Karsten Wiebe

The long noncoding MALAT-1 RNA indicates a poor prognosis in non-small cell lung cancer and induces migration and tumor growth.

Introduction: The functions of large noncoding RNAs (ncRNAs) have remained elusive in many cases. Metastasis-Associated-in-Lung-Adenocarcinoma-Transcript-1 (MALAT-1) is an ncRNA that is highly expressed in several tumor types. Methods: Overexpression and RNA interference (RNAi) approaches were used for the analysis of the biological functions of MALAT-1 RNA. Tumor growth was studied in nude mice. For prognostic analysis, MALAT-1 RNA was detected on paraffin-embedded non-small cell lung cancer (NSCLC) tissue probes (n = 352) using in situ hybridization. Results: MALAT-1 was highly expressed in several human NSCLC cell lines. MALAT-1 expression was regulated by an endogenous negative feedback loop. In A549 NSCLCs, RNAi-mediated suppression of MALAT-1 RNA suppressed migration and clonogenic growth. Forced expression of MALAT-1 in NIH 3T3 cells significantly increased migration. Upon injection into nude mice, NSCLC xenografts with decreased MALAT-1 expression were impaired in tumor formation and growth. In situ hybridization on paraffin-embedded lung cancer tissue probes revealed that high MALAT-1 RNA expression in squamous cell carcinoma of the lung was associated with a poor prognosis. On genetic level, MALAT-1 displays the strongest association with genes involved in cancer like cellular growth, movement, proliferation, signaling, and immune regulation. Conclusions: These data indicate that MALAT-1 expression levels are associated with patient survival and identify tumor-promoting functions of MALAT-1.

The Autoimmune Regulator AIRE in Thymoma Biology: Autoimmunity and Beyond

Thymomas are tumors of thymic epithelial cells. They associate more often than any other human tumors with various autoimmune diseases; myasthenia gravis is the commonest, occurring in 10–50% of thymoma patients, depending on the World Health Organization-defined histologic subtype. Most thymomas generate many polyclonal maturing T lymphocytes but in disorganized microenvironments Failure to induce self-tolerance may be a key factor leading to the export of potentially autoreactive CD4+ progeny, thus predisposing to autoimmune diseases. Normally, the master Autoimmune Regulator promotes expression of peripheral tissue-restricted antigens such as insulin by medullary thymic epithelial cells and induction of tolerance to them. The failure of ∼95% of thymomas to express autoimmune regulator is another feature potentially contributing to autoimmunity.

Thoracic surgical procedures supported by a pumpless interventional lung assist.

BACKGROUND For support of pulmonary function during complex thoracic surgical procedures, especially in respiratory compromised patients, a pumpless interventional lung assist (iLA) was applied. Feasibility and effectiveness for this novel indication were evaluated. METHODS Ten patients underwent thoracic surgery with respiratory support by iLA. Indication for iLA application was the need for intraoperative prolonged discontinuation of ventilation (tracheal surgery and lung resections after pneumonectomy [n = 6], and emergency procedures in patients with acute respiratory failure [n = 4]. The pumpless extracorporeal system was inserted percutaneously into the femoral blood vessels before surgery. Blood flow through the iLA, cardiac output, and gas exchange were monitored. RESULTS In all patients, the surgical procedure was successfully performed because of the support by the pumpless iLA. Mean blood flow across the iLA was 1.58 +/- 0.3 L/min (1.2 L/min to 2.2 L/min). Low-dose norepinephrine was required to maintain sufficient systemic blood pressure. There was a moderate improvement in oxygenation (49 mL/min transfer of O(2)) and a very efficient elimination of carbon dioxide (121 mL/min transfer of CO(2)). Thus, extended periods of apneic oxygenation were possible during surgery. The device was removed immediately after surgery in 6 patients. In 4 patients with severe respiratory insufficiency, the iLA was continued for a mean of 6.8 days to allow for protective postoperative ventilation. CONCLUSIONS The application of pumpless iLA was hemodynamically well tolerated, and allowed for safe procedures in respiratory compromised patients, avoiding the application and consequences of cardiopulmonary bypass or pump-driven extracorporeal membrane oxygenation.

Rapid response to systemic bevacizumab therapy in recurrent respiratory papillomatosis.

Recurrent respiratory papillomatosis (RRP) is a primary benign disease, which is characterized by papillomatous growth in the respiratory tract. Malignant transformation occurs in only 3–5% of cases, however, local growth of the benign papillomas is interpreted as clinically malignant in a markedly higher proportion of patients. Local surgical or endoscopic interventional debulking or excision is currently the commonly selected treatment method and antiviral therapy is a potential adjuvant approach. However, the long-term management of RRP patients, who commonly require multiple procedures over numerous years, is challenging and the overall therapeutic armamentarium remains unsatisfactory. The administration of systemic bevacizumab treatment in a series of five patients with long histories of RRP, who required repeated local interventions to control papilloma growth is evaluated. Treatment with the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab was administered at a dose of 5 mg/kg (n=1), 10 mg/kg (n=3) or 15 mg/kg (n=1) intravenously to the five RRP patients, who were clinically classified as exhibiting progressive disease. Endoscopic evaluations were performed prior to the first infusion of bevacizumab and intermittently at variable time points during the course of therapy. Histopathological analyses were performed using pre- and post-treatment papilloma biopsies, including immunohistochemical analyses of VEGF and phosphorylated VEGF receptor (VEGFR)-2 expression. The patients received between three and 16 courses of bevacizumab (median, six courses). The first course was initiated when progression following the previous intervention was observed. An immediate response to bevacizumab treatment was demonstrated in all five RRP patients. While the cumulative number of interventions in the five patients was 18 throughout the 12 months prior to the initiation of bevacizumab treatment, only one patient required interventional treatment due to a malignant transformation during the 12 months following treatment with bevacizumab (18 vs. 1 interventions, P=0.042). Histopathological analyses revealed regressive perivascular edema and normalization of the vascular structure, however, immunohistochemical analyses of the VEGF and phosphorylated VEGFR-2 expression did not demonstrate any changes following therapy. Due to the limited number of alternative treatments, VEGF-targeted therapies may represent a promising novel strategy in the treatment of RRP, which may have the potential to modify the current treatment standards, particularly in patients with poorly accessible papilloma lesions, however, this requires further investigation in clinical trials.

Mutations of the EPHB6 receptor tyrosine kinase induce a pro-metastatic phenotype in non-small cell lung cancer

Alterations of Eph receptor tyrosine kinases are frequent events in human cancers. Genetic variations of EPHB6 have been described but the functional outcome of these alterations is unknown. The current study was conducted to screen for the occurrence and to identify functional consequences of EPHB6 mutations in non-small cell lung cancer. Here, we sequenced the entire coding region of EPHB6 in 80 non-small cell lung cancer patients and 3 tumor cell lines. Three potentially relevant mutations were identified in primary patient samples of NSCLC patients (3.8%). Two point mutations led to instable proteins. An in frame deletion mutation (del915-917) showed enhanced migration and accelerated wound healing in vitro. Furthermore, the del915-917 mutation increased the metastatic capability of NSCLC cells in an in vivo mouse model. Our results suggest that EPHB6 mutations promote metastasis in a subset of patients with non-small cell lung cancer.

Pectus Excavatum and Cardiac Surgery: Simultaneous Correction Advocated

BACKGROUND Severe pectus excavatum may be present in combination with cardiac conditions requiring open-heart surgery. The best strategy for this situation has been debated controversially. PATIENTS AND METHODS In a retrospective study, we analyzed all our patients undergoing concurrent pectus excavatum correction and open-heart surgery. RESULTS Ten patients aged 9 to 70 years underwent a simultaneous combined surgical procedure between 2001 and 2013. Indications for cardiac surgery were various forms of congenital and acquired heart disease including coronary artery disease with internal thoracic artery grafts and ascending aortic aneurysms. A modified Ravitch procedure was performed for pectus excavatum correction (mean Haller-Index 5.0). Mean operating time was 364 (210-495) minutes and mean duration of cardiopulmonary bypass was 125 (54-222) minutes. All procedures were completed successfully. Postoperatively minor complications were observed in three patients. In-hospital and 30-day mortalities were nil. Good cosmetic and functional results were achieved in all patients. CONCLUSIONS Our data demonstrate that simultaneous pectus excavatum correction and cardiac surgery is effective and reliable. A combined approach is advocated if candidates for cardiac surgery present with significant pectus excavatum deformity.

Thoracic Wall Reconstruction with Acellular Porcine Dermal Collagen Matrix

BACKGROUND  Major thoracic wall resections require the implantation of foreign materials for reconstruction and stabilization. Recently, biological collagen matrixes have emerged as an alternative to the routinely used synthetic materials. MATERIALS AND METHODS  Retrospectively, we analyzed our initial experience of chest wall reconstruction on large defects using a cross-linked porcine dermal acellular collagen matrix mesh with a thickness of 1.5 mm. RESULTS  Six sarcoma patients with a mean age of 46 (22-66) years underwent chest wall resections. Complete thoracic wall defects (mean area 149 cm2) ranged from 8 × 10 to 15 × 20 cm in size. In the majority of cases, only mobilized subcutaneous tissue and skin were used for soft-tissue coverage of the implanted porcine collagen matrix patches. Implantation and postoperative courses were uneventful in all patients. No local infections or wound healing problems occurred. The collagen material resulted in durable and good to excellent chest wall stability in clinical follow-ups, and on computed tomography scans spanning over 3.5 years. Histological examination showed integration, neovascularization, and long-term persistence of the collagen matrix on late reoperation of one patient. CONCLUSION  Acellular porcine dermal collagen matrix is a feasible and reliable biological patch material for reconstruction of the thoracic wall. Excellent wound healing and long-term stability are achieved even in large defects or complete sternal replacements.

Persisting pleural effusion-intrauterine intervention and post partum surgical resection of a lung sequestration

Complications by lung sequestration may include massive pleural effusions that become evident during pregnancy and require immediate therapy. We report the case of a pregnant 34-year-old female, who was admitted in her 30th week of pregnancy for severe left-sided hydrothorax of the fetus. A lung sequestration was suspected by ultrasound. A double pigtail pleuro-amniotic shunt was implanted. The further course of the pregnancy was uneventful. The fetus was born spontaneously in the 38th week. Ultrasound and computed chest tomography of the newborn confirmed a sequestration of the left lower lobe. Massive left-sided effusion caused complete atelectasis of the left lung and a marked rightward mediastinal shift. The pleuro-amniotic shunt was dislocated into the left hemi-thorax and had to be removed surgically. A new pigtail catheter was inserted. However, progressive pleural effusions with respiratory insufficiency were observed. Therefore, surgical resection of the lung sequestration was required on the 20th postpartum day. Intraoperatively, a single large artery directly from the distal thoracic aorta provided vascular supply for the large and lobulated sequester, which was adjacent to a left lower lobe. Histologic evaluation revealed loss of draining lymphatic vessels in the sequestration. Following an uneventful postoperative course the neonate was discharged on the 10th postoperative day. This case demonstrates that severe, pleural effusion may be present as a sequela of pulmonalry sequestration. Early intervention, interdisciplinary management and surgical resection allowed for a safe correction of this rare but potentially life-threatening malformation.

Die chirurgische Therapie des Lungenkarzinoms – Konsensusfähige Empfehlungen anhand der aktuellen Leitlinien

Die chirurgische Therapie des nicht kleinzelligen Lungenkarzinoms (NSCLC) ist streng stadienorientiert. Eine exakte, gegebenenfalls auch invasive, Diagnostik ist Voraussetzung fur die richtige Behandlung. Fur die fruhen Stadien der Erkrankung (Stadium I, II und IIIA (T3, N1)) ist die chirurgische Resektion in kurativer Intention die Behandlung der Wahl. Im Rahmen von multimodalen Konzepten konnen aber auch gut selektionierte Patienten in fortgeschrittenen Stadien von einer chirurgischen Therapie profitieren. Kontrovers diskutiert wird die Rolle der Chirurgie dagegen bei lokal fortgeschrittenem oder metastasiertem NSCLC. Die chirurgische Therapie erfordert die Lobektomie mit einer systematischen Lymphadenektomie. Als Alternative zur Thorakotomie hat sich fur das Stadium I die thorakoskopische Lobektomie (VATS-Lobektomie) etabliert. Auch im fortgeschrittenen Alter oder bei stark eingeschrankter Lungenfunktion kann eine chirurgische Resektion eine praktikable und sichere Behandlungsoption sein, die mit einer annehmbaren Lebensqualitat einhergeht. Beim kleinzelligen Lungenkarzinom (SCLC) ist die Operation nur in wenigen Fallen gerechtfertigt.