Liquid Biopsy as a Prognostic and Theranostic Tool for the Management of Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinomas (PDAC) represent one of the deadliest cancers worldwide. Survival is still low due to diagnosis at an advanced stage and resistance to treatment. Herein, we review the main types of liquid biopsy able to help in both prognosis and adaptation of treatments.

OncoSNIPE® Study Protocol, a study of molecular profiles associated with development of resistance in solid cancer patients

Background Nowadays, evaluation of the efficacy and the duration of treatment, in context of monitoring patients with solid tumors, is based on the RECIST methodology. With these criteria, resistance and/or insensitivity are defined as tumor non-response which does not allow a good understanding of the diversity of the underlying mechanisms. The main objective of the OncoSNIPE® collaborative clinical research program is to identify early and late markers of resistance to treatment. Methods Multicentric, interventional study with the primary objective to identify early and / or late markers of resistance to treatment, in 600 adult patients with locally advanced or metastatic triple negative or Luminal B breast cancer, non-small-cell lung cancer or pancreatic ductal adenocarcinoma. Patients targeted in this study have all rapid progression of their pathology, making it possible to obtain models for evaluating markers of early and / or late responses over the 2-year period of follow-up, and thus provide the information necessary to understand resistance mechanisms. To explore the phenomena of resistance, during therapeutic response and / or progression of the pathology, we will use a multidisciplinary approach including high-throughput sequencing (Exome-seq and RNAseq), clinical data, medical images and immunological profile by ELISA. Patients will have long-term follow-up with different biological samples, at baseline (blood and biopsy) and at each tumoral evaluation or tumoral progression evaluated by medical imaging. Clinical data will be collected through a dedicated Case Report Form (CRF) and enriched by semantic extraction based on the French ConSoRe (Continuum Soins Recherche) initiative, a dedicated Semantic Clinical Data Warehouse (SCDW) to cancer. The study is sponsored by Oncodesign (Dijon, France) and is currently ongoing. Discussion The great diversity of intrinsic or acquired molecular mechanisms involved in resistance to treatment constitutes a real therapeutic issue. Improving understanding of mechanisms of resistance of cancer cells to anti-tumor treatments is therefore a major challenge. The OncoSNIPE cohort will lead to a better understanding of the mechanisms of resistance and will allow to explore new mechanisms of actions and to discover new therapeutic targets or strategies making it possible to circumvent the escape in different types of cancer. Trial registration Clinicaltrial.gov. Registered 16 September 2020, https://clinicaltrials.gov/ct2/show/NCT04548960?term=oncosnipe&draw=2&rank=1 and ANSM ID RCB 2017-A02018-45.

Epidemiology and Risk Factors for Resistance to Treatment of Kawasaki Disease in Cyprus.

Background: Kawasaki disease (KD) is one of the most common vasculitides of early childhood and the first cause of acquired heart disease in developed countries. There are no previous studies on KD in Cyprus. The aim of this study was to evaluate the epidemiology of KD in Cyprus, risk factors for resistance to treatment and the development of cardiac complications. Lastly, the Kobayashi and Egami scoring systems were evaluated in our population.Methods: This is a retrospective multicenter study of pediatric patients with KD hospitalized between January 2000 and-December 2019. The data were collected from medical records. Results: A total of 136 patients with KD were included in the study. 83% of patients were <5 years of age and 10% were <6 months. Median duration of fever before treatment was 6 days. 108/129 patients responded to initial treatment with IVIG. Thirty patients (22%) developed coronary artery lesions. Serum sodium ≤133mmol/L, albumin ≤ 3.2 g/dl, ALT≥ 80 U/L and neutrophils percentage≥ 80% at diagnosis, were identified as risk factors for resistance to IVIG. The Kobayashi and Egami scoring systems had low sensitivity of 57% and 62% respectively and a medium specificity of 76% and 76% respectively in predicting IVIG resistance.Conclusion: Clinical and epidemiological characteristics of KD in Cyprus population were similar to those reported in the literature. Although the majority of cases received appropriate treatment in time, cardiac complications still occurred. The Kobayashi and Egami scoring systems cannot be used in our population in order to predict responsiveness to IVIG.

Role of the processes of angiogenesis, proteolysis, iron transport and changes of morpho- functional status of immunocompetent cells in the pathogenesis of infiltrative endometriosis

The paper reports of the activation of the callikrein - kinine system, increased levels of vascular-endothelial growth factor, disturbances in the system of transport and exchange of iron and specific changes of morpho-functional status of immune- competent cells in peritoneal fluid in cases of infiltrative endometriosis, possibly responsible for aggressive course of this severe form of the disease and resistance to treatment.

MicroRNAs Regulate Cell Cycle and Cell Death Pathways in Glioblastoma

Glioblastoma (GBM), a grade IV brain tumor, is known for its heterogenicity and its resistance to the current treatment regimen. Over the last few decades, a significant amount of new molecular and genetic findings has been reported regarding factors contributing to GBM’s development into a lethal phenotype and its overall poor prognosis. MicroRNA (miRNAs) are small non-coding sequences of RNA that regulate and influence the expression of multiple genes. Many research findings have highlighted the importance of miRNAs in facilitating and controlling normal biological functions, including cell differentiation, proliferation, and apoptosis. Furthermore, miRNAs’ ability to initiate and promote cancer development, directly or indirectly, has been shown in many types of cancer. There is a clear association between alteration in miRNAs expression in GBM’s ability to escape apoptosis, proliferation, and resistance to treatment. Further, miRNAs regulate the already altered pathways in GBM, including P53, RB, and PI3K-AKT pathways. Furthermore, miRNAs also contribute to autophagy at multiple stages. In this review, we summarize the functions of miRNAs in GBM pathways linked to dysregulation of cell cycle control, apoptosis and resistance to treatment, and the possible use of miRNAs in clinical settings as treatment and prediction biomarkers.

Genomic and phenotypic characterization of Multisystem Inflammatory Syndrome in Children (MIS-C): a prospective multicenter study from the Middle East

ImportanceClinical, genetic and laboratory characteristics of patients with multisystem inflammatory syndrome in children (MIS-C) in the Middle East have not yet been documented.ObjectiveTo uncover rare genetic variants contributing to MIS-C in patients of primarily Arab and Asian origin.Design, Setting, and ParticipantsA prospective multicenter cohort study was conducted between September 2020 and August 2021 in the United Arab Emirates and Jordan. Forty-five patients meeting the case definition of MIS-C, and a matched control group of twenty-five healthy children with a confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection status, were recruited. Whole Exome Sequencing (WES) in all 70 participants was performed to identify rare likely deleterious variants in patients with MIS-C and to correlate genetic findings with the clinical course of illness.ExposuresSARS-CoV-2Main Outcomes and MeasuresFever, organ system complications, laboratory biomarkers, WES findings, treatments, and clinical outcomes. Mann–Whitney U test was used to assess the association between genetic variations and MIS-C attributes. Fisher’s exact test was used to compute the genetic burden in MIS-C relative to controls.ResultsIn 45 MIS-C patients (23 boys [51.1%]; average age, 7 years [range, 2-14 years]), key inflammatory markers were significantly dysregulated in all patients. Mucocutaneous and gastrointestinal manifestations were reported in 80% (95% CI 66% to 89%) while cardiac and neurological findings were reported in 49% (95% CI 35% to 63%) and 31% (95% CI 19.5% to 45.6%) of patients, respectively. Rare, likely deleterious heterozygous variants in immune-related genes including TLR3, TLR6, IFNAR2, IL22RA2, IFNB1, and IFNA6, were identified in 19 patients (42.2%, 95% CI 29% to 56.7%), of whom seven had more than one variant. There was significant enrichment of genetic variants in patients relative to the control group (29 versus 3, P<.0001). Those variants were significantly associated with earlier onset of disease (31.5%, 95% CI 15.4% to 54% of patients with versus 7.7%, 95% CI 2% to 24% without genetic findings were < 3 years) and resistance to treatment (42%, 95% CI 23% to 64% of patients with versus 11.5%, 95% CI 4% to 29% of patients without genetic findings received two doses of IVIG).Conclusions and RelevanceRare, likely deleterious genetic variants contribute to MIS-C onset and management.Key PointsQuestionWhat are the clinical, genetic, and laboratory characteristics of multisystem inflammatory syndrome in children (MIS-C) of the Middle East?FindingsIn this prospective study of 45 MIS-C patients of primarily Arab and Asian origins, we show that the clinical course was consistent with that of previously characterized patients from other backgrounds. However, we find an enrichment of rare, likely deleterious immune-related genetic variants, in MIS-C patients, and an association of genetic status with MIS-C onset and resistance to treatment.MeaningComprehensive genetic profiling of MIS-C patients of diverse ancestries is essential to characterize the genetic contribution to this disease.