A Minimum Of 100 Tumor Cells in a Single Biopsy Sample Is Required to Assess Programmed Cell Death Ligand 1 Expression in Predicting Patient Response to Nivolumab Treatment in Nonsquamous Non–Small Cell Lung Carcinoma

IntroductionProgrammed death ligand 1 (PD-L1) expression is a predictive biomarker for patient response to nivolumab in nonsquamous NSCLC. However, the number of biopsy samples and tumor cells (TCs) required to assess PD-L1 expression remains unclear.MethodsA total of 222 biopsy samples from 80 patients with nonsquamous NSCLC treated with nivolumab were collected. Number of TCs and PD-L1 score were compared among the sample containing the largest number of TCs (Max-TC), the sample containing the smallest number of TCs (Min-TC), and the total samples from each patient. The impact of the number of samples and TCs on the prediction of patient response to nivolumab with use of PD-L1 scores was evaluated.ResultsThere was a mismatch in PD-L1 scores less than 1% and those of at least 1% between Max-TC and the total samples in one patient (1%) and between Max-TC and Min-TC in six patients (8%). The optimal number of TCs to match PD-L1 expression less than 1% versus at least 1% between Max-TC and Min-TC was 100 (sensitivity = 0.676 and 1 – specificity = 0.333). PD-L1 expression of at least 1% in Min-TCs containing at least 100 TCs was associated with longer progression-free survival (median 7.6 versus 1.8 months [p < 0.01]) and overall survival (median not reached versus 9.9 months [p = 0.04]) compared with PD-L1 expression less than 1%. However, there were no differences in progression-free survival (median 3.9 versus 2.3 months [p = 0.37]) or overall survival (median 9.7 versus 7.6 months [p = 0.60]) between PD-L1 expression of at least 1% and PD-L1expression less than 1% in Min-TCs containing fewer than 100 TCs.ConclusionSingle biopsy samples containing at least 100 TCs are required to evaluate PD-L1 expression for predicting patient response to nivolumab.     

2005 - 2014年中国老年人肺癌发病的时间趋势分析

目的 分析2005 - 2014年我国老年人肺癌发病的时间趋势，为我国肺癌的防控工作提供依据。方法 根据2008 - 2017年《中国肿瘤登记年报》中肺癌的相关数据，分析2005 - 2014年我国老年人肺癌的发病情况，并通过年度变化百分比（annual percentage change，APC）分析其时间变化趋势。结果 2005 - 2014年我国老年人肺癌的发病率呈上升趋势（APC = 0.71%，P＜0.05），其中农村老年人肺癌的发病率从198.9/105上升至250.7/105，上升趋势更明显（APC = 2.81%，P＜0.05），尤以农村老年女性肺癌发病率的上升趋势最为明显（APC = 5.26%，P＜0.05）。2005 - 2014年中国老年人肺癌的发病在60～64岁和65～69岁组呈上升趋势（APC分别为2.83%和2.04%，均P＜0.05），而在农村地区，老年人所有年龄组的肺癌发病率都呈明显上升趋势（APC分别为3.49%，3.86%，1.66%，2.31%，3.49%及6.37%，均P＜0.05）。结论 2005 - 2014年我国老年人肺癌发病上升趋势明显，以农村老年女性最为突出，国家应针对高危人群及早开展筛查等工作，降低我国老年人肺癌的流行水平。     

Cellular immunotherapy in breast cancer: The quest for consistent biomarkers

Breast cancer is the most common malignancy in women worldwide, with a relatively high proportion of patients experiencing resistance to standard treatments. Cellular immunotherapy (CI), which is based on the extraction, modification, and re-infusion of the patient’s immune cells, is showing promising results in these patients. Among CI possible approaches, adoptive cell therapy (ACT) and dendritic cell (DC) vaccination are the most comprehensively explored in both primary/translational research studies and clinical trials. ACT may include the use of tumor-infiltrating lymphocytes (TILs), T cell receptor (TCR)-, or chimeric antigen receptor (CAR)-engineered T-cells. There are indications suggesting that a biomarker-based approach might be beneficial in effectively selecting breast cancer patients for CI. Here, we sought to provide the current knowledge of CI in breast cancer, focusing on candidate biomarkers, ongoing clinical trials, limitations, and immediate future perspectives.     

Ex Vivo Radiation Leads to Opposing Neurite Growth in Whole Ganglia vs Dissociated Cultured Pelvic Neurons

BackgroundProstatic radiation therapy (RT) often causes erectile dysfunction (ED) and the mechanisms governing RT-induced ED are unclear with a lack of therapeutic strategies.AimTo determine the effects of ex vivo RT on major pelvic ganglion (MPG) neuron survival, and neurite growth in whole vs dissociated culture.MethodsMPGs were removed and irradiated (0 or 8 Gy) from male Sprague Dawley rats. For dissociated culture, MPG neurons were digested in collagenase/dispase and cultured on coverslips. Immunofluorescent staining for beta-tubulin III (TUBB3; neuron marker), neuronal nitric oxide synthase (nNOS; nitrergic marker), tyrosine hydroxylase (TH; sympathetic marker), and terminal deoxynucleotidyl transferase dUTP nick end labeling assessed neurite length, branching, autonomic neuron density, and apoptosis. For whole organ culture, MPGs were grown in Matrigel. Gene expression of apoptotic markers (caspase 1, 3), TUBB3, nNOS, TH, and Schwann cells (Sox10, Krox20, glial fibrillary acid protein) was measured in whole organ cultured MPGs by quantitative polymerase chain reaction.OutcomesAfter 72 hours, neurite length, branching, autonomic neuron density, and apoptosis were assessed, and gene expression was measured.ResultsRT increased apoptosis in dissociated neurons measured by terminal deoxynucleotidyl transferase dUTP nick end labeling (P < .001) and whole MPG culture via upregulation of caspase 3 gene expression (P < .05). Nitrergic neurons were markedly decreased in irradiated dissociated culture (P < .05), while nNOS gene expression was upregulated in irradiated whole organ culture (P < .05). The proportion of dissociated sympathetic neurons and whole organ TH gene expression remained unchanged after RT. Interestingly, RT dissociated neurites were 22% shorter than controls, while RT whole organ neurites were 15% longer than controls (P < .01). MPG Schwann cells markers (Sox10, Krox20) were elevated after RT in whole organ culture.Clinical TranslationProstatic RT leads to increased neuronal cell death and less erectogenic nitrergic neurons contributing to ED.Strengths & LimitationsThe advantages of dissociated neuron culture include distinct neurites which are easily measured for apoptosis, length/branching, and specific neuron types. In contrast, whole MPG culture is advantageous as it contains all the supporting cells present in vivo.ConclusionThe 2 different culture methods demonstrated opposing neurite growth after RT indicating the importance of supporting cell network to promote pelvic neuron neuritogenesis and survival following RT.Randolph JT, Pak ES, Koontz BF, et al. Ex Vivo Radiation Leads to Opposing Neurite Growth in Whole Ganglia vs Dissociated Cultured Pelvic Neurons. J Sex Med 2020;17:1423–1433.     

Stereotactic Body Radiotherapy Versus Metastasectomy in Patients With Pulmonary Metastases From Soft Tissue Sarcoma

The lung is the preferred site of metastasis from soft tissue sarcoma (STS). This systematic review aims to evaluate the outcomes of stereotactic body radiotherapy (SBRT) and metastasectomy (MTS) for the treatment of lung metastases from STS. A systematic review was carried out according to the PRISMA protocol. PubMed, Medline, EMBASE, Cochrane Library, Ovid and Web of Knowledge databases were searched for English-language articles to December 2018 using a predefined strategy. Retrieved studies were independently screened and rated for relevance. Data were extracted by two researchers. In total, there were 1306 patients with STS: 1104 underwent MTS and 202 had SBRT. The mean age ranged from 40 to 55.8 years in the MTS group and from 47.9 to 64 years in the SBRT group. The cumulative death rate was 72% (95% confidence interval 59–85%) in the MTS group and 56% (38–74%) in the SBRT group. The cumulative mean overall survival time was 46.7 months (36.4–57.0%) in the MTS group and 47.6 months (33.7–61.5%) in the SBRT group. The cumulative rate of patients alive with disease was 5% (2–9%) in the MTS group and 15% (6–36%) in the SBRT group. Finally, the cumulative rate of patients alive without disease in the two groups was 19% (9–29%) and 20% (10–50%), respectively. Our study showed that local treatment of pulmonary metastases from STS with SBRT, compared with surgery, was associated with a lower cumulative overall death rate and similar overall survival time and survival rates without disease. By contrast, SBRT was associated with a higher survival rate with disease than MTS. Large randomised trials are necessary to confirm these findings and to establish whether SBRT may be a reliable option for early stage disease.     

丹参二萜醌类活性成分通过PKCδ/PKD1μ信号通路抗胰腺癌的作用研究

摘要 目的 验证丹参二萜醌类活性成分对胰腺癌和多发性骨髓瘤的抑制效应，阐明其诱导胰腺癌和多发性骨髓瘤凋亡的作用机制。方法 胰腺癌细胞AsPC-1、BxPC-3用含10% gibco胎牛血清的RPMI1640培养液培养，按隐丹参酮组（30μM）、丹参新酮组（15μM）、去氢丹参新酮组（15μM）分别加药处理。cell-counting-kit-8（CCK8）法检测细胞存活率；AnnexinⅤ-FITC/PI流式细胞术检测细胞凋亡；Western Blot检测相关PKC同工酶磷酸化水平；对AsPC-1和BxPC-3细胞进行siRNA转染，Western Blot检测相关PKC同工酶磷酸化水平。结果 隐丹参酮组AsPC-1、BxPC-3细胞存活率分别为40.1%±5.0%、36.2%±5.4%；丹参新酮组AsPC-1、BxPC-3细胞存活率分别为52.1%±5.1%、47.2%±5.7%；去氢丹参新组AsPC-1、BxPC-3细胞存活率分别为46.1%±5.0%、42.2%±5.4%(P<0.01)。流式细胞术结果显示：AsPC-1组内空白对照组、隐丹参酮组、丹参新酮组、去氢丹参新酮组细胞的凋亡率分别为4.71%、30.10%、52.26%、42.30%；BxPC-3组内空白对照组、隐丹参酮组、丹参新酮组、去氢丹参新酮组细胞的凋亡率分别为5.10%、30.66%、33.76%、51.76%（P<0.01）。Western Blot检测显示隐丹参酮组、丹参新酮组、去氢丹参新酮组较空白对照组，胰腺癌AsPC-1、BxPC-3细胞p-PKD/PKCμ ser916、p-PKCδ thr505、p-PKD/PKCμ ser744/748的水平降低。Western Blot检测显示，siRNA沉默胰腺癌AsPC-1、BxPC-3细胞PKCδ，胰腺癌AsPC-1、BxPC-3细胞PKD/PKCμ ser744/748的磷酸化水平下调。结论 隐丹参酮、丹参新酮、去氢丹参新酮通过抑制PKCδthr505的磷酸化水平，继而PKD1μser744/748磷酸化水平下调，从而显著促进胰腺癌AsPC-1和BxPC-3细胞凋亡发生。