The SYNERGY biodegradable polymer everolimus eluting coronary stent: Porcine vascular compatibility and polymer safety study.

AIMS: SYNERGY is a novel platinum chromium alloy stent that delivers abluminal everolimus from an ultrathin poly-lactide-co-glycide (PLGA) biodegradable polymer. This study evaluated the in vivo degradation of the polymer coating, everolimus release time course, and vascular compatibility of the SYNERGY stent. METHODS AND RESULTS: SYNERGY stents were implanted in arteries of domestic swine. Devices were explanted at predetermined time points (up to 120 days) and the extent of PLGA coating or everolimus remaining on the stents was quantified. Everolimus levels in the arterial tissue were also evaluated. A pathological analysis on coronary arteries of single and overlapping stents was performed at time points between 5 and 270 days. PLGA bioabsorption began immediately after implantation, and drug release was essentially complete by 90 days; PLGA absorption was substantially complete by 120 days (>90% of polymer was absorbed) leaving a bare metal SYNERGY stent. Vascular response was similar among SYNERGY and control stents (bare metal, polymer-only, and 3× polymer-only). Mild increases in para-strut fibrin were seen for SYNERGY at an early time point with no significant differences in all other morphological and morphometric parameters through 270 days or endothelial function (eNOS immunostaining) at 90 or 180 days. Inflammation was predominantly minimal to mild for all device types. CONCLUSION: In a swine model, everolimus was released by 90 days and PLGA bioabsorption was complete shortly thereafter. The SYNERGY stent and its biodegradable polymer, even at a 3× safety margin, demonstrated vascular compatibility similar to bare metal stent controls.

Palliative care and imaging utilisation for patients with cancer.

OBJECTIVE: This observational study explores the association between palliative care (PC) involvement and high-cost imaging utilisation for patients with cancer patients during the last 3 months of life. METHODS: Adult patients with cancer who died between 1 January 2012 and 31 May 2015 were identified. Referral to PC, intensity of PC service use, and non-emergent oncological imaging utilisation were determined. Associations between PC utilisation and proportion of patients imaged and mean number of studies per patient (mean imaging intensity (MII)) were assessed for the last 3 months and the last month of life. Similar analyses were performed for randomly matched case-control pairs (n = 197). Finally, the association between intensity of PC involvement and imaging utilisation was assessed. RESULTS: 3784 patients were included, with 3523 (93%) never referred to PC and 261 (7%) seen by PC, largely before the last month of life (61%). Similar proportions of patients with and without PC referral were imaged during the last 3 months, while a greater proportion of patients with PC referral were imaged in the last month of life. PC involvement was not associated with significantly different MII during either time frame. In the matched-pairs analysis, a greater proportion of patients previously referred to PC received imaging in the period between the first PC encounter and death, and in the last month of life. MII remained similar between PC and non-PC groups. Finally, intensity of PC services was similar for imaged and non-imaged patients in the final 3 months and 1 month of life. During these time periods, increased PC intensity was not associated with decreased MII. CONCLUSIONS: PC involvement in end-of-life oncological care was not associated with decreased use of non-emergent, high-cost imaging. The role of advanced imaging in the PC setting requires further investigation.

Utilization and Delivery of Specialty Palliative Care in the ICU: Insights from the Palliative Care Quality Network.

CONTEXT: Palliative care (PC) benefits critically ill patients but remains underutilized. Important to developing interventions to overcome barriers to PC in the ICU and address PC needs of ICU patients is to understand how, when, and for which patients PC is provided in the ICU. OBJECTIVES: Compare characteristics of specialty PC consultations in the ICU to those on medical-surgical wards. METHODS: Retrospective analysis of national Palliative Care Quality Network data for hospitalized patients receiving specialty PC consultation January 1, 2013 to December 31, 2019 in ICU or medical-surgical setting. 98 inpatient PC teams in 16 states contributed data. Measures and outcomes included patient characteristics, consultation features, process metrics and patient outcomes. Mixed effects multivariable logistic regression was used to compare ICU and medical-surgical units. RESULTS: Of 102,597 patients 63,082 were in medical-surgical units and 39,515 ICU. ICU patients were younger and more likely to have non-cancer diagnoses (all P < 0.001). While fewer ICU patients were able to report symptoms, most patients in both groups reported improved symptoms. ICU patients were more likely to have consultation requests for GOC, comfort care, and withdrawal of interventions and less likely for pain and/or symptoms (OR-all P < 0.001). ICU patients were less often discharged alive. CONCLUSION: ICU patients receiving PC consultation are more likely to have non-cancer diagnoses and less likely able to communicate. Although symptom management and GOC are standard parts of ICU care, specialty PC in the ICU is often engaged for these issues and results in improved symptoms, suggesting routine interventions and consultation targeting these needs could improve care.

Comparing the Palliative Care Needs of Patients Seen by Specialty Palliative Care Teams at Home Versus in Clinic.

CONTEXT: Understanding the unique needs of patients seen in clinic versus at home can help palliative care (PC) teams choose how to maximize available resources. OBJECTIVES: To compare the characteristics and PC needs of patients seen by PC teams in clinic versus at home. METHODS: We analyzed data from the Palliative Care Quality Network between August 2016 and September 2019 and compared demographics, diagnosis, reason for referral, PC needs, functional status, self-reported symptoms, and patient-reported quality of life. RESULTS: Compared to patients receiving PC in clinic, patients receiving PC at home were more likely to be of age 80 years or older (odds ratio [OR] 7.5, 95% CI 5.0, 10.9, P < 0.0001), have lower functional status (mean Palliative Performance Scale score 53% vs. 68%, P < 0.0001), and were less likely to screen positive for needing pain management (OR 0.31, 95% CI 0.22, 0.42, P < 0.0001) or other symptom management (OR 0.61, 95% CI 0.41, 0.90, P = 0.01). Patients receiving care at home were more likely to be referred for care planning (goals of care discussions or advance care planning) (OR 11.5, 95% CI 8.3, 16.0 P < 0.0001) and patient/family support (OR 5.9, 95% CI 4.2, 8.3, P < 0.0001). CONCLUSION: Patients seen by PC teams at home had worse function and were more likely to be referred for care planning, while patients seen in clinic had more PC needs related to pain and symptom management. Despite these differences, both populations have significant PC needs that support routine assessment and require appropriately staffed interdisciplinary teams to address these needs.

A Comparison of Hospitalized Patients With Heart Failure and Cancer Referred to Palliative Care.

Importance: Growing evidence shows that palliative care (PC) improves treatment outcomes in patients with heart failure (HF), but few large-scale studies have prospectively evaluated the processes and outcomes associated with PC consultation for such patients in the real world. Objective: To characterize processes and outcomes of PC consultations for hospitalized patients with HF compared with patients with cancer. Design, Setting, and Participants: This cohort study of inpatient encounters at community and academic hospitals in the Palliative Care Quality Network enrolled participants between 2013 and 2017. Of a total of 135 197 patients, 57 272 adults with a primary diagnosis of HF or cancer receiving PC consultation were enrolled. Data analysis was performed from April 2018 to December 2019. Exposures: Primary diagnosis of HF or cancer. Main Outcomes and Measures: Symptom improvement and changes in care planning documentation after PC consultation. Results: At the time of consultation, patients with HF were older (mean age, 75.3 years [95% CI, 75.0-75.5 years] vs 65.2 years [95% CI, 65.0-65.3 years]; P < .001), had lower Palliative Performance Scale scores (mean, 35.6% [95% CI, 35.3%-35.9%] vs 42.4% [95% CI, 42.2%-42.6%]; P < .001), and were more likely to be in a critical care unit (5808 of 16 741 patients [35.3%] vs 4985 of 40 531 patients [12.5%]; P < .001) or a telemetry or step-down unit (5802 of 16 741 patients [35.2%] vs 7651 of 40 531 patients [19.2%]; P < .001) compared with patients with cancer. Patients with HF were less likely than patients with cancer to be referred to PC within 24 hours of admission (6773 of 16 741 patients [41.2%] vs 19 348 of 40 531 patients [49.0%]; P < .001) and had longer hospitalizations before receiving PC consultation requests (mean, 4.6 days [95% CI, 4.4-4.8 days] vs 3.9 days [95% CI, 3.8-4.0 days]; P < .001). Patients with HF were referred less frequently for symptoms other than pain (1686 of 16 488 patients [10.2%] vs 8587 of 39 609 patients [21.7%]; P < .001), but were equally likely to report improvements in anxiety (odds ratio, 0.85; 95% CI, 0.71-1.02; P = .08) and more likely to report improvements in dyspnea (odds ratio, 2.17; 95% CI, 1.83-2.57; P < .001) compared with patients with cancer. Patients with HF were less likely than those with cancer to be discharged alive (odds ratio, 0.78; 95% CI, 0.64-0.96; P = .02) or to be referred to hospice (odds ratio, 0.50; 95% CI, 0.47-0.53; P < .001). Conclusions and Relevance: These findings suggest that PC referral comes late for patients with HF and is used primarily to discuss care planning. Practitioners caring for patients with HF should consider involving PC experts earlier for symptom management.

Trends in Hospital-Based Specialty Palliative Care in the United States From 2013 to 2017.

Importance: Although palliative care (PC) historically focused on patients with cancer and those near the end of life, evidence increasingly demonstrates a benefit to patients with a broad range of serious illnesses and to those earlier in their illness. The field of PC has expanded and evolved rapidly, resulting in a need to characterize practice over time to understand whether it reflects evolving evidence and guidelines. Objective: To characterize current practice and trends among patients cared for and outcomes achieved by inpatient specialty PC services in the United States. Design, Setting, and Participants: This retrospective cohort study was performed from January 1, 2013, to December 31, 2017, at 88 US hospitals in which PC teams voluntarily participate in the Palliative Care Quality Network (PCQN), a national quality improvement collaborative. A total of 135 197 patients were referred to PCQN teams during the study period. Initial analyses of the study data were conducted from March 3 to March 21, 2018. Exposure: Inpatient PC consultation. Main Outcomes and Measures: A total of 23 standardized data elements collected by PCQN teams that provided information about the characteristics of referred patients, including age, sex, Palliative Performance Scale score, and primary diagnosis leading to PC consult; reason(s) given for the consultation; and processes of care provided by the PC team, including disciplines involved, number of family meetings held, advance care planning documentation completed, and screened for and intervened on needs. Results: A total of 135 197 patients were referred to inpatient PC (51.0% female; mean age, 71.3 years [range, 57.8-82.5 years]) and were significantly debilitated (mean Palliative Performance Scale score, 34.7%; range, 14.9%-56.8%). Cancer was the most common primary diagnosis (32.0%; range, 11.3%-93.9%), although rates decreased from 2013 to 2017 (odds ratio [OR], 0.84; 95% CI, 0.79-0.91; P < .001). Pain and other symptoms were common and improved significantly during the consultation period (pain: χ2 = 5234.4, P < .001; anxiety: χ2 = 2020.7, P < .001; nausea: χ2 = 1311.8, P < .001; dyspnea: χ2 = 1993.5, P < .001). Most patients were discharged alive (78.7%; range, 44.7%-99.4%), and this number increased over time (OR, 1.36; 95% CI, 1.27-1.46; P < .001). Compared with 2013, rates of discharge referral to clinic-based (OR, 4.00; 95% CI, 2.95-5.43; P < .001) and home-based PC (OR, 2.63; 95% CI, 1.92-3.61; P < .001) also increased significantly by 2017, whereas referrals to hospice decreased (OR, 0.56; 95% CI, 0.51-0.62; P < .001). Conclusions and Relevance: Inpatient PC teams cared for an increasing percentage of patients with diagnoses other than cancer and saw more patients discharged alive, consistent with guidelines recommending specialty PC for all patients with serious illness earlier in their illnesses. Most patients with symptoms improved quickly. Variation in practice and outcomes among PCQN members suggests that there are opportunities for further improvements in care.

Outcomes of Palliative Care Consultations for Hospitalized Patients With Liver Disease.

CONTEXT: Although palliative care (PC) has been shown to improve symptoms and end-of-life (EOL) care for patients with cancer, data are lacking on the patterns of use and outcomes of PC consultations for hospitalized patients with liver disease. OBJECTIVES: We sought to characterize the patterns of use and outcomes of PC consultations for hospitalized patients with liver disease compared with patients with cancer. METHODS: We conducted an observational study using data from the Palliative Care Quality Network (PCQN). The PCQN contains prospectively collected data on 135,197 hospitalized patients receiving PC consultations at 88 PCQN sites between January 2013 and December 2017. The PCQN data set includes patient demographics, processes of care, and patient-level clinical outcomes. RESULTS: The cohort included 44,933 patients, of whom 4402 (9.8%) had liver disease and 40,531 (90.2%) had cancer. Patients with liver disease were younger (58.9 years vs. 65.2 years, P < 0.0001) and had higher in-hospital mortality (28% vs. 16.8%, P < 0.0001). Patients with liver disease were more likely to receive PC consultations to address goals of care (81.7% vs. 67.9%, P < 0.0001) as opposed to pain management (10.9% vs. 34.9%, P < 0.0001). Both groups had similar rates of symptom improvement and change in resuscitation preferences after PC consultation. CONCLUSION: Hospitalized patients with liver disease were more likely to have a PC referral to address goals of care compared with those with cancer and were more likely to die in the hospital. Despite late PC consultations, patients with liver disease experienced improvement in symptoms and clarification of their goals of care, similar to those with cancer.

Care Planning for Inpatients Referred for Palliative Care Consultation.

Importance: Care planning is a critical function of palliative care teams, but the impact of advance care planning and goals of care discussions by palliative care teams has not been well characterized. Objective: To describe the population of patients referred to inpatient palliative care consultation teams for care planning, the needs identified by palliative care clinicians, the care planning activities that occur, and the results of these activities. Design, Setting, and Participants: This was a prospective cohort study conducted between January 1, 2013, and December 31, 2016. Seventy-eight inpatient palliative care teams from diverse US hospitals in the Palliative Care Quality Network, a national quality improvement collaborative. Standardized data were submitted for 73 145 patients. Exposures: Inpatient palliative care consultation. Results: Overall, 52 571 of 73 145 patients (71.9%) referred to inpatient palliative care were referred for care planning (range among teams, 27.5%-99.4% of patients). Patients referred for care planning were older (73.3 vs 67.9 years; F statistic, 1546.0; P < .001), less likely to have cancer (30.0% vs 41.1%; P < .001), and slightly more often had a clinical order of full code at the time of referral (54.6% vs 52.1%; P < .001). Palliative care teams identified care planning needs in 52 825 of 73 145 patients (72.2%) overall, including 42 467 of 49 713 patients (85.4%) referred for care planning and in 10 054 of 17 475 patients (57.5%) referred for other reasons. Through care planning conversations, surrogates were identified for 10 571 of 11 149 patients (94.8%) and 9026 patients (37.4%) elected to change their code status. Substantially more patients indicated that a status of do not resuscitate/do not intubate was consistent with their goals (7006 [32.1%] preconsultation to 13 773 [63.1%] postconsultation). However, an advance directive was completed for just 2160 of 67 955 patients (3.2%) and a Physicians Orders for Life-Sustaining Treatment form was completed for 8359 of 67 955 patients (12.3%) seen by palliative care teams. Conclusions and Relevance: Care planning was the most common reason for inpatient palliative care consultation, and care planning needs were often found even when the consultation was for other reasons. Surrogates were consistently identified, and patients' preferences regarding life-sustaining treatments were frequently updated. However, a minority of patients completed legal forms to document their care preferences, highlighting an area in need of improvement.

The Palliative Care Quality Network: Improving the Quality of Caring.

OBJECTIVE: Describe the establishment of the palliative care quality network (PCQN) with guidance on how teams can develop similar collaborations. BACKGROUND: In the current healthcare environment, palliative care (PC) teams must be able to demonstrate value and provide efficient care while supporting the clinicians who provide that care. DESCRIPTION: The PCQN is a national quality improvement (QI) collaborative comprised of specialty PC teams from a diverse range of hospitals across the United States Results: PCQN members identified five core activities to support PC teams. 1) Collection of standardized data: 23 core items and 22 optional data elements document patient demographics, consultation characteristics, processes of care, and clinical outcomes. 2) Data analyses with benchmarking including reports generated in real time providing summary, trend, member comparison, and cross-tab analyses. 3) QI collaborative; QI initiatives have addressed pain management, surrogate decision-making, spiritual screening, and anxiety assessment. 4) Education and personal development provided through monthly conference calls, a listserv, PCQN website, and twice-yearly conferences. 5) Financial analysis; a software program enables PC teams to calculate the financial impact of the care provided. CONCLUSIONS: The central tenet of the PCQN is to improve quality of care for patients with serious illness and their families, increase the efficient use of healthcare resources, and support growth and sustainability of PC programs. Building and tending to this community takes time to ensure engagement of all members and remain responsive to evolving needs of patients, families, PC teams, and stakeholders.

Reducing Health Care Disparities for Minority Women in the Era of the Affordable Care Act: Opportunities within Primary Care.

Despite improvements in overall health of the American population, disparities persist, particularly for minority women. The Affordable Care Act (ACA) offers the potential to reduce disparities through expanded insurance coverage, greater access to high-quality care, and bolstered prevention efforts in the context of new models of care such as the patient-centered medical home (PCMH). We use case studies representing three clinical conditions (breast cancer, HIV, and coronary heart disease) to present strategies for how a PCMH could reduce disparities for minority women. The case studies highlight the opportunity that further implementation of the ACA provides to improve screening, risk assessment, and prevention for a range of conditions that impact the health of minority women, as well as areas ripe for future investigation.

Positioning Medical Assistants for a Greater Role in the Era of Health Reform.

Medical assistants (MAs) are one of the fastest-growing occupations in the United States. As of 2014 there were about 585,000 MAs in the United States, and the Bureau of Labor Statistics projected the MA workforce to grow by 29% from 2012 to 2022. The MA population is primarily female, ethnically and racially diverse, and paid about $15.01 per hour. MAs are primarily educated in private schools, many at for-profit institutions. The MA curriculum and length of training can be quite varied and can lead to uneven preparation for practice. Traditionally, the MA role has involved a limited clinical role and little involvement with team care, particularly in larger practices or clinics. Medical groups, clinics, and health systems are now taking a new look at MAs and how they can play a greater role in reforming health care delivery models. Expanded roles for MAs might include health coach, referral coordinator, disease registry manager, and health screener using protocols. In expanding MA roles, education and regulatory issues need to be addressed by the provider community including current inconsistent regulation and certification requirements and the lack of preparation for expanded roles in traditional MA training programs. MAs are well positioned to help address challenges in the health care delivery system including improving access to care while reducing overall cost. Successful model practices using MAs in expanded roles need further formal evaluation and replication across practice settings.

Efficacy of a complex multivitamin supplement.

OBJECTIVES: Multivitamin supplements are often sold to consumers with the claim that supplements modify risk factors associated with disease. Because few products are validated scientifically, we examined the effects of a 24-ingredient multivitamin formula in an open-label pilot investigation. METHODS: We examined 150 subjects for specific endpoints including blood concentrations of selected vitamins, homocysteine, lipids, and low-density lipoprotein (LDL) oxidation indices at baseline and at 12 and 24 wk. RESULTS: One hundred forty-one subjects were successfully assayed for and showed significant time effects for homocysteine and vitamin B6 (as pyridoxal-5'-phosphate), B12, and folic acid concentrations during treatment (P < 0.0001). Vitamin B6, B12, and folic acid concentrations were significantly elevated at weeks 12 and 24 (P < 0.05). Homocysteine concentration decreased significantly during the same periods (7.9 +/- 2.4 versus 6.7 +/- 1.7 versus 6.7 +/- 1.9 mM/mL; P < 0.05). There were correlations relating homocysteine to vitamins B6 (P = 0.001, r(2) = 0.03), B12 (P < 0.001, r(2) = 0.09), and folic acid (P = 0.001, r(2) = 0.10). Significant time effects were noted for 121 subjects successfully assayed for vitamin C, E, beta-carotene, LDL oxidation rate, and LDL lag time (P < 0.0001). Post hoc assessment showed elevations in vitamin C, E, and beta-carotene concentrations at 12 and 24 wk (P < 0.05). LDL oxidation lag time at baseline (57.5 +/- 13.9 min) increased by 12 wk (63.5 +/- 19.0 min; P < 0.05) and 24 wk (63.8 +/- 16.3 min; P < 0.05). LDL oxidation rate at baseline (9.7 +/- 3.0 microM x min(-1). g(-1)) was reduced at 12 wk (7.1 +/- 2.5 microM x min(-1) x g(-1); P < 0.05) and 24 wk (6.0 +/- 2.0 microM x min(-1) x g(-1); P < 0.05). Only vitamin C was significantly correlated with LDL oxidation rate (P = 0.05, r(2) = 0.003). CONCLUSIONS: A multi-ingredient vitamin formula with antioxidant properties has measurable effects on homocysteine and LDL oxidation indices.

Genome linkage screen for prostate cancer susceptibility loci: results from the Mayo Clinic Familial Prostate Cancer Study.

Prostate cancer is one of the most common cancers among men and has long been recognized to occur in familial clusters. Brothers and sons of affected men have a twofold to threefold increased risk of developing prostate cancer. However, identification of genetic susceptibility loci for prostate cancer has been extremely difficult. Several putative loci identified by genetic linkage have been reported to exist on chromosomes 1 (HPC1, PCAP, and CAPB), X (HPCX), 17 (HPC2), and 20 (HPC20), with genes RNASEL (HPC1) and ELAC2 (HPC2) tentatively defined. In this study, we report our genome linkage scan in 160 prostate cancer families, using the ABI Prism Linkage Mapping Set Version 2 with 402 microsatellite markers. The most significant linkage was found for chromosome 20, with a recessive model heterogeneity LOD score (HLOD) of 4.77, and a model-free LOD score (LOD - ZLR) of 3.46 for the entire group of pedigrees. Linkage for chromosome 20 was most prominent among families with a late age of diagnosis (average age at diagnosis >/= 66 years; maximum LOD - ZLR = 2.82), with <5 affected family members (LOD - ZLR = 3.02), with presence of hereditary prostate cancer (LOD - ZLR = 2.81), or with no male-to-male transmission of disease (LOD - ZLR = 3.84). No other chromosome showed significant evidence for linkage. However, chromosomes 6 and X showed suggestive results, with maximum LOD - ZLR values of 1.38 and 1.36, respectively. Subset analyses suggest additional chromosomal regions worth further follow-up.

Analysis of the RNASEL gene in familial and sporadic prostate cancer.

The RNASEL gene on chromosome 1q25 was recently identified as a candidate gene for hereditary prostate cancer (PC). To confirm these findings, we screened 326 patients from 163 families with familial PC for potential germline mutations, by use of conformation-sensitive gel electrophoresis, followed by direct sequence analysis. A total of six variants were identified, including one intronic and five exonic changes (three missense and two silent alterations). There were no unequivocal pathogenic changes. To further test for potential associations between genes and increased risk for disease, the three missense polymorphisms (Ile97Leu, Arg462Gln, and Glu541Asp) were genotyped in 438 patients with familial PC and in 510 population-based control subjects. Association testing revealed no significant differences between patients and control subjects for either the Leu97 variant (chi(2) trend test = 1.42; P=.23) or the Asp541 variant (chi2=1.52; P=.22). However, significant differences were detected for the Arg462Gln genotypes (chi2=5.20; P=.02; odds ratio [OR] = 0.54; 95% confidence interval [CI] 0.32-0.91) when the genotype Gln/Gln was compared with Arg/Arg. In subset analyses, associations were also observed in the younger group (age at diagnosis

Luteinizing hormone beta polymorphism and risk of familial and sporadic prostate cancer.

BACKGROUND: Circulating testosterone plays an important role in maintenance and growth of prostate cells. Luteinizing hormone (LH), secreted from the anterior pituitary, signals testicular Leydig cells to secrete testosterone. A genetic variant of the LH-beta protein, LH-betaV, exists in up to 40% of Caucasians and is more bioactive than the wild-type protein. We hypothesized that genetically determined variation in LH function might affect susceptibility to prostate cancer via altered testosterone secretion. METHODS: We determined the frequency of the LH-betaV polymorphism (two linked polymorphisms: Trp(8) --> Arg and Ile(15) --> Thr) in familial prostate cancer patients (n = 446), in sporadic prostate cancer patients (n = 388), and in population-based controls without prostate cancer (n = 510) to assess the role of this polymorphism in susceptibility to prostate cancer. RESULTS: A higher frequency of this variant genotype (LH-betaV: Arg(8)/Thr(15)) was observed in familial prostate cancer patients (18.6%) than in controls (13.7%), and after taking into account the correlation of the familial cases and adjusting for age and body mass index (BMI), there was a weak positive association between the variant LH-beta genotype, and risk of familial prostate cancer (OR = 1.29; 95% CI 0.96-1.75). The sporadic case group was also slightly more likely to have a variant genotype (15.2%) compared to the controls (13.7%), and after adjustment for age and BMI, a similar association with this variant was found (OR = 1.33; 95% CI 0.86-02.07). Surgical cases showed a slightly stronger association for the variant LH-beta genotype compared to non-surgical cases, but among the surgical cases there was little variability in risk across nodal status, stage, and tumor grade. CONCLUSIONS: These data are consistent with the hypothesis that the LH-beta variant is a weak risk factor for prostate cancer.

Mutations in CHEK2 associated with prostate cancer risk.

The DNA-damage-signaling pathway has been implicated in all human cancers. However, the genetic defects and the mechanisms of this pathway in prostate carcinogenesis remain poorly understood. In this study, we analyzed CHEK2, the upstream regulator of p53 in the DNA-damage-signaling pathway, in several groups of patients with prostate cancer. A total of 28 (4.8%) germline CHEK2 mutations (16 of which were unique) were found among 578 patients. Additional screening for CHEK2 mutations in 149 families with familial prostate cancer revealed 11 mutations (5 unique) in nine families. These mutations included two frameshift and three missense mutations. Importantly, 16 of 18 unique CHEK2 mutations identified in both sporadic and familial cases were not detected among 423 unaffected men, suggesting a pathological effect of CHEK2 mutations in prostate cancer development. Analyses of the two frameshift mutations in Epstein Barr virus-transformed cell lines, using reverse-transcriptase polymerase chain reaction and western blot analysis, revealed abnormal splicing for one mutation and dramatic reduction of CHEK2 protein levels in both cases. Overall, our data suggest that mutations in CHEK2 may contribute to prostate cancer risk and that the DNA-damage-signaling pathway may play an important role in the development of prostate cancer.