Genetic Factors Associated with Prostate Cancer Conversion from Active Surveillance to Treatment.

Men diagnosed with low-risk prostate cancer (PC) are increasingly electing active surveillance (AS) as their initial management strategy. While this may reduce the side effects of treatment for prostate cancer, many men on AS eventually convert to active treatment. PC is one of the most heritable cancers, and genetic factors that predispose to aggressive tumors may help distinguish men who are more likely to discontinue AS. To investigate this, we undertook a multi-institutional genome-wide association study (GWAS) of 5,222 PC patients and 1,139 other patients from replication cohorts, all of whom initially elected AS and were followed over time for the potential outcome of conversion from AS to active treatment. In the GWAS we detected 18 variants associated with conversion, 15 of which were not previously associated with PC risk. With a transcriptome-wide association study (TWAS), we found two genes associated with conversion (MAST3, p = 6.9×10-7 and GAB2, p = 2.0×10-6). Moreover, increasing values of a previously validated 269-variant genetic risk score (GRS) for PC was positively associated with conversion (e.g., comparing the highest to the two middle deciles gave a hazard ratio [HR] = 1.13; 95% Confidence Interval [CI]= 0.94-1.36); whereas, decreasing values of a 36-variant GRS for prostate-specific antigen (PSA) levels were positively associated with conversion (e.g., comparing the lowest to the two middle deciles gave a HR = 1.25; 95% CI, 1.04-1.50). These results suggest that germline genetics may help inform and individualize the decision of AS-or the intensity of monitoring on AS-versus treatment for the initial management of patients with low-risk PC.

Factors Associated with Time to Conversion from Active Surveillance to Treatment for Prostate Cancer in a Multi-Institutional Cohort.

PURPOSE: We examined the demographic and clinicopathological parameters associated with the time to convert from active surveillance to treatment among men with prostate cancer. MATERIALS AND METHODS: A multi-institutional cohort of 7,279 patients managed with active surveillance had data and biospecimens collected for germline genetic analyses. RESULTS: Of 6,775 men included in the analysis, 2,260 (33.4%) converted to treatment at a median followup of 6.7 years. Earlier conversion was associated with higher Gleason grade groups (GG2 vs GG1 adjusted hazard ratio [aHR] 1.57, 95% CI 1.36-1.82; ≥GG3 vs GG1 aHR 1.77, 95% CI 1.29-2.43), serum prostate specific antigen concentrations (aHR per 5 ng/ml increment 1.18, 95% CI 1.11-1.25), tumor stages (cT2 vs cT1 aHR 1.58, 95% CI 1.41-1.77; ≥cT3 vs cT1 aHR 4.36, 95% CI 3.19-5.96) and number of cancerous biopsy cores (3 vs 1-2 cores aHR 1.59, 95% CI 1.37-1.84; ≥4 vs 1-2 cores aHR 3.29, 95% CI 2.94-3.69), and younger age (age continuous per 5-year increase aHR 0.96, 95% CI 0.93-0.99). Patients with high-volume GG1 tumors had a shorter interval to conversion than those with low-volume GG1 tumors and behaved like the higher-risk patients. We found no significant association between the time to conversion and self-reported race or genetic ancestry. CONCLUSIONS: A shorter time to conversion from active surveillance to treatment was associated with higher-risk clinicopathological tumor features. Furthermore, patients with high-volume GG1 tumors behaved similarly to those with intermediate and high-risk tumors. An exploratory analysis of self-reported race and genetic ancestry revealed no association with the time to conversion.

Biogeography of the Relationship between the Child Gut Microbiome and Innate Immune System.

The gut microbiome is a well-recognized modulator of host immunity, and its compositions differ between geographically separated human populations. Systemic innate immune responses to microbial derivatives also differ between geographically distinct human populations. However, the potential role of the microbiome in mediating geographically varied immune responses is unexplored. We here applied 16S amplicon sequencing to profile the stool microbiome and, in parallel, measured whole-blood innate immune cytokine responses to several pattern recognition receptor (PRR) agonists among 2-year-old children across biogeographically diverse settings. Microbiomes differed mainly between high- and low-resource environments and were not strongly associated with other demographic factors. We found strong correlations between responses to Toll-like receptor 2 (TLR2) and relative abundances of Bacteroides and Prevotella populations, shared among Canadian and Ecuadorean children. Additional correlations between responses to TLR2 and bacterial populations were specific to individual geographic cohorts. As a proof of concept, we gavaged germfree mice with human donor stools and found murine splenocyte responses to TLR stimulation were consistent with responses of the corresponding human donor populations. This study identified differences in immune responses correlating to gut microbiomes across biogeographically diverse settings and evaluated biological plausibility using a mouse model. This insight paves the way to guide optimization of population-specific interventions aimed to improve child health outcomes.IMPORTANCE Both the gut microbiome and innate immunity are known to differ across biogeographically diverse human populations. The gut microbiome has been shown to directly influence systemic immunity in animal models. With this, modulation of the gut microbiome represents an attractive avenue to improve child health outcomes associated with altered immunity using population-specific approaches. However, there are very scarce data available to determine which members of the gut microbiome are associated with specific immune responses and how these differ around the world, creating a substantial barrier to rationally designing such interventions. This study addressed this knowledge gap by identifying relationships between distinct bacterial taxa and cytokine responses to specific microbial agonists across highly diverse settings. Furthermore, we provide evidence that immunomodulatory effects of region-specific stool microbiomes can be partially recapitulated in germfree mice. This is an important contribution toward improving global child health by targeting the gut microbiome.

A new set of eyes: development of a novel microangioscope for neurointerventional surgery.

BACKGROUND: Endovascular technological advances have revolutionized the field of neurovascular surgery and have become the mainstay of treatment for many cerebrovascular pathologies. Digital subtraction angiography (DSA) is the 'gold standard' for visualization of the vasculature and deployment of endovascular devices. Nonetheless, with recent technological advances in optics, angioscopy has emerged as a potentially important adjunct to DSA. Angioscopy can offer direct visualization of the intracranial vasculature, and direct observation and inspection of device deployment. However, previous iterations of this technology have not been sufficiently miniaturized or practical for modern neurointerventional practice. OBJECTIVE: To describe the evolution, development, and design of a microangioscope that offers both high-quality direct visualization and the miniaturization necessary to navigate in the small intracranial vessels and provide examples of its potential applications in the diagnosis and treatment of cerebrovascular pathologies using an in vivo porcine model. METHODS: In this proof-of-concept study we introduce a novel microangioscope, designed from coherent fiber bundle technology. The microangioscope is smaller than any previously described angioscope, at 1.7 F, while maintaining high-resolution images. A porcine model is used to demonstrate the resolution of the images in vivo. RESULTS: Video recordings of the microangioscope show the versatility of the camera mounted on different microcatheters and its ability to navigate external carotid artery branches. The microangioscope is also shown to be able to resolve the subtle differences between red and white thrombi in a porcine model. CONCLUSION: A new microangioscope, based on miniaturized fiber optic technology, offers a potentially revolutionary way to visualize the intracranial vascular space.

Insertion of an SVA-E retrotransposon into the CASP8 gene is associated with protection against prostate cancer.

Transcriptional and splicing anomalies have been observed in intron 8 of the CASP8 gene (encoding procaspase-8) in association with cutaneous basal-cell carcinoma (BCC) and linked to a germline SNP rs700635. Here, we show that the rs700635[C] allele, which is associated with increased risk of BCC and breast cancer, is protective against prostate cancer [odds ratio (OR) = 0.91, P = 1.0 × 10(-6)]. rs700635[C] is also associated with failures to correctly splice out CASP8 intron 8 in breast and prostate tumours and in corresponding normal tissues. Investigation of rs700635[C] carriers revealed that they have a human-specific short interspersed element-variable number of tandem repeat-Alu (SINE-VNTR-Alu), subfamily-E retrotransposon (SVA-E) inserted into CASP8 intron 8. The SVA-E shows evidence of prior activity, because it has transduced some CASP8 sequences during subsequent retrotransposition events. Whole-genome sequence (WGS) data were used to tag the SVA-E with a surrogate SNP rs1035142[T] (r(2) = 0.999), which showed associations with both the splicing anomalies (P = 6.5 × 10(-32)) and with protection against prostate cancer (OR = 0.91, P = 3.8 × 10(-7)).

Associations Between iCOGS Single Nucleotide Polymorphisms and Upgrading in Both Surgical and Active Surveillance Cohorts of Men with Prostate Cancer.

BACKGROUND: Associations have been documented recently between some of the 23 single nucleotide polymorphisms newly discovered with the Collaborative Oncological Gene-environment Study iCOGS array that indicate prostate cancer (PCa) risk and aspects of disease aggressiveness. The utility of these iCOGS SNPs remains to be determined in active surveillance (AS). OBJECTIVE: To determine associations between iCOGS SNPs and upgrading among men who underwent surgical treatment and AS for low-risk PCa. DESIGN, SETTING, AND PARTICIPANTS: The genotypes of the 23 iCOGS SNPs were determined for all white subjects with biopsy Gleason score (GS) 6 including 950 men who underwent definitive treatment with surgery and 209 men who elected AS. The clinical and pathologic characteristics were documented for all subjects. OUTCOME MEASURES AND STATISTICAL ANALYSIS: Men who underwent surgery were grouped according to their pathologic GS (upgraded was defined as GS ≥7; nonupgraded remained GS 6). Men who were enrolled in AS were also grouped according to their GS on subsequent surveillance biopsies. Statistical analyses were performed comparing the genotypes between the upgraded and nonupgraded groups. RESULTS AND LIMITATIONS: Overall, 31% and 34% of men were upgraded in the surgery and AS cohorts, respectively. Three iCOGS SNPs were significantly associated with the risk of upgrading in the surgical cohort. After correction for multiple testing, only rs11568818 on chromosome 11q22 remained significantly associated with upgrading. Assessment of this allele in the AS cohort reveals that it was present at noteworthy higher frequencies in men with high-grade disease on surveillance biopsies compared with nonupgraded men (p=0.003). This study was primarily limited by the homogeneous patient population. CONCLUSIONS: This is the first report of a SNP on chromosome 11q22 associated with higher grade disease in a surgical cohort that is also validated for eventual upgrading in a prospective AS cohort. PATIENT SUMMARY: We examined the relationship between a group of genetic markers and prostate cancer (PCa) aggressiveness in a group of patients who underwent surgery for PCa and a group of patients who were enrolled in active surveillance. We found that these genetic markers helped predict which patients had more aggressive disease in both groups.

Associations of prostate cancer risk variants with disease aggressiveness: results of the NCI-SPORE Genetics Working Group analysis of 18,343 cases.

Genetic studies have identified single nucleotide polymorphisms (SNPs) associated with the risk of prostate cancer (PC). It remains unclear whether such genetic variants are associated with disease aggressiveness. The NCI-SPORE Genetics Working Group retrospectively collected clinicopathologic information and genotype data for 36 SNPs which at the time had been validated to be associated with PC risk from 25,674 cases with PC. Cases were grouped according to race, Gleason score (Gleason ≤ 6, 7, ≥ 8) and aggressiveness (non-aggressive, intermediate, and aggressive disease). Statistical analyses were used to compare the frequency of the SNPs between different disease cohorts. After adjusting for multiple testing, only PC-risk SNP rs2735839 (G) was significantly and inversely associated with aggressive (OR = 0.77; 95 % CI 0.69-0.87) and high-grade disease (OR = 0.77; 95 % CI 0.68-0.86) in European men. Similar associations with aggressive (OR = 0.72; 95 % CI 0.58-0.89) and high-grade disease (OR = 0.69; 95 % CI 0.54-0.87) were documented in African-American subjects. The G allele of rs2735839 was associated with disease aggressiveness even at low PSA levels (<4.0 ng/mL) in both European and African-American men. Our results provide further support that a PC-risk SNP rs2735839 near the KLK3 gene on chromosome 19q13 may be associated with aggressive and high-grade PC. Future prospectively designed, case-case GWAS are needed to identify additional SNPs associated with PC aggressiveness.

A rare 8q24 single nucleotide polymorphism (SNP) predisposes North American men to prostate cancer and possibly more aggressive disease.

OBJECTIVE: To assess the frequency of a novel prostate cancer-associated single nucleotide polymorphism (SNP), rs188140481, in a North American population and to evaluate the clinical significance of this variant including annotated prostatectomy pathology. PATIENTS/SUBJECTS AND METHODS: We examined the frequency of the minor allele at rs188140481 in 4299 North American men including 1979 men with prostate cancer and 2320 healthy volunteers. We compared the clinicopathological features of prostate cancer between carriers and non-carriers of the SNP. RESULTS: The rs188140481[A] SNP was present in 1.6% of the cohort; it was significantly more likely to be carried by men with prostate cancer than healthy controls (odds ratio 3.14; 95% confidence interval [CI] 1.85-5.35). After adjusting for age and PSA levels, carriers were found to be 6.73-fold (95% CI 1.69-26.76) more likely to develop prostate cancer than non-carriers. Age at diagnosis, frequency of a positive family history of prostate cancer, and biochemical recurrence rates were similar between SNP carriers and non-carriers. Patients with the SNP had a proportionately higher frequency of stage ≥T2c disease (29.5% vs 20.1%; P = 0.13), Gleason ≥8 tumours (13.3% vs 6.5%; P = 0.10), and extracapsular extension (28.9% vs 18.8%; P = 0.12) compared with non-carriers. CONCLUSIONS: rs188140481[A] is a rare SNP that confers greater risk of prostate cancer compared with SNPs identified by genome-wide association studies. Because of its low frequency, larger studies are needed to validate the prognostic significance of this locus, and associations with adverse pathology.

Genetically adjusted prostate-specific antigen values may prevent delayed biopsies in African-American men.

OBJECTIVE: To evaluate whether genetic correction using the genetic variants prostate-specific antigen (PSA)-single nucleotide polymorphisms (SNPs) could reduce potentially unnecessary and/or delayed biopsies in African-American men. SUBJECTS AND METHODS: We compared the genotypes of four PSA-SNPs between 964 Caucasian and 363 African-American men without known prostate cancer (PCa). We adjusted the PSA values based on an individual's PSA-SNP carrier status, and calculated the percentage of men that would meet commonly used PSA thresholds for biopsy (≥ 2.5 or ≥ 4.0 ng/mL) before and after genetic correction. Potentially unnecessary and delayed biopsies were defined as those men who were below and above the biopsy threshold after genetic correction, respectively. RESULTS: Overall, 349 (96.1%) and 354 (97.5%) African-American men had measured PSA levels <2.5 and <4.0 ng/mL. Genetic correction in African-American men did not avoid any potentially unnecessary biopsies, but resulted in a significant (P < 0.001) reduction in potentially delayed biopsies by 2.5% and 3.9%, based on the biopsy threshold level. CONCLUSIONS: There are significant differences in the influence of the PSA-SNPs between African-American and Caucasian men without known PCa, as genetic correction resulted in an increased proportion of African-American men crossing the threshold for biopsy. These results raise the question of whether genetic differences in PSA might contribute to delayed PCa diagnosis in African-American men.

Prostate cancer risk alleles are associated with prostate cancer volume and prostate size.

PURPOSE: Genome-wide association studies have identified an increasing number of single nucleotide polymorphisms associated with prostate cancer risk. Some of these genetic variants are also associated with serum prostate specific antigen levels and lower urinary tract symptoms, raising the question of whether they are truly prostate cancer biomarkers or simply lead to detection bias. Therefore, we determined whether single nucleotide polymorphisms associated with prostate cancer risk are more strongly associated with tumor or prostate volume. MATERIALS AND METHODS: The genotypes of 38 validated prostate cancer risk single nucleotide polymorphisms were determined in 1,321 white men who underwent radical prostatectomy. Univariate and multivariate analyses were performed to compare the relationship of single nucleotide polymorphism frequency with total prostate and tumor volumes. RESULTS: On multivariate analysis 2 single nucleotide polymorphisms on chromosome 8q24, rs16901979 (A) and rs6983267 (G), were significantly associated with increased tumor volume (p=0.01 and 0.02, respectively). In contrast, rs17632542 (T) near the PSA gene on 19q13 was associated with significantly lower tumor volume and rs10788160 (A) on 10q26 was associated with significantly larger prostate volume (p=0.02 and 0.01, respectively). CONCLUSIONS: Analysis of 38 single nucleotide polymorphisms associated with prostate cancer risk revealed a significant association between several on chromosome 8q24 and increased tumor volume but not prostate volume. This suggests that they are bona fide markers of prostate cancer susceptibility and possibly more aggressive disease. Other prostate cancer risk alleles are associated with prostate specific antigen and increased prostate or decreased tumor volume, suggesting detection bias due to their phenotypic influence.

Hydroxyl radical formation in the gas phase oxidation of distonic 2-methylphenyl radical cations.

The reactions of distonic 4-(N,N,N-trimethylammonium)-2-methylphenyl and 5-(N,N,N-trimethylammonium)-2-methylphenyl radical cations (m/z 149) with O2 are studied in the gas phase using ion-trap mass spectrometry. Photodissociation (PD) of halogenated precursors gives rise to the target distonic charge-tagged methylphenyl radical whereas collision-induced dissociation (CID) is found to produce unreactive radical ions. The PD generated distonic radicals, however, react rapidly with O2 to form [M + O2]˙(+) and [M + O2- OH]˙(+) ions, detected at m/z 181 and m/z 164, respectively. Quantum chemical calculations using G3SX(MP3) and M06-2X theories are deployed to examine key decomposition pathways of the 5-(N,N,N-trimethylammonium)-2-methylphenylperoxyl radical and rationalise the observed product ions. The prevailing product mechanism involves a 1,5-H shift in the peroxyl radical forming a QOOH-type intermediate that subsequently eliminates ˙OH to yield charge-tagged 2-quinone methide. Our study suggests that the analogous process should occur for the neutral methylphenyl + O2 reaction, thus serving as a plausible source of ˙OH radicals in combustion environments.

Seroprevalence and risk factors for Toxocara infection in children from an urban large setting in Northeast Brazil.

OBJECTIVES: This study aimed to standardize an "in house" immunoassay to detect anti-Toxocara IgG antibodies in human serum to estimate the seroprevalence of Toxocara infection, and to identify its potential risk factors in children living in poor areas of Salvador, a large northeastern Brazilian city. METHODS: Parents of 1309 children answered a questionnaire containing possible risk factor for acquisition of this infection. Blood was collected and the presence of anti-Toxocara IgG antibodies was detected by indirect ELISA using T. canis larval excretory-secretory antigens in sera previously absorbed with Ascaris lumbricoides antigens. RESULTS: Seroprevalence of Toxocara infection was 48.4%. Children's age, low maternal schooling, contact with dogs and cats, and household located in paved streets were shown to be risk factors for Toxocara infection. CONCLUSIONS: The seroprevalence of Toxocara infection is high among children living in a poor urban setting of Brazil. The association of low maternal education with higher Toxocara infection supports studies showing that low socioeconomic status is a risk factor for the acquisition of this infection as a reflection of hygiene habits of the family. And both infected-dogs and cats may be involved in this parasite transmission in this children population.

Personalized prostate specific antigen testing using genetic variants may reduce unnecessary prostate biopsies.

PURPOSE: Recent studies have identified genetic variants associated with increased serum prostate specific antigen concentrations and prostate cancer risk, raising the possibility of diagnostic bias. By correcting for the effects of these variants on prostate specific antigen, it may be possible to create a personalized prostate specific antigen cutoff to more accurately identify individuals for whom biopsy is recommended. Therefore, we determined how many men would continue to meet common biopsy criteria after genetic correction of their measured prostate specific antigen concentrations. MATERIALS AND METHODS: The genotypes of 4 single nucleotide polymorphisms previously associated with serum prostate specific antigen levels (rs2736098, rs10788160, rs11067228 and rs17632542) were determined in 964 healthy Caucasian volunteers without prostate cancer. Genetic correction of prostate specific antigen was performed by dividing an individual's prostate specific antigen value by his combined genetic risk. Analyses were used to compare the percentage of men who would meet commonly used biopsy thresholds (2.5 ng/ml or greater, or 4.0 ng/ml or greater) before and after genetic correction. RESULTS: Genetic correction of serum prostate specific antigen results was associated with a significantly decreased percentage of men meeting biopsy thresholds. Genetic correction could lead to a 15% or 20% relative reduction in the total number of biopsies using a biopsy threshold of 2.5 ng/ml or greater, or 4.0 ng/ml or greater, respectively. In addition, genetic correction could result in an 18% to 22% reduction in the number of potentially unnecessary biopsies and a 3% decrease in potentially delayed diagnoses. CONCLUSIONS: Our results suggest that 4 single nucleotide polymorphisms can be used to adjust a man's measured prostate specific antigen concentration and potentially delay or prevent unnecessary prostate biopsies in Caucasian men.

A community engagement process for families with children with disabilities: lessons in leadership and policy.

This article examines a community engagement process developed as part of leadership training for clinical trainees in the Oregon Leadership Education for Neurodevelopmental and Related Disabilities (LEND) Program in a complex community with diverse families who have children with disabilities. The goal is to examine the process and lessons learned for clinical trainees and their mentors from such a process. This is a case study conducted as community-engaged action research by participant-observers involved in the Cornelius community for the past 4 years. The authors include faculty members and clinical trainees of the Oregon LEND Program at the Oregon Health & Science University, families with children with disabilities in the community, and city officials. It is a critical case study in that it studied a community engagement process in one of the poorest communities in the region, with an unusually high population of children with disabilities, and in a community that is over half Latino residents. Lessons learned here can be helpful in a variety of settings. Community engagement forum, community engagement processes, a debriefing using a seven-element feasibility framework, and trainee evaluations are key elements. A community engagement forum is a meeting to which community members and stakeholders from pertinent agencies are invited. Community engagement processes used include a steering committee made up of, and guided by community members which meets on a regular basis to prioritize and carry out responses to problems. Trainee evaluations are based on a set of questions to trigger open-ended responses. Lessons learned are based on assessments of initial and long-term outcomes of the community engagement processes in which families, community members, local officials and LEND trainees and faculty participate as well as by trainee participant-observations, end of year evaluations and trainee debriefings at the time of the initial community assessment forum. The thesis that emerges is that community engagement processes can afford significant opportunities for clinicians in training to develop their leadership skills toward improving maternal and child health for minority families with children with disabilities while building capacity in families for advocacy and facilitating change in the community.

Outcomes in patients with Gleason score 8-10 prostate cancer: relation to preoperative PSA level.

UNLABELLED: Study Type - Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? High-grade prostate cancers are associated with poor disease-specific outcomes. A proportion of these tumours produce little PSA. This study demonstrates that among Gleason 8-10 prostate cancers, some of the worst survival outcomes are associated with the lowest PSA levels. OBJECTIVE: • To assess outcomes of patients with Gleason score 8-10 prostate cancer (CaP) with a low (≤ 2.5 ng/mL) vs higher preoperative serum PSA levels. PATIENTS AND METHODS: • From 1983 to 2003, 5544 patients underwent open radical prostatectomy, of whom 354 had a Gleason 8-10 tumour in the prostatectomy specimen. • Patients were stratified according to preoperative PSA level into four strata: ≤ 2.5 ng/mL (n= 31), 2.6-4 ng/mL (n= 31), 4.1-10 ng/mL (n= 174), and >10 ng/mL (n= 118). • We compared biochemical progression-free survival (PFS), metastasis-free survival (MFS), and cancer-specific survival (CSS) as a function of preoperative PSA level. RESULTS: • Patients with PSA level ≤ 2.5 ng/mL were more likely to have seminal vesicle invasion (P= 0.003). • On Kaplan-Meier survival analysis, patients with a PSA level ≤ 2.5 ng/mL had proportionately worse outcomes than their counterparts with higher PSA levels. • The 7-year PFS in the PSA ≤ 2.5 ng/mL stratum was lower than those of the PSA 2.6-4 ng/mL and 4-10 ng/mL strata (36% vs 50 and 42%, respectively); however, the lowest 7-year PFS was found in those with a PSA level >10 ng/mL (32%, P= 0.02). • Gleason score 8-10 tumours with a PSA level ≤ 2.5 ng/mL also tended to have the lowest 7-year MFS (75, 93, 89 and 92% for PSA level ≤ 2.5, 2.6-4, 4.1-10 and >10 ng/mL, respectively, P= 0.2) and CSS (81, 100, 94 and 90% for PSA level ≤ 2.5, 2.6-4, 4.1-10 and >10 ng/mL, respectively, P= 0.3), although these differences were not statistically significant. • In the subset with palpable disease, Gleason grade 8-10 disease with PSA level ≤ 2.5 ng/mL also was associated with a worse prognosis. CONCLUSIONS: • In patients with Gleason grade 8-10 disease, a proportion of these tumours are so poorly differentiated that they produce relatively little PSA. • Patients with high-grade, low-PSA tumours had less favourable outcomes than many of those with higher PSA levels.

Association of prostate cancer risk alleles with unfavourable pathological characteristics in potential candidates for active surveillance.

OBJECTIVE: • To assess whether the carrier status of 35 risk alleles for prostate cancer (CaP) is associated with having unfavourable pathological features in the radical prostatectomy specimen in men with clinically low risk CaP who fulfil commonly accepted criteria as candidates for active surveillance. PATIENTS AND METHODS: • We studied men of European ancestry with CaP who fulfilled the commonly accepted clinical criteria for active surveillance (T1c, prostate-specific antigen <10 ng/mL, biopsy Gleason ≤6, three or fewer positive cores, ≤50% tumour involvement/core) but instead underwent early radical prostatectomy. • We genotyped these men for 35 CaP risk alleles. We defined 'unfavourable' pathological characteristics to be Gleason ≥7 and/or ≥ pT2b in their radical prostatectomy specimen. RESULTS: • In all, 263 men (median age 60 [46-72] years) fulfilled our selection criteria for active surveillance, and 58 of 263 (22.1%) were found to have 'unfavourable' pathological characteristics. • The frequencies of three CaP risk alleles (rs1447295 [8q24], P= 0.004; rs1571801 [9q33.2], P= 0.03; rs11228565 [11q13], P= 0.02) were significantly higher in men with 'unfavourable' pathological characteristics. • Two other risk alleles were proportionately more frequent (rs10934853 [3q21], P= 0.06; rs1859962 [17q24], P= 0.07) but did not achieve nominal statistical significance. • Carriers of any one of the significantly over-represented risk alleles had twice the likelihood of unfavourable tumour features (P= 0.03), and carriers of any two had a sevenfold increased likelihood (P= 0.001). • Receiver-operator curve analysis demonstrated an area under the curve of 0.66, suggesting that the number of single nucleotide polymorphisms carried provided discrimination between men with 'favourable' and 'unfavourable' tumour features in their prostatectomy specimen. CONCLUSION: • In potential candidates for active surveillance, certain CaP risk alleles are more prevalent in patients with 'unfavourable' pathological characteristics in their radical prostatectomy specimen.

Prostate cancer risk alleles and their associations with other malignancies.

OBJECTIVE: To determine whether certain risk alleles are responsible for the relationship between prostate cancer (CaP) and other malignancies. CaP has been associated with other common malignancies. Recently, numerous single nucleotide polymorphisms (SNPs) have been associated with CaP susceptibility. METHODS: We genotyped 1121 patients with CaP for 36 risk alleles known to be significantly associated with CaP susceptibility and determined their relationships to other malignancies in CaP probands and their first-degree relatives. RESULTS: The most common other malignancies in the CaP probands were nonmelanoma skin cancer (13.6%), leukemia (7.3%), melanoma (3.9%), non-Hodgkin's lymphoma (0.7%), colorectal cancer (0.6%), and multiple myeloma (0.3%). Among the probands, a significantly increased frequency of leukemia was found in the carriers of SNP rs2736098 (5p15, P = .03) and melanoma in the carriers of either SNP rs1512268 (8p21, P = .006) or SNP rs5759167 (22q13, P = .02). Multiple myeloma was more common in carriers of SNP rs9364554 (6q25, P = .02). The probands who were carriers of SNP rs16901979 (8q24) were significantly more likely to report a family history of melanoma (P = .03), and the probands with a family history of multiple myeloma and non-Hodgkin's disease were significantly more likely to be carriers of SNP rs12621278 (2q31, P = .04) and rs6465657 (7q21, P = .02), respectively. CONCLUSION: Certain alleles associated with CaP susceptibility might be associated with an increased or a decreased risk of other malignancies in CaP probands and their first-degree relatives. Additional studies are warranted to examine the underlying mechanisms of these SNPs in CaP and other malignancies.

Chronic virus infections supress atopy but not asthma in a set of children from a large Latin American city: a cross-section study.

BACKGROUND: The prevalence of allergic diseases has increased over recent decades in affluent countries, but remains low in rural populations and some non-affluent countries. An explanation for these trends is that increased exposure to infections may provide protection against the development of allergy. In this work we investigated the association between exposure to viral infections in children living in urban Brazil and the prevalence of atopy and asthma. METHODS: School age children living in poor neighborhoods in the city of Salvador were studied. Data on asthma symptoms and relevant risk factors were obtained by questionnaire. Skin prick tests (SPTs) were performed to seven aeroallergens, and specific IgE was measured to four of these. Viral infections were determined by the presence of specific IgG in serum to Herpes simplex (HSV), Herpes zoster (HZV), Epstein-Barr (EBV), and Hepatitis A (HAV) viruses. RESULTS: A total of 644 (49.7%) children had at least one allergen-specific IgE> 0.35 kU/L and 489 (37.7%) had specific IgE> 0.70 kU/L. A total of 391 (30.2%) children were skin test positive (SPT+), and 295 (22.8%) children were asthmatic. The seroprevalence of viral infections was 88.9% for EBV, 55.4% for HSV, 45.5% for VZV and 17.5% for HAV. Negative associations were observed between SPT+ and HSV (OR = 0.64, CI = 0.51, 0.82) and EBV (OR = 0.63, CI = 0.44, 0.89) infections, but no associations were seen between viral infections and the presence of allergen-specific IgE or asthma. CONCLUSION: These data do not support previous data showing a protective effect of HAV against atopy, but did show inverse associations between SPT+ (but not specific IgE+) and infections with HSV and EBV. These findings suggest that different viral infections may protect against SPT+ in different settings and may indicate an immunoregulatory role of such infections on immediate hypersensitivity responses. The data provide no support for a protective effect of viral infections against asthma in this population.