Deep representation learning of tissue metabolome and computed tomography annotates NSCLC classification and prognosis.

The rich chemical information from tissue metabolomics provides a powerful means to elaborate tissue physiology or tumor characteristics at cellular and tumor microenvironment levels. However, the process of obtaining such information requires invasive biopsies, is costly, and can delay clinical patient management. Conversely, computed tomography (CT) is a clinical standard of care but does not intuitively harbor histological or prognostic information. Furthermore, the ability to embed metabolome information into CT to subsequently use the learned representation for classification or prognosis has yet to be described. This study develops a deep learning-based framework -- tissue-metabolomic-radiomic-CT (TMR-CT) by combining 48 paired CT images and tumor/normal tissue metabolite intensities to generate ten image embeddings to infer metabolite-derived representation from CT alone. In clinical NSCLC settings, we ascertain whether TMR-CT results in an enhanced feature generation model solving histology classification/prognosis tasks in an unseen international CT dataset of 742 patients. TMR-CT non-invasively determines histological classes - adenocarcinoma/squamous cell carcinoma with an F1-score = 0.78 and further asserts patients' prognosis with a c-index = 0.72, surpassing the performance of radiomics models and deep learning on single modality CT feature extraction. Additionally, our work shows the potential to generate informative biology-inspired CT-led features to explore connections between hard-to-obtain tissue metabolic profiles and routine lesion-derived image data.

Altered splicing machinery in lung carcinoids unveils NOVA1, PRPF8 and SRSF10 as novel candidates to understand tumor biology and expand biomarker discovery.

BACKGROUND: Lung neuroendocrine neoplasms (LungNENs) comprise a heterogeneous group of tumors ranging from indolent lesions with good prognosis to highly aggressive cancers. Carcinoids are the rarest LungNENs, display low to intermediate malignancy and may be surgically managed, but show resistance to radiotherapy/chemotherapy in case of metastasis. Molecular profiling is providing new information to understand lung carcinoids, but its clinical value is still limited. Altered alternative splicing is emerging as a novel cancer hallmark unveiling a highly informative layer. METHODS: We primarily examined the status of the splicing machinery in lung carcinoids, by assessing the expression profile of the core spliceosome components and selected splicing factors in a cohort of 25 carcinoids using a microfluidic array. Results were validated in an external set of 51 samples. Dysregulation of splicing variants was further explored in silico in a separate set of 18 atypical carcinoids. Selected altered factors were tested by immunohistochemistry, their associations with clinical features were assessed and their putative functional roles were evaluated in vitro in two lung carcinoid-derived cell lines. RESULTS: The expression profile of the splicing machinery was profoundly dysregulated. Clustering and classification analyses highlighted five splicing factors: NOVA1, SRSF1, SRSF10, SRSF9 and PRPF8. Anatomopathological analysis showed protein differences in the presence of NOVA1, PRPF8 and SRSF10 in tumor versus non-tumor tissue. Expression levels of each of these factors were differentially related to distinct number and profiles of splicing events, and were associated to both common and disparate functional pathways. Accordingly, modulating the expression of NOVA1, PRPF8 and SRSF10 in vitro predictably influenced cell proliferation and colony formation, supporting their functional relevance and potential as actionable targets. CONCLUSIONS: These results provide primary evidence for dysregulation of the splicing machinery in lung carcinoids and suggest a plausible functional role and therapeutic targetability of NOVA1, PRPF8 and SRSF10.

Surgical Complications After Lung Transplantation: The Reina Sofía Hospital Experience.

OBJECTIVE: To assess the incidence of surgical complications after lung transplantation and its influence on early mortality and long-term survival. METHODS: Retrospective review of 792 lung transplants (LTs) performed from 1994 to 2022. Among them, 769 with complete data were selected. Patients with and without surgical complications were compared by univariable and multivariable analyses. RESULTS: There were 385 single LTs (50%), 371 double LTs (48%), 8 bilobar LTs (1%), and 5 combined liver LTs (1%). Two hundred forty-nine patients presented surgical complications (32%) as follows: bronchial (n = 61), vascular (n = 55), pneumothorax (n = 33), and phrenic nerve palsy (n = 22). Thirty-day mortality (noncomplicated vs complicated) was 57 (41%) vs 80 (59%), P < .001. Transplants for bronchiectasis (58%), pulmonary hypertension (50%), and re-transplants (78%) presented more surgical complications (P < .001). Double LT (40%), bilobar LT (88%), and combined liver LT (100%) presented more surgical complications (P < .001). Complicated recipients were younger (49 ± 15 vs 45 ± 17 years; P = .001), with longer ischemic times (429 ± 67 vs 450 ± 76 min [2nd graft]; P = .007), and required extracorporeal support (ECLS) more often (43% vs 57%; P < .001). Survival at 1, 5, 10, 15, and 20 years (noncomplicated vs complicated): 78%, 63%, 52%, 41%, 31% vs 52%, 42%, 35%, 26%, 22%; P < .001). Predictors of mortality were the need for ECLS (odds ratio [OR] 4.14; P < .001), postoperative ventilation (hours) (OR 1.01; P < .001), and vascular complications (OR 4.78; P < .001). CONCLUSION: Surgical complications remain an important source of morbidity and mortality after lung transplantation. Complex surgical procedures requiring ECLS develop frequent surgical complications needing long postoperative ventilation that are associated with early mortality and poorer long-term survival.

Influence of De Novo Malignancies on Long-Term Survival after Lung Transplantation.

(1) Background: Malignancies are an important cause of mortality after solid organ transplantation. The purpose of this study was to analyze the incidence of malignancies in patients receiving lung transplants (LT) and their influence on patients' survival. (2) Methods: Review of consecutive LT from 1994 to 2021. Patients with and without malignancies were compared by univariable and multivariable analyses. Survival was compared with Kaplan-Meier and Cox regression analysis. (3) Results: There were 731 LT malignancies developed in 91 patients (12.4%) with related mortality of 47% (n = 43). Native lung cancer, digestive and hematological malignancies were associated with higher lethality. Malignancies were more frequent in males (81%; p = 0.005), transplanted for emphysema (55%; p = 0.003), with cyclosporine-based immunosuppression (58%; p < 0.001), and receiving single LT (65%; p = 0.011). Survival was worse in patients with malignancies (overall) and with native lung cancer. Risk factors for mortality were cyclosporine-based immunosuppression (OR 1.8; 95%CI: 1.3-2.4; p < 0.001) and de novo lung cancer (OR 2.6; 95%CI: 1.5-4.4; p < 0.001). (4) Conclusions: Malignancies are an important source of morbidity and mortality following lung transplantation that should not be neglected. Patients undergoing single LT for emphysema are especially at higher risk of mortality due to lung cancer in the native lung.

Airway Complications after Lung Transplantation-A Contemporary Series of 400 Bronchial Anastomoses from a Single Center.

(1) Objective: To determine whether recent advances in lung transplantation (LT) have reduced the incidence and changed the risk factors for airway complications (AC). (2) Methods: Retrospective analysis of patients receiving a lung transplant between January 2007 and January 2019. An AC was defined as a bronchoscopic abnormality in the airway, either requiring or not requiring an endoscopic or surgical intervention. Both univariable and multivariable analyses were performed to identify risk factors for AC. (3) Results: 285 lung transplants (170 single and 115 bilateral lung transplants) were analysed, comprising 400 anastomoses at risk. A total of 50 anastomoses resulted in AC (12%). There were 14 anastomotic and 11 non-anastomotic stenoses, 4 dehiscences, and 3 malacias. Independent predictors for AC were: gender male (OR: 4.18; p = 0.002), cardiac comorbidities (OR: 2.74; p = 0.009), prolonged postoperative mechanical ventilation (OR: 2.5; p = 0.02), PaO2/FiO2 < 300 mmHg at 24 h post-LT (OR: 2.48; p = 0.01), graft infection (OR: 2.16; p = 0.05), and post-LT isolation of Aspergillus spp. (OR: 2.63; p = 0.03). (4) Conclusions: In spite of advances in lung transplantation practice, the risk factors, incidence, and lethality of AC after LT remains unchanged. Graft dysfunction, an infected environment, and the need of prolonged mechanical ventilation remain an Achilles heel for AC.

Case Report on Sternal Osteomyelitis by Trichosporon inkin Complicating Lung Transplantation: Effective Treatment With Vacuum-Assisted Closure and Surgical Reconstruction.

Sternal osteomyelitis is a serious complication that significantly increases morbidity and mortality after thoracic surgery. We describe a case of sternal osteomyelitis by Trichosporon inkin following lung transplantation and the excellent results achieved with vacuum-assisted closure therapy.

Incidence of Carcinoma in the Native Lung After Single Lung Transplantation.

BACKGROUND: This study aims to assess the incidence of primary lung cancer in the native lung and its impact on survival in patients undergoing single lung transplantation (SLT). METHODS: This study retrospectively analyzed 161 SLTs performed between June 2012 and June 2019. The incidence of carcinoma in the native lung and its influence on patient survival was determined. Recipient variables, tumor stage, and survival were analyzed and compared between patients with and without native lung cancer. The analysis was adjusted for transplant indication. Both univariable and multivariable analyses were performed. The present study followed the Declaration of Helsinki Ethical Principles for Medical Research involving human subjects. RESULTS: There were 161 patients (126 men/35 women; 57 ± 7 years) transplanted for chronic obstructive pulmonary disease (COPD) (n = 72), idiopathic pulmonary fibrosis (IPF) (n = 77), or other indications (n = 12). Eleven patients with COPD (7%) developed lung cancer in the native lung after SLT. Lung cancer did not appear in any of the SLTs for pulmonary fibrosis. Five participants were in stages I/II and underwent lung resection, and 6 participants were in stages III/IV and underwent chemotherapy/radiotherapy. Survival (1, 3, and 5 years) without vs with native lung carcinoma in patients with COPD was 89%, 86%, and 80% vs 86%, 71%, and 51% (P = .04). The occurrence of carcinoma in the native lung predicted survival in patients with COPD (odds ratio [OR]: 2.55; P = .07). CONCLUSIONS: Lung cancer in the native lung is a frequent and devastating complication after SLT in patients with COPD, which might negatively affect long-term survival. This should be considered when choosing the transplant procedure for patients with COPD.

Lung Transplantation in a Young Patient With Pulmonary Artery Hypertension After Arterial Switch Operation: A Case Report.

Pulmonary hypertension after surgical correction of D-transposition of the great vessels is a rare but serious complication. Lung transplantation may be the only option when treatment with vasodilators is insufficient. We present the case of a young male patient with a history of arterial switch in neonatal period who undergoes double lung transplantation owing to late pulmonary hypertension.

The influence of the native lung on early outcomes and survival after single lung transplantation.

OBJECTIVE: To determine whether problems arising in the native lung may influence the short-term outcomes and survival after single lung transplantation (SLT), and therefore should be taken into consideration when selecting the transplant procedure. PATIENTS AND METHODS: Retrospective review of 258 lung transplants performed between June 2012 and June 2019. Among them, 161 SLT were selected for the analysis. Complications in the native lung were recorded and distributed into two groups: early and late complications (within 30 days or after 30 days post-transplant). Donor and recipient preoperative factors, 30-day mortality and survival were analysed and compared between groups by univariable and multivariable analyses, and adjusting for transplant indication. RESULTS: There were 161 patients (126M/35F; 57±7 years) transplanted for emphysema (COPD) (n = 72), pulmonary fibrosis (IPF) (n = 77), or other indications (n = 12). Forty-nine patients (30%) presented complications in the native lung. Thirty-day mortality did not differ between patients with or without early complications (6% vs. 12% respectively; p = 0.56). Twelve patients died due to a native lung complication (7.4% of patients; 24% of all deaths). Survival (1,3,5 years) without vs. with late complications: COPD (89%, 86%, 80% vs. 86%, 71%, 51%; p = 0.04); IPF (83%, 77%, 72% vs. 93%, 68%, 58%; p = 0.65). Among 30-day survivors: COPD (94%, 91%, 84% vs. 86%, 71%, 51%; p = 0.01); IPF (93%, 86%, 81% vs. 93%, 68%, 58%; p = 0.19). Native lung complications were associated to longer ICU stay (10±17 vs. 33±96 days; p<0.001), longer postoperative intubation (41±85 vs. 99±318 hours; p = 0.006), and longer hospital stay (30±24 vs. 45±34 days; p = 0.03). The presence of late native lung problems predicted survival in COPD patients (OR: 2.55; p = 0.07). CONCLUSION: The native lung is a source of morbidity in the short-term and mortality in the long-term after lung transplantation. This should be taken into consideration when choosing the transplant procedure, especially in COPD patients.

Relationship Among Radiological Measurements of Anterior Mediastinal Fat and Outcomes of Lung Transplantation in Fibrotic Patients / Relación entre las medidas radiológicas de la grasa mediastínica anterior y los resultados del trasplante de pulmón en pacientes con fibrosis

OBJECTIVE: Lung transplantation (LT) for pulmonary fibrosis is related to higher mortality than other transplant indications. We aim to assess whether the amount of anterior mediastinal fat (AMF) was associated to early and long-term outcomes in fibrotic patients undergoing LT. METHODS: Retrospective analysis of 92 consecutive single lung transplants (SLT) for pulmonary fibrosis over a 10-year period. AMF dimensions were measured on preoperative CT-scan: anteroposterior axis (AP), transverse axis (T), and height (H). AMF volumes (V) were calculated by the formula: AP×T×H×3.14/6. According to the radiological AMF dimensions, patients were distributed into two groups: low-AMF (V < 20 cm3) and high-AMF (V > 20 cm3), and early and long-term outcomes were compared by univariable and multivariable analyses. RESULTS: There were 92 SLT: 73M/19F, 53 ± 11 [14-68] years old. 30-Day mortality (low-AMF vs. high-AMF): 5 (5.4%) vs. 15 (16.3%), p = 0.014. Patients developing primary graft dysfunction within 72 h post-transplant, and those dying within 30 days post-transplant presented higher AMF volumes: 21.1 ± 19.8 vs. 43.3 ± 24.7 cm3 (p = 0.03) and 24.4 ± 24.2 vs. 56.9 ± 63.6 cm3 (p < 0.01) respectively. Overall survival (low-AMF vs. high-AMF) (1, 3, and 5 years): 85%, 81%, 78% vs. 55%, 40%, 33% (p < 0.001). Factors predicting 30-day mortality were: BMI (HR = 0.77, p = 0.011), AMF volume (HR = 1.04, p = 0.018), CPB (HR = 1.42, p = 0.002), ischaemic time (HR = 1.01, p = 0.009). Factors predicting survival were: AMF volume (HR=1.02, p < 0.001), CPB (HR = 3.17, p = 0.003), ischaemic time (HR = 1.01, p = 0.001). CONCLUSION: Preoperative radiological assessment of mediastinal fat dimensions and volumes may be a useful tool to identify fibrotic patients at higher risk of mortality after single lung transplantation

OBJETIVO: El trasplante de pulmón (TP) para el tratamiento de la fibrosis pulmonar está relacionado con una mayor mortalidad que otras indicaciones de trasplante. Nuestro objetivo es evaluar si la cantidad de grasa mediastínica anterior (GMA) se asoció a los diferentes resultados tempranos y a largo plazo en pacientes con fibrosis a los que se les realizó un TP. MÉTODOS: Análisis retrospectivo de 92 trasplantes de pulmón unilaterales (TPU) consecutivos para el tratamiento de la fibrosis pulmonar durante un período de 10 años. Se midieron las dimensiones de la GMA en la TC preoperatoria: eje anteroposterior (AP), eje transversal (T) y altura (A). Los volúmenes de GMA (V) se calcularon mediante la fórmula: AP×T×A×3,14/6. Según las dimensiones radiológicas de la GMA, los pacientes se distribuyeron en 2 grupos: GMA baja (V < 20 cm3) y GMA alta (V > 20 cm3), y los resultados tempranos y a largo plazo se compararon mediante análisis univariables y multivariables. RESULTADOS: Se realizaron 92 TPU: 73V/19M, 53 ± 11 (14-68) años. Mortalidad a 30 días (GMA baja frente a GMA alta): 5 (5,4%) frente a 15 (16,3%); p = 0,014. Los pacientes que desarrollaron disfunción precoz del injerto dentro de las 72 h posteriores al trasplante, y los que murieron dentro de los 30 días posteriores al trasplante presentaron mayores volúmenes de GMA: 21,1±19,8 frente a 43,3 ± 24,7 cm3 (p = 0,03) y 24,4 ± 24,2 frente a 56,9 ± 63,6 cm3 (p < 0,01), respectivamente. Supervivencia global (GMA baja frente a GMA alta) (a los 1, 3 y 5 años): 85, 81 y 78% frente al 55, 40 y 33% (p < 0,001), respectivamente. Los factores que predijeron la mortalidad a los 30 días fueron: IMC (HR = 0,77; p = 0,011), volumen de la GMA (HR = 1,04; p = 0,018), CEC (HR = 1,42; p = 0,002), tiempo de isquemia (HR=1,01; p = 0,009). Los factores que predijeron la supervivencia fueron: volumen GMA (HR = 1,02; p < 0,001), CEC (HR = 3,17; p = 0,003) y tiempo de isquemia (HR = 1,01; p = 0,001)

Relationship Among Radiological Measurements of Anterior Mediastinal Fat and Outcomes of Lung Transplantation in Fibrotic Patients.

OBJECTIVE: Lung transplantation (LT) for pulmonary fibrosis is related to higher mortality than other transplant indications. We aim to assess whether the amount of anterior mediastinal fat (AMF) was associated to early and long-term outcomes in fibrotic patients undergoing LT. METHODS: Retrospective analysis of 92 consecutive single lung transplants (SLT) for pulmonary fibrosis over a 10-year period. AMF dimensions were measured on preoperative CT-scan: anteroposterior axis (AP), transverse axis (T), and height (H). AMF volumes (V) were calculated by the formula: AP×T×H×3.14/6. According to the radiological AMF dimensions, patients were distributed into two groups: low-AMF (V<20cm3) and high-AMF (V>20cm3), and early and long-term outcomes were compared by univariable and multivariable analyses. RESULTS: There were 92 SLT: 73M/19F, 53±11 [14-68] years old. 30-Day mortality (low-AMF vs. high-AMF): 5 (5.4%) vs. 15 (16.3%), p=0.014. Patients developing primary graft dysfunction within 72h post-transplant, and those dying within 30 days post-transplant presented higher AMF volumes: 21.1±19.8 vs. 43.3±24.7cm3 (p=0.03) and 24.4±24.2 vs. 56.9±63.6cm3 (p<0.01) respectively. Overall survival (low-AMF vs. high-AMF) (1, 3, and 5 years): 85%, 81%, 78% vs. 55%, 40%, 33% (p<0.001). Factors predicting 30-day mortality were: BMI (HR=0.77, p=0.011), AMF volume (HR=1.04, p=0.018), CPB (HR=1.42, p=0.002), ischaemic time (HR=1.01, p=0.009). Factors predicting survival were: AMF volume (HR=1.02, p<0.001), CPB (HR=3.17, p=0.003), ischaemic time (HR=1.01, p=0.001). CONCLUSION: Preoperative radiological assessment of mediastinal fat dimensions and volumes may be a useful tool to identify fibrotic patients at higher risk of mortality after single lung transplantation.

Metabolomic profiling of human lung tumor tissues - nucleotide metabolism as a candidate for therapeutic interventions and biomarkers.

Although metabolomics has attracted considerable attention in the field of lung cancer (LC) detection and management, only a very limited number of works have applied it to tissues. As such, the aim of this study was the thorough analysis of metabolic profiles of relevant LC tissues, including the most important histological subtypes (adenocarcinoma and squamous cell lung carcinoma). Mass spectrometry-based metabolomics, along with genetic expression and histological analyses, were performed as part of this study, the widest to date, to identify metabolic alterations in tumors of the most relevant histological subtypes in lung. A total of 136 lung tissue samples were analyzed and 851 metabolites were identified through metabolomic analysis. Our data show the existence of a clear metabolic alteration not only between tumor vs. nonmalignant tissue in each patient, but also inherently intrinsic changes in both AC and SCC. Significant changes were observed in the most relevant biochemical pathways, and nucleotide metabolism showed an important number of metabolites with high predictive capability values. The present study provides a detailed analysis of the metabolomic changes taking place in relevant biochemical pathways of the most important histological subtypes of LC, which can be used as biomarkers and also to identify novel targets.

The components of somatostatin and ghrelin systems are altered in neuroendocrine lung carcinoids and associated to clinical-histological features.

BACKGROUND: Lung carcinoids (LCs) are rare tumors that comprise 1-5% of lung malignancies but represent 20-30% of neuroendocrine tumors. Their incidence is progressively increasing and a better characterization of these tumors is required. Alterations in somatostatin (SST)/cortistatin (CORT) and ghrelin systems have been associated to development/progression of various endocrine-related cancers, wherein they may become useful diagnostic, prognostic and therapeutic biomarkers. OBJECTIVES: We aimed to evaluate the expression levels of ghrelin and SST/CORT system components in LCs, as well as to explore their putative relationship with histological/clinical characteristics. PATIENTS AND METHODS: An observational retrospective study was performed; 75 LC patients with clinical/histological characteristics were included. Samples from 46 patients were processed to isolate mRNA from tumor and adjacent non-tumor region, and the expression levels of SST/CORT and ghrelin systems components, determined by quantitative-PCR, were compared to those of 7 normal lung tissues. RESULTS: Patient cohort was characterized by mean age 53±15 years, 48% males, 34% with tobacco exposure; 71.4/28.6% typical/atypical carcinoids, 21.7% incidental tumors, 4.3% functioning tumors, 17.7% with metastasis. SST/CORT and ghrelin system components were expressed at variable levels in a high proportion of tumors, as well as in adjacent non-tumor tissues, while a lower proportion of normal lung samples also expressed these molecules. A gradation was observed from normal non-neoplastic lung tissues, non-tumor adjacent tissue and LCs, being SST, sst4, sst5, GHS-R1a and GHS-R1b overexpressed in tumor tissue compared to normal tissue. Importantly, several SST/CORT and ghrelin system components displayed significant correlations with relevant clinical parameters, such as necrosis, peritumoral and vascular invasion, or metastasis. CONCLUSION: Altogether, these data reveal a prominent, widespread expression of key SST/CORT/ghrelin system components in LCs, where they display clinical-histological correlations, which could provide novel, valuable markers for NET patient management.

Lung transplantation for cystic fibrosis: differential characteristics and outcomes between children and adults.

OBJECTIVES: The survival benefit of lung transplantation (LTx) for cystic fibrosis (CF) patients is well demonstrated. We aim to compare children and adult CF recipients to assess whether there are differences in survival and clinical outcomes, and to identify risk factors for mortality. METHODS: A retrospective analysis of 442 consecutive LTx performed at our institution in a 20-year period was conducted. CF patients were distributed into two groups: children (age <18 years) and adults (age ≥18 years). Donor and recipient general demographic data, perioperative and postoperative factors including 30-day mortality, survival, primary graft dysfunction (PGD), complications, acute rejection (AR) and chronic lung allograft dysfunction (CLAD) were analysed and compared between groups. Univariable, Kaplan-Meier and Cox regression analyses were performed. RESULTS: The study group included 120 consecutive CF patients: 50 children (13 ± 3 years) and 70 adults (25 ± 6 years) undergoing 111 bilateral, 4 lobar, 4 combined and 1 unilateral LTx. Comparative analysis (children versus adults): survival (overall; 5, 10 and 15 years) 57, 45, 35% vs 67, 55, 43% (P = 0.32); survival (1-year survivors; 5, 10 and 15 years): 75, 64, 46% vs 90, 75, 59% (P = 0.09); 30-day mortality: 14 vs 16% (P = 0.27); urgent LTx: 32 vs 17% (P = 0.04); use of cardiopulmonary bypass (CPB): 56 vs 28% (P = 0.002); intensive care unit stay: 20 ± 19 vs 10 ± 9 days (P = 0.006); AR episodes (n): 1.4 ± 0.7 vs 1.2 ± 0.8 (P = 0.004). Incidence of PGD and freedom from CLAD did not differ between groups. Predictors of mortality were: use of CPB (HR 3.12; 95% CI 1.33-7.35; P < 0.01), post-transplant diabetes mellitus (HR 2.49; 95% CI 1.13-5.43; P = 0.02) and pneumonia episodes within the first month post-transplant (HR 2.82; 95% CI 1.27-6.29; P = 0.01). CONCLUSION: Paediatric CF patients usually present with poorer pre-transplant status, require CPB more frequently and have a higher incidence of post-LTx diabetes and infections. This might explain the trend towards a better long-term survival observed in adult CF patients.

The Expression of the Ubiquitin Ligase SIAH2 (Seven In Absentia Homolog 2) Is Increased in Human Lung Cancer.

OBJECTIVES: Lung cancer is the leading cause of cancer-related deaths worldwide. Overall 5-year survival has shown little improvement over the last decades. Seven in absentia homolog (SIAH) proteins are E3 ubiquitin ligases that mediate proteasomal protein degradation by poly-ubiquitination. Even though SIAH proteins play a key role in several biological processes, their role in human cancer remains controversial. The aim of the study was to document SIAH2 expression pattern at different levels (mRNA, protein level and immunohistochemistry) in human non-small cell lung cancer (NSCLC) samples compared to surrounding healthy tissue from the same patient, and to analyse the association with clinicopathological features. MATERIALS AND METHODS: One hundred and fifty-two samples from a patient cohort treated surgically for primary lung cancer were obtained for the study. Genic and protein expression levels of SIAH2 were analysed and compared with clinic-pathologic variables. RESULTS: The present study is the first to analyze the SIAH2 expression pattern at different levels (RNA, protein expression and immunohistochemistry) in non-small cell lung cancer (NSCLC). We found that SIAH2 protein expression is significantly enhanced in human lung adenocarcinoma (ADC) and squamous cell lung cancer (SCC). Paradoxically, non-significant changes at RNA level were found, suggesting a post-traductional regulatory mechanism. More importantly, an increased correlation between SIAH2 expression and tumor grade was detected, suggesting that this protein could be used as a prognostic biomarker to predict lung cancer progression. Likewise, SIAH2 protein expression showed a strong positive correlation with fluorodeoxyglucose (2-deoxy-2(18F)fluoro-D-glucose) uptake in primary NSCLC, which may assist clinicians in stratifying patients at increased overall risk of poor survival. Additionally, we described an inverse correlation between the expression of SIAH2 and the levels of one of its substrates, the serine/threonine kinase DYRK2. CONCLUSIONS: Our results provide insight into the potential use of SIAH2 as a novel target for lung cancer treatment.

Extended recipients but not extended donors are associated with poor outcomes following lung transplantation.

OBJECTIVES: Extended donors (EDs) are safely used to increase the donor pool in lung transplantation (LT), but their influence in critically ill patients (extended recipients [ERs]) remains controversial. We compared LT outcomes matching optimal donors (ODs) or EDs with optimal recipients (ORs) or ERs. METHODS: Three hundred and sixty-five LTs were reviewed. ED criteria: age >55, PaO2/FiO2 < 350 mmHg, pulmonary infiltrates/purulent secretions and ischaemic times >6 h (single LT [SLT]) and >9 h (double LT [DLT]). ER criteria: pulmonary fibrosis or pulmonary hypertension, pretransplant intubation, age >60 years and bypass >2 h. Four groups were created: Group 1 (OD/OR), Group 2 (OD/ER), Group 3 (ED/OR) and Group 4 (ED/ER). Thirty-day mortality, primary graft dysfunction (PGD), onset of bronchiolitis obliterans syndrome (BOS), long-term survival and other transplant outcomes were compared between OD and ED, OR and ER and among the four groups of study. RESULTS: There were 151 SLTs and 214 DLTs. Donors: OD (n = 229) vs ED (n = 136); PGD 8 vs 10% (P = 0.43); 30-day mortality 19 vs 20% (P = 0.53) and survival (1, 5, 10 and 15 years) 67, 47, 34, 26 vs 69, 53, 46 and 29% (P = 0.33). Recipients: OR (n = 182) vs ER (n = 183); PGD 7 vs 10% (P = 0.10); 30-day mortality 15 vs 23% (P = 0.04) and survival (1, 5, 10 and 15 years): 73, 57, 46, 30 vs 61, 42, 29 and 23% (P = 0.002). Four donor/recipient (D/R) groups: Group 1 (n = 122), Group 2 (n = 106), Group 3 (n = 61), Group 4 (n = 76); PGD 10, 6, 3 and 16% (P = 0.05); 30-day mortality 13, 26, 19 and 20%, respectively (P = 0.13); survival (1, 5, 10 and 15 years) 74, 55, 44 and 35% (Group 1), 55, 39, 22 and 16% (Group 2), 70, 59, 48 and 26% (Group 3) and 68, 47, 37 and 22% (Group 4) (P = 0.004). No differences in the onset of BOS were observed among the four study groups. CONCLUSIONS: LT in critically ill recipients is associated with poor early and long-term outcomes, irrespective of the quality of the donor and length of ischaemic times.

Economic evaluation of botulinum toxin versus thoracic sympathectomy for palmar hyperhidrosis: data from a real-world scenario.

INTRODUCTION: Local botulinum toxin injections and endoscopic thoracic sympathectomy (ETS) have shown clinical effectiveness for the treatment of palmar hyperhidrosis in several studies. Although both strategies cause considerable costs for health-care systems, at the moment there are no studies examining directly their cost-effectiveness performance. The aim of the study was to assess the incremental cost-effectiveness of botulinum toxin when compared with ETS for palmar hyperhidrosis. MATERIALS AND METHODS: Costs, effectiveness, and incremental cost-effectiveness ratio (ICER) were calculated. Costs were assessed from a Spanish National Health System perspective in a historical cohort of patients with palmar hyperhidrosis attending a tertiary referral hospital. Effectiveness was evaluated by using the Hyperhidrosis Disease Severity Scale (HDSS). A responder was defined as a patient who reported at least a two-grade improvement on the HDSS scale with respect to the baseline value. The horizon of time was 1 year. RESULTS: Effectiveness was greater for ETS (n = 128) when compared with botulinum toxin (n = 100) for the treatment of palmar hyperhidrosis (92% vs. 68%; odds ratio (OR) = 6.22 [2.80, 13.80]; absolute risk ratio (ARR) = -0.24 [-0.45, -0.14]; number-needed-to-treat (NNT) = -4 [-2, -11]). Botulinum toxin had an ICER of 125 € when compared with ETS during the first year of treatment. CONCLUSIONS: In this retrospective real-world observational sample of patients with palmar hyperhidrosis, treatment with ETS appears to be more effective and less costly when compared with botulinum toxin during the first year of treatment. Analyses such as this give decision makers the tools to choose a better treatment option which is both highly effective and yet has a low cost.

Early lung retrieval from traumatic brain-dead donors does not compromise outcomes following lung transplantation.

OBJECTIVES: To determine whether lung retrieval from traumatic donors performed within 24 h of brain death has a negative impact on early graft function and survival after lung transplantation (LT), when compared with those retrieved after 24 h. METHODS: Review of lung transplants performed from traumatic donors over a 17-year period. Recipients were distributed into two groups: transplants from traumatic donor lungs retrieved within 24 h of brain death (Group A), and transplants from traumatic donor lungs retrieved after 24 h of brain death (Group B). Demographic data of donors and recipients, early graft function, perioperative complications and mortality were compared between both groups. RESULTS: Among 356 lung transplants performed at our institution, 132 were from traumatic donors (70% male, 30% female). Group A: 73 (55%); Group B: 59 (45%). There were 53 single, 77 double, and 2 combined LT. Indications were emphysema in 41 (31%), pulmonary fibrosis in 31 (23%), cystic fibrosis in 38 (29%), bronchiectasis in 9 (7%) and other indications in 13 patients (10%). Donor and recipient demographic data, need or cardiopulmonary bypass, postoperative complications and Intensive Care Unit and hospital stay did not differ between groups. Primary graft dysfunction (A vs B): 9 (16%) vs 13 (26%) P = 0.17. PaO2/FiO2 24 h post-transplant (A vs B): 303 mmHg vs 288 mmHg (P = 0.57). Number of acute rejection episodes (A vs B): 0.93 vs 1.49 (P = 0.01). Postoperative intubation time (A vs B): 99 vs 100 h (P = 0.99). 30-day mortality (A vs B): 7 (10%) vs 2 (3.5%) (P = 0.13). Freedom from bronchiolitis obliterans syndrome (A vs B): 82, 72, 37, 22 vs 78, 68, 42, 15%, at 3, 5, 10 and 15 years, respectively (P = 0.889). Survival (A vs B): 65, 54, 46, 42 and 27 vs 60, 50, 45, 43 and 29% at 3, 5, 7, 10 and 15 years, respectively (P = 0.937). CONCLUSIONS: In our experience, early lung retrieval after brain death from traumatic donors does not adversely affect early and long-term outcomes after LT.

Registro Español de Trasplante Pulmonar: primer informe de resultados (2006-2010) / The Spanish Lung Transplant Registry: First Report of Results (2006-2010)

El Registro Español de Trasplante Pulmonar (RETP) inició su actividad en 2006, participando en él todos los equipos de trasplante pulmonar (TP) con un programa activo en España. Este informe presenta por primera vez de forma global la descripción y resultados de los pacientes trasplantados de pulmón en España entre los años 2006 y 2010. La actividad de TP ha ido en progresivo aumento, trasplantándose en este periodo 951 adultos y 31 niños. La media de edad del receptor fue de 48,2 años, siendo 41,7 años en el donante pulmonar. En el TP adulto, la causa más frecuente de trasplante fue el enfisema/EPOC, seguido de la fibrosis pulmonar idiopática, representando ambas más del 60% del total de las indicaciones. La probabilidad de supervivencia tras el TP adulto a uno y 3 años es del 72 y del 60%, respectivamente, si bien en los pacientes que sobreviven al tercer mes postrasplante estas supervivencias son del 89,7 y del 75,2%. Los factores que más claramente inciden en la supervivencia del paciente son la edad del receptor y el diagnóstico que indicó el trasplante. En los trasplantes pediátricos, la fibrosis quística es la principal causa de trasplante (68%), y la supervivencia al año es del 80, y del 70% a los 3 años. Tanto en el trasplante adulto como en el pediátrico, la causa más frecuente de fallecimiento es la infección. Estos datos confirman la consolidación del TP en España como una opción terapéutica para la enfermedad respiratoria crónica avanzada, tanto en niños como en adultos(AU)

The Spanish Lung Transplant Registry (SLTR) began its activities in 2006 with the participation of all the lung transplantation (LT) groups with active programs in Spain. This report presents for the first time an overall description and results of the patients who received lung transplants in Spain from 2006 to 2010. LT activity has grown progressively, and in this time period 951 adults and 31 children underwent lung transplantation. The mean age of the recipients was 48.2, while the mean age among the lung donors was 41.7. In adult LT, the most frequent cause for lung transplantation was emphysema/COPD, followed by idiopathic pulmonary fibrosis, both representing more than 60% the total number of indications. The probability for survival after adult LT to one and three years was 72% and 60%, respectively, although in patients who survived until the third month post-transplantation, these survival rates reached 89.7% and 75.2%. The factors that most clearly influenced patient survival were the age of the recipient and the diagnosis that indicated the transplantation. Among the pediatric transplantations, cystic fibrosis was the main cause for transplantation (68%), with a one-year survival of 80% and a three-year survival of 70%. In adult as well as pediatric transplantations, the most frequent cause of death was infection. These data confirm the consolidated situation of LT in Spain as a therapeutic option for advanced chronic respiratory disease, both in children as well as in adults(AU)

Influence of donor-recipient gender mismatch on graft function and survival following lung transplantation.

OBJECTIVES: In current practice, donors and recipients are not matched for gender in lung transplantation. However, some data have suggested a possible effect of gender combinations on lung transplant outcomes. We examined whether donor-recipient (D/R) gender mismatch is related to adverse outcomes after lung transplantation in terms of early and long-term graft function and survival. METHODS: We reviewed 256 donors and lung transplant recipients over a 14-year period. Patients were distributed into four groups: Group A (D/R: female/female), Group B (D/R: male/male), Group C (D/R: female/male), Group D (D/R: male/female). Donor and recipient variables were compared among groups, including early graft function, 30-day mortality, freedom from bronchiolitis obliterans syndrome (BOS), and long-term survival. RESULTS: Group A: 57 (22%), Group B: 99 (39%), Group C: 62 (24%), Group D: 38 (15%) transplants (P = 0.001). Donor age was 29 ± 14, 27 ± 12, 33 ± 13 and 23 ± 12 years for Groups A, B, C and D, respectively (P = 0.004). Recipient age was 31 ± 15, 44 ± 17, 42 ± 16 and 30 ± 16 years for Groups A, B, C and D, respectively (P = 0.000). PaO2/FiO2 (mmHg) 24 h post-transplant was: Group A: 276 ± 144, Group B: 297 ± 131, Group C: 344 ± 133 and Group D: 238 ± 138 (P = 0.015). Primary graft dysfunction developed in 23, 14, 17 and 21% of recipients from Groups A, B, C and D, respectively (P = 0.45). Operative mortality was 4.4, 6.5, 5.2 and 2%, for recipients from Groups A, B, C and D, respectively (P = 0.66). Freedom from BOS was 73, 59 and 36% for gender-matched transplants vs 76, 67 and 40% for gender-mismatched transplants at 3, 5 and 10 years, respectively (P = 0.618), without differences among groups. A non-significant survival benefit was observed for female recipients, irrespective of the donor gender. CONCLUSIONS: Donor-recipient gender mismatch does not have a negative impact on early graft function and mortality following lung transplantation. There is a trend towards a survival benefit for female recipients, irrespective of the donor gender.