表皮生长因子受体少见突变型非小细胞肺癌临床病理特征及治疗分析

  目的  分析非小细胞肺癌患者表皮生长因子受体（epidermal growth factor receptor,EGFR）少见突变型的临床病理参数及EGFR-TKIs治疗的初步疗效。  方法  收集2012年1月至2016年4月新疆医科大学附属肿瘤医院经病理证实的29例非小细胞肺癌携带少见EGFR突变患者临床病理资料,分析少见突变型的临床病理特征及与EGFR-TKIs疗效之间的关系。  结果  在29例少见突变患者中,最常见的远处转移器官依次为同侧/对侧肺组织、骨、脑、肝、肾上腺,最常见的淋巴结转移依次为肺门淋巴结、锁骨上/下淋巴结、颈根部淋巴结及纵隔淋巴结。少见突变中单突变16例,L861Q 5例,G719X 5例,20ins 4例,S768I 2例。双突变型11例,S768I及20ins突变4例,L858R及S768I双突变1例,19Del及T790M双突变1例,L861Q及G719X双突变2例,19Del及S768I突变1例,20ins及G719X突变1例,T790M及G719X突变1例。三突变2例,L858R、L861Q及G719X突变1例,S768I、20ins及G719X突变1例。一线EGFR-TKIs治疗客观缓解率（objective response rate,ORR）43.75%,疾病控制率（disease control rate,DCR）50.00%,中位无疾病进展生存期（median progression-free survival,mPFS）5.50个月。二线EGFR-TKIs治疗ORR为28.57%,DCR为42.85%,mPFS为4.00个月。三线EGFR-TKIs治疗ORR为33.33%,DCR为50.00%,mPFS为2.67个月。  结论  EGFR少见突变对EGFRTKIs治疗的有效率及生存时间存在较大个体差异,EGFR少见突变患者的ORR及PFS均较经典突变患者低,部分高于野生型。对少见突变患者,EGFR-TKIs治疗一线疗效略优于二、三线,但无显著性差异。      

Clinical characteristics and response to tyrosine kinase inhibitors of patients with non-small cell lung cancer harboring uncommon epidermal growth factor receptor mutations

Objective:To investigate the clinical features of patients with non-small cell lung cancer (NSCLC) harboring uncommon epidermal growth factor receptor (EGFR) mutations,and the treatment outcomes of EGFR tyrosine kinase inhibitors (TKIs) in these patients.Methods:We retrospectively analyzed the data of 128 NSCLC patients pathologically diagnosed with uncommon EGFR mutation in the Department of Pathology,National Cancer Center/Cancer Hospital,Chinese Academy of Medical Sciences & Peking Union Medical College and Beijing Hospital from January 2010 to December 2015,including 40 advanced patients who received EGFR-TKI.Results:Among the total 128 patients,11 patients were non-adenocarcinoma,including squamous carcinoma (3.9％),adenosquamous carcinoma (2.3 ％),large cell carcinoma (0.8％),and composite neuroendocrine carcinoma (1.6％).Single mutations accounted for 75.0％ (96/128),including G719X (29.7％),S768I (18.0％),20 exon insertion (13.3％),L861Q (12.5％),De novo T790M (0.8％),and T725 (0.8％).Thirty-two patients harbored complex mutations.Forty advanced patients received EGFR-TKI,the objective response rate (ORR) was 20.0％,the disease control rate (DCR) was 85.0％,and the progression-free survival (PFS) was 6.4 [95％ confidence interval (95％ CI),4.8-7.9] months.The exploratory analysis of tumor response and PFS in 33 patients with G719X/S768I/L861Q subtypes showed that ORR was 21.2％ (7/33),the DCR was 93.9％ (31/33),and PFS was 7.6 (95％ CI,5.8-9.4) months.Patients with exon 20 insertion mutation and De novo T790M experienced rapid disease progression with PFS no more than 2.7 months.Conclusions:Uncommon EGFR-mutant NSCLCs are heterogeneous,EGFR-TKIs can have different efficacy in this specific subtype,and thus further individual assessment is required for each case.     

Uncommon breast tumors in perspective: incidence, treatment and survival in the Netherlands

The relatively small group of patients with breast tumors other than the ductal, lobular or mixed ducto-lobular types, has reached nonnegligible numbers due to the ongoing increase in the incidence of breast cancer. We investigated stage and grade distribution of uncommon breast tumors using the nation-wide Netherlands Cancer Registry (population 16.5 million) and incidence patterns, treatment and long-term survival (up to 19 years) using the regional Eindhoven Cancer Registry (population 2.4 million). Incidence of all uncommon breast tumors together was 9.2/100,000 person years (age-standardized, ESR). The proportion of stage I tumors was 70% among patients with tubular (n = 3,456) and 40-50% for mucinous (n = 3,482), papillary (n = 1,078), cribriform (n = 503) and neuroendocrine (n = 76) tumors, contrasting to 27, 28 and 36%, respectively among patients with Signet ring cell cancer (n = 75), Paget's disease (n = 818) and the common invasive ductal carcinomas (n = 121,656). A better age-, stage-, and grade-adjusted prognosis was observed for patients with lobular (death risk ratio 0.8, 95%CI: 0.7-0.9), mucinous (0.5, 0.3-0.9), medullary (0.5, 0.3-0.9) and tubular (0.4, 0.2-0.6) carcinoma or phyllodes tumor (0.02, 0.0-0.2), compared with invasive ductal carcinomas. For patients with papillary (0.6, 0.2-1.6) and cribriform (0.1, 0.0-5.1) tumors better prognosis was not statistically significant. In conclusion, histologic type was an essential determinant of survival for about 10% of all newly diagnosed women with invasive breast cancer. Because patients with mucinous, tubular, medullary and phyllodes tumors have such a good prognosis, less aggressive treatment should be considered in some cases whereby specific guidelines are becoming increasingly desirable. Communication to patients with these specific histological types should reflect this.     

新辅助化疗对宫颈小细胞癌的效果评价

目的探讨新辅助化疗(NACT)治疗宫颈小细胞癌(SCCC)的临床效果。方法按照患者是否于术前接受NACT,将62例SCCC患者分为实验组(接受NACT)33例和对照组(未接受NACT)29例,记录实验组患者近期疗效,比较两组患者入院时与术前病灶大小变化情况、远期疗效及复发情况。结果实验组患者CR 5例(15.15%),PR 24例(72.73%),SD 4例(12.12%),总有效率为87.88%;实验组患者经NACT后病灶均有不同程度缩小,术前病理检查测量肿瘤病灶最大直径显著小于入院时影像学测量肿瘤病灶最大直径,差异具有统计学意义(P<0.05);实验组患者术前病理检查测量肿瘤病灶最大直径显著小于对照组,差异具有统计学意义(P<0.05);两组患者3年总生存率、3年无瘤生存率和局部复发率比较,差异无统计学意义(P>0.05);实验组患者远处复发率显著低于对照组,差异具有统计学意义(P<0.05)。结论 SCCC术前经NACT可有效缩小靶病灶,降低远处复发率,临床效果显著,应用价值较高。     

44. Study the level of DNA breakage in workers exposed to styrene by single cell gel electrophoresis

Objective: Study the level of DNA breakage in workers exposed to styrene. Methods: 35 workers aging from 18 to 40 exposed to styrene half a year above were observed as exposed group, in the mean time, 57 workers in the same district who hadn't been exposed to known genotoxicant were selected as control. Bloods of them were sampled and DNA lesions were detected by single cell gel electrophoresis. Results: Compared with control, the ratio between the length of Comet tail and the total length of Comet in exposed group significantly increased, especially it raised following the styrene concentration exposed, but it was not different among different working age groups. Conclusions: DNA is damaged by styrene, and it appears as dose-response relationship.     

口腔鳞癌及癌前病变组织中iNOS基因的表达

背景与目的:通过检测口腔鳞癌及癌前病变组织中诱导型-氧化氮合酶(inducible nitric oxide synthase,iNOS)mRNA及其蛋白产物的表达情况,探讨iNOS基因在口腔鳞癌发生、发展过程中的作用.材料与方法:应用免疫组化(SABC法)和原位杂交(ISH)2种方法分别检测10例正常13腔黏膜、12例上皮单纯增生、28例上皮不典型增生及32例口腔鳞癌组织中iNOS蛋白和iNOSmRNA的表达.结果:iNOS蛋白及iNOS mRNA均表达于细胞浆.正常口腔黏膜组织中未发现iNOS蛋白及iNOS mRNA表达;上皮单纯增生组、上皮不典型增生组、13腔鳞癌组中iNOS基因用免疫组化法检测的阳性表达率分别为16.67%(2/12)、67.86%(19/28)和78.13%(25/32),用原位杂交方法分别为16.67%(2/12)、71.43%(20/28)和75%(24/32),免疫组化和原位杂交检测的结果显示两者具有良好的一致性;上述4组不同口腔黏膜组织中iNOS蛋白与iNOS mRNA表达差异有统计学意义(P＜0.01);随着上皮不典型增生程度的加重,iNOS蛋白及iNOS mRNA表达均显著增强(P＜0.05);但口腔鳞癌组与上皮不典型增生组之间iNOS蛋白及iNOS mRNA阳性表达差异均无统计学意义(P＞0.05).结论:iNOS基因在口腔黏膜上皮组织中的表达可能与口腔鳞癌的发生发展中起重要作用,对iNOS基因的检测可为口腔鳞癌早期诊断提供依据.     

Squamous cell carcinoma of the thyroid: outcome of treatment in 16 patients

AIMS AND METHODS: Squamous cell carcinoma of the thyroid is very rare and has a poor prognosis. Treatment and outcome were retrospectively analysed in a consecutive series of 16 patients treated at the Royal Marsden Hospital, with the aim of establishing guidelines for management. RESULTS: Twelve of the 16 patients had locoregional disease only at presentation and four had distant metastases. Eight of the 16 underwent surgery and four were given post-operative radiotherapy. Radiotherapy alone was used in six patients unsuitable for surgery. Median survival was 16 months. There were three long-term survivors; each had localized disease treated with surgery and post-operative radiotherapy. Patients treated with surgery alone all developed local recurrence. Two of six patients treated with radiotherapy alone had a partial response but all subsequently developed progressive local disease. Chemotherapy was used in two patients with no response. CONCLUSIONS: Long-term survival is possible if disease is diagnosed early and is completely resected. Surgery should be followed by radical dose radiotherapy.     

Carcinoma of the thyroid gland: current therapy

A therapeutic approach to thyroid cancer has been outlined. An effort was made to identify some areas of therapy which are controversial. Long-term follow-up of patients suggests that our approach is justified. It is recognized that there are still many unanswered questions and some of these may be concerned with immunological factors involved.     

Salivary and Serum Interleukin-6 Levels in Oral Premalignant Disorders and Squamous Cell Carcinoma: Diagnostic Value and Clinicopathologic Correlations

Aim: To assess the diagnostic utility of serum and salivary interleukin 6 (IL-6) levels in the differential diagnosis of potentially malignant lesions and conditions (PMLs/PMCs) and oral squamous cell carcinoma (OSCC) in a high oral cancer prevalence region. Methods: After appropriate ethical clearance and informed consent, salivary and blood samples were collected from 100 participants in each group (OSCC, PMLs, and healthy controls). Serum and salivary IL-6 levels were measured by enzyme-linked immunosorbent assay and data were subjected to appropriate statistical analysis. Results: Significant differences in IL-6 concentration were noted between OSCC and PML/C patients in both serum and saliva, with salivary levels being 2 to 3 fold higher than serum values in all the groups. Receiver operating characteristic curve analysis demonstrated 96% specificity and 99% sensitivity for salivary IL-6 in differentiating PML from OSCC. Conclusions: The results of the present study suggest that the pro-inflammatory cytokine, IL-6, is elevated in the saliva of patients with OSSC compared to PMD and controls, and thus may prove to have diagnostic and/or prognostic significance.     

Cellular immune deficiency in black patients with basal cell carcinoma

Skin cancer, the most common malignancy in white patients, is rare in black populations. Seventeen black patients have been diagnosed and treated for basal cell carcinoma in the past 20 years at the University of Mississippi Medical Center. Ten of them have died, six of various types of cancer. Of the seven living patients, one had two cancers at the time of study: a new basal cell carcinoma and generalized lymphoma. The majority of patients had some degree of mixed racial ancestry, with medium to light brown skin, a history of heavy sun exposure, and lesions appearing on the head or neck. Highly significant depression of cellular immunity was demonstrated in these patients by T-cell assay. Altered tumor surveillance is implied as an etiological factor in basal cell carcinogenesis in black patients.     

子宫内膜癌ras癌基因产物p21和DNA倍体的研究

为了观察ｒａｓ癌基因产物ｒａｓｐ２１在子宫内膜癌及癌前病变组织中的表达，及ｒａｓｐ２１与ＤＮＡ倍体的关系，应用流式细胞术和细胞免疫荧光技术检测了３２例子宫内膜癌、２６例癌前病变和１０例正常内膜组织中的ｒａｓｐ２１的表达情况。结果为正常内膜组织中ｒａｓｐ２１表达阴性，子宫内膜癌ｒａｓｐ２１的表达高于癌前病变。ｒａｓｐ２１表达的荧光指数随子宫内膜癌组织学分级的升高而增加，但与临床分期、肌层浸润和淋巴结转移无关。ＤＮＡ倍体与ｒａｓｐ２１的表达量有关。表明ｒａｓｐ２１在子宫内膜癌和癌前病变有较高的表达，这可能与子宫内膜癌的发生有关。检测ｐ２１蛋白和ＤＮＡ倍体有助于判断肿瘤的恶性程度和预后。     

Cancer risks in thyroid cancer patients.

Cancer risks were studied in 834 thyroid cancer patients given 131I (4,551 MBq, average) and in 1,121 patients treated by other means in Sweden between 1950 and 1975. Record-linkage with the Swedish Cancer Register identified 99 new cancers more than 2 years after 131I therapy [standardised incidence ratio (SIR) = 1.43; 95% confidence interval (CI) 1.17-1.75] vs 122 (SIR = 1.19; 95% CI 0.88-1.42) in patients not receiving 131I. In females treated with 131I overall SIR was 1.45 (95% CI 1.14-1.83) and significantly elevated were noted for tumours of the salivary glands, genital organs, kidney and adrenal gland. No elevated risk of a subsequent breast cancer or leukaemia was noted. SIR did not change over time, arguing against a strong radiation effect of 131I. Organs that were estimated to have received more than 1.0 Gy had together a significantly increased risk of a subsequent cancer following 131I treatment (SIR = 2.59; n = 18). A significant trend was seen for increasing activities of 131I with highest risk for patients exposed to greater than or equal to 3,664 MBq (SIR = 1.80; 95% CI 1.20-2.58). No specific cancer or group of cancers could be convincingly linked to high-dose 131I exposures since SIR did not increase after 10 years of observation. However, upper confidence intervals could not exclude levels of risk that would be predicted based on data from the study of atomic bomb survivors. We conclude that the current practice of extrapolating the effects of high-dose exposures to lower-dose situations is unlikely to seriously underestimate radiation hazards for low LET radiation.     

Differences in the Prognostic Significance of the SUVmax between Patients with Resected Pulmonary Adenocarcinoma and Squamous Cell Carcinoma

Background: The purpose of this study was to determine the prognostic significance of the maximumstandardized uptake value (SUVmax) on F-18-fluorodeoxyglucose (FDG)-positron emission tomography (PET)in patients undergoing surgical treatment for non-small cell lung cancer. Materials and Methods: Seventy-eightconsecutive patients (58 with adenocarcinomas, 20 with squamous cell carcinomas) treated with potentiallycurative surgery were retrospectively reviewed. Results: The SUVmax was significantly higher in the patientswith recurrent than with non-recurrent adenocarcinoma (p<0.01). However, among the patients with squamouscell carcinoma, there were no differences with or without recurrence (p=0.69). Multivariate analysis indicatedthat the SUVmax of adenocarcinoma lesions was a significant predictor of disease-free survival (p=0.04). Inaddition, an SUVmax of 6.19, the cut-off point based on ROC curve analysis of the patients with pathological IBor more advanced stage adenocarcinomas, was found to be a significant predictor of disease-free survival (p<0.01).Conclusions: SUVmax is a useful predictor of disease-free survival in patients with resected adenocarcinoma, butnot squamous cell carcinoma. Patients with adenocarcinoma exhibiting an SUVmax above 6.19 are candidatesfor more intensive adjuvant therapy.     

甲状腺乳头状癌与交界性病变的差异蛋白质组学研究*

目的：分析和鉴定甲状腺乳头状癌（papillary thyroid carcinoma ,PTC ）与交界性病变的差异表达蛋白,筛选新的蛋白标志物。方法：收集 2013 年4 月至 2015 年2 月云南省第一人民医院手术切除的甲状腺标本118 例。实验组分别为 PTC 43 例（含经典型 40 例、滤泡亚型 3 例）、交界性病变 33 例（具有 PTC 样细胞核及乳头状结构,而缺乏包膜、血管侵犯,未发生转移的病例。其中 8 例合并非典型腺瘤）,对照组为癌旁正常甲状腺组织42 例。每组用 10 例冰冻样本提取总蛋白进行双向凝胶电泳（two-dimensional electrophoresis,2-DE ）,经PDQUEST7.3 图像分析软件检测3 组的表达差异点,利用基质辅助激光解吸电离串联飞行时间质谱（MALDI-TOF/TOF-MS）和Swiss-Prot数据库对差异蛋白进行鉴定,选择其中6 种差异表达蛋白用118 例样本通过免疫组织化学（immunohistochemistry ,IHC ）染色进行验证。结果：3 组样本两两比较共发现24 个蛋白差异点,通过质谱分析鉴定出18 种差异表达蛋白。IHC 染色显示 6 种蛋白keratin ,type Ⅱcytoskeletal 8（CK8）、keratin ,type Ⅰcytoskeletal 18（CK18）、60kDaheatshockprotein（HSP 60）、actin ,cytoplasmic 2（γ -Actin）、14 -3-3 proteinbeta/alpha （14 -3-3 β / α）和14 -3-3 proteinepsilon（14 -3-3 ε）定位于细胞浆;在PTC 中6 种蛋白的表达均高于正常甲状腺组织（P<0.001）,同时CK8、CK18 、HSP 60 和γ -actin 的表达高于交界性病变组（P<0.01 ）;在交界性病变中,除CK8 无明显变化外,其它 5 种蛋白的表达均高于正常对照组（P<0.001）。结论：蛋白质组学分析有助于发现新的 PTC 和交界性病变的蛋白标志物,IHC 染色进一步确认这些蛋白在组织细胞中的表达模式,更有利于PTC 的早期病理诊断。     

影响食管癌FDG摄取的临床因素探讨

目的: 研究性别、年龄、病变长度、肿瘤浸润深度、以及淋巴结状况等因素对食管癌原发灶FDG摄取的影响。 方法: 收集2004年6月至2006年11月治疗前行FDG-PET/CT检查的食管鳞癌患者68例,根据术后病理确定其病变长度、浸润深度、以及淋巴结转移情况。分析性别、年龄、病变长度等因素对食管癌原发灶FDG摄取(SUVmax)的影响,并分析转移状态(无转移、局部淋巴结转移)、TNM分期与FDG摄取的相关性。 结果: 不同性别、不同年龄段食管癌患者的原发灶FDG摄取无明显差异。而病变长度影响FDG摄取:病变长度与其FDG摄取呈正相关(P=0.01)。不同TNM分期、不同转移状态间原发灶的FDG摄取也有显著性差异,浸润深度,淋巴结转移状态均与SUVmax呈正相关(P=0.000)。 结论: 食管癌原发灶FDG摄取与病变长度、TNM分期等因素有关,而不受性别和年龄影响关,键而词且FD食G管摄肿取瘤值较原高发还灶提示发已射经型有计淋算巴机结转脱移氧或葡分萄期糖较晚。     

血清鳞状细胞癌抗原在宫颈鳞状细胞癌中的变化及意义

[目的]探讨血清鳞状细胞癌抗原水平在宫颈鳞状细胞癌中的变化及其临床意义。[方法]应用微粒子酶免分析（MEIA）对2000年3月～2000年7月在浙江省肿瘤医院收治的宫颈鳞癌（包括5例鳞腺癌）165例患者进行血清鳞状细胞癌抗原水平检测并分析其与临床分期、肿瘤大小、病理分级、淋巴结转移之间关系,其中放射治疗的93例患者进行治疗前后的血清鳞状细胞癌抗原水平的自身比较,以及与近期疗效的关系。[结果]165例宫颈鳞癌患者血清鳞状细胞癌抗原阳性率为64.2％（106/165）。鳞状细胞癌抗原水平与临床分期、肿瘤大小有关（P<0.05）;与病理分级、淋巴结转移之间无统计学差异（P>0.05）;放射治疗前后患者血清鳞状细胞癌抗原水平变化有统计学意义（P<0.05）,且与疗效相关（P<0.05）。[结论]血清鳞状细胞癌抗原是宫颈鳞癌的相关的肿瘤标记物,在监测宫颈鳞癌的发生和评价疗效等方面具有重要价值,对判断宫颈鳞癌的预后具有一定的临床意义。