FATAL PROGNOSIS OF H1N1 INFLUENZA IN LATE TRIMESTER OF PREGNANCY: DESCRIPTIVE ANALYSIS OF FOUR CASES

Influenza infection in late trimester associated with complications is attributable risk factors for critical illness among pregnant women. We have analyzed the medical records of four pregnant women retrospectively who were admitted in a medical intensive care unit of tertiary care center with influenza-like symptoms of breathlessness, fever, headache, myalgia and cough. Their mean age was 26.5 (19-30). They were confirmed to have H1N1infection by real-time reverse transcriptase polymerase chain reaction assay. Chest x-ray of all patients showed abnormalities like pulmonary edema and suggestive of acute respiratory distress syndrome. Arterial blood gas analysis of all four patients shown severe hypoxia and all of them was mechanically ventilated. Oseltemivir was started for all four from the day of admission. Pipracillin-tazobactum combination along with other antibiotics was given as prophylaxis and treatment of different infections. Midazolam and morphine were given together to reduce the restlessness and ventilator-associated distress. Furosemide was given to all for breathing problems and pulmonary edema. Despite of all the management provided none of the patients survived due to the progression of H1N1 into septic shock and multiple organs dysfunction syndromes.Â

Genomic Testing in Localized Prostate Cancer Can Identify Subsets of African Americans With Aggressive Disease

BACKGROUND: Personalized genomic classifiers have transformed the management of prostate cancer (PCa) by identifying the most aggressive subsets of PCa. Nevertheless, the performance of genomic classifiers to risk classify African American men is thus far lacking in a prospective setting. METHODS: This is a prospective study of the Decipher genomic classifier for National Comprehensive Cancer Network low- and intermediate-risk PCa. Study-eligible non-African American men were matched to African American men. Diagnostic biopsy specimens were processed to estimate Decipher scores. Samples accrued in NCT02723734, a prospective study, were interrogated to determine the genomic risk of reclassification (GrR) between conventional clinical risk classifiers and the Decipher score. RESULTS: The final analysis included a clinically balanced cohort of 226 patients with complete genomic information (113 African American men and 113 non-African American men). A higher proportion of African American men with National Comprehensive Cancer Network-classified low-risk (18.2%) and favorable intermediate-risk (37.8%) PCa had a higher Decipher score than non-African American men. Self-identified African American men were twice more likely than non-African American men to experience GrR (relative risk [RR] = 2.23, 95% confidence interval [CI] = 1.02 to 4.90; P = .04). In an ancestry-determined race model, we consistently validated a higher risk of reclassification in African American men (RR = 5.26, 95% CI = 1.66 to 16.63; P = .004). Race-stratified analysis of GrR vs non-GrR tumors also revealed molecular differences in these tumor subtypes. CONCLUSIONS: Integration of genomic classifiers with clinically based risk classification can help identify the subset of African American men with localized PCa who harbor high genomic risk of early metastatic disease. It is vital to identify and appropriately risk stratify the subset of African American men with aggressive disease who may benefit from more targeted interventions

Abstract 3509: Racial variation in molecularly-defined prostate cancer subtypes

Abstract Background: Socioeconomic, environmental, and healthcare utilization factors are likely drivers of the persistent prostate cancer disparities between African-American (AA) and European-American (EA) men. Tumor molecular heterogeneity may also contribute, and Eurocentric studies and initiatives have the potential to widen disparities through the development of prognostic signatures and targeted therapeutics that do not account for genetic diversity. Methods: The Decipher Genomics Resource Information Database (GRID) contains tumor mRNA expression and clinical data generated through use of the Decipher test to predict prostate cancer prognosis. We matched 426 AA and 426 EA patients with localized prostate cancer using a propensity score accounting for age and tumor clinicopathological factors. We then applied five validated prostate cancer molecular subtype classifiers by Alshalalfa et al (Neuroendocrine, Adenocarcinoma), Kamoun et al (S1-S3), Tomlins et al(ERG+, ETS+, SPINK1+, ERG-/ETS-/SPINK1-), You et al (PCS1-PCS3), and Zhang et al (Basal, Luminal) to assign tumor subtypes. Heterogeneity in subtype frequency by self-identified race (SIR) was evaluated using chi-squared tests. Differences in subtype prognostic value by SIR were evaluated in logistic regression models using a high Decipher tumor genomic risk score of ≥0.6 as a surrogate for higher risk of metastases. Results: AA men were more likely to have a Decipher score ≥0.6 than EA men (25.6% vs. 20.0%, p<0.001). Subtypes reflecting SPINK1 overexpression were more frequent among AA men, while subtypes reflecting the presence of ERG or ETS fusions were more common among EA men (all p<0.001). The distribution of Basal vs. Luminal tumors did not differ by SIR (p=0.19), nor did Neuroendocrine vs. Adenocarcinoma (p=0.14). Across SIR groups, the ERG+, Basal, PCS1, and Neuroendocrine tumors were the most likely to have high Decipher scores, while the S2 subtype was associated with a lower Decipher score. However, associations between subtypes and the Decipher score differed by SIR for three of five classifiers. The ERG+ subtype (relative to ERG-/ETS-/SPINK1-) was associated with a higher risk of metastases in AA men (OR=3.18 95% CI 1.59-6.37), but not in EA men (OR=0.69, 95% CI 0.39-1.24, p-het=0.002). A similar pattern was observed in the PCS3 subtype, which is also characterized by the presence of ERG or ETS fusions (p-het=0.003). The hypothesized low-risk S2 subtype was associated with lower risk of metastases (relative to S1) among EA men (OR=0.31, 95% CI 0.15-0.61), but not among AA men (OR=0.99, 95% CI 0.39-2.49, p-het=0.001). The Zhang (p-het=0.36) and Alshalalfa (p-het=0.85) classifiers did not show heterogeneous associations between subtype and Decipher score by SIR. Conclusions: Prostate cancer molecular subtype distributions differed by SIR, with AA men generally more likely to have aggressive subtypes across classification schemes. Furthermore, AA and EA had a heterogeneous risk of metastases (defined by Decipher genomic risk score) for several subtypes. Further research is needed to better define subtyping classifiers and the prognostic value thereof in AA men. Citation Format: Kevin H. Kensler, Mohamed Alshalalfa, Brandon A. Mahal, Yang Liu, Elai Davicioni, Shivanshu Awasthi, Kosj Yamoah, Timothy R. Rebbeck. Racial variation in molecularly-defined prostate cancer subtypes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3509

Prostate tumors of native men from West Africa show biologically distinct pathways-A comparative genomic study

Background Native African men (NAM) experience a disproportionate burden of prostate cancer (PCa) and have higher mortality rates compared to European American men (EAM). While socioeconomic status has been implicated as a driver of this disparity, little is known about the genomic mechanisms and distinct biological pathways that are associated with PCa of native men of African origin. Methods To understand biological factors that contribute to this disparity we utilized a total of 406 multi-institutional localized PCa samples, collected by Men of African Descent and Carcinoma of the Prostate biospecimen network and Moffitt Cancer Center/University of Pennsylvania Health science system. We performed comparative genomics and immunohistochemistry to identify the biomarkers that are highly enriched in NAM from west Africa and compared them with African American Men (AAM) and EAM. Quantified messenger RNA expression and Median H scores based on immune reactivity of staining cells, were compared using Mann Whitney test. For gene expression analysis, p values were further adjusted for multiple comparisons using false discovery rates. Results Immunohistochemical analysis on selected biomarkers showed a consistent association between ETS related gene (ERG) status and race with 83% of NAM exhibiting tumors that lacked TMPRSS2-ERG translocation (ERG(negative)) as compared to AAM (71%) and EAM (52%). A higher proportion of NAM (29%) were also found to be double negative (ERG(negative) and PTENLoss) as compared to AAM (6%) and EAM (7%). NAM tumors had significantly higher immunoreactivity (H-score) for PSMA, and EZH2, whereas they have lower H-score for PTEN, MYC, AR, RB and Racemase, (all p < .05). Comparative genomics revealed that NAM had significant transcriptomic variability in AR-activity score. In pathways enrichment analysis NAM tumors exhibited the enrichment of proinflammatory pathways including cytokine, interleukins, inflammatory response, and nuclear factor kappa B signaling. Conclusions Prostate tumors in NAM are genomically distinct and are characterized by the dysregulation of several biomarkers. Furthermore, these tumors are also highly enriched for the major proinflammatory pathways. These distinct biological features may have implications for diagnosis and response to targeted therapy among Black men, globally

Racial and Ethnic Disparities in Prostate Cancer Outcomes in the Veterans Affairs Health Care System.

IMPORTANCE: Prostate cancer (PCa) disproportionately affects African American men, but research evaluating the extent of racial and ethnic disparities across the PCa continuum in equal-access settings remains limited at the national level. The US Department of Veterans Affairs (VA) Veterans Hospital Administration health care system offers a setting of relatively equal access to care in which to assess racial and ethnic disparities in self-identified African American (or Black) veterans and White veterans. OBJECTIVE: To determine the extent of racial and ethnic disparities in the incidence of PCa, clinical stage, and outcomes between African American patients and White patients who received a diagnosis or were treated at a VA hospital. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study included 7 889 984 veterans undergoing routine care in VA hospitals nationwide from 2005 through 2019 (incidence cohort). The age-adjusted incidence of localized and de novo metastatic PCa was estimated. Treatment response was evaluated, and PCa-specific outcomes were compared between African American veterans and White veterans. Residual disparity in PCa outcome, defined as the leftover racial and ethnic disparity in the outcomes despite equal response to treatment, was estimated. EXPOSURES: Self-identified African American (or Black) and White race and ethnicity. MAIN OUTCOMES AND MEASURES: Time to distant metastasis following PCa diagnosis was the primary outcome. Descriptive analyses were used to compare baseline demographics and clinic characteristics. Multivariable logistic regression was used to evaluate race and ethnicity association with pretreatment clinical variables. Multivariable Cox regression was used to estimate the risk of metastasis. RESULTS: Data from 7 889 984 veterans from the incidence cohort were used to estimate incidence, whereas data from 92 269 veterans with localized PCa were used to assess treatment response. Among 92 269 veterans, African American men (n = 28 802 [31%]) were younger (median [IQR], 63 [58-68] vs 65 [62-71] years) and had higher prostate-specific antigen levels (\u3e20 ng/mL) at the time of diagnosis compared with White men (n = 63 467; [69%]). Consistent with US population-level data, African American veterans displayed a nearly 2-fold greater incidence of localized and de novo metastatic PCa compared with White men across VA centers nationwide. Among veterans screened for PCa, African American men had a 29% increased risk of PCa detection on a diagnostic prostate biopsy compared with White (hazard ratio, 1.29; 95% CI, 1.27-1.31; P \u3c .001). African American men who received definitive primary treatment of PCa experienced a lower risk of metastasis (hazard ratio, 0.89; 95% CI, 0.83-0.95; P \u3c .001). However, African American men who received nondefinitive treatment classified as “other” were more likely to develop metastasis (adjusted hazard ratio, 1.29; 95% CI, 1.17-1.42; P \u3c .001). Using the actual rate of metastasis from veterans who received definitive primary treatment, a persistent residual metastatic burden for African American men was observed across all National Comprehensive Cancer Network risk groups (low risk, 4 vs 2 per 100 000; intermediate risk, 13 vs 6 per 100 000; high risk, 19 vs 9 per 100 000). CONCLUSIONS AND RELEVANCE: This cohort analysis found significant disparities in the incidence of localized and metastatic PCa between African American veterans and White veterans. This increased incidence is a major factor associated with the residual disparity in PCa metastasis observed in African American veterans compared with White veterans despite their nearly equal response to treatment

Identifying and overcoming barriers to participation of minority populations in clinical trials: Lessons learned from the VanDAAM study

Abstract 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

KLK3 SNP–SNP interactions for prediction of prostate cancer aggressiveness

Abstract: 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 × 10–9) and 3145 (P < 1 × 10–5) 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

KLK3 SNP–SNP interactions for prediction of prostate cancer aggressiveness

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 –9) and 3145 (P –5) 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.</p