Optimising Hormone Therapy in Advanced Disease

Although most prostate cancer (PCa) patients nowadays are diagnosed at an early stage of disease, unfortunately still a significant number of patients will develop advanced PCa or will be diagnosed at an advanced (or metastatic) stage of disease. The group of patients showing the highest increase in incidence are those with rising prostate specific antigen (PSA) after radical therapy.In the last quarter of 2004, a Medline search has been performed targeting publications on patients diagnosed with advanced PCa, as well as with PSA relapse after previous radical therapy. This review aims at providing guidance to optimise hormone therapy in those selected groups of patients by addressing three pivotal questions; (i) who should receive hormonal treatment, (ii) what type of hormonal therapy should the patient be offered and (iii) what is the best timing of starting hormonal treatment.In patients relapsing after radical therapy, the PSA doubling time (PSA DT) has become a critical instrument to distinguish patients to have innocuous PSA evolution from patients at high risk for disease progression. A PSA DT of 3 months seems to be the cut-off point for identifying patients at risk. Therefore patients with a PSA DT of less than 3 months should be advised to initiate hormonal therapy. Antiandrogen monotherapy may be considered in this setting as it has been shown to delay progression; however, significant survival data are not yet available. Whether luteinising hormone releasing hormone (LHRH) agonists should be given continuously or intermittently (IHT) remains subject of debate.Surgical castration has been the standard of care in patients diagnosed with advanced PCa. Currently, LHRH agonists have become the preferred way of suppressing testosterone.Combination of an antiandrogen and a LHRH agonist (CAB) shows a modest benefit over LHRH agonist monotherapy. As CAB leads to increased side effects and costs, LHRH agonist monotherapy is preferred in the majority of patients.Conflicting data have been published concerning the optimal timing of LHRH agonist therapy. So it is not clear whether LHRH agonist therapy should be started immediately or deferred until appearance of symptoms. When initiating continuous hormone therapy, patients should be carefully monitored for the risk of long term androgen deprivation (anaemia, osteopenia and osteoporosis).     

Therapeutic effects of the combined androgen blockade therapy versus luteinizing hormone-releasing hormone analog monotherapy in patients with hormone naïve metastatic prostate cancer: a multi-institutional comparative analysis

BackgroundThe clinical benefit of the combined androgen blockade (CAB) therapy over luteinizing hormone-releasing hormone analog (LH-RHa) monotherapy for hormone naïve metastatic prostate cancer (mHNPC) is unclear. Therefore, we retrospectively compare the effectiveness of CAB with the LH-RHa monotherapy on the prognosis of Japanese patients with mHNPC.MethodsWe retrospectively evaluated the prognosis of 517 patients diagnosed with mHNPC between August 2001 and May 2017. The patients’ data were obtained from the Michinoku Urological Cancer Research Group database and Hirosaki University-related hospitals. Patients were divided into the CAB and LH-RHa monotherapy groups based on primary androgen deprivation therapy (ADT). Overall survival (OS), cancer-specific survival (CSS), and castrate-resistant prostate cancer-free survival (CRPC-FS) were compared between the two groups using the Kaplan-Meier curve analysis. Inverse probability of treatment weighting (IPTW)-adjusted Cox hazard proportional analyses was performed to investigate the effect of primary ADT on oncological outcomes.ResultsThe median age was 73 years old. The numbers of patients in the CAB and LH-RHa monotherapy groups were 447 and 70, respectively. The Kaplan-Meier curve analysis showed no significant differences in either 5-year OS (56.7% vs. 52.5%, P=0.277), CSS (61.1% vs. 56.4%, P=0.400), and CRPC-FS (33.1% vs. 31.1%, P=0.529) between the groups. IPTW-adjusted multivariate Cox hazard proportional analyses showed no significant differences in OS, CSS, and CRPC-FS between the two groups.ConclusionsNo significant differences in oncological outcomes were observed between the CAB and LH-RHa monotherapy groups in patients with mHNPC.     

New-onset diabetes after androgen-deprivation therapy for prostate cancer: A nationwide propensity score-matched four-year longitudinal cohort study

Introduction

Androgen-deprivation therapy (ADT) is important in the treatment of prostate cancer. However, the relationship between ADT and the risk of diabetes remains unclear, and the association between duration and types of ADT has not been fully investigated.

The use of caffeinated alcoholic beverages among underage drinkers: Results of a national survey

Objective

The mixing of alcoholic beverages with caffeine has been identified as a public health problem among college students; however, little is known about the consumption of such drinks among younger adolescents. We estimated the prevalence of caffeinated alcoholic beverage (CAB) use among a wide age range of underage drinkers, examined differences in traditional (i.e. self-mixed alcoholic beverages with soda, coffee and tea) and non-traditional CAB use (pre-mixed caffeinated alcoholic beverages or self-mixed alcoholic beverages with energy drinks or energy shots) among underage drinkers by age and other demographic characteristics, and examined differences in hazardous drinking behavior between CAB and non-CAB users.

Methods

We used an existing Internet panel maintained by Knowledge Networks, Inc. to assess the use of pre-mixed and self-mixed CABs in the past 30 days among a national sample of 1031 youth drinkers age 13–20. We conducted logistic regression analyses to estimate the relationship between traditional and non-traditional CAB use and risky drinking behavior as well as adverse outcomes of drinking, while controlling for age, gender, race/ethnicity, income, and general risk-taking (seat belt use).

Results

The overall prevalence of CAB use in the sample of underage drinkers was 52.4% (95% confidence interval [CI], 47.4%–57.4%). CAB prevalence was 48.4% among 13–15 year-old drinkers, 45.3% among 16–18 year-old drinkers, and 58.4% among 19–20 year-old drinkers. After controlling for other variables, we found a continuum of risk with non-traditional CAB use most significantly associated with binge drinking (odds ratio [OR] = 6.3), fighting (OR = 4.4), and alcohol-related injuries (OR = 5.6).

Conclusions

The problem of caffeinated alcoholic beverage use is not restricted to college-aged youth. The prevalence of CAB use among underage drinkers is higher than previously thought and begins in early adolescence. Adolescents who consume CABs, and particularly non-traditional CABs, are at increased risk of adverse outcomes.     

Epigenetic Landscape Analysis of the Long Non-Coding RNA and Messenger RNA in a Mouse Model of Corneal Alkali Burns

PurposeCorneal alkali burns (CABs) are a common clinical ocular disease, presenting a poor prognosis. Although some long noncoding RNAs (lncRNAs) reportedly play a key role in epigenetic regulation associated with CABs, studies regarding the lncRNA signature in CABs remain rare and elusive.MethodsA CAB model was established in C57BL/6J mice and profiling of lncRNA expressions was performed by RNA-Seq. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted to predicate the related pathological pathways and candidate genes. RT-qPCR was used to verify the expression pattern of lncRNAs and related mRNAs, both in vitro and in vivo. Data were statistically analyzed by GraphPad Prism version 6.0.ResultsIn all, 4436 aberrantly expressed lncRNAs were identified in CAB mice when compared with control mice. In the top 13 aberrantly expressed lncRNAs, {"type":"entrez-nucleotide","attrs":{"text":"Bc037156","term_id":"22477581"}}Bc037156 and 4930511E03Rik were confirmed as the most significantly altered lncRNAs. Pathway analysis revealed that mitogen-activated protein kinase (MAPK) signaling pathway was most enriched. Following 4930511E03Rik siRNA treated, Srgn, IL-1β and Cxcr2 were significant upregulated in corneal epithelial cells, corneal keratocytes, and bone marrow dendritic cells, with NaOH treatment. Moreover, after {"type":"entrez-nucleotide","attrs":{"text":"Bc037156","term_id":"22477581"}}Bc037156 siRNA treated, expression levels of IL-1β and Srgn were significantly downregulated in the three cell lines.ConclusionsOur study suggests that {"type":"entrez-nucleotide","attrs":{"text":"Bc037156","term_id":"22477581"}}Bc037156 and 4930511E03Rik may be involved in inflammation, immune response, and neovascularization by regulating Srgn, IL-1β, and Cxcr2 expression after CAB. These candidate lncRNAs and mRNAs may be the potential targets for the treatment strategy of the alkali injured cornea.     

Characterization of the putative cholesterol transport protein metastatic lymph node 64 in the brain

Intracellular management of cholesterol is a critical process in the brain. Deficits with cholesterol transport and storage are linked to neurodegenerative disorders such as Neimann-Pick disease type C and Alzheimer's disease. One protein putatively involved in cholesterol transport is metastatic lymph node 64 (MLN64). MLN64 localizes to late endosomes which are part of the cholesterol internalization pathway. However, a detailed pattern of MLN64 expression in the brain is unclear. Using immunocytochemical and immunoblot analyses, we demonstrated the presence of MLN64 in several tissue types and various regions within the brain. MLN64 immunostaining in the CNS was heterogeneous, indicating selective expression in discrete specific cell populations and regions. MLN64 immunoreactivity was detected in glia and neurons, which displayed intracellular labeling consistent with an endosomal localization. Although previous studies suggested that MLN64 may promote steroid production in the brain, MLN64 immunoreactivity did not colocalize with steroidogenic cells in the CNS. These results demonstrate that MLN64 is produced in the mouse and human CNS in a restricted pattern of expression, suggesting that MLN64 serves a cell-specific function in cholesterol transport.     

以肺转移癌为首发表现的前列腺癌长期存活1例报告并文献复习

目的:探讨转移性去势抵抗前列腺癌长期存活的特点及治疗方法。方法:对1例以肺转移为首发表现的前列腺癌长期存活病人的临床资料进行回顾性分析,并复习相关文献。结果:本例发现时即有肺转移的前列腺癌晚期病人,经过手术去势和间断的联合药物激素阻断治疗、化疗和新型抗前列腺癌药物阿比特龙等综合治疗,存活19年,且目前仍病情较平稳。结论:对于转移性前列腺癌应采取个体化的综合治疗,以期达到最佳的治疗效果。     

Postplasmic/PEM RNAs: a class of localized maternal mRNAs with multiple roles in cell polarity and development in ascidian embryos.

Ascidian is a good model to understand the cellular and molecular mechanisms responsible for mRNA localization with the discovery of a large family of localized maternal mRNAs, called postplasmic/PEM RNAs, which includes more than 40 members in three different ascidian species (Halocynthia roretzi, Ciona intestinalis, and C. savignyi). Among these mRNAs, two types (Type I and Type II) have been identified and show two different localization patterns from fertilization to the eight-cell stage. At the eight-cell stage, both types concentrate to a macromolecular cortical structure called CAB (for Centrosome Attracting Body) in the posterior-vegetal B4.1 blastomeres. The CAB is responsible for unequal cleavages and the partitioning of postplasmic/PEM RNAs at the posterior pole of embryos during cleavage stages. It has also been suggested that the CAB region could contain putative germ granules. In this review, we discuss recent data obtained on the distribution of Type I postplasmic/PEM RNAs from oogenesis to late development, in relation to their localization and translational control. We have first regrouped localization patterns for Type I and Type II into a comparative diagram and included all important definitions in the field. We also have made an exhaustive classification of their embryonic expression profiles (Type I or Type II), and analyzed their functions after knockdown and/or overexpression experiments and the role of the 3'-untranslated region (3'UTR) controlling both their localization and translation. Finally, we propose a speculative model integrating recent data, and we also discuss the relationship between postplasmic/PEM RNAs, posterior specification, and germ cell formation in ascidians.     

Identification of the CAB2/hCOS16 Gene Required for the Repair of DNA Double-strand Breaks on a Core Amplified Region of the 17ql2 Locus in Breast and Gastric Cancers

We previously reported that CAB1 and c -ERBB-2 genes were found to be located in a core amplified region of the 17q12 locus, which is frequently amplified in various cancers. During identification of this core region, CAB2 , a human homologue of the yeast COS16 required for the repair of DNA double-strand breaks was cloned. Autofluorescence analysis of cells transfected with its GFP fusion protein demonstrated that CAB2 translocates into vesicles, suggesting that overexpression of CAB2 may decrease intercellular Mn²⁺ by accumulating it in the vesicles, in the same way as yeast COS16. This is the first report identifying all of the genes on the core amplified region of the 17q12 locus in breast and gastric cancers.