Transcriptional Landscape of Human Tissue Lymphocytes Unveils Uniqueness of Tumor-Infiltrating T Regulatory Cells.

Tumor-infiltrating regulatory T lymphocytes (Treg) can suppress effector T cells specific for tumor antigens. Deeper molecular definitions of tumor-infiltrating-lymphocytes could thus offer therapeutic opportunities. Transcriptomes of T helper 1 (Th1), Th17, and Treg cells infiltrating colorectal or non-small-cell lung cancers were compared to transcriptomes of the same subsets from normal tissues and validated at the single-cell level. We found that tumor-infiltrating Treg cells were highly suppressive, upregulated several immune-checkpoints, and expressed on the cell surfaces specific signature molecules such as interleukin-1 receptor 2 (IL1R2), programmed death (PD)-1 Ligand1, PD-1 Ligand2, and CCR8 chemokine, which were not previously described on Treg cells. Remarkably, high expression in whole-tumor samples of Treg cell signature genes, such as LAYN, MAGEH1, or CCR8, correlated with poor prognosis. Our findings provide insights into the molecular identity and functions of human tumor-infiltrating Treg cells and define potential targets for tumor immunotherapy.

Read-through transcripts in lung: germline genetic regulation and correlation with the expression of other genes.

Transcripts originating from the transcriptional read through of two adjacent, similarly oriented genes have been identified in normal and neoplastic tissues, but their functional role and the mechanisms that regulate their expression are mostly unknown. Here, we investigated whether the expression of read-through transcripts previously identified in the non-involved lung tissue of lung adenocarcinoma patients was genetically regulated. Data on genome-wide single nucleotide variant genotypes and expression levels of 10 read-through transcripts in 201 samples of lung tissue were combined to identify expression quantitative trait loci (eQTLs). Then, to identify genes whose expression levels correlated with the 10 read-through transcripts, we used whole transcriptome profiles available for 154 patients. For 8 read-though transcripts, we identified 60 eQTLs (false discovery rate <0.05), including 17 cis-eQTLs and 43 trans-eQTLs. These eQTLs did not maintain their behavior on the 'parental' genes involved in the read-through transcriptional event. The expression levels of 7 read-through transcripts were found to correlate with the expression of other genes: CHIA-PIFO and CTSC-RAB38 correlated with CHIA and RAB38, respectively, while 5 other read-through transcripts correlated with 43 unique non-parental transcripts; thus offering indications about the molecular processes in which these chimeric transcripts may be involved. We confirmed 9 eQTLs (for 4 transcripts) in the non-involved lung tissue from an independent series of 188 lung adenocarcinoma patients. Therefore, this study indicates that the expression of four read-through transcripts in normal lung tissue is under germline genetic regulation, and that this regulation is independent of that of the genes involved in the read-through event.

Germline polymorphisms and survival of lung adenocarcinoma patients: a genome-wide study in two European patient series.

In lung cancer, the survival of patients with the same clinical stage varies widely for unknown reasons. In this two-phase study, we examined the hypothesis that germline variations influence the survival of patients with lung adenocarcinoma. First, we analyzed existing genotype and clinical data from 289 UK-resident patients with lung adenocarcinoma, identifying 86 single nucleotide polymorphisms (SNPs) that associated with survival (p < 0.01). We then genotyped these candidate SNPs in a validation series of 748 patients from Italy that resulted genetically compatible with the UK series based on principal component analysis. In a Cox proportional hazard model adjusted for age, sex and clinical stage, four SNPs were confirmed on the basis of their having a hazard ratio (HR) indicating the same direction of effect in the two series and p < 0.05. The strongest association was provided by rs2107561, an intronic SNP of PTPRG, protein tyrosine phosphatase, receptor type, G; the C allele was associated with poorer survival in both patient series (pooled analysis loge HR = 0.31; 95% CI: 0.15-0.46, p = 8.5 × 10(-5) ). PTPRG mRNA levels in 43 samples of lung adenocarcinoma were 40% of those observed in noninvolved lung tissue from the same patients. PTPRG overexpression significantly inhibited the clonogenicity of A549 lung carcinoma cells and the anchorage-independent growth of the NCI-H460 large cell lung cancer line. These four germline variants represent promising candidates that, with further study, may help predict clinical outcome. In addition, the PTPRG locus may have a role in tumor progression.

Do we need to cool the lung graft after ex vivo lung perfusion? A preliminary study.

BACKGROUND: After normothermic ex vivo lung perfusion (EVLP), pulmonary grafts are usually flush-cooled and stored on ice until implantation although evidence for this practice lacks. We compared outcomes between 2 post-EVLP preservation strategies in a porcine left single-lung transplantation model. MATERIAL AND METHODS: After cold flush and 2-h EVLP, donor lungs were prepared and split. In [C], (n = 5) lungs cooled on device to 15°C were preserved in ice-water; in [W] (n = 5), lungs were disconnected from EVLP at 37°C and kept at room temperature. The left lung was transplanted in a recipient animal. Posttransplant, 6 h-monitoring included hourly assessment of pulmonary vascular resistance, pulmonary artery pressure, plateau airway pressure, compliance, and oxygenation before and after exclusion of the right lung. Lung biopsies and bronchoscopy with bronchoalveolar lavage (BAL) were performed at retrieval, at the end of EVLP (R lung), and 1 and 6 h after reperfusion (L lung). RESULTS: Lungs in [W] showed the highest compliance (P < 0.05) and the lowest plateau airway pressure (not statistically significant) throughout the whole reperfusion period. Oxygenation and pulmonary artery pressure were similar between groups. Pulmonary vascular resistance was stable in [C], but rose after reperfusion in [W]. Histologic signs of lung injury and BAL neutrophilia were more pronounced in [C] at 1 h (not statistically significant and P < 0.05, respectively). BAL cytokine levels and lung tissue expression of intercellular adhesion molecule 1 did not differ between groups. CONCLUSIONS: Normothermic preparation after EVLP results in similar graft performances compared with lung cooling after EVLP.

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).

Multiple isoforms and differential allelic expression of CHRNA5 in lung tissue and lung adenocarcinoma.

CHRNA5 gene expression variation may play a role in individual susceptibility to lung cancer. Analysis of CHRNA5 transcripts expressed in normal lung tissue detected the full-length transcript (isoform-1) and four splicing transcripts (isoform-2 to isoform-5), derived from the recognition of other splice sites in exon 5. Isoforms-2, -3 and -4 were found by protein modeling to form a completely folded, potentially functional extracellular domain and were observed at the protein level, whereas isoform-5 lacked a consistent part of the distorted ß sandwich and was not seen at the protein level. Only isoform-1 appeared to encode a complete, functional subunit able to fulfill the ion channel function. We previously reported that CHRNA5 expression is associated with genetic polymorphisms at this locus and that three haplotypes in its promoter region show functional regulation in vitro. Analysis of differential allelic expression (DAE) of three single nucleotide polymorphisms (rs503464, rs55853698 and rs55781567) tagging the expression haplotypes of the CHRNA5 promoter indicated statistically significant DAE at rs55853698 and rs55781567, in both normal lung and lung adenocarcinoma. Overall, our findings provide evidence for the presence of multiple CHRNA5 messenger RNA (mRNA) isoforms that may modulate the multimeric nicotine receptor and cis-regulatory variations in the CHRNA5 locus that act in vivo in the control of CHRNA5 mRNA expression, in normal lung tissue and in lung adenocarcinoma.

Gene expression signature of non-involved lung tissue associated with survival in lung adenocarcinoma patients.

Lung adenocarcinoma patients of similar clinical stage and undergoing the same treatments often have marked interindividual variations in prognosis. These clinical discrepancies may be due to the genetic background modulating an individual's predisposition to fighting cancer. Herein, we hypothesized that the lung microenvironment, as reflected by its expression profile, may affect lung adenocarcinoma patients' survival. The transcriptome of non-involved lung tissue, excised from a discovery series of 204 lung adenocarcinoma patients, was evaluated using whole-genome expression microarrays (with probes corresponding to 28 688 well-annotated coding sequences). Genes associated with survival status at 60 months were identified by Cox regression analysis (adjusted for gender, age and clinical stage) and retested in a validation series of 78 additional cases. RNA-Seq analysis from non-involved lung tissue of 12 patients was performed to characterize the different isoforms of candidate genes. Ten genes for which the loge-transformed hazard ratios expressed the same direction of effect in the discovery (P < 1.0 × 10(-3)) and validation series comprised the gene expression signature associated with survival: CNTNAP1, PKNOX1, FAM156A, FRMD8, GALNTL1, TXNDC12, SNTB1, PPP3R1, SNX10 and SERPINH1. RNA sequencing highlighted the complex expression pattern of these genes in non-involved lung tissue from different patients and permitted the detection of a read-through gene fusion between PPP3R1 and the flanking gene (CNRIP1) as well as a novel isoform of CNTNAP1. Our findings support the hypothesis that individual genetic characteristics, evidenced by the expression pattern of non-involved tissue, influence the outcome of lung adenocarcinoma patients.

EGFR-targeted therapy for non-small cell lung cancer: focus on EGFR oncogenic mutation.

The two essential requirements for pathologic specimens in the era of personalized therapies for non-small cell lung carcinoma (NSCLC) are accurate subtyping as adenocarcinoma (ADC) versus squamous cell carcinoma (SqCC) and suitability for EGFR molecular testing, as well as for testing of other oncogenes such as EML4-ALK and KRAS. Actually, the value of EGFR expressed in patients with NSCLC in predicting a benefit in terms of survival from treatment with an epidermal growth factor receptor targeted therapy is still in debate, while there is a convincing evidence on the predictive role of the EGFR mutational status with regard to the response to tyrosine kinase inhibitors (TKIs).This is a literature overview on the state-of-the-art of EGFR oncogenic mutation in NSCLC. It is designed to highlight the preclinical rationale driving the molecular footprint assessment, the progressive development of a specific pharmacological treatment and the best method to identify those NSCLC who would most likely benefit from treatment with EGFR-targeted therapy. This is supported by the belief that a rationale for the prioritization of specific regimens based on patient-tailored therapy could be closer than commonly expected.

Association of lung adenocarcinoma clinical stage with gene expression pattern in noninvolved lung tissue.

Associations between clinical outcome of cancer patients and the gene expression signature in primary tumors at time of diagnosis have been reported. To test whether gene expression patterns in noninvolved lung tissue might correlate with clinical stage in lung adenocarcinoma (ADCA) patients, we compared the transcriptome of noninvolved lung samples from 60 ADCA smoker patients of clinical stage I versus 60 patients with stage>I. Quantitative PCR of 10 genes with the most significant differential expression confirmed the statistical association with clinical stage in eight genes, six of which were downregulated in high-stage patients. Five of these six genes were also downregulated in lung ADCA tissue as compared to noninvolved tissue. Studies in vitro indicated that four of the genes (SLC14A1, SMAD6, TMEM100 and TXNIP) inhibited colony formation of lung cancer cell lines transfected to overexpress the genes, suggesting their potential tumor-suppressor activity. Our findings suggest that individual variations in the transcriptional profile of noninvolved lung tissue may reflect the lung ADCA patient's predisposition to tumor aggressiveness.

Genome-wide association study in discordant sibships identifies multiple inherited susceptibility alleles linked to lung cancer.

We analyzed a series of young (median age = 52 years) non-smoker lung cancer patients and their unaffected siblings as controls, using a genome-wide 620 901 single-nucleotide polymorphism (SNP) array analysis and a case-control DNA pooling approach. We identified 82 putatively associated SNPs that were retested by individual genotyping followed by use of the sib transmission disequilibrium test, pointing to 36 SNPs associated with lung cancer risk in the discordant sibs series. Analysis of these 36 SNPs in a polygenic model characterized by additive and interchangeable effects of rare alleles revealed a highly statistically significant dosage-dependent association between risk allele carrier status and proportion of cancer cases. Replication of the same 36 SNPs in a population-based series confirmed the association with lung cancer for three SNPs, suggesting that phenocopies and genetic heterogeneity can play a major role in the complex genetics of lung cancer risk in the general population.

Identification of potential therapeutic targets in malignant mesothelioma using cell-cycle gene expression analysis.

Cell-cycle defects are responsible for cancer onset and growth. We studied the expression profile of 60 genes involved in cell cycle in a series of malignant mesotheliomas (MMs), normal pleural tissues, and MM cell cultures using a quantitative polymerase chain reaction-based, low-density array. Nine genes were significantly deregulated in MMs compared with normal controls. Seven genes were overexpressed in MMs, including the following: CDKN2C, cdc6, cyclin H, cyclin B1, CDC2, FoxM1, and Chk1, whereas Ube1L and cyclin D2 were underexpressed. Chk1 is a principal mediator of cell-cycle checkpoints in response to genotoxic stress. We confirmed the overexpression of Chk1 in an independent set of 87 MMs by immunohistochemistry using tissue microarrays. To determine whether Chk1 down-regulation would affect cell-cycle control and cell survival, we transfected either control or Chk1 siRNA into two mesothelioma cell lines and a nontumorigenic (Met5a) cell line. Results showed that Chk1 knockdown increased the apoptotic fraction of MM cells and induced an S phase block in Met5a cells. Furthermore, Chk1 silencing sensitized p53-null MM cells to both an S phase block and apoptosis in the presence of doxorubicin. Our results indicate that cell-cycle gene expression analysis by quantitative polymerase chain reaction can identify potential targets for novel therapies. Chk1 knockdown could provide a novel therapeutic approach to arrest cell-cycle progression in MM cells, thus increasing the rate of cell death.

Transcription deregulation at the 15q25 locus in association with lung adenocarcinoma risk.

PURPOSE: We characterized the candidacy of the six candidate genes mapping in the chromosome 15q25 locus, which was previously reported as associated with lung cancer risk, and confirmed the locus association with lung cancer risk in an Italian population of lung adenocarcinoma patients and controls. EXPERIMENTAL DESIGN: We did a quantitative analysis of mRNA levels of IREB2 (iron-responsive element-binding protein 2), LOC123688, PMSA4 [proteasome (prosome, macropain) subunit alpha type 4], CHRNB4 (cholinergic receptor nicotinic beta 4), CHRNA3 (cholinergic receptor nicotinic alpha 3), and CHRNA5 (cholinergic receptor nicotinic alpha 5) genes in paired normal lung and lung adenocarcinoma tissue, and an immunohistochemical localization of CHRNA3- and CHRNA5-encoded proteins. We also examined the association of CHRNA5 D398N polymorphism with lung cancer risk and with CHRNA5 mRNA levels in the normal lung. RESULTS: Expression analysis of the six candidate genes mapping in the lung cancer risk-associated chromosome 15q25 locus revealed a 30-fold up-regulation of the gene encoding the CHRNA5 subunit and a 2-fold down-regulation of the CHRNA3 subunit in lung adenocarcinoma as compared with the normal lung. The expression of the four other candidate genes resulted either unchanged or absent. The carrier status of the 398N allele at the D398N polymorphism of the CHRNA5 gene was associated with lung adenocarcinoma risk (odds ratio, 1.5; 95% confidence interval, 1.2-2.0) in a population-based series of lung adenocarcinoma patients (n=467) and healthy controls (n=739). Analysis of a family-based series of nonsmoker lung cancer cases (n=80) and healthy sib controls (n=80) indicated a similar trend. In addition, the same D398N variation correlated with CHRNA5 mRNA levels in normal lung of adenocarcinoma patients. CONCLUSIONS: Our results point to the candidacy of the CHRNA5 gene for the 15q25 locus.

FGFR4 Gly388Arg polymorphism may affect the clinical stage of patients with lung cancer by modulating the transcriptional profile of normal lung.

The association of the fibroblast growth factor receptor 4 (FGFR4) Gly388Arg polymorphism with clinical stage and overall survival in a series of 541 Italian lung adenocarcinoma (ADCA) patients indicated a significantly decreased survival in patients carrying the rare Arg388 allele as compared to that in Gly/Gly homozygous patients [hazard ratio (HR) = 1.5; 95% confidence interval (CI) 1.1-1.9], with the decrease related to the association of the same polymorphism with clinical stage (HR = 1.8, 95% CI 1.3-2.6). By contrast, no significant association was detected in small series of either Norwegian lung ADCA patients or Italian lung squamous cell carcinoma (SQCC) patients. Single nucleotide polymorphisms of known FGFR4 ligands expressed in lung (FGF9, FGF18 and FGF19) were not associated with clinical stage or survival and showed no interaction with FGFR4. Analysis of gene expression profile in normal lungs according to FGFR4 genotype indicated a specific transcript pattern associated with the allele carrier status, suggesting a functional role for the FGFR4 polymorphism already detectable in normal lung. These findings confirm the significant association of the FGFR4 Gly388Arg polymorphism with clinical stage and overall survival in an Italian lung ADCA population and demonstrate a FGFR4 genotype-dependent transcriptional profile present in normal lung tissue.

Outcomes and risk factors identification in urgent lung transplantation: a multicentric study.

BACKGROUND: In rapidly lung deteriorating patients, urgent lung transplantation (ULT) seems the only definitive therapy. Few publications on this topic report conflicting results, putting a word of caution about ULT programs. METHODS: A national ULT program was introduced in 2010: patients on mechanical support may be transplanted with the first available graft. We reviewed the experience of three national center, focusing on post-operative outcomes after ULT. RESULTS: Ten patients (17.5%) died awaiting transplantation, while 47 underwent LT with a median urgent waiting list time of 6 days. Pre-operatively, 4.3% of patients were supported only by mechanical ventilation (MV), 55.3% by extracorporeal membrane oxygenation (ECMO) and the remaining 40.4% by both. The main indication was cystic fibrosis (64%). Median recipient lung allocation score was 72. In-hospital mortality was 19%. MV and ECMO median duration of 7 and 3 days, respectively while intensive care unit (ICU) and hospital stay were 20 and 46 days, respectively. At long-term, 1- and 3-year survival rate were 74% and 70%, respectively. Highly impact risk factors for in-hospital mortality were both presence and duration of preoperative veno-arterial ECMO and pre-transplant C-reactive protein level. CONCLUSIONS: ULT program allows transplantation in a significant percentage of patients with acceptable results. Pre-operative recipient selection is mandatory to improve clinical outcomes.

Cigarette smoke alters the transcriptome of non-involved lung tissue in lung adenocarcinoma patients.

Alterations in the gene expression of organs in contact with the environment may signal exposure to toxins. To identify genes in lung tissue whose expression levels are altered by cigarette smoking, we compared the transcriptomes of lung tissue between 118 ever smokers and 58 never smokers. In all cases, the tissue studied was non-involved lung tissue obtained at lobectomy from patients with lung adenocarcinoma. Of the 17,097 genes analyzed, 357 were differentially expressed between ever smokers and never smokers (FDR < 0.05), including 290 genes that were up-regulated and 67 down-regulated in ever smokers. For 85 genes, the absolute value of the fold change was ≥2. The gene with the smallest FDR was MYO1A (FDR = 6.9 × 10-4) while the gene with the largest difference between groups was FGG (fold change = 31.60). Overall, 100 of the genes identified in this study (38.6%) had previously been found to associate with smoking in at least one of four previously reported datasets of non-involved lung tissue. Seven genes (KMO, CD1A, SPINK5, TREM2, CYBB, DNASE2B, FGG) were differentially expressed between ever and never smokers in all five datasets, with concordant higher expression in ever smokers. Smoking-induced up-regulation of six of these genes was also observed in a transcription dataset from lung tissue of non-cancer patients. Among the three most significant gene networks, two are involved in immunity and inflammation and one in cell death. Overall, this study shows that the lung parenchyma transcriptome of smokers has altered gene expression and that these alterations are reproducible in different series of smokers across countries. Moreover, this study identified a seven-gene panel that reflects lung tissue exposure to cigarette smoke.

A polygenic model with common variants may predict lung adenocarcinoma risk in humans.

Genome-wide screening for genetic loci associated with risk of lung adenocarcinoma (ADCA) was carried out in pooled DNA using the Illumina 300K single-nucleotide polymorphism (SNP) array, in a joint analysis of 2 Italian case-control series matched by age, gender and smoking habit. The rare allele carrier status of 8 SNPs was associated with a decreased lung ADCA risk [odds ratios (OR): 0.6-0.8]. In a polygenic model characterized by additive and interchangeable effects, individuals carrying 2 to 6 rare alleles at these 8 SNPs showed a significant trend toward a decreased risk of lung ADCA (up to OR of 0.3). These results suggest the relevance of a polygenic model in the modulation of individual risk of lung ADCA in the general population.

Solitary fibrous tumor of the pleura presenting with syncope episodes when coughing.

BACKGROUND: Solitary fibrous tumor of the pleura is a rarely encountered clinical entity which may have different clinical pictures. Although the majority of these neoplasms have a benign course, the malignant form has also been reported. CASE PRESENTATION: We herein describe a case of 72 year-old man with head, facial, and thoracic traumas caused by neurally-mediated situational syncope when coughing. The diagnostic work-up including chest x-ray, CT and PET, revealed a large solitary mass of the left hemithorax. Radical surgical resection of the mass was performed through a left lateral thoracotomy and completed with a wedge resection of the lingula. Hystological examination of the surgical specimen showed an encapsulated mass measuring 12 x 11.5 x 6 cm consistent with a solitary fibrous tumor of the pleura. It's surgical removal definitively resolved the neurologic manifestations. The patient had no postoperative complications. At two years follow-up the patient is free from recurrence and without clinical manifestations. CONCLUSION: In our case its resection definitively resolved the episodes of situational syncope due, in our opinion, to the large thoracic mass compressing the phrenic nerve.

Staging non-small lung cancer with positron emission tomography: diagnostic value, impact on patient management, and cost-effectiveness.

The aim of this study was to compare two preoperative staging procedures of non-small cell lung cancer (NSCLC): one using positron emission tomography (PET) and one using conventional imaging studies. Accuracy, effects on patient management, and costs were calculated. Four hundred thirteen consecutive patients with NSCLC were prospectively examined with PET and conventional imaging studies. A simulation calculated the costs of the two strategies. The accuracy of PET for metastases was 97.5% versus 84% of conventional imaging (P < 0.001). The accuracy of PET for mediastinal staging was 97%, whereas that of computed tomography was 68% (P < 0.001). The expected number of unnecessary surgeries was 24 for the conventional strategy and 8 for the PET strategy (P= 0.007). The PET strategy was less expensive. This study shows that PET is an economical tool in NSCLC staging (even in the European economic environment), with high accuracy and important management aspects.

Transplant options for end stage chronic obstructive pulmonary disease in the context of multidisciplinary treatments.

Lung transplantation (LTx) in advanced stage chronic obstructive pulmonary disease (COPD) patients is associated with significant improvement in lung function and exercise capacity. However, demonstration that the procedure also provides a survival benefit has been more elusive compared to other respiratory conditions. Identification of patients with increased risk of mortality is crucial: a low forced expiratory volume in 1 second (FEV1) is perhaps the most common reason for referral to a lung transplant center, but in itself is insufficient to identify which COPD patients will benefit from LTx. Many variables have to be considered in the selection of candidates, time for listing, and choice of procedure: age, patient comorbidities, secondary pulmonary hypertension, the balance between individual and community benefit. This review will discuss patient selection, transplant listing, potential benefits and critical issues of bilateral (BLTx) and single lung (SLTx) procedure, donor-to-recipient organ size-matching; furthermore, it will describe LTx outcomes and its effects on recipient survival and quality of life.

Is "lung repair centre" a possible answer to organ shortage?-transplantation of left and right lung at two different centres after ex vivo lung perfusion evaluation and repair: case report.

Ex vivo lung perfusion (EVLP) has become a reality as a technique to evaluate and recondition lungs from marginal donors. We report the first case on the use of EVLP followed by separate transplantation in two different centres. The local organ procurement organization proposed the lungs of a 53-year-old non-smoker donor who died for cerebral haemorrhage. P/F ratio was 294 after lung recruitment manoeuvres. Oto score was 10. Two centres accepted the grafts for two single transplantations under the condition of EVLP evaluation. After usual retrieval, the bi-pulmonary block was transferred to Centre 1 and EVLP was run as previously described. At the end of the procedure the two lungs were evaluated separately and both judged suitable for transplantation. After cooling and storage on ice, the block was separated on the back table. The left lung was transplanted in a patient with pulmonary fibrosis at Centre 1; surgery was complicated by cardiac arrhythmias that required several defibrillations. The right lung was transferred on ice to Centre 2, 250 km away from Centre 1, and transplanted in a patient with idiopathic pulmonary fibrosis. Thirty months after transplantations Patient 1 and Patient 2 are both alive, in good clinical conditions. This is the first report of the separate use of lungs after EVLP for non-urgent recipients in two different centres. This experience opens the door to a new allocation model with great potentials on organ shortage. Actually, we demonstrated that the perspective of a 'lung repair centre' is feasible and effective.