EpiGe: A machine-learning strategy for rapid classification of medulloblastoma using PCR-based methyl-genotyping

Molecular classification of medulloblastoma is critical for the treatment of this brain tumor. Array-based DNA methylation profiling has emerged as a powerful approach for brain tumor classification. However, this technology is currently not widely available. We present a machine-learning decision support system (DSS) that enables the classification of the principal molecular groups—WNT, SHH, and non-WNT/non-SHH—directly from quantitative PCR (qPCR) data. We propose a framework where the developed DSS appears as a user-friendly web-application—EpiGe-App—that enables automated interpretation of qPCR methylation data and subsequent molecular group prediction. The basis of our classification strategy is a previously validated six-cytosine signature with subgroup-specific methylation profiles. This reduced set of markers enabled us to develop a methyl-genotyping assay capable of determining the methylation status of cytosines using qPCR instruments. This study provides a comprehensive approach for rapid classification of clinically relevant medulloblastoma groups, using readily accessible equipment and an easy-to-use web-application.The study was supported by Associations of Parents and Families of Children with Cancer and by funding of the Spanish Ministry of for Science, Innovation and University (grant PI20/00519; PI CL) and the Foundation La Marató TV3 (grant 201921-30; PI CL). We acknowledge the multidisciplinary team who helped in the molecular analyses and care of patients, and the BioBank Hospital Sant Joan de Déu of the Spanish BioBank Network for sample procurement. We also acknowledge Marta Fortuny for communication strategy advice and Eduard Puig for legal assistance and data protection regulations. Authors acknowledge the SJD Fundraising Team.Peer ReviewedArticle signat per 23 autors/es: Soledad Gómez-González, Joshua Llano, Marta Garcia, Alicia Garrido-Garcia, Mariona Suñol, Isadora Lemos, Sara Perez-Jaume, Noelia Salvador, Nagore Gene-Olaciregui, Raquel Arnau Galán, Vicente Santa-María, Marta Perez-Somarriba, Alicia Castañeda, José Hinojosa, Ursula Winter, Francisco Barbosa Moreira, Fabiana Lubieniecki, Valeria Vazquez, Jaume Mora, Ofelia Cruz, Andrés Morales La Madrid, Alexandre Perera, Cinzia Lavarino.Postprint (published version

Effectiveness and safety of integrase strand transfer inhibitors in Spain: a prospective real-world study

IntroductionSecond-generation integrase strand transfer inhibitors (INSTIs) are preferred treatment options worldwide, and dolutegravir (DTG) is the treatment of choice in resource-limited settings. Nevertheless, in some resource-limited settings, these drugs are not always available. An analysis of the experience with the use of INSTIs in unselected adults living with HIV may be of help to make therapeutic decisions when second-generation INSTIs are not available. This study aimed to evaluate the real-life effectiveness and safety of dolutegravir (DTG), elvitegravir/cobicistat (EVG/c), and raltegravir (RAL) in a large Spanish cohort of HIV-1-infected patients.MethodsReal-world study of adults living with HIV who initiated integrase INSTIs DTG, EVG/c, and RAL-based regimens in three settings (ART-naïve patients, ART-switching, and ART-salvage patients). The primary endpoint was the median time to treatment discontinuation after INSTI-based regimen initiation. Proportion of patients experiencing virological failure (VF) (defined as two consecutive viral loads (VL) ≥200 copies/mL at 24 weeks or as a single determination of VL ≥1,000 copies/mL while receiving DTG, EVG/c or RAL, and at least 3 months after INSTI initiation) and time to VF were also evaluated.ResultsVirological effectiveness of EVG/c- and RAL-based regimens was similar to that of DTG when given as first-line and salvage therapy. Treatment switching for reasons other than virological failure was more frequent in subjects receiving EVG/c and, in particular, RAL. Naïve patients with CD4+ nadir <100 cells/μL were more likely to develop VF, particularly if they initiated RAL or EVG/c. In the ART switching population, initiation of RAL and EVG/c was associated with both VF and INSTI discontinuation. There were no differences in the time to VF and INSTI discontinuation between DTG, EVG/c and RAL. Immunological parameters improved in the three groups and for the three drugs assessed. Safety and tolerability were consistent with expected safety profiles.DiscussionWhereas second-generation INSTIs are preferred treatment options worldwide, and DTG is one of the treatment of choices in resource-limited settings, first-generation INSTIs may still provide high virological and immunological effectiveness when DTG is not available