Antibody to Interleukin-6 Receptor Inhibits In Vivo Growth of Human Colorectal Carcinoma Cell Xenografts.

BACKGROUND: Interleukin-6 receptor antibody (IL6R) inhibits colony formation and invasion by colorectal carcinoma (CRC) in vitro. We examined the effect of IL6R antibody on tumor growth of CRC xenografts in vivo. MATERIALS AND METHODS: SW480 cells inoculated subcutaneously into NU/NU mice were treated with anti-IL6R and tumor histology and growth-related signaling were subsequently estimated by hematoxylin and eosin and immunohistochemical staining. RESULTS: Tumor growth was inhibited by anti-IL6R treatment at dosages of both 0.1 and 1.0 mg/kg. Tumor cells had invaded into surrounding tissues in untreated mice, while there was no invasion of tumors in the IL6R antibody-treated mice. The expression of Ki-67, signal transducer and activator of transcription protein 3 (STAT3) and phosphor-extracellular signal-regulated kinase 1 and 2 (ERK1/2) were suppressed in anti-IL6R-treated tumors. CONCLUSION: IL6R antibody inhibited tumor growth and invasiveness in vivo by suppressing the expression of Ki-67, STAT3 and phosphor-ERK1/2. The results imply that the anti-IL6R may be a promising targeted drug for CRC.

Noninferiority clinical trial comparing the bowel cleansing efficacy of sodium phosphate tablets (Quiklean®) with a polyethylene glycol/bisacodyl kit.

BACKGROUND: Efficient bowel cleansing is essential for a successful colonoscopy, but the ideal cleansing agent, volume, and pharmaceutical dosage form have yet to be determined. Small-volume cleansers enhance patient compliance. AIM: To compare the bowel cleansing efficacy of 32-tablet sodium phosphate (Quiklean®) with 2-L polyethylene glycol (PEG)/bisacodyl (Klean-Prep/ Dulcolax®) under identical dietary recommendations. METHODS: This multicenter, randomized, parallel-group, noninferiority clinical trial enrolled 472 outpatients, randomized 456 subjects, and scheduled 442 subjects to undergo colonoscopy (Quiklean® = 222 and Klean-Prep/Dulcolax® = 220). After bowel preparation, a colonoscopist performed the colonoscopy with video recorded for rating. The primary efficacy endpoint was the bowel cleansing quality using the Aronchick Scale. The secondary endpoints were the bowel cleansing efficacy of three colon segments, tolerability and acceptability, safety using the Ottawa bowel preparation scale, questionnaires by subjects, and monitoring of adverse events. RESULTS: Success rates (Excellent + Good) of the bowel cleansing quality by Aronchick Scale were 98.6% (n = 205) and 97.6% (n = 204) in the Quiklean® and Klean-Prep/Dulcolax® groups, respectively. Quiklean® demonstrated noninferiority over Klean-Prep/Dulcolax® in colon cleansing efficacy. Quicken showed better tolerability and acceptability in the overall experience (was rated as excellent; 24.0% vs 17.2%; P = 0.0016) and the taste of the study preparation (was rated as excellent, 23.1% vs 13.4%; P < 0.0001) than Klean-Prep/Dulcolax®. Safety profiles did not differ between the two groups. Our data indicate that Quiklean® is an adequate, well-tolerated bowel cleansing preparation compared with the standard comparator Klean-Prep/Dulcolax®. CONCLUSION: Quiklean® is sodium phosphate tablets available on Taiwan's market for bowel preparation; it potentially offers patients an alternative to standard large-volume bowel preparation regimens and may, therefore, increase positive attitudes toward colonoscopies and participation rates.

Longan flower proanthocyanidins induce apoptosis in HT-29 colorectal carcinoma spheroids.

AIM OF STUDY: Proanthocyanidin-rich longan flower extract (LFP) has been previously shown to inhibit the proliferation and anchorage-independent growth in soft agar of two colorectal carcinoma (CRC) cells in vitro. In this report, we further examined the effects of LFP in a CRC spheroid model. MATERIALS AND METHODS: A liquid-overlay assay employing HT-29 spheroids was used to evaluate the effects of LFP on cancer cell tumorigenesis, viability, and apoptosis. Associated effects on signaling path ways (epidermal growth factor receptor [EGFR], Akt) and apoptotic regulators were measured using Western blot. RESULTS: Treatment with LFP up to 200 µg/ml inhibited tumor growth in a dose-dependent manner and induced prominent apoptosis as measured by annexin V staining. Cells treated with LFP showed decreased EGFR and Akt phosphorylation with decreased expression of B-cell lymphoma 2. CONCLUSION: The ability of LFP to induce apoptosis in CRC spheroids warrants further investigation of its composition and identification of tumor-active components.

A Comparative Effectiveness Study of Two Oral Chemotherapy Drugs (UFT vs. Capecitabine) in Neoadjuvant Concurrent Chemoradiotherapy for Patients with Locally Advanced Rectal Cancer.

BACKGROUND/AIM: Capecitabine is the current standard oral chemotherapy used in neoadjuvant concurrent chemoradiotherapy (NCCRT) for locally advanced rectal cancer (LARC) in North America. We compared the effectiveness of another oral chemotherapy agent, UFT (an oral combination of uracil and tegafur), to that of capecitabine. MATERIALS AND METHODS: We identified LARC patients diagnosed from 2007 to 2011 using a population-based registry in Taiwan (Health and Welfare Data Science Center, HWDC) and constructed a propensity score matched cohort to balance observable potential confounders. We compared the hazard ratio (HR) of death between the UFT and capecitabine groups. We performed supplementary analysis (SA) to evaluate the robustness of our finding regarding potential unobserved confounders (SA-1) and the robustness of the result in a subgroup when an additional potential confounder was taken into account (SA-2). RESULTS: Our study population comprised of 200 patients balanced with respect to observed co-variables. UFT lowered the hazard of death significantly more than capecitabine (HR=0.58, 95% confidence interval (CI)=0.35-0.95, p=0.03). Our result was moderately sensitive in SA-1 but not significant in SA-2. CONCLUSION: The effectiveness of UFT in NCCRT for LARC is probably non-inferior to that of capecitabine.

Effectiveness of neoadjuvant concurrent chemoradiotherapy versus up-front proctectomy in clinical stage II-III rectal cancer: A population-based study.

AIMS: Neoadjuvant concurrent chemoradiotherapy (NCCRT) is currently the preferred treatment for rectal cancer of clinical stage II-III based on its efficacy in clinical trials. The population-based effectiveness of NCCRT is rarely reported on in the literature. The purpose of our study is to investigate the nationwide population-based effectiveness of NCCRT as compared with up-front proctectomy. METHODS: In this retrospective cohort study, we identified the study population by linking datasets including the cancer registry, death registry and other related files in Taiwan. We identified all patients with rectal adenocarcinoma of American Joint Committee on Cancer clinical stage II or III who were diagnosed in 2007 or 2008 and received either NCCRT or up-front proctectomy. We included patients' age, gender, residence, socioeconomic status and clinical stage as covariables. We used overall survival as the measure of effectiveness. The Cox proportional-hazards regression model was used for statistical analyses. We further conducted sensitivity analyses, one in only those who received optimal postoperative chemotherapy and one in two subgroups matched for propensity score. RESULTS: We included 1933 patients (NCCRT: 424; up-front proctectomy: 1509) in the study population. NCCRT was associated with improved survival as compared with up-front proctectomy (adjusted hazard ratio of death 0.656; 95% confidence interval 0.495-0.871). Our results were robust in the sensitivity analyses. CONCLUSION: We demonstrated that the use of neoadjuvant concurrent systemic therapy and radiotherapy is associated with better effectiveness in rectal adenocarcinoma of clinical stage II-III as compared with up-front proctectomy. Further studies are needed to elucidate the subgroups most likely to benefit and to clarify NCCRT's cost-effectiveness.

Association Between Genetic Polymorphism of the MIF Gene and Colorectal Cancer in Taiwan.

BACKGROUND: Colorectal cancer (CRC) is the highest leading cause of cancer-related mortality in Taiwan. Macrophage migration inhibitory factor (MIF) has recently been defined as a novel protumorigenic factor that promotes cell proliferation, migration, and invasion. The aim of the present study is to identify the association between MIF gene polymorphism and CRC. METHODS: A case-control study was designed to test the hypothesis. A total of 192 biopsy-diagnosed CRC patients (CRC) and 256 healthy subjects (control) were recruited. Genotyping of four single nucleotide polymorphism (SNPs; rs755662, rs11548059, rs1049829, rs1803976) at chromosome positions 755662 (5' UTR), 11548059 (exon2), 1049829 (exon2), 1803976 (exon3) was performed using a Taqman SNP genotyping assay. RESULTS: There is a significant difference in genotype frequency distribution of rs755662 polymorphism between CRC patients and controls (P = 0.011). No significant difference was found in the frequency distribution of rs11548059, rs1049829, rs1803976 polymorphism in CRC patients and controls (P = 0.660, P = 0.700, and P = 0.959, respectively). Moreover, the MIF-173 SNP was also significantly associated with young patients (age < 50 years, P = 0.026) late stage (Stage IV, P = 0.038) and poor differentiation group (P = 0.040). Compared to the control group, the MIF-173 SNP also significantly associated with patients with stages III and IV (P = 0.034 and 0.003, respectively). CONCLUSION: The presence of MIF-173 (G/C) gene polymorphism (rs755662) was associated with susceptibility, patient age, and stages of CRC in Taiwanese.

Effectiveness of a novel herbal agent MB-6 as a potential adjunct to 5-fluoracil-based chemotherapy in colorectal cancer.

Natural products, such as fermented soybeans, have been used to treat various physical conditions, including cancer. MB-6 is a botanical preparation composed of fermented soybean extract, green tea extract, Antrodia camphorata mycelia, spirulina, grape seed extract, and curcumin extract. Based on this, we hypothesized that MB-6 would increase the effectiveness of chemotherapy in patients with colon cancer. In a rodent study, MB-6, in combination with leucovorin/5-fluorouracil chemotherapy, increased the survival rate and life span of colon cancer tumor-bearing BALB/c mice as compared with treatment with chemotherapy alone. In a proof-of-concept clinical study, 72 patients with metastatic colorectal cancer were randomized to receive leucovorin, 5-fluorouracil, and oxaliplatin in combination with either MB-6 or placebo for 16 weeks. The primary outcome was the best overall response, and secondary outcomes included progression-free survival, overall survival, and adverse effects. Up to 77 weeks after treatment, there was follow-up with the patients. No significant difference in the best overall response rate and overall survival was observed between the 2 groups. Patients in the MB-6 group had a significantly lower disease progression rate than patients in the placebo group, during the study period (0.0% vs 15.8%, P = .026). The placebo group had a significantly higher incidence of adverse events at least grade 4 compared with the MB-6 group (28.9% vs 2.9%, respectively, P = .004) and a significantly higher occurrence of increased serum creatinine compared with the MB-6 group (29% vs 5.9%, P = .014). MB-6 is a promising botanical supplement that may increase the effectiveness of chemotherapy in patients with metastatic colorectal cancer.

Correlation between PET/CT parameters and KRAS expression in colorectal cancer.

PURPOSE: The objective of this study was to correlate the association between mutated KRAS and wild-type colorectal cancer (CRC) by using various F-FDG PET-related parameters. METHODS: One hundred twenty-one CRC patients who had undergone preoperative PET/CT were included in this study. Several PET/CT-related parameters, including SUVmax and various thresholds of metabolic tumor volume, total lesion glycolysis, and PET/CT-based tumor width, were measured. Tumor- and PET/CT-related parameters were correlated with genomic expression between KRAS mutant and wild-type groups, using a Mann-Whitney U test and logistic regression analysis. RESULTS: Colorectal cancer tumors with a mutated KRAS exhibited higher SUVmax and an increased accumulation of FDG among several threshold methods. Multivariate analysis showed that SUVmax and using a 40% threshold level for maximal uptake of TW (TW40%) were the 2 predictors of KRAS mutations. The odds ratio was 1.23 for SUVmax (P = 0.02; 95% confidence interval, 1.01-1.52) and 1.15 for TW40% (P = 0.02; 95% confidence interval, 1.02-1.30). The accuracy of SUVmax for predicting mutated KRAS was higher in patients with colon or sigmoid colon cancers, whereas it was TW40% in those with rectal cancers. CONCLUSIONS: SUVmax and TW40% were associated in CRC with KRAS mutations. PET/CT parameters can supplement genomic analysis to determine KRAS expression in CRC.

Grape-seed procyanidins inhibit the in vitro growth and invasion of pancreatic carcinoma cells.

OBJECTIVES: Grape-seed procyanidins (GSPs) can inhibit cell proliferation and invasiveness in various human cancers. However, the effect of GSP on pancreatic carcinoma cells has not been investigated. METHODS: Pancreatic carcinoma cell lines MIA PaCa-2 and BxPC-3 treated with GSP were assessed for viability by trypan blue exclusion, for cell cycle distribution by flow cytometry, for increased apoptosis by annexin V labeling, for their adhesion and invasion potential by evaluating their ability to penetrate through a matrix gel-coated Boyden chamber, and for changes in the levels of proteins involved in cellular events by immunoblotting. RESULTS: Grape-seed procyanidin inhibited MIA PaCa-2 and BxPC-3 proliferation in a dose-dependent manner and induced G1-phase arrest of the cell cycle in BxPC-3 or mitochondria-mediated apoptosis in MIA PaCa-2. Grape-seed procyanidin also inhibited the adhesion and invasion potential of both cell lines in a dose-dependent manner, which are associated with the suppression of metalloproteases matrix metalloproteinase 9 or 2 (MMP-9 or -2) expression. CONCLUSIONS: Grape-seed procyanidin inhibited the proliferation of pancreatic carcinoma cells by cell cycle blockage or apoptotic induction. The invasiveness was also suppressed by GSP through down-regulation of MMP-2 or MMP-9 in pancreatic carcinoma cells. Grape-seed procyanidin is a potential chemotherapeutic or preventive agent for pancreatic carcinoma.

Single-incision laparoscopic versus conventional laparoscopic right hemicolectomy: a comparison of short-term surgical results.

BACKGROUND: Since the introduction of laparoscopic colectomy, improved short-term surgical results have been noted in the literature. Therefore, efforts have shifted to reducing the invasiveness of laparoscopic surgery, resulting in the invention of single-incision laparoscopic surgery (SILS). Due to its comparable capabilities and feasibility, the implementation of SILS has rapidly grown in different fields. However, few studies discuss its true benefit compared with conventional laparoscopy. This study is the first to use SILS colectomy as an approach for malignant colon cancer. The goal of this cohort series is to compare the short-term surgical outcomes between SILS and conventional right hemicolectomy. METHODS: This was a case-control study comparing SILS right hemicolectomy patients to traditional laparoscopic right hemicolectomy. The inclusion criteria were only ascending colon cecal lesions. Cases of obstruction or perforation that required emergent operation or previous abdominal surgery were excluded. These patients were specifically matched in regard to patient's age, gender, perioperative condition, surgical indication, and tumor size. No consideration or analysis of operative parameters and outcomes was made until this group was definitively selected as the best comparison cohort based on preoperative variables only. RESULTS: A total of 18 patients were included for SILS and the other 21 patients were completed by conventional laparoscopic right hemicolectomy. The SILS and traditional laparoscopic groups were similar in regard to age, gender, body mass index, and perioperation outcomes. Initial oncologic results were no different, including equal length of distal cut margin, numbers of harvested lymph nodes, and TMN stage. Three patients in the SILS colectomy group were converted (16.6%), and there were no conversions in the traditional laparoscopic colectomy group. CONCLUSIONS: Our preliminary experience with SILS right hemicolectomy demonstrated the safety of the procedure and its feasibility in malignant colon cancer. Although SILS right hemicolectomy may provide a subjective cosmetic advantage, there was no benefit in the short-term surgical outcomes. SILS is very situational, requires more effort from the surgeon, and may not offer more patient comfort. More experience with SILS and prospective trials are needed to validate it as a more favorable alternative to conventional laparoscopic colectomy.

Identification of biomarkers to improve diagnostic sensitivity of sporadic colorectal cancer in patients with low preoperative serum carcinoembryonic antigen by clinical proteomic analysis.

BACKGROUND: Colorectal cancer (CRC) is the third most common type of cancer worldwide. Carcinoembryonic antigen (CEA) assays usually give false negative results. To improve the diagnosis of primary sporadic CRC, there is an urgent need to identify new biomarkers. METHODS: We used laser pressure catapulting and proteomics to analyze overexpressed cancer associated proteins from 48 sporadic CRC patients with low preoperative serum CEA (LPSC) (<5 ng/ml). Real-time Q-PCR was used to identify the target gene transcripts. Immunoblots were carried out to validate the biomarkers. RESULTS: Alpha-enolase, HSP27 and macrophage migration inhibitory factor (MIF) were overexpressed in all tumor tissues from 48 LPSC CRC patients, as assessed by 2DE image analysis. The genes were also overexpressed at the transcript level in all tumor tissues from the same patients. In the immunoblot assay, only serum levels of Alpha-enolase and MIF were significantly overexpressed in the LPSC group compared to the mean levels in the control group. Combined with the determinations of preoperative CEA levels, screening for serum Alpha-enolase and MIF were shown to improve the diagnosis of primary CRC. CONCLUSIONS: Serum Alpha-enolase and MIF may be potential biomarkers that can be used to improve clinical predication of primary CRC with LPSC.

Laparoscopic excision is an alterative method for rectal gastrointestinal stromal tumor.

Gastrointestinal stromal tumors (GISTs) are rarely found in the anorectum and account for less than 0.3% of all rectal malignancies. The major treatment of rectal GISTs is complete resection of the primary tumor with negative microscopic margin. Here, we present an alternative method-laparoscopic-assisted local excision of rectal GIST. The patient had a 5x4x3 cm GIST located 4 cm above the dentate line in the right rectal wall. The tumor was mobilized by laparoscopic dissection with a clear safe margin and the specimen was removed from anus. The patient had a smooth recovery and no recurrence was observed 31 months after the procedure. This experience suggests that laparoscopic excision is a safe alternative for rectal GIST, offering the advantage of better visualization of structures and sparing the patient from unnecessary abdominoperineal resections.