Changes of Androgen Receptor and Insulin-Like Growth Factor-1 in LNCaP Prostate Cancer Cells Treated with Sex Hormones and Flutamide

Changes of androgen receptor (AR) and insulin-like growth factor-1 (IGF-1) were investigated in LNCaPcells treated with 5α-dihydrotestosterone (DHT), estrone and flutamide. Real-time PCR, immunocytochemistryand western blotting were used to detect the expression of AR and IGF-1 in the presence or absence of variouskinase inhibitors. Low concentrations of DHT, estrone and flutamide increased the expression of AR and IGF-1,especially estrone, with concentration and time dependence. With DHT and flutamide, there was a significantalteration in AR expression (p<0.001). The results indicated expression of AR and IGF-1 genes to be influencedby DHT, estrone and flutamide in LNCaP cells, regulated by multiple signal pathways.     

The Relationship of PSA, PSAD and Clinicopathological Stage in Patients with Prostate Cancer

OBJECTIVE To investigate the relationship between the clinicopatho- logical stage and serum prostate specific antigen(PSA)concentration and PSAdensity(PSAD)in patients with prostate cancer. METHODS The clinicopathological stage was determined on the basis of a pathological examination and clinical data in 65 prostate cancer patients treated by radical prostatectomy.PSA and PSAD were measured before the operation.The Spearman rank correlation was applied to evaluate the relationship between the clinicopathological stage,serum PSAconcentration and PSAD. RESULTS Patients with higher PSA and PSAD were significantly more likely to have higher clinical stages,a higher Gleason score,positive surgical margins,capsular penetration,and seminal vesicle invasion(each P<0.05). But there was no significant association between PSA and lymph node metastasis(P=0.053).The levels of serum PSA concentration and PSAD were significantly correlated with the clinical stage(P<0.05)in the prostate cancer patients. CONCLUSION The level of both PSA and PSAD were significantly correlated with the clinical stage(P<0.05)in the prostate cancer patients.But PSAD may be a more powerful predictor of clinical stage and prognosis than PSA.     

Lower Circulating Androgens Are Associated with Overall Cancer Risk and Prostate Cancer Risk in Men Aged 25–84 Years from the Busselton Health Study

Androgens, notably testosterone (T), have been implicated in development of several common cancers and prostate cancer; however, precise mechanisms remain unclear. This study assessed prospective associations of serum T, dihydrotestosterone (DHT) and estradiol (E2) with overall cancer (excluding skin cancer), prostate, colorectal and lung cancer risk in 1574 community-dwelling men aged 25–84 years. Sex hormones were assayed using mass spectrometry and men were followed for 20 years with outcomes ascertained using data linkage. Over 20 years, there were 289, 116, 48 and 22 men who developed any cancer, prostate cancer, colorectal cancer and lung cancer, respectively. Androgens in the lowest quartile were associated with an increased overall cancer risk (HR?=?1.36, 95% CI 1.05–1.76, p?=?0.020 for T; and HR?=?1.30, 95% CI 1.00–1.69, p?=?0.049 for DHT comparing the lowest vs other quartiles). T in the lowest quartile was associated with an increased risk of prostate cancer (HR?=?1.53, 95% CI 1.02–2.29, p?=?0.038 comparing the lowest vs other quartiles). The association between androgens and overall cancer risk remained similar after excluding prostate cancer outcomes; however, results were not significant. There were no associations of T, DHT or E2 with colorectal or lung cancer risk; however, LH in the highest quartile was associated with an increased risk of lung cancer (HR?=?4.55, 95% CI 1.70–12.19, p?=?0.003 for the highest vs other quartiles). Whether T is a biomarker of poor health in men with any cancer or prostate cancer requires further confirmation as does the nature and mechanism of the association of a high LH with future lung cancer.     

Results of the FLAC European Database of Metastatic Castration-Resistant Prostate Cancer Patients Treated With Docetaxel,Cabazitaxel, and Androgen Receptor–Targeted Agents

Background

Several agents have demonstrated an overall survival (OS) benefit in patients with metastatic castration-resistant prostate cancer (mCRPC); however, the optimal sequencing of these therapies is unknown as a result of a lack of prospective randomized controlled trials. This retrospective study aimed to identify clinical factors influencing outcomes and to determine optimal treatment sequencing in patients with mCRPC treated with cabazitaxel (CABA) and/or androgen receptor–targeted agents (ART) after androgen-deprivation therapy (ADT) and docetaxel (DOC).

Combination Androgen Receptor Inhibition and Docetaxel in Metastatic Castration-sensitive Prostate Cancer: The Next Step in First-line Treatment?

The addition of docetaxel and abiraterone to androgen deprivation therapy (ADT) heralded a new era in the first-line treatment of metastatic castration-sensitive prostate cancer (mCSPC). Following the success of these combination regimens, 3 new trials presented data on using enzalutamide or apalutamide in men with mCSPC, which showed similar success. These seminal trials collectively established the addition of docetaxel, enzalutamide, apalutamide, or abiraterone to ADT as standards in the upfront treatment of mCSPC. Notably, a subset of patients in these more recent trials were treated with a combination of docetaxel, ADT, and androgen receptor signaling inhibitors or maintenance androgen receptor signaling inhibitors after docetaxel and ADT that provided an initial glimpse into the efficacy of these triplet or maintenance strategies. We discuss the implications of these recent findings and place them in context of the current mCSPC treatment landscape.     

Are Findings from Studies of Obesity and Prostate Cancer Really in Conflict?

Recent studies on the association between obesity and prostate cancer appear to be in conflict. A recent prospective cohort study reported that the incidence of prostate cancer was lower among obese men under the age of 60 years and among those men with a family history of prostate cancer. Similarly, a case–control study found obesity was inversely associated with prostate cancer risk in men aged 40–64 years. However, several prospective cohort studies found that obese men are more likely to die from prostate cancer than non-obese men. Finally, two recent studies found that among men with prostate cancer, obese men were more likely to have a biochemical progression after surgery. We postulate that by closely examining the comparison groups used in these studies, these findings may, in fact, be in agreement. Specifically, this paradox within the literature may result from the possibility that obesity influences the development of aggressive (i.e., higher stage, higher grade, recurrence, death) and non-aggressive disease differently. We suggest that obesity may reduce the risk of non-aggressive disease but simultaneously increase the risk of aggressive disease. Finally, additional methodological issues are discussed that investigators need to be aware of to be able to draw inferences across studies of obesity and prostate cancer outcomes. Supported by the NIH Specialized Programs of Research Excellence Grant P50CA58236 (EAP) and P50CA90381 (EG), the Department of Defense, Prostate Cancer Research Program, PC030666 (SJF) and DAMD 17-03-1-0273 (EAP), Fund for Research and Progress in Urology (EAP), and the American Foundation for Urological Disease/American Urological Association Education and Research Scholarship Award (SJF). Views and opinions of, and endorsements by the author(s) do not reflect those of the US Army or the Department of Defense     

No Association of Hypoxia Inducible Factor-1α Gene Polymorphisms with Breast Cancer in North-West Indians

Background: Hypoxia inducible factor-1 alpha (HIF-1α) is the key regulator of cellular responses to hypoxiaand plays a central role in tumour growth. Presence of Single nucleotide polymorphisms (SNPs) in the criticalregulatory domains of HIF-1α may result in the overexpression of the protein and subsequent changes in theexpression of the downstream target genes. The aim of study was to investigate the association of three SNPs(g.C111A, g.C1772T and g.G1790A) of HIF-1α with the risk of breast cancer in North Indian sporadic breastcancer patients. Materials and Methods: A total of 400 subjects, including 200 healthy controls and 200 patientswith breast cancer were recruited in this study. Genotypes were determined using polymerase chain reaction -restriction fragment length polymorphism (PCR-RFLP) method. Results: The CC and CA genotype frequencyof HIF-1α g.C111A polymorphism was 100 vs 99% and 0 vs 1% in breast cancer patients and healthy controlsrespectively. The frequencies of CC, CT and TT genotype of g.C1772T polymorphism were 76 vs 74.5%, 19vs 21% and 5 vs 4.5% in breast cancer patients and control individuals respectively. There was no significantdifference in genotype and allele frequencies of HIF-1α g.C1772T polymorphism between cases and controlindividuals (p>0.05). For g.G1790A genotypes, all patients and controls had only GG genotype. Conclusions:The three HIF-1α polymorphisms (g.C111A, g.C1772T and g.G1790A) are not associated with breast cancerrisk in North-West Indian patients.     

Are Neutrophil/Lymphocyte and Platelet/Lymphocyte Rates in Patients with Non-Small Cell Lung Cancer Associated with Treatment Response and Prognosis?

Background: Inflammation is a critical component of tumor progression. Many cancers arise from sites ofinfection, chronic irritation, and inflammation. It is now becoming clear that the tumour microenvironment,which is largely orchestrated by inflammatory cells, is an essential participant in the neoplastic process, promotingproliferation, survival and migration. Platelets can release some growth factors such as platelet-derived growthfactor, platelet factor 4, and thrombospondin. Such factors have been shown to promote hematogenous tumourspread, tumor cell adhesion and invasion, and angiogenesis and to play an important role in tumor progression.In this study, we aimed to investigate effects of the pretreatment neutrophil to lymphocyte ratio (NLR) and theplatelet to lymphocyte ratio (PLR) on survival and response to chemoradiotherapy in patients with non-small-celllung cancer (NSCLC). Materials and Methods: Ninety-four patients with non-metastatic NSCLC were includedand separated into two groups according to median valuse of NLR and PLR (low:<3.44 or high:≥3.44 andlow:<194 or high≥194, respectively). Results: Pretreatment high NLR and PLR were associated with significantlyshorter disease-free and overall survival rates. Multivariate analysis revealed that the overall survival rateswere significantly linked with PLR (OR: 1.87, CI: 1.20-2.91, p: 0.006) and response to chemoradiotherapy (OR:1.80, CI: 1.14-2.81, p: 0.012) and the disease-free survival rates were significantly associated with NLR (OR:1.81, CI: 1.16-2.82, p: 0.009) and response to chemoradiotherapy (OR: 2.30, CI: 1.45-3.66, p: 0.001). There wasno significant difference between patients with high and low NLR in terms of response to chemoradiotherapy.Similarly, there was no significant influence of the PLR. Conclusions: Pretreatment NLR and PLR measurementscan provide important prognostic results in patients with NSCLC and assessment of the two parameters togetherappears to better predict the prognosis in patients with NSCLC. The effect of inflammation, indicators of NLRand PLR, on survival seems independent of the response to chemoradiotherapy.     

p53 and Cyclooxygenase-2 Expression are Directly Associated with Cyclin D1 Expression in Radical Prostatectomy Specimens of Patients with Hormone-Naïve Prostate Cancer

Prostate cancer (PCa) is a potentially curable disease when diagnosed in early stages and subsequently treated with radical prostatectomy (RP). However, a significant proportion of patients tend to relapse early, with the emergence of biochemical failure (BF) as an established precursor of progression to metastatic disease. Several candidate molecular markers have been studied in an effort to enhance the accuracy of existing predictive tools regarding the risk of BF after RP. We studied the immunohistochemical expression of p53, cyclooxygenase-2 (COX-2) and cyclin D1 in a cohort of 70 patients that underwent RP for early stage, hormone naïve PCa, with the aim of prospectively identifying any possible interrelations as well as correlations with known prognostic parameters such as Gleason score, pathological stage and time to prostate-specific antigen (PSA) relapse. We observed a significant (p?=?0.003) prognostic role of p53, with high protein expression correlating with shorter time to BF (TTBF) in univariate analysis. Both p53 and COX-2 expression were directly associated with cyclin D1 expression (p?=?0.055 and p?=?0.050 respectively). High p53 expression was also found to be an independent prognostic factor (p?=?0.023). Based on previous data and results provided by this study, p53 expression exerts an independent negative prognostic role in localized prostate cancer and could therefore be evaluated as a useful new molecular marker to be added in the set of known prognostic indicators of the disease. With respect to COX-2 and cyclin D1, further studies are required to elucidate their role in early prediction of PCa relapse after RP.     

Tumor Necrosis Factor-α Gene Polymorphisms and Risk of Oral Cancer: Evidence from a Meta-analysis

Numerous studies have been conducted regarding association between TNF-α and oral cancer risk, but theresults remain controversial. The present meta-analysis is performed to acquire a more precise estimation ofrelationships. Databases of Pubmed, the Cochrane library and the China National Knowledge Internet (CNKI)were retrieved until August 10, 2013. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) werecalculated with fixed- or random-effect models. The heterogeneity assumption was assessed by I-squared test.Among the eight included case-control studies, all were focused on TNF-α-308G>A and four also concernedthe TNF-α-238G>A polymorphism. It was found that oral cancer risk were significant decreased with theTNF-α-308G>A polymorphism in the additive genetic model (GG vs. AA, OR=0.19, 95% CI: [0.04, 1.00],P=0.05, I2=68.9%) and the dominant genetic model (GG+GA vs. AA, OR=0.22, 95% CI: [0.06, 0.82], P=0.03,I2=52.4%); however, no significant association was observed in allele contrast (G vs. A, OR=0.70, 95% CI: [0.23,2.16], P=0.54, I2=95.9%) and recessive genetic models (GG vs. GA+AA, OR=0.72, 95% CI: [0.33, 1.57], P=0.41,I2=93.1%). For the TNF-α-238G>A polymorphism, significant associations with oral cancer risk were found inthe allele contrast (G vs. A, OR=2.75, 95% CI: [1.25, 6.04], P=0.01, I2=0.0%) and recessive genetic models (GGvs. GA+AA, OR=2.23, 95%CI: [1.18, 4.23], P=0.01, I2=0.0%). Conclusively, this meta-analysis indicates thatTNF-α polymorphisms may contribute to the risk of oral cancer. Allele G and the GG+GA genotype of TNF-α-308G>A may decrease the risk of oral cancer, while allele G and the GG genotype of TNF-α-238G>A may causean increase.     

Dose Escalation with Three-dimensional Conformal Radiotherapy for Prostate Cancer. Is More Dose Really Better in High-risk Patients Treated with Androgen Deprivation?

AimsTo determine the effect of radiation dose on biochemical control in prostate cancer patients treated in a single institution with three-dimensional conformal radiotherapy (3DCRT) and the additional effect of androgen deprivation in prostate cancer patients.Materials and methodsIn total, 363 men with T1–T3b prostate cancer treated in a sequential radiation dose-escalation trial from 66.0 to 84.1 Gy (International Commission Radiation Units and Measurement [ICRU] reference point) between 1995 and 2003, and with a minimum follow-up of 24 months, were included in the analysis. One hundred and forty-eight (41%) men were treated with 3DCRT alone; 74 (20%) men received neoadjuvant androgen deprivation (NAD) 4–6 months before and during 3DCRT; and 141 (39%) men received NAD and adjuvant androgen deprivation (AAD) 2 years after 3DCRT. Univariate, stratified and multivariate analyses were carried out separately for defined risk groups (low, intermediate and high) to determine the effect of radiation dose on biochemical control and its interaction with hormonal manipulation and clinical prognostic variables.ResultsThe median follow-up was 59 months (range 24–147 months). The actuarial biochemical disease-free survival (bDFS) at 5 years for all patients was 75% (standard error 3%). For low-risk patients, the bDFS was 82% (standard error 5%), for intermediate-risk patients it was 64% (standard error 6%) and for high-risk patients it was 77% (standard error 3%) (P = 0.031). In stratified and multivariate analyses, high-dose 3DCRT for all risk groups, and for high-risk patients, the use of long-term AAD vs NAD, contributed independently and significantly to improve the outcome of prostate cancer patients.ConclusionThe present study indicates an independent benefit on biochemical outcome of high-dose 3DCRT for low-, intermediate- and high-risk patients and of long-term AAD in high-risk prostate cancer patients.     

Are PIK3CA Mutation and Amplification Associated with Clinicopathological Characteristics of Gastric Cancer?

Alterations in mitochondrial DNA (mtDNA) have been studied in various cancers. However, the clinical valueof mtDNA copy number (mtCN) alterations in gastric cancer (GC) is poorly understood. In the present study,we investigated whether alterations in mtCNs might be associated with clinicopathological parameters in GCcases. mtCN was measured in 109 patients with GC by real-time PCR. Then, correlations with clinicopathologicalcharacteristics were analyzed. mtCN was elevated in 64.2% of GC tissues compared with paired, adjacent, noncanceroustissue. However, the observed alterations in mtCN were not associated with any clinicopathologicalcharacteristics, including age, gender, TN stage, Lauren classification, lymph node metastasis, and depth ofinvasion. Moreover, Kaplan-Meier survival curves revealed that mtCN was not significantly associated with thesurvival of GC patients. In this study, we demonstrated that mtCN was not a significant marker for predictingclinical characteristics or prognosis in GC.