Statin Concentration in Prostatic Tissue is Subtype- and Dose-dependent.

OBJECTIVE: To evaluate for the first time, comparative serum and prostate tissue concentrations of lipophilic and hydrophilic statins. METHODS: After reviewing all patients who underwent radical prostatectomy between 1993 and 2019, we selected 80 patients taking atorvastatin (lipophilic) or rosuvastatin (hydrophilic) for cholesterol control and with available banked fresh-frozen tissue from the prostatectomy. Primary endpoint was serum and prostate statin concentration measured by HPLC-mass spectrometry analysis. Serum/prostate statin concentrations were compared between patients on atorvastatin and rosuvastatin, and patients receiving high- and low-dose statin, using the Mann-Whitney U test. RESULTS: In total, 39 patients were taking atorvastatin and 41 were taking rosuvastatin. Thirty-eight and 42 were taking high- and low-dose statin, respectively. Statin concentration was measurable in the prostatic tissue of 15 patients (38.4%) taking atorvastatin (33.3% high-dose vs 42.8% low-dose) compared to 22 (53.6%) taking rosuvastatin (55% high-dose vs 52.3% low-dose). Median tissue concentration of rosuvastatin was greater than atorvastatin (3.98 ng/g vs 0.96 ng/g, P <.001). Dose-dependency was observed: median prostate concentration was higher in those taking high-dose versus low-dose statin for both atorvastatin (1.22 ng/g vs 0.79 ng/g, P = .69) and rosuvastatin (5.21 ng/g vs 1.99 ng/g, P <.001). CONCLUSION: We have shown, for the first time, that lipophilic and hydrophilic statins can be measured in the prostate of patients with prostate cancer and that the concentrations are dependent on dose. Moreover, rosuvastatin, a hydrophilic statin, achieves a 4-fold higher concentration in the prostate.

Testicular Germ Cell Tumors with Venous Tumor Thrombus: Prevalence, Presentation, and Management.

BACKGROUND AND OBJECTIVE: There are limited data on the prevalence and management of testicular germ cell tumor (TGCT) cases presenting with venous tumor thrombus (VTT). Our objectives were to describe the prevalence of TGCT with VTT, to identify a multicenter retrospective cohort, and to ascertain expert opinion regarding optimal management of this entity. METHODS: Using the IBM Marketscan database, we identified men with testicular cancer who underwent retroperitoneal lymph node dissection (RPLND) with concurrent VTT or inferior vena cava (IVC) tumor thrombectomy to estimate the prevalence of VTT in TGCT. To identify a multicenter retrospective cohort of patients, we surveyed surgeons and described the presentation, management, and outcomes for the cohort. KEY FINDINGS AND LIMITATIONS: The prevalence of TGCT with VTT in the IBM Marketscan database was 0.3% (n = 7/2517) when using stringent criteria and 3.1% (n = 79/2517) when using broad criteria. In response to our survey, 16 surgeons from ten centers contributed data for 34 patients. Most patients (n = 29, 85%) presented with nonseminomatous germ cell tumor. Surgical management was used for 93.9% (n = 31), including postchemotherapy tumor thrombectomy with primary cavorrhaphy in 63%. The Marketscan analysis was limited to insured individuals and did not include clinicopathological details, and use of billing codes may have included patients with stromal tumors. In addition, lack of responses to the anonymous survey limited data capture, and the RedCap survey did not address symptoms specific to IVC obstruction or allow central review of the imaging leading to VTT diagnosis. CONCLUSIONS AND CLINICAL IMPLICATIONS: VTT among males with TGCT is rare and requires complex multidisciplinary management, including venous tumor thrombectomy at the time of postchemotherapy RPLND. PATIENT SUMMARY: Using a medical database, we estimated that the frequency of testicular cancer cases in which the tumor extends into a blood vessel (called venous tumor thrombus, VTT) is just 0.3-3.1%. We carried out a survey of surgeons with experience of this condition. Our results indicate that although testicular cancers respond well to chemotherapy, VTT is less responsive and complex surgery is necessary for this rare condition.

Cognitive function in long-term testicular cancer survivors: Impact of modifiable factors.

No study has comprehensively examined associated factors (adverse health outcomes, health behaviors, and demographics) impacting cognitive function in long-term testicular cancer survivors (TC-survivors). TC-survivors given cisplatin-based chemotherapy completed comprehensive, validated surveys, including those which assessed cognition. Medical record abstraction provided cancer and treatment history. Multivariable logistic regression examined relationships between potential associated factors and cognitive impairment. Among 678 TC-survivors [median age: 46 (IQR: 38, 54); median time-since-chemotherapy: 10.9 years (IQR = 7.9, 15.9)], 13.7% reported cognitive dysfunction. Hearing loss (OR = 2.02; P = .040), neuropathic-pain (OR = 2.06; P = .028), fatigue (OR = 6.11; P<.001), and anxiety/depression (OR = 1.96; P = .029) were associated with cognitive impairment in multivariable analyses. Being on disability (OR = 9.57; P = .002) or retired (OR = 3.64; P = .029) were also associated with cognitive declines. Factors associated with impaired cognition identify TC-survivors requiring closer monitoring, counseling, and focused interventions. Hearing loss, neuropathic-pain, fatigue, and anxiety/depression constitute potential targets for prevention or reduction of cognitive impairment in long-term TC-survivors.

Venom Component Allergen IgE Measurement in the Diagnosis and Management of Insect Sting Allergy.

Accurate identification of allergy-eliciting stinging insect(s) is essential to ensuring effective management of Hymenoptera venom-allergic individuals with venom-specific immunotherapy. Diagnostic testing using whole-venom extracts with skin tests and serologic-based analyses remains the first level of discrimination for honeybee versus vespid venom sensitization in patients with a positive clinical history. As a second-level evaluation, serologic testing using molecular venom allergens can further discriminate genuine sensitization (honeybee venom: Api m 1, 3, 4, and 10 vs yellow jacket venom/Polistes dominula venom Ves v 1/Pol d 1 and Ves v 5/Pol d 5) from interspecies cross-reactivity (hyaluronidases [Api m 2, Ves v 2, and Pol d 2] and dipeptidyl peptidases IV [Api m 5, Ves v 3, and Pol d 3]). Clinical laboratories use a number of singleplex, oligoplex, and multiplex immunoassays that employ both extracted whole-venom and molecular venom allergens (highlighted earlier) for confirmation of allergic venom sensitization. Established quantitative singleplex autoanalyzers have general governmental regulatory clearance worldwide for venom-allergic patient testing with maximally achievable analytical sensitivity (0.1 kUA/L) and confirmed reproducibility (interassay coefficient of variation <10%). Emerging oligoplex and multiplex (fixed-panel) assays conserve on serum and are more cost-effective, but they need regulatory clearance in some countries and are prone to higher rates of detecting asymptomatic sensitization. Ultimately, the patient's clinical history, combined with proof of sensitization, is the final arbiter in the diagnosis of Hymenoptera venom allergy.

Lymph node density as a prognostic marker of relapse in patients who underwent primary retroperitoneal lymph node dissection.

INTRODUCTION: Primary retroperitoneal lymph node dissection (pRPLND) is a treatment option for clinical stage (CS) II testicular germ cell tumors (TGCTs) and CS I with retroperitoneal relapse. Increasing raw lymph node yield during pRPLND has been associated a decreased relapse risk. However, this metric has limitations due to variations in surgical templates and specimen processing methods. We aimed to evaluate the lymph node density (LND), which is the ratio of positive lymph nodes to the total number of nodes removed, as a prognostic marker for relapse after pRPLND. METHODS: We reviewed all patients who underwent pRPLND at the Princess Margaret Cancer Centre between 1990 and 2022. The primary endpoint was relapse-free survival (RFS). RFS was calculated using the Kaplan-Meier product-limit method. The log-rank test was used to assess the impact of LND, and recursive binary partitioning was used to determine the threshold LND that provides optimum separation in RFS. RESULTS: In this study, 178 patients were treated with pRPLND. A total of 137 (77%) patients had pathological evidence of nodal metastasis, 96 were treated with open RPLND, and 41 with robotic RPLND. The median number of lymph nodes harvested was 32 (IQR 23-43) and median total positive nodes was 2 (IQR 1-36). This translated into a median LND of 3.1% (IQR 1.7-57.1). There was no significant difference in the LND between robotic and open approaches (P = 0.6664). After a median follow-up of 38.6 months, 11 patients (8.02%) had relapsed. LND was not significantly associated with relapse (HR 1.018, 95% CI, 0.977-1.061). The optimal threshold to dichotomize LND that provides optimum separation in RFS was ≥ 26.75%, however, it did not reach statistical significance (P = 0.0651). CONCLUSION: In conclusion, the LND was not associated with RFS after pRPLND in patients with TGCTs. The unique characteristics of TGCTs and the presence of other established risk factors limit the utility of the LND alone in predicting relapse.

5-α Reductase Inhibitors and Prostate Cancer Mortality.

Importance: 5-alpha-reductase-inhibitors (5-ARIs) are approved for treating benign prostatic hyperplasia (BPH) and have been found to reduce prostate cancer (PCa) risk by 25%. However, trials also have shown 5-ARIs to be associated with high-grade PCa. Whether 5-ARIs increase mortality among those with a diagnosis of PCa remains unclear. Objective: To determine long-term outcomes of clinically localized PCa arising in individuals taking 5-ARIs compared with nonusers. Design, Setting, and Participants: This population-based cohort study was conducted between January 2003 and October 2017. Eligible participants were men aged 65 years or older in Ontario, Canada, who developed clinically localized PCa with complete pathological abstraction from the Ontario Health Administrative Databases. Data analysis occurred from November 2017 to November 2022. Exposure: 5-ARIs before PCa diagnosis. Main Outcomes and Measures: The primary outcomes were overall mortality and PCa-specific mortality. Cause-specific hazard models with inverse probability treatment weights (IPTW) were used to examine associations of 5-ARI use with mortality outcomes. Sensitivity analyses based on prediagnostic 5-ARI use, Gleason score, comorbidity, 5-ARI indication, prostate-specific antigen modeling, and statin use were also performed. Results: The cohort included 19 938 patients with PCa. Of these, 2112 (10.6%; median [IQR] age, 74 [70-79] years) were 5-ARI users and 17 826 (89.4%; median [IQR] age, 71 [68-76] years) were nonusers. During a median (IQR) follow-up of 8.96 (6.28-12.17) years, 6053 (30.4%) died, including 1047 (5.3%) from PCa. 5-ARI use appeared to be associated with increased overall and PCa specific mortality in crude analyses; however, after IPTW, 5-ARI use was not associated with overall mortality (hazard ratio, 0.98; 95% CI, 0.90-1.07; P = .77) or PCa-specific mortality (hazard ratio, 1.02; 95% CI, 0.83-1.25; P = .84). Conclusions and Relevance: In this population-based cohort study of 5-ARI use prior to PCa diagnosis including long-term follow-up and clinicopathologic details, prediagnostic 5-ARI use was not associated with PCa-specific or all-cause mortality. This study offers reassuring safety data for patients using 5-ARIs before PCa diagnosis for both BPH and chemopreventive reasons.

A human monoclonal antibody based immunoenzymetric assay to measure Fel d 1 concentrations in cat hair and pelt allergenic extracts.

In the United States, 19 allergen extracts of different specificities are standardized, which means that their potencies are determined in comparison to a US reference standard. For cat allergen extracts, potency is determined by measuring Fel d 1 content expressed in in Fel d 1 units, and with a unitage that correlates with skin test reactions (bioequivalent allergy units or BAU). Currently, Fel d 1 content is measured with a radial immunodiffusion (RID) assay that uses polyclonal sheep antisera to detect the allergenic protein by producing a white precipitin line in agar gel. However, the RID is considered cumbersome, and the polyclonal sera may qualitatively vary among animals and may recognize epitopes irrelevant to human allergic disease. In this report, we describe a quantitative two-site immunoenzymetric assay (IEMA) for Fel d 1 that uses immobilized capture and soluble biotin-labeled detection Fel d 1-specific human IgE monoclonal antibodies (mAb) that have been class-switched to IgG4. Together, they sandwich Fel d 1 molecules from extracts. Using purified natural Fel d 1 as a calibrator, the historically reported ∼4 micrograms Fel d 1/Fel d 1 unit assignment was directly measured in this mAb-based IEMA at 3.12 ± 0.24 micrograms of Fel d 1 per Fel d 1 unit. This IEMA appears to be equivalent to RID in the measurement of biological potencies of commercial cat hair and cat pelt extracts marketed in the United States.

Primary retroperitoneal lymph node dissection for metastatic non-seminomatous germ cell tumours: outcomes and adjuvant chemotherapy.

OBJECTIVES: To compare the outcomes and treatment burden of primary retroperitoneal lymph node dissection (pRPLND) alone versus pRPLND + adjuvant chemotherapy (AC) in patients with pathological stage II (PSII) non-seminomatous germ cell tumours (NSGCT). PATIENTS AND METHODS: Retrospective review of the Princess Margaret Cancer Center eTestes cancer database identified patients with PSII NSGCT after pRPLND between 1995 and 2020. The primary outcome was relapse-free survival (RFS). Secondary outcomes included disease-specific survival (DSS), burden of relapse treatment, and factors associated with relapse. RESULTS: A total of 109 PSII patients were included in the study. There were 96 patients treated with pRPLND alone and 13 treated with pRPLND + AC. The median follow-up was 61 months. The 5-year RFS was 72% for the pRPLND-only group vs 92% for the pRPLND + AC group (hazard ratio [HR] 4.372, 95% confidence interval [CI] 0.59-32.36; P = 0.11). Within the pRPLND-only group the 5-year RFS differed by pN stage (pN1 = 94% vs pN2/N3 = 67%, P = 0.03). Despite a higher relapse rate within the pRPLND-only group, the DSS was similar at 5 years (98% pRPLND only vs 100% pRPLND + AC, P = 0.48). Only 24 (25%) of the patients in the pRPLND-only group required any subsequent chemotherapy. Despite achieving similar survival, the cumulative post-RPLND treatment burden was less for the pRPLND-only group than the pRPLND+AC group overall (average 1.23 vs 2.46 cycles of chemotherapy per patient in group). CONCLUSION: The majority of patients with PSII NSGCT treated with pRPLND alone do not experience a recurrence or require chemotherapy. Despite a lower relapse risk when AC is given, no difference in survival was seen but higher chemotherapy burden was entertained. AC may constitute overtreatment for most patients with PSII NSGCT treated with pRPLND.

Preclinical efficacy of peanut-specific IgG4 antibody therapeutic IGNX001.

BACKGROUND: Existing therapeutic strategies are challenged by long times to achieve effect and often require frequent administration. Peanut-allergic individuals would benefit from a therapeutic that provides rapid protection against accidental exposure within days of administration while carrying little risk of adverse reactions. OBJECTIVE: Guided by the repertoire of human IgE mAbs from allergic individuals, we sought to develop a treatment approach leveraging the known protective effects of allergen-specific IgG4 antibodies. METHODS: We applied our single-cell RNA-sequencing SEQ SIFTER platform (IgGenix, Inc, South San Francisco, Calif) to whole blood samples from peanut-allergic individuals to discover IgE mAbs. These were then class-switched by replacing the IgE constant region with IgG4 while retaining the allergen-specific variable regions. In vitro mast cell activation tests, basophil activation tests, ELISAs, and an in vivo peanut allergy mouse model were used to evaluate the specificity, affinity, and activity of these recombinant IgG4 mAbs. RESULTS: We determined that human peanut-specific IgE mAbs predominantly target immunodominant epitopes on Ara h 2 and Ara h 6 and that recombinant IgG4 mAbs effectively block these epitopes. IGNX001, a mixture of 2 such high-affinity IgG4 mAbs, provided robust protection against peanut-mediated mast cell activation in vitro as well as against anaphylaxis upon intragastric peanut challenge in a peanut allergy mouse model. CONCLUSIONS: We developed a peanut-specific IgG4 antibody therapeutic with convincing preclinical efficacy starting from a large repertoire of human IgE mAbs from demographically and geographically diverse individuals. These results warrant further clinical investigation of IGNX001 and underscore the opportunity for the application of this therapeutic development strategy in other food and environmental allergies.

Cardiovascular Outcomes in Fontan Patients With Right vs Left Univentricular Morphology: A Multicenter Study.

Background: There is a paucity of data on long-term outcomes after Fontan palliation in patients with a dominant morphological univentricular right (uRV) vs left (uLV) ventricle. Objectives: The purpose of this study was to compare the incidence of atrial arrhythmias, thromboembolic events, cardiac transplantation, and death following Fontan palliation in patients with uRV vs uLV. Methods: The Alliance for Adult Research in Congenital Cardiology conducted a multicenter retrospective cohort study on patients with total cavopulmonary connection Fontan palliation across 12 centers in North America. All components of the composite outcome, that is, atrial arrhythmias, thromboembolic events, cardiac transplantation, and death, were reviewed and classified by a blinded adjudicating committee. Time-to-event analyses were performed that accounted for competing risks. Results: A total of 384 patients were followed for 10.5 ± 5.9 years. The composite outcome occurred in 3.7 vs 1.7 cases per 100 person-years for uRV (N = 171) vs uLV (N = 213), respectively (P < 0.001). In multivariable analyses, uRV conferred a >2-fold higher risk of the composite outcome (HR: 2.17, 95% CI: 1.45-3.45, P < 0.001). In secondary analyses of components of the primary outcome, uRV was significantly associated with a greater risk of cardiac transplantation or death (HR: 9.09, 95% CI: 2.17-38.46, P < 0.001) and atrial arrhythmias (HR: 2.17, 95% CI: 1.20-4.00, P = 0.010) but not thromboembolic events (HR: 1.64, 95% CI: 0.86-3.16, P = 0.131). Conclusions: Fontan patients with uRV vs uLV morphology have a higher incidence of adverse cardiovascular events, including atrial arrhythmia, cardiac transplantation, and all-cause mortality.

MicroRNA for Prediction of Teratoma and Viable Germ Cell Tumor after Chemotherapy.

MicroRNAs (miRNAs) are emerging as highly sensitive and specific markers for testicular germ cell tumors (GCTs) across the spectrum of disease. However, their utility in specific clinical scenarios requires further study. Here, we review the current evidence for miRNAs as tumor markers for the evaluation of treatment response in patients undergoing chemotherapy for the treatment of advanced testicular GCT.

Sterol-like drugs potentiate statin-triggered prostate cancer cell death by inhibiting SREBP2 nuclear translocation.

There is an urgent need to provide immediate and effective options for the treatment of prostate cancer (PCa) to prevent progression to lethal castration-resistant PCa (CRPC). The mevalonate (MVA) pathway is dysregulated in PCa, and statin drugs commonly prescribed for hypercholesterolemia, effectively target this pathway. Statins exhibit anti-PCa activity, however the resulting intracellular depletion of cholesterol triggers a feedback loop that restores MVA pathway activity, thus diminishing statin efficacy and contributing to resistance. To identify drugs that block this feedback response and enhance the pro-apoptotic activity of statins, we performed a high-content image-based screen of a 1508 drug library, enriched for FDA-approved compounds. Two of the validated hits, Galeterone (GAL) and Quinestrol, share the cholesterol-related tetracyclic structure, which is also evident in the FDA-approved CRPC drug Abiraterone (ABI). Molecular modeling revealed that GAL, Quinestrol and ABI not only share structural similarity with 25-hydroxy-cholesterol (25HC) but were also predicted to bind similarly to a known protein-binding site of 25HC. This suggested GAL, Quinestrol and ABI are sterol-mimetics and thereby inhibit the statin-induced feedback response. Cell-based assays demonstrated that these agents inhibit nuclear translocation of sterol-regulatory element binding protein 2 (SREBP2) and the transcription of MVA genes. Sensitivity was independent of androgen status and the Fluva-GAL combination significantly impeded CRPC tumor xenograft growth. By identifying cholesterol-mimetic drugs that inhibit SREBP2 activation upon statin treatment, we provide a potent "one-two punch" against CRPC progression and pave the way for innovative therapeutic strategies to combat additional diseases whose etiology is associated with SREBP2 dysregulation.

Cardiac arrhythmia and epilepsy genetic variants in sudden unexpected death in epilepsy.

Introduction: Sudden Unexpected Death in Epilepsy (SUDEP) is the leading epilepsy-related cause of death, affecting approximately 1 per 1,000 individuals with epilepsy per year. Genetic variants that affect autonomic function, such as genes associated with cardiac arrhythmias, may predispose people with epilepsy to greater risk of both sudden cardiac death and SUDEP. Advances in next generation sequencing allow for the exploration of gene variants as potential biomarkers. Methods: Genetic testing for the presence of cardiac arrhythmia and epilepsy gene variants was performed via genetic panels in 39 cases of SUDEP identified via autopsy by the Ontario Forensic Pathology Service. Variants were summarized by in-silico evidence for pathogenicity from 4 algorithms (SIFT, PolyPhen-2, PROVEAN, Mutation Taster) and allele frequencies in the general population (GnomAD). A maximum credible population allele frequency of 0.00004 was calculated based on epilepsy prevalence and SUDEP incidence to assess whether a variant was compatible with a pathogenic interpretation. Results: Median age at the time of death was 33.3 years (range: 2, 60). Fifty-nine percent (n=23) were male. Gene panels detected 62 unique variants in 45 genes: 19 on the arrhythmia panel and 26 on the epilepsy panel. At least one variant was identified in 28 (72%) of decedents. Missense mutations comprised 57 (92%) of the observed variants. At least three in silico models predicted 12 (46%) cardiac arrhythmia panel missense variants and 20 (65%) epilepsy panel missense variants were pathogenic. Population allele frequencies were <0.00004 for 11 (42%) of the cardiac variants and 10 (32%) of the epilepsy variants. Together, these metrics identified 13 SUDEP variants of interest. Discussion: Nearly three-quarters of decedents in this SUDEP cohort carried variants in comprehensive epilepsy or cardiac arrhythmia gene panels, with more than a third having variants in both panels. The proportion of decedents with cardiac variants aligns with recent studies of the disproportionate cardiac burden the epilepsy community faces compared to the general population and suggests a possible cardiac contribution to epilepsy mortality. These results identified 13 priority targets for future functional studies of these genes potential role in sudden death and demonstrates the necessity for further exploration of potential genetic contributions to SUDEP.

Reduced kinase function in two ultra-rare TNNI3K variants in families with congenital junctional ectopic tachycardia.

Genetic missense variants in TNNI3K, encoding troponin-I interacting kinase, have been associated with dilated cardiomyopathy (DCM) and observed in families with supraventricular tachycardias (SVT). Previously, a family harboring the TNNI3K-c.1615A > G (p.Thr539Ala) variant presented with congenital junctional ectopic tachycardia (CJET), an arrhythmia that arises from the atrioventricular (AV) node and His bundle. However, this was a relatively small four-generational family with limited genetic testing (N = 3). We here describe a multigenerational family with CJET harboring a novel ultra-rare TNNI3K variant: TNNI3K-c.1729C > T (p.Leu577Phe). Of all 18 variant carriers, 13 individuals presented with CJET, resulting in a genetic penetrance of 72%. In addition, CJET is reported in another small family harboring TNNI3K-c.2225C > T (p.Pro742Leu). Similar to the previously published CJET family, both TNNI3K variants demonstrate a substantial reduction of kinase activity. Our study contributes novel evidence supporting the involvement of TNNI3K genetic variants as significant contributors to CJET, shedding light on potential mechanisms underlying this cardiac arrhythmia.

Addressing controversial areas in the management of advanced prostate cancer in Canada Areas of consensus and controversy from the third Canadian consensus forum.

INTRODUCTION: The management of prostate cancer (PCa) is rapidly evolving. Treatment and diagnostic options grow annually, however, high-level evidence for the use of new therapeutics and diagnostics is lacking. In November 2022, the Genitourinary Research Consortium held its 3rd Canadian Consensus Forum (CCF3) to provide guidance on key controversial areas for management of PCa. METHODS: A steering committee of eight multidisciplinary physicians identified topics for discussion and adapted questions from the Advanced Prostate Cancer Consensus Conference 2022 for CCF3. Questions focused on management of metastatic castration-sensitive prostate cancer (mCSPC); use of novel imaging, germline testing, and genomic profiling; and areas of non-consensus from CCF2. Fifty-eight questions were voted on during a live forum, with threshold for "consensus agreement" set at 75%. RESULTS: The voting panel consisted of 26 physicians: 13 urologists/uro-oncologists, nine medical oncologists, and four radiation oncologists. Consensus was reached for 32 of 58 questions (one ad-hoc). Consensus was seen in the use of local treatment, to not use metastasis-directed therapy for low-volume mCSPC, and to use triplet therapy for synchronous high-volume mCSPC (low prostate-specific antigen). Consensus was also reached on sufficiency of conventional imaging to manage disease, use of germline testing and genomic profiling for metastatic disease, and poly (ADP-ribose) polymerase (PARP) inhibitors for BRCA-positive prostate cancer. CONCLUSIONS: CCF3 identified consensus agreement and provides guidance on >30 practice scenarios related to management of PCa and nine areas of controversy, which represent opportunities for research and education to improve patient care. Consensus initiatives provide valuable guidance on areas of controversy as clinicians await high-level evidence.

Screening asthmatics for atopic status using the ALergy EXplorer (ALEX2) macroarray.

BACKGROUND: Screening asthma patients for atopy facilitates management. Since 2010, the core biomarker for screening asthma subjects for atopic status has been the qualitative Phadiatop. multi-aeroallergen screen. A more quantitative macroarray, the Allergy Explorer (ALEX2), shows promise as an alternative. OBJECTIVE: The study's goal was to examine the pros and cons of the use of ALEX2 in the screening of asthma patients for atopic status. METHODS: We evaluated the atopic (IgE-sensitization) status in asthmatic Amish and Hutterite farm children using the ImmunoCAP and ALEX2 assays in Phadiatop equivocal and positive subjects. RESULTS: All 42 asthmatic children were analyzed by Phadiatop and total serum IgE. Of these, 22 had a negative Phadiatop (<0.1 kUa/L) and total IgE <100 kU/L which defined them as non-atopic and they were excluded from ALEX2 testing. Of six children with equivocal Phadiatops (0.1-0.2 kUa/L-Group 1) and three children with a negative Phadiatop but total IgE >100 kUa/L (group 3), 44% (n = 4) had detectable IgE antibody by ALEX2 to mite, tree pollen, and other allergens not detected by Phadiatop, but confirmed by allergen-specific ImmunoCAP testing. In 11 Phadiatop positive subjects (>0.2 kUa/L-group 2), all but one were positive by ALEX2. IgE antibody specific for mold and rabbit aeroallergens matched their agricultural and pet exposure history. Three children were positive for IgE antibody to allergens in the profilin, nsLTP, or PR-10 cross-reactive protein families. CONCLUSION: Judicious use of ALEX2's enhanced specificity data not provided by the Phadiatop can aid in the interpretation of sensitization patterns and planning management of atopic asthmatics, but sensitization relevance must be confirmed by the patient's clinical history.

Impact of Fontan Fenestration on Adverse Cardiovascular Outcomes: A Multicentre Study.

BACKGROUND: Fenestrating a Fontan baffle has been associated with improved perioperative outcomes in patients with univentricular hearts. However, longer-term potential adverse effects remain debated. We sought to assess the impact of a fenestrated Fontan baffle on adverse cardiovascular events including all-cause mortality, cardiac transplantation, atrial arrhythmias, and thromboemboli. METHODS: A multicentre North American retrospective cohort study was conducted on patients with total cavopulmonary connection Fontan baffle, with and without fenestration. All components of the composite outcome were independently adjudicated. Potential static and time-varying confounders were taken into consideration, along with competing risks. RESULTS: A total of 407 patients were followed for 10.4 (7.1-14.4) years; 70.0% had fenestration of their Fontan baffle. The fenestration spontaneously closed or was deliberately sealed in 79.9% of patients a median of 2.0 years after Fontan completion. In multivariable analysis in which a persistent fenestration was modelled as a time-dependent variable, an open fenestration did not confer a higher risk of the composite outcome (hazard ratio, 1.18; 95% confidence interval, 0.71-1.97; P = 0.521). In secondary analyses, an open fenestration was not significantly associated with components of the primary outcome: that is, mortality or transplantation, atrial arrhythmias, or thromboemboli. However, sensitivity analyses to assess the possible range of error resulting from imprecise dates for spontaneous fenestration closures could not rule out significant associations between an open fenestration and atrial arrhythmias or thromboemboli. CONCLUSIONS: In this multicentre study, no significant association was identified between an open fenestration in the Fontan baffle and major adverse cardiovascular events.