[Operability and Pathological Response of Non-Small Cell Lung Cancer (NSCLC) after Neoadjuvant Therapy with Immune Checkpoint Inhibition]. / Operabilität und pathologisches Ansprechen des Lungenkarzinoms nach neoadjuvanter Therapie mit Immun-Checkpoint-Inhibitoren.

BACKGROUND: The blockade of immune escape mechanisms (e. g. PD1 /PD-L1) using immune checkpoint inhibition (ICI) can significantly prolong survival and induce remission in patients with advanced non-small cell lung cancer (NSCLC). Less is known about neoadjuvant ICI in patients with resectable (UICC stage III) or oligometastatic (UICC stage IVa) NSCLC. METHODS: Tissue biopsies from patients with advanced or oligometastatic NSCLC were screened for PD-L1 expression. In case of PD-L1-expression > 50 %, ECOG status of 0 or 1 and expected operability, patients received ICI. After about four weeks, patients underwent thoracic surgical resection. In all patients, a complete staging, including PET-CT, cMRI, and endobronchial ultrasound, was performed. The tolerability, the radiological and the histopathological tumor response as well as the surgical and oncological outcomes were analyzed. FINDINGS: Four patients (2 male, 2 female, age 56 - 78 years, n = 3 adenocarcinoma, n = 1 squamous cell carcinoma) with local advanced tumors received ICI before surgical resection. In three cases the mediastinal lymph nodes were positive. One patient had a single cerebral metastasis which was treated with radiotherapy. All four patients underwent therapy with two to six cycles of ICI (3â€Š× pembrolizumab, 1â€Š× atezolizumab) without any complication, and ICI did not delay the time of surgical resection. According to iRECIST, three patients showed partial response (PR), one patient had stable disease (SD). All tumors were completely resected. The thoracic surgical procedures proved to be technically unproblematic despite inflammatory changes. There were neither treatment-related deaths nor perioperative complications. In the resectates, complete pathological response (CPR, regression grade III ) and regression grade IIb were detected twice. The average time of follow-up was 12 (1 - 24) months. Patients with PPR developed distant metastasis after six months or a local recurrence after four months. The CPR patient is relapse free to date. CONCLUSION: In selected patients, neoadjuvant therapy with ICI is well tolerated and can induce a complete remission of the tumor. Treatment with ICI has no negative impact on the surgical procedure. Prognosis seems to be promising in CPR and limited in PPR.

[Pneumothorax]. / Pneumothorax.

The presence of air between the visceral pleura and the parietal pleura with consecutive retraction of the lung from the chest wall is called pneumothorax. Regarding the genesis of the pneumothorax, a distinction is drawn between spontaneous and traumatic pneumothorax. The spontaneous pneumothorax is, depending on whether a congenital or an acquired pulmonary disease can be found, grouped into a primary spontaneous pneumothorax (PSP) without underlying lung disease and a secondary spontaneous pneumothorax (SSP) with the presence of a known lung disease. The traumatic pneumothorax is classified, depending on the cause, into penetrating and non-penetrating (blunt) traumatic events. A special form of the traumatic pneumothorax is the iatrogenic pneumothorax occurring as a result of diagnostic and/or therapeutic interventions. Clinically, a pneumothorax can range from an asymptomatic to an acute life-threatening situation. The required initial measures depend primarily on the patient's clinical condition. They vary from immediate insertion of a chest tube to wait and see with monitoring. The insertion of a chest tube is still the accepted therapeutic standard, but other procedures like aspiration of air through a needle or small catheter, particularly for small spontaneous pneumothoraces, represent alternative therapy options as well. The short-term goal is to treat possibly existing dyspnea and pain; in the long run a recurrence of the pneumothorax should be prevented. Until now, no uniform treatment algorithms or standardised therapy principles exist to achieve the therapeutic intentions of lung expansion and freedom from pain and late relapse.

[Biomedicine in thoracic surgery: state of the art]. / Biomedizin in der Thoraxchirurgie: eine Standortbestimmung.

Biomedicine represents a new scientific field at the interface of human, molecular and cell biology and medicine. Comprising the diverse disciplines of stem cell research, tissue engineering and material sciences, biomedicine gives rise to new approaches in research and therapy for - to date - unmet medical issues. Biomedical research is currently conducted in many medical, especially surgical subspecialties, and a number of successful developments have already been brought to clinical application. Concerning thoracic surgery, biomedical approaches are pursued primarily for tissue and organ replacement of the upper airways, lung and thoracic wall. In spite of a comparatively small research foundation, five different concepts have been clinically implemented worldwide, due to a lack of established treatment options in the case of extensive disease of the greater airways. In this review, the clinical background and the tissue-specific basics of tracheobronchial biomedicine are presented.

Canine scent detection in the diagnosis of lung cancer: revisiting a puzzling phenomenon.

Patient prognosis in lung cancer largely depends on early diagnosis. The exhaled breath of patients may represent the ideal specimen for future lung cancer screening. However, the clinical applicability of current diagnostic sensor technologies based on signal pattern analysis remains incalculable due to their inability to identify a clear target. To test the robustness of the presence of a so far unknown volatile organic compound in the breath of patients with lung cancer, sniffer dogs were applied. Exhalation samples of 220 volunteers (healthy individuals, confirmed lung cancer or chronic obstructive pulmonary disease (COPD)) were presented to sniffer dogs following a rigid scientific protocol. Patient history, drug administration and clinicopathological data were analysed to identify potential bias or confounders. Lung cancer was identified with an overall sensitivity of 71% and a specificity of 93%. Lung cancer detection was independent from COPD and the presence of tobacco smoke and food odours. Logistic regression identified two drugs as potential confounders. It must be assumed that a robust and specific volatile organic compound (or pattern) is present in the breath of patients with lung cancer. Additional research efforts are required to overcome the current technical limitations of electronic sensor technologies to engineer a clinically applicable screening tool.

[Case studies of iatrogenic tracheal injury during intraoperative ventral positioning. Symptoms, diagnostics, and differential therapy]. / Iatrogene Trachealverletzung bei intraoperativer Bauchlagerung. Fallbeispiele mit Klinik, Diagnostik und Differenzialtherapie.

Two patients 16 and 21 years old developed tracheal rupture during elective surgery following trouble-free orotracheal intubation and intraoperative ventral positioning. The injuries remained undetected in both patients for more than 12 h. Diagnostic investigation after the onset of first symptoms indicated in each a tear in the posterior tracheal wall. Early operation prevented the development of serious complications in both patients. The casuistics indicate that tracheal injuries can emerge in minor elective surgery that may be carried out on an outpatient basis, and ventral positioning for surgery may represent a risk factor for their occurrence. Clinical symptoms, diagnostic procedure, findings, and therapy are discussed.

Acellularized porcine heart valve scaffolds for heart valve tissue engineering and the risk of cross-species transmission of porcine endogenous retrovirus.

OBJECTIVE: Acellularized porcine heart valve scaffolds have been successfully used for heart valve tissue engineering, creating living functioning heart valve tissue. However, there is concern about the possibility of porcine endogenous retrovirus transmission. In this study we investigated whether acellularized porcine heart valve scaffold causes cross-species transmission of porcine endogenous retrovirus in a sheep model. METHODS: Acellularized porcine pulmonary valve conduits (n = 3) and in vitro autologous repopulated porcine pulmonary valve conduits (n = 5) were implanted into sheep in the pulmonary valve position. Surgery was carried out with cardiopulmonary bypass support. The animals were killed 6 months after the operation. Blood samples were collected regularly up to 6 months after the operation and tested for porcine endogenous retrovirus by means of polymerase chain reaction and reverse transcriptase-polymerase chain reaction. In addition, explanted tissue-engineered heart valves were tested for porcine endogenous retrovirus after 6 month in vivo. RESULTS: Porcine endogenous retrovirus DNA was detectable in acellularized porcine heart valve tissue. However, 6 months after implantation of in vitro and in vivo repopulated acellularized porcine heart valve scaffolds, no porcine endogenous retrovirus sequences were detectable in heart valve tissue and peripheral blood. CONCLUSION: Acellularized porcine matrix scaffolds used for creation of tissue-engineered heart valves do not transmit porcine endogenous retrovirus.

Minimally invasive removal of a dislocated stent from the right atrium after previous CABG.

Repeat sternotomy after previous open heart operations constitutes a serious risk factor for cardiac injury, particularly in the presence of a patent internal thoracic artery. We report a case of successful minimally invasive removal of a dislocated subclavian vein stent entangled in the tricuspid valve in a patient 5 years after coronary artery bypass surgery.

Acellular scaffold implantation--no alternative to tissue engineering.

OBJECTIVE: Degradation mechanisms of cardiovascular bioprostheses may play an important role in bioartificial implants. The fate of acellular implanted and cellular cardiovascular scaffolds was examined in an in vivo model. METHODS: Decellularized or native ovine carotid artery (CA, n=42) and aorta (AO, n=42) were implanted subcutaneously into rats for 2, 4 and 8 weeks. Immunohistochemical methods were used to monitor repopulation. Desmin-vimentin, CD31-, CD4- and CD18-antibodies for myocytes, endothelium, and inflammatory cell-infiltration, respectively. Calcification was detected by von-Kossa staining. Cell density was quantified by DNA-isolation. RESULTS: Acellular AO and CA matrices showed progressive calcification. Cellular AO and CA matrices trigger a strong inflammatory reaction which subsides after two weeks. CA scaffolds are revascularized progressively, whereas AO biocomposites degenerate. Calcification is less pronounced in cellular AO scaffolds and lacking in CA. CONCLUSION: Acellular bioartificial implants demonstrate degradation mechanisms similar to currently applied cardiovascular bioprostheses. Cellularized viable implants are promising clinical alternatives.

Generation of a bioartificial fibromuscular tissue with autoregenerative capacities for surgical reconstruction.

INTRODUCTION: Anecdotal clinical reports denote first tissue engineering applications entering medical practice. Currently it is still unknown, if these new types of implants will tolerate the specific needs in cancer patients undergoing postoperative chemo- and radiotherapy. METHODS: We implemented a radiotherapy protocol (cumulative dosis 40 Gy) on generated human bioartificial fibromuscular tissues in vitro. We monitored tissue vitality during radiotherapy and tissue recovery (8 weeks follow up period) applying histological methods. RESULTS: The biopsy procedure and seeding techniques yielded a viable 3 dimensional bioartificial human tissue. Radiation resulted in immediate devitalization without destroying tissue integrity. The bioartificial tissue recovered entirely in vitro within 6 weeks. CONCLUSION: Bioartificial human implants appear applicable for surgical reconstruction in oncologic patients potentially facing postoperative radiotherapy.

Density of dendritic cells in the human tracheal mucosa is age dependent and site specific.

BACKGROUND: The mucosal immune system undergoes extensive changes in early childhood in response to environmental stimuli. Dendritic cells (DC) play a major role in the development of the immune system. However, few data exist on the influence of continuous environmental stimulation on the distribution and phenotype of human airway DC. METHODS: Human tissue samples are mostly paraffin embedded which limits the use of several antibodies, and respiratory tissue for cryopreservation is difficult to obtain. Human frozen post mortem tracheal tissue was therefore used for this study. Only samples with epithelial adherence to the basement membrane were included (n = 34). Immunohistochemical staining and sequential overlay immunofluorescence were performed with DC-SIGN and a panel of leucocyte markers co-expressed by DC. RESULTS: DC detected in the human tracheal mucosa using DC-SIGN correlated with the expression of HLA-DR, co-stimulatory and adhesion molecules. Higher cell densities were found at the ventral tracheal site of patients older than 1 year than in infants in the first year of life. CONCLUSION: The increasing population of mucosal DC with age could reflect immunological maturation.

Endothelium-dependent vasodilatation in Sprague-Dawley rats with postinfarction hypertrophy: lack of endothelial dysfunction in vitro.

The hypothesis was tested whether postinfarction hypertrophy/congestive heart failure in rats is associated with endothelial dysfunction and increased vascular generation of reduced oxygen species. Myocardial infarction was induced in Sprague-Dawley rats by ligation of the left coronary artery. After 16 weeks, endothelium-dependent (with acetylcholine) and -independent (with sodium nitro-prusside) relaxations were studied in isolated aortic rings, and isolated rings from the femoral and mesenteric arteries. The generation of superoxide, hydrogenperoxide, and peroxynitrite was measured in arteries using lucigenin- and luminol-enhanced chemiluminescence techniques. Systolic blood pressure decreased over the 16 week study period as compared to shamoperated control rats; organ weights (lungs, right and left ventricles) significantly increased in coronary artery ligated rats indicating development of congestive heart failure. Surprisingly, concentration response curves with acetylcholine and sodium nitroprusside were almost identical in myocardial infarction rats as compared to control animals, irrespective of which type of vessel was studied (aorta, femoral or mesenteric arteries). In addition, no differences in the production of reduced radical species were found in aortic tissue from heart failure rats as compared to control rats.

Myocardial postischemic injury is reduced by polyADPripose polymerase-1 gene disruption.

BACKGROUND: PolyADPribose polymerase (PARP) is activated by DNA strand breaks to catalyze the addition of ADPribose groups to nuclear proteins, especially PARP-1. Excessive polyADPribosylation leads to cell death through depletion of NAD+ and ATP. MATERIALS AND METHODS: In vivo PARP activation in heart tissue slices was assayed through conversion of [33P]NAD+ into polyADPribose (PAR) following ischemia-reperfusion (I/R) and also monitored by immunohistochemical staining for PAR. Cardiac contractility, nitric oxide (NO), reactive oxygen species (ROS), NAD+ and ATP levels were examined in wild type (WT) and in PARP-1 gene-deleted (PARP-1(-/-)) isolated, perfused mouse hearts. Myocardial infarct size was assessed following coronary artery occlusion in rats treated with PARP inhibitors. RESULTS: Ischemia-reperfusion (I/R) augmented formation of nitric oxide, oxygen free radicals and PARP activity. I/R induced decreases in cardiac contractility and NAD+ levels were attenuated in PARP-1(-/-) mouse hearts. PARP inhibitors reduced myocardial infarct size in rats. Residual polyADPribosylation in PARP-1(-/-) hearts may reflect alternative forms of PARP. CONCLUSIONS: PolyADPribosylation from PARP-1 and other sources of enzymatic PAR synthesis is associated with cardiac damage following myocardial ischemia. PARP inhibitors may have therapeutic utility in myocardial disease.

Pancreatic metastasis of a pleuropulmonary blastoma in an adult.

Pleuropulmonary blastoma (PPB) is a rare dysontogenetic tumor that usually develops in the first decade of life and has been recognized as a distinct clinico-pathological entity different from the ordinary pulmonary blastoma of adulthood. Since the tumor grows aggressively and tends to metastasize early, physicians have to be aware of late onset of symptoms and uncommon manifestations. We report a case of PPB in a young adult and its recurrence in the pancreas after primary surgical treatment and adjuvant chemotherapy. Keeping in mind the moderate prognosis of PPB in children, accurate assessment and treatment of PPB require a team approach of oncology, radiology and surgery to establish new therapeutic guidelines in the future.