Hans Hoffmann

Universität Heidelberg, Heidelburg, Baden-Württemberg, Germany

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Publications (150)340.83 Total impact

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    ABSTRACT: The purpose of this study was to evaluate postoperative radiotherapy regarding outcome and toxicity in patients with thymic epithelial tumors (TET) after surgery.
    Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft ... [et al]. 08/2014;
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    ABSTRACT: Treatment of locally advanced non-small-cell lung cancer is based on a combined approach. To study the impact of trimodal therapy for stage III-N2 NSCLC a single centre retrospective evaluation focusing on survival and therapy-related toxicity was performed.
    BMC Cancer 08/2014; 14(1):572. · 3.33 Impact Factor
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    ABSTRACT: Background:Uncontrolled proliferation is a hallmark of malignant tumour growth. Its prognostic role in non-small cell lung cancer (NSCLC) has been investigated in numerous studies with controversial results. We aimed to resolve these controversies by assessing the Ki-67 proliferation index (PI) in three large, independent NSCLC cohorts.Methods:Proliferation index was retrospectively analysed by immunohistochemistry in a cohort of 1065 NSCLC and correlated with clinicopathological data including outcome and therapy. Results were validated in two independent cohorts of 233 squamous cell carcinomas (SQCC) and 184 adenocarcinomas (ADC).Results:Proliferation index (overall mean: 40.7%) differed significantly according to histologic subtypes with SQCC showing a mean PI (52.8%) twice as high as ADC (25.8%). In ADC PI was tightly linked to growth patterns. In SQCC and ADC opposing effects of PI on overall (OS), disease-specific and disease-free survival were evident, in ADC high PI (optimised validated cut-off: 25%) was a stage-independent negative prognosticator (hazard ratio, HR OS: 1.56, P=0.004). This prognostic effect was largely attenuated by adjuvant radio-/chemotherapy. In SQCC high PI (optimised validated cut-off: 50%) was associated with better survival (HR OS: 0.65, P=0.007).Conclusions:Our data demonstrate that PI is a clinically meaningful biomarker in NSCLC with entity-dependent cut-off values that allow reliable estimation of prognosis and may potentially stratify ADC patients for the need of adjuvant therapy.British Journal of Cancer advance online publication, 22 July 2014; doi:10.1038/bjc.2014.402 www.bjcancer.com.
    British journal of cancer. 07/2014;
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    ABSTRACT: Malignant pleural mesothelioma (MPM) is associated with asbestos exposure and is a cancer that has not been significantly impacted by small molecule-based targeted therapeutics. Previously, we demonstrated the existence of functional subsets of lung cancer and head and neck squamous cell carcinoma (HNSCC) cell lines in which fibroblast growth factor receptor (FGFR) autocrine signaling functions as a non-mutated growth pathway. In a panel of pleural mesothelioma cell lines, FGFR1 and FGF2 were co-expressed in 3 of 7 cell lines and were significantly associated with sensitivity to the FGFR-active tyrosine kinase inhibitor (TKI), ponatinib, both in vitro and in vivo using orthotopically propagated xenografts. Furthermore, RNAi-mediated silencing confirmed the requirement for FGFR1 in specific mesothelioma cells and sensitivity to the FGF ligand trap, FP-1039, validated the requirement for autocrine FGFs. None of the FGFR1-dependent mesothelioma cells exhibited increased FGFR1 gene copy number, based on a FISH assay, indicating that increased FGFR1 transcript and protein expression were not mediated by gene amplification. Elevated FGFR1 mRNA was detected in a subset of primary MPM clinical specimens and like MPM cells, none harbored increased FGFR1 gene copy number. These results indicate that autocrine signaling through FGFR1 represents a targetable therapeutic pathway in MPM and that biomarkers distinct from increased FGFR1 gene copy number such as FGFR1 mRNA would be required to identify MPM patients bearing tumors driven by FGFR1 activity. Implications: FGFR1 is a viable therapeutic target in a subset of malignant pleural mesotheliomas, but FGFR TKI-responsive tumors will need to be selected by a biomarker distinct from increased FGFR1 gene copy number, possibly FGFR1 mRNA or protein levels.
    Molecular cancer research : MCR. 06/2014;
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    ABSTRACT: The purpose of this study was to characterize the prevalence of insulin-like growth factor 1 receptor (IGF1R) mutations, single nucleotide polymorphisms (SNP), and protein overexpression in surgically resected non-small cell lung cancers in relation to patient characteristics and prognosis. This retrospective study was conducted on 304 patients with non-small cell lung cancers who underwent curative pulmonary resection (median follow-up for surviving patients, 3.6 years). IGF1R gene alterations (n = 304) and protein expression (n = 181) were evaluated by polymerase chain reaction-based assays and immunohistochemistry, respectively. Membranous and cytoplasmic staining were analyzed separately. In an exploratory analysis, 1 silent mutation in exon 16 and 3 mutations in introns of the IGF1R gene comprising the tyrosine kinase domain were detected. Moreover, evaluating selected IGF1R SNPs, patients with adenocarcinomas and homozygous for the rs8038415 T-allele had a significantly better survival (P = .025) but no different disease-free survival. Regarding expression, membranous but not cytoplasmic IGF1R staining was higher in squamous cell carcinomas versus other histologies (P < .0001) and showed a trend to longer survival (P = .08). No association between SNP variations and protein expression was found. Membranous IGF1R protein expression is higher in squamous cell versus other histologies but does not correlate with prognosis. SNPs and mutations can be detected and may harbor prognostic value. These alterations may be of interest when evaluating the IGF1R as potential therapeutic target and should receive further research.
    Human pathology 01/2014; · 3.03 Impact Factor
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    ABSTRACT: Objective The purpose of this study was to characterize the prevalence of insulin-like growth factor-1 receptor (IGF-IR) mutations, single nucleotide polymorphisms (SNP), and protein overexpression in surgically resected non–small-cell lung cancers (NSCLC) in relation to patient characteristics and prognosis. Patients and Methods This retrospective study was conducted on 304 patients with NSCLC who underwent curative pulmonary resection (median follow-up for surviving patients, 3.6 years). IGF-IR gene alterations (n=304) and protein expression (n=181) were evaluated by PCR-based assays and immunohistochemistry, respectively. Membranous and cytoplasmic staining was analysed separately. Results In an exploratory analysis, 1 silent mutation in exon 16 and 3 mutations in introns of the IGF-IR gene comprising the tyrosine kinase domain were detected. Moreover, evaluating selected IGF-IR SNPs, patients with adenocarcinomas and homozygous for the rs8038415 T-allele had a significantly better survival (p= 0.025) but no different disease-free survival. Regarding expression, membranous but not cytoplasmic IGF-IR staining was higher in squamous cell carcinomas versus other histologies (P <0.0001) and showed a trend to longer survival (p=0.08). No association between SNP variations and protein expression was found. Conclusions Membranous IGF-IR protein expression is higher in squamous cell versus other histologies but does not correlate with prognosis. SNPs and mutations can be detected and may harbour prognostic value. These alterations may be of interest when evaluating the IGF-IR as potential therapeutic target and should receive further research.
    Human pathology 01/2014; · 3.03 Impact Factor
  • Journal of Bioinformatics Research Studies. 01/2014; 1(1).
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    ABSTRACT: Background In the era of improving overall survival rates of malignant diseases, the impact of a previous malignancy (PM) on treatment and outcome of lung cancer (LC) remains unclear. Methods We reviewed all LC patients from our institution that were treated from 2004 to 2006 for the occurrence of LC with PM excluding patients with multiple primary LC. Results A total of 444 and 2698 LC patients with and without a history of a PM were identified (prevalence of 14.1%). PM were most often located in breast (15.5%), prostate (14.9%), bladder (9.0%) and kidney (8.8%). Compared to never smokers, patients with nicotine consumption had more often a cancer history of prostate, gastrointestinal, and the head-neck region. The median interval until diagnosis of LC was 72.2 months (range 0-537 months) with most LC diagnosed 5 years after PM diagnosis. With a similar distribution of histology, stage and localization compared to controls, NSCLC patients with PM and stage IV disease showed a favourable overall survival (p<0.0001). In contrast, SCLC patients had similar survival curves (n.s.). Conclusions A considerable subgroup of LC patients has a history of PM that may indicate a favorable prognostic factor. However, these patients should be treated similar to other LC patients.
    Respiratory medicine 01/2014; · 2.33 Impact Factor
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    ABSTRACT: Most patients with metastatic non-small cell lung cancer (NSCLC) will face treatment with systemic therapy. Current clinical studies are demonstrating improvements in chemotherapy and overall survival. However, it remains unclear whether these results are translated into clinical practice. We reviewed all stage IV NSCLC patients without second malignancies that were diagnosed from 2004 to 2006 at our institution. 493 consecutive patients were included into this retrospective analysis and were followed-up until end of 2011. 352 patients (71.4%) received systemic therapy for up to 7 lines. For most patients, adjustments of dosages or applications had to be made at some point of the treatment, but the total applied dose remained generally close to the intended dose. The best disease control (BDC) rate decreased with increasing therapy lines from 59.7% to about 35%. Patients with palliative local therapy but no systemic treatment demonstrated inferior survival (median 2.9 versus 8.7 months, p < 0.001). The median interval between last treatment and death was 50 days and 15 days for chemotherapy and anti-EGFR therapy, respectively. BDC to the previous therapy lines was predictive for improved BDC to third- but not second-line therapy. Performing multivariate analysis, BDC to previous therapy, never-/ former-smoking status, and age > 70 years were associated with improved survival performing third-line therapy. Stage IV NSCLC patients may receive substantial systemic therapy resulting in response and median survival rates that are comparable to data from clinical studies. However, preselection factors are increasingly important to improve therapy outcome and life quality.
    Respiratory research 12/2013; 14(1):139. · 3.64 Impact Factor
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    ABSTRACT: Numerous studies have been published on single aspects of pulmonary adenocarcinoma (ADC). To comprehensively link clinically relevant ADC characteristics, we evaluated established morphologic, diagnostic, and predictive biomarkers in 425 resected ADC.Morphology was reclassified. CK7, TTF1, napsin A, thymidylate synthase (TS), and ERCC1 expression, ALK rearrangements as well as EGFR, KRAS and BRAF mutations were analysed. All characteristics were correlated with clinical and survival parameters.Morphologic ADC subtypes were significantly associated with smoking history and distinct patterns of diagnostic biomarkers. KRAS mutations were prevalent in male smokers while EGFR mutations were associated with female sex, non-smoking and lepidic as well as micropapillary growth patterns. TTF1 expression (HR for OS=0.61, p=0.021) and BRAF mutations (HR for DFS=2.0, p=.046) were found as morphology- and stage-independent predictors of survival in multivariate analysis. Adjuvant radio-/chemotherapy in some instances strongly impacted on the prognostic effect of both diagnostic and predictive biomarkers.Our data draw a comprehensive picture of the prevalence and interplay of yet established histological and molecular ADC characteristics. This data will help to develop time and cost effective diagnostic and treatment algorithms for ADC.
    European Respiratory Journal 08/2013; · 6.36 Impact Factor
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    ABSTRACT: BACKGROUND: Sleeve pneumonectomy is a challenging therapeutic strategy for patients with non-small cell lung cancer (NSCLC) invading the carina. The aim of this study was to illustrate common indications and individual concepts for surgery and to investigate oncologic outcomes and complications. METHODS: Sixty-four consecutive sleeve pneumonectomies were performed between September 2000 and November 2011. All patients had histologically proven central NSCLC. Data were retrospectively reviewed for indications, complications, and factors influencing long-term survival. RESULTS: Sixty-four patients underwent sleeve pneumonectomy for curative (n = 50, 78%) or palliative therapy (n = 14, 22%). Complete resection was achieved in 83%. Pathologic N2 disease was found in 41%. Complications occurred in 41%, with severe anastomotic problems in 8% of cases. Thirty-day mortality was 3% (n = 2). Outcome was significantly influenced by pathologic nodal status with 5-year survival rates of 70%, 35%, and 9% for N0, N1, and N2 subgroups, respectively. Patients with multilevel N2 disease and contraindications for chemotherapy or radiotherapy had a mean survival of 13 months after palliative surgery. CONCLUSIONS: Sleeve pneumonectomy for central NSCLC invading the carina or proximal main bronchus can be performed with tolerable risk and encouraging survival rates in selected cases. Palliative sleeve pneumonectomy displays an option in the absence of alternative therapeutic strategies.
    The Annals of thoracic surgery 05/2013; · 3.45 Impact Factor
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    ABSTRACT: We characterized genome alterations in 1255 clinically annotated lung tumors of all histological subgroups to identify genetically defined and clinically relevant subtypes. More than 55% of all cases had at least one oncogenic genome alteration potentially amenable to specific therapeutic intervention, including several personalized treatment approaches that are already in clinical evaluation. Marked differences in the pattern of genomic alterations existed between and within histological subtypes, thus challenging the original histomorphological diagnosis. Immunohistochemical studies confirmed many of these reassigned subtypes. The reassignment eliminated almost all cases of large cell carcinomas, some of which had therapeutically relevant alterations. Prospective testing of our genomics-based diagnostic algorithm in 5145 lung cancer patients enabled a genome-based diagnosis in 3863 (75%) patients, confirmed the feasibility of rational reassignments of large cell lung cancer, and led to improvement in ov
    Science translational medicine 01/2013; 5(209):209ra153. · 10.76 Impact Factor
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    ABSTRACT: We characterized genome alterations in 1255 clinically annotated lung tumors of all histological subgroups to identify genetically defined and clinically relevant subtypes. More than 55% of all cases had at least one oncogenic genome alteration potentially amenable to specific therapeutic intervention, including several personalized treatment approaches that are already in clinical evaluation. Marked differences in the pattern of genomic alterations existed between and within histological subtypes, thus challenging the original histomorphological diagnosis. Immunohistochemical studies confirmed many of these reassigned subtypes. The reassignment eliminated almost all cases of large cell carcinomas, some of which had therapeutically relevant alterations. Prospective testing of our genomics-based diagnostic algorithm in 5145 lung cancer patients enabled a genome-based diagnosis in 3863 (75%) patients, confirmed the feasibility of rational reassignments of large cell lung cancer, and led to improvement in ov
    Science translational medicine 01/2013; 5(209):209ra153. · 10.76 Impact Factor
  • Hans Hoffmann, M. Thomas, P. Huber, H. Dienemann
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    ABSTRACT: Das maligne Pleuramesotheliom (MPM) ist ein aggressiver Tumor mit einer schlechten Prognose. Die mediane Überlebenszeit ohne tumorspezifische Therapie beträgt ca. 6–9 Monate, mit Chemotherapie ca. 12–15 Monate, im multimodalen Therapiekonzept unter Einschluss einer maximal zytoreduktiven Operation ca. 24–30 Monate. Der Tumor ist mit keiner Therapie heilbar, aber mit einer individuell optimierten Therapie kann viel Lebensqualität und Lebenszeit gewonnen werden. Wenn Tumor und Patient operabel sind, ist die multimodale Therapie unter Einschluss einer maximal zytoreduktiven Operation die Therapie der Wahl. Dies gilt für ca. 20 % der Patienten bei Diagnosestellung. Durch lungenschonende Chirurgie (Pleurektomie/Dekortikation) in einem multimodalen Therapiekonzept mit adjuvanter oder neoadjuvanter Chemotherapie und nachfolgender IMRT-Strahlentherapie lässt sich dabei ein besseres Überleben erreichen als durch extrapleurale Pneumonektomie. Patienten mit MPM sollten immer an einem Zentrum behandelt werden.
    best practice onkologie 01/2013; 8(6).
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    ABSTRACT: Invasion is a critical step in lung tumor progression. The interaction between tumor cells and their surroundings may play an important role in tumor invasion and metastasis. To better understand the mechanisms of tumor invasion and tumor-microenvironment interactions in lung tumors, total RNA was isolated from the inner tumor, tumor invasion front, adjacent lung, and distant normal lung tissue from 17 patients with primary squamous cell lung carcinoma using punch-aided laser capture microdissection. Messenger RNA expression profiles were obtained by microarray analysis, and microRNA profiles were generated from eight of these samples using TaqMan Low Density Arrays. Statistical analysis of the expression data showed extensive changes in gene expression in the inner tumor and tumor front compared with the normal lung and adjacent lung tissue. Only a few genes were differentially expressed between tumor front and the inner tumor. Several genes were validated by immunohistochemistry. Evaluation of the microRNA data revealed zonal expression differences in nearly a fourth of the microRNAs analyzed. Validation of selected microRNAs by in situ hybridization demonstrated strong expression of hsa-miR-196a in the inner tumor; moderate expression of hsa-miR-224 in the inner tumor and tumor front, and strong expression of hsa-miR-650 in the adjacent lung tissue. Pathway analysis placed the majority of genes differentially expressed between tumor and nontumor cells in intrinsic processes associated with inflammation and extrinsic processes related to lymphocyte physiology. Genes differentially expressed between the inner tumor and the adjacent lung/normal lung tissue affected pathways of arachidonic acid metabolism and eicosanoid signaling. © 2012 Wiley Periodicals, Inc.
    Genes Chromosomes and Cancer 10/2012; · 3.55 Impact Factor
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    ABSTRACT: Patients with lung cancer are at risk for developing a second primary lung cancer (SPLC). However, characteristics of patients at risk remain largely speculative. We reviewed 2816 lung cancer patients from our institution for the occurrence of SPLC. Any SPLC was categorized as synchronous when diagnosed within 2 years after first primary lung cancer (FPLC) and after direct histologic comparison of both tumours. All other SPLC were considered as metachronous. 139 patients developed a second malignancy including 69 NSCLC and 9 SCLC. The median interval for diagnosis of metachronous SPLC (n=59) after occurrence FPLC was 72 months. SPLC detected within 5 years after FPLC diagnosis had a more favorable stage distribution (p=0.02). After diagnosis of SPLC, patients had a superior median overall survival compared to controls (57.7 versus 18.1 months; p<0.0001). Interestingly, comparing only stage IV NSCLC patients, a history of FPLC was also associated with a favorable survival (median 27.4 versus 8.97 months; p=0.007). In summary, previous lung cancer treatment does not lead to impaired prognosis after diagnosis of SPLC. Improved surveillance programs beyond 5 years after FPLC treatment may result in more favorable disease stages for detected SPLC.
    European Respiratory Journal 10/2012; · 6.36 Impact Factor
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    ABSTRACT: Background: In recent years experience has been accumulated in percutaneous radiofrequency ablation (RFA) of lung malignancies in nonsurgical patients. Objectives: In this study, we retrospectively evaluated a simultaneous diagnostic and therapeutic approach including CT-guided biopsy followed immediately by RFA of solitary malignant pulmonary lesions. Methods: CT-guided transthoracic core needle biopsy of solitary pulmonary lesions suspicious for malignancy was performed and histology was proven based on immediate frozen sections. RFA probes were placed into the pulmonary tumors under CT guidance and the ablation was performed subsequently. The procedure-related morbidity was analyzed. Follow-up included a CT scan and pulmonary function parameters. Results: A total of 33 CT-guided biopsies and subsequent RFA within a single procedure were performed. Morbidity of CT-guided biopsy included pulmonary hemorrhage (24%) and a mild pneumothorax (12%) without need for further interventions. The RFA procedure was not aggravated by the previous biopsy. The rate of pneumothorax requiring chest tube following RFA was 21%. Local tumor control was achieved in 77% with a median follow-up of 12 months. The morbidity of the CT-guided biopsy had no statistical impact on the local recurrence rate. Conclusions: The simultaneous diagnostic and therapeutic approach including CT-guided biopsy followed immediately by RFA of solitary malignant pulmonary lesions is a safe procedure. The potential of this combined approach is to avoid unnecessary therapies and to perform adequate therapies based on histology. Taking the local control rate into account, this approach should only be performed in those patients who are unable to undergo or who refuse surgery.
    Respiration 10/2012; · 2.62 Impact Factor
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    ABSTRACT: Small-cell lung cancer (SCLC) is an aggressive lung tumor subtype with poor prognosis. We sequenced 29 SCLC exomes, 2 genomes and 15 transcriptomes and found an extremely high mutation rate of 7.4 ± 1 protein-changing mutations per million base pairs. Therefore, we conducted integrated analyses of the various data sets to identify pathogenetically relevant mutated genes. In all cases, we found evidence for inactivation of TP53 and RB1 and identified recurrent mutations in the CREBBP, EP300 and MLL genes that encode histone modifiers. Furthermore, we observed mutations in PTEN, SLIT2 and EPHA7, as well as focal amplifications of the FGFR1 tyrosine kinase gene. Finally, we detected many of the alterations found in humans in SCLC tumors from Tp53 and Rb1 double knockout mice. Our study implicates histone modification as a major feature of SCLC, reveals potentially therapeutically tractable genomic alterations and provides a generalizable framework for the identification of biologically relevant genes in the context of high mutational background.
    Nature Genetics 09/2012; 44(10):1104-10. · 35.21 Impact Factor
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    ABSTRACT: Recently, a novel classification system based on tumour architecture and with high prognostic impact has been proposed for pulmonary adenocarcinomas (ADC). For imaging-based prediction of histologic ADC subtypes and thus prognosis, it is of paramount importance to investigate the correlations of radio- and histomorphological parameters.Associations between histomorphologic ADC growth patterns (lepidic, acinar, papillary, micropapillary, solid) and data from preoperative assessment by computed tomography (CT) imaging of 174 resected pulmonary ADC were analysed.Margin configuration as well as solidity/ground glass opacity (GGO) of ADC was associated with distinct histomorphological ADC growth patterns. Solid predominant ADC usually had smooth margins and were also solid in CT scans, while lepidic predominant ADC had no predominant margin pattern, were located in the periphery, showed a positive bronchogram, and were frequently associated with GGO. In addition, non-spherical tumour growth was a negative predictor of overall and disease specific patient survival.We defined CT morphologic parameters which were associated with histomorphologic growth patterns of pulmonary ADC. These data may form the basis for the development of future prognostic algorithms in the palliative setting which include an integrated evaluation of biopsy histomorphology and CT scan morphology of non-resectable pulmonary ADC.
    European Respiratory Journal 07/2012; · 6.36 Impact Factor
  • H Dienemann, H Hoffmann
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    ABSTRACT: Video-assisted thoracoscopic surgery (VATS) for lobectomy in stage I non-small cell lung cancer (NSCLC) was introduced in 1991 and has been accompanied by concerns in terms of safety and oncological adequacy over a long period. Only few randomised controlled trials including a small number of patients have been performed, demonstrating non-inferiority of the technical feasibility, patient comfort and long-term prognosis compared with the open technique. The evolving acceptance of VATS lobectomy, however, is based on case-control series and case series including up to 1100 patients as well as reviews and metaanalyses demonstrating its overall advantages. Presuming appropiate training the VATS procedure can be accomplished rapidly, safely and without violation of oncological principles. Patients experience a less traumatic procedure and a shorter recovery. The 5-year survival is not different from that after open thoracotomy. In conclusion, VATS lobectomy may be regarded as standard in stage I NSCLC as long as the preconditions in terms of surgical training, patient selection and infrastructure are fulfilled.
    Zentralblatt für Chirurgie 06/2012; 137(3):228-33. · 0.69 Impact Factor

Publication Stats

1k Citations
340.83 Total Impact Points

Institutions

  • 2003–2014
    • Universität Heidelberg
      • • Department of Thoracic Surgery
      • • Institute of Pathology (Mannheim)
      Heidelburg, Baden-Württemberg, Germany
  • 2012
    • Charité Universitätsmedizin Berlin
      • Institute of Pathology
      Berlín, Berlin, Germany
  • 2008
    • German Cancer Research Center
      • Division of Molecular Genome Analysis
      Heidelberg, Baden-Wuerttemberg, Germany
  • 1999
    • National Cerebral and Cardiovascular Center
      Ōsaka, Ōsaka, Japan
  • 1993–1997
    • Ludwig-Maximilian-University of Munich
      • • Cardiac Surgery Clinic
      • • Department of Surgery
      München, Bavaria, Germany