Efficacy and safety of pembrolizumab for the treatment of advanced biliary cancer: Results from the KEYNOTE-158 and KEYNOTE-028 studies

We present data from patients with advanced biliary tract cancer (BTC) receiving pembrolizumab in the KEYNOTE-158 (NCT02628067; phase 2) and KEYNOTE-028 (NCT02054806; phase 1b) studies. Eligible patients aged ≥18 years from both studies had histologically/cytologically confirmed incurable BTC that progressed after standard treatment regimen(s), measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, Eastern Cooperative Oncology Group performance status 0/1, and no prior immunotherapy. Programmed death ligand 1 (PD-L1)-positive tumors were required for eligibility in KEYNOTE-028 only. Patients received pembrolizumab 200 mg every three weeks (KEYNOTE-158) or 10 mg/kg every two weeks (KEYNOTE-028) for ≤2 years. Primary efficacy endpoint was objective response rate (ORR) by RECIST v1.1. Response assessed by independent central review is reported. KEYNOTE-158 enrolled 104 patients and KEYNOTE-028 enrolled 24 patients. Median (range) follow-up was 7.5 months (0.6-34.3) in KEYNOTE-158 and 5.7 months (0.6-55.4) in KEYNOTE-028. In KEYNOTE-158, ORR was 5.8% (6/104; 95% CI, 2.1%-12.1%); median duration of response (DOR) was not reached (NR) (range, 6.2-26.6+ months). Median (95% CI) OS and PFS were 7.4 (5.5-9.6) and 2.0 (1.9-2.1) months. Among PD-L1-expressers (n = 61) and PD-L1-nonexpressers (n = 34), respectively, ORR was 6.6% (4/61) and 2.9% (1/34). In KEYNOTE-028, ORR was 13.0% (3/23; 95% CI, 2.8%-33.6%); median DOR was NR (range, 21.5-53.2+ months). Median (95% CI) OS and PFS were 5.7 (3.1-9.8) and 1.8 (1.4-3.1) months. Grade 3 to 5 treatment-related adverse events occurred in 13.5% of patients in KEYNOTE-158 (no grade 4; grade 5 renal failure, n = 1) and 16.7% in KEYNOTE-028 (no grade 4/5). In summary, pembrolizumab provides durable antitumor activity in 6% to 13% of patients with advanced BTC, regardless of PD-L1 expression, and has manageable toxicity.     

Measuring hope amongst Tanzanian women who participate in microfinance: An evaluation of the Snyder hope scale

ABSTRACT

Measuring hope reliably and accurately remains an important research objective, not least in less prosperous settings where ‘holding on to hope’ may be critically important in the struggle against adverse life conditions. The State Hope Scale was designed for use in the US. Despite reported application in diverse cultures and using translations the scale has not been extensively validated outside US populations. This study contributes to a larger project exploring the measurement of hope and provides a critique of Snyder’s scale as used in a Tanzanian female population of 1021 urban microfinance participants. We evaluate the scale’s validity through assessment of the empirical distribution of scores, item response profiles, internal consistency and discriminatory ability. Participants mostly scored very high and many reached very near the maximum attainable score. Hardly any endorsed the negative half of the response scale. Several problems are discussed including poor discrimination and strong evidence of acquiescence response bias. We also found little association of the scale scores with hypothesised correlates of hope. Future improvements on the measurement of hope are recommended, especially in studies outside the narrow Western context in which the scale was devised.     

CDC25B and CDC25C overexpression in nonmelanoma skin cancer suppresses cell death

Non‐melanoma skin cancer frequently results from chronic exposure to ultraviolet (UV) irradiation. UV‐induced DNA damage activates cell cycle arrest checkpoints through degradation of the cyclin‐dependent kinase activators, the cell division cycle 25 (CDC25) phosphatases. We previously reported increased CDC25A in nonmelanoma skin cancer, but CDC25B and CDC25C had not been previously examined. Consequently, we hypothesized that increased expression of CDC25B and CDC25C increases tumor cell proliferation and skin tumor growth. We found that CDC25B and CDC25C were increased in mouse and human skin cancers. CDC25B was primarily cytoplasmic in skin and skin tumors and was significantly increased in the squamous cell carcinoma (SCC), while CDC25C was mostly nuclear in the skin, with an increased cytoplasmic signal in the premalignant and malignant tumors. Surprisingly, forced expression of CDC25B or CDC25C in cultured SCC cells did not affect proliferation, but instead suppressed apoptosis, while CDC25C silencing increased apoptosis without impacting proliferation. Targeting CDC25C to the nucleus via mutation of its nuclear export sequence, however, increased proliferation in SCC cells. Overexpression of CDC25C in the nuclear compartment did not hinder the ability of CDC25C to suppress apoptosis, neither did mutation of sites necessary for its interaction with 14‐3‐3 proteins. Analysis of apoptotic signaling pathways revealed that CDC25C increased activating phosphorylation of Akt on Ser⁴⁷³, increased inhibitory phosphorylation of proapoptotic BAD on Ser¹³⁶, and increased the survival protein Survivin. Silencing of CDC25C significantly reduced Survivin levels. Taken together, these data suggest that increased expression of CDC25B or CDC25C are mechanisms by which skin cancers evade apoptotic cell death.     

基于1H-NMR植物代谢组学技术分析青海产区枸杞子的化学特征

目的:采用核磁共振氢谱(~1H-NMR)植物代谢组学技术比较青海产区枸杞子与其他产区(宁夏、甘肃、新疆、内蒙古)枸杞子的化学成分差异。方法:收集5个产区共97份枸杞子样本,其中青海61个样本,采用50%甲醇提取,检测~1H-NMR图谱,结合多元统计分析,对比青海产区枸杞子与其他产区枸杞子的化学差异性,并对各产区样本的枸杞多糖进行含量测定(以无水葡萄糖计),检测波长490 nm。结果:枸杞子的~1H-NMR图谱共检测到32个化学成分,多元统计分析表明青海产区枸杞子与其他产区样本相比,无明显分离趋势;青海产区枸杞子与宁夏产区相比,以及青海省6个不同地区的枸杞子相比,重叠样品较多,均不能显著分开。相似度结果表明,大多数样品的相似度0.85;化合物的单变量分析结果显示,除了蔗糖、葡萄糖、脯氨酸等个别代谢物在各产区样本中存在显著差异外,其余代谢物在各产区样品中的含量分布基本一致。青海与其他产区样本中枸杞多糖含量无显著性差异,且枸杞多糖含量与~1H-NMR指认的小分子化合物的相关系数处于-0.2～0.4。结论:采用~1HNMR植物代谢组学技术从整体化学组成上分析了青海产区枸杞子的化学特征,并结合枸杞多糖含量测定,显示青海产区枸杞子与其他产区枸杞子的化学差异较小。建立的基于~1H-NMR的枸杞子质量评价方法可为其质控水平提升及种植产区选择提供科学依据。     

宫腹腔镜联合手术诊治不孕症150例分析

目的:探讨宫腹腔镜联合手术在诊治不孕症中的应用。方法:对150例不孕症患者行宫腹腔镜联合手术,对不孕症病因进行诊断,同时行治疗。结果:盆腔粘连和输卵管阻塞是不孕症的主要原因。子宫内膜息肉和正常盆腔占次要比例。子宫内膜异位症和多囊卵巢也是主要病因。150例同时行宫腹腔镜输卵管通液和各种疾病的治疗。联合手术后妊娠率为48.8%。结论:腹腔镜联合手术,在一次麻醉下,可以对不孕的原因全面评价和明确诊断,在诊断同时进行治疗,对不孕症的诊断和治疗有重大的意义,值得推广。     

Clinical versus ultrasonographic evaluation of scrotal disorders

Clinical and ultrasonographic examinations of scrotal disorders were compared in 166 patients in order to determine their ability to distinguish between those diseases requiring surgery and those requiring clinical follow-up only. Ultrasound examinations were efficient in discriminating between normal and pathological findings. Extra-testicular lesions were readily differentiated from testicular ones. Although both clinical and ultrasonographic examinations had high sensitivity (90%) in detecting testicular cancer, the number of false positive findings was smaller after ultrasound examination. This gave a predictive value of a positive test of 53% after ultrasound examination but only 33% after clinical examination. Ultrasound examination may, therefore, reduce the number of surgical explorations in the scrotum and should be performed in patients with suspected testicular pathology based on history and palpatory findings.