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Articles by P. A Thompson
Total Records ( 5 ) for P. A Thompson
  P. A Thompson , B. C Wertheim , D. J Roe , E. L Ashbeck , E. T Jacobs , P Lance , M. E Martinez and D. S. Alberts
 

Purpose: Ursodeoxycholic acid (UDCA) was one of the earliest agents investigated as a drug for colorectal cancer prevention. However, UDCA failed to show efficacy to prevent the development of colorectal adenomas in a large, phase III, randomized, placebo-controlled trial. We re-evaluated the effect of UDCA in men and women separately, based on sex-specific differences in bile acid metabolism and suspected variation in etiologic factors contributing to colorectal cancer risk.

Experimental Design: We conducted a secondary analysis of the efficacy of UDCA to prevent colorectal adenoma in men (n = 804) and women (n = 388).

Results: We found no reduction in risk of any metachronous adenoma with UDCA treatment in men or women. However, UDCA treatment significantly lowered the odds of advanced lesions [odds ratio (OR), 0.62; 95% confidence interval (CI), 0.43-0.89] in men, but not women. We also observed significantly higher odds of advanced lesions with UDCA treatment in women who were younger (age, <65 years; OR, 3.24; 95% CI, 1.10-9.56), obese (body mass index, ≥30 kg/m2; OR, 5.45; 95% CI, 1.42-20.9), or in the highest tertile of total dietary fat (≥56.2 g/day; OR, 3.48; 95% CI, 1.35-8.95). In a multivariate model, the interactive effect of fat intake accounted for the modulating effects of age and body mass index in women.

Conclusion: Our findings support the use of UDCA for preventing advanced colorectal adenomas in men. The increased odds of adenoma among women with high fat intake suggest a previously unrecognized harm that warrants further study, especially given the chronic exposure to UDCA in patients with primary biliary cirrhosis and the increasing investigational use of UDCA for several other conditions.

  P. A Thompson , C. H Hsu , S Green , A. T Stopeck , K Johnson , D. S Alberts and H H. S. Chow
 

Regular use of nonsteroidal anti-inflammatory drugs (NSAID) has been associated with reduced risk of breast cancer. Sulindac, a nonselective NSAID with both cyclooxygenase-2–dependent and –independent activities, is a candidate for breast chemoprevention. We conducted a phase Ib trial in 30 women at increased risk for breast cancer to evaluate the breast tissue distribution of sulindac at two dose levels (150 mg daily and 150 mg twice daily for 6 weeks), using nipple aspirate fluid (NAF) as a surrogate of breast tissue drug exposure. We also explored the effect of sulindac on drug-induced biomarkers in NAF. We show that sulindac and its metabolites partition to human breast as measured by NAF levels. Sulindac intervention did not decrease 13,14-dihydro-15-keto prostaglandin A2, a stable derivative of prostaglandin E2, in NAF, but exposure was associated with a significant trend towards higher levels of growth differentiation factor 15 in NAF in women receiving 150 mg twice daily (P = 0.038). These results are the first to show partitioning of sulindac and metabolites to human breast tissue and the first evidence for a potential dose-dependent effect of sulindac on growth differentiation factor 15 levels in NAF. Cancer Prev Res; 3(1); 101–7

  M. S Stratton , A. M Algotar , J Ranger Moore , S. P Stratton , E. H Slate , C. H Hsu , P. A Thompson , L. C Clark and F. R. Ahmann
 

The Nutritional Prevention of Cancer trial showed a 52% lower incidence of prostate cancer in men supplemented with selenium. As a result, our study was designed to assess whether selenium supplementation attenuates the progression of prostate cancer. A phase 2 randomized, double-blind, placebo-controlled clinical trial was conducted in men with localized nonmetastatic prostate cancer who had elected to forgo active treatment and be followed by active surveillance. A total of 140 men were randomized to placebo (n = 46), 200 µg/d (n = 47), or 800 µg/d (n = 47) selenium p.o. (as selenized yeast) and followed every 3 months for up to 5 years. Prostate-specific antigen (PSA) velocity was used as a marker of prostate cancer progression and was estimated using mixed-effects regression. Adjusting for age, body mass index, baseline selenium, smoking, baseline PSA, race, PSA method, and Gleason score, PSA velocities for the 200 µg/d and 800 µg/d treatment groups were not statistically significantly different from placebo (P = 0.32 and P = 0.61, respectively). In the highest quartile of baseline selenium, men supplemented with 800 µg selenium showed statistically significantly higher PSA velocity as compared with placebo (P = 0.018). Selenium supplementation did not show a protective effect on PSA velocity in subjects with localized prostate cancer. On the contrary, supplementation with high-dose selenium was observed to be a risk factor for increased PSA velocity in men with high baseline plasma selenium concentrations. Cancer Prev Res; 3(8); 1035–43. ©2010 AACR.

  E. T Jacobs , M. E Martinez , P. T Campbell , D. V Conti , D Duggan , J. C Figueiredo , R. W Haile , E. C LeRoy , J. N Poynter , P. A Thompson and J. A. Baron
 

Genetic variants in the calcium/vitamin D metabolic pathway may be related to risk for colorectal cancer. While several investigations of vitamin D receptor (VDR) polymorphisms and colorectal cancer have been conducted, no studies to date have evaluated the association of genetic variation in the heterodimer partner for VDR, the retinoid X receptor (RXR). Another important gene in this pathway is the calcium-sensing receptor (CASR). Employing a discordant-sibship case–control design, we examined the association between single nucleotide polymorphisms (SNPs) in RXRA and CASR and risk for colorectal cancer overall and by colorectal subsite and microsatellite instability (MSI) status using data from the Colon Cancer Family Registry. No gene-level relationships between RXRA or CASR and colorectal cancer overall were observed. However, for RXRA SNP rs7861779, a high-interest SNP selected for study a priori, there was a statistically significantly increased risk for proximal colorectal cancer among those with at least one A allele [odds ratio (OR) = 1.42; 95% confidence interval (CI) = 1.03–1.97]. Another selected RXRA SNP, rs12004589, was significantly associated with risk of MSI-high cancers (OR = 2.27; 95% CI = 1.13–4.56). Additionally, CASR SNP rs1801726 was significantly associated with a reduced risk for rectal cancer (OR = 0.53; 95% CI = 0.29–0.96). These results provide support that RXRA SNPs rs7861779 and rs12004589 and CASR SNP rs1801726 may be important markers for colorectal neoplasia. Further work is needed to elucidate their role in the carcinogenic pathway.

  A. B Chapman , V. E Torres , R. D Perrone , T. I Steinman , K. T Bae , J. P Miller , D. C Miskulin , F. R Oskoui , A Masoumi , M. C Hogan , F. T Winklhofer , W Braun , P. A Thompson , C. M Meyers , C Kelleher and R. W. Schrier
 

Background and objectives: Two HALT PKD trials will investigate interventions that potentially slow kidney disease progression in hypertensive autosomal dominant polycystic kidney disease (ADPKD) patients. Studies were designed in early and later stages of ADPKD to assess the impact of intensive blockade of the renin-angiotensin-aldosterone system and level of BP control on progressive renal disease.

Design, settings, participants, and measurements: PKD-HALT trials are multicenter, randomized, double-blind, placebo-controlled trials studying 1018 hypertensive ADPKD patients enrolled over 3 yr with 4 to 8 yr of follow-up. In study A, 548 participants, estimated GFR (eGFR) of >60 ml/min per 1.73 m2 were randomized to one of four arms in a 2-by-2 design: combination angiotensin converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) therapy versus ACEi monotherapy at two levels of BP control. In study B, 470 participants, eGFR of 25 to 60 ml/min per 1.73 m2 compared ACEi/ARB therapy versus ACEi monotherapy, with BP control of 120 to 130/70 to 80 mmHg. Primary outcomes of studies A and B are MR-based percent change kidney volume and a composite endpoint of time to 50% reduction of baseline estimated eGFR, ESRD, or death, respectively.

Results: This report describes design issues related to (1) novel endpoints such as kidney volume, (2) home versus office BP measures, and (3) the impact of RAAS inhibition on kidney and patient outcomes, safety, and quality of life.

Conclusions: HALT PKD will evaluate potential benefits of rigorous BP control and inhibition of the renin-angiotensin-aldosterone system on kidney disease progression in ADPKD.

 
 
 
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