Distribution of alpha1 antitrypsin rare alleles in six countries: Results from the Progenika diagnostic network.

BACKGROUND: Knowledge of the frequency of rare SERPINA1 mutations could help in the management of alpha1 antitrypsin deficiency (AATD). The present study aims to assess the frequencies of rare and null alleles and their respiratory and hepatic pathogenicity. METHODS: This is a secondary analysis of a study that evaluated the viability of the Progenika diagnostic genotyping system in six different countries by analyzing 30,827 samples from cases of suspected AATD. Allele-specific genotyping was carried out with the Progenika A1AT Genotyping Test which analyses 14 mutations in buccal swabs or dried blood spots samples. SERPINA1 gene sequencing was performed for serum AAT-genotype discrepancies or by request of the clinician. Only cases with rare mutations were included in this analysis. RESULTS: There were 818 cases (2.6%) carrying a rare allele, excluding newly identified mutations. All were heterozygous except for 20 that were homozygous. The most frequent alleles were the M-like alleles, PI*Mmalton and PI*Mheerlen. Of the 14 mutations included in the Progenika panel, there were no cases detected of PI*Siiyama, PI*Q0granite falls and PI*Q0west. Other alleles not included in the 14-mutation panel and identified by gene sequencing included PI*Mwürzburg, PI*Zbristol, and PI*Zwrexham, and the null alleles PI*Q0porto, PI*Q0madrid, PI*Q0brescia, and PI*Q0kayseri. CONCLUSIONS: The Progenika diagnostic network has allowed the identification of several rare alleles, some unexpected and not included in the initial diagnostic panel. This establishes a new perspective on the distribution of these alleles in different countries. These findings may help prioritize allele selection for routine testing and highlights the need for further research into their pathogenetic role.

Feasibility of a genotyping system for the diagnosis of alpha1 antitrypsin deficiency: a multinational cross-sectional analysis.

INTRODUCTION: Currently, strategies for improving alpha1 antitrypsin deficiency (AATD) diagnosis are needed. Here we report the performance of a multinational multiplex-based genotyping test on dried blood spots and buccal swabs sent by post or courier and with web registration for subjects with suspected AATD in Argentina, Brazil, Chile, Colombia, Spain, and Turkey. METHODS: This was an observational, cross-sectional analysis of samples from patients with suspected AATD from March 2018 to January 2022. Samples were coded on a web platform and sent by post or courier to the central laboratory in Northern Spain. Allele-specific genotyping for the 14 most common mutations was carried out with the A1AT Genotyping Test (Progenika-Grifols, Spain). SERPINA1 gene sequencing was performed if none of the mutations were found or one variant was detected in heterozygous status and the AAT serum level was < 60 mg/dl, or if requested by the clinician in charge. RESULTS: The study included 30,827 samples: 30,458 (94.7%) with final results after direct genotyping and 369 (1.1%) with additional gene sequencing. Only 0.3% of the samples were not processed due to their poor quality. The prevalence of the most frequent allele combinations was MS 14.7%, MZ 8.6%, SS 1.9%, SZ 1.9%, and ZZ 0.9%. Additionally, 70 cases with new mutations were identified. Family screening was conducted in 2.5% of the samples. Samples from patients with respiratory diseases other than COPD, including poorly controlled asthma or bronchiectasis, also presented AATD mutations. CONCLUSIONS: Our results confirm the viability of this diagnostic system for genotyping AATD conducted simultaneously in different countries. The system has proved satisfactory and can improve the timely diagnosis of AATD.

Incorporando nuevas evidencias sobre medicamentos inhalados en la EPOC. Asociación Latinoamericana de Tórax (ALAT) 2019 / Incorporating New Evidence on Inhaled Medications in COPD. The Latin American Chest Association (ALAT) 2019

Este documento sobre EPOC de la Asociación Latinoamericana de Tórax (ALAT) 2019 analiza las nuevas evidencias de medicación inhalada utilizando la metodología de preguntas clínicas en formato PICO. Surgen de este análisis los siguientes puntos claves: 1) no hay evidencia que compare el uso de broncodilatadores de acción corta vs. larga en pacientes con EPOC leve; en aquellos con EPOC moderada-grave existe mayor beneficio de los broncodilatadores de acción larga, 2) beneficios similares de la monoterapia con antimuscarínicos de acción prolongada (LAMA) y la terapia combinada β2-agonistas de acción larga/corticosteroides inhalados (LABA/CIS), asociada esta última a mayor riesgo de neumonía, 3) mayores beneficios del LABA/LAMA en función pulmonar y riesgo de exacerbación vs. LABA/CIS (esta última con mayor riesgo de neumonía) y 4) mayores beneficios de la terapia LAMA/LABA/CIS comparada con LABA/LAMA sobre el riesgo de exacerbaciones moderadas-severas. En relación al rol de los eosinófilos para guiar el uso de los CIS: debe considerarse su retiro cuando la indicación inicial fue errada o sin respuesta, en pacientes con efectos secundarios como neumonía, y en aquellos con bajo riesgo de exacerbación con recuento de eosinófilos en sangre < 300 cél/μl. Incorporando estas evidencias según la gravedad de la obstrucción, síntomas y riesgo de exacerbaciones se genera un algoritmo para el uso de medicación inhalada en la EPOC

This document on COPD from the Latin American Chest Association (ALAT-2019) uses PICO methodology to analyze new evidence on inhaled medication and answer clinical questions. The following key points emerged from this analysis: 1) evidence is lacking on the comparison of short-acting vs. long-acting bronchodilators in patients with mild COPD; patients with moderate-to-severe COPD obtain greater benefit from long-acting bronchodilators; 2) the benefits of monotherapy with long-acting antimuscarinic agents (LAMA) and combined therapy with long-acting β2-agonists and inhaled corticosteroids (LABA/ICS) are similar, although the latter is associated with a greater risk of pneumonia; 3) LABA/LAMA offer greater benefits in terms of lung function and risk of exacerbation than LABA/ICS (the latter involve an increased risk of pneumonia), 4) LAMA/LABA/ICS have greater therapeutic benefits than LABA/LAMA on the risk of moderate-severe exacerbations. With regard to the role of eosinophils in guiding the use of ICS, ICS withdrawal must be considered when the initial indication was wrong or no response is elicited, in patients with side effects such as pneumonia, and in patients with a low risk of exacerbation and an eosinophil blood count of <300 cells/μl. All this evidence, categorized according to the severity of the obstruction, symptoms, and risk of exacerbations, has been used to generate an algorithm for the use of inhaled medication in COPD

Incorporating New Evidence on Inhaled Medications in COPD. The Latin American Chest Association (ALAT) 2019. / Incorporando nuevas evidencias sobre medicamentos inhalados en la EPOC. Asociación Latinoamericana de Tórax (ALAT) 2019.

This document on COPD from the Latin American Chest Association (ALAT-2019) uses PICO methodology to analyze new evidence on inhaled medication and answer clinical questions. The following key points emerged from this analysis: 1) evidence is lacking on the comparison of short-acting vs. long-acting bronchodilators in patients with mild COPD; patients with moderate-to-severe COPD obtain greater benefit from long-acting bronchodilators; 2) the benefits of monotherapy with long-acting antimuscarinic agents (LAMA) and combined therapy with long-acting ß2-agonists and inhaled corticosteroids (LABA/ICS) are similar, although the latter is associated with a greater risk of pneumonia; 3) LABA/LAMA offer greater benefits in terms of lung function and risk of exacerbation than LABA/ICS (the latter involve an increased risk of pneumonia), 4) LAMA/LABA/ICS have greater therapeutic benefits than LABA/LAMA on the risk of moderate-severe exacerbations. With regard to the role of eosinophils in guiding the use of ICS, ICS withdrawal must be considered when the initial indication was wrong or no response is elicited, in patients with side effects such as pneumonia, and in patients with a low risk of exacerbation and an eosinophil blood count of <300 cells/µl. All this evidence, categorized according to the severity of the obstruction, symptoms, and risk of exacerbations, has been used to generate an algorithm for the use of inhaled medication in COPD.

Does neoadjuvant chemoradiation downstage locally advanced pancreatic cancer?

Recent studies suggest that neoadjuvant chemoradiation can downstage locally advanced pancreatic tumors. There is limited evaluable data to support this approach. We review our experience with preoperative chemoradiation for surgically staged, locally advanced pancreatic cancer to determine whether patients are downstaged with multimodal therapy allowing for curative resection. A prospectively collected database from Memorial Sloan-Kettering Cancer Center was reviewed. Patients admitted between January 1993 and March 1999 with locally advanced pancreatic adenocarcinoma were identified (N = 163). Chemoradiation was administered to 87 (53.3%) of 163, and regimens varied from standard 5-fluorouracil/gemcitabine-based therapies to experimental protocols. Only three patients (3/87; 3.4%) had a sufficient clinical response on restaging to warrant reexploration. Of these, two thirds were unresectable on subsequent laparoscopy because of extensive vascular involvement or metastatic disease. Only one patient underwent a potentially curative resection, with a survival of 18 months despite negative margins and no nodal involvement. The overall median survival for all patients with locally advanced disease treated with chemoradiation was 11 months (6.5 months without multimodal therapy; P = 0.004). Although chemoradiation is associated with improved overall survival in locally advanced disease, it rarely leads to surgical "downstaging" allowing for potentially curative pancreatic resections. Novel multimodality approaches are required.