Anti-tumour activity in vitro and in vivo of selective differentiating agents containing hydroxamate

A series of hydroxamates, which are not metalloprotease inhibitors, have been found to be selectively toxic to a range of transformed and human tumour cells without killing normal cells (fibroblasts, melanocytes) at the same concentrations. Within 24 h of treatment, drug action is characterized by morphological reversion of tumour cells to a more normal phenotype (dendritic morphology), and rapid and reversible acetylation of histone H4 in both tumour and normal cells. Two; hydroxamates inhibited growth of xenografts of human melanoma cells in nude mice; resistance did not develop in vivo or in vitro. A third hydroxamate, trichostatin A, was active in vitro but became inactivated and had no anti-tumour activity in vivo. Development of dendritic morphology was found to be dependent upon phosphatase activity, RNA and protein synthesis. Proliferating hybrid clones of sensitive and resistant cells remained sensitive to ABHA, indicating a dominant-negative mechanism of sensitivity. Histone H4 hyperacetylation suggests that these agents act at the chromatin level. This work may lead to new drugs that are potent, and selective anti-tumour agents with low toxicity to normal Cells

Risk prediction tools for cancer in primary care.

Numerous risk tools are now available, which predict either current or future risk of a cancer diagnosis. In theory, these tools have the potential to improve patient outcomes through enhancing the consistency and quality of clinical decision-making, facilitating equitable and cost-effective distribution of finite resources such as screening tests or preventive interventions, and encouraging behaviour change. These potential uses have been recognised by the National Cancer Institute as an 'area of extraordinary opportunity' and an increasing number of risk prediction models continue to be developed. The data on predictive utility (discrimination and calibration) of these models suggest that some have potential for clinical application; however, the focus on implementation and impact is much more recent and there remains considerable uncertainty about their clinical utility and how to implement them in order to maximise benefits and minimise harms such as over-medicalisation, anxiety and false reassurance. If the potential benefits of risk prediction models are to be realised in clinical practice, further validation of the underlying risk models and research to assess the acceptability, clinical impact and economic implications of incorporating them in practice are needed.This is the final version of the article. It was first available from NPG via http://dx.doi.org/10.1038/bjc.2015.40

Screening Patients with a Family History of Colorectal Cancer

OBJECTIVES: To compare screening practices and beliefs in patients with and without a clinically important family history. DESIGN: We mailed a brief questionnaire asking about family history and a second, longer survey asking about knowledge of and beliefs about colorectal cancer to all respondents with a family history and a random sample of respondents without a family history of colorectal cancer. We reviewed electronic medical records for screening examinations and recording of family history. PARTICIPANTS: One thousand eight hundred seventy of 6,807 randomly selected patients ages 35–55 years who had been continuously enrolled in a large multispecialty group practice for at least 5 years. MEASUREMENTS: Recognition of increased risk, screening practices, and beliefs—all according to strength of family history and patient’s age. RESULTS: Nineteen percent of respondents reported a family history of colorectal cancer. In 11%, this history was strong enough to warrant screening before age 50 years. However, only 39% (95% CI 36, 42) of respondents under the age of 50 years said they had been asked about family history and only 45% of those with a strong family history of colorectal cancer had been screened appropriately. Forty-six percent of patients with a strong family history did not know that they should be screened at a younger age than average risk people. Medical records mentioned family history of colorectal cancer in 59% of patients reporting a family history. CONCLUSIONS: More efforts are needed to translate information about family history of colorectal cancer into the care of patients

Primary care physicians' use of family history for cancer risk assessment

<p>Abstract</p> <p>Background</p> <p>Family history (FH) assessment is useful in identifying and managing patients at increased risk for cancer. This study assessed reported FH quality and associations with physician perceptions.</p> <p>Methods</p> <p>Primary care physicians practicing in two northeastern U.S. states were surveyed (n = 880; 70% response rate). Outcome measures of FH quality were extent of FH taken and ascertaining age at cancer diagnosis for affected family members. Predictors of quality measured in this survey included: perceived advantages and disadvantages of collecting FH information, knowledge of management options, access to supportive resources, and confidence in ability to interpret FH.</p> <p>Results</p> <p>Reported collection of information regarding second degree blood relatives and age of diagnosis among affected relatives was low. All hypothesized predictors were associated with measures of FH quality, but not all were consistent independent predictors. Perceived advantages of taking a family history, access to supportive resources, and confidence in ability to identify and manage higher risk patients were independent predictors of both FH quality measures. Perceived disadvantages of taking a family history was independently associated one measure of FH quality. Knowledge of management options was not independently associated with either quality measure.</p> <p>Conclusions</p> <p>Modifiable perception and resource factors were independently associated with quality of FH taking in a large and diverse sample of primary care physicians. Improving FH quality for identification of high risk individuals will require multi-faceted interventions.</p

Early Initiation of Colorectal Cancer Screening in Individuals with Affected First-degree Relatives

BACKGROUND: Several guidelines recommend initiating colorectal cancer screening at age 40 for individuals with affected first-degree relatives, yet little evidence exists describing how often these individuals receive screening procedures. OBJECTIVES: To determine the proportion of individuals in whom early initiation of colorectal cancer screening might be indicated and whether screening disparities exist. DESIGN: Population-based Supplemental Cancer Control Module to the 2000 National Health Interview Survey. PARTICIPANTS: Respondents, 5,564, aged 40 to 49 years were included within the analysis. MEASUREMENTS: Patient self-report of sigmoidoscopy, colonoscopy, or fecal occult blood test. RESULTS: Overall, 279 respondents (5.4%: 95% C.I., 4.7, 6.2) reported having a first-degree relative affected with colorectal cancer. For individuals with a positive family history, 67 whites (27.9%: 95% C.I., 21.1, 34.5) and 3 African American (9.3%: 95% C.I., 1.7, 37.9) had undergone an endoscopic procedure within the previous 10 years (P-value = .03). After adjusting for age, family history, gender, educational level, insurance status, and usual source of care, whites were more likely to be current with early initiation endoscopic screening recommendations than African Americans (OR = 1.38: 95% C.I., 1.01, 1.87). Having an affected first-degree relative with colorectal cancer appeared to have a stronger impact on endoscopic screening for whites (OR = 3.21: 95% C.I., 2.31, 4.46) than for African Americans (OR = 1.05: 95% C.I., 0.15, 7.21). CONCLUSIONS: White participants with a family history are more likely to have endoscopic procedures beginning before age 50 than African Americans

Colorectal cancer risk assessment and screening recommendation: a community survey of healthcare providers' practice from a patient perspective

<p>Abstract</p> <p>Background</p> <p>Family history is a common risk factor for colorectal cancer (CRC), yet it is often underused to guide risk assessment and the provision of risk-appropriate CRC screening recommendation. The aim of this study was to identify from a patient perspective health care providers' current practice relating to: (i) assessment of family history of CRC; (ii) notification of "increased risk" to patients at "moderately/potentially high" familial risk; and (iii) recommendation that patients undertake CRC screening.</p> <p>Methods</p> <p>1592 persons aged 56-88 years randomly selected from the Hunter Community Study (HCS), New South Wales, Australia were mailed a questionnaire. 1117 participants (70%) returned a questionnaire.</p> <p>Results</p> <p>Thirty eight percent of respondents reported ever being asked about their family history of CRC. Ever discussing family history of CRC with a health care provider was significantly more likely to occur for persons with a higher level of education, who had ever received screening advice and with a lower physical component summary score. Fifty one percent of persons at "moderately/potentially high risk" were notified of their "increased risk" of developing CRC. Thirty one percent of persons across each level of risk had ever received CRC screening advice from a health care provider. Screening advice provision was significantly more likely to occur for persons who had ever discussed their family history of CRC with a health care provider and who were at "moderately/potentially high risk".</p> <p>Conclusions</p> <p>Effective interventions that integrate both the assessment and notification of familial risk of CRC to the wider population are needed. Systematic and cost-effective mechanisms that facilitate family history collection, risk assessment and provision of screening advice within the primary health care setting are required.</p

Lynch syndrome: barriers to and facilitators of screening and disease management

Background Lynch syndrome is a hereditary cancer with confirmed carriers at high risk for colorectal (CRC) and extracolonic cancers. The purpose of the current study was to develop a greater understanding of the factors influencing decisions about disease management post-genetic testing. Methods The study used a grounded theory approach to data collection and analysis as part of a multiphase project examining the psychosocial and behavioral impact of predictive DNA testing for Lynch syndrome. Individual and small group interviews were conducted with individuals from 10 families with the MSH2 intron 5 splice site mutation or exon 8 deletion. The data from confirmed carriers (n = 23) were subjected to re-analysis to identify key barriers to and/or facilitators of screening and disease management. Results Thematic analysis identified personal, health care provider and health care system factors as dominant barriers to and/or facilitators of managing Lynch syndrome. Person-centered factors reflect risk perceptions and decision-making, and enduring screening/disease management. The perceived knowledge and clinical management skills of health care providers also influenced participation in recommended protocols. The health care system barriers/facilitators are defined in terms of continuity of care and coordination of services among providers. Conclusions Individuals with Lynch syndrome often encounter multiple barriers to and facilitators of disease management that go beyond the individual to the provider and health care system levels. The current organization and implementation of health care services are inadequate. A coordinated system of local services capable of providing integrated, efficient health care and follow-up, populated by providers with knowledge of hereditary cancer, is necessary to maintain optimal health