Androgen receptor in advanced breast cancer: is it useful to predict the efficacy of anti-estrogen therapy?

BACKGROUND: Androgen receptor (AR) is widely expressed in breast cancer (BC) but its role in estrogen receptor (ER)-positive tumors is still controversial. The AR/ER ratio has been reported to impact prognosis and response to antiestrogen endocrine therapy (ET). METHODS: We assessed whether AR in primary tumors and/or matched metastases is a predictor of efficacy of first-line ET in advanced BC. Patients who had received first-line ET (2002-2011) were recruited, while those given concomitant chemotherapy or trastuzumab or pretreated with > 2 lines of chemotherapy were excluded. ER, progesterone receptor (PgR), Ki67 and AR expression were assessed by immunohistochemistry, and HER2 mainly by fluorescent in-situ hybridization. Cut-offs of 1 and 10% immunostained cells were used to categorize AR expression. RESULTS: Among 102 evaluable patients, biomarkers were assessed in primary tumors in 70 cases and in metastases in 49, with 17 patients having both determinations. The overall concordance rate between primary tumors and metastases was 64.7% (95% CI 42%-87.4%) for AR status. AR status did not affect TTP significantly, whereas PgR and Ki67 status did. AR/PgR ≥0.96 was associated with a significantly shorter TTP (HR = 1.65, 95% CI 1.05-2.61, p = 0.028). AR status in primary tumors or metastases was not associated with progressive disease (PD) as best response. In contrast, Ki67 ≥ 20% and PgR < 10% showed a statistically significant association with PD as best response. CONCLUSIONS: AR expression does not appear to be useful to predict the efficacy of ET in advanced BC, whereas Ki67 and PgR exert a greater impact on its efficacy.

Targeting Angiogenesis in Biliary Tract Cancers: An Open Option.

Biliary tract cancers (BTCs) are characterized by a bad prognosis and the armamentarium of drugs for their treatment is very poor. Although the inflammatory status of biliary tract represents the first step in the cancerogenesis, the microenvironment also plays a key role in the pathogenesis of BTCs, promoting tumor angiogenesis, invasion and metastasis. Several molecules, such as vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF), are involved in the angiogenesis process and their expression on tumor samples has been explored as prognostic marker in both cholangiocarcinoma and gallbladder cancer. Recent studies evaluated the genomic landscape of BTCs and evidenced that aberrations in several genes enrolled in the pro-angiogenic signaling, such as FGF receptor-2 (FGFR-2), are characteristic of BTCs. New drugs targeting the signaling pathways involved in angiogenesis have been tested in preclinical studies both in vitro and in vivo with promising results. Moreover, several clinical studies tested monoclonal antibodies against VEGF and tyrosine kinase inhibitors targeting the VEGF and the MEK/ERK pathways. Herein, we evaluate both the pathogenic mechanisms of BTCs focused on angiogenesis and the preclinical and clinical data available regarding the use of new anti-angiogenic drugs in these malignancies.

Obesity and Breast Cancer: Molecular Interconnections and Potential Clinical Applications.

UNLABELLED: Obesity is an important risk factor for breast cancer (BC) in postmenopausal women; interlinked molecular mechanisms might be involved in the pathogenesis. Increased levels of estrogens due to aromatization of the adipose tissue, inflammatory cytokines such as tumor necrosis factor-α, interleukin-6, and prostaglandin E2, insulin resistance and hyperactivation of insulin-like growth factors pathways, adipokines, and oxidative stress are all abnormally regulated in obese women and contribute to cancerogenesis. These molecular factors interfere with intracellular signaling in the mitogen-activated protein kinase and phosphatydilinositol-3-phosphate/mammalian target of rapamycin (mTOR) pathways, which regulate the progression of the cell cycle, apoptosis, and protein synthesis. In this context, structural defects of typical genes related to both BC and obesity, such as leptin, leptin receptor, serum paraoxonase/arylesterase 1, the fat mass and obesity-associated gene and melanocortin receptor 4, have been associated with a high or low risk of BC development. The early detection of these gene alterations might be useful as risk predictors in obese women, and targeting these pathways involved in the BC pathogenesis in obese women is a potential therapeutic tool. In particular, mTOR pathway deregulation concurs in both obesity and BC, and inhibition of this might disrupt the molecular interlinks in a similar manner to that of metformin, which exerts definite anticancer activity and is currently used as an antidiabetic drug with a weight-reducing property. The identification of both genetic and pharmacological implications on the prevention and management of BC is the ultimate aim of these studies. IMPLICATIONS FOR PRACTICE: Obese women are at risk of breast cancer, but clinicians lack concrete tools for the prevention or early diagnosis of this risk. The present study, starting from the biology and the molecular defects characterizing both obesity and breast cancer, analyzed the potential molecules and genetic defects whose early identification could delineate a risk profile. Three steps are proposed that are potentially achievable in the clinical assessment of obese women, namely the evaluation of altered levels of serum molecules, the identification of genetic polymorphisms, and the study of the transcriptomic profile of premalignant lesions. Finally, the therapeutic implications of this molecular assessment were evaluated.

Reviewing the Osteotropism in Neuroendocrine Tumors: The Role of Epithelial-Mesenchymal Transition.

BACKGROUND: Neuroendocrine tumors (NETs) metastasize to the bone. However, the incidence, clinical features, management and pathogenesis of bone involvement in NET patients have been poorly investigated. METHODS: We reviewed all published reports of histologically confirmed bone metastatic NETs and explored clinical, radiological, prognostic and therapeutic characteristics in a population of 152 patients. We then evaluated immunohistochemical expression of a panel of eight epithelial-mesenchymal transition (EMT)-related factors including SNAIL, TGF-ß1, CTGF, IL-11, PTHrP, EpCAM, CXCR4 and RANK in an independent cohort of 44 archival primary NETs. Biomarker expression was correlated with clinicopathological variables, including skeletal involvement, and tested for survival prediction. RESULTS: We found that 55% of NET patients with bone metastases were male, with a median age of 55 years at diagnosis. Metastases were restricted to the skeleton in 34% of the NET population, and axial and osteoblastic lesions were prevalent. NETs differently expressed proteins involved in EMT activation. High CXCR4 (p < 0.0001) and low TGF-ß1 levels (p = 0.0015) were significantly associated with increased risk of skeletal metastases, suggesting that EMT is implicated in NET osteotropism. By applying an algorithm measuring distinct immunohistochemical predictors of osteotropism on primary tumors, we were able to identify NET patients with bone metastases with a sensitivity and specificity of 91 and 100%, respectively (p < 0.0001). Patients whose primary tumors expressed CTGF (p = 0.0007) as well as the truncated form of EpCAM (p = 0.06) showed shorter survival. CONCLUSION: Although underestimated, bone metastases are a prominent feature of NETs, and the tumor expression of EMT markers at diagnosis may predict concurrent or subsequent skeleton colonization.

Everolimus restrains the paracrine pro-osteoclast activity of breast cancer cells.

BACKGROUND: Breast cancer (BC) cells secrete soluble factors that accelerate osteoclast (OC) differentiation, leading to the formation of osteolytic bone metastases. In the BOLERO-2 trial, BC patients with bone involvement who received Everolimus had a delayed tumor progression in the skeleton as a result of direct OC suppression through the inhibition of mTOR, in addition to the general suppressor effect on the cancer cells. Here, we explored the effect of Everolimus, as mTOR inhibitor, on the pro-OC paracrine activity of BC cells. METHODS: Both MDA-MB-231 and MCF-7 BC cell lines were incubated with sub-lethal amounts of Everolimus, and their conditioned supernatants were assessed for their capacity to differentiate OCs from PBMC from healthy donors, as well as to interfere with their bone resorbing activity shown on calcium phosphate slices. We also measured the mRNA levels of major pro-OC factors in Everolimus-treated BC cells and their secreted levels by ELISA, and evaluated by immunoblotting the phosphorylation of transcription factors enrolled by pathways cooperating with the mTOR inhibition. Finally, the in vivo pro-OC activity of these cells was assessed in SCID mice after intra-tibial injections. RESULTS: We found that Everolimus significantly inhibited the differentiation of OCs and their in vitro bone-resorbing activity, and also found decreases of both mRNA and secreted pro-OC factors such as M-CSF, IL-6, and IL-1ß, whose lower ELISA levels paralleled the defective phosphorylation of NFkB pathway effectors. Moreover, when intra-tibially injected in SCID mice, Everolimus-treated BC cells produced smaller bone metastases than the untreated cells. CONCLUSIONS: mTOR inhibition in BC cells leads to a suppression of their paracrine pro-OC activity by interfering with the NFkB pathway; this effect may also account for the delayed progression of bone metastatic disease observed in the BOLERO-2 trial.

Vulnerability of Brazilian municipalities to hantavirus infections based on multi-criteria decision analysis.

BACKGROUND: Hantavirus infection is an emerging zoonosis transmitted by wild rodents. In Brazil, high case-fatality rates among humans infected with hantavirus are of serious concern to public health authorities. Appropriate preventive measures partly depend on reliable knowledge about the geographical distribution of this disease. METHODS: Incidence of hantavirus infections in Brazil (1993-2013) was analyzed. Epidemiological, socioeconomic, and demographic indicators were also used to classify cities' vulnerability to disease by means of multi-criteria decision analysis (MCDA). RESULTS: From 1993 to 2013, 1752 cases of hantavirus were registered in 16 Brazilian states. The highest incidence of hantavirus was observed in the states of Mato Grosso (0.57/100,000) and Santa Catarina (0.13/100,000). Based on MCDA analysis, municipalities in the southern, southeastern, and midwestern regions of Brazil can be classified as highly vulnerable. Most municipalities in northern and northeastern Brazil were classified as having low vulnerability to hantavirus cardiopulmonary syndrome. CONCLUSIONS: Although most human infections by hantavirus registered in Brazil occurred in the southern region of the country, a greater vulnerability to hantavirus was found in the Brazilian Midwest. This result reflects the need to strengthen surveillance where the disease has thus far gone unreported.

New insights into the molecular pathogenesis of langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH) is a rare proliferative disorder characterized by an accumulation of cells sharing the major phenotypic features of cutaneous Langerhans cells. Given its variable clinical evolution, ranging from self-limiting lesions to multisystemic forms with a poor prognosis, in the last decades it has been debated whether LCH might not have a neoplastic rather than an inflammatory nature. However, although the fundamental events underlying the pathogenesis of LCH are still elusive, recent advances have strikingly improved our understanding of the disease. In particular, the identification of multiple interplays between LCH cells and their tumor microenvironment, along with the recognition of the lesional cytokine storm as a key determinant of LCH progression, has substantiated new opportunities for devising targeted therapeutic approaches. Strikingly, the detection of the rapidly accelerated fibrosarcoma isoform B(V600E) gain-of-function mutation as a genetic alteration recurring in more than 50% of patients has fueled the paradoxical picture of LCH as a tumor of the antigen-presenting cells that can evade rejection by the immune system. Thus, new evidence regarding the ontogeny of LCH cells, as well as a better understanding of the putative immune system frustrating strategy in LCH, may help to define the precise pathogenesis.

The Ketogenic Diet in Children with Epilepsy: A Focus on Parental Stress and Family Compliance.

(1) Background: The aim of our study was to evaluate parental stress after 6 and 12 months of a ketogenic diet, considering demographic and clinical variables (epilepsy type, epilepsy duration, seizure number, antiseizure medications, comorbidities, efficacy, and adverse events). (2) Methods: We consecutively enrolled 36 children aged between 3 and 10 years who had been diagnosed with various types of drug-resistant epilepsy and who were in therapy with a ketogenic diet for better seizure control. A standardized neuropsychological questionnaire (Parenting Stress Index-PSI) was administered to the parents evaluating parental stress at baseline (T0), after 6 (T1) months, and after 12 months (T2). (3) Results: After 6 and 12 months of dietary treatment, Parental Distress and Total Stress mean scores were statistically significantly increased. Post hoc analysis showed no significant changes in the scores between T0 and T1, although there was a significant increase between T1 and T2. We did not find statistically significant relationships between parental stress and the other variables considered. (4) Conclusions: The ketogenic diet can be challenging for parents and can affect the perception of parental stress, especially in the long term. Parents may feel inadequate in their role; therefore, they should be helped and encouraged through additional supports in order to maximize the adherence to diet therapy.

Digital Devices Use and Fine Motor Skills in Children between 3-6 Years.

(1) Background: The principal aim of our research was to explore the relationship between digital devices use and fine motor skills in children aged three to six years and to explore the effect of some socio-demographic factors. (2) Methods: we enrolled 185 children aged between three to six years. The parents of all the participants fulfilled a questionnaire to explore the digital device use, and their children performed a standardized test to assess fine motor skills (APCM-2). We performed the Spearman correlation test to explore the relationship between different variables. (3) Results: the children spent an average of 3.08 ± 2.30 h/day on digital devices. We did not find a significant association between the time of use of digital devices and fine motor skills (p = 0.640; r = -0.036). The youngest children experienced digital tools earlier than older ones (p < 0.001; r = 0.424) and they were also the ones who used digital tools more time afterwards (p = 0.012; -0.202). The children who had working parents spent more time on digital devices (p = 0.028; r = 0.164/p = 0.037; r = 0.154) and used digital devices earlier (p = 0.023; r = 0.171). (4) Conclusions: This data suggest that it would be useful to monitor the use of digital tools, especially in the very first years of life. Future studies are needed to further explore this topic.

SHH medulloblastoma and very early onset of bowel polyps in a child with PTEN hamartoma tumor syndrome.

Phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS) is a cancer predisposition syndrome characterized by an increased risk of developing benign and malignant tumors, caused by germline pathogenic variants of the PTEN tumour suppressor gene. PTEN gene variants often present in childhood with macrocephaly, developmental delay, and/or autism spectrum disorder while tumors and intestinal polyps are commonly detected in adults. PHTS is rarely associated with childhood brain tumors with only two reported cases of medulloblastoma (MB). We report the exceptional case of an infant carrying a germline and somatic pathogenic variant of PTEN and a germline and somatic pathogenic variant of CHEK2 who developed a MB SHH in addition to intestinal polyposis.

[Cell-based strategies: novel perspectives for cancer therapy]. / Terapie cellulari in oncologia: recenti acquisizioni e sviluppi futuri.

Cellular therapies represent an emerging field in oncology. Several studies support the efficacy of cell-based immunotherapies for different solid tumors. Recent approaches, however, have been optimized in using adult stem cells, genetically modified to produce cytotoxic molecules for fighting cancer. In this review, we focused major preclinical and clinical results in this fascinating field of cell-based strategies against cancer.

[Bone health in the oncologic patient]. / La "bone health" nel paziente oncologico.

Progressive bone loss, resulting in both osteoporosis and osteomalacia, is a frequent long-term complication in cancer patients undergoing common anti-tumor treatment programs. Monitoring of bone health by both imaging techniques and biochemical markers measurement, is useful in preventing the severe skeleton default.

Migraine and epilepsy: Social cognition skills in pediatric population.

INTRODUCTION: The goal of the present study was to comparatively analyze Social Cognition skills in a pediatric population diagnosed with Migraine or Epilepsy, compared to Typically Developing children (TD). The secondary aim was to relate Social Cognition skills with other migraine- or epilepsy-related variables and with executive and cognitive functions. MATERIALS AND METHODS: In our cross-sectional observational study 119 children and adolescents (aged 6-16) with Migraine or Focal Epilepsy and 61 TD peers were recruited. Both the clinical groups and TD peers performed a neuropsychological evaluation through standardized test to assess Theory of Mind (TM), Emotion Recognition through facial expression (ER), executive function and non-verbal cognitive abilities. RESULTS: Children and adolescents with Migraine or Focal Epilepsy showed comparable scores between each other, however their scores were significantly lower than their TD peers, in both ER and TM. Social Cognition skills were significantly related to executive functions. CONCLUSION: Our study suggests that some chronic neurological conditions in childhood, such as Migraine and Epilepsy, may be associated with difficulties in Social Cognition skills, and that these difficulties may be related to a deficit in executive functions. The relationship between these two higher cognitive abilities should be further explored in future studies. Our results also suggest the importance of monitoring cognitive abilities in pediatric patients with Migraine or Epilepsy, in order to detect early impairment and ensure the necessary support.

Perampanel and childhood absence epilepsy: A real life experience.

Objectives: The aim of our study was to evaluate the effectiveness and tolerability of perampanel (PER) as first add-on and as second line monotherapy in subjects with childhood absence epilepsy. Methods: Our sample consisted of 20 patients with childhood absence epilepsy, aged between 8 and 10, already in therapy with a first antiseizure medication with incomplete seizure control. PER was added as first add-on in a dose ranging from 3 to 8 mg/die with 1- 2 mg/week increments. The patients that were seizure-free were shifted to a PER monotherapy. All patients underwent a standardized neuropsychological evaluation in order to assess non-verbal intelligence and executive functions before adding PER and after 6 months of drug therapy. All parents completed two questionnaires, in order to assess the emotional-behavioral problems and parental stress. Results: 15/20 patients responded to add-on PER and were seizure-free, in 3/20 patients we observed a reduction of seizure frequency <50%, and in the 2 remaining patients the add-on therapy with PER did not lead to a reduction in seizures frequency from baseline. The patients who were seizure-free were switched to PER monotherapy. 9/15 patients remained seizure-free in monotherapy with PER. In the first month of therapy with PER 2/20 patients (10%) reported mild, transient side effects of irritability, headache and dizziness, which did not lead to discontinuation of therapy. Adjunctive treatment with PER did not negatively affect non-verbal intelligence, executive functions, emotional/behavioral symptoms of children and parental stress levels. Significance: Our clinical experience in real life showed that PER appears to be effective in the control of absence seizures in childhood absence epilepsy, with a favorable tolerability profile. PER would seem effective on absence seizures even in monotherapy. Further studies with larger samples, longer follow-up and controlled vs. placebo (or other first choice antiseizure medications) are needed to confirm our data.

Impact of COVID-19 Pandemic on Children and Adolescents with Neuropsychiatric Disorders: Emotional/Behavioral Symptoms and Parental Stress.

The objective of our study was to evaluate the impact of the COVID-19 pandemic on the emotional and behavioral symptoms in minors with neuropsychiatric disorders and on parental stress through a standardized neuropsychological assessment, comparing the data collected before the pandemic with those collected during the lock-down. Another goal of our study was to analyze the relationship between parental stress and behavioral/emotional symptoms in children. Our study was conducted on 383 families of patients who had already been referred at the Child Neuropsychiatry Unit of the University Hospital of Salerno for different neuropsychiatric conditions. All the parents completed two neuropsychological standardized questionnaires for the assessment of parental stress (PSI-Parenting Stress Index-Short Form) and the emotional/behavioral problems of their children (Child Behaviour CheckList). The data collected during the pandemic were compared with those collected from questionnaires administered during the six months preceding the pandemic, as is our usual clinical practice. The comparison between the mean scores of PSI and CBCL before and after the pandemic showed a statistically significant increase in all subscales analyzed in the total sample. The correlation analysis showed significant positive relationship between the subscale Total Stress of PSI and the subscales Total Problems and Internalizing Problems of CBCL. Our study suggested that the COVID-19 pandemic and the corresponding measures adopted led to an increase in internalizing and externalizing symptoms in children and adolescents with neuropsychiatric disorder. Similarly, parental stress increased during COVID-19 and ahigher level of stress in parents can be related to the internalizing symptoms of their children.

Infantile Brain Tumors: A Review of Literature and Future Perspectives.

Brain tumors in infants including those diagnosed in fetal age, newborns and under a year old represent less than 10% of pediatric nervous system tumors and present differently when compared with older children in terms of clinical traits, location and histology. The most frequent clinical finding is a macrocephaly but non-specific symptoms can also be associated. The prognosis is usually poor and depends on several factors. Surgery continues to be the main option in terms of therapeutic strategies whereas the role of chemotherapy is not yet well defined and radiotherapy is exceptionally undertaken. In view of this situation, a molecular characterization could assist in providing therapeutic options for these tumors. This review highlights the recent advances in the diagnosis and treatment of brain tumors in infants with a particular focus on the molecular landscape and future clinical applications.

Epidemiology of human leptospirosis in urban and rural areas of Brazil, 2000-2015.

BACKGROUND: Leptospirosis is one of the most widespread zoonosis in the world and Brazil has the highest number of cases in Latin America. Transmission occurs mainly through exposure to water and soil contaminated by the urine of infected animals. The goals of this study are to describe the geographic distribution, demographic characteristics and exposure factors of urban and rural cases of leptospirosis, and identify spatial clusters in urban and rural areas of Brazil. METHODS/RESULTS: A retrospective epidemiological study was carried out using 16 years (2000-2015) of surveillance data from the Brazilian Ministry of Health. Cases were described by age, sex and race, and exposure factors were characterized in urban and rural areas. A spatial autocorrelation analysis was conducted using local Moran's I to identify urban and rural clusters of disease. On average 3,810 leptospirosis cases were reported annually with higher numbers in urban areas. National urban and rural incidence rates were the same (1.9 cases/100,000 population), however, regional differences were observed. Urban incidence rates were higher in the North and Northeast regions, while rural incidence rates were higher in the Southeast and South. The main exposure factor reported in urban and rural areas was exposure to places with signs of rodents, followed by flood in urban areas and agriculture and animal farming in rural areas. Clusters of leptospirosis were identified in densely populated urban areas of the North, Southeast and South regions, while rural clusters were concentrated in of the Southern region with large agriculture and animal farming practices. CONCLUSIONS: This study highlights that leptospirosis is an important public health problem in both urban and rural areas of Brazil. The results provide decision-makers with detailed information about where disease incidence is high and can be used in the development of prevention and control strategies for priority areas and risk groups.

Adaptive Behavior, Emotional/Behavioral Problems and Parental Stress in Children With Autism Spectrum Disorder.

Background: The aim of our study was to compare adaptive skills, emotional/behavioral problems, and parental stress among children with different severity levels of Autism Spectrum Disorder (ASD) symptoms. Methods: This study included a sample of 88 subjects with ASD (mean age = 6.00 ± 2.70). All subjects underwent standardized neuropsychological tests for the assessment of symptoms of the autism spectrum (Autism Diagnostic Observation Schedule-Second Edition), adaptive level (The Vineland Adaptive Behavior Scales, Survey Interview, 2nd edition), behavioral and emotional problems (Child Behavior CheckList CBCL), and parental stress (Parental Stress Index Short Form-PSI-SF). Non-parametric statistical methods (Kruskal-Wallis test and Mann-Whitney U-test for post hoc analysis) and linear regression analysis were used in this study. Results: Children who had higher severity levels of ASD symptoms had less adaptive functioning; younger children showed more severe symptoms of ASD; older children had better communication skills. The presence of greater adaptive difficulties was related to a greater presence of internalizing problems. An increase in parental stress levels was related to an higher severity of ASD symptoms, fewer adaptive skills, and a greater presence of internalizing and externalizing problems. Conclusion: This study suggests that the adaptive behavior should be considered in order to planning a habilitation intervention in children with autism. It is also important to monitor emotional/behavioral problems and parental stress levels in order to provide parenting support and improve the family quality of life.

Peripheral Vascular Function in Dilated Cardiomyopathy of Different Etiology.

Vascular function in dilated cardiomyopathy of different etiology has been poorly investigated. Moreover, reference values of flow-mediated dilation (FMD) in chronic heart failure (CHF) need to be updated according to the new standardized protocols. We characterized the vascular impairment in different stages of post-ischemic dilated cardiomyopathy (PI-DC) or idiopathic dilated cardiomyopathy (I-DC). Eighty consecutive outpatients with CHF in different New York Heart Association (NYHA) classes (45 PI-DC, 35 I-DC) and 50 control subjects underwent FMD and brachial distensibility coefficient measurement. Patients with CHF showed a marked impairment in FMD compared with controls that worsened from classes NYHA I-II to III-IV, independently of etiology (P < .05). New York Heart Association I-II PI-DC patients showed a worse FMD compared with NYHA I-II I-DC patients (P < .05). Brachial distensibility coefficient values were significantly lower in patients with CHF compared with controls (P < .001) without differences between PI-DC and I-DC. In conclusion, advanced CHF is characterized by vascular impairment that is independent of etiology. In the early stages of CHF, endothelial dysfunction is more severe in patients with PI-DC compared with I-DC probably due to the high cardiovascular risk profile. In I-DC, vascular function impairment is independent of cardiovascular risk factors and could participate in the pathogenesis of I-DC.