The Cell‐CT 3‐dimensional cell imaging technology platform enables the detection of lung cancer using the noninvasive LuCED sputum test

The war against cancer has yielded important advances in the early diagnosis and treatment of certain cancer types, but the poor detection rate and 5‐year survival rate for lung cancer has changed little over the past 40 years. Early detection through emerging lung cancer screening programs promise the most reliable means of improving mortality. Sputum cytology has been tried without success because sputum contains few malignant cells that are difficult for cytologists to detect. However, research has shown that sputum contains diagnostic malignant cells and could serve as a means of lung cancer detection if those cells could be detected and correctly characterized. Recently, the National Lung Screening Trial reported that screening using 3 consecutive low‐dose x‐ray computed tomography scans provides a 20% reduction in lung cancer mortality compared with chest x‐ray. However, this reduction in mortality comes with an unacceptable false‐positive rate that increases patient risks and the overall cost of lung cancer screening. The LuCED test for detection of early lung cancer is reviewed in the current article. LuCED is based on patient sputum that is enriched for bronchial epithelial cells. The enriched sample is then processed on the Cell‐CT, which images cells in 3 dimensions with submicron resolution. Algorithms are applied to the 3‐dimensional cell images to extract morphometric features that drive a classifier to identify cells that have abnormal characteristics. The final status of these candidate abnormal cells is established by the pathologist's manual review. LuCED promotes accurate cell classification that could enable the cost‐effective detection of lung cancer. Cancer (Cancer Cytopathol) 2015;123:512–523. © 2015 American Cancer Society.     

Lung cancer epigenetics and genetics

Lung cancer is the leading cause of cancer-related death and thus a major health problem. The efficiency of current treatment modalities for lung cancer depends strongly on the time of diagnosis, with better chances of survival if a tumor has been detected at an early stage. Thus, there is an urgent need for rapid and efficient early detection methods. Biomarkers represent a possible alternative to current, rather expensive, screening tools such as spiral computer tomography (CT), or may allow the identification of high risk groups for whom screening would be cost efficient. Although most lung cancers are the consequence of smoking, a substantial fraction of molecular-epidemiological studies point to high-prevalence, low-penetrance genetic polymorphisms as modifiers of environmental lung cancer risk. In the past the genomics field has also made significant advances in identifying genetic lesions that can now be harvested with the goal of identifying novel biomarkers for lung cancer. Furthermore, the importance of epigenetic changes that occur during lung cancer development has been reported, but has been underestimated in the past. Novel high-throughput, quantitative assays for the detection of DNA methylation or histone tail modifications are now applied, to search for alterations in the lung cancer genome and will identify novel cancer-related genes that may become attractive targets for treatment, provide new insight into the biology of lung cancers, and could also become useful biomarkers for the early detection of lung cancer in sputum, or may be used as prognostic markers. Thus, an integrative approach in lung cancer research combining epidemiological, genetic and epigenetic information becomes an important concept for the future.     

肺癌的早期诊断

肺癌已成为人类癌症死亡的主要原因之一,5年生存率仅10％。既往应用胸部X线和痰细胞学进行筛查和早期诊断的研究没有达到诊断筛查的目的－－肺癌死亡率的下降。随着新技术的发展,人们对肺癌筛查重新产生了兴趣。本文回顾了肺癌早期诊断最新进展,有低剂量CT、液基细胞学技术、荧光内镜和分子病理学等方面。     

A bottleneck of sputum cytology in mass survey for lung cancer: An approach to detect early stage lung cancer by sputum cytology

Aiming at early detection of “hilar-type” lung cancer by sputum examination, we examined the morphological characteristics of what we call “early cancer” cells which were observed in the sputum of 22 cases of hilar-type early stage lung cancer. Two types of cells were found: “superficial-type” cancer cells and “parabasal-type” cancer cells. Cytological screening needs great care, because the cytoscreener is liable to mistake these cancer cells for normal-ranged epithelial cells. It has become easier to detect early lung cancer by looking for not only superficial-type cells but also parabasal-type cells.     

An evaluation of screening for lung cancer in Niigata Prefecture, Japan: a population-based case-control study.

Although an annual screening programme for lung cancer has been carried out widely in Japan since 1987, there is insufficient evidence to confirm its efficacy in terms of reducing mortality. In order to evaluate the efficacy of the lung cancer screening which has been widely carried out in Japan since 1987, a case-control study was conducted in Niigata Prefecture, Japan. In the study area, chest X-ray examinations for all participants and sputum cytology for high-risk participants were offered annually. Case subjects, who had died from lung cancer (174), and control subjects matched by sex, year of birth, residence and smoking status (801), who had been alive at the time of diagnosis of the corresponding case, were selected from the National Health Insurance holders. Screening histories of the subjects were compared between cases and matched controls for the identical calendar period before the time of diagnosis of the cases. The odds ratio of death from lung cancer for those screened within 12 months vs those not screened was 0.401 (95% CI: 0.272-0.591) with adjustment by smoking index. Our results suggest that annual lung cancer screening might reduce mortality from lung cancer by approximately 60%.     

肺癌的筛查

肺癌的筛查目前仍是一个有争议的问题.本文讨论了肺癌筛查的必要性和可行性,对肺癌筛查的历史和现状以及新的影像学和分子生物学技术在肺癌筛查和早期诊断中的价值和应用前景进行了回顾.利用生物标志物进行肺癌的筛查仍处于研究阶段,尚需前瞻性的研究对其效果进行评价.低剂量螺旋CT是目前最有希望用于人群肺癌筛查的新技术.肺癌的筛查应根据不同的卫生资源情况利用多种筛查技术采取不同的筛查策略在肺癌高危人群中进行.     

基因点突变检测肺癌分子生物学筛查的方法及进展

利用痰标本通过对相关基因点突变的检测,是肺癌早期筛查的有效方法.随着基因芯片、PCR、DNA序列分析等多种分子生物学新技术的广泛应用,肺癌高危人群的筛查有了新的更多的选择.本文对此进行简要综述.     

单抗检测痰液脱落细胞的诊断学意义

目的 建立一种快速而特异的肺癌辅助诊断方法。方法 制备特异性识别肺癌细胞的鼠单克隆抗体,通过细胞免疫化学和ELJSA方法检测抗体与痰液中脱落细胞的反应情况。结果 两种方法都显示,抗体2C25可选择性结合肺癌患者痰液中的脱落细胞,而不与肺炎患者和正常人痰液中的细胞发生反应。结论 抗体2C25在肺癌痰液免疫诊断中具有潜在的临床应用价值。     

肺癌筛查和早期诊断研究进展

在我国肺癌已居肿瘤相关死亡的首位,虽然进展期肺癌患者预后很差,但大部分早期肺癌是可以治愈的.早期诊断、外科治疗仍是提高肺癌治愈率的主要手段.本文复习有关胸片(CXR)、痰细胞学、荧光纤支镜、低剂量CT(LDCT)以及分子生物学技术等在肺癌筛查和早期诊断中应用的相关文献,并对它们的效果加以评估.LDCT是目前对高危人群筛查最有效的方法,荧光纤支镜、痰液基细胞学、分子生物学技术的进展则对早期诊断有重要作用.     

Sensitivity and specificity of lung cancer screening using chest low-dose computed tomography

Lung cancer screening programmes using chest X-ray and sputum cytology are routinely performed in Japan; however, the efficacy is insufficient. Screening using low-dose computed tomography (CT) is a more effective approach and has the potential to detect the disease more accurately. A total of 7183 low-dose CT screening tests for 4689 participants and 36 085 chest X-ray screening tests for 13 381 participants were conducted between August 1998 and May 2002. Sensitivity and specificity of lung cancer screening were calculated by both the detection method and the incidence method by linkage of the screening database and the Cancer Registry database. The preclinical detectable phase was assumed to be 1 year. Sensitivity and specificity by the detection method were 88.9 and 92.6% for low-dose CT and 78.3 and 97.0% for chest X-ray, respectively. Sensitivity of low-dose CT by the incidence method was 79.5%, whereas that of chest X-ray was 86.5%. Lung cancer screening using low-dose CT resulted in higher sensitivity and lower specificity than traditional screening according to the detection method. However, sensitivity by the incidence method was not as high as this. These findings demonstrate the potential for overdiagnosis in CT screening-detected cases.     

Lung cancer screening-its present situation, problems and perspectives

Mortality from lung cancer is increasing at the rate of more than 7% annually, becoming 31.7 per 100,000 among males in 1983. Out of 3,278 cities, towns and villages all over Japan, 21% of them were carrying out mass screening programs for lung cancer in 1982, and many other municipalities have followed suit over the last few years. Lung cancer screening has spread because of the widespread use of mass miniature radiophotography (MMR) for tuberculosis which has been adopted for use for lung cancer on the one hand, and because many research programs have revealed rather high detection rats with excellent prognosis for occult lung cancer using sputum cytology on the other. As screening procedures differ from one area to another, evaluation of the various methods of screening has been made. Emphasis is laid on the importance of double reading of X-ray film, comparisons of X-ray findings with those of previous one, criteria of screening for doubtful lung cancer cases, criteria for high-risk groups in sputum cytology, and so on. Epidemiological effects of lung cancer screening have not yet been confirmed, but so many lung cancer cases have been detected and treated, that a realistic approach for the improvement of screening programs was discussed.     

肺癌早期诊断研究进展

肺癌是绝大多数国家主要的癌症死亡原因,早期诊断和早期治疗尤为重要.以胸部X光片、螺旋CT、支气管内镜、痰液细胞学等检测手段用于肺癌的筛检和早诊已有较多报道,但鉴于以上检查手段的敏感性、特异性、适用度等方面的局限,近年来国内外学者对有关肺癌早期诊断的分子标志物做了大量有益的探索,本文拟就该领域的相关进展作一综述.     

CT扫描与痰液肿瘤标志物检测对周围型肺癌的早期诊断价值

目的 :研究CT扫描与肺活检后痰液脱落细胞的端粒酶活性和p16甲基化检测对早期周围型肺癌的诊断意义。方法 :用PCR TRAP ELSA半定量及PCR TRAP银染定性法、甲基化相关的PCR法 ,前瞻性检测 5 5例经CT扫描而发现的肺部孤立性结节 (直径≤ 30mm)、并疑诊为早期周围型肺癌的患者 (T1N0 M0 ) ,行CT导向肺活检 (纤维支气管镜肺活检 33例 ,经皮肺针刺活检 2 2例 )后 2 4h内痰液脱落细胞端粒酶活性及p16甲基化状态 ,并将检测结果与组织病理进行对照研究。结果 :CT扫描对周围型肺癌诊断的敏感性为 10 0 % ,但特异性只有 6 1 8% (34/ 5 5 )。端粒酶活性的敏感性为 79 4 % ,特异性为 90 5 % ,准确性为 83 6 % ;p16甲基化的敏感性为 32 4 % ,特异性为 10 0 % ,准确性为 5 8 2 % ,3者联合检测的敏感性为 86 1% ,特异性为 90 5 % ,准确性为 87 3%。对照组端粒酶阳性率 9 5 % (2 / 2 1) ,无1例检测到p16甲基化。结论 :CT扫描与端粒酶活性、p16甲基化联合可弥补痰液的细胞学检查的不足 ,提高肺癌痰检的敏感性 ,有助于周围型肺癌早期诊断和肺部孤立性结节的鉴别诊断     

早期肺癌的诊断

目的 :通过对 4 8例早期肺癌的分析 ,提出了发现和诊断早期肺癌的方法。方法 :收集我院1995～ 1999年万余例肺部疾病患者进行纤维支气管镜检查 ,经病理和细胞检查确诊肺癌 3648例 ,对其中属早期肺癌 4 8例进行分析。结果 :早期中心型肺癌和周围型肺癌的发生部位、进展形态和临床症状不同 ,其早期发现的诊断也不同。结论 :凡临床表现干咳、痰血、肺部同一部位反复出现炎症者 ,应及时通过胸部X线、CT、痰细胞学和纤支镜检查以明确诊断。对高危人群和高发地区前瞻性普查是发现无症状小肺癌的重要手段     

Premalignant and malignant cells in sputum from lung cancer patients

BACKGROUND:

The objective of this study was to assess the frequency of premalignant and malignant cells in sputum from patients with lung cancer and to measure the dependence of these cells on cancer stage, histologic type, tumor size, and tumor location.

METHODS:

This analysis included 444 patients with lung cancer. First, all patients were asked to produce sputum spontaneously; then, they underwent sputum induction. Slide preparations of the sputa were screened for the presence of abnormal cells.

RESULTS:

Of all patients with lung cancer who had produced adequate specimens, 74.6% had sputum that was positive for premalignant or worse cells, whereas 48.7% had sputum that was positive for malignant cells alone. Surprisingly, the presence of premalignant or worse cells in sputum depended only moderately on disease stage (82.9% of stage IV cancers vs 65.9% of stage I cancers), tumor size (78.6% of tumors >2 cm vs 64.7% of tumors ≤2 cm), and location (83.3% of central lesions vs 68% of peripheral lesions) and was found to be independent of histologic tumor type (78.4% of squamous cell carcinomas vs 71.5% of adenocarcinomas, 74.5% of small cell carcinomas, and 75% of large cell carcinomas).

CONCLUSIONS:

The findings of the current study suggested the important potential of sputum cytology for lung cancer detection and risk assessment across all stages, histologic types, tumor sizes, and locations. However, the high sensitivities in this study were achieved with a level of scrutiny not feasible in the laboratory routine. The diagnostic potential of sputum cytology may be exploited better through the standardization and automation of sputum preparation and analysis. Cancer (Cancer Cytopathol) 2009. © 2009 American Cancer Society.     

非小细胞肺癌循环核酸的研究进展

对于肺癌患者临床前期和无症状期,临床诊断往往缺少最有效的无创性检测方法。非小细胞肿癌(NSCLC)患者血循环中核酸含量明显高于正常人,研究证实其抗酸来源于肿瘤细胞,并且与原发肿瘤有着结构或功能上的某些一致性,因此循环核酸对肿瘤的早期发现和早期诊断及治疗都具有重要价值。近年随着细胞分子生物学技术的发展,循环核酸的检测成为可能,这方面的研究也成为热点,本文综述国内外关于NSCLC的循环核酸研究进展。     

肺癌病人痰液标本p53基因突变临床流行病学分析

[目的]探讨痰液标本p53基因突变检测用于肺癌高危人群筛查和肺癌早期诊断方面的意义。[方法]应用PCR鄄SSCP对63例肺癌患者和30例肺良性疾病的肺组织和痰液细胞中p53基因5～8外显子的突变进行了检测,并采用临床流行病学的方法进行分析。[结果]肺癌病人组肺癌组织中p53基因突变率为49.2%(31/63),对照组组织中突变率为3.3%(1/30),两组差别有统计学意义(P<0.001)。肺癌组痰液标本中p53突变率为23.8%(15/63);肺良性疾病患者痰液中未发现p53基因突变。以痰液标本p53基因突变为诊断指标,诊断的敏感度为45.2%,特异度为96.8%,标化阳性预告值为93.5%,标化阴性预告值为63.9%,标化一致性为71.0%。[结论]检测痰液中p53基因突变能间接反映其在肺组织中的改变,该方法可作为肺癌高危人群筛查以及肺癌诊断的无创性手段之一。     

Sensitivity and Specificity of Lung Cancer Screening in Osaka, Japan

Sensitivity and specificity were evaluated for lung cancer screening conducted at 8 municipalities in Osaka Prefecture during 1981–1985. As a screening policy, all attendants were examined by miniature chest X-ray, and the high-risk group, defined as those who smoked cigarettes or had bloody sputum, were also examined by 3-day pooled sputum cytology. A total of 33,599 screening tests for 19,028 people who were 40 years old or more at the time of screening were conducted, resulting in 33,490 miniature chest X-ray examinations for 18,992 people and 11,420 sputum cytologies for 7,070 people. As a result, 43 lung cancer cases were detected. All test-negatives were followed by means of record linkage with the files of the Osaka Cancer Registry up to the end of 1986. There were 24 cases who were diagnosed as having lung cancer without having given a positive screening result in 1981-1986. Assuming the preclinical detectable phase of lung cancer to be one year uniformly, the sensitivity and specificity for the lung cancer screening were estimated to be 71.6% and 95.3%, respectively. The feasibility of increasing the sensitivity is discussed.     

Identification of ENO1 As a Potential Sputum Biomarker for Early-Stage Lung Cancer by Shotgun Proteomics

BackgroundLung cancer is the leading cancer killer. Early detection will reduce the related deaths. The objective of this study was to identify potential biomarkers for early-stage lung cancer in sputum supernatant.Materials and MethodsUsing shotgun proteomics, we detected changes in protein profiles that were associated with lung cancer by analyzing sputum supernatants from 6 patients with early-stage lung cancer and 5 cancer-free controls. Using western blotting, we validated the proteomic results in 22 lung cancer cases and 22 controls. Using enzyme-linked immunosorbent assay (ELISA), we evaluated the diagnostic performance of the biomarker candidates in an independent set of 35 cases and 36 controls.ResultsProteomics identified 8 biomarker candidates for lung cancer. Western blotting validation of the candidates showed that enolase 1 (ENO1) displayed a higher expression level in patients with cancer than in cancer-free individuals (P = .015). ELISA revealed that the assessment of ENO1 expression in sputum supernatant had 58.33% sensitivity and 80.00% specificity in distinguishing patients with stage I lung cancer from cancer-free individuals.ConclusionThe analysis of protein biomarkers in sputum may provide a potential approach for the early detection of lung cancer. Future validation of all the candidates defined by shotgun proteomics in a large cohort study may help develop additional biomarkers that can be added to ENO1 to provide more diagnostic efficacy for lung cancer.     

肺癌流行病学和早期诊断新技术

肺癌是当今世界各国常见的恶性肿瘤 ,并已成为癌症死亡的主要原因。 2 0 0 0年美国新发病例达 16 94万人 ,近年来通过采用控制吸烟及大气污染等措施 ,发达国家的肺癌发病率有所下降 ,但我国肺癌发病率及死亡率仍占据首位。原发性肺癌的早期诊断非常重要 ,临床诊疗技术和先进仪器的使用有助于早期发现肺癌。就低剂量螺旋CT、荧光支气管镜、CT PET等在肺癌早期诊断中的应用及进展。