International Tailored Chemotherapy Adjuvant (ITACA) trial, a phase III multicenter randomized trial comparing adjuvant pharmacogenomic-driven chemotherapy versus standard adjuvant chemotherapy in completely resected stage II-IIIA non-small-cell lung cancer.

BACKGROUND: Several strategies have been investigated to improve the 4% survival advantage of adjuvant chemotherapy in early-stage non-small-cell lung cancer (NSCLC). In this investigator-initiated study we aimed to evaluate the predictive utility of the messenger RNA (mRNA) expression levels of excision repair cross complementation group 1 (ERCC1) and thymidylate synthase (TS) as assessed in resected tumor. PATIENTS AND METHODS: Seven hundred and seventy-three completely resected stage II-III NSCLC patients were enrolled and randomly assigned in each of the four genomic subgroups to investigator's choice of platinum-based chemotherapy (C, n = 389) or tailored chemotherapy (T, n = 384). All anticancer drugs were administered according to standard doses and schedules. Stratification factors included stage and smoking status. The primary endpoint of the study was overall survival (OS). RESULTS: Six hundred and ninety patients were included in the primary analysis. At a median follow-up of 45.9 months, 85 (24.6%) and 70 (20.3%) patients died in arms C and T, respectively. Five-year survival for patients in arms C and T was of 65.4% (95% CI (confidence interval): 58.5% to 71.4%) and 72.9% (95% CI: 66.5% to 78.3%), respectively. The estimated hazard ratio (HR) was 0.77 (95% CI: 0.56-1.06, P value: 0.109) for arm T versus arm C. HR for recurrence-free survival was 0.89 (95% CI: 0.69-1.14, P value: 0.341) for arm T versus arm C. Grade 3-5 toxicities were more frequently reported in arm C than in arm T. CONCLUSION: In completely resected stage II-III NSCLC tailoring adjuvant chemotherapy conferred a non-statistically significant trend for OS favoring the T arm. In terms of safety, the T arm was associated with better efficacy/toxicity ratio related to the different therapeutic choices in the experimental arm.

[Laryngo-Tracheal Resection as an Alternative to Permanent Tracheostomy]. / Die laryngotracheale Resektion als Alternative zum permanenten Tracheostoma.

INTRODUCTION: Cervical stenosis of the trachea caused by tracheotomy, tumor or without defined reason (idiopathic) can be treated by resection and anastomosis with good early and long-term results. Involvement of the ring cartilage makes the procedure technically demanding and increases the risk of morbidity. We describe our technique of laryngotracheal resection and reconstruction and compare the perioperative results with standard tracheal resection. PATIENTS AND METHODS: Between January 2005 and December 2015, we performed about 800 procedures on the trachea including 76 standard cervical tracheal resections and 35 laryngotracheal resection. Resections were carried out with direct anastomosis without intraoperative tracheotomy or intralaryngeal stenting. Patient records were retrospectively analysed for perioperative data. RESULTS: The main cause of stenosis or defect of the trachea and operation was preceding tracheotomy. Idiopathic stenosis, tumors and subglottic stenosis in Wegener disease were less common. There were no disturbances of healing of the anastomosis in any patient. Tracheotomy in the course of treatment for intralaryngeal swelling or recurrent nerve palsy was necessary in 3 (standard) and 2 (laryngotracheal) patients. Postoperative tracheostomy was closed in all patients within 3 months. Pulmonary complications and recurrent nerve palsy occurred in 5/4 and 2/2 of the patients without significant differences between the 2 groups. One patient died in each group from pulmonary complications. CONCLUSION: The laryngotracheal resection is a relevant part of cervical tracheal surgery. It can be performed without significantly higher morbidity and can restore lung function and quality of voice.

[Diagnosis and Treatment of Diaphragmatic Dysfunction]. / Diagnostik und Therapie der gestörten Zwerchfellfunktion.

There are many reasons for an impairment of the diaphragmatic function potentially affecting all components of the respiratory pump. Particularly, diagnosis and treatment of unilateral and bilateral phrenic nerve paralysis are challenging. Neuromuscular disorders, trauma, iatrogenic conditions, tumor compression, but also infectious and inflammatory conditions in addition to neuralgic amyotrophy and idiopathic phrenic nerve paralysis are reasons for phrenic nerve paralysis. Primarily, diagnostic procedures include the anamnesis, physical examination, blood gas analysis, lung function testing and the diagnosis of the underlying disease. In addition, specific respiratory muscle testing and respiratory imaging are available today. Current established treatment options include respiratory muscle training, long-term non-invasive ventilation and surgical diaphragm plication in selected patients.

[Review of the Literature for Interpretation of Endobronchial Wound Healing after Tracheobronchial Sleeve Resection]. / Literaturbasierte Empfehlung zur bronchoskopischen Interpretation einer Anastomose nach Manschettenresektion.

Sleeve resection comprises 3.1 % to 27.7 % of all anatomic lung resections performed in Germany. Anastomotic insufficiency is a feared complication that should be avoided. When anastomotic insufficiency does lead to secondary pneumonectomy, postoperative morbidity and mortality is high (30 % to 80 %). It is therefore very important to standardize the technique of sleeve resection as well as postoperative care. The time-point of postoperative follow-up and the interpretation of endobronchial healing have not yet been defined. In this paper anastomotic healing is described and interpreted with the help of a 5-step classification that allows bronchoscopic evaluation and classification of the anastomosis. The aim is to provide a standardized algorithm for postoperative care after sleeve resection. The basis of this classification and postoperative care measures derived from it are described and illustrated with the help of clinical examples.

[Unilateral agenesis of pulmonal artery in adults: a rare disease frequently undiagnosed]. / Unilaterale Agenesie der Pulmonalarterie bei Erwachsenen. Eine häufig nicht diagnostizierte seltene Erkrankung.

INTRODUCTION: Unilateral absence of a pulmonary artery (UAPA) in adults without any other cardiovascular anomalies is a very rare clinical entity. Usually UAPA in adults remains undetected because of the symptom-free clinical course. The most common symptoms are hemoptysis and recurrent pulmonary infections. PATIENTS AND THERAPY: During 2006 - 2014 four adult patients with UAPA were diagnosed and treated in our institution. Recurrent pulmonary infections in combination with existing bronchiectasis and hemoptysis led to hospital treatment for three of the patients. In two cases, because of persevering hemoptysis and pathologically enlarged systemic arteries (intercostal, bronchial, diaphragm), pneumonectomy was indicated. Preoperative embolization of the enlarged arteries reduced the systemic arterial perfusion of the lung and led to minimal intraoperative blood loss. DISCUSSION: UAPA in the adulthood can frequently lead to hypertrophic systemic arterial perfusion of the lung. This abnormal systemic perfusion in combination with the co-existing bronchiectasis and persevering hemoptysis can cause a life-threatening clinical scenario. A combined interdisciplinary treatment through pneumology, thoracic surgery and radiology is therefore indicated.

[Reduction of Tracheotomy Associated Tracheal Stenosis by Surgical Closure of the Tracheostomy]. / Reduktion Tracheostoma-assoziierter Trachealstenosen durch chirurgischen Stomaverschluss.

BACKGROUND: The most common long-term complication of tracheotomy is the benign stenosis of the trachea, which is described for up to 20% of the cases. Typically, the stenosis occurs after decannulation in the context of secondary wound healing. This study examined whether the closure of the tracheostomy by surgical procedure reduces stenosis. METHOD: With the help of our clinical database a retrospective analysis of 401 surgical tracheotomies was performed. Variables that were recorded were the indication for tracheotomy, the clinical course and complications occurred. RESULTS: 155 patients were successfully decannulated. In 92 of these patients the tracheostomy was closed by a surgical procedure, in 63 cases the closure occurred spontaneously by wound healing. After decannulation 3% (n=3) of the surgically closed and 22% (n=14) of the spontaneously closed tracheostomies developed a symptomatic tracheal stenosis (p<0.001). CONCLUSION: Secondary wound healing of the tracheostomy often leads to symptomatic tracheal stenosis. The incidence of symptomatic tracheal stenosis was significantly reduced applying closure of the tracheostomy by surgical procedure.

[Perioperative anticoagulant and antiplatelet treatment in general thoracic surgery]. / Perioperativer Umgang mit Antikoagulanzien und Thrombozytenaggregationshemmern in der Thoraxchirurgie.

The perioperative use of anticoagulants in general thoracic surgery can be considered to be a "two-edged sword": the goal to minimise the risk of a thromboembolic episode is contrary to the ongoing effort of the surgeon to minimise the risk of intra- and postoperative blood loss. Dispositional factors such as excessive tobacco use are common for thoracic surgery patients and often lead to cardiovascular comorbidity which necessitates the use of anticoagulants or antiplatelet drugs. For deep venous thrombosis prophylaxis and for the indication and use of vitamin K antagonists or antiplatelet drugs it is proven in the literature that the risk profile of the patient and his/her classification in the appropriate risk group are of major importance. Through the individual risk profile of the patient it is possible to plan the appropriate perioperative anticoagulant therapy which will safely assist the surgeon and his/her patient during the peri- and postoperative phase on the knife-edge between blood loss and eminent thromboembolism. Unfortunately there are not enough existing data and published literature for evidence-based guidelines referring to the correct perioperative management for the new oral anticoagulants. Management algorithms are being recommended according to the multiple aspects of anticoagulant-treatment.

[The small lung nodule: dealing with a frequent radiological finding]. / Der kleine Lungenrundherd: Umgang mit einem häufigen radiologischen Befund.

Small pulmonary nodules less than 10 mm in size are frequently found by multidetector CT in high-risk patients. The risk of malignancy is rather low. The individual cancer risk, the radiological appearance and the presence or absence of growth are guides towards the indication for invasive procedures. A risk adjusted algorithm should avoid unnecessary invasive procedures without missing a lung cancer.

[Bronchus insufficiency: prevention and therapy]. / Bronchusinsuffizienz: Prävention und Therapie.

In order to achieve respectable postoperative outcomes after lung resection it is essential to understand the mechanism of bronchus healing. The bronchus seal should be air-tight and consist of monofilament suture or staples. The bronchus suture should be covered with vital tissue (lung, mediastinum, muscle flap). A complication in the process of bronchus healing should be diagnosed as early as possible in order to stop the destructive effect of the infection as rapidly as possible.

[Influence of nosocomial infections on resection of tracheal stenosis after tracheotomy]. / Bedeutung nosokomialer Infektionen bei derResektion trachealer Stenosen nach Tracheotomie.

BACKGROUND: Complications located at the tracheostoma often occur in combination with nosocomial infections. We posed the question: how is the surgical result in tracheal resections influenced by bacterial contamination with multiresistant germs? PATIENTS AND METHODS: Between 2005 and 2009 we performed a primary end-to-end-resection of the trachea after tracheotomy in 30 patients. The demographic basic data, the diagnostic data on tracheal stenosis after decanullation and type of tracheotomy were documented. Preoperatively all patients underwent a flexible bronchoscopy with bronchial lavage. All patients received an antibiotic inhalation therapy postoperatively. RESULTS: 16 patients presented a status post-permanent tracheotomy (PT), in 14 cases after percutaneous dilatative tracheotomy (PDT). In 64 % of all cases the preoperative bronchial lavage was positive for bacterial contamination. The major pathogen was with 23 % a multiresistant Pseudomonas aeruginosa (MR). In three cases long-term-complications occurred, all of which were bacterially contaminated. CONCLUSION: After long-term intubation a bacterial contamination is very common and presents a negative predictor for the outcome of primary tracheal end-to-end resections. A prophylactic postoperative antibiotic therapy can improve the short- and long-term results.

[Interventional lung assist membrane ventilator. Successful use despite heparin-induced thrombocytopenia type II]. / "Interventional-lung-assist"-Membranventilator. Erfolgreiche Anwendung trotz heparininduzierter Thrombozytopenie II.

Pumpless extracorporeal carbon dioxide elimination using the interventional lung assist (iLA) membrane ventilator is a modern concept for the treatment of hypercapnia due to respiratory failure which cannot be sufficiently treated by conventional strategies. Heparin-induced thrombocytopenia type II (HIT II) is considered to be an absolute contraindication for placement of an iLA because of the system's heparin-coated diffusion membrane. The example demonstrates that iLA therapy can be continued despite occurrence of a HIT II in terms of an "off label use". In the case described, postoperative therapy using the iLA membrane ventilator was installed in a 69-year-old patient with severe ARDS after elective lung resection. Despite a confirmed HIT II detected in the course of iLA, this therapy was continued after changing systemic anticoagulation to argatroban. The platelet count increased again and the patient could be successfully weaned from the iLA membrane and finally transferred to a rehabilitation centre.

[Multimodality therapy for lung cancer]. / Multimodale Therapie des Lungenkarzinoms.

The primary treatment of lung cancer depends on tumor stage. In case of lung cancer in clinical stage I to IIb and T3N1 surgical treatment is recommended. The use of adjuvant chemotherapy is indicated in stage II and IIIa. In case of limited N2-disease trimodality therapy with chemo- or radiochemotherapy followed by surgery and eventual adjuvant radiotherapy leads to five year survival rate of about 20-40. Non resectable or extended mediastinal lymph node metastases are an indication for definite combined radiochemotherapy. Secondary resection may be evaluated in experienced centers. If the tumor has infiltrated the mediastinum or the upper sulcus (T3/4) or in case of solitary metastasis an individual trimodal treatment plan has to be elaborated. Also for small cell lung cancer surgery combined with chemotherapy can be applied in stage I and II, else and especially in stage III radiochemotherapy should be applied. Additional prophylactic cranial irradiation is used. The majority of lung cancer patients suffers from metastatic disease. The value of systemic chemotherapy is limited with significant, but small improvement in overall survival. Also treatment with the new molecularly targeted drugs does not result in a breakthrough in unselected patient cohorts. Recently, substantial progress could be achieved by personalized treatment approaches for patients harbouring special genetic alterations.

[Pulmonary nodules in underlying malignant diseases--not necessarily metastases of the primary tumour]. / Der pulmonale Rundherd bei maligner Grunderkrankung--nicht zwingend eine Metastase des Primärtumors.

BACKGROUND: In this study the histological examination of pulmonary nodules and a comparison of the number of pre-, intra- and post-operative lung metastases in patients with a previous history of malignant disease were assessed. PATIENTS AND METHODS: Between 1998 and 2003 we operated on 276 patients with suspected lung metastases. The histology of the primary tumour, the number of preoperatively diagnosed nodules, the number of lesions removed during surgery and the number of histologically confirmed metastases of 276 patients are presented. RESULTS: In 276 patients a resection was performed. 161 of the patients were men (58.1%). The median age was 62 years (range: 21-86 years). In 110 cases a left-sided thoracotomy was performed (39.8%), in another 110 cases a right-sided thoracotomy was performed and in 56 cases we performed a bilateral thoracotomy (20.4%). In 15.2% the histology of the resected nodules was benign. In 8.6% of the cases the histological examination showed a primary lung cancer in stage I, in 74.4% of the cases the histology confirmed a metastasis of the primary cancer. CONCLUSIONS: Solitary pulmonary nodules in patients with a previous history of malignant disease should always be resected for histological examination. Multiple pulmonary nodules should be histologically reappraised if there is any doubt about the entity.

Newcastle disease virus-infected intact autologous tumor cell vaccine for adjuvant active specific immunotherapy of resected colorectal carcinoma.

An active specific immunization (ASI) procedure with two types of autologous tumor cell vaccines (ATVs) is tested for adjuvant immunotherapy of resected colorectal carcinoma to provide preliminary information on local immunological skin responses, side effects, and 2-year survival rates. For vaccine preparation, the tumor-derived freshly isolated and cryopreserved cells were thawed, purified by Percoll density centrifugation, and depleted of tumor-infiltrating lymphocytes by immunomagnetic beads. After inactivation by 200 Gy, the cells of this ATV were either infected by Newcastle disease virus (NDV) or they were admixed with Bacillus Calmette Guérin (BCG) organisms. Vaccination was performed in the arm beginning 6-8 weeks after operation, three times at 2-week intervals. Of 57 patients that received ASI, 48 were treated by virus-infected ATV (ATV-NDV) and 9 were treated with the BCG-admixed vaccine (ATV/BCG). The mean value of delayed hypersensitivity skin reactions from ATV-NDV-treated patients was 18 mm for the first vaccination and 26 and 29 mm for the succeeding ones. Although the application of ATV-NDV was associated with only mild side effects, the ATV/BCG vaccine led to long-lasting ulcers and to more serious side effects. The 2-year survival rate obtained with ATV-NDV was 97.9%, whereas the survival rate with ATV/BCG was 66.7%. The mean survival of 661 patients from a historical control was 73.8%. These data suggest that the type and quality of the tumor vaccine for ASI treatment is important. The findings with ATV-NDV necessitate corroboration in a prospective, randomized controlled study.

[Completion pneumonectomy. Indications and results]. / Sekundäre Pneumonektomien. Indikationen und Langzeitergebnisse.

Completion pneumonectomy (CP) is widely known to be associated with high morbidity and lethality. However, in certain instances, it offers the only chance for cure. The results of the following CPs (N=86) were investigated: progressive or recurrent benign disease (N=6, group I), recurrence of a malignant tumor (N=41, group II), and complication after lung resection (N=39, group III). Right completion pneumonectomy was carried out in 48 cases and left completion pneumonectomy in 38. The overall 30-day lethality of CP was 20.2%, 0% in group I, 10% n group II, and 33.3% n group III. This lethality was significantly higher on the right side (29.8%) than on the left (7.7%; P=0.014). Differentiation between emergency and urgent indications resulted in 30-day lethalities of 54% and 23%, respectively. This difference is significant (P=0.002). The 30-day lethality for patients with anastomotic or stump insufficiency was 41% (P=0.002). Five-year survival was 26% in the group of patients with malignant disease and 32% in those with complications after lung resection. The results show: the lethality of CP remains high, especially after complications from operating in emergency conditions. However, considering the long-term survival, CP is certainly justified.

[Radiofrequency ablation of malignant lung tumours. Judicious approach?]. / Radiofrequenzablation maligner Lungentumore. Eine sinnvolle Methode?

BACKGROUND: Radiofrequency ablation (RFA) is a minimally invasive technique and well established in the treatment of malignant hepatic tumours. This method could also find application in patients with malignant lung tumours who, for functional reasons, have to be excluded from standard surgery. Until now, however, very little data have been available on the application of RFA in malignant pulmonary tumours. PATIENTS AND METHODS: From November 2001 to January 2004, eleven malignant lesions of the lung were treated with RFA. The indication for RFA resulted from an inadequate pulmonary reserve and additional severe risk factors. RESULTS: Eleven lesions were treated in ten patients with RFA. The malignancies were primary non-small cell bronchial carcinomas (n=9) as well as metastases of non-small cell carcinomas (n=2). Early complications of RFA were pneumothorax, hemorrhagic intrapleural effusion, bronchopleural fistula and pericarditis. Two weeks after RFA, pneumonia appeared as a late complication. No patient's death was related to the RFA procedure. After a mean follow-up of 8.5 months five patients died. Five patients are still alive, two of whom exhibit no tumour recurrence. CONCLUSION: RFA in patients with lung tumours is possible from a technical viewpoint. It is possibly a therapeutic alternative for patients with localized tumours that are inoperable. However, in this series, the morbidity of the procedure -- taking the degree of invasiveness into account -- is high, and the oncological results are unsatisfactory, possibly due to a small cohort of patients.

Immunotherapy of metastatic melanoma with interferon-alpha and interleukin-2: pattern of progression in responders and patients with stable disease with or without resection of residual lesions.

This evaluation was performed in melanoma patients after successful immunotherapy to describe the pattern of relapse. 63 patients received interferon (IFN)-alpha and high-dose interleukin (IL)-2, resulting in three complete responses (CR), 13 partial responses (PR), three mixed responses (MR) and 17 stable diseases (SD). Median duration of response was 7 months (range 3-28) without surgery. Most relapses occurred at pre-existing sites. Duration of CR was 14-37+ months. In 11 patients, residual tumour lesions were resected. Interestingly, histology revealed almost complete tumour regression in 6 patients, including 2 of 4 with SD. 5 of these 11 patients have relapsed so far, 6 patients are still free of disease with a median of 17 months (range 8-34). Following relapse, 4 of 6 patients responded to retreatment with the identical IFN alpha/IL-2 protocol. The authors conclude that initial disease progression is mostly at previous sites of disease. Resection of residual lesions may offer a chance for extended disease-free survival similar to patients with CR to immunotherapy. Retreatment of relapsing patients is favourable.

Completion pneumonectomy for lung metastases.

OBJECTIVE: Completion pneumonectomy (CP) for malignant disease is generally accepted but controversial for lung metastases. The data available show a high perioperative morbidity and mortality with a poor long-term prognosis. We analysed the postoperative outcome and long-term results of our patients undergoing CP. PATIENTS AND METHODS: Between January 1986 and May 2003, nine patients underwent completion pneumonectomy for lung metastases. This represents 10% (9/86) of all CPs performed and 1.7% (9/525) of all pneumonectomies. RESULTS: One to three metastasectomies in the form of wedge resection (16), segment resection (5) and lobectomies (3) were performed prior to CP. The mean time interval between the operation of the primary tumour and the first metastasectomy was 38 months, the first and second metastasectomy 12 months, the second and third metastasectomy 14 months, and the third metastasectomy and CP 25 months. Six patients had an extended completion pneumonectomy. Operative morbidity and mortality was 0%. One patient is still alive and recurrence-free 9 months after CP. Two patients have recurrent pulmonary contralateral metastases under chemotherapy and six patients died of metastatic disease. Actual survival is 33%, recurrence-free survival (RFS) is 11%. The 3-year survival is 34%. CONCLUSION: Since there was no morbidity and mortality in our series, CP for lung metastases seems to be justified but the long-term survival is limited by the occurrence of contralateral or extrapulmonary metastatic disease. Multiple resections of metastases have a positive influence on survival, but the last step of resection in the form of CP does not seem to improve long-term survival.

Video-assisted thoracoscopic resection of pulmonary lesions.

AIMS: To determine the role of video-assisted thoracoscopic resection in the diagnosis of benign or malignant peripheral pulmonary lesions. PATIENTS AND METHOD: In 157 patients, between 1996 and 2001, video-assisted thoracoscopy was used to remove a pulmonary lesion. Conversion rate, complications and histology are presented. RESULTS: In 21 patients, conversion to a thoracotomy was necessary, four times because the pulmonary lesion was malignant and seventeen times due to technical difficulties. In patients without any previous history of malignant disease (n=100), 80% of the lesions were benign. In patients with malignant pulmonary lesions (n=21), curative resection was possible, 3 through VATS and 4 through thoracotomy. Pulmonary lesions in patients with a previous history of malignant disease were malignant in 42 patients. Curative VATS resection of a solitary lesion was performed in 9 patients, in 10 patients thoracotomy was necessary to remove multiple lesions. CONCLUSIONS: With a pre-operative selection of the patients the rate of secondary thoracotomies due to bronchial carcinoma is low (4%). In patients with a previous history of malignant disease, 22% of the pulmonary lesions are benign. VATS is a safe diagnostic method, with little discomfort for the patient.