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The incidence of adenocarcinoma of the esophagogastric junction (AEG) and proximal gastric cancer (PGC) is rising worldwide. Recently, the use of indocyanine green (ICG) tracer-guided surgery has been reported; however, its efficacy for total/proximal gastrectomy has not been clarified. We evaluated the feasibility and safety of ICG fluorescent marking for tumor localization in AEG/PGC treatment by laparoscopic surgery.We enrolled patients with AEG/PGC from October 2016 to March 2019 from a prospectively registered database. On the day before surgery, ICG markings were made at four locations just at the edge of the tumor by gastrointestinal fiberscope examination. Surgery was performed while viewing the fluorescence image of ICG, and the proximal portions of the esophagus and the distal portion of the stomach were resected at the edge of the area where ICG had spread.We enrolled 130 patients with AEG/PGC. Overall, 107 patients were eventually included in the study: AEG n = 64 (60%) and PGC n = 43 (40%). ICG markings were detected intraoperatively in all cases, and cancer invasion into the resection lines of the esophagus and stomach, performed based on ICG fluorescence images, was negative in all cases. The median visible range of ICG fluorescence was 22.5 mm. ICG diffusion expanded 20 mm proximal for AEG. There were no adverse events associated with endoscopic ICG injection.ICG fluorescence imaging is feasible and safe and can potentially be used as a tumor-marking agent for determining the surgical resection line for total/proximal gastrectomy in AEG and PGC treatment.

Laparoscopic Billroth-I gastroduodenostomy using a delta-shaped anastomosis is safe and feasible. However, it is often difficult to perform in patients who have a short posterior wall of the duodenum. Thus, we have developed a new method named duodenal overlap functional anastomosis with linear stapler (DOLFIN). We hereby report the technical details of the new method and our preliminary experience performing it.After the completion of lymphadenectomy, the duodenum was transected craniocaudally with an endoscopic linear stapler. The hepatoduodenal mesentery was dissected approximately 4 cm along the duodenal bulb, and the anastomosis between the posterior wall of the stomach and the lesser curvature of the duodenum was created. The common entry hole was then transected using an endoscopic linear stapler, and the anastomosis was finally completed.There were 36 patients with gastric cancer who underwent laparoscopic distal gastrectomy (LDG) or robotic distal gastrectomy (RDG) with B-I reconstruction using DOLFIN. There were no postoperative complications classified as C-D grade 3 or more and complications related to anastomosis, such as anastomotic leak or stenosis.Our DOLFIN gastroduodenostomy can be performed safely. In addition, it results in good postoperative outcomes. A long-term comparative study is required to further evaluate the clinical usefulness of this method.

Colorectal cancer (CRC) is a major cause of cancer-related deaths. Metastasis is enhanced through epithelial-mesenchymal transition (EMT), a process primarily induced by the transforming growth factor beta (TGF-β)-mediated canonical Smad pathway. This study focused on plexin D1 (PLXND1), a chemoreceptor for the ligand SEMA3E to mechanosensory, showing that PLXND1 induces EMT via activation of the PI3K/AKT pathway in CRC cells. The findings showed that PLXND1-knockdown decreases cell migration and invasion significantly, and that the binding of p61-SEMA3E to the PLXND1 enhances the invasiveness and migration through EMT. Furin inhibitor suppresses EMT, decreasing cell migration and invasion. Furin cleaves full-length SEMA3E and converts it to p61-SEMA3E, suggesting that furin inhibitors block PLXND1 and p61-SEMA3E binding. Furin is a potential therapeutic target for the purpose of suppressing EMT by inhibiting the binding of p61-SEMA3E to PLXND1. In vivo experiments have shown that PLXND1-knockdown suppresses EMT. Mesenchymal cells labeled with ZEB1 showed heterogeneity depending on PLXND1 expression status. The high-expression group of PLXND1 in 182 CRC samples was significantly associated with poor overall survival compared with the low-expression group (P = 0.0352, median follow-up period of 60.7 months) using quantitative real-time polymerase chain reaction analysis. Further research is needed to determine whether cell fractions with a different expression of PLXND1 have different functions.

BackgroundTotal mesorectal excision (TME) and lateral lymph node dissection (LLND) without radiotherapy (RT) are standard treatment for lower cT3/4 rectal cancers in Eastern countries. In comparative studies, both TME + LLND and RT + TME yield good local control. Although Japanese guidelines recommend LLND for locally advanced rectal cancers below the peritoneal reflection, LLND dissection of clinically negative lateral pelvic lymph nodes (LPLN) is controversial, and laparoscopic TME + LLND is technically challenging and time-consuming. New optical instruments for laparoscopy allow easy perioperative sentinel lymph node (SLN) identification using ICG. The SLN concept may facilitate accurate diagnosis of LPLN involvement, and thus reduce LLND in laparoscopic rectal cancer surgery. Here we investigated lateral pelvic SLN navigation surgery for SLN detection during laparoscopic rectal cancer surgery.MethodsThis study included 21 patients with clinical StageII/III lower rectal cancer without LPLN enlargement, who underwent curative laparoscopic surgery. All patients underwent TME, followed by lateral SLN identification and biopsy using ICG, and then laparoscopic LLND. ICG fluorescence imaging was conducted using the laparoscopic near-infrared camera system.ResultsLateral SLNs were successfully identified in 16 (76.2%) of the 21 patients. Among the 15 patients without SLN tumor metastasis, the dissected lateral non-SLNs were all negative.ConclusionsA lack of metastasis in the lateral pelvic SLN seems to reflect a lack of metastases to all lateral LNs. Our present results suggest that this laparoscopic ICG-guided SLN strategy may be a low-risk and time-saving method to prevent laparoscopic LLND in cases with negative lateral pelvic lymph nodes.

Previous studies have shown that postoperative adjuvant chemotherapy improves overall survival in patients with stage III colorectal cancer (CRC). However, adjuvant chemotherapy may not be necessary for some patients. This study aimed to develop a new nutritional-inflammation score, which would be useful in identifying a favorable prognosis group among stage III CRC patients.This retrospective study included 262 patients with stage III CRC who underwent curative surgery and were divided into two groups: a training set (TS) of 162 patients and a validation set (VS) of 100 patients. In the TS, clinicopathological factors were tested using a Cox regression model, and a new prognostic model was developed.Multivariate analyses in TS revealed that lymph node metastasis (N2) (p=0.002), low albumin (p=0.017), high monocyte counts (p=0.008), and low platelet counts (p=0.018) were independent risk factors for disease free survival (DFS). The Kansai prognostic score (KPS) was assessed by 1 point each for3.5 g/dl albumin level,450 monocyte counts, and1.65×10KPS serves as a new model for the prognosis of patients with stage III CRC.

Endoscopic treatment is one of the options for superficial esophageal cancer, but additional therapy such as esophagectomy or chemoradiotherapy (CRT) is sometimes needed due to noncurative resection. However, the outcome of additional therapy after endoscopic treatment has not been fully evaluated. In 160 patients with superficial esophageal cancer, including 37 patients who underwent esophagectomy and 123 patients who underwent CRT after noncurative endoscopic resection, outcomes were investigated. The CRT group included more elderly patients than the surgery group, although there were no significant differences in tumor depth or lymphovascular invasion between the two groups. Overall survival was significantly better in the surgery group than in the CRT group (5-year overall survival: 94.3% vs. 79.9%; p = 0.039). Two (5.4%) patients in the surgery group who developed lymph node recurrence achieved complete response by chemotherapy or CRT, and 9 of 16 patients (13.0%) in the CRT group who developed recurrence underwent salvage esophagectomy or lymphadenectomy. As a result, the 5-year cause-specific survival was 100% in the surgery group and 92.8% in the CRT group. SM2 invasion (≥ SM2) was significantly associated with recurrence after CRT, while lymphatic invasion was associated with lymph node metastasis in the surgery group. Endoscopic treatment combined with esophagectomy or CRT can be a curative treatment option in patients with superficial esophageal cancer. However, esophagectomy rather than CRT should be recommended for patients with massive submucosal tumor invasion due to the risk of recurrence after CRT.

Lessons Learned The 3-year disease-free survival rate of the twice-daily regimen was not inferior to that of the conventional three-times-daily regimen, and the twice-daily regimen did not lead to an increase in adverse events. The effectiveness of the twice-daily regimen highlights an increased number of treatment options for patients. This will facilitate personalized medicine, particularly for elderly or frail patients who may experience more severe side effects from the combination therapy. Background Tegafur-uracil (UFT)/leucovorin calcium (LV) is an adjuvant chemotherapy treatment for colorectal cancer. We conducted a multicenter randomized trial to assess the noninferiority of a twice-daily compared with a three-times-daily UFT/LV regimen for stage II/III colorectal cancer in an adjuvant setting. Methods Patients were randomly assigned to group A (three doses of UFT [300 mg/m2 per day]/LV [75 mg per day]) or B (two doses of UFT [300 mg/m2 per day]/LV [50 mg per day]). The primary endpoint was 3-year disease-free survival. Results In total, 386 patients were enrolled between July 28, 2011, and September 27, 2013. The 3-year disease-free survival rates of group A (n = 194) and B (n = 192) were 79.4% and 81.4% (95% confidence interval, 72.6–84.4–74.5–85.9), respectively. The most common grade 3/4 adverse events in group A and B were diarrhea (3.9% vs. 7.3%), neutropenia (2.9% vs. 1.6%), increase in aspartate aminotransferase (4.0% vs. 3.9%), increase in alanine aminotransferase (6.2% vs. 6.8%), nausea (1.7% vs. 3.4%), and fatigue (1.1% vs. 2.3%). Conclusion Group B outcomes were not inferior to group A outcomes, and adverse events did not increase.

Olanzapine has exhibited efficacy as an antiemetic agent when used with 5-HT3 receptor antagonists, dexamethasone, and NK1 receptor antagonists for patients receiving highly emetogenic chemotherapy. In addition, several studies have reported the efficacy or safety of olanzapine in patients receiving moderately emetogenic chemotherapy, including carboplatin, irinotecan, and oxaliplatin. However, no reports of olanzapine use have focused on patients receiving oxaliplatin-based chemotherapy. Therefore, we analyzed the safety of antiemetic therapy using olanzapine, palonosetron, aprepitant, and dexamethasone in colorectal cancer patients undergoing oxaliplatin-based chemotherapy. This study was a prospective phase II single-institution study of 40 patients (median age 60 years, 23 patients were male). The primary endpoint was the incidence of adverse events, and the exploratory endpoints were the rate of chemotherapy-induced nausea and vomiting. Almost all patients (90%) had a performance status of 0. All patients received the scheduled antiemetic therapy. The most common adverse event was somnolence (n = 7 patients, 17.5%). All adverse events were grade 1. Thirty-six patients were included in the exploratory analysis of efficacy. No patients experienced vomiting during the first 120 h after chemotherapy, and complete response and complete control were both 86.1%. The rate of total control was 55.6% during the same time period. Olanzapine use with 5-HT3 receptor antagonists, dexamethasone, and NK1 receptor antagonists was safe for colorectal cancer patients receiving oxaliplatin-based chemotherapy.

Malnutrition has been considered to be associated with the prognosis of cancer. The Geriatric Nutritional Risk Index (GNRI), based on serum albumin levels, present body weight, and ideal body weight, is a simple screening tool to predict the risk of nutrition-related morbidity and mortality in elderly patients. We aimed to evaluate whether preoperative GNRI was associated with postoperative complications and prognosis in elderly patients with colorectal cancer (CRC). We retrospectively enrolled 313 CRC patients aged ≥65 years after curative surgery and classified them into an all-risk GNRI (≤98) group and a no-risk GNRI (>98) group. Kaplan-Meier analysis showed overall survival was significantly worse in the all-risk GNRI group than in the no-risk GNRI group (P = 0.009). Multivariable analyses showed low GNRI (≤98) was an independent risk factor for postoperative complications (P = 0.048) and overall survival (P = 0.001) in the patients. Among the complications, the incidence of surgical site infection, in particular, was significantly higher in the all-risk GNRI group (P = 0.008). In conclusion, low preoperative GNRI (≤98) was associated with increased postoperative complications and poor prognosis. Preoperative GNRI can be used as an identifier for potential high-risk group of morbidity and mortality in elderly CRC patients.

Background Gastric cancer with portal vein tumor thrombus (PVTT) is poor prognosis, and the treatment remains challenging. Regarding surgery, there are only reports of highly invasive laparotomy. We report some techniques of the completely robotic total gastrectomy with thrombectomy and portal vein reconstruction for the patient with gastric cancer and PVTT for the first time. Case presentation A 79-year-old man was diagnosed with a 5-cm gastric cancer on the side of the lesser curvature from the middle of the gastric body to the cardia. Computed tomography revealed a massive PVTT extending from the left gastric vein to the portal trunk (28 x 16 mm). There were no other distant metastases. After 3 cycles of the chemotherapy, the PVTT shrank to 19 x 12 mm. After obtaining informed consent from the patient, robotic total gastrectomy with regional lymphadenectomy and thrombectomy were performed. We used the da Vinci Xi Surgical System. A 3-cm incision was made at the umbilicus, and a wound retractor was placed. Five additional ports were placed. The right side suprapancreatic lymph nodes were performed at the time of the thrombectomy. It was important to identify the precise extent of the PVTT with intraoperative ultrasonography before the thrombectomy. After PVTT identification, the portal trunk was clamped above and below the tumor thrombus with vascular clips. The membrane on the anterior wall of the portal trunk around the PVTT was carefully incised with da Vinci Scissors. The tumor thrombus was completely enucleated without separation. The incised part of the portal trunk was reconstructed with continuous 5-0 synthetic monofilament nonabsorbable polypropylene sutures. After removing the vascular clamps, we made sure there was no leakage from the portal vein and no tumor thrombus remnants with intraoperative ultrasonography. Robotic total gastrectomy with lymphadenectomy and Roux-en-Y reconstruction were performed. The patient was discharged without complications. The patient has remained alive for 30 months after surgery. Conclusions Robotic total gastrectomy with thrombectomy and portal vein reconstruction is a safe, minimally invasive, and precise surgery. It may contribute to improved prognosis of gastric cancer with PVTT when combined with chemotherapy.

We previously reported the stump closure method for the remnant pancreas in distal pancreatectomy, in which soft coagulation and polyglycolic acid felt attached with fibrin glue were utilized. Transpancreatic mattress suture with polyglactin 910 woven mesh was recently reported as a novel stump closure technique. We developed the modified transpancreatic mattress suture with polyglactin 910 woven mesh method, which combined our polyglycolic acid felt method with the transpancreatic mattress suture with polyglactin 910 woven mesh method.The polyglycolic acid felt group included patients undergoing distal pancreatectomy in whom the pancreatic stump was closed with the polyglycolic acid felt method from 2017 to 2018 (n = 54); whereas the modified transpancreatic mattress suture with polyglactin 910 woven mesh group included those whose stump was closed with the modified transpancreatic mattress suture with polyglactin 910 woven mesh method from 2019 to 2020 (n = 51). Perioperative parameters, including grade B/C postoperative pancreatic fistula (clinically relevant postoperative pancreatic fistula), were assessed according to the stump closure method.The incidence of clinically relevant postoperative pancreatic fistula was significantly lower in the modified transpancreatic mattress suture with polyglactin 910 woven mesh group than in the polyglycolic acid felt group (7.8% vs 22.2%, P = .036). In multivariate analysis, the use of neoadjuvant chemoradiotherapy and the transpancreatic mattress suture with polyglactin 910 woven mesh method were independent factors for preventing clinically relevant postoperative pancreatic fistula (P = .011 and 0.0038, respectively). Moreover, in the modified transpancreatic mattress suture with polyglactin 910 woven mesh group, the incidence of clinically relevant postoperative pancreatic fistula in patients with a thick pancreas (≥13 mm, 6.7%) was comparably as low as that in patients with a thin pancreas (13 mm, 9.5%).The modified transpancreatic mattress suture with polyglactin 910 woven mesh method is an effective stump closure technique to prevent clinically relevant postoperative pancreatic fistula after distal pancreatectomy. Our results warrant further prospective investigation to evaluate the efficacy of the modified transpancreatic mattress suture with polyglactin 910 woven mesh method compared with other standard closure methods (eg, stapler closure or hand-sewn closure).

Purpose Pathological extramural venous invasion (EMVI) is defined as the active invasion of malignant cells into veins beyond the muscularis propria in colorectal cancer. It is associated with poor prognosis and increases the risk of disease recurrence. Specific findings on MRI (termed MRI-EMVI) are reportedly associated with pathological EMVI. In this study, we aimed to identify risk factors for lateral lymph node (LLN) metastasis related to rectal cancer and to evaluate whether MRI-EMVI could be a new and useful imaging biomarker to help LLN metastasis diagnosis besides LLN size. Methods We investigated 67 patients who underwent rectal resection and LLN dissection for rectal cancer. We evaluated MRI-EMVI grading score and examined the relationship between MRI-EMVI and LLN metastasis. Results Pathological LLN metastasis was detected in 18 cases (26.9%), and MRI-EMVI was observed in 32 cases (47.8%). Patients were divided into two cohorts, according to LLN metastasis. Multivariate analyses demonstrated that higher risk of LLN metastasis was significantly associated with MRI-EMVI (P = 0.0112) and a short lateral lymph node axis (≥ 5 mm) (P = 0.0002). The positive likelihood ratios of MRI-EMVI alone, LLN size alone, and the combination of both factors were 2.12, 4.84, and 16.33, respectively. Patients negative for both showed better 2-year relapse-free survival compared to other patients (84.4% vs. 62.1%, P = 0.0374). Conclusions MRI-EMVI was a useful imaging biomarker for identifying LLN metastasis in patients with rectal cancer. The combination of MRI-EMVI and LLN size can improve diagnostic accuracy.

Chemotherapy with panitumumab is expected to be well tolerated and improve survival in patients with metastatic colorectal cancer (mCRC). However, skin toxicities are its most common adverse events. The aim of this trial was to evaluate the efficacy and safety of pre-emptive antibiotic treatment with clarithromycin (CAM) to prevent panitumumab skin toxicities.We conducted a phase lll, multicenter, open-label, randomized clinical trial on mCRC patients treated with panitumumab. Eligible patients were randomly assigned 1:1 to pre-emptive antibiotic and control groups. In the pre-emptive group, CAM administration (200 mg twice per day) continued daily through the panitumumab treatment period. The control regimen consisted of skin care only. The primary end point was the incidence of grade ≥ 2 skin toxicities during the 6-week skin treatment period.Of 156 enrolled patients, 78 received pre-emptive antibiotic treatment, and 78 received reactive treatment. The number and incidence of grade ≥ 2 skin toxicities during the 6-week skin treatment period were 16 (21.3%) and 41 (54.7%) for the pre-emptive and control groups, respectively (HR, 0.32; 95% CI, 0.17-0.56). There was almost no difference in the rate of other adverse events between the two groups, but the incidence of grade ≥ 3 diarrhea in the pre-emptive group was high, at 8% vs. 1.3% in the control group. There were no treatment-related deaths.Prophylactic oral CAM together with relatively simple skin care was found to be effective in suppressing the development of grade ≥ 2 skin toxicities induced by panitumumab.UMIN000011485 DATE OF REGISTRATION: Sep 1st, 2013.

Doublecortin-like kinase 1 (DCLK1) promotes tumour proliferation in human colorectal cancer (CRC). To elucidate the mechanism and clinical relevance of this association, we performed expression analysis using commercially available colon carcinoma cell lines (SW480, HCT116, CaCO2, SW48 and SKCO1) and immunohistochemical analysis of 200 resected CRC samples for correlation with clinical features. DCLK1 showed a high level of expression, especially in SW480 and HCT116 cells. Silencing DCLK1 expression using short hairpin DCLK1 (shDCLK1) RNA inhibited the growth and invasion capacities of these cell lines, which showed signs of entering into the mesenchymal–epithelial transition (MET). We found evidence of a strong correlation of DCLK1 expression with that of Tribbles homolog 3 (TRIB3), and silencing TRIB3 also led to the MET phenotype in these cells. In the clinical samples, compared with samples showing low expression of DCLK1, high expression was associated with poor prognosis in terms of overall and recurrence-free survival (P < 0.0001). The results of univariate and multivariate analysis suggested that high expression of DCLK1 in clinical colon cancer samples was tied to poor prognosis, cancer invasion depth and lymph node metastasis. DCLK1 expression correlates with malignant grade of colon cancer and offers a potential treatment target.

We examined the association between pathological lateral pelvic lymph node (LPLN) metastasis and the LPLN diameter in patients with locally advanced rectal cancer (LARC) who received a neoadjuvant chemotherapy (NAC) regimen based on oxaliplatin as induction chemotherapy. We aimed to determine whether or not the LPLN size predicts LPLN metastasis in NAC cases. We retrospectively examined data from 3 institutes for 60 patients with LARC who received mesorectal excision and LPLN dissection after NAC. We evaluated the LPLN size on magnetic resonance imaging (MRI) scans acquired before and after NAC. We performed multivariate analyses to analyze the relationship between the LPLN size and clinicopathological factors. For patients with visible LPLNs, the median short-axis diameter (SA) was significantly reduced from 5.1 mm (range 2.0–17.4) before NAC to 3.7 mm (range 2.1–19.0) after NAC (p = 0.0479). SA diameters were significantly larger in pathological LPLNs than in healthy LPLNs, both before (p = 0.0002) and after NAC (p

We assessed the feasibility and safety of single-site laparoscopic surgery for patients with colorectal cancer who required perioperative heparinization. This retrospective study reviewed the medical records of 390 patients who underwent single-site laparoscopic surgery for colorectal cancer from January 2010 to December 2016. Antithrombotic drugs were stopped preoperatively and heparin was administered according to the operative risk of each patient, based on consultation with the cardiologist physician or neurosurgeon. Propensity score modeling was utilized to adjust for baseline characteristics. Of 390 patients, 29 were treated with standard bridging intravenous heparin therapy. Propensity matching identified 119 patients: 22 patients in the heparinization group and 97 in the control group. The matched groups were not significantly different in operation times, bleeding volumes, or conversion rate. The mean postoperative hospital stay was 17.9 days in the heparinization group and 9.5 days in the control group (p = 0.034). Postoperative bleeding was observed in 4 patients (18.2%) in the heparinization group and 11 patients (11.4%) in the control group (p = 0.646), while other complications were similar in the two study groups (p = 0.502). Of these other complications, thromboembolic events were observed in two patients in the heparinization group and one patient in the control group. We found that single-site laparoscopic surgery for colorectal cancer with heparinization was feasible and safe. Heparinization did not increase the risk of postoperative bleeding complications, but postoperative hospital stay was prolonged.

PURPOSE The International Union Against Cancer highlighted tumor budding as a tumor-related prognostic factor. International assessment criteria for tumor budding were recently defined by the 2016 International Tumor Budding Consensus Conference (ITBCC2016). This study aimed to clarify the prognostic and predictive values of tumor budding in a randomized controlled trial evaluating the superiority of adjuvant chemotherapy with oral tegafur-uracil over surgery alone for stage II colon cancer (SACURA trial; ClinicalTrials.gov identifier: NCT00392899 ). PATIENTS AND METHODS Between 2006 and 2010, we enrolled 991 patients from 123 institutions with stage II colon cancer. Tumor budding was diagnosed by central review on the basis of the criteria adopted in the ITBCC2016. We prospectively recorded all clinical and pathologic data, including the budding grade, and performed prognostic analyses after 5 years of completing the patients’ registration. RESULTS Of 991 tumors, 376, 331, and 284 were classified as BD1, BD2, and BD3, respectively; the 5-year relapse-free survival (RFS) rate was 90.9%, 85.1%, and 74.4%, respectively ( P < .001), and ranged widely in T4 tumors (86.6% to 53.3%). The budding grade significantly correlated with recurrence in the liver, lungs, lymph nodes, and peritoneum ( P < .001 to .01). Multivariable analysis revealed that budding and T stage exerted an independent impact on RFS, and on the basis of the Harrell concordance index, these two factors substantially contributed to the improvement of the Cox model for predicting RFS. Both the BD2 and BD3 groups demonstrated greater improvement in the 5-year recurrence rate in the adjuvant chemotherapy group than the surgery-alone group by approximately 5%, but the difference was statistically nonsignificant. CONCLUSION Tumor budding grade on the basis of the ITBCC2016 criteria should be routinely evaluated in pathologic practice and could improve the benefit of adjuvant chemotherapy for stage II colon cancer.

Background/Aims: Endoscopic recurrence (ER) after intestinal resection for Crohn’s disease (CD) precedes the clinical recurrence, and the severity of ER correlates with the severity of the subsequent clinical recurrence. This study aimed to identify risk factors related to early ER after intestinal resection for CD and to create a prediction model. Methods: The patients who underwent intestinal resection for CD between April 2008 and April 2017 and took endoscopic evaluation between 6 and 12 months after surgery were retrospectively analyzed. Results: A total of 15 out of 52 (29%) patients developed early ER. A univariate analysis demonstrated that early ER was significantly correlated with history of prior intestinal resections for CD (p = 0.005), low preoperative albumin levels (p = 0.035), and excessive perioperative inflammation (i.e., high C-reactive protein levels in both preoperative and postoperative periods; p = 0.034). Based on these clinical factors, a nomogram for predicting early ER was created with the area under the curve 0.808. Conclusion: We developed a novel predictive nomogram for early ER after intestinal resection for CD. This prediction model might assist clinicians in managing patients with CD after an intestinal resection. Additional validation studies are currently being developed.

Objectives: The aim of this study was to determine the recommended dose (RD) of capecitabine combined with oxaliplatin and irinotecan (XELOXIRI) as a neoadjuvant chemotherapy in patients with locally advanced rectal cancer. Method: Patients received irinotecan and oxaliplatin (85 mg/m2) on day 1, and capecitabine (1,000 mg/m2 orally twice daily) on days 1–7 of a biweekly schedule. Three dose levels, ranging from 100 to 150 mg/m2, were explored for irinotecan in sequential cohorts of 6 patients. Dose-limiting toxicities (DLTs) were assessed in the first cycle to determine the RD. Results: Six patients were enrolled. The DLT was grade 3 febrile neutropenia, which was observed in 2 of the 6 patients at dose level 1. The RD of irinotecan was defined as 150 mg/m2. Toxicity was manageable: the most common grade ≥3 toxicities were neutropenia (2 patients), anemia (1 patient), and anorexia (1 patient). Nodal downstaging (cN+ to ypN0) was detected in 2 patients and the T stage was downstaged in 3 patients. Conclusions: XELOXIRI is a feasible and active regimen for patients with locally advanced rectal cancer. Febrile neutropenia was the DLT, and the RD of irinotecan is 150 mg/m2.

Polymerase (Pol) III dependent transcription controls the abundance of transfer RNAs, 5S ribosomal RNA and small non coding RNAs within cells, and is known to serve an essential role in the maintenance of intracellular homeostasis. However, its contribution to cancer progression has not been extensively explored. The present study demonstrated that the evolutionarily conserved MAF1 homolog, negative regulator of RNA Pol III (MAF1) may be closely associated with malignant potential and poor prognosis in colorectal cancer (CRC). Notably, immunohistochemical analysis of 146 CRC surgical specimens revealed that high expression levels of MAF1 were associated with advanced tumor depth, lymph node metastasis, distant metastasis and poor prognosis. In vitro loss of function assays revealed that MAF1 knockdown suppressed chemoresistance and migration of CRC cancer cells. Furthermore, detailed analysis of an independent CRC dataset (n=615) demonstrated that the prognostic impact of MAF1 gene expression was particularly marked in microsatellite instability (MSI)-positive patients, who benefit from immune checkpoint blockade. High expression levels of MAF1 were revealed to be an independent prognostic indicator in MSI-positive CRC. These findings suggested that MAF1 may have an essential role in CRC progression, particularly in MSI positive cases.

POU5F1-expressing cells can self-renew and differentiate, contributing to metastasis formation in colorectal cancer (CRC), but it plays an important role in normal pluripotent stem cells. Here, we identified the CRC-specific gene, HNF1A, which is the downstream of POU5F1. HNF1A associates with fatty acid and glucose metabolism, and CRC cells highly expressed it. In 198 CRC patients, high HNF1A expression was an independent predictor of disease-free (P = 0.031) and overall (P = 0.007) survival. HNF1A-knockdown showed significantly reduced cell growth, increased apoptosis, and improved anticancer drug sensitivity. We revealed that HNF1A regulated controlled GLUT1 expression via HIF1A and multidrug resistance protein function to suppress SRI. HNF1A expression was elevated in persister cells after exposure to anticancer drugs, and anticancer drug sensitivity was also improved in persister cells via the inhibition of HNF1A. In conclusion, HNF1A expression can reflect resistance to anticancer drug treatment, and its suppression improves anticancer drug sensitivity as a new therapeutic target.

To evaluate the efficacy and safety of CAPOX plus bevacizumab as second-line chemotherapy for metastatic colorectal cancer.In this multicenter phase Ⅱ study, the planned number of patients was 48, but owing to poor case accumulation, registration was discontinued for 20 patients. The primary endpoint was the response rate(RR). Secondary endpoints were progression-free survival(PFS), overall survival(OS), disease control rate(DCR), and safety.First-line treatment was combined with irinotecan in 14 cases and bevacizumab in 12 cases. The median number of second- line treatment courses was 7, and the median treatment period was 203 days. The reason for discontinuation of treatment was disease progression in 13 cases, adverse events in 4 cases, and other reasons in 3 cases. The best response was PR in 5 cases, SD in 8 cases, and NE in 4 cases. The RR was 25%, and the DCR was 65%. The median PFS was 7.2 months, and the median OS was 18.6 months. Grade≥3 adverse events were neutropenia in 3 cases and diarrhea and peripheral neuropathy in 2 cases each. There were no treatment-related deaths.CAPOX plus bevacizumab was a safe and effective second-line treatment option for metastatic colorectal cancer.

Background Although chemotherapy for metastatic colorectal cancer (mCRC) has improved, the standard chemotherapy regimens for patients with RAS wild-type mCRC remain debated. This study aimed to compare S-1 and oxaliplatin (SOX) + bevacizumab (B-mab) with SOX + cetuximab (C-mab) in patients with previously untreated recurrent advanced CRC with wild-type KRAS. Methods This randomized phase II, open-label, multicenter study compared the efficacy and safety of SOX+B-mab with SOX+C-mab in patients with previously untreated advanced CRC with wild-type KRAS. Between February 2012 and October 2016, 45 patients were enrolled. Results Overall response rates were 59.1 and 43.5% (p = 0.29) and disease control rates were 90.9 and 91.3% (p = 0.96) in the SOX+B-mab and SOX+C-mab groups, respectively. Median overall survival (OS) was 25.3 and 15.5 months (HR = 0.607, p = 0.167) and median progression-free survival (PFS) were 11.7 and 5.5 months (HR = 0.558, p = 0.077) in the SOX+B-mab and SOX+C-mab groups, respectively. The OS and PFS of patients with early tumor shrinkage (ETS) were not significantly different in the SOX+B-mab group. However, they were significantly better when ETS was ≥20 in the SOX+C-mab group (p = 0.032 and p = 0.003, respectively). Conclusions The efficacy and safety of SOX+B-mab and SOX+C-mab for wild-type KRAS recurrent advanced CRC as first-line chemotherapy were almost the same. Consideration of the treatment strategy based on ETS may improve patient prognosis, especially in patients receiving the SOX+C-mab regimen. Trial registration UMIN Clinical Trials Registry (UMIN000006706). Date of registration: NOV/11/2011. URL of trial registry record: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000007920

PURPOSE Intraoperative fluid restriction is reported to be associated with reduced postoperative tissue edema and decreased incidence of postoperative pancreatic fistula (POPF) in pancreatic surgery. However, there is limited information regarding the postoperative approach to prevent postoperative tissue edema and reduce POPF. METHODS Patients undergoing distal pancreatectomy from 2013 to 2018 in our institute were retrospectively enrolled (n = 128). The patients were classified into the two groups: an early diuresis group (ED group: patients administered diuretic agents on postoperative day 2 or earlier between 2016 and 2018, n = 69) and a conventional diuresis group (CD group: patients administered diuretic agents on postoperative day 3 or later between 2013 and 2015, n = 59). Postoperative tissue edema assessed by CT imaging and the incidence of clinically relevant POPF (CR-PF; grade B or C) were compared. RESULTS Postoperative tissue edema was significantly reduced in the ED group (p

Robot-assisted laparoscopic surgery(RALS)for rectal cancer has been covered by National Health Insurance in Japan since April 2018. We launched RALS in our hospital in October 2019 and now report the short-term results(up to January 2020). Altogether, 15 consecutive patients(12 men, 3 women: median age 70 years)with rectal cancer underwent RALS during that period. For the first 2 cases, we performed RALS under the instruction of an experienced proctor from another institution. Among the 15 patients, 6 underwent high anterior resection and 9 low anterior resection. Median operating time was 358 min, median intraoperative blood loss was 0 mL, and there were no apparent intraoperative complications. Median postoperative length of hospital stay was 13 days, and only 1 patient developed a high-grade complication(Clavien-Dindo Grade Ⅲb)postoperatively. Hence, RALS for rectal cancer was launched successfully in our institution.

Background Peutz–Jeghers syndrome (PJS) is a very rare autosomal dominant genetic disorder characterized by hamartomatous polyps in the gastrointestinal tract and hyperpigmentation of the lips, hands, and feet. The hamartomatous polyps in the small intestine often cause intussusception and bleeding. Case presentation A 62-year-old male was hospitalized for treatment of deep vein thrombosis and pulmonary embolism. In the small intestine, computed tomography showed three small polyps with intussusceptions. Since the patient had gastrointestinal polyposis and pigmentation of his lips, fingers, and toes, he was diagnosed with PJS. After an inferior vena cava filter was placed, he underwent laparoscopic-assisted surgery. The polyps causing intussusception were resected as far as possible without intestinal resection, since they had caused progressive anemia and might cause intestinal obstruction in the future. The patient was discharged from the hospital on postoperative day 9 without complications. Conclusions Laparoscopic-assisted disinvagination and polypectomy is a useful, minimally invasive treatment for multiple intussusceptions caused by small intestinal polyps in patients with PJS.

Transcription-reverse transcription concerted reaction (TRC) is recognized as a useful method for detecting free cancer cells in the peritoneal cavity and predicting peritoneal recurrence in patients with gastric cancer. Nonetheless, the clinical significance of TRC in laparoscopic surgery remains unclear. This study aimed to evaluate the clinical importance of carcinoembryonic antigen (CEA) messenger RNA (mRNA) level in peritoneal lavage fluids measured by TRC in laparoscopic surgery for locally advanced gastric cancer. We enrolled patients with locally advanced gastric cancer who underwent laparoscopic gastrectomy. Peritoneal lavage fluids were collected prior to gastrectomy, and the TRC method was employed to quantify CEA mRNA in peritoneal washes. Overall survival (OS), recurrence-free survival (RFS), and peritoneal recurrence-free survival (PRFS) were analyzed using the Kaplan–Meier method and compared using the log-rank test. Adjusted Cox proportional hazards regression models were used to calculate the hazard ratios (HRs) for CEA mRNA positivity. A total of 100 patients were analyzed in this study. Overall, 22 patients (22%) exhibited CEA mRNA positivity in peritoneal lavage fluids, as measured by TRC. No significant association between CEA mRNA levels and clinicopathological characteristics was observed. Patients who were CEA mRNA-positive in peritoneal lavage fluids had significantly worse OS, RFS, and PRFS than those who were CEA mRNA-negative (p = 0.0059, p

Histological examination of the lymph nodes (LNs) is crucial to determine the colorectal cancer (CRC) stage. We previously reported a new fat-dissociation method (FM) to detect LNs from surgically resected mesentery. This study aimed to examine the effectiveness of FM compared with that of conventional palpation method (PM) in CRC. This single-center, open-label, randomized controlled study was performed at Osaka International Cancer Institute in Japan in 2014. Randomization was performed using a computer-generated permuted-block sequence. Patients were stratified by surgical procedures and the LN dissection area. The primary endpoint was the time required for LN identification. The secondary endpoint was the number of LNs and 5-year cancer-specific survival. The 130 enrolled patients were randomly assigned in a 1:1 ratio to the FM and the PM groups. LN identification times were 45 (range 15–80) and 15 (range 7–30) minutes in the PM and the FM groups, respectively (P P = 0.047). The number of LN which could be examined pathologically was 16 (range 2–48) and 18 (range 4–95) in the PM and FM groups, respectively (P = 0.546). In right-sided CRC, the number of LNs was higher in the FM group than in the PM group (P = 0.031). Relapse-free survival rates and cancer-specific survival rates did not differ between the groups. In conclusion, FM reduced the time required for LN detection without reducing the number of detected LNs, making it is a useful method to detect LNs in surgical specimens.

The intestinal environment plays important roles in mucosal barrier homeostasis and intestinal inflammation, as clarified in studies using experimental animals but not in humans. We investigated whether environmental changes in the fecal stream cause phenotypic changes in the human mucosal barrier. We obtained human ileal samples after fecal stream diversions in patients with rectal cancer or Crohn’s disease. We investigated the bacterial load and diversity in the human defunctioned ileum, defined as the anal side of the ileum relative to the ileostomy. We also examined the epithelium and lamina propria cell phenotypes in the defunctioned ileum. After fecal stream diversion, bacterial loads decreased significantly in the defunctioned ileum. Based on the Chao1, Shannon, and observed species indices, the diversity of mucosa-associated microbiota was lower in the defunctioned ileum than in the functional ileum. Moreover, the healthy defunctioned ileum showed reductions in villous height, goblet cell numbers, and Ki-67+ cell numbers. Additionally, interferon-γ+, interleukin-17+, and immunoglobulin A+ cell abundance in the lamina propria decreased. After the intestinal environment was restored with an ileostomy closure, the impaired ileal homeostasis recovered. The defunctioned ileum samples from patients with Crohn’s disease also showed reductions in interferon-γ+ and interleukin-17+ cell numbers. Fecal stream diversion reduced the abundance and diversity of intestinal bacteria. It also altered the intestinal mucosal barrier, similar to the alterations observed in germ-free animals. In patients with Crohn’s disease, Th1 and Th17 cell numbers were attenuated, which suggests that the host–microbiome interaction is important in disease pathogenesis.

Recently developed molecularly targeted therapies such as EGFR inhibitors have notably improved the prognosis of patients with cancer. However, patients with KRAS and BRAF mutations do not currently benefit from these therapies. Here, we aimed to examine potential effects of crenolanib as a new molecularly targeted therapy in colorectal cancer. We used multiple colorectal cancer cell lines to investigate the growth-inhibitory effect of crenolanib and its effect in combination with other cytotoxic agents. Primary cultures of patient-derived organoids (PDO), a model that reflects the heterogeneity of clinical colorectal cancer, were used to further validate the effects of crenolanib. Unlike cetuximab, crenolanib remarkably suppressed ERK and AKT/mTOR pathways in HT29 cells with BRAF mutation and in HCT116 cells with KRAS mutation with corresponding growth-suppressing effects. Additive or synergistic effects were observed in treatments with combination of crenolanib and other cytotoxic drugs. Moreover, crenolanib suppressed the expression of stem cell markers, such as OCT4, NANOG, and SOX2. These observations were substantiated in seven PDOs with KRAS mutation and two PDOs without KRAS/BRAF mutations, with crenolanib suppressing the growth of all PDOs regardless of their KRAS mutation status. Furthermore, crenolanib abrogated PDGF- and TGFβ-induced increase of OCT4-positive cells in PDOs. Together, these findings suggest that crenolanib may have clinical utility for patients with colorectal cancer, especially patients with KRAS/BRAF mutations. Implications: These findings indicate that crenolanib can be a useful target agent for patients with colorectal cancer, especially patients with KRAS/BRAF mutations.

Chromosome instability is one of the hallmarks of cancer. Stromal antigen (STAG) 3 is a core component of the meiosis-specific cohesin complex, which regulates sister chromatid cohesion. Although aberrantly activated genes encoding the cohesin complex have been identified in cancers, little is known about the role of STAG3 in colorectal cancer (CRC). Here, we evaluated the prognostic impact and role of STAG3 in CRC. Analysis of 172 CRC surgical specimens revealed that high STAG3 expression was associated with poor prognosis. STAG3 knockdown inhibited cell migration and increased drug sensitivity to oxaliplatin, 5-fluorouracil, irinotecan hydrochloride hydrate, and BRAF inhibitor in CRC cell lines. The enhanced drug sensitivity was also confirmed in a human organoid established from a CRC specimen. Moreover, suppression of STAG3 increased γH2AX foci. Particularly, in BRAF-mutant CRC cells, STAG3 silencing suppressed the expression of snail family transcriptional repressor 1 and phosphorylation of extracellular signal-regulated kinase via upregulation of dual-specificity phosphatase 6. Our findings suggest that STAG3 is related to poor clinical outcomes and promotes metastasis and chemotherapeutic resistance in CRC. STAG3 may be a novel prognostic marker and potential therapeutic target for CRC.

Two cases of neuroendocrine carcinoma, complicated with ulcerative colitis, were examined. Case 1:The patient developed ulcerative colitis at the age of 38, surgery was performed after a diagnosis of rectal cancer at the age of 53, and the patient was diagnosed with neuroendocrine carcinoma by pathological examination after resection. Post-surgery, metastatic nodules were detected in the liver and lungs. The patient is undergoing chemotherapy at this time. Case 2:The patient developed ulcerative colitis at the age of 59;at 72, a sigmoid colon tumor, in addition to multiple liver tumors, was detected. The patient was diagnosed with neuroendocrine carcinoma following biopsy. Chemotherapy was initiated;however, the patient died of cancer 12 months later.

In recent years, systemic chemotherapy has significantly improved the prognosis of metastatic colorectal cancer (CRC); however, different patients have different responses to chemotherapeutics. Dipeptidyl peptidase 9 (DPP9) is an enzyme in the dipeptidyl peptidase IV family that has been reported to increase drug sensitivity in acute myeloid leukemia. In this study, we examined the relationship between DPP9 expression and the prognosis of patients with CRC, as well as the role of DPP9 in anticancer drug resistance. Moreover, the effects of the DPP9 inhibitors talabostat and vildagliptin in CRC cell lines and primary cultured cells were assessed. High expression of DPP9 was associated with worse prognosis in 196 patients with CRC. Cell viability was markedly inhibited in CRC cell lines transfected with DPP9 small interfering RNA or small hairpin RNA. Talabostat suppressed proliferation in CRC cell lines and primary cultured cells, and increased their sensitivity to chemotherapy. Vildagliptin, a DPP family inhibitor currently administered for diabetes, also increased the sensitivity of CRC cells to anticancer drugs. DPP9 was a poor prognostic factor for CRC and could be a new therapeutic target, while vildagliptin could be used as a repositioned drug for CRC treatment.

For patients at high risk, such as those with lower-gastrointestinal perforations, it is important to establish a preventive method that reduces the incidence of surgical site infections (SSIs) significantly. We applied negative-pressure wound therapy (NPWT) as part of a delayed primary closure approach to prevent SSIs. This study evaluated the value of this technique.We included prospectively 28 patients undergoing abdominal surgery for peritonitis caused by a lower-gastrointestinal perforation between May 2014 and November 2015. Historical controls comprised retrospective data on 19 patients who had undergone primary suturing for managing peritonitis incisions for a lower-gastrointestinal perforation from January to December 2013.We found a significant association between the SSI incidence and the type of incision management (10.7% with NPWT and delayed closure vs. 63.2% with primary suturing; p 0.001). There was no significant difference between the groups in the length of the hospital stay (22 days for NPWT and delayed closure vs. 27 days for primary suturing; p = 0.45). No severe adverse events were observed related to NPWT.The use of NPWT and delayed primary closure was an effective measure for preventing SSI in patients undergoing abdominal surgery for peritonitis caused by lower-gastrointestinal perforation.

Crohn’s disease causes chronic inflammation in the gastrointestinal tract and its pathogenesis remains unclear. In the intestine of Crohn’s disease patients, CD14+CD11+CD163low macrophages contribute to inflammation through the induction of Th17 cells and production of inflammatory cytokines; the CD14+CD11c+163high fraction is anti-inflammatory through the production of IL-10 in normal cases. In this report, the 16S rRNA gene amplicon sequencing method was used to identify bacteria that are specifically present in intestinal CD14+CD11c+ macrophages of Crohn’s disease patients. Bacteria present in intestinal CD14+CD11c+ macrophages and mucus of Crohn’s disease patients were separated into different clusters in principal coordinates analysis. There was a statistically significant increase in the relative composition of CD14+CD11c+ macrophages from mucus in two phyla (Proteobacteria [p = 0.01] and Actinobacteria [p = 0.02]) and two families (Moraxellaceae [p

Minimally invasive treatment is getting more and more important in an aging society. The purpose of this study was to explore the possibility of ICG loaded on super carbonate apatite (sCA) nanoparticles as a novel photodynamic therapy (PDT) against cancers. Using colon cancer cells, ICG uptake and anti-tumor effects were examined between the treatments of ICG and sCA-ICG. Reactive oxygen species (ROS) production and temperature rise were also evaluated to explore the underlying mechanism. Atomic force microscopy revealed that the size of sCA-ICG ranged from 10 to 20 nm. In aqueous solution with 0.5% albumin, the temperature increase after laser irradiation was 27.1°C and 23.1°C in sCA-ICG and ICG, respectively (control DW: 5.7°C). A significant increase in ROS generation was noted in cell cultures treated with sCA-ICG plus irradiation compared with those treated with ICG plus irradiation (P < 0.01). Uptake of ICG in the tumor cells significantly increased in sCA-ICG compared with ICG in vitro and in vivo. The fluorescence signals of ICG in the tumor, liver, and kidney faded away in both treatments by 24 hours. Finally, the HT29 tumors treated with sCA-ICG followed by irradiation exhibited drastic tumor growth retardation (P < 0.01), whereas irradiation of tumors after injection of ICG did not inhibit tumor growth. This study shows that sCA is a useful vehicle for ICG-based PDT. Quick withdrawal of ICG from normal organs is unique to sCA-ICG and contrasts with the other nanoparticles remaining in normal organs for a long time. Mol Cancer Ther; 17(7); 1613–22. ©2018 AACR.

Pre-operative chemotherapy is an option for patients with local advanced rectal cancer, but the response rate to pre-operative chemotherapy with oxaliplatin is still low. If the therapeutic effect of pre-operative chemotherapy could be assessed, we may be able to convert to surgery early. The purpose of the present study was to validate the correlation between the maximum standardized uptake value (SUVmax) in 18F-fluorodeoxyglucose positron emission tomography–computed tomography (PET–CT) of the primary tumor and the therapeutic effect of pre-operative chemotherapy in advanced colorectal cancer. Retrospective cohort study from January 2011 to October 2015. We examined 28 patients with pathologically confirmed sigmoid or rectal cancer that underwent pre-operative chemotherapy and surgery. The correlation between Response Index (RI), calculated as (SUVmax after chemotherapy)/(SUVmax before chemotherapy), and the therapeutic effect on the primary tumor in advanced colorectal cancer. The degree of differentiation (p = 0.04), SUVmax in the primary tumor after chemotherapy (p = 0.02), and RI (p = 0.008) were significant predictors of the therapeutic effect in univariate analysis. The areas under the ROC curve constructed with RI and therapeutic effect was 0.77. The optimal cut-off values for the RI in the responder group was

Lateral lymph node dissection (LLND) is performed for advanced rectal cancers in Japan; however, it can cause sexual and urinary dysfunction. The incidence of lateral LN metastasis is estimated at 7–13.9%; therefore, excessive rectal surgery with LLND should be avoided, especially for prophylactic purposes. To identify the patients who require LLND, we examined metastases in perirectal LNs by using a one-step nucleic acid amplification (OSNA) assay to predict lateral LN metastases. Twenty-five patients who underwent surgery with bilateral LN dissection due to T3–T4 rectal cancers were prospectively included in this study. Twenty-two patients (88.0%) received preoperative chemotherapy. Among 1052 LNs from 25 patients (median 40 per case), 135 perirectal LNs (median 6 per patient) were divided into three pieces and analyzed by OSNA, reverse transcriptase-polymerase chain reaction for carcinoembryonic antigen mRNA, and pathological examination after surgery. These results were compared with the pathological diagnosis of lateral LNs. Lateral LN metastases were present in 4 of 25 patients (16.0%). All of these patients were positive by OSNA for perirectal LN metastases. The OSNA assay had a sensitivity of 100%, specificity of 86%, positive predictive value of 57%, and negative predictive value (NPV) of 100% for predicting lateral LN metastases. The findings from this prospective study suggest that the OSNA assay of perirectal LNs may be useful for determining when LLND is necessary because of its high NPV, even in patients treated with preoperative chemotherapy.

Background: Human intestinal innate myeloid cells can be divided into 3 subsets: HLA-DRCD14 cells, HLA-DRCD103 dendritic cells (DCs), and HLA-DRCD14CD103 cells. CD103 DCs generate Treg cells and Th17 cells in the ileum, but their function in the colon remains largely unknown. This study characterized CD103 DCs in the colon and investigated whether these cells are implicated in the pathogenesis of ulcerative colitis (UC). Methods: Normal intestinal mucosa was obtained from intact sites of patients with colorectal cancer (n = 24). Noninflamed and inflamed colonic tissues were obtained from surgically resected specimens of patients with UC (n = 13). Among LinCD45HLA-DR intestinal lamina propria cells, CD14 cells and CD103 DCs were sorted and analyzed for microRNA expression of cytokines and toll-like receptors by quantitative real-time polymerase chain reaction. In addition, IL-4/IL-5/IL-13/IL-17/IFN-γ production and Foxp3 expression by naive T cells cultured with CD14 cells and CD103 DCs were analyzed. Results: CD103 DCs in the normal colon showed lower expression of toll-like receptors and proinflammatory cytokines than CD14 cells. Coculture with naive T cells revealed that CD103 DCs generated Treg cells. CD103 DCs from patients with UC did not generate Treg cells, but they induced IFN-γ-, IL-13-, and IL-17-producing CD4 T cells and showed higher expression of IL6 (P < 0.0001), IL23A (P < 0.05), IL12p35 (P < 0.05), and TNF (P < 0.05). Conclusions: In patients with UC, CD103 DCs show the impaired ability to generate Treg cells, but exhibit a colitogenic function inducing Th1/Th2/Th17 responses. These findings show how human CD103 DCs could contribute to the pathogenesis of UC.

An elemental diet (ED) can suppress inflammation in patients with Crohn’s disease (CD); however, adherence to this diet is difficult. We examined the correlation between ED adherence and the postoperative recurrence of CD. The subjects of this study were 38 patients who underwent intestinal resection with anastomosis. We defined ED adherence as consuming the average daily ED dose (≥900 kcal/day) for 2 years after surgery. Patients who did not adhere to the ED were allocated to the non-ED group. We diagnosed symptomatic recurrence using the CD activity index and endoscopic recurrence using the Rutgeerts’ score. The ED and non-ED groups comprised 21 and 17 patients, respectively, with ED adherence of 55.3% (21/38). At the initial endoscopy, symptomatic and endoscopic recurrence rates were 4.8 and 14.3%, respectively, in the ED group, and 23.5 and 41.2%, respectively, in the non-ED group (P = 0.152 and P = 0.078, respectively). The overall symptomatic recurrence-free duration was significantly longer than the endoscopic recurrence-free duration (P = 0.022). Symptomatic and endoscopic recurrence-free durations were longer in the ED group than in the non-ED group (P = 0.003 and P = 0.021, respectively), and ED adherence was a prognostic factor for endoscopic recurrence (HR = 2.777, 95% CI = 1.036–8.767, P = 0.042). Maintaining ED adherence for 2 years after surgery improved the symptomatic and endoscopic recurrence-free durations.

We aimed to determine the recommended dose for bi-weekly XELIRI plus bevacizumab for second-line chemotherapy and examined its safety and efficacy in patients with metastatic colorectal cancer resistant to oxaliplatin-based first-line chemotherapy. Irinotecan and bevacizumab were administered as a continuous intravenous infusion on Day 1 at 150 mg/mm2 and 5 mg/kg, respectively. Capecitabine was orally administered in two divided doses on Days 2–8. Each 2-week treatment cycle was defined as a single course of treatment. During Phase I, we determined the recommended dose for capecitabine. In Phase II trials, efficacy and treatment safety was verified (UMIN000003934). The recommended dose of capecitabine was determined to be 2000 mg/m2. Median progression-free survival was 7.8 months [95% confidence interval (CI) 6.1–10.9 months], and median overall survival was 18.9 months (95% CI 11.6–28.4 months). Response rate was 17.4% (95% CI 6.4–28.3%). The most common Grade ≥3 hematotoxic adverse events were anemia (10.9%), neutropenia (10.9%), and leukopenia (8.7%), while the occurrence rate of Grade ≥3 non-hematotoxic adverse events was relatively low (

BACKGROUND Small bowel adenocarcinoma (SBA) is rare. For unresectable or recurrent SBA, systemic treatment is the only potentially promising option. PATIENTS AND METHODS This retrospective study included 13 patients with SBA treated at our Institute. All patients received fluorouracil- or fluoropyrimidine-based regimens. We analyzed associations between the progression-free interval (PFI) and therapeutic regimen (n=17) and patient characteristics. RESULTS The 5-year overall survival of patients with SBA was 23.5%. The 5-year relapse-free survival of patients with curatively resected (R0 or R1) SBA (n=6) was 45%. Patients with unresectable or recurrent SBA (n=10) had a median overall survival time of 28.0 months. No factor was significantly associated with PFI, except the number of treatment regimens required: patients that received only one line of treatment survived significantly longer than those receiving multiple lines. CONCLUSION Fluorouracil- or fluoropyrimidine-based regimens might effectively treat unresectable or recurrent SBA. We did not investigate any additive agents that might have increased efficacy of these regimens.

Recent studies have shown that microRNAs (miRNAs) are involved in the progression of colorectal cancer (CRC). The aim of this study is to identify a novel miRNA that especially relates to liver metastasis and to explore the underlying mechanism. Differentially expressed miRNAs were analyzed using microarray, in primary CRC tumors without metastasis (n=16), those with liver metastasis (n=12), and liver metastatic lesions (n=8). We found that miR-487b level decreased in liver metastatic lesions, and qRT-PCR confirmed the results in the validating cohort (n=134). Survival analysis indicated that high expression of miR-487b was associated with better prognosis. In vitro studies were also performed to investigate the functional significance of miR-487b in human CRC cell lines. miR-487b showed an inhibitory effect on cell proliferation and invasion of CRC cells. miR-487b downregulated KRAS and inhibited its downstream signal pathways, and the luciferase reporter assay revealed that miR-487b directly targeted LRP6, a receptor for WNT/β-catenin signaling. These findings showed that decrease in miR-487b was related with liver metastasis. Our data suggest a possibility that miR-487b may suppress metastasis of CRC progression through inhibition of KRAS.

Hypoxia is an essential feature of cancer malignancy, but there are no methods for the routine detection of hypoxia-inducible prognostic factors and potential therapeutic targets. We reported previously that the hypoxic tumor cells of metastatic liver tissue from patients with colorectal cancer (CRC) could be used as an 'in vivo' hypoxia culture model. Several potential hypoxia-inducible genes were identified using this model. Among them, one glycolytic enzyme was of special interest. There is currently increasing attention on glycolytic enzymes as potential therapeutic targets due to their association with cancer-specific metabolism. To better understand the molecular mechanisms of cancer malignancy, we investigated the expression of fructose-bisphosphate aldolase A (ALDOA) and its relationship with cancer metabolism. We found that ALDOA was induced by hypoxia in CRC-derived cell lines, and univariate and multivariate analyses of microarray data from the resected CRC samples of 222 patients revealed that ALDOA was an independent prognostic factor for CRC. We also analyzed the malignant potential of ALDOA in vitro using overexpression and knockdown assays. We found that ALDOA was negatively related to chemosensitivity and radiosensitivity and positively associated with proliferation, sphere formation and invasion in both normoxia and hypoxia. These associations were due to the roles of ALDOA in regulating glycolysis, the epithelial-mesenchymal transition and the cell cycle. These findings demonstrate that ALDOA is a hypoxia-inducible prognostic factor that is closely related to CRC malignancy, and also provide new insights into the importance of ALDOA and glycolysis in cancer and suggest new targets for anticancer therapies.

Purpose: Dose adjustment of 5-fluorouracil (FU) based on pharmacokinetic monitoring has been shown to reduce toxicities and increase efficacy compared with dosing based on body surface area in patients with metastatic colorectal cancer (mCRC). We evaluated the efficacy and safety of pharmacokinetic dose adjustment of FU in a modified FOLFOX7 (mFOLFOX7) plus bevacizumab regimen in Japanese patients with previously untreated mCRC. Methods: This single-arm, multicenter phase II trial enrolled 48 patients with mCRC. Treatment consisted of 5 mg/kg intravenous bevacizumab followed by mFOLFOX7 (oxaliplatin 85 mg/m2 on day 1, infused leucovorin 200 mg/m2, followed by a 2400 mg/m2 infusion of FU for 46 h starting on day 1), repeated every 2 weeks. FU concentrations were measured by immunoassay between 18 and 36 h after the start of continuous FU infusion, and the FU dose was then adjusted if required in subsequent cycles. The primary endpoint was response rate. Results: The median initial area under the concentration–time curve for FU was 23 mg h/L. Twenty-nine patients (60%) achieved the target concentration at the first cycle, and all 48 achieved it within the fourth cycle. The overall frequency of grade 3/4 adverse effects was 38%, with no significant difference between patients who did and not require dose adjustments. The overall response rate was 48% (95% confidence intervals = 34–62%). The median progression-free and overall survival rates were 11.3 and 24.1 months, respectively. Conclusions: Pharmacokinetic dose adjustment of FU in mFOLFOX7 plus bevacizumab can optimize FU concentrations promptly and is safe in Japanese patients with mCRC.

Innate lymphoid cells (ILC) are responsible for mucosal tissue homeostasis and are involved in the progression and suppression of several types of cancer. However, the effects of ILCs on colorectal cancer are poorly understood. We characterized human ILCs in normal colon and colorectal cancer tissue, investigating their role in the tumor immune microenvironment. Normal mucosa and tumor tissues were obtained from patients with colorectal cancer, and the cells were isolated by enzymatic digestion. NKp44

Background Preoperative 5-FU-based chemoradiation is currently a standard treatment for advanced rectal cancer, particularly in Western countries. Although it reduced the local recurrence, it could not necessarily improve overall survival. Furthermore, it can also produce adverse effects and long-term sphincter function deficiency. Adjuvant oxaliplatin plus capecitabine (XELOX) is a recommended regimen for patients with curatively resected colon cancer. However, the efficacy of postoperative adjuvant therapy for rectal cancer patients who have not undergone preoperative chemoradiation remains unknown. We aimed to evaluate the efficacy of surgery and postoperative XELOX without preoperative chemoradiation for treating rectal cancer. Methods We performed a prospective, multicenter, open-label, single arm phase II study. Patients with curatively resected high-risk stage II and stage III rectal cancer who had not undergone preoperative therapy were treated with a 120 min intravenous infusion of oxaliplatin (130 mg/m2) on day 1 and capecitabine (2000 mg/m2/day) in 2 divided doses for 14 days of a 3-week cycle, for a total of 8 cycles (24 weeks). The primary endpoint was 3-year disease-free survival (DFS). Results Between August 2012 and June 2015, 60 men and 47 women with a median age was 63 years (range: 29–77 years) were enrolled. Ninety-three patients had Eastern Cooperative Oncology Group performance status scores of ‘0’ and 14 had scores of ‘1’. Tumors were located in the upper and lower rectums in 54 and 48 patients, respectively; 8 patients had stage II disease and 99 had stage III. The 3-year DFS was 70.1% (95% confidence interval, 60.8–78.0%) and 33 patients (31%) experienced recurrence, most commonly in the lung (16 patients) followed by local recurrence (9) and hepatic recurrence (7). Conclusions Postoperative XELOX without preoperative chemoradiation is effective for rectal cancer and provides adequate 3-year DFS prospects. Trial registration This clinical trial was registered in the University Hospital Medical Information Network registry system as UMIN000008634 at Aug 06, 2012.

Background It is important to establish cancer stem cell (CSC)-targeted therapies to eradicate cancer. As it is a CSC marker, we focused on Kruppel-like factor 5 (KLF5) in this study. Methods We searched for candidate microRNAs (miRNAs) that inhibited KLF5 expression by in silico analyses and screened them in colon cancer cell lines. Results We identified one promising miRNA, miR-4711-5p, that downregulated KLF5 expression by direct binding. This miRNA suppressed cell proliferation, migration and invasion ability, as well as stemness, including decreased stem cell marker expression, reactive oxygen species activity and sphere formation ability. MiR-4711-5p inhibited the growth of DLD-1 xenografts in nude mice with no adverse effects. We found that miR-4711-5p provoked G1 arrest, which could be attributed to direct binding of miR-4711-5p to TFDP1 (a heterodimeric partner of the E2F family). Our findings also suggested that direct binding of miR-4711-5p to MDM2 could upregulate wild-type p53, leading to strong induction of apoptosis. Finally, we found that miR-4711-5p had a potent tumour-suppressive effect compared with a putative anti-oncomiR, miR-34a, in tumour cell cultures derived from five patients with colorectal cancer. Conclusions Our data suggest that miR-4711-5p could be a promising target for CSC therapy.

Inflammation and the nutritional and immunologic status are known to be associated with the prognosis of malignant tumors. We aimed to examine inflammation–nutrition scores and predict the prognosis of colorectal cancer (CRC) patients by integrating nutritional and immunologic factors and tumor stage. This study investigated 511 patients with CRC from 2007 to 2013: 380 in a training set (TS) and 131 in a validation set (VS). The Osaka Prognostic Score (OPS) used comprised 1 point each for C-reactive protein > 1.0 mg/dL, albumin (