Bettina Wiegmann

Normothermic perfusion of donor lungs for preservation and assessment with the Organ Care System Lung before bilateral transplantation: a pilot study of 12 patients

BACKGROUND Cold flush and static cold storage is the standard preservation technique for donor lungs before transplantations. Several research groups have assessed normothermic perfusion of donor lungs but all devices investigated were non-portable. We report first-in-man experience of the portable Organ Care System (OCS) Lung device for concomitant preservation, assessment, and transport of donor lungs. METHODS Between Feb 18, and July 1, 2011, 12 patients were transplanted at two academic lung transplantation centres in Hanover, Germany and Madrid, Spain. Lungs were perfused with low-potassium dextran solution, explanted, immediately connected to the OCS Lung, perfused with Steens solution supplemented with two red-cell concentrates. We assessed donor and recipient characteristics and monitored extended criteria donor lung scores; primary graft dysfunction scores at 0, 24, 48, and 72 h; time on mechanical ventilation after surgery; length of stays in hospital and the intensive-care unit after surgery; blood gases; and survival of grafts and patients. FINDINGS Eight donors were female and four were male (mean age 44·5 years, range 14-72). Seven recipients were female and five were male (mean age 50·0 years, range 31-59). The preharvest donor ratio of partial pressure of oxyen (PaO(2)) to fractional concentration of oxygen in inspired air (F(I)O(2)) was 463·9 (SD 91·4). The final ratio of PaO(2) to F(I)O(2) measured with the OCS Lung was 471·58 (127·9). The difference between these ratios was not significant (p=0·72). All grafts and patients survived to 30 days; all recipients recovered and were discharged from hospital. INTERPRETATION Lungs can be safely preserved with the OCS Lung, resulting in complete organ use and successful transplantation in our series of high-risk recipients. In November, 2011, we began recruitment for a prospective, randomised, multicentre trial (INSPIRE) to compare preservation with OCS Lung with standard cold storage. FUNDING TransMedics and German Federal Ministry of Education and Research.

Ambient hemolysis and activation of coagulation is different between HeartMate II and HeartWare left ventricular assist devices

BACKGROUND Thromboembolic and bleeding events in patients with a left ventricular assist device (LVAD) are still a major cause of complications. Therefore, the balance between anti-coagulant and pro-coagulant factors needs to be tightly controlled. The principle hypothesis of this study is that different pump designs may have an effect on hemolysis and activation of the coagulation system. Referring to this, the HeartMate II (HMII; Thoratec Corp, Pleasanton, CA) and the HeartWare HVAD (HeartWare International Inc, Framingham, MA) were investigated. METHODS For 20 patients with LVAD support (n = 10 each), plasma coagulation, full blood count, and clinical chemistry parameters were measured. Platelet function was monitored using platelet aggregometry, platelet function analyzer-100 system ( Siemens, Marburg, Germany), vasodilator-stimulated phosphoprotein phosphorylation assay, immature platelet fraction, platelet-derived microparticles, and von Willebrand diagnostic. RESULTS Acquired von Willebrand syndrome could be detected in all patients. Signs of hemolysis, as measured by lactate dehydrogenase levels (mean, 470 U/liter HMII, 250 U/liter HVAD; p < 0.001), were more pronounced in the HMII patients. In contrast, D-dimer analysis indicated a significantly higher activation of the coagulation system in HVAD patients (mean, 0.94 mg/liter HMII, 2.01 mg/liter HVAD; p < 0.01). The efficacy of anti-platelet therapy using clopidogrel was not sufficient in more than 50% of the patients. CONCLUSIONS Our results support the finding that all patients with rotary blood pumps suffered from von Willebrand syndrome. In addition, a distinct footprint of effects on hemolysis and the coagulation system can be attributed to different devices. As a consequence, the individual status of the coagulation system needs to be controlled in long-term patients.

Biological materials in chest wall reconstruction: initial experience with the Peri-Guard Repair Patch.

OBJECTIVE This study analyses the efficacy of the bovine Peri-Guard Repair Patch for chest wall reconstruction. METHODS Nine consecutive patients (seven males, median age: 61 years) underwent chest wall repair due to either secondary incisional herniation development after lung transplantation (LTX, n=3 patients) or malignant disease with chest wall infiltration. In all cases, repair was performed with a Peri-Guard Repair Patch (Synovis, St. Paul, MN, USA). At follow-up (4+/-2 months), quality of life, signs of re-herniation and incorporation of mesh (radiograph, blood samples and ultrasound) were assessed. RESULTS In all patients, a successful chest wall repair could be achieved and no signs of re-herniation were found. Oncologic patients with a diagnosis of desmoid tumour, primary histiocytosis of ribs, sarcoma or lung cancers were accessed through posterolateral thoracotomy and received a resection of two to four ribs. Post-LTX repair was performed by anterior mini-thoracotomy without rib resection. At follow-up, 80% of the patients presented with totally regained quality of life, with no signs of local infection, altered white blood cell (WBC) counts or elevated C-reactive protein (CRP) levels. On chest X-ray, only one patient showed areas of patch calcification, while all others were unremarkable. Chest ultrasound imaging confirmed the absence of adhesions, haematoma or seroma. In all cases, normal expansion and respiratory movement of the underlying lung were observed. CONCLUSIONS To achieve satisfactory results after chest wall reconstruction, a material with high-tensile strength, preferably soft structure, availability, ease of use and high biocompatibility is required. Especially in immunosuppressed patients, the biological Peri-Guard Repair Patch might be superior to the use of an artificial material.

Dose-dependent surface endothelialization and biocompatibility of polyurethane noble metal nanocomposites.

Surface pre-endothelialization is a promising approach to improve the hemocompatibility of implants, medical devices, and artificial organs. To promote the adhesive property of thermoplastic polyurethane (TPU) for endothelial cells (ECs), up to 1 wt % of gold (Au) or platinum (Pt) nanoparticles, fabricated by pulsed laser ablation in polymer solution, were embedded into the polymer matrix. The analysis of these nanocomposites showed a homogenous dispersion of the nanoparticles, with average diameters of 7 nm for Au or 9 nm for Pt. A dose-dependent effect was found when ECs were seeded onto nanocomposites comprising different nanoparticle concentrations, resulting in a fivefold improvement of proliferation at 0.1 wt % nanoparticle load. This effect was associated with a nanoparticle concentration-dependent hydrophilicity and negative charge of the nanocomposite. In dynamic flow tests, nanocomposites containing 0.1 wt % Au or Pt nanoparticles allowed for the generation of a confluent and resistant EC layer. Real-time polymerase chain reaction quantification of specific markers for EC activation indicated that ECs cultivated on nanocomposites remain in an inactivated, nonthrombogenic and noninflammatory state; however, maintain the ability to trigger an inflammatory response upon stimulation. These findings were confirmed by a platelet and leukocyte adhesion assay. The results of this study suggest the possible applicability of TPU nanocomposites, containing 0.1 wt % Au or Pt nanoparticles, for the generation of pre-endothelialized surfaces of medical devices.

Survival and spirometry outcomes after lung transplantation from donors aged 70 years and older

BACKGROUND Mediocre donation rates and increasing demand for lung transplantation leads transplant centers to consider extended-criteria donor lungs. Arguably, the largest remaining non-utilized lung donor segment is the elderly individual, already considered for visceral organ donation but not thoracic. So far, transplantation of donor lungs aged ≥ 70 years is rarely reported, and recipient outcomes are unknown. Accordingly, we report a single-center series of lung transplantations from donors aged ≥ 70 years and compare outcomes with contemporary lung transplantations from younger donors. METHODS All bilateral lung transplantations performed at our center between March 2011 and July 2014 were analyzed, and 2 cohorts were built according to lung donor age. RESULTS A total of 440 bilateral lung transplantations were performed from 413 donors aged <70 years, and 27 donors aged ≥70 years. Donor characteristics did not differ in sex, donor time on mechanical ventilation before retrieval, or donor partial pressure of arterial oxygen/fraction of inspired oxygen ratio. Older donors were significantly less often positive for smoking history (43.7% vs 14.8%, p = 0.003) or for abnormal bronchoscopy results (52.9% vs 15.8%, p = 0.002). Recipients receiving donor lungs aged <70 years were younger than those receiving older donor lungs ≥ 70 (49.8 [range, 35-58] vs 58 [range, 53-62] years, p < 0.0001). Underlying diagnoses did not differ significantly between the groups. Post-operative mechanical ventilation times (15 [range, 10-59] vs 27.5 [range, 10-75.8] hours), intensive care unit stays (3 [range, 1-5] vs 3 [range, 1-8] days), and total hospital lengths of stay (24 [range, 22-40.5] vs 24 [range, 22-40] days) of the recipients did not differ significantly between the two groups. The percentage predicted forced expiratory volume in 1 second was 86.5% ± 26.2% 12 months after transplantation of younger lungs vs 72.2% ± 23.8% (p = 0.01) after transplantation of older lungs. Differentiating the spirometry findings according to underlying diseases showed significantly lower forced expiratory volume in 1 second values after transplantation of donor lungs aged ≥70 only in idiopathic pulmonary fibrosis recipients but not in emphysema patients. Patient survival up to 36 months was not significantly different, with 1-year survival being 92.9% for younger vs 95.5% for older donor lungs. CONCLUSION Use of donor lungs aged ≥70 years for transplantation is safe, without compromising survival. However, spirometry findings after transplantation with donors ≥70 years indicate better functional outcomes in emphysema recipients than in idiopathic pulmonary fibrosis recipients.

Endobronchial ultrasound guided fine needle aspiration versus transcervical mediastinoscopy in nodal staging of non small cell lung cancer: a prospective comparison study

BackgroundAt present only few studies directly compare the diagnostic yield of endobronchial ultrasound guided fine needle aspiration (EBUS-FNA) and transcervical video-assisted mediastinoscopy (TM) for mediastinal lymph node staging in patients with NSCLC. If and when EBUS-FNA may replace TM as Gold Standard remains controversial.MethodsFrom April 2008 to December 2009, 36 patients with mediastinal lymphadenopathy underwent simultaneous EBUS-FNA/ TM at our institution. Among them were 26 patients with confirmed or suspected NSCLC.ResultsA total of 133 samples were obtained by EBUS-FNA and 157 samples by TM. EBUS-FNA achieved significantly less conclusive, but more indeterminate pathological results in comparison to TM (78.7% vs. 98.6%, p < 0.001; 14.9% vs. 1.4%, p = 0.007). Less paratracheal nodes were sampled by EBUS-FNA (right: 46.2% vs. 88.5%, p = 0.003; left: 23.1% vs. 65.4%, p = 0.005), while sampling rates in the subcarinal localisation were comparable (96.2% vs. 80.8%, p = NS). Among patients with confirmed NSCLC and conclusive EBUS-FNA/ TM findings (n = 18), the prevalence of N2/N3 disease was 66.7% (n = 12) according to TM findings. Diverging nodal stages were found in five patients (27.8%). Three patients who were N2 negative in EBUS-FNA were upstaged to N2 or N3 by TM, two patients with N2 status in EBUS-FNA were upstaged to N3 by TM.ConclusionsCompared to TM, EBUS-FNA had a lower diagnostic yield and resulted in systematic mediastinal nodal understaging. At this point we suggest corroborating negative EBUS-FNA results by transcervical mediastinoscopy.

Prevention of rejection of allogeneic endothelial cells in a biohybrid lung by silencing HLA-class I expression.

Variability in Human Leukocyte Antigens (HLA) remains a hurdle to the application of allogeneic cellular products. Due to insufficient autologous endothelial cell harvesting for the biohybrid lung, allogeneic human cord blood derived endothelial cells (HCBEC) were used for the endothelialization of poly-4-methyl-1-pentene (PMP) gas exchange membranes. Therefore, HLA class I expression was silenced stably in HCBECs to prevent rejection. The capacity of HLA class I-silenced HCBEC to abrogate allogeneic immune responses, their functional properties and suitability for endothelialization of PMP membranes were investigated. Delivery of β2-microglobulin (β2m)-specific shRNAs reduced β2m mRNA levels by up to 90% and caused a knockdown of HLA class I expression by up to 85%. HLA-silenced HCBEC abrogated T-cell responses and escaped antibody-mediated complement-dependent cytotoxicity. The EC phenotype and cytokine secretion profiles between HLA-expressing or -silenced HCBEC remained unaltered. EC specific activation (e.g. ICAM) and thrombogenic markers (e.g. thrombomodulin) remained unaffected by HLA-silencing, but their expression was upregulated by TNFα-stimulation. Furthermore, HLA-silenced HCBECs showed high proliferation rates and built an EC monolayer onto PMP membranes. This study represents a new therapeutic concept in the field of cell and organ transplantation and may bring the bioartificial lung as an alternative to lung transplantation closer to reality.

Cellular Differentiation of Human Monocytes Is Regulated by Time-Dependent Interleukin-4 Signaling and the Transcriptional Regulator NCOR2

Summary Human in vitro generated monocyte‐derived dendritic cells (moDCs) and macrophages are used clinically, e.g., to induce immunity against cancer. However, their physiological counterparts, ontogeny, transcriptional regulation, and heterogeneity remains largely unknown, hampering their clinical use. High‐dimensional techniques were used to elucidate transcriptional, phenotypic, and functional differences between human in vivo and in vitro generated mononuclear phagocytes to facilitate their full potential in the clinic. We demonstrate that monocytes differentiated by macrophage colony‐stimulating factor (M‐CSF) or granulocyte macrophage colony‐stimulating factor (GM‐CSF) resembled in vivo inflammatory macrophages, while moDCs resembled in vivo inflammatory DCs. Moreover, differentiated monocytes presented with profound transcriptomic, phenotypic, and functional differences. Monocytes integrated GM‐CSF and IL‐4 stimulation combinatorically and temporally, resulting in a mode‐ and time‐dependent differentiation relying on NCOR2. Finally, moDCs are phenotypically heterogeneous and therefore necessitate the use of high‐dimensional phenotyping to open new possibilities for better clinical tailoring of these cellular therapies. HighlightsIn vitro monocyte cultures model in vivo inflammatory dendritic cells and macrophagesMonocyte‐derived dendritic cells integrate interleukin‐4 signaling time dependentlyNCOR2 controls differentiation of in vitro generated monocyte‐derived dendritic cellsIn vitro generated monocyte‐derived cells are phenotypically heterogeneous &NA; Monocyte‐derived cellular derivatives are used clinically and are a crucial tool in basic research. Sander and colleagues now show that they transcriptionally relate to in vivo inflammatory monocytes, that they integrate differentiation cues time dependently, and that in vitro differentiated monocytes are phenotypically heterogeneous.

Simultaneous cardiac and lung surgery for incidental solitary pulmonary nodule: learning from the past.

BACKGROUND Incidental solitary pulmonary nodules (ISPN) detected prior to scheduled cardiac surgery are rare but challenging. We evaluated the long-term outcome of patients with ISPN undergoing simultaneous cardiac and lung surgery. METHODS The clinical records of 33 consecutive patients with ISPN undergoing cardiac and lung surgery, either simultaneously (n = 30) or sequentially (n = 3), were retrospectively evaluated and completed by detailed follow-up. RESULTS On histological examination, 14 cases (42.4%) of primary NSCLC were identified. Benign findings consisted mostly of hamartoma and inflammation. Malignant ISPN were larger in size (22.5 ± 12.4 vs. 13.6 ± 8.6 mm) and ISPN with a diameter >10 mm had a higher incidence of malignancy compared to those ≤10 mm (56.0% vs. 0%). Patients undergoing concomittant heart and lung surgery received either a wedge resection (n = 26) or a lobectomy (n = 4). The 5-year survival of patients with malignant ISPN was lower than that of patients with benign ISPN (43.6% vs. 85.6%). CONCLUSIONS Our results corroborate a high incidence of malignancy in ISPN detected prior to scheduled cardiac surgery. Simultaneous cardiac and lung surgery for NSCLC appears to be associated with a poor long-term outcome.

First series of left ventricular assist device exchanges to HeartMate 3

OBJECTIVES Left ventricular assist device (LVAD) exchange is becoming a standard surgical procedure. The exchange procedure is an opportunity to upgrade patients to a new generation pump that offers advanced reduction of adverse events or longer battery hours. METHODS We performed an analysis of 6 consecutive patients who underwent LVAD exchange to HeartMate 3 either from a HeartWare or HeartMate (HM) II device. Minimally invasive operations were performed through a lateral thoracotomy. Follow-up time was 6 months after LVAD exchange. RESULTS We present 4 patients with the HM II and 2 patients with the HeartWare ventricular assist device (HVAD) who underwent LVAD exchange to HM III. The average age was 57.5 years. At the time of the LVAD exchange, all patients were classified as Interagency Registry for Mechanically Assisted Circulatory Support level 3. In 5 cases, LVAD infection led to LVAD exchange (83%, 5/6). The remaining patient underwent LVAD exchange due to pump thrombosis (16%, 1/6). The 6-month survival rate after LVAD exchange was 100% (6/6). None of the patients was postoperatively supported by extracorporeal membrane oxygenation. No patient experienced postoperative relevant bleeding. One patient suffered minor cerebral bleeding (16.6%, 1/6). At the 6-month follow-up examination, 1 patient reported a single syncope and several low-flow alarms (1/6). The remaining 5 patients showed no adverse events or technical malfunctions of the VAD (5/6). CONCLUSIONS LVAD exchanges from HM II as well from HVAD to HM 3 are proven to be technically feasible. Due to the advantages and technical improvements of the new-generation pumps, this procedure is an excellent opportunity to give patients access to a superior generation of assist device.