Exploring polyps to colon carcinoma voyage: can blocking the crossroad halt the sequence?

Colorectal cancer is an important public health concern leading to significant cancer associate mortality. A vast majority of colon cancer arises from polyp which later follows adenoma, adenocarcinoma, and carcinoma sequence. This whole process takes several years to complete and recent genomic and proteomic technologies are identifying several targets involved in each step of polyp to carcinoma transformation in a large number of studies. Current text presents interaction network of targets involved in polyp to carcinoma transformation. In addition, important targets involved in each step according to network biological parameters are also presented. The functional overrepresentation analysis of each step targets and common top biological processes and pathways involved in carcinoma indicate several insights about this whole mechanism. Interaction networks indicate TP53, AKT1, GAPDH, INS, EGFR, and ALB as the most important targets commonly involved in polyp to carcinoma sequence. Though several important pathways are known to be involved in CRC, the central common involvement of PI3K-AKT indicates its potential for devising CRC management strategies. The common and central targets and pathways involved in polyp to carcinoma progression can shed light on its mechanism and potential management strategies. The data-driven approach aims to add valuable inputs to the mechanism of the years-long polyp-carcinoma sequence.

Analysis of related risk factors of lung metastasis after laparoscopic radical hysterectomy of cervical cancer.

ABSTRACT: To explore the risk factors of lung metastasis in patients after laparoscopic radical hysterectomy (LRH) of cervical cancer (CC).The clinical data of CC patients with clinical stage of IA1-IIA2 diagnosed in our hospital from April 2007 to October 2015 were collected. According to the situation of metastasis, the patients were divided into lung metastasis (n = 73) and non-lung metastasis group (n = 2076). The clinical data were compared between 2 groups, and logistic stepwise regression model was used to analyze the risk factors of lung metastasis in patients with CC after LRH.The incidence of lung metastasis after LRH of CC was 3.39%, and 67.13% of patients with lung metastases had no obvious clinical symptoms. 15.06% patients had lung metastasis in the first year, 38.35% in the second year, 43.83% in the third year and later. The postoperative lung metastasis of CC was related to tumor diameter (P < .001), pathological type (P < .001), interstitial invasion depth (P < .001), pelvic lymph node metastasis (PLNM, P < .001), vascular tumor thrombus (P = .011), tumor uterine invasion (P = .002), and abnormal preoperative tumor markers (P = .015). However, it was not related to age, clinical stage, tumor growth pattern, tumor differentiation, and para-aortic lymph node metastasis (P > .05). Logistic regression analysis revealed non-squamous cell carcinoma (P = .022), tumor diameter ≥4 cm (P = .008), interstitial invasion depth >2/3 (P = .003), PLNM (P = .007), and tumor uterine invasion (P = .037) is an independent risk factor for lung metastasis after LRH of CC.Non-squamous cell carcinoma, tumor diameter ≥4 cm, tumor interstitial invasion depth >2/3, PLNM, and tumor uterine invasion are independent risk factors for lung metastasis after LRH of CC.

5-Aminosalicylic acid inhibits stem cell function in human adenoma-derived cells: implications for chemoprophylaxis in colorectal tumorigenesis.

BACKGROUND: Most colorectal cancers (CRC) arise sporadically from precursor lesions: colonic polyps. Polyp resection prevents progression to CRC. Risk of future polyps is proportional to the number and size of polyps detected at screening, allowing identification of high-risk individuals who may benefit from effective chemoprophylaxis. We aimed to investigate the potential of 5-aminosalicylic acid (5-ASA), a medication used in the treatment of ulcerative colitis, as a possible preventative agent for sporadic CRC. METHODS: Human colorectal adenoma (PC/AA/C1, S/AN/C1 and S/RG/C2), transformed adenoma PC/AA/C1/SB10 and carcinoma cell lines (LS174T and SW620) were treated with 5-ASA. The effect on growth in two- and three-dimensional (3D) culture, ß-catenin transcriptional activity and on cancer stemness properties of the cells were investigated. RESULTS: 5-ASA was shown, in vitro, to inhibit the growth of adenoma cells and suppress ß-catenin transcriptional activity. Downregulation of ß-catenin was found to repress expression of stem cell marker LGR5 (leucine-rich G protein-coupled receptor-5) and functionally suppress stemness in human adenoma and carcinoma cells using 3D models of tumorigenesis. CONCLUSIONS: 5-ASA can suppress the cancer stem phenotype in adenoma-derived cells. Affordable and well-tolerated, 5-ASA is an outstanding candidate as a chemoprophylactic medication to reduce the risk of colorectal polyps and CRC in those at high risk.

Curcumin Chemoprevention Reduces the Incidence of Braf Mutant Colorectal Cancer in a Preclinical Study.

BACKGROUND: Colorectal cancer is a leading cause of cancer-related death worldwide and approximately 20% of cases can be attributed to a mutation in the BRAF oncogene. Curcumin is a promising chemopreventive agent with various anti-cancer benefits. Although curcumin has been reported to have poor bioavailability, this limitation has been overcome by the formulation of nano-carriers. In this preclinical study, we investigated the ability of an improved formulation of curcumin to reduce the incidence of Braf mutant carcinoma. AIM: To investigate curcumin as a chemopreventive for Braf mutant colorectal cancer in a preclinical study utilizing a murine model of serrated neoplasia. METHODS: An intestine-specific Braf mutant murine model (BrafV637E/+/Villin-CreERT2/+) was administered curcumin micelles (240 mg/kg, n = 69) in normal drinking water. Mice in the control group consumed normal drinking water (n = 83). Mice were euthanized at 14 months and the incidence of murine serrated lesions and carcinoma in each cohort were determined by histologic examination. RESULTS: At completion of the study (14 months), it was found that curcumin did not reduce the incidence or multiplicity of murine serrated lesions but did significantly reduce the number of invasive carcinomas (RR 0.83, 95% CI 0.69-0.9985, P = 0.0360) compared to control. CONCLUSIONS: We have performed the first long-term study assessing curcumin's effect on the development of serrated neoplasia. We found that curcumin significantly reduces the risk of developing Braf mutant colorectal cancer. Our data supports further investigation of curcumin as a chemopreventive to reduce the risk of colorectal cancer arising via the serrated pathway.

Dynamic Changes of Convolutional Neural Network-based Mammographic Breast Cancer Risk Score Among Women Undergoing Chemoprevention Treatment.

INTRODUCTION: We investigated whether our convolutional neural network (CNN)-based breast cancer risk model is modifiable by testing it on women who had undergone risk-reducing chemoprevention treatment. MATERIALS AND METHODS: We conducted a retrospective cohort study of patients diagnosed with atypical hyperplasia, lobular carcinoma in situ, or ductal carcinoma in situ at our institution from 2007 to 2015. The clinical characteristics, chemoprevention use, and mammography images were extracted from the electronic health records. We classified two groups according to chemoprevention use. Mammograms were performed at baseline and subsequent follow-up evaluations for input to our CNN risk model. The 2 chemoprevention groups were compared for the risk score change from baseline to follow-up. The change categories included stayed high risk, stayed low risk, increased from low to high risk, and decreased from high to low risk. Unordered polytomous regression models were used for statistical analysis, with P < .05 considered statistically significant. RESULTS: Of 541 patients, 184 (34%) had undergone chemoprevention treatment (group 1) and 357 (66%) had not (group 2). Using our CNN breast cancer risk score, significantly more women in group 1 had shown a decrease in breast cancer risk compared with group 2 (33.7% vs. 22.9%; P < .01). Significantly fewer women in group 1 had an increase in breast cancer risk compared with group 2 (11.4% vs. 20.2%; P < .01). On multivariate analysis, an increase in breast cancer risk predicted by our model correlated negatively with the use of chemoprevention treatment (P = .02). CONCLUSIONS: Our CNN-based breast cancer risk score is modifiable with potential utility in assessing the efficacy of known chemoprevention agents and testing new chemoprevention strategies.

Do Histopathology and Clinical Outcomes of Breast Atypia Vary by Race/Ethnicity?

BACKGROUND: The clinical behavior of breast cancer varies by racial and ethnic makeup (REM), but the impact of REM on the clinical outcomes of breast atypia remains understudied. We examined the impact of REM on risk of underlying or subsequent carcinoma following a diagnosis of breast atypia. METHODS: In this retrospective, single-institution chart review, adult women diagnosed with breast atypia (atypical ductal hyperplasia, atypical lobular hyperplasia, or lobular carcinoma in situ) were stratified by REM. Regression modeling was used to estimate risk of underlying or subsequent carcinoma. RESULTS: We identified 539 patients with breast atypia, including 15 Hispanic (2.8%), 127 non-Hispanic black (23.6%), and 397 non-Hispanic white women (73.7%). Diagnoses included 75.1% atypical ductal hyperplasia (n = 405), 4.6% atypical lobular hyperplasia (n = 25), and 20.2% lobular carcinoma in situ (n = 109). Rates for each type of atypia did not vary by REM (P = 0.33). Of those with atypia on needle biopsy, the rate of underlying carcinoma at excision was 17.3%. After adjustment, REM was not associated with greater risk for carcinoma at excision (P = 0.41). Of those with atypia alone on surgical excision, the rate of a subsequent carcinoma diagnosis was 15.4% (median follow-up 49 mo). REM was not associated with a long-term risk for carcinoma (P = 0.37) or differences in time to subsequent carcinoma (log-rank P = 0.52). Chemoprevention uptake rates were low (10.6%), especially among Hispanic (0%) and non-Hispanic black (3.8%) patients (P = 0.01). CONCLUSIONS: Among patients with atypia, REM does not appear to influence type of histologic atypia, risk for carcinoma, or clinical outcome, despite differences in chemoprevention rates.

Pharmacokinetic and Metabolic Profiling of Key Active Components of Dietary Supplement Magnolia officinalis Extract for Prevention against Oral Carcinoma.

Among the three key active components (KACs) of Magnolia officinalis bark extract (ME), 4-O-methylhonokiol and honokiol showed higher antiproliferation activities than magnolol in the oral squamous cancer cell lines (Cal-27, SCC-9, and SCC-4). Oral bioavailabilities of ME-KACs were poor (<0.2%) in C57BL/6 mice primarily due to their extensive first-pass phase II metabolism and poor solubilities. High plasma concentration of glucuronides upon oral administration and faster rate of glucuronidation by intestinal microsomes indicated intestine as one of the major metabolic organs for ME-KACs. Despite the increase in bioavailabilities of ME-KACs (∼8-10-fold) and decrease in AUC0-24 of glucuronides (∼10-fold) upon ME solubility enhancement, systemic exposure of ME-KACs failed to improve meaningfully. In conclusion, we propose a quality-controlled and chemically defined ME mixture, containing an optimized ratio of three KACs, delivered locally in the oral cavity as the most promising strategy for ME use as an oral cancer chemopreventive dietary supplement.

Prevention versus early detection for long-term control of melanoma and keratinocyte carcinomas: a cost-effectiveness modelling study.

OBJECTIVE: To compare the long-term economic impact of melanoma prevention by sun protection, with the corresponding impact of early detection of melanoma to decrease melanoma deaths. DESIGN: Cost-effectiveness analysis using Markov cohort model. Data were primarily from two population-based randomised controlled trials, epidemiological and costing reports, and included flow-on effects for keratinocyte cancers (previously non-melanoma skin cancers) and actinic keratoses. SETTING: Queensland, Australia. PARTICIPANTS: Men and women with a mean age 50 years modelled for 30 years. INTERVENTIONS: Daily sunscreen use (prevention) compared with annual clinical skin examinations (early detection) and comparing these in turn with the status quo. PRIMARY AND SECONDARY OUTCOMES: Costs, counts of melanoma, melanoma deaths, keratinocyte cancers, life years and quality-adjusted life years. RESULTS: Per 100 000 individuals, for early detection, primary prevention and without intervention, there were 2446, 1364 and 2419 new melanomas, 556, 341 and 567 melanoma deaths, 64 452, 47 682 and 64 659 keratinocyte cancers and £493.5, £386.4 and £406.1 million in economic costs, respectively. There were small differences between prevention and early detection in life years saved (0.09%) and quality-adjusted life years gained (0.10%). CONCLUSIONS: Compared with early detection of melanoma, systematic sunscreen use at a population level will prevent substantial numbers of new skin tumours, melanoma deaths and save healthcare costs. Primary prevention through daily use of sunscreen is a priority for investment in the control of melanoma.

Preventable incidence of carcinoma associated with adiposity, alcohol and physical inactivity according to smoking status in the United States.

The changing profile of lifestyles and their intricate relationships with smoking indicate the importance of accounting for smoking status when assessing cancer preventability. We assessed the association of body mass index, weight change, alcohol intake and physical activity with risk of total carcinoma among 53,195 smokers and 62,842 nonsmokers in two prospective cohorts. Then, leveraging the national prevalence estimates, we calculated the population attributable risk (PAR) for healthy lifestyle defined as body mass index ≥18.5 and <27.5 kg/m2 , mid-life weight change of ≤20 pounds, no or moderate alcohol drinking (≤1 and 2 drinks/day for women and men, respectively) and weekly moderate or vigorous physical activity of at least 150 min. The PAR (95% CI) for healthy lifestyle was 18% (14-22%) in nonsmokers and 14% (10-19%) in smokers among women, and 20% (12-27%) in nonsmokers and 11% (5-17%) in smokers among men. While adiposity accounted for a substantially higher proportion of carcinoma cases in nonsmokers than smokers (16% vs. 2% in women, 15% vs. 2% in men), alcohol contributed more in smokers than nonsmokers (7% vs. 3% in women, 8% vs. 1% in men). When more strict criteria were used to define healthy lifestyle, the PAR estimates further increased (for women: 37% in smokers and 32% in nonsmokers; for men: 15% and 24%, respectively). In conclusion, lifestyle modification has great potential to reduce cancer risk in both smokers and nonsmokers. Weight control and reducing alcohol consumption should be prioritized for cancer prevention in nonsmokers and smokers, respectively.

Effects of increased actinic keratosis count on skin-related quality of life: results from the Veterans Affairs Keratinocyte Carcinoma Chemoprevention (VAKCC) Trial.

BACKGROUND: Actinic keratoses (AKs) are very common and it is therefore important to consider how morbidity of this disease impacts quality of life (QoL). Previous longitudinal studies of skin-related QoL in a high-risk population found no effect of increased AK counts on subsequent skin-related QoL, even though higher AK counts were associated with worse skin-related QoL cross-sectionally. OBJECTIVES: To determine if development of new actinic keratoses (AKs) are associated with worse skin-related QoL in those at high risk of keratinocyte carcinoma (KC). MATERIALS AND METHODS: A prospective analysis was performed using data from the Veterans Affairs Keratinocyte Carcinoma Chemoprevention Trial, a randomized, double-blinded, placebo-controlled trial of topical 5-fluorouracil for chemoprevention of KC. We report correlates of skin-related quality of life, a secondary outcome of the trial. Demographic and health-related information were self-reported and AK multiplicity on the face/ears were noted on semi-annual skin exams. Skindex-29 and Skin Cancer Index instruments were used to assess skin-related QoL yearly. RESULTS: Participants with increased AK counts had worse skin-related QoL compared to those with unchanged or decreased counts, particularly in Year 1. CONCLUSION: Our findings of impaired skin-related QoL associated with AKs underscore the importance of appropriate management to reduce the burden of disease.

Autologous hybrid cell fusion vaccine in a spontaneous intermediate model of breast carcinoma.

Breast cancer is among the most common malignancies affecting women and reproductively intact female dogs, resulting in death from metastatic disease if not treated effectively. To better manage the disease progression, canine mammary tumor (CMT) cells derived from malignant canine mammary cancers were fused to autologous dendritic cells (DCs) to produce living hybrid-cell fusion vaccines for canine patients diagnosed with spontaneous mammary carcinoma. The high-speed sorting of rare autologous canine patient DCs from the peripheral blood provides the autologous component of fusion vaccines, and fusion to major histocompatibility complex-unmatched CMT cells were produced at high rates. The vaccinations were delivered to each patient following a surgical resection 3 times at 3-week intervals in combination with immuno-stimulatory oligonucleotides and Gemcitabine adjunct therapy. The immunized patient animals survived 3.3-times longer (median survival 611 days) than the control patients (median survival 184 days) and also appeared to exhibit an enhanced quality of life. A comparison of vaccinated patients diagnosed with inflammatory mammary carcinoma resulted in a very short median survival (42 days), suggesting no effect of vaccination. The data showed that the development of autologous living DC-based vaccine strategies in patient animals designed to improve the management of canine mammary carcinoma can be successful and may allow an identification of the antigens that can be translatable to promote effective immunity in canine and human patients.

Role of endoscopic ultrasound in the screening and follow-up of high-risk individuals for familial pancreatic cancer.

Managing familial pancreatic cancer (FPC) is challenging for gastroenterologists, surgeons and oncologists. High-risk individuals (HRI) for pancreatic cancer (PC) (FPC or with germline mutations) are a heterogeneous group of subjects with a theoretical lifetime cumulative risk of PC over 5%. Screening is mainly based on annual magnetic resonance imaging (MRI) and endoscopic ultrasound (EUS). The goal of screening is to identify early-stage operable cancers or high-risk precancerous lesions (pancreatic intraepithelial neoplasia or intraductal papillary mucinous neoplasms with high-grade dysplasia). In the literature, target lesions are identified in 2%-5% of HRI who undergo screening. EUS appears to provide better identification of small solid lesions (0%-46% of HRI) and chronic-pancreatitis-like parenchymal changes (14%-77% of HRI), while MRI is probably the best modality to identify small cystic lesions (13%-49% of HRI). There are no specific studies in HRI on the use of contrast-enhanced harmonic EUS. EUS can also be used to obtain tissue samples. Nevertheless, there is still limited evidence on the accuracy of imaging procedures used for screening or agreement on which patients to treat. The cost-effectiveness of screening is also unclear. Certain new EUS-related techniques, such as searching for DNA abnormalities or protein markers in pancreatic fluid, appear to be promising.

Health behaviours and beliefs in individuals with familial pancreatic cancer.

Individuals at high risk for pancreatic cancer are recommended surveillance and healthy lifestyle behaviours and patient experience with recommendations are understudied. To describe engagement and experience with surveillance, tobacco and alcohol use, health beliefs and motivation (Champion Health Belief Measure) and the relationship with personal, psychosocial (Impact of Event Scale), and familial characteristics. Interest in integrative therapies (complementary therapies) are described. A multi-site cross-sectional survey including individuals at high risk for pancreatic cancer with no diagnosis of pancreatic cancer who have been evaluated at a comprehensive cancer center. Descriptive statistics and Wilcoxon rank sum test and Fisher's exact test were used to assess univariate associations. Of the 132 respondents (72% response rate), 92 (70%) reported undergoing surveillance which was associated with older age (p = 0.001). Of which, 36% and 51% report that magnetic resonance imaging (MRI) or endoscopic ultrasound (EUS), respectively, were uncomfortable; 22% and 30% dread the next MRI or EUS, respectively. Of those who reported alcohol consumption (n = 88); 15% consumed 1 or more drinks daily and no alcohol consumption was associated with higher Impact of Event scale scores (p = 0.024). A total of six participants were currently smoking every day or some days. Participants reported high motivation to engage in heathy behaviours and 92% were interested in integrative therapies. In these select participants, most were engaging in pancreatic cancer surveillance, alcohol intake was moderate, and tobacco intake was minimal. Modifiable factors, such as experience and comfort with surveillance could be addressed. The sample is motivated to engage in behavioural health intervention.

Elucidation of the Chemopreventive Role of Stigmasterol Against Jab1 in Gall Bladder Carcinoma.

BACKGROUND: Plant sterols have proven a potent anti-proliferative and apoptosis inducing agent against several carcinomas including breast and prostate cancers. Jab1 has been reported to be involved in the progression of numerous carcinomas. However, antiproliferative effects of sterols against Jab1 in gall bladder cancer have not been explored yet. OBJECTIVE: In the current study, we elucidated the mechanism of action of stigmasterol regarding apoptosis induction mediated via downregulation of Jab1 protein in human gall bladder cancer cells. METHODS: In our study, we performed MTT and Trypan blue assay to assess the effect of stigmasterol on cell proliferation. In addition, RT-PCR and western blotting were performed to identify the effect of stigmasterol on Jab1 and p27 expression in human gall bladder cancer cells. We further performed cell cycle, Caspase-3, Hoechst and FITC-Annexin V analysis, to confirm the apoptosis induction in stigmasterol treated human gall bladder cancer cells. RESULTS: Our results clearly indicated that stigmasterol has up-regulated the p27 expression and down-regulated Jab1 gene. These modulations of genes might occur via mitochondrial apoptosis signaling pathway. Caspase-3 gets activated with the apoptotic induction. Increase in apoptotic cells and DNA were confirmed through annexin V staining, Hoechst staining, and cell cycle analysis. CONCLUSION: Thus, these results strongly suggest that stigmasterol has the potential to be considered as an anticancerous therapeutic agent against Jab1 in gall bladder cancer.

Cancer risk in primary sclerosing cholangitis: Epidemiology, prevention, and surveillance strategies.

Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease characterized by progressive fibroinflammatory destruction of the intra- and/or extrahepatic biliary ducts. While its features and disease course can be variable, most patients with PSC have concurrent inflammatory bowel disease and will eventually develop liver cirrhosis and end-stage liver disease, with liver transplantation representing the only potentially curative option. Importantly, PSC is associated with a significantly increased risk of malignancy compared to the general population, mainly cholangiocarcinoma, gallbladder carcinoma, hepatocellular carcinoma, and colorectal cancer, with nearly 50% of deaths in patients with PSC being due to cancer. Therefore, robust surveillance strategies are needed, though uncertainty remains regarding how to best do so. In this review, we discuss the epidemiology, prevention, and surveillance of cancers in patients with PSC. Where evidence is limited, we present pragmatic approaches based on currently available data and expert opinion.

Volatile oil from alpinia officinarum promotes lung cancer regression in vitro and in vivo.

The anti-lung cancer activity of volatile oil from Alpinia officinarum (VOAO) and the underlying mechanism has not been studied. Herein, VOAO was extracted by steam distillation and its components were identified by GC-MS analysis. Cells viability was measured by an MTT assay and the cell survival capacity was tested via a colony formation assay. Apoptosis cells were detected using the Annexin V-FITC/PI method. Hoechst 33342 cell unclear staining was employed to evaluate the nuclear morphology change. The mitochondrial membrane potential was detected by a JC-1 staining assay. Bcl-2, Mcl-1 and cleaved caspase-3 proteins were quantified by immune blotting. Furthermore, VOAO anti-cancer activity was evaluated on an A549 cell xenograft nude mice model. Our results have revealed that VOAO could inhibit the cell viability of lung carcinoma cells and the colony formation capacity. VOAO downregulates Bcl-2 and Mcl-1 and triggers dysfunction of the mitochondrial membrane potential. VOAO further activates caspase-3 cleavage and induces lung cancer cells apoptosis. In addition, VOAO administration significantly suppresses lung cancer growth in xenograft mice without obvious hepatotoxicity. We conclude that VOAO could be an effective, low cytotoxicity natural component for treatment of lung carcinoma.

CX3CL1/fractalkine enhances prostate cancer spinal metastasis by activating the Src/FAK pathway.

Chemokines serve important roles in the development of cancer. C-X3-C motif chemokine ligand 1 (CX3CL1) has been demonstrated to promote metastases in different types of tumors. The authors' previous studies demonstrated that the CX3CL1 (also termed fractalkine)/steroid receptor coactivator (Src)/focal adhesion kinase (FAK) signaling pathway is associated with spinal metastasis. In the present study, it was observed that CX3CL1/C-X3-C motif chemokine receptor 1 (CX3CR1) was overexpressed in prostate cancer tissues with spinal metastasis compared with primary tumors. Overexpression of CX3CR1 induced cell proliferation, migration and invasion, and inhibited cellular apoptosis. However, repression of CX3CR1 reduced cell proliferation, migration and invasion, and increased cellular apoptosis. In addition, the Src/FAK pathway was activated by CX3CL1, which depends on the Tyr992 residue of epidermal growth factor receptor (EGFR) for phosphorylation. The inhibitors of these kinases repressed the cell migration induced by CX3CL1 or CX3CR1 overexpression. Furthermore, overexpression of CX3CR1 induced the spinal metastasis of prostate cancer in an in vivo mouse model. Therefore, CX3CL1 and its regulation of the EGFR, Src and FAK pathways may be potential targets for the early prevention of spinal metastasis in prostate cancer.