Abstract
Randomized clinical trials have demonstrated the efficacy of opioid analgesics for the treatment of acute and chronic pain conditions, and for some patients, these medications may be the ...only effective treatment available. Unfortunately, opioid analgesics are also associated with major risks (eg, opioid use disorder) and adverse outcomes (eg, respiratory depression and falls). The risks and adverse outcomes associated with opioid analgesics have prompted efforts to reduce their use in the treatment of both acute and chronic pain. This article presents Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consensus recommendations for the design of opioid-sparing clinical trials. The recommendations presented in this article are based on the following definition of an opioid-sparing intervention: any intervention that (1) prevents the initiation of treatment with opioid analgesics, (2) decreases the duration of such treatment, (3) reduces the total dosages of opioids that are prescribed for or used by patients, or (4) reduces opioid-related adverse outcomes (without increasing opioid dosages), all without causing an unacceptable increase in pain. These recommendations are based on the results of a background review, presentations and discussions at an IMMPACT consensus meeting, and iterative drafts of this article modified to accommodate input from the co-authors. We discuss opioid sparing definitions, study objectives, outcome measures, the assessment of opioid-related adverse events, incorporation of adequate pain control in trial design, interpretation of research findings, and future research priorities to inform opioid-sparing trial methods. The considerations and recommendations presented in this article are meant to help guide the design, conduct, analysis, and interpretation of future trials.
Management and technical approaches that achieve a sustainable level of fish production while at the same time minimizing or limiting the wider ecological effects caused through fishing gear contact ...with the seabed might be considered to be ‘best practice’. To identify future knowledge‐needs that would help to support a transition towards the adoption of best practices for trawling, a prioritization exercise was undertaken with a group of 39 practitioners from the seafood industry and management, and 13 research scientists who have an active research interest in bottom‐trawl and dredge fisheries. A list of 108 knowledge‐needs related to trawl and dredge fisheries was developed in conjunction with an ‘expert task force’. The long list was further refined through a three stage process of voting and scoring, including discussions of each knowledge‐need. The top 25 knowledge‐needs are presented, as scored separately by practitioners and scientists. There was considerable consistency in the priorities identified by these two groups. The top priority knowledge‐need to improve current understanding on the distribution and extent of different habitat types also reinforced the concomitant need for the provision and access to data on the spatial and temporal distribution of all forms of towed bottom‐fishing activities. Many of the other top 25 knowledge‐needs concerned the evaluation of different management approaches or implementation of different fishing practices, particularly those that explore trade‐offs between effects of bottom trawling on biodiversity and ecosystem services and the benefits of fish production as food.
Precision prevention of TMPRSS2:ERG prostate cancer Mucci, Lorelei A.; Ahearn, Thomas; Penney, Kathryn ...
JOURNAL OF CLINICAL ONCOLOGY,
01/2016, Letnik:
34, Številka:
2_suppl
Journal Article, Conference Proceeding
Recenzirano
Abstract only
78
Background: Increased integration of tumor biomarker data into prostate cancer epidemiology studies is needed to identify molecular subtypes that underlie its etiology and ...progression. We hypothesize that the TMPRSS2:ERG gene fusion is a unique prostate cancer subtype that is etiologically distinct from cancers lacking TMPRSS2:ERG. Methods: We leveraged the Physicians’ Health Study and Health Professionals Follow-up Study cohort data on pre- and post-diagnostic lifestyle factors, inherited genetic variants, circulating biomarkers, and clinical data and follow-up for 30 years. We have a tumor repository of men with prostate cancer and tumor tissue microarrays. Using immunohistochemistry, we characterized TMPRSS2:ERG status for 1,491 incident prostate cancer cases in these cohorts, and also have biomarker data on a range of additional markers from immunohistochemistry and mRNA expression profiling. Results: Fifty percent of prostate cancer cases were ERG-positive. ERG-positive cancers show much higher expression of insulin/IGF signaling, PTEN loss, higher VDR expression, as well as expression of mismatch repair genes. In contrast, ERG-negative prostate cancer is characterized by increased presence of chronic inflammation and atrophy. We found higher pre-diagnostic free testosterone levels, but not other sex hormones, were associated with increased risk of ERG-positive (OR = 1.4, 95% CI = 1.0-1.8) but not ERG-negative disease (OR = 0.9, 95% CI = 0.7-1.2). Of 39 known genetic risk loci, six were significantly associated (p < 0.05) with ERG+ versus ERG- cancer (2 expected by chance). Prostate cancer risk factors such as taller height (an indicator of growth factors in puberty) are uniquely associated with ERG-positive prostate cancer. Moreover, we observe a complex interaction of components of insulin/IGF and ERG-status on prostate cancer mortality. Conclusions: TMPRSS2:ERG is a highly prevalent somatic event in prostate cancer that likely defines a unique molecular subtype of this common disease. Understanding the differences between these two prostate cancer subtypes may enhance opportunities for prevention.
BRCA1 functions as a tumor suppressor; recent work suggests that BRCA1 may also induce cell cycle arrest to allow for DNA repair. We hypothesized that BRCA1 expression in prostate tumor tissue may be ...associated with prostate cancer progression through regulation of the cell cycle. We used immunohistochemistry to evaluate BRCA1 protein expression in archival tumor samples from 393 prostate cancer cases in the Physicians' Health Study. The men were followed prospectively from diagnosis to development of metastases and mortality. Fifteen percent of tumors stained positive for BRCA1. BRCA1-positive tumors had substantially increased tumor proliferation index compared with negative tumors (47.0 Ki67-positive nuclei versus 10.3, P = 0.0016) and were more likely to develop lethal cancer compared with BRCA1-negative tumors (hazard ratio, 4.6; 95% confidence interval, 2.4-8.7). These findings strengthen the hypothesis that BRCA1 plays a role in cell cycle control and show that BRCA1 is a marker of clinical prostate cancer prognosis. Cancer Res; 70(8); 3136-9. (c)2010 AACR.
Abstract
BACKGROUND:
Recent evidence suggests that dysregulation of tumor metabolism is a key feature in the progression of normal prostate epithelium to cancer, and may also reflect disease ...aggressiveness and metastatic potential. Identifying the altered metabolic processes driving prostate cancer progression is of particular importance in understanding the biology of this disease.
METHODS:
mRNA was extracted from the tumors of 404 participants of the Health Professionals Follow-up Study and the Physicians’ Health Study diagnosed with incident prostate cancer (113 lethal (prostate cancer death or metastases) and 291 non-lethal cases), and from adjacent histologically normal tissue available for 202 of these cases. mRNA expression was analyzed for 426 metabolic genes encoding enzymes involved in seven metabolic pathways: Fatty Acid metabolism, Glycolysis/Gluconeogenesis, Oxidative Phosphorylation, Pentose Phosphate, Purine metabolism, Pyrimidine metabolism and the TCA cycle. Gene and pathway-level differences in expression between lethal and non-lethal tumors were assessed, and the findings compared to the expression patterns in adjacent normal tissue. Potential confounders and effect modifiers including cohort, age, year of diagnosis, BMI at diagnosis, clinical tumor stage and Gleason grade were explored and multiple testing was accounted for.
RESULTS:
Two thirds (99/130) of the genes significantly (p<0.05) associated with lethality were overexpressed in the lethal compared to non-lethal tumors, including POLR2K (p = 5.8×10-9), RRM2 (p = 7.7×10-9), ATP6V1A (p = 7.8×10-8) and POLE2 (p = 7.4×10-7). ALDH2 (p = 4.7×10-8) and PDE4DE (p = 7.1×10-8) were the top genes expressed at lower levels in lethal vs. non-lethal cancer. Purine metabolism (p = 5.6×10-9) Pyrimidine metabolism (p = 1.3×10-7) and Oxidative Phosphorylation (p = 5.3×10-6) were the metabolic pathways most strongly upregulated in lethal tumors, while Glycolysis/Gluconeogenesis (p = 8.7×10-12) was inversely associated with lethality. There was no difference in expression of metabolic genes in normal adjacent tissue among the lethal compared to non-lethal cases, however genes in the Pentose Phosphate, Glycolysis/Gluconeogenesis and Fatty acid metabolism pathways were differentially expressed in normal compared to tumor tissue. Results were robust to adjustment for, and stratification by potential confounders including Gleason grade.
CONCLUSIONS:
These results support the hypothesis that metabolic changes in tumors may have utility in predicting and understanding lethality. A better comprehension of the dysregulation in specific metabolic genes and pathways may offer novel therapeutic targets for the treatment of prostate cancer.
Citation Format: Rachel S. Kelly, Jennifer A. Sinnott, Jennifer R. Rider, Ericka Ebot, Travis Gerke, Kathryn Penney, Michaela Bowden, Massimo Loda, Philip W. Kantoff, Neil E. Martin, Edward L. Giovannucci, Andreas Pettersson Pettersson, Svitlana Tyekucheva, Kathryn M. Wilson, Matthew Vander Heiden, Lorelei A. Mucci. Tumor metabolism as a driver of lethal prostate cancer. abstract. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5168. doi:10.1158/1538-7445.AM2015-5168
PTEN frequently shows loss of heterozygosity in breast and prostate cancers, and mutations in this gene are responsible for Cowden
disease, a rare Mendelian syndrome that includes breast cancer as ...part of its phenotype. Thus, PTEN serves as a candidate susceptibility gene for both breast and prostate cancer risk. Whether common inherited variation (either
coding or noncoding) at the PTEN locus contribute to nonfamilial, sporadic breast and prostate cancer risk is not known. In this study, we employed a linkage
disequilibrium–based approach to test for association between common genetic variation at the PTEN locus and breast and prostate cancer risk in African-American, Native Hawaiian, Japanese, Latina, and White men and women
in the Multiethnic Cohort Study. We genotyped 17 common single nucleotide polymorphisms (SNP; ≥5% frequency in at least one
ethnic group) spanning the PTEN gene to define the common alleles in these populations. These SNPs were in strong linkage disequilibrium, indicating that
our survey captured most of the common sequence variation across this locus. Eight tagging SNPs were selected to predict the
common PTEN haplotypes (≥0.05 frequency) in these populations (two additional tagging SNPs were required for African Americans). These
SNPs were evaluated in a breast cancer case-control study (cases, n = 1,615; controls, n = 1,962) and prostate cancer case-control study (cases, n = 2,320; controls, n = 2,290) nested within the Multiethnic Cohort Study. Multiple testing was explicitly accounted for by applying a permutation-based
framework. We found no strong association with any common haplotype in relation to breast or prostate cancer risk. In summary,
our results show that common variants in PTEN do not substantially influence risk of these two common cancers. (Cancer Epidemiol Biomarkers Prev 2006;15(5):1021-1024)
Abstract
Background: The TMPRSS2:ERG gene fusion is a common genomic abnormality in prostate cancer that has been studied as a possible biomarker of prognosis.
Methods: We undertook a prospective ...cohort study and meta-analysis to evaluate whether TMPRSS2:ERG is associated with more aggressive prostate cancers. The cohort consisted of 1,052 men with prostate cancer treated by radical prostatectomy between 1982 and 2005 nested within the Physicians' Health Study and Health Professionals Follow-Up Study. We identified presence of the fusion by immunohistochemical assessment of ERG protein expression. We used Cox proportional hazards models for associations of the fusion with biochemical recurrence and lethal prostate cancer. The meta-analysis included 6,448 subjects with prostate cancer from 43 studies (including our cohort) published since 2005. Studies characterized presence of the fusion by fluorescence in situ hybridization, polymerase chain reaction, or immunohistochemistry.
Results: During a median follow-up of 12.5 years, 245 men in the cohort experienced biochemical recurrence, and 95 developed lethal disease (distant metastases or cancer-specific mortality). Men whose tumors harbored the fusion were more likely to be diagnosed at a higher stage (p=0.02). There was no association, however, between the fusion and Gleason score (Gleason 8–10 vs. 2–6; p=0.45), biochemical recurrence (HR: 0.93; 95% CI: 0.72–1.20), and lethal disease (HR: 0.81; 95% CI: 0.54–1.22). For men treated with radical prostatectomy, the meta-analysis yielded similar results. Fusion status was associated with higher stage at diagnosis (RR: 1.19; 95% CI: 1.11–1.28), but not with Gleason score (RR: 0.91; 95% CI: 0.76–1.10), biochemical recurrence (RR: 1.01; 95% CI: 0.84–1.22) or lethal disease (RR: 0.93; 95% CI: 0.44–1.99).
Conclusions: The results suggest that TMPRSS2:ERG fusion status and ERG expression are associated with higher stage at diagnosis but are not strong predictors of Gleason score, biochemical recurrence or cancer-specific death among men with prostate cancer treated with radical prostatectomy.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):A29.
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