[Local treatment of solitary intrapulmonary, malignant nodules]. / Lokaltherapie solitärer intrapulmonaler maligner Rundherde.

DEFINITION: Intrapulmonary nodules generally represent an incidental finding in the roentgenogram or computed tomography (CT) scan of the chest. They are defined as single, well-circumscribed, radiographic opaque lesions that measures up to 3 cm in diameter and are surrounded completely by aerated lung. The probability of malignancy directly correlates with increasing diameter. Lesions that have a diameter of 1 cm or larger require direct evaluation. THERAPY: Surgery is the first option for patients with a malignant lesion, given an acceptable perioperative risk; for high-risk patients either radiofrequency ablation (RFA) or stereotactic body radiation therapy (SBRT) should be offered. In these cases the malignant histology has to be established beforehand or verified by radiologic proven growth. OUTCOME: Complete surgical resection is superior to RFA and SBRT with respect to local tumor control.

[Tracheobronchoplasty for Severe Diffuse Tracheomalacia]. / Tracheobronchoplastie bei schwerer diffuser Tracheobronchomalazie.

Patients with diffuse airway instability due to tracheobronchomalacia or excessive dynamic airway collapse are typically highly symptomatic, with marked dyspnoea, recurrent bronchopulmonary infections and excruciating intractable cough. Silicone stents achieve immediate symptom control, but are - due to the typical complications associated with stent treatment - usually not an option for long-term treatment. The aim of surgical intervention is definitive stabilisation of the trachea and of both main bronchi by posterior splinting of the Paries membranaceus with a polypropylene mesh. This operation is an appropriate treatment option for patients with documented severe tracheobronchomalacia or excessive dynamic airway collapse and is ultimately the only therapy that can achieve permanent symptom control. The success of the operation, however, depends on many factors and requires close interdisciplinary collaboration.

Serum inflammatory factors and circulating immunosuppressive cells are predictive markers for efficacy of radiofrequency ablation in non-small-cell lung cancer.

In recent years, percutaneous radiofrequency ablation (RFA) has been developed as a new tool in the treatment of non-small-cell lung cancer (NSCLC) in non-surgical patients. There is growing evidence that RFA-mediated necrosis can modulate host immune responses. Here we analysed serum inflammatory factors as well as immunosuppressive cells in the peripheral blood to discover possible prognostic indicators. Peripheral blood and serum samples were collected before RFA and within 3 months after the treatment in a total of 12 patients. Inflammatory cytokines and growth factors were measured in serum by the Bio-Plex assay. Myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs ) were evaluated in the peripheral blood via flow cytometry. In patients developing local or lymphogenic tumour relapse (n=4), we found an early significant increase in the concentration of tumour necrosis factor (TNF)-α as well as chemokine (C-C motif) ligand (CCL)-2 and CCL-4 compared to patients without relapse (n=4) and healthy donors (n=5). These changes were associated with an elevated activity of circulating MDSC indicated by an increased nitric oxide (NO) production in these cells. Elevated serum levels of TNF-α, CCL-2 and CCL-4 associated with an increased NO production in circulating MDSCs might be an early indicator of the incomplete RFA and subsequently a potential tumour relapse in NSCLC.

[Pulmonary Echinococcosis: Surgical Aspects]. / Pulmonale Echinokokkose: chirurgische Aspekte.

Pulmonary cystic echinococcosis is a very rare disease in Germany. It is caused by the larvae of the dog tapeworm (echinococcus granulosus). The liver is the most affected organ, followed by the lungs. Surgery remains the main therapeutic approach for pulmonary CE. Whenever possible, parenchyma-preserving lung surgery should be preferred over anatomic lung resections. To ensure best therapeutic results, surgery needs to be performed under precise consideration of important infectiological aspects and patients should be treated in specialised centres based on interdisciplinary consensus. In addition to surgical aspects, this review summarises special infectiological features of this disease, which are crucial to the surgical approach.

Tumour cell proliferation (Ki-67) in non-small cell lung cancer: a critical reappraisal of its prognostic role.

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.

Tumour-site-dependent expression profile of angiogenic factors in tumour-associated stroma of primary colorectal cancer and metastases.

BACKGROUND: Tumour-associated stroma has a critical role in tumour proliferation. Our aim was to determine a specific protein expression profile of stromal angiogenic cytokines and matrix metalloproteinases (MMPs) to identify potential biomarkers or new therapy targets. METHODS: Frozen tissue of primary colorectal cancer (n=25), liver (n=25) and lung metastases (n=23) was laser-microdissected to obtain tumour epithelial cells and adjacent tumour-associated stroma. Protein expression of nine angiogenic cytokines and eight MMPs was analysed using a multiplex-based protein assay. RESULTS: We found a differential expression of several MMPs and angiogenic cytokines in tumour cells compared with adjacent tumour stroma. Cluster analysis displayed a tumour-site-dependent stromal expression of MMPs and angiogenic cytokines. Univariate analysis identified stromal MMP-2 and MMP-3 in primary colorectal cancer, stromal MMP-1, -2, -3 and Angiopoietin-2 in lung metastases and stromal MMP-12 and VEGF in liver metastases as prognostic markers (P>0.05, respectively). Furthermore, stroma-derived Angiopoietin-2 proved to be an independent prognostic marker in colorectal lung metastases. CONCLUSION: Expression of MMPs and angiogenic cytokines in tumour cells and adjacent tumour stroma is dependent on the tumour site. Stroma-derived MMPs and angiogenic cytokines may be useful prognostic biomarkers. These data can be helpful to identify new agents for a targeted therapy in patients with colorectal cancer.

Simultaneous computed tomography-guided biopsy and radiofrequency ablation of solitary pulmonary malignancy in high-risk patients.

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.

[VATS lobectomy in stage I lung cancer: standard or experimental procedure]. / VATS-Lobektomie beim Stadium-I-Lungenkarzinom: Standard oder Experiment.

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.

Management of chylothorax in adults: when is surgery indicated?

BACKGROUND: The aim of this retrospective study was to analyze the etiology, management and outcome of patients with chylothorax and identify clinical parameters for appropriate treatment decisions. METHODS: We analyzed 82 cases of chylothorax in 75 patients. In 37 cases (45 %) the cause of chylothorax was surgery, in 45 cases (55 %), the etiology was nonsurgical (malignancy n = 17 [21 %], lymphatic disorders n = 5 [6 %], hepatic cirrhosis, n = 4 [5 %], trauma n = 1 and other causes n = 18 [22 %]). RESULTS: Conservative treatment was successful in 13 (16 %) cases. In 25 cases (total 31 %, postsurgical n = 19 [51 %], nonsurgical n = 6 [13 %]) a (redo) thoracotomy with ligation of the thoracic duct or repeat surgical procedure was performed. The quantity of chyle drained per 24 hours appeared to be the best indicator to guide management decisions. CONCLUSION: Chylothoraces that occur postoperatively following thoracic procedures require redo operations in approximately 50 % of cases, whereas nonsurgical causes rarely require surgical intervention. In postoperative chylothoraces with a high flow leak > 900 mL/24 h revision should be performed early on, since conservative management is likely to be unsuccessful.

Survival after pulmonary metastasectomy in patients with malignant melanoma.

BACKGROUND: Surgical resection is an important interdisciplinary treatment for pulmonary metastases of metastatic malignant melanoma. The purpose of this study was to determine the clinical course, outcome and prognostic factors in a subset of patients recently treated by metastasectomy. MATERIAL AND METHODS: Between 1995 and 2007, 30 patients (19 men, 11 women) with pulmonary metastases from malignant melanoma underwent pulmonary resection. Exclusion of primary tumor recurrence and other extrapulmonary metastases was mandatory for inclusion in the study. The median follow-up was 93.7 months. These patients' records were subsequently reviewed. RESULTS: Cumulative 5-year survival rate after pulmonary resection was 35.1% with a median survival of 18.3 months. Complete pulmonary resection was achieved in 27 patients who had a median survival of 20.5 months compared to 13.0 months after incomplete resection; however, completeness of resection was not a statistically prognostic factor for survival. Multivariate analysis identified gender as the only significant prognostic parameter for overall survival in the group of patients after complete resection of pulmonary metastases, with 9.4 months versus 25.0 months for the female and male group, respectively ( P = 0.022). CONCLUSIONS: We conclude that pulmonary metastasectomy for metastases of malignant melanoma is a safe treatment modality which may actually be of benefit in selected patients with stage IV malignant melanoma. When pulmonary metastases of malignant melanoma are present, every attempt should be made to completely resect all clinically detected metastases.

Guidelines of the European Respiratory Society and the European Society of Thoracic Surgeons for the management of malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a rare tumour but with increasing incidence and a poor prognosis. In 2008, the European Respiratory Society/European Society of Thoracic Surgeons Task Force brought together experts to propose practical and up-to-dated guidelines on the management of MPM. To obtain an earlier and reliable diagnosis of MPM, the experts recommend performing thoracoscopy, except in cases of pre-operative contraindication or pleural symphysis. The standard staining procedures are insufficient in approximately 10% of cases. Therefore, we propose using specific immunohistochemistry markers on pleural biopsies. In the absence of a uniform, robust and validated staging system, we advice use of the most recent TNM based classification, and propose a three step pre-treatment assessment. Patient's performance status and histological subtype are currently the only prognostic factors of clinical importance in the management of MPM. Other potential parameters should be recorded at baseline and reported in clinical trials. MPM exhibits a high resistance to chemotherapy and only a few patients are candidates for radical surgery. New therapies and strategies have been reviewed. Because of limited data on the best combination treatment, we emphasise that patients who are considered candidates for a multimodal approach should be included in a prospective trial at a specialised centre.

Identification of immunohistochemical prognostic markers for survival after resection of pulmonary metastases from colorectal carcinoma.

BACKGROUND: Although aggressive resection of pulmonary metastases prolongs the survival of patients with metastatic colorectal cancer, there is a need for predictive pathologic parameters to understand the key molecular events of metastatic progression. The aim of this study was to verify immunohistochemical markers in addition to established clinical parameters after surgery. METHODS: From our subset of patients undergoing resection of pulmonary metastases from metastatic colorectal carcinoma, we analyzed 39 patients (23 men and 16 women) between 2003 and 2007. Only patients who met the criteria for a potentially curative operation were included. All patients were analyzed with regard to age and sex, primary tumor location, stage of the primary tumor, history of hepatic metastases, number of pulmonary metastases, pre-thoracotomy carcinoembryonic (CEA) serum antigen level, and the presence of thoracic lymph node metastasis. Furthermore, we immunohistochemically investigated the expression of vascular endothelial growth factor (VEGF)-D, FBJ murine osteosarcoma viral oncogene homolog B (FOS-B), and melanoma antigen (MAGE)-A in the surgical specimens of pulmonary metastatic lesions. RESULTS: The overall 3-year survival was 50.6 %. A significantly longer survival was observed with multivariate analysis in patients with a pre-thoracotomy serum carcinoembryonic antigen level of no more than 4.2 ng/mL ( P = 0.001), and Dukes stage A or B primary tumor ( P = 0.001). A significantly longer recurrence-free survival was observed with multivariate analysis in patients without thoracic lymph node involvement compared to patients with pulmonary and/or mediastinal lymph node metastases ( P = 0.006). The stage of the primary tumor remained significant ( P = 0.029), and FOS-B expression in tumor cells showed a trend towards favorable recurrence-free survival after pulmonary metastasectomy ( P = 0.059). No statistically significant difference was found in the overall survival rate or recurrence-free survival rate of patients with expression of VEGF-D or MAGE-A antigen in pulmonary metastatic tumor cells. CONCLUSIONS: Our results suggest that in addition to clinically prognostic factors, FOS-B expression has a debatable impact on patient survival. We conclude that the evaluation of molecular and clinical prognostic parameters at the time of pulmonary metastasectomy offers a greater understanding of the metastatic process and provides important information for patient selection.

[Current surgical management of pulmonary metastases]. / Aktueller Stand in der chirurgischen Therapie von Lungenmetastasen.

Surgical resection has been the first choice for the treatment of isolated pulmonary metastases secondary to extrapulmonary malignancies. Despite recent advances, systemic chemotherapy for metastatic disease without the use of surgery is considered to be merely palliative, as there are rarely long-term survivors. Criteria for resection and prognostic parameters help facilitate patient selection. In addition to the established parameters the most significant factors in selecting patients for operation include the number of pulmonary metastases, disease-free interval, serum tumour marker level, and the question of mediastinal and hilar lymph node metastases. Complete surgical resection is critical to achieving long-term survival and is best accomplished via open thoracotomy accompanied by a systematic mediastinal and hilar lymph node dissection. The recent development of video-assisted thoracoscopic surgery (VATS) and advances in thoracic imaging technique has made the VATS approach more amenable for resection of small pulmonary nodules. However, the oncological radicality of VATS is questionable for pulmonary metastasectomy, thus the VATS approach is mostly limited to diagnostic purposes and in highly selected groups of patients with limited, peripherally located lesions. These operations should be performed preferably within a prospective study setting. All results together demonstrate that resection and re-resection of pulmonary metastases can be beneficial in patients, carefully selected by a multidisciplinary tumour board of thoracic surgeons and medical oncologists.

Mediastinal angiomyolipomas in a male patient affected by tuberous sclerosis.

Classical angiomyolipomas are benign tumours composed of various tissues, including components of fat, abnormal blood vessels and smooth muscle cells. They are often found in association with tuberous sclerosis complex (TSC). The present study reports a male patient affected by TSC with intermittent, massive chylous pleural effusions, who developed recurrent mediastinal angiomyolipomas. The tumours were characterised via histological and immunohistochemical methods. Although angiomyolipomas frequently occur in the kidneys of TSC patients, this case is the first report of mediastinal angiomyolipomas associated with TSC. Besides lymphangioleiomyomatosis, this differential diagnosis has to be taken into account in the case of chylous pleural effusions and mediastinal masses in tuberous sclerosis complex patients.

[Treatment of pleural empyema]. / Behandlung des Pleuraempyems.

Pleural empyema remains a frequently encountered clinical problem and is responsible for significant morbidity and mortality worldwide. Its diagnosis may be difficult; delays in diagnosis and treatment may contribute to morbidity, complications, and mortality. The management of parapneumonic effusion and empyema depends on timely, stage-dependent therapy and the underlying etiology. Thoracentesis and antibiotics remain the cornerstones of treatment in stage I disease. In the early fibrinopurulent phase (stage II) thoracoscopic methods should be considered. As treatment strategy for this stage, fibrinopurulent pleural empyema entails thorough debridement of multiloculated collections from the pleural cavity by video-assisted thoracic surgery. After evacuation of multilocular effusions and the removal of fibrin deposits with drainage by two intercostal chest tubes, irrigation treatment helps to achieve clarity of the pleural discharge. Open thoracotomy and decortication are reserved for organized, multiloculated empyema with lung entrapment (stage III disease). Early drain removal may lead to rapid symptomatic recovery and complete resolution.

[Plastic surgical reconstruction of extensive thoracic wall defects after oncologic resection]. / Plastisch-chirurgische Rekonstruktion von Defekten der Thoraxwand nach onkologischen Resektionen. Interdisziplinäre Strategien.

In defect reconstruction following radical oncologic resection of malignant chest wall tumors, adequate soft-tissue reconstruction must be achieved along with function, stability, integrity, and aesthetics of the chest wall. The purpose of this retrospective analysis was to evaluate the oncoplastic concept following radical resection of malignant chest wall infiltration with an interdisciplinary approach. Between 1999 and 2005, 36 consecutive patients (nine males, 27 females, mean age 55 years, range 20-78) were treated with resection for malignant tumors of the chest wall. Indications were locally recurrent breast carcinoma (patient n=22), thymoma (n=1), and desmoid tumor (n=1). Primary lesions of the chest wall were spinalioma (n=1), sarcoma (n=7), and non-small-cell lung cancer (n=2). There were distant metastases of colon and cervical cancer in one patient each. Soft-tissue reconstruction was carried out using primary closure (n=1), external oblique flap (n=1), pectoralis major myocutaneous flap (n=3), latissimus dorsi myocutaneous flap (n=18), vertical or transversal rectus abdominis myocutaneous flap (n=9), free tensor fascia lata- flap (n=6), trapezius flap (n=1), serratus flap (n=1), and one filet flap. In 15 reconstructive procedures microvascular techniques were used. An average of 3.4 ribs were resected. Stability of the chest wall was obtained with synthetic meshes. The latissimus dorsi flap is considered the flap of choice in chest wall reconstruction. However, alternatives such as pectoralis major flap, VRAM/TRAM flap, free TFL flap, and serratus flap must also be considered. Low mortality and morbidity rates allow tumor resection and chest wall reconstruction even in a palliative setting.

Expression ratio of the TGFß-inducible gene MYO10 is prognostic for overall survival of squamous cell lung cancer patients and predicts chemotherapy response.

In lung cancer a deregulation of Transforming Growth Factor-ß (TGFß) signaling has been observed. Yet, the impact of TGFß in squamous cell carcinoma of the lung (LUSC) remained to be determined. We combined phenotypic and transcriptome-wide studies and showed that the stimulation of the LUSC cell line SK-MES1 with TGFß results in an increase of migratory invasive properties. The analysis of the dynamics of gene expression by next-generation sequencing revealed that TGFß stimulation orchestrates the upregulation of numerous motility- and actin cytoskeleton-related genes. Among these the non-muscle myosin 10 (MYO10) showed the highest upregulation in a LUSC patient cohort of the Cancer Genome Atlas (TCGA). Knockdown of MYO10 abrogated TGFß-induced collagen gel invasion of SK-MES1 cells. The analysis of MYO10 mRNA expression in paired tissues of 151 LUSC patients with corresponding 80-month clinical follow-up data showed that the mRNA expression ratio of MYO10 in tumor and tumor-free tissue is prognostic for overall survival of LUSC patients and predictive for the response of these patients to adjuvant chemotherapy. Thus, MYO10 represents a new clinical biomarker for this aggressive disease and due to its role in cellular motility and invasion could serve as a potential molecular target for therapeutic interventions in patients with LUSC.

[Treatment of pneumothorax]. / Behandlung des Pneumothorax.

Pneumothorax is defined as air in the pleural space, i.e. between the lung and the chest wall. Primary pneumothoraces (PSP) arise in otherwise healthy people without any lung disease. Secondary pneumothoraces (SSP) arise in subjects with underlying lung disease. Observation alone is recommended only in patients with small primary or secondary pneumothoraces of less than 1 cm depth or isolated apical pneumothoraces in asymptomatic patients. In symptomatic patients observation alone is inappropriate and active intervention is required. Although simple aspiration may be an option for first-line treatment in clinically stable patients with PSP, intercostal tube drainage is strongly recommended in all primary and secondary pneumothoraces requiring intervention. There are two objectives in the surgical management of pneumothorax. The first widely accepted objective is resection of blebs or the suture of apical perforations to treat the underlying defect. The second objective is to create a pleural symphysis to prevent recurrence. While video-assisted thoracic surgery may be the preferred surgical procedure for young, fit people with complicated or recurrent primary pneumothoraces, it is less reliable in cases of secondary pneumothorax. For the latter, open thoracotomy and repair is still the recommended approach.

Outcome following lung resections for pT1 non-small cell lung cancer.

AIMS: To analyse the outcome of patients with pT1 NSCLC treated at our institution by antero-lateral thoracotomy, anatomical lung resections and mediastinal lymph node dissection between 1980 and 2001. METHODS: Follow-up data were obtained retrospectively from 1980 to 1990 and prospectively after 1990. Survival was analysed using the Kaplan-Meier method. RESULTS: Histopathological examinations revealed mediastinal lymph node infiltration in 27.6% (pN1 17.8% and pN2 9.8%). pN2 was classified in 14.1% of adenocarcinomas compared to 6.2% of squamous cell carcinomas. Median overall survival of patients with pT1 carcinomas was 89+16 months (median+standard error). Histopathological N-classification indicates differential prognostic and therapeutic implications in pT1 adeno- and squamous cell carcinomas. CONCLUSIONS: Complete lymph node dissection is required for all patients with T1 NSCLC treated by either open surgery or VATS resection. Histopathological N-classification indicates differential prognostic and therapeutic implications in pT1 adeno- and squamous cell carcinomas.