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Background Heterogeneous results of published studies led to conduct a randomized clinical trial to assess the efficacy of a new formulation of four probiotics as prophylaxis for complications after colorectal surgery. Methods A double-blind, placebo-controlled randomized study was conducted enrolling patients undergoing colorectal surgery for cancer. Capsules of placebo or of a formulation containing Lactobacillus acidophilus , L. p lantarum , Bifidobacterium lactis and Saccharomyces boulardii were administered starting one day before operation and continuing for another 15 days postoperatively. Patients were followed up for 30 days with the development of postoperative complications as the primary outcome. Gene expression and serum levels of cytokines were measured on postoperative day 4 ( www.clinicaltrials.gov NCT02313519). Results The study was prematurely stopped after enrolment due to efficacy in the primary outcome. Administration of probiotics significantly decreased the rate of all postoperative major complication (28.6 vs. 48.8 % of the placebo arm, p 0.010, odds ratio 0.42). Major benefit was found in the reduction of the rate of postoperative pneumonia (2.4 vs. 11.3 %, p 0.029), of surgical site infections (7.1 vs. 20.0 %, p 0.020) and of anastomotic leakage (1.2 vs. 8.8 %, p 0.031). The time until hospital discharge was shortened as well. Gene expression of SOCS3 was positively related with gene expression of TNF and of circulating IL-6 in the probiotic group but not in the placebo group. Conclusions The studied probiotic formulation significantly decreased the risk of postoperative complications, namely mechanical ventilation, infections and anastomotic leakage. Modulation of the gene expression of SOCS3 is one suggested mechanism ( www.clinicaltrials.gov NCT02313519).

Background Colon cancer is a public health problem worldwide. Adjuvant chemotherapy after surgical resection for stage III colon cancer has been shown to improve both progression-free and overall survival, and is currently recommended as standard therapy. However, its value for patients with stage II disease remains controversial. When this study was designed 5-fluorouracil (5FU) plus leucovorin (LV) was standard adjuvant treatment for colon cancer. Irinotecan (CPT-11) is a topoisomerase I inhibitor with activity in metastatic disease. In this multicenter adjuvant phase III trial, we evaluated the addition of irinotecan to weekly 5FU plus LV in patients with stage II or III colon cancer. Methods The study included 873 eligible patients. The treatment consisted of weekly administration of irinotecan 80 mg/m 2 intravenously (IV), LV 200 mg/m 2 and 5FU 450 mg/m 2 bolus (Arm A) versus LV 200 mg/m 2 and 5FU 500 mg/m 2 IV bolus (Arm B). In Arm A, treatments were administered weekly for four consecutive weeks, followed by a two-week rest, for a total of six cycles, while in Arm B treatments were administered weekly for six consecutive weeks, followed by a two-week rest, for a total of four cycles. The primary end-point was disease-free survival (DFS) at three years. Results The probability of overall survival (OS) at three years was 0.88 for patients in Arm A and 0.86 for those in Arm B, while the five-year OS probability was 0.78 and 0.76 for patients in Arm A and Arm B, respectively (P = 0.436). Furthermore, the probability of DFS at three years was 0.78 and 0.76 for patients in Arm A and Arm B, respectively ( P = 0.334). With the exception of leucopenia and neutropenia, which were higher in patients in Arm A, there were no significant differences in Grades 3 and 4 toxicities between the two regimens. The most frequently recorded Grade 3/4 toxicity was diarrhea in both treatment arms. Conclusions Irinotecan added to weekly bolus 5FU plus LV did not result in improvement in disease-free or overall survival in stage II or III colon cancer, but did increase toxicity. Trial registration Australian New Zealand Clinical Trials Registry: ACTRN12610000148077

Background The myofibroblasts play a central role in wound healing throughout the body. The process of wound healing in the colon was evaluated with emphasis on the role of myofibroblasts. Methods One hundred male Wistar rats weighing 274 ± 9.1 g (mean age: 3.5 months) were used. A left colonic segment was transected and the colon was re-anastomosed. Animals were randomly divided into two groups. The first group experimental animals (n = 50) were sacrificed on postoperative day 3, while the second group rats (n = 50) were sacrificed on postoperative day 7. Healing of colonic anastomosis was studied in terms of anastomotic bursting pressure, as well as myofibroblastic reaction and expression of α-smooth muscle actin (α-SMA), adhesion formation, inflammatory reaction and neovascularization. Results The mean anastomotic bursting pressure increased from 20.6 ± 3.5 mmHg on the 3 rd postoperative day to 148.8 ± 9.6 Hg on the 7 th postoperative day. Adhesion formation was increased on the 7 th day, as compared to the 3 rd day. In addition, the myofibroblastic reaction was more profound on the 7 th postoperative day in comparison with the 3 rd postoperative day. The staining intensity for α-SMA was progressive from the 3rd to the 7th postoperative day. On the 7 th day the α-SMA staining in the myofibroblats reached the level of muscular layer cells. Conclusions Our study emphasizes the pivotal role of myofibroblasts in the process of colonic anastomosis healing. The findings provide an explanation for the reduction in the incidence of wound dehiscence after the 7th postoperative day.

Background The aim of the trial was to compare two active adjuvant chemotherapy regimens in patients with early stage colorectal cancer (CRC). Methods Patients were assigned to oxaliplatin, leucovorin and 5-FU for 12 cycles (group A, FOLFOX6) or oxaliplatin and capecitabine for eight cycles (group B, CAPOX). Primary endpoint was disease-free survival (DFS). Tumors were classified as mismatch repair proficient (pMMR) or deficient (dMMR) according to MLH1, PMS2, MSH2 and MSH6 protein expression. KRAS exon two and BRAF V600E mutational status were also assessed. Results Between 2005 and 2008, 441 patients were enrolled, with 408 patients being eligible. After a median follow-up of 74.7 months, 3-year DFS was 79.8 % (95 % CI 76.5–83.4) in the FOLFOX group and 79.5 % (95 % CI 75.9–83.1) in the CAPOX group (p = 0.78). Three-year OS was 87.2 % (95 % CI 84.1-91.1) in the FOLFOX and 86.9 % (95 % CI 83.4–89.9) in the CAPOX group (p = 0.84). Among 306 available tumors, 11.0 % were dMMR, 34.0 % KRAS mutant and 4.9 % BRAF mutant. Multivariate analysis showed that primary site in the left colon, earlier TNM stage and the presence of anemia at diagnosis were associated with better DFS and overall survival (OS), while grade one–two tumors were associated with better OS. Finally, a statistically significant interaction was detected between the primary site and MMR status (p = 0.010), while KRAS mutated tumors were associated with shorter DFS. However, the sample was too small for safe conclusions. Conclusions No significant differences were observed in the efficacy of FOLFOX versus CAPOX as adjuvant treatment in high-risk stage II or stage III CRC patients, but definitive conclusions cannot be drawn because of the small sample size. Trial registration ANZCTR 12610000509066 . Date of Registration: June 21, 2010.

Background Surgical interventions activate a cascade of reactions that result in an aseptic inflammatory reaction. This inflammatory response initiates the organism’s innate immunity. Laparoscopic surgery reduces the trauma, and patients benefit from diminished surgical trauma and maintained immune function. Cytokine levels and C-reactive protein (CRP) are related to the magnitude of surgical trauma and surgical stress. Toll-like receptors (TLRs) 2 and 4 are the first sensor-recognition receptors of the invading pathogens for the innate immune response. This study aimed to compare the inflammatory response and then the stress response during laparoscopic and open colectomy for cancer by calculating TLR-2 and TLR-4 as the first sensor-recognition receptors together with interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and high-sensitivity CRP (hsCRP). Methods A total 40 patients with colorectal cancer were randomized in two groups: group A (open colectomy, n  = 20) and group B (laparoscopic colectomy, n  = 20). An epidural catheter was placed in all patients 1 h preoperatively. Rupivocaine was administered perioperatively and 48 h postoperatively. Blood samples were taken for calculation of IL-6, TNF-α, hsCRP, TLR-2, and TLR-4 preoperatively and 5 min after deflation of pneumoperitoneum (group B) or 5 min after division of the colon (group A), then 6 and 24 h postoperatively. Results The mean operative time was 115 for group A and 142 min for group B. The mean blood loss was respectively 240 and 105 ml ( P  < 0.001), and the mean hospital stay was respectively 8 and 5 days ( P  < 0.05). The IL-6 level was significant higher in group A than in group B at 6 and 24 h postoperatively ( P  < 0.0001), and the hsCRP level was significant higher in group A than in group B at 24 h postoperatively ( P  < 0.001). The TNF-α values did not differ between the two groups. The TLR-2 level was significantly higher in group A than in group B at 5 min ( P  = 0.013) and 24 h ( P  = 0.007) postoperatively. The TLR-4 level was significant higher in group A than in group B at 5 min postoperatively ( P  = 0.03). Conclusion The inflammatory response and the resultant stress response are significantly less during laparoscopic colectomy than during open colectomy for colorectal cancer. This is an obvious short-term clinical benefit for the patient, providing tinder for further study to investigate the long-term results of laparoscopic colectomy versus open colectomy for colorectal cancer (Registered clinical trial no. NCT00942461; www.clinicaltrials.gov ).

Background Bevacizumab, an antibody neutralizing Vascular Endothelial Growth Factor (VEGF), is licensed for the management of patients with advanced colon cancer. However, tumor biomarkers identifying the molecular tumor subsets most amenable to angiogenesis modulation are lacking. Methods We profiled expession of 24526 genes by means of whole genome 24 K DASL (c-DNA-mediated, Annealing, Selection and Ligation) arrays, (Illumina, CA) in 16 bevacizumab-treated patients with advanced colon cancer (Test set). Genes with correlation to 8-month Progression-free status were studied by means of qPCR in two independent colon cancer cohorts: 49 patients treated with bevacizumab + chemotherapy (Bevacizumab qPCR set) and 72 patients treated with chemotherapy only (Control qPCR set). Endpoints were best tumor response before metastasectomy (ORR) and progression-free survival (PFS). Results Five genes were significantly correlated to 8-month progression-free status in the Test set: overexpression of KLF12 and downregulation of AGR2, ALDH6A1, MCM5, TFF2. In the two independent datasets, irinotecan- or oxaliplatin-based chemotherapy was administered as first-line treatment and metastasectomies were subsequently applied in 8-14% of patients. No prognostically significant gene classifier encompassing all five genes could be validated in the Bevacizumab or Control qPCR sets. The complex gene expression profile of all-low tumor (ALDH6A1 + TFF2 + MCM5) was strongly associated with ORR in the Bevacizumab qPCR set (ORR 85.7%, p = 0.007), but not in the Control set (ORR 36.4%, p = 0.747). The Odds Ratio for response for the all-low tumor (ALDH6A1 + TFF2 + MCM5) profile versus any other ALDH6A1 + TFF2 + MCM5 profile was 15 (p = 0.018) in the Bevacizumab qPCR set but only 0.72 (p = 0.63) in the Control set. The tumor expression profile of (KLF12-high + TFF2-low) was significantly associated with PFS only in the Bevacizumab qPCR set: bevacizumab-treated patients with (KLF12-high + TFF2-low) tumors had superior PFS (median 14 months, 95% CI 2-21) compared to patients with any other (KLF12 + TFF2) expression profile (median PFS 7 months, 95% CI 5-10, p = 0.021). The Hazard Ratio for disease progression for (KLF12-high + TFF2-low) versus any other KLF12 + TFF2 expression profile was 2.92 (p = 0.03) in the Validation and 1.29 (p = 0.39) in the Control set. Conclusions Our «three-stage» hypothesis-generating study failed to validate the prognostic significance of a five-gene classifier in mCRC patients. Exploratory analyses suggest two gene signatures that are potentially associated with bevazicumab benefit in patients with advanced colon cancer.

Background Surgical procedures are related to the activation of the inflammatory reaction. This is called surgical stress. It is believed that diminished surgical trauma reduces surgical stress. The laparoscopic approach reduces trauma, but the systemic immune responses are still invariably activated. Cytokines and C-reactive protein (CRP) are the main markers in the study of inflammatory or stress response. α-Defensins play an important role in host defense, acting early in phagocytosis. α-Defensins, as early markers—earlier than cytokines—of the inflammatory response, have been used, together with high-sensitivity CRP (hs-CRP) and interleukin-6 (IL-6), to determine the inflammatory response in laparoscopic and open colectomy for cancer. Materials and methods A total of 40 patients with colorectal cancer were randomized to two groups: group A ( n  = 20), open colectomy; group B ( n  = 20), laparoscopic colectomy. One hour preoperatively an epidural catheter was placed in all patients and rupivacaine was administered perioperatively and again 48 h postoperatively. Blood samples were taken for calculating α-defensins, IL-6, and hs-CRP levels preoperatively, 5 min after division of the colon (group A), or 5 min after deflation of pneumoperitoneum (group B), 6 h and 24 h postoperatively. Results The mean operative time was 115 min for group A and 142 min for group B ( p  < 0.05). The mean blood loss was 240 ml and 105 ml, respectively ( p  < 0.001). The mean hospital stay was 8 days and 5 days, respectively ( p  < 0.05). α-Defensin levels were statistically significantly lower in group B than in group A, 5 min and 24 h postoperatively ( p  < 0.002 and p  < 0.007, respectively). The IL-6 levels were statistically significantly lower in group B than in group A, 6 h and 24 h postoperatively ( p  < 0.0001 at both time intervals), whereas the levels of hs-CRP were significantly lower in group B than in group A 24 h postoperatively ( p  < 0.001). Conclusions The present study confirms the results of previous studies, that the inflammatory immune response and surgical stress are significantly less after laparoscopic colectomy versus open colectomy for colorectal cancer. More investigation is needed to study if surgical stress has any influence on survival of these patients.

Surgical procedures are related to the activation of the inflammatory reaction. This is called surgical stress. It is believed that diminished surgical trauma reduces surgical stress. The laparoscopic approach reduces trauma, but the systemic immune responses are still invariably activated. Cytokines and C-reactive protein (CRP) are the main markers in the study of inflammatory or stress response. α-Defensins play an important role in host defense, acting early in phagocytosis. α-Defensins, as early markers--earlier than cytokines--of the inflammatory response, have been used, together with high-sensitivity CRP (hs-CRP) and interleukin-6 (IL-6), to determine the inflammatory response in laparoscopic and open colectomy for cancer. A total of 40 patients with colorectal cancer were randomized to two groups: group A (n = 20), open colectomy; group B (n = 20), laparoscopic colectomy. One hour preoperatively an epidural catheter was placed in all patients and rupivacaine was administered perioperatively and again 48 h postoperatively. Blood samples were taken for calculating α-defensins, IL-6, and hs-CRP levels preoperatively, 5 min after division of the colon (group A), or 5 min after deflation of pneumoperitoneum (group B), 6 h and 24 h postoperatively. The mean operative time was 115 min for group A and 142 min for group B (p < 0.05). The mean blood loss was 240 ml and 105 ml, respectively (p < 0.001). The mean hospital stay was 8 days and 5 days, respectively (p < 0.05). α-Defensin levels were statistically significantly lower in group B than in group A, 5 min and 24 h postoperatively (p < 0.002 and p < 0.007, respectively). The IL-6 levels were statistically significantly lower in group B than in group A, 6 h and 24 h postoperatively (p < 0.0001 at both time intervals), whereas the levels of hs-CRP were significantly lower in group B than in group A 24 h postoperatively (p < 0.001). The present study confirms the results of previous studies, that the inflammatory immune response and surgical stress are significantly less after laparoscopic colectomy versus open colectomy for colorectal cancer. More investigation is needed to study if surgical stress has any influence on survival of these patients.[PUBLICATION ABSTRACT]

The aim of the trial was to compare two active adjuvant chemotherapy regimens in patients with early stage colorectal cancer (CRC). Between 2005 and 2008, 441 patients were enrolled, with 408 patients being eligible. After a median follow-up of 74.7 months, 3-year DFS was 79.8 % (95 % CI 76.5-83.4) in the FOLFOX group and 79.5 % (95 % CI 75.9-83.1) in the CAPOX group (p = 0.78). Three-year OS was 87.2 % (95 % CI 84.1-91.1) in the FOLFOX and 86.9 % (95 % CI 83.4-89.9) in the CAPOX group (p = 0.84). Among 306 available tumors, 11.0 % were dMMR, 34.0 % KRAS mutant and 4.9 % BRAF mutant. Multivariate analysis showed that primary site in the left colon, earlier TNM stage and the presence of anemia at diagnosis were associated with better DFS and overall survival (OS), while grade one-two tumors were associated with better OS. Finally, a statistically significant interaction was detected between the primary site and MMR status (p = 0.010), while KRAS mutated tumors were associated with shorter DFS. However, the sample was too small for safe conclusions. No significant differences were observed in the efficacy of FOLFOX versus CAPOX as adjuvant treatment in high-risk stage II or stage III CRC patients, but definitive conclusions cannot be drawn because of the small sample size.

It has been shown in randomized studies that adjuvant treatment with the combination of fluorouracil (FU) and levamisole reduced the risk of recurrence and deaths of patients with stage III colon cancer. Pharmacological studies of FU led to its use in combination with a number of modulating agents including interferon-alpha and leucovorin (LV) that appear to enhance its activity in vitro. Furthermore, a meta-analysis suggested that the combination of FU with LV increased the response rate as compared to FU monotherapy in patients with advanced colorectal cancer. To evaluate the impact of adjuvant treatment with the combination of FU and LV with or without interferon alfa-2a (IFN) on disease-free survival (DFS) and overall survival (OS) for patients with stage II or III colon cancer. From August 1989 to July 1997, 280 patients with stage II and III colon cancer entered the study and were randomly assigned to receive either the combination of FU (600 mg/m(2)/week x 6, followed by a 2-week rest) and LV (500 mg/m(2)/week x 6 as a 2-hour infusion, followed by a 2-week rest) for 4 cycles (group A, 139 patients), or the same chemotherapy plus recombinant IFN (3 MU subcutaneously 3 times a week) for 1 year (group B, 141 patients). A total of 109 patients (78.9%) of group A and 119 (84.4%) of group B completed four cycles of chemotherapy. Also, 51.4% of patients of group A and 53.9% of group B received > or =80% of the planned dose of FU. One patient (group A) was found to be ineligible and was not included in the analysis. The median relative dose intensity of FU in the two groups was 0.90 and 0.85, respectively. As of August 1998, after a median follow up of 4 years, there was no significant difference in either 3-year DFS (group A, 83.1%; group B, 75.9%, p = 0.14) or OS (group A, 84.5%; group B, 80.0%, p = 0.27). In the Cox model, stage of disease, number of infiltrated nodes, tumor grade and presence of regional implants were identified as significant prognostic factors for OS. Grade 3-4 toxicities, mainly diarrhea, were observed in 26.1% of patients of group A and in 24.8% of group B. There were no treatment-related deaths. The addition of IFN to the combination of FU with LV postoperatively does not improve DFS and OS of patients with stage II or III colon cancer.