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—ICSHigh/DecipherHigh. Subsequent analyses within the GG-45 patient samples (n = 1420) revealed that the ICSHigh/DecipherHigh subtype was associated with increased genomic radiosensitivity. Additionally, in a multivariable model (n = 335), ICSHigh/DecipherHigh 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 ICSLow/DecipherLow. 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.
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.
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 grade group 4 and 5 patients. Our results will aid in the subtyping of aggressive prostate cancer patients who may benefit from combined immune-radiotherapy modalities.
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.
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.
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).
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.
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.
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).
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.
Combination of nivolumab with ADT and HDR is well tolerated and associated with evidence of increased immune infiltration and antitumor activity.
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.
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.
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.
Study will evaluate if AAM continued to experience poor Prostate Cancer (PCa) outcomes and factors that may contribute to racial disparities in PCa.
Participation in cancer research trials by minority populations is imperative in reducing disparities in clinical outcomes. Even with increased awareness of the importance of minority patient ...inclusion in clinical research to improve cancer care and survival, significant barriers persist in accruing and retaining minority patients into clinical trials. This study sought to identify and address barriers to minority accrual to a minimal risk clinical research study in real‐time.
Participation in cancer research trials by minority populations is imperative in reducing disparities in clinical outcomes. Even with increased awareness of the importance of minority patient inclusion in clinical research to improve cancer care and survival, significant barriers persist in accruing and retaining minority patients into clinical trials. This study sought to identify and address barriers to minority accrual to a minimal risk clinical research study in real time.
We observed that the frequency of prostate tumor molecular subtypes differed between Black and White patients and some subtypes showed differential associations with a genomic risk score by race. ...Further understanding of prostate tumor heterogeneity across racial groups may provide insights for the clinical use of subtyping classifiers.
Socioeconomic and health care utilization factors are major drivers of prostate cancer (PC) mortality disparities in the USA; however, tumor molecular heterogeneity may also contribute to the higher mortality among Black men.
To compare differences in PC subtype frequency and genomic aggressiveness by self-identified race.
Five molecular subtype classifiers were applied for 426 Black and 762 White PC patients in the Decipher Genomics Resource Information Database (GRID).
Differences in subtype frequency and tumor genomic risk (Decipher score >0.6) by race were evaluated using χ2 tests and multivariable-adjusted logistic regression models.
Subtype frequencies differed by race for four classifiers. Subtypes characterized by the presence of SPOP mutations, SPINK1 overexpression, and neuroendocrine differentiation were more common among Black men. ERG and ETS fusion-positive subtypes were more frequent among White men, with no clear differences for subtypes reflecting luminal versus basal lineage. The hypothesized low-risk Kamoun S2 subtype was associated with a lower Decipher score among White men only (p = 0.01 for heterogeneity), while the aggressive You PCS1 subtype was associated with a higher Decipher score among White men only (p = 0.001 for heterogeneity). The Tomlins ERG+ subtype was associated with a higher Decipher score relative to all other subtypes among Black men, with no association among White men (p = 0.007 for heterogeneity).
The frequency of PC molecular subtypes differed by self-identified race. Additional studies are required to evaluate whether our observations suggest differences in the tumor genomic risk of progression by self-identified race.
We studied five classifiers that identify subtypes of prostate tumors and found that subtypes differed in frequency between Black and White patients. Further research is warranted to evaluate how differences in tumor subtypes may contribute to disparities in prostate cancer mortality.
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.
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.
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 %.
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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