Poor Prognosis In Men Research Articles

Clinical validation of circulating GDF15/MIC-1 as a marker of response to docetaxel and survival in men with metastatic castration-resistant prostate cancer.

Elevated circulating growth differentiation factor (GDF15/MIC-1), interleukin 4 (IL4), and IL6 levels were associated with resistance to docetaxel in an exploratory cohort of men with metastatic castration-resistant prostate cancer (mCRPC). This study aimed to establish level 2 evidence of cytokine biomarker utility in mCRPC. IntVal: Plasma samples at baseline (BL) and Day 21 docetaxel (n = 120). ExtVal: Serum samples at BL and Day 42 of docetaxel (n = 430). IL4, IL6, and GDF15 levels were measured by ELISA. Monocytes and dendritic cells were treated with 10% plasma from men with high or low GDF15 or recombinant GDF15. IntVal: Higher GDF15 levels at BL and Day 21 were associated with shorter overall survival (OS) (BL; p = 0.03 and Day 21; p = 0.004). IL4 and IL6 were not associated with outcomes. ExtVal: Higher GDF15 levels at BL and Day 42 predicted shorter OS (BL; p < 0.0001 and Day 42; p < 0.0001). Plasma from men with high GDF15 caused an increase in CD86 expression on monocytes (p = 0.03), but was not replicated by recombinant GDF15. Elevated circulating GDF15 is associated with poor prognosis in men with mCRPC receiving docetaxel and may be a marker of changes in the innate immune system in response to docetaxel resistance. These findings provide a strong rationale to consider GDF15 as a biomarker to guide a therapeutic trial of drugs targeting the innate immune system in combination with docetaxel in mCRPC.

Sex Differences under Vitamin D Supplementation in an Animal Model of Progressive Multiple Sclerosis.

A central role for vitamin D (VD) in immune modulation has recently been recognized linking VD insufficiency to autoimmune disorders that commonly exhibit sex-associated differences. Similar to other autoimmune diseases, there is a higher incidence of multiple sclerosis (MS) in women, but a poorer prognosis in men, often characterized by a more rapid progression. Although sex hormones are most likely involved, this phenomenon is still poorly understood. Oxidative stress, modulated by VD serum levels as well as sex hormones, may act as a contributing factor to demyelination and axonal damage in both MS and the corresponding preclinical models. In this study, we analyzed sex-associated differences and VD effects utilizing an animal model that recapitulates histopathological features of the progressive MS phase (PMS). In contrast to relapsing-remitting MS (RRMS), PMS has been poorly investigated in this context. Male (n = 50) and female (n = 46) Dark Agouti rats received either VD (400 IU per week; VD+) or standard rodent food without extra VD (VD-) from weaning onwards. Myelination, microglial activation, apoptotic cell death and neuronal viability were assessed using immunohistochemical markers in brain tissue. Additionally, we also used two different histological markers against oxidized lipids along with colorimetric methods to measure protective polyphenols (PP) and total antioxidative capacity (TAC) in serum. Neurofilament light chain serum levels (sNfL) were analyzed using single-molecule array (SIMOA) analysis. We found significant differences between female and male animals. Female rats exhibited a better TAC and higher amounts of PP. Additionally, females showed higher myelin preservation, lower microglial activation and better neuronal survival while showing more apoptotic cells than male rats. We even found a delay in reaching the peak of the disease in females. Overall, both sexes benefitted from VD supplementation, represented by significantly less cortical, neuroaxonal and oxidative damage. Unexpectedly, male rats had an even higher overall benefit, most likely due to differences in oxidative capacity and defense systems.

Linear and non‑linear indices of vagal nerve in relation to sex and inflammation in patients with Covid‑19.

Hyperinflammation is one of the most important pathophysiological risk factors for poor prognosis in patients with coronavirus disease-2019 (Covid-19). Low vagal neuro-immune modulation can lead into this kind of immune dysregulation. The association between vagal activity, sex and inflammatory markers were investigated in patients with Covid-19. A total of 19 patients with Covid-19 were included in the present study. Vagus nerve activity was indexed by heart rate variability (HRV) derived from electrocardiogram at hospital admission. Linear HRV parameters included the root mean square of successive RR interval differences (RMSSD) and high-frequency HRV (HF-HRV), while non-linear parameters included 2 UV%. Immune/inflammatory parameters included C-reactive protein (CRP), interleukin-6 (IL-6), neutrophil/lymphocyte ratio (NLR), systemic inflammatory index (SII), and procalcitonin (PCT). It has been revealed that both linear HRV indices HF-HRV and RMSSD, are significantly negatively correlated with CRP and IL-6, independent of age. The non-linear index of 2 UV% is significantly negatively correlated with NLR and SII, which reflect subtle changes in the response of immunocompetent cells. Patients that received high-flow nasal oxygen therapy had significantly higher IL-6 and CRP levels and lower levels of HF-HRV and RMSSD. These patients also had a significantly longer length of stay in hospital (LOS) than patients receiving low-flow oxygen therapy. Men had higher plasma PCT levels and longer LOS in hospital than women, and PCT statistically explained (mediated) the association between sex and LOS. The present study showed different correlations of linear and non-linear vagal indexes of HRV and inflammatory markers in patients with Covid-19. Significant sex differences in certain inflammatory markers were also observed, which may very well verify previous findings of poor prognosis in men with Covid-19. HRV reflects a continuous interaction between the sympathetic and parasympathetic autonomic nervous systems, which are affected by mental or physical stress, and certain disease states. The increased sympathetic and decreased parasympathetic vagal tone contribute to a higher risk of diseases associated with inflammation, cardiovascular disease, cancer, pulmonary diseases and other pathologies, including infectious diseases such as Covid-19. The present study showed that higher RMSSD (a marker of vagal activity) in Covid-19 patients is associated with lower levels of inflammatory biomarkers, a lower need for treatment and is negatively correlated with intensive care unit admission, leading to a shorter hospital stay. These findings support the idea that activation of vagus nerve may help certain Covid-19 patients by reducing the cytokine storm and excessive inflammation.

Bulk RNA-Seq Combined with Single-Cell Transcriptome Sequencing Reveals the Possible Mechanisms by Which HDGFL3 Involves in Prostate Cancer Growth and Metastasis.

Based on publicly available transcriptome and single-cell sequencing data, the current study aimed to explore the molecular mechanisms underlying the involvement of hepatocellular carcinoma-derived growth factor-like 3 (HDGFL3) in prostate cancer (PCA) growth and metastasis. The Gene Expression Omnibus database was used to download the single cell transcriptome of PCA (GSE193337). Single-cell RNA sequencing (scRNA-seq) data were examined to identify which genes are essential for endothelial cell function. The Cancer Genome Atlas Prostate Adenocarcinoma database provided the RNA sequencing data, and univariate COX regression analysis was introduced to identify the genes that were associated with the prognosis of patients with PCA. Human PCA cell lines PC-3 and DU145 were used in in vitro cellular studies to test the effect of silencing HDGFL3. The results were validated using Transwell® assay, scratch assay, and cell counting kit-8 assay. To support the role of HDGFL3 in PCA, an in vivo animal model of PCA transplantation tumor in nude mice was established. Quantitative reverse transcription polymerase chain reaction was introduced to measure HDGFL3 messenger ribonucleic acid (mRNA) expression levels in tumor tissues from nude mice, and Hematoxylin and Eosin staining was used to identify lung metastasis. Immunohistochemical staining was employed to identify the expression levels of HDGFL3 and hematopoietic progenitor cell antigen CD34+. It was discovered through analysis of the scRNA-seq dataset that HDGFL3, a gene specific to endothelial cells, is linked to a poor prognosis in men with PCA. In addition, HDGFL3 and the expression of genes linked to angiogenesis have a substantial association. Studies on cells in vitro revealed that silencing HDGFL3 prevented PC-3 and DU145 cells from proliferation, migrating and invading. Silencing HDGFL3 decreased the weight of prostate tumors, the number of lung metastases, and the area occupied by CD34+ vascular endothelial cells, according to in vivo investigations. This study identified HDGFL3 as a key gene in endothelial cells that may stimulate tumor angiogenesis to increase the growth and spread of PCA. These results imply that HDGFL3 may represent a possible target for antiangiogenic therapy in the management of PCA.

GENDER DIFFERENCES IN THE INFLUENCE OF COMORBID CONDITIONS ON THE LONG-TERM OUTCOMES OF PATIENTS WITH ACUTE CORONARY SYNDROME

Background. Gender differences in the baseline characteristics of patients with the acute coronary syndrome (ACS) have been widely acknowledged. Women are known to be generally older with a higher prevalence of comorbidities. &#x0D; Objectives. Gender differences in the baseline characteristics of patients with the acute coronary syndrome (ACS) have been widely acknowledged. Women are known to be generally older with a higher prevalence of comorbidities. At the same time, it is now yet clear which comorbid conditions have the most significant impact on the long-term outcomes of patients with ACS and if there are any gender differences in this respect. &#x0D; Methods. We performed a retrospective cohort study of 167 patients (109 men and 58 women) admitted to the acute coronary unit of Ternopil Municipal Hospital with ACS in 2016-2017. All relevant clinical information has been recorded in the pre-designed data charts. The incidence of repeated major adverse cardiovascular events (MACEs) has been assessed over 36 months after the hospital discharge via an e-Health electronic system. &#x0D; Results. In this cohort, female patients with ACS had a higher prevalence of comorbid conditions: 15.5% of women vs. 11% of men with ACS had ≥5 comorbidities, 65.5% of women and 60% of men had 2-4 comorbid conditions, and 19% of women vs. 29% ≤1 concomitant disease. The comorbidity structure also differed between genders. Women more often had concomitant cerebrovascular diseases (17.2% vs. 7.3%, p=0.05), dementia (15.5% vs. 5.5 %, p=0.03), connective tissue disorders (17.25 vs. 6.42%, p=0.03) and thyroid disease (12.1% vs. 2.8%, p=0.02). Men more often suffered from peptic ulcer (13.7% vs. 3.4%, p=0.05). The incidence of MACEs during the follow-up period rose sharply with age and was higher in females (55% vs. 33%, p=0.003). In the multivariable model, PAD (OR 9.5, 95% CI: 1.7-52.3, p=0.01) and thyroid disease (OR 7.2, 95% CI: 1.19-43.2, p=0.03) demonstrated the most significant impact on the long-term event-free survival of females in the cohort. In turn, a solid metastatic tumor was the most significant predictor of poor prognosis in men (OR 6.3, 95% CI: 2.13-18.9, p=0.001). &#x0D; Conclusions. We observed significant gender differences in the prevalence of comorbid conditions and their influence on the three-year event-free survival of patients with ACS. The predictive value of comorbidities should be further investigated, preferably, with the involvement of larger cohorts. &#x0D; &#x0D; &#x0D;

Gender differences in organ involvement and survival in systemic sclerosis – experience of a EUSTAR center

Introduction. The low overall prevalence of systemic sclerosis (SSc) and the low proportion of male patients have resulted in a scarcity of studies assessing sex differences in SSc patients, and contradictory results have often been observed. Material and method. We performed a retrospective observational study using data extract from the EULAR scleroderma trials and research (EUSTAR) cohort 096 . We looked at sex influence on disease characteristics at baseline and then focused on patients with at least 2 years of follow-up to estimate the effects of sex on disease progression and survival. Results. 173 patients with SSc were available for the baseline analyses. In the longitudinal analysis after a mean follow-up of 3.5(±0.65) years, male sex was associated with a higher risk of scleroderma renal crisis (OR:9.45 (1.49 to 59.69); p = 0.004), digital contractures (OR:8.2 (3.1 to 21.9); p &lt; 0.001), arrhythmias (OR: 3.37 (1.36 to 8.34); p = 0.006), pulmonary fibrosis (OR: 3.56, (1.51 to 8.41); p = 0.003), pulmonary hypertension (OR: 3.01 (1.19 to 7.59); p = 0.016), severe vascular involvement (OR:2.86, (1.22 to 6.73); p = 0.013) and low ventricular ejection fraction (OR: 2.84, (1.2 to 6.73); p = 0.014). Males had significantly reduced survival time after diagnosis (p = 0.004). The most frequent causes of death were scleroderma renal crisis in males and pulmonary hypertension in females. Conclusions. Although more common in women, SSc appears as strikingly more severe in men. Our results demonstrate a higher risk of severe organ involvement and poor prognosis in men. These results raise the point of including sex in the management and the decision-making process.

Mesoporous silica nanoparticles with surface transformation ability for prostate cancer treatment

Prostate cancer is one of most devastating disease with the poor prognosis in men. The efficacy of conventional therapies is far from satisfactory due to the insufficient chemotherapeutic delivery to the cancer cells which requires the extremely high or toxic dose to reach the therapeutic window. In this work, a charge reversal nanoplatform based on mesoporous silica nanoparticle (MSN) with a core-shell structure is developed to programmatically overcome persistent obstacles in drug delivery to prostate cancer. MSN is served as a container to high-efficiently pack chemotherapeutic drug of triptolide. 2, 3-dimethylmaleic anhydride grafted poly-(allylamine hydrochloride) (PAH-DA) is used as the out shell with a negative charge for pH-triggered charge reversal, which can facilitate the cellular uptake. Furthermore, PAH-DA shell can also act as pH-sensitive gatekeepers while will elegantly shed from MSN under acidic tumor microenvironment for controlling drug release. As expected, in vitro cell experiments demonstrated that the as-prepared nanoplatform (denoted as MSN-T@PAH-DA) could be efficiently uptaken by LNCaP prostate cancer cells and exhibited a better anti-cancer effect at pH 6.5 as compared to that at pH 7.4. After intravenous injection, MSN-T@PAH-DA had a relatively higher tumor accumulation than MSN-T@PAH-SA counterpart without charge conversion ability, and thus achieving enhanced tumor growth suppression in mouse model of prostate cancer. Therefore, the pH-response surface charge reversal capacity of PAH-DA shell could enable multitasking in controlling drug release, regulating tumor accumulation and cellular internalization, which provided a promising strategy for efficient prostate tumor treatment.

Pilot study of anti-prostate-specific membrane antigen (PSMA) antibody J591 for men with metastatic castration-resistant prostate cancer (mCRPC) and unfavorable circulating tumor cell (CTC) count.

120 Background: Elevated CTC counts are associated with a poor prognosis in men with mCRPC. PSMA targeted radionuclide therapy has been associated with decline in CTC count, but it remains unclear whether this effect results from radionuclide-induced cytotoxicity. J591 was engineered to have antibody-dependent cytotoxicity. A subset of patients was observed to have CTC count decline following imaging with 111In-J591, so a prospective study was launched to test the hypothesis that “naked” J591 leads to CTC count decline. Methods: In a Simon 2-stage dose de-escalation study, men with progressive mCRPC and unfavorable CTC count (CellSearch &gt; 4) received a single dose of J591. Initial dose cohort 300 mg with de-escalation to 20 mg. CTC count was re-assessed 4, 8, and 12 weeks following therapy along with PSA and standard imaging. An optional PSMA PET was included prior to treatment. The primary endpoint was proportion of subjects with conversion to favorable CTC count ( &lt; 5 CTCs/7.5 mL blood) and/or &gt; 30% decline from baseline within 12 weeks post-treatment. Results: 10 men were enrolled, 9 of whom were evaluable (1 died of progressive mCRPC prior to post-treatment CTC count). Median age was 71.5 years (range 60-81), 78% had prior chemo, ECOG PS 1 in 45% and 2 in 55%. 7 of 9 (78%) evaluable subjects were Halabi CALGB prognostic poor risk category and 2 (22%) intermediate. 6 of 9 had pre-treatment PSMA PET/CT (three 89Zr-J591 and three 68Ga-PSMA11). Though not required, all scans showed &gt; 1 lesion with SUVmax &gt; liver SUV (range 9.12-70.15). 2 of 6 in the 300 mg cohort had CTC count decline; 1 of 6 converted to favorable count (9 to 0 with decrease of 35 to 12 in other). 3 were treated with 20 mg; 1 had CTC count decline of 316 to 112, but 0 converted to favorable count. Across both cohorts, 3 of 9 had a CTC count decline at any point in time, ranging from 65-100% decline. With the pre-specified 2-stage design, enrollment was halted for futility based upon the primary endpoint of 12-week CTC count. PSA values post-treatment increased in 8 (89%) patients and remained unchanged in 1 (11%) patient. Conclusions: Single-agent anti-PSMA antibody J591 may lead to decline in CTC count, though the study did not meet its primary endpoint. A combination or maintenance approach might be preferable and is worthy of exploration.

Distinctive landscape of genetic mutation in patients with intraductal carcinoma of the prostate (IDC-P).

192 Background: Intraductal carcinoma of the prostate (IDC-P) is an independent predictor associated with poor prognosis in men with prostate cancer (PCa) of different stages. Yet, little is known concerning the characteristics of IDC-P at genetic level. The object of this study is to determine the mutation characteristics of patients with IDC-P, aiming at identifying new therapeutic targets for the treatment of IDC-P. Methods: Totally, data of 104 and 35 patients histopathological documented with prostatic adenocarcinoma concomitant with and without IDC-P were included into the current study, respectively. cfDNA was extracted from blood samples for the PCa-related mutation testing through a 90-gene NGS panel. The mutation frequency of different genes was compared between IDC-P positive and negative cases. Results: Almost all the pathogenetic germline mutations were detected from patients with IDC-P [15/104 (14.4%) vs. 1/35 (2.9%), p=0.064]. Pathogenetic germline BRCA2 mutations were all found in IDC-P positive patients [10/104 (9.6%) vs.0/35 (0.0%), p=0.057]. Besides, in terms of somatic mutations, men with IDC-P had significantly higher proportion of mutations in EGFR [30/104 (28.9%) vs. 2/35 (5.7%), p=0.005], KMT2C [20/104 (19.2%) vs. 1/35 (2.9%), p=0.019] and NCOR2 [19/104 (18.3%) vs. 0/35 (0.0%), p=0.006]. Three high frequently mutated sites of EGFR were identified in men with IDC-P, i.e. p.L861Q (12/104, 11.5%), p.L858R (11/104, 10.6%) and p.G719A/C (12/104, 11.5%). These mutated sites have been proved to be associated with therapeutic response from EGFR tyrosine kinase inhibitors (TKIs) in the treatment of lung carcinoma. Conclusions: Patients with IDC-P are candidates for germline and somatic mutations testing for the high frequency of mutations. Germline DDRs and somatic EGFR mutations were frequently occurred in IDC-P positive patients. Though further verification is needed, these mutations had great potential to be used as therapeutic targets in treating patients with IDC-P.

Abstract 4356: Methylation and expression of androgen receptor in Papillary Thyroid Cancer

Abstract Papillary Thyroid Cancer (PTC) accounts for the vast majority of thyroid cancers and comprises more than 90% of neoplasms in the endocrine system. In the last 30 years, the incidence and prevalence of PTC has dramatically risen in developed countries, with a three-fold higher incidence in women than in men. With an overall five-year survival rate of 98.1%, early stage PTC has a favorable prognosis. However, PTC exhibits increased aggressiveness with poor prognosis in men diagnosed with the disease. These striking observations led us to explore the role of androgen and androgen receptor (AR) in this disease. We found an approximately 70% decrease in median AR RNA expression (p&amp;lt;0.0001) in 24 PTC patient tissue samples (from New York Eye and Ear Infirmary), compared to matched, normal thyroid tissue. A similar trend was also observed in about 500 PTC samples in the TCGA database, compared with 60 normal thyroid samples. Methylation was explored as a cause for the down-regulation of the AR mRNA in disease pathogenesis, using in-silico methods such as Wanderer, a Maplab tool for TCGA RNA data visualization, and MethylPlotter. A methylation pattern of the AR gene, spanning 7 exons, was generated with 30 methylation sites and, AR in PTC was found to be predominantly methylated at ten sites, compared to matched normal thyroid tissue samples, in the TCGA. Patients with ten or more hypermethylated sites on the AR gene in tumor tissue exhibited a significant decrease in the AR RNA expression in the tumor, versus matched normal thyroid tissue. Methylation of AR (10 or more sites) was accompanied by a nine-fold reduction in AR expression in male PTC, and a five-fold decrease in female PTC. This reduction was not observed in hyper- or equally-methylated normal thyroid tissue. We selected eleven methylation sites in the CpG islands that we predict are essential for AR silencing, with four sites in the AR promoter region. Additionally, we found AR gene-specific and global transcription activators to be downregulated, and repressors up-regulated in the PTC samples. The data adds importance to our previous studies showing induction of senescence in AR-transfected PTC cells in culture, when AR is stimulated with 5α-dihydrotestosterone. In conclusion, our study demonstrates a fine regulation and differential expression of AR associated with methylation, and highlights the significance of epigenetic modifications in thyroid cancer progression. Citation Format: Anvita Gupta, Timmy O'Connell, Melanie Jones, Karnika Singh, Monica Schwarcz, JK Rasamny, Dorota Halicka, Jiangwei Li, Codrin Iacob, Nina Suslina, Stimson Schantz, Edward Shin, Zbigniew Darzynkiewicz, Raj Tiwari, Jan Geliebter. Methylation and expression of androgen receptor in Papillary Thyroid 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 4356. doi:10.1158/1538-7445.AM2017-4356

P-03-013 Malignant priapism and non urologic primitive tumors are related with the poorer prognosis in men with penile metastases: Results of a systematic review

P-03-013 Malignant priapism and non urologic primitive tumors are related with the poorer prognosis in men with penile metastases: Results of a systematic review

Abstract 2841: Continuous androgen receptor stimulation in thyroid cancer cells induces irreversible senescence

Abstract Cancer of the thyroid gland accounts for 3.8% of all cancer cases in the United States as indicated by the SEER report by the NCI. The incidence of thyroid cancer has increased three-fold over the last thirty years and the American Cancer Society estimates that there will be approximately 62,450 new cases and 1,950 deaths due to the disease in the country in 2015. Papillary Thyroid Cancer (PTC) is the most common endocrine malignancy with a three-fold higher incidence in women than in men. However, PTC exhibits increased aggressiveness with poor prognosis in men diagnosed with the disease. These incongruent observations led us to explore the role of androgen and androgen receptor in this disease. We found an approximately 70% decrease in median AR expression (p&amp;lt;0.0001) in 24 PTC patient tissue samples, compared to matched, normal thyroid tissue. Preliminary data from our lab indicate that androgen receptor (AR) acts as a negative regulator of growth as evidenced by a statistically significant 48% decrease in proliferation over 72 hours upon 5α-dihydrotestosterone (DHT) addition to 8505c anaplastic/PTC cells stably transfected with AR (clone 84E7). Transcriptional profiling using RNAseq and gene ontology analysis, on 48 hour DHT treated 84E7 cells revealed significant changes in gene expression associated with proliferation (474 genes, p = 2.4E-24) and cell cycle progression (129 genes, p = 6.54E-6). Continuous AR activation (3 to 6 days) resulted in G1 growth arrest, not accompanied by cell death, but rather a flattened, vacuolized cell morphology, indicative of senescence. This was substantiated by an increase in SA-βGal positivity from background 2.47% to approximately 65.5%, which was attenuated by the AR antagonist, flutamide. Three to six day DHT exposure resulted in increased total RNA and protein content measured using Acridine Orange and Sulforhodamine B, respectively. Senescent 84E7 cells failed to resume growth when transferred into DHT-free medium for 3 days, suggesting a permanent growth arrest. Reactive oxygen species (ROS), implicated in Rb-mediated senescence, were found to be doubled by day 6 of AR activation, compared to control cells. Additionally, using flow cytometry, we found increased p21, p27, cyclin D1, FOXO1, and phosphorylation of FOXO1 by days 3-6, suggesting that AR-dependent senescence is mediated via p21 and p27 by FOXO1/3 proteins. Furthermore, cytokine profiling of the senescence-associated secretory phenotype (SASP) would aid in defining the pro-tumorigenic or tumor-suppressive potential of androgen-induced senescent thyroid cancer cells. Our study elucidates the induction of senescence as a novel function of AR activation in thyrocytes and may indicate a protective role of AR activation in the decreased incidence of thyroid cancer in men. Citation Format: Anvita Gupta, Melanie Jones, Timmy O’Connell, Dorota Halicka, Jiangwei Li, Hong Zhao, Augustine Moscatello, Zbigniew Darzynkiewicz, Raj Tiwari, Jan Geliebter. Continuous androgen receptor stimulation in thyroid cancer cells induces irreversible senescence. [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 2841.

P-05-016 Malignant priapism and non urologic primitive tumors are related with the poorer prognosis in men with penile metastases: results of a systematic review

P-05-016 Malignant priapism and non urologic primitive tumors are related with the poorer prognosis in men with penile metastases: results of a systematic review

Obesity and Prostate Cancer.

Prostate cancer is a complex, heterogeneous disease. Factors related to detection, particularly PSA screening, further increase heterogeneity in the manifestation of the disease. It is thus not possible to provide a simple summary of the relationship between obesity and prostate cancer. Findings on obesity, often defined using body mass index (BMI), and total prostate cancer risk have been mixed; however, obesity is relatively consistently associated with ahigher risk of aggressive prostate cancer, with aggressiveness defined in various ways (e.g., advanced stage, fatal, poorer prognosis in men with prostate cancer). Many methodologic issues (e.g., influence of PSA screening, detection bias and treatment) need to be thoroughly considered in both existing and future etiologic and prognostic research. Biological mechanisms supporting the link are under investigation, but may involve insulin and IGF axis, sex steroid hormones and alterations in metabolism. Some promising data suggest that molecular sub-types of prostate cancer may offer insights into etiology, but further study is required. A full evaluation of body fatness and weight change over the life course would not only provide insights to the underlying mechanisms but also allow more effective interventions.

Abstract 3926: RhoB expression is upregulated by androgen in thyroid cancer cells

Abstract The incidence of thyroid cancer has increased three-fold over the last thirty years and the American Cancer Society estimates that there will be 62,980 new cases and 1,890 deaths due to the disease in the United States in 2014. Papillary Thyroid Cancer (PTC) is the most common endocrine malignancy and develops in premenopausal women, at a four-fold higher incidence, than in men. However, PTC exhibits increased aggressiveness with poor prognosis in men diagnosed with the disease. These observations led us to explore the role of androgen and androgen receptor in this disease. Preliminary data from our lab indicates that androgen receptor (AR) acts as a negative regulator of growth as evidenced by a statistically significant decrease in proliferation upon DHT addition to 8505c anaplastic/PTC cells stably transfected with AR. Transcriptional profiling using RNA-Seq and gene ontology analysis, on a 48 hour DHT treated 8505c-AR transfected clone, 84E7, revealed significant changes in the expression of genes associated with proliferation (474 genes, p = 2.4E-24), cell cycle progression (129 genes, p = 6.54E-6) and migration (301 genes, p = 3.77E-30). Amongst the genes which showed the highest significant differential expression was RhoB, a Rho GTPase, with an approximately 50-fold upregulation. Rho proteins are small molecules belonging to the Ras superfamily, known to regulate cell morphology, actin/microtubule cytoskeleton reorganization along with vesicle trafficking. While RhoA and RhoC promote cancer progression and metastasis, the functions of their structural homolog, RhoB, are largely context dependent. Evidence has emerged that RhoB expression may support malignancy in certain cancers, while exhibiting a tumor-suppressor gene function in others. In our system, addition of DHT to 84E7 cells for short time periods of 1, 3 and 6 hours resulted in rapid RhoB mRNA upregulation by 2.5, 8, and 17 fold, respectively, compared to untreated cells. This quick, time-dependent increase in androgen-responsive RhoB may play an integral protective and reparative role which is possibly lost during neoplasticity of thyrocytes. Investigations into various pathways linking RhoB and effector proteins with carcinogenesis would be crucial in assessing the potential of RhoB as a bio-marker for metastatic PTC and thence opening avenues for development of viable therapies for better management of the disease. Citation Format: Anvita Gupta, Melanie Jones, Augustine Moscatello, Edward Shin, Raj K. Tiwari, Jan Geliebter. RhoB expression is upregulated by androgen in thyroid cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3926. doi:10.1158/1538-7445.AM2015-3926

Mesangioproliferative Glomerulonephritis: A 30-Year Prognosis Study

Background: Diffuse mesangioproliferative glomerulonephritis (MesP) is the most commonly diagnosed type of glomerulonephritis (GN) in Denmark, with an incidence of 10.8 million per year. In the present study, the 30-year renal survival was estimated. Methods: A retrospective cohort investigation of 140 patients with biopsy-proven MesP was performed between the period 1967-2006. Factors influencing renal survival were investigated using Cox regression analysis. Results: Renal survival at 5, 10, 20 and 30 years was 87, 78, 59 and 50%, respectively. Female survival after 30 years was significantly better than male survival (70 vs. 40%, p = 0.049). Multivariate analysis, adjusted for age, estimated glomerular filtration rate (GFR) and nephrotic syndrome (NS) was performed for each sex individually. An increase in GFR was associated with a hazard risk (HR) of 0.98 (p = 0.02) in women and 0.99 (p = 0.006) in men. Older age was associated with a HR of 1.04 (p = 0.02) in women and 1.03 (p = 0.004) in men. NS had a poorer prognosis in men (HR 2.53, p = 0.01), but not in women (HR 0.54, p = 0.38). Conclusion: Increasing age and decreasing GFR were adversely associated with renal death. Renal prognosis was better for women after 30 years, and NS resulted in a poorer prognosis in men. This suggests that disease course and prognosis are different between men and women.

Skeletal Related Events, Bone Metastasis and Survival of Prostate Cancer: A Population Based Cohort Study in Denmark (1999 to 2007)

We describe mortality in patients with prostate cancer with and without bone metastasis further characterized by skeletal related events. We performed a cohort study of 23,087 incident patients with prostate cancer with a median 2.2-year followup identified through the Danish National Patient Registry from 1999 to 2007. We estimated the cumulative incidence of bone metastasis and skeletal related events, and described survival using the Kaplan-Meier method. Based on a Cox proportional hazard model we estimated mortality rate ratios and associated 95% CIs comparing mortality rates between patients by bone metastasis with and without skeletal related events, adjusting for age and comorbidity. Of the patients 569 (almost 3%) presented with bone metastasis at prostate cancer diagnosis, of whom 248 (43.6%) experienced a skeletal related event during followup. Of the 22,404 men (97% overall) without bone metastasis at diagnosis 2,578 (11.5%) were diagnosed with bone metastasis and 1,329 (5.9%) also experienced a skeletal related event during followup. One and 5-year survival was 87% and 56% in patients with prostate cancer without bone metastasis, 47% and 3% in those with bone metastasis, and 40% and less than 1% in those with bone metastasis and skeletal related events, respectively. Compared with men with prostate cancer without bone metastasis the adjusted 1-year mortality rate ratio was 4.7 (95% CI 4.3-5.2) in those with bone metastasis and no skeletal related events, and 6.6 (95% CI 5.9-7.5) in those with bone metastasis and a skeletal related event. Bone metastasis and skeletal related events predict poor prognosis in men with prostate cancer.

Nódulo Mamario (varón de 77 años)

Breast lump (77 year old man) Male breast cancer is rare accounting for 1% of total breast cancer cases. Its incidence is higher in patients with a family history of breast cancer of with testicular diseases that cause high oestrogen levels. Symptoms are the same as those in women. Most cases are diagnosed at an advanced stage and this explains the poor prognosis in men. We describe a case of a 77 year old man diagnosed with infiltrating ductal carcinoma.

A nomogram predicting metastatic progression after radical prostatectomy

To develop and internally validate a nomogram predicting the individual probability of metastatic progression after radical prostatectomy according to the length of disease-free interval. Cox regression modeled the probability of metastatic progression of prostate cancer in 752 patients treated with radical prostatectomy with a mean follow up of 11.6 years (median 11.4; range 0.1-40.5). The significance of the predictors was confirmed in competing risks analysis, which accounts for other causes of mortality. The Cox regression model-based nomogram was internally validated with 200 bootstrap resamples. Eighty-five of 752 patients (11.3%) developed metastatic progression. The 5, 10, 15 and 20-year actuarial rates of metastatic progression-free survival were, respectively, 95.9, 90.5, 84.8 and 80.5%. Pathological stage T3, elevated radical prostatectomy Gleason sum and delivery of adjuvant radiotherapy represented independent predictors of metastatic progression in both Cox and competing risks regression models, and constituted the nomogram predictors along with a fourth variable describing the presence of co-morbidities. After 200 bootstrap resamples the nomogram achieved 80.2, 77.7, 77.6 and 76.0% accuracy in predicting metastatic progression at 5, 10, 15 and 20 years after radical prostatectomy. Metastatic progression is a sign of poor prognosis in men with prostate cancer. Our nomogram is able to accurately predict the conditional probability of metastatic progression up to 20 years after radical prostatectomy.

What are the Factors Associated With Short Prostate Specific Antigen Doubling Time After Radical Prostatectomy? A Report From the SEARCH Database Group

Short prostate specific antigen doubling time following recurrence after radical prostatectomy portends a poor prognosis in men with prostate cancer. We determined which demographic and clinicopathological variables were predictive of a short prostate specific antigen doubling time in a cohort of men with clinically localized prostate cancer treated with radical prostatectomy. Data on 856 men from the Shared Equal Access Regional Cancer Hospital database who underwent radical prostatectomy for node negative prostate cancer between 1988 and 2003 were included in the analysis. We used logistic regression analysis to determine the independent factors associated with a short prostate specific antigen doubling time of less than 9 months vs a longer doubling time of 9 months or greater, or no recurrence. The variables analyzed were patient age, race, logarithmically transformed preoperative prostate specific antigen, body mass index, year of surgery, pathological Gleason sum, extraprostatic extension, surgical margin status and seminal vesicle invasion. On multivariate analysis higher preoperative prostate specific antigen (OR 2.20, 95% CI 1.52-3.19, p <0.001), pathological Gleason sum 8-10 (OR 4.70, 95% CI 2.11-10.43, p <0.001) and 7 (OR 2.11, 95% CI 1.09-4.08, p = 0.026), tumors with extraprostatic extension and/or positive surgical margins (OR 2.08, 95% CI 1.48-3.91, p = 0.023), and seminal vesicle invasion (OR 3.26, 95% CI 1.48-7.21, p = 0.003) were independent predictors of a short prostate specific antigen doubling time. Based on these risk factors we developed a table to estimate the risk of recurrence with a prostate specific antigen doubling time of less than 9 months. The factors that are invariably used to predict overall biochemical recurrence following radical prostatectomy, including high prostate specific antigen, high grade and adverse pathological findings, also predict aggressive recurrence.