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Aim Accurate preoperative diagnosis of lateral lymph node metastasis (LLNM) from lower rectal cancer is important to identify patients who require lateral lymph node dissection (LLND). We aimed to create an effective prediction model for LLNM using machine learning by combining preoperative information. Methods We retrospectively examined patients who underwent primary rectal cancer surgery with unilateral or bilateral LLND between April 2010 and March 2020 at a single institution. Using the machine learning software “Prediction One” (Sony Network Communications), we developed a prediction model in the training cohort that included 267 consecutive patients (500 sides) from April 2010. Clinicopathological data obtained from the preoperative examinations were used as the learning items. In the validation cohort that included subsequent patients until March 2020, we compared the discriminating powers of the prediction model and the conventional method using the short‐axis diameter of the largest lateral lymph node, as detected on magnetic resonance imaging. Results The area under the receiver operating characteristic curve (AUC) of the prediction model was 0.903 in the validation cohort comprising 56 patients (107 sides). This indicated significantly higher predictive power than that of the conventional method (AUC = 0.754; P = .022). Using the cutoff values defined in the training cohort, the accuracy, sensitivity, and specificity of the prediction model were 80.4%, 90.0%, and 79.4%, respectively. The model was able to correctly predict four of five sides comprising LLNM with the short‐axis diameters ≤4 mm. Conclusion Machine learning contributed to the creation of an effective prediction model for LLNM., Accurate preoperative diagnosis of lateral lymph node metastasis from lower rectal cancer is important to identify patients who require lateral lymph node dissection. Machine learning based on deep learning contributed to the creation of an effective prediction model for lateral lymph node metastasis.

PURPOSE 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. PATIENTS AND METHODS 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. RESULTS 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. CONCLUSION 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 There are no established treatment strategies for patients with hepatic and pulmonary metastases at the time of primary colorectal cancer (CRC) diagnosis. This study assessed patients undergoing complete resection of primary CRC and hepatic and pulmonary metastases, to evaluate long-term outcomes and clarify clinicopathological factors associated with failure of complete resection. Methods This retrospective analysis enrolled patients at Shizuoka Cancer Center between 2002 and 2018 who underwent colorectal resection with curative intent for primary CRC with hepatic and pulmonary metastases. The curative resection (CR) group comprised patients who underwent complete resection of the primary tumor and metastatic lesions, and the non-curative resection (Non-CR) group consisted of those in whom resection of the metastatic lesions was not performed. Univariate and multivariate analyses were conducted to determine clinicopathological factors associated with non-curative resection. Results Of 26 total patients, the CR and Non-CR groups consisted of 14 (54%) and 12 patients (46%), respectively. In the CR group, the 3-year overall and relapse-free survival rates were 92.9% and 28.6%, respectively. Multivariate analysis showed that pathological stage T4 (odds ratio 8.58, 95% confidence interval 1.13-65.20, p = 0.04) was independently associated with non-curative resection. Conclusion The percentage of patients undergoing complete resection of primary CRC and metastatic lesions was 56%, and the 3-year OS rate was 92.9%. Resection of primary CRC and metastatic lesions was considered to be appropriate in this population, and pathological stage T4 tumor was associated with incomplete resection of metastatic tumors.

Aim Recent reports have described the use and efficacy of several types of transanal tube (TAT) for preventing anastomotic leakage by reducing intraluminal pressure. The aim of this study was to evaluate the safety and efficacy of a newly developed TAT for the prevention of anastomotic leakage after low anterior resection (LAR) for rectal cancer. Method A multicentre confirmatory single-arm trial was designed to evaluate the safety and efficacy of a new TAT after LAR for rectal cancer. A total of 115 patients were registered in the trial at several cancer centres and other hospitals. All patients initially received reconstruction with a stapled anastomosis, but 18 then underwent creation of a diverting stoma. Of the remaining 97 patients, the first 96 were included in the protocol-defined primary analysis set. The primary outcome was the incidence of symptomatic leakage and the secondary endpoint was the incidence of complications associated with use of the TAT. The TAT was placed during LAR without creating a covering stoma and the drain was removed 4 or 5 days postoperatively. Results The rate of symptomatic leakage was 5.2% (95% confidence interval 1.7-11.7), which was significantly lower than the predetermined threshold value of 15.8% (one-sided p-value 0.0013). Only one patient had Grade 3 rectal bleeding that might have been related to use of the TAT. Conclusion This nonrandomized study shows that the TAT appears to be safe and results in lower rates of anastomotic leakage in LAR compared with previous studies.

Lateral lymph node (LLN) metastasis is a determinant of local recurrence in advanced low rectal cancer. Lateral lymph node dissection (LLND) is effective in removing metastatic lymph nodes, and has been shown to have a decreased local recurrence rate. However, because of its complexity and complications it induces, there is still tremendous controversy about its usage. Neoadjuvant chemoradiotherapy (nCRT) and total mesorectal excision (TME) are recommended as a conventional treatment for advanced rectal cancer. However, LLN metastasis and local recurrence still occur despite nCRT with TME. In Japan, TME with LLND is the standard surgical treatment for Stage II/III of advanced low rectal cancer. Before surgery, a proper evaluation of LLN status should be performed. Laparoscopic LLND and robotic-assisted LLND are useful for this. More research is necessary to improve the oncological outcomes of LLND. In this review, we retrospectively examine previous reports about LLND, aiming to emphasize its application prospects to improve patient survival and life quality.

We present a very rare case of rectal cancer in a patient with situs inversus totalis (SIT), which is a complete transposition of the thoracic and abdominal viscera. A woman in her 60s visited a local hospital reporting bloody stool and was diagnosed with upper rectal cancer and SIT. We made careful preoperative preparations for the congenital anomaly, and robotic-assisted high anterior resection with D3 lymph node dissection was performed. Although we adopted an unusual six-port placement, the operation was performed safely and efficiently without any adverse events. The patient recovered uneventfully. The pathological specimen was classified as pT3N2bM0 with negative resection margins. Robotic-assisted surgery is advantageous for rectal cancer treatment even when anatomical abnormalities make the surgical procedure more difficult.

Background: Tumor mutation burden (TMB) is the total exonic mutation count per megabase of tumor DNA. Recent advances in precision medicine occasionally detect Lynch syndrome (LS) by germline sequencing for mismatch-repair (g.MMR) genes but not using TMB. The current study analyzes the utility of TMB in detecting LS. Methods: Whole-exome sequencing (ion-semiconductor sequencing) was performed for somatic and germline DNA from 2,501 various cancer patients to detect TMB and g.MMR sequencing. MMR IHC was conducted when high TMB (≥10) was detected in LS-related cancers with an additional condition of wild-type BRAF in colorectal cancers. Target sequencing and multiplex ligation-dependent probe amplification (MLPA) were further performed for g.MMR genes in MMR-deficient cancers (TMB-based g.MMR target sequencing). We compared universal sequencing and TMB-based target sequencing in their sensitivity for detecting LS. Results: LS was detected in 16 (0.6%) of the 2,501 patients: 1.1% (9/826) of colorectal cancer patients, 16.2% (6/37) of endometrial cancer patients, and 14.3% (1/7) of small intestine cancer patients. TMB-based g.MMR target sequencing (81.3%) showed superior sensitivity for detecting LS than universal g.MMR sequencing (56.3%; P = 0.127) but missed 3 LS patients (1 with a low-TMB cancer, 1 with a BRAF-mutant colorectal cancer, and 1 with an MMR-proficient cancer). Ion-semiconductor sequencing could detect single-nucleotide substitutions but not large deletions. POL-mutated cancers showed extremely high TMBs (48.4–749.2). Conclusions: g.MMR target sequencing, combined with TMB, somatic BRAF mutation, and MMR IHC is an effective strategy for detecting LS. Impact: TMB can be a biomarker for detecting LS in precision medicine.

The aim of the study was to investigate the effect of chemo-radiation on the genetic and immunological status of rectal cancer patients who were treated with preoperative chemoradiotherapy (CRT). The expression of immune response-associated genes was compared between rectal cancer patients treated (n = 9) and not-treated (n = 10) with preoperative CRT using volcano plot analysis. Apoptosis and epithelial-to-mesenchymal transition (EMT) marker genes were analysed by quantitative PCR (qPCR). Other markers associated with the tumor microenvironment (TME), such as tumor-infiltrating lymphocytes (TIL) and immune checkpoint molecules, were investigated using immunohistochemistry (IHC). The clinical responses of preoperative CRT for 9 rectal cancer patients were all rated as stable disease, while the pathological tumor regression score (TRG) revealed 6 cases of grade2 and 3 cases of grade1. According to the genetic signature of colon cancers, treated tumors belonged to consensus molecular subtype (CMS)4, while not-treated tumors had signatures of CMS2 or 3. CRT-treated tumors showed significant upregulation of EMT-associated genes, such as CDH2, TGF-beta and FGF, and cancer stem cell-associated genes. Additionally, qPCR and IHC demonstrated a suppressive immunological status derived from the upregulation of inflammatory cytokines (IL-6, IL-10 and TGF-beta) and immune checkpoint genes (B7-H3 and B7-H5) and from M2-type macrophage accumulation in the tumor. The induction of EMT and immune-suppressive status in the tumor after strong CRT treatment urges the development of a novel combined therapy that restores immune-suppression and inhibits EMT, ultimately leading to distant metastasis control.

If patients with surgically resectable colorectal cancershave synchronous colorectal neoplasms that are difficult to remove by endoscopic mucosal resection, preemptive endoscopic submucosal dissection (ESD) can avoid excessive colorectal resection. The aim of this study was to evaluate the efficacy of the strategy of preemptive ESD and surgery for synchronous colorectal neoplasms.Patients who underwent preemptive ESD and surgery for synchronous colorectal neoplasms between September 2002 and December 2017 were enrolled in this retrospective cohort study. The proportion of cases in which extended surgery could be avoided following curative ESD was calculated. Clinicopathological characteristics were evaluated for all patients and long-term outcomes were analyzed for patients who underwent curative ESD and surgery.A total of 45 consecutive patients with 47 endoscopically-resected lesions and 46 surgically-resected lesions were retrospectively evaluated. Curative ESD was achieved in 44 lesions (93.6%) and an extended surgical procedure could be avoided in 42 patients (93.3%). Intraoperative perforation occurred in two lesions (4.3%), delayed perforation in one lesion (2.1%), and delayed bleeding in two lesions (4.3%). Final stages were as follows: stage 0, 3 patients (7.1%); stage I, 23 patients (54.8%); stage II, 3 patients (7.1%); stage III, 12 patients (28.6%); and stage IV, 1 patient (2.4%). The 5-year overall survival rates of patients with all pathological stages, stage 0-II, and stage III-IV were 93.7%, 100%, and 79.1%, respectively.The strategy of preemptive ESD and surgery for synchronous colorectal neoplasms is minimally invasive and has a favorable prognosis.

Summary: Background/objective: Paraaortic lymph node (PALN) metastasis influences treatment strategy for colorectal cancer. The aims of this study were to elucidate the diagnostic value of computed tomography (CT) and positron emission tomography (PET) for PALN metastasis from left-sided colorectal cancer. Methods: A total of 108 patients who underwent radical surgery including PALN dissection were included. Size and morphology of PALN were evaluated using CT, and presence of higher FDG uptake was evaluated using PET. Findings of CT and PET were compared with pathological status. Results: The largest major axis ≥11 mm and heterogeneous internal density were predictive factors on multivariate analysis. Eighty five percent of the PALNs ≥11 mm with heterogeneous internal density were pathologically metastatic, whereas 94.1% without them were not metastatic. PET had an accuracy, sensitivity, and specificity of 85.7%, 66.7%, and 94.1%, respectively. In patients with PALNs

Urinary dysfunction (UD) remains a significant complication of rectal cancer surgery. In modern surgical treatment for rectal cancer, multiple operative approaches are used. Such approaches include open, laparoscopic, and robotic-assisted surgery; and multiple procedures, including anterior, intersphincteric, and abdominoperineal resection. Thus, modern surgical treatments for rectal cancer have diversified. This study aimed to identify risk factors for early UD (EUD) after total mesorectal excision (TME) and to explore the methods for decreasing postoperative EUD in diverse surgical treatments for rectal cancer. In our retrospective cohort study, we enrolled patients with lower rectal cancer who underwent TME alone at a single high-volume cancer center between 2010 and 2017. EUD was defined as the presence of ≥ 50 mL residual urine volume. Multivariate analysis was performed to determine clinicopathological factors significantly associated with postoperative EUD. Of a total of 337 eligible patients, 32 patients (10%) had postoperative EUD. Multivariate analysis revealed that only the operative approach (laparoscopic surgery: odds ratio [OR], 8.93; 95% confidence interval [CI], 2.94–27.14, open surgery: OR, 11.55; 95% CI 2.10–63.83) was significantly associated with an increase in postoperative EUD. Robotic-assisted surgery was associated with significant reduction in postoperative EUD. Only robotic-assisted surgery was inversely correlated with postoperative EUD. Robotic-assisted surgery may be a useful approach to protect urinary function in lower rectal cancer surgery.

Aim To compare the surgical outcomes of laparoscopic colectomy (LAC) with Japanese D3 dissection for descending colon cancer (DCC) with those of open colectomy (OC). Patients and methods Seventy-two patients who underwent OC or LAC with D3 dissection for clinical stage II/III DCC between September 2002 and June 2019 were evaluated in terms of short-term outcomes. The long-term outcomes of the 59 patients who underwent surgery between September 2002 and June 2016 were evaluated. Results Twenty-six patients underwent OC and 46 patients underwent LAC. The blood loss was significantly less in the LAC group. The complication rate was similar in both groups. The rates of 5-year overall survival (95.8% in the OC group vs. 89.9% in the LAC group) and relapse-free survival (79.2% in the OC group vs. 82.1% in the LAC group) were similar in both groups. Conclusion LAC is an acceptable treatment option for stage II/III DCC.

Project High-tech Omics-based Patient Evaluation (HOPE), which used whole-exome sequencing and gene expression profiling, was launched in 2014. A total of ~2,000 patients were enrolled until March 2016, and the survival time was observed up to July 2019. In our previous study, a tumor microenvironment immune type classification based on the expression levels of the programmed death-ligand 1 (PD-L1) and CD8B genes was performed based on four types: A, adaptive immune resistance; B, intrinsic induction; C, immunological ignorance; and D, tolerance. Type A (PD-L1+ and CD8B+) exhibited upregulated features of T helper 1 antitumor responses. In the present study, survival time analysis at 5 years revealed that patients in type A had a better prognosis than those in other categories [5 year survival rate (%); A (80.5) vs. B (73.9), C (73.4) and D (72.6), P=0.0005]. Based on the expression data of 293 immune response-associated genes, 62 specific genes were upregulated in the type A group. Among these genes, 18 specific genes, such as activated effector T-cell markers (CD8/CD40LG/GZMB), effector memory T-cell markers (PD-1/CD27/ICOS), chemokine markers (CXCL9/CXCL10) and activated dendritic cell markers (CD80/CD274/SLAMF1), were significantly associated with a good prognosis using overall survival time analysis. Finally, multivariate Cox proportional hazard regression analyses of overall survival demonstrated that four genes (GZMB, HAVCR2, CXCL9 and CD40LG) were independent prognostic markers, and GZMB, CXCL9 and CD40LG may contribute to the survival benefit of patients in the immune type A group.

Background Sphincter-preserving operations for ultra-low rectal cancer include low anterior resection and intersphincteric resection. In low anterior resection, the distal rectum is divided by a transabdominal approach, which is technically demanding. In intersphincteric resection, a perineal approach is performed. We aimed to evaluate whether robotic-assisted surgery is technically superior to laparoscopic surgery for ultra-low rectal cancer. The frequency of conducting low anterior resection by a specific procedure can indicate the technical superiority of that procedure for ultra-low rectal cancer. Thus, we compared the frequency of low anterior resection between robotic-assisted and laparoscopic surgery in cases of sphincter-preserving operations. Methods We investigated 183 patients who underwent sphincter-preserving robotic-assisted or laparoscopic surgery for ultra-low rectal cancer (lower border within 5 cm of the anal verge) between April 2010 and March 2020. The frequency of low anterior resection was compared between laparoscopic and robotic-assisted surgeries. The clinicopathological factors associated with an increase in performing low anterior resection were analyzed by multivariate analyses. Results Overall, 41 (22.4%) and 142 (77.6%) patients underwent laparoscopic and robotic-assisted surgery, respectively. Patient characteristics were similar between the groups. Low anterior resection was performed significantly more frequently in robotic-assisted surgery (67.6%) than in laparoscopic surgery (48.8%) (p = 0.04). Multivariate analyses showed that tumor distance from the anal verge (p

Background. The optimal radical surgical approach for rectal neuroendocrine tumor (NET) is unknown. Methods. This study evaluated the short- and long-term outcomes of 27 patients who underwent robotic radical surgery for rectal NET between 2011 and 2019. Results. The median distance from the lower border of the tumor to the anal verge was 5.0 cm. The median tumor size was 9.5 mm. Six patients (22%) had lymph node metastasis. The incidences of postoperative complications of grade II and grade III or more according to the Clavien–Dindo classification were 11% and 0%, respectively. All patients underwent sphincter-preserving surgery, and no patients required conversion to open surgery. The median follow-up time was 48.9 months, and both the 3-year overall survival and relapse-free survival rates were 100%. Conclusions. Short- and long-term outcomes of robotic surgery for rectal NET tumor were favorable. Robotic surgery may be a useful surgical approach for rectal NET.

An 85‐year‐old woman was admitted to a hospital with abdominal pain. Five years prior to admission, she had a history of hilar cholangiocarcinoma of pStage IIIC. Contrast‐enhanced computed tomography showed a mass between the rectum and uterus as well as bowel obstruction due to the lesion. Colonoscopy showed severe stenosis at the lower rectum and elevation of the submucosal layer with linear erosion. Rectal cancer was suspected, and pelvic recurrence of hilar cholangiocarcinoma or endometrial carcinoma infiltrating the rectum was considered as differential diagnosis. She underwent robot‐assisted low anterior resection combined with partial resection of the uterus. The immunohistopathological findings of the resected specimen favored a diagnosis of metastasis of cholangiocarcinoma, rather than primary rectal cancer or endometrial carcinoma. There were no signs of recurrence after 10 months of follow‐up. Hilar cholangiocarcinoma is a disease with poor prognosis. Recurrence is frequently experienced even after curative resection. Patients with recurrence are rarely candidates for re‐resection. However, better prognosis is reported for those with complete resection., Hilar cholangiocarcinoma is a disease with poor prognosis; recurrences are frequently experienced even after curative resection. However, very few reports focus on resection of the recurrence site. We herein report a unique case of rectal stenosis due to solitary pelvic recurrence of cholangiocarcinoma which was successfully resected.

Although a “no-touch isolation” technique is used in colorectal cancer surgery to reduce the risk of metastatic induction, endoscopic resection (ER) prior to surgery may work against this aim. This study evaluated the effects of initial ER on short- and long-term outcomes in T1 colorectal cancer. This retrospective cohort study enrolled patients with pathological T1 colorectal cancer who underwent colorectal surgical resection at a Japanese tertiary cancer center between 2002 and 2012. A total of 548 eligible patients were divided into two groups: patients initially treated using surgical resection with lymph node dissection (LND) (primary group, n = 304) and patients treated using initial ER and additional surgical resection with LND (secondary group, n = 244). The inverse probability of treatment weighting (IPTW) method based on propensity score was used to compare postoperative complications and long-term recurrence. The incidence of postoperative complications with Clavien–Dindo classification grade ≥ II was 10.9% and 7.4% in the primary and secondary groups, respectively (p = 0.16). Multivariate analysis with a logistic proportional hazard regression model using IPTW revealed no significant differences in postoperative complications between the two groups (p = 0.79). During a median follow-up after surgery of 61.4 months, recurrence was observed in 3 (1.0%) and 8 (3.3%) patients, respectively (p = 0.06). Multivariate analysis with a Cox proportional hazard regression model using IPTW revealed no significant differences in recurrence between the two groups (p = 0.07). Our results suggest no significant adverse effects of initial ER prior to surgery on surgical complications and long-term recurrence in T1 colorectal cancer.

Mutually exclusive KIT and PDGFRA mutations are considered to be the earliest events in gastrointestinal stromal tumors (GIST), but insufficient for their malignant progression. Herein, we aimed to identify driver genes and signaling pathways relevant to GIST progression. We investigated genetic profiles of 707 driver genes, including mutations, gene fusions, copy number gain or loss, and gene expression for 65 clinical specimens of surgically dissected GIST, consisting of six metastatic tumors and 59 primary tumors from stomach, small intestine, rectum, and esophagus. Genetic alterations included oncogenic mutations and amplification‐dependent expression enhancement for oncogenes (OG), and loss of heterozygosity (LOH) and expression reduction for tumor suppressor genes (TSG). We assigned activated OG and inactivated TSG to 27 signaling pathways, the activation of which was compared between malignant GIST (metastasis and high‐risk GIST) and less malignant GIST (low‐ and very low‐risk GIST). Integrative molecular profiling indicated that a greater incidence of genetic alterations of driver genes was detected in malignant GIST (96%, 22 of 23) than in less malignant GIST (73%, 24 of 33). Malignant GIST samples groups showed mutations, LOH, and aberrant expression dominantly in driver genes associated with signaling pathways of PI3K (PIK3CA, AKT1, and PTEN) and the cell cycle (RB1, CDK4, and CDKN1B). Additionally, we identified potential PI3K‐related genes, the expression of which was upregulated (SNAI1 and TPX2) or downregulated (BANK1) in malignant GIST. Based on our observations, we propose that inhibition of PI3K pathway signals might potentially be an effective therapeutic strategy against malignant progression of GIST., Signaling pathways involved in 65 GIST samples were investigated. Pathways were curated by genetic alterations, including oncogenic mutations and amplification‐dependent expression enhancement for oncogenes, and loss of heterozygosity and expression reduction for tumor suppressor genes. Malignant GIST with metastasis and high‐risk showed mutations, LOH, and aberrant expression dominantly in driver genes associated with signaling pathways of PI3K and the cell cycle.

Objectives To evaluate the relationships between adenine-thymine-rich interactive domain 1A (ARID1A) expression and the clinicopathologic features in T1 colorectal cancer (CRC) and to investigate whether the presence of ARID1A protein is related to genetic changes. Methods We retrospectively studied 219 surgically resected T1 CRCs. ARID1A expression was assessed by immunohistochemical methods, and the correlation between ARID1A expression and clinicopathologic features was evaluated. The relationship between ARID1A expression and 409 cancer-related gene mutations was also evaluated using next-generation sequencing (NGS). Results Immunohistochemical staining indicated negative ARID1A expression in 4.6%. Loss of ARID1A expression was significantly associated with younger age, lymphatic invasion, and lymph node metastasis (LNM). NGS showed that PKHD1, RNF213, and MSH6 mutations were more frequent in ARID1A-negative tumors, whereas KRAS mutations were more common in ARID1A-positive tumors. Conclusions In T1 CRC, negative ARID1A expression was correlated with early onset, lymphatic invasion, and LNM. Mutations in some cancer-related genes were possibly related with ARID1A expression.

Here, we investigated the clinicopathological and mutation profiles of colorectal cancer (CRC) with POLE mutations. Whole‐exome sequencing was performed in 910 surgically resected primary CRCs. Tumors exceeding 500 counts of nonsynonymous single nucleotide variants (SNVs) were classified as hypermutators, whereas the remaining were classified as nonhypermutators. The hypermutators were subdivided into 2 groups. CRCs harboring more than 20% C‐to‐A and less than 3% C‐to‐G transversions were classified as POLE category tumors, whereas the remaining were classified as common‐hypermutators. Gene expression profiling (GEP) analysis was performed in 892 (98.0%) tumors. Fifty‐seven (6.3%) and 10 (1.1%) tumors were classified common‐hypermutators and POLE category tumors, respectively. POLE category tumors harbored a significantly higher SNV count than common‐hypermutators, and all POLE category tumors were associated with exonuclease domain mutations, such as P286R, F367C, V411L, and S297Y, in the POLE gene. Patients with POLE category tumors were significantly younger than those with nonhypermutators and common‐hypermutators. All POLE mutations in the early‐onset (age of onset ≤50 years old) POLE category (7 tumors) were P286R mutations. GEP analysis revealed that PD‐L1 and PD‐1 gene expression levels were significantly increased in both common‐hypermutators and POLE category tumors compared with those in nonhypermutators. CD8A expression was significantly upregulated in POLE category tumors compared with that in nonhypermutators. Thus, we concluded that CRCs with POLE proofreading deficiency had characteristics distinct from those of other CRCs. Analysis of POLE proofreading deficiency may be clinically significant for personalized management of CRCs.

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.

Background: In node-positive colon cancer, the impact of MLN size on prognosis is controversial. The aim of this study was to clarify the impact of metastatic lymph node (MLN) size on long-term outcomes in patients undergoing curative resection for pStage III colon cancer.Methods: This study enrolled patients who underwent curative colectomy for pStage III colon cancer between January 2013 and December 2015. All eligible patients were divided into four groups based on the short-axis diameter of the largest MLN: Group A, < 5 mm; Group B, ≥ 5 mm and < 10 mm; Group C, ≥ 10 mm and < 15 mm; and Group D, ≥ 15 mm. We performed univariate and multivariate analysis using Cox proportional hazard regression models to identify clinicopathological factors affecting recurrence-free survival (RFS).Results: A total of 209 patients were analyzed. We evaluated 7305 LNs, of which 644 were metastatic. The 5-year RFS rates of Groups A, B, C, and D were 82.3%, 74.6%, 74.5%, and 60.7%, respectively. In univariate analysis, age older than 70 years, Group D (largest MLN ≥ 15 mm), and the absence of adjuvant chemotherapy were significantly associated with RFS. In multivariate analysis, Group D (hazard ratio [HR], 3.95; 95% confidence interval [CI], 1.34–11.65; p=0.01) and the absence of adjuvant chemotherapy (HR, 2.44; 95% CI, 1.26-4.72; pConclusion: A maximum MLN ≥ 15 mm was significantly associated with worse RFS in stage III colon cancer. Bulky MLNs might be a poor prognostic factor in node-positive colon cancer.

A depth of submucosal invasion (DSI) of ≥1000 μm is an important risk factor for lymph node metastasis (LNM) in patients with submucosal invasive (pT1) colorectal cancer (CRC), according to the European Society of Gastrointestinal Endoscopy and the Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines. According to the latter, if the location of the muscularis mucosae in the invasive area is not confirmed, the DSI can be measured from the surface. In these cases, a ‘remaining intramucosal lesion’ (rIL), which is in the invasive area, is sometimes observed. To avoid over-measuring the DSI, we proposed a ‘modified DSI’ (mDSI), which excludes the rIL from the JSCCR DSI. We investigated the characteristics and effectiveness of the rIL and mDSI by grouping cases with polypoid growth (PG) and non-polypoid growth (NPG) histologically. Three hundred and thirty-nine consecutive patients with pT1 CRC were examined. LNM was detected in 37 cases. The distribution of the DSI and rIL was significantly higher in PG than in NPG cases (P

Recent studies have revealed that colorectal cancer (CRC) displays intratumor genetic heterogeneity, and that the cancer microenvironment plays an important role in the proliferation, invasion and metastasis of CRC. The present study performed genomic analysis on paired primary CRC and synchronous colorectal liver metastasis (CRLM) tissues collected from 22 patients using whole-exome sequencing, cancer gene panels and microarray gene expression profiling. In addition, immunohistochemical analysis was used to confirm the protein expression levels of genes identified as highly expressed in CRLM by DNA microarray analysis. The present study identified 10 genes that were highly expressed in CRLM compared with in CRC, from 36,022 probes obtained from primary CRC, CRLM and normal liver tissues by gene expression analysis with DNA microarrays. Of the 10 genes identified, five were classified as encoding 'matricellular proteins' [(osteopontin, periostin, thrombospondin-2, matrix Gla protein (MGP) and glycoprotein nonmetastatic melanoma protein B (GPNMB)] and were selected for immunohistochemical analysis. Osteopontin was strongly expressed in CRLM (6 of 22 cases: 27.3%), but not in CRC (0 of 22: 0%; P=0.02). Periostin also exhibited strong immunoreactivity in CRLM (17 of 22: 68.2%) compared with in CRC (7 of 22: 31.8%; P=0.006). Thrombospondin-2 exhibited strong immunoreactivity in both CRC and CRLM (54.5% in CRC, 45.5% in CRLM; P=0.55). GPNMB and MGP were rarely positive for both CRC and CRLM. A comparison of immunoreactive positive factors for these five genes revealed the complexities of gene expression in CRLM. Of the cases examined, 16 (72.7%) cases of CRC showed zero or only one positive immunoreactive factor. By contrast, CRLM showed more frequent and multiple immunoreactive factors; for example, 16 cases (72.7%) shared two or more factors, which was statistically more frequent than in CRC (P=0.007). The present study revealed the genomic heterogeneity between paired primary CRC and CRLM, in terms of cancer cell microenvironment. This finding may lead to novel diagnostic and therapeutic targets in the era of genome-guided personalized cancer treatment.

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.

Although robotic surgery for rectal cancer can overcome the shortcomings of laparoscopic surgery, studies focusing on abdominoperineal resection are limited. The aim of this study was to compare the operative outcomes between robotic and laparoscopic abdominoperineal resection. This retrospective cohort study was conducted from April 2010 to March 2020. Patients with rectal cancer who underwent robotic or laparoscopic abdominoperineal resection without lateral lymph node dissection were enrolled. The perioperative and oncological outcomes were compared. We evaluated 33 and 20 patients in the robotic and laparoscopic groups, respectively. The median operative time and blood loss were comparable between the two groups. No significant differences in the overall complication rates were noted, whereas the rates of urinary dysfunction (3% vs. 26%, p = 0.02) and perineal wound infection (9% vs. 35%, p = 0.03) in the robotic group were significantly lower in comparison to the laparoscopic group. The median postoperative hospital stay was significantly shorter in the robotic group (8 days vs. 11 days, p

Background: There are no standardised criteria for the determination of the ‘regional’ pericolic node in colon cancer surgery, which represents a major cause of the international uncertainty regarding the optimal bowel resection margin. This prospective cohort study aimed to determine ‘regional’ pericolic nodes based on detailed mapping for feeding arteries and lymph nodes. Methods: In all, 2,996 patients with stages I–III colon cancer who underwent curative surgery between June 2013 and December 2017 at 25 institutions in Japan were included. The anatomical distributions of the feeding artery and lymph nodes were determined in resected fresh surgical specimens based on in vivo measurements of the bowel. Findings: The mean number of retrieved pericolic nodes was 20·9 per patient. In all patients except seven (0·2%), the primary feeding artery was distributed within 10 cm of the primary tumour. The metastatic pericolic node location most distant from the primary tumour was within 3 cm in 837 patients, 3–5 cm in 130 patients, 5–7 cm in 39 patients and 7–10 cm in 34 patients. Only four patients (0·1%) had pericolic lymphatic spread beyond 10 cm; all of whom had T3/4 tumours accompanying extensive mesenteric lymphatic spread, and three developed systemic recurrence. The positive pericolic node distance from the primary tumour did not differ depending on the primary tumour location or the distribution of the feeding arteries. Postoperatively, none of the 2996 patients developed recurrence in the remaining pericolic nodes. Interpretation: Based on the distribution of metastatic lymph nodes and prognostic outcomes, the pericolic nodes designated as ‘regional’ were those located within 10 cm of the primary tumours. Despite the fact that surgeons tend to prefer complete mesocolic excision, these findings should be fully considered when determining the bowel resection margin. Funding: Japanese Society for Cancer of the Colon and Rectum Declaration of Interest: All authors declare no competing interests. Ethical Approval: This study was conducted according to the Declaration of Helsinki and comparable Japanese ethical standards. The study was approved by the Institutional Review Boards of the JSCCR and each participating institution. Written informed consent was obtained from all study participants

This is a prospective observational cohort study aiming to include 4000 patients with stages I to III colon cancer treated at 35 specialist institutions in Japan, South Korea, Germany, Russia, Lithuania and Taiwan. The anatomical distribution of lymph nodes and feeding arteries are investigated using surgical specimens according to pre-specified categorizing methods using intraoperative anatomical markings. Primary analyses are performed to identify the general principles of metastatic lymph node distribution in terms of its relation to the location of the primary tumor and feeding arteries. Secondary analyses will be used to estimate prognostic outcomes according to bowel resection length and central radicality and will be used to evaluate the quality of resected surgical specimens. Through in-depth lymph node mapping, standardized criteria for the definite area of ‘regional’ lymph node resection in routine surgical procedures can be identified, which is expected to contribute to international standardization in colon cancer surgery (ClinicalTrials.gov NCT02938481)., The T-REX study is an international initiative to determine standardized criteria for regional lymph node resection in colon cancer surgery using in-depth lymph node mapping.

Clinical evidence demonstrating risk factors for anastomotic leakage including robotic staplers has remained limited, even though the use of robotic surgery has increased substantially. The purpose of this study was to evaluate the effects of robotic staplers on symptomatic anastomotic leakage in robotic low anterior resection for rectal cancer. A total of 427 consecutive patients with primary rectal cancer who underwent robotic low anterior resection without diverting stoma were investigated retrospectively. Symptomatic anastomotic leakage was defined as anastomotic leakage of Clavien–Dindo Grade ≥ II. We compared the symptomatic anastomotic leakage rates between manual and robotic staplers using propensity score matching and investigated the risk factors for symptomatic anastomotic leakage. After propensity score matching, 168 pairs of manual and robotic stapler cases were selected. The symptomatic anastomotic leakage rate was significantly higher for manual staplers (6.5%) than for robotic staplers (1.2%, p = 0.02). In a multivariate analysis, the use of a manual stapler (p = 0.04, OR 4.86, 95% CI 1.08–21.8) and anastomosis

Endoscopic tattooing failure by deep mural injection or tattoo leakage-induced massive staining causes localization errors or decreased laparoscopic visualization. To overcome these, we developed a novel tattoo needle with comparatively shorter needle (length, 2.5 mm) and minimal-caliber catheter (volume, 0.3 mL). The single-center, prospective observational study aimed to determine the efficacy and safety of a small-doze endoscopic tattooing prior to laparoscopic surgery for colorectal cancer, using the needle. Patients with colorectal cancer indicated for laparoscopic surgery were recruited. With the novel needle, a single tattoo was created at the anterior wall close to the lesion. During laparoscopic surgery, surgeons assessed the tattoo visibility, tattoo leakage, and the disturbance of laparoscopic view by tattoo leakage. The primary endpoint was an accurate localization by visible tattoo. Secondary endpoints were adverse events related to tattooing, the need for intraoperative endoscopy, and tattoo leakage. A total of 383 tattoos in 358 patients were analyzed. Accurate tumor localization rate was 96.6% (95% confidence interval [CI]: 94.3–98.0%). No adverse events occurred. Intraoperative colonoscopy was performed in 7 (1.8%) patients with invisible tattoo. Tattoo leakage was found in 4.2% (95%CI: 2.6–6.7%), and leakage disturbed the laparoscopic view of the surgical plane in 0.7% (95%CI: 0.3–2.3%). Prior to laparoscopic surgery for colorectal cancer, our endoscopic tattooing with a standardized protocol using a novel needle is considered a simple, highly reliable localization technique with an extremely safe profile, which would be valuable to reduce physician’s efforts and redundant medical resources. Trial registration number UMIN000021012. Date of registration: June 2016

Despite the frequent detection of KRAS driver mutations in patients with colorectal cancer (CRC), no effective treatments that target mutant KRAS proteins have been introduced into clinical practice. In this study, we identified potential effector molecules, based on differences in gene expression between CRC patients carrying wild-type KRAS (n = 390) and those carrying KRAS mutations in codon 12 (n = 240). CRC patients with wild-type KRAS harboring mutations in HRAS, NRAS, PIK3CA, PIK3CD, PIK3CG, RALGDS, BRAF, or ARAF were excluded from the analysis. At least 11 promising candidate molecules showed greater than two-fold change between the KRAS G12 mutant and wild-type and had a Benjamini-Hochberg-adjusted P value of less than 1E-08, evidence of significantly differential expression between these two groups. Among these 11 genes examined in cell lines transfected with KRAS G12 mutants, BMP4, PHLDA1, and GJB5 showed significantly higher expression level in KRAS G12A, G12D, and G12V transfected cells than in the wild-type transfected cells. We expect that this study will lead to the development of novel treatments that target signaling molecules functioning with KRAS G12-driven CRC.

Objectives Preoperative colonoscopy is often incomplete for stenotic colorectal cancers (CRC). This prospective observational study aimed to evaluate the ability of an ultrathin colonoscope (UTC) to inspect the whole colon by passing through the stenotic CRC. Methods All patients who underwent preoperative colonoscopy for stenotic CRCs at Shizuoka Cancer Center were examined for eligibility. If a standard colonoscope (PCF-H290ZI) could not pass because of a stenosis, the patients were recruited. All of the eligible patients were prospectively enrolled when informed consent could be obtained, and complete colonoscopy was attempted again using an UTC (PCF-PQ260L). Patients with stent placement and those requiring right hemicolectomy were not recruited. Primary endpoints were pass-through and cecal intubation rates. The detected synchronous neoplasias (adenomas and cancers) and their pathological findings after resection were evaluated. Results A total of 100 patients were enrolled between September 2017 and February 2019. The mean age was 65.6 ± 10.8 years, and 59% were male. The pass-through and cecal intubation rates were 67% (67/100) and 58% (58/100), respectively. Synchronous lesions located proximal to the stenoses were detected in 65.5% (38/58) of the complete colonoscopies, with a total of 86 lesions, including 18 advanced neoplasias with three invasive cancers. Conclusion When standard colonoscopy cannot pass through stenotic CRC, ultrathin colonoscopy can be considered as an option to inspect the whole colon proximal to the stenosis because treatment strategy can potentially be changed by detecting synchronous neoplasias proximal to the stenosis before surgery. (UMIN000028505).

(Background)Recent studies have revealed that colorectal cancer (CRC) displays intratumor genetic heterogeneity, and the cancer microenvironment play an important role in the proliferation, invasion, and metastasis of CRC.(Methods)We performed genomic analysis on 22 paired patients with primary CRC and synchronous colorectal liver metastasis (CRLM) using whole-exome sequencing, cancer gene panels, and microarray gene expression profiling. In addition, immunohistochemical analysis was used to confirm the protein expression of genes identified as highly expressed in CRLM by DNA microarray analysis.(Results)A total of 22 paired patients were enrolled in this study, including 13 (59.1%) colon and 9 (40.9%) rectal cancer patients. All patients had synchronous liver metastasis and did not have any other extrahepatic metastases. We identified 11 probes (10 genes) that were highly expressed in CRLM compared to CRC, from 36022 probes obtained from primary CRC, CRLM, and normal liver tissues, using gene expression analysis with DNA microarray. Of the 11 probes (10 genes), 5 genes classified as encoding “matricellular proteins” (osteopontin, periostin, thrombospondin-2, MGP, and GPNMB) were selected for immunohistochemical analysis.Osteopontin was strongly expressed in CRLM (6 of 22 cases: 27.3%) but not in CRC (0 of 22: 0%; p=0.02). Periostin also showed strong immunoreactivity in CRLM (17 of 22: 68.2%) compared to 7 of 22 (31.8%) in CRC (p=0.006). Thrombospondin-2 showed strong immunoreactivity both in CRC and CRLM (54.5% in CRC, 45.5% in CRLM; p=0.55). GPNMB and MGP were rarely positive for both CRC and CRLM. A comparison of immunoreactive positive factors for these 5 genes revealed the complexities of gene expression in CRLM. Of the cases, 16 (72.7%) CRC revealed zero or only one positive immunoreactivity. On the other hand, CRLM revealed more frequent multiple immunoreactivity; 16 cases (72.7%) shared 2 or more factors, which was statistically more frequent in CRLM than in CRC (p=0.007).(Conclusions)This study revealed the genomic heterogeneity between paired primary CRC and CRLM in terms of cancer cell microenvironment. This finding will lead to new diagnostic and therapeutic targets in the era of genome-guided personalized cancer treatment.(Trial registration)This study was retrospectively registered.

The optimal surgical approach for clinical T4 (cT4) rectal cancer is unknown. This study was conducted to clarify short- and long-term outcomes of robotic surgery for cT4 rectal cancer. In our retrospective cohort study, we enrolled patients who underwent robotic surgery for cT4 rectal cancer within 15 cm from the anal verge between 2011 and 2018. The short- and long-term outcomes were evaluated. Of a total of 122 eligible patients, 70 (57%) had cT4a tumors and 52 (43%) had cT4b tumors. Thirty-five patients (29%) had distant metastasis and 21 (17%) underwent preoperative chemoradiotherapy. Thirty-four patients (28%) underwent combined resection of adjacent organs and 43 (35%) underwent lateral lymph node dissection. The median operative time was 288 min and the median blood loss was 11 ml. No patients required conversion to open surgery. The incidences of postoperative complications of grades II, III, and IV or more according to the Clavien–Dindo classification were 17.2%, 3.5%, and 0%, respectively. Seventy-three patients (60%) had pathological T4 tumors, and the incidence of positive resection margins was 4.9%. The median follow-up time was 42.9 months. The 3-year overall survival, disease-free survival, and cumulative local recurrence rates were 87.5%, 70.4%, and 4.0%, respectively. The short- and long-term outcomes of robotic surgery for cT4 rectal cancer were favorable. Robotic surgery is considered to be a useful approach for cT4 rectal cancer.

Scientific evidence supporting robotic-assisted laparoscopic surgery (RALS) for rectal cancer remains inconclusive because most previous reports were retrospective case series or case-control studies, with few reports focusing on long-term oncological outcomes with a large volume of patients. The aim of this study was to clarify the short- and long-term outcomes of a large number of consecutive patients with rectal cancer who underwent RALS in a single high-volume center. The records of 551 consecutive patients who underwent RALS for rectal adenocarcinoma between December 2011 and March 2017 were examined to reveal the short-term outcomes. The oncological outcomes of the 204 patients who underwent surgery between December 2011 and March 2014 were evaluated. Most patients had tumors located in the lower or mid-rectum (86.0%). Only 7.6% of patients underwent neoadjuvant chemoradiotherapy. Lateral lymph node dissection was performed for 191 patients (34.7%). The median operative time was 257 min, median blood loss was 10 mL, and no transfusions were needed. No conversion to open surgery was necessary. Eighteen patients (3.3%) had Clavien-Dindo grade III postoperative complications. Six patients (1.1%) had positive resection margins. The mean follow-up duration of the 204 patients was 43.6 ± 9.8 (months). The 5-year cancer-specific survival rate for stage I/II/III/IV was 100%/100%/100%/not reached, respectively. The 5-year relapse-free survival rate for stage I/II/III/IV was 93.6%/75.0%/77.6%/ not reached, respectively. The rate of local recurrence was 0.5%. Our results suggest that RALS is technically feasible for rectal cancer and has good short- and long-term outcomes.

Various predictors of the difficulty of total mesorectal excision for rectal cancer have been described. Although a bulky mesorectum was considered to pose technical difficulties in total mesorectal excision, no studies have evaluated the influence of mesorectum morphology on the difficulty of total mesorectal excision. Mesorectal fat area at the level of the tip of the ischial spines on magnetic resonance imaging was described as a parameter characterizing mesorectum morphology. This study aimed to evaluate the influence of clinical and anatomical factors, including mesorectal fat area, on the difficulty of total mesorectal excision for rectal cancer. This study enrolled 98 patients who underwent robotic-assisted laparoscopic low anterior resection with total mesorectal excision for primary rectal cancer, performed by a single expert surgeon, between 2010 and 2015. Magnetic resonance imaging-based pelvimetry data were collected. Linear regression was performed to determine clinical and anatomical factors significantly associated with operative time of the pelvic phase, which was defined as the time interval from the start of rectal mobilization to the division of the rectum. The median operative time of the pelvic phase was 68 min (range 33–178 min). On univariate analysis, the following variables were significantly associated with longer operative time of the pelvic phase: male sex, larger tumor size, larger visceral fat area, larger mesorectal fat area, shorter pelvic outlet length, longer sacral length, shorter interspinous distance, larger pelvic inlet angle, and smaller angle between the lines connecting the coccyx to S3 and to the inferior middle aspect of the pubic symphysis. On multiple linear regression analysis, only larger mesorectal fat area remained significantly associated with longer operative time of the pelvic phase (p = 0.009). Mesorectal fat area may serve as a useful predictor of the difficulty of total mesorectal excision for rectal cancer.

Introduction The safety and feasibility of laparoscopic reoperation for anastomotic leakage remain unclear. Methods A total of 3321 patients underwent laparoscopic surgery for primary colorectal cancer at a tertiary referral center from September 2002 to May 2016. Of these, 31 patients who underwent reoperation for treatment of anastomotic leakage were enrolled in this study and divided into two reoperation groups: laparoscopic (n = 15) and open (n = 16). Data regarding patient demographics, operative outcomes, morbidity, length of hospital stay, mortality, and stoma closure after reoperation in the two groups were compared. Results No significant difference was observed in the primary surgery procedure between the two groups. Estimated blood loss (1 vs 9 mL, P = 0.020), total postoperative complications (26.7% vs 68.8%, P = 0.032), wound infection (0.0% vs 31.2%, P = 0.043), and postoperative hospital stay (18 vs 31 days, P = 0.017) were significantly better in the laparoscopic group than in the open group. Although the rate of stoma closure after reoperation was higher in the laparoscopic group, the difference was not significant (86.7% vs 62.5%, P = 0.220). Conclusions Laparoscopic reoperation exhibited better short-term outcomes than open reoperation for selected patients with anastomotic leakage.

We present a case of rectal cancer with rare variations of the left renal vessels. A man in his 60s underwent endoscopic mucosal resection for an Ip-type lesion in the upper rectum. Histologically, the lesion was a well-differentiated adenocarcinoma that had invaded the deep submucosal layer. Therefore, additional resection of the rectum with regional lymph node dissection was recommended. Preoperative CT revealed rare variations of the left renal vessels. There were two left renal arteries and veins; the caudal left renal artery and vein were located between the inferior mesenteric artery and the abdominal aorta. During the operation, these renal vessels were confirmed, and laparoscopic high anterior resection was performed safely without any injury to these renal vessels. To avoid the risk of unexpected intraoperative injuries, it is important to preoperatively check whether there are any variations in the renal vessels, even before colorectal surgery.

What qualifies as optimal lymph node (LN) dissection in the surgical management of splenic flexure colon cancer (SFCC) still remains controversial because few studies have evaluated the distribution of LN metastasis of SFCC. The aim of this study was to clarify detailed distribution of LN metastasis and long-term outcomes of SFCC. This retrospective study enrolled patients who had curative colectomy for primary transverse or descending colon cancer of pathological stage I, II, or III at a single high-volume cancer center between April 2002 and December 2018. The 538 eligible patients were divided into three groups: patients with SFCC (SFCC group, n = 168), patients with proximal transverse colon cancer (PTCC group, n = 290), and patients with distal descending colon cancer (DDCC group, n = 80). LNs were classified into horizontal (pericolic) and vertical (intermediate and main) nodes. Intermediate and main LN station numbers were defined according to the Japanese Society for Cancer of the Colon and Rectum classification. Distributions of LN metastasis and long-term outcomes were compared. In the SFCC group, the mean age was 67.3 ± 10.5 years and 110 patients (65.5%) were male. The proportion of patients with LN metastasis in the intermediate or main region was significantly lower in the SFCC group (8%) than in the PTCC (37%) (p

Persistent descending mesocolon (PDM) is typically asymptomatic. However, features such as adhesion and variations in vessel anatomy could affect the surgical techniques for colorectal cancer (CRC). This study aimed to investigate the frequency and radiological features of PDM. Short-term outcomes after conventional laparoscopic surgery (CLS) for CRC with PDM were also investigated to assess the feasibility of CLS and identify strategies for minimally invasive surgery (MIS) in CRC with PDM. Patients who underwent MIS, including CLS and robot-assisted laparoscopic surgery (RALS), for left-sided CRC between April 2016 and June 2019, were investigated. PDM was defined as the existence of the right border of the descending colon inside the right border of the left kidney based on preoperative computed tomography findings. Radiological findings of 837 patients were examined, and PDM was found in 19 (2.3%) patients. Radiality of the inferior mesenteric artery (IMA) was found in 5 of 19 (26.3%) PDM cases, which was significantly higher than that in non-PDM cases. The median lengths between the IMA and inferior mesenteric vein (IMV) and between the IMV and descending colon in PDM cases were 14.8 mm and 17.2 mm, respectively, which were significantly shorter than those in non-PDM cases. Short-term outcomes were evaluated only in CLS cases since the rate of hybrid surgery among RALS cases differed between non-PDM and PDM cases (0% vs. 44.4%), which would affect the surgical outcomes. The short-term outcomes in 447 CLS cases were similar between PDM and non-PDM cases. The frequency of extracorporeal division of the left colic artery (LCA) and IMV was significantly higher in PDM than in non-PDM cases (70.0% vs. 5.7%). This radiological definition of PDM was feasible. CLS for left-sided CRC with PDM was feasible, and dividing the LCA and IMV extracorporeally would be vital for safe surgery.

60 Background: Colorectal cancer (CRC) incidence and mortality have decreased since the 1970s but several data such as the SEER CRC registry show that the incidence of early onset colon cancer (eoCC, age 20-49) and RC keep increasing. There is limited results suggesting eoCC may have different behaviors compared to traditional CC (tCC, age ≥ 50). Methods: Individual patient data of 1,805 high-risk stage II/III colon cancer (CC) patients (pts) as the modified ITT population in ACHIEVE and ACHIEVE-2 trials were investigated. Clinicopathological features and treatment-related data were assessed by age group. Disease-free survival (DFS) was assessed by Kaplan-Meier curves and Cox multivariable models adjusted by trials, regimen, T and N. Results: Of the 1,805 pts, eoCC were 155 pts (8.6%). Using 5% difference between age groups as clinically meaningful cutoff, eoCC had similar gender (female, 52 vs 48%), PS (PS = 1, 1 vs 4%), risk group (high-risk, 43 vs 42%) and T stage (T4, 30 vs 30%) as tCC, while eoCC were less likely right-sided colon primary (32 vs 39%), had N1 disease (48 vs 54%), and treated by FOLFOX (16 vs 23%). Overall, eoCC significantly had a worse DFS than tCC (3y-DFS, 75 vs 82%; Adjusted Hazard Ratio = 1.40: 95% Confidence Interval, 1.00-1.95: p= 0.0478); in addition, similar DFS were observed among tCC pts (age 50-69 vs >70). eoCC experienced less neutropenia, thrombocytopenia and stomatitis, but had more diarrhea, nausea and/or vomiting. There were 38 and 297 pts with an initial relapse in eoCC and tCC, respectively. Of those, peritoneal metastases were more frequently seen in eoCC (n = 13, 34%) than in tCC (n = 63, 21%) (p = 0.097), whereas liver and lung metastases were similar between the two groups. Impact on DFS of 3 versus 6 months of adjuvant chemotherapy in eoCC (3y-DFS, 75% vs 76%) is similar to that in tCC (83% vs 81%). Conclusions: eoCC had unique characteristics; the difference in DFS between eoCC and tCC were potentially due to a different metastatic spread. eoCC had a different adverse event profile compared to tCC. No impact on DFS of treatment duration in eoCC was suggested. Clinical trial information: UMIN000013036.

Introduction In laparoscopic or robotic surgery, surgeons cannot directly palpate lymph nodes (LN), which could be considered a shortcoming in that procedure. This study was performed to evaluate the importance of palpation diagnosis of LN metastasis in colorectal cancer surgery. Methods This study enrolled 408 patients who underwent curative resection for primary colorectal cancer in our department in 2014. The diameter of each manually dissected LN was measured, and the LN was then examined by palpation to determine whether it was metastatic based on its consistency. The palpation and pathological diagnoses of each LN were compared. Sensitivities, specificities, positive predictive values, negative predictive values, and accuracies were calculated for palpation diagnosis of LN metastasis in a node-by-node analysis, according to LN size. Results Of the 13 750 dissected LN, 444 LN (3.2%) were metastatic. Overall, palpation diagnosis of LN metastasis revealed node-by-node sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 50%, 98%, 52%, 98%, and 97%, respectively. The sensitivity for LN 3 mm and smaller and for LN 15 mm and larger was 3% and 90%, respectively. Conclusion Palpation diagnosis of LN metastasis in colorectal cancer surgery was unreliable. Although poor haptics is considered to be a disadvantage in laparoscopic and robotic surgery, they are not inferior to open surgery in terms of LN dissection.

4011 Background: The IDEA collaboration for high-risk stage 2 colorectal cancer patients (pts) demonstrated that for CAPOX, 3 months was non-inferior to 6 months treatment, while for FOLFOX, 6 months was superior to 3 months treatment. We investigated the impact of high risk features on disease-free survival (DFS). Methods: ACHIEVE-2, one of the 4 IDEA studies (SCOT, TOSCA, ACHIEVE-2, HORG), was an open-label, multicenter randomized trial for high-risk stage II colon cancer. High risk features are defined as one or more: T4, inadequate nodal harvest < 12, poorly differentiated, clinical sign of obstruction and perforation or vascular invasion. The association of high risk features with DFS were measured by Cox regression analyses. Results: Between 2014 and 2017, ACHIEVE-2 enrolled 525 pts, out of whom 514 pts were the modified ITT (mITT) population; 432 received CAPOX (84.0%) and 82 did mFOLFOX6 (16.0%). High-risk features included 35.8% of T4, 12.8% of inadequate nodal harvest, 11.5% of poorly differentiated, 19.3% of obstruction, 6.4% of perforation and 87.5% of vascular invasion; 47.3% had one features, 35.2% had two, 14.6% had three, and 2.9% had four or more. With a median follow-up of 36.1 months, 3-year DFS rates were 88% in both arms, with a hazard ratio (HR) of 1.12 (95% CI, 0.67-1.87, p=0.67). In multivariate analysis, T4 (HR 3.77 [2.18-6.53], p< 0.0001) and inadequate nodal harvest (HR 2.98 [1.59-5.59], p= 0.0006) remained independent significant negative prognostic factors. The 3-year DFS rates in T4 and Non-T4 diseases were 78% and 94% (p

4005 Background: The role of adjuvant chemotherapy after hepatectomy is controversial for liver only metastases from colorectal cancer (LM). Current recommendations for oxaliplatin-containing adjuvant regimen (FOLFOX) for LM are based on extrapolation of the results of the EORTC intergroup trial 40983, which showed that perioperative FOLFOX confirmed a progression-free survival benefit but did not affect overall survival (OS) in LM patients. We conducted a randomized controlled trial to determine if adjuvant modified FOLFOX (mFOLFOX) is superior to hepatectomy alone for LM. Methods: Eligible patients aged 20-75 years who had histologically proven colorectal adenocarcinoma with an unlimited number of LM were randomly assigned (1:1) to receive either adjuvant mFOLFOX6 (oxaliplatin 85mg/m2, l-LV 200 mg/m2, 5-FU bolus 400 mg/m2 and 2400mg/m2 over 48 h), for 12 cycles after surgery (CTX arm), or surgery alone (S alone arm). When treatment compliance after 9 courses of CTX was as high as expected in phase II, the registration was continued in phase III. The primary endpoint of phase III was disease-free survival (DFS), and the secondary endpoints were OS, toxicity, and sites of relapse. The planned sample size was 150 patients (pts) per arm, with a one-sided alpha of 5%, and 80% power detecting a 5y-DFS difference of 12% (25% with S alone vs. 37% with CTX). Results: Between Mar. 2007 and Jan. 2019, 300 patients were randomized. 151 pts were allocated to CTX, and 149 pts to S alone. When the third interim analysis of phase III was performed in Dec. 2019, the DSMC recommended the early termination of the trial because a statistically significant difference in terms of DFS but the futility in terms of OS was found. With a median follow-up period of 54 months for disease-free surviving patients, the 3y-DFS was 52.1% (95% CI 43.2 – 60.2) with CTX and 41.5% (33.2 – 49.6) with S alone (hazard ratio 0.63 [0.45 – 0.89], one-sided p = 0.002 < 0.0163 for the one-sided alpha level at the interim analysis). However, the 3y-OS was 86.6% (79.2-91.4) with CTX and 92.2% (86.0 – 95.8) with S alone (hazard ratio 1.35 [0.84 – 2.19]). The 5y-OS was 69.5% (59.6-77.5) with CTX and 83.0% (74.5-88.9) with S alone. Median OS after recurrence was 38.4 months in the CTX arm and 87.6 in the S alone arm. Conclusions: DFS did not correlate with OS for LM. Postoperative chemotherapy with mFOLFOX6 improves DFS but worsens OS over surgery alone due to more deaths after recurrence in the CTX arm. Adjuvant mFOLFOX is not beneficial to patients after hepatectomy for LM. Clinical trial information: UMIN000000653 .