[A 30-Month Survival Case of Undifferentiated Carcinoma of the Duodenum Treated by Pancreaticoduodenectomy].

The patient was an elderly man in his early 80s who was admitted to our hospital due to anemia and tarry stools. An upper gastrointestinal endoscopy revealed a type 2 tumor in the second portion of the duodenum. An endoscopic biopsy revealed poorly differentiated adenocarcinoma. We performed a pancreaticoduodenectomy because neither lymphadenopathy nor distant metastases were found. Macroscopic findings revealed that the lesion was mainly in the second portion of the duodenum, and there was no evidence of invasion of the main pancreatic duct, the bile duct, or the ampulla of Vater. Histologically, the tumor was composed of atypical cells with polymorphic or spindle-shaped nuclei proliferating in a scattered fashion, and immunohistological examinations showed weakly positive results for cytokeratin(CK)AE1/AE3 and CK20 and positive results for vimentin but negative results for CK7. The tumor was diagnosed as undifferentiated carcinoma of the duodenum(pT4N0M0, pStage ⅡB). The patient recovered enough to be discharged and was followed up without postoperative adjuvant chemotherapy. He maintained recurrence-free survival for 27 months, after which lymph node and lung metastases reoccurred. This is a rare case of undifferentiated carcinoma of the duodenum treated by curative resection with a relatively favorable prognosis.

RAD51 Expression as a Biomarker to Predict Efficacy of Preoperative Therapy and Survival for Esophageal Squamous Cell Carcinoma: A Large-cohort Observational Study (KSCC1307).

OBJECTIVE: The aim of this study is to identify biomarkers that predict efficacy of preoperative therapy and survival for esophageal squamous cell carcinoma (ESCC). BACKGROUND: It is essential to improve the accuracy of preoperative molecular diagnostics to identify specific patients who will benefit from the treatment; thus, this issue should be resolved with a large-cohort, retrospective observational study. METHODS: A total of 656 patients with ESCC who received surgery after preoperative CDDP + 5-FU therapy, docetaxel + CDDP + 5-FU therapy or chemoradiotherapy (CRT) were enrolled. Immunohistochemical analysis of TP53, CDKN1A, RAD51, MutT-homolog 1, and programmed death-ligand 1 was performed with biopsy samples obtained before preoperative therapy, and expression was measured by immunohistochemistry. RESULTS: In all therapy groups, overall survival was statistically separated by pathological effect (grade 3 > grade 2 > grade 0, 1, P < 0.0001). There was no correlation between TP53, CDKN1A, MutT-homolog 1, programmed death-ligand 1 expression, and pathological effect, whereas the proportion of positive RAD51 expression (≥50%) in cases with grade 3 was lower than that with grade 0, 1, and 2 (P = 0.022). In the CRT group, the survival of patients with RAD51-positive tumor was significantly worse than RAD51-negative expressors (P = 0.0119). Subgroup analysis of overall survival with respect to positive RAD51 expression indicated preoperative chemotherapy (CDDP + 5-FU or docetaxel + CDDP + 5-FU) was superior to CRT. CONCLUSIONS: In ESCC, positive RAD51 expression was identified as a useful biomarker to predict resistance to preoperative therapy and poor prognosis in patients who received preoperative CRT. Administration of preoperative chemotherapy may be warranted for patients with positive RAD51 expression.

Efficacy of neoadjuvant chemotherapy in patients with high-risk resectable colorectal liver metastases.

BACKGROUND: The role of preoperative neoadjuvant chemotherapy (NAC) in patients with resectable colorectal liver metastases (CRLM) remains undetermined. This study aimed to assess the efficacy of NAC in patients with resectable CRLM, especially in high-risk subgroups for recurrence, with special reference to synchronicity and the CRLM grade in the Japanese classification system. METHODS: A retrospective analysis of a multi-institutional cohort who was diagnosed with resectable CRLM was performed. CRLM was classified into three grades (A, B, and C) according to the combination of H stage (H1: ≤ 4 lesions and ≤ 5 cm, H2: ≥ 5 lesions or > 5 cm, H3: ≥ 5 lesions and > 5 cm), nodal status of the primary tumor (pN0/1: ≤ 3 metastases, pN2: ≥ 4 metastases), and the presence of resectable extrahepatic metastases. RESULTS: Among 222 patients with resectable CRLM, 97 (43.7%) had synchronous CRLM. The surgical failure-free survival (SF-FS) of patients with synchronous CRLM (without NAC) was significantly worse than that of patients with metachronous CRLM (P = 0.0264). The SF-FS of patients with Grade B/C was also significantly worse than that of Grade A (P = 0.0058). Among the 53 patients with synchronous and Grade B/C CRLM, 31 were assigned to NAC, and all of them underwent liver surgery. In this high-risk subgroup, the SF-FS and OS in the NAC group were significantly better than those in the upfront surgery group (P < 0.0001 and P = 0.0004, respectively). CONCLUSIONS: Patients with synchronous and Grade B/C CRLM could be good candidates for indication of NAC.

Safety and efficacy of S-1 plus oxaliplatin 130 mg/m2 combination therapy in patients with previously untreated HER2-negative unresectable, advanced, or recurrent gastric/gastroesophageal junction cancer: a phase II trial (KSCC1501A).

BACKGROUND: In a randomized pivotal global phase III study, S-1 and oxaliplatin 100 mg/m2 (SOX100) combination chemotherapy was as effective as S-1 and cisplatin for advanced gastric cancer (AGC) and showed a favorable safety profile. In this phase II study, we analyzed survival outcomes to assess the efficacy and safety of the SOX regimen with oxaliplatin 130 mg/m2 (SOX130) in AGC. METHODS: Patients with HER2-negative AGC received 80 mg/m2/day S-1 orally on days 1-14 and 130 mg/m2 oxaliplatin intravenously on day 1 of each 21-day cycle until the criteria for treatment withdrawal were fulfilled. The primary endpoint was the response rate (RR), and the null hypothesis of RR in the current trial was 45%. The secondary endpoints were progression-free survival (PFS) and overall survival (OS). Adverse events (AEs) were recorded according to CTCAE version 4.0. RESULTS: Seventy-one patients were enrolled from June 2015 to November 2016, but eight were excluded for ineligibility. Therefore, all final analyses were conducted with 63 patients. The confirmed RR was 46.0% (90% confidence interval [CI]: 36.1-56.3), and the disease control rate was 77.8% (90% CI: 68.1-85.1). The median PFS and OS were 4.9 (95% CI: 4.2-7.1) and 14.8 (95% CI: 11.1-18.9) months, respectively. Incidences of grade 3-4 AEs > 10% were anorexia (19.0%), peripheral neuropathy (12.7%), nausea (11.1%), and thrombocytopenia (11.1%). CONCLUSIONS: This study represents the first evaluation of SOX130 in patients with HER2-negative AGC. SOX130 showed an acceptable safety profile, but the prespecified statistical efficacy targets were not achieved.

Efficacy and feasibility of S-1 plus oxaliplatin (C-SOX) for treating patients with stage III colon cancer (KSCC1303): final analysis of 3-year disease-free survival.

BACKGROUND: Adjuvant chemotherapy is an accepted treatment to improve survival rates in patients with stage III colon cancer, and regimens including oxaliplatin have been shown to be superior to those containing 5-FU alone. The purpose of this study was to examine the efficacy and feasibility of S-1 plus oxaliplatin (C-SOX) as adjuvant chemotherapy for patients with stage III colon cancer following curative resection. METHODS: Patients with colon cancer who underwent curative resection were enrolled and received oral S-1 40-60 mg twice daily on days 1-14 every 3 weeks plus intravenous oxaliplatin 130 mg/m2 on day 1 for eight courses. The primary endpoint was 3-year disease-free survival rate. Secondary endpoints were the rate of treatment completion, adverse events, relative dose intensity, and overall survival. RESULTS: Between February 2014 and December 2014, 89 patients were enrolled. One patient was excluded from the analysis because of ineligibility, and the remaining 88 patients were included. The rate of protocol treatment completion was 72.3%. The relative dose intensity of S-1 and oxaliplatin was 72% and 76.3%, respectively. Hematological severe adverse events (Grade 3/4) were neutropenia (21.3%) and thrombocytopenia (15.7%). The most frequent symptom was diarrhea (Grade 3/4: 5.6%). The incidence of grade 2 neuropathy has decreased from 8.1 to 2.7% after 3 years of the therapy. Three-year disease-free survival rate was 73.9% (95% CI 63.8-81.9), and 3-year overall survival rate was 94.3% (95% CI 86.8-97.6) CONCLUSIONS: C-SOX is a safe and feasible adjuvant chemotherapy regimen in patients with stage III colon cancer undergoing curative resection.

Randomised phase II trial of mFOLFOX6 plus bevacizumab versus mFOLFOX6 plus cetuximab as first-line treatment for colorectal liver metastasis (ATOM trial).

BACKGROUND: Chemotherapy with biologics followed by liver surgery improves the resection rate and survival of patients with colorectal liver metastasis (CRLM). However, no prospective study has compared the outcomes of chemotherapy with bevacizumab (BEV) versus cetuximab (CET). METHODS: The ATOM study is the first randomised trial comparing BEV and CET for initially unresectable CRLM. Patients were randomly assigned in a 1:1 ratio to receive mFOLFOX6 plus either BEV or CET. The primary endpoint was progression-free survival (PFS). RESULTS: Between May 2013 and April 2016, 122 patients were enrolled. Median PFS was 11.5 months (95% CI 9.2-13.3 months) in the BEV group and 14.8 months (95% CI 9.7-17.3 months) in the CET group (hazard ratio 0.803; P = 0.33). Patients with a smaller-number but larger-sized metastases did better in the CET group. In the BEV and CET groups, the response rates were 68.4% and 84.7% and the resection rates were 56.1% and 49.2%, respectively. CONCLUSION: Although CET achieved a better response rate than BEV for patients with a small number of large liver metastases, both biologics had similar efficacy regarding liver resection and acceptable safety profiles. To achieve optimal PFS, biologics should be selected in accordance with patient conditions. TRIAL REGISTRATION: This trial is registered at ClinicalTrials.gov (number NCT01836653), and UMIN Clinical Trials Registry (UMIN-CTR number UMIN000010209).

Survival Outcomes of Two Phase 2 Studies of Adjuvant Chemotherapy with S-1 Plus Oxaliplatin or Capecitabine Plus Oxaliplatin for Patients with Gastric Cancer After D2 Gastrectomy.

BACKGROUND: Two phase 2 trials of oxaliplatin-containing adjuvant therapy for patients with gastric cancer (GC) after D2 gastrectomy were conducted in Japan. The SOXaGC trial evaluated the tolerability and safety of adjuvant therapy with S-1 plus oxaliplatin (SOX), whereas the J-CLASSIC trial evaluated the feasibility of adjuvant therapy with capecitabine plus oxaliplatin (CAPOX). Because both were studies that did not evaluate survival results as study end points, the authors evaluated the survival outcomes for the patients in the two trials. METHODS: All 62 and 100 patients in the full analysis set of the SOXaGC and J-CLASSIC trials, respectively, were included in the current study. Their information about survival outcome was collected. The primary end point was relapse-free survival (RFS), and the secondary end point was overall survival (OS). RESULTS: For the pathologic stage (pStage 2) patients treated with CAPOX, the 3-year RFS rate was 87.8% and the 3-year OS rate was 92.7%. For the pStage 3 patients treated with SOX and CAPOX, the 3-year RFS rates were respectively 70.9% and 67.8% (hazard ratio [HR], 0.93; 95% confidence interval [CI], 0.50-1.72), whereas the 3-year OS rates were respectively 75.7% and 79.3% (HR, 1.10; 95% CI, 0.54-2.26). Subgroup analysis showed significant interactions between the treatment (SOX vs. CAPOX) and both sex (male vs. female; P = 0.024) and histologic type (diffuse vs. other, P = 0.069). CONCLUSIONS: This exploratory analysis demonstrated that SOX and CAPOX are suggested to have similar efficacy for pStage 3 GC patients after D2 gastrectomy. Differences in the treatment effect according to sex and histologic type warrant further evaluation.

[Retrospective Examination of Usefulness and Adverse Effects of Tapentadol in Patients with Cancer Pain during Anticancer Treatment].

We retrospectively examined 106 cases of tapentadol use in Japan in August 2014 for cancer pain at our hospital.The advantage of the opioid medication tapentadol is that its introduction is suitable in patients undergoing anti-cancer treatment because of the low incidence of gastrointestinal symptoms, with glucuronidation involved in the metabolism, and lack of interactions with other drugs.However, depending on the dosage form and presence of swallowing disorders, the administration should be considered carefully.

Prophylactic Effect of Dexamethasone on Regorafenib-Related Fatigue and/or Malaise: A Randomized, Placebo-Controlled, Double-Blind Clinical Study in Patients with Unresectable Metastatic Colorectal Cancer (KSCC1402/HGCSG1402).

BACKGROUND: Regorafenib is an oral multikinase inhibitor with a proven survival benefit for metastatic colorectal cancer patients. The KSCC1402/HGCSG1402 study investigated the prophylactic effect of oral dexamethasone (DEX) on regorafenib-related fatigue and/or malaise. PATIENTS AND METHODS: Patients who progressed after standard chemotherapy were randomized 1: 1 to a DEX group (2 mg/day; days 1-28) with regorafenib or a placebo group with regorafenib. The primary endpoint was the incidence of fatigue and/or malaise, based on version 4.0 of the National Cancer Institute's CTCAE (Common Terminology Criteria for Adverse Events). One of the secondary endpoints was the in-cidence of fatigue and/or malaise based on the CTCAE assessed by patient-reported outcome (PRO). RESULTS: The incidence of any grade of fatigue and/or malaise assessed by the investigators was 58.8% in the DEX group and 61.1% in the placebo group (p = 0.8101), and that assessed by PRO was 47.2 and 58.3%, respectively (p = 0.3450). The incidence of grade ≥2 fatigue and/or malaise, as assessed by the investigators, was 19.4% for the DEX group and 38.9% for the placebo group (p = 0.0695), and that assessed by PRO was 27.8 and 52.8%, respectively (p = 0.0306). CONCLUSION: Our results suggest that prophylactic oral DEX is clinically effective in improving regorafenib-related fatigue and/or malaise.

Study protocol of a phase II clinical trial (KSCC1501A) examining oxaliplatin + S-1 for treatment of HER2-negative advanced/recurrent gastric cancer previously untreated with chemotherapy.

BACKGROUND: Oxaliplatin + S-1 is a recognized treatment regimen in Japan, but there are no Japanese clinical data on an oxaliplatin dose of 130 mg/m2. The current research involves a single-arm, prospective, phase II clinical trial to examine the efficacy and safety of oxaliplatin + S-1 with an oxaliplatin dose of 130 mg/m2 to treat HER2-negative advanced/recurrent gastric cancer previously untreated with chemotherapy in Japan. METHODS/DESIGN: The primary endpoint of this trial will be the response rate, and the secondary endpoints will be the safety profile of oxaliplatin + S-1, progression-free survival, the response rate in subjects under the age of 75, overall survival, time to treatment failure, duration of treatment, time to failure of strategy, and dose intensity. The threshold response rate is 45% and the expected response rate is 60%. Assuming that a one-tailed score test will be performed with an α of 0.05, 68 patients are needed to ensure a statistical power of 80%. Planned enrollment is 70 subjects and the total duration of this trial is expected to be 3 years. DISCUSSION: Since replacing cisplatin with oxaliplatin should provide the same level of therapeutic efficacy while limiting adverse events and simplifying treatment, oxaliplatin + S-1 may be increasingly used to treat gastric cancer in Japan. Verifying the efficacy and safety of oxaliplatin + S-1 with an oxaliplatin dose of 130 mg is an important task that the current trial has set out to achieve. TRIAL REGISTRATION: The protocol was registered at the website of the University Hospital Medical Information Network (UMIN), Japan (protocol ID UMIN000017550) on May 29, 2015. The details are available at the following web address: http://www.umin.ac.jp/ctr/ .

Correction to: S-1 and irinotecan plus bevacizumab as second-line chemotherapy for patients with oxaliplatin-refractory metastatic colorectal cancer: a multicenter phase II study in Japan (KSCC1102).

In the original publication, in Abstract, the sentence that reads as, "Oral S-1 at a dose of 80 mg/m2 was…………. drug-free interval" should read as, "Oral S-1 at a dose of 40 mg/m2 was administered twice daily for 2 weeks, followed by a 1-week drug-free interval.

[A New Twist on the Administration of Naldemedine for Opioid-Induced Constipation in an Outpatient].

Opioid-induced constipation(OIC)occurs with high frequency in patients with cancer undergoing pain treatment using opioids. Osmotic or irritant laxatives are usually used to prevent OIC. Recently, naldemedine has become operational for OIC. Although naldemedine achieved the desired effect, diarrhea is a little feared from the results of clinical phase III study(V9236 clinical trial). We herein report the use of naldemedine to alleviate diarrhea and expect the improvement of the quality of the bowel habits in outpatients with cancer undergoing pain treatment using opioids.

[Combinatorial Use of Rapid-Onset Opioid and Short-Acting Opioid Is Effective against Breakthrough Cancer Pain].

Breakthrough cancer pain is divided into "predictable breakthrough pain" and "unpredictable breakthrough pain". Uncontrolled breakthrough pain in cancer negatively affects the quality of life of the patients. The short-acting opioid(SAO) requires considerable time to produce analgesia, and is not adequate as a rescue drug. The rapid-onset opioid(ROO)immediately produces analgesia, but its appropriate usage is difficult. For instance, the frequency and interval of ROO usage is limited, making the optimization of dosage cumbersome. Therefore, ROO has not yet gained popularity. Here, we report that a combinatorial use of ROO and SAO is effective against breakthrough cancer pain, with SAO and ROO being suitable for "predictable breakthrough pain", and "unpredictable breakthrough pain", respectively. The effectiveness and safety of this combination were assessed for many patients with breakthrough cancer pain.

Phase II study of adjuvant chemotherapy of S-1 plus oxaliplatin for patients with stage III gastric cancer after D2 gastrectomy.

BACKGROUND: The Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer (ACTS-GC) demonstrated a survival benefit by adjuvant S-1 monotherapy in patients who had undergone curative resection of stage II/III gastric cancer, but there is still a need to improve the efficacy of treatment of stage III disease. We investigated the tolerability and safety of S-1 and oxaliplatin as adjuvant chemotherapy for stage III gastric cancer. METHODS: Japanese patients with stage III gastric cancer who had undergone D2 or more extensive lymphadenectomy were enrolled. In the first cycle, S-1 (40-60 mg/m2 twice daily) alone was given orally for 2 weeks of a 3-week cycle. From the second cycle, S-1 was administered as in the first cycle and oxaliplatin (100 mg/m2) was infused intravenously on day 1. Treatment was continued for 8 cycles. The primary end point was the treatment completion rate for eight cycles. RESULTS: Sixty-three patients were enrolled and 62 patients were included in analysis. The treatment completion rate was 74.2 %, which was higher than the expected completion rate of 72.0 %. The median relative dose intensities were 77.1 % for S-1 and 72.6 % for oxaliplatin, with 41.9 and 61.7 % patients requiring dose reduction of S-1 and oxaliplatin, respectively. Neutropenia was the only grade 3 or higher adverse event with an incidence 10 % or greater (32.3 %). There was no grade 3 or higher peripheral sensory neuropathy or treatment-related death. CONCLUSIONS: S-1 and oxaliplatin therapy is suggested to be manageable and safe with optimal dose reduction and delay in selected patients for stage III gastric cancer after D2 gastrectomy, and warrants further evaluation in larger studies.

Adjuvant capecitabine plus oxaliplatin after D2 gastrectomy in Japanese patients with gastric cancer: a phase II study.

BACKGROUND: Adjuvant chemotherapy with XELOX (capecitabine plus oxaliplatin) has been shown to be beneficial following resection of gastric cancer in South Korean, Chinese, and Taiwanese patients. This phase II study (J-CLASSIC-PII) was undertaken to evaluate the feasibility of XELOX in Japanese patients with resected gastric cancer. METHODS: Patients with stage II or III gastric cancer who underwent curative D2 gastrectomy received adjuvant XELOX (eight 3-week cycles of oral capecitabine, 1000 mg/m2 twice daily on days 1-14, plus intravenous oxaliplatin 130 mg/m2 on day 1). The primary endpoint was dose intensity. Secondary endpoints were safety, proportion of patients completing treatment, and 1-year disease-free survival (DFS) rate. RESULTS: One hundred patients were enrolled, 76 of whom completed the study as planned. The mean dose intensity was 67.2 % (95 % CI, 61.9-72.5 %) for capecitabine and 73.4 % (95 % CI, 68.4-78.4 %) for oxaliplatin, which were higher than the predefined age-adjusted threshold values of 63.4 % and 69.4 %, respectively, and the study therefore met its primary endpoint. The 1-year DFS rate was 86 % (95 % CI, 77-91 %). No new safety signals were identified. CONCLUSIONS: The feasibility of adjuvant XELOX in Japanese patients with resected gastric cancer is similar to that observed in South Korean, Chinese, and Taiwanese patients in the Capecitabine and Oxaliplatin Adjuvant Study in Stomach Cancer (CLASSIC) study. Based on findings from this study and the CLASSIC study, the XELOX regimen can be considered an adjuvant treatment option for Japanese gastric cancer patients who have undergone curative resection.

A prospective study of XELIRI plus bevacizumab as a first-line therapy in Japanese patients with unresectable or recurrent colorectal cancer (KSCC1101).

BACKGROUND: This study was designed to evaluate the efficacy and toxicity of XELIRI plus bevacizumab for the treatment of Japanese patients with unresectable or recurrent colorectal cancer (CRC). METHODS: This was a multicenter, single-arm, open-label prospective study. The major inclusion criteria were previously untreated unresectable or recurrent CRC, presence of measurable lesions, ≥20 years of age, Eastern Cooperative Oncology Group performance status 0 or 1, and adequate organ function. Patients received bevacizumab (7.5 mg/kg on day 1) and XELIRI (irinotecan 200 mg/m2 on day 1 plus capecitabine 800 mg/m2 b.i.d. on days 1-14) every 3 weeks. The primary endpoint was the objective tumor response rate. RESULTS: A total of 36 patients were enrolled in this study from July 2011 to September 2012. One patient did not fulfill the eligibility criteria and one patient withdrew their consent before the start of the treatment protocol. The confirmed objective response rate was 58.8% (95% CI 35.1-70.2%). The median progression-free survival was 9.6 months (95% CI 5.1-11.1 months) and the median overall survival was 23.1 months (95% CI 11.3-36.7 months). The grade ≥3 adverse events that were frequently encountered in this study were neutropenia (31.4%), leukopenia (22.9%), diarrhea (22.9%), anemia (20.0%), anorexia (20.0%) and febrile neutropenia (17.2%). The frequency of grade 3/4 adverse events, such as neutropenia and leukopenia, was much higher in patients with a UGT1A1 polymorphism. CONCLUSIONS: A first-line therapy comprising XELIRI plus bevacizumab yielded a promising response rate. However, careful attention should be given to adverse clinical events in Japanese patients receiving treatment with unresectable or recurrent CRC.

Final report of KSCC0803: feasibility study of capecitabine as adjuvant chemotherapy for stage III colon cancer in Japan.

BACKGROUND: The impact of oral capecitabine as adjuvant chemotherapy for Japanese patients with resected colon cancer was unclear. We previously planned and conducted a prospective feasibility study (KSCC0803) and reported on the safety of oral capecitabine as adjuvant chemotherapy for Japanese patients with resected stage III colon cancer. The purpose of the current study was to assess the survival results from that study. METHODS: The study subjects were Japanese patients with resected stage III colon cancer. The protocol adjuvant regimen consisted of oral capecitabine 1250 mg/m2 twice daily on days 1-14 of a 3-week cycle for a total of eight cycles. The 3- and 5-year disease free survival (DFS) rates and overall survival (OS) rates were analyzed in the eligible cohort. RESULTS: Ninety-seven patients were registered between September 2008 and August 2009 and treated with the protocol regimen. The median follow-up time was 60.7 months. The 3- and 5-year DFS rates were 71.2% [95% confidence interval (CI): 61.7-79.8%] and 69.7% (95% CI: 59.4-77.8%), respectively. The 3- and 5-year OS rates were 92.6% (95% CI: 85.2-96.4%) and 84.5% (95% CI: 75.1-90.5%), respectively. CONCLUSIONS: The survival results in this study are in line with those of previously reported, reliable, studies. The safety and tolerability of the protocol regimen have already been confirmed. Oral capecitabine is acceptable as adjuvant chemotherapy for Japanese patients with resected stage III colon cancer.

Erratum to: Impact of intra-abdominal absorbable sutures on surgical site infection in gastrointestinal and hepato-biliary-pancreatic surgery: results of a multicenter, randomized, prospective, phase II clinical trial.

In the original publication, the article category was published as "Review Article". The correct category should read as "Original Article".

Impact of intra-abdominal absorbable sutures on surgical site infection in gastrointestinal and hepato-biliary-pancreatic surgery: results of a multicenter, randomized, prospective, phase II clinical trial.

BACKGROUND: The use of absorbable sutures in wound closure has been shown to reduce the incidence of surgical site infection (SSI); however, there is no evidence that the intra-abdominal use of absorbable rather than silk sutures reduces the incidence of SSI after gastrointestinal surgery. We report the findings of a phase II trial, designed to evaluate the impact of the intra-abdominal use of absorbable sutures on the incidence of SSI. METHODS: At 19 Japanese hospitals, 1147 patients undergoing elective gastrectomy, colorectal surgery, hepatectomy, or pancreaticoduodenectomy (PD) were randomly assigned to absorbable or silk intra-abdominal suture groups. The primary efficacy endpoint was the incidence of SSI. The secondary efficacy endpoints were the locations of SSI, time to resolution of SSI, length of hospital stay, and the incidence of bile leakage in hepatectomy and pancreatic fistula. RESULTS: The incidence of SSI was 11.3%, 15.5%, 11.3%, and 36.9% after gastrectomy, colorectal surgery, hepatectomy, and PD, respectively. The incidence of SSI was higher in the absorbable suture group than in the silk suture group for all the surgical procedures, but the difference was not significant. CONCLUSION: The intra-abdominal use of absorbable sutures did not have enough of an effect on the reduction of SSI in this phase II trial to justify the planning of a large-scale phase III trial.

S-1 plus leucovorin versus S-1 plus leucovorin and oxaliplatin versus S-1 plus cisplatin in patients with advanced gastric cancer: a randomised, multicentre, open-label, phase 2 trial.

BACKGROUND: Although leucovorin enhances the efficacy of fluorouracil, the anti-tumour activity of S-1 and leucovorin and their combination with oxaliplatin for patients with advanced gastric cancer is unknown. We compared the activity and safety of S-1 plus leucovorin, S-1 plus leucovorin and oxaliplatin, and S-1 plus cisplatin as first-line chemotherapy for advanced gastric cancer. METHODS: In this multicentre, randomised, open-label, phase 2 trial, we recruited chemotherapy-naive patients with unresectable or recurrent gastric cancer with measurable lesions aged 20 years or older from 25 general hospitals and specialist centres in Japan. Patients were randomly assigned (1:1:1) centrally to receive S-1 plus leucovorin (S-1 40-60 mg orally plus oral leucovorin 25 mg twice a day for 1 week, every 2 weeks), S-1 plus leucovorin and oxaliplatin (S-1 plus leucovorin and intravenous oxaliplatin 85 mg/m(2) on day 1, every 2 weeks), or S-1 plus cisplatin (S-1 40-60 mg orally twice a day for 3 weeks, plus intravenous cisplatin 60 mg/m(2) on day 8, every 5 weeks). Randomisation was done with the minimisation method using performance status (0 vs 1) and tumour stage (stage IV vs recurrent) as stratification factors. The primary endpoint was independently reviewed overall response in the full analysis set. This trial is registered with Japic CTI, number 111635. FINDINGS: Between Oct 20, 2011, and Dec 17, 2012, we enrolled and randomly assigned 145 patients: 49 patients were assigned to S-1 plus leucovorin, 47 to S-1 plus leucovorin and oxaliplatin, and 49 to S-1 plus cisplatin. An objective response assessed by the independent review committee was achieved in 20 (43% [95% CI 28·3-57·8]) of the 47 patients in the S-1 plus leucovorin group, 31 (66% [50·7-79·1]) of the 47 patients in the S-1 plus leucovorin and oxaliplatin group, and 22 (46% [31·4-60·8]) of the 48 patients in the S-1 plus cisplatin group (Fisher's exact test, p=0·84 for S-1 plus leucovorin vs S-1 plus cisplatin, p=0·063 for S-1 plus leucovorin and oxaliplatin vs S-1 plus cisplatin, and p=0·038 for S-1 plus leucovorin and oxaliplatin vs S-1 plus leucovorin). The most common grade 3-4 adverse events were neutropenia (three [6%] of 48 patients in the S-1 plus leucovorin group vs 12 [26%] of 47 patients in the S-1 plus leucovorin and oxaliplatin group vs 17 [35%] of 49 patients in the S-1 plus cisplatin group), decreased appetite (six [13%] vs 14 [30%] vs 12 [24%]), anaemia (five [10%] vs seven [15%] vs 13 [27%]), and hyponatraemia (two [4%] vs two [4%] vs nine [18%]). INTERPRETATION: S-1 plus leucovorin and oxaliplatin was more active than S-1 plus leucovorin or S-1 plus cisplatin with acceptable toxic effects for patients with advanced gastric cancer. A phase 3 trial comparing S-1 plus leucovorin and oxaliplatin with S-1 plus cisplatin is underway. FUNDING: Taiho Pharmaceutical.