Effects of the testicular feminization mutation (tfm) of the androgen receptor gene on BSTMPM volume and morphology in rats

The posteromedial bed nucleus of the stria terminalis (BSTMPM) is an important component of the extended amygdala that is sexually dimorphic in rats. We examined the effect of the testicular feminization mutation (tfm), which renders the androgen receptor (AR) dysfunctional, on BSTMPM volume and average somal area. As expected, we found a significant sex difference in the volume of the BSTMPM, with females having a smaller BSTMPM than wild type males. Size of the BSTMPM in tfm males was also significantly smaller than that of wildtype males, although this difference was significant only on the left side. We found no sex difference in BSTMPM somal areas. These findings support the role of androgen receptors in the sexual differentiation of this nucleus.     

Distribution of androgen receptor and steroid hormone concentrations in ovaries of immature bank voles: effect of photoperiod

Immunolocalisation of androgen receptor (AR) and steroid contents were analyzed in the ovaries of 7- and 14-day-old bank voles, reared in a long (LD) and short (SD) photoperiod. The strongest AR immunoreaction was found in the stromal cells, especially in the ovaries of 7-day-old animals, and in the granulosa cells of all types of ovarian follicles. Oocytes and the cells of surface epithelium were AR positive. The amount of ovarian androgens was relatively high, whereas the level of estradiol was negligible. This finding, and the presence of numerous ARs in various ovarian compartments, suggest that aromatization was very low during development and the primary function of androgens was hormonal action via a receptor-mediated pathway. Age- and photoperiod-related differences in ovarian progesterone (P₄) levels were higher in animals kept in LD than in SD, rising significantly on day 14. Androgen content tended to be lower in LD voles and slightly decreased on day 14. Photoperiod-related differences concerning AR immunolabeling were apparent only in 14-day-old animals. In LD, ovaries already possessed early antral follicles, showing strong AR immunolabeling in the cumulus cells. Immunoreaction of 3β-hydroxysteroid dehydrogenase (3β-HSD) showed that the primary interstitial and theca cells were the first to be active in ovarian steroidogenesis. In conclusion, AR is present in juvenile vole ovaries as early as day 7. The influence of the photoperiod on their number is observed beginning on day 14. Differences in steroid contents due to LD conditions occur in 7-day-old, and progresses in 14-day-old animals.     

多西他赛联合内分泌疗法治疗转移性激素敏感性前列腺癌的疗效研究

目的探讨多西他赛联合内分泌疗法治疗转移性激素敏感性前列腺癌的临床疗效。方法回顾性分析长海医院2004年1月至2018年7月收治的497例转移性激素敏感性前列腺癌患者的病例资料。患者确诊年龄为(72.1±8.7)岁。治疗前中位PSA为100.0(42.3~999.0)ng/ml。TNM临床分期分别为:T2期213例(42.9%)、T3期160例(32.2%)、T4期124例(24.9%);N0期319例(64.2%)、N1期144例(29.0%)、Nx期34例(6.8%);M0期100例(20.1%)、M1a期51例(10.3%)、M1b期332例(66.8%),M1c期9例(1.8%)、Mx期5例(1.0%)。穿刺Gleason评分≤7分146例(29.4%)、8分103例(20.7%)、≥9分248例(49.9%)。根据治疗方式分为2组,采用单独内分泌治疗(单独治疗组)459例,多西他赛联合内分泌治疗(联合治疗组)38例。采用倾向评分匹配方法,卡钳值设置为0.02,对两组数据实行1∶1匹配。共37对匹配成功,匹配后两组的年龄(P=0.102)、PSA(P=0.713)、T分期(P=0.113)、N分期(P=0.226)、M分期(P=0.514)、Gleason评分(P=0.612)、肿瘤负荷(P=0.812)比较差异均无统计学意义。采用log-rank和Breslow-wilcoxon检验比较两组的无进展生存期和肿瘤特异性生存期。绘制两组患者年龄、临床TNM分期、Gleason评分、肿瘤负荷及是否接受过姑息性电切手术等各亚组生存情况的森林图,并针对高肿瘤负荷亚组比较两组间的无进展生存期差异。结果匹配后单独治疗组和联合治疗组的中位随访时间分别为22.6个月和13.7个月;发生去势抵抗的患者例数分别为23例和17例;死亡患者例数分别为3例和6例。单独治疗组和联合治疗组患者进展为去势抵抗的中位时间差异无统计学意义(10.3个月与16.5个月,P>0.05);平均前列腺癌特异性生存期分别为21.9个月和14.8个月,但均未达到中位生存期,且差异无统计学意义(P>0.05)。高肿瘤负荷亚组中,联合治疗组的中位无进展生存期明显优于单独治疗组(10.6个月与7.2个月,P=0.044),但低肿瘤负荷亚组中两组平均无进展生存期分别为10.5个月和12.6个月,均未达到中位生存期,且差异无统计学意义(P>0.05)。结论多西他赛联合内分泌治疗可以延长高肿瘤负荷激素敏感性前列腺癌患者的无进展生存期,但低肿瘤负荷患者无明显获益。     

AR-V7表达与去势抵抗性前列腺癌阿比特龙治疗敏感性的相关性研究

目的:探讨去势抵抗性前列腺癌(CRPC)患者中雄激素受体剪切变异体7(AR-V7)的表达与阿比特龙治疗敏感性的相关性。方法:采用前瞻性队列研究对2016年1月至2019年1月北京大学肿瘤医院收治的年龄≥18岁,存在1≥处全身转移,拟使用阿比特龙治疗的新发CRPC患者行外周血循环肿瘤细胞(CTCs)AR-V7检测,根据检测结果将患者分为AR-V7阳性组和AR-V7阴性组,对两组患者PSA下降时间、PSA无进展生存(PFS)、临床状态PFS、影像学PFS以及总生存进行统计分析。结果:共入组77例患者,其中AR-V7阴性组49例,AR-V7阳性组28例。AR-V7阴性组PSA下降时间[(72.04±66.92)d与(190.11±102.44)d,P=0.000]、PSA无应答率[6.12%(3/49)与21.4%(6/28),P=0.040]明显小于AR-V7阳性组,而PSA PFS[(489.17±269.39)d与(130.56±120)d,P=0.010]、临床状态PFS[(551.91±322.05)d与(261.44±200.85)d,P=0.018]、影像学PFS[(523.7±223.28)d与(247.56±202.80)d,P=0.003]明显长于AR-V7阳性组。AR-V7阳性组和AR-V7阴性组的肿瘤特异性生存时间分别为(1246.89±375.65)d和(1001.42±248.94)d(P=0.159),总生存率分别为89.8%(44/49)和89.3%(25/28)(P=0.176),差异均无统计学意义。结论:CRPC患者中,AR-V7表达与阿比特龙治疗敏感性及患者预后密切相关,阳性表达患者阿比特龙治疗效果及预后较差。     

Cardiovascular Morbidity Associated with Gonadotropin Releasing Hormone Agonists and an Antagonist

Background

Androgen deprivation therapy (ADT) is associated with increased cardiovascular morbidity.

Objective

To determine whether cardiovascular morbidity differs following initiation of gonadotropin-releasing hormone (GnRH) agonists compared with an antagonist.

Design, setting, and participants

Pooled data from six phase 3 prospective randomized trials that recruited 2328 men between 2005 and 2012 to compare the efficacy of GnRH agonists against an antagonist. Men recruited had pathologically confirmed prostate cancer, an Eastern Cooperative Oncology Group score <2, a minimum life expectancy of 12 mo, and were naïve to ADT. Men were excluded if they had a prolonged baseline QT/corrected QT interval, other risk factors for heart failure, hypokalemia or a family history of long QT syndrome, or had another cancer diagnosed within 5 yr.

Intervention

Men were randomized to receive a GnRH agonist or an antagonist for either 3–7 mo (n = 642) or 12 mo (n = 1686). Treatment groups were balanced for common baseline characteristics.

Outcome measurements and statistical analysis

Event analysis was based on death from any cause or cardiac events. Data documenting adverse experiences were classified based on the Medical Dictionary for Regulatory Activities. The following conditions defined a cardiac event: arterial embolic or thrombotic events, hemorrhagic or ischemic cerebrovascular conditions, myocardial infarction, and other ischemic heart disease. Kaplan-Meier curves and log-rank tests were used to compare time to a cardiovascular event or death.

Results and limitations

Among men with preexisting cardiovascular disease, the risk of cardiac events within 1 yr of initiating therapy was significantly lower among men treated with a GnRH antagonist compared with GnRH agonists (hazard ratio: 0.44; 95% confidence interval, 0.26–0.74; p = 0.002). Since our analysis is post hoc, our findings should only be interpreted as hypothesis generating.

Conclusions

GnRH antagonists appear to halve the number of cardiac events experienced by men with preexisting cardiovascular disease during the first year of ADT when compared to GnRH agonists.     

乳腺大汗腺癌临床和病理学特征研究

目的：探讨乳腺大汗腺癌（AC）的临床和病理学特征。方法：筛选出的8例乳腺大汗腺癌进行临床病理分析,采用过碘酸雪夫（PAS）、阿辛蓝（AB）染色及免疫组织化学A-P法检测GCDFP-15、Mucin-1、Ki-67、雄激素受体（Androgen receptor,AR）、雌激素受体（estrogen receptor,ER）、C-erbB-2。结果：8例均发生于中老年女性,因发现乳房包块就诊。组织学8例均为高级核,其中大汗腺导管原位癌（ADCIS）1例, ADCIS伴浸润性大汗腺癌（IAC）5例,IAC伴非大汗腺型DCIS灶2例。镜下主要有2种形态：A型,胞质嗜伊红染的粗颗粒状;B型,胞质淡染,呈细粉尘颗粒状,如毛玻璃样。8例AC的PAS染色阳性,AB染色在ADCIS阴性,在IAC可有50%细胞阳性,并同时表达GCDPF-15,AR,Mucin-1及Ki-67;除1例外,ER均不表达。结论：乳腺大汗腺癌的临床表现和大体形态与非乳腺大汗腺癌相似,多发生于单侧并且多数伴有同侧腋窝淋巴结转移,预后较好。其诊断主要依靠病理：（1）特征性的AC型细胞;（2）GCDPF-15阳性率高;（3） AR阳性率高,ER阳性率低。