Role of luteinizing hormone urinary levels in the diagnostic and therapeutic management of female central precocious puberty.

BACKGROUND: Diagnosing central precocious puberty (CPP) requires an integrated approach based on clinical, biochemical and instrumental data. The diagnostic gold standard is represented by GnRH (gonadotropin-releasing hormone) stimulation test. Some undoubted limitations of this procedure led the international scientific community to look for cheaper and less invasive alternative diagnostic methods, such as luteinizing hormone urinary levels (uLH) measurement. This study aims to define the reliability of urinary LH levels as a biomarker of pubertal development, both concerning the initial diagnostic management and the monitoring of patients with central precocious puberty undergoing therapy with GnRH analogues. Furthermore, the study plans to detect the potential association between LH peak serum (pLH) and urinary LH in patients undergoing diagnostic tests with GnRH and to identify a possible cut-off of uLH that may be suggestive of ensued successful hormonal stimulation. METHODS: The study includes 130 female patients with suspected precocious puberty or in follow-up during suppressive therapy. After the collection of the informed consent, the patients underwent clinical evaluation, auxological assessment, and hormone assays (basal levels of LH, FSH, and oestradiol; GnRH stimulating test in patients with suspected precocious puberty; urinary LH assay on the first-morning urine sample, collected after waking up). RESULTS: Two uLH cut-off values have been identified: the first of 0.25 UI/L [C.I. 95% 0.23-0.27], able to distinguish between pubertal and pre-pubertal patients, the second of 0.45 UI/L [C.I. 95% 0,20 - 0,70] suggestive of occurred hormonal stimulation in patients with diagnosis of CPP at GnRH test. All 30 patients with CPP in follow-up during suppressive therapy presented uLH values ≤ 0.45 IU/L (pU < 0.05), and uLH collected in prepubertal group control. CONCLUSIONS: uLH assays on the first morning urine specimen could be considered a low-cost and minimally invasive tool for precocious puberty diagnosing and monitoring, making possible to be easily performed even by a general pediatrician. Thus, this could help referring only selected patients to pediatric endocrinologists. After an appropriate validation, this approach could reasonably reduce hospital attendance and costs of performing more invasive procedures, with a more significant emotional impact on the pediatric patient.

46, XY Disorders of Sexual Development: a case report and theoretical framework.

BACKGROUND AND AIM: Disorders of sexual differentiation (DSD) with karyotype 46,XY include gonadal developmental differences such as complete gonadal dysgenesis, partial gonadal dysgenesis, testicular regression and ovotesticular sexual differentiation disorder, differences in androgen synthesis or action, such as androgen synthesis deficiency, androgen action deficits, LH receptor deficiency, AMH synthesis or action deficits, and other conditions such as severe hypospadias, cloaca estrophy, etc. Methods: A 17 years-old girl came to our attention for hirsutism, clitoral hypertrophy, primary amenorrhea, and bilateral mammary hypoplasia. According to clinical features and anamnesis, the diagnosis of 46, XY DSD was made. For diagnostic purposes, she underwent an extensive genetic analysis, hormone dosage and instrumental examinations. After a clitoridoplasty and hormone replacement treatment, the patient performs appropriate multidisciplinary follow-up and regular psychotherapy. RESULTS: The clinical case reported falls, according to the recent classification developed by the Chicago Consensus, within the scope of DSD with karyotype 46, XY. About 160 cases of patients with 17ß-HSD3 deficiency, diagnosed at a mean age of 12 years, are described in the literature, most of them coming from Western Asia and Europe and only three cases from Eastern Asia. Clinically, about 30% of patients showed virilization, 20% clitoromegaly, ambiguous genitalia, inguinal/labial mass, 16% primary amenorrhea, and 5% absence of mammary development, features that are partly traced in the case described here. CONCLUSIONS: This case underscores the complexity of managing individuals with DSD. Having acquired the concept that irreversible surgery should be avoided, except in cases where failure to do so would determine health risks, the primary objective of the medical decision lies in meeting conditions aimed at harmonious sexual identification, especially regarding sexual activity and fertility, involving a team of experienced professionals (psychologists, pediatricians, surgeons, endocrinologists, radiologists), capable of promptly identifying suggestive clinical signs.

An Overview of The Role of Tumor Necrosis Factor-Alpha in Epileptogenesis and Its Terapeutic Implications.

The complex association between neuroinflammation and seizures has been widely investigated in recent years. As mediators of inflammatory response, cytokines like tumor necrosis factor- a (TNF-a) are potential therapeutic targets for epileptic disorders. TNF-a is a pleiotropic cytokine with a controversial role in epileptogenesis, seemingly capable to both favor the genesis of seizures and elicit neuromodulatory responses. Anti-TNF agents are a group of monoclonal antibodies engineered to inhibit the response to this cytokine for antinflammatory purposes. The clinical experience of the use of these drugs in neurological conditions like multiple sclerosis showed controversial results. Evidence in favor of the employment of anti-TNF agents for the treatment of epilepsy are still limited to certain forms of disorders, notably Rasmussen encephalitis, and in carefully selected patients.

Gene Polymorphisms Increasing the Risk of Intracranial Aneurysms: Interleukin-6 -174G>C and -572G>C (Part II).

Introduction The interleukin-6 (IL-6), a proinflammatory cytokine, supports the adaptive immune response and regulates inflammatory processes. The -174 G>C and -572 G>C promoter polymorphisms of the IL-6 gene take part in the pathogenesis of intracranial aneurysms (IAs) and influence the clinical presentation of subarachnoid hemorrhage. This meta-analysis purposes to evaluate whether and which IL-6 allelic variations are related to a risk of IAs formation. Methods A PRISMA-based literature search was performed on the PubMed/Medline and Web of Science databases. The keywords used were "interleukin-6," "IL-6," "polymorphism," "interleukin-6 genotype," combined with "intracranial aneurysms" and "subarachnoid hemorrhage." Only human case-control studies, with a study (IAs) and a control group, written in English, and published in the last 15 years were selected. A meta-analysis was performed, estimating odds ratios and 95% confidence intervals in fixed- or random-effects models, as applicable. Statistical analysis was conducted with RevMan 5.0 software. Results 9 studies were eligible. No associations were found between -174 G>C polymorphisms and IAs susceptibility. Notable results were reported by the analysis of -572G>C polymorphisms. -572GG/GC/CC genotypes were strongly related to IAs occurrence with a statistical significance of p=0.03, p=0.0009, and p=0.00001, respectively. Conclusion A higher incidence of -572G>C promoter polymorphisms were demonstrated in the IAs group, highlighting the pivotal role of inflammatory genes in the natural history of brain aneurysms. Additional studies are required considering the racial heterogenicity and the need to widen the population sample.

Scoliosis with peculiar radiological features in a patient with McCune-Albright syndrome.

Patients with McCune-Albright Syndrome (MAS) should always attend regular follow-up. Beside the endocrinological aspects, the screening must take into account osteoarticular complications such as scoliosis, even in patients without fibrous dysplasia.

An update on the role of chronic rhinosinusitis with nasal polyps as a co-morbidity in severe asthma.

INTRODUCTION: Chronic rhinosinusitis and asthma are heterogeneous diseases with complex pathogenesis. The presence of chronic rhinosinusitis with nasal polyps has been associated with increased asthma exacerbation frequency and may represent a predictor of future exacerbations in severe asthma. AREAS COVERED: This review provides the clinician with an overview of the prevalence and clinical impact of the chronic rhinosinusitis with nasal polyps in severe asthma and summarizes recommended therapeutic approaches, including innovative biologic therapies. To select relevant literature for inclusion in this review, we conducted a literature search using the PubMed and ClinicalTrials.gov databases, using terms 'chronic rhinosinusitis with nasal polyps' AND 'asthma' OR 'severe asthma.' The literature review was performed for publication years 2010-2020, restricting the articles to humans and English language publications. EXPERT OPINION: Biological therapies have opened new perspectives in the treatment of upper and lower airway allergic diseases. Care pathways in severe asthma are almost consolidated, while they still rely on phenotypic rather than endotypic features in chronic rhinosinusitis with nasal polyps. Unveiling the correlation between clinical phenotypes and molecular endotypes will allow better stratification of patients with chronic rhinosinusitis with nasal polyps to identify candidates who benefit most from biological therapy.

Innovative therapies for malignant brain tumors: the road to a tailored cure.

BACKGROUND: Immune tolerance, immune escape, neoangiogenesis, phenotypic changes, and glioma stem cells are all responsible for the resistance of malignant brain tumors to current therapies and persistent recurrence. The present study provides a panoramic view of innovative therapies for malignant brain tumors, especially glioblastoma, aimed at achieving a tailored approach. METHODS: PubMed/Medline and ClinicalTrials.gov were the main sources of an extensive literature review in which "Regenerative Medicine," "Cell-Based Therapy," "Chemotherapy," "Vaccine," "Cell Engineering," "Immunotherapy, Active," "Immunotherapy, Adoptive," "Stem Cells," "Gene Therapy," "Target Therapy," "Brain Cancer," "Glioblastoma," and "Malignant Brain Tumor" were the search terms. Only articles in English published in the last 5 years were included. A further selection was made according to the quality of the studies and level of evidence. RESULTS: Cell-based and targeted therapies represent the newest frontiers of brain cancer treatment. Active and adoptive immunotherapies, stem cell therapies, and gene therapies represent a tremendous evolution in recent years due to many preclinical and clinical studies. Clinical trials have validated the effectiveness of antibody-based immunotherapies, including an in-depth study of bevacizumab, in combination with standard of care. Preclinical data highlights the role of vaccines, stem cells, and gene therapies to prevent recurrence. CONCLUSION: Monoclonal antibodies strengthen the first-line therapy for high grade gliomas. Vaccines, engineered cells, stem cells, and gene and targeted therapies are good candidates for second-line treatment of both newly diagnosed and recurrent gliomas. Further data are necessary to validate this tailored approach at the bedside.

Gene therapies for high-grade gliomas: from the bench to the bedside.

BACKGROUND: Gene therapy is the most attractive therapeutic approach against high-grade gliomas (HGGs). This is because of its theoretical capability to rework gene makeup in order to yield oncolytic effects. However, some factors still limit the upgrade of these therapies at a clinical level of evidence. We report an overview of glioblastoma gene therapies, mainly focused on the rationale, classification, advances and translational challenges. METHODS: An extensive review of the online literature on gene therapy for HGGs was carried out. The PubMed/MEDLINE and ClinicalTrials.gov websites were the main sources. Articles in English published in the last five years were sorted according to the best match with the multiple relevant keywords chosen. A descriptive analysis of the clinical trials was also reported. RESULTS: A total of 85 articles and 45 clinical trials were selected. The main types of gene therapies are the suicide gene, tumor suppressor gene, immunomodulatory gene and oncolytic therapies (virotherapies). The transfer of genetic material entails replication-deficient and replication-competent oncolytic viruses and nanoparticles, such as liposomes and cationic polymers, each of them having advantages and drawbacks. Forty-eight clinical trials were collected, mostly phase I/II. CONCLUSION: Gene therapies constitute a promising approach against HGGs. The selection of new and more effective target genes, the implementation of gene-delivery vectors capable of greater and safer spreading capacity, and the optimization of the administration routes constitute the main translational challenges of this approach.

The impact of stem cells in neuro-oncology: applications, evidence, limitations and challenges.

BACKGROUND: Stem cells (SCs) represent a recent and attractive therapeutic option for neuro-oncology, as well as for treating degenerative, ischemic and traumatic pathologies of the central nervous system. This is mainly because of their homing capacity, which makes them capable of reaching the inaccessible SC niches of the tumor, therefore, acting as living drugs. The target of the study is a comprehensive overview of the SC-based therapies in neuro-oncology, also highlighting the current translational challenges of this type of approach. METHODS: An online search of the literature was carried out on the PubMed/MEDLINE and ClinicalTrials.gov websites, restricting it to the most pertinent keywords regarding the systematization of the SCs and their therapeutic use for malignant brain tumors. A large part of the search was dedicated to clinical trials. Only preclinical and clinical data belonging to the last 5 years were shortlisted. A further sorting was implemented based on the best match and relevance. RESULTS: The results consisted in 96 relevant articles and 31 trials. Systematization involves a distinction between human embryonic, fetal and adult, but also totipotent, pluripotent or multipotent SCs. Mesenchymal and neuronal SCs were the most studied for neuro-oncological illnesses. 30% and 50% of the trials were phase I and II, respectively. CONCLUSION: Mesenchymal and neuronal SCs are ideal candidates for SCs-based therapy of malignant brain tumors. The spectrum of their possible applications is vast and is mainly based on the homing capacity toward the tumor microenvironment. Availability, delivery route, oncogenicity and ethical issues are the main translational challenges concerning the use of SCs in neuro-oncology.

Adoptive immunotherapies in neuro-oncology: classification, recent advances, and translational challenges.

BACKGROUND: Adoptive immunotherapies are among the pillars of ongoing biological breakthroughs in neuro-oncology, as their potential applications are tremendously wide. The present literature review comprehensively classified adoptive immunotherapies in neuro-oncology, provides an update, and overviews the main translational challenges of this approach. METHODS: The PubMed/MEDLINE platform, Medical Subject Heading (MeSH) database, and ClinicalTrials.gov website were the sources. The MeSH terms "Immunotherapy, Adoptive," "Cell- and Tissue-Based Therapy," "Tissue Engineering," and "Cell Engineering" were combined with "Central Nervous System," and "Brain." "Brain tumors" and "adoptive immunotherapy" were used for a further unrestricted search. Only articles published in the last 5 years were selected and further sorted based on the best match and relevance. The search terms "Central Nervous System Tumor," "Malignant Brain Tumor," "Brain Cancer," "Brain Neoplasms," and "Brain Tumor" were used on the ClinicalTrials.gov website. RESULTS: A total of 79 relevant articles and 16 trials were selected. T therapies include chimeric antigen receptor T (CAR T) cell therapy and T cell receptor (TCR) transgenic therapy. Natural killer (NK) cell-based therapies are another approach; combinations are also possible. Trials in phase 1 and 2 comprised 69% and 31% of the studies, respectively, 8 of which were concluded. CAR T cell therapy targeting epidermal growth factor receptor variant III (EGFRvIII) was demonstrated to reduce the recurrence rate of glioblastoma after standard-of-care treatment. CONCLUSION: Adoptive immunotherapies can be classified as T, NK, and NKT cell-based. CAR T cell therapy redirected against EGFRvIII has been shown to be the most promising treatment for glioblastoma. Overcoming immune tolerance and immune escape are the main translational challenges in the near future of neuro-oncology.

Potential roads for reaching the summit: an overview on target therapies for high-grade gliomas.

The tailored targeting of specific oncogenes represents a new frontier in the treatment of high-grade glioma in the pursuit of innovative and personalized approaches. The present study consists in a wide-ranging overview of the target therapies and related translational challenges in neuro-oncology. METHODS: A review of the literature on PubMed/MEDLINE on recent advances concerning the target therapies for treatment of central nervous system malignancies was carried out. In the Medical Subject Headings, the terms "Target Therapy", "Target drug" and "Tailored Therapy" were combined with the terms "High-grade gliomas", "Malignant brain tumor" and "Glioblastoma". Articles published in the last five years were further sorted, based on the best match and relevance. The ClinicalTrials.gov website was used as a source of the main trials, where the search terms were "Central Nervous System Tumor", "Malignant Brain Tumor", "Brain Cancer", "Brain Neoplasms" and "High-grade gliomas". RESULTS: A total of 137 relevant articles and 79 trials were selected. Target therapies entailed inhibitors of tyrosine kinases, PI3K/AKT/mTOR pathway, farnesyl transferase enzymes, p53 and pRB proteins, isocitrate dehydrogenases, histone deacetylases, integrins and proteasome complexes. The clinical trials mostly involved combined approaches. They were phase I, II, I/II and III in 33%, 42%, 16%, and 9% of the cases, respectively. CONCLUSION: Tyrosine kinase and angiogenesis inhibitors, in combination with standard of care, have shown most evidence of the effectiveness in glioblastoma. Resistance remains an issue. A deeper understanding of the molecular pathways involved in gliomagenesis is the key aspect on which the translational research is focusing, in order to optimize the target therapies of newly diagnosed and recurrent brain gliomas.

Targeting the medulloblastoma: a molecular-based approach.

BACKGROUND: The lack of success of standard therapies for medulloblastoma has highlighted the need to plan a new therapeutic approach. The purpose of this article is to provide an overview of the novel treatment strategies based on the molecular characterization and risk categories of the medulloblastoma, also focusing on up-to-date relevant clinical trials and the challenges in translating tailored approaches into clinical practice. METHODS: An online search of the literature was carried out on the PubMed/MEDLINE and ClinicalTrials.gov websites about molecular classification of medulloblastomas, ongoing clinical trials and new treatment strategies. Only articles in the English language and published in the last five years were selected. The research was refined based on the best match and relevance. RESULTS: A total 58 articles and 51 clinical trials were analyzed. Trials were of phase I, II, and I/II in 55%, 33% and 12% of the cases, respectively. Target and adoptive immunotherapies were the treatment strategies for newly diagnosed and recurrent medulloblastoma in 71% and 29% of the cases, respectively. CONCLUSION: Efforts are focused on the fine-tuning of target therapies and immunotherapies, including agents directed to specific pathways, engineered T-cells and oncoviruses. The blood-brain barrier, chemoresistance, the tumor microenvironment and cancer stem cells are the main translational challenges to be overcome in order to optimize medulloblastoma treatment, reduce the long-term morbidity and increase the overall survival.

Comparison of triptorelin acetate vs triptorelin pamoate in the treatment of Central precocious puberty (CPP): a retrospective study.

The aim of this study is to compare the clinical and biochemical outcomes of triptorelin acetate (TPA) versus triptorelin pamoate (TPP) treatment in girls with central precocious puberty. A total of 60 patients with idiopathic CPP were retrospectively recruited. Thirty girls were treated with triptorelin acetate 3.75 mg/month (TPA group) and thirty girls in a second group received triptorelin pamoate 3.75 mg/4 weeks (TPP group). Patient follow-up at 12 and 24 months included GnRH Test at 12 months and baseline LH at 24 months. Patients were monitored with pelvic ultrasound, X-Ray of the hand and wrist and anthropometric evaluations. A total of 60/60 girls showed a good response to both formulations. Significant reductions in basal and LH peaks, estradiol values, breast pubertal stage, progression of bone age and growth velocity rate after 12 months treatment were obtained in both groups, demonstrating the equivalence of the two formulations in regulating the hypothalamic-pituitary-gonadal (HPG) axis. Triptorelin pamoate provided a more effective and significant reduction in LH peak after 12 months in comparison with triptorelin acetate more effective in reducing ovarian volume and endometrial thickness. Both formulations were equivalent, even though the LH peak was significantly lower in girls treated with triptorelin pamoate.

Pediatric Obesity and the Immune System.

Obesity has reached pandemic proportion and represents a major risk for several comorbidities. In addition to metabolic and cardiovascular obesity-related diseases, recent evidence suggested that obesity might affect immune system function. Adipose tissue is considered an endocrine organ that actively secretes cytokines also referred to as "adipokines." Adipokines play an important role in the control of human metabolism. The dysfunctional adipose tissue in obese individuals is characterized by an altered cytokine secretion pattern that promotes chronic low-grade inflammation. Epidemiological evidence highlights the association between obesity and allergic and immune-mediated diseases, such as asthma, allergic rhinitis, rheumatic arthritis, and psoriasis. Less is known about underlying pathogenic mechanisms. However, several recent in vivo and in vitro studies have reported that adipokines are involved in inflammatory and autoimmune disorders by influencing both innate and acquired immune responses. In addition, obesity has been associated with reduced immune surveillance and increased risk of cancer. This paper reviews the evidence regarding the role of adipokines in immune system regulation, with particular emphasis on autoimmune, allergic, and inflammatory disorders. Understanding how obesity affects immune system functions may enable researchers to find new potential therapeutic targets in the management of allergic and autoimmune diseases.

HLA-DQB1*02 allele in children with celiac disease: Potential usefulness for screening strategies.

Through a retrospective analysis of a real-life cohort of children with celiac disease (CD), who underwent HLA-DQ genotyping, we supported our previous findings indicating the presence of HLA-DQB1*02 allele in at least 90%-95% of pediatric patients. In the present study, reporting the HLA-DQ analysis from 184 children (age range: 1-16 years) diagnosed with CD in a single centre, we found that 97.29% of all these CD children (n = 179 out of 184 genotyped patients) resulted to be carriers of at least one copy of HLA-DQB1*02 allele. If a widened screening for CD should result to be appropriate in the pediatric population after further clinical research, this observation might be potentially exploited to consider a two-step screening strategy, starting with the HLA-DQB1*02 targeted analysis followed by the specific serology for CD in these predisposed patients only. However, additional and larger studies are needed to support our findings.

Gastroesophageal reflux and respiratory diseases: does a real link exist?

INTRODUCTION: Gastro-esophageal reflux disease (GERD) indicates a gastroesophageal reflux that causes symptoms such as pain, and needs medical therapy, and may result in complications such as erosive esophagitis, aspiration pneumonia. Here, we review if it exists a real link between clinical presentation of some respiratory diseases such as asthma, chronic cough, cystic fibrosis and laryngopharyngitis and GERD. EVIDENCE ACQUISITION: This review was conducted employing 2 databases: PubMed and Science Direct. EVIDENCE SYNTHESIS: Asthma may lead to reflux, and reflux could exacerbate asthma or cause asthma-like symptoms. Prevalence of GERD in children with asthma ranged from as low 32% to as high 80%. There are several studies where the use of proton pump inhibitors (PPIs) and histamine H2 receptor antagonists lead to inconclusive results. The relation of chronic unexplained cough to GERD remains controversial in children and pediatric guidelines do not currently recommend empirical GERD treatment trials for pediatric chronic cough. Gastroesophageal reflux is more frequent in patients with cystic fibrosis (CF) than general population. Although PPIs are regularly prescribed in approximately half of the patients with CF, there are no specific guidelines for treatment of reflux in CF and it was shown that chronic treatment with PPIs was correlated to possible increased risk of exacerbations. CONCLUSIONS: The pathogenesis of GER-related respiratory symptoms is multifactorial. The causal relationship between these two conditions may be difficult to prove also with the aid of supporting tests. Multichannel intraluminal impedance associated with pH-metry (pH/MII) detect all gastroesophageal reflux episodes accompanied with a bolus movement and classify GER episodes according to their content (liquid, gas and mixed), pH value and proximal extension. There are no consistent evidences confirming the validity of medical therapy in reflux with respiratory symptoms.

Ibuprofen for Pain Control in Children: New Value for an Old Molecule.

BACKGROUND: Acute pain is one of the major complaints reported in pediatric emergency departments and general wards. Recently, both the US Food and Drug Administration and European Medicine Agency emitted some warnings regarding the use of opioids, including codeine, in children. OBJECTIVE: The aims of this study were summarizing the main pharmacological aspects of ibuprofen, discussing the current evidence about the use of ibuprofen in different and specific clinical settings, and providing a comparison with acetaminophen and/or codeine, according to available studies. STUDY DESIGN AND METHODS: Studies evaluating ibuprofen for the management of acute pain in children were extracted from the PubMed and MEDLINE database within the period ranging from 1985 through 2017. After discussing safety of ibuprofen and its concomitant use with acetaminophen, the specific indications for the clinical practice were considered. RESULTS: Ibuprofen resulted to be more effective than acetaminophen, and comparable to the combination acetaminophen-codeine, for the control of acute pain related to musculoskeletal pain. Moreover, similar results have been reported also in the management of toothache and inflammatory diseases of the oral cavity and pharynx. Ibuprofen resulted to be useful as a first approach to episodic headache. Finally, the role of ibuprofen in the management of postoperative pain and, particularly, after tonsillectomy and/or adenoidectomy has been reconsidered recently. CONCLUSIONS: Ibuprofen resulted to be the most studied nonsteroidal anti-inflammatory drug in the management of acute pain in children; in general, it showed a good safety profile and provided evidence of effectiveness, despite some differences according to the specific clinical context.

Pediatric rhinosinusitis and asthma.

Both asthma and rhinosinusitis are complex and heterogeneous diseases and, importantly, they often coexist: these diseases can be concomitant in 35-65% of affected children, according to different studies. Thus, evaluating this comorbidity in the clinical practice should be paramount. In this review, we focused our discussion on the multiple pathophysiological aspects that may link rhinosinusitis and asthma in the pediatric population. Although rhinosinusitis may exacerbate asthma through several mechanisms occurring by contiguity, actually this aspect seems to be only one component of the complex interplay between upper and lower airways. In particular, the onset of an important and persistent Th2-driven inflammatory process dominated by eosinophils presence at one site of the airways, may release into the bloodstream several cytokines; in their turn, those can lead to the stimulation of the bone marrow, which may function as a systemic amplifier of such an eosinophilic inflammation.