Cerebrospinal fluid levels of AFP and hCG: Validation of the analytical method and application in the diagnosis of central nervous system germ cell tumors

The determination of Human Chorionic Gonadotropin (hCG) and Alpha Fetoprotein (AFP) levels on serum and amniotic fluid plays a fundamental role in the diagnosis and follow-up of specific physiological or pathological conditions (e.g., pregnancy, threat of abortion or germ cell tumors). Recently, the quantification of hCG and AFP in other biological fluids has gained great attention to support the diagnosis, prognosis and follow-up of neoplastic diseases deriving from trophoblastic cells, such as germinomas. Most of the commercial kits for hCG and AFP assays are developed to be used on biological fluids such as serum/plasma and/or urine by manufacturing companies. The aim of this work was to evaluate the suitability of the analytical method certified for the use on serum, and/or amniotic fluid for the quantification of hCG and AFP in cerebrospinal fluid, carrying out an internal validation protocol. The data reported here show that the automated immunochemical method is fit for quantification of hCG and AFP in cerebrospinal fluid (CSF), allowing selective and specific diagnosis of secreting germ cell tumors. This is confirmed by the positive correlation between elevated levels of hCG or AFP and the diagnosis of brain tumors

Infantile/congenital high-grade gliomas: molecular features and therapeutic perspectives

Brain tumors in infants account for less than 10% of all pediatric nervous system tumors. They include tumors diagnosed in fetal age, neonatal age and in the first years of life. Among these, high-grade gliomas (HGGs) are a specific entity with a paradoxical clinical course that sets them apart from their pediatric and adult counterparts. Currently, surgery represents the main therapeutic strategy in the management of these tumors. Chemotherapy does not have a well-defined role whilst radiotherapy is rarely performed, considering its late effects. Information about molecular characterization is still limited, but it could represent a new fundamental tool in the therapeutic perspective of these tumors. Chimeric proteins derived from the fusion of several genes with neurotrophic tyrosine receptor kinase mutations have been described in high-grade gliomas in infants as well as in neonatal age and the recent discovery of targeted drugs may change the long-term prognosis of these tumors, along with other target-driven therapies. The aim of this mini review is to highlight the recent advances in the diagnosis and treatment of high-grade gliomas in infants with a particular focus on the molecular landscape of these neoplasms and future clinical applications

Canonical and noncanonical roles of Fanconi anemia proteins: Implications in cancer predisposition

Fanconi anemia (FA) is a clinically and genetically heterogeneous disorder characterized by the variable presence of congenital somatic abnormalities, bone marrow failure (BMF), and a predisposition to develop cancer. Monoallelic germline mutations in at least five genes involved in the FA pathway are associated with the development of sporadic hematological and solid malignancies. The key function of the FA pathway is to orchestrate proteins involved in the repair of interstrand cross-links (ICLs), to prevent genomic instability and replication stress. Recently, many studies have highlighted the importance of FA genes in noncanonical pathways, such as mitochondria homeostasis, inflammation, and virophagy, which act, in some cases, independently of DNA repair processes. Thus, primary defects in DNA repair mechanisms of FA patients are typically exacerbated by an impairment of other cytoprotective pathways that contribute to the multifaceted clinical phenotype of this disease. In this review, we summarize recent advances in the understanding of the pathogenesis of FA, with a focus on the cytosolic noncanonical roles of FA genes, discussing how they may contribute to cancer development, thus suggesting opportunities to envisage novel therapeutic approaches

Gata2 related conditions and predisposition to pediatric myelodysplastic syndromes

Myelodysplastic syndromes (MDS) are hematopoietic disorders rare in childhood, often occurring in patients with inherited bone marrow failure syndromes or germinal predisposition syndromes. Among the latter, one of the most frequent involves the gene GATA binding protein 2 (GATA2), coding for a transcriptional regulator of hematopoiesis. The genetic lesion as well as the clinical phenotype are extremely variable; many patients present hematological malignancies, especially MDS with the possibility to evolve into acute myeloid leukemia. Variable immune dysfunction, especially resulting in B-and NK-cell lymphopenia, lead to severe infections, including generalized warts and mycobacterial infection. Defects of alveolar macrophages lead to pulmonary alveolar proteinosis through inadequate clearance of surfactant proteins. Currently, there are no clear guidelines for the monitoring and treatment of patients with GATA2 mutations. In patients with MDS, the only curative treatment is allogeneic hematopoietic stem cell transplantation (HSCT) that restores normal hematopoiesis preventing the progression to acute myeloid leukemia and clears long-standing infections. However, to date, the donor type, conditioning regimen, and the optimal time to proceed to HSCT, as well as the level of chimerism needed to reverse the phenotype, remain unclear highlighting the need for consensus guidelines

A chart review on the feasibility and safety of the Vincristine Irinotecan Pazopanib (VIPaz) association in children and adolescents with resistant or relapsed sarcomas

Background: Pediatric patients with relapsed or refractory sarcomas have poor outcome and need novel therapies that provide disease control while maintaining an acceptable quality of life. The safety of vincristine, irinotecan, and pazopanib (VIPaz) association has not yet been published in this population. Methods: A chart review was conducted in children and adolescents with relapsed or refractory bone and soft tissue sarcomas who received VIPaz in our institution. Results: One hundred sixty-six patients with a diagnosis of soft or bone sarcoma were admitted to our hospital in the period between March 2015 and August 2018, 30 were relapsed or resistant. Seventeen out of 30 resistant or relapsed patients (median age, 14 years) received 114 VIPaz cycles (median six cycles per patient, range 1–17). Sixteen courses (15%) resulted in gastrointestinal toxicity with Grade two diarrhea; 35 courses (30%) resulted in Grade ≥3 neutropenia. One patient presented Grade two hypothyroidism after nine courses, and another one had Grade two hyperbilirubinemia after 12 courses. Two and five patients required a 25% dose reduction of irinotecan (because of diarrhea) and pazopanib (because of neutropenia four and hyperbilirubinemia 1), respectively. No patient experienced heart failure, hypertension, nor posterior reversible encephalopathy syndrome. Pneumothorax was not reported in any case even in lung metastatic patients. After two and four VIPaz cycles, we observed one complete response (CR), five partial responses (PRs), seven stable diseases (SDs), and four progressive diseases (PDs). With a median follow-up of 15 months (range 3–32), five out of 17 (29%) patients were alive, and four patients were in continuous CR after 12 VIPaz cycles. Conclusions: The VIPaz regimen might be a safe option in children and adolescents with relapsed or refractory sarcomas otherwise unable to be enrolled in other clinical trials; on the other hand, the efficacy of pazopanib observed cannot be sustained from the current study

Vemurafenib treatment of pleomorphic xanthoastrocytoma in a child with Down syndrome

Brain tumors are the most common solid neoplasms of childhood, but they are very rarely reported in children with Down Syndrome (DS), who develop more commonly different types of malignancies. In particular, we hereby report the case of an 8-years-old child with DS that presented to our attention for neurological and endocrinological issues. Brain imaging revealed the presence of a mass that was partially resected revealing a histological diagnosis of Pleomorphic Xanthoastrocytoma (PXA), a rare WHO grade II tumor extending from the diencephalic region into the surrounding brain tissue. These tumors can harbor the BRAF mutation p.V600E, targetable by the specific inhibitor Vemurafenib. After confirming the presence of the mutation in the tumor, the patient was treated with Vemurafenib. The treatment proved to be effective, leading to a partial response and a stabilization of the disease. Usually, in patients with DS a reduction of the dose of chemotherapeutic drugs is necessary. Vemurafenib was instead well-tolerated as the only observed adverse effect was grade I skin toxicity. This is, to our knowledge, the first case of a PXA reported in a child with DS and the first DS patient treated with Vemurafenib

Inter and intra-tumor heterogeneity of paediatric type diffuse high-grade gliomas revealed by single-cell mass cytometry

Paediatric-type diffuse high-grade gliomas (PDHGG) are aggressive tumors affecting children and young adults, with no effective treatment. These highly heterogeneous malignancies arise in different sites of the Central Nervous System (CNS), carrying distinctive molecular alterations and clinical outcomes (inter-tumor heterogeneity). Moreover, deep cellular and molecular profiling studies highlighted the coexistence of genetically and phenotypically different subpopulations within the same tumor mass (intra-tumor heterogeneity). Despite the recent advances made in the field, the marked heterogeneity of PDHGGs still impedes the development of effective targeted therapies and the identification of suitable biomarkers. In order to fill the existing gap, we used mass cytometry to dissect PDHGG inter- and intra-heterogeneity. This is one of the most advanced technologies of the “-omics” era that, using antibodies conjugated to heavy metals, allows the simultaneous measurement of more than 40 markers at single-cell level. To this end, we analyzed eight PDHGG patient-derived cell lines from different locational and molecular subgroups. By using a panel of 15 antibodies, directly conjugated to metals or specifically customized to detect important histone variants, significant differences were highlighted in the expression of the considered antigens. The single-cell multiparametric approach realized has deepened our understanding of PDHGG, confirming a high degree of intra- and inter-tumoral heterogeneity and identifying some antigens that could represent useful biomarkers for the specific PDHGG locational or molecular subgroups

Relative sea-level rise and potential submersion risk for 2100 on 16 coastal plains of the mediterranean sea

The coasts of the Mediterranean Sea are dynamic habitats in which human activities have been conducted for centuries and which feature micro-tidal environments with about 0.40 m of range. For this reason, human settlements are still concentrated along a narrow coastline strip, where any change in the sea level and coastal dynamics may impact anthropic activities. In the frame of the RITMARE and the Copernicus Projects, we analyzed light detection and ranging (LiDAR) and Copernicus Earth Observation data to provide estimates of potential marine submersion for 2100 for 16 small-sized coastal plains located in the Italian peninsula and four Mediterranean countries (France, Spain, Tunisia, Cyprus) all characterized by different geological, tectonic and morphological features. The objective of this multidisciplinary study is to provide the first maps of sea-level rise scenarios for 2100 for the IPCC RCP 8.5 and Rahmstorf (2007) projections for the above affected coastal zones, which are the locations of touristic resorts, railways, airports and heritage sites. On the basis of our model (eustatic projection for 2100, glaciohydrostasy values and tectonic vertical movement), we provide 16 high-definition submersion maps. We estimated a potential loss of land for the above areas of between about 148 km2 (IPCC-RCP8.5 scenario) and 192 km2 (Rahmstorf scenario), along a coastline length of about 400 km

Multidisciplinary assessment and prediction tools addressing coastal vulnerability to erosion and sea level rise. Lesson learnt from the RITMARE Project

Natural processes and human activities are strongly connected, and sometimes con icting, in the evolution of coastal and transitional environments. The strong anthropic pressure on coastal regions, together with the e ects of a changing climate, demands nowadays more pressingly for e cient tools to characterise and predict the behaviour of such systems in order to de ne appropriate response strategies. This requires a deep understanding of the connections among di erent drivers and di erent scales, a multidisciplinary challenge in which heterogeneous data, approaches and scales need to be framed within a consistent dynamical description. To this aim, a speci c research line was dedicated to \u201cCoastal Vulnerability to Erosion and Sea Level Rise\u201d within the RITMARE Project, supported by the Italian Ministry of University and Research with the purpose of integrating the Italian Marine community in shared research elds in the period 2012-2017. The activities carried out in this framework have been moving along interconnected branches tackling the themes related with sea level rise, ocean modelling, and geomorphological assessment in present conditions and in di erent climate change scenarios, with an eye on the exploitation of marine sand as a strategic resource. In this contribution we review the main outcomes of this multidisciplinary and coordinated research. Besides discussing the advances and the possibilities from state-of-the art technologies and methodologies, we point out that a coordinated use of the described tools should be promoted in the design of survey and monitoring activities, as well as in the exploitation of already collected data. Expected outcomes of this strategy include the implementation of improved policies and infrastructures for coastal protection, anked by reliable short-term forecasting systems and e cient rapid response protocols, in the framework of an integrated coastal planning at the multi-decadal scale

Expanding the spectrum of EWSR1-PATZ1 rearranged CNS tumors: An infantile case with leptomeningeal dissemination

We report on a case of EWSR1-PATZ1 rearranged brain tumor occurring in a 17 month-old child, originally interpreted as an infantile glioblastoma. Our case shows important analogies with the 2 previously reported cases, including the intraventricular location, the histologic appearance (pushing borders, oligodendrocyte-like morphology, rich vascular network) and the glioneural immunophenotype, supporting the role of these features as relevant clues to the diagnosis. On the other hand, our case displays unique characteristics, i.e. the onset in an infant, the presence of a focal high-grade component and the leptomeningeal dissemination, pointing to the importance of considering this entity in the differential diagnosis of an infantile glial/glioneural tumor