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Circulating tumor DNA (ctDNA) has demonstrated great potential as a noninvasive biomarker to assess minimal residual disease (MRD) and profile tumor genotypes in patients with non-small-cell lung cancer (NSCLC). However, little is known about its dynamics during and after tumor resection, or its potential for predicting clinical outcomes. Here, we applied a targeted-capture high-throughput sequencing approach to profile ctDNA at various disease milestones and assessed its predictive value in patients with early-stage and locally advanced NSCLC. We prospectively enrolled 33 consecutive patients with stage IA to IIIB NSCLC undergoing curative-intent tumor resection (median follow-up: 26.2 months). From 21 patients, we serially collected 96 plasma samples before surgery, during surgery, 1-2 weeks postsurgery, and during follow-up. Deep next-generation sequencing using unique molecular identifiers was performed to identify and quantify tumor-specific mutations in ctDNA. Twelve patients (57%) had detectable mutations in ctDNA before tumor resection. Both ctDNA detection rates and ctDNA concentrations were significantly higher in plasma obtained during surgery compared with presurgical specimens (57% versus 19% ctDNA detection rate, and 12.47 versus 6.64 ng·mL -1 , respectively). Four patients (19%) remained ctDNA-positive at 1-2 weeks after surgery, with all of them (100%) experiencing disease progression at later time points. In contrast, only 4 out of 12 ctDNA-negative patients (33%) after surgery experienced relapse during follow-up. Positive ctDNA in early postoperative plasma samples was associated with shorter progression-free survival (P = 0.013) and overall survival (P = 0.004). Our findings suggest that, in early-stage and locally advanced NSCLC, intraoperative plasma sampling results in high ctDNA detection rates and that ctDNA positivity early after resection identifies patients at risk for relapse., (© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

The European Early Lung Cancer (EUELC) project aims to determine if specific genetic alterations occurring in lung carcinogenesis are detectable in the respiratory epithelium. In order to pursue this objective, nonsmall cell lung cancer (NSCLC) patients with a very high risk of developing progressive lung cancer were recruited from 12 centres in eight European countries: France, Germany, southern Ireland, Italy, the Netherlands, Poland, Spain and the UK. In addition, NSCLC patients were followed up every 6 months for 36 months. A European Bronchial Tissue Bank was set up at the University of Liverpool (Liverpool, UK) to optimise the use of biological specimens. The molecular-pathological investigations were subdivided into specific work packages that were delivered by EUELC Partners. The work packages encompassed mutational analysis, genetic instability, methylation profiling, expression profiling utilising immunohistochemistry and chip-based technologies, as well as in-depth analysis of FHIT and RARbeta genes, the telomerase catalytic subunit hTERT and genotyping of susceptibility genes in specific pathways. The EUELC project engendered a tremendous collaborative effort, and it enabled the EUELC Partners to establish protocols for assessing molecular biomarkers in early lung cancer with the view to using such biomarkers for early diagnosis and as intermediate end-points in future chemopreventive programmes.

The development of endobronchial ultrasound (EBUS) is one of the most important advances in bronchoscopy in recent years. Two different techniques are available which improve sonographic diagnostics of the mediastinum and staging in patients with lung and non-lung cancer. Radial EBUS and the technique of ultrasound-controlled transbronchial needle aspiration (TBNA) are now routine practice in many pulmonary centers. Their clinical application and diagnostic benefit have been established in many studies comparing them with conventional radiologic methods and other diagnostic procedures. Endobronchial ultrasound as a diagnostic tool is expected to gain importance in the near future. Especially the method combining EBUS and TBNA may replace more invasive methods such as mediastinoscopy for evaluating patients with unknown mediastinal lesions or for staging patients with lung cancer.

Background: The potential of autofluorescence bronchoscopy (AFB) to detect precancerous lesions in the central airways and its role in lung cancer screening is uncertain. A study was undertaken to evaluate the prevalence of moderate/severe dysplasia (dysplasia II-III) and carcinoma in situ (CIS) using a newly developed AFB system in comparison with conventional white light bronchoscopy (WLB) alone., Methods: In a prospective randomised multicentre trial, smokers > or = 40 years of age (> or = 20 pack-years) were stratified into four different risk groups and investigated with either WLB+AFB (arm A) or WLB alone (arm B)., Results: 1173 patients (916 men) of mean age 58.7 years were included. Overall (arms A and B), preinvasive lesions (dysplasia II-III and CIS) were detected in 3.9% of the patients. The prevalence of patients with preinvasive lesions in the WLB arm was 2.7% compared with 5.1% in the WLB+AFB arm (p = 0.037). For patients with dysplasia II-III, WLB+AFB increased the detection rate by a factor of 2.1 (p = 0.03), while for CIS the factor was only 1.24 (p = 0.75). The biopsy based sensitivity of WLB alone and WLB+AFB for detecting dysplasia II-III and CIS was 57.9% compared with 82.3% (1.42-fold increase). The corresponding specificity was 62.1% compared with 58.4% (0.94-fold decrease)., Conclusions: This first randomised study of AFB showed that the combination of WLB+AFB was significantly superior to WLB alone in detecting preneoplastic lesions. Our findings do not support the general use of AFB as a screening tool for lung cancer, but suggest that it may be of use in certain groups. The precise indications await further study.

Conventional imaging procedures proved to be insufficient for staging of lung cancer especially with respect of N-stage, infiltration of mediastinal structures and early lung cancer. As also the view of the endoscopist is restricted we developed the new method of endobronchial ultrasonography (EBUS) as adjunct to conventional bronchoscopy. The initial technical problems were solved by development of a balloon catheter for application of miniaturized 20 MHz probes. EBUS is a new technology that can be easily applied and is well tolerated. It improves the results of bronchoscopy in addition to conventional diagnostic procedures. Further developments will be made in future to improve the application of ultrasound in chest medicine.

Pulmonary clear cell or sugar tumor is a rare entity of unknown etiology and histogenesis. As primary extrapulmonal sugar tumor (PEST) this neoplasia can also be found in the trachea, vulva, rectum, pancreas or atrial-septal region. So far about 40 case reports have been published in english literatur. We present the case report of a patient with a pulmonal sugar tumor, who previously underwent nephrectomy because of clear cell renal carcinoma. Clinical aspects, differential diagnosis, therapy and histogenetic aspects are discussed.

Background: Autofluorescense (AF) bronchoscopy is an established method to detect dysplasia and carcinoma in situ (CIS). Several different systems are currently available., Objectives: This study aimed to directly compare the LIFE system (Xillix Technologies, Vancouver, Canada) and the D-light system (Storz, Tuttlingen, Germany)., Methods: In a prospective study performed between May 1999 and October 2000, we examined patients with risk factors for lung cancer that underwent bronchoscopy with both (LIFE and D-light) systems in a crossover design. The findings were classified into normal, abnormal and suspicious lesions by independent investigators and then compared., Results: This study comprised 332 patients (220 males, 112 females, mean age 62.7 years, range 40-85); 1,117 biopsies were studied (mean biopsy rate 3.4/patient). In 817 biopsies, mucosal areas were classified as normal with respect to control biopsy specimens, 113 as abnormal and 187 as suspicious using AF bronchoscopy. The histological examination showed normal tissue in 850 cases, in 55 cases scarring or inflammation, in 62 meta- or dysplasias, in 11 carcinomas in situ and in 127 invasive tumors. In only 5 cases, classifications were found to be different between the two systems (2 normal, 2 dysplasias, 1 invasive tumor). The mean time for the LIFE system examination amounted to 11.7 min (range 6.2-19.5) and for the D-light system to 7.4 min (range 4.3-11.9). This difference was statistically significant (p < 0.001)., Conclusion: Both systems yielded comparable results. The examination time was significantly shorter with the D-light system, which may be explained by the more comfortable handling and the direct switch between white light and AF imaging. Different trials using either methodology could be compared directly., (Copyright 2003 S. Karger AG, Basel)

Clear cell tumors of the lung are commonly primary, clear-cell, bronchial carcinomas or metastasis of a renal cell carcinoma. Compared to this, pulmonary sugar tumor is a rare entity. A large intracellular content of glycogen and immunohistochemical procedures lead to diagnosis. The demonstration of the premelanosomal protein HMB-45 is considered as proof, but this is not airtight. We present a case of metachronic, benign, and HMB-45-negative sugar tumor of the lung after hypernephroma and give a review of the literature.

Objective: A frequent problem in patients with intrathoracic malignancies neighboring central airways is the question of whether the airway wall is infiltrated by the tumor or if it is merely compressed. This distinction can often not be made with certainty with the help of chest CT alone, but frequently necessitates surgical biopsy or exploration. We prospectively studied the utility of endobronchial ultrasound (EBUS) in this clinical circumstance., Methods and Patients: Between May 1999 and July 2000, 131 consecutive patients with central thoracic malignancies potentially involving the airways were enrolled into the study. Patients underwent chest CT followed by standard bronchoscopy together with EBUS and subsequent surgical evaluation. The bronchoscopists did not know the radiologist's interpretation of the chest CT before performing EBUS. The ability of chest CT and EBUS to distinguish between compression and infiltration was measured against the histologic results., Results: One hundred five patients completed the trial by undergoing surgery. In 81 patients (77%), the CT scan was read as consistent with tumor invasion. EBUS only showed invasion in 49 cases (47%). Histology after surgery revealed a specificity of 100%, a sensitivity of 89%, and an accuracy of 94% for EBUS. Chest CT was far inferior, with a specificity of 28%, a sensitivity of 75%, and an accuracy of 51%., Conclusion: We conclude that EBUS is a highly accurate diagnostic tool and superior to chest CT in evaluating the question of airway involvement by central intrathoracic tumors. In the hands of experienced endoscopists, EBUS may become the procedure of choice for this question.

Transbronchial biopsy (TBBX) for peripheral lung lesions is usually performed with the help of fluoroscopy, but the yield varies widely. This feasibility study aimed to assess the ability of endobronchial ultrasound (EBUS) to provide imaging guidance for TBBX. In a prospective study, 50 consecutive patients referred for TBBX for peripheral lesions underwent fluoroscopy-guided and EBUS-guided TBBX in random order. Diagnostic yields were compared for both modalities and feasibility was assessed for EBUS. Diagnostic material was obtained in 80% of patients with EBUS and 76% of patients with fluoroscopy. There was a nonsignificant trend for EBUS to be better than fluoroscopy for lesions <3 cm in diameter. Four lesions could not be visualised with EBUS. There were no significant complications associated with the use of EBUS. Endobronchial ultrasound-guided transbronchial biopsy is feasible. It appears to be at least equivalent to fluoroscopy without the accompanying radiation exposure. Further large-scale studies are indicated to assess the possible role of endobronchial ultrasound as a potential imaging method of choice for the biopsy of peripheral lung lesions.

Aim: Lung cancer is a common disease and exact staging is of extreme importance in order to plan therapy. A frequent problem in assessing the extent of tumour spread is the question of infiltration versus compression of central airways by central tumours and a correct lymph node staging. Chest CT as the general imaging procedure of choice is often not helpful with these questions. Endobronchial ultrasound (EBUS) has been available for several years, and we were interested to find out if the addition of EBUS to regular bronchoscopy can help to differentiate between airway infiltration and external compression and improves the yield of transbronchial needle aspiration (TBNA)., Method: Patients with central tumour growth and enlarged lymph nodes were examined with EBUS and CT, classified according to local tumour invasion, and a needle biopsy of the lymph nodes was performed after EBUS detection., Results: 50 patients were examined and subsequently operated. Relative to the local T-staging EBUS resulted in a sensitivity of 89 % and a specificity of 100 %. The results were highly improved statistically compared to the CT results (sensitivity 25 %, specificity 80 %). With EBUS-guided TBNA the results of correct N-staging could be improved to 86 %., Conclusion: Our study suggests that EBUS, if performed by experienced endoscopists for the detection of airway wall infiltration or compression is highly accurate and superior to chest CT in assessing potential airway infiltration by a malignant tumour. Furthermore, the results of the lymph node staging could be improved through the additional use of EBUS. It is easily performed within the context of a standard bronchoscopy and may spare many patients unnecessary surgical biopsies.

Endobronchial ultrasound (EBUS) is a new diagnostic tool, which has expanded the view of the bronchoscopist beyond the confinements of the airways. It has great potential for diagnosis of mediastinal processes and staging of lung cancer. These will be discussed and illustrated. EBUS will become a superior tool for staging of lung cancer, and several comparative studies on EBUS as compared with standard techniques in order to assess its role in the staging procedure are just on their way or already completed.

Study Objective: To provide current data on the long-term outcome and incidence of lung cancer in a large cohort of patients with hemoptysis of unknown origin., Design: A retrospective chart review followed by a telephone interview for follow-up., Setting: A university-affiliated tertiary referral center for pulmonary diseases., Patients: Seven hundred twenty-two patients who presented with hemoptysis from January 1990 to December 1993. One hundred thirty-five patients were identified as having hemoptysis of unknown origin., Results: One hundred thirty-five patients (19%) had hemoptysis of unknown origin; follow-up data were obtained in 115 patients, of whom 100 were still alive. The mean time of observation was 6.6 years after initial presentation. Lung cancer developed in 7 of 115 patients (6%) and was unresectable once detected; all of these patients were smokers > 40 years old, and malignancy developed within 3 years after first presentation., Conclusions: Hemoptysis of unknown origin is present in a minority of patients presenting with hemoptysis if evaluated at a referral center for pulmonary diseases. Lung cancer seems to be increasing in these patients compared to previous studies, and closer follow-up or additional testing may be indicated in the defined population at risk.

Aim: Evaluation of prognosis-associated parameters in patients with small cell lung carcinoma., Material and Methods: Biopsies of 46 patients suffering from a non-treated small cell lung carcinoma were stained with Feulgen and immunohistochemically with Ki-67 antibody. The integrated optical density (IOD) and proliferation rate was measured by syntactic structure analysis and correlated with survival., Results: About 85% of patients had a smoking history (46 pack years on average). The median survival time was 13.5 months, the proliferation rate (Ki-67 positive tumor cell nuclei) 68.2% and S-phase percentage 9.2%. Ot average, 25 proliferating tumor cell nuclei formed clusters (mean diameter 95 microns). The prognosis was associated with the proliferation rate (p < 0.04), tumor stage (stage I versus lib, p < 0.05), at threshold limits with S-phase rate (p < 0.07) and serum levels of LDH and NSE (p < 0.06 and p < 0.07 respectively)., Conclusions: Immune histochemical determination of the Ki-67 protein is a useful method to estimate the prognosis of patients with small cell lung carcinoma.

Lung cancer is a leading cause of cancer death worldwide; however, despite major advances in cancer treatment during the past two decades, the prognostic outcome of lung cancer patients has improved only minimally. This is largely due to the inadequacy of the traditional screening approach, which detects only well-established overt cancers and fails to identify precursor lesions in premalignant conditions of the bronchial tree. In recent years this situation has fundamentally changed with the identification of molecular abnormalities characteristic of premalignant changes; these concern tumour suppressor genes, loss of heterozygosity at crucial sites and activation of oncogenes. After considering the morphological modifications that occur in premalignant lesions of the bronchial tree, we analyse the alterations occurring in a series of relevant genes: p53 and its functional regulation by MDM2 and p14ARF, p16INK4, p15INK4b, FHIT, as well as LOH at important sites such as 3p, 8p, 9p and 5q. Activation of oncogenes is considered for K-ras, the cyclin D1, the heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2/B1), and finally the c-myc oncogene. The expression of c-myc is influenced strongly by the presence of growth factors (GFs), among which EGF is of prime importance, as well as its receptor coded for by the c-erbB-2 oncogene. Basic knowledge at the molecular level has extremely important clinical implications with regard to early diagnosis, risk assessment and prevention, and therapeutic targets. The novel techniques for early diagnosis and screening of premalignant lung lesions, such as fluorescence bronchoscopy, endobronchial ultrasound, spiral computed tomography combined with precise spatial localization techniques, should basically change the approach to the problems raised by this disease and allow for an increased discovery rate of incipient lesions. Sequential applications will lead to the identification of individuals/populations at high risk, while the availability of accurate 'intermediate end points' will enable the effects of preventive trials to be monitored. Finally, the same molecular abnormalities may serve as 'starting points' for innovative treatments designed to restore the altered functions to normality. Recent developments in our knowledge and understanding of the molecular genetic abnormalities in premalignant lung lesions open an era of hope.

Background and Objective: Conventional imaging procedures proved to be insufficient for staging of lung cancer, especially with respect to N-stage, infiltration of mediastinal structures, and early lung cancer. As also the view of the endoscopist is restricted, we developed the new method of endobronchial ultrasonography (EBUS) as an adjunct to conventional bronchoscopy. The initial technical problems were solved by development of a balloon catheter for application of miniaturized 20-MHz probes., Patients and Methods: Between January and December, 1999 all patients with an indication for bronchoscopy and additional EBUS were documented prospectively., Results: In 648 patients we used additional EBUS. Of these, 242 (37%) were female and 406 (63%) were male. The mean age was 49.2 (range 0-83) years. The mean procedure time for the bronchoscopies was 18.9 (range 5.7-38.9) min, and the mean time for EBUS was 6.3 (range 3.1-14.4) min. Side effects were comparatively rare. 34 patients (5%) needed supplementary oxygen during the examination, the others tolerated EBUS without any desaturation., Conclusion: EBUS is a new technology that can be easily applied and is well tolerated. It improves the results of bronchoscopy in addition to conventional diagnostic procedures. Further developments will be made in future to improve the application of ultrasound in chest medicine., (Copyright 2001 S. Karger GmbH, Freiburg)

RT-PCR-based amplification of transcripts expressed in cancer but not in normal non-neoplastic cells is increasingly used for the sensitive detection of rare disseminated or exfoliated cancer cells to improve cancer staging and early detection protocols. However, these assays are frequently hampered by false-positive test results due to low-level transcription of the marker genes in normal cells. To overcome these limitations, target transcripts have to be identified that are tightly suppressed in normal non-neoplastic tissues, whereas they should be actively transcribed in the respective cancer cells. Here, we tested RT-PCR assays for 7 neuroendocrine marker transcripts including NCAM, PGP 9.5, gastrin, gastrin receptor, synaptophysin, preprogastrin-releasing peptide (preproGRP) and GRP-receptor to detect rare exfoliated tumor cells in peripheral venous blood and sputum samples from patients with lung cancer. Among these preproGRP RT-PCR was the only assay with which illegitimate transcription in blood or sputum samples from healthy donors or patients with unrelated diseases did not interfere. However, it reproducibly detected up to 10 small-cell lung cancer cells diluted in either 10 ml blood or 5 ml sputum samples. Single blood and sputum samples were collected directly before diagnostic bronchoscopy from 175 patients suspected to have lung cancer. Twenty-six of these had small-cell lung cancer (SCLC). Thereof, 13 patients (50%) tested positive in the blood sample and 5 of 23 patients (22%) tested positive in the sputum sample. Moreover, among 92 patients with non-small-cell lung cancer (NSCLC) 25 patients (27%) had disseminated cancer cells in peripheral blood. Amplification of preproGRP transcripts from clinical samples is a sensitive and specific assay to detect disseminated or exfoliated lung cancer cells either in peripheral blood or sputum samples., (Copyright 2001 Wiley-Liss, Inc.)

Aim: To assess effect and toxicity of high-dose-rate afterloading (HDR) alone or in combination with external beam radiotherapy (EBRT) in centrally located tumors of the upper respiratory tract., Patients and Methods: From 1987 to 1996, 55 patients were treated. Twenty-one patients (group A1: 17 non-small-cell lung cancer [NSCLC], A2: 4 metastases from other malignancies) were treated using HDR alone due to a relapse after external beam irradiation. In 34 previously untreated and inoperable patients (group B1: 27 NSCLC, B2: 7 metastases from other malignancies) HDR was given as a boost after EBRT (30 to 60 Gy, median 50). HDR was carried out with a 192Ir source (370 GBq). The brachytherapy dose (group A: 5 to 27 Gy, median 20; B: 10 to 20 Gy, median 15) was prescribed to 1 cm distance from the source axis. A distanciable applicator was used in 39/55 patients., Results: In group A1, a response rate (CR, PR) of 53% (group B1: 77%) was reached. The median survival (Kaplan-Meier) was 5 months in group A1 (B1: 20 months). The 1-, 3- and 5-year local progression free survival rates (Kaplan-Meier) were 66% (15%), 52% (0%), and 37% (0%) in group B1 (group A1). Prognostic favorable factors in group B1 were a tumor diameter < 20 mm, the lack of radiological mediastinal involvement, a complete remission, and a Karnofsky performance status > 70. Grade-1 or 2 toxicity (RTOG/EORTC) occurred in 0% in group A and in 6% in group B. We observed no Grade-3 or 4 toxicity. Complications caused by persistent or progressive local disease occurred in 3 patients in group A (fatal hemorrhage, tracheomediastinal fistula, hemoptysis) and in 2 patients in group B (fatal hemorrhage, hemoptysis)., Conclusions: HDR brachytherapy is an effective treatment with moderate side effects. In combination with external beam irradiation long-term remissions can be reached in one third of the patients.

Aim: To analyze the diagnostic accuracy of telediagnostic procedures for transbronchial fine needle aspirations., Material and Methods: A double blind study was performed on cytological slides of 54 randomly selected cases with transbronchial fine needle aspirations. The slides were digitized using a Leica digital camera DC100 mounted on a microscope Leica Laborlux S, and analyzed by an experienced pathologist without knowing the definite diagnosis or any additional clinical data. The diagnoses stated by analyzing the digital images were compared to the final conventional diagnoses. In addition, the duration of the digital diagnosis, used magnifications, and difficulties for correct sampling were documented., Results: The "digital" diagnoses of the 54 cases were all in general agreement with the definite diagnoses. No wrong positive or wrong negative case in respect to malignant/non-malignant (31/23) or to small cell/non-small cell (9/22) occurred. The performance of a digital diagnosis lasted for 115 s at average (15-260 s), and is significantly longer compared to that of conventional fine needle aspiration judgement (20 s). The screening magnification was commonly set to x2.5, that for definite diagnostic analysis x40. Benign diseases (2 tuberculosis and 3 sarcoidosis cases) were correctly classified., Conclusions: Telepathology systems can probably be used for fine needle aspiration analysis without major diagnostic errors. Their use can improve the endoscopic sampling and avoid second anesthesia when missing the lesion of request during the first examination.

Aim: Since the view of the endoscopist is restricted and radiological procedures are unreliable in the diagnosis of mediastinal disease, we investigated endobronchial ultrasound in a preliminary clinical study., Methods: Two of the systems tested, Olympus and Sonotron (CVIS), proved to be applicable after some modifications. They were tested in a phantom, in resection specimens and in 500 bronchoscopies., Results: In tumor staging infiltration of the bronchial wall and parabronchial structures could be assessed. Lymph nodes could be detected down to 3 mm, but not even by in vitro examination of 84 resected lymph nodes could we find reliable signs for malignancy. Infiltration of the bronchial wall and involvement of large vessels by mediastinal masses was frequently diagnosed. Involvement of the airways by vascular anomalies, pleural effusion or solid masses could be differentiated., Conclusions: In view of the fact that the procedure costs around $20, it seems feasible and we are currently examining its value in a prospective study.

Although the exact proportion of patients with carcinoma in situ in whom disease will progress to invasive lung cancer is not known, and although there have been reports that some individuals may continue to show malignant cells in sputum for several years without symptoms or abnormality on chest radiograph, untreated or suboptimally treated carcinoma in situ has been shown to progress to invasive cancer or metastatic disease. A study by Frost and co-workers showed that cancer developed in approximately 10% of individuals with moderate atypia and 40% of those with severe atypia in sputum cytology. Therefore, the proportion of individuals with carcinoma in situ in whom invasive cancer will develop is likely to be greater than 40%. Lung cancer is almost uniformly fatal when untreated, and, if the disease is allowed to progress to the invasive stage, the results of currently available therapy are poor. A lesson must be learned from cervical cancer screening. As has been shown by Anderson and co-workers, if individuals harboring dysplasia or carcinoma in situ are actively sought for and treated by laser or cryotherapy, the incidence and mortality of invasive cervical cancer can be reduced to extremely low levels. If current work directed toward detecting early lung cancer in sputum cytology specimens in high-risk groups using quantitative image cytometry or molecular markers is successful, the ability to localize small preinvasive lesions with fluorescence bronchoscopy will become even more important for the pulmonologist or thoracic surgeon. Endoscopic ultrasound can be used to determine the depth of tumor infiltration into the bronchial wall or adjacent structures. Biopsy of mediastinal and peribronchial lymph nodes can be performed under sonographic guidance for more accurate staging. By coupling sensitive diagnostic tools to new treatment modalities, such as chemoprevention and various endobronchial therapies, it is hoped that the traditionally poor prognosis for patients with lung cancer can be altered in the near future.

Expression of alternatively spliced CD44 adhesion molecules has been implicated in metastatic spread of various rodent and human tumors. To determine whether specific CD44 splice variants contribute to metastatic spread of bronchial cancers, we compared the expression of CD44 splice variants in normal bronchial epithelium and bronchial cancers, including tumors which already spread to regional lymph nodes or distant organs. Variant CD44 expression was analysed by immunohistochemistry using variant exon-specific monoclonal antibodies. The precise composition of CD44 transcripts was delineated by exon-specific RT-PCR. The concurring data obtained by both methods revealed that high levels of standard CD44 and variants v5 and v6 as well as low levels of variants v7 and v10 are expressed both in normal bronchial epithelium and squamous cell lung cancers. No CD44 expression was observed in the highly metastatic small cell lung cancers and adenocarcinomas with the exception of bronchioalveolar cancers showing weak expression of standard CD44. These data suggest that expression of alternatively spliced CD44 molecules in the bronchial tract is related to the distinct differentiation of the respiratory epithelium. No correlation between expression of specific CD44 splice variants and metastasis of bronchial cancers was observed.

In a German multicenter trial, previously untreated patients with unresectable stages IIIA and IIIB non-small cell lung cancer were randomly assigned to receive either radiotherapy alone (arm A) or chemotherapy followed by radiotherapy (arm B). Chemotherapy in arm B consisted of ifosfamide 1,500 mg/m2 intravenously on days 1 to 5 and 29 to 33, and vindesine 3 mg/m2 intravenously on days 1 and 5 and 29 and 33. Radiotherapy started on day 1 in arm A and on day 56 in arm B. Single doses of 2 Gy were given 5 days a week for 3 weeks and after a 2-week interval for an additional 2 weeks. The total radiation dose was 50 Gy. Concurrent to radiotherapy, cisplatin was given as a radiosensitizer at a dose of 20 mg/m2 once a week. From July 1986 to March 1989, 85 patients were randomized, of whom 78 were evaluable. Main prognostic factors were well balanced. Of the patients receiving chemotherapy, 25% had a partial remission after two cycles, 46% showed no change, and 29% had progressive disease. After radiotherapy, response rates were 49% in arm A and 58% in arm B, including a 10% complete remission rate in both groups. After two thirds of the projected sample size had been included, an analysis of survival was performed and showed a statistically significant advantage for the treatment group including chemotherapy (P = .016). Median survival was 9.0 months versus 13.7 months and 2-year survival was 12% versus 24%, both in favor of the group receiving chemotherapy. These results caused premature discontinuation of patient accrual according to the study protocol and the recommendations of the Ethics Review Board of the Philipps-University Hospital. The results of this trial indicate that chemotherapy is able to prolong survival of patients with locally advanced unresectable non-small cell lung cancer and should be considered for treatment of these patients.

Between November 1987 and July 1991 34 patients with a non-small-cell lung cancer were treated with an endobronchial iridium-192 high-dose-rate afterloading therapy. In 13 patients with relapses after percutaneous irradiation brachytherapy was the sole radiotherapy modality with 20 (5 to 29) Gy within 14 (one to 42) days in four (one to six) fractions in a palliative sense. Endoscopically controlled, seven remissions (four complete, three partial) could be achieved. The median duration to local progression was two months, the median survival of this group was nine months. In 21 patients with a medically or surgically unresectable tumor a combined percutaneous (51 [46 to 60] Gy within 4.5 to six weeks) and endobronchial irradiation was done. This patient group consisted of one stage IV, eight stage IIIb, 8 stage IIIa, 1 stage II, 1 stage I patients and two patients with tumor relapses after surgery. Patients were selected for combined therapy by a mostly endo/peribronchial tumor volume. The brachytherapy was applied after an interval of 16 (one to 48) days with 17.5 (9 to 20) Gy in three to four fractions. In 13 patients six to eight weeks after treatment a complete remission by endoscopy was found. Patients with a complete remission had a statistically better survival than the remaining patients. The median estimated survival of this group until local progression was 16 months, the median survival 20 months. In all patients there were two occurrences of hemorrhage (one group I, one group II) and one tracheo-mediastinal fistula (group II), but in no case of these fatal events a local tumor control had been reached. In three patients radiogenic bronchitis occurred up to a degree, which demanded endoscopic interventions. This study suggests, that there might be a subgroup of centrally located lung cancer with endo/peribronchial tumor mass, which gains by a combined radiation treatment with an acceptable risk of side effects. The results should be evaluated in further randomized studies.

We report a 25-year-old male patient with primitive neuroectodermal tumor presenting as a subcutaneous tumor on the right buttock, which was initially diagnosed as neuroendocrine carcinoma of the skin. Subsequently, local recurrence and metastatic spread to the lung occurred. The tumor was resistant to highly aggressive chemotherapy. The patient died 6 months later with severe pulmonary and lymph node involvement.

A new bronchial applicator for afterloading irradiation is introduced which can be positioned to the center of the tracheobronchial lumen. The central position in the lumen leads to a clear improvement of dose distribution. The applicator is built on the principle of a coaxial tube. Parts of the outer cover can be expanded to baskets and effect a distance of the radiation source from the bronchial mucosa or tumor surface, and at the same time, expend a relief of extreme contact doses. No obstruction of the respiratory system through the positioning device will be caused. The positionable bronchial applicator seems to be suitable for reducing complications caused through high contact doses and irregular dose distributions and may be able to improve the results of endoluminal radiotherapy.

To test whether alternating chemotherapy is a favorable treatment modality in small-cell lung cancer (SCLC), 334 patients were randomized to receive either fixed cyclic-alternating treatment with ifosfamide/etoposide (IE), cyclophosphamide, doxorubicin, and vincristine (CAV), or response-oriented treatment with IE therapy up to maximal response and subsequently an immediate switch to CAV. In both arms, six cycles were given in 3-week intervals. After chemotherapy, patients with limited-stage disease received chest irradiation with 45 Gy. Prophylactic cranial irradiation with 30 Gy was applied to all complete responders. No maintenance therapy was given to patients with complete response. Minimum follow-up was 2 years. Of 321 assessable patients, the overall response rate was 70% for cyclic alternating and 77% for response-oriented treatment. Complete remission (CR) rates were 26% versus 26%. The median survival times were 9.7 months for cyclic-alternating versus 10.7 months for response-oriented treatment; the 2-year survival rates were 11% versus 9%. In limited-stage disease (LD) patients, there was a median survival of 12.5 months versus 12.3 months and a 2-year survival rate of 21% versus 18%. In extensive-stage disease (ED) patients, median survival was 8.5 versus 9.1 months, and the 2-year survival rate 3% versus 4%. From these results, we conclude that the cyclic-alternating treatment according to the hypothesis of Goldie et al has no advantage in comparison to a sequential treatment strategy with an immediate switch to a second-line protocol at the time no further response to first-line therapy is seen. Our major aim in the treatment of SCLC is to administer an active regimen at any time during the course of treatment regardless of whether sequential or alternating therapy is used.

Bronchoscopic laser application and radiotherapy are very effective in treating the recurrence of bronchogenic carcinoma. Reoperation is rarely possible. During the period from January 1981 to June 1989, 242 patients underwent lung resection at the Bundeswehrhospital Ulm because of malignant airway disease. In ten of these patients reoperation was performed in case of tumour recurrence. The median survival time was 17 months (2 to 60 months). Comparing the literature with our own experience we conclude that operative treatment of bronchogenic recurrences is possible in few selected cases. The indication for reoperation depends on the stage of the primary tumour, the spread of the recurrence and the physiological status of the patient.

The practice of therapeutic trials is indispensable in the management of bronchial carcinoma if one hopes to improve the results. We have questioned 134 doctors in the Alsace region who are involved in the diagnosis and treatment of bronchial cancer. We asked how they would wish to be treated if they had a small cell cancer, and if they would agree to participate in a therapeutic trial should the occasion arise. Four different clinical situations of small cell carcinoma localised to the hemithorax were presented, illustrating current controversy on the best treatment or treatments to apply. The 4 proposed protocols were refused by 50% to 84% of the doctors questioned in different cases. The greater the level of consensus on a therapeutic treatment in a given clinical situation the greater the level of refusal to participate in a randomised protocol was. The fact that at least half of the specialist doctors questioned would refuse to be included in a current therapeutic protocol which is underway for patients in Europe leads to the suggestion that before the application for new protocols experts surrogates should give their opinion in association with ethical committee.

The Nd-YAG-laser is an ideal tool for surgery within the narrow bronchial system, provided indications, contraindications and a safe technique are observed. Complications of advanced tumors in the central bronchial system can be averted and patients can be treated by adjuvant therapy with reasonable median and long-term prognosis. In many cases of benign lesions patients can be spared the risks of major thoracic surgery. Complications are comparatively rare.

Two cases of synchronous pulmonary carcinoid tumour and non-Hodgkin's lymphoma are described.

A total of 166 patients with non-small cell lung cancer (NSCLC) were included in two multicenter trials testing different treatment regimens. In study I, 116 patients received 4 cycles of aggressive polychemotherapy consisting of cis-platinum 100 mg/m2 (day 1), etoposide 100 mg/m2 (days 4-6), and vindesine 3 mg/m2 (day 1) (CEV); patients without distant metastases subsequently received chest irradiation with 50 Gy. In study II, 50 patients were treated with monochemotherapy consisting of etoposide 250 mg/m2 (days 1-3), and ifosfamide 5 g/m2 as 24-h infusion (day 29). While this program was repeated in responders with extensive disease (ED), patients with limited disease (LD) subsequently received chest irradiation with 50 Gy using 20 mg/m2 cis-platinum weekly as a radiosensitizer. Response rates (CR + PR) to chemotherapy were higher in study I than in study II, and were 26% (CR 3%) vs. 8% (CR 0%) for all patients, 18% (CR 0%) vs. 4% (CR 0%) for ED, and 45% (CR 11%) vs. 13% (CR 0%) for LD. The increase in response rates by radiotherapy was marginal in study I (CR + PR 47%, CR 18%), but remarkable in study II (CR + PR 42%, CR 29%). While median survival was slightly longer in study I than in study II for ED (7.7 vs. 6.6 months) and LD (14.4 vs. 12.0 months), the 2-year survival rate was in favor of study II (10% vs. 25%). Toxicity was clearly more pronounced in study I, including 3 lethal complications and 16 discontinuations of therapy due to side effects or refusal. Thus, while in ED the efficacy of both treatment regimens was very restricted, in LD radiotherapy with cis-platinum as a radiosensitizer achieved a relatively high 2-year survival rate which justifies further testing of this treatment strategy.

In three German multicenter randomized trials, which included 718 patients, the activity of ifosfamide in small cell lung cancer (SCLC) was tested. In study 1, IE (ifosfamide, 1.5 g/m2, days 1 through 5; etoposide, 120 mg/m2, days 3 through 5) alternating with CAV (cyclophosphamide, 600 mg/m2, days 1 and 2; doxorubicin, 50 mg/m2, day 1; vincristine, 2 mg, day 1) was compared with a response-oriented treatment with IE therapy up to maximum response and subsequently an immediate switch to CAV. After chemotherapy, patients with limited disease received chest irradiation with 45 Gy. Prophylactic cranial irradiation (30 Gy) was given to all patients who achieved complete response (CR). A total of 324 patients were evaluable. Total response rate (CR + partial response [PR]) was 75% v 78% for the two treatment groups; the CR rate was 29% for both groups. Survival was nearly identical in both arms, with a median survival of 10.0 months for all patients, 12.0 months for those with limited disease (LD), and 7.5 months for those with extensive disease (ED). The 2-year survival rate was 11%. In study 2, IE was compared with PE (cisplatin, 90 mg/m2, day 1; etoposide, 150 mg/m2, days 3 through 5). A total of 141 patients were evaluable. Total response (CR + PR) rate was 65% for PE and 68% for IE; the CR rate for PE was 32% v 20% for IE. Survival favored PE with a median survival of 11.6 months v 9.4 months for all patients, 14.8 months v 11.0 months for LD, and 8.9 months v 7.5 months for ED. Two-year survival rates were 12% v 9% for all patients, 23% v 10% for those with LD, and 5% v 9% for those with ED. From these trials, we conclude that IE is an active and well-tolerated regimen for SCLC, and that PE may be superior to IE in limited-stage disease. Taking these results into account, we modified our chemotherapy protocols in study 3 and compared IAV (ifosfamide, 2 g/m2, days 1 to 5; doxorubicin, 25 mg/m2, days 1 and 2; vincristine, 2 mg, day 1) alternating with either PE or JE (carboplatin, 300 mg/m2, day 1; etoposide, 120 mg/m2, days 1 to 3). Interim results of 253 evaluable patients are as follows: CR + PR rate after 4 cycles was 68%; the CR rate was 28%; median survival was 11.6 months for all patients, 14.8 months for LD, and 10.2 months for ED.(ABSTRACT TRUNCATED AT 400 WORDS)

The effect of tumour size, as determined surgically, and tumour position, as determined by bronchoscopy, on ventilation and perfusion scintigraphy was examined in 53 patients with squamous cell carcinomas of the lung. The findings were compared with reduction in one-second-capacity. Central tumours were frequently associated with marked reduction in perfusion. In these patients there was a linear positive correlation between ventilation and one-second-capacity. The reduction in perfusion, and the need to measure this, became with more peripheral tumours. There was a correlation between ventilation and tumour size in patients with V/Q quotient of greater than 1.2. The results show that tumour size and position do not necessarily indicate operability. For planning surgery of central tumours, perfusion scintigraphy therefore occupies an important position.

In a retrospective study (1969--1979) of 530 resections performed because of bronchial carcinoma, there were 70 patients older than 70 years (13.2%). Two-thirds of their resections were carried out on T 1--2 N0M0 and one-third on T 1--2-N1M0. For 22 central and 48 peripheral carcinomas, 25 pneumonectomies, 40 lobectomies, and 5 bilobectomies were performed. The mortality was 14.2% (lung embolism, pneumonia, apoplexia, and one insufficiency of the bronchial resection stump). Postoperative complications were atelectasis (28.5%), pneumonia (4%), lung embolism (6%), and two pleura empyemas. Of the patients operated on from 1976 to 1978, 40% (T1N0M0) and 30% (T2N0M0) and 30% (T2N0M0) are alive after 2.5 years.

192 untreated patients with a histologically verified non-small cell lung carcinoma were treated within 3 phase-II studies with different chemotherapy regimens: ifosfamide 2 g/m2 day 1-5 and cis-platinum 75 mg/m2 on day 1 (study I); ifosfamide 2 g/m2 days 1-5 and etoposide 120 mg/m2 days 1-3 (study II); ifosfamide 2 g/m2 days 1-5 and vindesine 3 mg/m2 on days 1 and 8 (study III). All chemotherapy combinations were repeated every 4 weeks. One therapy with at least 2 courses was the minimum criterion for evaluating the remission rate. We observed complete remissions in 5 patients, and partial remissions in 54 patients (remission rate 31%). The median duration of remission was 7 months, the time to progression 5 months. The median survival time of all 192 patients was calculated as 8.5 months. The performance status had a significant influence on the remission state and the survival time of the patients. The sex and age of the patients as well as the extension and the histological type of the tumor had no influence. Concerning the remission rate and the survival time, there was no significant difference between the 3 therapy regimens. Due to the lesser toxicity, the combination ifosfamide/etoposide was the best.

A total of 126 resection specimens from malignant lung tumors were cut into serial sections, and tumor volume and macroscopic growth pattern were computed. Four characteristic tumor growth patterns could be separated: Tumors growing in bizarre, irregular shapes; Tumors growing in spheroid shapes; Tumors growing in ellipsoid shapes; Tumors growing in mixed growth pattern. The immunologic response of the host tissue was analyzed grading the number of lymphocytes, plasma cells, macrophages in and at the boundary of the tumor tissue. Lymphocytic subpopulations were analyzed in 46 cases using monoclonal antibodies (BS3/BS4; T3, OKT4, OKT8, OKT11, OKT14). The majority of lymphocytes were T-lymphocytes and monocytes in cases with inflammatory response of host tissue. The ratio of inducer/helper subset (OKT4+) compared to suppressor/cytotoxic subset (OKT8+) was similar in expression as reported for circulating peripheral T-lymphocytes. The different growth patterns depend upon cell type of tumor, immunologic response of the host tissue, and tumor volume. The findings indicate that tumor progression into lung tissue is partly due to "localized metastatic growth" of different tumor cell subpopulations.

In 87 patients with histologically proven bronchogenic carcinoma, computerised tomography (CT) and bronchoscopy were performed to assess the accuracy of CT in detecting bronchial stenosis. Whereas patent airways and mainstem stenosis were recognised in 85% of the cases, the overall accuracy was only 57%. Furthermore, the results of both methods were compared to scintigraphy (ventilation, perfusion) to evaluate the functional impairment due to altered lung morphology and bronchial stenosis. With an increasing number of CT-diagnosed atelectatic or infiltrated segments an almost linear decrease in ventilation and perfusion values was observed. In comparison, bronchoscopy-diagnosed tumour stenosis resulted in decreased ventilation and perfusion data only if the lesion was centrally located.