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Multi-tissue transcriptomics of a unique monozygotic discordant twin case of severe progressive osseous heteroplasia

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Genes & Diseases 2024年第3期11卷 22-25页

作者： Alberto Gomez-Carballa Maria Jose Curras-Tuala Sara Pischedda Miriam Cebey-Lopez Jose Gomez-Rial Irene Rivero-Cale Jacobo Pardo-seco xabier Bello Sandra Viz-Lasheras Antonio Justicia-Grande Julian Montoto-Louzao Alba Camino-Mera Isabel Ferreiros-Vidal Maximo Fraga Jose RAntunez Rodolfo Gomez Federico Martinon-Torres Antonio Salas Genetics Vaccines and Infections Research Group(GENVIP)Instituto de Investigacion Sanitaria de SantiagoSantiagode CompostelaGalicia 15706Spain Translational Pediatrics and Infectious Diseases Department of PediatricsHospital Clinico Universitario de Santiago de CompostelaServicio Galego de Saude(SERGAS)Galicia 15706Spain Laboratorio de Inmunologia Servicio de Andlisis ClinicosHospital Clinico Universitario de Santiago de CompostelaServicio Galego de Saude(SERGAS)Galicia 15706Spain Unidade de Xenetica Instituto de Ciencias Forenses(INCIFOR)Facultade de MedicinaUniversidade de Santiago de Compostelaand GenPoB Research GroupInstituto de Investigacion SanitariaHospital Clinico Universitario de Santiago de CompostelaServicio Galego de Saude(SERGAS)Galicia 15706Spain Musculoskeletal Pathology Group Instituto de Investigacion Sanitaria de SantiagoServicio Galego de Saude(SERGAS)Santiago de CompostelaGalicia 15706Spain Department of Pathology Hospital Clinico Universitario de Santiago de Compostela(SERGAS)Galicia 15706Spain Unidad Integrada de BiobancosBiomodelos 3D y Modelos Animales IDIS(lnstituto de Investigacion Sanitaria de Santiagode Compostela)Galicia15706Spain Centro de Investigacion Biomedica en Red de Enfermedades Respiratorias(CIBER-ES) MadridSpain

Progressive osseous heteroplasia(POH)is an ultra-rare autosomal dominant disabling disorder characterized by heterotopic ossification(HO).It is caused by heterozygous inactivating mutations in the GNAS(guanine nucleotide-binding protein alpha-stimulating activity polypeptide)gene.However,the molecular mechanisms underlying HO remain poorly understood.As a treatment for POH is not yet available,the identification of the mechanisms driving POH in affected tissues using gene expression may be of great help to underestand the molecular basis of POH and develop new therapeutic approaches.

关键词： stimulating driving asi

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Clinical-pathological and molecular characterization of long-term survivors with advanced non-small cell lung cancer

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Cancer Biology & Medicine 2020年第2期17卷 444-457页

作者： Juan Moreno-Rubio Santiago Ponce Rosa Alvarez Maria Eugenia Olmedo Sandra Falagan xabier mielgo Fatima Navarro Patricia Cruz Luis Cabezon-Gutierrez Carlos Aguado Gonzalo Colmenarejo Marta Munoz-Fernandez de Leglaria Ana Belen Enguita Maria Cebollero Amparo Benito Isabel Alemany Carolina del Castillo Ricardo Ramos Ana Ramirez de Molina Enrique Casado Maria Sereno Ana Ramirez de Molina1 Enrique Casado5Maria Sereno5 XIMDEA Food InstituteCEI UAM+CSICMadrid 28702Spain 12 de Octubre University Hospital Madrid 28041Spain Gregorio Maranon University Hospital Madrid 28009Spain Ramon y Cajal University Hospital Madrid 28034Spain Infanta Sofia University Hospital San Sebastian De Los ReyesMadrid 28702Spain Fundacion Alcorcon University Hospital AlcorconMadrid 28922Spain Prlncipe de Asturias University Hospital Alcala De HenaresMadrid 28805Spain La Paz University Hospital Madrid 28046Spain University Hospital of Torrejon Torrejon De ArdozMadrid 28850Spain Clinico San Carlos University Hospital Madrid 28040Spain Parque Cientifico de Madrid Foundation Madrid 28049Spain

Objective:Long-term survivors(LS)of non-small cell lung cancer(NSCLC)without driver alterations,displaying an overall survival(OS)of more than 3 years,comprise around 10%of cases in several series treated with chemotherapy.There are classical prognosis factors for these cases[stage,Eastern Cooperative Oncology Group(ECOG),etc.],but more data are required in the literature.In this multi-center study,we focused on LS of advanced NSCLC with OS above 36 months to perform a clinical-pathological and molecular characterization.Methods:In the first step,we conducted a clinical-pathological characterization of the patients.Afterwards,we carried out a genetic analysis by comparing LS to a sample of short-term survivors(SS)(with an OS less than 9 months).We initially used whole-genome RNA-seq to identify differentiating profiles of LS and SS,and later confirmed these with reverse transcription-polymerase chain reaction(RT-PCR)for the rest of the samples.Results:A total of 94 patients were included,who were mainly men,former smokers,having adenocarcinoma(AC)-type NSCLC with an ECOG of 0-1.We obtained an initial differential transcriptome expression,displaying 5 over-and 33 under-expressed genes involved in different pathways:namely,the secretin receptor,surfactant protein,trefoil factor 1(T FF1),serpin,Ca-channels,and Tolllike receptor(TLRs)families.Finally,RT-PCR analysis of 40(20 LS/20 SS)samples confirmed that four genes(surfactant proteins and SFTP)were significantly down-regulated in SS compared to LS by using an analysis of covariance(ANCOVA)model:SFTPA1(P=0.023),SFTPA2(P=0.027),SFTPB{P=0.02),and SFT PC(P=0.047).Conclusions:We present a sequential genetic analysis of a sample of NSCLCLS with no driver alterations,obtaining a differential RNA-seq/RT-PCR profile showing an abnormal expression of SF genes.

关键词： Long-term survivors non-small cell lung cancer surfactant proteins

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New challenges in the combination of radiotherapy and immunotherapy in non-small cell lung cancer

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World Journal of Clinical Oncology 2021年第11期12卷 983-999页

作者： Javier Luna Juan Zafra Ma Carmen Areses Manrique Aurora Rodríguez Amalia Sotoca Jose Luis Fírvida Rodolfo Chicas-Sett xabier mielgo Juan Carlos Trujillo Reyes Felipe Couñago Department of Radiation Oncology Oncohealth InstituteFundación Jiménez DíazMadrid 28040Spain Department of Radiation Oncology Dr.Negrín University Hospital of Gran CanariaLas Palmas 35010Spain Department of Medical Oncology Ourense University HospitalOurense 32005Spain Department of Radiation Oncology Ruber International HospitalMadrid 28034Spain Department of Medical Oncology Hospital Universitario Fundación AlcorcónAlcorcón 28922Spain Department of Thoracic Surgery Hospital de la Santa Creu i Sant PauBarcelona 08029Spain Department of Radiation Oncology Hospital Universitario QuirónSalud MadridHospital La LuzUniversidad Europea de MadridMadrid 28223Spain

Immunotherapy has represented one of the main medical revolutions of recent decades,and is currently a consolidated treatment for different types of tumors at different stages and scenarios,and is present in a multitude of clinical trials.One of the diseases in which it is most developed is non-small cell lung cancer.The combination of radiotherapy and immunotherapy in cancer in general and lung cancer in particular currently represents one of the main focuses of basic and clinical research in oncology,due to the synergy of this interaction,which can improve tumor response,resulting in improved survival and disease control.In this review we present the biochemical and molecular basis of the interaction between radiotherapy and immunotherapy.We also present the current clinical status of this interaction in each of the stages and cases of non-small cell lung cancer,with the main results obtained in the different studies both in terms of tumor response and survival as well as toxicity.Finally,we mention the main studies underway and the challenges of this interaction in the coming years,including how these treatments should be combined to achieve the greatest efficacy with the fewest possible side effects(dose,type of radiotherapy and drugs,sequence of treatments).

关键词： Lung cancer Radiotherapy Immunotherapy Main trials

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Neoadjuvant immunotherapy in non-small-cell lung cancer:Times are changing—and fast

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World Journal of Clinical Oncology 2022年第9期13卷 758-761页

作者： Carlos Aguado Unai Jiménez Maestre xabier mielgo-Rubio Department of Medical Oncology Hospital Universitario Clínico San CarlosMadrid 28040Spain Department of Thoracic Surgery Hospital Universitario CrucesBarakaldo 48903BizkaiaSpain Department of Medical Oncology Hospital Universitario Fundación AlcorcónAlcorcón 28922MadridSpain

Recent data from a phase 3 trial have shown that the addition of immunotherapy to neoadjuvant chemotherapy improves event-free survival in patients with nonsmall-cell lung cancer(NSCLC).This is the first positive phase 3 trial in this setting,although several phase 3 trials are currently investigating the efficacy of neoadjuvant and adjuvant immunotherapy in resectable NSCLC.

关键词： Neoadjuvant Immunotherapy NSCLC Perioperative Checkmate-816 nivolumab Chemo-immunotherapy

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Neoadjuvant treatment in non-small cell lung cancer:New perspectives with the incorporation of immunotherapy

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World Journal of Clinical Oncology 2022年第5期13卷 314-322页

作者： Carlos Aguado Luis Chara Mónica Antonanzas Jose Maria Matilla Gonzalez Unai Jiménez Raul Hernanz xabier mielgo-Rubio Juan Carlos Trujillo-Reyes Felipe Counago Department of Medical Oncology Hospital Clínico Universitario San CarlosMadrid 28040Spain Department of Medical Oncology Hospital Universitario de GuadalajaraGuadalajara 19002Spain Department of Thoracic Surgery Hospital Clínico Universitario de ValladolidValladolid 47005Spain Department of Thoracic Surgery Hospital Universitario CrucesBarakaldoBizkaia 48903Basque CountrySpain Department of Radiation Oncology Hospital Universitario Ramón y CajalMadrid 28034Spain Department of Medical Oncology Hospital Universitario Fundación AlcorcónAlcorcón 28922MadridSpain Department of Thoracic Surgery Hospital de la Santa Creu I Sant PauBarcelona 08029CataloniaSpain Department of Surgery Universitat Autonoma de BarcelonaBarcelona 08029CataloniaSpain Department of Radiation Oncology Hospital Universitario Quirónsalud MadridPozuelo de Alarcón 28223MadridSpain Department of Radiation Oncology Hospital La LuzMadrid 28003Spain Medicine Department School of Biomedical SciencesUniversidad Europea de MadridVillaviciosa de Odón 28670MadridSpain

The aim of neoadjuvant treatment in non-small cell lung cancer(NSCLC)is to eliminate micrometastatic disease to facilitate surgical resection.Neoadjuvant chemotherapy(ChT)in localised NSCLC has numerous advantages over other therapeutic modalities and is considered standard treatment in resectable disease.Treatment with immune checkpoint inhibitors(ICI)improves long-term survival in advanced disease and has a better toxicity profile than conventional therapies.These immunotherapy agents(anti-PD1/PD-L1),administered with or without ChT,are currently being evaluated in the preoperative setting,with initial results showing better pathological response rates and more long-term benefits.Importantly,these drugs do not appear to increase the rate of severe adverse effects and/or postoperative complications.However,several questions still need to be resolved,including the identification of predictive biomarkers;comparative studies of immunotherapy alone vs combined treatment with ChT and/or radiotherapy;the optimal duration of treatment;the timing of surgery;the need for adjuvant treatment;appropriate radiologic evaluation and mediastinal staging;and the correlation between pathological response and survival outcomes.Here we review the current evidence for immunotherapy from a multidisciplinary perspective and discuss current and future controversies.

关键词： Non-small cell lung cancer Neoadjuvant Immune checkpoint inhibitors Immunotherapy Anti-PD1 Anti-PD-L1 Complete pathological response

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Simultaneous analysis of the intestinal parasites and diet through eDNA metabarcoding

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Integrative Zoology 2023年第3期18卷 399-413页

作者： xabier CABODEVILLA Benjamín Juan GÓMEZ-MOLINER Naiara ABAD María JoséMADEIRA Department of Zoology and Animal Cell Biology Faculty of PharmacyUniversity of the Basque Country(UPV/EHU)AlavaSpain Instituto de Investigación en Recursos Cinegéticos(IREC)(CSIC-UCLM-JCCM) Ciudad RealSpain

Agricultural expansion and intensiﬁcation are having a huge impact on plant and arthropod diversity and abun-dance,affecting food availability for farmland birds.Difﬁcult food access,in turn,can lead to immunosuppression and a higher incidence of parasites.In the studies designed to examine changes in the diet of birds and their par-asites,metabarcoding is proving particularly useful.This technique requires mini-barcodes capable of amplifying the DNA of target organisms from fecal environmental DNA.To help to understand the impact of agricultural expansion on biodiversity,this study sought to design and identify mini-barcodes that might simultaneously as-sess diet and intestinal parasites from the feces of farmland birds.The capacity to identify diet and parasites of 2 existing and 3 newly developed mini-barcodes was tested“in silico”in relation to the behavior of a reference eukaryotic barcode.Among the newly designed mini-barcodes,MiniB18S_81 showed the higher taxonomic cover-age of eukaryotic taxa and a greater ampliﬁcation and identiﬁcation capacity for diet and parasite taxa.Moreover,when it was tested on fecal samples from 5 different steppe bird species,MiniB18S_81 showed high taxonomic resolution of the most relevant diet and parasite phyla,Arthropoda,Nematoda,Platyhelminthes,and Apicomplexa at the order level.Thus,the mini-barcode developed emerges as an excellent tool to simultaneously provide detailed information regarding the diet and parasites of birds,essential for conservation and management.

关键词： biomonitoring broad-spectrum primers eukaryotic mini-barcodes fecal eDNA farmland birds parasitology

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Tsunami of immunotherapy reaches mesothelioma

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World Journal of Clinical Oncology 2022年第4期13卷 267-275页

作者： xabier mielgo-Rubio Ana Cardena Gutierrez Veronica Sotelo Pena Maria Virginia Sanchez Becerra Andrea Maria Gonzalez Lopez Adriana Rosero Juan Carlos Trujillo-Reyes Felipe Counago Department of Medical Oncology Hospital Universitario Fundacion AlcorconAlcorcon 28922MadridSpain Department of Medical Oncology Hospital Universitario Nuestra Senora de CandelariaSanta Cruz de TenerifeCanarias 38010Spain Department of Medical Oncology Hospital Virgen de La LuzCuenca 16002Spain Department of Medical Oncology Hospital Universitario Del HenaresCoslada 28822MadridSpain Department of Thoracic Surgery Hospital Universitari de la Santa Creu i Sant PauUniversitat Autonoma de BarcelonaBarcelona 08029Spain Department of Radiation Oncology Hospital Universitario Quironsalud MadridPozuelo de Alcorcon 28223MadridSpain Department of Radiation Oncology Hospital La LuzMadrid 28003Spain Medicine Department Universidad Europea de MadridVillaviciosa de Odon 28670MadridSpain

Malignant pleural mesothelioma(MPM) is the most common type of malignant mesothelioma. It is a rare tumor linked to asbestos exposure and is associated with a poor prognosis. Until very recently, patients with advanced or unresectable disease had limited treatment options, primarily based on doublet chemotherapy with cisplatin and pemetrexed. In 2020 and 2021, after more than a decade with no major advances or new drugs, two phase Ⅲ clinical trials published results positioning immunotherapy as a promising option for the first-and second-line treatment of MPM. Immunotherapy has revolutionized the treatment of many cancers and is also showing encouraging results in malignant mesothelioma. Both immune checkpoint inhibition and dual cytotoxic T-lymphocyte–associated antigen 4 and programmed death-ligand 1 pathway blockade resulted in significantly improved overall survival in randomized phase Ⅲ trials. In the Check Mate 743 trial, first-line therapy with nivolumab plus ipilimumab outperformed standard chemotherapy, while in the CONFIRM trial, nivolumab outperformed placebo in patients previously treated with chemotherapy. These two trials represent a major milestone in the treatment of MPM and are set to position immunotherapy as a viable alternative for treatment-naive patients and patients with progressive disease after chemotherapy.

关键词： Mesothelioma Malignant pleural mesothelioma Immunotherapy Immune checkpoint inhibitors Cytotoxic T-lymphocyte–associated antigen 4 Programmed cell death protein 1 Nivolumab Ipilimumab Immunotherapy combo Check Mate 743 CONFIRM

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New horizons for uncommon mutations in non-small cell lung cancer: BRAF, KRAS, RET, MET, NTRK, HER2

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World Journal of Clinical Oncology 2022年第4期13卷 276-286页

作者： Maria Eugenia Olmedo Raquel Cervera Luis Cabezon-Gutierrez Yolanda Lage Elena Corral de la Fuente Ana Gomez Rueda1,xabier mielgo-Rubio Juan Carlos Trujillo Felipe Counago Department of Medical Oncology Ramon y Cajal University HospitalMadrid 28034Spain Department of Medical Oncology Del Henares University HospitalCoslada 28822MadridSpain Medical Oncology Hospital Universitario de TorrejonTorrejon de Ardoz 28850MadridSpain Medical Oncology Department Hospital Universitario Ramon y CajalMadrid 28034Spain Department of Medical Oncology Foundation Alcorcon University HospitalAlcorcón 28922MadridSpain Department Thoracic Surgery Hospital de la Santa Creu I Sant PauBarcelona 08029CataloniaSpain Department of Surgery Universitat Autonoma de BarcelonaBarcelona 08029CataloniaSpain Department of Radiation Oncology Hospital Universitario Quironsalud MadridPozuelo 28223MadridSpain Department of Radiation Oncology Hospital La LuzMadrid 28003Spain Medicine Department School of Biomedical SciencesUniversidad Europea de MadridMadrid 28670Spain

The 2004 discovery of EGFR mutations,followed by ALK rearrangements,ushered in a targeted therapy era for advanced non-small cell lung cancer(NSCLC).Tyrosine kinase inhibitors targeting gene alterations have substantially improved survival and quality of life for patients with NSCLC.In the last decade,rearrangements of the ROS1 oncogene have been incorporated into healthcare practice that are applicable to another small subgroup of patients who benefit from similar targeted strategies.Recent genome studies of lung adenocarcinoma have identified other possible therapeutic targets,including RET,NTRK fusions,c-MET alterations,and activating mutations in KRAS,BRAF,and HER2,all with frequencies greater than 1%.Lung cancers harbouring these genome changes can potentially be treated with agents approved for other indications or under clinical development.This review updates the therapeutic arsenal that especially targets those genes.

关键词： BRAF NTRK KRAS MET RET HER2 Non-small cell lung cancer Targeted therapy Uncommon mutations

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New perspectives in the management of small cell lung cancer

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World Journal of Clinical Oncology 2022年第6期13卷 429-447页

作者： Cristina Pangua Jacobo Rogado Gloria Serrano-Montero JoséBelda-Sanchís BeatrizÁlvarez Rodríguez Laura Torrado Nuria Rodríguez De Dios xabier mielgo-Rubio Juan Carlos Trujillo Felipe Couñago Department of Medical Oncology Hospital Universitario Infanta LeonorMadrid 28031Spain Department of Thoracic Surgery Hospital de la Santa Creu i Sant Pau&Hospital de MarUniversitat Autònoma de BarcelonaBarcelona 08041CataloniaSpain Department of Radiation Oncology Hospital Universitario HM SanchinarroHM HospitalesHM CIOCC Centro Integral Oncológico Clara CampalMadrid 28050Spain Department of Radiation Oncology Hospital Universitario Lucus Augusti&Instituto de Investigación Sanitaria Santiago de Compostela(IDIS)Lugo 27003Spain Department of Radiation Oncology Hospital Del Mar&Hospital Del Mar Medical Research Institute(IMIM)&Pompeu Fabra UniversityBarcelona 08003CataloniaSpain Department of Medical Oncology Alcorcón Foundation University HospitalAlcorcón 28922MadridSpain Department of Thoracic Surgery Hospital de la Santa Creu i Sant PauBarcelona 08029Spain Department of Radiation Oncology Hospital Universitario Quirónsalud MadridHospital La LuzUniversidad Europea de MadridMadrid 28223Spain

The treatment of small cell lung cancer(SCLC)is a challenge for all specialists involved.New treatments have been added to the therapeutic armamentarium in recent months,but efforts must continue to improve both survival and quality of life.Advances in surgery and radiotherapy have resulted in prolonged survival times and fewer complications,while more careful patient selection has led to increased staging accuracy.Developments in the field of systemic therapy have resulted in changes to clinical guidelines and the management of patients with advanced disease,mainly with the introduction of immunotherapy.In this article,we describe recent improvements in the management of patients with SCLC,review current treatments,and discuss future lines of research.

关键词： Small cell lung cancer Whole-brain radiotherapy Prophylactic cranial irradiation Stereotactic body radiotherapy Immunotherapy Atezolizumab Durvalumab

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Stereotactic body radiation therapy:A good dance partner of oligometastatic non-small cell lung cancer to the sound of SINDAS study

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World Journal of Clinical Oncology 2020年第12期11卷 983-989页

作者： xabier mielgo-Rubio Javier Garde-Noguera Oscar Juan Felipe Couñago Department of Medical Oncology Hospital Universitario Fundación AlcorcónMadrid 28922Spain Department of Medical Oncology Hospital Arnau de VilanovaC/Sant ClimentValencia 46015Spain Department of Medical Oncology La Fe University HospitalValencia 46026Comunitat ValencianaSpain School of Medicine Catholic University San Vicente MartirValencia 46001Comunitat ValencianaSpain Department of Radiation Oncology Hospital Universitario Quirónsalud MadridHospital La LuzUniversidad Europea de MadridMadrid 28028Spain

The European Organization for Research on Treatment of Cancer Research published a consensus statement to establish the key criteria to define oligometastatic disease(OMD).According to those criteria,all lesions(both primary and metastatic)should be amenable to radical intent treatment with acceptable toxicity.Several retrospective studies have shown that adding local ablative therapy to the treatment of OMD improves outcomes;however,due to the diverse selection criteria and treatment strategies used in those studies,it is difficult to compare directly results to draw definitive conclusions.In recent years,prospective phase II trials,such as the SABR-COMET and"Oligomez"trials,have shown that stereotactic body radiation therapy(SBRT)improves outcomes in patients with OMD.More recently,interim results of the randomised phase 3 SINDAS trial were reported at the annual meeting of the American Society of Clinical Oncology 2020 demonstrating that upfront SBRT added to systemic treatment with tyrosine kinase inhibitors yielded a significant benefit in both progression-free survival and overall survival in patients with epidermal growth factor receptor-mutant oligometastatic non-small cell lung cancer.In the present editorial,we review the definition and historical context of advanced non-small cell lung cancer with OMD.In addition,we review the scientific evidence for local ablative therapy and SBRT and discuss the results of recently published prospective studies.We also discuss in depth the results of the SINDAS study,including the strengths and weaknesses of the study and the barriers to extrapolating these results to routine clinical practice.

关键词： Oligometastatic Non-small cell lung cancer Stereotactic body radiation therapy SINDAS Local ablative therapy Epidermal growth factor receptor mutations Epidermal growth factor receptor-mutated

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