsed since 2001. Rapidly ageing populations have major impacts on society, particularly in the medical field. The purpose of this study was therefore to examine the present situation for spine surgery in Japan. The JSSR research team prepared a computerized questionnaire made up of two categories in order to capture clinicopathological information and surgical information. A recordable optical disc for data storage was sent to surgeons who were certified for spine surgery by JSSR. The data was analyzed. The JSSR carried out a nationwide survey of complications of 31,380 patients. Patients aged 60 years or older comprised 63.1 % of the overall cohort. This was considerably higher than observed in previous surveys. Degenerative spinal diseases increased 79.7 %. With regard to surgical approach, the incidence of anterior surgery has decreased, while that of posterior surgery has increased compared to the earlier surveys (both p < 0.05). Spinal instrumentation was applied in 30.2 % cases, compared to 27.0 and 34.0 % cases in the 1994 and 2001 surveys, respectively. Intraoperative and postoperative complications were reported in 10.4 % and were slightly increased compared to 8.6 % in the earlier surveys (both p < 0.05). Diseases associated with a high incidence of complication included intramedullary tumor (29.3 %) and primary malignant tumor (22.0 %). The highest incidence of complication was dural tear (2.1 %), followed by neurological complication (1.4 %).

<h2>ABSTRACT</h2><h3>Background</h3> The phase III RAINBOW trial demonstrated that the addition of ramucirumab to paclitaxel improved overall survival, progression-free survival, and tumor response rate in fluoropyrimidine–platinum previously treated patients with advanced gastric/gastroesophageal junction (GEJ) adenocarcinoma. Here, we present results from quality-of-life (QoL) and performance status (PS) analyses. <h3>Patients and methods</h3> Patients with Eastern Cooperative Oncology Group PS of 0/1 were randomized to receive ramucirumab (8 mg/kg i.v.) or placebo on days 1 and 15 of a 4-week cycle, with both arms receiving paclitaxel (80 mg/m²) on days 1, 8, and 15. Patient-reported outcomes were assessed with the QoL/health status questionnaires EORTC QLQ-C30 and EQ-5D at baseline and 6-week intervals. PS was assessed at baseline and day 1 of every cycle. Time to deterioration (TtD) in each QLQ-C30 scale was defined as randomization to first worsening of ≥10 points (on 100-point scale) and TtD in PS was defined as first worsening to ≥2. Hazard ratios (HRs) for treatment effect were estimated using stratified Cox proportional hazards models. <h3>Results</h3> Of the 665 patients randomized, 650 (98%) provided baseline QLQ-C30 and EQ-5D data, and 560 (84%) also provided data from ≥1 postbaseline time point. Baseline scores for both instruments were similar between arms. Of the 15 QLQ-C30 scales, 14 had HR < 1, indicating similar or longer TtD in QoL for ramucirumab + paclitaxel. Treatment with ramucirumab + paclitaxel was also associated with a delay in TtD in PS to ≥2 (HR = 0.798, <i>P</i> = 0.0941). Alternate definitions of PS deterioration yielded similar results: PS ≥ 3 (HR = 0.656, <i>P</i> = 0.0508), deterioration by ≥1 PS level (HR = 0.802, <i>P</i> = 0.0444), and deterioration by ≥2 PS levels (HR = 0.608, <i>P</i> = 0.0063). EQ-5D scores were comparable between treatment arms, stable during treatment, and worsened at discontinuation. <h3>Conclusion</h3> In patients with previously treated advanced gastric/GEJ adenocarcinoma, addition of ramucirumab to paclitaxel prolonged overall survival while maintaining patient QoL with delayed symptom worsening and functional status deterioration. <h3>ClinicalTrials.gov</h3> NCT01170663.

Intertumoral heterogeneity represents a significant hurdle to identifying optimized targeted therapies in gastric cancer (GC). To realize precision medicine for GC patients, an actionable gene alteration-based molecular classification that directly associates GCs with targeted therapies is needed.A total of 207 Japanese patients with GC were included in this study. Formalin-fixed, paraffin-embedded (FFPE) tumor tissues were obtained from surgical or biopsy specimens and were subjected to DNA extraction. We generated comprehensive genomic profiling data using a 435-gene panel including 69 actionable genes paired with US Food and Drug Administration-approved targeted therapies, and the evaluation of Epstein-Barr virus (EBV) infection and microsatellite instability (MSI) status.Comprehensive genomic sequencing detected at least one alteration of 435 cancer-related genes in 194 GCs (93.7%) and of 69 actionable genes in 141 GCs (68.1%). We classified the 207 GCs into four The Cancer Genome Atlas (TCGA) subtypes using the genomic profiling data; EBV (N = 9), MSI (N = 17), chromosomal instability (N = 119), and genomically stable subtype (N = 62). Actionable gene alterations were not specific and were widely observed throughout all TCGA subtypes. To discover a novel classification which more precisely selects candidates for targeted therapies, 207 GCs were classified using hypermutated phenotype and the mutation profile of 69 actionable genes. We identified a hypermutated group (N = 32), while the others (N = 175) were sub-divided into six clusters including five with actionable gene alterations: ERBB2 (N = 25), CDKN2A, and CDKN2B (N = 10), KRAS (N = 10), BRCA2 (N = 9), and ATM cluster (N = 12). The clinical utility of this classification was demonstrated by a case of unresectable GC with a remarkable response to anti-HER2 therapy in the ERBB2 cluster.This actionable gene-based classification creates a framework for further studies for realizing precision medicine in GC.

Efficacy of adjuvant chemotherapy in patients with stage II colon cancer is still controversial. The SACURA trial is a randomised-controlled study evaluating the superiority of 1-year adjuvant treatment with oral tegafur-uracil (UFT) to surgery alone for stage II colon cancer.Patients were randomly assigned to the surgery-alone group or UFT group (UFT at 500-600 mg/day for 5 days, followed by 2-day rest, for 1 year). The primary end-point was disease-free survival (DFS). Target sample size was 2000, determined with one-sided alpha of 0.05, power of 0.9 and assumed hazard ratio (HR) 0.729.A total of 1982 patients (997 in the surgery-alone group and 985 in the UFT group) were analysed. Median follow-up was 69.5 months, median age was 66 years and for stage IIA/IIB/IIC, the distribution was 84%/13%/3%. The 5-year DFS rate was 78.4% in the surgery-alone group and 80.2% in the UFT group. The HR for DFS was 0.91 (95% confidence interval [CI], 0.75-1.10; p = 0.31); superiority of UFT was not demonstrated. Approximately 9% of patients experienced second cancers, which consist 40.7% of the DFS events. The 5-year relapse-free and overall survival rates of the surgery-alone and UFT group were 84.6% and 87.2% (HR, 0.82; 95% CI, 0.65-1.04) and 94.3% and 94.5% (HR, 0.93; 95% CI, 0.66-1.31), respectively. Subgroup analysis failed to disclose superiority in prognosis of adding UFT to the patients with risk factors for recurrence.Superiority of 1-year adjuvant UFT over surgery alone was not demonstrated in stage II colon cancer. Patients with risk factors for recurrence did not benefit from UFT.ClinicalTrials. Gov. #NCT00392899.

This study aimed to compare common histologic markers at the invasive front of colon adenocarcinoma in terms of prognostic accuracy and interobserver agreement. Consecutive patients who underwent curative resection for stages I to III colon adenocarcinoma at a single institution in 2007 to 2014 were identified. Poorly differentiated clusters (PDCs), tumor budding, perineural invasion, desmoplastic reaction, and Crohn-like lymphoid reaction at the invasive front, as well as the World Health Organization (WHO) grade of the entire tumor, were analyzed. Prognostic accuracies for recurrence-free survival (RFS) were compared, and interobserver agreement among 3 pathologists was assessed. The study cohort consisted of 851 patients. Although all the histologic markers except WHO grade were significantly associated with RFS (PDCs, tumor budding, perineural invasion, and desmoplastic reaction: P &lt;0.001; Crohn-like lymphoid reaction: P =0.021), PDCs (grade 1 [G1]: n=581; G2: n=145; G3: n=125) showed the largest separation of 3-year RFS in the full cohort (G1: 94.1%; G3: 63.7%; hazard ratio [HR], 6.39; 95% confidence interval [CI], 4.11-9.95; P &lt;0.001), stage II patients (G1: 94.0%; G3: 67.3%; HR, 4.15; 95% CI, 1.96-8.82; P &lt;0.001), and stage III patients (G1: 89.0%; G3: 59.4%; HR, 4.50; 95% CI, 2.41-8.41; P &lt;0.001). PDCs had the highest prognostic accuracy for RFS with the concordance probability estimate of 0.642, whereas WHO grade had the lowest. Interobserver agreement was the highest for PDCs, with a weighted kappa of 0.824. The risk of recurrence over time peaked earlier for worse PDCs grade. Our findings indicate that PDCs are the best invasive-front histologic marker in terms of prognostic accuracy and interobserver agreement. PDCs may replace WHO grade as a prognostic indicator.

We identified TPX2 and AURAKA as novel co-regulators on the MYC pathway and proposed a new model of MYC-driven cancer. Co-amplification between 8q24 and 20q leads to co-overexpression of MYC and AURKA/TPX2, which cooperatively induce MYC downstream target genes. Based on this model, inhibiting the AURKA/TPX2 axis would be a novel synthetic lethal therapeutic approach for MYC-driven cancers.BackgroundThe MYC oncogene has long been established as a central driver in many types of human cancers including colorectal cancer. However, the realization of MYC-targeting therapies remains elusive; as a result, synthetic lethal therapeutic approaches are alternatively being explored. A synthetic lethal therapeutic approach aims to kill MYC-driven tumors by targeting a certain co-regulator on the MYC pathway.Patients and methodsWe analyzed copy number and expression profiles from 130 colorectal cancer tumors together with publicly available datasets to identify co-regulators on the MYC pathway. Candidates were functionally tested by in vitro assays using colorectal cancer and normal fibroblast cell lines. Additionally, survival analyses were carried out on another 159 colorectal cancer patients and public datasets.ResultsOur in silico screening identified two MYC co-regulator candidates, AURKA and TPX2, which are interacting mitotic regulators located on chromosome 20q. We found the two candidates showed frequent co-amplification with the MYC locus while expression levels of MYC and the two genes were positively correlated with those of MYC downstream target genes across multiple cancer types. In vitro, the aberrant expression of MYC AURKA and TPX2 resulted in more aggressive anchorage-independent growth in normal fibroblast cells. Furthermore, knockdown of AURKA or TPX2, or treatment with an AURKA-specific inhibitor effectively suppressed the proliferation of MYC-expressing colorectal cancer cells. Additionally, combined high expression of MYC AURKA and TPX2 proved to be a poor prognostic indicator of colorectal cancer patient survival.ConclusionsThrough bioinformatic analyses and experiments, we proposed TPX2 and AURKA as novel co-regulators on the MYC pathway. Inhibiting the AURKA/TPX2 axis would be a novel synthetic lethal therapeutic approach for MYC-driven cancers.

Recent progress in genomic analysis using next-generation sequencing technology has enabled the comprehensive detection of mutations and tumor mutation burden (TMB) in patients. A high TMB (TMB-H) tumor is defined as one with high somatic mutational rates, which correlates with clinical responses to certain treatments such as immunotherapies. We determined TMB in lung adenocarcinoma and clarified the characteristics of patients with TMB-H in relation to common driver mutations and smoking history.Genomic aberrations and TMB were determined in Japanese patients with lung adenocarcinoma (n = 100) using next-generation sequencing of 415 known cancer genes. TMB-H was defined as > 20 mutations per megabase (Mb) of sequenced DNA.The median TMB was 13.5 (5-33) mutations/Mb. Ten of 100 (10%) patients showed TMB-H, and the others showed low TMB (TMB-L). Only two of 10 (20%) patients with TMB-H had one of the common driver mutations (ALK and ERBB2 mutation), whereas 57 of 90 (63%) patients with TMB-L had one of the driver mutations, including ALK, EGFR, ERBB2, ROS, RET, and MET (P < 0.05). Notably, no EGFR mutation was observed in patients with TMB-H. Eight of 10 (80%) patients with TMB-H had recent smoking history, whereas only 17 of 90 (19%) patients with TMB-L had recent smoking history (P < 0.001).We found that TMB-H is associated with smoking history, whereas TMB-L is associated with the common driver mutations in lung adenocarcinoma, which may impact treatment strategies for these patients.

Abstract It remains unclear whether the immunologic status of cells in peripheral blood can be used as a prognostic indicator of response to treatment for patients with unresectable metastatic colorectal cancer (MCRC). We therefore investigated the relationship between the pretreatment immunologic status of 40 patients with MCRC who planned to receive the first-line chemotherapy and their progression-free survival. Twenty-five immune cell subsets, including monocytic myeloid-derived suppressor cells (M-MDSC) and effector memory T cells (TEM), were measured by multicolor-flow cytometry. We divided patients into high and low (above and below the median, respectively) groups based on the median value for each immune cell subset and compared progression-free survival of the two groups. Patients with high M-MDSC, low CD4+ TEM, or low CD8+ TEM quantities had significantly shorter progression-free survival (P = 0.004, 0.005, and 0.002, respectively). Patients were classified into two prognostic groups based on numbers of adverse factors; having two or three adverse factors (n = 21, 52.5%) was correlated with significantly shorter progression-free survival compared with none or one (n = 19, 47.5%; P &amp;lt; 0.001). The presence of two or three adverse factors was an independent poor prognostic factor for progression-free survival (HR, 9.2; 95% confidence interval, 2.5–34.2; P &amp;lt; 0.001). These results provide evidence that pretreatment peripheral immune status can inform the outcome of patients with MCRC treated with first-line chemotherapy. Cancer Immunol Res; 4(7); 592–9. ©2016 AACR.

To identify baseline prognostic factors for survival in patients with disease progression, during or after chemotherapy for the treatment of advanced gastric or gastroesophageal junction (GEJ) cancer.We pooled data from patients randomized between 2009 and 2012 in 2 phase III, global double-blind studies of ramucirumab for the treatment of advanced gastric or GEJ adenocarcinoma following disease progression on first-line platinum- and/or fluoropyrimidine-containing therapy (REGARD and RAINBOW). Forty-one key baseline clinical and laboratory factors common in both studies were examined. Model building started with covariate screening using univariate Cox models (significance level=0.05). A stepwise multivariable Cox model identified the final prognostic factors (entry+exit significance level=0.01). Cox models were stratified by treatment and geographic region. The process was repeated to identify baseline prognostic quality of life (QoL) parameters.Of 1,020 randomized patients, 953 (93%) patients without any missing covariates were included in the analysis. We identified 12 independent prognostic factors of poor survival: 1) peritoneal metastases; 2) Eastern Cooperative Oncology Group (ECOG) performance score 1; 3) the presence of a primary tumor; 4) time to progression since prior therapy <6 months; 5) poor/unknown tumor differentiation; abnormally low blood levels of 6) albumin, 7) sodium, and/or 8) lymphocytes; and abnormally high blood levels of 9) neutrophils, 10) aspartate aminotransferase (AST), 11) alkaline phosphatase (ALP), and/or 12) lactate dehydrogenase (LDH). Factors were used to devise a 4-tier prognostic index (median overall survival [OS] by risk [months]: high=3.4, moderate=6.4, medium=9.9, and low=14.5; Harrell's C-index=0.66; 95% confidence interval [CI], 0.64-0.68). Addition of QoL to the model identified patient-reported appetite loss as an independent prognostic factor.The identified prognostic factors and the reported prognostic index may help clinical decision-making, patient stratification, and planning of future clinical studies.

The aim of this phase II study was to evaluate the efficacy and safety of two doses (10 and 5 mg) of olanzapine in combination with standard antiemetic treatment (aprepitant, palonosetron, and dexamethasone) for patients receiving highly emetogenic chemotherapy (HEC). A multi-institutional, double-blind, randomized phase II, dose-finding study of olanzapine was performed in patients with a malignant solid tumor who were receiving HEC with cisplatin (≥ 50 mg/m2). Patients were randomly assigned either olanzapine 10 or 5 mg orally on days 1–4, combined with standard antiemetic treatment. The primary endpoint was a complete response (CR; no emesis and no use of rescue medications) in the delayed phase (24–120 h after the start of cisplatin treatment). 153 patients were randomized to the 10 mg group (n = 76) or the 5 mg group (n = 77). The CR rate in the delayed phase was 77.6% (80% CI: 70.3–83.8, P = 0.01) in the 10 mg group and 85.7% (80% CI: 79.2–90.7, P < 0.001) in the 5 mg group (P value for H 0: complete response rate ≤ 65%). The most common adverse event was somnolence, which had an incidence of 53.3 and 45.5% in the 10 and 5 mg olanzapine groups, respectively. Both doses of 10 and 5 mg olanzapine provided a significant improvement in delayed emesis. A dose of 5 mg olanzapine was determined as the recommended dose for a further phase III study based on higher CR and lower somnolence rates. UMIN000014214

This study aimed to clarify the incidence and risk factors of neuropathic pain after thoracic surgery, focusing especially on patients who underwent complete video-assisted thoracoscopic surgery (VATS).We retrospectively identified 185 patients who underwent thoracic surgery at our hospital over a 2-year period. Logistic regression analysis was used to analyze the association of various factors with postoperative neuropathic pain.Forty-eight (25.9%) patients developed postoperative neuropathic pain, and 9 (18.8%) of these patients reported persistent pain 1 year postoperatively. The median interval from surgical treatment to the onset of neuropathic pain was 7 days, and the duration was 50 days. Multivariate logistic regression analysis revealed a significant positive correlation between postoperative neuropathic pain and preoperative use of hypnotic medication [odds ratio (OR), 5.45; 95% confidence interval (CI); 2.52-12.17] and duration of surgery ≥2.5 hours (OR, 2.72; 95% CI, 1.27-6.09), and a significant negative association with the complete VATS approach (OR, 0.18; 95% CI, 0.073-0.42).Preoperative use of hypnotic medication, the thoracotomy approach, and duration of surgery ≥2.5 hours are associated with increased risk of neuropathic pain after thoracic surgery. The complete VATS approach could decrease the incidence of postoperative neuropathic pain, regardless of the duration of surgery.

The phase II J003 (N = 169) and phase III RECOURSE (N = 800) trials demonstrated a significant improvement in survival with trifluridine (FTD)/tipiracil (TPI) versus placebo in patients with refractory metastatic colorectal cancer. This post hoc analysis investigated pharmacokinetic data of FTD/TPI exposure and pharmacodynamic markers, such as chemotherapy-induced neutropenia (CIN) and clinical outcomes.A total of 210 patients from RECOURSE were enrolled in this substudy. A limited sampling approach was used, with three pharmacokinetic samples drawn on day 12 of cycle 1. Patients were categorized as being above or below the median area under the plasma concentration-time curve (AUC) for FTD and TPI. We conducted a post hoc analysis using the entire RECOURSE population to determine the correlations between CIN and clinical outcome. We then carried out a similar analysis on the J003 trial to validate the results.In the RECOURSE subset, patients in the high FTD AUC group had a significantly increased CIN risk. Analyses of the entire population demonstrated that FTD/TPI-treated patients with CIN of any grade in cycles 1 and 2 had significantly longer median overall survival (OS) and progression-free survival (PFS) than patients who did not develop CIN and patients in the placebo group. Patients who required an FTD/TPI treatment delay had increased OS and PFS versus those in the placebo group and those who did not develop CIN. Similar results were obtained in the J003 cohort.In RECOURSE, patients with higher FTD drug exposure had an increased CIN risk. FTD/TPI-treated patients who developed CIN had improved OS and PFS versus those in the placebo group and those who did not develop CIN. Similar findings were reported in the J003 cohort, thus validating the RECOURSE results. The occurrence of CIN may be a useful predictor of treatment outcomes for FTD/TPI-treated patients. CLINICALTRIALS.NCT01607957 (RECOURSE).JapicCTI-090880 (J003).

PURPOSE Clinical calculators and nomograms have been endorsed by the American Joint Committee on Cancer (AJCC), as they provide the most individualized and accurate estimate of patient outcome. Using molecular and clinicopathologic variables, a third-generation clinical calculator was built to predict recurrence following resection of stage I-III colon cancer. METHODS Prospectively collected data from 1,095 patients who underwent colectomy between 2007 and 2014 at Memorial Sloan Kettering Cancer Center were used to develop a clinical calculator. Discrimination was measured with concordance index, and variability in individual predictions was assessed with calibration curves. The clinical calculator was externally validated with a patient cohort from Washington University's Siteman Cancer Center in St Louis. RESULTS The clinical calculator incorporated six variables: microsatellite genomic phenotype; AJCC T category; number of tumor-involved lymph nodes; presence of high-risk pathologic features such as venous, lymphatic, or perineural invasion; presence of tumor-infiltrating lymphocytes; and use of adjuvant chemotherapy. The concordance index was 0.792 (95% CI, 0.749 to 0.837) for the clinical calculator, compared with 0.708 (95% CI, 0.671 to 0.745) and 0.757 (0.715 to 0.799) for the staging schemes of the AJCC manual's 5th and 8th editions, respectively. External validation confirmed robust performance, with a concordance index of 0.738 (95% CI, 0.703 to 0.811) and calibration plots of predicted probability and observed events approaching a 45° diagonal. CONCLUSION This third-generation clinical calculator for predicting cancer recurrence following curative colectomy successfully incorporates microsatellite genomic phenotype and the presence of tumor-infiltrating lymphocytes, resulting in improved discrimination and predictive accuracy. This exemplifies an evolution of a clinical calculator to maintain relevance by incorporating emerging variables as they become validated and accepted in the oncologic community.

Poly-trans-[(2-carboxyethyl)germasesquioxane] (Ge-132), an organogermanium, is hydrolyzed to 3-(trihydroxygermyl)propanoic acid (THGP) in aqueous solutions, and reduces inflammation, pain and cancer, whereas the underlying mechanisms remain unknown. Sulfides including H2S, a gasotransmitter, generated from l-cysteine by some enzymes including cystathionine-γ-lyase (CSE), are pro-nociceptive, since they enhance Cav3.2 T-type Ca2+ channel activity expressed in the primary afferents, most probably by canceling the channel inhibition by Zn2+ linked via coordinate bonding to His191 of Cav3.2. Given that germanium is reactive to sulfur, we tested whether THGP would directly trap sulfide, and inhibit sulfide-induced enhancement of Cav3.2 activity and sulfide-dependent pain in mice. Using mass spectrometry and 1H NMR techniques, we demonstrated that THGP directly reacted with sulfides including Na2S and NaSH, and formed a sulfur-containing reaction product, which decreased in the presence of ZnCl2. In Cav3.2-transfected HEK293 cells, THGP inhibited the sulfide-induced enhancement of T-type Ca2+ channel-dependent membrane currents. In mice, THGP, administered systemically or locally, inhibited the mechanical allodynia caused by intraplantar Na2S. In the mice with cyclophosphamide-induced cystitis and cerulein-induced pancreatitis, which exhibited upregulation of CSE in the bladder and pancreas, respectively, systemic administration of THGP as well as a selective T-type Ca2+ channel inhibitor suppressed the cystitis-related and pancreatitis-related visceral pain. These data suggest that THGP traps sulfide and inhibits sulfide-induced enhancement of Cav3.2 activity, leading to suppression of Cav3.2-dependent pain caused by sulfide applied exogenously and generated endogenously.

The pharmacokinetics of UCN-01 after administration as a 72- or 3-h infusion to cancer patients in initial Phase I trials displayed distinctive features that could not have been predicted from preclinical data. The distribution volumes (0.0796-0.158 liters/kg) and the systemic clearance (0.0407-0.252 ml/h/kg) were extremely low, in contrast to large distribution volume and rapid systemic clearance in experimental animals. The elimination half-lives (253-1660 h) were unusually long. In vitro protein binding experiments demonstrated that UCN-01 was strongly bound to human alpha1-acid glycoprotein. The results suggest that unusual pharmacokinetics of UCN-01 in humans could be due, at least in part, to its specifically high binding to alpha1-acid glycoprotein.

The magnetic resonance imaging (MRI) technique is primarily used to obtain still pictures of body sections, but it also provides a practical means for motion imaging. In this work, the synchronized sampling method originally developed for cardiac motion imaging was applied to the recording of articulatory movements while the subject repeated a short utterance synchronized with the scan sequence. Results showed dynamic movements ofthe speech organs in the midsagittal plane. A few key frames from the movie sequence are presented as an example of its application to speech production research.

A 3D cine-MRI technique was developed based on a synchronized sampling method [Masaki et al., J. Acoust. Soc. Jpn. E 20, 375-379 (1999)] to measure the temporal changes in the vocal tract area function during a short utterance /aiueo/ in Japanese. A time series of head-neck volumes was obtained after 640 repetitions of the utterance produced by a male speaker, from which area functions were extracted frame-by-frame. A region-based analysis showed that the volumes of the front and back cavities tend to change reciprocally and that the areas near the larynx and posterior edge of the hard palate were almost constant throughout the utterance. The lower four formants were calculated from all the area functions and compared with those of natural speech sounds. The mean absolute percent error between calculated and measured formants among all the frames was 4.5%. The comparison of vocal tract shapes for the five vowels with those from the static MRI method suggested a problem of MRI observation of the vocal tract: data from static MRI tend to result in a deviation from natural vocal tract geometry because of the gravity effect.

Factors related to long-term surgical outcome of thoracic myelopathy caused by ossification of the ligamentum flavum (OLF) have not been fully investigated. To evaluate these factors, the authors reviewed medical records obtained in patients who had undergone decompressive surgery for thoracic OLF.Thirty-four patients in whom decompressive surgery was performed for thoracic OLF (mean follow-up period 8 years) were recruited. Fourteen patients underwent simultaneous decompressive surgery for cervical or lumbar lesions. Patient age, duration of symptoms, OLF type, dural adhesion, neurological status classified by the Japanese Orthopaedic Association (JOA) scale before and after surgery (1 month postoperatively and at final follow up), and recovery rate were reviewed. The ossified ligamentum flavum was classified into five types according to Sato's classification by assessing preoperative computerized tomography scans. The mean preoperative JOA score (5) was significantly improved at 1 month after surgery (7.1) and at final follow up (7.9) (p < 0.05). Recovery rates at 1 month and at final follow up were 34.6 and 44.2%, respectively. No significant correlations were found between age, OLF type, and neurological status before and after surgery. In patients with dural adhesion, which was observed in cases of larger-type OLF (p < 0.02), lower JOA scores were observed compared with those in patients without dural adhesion both preoperatively and at 1 month after surgery (p < 0.05) but not at the final follow-up examination. Higher JOA scores and recovery rates were demonstrated in patients who had undergone simultaneous surgery than in those who had not undergone simultaneous surgery at 1 month (p < 0.05) but not at the final follow up. Using multiple regression analysis, the authors identified the duration of preoperative symptoms as the most important predictor of a high JOA score and recovery rate at the final follow up.Duration of preoperative symptoms represents the most important predictor of long-term surgery-related outcome in patients treated for thoracic OLF. The type of ossified ligamentum flavum, dural adhesion, and simultaneous surgery for coexistent cervical or lumbar lesions do not appear to influence the long-term postoperative prognosis.

Editor’s Note This report is a summary of a conference held in Nagoya, Japan in December 1988. The purpose of this conference was to bring together a group of active researchers in Japan to discuss how pressure support design features interact with patient neuromuscular function and ventilatory demands. Dr. Shimada served as moderator of the proceeding. Dr. MacIntyre functioned as both a speaker and as an editor of this final report. Drs. Nishimura, Usuda, Tokioka, and Takezawa each led discussions regarding specific aspects of patient interactions with pressure support ventilation design characteristics. Editor’s Note This report is a summary of a conference held in Nagoya, Japan in December 1988. The purpose of this conference was to bring together a group of active researchers in Japan to discuss how pressure support design features interact with patient neuromuscular function and ventilatory demands. Dr. Shimada served as moderator of the proceeding. Dr. MacIntyre functioned as both a speaker and as an editor of this final report. Drs. Nishimura, Usuda, Tokioka, and Takezawa each led discussions regarding specific aspects of patient interactions with pressure support ventilation design characteristics.

A serine/threonine protein kinase, Cot/Tpl2, is indispensable for extracellular signal-regulated kinase (ERK) activation and production of TNF-alpha and PGE2 in LPS-stimulated macrophages. We show here that Cot/Tpl2 is also activated by other Toll-like receptor (TLR) ligands. Bacterial DNA rich in the dinucleotide CG (CpG-DNA), unlike LPS or synthetic lipopeptide, activated ERK in a Cot/Tpl2-independent manner. Peritoneal macrophages and bone marrow-derived DCs from Cot/Tpl2-/- mice produced significantly more IL-12 in response to CpG-DNA than those from WT mice. Enhanced IL-12 production in Cot/Tpl2-/- macrophages is, at least partly, regulated at the transcriptional level, and the elevated IL-12 mRNA level in Cot/Tpl2-/- macrophages is accompanied by decreased amounts of IL-12 repressors, such as c-musculoaponeurotic fibrosarcoma (c-Maf) and GATA sequence in the IL-12 promoter-binding protein (GA-12-binding protein; GAP-12) in the nucleus. Consistently, Cot/Tpl2-/- mice showed Th1-skewed antigen-specific immune responses upon OVA immunization and Leishmania major infection in vivo. These results indicate that Cot/Tpl2 is an important negative regulator of Th1-type adaptive immunity, that it achieves this regulation by inhibiting IL-12 production from accessory cells, and that it might be a potential target molecule in CpG-DNA-guided vaccination.

Endoscopic biopsy prior to chemotherapy provides an opportunity for studying biomarkers to predict the overall survival in gastric cancer patients. This prospective study was performed to identify prognostic biomarkers in patients with unresected gastric cancer. Fifty-nine cases of chemotherapy-naive metastatic gastric cancer were enrolled in this study. A microarray analysis was performed using 40 biopsy samples to identify candidate genes whose expressions might be correlated with the overall survival. After adjusting for clinical covariates based on a multivariate analysis, the identified genes were validated using real-time reverse transcription polymerase chain reaction (RT-PCR) analysis in 19 independent validation samples. Ninety-eight candidate genes whose expression levels were significantly correlated with the overall survival were identified using a microarray analysis based on a proportional hazards model (P < 0.005). Multivariate analysis was performed to assess 10 of these genes, and the results yielded a statistical significance level for DACH1 and PDCD6. We further evaluated these two genes in independent samples using real-time RT-PCR and found that lower mRNA expression levels of PDCD6 were correlated significantly with a poor overall survival. We identified PDCD6 as a prognostic biomarker in patients with unresected gastric cancer using endoscopic biopsy samples. Our PCR-based single gene prediction strategy successfully predicted the overall survival and may lead to a better understanding of this disease subgroup.

To determine whether administration of pre-warmed colloid followed by pre-warmed crystalloid solution prevents the development of hypothermia in patients undergoing Cesarean delivery. Randomized, double-blind, placebo-controlled study. 30 parturients scheduled to undergo elective Cesarean delivery during spinal anesthesia. Patients assigned to the warmed fluid group (n=15) received pre-warmed colloid with average molecular weight of 70,000 daltons and substitution ratio of 0.55, followed by pre-warmed crystalloid (kept in warmed storage maintained at 41 °C) during surgery. Patients assigned to the unwarmed fluid group (n=15) received non-warmed infusion. All patients received 400 mL before spinal anesthesia followed by another 300 mL before delivery of the newborn. After completion of a 1,000 mL infusion of colloid fluid, acetate Ringer's solution was infused. Core temperature measured at the tympanic membrane, and forearm and fingertip skin temperatures were recorded just after arrival at the operating room (baseline), after administration of spinal anesthesia (spinal ), at incision (incision), at delivery of the newborn (delivery), and at 15, 30, and 45 minutes after delivery. Rectal temperature of the baby, Apgar scores at one and 5 minutes after delivery, and umbilical artery pH were evaluated. Core temperature was significantly higher in the warmed fluid group from the time of delivery to 45 minutes after delivery. Apgar scores at one minute after delivery and umbilical arterial pH were significantly higher in the warmed fluid group. Administration of pre-warmed intravenous colloid followed by crystalloids maintained core temperature during Cesarean delivery and induced higher Apgar scores and umbilical arterial pH.

Two phase II studies of S-1 monotherapy have shown promising response rates (RR) of 35-40% with good tolerability in patients with untreated metastatic colorectal cancer. To investigate the usefulness of S-1 plus oxaliplatin (SOX) as an alternative to infusional 5-fluorouracil/leucovorin plus oxaliplatin, the recommended dose (RD) of SOX was determined, and its safety and preliminary efficacy were evaluated in a phase I/II study. Oxaliplatin was administered at a dose of 100 mg m(-2) (level 1) or 130 mg m(-2) (level 2) on day 1, and S-1 (80-120) was given twice daily for 2 weeks followed by a 1-week rest. This schedule was repeated every 3 weeks. Level 2 was determined to be the RD. For the 28 patients who received the RD, the median treatment course was 6.5 cycles (2-14), RR of 50% (1 CR and 13 PR: 95% CI 31-69%), with a median progression-free survival of 196 days. Survival rate (1 year) was 79%. Peripheral neuropathy was observed in all patients but with no functional disorders. Major grade 3 or 4 adverse reactions at the RD were neutropaenia (14%), thrombocytopaenia (28%), and diarrhoea (3%). SOX regimen is effective and easily manageable without central vein access.

We have developed a ferroelectric-gate field-effect transistor (FeFET) composed of heteroepitaxially stacked oxide materials. A semiconductor film of ZnO, a ferroelectric film of Pb(Zr,Ti)O3 (PZT), and a bottom gate electrode of SrRuO3 (SRO) are grown on a SrTiO3 (STO) substrate. Structural characterization shows a heteroepitaxy of the fabricated ZnO/PZT/SRO/STO structure with good crystalline quality and the absence of an interface reaction layer. When the polarization direction of the PZT film is downward, all the electrons across the ZnO film are depleted. When the polarization direction is upward, on the other hand, quasi-two-dimensional electron gas is accumulated at the ZnO/PZT interface. The switching of the quasi-two-dimensional electron gas between the two states is confirmed by capacitance–voltage measurements. Drain and source electrodes of Pt/Ti are formed on the ZnO film and in-plane conduction at the ZnO/PZT interface is probed. When gate voltages applied to the bottom electrode are swept between -10 and 10 V, the on/off ratio of drain currents is higher than 105. Such a high on/off ratio is preserved even after 105 s and the extrapolation of the retention behavior predicts a definite memory window of more than 10 years.

A randomized controlled trial is being conducted in Japan to compare hepatectomy alone with hepatectomy followed by adjuvant chemotherapy as treatment in patients with curatively resected liver metastases from colorectal cancer to improve survival with intensive chemotherapy. Between 42 and 70 days after liver resection, patients are randomly assigned to either hepatectomy alone or hepatectomy followed by 12 cycles of modified FOLFOX6 (mFOLFOX6) regimen. A total of 300 patients (including 78 patients in Phase II) will be accrued from 38 institutions within 3 years. The primary endpoint is treatment compliance at nine courses of mFOLFOX6 regimen in Phase II and disease-free survival in Phase III. The secondary endpoints are overall survival, incidence of adverse events and patterns of recurrence.

Abstract Bevacizumab (BV) is an antivascular endothelial growth factor antibody. When administered with other chemotherapeutic drugs, BV‐combined regimens prolong survival of colorectal cancer patients. We conducted a phase II trial to confirm the pharmacokinetic parameters from 3‐Tesla dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) as surrogate biomarkers of BV + FOLFIRI regimen efficacy in colorectal cancer with liver metastases. DCE‐MRI was performed before treatment, on the seventh day after first treatment and every 8 weeks thereafter using a 3‐Tesla MRI system. DCE‐MRI parameters‐area under the contrast concentration versus time curve at 90 and 180 s (AUC90 and AUC180, respectively) after contrast injection, and volume transfer constant of contrast agents ( K trans and K ep ) were calculated from liver metastases. Fifty‐eight liver metastases were analyzed. Univariate analysis revealed that a decrease in K trans ratios (Δ K trans ), K ep ratios (Δ K ep ), AUC90 ratios (ΔAUC90) and AUC180 ratios (ΔAUC180) correlated with higher response (all p &lt; 0.0001) and longer time to progression (TTP) (Δ K trans : p = 0.001; Δ K ep : p = 0.004; ΔAUC90: p = 0.006; ΔAUC180: p &lt; 0.0001). Multivariate analysis showed that ΔAUC180 was correlated with higher response ( p = 0.009), and Δ K trans and ΔAUC180 were correlated with longer TTP (Δ K trans : p = 0.001; ΔAUC180: p = 0.024). Δ K trans and ΔAUC180 are pharmacodynamic biomarkers of the blood perfusion of BV + FOLFIRI. Our data suggest that Δ K trans and Δ K ep can predict response to chemotherapy at 1 week. Changes in 3‐Tesla DCE‐MRI parameters confirmed the potential of these biomarkers of blood perfusion as surrogate predictors of response and TTP.

Background This study clarified the long-term results of conservative treatment of rotator cuff tears. Materials and methods This study focused on 103 shoulders diagnosed with rotator cuff tears by magnetic resonance imaging or arthrography at our institution from 1996 to 1999. Sixty-five shoulders were followed up by telephone survey and 43 of these shoulders were evaluated; 11 shoulders were excluded because the patient had died, 10 shoulders because of severe dementia, and 1 shoulder that had undergone trauma. The mean patient age for these 43 shoulders at the time of diagnosis was 62 years, and the mean follow-up period was 13 years. The pain score (30 points) and the activities-of-daily-life score (10 points) of the Japanese Orthopaedic Association shoulder scoring system were determined. Results The mean pain score was 25.4 points, and the proportion of patients with no pain or with only slight pain was 88%. The mean score for activities of daily life was 9.4 points, and the proportion of patients with no disturbance in daily life was 72%. The patients with fewer than 20 points out of the possible 40 points (30 points for pain score plus 10 points for activities-of-daily-life score) were significantly younger than the other patients. Conclusions In cases of rotator cuff tears treated conservatively, at 13 years after diagnosis, about 90% of patients had no or only slight pain and about 70% had no disturbance in activities of daily life. However, the younger patients tended to have more significant pain or disorder in daily life more than 10 years after diagnosis. This study clarified the long-term results of conservative treatment of rotator cuff tears. This study focused on 103 shoulders diagnosed with rotator cuff tears by magnetic resonance imaging or arthrography at our institution from 1996 to 1999. Sixty-five shoulders were followed up by telephone survey and 43 of these shoulders were evaluated; 11 shoulders were excluded because the patient had died, 10 shoulders because of severe dementia, and 1 shoulder that had undergone trauma. The mean patient age for these 43 shoulders at the time of diagnosis was 62 years, and the mean follow-up period was 13 years. The pain score (30 points) and the activities-of-daily-life score (10 points) of the Japanese Orthopaedic Association shoulder scoring system were determined. The mean pain score was 25.4 points, and the proportion of patients with no pain or with only slight pain was 88%. The mean score for activities of daily life was 9.4 points, and the proportion of patients with no disturbance in daily life was 72%. The patients with fewer than 20 points out of the possible 40 points (30 points for pain score plus 10 points for activities-of-daily-life score) were significantly younger than the other patients. In cases of rotator cuff tears treated conservatively, at 13 years after diagnosis, about 90% of patients had no or only slight pain and about 70% had no disturbance in activities of daily life. However, the younger patients tended to have more significant pain or disorder in daily life more than 10 years after diagnosis.

Ligands of transmembrane receptor tyrosine kinases have important roles in cell proliferation, survival, migration and differentiation in solid tumours. We conducted this study to evaluate the relationship between concentration of serum ligands and prognosis of patients with metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (EGFR) antibodies.Between August 2008 and August 2011, serum samples were obtained from KRAS wild-type patients who met the inclusion criteria and received an anti-EGFR antibody treatment. Serum concentration of ligands was measured by an enzyme-linked immunosorbent assay, and somatic mutations of KRAS, BRAF, PIK3CA and BRAF were analysed by direct sequencing.A total of 103 patients were enrolled in the present study. At the pretreatment serum levels, patients with high levels of hepatocyte growth factor (HGF) had shorter progression-free survival (PFS) and overall survival (OS) compared with those with low levels of HGF (median PFS: 6.4 months vs 4.4 months; P<0.001, median OS: 15.3 months vs 8.0 months; P<0.001, respectively). Patients with high levels of epiregulin (EREG) also had shorter PFS and OS compared with those with low levels of EREG (median PFS: 6.6 months vs 4.9 months; P=0.016, median OS: 13.8 months vs 7.4 months; P=0.048, respectively). In addition, patients whose serum levels of ligands were elevated at progressive disease had shorter PFS and OS compared with other patients.Our study indicated that high levels of HGF and EREG were associated with resistance to treatment with anti-EGFR antibodies in KRAS wild-type patients with mCRC. Our findings will contribute to the newly combination therapy on the treatment of anti-EGFR antibodies.

LBA7 Background: RAM is a human IgG1 monoclonal antibody VEGF-receptor 2 antagonist. We conducted a global, placebo-controlled, double-blind, phase III trial to evaluate the efficacy and safety of PTX +/- RAM in patients with metastatic GEJ or gastric adenocarcinoma who had disease progression on or within 4 months after first-line platinum- and fluoropyrimidine-based combination therapy. Methods: Pts received RAM (8 mg/kg IV q2w) or placebo (PL) plus PTX (80 mg/m 2 d1, 8, 15 of a 4 week cycle) until disease progression, unacceptable toxicity, or death. Eligible pts had ECOG PS ≤ 1; and adequate organ function. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), time to progression (TTP), and safety. Results: From Dec 2010 to Sep 2012, 665 pts were randomized (RAM+PTX: 330; PTX: 335). Baseline characteristics were generally balanced between arms. The OS hazard ratio (HR) was 0.807 (95% CI 0.678, 0.962; p=0.0169). Median OS was 9.63m for RAM+PTX and 7.36m for PTX. The HR for PFS was 0.635 (95% CI 0.536, 0.752; p &lt;0.0001). Median PFS was 4.40m and 2.86m. Median TTP was 5.5m RAM+PTX; 3.0m PTX (p &lt;0.0001). ORR was 28% RAM+PTX;16% PTX (p=0.0001). Grade ≥ 3 adverse events (AEs) occurring in &gt;5% of patients on RAM+PTX were: neutropenia (40.7% RAM+PTX;18.8% PTX), leukopenia (17.4% vs 6.7% ), hypertension (14.1% vs 2.4%), anemia (9.2% vs 10.3%), fatigue (7.0% vs 4.0%), abdominal pain (5.5% vs 3.3%), and asthenia (5.5% vs 3.3%). Febrile neutropenia was reported in 3.1% RAM+PTX; 2.4% PTX. Conclusions: The primary endpoint of improved OS was met. A statistically significant and clinically meaningful OS benefit of &gt; 2 months was observed for RAM+PTX vs. PTX in gastric and GEJ cancer after progression on 1st-line therapy, as were significant benefits in PFS and ORR. Neutropenia was more frequently reported in the RAM+PTX arm but incidence of febrile neutropenia was comparable between arms. Clinical trial information: NCT01170663.

Precision medicine is only possible in oncology practice if targetable genes in fragmented DNA, such as DNA from formalin-fixed paraffin-embedded (FFPE) samples, can be sequenced using next generation sequencing (NGS). The aim of this study was to examine the quality and quantity of DNA from FFPE cancerous tissue samples from surgically resected and biopsy specimens.DNA was extracted from unstained FFPE tissue sections prepared from surgically resected specimens of breast, colorectal and gastric cancer, and biopsy specimens of breast cancer. A total quantity of DNA ≥60 ng from a sample was considered adequate for NGS. The DNA quality was assessed by Q-ratios, with a Q-ratio >0.1 considered sufficient for NGS.The Q-ratio for DNA from FFPE tissue processed with neutral-buffered formalin was significantly better than that processed with unbuffered formalin. All Q-ratios for DNA from breast, colorectal and gastric cancer samples indicated DNA levels sufficient for NGS. DNA extracted from gastric cancer FFPE samples prepared within the last 7 years is suitable for NGS analysis, whereas those older than 7 years may not be suitable. Our data suggested that adequate amounts of DNA can be extracted from FFPE samples, not only of surgically resected tissue but also of biopsy specimens.The type of formalin used for fixation and the time since FFPE sample preparation affect DNA quality. Sufficient amounts of DNA can be extracted from FFPE samples of both surgically resected and biopsy tissue, thus expanding the potential diagnostic uses of NGS in a clinical setting.

Background Given the extent of the surgical indications for pulmonary lobectomy in breathless patients, preoperative care and evaluation of pulmonary function are increasingly necessary. The aim of this study was to assess the contribution of preoperative pulmonary rehabilitation ( PR ) for reducing the incidence of postoperative pulmonary complications in non‐small cell lung cancer ( NSCLC ) patients with chronic obstructive pulmonary disease ( COPD ). Methods The records of 116 patients with COPD , including 51 patients who received PR , were retrospectively analyzed. Pulmonary function testing, including slow vital capacity ( VC ) and forced expiratory volume in one second ( FEV 1 ), was obtained preoperatively, after PR , and at one and six months postoperatively. The recovery rate of postoperative pulmonary function was standardized for functional loss associated with the different resected lung volumes. Propensity score analysis generated matched pairs of 31 patients divided into PR and non‐ PR groups. Results The PR period was 18.7 ± 12.7 days in COPD patients. Preoperative pulmonary function was significantly improved after PR ( VC 5.3%, FEV 1 5.5%; P &lt; 0.05). The FEV 1 recovery rate one month after surgery was significantly better in the PR (101.6%; P &lt; 0.001) than in the non‐ PR group (93.9%). In logistic regression analysis, predicted postoperative FEV 1 , predicted postoperative % FEV 1 , and PR were independent factors related to postoperative pulmonary complications after pulmonary lobectomy ( odds ratio 18.9, 16.1, and 13.9, respectively; P &lt; 0.05). Conclusions PR improved the recovery rate of pulmonary function after lobectomy in the early period, and may decrease postoperative pulmonary complications.

Avelumab is a human anti-PD-L1 IgG1 monoclonal antibody that has shown antitumor activity in several advanced cancers. We report results from JAVELIN Solid Tumor JPN, a phase 1 trial of avelumab in Japanese patients with advanced solid tumors with expansion in patients with advanced gastric cancer/gastroesophageal junction cancer. In the dose-escalation part, eligible patients had various previously treated metastatic or advanced solid tumors. In the dose-expansion part, patients had stage IV gastric cancer/gastroesophageal junction adenocarcinoma and disease progression after prior therapy that included a platinum and fluoropyrimidine agent. Patients received avelumab every 2 weeks intravenously at 3, 10, or 20 mg/kg during dose escalation and 10 mg/kg during dose expansion. Among 17 patients who received avelumab in the dose-escalation part, no dose-limiting toxicities occurred, and the maximum tolerated dose was not reached. 40 patients were enrolled in the dose-expansion part, of whom 21 (52.5%) had received ≥ 3 prior lines of therapy for advanced disease. In these patients, the objective response rate was 10.0% (95% CI, 2.8–23.7%) and median overall survival was 9.1 months (95% CI, 7.2–11.2 months). Three of 40 patients (7.5%) had a grade 3 treatment-related adverse event (alanine aminotransferase increase, anemia, and hyponatremia), and no grade ≥ 4 treatment-related adverse events occurred. Five patients (12.5%) had an immune-related adverse event (all grade 1/2). Avelumab showed acceptable safety in Japanese patients with advanced solid tumors and clinical activity in patients with advanced gastric cancer/gastroesophageal junction cancer and disease progression after chemotherapy.

Abstract Ramucirumab is an IgG1 monoclonal antibody specific for the vascular endothelial growth factor receptor-2. Ramucirumab, 8 mg/kg every 2 weeks, administered as monotherapy (REGARD) or in combination with paclitaxel (RAINBOW), was safe and effective in patients with previously treated advanced gastric or gastroesophageal junction (GEJ) cancer. We evaluated exposure–efficacy and exposure–safety relationships of ramucirumab from two randomized, placebo-controlled phase III trials. Sparse pharmacokinetic samples were collected, and a population pharmacokinetic analysis was conducted to predict ramucirumab minimum trough concentration at steady state (Cmin,ss). Kaplan–Meier methods and Cox proportional hazards models were used to evaluate the ramucirumab exposure (Cmin,ss)–efficacy relationship to overall survival (OS) and progression-free survival (PFS). Logistic regression analyses were used to evaluate exposure–safety relationships. Analyses included 321 ramucirumab + paclitaxel and 335 placebo + paclitaxel patients from RAINBOW and 72 ramucirumab and 35 placebo patients from REGARD. Exposure–efficacy analysis showed ramucirumab Cmin,ss was a significant predictor of OS and PFS in both trials. Higher ramucirumab exposure was associated with longer OS and PFS. In RAINBOW, grade ≥3 hypertension, leukopenia, and neutropenia, but not febrile neutropenia, significantly correlated with Cmin,ss, with increased exposure leading to increased incidence. Exploratory exposure–response analyses suggest a positive relationship between efficacy and ramucirumab exposure with manageable toxicities at exposures generated from a dose of 8 mg/kg ramucirumab given every 2 weeks for patients with advanced gastric/GEJ cancer. These findings suggest an opportunity to further optimize benefit versus risk profiles of ramucirumab treatment in patients with gastric/GEJ cancer. Mol Cancer Ther; 16(10); 2215–22. ©2017 AACR.