Publications by authors named "Shivanshu Awasthi"

19 Publications

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Immunologic disparities in prostate cancer between American men of African and European descent.

Crit Rev Oncol Hematol 2021 Jul 14;164:103426. Epub 2021 Jul 14.

Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA; Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA. Electronic address:

Health disparities between American men of African and European descent (AA and EA, respectively) can be attributed to multiple factors, including disparities in socioeconomic status, access to healthcare, lifestyle, ancestry, and molecular aberrations. Numerous clinical trials and research studies are being performed to identify new and better therapeutic approaches to detect and treat prostate cancer. Of potential concern is the fact that the majority of the patients enrolled on these trials are EA. This disproportionate enrollment of EA could have implications when disease management recommendations are proposed without regard to the existing disparities in prostate cancer between races. With increasing advancements in immunotherapies, the immunological disparities between men of diverse ethnicities will need to be fully explored to develop novel and effective therapeutic approaches for prostate cancer patients globally. To help address this need, this review fully describes inequalities in prostate cancer at the immunological level between AA and EA.
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http://dx.doi.org/10.1016/j.critrevonc.2021.103426DOI Listing
July 2021

Neoadjuvant or Adjuvant Chemotherapy for Breast Cancer in Sub-Saharan Africa: A Retrospective Analysis of Recurrence and Survival in Women Treated for Breast Cancer at the Korle Bu Teaching Hospital in Ghana.

JCO Glob Oncol 2021 Jun;7:965-975

H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL.

Purpose: It is established that addition of systemic therapy to locoregional treatment for breast cancer improves survival. However, reliable data are lacking about the outcomes of such treatment in women with breast cancer in low middle-income countries. We compared the outcomes of treatment in patients who had received neoadjuvant chemotherapy (NACT) or adjuvant chemotherapy and examined the factors associated with breast cancer recurrence and survival at the National Radiotherapy Oncology and Nuclear Medicine Centre, Korle Bu Teaching Hospital, Ghana.

Methods: This was a retrospective cohort study. The medical charts of women with breast cancer managed at the National Radiotherapy Oncology and Nuclear Medicine Centre from 2005 to 2014 were reviewed. A total of 388 patients with a median follow-up of 48 months were included in the study. Logistic regression was used to estimate the risk of recurrence. Survival was estimated using cox proportional hazards model. All models were adjusted with clinicopathologic variables. A value of < .05 was considered statistically significant.

Results: Fifty-nine percent received adjuvant chemotherapy. In an adjusted logistic model, no difference was observed in locoregional recurrence between patients receiving NACT compared with those receiving adjuvant chemotherapy (odds ratio = 1.05; 95% CI, 0.44 to 2.47). However, NACT recipients had a higher likelihood of distant recurrence (odds ratio = 1.97; 95% CI, 1.24 to 3.15). In a multivariable analysis, no differences were observed in overall survival between the two chemotherapy groups (hazard ratio = 1.43; 95% CI, 0.91 to 2.26).

Conclusion: NACT yields similar outcomes compared with adjuvant chemotherapy; however, recipients of NACT with advanced disease may have more distant failures. Early detection in a resource-limited setting is therefore crucial to optimal outcomes, significantly limiting recurrence and improving survival.
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http://dx.doi.org/10.1200/GO.20.00664DOI Listing
June 2021

Comparative analysis of 1152 African-American and European-American men with prostate cancer identifies distinct genomic and immunological differences.

Commun Biol 2021 Jun 3;4(1):670. Epub 2021 Jun 3.

Department of Radiation Oncology, Moffitt Cancer Center, Tampa, FL, USA.

Racial disparities in prostate cancer have not been well characterized on a genomic level. Here we show the results of a multi-institutional retrospective analysis of 1,152 patients (596 African-American men (AAM) and 556 European-American men (EAM)) who underwent radical prostatectomy. Comparative analyses between the race groups were conducted at the clinical, genomic, pathway, molecular subtype, and prognostic levels. The EAM group had increased ERG (P < 0.001) and ETS (P = 0.02) expression, decreased SPINK1 expression (P < 0.001), and basal-like (P < 0.001) molecular subtypes. After adjusting for confounders, the AAM group was associated with higher expression of CRYBB2, GSTM3, and inflammation genes (IL33, IFNG, CCL4, CD3, ICOSLG), and lower expression of mismatch repair genes (MSH2, MSH6) (p < 0.001 for all). At the pathway level, the AAM group had higher expression of genes sets related to the immune response, apoptosis, hypoxia, and reactive oxygen species. EAM group was associated with higher levels of fatty acid metabolism, DNA repair, and WNT/beta-catenin signaling. Based on cell lines data, AAM were predicted to have higher potential response to DNA damage. In conclusion, biological characteristics of prostate tumor were substantially different in AAM when compared to EAM.
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http://dx.doi.org/10.1038/s42003-021-02140-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175556PMC
June 2021

KLK3 SNP-SNP interactions for prediction of prostate cancer aggressiveness.

Sci Rep 2021 Apr 29;11(1):9264. Epub 2021 Apr 29.

Center for Genetic Epidemiology, Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, 90015, USA.

Risk classification for prostate cancer (PCa) aggressiveness and underlying mechanisms remain inadequate. Interactions between single nucleotide polymorphisms (SNPs) may provide a solution to fill these gaps. To identify SNP-SNP interactions in the four pathways (the angiogenesis-, mitochondria-, miRNA-, and androgen metabolism-related pathways) associated with PCa aggressiveness, we tested 8587 SNPs for 20,729 cases from the PCa consortium. We identified 3 KLK3 SNPs, and 1083 (P < 3.5 × 10) and 3145 (P < 1 × 10) SNP-SNP interaction pairs significantly associated with PCa aggressiveness. These SNP pairs associated with PCa aggressiveness were more significant than each of their constituent SNP individual effects. The majority (98.6%) of the 3145 pairs involved KLK3. The 3 most common gene-gene interactions were KLK3-COL4A1:COL4A2, KLK3-CDH13, and KLK3-TGFBR3. Predictions from the SNP interaction-based polygenic risk score based on 24 SNP pairs are promising. The prevalence of PCa aggressiveness was 49.8%, 21.9%, and 7.0% for the PCa cases from our cohort with the top 1%, middle 50%, and bottom 1% risk profiles. Potential biological functions of the identified KLK3 SNP-SNP interactions were supported by gene expression and protein-protein interaction results. Our findings suggest KLK3 SNP interactions may play an important role in PCa aggressiveness.
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http://dx.doi.org/10.1038/s41598-021-85169-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084951PMC
April 2021

Novel Transcriptomic Interactions Between Immune Content and Genomic Classifier Predict Lethal Outcomes in High-grade Prostate Cancer.

Eur Urol 2020 Dec 7. Epub 2020 Dec 7.

University of California, San Francisco, CA, USA.

Grade group 4 and 5 (GG-45) prostate cancer (PCa) patients are at the highest risk of lethal outcomes, yet lack genomic risk stratification for prognosis and treatment selection. Here, we assess whether transcriptomic interactions between tumor immune content score (ICS) and the Decipher genomic classifier can identify most lethal subsets of GG-45 PCa. We utilized whole transcriptome data from 8071 tumor tissue (6071 prostatectomy and 2000 treatment-naïve biopsy samples) to derive four immunogenomic subtypes using ICS and Decipher. When compared across all grade groups, GG-45 samples had the highest proportion of most aggressive subtype-ICS/Decipher. Subsequent analyses within the GG-45 patient samples (n = 1420) revealed that the ICS/Decipher subtype was associated with increased genomic radiosensitivity. Additionally, in a multivariable model (n = 335), ICS/Decipher subtype had a significantly higher risk of distant metastasis (hazard ratio [HR] = 5.41; 95% confidence interval [CI], 2.76-10.6; p ≤  0.0001) and PCa-specific mortality (HR = 10.6; 95% CI, 4.18-26.94; p ≤  0.0001) as compared with ICS/Decipher. The novel immunogenomic subtypes establish a very strong synergistic interaction between ICS and Decipher in identifying GG-45 patients who experience the most lethal outcomes. PATIENT SUMMARY: In this analysis, we identified a novel interaction between the total immune content of prostate tumors and genomic classifier to identify the most lethal subset of patients with grade groups 4 and 5. Our results will aid in the subtyping of aggressive prostate cancer patients who may benefit from combined immune-radiotherapy modalities.
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http://dx.doi.org/10.1016/j.eururo.2020.11.038DOI Listing
December 2020

TMPRSS2-ERG fusion impacts anterior tumor location in men with prostate cancer.

Prostate 2021 02 3;81(2):109-117. Epub 2020 Nov 3.

Dana Farber Cancer Institute and Harvard TH Chan School of Public Health, Boston, Massachusetts, USA.

Background: In prostate cancer (PCa), lack of androgen receptor (AR) regulated TMPRSS2-ETS-related gene (ERG) gene fusion (ERG ) status has been associated with African American race; however, the implications of ERG status for the location of dominant tumors within the prostate remains understudied.

Methods: An African American-enriched multiinstitutional cohort of 726 PCa patients consisting of both African American men (AAM; n = 254) and European American men (EAM; n = 472) was used in the analyses. Methods of categorical analysis were used. Messenger RNA (mRNA) expression differences between anterior and posterior tumor lesions were analyzed using Wilcoxon rank-sum tests with multiple comparison corrections.

Results: Anti-ERG immunohistochemistry staining showed that the association between ERG status and anterior tumors is independent of race and is consistently robust for both AAM (ERG 81.4% vs. ERG 18.6%; p = .005) and EAM (ERG 60.4% vs. ERG 39.6%; p < .001). In a multivariable model, anterior tumors were more likely to be IHC-ERG (odds ratio [OR]: 3.20; 95% confidence interval [CI]: 2.14-4.78; p < .001). IHC-ERG were also more likely to have high-grade tumors (OR: 1.73; 95% CI: 1.06-2.82; p = .02). In the exploratory genomic analysis, mRNA expression of location-dependent genes is highly influenced by ERG status and African American race. However, tumor location did not impact the expression of AR or the major canonical AR-target genes (KLK3, AMACR, and MYC).

Conclusions: ERG tumor status is the strongest predictor of anterior prostate tumors, regardless of race. Furthermore, AR expression and canonical AR signaling do not impact tumor location.
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http://dx.doi.org/10.1002/pros.24086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810127PMC
February 2021

Comparative Genomics Reveals Distinct Immune-oncologic Pathways in African American Men with Prostate Cancer.

Clin Cancer Res 2021 Jan 9;27(1):320-329. Epub 2020 Oct 9.

Department of Cancer Epidemiology, H Lee Moffitt Cancer Center & Research Institutes, Tampa, Florida.

Purpose: The role of immune-oncologic mechanisms of racial disparities in prostate cancer remains understudied. Limited research exists to evaluate the molecular underpinnings of immune differences in African American men (AAM) and European American men (EAM) prostate tumor microenvironment (TME).

Experimental Design: A total of 1,173 radiation-naïve radical prostatectomy samples with whole transcriptome data from the Decipher GRID registry were used. Transcriptomic expressions of 1,260 immune-specific genes were selected to assess immune-oncologic differences between AAM and EAM prostate tumors. Race-specific differential expression of genes was assessed using a rank test, and intergene correlational matrix and gene set enrichment was used for pathway analysis.

Results: AAM prostate tumors have significant enrichment of major immune-oncologic pathways, including proinflammatory cytokines, IFNα, IFNγ, TNFα signaling, ILs, and epithelial-mesenchymal transition. AAM TME has higher total immune content score (ICS) compared with 0 (37.8% vs. 21.9%, = 0.003). AAM tumors also have lower DNA damage repair and are genomically radiosensitive as compared with EAM. (IFN-inducible transmembrane protein 3) was one of the major proinflammatory genes overexpressed in AAM that predicted increased risk of biochemical recurrence selectively for AAM in both discovery [HR = 2.30; 95% confidence interval (CI), 1.21-4.34; = 0.01] and validation (HR = 2.42; 95% CI, 1.52-3.86; = 0.0001) but not in EAM.

Conclusions: Prostate tumors of AAM manifest a unique immune repertoire and have significant enrichment of proinflammatory immune pathways that are associated with poorer outcomes. Observed immune-oncologic differences can aid in a genomically adaptive approach to treating prostate cancer in AAM.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042600PMC
January 2021

Proof-of-principle Phase I results of combining nivolumab with brachytherapy and external beam radiation therapy for Grade Group 5 prostate cancer: safety, feasibility, and exploratory analysis.

Prostate Cancer Prostatic Dis 2021 03 10;24(1):140-149. Epub 2020 Jul 10.

Departments of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA.

Background: To determine whether combining brachytherapy with immunotherapy is safe in prostate cancer (PCa) and provides synergistic effects, we performed a Phase I/II trial on the feasibility, safety, and benefit of concurrent delivery of anti-PD-1 (nivolumab) with high-dose-rate (HDR) brachytherapy and androgen deprivation therapy (ADT) in patients with Grade Group 5 (GG5) PCa.

Methods: Eligible patients were aged 18 years or older with diagnosis of GG5 PCa. Patients received ADT, nivolumab every two weeks for four cycles, with two cycles prior to first HDR, and two more cycles prior to second HDR, followed by external beam radiotherapy. The primary endpoint was to determine safety and feasibility. This Phase I/II trial is registered with ClinicalTrials.gov (NCT03543189).

Results: Between September 2018 and June 2019, six patients were enrolled for the Phase I safety lead-in with a minimum observation period of 3 months after nivolumab administration. Overall, nivolumab was well tolerated in combination with ADT and HDR treatment. One patient experienced a grade 3 dose-limiting toxicity (elevated Alanine aminotransferase and Aspartate aminotransferase) after the second cycle of nivolumab. Three patients (50%) demonstrated early response with no residual tumor detected in ≥4 of 6 cores on biopsy post-nivolumab (4 cycles) and 1-month post-HDR. Increase in CD8+ and FOXP3+/CD4+ T cells in tissues, and CD4+ effector T cells in peripheral blood were observed in early responders.

Conclusion: Combination of nivolumab with ADT and HDR is well tolerated and associated with evidence of increased immune infiltration and antitumor activity.
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http://dx.doi.org/10.1038/s41391-020-0254-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882397PMC
March 2021

Commercial Gene Expression Tests for Prostate Cancer Prognosis Provide Paradoxical Estimates of Race-Specific Risk.

Cancer Epidemiol Biomarkers Prev 2020 01 22;29(1):246-253. Epub 2019 Nov 22.

Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.

Background: Commercial gene expression signatures of prostate cancer prognosis were developed and validated in cohorts of predominantly European American men (EAM). Limited research exists on the value of such signatures in African American men (AAM), who have poor prostate cancer outcomes. We explored differences in gene expression between EAM and AAM for three commercially available panels recommended by the National Comprehensive Cancer Network for prostate cancer prognosis.

Methods: A total of 232 EAM and 95 AAM patients provided radical prostatectomy specimens. Gene expression was quantified using NanoString for 60 genes spanning the Oncotype DX Prostate, Prolaris, and Decipher panels. A continuous expression-based risk score was approximated for each. Differential expression, intrapanel coexpression, and risk by race were assessed.

Results: Clinical and pathologic features were similar between AAM and EAM. Differential expression by race was observed for 48% of genes measured, although the magnitudes of expression differences were small. Coexpression patterns were more strongly preserved by race group for Oncotype DX and Decipher than Prolaris. Poorer prognosis was estimated in EAM versus AAM for Oncotype DX ( < 0.001), whereas negligible prognostic differences were predicted between AAM and EAM using Prolaris or Decipher ( > 0.05).

Conclusions: Because of observed racial differences across three commercial gene expression panels for prostate cancer prognosis, caution is warranted when applying these panels in clinical decision-making in AAM.

Impact: Differences in gene expression by race for three commercial panels for prostate cancer prognosis indicate that further study of their effectiveness in AAM with long-term follow-up is warranted.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7942810PMC
January 2020

Biology vs Access to Care-Relative Contribution to Racial Disparities in Prostate Cancer.

JAMA Oncol 2019 12;5(12):1809-1810

Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center, Tampa, Florida.

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http://dx.doi.org/10.1001/jamaoncol.2019.4497DOI Listing
December 2019

Definitive Radiation Treatment Patterns and Outcomes for Low and Intermediate Risk Prostate Cancer Patients: A Cross-Continental Comparative Study.

Am J Clin Oncol 2019 12;42(12):937-944

Departments of Radiation Oncology.

Purpose: To evaluate early-stage prostate cancer (PCa) radiotherapy treatment patterns and outcomes among Ghanaian men (GM) compared with US men (USM).

Materials And Methods: This retrospective study consists of 987 National Comprehensive Cancer Network low risk, favorable intermediate risk, and unfavorable intermediate risk PCa patient subgroups; GM (173) and USM (814). Differences in baseline covariates and clinical characteristics between GM and USM were analyzed using χ and Mann-Whitney test while Cox Proportional Hazards model was used to assess freedom from biochemical failure differences between the study groups.

Results: Median follow-up for this study was 40 months. GM were diagnosed at a younger median age (64 vs. 68 y, P<0.001) with heavier unfavorable intermediate risk disease burden (32.4% vs. 19.2%) compared with USM. Significant differences were identified in median external beam radiotherapy dose (72.4 vs. 78 Gy, P<0.001); brachytherapy utilization (49.7% vs. 80.6%, P<0.001) and androgen deprivation therapy for intermediate risk disease (48.4% vs. 21.0%, P<0.001) between GM and USM, respectively. GM with low risk and favorable intermediate risk PCa were at increased risk of biochemical recurrence compared with USM with adjusted hazard ratio: 5.15 (1.27 to 20.7), P=0.02 and 4.64 (1.20 to 17.92), P=0.02, respectively.

Conclusions: Compared with USM, GM with low and favorable intermediate risk PCa may experience less durable disease control following standard treatment recommendations. Results suggest differences in radiation treatment and possible inherent differences between the 2 populations. This data will aid in developing research strategies to improve treatment outcomes in GM.
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http://dx.doi.org/10.1097/COC.0000000000000589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6887629PMC
December 2019

African American Specific Gene Panel Predictive of Poor Prostate Cancer Outcome.

J Urol 2019 08 8;202(2):247-255. Epub 2019 Jul 8.

H. Lee Moffitt Cancer Center and Research Institute , Tampa , Florida.

Purpose: Most prostate cancer in African American men lacks the ETS (E26 transforming specific) family fusion event (ETS-). We aimed to establish clinically relevant biomarkers in African American men by studying ETS dependent gene expression patterns to identified race specific genes predictive of outcomes.

Materials And Methods: Two multicenter cohorts of a total of 1,427 men were used for the discovery and validation (635 and 792 men, respectively) of race specific predictive biomarkers. We used false discovery rate adjusted q values to identify race and ETS dependent genes which were differentially expressed in African American men who experienced biochemical recurrence within 5 years. Principal component modeling along with survival analysis was done to assess the accuracy of the gene panel in predicting recurrence.

Results: We identified 3,047 genes which were differentially expressed based on ETS status. Of these genes 362 were differentially expressed in a race specific manner (false discovery rate 0.025 or less). A total of 81 genes were race specific and over expressed in African American men who experienced biochemical recurrence. The final gene panel included APOD, BCL6, EMP1, MYADM, SRGN and TIMP3. These genes were associated with 5-year biochemical recurrence (HR 1.97, 95% CI 1.27-3.06, p = 0.002) and they improved the predictive accuracy of clinicopathological variables only in African American men (60-month time dependent AUC 0.72).

Conclusions: In an effort to elucidate biological features associated with prostate cancer aggressiveness in African American men we identified ETS dependent biomarkers predicting early onset biochemical recurrence only in African American men. Thus, these ETS dependent biomarkers representing ideal candidates for biomarkers of aggressive disease in this patient population.
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http://dx.doi.org/10.1097/JU.0000000000000193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882398PMC
August 2019

Interrelationship Between Health Insurance Status and Prostate Cancer Grade Can Have Critical Impact on Prostate Cancer Disease Control: A Retrospective Cohort Study.

Cancer Control 2019 Jan-Dec;26(1):1073274819837184

1 Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.

The extent to which prostate cancer (PCa) pathology interacts with health insurance to predict PCa outcomes remains unclear. This study will assess the overall association of health insurance on PCa disease control and analyze its interrelationship PCa pathology. A total of 674 PCa patients, treated with prostatectomy from 1987 to 2015, were included in the study. Freedom from biochemical failure (FFbF) was used as a measure of PCa disease control. Methods of categorical and survival analysis were used to analyze the relationships between health insurance, PCa pathology, and FFbF. A total of 63.3% patients were privately insured, 27.1% were publicly insured, and 9.5% were uninsured. In a multivariable model, privately (hazard ratio [HR] = 0.64, 95% confidence interval [CI]: 0.42-0.97, P = .03) and publicly (HR = 0.65, 95% CI: 0.41-1.04, P = .07) insured patients showed improvement in FFbF compared to uninsured patients. The association of health insurance was significantly stronger for the patients with pathologically low grade PCa (pathologic Gleason Score 3+3 & preoperative prostate-specific antigen ≤10 ng/mL), likelihood ratio P = .009. Privately (HR = 0.22, 95% CI: 0.10-0.46) or publicly (HR = 0.26, 95% CI: 0.11-0.60) insured patients with low grade PCa demonstrated favorable association with FFbF. Patients with private and public insurance were more likely to experience favorable treatment. The association of health insurance on PCa disease control is significantly stronger among patients with pathologically low grade PCa. This study identifies health insurance status as pretreatment surrogate for PCa disease control.
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http://dx.doi.org/10.1177/1073274819837184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446254PMC
August 2019

Optimizing Time to Treatment to Achieve Durable Biochemical Disease Control after Surgery in Prostate Cancer: A Multi-Institutional Cohort Study.

Cancer Epidemiol Biomarkers Prev 2019 03 9;28(3):570-577. Epub 2018 Nov 9.

Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.

Background: The impact of treatment delays on prostate cancer-specific outcomes remains ill-defined. This study investigates the effect of time to treatment on biochemical disease control after prostatectomy.

Methods: This retrospective study includes 1,807 patients who received a prostatectomy as a primary treatment at two large tertiary referral centers from 1987 to 2015. Multivariate cox model with restricted cubic spline was used to identify optimal time to receive treatment and estimate the risk of biochemical recurrence.

Results: Median follow-up time of the study was 46 (interquartile range, 18-86) months. Time to treatment was subcategorized based on multivariate cubic spline cox model. In multivariate spline model, adjusted for all the pertinent pretreatment variables, inflection point in the risk of biochemical recurrence was observed around 3 months, which further increased after 6 months. Based on spline model, time to treatment was then divided into 0 to 3 months (61.5%), >3 to 6 months (31.1%), and 6 months (7.4%). In the adjusted cox model, initial delays up to 6 months did not adversely affect the outcome; however, time to treatment >6 months had significantly higher risk of biochemical recurrence (HR, 1.84; 95% confidence interval, 1.30-2.60; < 0.01).

Conclusions: The initial delays up to 6 months in prostate cancer primary treatment may be sustainable without adversely affecting the outcome. However, significant delays beyond 6 months can unfavorably affect biochemical disease control.

Impact: Time to treatment can aid clinicians in the decision-making of prostate cancer treatment recommendation and educate patients against unintentional treatment delays.
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http://dx.doi.org/10.1158/1055-9965.EPI-18-0812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100999PMC
March 2019

Distinct transcriptional repertoire of the androgen receptor in ETS fusion-negative prostate cancer.

Prostate Cancer Prostatic Dis 2019 05 26;22(2):292-302. Epub 2018 Oct 26.

Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.

Background: Prostate cancer (PCa) tumors harboring translocations of ETS family genes with the androgen responsive TMPRSS2 gene (ETS+ tumors) provide a robust biomarker for detecting PCa in approximately 70% of patients. ETS+ PCa express high levels of the androgen receptor (AR), yet PCa tumors lacking ETS fusions (ETS-) also express AR and demonstrate androgen-regulated growth. In this study, we evaluate the differences in the AR-regulated transcriptomes between ETS+ and ETS- PCa tumors.

Methods: 10,608 patient tumors from three independent PCa datasets classified as ETS+ (samples overexpressing ERG or other ETS family members) or ETS- (all other PCa) were analyzed for differential gene expression using false-discovery-rate adjusted methods and gene-set enrichment analysis (GSEA).

Results: Based on the expression of AR-dependent genes and an unsupervised Principal Component Analysis (PCA) model, AR-regulated gene expression alone was able to separate PCa samples into groups based on ETS status in all PCa databases. ETS status distinguished several differentially expressed genes in both TCGA (6.9%) and GRID (6.6%) databases, with 413 genes overlapping in both databases. Importantly, GSEA showed enrichment of distinct androgen-responsive genes in both ETS- and ETS+ tumors, and AR ChIP-seq data identified 131 direct AR-target genes that are regulated in an ETS-specific fashion. Notably, dysregulation of ETS-dependent AR-target genes within the metabolic and non-canonical WNT pathways was associated with clinical outcomes.

Conclusions: ETS status influences the transcriptional repertoire of the AR, and ETS- PCa tumors appear to rely on distinctly different AR-dependent transcriptional programs to drive and sustain tumorigenesis.
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http://dx.doi.org/10.1038/s41391-018-0103-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760558PMC
May 2019

Tristetraprolin Is a Prognostic Biomarker for Poor Outcomes among Patients with Low-Grade Prostate Cancer.

Cancer Epidemiol Biomarkers Prev 2018 11 14;27(11):1376-1383. Epub 2018 Aug 14.

Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida.

We studied the utility of the tumor suppressor Tristetraprolin (TTP, ZFP36) as a clinically relevant biomarker of aggressive disease in prostate cancer patients after radical prostatectomy (RP). RNA expression was measured in an RP cohort of patients treated at Moffitt Cancer Center (MCC) and obtained from six publically available RP datasets with biochemical recurrence (BCR; total = 1,394) and/or metastatic outcome data (total = 1,222). TTP protein expression was measured by immunohistochemistry in a tissue microarray of 153 MCC RP samples. The time to BCR or metastasis based on TTP RNA or protein levels was calculated using the Kaplan-Meier analysis. Univariable and multivariable Cox proportional hazard models were performed on multiple cohorts to evaluate if TTP is a clinically relevant biomarker and to assess if TTP improves upon the Cancer of the Prostate Risk Assessment postsurgical (CAPRA-S) score for predicting clinical outcomes. In all of the RP patient cohorts, prostate cancer with low TTP RNA or protein levels had decreased time to BCR or metastasis versus TTP-high tumors. Further, the decreased time to BCR in TTP-low prostate cancer was more pronounced in low-grade tumors. Finally, pooled survival analysis suggests that RNA expression provides independent information beyond CAPRA-S to predict BCR. TTP is a promising prostate cancer biomarker for predicting which RP patients will have poor outcomes, especially for low-grade prostate cancer patients. This study suggests that RNA expression can be used to enhance the accuracy of CAPRA-S to predict outcomes in patients treated with RP.
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http://dx.doi.org/10.1158/1055-9965.EPI-18-0369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6214732PMC
November 2018

Contemporary Radiation Treatment of Prostate Cancer in Africa: A Ghanaian Experience.

J Glob Oncol 2018 07;4:1-13

Francis A. Asamoah, Shivanshu Awasthi, Puja S. Venkat, Angelina K. Fink, Arash O. Naghavi, Peter A.S. Johnstone, and Kosj Yamoah, Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL; and Francis A. Asamoah, Joel Yarney, Verna Vanderpuye, Afua Abrahams, James E. Mensah, Evans Sasu, and Samuel N.A. Tagoe, Korle Bu Teaching Hospital, Accra, Ghana, West Africa.

Purpose Data on prostate cancer (PCa) treatment in Africa remains under-reported. We present a review of the management of PCa at the cancer center of the largest tertiary referral facility in Ghana, with emphasis on curative treatment. Methods We retrospectively reviewed data on 1,074 patients seen at the National Center for Radiotherapy and Nuclear Medicine from 2003 to 2016. Patient and disease characteristics at presentation are presented using descriptive statistics. The χ and Fisher's exact tests and Mann-Whitney U test were used to analyze differences between categorical and continuous variables, respectively. Methods of survival analysis were used to evaluate the relative risk of biochemical disease-free survival (bDFS). Results Seventy percent of the study population presented with localized disease. High-risk disease presentation accounted for 64.4% of these patients. Only 57.6% of patients with localized disease received curative radiotherapy. The 5-year overall survival for the curative cohort was 96% (interquartile range, 93% to 98%). The 5-year bDFS rates for low-, intermediate-, and high-risk groups were 95%, 70%, and 48%, respectively. Both Gleason score and pretreatment prostate-specific antigen were significant predictors for bDFS in multivariable analysis. Conclusion We show that the majority of patients with PCa have locally advanced disease at the time of presentation for radiotherapy. bDFS was significantly better for low- and intermediate-risk than for high-risk disease. These data emphasize the dire need to re-evaluate screening and patient education of PCa in regions of the world with high incidence and mortality as well as the need for improved access to care and treatment delivery.
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http://dx.doi.org/10.1200/JGO.17.00234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6223508PMC
July 2018

African-American men and prostate cancer-specific mortality: a competing risk analysis of a large institutional cohort, 1989-2015.

Cancer Med 2018 05 30;7(5):2160-2171. Epub 2018 Mar 30.

Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida.

Significant racial disparities in prostate cancer (PCa) outcomes have been reported, with African-American men (AAM) more likely to endure adverse oncologic outcomes. Despite efforts to dissipate racial disparities in PCa, a survival gap persists and it remains unclear to what extent this disparity can be explained by known clinicodemographic factors. In this study, we leveraged our large institutional database, spanning over 25 years, to investigate whether AAM continued to experience poor PCa outcomes and factors that may contribute to racial disparities in PCa. A total of 7307 patients diagnosed with PCa from 1989 through 2015 were included. Associations of race and clinicodemographic characteristics were analyzed using chi-square for categorical and Mann-Whitney U-test for continuous variables. Racial differences in prostate cancer outcomes were analyzed using competing risk analysis methods of Fine and Gray. Median follow-up time was 106 months. There were 2304 deaths recorded, of which 432 resulted from PCa. AAM were more likely to be diagnosed at an earlier age (median 60 vs. 65 years, P = <0.001) and were more likely to have ≥1 comorbidities (13.6% vs. 7.5%, P < 0.001). In a multivariate competing risk model, adjusted for baseline covariates, AAM experienced significantly higher risk of PCSM compared to NHW men (HR, 1.62, 95% CI, 1.02-2.57, P = 0.03) NHW. Among men diagnosed at an older age (>60 years), racial differences in PCSM were more pronounced, with AAM experiencing higher rates of PCSM (HR, 2.05, 95% CI, 1.26-3.34, P = 0.003). After adjustment of clinicodemographic and potential risk factors, AAM continue to experience an increased risk of mortality from PCa, especially older AAM. Furthermore, AAM are more likely to be diagnosed at an early age and more likely to have higher comorbidity indices.
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http://dx.doi.org/10.1002/cam4.1451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5943433PMC
May 2018

Descriptive Analysis of Mortality Predictors in H1n1 Influenza in South Indian Patients.

Infect Disord Drug Targets 2017 ;17(2):106-115

Department of General Medicine, Kasturba Medical College and Hospital, Manipal University, Manipal-576104, India.

Background: H1N1 (hemagglutinin-H-neuroaminidase-N) influenza infection is associated with high morbidity and mortality because of associated complications and related factors. Predictors of mortality in H1N1 patients are studied with very few without seasonal/pandemic declaration. This study was carried out to describe the clinical features, complications and different risk factors that affect the outcome in the patients with confirmed H1N1influenza infection.

Methods: A retrospective study was done in Kasturba Medical College Hospital, Manipal, India by analyzing the medical records of 141 patients admitted from January, 2011 to June, 2015.

Results: Of the 141 patients in the study, 51.1% of the patients were female with a mean age of 32±16.2 years. Fever with headache was observed in 92.9% patients while cough in 78.7% patients and breathlessness in 54.6% patients. On the basis of disease severity, 53.2% of the patients were put on mechanical ventilation. For all the patients, treatment for influenza management began with oseltemivir. Diuretics, antianxiety and corticosteroids were given as supportive and symptomatic care which contributed to high mortality in hospitalized patients. Mean hospitalization period was 8.5 days. During the hospitalization, patients developed different complications i.e. 31.20% patients developed respiratory tract infections, while 17.7% patients developed ARDS and 14.4% patients developed sepsis. The mortality rate of this study population was found to be 29.1 %.

Conclusion: It was observed that low oxygen saturation during admission, high blood urea level, use of diuretics, corticosteroids, anti-anxiety drugs and complications like ARDS, sepsis influence the mortality rate of patients with H1N1 infection.
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http://dx.doi.org/10.2174/1871526517666170407155558DOI Listing
May 2018