Comparison of high-dose dual therapy with bismuth-containing quadruple therapy in Helicobacter pylori-infected treatment-naive patients: An open-label, multicenter, randomized controlled trial.

OBJECTIVE: Bismuth-containing quadruple therapy for Helicobacter pylori (H. pylori) eradication has a relatively high rate of side effects and high cost, thus the option of a high-dose dual therapy with a high eradication rate and fewer adverse events is a consideration. However, studies of dual therapy are still scarce and are mostly single-center studies with limited generalizability. Large-scale, multicenter studies are required. Our study investigated and compared the effectiveness, adverse events, patient compliance, and costs of high-dose dual therapy with those of bismuth-containing quadruple therapy in H. pylori-infected treatment-naive patients in a prospective, multicenter, open-label, randomized controlled trial. METHOD: Treatment-naive patients infected with H. pylori were randomly assigned to receive high-dose dual therapy (esomeprazole 20 mg 4 times daily and amoxicillin 1000 mg 3 times daily, for 14 days) or bismuth-containing quadruple therapy (esomeprazole 20 mg, amoxicillin 1000 mg, clarithromycin 500 mg, and bismuth potassium citrate 220 mg, all twice daily for 14 days). The effectiveness, adverse events, patient compliance, and costs of both groups were compared. RESULTS: A total of 700 patients were enrolled. The high-dose dual therapy group (N = 350) achieved eradication rates of 89.4% (intention-to-treat), 90.4% (modified intention-to-treat), and 90.6% (per-protocol), which were similar to rates in the bismuth-containing quadruple therapy group (N = 350), 84.6%, 88.0%, and 88.2%, respectively (p > 0.05). The high-dose dual therapy group had a lower rate of adverse events (12.9% vs. 28.1%, p < 0.001) and lower costs (¥590.2 vs. ¥723.22) compared with the quadruple therapy group, respectively. The compliance of both groups was satisfactory (97.7% high-dose dual vs. 96.8% quadruple, p > 0.05). CONCLUSION: High-dose dual therapy for H. pylori eradication had similar efficacy and compliance, fewer adverse events, and lower costs than bismuth-containing quadruple therapy for treatment-naive patients.

Pirfenidone prevents radiation-induced intestinal fibrosis in rats by inhibiting fibroblast proliferation and differentiation and suppressing the TGF-ß1/Smad/CTGF signaling pathway.

Radiation-induced intestinal fibrosis (RIF) is a chronic toxicity following radiation, and can be very difficult to treat. Pirfenidone is a promising anti-fibrotic agent that inhibits fibrosis progression in various clinical and experimental studies. This study was aimed to explore whether pirfenidone could protect against RIF, and to evaluate the underlying mechanism. An animal model of RIF was induced by exposure of a single dose of 20 Gy to the pelvis. Rats were orally administered with pirfenidone (200, 400 md/kg/d) for 12 weeks. Primary rat intestinal fibroblasts were cultured to determine the effects of pirfenidone on TGF-ß1-induced (5 ng/ml) proliferation and transdifferentiation of fibroblasts. The expression of collagen I, α-SMA, and TGF-ß1/Smad/CTGF pathway proteins were analyzed by qRT-PCR and/or western blot analysis. The cell proliferation rate was determined by CCK-8 assay. The results indicated that pirfenidone significantly attenuated fibrotic lesion in irradiated intestines and reduced collagen deposition by inhibiting TGF-ß1/Smad/CTGF pathway in rat models. Moreover, in primary rat intestinal fibroblasts, pirfenidone decreased the up-regulation of TGF-ß1-induced collagen I and α-SMA by suppressing TGF-ß1/Smad/CTGF signaling pathway. Altogether, our findings suggested that pirfenidone attenuated RIF by inhibiting the proliferation and differentiation of intestinal fibroblasts and suppressing the TGF-ß1/Smad/CTGF signaling pathway.

Monitoring neoadjuvant therapy responses in rectal cancer using multimodal nonlinear optical microscopy.

Most patients with rectal cancer have a better prognosis after receiving neoadjuvant therapy because of its remarkable curative effect. However, no device delivers real-time histopathologic information on treatment response to help clinicians tailor individual therapeutic strategies. We assessed the potential of multimodal nonlinear optical microscopy to monitor therapeutic responses, including tumoral and stromal responses. We found that two-photon excited fluorescence imaging can, without labeling, identify colloid response, inflammatory cell infiltration, vascular proliferation, and tumor regression. It can also directly detect rare residual tumor cells, which may be helpful for distinguishing tumor shrinkage from tumor fragmentation. In addition, second harmonic generation imaging shows the ability to monitor three types of fibrotic responses: mature, intermediate, and immature. We also determined nonlinear spectra, collagen density, and collagen orientation indexes to quantitatively analyze the histopathologic changes induced by neoadjuvant therapy in rectal cancer. Our work demonstrates that nonlinear optical microscopy has the potential to become a label-free, real-time, in vivo medical imaging technique and provides the groundwork for further exploration into the application of nonlinear optical microscopy in a clinical setting.

Foxp3 expression in CD4+CD25+Foxp3+ regulatory T cells promotes development of colorectal cancer by inhibiting tumor immunity.

The mechanism underlying CD4+CD25+Foxp3+ regulatory T cells (Tregs) promoting the development of colorectal cancer (CRC) was elucidated in the present study. Forty-eight cases of colorectal carcinomas, 22 cases of colon polyps and 21 cases of normal colorectal tissues were collected. The correlation among Foxp3, IL-10 and Stat3, and the clinical relevance of these three indexes were analyzed. The results showed that the levels of Foxp3 expressed in infiltrating CD4+CD25+Foxp3+Tregs, and IL-10 and Stat3 in CRC tissues were all significantly higher than those in polypus tissues and normal colon tissues (P< 0.01). Pearson correlation analysis indicated that the expression level of Foxp3 was positively correlated with Stat3 at mRNA level (r=0.526, P=0.036), and was positively correlated with IL-10 at protein level (r=0.314, P=0.030). The Foxp3 expressed in CD4+CD25+Foxp3+Tregs was correlated with the histological grade, lymph node metastasis and TNM stage of CRC (P<0.05 for all). The IL-10 expression was correlated with the histological grade and TNM stage (both P<0.05). The Stat3 expression was correlated with the lymph node metastasis and TNM stage (both P<0.05). It was concluded that CD4+CD25+Foxp3+Tregs can inhibit tumor immunity in combination with some other related inhibitory cytokines and that Foxp3 expression in CD4+CD25+Foxp3+Tregs correlates with CRC progression.

Multiphoton microscopy for tumor regression grading after neoadjuvant treatment for colorectal carcinoma.

AIM: To evaluate the feasibility of using multiphoton microscopy (MPM) to assess a tumor regression grading (TRG) system. METHODS: Fresh specimens from seven patients with colorectal carcinoma undergoing neoadjuvant radiochemotherapy at the Fujian Medical University Union Hospital were obtained immediately after proctectomy. Specimens were serially sectioned (10 µm thickness) and used for MPM or stained with hematoxylin and eosin for comparison. Sections were imaged by MPM using 810 nm excitation, and images were collected in two wavelength channels corresponding to second-harmonic generation (SHG) and two-photon excited fluorescence (TPEF) signals. The ratio of these signal intensities was used to distinguish fibrosis from normal mucosal and serosal tissues. RESULTS: TRG of specimens assessed by MPM were in complete agreement with histologic grading performed by a consulting pathologist. SHG and TPEF images clearly revealed collagen fibers and fragmented elastic fibers in the muscularis propria specimens following neoadjuvant radiochemotherapy. Additionally, blood vessel hyperplasia was observed as thickening and fibrosis of the intima and media, which was accompanied by minimal inflammatory cell infiltration. Furthermore, the SHG/TPEF ratio in stromal fibrosis (4.15 ± 0.58) was significantly higher than those in the normal submucosal (2.31 ± 0.52) and serosal (1.47 ± 0.10) tissues (P < 0.001 for both). Analysis of emission spectra from cancerous tumor cells revealed two peaks corresponding to nicotinamide adenine dinucleotide hydrogen and flavin adenine dinucleotide signals; the ratio of these values was 1.19 ± 0.02, which is close to a normal metabolic state. CONCLUSION: MPM can be used to perform real-time diagnosis of tumor response after neoadjuvant treatment, and can be applied to evaluate TRG.

Laparoscopic transabdominal approach partial intersphincteric resection for low rectal cancer: surgical feasibility and intermediate-term outcome.

BACKGROUND: Traditionally, conventional intersphincteric resection requires a combined abdominal and perineal approach and a handsewn coloanal anastomosis procedure, which is difficult to accomplish via the perineal approach. A completely abdominal approach partial intersphincteric resection (APISR) with laparoscopy can simplify the anastomosis procedure. This study evaluated the intermediate-term oncological and functional results of laparoscopic versus open APISR for low rectal cancer. METHODS: A total of 137 consecutive patients with low rectal cancer who underwent APISR from January 2006 to August 2013 were retrospectively evaluated. Patient groups were classified into as open surgery (OP, n = 48) group and laparoscopy (LAP, n = 89). The primary endpoint was 3-year disease-free survival and the Wexner score for anal function. RESULTS: The LAP group had longer operating time, less intraoperative blood loss, and shorter hospital stay after surgery compared with the OP group. Median follow-up was 32.3 months. The local recurrence rates were similar in the two groups (LAP 3.2% vs. OP 6.1%; P = 0.652). The combined 3-year disease-free survival rate was 83.2% in the LAP group and 83.8% in the OP group (P = 0.857). Wexner scores were similar in the two groups (LAP 2.9 ± 4.5 vs. OP 3.1 ± 5.0). In the LAP group, 89.7% of patients had good continence compared with 91.4% in the OP group (P = 0.311). CONCLUSIONS: Laparoscopic APISR can be performed safely and offers similar intermediate-term oncological and functional outcome compared with the open procedure. The oncological adequacy requires long-term follow-up data.

Evodiamine activates AMPK and promotes adiponectin multimerization in 3T3-L1 adipocytes.

Adiponectin, an adipokine with insulin-sensitizing effect, is secreted from adipocytes into circulation as high, medium, and low molecular weight (HMW, MMW, and LMW) forms. The HMW adiponectin is more metabolically active and the ratio of HMW adiponectin to total adiponectin directly correlates with insulin sensitivity. Evodiamine is an indole alkaloid found in the traditional Chinese medicinal plant Evodia rutaecarpa. In this study, evodiamine was found to activate AMP-activated protein kinase (AMPK) in both 3T3-L1 adipocytes and 293T cells. Activation of AMPK by evodiamine promoted the assembly of HMW adiponectin and increased the HMW/total ratio of adiponectin in 3T3-L1 adipocytes. The Ca(2+)-dependent PI3K/Akt/CaMKII-signaling pathway was demonstrated to be involved in evodiamine-induced AMPK activation. This study revealed a novel role of this Ca(2+)-mediated signaling pathway in promoting the multimerization of adiponectin.

[Meta analysis of postoperative complications between laparoscopic resection and traditional open resection of mid-low rectal carcinoma].

OBJECTIVE: To conduct a meta-analysis of postoperative complications between laparoscopic resection (Group LR) and traditional open resection (Group OR) of mid-low rectal carcinoma. METHODS: Meta analysis was performed by two reviewers, who independently selected and extracted data retrieved from literatures and papers published in China Knowledge Resource Integrated Database (CNKI), Wangfang Data, Foreign Medical Journal Service (FMJS), PubMed, EMBASE and The Cochrane before August 2012 on comparison between two groups. The statistical analysis for research of complex standard was conducted through Revman 5.0. RESULTS: Thirteen clinical case-control studies with a total of 2733 cases were enrolled for analysis, including 1368 cases in Group LR and 1365 in Group OR. The result showed that, compared with Group OR, Group LR had lower overall rate of postoperative complication (OR=0.76, 95%CI:0.62-0.92, P<0.01), lower rate of postoperative intestinal obstruction (OR=0.53, 95%CI:0.35-0.80, P<0.01), lower rate of incision complications (OR=0.43, 95%CI:0.28-0.67, P<0.01), similar incidence of anastomotic bleeding and fistula, and similar incidence of bleeding in abdominal cavity and pelvic cavity (all P>0.05). CONCLUSIONS: The overall rate of postoperative complications of laparoscopic resection for mid-low rectal carcinoma is obviously lower than that of open resection. Laparoscope can be applied safely in the resection of mid-low rectal carcinoma.

[Efficacy and safety of sunitinib on patients with imatinib-resistant gastrointestinal stromal tumor].

OBJECTIVE: To investigate the efficacy and safety of sunitinib on the management of gastrointestinal stromal tumors (GIST) patients with imatinib resistance. METHODS: Clinical data of 48 patients with imatinib-resistant GIST received sunitinib therapy from May 2008 to April 2012 in the Union Hospital of Fujian Medical University were analyzed retrospectively. Eighteen patients received 50 mg/d of sunitinib in a protocol of 4/2 (4 weeks on and 2 weeks off) [50 mg/d (4/2)], and 30 patients received a protocol of 37.5 mg of sunitinib continuous daily dose (37.5 mg/d CDD). RESULTS: The median duration of sunitinib administration of all the 48 patients was 56 weeks, and the short-term efficacy was evaluated at 24 weeks after the initial treatment according to the Choi criteria. The response rate was 27.1% (13/48), including 1 case with complete response (CR), 12 cases with partial response (PR), and 21 cases with stationary disease (SD). The disease control rate was 70.8% (34/48). The mean follow-up time of 48 patients was 89 weeks. The median progression-free survival (PFS) and overall survival (OS) were 48 weeks and 92 weeks respectively. Stratified analyses indicated that the median PFS of patients previously treated by imatinib 400 mg/d and >400 mg/d were 53 weeks and 35 weeks respectively (P=0.018), and the median OS of these two groups were 157 weeks and 71 weeks respectively (P=0.003). Patients with exon 11 mutations had a significantly shorter OS compared with those with exon 9 mutations (71 weeks vs 157 weeks, P=0.008). Hand-foot syndrome was the most common adverse effect (25/48, 52.1%), followed by nausea (24/48, 50.0%), fatigue (23/48, 47.9%), neutropenia(21/48, 41.7%). The sub-group analysis of two protocols of sunitinib administration showed that the incidence of diarrhea and hand-foot syndrome were higher in 50 mg/d (4/2) group than those in 37.5 mg/d CDD group (P=0.027, P=0.048). CONCLUSIONS: Sunitinib is effective for the patients with imatinib-resistant GIST. After 400 mg/d imatinib treatment failure, sunitinib should be prescribed instead of increased dosage of imatinib. Patients with KIT exon 9 mutations present better prognosis than those with KIT exon 11 mutations. The protocol of sunitinib 37.5 mg/d CDD possesses better safety.

Laparoscopic extralevator abdominoperineal resection for rectal carcinoma with transabdominal levator transection.

BACKGROUND: The extralevator abdominoperineal resection (ELAPR) is a new surgical technique for patients with low advanced rectal cancer. This technique requires an extra excision of the levator muscles to avoid the surgical waist caused by the conventional abdominoperineal resection, with the patient's position changed to a prone jackknife position and using a myocutaneous flap to repair the pelvic defect. To simplify this operation, we applied a laparoscopic technique to perform controlled transabdominal transection of the levator muscles under direct visualization without a position change and pelvic floor reconstruction using human acellular dermal matrix (HADM). METHODS: In our department from 2010-2011, six patients with rectal adenocarcinoma within 3 cm of the anal verge underwent laparoscopic ELAPR with transabdominal levator transection, with no position change during the perineal operation. In three patients, pelvic reconstruction was performed with HADM. RESULTS: All procedures were successfully performed without any intraoperative complications, laparoscopy-associated morbidity, or conversion to the open approach. The mean operation time and intraoperative blood loss were 186.7 min and 101.7 ml. All specimens had a cylindrical shape with levator muscles attached to the mesorectum and negative circumferential margins. No complications were seen with the use of HADM. CONCLUSIONS: Laparoscopic transabdominal transection of the levator muscles without position change and with pelvic floor reconstruction using human acellular dermal matrix mesh is feasible. With the transection of the levator muscles under laparoscopic surveillance, the procedure of the extralevator abdominoperineal resection, which is aggressively invasive and operatively complicated, is simplified and has an advantage of minimal invasiveness.

Interleukin-18 and -12 synergistically enhance cytotoxic functions of tumor-infiltrating lymphocytes.

BACKGROUND: The role of tumor-infiltrating lymphocytes (TILs) in the immunopathogenesis of individual cancer is not clear and is a challenge for anti-tumor immunotherapy. This study aimed to investigate the effects of interleukin (IL)-18 and -12 on cytotoxic functions of TILs. METHODS: TILs from postoperative gastric cancer patients were costimulated with IL-18 and IL-12. SGC-7901 tumor cells were pre-incubated with TILs and subcutaneously injected into BALB/C SCID mice. The function of TILs was evaluated by measuring tumor sizes in tumor-bearing mice, T helper (Th)1 (tumor necrosis factor (TNF)-α, interferon (IFN)-γ) and Th2 cytokine levels (IL-10 and IL-4) in serum and cytotoxicity of mouse natural killer (NK) and CD8(+) T cells. RESULTS: IL-18 and IL-12 synergistically inhibited the growth of SGC-7901 cells in vivo and significantly extended the survival rate of SGC-7901-bearing mice (66.7% vs. 13.7%, P < 0.01). Moreover, TILs could promote the secretion of TNF-α and IFN-γ ((130.34 ± 7.65) vs. (210.63 ± 12.31) pg/ml, P < 0.01; (14.23 ± 1.97) vs. (30.52 ± 2.12) pg/ml, P < 0.01), and downregulate IL-10 and IL-4 secretion ((103.72 ± 11.21) vs. (61.36 ± 5.41) pg/ml, P = 0.021; (49.36 ± 4.67) vs. (28.48 ± 3.86) pg/ml, P = 0.024). CONCLUSION: IL-18 and IL-12 can synergistically enhance cytotoxic functions of TILs from human gastric cancer.

[Laparoscopic cylindrical abdominoperineal resection with transabdominal approach for lower rectal cancer].

OBJECTIVE: To evaluate the safety and feasibility of laparoscopic cylindrical abdominoperineal resection. METHODS: Six patients with rectal adenocarcinoma within 3 cm above the anal verge underwent laparoscopic cylindrical abdominoperineal resection. Transabdominal levator transaction was performed laparoscopically, with no position change during the perineal operation. Pelvic reconstruction was achieved using human acellular dermal matrix mesh in 3 patients. RESULTS: All the procedures were successfully performed without any intraoperative complications, laparoscopy-associated complications, or conversion to the open approach. The mean operation time was 186.7 minutes and intraoperative blood loss was 101.7 ml. All the specimens had a cylindrical shape with levator muscles attached to the mesorectum and circumferential margins were all negative. No adverse incidence followed the pelvic reconstruction using human acellular dermal matrix mesh. CONCLUSIONS: Laparoscopic transabdominal transection of the levator muscles without position change and pelvic floor reconstruction with human acellular dermal matrix mesh is feasible. This procedure simplifies cylindrical abdominoperineal resection which is aggressively invasive and technically complicated. The oncologic outcomes are acceptable and complications are less.

[Short-term efficacy of laparoscopic-assisted right hemicolectomy with D3 lymph node dissection in colon cancer].

OBJECTIVE: To explore the feasibility and short-term efficacy of laparoscopic-assisted D3 lymph node dissection for right colon cancer with a medial-to-lateral approach. METHODS: Clinical data of 61 patients with right colon cancer undergoing D3 lymph node dissection from March 2006 to June 2010 were analyzed retrospectively. Among them,29 underwent laparoscopic-assisted right hemicolectomy (LARH group) and 32 underwent open right hemicolectomy (ORH group). The number of lymph node harvest, operative details, and complication rate were compared between the two groups. RESULTS: The mean number of lymph node harvest did not differ significantly between the two groups (16.9±3.8 vs. 15.4±3.6). As compared to ORH group, although the operative time was significantly longer [(214.4±37.9) min vs. (193.3±28.8) min] in LARH group, the mean blood loss [(83.4±38.0) ml vs. (192.7±43.6) ml], time to first flatus [(44.6±20.8) h vs. (70.4±80.0) h], time to resumption of soft diet[(32.5±10.6) h vs. (59.7±10.4) h], and postoperative hospital stay [(11.2±2.2) d vs. (13.8±2.8) d] were more favorable(all P<0.05). Complication rate was lower in LARH group(10.4% vs. 9.4%), however the difference was not statistically significant. CONCLUSIONS: LARH with D3 lymph node dissection is oncologically comparable with ORH for right colon cancer. It is a safe and feasible procedure associated with rapid postoperative recovery.

(R)-1,1'-Binaphthalene-2,2'-diyl dicinnamate.

In the title compound, C(38)H(26)O(4), two cinnamo-yloxy groups are linked in a trans fashion to the two O atoms of optically active (R)-1,10-bi-2-naphthol. The dihedral angle between the mean planes of the two naphthyl groups is 71.8 (1)°. The crystal structure contains inter-molecular C-H⋯O and C-H⋯π inter-actions.

Syndecan-1 and E-cadherin expression in differentiated type of early gastric cancer.

AIM: To elucidate the role and alterations of syndecan-1 and E-cadherin expression in different cellular phenotypes of differentiated-type gastric cancers (DGCs). METHODS: A total of 120 DGCs at an early stage, and their adjacent mucosa, were studied both by immunohistochemistry. Syndecan-1 and E-cadherin were assessed by immunohistochemical staining with anti-syndecan-1 and anti-E-cadherin antibodies, respectively. Based on immunohistochemistry, DGCs and their surrounding mucosa were divided into four types: gastric type (G-type), ordinary type (O-type), complete-intestinal type (CI-type), and null type (N-type). RESULTS: Syndecan-1 expression was significantly lower in G-type cancers (29.4%) than in O-type (79.6%) and CI-type cancers (90%) (P<0.05, respectively), but E-cadherin did not show this result. In addition, syndecan-1 expression was significantly reduced in DGCs comprised partly of poorly differentiated adenocarcinoma or signet-ring cell carcinoma, compared to DGCs demonstrating papillary and/or tubular adenocarcinoma (P<0.05). G-type intestinal metaplasia (IM) surrounding the tumors was observed in 23.8% of G-type, 4.9% of O-type, and 6.7% of CI-type cancers (P<0.05; G-type vs O-type). Reduction of syndecan-1 expression was significant in G-type IM (25%) compared to non-G-type IM (75%; P<0.05). CONCLUSION: Loss of syndecan-1 plays a role in the growth of G-type cancers of DGCs at an early stage, and the reduction of syndecan-1 expression in IM surrounding the tumors may influence the growth of G-type cancer.