Brachytherapy: An emblematic example of extreme hypofractionated regimen

In order to provide more convenient irradiation regimens for patient comfort, radiation facility organization and health expenses, new hypofractionated protocols have been evaluated. Moderately (dose/fraction: 2.3 to 3 Gy), then ultra (dose/fraction: 5.2 to 6.1 Gy) hypofractionated irradiations were first validated. The current question is: is it possible to go forward using extreme hypofractionated regimens (EHR) based on 1 to 3 fractions. Different irradiation techniques are under investigation. However, brachytherapy remains the smartest way to deliver a high dose in a small volume. We report prospective and retrospective study results which evaluated EHR for breast and prostate brachytherapy. While oncological outcome and toxicity profile appear extremely encouraging for low-risk breast cancer after a 1 to 4 fractions (6.25 to 20 Gy/fraction), the use of a single fraction of 19 to 23 Gy appears debatable for prostate cancer. Brachytherapy represents an emblematic example of EHR but longer follow-up and more mature results are awaited in order to specify the right indications and refine the EQD2 calculation method including new biological and technical factors.     

¿Es el intervalo libre de docetaxel un factor predictivo para el cáncer de próstata resistente a la castración?

ObjectiveProstate cancer (PCa) is the second most common solid tumor in men and the fifth leading cause of cancer-related death. In advanced stage, palliative treatments are used instead of curative therapies. Therefore, finding predictive indicators seems crucial. Patients with castration-resistant prostate cancer (CRPC) that received Dx chemotherapy have been retrospectively reviewed. The aim of this study was to investigate whether docetaxel (Dx)-free interval could have a predictive value for PCa and influence other sequential therapies.Material and methodsThis clinical trial study was performed on 104 patients at Medeniyet University Oncology Clinic in 2018-2020. All CRPC patients had metastases, received Dx as first-line treatment and underwent androgen receptor axis targeted (ARAT) therapy after disease progression. We analyzed patients’ progression time after Dx therapy and the effects on sequential treatment.ResultsAfter Dx therapy, all patients received ARAT (abiraterone (ABI) n: 49 (47.1%) and enzalutamide (ENZ) n: 54 (51.9%)) as a second-line treatment, except for one patient who received cabazitaxel. There was a statistically significant relationship between the Dx-free interval and duration of response to ARAT (P<.001). The response time of ARAT treatment was <10.5 months in all patients whose Dx-free interval period was <9 months.ConclusionsOur findings support the theory that Dx-free interval can be a predictive factor for CRPC. CRPC disease can be classified as Dx-sensitive disease or Dx-resistance disease, based on the Dx-free interval. Decision on subsequent treatments could be made considering this information.     

Control of immunity and allergy by steroid hormones

Steroid hormones, especially glucocorticoids, androgens, and estrogens, have profound influence on immunity. Recent studies using cell-type specific steroid hormone receptor-deficient mice have revealed the precise roles of some of these hormones in the immune system. Glucocorticoids are known to have strong anti-inflammatory and immunosuppressive effects and pleiotropic effects on innate and adaptive immune responses. They suppress the production of inflammatory cytokines by macrophages and DCs and the production of IFN-γ by NK cells, thus inhibiting innate immunity. By contrast, glucocorticoids enhance the immune response by inducing the expression of IL-7R and CXCR4 in T cells and the accumulation of T cells in lymphoid organs in accordance with the diurnal change of the glucocorticoid concentration. Thus, glucocorticoids suppress innate immunity but enhance adaptive immunity. Androgens suppress the homeostasis and activation of ILC2s and the differentiation of Th2 and Th17 cells and enhance the suppressive function of Tregs, thereby alleviating allergic airway inflammation. Thus, these steroid hormones have pleiotropic functions in the immune system. Further investigations are awaited on the regulation of immunity and allergy by estrogens using cell-specific steroid hormone receptor-deficient mice.     

黄芪丹参对多囊卵巢综合征大鼠雄激素/胰岛素受体表达影响的研究

目的：研究黄芪联合丹参对多囊卵巢综合征（PCOS）模型大鼠雄激素(AR)及胰岛素受体（INSR）表达的影响。方法：通过对大鼠注射外源性雄激素建立高雄激素无排卵模型，将建模成功的大鼠随机分为黄芪组、丹参组、黄芪＋丹参联合组以及模型组，每组10只，分别以黄芪、丹参、黄芪＋丹参联合用药行不同干预治疗，模型组用生理盐水灌胃。比较各组大鼠血清雄激素、胰岛素水平；卵巢AR、INSR mRNA及蛋白水平。结果：1）与模型组比较，黄芪组血清睾酮水平明显下降，丹参组血清胰岛素水平明显下降；联合组血清睾酮及胰岛素水平均明显下降。2）与模型组比较，黄芪组INSR蛋白水平明显下降，丹参组INSR蛋白水平明显上升；黄芪＋丹参联合组AR蛋白水平明显下降，同时INSR蛋白水平明显升高。3）与模型组比较，黄芪组AR mRNA水平明显下降，丹参组INSR mRNA水平明显上升；黄芪＋丹参联合组AR mRNA水平明显下降，同时卵巢INSR mRNA水平明显升高。结论：黄芪可改善PCOS的高雄激素状态，丹参可改善PCOS的高胰岛素状态，联合用药兼具抗雄激素及降低胰岛素的作用，AR、INSR表达的改变是其可能的作用机制之一。     

Androgen receptors in colorectal adenomas

Summary To evaluate the potential effect of androgens on the development and growth of human colorectal adenomas, the prevalence and concentration of cytosolic androgen receptors (AR) were analysed in 26 adenomas and 19 samples of normal colonic mucosa by a hybrid ligand receptor-binding assay. AR were detected in 7 of the adenomas (26.9%), and in 6 of the normal mucosa samples (31.6%). In the adenomas, AR levels demonstrated were low, ranging from 6 to 31 fmol/mg cytosol protein, and dissociation constants (Kds) ranged from 0.17–2.7x10^-9 M. Of 13 adenomas excised from men, 6 (46%) had positive receptor activity, whereas only 1 of 13 (7.7%) from women was positive (P=0.03, Fisher's exact test). There was no correlation between AR titre and patient age, or between adenoma size and histological type or degree of dysplasia. In normal mucosa, AR levels ranged from 7 to 33 fmol/mg and Kds ranges from 0.24–3.1x10^-9 M. There was no significant difference between either AR prevalence or levels in the adenomas and normal mucosa. The sex difference was exclusive to the adenoma. Endogenous androgen may play a role in adenoma development early in the promotional process.     

Metabolism and binding of androgens in the spinal cord of the rat

The binding of [3H]androgens and estrogens, and the metabolism of [3H]androgens, were studied in the spinal cord of the adult rat. High-affinity, specific binding sites for [3H]testosterone and [3H]estradiol were detected in cytosol fractions from the spinal cords of castrate animals. Equilibrium dissociation constants for reaction of these sites with their respective ligands were similar to those of androgen and estrogen receptors from other regions of the central nervous system. Nuclear binding of [3H]estradiol was observed in the spinal cord 1 h after intravenous administration of the isotope. Likewise, exchange assay demonstrated the presence of high-affinity androgen binding sites in spinal cord nuclei from orchidectomized, testosterone propionate treated animals. 5 alpha-Reductase activity in homogenates of the spinal cord was relatively high, approximately 3 times that in the pooled hypothalamus, preoptic area, septum and amygdala. However, in contrast to the latter brain regions, estrogen formation was not detectable in spinal cord tissue. No sex differences were observed in the metabolism of [3H]testosterone by spinal cord homogenates. These results confirm the presence of androgen and estrogen receptors in the rat spinal cord. The lack of detectable aromatase activity in the spinal cord is consistent with the hypothesis that the effects of circulating testosterone on spinal reflex function are mediated primarily through the androgen receptor system.     

性激素对心钠素基因表达影响的实验研究

为研究雄激素和雌激素对心钠素基因表达的影响,给完整的、去势的雄性大鼠皮下注射丙酸睾丸酮或雌二醇,持续2周。用冷酚法提取心房总RNA,用α-~(32)P标记ANF—cD-NA探针,经RNA电泳转移杂交和斑点吸印杂交。结果表明去势后ANF—mRNA含量下降,睾丸酮和雌二醇均使ANF—mRNA增加,然而小剂量的睾丸酮、雌二醇对去势大鼠ANF基因表达作用还需进一步研究。     

D期前列腺癌药物去势的疗效与AR、PSA的相关性研究

目的:探讨D期前列腺癌(PCa)患者药物去势治疗的效果与雄激素受体(AR)、前列腺特异性抗原(PSA)的相关性。方法:对33例D期PCa患者给予LHRH类似物 抗雄激素药物进行药物去势治疗,结合免疫组化进行统计分析。结果:AR、PSA与癌组织分化程度的之间的差异有统计学意义。Gleason不同评分组间血清PSA水平之间差异有统计学意义(P<0.05),PCa Gleason评分值与原位PSA免疫标记表达呈明显的负相关性(P<0.01);原位PSA免疫标记表达与血清PSA不具有相关性。结论:PCa组织中AR、PSA表达与D期PCa患者行药物去势疗法疗效有密切关系;血清PSA变化是监测PCa肿瘤复发与疗效的可靠瘤标。