The value of intraoperative extracorporeal membrane oxygenation (ECMO) in lung transplantation remains controversial. In our department, ECMO has been used routinely for intraoperatively unstable ...patients for more than 15 years. Recently, we have extended its indication to a preemptive application in almost all cases. In addition, we prolong ECMO into the early postoperative period whenever graft function does not meet certain quality criteria or in patients with primary pulmonary hypertension. The objective of this study was to review the results of this strategy.
All standard bilateral lung transplantations performed between January 2010 and June 2016 were included in this single-center, retrospective analysis. Patients were divided into 3 groups: group I—no ECMO (n = 116), group II—intraoperative ECMO (n = 343), and group III—intraoperative and prolonged postoperative ECMO (n = 123). The impact of different ECMO strategies on primary graft function, short-term outcomes, and patient survival were analyzed.
The use of intraoperative ECMO was associated with improved 1-, 3-, and 5-year survival compared with non-ECMO patients (91% vs 82%, 85% vs 76%, and 80% vs 74%; log-rank P = .041). This effect was still evident after propensity score matching of both cohorts. Despite the high number of complex patients in group III, outcome was excellent with higher survival rates than in the non-ECMO group at all time points.
Intraoperative ECMO results in superior survival when compared with transplantation without any extracorporeal support. The concept of prophylactic postoperative ECMO prolongation is associated with excellent outcomes in recipients with pulmonary hypertension and in patients with questionable graft function at the end of implantation.
The value of induction therapy in lung transplantation is controversial. According to the ISHLT, only about 50% of patients transplanted within the last 10 years received induction therapy. We ...reviewed our institutional experience to investigate the impact of induction therapy on short- and long-term outcomes.
Between 2007 and 2015, 446 patients with a complete follow-up were included in this retrospective analysis. Analysis comprised long-term kidney function, infectious complications, incidence of rejection and overall survival.
A total of 231 patients received alemtuzumab, 50 patients antithymocyte globulin (ATG) and 165 patients did not receive induction therapy (NI). The alemtuzumab group revealed the lowest rate of chronic kidney insufficiency (NI: 52.2%; ATG: 60%; alemtuzumab: 36.6%; p = 0.001). Both, the NI group (p<0.001) and the ATG group (p = 0.010) showed a significant increase of serum creatinine during follow-up compared to alemtuzumab patients. Furthermore, alemtuzumab group experienced the lowest rate of infection in the first year after transplantation. Finally, improved survival, low rates of acute cellular rejection (ACR), lymphocytic bronchiolitis (LB) and chronic lung allograft dysfunction (CLAD) were found in patients treated either with alemtuzumab or ATG.
Alemtuzumab induction therapy followed by reduced maintenance immunosuppression is associated with a better kidney function compared to no induction and ATG. Survival rate as well as freedom from ACR and CLAD were comparable between alemtuzumab and ATG.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The major aim of this study was to investigate the role of DNA methylation (referred to as methylation) on miRNA silencing in non-small cell lung cancers (NSCLC).
We conducted microarray expression ...analyses of 856 miRNAs in NSCLC A549 cells before and after treatment with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (Aza-dC) and with a combination of Aza-dC and the histone deacetylase inhibitor trichostatin A. miRNA methylation was determined in 11 NSCLC cell lines and in primary tumors and corresponding nonmalignant lung tissue samples of 101 patients with stage I-III NSCLC.
By comparing microarray data of untreated and drug-treated A549 cells, we identified 33 miRNAs whose expression was upregulated after drug treatment and which are associated with a CpG island. Thirty (91%) of these miRNAs were found to be methylated in at least 1 of 11 NSCLC cell lines analyzed. Moreover, miR-9-3 and miR-193a were found to be tumor specifically methylated in patients with NSCLC. We observed a shorter disease-free survival of patients with miR-9-3 methylated lung squamous cell carcinoma (LSCC) than patients with miR-9-3 unmethylated LSCC by multivariate analysis HR = 3.8; 95% confidence interval (CI), 1.3-11.2, P = 0.017 and a shorter overall survival of patients with miR-9-3 methylated LSCC than patients with miR-9-3 unmethylated LSCC by univariate analysis (P = 0.013).
Overall, our results suggest that methylation is an important mechanism for inactivation of certain miRNAs in NSCLCs and that miR-9-3 methylation may serve as a prognostic parameter in patients with LSCC.
Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by excessive deposition of extracellular matrix (ECM).
We investigated the regulation of matrix metalloproteinases (MMPs) and ...their inhibitors (TIMPs) in lung fibrosis.
MMP and TIMP expression, collagenolytic activity and collagen content was assessed in IPF (n=16) versus donor (n=6) lung homogenates and accomplished by in-situ-zymography for gelatinolytic and collagenolytic activities, combined with MMP antigen detection. Role of MMP13 was assessed employing the bleomycin model of lung fibrosis in MMP-13(-/-) versus wild-type mice.
In IPF, MMPs-1, 2, 7, 9 and 13, but not MMP-8, were significantly upregulated, whereas none of the TIMPs (1-4) were significantly altered. Collagen content was slightly increased and collagenolytic activity was most prominent in the airways and co-localized with MMP-13. We observed an exaggerated early inflammatory response and an augmented lung fibrosis in bleomycin-challenged MMP-13(-/-) versus wild-type mice, with elevated lung collagen content 28d after bleomycin challenge in the MMP-13(-/-) mice.
Our data suggest that i) collagen deposition in IPF lungs is not primarily due to excessive TIMP production, but rather due to overwhelming ECM production in face of an overall increased, but spatially imbalanced collagenolytic activity, ii) preferential distribution of collagenolytic activity, largely MMP-13, in the airways offers an explanation for the development of honeycomb cysts and iii) despite an overall increase in inflammatory cell content the presence of MMP-13 seems to limit the overall extent of ECM deposition in lung fibrosis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background Anastomotic failure is a rare but severe complication after airway surgery. A sufficient blood supply is crucial for the healing of the anastomosis. Currently, judging the appearance of ...the mucosa by conventional bronchoscopy is the only available technique to monitor the anastomosis. Near-infrared imaging using indocyanine green (ICG) as an intravasal fluorescent can be used to directly assess tissue perfusion. For technical reasons, bronchoscopic ICG angiography to evaluate blood supply of airway anastomosis was unavailable in the past. We sought to investigate the technical feasibility of ICG perfusion using a newly developed bronchoscopy unit with an integrated near-infrared filter to monitor perfusion during the healing of tracheal anastomosis. Methods Twelve patients who underwent elective airway surgery were included in this prospective, single-center feasibility study. The ICG was administered intravenously at 0.2 mg/kg body weight at three timepoints: at the end of surgery; 3 to 5 days postoperatively; and 2 months postoperatively. A custom-made bronchoscopy unit (Karl Storz, Tuttlingen, Germany) was used to assess the anastomosis with white light and additionally with near-infrared light to monitor the distribution and intensity of the fluorescence signal. Results A total of 32 ICG fluorescence bronchoscopies were performed in our study cohort. In all measurements, a sufficient fluorescence signal was detected. A lack of perfusion was detected in all patients confined to the anastomotic suture line immediately after the operation. This malperfusion resolved gradually after 3 to 5 days and disappeared completely after 2 months. No anastomotic complication developed in our series of patients during follow-up (median 7 months). Conclusions To the best of our knowledge, this is the first report on ICG fluorescence bronchoscopy in the literature. It is an easy and effective method to evaluate the perfusion at the tracheal anastomosis. In the future, it might contribute to an early detection of anastomotic failure and reduce morbidity and mortality after airway surgery.
Background
Pulmonary metastasectomy is an integral part of the interdisciplinary treatment of patients with pulmonary metastases (PMs) from colorectal carcinoma (CRC). Although alterations in the ...epidermal growth factor receptor (EGFR) pathway are common in CRC, there is still insufficient data regarding PM. We hypothesized that EGFR expression and Kirsten rat sarcoma viral oncogene homolog (
KRAS
)/
BRAF
mutations (Mts) might be associated with clinicopathological variables and the outcome in patients undergoing pulmonary metastasectomy.
Methods
In this single-center study, 44 patients undergoing pulmonary metastasectomy from primary CRC were included and prospectively followed up. Tissue specimens of resected PMs were assessed. Restriction fragment length analysis was used for
BRAF V600E
and
KRAS
codons 12 and 13 Mt analyses. EGFR expression was evaluated by immunohistochemistry. Patients were followed up in 3–6-month intervals.
Results
EGFR expression was evident in 49 % of the PMs, whereas Mts in
KRAS
and
BRAF
were detected in 48 and 0 %, respectively. Time to lung-specific recurrence after metastasectomy was significantly decreased in patients with
KRAS
mutated PMs in univariate (
p
= 0.013) and multivariate analysis (
p
= 0.035), whereas EGFR expression had no impact on recurrence free survival. Moreover, KRAS Mts were associated with the number of PMs (
p
= 0.037) and with the lung as first site of recurrence after metastasectomy (
p
= 0.047).
Discussion
This is the first evaluation of EGFR pathway alterations in the setting of pulmonary metastasectomy. Our data suggest that patients with
KRAS
Mts are at high risk for early pulmonary recurrence and have a more diffuse pattern of metastasis. These findings may have impact on the therapeutic management of CRC patients with pulmonary spreading.
Summary
The aim of this study was to investigate whether there is an impact of donation rates on the quality of lungs used for transplantation and whether donor lung quality affects post‐transplant ...outcome in the current Lung Allocation Score era. All consecutive adult LTx performed in Eurotransplant (ET) between January 2012 and December 2016 were included (N = 3053). Donors used for LTx in countries with high donation rate were younger (42% vs. 33% ≤45 years, P < 0.0001), were less often smokers (35% vs. 46%, P < 0.0001), had more often clear chest X‐rays (82% vs. 72%, P < 0.0001), had better donor oxygenation ratios (20% vs. 26% with PaO2/FiO2 ≤ 300 mmHg, P < 0.0001), and had better lung donor score values (LDS; 28% vs. 17% with LDS = 6, P < 0.0001) compared with donors used for LTx in countries with low donation rate. Survival rates for the groups LDS = 6 and ≥7 at 5 years were 69.7% and 60.9% (P = 0.007). Lung donor quality significantly impacts on long‐term patient survival. Countries with a low donation rate are more oriented to using donor lungs with a lesser quality compared to countries with a high donation rate. Instead of further stretching donor eligibility criteria, the full potential of the donor pool should be realized.
Background The international experience with resection of advanced thoracic malignancies performed with extracorporeal membrane oxygenation (ECMO) support is limited. We examined our results to ...assess the risks and benefits of this approach. Methods We retrospectively analyzed all patients with thoracic malignancies who underwent tumor resection with ECMO support in our department between 2001 and 2010. Results Nine patients (aged 21 to 71 years; mean, 54.8 ± 7.5 years) underwent complex tracheobronchial resections (n = 6) or resections of greater thoracic vessels (n = 3) under venoarterial (VA) ECMO support. In 7 patients the underlying pathologic condition was non-small cell lung cancer, in 1 patient it was carcinoid tumor, and in 1 patient it was synovial sarcoma. The indication for extracorporeal support was complex tracheobronchial reconstruction (n = 5), resection of the descending aorta (n = 2), and resection of the inferior vena cava (n = 1). ECMO cannulation was central (n = 4), peripheral (n = 4), or combined (n = 1). Mean time on bypass was 110 ± 19 minutes (range 40 to 135 minutes). A complete resection (R0) was achieved in 8 patients (89%). One patient died perioperatively as a result of hepatic necrosis. Eight patients were discharged from the hospital after 7 to 42 days (median, 10 days). Median time in the intensive care unit was 1 day (range, 0 to 36 days). The only complication related to the use of ECMO was a lymphatic fistula in the groin. Mean follow-up time was 38 ± 42 months (range, 9 to 111 months). The actuarial 3-month survival was 88.9%, and the 1-year, 3-year, and 5-year survival was 76.7%. Conclusions Based on this experience, we consider VA ECMO support to be a safe alternative to cardiopulmonary bypass (CPB) for advanced general thoracic operations.
TSLC1 (tumor suppressor in lung cancer-1, IGSF4) encodes a member of the immunoglobulin superfamily molecules, which is involved in cell-cell adhesion. TSLC1 is connected to the actin cytoskeleton by ...DAL-1 (differentially expressed in adenocarcinoma of the lung-1, EPB41L3) and it directly associates with MPP3, one of the human homologues of a Drosophila tumor suppressor gene, Discs large. Recent data suggest that aberrant promoter methylation is important for TSLC1 inactivation in lung carcinomas. However, little is known about the other two genes in this cascade, DAL-1 and MPP3. Thus, we investigated the expression and methylation patterns of these genes in lung cancer cell lines, primary lung carcinomas and nonmalignant lung tissue samples. By reverse transcription-polymerase chain reaction, loss of TSLC1 expression was observed in seven of 16 (44%) non-small-cell lung cancer (NSCLC) cell lines and in one of 11 (9%) small-cell lung cancer (SCLC) cell lines, while loss of DAL-1 expression was seen in 14 of 16 (87%) NSCLC cell lines and in four of 11 (36%) SCLC cell lines. By contrast, MPP3 expression was found in all tumor cell lines analysed. Similar results were obtained by microarray analysis. TSLC1 methylation was seen in 13 of 39 (33%) NSCLC cell lines, in one of 11 (9%) SCLC cell lines and in 100 of 268 (37%) primary NSCLCs. DAL-1 methylation was observed in 17 of 39 (44%) NSCLC cell lines, in three of 11 (27%) SCLC cell lines and in 147 of 268 (55%) primary NSCLCs. In tumors of NSCLC patients with stage II-III disease, DAL-1 methylation was seen at a statistically significant higher frequency compared to tumors of patients with stage I disease. A significant correlation between loss of expression and methylation of the genes in lung cancer cell lines was found. Overall, 65% of primary NSCLCs had either TSLC1 or DAL-1 methylated. Methylation of one of these genes was detected in 59% of NSCLC cell lines; however, in SCLC cell lines, methylation was much less frequently observed. The majority of nonmalignant lung tissue samples was not TSLC1 or DAL-1 methylated. Re-expression of TSLC1 and DAL-1 was seen after treatment of lung cancer cell lines with 5-aza-2'-deoxycytidine. Our results suggest that methylation of TSLC1 and/or DAL-1, leading to loss of their expression, is an important event in the pathogenesis of NSCLC.
Lung transplantation is an established treatment for a variety of end-stage lung diseases; however, chest wall deformities such as an asymmetric pectus excavatum are often considered a ...contraindication for lung transplantation. Consequently, the published experience of lung transplants and simultaneous chest wall reconstruction is limited to a few case reports. This article aims to provide a detailed description of surgical steps as well as technical challenges and pitfalls of lung transplantation with a simultaneous modified Ravitch procedure. Exemplary technical aspects will be discussed for a pediatric patient in whom such a combined procedure resulted in an excellent outcome.
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