Three-year outcomes of preoperative chemoradiotherapy plus nivolumab in microsatellite stable and microsatellite instability-high locally advanced rectal cancer.

BACKGROUND: Preoperative chemoradiotherapy (CRT) followed by surgery is the standard treatment for locally advanced rectal cancer (LARC). We reported the short-term outcomes of the VOLTAGE trial that investigated the safety and efficacy of preoperative CRT followed by nivolumab and surgery. Here, we present the 3-year outcomes of this trial. METHODS: Thirty-nine patients with microsatellite stable (MSS) LARC and five patients with microsatellite instability-high (MSI-H) LARC underwent CRT (50.4 Gy) followed by five doses of nivolumab (240 mg) and surgery. The 3-year relapse-free survival (RFS), overall survival (OS), and associations with biomarkers were evaluated. RESULTS: The 3-year RFS rates in patients with MSS and MSI-H were 79.5% and 100%, respectively, and the 3-year OS rates were 97.4% and 100%, respectively. Of the MSS patients, those with pre-CRT PD-L1 positivity, pre-CRT high CD8 + T cell/effector regulatory T cell (eTreg) ratio, pre-CRT high expression of Ki-67, CTLA-4, and PD-1 had a trend toward better 3-year RFS than those without. CONCLUSIONS: Three-year outcomes of patients with MSI-H were better than those of patients with MSS. PD-L1 positivity, elevated CD8/eTreg ratio, and high expression of Ki-67, CTLA-4, and PD-1 could be positive predictors of prognosis in patients with MSS. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02948348.

Expression Analysis of Early Metastatic Seeding of Colorectal Cancer.

BACKGROUND: Distant metastasis is the leading cause of death in patients with colorectal cancer (CRC). Tumor dissemination for metastasis formation occurs in advanced cancers and also during early stages of tumorigenesis. Here, we investigated the genes involved in early metastatic seeding of CRC using gene expression analysis. PATIENTS AND METHODS: We performed a cDNA microarray using specimens resected from stages I-II CRC with and without metachronous metastatic recurrence. For the candidate genes, we immunohistochemically validated protein expression using a tissue microarray of stages I-III CRC. RESULTS: The expression of TROP2, VWCE, and BMP7 was upregulated in the recurrence group rather than in the non-recurrence group. Protein expression analysis revealed significant association of these genes with distant metastatic recurrence. The specimens with high expression of BMP7 showed worse recurrence-free survival (RFS; p = 0.02). Those with high expression of TROP2 and VWCE showed worse overall survival (OS) and RFS (TROP2: p = 0.01 and p = 0.03; VWCE: p < 0.05 and p < 0.001, respectively). In the multivariate analysis, high expression of VWCE and BMP7 was an independent predictor of recurrence [VWCE: hazard ratio (HR) 3.41, p < 0.001; BMP7: HR 2.93, p = 0.005]. In contrast, TROP2 was an independent prognostic factor for OS (HR 4.58, p = 0.03). CONCLUSIONS: Gene expression analysis revealed that TROP2, VWCE, and BMP7 were involved in early metastatic seeding. The high expression of these genes may warrant careful surveillance or adjuvant therapy, even in stages I-II CRC cases.

Endoscopic Surgical Skill Qualification System: propensity-score matched cohort analysis of accredited supervisors in laparoscopic rectal cancer surgery.

BACKGROUND: The Endoscopic Surgical Skill Qualification System (ESSQS) in Japan evaluates the surgical skills required for laparoscopic surgery as an operator as well as a supervisor. This study aimed to demonstrate the benefits of an ESSQS-certified surgeon's participation in laparoscopic rectal resections as a supervisor (assistant or advisor). METHODS: We retrospectively reviewed laparoscopic resection results for cStage II and III rectal cancer performed at 56 Japanese hospitals between 2014 and 2016. We used propensity score matching to generate paired cohorts with or without an ESSQS-certified supervisor at a one-to-one ratio. The impact of ESSQS-certified supervisors' participation on short-term outcomes was assessed. In the matched cohort, multivariable logistic regression analysis and multivariable regression analysis of postoperative complication rate and intraoperative blood loss were performed to further mitigate the impact of pathological factors. RESULTS: Two groups (n = 399 each) with or without an ESSQS-certified supervisor were well matched by clinical factors. The group with an ESSQS-certified supervisor had lower blood loss (68 mL vs. 98 mL, P = 0.036) and a lower incidence of severe morbidities of Clavien-Dindo grade ≥IIIa (8.0% vs. 13.3%, P = 0.016). Multivariable logistic regression analysis and multivariable regression analysis confirmed that the attendance of ESSQS-certified supervisors reduced postoperative complication occurrence (adjusted odds ratio: 2.28, 95% confidence interval: 1.38 - 3.80, P = 0.001) and intraoperative blood loss (estimated difference: -15.7 mL, P = 0.016). CONCLUSION: This study demonstrated the educational benefits of ESSQS-certified supervisors, including assistants and advisors, evidenced by their superior short-term outcomes.

[A Case of Pathological Complete Response of Advanced Rectal Cancer with Direct Invasion of the Prostate and Extra-Regional Lymph Node Metastasis after Chemotherapy].

A 62-year-old man was diagnosed as having advanced rectal cancer with an invasive carcinoma of the prostate and the right inguinal lymph node metastasis. He received chemotherapy consisting of combination of 5-FU, oxaliplatin, Leucovorin (mFOLFOX6)and bevacizumab. After 5 courses of the chemotherapy, CT and MRI findings revealed the tumor shrinkage. After 6 courses of the chemotherapy, a laparoscopic abdominoperineal resection, bilateral lymph node dissection and a resection of right inguinal lymph node were performed. The pathological findings showed a pCR. NAC with mFOLFOX6 and bevacizumab may contribute to the reduction of the surgical stress for the patients and be an effective treatment for advanced rectal cancer with distant lymph node metastasis.

STAT1-mediated induction of Ly6c-expressing macrophages are involved in the pathogenesis of an acute colitis model.

BACKGROUND: The development of inflammatory bowel diseases is thought to be multifactorial, but the exact steps in pathogenesis are poorly understood. In this study, we investigated involvement of the activation of STAT1 signal pathway in the pathogenesis of an acute colitis model. METHODS: A dextran sulfate sodium-induced acute colitis model was established by using wild-type C57BL/6 mice and STAT1-deficient mice. Disease indicators such as body weight loss and clinical score, induction of cytokines, chemokines, and inflammatory cells were evaluated in the acute colitis model. RESULTS: Disease state was significantly improved in the acute colitis model using STAT1-deficient mice compared with wild-type mice. The induction of Ly6c-highly expressing cells in colorectal tissues was attenuated in STAT1-deficient mice. IL-6, CCL2, and CCR2 gene expressions in Ly6c-highly expressing cells accumulated in the inflamed colon tissues and were significantly higher than in Ly6c-intermediate-expressing cells, whereas TNF-α and IFN-α/ß gene expression was higher in Ly6c-intermediate-expressing cells. Blockade of CCR2-mediated signaling significantly reduced the disease state in the acute colitis model. CONCLUSIONS: Two different types of Ly6c-expressing macrophages are induced in the inflamed tissues through the IFN-α/ß-STAT1-mediated CCL2/CCR2 cascade and this is associated with the pathogenesis such as onset, exacerbation, and subsequent chronicity of acute colitis.

Modified complete mesocolic excision with central vascular ligation by the squeezing approach in laparoscopic right colectomy.

PURPOSE: Complete mesocolic excision (CME) and central vascular ligation (CVL) are becoming the standard procedure in laparoscopic right-sided colectomy. However, the approach to CME and CVL has not been established, although several useful approaches have been reported. The squeezing approach described herein is a novel procedure to perform modified CME and CVL in laparoscopic right colectomy. METHODS: The squeezing approach features retroperitoneal mobilization followed by cranial mesocolic mobilization and lymph node dissection using a cranial approach followed by a caudal approach. Dissection of the regional lymph nodes along with central vascular ligation was performed along the anterior wall of the superior mesenteric vein. In total, 177 patients (mean age, 70.6 years; male-to-female ratio, 90:87) who underwent laparoscopic right-sided colectomy were retrospectively assessed. Descriptive statistics for patient characteristics were calculated. RESULTS: The mean operative time and blood loss were 169 min and 37 mL, respectively. Seven patients (4.0%) required conversion to open surgery, and major postoperative complications occurred in five patients (2.8%) with no anastomotic leakage. Histological R0 resection was achieved in all cases of stages 0-III colon cancer. The 5-year recurrence-free survival rates were 100% (n = 19), 100% (n = 40), 87% (n = 46), and 81% (n = 43) in pathological stages 0, I, II, and III, respectively. Node recurrence occurred in one case near the root of the middle colic artery. CONCLUSION: The novel squeezing approach in laparoscopic right colectomy could be safely performed in terms of the technical and oncological aspects.

The survival impact of preoperative FOLFOX for resectable locally advanced rectal cancer: the R-NAC-01 study.

PURPOSE: In this follow-up of the R-NAC-01 study, we assessed the long-term oncological benefit of four courses of modified leucovorin, 5-fluorouracil (FU), and oxaliplatin (mFOLFOX6) chemotherapy before rectal surgery. METHODS: In this prospective, multicenter study (UMIN 000012559) involving 11 hospitals in Japan, patients with lower rectal cancer underwent four cycles of mFOLFOX6 chemotherapy and subsequent surgery within four to six weeks. The 3-year recurrence-free survival and local recurrence rates were then reported. RESULTS: Of 41 patients (36 males, 5 females; mean age: 60.8 years old) who received 4 courses of chemotherapy, 40 underwent total mesorectal excision, and 1 underwent total pelvic exenteration. R0 resection was achieved in 40 patients, but none showed a pathological complete response. Twenty-nine patients received adjuvant chemotherapy for an average of 4 months. The 3 year recurrence-free survival and local recurrence rates in patients undergoing curable resection were 72.8% and 8.5%, respectively. cStage III patients with adjuvant chemotherapy had a significantly higher 3 year recurrence-free survival than those without adjuvant chemotherapy (76.6 vs. 40.0%, log-rank p = 0.03). CONCLUSION: Four courses of mFOLFOX6 chemotherapy before surgery may be a promising treatment strategy for locally advanced rectal cancer. Adjuvant chemotherapy might be needed for cStage III patients, even after four courses of neoadjuvant mFOLFOX6.

Prognostic Significance of Circulating Tumor Cells with Mesenchymal Phenotypes in Patients with Gastric Cancer: A Prospective Study.

BACKGROUND: Circulating tumor cells (CTCs) have been shown to be heterogeneous. Focusing on the epithelial-mesenchymal transition and perioperative kinetics, we evaluated CTCs with mesenchymal phenotypes as a potential prognostic biomarker for patients with gastric cancer. METHODS: Peripheral blood was collected from 54 patients with gastric cancer before surgery and at 1 week and 1 month after surgery. CTCs were enriched using density-gradient centrifugation and magnetic-activated cell sorting (negative selection). Cell suspensions were characterized by multi-immunofluorescence staining against cytokeratin and N-cadherin, and by 4',6'-diamidino-2-phenyldole staining. RESULTS: CTCs were detected in five patients (17%) with early cancer and 14 patients (56%) with advanced cancer (p < 0.05). In our system, N-cadherin, but not cytokeratin, was expressed in the CTCs of 90% (19/21) of patients. Postoperative recurrence was detected in 10 patients, all of whom had N-cadherin+/cytokeratin-/CD45- CTCs preoperatively. Regarding perioperative kinetics, we divided patients into three risk groups: a high-risk group, with one or more preoperative CTCs and increased CTCs postoperatively; an intermediate-risk group, with one or more preoperative CTCs and decreased CTCs postoperatively; and a low-risk group, with no preoperative CTCs. Recurrence rates were 57% (4/7), 33% (4/12), and 6% (2/35), respectively. The relapse-free survival rate was lower in patients at high risk versus those at intermediate or low risk, for all patients (p = 0.00024) and in patients with advanced cancer (p = 0.00103). CONCLUSIONS: N-cadherin is a highly useful marker to detect CTCs lacking cytokeratin, and the perioperative kinetics of CTC numbers is beneficial in risk stratification for survival in patients with gastric cancer.

An increase in the peripheral lymphocyte-to-monocyte ratio after primary site resection is associated with a prolonged survival in unresectable colorectal carcinoma.

PURPOSE: The prognostic benefits of primary tumor resection in patients with unresectable distant metastatic colorectal cancer remain unclear. A high pre-treatment lymphocyte-to-monocyte ratio (LMR) was previously shown to be associated with a better prognosis. We assessed whether or not primary tumor resection was associated with an improved survival if the peripheral lymphocyte-to-monocyte ratio increased after primary site resection. METHODS: The survival in 64 and 59 patients with and without primary tumor resection, respectively, was retrospectively compared. After resection, the survival in 39 patients with a postoperatively increased LMR (LMR-increase) and 25 patients with a decreased LMR (LMR-decrease) was compared. RESULTS: Primary tumor resection prolonged the median survival more frequently in cases of non-differentiated adenocarcinoma, obstructive symptoms, high serum albumin levels, and no lymph-node metastasis than in others. Cox regression showed that the potential independent prognostic variable was non-resection of the primary lesion. After resection, the median survival in the LMR-increase vs. LMR-decrease groups was significantly different (27.3 vs. 20.8 months). There were no marked differences in patient background characteristics between the groups, except for in the number of pre-operative peripheral blood lymphocytes. The resected specimens showed significantly lower CD8+:CD163+ invading leukocyte ratios in the LMR-increase group than in the LMR-decrease group. CONCLUSIONS: Primary tumor resection in patients with unresectable metastatic colorectal cancer may be associated with an improved survival, especially when the LMR is increased after primary tumor resection.

Chorionic Gonadotropin-ß Modulates Epithelial-Mesenchymal Transition in Colorectal Carcinoma Metastasis.

Ectopic production of free ß human chorionic gonadotropin (hCGß) has been associated with aggressive behavior in non-trophoblastic tumors. hCGß shares common evolutionary sequences with transforming growth factor-ß (TGF-ß), which represents a major driving force of epithelial-to-mesenchymal transition (EMT). In this study, we examined the biological roles of hCGß during EMT and its clinical significance in colorectal cancer (CRC) progression. Eighty CRC specimens and 54 preoperative serum samples were analyzed. hCGß-overexpressing human CRC cell lines were examined for invasiveness and tumorigenicity, and the expression of EMT-associated genes was investigated. In human CRC, histologic hCGß positivity [13/80 (16.3%)] was lower than serologic hCGß positivity [13/54 (24.1%)]. However, it was significantly correlated with several clinicopathological features and unfavorable outcome (P < 0.05). hCGß-overexpressing cell lines had increased invasiveness, migratory ability, and metastatic potential in mice (P < 0.01). Western blot, PCR, and microarray analyses showed hCGß altered expression of EMT-related genes, including E-cadherin, phosphorylated SMAD2, SNAIL, and TWIST. hCGß-induced SNAIL and TWIST overexpression levels were reversible by type I and type II TGF-ß receptor inhibitors (P < 0.05). hCGß thus induces EMT via the TGF-ß signaling pathway, and it may represent a molecular target in CRC treatment.

Preoperative FOLFOX in resectable locally advanced rectal cancer can be a safe and promising strategy: the R-NAC-01 study.

PURPOSE: The aim of this study was to assess the safety of rectal surgery after 5-fluorouracil-leucovorin-oxaliplatin chemotherapy (FOLFOX6). METHODS: This was a prospective, multicenter study in 11 Japanese hospitals. We included patients with rectal cancer who received 4 courses of modified FOLFOX6 (mFOLFOX6) before rectal surgery and examined the postoperative complication rate, the clinicopathological response, and the rate of chemotherapy-related adverse events (UMIN 000012559). RESULTS: The study population included 36 men and 5 women. The average age of the patients was 60.8 years and the average body mass index was 23.1 kg/m2. After 4 courses of chemotherapy, grade 2 peripheral nerve disorder and other grade 3 adverse events were seen in 3 patients each (7.3%). Twenty-eight (73.7%) and 8 (21.1%) patients underwent low anterior resection and abdominoperineal resection, respectively. The pelvic nerves were preserved in 35 patients. Surgical morbidity (grade ≥ 3) occurred in 4 patients (10.5%). Anastomotic leakage occurred after surgery in 2 patients (7.1%). No patients achieved pathologically complete remission. However, downstaging of the clinical stage and N stage was seen in 17 (41.5%) and 22 (53.7%) patients, respectively. CONCLUSIONS: Surgery after four courses of mFOLFOX6 chemotherapy can be a safe and promising strategy for patients with locally advanced rectal cancer.

Supervision by a technically qualified surgeon affects the proficiency and safety of laparoscopic colectomy performed by novice surgeons.

BACKGROUND: The use of laparoscopic colectomy is becoming widespread and acquisition of its technique is challenging. In this study, we investigated whether supervision by a technically qualified surgeon affects the proficiency and safety of laparoscopic colectomy performed by novice surgeons. METHODS: The outcomes of 23 right colectomies and 19 high anterior resections for colon cancers performed by five novice surgeons (experience level of <10 cases) between 2014 and 2016 were assessed. A laparoscopic surgeon qualified by the Endoscopic Surgical Skill Qualification System (Japan Society for Endoscopic Surgery) participated in surgeries as the teaching assistant. RESULTS: In the right colectomy group, one patient (4.3%) required conversion to open surgery and postoperative morbidities occurred in two cases (8.6%). The operative time moving average gradually decreased from 216 to 150 min, and the blood loss decreased from 128 to 28 mL. In the CUSUM charts, the values for operative time decreased continuously after the 18th case, as compared to the Japanese standard. The values for blood loss also plateaued after the 18th case. In the high anterior resection group, one patient (5.2%) required conversion to open surgery and no postoperative complication occurred in any patient. The operative time moving average gradually decreased from 258 to 228 min, and the blood loss decreased from 33 to 18 mL. The CUSUM charts showed that the values of operative time plateaued after the 18th case, as compared to the Japanese standard. In the CUSUM chart for blood loss, no distinguishing peak or trend was noted. CONCLUSIONS: Supervision by a technically qualified surgeon affects the proficiency and safety of laparoscopic colectomy performed by novice surgeons. The trainee's learning curve in this study represents successful mentoring by the laparoscopic surgeon qualified by the Endoscopic Surgical Skill Qualification System.

Interleukin-6/STAT3 signaling as a promising target to improve the efficacy of cancer immunotherapy.

Overcoming the immunosuppressive state in tumor microenvironments is a critical issue for improving the efficacy of cancer immunotherapy. Interleukin (IL)-6, a pleiotropic cytokine, is highly produced in the tumor-bearing host. Previous studies have indicated that IL-6 suppresses the antigen presentation ability of dendritic cells (DC) through activation of signal transducer and activator of transcription 3 (STAT3). Thus, we focused on the precise effect of the IL-6/STAT3 signaling cascade on human DC and the subsequent induction of antitumor T cell immune responses. Tumor-infiltrating CD11b+ CD11c+ cells isolated from colorectal cancer tissues showed strong induction of the IL-6 gene, downregulated surface expression of human leukocyte antigen (HLA)-DR, and an attenuated T cell-stimulating ability compared with those from peripheral blood mononuclear cells, suggesting that the tumor microenvironment suppresses antitumor effector cells. In vitro experiments revealed that IL-6-mediated STAT3 activation reduced surface expression of HLA-DR on CD14+ monocyte-derived DC. Moreover, we confirmed that cyclooxygenase 2, lysosome protease and arginase activities were involved in the IL-6-mediated downregulation of the surface expression levels of HLA class II on human DC. These findings suggest that IL-6-mediated STAT3 activation in the tumor microenvironment inhibits functional maturation of DC to activate effector T cells, blocking introduction of antitumor immunity in cancers. Therefore, we propose in this review that blockade of the IL-6/STAT3 signaling pathway and target molecules in DC may be a promising strategy to improve the efficacy of immunotherapies for cancer patients.

Lack of interleukin-6 in the tumor microenvironment augments type-1 immunity and increases the efficacy of cancer immunotherapy.

Conquering immunosuppression in tumor microenvironments is crucial for effective cancer immunotherapy. It is well known that interleukin (IL)-6, a pleiotropic cytokine, is produced in the tumor-bearing state. In the present study, we investigated the precise effects of IL-6 on antitumor immunity and the subsequent tumorigenesis in tumor-bearing hosts. CT26 cells, a murine colon cancer cell line, were intradermally injected into wild-type and IL-6-deficient mice. As a result, we found that tumor growth was decreased significantly in IL-6-deficient mice compared with wild-type mice and the reduction was abrogated by depletion of CD8+ T cells. We further evaluated the immune status of tumor microenvironments and confirmed that mature dendritic cells, helper T cells and cytotoxic T cells were highly accumulated in tumor sites under the IL-6-deficient condition. In addition, higher numbers of interferon (IFN)-γ-producing T cells were present in the tumor tissues of IL-6-deficient mice compared with wild-type mice. Surface expression levels of programmed death-ligand 1 (PD-L1) and MHC class I on CT26 cells were enhanced under the IL-6-deficient condition in vivo and by IFN-γ stimulation in vitro. Finally, we confirmed that in vivo injection of an anti-PD-L1 antibody or a Toll-like receptor 3 ligand, polyinosinic-polycytidylic acid, effectively inhibited tumorigenesis under the IL-6-deficient condition. Based on these findings, we speculate that a lack of IL-6 produced in tumor-bearing host augments induction of antitumor effector T cells and inhibits tumorigenesis in vivo, suggesting that IL-6 signaling may be a promising target for the development of effective cancer immunotherapies.

Anastomotic complications after laparoscopic total gastrectomy with esophagojejunostomy constructed by circular stapler (OrVil™) versus linear stapler (overlap method).

BACKGROUND: Esophagojejunostomy after laparoscopic total gastrectomy (LTG) is the most technically difficult type of anastomosis; thus, anastomotic complications such as leakage and stenosis sometimes occur. Identification of the safest anastomotic procedure is important for successful LTG. We have performed LTG since 2004 either with a circular stapler using an OrVil™ anvil or via the overlap Orringer method with a linear stapler. This retrospective study aimed to determine which method results in a lower incidence of anastomotic complications in patients undergoing LTG. METHODS: Data on 188 consecutive patients who underwent LTG between April 2004 and August 2016 were retrospectively reviewed. Patients were divided into those who underwent esophagojejunostomy performed via a circular stapler using an OrVil™ anvil (group C, n = 49) or via the overlap method (group L, n = 139). RESULTS: Anastomotic complications occurred in five of 188 esophagojejunostomies (2.7%). They comprised three cases of leakage (1.6%), and two of stenosis (1.1%). There was no significant difference in patient characteristics or hematological variables between groups C and L. There was no significant difference between groups in operation time, blood loss, lymph node dissection, and intraoperative anastomotic problems. The rate of anastomotic complications was significantly lower in group L (0.7%, 1/139) than in group C (8.2%, 4/49; p = 0.005). In particular, anastomotic leakage in group L tended to be lower (0.7% 1/139) than in group C (4.1% 2/49), although this difference was not significant. The rate of anastomotic stenosis in group L was significantly lower (0%, 0/139) than in group C (4.1%, 2/49; p = 0.017). Furthermore multivariate analysis showed anastomotic procedure was an independent factor for anastomotic complication. CONCLUSIONS: There were fewer anastomotic complications after overlap esophagojejunostomy than after esophagojejunostomy via the OrVil™ procedure, especially regarding anastomotic stenosis. We therefore recommend the overlap technique when performing esophagojejunostomy.

Postoperative analgesia using fentanyl plus celecoxib versus epidural anesthesia after laparoscopic colon resection.

PURPOSE: Effective postoperative analgesia is essential to a patient's recovery after laparoscopic colon resection (LCR). We introduce a new analgesic protocol using fentanyl plus celecoxib following LCR. METHODS: The subjects of this retrospective comparative study were 137 patients who underwent LCR, 63 of whom were treated with 72 h of epidural anesthesia (group E), and 74 of whom were treated with 24 h of fentanyl intravenous injection followed by 7 days of oral celecoxib (group FC). We evaluated the safety and efficacy of this new protocol. RESULTS: The combination of fentanyl and celecoxib maintained a low postoperative pain score (<1.5, evaluated by the FACES Pain Scale) and reduced the need for rescue analgesic drugs for 7 days (groups E vs. FC: 5.39 ± 3.77 vs. 2.79 ± 2.92, p < 0.001). The postoperative hospital stay was almost equal for the two groups (E vs. FC: 11.1 ± 4.5 vs. 10.3 ± 4.8 days, p = 0.315). The operating room stay other than for surgery was significantly shorter for group FC (E vs. FC: 128.7 ± 30.5 vs. 107.2 ± 17.0 min, p < 0.001). Neither group experienced complications, apart from one group FC patient, who suffered transient nausea and vertigo. CONCLUSIONS: The new analgesic protocol using fentanyl plus celecoxib is an effective and time-saving strategy for LCR.

Serosal Laceration During Firing of Powered Linear Stapler Is a Predictor of Staple Malformation.

BACKGROUND: Although several types of staplers have been developed, staple-line leaks have been a great problem in gastrointestinal surgery. Powered linear staplers were recently developed to further reduce the risk of tissue trauma during laparoscopic surgery. The aim of this study was to identify the factors that predict staple malformation and determine the effect of precompression and slow firing on the staple formation of this novel powered stapling method. METHODS: Porcine stomachs were divided using an endoscopic powered linear stapler with gold reloads. We divided the specimens into 9 groups according to the precompression time (0/60/180 seconds) and firing time (0/60/180 seconds). The occurrence and length of laceration and the shape of the staples were evaluated. We examined the factors influencing successful stapling and investigated the key factors for staple malformation. RESULTS: Precompression significantly decreased the occurrence and length of serosal laceration. Precompression and slow firing significantly improved the optimal stapling formation rate. Univariate analysis showed that the precompression time (0 seconds), firing time (0 seconds), and presence of serosal laceration were significantly associated with a low optimal formation rate. Multivariate analysis showed that these three factors were associated independently with low optimal formation rate and that the presence of serosal laceration was the only factor that could be detected during the stapling procedure. CONCLUSIONS: We have shown that serosal laceration is a predictor of staple malformation and demonstrated the importance of precompression and slow stapling when using the powered stapling method.

IL-6 down-regulates HLA class II expression and IL-12 production of human dendritic cells to impair activation of antigen-specific CD4(+) T cells.

Immunosuppression in tumor microenvironments critically affects the success of cancer immunotherapy. Here, we focused on the role of interleukin (IL)-6/signal transducer and activator of transcription (STAT3) signaling cascade in immune regulation by human dendritic cells (DCs). IL-6-conditioned monocyte-derived DCs (MoDCs) impaired the presenting ability of cancer-related antigens. Interferon (IFN)-γ production attenuated by CD4(+) T cells co-cultured with IL-6-conditioned MoDCs corresponded with decreased DC IL-12p70 production. Human leukocyte antigen (HLA)-DR and CD86 expression was significantly reduced in CD11b(+)CD11c(+) cells obtained from peripheral blood mononuclear cells (PBMCs) of healthy donors by IL-6 treatment and was STAT3 dependent. Arginase-1 (ARG1), lysosomal protease, cathepsin L (CTSL), and cyclooxygenase-2 (COX2) were involved in the reduction of surface HLA-DR expression. Gene expressions of ARG1, CTSL, COX2, and IL6 were higher in tumor-infiltrating CD11b(+)CD11c(+) cells compared with PBMCs isolated from colorectal cancer patients. Expression of surface HLA-DR and CD86 on CD11b(+)CD11c(+) cells was down-regulated, and T cell-stimulating ability was attenuated compared with PBMCs, suggesting that an immunosuppressive phenotype might be induced by IL-6, ARG1, CTSL, and COX2 in tumor sites of colorectal cancer patients. There was a relationship between HLA-DR expression levels in tumor tissues and the size of CD4(+) T and CD8(+) T cell compartments. Our findings indicate that IL-6 causes a dysfunction in human DCs that activates cancer antigen-specific Th cells, suggesting that blocking the IL-6/STAT3 signaling pathway might be a promising strategy to improve cancer immunotherapy.

A comparison between fentanyl plus celecoxib therapy and epidural anesthesia for postoperative pain management following laparoscopic gastrectomy.

PURPOSE: To clarify the efficacy of postoperative pain management following laparoscopic gastrectomy (LG), we retrospectively compared pain assessments in patients who received fentanyl plus celecoxib with those who received epidural anesthesia. METHODS: From 2011 to 2012, 55 consecutive LG patients at our institution received 48 h of epidural anesthesia for postoperative pain management (group-E). Since September 2013, epidural anesthesia was replaced with 24 h of intravenous fentanyl and 4 days of oral celecoxib. Thirty-three consecutive LG patients who received this analgesic method (group-FC) were included in this analysis. The severity of postoperative pain as assessed by the FACES Pain Rating Scale and the frequency of rescue pain medication were retrospectively compared between the two groups. RESULTS: No significant difference in the severity of postoperative pain on postoperative day (POD) 0 or 1 was observed between the two groups. In contrast, pain was significantly lower in group-FC than group-E on PODs 2, 3, 4, and 7. The total use of rescue pain medications during the first 7 days following LG did not differ between the two groups. CONCLUSION: Pain management using 24 h of intravenous fentanyl and 4 days of oral celecoxib is comparable to epidural anesthesia following LG.

Colorectal cancer-the history and current status of clinical and research-.

The history of clinical and research of colorectal cancer, beginning from surgery therapy, a variety of fields have evolved from there, the results have been stacked. Safety of the establishment and the usefulness of the proof of the surgery, the development of diagnostic methods, advances in chemotherapy, the discovery of hereditary colon cancer, due to the development and application of basic research to support these, research and treatment results for colorectal cancer. It has been made great strides. Advances in establishment and chemotherapy safe surgical treatment, even for colorectal cancer has been considered to unresectable ever, it has become possible to perform a surgical treatment in combination with perioperative chemotherapy. In addition, even for recurrent colon cancer, by combining the surgery therapy sure to allow timing as well as chemotherapy, likely to be observed extension of further survival are coming out Occurrence for colorectal cancer, by the elucidation of the treatment mechanism, to expect that the study of the optimization of colon cancer treatment progresses.