Search

Background: Metastatic castration-resistant prostate cancer (mCRPC) disproportionately affects older individuals. While the molecular landscape of mCRPC is well established, less is understood about how genomic alterations differ with age. We compared cell-free DNA (cfDNA) profiles of younger (age<70) and older (age>=70) men with mCRPC and assessed the relative prognostic impact of genomic alterations between age categories. Method(s): Plasma cfDNA from 276 patients across two independent prospective cohorts (Australian, n=123; US, n=153) was sequenced using the PredicineTM cfDNA assay. Genomic alteration frequency (copy number variants and mutations) and circulating tumour DNA fraction (ctDNA%) were compared between age categories using the chi-squared and Wilcoxon rank-sum tests, respectively. Kaplan-Meier survival estimates, and Cox regression analysis were used to assess associations between age, genomic alterations, and overall survival. Result(s): Median age was 72 years (IQR 66-78), with 170 (62%) patients >=70. There was no significant difference in ctDNA% between older and younger patients (median 22% vs 30%, p=0.6). Similarly, no significant difference in alteration frequency was observed in prostate cancer driver genes, including AR (<70 vs >=70: 46% vs 49%, p=0.6), PTEN (39% vs 31%, p=0.2), BRCA2 (29% vs 21%, p=0.13) and ATM (17% vs 14%, p=0.4). The impact of established poor prognostic alterations was evident in both age categories. In an exploratory analysis, certain alterations may have a more pronounced effect in younger patients, including PIK3CA gain (HR 4.2 for <70, HR 1.9 for >=70 years; HR for interaction 2.2, p = 0.03) and MYC gain (HR 3.6 for <70, HR 2.1 for >=70 years; HR for interaction 1.8, p = 0.1). Conclusion(s): The frequency of clinically relevant genomic alterations was comparable between older and younger mCRPC patients. Screening for alterations that confer sensitivity to precision medicine therapies should be considered regardless o

Background: Androgen receptor splice variant (AR-V) expression has previously been regarded as a negative predictive biomarker for response to abiraterone and enzalutamide in mCRPC patients. However, recent data questions this association. We designed a whole blood assay to detect AR-V7 and AR-V9, the two most abundantly expressed AR-Vs, and correlated expression with clinical outcomes in patients commencing abiraterone or enzalutamide. Method(s): We developed a quantitative real-time polymerase chain reaction assay to detect AR-V7 and AR-V9 from whole blood collected in PAXgene tubes. The assay was applied to samples prospectively collected from 37 mCRPC patients prior to commencing abiraterone or enzalutamide, and at treatment cessation. Patients positive for either AR-V7 or AR-V9 were defined as AR-V-positive, and AR-V-negative if neither variant was detected. AR-V expression was correlated with PSA response rate (chi-square test) and PSA progression-free survival (PSA-PFS) (log-rank test). Assay sensitivity was determined by serially diluting RNA from VCaP prostate cancer cells (known to express AR-V7) to establish a lower limit of detection. Result(s): The median follow-up was 7.29 months (IQR 4.21-10.55); 9 of 37 patients (24%) were AR-V-positive. We observed similar response rates in AR-V-positive (6/9) and AR-V-negative (18/28) patients (66% vs. 64%, p = 0.896). PSA-PFS did not differ significantly between groups (9.2 months vs. not reached, p = 0.355). Two patients converted from AR-V-negative to AR-V-positive (PSA-PFS 3.35 and 0.60 months respectively), and one patient remained AR-V-positive at baseline and end-of-treatment sampling. The lower limit of detection for AR-V7 was 0.1%, and AR-V7/V9 was not detected in any of the 13 normal male controls. Conclusion(s): We developed a sensitive and specific whole blood assay for AR-V7 and AR-V9 detection in patients with mCRPC. Neither PSA response rates nor PSA-PFS differed significantly between AR-V-positive a

In 2014, a landmark study was published demonstrating that androgen receptor splice variant (AR-V) AR-V7 expression was a negative predictive biomarker for response to abiraterone acetate and enzalutamide in metastatic castration-resistant prostate cancer (mCRPC) patients. However, these results were not supported by the recently reported ARMOR3-SV phase III clinical trial, which employed an identical circulating tumor cell assay to assess AR-V7 expression. Therefore, the predictive utility of AR-V7 expression in mCRPC remains uncertain, as does any potential association between other AR splice variants and treatment response. To further investigate, we designed a highly sensitive and specific whole blood assay for detecting AR-V7 and AR-V9. We then examined for a correlation between baseline AR-V7/V9 status and treatment outcome in 37 mCRPC patients commencing abiraterone or enzalutamide. Blood was taken in a PAXgene RNA tube at baseline prior to the commencement of therapy and at end of treatment (if applicable). 24% (9/37) of patients were AR-V-positive. Notably, PSA response rates did not significantly differ between AR-V-positive (6/9) and AR-V-negative (18/28) patients (66% vs. 64%, p=0.896). Likewise, median PSA progression-free survival was not significantly different between AR-V-positive and AR-V-negative patients (9.2 months vs. not reached; p=0.894). Additionally, we identified 2 patients who were AR-V7 negative at baseline but had converted to AR-V7 positive in their end-of-treatment sample. This was associated with much shorter PSA-PFS than those that remained negative (2.58 months vs. no reached), suggesting gain of AR-V expression may be a marker of acquired resistance. These data, which support the findings of the pivotal ARMOR3-SV clinical trial, suggest that baseline AR-V expression does not predict outcomes in mCRPC patients receiving abiraterone or enzalutamide.

Much has been written on Michel Foucault’s reluctance to clearly delineate a research method, particularly with respect to genealogy (Harwood 2000; Meadmore, Hatcher, & McWilliam 2000; Tamboukou 1999). Foucault (1994, p. 288) himself disliked prescription stating, “I take care not to dictate how things should be” and wrote provocatively to disrupt equilibrium and certainty, so that “all those who speak for others or to others” no longer know what to do. It is doubtful, however, that Foucault ever intended for researchers to be stricken by that malaise to the point of being unwilling to make an intellectual commitment to methodological possibilities. Taking criticism of “Foucauldian” discourse analysis as a convenient point of departure to discuss the objectives of poststructural analyses of language, this paper develops what might be called a discursive analytic; a methodological plan to approach the analysis of discourses through the location of statements that function with constitutive effects.

The correlation between the measured velocity component and the instantaneous particle rate in laser anemometry leads to a statistical bias of most commonly used estimators. An additional bias may occur in non-homogeneously seeded flows if a correlation exists between the velocity and the particle density. These statistical bias effects are investigated using numerical simulations. Models for the particle arrival statistics are derived using autoregressive (AR) time series of the first order, generated for three velocity components with prescribed means, Reynolds stress tensor and time scales of the three normal stress tensor terms. The expected results obtained with commonly used processors and sampling techniques are investigated for various prescribed homogeneous and inhomogeneous particle densities. The numerical results are compared to existing theoretical solutions and to some initial experimental results, obtained in an axisymmetric, co-flowing free jet. Some comparisons between one-dimensional and three-dimensional flowfields are also presented. (Author)