Cancer health disparities in racial/ethnic minorities in the United States.

There are well-established disparities in cancer incidence and outcomes by race/ethnicity that result from the interplay between structural, socioeconomic, socio-environmental, behavioural and biological factors. However, large research studies designed to investigate factors contributing to cancer aetiology and progression have mainly focused on populations of European origin. The limitations in clinicopathological and genetic data, as well as the reduced availability of biospecimens from diverse populations, contribute to the knowledge gap and have the potential to widen cancer health disparities. In this review, we summarise reported disparities and associated factors in the United States of America (USA) for the most common cancers (breast, prostate, lung and colon), and for a subset of other cancers that highlight the complexity of disparities (gastric, liver, pancreas and leukaemia). We focus on populations commonly identified and referred to as racial/ethnic minorities in the USA-African Americans/Blacks, American Indians and Alaska Natives, Asians, Native Hawaiians/other Pacific Islanders and Hispanics/Latinos. We conclude that even though substantial progress has been made in understanding the factors underlying cancer health disparities, marked inequities persist. Additional efforts are needed to include participants from diverse populations in the research of cancer aetiology, biology and treatment. Furthermore, to eliminate cancer health disparities, it will be necessary to facilitate access to, and utilisation of, health services to all individuals, and to address structural inequities, including racism, that disproportionally affect racial/ethnic minorities in the USA.

Metformin does not reduce markers of cell proliferation in esophageal tissues of patients with Barrett's esophagus.

BACKGROUND & AIMS: Obesity is associated with neoplasia, possibly via insulin-mediated cell pathways that affect cell proliferation. Metformin has been proposed to protect against obesity-associated cancers by decreasing serum insulin. We conducted a randomized, double-blind, placebo-controlled, phase 2 study of patients with Barrett's esophagus (BE) to assess the effect of metformin on phosphorylated S6 kinase (pS6K1), a biomarker of insulin pathway activation. METHODS: Seventy-four subjects with BE (mean age, 58.7 years; 58 men [78%; 52 with BE >2 cm [70%]) were recruited through 8 participating organizations of the Cancer Prevention Network. Participants were randomly assigned to groups given metformin daily (increasing to 2000 mg/day by week 4, n = 38) or placebo (n = 36) for 12 weeks. Biopsy specimens were collected at baseline and at week 12 via esophagogastroduodenoscopy. We calculated and compared percent changes in median levels of pS6K1 between subjects given metformin vs placebo as the primary end point. RESULTS: The percent change in median level of pS6K1 did not differ significantly between groups (1.4% among subjects given metformin vs -14.7% among subjects given placebo; 1-sided P = .80). Metformin was associated with an almost significant reduction in serum levels of insulin (median -4.7% among subjects given metformin vs 23.6% increase among those given placebo, P = .08) as well as in homeostatic model assessments of insulin resistance (median -7.2% among subjects given metformin vs 38% increase among those given placebo, P = .06). Metformin had no effects on cell proliferation (on the basis of assays for KI67) or apoptosis (on the basis of levels of caspase 3). CONCLUSIONS: In a chemoprevention trial of patients with BE, daily administration of metformin for 12 weeks, compared with placebo, did not cause major reductions in esophageal levels of pS6K1. Although metformin reduced serum levels of insulin and insulin resistance, it did not discernibly alter epithelial proliferation or apoptosis in esophageal tissues. These findings do not support metformin as a chemopreventive agent for BE-associated carcinogenesis. ClinicalTrials.gov number, NCT01447927.

A combination of esomeprazole and aspirin reduces tissue concentrations of prostaglandin E(2) in patients with Barrett's esophagus.

UNLABELLED: BACKGROUND& AIMS: Proton pump inhibitors and nonsteroidal anti-inflammatory drugs might prevent esophageal adenocarcinoma in patients with Barrett's esophagus (BE), but there are limited data from clinical trials to support this concept. We conducted a randomized, double-blind, placebo-controlled, phase 2 trial to assess the effects of the combination of aspirin (3 different doses) and esomeprazole on tissue concentrations of prostaglandin (PG) E(2) in patients with BE with no dysplasia or low-grade dysplasia. METHODS: Participants were recruited through the multicenter Cancer Prevention Network and randomly assigned to groups that were given 40 mg esomeprazole twice daily in combination with an aspirin placebo once daily (arm A; n = 30), with 81 mg aspirin once daily (arm B; n = 47), or with 325 mg aspirin once daily (arm C; n = 45) for 28 days. We collected esophageal biopsy specimens before and after the intervention period to determine the absolute change in mean concentration of PGE(2) (the primary end point). RESULTS: Based on data from 114 patients, baseline characteristics were similar among groups. The absolute mean tissue concentration of PGE(2) was reduced by 67.6 ± 229.68 pg/mL in arm A, 123.9 ± 284.0 pg/mL in arm B (P = .10 vs arm A), and 174.9 ± 263.62 pg/mL in arm C (P = .02 vs arm A). CONCLUSIONS: In combination with esomeprazole, short-term administration of higher doses of aspirin, but not lower doses or no aspirin, significantly reduced tissue concentrations of PGE(2) in patients with BE with either no dysplasia or low-grade dysplasia. These data support further evaluation of higher doses of aspirin and esomeprazole to prevent esophageal adenocarcinoma in these patients. Clinical trial registration number NCT00474903.

Case-case study of factors associated to hMLH1, hMSH2, and hMSH6 protein expression among endometrial cancer patients of the University District Hospital of San Juan, Puerto Rico.

UNLABELLED: Lynch syndrome (LS) is an autosomal dominant disorder caused by DNA mismatch repair (MMR) system deficiencies. Women affected by LS present a 40% to 60% lifetime risk of endometrial cancer (EC). OBJECTIVE: This case-case study aims to determine the frequency of the hMLH1, hMSH2, and hMSH6 MMR proteins and the factors (age, family history of cancer [FHC] related to LS, and body mass index [BMI]) associated to their absence in EC patients attending the University District Hospital of San Juan, Puerto Rico. MATERIALS AND METHODS: Twenty cases were preliminary evaluated for the MMR protein expression by immunohistochemistry testing and classified as positive cases (presence of protein) or negative cases (absence of protein). The statistical analysis was based on the logistic regression model using the maximum likelihood estimation (MLE). The Bayesian approach was used to determine the posterior probability (posterior Pr[odds ratio {OR} > 1]). RESULTS: Results showed absence for at least 1 MMR protein in 25% of the cases, 15% for hMLH1, and 10% for hMSH2. None of the cases showed an absence for hMSH6. The MLE demonstrated that women diagnosed with EC before the age of 50 (OR: 12.4; 95% confidence interval [CI] = 0.5-322.7), having FHC related to LS (OR: 17.7; 95% CI = 0.6-534.6), and having lower BMI (OR: 2.38; 95% CI = 0.39-14.28) present higher odds than their counterparts of lacking an MMR protein, once adjusted for potential predictors (P > 0.05). The posterior probability that an excess risk of lacking an MMR protein occurs was 95% or greater for each predictor. CONCLUSIONS: Our study in this Hispanic population supports previous studies in that younger age, FHC, and lower BMI are associated with increased odds of having an absence of MMR protein expression. Further studies with larger sample sizes should be performed.

Oncogenic KRAS modulates mitochondrial metabolism in human colon cancer cells by inducing HIF-1α and HIF-2α target genes.

BACKGROUND: Activating KRAS mutations are important for cancer initiation and progression; and have recently been shown to cause primary resistance to therapies targeting the epidermal growth factor receptor. Therefore, strategies are currently in development to overcome treatment resistance due to oncogenic KRAS. The hypoxia-inducible factors-1α and -2α (HIF-1α and HIF-2α) are activated in cancer due to dysregulated ras signaling. METHODS: To understand the individual and combined roles of HIF-1α and HIF-2α in cancer metabolism and oncogenic KRAS signaling, we used targeted homologous recombination to disrupt the oncogenic KRAS, HIF-1α, and HIF-2α gene loci in HCT116 colon cancer cells to generate isogenic HCT116WT KRAS, HCT116HIF-1α-/-, HCT116HIF-2α-/-, and HCT116HIF-1α-/-HIF-2α-/- cell lines. RESULTS: Global gene expression analyses of these cell lines reveal that HIF-1α and HIF-2α work together to modulate cancer metabolism and regulate genes signature overlapping with oncogenic KRAS. Cancer cells with disruption of both HIF-1α and HIF-2α or oncogenic KRAS showed decreased aerobic respiration and ATP production, with increased ROS generation. CONCLUSION: Our findings suggest novel strategies for treating tumors with oncogenic KRAS mutations.

Novel methylated DNA markers accurately discriminate Lynch syndrome associated colorectal neoplasia.

Aim: Acquired molecular changes in Lynch syndrome (LS) colorectal tumors have been largely unstudied. We identified methylated DNA markers (MDMs) for discrimination of colorectal neoplasia in LS and determined if these MDMs were comparably discriminant in sporadic patients. Patients & methods: For LS discovery, we evaluated DNA from 53 colorectal case and control tissues using next generation sequencing. For validation, blinded methylation-specific PCR assays to the selected MDMs were performed on 197 cases and controls. Results:OPLAH was the most discriminant MDM with areas under the receiver operating characteristic curve ≥0.97 for colorectal neoplasia in LS and sporadic tissues. ALKBH5, was uniquely hypermethylated in LS neoplasms. Conclusion: Highly discriminant MDMs for colorectal neoplasia in LS were identified with potential use in screening and surveillance.

Colorectal cancer prevention in inflammatory bowel disease and the role of 5-aminosalicylic acid: a clinical review and update.

A roundtable consensus meeting was held to consolidate current knowledge on the etiology of colorectal cancer in patients with inflammatory bowel disease and to review current strategies, both diagnostic and preventive, specifically addressing the role of 5-aminosalicylic acid. Specific topics that were addressed included: the epidemiology of colorectal cancer, including an assessment of risk factors and the impact of colonoscopy on colorectal cancer incidence and mortality; the origin and evolution of dysplasia nomenclature and the natural history of dysplasia; review of the experience of St. Mark's Hospital (London) as gleaned from its surveillance database; mechanisms by which 5-aminosalicylic acid is thought to exert a chemopreventive effect; the potential future role of 5-aminosalicylic acid in chemopreventive strategies; chemoprevention in familial adenomatous polyposis; and other future research directions. This article provides a comprehensive overview of the issues discussed and should act as a guide to shaping the design of future studies in this area.

MSH-2 and MLH-1 protein expression in Muir Torre syndrome-related and sporadic sebaceous neoplasms.

BACKGROUND: Muir-Torre Syndrome (MTS) is a rare autosomal-dominant disorder characterized by the predisposition to both sebaceous neoplasm and internal malignancies. MTS-associated sebaceous neoplasms reveal mutations in DNA mismatch repair (MMR) genes and microsatellite instability. A significant part of MTS patients represents a phenotypic variant, the hereditary nonpolyposis colorectal cancer (HNPCC). A strong correlation between microsatellite instability and immunostaining has been demonstrated. The early recognition of sebaceous neoplasm as part of MTS, and their differentiation from sporadic sebaceous neoplasm may have an important application in a clinical setting. The absence of MLH-1 or MSH-2 expression by immunostaining identifies tumors with mismatch repair deficiency. OBJECTIVES: Our aim is to determine whether an immunohistochemical approach, targeting DNA repair proteins MSH-2 and MLH-1 in MTS-related sebaceous neoplasm and their sporadic counterparts, can be used for their identification. METHODS: We examined 15 sebaceous neoplasms (including 6 internal malignancy- associated sebaceous neoplasms and 8 sporadic sebaceous neoplasms) from 11 patients for the expression of MSH-2 and MLH-1 by immunohistochemistry. RESULTS: Four of 5 internal malignancy-associated sebaceous neoplasms showed loss of expression of MSH-2 or MLH-1. Correlation of the immunostaining pattern of the sebaceous neoplasms and the patients' positive history of colon carcinoma was 80%. Seven of 8 sporadic sebaceous neoplasms showed a positive expression of MSH-2 and MLH-1. The prevalence for loss of expression of MMR proteins in sebaceous neoplasms was 38.5%. MMR immunostaining had 87.5% specificity and 80% sensitivity. LIMITATIONS: This study is limited by a small sample size, and by bias selection due to the use of non nationwide data-base as the resource of cases. CONCLUSIONS: Our findings demonstrate that immunohistochemical testing for internal malignancy-associated sebaceous neoplasms is a practical approach to confirm a suspected inherited MMR gene defect, and an accurate method to distinguish between sporadic and MTS-associated sebaceous lesions.

Emergency Presentation and Short-Term Survival Among Patients With Colorectal Cancer Enrolled in the Government Health Plan of Puerto Rico.

OBJECTIVE: In this study, we examine factors associated with the use of the emergency room (ER) as an entry point into the health-care system to initiate a cancer diagnosis among Puerto Rico's Government Health Plan (GHP) patients and compare the 1-year survival of GHP patients that initiated cancer diagnosis in the emergency room (ER) presentation with those that initiated the diagnosis in a physician's office. METHODS: Data for patients with colorectal cancer (CRC) aged 50 to 64 years and diagnosed in 2012 were obtained from the Puerto Rico Central Cancer Registry and linked to the Puerto Rico Health Insurance Administration database (n = 190). Crude odds ratio, adjusted odds ratio, and their 95% confidence intervals were reported. We used the Kaplan-Meier method to generate survival curves. Multivariate Cox regression analysis was performed to evaluate the association between ER presentation and 1-year cause-specific survival. RESULTS: We found that 37.37% of the study population had an ER presentation. Male patients had a higher occurrence of having an ER presentation (66.20%), while 76.06% of the patients with an ER presentation were diagnosed in late stage. Emergency room presentation was a highly predictive factor for cancer mortality in the year following the diagnosis. These patients had between 3.99 to 4.24 times higher mortality risk than non-ER presentation patients (P < .05). CONCLUSION: Late presentation for CRC diagnosis through an ER visit is a significant concern that influences negatively on the patient's outcome. Efforts at increasing primary care visits and routine screening tests among GHP beneficiaries could improve survival.

Variability in Cancer Risk and Outcomes Within US Latinos by National Origin and Genetic Ancestry.

Latinos have lower rates for most common cancer sites and higher rates of some less common cancers (gallbladder, liver, gastric, and cervical) than other ethnic/racial groups. Latinos are a highly heterogeneous population with diverse national origins, unique genetic admixture patterns, and wide spectrum of socio-demographic characteristics. Across the major cancers (breast, colorectal, prostate, lung, and liver) US-born Latinos have higher incidence and worse survival than foreign-born, and those with low-socioeconomic status have the lowest incidence. Puerto Rican and Cuban Latinos have higher incidence rates than Mexican Latinos. We have identified the following themes as understudied and critical to reduce the cancer burden among US Latinos: (1) etiological studies considering key sources of heterogeneity, (2) culturally sensitive cancer prevention strategies, (3) description of the molecular tumor landscape to guide treatments and improve outcomes, and (4) development of prediction models of disease risk and outcomes accounting for heterogeneity of Latinos.

Prevalence of Helicobacter pylori seropositivity among patients undergoing bariatric surgery: a preliminary study.

BACKGROUND: The objective of this study was to compare the prevalence of Helicobacter pylori (HP) seropositivity in patients undergoing bariatric surgery with that of the general population. METHODS: H. pylori serologies, tested by ELISA, were collected on 240 morbidly obese patients seen at the Cleveland Clinic Florida and on 2444 randomly selected patients seen at the Cleveland Clinic Health System from 2003-2005. RESULTS: H. pylori prevalence was 61.3% in the bariatric surgery group versus 48.2% in the general population control group (p < 0.001). Bariatric patients had a 1.7-fold increased likelihood of having HP when compared with controls (95% CI = 1.3-2.2). Age over 35 years was an independent risk factor for HP seropositivity (p < 0.01) in both the bariatric and control groups. There was no association found between body mass index and seropositivity within the bariatric group. There was no significant association between seropositivity and gender (p = 0.776). However, there was a significant association between seropositivity and race (p < 0.01). African-Americans had four times more (OR = 4.05) probability of having HP seropositivity than Caucasians (p < 0.01). Hispanics had almost three times (OR = 2.6) more probability of having HP seropositivity than Caucasians (p < 0.01). CONCLUSION: The prevalence of HP seropositivity among bariatric patients is significantly higher than the general population control group.

Endoscopic cryotherapy for the treatment of bleeding mucosal vascular lesions of the GI tract: a pilot study.

BACKGROUND: Thermal therapy is the cornerstone of endoscopic treatment of bleeding mucosal lesions of the GI tract. However, there is a 20% failure rate and contact devices may be cumbersome in the treatment of large bleeding areas. A pilot study was conducted to evaluate the safety and efficacy of endoscopic cryotherapy for bleeding mucosal vascular lesions. METHODS: Patients with recurrent bleeding from diffuse mucosal vascular lesions were treated with cryotherapy and had endoscopic and clinical follow-up. RESULTS: Twenty-six patients with gastric and duodenal arteriovenous malformations (n = 7), watermelon stomach (n = 7), radiation-induced gastritis (n = 5), and radiation-induced proctitis (n = 7) were treated with mean of 3.4 (1.6) sessions. The best results were achieved in patients with radiation-induced proctitis, with cessation of bleeding in all 7 patients. Cryotherapy was also effective in patients with multiple arteriovenous malformations (86%) and watermelon stomach (71%). It was less effective in patients with radiation-induced damage to stomach and duodenum, although all patients in this group were debilitated because of disseminated malignancy. CONCLUSIONS: Cryotherapy is a safe and effective treatment for bleeding from diffuse mucosal lesions of the GI tract. Bleeding from radiation-induced proctitis and multiple arteriovenous malformations is particularly responsive to endoscopic cryotherapy.

Cerebral thrombosis associated with active Crohn's disease

An increased incidence of cerebral thromboembolic events has been reported in young patients with inflammatory bowel disease (IBD). It has been suggested that a hypercoagulable state is associated with clinical activity of the disease, with elevation of factors V, VIII, fibrinogen and platelets and a lowering of anti-thrombin III. We present the case of a 35 y/o male with refractory Crohn's disease who complained of headaches, blurred vision and tonic-clonic seizures. The studies demonstrated an ischemic stroke of the left cerebral hemisphere, without vascular abnormalities. Elevation of factor VIII, platelets, and antithrombin III were found. The symptoms were relieved with medical treatment and the patient has continued in good health after resection of the diseased terminal ileum.