Daikenchuto accelerates the recovery from prolonged postoperative ileus after open abdominal surgery: a subgroup analysis of three randomized controlled trials.

PURPOSE: Prolonged postoperative ileus (POI) is a common complication after open abdominal surgery (OAS). Daikenchuto (DKT), a traditional Japanese medicine that peripherally stimulates the neurogenic pathway, is used to treat prolonged POI in Japan. To analyze whether DKT accelerates the recovery from prolonged POI after OAS, we conducted a secondary analysis of three multicenter randomized controlled trials (RCTs). METHODS: A secondary analysis of the three RCTs supported by the Japanese Foundation for Multidisciplinary Treatment of Cancer (project numbers 39-0902, 40-1001, 42-1002) assessing the effect of DKT on prolonged POI in patients who had undergone OAS for colon, liver, or gastric cancer was performed. The subgroup included 410 patients with no bowel movement (BM) before the first diet, a DKT group (n = 214), and a placebo group (n = 196). Patients received either 5 g DKT or a placebo orally, three times a day. The primary endpoint was defined as the time from the end of surgery to the first bowel movement (FBM). A sensitivity analysis was also performed on the age, body mass index and dosage as subgroup analyses. RESULTS: The primary endpoint was significantly accelerated in the DKT group compared with the placebo group (p = 0.004; hazard ratio 1.337). The median time to the FBM was 113.8 h in the placebo group and 99.1 h in the DKT treatment group. CONCLUSIONS: The subgroup analysis showed that DKT significantly accelerated the recovery from prolonged POI following OAS. TRIAL REGISTRATION NUMBER: UMIN000026292.

Repeat hepatectomy with systemic chemotherapy might improve survival of recurrent liver metastasis from colorectal cancer-a retrospective observational study.

BACKGROUND: Although hepatectomy for metastatic colorectal cancer (mCRC) prolongs survival in up to 40% of people, recurrence rates approach 70%. We used a multidisciplinary approach to treat recurrent liver metastases, including chemotherapy, surgery, and palliative care. On the other hand, development of chemotherapeutic agents is remarkable and improves long-term survival. However, whether chemotherapy and repeat hepatectomy combination therapy improve survival or not is still unclear. The aim of this study was to analyze the outcomes of repeat hepatectomy with systemic chemotherapy for mCRC. METHODS: Following Institutional Review Board approval, we reviewed the records of all patients who underwent hepatectomy for mCRC between 1974 and 2015 at Fujita Health University Hospital. We used the Kaplan-Meier method to estimate overall survival from the first and last hepatectomy in multi hepatectomy cases after 2005 and compared outcomes between groups using the log-rank test. RESULTS: A total of 426 liver resections were performed for mCRC; of these, 236 cases were performed after 2005 (late group). In 118 (50%) cases, the site of recurrence was the liver, 59 (50%) underwent repeat hepatectomy, and 14 cases had ≥ 2 repeat hepatectomies. Overall survival (OS) before and after 2005 was 42.2 and 64.1 months, respectively, with the late group having better OS compared to the early (1974-2004) group. OS for single hepatectomy cases was 83.2 months, for two hepatectomies was 42.9 months, and for three hepatectomies was 35.3 months. In total, 59 patients did not undergo surgery after recurrence with an OS of 28.7 months. Mortality of the second and third repeat hepatectomy was 1.7% and 15.3%, respectively. CONCLUSION: Repeat hepatectomy with systemic chemotherapy for mCRC is feasible and might achieve improved survival in carefully selected patients.

A case of locally advanced adenosquamous carcinoma of the cecum with long-term survival.

A 63-year-old woman was admitted to our hospital with a right lower abdominal mass and general fatigue. Preoperative examination suggested a large ovarian tumor or cecal carcinoma. However, her intraoperative diagnosis was colon cancer; we therefore performed an ileocecal resection with oophorectomy. The tumor was pathologically diagnosed as adenosquamous carcinoma T4bN1M-stage IIIa. We administrated CapeOX adjuvant chemotherapy for 6 months. Adenosquamous carcinoma is extremely rare, at around 0.1% of all colorectal cancers, and usually has a poor prognosis. The patient is still alive without recurrence after 84 post-operative months, even with later developments of metachronous early colorectal cancer and breast cancer. We herein report a rare case of cecal ASC with good prognosis.

Preplanned safety analysis of the JFMC37-0801 trial: a randomized phase III study of six months versus twelve months of capecitabine as adjuvant chemotherapy for stage III colon cancer.

BACKGROUND: Six months of adjuvant chemotherapy is regarded as the standard of care for patients with stage III colon cancer. However, whether longer treatment can improve prognosis has not been fully investigated. We conducted a phase III study comparing 6 and 12 months of adjuvant capecitabine chemotherapy for stage III colon cancer, and report here the results of our preplanned safety analysis. METHODS: Patients aged 20-79 years with curatively resected stage III colon cancer were randomly assigned to receive 8 cycles (6 months) or 16 cycles (12 months) of capecitabine (2500 mg/m2/day on days 1-14 of each 21-day cycle). Treatment exposure and adverse events (AEs) were evaluated. RESULTS: A total of 1304 patients (642 and 636 in the 6-month and 12-month groups, respectively) were analyzed. The most common AE was hand-foot syndrome (HFS). HFS, leukocytopenia, neutropenia, and hyperbilirubinemia (any grade) occurred more frequently in the 12-month group than in the 6-month group. HFS was the only grade ≥3 AE to have a significantly higher incidence in the 12-month group (23 vs 17%, p = 0.011). The completion rate for 8 cycles was 72% in both groups, while that for 16 cycles was 46% in the 12-month group. HFS was the most common AE requiring dose reduction and treatment discontinuation. CONCLUSIONS: Twelve months of adjuvant capecitabine demonstrated a higher cumulative incidence of HFS compared to the standard 6-month treatment period, while toxicities after 12 months of capecitabine were clinically acceptable. TRIAL REGISTRATION: UMIN-CTR, UMIN000001367.

Clinical outcomes of stage IV colorectal cancer after R0 resection: a multi-institutional retrospective analysis.

BACKGROUND: We analyzed the treatment outcomes after curative surgery for stage IV colorectal cancer to develop outcome-based follow-up protocols and treatment strategies. METHODS: This study was a multi-institutional retrospective analysis of treatment outcomes in patients who underwent R0 surgery for stage IV colorectal cancer. RESULTS: A total of 1133 patients, of whom 837 had recurrence, were included in this study. Recurrence occurred within 12 and 24 months after R0 surgery in 452 (54.0 %) and 652 (77.9 %) patients, respectively. Surgical resection was performed less frequently for recurrence within 12 months of R0 surgery than for recurrence after more than 12 months (p = 0.003). Prognosis was significantly better in patients who had recurrence more than 24 months after R0 surgery than in those who had recurrence within 24 months; this was not only for all patients but also specifically for patients with resection for recurrent disease. Recurrence was less frequent in patients who received preoperative chemotherapy than in patients who did not receive preoperative chemotherapy (p = 0.04). Of significance, fewer patients who received preoperative chemotherapy (57.5 %) had recurrence within 24 months compared with patients who did not receive preoperative chemotherapy (79.8 %) (p = 0.00001). CONCLUSIONS: Intensive follow-up for at least 24 months was considered appropriate for monitoring disease recurrence after R0 surgery for stage IV colorectal cancer. In addition, preoperative chemotherapy contributed to improved outcomes.

[Treatment Outcome of Anal Squamous Cell Carcinoma Treated with Radical Chemoradiotherapy].

We reviewed the clinical records of 7 patients with anal squamous cell carcinoma(SCC)to evaluate the effectiveness of radical chemoradiotherapy(CRT). The radiotherapy(RT)consisted of 40 Gy delivered to the pelvis and bilateral inguinal lesions, and a perianal booster dose of 20 Gy, in fractions of 2.0 Gy per day, 5 days per week. 5-fluorouracil(5-FU)and mitomycin C(MMC)were administered 3 times every 4weeks as standard chemotherapy. On the first day of RT, 750mg/m2 of 5-FU in the form of a continuous 24-hour infusion, for 5 days was administered. On the first day of chemotherapy, 10mg/ m2 of MMC was also administered as a single bolus infusion. One patient with a T3 tumor was administered oral TS-1 during RT because of advanced age. In the CRT group, there was 1 case each of T1 and T3, and the others were T2. Grade 2 adverse effects occurred in 5 patients, and Grade 3 in 2, but completion of CRT was achieved in all 7 patients. All patients had a complete response in the anal lesion after CRT. Three patients, including those with the T3 tumor treated with TS-1, developed recurrence of the anal lesion. Two patients with T2 tumors, who were treated with CRT comprising 5-FU and MMC, developed recurrence of the anal lesion more than 60 months after CRT. CRT is expected to be a safe and effective treatment to improve the prognosis for anal squamous carcinoma; however, sufficient and appropriate follow-up is necessary after a complete response.

Comparison of symptomatic anastomotic leakage following laparoscopic and open low anterior resection for rectal cancer: a propensity score matching analysis of 1014 consecutive patients.

BACKGROUND: This observational study was conducted to compare the rate of symptomatic anastomotic leakage (AL), as defined by precise criteria, between laparoscopic and open surgery in patients with mid-to-low rectal cancer using a relatively novel statistical technique. METHODS: A total of 1014 consecutive low anterior resection (LAR) patients were registered, of whom 936 were included in this prospective, multicenter, and cohort study (UMIN-CTR, Number 000004017). Patients with rectal cancer within 10 cm from the anal verge underwent either open or laparoscopic LAR at one of the 40 institutions in Japan from June 2010 to February 2013. The primary endpoint of this study was to compare the rate of symptomatic AL between the two groups before and after propensity score matching (PSM). The secondary endpoint was to analyze the risk factors for symptomatic AL in open and laparoscopic surgery. RESULTS: After PSM, the incidence of symptomatic AL in open and laparoscopic surgery was 12.4 and 15.3 %, respectively (p = 0.48). AL requiring relaparotomy occurred after 3.8 % of open surgeries and 6.2 % of laparoscopic surgeries (p = 0.37). Multivariate analysis identified male gender as an independent risk factor for symptomatic AL following laparoscopic surgery (p = 0.001; odds ratio 5.2; 95 % CI 2.0-13.8), and male gender (p = 0.004; odds ratio 2.6; 95 % CI 1.3-5.6), tumor size (p = 0.002; odds ratio 1.2; 95 % CI 0.7-0.9), and number of stapler firing (p = 0.04; odds ratio 4.1; 95 % CI 1.0-15.0) following open surgery. CONCLUSION: The rate of symptomatic AL was comparable following laparoscopic and open LAR in this large, multicenter, cohort study after PSM. Male gender was associated with an increased risk of symptomatic AL after laparoscopic LAR.

Clinical pharmacology of daikenchuto assessed by transit analysis using radiopaque markers in patients with colon cancer undergoing open surgery: a multicenter double-blind randomized placebo-controlled study (JFMC39-0902 additional study).

BACKGROUND: This exploratory trial was conducted to investigate whether daikenchuto accelerates the recovery of gastrointestinal function in patients undergoing open surgery for sigmoid or rectosigmoid cancer. METHODS: Eighty-eight patients who underwent colectomy at one of the 11 clinical trial sites in Japan from January 2009 to June 2011 were registered in the study. Patients received either placebo or daikenchuto (15.0 g/day, 5 g three times a day) from postoperative day 2 to postoperative day 8. The study end points included the gastrointestinal tract transit time evaluated with radiopaque markers and the time to first flatus. The safety profile of daikenchuto was also evaluated until postoperative day 8. RESULTS: Seventy-one patients (daikenchuto, n = 38; placebo, n = 33) were statistically analyzed. Although the number of radiopaque markers in the anal side of the small intestine at 6 h was significantly greater in the daikenchuto group than in the placebo group (15.19 vs 10.06, p = 0.008), the total transit analysis results and the mean time to first flatus did not differ significantly between the two groups. CONCLUSIONS: Daikenchuto has a positive effect on the resolution of delayed gastric emptying, but has a limited effect on the resolution of postoperative paralytic ileus after open surgery in patients with sigmoid or rectosigmoid cancer. Daikenchuto may contribute to early oral intake in the postoperative course.

Current status of local treatment for early rectal cancer in Japan: a questionnaire survey by the 81st Congress of the Japanese Society for Cancer of the Colon and Rectum (JSCCR) in 2014.

PURPOSE: The aim of this questionnaire survey was to assess the change in treatment modality over time and the current status of clinical outcomes of local treatment in Japanese patients with pathological T1 (pT1) rectal tumors. METHODS: A questionnaire survey was conducted by the 81st Congress of the Japan Society for Cancer of the Colon and Rectum. Clinical and pathological outcomes of all eligible patients undergoing local treatment were retrospectively collected from the medical records of each participating hospital. RESULTS: A total of 1371 pT1 patients from January 2006 to December 2008 (Period A), and 659 patients in 2013 (Period B) were registered. Approximately 70 % of patients underwent radical surgery in both periods. The rate of patients undergoing laparoscopic surgery increased from 46.5 % in Period A to 84.7 % in Period B. The indications for local excision were comparable with those for endoscopic intervention in 78 % of institutions. The rate of endoscopic submucosal dissection (ESD) increased from 20.1 % in Period A to 37.9 % in Period B, whereas local excision decreased from 36.9 to 24.1 %. Few patients received adjuvant therapy, and approximately 40 % of patients underwent additional surgery in both periods. Local recurrence was observed in 9.2 % of patients in Period A, with the median follow-up period being 59 months. Eighty-two percent of patients with local recurrence underwent salvage surgery. CONCLUSIONS: Local treatment with various modalities was properly performed for early rectal cancer. The number of less invasive modalities, such as laparoscopic surgery and ESD, increased between study periods.

Kono-S Anastomosis for Surgical Prophylaxis of Anastomotic Recurrence in Crohn's Disease: an International Multicenter Study.

INTRODUCTION: The Kono-S (antimesenteric functional end-to-end handsewn) anastomosis has been used for Crohn's disease in Japan and the USA since 2003 and 2010, respectively. This technique was designed to reduce the risk of anastomotic surgical recurrence. This study reviews the outcomes a decade after the introduction of the Kono-S anastomosis to clinical practice. METHODS: This study was conducted at five hospitals (four in Japan and one in the USA). A total of 187 patients in Japan (144 patients, group J) and the USA (43 patients, group US) who underwent Kono-S anastomosis for Crohn's disease between September 2003 and September 2011 were included. RESULTS: With a median follow-up of 65 months, two surgical anastomotic recurrences have occurred in group J. Kaplan-Meier analysis showed that 5 and 10 years surgical recurrence-free survival rate was 98.6% in group J. No surgical anastomotic recurrences have been detected in group US with a median follow-up of 32 months. The Kono-S anastomosis was technically feasible and performed in all patients. CONCLUSION: The Kono-S anastomosis appears to be safe and effective in reducing the risk of surgical recurrence in Crohn's disease.

Technique of Robotic-assisted Total Proctocolectomy with Lymphadenectomy and Ileal Pouch-Anal Anastomosis for Transverse Colitic Cancer of Ulcerative Colitis, Using the Single Cart Position.

Robotic surgery offers advantages for operating in a narrow space such as inside the pelvis. We report on the technique of robotic-assisted laparoscopic total proctocolectomy with lymphadenectomy and ileal pouch-anal anastomosis for ulcerative colitis with transverse colitic cancer, using the single cart position. A 46-year-old female patient was diagnosed with colitic cancer of the transverse colon during the surveillance of ulcerative colitis. Six port sites were used. Mobilization of the left-sided colon through to the rectum and mobilization of the transverse colon with lymphadenectomy around the middle colic artery were performed using the robotic surgical system. After rectal mobilization was conducted near the anus, the right side of the colon was mobilized and the ileum resected laparoscopically. Thereafter, a mucosectomy of the proctorectum was carried out through a trans-anal approach, and a hand-sewn J-pouch was performed. Finally, a diverting ileostomy was constructed through the right lower abdomen. The operative time was 460 minutes, including the console time of 361 minutes. The amount of blood loss was 76 g. The patient was discharged on postoperative day nine. Pathological results demonstrated that the depth of the lesion was T3, and the positive lymph node was 1 of 115 retrieved lymph nodes. There were no complications or mortality. Robotic-assisted total proctocolectomy and lymphadenectomy with ileal pouch-anal anastomosis for transverse colitic cancer of ulcerative colitis was performed safely using the single cart position.

Clinical efficacy of Daikenchuto for gastrointestinal dysfunction following colon surgery: a randomized, double-blind, multicenter, placebo-controlled study (JFMC39-0902).

OBJECTIVE: This exploratory trial was performed to determine whether Daikenchuto accelerates recovery of gastrointestinal function in patients undergoing open colectomy for colon cancer. METHODS: A total of 386 patients undergoing colectomy at 1 of the 51 clinical trial sites in Japan from January 2009 to June 2011 were registered for the study (JFMC39-0902). Patients received either placebo or Daikenchuto (15.0 g/day, t.i.d) between post-operative day 2 and post-operative day 8. Primary end-points included time to first bowel movement, frequency of bowel movement and stool form. The incidence of intestinal obstruction was evaluated post-operatively. The safety profile of Daikenchuto until post-operative day 8 was also evaluated. RESULTS: The results for 336 patients (Daikenchuto, n = 174; placebo, n = 162) were available for statistical analysis. The time to first bowel movement did not differ significantly between the two groups. All patients reported having diarrhea or soft stools immediately after surgery, and the time until stool normalization (50th percentile) in the Daikenchuto and placebo groups was 6 days and 7 days, respectively. The placebo group had a significantly greater number of hard stools at post-operative day 8 (P = 0.016), and bowel movement frequency continued to increase until post-operative day 8 as well. In contrast, bowel movement frequency in the Daikenchuto group increased until post-operative day 6, however decreased from post-operative day 7 and was significantly lower at post-operative day 8 compared with the placebo group (P = 0.024). CONCLUSION: The moderate effects of Daikenchuto were observed ∼1 week after the operation. Although Daikenchuto had an effect on gastrointestinal function after open surgery in patients with colon cancer, this study did not show its clinical benefits adequately.

Novel antimesenteric functional end-to-end handsewn (Kono-S) anastomoses for Crohn's disease: a report of surgical procedure and short-term outcomes.

INTRODUCTION: Anastomotic surgical recurrence after bowel resection is a major problem in patients with Crohn's disease. The aim of this prospective observational study was to evaluate the efficacy of a novel technique for restoring bowel continuity after resection involving either the small or the large intestine. METHODS: The first case was instructed by Dr. Kono at Fujita Health University. The involved bowel segment was divided transversely with a linear stapler. The edges of two stapled lines are then connected to create a supporting column, which prevented surgical recurrence from anastomotic distortion due to mesenteric longitudinal ulcers. Thereafter, an antimesenteric longitudinal enterotomy was performed on each side to create a large-sized handsewn end-to-end anastomosis. RESULTS: Thirty consecutive patients underwent Kono-S anastomoses from December 2009 to August 2013. Neither anastomotic leakage nor surgical recurrence was observed during a median follow-up period of 35 months. Endoscopic surveillance was performed in 18 cases (69.2%) undergoing ileo-colonic or ileo-rectal anastomosis with an average Rutgeert's score of 0.78 (0-3) at a mean of 14.5 months postoperatively. CONCLUSION: The Kono-S anastomosis for Crohn's disease has been a safe and feasible technique. Long-term outcomes are required to confirm its advantage in preventing surgical recurrence at the anastomosis.

Gigantic lymphangioma with marked extraluminal progression of the ascending colon: report of a case.

We report a case of gigantic cystic lymphangioma of the ascending colon excised through an open laparotomy. A 34-year-old woman consulted a gynecologist for treatment of infertility. Transvaginal ultrasonography revealed a cystic mass in the pelvis, and she was transferred to our hospital for further investigation. Abdominal enhanced computed tomography (CT) showed a bulky cystic mass, 25 cm or larger, in the abdominal and pelvic cavity. Colonoscopy revealed a cystic submucosal tumor with a cushion sign. Cystic lymphangioma was diagnosed and excised via open surgery as we could not exclude its malignant potential. Pathological examination confirmed lymphangioma. To our knowledge, this is the most gigantic lymphangioma of the colon documented in the literature. About 3 months after surgery, the patient discovered that she was pregnant and her first baby was delivered at term, uneventfully.

Clinical characteristics of ischemic colitis after surgery for colorectal cancer.

PURPOSE: This study was performed to clarify the clinical features of ischemic colitis (IC) after colorectal cancer surgery. METHODS: This study retrospectively reviewed the medical records of 35 patients with IC. Patients were divided into two groups: those who had undergone colorectal cancer surgery (POIC group, n = 13) and those who had not undergone colorectal cancer surgery (NOIC group, n = 22). Gangrenous colitis was seen in one patient in the POIC group, and transient colitis was seen in the remaining 34 patients. RESULTS: Among the patients with transient colitis, there were significantly more patients without underlying diseases or promoting factors in the POIC group than in the NOIC group (P = 0.01). Abdominal pain was more frequently reported in the NOIC group than in the POIC group as both the initial symptom (P = 0.02) and throughout the disease course (P = 0.02). Ischemic changes occupying more than half the circumference of the intestinal wall were more frequently found in the NOIC group than in the POIC group (P = 0.03). CONCLUSIONS: Although transient POIC may occur without any underlying disease, severe symptoms rarely occur. However, if POIC occurs in a patient with severe underlying disease, then the occurrence of severe colitis should be considered.

Clinical benefit of surgery for stage IV colorectal cancer with synchronous peritoneal metastasis.

BACKGROUND: Peritoneal metastasis is well-known as a poor prognostic factor in patients with colorectal cancer. It is important to improve the prognosis of patients with colorectal cancer and synchronous peritoneal metastasis. This study aimed to clarify the factors affecting R0 resection and the prognosis of colorectal cancer patients with synchronous peritoneal metastasis. METHODS: We investigated the data of patients with stage IV colorectal cancer between 1991 and 2007 in 16 hospitals that were members of the Japanese Society for Cancer of the Colon and Rectum. RESULTS: Of the 564 colorectal cancer patients with synchronous peritoneal metastases, 341 also had hematogenous metastases. The 5-year overall survival rates in patients with and without R0 resection were 32.4 and 4.7 %, respectively. A Cox proportional hazards model showed that histologic type of poorly differentiated adenocarcinoma, regional lymph node metastasis, liver metastasis, chemotherapy after surgery, R0 resection, the Japanese classification of peritoneal metastasis, and the size of peritoneal metastases were independent prognostic factors. Of the 564 patients, 28.4 % had R0 resection. The Japanese classification of peritoneal metastasis (P1-P2, p = 0.0024) and absence of hematogenous metastases (p < 0.0001) were associated with R0 resection. CONCLUSIONS: P1-P2 peritoneal metastasis and the absence of hematogenous metastasis were the most favorable factors benefiting from synchronous resection of peritoneal metastasis. In addition, chemotherapy after surgery was essential.