Exosome-Based Liquid Biopsy Approaches in Bone and Soft Tissue Sarcomas: Review of the Literature, Prospectives, and Hopes for Clinical Application.

The knowledge of exosome impact on sarcoma development and progression has been implemented in preclinical studies thanks to technological advances in exosome isolation. Moreover, the clinical relevance of liquid biopsy is well established in early diagnosis, prognosis prediction, tumor burden assessment, therapeutic responsiveness, and recurrence monitoring of tumors. In this review, we aimed to comprehensively summarize the existing literature pointing out the clinical relevance of detecting exosomes in liquid biopsy from sarcoma patients. Presently, the clinical utility of liquid biopsy based on exosomes in patients affected by sarcoma is under debate. The present manuscript collects evidence on the clinical impact of exosome detection in circulation of sarcoma patients. The majority of these data are not conclusive and the relevance of liquid biopsy-based approaches in some types of sarcoma is still insufficient. Nevertheless, the utility of circulating exosomes in precision medicine clearly emerged and further validation in larger and homogeneous cohorts of sarcoma patients is clearly needed, requiring collaborative projects between clinicians and translational researchers for these rare cancers.

A 7-Year-Old Boy and a 14-Year-Old Girl Initially Diagnosed with Toxic Shock Syndrome and Tested Positive for SARS-CoV-2 Infection, Supporting a Diagnosis of Multisystem Inflammatory Syndrome in Children (MIS-C).

BACKGROUND Multisystem inflammatory syndrome in children (MIS-C) has recently been described in children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This report describes 2 children with MIS-C who were initially diagnosed with toxic shock syndrome but who tested positive for SARS-CoV-2 infection on reverse transcription-polymerase chain reaction, supporting the diagnosis of MIS-C. CASE REPORT Case 1. A 7-year-old boy with fever, cough, and dyspnea was treated with oxygen, intravenous immunoglobulin (IVIG) infusion, and methylprednisolone and showed a worsening of clinical conditions, persistent fever, hypotension, and hematological parameters compatible with macrophage activation syndrome (MAS). Three intravenous boluses of methylprednisolone (30 mg/kg/day) were followed by a progressive resolution. Case 2. A 14-year-old girl with syncope, fever, diarrhea, oliguria, and increased creatinine levels required fluid infusion and correction of electrolyte imbalance. The increase of creatine phosphokinase (CPK), myoglobin, troponin, and creatine kinase-MB (CK-MB) was associated with grade I atrioventricular block and pericardial effusion. The patient showed myositis and severe muscular weakness, with hematological parameters compatible with MIS-C. She started IVIG and 3 intravenous boluses of methylprednisolone. However, bradycardia, tachypnea, severe hypotension, loss of consciousness, oliguria, bilateral ground-glass pneumonia, bilateral pleural, and peritoneal effusion, in the absence of thromboembolism, required treatment with furosemide, albumin, and enoxaparin, and was followed by a prompt resolution. CONCLUSIONS These 2 pediatric cases highlight the importance of SARS-CoV-2 testing in all patients with acute symptoms and signs of infection during the COVID-19 pandemic. As new variants of SARS-CoV-2 emerge, cases of MIS-C can become more prevalent, and pediatricians should be aware of diagnostic and management guidelines.

Chest conformation spuriously influences strain parameters of myocardial contractile function in healthy pregnant women.

AIMS: Left ventricular (LV) contractility during noncomplicated pregnancy has been previously investigated by two-dimensional speckle-tracking echocardiography (2D-STE), with conflicting results. Chest abnormalities might affect myocardial strain parameters, yet this issue has not been previously investigated during pregnancy. We evaluated the influence of chest conformation on myocardial strain parameters in healthy pregnant women. METHODS: Between October 2019 and February 2020, 50 healthy pregnant women (32.3 ±â€Š4.0 years old) were consecutively studied. They underwent obstetric visit, assessment of chest shape by modified Haller index (MHI; chest transverse diameter over the distance between sternum and spine) and transthoracic echocardiography implemented with 2D-STE analysis of all myocardial strain parameters in the first trimester (12-14 weeks), third trimester (36-38 weeks) and 6-9 weeks after delivery. RESULTS: LV ejection fraction remained substantially unchanged (P = 0.13), while on the average all myocardial strain parameters showed a small but significant decrease during pregnancy, and recovered postpartum (all P < 0.001). Women with concave-shaped chest wall (MHI > 2.5, n = 29), and those with normal chest conformation (MHI ≤ 2.5, n = 21) were then separately analyzed. Pregnant women with MHI above 2.5, but not those with MHI 2.5 or less, showed a progressive but reversible decrease in all myocardial strain parameters (all P < 0.001). MHI was strongly correlated with LV global longitudinal strain (r = -0.87) and LV global circumferential strain (r = -0.83) in the third trimester of pregnancy. CONCLUSION: Myocardial strain impairment during healthy pregnancy may not reflect intrinsic myocardial dysfunction but rather intraventricular dyssynchrony related to a narrow antero-posterior chest diameter and rise in the diaphragm, with consequent extrinsic myocardial compression.

Heterogeneous Circulating Tumor Cells in Sarcoma: Implication for Clinical Practice.

Bone and soft tissue sarcomas (STSs) represent a group of heterogeneous rare malignant tumors of mesenchymal origin, with a poor prognosis. Due to their low incidence, only a few studies have been reported addressing circulating tumor cells (CTCs) in sarcoma, despite the well-documented relevance for applications of liquid biopsy in precision medicine. In the present review, the most recent data relative to the detection and isolation of viable and intact CTCs in these tumors will be reviewed, and the heterogeneity in CTCs will be discussed. The relevance of epithelial-mesenchymal plasticity and stemness in defining the phenotypic and functional properties of these rare cells in sarcoma will be highlighted. Of note, the existence of dynamic epithelial-mesenchymal transition (EMT)-related processes in sarcoma tumors has only recently been related to their clinical aggressiveness. Also, the presence of epithelial cell adhesion molecule (EpCAM)-positive CTC in sarcoma has been weakly correlated with poor outcome and disease progression, thus proving the existence of both epithelial and mesenchymal CTC in sarcoma. The advancement in technologies for capturing and enumerating all diverse CTCs phenotype originating from these mesenchymal tumors are presented, and results provide a promising basis for clinical application of CTC detection in sarcoma.

Association between neutrophil to lymphocyte ratio and carotid artery wall thickness in healthy pregnant women.

OBJECTIVE: Pregnancy may elicit a state of mild inflammation that might affect, either directly or indirectly, haematological parameters associated with systemic inflammation. In particular, both Neutrophil-to-lymphocyte ratio (NLR) and Red blood cells Distribution Width (RDW) have been found to be elevated in complicated pregnancy. However, data regarding the association of these haematological parameters with common carotid artery (CCA) intima-media thickness (IMT) in healthy pregnancy are scanty. Aim of this study was to evaluate possible changes in CCA-IMT during normal pregnancy and in the postpartum period, and to correlate these changes with NLR and RDW. STUDY DESIGN: Between October 2019 and February 2020, a prospective study was carried out on 73 consecutive healthy pregnant women (32.8 ± 4.9 yrs/old). Women underwent obstetric assessment, complete blood cell counts with calculation of NLR and RDW, two-dimensional transthoracic echocardiography and carotid Doppler ultrasonography. RESULTS: During normal pregnancy, both NLR and RDW progressively increased (p < 0.0001); likewise, parameters of carotid dimensions also significantly increased (p < 0.0001). Hematological and morphological changes all decreased in postpartum period. By univariable logistic regression, the variables which showed the greatest independent association with CCA-IMT (defined as CCA-IMT ≥0.55 mm) were: age (HR 1.33, 95% CI 1.15-1.53, p < 0.0001), pre-pregnant BMI (HR 2.75, 95% CI 1.72-4.41, p < 0.0001), third trimester E/e' ratio (HR 1.64, 95% CI 1.34-2.02, p < 0.0001), and third trimester NLR (HR 3.00, 95% CI 1.64-5.50, p < 0.0001). Multivariable logistic regression analysis demonstrated that third trimester NLR was the only variable that retained statistical significance (HR 2.49, 95% CI 1.35-4.59, p = 0.003). An NLR ≥ 2 reached 83% of sensitivity and 99% of specificity in identifying a CCA-IMT ≥0.55 mm (AUC = 0.95). A strong linear correlation of both third trimester NLR and RDW with CCA-IMT was observed (r = 0.89 and 0.83, respectively). CONCLUSIONS: Pregnancy is a state of chronic mild inflammation and the progressive increase in NLR and RDW during normal pregnancy is significantly associated with CCA intimal-medial thickening.

Corrigendum: Next-Generation Sequencing Approaches for the Identification of Pathognomonic Fusion Transcripts in Sarcomas: The Experience of the Italian ACC Sarcoma Working Group.

[This corrects the article DOI: 10.3389/fonc.2020.00489.].

Next-Generation Sequencing Approaches for the Identification of Pathognomonic Fusion Transcripts in Sarcomas: The Experience of the Italian ACC Sarcoma Working Group.

This work describes the set-up of a shared platform among the laboratories of the Alleanza Contro il Cancro (ACC) Italian Research Network for the identification of fusion transcripts in sarcomas by using Next Generation Sequencing (NGS). Different NGS approaches, including anchored multiplex PCR and hybrid capture-based panels, were employed to profile a large set of sarcomas of different histotypes. The analysis confirmed the reliability of NGS RNA-based approaches in detecting sarcoma-specific rearrangements. Overall, the anchored multiplex PCR assay proved to be a fast and easy-to-analyze approach for routine diagnostics laboratories.

Pharmacogenomics Biomarkers of Soft Tissue Sarcoma Therapies.

Soft tissue sarcomas (STS) are heterogeneous rare malignancies comprising ~1% of all solid cancers in adults and including more than 70 histological and molecular subtypes with different pathological and clinical development characteristics. Over the last two decades, the increased knowledge of the new molecular and genomic mechanisms of different STS histotypes allowed for a reclassification of these tumors and consequently to the development of novel chemotherapeutic agents. Generally, surgery, in combination with radiotherapy only in selected cases of localized disease, represents the most common treatment of primary STS, whereas the principal treatment modality for locally advanced or metastatic disease is first-line chemotherapy. The principal treatment for the preponderance of STS patients is usually an anthracycline (epirubicin and doxorubicin) in monotherapy or in combination with other drug novel chemotherapeutic agents. However, survival for treated patients with metastatic disease is poor, and a 2-years survival rate is about 30%. In this scenario, Pharmacogenomics (PGx) biomarkers that can predict drug response play an important role in the improvement of molecular diagnostics in clinical routines and contribute to elucidating the genetic basis for the differences in treatment efficacy and toxicity among STS patients. This review focuses on recent insight in the PGx biomarkers that have been described to modulate responsiveness and toxicity parameters of conventional and new chemotherapeutics drugs in several STS histotypes.

First ecotoxicological assessment of Caretta caretta (Linnaeus, 1758) in the Mediterranean Sea using an integrated nondestructive protocol.

The loggerhead sea turtle (Caretta caretta) is a long-lived carnivorous reptile included in the IUCN Red List. The IUCN assessment for this species underlines the lack of information regarding pollution and pathogens and indicates as a priority effort to investigate and reduce the impacts of these threats. In this contest, the aim of our study was to conduct the first ecotoxicological assessment of this species in the Mediterranean Sea using a nondestructive integrated methodology. We set up and applied a monitoring protocol which includes endpoints, such as CYP1A, LPO, ENA assay, B esterases, never investigated before in this species. Seventy-five loggerhead turtles were sampled in a nondestructive way in Italian Sea Turtle Rescue Centers or free-ranging along the Spanish coasts. Blood, skin and carapace samples were used to test biomarker responses (CYP1A, VTG, LPO, Comet and ENA assay, BChE, GGT) and contaminant (OCs, PAHs, Pb, Cd, Hg) levels. Elaboration of experimental results was carried out taking also into consideration different age classes of the specimens. Among the main results obtained we should underline the statistically significant correlation between carcinogenic PAHs in blood and DNA fragmentation as well as between Cd in carapace and GGT in plasma. We also evidenced as youngest animals showed significantly higher DNA fragmentations, BChE inhibition and increase of GGT. Older specimens showed the highest levels of erythrocyte nuclear abnormalities which may indicate a long term toxicological stress. This study contributed to expand the knowledge about the ecotoxicology of C. caretta in the Mediterranean. The nondestructive protocol could also be applied to other marine ecosystems and other sea turtle species.

Relationship between cognitive impairment and nutritional assessment on functional status in Calabrian long-term-care.

OBJECTIVE: The interaction between dementia and nutritional state is very complex and not yet fully understood. The aim of the present study was to assess the interaction between cognitive impairment and nutritional state in a cohort of residential elderly in relationship with functional condition of patients and their load of assistance in long-term-care facilities of the National Association of Third Age Structures (ANASTE) Calabria. METHODS: One hundred seventy-four subjects (122 female and 52 male) were admitted to the long-term-care ANASTE Calabria study. All patients underwent multidimensional geriatric assessment. Nutritional state was assessed with the Mini Nutritional Assessment (MNA), whereas cognitive performance was evaluated by the Mini-Mental State Examination (MMSE). The functional state was assessed by Barthel Index (BI) and Activity Daily Living (ADL). The following nutritional biochemical parameters were also evaluated: albumin, cholesterol, iron, and hemoglobin. All patients were reassessed 180 days later. RESULTS: A severe cognitive impairment in MMSE performance was displayed in 49.7% patients, while 39.8% showed a moderate deficit; 6.9% had a slight deficit; and 3.4% evidenced no cognitive impairment. In MNA, 30% of patients exhibited an impairment of nutritional state; 56% were at risk of malnutrition; and 14% showed no nutritional problems. Malnutrition was present in 42% of patients with severe cognitive impairment, but only 4% of malnourished patients showed moderate cognitive deficit. The statistical analysis displayed a significant correlation between MNA and MMSE (P<0.001), as did MMSE correlated with Activity Daily Living (P<0.001) and BI (P<0.05). MNA correlated with BI (P<0.001) and albumin (P<0.001). The follow-up showed a strong correlation between cognitive deterioration and worsening of nutritional state (P<0.005) as well as with the functional state (P<0.05) and mortality (P<0.01). CONCLUSION: The present study clearly shows that malnutrition may play an important role in the progression of cognitive loss.