Proteomic analysis identifies argininosuccinate synthetase 1 and special AT-rich sequence binding protein 1 as reliable markers for the immunohistochemical distinction between WHO types A and B3 thymomas.

AIMS: The reliable classification of type A versus type B3 thymomas has prognostic and therapeutic relevance, but can be problematic due to considerably overlapping morphology. No immunohistochemical markers aiding in this distinction have been published so far. METHODS AND RESULTS: We identified and quantified numerous differentially expressed proteins using an unbiased proteomic screen by mass spectrometry in pooled protein lysates from three type A and three type B3 thymomas. From these, candidates were validated in a larger series of paraffin-embedded type A and B3 thymomas. We identified argininosuccinate synthetase 1 (ASS1) and special AT-rich sequence binding protein 1 (SATB1) as highly discriminatory between 34 type A and 20 type B3 thymomas (94% sensitivity, 98% specificity and 96% accuracy). Although not the focus of this study, the same markers also proved helpful in the diagnosis of type AB (n = 14), B1 (n = 4) and B2 thymomas (n = 10). CONCLUSIONS: Mutually exclusive epithelial expression of ASS1 in 100% of type B3 thymomas and ectopic nuclear expression of SATB1 in 92% of type A thymomas support the distinction between type A and type B3 thymomas with 94% sensitivity, 98% specificity and 96% accuracy.

[Sustainable Handling of OR Waste - a Difficult Issue with Great Potential]. / Nachhaltiger Umgang mit Abfällen im OP ­ ein schwieriges Thema mit großem Potential.

Surgical interventions often result in large amounts of waste. Contaminated waste must not be separated in recyclable fractions but must directly be burned for thermal recycling. Clinical waste is classified according to the potential dangers in accordance with the European Waste List (EWL). Unfortunately the waste number does not contain information about recyclable material. Only about 5% of clinical waste is hazardous waste resulting from contact with notifiable diseases in accordance with the definition of § 6, German Law on Infection Protection. This waste must be burned or be further sterilised. By using separate collection of packaging material without contamination with body secretions, up to 50% of waste from operating rooms can be disposed of via the German "Dual System" free of charge. Nearly 30% of packaging waste will undergo material recycling. The recycling of contaminated high-class single use surgical instruments (SUSI) is not allowed unless they pass through a disinfection procedure that is certified by the responsible authorities. Two examples will be presented. Other separated waste fractions (for example paper, pasteboard, cardboard packaging or light packaging like PET etc.) can be sold directly to specialised recycling companies. Conclusion: Responsible handling of clinical waste from operating theatres preserves our environment, can save money and motivates staff members who care for the future of our planet earth. When sustainable waste management is introduced, all staff members must be introduced from the start. Doctors must function as role models.

Functional apoptosis profiling identifies MCL-1 and BCL-xL as prognostic markers and therapeutic targets in advanced thymomas and thymic carcinomas.

BACKGROUND: Multi-omics studies have shown a high and lack of common driver mutations in most thymomas (TH) and thymic carcinomas (TC) that hamper the development of novel treatment approaches. However, deregulation of apoptosis has been proposed as a common hallmark of TH and TC. BH3 profiling can be utilized to study the readiness of living cancer cells to undergo apoptosis and their dependency on pro-survival BCL-2 family proteins. METHODS: We screened a cohort of 62 TH and TC patient samples for expression of BCL-2 family proteins and used the TC cell line 1889c and native TH for dynamic BH3 profiling and treatment with BH3 mimetics. RESULTS: Immunohistochemical overexpression of MCL-1 and BCL-xL was a strong prognostic marker of TH and TC, and BH3 profiling indicated a strong dependency on MCL-1 and BCL-xL in TH. Single inhibition of MCL-1 resulted in increased binding of BIM to BCL-xL as an escape mechanism that the combined inhibition of both factors could overcome. Indeed, the inhibition of MCL-1 and BCL-xL in combination induced apoptosis in a caspase-dependent manner in untreated and MCL-1-resistant 1889c cells. CONCLUSION: TH and TC are exquisitely dependent on the pro-survival factors MCL-1 and BCL-xL, making them ideal candidates for co-inhibition by BH3 mimetics. Since TH show a heterogeneous dependency on BCL-2 family proteins, upfront BH3 profiling could select patients and tailor the optimal therapy with the least possible toxicity.

Joint Statement of the German Respiratory Society and German Society of Thoracic Surgery in Cooperation with the German Radiological Society: Structural Prerequisites of Centres for Interventional Treatment of Emphysema.

Interventional treatment of emphysema offers a wide range of surgical and endoscopic options for patients with advanced disease. Multidisciplinary collaboration of pulmonology, thoracic surgery, and imaging disciplines in patient selection, therapy, and follow-up ensures treatment quality. The present joint statement describes the required structural and quality prerequisites of treatment centres. This is a translation of the German article "Positionspapier der Deutschen Gesellschaft für Pneumologie und Beatmungsmedizin und der Deutschen Gesellschaft für Thoraxchirurgie in Kooperation mit der Deutschen Röntgengesellschaft: Strukturvoraussetzungen von Zentren für die interventionelle Emphysemtherapie" Pneumologie. 2020;74:17-23.

Independent Predictors for Higher Postoperative Pain Intensity During Recovery After Open Thoracic Surgery: A Retrospective Analysis in 621 Patients.

Objective: To evaluate two standard procedure-specific pain regimens and to assess independent predictors for higher pain intensity after thoracic surgery. Methods: Patients received either oral opioid analgesia (Opioid Group) or epidural analgesia and were then bridged to systemic opioid analgesia (EDA + O Group) in this retrospective observational study. Medical history, discharge letters, anesthetic protocols, and pain protocols were evaluated in 621 patients after open thoracotomy and assessed with a stepward back elimination in a multivariate logistic regression model. Results: Data of 621 thoracotomies in 2014 were analyzed, 309 patients in the Opioid Group and 312 patients in the EDA + O Group. Pain scores at rest and on coughing were significantly lower in the EDA + O Group on postoperative days (PODs) 1-4 (P < 0.001). Stepwise backward elimination in multivariate logistic regression identified preexisting pain disease (P = 0.034), no epidural analgesia (P < 0.001), opioids in preoperative pain therapy (P < 0.001), and antidepressant medication (P = 0.003) as independent risk factors for higher pain intensity at rest on PODs 1-4. Same on PODs 5-8 with regard to opioids in preoperative pain therapy (P < 0.001) and antidepressant medication (P = 0.018). Moreover, on PODs 5-8, male gender had a lower risk (P < 0.003) for pain, and preexisting musculosceletal disease had a lower risk for more postoperative pain (P = 0.009). On coughing, male gender and younger age proved to have a lower risk for postoperative pain on PODs 1-8 and on PODs 1-4, respectively. Opioids in preexisting pain therapy and antidepressant medication were identified as risk factors for pain on PODs 1-8 on coughing, and pain disease was identified as a risk factor for more pain on PODs 1-4 (P = 0.041). Moreover, preexisting cardiac disease indicated more pain on PODs 1-4 (P = 0.05), and musculoskeletal disease and neurological disease indicated more pain on PODs 5-8 (P = 0.041, and P = 0.023). Conclusions: We present data on independent risk factors for higher pain intensity during recovery after thoracotomy. The lack of postoperative epidural analgesia, female gender, preexisting opioid pain therapy, and chronic pain are the strongest risk factors for higher pain intensity. Antidepressant medication was identified as an independent risk factor at rest and on coughing on all PODs. Study limitations: The study design is retrospective.

Same-day Routine Chest-X Ray After Thoracic Surgery is Not Necessary!

INTRODUCTION: Performing a routine postoperative chest X-ray (CXR) after general thoracic surgery is daily practice in many thoracic surgery departments. The quality, frequency of pathological findings and the clinical consequences have not been well evaluated. Furthermore, exposure to ionising radiation should be restricted to a minimum and therefore routine practice can be questioned. METHODS: As a hospital standard, each patient was given a routine CXR after opening of the pleura and inserting a chest tube. From October 2015 to March 2016, each postoperative patient with a routine CXR was included in a prospective database, including film quality, pathological findings, clinical and laboratory results and cardiorespiratory monitoring, as well as clinical consequences. RESULTS: 546 patients were included. Risk factors for postoperative complications were obesity in 50 patients (9.2%), emphysema in 127 patients (23.3%), coagulopathy in 34 patients (6.2%), longer operation time (more than two hours) in 242 patients (44.3%) and previous lung irradiation in 29 (5.3%) of patients. Major lung resections were performed in 191 patients (35.9%). 263 (48.2%) patients had procedures with minimally invasive access. The quality of the X-ray film was insufficient in 8.2% of patients. 90 (16.5%) of CXRs were found to show pathological findings, with a trend for more pathological findings after open surgery (55/283; 19.4%) compared to minimally invasive surgery (35/263; 13.3%) (p = 0.064). 11 (2.0%) patients needed a surgical or clinical intervention during postoperative observation; this corresponds to 12.2% of patients with a pathological finding on CXR. Nine of these 11 patients were clinically symptomatic and only two (0.37%) patients were asymptomatic with a relevant pneumothorax. CONCLUSIONS: Our study cannot support routine postoperative CXR after general thoracic procedures and we believe that restriction to clinically symptomatic cases should be a safe option.

Bronchoscopic Lung Volume Reduction with Endobronchial Valves in Low-FEV1 Patients.

BACKGROUND: Bronchoscopic lung volume reduction (BLVR) with valves has been shown to improve lung function, exercise capacity, and quality of life in patients with emphysema, but only few patients with forced expiratory volume in 1 s (FEV1) ≤20% predicted have been included in former studies. Although the procedure can be performed safely, pneumothorax is a frequent complication, which can be critical for these very severely diseased patients. OBJECTIVES: The aim of the study was to assess the safety of BLVR in patients with a very advanced stage of emphysema, as indicated by FEV1 ≤20% predicted. PATIENTS AND METHODS: Patients in whom BLVR was performed between January 2013 and August 2015 were included in this analysis if their baseline predicted FEV1 was ≤20%. BLVR, performed only if collateral ventilation was absent, achieved complete occlusion of the target lobe. All patients were closely monitored and were not discharged before the fourth day after BLVR. RESULTS: Twenty patients with FEV1 ≤20% predicted were included in the analysis. Lung volume reduction was achieved in 65% of the cases. Pneumothorax occurred in 4 cases (20%). No patient died. Lung function and exercise tolerance improved after 1 and 3 months, respectively. CONCLUSIONS: BLVR with valves can be safely performed in patients with FEV1 ≤20% predicted when close postprocedural monitoring is provided. Improvement in lung function and exercise capacity can be achieved.

Short- and Mid-Term Changes in Lung Function after Bilateral Pulmonary Metastasectomy.

INTRODUCTION: The resection of pulmonary metastases is associated with a loss of lung function. The amount of functional impairment after bilateral metastasectomy remains unclear. Because only around 35% of those patients may expect long-term survival, it is important to preserve enough pulmonary function for an adequate quality of life. This analysis of 31 bilaterally operated patients was performed to describe the amount of pulmonary function loss. METHODS: This is a post-hoc subanalysis and comparison of a population that was published before. All pulmonary metastasectomies were performed through an anteroaxillary thoracotomy in all patients. Resections were performed with staplers, electrocautery, or laser. All patients had pulmonary function tests (PFTs) preoperative and after 3 months at the follow-up visit, including spirometry, diffusing capacity of lung for carbon monoxide (Dlco) and blood gases. Of the 31 bilaterally operated cases, 15 had additional PFTs after each staged operation before discharge from hospital. RESULTS: Altogether, 271 nodules (median 7, mean 8.2) were removed from the 31 patients with a lobectomy in 2, a segmentectomy in 8, and multiple wedge resections in 21 patients, with this being the largest resection. The mean loss of pulmonary function at follow-up visit was forced vital capacity (FVC) - 15.2%, total lung capacity (TLC) - 13.8%, forced expiratory volume in 1 second (FEV1) - 16.3%, and Dlco - 10.3%, all of which were significant (p = < 0.001). The 15 patients with PFTs after each operation showed a stepwise decrease of volume parameters and Dlco with deepest values after the second surgery of around - -40% from preoperative values. At this time, Po 2 was also significantly reduced by 10 mm Hg (p = 0.01). Comparing the bilateral group with 86 patients after unilateral metastasectomy, we found significantly more nodules removed in the bilateral group (8.2 vs. 3.1; p < 0.001) and that the loss of volume parameters was twice that of the unilateral group after metastasectomy. Dlco impairment did not differ between the groups (- 10.3 vs. - 9.5%; p = 0.868) after 3 months. CONCLUSION: Midterm pulmonary function impairment after bilateral pulmonary metastasectomy is 15% of spirometry values and 10% of Dlco. Reduction of spirometry values is almost twice compared with the group after unilateral surgery. Early functional loss after the second intervention causes FVC, TLC, and FEV1 reduction of around 40% and is associated with lower Po 2 (- 10 mm Hg). Therefore, bilateral metastasectomy can be offered to patients who do not have greater pulmonary limitations.

Prognostic model for long-term survival of locally advanced non-small-cell lung cancer patients after neoadjuvant radiochemotherapy and resection integrating clinical and histopathologic factors.

BACKGROUND: Outcome of consecutive patients with locally advanced non-small cell lung cancer and histopathologically proven mediastional lymph node metastases treated with induction chemotherapy, neoadjuvant radiochemotherapy and thoracotomy at the West German Cancer Center between 08/2000 and 06/2012 was analysed. A clinico-pathological prognostic model for survival was built including partial or complete response according to computed tomography imaging (CT) as clinical parameters as well as pathologic complete remission (pCR) and mediastinal nodal clearance (MNC) as histopathologic factors. METHODS: Proportional hazard analysis (PHA) and recursive partitioning analysis (RPA) were used to identify prognostic factors for survival. Long-term survival was defined as survival ≥ 36 months. RESULTS: A total of 157 patients were treated, median follow-up was 97 months. Among these patients, pCR and MNC were observed in 41 and 85 patients, respectively. Overall survival was 56 ± 4% and 36 ± 4% at 24 and 60 months, respectively. Sensitivities of pCR and MNC to detect long-term survivors were 38% and 61%, specificities were 84% and 52%, respectively. Multivariable survival analysis revealed pCR, cN3 category, and gender, as prognostic factors at a level of α < 0.05. Considering only preoperative available parameters, CT response became significant. Classifying patients with a predicted hazard above the median as high risk group and the remaining as low risk patients yielded better separation of the survival curves by the inclusion of histopathologic factors than by preoperative factors alone (p < 0.0001, log rank test). Using RPA, pCR was identified as the top prognostic factor above clinical factors (p = 0.0006). No long term survivors were observed in patients with cT3-4 cN3 tumors without pCR. CONCLUSIONS: pCR is the dominant histopathologic response parameter and improves prognostic classifiers, based on clinical parameters. The validated prognostic model can be used to estimate individual prognosis and forms a basis for patient selection for treatment intensification.

Surgery of primary lung cancer with oligometastatic m1b synchronous single brain metastasis: analysis of 37 cases.

BACKGROUND: At the time of diagnosis, lung cancer has often metastasized already. Brain metastases, however, are associated with a poor prognosis (median survival of less than 1 year). We evaluated the changes of the median survival after resection of the cerebral metastases and primary non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Between January 1999 and December 2009, 37 patients (22 men, 15 women; median age: 55.64 years; age range: 38-72 years) underwent surgery for primary NSCLC after craniotomy and removal of the synchronous single brain metastasis. The overall survival was evaluated and risk factors identified. RESULTS: Mediastinal lymph node involvement was excluded with mediastinoscopy in 26 of the 37 patients. Postoperative N-stage was N0, N1, and N2 in 16 (43%), 10 (27%), and 11 (30%) patients, respectively. Histology was squamous cell carcinoma in 10 (27%), adenocarcinoma in 20 (54%), and large cell carcinoma in 7 (19%). The employed type of resection was anatomical segmentectomy in 6 and lobectomy in 31 patients. The 30-day mortality was 0% and postoperative complications occurred in 12 patients only (32%). The overall 1 and 2 years survival were 62 and 24%, respectively. None of the factors age, sex, tumor histology, primary location of the tumor, type of resection, adjuvant chemotherapy, or nodal status affected survival in the univariate analysis. CONCLUSIONS: The oncologic lung resection of NSCLC after the resection of a single brain metastasis can be implemented without an increased risk of complications or mortality. Despite the stage IV disease, the median survival appears encouraging.

Evaluation of a novel endobronchial ultrasound-guided lymph node forceps in enlarged mediastinal lymph nodes.

BACKGROUND: Endobronchial ultrasound-transbronchial nee dle aspiration (EBUS-TBNA) is a useful technique for cytological assessment of enlarged mediastinal lymph nodes with a high diagnostic yield for lung cancer. However, the small sample volume can be problematic in diagnosing benign diseases and for molecular analysis of malignant tumours. OBJECTIVES: The aim of the study was to evaluate a novel lymph node forceps for EBUS-guided lymph node biopsy (EBUS-transbronchial forceps biopsy; EBUS-TBFB) in malignant and benign conditions concerning safety, feasibility, and diagnostic yield. METHODS: Patients with enlarged mediastinal or hilar lymph nodes were included. EBUS-TBNA was performed followed by EBUS-guided TBFB with the lymph node forceps. Three biopsy specimens were obtained. The diagnostic yields of EBUS-TBFB, EBUS-TBNA, and the combination of both sampling techniques were compared. Complications were systematically recorded. RESULTS: Fifty-five patients with enlarged mediastinal nodes were enrolled into this study. Specimens adequate for histological analysis were obtained in all but one case using EBUS-TBFB. EBUS-TBFB increased the diagnostic yield of EBUS-TBNA from 64 to 93% in benign conditions. The overall diagnostic yield was higher compared to EBUS-TBNA alone. EGFR mutation analysis could be achieved in the forceps biopsy samples as needed. No complications were observed. CONCLUSIONS: EBUS-TBFB with a novel lymph node forceps is safe and provides adequate histological specimens of enlarged mediastinal lymph nodes. EBUS-TBFB increases the diagnostic yield in benign conditions and may add value in molecular analysis of non-small cell lung cancer.

A unique case of thoracic endometriosis syndrome and pulmonary Langerhans' cell histiocytosis: Six recurrent pneumothoraces.

Spontaneous pneumothorax (SP) in women of reproductive age with causes such as thoracic endometriosis syndrome (TES) presents a diagnostic and therapeutic challenge. A 33-year-old women was treated conservatively with chest tube insertion for a first occurrence of a right-sided pneumothorax in September 2015. In January 2016, a right-sided video-assisted thoracoscopic surgery (VATS) wedge resection and partial parietal pleurectomy was performed due to a recurrence. A right-sided VATS was again performed in December 2016 with multiple wedge resections and a total pleurectomy revealing a pulmonary Langerhans' cell histiocytosis (PLCH) in the histological and immunohistochemical examinations. The patient was recommended an abstinence of smoking and further course was unremarkable until May 2019, when due to a recurrent pneumothorax, she received a talc pleurodesis via right-sided VATS. Due to yet another recurrence, she underwent a talc slurry pleurodesis over a right sided chest drain. In March 2020 due to recurrence, a right-sided VATS was performed and a blueish nodular lesion was resected from the diaphragm. The histological examination revealed an endometriosis with a diagnosis of TES. Since the patient did not exhibit a temporal relationship between her periods and the onset of pneumothorax symptoms, a final diagnosis of non-catamenial endometriosis-related pneumothorax was made. The patient is currently continuing smoking abstinence and is under hormone therapy. She has not presented with a recurrence. In clinical practice, it is important not to just relay on the information available to us, but to reevaluate the patient history to uncover new clues leading to a new diagnosis.

Phosphoproteomic Analysis Identifies TYRO3 as a Mediator of Sunitinib Resistance in Metastatic Thymomas.

BACKGROUND: After initially responding to empiric radio-chemotherapy, most advanced thymomas (TH) and thymic carcinomas (TC) become refractory and require second-line therapy. The multi-target receptor tyrosine kinase (RTK) inhibitor, sunitinib, is one of the few options, especially in patients with thymic carcinomas, and has resulted in partial remissions and prolonged overall survival. However, sunitinib shows variable activity in thymomas, and not all patients benefit equally. A better understanding of its mode of action and the definition of predictive biomarkers would help select patients who profit most. METHODS: Six cell lines were treated with sunitinib in vitro. Cell viability was measured by MTS assay and used to define in vitro responders and non-responders. A quantitative real-time assay simultaneously measuring the phosphorylation of 144 tyrosine kinase substrates was used to correlate cell viability with alterations of the phospho-kinome, calculate a sunitinib response index (SRI), and impute upstream tyrosine kinases. Sunitinib was added to protein lysates of 29 malignant TH and TC. Lysates were analyzed with the same phosphorylation assay. The SRI tentatively classified cases into potential clinical responders and non-responders. In addition, the activation patterns of 44 RTKs were studied by phospho-RTK arrays in 37 TH and TC. RESULTS: SRI application separated thymic epithelial tumors (TET) in potential sunitinib responders and resistant cases. Upstream kinase prediction identified multiple RTKs potentially involved in sunitinib response, many of which were subsequently shown to be differentially overexpressed in TH and TC. Among these, TYRO3/Dtk stood out since it was exclusively present in metastatic TH. The function of TYRO3 as a mediator of sunitinib resistance was experimentally validated in vitro. CONCLUSIONS: Using indirect and direct phosphoproteomic analyses to predict sunitinib response in malignant TET, we have shown that TH and TC express multiple important sunitinib target RTKs. Among these, TYRO3 was identified as a potent mediator of sunitinib resistance activity, specifically in metastatic TH. TYRO3 may thus be both a novel biomarker of sunitinib resistance and a potential therapeutic target in advanced thymomas and thymic carcinomas.

Lymphadenectomy in pulmonary metastasectomy.

Lymph node (LN) removal during pulmonary metastasectomy is a prerequisite to achieve complete resection or at least collect prognostic information, but is not yet generally accepted. On average, the rate of unexpected lymph node involvement (LNI) is less than 10% in sarcoma, 20% in colorectal cancer (CRC) and 30% in renal cell carcinoma (RCC) when radical LN dissection is performed. LNI is a negative prognostic factor and presence of preoperative mediastinal disease usually leads to exclusion of the patient from metastasis surgery. Nonetheless, some authors found excellent prognoses even with mediastinal LNI in colorectal and RCC metastases when radical LN dissection was performed (median survival of 37 and 36 months, respectively). Multiple metastases, central location of the lesion followed by anatomical resections are associated with a higher LNI rate. The real prognostic influence of systematic LN dissection remains unclear. Two positive effects were described after radical lymphadenectomy: a trend for improved survival in RCC patients and a reduction of mediastinal recurrences from 23% to 0% in CRC patients. Unfortunately, there is a great number of studies that do not demonstrate any positive effect of lymphadenectomy during pulmonary metastasectomy except a pseudo stage migration effect. Future studies should not only focus on survival, but also on local and LN recurrence.

A rare diagnostic challenge in a female patient with a rapid recurrent pleural effusion: Autopsy revealed cardiac angiosarcoma with bilateral pleural and pulmonary metastases. A case report.

INTRODUCTION: We present a very rare case with diffuse cardiac angiosarcoma. Because all symptoms are often non-specific, this diagnosis is difficult to establish. To our knowledge this is the first clinical description of this rare disease. PRESENTATION OF CASE: A 47-year-old female presented with bilateral pulmonary infiltrates and non-specific symptoms as fever, chest pain and dyspnoea on exertion. She was treated with antibiotics for suspected lung infection but deteriorated developing rapid recurrent pleural effusion. Her transthoracic- and transoesophageal-echocardiography as well as the thoracentesis and endobronchial ultrasound findings were normal. A minimally invasive pulmonary wedge resection, partial pleurectomy and pericardial fenestration was performed. The pathologic interpretation of these specimen was very difficult and a correct diagnosis could be made only by the second reference pathologist. While awaiting reference histology report she was administered high-flow oxygen therapy for hypoxia, antibiotics, catecholamines and corticosteroids. The patient deteriorated very rapidly and died in the ICU. DISCUSSION: As in earlier studies, misdiagnosis delayed the actual diagnosis, especially because there was no clinical suspicion for angiosarcoma. Pathologic evaluation may be difficult because different growth patterns may be present in the same tumour and pleural or lung specimen may show only very tiny tumour formations within a fibrosing tissue changes. CONCLUSION: This case report highlights the difficulties to establish a diagnosis of diffuse angiosarcoma in time. An early diagnosis, to initiate oncologic treatment, require a high level of clinical suspicion and a histological proof from pericardial or myocardial biopsy.

DNA methylation of PTGER4 in peripheral blood plasma helps to distinguish between lung cancer, benign pulmonary nodules and chronic obstructive pulmonary disease patients.

BACKGROUND/INTRODUCTION: In contrast to patients who present with advanced stage lung cancer and associated poor prognosis, patients with early-stage lung cancer may be candidates for curative treatments. The results of the NELSON lung cancer screening trial are expected to stimulate the development and implementation of a lung cancer screening strategy in most countries. Widespread use of chest computed tomography scans will also result in the detection of solitary pulmonary nodules. Because reliable biomarkers to distinguish between malignant and benign lesions are lacking, tissue-based histopathological diagnostics remain the gold standard. In this study, we aimed to establish a test to assess the predictive ability of DNA hypermethylation of SHOX2 and PTGER4 in plasma to discriminate between patients with 1.) lung cancer, 2.) benign lesions, and 3.) patients with chronic obstructive pulmonary disease (COPD). PATIENTS AND METHODS: We retrospectively analysed SHOX2 and PTGER4 methylation in 121 prospectively collected plasma samples of patients with lung cancer (group 1A), benign lesions (group 1B), and COPD without nodules (group 2). RESULTS: PTGER4 DNA hypermethylation was more frequently observed in patients with lung cancer than in controls (p = 0.0004). Results remained significant after correction for tumour volume, smoking status, age, and eligibility for the NELSON trial. CONCLUSIONS: Detection of methylated PTGER4 in plasma DNA may serve as a biomarker to support clinical decision-making in patients with pulmonary lesions at lung cancer screening in high-risk populations. Further exploration in prospective studies is warranted.

Management of tracheobronchial injuries.

Tracheobronchial injuries (TBI) are a heterogenous group of sometimes life-threatening traumas with different management approaches. Symptoms are mediastinal and subcutaneous emphysema, bloody secretions from the airway or haemoptysis in alert patients, and high air leakage along the cuff or increased ventilatory resistance may be signs for TBI in intubated patients. The necessity of immediate clinical evaluation, CT-scan and bronchoscopic evaluation are essential for prompt diagnosis and classification as well as experienced air way management and treatment, these patients are best managed from interdisciplinary teams including thoracic surgeons. While iatrogenic tracheal membrane laceration from intubation can be treated by lesion bridging with ventilation tube, stent application, open operative repair or endoluminal repair, intraoperative accidental cuts should be repaired by direct suture or with vital tissue coverage in case of local ischemia. The management of blunt or penetrating injury is sequential and needs immediate establishment and maintenance of a secure patent airway to provide adequate oxygenation. The next step is the treatment of life-threatening collateral injuries like major hemorrhage, cranial trauma or major organ damage arranged in the trauma team. The treatment of penetrating injuries to the airway need operative exploration in almost every case with minimal local dissection and debridement followed by direct repair. Muscle flap coverage is useful in case of combined esophageal injury. Damage of the tracheobronchial tree after blunt trauma must be repaired by direct suture or local tissue sparing resection and anastomosis. These lesions can be missed in the initial phase and may become prominent with scar tissue formation, stenosis and atelectasis in the later phases.

Correction of a postpneumonectomy syndrome with congenital pectus excavatum using Ravitch's procedure and silicone breast implants. Report of a case.

INTRODUCTION: Mediastinal repositioning and the use of allogenic implants to obliterate the postpneumonectomy space is the main principle of postpneumonectomy syndrome (PPS) correction. We present a rare case with a PPS in combination with a congenital pectus excavatum. As a pectus excavatus deformity reduces retrosternal space, simple repositioning of the heart is impossible unless combined with a sternum elevation. PRESENTATION OF CASE: Two years after left sided pneumonectomy a 30 year old female was admitted with progressive exertional dyspnea and stridor and not able to do her basic activities. Chest CT-scan and bronchoscopy revealed severe right main bronchus stenosis, compression of hilar vessels and the presence of a pectus excavatum deformity. A single stage operative correction was performed with sternum repositioning by a Ravitch's procedure, pericardial fixation to the right sternal edge and obliteration of the left thoracic cavity with two silicone breast implants. All complaints disappeared within 48 h. DISCUSSION: To the best of our knowledge, this is the first report about successful treatment of PPS aggravated by a preexisting pectus excavatum in an adult patient. The durability and migration of the silicone implants and the volume reduction of the pericardial sac during fixation to the sternum continues to remain a concern. CONCLUSION: Single stage correction of PPS and pectus deformity is feasible and seems to be the appropriate treatment for both pathologies.

Prognostic markers in resected large cell neuroendocrine carcinoma: a multicentre retrospective analysis.

BACKGROUND: Large cell neuroendocrine carcinomas (LCNEC) are rare pulmonary malignancies. Reported survival rates are heterogeneous and the optimal therapeutic strategy is still debated. The prognosis of LCNEC is generally inferior compared to other non-small lung cancers. In early stages, surgery is recommended but might not be sufficient alone. METHODS: We retrospectively analyzed all consecutive LCNEC patients operated at three institutions with curative intent between May 2005 and January 2017. Data retrieved from individual clinical databases were analyzed with the aim to identify prognostic parameters. RESULTS: A total of 251 patients with LCNEC underwent curative intent surgery during the observation period. The median age was 64 years, 156 patients (62.2%) were male and 88.4% were smokers. The pathologic AJCC stage was I in 136 patients, II in 77, III in 33, and IV in 5 patients. Median follow-up was 26 months. Lymphatic vessel invasion (P=0.031) was identified as significant prognostic factor by multivariable analysis. There was a trend towards decreased survival in patients with blood vessel invasion (P=0.067). Even in earlier tumor stages, adjuvant chemotherapy had a positive effect on survival. The overall 1-, 3- and 5-year survival rates were 79.2%, 48.6% and 38.8% respectively. CONCLUSIONS: Lymphatic invasion (L1) is an independent prognostic factor. Surgery in LCNEC is beneficial in early tumor stages and platinum-based adjuvant chemotherapy may help in achieving better long-term outcomes resulting in most obvious survival differences in stage Ib.

Difficult diagnosis and rare morphology of lymphangioleiomyomatosis with giant cysts.

We report on a 32-year-old woman with a second manifestation of a tension pneumothorax two weeks after drainage therapy. The chest CT-scan revealed multiple large bilateral pulmonary cysts. She underwent minimally invasive wedge resection and pleurectomy for treatment. The extensive histologic evaluation revealed the diagnosis of a lymphangioleiomyomatosis (LAM) with an uncommon pattern of lung cysts. Initial staining for HMB-45 was negative. Repeated evaluation of other sections and reference pathology examination detected minimal expression of HMB-45. This case illustrates that immunohistochemistry for HMB-45 may be negative, although LAM is present and repeated immunohistochemistry may be necessary to establish the correct diagnosis.