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.     

Bladder Cancer Stage Development, 2004-2014 in Europe Compared With the United States: Analysis of European Population-based Cancer Registries,the United States SEER Database,and a Large Tertiary Institutional Cohort

BackgroundThe purpose of this study was to analyze trends of bladder cancer (BC) stages and incidence in Europe and the United States (US).Materials and MethodsTumor stages after radical cystectomy were assessed in a monocentric cohort from 2006 to 2016. BC incidence was assessed between 2004 and 2014 based on the German Center for Cancer Registry Data dataset at the Robert Koch Institute (n = 111,002), the Netherland Cancer Registry (n = 64,226), cancer registration statistics of England (n = 179,883), and the pooled data from the Scandinavian cancer registries, NORDCAN (n = 77,585) and the SEER (Surveillance, Epidemiology, and End Results) database (n = 184,519) for the complete populations and gender-specific subgroups. The average annual percent changes (AAPC) were used for statistical evaluation.ResultsNon–muscle-invasive BC (NMIBC) and muscle-invasive BC (MIBC) did not change in the institutional cohort at the point of radical cystectomy. The incidence of total BC (AAPC, −0.3), NMIBC (AAPC, −0.1), and non-metastasized MIBC (AAPC, 0.1) did not change in Germany during the time period under survey. BC total incidence in the Netherlands did not change significantly. In England and the Nordic countries, the incidence of total BC increased (AAPC, 0.8 and 0.5, respectively). In contrast, both the incidence of total BC (AAPC, −1.4), NMIBC (AAPC, −1.6), and non-metastasized MIBC (AAPC, −1.6) significantly decreased in the US.ConclusionsBetween 2004 and 2014 the incidence of BC was significantly sinking in the US, was stable in Germany and the Netherlands, and increased in England and the Nordic countries. Predominantly, differences in the smoking prevalence within the last decades but also gender-specific factors might be responsible for this discrepancy.     

两种不同放疗技术治疗鼻咽癌的疗效及计量学差异比较

目的:分析探讨两种不同放疗技术治疗鼻咽癌的疗效及计量学差异。方法:选取我院于2016年4月至2019年4月期间收治的63例鼻咽癌患者，根据鼻咽癌2008分期，其中T4期鼻咽癌患者有21例，T3期鼻咽癌患者有21例，T1-2期鼻咽癌患者有21例；所有入选患者均根据其具体情况制定固定野IMRT计划和旋转容积调强放疗计划，分别比较各期患者两套计划的计量学参数；分析两套计划的治疗时间和跳数、危及器官剂量、靶区覆盖等差异。结果:两种不同放疗技术均具备较好的靶区剂量分布，其中PTV1和PGTV的适行性和均匀性相当，两者剂量分布差异并没有统计学意义（均P>0.05）。IMRT组的PTV2剂量显著高于RapidArc组，并且前者的均匀性显著优于后者（均P<0.05），但是RapidArc组的剂量分布也能够满足临床需要。在按照患者T分期进行分层比较时，T3期患者和T1-2期患者的两种不同放疗技术靶区剂量分布相似，并且适形性和均匀性均相当。对于T4期患者而言，RapidArc组的PTV2、PTV1、PGTV靶区剂量均显著高于IMRT组（均P<0.05）；RapidArc组T4期患者的PGVT均匀指数优于IMRT组，两组数据比较差异虽无统计学意义（P=0.059），但P值接近0.05。RapidArc组治疗时间和治疗跳数分别为（185.92±32.19）s和（651.29±112.20）MUs，分别低于IMRT组的（522.29±73.39）s和（1 891.28±253.39）MUs，两组数据比较差异具有统计学意义（t=13.283，t=22.192，均P<0.05）。结论:对鼻咽癌患者采用9野IMRT和RapidArc治疗均能够达到临床要求，但是后者的治疗时间和治疗跳数更短，可以显著降低正常器官的剂量，在T4期鼻咽癌患者的治疗方面可以将高剂量区集中在靶区，从而大大减少正常器官的受照剂量，值得在临床上加以推广运用。     

四君子汤合沙参麦冬汤加减联合IMRT放疗治疗局部复发食管鳞癌的疗效和安全性

目的:初步探讨四君子汤合沙参麦冬汤加减联合IMRT放疗治疗局部复发食管鳞癌的有效性和安全性。方法:43例食管癌患者随机分为2组，试验组22例，在IMRT放疗的基础上联用四君子汤合沙参麦冬汤加减，水煎服，每日一剂，早晚服用，于放疗第1天开始，放疗结束两周后停用；对照组21例只行IMRT放疗。结果:试验组与对照组的近期有效率（RR）和疾病控制率（DCR）分别为59.1%、86.4%和42.9%、61.9%，差异无统计学意义(P>0.05）；1、2、3年生存率虽然治疗组较对照组确有提高，但差异无统计学意义(P>0.05）；试验组白细胞减少、血小板减少、血红蛋白减少、放射性肺炎均较对照组发生率明显降低，差异有统计学意义（P<0.05)。结论:四君子汤合沙参麦冬汤加减联合IMRT放疗治疗局部复发食管鳞癌患者可以明显降低放疗所致不良反应，一定程度改善患者的治疗效果和1、2、3年生存率。     

动态对比增强磁共振成像对鼻咽癌临床分期的诊断价值评价

目的:探讨DCE-MRI各项参数对鼻咽癌临床分期的诊断价值。方法:纳入2016年1月至2019年12月确诊的208例NPC初诊患者为研究对象，均行DCE-MRI、DWI检查，分析临床分期不同的患者感兴趣区的转运常数（Ktrans）、血管外细胞外间隙体积百分数（Ve）、速率常数（Kep）、容积分数（fPV）、DWI表观扩散系数（ADC值），考察指标与NPC临床分期的相关性。结果:Ktrans、Ve值随NPC临床分期增加而增大，而ADC值则随之减小，随着T分期增加Ve值增加，Kep、fPV值则在不同分期均未见明显差异（P＞0.05）；相关性结果显示，Ktrans、Ve值与临床分期、T分期呈正相关，而ADC值呈负相关（P均<0.05）；ROC曲线分析结果显示，Ktrans曲线下面积最高，为0.915，而早期（I期、Ⅱ期）、晚期（Ⅲ期与Ⅳ期）的AUC分别为0.906、0.920，均高于DWI ADC（AUC分别为0.824、0.807）。结论:DCE-MRI测量参数可反映不同临床分期NPC的变化，可考虑用于NPC不同分期的诊断、疗效评价。     

Establishment of epigenetic markers to predict irradiation efficacy against oropharyngeal cancer

Irradiation, or chemoradiotherapy, is a curative treatment for oropharyngeal squamous cell carcinoma (OPSCC). Its invasiveness, however, can often negate its efficacy. Therefore, developing methods to predict which patients would benefit from irradiation is urgent. Promoter DNA hypermethylation was recently reported to correlate with favorable OPSCC prognosis. It is still unclear, however, whether there is an association between promoter DNA methylation and response to irradiation. In this study, we analyzed DNA methylation in the specimens from 40 OPSCC patients who had undergone irradiation, using the Infinium assay. Our results showed significant correlation between high levels of promoter DNA methylation and better response to treatment (P < 0.01). We used the 10 most differentially‐methylated genes between responders and non–responders to develop a panel of predictive markers for efficacy. Our panel had high sensitivity, specificity and accuracy (92%, 93% and 93%, respectively). We conducted pyrosequencing to quantitatively validate the methylation levels of 8 of the 10 marker genes (ROBO1, ULK4P3, MYOD1, LBX1, CACNA1A, IRX4, DPYSL3 and ELAVL2) obtained by Infinium. The validation by pyrosequencing showed that these 8 genes had a high prediction performance for the training set of 40 specimens and for a validation set of 35 OPSCC specimens, showing 96% sensitivity, 89% specificity and 94% accuracy. Methylation of these markers correlated significantly with better progression‐free and overall survival rates, regardless of human papillomavirus status. These results indicate that increased DNA methylation is associated with better responses to irradiation therapy and that DNA methylation can help establish efficacy prediction markers in OPSCC.     

Intracellular claudin‐1 at the invasive front of tongue squamous cell carcinoma is associated with lymph node metastasis

Claudins are the major component of tight junctions, which form a primary barrier to paracellular diffusion and maintain cell polarity in normal epithelia and endothelia. In cancer cells, claudins play additional roles besides serving as components of the tight junctions, and participate in anoikis or invasion. Among the claudin family proteins, claudin‐1 has the most promising potential, both diagnostically and prognostically, in many types of cancers, including oral, gastric, liver, and colon cancers. However, conflicting results have been reported in relation to the degree of claudin‐1 expression and the prognosis, suggesting that the expression level of claudin‐1 alone is not sufficient to analyze the relationship between claudin‐1 and cancer progression. As endocytic trafficking of claudin‐1 has been reported in several epithelial cell types in vitro, we aimed to determine whether intracellular localization of claudin‐1 is the missing aspect between claudin‐1 and cancer. We investigated the expression of claudin‐1 in 83 tongue squamous cell carcinoma (TSCC) pathological specimens. Although the expression level of claudin‐1 based on immunohistochemistry was not associated with TSCC progression, within the high claudin‐1 expression group, the incidence of intracellular localization of claudin‐1 was correlated with cervical lymph node metastasis. In an in vitro experiment, claudin‐1 was constitutively internalized in TSCC‐derived cells. Motility of TSCC‐derived cells was increased by deficiency of claudin‐1, suggesting that the decrease in cell‐surface claudin‐1 promoted the cell migration. Therefore, intracellular localization of claudin‐1 at the invasion front may represent a promising diagnostic marker of TSCC.     

Risk factors of rib metastases in nasopharyngeal carcinoma patients with rib 99mTc- MDP foci on whole-body bone scansCSCD

Objective To investigate the correlation of rib 99mTc-MDP foci on whole-body bone scan with clinical variables and rib metastases in nasopharyngeal carcinoma(NPC) patients, and to screen the risk factors of rib metastases. Methods We retrospectively reviewed 312 NPC patients with rib 99mTc-MDP foci on wholebody bone scan. Chi-square test and logistic regression were performed to evaluate the correlation between clinical variables and rib metastases. Results In all 312 NPC patients, rib metastases were associated with T stage, skull base bone invasion, other bone metastasis, number of rib foci, lateral localization on rib and foci type (P<0.01), and the risk factors of rib metastasis included skull base bone invasion, other bone metastases, lateral localization on rib and foci type (P<0.05). In 176 patients with pure rib foci, rib metastases were closely related to T stage, skull base bone invasion, other bone metastasis, number of rib foci and lateral localization on rib (P<0.05), while only lobar distribution (P=0.029) was the effective risk factor. In 198 patients with single rib focus, rib metastases were affected by skull base bone invasion and foci type (P<0.01), while only foci type (P=0.000) was the effective risk factor. In all 566 rib foci, uptake level and localization on rib were the effective risk factors of rib metastases(P<0.01). Conclusion In NPC patients with rib foci on whole body bone scan, the effective risk factors of rib metastases include skull base bone invasion, other bone metastases, lateral localization on rib, foci type, uptake level and anterior and posterior localization on rib. Follow up should be the main way for the pure rib foci on unilateral ribs. For multiples rib foci on bilateral ribs or single rib focus combined with other bones foci, additional image modalities should be required to exclude bone metastasis. © 2020, CHINA RESEARCH ON PREVENTION AND TREATMENT. All rights reserved.     

FOLFOX4化疗方案联合免疫治疗在中晚期肝癌中的应用价值(附2例报告)

目的:探讨FOLFOX4化疗方案联合全身免疫治疗在中晚期肝细胞癌中的应用价值及疗效。方法:回顾性分析2例在空军军医大学唐都医院就诊的中晚期肝癌患者资料，给予FOLFOX4全身化疗联合胸腺法新的免疫治疗后患者病情缓解，疾病完全控制。分析FOLFOX4化疗方案在中晚期肝癌中的应用价值，及联合应用时机选择。结果:2例中晚期患者中，其中1例患者合并有双肺转移瘤，全身化疗后7个周期肺转移瘤消失，肿瘤标志物降至正常。另1例患者肝癌破裂根治术后，患者腹腔转移瘤切除术后，给予全身联合治疗，患者2年内病情稳定，肿瘤标志物正常。结论:FOLFOX4化疗方案在中晚期肝癌患者中的效果是肯定的，联合胸腺法新的全身辅助免疫治疗有助于增强全身化疗的疗效，改善患者的总体生存预后。