Cdx4 and Menin Co-Regulate Hoxa9 Expression in Hematopoietic Cells

BACKGROUND: Transcription factor Cdx4 and transcriptional coregulator menin are essential for Hoxa9 expression and normal hematopoiesis. However, the precise mechanism underlying Hoxa9 regulation is not clear. METHODS AND FINDINGS: Here, we show that the expression level of Hoxa9 is correlated with the location of increased trimethylated histone 3 lysine 4 (H3K4M3). The active and repressive histone modifications co-exist along the Hoxa9 regulatory region. We further demonstrate that both Cdx4 and menin bind to the same regulatory region at the Hoxa9 locus in vivo, and co-activate the reporter gene driven by the Hoxa9 cis-elements that contain Cdx4 binding sites. Ablation of menin abrogates Cdx4 access to the chromatin target and significantly reduces both active and repressive histone H3 modifications in the Hoxa9 locus. CONCLUSION: These results suggest a functional link among Cdx4, menin and histone modifications in Hoxa9 regulation in hematopoietic cells

Longitudinal, population-based study of racial/ethnic differences in colorectal cancer survival: impact of neighborhood socioeconomic status, treatment and comorbidity

<p>Abstract</p> <p>Background</p> <p>Colorectal cancer, if detected early, has greater than 90% 5-year survival. However, survival has been shown to vary across racial/ethnic groups in the United States, despite the availability of early detection methods.</p> <p>Methods</p> <p>This study evaluated the joint effects of sociodemographic factors, tumor characteristics, census-based socioeconomic status (SES), treatment, and comorbidities on survival after colorectal cancer among and within racial/ethnic groups, using the SEER-Medicare database for patients diagnosed in 1992–1996, and followed through 1999.</p> <p>Results</p> <p>Unadjusted colorectal cancer-specific mortality rates were higher among Blacks and Hispanic males than whites (relative rates (95% confidence intervals) = 1.34 (1.26–1.42) and 1.16 (1.04–1.29), respectively), and lower among Japanese (0.78 (0.70–0.88)). These patterns were evident for all-cause mortality, although the magnitude of the disparity was larger for colorectal cancer mortality. Adjustment for stage accounted for the higher rate among Hispanic males and most of the lower rate among Japanese. Among Blacks, stage and SES accounted for about half of the higher rate relative to Whites, and within stage III colon and stages II/III rectal cancer, SES completely accounted for the small differentials in survival between Blacks and Whites. Comorbidity did not appear to explain the Black-White differentials in colorectal-specific nor all-cause mortality, beyond stage, and treatment (surgery, radiation, chemotherapy) explained a very small proportion of the Black-White difference. The fully-adjusted relative mortality rates comparing Blacks to Whites was 1.14 (1.09–1.20) for all-cause mortality and 1.21 (1.14–1.29) for colorectal cancer specific mortality. The sociodemographic, tumor, and treatment characteristics also had different impacts on mortality within racial/ethnic groups.</p> <p>Conclusion</p> <p>In this comprehensive analysis, race/ethnic-specific models revealed differential effects of covariates on survival after colorectal cancer within each group, suggesting that different strategies may be necessary to improve survival in each group. Among Blacks, half of the differential in survival after colorectal cancer was primarily attributable to stage and SES, but differences in survival between Blacks and Whites remain unexplained with the data available in this comprehensive, population-based, analysis.</p

Impact of Cerebral Microbleeds in Stroke Patients with Atrial Fibrillation

OBJECTIVES: Cerebral microbleeds are associated with the risks of ischemic stroke and intracranial hemorrhage, causing clinical dilemmas for antithrombotic treatment decisions. We aimed to evaluate the risks of intracranial hemorrhage and ischemic stroke associated with microbleeds in patients with atrial fibrillation treated with Vitamin K antagonists, direct oral anticoagulants, antiplatelets, and combination therapy (i.e. concurrent oral anticoagulant and antiplatelet) METHODS: We included patients with documented atrial fibrillation from the pooled individual patient data analysis by the Microbleeds International Collaborative Network. Risks of subsequent intracranial hemorrhage and ischemic stroke were compared between patients with and without microbleeds, stratified by antithrombotic use. RESULTS: A total of 7,839 patients were included. The presence of microbleeds was associated with an increased relative risk of intracranial hemorrhage (aHR 2.74, 95% confidence interval 1.76 - 4.26) and ischemic stroke (aHR 1.29, 95% confidence interval 1.04 - 1.59). For the entire cohort, the absolute incidence of ischemic stroke was higher than intracranial hemorrhage regardless of microbleeds burden. However, for the subgroup of patients taking combination of anticoagulant and antiplatelet therapy, the absolute risk of intracranial hemorrhage exceeded that of ischemic stroke in those with 2-4 microbleeds (25 vs 12 per 1,000 patient-years) and ≥11 microbleeds (94 vs 48 per 1,000 patient-years). INTERPRETATION: Patients with atrial fibrillation and high burden of microbleeds receiving combination therapy have a tendency of higher rate of intracranial hemorrhage than ischemic stroke, with potential for net harm. Further studies are needed to help optimize stroke preventive strategies in this high-risk group. This article is protected by copyright. All rights reserved

Incidence, Prognosis, and Treatment Options for Patients With Synchronous Peritoneal Carcinomatosis and Liver Metastases from Colorectal Origin

BACKGROUND: Peritoneal carcinomatosis and liver metastases are common metastatic sites in patients who have colorectal cancer. Quite frequently, patients present with both synchronous liver and peritoneal metastases, which may result in a dilemma regarding the optimal treatment. OBJECTIVE: In the absence of reliable data, the aim of the current study was to provide population-based data on such patients and to review the literature for possible treatment options. DESIGN: This study is a retrospective analysis of a prospective database and a review. PATIENTS: All patients diagnosed between 1995 and 2010 with synchronous peritoneal carcinomatosis and liver metastases were identified from the Eindhoven Cancer Registry. OUTCOME MEASURES: Incidence and survival were analyzed. Next, the literature was reviewed for articles reporting on the results of treatment with curative intent. RESULTS: In total, 27,632 patients were diagnosed with colorectal cancer, of whom 5638 patients (20%) presented with metastasized disease. Synchronous liver metastasis and peritoneal carcinomatosis were present in 440 patients, being 11% of patients with liver metastases, 34% of patients with peritoneal carcinomatosis, 8% of patients with metastasized disease, and 2% of all patients diagnosed with colorectal cancer. Median survival for patients with liver metastasis and peritoneal carcinomatosis LIMITATIONS: No data on the extent of peritoneal carcinomatosis and liver metastases were available in the population-based study. This complicates comparison with treated patients from the literature review, which probably reflects a highly selected patient population. CONCLUSIONS: Both liver metastasis and peritoneal carcinomatosis were present in 8% of patients presenting with metastasized colorectal cancer. Population-based survival was only 5 months, with none of the patients undergoing treatment with curative intent. Median survival rates of up to 36 months after treatment with curative intent as published in the literature may be regarded as promising for selected patients

Predictors and survival of synchronous peritoneal carcinomatosis of colorectal origin: a population-based study

The aim of our study was to provide population-based data on incidence and prognosis of synchronous peritoneal carcinomatosis and to evaluate predictors for its development. Diagnosed in 1995-2008, 18,738 cases of primary colorectal cancer were included. Predictors of peritoneal carcinomatosis were analysed by multivariable logistic regression analysis. Median survival in months was calculated by site of metastasis. In the study period, 904 patients were diagnosed with synchronous peritoneal carcinomatosis (4.8% of total, constituting 24% of patients presenting with M1 disease). The risk of peritoneal carcinomatosis was increased in case of advanced T stage [T4 vs. T1,2: odds ratio (OR) 4.7, confidence limits 4.0-5.6), advanced N stage [N0 vs. N1,2: OR 0.2 (0.1-0.2)], poor differentiation grade [OR 2.1 (1.8-2.5)], younger age [<60 years vs. 70-79 years: OR 1.4 (1.1-1.7)], mucinous adenocarcinoma [OR 2.0 (1.6-2.4)] and right-sided localisation of primary tumour [left vs. right: OR 0.6 (0.5-0.7)]. Median survival of patients with peritoneum as single site of metastasis remained dismal [1995-2001: 7 (6-9) months; 2002-2008: 8 (6-11) months], contrasting the improvement among patients with liver metastases [1995-2001: 8 (7-9) months; 2002-2008: 12 (11-14) months]. To conclude, synchronous peritoneal metastases from colorectal cancer are more frequent among younger patients and among patients with advanced T stage, mucinous adenocarcinoma, right-sided tumours and tumours that are poorly differentiated. The prognosis of synchronous peritoneal carcinomatosis remains poor with a median survival of 8 months and even worse if concomitant metastases in other organs are present

Nationwide Improvement of Only Short-Term Survival After Resection for Pancreatic Cancer in The Netherlands

Objectives: Evaluation of incidence, treatment, and survival trends after resection of pancreatic cancer at a national level. Methods: Using data on patient and tumor characteristics from the nationwide Netherlands Cancer Registry trends were analyzed for the period 1989-2008. Results: A total of 30,025 patients diagnosed with pancreatic cancer were included. The incidence remained stable over the 20-year study period at approximately 9 per 100,000 inhabitants. Resection rates increased from 8% in 1989 to 12% in 2008, adjuvant chemotherapy rates increased from 7% to 29%, and palliative chemotherapy rates increased from 5% to 19% (P < 0.0001 each). Relative survival proportions did not change over time; besides a minimal, nonsignificant increase at 3 months from 53% to Conclusions: The increased short-term survival among patients who underwent resection probably reflects decreased postoperative mortality driven by ongoing centralization efforts. However, longer-term survival remained poor irrespective of the changes in management in the past decades

Peritoneal carcinomatosis of gastric origin: A population-based study on incidence, survival and risk factors

Peritoneal carcinomatosis (PC) is an important cause of morbidity and mortality among patients with gastric cancer. The aim of the current study was to provide reliable population-based data on the incidence, risk factors and prognosis of PC of gastric origin. All patients diagnosed with gastric cancer in the area of the Eindhoven Cancer Registry between 1995 and 2011 were included. Incidence and survival were computed and risk factors for peritoneal carcinomatosis were determined using multivariate logistic regression analysis. In total, 5,220 patients were diagnosed with gastric cancer, of whom 2,029 (39%) presented with metastatic disease. PC was present in 706 patients (14%) of whom 491 patients (9%) had PC as the only metastatic site. Younger age (<60 years), female gender, advanced T- and N-stage, primary tumor of signet ring cells or linitis plastica and primary tumors covering multiple anatomical locations of the stomach were all associated with a higher odds ratios of developing PC. Median survival of patients without metastases was 14 months, but only 4 months for patients with PC. PC is a frequent condition in patients presenting with gastric cancer, especially in younger patients with advanced tumor stages. Given the detrimental influence of PC on survival, efforts should be undertaken to further explore the promising results that were obtained in preventing or treating this condition with multimodality strategies. What's new? Until recently, peritoneal carcinomatosis (PC), in which malignant ascites forms in the peritoneum, was considered to be an untreatable condition. But new treatment options have raised hope for improved survival, as well as created a need to better understand risk factors and prevention. Here, analysis of data from the Eindhoven Cancer Registry from 1995-2011 reveals that more than one-third of patients with metastatic gastric cancer presented with PC. Younger patients and females with advanced disease were at greatest risk for this condition. The findings may have implications for PC diagnosis and treatment