HACOR score to predict NIV failure in patients with COVID-related hypoxemic respiratory failure managed in the ordinary ward and in the critical care setting.

We evaluated the prevalence of non-invasive ventilation (NIV) failure among patients with COVID-19-related pneumonia, managed in the ordinary ward and in the HDU/ICU and we tested the prognostic role of the HACOR score in those different settings. This is a retrospective study, conducted in the University-Hospital Careggi. We included all subjects with COVID-19 and ARF requiring NIV between March 2020 and May 2021, respectively managed in the ordinary ward (G1) and in the critical care setting (G2). Clinical parameters, HACOR and SOFA score were evaluated at Day 0 and after 1, 2 and 5 days of treatment. The primary outcome was NIV failure. 13% G1 patients and 40% G2 patients underwent endotracheal intubation (ETI). NIV was successful in 60% G1 AND 43% G2 patients (p < 0.001). In G1, compared to those with successful NIV, patients who underwent ETI, had a higher HACOR since the baseline evaluation (T0: 6 [5-6] vs 5 [3-6]; T1: 6 [5-6] vs 5 [3-6], all p < 0.05). An HACOR score > 5 was associated with an increased prevalence of ETI independent to an advanced age and a SOFA score > 5 both in G1 (T1: RR 4.87, 95% CI 1.462-16.275; T5: 3.630, 95% CI 0.979-13.462) and G2 (T0: 1.76, 95% CI 0.906-3.422; T1: 3.38, 95% CI 1.386-8.265). Among patients with COVID-related-ARF, NIV could be managed in the ordinary ward in a consistent proportion of patients and, among them, an HACOR score > 5 was independently associated with increased NIV failure from the earliest evaluations.

The Impact of potential 'confounders' on the diagnostic sensitivity of circulating free DNA in management of FIT+ patients: a pilot study.

Cell-free DNA (cfDNA) has long been established as a useful diagnostic and prognostic tool in a variety of clinical settings, ranging from infectious to cardiovascular and neoplastic diseases. However, non-neoplastic diseases can act as confounders impacting on the amount of cfDNA shed in bloodstream and on technical feasibility of tumour derived free circulating nucleic acids selecting patients with cancer. Here, we investigated the potential impact of other pathological processes in the clinical stratification of 637 FIT+ patients. A single and multiple logistic regression yielded similar results. Crude sensitivity was 75.9% versus adjusted sensitivity of 74.1%, relative risk 0.9761 (0.8516 to 1.1188), risk difference 0.0181 (-0.0835 to 0.1199) and OR 0.9079 (0.5264 to 1.5658). Potential confounding effect from other source of cfDNA plays a pivotal role in the clinical stratification of FIT+ patients.

Circulating biomarkers as predictors of response to immune checkpoint inhibitors in NSCLC: Are we on the right path?

Immune checkpoints inhibitors (ICIs) have markedly improved the therapeutic management of advanced NSCLC and, more recently, they have demonstrated efficacy also in the early-stage disease. Despite better survival outcomes with ICIs compared to standard chemotherapy, a large proportion of patients can derive limited clinical benefit from these agents. So far, few predictive biomarkers, including the programmed death-ligand 1 (PD-L1), have been introduced in clinical practice. Therefore, there is an urgent need to identify novel biomarkers to select patients for immunotherapy, to improve efficacy and avoid unnecessary toxicity. A deeper understanding of the mechanisms involved in antitumor immunity and advances in the field of liquid biopsy have led to the identification of a wide range of circulating biomarkers that could potentially predict response to immunotherapy. Herein, we provide an updated overview of these circulating biomarkers, focusing on emerging data from clinical studies and describing modern technologies used for their detection.

The biomarkers ATLAS: An audit on 1100 non-small cell lung cancer from an Italian knowledge-based database.

AIMS: To date, precision medicine has revolutionized the clinical management of Non-Small Cell Lung Cancer (NSCLC). International societies approved a rapidly improved mandatory testing biomarkers panel for the clinical stratification of NSCLC patients, but harmonized procedures are required to optimize the diagnostic workflow. In this context a knowledge-based database (Biomarkers ATLAS, https://biomarkersatlas.com/) was developed by a supervising group of expert pathologists and thoracic oncologists collecting updated clinical and molecular records from about 80 referral Italian institutions. Here, we audit molecular and clinical data from n = 1100 NSCLC patients collected from January 2019 to December 2020. METHODS: Clinical and molecular records from NSCLC patients were retrospectively collected from the two coordinating institutions (University of Turin and University of Naples). Molecular biomarkers (KRAS, EGFR, BRAF, ROS1, ALK, RET, NTRK, MET) and clinical data (sex, age, histological type, smoker status, PD-L1 expression, therapy) were collected and harmonized. RESULTS: Clinical and molecular data from 1100 (n = 552 mutated and n = 548 wild-type) NSCLC patients were systematized and annotated in the ATLAS knowledge-database. Molecular records from biomarkers testing were matched with main patients' clinical variables. CONCLUSIONS: Biomarkers ATLAS (https://biomarkersatlas.com/) represents a unique, easily managing, and reliable diagnostic tool aiming to integrate clinical records with molecular alterations of NSCLC patients in the real-word Italian scenario.

Sustainable waste management and waste-to-energy in the context of a circular economy through various waste management technologies.

Inappropriate waste management is a considerable ecological risk, leading to detrimental effects on the soil, air, and water quality. It is imperative to address these concerns promptly to minimize the repercussions of solid waste on public health and the ecosystem. It is evident that the level of economic growth directly impacts waste generation. This study intends to use the life cycle assessment (LCA) technique to evaluate the environmental impacts of four alternative municipal solid waste (MSW) management scenarios in Peshawar City, Pakistan. The goal is to discover an option that is both sustainable and minimizes environmental damage. The study examined the system boundaries encompassing the collection and transportation of MSW, along with its processing and final disposal, employing composting, anaerobic digestion (AD), material recovery facilities (MRF), and landfill methods. Comprehensive field studies and an in-depth literature review provided the data regarding Peshawar's existing MSW management system and the proposed scenarios, all of which was inventoried in the OpenLCA 1.10.3 database. Following data collection, the CML-IA technique was employed to analyze the data, measuring the environmental footprint in terms of climate change potential, human toxicity, acidification potential, photochemical oxidation, and eutrophication. A sensitivity analysis was also performed to identify the influence of varying recycling rates on the environmental strain correlated with the proposed scenarios. The analysis results indicated that scenario S2, which combined composting, landfilling, and MRF, exhibited the least environmental impact compared to the other considered scenarios. Furthermore, the sensitivity analysis reflected an inverse correlation between alterations in the recycling rate and the total environmental impact. To counter the environmental problems arising from waste generation, it is essential to incorporate principles of the circular economy into the MSW management approach.

Economic assessment of NGS testing workflow for NSCLC in a healthcare setting.

Background: The molecular diagnostic and therapeutic pathway of Non-Small Cell Lung Cancer (NSCLC) stands as a successful example of precision medicine. The scarcity of material and the increasing number of biomarkers to be tested have prompted the routine application of next-generation-sequencing (NGS) techniques. Despite its undeniable advantages, NGS involves high costs that may impede its broad adoption in laboratories. This study aims to assess the detailed costs linked to the integration of NGS diagnostics in NSCLC to comprehend their financial impact. Materials and methods: The retrospective analysis encompasses 210 cases of early and advanced stages NSCLC, analyzed with NGS and collected at the IRCCS San Gerardo dei Tintori Foundation (Monza, Italy). Molecular analyses were conducted on FFPE samples, with an hotspot panel capable of detecting DNA and RNA variants in 50 clinically relevant genes. The economic analysis employed a full-cost approach, encompassing direct and indirect costs, overheads, VAT (Value Added Tax). Results: We estimate a comprehensive cost for each sample of €1048.32. This cost represents a crucial investment in terms of NSCLC patients survival, despite constituting only around 1% of the expenses incurred in their molecular diagnostic and therapeutic pathway. Conclusions: The cost comparison between NGS test and the notably higher therapeutic costs highlights that the diagnostic phase is not the limiting economic factor. Developing NGS facilities structured in pathology networks may ensure appropriate technical expertise and efficient workflows.

Identification of a Novel Non-V600E BRAF Mutation in Papillary Thyroid Cancer.

Papillary thyroid cancer (PTC) is a common endocrine malignancy, and its incidence is reported to be constantly increasing. BRAF mutation is detected in approximately 44% of PTCs, and the most common BRAF mutation is thymine (T) to adenine (A) missense mutation in nucleotide 1796 (T1796A, V600E). Although BRAFV600E represents 95% of all BRAF mutations, uncommon BRAF mutations have been reported in thyroid carcinomas and represent an alternative mechanism of BRAF activation with unclear clinical significance. We report a novel non-V600E mutation (c.1799_1812delinsAT, p.V600_W604delinsD), identified preoperatively with next-generation sequencing (NGS) on the material obtained with fine-needle aspiration cytology (FNAC) performed on a thyroid nodule cytologically suspicious for malignancy in a 35-year-old male patient. The presence of this new variant of BRAF mutation was subsequently confirmed in the postoperative phase by direct Sanger sequencing. In conclusion, we report a new non-V600E variant previously undetected in papillary thyroid cancer. In addition, this case report shows that the NGS technique on cytological tissue allows to detect the presence of rare mutations, thus increasing the diagnostic specificity of molecular analysis.

PIK3CA testing in hormone receptor-positive/HER2-negative metastatic breast cancer: real-world data from Italian molecular pathology laboratories.

Introduction: PIK3CA gene mutations occur in approximately 40% of hormone receptor-positive/HER2-negative (HR+/HER2-) metastatic breast cancers (MBCs), electing them to targeted therapy. Testing PIK3CA status is complex due to selection of biological specimen and testing method. Materials & methods: This work investigates real-life experience on PIK3CA testing in HR+/HER2- MBC. Clinical, technical and molecular data on PIK3CA testing were collected from two referral laboratories. Additionally, the results of a nationwide PIK3CA survey involving 116 institutions were assessed. Results: Overall, n = 35 MBCs were PIK3CA-mutated, with mutations mostly occurring in exons 9 (n = 19; 51.4%) and 20 (n = 15; 40.5%). The nationwide survey revealed significant variability across laboratories in terms of sampling methodology, technical assessment and clinical report signing healthcare figures for PIK3CA molecular testing in diagnostic routine practice. Conclusion: This study provides insights into the real-world routine of PIK3CA testing in HR+/HER2- MBC and highlights the need for standardization and networking in predictive pathology.

4C mortality score and COVID-19 mortality risk score: an analysis in four different age groups of an Italian population.

To evaluate the prognostic stratification ability of 4C Mortality Score and COVID-19 Mortality Risk Score in different age groups. Retrospective study, including all patients, presented to the Emergency Department of the University Hospital Careggi, between February, 2020 and May, 2021, and admitted for SARS-CoV2. Patients were divided into four subgroups based on the quartiles of age distribution: patients < 57 years (G1, n = 546), 57-71 years (G2, n = 508), 72-81 years (G3, n = 552), and > 82 years (G4, n = 578). We calculated the 4C Mortality Score and COVID-19 Mortality Risk Score. The end-point was in-hospital mortality. In the whole population (age 68 ± 16 years), the mortality rate was 19% (n = 424), and increased with increasing age (G1: 4%, G2: 11%, G3: 22%, and G4: 39%, p < 0.001). Both scores were higher among non-survivors than survivors in all subgroups (4C-MS, G1: 6 [3-7] vs 3 [2-5]; G2: 10 [7-11] vs 7 [5-8]; G3: 11 [10-14] vs 10 [8-11]; G4: 13 [12-15] vs 11 [10-13], all p < 0.001; COVID-19 MRS, G1: 8 [7-9] vs 9 [9-11], G2: 10 [8-11] vs 11 [10-12]; G3: 11 [10-12] vs 12 [11-13]; G4: 11 [10-13] vs 13 [12-14], all p < 0.01). The ability of both scores to identify patients at higher risk of in-hospital mortality, was similar in different age groups (4C-MS: G1 0.77, G2 0.76, G3 0.68, G4 0.72; COVID-19 MRS: G1 0.67, G2 0.69, G3 0.69, G4 0.72, all p for comparisons between subgroups = NS). Both scores confirmed their good performance in predicting in-hospital mortality in all age groups, despite their different mortality rate.

Non-Small Cell Lung Cancer Testing on Reference Specimens: An Italian Multicenter Experience.

INTRODUCTION: Biomarker testing is mandatory for the clinical management of patients with advanced non-small cell lung cancer (NSCLC). Myriads of technical platforms are now available for biomarker analysis with differences in terms of multiplexing capability, analytical sensitivity, and turnaround time (TAT). We evaluated the technical performance of the diagnostic workflows of 24 representative Italian institutions performing molecular tests on a series of artificial reference specimens built to mimic routine diagnostic samples. METHODS: Sample sets of eight slides from cell blocks of artificial reference specimens harboring exon 19 EGFR (epidermal growth factor receptor) p.E746_AT50del, exon 2 KRAS (Kirsten rat sarcoma viral oncogene homologue) p.G12C, ROS1 (c-ros oncogene 1)-unknown gene fusion, and MET (MET proto-oncogene, receptor tyrosine kinase) Δ exon 14 skipping were distributed to each participating institution. Two independent cell block specimens were validated by the University of Naples Federico II before shipment. Methodological and molecular data from reference specimens were annotated. RESULTS: Overall, a median DNA concentration of 3.3 ng/µL (range 0.1-10.0 ng/µL) and 13.4 ng/µL (range 2.0-45.8 ng/µL) were obtained with automated and manual technical procedures, respectively. RNA concentrations of 5.7 ng/µL (range 0.2-11.9 ng/µL) and 9.3 ng/µL (range 0.5-18.0 ng/µL) were also detected. KRAS exon 2 p.G12C, EGFR exon 19 p.E736_A750del hotspot mutations, and ROS1 aberrant transcripts were identified in all tested cases, whereas 15 out of 16 (93.7%) centers detected MET exon 14 skipping mutation. CONCLUSIONS: Optimized technical workflows are crucial in the decision-making strategy of patients with NSCLC. Artificial reference specimens enable optimization of diagnostic workflows for predictive molecular analysis in routine clinical practice.

The role of liquid biopsy in epithelial ovarian cancer: State of the art.

The clinical implementation of liquid biopsy has dramatically modified the analytical paradigm for several solid tumors. To date, however, only circulating free DNA (cfDNA) has been approved in clinical practice to select targeted treatments for patients with colorectal cancer (CRC), non-small cell lung cancer (NSCLC), and breast cancer (BC). Interestingly, emerging liquid biopsy analytes in peripheral blood, including circulating tumor cells (CTC), miRNA, and extracellular vesicles (EVs), have been shown to play a crucial role in the clinical management of solid tumor patients. Here, we review how these blood-based biomarkers may positively impact early diagnosis, prognosis, and treatment response in ovarian cancer (OC) patients.

Clinical characteristics of patients hospitalized for COVID-19: comparison between different age groups.

BACKGROUND: To test whether known prognosticators of COVID-19 maintained their stratification ability across age groups. METHODS: We performed a retrospective study. We included all patients (n = 2225), who presented to the Emergency Department of the Careggi University Hospital for COVID-19 in the period February 2020-May 2021, and were admitted to the hospital. The following parameters were analyzed as dichotomized: 1) SpO2/FiO2 ≤ or > 214; 2) creatinine < or ≥ 1.1 mg/dL; 3) Lactic dehydrogenase (LDH) < or ≥ 250 U/mL; 4) C Reactive Protein (CRP) < or ≥ 60 mg/100 mL. We divided the study population in four subgroups, based on the quartiles of distribution of age (G1 18-57 years, G2 57-71 years, G3 72-81 years, G4 > 82). The primary end-point was in-hospital mortality. RESULTS: By the univariate analysis, the aforementioned dichotomized variables demonstrated a significant association with in-hospital mortality in all subgroups. We introduced them in a multivariate model: in G1 SpO2/FiO2 ≤ 214 (Relative Risk, RR 15.66; 95%CI 3.98-61,74), in G2 creatinine ≥ 1.1 mg/L (RR 2.87, 95%CI 1.30-6.32) and LDH ≥ 250 UI/L (RR 8.71, 95%CI 1,15-65,70), in G3 creatinine ≥ 1.1 mg/L (RR 1.98, 95%CI 1,17-3.36) and CRP ≥ 60 ng/L (RR 2.14, 95%CI 1.23-3.71), in G4 SpO2/FiO2 ≤ 214 (RR 5.15, 95%CI 2.35-11.29), creatinine ≥ 1.1 mg/L (RR 1.75, 95%CI 1.09-2.80) and CRP ≥ 60 ng/L (RR 1.82, 95%CI 1.11-2.98) were independently associated with an increased in-hospital mortality. CONCLUSIONS: A mild to moderate respiratory failure showed an independent association with an increased mortality rate only in youngest and oldest patients, while kidney disease maintained a prognostic role regardless of age.

Liquid biopsy: A promising tool for driving strategies and predicting failures in patients with classic Hodgkin lymphoma.

Classic Hodgkin lymphoma (cHL) consists of a heterogeneous group of haematological disorders that covers undifferentiated B cell neoplasms originating from germinal centre B cells. The HL molecular characterization still represents an ongoing challenge due to the low fraction of tumour Hodgkin and Reed-Sternberg cells mixed with a plethora of non-tumour haematological cells. In this scenario, next generation sequencing of liquid biopsy samples is emerging as a useful tool in HL patients' management. In this review, we aimed to overview the clinical and methodological topics regarding the implementation of molecular analysis in cHL, focusing on the role of liquid biopsy in diagnosis, follow-up, and response prediction.

Standardized and simplified reporting of next-generation sequencing results in advanced non-small-cell lung cancer: Practical indications from an Italian multidisciplinary group.

Molecular biomarker testing is increasingly becoming standard of care for advanced non-small cell lung cancer (NSCLC). Tissue and liquid biopsy-based next-generation sequencing (NGS) is now highly recommended and has become an integral part of the routine management of advanced NSCLC patients. This highly sensitive approach can simultaneously and efficiently detect multiple biomarkers even in scant samples. However full optimization of NGS in clinical practice requires accurate reporting and interpretation of NGS findings. Indeed, as the number of NSCLC biomarkers continues to grow, clinical reporting of NGS data is becoming increasingly complex. In this scenario, achieving standardization, simplification, and improved readability of NGS reports is key to ensuring timely and appropriate treatment decisions. In an effort to address the complexity and lengthy reporting of NGS mutation results, an Italian group of 14 healthcare professionals involved in NSCLC management convened in 2023 to address the content, structure, and ease-of-use of NGS reporting practices and proposed a standard report template for clinical use This article presents the key discussion points addressed by the Italian working group and describes the essential elements of the report template.

Genomic profiling of tissue and blood predicts survival outcomes in patients with resected pleural mesothelioma.

PURPOSE: Pleural mesothelioma (PM) is an aggressive tumor still considered incurable, in part due to the lack of predictive biomarkers. Little is known about the clinical implications of molecular alterations in resectable PM tissues and blood. Here, we characterized genetic alterations to identify prognostic and predictive biomarkers in patients with resected PM. EXPERIMENTAL DESIGN: Targeted next-generation sequencing was performed in retrospective pleural tumor tissue and paired plasma samples from stage IB-IIIB resected PM. Association between prognosis and presence of specific mutations was validated in silico. RESULTS: Thirty PM tissues and paired blood samples from 12 patients were analyzed. High tissue tumor mutational burden (TMB) (>10 mutations/Mb), tissue median minor allele frequency (MAF) (>9 mutations/Mb), and blood TMB (>6 mutations/Mb), tissue KMT2C, PBRM1, PKHD1,EPHB1 and blood LIFR mutations correlated with longer disease-free survival and/or overall survival. High concordance (>80%) between tissue and blood was found for some mutations. CONCLUSIONS: Tissue TMB and MAF, blood TMB, and specific mutations correlated with outcomes in patients with resected PM and should be further studied to validate their role as prognostic biomarkers and potentially predictive factors for combinations with immune-checkpoint inhibitors. This suggest that molecular profiling could identify longer survivors in patients with resected PM.

The Influence of Substrate on the Optical Properties of Gold Nanoslits.

Nanoslits have various applications, including localized surface plasmon resonance (LSPR)-based nanodevices, optical biosensors, superfocusing, high-efficiency refractive index sensors and chip-based protein detection. In this study, the effect of substrates on the optical properties of gold nanoslits placed in free space is discussed; for this purpose, glass BK7 and Al2O3 are used as substrates and the wavelength of incident light is supposed to be 650 nm. The optical properties, power flow and electric field enhancement for gold nanoslits are investigated by using the finite element method (FEM) in COMSOL Multiphysics software. The effect of polarization of an incident electromagnetic wave as it propagates from a gold nanoslit is also analyzed. As special case, the effect of glass and alumina substrate on magnetic field, power flow and electric field enhancement is discussed. The goal of this research is to investigate the phenomenon of power flow and electric field enhancement. The study of power flow in gold nanoslits provides valuable insights into the behavior of light at the nanoscale and offers opportunities for developing novel applications in the field of nanophotonics and plasmonics. The consequences of this study show the significance of gold nanoslits as optical nanosensors.

Overview of environmental and economic viability of activated carbons derived from waste biomass for adsorptive water treatment applications.

In adsorptive water treatment applications, the exploration of waste-derived activated carbon (AC) has gained substantial attention in scientific research. The use of waste materials as precursors for AC has gained attention due to its economic viability and potential to reduce the consumption of non-renewable resources. However, there is a lack of comprehensive literature regarding the costs and environmental impacts associated with the waste-based AC production and application. As sustainability practices gain importance, there has been an increase in research dedicated to estimating costs and conducting life cycle assessment (LCA) of AC production from waste sources. However, there is a need for thorough literature reviews that cover various methodologies and conclusions. The primary objective of this study is to provide a comprehensive overview and analysis of the economic and environmental factors related to the use of waste-derived AC in water treatment. LCA studies indicate that utilizing waste materials for AC production can lead to significant resource and energy savings compared to conventional methods relying on fossil resources. The cost of AC is influenced by factors such as precursor material cost, energy requirements during production (optimizable on an industrial scale), and properties of the resulting material. Additionally, the review emphasizes the significance of waste-based AC regeneration for sustainable viability. Evaluating the environmental and economic costs is crucial to support sustainability claims and avoid unsupported assertions. Overall, this study contributes to understanding the potential of waste-derived AC in water treatment and highlights the need for further research in this area.

Deep learning approach for denoising low-SNR correlation plenoptic images.

Correlation Plenoptic Imaging (CPI) is a novel volumetric imaging technique that uses two sensors and the spatio-temporal correlations of light to detect both the spatial distribution and the direction of light. This novel approach to plenoptic imaging enables refocusing and 3D imaging with significant enhancement of both resolution and depth of field. However, CPI is generally slower than conventional approaches due to the need to acquire sufficient statistics for measuring correlations with an acceptable signal-to-noise ratio (SNR). We address this issue by implementing a Deep Learning application to improve image quality with undersampled frame statistics. We employ a set of experimental images reconstructed by a standard CPI architecture, at three different sampling ratios, and use it to feed a CNN model pre-trained through the transfer learning paradigm U-Net architecture with VGG-19 net for the encoding part. We find that our model reaches a Structural Similarity (SSIM) index value close to 1 both for the test sample (SSIM = [Formula: see text]) and in 5-fold cross validation (SSIM = [Formula: see text]); the results are also shown to outperform classic denoising methods, in particular for images with lower SNR. The proposed work represents the first application of Artificial Intelligence in the field of CPI and demonstrates its high potential: speeding-up the acquisition by a factor 20 over the fastest CPI so far demonstrated, enabling recording potentially 200 volumetric images per second. The presented results open the way to scanning-free real-time volumetric imaging at video rate, which is expected to achieve a substantial influence in various applications scenarios, from monitoring neuronal activity to machine vision and security.

Uterine Tumours Resembling Ovarian Sex-Cord Tumors: A Case Report and Review of the Literature.

Uterine tumors resembling ovarian sex-cord tumors (UTROSCT) are thought to develop from pluripotent uterine mesenchymal cells or endometrial stromal cells with secondary sex-cord differentiation. The patient was a 73-year-old postmenopausal woman who had abnormal vaginal bleeding, and she underwent a laparoscopic hysterectomy with bilateral salpingo-oophorectomy. The diagnosis was a case of UTROSCT. A scoping review of the UTROSCT case report present in the literature has been conducted, and 63 articles were found, of which 45 were considered for the 66 clinical cases examined. At the time of diagnosis, six metastatic localizations were found in 59 patients undergoing demolitive surgery (10.2%). Recurrences were diagnosed in 13/59 (22%) patients with multiple locations. A molecular study was performed in 18/66 cases (27.3%) and genetic alterations were found in 10/18 (55.6%) patients. UTROSCTs are considered rare uterine tumors, typically with a favorable prognosis, and are generally considered to have a good prognosis. But, from the review done, they may already manifest themselves at advanced stages, with the possibility of recurrences even at a distance. It would, therefore, be important to be able to define the most aggressive forms and, perhaps, molecular investigation with sequencing could help identify patients most at risk.