Summary Neuroschistosomiasis, referring to schistosomal involvement of the CNS, when symptomatic, is a severe disorder in which prognosis depends largely on early diagnosis and treatment. It is an ...underdiagnosed disorder, but has been increasingly reported in populations in endemic areas and in tourists. CNS involvement can occur at any time during schistosomal infection. Both the brain and the spinal cord can be affected. Schistosoma mansoni and Schistosoma haematobium usually cause myelopathy, whereas Schistosoma japonicum usually causes encephalic disease. There are substantial differences in the pathogenesis, clinical presentation, and outcome of the neurological disorder, depending on the phase and clinical form of schistosomiasis in which it occurs.
Angiogenesis is a complex biological process that plays a central role in progression of tumor growth and metastasis. It led to a search for antiangiogenic molecules, and to design antiangiogenic ...strategies for cancer treatment. Noninvasive molecular imaging, such as positron emission tomography (PET) and single photon emission computed tomography (SPECT), could be useful for lesion detection, to select patients likely to respond to antiangiogenic therapies, to confirm successful targeting, and dose optimization. Additionally, nuclear imaging techniques could also aid in the development of new angiogenesis-targeted drugs and their validation. Angiogenesis imaging can be categorized as targeted at three major cell types: (I) non-endothelial cell targets, (II) endothelial cell targets, and (III) extracellular matrix proteins and matrix proteases. Even if radiopharmaceuticals studying the metabolism and hypoxia can be also used for the study of angiogenesis, many of the agents used in nuclear imaging for this purpose are yet to be investigated. The purpose of this review is to describe the role of molecular imaging in tumor angiogenesis, highlighting the advances in this field.
The myocardium and the cardiovascular system are often involved in patients with sarcoidosis. As therapy should be started as early as possible to avoid complications such as left ventricular ...dysfunction, a prompt and reliable diagnosis by means of non-invasive tests would be highly warranted. Among other techniques,
F-fluorodeoxyglucose (FDG) positron emission tomography (PET) has emerged as a high sensitive tool to detect sites of inflammation before morphological changes are visible to conventional imaging techniques. We therefore aim at summarizing the most relevant findings in the literature on the use of
F-fluorodeoxyglucose PET in the diagnostic workup of cardiac sarcoidosis and to underline future perspectives.
The treatment of metastatic osteosarcoma (OS) remains a challenge for oncologists, and novel therapeutic strategies are urgently needed. An understanding of the pathways that regulate OS ...dissemination is required for the design of novel treatment approaches. We recently identified Rho-associated coiled-coil containing protein kinase 2 (ROCK2) as a crucial driver of OS cell migration. In this study, we explored the impact of ROCK2 disruption on the metastatic capabilities of OS cells and analyzed its functional relationship with Yes-associated protein-1 (YAP), the main transcriptional mediator of mechanotransduction signaling.
The effects of ROCK2 depletion on metastasis were studied in NOD Scid gamma (NSG) mice injected with U-2OS cells in which ROCK2 expression had been stably silenced. Functional studies were performed in vitro in human U-2OS cells and in three novel cell lines derived from patient-derived xenografts (PDXs) by using standard methods to evaluate malignancy parameters and signaling transduction. The nuclear immunostaining of YAP and the evaluation of its downstream targets Cysteine Rich Angiogenic Inducer 6, Connective Tissue Growth Factor and Cyclin D1 by quantitative PCR were performed to analyze YAP activity. The effect of the expression and activity of ROCK2 and YAP on tumor progression was analyzed in 175 OS primary tumors.
The silencing of ROCK2 markedly reduced tumor growth and completely abolished the metastatic ability of U-2OS cells. The depletion of ROCK2, either by pharmacological inhibition or silencing, induced a dose- and time-dependent reduction in the nuclear expression and transcriptional activity of YAP. The nuclear expression of YAP was observed in 80/175 (46%) tumor samples and was significantly correlated with worse patient prognosis and a higher likelihood of metastasis and death. The use of verteporfin, a molecule that specifically inhibits the TEAD-YAP association, remarkably impaired the growth and migration of OS cells in vitro. Moreover to inhibiting YAP activity, our findings indicate that verteporfin also affects the ROCK2 protein and its functions.
We describe the functional connection between ROCK2 and YAP in the regulation of OS cell migration and metastasis formation. These data provide support for the use of verteporfin as a possible therapeutic option to prevent OS cell dissemination.
Abstract
Background
The outcomes of patients with lung metastases from giant cell tumor of bone (GCTB) vary from spontaneous regression to uncontrolled growth. To investigate whether observation is ...an appropriate first-line management approach for patients with lung metastases from GCTB, we evaluated the outcomes of patients who were initially managed by observation.
Methods
We retrospectively reviewed the data of 22 patients with lung metastases from histologically confirmed GCTB who received observation as a first-line treatment approach. The median follow-up period was 116 months.
Results
Disease progression occurred in 12 patients (54.5%). The median interval between the discovery of lung metastases and progression was 8 months. Eight patients underwent metastasectomy following initial observation. The median interval between the discovery of lung metastases and treatment by metastasectomy was 13.5 months. None of the patients experienced spontaneous regression. Of the 22 patients, 36.4% needed a metastasectomy, and 9.1% required denosumab treatment during the course of the follow-up period. Disease progression occurred in 45.5% of the 11 patients with lung nodules ≤ 5 mm, while all five of the patients with lung nodules > 5 mm experienced disease progression. Progression-free survival was significantly worse in the group with lung nodules > 5 mm compared to the group with lung nodules ≤ 5 mm (
p
= 0.022).
Conclusions
Observation is a safe first-line method of managing patients with lung metastases from GCTB. According to radiological imaging, approximately half of the patients progressed, and approximately half required a metastasectomy or denosumab treatment. However, patients with lung nodules > 5 mm should receive careful observation because of the high rate of disease progression in this group.
Summary
Infective endocarditis (IE) is the cardiac disease with the highest rates of mortality. New biomarkers that are able to identify patients at risk for death are required to improve patient ...management and outcome. This study aims to investigate if cytokines, chemokines and growth factors measured at IE diagnosis can predict mortality. Patients with definite IE, according to the Duke’s modified criteria, were included. Using high‐performance Luminex assay, 27 different cytokines, chemokines and growth factors were analyzed. Machine learning techniques were used for the prediction of death and subsequently creating a decision tree, in which the cytokines, chemokines and growth factors were analyzed together with C‐reactive protein (CRP). Sixty‐nine patients were included, 41 (59%) male, median age 54 interquartile range (IQR) = 41–65 years and median time between onset of the symptoms and diagnosis was 12 days (IQR = 5–30 days). The in‐hospital mortality was 26% (n = 18). Proinflammatory cytokines interkeukin (IL)‐15 and C‐C motif chemokine ligand (CCL4) were found to predict death, adding value to CRP levels. The decision tree predicted correctly the outcome of 91% of the patients at hospital admission. The high‐risk group, defined as CRP ≥ 72 mg/dL, IL‐15 ≥ 5·6 fg/ml and CCL4 ≥ 6·35 fg/ml had an 88% in‐hospital mortality rate, whereas the patients classified as low‐risk had a mortality rate of 8% (P = < 0·001). Cytokines IL‐15 and CCL4 were predictors of mortality in IE, adding prognostic value beyond that provided by CRP levels. Assessment of cytokines has potential value for clinical risk stratification and monitoring in IE patients.
Predictive factors of in‐hospital mortality among patients with infective endocarditis were investigated. Clinical and laboratorial data at diagnosis, including measurements of 27 cytokines, chemokines and growth‐factors, were used to build a decision‐tree that stratified patients according to their mortality risk. Based on the values of IL‐15, CRP and CCL4, the model presented an accuracy greater than 90% to predict death.
Infective endocarditis (IE) is a severe disease with high mortality rate. Cytokines participate in its pathogenesis and may contribute to early diagnosis improving the outcome. This study aimed to ...evaluate the cytokine profile in IE. Serum concentrations of interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-12 and tumor necrosis factor (TNF)-α were measured by cytometric bead array (CBA) at diagnosis in 81 IE patients, and compared with 34 healthy subjects and 30 patients with non-IE infections, matched to the IE patients by age and gender. Mean age of the IE patients was 47±17 years (range, 15-80 years), and 40 (50%) were male. The IE patients had significantly higher serum concentrations of IL-1β, IL-6, IL-8, IL-10 and TNF-α as compared to the healthy individuals. The median levels of IL-1β, TNF-α and IL-12 were higher in the IE than in the non-IE infections group. TNF-α and IL-12 levels were higher in staphylococcal IE than in the non-staphylococcal IE subgroup. There was a higher proportion of both low IL-10 producers and high producers of IL-1β, TNF-α and IL-12 in the staphylococcal IE than in the non-staphylococcal IE subgroup. This study reinforces a relationship between the expression of proinflammatory cytokines, especially IL-1β, IL-12 and TNF-α, and the pathogenesis of IE. A lower production of IL-10 and impairment in cytokine network may reflect the severity of IE and may be useful for risk stratification.
Head and neck squamous cell carcinoma (HNSCC) represents the 6th leading cancer worldwide. In most cases, patients present a locally advanced disease at diagnosis and non-surgical curative treatment ...is considered the standard of care. Nowadays,
FFDG PET/CT is a validated tool in post-treatment evaluation, with a high level of evidence. However, to standardize imaging response, several visual scales have been proposed with none of them approved yet. The study's aim is a head-to-head comparison between the diagnostic performance of the Hopkins criteria, the Deauville score, and the new proposed Cuneo score, to establish their prognostic role. Secondly, we investigate the possible value of semiquantitative analysis, evaluating SUV
and ΔSUV
of the lymph node with the highest uptake on the restaging PET scan. Moreover, we also considered morphological features using the product of diameters measured on the co-registered CT images to assess the added value of hybrid imaging.
We performed a retrospective analysis on histologically proven HNSCC patients who underwent baseline and response assessment
FFDG PET/CT. Post-treatment scans were reviewed according to Hopkins, Deauville, and Cuneo criteria, assigning a score to the primary tumor site and lymph nodes. A per-patient final score for each scale was chosen, corresponding to the highest score between the two sites. Diagnostic performance was then calculated for each score considering any evidence of locoregional progression in the first 3 months as the gold standard. Survival analysis was performed using the Kaplan-Meier method. SUV
and its delta, as well as the product of diameters of the lymph node with the highest uptake at post-treatment scan, if present, were calculated.
A total of 43 patients were finally included in the study. Sensitivity, specificity, PPV, NPV, and accuracy were 87%, 86%, 76%, 92%, and 86% for the Hopkins score, whereas 93%, 79%, 70%, 96%, and 84% for the Deauville score, respectively. Conversely, the Cuneo score reached the highest specificity and PPV (93% and 78%, respectively) but the lowest sensitivity (47%), NPV (76%), and accuracy (77%). Each scale significantly correlated with PFS and OS. The ROC analysis of the combination of SUV
and the product of diameters of the highest lymph node on the restaging PET scan reached an AUC of 0.822. The multivariate analysis revealed the Cuneo criteria and the product of diameters as prognostic factors for PFS.
Each visual score statistically correlated with prognosis thus demonstrating the reliability of point-scale criteria in HNSCC. The novel Cuneo score showed the highest specificity, but the lowest sensibility compared to Hopkins and Deauville criteria. Furthermore, the combination of PET data with morphological features could support the evaluation of equivocal cases.
Ewing sarcoma (EWS), the second most common malignant bone tumor in children and adolescents, occurs abruptly without clear evidence of tumor history or progression. Previous association studies have ...identified some inherited variants associated with the risk of developing EWS but a common picture of the germline susceptibility to this tumor remains largely unclear. Here, we examine the association between thirty single nucleotide polymorphisms (SNPs) of the
IGF2BP3
, a gene that codes for an oncofetal RNA-binding protein demonstrated to be important for EWS patient’s risk stratification, and five SNPs of
SENCR
, a long non-coding RNA shown to regulate
IGF2BP3
. An association between polymorphisms and EWS susceptibility was observed for three
IGF2BP3
SNPs - rs112316332, rs13242065, rs12700421 - and for four
SENCR
SNPs - rs10893909, rs11221437, rs12420823, rs4526784 -. In addition,
IGF2BP3
rs34033684 and
SENCR
rs10893909 variants increased the risk for female respect to male subgroup when carried together, while
IGF2BP3
rs13242065 or rs76983703 variants reduced the probability of a disease later onset (> 14 years). Moreover, the absence of
IGF2BP3
rs10488282 variant and the presence of rs199653 or rs35875486 variant were significantly associated with a worse survival in EWS patients with localized disease at diagnosis. Overall, our data provide the first evidence linking genetic variants of
IGF2BP3
and its modulator
SENCR
to the risk of EWS development and to disease progression, thus supporting the concept that heritable factors can influence susceptibility to EWS and may help to predict patient prognosis.
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