[Robot-assisted minimally invasive lobectomy with systematic lymphadenectomy for lung cancer]. / Roboterassistierte minimalinvasive Lobektomie mit systematischer Lymphadenektomie zur Behandlung des Bronchialkarzinoms.

BACKGROUND AND INTRODUCTION: Lobectomy for lung cancer is the standard therapy for lung cancer in limited stages. The adoption of minimally invasive lobectomy (video-assisted thoracic surgery or VATS lobectomy) has increased worldwide since its first description more than 15 years ago. However, the VATS technique has a long learning curve and sometimes limitations in terms of precise preparation and presentability of the central structures of the lung hilus due to the limited mobility of the standard thoracoscopic instruments. By using a four-arm robotic platform (DaVinci®), not only the preparation of the hilus structures but also the central lymphadenectomy can be performed in a comfortable and safe way under a clear and precise view. INDICATION: Surgical treatment of locally limited lung cancer in the right lower lobe (squamous cell carcinoma). PROCEDURE: Robot-assisted, minimally invasive right lower lobectomy with systematic lymphadenectomy. CONCLUSION: Robot-assisted minimal invasive lobectomy is feasible with special regard to oncological and technical aspects. Especially the intrathoracic precise dissection of the tissue under a perfect view allow a comfortable and safe operation technique.

[Coagulation and formation of malignant effusions]. / Die Rolle des Gerinnungssystems bei der Entstehung maligner Ergüsse.

Malignant effusions are a frequent problem for cancer patients. Due to the high resistance of tumor cells within these effusions, no effective treatment has been defined yet. Most patients exhibit additional phenomena related to hyper-coagulability such as elevated levels for d-dimers and prothrombin fragments f1.2; half of them suffer from manifest thrombosis or complications. We followed the hypothesis that the activated coagulation system contributes to the resistance of tumor cells and analyzed the effusions from cancer patients. The majority of isolated tumor cells aberrantly expressed PAR-1 thrombin receptors. In vitro pre-incubation of PAR-1 expressing human leukemia cells with thrombin resulted in a dose-dependent resistance to idarubicin. Within the effusions, we did not only find high concentrations of VEGF and tissue factor, but also all coagulation factors of the tissue factor pathway. Very high levels of prothrombin fragments f1.2 indicate constant thrombin generation. Upon the basis of these findings, we developed a multistep model elucidating the pathophysiological generation of malignant effusions, which might serve as a basis for further examinations.

Activation of the coagulation system in cancerogenesis and metastasation.

The activation of the coagulation system in cancer patients is a well-known phenomenon responsible for recurrent clinical problems. A number of fascinating molecular mechanisms have been recognized showing that the tumor not only activates the coagulation system, but vice versa, activated coagulation proteins are able to induce molecular effects in tumor cells. The molecular basis is the expression of defined membrane receptors by tumor cells that are activated, for example, by thrombin. As the liberation of thrombin from prothrombin is one of the key events in coagulation, it's impact upon biological processes, such as cancerogenesis and metastasation, seems to be a regular pathophysiological consequence. These perceptions are not only interesting for the comprehension of cancerogenesis, metastasation, and clinical phenomena, but they also have a high impact upon modern strategies of tumor therapy. Especially, the development of clinically useful coagulation inhibitors, such as modern low molecular weight heparins or melagatran, created the possibility of therapies that combine cell biological approaches with apoptosis-inducing principals such as chemotherapy. Several clinical studies that demonstrate the implication of these strategies have already been published recently. In this article the cell biological basics for these approaches are reviewed.

Apoptosis by gemcitabine in non-small cell lung cancer cell line KNS62 is induced downstream of caspase 8 and is profoundly blocked by Bcl-xL over-expression.

BACKGROUND: This study assesses the chemotherapeutic drug gemcitabine in the human non-small cell lung cancer (NSCLC) cell line KNS62 in relation to the CD95-induced apoptotic pathway, and the role of the anti-apoptotic protein Bcl-xL in vitro and in vivo. MATERIALS AND METHODS: Apoptosis was determined by JAM assay and DAPI staining analysis. Activation of key apoptotic proteins, including caspases 3, 8 and 9 and BID, as well as cytochrome c release and mitochondrial transmembrane potential (MTP), were measured. The impact of the caspase inhibitor zVAD on gemcitabine-induced apoptosis was quantified. The in vitro results were verified in vivo in an orthotopic murine xenotransplantation model. RESULTS: Gemcitabine treatment, as well as stimulation of CD95, resulted in cleavage of effector caspase 3 as well as its substrate PARP and caspase 9, followed by DNA fragmentation. Cleavage of caspase 8 was demonstrated after CD95 activation but not after the application of gemcitabine. In KNS62-Bcl-xL clones, release of cytochrome c and loss of mitochondrial transmembrane potential were suppressed. Consequently, apoptosis after gemcitabine therapy, as well as CD95-induced apoptosis, were significantly inhibited. Caspase inhibitor zVAD only partly reversed gemcitabine-induced DNA fragmentation. In vivo, there was a significant reduction in tumour volume under gemcitabine therapy. Bcl-xL over-expressing tumours were completely resistant to gemcitabine therapy. CONCLUSIONS: In NSCLC cell line KNS62 gemcitabine activated the mitochondrial apoptotic pathway downstream of mitochondria without activation of initiator caspases. Bcl-xL over-expression induced significant resistance to gemcitabine. In vivo, the anti-apoptotic effect of Bcl-xL was more pronounced than in vitro. Gemcitabine also induced caspase-independent DNA fragmentation in KNS62 cells.

Human endostatin inhibits growth of human non-small-cell lung cancer in a murine xenotransplant model.

Overall prognosis in human NSCLC remains poor. Antiangiogenic treatment has become a promising concept for the treatment of solid malignancies. Our purpose was to evaluate the efficacy of recombinant HSENDO for the treatment of human NSCLC in an orthotopic murine xenotransplantation model. The efficacy of HSENDO was tested in vitro in cell-proliferation, cell-migration and tube-formation assays. In vivo, the effect of HSENDO on tumor growth was tested in s.c. xenotransplanted human NSCLC and on intrapulmonary induced human NSCLC. In vitro, HSENDO inhibited both human and rodent endothelial cell proliferation in a time- and dose-dependent fashion. Endothelial cell migration was inhibited by 97%. Tube formation of murine endothelial cells was inhibited and preexisting tubes degenerated after HSENDO exposure. In vivo, HSENDO delayed growth of s.c. xenotransplanted tumors. Immunohistochemic staining demonstrated no change in microvessel density but a significant reduction of proliferating tumor cells and an increase in bFGF and VEGF expression, reflecting the antiangiogenic effect of HSENDO. Intrapulmonary tumor induction caused death subsequent to metastatic disease. Systemic HSENDO application extended survival significantly. HSENDO was demonstrated to inhibit endothelial cell proliferation, migration and tube formation effectively. In vivo growth of s.c. transplanted tumors was delayed and survival extended by 32% and 69%, respectively, after intrapulmonary NSCLC induction.

Overexpression of phosphatidylinositol 3-kinase in human lung cancer.

BACKGROUND: This study was conducted to investigate the expression of phosphatidylinositol 3-kinase (PI3K) and AKT2, a downstream effector, in primary human lung carcinomas of different histological type. METHODS: Specimens from 105 human lung carcinomas and their corresponding lymph nodes and liver metastases were examined using immunohistochemistry and Northern-blot assays to study the PI3K p85 and p110 subunits and the AKT2-expression patterns. RESULTS: The p85 and p110 subunits of PI3K were overexpressed at the protein level in 77% and 59% of 80 primary lung carcinomas, respectively, irrespective of the histological type. PI3K overexpression was correlated with tumor grading. In contrast, no overexpression of PI3K subunits was observed in normal lung tissue and benign lung tumors. Consistent with these findings, upregulation of p110 mRNA transcripts was restricted to primary lung carcinomas. Overexpression of AKT2 was observed in 10% of the investigated lung tumor specimens, but in none of the healthy lung sections. A profound increase of PI3K expression was uniformly observed in lung tissue specimens and in corresponding extra-pulmonary lymph-node and liver metastases with low-differentiation grades. CONCLUSION: PI3K appears to be associated with the process of tumor-cell transformation and proliferation. One of its major downstream effector molecules, AKT2, which contributes to apoptotic cell death, was not upregulated by PI3K overexpression in primary lung carcinomas.

Combretastatin A-4 prodrug inhibits growth of human non-small cell lung cancer in a murine xenotransplant model.

BACKGROUND: Combretastatin A-4 prodrug (CA-4PD) has been identified as a potent antivascular agent in various rodent tumor models. The aim of this study was to investigate the effect of CA-4PD on human non-small cell lung cancer (NSCLC). METHODS: Cytostatic and cytotoxic effects of CA-4PD on selected NSCLC cells, Colo-699 and KNS-62, were studied in vitro. After subcutaneous xenotransplantation the effect of systemically administrated CA-4PD on tumor growth was investigated in vivo. A newly established orthotopic xenotransplant model was employed to estimate prolongation of survival after intrapulmonary tumor induction with secondary metastatic disease. RESULTS: In vitro, CA-4PD displayed a time and dose dependent antiproliferative effect on human lung cancer cells. In vivo, CA-4PD significantly delayed growth of subcutaneously induced lung cancer. This growth delay was translated into a prolongation of survival in the metastasizing orthotopic xenotransplant model. CONCLUSIONS: In vitro CA-4PD inhibits proliferation of NSCLC cells, most likely by disruption of microtubule assembly. In vivo, systemic treatment inhibits growth of subcutaneously xenotransplanted tumors by an antivascular effect. In the case of metastasizing human lung cancer this translated into a prolongation of survival.

Effective treatment of malignant pleural effusion by minimal invasive thoracic surgery: thoracoscopic talc pleurodesis and pleuroperitoneal shunts in 101 patients.

BACKGROUND: For effective palliation of patients with malignant pleural effusion due to advanced neoplastic disease, any proposed treatment should have low procedure-related mortality and morbidity. METHODS: The clinical outcome of 119 thoracoscopies in 101 patients (56 women, 45 men), from 42 to 91 years of age (mean, 68 +/- 9 years) with malignant pleural effusions was evaluated in a retrospective study. Video-assisted thoracoscopy (VATS) talc pleurodesis was done in 105 instances, and a pleuroperitoneal shunt was performed 14 times as an alternative when complete expansion of the lung could not be achieved due to tumor implants on the visceral pleura. RESULTS: The VATS talc pleurodesis resulted in clinically significant improvement of dyspnea in 92.2% of the patients. Thirty-day mortality was 2.8% and morbidity was 2.8%. The mean duration of postoperative survival was 6.7 months. Recurrent pleural effusion occurred in 5.7% of patients after a mean interval of 6 months. Clinical relief of dyspnea was obtained in 73% of the patients treated with pleuroperitoneal shunts. Thirty-day mortality in this group was 21% and morbidity was 14.3%. The mean duration of survival was 4.2 months. CONCLUSIONS: The VATS talc pleurodesis is appropriate for palliation of patients with malignant pleural effusions and should be performed once the diagnosis has been confirmed. Patients with lungs trapped by visceral carcinomatosis may benefit from placement of a pleuroperitoneal shunt as an alternative.

Chronic spontaneous pneumothorax decortication after 130 days.

The case of a 21-year-old male with neglected and protracted spontaneous pneumothorax is reported. Video-assisted thoracoscopy after 130 days showed the lung to be trapped solely by a thick pleurovisceral membrane, which required open surgical decortication. Chronic pneumothorax is a rare complication of spontaneous pneumothorax. This is the second report on a chronic pneumothorax solely due to a pleurovisceral membrane and the longest reported interval until decortication.

Percutaneous endoscopic laser discectomy.

BACKGROUND: The aim of the present paper was to systematically review the literature on percutaneous endoscopic laser discectomy (PELD) with respect to the safety and efficacy of the procedure. Where possible the procedure was compared with open discectomy. METHODS: Studies on PELD were identified using MEDLINE (1984 to December 1999), EMBASE (1974 to December 1999) and Current Contents (1993 to Week 1, 2000). A number of search terms were used: PELD; PLDD (percutaneous laser disc decompression); and laser and (spine or lumbar) and (disc* or disk*). The Cochrane Library was searched from 1966 to issue 4, 1999, using the search terms 'discectomy' or 'discotomy'. Live human studies of patients with lumbar disc prolapses for whom surgery was appropriate were included. Cadaver studies were also included. A surgeon and reviewer independently assessed the retrieved articles for their inclusion in the review. RESULTS: Only 12 papers were identified that related to PELD. The level of evidence for safety and efficacy was low; there were no controlled, blinded or randomized studies. The highest level of evidence came from time series studies. No quantitative analysis could be undertaken for the present review. CONCLUSIONS: Given the extremely low level of evidence available for this procedure it was recommended that the procedure be regarded as experimental until results are available from a controlled clinical trial, ideally with random allocation to an intervention and control group.

An improved orthotopic xenotransplant procedure for human lung cancer in SCID bg mice.

BACKGROUND: Overall prognosis in human lung cancer is still poor. A highly reproducible, easy to perform in vivo model, which closely resembles the clinical features of advanced human lung cancer, is required for the evaluation of novel therapies. METHODS: Tumor cells, originated from a human adenocarcinoma, a squamous cell carcinoma, and an undifferentiated large cell carcinoma, were xenotransplanted heterotopically by subcutaneous and intravenous injection and compared with orthotopic intrapleural and intrapulmonary xenotransplantation by a facilitated engraftment procedure into SCID bg mice. RESULTS: Subcutaneous injection of tumor cells resulted in a 100% engraftment rate with establishment of solid tumors without clinically relevant metastases. Intravenous injection had poor engraftment rates by hematogenous spread. Depending on the cell line, a 80% to 100% engraftment rate in orthotopic xenotransplantation was achieved, resulting in a consistent pattern of mediastinal and bilateral pulmonary metastases. CONCLUSIONS: The facilitated orthotopic xenotransplantation of human lung cancer is easy to perform and results in a reproducible in vivo model that closely resembles the clinical features of advanced human lung cancer. Consequently, this model appears suitable for in vivo evaluation of novel cancer therapies in preclinical tests.

[Pain therapy after thoracoscopic interventions. Do regional analgesia techniques (intercostal block or interpleural analgesia) have advantages over intravenous patient-controlled opioid analgesia (PCA)?]. / Schmerztherapie nach thoracoskopischen Eingriffen. Haben Regionalanalgesieverfahren (Intercostalblockade oder Interpleuralanalgesie) Vorteile gegenüber einer intravenösen patientenkontrollierten Opioidanalgesie (PCA)?

Systemic opioids and thoracic epidural analgesia are common techniques used to provide post-operative analgesia following thoracoscopy (video-assisted thoracic surgery). The aim of the present prospective randomised study was to evaluate the efficacy of two less invasive analgesic techniques, intercostal blocks (ICB) and interpleural analgesia (IPA). After approval from the ethics committee and informed consent from the patients, 36 patients scheduled for thoracoscopic surgery were randomly assigned to a group for postoperative pain management: group ICB: intercostal blocks of the segments involved with 5 ml 0.5% bupivacaine at the end of surgery and 6 h later; group IPA: interpleural analgesia with 20 ml 0.25% bupivacaine applied every 4 h using a catheter placed during surgery near the apex of the interpleural space; control group: IV-opiod-PCA with piritamide. Patients in the ICB and IPA groups had access to pain relief by PCA with piritramide as well. Additional medication for all groups if the analgesia was insufficient consisted of metamizol. There were no significant differences in piritramide consumption between the two regional analgesia groups and the control group up to the 3rd and 7th postoperative day. Up to the 7th day piritramide consumption in group ICB was 78 mg, in group IPA 75 mg and 80 mg in the control group. Patients in group ICB showed significantly less pain at rest measured by the visual analogue scale (VAS) on the 1st postoperative day (U-test, P < 0.05), but otherwise there were no statistical differences regarding pain scores. Respiratory parameters such as forced vital capacity, forced expiratory volume, peak flow and the Tiffeneau test (FVC, FEV1, PF, FEV1/FVC) were reduced significantly after thoracoscopy and showed a slow recovery in all three groups without significant intergroup differences. Thoracoscopic surgery causes less and shorter lasting pain in comparison to thoracotomy. Nevertheless, effective pain management is necessary. We could not demonstrate a significant reduction in piritramide consumption for the techniques of regional analgesia tested here (ICB, IPA). We conclude that the use of these techniques is not complementary after thoracoscopy, since an opioid (PCA with piritramide) combined with a non-opioid (metamizol) resulted in satisfactory analgesia.

Acute respiratory insufficiency in an infant caused by a tracheogenic cyst.

The unusual case of acute respiratory insufficiency in an infant of 5 months caused by a large cyst of true tracheal origin is presented.

[Effective treatment of malignant pleural effusion: Thoracoscopic talcum pleurodesis and pleuro-peritoneal shunt]. / Die effektive Behandlung des malignen Pleuraergusses. Thorakoskopische Talkumpleurodese--pleuroperitonealer Shunt.

BASIC PROBLEM: Definitive palliation of malignant pleural effusion demands a therapeutic procedure that is efficient with a low risk of complication and death. This study was undertaken to evaluate the outcome of thoracoscopic talcum pleurodesis (TTP), with insertion of pleuro-peritoneal shunt (PPS) for permanent drainage, if indicated. PATIENTS AND METHODS: The results of treating malignant pleural effusions were analysed retrospectively in 36 patients (15 men, 21 women; mean age 65 [48-89] years) who had undergone 37 video-assisted TTP and 6 PPS. RESULTS: TTP achieved significant improvement of dyspnoea in 89% of patients and PPS succeeded in providing permanent internal drainage even in cases of adherent pleura. CONCLUSION: Video-assisted TTP is the method of choice in the palliative treatment of malignant pleural effusions in the still expanding lung. In case of an adherent nonexpanding lung PPS provides effective and permanent palliation.

RAD53 regulates DBF4 independently of checkpoint function in Saccharomyces cerevisiae.

The Cdc7p and Dbf4p proteins form an active kinase complex in Saccharomyces cerevisiae that is essential for the initiation of DNA replication. A genetic screen for mutations that are lethal in combination with cdc7-1 led to the isolation of seven lsd (lethal with seven defect) complementation groups. The lsd7 complementation group contained two temperature-sensitive dbf4 alleles. The lsd1 complementation group contained a new allele of RAD53, which was designated rad53-31. RAD53 encodes an essential protein kinase that is required for the activation of DNA damage and DNA replication checkpoint pathways, and that is implicated as a positive regulator of S phase. Unlike other RAD53 alleles, we demonstrate that the rad53-31 allele retains an intact checkpoint function. Thus, the checkpoint function and the DNA replication function of RAD53 can be functionally separated. The activation of DNA replication through RAD53 most likely occurs through DBF4. Two-hybrid analysis indicates that the Rad53p protein binds to Dbf4p. Furthermore, the steady-state level of DBF4 message and Dbf4p protein is reduced in several rad53 mutant strains, indicating that RAD53 positively regulates DBF4. These results suggest that two different functions of the cell cycle, initiation of DNA replication and the checkpoint function, can be coordinately regulated through the common intermediate RAD53.

Oligomers of the Cdc7/Dbf4 protein kinase exist in the yeast cell.

Cdc7/Dbf4 protein kinase is required for the initiation of DNA replication in Saccharomyces cerevisiae. Cdc7/Dbf4 protein kinase is not a cyclin-dependent kinase (CDK), but is regulated in a similar fashion in that the Cdc7 kinase subunit is inactive in the absence of the regulatory subunit Dbf4. In contrast to what is known about CDKs, Cdc7/Dbf4 protein kinase is shown to be an oligomer in the cell in this report. Genetic data that support this claim include interallelic complementation between several cdc7ts alleles and the cdc7T281A allele and also the results of experiments using the two-hybrid system with Cdc7 in both DNA-binding and transactivation domain plasmids. A molecular interaction between two different Cdc7 molecules was shown by using a HA-tagged Cdc7 protein that differs in size from the wild-type Cdc7 protein: an anti-HA antibody immunoprecipitates both proteins in approximately equal stoichiometry. Analysis of the native molecular weight of Cdc7/Dbf4 protein kinase is consistent with oligomerization of the Cdc7 protein in that complexes of about 180 and 300 kDa were found. Oligomers of Cdc7 protein may exist for the purpose of allosteric regulation or to allow phosphorylation of multiple substrate protein molecules.

New method of radiotherapy for anal cancer with three-dimensional tumor reconstruction based on endoanal ultrasound and ultrasound-guided afterloading therapy.

PURPOSE: Standard treatment of anal cancer is a protocol of combined chemotherapy and percutaneous radiotherapy. We developed a new endosonography-based radiation target simulation method, because endoanal sonography gives the best opportunity to stage the tumor accurately. Based on this method, an afterloading needle application procedure could be performed to optimize the radiation target geometry and to control the application of afterloading needles. In a prospective study, this new method was evaluated, with special regard for complications and tumor recurrence. METHODS: Anal cancer was restaged endosonographically six weeks after external beam radiation with 45 Gy. A computer-generated three-dimensional reconstruction of the tumor and radiation target simulation was performed based on endoanal sonographic imaging. By using a new type of applicator, which is permeable to ultrasound waves, the transperineal implantation procedure of afterloading needles could be controlled. Application needles were inserted into the target area according to the endoanal sonography-based dosimetry planing. The dose of the (high-dose rate) brachytherapy boost was started with two 6-Gy fractions, each within eight days. The fraction dose was reduced to 4 Gy to minimize side effects. Lymph node-positive tumors got additional chemotherapy (5-fluorouracil and mitomycin C). RESULTS: From January 1992 until August 1996, we performed 42 endosonography-guided afterloading procedures in 18 patients. One patient underwent percutaneous radiation two years before and was treated only by afterloading radiation. In every patient, we found complete tumor remission at the end of radiotherapy. Three patients with a high-dose rate of 2 x 6 Gy developed radiogenic proctitis, and two patients developed ulceration, which lead to reduction of the dose. After reduction to 4 Gy per fraction, no more side effects could be seen. In follow-up (median, 24 (range, 1-56) months), we detected two anal cancer recurrences (2/18 patients). CONCLUSION: The radiation target field can be optimized by individual endosonography-based three-dimensional tumor reconstruction and radiotherapy simulation. Endosonography-guided transperineal implantation of afterloading needles can be performed according to the computer-generated simulation by using a new type of applicator. We could achieve total primary tumor remission in every patient. After reduction of the afterloading dose to 2 x 4 Gy, no brachytherapy-related side effects could be seen.

[Implementing the employment schedule act at a university clinic--"surgical research during illegal time periods"]. / Realisierung des Arbeitszeitgesetzes an einer Universitätsklinik--"Chirurgische Forschung im illegalen Zeitraum".

The realisation of the new regulations for working time in hospitals by law (ArbZG) creates a new status for clinical research. The ArbZG clearly includes regulations for times spent on research and teaching. The strict regulations for resting periods, which have to be respected, allow research activities almost only in time spans other than official working time. The council of the European Union has excluded research activities from the guidelines for working time regulations, so there are no limitations on the time spent on research. In contrast, the German regulations for working time include time spent on research, so there is a national disadvantage for research in comparison to other European countries.

[Video-assisted thoracoscopy for effective palliation of malignant pleural effusion. Pleurodesis--pleuroperitoneal shunt]. / Die videoassistierte Thorakoskopie zur effektiven Palliation maligner Pleuraergüsse. Pleurodese--Pleuroperitonealer Shunt.

Dyspnea and reduced physical capability mean a significant reduction in quality of life of patients with advanced tumor disease. Video-assisted thoracoscopic talc poudrage or alternatively placement of pleuroperitoneal shunts were retrospectively evaluated as procedures for definitive palliation.