Preoperative and postoperative prognostic factors of patients with stage II/III lower rectal cancer without neoadjuvant therapy in the clinical trial (JCOG0212).

BACKGROUND: The JCOG0212 trial was a randomized controlled trial comparing mesorectal excision alone to mesorectal excision with lateral lymph node dissection for stage II/III lower rectal cancer patients without clinical lateral lymph node enlargement. This study aimed to identify clinicopathological prognostic factors for relapse-free survival and overall survival of lower rectal cancer in the trial. METHODS: Prospective data were selected from 663 patients with complete data. Uni and multivariable Cox regression model was applied to evaluate the preoperative and the combined preoperative and postoperative factors, respectively. Preoperative factors included age, sex, performance status, clinical T, clinical N and operative procedures. Postoperative factors included histological grade, pathological T, number of metastatic lymph nodes and number of dissected lymph nodes. No patient received neoadjuvant treatment. RESULTS: Regarding preoperative factors, multivariable analysis revealed that performance status 1 (vs. 0: HR 2.079, P = 0.0041) and cT4a (vs. cT2-3: HR 2.721, P = 0.0002) were independent risk factors for relapse-free survival, and those for overall survival were male (vs. female: HR 1.660, P = 0.0228) and cT4a (vs. cT2-3: HR 2.486, P = 0.0473). The only independent preoperative risk factor common for relapse-free survival and overall survival was cT4a. Taking preoperative and postoperative factors together, the number of metastatic lymph nodes was the only independent risk factor common for relapse-free survival and overall survival. CONCLUSIONS: Clinical stage II/III lower rectal cancer patients with cT4a should be a target of therapeutic development of neoadjuvant therapy. Postoperatively, intensive chemotherapy should be investigated for patients with more metastatic lymph nodes.

Risk factors for surgical site infection and association of surgical site infection with survival of lower rectal cancer patients without clinical lateral pelvic lymph node metastasis (clinical Stage II/III): Analysis of data from JCOG0212.

This study aimed to examine the risk factors for surgical site infection (SSI) and the association of that with recurrence in JCOG0212. The results for secondary endpoints showed that compared with the mesorectal excision (ME) alone group, ME with lateral lymph node dissection (LLND) group showed significantly longer operative time and significantly higher blood loss. These results suggested that LLND was a risk factor for SSI. All 701 patients registered in JCOG0212 were analyzed in this study. Wound infection was defined as incisional/deep SSI, and pelvic abscess and anastomotic leakage were defined as organ/space SSI. The risk factors for the incidence of SSI and the effect of SSI on relapse-free survival (RFS) were investigated. Multivariable odds ratio of Grade 2 or higher all SSI was 0.58 [95% Confidence interval: 0.36-0.93] for female (vs. male) and that of Grade 2 or higher incisional/deep SSI was 2.24 [1.03-4.86] for blood infusion. For RFS, patients with Grade 3 or higher all SSI showed poor prognosis (multivariable hazard ratio: 1.66 [1.03-2.68]). LLND is not significant factor for the incidence of all SSI. Male sex might be a risk factor of Grade 2 or higher SSI, and blood transfusion is a possible risk factor of Grade 2 or higher incisional/deep SSI. Grade 3 or higher all SSI might be a significant worse prognostic factor for lower rectal cancer.

Application of targeted nanopore sequencing for the screening and determination of structural variants in patients with Lynch syndrome.

Lynch syndrome is a hereditary disease characterized by an increased risk of colorectal and other cancers. Germline variants in the mismatch repair (MMR) genes are responsible for this disease. Previously, we screened the MMR genes in colorectal cancer patients who fulfilled modified Amsterdam II criteria, and multiplex ligation-dependent probe amplification (MPLA) identified 11 structural variants (SVs) of MLH1 and MSH2 in 17 patients. In this study, we have tested the efficacy of long read-sequencing coupled with target enrichment for the determination of SVs and their breakpoints. DNA was captured by array probes designed to hybridize with target regions including four MMR genes and then sequenced using MinION, a nanopore sequencing platform. Approximately, 1000-fold coverage was obtained in the target regions compared with other regions. Application of this system to four test cases among the 17 patients correctly mapped the breakpoints. In addition, we newly found a deletion across an 84 kb region of MSH2 in a case without the pathogenic single nucleotide variants. These data suggest that long read-sequencing combined with hybridization-based enrichment is an efficient method to identify both SVs and their breakpoints. This strategy might replace MLPA for the screening of SVs in hereditary diseases.

Narrow pelvic inlet plane area and obesity as risk factors for anastomotic leakage after intersphincteric resection.

BACKGROUND: Intersphincteric resection (ISR) has been increasingly used as the ultimate sphincter-preserving procedure in extremely low rectal cancer. The most critical complication of this technique is anastomotic leakage. The incidence rate of anastomotic leakage after ISR has been reported to range from 5.1% to 20%. AIM: To investigate risk factors for anastomotic leakage after ISR based on clinicopathological variables and pelvimetry. METHODS: This study was conducted at Department of Colorectal Surgery, Japanese Red Cross Medical Center, Tokyo, Japan, with a total of 117 patients. We enrolled 117 patients with extremely low rectal cancer who underwent laparotomic and laparoscopic ISRs at our hospital. We conducted retrospective univariate and multivariate regression analyses on 33 items to elucidate the risk factors for anastomotic leakage after ISR. Pelvic dimensions were measured using three-dimensional reconstruction of computed tomography images. The optimal cutoff value of the pelvic inlet plane area that predicts anastomotic leakage was determined using a receiver operating characteristic (ROC) curve. RESULTS: We observed anastomotic leakage in 10 (8.5%) of the 117 patients. In the multivariate analysis, we identified high body mass index (odds ratio 1.674; 95% confidence interval: 1.087-2.58; P = 0.019) and smaller pelvic inlet plane area (odds ratio 0.998; 95% confidence interval: 0.997-0.999; P = 0.012) as statistically significant risk factors for anastomotic leakage. According to the receiver operating characteristic curves, the optimal cutoff value of the pelvic inlet plane area was 10074 mm2. Narrow pelvic inlet plane area (≤ 10074 mm2) predicted anastomotic leakage with a sensitivity of 90%, a specificity of 85.9%, and an accuracy of 86.3%. CONCLUSION: Narrow pelvic inlet and obesity were independent risk factors for anastomotic leakage after ISR. Anastomotic leakage after ISR may be predicted from a narrow pelvic inlet plane area (≤ 10074 mm2).

Correction: Importance of gastric cancer for the diagnosis and surveillance of Japanese Lynch syndrome patients.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Importance of gastric cancer for the diagnosis and surveillance of Japanese Lynch syndrome patients.

Lynch syndrome (LS) is an autosomal dominantly inherited disease predisposed to not only colorectal cancer but also other LS-related tumors. Although the clinical and genetic characteristics of LS in Western countries have been well characterized, the information of Japanese LS is limited. As a collaborative study of Japanese Society for Cancer of the Colon and Rectum (JSCCR), we registered colorectal cancer (CRC) patients who fulfilled the modified Amsterdam II criteria including gastric cancer as an LS-related tumor. Among 4030 CRC patients initially registered in this project, 85 patients (2.1%) fulfilled the modified criteria. An additional 26 patients who met the same criteria were enrolled in the analysis. We analyzed three major responsible genes, MLH1, MSH2, and MSH6 by direct sequencing, and further performed multiplex ligation-dependent probe amplification for MLH1 and MSH2. Consequently, we identified pathogenic variants in 64 of the 111 patients comprising of 34 patients in MLH1, 28 in MSH2, and 2 in MSH6. It is of note that large structural alterations were found in 17 patients. Among the 64 patients, 11 patients would not have been enrolled in the analysis if gastric cancer were not included in the modified criteria. In addition, 10 of the 64 variant carriers (15.6%) had medical history of gastric cancer. Furthermore, the standardized incidence ratio of gastric cancer in the LS patients to the Japanese population is estimated to be as high as 20.2. These data underscore the importance of gastric cancer in the diagnosis and healthcare of Japanese LS patients.

Predictive factors of pathological lateral pelvic lymph node metastasis in patients without clinical lateral pelvic lymph node metastasis (clinical stage II/III): The analysis of data from the clinical trial (JCOG0212).

BACKGROUND: Mesorectal excision (ME) is the standard surgical procedure for lower rectal cancer. However, in Japan, total or tumor-specific ME with lateral pelvic lymph node dissection (LLND) is the standard surgical procedure for patients with clinical stages II or III lower rectal cancer, because lateral pelvic lymph node metastasis occasionally occurs in these patients. The aim of study was to elucidate the predictive factors of pathological lateral pelvic lymph node metastasis in patients without clinical lateral pelvic lymph node metastasis. METHODS: Data form the clinical trial (JCOG0212) was analyzed. The JCOG0212 was a randomized controlled trial to confirm the non-inferiority of mesorectal excision alone to mesorectal excision with lateral lymph node dissection for clinical stage II/III patients who don't have clinical lateral pelvic lymph node metastasis in terms of relapse free survival. This study was conducted at a multitude of institution33 major hospitals in Japan. Among the 351 patients who underwent lateral lymph node dissection in the JCOG0212 study, 328 patients were included in this study. Associations between pathological lateral pelvic lymph node metastasis and preoperative and postoperative factors were investigated. The preoperative factors were age, sex, clinical stage, tumor location, distance from anal verge, tumor size, and short-axis diameter of lateral pelvic lymph node on computed tomography and the postoperative factors were pathological T, pathological N, and histological grade. RESULTS: Among the 328 patients, 24 (7.3%) had pathological lateral pelvic lymph node metastasis. In multivariable analysis of the preoperative factors, patient age (p = 0.067), tumor location (p = 0.025), and short-axis diameter of lateral pelvic lymph node (p = 0.002) were significantly associated with pathological lateral pelvic lymph node metastasis. CONCLUSIONS: Patient age, tumor location, and short-axis diameter of lateral pelvic lymph node were predictive factors of pathological lateral pelvic lymph node metastasis.

Urinary dysfunction after rectal cancer surgery: Results from a randomized trial comparing mesorectal excision with and without lateral lymph node dissection for clinical stage II or III lower rectal cancer (Japan Clinical Oncology Group Study, JCOG0212).

BACKGROUND: Postoperative urinary dysfunction is a major complication of rectal cancer surgery. A randomized controlled trial (JCOG0212) concluded that the noninferiority of mesorectal excision alone to mesorectal excision with lateral lymph node dissection was not confirmed in terms of relapse-free survival. METHODS: Eligibility criteria included histologically proven clinical stage II/III rectal cancer, a main lesion located in the rectum with the lower margin below the peritoneal reflection, and the absence of lateral lymph node enlargement. After confirming R0 resection by mesorectal excision, patients were randomized intraoperatively. The residual urine volume was measured three times. Urinary dysfunction was defined as ≥50 mL residual urine occurring at least once or no measurement of residual urinary volume. This trial was registered with the UMIN Clinical Trials Registry, number C000000034. RESULTS: In the mesorectal excision alone and the mesorectal excision with lateral lymph node dissection groups, the incidence of early urinary dysfunction were 58% and 59%, respectively. A tumor location in the lower rectum (vs. upper rectum) and a blood loss of ≥500 mL (vs. <500 mL) were associated with an increased risk of early urinary dysfunction. However, only blood loss was independently predictive of early urinary dysfunction (relative risk, 1.25 [95% CI: 1.10-1.55], p = .04). CONCLUSIONS: Mesorectal excision with lateral lymph node dissection is not associated with a significant increase in the incidence of urinary dysfunction. Urinary dysfunction is associated with tumor location and blood loss.

Capecitabine versus S-1 as adjuvant chemotherapy for patients with stage III colorectal cancer (JCOG0910): an open-label, non-inferiority, randomised, phase 3, multicentre trial.

BACKGROUND: Adjuvant chemotherapy with oral fluoropyrimidine alone after D3/D2 lymph node dissection improves disease-free survival and overall survival in patients with stage III colon cancer. Adjuvant S-1 has been shown to be non-inferior to uracil and tegafur plus leucovorin in terms of disease-free survival. This study aims to confirm the non-inferiority of S-1 compared with capecitabine as adjuvant treatment in patients with stage III colorectal cancer. METHODS: This study was an open-label, non-inferiority, randomised, phase 3, multicentre trial done in 56 Japanese centres to assess the non-inferiority of S-1 to capecitabine as adjuvant chemotherapy. Eligible patients were aged 20-80 years with stage III colorectal adenocarcinoma, as defined by the presence of an inferior margin of the primary tumour above the peritoneal reflection; R0 resection; and colectomy with D3 or D2 lymph node dissection. Patients were randomly assigned (1:1) to receive eight courses of capecitabine (1250 mg/m2 orally twice daily, days 1-14, every 21 days) or four courses of S-1 (40 mg/m2 orally twice daily, days 1-28, every 42 days). Randomisation was done via phone call, fax, or web-based systems to the Japan Clinical Oncology Group Data Center and used a minimisation method with a random component adjusted by institution, tumour location (colon vs rectosigmoid and upper rectum), number of positive lymph node metastases (≤3 vs ≥4), and surgical technique (conventional vs non-touch isolation). The primary endpoint was disease-free survival with a non-inferiority margin for the hazard ratio (HR) set at 1·24, analysed by intention to treat. This trial was registered with UMIN Clinical Trial Registry, number UMIN000003272. FINDINGS: Between March 1, 2010, and Aug 23, 2013, 1564 patients were randomly assigned to capecitabine (n=782) or S-1 (n=782), all of whom were included in the efficacy analysis; 777 patients in the capecitabine group and 768 in the S-1 group were included in the safety analysis. At the prespecified second interim analysis after final accrual, 258 (48%) of 535 required events were reported, and the Data and Safety Monitoring Committee recommended early publication because S-1 could not show non-inferiority compared with capecitabine for disease-free survival. With a median follow-up of 23·7 months (IQR 14·1-35·2), 3-year disease-free survival was 82·0% (95% CI 78·5-85·0) for the capecitabine group and 77·9% (74·1-81·1) for the S-1 group (HR 1·23, 99·05% CI 0·89-1·70; one-sided pnon-inferiority=0·46). The most frequent grade 3 or higher adverse events in the capecitabine group were hand-foot skin reactions (123 [16%] of 777 patients), and in the S-1 group were diarrhoea (64 [8%] of 768 patients) and neutropenia (61 [8%]). There was one (<1%) treatment-related death in each group. INTERPRETATION: Adjuvant capecitabine remains one of the standard treatments for stage III colorectal cancer in Japan; S-1 is not recommended. FUNDING: National Cancer Center and Ministry of Health, Labour and Welfare of Japan.

Is There Any Reason to Still Consider Lateral Lymph Node Dissection in Rectal Cancer? Rationale and Technique.

Nodal dissemination in locally advanced rectal cancer occurs mainly in two directions: upward and lateral. Lateral node involvement has been demonstrated; however, lateral lymph node dissection (LLND) is not routinely performed in Western countries and the focus is more on neoadjuvant treatment regimens. The main reasons for this are the high morbidity associated with the operation and the uncertain oncological benefit. There is, however, recent evidence that in selected cases, neoadjuvant treatment combined with total mesorectal excision only might not be sufficient. In this article, the historical developments in the East and the West, the current evidence regarding lateral nodal disease, and the surgical steps in the LLND are discussed.

Japanese genome-wide association study identifies a significant colorectal cancer susceptibility locus at chromosome 10p14.

Genome-wide association studies are a powerful tool for searching for disease susceptibility loci. Several studies identifying single nucleotide polymorphisms (SNP) connected intimately to the onset of colorectal cancer (CRC) have been published, but there are few reports of genome-wide association studies in Japan. To identify genetic variants that modify the risk of CRC oncogenesis, especially in the Japanese population, we performed a multi-stage genome-wide association study using a large number of samples: 1846 CRC cases and 2675 controls. We identified 4 SNP (rs7912831, rs4749812, rs7898455 and rs10905453) in chromosome region 10p14 associated with CRC; however, there are no coding or non-coding genes within this region of fairly extensive linkage disequilibrium (a 500-kb block) on 10p14. Our study revealed that the 10p14 locus is significantly correlated with susceptibility to CRC in the Japanese population, in accordance with the results of multiple studies in other races.

Postoperative Chemoradiotherapy After Local Resection for High-Risk T1 to T2 Low Rectal Cancer: Results of a Single-Arm, Multi-Institutional, Phase II Clinical Trial.

BACKGROUND: After treatment with local excision for TNM stage I low rectal cancer, the risk of local recurrence is not only high for T2 lesions but also for T1 lesions with features of massive invasion to the submucosal layer and/or lymphovascular invasion. OBJECTIVE: The purpose of this study was to determine the efficacy of chemoradiotherapy combined with local excision in the treatment of T1 to T2 low rectal cancer. DESIGN: We conducted a prospective, single-arm, phase II trial. SETTINGS: This was a multicenter study. PATIENTS: From April 2003 to October 2010, 57 patients were treated with local excision after additional external beam irradiation (45 Gy) plus continuous 5-week intravenous injection of 5-fluorouracil (250 mg/m per day) at 10 domestic hospitals. Fifty-three patients had clinical T1N0 lesions, and 4 had T2N0 lesions in the low rectum, located below the peritoneal reflection. MAIN OUTCOMES MEASURES: The primary end point was disease-free survival at 5 years. RESULTS: The completion rate for full-dose chemoradiotherapy was 86% (49/57). Serious, nontransient treatment-related complications were not reported. With a median follow-up of 7.3 years after local excision, the 5-year disease-free survival rate was 94% for the 53 patients with T1 lesions and 75% for the 4 patients with T2 lesions. There were 2 local recurrences during the entire observation period. Anal function after local excision and chemoradiation were kept at almost the same levels as observed before treatment. LIMITATIONS: The study was limited by the small number of registered T2 rectal cancers, retrospective evaluations of quality of life, and the exclusion of poorly differentiated adenocarcinoma (a high-risk feature of T1 lesions). CONCLUSIONS: The addition of chemoradiotherapy to local excision of T1 rectal adenocarcinomas with poor prognostic features including deep submucosal invasion and lymphovascular invasion could improve on less favorable historic oncologic outcomes of local excision alone in this high-risk group for lymph node metastasis. See Video Abstract at http://links.lww.com/DCR/A421.

Prognostic Impact of Intra-abdominal/Pelvic Inflammation After Radical Surgery for Locally Recurrent Rectal Cancer.

BACKGROUND: The influence of postoperative infectious complications, such as anastomotic leakage, on survival has been reported for various cancers, including colorectal cancer. However, it remains unclear whether intra-abdominal/pelvic inflammation after radical surgery for locally recurrent rectal cancer is relevant to its prognosis. OBJECTIVE: The purpose of this study was to evaluate factors associated with survival after radical surgery for locally recurrent rectal cancer. DESIGN: The prospectively collected data of patients were retrospectively evaluated. SETTINGS: This study was conducted at a single-institution tertiary care cancer center. PATIENTS: Between 1983 and 2012, patients who underwent radical surgery for locally recurrent rectal cancer with curative intent at the National Cancer Center Hospital were reviewed. MAIN OUTCOME MEASURES: Factors associated with overall and relapse-free survival were evaluated. RESULTS: During the study period, a total of 180 patients were eligible for analyses. Median blood loss and operation time for locally recurrent rectal cancer were 2022 mL and 634 minutes. Five-year overall and 3-year relapse-free survival rates were 38.6% and 26.7%. Age (p = 0.002), initial tumor stage (p = 0.03), pain associated with locally recurrent rectal cancer (p = 0.03), CEA level (p = 0.004), resection margin (p < 0.001), intra-abdominal/pelvic inflammation (p < 0.001), and surgery period (p = 0.045) were independent prognostic factors associated with overall survival, whereas CEA level (p = 0.01), resection margin (p = 0.002), and intra-abdominal/pelvic inflammation (p = 0.001) were associated with relapse-free survival. Intra-abdominal/pelvic inflammation was observed in 45 patients (25.0%). A large amount of perioperative blood loss was the only factor associated with the occurrence of intra-abdominal/pelvic inflammation (p = 0.007). LIMITATIONS: This study was limited by its retrospective nature and heterogeneous population. CONCLUSIONS: Intra-abdominal/pelvic inflammation after radical surgery for locally recurrent rectal cancer is associated with poor prognosis. See Video Abstract at http://journals.lww.com/dcrjournal/Pages/videogallery.aspx.

Survival outcomes following laparoscopic versus open D3 dissection for stage II or III colon cancer (JCOG0404): a phase 3, randomised controlled trial.

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.

Mesorectal Excision With or Without Lateral Lymph Node Dissection for Clinical Stage II/III Lower Rectal Cancer (JCOG0212): A Multicenter, Randomized Controlled, Noninferiority Trial.

OBJECTIVE: The aim of the study was to confirm the noninferiority of mesorectal excision (ME) alone to ME with lateral lymph node dissection (LLND) in terms of efficacy. BACKGROUND: Lateral pelvic lymph node metastasis is occasionally found in clinical stage II or III lower rectal cancer, and ME with LLND is the standard procedure in Japan. ME alone, however, is the international standard surgical procedure for rectal cancer. METHODS: Eligibility criteria included histologically proven rectal cancer at clinical stage II/III; main lesion located in the rectum, with the lower margin below the peritoneal reflection; no lateral pelvic lymph node enlargement; Peformance Status of 0 or 1; and age 20 to 75 years. Patients were intraoperatively allocated to undergo ME with LLND or ME alone in a randomized manner. The primary endpoint was relapse-free survival, with a noninferiority margin for the hazard ratio of 1.34. Secondary endpoints included overall survival and local-recurrence-free survival. Analysis was by intention to treat. RESULTS: In total, 701 patients were randomized to the ME with LLND (n = 351) and ME alone (n = 350) groups. The 5-year relapse-free survival in the ME with LLND and ME alone groups were 73.4% and 73.3%, respectively (hazard ratio: 1.07, 90.9% confidence interval 0.84-1.36), with a 1-sided P value for noninferiority of 0.0547. The 5-year overall survival, and 5-year local-recurrence-free survival in the ME with LLND and ME alone groups were 92.6% and 90.2%, and 87.7% and 82.4%, respectively. The numbers of patients with local recurrence were 26 (7.4%) and 44 (12.6%) in the ME with LLND and ME alone groups, respectively (P = 0.024). CONCLUSIONS: The noninferiority of ME alone to ME with LLND was not confirmed in the intent-to-treat analysis. ME with LLND had a lower local recurrence, especially in the lateral pelvis, compared to ME alone.

Characteristics and Clinical Outcomes of Duodenal Neoplasia in Japanese Patients With Familial Adenomatous Polyposis.

BACKGROUND: After colorectal cancer and desmoid tumors, duodenal adenocarcinoma is the next leading cause of death in familial adenomatous polyposis (FAP) patients, but it has not been thoroughly investigated. PATIENTS AND METHODS: To investigate the clinical course of duodenal neoplasia, including adenoma and cancer, we investigated 77 Japanese FAP patients treated at the National Cancer Center Hospital, Tokyo, Japan. We evaluated the clinicopathologic features, Spigelman severity score, and management of duodenal neoplasms. Data were acquired from a prospectively enrolled database. RESULTS: Fifty-one (66%) of the 77 FAP patients had duodenal neoplasia during this observational period, and 47 of 51 patients had extra-ampulla duodenal neoplasia; 42 (58%) had duodenal neoplasms (extra-ampulla), 4 had duodenal adenomas with high-grade dysplasia (HGD), and 1 had invasive carcinoma. Among the 45 patients (extra-ampulla) with duodenal adenoma with HGD or low-grade dysplasia, 8 (18%) patients were treated using endoscopic resection (ER). During the short observation period, ER was performed only in HGD cases. None of the patients died from duodenal neoplasia. In total, during the surveillance period, duodenal HGD was detected in 5 (63%) of 8 patients graded as Spigelman stage IV; HGD was not detected in stage 0 (n=33), I (n=0), II (n=12), or III (n=20) patients. CONCLUSIONS: Short-interval endoscopic surveillance and appropriate ER may help prevent duodenal invasive carcinoma. In addition, there was little development of invasive carcinoma during the follow-up. The Spigelman classification is beneficial for the risk assessment of duodenal neoplasia in Japanese FAP patients.

Relationship between smoking and multiple colorectal cancers in patients with Japanese Lynch syndrome: a cross-sectional study conducted by the Japanese Society for Cancer of the Colon and Rectum.

The positive correlation between smoking and cancer risk is well estimated in sporadic colorectal cancer, whereas little is known with regard to Lynch syndrome-associated colorectal cancer. A total of 118 familial colorectal cancer patients from the Hereditary Nonpolyposis Colorectal Cancer Registry and Genetic Testing Project of the Japanese Society for Cancer of the Colon and Rectum, were assessed to determine whether smoking alters the incidence of multiple colorectal cancers. In male patients with Lynch syndrome (n = 29), the incidence of multiple colorectal cancers in patients who had ever smoked (smoking duration: median of 19 years) was higher than that in those who never smoked (58.8% vs. 10.0%, P = 0.02). The cumulative risk for metachronous colorectal cancer was significantly higher in male Lynch syndrome patients who had previously smoked than in those who had never smoked (P = 0.03). Our data suggest that long-term cigarette smoking might be a strong risk factor for the development of multiple colorectal cancers in male Lynch syndrome patients.

Comparison of clinical features between suspected familial colorectal cancer type X and Lynch syndrome in Japanese patients with colorectal cancer: a cross-sectional study conducted by the Japanese Society for Cancer of the Colon and Rectum.

OBJECTIVE: The characteristics of familial colorectal cancer type X are poorly defined. Here we aimed to clarify the differences in clinical features between suspected familial colorectal cancer type X and Lynch syndrome in Japanese patients. METHODS: We performed germline mutation analyses of mismatch repair genes in 125 patients. Patients who met the Amsterdam Criteria I but lacked mismatch repair gene mutations were diagnosed with suspected familial colorectal cancer type X. RESULTS: We identified 69 patients with Lynch syndrome and 25 with suspected familial colorectal cancer type X. The frequencies of gastric and extracolonic Lynch syndrome-associated cancers were lower with suspected familial colorectal cancer type X than with Lynch syndrome. The number of organs with Lynch syndrome-associated cancer was significantly lower with suspected familial colorectal cancer type X than with Lynch syndrome. The cumulative incidence of extracolonic Lynch syndrome-associated cancer was significantly lower with suspected familial colorectal cancer type X than with Lynch syndrome. We estimated that the median cancer risk in 60-year-old patients with Lynch syndrome was 89, 36 and 24% for colorectal, endometrial and gastric cancers, respectively. Analyses of family members, including probands, revealed that the median age at diagnosis of extracolonic Lynch syndrome-associated cancer was significantly older with suspected familial colorectal cancer type X than with Lynch syndrome. The frequency of extracolonic Lynch syndrome-associated cancer was significantly lower with suspected familial colorectal cancer type X than with Lynch syndrome. CONCLUSION: A significant difference in extracolonic Lynch syndrome-associated cancer was evident between suspected familial colorectal cancer type X and Lynch syndrome.

A phase I trial of preoperative S-1 in combination with oxaliplatin and pelvic radiation for lower rectal cancer with T4 and lateral pelvic lymph node metastasis.

BACKGROUND: The purpose of this phase I study of the dose escalation of oxaliplatin in combination with oral S-1 and pelvic radiation preoperatively for poor-risk lower rectal cancer was to determine the dose-limiting toxicity (DLT) and recommended dose of oxaliplatin. METHODS: Patients with cT4 and lateral pelvic lymph node metastasis, and without distant metastasis (cM0), were treated with weekly oxaliplatin, oral S-1 40 mg/m(2) twice daily for 5 days a week, and radiation. A total of 5 weekly doses of oxaliplatin were planned. RT was administered to a total dose of 50.4 Gy in 28 fractions. RESULTS: We enrolled 11 patients between December 2009 and January 2012. DLTs were observed at dose level 1 (50 mg/m(2)) in two patients, one of whom experienced grade 3 aspartate aminotransferase elevation and a grade 3 alanine aminotransferase increase, and the other developed grade 4 hypokalemia and a grade 3 alanine aminotransferase increase. Five patients at dose level 2 (60 mg/m(2)) showed no DLTs. The hematological toxicities in all patients were mild and reversible. One patient showed distant metastasis after chemoradiation. Ten of the 11 patients achieved R0 resection by mesorectal resection and lateral lymph node dissection; three of the 10 underwent combined resection of the other organs. CONCLUSION: This phase I trial of preoperative S-1 in combination with oxaliplatin and radiation for lower rectal cancer with T4 and lateral pelvic lymph node metastasis revealed that the recommended dose of oxaliplatin was 60 mg/m(2) weekly.