Search

Introduction: Corneal Melanoma (CM) is a rare malignancy that develops from melanocytes within the cornea, constituting a minority of all ocular tumors. In this study, we sought to investigate the clinicopathological characteristics correlated with the prognosis of CM patients., Methods: We collected patients with CM between 1983 and 2018 from the Surveillance, Epidemiology, and End Results (SEER) database. Cox proportional hazards regression was used for univariate analysis to value hazard ratio (HR) of malignant CM versus spindle cell melanoma and nodular melanoma subgroups. Kaplan-Meier survival analysis and log-rank test were also performed to identify additional prognostic markers and confirm the findings of the Cox Hazard Ratio., Results: A total of 29 eligible patients were collected in our study. Age at diagnosis, laterality, primary site, tumor size, the extent of disease, marital status, income, residential area, and treatment showed no significant prognostic factors for CM patients (P > 0.05). However, when concerned with the primary site of malignant melanoma, spindle cell melanoma (P < 0.05) and nodular melanoma (P < 0.05) were found to show significantly poorer prognosis in CM patients., Conclusion: Age at diagnosis, laterality, primary site, tumor size, the extent of disease, and treatment were not significant prognostic indicators for CM patients. Spindle cell melanoma and nodular melanoma were notable for showing worse survival outcomes than malignant melanoma. Although the sample size in the SEER database was limited, our findings may provide motivation for tailoring individualized treatments for patients with CM with different primary sites.

The phase 3 VISION trial demonstrated that [ 177 Lu]Lu-PSMA-617 prolonged progression-free survival and overall survival (OS) in prostate-specific membrane antigen [PSMA]-positive metastatic castration-resistant prostate cancer (mCRPC) patients who progressed on taxane-based chemotherapy and androgen receptor-signaling inhibitors (ARSIs). The U.S. expanded-access program (EAP; NCT04825652) was opened to provide access to [ 177 Lu]Lu-PSMA-617 for eligible patients until regulatory approval was obtained. This study aimed to evaluate the efficacy and safety profile of [ 177 Lu]Lu-PSMA-617 within the EAP and compare the results with those from the VISION trial. Methods: Patients enrolled in the EAP at 4 institutions in the United States with available toxicity and outcome data were included. Outcome measures included OS, a prostate-specific antigen (PSA) response rate (RR) of at least 50%, and incidences of toxicity according to Common Terminology Criteria for Adverse Events version 5.0. Differences in baseline characteristics, outcome data, and toxicity between the EAP and VISION were evaluated using t testing of proportions and survival analyses. Results: In total, 117 patients with mCRPC who received [ 177 Lu]Lu-PSMA-617 within the EAP between May 2021 and March 2022 were eligible and included in this analysis. Patients enrolled in the EAP were more heavily pretreated with ARSI (≥2 ARSI regimens: 70% vs. 46%; P < 0.001) and had worse performance status at baseline (Eastern Cooperative Oncology Group score ≥ 2: 19% vs. 7%; P < 0.001) than VISION patients. EAP and VISION patients had similar levels of grade 3 or higher anemia (18% vs. 13%; P = 0.15), thrombocytopenia (13% vs. 8%; P = 0.13), and neutropenia (3% vs. 3%; P = 0.85) and similar PSA RRs (42% vs. 46%; P = 0.50) and OS (median: 15.1 vs. 15.3 mo; P > 0.05). Conclusion: Patients with PSMA-positive mCRPC who received [ 177 Lu]Lu-PSMA-617 within the EAP were later in their disease trajectory than VISION patients. Patients enrolled in the EAP achieved similar PSA RRs and OS and had a safety profile similar to that of the VISION trial patients., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Orthopaedic surgeons routinely assess the biomechanical environment of a fracture to create a fixation construct that provides the appropriate amount of stability in efforts to optimize fracture healing. Emerging concepts and technologies including reverse dynamization, "smart plates" that measure construct strain, and FractSim software that models fracture strain represent recent developments in optimizing construct biomechanics to accelerate bone healing and minimize construct failure., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Orthopaedic Trauma Association.)

177 Lu-PSMA-617 and 177 Lu-PSMA I&T (collectively termed 177 Lu-PSMA) are currently being used for the treatment of selected metastatic castration-resistant prostate cancer (mCRPC) patients with PSMA PET-positive disease, but biomarkers for these agents remain incompletely understood. Methods: Pretreatment circulating tumor DNA (ctDNA) samples were collected from 44 mCRPC patients receiving 177 Lu-PSMA treatment. Prostate-specific antigen responders and nonresponders were assessed relative to the ctDNA findings at baseline. Results: The ctDNA findings indicated that nonresponders were more likely to have gene amplifications than were responders (75% vs. 39.2%, P = 0.03). In particular, amplifications in FGFR1 (25% vs. 0%, P = 0.01) and CCNE1 (31.2% vs. 0%, P = 0.001) were more likely to be present in nonresponders. CDK12 mutations were more likely to be present in nonresponders (25% vs. 3.6%, P = 0.05). Conclusion: Our analyses indicate that ctDNA assays may contain specific biomarkers predictive of response or resistance for 177 Lu-PSMA-treated mCRPC patients. Additional confirmatory studies are required before clinicians can use these findings to make personalized treatment decisions., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Molecular genetics is increasingly used to define the course and prognosis of prostate cancer. Hypercalcaemia of malignancy is a rare complication of metastatic prostate cancer associated with poor outcomes. However, no associations have yet been made in literature between pathogenic genetic mutations and hypercalcaemia in patients with prostatic malignancy.We report of a patient with bone-metastatic prostate cancer. He received sequential genetic tests for pathogenic mutations. A somatic BRCA2 truncation mutation was identified at diagnosis and suppressed on olaparib. Six months after stopping olaparib, several pathogenic mutations, including biallelic BRCA2 mutations, were identified. The patient developed large lytic bone lesions and a severe symptomatic hypercalcaemia. He was hospitalised and treated aggressively for hypercalcaemia but died shortly thereafter. To our knowledge, this is the first case of hypercalcaemia in metastatic prostate cancer to be contextualised within complex genetic mutations., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Black men are at higher risk for prostate cancer death. Previous studies showed a benefit of different therapies, including immune-based therapy, for Black men with metastatic prostate cancer. We sought to explore the efficacy of the PD-L1 inhibitor avelumab in Black men with metastatic castrate-resistant prostate cancer (mCRPC) progressing after abiraterone or enzalutamide., Methods: This pilot phase II study enrolled self-identified Black patients who developed mCRPC on next-generation hormonal therapies (NHTs) abiraterone acetate or enzalutamide (NCT03770455). Enrolled patients received avelumab 10mg/kg IV every 2 weeks while remaining on the same NHTs. The primary endpoint of our study was ≥ 50% reduction in prostate specific antigen (PSA) at ≥8 weeks., Results: A total of eight patients were enrolled. The median duration on NHTs prior to enrollment was 364 days (95% CI, 260.9-467.1). The median time to initiate avelumab was 8 days (3-14). With a median follow-up of 196 days, no patients achieved the primary endpoint. The median time to PSA progression was 35 days (95 CI%, 0-94.8) and the median time to radiographic and/or clinical progression was 44 days (95 CI%, 0-118.5). The study was closed prematurely due to safety concerns related to the rapid clinical progression observed in the patients enrolled on study., Conclusion: In conclusion, the addition of avelumab to NHT did not demonstrate clinical activity in Black men with new mCRPC. The unexpected short interval between PSA and radiographic and/or clinical progression observed in this study has potential clinical implications.ClinicalTrials.gov Identifier: NCT03770455 (IND number 139559)., (© The Author(s) 2022. Published by Oxford University Press.)

The vast majority of p53 missense mutants lose the wild-type (wt) function and/or exert 'dominant-negative' effects on their wt counterpart. Here, we identify a novel form of p53 mutation with an extended C-terminus (p53 long C-terminus, p53LC) in a variety of human cancers. Interestingly, the two representative mutants (named 'p53-374*48' and 'p53-393*78') as tested in this study show both loss-of-function and dominant-negative phenotypes in cell proliferation and colony formation assays. Mechanistically, p53LCs interact with and retain wt p53 in the cytoplasm and prevent it from binding to the promoters of target genes, consequently inhibiting its transcriptional activity. Also, p53LCs are very stable, though not acetylated in cells. Remarkably, the p53LCs can desensitize wt p53-containing cancer cells to p53-activating agents. Together, our results unveil a longer form of p53 mutant that possesses a dominant-negative effect on its wt counterpart, besides losing its wt activity., (© The Author(s) (2021). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, CEMCS, CAS.)

Importance: DNA repair gene aberrations occur in 20% to 30% of patients with castration-resistant prostate cancer (CRPC), and some of these aberrations have been associated with sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition platinum-based treatments. However, previous trials assessing platinum-based treatments in patients with CRPC have mostly included a biomarker-unselected population; therefore, efficacy in these patients is unknown., Objective: To characterize the antitumor activity of platinum-based therapies in men with CRPC with or without DNA repair gene alterations., Design, Setting, and Participants: In this case series, data from 508 patients with CRPC treated with platinum-based therapy were collected from 25 academic centers from 12 countries worldwide. Patients were grouped by status of DNA repair gene aberrations (ie, cohort 1, present; cohort 2, not detected; and cohort 3, not tested). Data were collected from January 1986 to December 2018. Data analysis was performed in 2019, with data closure in April 2019., Exposure: Treatment with platinum-based compounds either as monotherapy or combination therapy., Main Outcomes and Measures: The primary end points were as follows: (1) antitumor activity of platinum-based therapy, defined as a decrease in prostate-specific antigen (PSA) level of at least 50% and/or radiological soft tissue response in patients with measurable disease and (2) the association of response with the presence or absence of DNA repair gene aberrations., Results: A total of 508 men with a median (range) age of 61 (27-88) years were included in this analysis. DNA repair gene aberrations were present in 80 patients (14.7%; cohort 1), absent in 98 (19.3%; cohort 2), and not tested in 330 (65.0%; cohort 3). Of 408 patients who received platinum-based combination therapy, 338 patients (82.8%) received docetaxel, paclitaxel, or etoposide, and 70 (17.2%) received platinum-based combination treatment with another partner. A PSA level decrease of at least 50% was seen in 33 patients (47.1%) in cohort 1 and 26 (36.1%) in cohort 2 (P = .20). In evaluable patients, soft tissue responses were documented in 28 of 58 patients (48.3%) in cohort 1 and 21 of 67 (31.3%) in cohort 2 (P = .07). In the subgroup of 44 patients with BRCA2 gene alterations, PSA level decreases of at least 50% were documented in 23 patients (63.9%) and soft tissue responses in 17 of 34 patients (50.0%) with evaluable disease. In cohort 3, PSA level decreases of at least 50% and soft tissue responses were documented in 81 of 284 patients (28.5%) and 38 of 185 patients (20.5%) with evaluable disease, respectively., Conclusions and Relevance: In this study, platinum-based treatment was associated with relevant antitumor activity in a biomarker-positive population of patients with advanced prostate cancer with DNA repair gene aberrations. The findings of this study suggest that platinum-based treatment may be considered an option for these patients.

To report a multi-institutional case series of patients with advanced microsatellite instability high (MSI-H) prostate adenocarcinoma identified with clinical cell-free DNA (cfDNA) next-generation sequencing (NGS) testing and treated with immune checkpoint inhibitors. Retrospective analysis of patients with metastatic castration-resistant prostate cancer (mCRPC) and MSI-H tumor detected by a commercially available cfDNA NGS assay Guardant360 (G360, Guardant Health) at eight different Academic Institutions in the USA, from September 2018 to April 2020. From a total of 14 MSI-H metastatic prostate cancer patients at participating centers, nine patients with mCRPC with 56% bone, 33% nodal, 11% liver and 11% soft-tissue metastases and a median PSA of 29.3 ng/dL, were treated with pembrolizumab after 2 lines of therapy for CRPC. The estimated median time on pembrolizumab was 9.9 (95% CI 1.0 to 18.8) months. Four patients (44%) achieved PSA50 after a median of 4 (3-12) weeks after treatment initiation including three patients with >99% PSA decline. Among the patients evaluable for radiographic response (n=5), the response rate was 60% with one complete response and two partial responses. Best response was observed after a median of 3.3 (1.4-7.6) months. At time of cut-off, four patients were still on pembrolizumab while four patients discontinued therapy due to progressive disease and one due to COVID-19 infection. Half of the patients with PSA50 had both MSI-H and pathogenic alterations in BRCA1 and BRCA2 in their G360 assays. The use of liquid biopsy to identify metastatic prostate cancer patients with MSI-H is feasible in clinical practice and may overcome some of the obstacles associated with prostate cancer tumor tissue testing. The robust activity of pembrolizumab in selected patients supports the generalized testing for MSI-H., Competing Interests: Competing interests: PB has a consulting/advisory role (Institution) with Exelixis, Caris, Bayer, Janssen, EMD/Serono, Pfizer, Astellas, Dendreon, Clovis and Sanofi. Contracted Research (Institution) from Seattle Genetics, BlueEarth Diagnostics, Nektar, AstraZeneca and Seattle Genetics. NA has a consulting/advisory role with Astellas, Astra Zeneca, Bayer, Bristol Myers Squibb, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Foundation Medicine, Genentech, Janssen, Merck, Nektar, Novartis, Pfizer, Pharmacyclics and Seattle Genetics. Contracted Research (Instituion) from Astra Zeneca, Bavarian Nordic, Bayer, BN immunotherapeutics, Bristol Myers Squibb, Calithera, Celldex, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, Glaxo Smith Kline, Immunomedics, Janssen, Medivation, Merck, Nektar, New Link Genetics, Novartis, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle Genetics, Takeda and Tracon. HB has a consulting/advisory role with Endocyte, Celgene, Guardant360, Tracon. Honoraria: SirTex, Bayer. Speaker Bureau: Guardant360. LK is employee of Guardant Health. OS has a consulting/advisory role with AAA, Astellas, Astrazeneca, Bayer, Blue Earth Diagnostics, EMD Serono, Endocyte, Pfizer, Progenics, Sanofi, Invitae, Merck, Novartis, Janseen, Constellation, Dendreon, BMS, Bravarin Nordic, Clovis, Myriad, Noria Therapeutics, Noxopharm, Point Biopharma and Tenebio. Contracted Research from Innocrin, Sotio. He also serves as consultant on NCI Scientific Board Counselors and is a cochairman of GU Committee at NRG., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

African American men with prostate cancer are understudied relative to Caucasians with prostate cancer with regard to testing for pathogenic germline DNA repair gene mutations. Herein we evaluate these two populations in a large commercial dataset and compare the detection of pathogenic/likely pathogenic alterations in 14 well annotated DNA repair genes (BRCA2, BRCA1, PALB2, ATM, RAD51C, CHEK2, PMS2, BARD1, BRIP1, MLH1, MSH2, MSH6, NBN, and RAD51D). Overall, pathogenic or likely pathogenic alterations in these 14 DNA repair genes were less likely to be detected in African Americans as compared to Caucasians. Upon a more in-depth analysis, the risk of germline pathogenic/likely pathogenic BRCA mutations was similar between the two populations whereas there was a lower risk among African Americans for the non-BRCA mutations. No African American men were noted to have mutations in BARD1, BRIP1, MLH1, MSH2, MSH6, NBN, and RAD51D in this data set. Stage, grade, and metastatic status were not assessed in this group of patients. Larger and more detailed studies conducted in men with prostate cancer are required to confirm these findings., Competing Interests: CONFLICTS OF INTEREST Shan Yang and Piper Nicolosi are employed by Invitae Corporation. Invitae Corporation has provided free germline genetic tests to Tulane University as part of grant to Dr. Oliver Sartor.

Introduction: Castration resistant prostate cancer (CRPC) has been characterized by a reactivation of the androgen receptor (AR) signaling pathway via alterations in androgen metabolism and AR aberrations. High-dose testosterone (HDT) is emerging as an active treatment in metastatic CRPC, however, biomarkers of response are unknown. We hypothesized that responses to HDT might impact the genomic expression of AR alterations found in circulating-tumor DNA (ctDNA)., Methods: Retrospective analysis of mCRPC patients treated with HDT (testosterone cypionate q 2-4 weeks) with available clinical and somatic genomic data using a commercially available assay (Guardant360, Redwood City, CA). Clinical outcomes included PSA response (PSA50), time to PSA progression (TPP) and safety., Results: A total of 33 mCRPC patients were treated with ≥2 testosterone cypionate injections. ctDNA testing revealed alterations in AR (39%), TP53 (48%), and DNA repair genes (12%). HDT was given for median of 4.0 months (95% CI, 2.6-5.3) with 24% of PSA50. Twenty patients were re-challenged with abiraterone ( n = 2) or enzalutamide ( n = 18) with 30% PSA50. Significant (grade ≥3) adverse events were observed in 5% of patients (grade 4 thrombocytopenia and asthenia). Patients with median baseline ctDNA% of ≥1.10 had numerically worse TPP outcomes and all patients with AR alterations exhibited decreased AR expression post-HDT ( n = 9), yet no association between clinical outcomes and ctDNA findings was observed., Conclusions: HDT led to a decrease in AR copy number and mutations which was independent from responses to therapy. Further understanding of the genomic alterations as potential predictor of response to HDT is needed., Competing Interests: CONFLICTS OF INTEREST None.

Background: The crossover from abiraterone acetate (AA) to enzalutamide (ENZA) is a frequent approach in clinical practice. Our aim was to explore the role of genomic alterations as putative biomarkers of response to sequential AA followed by ENZA in mCRPC and their association with clinical outcomes., Patients and Methods: This was a multi-center, retrospective analysis of mCRPC patients with circulating-tumor DNA (ctDNA) post-AA and prior to ENZA treatment. Objectives of this analysis were to assess PSA response, time to PSA progression (TTP) and overall survival (OS) in mCRPC patients treated with ENZA following progression on AA with respect to genomic aberrations detected by ctDNA., Results: A total of 28 patients with mCRPC were identified. Median time between AA and ENZA was 3.1 months and median initial PSA prior to ENZA was 35.0 ng/mL. Nine patients (32.1%) achieved PSA responses to ENZA. Most patients (79.0%) achieved confirmed PSA progression with median TTP of 1.6 months (95% CI, 0.7-2.4). Somatic alterations in AR genes were detected in 36.0% of patients with other common alterations detected including 39.0% TP53, 11.0% DNA repair, and 11.0% PTEN. A lack of AR alterations was associated with better PSA response to ENZA (p = 0.04)., Conclusion: While lack of AR alterations in ctDNA was associated with more favorable outcomes, the present dataset is insufficient to recommend the use of ctDNA to impact clinical decision-making in this setting. Further understanding of the implications of the genomic phenotype in ctDNA of castration-resistant tumors and the potential therapeutic implications is required., Competing Interests: Declaration of Competing Interest None, (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Deregulated expression of circular RNAs (circRNAs) is associated with various human diseases, including many types of cancer. Despite their growing links to cancer, there has been limited characterization of circRNAs in metastatic castration-resistant prostate cancer, the major cause of prostate cancer mortality. Here, through the analysis of an exome-capture RNA-seq dataset from 47 metastatic castration-resistant prostate cancer samples and ribodepletion and RNase R RNA-sequencing of patient-derived xenografts (PDXs) and cell models, we identified 13 circRNAs generated from the key prostate cancer driver gene-androgen receptor (AR). We validated and characterized the top four most abundant, clinically relevant AR circRNAs. Expression of these AR circRNAs was upregulated during castration-resistant progression of PDXs. The upregulation was not due to global increase of circRNA formation in these tumors. Instead, the levels of AR circRNAs correlated strongly with that of the linear AR transcripts (both AR and AR variants) in clinical samples and PDXs, indicating a transcriptional mechanism of regulation. In cultured cells, androgen suppressed the expression of these AR circRNAs and the linear AR transcripts, and the suppression was attenuated by an antiandrogen. Using nuclear/cytoplasmic fractionation and RNA in-situ hybridization assays, we demonstrated predominant cytoplasmic localization of these AR circRNAs, indicating likely cytoplasmic functions. Overall, this is the first comprehensive characterization of circRNAs arising from the AR gene. With greater resistance to exoribonuclease compared to the linear AR transcripts and detectability of AR circRNAs in patient plasma, these AR circRNAs may serve as surrogate circulating markers for AR/AR-variant expression and castration-resistant prostate cancer progression.

Background: Abiraterone is an important agent in the treatment of advanced prostate cancer. Early changes in prostate-specific antigen while on abiraterone in patients with metastatic castrate-resistant prostate cancer potentially have financial and health implications for patients. Limited data is available on early prostate-specific antigen change and subsequent survival given phase III trials did not measure prostate-specific antigen changes before 12 weeks., Methods: A single-center retrospective study was performed. Metastatic castrate-resistant prostate cancer patients treated with abiraterone (without prior enzalutamide) at Tulane Cancer Center were reviewed with a focus on early prostate-specific antigen decline and relationship to overall survival., Results: A total of 110 patients were analyzed for prostate-specific antigen response of ≥ 30 and > 50% at 4, 8, and 12 weeks. A prostate-specific antigen response of either > 30% or > 50% at 4, 8, or 12 weeks was associated with improved overall survival at all time points except > 50% decline at 8 weeks. Multivariate analysis indicated, for all time points, that early prostate-specific antigen declines were predictive of overall survival. The neutrophil to lymphocyte ratio and docetaxel pretreatment also were predictive in many, but not all, of the multivariate analyses., Conclusions: A > 30% or > 50% prostate-specific antigen decline at 4, 8, or 12 weeks provides important information regarding subsequent overall survival for patients with metastatic castrate-resistant prostate cancer. While these data require validation with a large, multi-institutional trial, they can provide physicians with information regarding prognosis and the timing of expected outcomes. These data affirms the notion that prostate-specific antigen responses as early as 4 weeks after abiraterone initiation can be used to inform both patients and physicians about metastatic castrate-resistant prostate cancer outcomes after initiating treatment with this important but costly therapeutic choice.

Prostate cancer is the second leading cause of cancer death in American men. Despite the common nature of this disease, there is a poor understanding of biomarkers that predict responsiveness to immunotherapeutic agents such as the programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors. Herein we describe a case of complete remission with pembrolizumab therapy in a metastatic castrate-resistant prostate cancer patient with a complex germline MSH2 alteration (Boland inversion) in association with a tumor demonstrating high microsatellite instability. Potential utility of high mutational burden assessed by an experimental circulating tumor DNA assay is also shown. The literature concerning biomarkers for PD-1 inhibition is reviewed, including data for various mismatch repair gene deficiencies, microsatellite instability, tumor mutational burden, PD-L1 3' untranslated region mutations, selected POLE mutations, and biallelic CDK12 mutations. Taken together, although prostate cancer is generally believed to be a tumor unresponsive to PD-1 inhibition, careful dissection of tumor biology is able to provide an approach toward predictive biomarkers that has the potential for expanded clinical utility. KEY POINTS: Biomarkers for anti-PD1 and anti-PDL1 therapy are poorly defined in prostate cancer.Recent advances are defining new important classes of responsive patients., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2018.)

Prostate cancer that has progressed after androgen deprivation, abiraterone, and taxane therapy is challenging to treat successfully. Herein we report a dramatic response to continuous-infusion 5-fluorouracil (5-FU) at a dose of 200 mg/m 2 in a patient with rapidly progressive, heavily pretreated, metastatic castrate-resistant prostate cancer. Baseline prostate-specific antigen values declined from 1,890 ng/mL to <1 ng/mL after 5-FU therapy. We hypothesized that prostate-specific membrane antigen overexpression may result in cancer cells uniquely susceptible to antifolate therapies., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2017.)

Docetaxel-based chemotherapy is established as a first-line treatment and standard of care for patients with metastatic castration-resistant prostate cancer. However, half of the patients do not respond to treatment and those do respond eventually become refractory. A better understanding of the resistance mechanisms to taxane chemotherapy is both urgent and clinical significant, as taxanes (docetaxel and cabazitaxel) are being used in various clinical settings. Sustained signaling through the androgen receptor (AR) has been established as a hallmark of CRPC. Recently, splicing variants of AR (AR-Vs) that lack the ligand-binding domain (LBD) have been identified. These variants are constitutively active and drive prostate cancer growth in a castration-resistant manner. In taxane-resistant cell lines, we found the expression of a major variant, AR-V7, was upregulated. Furthermore, ectopic expression of two clinically relevant AR-Vs (AR-V7 and ARV567es), but not the full-length AR (AR-FL), reduced the sensitivities to taxanes in LNCaP cells. Treatment with taxanes inhibited the transcriptional activity of AR-FL, but not those of AR-Vs. This could be explained, at least in part, due to the inability of taxanes to block the nuclear translocation of AR-Vs. Through a series of deletion constructs, the microtubule-binding activity was mapped to the LBD of AR. Finally, taxane-induced cytoplasm sequestration of AR-FL was alleviated when AR-Vs were present. These findings provide evidence that constitutively active AR-Vs maintain the AR signaling axis by evading the inhibitory effects of microtubule-targeting agents, suggesting that these AR-Vs play a role in resistance to taxane chemotherapy.

Prostate cancer has a strong familial component but uncovering the molecular basis for inherited susceptibility for this disease has been challenging. Recently, a rare, recurrent mutation (G84E) in HOXB13 was reported to be associated with prostate cancer risk. Confirmation and characterization of this finding is necessary to potentially translate this information to the clinic. To examine this finding in a large international sample of prostate cancer families, we genotyped this mutation and 14 other SNPs in or flanking HOXB13 in 2,443 prostate cancer families recruited by the International Consortium for Prostate Cancer Genetics (ICPCG). At least one mutation carrier was found in 112 prostate cancer families (4.6 %), all of European descent. Within carrier families, the G84E mutation was more common in men with a diagnosis of prostate cancer (194 of 382, 51 %) than those without (42 of 137, 30 %), P = 9.9 × 10(-8) [odds ratio 4.42 (95 % confidence interval 2.56-7.64)]. A family-based association test found G84E to be significantly over-transmitted from parents to affected offspring (P = 6.5 × 10(-6)). Analysis of markers flanking the G84E mutation indicates that it resides in the same haplotype in 95 % of carriers, consistent with a founder effect. Clinical characteristics of cancers in mutation carriers included features of high-risk disease. These findings demonstrate that the HOXB13 G84E mutation is present in ~5 % of prostate cancer families, predominantly of European descent, and confirm its association with prostate cancer risk. While future studies are needed to more fully define the clinical utility of this observation, this allele and others like it could form the basis for early, targeted screening of men at elevated risk for this common, clinically heterogeneous cancer.

Race, family history and age are the unequivocally accepted risk factors for prostate cancer (PCa). Androgen receptor (AR)-dependent signaling is an important element in prostate carcinogenesis and its progression to metastatic disease. We examined the possibility of genomic changes in the AR in association with familial PCa in African Americans who have a higher incidence and mortality rate and a clinically more aggressive disease presentation than Caucasians. Genomic DNAs of 60 patients from 30 high-risk African American and Caucasian families participating in the Louisiana State University Health Sciences Center genetic linkage study of PCa were studied. Exon-specific polymerase-chain reaction, bi-directional automated sequencing and restriction enzyme genotyping were used to analyze for mutations in the coding region of the AR gene. We identified a germline AR (A1675T) (T559S) substitution mutation in the DNA-binding domain in three PCa-affected members of an African-American family with a history of early-onset disease. The present study describes the first AR germline mutation in an African-American family with a history of familial PCa. The AR (T559S) mutation may contribute to the disease by altering AR DNA-binding affinity and/or its response to androgens, non-androgenic steroids or anti-androgens. Additional studies will be required to define the frequency and contribution of the AR (A1675T) allele to early-onset and/or familial PCa in African Americans.

Alkanes at the air-sea interface were analyzed in 118 surface samples collected at five different intervals over a 12-month period from Timbalier Bay (Louisiana), ogfshore Louiisiana, and offshore Florida. The alkanes were characterized by gas chromatography and mass spectrometry. Unexpectedly, methyl branched alkanes ranging in chain length froin C(15) to C(35) and cycloalkanes were frequently the predominant components. This suggests that the alkanes are produced by natural biological sources as well as human activities.

The characteristics of 2-D holographic scanners utilizing a concave auxiliary reflector are analyzed. The total resolution capability of the scanner is discussed in detail for the scanner operated at both finite and infinite conjugations, and the factors limiting resolution are indicated. The resolution considerations lead to a near-optimal design procedure which is used in design examples for typical applications in the visible, millimeter, and ultrasonic wavelength regions.