Comparison of K-ras gene mutations in tumour and sputum DNA of patients with lung cancer.

Mutations in the K-ras gene are frequently found in lung tumours and are implicated in the development of lung cancer. In order to investigate the clinical usefulness of these mutations in lung cancer, we applied a sensitive method to compare mutations in codon 12 of the K-ras gene in DNA extracted from lung tumours and the matched sputum samples obtained from 22 lung cancer patients. K-ras mutations were identified in the lung tumours of 12 patients (54.5%) and in the sputum samples of 10 patients (45.5%). Nine patients showed an identical mutation in both the tumour and the matched sputum samples. There was a significant association between the presence of a K-ras mutation in a lung tumour and the detection of an identical mutation in the matched sputum sample of the lung cancer patient (kappa = 0.64, 95% confidence interval 0.32-0.95, p <0.01). K-ras mutations were detected in sputum samples from cancer patients with all lung tumour grades, and both in the presence and the absence of lymph node metastasis. Therefore, K-ras mutations may provide useful diagnostic markers for lung cancer.     

Comparison of K-ras gene mutations in tumour and sputum DNA of patients with lung cancer

Mutations in the K-ras gene are frequently found in lung tumours and are implicated in the development of lung cancer. In order to investigate the clinical usefulness of these mutations in lung cancer, we applied a sensitive method to compare mutations in codon 12 of the K-ras gene in DNA extracted from lung tumours and the matched sputum samples obtained from 22 lung cancer patients. K-ras mutations were identified in the lung tumours of 12 patients (54.5%) and in the sputum samples of 10 patients (45.5%). Nine patients showed an identical mutation in both the tumour and the matched sputum samples. There was a significant association between the presence of a K-ras mutation in a lung tumour and the detection of an identical mutation in the matched sputum sample of the lung cancer patient (κ = 0.64, 95% confidence interval 0.32-0.95, p <0.01). K-ras mutations were detected in sputum samples from cancer patients with all lung tumour grades, and both in the presence and the absence of lymph node metastasis. Therefore, K-ras mutations may provide useful diagnostic markers for lung cancer.     

Fine needle aspiration biopsy versus sputum and bronchial material in the diagnosis of lung cancer. A comparative study of 168 patients

A group of 168 consecutive lung cancer patients in whom a definitive diagnosis of primary lung cancer was established either in a conventional cytologic specimen of sputum or bronchial material or in a specimen obtained by fine needle aspiration (FNA) biopsy was reviewed to compare the relative accuracies between the modalities of sputum and bronchial material on one hand versus FNA cytology on the other in the diagnosis of lung cancer. The patients included in the study were selected from a total of 1,093 patients who had been diagnosed and treated for lung cancer at Duke University Medical Center over the five-year period of January 1, 1980, through December 31, 1984. In 325 (29.8%) of the 1,093 patients, a definitive cancer diagnosis was established from histopathologic study alone, without any cytologic diagnoses. In 420 patients (38.4%), both histologic and cytologic material had been interpreted as being conclusively diagnostic for lung cancer. In 348 patients (31.8%), a cytologic diagnosis of lung cancer was made without a histologic confirmation. Thus, in a total of 768 (70.3%) of the 1,093 cases, a definitive cytologic diagnosis of cancer had been made. Of these 768 patients, 168 had been evaluated by both conventional respiratory cytologic methods (examination of sputum and bronchial material) and with FNA biopsy cytology. In 9 patients (5.4%), only conventional respiratory cytologic specimens were conclusively diagnostic for cancer. In 122 patients (72.6%), only the FNA biopsy specimen was diagnostic. In 37 patients (22.0%), both conventional respiratory specimens and FNA specimens yielded a definitive lung cancer diagnosis. The FNA specimen was the only positive cytologic specimen in 90.2% of large cell undifferentiated carcinomas, 79.5% of adenocarcinomas, 66.7% of small cell undifferentiated carcinomas and 58.2% of squamous cell carcinomas. In 26.5% of the patients, a diagnosis of cancer could have been established on conventional cytologic specimens, without the necessity of proceeding to percutaneous FNA biopsy. From this study, it is concluded that the techniques of conventional respiratory cytology and FNA biopsy cytology are complementary in the diagnosis of lung cancer. While the percentage of lung cancers diagnosed by FNA biopsy cytology alone is much greater than that obtained by conventional respiratory cytology alone, more than one-fourth of these cancers could be detected by the less invasive techniques of sputum collection and bronchoscopy.     

Relationship between patient characteristics and the sputum cytologic diagnosis of lung cancer

In 421 patients with a malignant lung process, from whom samples of sputum of satisfactory quality were received, patient characteristics relevant to the cytologic diagnosis of malignancy were investigated. In patients with primary lung cancer, the presence of blood in the sputum was highly significant from the point of view of its association with a correct positive cytologic diagnosis on sputum. The same relationship was noted in patients with metastatic lung cancer. In patients producing bloody sputum, the examination of at least three sputum samples gave a proportion of correct positive diagnoses of 0.88 in primary lung cancer patients and of 0.77 in patients with metastatic lung disease. Furthermore, a high sensitivity of the sputum cytology diagnosis of malignancy was found in primary lung cancer patients with low forced expiratory volume values (less than 50% of the vital capacity), with large tumors (greater than 24 mm in diameter) and with squamous-cell cancers. A central location of the tumor correlated with significantly better cytodiagnostic results in patients with both primary and metastatic cancers.     

Increased numbers of alveolar macrophages with apoptotic bodies predict lung carcinoma

In our previous study on fixed tissue blocks, we reported a high apoptotic rate in patients with operated small cell lung carcinomas. In addition to tumour cells, numerous apoptotic bodies could also be found within alveolar macrophages within and close to tumour tissue. In order to test if such cells could be found in sputum smears and if their presence could be utilized as a marker in tumour diagnosis, we analyzed the occurrence of alveolar macrophages with apoptotic bodies (AMWABs) in a set of sputum smear and BAL samples from patients with and without a pulmonary malignancy. An increased amount of AMWABs in the cytoplasm could be found in sputum and BAL samples from patients with lung cancer. Interestingly, AMWABs could also be seen in patients with a histologically confirmed pulmonary malignancy, but with no detectable tumour cells in their sputum smear. Thus, the presence AMWABs in sputum smears could serve as a more sensitive marker of pulmonary malignancy than the prese nce of malignant cells per se. This is the first report describing apoptotic bodies in macrophages and the utility of their detection in cancer diagnosis.     

Smoking,Chronic Bronchitis,and Lung Cancer

A follow-up was carried out on 21,579 male mass radiography volunteers aged at least 40 who had been the subject of an earlier investigation in which their smoking habits and sputum production were recorded and the prevalence of lung cancer was determined after chest x-ray examination. During the follow-up period, which was a minimum of 36 months and a maximum of 56 months, 64 new cases of lung cancer were identified by cross checking records with the registers of the regional cancer registration bureau. A significantly higher incidence of lung cancer was found in those with chronic bronchitis than in those without this disease. In the smoking categories, cigarette smokers with chronic bronchitis had a higher incidence than those without it, and this relationship was maintained irrespective of age and amount smoked. It is concluded that persons who smoke run a higher risk of chronic bronchitis than non-smokers and those who develop bronchitis run a higher risk of developing lung cancer.     

Diagnosis of bronchial carcinoma on sections of paraffin-embedded sputum. Sensitivity and specificity of an alternative to routine cytology.

The diagnostic accuracy of sputum cytology for the diagnosis of bronchial carcinoma using paraffin-embedded, serially sectioned and hematoxylin and eosin-stained specimens was tested in 4,297 sputum samples from 1,889 patients, 219 of whom had bronchial carcinoma. The diagnostic sensitivity depended mainly on the number of investigated samples and was 85.4% with three sufficient sputa. The sensitivity was not influenced by the histologic types, location or TNM stage of the tumor. The specificity of the method was 99.5%. In three cases localization of sputum cytologically diagnosed bronchial carcinomas was not possible immediately (occult carcinomas, pTx); in two of these cases the bronchial carcinomas were located during follow-up. The third patient died without verification of the cytologic diagnosis. According to our results, sputum cytology on serial sections is a valuable instrument for mass screening of high-risk groups for the early detection of bronchial carcinoma. Lower sensitivities of sputum cytology in mass screening programs for the early diagnosis of lung cancer are discussed critically.     

Earlier diagnosis and survival in lung cancer

In a controlled investigation the survival prospects of lung cancer in a population of men aged 40 and over who had been offered six-monthly chest radiographs over a period of three years were compared with lung cancer in a similar population without such x-ray facilities. The five-year survival rate of lung cancer in the study series was 15%, and in cases discovered by six-monthly examination 23%, compared with 6% in the control series. The average expectation of life after diagnosis was 2·5 years for the test cases and 1·2 for the control cases. Survival declined with age. Of resected lung cancer, 32% survived five years in the test series and 23% in the control series. The five-year survival rate for squamous carcinoma and adenocarcinoma in the test series was 28% and 25% respectively, compared with 15% and nil in the control series.On the basis of these results it is concluded that through earlier radiological detection a modest improvement in the prognosis of lung cancer can be achieved.     

Self examination of the breast: is it beneficial? Meta-analysis of studies investigating breast self examination and extent of disease in patients with breast cancer.

The question whether the aggregated published research suggests that breast self examination is beneficial was explored in a meta-analysis of 12 studies including a total of 8118 patients with breast cancer that related the practice of breast self examination to regional lymph node state or tumour diameter. Based on the six studies for which data were available, 39% of patients (1115/2852) who reported having done breast self examination at least once before their illness had evidence of cancer in the lymph nodes compared with 50% of women (1348/2713) who had not done the examination. Logistic regression analysis showed this difference to be significant (odds ratio 0.66, confidence interval 0.59 to 0.74). Combining six studies which reported the circumstances of detection disclosed that 42% of women (272/652) who found their tumour while doing breast self examination had evidence of cancer in the nodes compared with 46% of women (871/1901) who found the tumour accidentally; this difference was not significant. Analysis of eight studies which used the diameter of the tumour to indicate the extent of disease tended to confirm the findings on lymph node state, in particular the benefit of premorbid breast self examination. Significantly fewer women who had practised the examination before the illness (56%; 1205/2137) had tumours of 2 cm or more diameter compared with women who had not practised the examination (66%; 1500/2260). The combined odds ratio for that analysis was 0.56, confidence interval 0.38 to 0.81. These findings appear to be good evidence of the benefit of encouraging women to practise self examination of the breasts regularly.     

肺放线菌病1例报告并文献复习

目的：分析肺放线菌病的临床表现、诊断及治疗,提高对肺放线菌病的认识。方法：回顾性分析我科收治的1例肺放线菌病患者的临床资料,并对相关文献进行复习。结果：本例患者,43岁,男性,以咳嗽、咳血性痰为主要临床表现,胸部CT提示右肺上叶结节,经皮肺穿刺活检结果确诊肺放线菌病,青霉素治疗效果好。结论：肺放线菌病是放线菌感染引起的一种少见的呼吸系统疾病,起病隐匿,呈渐进性过程,临床表现及影像学检查均无特异性,放线菌可在肺部引起化脓性肺炎,并经叶间隙、胸膜侵犯胸壁、肋骨,形成窦道及破坏骨质。确诊有赖于病理学或微生物学证据,主要可采用青霉素抗感染治疗,在疑似肿瘤的情况下,需通过外科手术治疗,既可以明确诊断也避免病变进一步引起肺、胸壁等组织的不可逆性破坏。     

肺放线菌病1 例报告并文献复习

目的：分析肺放线菌病的临床表现、诊断及治疗,提高对肺放线菌病的认识。方法：回顾性分析我科收治的1 例肺放线菌病 患者的临床资料,并对相关文献进行复习。结果：本例患者,43 岁,男性,以咳嗽、咳血性痰为主要临床表现,胸部CT 提示右肺上 叶结节,经皮肺穿刺活检结果确诊肺放线菌病,青霉素治疗效果好。结论：肺放线菌病是放线菌感染引起的一种少见的呼吸系统 疾病,起病隐匿,呈渐进性过程,临床表现及影像学检查均无特异性,放线菌可在肺部引起化脓性肺炎,并经叶间隙、胸膜侵犯胸 壁、肋骨,形成窦道及破坏骨质。确诊有赖于病理学或微生物学证据,主要可采用青霉素抗感染治疗,在疑似肿瘤的情况下,需通 过外科手术治疗,既可以明确诊断也避免病变进一步引起肺、胸壁等组织的不可逆性破坏。     

Detection of prostate cancer in unselected young men: prospective cohort nested within a randomised controlled trial

Objective To investigate the feasibility of testing for prostate cancer and the prevalence and characteristics of the disease in unselected young men.Design Prospective cohort nested within a randomised controlled trial, with two years of follow-up.Setting Eight general practices in a UK city.Participants 1299 unselected men aged 45-49.Intervention Prostate biopsies for participants with a prostate specific antigen level of 1.5 ng/ml or more and the possibility of randomisation to three treatments for those with localised prostate cancer.Main outcome measures Uptake of testing for prostate specific antigen; positive predictive value of prostate specific antigen; and prevalence of prostate cancer, TNM disease stage, and histological grade (Gleason score).Results 442 of 1299 men agreed to be tested for prostate specific antigen (34%) and 54 (12%) had a raised level. The positive predictive value for prostate specific antigen was 21.3%. Ten cases of prostate cancer were detected (2.3%) with eight having at least two positive results in biopsy cores and three showing perineural invasion. One tumour was of high volume (cT2c), Gleason score 7, with a positive result on digital rectal examination; nine tumours were cT1c, Gleason score 6, and eight had a negative result on digital rectal examination. Five of the nine eligible participants (55%) agreed to be randomised. No biochemical disease progression in the form of a rising prostate specific antigen level occurred in two years of follow-up.Conclusions Men younger than 50 will accept testing for prostate cancer but at a much lower rate than older men. Using an age based threshold of 1.5 ng/ml, the prevalence of prostate cancer was similar to that in older men (3.0 ng/ml threshold) and some cancers of potential clinical significance were found.Trial registration Current Controlled Trials ISRCTN20141297     

An approach to the detection and management of early breast cancer

The mortality rate for breast cancer has not changed for 40 years. The ultimate results using the various surgical techniques differ very little. Local tumour excision produces survival rates comparable with those for more radical operations. Ideal treatment should give optimal quality and quantity of survival with minimal trauma. Survival is mainly determined by the ability to live in symbiosis with the disease and in most cases clinically obvious tumours are already incurable. Clinical examination alone will not detect disease at a stage early enough for more effective treatment. Mammography and thermography can detect occult breast cancer and, in particular, thermography can be used for serial examinations in high-risk patients because the procedure is simple and without hazard.     

Patterns of preventive practice in New Brunswick

A survey of active general practitioners was conducted in New Brunswick to ascertain their patterns of preventive practice with respect to cancer of four anatomic sites: the breast, the cervix, the colon and rectum, and the lung. Ninety-two percent of the physicians reported that they taught breast self-examination to their female patients, 98% that they performed breast examinations, 98% that they did Papanicolaou smears routinely, and 97% that they provided counselling against smoking. Few of the physicians reported that they submitted women aged 50 to 59 years to annual mammography (3%) or examined stool samples from asymptomatic patients over 44 years of age for occult blood (20%). Many (77%) said they still routinely performed chest roentgenography for early detection of lung cancer; an estimated 49% of the physicians said they performed cytologic screening of sputum samples for the same purpose. Preventive practices, when used, were usually carried out during major encounters with patients, such as general check-ups. The potential for prevention through this clinically based approach is still largely unrealized.     

Autoantibodies against tumor-associated antigens in sputum as biomarkers for lung cancer

Tumor antigens (TAs) can initiate host immune responses and produce TA-associated autoantibody (TAAbs), potential cancer biomarkers. Sputum is directly generated from the upper and lower airways, and thus can be used as a surrogate sample for the diagnosis of lung cancer based on molecular analysis. To develop sputum TAAb biomarkers for the early detection of lung cancer, the leading cause of cancer death, we probed a protein microarray containing more than 9,000 antigens with sputum supernatants of a discovery set of 30 lung cancer patients and 30 cancer-free smokers. Twenty-eight TAs with higher reactivity in sputum of lung cancer cases vs. controls were identified. The diagnostic significance of TAAbs against the TAs was determined by enzyme-linked immunosorbent assays (ELISAs) in sputum of the discovery set and additional 166 lung cancer patients and 213 cancer-free smokers (validation set). Three sputum TAAbs against DDX6, ENO1, and 14–3-3ζ were developed as a biomarker panel with 81% sensitivity and 83% specificity for diagnosis of lung cancer, regardless of stages, locations, and histological types of lung tumors. This study provides the first evidence that sputum TAAbs could be used as biomarkers for the early detection of lung cancer.     

Use of neostigmine to increase the rate of lung cancer detection by sputum cytology

Neostigmine induction was investigated as a method for increasing the rate of detection of lung cancer in respiratory cytology samples. Eleven patients with dry and essentially nonproductive cough were given neostigmine, 15 mg by mouth or 0.5 mg by hypodermic injection. The quality of sputum produced was increased in all cases; the sputum was also more easily expectorated. Eight patients suspected of having lung cancer had previously negative cytologic examinations of sputum obtained by conventional methods. Following the administration of neostigmine, malignant cells indicating squamous-cell carcinoma were found in the sputum samples of three of these patients while dysplastic cells were detected in the samples from two patients. It is postulated that neostigmine intake may increase the excretion of mucous glands in the bronchial submucosa as well as the bronchial epithelium itself.     

Type A behaviour and ischaemic heart disease in middle aged British men.

The Bortner questionnaire, which measures aspects of type A (coronary prone) behaviour was completed by 5936 men aged 40-59 selected at random from one general practice in each of 19 British towns. The presence of ischaemic heart disease was determined at initial examination and the men were followed up for an average of 6.2 years for morbidity and mortality from myocardial infarction and for sudden cardiac death. Non-manual workers had significantly higher scores (more type A) than manual workers and the score decreased (less type A) with increasing age. After adjustment for social class and age men with higher scores had higher prevalences of ischaemic heart disease less marked for electrocardiographic evidence and more marked for response to a chest pain questionnaire (angina or possible myocardial infarction). A man''s recall of a doctor''s diagnosis of ischaemic heart disease, however, did not relate to his Bortner score. There was no significant relation between the Bortner score and the attack rate or incidence of major ischaemic heart disease events. In this study type A behaviour, as measured by the Bortner questionnaire, did not predict major ischaemic heart disease events in British middle aged men.     

Smoking Habits of Men Employed in Industry,and Mortality

A study of the relation between smoking habits and lung cancer in male industrial workers over a period of three years has confirmed the earlier findings in doctors that the death-rate from lung cancer correlates closely with the number of cigarettes smoked. Of 54,460 men studied 68.7% were current cigarette smokers. The annual mortality rate from lung cancer was 0.33 per thousand in non-smokers and ex-smokers, and 1.2 per thousand for all cigarette smokers, and higher in heavy smokers.Heavy cigarette smokers who retained the cigarette in the mouth between puffs (“drooping” cigarette habit) had an annual mortality rate of 4.1 per thousand.The mortality from coronary thrombosis in smokers was nearly three times that in non-smokers. A mortality gradient with rising consumption of cigarettes was observed.Some correlation between smoking and cancer of other sites and from non-neoplastic lung disease was observed in older men, but no correlation was found with other cardiovascular diseases and cerebrovascular diseases.     

痰液脱落细胞中p16 基因和RASSF1A 基因甲基化与周边型非小细胞 肺癌关系的研究

目的:探讨p16基因和RASSF1A基因甲基化与肺癌发生发展的关系和应用于诊断的意义。方法:采用甲基化特异性PCR(Methylation Specific PCR,MSP)检测120例周边型非小细胞肺癌患者癌组织、痰液脱落细胞和120例非肺癌人群的痰液脱落细胞中p16基因和RASSF1A基因甲基化,分析它们与临床特征的关系以及非肺癌人群与肿瘤患者之间的差异。结果:(1)120例周边型非小细胞肺癌组织中,p16基因甲基化率46.7%(56例),RASSF1A基因甲基化率53.3%(64例)。P16和RASSF1A基因甲基化与吸烟程度、肿瘤大小和临床分期正相关(P<0.05)。(2)肺癌痰液脱落细胞中有28例p16基因出现甲基化(23.3%),20例RASSF1A基因出现甲基化(16.7%),其中32例至少存在一个基因的甲基化(26.7%);66例重度吸烟者中只有4例痰液脱落细胞出现p16基因甲基化(6%),4例出现RASSF1A基因甲基化(6%);54例非重度吸烟正常人中仅有2例出现p16基因甲基化(3.7%),RASSF1A基因无甲基化。(3)液基痰细胞病理学检查与痰脱落细胞p16和RASSF1a基因甲基化检测结合起来可有效提高诊断的灵敏度(P<0.05)。结论:烟草可能具有潜在的诱导抑癌基因p16和RASSF1A发生甲基化的作用;p16和RASSF1A基因甲基化可能参与肺癌的生长过程。痰脱落细胞p16和RASSF1a基因甲基化检测结合液基痰细胞病理学诊断,可提高非小细胞肺癌诊断的灵敏度。     

Modifying risk of developing lung cancer by changing habits of cigarette smoking.

Data from a hospital based case-control study of lung cancer in Western Europe were used to examine changes in the risk of developing lung cancer after changes in habits of cigarette smoking. Only data for subjects who had smoked regularly at some time in their lives were included. The large size of the study population (7181 patients and 11 006 controls) permitted precise estimates of the effect of giving up smoking. Risks of developing lung cancer for people who had given up smoking 10 or more years before interview were less than half of those for people who continued to smoke. The reduction in risk was seen in men and women and in former smokers of both filter and non-filter cigarettes but varied by duration of smoking habit before giving up. The protective effect of giving up became progressively greater with shorter duration of smoking habit. The risks after not smoking for 10 years for both men and women who had previously smoked for less than 20 years were roughly the same as those for lifelong non-smokers. Reducing the number of cigarettes smoked a day or switching from non-filter to filter cigarettes also lowered the risk of developing lung cancer but not to the extent associated with giving up smoking.