Lorenzo Rosso

Extracorporeal membrane oxygenation with spontaneous breathing as a bridge to lung transplantation

OBJECTIVESnA large number of transplantation centres consider extracorporeal membrane oxygenation as an inappropriate option for bridging critical patients to lung transplantation. Technical improvements such as the introduction of a polymethylpentene membrane, new centrifugal pumps and heparin-coated circuits have led to a safer application of extracorporeal membrane oxygenation, and an increasing number of centres are reporting their positive experiences. The aim of this study was to review our practice in bridging critical candidates to lung transplantation with extracorporeal membrane oxygenation, by comparing patients with invasive mechanical ventilation with patients with spontaneous breathing.nnnMETHODSnThe records of candidates for lung transplantation treated with extracorporeal membrane oxygenation have been revised.nnnRESULTSnFrom February 2008 to 2012, 11 patients who experienced an abrupt worsening of their respiratory conditions were treated with extracorporeal membrane oxygenation; mean age: 33.9 ± 13.2 years, male/female ratio: 5/6, 6 patients were affected by cystic fibrosis, 2 had chronic rejection after transplantation, 2 had pulmonary fibrosis and 1 had systemic sclerosis. Seven patients were awake, while 4 patients received invasive mechanical ventilation. The sequential organ failure assessment score significantly increased during bridging time and this increase was significantly higher in the intubated patients. All the patients had bilateral lung transplantation. Spontaneously breathing patients showed a tendency to require a shorter duration of invasive mechanical ventilation, intensive care unit stay and hospital stay after transplantation. One-year survival rate was 85.7% in patients with spontaneous breathing vs 50% in patients with invasive mechanical ventilation.nnnCONCLUSIONSnExtracorporeal membrane oxygenation in spontaneously breathing patients is a feasible, effective and safe bridge to lung transplantation.

Pulmonary lobectomy for lung cancer: a prospective study to compare patients with forced expiratory volume in 1 s more or less than 80% of predicted.

OBJECTIVEnTo compare post-operative course, lung function and survival of lung cancer patients with a forced expiratory volume in 1 s (FEV1) more or less than 80% of predicted submitted to lobectomy.nnnMETHODSnThe data of patients undergoing lobectomy for non small cell carcinoma at the Thoracic Surgery Unit of the Ospedale Maggiore Policlinico of Milan, Italy, were prospectively collected. Inclusion criteria were a radical resectable tumor with size less than 2.5 cm, negative mediastinal nodes, capability to complete pulmonary function tests, Exclusion criteria were FEV1 <40% of predicted, pre- or post-operative chemo or radiotherapy, lobe to be resected receiving more than 30% of the perfusion, incapacity to quit smoking.nnnRESULTSnEighty-eight patients entered the study and were divided into two groups according to their FEV1%: 45 patients were included in control group (mean FEV1: 92.2%) and 42 in chronic obstructive pulmonary disease group (mean FEV1: 64.2%). Post-operative complications, operative mortality and actuarial survival were the same in the 2 groups. Six months after lobectomy, the mean changes in FEV1 were -14.9% for first group and -3.2% for second group (P<0.001).nnnCONCLUSIONnLobectomy for cancer can be performed successfully also in selected patients with chronic obstructive pulmonary disease. Post-operative course and survival of these patients is not different from that of patients with normal FEV1, on the contrary, patients with low FEV1 may lose less pulmonary function or even mend it.

Intratumor Heterogeneity of ALK-Rearrangements and Homogeneity of EGFR-Mutations in Mixed Lung Adenocarcinoma.

Background Non Small Cell Lung Cancer is a highly heterogeneous tumor. Histologic intratumor heterogeneity could be ‘major’, characterized by a single tumor showing two different histologic types, and ‘minor’, due to at least 2 different growth patterns in the same tumor. Therefore, a morphological heterogeneity could reflect an intratumor molecular heterogeneity. To date, few data are reported in literature about molecular features of the mixed adenocarcinoma. The aim of our study was to assess EGFR-mutations and ALK-rearrangements in different intratumor subtypes and/or growth patterns in a series of mixed adenocarcinomas and adenosquamous carcinomas. Methods 590 Non Small Cell Lung Carcinomas tumor samples were revised in order to select mixed adenocarcinomas with available tumor components. Finally, only 105 mixed adenocarcinomas and 17 adenosquamous carcinomas were included in the study for further analyses. Two TMAs were built selecting the different intratumor histotypes. ALK-rearrangements were detected through FISH and IHC, and EGFR-mutations were detected through IHC and confirmed by RT-PCR. Results 10/122 cases were ALK-rearranged and 7 from those 10 showing an intratumor heterogeneity of the rearrangements. 12/122 cases were EGFR-mutated, uniformly expressing the EGFR-mutated protein in all histologic components. Conclusion Our data suggests that EGFR-mutations is generally homogeneously expressed. On the contrary, ALK-rearrangement showed an intratumor heterogeneity in both mixed adenocarcinomas and adenosquamous carcinomas. The intratumor heterogeneity of ALK-rearrangements could lead to a possible impact on the therapeutic responses and the disease outcomes.

Bridge to Lung Transplantation by Venovenous Extracorporeal Membrane Oxygenation: A Lesson Learned on the First Four Cases

Extracorporeal membrane oxygenation (ECMO) is the only therapeutic option for patients with ventilation-refractory hypercapnia while awaiting lung transplantation. Moreover, there is increasing success using ECMO for definitive respiratory failure in formerly healthy patients. This report describes the use of membrane oxygenation as a bridge to lung transplantation in 2 patients on the waiting list and in 2 previously healthy patients. Our experience showed that coagulation management, critical illness myopathy, and psychological disorders were the most critical problems. One patient died at 2 days after transplantation, 1 at 3 months, and 2 returned to their pretransplantation activities. We concluded that ECMO is an adequate bridge to lung transplantation but, especially in formerly healthy patients, an awake procedure is advisable for a successful outcome.

Ex vivo lung perfusion to improve donor lung function and increase the number of organs available for transplantation

This paper describes the initial clinical experience of ex vivo lung perfusion (EVLP) at the Fondazione Ca’ Granda in Milan between January 2011 and May 2013. EVLP was considered if donor PaO2/FiO2 was below 300 mmHg or if lung function was doubtful. Donors with massive lung contusion, aspiration, purulent secretions, pneumonia, or sepsis were excluded. EVLP was run with a low‐flow, open atrium and low hematocrit technique. Thirty‐five lung transplants from brain death donors were performed, seven of which after EVLP. EVLP donors were older (54 ± 9 years vs. 40 ± 15 years, EVLP versus Standard, P < 0.05), had lower PaO2/FiO2 (264 ± 78 mmHg vs. 453 ± 119 mmHg, P < 0.05), and more chest X‐ray abnormalities (P < 0.05). EVLP recipients were more often admitted to intensive care unit as urgent cases (57% vs. 18%, P = 0.05); lung allocation score at transplantation was higher (79 [40–84] vs. 39 [36–46], P < 0.05). After transplantation, primary graft dysfunction (PGD72 grade 3, 32% vs. 28%, EVLP versus Standard, P = 1), mortality at 30 days (0% vs. 0%, P = 1), and overall survival (71% vs. 86%, EVLP versus Standard P = 0.27) were not different between groups. EVLP enabled a 20% increase in available donor organs and resulted in successful transplants with lungs that would have otherwise been rejected (ClinicalTrials.gov number: NCT01967953).

Muscle sparing versus posterolateral thoracotomy for pulmonary lobectomy: randomised controlled trial

Muscle sparing thoracotomy (MST) has been proposed as an alternative to posterolateral thoracotomy (PLT) for pulmonary lobectomy. This issue has been addressed by few clinical reports. To explore that subject, a prospective, controlled randomised, double-blind trial comparing MST through the auscultatory triangle and PLT was planned. The study included patients scheduled for pulmonary lobectomy for stage I or II non-small-cell lung cancer and were followed for three years. The primary endpoints were pain, analgesic consumption and post-thoracotomy pain syndrome. The secondary endpoints included morbidity plus shoulder and pulmonary functions. The trial randomised 100 patients into two groups. Postoperative pain results were similar, although analgesic consumption was higher in the PLT group (P=0.001). The MST group had a shorter hospital stay (P=0.003). Three years post-thoracotomy syndrome was unaffected by the type of incision. The women suffered more than men during the early and late postoperative time. An inverse correlation between incision length and pain was found. Immediate shoulder strength was significantly better in the MST group (P=0.004) but postoperative pulmonary function and complications were comparable. The two incisions results were very similar in the patient outcome, however, few aspects indicated the MST as the more suitable incision for pulmonary lobectomy.

Alveolar adenoma of the lung: unusual diagnosis of a lesion positive on PET scan. A case report.

The authors report a clinical case of alveolar adenoma presenting as a solitary pulmonary nodule which was positive to PET and deeply located in the lung. Few cases of alveolar adenomas have been reported in literature; these lesions are considered pulmonary neoplasms with benign behaviour, usually presenting as a peripheral or subpleural coin lesion; the PET activities of such neoplasms were unknown.The present clinical case was singular for the deep location of the nodule and its tight adhesion to left inferior pulmonary vein requiring a lobectomy. In addition, alveolar adenoma PET behaviour has been reported as light positivity.

β-Adrenergic agonist infusion during extracorporeal lung perfusion: Effects on glucose concentration in the perfusion fluid and on lung function

BACKGROUNDnWe recently showed in a pig model of ex vivo lung perfusion (EVLP) that lung edema correlates with glucose consumption. We investigated whether salbutamol, a β-adrenergic receptor agonist known to upregulate fluid transport in the lung, modulates glucose concentration in the perfusate during EVLP.nnnMETHODSnLungs from domestic pigs underwent normothermic EVLP. At the end of controlled reperfusion, lungs were ventilated and perfused for 60 minutes, then randomized to salbutamol (β-Agonist) infusion or placebo (Control) for 180 minutes. Functional parameters were assessed.nnnRESULTSnIn the β-Agonist group, glucose concentration decreased over time more than corresponding Control values (analysis of variance [ANOVA], p = 0.05). Mean pulmonary artery pressure (mPAP) was 16 ± 1 mm Hg in the β-Agonist group vs 21 ± 1 mm Hg in the Controls (ANOVA p < 0.05). Baseline mPAP was correlated with the drop of mPAP after the β-agonist infusion (R(2) = 0.856, p < 0.05). Dynamic compliance dropped from 51 ± 10 to 31 ± 6 ml/cm H(2)O in the β-Agonist group and from 60 ± 4 to 21 ± 3 ml/cm H(2)O in the Control group (ANOVA, p < 0.05 β-agonist vs Control). The Δ partial pressure of oxygen/fraction of inspired oxygen was 418 ± 15 and 393 ± 12 mm Hg in the β-Agonist and Control groups, respectively (t-test p = 0.106).nnnCONCLUSIONSnGlucose concentration in the perfusate was affected by salbutamol. Salbutamol was associated with lower pulmonary pressures and better lung mechanics. These data suggest a possible role for salbutamol as a pharmacologic adjunct during EVLP before transplantation.

The consumption of glucose during ex vivo lung perfusion correlates with lung edema.

INTRODUCTIONnEx vivo lung perfusion (EVLP) has been recently proposed to recondition organs before transplantation from donors with marginal or unacceptable features. The aim of our investigation was to explore glucose consumption during EVLP.nnnMATERIALS AND METHODSnWe investigated 8 domestic pigs (mean weight, 21 ± 0.8 kg). After perfusion with Perfadex, retrieval, and back table surgery, we initiated EVLP. The lungs were perfused with Steen solution with added methylprednisolone, cefazoline, and heparin. The blood flow was gradually increased with a target of 40% of the estimated cardiac output (or less if the pulmonary artery pressure was >15 mm Hg), while keeping the left atrial pressure between 3 and 5 mm Hg. The temperature of the perfusate was increased from 25 °C to 37 °C. Once the temperature of the lung outflow was >32 °C, we began gas flow (4 L/min, 5%-8% CO(2) in air) and mechanical ventilation. EVLP parameters and blood gases were measured throughout the experiment; glucose consumption was calculated as (glucose initial-glucose final)/time. The wet to dry ratio was also calculated as an index of lung edema.nnnRESULTSnWhen stratified by median glucose consumption (0.237 mg/min), high glucose consumers (0.588 ± 0.17) were characterized by worse lung function, as assessed by oxygenation (partial pressure of oxygen/inspiratory fraction of oxygen [PaO(2)/FiO(2)] 326 ± 63 mm Hg vs 218 ± 84; P=.083 low vs high, respectively), and lung edema (wet/dry ratio 6.5 ± 0.7 vs 8.6 ± 0.9; P=.012). Glucose consumption correlated with wet to dry ratio (R(2)=0.663; P=.014).nnnCONCLUSIONSnWe found that the worse the lung function, the greater the consumption of glucose during EVLP. This observation suggests the need to explore lung metabolism during EVLP to possibly obtain metrics for evaluation.

Autocrine inhibitory influences of α-melanocyte-stimulating hormone in malignant pleural mesothelioma

Malignant pleural mesothelioma is a highly aggressive tumor arising from the mesothelial cells that line the pleural cavities. This tumor is resistant to most conventional anticancer treatments and appears to be very sensitive to growth‐promoting influences of cytokines and growth factors. Identification of natural inhibitory pathways that control growth should aid discovery of novel therapeutic approaches. We hypothesized that α‐melanocyte‐stimulating hormone (α‐MSH), which is produced by many cell types and antagonizes cytokines and growth factors, could be an endogenous inhibitory molecule in mesothelioma. Twelve mesothelioma cell lines were established from pleural effusions of patients with malignant mesothelioma. Mesothelioma cells were found to express mRNA for proopiomelanocortin and its processing enzymes; release α‐MSH peptide into supernatants; and express melanocortin 1 receptor (MC1R), the high‐affinity receptor for α‐MSH. Immunoneutralization of MC1R in the cell lines enhanced expression of interleukin‐8 (IL‐8), IL‐6, and transforming growth factor‐β. These molecules promote mesothelioma proliferation and are considered therapeutic targets in this tumor. Coincubation of mesothelioma cells with synthetic α‐MSH significantly reduced cell proliferation. The present research shows an autocrine‐inhibitory circuit based on α‐MSH and its receptor MC1R. Activation of MC1R by selective peptides or peptidomimetics might provide a novel strategy to reduce mesothelioma cell proliferation by taking advantage of this endogenous inhibitory circuit.