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Panel-based next-generation sequencing (NGS) is increasingly used for the diagnosis of EGFR-mutated non-small-cell lung cancer (NSCLC) and could improve risk assessment in combination with clinical parameters.To this end, we retrospectively analyzed the outcome of 400 tyrosine kinase inhibitor (TKI)-treated EGFREGFR alterations other than exon 19 deletions (non-del19), TP53 co-mutations, and brain metastases at baseline showed independent associations of similar strengths with progression-free (PFS hazard ratios [HR] 2.1-2.3) and overall survival (OS HR 1.7-2.2), in combination defining patient subgroups with distinct outcome (EGFREGFR variant, TP53 status and brain metastases predict TKI efficacy and survival in EGFR

The complexity of the lung microenvironment together with changes in cellular composition during disease progression make it exceptionally hard to understand the molecular mechanisms leading to the development of chronic lung diseases. Although recent advances in cell type resolved and single-cell sequencing approaches hold great promise for studying complex diseases, their implementation greatly relies on local access to fresh tissue, as traditional methods to process and store tissue do not allow viable cell isolation. To overcome these hurdles, we developed a novel, versatile workflow that allows long-term storage of human lung tissue with high cell viability, permits thorough sample quality check before cell isolation, and is compatible with next generation sequencing-based profiling, including single-cell approaches. We demonstrate that cryopreservation is suitable for isolation of multiple cell types from different lung locations and is applicable to both healthy and diseased tissue, including COPD and tumor samples. Basal cells isolated from cryopreserved airways retain the ability to differentiate, indicating that cellular identity is not altered by cryopreservation. Importantly, using RNA sequencing (RNA-seq) and Illumina EPIC Array, we show that genome-wide gene expression and DNA methylation signatures are preserved upon cryopreservation, emphasizing the suitability of our workflow for -omics profiling of human lung cells. In addition, we obtained high-quality single-cell RNA sequencing data of cells isolated from cryopreserved human lung, demonstrating that cryopreservation empowers single-cell approaches. Overall, thanks to its simplicity, our cryopreservation workflow is well-suited for prospective tissue collection by academic collaborators and biobanks, opening worldwide access to human tissue.

Tyrosine kinase inhibitors (TKI) have improved prognosis in metastatic anaplastic lymphoma kinase (ALK)-driven lung adenocarcinoma, but patient outcomes vary widely. We retrospectively analyzed the clinical course of all cases with assessable baseline TP53 status and/or ALK fusion variant treated at our institutions (n = 102). TP53 mutations were present in 17/87 (20%) and the echinoderm microtubule-associated protein-like 4 (EML4)-ALK variant 3 (V3) in 41/92 (45%) patients. The number of metastatic sites at diagnosis was affected more by the presence of V3 than by TP53 mutations, and highest with both factors (mean 5.3, p0.001). Under treatment with ALK TKI, progression-free survival (PFS) was shorter with either TP53 mutations or V3, while double positive cases appeared to have an even higher risk (hazard ratio [HR] = 2.9, p = 0.015). The negative effect of V3 on PFS of TKI-treated patients was strong already in the first line (HR = 2.5, p = 0.037) and decreased subsequently, whereas a trend for PFS impairment under first-line TKI by TP53 mutations became stronger and statistically significant only when considering all treatment lines together. Overall survival was impaired more by TP53 mutations (HR = 4.9, p = 0.003) than by V3 (HR = 2.4, p = 0.018), while patients with TP53 mutated V3-driven tumors carried the highest risk of death (HR = 9.1, p = 0.02). Thus, TP53 mutations and V3 are independently associated with enhanced metastatic spread, shorter TKI responses and inferior overall survival in ALK

Background Osimertinib is the preferable therapeutic option for many epidermal growth factor receptor (EGFR)+ non-small cell lung cancer (NSCLC) patients failing other tyrosine kinase inhibitors (TKI), but implementation of EGFR TKI sequencing is often problematic. Methods We retrospectively studied the clinical course of EGFR+ NSCLC patients that received first-/second-generation TKI at our institutions and had their last follow-up after osimertinib approval (02/2016). Results A total of n = 283 EGFR+ NSCLC patients received erlotinib (45%), gefitinib (19%) and/or afatinib (36%) in the 1st-4th treatment lines with a median age of 66 years, a median ECOG performance status of 0 (137/266 patients with available data) and a predominance of female (183/283=65%) never-/light-smokers (177/283=63%). Median overall survival (OS) from treatment start was 32.7 months (95% confidence interval [CI] 28.1 – 37.3) with 2.2 treatment lines on average (standard deviation 1.4). EGFR T790M testing was performed for 139/203 (68%) patients after TKI failure, with a positive result in 77/139 (55%) and subsequent treatment with osimertinib in 50/77 (65%). Overall, 50/203 (25%) of patients received osimertinib, with a median OS of 44.9 (27.9 – 62.1) months, significantly longer than the 30.4 (20.6 – 40.3) months for patients with alternative or no subsequent therapies (logrank p = 0.053, Breslow p = 0.002). Among the 134 deceased patients with complete follow-up, 84 (63%) received additional systemic treatment (37% chemotherapy, 16% osimertinib, 8% only alternative EGFR inhibitors, 2% only immunotherapy), while 50/134 (37%) died without next-line therapy. For patients that subsequently received chemotherapy, median time to start of chemotherapy was 11.6 (8.9 – 14.3) months. Conclusions Sequential treatment with osimertinib after first- or second-generation EGFR inhibitors significantly prolongs OS, but in the real-world setting a considerable fraction of patients will not be able to benefit from that. Main obstacles in our cohort were lack of EGFR T790M testing (32% of total cases), T790M-negative progression (45% of tested cases), and rapid clinical deterioration without the chance of next-line therapy (about one-third of patients). Legal entity responsible for the study Thoraxklinik at Heidelberg University Hospital. Funding Thoraxklinik at Heidelberg University Hospital AstraZeneca. Disclosure P. Christopoulos: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy: Chugai; Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Boehringer; Research grant / Funding (institution): Takeda. F. Bozorgmehr: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Honoraria (self): MSD. J.B. Kuon: Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Cellgene. V. Endris: Honoraria (self), Advisory / Consultancy: ThermoFisher; Honoraria (self), Advisory / Consultancy: AstraZeneca. T. Bochtler: Honoraria (institution), Research grant / Funding (institution): Roche. F.J.F. Herth: Honoraria (self), Research grant / Funding (institution): Lilly; Honoraria (self), Research grant / Funding (institution): Roche; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Novartis; Honoraria (self), Research grant / Funding (institution): Boehringer; Honoraria (self), Research grant / Funding (institution): Chiesi; Honoraria (self), Research grant / Funding (institution): Teva; Honoraria (self): Pulmonx BTG; Honoraria (self): Olympus. C. Heussel: Honoraria (self), Honoraria (institution): Novartis, Basilea, Bayer, Grifols, Boehringer, Pierre Fabre, Covidien, Siemens, Chiesi, Intermune, MEDA Pharma, Bracco, Pfizer, MSD, Roche, Lilly, AstraZeneca, Schering-Plough, Essex, Gilead, MeVis, Fresenius, Astellas; Shareholder / Stockholder / Stock options: GSK. T. Muley: Honoraria (self), Research grant / Funding (self), Research grant / Funding (institution): Roche. J.R. Fischer: Advisory / Consultancy: Boehringer, Roche, Celgene and AstraZeneca. A. Stenzinger: Honoraria (self), Advisory / Consultancy: Novartis, AstraZeneca, ThermoFisher, BMS; Honoraria (self): BMS, Illumina, AstraZeneca, Novartis, ThermoFisher, MSD, Roche; Research grant / Funding (institution): Chugai; Honoraria (self): Illumina, AstraZeneca, Novartis, ThermoFisher . M. Thomas: Honoraria (self), Advisory / Consultancy: Novartis, Lilly, BMS, MSD, Roche, Celgene, Takeda, AbbVie, Boehringer, Lilly, MSD, Takeda; Research grant / Funding (institution): AstraZeneca, BMS, Celgene, Novartis, Roche, Takeda. All other authors have declared no conflicts of interest.

Background SCLC is an aggressive disease with poor prognosis. Despite initial response to chemotherapy and radiotherapy, relapse occurs in most cases. To characterize genomic changes in SCLC over the course of therapy, we explored tracking tumor mutations in cell-free DNA (cfDNA) across post-treatment blood draws and comparing them to pre-treatment plasma and tissue profiles. Methods We retrospectively evaluated 235 samples collected from 24 subjects with late stage SCLC treated with first-line chemotherapy or chemoradiation in a prospective observational study. Tumor tissue samples were analyzed with the AVENIO Tumor Tissue Surveillance Kit (For Research Use Only, not for use in diagnostic procedures), a 198-kb next-generation sequencing panel covering 197 cancer genes. Matched peripheral blood mononuclear cells (PBMC), pre-treatment plasma, and multiple plasma from post-treatment timepoints were analyzed with the same panel using the AVENIO ctDNA Surveillance Kit (For Research Use Only, not for use in diagnostic procedures). A median input amount of 29 ng cfDNA, 129 ng tumor tissue DNA, and 50 ng PBMC DNA were sequenced to median deduplicated depths of 4491, 1315, and 6512, respectively. Somatic single nucleotide variants (SNVs) in tissue and plasma were identified by removing PBMC-matched germline or clonal hematopoietic mutations. Results We detected a median of 4 SNVs in tissue samples and a median of 100% (range 66 - 100%) of tissue SNVs in matched pre-treatment plasma. 96% (23/24) of subjects had at least one shared SNV between tissue and plasma, most commonly a TP53 mutation. A median of 7 SNVs were detected in pre-treatment plasma, whereas across all available post-treatment plasma (range 2 - 20 time points per subject), a median of 4 SNVs were detected. 53% of these mutations were not present in pre-treatment plasma or tissue. Conclusions Somatic mutations found in pre-treatment plasma were concordant with matched tissue, consistent with the highly metastatic nature of SCLC. ctDNA sequencing can provide additional molecular insights; in particular, detecting emergent mutations in ctDNA during treatment could advance our knowledge of SCLC. Legal entity responsible for the study Roche Sequencing Solutions, Inc. Funding Roche Sequencing Solutions, Inc. Disclosure S. Yaung: Full / Part-time employment: Roche. C. Woestmann: Full / Part-time employment: Roche. L. Xi: Full / Part-time employment: Roche. C. Ju: Full / Part-time employment: Roche. B. Hinzmann: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche. M. Thomas: Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche. F. Lasitschka: Research grant / Funding (institution): Roche. M. Meister: Research grant / Funding (institution): Roche. M. Schneider: Research grant / Funding (institution): Roche. F.J.F. Herth: Honoraria (institution): Roche. T. Muley: Research grant / Funding (institution), Licensing / Royalties: Roche. B. Wehnl: Full / Part-time employment: Roche. J. Palma: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche. X.M. Ma: Shareholder / Stockholder / Stock options, Licensing / Royalties, Full / Part-time employment: Roche.

The lung research specimen biobank located at the Thoraxklinik Heidelberg (TK-HD) is an accredited subsidiary (DAP-IS-4153.04 according to DIN EN ISO/IEC 17020) of the National Center for Tumor Diseases Heidelberg (NCT), which is integrated into the BioMaterialBank Heidelberg (BMBH). The NCT Tissue Bank is registered with the German Technology and Method Platform for Medical Research Networks (TMF) and the European Biobanking and Biomolecular Resources Research Infrastructure (BBMRI). Each year about 400 – 500 new tissue specimens and around 1000 new blood samples are collected with high quality using standard operating procedures. About two thirds of tissue samples are derived from lung cancer patients (tumor tissue plus matched normal lung tissue, lymph nodes). In addition, tissue of other thoracic malignancies (carcinoids, mesothelioma, thymoma, lung sarcomas), metastatic cancer to the lung (colorectal carcinoma, renal cell carcinoma etc.), and to a lesser extent benign lung diseases (hamartomas, interstitial lung diseases, COPD, pneumothorax) are collected. Currently the tissue bank comprises tissue sample with several aliquots from 4700 patients. There are 68% lung cancer patients, 2% lung cancer recurrences, 14% lung metastases from extrathoracic cancers, 2% carcinoids, 2% mesotheliomas, 8% benign lung diseases and 4% various diseases. In addition, several aliquots from more than 8800 blood samplings of patients with various lung diseases are processed and stored under standardized conditions. The samples can be connected to highly annotated clinical data. The lung biobank also provides services for nucleic acid extraction, production of specific tissue microarrays and for primary cell culture. High quality samples are an indispensable prerequisite for adequate research. The expertise of the Lung Biobank Heidelberg is acknowledged worldwide and therefore involved in several national and international studies and consortia i.e. the German Lung Research Centre (DZL), Canceralia, LungSys, ETOP Lungscape and The Cancer Genome Atlas (TCGA) Project. *Presenting author

The purpose of this study was to determine the prognostic significance of a high pretreatment serum CYFRA 21-1 level (a cytokeratin 19 fragment) adjusted for the effects of well-known co-variables in non-small-cell lung cancer (NSCLC). This meta-analysis based on individual updated data gathered comprehensive databases from published or unpublished controlled studies dealing with the prognostic effect of serum CYFRA 21-1 level at presentation in NSCLC of any stage (nine institutions, 2063 patients). Multivariate regression was carried out with the Cox model. The proportional hazard assumption for each of the selected variables retained in the final model was originally checked by log minus log plots baseline hazard ratio. The follow-up ranged from 25 to 78 months. A total of 1616 events were recorded. In the multivariate analysis performed at the 1-year end point, a high pretreatment CYFRA 21-1 level was an unfavourable prognostic determinant in all centres except one (Hazard ratio (95% confidence interval): 1.88 (1.64-2.15), P

Hintergrund: Retrospektive Daten lassen vermuten, dass der gastroosophageale Reflux (GERD) in der ILD Pathogenese eine Rolle spielt. Daruber hinaus wurde eine Assoziation von Helicobacter Pylori (HP) Antikorpern mit einer schweren IPF Erkrankung geschildert. Wir berichten hier uber das Screening in Lungenbiopsaten von ILD Patienten mittels PCR auf HP. Methode: In zwei ILD Schwerpunktzentren wurde aus Lungenbiopsaten von ILD Patienten mittels Proteinase K genomische DNA isoliert und eine spezifische PCR auf HP durchgefuhrt (Primer: HP 16S rRNA 5'- CTG GAG AGA CTA AGC CCT CC-3' and HP 16S rRNA 5'- ATT ACT GAC GCT GAT TGT GC-3'). HP+ Magenbiopsate dienten als Positivkontrolle. Zudem wurden klinische (vor allem auf Vorkommen von GERD und eine antazide Medikation) sowie radiologische Daten analysiert. Ergebnisse: Ausgewertet wurden Daten von 44 ILD Patienten (39 IPF, 3 CTD-ILD, 1 chronische EAA, 1 NSIP), median 66 Jahre, 80% Manner, 68% Ex-/Raucher, mediane FVC 79%, mediane DLCO-SB 53%. Komorbiditaten: 25% GERD, 15% Hiatushernien (CT-Diagnose), Schlafapnoe 11%. 21% waren unter antazider Medikation, 16% unter Steroiden. Das HRCT-Muster zeigte 43% UIP, 43% mogliches UIP, 2% NSIP, 2% COP, 10% unklassifizierbar. Die Lungenbiopsate waren in 84% chirurgisch, in 16% transbronchial. Die mediane Nachbeobachtungszeit betrug 25 Monate mit einem Todesfall 69 Monaten nach IPF-Erstdiagnose, einer Lungentransplantation, 8 Patienten erlitten eine akute Exazerbation. HP DNA wurde in keiner der ILD Lungenbiopsate nachgewiesen bei jeweils regelrechter Positivkontrolle. Beurteilung: Die hier berichteten negativen Untersuchungen auf HP-DNA in Lungenbiopsaten stellen die Hypothese einer direkten Mitbeteiligung von Helicobacter pylori in der ILD Pathogenese in Frage.

Nach Lungenresektion und ipsilateraler Lymphknotendissektion wegen Bronchialcarcinoms verblieb in 88 von 2464 Fallen (3,6 %) mikroskopisch Residualtumor (R1) am zentralen Bronchusresektionsrand. Sieben Patienten entwickelten eine Insuffizienz der Bronchusnaht, 2 weitere eine Nachblutung bzw. eine Herzluxation (Morbiditat 8,0 %). Die Hospitalletalitat betrug 16,6 %. Todesursachen waren Bronchusnahtinsuffizienz (n = 7), Arrosionsblutung (n = 4), respiratorische Insuffizienz (n = 1) und Pleuraempyem (n = 1). Eine postoperative Bestrahlung wurde bei 43 Patienten durchgefuhrt. Die mediane Uberlebenszeit aller Patienten nach R1-Resektion war 16 Monate gegenuber 37 Monaten nach R0-Resektion (p < 0,001). Die Uberlebenszeit war unabhangig von Tumorstadium und -histologie, Lokalisation des Residualtumors in der Bronchuswand und einer Nachbestrahlung. Inkomplette Resektionen sind durch intraoperativen Schnellschnitt zu verifizieren. Sofern funktionell vertretbar, sollte in den Stadien I und II eine Nachresektion (R0) angestrebt werden; auch in den Stadien III a und III b ist bei R0-Resektion ein statistisch signifikanter Uberlebensvorteil gegenuber R1-Resektion zu verzeichnen, jedoch weniger deutlich als in niedrigeren Stadien.

The cleavage of synthetic tetradecapeptide renin substrate has been used to infer the presence of renin in the walls of isolated blood vessels; however, the conversion of natural angiotensinogen to angiotensin in isolated blood vessels has not been reported. We studied the release of angiotensinogen and the formation of angiotensins in a bloodless, perfused, isolated hind limb preparation of the rat. Perfusion with a modified Tyrode's solution resulted in spontaneous release of 4.7 +/- 1.5 pmol per 30 minutes of angiotensinogen as measured directly by radioimmunoassay. Western blot further identified the released material as angiotensinogen. Spontaneous release of angiotensins I and II was demonstrated by high performance liquid chromatography and radioimmunoassay. When highly purified rat angiotensinogen was added to the perfusate, release of angiotensin II was increased 14-fold compared with saline infusion. Captopril (10 mumol/L) inhibited angiotensinogen-induced angiotensin II release by 67% and led to an increase in angiotensin I release by 301%. Bilateral nephrectomy 24 hours before the experiments reduced basal angiotensin release below the detection limit and blunted angiotensinogen-induced angiotensin II formation by 95%. We conclude that active renin is present in the vessel wall and interacts with its natural substrate to form angiotensin peptides. Our data support the notion that the bulk of vascular renin is taken up from the circulation.

The importance of accurate staging according to the international TNM staging system of non-small cell lung cancer (NSCLC) for patient management and ascertaining individual prognosis cannot be overemphasized. The TNM classification is scheduled to be revised in 2007. In a large single-center collective we investigated the prognosis for patients who had complete resection of a NSCLC.We retrospectively reviewed hospital records and follow-up data of 2,378 patients operated on between 1996 and 2005 for NSCLC. Complete resection was achieved in 2,083 patients. Systematic hilar and mediastinal lymph node dissection was performed concurrently. Probability of survival was then analysed with the Kaplan-Meier method. The significance of differences between subgroups was calculated using the log-rank test. Odds ratios with 95 % confidence intervals (CI) were calculated for each characteristic. The Cox model was used for multivariate analyses.The 5-year survival for patients after complete resection was 50.7 %. The 5-year survival rates for clinical stages were 72 % for stage IA, 59.8 % for stage IB, not defined for stage IIA, 47,8 % for stage IIB, 45 % for stage IIIA, 38.7 % for stage IIIB, and not defined for stage IV. There were significant differences in survival between stages IIIB and IV (p = 0.013). There was a trend towards significance between patients with IA and IB (p = 0.052). However, there was no significant difference between patients with all the other stages. 5-year survival according to pathological stages was: stage IA 68.5 %; stage IB 66.6 %; stage IIA 55.3 %; stage IIB 49.0 %; stage IIIA 35.8 %; stage IIIB 35.4 %; stage IV not defined. Gender, age and type of histology were found by multivariate analysis to be significant independent prognostic factors for survival.The TNM and stage grouping classification is valid for defining prognosis and prognosis-related criteria in patients with NSCLC. The difference in prognosis between clinical stages IIIB and IV was significant, but not that between all the other related subgroups. Concordance with histological staging demonstrated the quality of existing clinical staging methods and related strategies. Complete surgical resection, age, gender, histology and stage of the disease significantly influenced long-term survival.

Due to local invasion of the chest wall, patients with non small cell carcinoma (NSCLC) of the superior sulcus have been treated mainly by the Paulson regime with radiotherapy followed by surgical resection. Recent published data on the use of concurrent irradiation and chemotherapy followed by surgical resection seemed very promising. The aim of the present study was to determine the value and benefit of a combined preoperative and postoperative radiotherapy regime (Sandwich irradiation), and which factors predict prognosis following resection.Between 1986 and 2003, 64 patients with non-small cell carcinoma of the superior sulcus were managed in our department. 28 underwent surgical resection with combined preoperative 40 Gy and postoperative 20 Gy external beam radiotherapy. Time to death was calculated using the method of Kaplan and Meier. Survival after surgery was the end point of the study. The association of factors to end of life end points was analyzed using the log-rank test for univariate analysis. Median follow up was 13.1 months.The actuarial 5-year-survival for the overall population was 30.2 %. For surgically-rendered complete resection (CR) patients with no mediastinal lymph node metastases, the 5-year-survival-rate was 53.2 %. The 30-day-mortality-rate was 0 %. Most significant prognostic factors were the mediastinal lymph node involvement and the stage of the disease.Results of this retrospective study show that patients with non-small cell carcinoma of the superior sulcus can experience a long-term survival which is well comparative to other patients with NSCLC. Surgical resection with a combined preoperative and postoperative radiotherapy regime is well accepted. Special care should be taken in patient selection to identify patients with advanced stage of the disease and mediastinal lymph node metastases.

Tumor-Marker sind Substanzen, deren Auftreten bzw. erhohte Konzentration in Korperflussigkeiten (humorale Tumormarker) oder verstarkte zellulare Expression (zellulare Tumormarker) Ruckschlusse aufdas Vorliegenden Verlauf oder die Prognose einer bestehenden Tumorerkrankung erlauben. Diese Substanzen werden neuerdings als „klassische“ Tumor-Marker bezeichnet, um sie von den so genannten „biologischen oder Surrogat-Markern“ abzugrenzen, von denen erhofft wird, dass sie in Zukunft zur Patientenstratifizierung fur neue Therapiekonzepte herangezogen werden konnen.

The introduction of new regimens in the chemotherapy of inoperable non-small cell lung cancer (NSCLC) patients provides a useful extension of survival probability that may now justify the application of tumor markers for the disease monitoring. In a prospective study of 48 consecutive NSCLC patients with TNM stages IIIB/IV we compared changes in the serum levels of the cytokeratin 19 fragment CYFRA 21-1 with the clinical evaluations of response to therapy. CYFRA 21-1 levels were measured using the enzyme immunoassay of Boehringer, Mannheim (Germany). Clinical response to therapy was evaluated according to standard criteria of the WHO. For the assessment of response to therapy by changes in the marker levels the difference between two consecutive levels must exceed 30%. This value is based on the formula: Difference = 2 square root of 2 x CV (CV: inter-assay coefficient of variation of the marker test). CYFRA 21-1 was found to be elevated in 29/48 (60.4%) patients prior to therapy and in 10/48 (20.8%) patients at tumor progression. 91 evaluations have been recorded in these 39 patients. The overall concordance between changes in the marker levels and the clinical assessment was 59.3%. The decrease of CYFRA 21-1 levels at remission was rather low resulting in a concordance of only 42.9%, i.e. marker assays cannot replace the clinical restaging by imaging modalities. In contrast, changes in the marker levels at progression did exceed the required 30% in the majority of cases (64.7%). Most of discordant results (40.7%) could be explained by insufficient decrease or increase of CYFRA 21-1 levels or by extended lead-time. The most striking result was the detection of progressive disease by rising marker levels. Except one case, there was no false-positive elevation of CYFRA 21-1 levels. It is concluded that the detection of progressive disease by rising CYFRA 21-1 levels may avoid continuation of ineffective treatment.

The development of diffuse malignant pleural mesothelioma is associated with exposure to asbestos. The surgical treatment comprises a radical pleuropneumonectomy with resection of the pericardium and diaphragm (P3D) or palliative pleurectomy/decortication of the tumor. The prognosis in general is poor. P3D is most effective in patients with epithelial mesothelioma at an early stage. Complete resection has the best prognosis. Palliative tumor decortication is restricted to symptomatic patients with acceptable performance status. The prognosis of patients after radical resection is not significantly different from patients with pleurectomy/decortication. Preliminary results of multimodal therapy concepts, including additional chemo- and/or radiotherapy, suggest an improvement in survival. Nevertheless, so far treatment has been focused on the palliation of clinical symptoms like pain and dyspnee.

The principle of surgery for lung metastases is the removal of all lesions in the lung that are either visible or detectable by palpation. This may be combined with complete dissection of all ipsilateral lymph nodes. Therefore, "tumor reduction" rather than "complete" or "radical resection" may be an adequate description of this surgical approach. Since the dissemination of--macroscopically not detectable--tumor cells represents the major mannerism of every metastatic disease, any local therapy appears to be a discrepancy. However, in most cases the rationale of surgery for lung metastases is the lack of effective systemic therapy and the low morbidity of surgery, along with up to 60% 5-year survival rates.

From 1973 to 1994, 38 tracheal and/or bifurcation resections were performed in 37 children aged 1 month to 18 years. Twenty-four children had an acquired stenosis, 8 a congenital and 5 a combined stenosis. In 16 children, the stenosis was located in the lower trachea or bifurcation. Other malformations were found in 12 children. The most common intervention was the trachea segment resection in 30 patients; resection of the cricoid cartilage was performed in another 6 cases. The resection was expanded to the bifurcation 5 times, 1 being a left sleeve pneumonectomy. The extent of resection was between 10 and 50 mm. In the 22 children with resections of the upper and middle trachea, 96% were decannulated with 0% morbidity. In the 15 children with distal resections, decannulation was performed in 87% with 6% morbidity. There were no recurrent stenoses caused by growth disorder. With interdisciplinary cooperation, single-session resection is a safe procedure.

Residual tumor (R1) was proven at the proximal bronchial resection margin in 88 (3.6%) of 2464 cases of lung cancer following lung resection and standard lymph node dissection. Postoperative complications (8%) were: fistula of the bronchial suture line (n = 7), bleeding (n = 2) and heart luxation (n = 1). The in-hospital mortality was 16.6%. Causes of death were: bronchial fistula (n = 7), erosion of the pulmonary artery (n = 4), respiratory failure (n = 1), and empyema (n = 1). Forty-three patients received postoperative radiation therapy. Median survival of all patients following incomplete resection was 16 months, compared to 37 months following complete resection (P0.001). Length of survival was independent of tumor stage, histology, site of infiltration and postoperative radiation. In conclusion, in resection for lung cancer clear margins should be verified by intraoperative frozen section. In the case of residual tumor at the bronchial resection margin, wider resection is mandatory in stage I and II if the patient meets the functional criteria. Even in stage III a and III b prognosis is significantly better after complete resection than R1-resection; the difference, however, is smaller than in lower stages.

Chirurgische Verfahren zur Behandlung von Lungenmetastasen beruhen auf dem Prinzip der Elimination aller sicht- bzw. tastbaren Lasionen in der Lunge, ggf. in Kombination mit einer vollstandigen ipsilateralen Lymphknotendissektion. Folgerichtig wird diesem Eingriff der Terminus „Tumorreduktion“ eher gerecht als Begriffe wie „komplette“ oder „radikale Resektion“, denn eine Dissemination von — makroskopisch nicht fasbaren — Tumoreinzelzellen bzw. Tumorzellverbanden ist das Wesen einer metastasierenden Erkrankung und last ein lokales Verfahren als Widerspruch erscheinen. Die Berechtigung zum operativen Eingriff bei Lungenmetastasen leitet sich jedoch vielfach ab aus einem Mangel an effizienten systemischen Verfahren bei niedriger Komplikationsrate und 5-Jahres-Uberlebensraten bis zu 60%.

46 Patienten mit Pancoast-Tumor wurden zwischen 1986 und 1995 kombiniert chirurgisch-strahlentherapeutisch oder nur chirurgisch behandelt. Signifikante Prognosefaktoren waren: Die Radikalitat der Resektion (R0 bei n = 24) und der Tumorbefall mediastinaler Lymphknoten (N2/N3). Das 5-Jahres-Uberleben im Gesamtkollektiv betrug 28%. In 50% der Falle wurde die subjektive Beschwerdesymptomatik deutlich gebessert. Aus prognostischen Grunden sollten Patienten mit mediastinalem Lymphknotenbefall aufgedeckt und von der Operation ausgeschlossen werden. Eine R1/2-Situation war in einigen Fallen nicht vermeidbar und aufgrund der begrenzten Aussagekraft der praoperativen Diagnostik nicht vorhersehbar.

Als chirurgische Behandlungsoptionen des diffusen malignen Pleuramesothelioms kommen die Pleuropneumonektomie mit Perikard- und Diaphragmaresektion (P3D) und die palliative Tumorpleurektomie/Dekortikation zum Einsatz. Die Prognose ist allgemein ungunstig. Fur die potentiell kurative P3D ist das epitheliale Pleuramesotheliom bei niedriger Tumorformel geeignet. Die R0-Resektion hat die beste Prognose. Zur palliativen Tumordekortikation werden nur symptomatische Patienten bei gegebener Operabilitat vorgesehen. Die P3D weist keine signifikanten Uberlebensvorteile gegenuber der palliativen Tumordekortikation auf. Multimodale Therapie mit zusatzlicher Chemo/Radiotherapie zeigen erste Trends, die zu einer Verbesserung im Uberleben fuhren konnten. Die Linderung der klinischen Symptome wie Schmerzen und Dyspnoe steht zur Zeit im Vordergrund der Behandlung.

Von 1973 bis 1994 wurden bei 37 Kindern im Alter von 1 Monat bis 18 Jahre 38 Resektionen der Trachea und/oder der Bifurkation durchgefuhrt. Bei 24 Kindern lag eine erworbene, bei 8 eine angeborene und bei 5 lag eine kombinierte Stenose vor. Bei 16 Kindern war die Stenose in der unteren Trachea oder in der Bifurkation lokalisiert. Die Tracheasegmentresektion war mit 30 Eingriffen der haufigste Eingriff, in 6 Fallen wurde zusatzlich eine Kehlkopferweiterungsplastik durchgefuhrt. In 5 Fallen muste die Resektion auf die Bifurkation erweitert werden. Das Resektionsausmas betrug zwischen 10 und 50 mm. Von den 22 Kindern mit Resektionen der oberen und mittleren Trachea sind 96% dekanuliert bei 0% Morbiditat. Von den 15 Kindern mit distalen Resektionen sind 87% dekanuliert bei einer Morbiditat von 6%. Spatstenosen durch Wachstumsstorungen sind nicht aufgetreten. Die einzeitige Resektionsbehandlung ist in der interdisziplinaren Kooperation ein sicheres Verfahren.

Im Sektionsgut der an malignen Tumoren gestorbenen Patienten findet sich zu 30% eine Metastasierung in die Lunge (Willis 1967). Gilbert u. Kagan (1976) fanden bei mehr als 20% der Patienten eine Metastasierung, die allein auf dieses Organ beschrankt war. Nierenzellkarzinome, Hodentumoren und Mammakarzinome haben eine besondere Tendenz der Metastasierung in die Lunge. Fur Osteo- und Weichteilsarkome ist sie haufig das einzige Organ (Roth 1985).

Unter Tumormarkern versteht man Substanzen, die bei bestehendem malignen Leiden in erhohter Konzentration in Korperflussigkeiten vorkommen oder verstarkt zellular exprimiert werden.