Efficacy and safety of Shenbai Granules for recurrent colorectal adenoma: A multicenter randomized controlled trial.

BACKGROUND: Colorectal adenoma is benign glandular tumor of colon, the precursor of colorectal cancer. But no pharmaceutical medication is currently available to treat and prevent adenomas. PURPOSE: To evaluate efficacy of Shenbai Granules, an herbal medicine formula, in reducing the recurrence of adenomas. STUDY DESIGN: This multicenter, randomized, double-blind, placebo-controlled clinical trial was conducted by eight hospitals in China. METHODS: Patients who had received complete polypectomy and were diagnosed with adenomas within the recent 6 months were randomly assigned (1:1) to receive either Shenbai granules or placebo twice a day for 6 months. An annual colonoscopy was performed during the 2-year follow-up period. The primary outcome was the proportion of patients with at least one adenoma detected in the modified intention-to-treat (mITT) population during follow-up for 2 years. The secondary outcomes were the proportion of patients with sessile serrated lesions and other specified polypoid lesions. The data were analyzed using logistic regression. RESULTS: Among 400 randomized patients, 336 were included in the mITT population. We found significant differences between treatment and placebo groups in the proportion of patients with at least one recurrent adenoma (42.5 % vs. 58.6 %; OR, 0.47; 95 % CI, 0.29-0.74; p = 0.001) and sessile serrated lesion (1.8 % vs. 8.3 %; OR, 0.20; 95 % CI, 0.06-0.72; p = 0.01). There was no significant difference in the proportion of patients developing polypoid lesions (70.7 % vs. 77.5 %; OR, 1.43; 95 % CI, 0.88-2.34; p = 0.15) or high-risk adenomas (9.0 % vs. 13.6 %; OR, 0.63; 95 % CI, 0.32-1.25; p = 0.18). CONCLUSION: Shenbai Granules significantly reduced the recurrence of adenomas, indicating that they could be an effective option for adenomas. Future studies should investigate its effects in larger patient populations and explore its mechanism of action to provide more comprehensive evidence for the use of Shenbai Granules in adenoma treatment.

Effect of ginger supplementation on the fecal microbiome in subjects with prior colorectal adenoma.

Ginger has been associated with a decreased incidence of colorectal cancer (CRC) through reduction in inflammatory pathways and inhibition of tumor growth. Recent pre-clinical models have implicated changes in the gut microbiome as a possible mediator of the ginger effect on CRC. We hypothesized that, in adults previously diagnosed with a colorectal adenoma, ginger supplementation would alter the fecal microbiome in the direction consistent with its CRC-inhibitory effect. Sixty-eight adults were randomized to take either ginger or placebo daily for 6 weeks, with a 6-week washout and longitudinal stool collection throughout. We performed 16S rRNA sequencing and evaluated changes in overall microbial diversity and the relative abundances of pre-specified CRC-associated taxa using mixed-effects logistic regression. Ginger supplementation showed no significant effect on microbial community structure through alpha or beta diversity. Of 10 pre-specified CRC-associated taxa, there were significant decreases in the relative abundances of the genera Akkermansia (p < 0.001), Bacteroides (p = 0.018), and Ruminococcus (p = 0.013) after 6-week treatment with ginger compared to placebo. Ginger supplementation led to decreased abundances of Akkermansia and Bacteroides, which suggests that ginger may have an inhibitory effect on CRC-associated taxa. Overall, ginger supplementation appears to have a limited effect on gut microbiome in patients with colorectal adenomas.

Establishment of a large-scale patient-derived high-risk colorectal adenoma organoid biobank for high-throughput and high-content drug screening.

BACKGROUND: Colorectal adenoma (CA), especially high-risk CA (HRCA), is a precancerous lesion with high prevalence and recurrence rate and accounts for about 90% incidence of sporadic colorectal cancer cases worldwide. Currently, recurrent CA can only be treated with repeated invasive polypectomies, while safe and promising pharmaceutical invention strategies are still missing due to the lack of reliable in vitro model for CA-related drug screening. METHODS: We have established a large-scale patient-derived high-risk colorectal adenoma organoid (HRCA-PDO) biobank containing 37 PDO lines derived from 33 patients and then conducted a series of high-throughput and high-content HRCA drug screening. RESULTS: We established the primary culture system with the non-WNT3a medium which highly improved the purity while maintained the viability of HRCA-PDOs. We also proved that the HRCA-PDOs replicated the histological features, cellular diversity, genetic mutations, and molecular characteristics of the primary adenomas. Especially, we identified the dysregulated stem genes including LGR5, c-Myc, and OLFM4 as the markers of adenoma, which are well preserved in HRCA-PDOs. Based on the HRCA-PDO biobank, a customized 139 compound library was applied for drug screening. Four drugs including metformin, BMS754807, panobinostat and AT9283 were screened out as potential hits with generally consistent inhibitory efficacy on HRCA-PDOs. As a representative, metformin was discovered to hinder HRCA-PDO growth in vitro and in vivo by restricting the stemness maintenance. CONCLUSIONS: This study established a promising HRCA-PDO biobank and conducted the first high-throughput and high-content HRCA drug screening in order to shed light on the prevention of colorectal cancer.

Chemoprevention of colorectal cancer in general population and high-risk population: a systematic review and network meta-analysis.

BACKGROUND: Many nutritional supplements and pharmacological agents have been reported to show preventive effects on colorectal adenoma and colorectal cancer (CRC). We performed a network meta-analysis to summarize such evidence and assess the efficacy and safety of these agents. METHODS: We searched PubMed, Embase, and the Cochrane Library for studies published in English until October 31, 2021 that fit our inclusion criteria. We performed a systematic review and network meta-analysis to assess the comparative efficacy and safety of candidate agents (low-dose aspirin [Asp], high-dose Asp, cyclooxygenase-2 inhibitors [coxibs], calcium, vitamin D, folic acid, ursodeoxycholic acid [UDCA], estrogen, and progesterone, alone or in combination) for preventing colorectal adenoma and CRC. Cochrane risk-of-bias assessment tool was employed to evaluate the quality of each included study. RESULTS: Thirty-two randomized controlled trials (278,694 participants) comparing 13 different interventions were included. Coxibs significantly reduced the risk of colorectal adenoma (risk ratio [RR]: 0.59, 95% confidence interval [CI]: 0.44-0.79, six trials involving 5486 participants), advanced adenoma (RR: 0.63, 95% CI: 0.43-0.92, four trials involving 4723 participants), and metachronous adenoma (RR: 0.58, 95% CI: 0.43-0.79, five trials involving 5258 participants) compared with placebo. Coxibs also significantly increased the risk of severe adverse events (RR: 1.29, 95% CI: 1.13-1.47, six trials involving 7109 participants). Other interventions, including Asp, folic acid, UDCA, vitamin D, and calcium, did not reduce the risk of colorectal adenoma in the general and high-risk populations compared with placebo. CONCLUSIONS: Considering the balance between benefits and harms, regular use of coxibs for prevention of colorectal adenoma was not supported by the current evidence. Benefit of low-dose Asp for chemoprevention of colorectal adenoma still requires further evidence. REGISTRATION: PROSPERO, No. CRD42022296376.

The Efficacy and Mechanism of Qinghua Jianpi Recipe in Inhibiting Canceration of Colorectal Adenoma Based on Inflammatory Cancer Transformation.

Objective: This study is aimed at exploring the effect of Qinghua Jianpi Recipe on preventing colon polyp recurrence and inhibiting the progress of "inflammatory cancer transformation." And another goal is to explore the changes of intestinal flora structure and intestinal inflammatory (immune) microenvironment of mice with colon polyps treated by Qinghua Jianpi Recipe and to clarify its mechanism. Methods: Clinical trials were conducted to confirm the therapeutic effect of Qinghua Jianpi Recipe on patients with inflammatory bowel disease. The inhibitory effect of Qinghua Jianpi Recipe on "inflammatory cancer transformation" of colon cancer was confirmed by an adenoma canceration mouse model. Histopathological examination was used to evaluate the effects of Qinghua Jianpi Recipe on intestinal inflammatory state, adenoma number, and pathological changes of adenoma model mice. The changes of inflammatory indexes in intestinal tissue were tested by ELISA. Intestinal flora was detected by 16S rRNA high-throughput sequencing. Short-chain fatty acid metabolism in the intestine was analyzed by targeted metabolomics. Network pharmacology analysis of possible mechanism of Qinghua Jianpi Recipe on colorectal cancer was performed. Western blot was used to detect the protein expression of the related signaling pathways. Results: Qinghua Jianpi Recipe can significantly improve intestinal inflammation status and function in patients with inflammatory bowel disease. Qinghua Jianpi Recipe could significantly improve the intestinal inflammatory activity and pathological damage of adenoma model mice and reduce the number of adenoma. Qinghua Jianpi Recipe significantly increased the levels of Peptostreptococcales_Tissierellales, NK4A214_group, Romboutsia, and other intestinal flora after intervention. Meanwhile, the treatment group of Qinghua Jianpi Recipe could reverse the changes of short-chain fatty acids. Network pharmacology analysis and experimental studies showed that Qinghua Jianpi Recipe inhibited the "inflammatory cancer transformation" of colon cancer by regulating intestinal barrier function-related proteins, inflammatory and immune-related signaling pathways, and free fatty acid receptor 2 (FFAR2). Conclusion: Qinghua Jianpi Recipe can improve the intestinal inflammatory activity and pathological damage of patient and adenoma cancer model mice. And its mechanism is related to the regulation of intestinal flora structure and abundance, short-chain fatty acid metabolism, intestinal barrier function, and inflammatory pathways.

Dopamine agonists for the treatment of pituitary tumours: From ergot extracts to next generation therapies.

Dopamine agonists are a key tool in the therapeutic arsenal of endocrinologists worldwide. They exert their effects by binding to dopamine-2 (D2) receptors expressed by pituitary tumour cells to modulate hormonal secretion and tumour size. They are the established first-line treatment for prolactinomas which express high levels of D2 receptors. Growing data support their use as an adjuvant treatment option for other pituitary tumours including growth hormone, adrenocorticotrophic hormones, thyroid hormone secreting adenomas and nonfunctional pituitary tumours, all of which have been shown to express D2 receptors as well, albeit to varying extents. For those pituitary tumours inadequately treated by dopamine agonist alone, combined agonism of D2 and somatostatin receptors represent a new frontier in clinical development. Here we review the development and role of dopamine agonist for the treatment of prolactinomas, the literature supporting their adjuvant use for the treatment of all other pituitary tumours, and recent progress in the development of the next generation of chimeric compounds that target D2 and other receptor subtypes highly expressed on pituitary tumour cells.

Ex vivo explant model of adenoma and colorectal cancer to explore mechanisms of action and patient response to cancer prevention therapies.

Colorectal cancer (CRC) is the second leading cause of cancer death in the UK. Novel therapeutic prevention strategies to inhibit the development and progression of CRC would be invaluable. Potential contenders include low toxicity agents such as dietary-derived agents or repurposed drugs. However, in vitro and in vivo models used in drug development often do not take into account the heterogeneity of tumours or the tumour microenvironment. This limits translation to a clinical setting. Our objectives were to develop an ex vivo method utilizing CRC and adenoma patient-derived explants (PDEs) which facilitates screening of drugs, assessment of toxicity, and efficacy. Our aims were to use a multiplexed immunofluorescence approach to demonstrate the viability of colorectal tissue PDEs, and the ability to assess immune cell composition and interactions. Using clinically achievable concentrations of curcumin, we show a correlation between curcumin-induced tumour and stromal apoptosis (P < .001) in adenomas and cancers; higher stromal content is associated with poorer outcomes. B cell (CD20+ve) and T cell (CD3+ve) density of immune cells within tumour regions in control samples correlated with curcumin-induced tumour apoptosis (P < .001 and P < .05, respectively), suggesting curcumin-induced apoptosis is potentially predicted by baseline measures of immune cells. A decrease in distance between T cells (CD3+ve) and cytokeratin+ve cells was observed, indicating movement of T cells (CD3+ve) towards the tumour margin (P < .001); this change is consistent with an immune environment associated with improved outcomes. Concurrently, an increase in distance between T cells (CD3+ve) and B cells (CD20+ve) was detected following curcumin treatment (P < .001), which may result in a less immunosuppressive tumour milieu. The colorectal tissue PDE model offers significant potential for simultaneously assessing multiple biomarkers in response to drug exposure allowing a greater understanding of mechanisms of action and efficacy in relevant target tissues, that maintain both their structural integrity and immune cell compartments.

Effects of Jianpi Lishi Jiedu granules on colorectal adenoma patients after endoscopic treatment: study protocol for a randomized, double-blinded, placebo-controlled clinical trial.

BACKGROUND: Colorectal adenomas (CRAs) are precancerous lesions of the large intestine presenting as colorectal polyps. At present, the conventional treatment methods for CRA mainly include high-frequency electrocoagulation and electroexcision, biopsy forceps polypectomy, cauterization by laser and microwave, and other endoscopic interventions. The principal advantages conferred by these treatment strategies include less trauma, quick postoperative recovery, and simplicity to perform. However, the higher recurrence rates and insignificant improvement of postoperative symptoms after endoscopic surgery are considerable drawbacks to this approach. Besides, there is currently no effective pharmacotherapy to prevent the recurrence of CRA. Jianpi Lishi Jiedu (JLJ) granules are a form of traditional Chinese medicine (TCM) used to manage postoperative patients with CRA, which has shown a certain degree of efficacy in clinical practice. However, its effectiveness and safety profile have not been convincingly evaluated. The purpose of this study is to evaluate the clinical efficacy and safety profile of JLJ granules in the management of postoperative patients with CRA and to observe the recurrence rate of adenoma in these patients. METHODS: A randomized, double-blind, and placebo-controlled clinical trial is performed in this study. A total of 80 postoperative patients with CRA will be randomly classified into the Jianpi Lishi Jiedu granules group or the placebo control group. Patients in both groups shall receive 3 months of intervention, after which medical follow-up and safety evaluation will be performed for all of the patients. The primary outcome is the recurrence rate of adenomas within 12 months. The secondary outcomes are the cardinal TCM symptom scores, minor TCM symptom scores, Bristol Stool Scale, efficacy of TCM symptoms, safety indicators, and blinding assessment. DISCUSSION: In this study, the impact on the recurrence of adenomas and the efficacy and safety of JLJ granules in terms of improving the clinical symptoms of postoperative patients with CRA will be evaluated. TRIAL REGISTRATION: Trial registration Chinese Clinical Trial Registry ChiCTR 2100044297. Registered on March 16, 2021.

Aspirin and omega-3 polyunsaturated fatty acid use and their interaction in cardiovascular diseases and colorectal adenomas.

Aspirin (acetylsalicylic acid, ASA) is inexpensive and is established in preventing cardiovascular disease (CVD) and colorectal adenomas. Omega-3 (n3) polyunsaturated fatty acids (PUFA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have also shown benefit in preventing CVD. The combination could be an effective preventative measure in patients with such diseases. ASA and n3 PUFA reduced the risk of CVD in ASA-resistant or diabetic patients. EPA- and DHA-deficient patients also benefited the most from n3 PUFA supplementation. Synergistic effects between ASA and EPA and DHA are 'V-shaped' such that optimal ASA efficacy is dependent on EPA and DHA concentrations in blood. In colorectal adenomas, ASA (300 mg/d) and EPA reduced adenoma burden in a location- and subtype-specific manner. Low doses of ASA (75-100 mg/d) were used in CVD prevention; however, ultra-low doses (30 mg/d) can also reduce thrombosis. EPA-to-DHA ratio is also important with regard to efficacy. DHA is more effective in reducing blood pressure and modulating systemic inflammation; however, high-dose EPA can lower CVD events in high-risk individuals. Although current literature has yet to examine ASA and DHA in preventing CVD, such combination warrants further investigation. To increase adherence to ASA and n3 PUFA supplementation, combination dosage form may be required to improve outcomes.

Efficacy and safety of berberine in preventing recurrence of colorectal adenomas: A systematic review and meta-analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Berberine(BBR) is a kind of isoquinoline alkaloids extracted from the rhizomes of Coptis chinensis Franch., which was the main active ingredient. Accumulating evidence has shown that it has potential pharmacological effects in preventing the recurrence of colorectal adenomas. AIM OF THE STUDY: The roles of BBR in the overall recurrence of colorectal adenoma have still not been assessed because of the limitations of the available data and the restriction of a single study. Therefore, we evaluated the effectiveness and safety of BBR in preventing the recurrence of colorectal adenomas through a systematic review and meta-analysis of available data. MATERIALS AND METHODS: We searched four English databases (PubMed (MEDLINE), the Cochrane Central Register of Controlled Trials (CENTRAL), Embase and Web of Science) and four Chinese language databases (Chinese Biomedicine (CBM), China National Knowledge Infrastructure (CNKI), Chinese Scientific Journals Database (VIP) and the WanFang Database) from their inception through October 2020. Meta-analysis was performed with RevMan5.3 software after data extraction and the quality of studies assessment. RESULTS: Three randomized controlled clinical trials were included with 1076 patients. Our results illustrated that 1-year and 2-year supplementation with BBR was associated with lower recurrence rate of colorectal adenoma (RR 0.69, 95% CI 0.57 to 0.84, p=0.0001; RR 0.75, 95% CI 0.64 to 0.88, p=0.0004). The relative risk of oral BBR for 1 year and 2 years is not comparable, for 2-year efficacy outcomes were assessed in all participants who had at least one colonoscopy with pathological evaluation after baseline (lots of participants completed the first colonoscopy but discontinued during the second follow-up interval.). Moreover, the results also suggest that BBR had more adverse events than placebo (RR 2.91, 95% CI 1.24 to 6.85, p=0.01). Through the full-text reading, no serious adverse events were observed, and constipation was the most common event which disappears once the drug is discontinued. CONCLUSION: Generally, the present study indicated that BBR has a comparable therapeutic effect on the prevention of colorectal adenomas recurrence. Adverse reactions are worthy of attention which requires additional studies to obtain a precise conclusion. PROSPERO REGISTRATION NO: CRD42020209135.

Tiaochang Xiaoliu Decoction Granules prevent the recurrence of colorectal adenoma: a study protocol for a randomized controlled trial.

BACKGROUND: With the changes in lifestyle and diet, the incidence and mortality of colorectal cancer (CRC) is increasing in China. CRC mainly develops from colorectal adenomas (CRAs). There is a lack of chemopreventative drugs with definite efficacy for CRAs. Tiaochang Xiaoliu Decoction (TXD) was developed by Professor Yunjian Luo and has been used clinically over the last ten years for the prevention of CRA recurrence. To facilitate its clinical use, TXD was further standardized and produced as "Tiaochang Xiaoliu Decoction Granules (TXDG)". A study was designed to investigate the preventive effects of TXDG on the recurrence of CRA. METHODS: A randomized, double-blinded, controlled, and multi-center experiment is proposed to assess the effectiveness and safety of TXDG. Patients with CRAs (after complete polypectomy under colonoscopy) will be randomly divided into two groups, one will be treated with TXDG (the TXDG group) and the other will be treated with a TXDG mimetic agent (the TXDG mimetic group). The patients will be treated for 6 months and followed up for 3 years. Follow-up colonoscopy is expected to be carried out within 1 to 3 years after the baseline examinations. The primary outcome measure is adenoma detection rate within 1 to 3 years. The secondary outcome measures are the number, location, and pathology of the adenomas, and the polyp detection rate. DISCUSSION: Reliable objective evidence will be provided to evaluate the efficacy and safety of TXDG as an accessorial therapy for CRA occurrence in post-polypectomy patients. TRIAL REGISTRATION: ChiCTR2000035257.

Effects of Supplemental Calcium and Vitamin D on Circulating Biomarkers of Gut Barrier Function in Patients with Colon Adenoma: A Randomized Clinical Trial.

Gut barrier dysfunction promotes chronic inflammation, contributing to several gastrointestinal diseases, including colorectal cancer. Preliminary evidence suggests that vitamin D and calcium could prevent colorectal carcinogenesis, in part, by influencing gut barrier function. However, relevant human data are scarce. We tested the effects of supplemental calcium (1,200 mg/day) and/or vitamin D3 (1,000 IU/day) on circulating concentrations of biomarkers of gut permeability (anti-flagellin and anti-lipopolysaccharide IgA and IgG, measured via ELISA) from baseline to 1 and 3 or 5 years postbaseline among 175 patients with colorectal adenoma in a randomized, double-blinded, placebo-controlled clinical trial. We also assessed factors associated with baseline concentrations of these biomarkers. We found no appreciable effects of supplemental vitamin D3 and/or calcium on individual or aggregate biomarkers of gut permeability. At baseline, a combined permeability score (the summed concentrations of all four biomarkers) was 14% lower among women (P = 0.01) and 10% higher among those who consumed >1 serving per day of red or processed meats relative to those who consumed none (P trend = 0.03). The permeability score was estimated to be 49% higher among participants with a body mass index (BMI) > 35 kg/m2 relative to those with a BMI < 22.5 kg/m2 (P trend = 0.17). Our results suggest that daily supplemental vitamin D3 and/or calcium may not modify circulating concentrations of gut permeability biomarkers within 1 or 3-5 years, but support continued investigation of modifiable factors, such as diet and excess adiposity, that could affect gut permeability. PREVENTION RELEVANCE: Calcium and vitamin D may be involved in regulating and maintaining the integrity of the intestinal mucosal barrier, the dysfunction of which results in exposure of the host to luminal bacteria, endotoxins, and antigens leading to potentially cancer-promoting endotoxemia and chronic colon inflammation. While our results suggest that daily supplementation with these chemopreventive agents does not modify circulating concentrations of gut permeability biomarkers, they support continued investigation of other potential modifiable factors, such as diet and excess adiposity, that could alter gut barrier function, to inform the development of treatable biomarkers of risk for colorectal neoplasms and effective colon cancer preventive strategies.

Effects of Sesamin, the Major Furofuran Lignan of Sesame Oil, on the Amplitude and Gating of Voltage-Gated Na+ and K+ Currents.

Sesamin (SSM) and sesamolin (SesA) are the two major furofuran lignans of sesame oil and they have been previously noticed to exert various biological actions. However, their modulatory actions on different types of ionic currents in electrically excitable cells remain largely unresolved. The present experiments were undertaken to explore the possible perturbations of SSM and SesA on different types of ionic currents, e.g., voltage-gated Na+ currents (INa), erg-mediated K+ currents (IK(erg)), M-type K+ currents (IK(M)), delayed-rectifier K+ currents (IK(DR)) and hyperpolarization-activated cation currents (Ih) identified from pituitary tumor (GH3) cells. The exposure to SSM or SesA depressed the transient and late components of INa with different potencies. The IC50 value of SSM needed to lessen the peak or sustained INa was calculated to be 7.2 or 0.6 µM, while that of SesA was 9.8 or 2.5 µM, respectively. The dissociation constant of SSM-perturbed inhibition on INa, based on the first-order reaction scheme, was measured to be 0.93 µM, a value very similar to the IC50 for its depressant action on sustained INa. The addition of SSM was also effective at suppressing the amplitude of resurgent INa. The addition of SSM could concentration-dependently inhibit the IK(M) amplitude with an IC50 value of 4.8 µM. SSM at a concentration of 30 µM could suppress the amplitude of IK(erg), while at 10 µM, it mildly decreased the IK(DR) amplitude. However, the addition of neither SSM (10 µM) nor SesA (10 µM) altered the amplitude or kinetics of Ih in response to long-lasting hyperpolarization. Additionally, in this study, a modified Markovian model designed for SCN8A-encoded (or NaV1.6) channels was implemented to evaluate the plausible modifications of SSM on the gating kinetics of NaV channels. The model demonstrated herein was well suited to predict that the SSM-mediated decrease in peak INa, followed by increased current inactivation, which could largely account for its favorable decrease in the probability of the open-blocked over open state of NaV channels. Collectively, our study provides evidence that highlights the notion that SSM or SesA could block multiple ion currents, such as INa and IK(M), and suggests that these actions are potentially important and may participate in the functional activities of various electrically excitable cells in vivo.

Bioactive Immunomodulatory Compounds: A Novel Combinatorial Strategy for Integrated Medicine in Oncology? BAIC Exposure in Cancer Cells.

The Standardized Cultured Extract of Lentinula edodes Mycelia (also known as Active Hexose Correlated Compound, AHCC) and Wasabia japonica (Wasabi) are natural nutritional supplements known for their immunomodulatory and anticancer potential. The aim of this study was to evaluate the combinatorial effect of the bioactive immunomodulatory compound (BAIC), obtained by combining Wasabi and AHCC, on human breast (MCF-7) and pancreatic (Panc02) adenocarcinoma cell lines. Data obtained revealed that BAIC determines a striking decline in cancer cell growth at minimal concentrations compared with the use of Wasabi and AHCC as single agents. A significant increase in the G0/G1 subpopulation together with a marked augmentation in the percentage of apoptotic cells was demonstrated by flow cytometry, together with a significant upregulation in the expression of genes associated to the apoptotic cascade in both cell lines. The inhibitory role BAIC plays in mammospheres formation from MCF-7-derived cancer stem cells was shown with a marked reduction in size and number. Interestingly, when BAIC was exposed to monocytic cells, no cytotoxic effects were observed. A monocytes-to-macrophages differentiation was rather observed with the concomitant acquisition of an anti-inflammatory phenotype. Taken together, our findings suggest that BAIC could be used as a potential integration of standard chemotherapy treatments because of the improved inhibitory activity on cancer cell proliferation and reduced potential adverse effects.

Body Composition and Aspirin Dose for Colorectal Adenoma Prevention in a Randomized Clinical Trial.

BACKGROUND: Visceral adiposity is a risk factor for colorectal adenomas, and aspirin is an established chemopreventive agent. Evidence from clinical trials suggests the effectiveness of aspirin at preventing cardiovascular disease and cancer may require higher doses for higher body weight. METHODS: Body mass index, body surface area, fat-free mass, and fat mass were calculated from baseline height and weight in 1,121 participants of the Aspirin/Folate Polyp Prevention Study, a double-blind, placebo-controlled, 3 × 2 factorial randomized clinical trial of low-dose (81 mg/day) or high-dose (325 mg/day) aspirin and/or 1 mg/day folic acid to prevent metachronous colorectal adenomas. Participants were treated during a surveillance colonoscopy interval of approximately 3 years. Risk ratios (RR) with 95% confidence intervals (CI) for any colorectal neoplasia and high-risk adenoma (HRA, advanced or ≥3 adenomas) were estimated from log-linear regression. RESULTS: We did not find evidence to suggest aspirin dose-response differed by body composition measurements, including weight alone. Among those weighing ≥ 80 kg, treatment effects for low-dose aspirin (RR for colorectal neoplasia, 0.75; 95% CI, 0.60-0.94; RR for HRA, 0.52; 95% CI, 0.31-0.86) and high-dose aspirin (RR for colorectal neoplasia, 0.88; 95% CI, 0.72-1.08; RR for HRA, 0.68; 95% CI, 0.43-1.09) were not meaningfully different than for those weighing 70-79 kg or <70 kg. CONCLUSIONS: Measurements of body composition calculated from height and weight did not modify aspirin treatment effects for colorectal adenoma prevention. IMPACT: Aspirin dosing strategies accounting for body weight suggested in previous trials of colorectal cancer may not apply to adenomas.

Efficacy of XELOX adjuvant chemotherapy for gastric mixed adenoneuroendocrine carcinoma: A case report.

RATIONALE: Mixed adenoneuroendocrine carcinoma (MANEC) is a rare neoplasm, and consensus on the treatment is unavailable. PATIENT CONCERN: A 60-year-old Chinese man presented with obstructive symptoms while eating and paroxysmal stomach pain for more than a month. DIAGNOSIS: MANEC was diagnosed based on clinical manifestations, imaging findings, and pathological examinations. INTERVENTIONS: The patient underwent radical gastrectomy and received XELOX adjuvant chemotherapy (oxaliplatin 200 mg day 1 + capecitabine 1.5 g twice a day) after surgery. OUTCOMES: After 4 cycles of XELOX adjuvant chemotherapy were administered, abdominal computerized tomography and liver magnetic resonance showed liver metastasis. LESSONS: The therapy of gastric MANEC is based on surgical operation, and adjuvant chemotherapy program has an important influence on its prognosis. Therefore, further studying the effectiveness of XELOX adjuvant chemotherapy for gastric MANEC is necessary.

Selenium supplementation and insulin resistance in a randomized, clinical trial.

Objective: While controversial, observational and randomized clinical trial data implicate the micronutrient selenium (Se) in the development of type 2 diabetes (T2D). The aim of this study was to test the hypothesis that Se supplementation adversely affects pancreatic ß-cell function and insulin sensitivity. Research design and methods: In a subset of 400 individuals participating in a randomized, placebo-controlled trial of Se at 200 µg/day for colorectal adenomatous polyps, fasting plasma glucose and insulin were measured before randomization and within 6 months of completing intervention. Change in the homeostasis model assessment-ß cell function (HOMA2-%ß) and insulin sensitivity (HOMA2-%S) were compared between arms. A subgroup of 175 (79 Se and 96 placebo) participants underwent a modified oral glucose tolerance test (mOGTT) at the end of intervention and change in glucose values was assessed. Results: No statistically significant differences were observed for changes in HOMA2-%ß or HOMA2-%S between those who received Se compared with placebo. After a mean of 2.9 years on study, mean HOMA2-%ß values were 3.1±24.0 and 3.1±29.8 for the Se and placebo groups, respectively (p=0.99). For HOMA2-%S, the values were -0.5±223.2 and 80.9±1530.9 for the Se and placebo groups, respectively (p=1.00). Stratification by sex or age did not reveal any statistically significant effects on insulin sensitivity by treatment group. For mOGTT, mean baseline fasting blood glucose concentrations were significantly higher among participants in the placebo group compared with the Se group (96.6±14.6 and 92.3±12.0, respectively; p=0.04), a trend which remained through the 20 min assessment. Conclusions: These findings do not support a significant adverse effect of daily Se supplementation with 200 µg/day of selenized yeast on ß-cell function or insulin sensitivity as an explanation for previously reported associations between Se and T2D. Further clarification of longer term effects of Se is needed. Clinical trial registry: NIH Clinical Trials.gov number NCT00078897.

Surgical-pharmacological interactions in the treatment of acromegaly.

INTRODUCTION: Acromegaly requires a multimodal treatment approach that includes surgery by an expert pituitary neurosurgeon, pharmacological treatment with one or more of the available drugs and radiation therapy. These treatment alternatives are not mutually exclusive but rather complement each other when properly indicated in the individual patient. In this review, we summarize and analyze the available data concerning the choice of the surgical approach (microscopy vs. endoscopy) and the interactions between medical treatment with somatostatin analogs and pituitary surgery. AREAS COVERED: Technical aspects, complications and outcome of transsphenoidal surgery (TSS); Advantages and disadvantages of the microscopic and endoscopic approaches; Safety and efficacy of somatostatin analogs (SSA); Primary pharmacological therapy versus primary TSS; Benefits of the preoperative treatment with SSA; and the effect of surgical tumor debulking in the therapeutic response to SSA. EXPERT COMMENTARY: Continuing efforts at improving surgical techniques and at generating more efficacious pharmacological therapies for acromegaly are likely to improve the outcome of these patients. However, an integral approach of the patient aimed not only at achieving biochemical criteria of cure but also at treating the individual comorbidities is mandatory to improve the quality of life of these patients and to reduce their mortality rate.

Effects of vitamin D and calcium on expression of MSH2 and transforming growth factors in normal-appearing colorectal mucosa of sporadic colorectal adenoma patients: A randomized clinical trial.

Abnormal expression of the DNA mismatch repair protein MSH2 and autocrine/paracrine transforming growth factors TGFα (growth promoter) and TGFß1 (growth inhibitor) is common during colorectal carcinogenesis. To estimate vitamin D and calcium effects on these biomarkers in the normal-appearing colorectal mucosa of sporadic colorectal adenoma patients, we conducted a pilot, randomized, double-blinded, placebo-controlled, modified 2 × 2 factorial chemoprevention clinical trial (N = 104) of supplemental vitamin D3 (1000 IU daily) and calcium (1200 mg daily), alone and in combination, versus placebo over 1 year. The expression of the three biomarkers and Ki-67/mib-1 in colorectal crypts in biopsies of normal-appearing rectal mucosa were detected using automated immunohistochemistry and quantified using image analysis. In the vitamin D3 and vitamin D3 plus calcium groups, relative to their reference groups, in the upper 40% (differentiation zone) of crypts, it was estimated that, respectively, the MSH2/mib-1 ratio increased by 47% (P = 0.14) and 62% (P = 0.08), TGFß1 expression increased by 41% (P = 0.25) and 78% (P = 0.14), and the TGFα/TGFß1 ratio decreased by 25% (P = 0.31) and 44% (P = 0.13). Although not statistically significant, these results support further research into (i) whether supplemental vitamin D3 , alone or in combination with calcium, may increase DNA mismatch repair relative to proliferation, increase TGFß1 expression, and decrease autocrine/paracrine growth promotion relative to growth inhibition in the colorectal epithelium, all hypothesized to reduce risk for colorectal carcinogenesis; and (ii) the expression of MSH2 relative to mib-1, TGFß1 alone, and TGFα relative to TGFß1 in the normal-appearing rectal mucosa as potential modifiable, pre-neoplastic markers of risk for colorectal neoplasms.