CPAMD8 loss-of-function underlies non-dominant congenital glaucoma with variable anterior segment dysgenesis and abnormal extracellular matrix.

Abnormal development of the ocular anterior segment may lead to a spectrum of clinical phenotypes ranging from primary congenital glaucoma (PCG) to variable anterior segment dysgenesis (ASD). The main objective of this study was to identify the genetic alterations underlying recessive congenital glaucoma with ASD (CG-ASD). Next-generation DNA sequencing identified rare biallelic CPAMD8 variants in four patients with CG-ASD and in one case with PCG. CPAMD8 is a gene of unknown function and recently associated with ASD. Bioinformatic and in vitro functional evaluation of the variants using quantitative reverse transcription PCR and minigene analysis supported a loss-of-function pathogenic mechanism. Optical and electron microscopy of the trabeculectomy specimen from one of the CG-ASD cases revealed an abnormal anterior chamber angle, with altered extracellular matrix, and apoptotic trabecular meshwork cells. The CPAMD8 protein was immunodetected in adult human ocular fluids and anterior segment tissues involved in glaucoma and ASD (i.e., aqueous humor, non-pigmented ciliary epithelium, and iris muscles), as well as in periocular mesenchyme-like cells of zebrafish embryos. CRISPR/Cas9 disruption of this gene in F0 zebrafish embryos (96 hpf) resulted in varying degrees of gross developmental abnormalities, including microphthalmia, pharyngeal maldevelopment, and pericardial and periocular edemas. Optical and electron microscopy examination of these embryos showed iridocorneal angle hypoplasia (characterized by altered iris stroma cells, reduced anterior chamber, and collagen disorganized corneal stroma extracellular matrix), recapitulating some patients' features. Our data support the notion that CPAMD8 loss-of-function underlies a spectrum of recessive CG-ASD phenotypes associated with extracellular matrix disorganization and provide new insights into the normal and disease roles of this gene.

Executive summary of the SEPAR recommendations for the diagnosis and treatment of non-small cell lung cancer. / Sumario ejecutivo de las recomendaciones SEPAR de diagnóstico y tratamiento del cáncer de pulmón de células no pequeñas.

The Thoracic Surgery and Thoracic Oncology groups of the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR) have backed the publication of a handbook on recommendations for the diagnosis and treatment of non-small cell lung cancer. Due to the high incidence and mortality of this disease, the best scientific evidence must be constantly updated and made available for consultation by healthcare professionals. To draw up these recommendations, we called on a wide-ranging group of experts from the different specialties, who have prepared a comprehensive review, divided into 4 main sections. The first addresses disease prevention and screening, including risk factors, the role of smoking cessation, and screening programs for early diagnosis. The second section analyzes clinical presentation, imaging studies, and surgical risk, including cardiological risk and the evaluation of respiratory function. The third section addresses cytohistological confirmation and staging studies, and scrutinizes the TNM and histological classifications, non-invasive and minimally invasive sampling methods, and surgical techniques for diagnosis and staging. The fourth and final section looks at different therapeutic aspects, such as the role of surgery, chemotherapy, radiation therapy, a multidisciplinary approach according to disease stage, and other specifically targeted treatments, concluding with recommendations on the follow-up of lung cancer patients and surgical and endoscopic palliative interventions in advanced stages.

[Resection of pulmonary metastases in 148 patients: analysis of prognostic factors]. / Cirugía de metástasis pulmonares en 148 pacientes. Análisis de sus factores pronósticos.

OBJECTIVE: To evaluate the prognostic factors for survival in a series of patients who underwent surgery for pulmonary metastases from primary tumors in distinct organs. PATIENTS AND METHODS: This was a retrospective study of 148 patients operated between May 2001 and May 2007. Multivariate analysis was used to evaluate overall survival. Patients scheduled for tumorectomy were included provided their primary tumor was controlled and they had no extrathoracic recurrence and adequate cardiorespiratory function. The influence of the following prognostic factors was analyzed: number and diameter of the metastases, lymph node infiltration, complete resection, and, above all, histological type. A significance level of 95% was used. RESULTS: A total of 90 men (60.81%) and 58 women (39.19%) were operated. The mean (SD) age was 56.5 (9.7) years. The actuarial survival at 6 years was 30.3% (n=45) and the median survival was 34 months. The factors that affected survival were the number of metastases (P< .05), diameter of the lesions (P< .05), lymph node infiltration (P< .05), complete resection (P< .05), and, above all, histological type (P< .05). Tumorectomy was the most commonly performed operation. CONCLUSIONS: These results suggest that, in the absence of other therapeutic options and contraindications, we should operate on patients in whom the primary tumor is controlled and in whom complete resection can be performed. Even if factors associated with poor prognosis are present, the outcomes are always better than when surgery is not performed, particularly in view of the relatively low morbidity and mortality associated with this type of surgery.