Cause Of Mortality In Men Research Articles

ROLE OF THE REACTIVE OXYGEN AND NITROGEN SPECIES IN THE DEVELOPMENT OF FIBROSIS IN THE TESTES OF RATS WITH PROLONGED CENTRAL DEPRIVATION OF TESTOSTERONE SYNTHESIS

Prostate cancer is the second most common diagnosis in oncology and ranks the fifth among the causes of mortality in men around the world. 1,276,106 cases of newly diagnosed prostate cancer were recorded in 2018. Androgens play a large role in the development of prostate cancer. Elimination of androgens and blockade of their synthesis are key pathogenetic steps in the treatment of prostate cancer. Metabolic and morphological changes in the testes under prolonged central deprivation of testosterone synthesis are currently not well understood. The aim of this study was to establish the role of reactive oxygen and nitrogen species in the development of morphological changes in the testes of rats under prolonged central deprivation of testosterone synthesis. Materials and methods. The experiments were conducted on 20 sexually mature male Wistar rats. Animals were divided into 4 groups of 5 animals in each. The first group (control) received a subcutaneous injection of 0.9% sodium chloride for 180 days. The second group received a subcutaneous injection of diphereline (triptoreline) in a dose of 0.3 mg/kg of active agent for 30 days in order to simulate the central deprivation of testosterone synthesis. In the third group, diphereline was administered in a dose of 0.3 mg/kg of the active agent for 90 days. The fourth group received a subcutaneous injection of diphereline in a dose of 0.3 mg/kg of the active agent for 180 days. Small pieces of testes were fixed and enclosed in paraffin blocks; then 4-μm thick sections were made and stained with hematoxylin and eosin. Histological preparations were studied using an optical microscope with a digital microphotographic nozzle Olympus C 3040-ADU with programs adapted for these studies. The total activity of NO synthases (gNOS), the activity of the inducible isoform of NO synthase (iNOS) and constitutive isoforms (cNOS), as well as the production of superoxide anion radical (O2•-) were determined in 10% homogenate of testes. Results. Long-term central deprivation of testosterone synthesis leads to an increase in the interstitial space volume with the development of fibrotic changes in the testes on the 180th day of the experiment. The wall of seminiferous tubules was compacted, swollen, there were a large number of parietal macrophages from the outside compared to previous periods of the experiment. In the structure of some convoluted seminiferous tubules, first there was discompletion and disorientation, and then desquamation of spermatids. The number of spermatogonia type A and B decreased. Hypochromia and pycnosis were noted in the nuclei. The activities of gNOS and iNOS increased until the 90th day and decreased by 180th when compared with 90th day, remaining higher than the activities of the control group. Activity of cNOS was reduced in all experimental groups. O2•- production increased in all experimental groups. Conclusion: an increase in the production of nitric oxide by the inducible isoform of NO synthase leads to destructive changes in the testes of rats with the subsequent development of fibrotic changes on the 180th day of central deprivation of testosterone synthesis by enhancing the production of superoxide anion radical.

Эпидемиологические особенности рака предстательной железы в Дальневосточном федеральном округе

Background. Recent decades in the Far East Federal District have been characterized by a constant increase in the number of patients with oncological pathology, in the structure of which prostate tumors are the second largest cause of mortality in men. The goal of this study was a scientific assessment of the main rates of morbidity and mortality of prostate cancer in the male population in the Far East Federal District for the last ten years (2009–2018). Material and methods. During the study, the indicators of morbidity and mortality, reporting forms of statistical registration of oncological patients and regulatory documents of higher-level organizations, information on ten-year observations of the dynamics of changes in digital indicators of the investigated pathology were used. Results of the research. The main rates of morbidity and mortality of prostate cancer patients in the Far East Federal District are given, where 33,111 new cases of malignant neoplasms were registered in 2018, that is 24,6 % higher than ten years ago (20 191 people in 2009). In Russia, such increase was 21,6 % higher. 9 324 patients, i.e. 0,12 % population of the region, were under medical supervision. The number of patients with I-II stages of the disease (60,9 %) increased during the investigated period with simultaneous reduction of the number of patients with neglected forms (38,1 %) of the disease. Morbidity and mortality rates have been increasing steadily over the past 10 years. The percentage of actively identified patients has increased, as well as the year-end accumulation index. Morphological confirmation of the diagnosis (over 95 %) did not exceed the average republican indicators (95,9 %). The proportion of patients registered for 5 years or more was lower than averagely in Russia, but mortality rates improved in the first year from the time of the initial diagnosis (2009 – 17,3 %; 2018 – 10,1 %; Russian Federation – 7,8 %). As far as the localizations in the male reproductive organs, neglected prostate cancer remains at the highest level.

Abstract A38: Targeting the androgen receptor to increase sensitivity to checkpoint immunotherapy

Abstract Advanced prostate cancer is the second leading cause of cancer-associated mortality in men with ~32,000 deaths each year. Castration-resistant prostate cancer has no cure and an overall survival of approximately 5 years. Strategies to block androgen receptor (AR) signaling form the backbone of prostate-cancer therapy and despite suppression of serum testosterone, intratumor concentrations of androgens can remain high. Blocking AR nuclear translocation and its transcriptional function delays disease progression, but not overall survival, in castration-resistant prostate cancer patients. In a paradigm-challenging clinical trial, anti-PD-1 blockade induced long-term durable responses in a subset of metastatic castration-resistant prostate cancer patients treated with the AR inhibitor, enzalutamide. Interestingly, T cells also express AR and their function can be directly modulated by changes in androgen availability. Given this and the success of this clinical trial, we asked if enzalutamide sensitized T cells to checkpoint immunotherapy. Using in vitro and in vivo assays, we reveal a direct effect of enzalutamide on T-cell proliferation and function. In a novel implantable mouse model of advanced prostate cancer, we highlight a requirement for androgen receptor blockade to sensitize prostate tumor-bearing animals to immunotherapy. Transcriptomic analysis of leukocytes from the tumor and draining lymph node revealed a small cohort of genes differentially regulated by enzalutamide that are consistent with increased sensitivity to checkpoint blockade. Perhaps most significant, in patients who responded to anti-PD-1 therapy, some of these same genes were upregulated prior to treatment, suggesting these could be a biomarker for immunotherapy sensitization in advanced prostate cancer patients. Taken together, our data suggest a novel mechanism targeting androgen receptor-mediated immune suppression to improve immunotherapy outcomes in advanced prostate cancer. Note:This abstract was not presented at the conference. Citation Format: Archana Sehrawat, Fanny Polesso, Christina Hipfinger, Xiangnan Guan, Zheng Xia, Julie Graff, Amy Moran. Targeting the androgen receptor to increase sensitivity to checkpoint immunotherapy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A38.

Survival of the Fittest: Impact of Cardiorespiratory Fitness on Outcomes in Men and Women with Cardiovascular Disease

Cardiovascular disease (CVD) in general and myocardial infarction in particular are the leading causes of mortality in men and women globally. Sex differences in CVD recovery exist, with higher rates of mortality, recurrent myocardial infarction, and poor functional outcomes seen in women compared to men with CVD. Physical inactivity has been identified as a crucial modifiable risk factor linked with poor survival and recovery in patients with CVD. Cardiac rehabilitation programs that aim to improve physical inactivity and cardiorespiratory fitness (CRF), a measure of physical fitness in patients with CVD, have gained popularity. The goals of this commentary were to summarize the existing literature on the impact of CRF on survival in patients with CVD, to document the impact of sex on CVD outcomes, and to highlight any gaps in current knowledge. Even minor improvements in CRF have been linked with improved survival, although contemporary data from randomized controlled trials have shown mixed results. Gender differences in cardiac rehabilitation have been well documented, with lower referral, enrollment, and completion rates noted in women compared to men with CVD. However, data on sex differences in CRF with cardiac rehabilitation are scant, mostly indicating lower peak CRF observed in female compared to male patients on completion. It is unclear whether similar thresholds of peak CRF are needed in male and female patients to improve survival after onset of CVD, and whether exercise prescriptions need to be adapted to include additional forms of exercise. CRF is also influenced by age, with a decline in peak exercise capacity with advancing age observed in both sexes, but steeper declines noted in men than women. From this perspective, we review the data intersecting age, sex, and exercise on survival in patients with CVD, as well as the biological mechanisms at play, and we identify areas for future research (Clin Ther. 2020; 42:XXX–XXX) © 2020 Elsevier Inc.

Tumor-infiltrating lymphocytes from human prostate tumors reveal anti-tumor reactivity and potential for adoptive cell therapy

ABSTRACTAdvanced prostate cancer remains incurable and is the second leading cause of mortality in men. Immunotherapy based on the adoptive transfer of tumor-infiltrating lymphocytes (TIL) has demonstrated promising clinical results in patients with metastatic melanoma and lately also in other solid tumors. However, the ability to obtain TIL from patients with prostate cancer, considered poorly immunogenic, remains unknown. In this study, we investigate the feasibility of isolating and expanding TIL from primary prostate tumors. We collected tumor specimens from eight patients with diagnosed prostate adenocarcinoma undergoing radical prostatectomy and were able to successfully expand multiple autologous TIL cultures from all patients. Twenty-eight prostate-TIL cultures were further expanded using a standard rapid expansion procedure under Good Manufacturing Practice conditions. TIL cultures were phenotypically characterized for T cell subset composition, differentiation status and co-inhibitory/stimulatory markers such as PD-1, TIM-3, LAG-3, and CD28 and were found to have in general similarity to TIL obtained from patients with melanoma and lung carcinoma previously treated at our center. All analyzed TIL cultures were functional as determined by the capability to produce high level of IFNγ upon stimuli. Most importantly, co-culture assays of prostate-TIL with autologous tumors demonstrated anti-tumor reactivity.In conclusion, these findings demonstrate that functional and anti-tumor reactive TIL can be obtained, despite the immunosuppressive microenvironment of the cancer, thus this study supports the development of TIL therapy for prostate cancer patients.

Pattern and Prevalence of Dyslipidemia among Patients with Acute Coronary Syndrome Admitted in a Tertiary Level Hospital

Background: The leading cause of mortality in men and women worldwide is coronary artery disease (CAD). For hospitalization in our country, acute coronary syndrome (ACS) is a major reason. Dyslipidemia is found one of the most important modifiable risk factors for CAD.
 Aim: The aim of the study was to determine the pattern and prevalence of dyslipidemia among patients with ACS admitted in National Institute of Cardiovascular Diseases (NICVD), Dhaka.
 Subjects and methods: One thousand (1000) patients with ACS were included and classified according to clinical presentation, the findings on the admission electrocardiogram (ECG) and the results of serial cardiac troponin levels, into myocardial infarction(MI), either STelevation or non ST- elevation MI, and unstable angina(UA) subgroups. In the other group 500 healthy subjects were included as controls. All subjects were subjected determination lipid profile. ECG and Troponin- I were done for diagnosis and follow up of the patients.
 Results: In patients with ACS, high levels of TC (>200 mg/dl) were found in 60.67%,high levels of LDL (> 130 mg/dl) were found in 58%, high levels of TG (>150 mg/ dl) were found in 63.33%, however, low levels of HDL (< 40 mg/dl) were found in 66%. There was a statistically significant elevation in TC, LDL, TG serum levels in patients with ACS compared to control subjects (p<0.05) while the HDL was significantly low in ACS patient compared to control subjects (p <0.05). TC/HDL > 5 and TG/HDL> 4 were significantly higher in patients with ACS than controls. There was no significant difference between MI and UA patients regarding all lipid profile parameters. TC, LDL, TG were significantly higher in males than in females while HDL was significantly higher in females compared to males. Also TC/HDL and TG/HDL ratios were significantly higher in males compared to females. All lipid components were significantly more prevalent in males than in females except TG where there was no significant difference between males and females. Stepwise regression analysis of lipid parameters revealed that TC/HDL and TG/HDL ratios were independent risk factors for ACS.
 Conclusion: Dyslipidemia is one the major risk factors which is widely prevalent in patients with ACS and is more prevalent in males than in females. We recommend paying more attention to serum lipids and other modifiable risk factors for prevention of ACS and more studies about them as risk factors of atherosclerosis and its impact on other systems is advised.
 Bangladesh Heart Journal 2019; 34(1) : 31-36

Metastatic Cervical and Supraclavicular Lymphadenopathy from Prostate Mimicking Lymphoma: A Case Series

Prostate cancer is the second most common cancer in men worldwide and the commonest cause of mortality in men. It is the commonest diagnosed cancer in African men. The earliest and common sites of metastasis are the axial skeleton and regional lymph nodes. Initial presentation of the metastatic disease with cervical or supraclavicular lymphadenopathy is rarely reported. We report 3 cases of metastatic cancer of the prostate presenting initially to physicians with huge cervical and supraclavicular lymph nodes enlargement which on biopsy revealed metastatic adenocarcinoma. On further evaluation, there were non-bothersome storage symptoms, elevated prostate specific antigen and abnormal digital rectal examination. Transrectal ultrasound (TRUS)-guided biopsy of hypoechoic nodules revealed high-grade adenocarcinoma of the prostate on histopathological examination. The cervical and supraclavicular lymphadenopathy resolved after commencement of androgen deprivation therapy. We advocate for prostate cancer screening in African men above 50 years of age presenting with cervical or supraclavicular lymphadenopthy to primary care physicians even in the absence of lower urinary tract symptoms.

Abstract 007: Exogenous Delivery of Alpha-Calcitonin Gene Related Peptide Inhibits Apoptosis and Oxidative Stress and Protects Against Pressure-Induced Congestive Heart Failure

Congestive heart failure (CHF) is the leading cause of mortality in men and women world-wide, despite multiple but limited treatment modalities. Our laboratory and others have established that α-calcitonin gene-related peptide (αCGRP) plays a significant protective role in several cardiovascular diseases. αCGRP is a 37-amino acid neuropeptide and potent vasodilator. In αCGRP-knockout mice, pressure overload significantly exacerbates cardiac hypertrophy, dysfunction and fibrosis. The present study was performed to determine if exogenous delivery of native αCGRP was cardio-protective against pressure overload-induced CHF. Transverse aortic constriction (TAC) was performed to induce pressure overload CHF in nine week old C57/BL6 mice. One group were sham-treated, one TAC alone, and one TAC plus αCGRP (4 mg/kg bwt/day) via an implanted mini-osmotic pump. All mice had serial echocardiography performed and were sacrificed and hearts collected after 28 days. ELISA data showed that αCGRP levels in the TAC left ventricle (LV) were significantly lower compared to sham LV, while αCGRP in the TAC-CGRP LVs was similar to sham levels. TAC alone significantly decreased fractional shortening (FS) and ejection fraction (EF), and increased cardiac hypertrophy, apoptosis, and fibrosis in the LV compared to sham mice. αCGRP in the TAC mice significantly preserved LV FS and EF, (FS ±SEM: sham 46.2±1.8%, TAC 25.4±1.1%, and TAC-CGRP 36.6±1.2%; EF ±SEM: sham 78±1.9%, TAC 51.3±1.5%, and TAC-CGRP 67.4±1.5%) and attenuated apoptosis (measured by cleaved caspase-3 and TUNEL staining), fibrosis, and oxidative stress (measured by lipid peroxidation, glutathione, and 8-OHdG levels) compared to TAC alone. Moreover, TAC increased the expression of sirtuin proteins (Sirt1, 2, 3, 5, and 7) and phosphorylation of AMPK, both of which are involved in oxidative stress and energy metabolism. This increase in Sirt-1 and -2 protein level was significantly attenuated by αCGRP. In addition, αCGRP markedly reduced phospho-AMPK level in the TAC LV back to control levels. Our results show that αCGRP protects against pressure-induced CHF which may be mediated by the inhibition of myocyte apoptosis and reduction in oxidative stress. Thus, αCGRP is an exciting therapeutic agent in CHF.

Inhibition of atypical protein kinaseC‑ι effectively reduces the malignancy of prostate cancer cells by downregulating the NF-κB signaling cascade.

Prostate cancer (PC) is the most common type of cancer among men. Aggressive and metastatic PC results in life- threatening tumors, and represents one of the leading causes of mortality in men. Previous studies of atypical protein kinase C isoforms (aPKCs) have highlighted its role in the survival of cultured prostate cells via the nuclear factor (NF)-κB pathway. The present study showed that PKC-ι was overexpressed in PC samples collected from cancer patients but not in non-invasive prostate tissues, indicating PKC-ι as a possible prognostic biomarker for the progression of prostate carcinogenesis. Immunohistochemical staining further confirmed the association between PKC-ι and the prostate malignancy. The DU-145 and PC-3 PC cell lines, and the non-neoplastic RWPE-1 prostatic epithelial cell line were cultured and treated with aPKC inhibitors 2-acetyl-1,3-cyclopentanedione (ACPD) and 5-amino-1-(1R,2S,3S,4R)-2,3-dihydroxy-4-methylcyclopentyl)-1H-imidazole-4-carboxamide (ICA-1). Western blot data demonstrated that ICA-1 was an effective and specific inhibitor of PKC-ι and that ACPD inhibited PKC-ι and PKC-ζ. Furthermore, the two inhibitors significantly decreased malignant cell proliferation and induced apoptosis. The inhibitors showed no significant cytotoxicity towards the RWPE-1 cells, but exhibited cytostatic effects on the DU-145 and PC-3 cells prior to inducing apoptosis. The inhibition of aPKCs significantly reduced the translocation of NF-κB to the nucleus. Furthermore, this inhibition promoted apoptosis, reduced signaling for cell survival, and reduced the proliferation of PC cells, whereas the normal prostate epithelial cells were relatively unaffected. Overall, the results suggested that PKC-ι and PKC-ζ are essential for the progression of PC, and that ACPD and ICA-1 can be effectively used as potential inhibitors in targeted therapy.

Abstract 4396: Targeting survivin to overcome docetaxel resistance in prostate cancer

Abstract Despite therapeutic advancements, castration-resistant prostate cancer (CRPC) remains the second most common cause of cancer-related mortality in men. Docetaxel is the first cytotoxic agent to show modest improvements in overall survival rate in patients with CRPC. Unfortunately, over half of these patients do not respond to treatment and ultimately all develop resistance. The mechanism mediating docetaxel resistance remains unknown. However, survivin, an inhibitor of apoptosis (IAP) family member, and known mediator of chemo-resistance has been previously associated with docetaxel resistance, as inhibition of survivin expression sensitized prostate cancer cells to docetaxel in vitro, and a small molecule inhibitor targeting survivin expression led to a significant regression in prostate cancer xenograft tumors when given in combination with docetaxel. However, how survivin may mediate docetaxel resistance in prostate cancer remains unknown. In this study, we tested the hypothesis that overexpression of nuclear survivin contributes to docetaxel resistance in prostate cancer cells. First, utilizing western blot to assess protein level and methylene blue assays to determine ability to proliferate under cytotoxic conditions, we found that survivin expression and docetaxel IC50 correlates strongly in five prostate cancer cell lines. Furthermore, using paired parental drug sensitive and stepwise selected docetaxel resistant cell lines, we determined that resistant cells overexpress survivin as compared to parental cells, and knockdown of survivin decreases resistance to docetaxel. Our studies suggest that survivin is likely implicated in CRPC and treatment with a direct survivin inhibitor may sensitize resistant cells to docetaxel. We are in the process of determining how this IAP may mechanistically mediate docetaxel resistance. Citation Format: Robert C. Peery. Targeting survivin to overcome docetaxel resistance in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4396.

CMET-10. EFFECT OF EGFR AND ALK MUTATIONS ON THE OUTCOME OF STAGE III LUNG CARCINOMA PATIENTS WITH BRAIN METASTASIS - CLEVELAND CLINIC EXPERIENCE

Lung Cancer is the leading cause of mortality in men and women diagnosed with cancer world-wide. Among patients diagnosed with lung cancer, non-small cell lung cancer (NSCLC) is one of the most common type consisting predominantly Adenocarcinoma, Squamous cell carcinoma, and large cell carcinoma. Patients with stage III NSCLC are referred to multi-modality treatment protocols which includes chemo-therapy, radio-therapy or both and surgery when feasible. Molecular technology has enabled identification of mutations like EGFR (Epidermal growth factor receptor) and ALK (Anasplatic lymphoma kinase). With the advances in targeted therapy, the aim of the study is to compare the PFS and OS in the patients with positive mutations having brain metastasis to those who had negative mutation. In a retrospective study, the Cleveland Clinic’s database was used to identify stage III NSCLC patients treated through 2003–2014. There were a total of 734 patients in the study. NSCLC Stage III was characterized by clinical or pathological stage. Kaplan-Meier estimate was used to determine the survival of patients by conducting a regression of OS and PFS against time since treatment was begun. 2-year survival and 5-year survival were treated as binary variables. There were a total of 734 patients in the study. Overall 130 patients had brain metastasis out of 734 patients i.e. approximately 18%. 202 patients had a mutation status which was observed to be either positive or negative. 23 patients with mutation negative status had brain metastasis, 2 patients with EGFR positive and 1 patient with ALK positive mutation had brain metastasis. Hazard Ratio (HR) (95% CI); Overall Survival 0.36 (0.047, 2.80) p = 0.33; PFS 0.27 (0.035, 2.13) p = 0.21. In stage 3 lung carcinoma patients, no statistically significant difference was observed in the OS and PFS for patients with brain metastasis having positive mutation status.

Abstract LB-185: A PSMA-directed natural killer cell approach for prostate cancer immunotherapy

Abstract Prostate Cancer (PCa) is the third leading cause of cancer mortality in men in the United States. Locally advanced or metastatic PCa is clinically managed with androgen deprivation therapy (ADT), androgen receptor antagonists, and/or taxane chemotherapy. While initially effective, patients eventually develop resistance, leading to onset of a lethal castration-resistant disease state for which no curative interventions currently exist. Cell-based immunotherapy—which is centered on infusion of modified, tumor-directed immune cells intended to drive a more potent anti-tumor response—could potentially provide a new approach to treating advanced PCa. In this study, we describe the modification of an allogeneic, immortalized human natural killer cell line, NK-92, with a chimeric antigen receptor (CAR) directed against prostate-specific membrane antigen (PSMA), a cell-surface antigen expressed by most prostate tumors. We observed that both unmodified and CAR-bearing NK-92 cells display potent cytolytic activity against the majority of PCa cell lines tested in vitro. Expression of PSMA on PCa cell lines affected the activity of CAR-modified, but not unmodified, NK-92. Combination of NK-92 immunotherapy with ADT and taxanes is also discussed, as well as ongoing in vivo preclinical modeling. Overall, CAR-modified NK-92 cells show promise as a novel immunotherapeutic agent for the treatment of PCa. Citation Format: Lucas J. Brand, Alexander B. Zaslavsky, Ganesh S. Palapattu, Karen E. Knudsen. A PSMA-directed natural killer cell approach for prostate cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-185. doi:10.1158/1538-7445.AM2017-LB-185

Abstract 3569: Comparative RNA-seq analysis reveals dys-regulation of major canonical pathways in ERG-inducible LNCaP cell progression model of prostate cancer

Abstract Prostate Cancer (CaP) is the most common non-cutaneous form of cancer in men and is the second leading cause of cancer mortality in men in the USA. In human CaP, gene fusion between androgen responsive regulatory elements at the 5' untranslated region of TMPRSS2 and ETS-related genes (ERG) is present in at least 50% of the prostate tumors. To identify and investigate the underlying mechanisms of ERG-associated CaP, we developed ERG-inducible LNCaP cell system. In this present study, we investigated the unique cellular transcriptome associated with over-expressed ERG in CaP cells. Our data from comprehensive transcriptome analyses, illustrate a distinct signature that distinguishes ERG-dependent and ERG-independent CaP. The data highlight the significant heterogeneity among the transcript. Out of the 527 differentially expressed genes, 232 genes were up-regulated and 295 genes were down-regulated in response to ERG. Subsequent, in silico analyses indicate that these differentially expressed genes were associated with many pathways and functions. The most significantly differentially expressed genes were associated with cell cycle regulation. The top-ranked biological functions affected by ERG over-expression include Cell Cycle (p < 1.42E-04), Cellular Growth and Proliferation (p < 1.23E-04), Cellular Development (p <1.23E-04), Cell Death and Survival (p < 1.37E-04), and Cellular Assembly and Organization (p < 1.42E-04). Further analyses indicate a strong association with known cancer networks. The top-ranked canonical pathways enriched in ERG-positive compared to ERG-negative LNCaP cells include, Cell Cycle Control of Chromosomal Replication (p=2.69E-16), Role of CHK Proteins in Cell Cycle Checkpoint Control (p=3.16E-11), Cell Cycle: G2/M DNA Damage Checkpoint Regulation (p=1.34E-09), Role of BRCA1 in DNA Damage Response (p=4.05E-08) and Estrogen-mediated S-phase Entry (p =5.51E-08). These findings indicate new insights into the complexity of TMPRESS2-ERG gene fusion, and may help understand mechanistic pathways which promote growth and progression of CaP. Citation Format: Parameet Kumar, Joyeeta Chakraborty, Raghunath Chatterjee, Gauthaman Sukumar, Clifton L. Dalgard, Kevin Babcock, Albert Dobi, Taduru L. Sreenath, Roopa Biswas. Comparative RNA-seq analysis reveals dys-regulation of major canonical pathways in ERG-inducible LNCaP cell progression model of prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3569. doi:10.1158/1538-7445.AM2017-3569

PD09-06 CAN A SIMPLE COUNT OF SEVERAL COMMON COMORBIDITIES ACCURATELY PREDICT LONG-TERM, OTHER CAUSE MORTALITY IN MEN WITH PROSTATE CANCER?

You have accessJournal of UrologyGeneral & Epidemiological Trends & Socioeconomics: Practice Patterns, Quality of Life and Shared Decision Making II1 Apr 2017PD09-06 CAN A SIMPLE COUNT OF SEVERAL COMMON COMORBIDITIES ACCURATELY PREDICT LONG-TERM, OTHER CAUSE MORTALITY IN MEN WITH PROSTATE CANCER? Kian Asanad, Douglas Skarecky, Thomas Ahlering, Stephen Freedland, and Timothy Daskivich Kian AsanadKian Asanad More articles by this author , Douglas SkareckyDouglas Skarecky More articles by this author , Thomas AhleringThomas Ahlering More articles by this author , Stephen FreedlandStephen Freedland More articles by this author , and Timothy DaskivichTimothy Daskivich More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.556AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Physicians need practical methods to accurately estimate life expectancy when counseling older men with comorbidities regarding treatment of prostate cancer. Although numerous nomograms exist for prediction of life expectancy (LE), few are used in practice due to the difficulty of integration into busy clinical workflows. We sought to determine if survival could be accurately predicted if reduced to a count of several common comorbidities that pose a high risk to mortality. In selecting these comorbidities, we aimed to balance frequency and risk in order to maximize identification of men at risk for overtreatment based on <10-year LE. METHODS We sampled 1,598 men with newly diagnosed prostate cancer at two Southern California Veterans Affairs Medical Centers from 1998 to 2004. We created rank-ordered lists of comorbidities organized by frequency and highest risk of mortality. Separate ranked lists were then created by differentially weighting comorbidities by frequency to risk ratios: 1:6, 1:4, 1:2, 1:1, 2:1, 4:1, and 6:1. By successively adding comorbidities from highest- to tenth highest-ranked, a set of 10 candidate comorbidity indices was constructed for each list. Using competing risks regression analysis, we determined c-index, the number of men with <10-year LE, and the number of men with <10-year LE treated with surgery or radiation for each index. RESULTS Candidate comorbidity indices heavily weighted by frequency were poor at identifying men with <10-year LE, while indices heavily weighted by risk of mortality failed to identify men who were overtreated. Six candidate indices each found more than 300 men with <10-year LE (range 303-392); all six were weighted either 2:1, 1:1, or 1:2 by frequency to risk ratio and included highly similar comorbidities. Two of the six indices identified more than 200 men with <10-year LE overtreated with surgery or radiation (range 173-203). The candidate index with the highest number overtreated was weighted 1:1 by frequency to risk and included six comorbidities: 1) chronic obstructive pulmonary disease 2) congestive heart failure 3) peripheral vascular disease 4) stroke 5) myocardial infarction 6) exertional angina. C-index for this index was 0.66. CONCLUSIONS A simple count of six comorbidities predicts the risk of 10-year other-cause mortality and robustly identifies men who are overtreated for early stage prostate cancer. Simplifying estimation of life expectancy may be key to operationalizing this critical variable for prostate cancer decision-making. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e196 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Kian Asanad More articles by this author Douglas Skarecky More articles by this author Thomas Ahlering More articles by this author Stephen Freedland More articles by this author Timothy Daskivich More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

A comparison of surrogate endpoints for all cause mortality in men with localized unfavorable-risk prostate cancer.

21 Background: Several surrogates for prostate cancer-specific mortality exist, but whether these are surrogates for all cause mortality (ACM), and how their performance compares, is unknown. We investigated the relative efficacy of 4 candidate surrogates for ACM using the proportion of treatment effect (PTE) metric. Methods: Two-hundred and six men with localized unfavorable-risk prostate cancer were randomized to radiation therapy (RT) or RT and 6 months of androgen-deprivation therapy (ADT) from 1995 to 2001 and followed for a median of 16.62 years. Among the 159 men with no or minimal comorbidity, a significant reduction in the risk of death was observed in those randomized to RT and ADT versus RT alone; these 159 men formed the study cohort. In order to assess whether the candidate surrogated satisfied Prentice’s criteria for surrogacy, Cox regression analyses were performed to assess the risk of death for each of the candidate surrogates and treatment before and after adjusting for prostate-specific antigen (PSA), age at randomization, T category, and Gleason score. Results: PSA nadir &gt; 0.5 ng/mL, PSA doubling time &lt; 9 months and interval to PSA failure &lt; 30 months met Prentice’s criteria for surrogacy (P = 0.01, 0.003, and 0.03 for the surrogate covariate in the multivariable model, respectively) for ACM, while PSA failure did not (P = 0.10). For the three surrogates, the PTE values were 103.86%, 43.09%, and 41.26%, respectively. Conclusions: A PSA nadir value of &gt; 0.5 ng/mL following RT and ADT identified men prior to PSA failure who were at high-risk for death and therefore could be used to select men for entry, at the time of PSA nadir and before PSA failure, onto randomized trials evaluating the impact on survival of salvage ADT with or without agents shown to prolong survival in men with castrate-resistant metastatic prostate cancer. By enriching study cohorts with men who have achieved a surrogate endpoint for ACM, one can enhance the likelihood that the study will be able to observe whether survival is prolonged when novel treatment is added to ADT, as compared to ADT alone, in an abbreviated time period. Clinical Trial Number: NCT00116220

Novel Lipid Indices as a Better Marker of Cardiovascular Disease Risk in Postmenopausal Women

ABSTRACT Introduction Cardiovascular disease (CVD) is the major leading cause of mortality in men and women around the globe. The incidence of CVD increases with age in both the sexes, whereas it has been noted that there is a marked increase in risk among women after menopause. The hormonal changes associated with the menopause like low level of plasma estrogen and marked increase in follicle stimulating hormone levels exert a significant effect on metabolism of plasma lipids and lipoproteins leading to atherosclerosis, thereby increasing the risk of CVD in postmenopausal women. Objectives To study the lipid profile parameters and to calculate and compare the lipid indices with lipid profile parameters in pre- and postmenopausal women. Materials and methods The study group included 90 women comprising 45 postmenopausal (cases) and 45 premenopausal (control) women. To estimate lipid profile, enzymatic method was used and for calculation of lipid indices appropriate formula was used. Results Altered lipid profile was observed in postmenopausal women, but it was not statistically significant. Atherogenic Index of Plasma, Castelli's risk index-I, atherogenic coefficient, and nonhigh-density lipoprotein cholesterol were significantly increased in postmenopausal women compared with premenopausal women, but there was no significant increase in Castelli's risk index-II. Conclusion Lipid indices may be considered as a better and cost-effective tool in assessing the risk of CVD in postmenopausal women. How to cite this article Sirigere M, Meera S. Novel Lipid Indices as a Better Marker of Cardiovascular Disease Risk in Postmenopausal Women. Indian J Med Biochem 2017;21(1):38-41.

Abstract 3420: Clinical prognostic factors in adult with astrocytoma: Historic cohort

Abstract Introduction: Malignant tumors of the central nervous system contribute extremely to cancer mortality especially in the high risk age groups. In USA are the second and the fifth leading cause of cancer mortality in men and women aged 20 to 39 years respectively. Astrocytomas are the most common and lethal tumors of the CNS, being the most common grade IV (glioblastoma) (4.37 per 100,000 population). The prognosis of astrocytomas can be predicted by specific clinical factors allowing neurosurgeons and neuro-oncologists to define the best treatment for each patient. Some patients’ features like age, gender, performance status and tumor localization have been studied as potential prognostic factors. In Mexico there are few reports on demographic, clinical characteristics and prognostic factors in adults. Objective: To explore the clinical prognostic factors for adults affected with astrocytoma Methods: Using a historic cohort, we selected by simple randomization, 155 clinical files from patients with astrocytoma. The main outcome variable was overall survival time (OS). To identify clinical prognosis factors we used: bivariate analysis, Cox regression models, log rank test and Kaplan-Meier survival function. Results: The mean age at diagnosis was 45.7 years. Compared with other studies, our population was 15 years younger when diagnosed. Analysis by stage in grade II, III and IV also showed a younger age of presentation. The OS was 15 months, 9% (n = 14) presented a survival of 2 years and 3% of 3 years. Kaplan-Meier survival estimate showed that the variables grade, Karnofsky Performance Status (KPS)&amp;gt;70, the type of resection, chemotherapy, radiotherapy, alcohol consumption, familiar history of cancer and clinical presentation were significantly associated to survival time. Using proportional Hazard Model the variables: age, grade IV, resection, chemotherapy + radiotherapy and KPS where prognosis factors. Conclusion: Astrocytoma in our study was present in young adults. The OS was 15 months, 9% (n = 14) presented a survival of 2 years and 3% of 3 years. The variables alcoholism, family history of cancer and clinical presentation influenced significantly survival time, and showed a tendency in the mortality analyses. Citation Format: Talia Wegman-Ostrosky, Nancy Reynoso Noverón, Sonia Iliana Mejía-Pérez, Thalía Estefania Sánchez-Correa MD, Rosa María Álvarez, Bernardo Cacho, Luis A. Montalvo, Teresita Corona. Clinical prognostic factors in adult with astrocytoma: Historic cohort. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3420.

Abstract 1174: AZD4547 and AZD5363 synergistically inhibit prostate cancer progression by modulating MAPK and AKT activation

Abstract Prostate cancer (PCa) is the second most common cancer and the second most common cause of cancer mortality in men in the United States. Multiple approved therapies target the androgen signaling axis in this metastatic disease, however, after advancing to the androgen-independent stage, PCa is unresponsive to androgen ablation therapy and is refractory to further curative treatment. Recent advances have demonstrated that two intracellular signaling pathways promote prostate cancer progression, one is the Fibroblast Growth Factor (FGF) pathway included multiple FGFs and 4 kinds of FGF receptors (FGFR), which remains activated in the cancer cells, the other is the oncogenic PI3K/AKT pathway, which is constantly active due to the loss of an important tumor suppressor gene. Targeted inhibition of FGF and AKT signaling pathways has shown promising both in vitro and in vivo studies. However, FGFR or AKT inhibitor, as a single agent, would result in a reciprocal feedback loop. Therefore, it is imperative that both pathways be targeted simultaneously in the treatment of advanced prostate cancer. In this study, we evaluated the effect of combined treatment of FGFR inhibitor AZD4547 and AKT inhibitor AZD5363 on PCa progression. Proliferation assay shows that AZD4547 just weakly, or not inhibits PCa cell proliferation, AZD5363 significantly inhibits PCa cell proliferation; the combined treatment of AZD4547 and AZD5363 shows similar inhibition effect to AZD5363. Both AZD4547 and AZD5363 inhibit PCa cell anchorage-independent growth and invasion, which are synergistically decrease by the combined treatment. AZD4547 significantly inhibits phosporylation of FGFR1 and FGFR4 in PCa cells; AZD5363 increases FGFR1 and FGFR4 phosphorylation, which was significantly repressed in combined treatment. The activation of FGFR2α, MEK1/2, and Erk1/2 in PCa cells was remarkably inhibited by AZD4547 but increased by AZD5363, and synergistically inhibited by the combined treatment. AKT was hyperphosphorylated by AZD5363 and inhibited by AZD4547. The phosporylation of AKT downstream molecules PRAS40, GSK3β and S6, was slightly decreased by AZD4547 but strongly inhibited by AZD5363 and the combined treatment. Both AZD4547 and AZD5363 suppress STAT3 phosphorylation in PCa cells and the combind treatment shows synergistic inhibition effect. Both AZD4547 and AZD5363 promote AR and PTEN expression at both RNA and protein levels in VCaP and 22RV1cells, and the combination treatment remains the promotion effect. In LNCaP cells, AZD5363, but not AZD4547, stimulates AR mRNA and protein expression, which keep increased in combined treatment. This study provides a preclinical proof of concept that combination of a FGFR inhibitor with an AKT inhibitor has a profound potential to treat PCa. Acknowledgement: This project was supported by the DOD Prostate Cancer Program, PCRP-IDEA-PC120481 (Ittmann), the Prostate Cancer Foundation (Ittmann) Citation Format: Shu Feng, Michael Ittmann. AZD4547 and AZD5363 synergistically inhibit prostate cancer progression by modulating MAPK and AKT activation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1174.

The association of serum uric acid with total white blood cell count in a healthy Indian adult population

Background: Atherosclerosis is the underlying cause for nearly all cases of Coronary Artery Disease (CAD) which is a major cause of mortality in men and women. Numerous studies state that the basic pathology behind atherosclerosis is inflammation and oxidative stress. Though uric acid is an anti oxidant, recently studies show that it can be transported across the cell membrane and exert harmful intracellular actions such as oxidation and inflammation. These observations led to many epidemiological studies suggesting that uric acid is linked to and may be a risk factor for CAD. The aim of this study was to evaluate whether there is an association between serum uric acid and total white blood cell count, a simple marker of inflammation, in a healthy Indian adult population. Method: This is a cross sectional study. Samples were collected for assaying serum uric acid, total white blood cell count and plasma glucose, along with the medical history from 203 apparently healthy individuals who attended health examination at Sri Ramachandra Medical Centre in Chennai. Result: The results obtained were subjected to statistical analysis in SPSS software version 16. There was a strong positive correlation between uric acid and total white cell count and the study revealed no significant difference in mean levels of uric acid in tobacco users and non-users. And there was no statistically significant difference between genders in the mean uric acid level. Conclusion: A strongly positive correlation was found between serum uric acid and total white cell count, both in men and women. It appears likely that additionally larger well designed prospective studies that adjust for all possible confounding factors may help to strongly establish the correlation between serum uric acid and total white cell count and their role in pro-inflammatory states as in atherosclerosis. Keywords: Uric acid, White blood cell count, Inflammation, Coronary artery disease, Atherosclerosis

Cardiology Patient Page: Vitamin D and Your Heart.

Heart disease remains the leading cause of mortality for men and women in the United States and worldwide. Originally known for its crucial role in the maintenance of bone health, vitamin D has emerged as a potential therapeutic target in the prevention of cardiovascular disease. A growing body of evidence suggests an association between vitamin D deficiency and increased cardiovascular disease morbidity and mortality; however, optimal levels of vitamin D for heart health remain undefined. Vitamin D is a hormone precursor that can be obtained from natural or fortified foods, dietary supplements, or exposure of the skin to the ultraviolet rays of sunlight. It is uniquely different from all other vitamins because of our body’s own ability to produce it in adequate quantities from exposure to ultraviolet B light, which initiates the skin synthesis of vitamin D3 (cholecalciferol). Vitamin D3 then undergoes modification by the liver to 25(OH)D, which is the best indicator of vitamin D exposure and is easily measured in the blood. Vitamin D ultimately undergoes final hydroxylation by our kidneys to its biologically active form, 1,25(OH)2 …