Inhibition of HSP90 in Driver Oncogene-Defined Lung Adenocarcinoma Cell Lines: Key Proteins Underpinning Therapeutic Efficacy.

The use of 90 kDa heat shock protein (HSP90) inhibition as a therapy in lung adenocarcinoma remains limited due to moderate drug efficacy, the emergence of drug resistance, and early tumor recurrence. The main objective of this research is to maximize treatment efficacy in lung adenocarcinoma by identifying key proteins underlying HSP90 inhibition according to molecular background, and to search for potential biomarkers of response to this therapeutic strategy. Inhibition of the HSP90 chaperone was evaluated in different lung adenocarcinoma cell lines representing the most relevant molecular alterations (EGFR mutations, KRAS mutations, or EML4-ALK translocation) and wild-type genes found in each tumor subtype. The proteomic technique iTRAQ was used to identify proteomic profiles and determine which biological pathways are involved in the response to HSP90 inhibition in lung adenocarcinoma. We corroborated the greater efficacy of HSP90 inhibition in EGFR mutated or EML4-ALK translocated cell lines. We identified proteins specifically and significantly deregulated after HSP90 inhibition for each molecular alteration. Two proteins, ADI1 and RRP1, showed independently deregulated molecular patterns. Functional annotation of the altered proteins suggested that apoptosis was the only pathway affected by HSP90 inhibition across all molecular subgroups. The expression of ADI1 and RRP1 could be used to monitor the correct inhibition of HSP90 in lung adenocarcinoma. In addition, proteins such as ASS1, ITCH, or UBE2L3 involved in pathways related to the inhibition of a particular molecular background could be used as potential response biomarkers, thereby improving the efficacy of this therapeutic approach to combat lung adenocarcinoma.

Complicaciones obstétricas y perinatales por el SARS-CoV-2 en un hospital de referencia de la región Huancavelica / Obstetric and perinatal complications due to SARS-CoV-2 in a referral hospital in the Huancavelica region / Complicações obstétricas e perinatais devidas à SRA-CoV-2 em um hospital de referência na região de Huancavelica

Objetivos determinar las repercusiones obstétricas y perinatales gestantes SARS-CoV-2 positivas del Hospital Departamental de Huancavelica. Métodos estudio descriptivo de marzo 2020 a octubre 2021.Se realizó análisis documental de historias clínicas de gestantes con culminación del embarazo en la institución, y de los recién nacidos. Se empleó una ficha de recolección de datos validada Las gestantes admitidas eran positivas al SARS-CoV-2 con una prueba de laboratorio. Se realizó una estadística descriptiva. El estudio figura en el Registro Nacional de Investigaciones en Salud (CÓDIGO: EI00002480). Resultados Se admitieron 148 gestantes, con edad promedio de 27 años. Un 53,4% fueron controladas. La mayoría multíparas (80/54,1%). El diagnóstico del SARS-CoV-2 se realizó con detección de anticuerpos (85,6%). El 90,5% (134/148) fueron asintomáticas. Se registró neumonía por el SARS-Cov-2 en 8 casos. El aborto representó el 16,2%. La mayoría tenía edad gestacional a término (109/86,5%). La vía del parto fue similar para cesárea/parto vaginal (51,6%/48.4%). No hubo complicaciones obstétricas en 65,5%. Las complicaciones más frecuentes fueron: ruptura prematura de membranas y pre eclampsia. Los recién nacidos tuvieron puntajes de Apgar adecuados (94,4% al minuto/96,8% a los cinco minutos). Los prematuros representaron el 11,9%. En la mayoría hubo peso adecuado (86,5%). No se registraron neonatos positivos al SARS Cov-2. Conclusiones las gestantes atendidas en el Hospital Departamental de Huancavelica positivas al SARS-CoV-2 son asintomáticas en su mayoría, con complicaciones obstétricas más comunes la rotura prematura de membranas y la pre eclampsia. Los resultados perinatales de los recién nacidos son adecuados en la gran mayoría.

Objective. To determine obstetric and perinatal complications in SARS-CoV-2 pregnant women at the Departmental Hospital of Huancavelica. Methods. A descriptive, with documentary analysis of the medical records of pregnant women who completed their pregnancy at the institution and of the newborns. A validated data collection form was used. Admitted pregnant women were positive for SARS-CoV-2 with a laboratory test. Descriptive statistics were performed, establishing frequencies, averages and percentages. The study is included in the National Health Research Registry. Results. A total of 148 pregnant women were admitted, average age 27 years. A 53.4 % were controlled. The majority, 54.1 % (80), were multiparous. The diagnosis of SARS-CoV-2 was made by detection of antibodies (85.6 %). A total of 90.5 % (134/148) were asymptomatic. SARS-Cov-2 pneumonia was recorded in 8 cases. Abortion accounted for 16.2 %. The majority, 86.5 % (109), were of term gestational age. The route of delivery was similar for cesarean/vaginal delivery (51.6 %/48.4 %). There were no obstetric complications (65.5 %). The most frequent complications were: premature rupture of membranes and preeclampsia. The newborns had adequate Apgar scores (94.4 % at one minute/96.8 % at fve minutes). Preterm infants accounted for 11.9 %. Most of them had adequate weight (86.5 %). There were no SARS Cov-2 positive neonates. Conclusions. Most of the pregnant women attended at the Departmental Hospital, positive for SARS-CoV-2, were asymptomatic. The most frequent obstetric complications were premature rupture of membranes and preeclampsia. The perinatal outcomes of the newborns were adequate in the great majority

Para determinar as complicações obstétricas e perinatais em mulheres grávidas com SARS-CoV-2 no Hospital Departamental de Huancavelica. Métodos. Estudo estudo descritivo, com análise documental das histórias clínicas de mulheres grávidas com gravidez na instituição e dos recém-nascidos. Um validado foi utilizado um formulário de coleta de dados validado. As mulheres grávidas admitidas foram positivas para SARS-CoV-2 com um teste de laboratório. Foram realizadas estatísticas descritivas, freqüências, médias e porcentagens foram estabelecidas. O estudo está incluído no Registro Nacional de Pesquisa em Saúde. Resultados. Um total de 148 mulheres grávidas foram admitidas. mulheres grávidas, idade média de 27 anos. Cerca de 53,4 % foram controlados. A maioria, 54,1 % (80) eram multiparos. O diagnóstico do SARS-CoV-2 foi feito pela detecção de anticorpos (85,6 %). detecção de anticorpos (85,6 %). 90,5 % (134/148) eram assintomáticos. Pneumonia devido à SARS foi A pneumonia SARS-Cov-2 foi registrada em 8 casos. O aborto representou 16,2 %. O A maioria, 86,5 % (109), era de idade gestacional. A rota de entrega foi semelhante para cesariana/vaginal (51,6 %/48,4 %). Não houve complicações obstétricas (65,5 %). As complicações mais freqüentes foram: ruptura prematura de membranas e pré-eclâmpsia. membranas e pré-eclâmpsia. Os recém-nascidos tiveram pontuações Apgar adequadas (94,4% a um minuto). pontuações (94,4 % a um minuto/96,8 % a cinco minutos). Bebês prematuros representou 11,9 %. A maioria tinha peso adequado ao nascimento (86,5 %). Sem SAR positivo não foram registrados neonatos positivos SARS Cov-2. Conclusões. A maioria dos A maioria das gestantes positivas do SARS-CoV-2 vistas no hospital eram assintomáticas. As complicações obstétricas mais freqüentes foram a ruptura prematura das membranas e a pré-eclâmpsia. membranas e pré-eclâmpsia. Os resultados perinatais dos recém-nascidos foram adequados em sua grande maioria.

Comprehensive Characterization of Human Lung Large Cell Carcinoma Identifies Transcriptomic Signatures with Potential Implications in Response to Immunotherapy.

Lung cancer is the leading cause of cancer mortality worldwide, with non-small cell lung cancer (NSCLC) being the most prevalent histology. While immunotherapy with checkpoint inhibitors has shown outstanding results in NSCLC, the precise identification of responders remains a major challenge. Most studies attempting to overcome this handicap have focused on adenocarcinomas or squamous cell carcinomas. Among NSCLC subtypes, the molecular and immune characteristics of lung large cell carcinoma (LCC), which represents 10% of NSCLC cases, are not well defined. We hypothesized that specific molecular aberrations may impact the immune microenvironment in LCC and, consequently, the response to immunotherapy. To that end, it is particularly relevant to thoroughly describe the molecular genotype-immunophenotype association in LCC-to identify robust predictive biomarkers and improve potential benefits from immunotherapy. We established a cohort of 18 early-stage, clinically annotated, LCC cases. Their molecular and immune features were comprehensively characterized by genomic and immune-targeted sequencing panels along with immunohistochemistry of immune cell populations. Unbiased clustering defined two novel subgroups of LCC. Pro-immunogenic tumors accumulated certain molecular alterations, showed higher immune infiltration and upregulated genes involved in potentiating immune responses when compared to pro-tumorigenic samples, which favored tumoral progression. This classification identified a set of biomarkers that could potentially predict response to immunotherapy. These results could improve patient selection and expand potential benefits from immunotherapy.

The role of bronchoscopy in patients with SARS-CoV-2 pneumonia.

BACKGROUND: The role of bronchoscopy in coronavirus disease 2019 (COVID-19) is a matter of debate. PATIENTS AND METHODS: This observational multicentre study aimed to analyse the prognostic impact of bronchoscopic findings in a consecutive cohort of patients with suspected or confirmed COVID-19. Patients were enrolled at 17 hospitals from February to June 2020. Predictors of in-hospital mortality were assessed by multivariate logistic regression. RESULTS: A total of 1027 bronchoscopies were performed in 515 patients (age 61.5±11.2 years; 73% men), stratified into a clinical suspicion cohort (n=30) and a COVID-19 confirmed cohort (n=485). In the clinical suspicion cohort, the diagnostic yield was 36.7%. In the COVID-19 confirmed cohort, bronchoscopies were predominantly performed in the intensive care unit (n=961; 96.4%) and major indications were: difficult mechanical ventilation (43.7%), mucus plugs (39%) and persistence of radiological infiltrates (23.4%). 147 bronchoscopies were performed to rule out superinfection, and diagnostic yield was 42.9%. There were abnormalities in 91.6% of bronchoscopies, the most frequent being mucus secretions (82.4%), haematic secretions (17.7%), mucus plugs (17.6%), and diffuse mucosal hyperaemia (11.4%). The independent predictors of in-hospital mortality were: older age (OR 1.06; p<0.001), mucus plugs as indication for bronchoscopy (OR 1.60; p=0.041), absence of mucosal hyperaemia (OR 0.49; p=0.041) and the presence of haematic secretions (OR 1.79; p=0.032). CONCLUSION: Bronchoscopy may be indicated in carefully selected patients with COVID-19 to rule out superinfection and solve complications related to mechanical ventilation. The presence of haematic secretions in the distal bronchial tract may be considered a poor prognostic feature in COVID-19.

Prospective Clinical Integration of an Amplicon-Based Next-Generation Sequencing Method to Select Advanced Non-Small-Cell Lung Cancer Patients for Genotype-Tailored Treatments.

INTRODUCTION: A substantial fraction of non-small-cell lung cancers (NSCLCs) harbor targetable genetic alterations. In this study, we analyzed the feasibility and clinical utility of integrating a next-generation sequencing (NGS) panel into our routine lung cancer molecular subtyping algorithm. PATIENTS AND METHODS: After routine pathologic and molecular subtyping, we implemented an amplicon-based gene panel for DNA analysis covering mutational hot spots in 22 cancer genes in consecutive advanced-stage NSCLCs. RESULTS: We analyzed 109 tumors using NGS between December 2014 and January 2016. Fifty-six patients (51%) were treatment-naive and 82 (75%) had lung adenocarcinomas. In 89 cases (82%), we used samples derived from lung cancer diagnostic procedures. We obtained successful sequencing results in 95 cases (87%). As part of our routine lung cancer molecular subtyping protocol, single-gene testing for EGFR, ALK, and ROS1 was attempted in nonsquamous and 3 squamous-cell cancers (n = 92). Sixty-nine of 92 samples (75%) had sufficient tissue to complete ALK and ROS1 immunohistochemistry (IHC) and NGS. With the integration of the gene panel, 40 NSCLCs (37%) in the entire cohort and 30 NSCLCs (40%) fully tested for ALK and ROS1 IHC and NGS had actionable mutations. KRAS (24%) and EGFR (10%) were the most frequently mutated actionable genes. Ten patients (9%) received matched targeted therapies, 6 (5%) in clinical trials. CONCLUSION: The combination of IHC tests for ALK and ROS1 and amplicon-based NGS is applicable in routine clinical practice, enabling patient selection for genotype-tailored treatments.

Oki stenting for anastomotic bronchomalacia in lung transplantation.

Anastomotic airway complications are a frequent cause of disease in lung transplantation. However, there is no consensus on the type of treatment to be performed with prosthetic devices. While some recent gadgets such as the Oki stent have been proposed for main right bronchus stenosis, there are no reports of stenting using this prosthesis in cases where the main complication is malacia rather than stenosis. We present 2 patients diagnosed with main right bronchus bronchomalacia, also involving bronchius intermedius. After several attempts to bypass the anastomosis employing different types of stent, including a T-tube Montgomery device, normal sputum drainage was not possible. Oki stenting was performed without complications, with a remarkable reduction in endoscopic procedures as well as important functional improvement. For both stenosis and bronchomalacia in lung transplantation, we propose Oki stenting as the first choice of treatment.