Epidemiology and Risk Factors for Cancer After Lung Transplantation.

Cancer is the third most common cause of death among lung transplant (LT) recipients who survive for more than 1 year. The purpose of this study was to analyze the incidence and risk factors for cancer after LT in a Spanish cohort. The epidemiology and risk factors for cancer were retrospectively analyzed in LT recipients from 2 cities in Spain, Madrid and Barcelona. Of the 1353 LT patients initially included in the study, 125 (9.2%) developed cancer after a mean of 3.7 years. This frequency was 5-fold higher than in the general population. The most prevalent tumors were skin cancer (32%), lymphoproliferative disease (18%), and lung cancer (16.5%). In 4 patients, lung cancer was diagnosed on the day of the operation. The risk of cancer increased with age >55 year (hazard ratio [HR] 2.89 [1.64-5.09]; P < .001), in men (HR 2.8 [1.4-5.6]; P = .004), and in heavy smokers (>20 pack-years) (HR 2.94 [1.64-5.27]; P < .001). Other factors such as sun exposure were not found to be risk factors. In conclusion, prevalence of cancer is high in LT recipients in a Mediterranean country. Skin tumors, lymphoproliferative disease, and lung cancer are the most prevalent cancers. Age, male sex, and smoking were the main risk factors for cancer in this population.

An homozygous mutation in KCNK3 is associated with an aggressive form of hereditary pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a rare devastating disease characterized by a high genetic heterogeneity with several related genes recently described, including BMPR2,TBX4 and KCNK3. The association between KCNK3 and PAH has been recently identified, but the prognosis and phenotype associated with these mutations have been poorly described. We studied a series of 136 idiopathic and hereditary PAH Spanish patients for BMPR2, TBX4 and KCNK3 mutations. We report the results of KCNK3 in which we were able to describe two new mutations (p.Gly106Arg and p.Leu214Arg) in three patients. The first one was found in a patient belonging to a consanguineous Romani family, who carried a homozygous mutation in KCNK3 and developed a severe and early form of the disease. To the best of our knowledge, this is the first time that a homozygous mutation in KCNK3 is reported in a PAH patient. The second one was found in a patient who presented at the young adult age a severe form of the disease. The present report supports the contribution of KCNK3 mutations to the genetic etiology of PAH and strongly suggests that mutations in KCNK3 follow incomplete dominance with worsening of the clinical features in homozygous patients.

A founder EIF2AK4 mutation causes an aggressive form of pulmonary arterial hypertension in Iberian Gypsies.

Pulmonary arterial hypertension (PAH) is a pathological condition characterized by a persistent and progressive elevation of pulmonary vascular resistance with devastating consequences if untreated. In the past recent years, several genes have been related to PAH, however, the molecular defect remains unknown in a significant proportion of patients with familial PAH (∼20%). During the past few years, we have observed that PAH shows a particular behavior in Iberian Gypsies, with more aggressive course and frequently affecting multiple members of the same family. We studied five Gypsy families in whom at least one individual from each family developed a severe form of PAH and in whom no mutation had been identified in the common genes. We applied SNP-array-based homozygosity mapping in three families and obtained, among others, one of which included the gene EIF2AK4, recently reported in patients with PAH from group-1' pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH). Subsequently, we sequenced EIF2AK4 and found a homozygous mutation in all five families: c.3344C>T(p.P1115L). The majority of our patients required early lung transplantation. Hence, this mutation appeared with a more severe phenotype than previously reported for other EIF2AK4 mutations. The finding of this novel mutation is important for genetic counseling and calculation of population recurrence risks.

Biomarkers of pulmonary rejection.

Immunologic complications after lung transplantation (LT) include acute cellular rejection (ACR), antibody-mediated rejection (AMR), and most forms of chronic allograft dysfunction (CAD). ACR is an inflammatory process in which the reaction is mediated by the T-cell population. Most episodes of ACR fully recover with treatment, but repeated bouts are considered to be a risk factor for CAD. Biomarker cytokines interleukin (IL)-10, IL-15, IL-6, CCL5, CCR2 and IFNγ may play significant roles in this complication. Formerly bronchiolitis obliterans syndrome (BOS) or chronic rejection or most forms of CAD were considered to be immunologic complications not amenable therapeutic measures. CAD, the main limitation for long-term survival in LT, is characterized histologically by airway epithelial cell apoptosis and luminal fibrosis in the respiratory bronchioles causing airflow obstruction and, in some cases, lung parenchymal affectations causing restrictive lung disease. Several biomarkers have been studied in CAD, IL-6, IL-8, IL-17, IL-23, IL-13, IFN γ, and TGF ß cytokines, pH, bile acid, and tripsine of gastroesophageal reflux and toll-like receptors of innate immunity. Herein we have reviewed the literature of biomarkers involved in lung rejection.

Inhaled iloprost plus oral sildenafil in patients with severe pulmonary arterial hypertension delays the need for lung transplantation.

BACKGROUND: Accepted treatment for severe pulmonary arterial hypertension (PAH) includes intravenous epoprostenol and lung transplantation (LT). Inhaled iloprost plus oral sildenafil (Ilo-Sil) is an alternative strategy that may also delay the need for LT. PATIENTS AND METHODS: This was a long-term descriptive study in eight patients with PAH functional class (FC) IV with right heart failure, four of them potential candidates for LT, who were treated with Ilo-Sil as an alternative to epoprostenol. RESULTS: At the start of the study, patients (seven women; mean age, 43.8 [range, 34-66] years) were in FC IV and unable to perform the 6-minute walk test. Mean cardiac index was 1.9 (range, 1.4-2.1) L/min/m(2). Treatment with Ilo-Sil provoked a rapid and sustained improvement; mean walking distance at 3 months was 322 ± 90 m and no patient remained in FC IV. Survival at 1 and 5 years was 100% and 75%, respectively. Of the four potential LT candidates, one underwent transplantation after 6.8 years and one died after 1.2 years. CONCLUSIONS: These results suggest that therapy with Ilo-Sil represents an acceptable alternative in patients with severe and unstable PAH.