The REDUCE metagram: a comprehensive prediction tool for determining the utility of dutasteride chemoprevention in men at risk for prostate cancer.

INTRODUCTION: 5-alpha reductase inhibitors can reduce the risk of prostate cancer (PCa) but can be associated with significant side effects. A library of nomograms which predict the risk of clinical endpoints relevant to dutasteride treatment may help determine if chemoprevention is suited to the individual patient. METHODS: Data from the REDUCE trial was used to identify predictive factors for 9 endpoints relevant to dutasteride treatment. Using the treatment and placebo groups from the biopsy cohort, Cox proportional hazards (PH) and competing risks regression (CRR) models were used to build 18 nomograms, whose predictive ability was measured by concordance index (CI) and calibration plots. RESULTS: A total of 18 nomograms assessing the risks of cancer, high grade cancer, high grade prostatic intraepithelial neoplasia (HGPIN), atypical small acinar proliferation (ASAP), erectile dysfunction (ED), acute urinary retention (AUR), gynecomastia, urinary tract infection (UTI) and BPH-related surgery either on or off dutasteride were created. The nomograms for cancer, high grade cancer, ED, AUR, and BPH-related surgery demonstrated good discrimination and calibration while those for gynecomastia, UTI, HGPIN, and ASAP predicted no better than random chance. CONCLUSIONS: To aid patients in determining whether the benefits of dutasteride use outweigh the risks, we have developed a comprehensive metagram that can generate individualized risks of 9 outcomes relevant to men considering chemoprevention. Better models based on more predictive markers are needed for some of the endpoints but the current metagram demonstrates potential as a tool for patient counseling and decision-making that is accessible, intuitive, and clinically relevant.

Prediction tools in surgical oncology.

Artificial neural networks, prediction tables, and clinical nomograms allow physicians to transmit an immense amount of prognostic information in a format that exhibits comprehensibility and brevity. Current models demonstrate the feasibility to accurately predict many oncologic outcomes, including pathologic stage, recurrence-free survival, and response to adjuvant therapy. Although emphasis should be placed on the independent validation of existing prediction tools, there is a paucity of models in the literature that focus on quality of life outcomes. The unification of tools that predict oncologic and quality of life outcomes into a comparative effectiveness table will furnish patients with cancer with the information they need to make a highly informed and individualized treatment decision.

Induction of intestinalization in human esophageal keratinocytes is a multistep process.

Barrett's esophagus (BE) is the replacement of normal squamous esophageal mucosa with an intestinalized columnar epithelium. The molecular mechanisms underlying its development are not understood. Cdx2 is an intestine-specific transcription factor that is ectopically expressed in BE, but its role in this process is unclear. Herein, we describe a novel cell culture model for BE. Retroviral-mediated Cdx2 expression in immortalized human esophageal keratinocytes [EPC-human telomerase reverse transcriptase (hTERT)] could transiently be established but not maintained and was associated with a reduction in cell proliferation. Coexpression of cyclin D1, but not a dominant-negative p53, rescued proliferation in the Cdx2-expressing cells. Cdx2 expression in the EPC-hTERT.D1 cells decreased cell proliferation but did not induce intestinalization. We investigated for other treatments to enhance intestinalization and found that acidic culture conditions uniformly killed EPC-hTERT.D1.Cdx2 cells. However, treatment with 5-aza-2-deoxycytidine (5-AzaC) to demethylate epigenetically silenced genes did appear to be tolerated. Multiple Cdx2 target genes, markers of intestinal differentiation and markers of BE, were induced by this 5-AzaC treatment. More interestingly, the expression level of several of these genes was enhanced only in the EPC-hTERT.D1-Cdx2 cells treated with 5-AzaC. Two of these, SLC26a3/DRA (downregulated in adenoma) and Na+/H+ exchanger 2 (NHE2), were not previously known to be elevated in BE; however, we confirmed their elevation in BE tissue samples. 5-AzaC treatment also induced cell senescence, even at low doses. We conclude that ectopic proliferation signals, alterations in epigenetic gene regulation and the inhibition of tumor suppressor mechanisms are required for Cdx2-mediated intestinalization of human esophageal keratinocytes in BE.

Significant discrepancies between diagnostic and pathologic Gleason sums in prostate cancer: the predictive role of age and prostate-specific antigen.

OBJECTIVES: To assess the discrepancies between diagnostic and pathologic Gleason sums and the predictive role of age and prostate-specific antigen (PSA) level on Gleason sum discrepancies. METHODS: A total of 2963 patients receiving radical prostatectomy at Duke University from 1988 to 2006 were divided into two groups according to year of diagnosis: 1988 to 1999 and 2000 to 2006. The Gleason sum discrepancies were evaluated in the above groups. The predictive roles of diagnostic age (less than 50, 50 to 60, 60.1 to 70, and greater than 70 years), PSA level (less than 10, 10 to 20, and greater than 20 ng/mL), race, body mass index, and prostate weight on the discrepancies were analyzed. RESULTS: Overall, 55.8% of diagnostic Gleason sums differed from those on final surgical pathology (58.6% in the 1988 to 1999 and 49.3% in the 2000 to 2006 groups). Diagnostic Gleason sums were undergraded in 41.2% of cases and overgraded in 12.8% of cases. Men older than 60 years were more likely to have their diagnostic Gleason sums undergraded than men younger than 50 (odds ratio in age groups less than 50, 50 to 60, 60.1 to 70, and greater than 70 years: 1.00, 2.30, 4.03, and 3.96, respectively). Biopsy Gleason sums in men with a high PSA level were more likely to be undergraded compared with the PSA group less than 10 ng/mL (odds ratio in PSA groups less than 10, 10 to 20, and greater than 20 ng/mL: 1.00, 2.11, and 3.64, respectively). CONCLUSIONS: Significant discrepancies between diagnostic and pathologic Gleason sums remain in recent years. The rate of diagnostic Gleason sum undergrading was 3.2-fold that of overgrading. Advanced age and high PSA level were predictive of diagnostic Gleason sum undergrading, and caution should be exercised when recommending active surveillance in older men.