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We describe a 46,XX girl with Denys-Drash syndrome (DDS), showing both kidney disease and genital abnormalities, in whom a misdiagnosis of hyperandrogenism was made. A 15 year-old girl was affected by neonatal nephrotic syndrome, progressing to end stage kidney failure. Hair loss and voice deepening were noted during puberty. Pelvic ultrasound and MRI showed utero-tubaric agenesis, vaginal atresia and urogenital sinus, with inguinal gonads. Gonadotrophin and estradiol levels were normal, but testosterone levels increased up to 285 ng/dL at Tanner stage 3. She underwent prophylactic gonadectomy and histopathology reported fibrotic ovarian cortex containing numerous follicles in different maturation stages and rudimental remnants of Fallopian tubes. No features of gonadoblastoma were detected. Unexpectedly, testosterone levels were found elevated 4 months after gonadectomy (157 ng/dL). Recent medical history revealed a chronic assumption of a high daily dose of biotin, as a therapeutic support for hair loss. Laboratory immunoassay instruments used streptavidin-biotin interaction to detect hormones and, in competitive immunoassays, high concentrations of biotin can result in false high results. Total testosterone, measured using liquid chromatography tandem mass spectrometry (LC-MS/MS), was found within reference intervals. Similar testosterone levels were detected repeating the immunoassay two weeks after biotin uptake interruption. Discordance between clinical presentation and biochemical results in patients taking biotin, should rise the suspicion of erroneous results. Improved communication among patients, health care providers, and laboratory professionals is required concerning the likelihood of biotin interference with immunoassays.

Aims Histiocytoses are a heterogeneous group of localized or disseminated diseases. Clinical presentation and patients' outcome vary greatly, ranging from mild to life-threatening disorders. Rare cases of systemic or localized histiocytosis harboring ALK rearrangement have been reported. Methods Two cases of CNS histiocytosis were thoroughly investigated by implementing multiple molecular tests, i.e. FISH, RT-qPCR, NGS analysis. Results In a 10-month old girl (patient #1), MRI showed two left hemispheric lesions and a right fronto-mesial lesion histologically consisting of a moderately cellular infiltrative proliferation, composed by CD68(PGM1)+/CD163+ spindle cells. ALK 5'/3'-imbalance and a KIF5B(exon 24)-ALK(exon 20) fusion were documented by RT-qPCR and NGS analysis, respectively. A subsequent CT scan showed multiple hepatic and pulmonary lesions. The patient was started on chemotherapy (vinblastine) associated to an ALK-inhibitor (Alectinib) with remarkable response. In a 11-year-old girl (patient #2), MRI showed a right frontal 1.5 cm lesion. Neuropathological examination revealed a histiocytic proliferation composed by medium sized CD68(PGM1)+/HLA-DR+ cells, showing moderate ALK1 positivity. ALK rearrangement and a KIF5B(exon 24)-ALK(exon 20) fusion were demonstrated also in this case. Subsequent CT, 18F-FDG-PET and MRI scans showed the presence of a single right femoral lesion, proved to be a fibrous cortical defect. Conclusions In ALK-histiocytoses, CNS involvement may occur as part of a systemic disease or, rarely, as its only primary disease localization, which could remain otherwise asymptomatic. The diagnosis often relies on neuropathological examination of brain biopsy, which may pose a diagnostic challenge due to the variable histopathological features. An integrated histological and molecular approach in such cases is recommended.

Item does not contain fulltext C3 glomerulopathy is a relatively new clinical entity that represents a challenge both to diagnose and to treat. As new therapeutic agents that act as complement inhibitors become available, many with an oral formulation, a better understanding of this disease and of the underlying complement dysregulation driving it has become increasingly useful to optimize patient care. Moreover, recent advances in research have clarified the role of complement in other glomerular diseases in which its role was less established, namely in immune-complex membranoproliferative glomerulonephritis (IC-MPGN), ANCA-vasculitis, IgA nephropathy, and idiopathic membranous nephropathy. Complement inhibitors are being studied in adult and adolescent clinical trials for these indications. This review summarizes current knowledge and future perspectives on every aspect of the diagnosis and management of C3 glomerulopathy and elucidates current understanding of the role of complement in this condition and in other glomerular diseases in children. An overview of ongoing trials involving therapeutic agents targeting complement in glomerular diseases is also provided.

Membranous nephropathy results from subepithelial antigen-antibody complex deposition along the glomerular basement membrane. Although PLA2R, THSD7A, and NELL-1 account for a majority (about 80%) of the target antigens, the target antigen in the remaining cases is not known. Using laser microdissection of PLA2R-negative glomeruli of patients with membranous nephropathy followed by mass spectrometry we identified a unique protein, Semaphorin 3B, in three cases. Mass spectrometry failed to detect Semaphorin-3B in 23 PLA2R-associated cases of membranous nephropathy and 88 controls. Semaphorin 3B in all three cases was localized to granular deposits along the glomerular basement membrane by immunohistochemistry. Next, an additional eight cases of Semaphorin 3B-associated membranous nephropathy were identified in three validation cohorts by immunofluorescence microscopy. In four of 11 cases, kidney biopsy also showed tubular basement membrane deposits of IgG on frozen sections. Confocal microscopy showed that both IgG and Semaphorin 3B co-localized to the glomerular basement membrane. Western blot analysis of five available sera showed reactivity to reduced Semaphorin 3B in four of four patients with active disease and no reactivity in one patient in clinical remission; there was also no reactivity in control sera. Eight of the 11 cases of Semaphorin 3B-associated membranous nephropathy were pediatric cases. Furthermore, in five cases, the disease started at or below the age of two. Thus, Semaphorin 3B-associated membranous nephropathy appears to be a distinct type of disease; more likely to be present in pediatric patients.

Background Cerebellar ectopy is a rare finding, with few cases previously reported. Intraventricular localized cerebellar ectopy was described in only 1 case within the fourth ventricle. Case Description A 9-year-old girl suffered for 2 years from bilateral frontoparietal headaches, sometimes accompanied by vomiting and photophobia. Magnetic resonance imaging demonstrated an oval-shaped lesion within the left lateral ventricle, characterized by well-defined margins without a clear cleavage plane from the adjacent choroid plexus. The mass presented an intermediate signal on T1- and T2-weighted sequences, similar to gray matter, and reduced ADC values on ADC maps compared with white matter, with no enhancement after gadolinium-based contrast injection. After resection, macroscopic examination revealed an organoid structure with leptomeningeal lining and a clear-cut cortex and white matter components. Histology demonstrated normal cerebellum with a double-layered cortex and normal underlying white matter. The cerebellar ectopy was focally covered by bundles of capillary vascular structures covered by a monostratified ependymal cell lining, consistent with choroid plexus. Conclusions We describe, for the first time to our knowledge, the case of a child with ectopic cerebellar tissue harboring the supratentorial ventricular system. Plausible etiologic mechanism consists in the herniation of the cerebellar germinal tissue into the ventricular system through the ependyma, allowing cell migration to the supratentorial compartment, followed by maturation into the normal cerebellum.

Infant high-grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histologic review, methylation profiling, and custom panel, genome, or exome sequencing. After excluding tumors representing other established entities or subgroups, we identified 130 cases to be part of an “intrinsic” spectrum of disease specific to the infant population. These included those with targetable MAPK alterations, and a large proportion of remaining cases harboring gene fusions targeting ALK (n = 31), NTRK1/2/3 (n = 21), ROS1 (n = 9), and MET (n = 4) as their driving alterations, with evidence of efficacy of targeted agents in the clinic. These data strongly support the concept that infant gliomas require a change in diagnostic practice and management. Significance: Infant high-grade gliomas in the cerebral hemispheres comprise novel subgroups, with a prevalence of ALK, NTRK1/2/3, ROS1, or MET gene fusions. Kinase fusion–positive tumors have better outcome and respond to targeted therapy clinically. Other subgroups have poor outcome, with fusion-negative cases possibly representing an epigenetically driven pluripotent stem cell phenotype. See related video: https://vimeo.com/438254885 See related commentary by Szulzewsky and Cimino, p. 904. This article is highlighted in the In This Issue feature, p. 890

BACKGROUND Brain death secondary to traumatic brain injury is one of the main sources of organs for transplantation but it can be associated with disseminated intravascular coagulation, which has been considered a relative contraindication for kidney donation. METHODS We describe two successful pediatric cases of kidney transplantation from a single donor with disseminated intravascular coagulation. RESULTS A 17-year-old male donor died from head injury and both kidneys were offered to our center. Within 24 h, donor's Hb and platelets dropped to 8.3 g/dl and 32 000/mcl, respectively, serum creatinine reached 2.01 mg/dl, and urinalysis showed proteinuria (300 mg/dl). Pre-implant biopsy showed massive occlusion of glomerular capillaries by fibrin thrombi containing fragmented red blood cells and inflammatory cells, and acute tubular damage. Arterioles and small arteries were spared. A diagnosis of DIC was made. The kidneys were transplanted in a 16-year-old girl and a 13-year-old boy. Slow recovery of graft function was observed in both recipients. On post-operative day 3, platelets dropped to a minimum value of 66 000 and 86 000/mcl, respectively. Diuresis was always present. On day 4, platelets started to rise. Six months later, both recipients attained normal renal function. A six-month protocol biopsy showed no microthrombi or other signs of disseminated intravascular coagulation. CONCLUSIONS Despite the limited data available in literature, the outcome of these two cases is positive. Thus, pre-implant kidney biopsy, even if it reveals massive thrombotic occlusion of glomerular capillaries compatible with diagnosis of disseminated intravascular coagulation, should not be considered an absolute contraindication to transplantation.

Purpose: Testicular germ cell tumors are the fourth most common neoplasm in adolescents, accounting for 8% of all tumors in the age group 15–19 years. On rare instances, the primary testicular lesion is not clinically or radiologically evident while nodal or visceral metastases represent the clinical manifestations of the disease. This phenomenon is described as “burned-out testicular tumor.” In this paper, the authors report a single-institution experience with burned-out testicular tumors in adolescents and discuss their clinical implications.Patients and Methods: All the patients diagnosed with metastatic testicular germ cell tumors at Bambino Gesù Children Hospital between January 1, 2010, and June 30, 2020, were included in the study. Patients were categorized into two groups: “primary testicular” and “burned out.” All the patients were staged and treated according to the AIEOP–TCGM 2004 protocol.Results: Eleven patients were classified as “primary testicular,” and five patients were classified as “burned out.” “Burned-out” tumors were associated with the presence of systemic symptoms compared to “primary testicular” tumors (80 vs. 0%; p = 0.0027) and higher aFP, hCG, and LDH levels (p < 0.00001). The “burned-out” population had a statistically significant higher incidence of relevant toxicity than the “primary testicular” population (80 vs. 18%; p = 0.0357) and a worse outcome in terms of both mean overall survival (15 vs. 43 months; p = 0.0299) and mean event-free survival (12 vs. 38 months; p = 0.0164).Conclusion: “Burned-out” testicular tumors seem to be a well-distinct clinical entity with a high treatment-related toxicity and poor prognosis. Further studies are needed to clarify the “burned-out phenomenon” and to identify more effective therapeutic strategies for these patients.

The rare nevus sebaceous (NS) syndrome (NSS) includes cortical malformations and drug-resistant epilepsy. Somatic RAS-pathway genetic variants are pathogenetic in NS, but not yet described within the brain of patients with NSS. We report on a 5-year-old boy with mild psychomotor delay. A brown-yellow linear skin lesion suggestive of NS in the left temporo-occipital area was evident at birth. Epileptic spasms presented at aged six months. EEG showed continuous left temporo-occipital epileptiform abnormalities. Brain MRI revealed a similarly located diffuse cortical malformation with temporal pole volume reduction and a small hippocampus. We performed a left temporo-occipital resection with histopathological diagnosis of focal cortical dysplasia type Ia in the occipital region and hippocampal sclerosis type 1. Three years after surgery, he is seizure-and drug-free (Engel class Ia) and showed cognitive improvement. Genetic examination of brain and skin specimens revealed the c.35G > T (p.Gly12Val) KRAS somatic missense mutation. Literature review suggests epilepsy surgery in patients with NSS is highly efficacious, with 73% probability of seizure freedom. The few histological analyses reported evidenced disorganized cortex, occasionally with cytomegalic neurons. This is the first reported association of a KRAS genetic variant with cortical malformations associated with epilepsy, and suggests a possible genetic substrate for hippocampal sclerosis.

Treatment of post-transplant focal segmental glomerulosclerosis (FSGS) recurrence is still debated. The use of the fully human anti-CD20 monoclonal antibody ofatumumab has been suggested. Two boys with FSGS received a kidney transplantation at the age of 15 years from a deceased and a living donor. Maintenance therapy consisted of calcineurin inhibitors, antiproliferative agents, and prednisone. Early post-transplant FSGS recurrence was observed after 2 and 3 days. Rituximab infusion and plasmapheresis sessions were performed with transient clinical improvement in the first patient, and no apparent response in the second patient. Both patients were treated with two ofatumumab infusions, which induced in patient #1 a complete and stable remission for more than 12 months and in patient #2 a partial remission with a progressive reduction of proteinuria and normalization of serum protein levels. Ofatumumab may be a therapeutic option for post-transplant FSGS recurrence in patients who respond poorly to rituximab.

Von Hippel–Lindau (VHL) disease is a heritable cancer syndrome in which benign and malignant tumors and/or cysts develop throughout the central nervous system (CNS) and visceral organs. The disease results from mutations in the VHL tumor suppressor gene located on chromosome 3 (3p25-26). A majority of individuals (60–80%) with VHL disease will develop CNS hemangioblastomas (HMG). Endolymphatic sac tumor (ELST) is an uncommon, locally aggressive tumor located in the medial and posterior petrosal bone region. Its diagnosis is based on clinical, radiological, and pathological correlation, and it can occur in the setting of VHL in up to 10–15% of individuals. We describe a 17-year-old male who presented with a chief complaint of hearing loss. Brain and spine Magnetic Resonance Imaging documented the presence of an expansive lesion in the left cerebellar hemisphere, compatible with HMG in association with a second cerebellopontine lesion compatible with ELST. The peculiarity of the reported case is due to the simultaneous presence of two typical characteristics of VHL, which led to performing comprehensive genetic testing, thus allowing for the diagnosis of VHL. Furthermore, ELST is rare before the fourth decade of life. Early detection of these tumors plays a key role in the optimal management of this condition.

Proteinuria is one of the most typical manifestations of kidney involvement in Systemic Lupus Erythematosus (SLE). We report the case of a 23-year-old woman with a 6-year-long history of SLE presenting with proteinuria after a three-year remission on hydroxychloroquine. Kidney histological examination showed alterations inconsistent with lupus nephritis and suggestive of hydroxychloroquine toxicity or Fabry disease. The latter was confirmed by genetic assay.

We report on a case of EWSR1-PATZ1 rearranged brain tumor occurring in a 17 month-old child, originally interpreted as an infantile glioblastoma. Our case shows important analogies with the 2 previously reported cases, including the intraventricular location, the histologic appearance (pushing borders, oligodendrocyte-like morphology, rich vascular network) and the glioneural immunophenotype, supporting the role of these features as relevant clues to the diagnosis. On the other hand, our case displays unique characteristics, i.e. the onset in an infant, the presence of a focal high-grade component and the leptomeningeal dissemination, pointing to the importance of considering this entity in the differential diagnosis of an infantile glial/glioneural tumor.

Pediatric low-grade gliomas (pLGGs) are the most frequent brain tumor in children. Adjuvant treatment, consisting in chemotherapy and radiotherapy, is often necessary if a complete surgical resection cannot be obtained. Traditional treatment approaches result in a significant long-term morbidity, with a detrimental impact on quality of life. Dysregulation of the mitogen-activated protein kinase (MAPK) pathway is the molecular hallmark of pLGGs and hyper-activation of the downstream mammalian target of rapamycin (mTOR) pathway is frequently observed. We report clinical and radiological results of front-line treatment with everolimus in 10 consecutive patients diagnosed with m-TOR positive pLGGs at the Bambino Gesu Children's Hospital in Rome, Italy. Median duration of treatment was 19 months (range from 13-60). Brain magnetic resonance imaging showed stable disease in 7 patients, partial response in 1 and disease progression in 2. Therapy-related adverse events were always reversible after dose reduction or temporary treatment interruption. To the best of our knowledge, this is the first report of everolimus treatment for chemo- and radiotherapy-naive children with pLGG. Our results provide preliminary support, despite low samples size, for the use of everolimus as target therapy in pLGG showing lack of progression with a manageable toxicity profile.

Background: Low-grade epilepsy-associated neuroepithelial tumors (LEATs) are a frequent etiology in pediatric patients with epilepsy undergoing surgery. Objective: To identify differences in clinical and post-surgical follow-up between patients with focal meningeal involvement (MI) and those without MI within our cohort of pediatric patients with LEATs. Methods: We retrospectively reviewed all pediatric patients (Results: We identified 37 patients: five with MI and 32 without. Half of patients (19) were drug sensitive at surgery; similar between groups. The group with MI differed mainly for age of epilepsy-onset (0.6 vs. 7.0 y) but not for epilepsy duration (0.9 vs. 1.5 y). Post-surgery radiological follow-up (median 4.0 y; IQR 2.8–5.0 y) did not indicate disease progression. Seizure outcome was excellent in both groups, with 34 patients overall being both drug- and seizure-free. Conclusions: Our study identified a new subgroup of LEATs with focal MI and excellent post-surgical outcome. Moreover, this highlights the effectiveness of early surgery in pediatric LEATs.

Although IgA nephropathy (IgAN) is a common cause of glomerulonephritis in children, the absence of a method to predict disease progression limits personalized risk-based treatment decisions. The adult International IgAN Prediction Tool comprises two validated Cox survival models that predict a 50% decline in estimated glomerular filtration rate (eGFR) or end stage kidney disease (ESKD) using clinical risk factors and Oxford MEST histology scores. Here, we updated the Prediction Tool for use in children using a multiethnic international cohort of 1,060 children with IgAN followed into adulthood. The updated pediatric Prediction Tool had better model fit than the original adult tool with lower Akaike Information Criterion, higher R2D and similar C-statistics. However, calibration showed very poor agreement between predicted and observed risks likely due to the observed disease trajectory in children. Therefore, the Tool was updated using a secondary outcome of a 30% reduction in eGFR or ESKD, resulting in better R2D (30.3%/22.2%) and similar C-statistics (0.74/0.68) compared to the adult tool but with good calibration. The trajectory of eGFR over time in children differed from adults being highly non-linear with an increase until 18 years old followed by a linear decline similar to that of adults. A higher predicted risk was associated with a smaller increase in eGFR followed by a more rapid decline, suggesting that children at risk of a 30% decrease in eGFR will eventually experience a larger 50% decrease in eGFR when followed into adulthood. As such, these two outcomes are analogous between pediatric and adult Prediction Tools. Thus, our pediatric Prediction Tool can accurately predict the risk of a 30% decline in eGFR or ESKD in children with IgAN.

Whereas 90% of patients with Wilms tumor (WT) reach cure, approximately half of patients developing a recurrent tumor die of the disease. Therefore, to disclose events leading to recurrence represents a clinical need. To study paired primary/recurrent tumor samples, being aware of the intra-tumoral heterogeneity, might help finding these answers. We previously suggested that mutations in SIX1 and DROSHA underlie WT recurrence. With the aim to better investigate this scenario, we collected 19 paired primary/recurrent tumors and 10 primary tumors from relapsing patients and searched for mutations in the SIX1/2 genes and microRNA processing genes (miRNAPGs). We found SIX1 mutation in one case, miRNAPGs mutations in seven cases, and the co-occurrence of SIX1 and miRNAPG mutations in one case. We could observe that, whereas in primary tumors the mutations could be heterogeneously present, in all cases they were positively selected and homogeneously present in the recurrent disease, as also indicated by a “moderate” and “almost perfect” agreement (according to the Landis and Koch classification criteria) between paired samples. Analysis of SIX1/2 genes and miRNAPGs in 50 non-relapsing WTs disclosed SIX2 mutation in one case and miRNAPGs mutations in seven. A borderline statistically significant association was observed between miRNAPGs mutations and the occurrence of relapse (p value: 0.05). These data suggest that SIX1 and miRNAPGs mutations may provide an advantage during tumor progression to recurrence and can represent oncogenic drivers in WT development.

Noonan syndrome (NS) is a congenital autosomic dominant condition characterized by a variable spectrum from a clinical and genetical point of view. Germline mutations in more than ten genes involved in RAS–MAPK signal pathway have been demonstrated to cause the disease. An higher risk for leukemia and solid malignancies, including brain tumors, is related to NS. A review of the published literature concerning low grade gliomas (LGGs) in NS is presented. We described also a 13-year-old girl with NS associated with a recurrent mutation in PTPN11, who developed three different types of brain tumors, i.e., an optic pathway glioma, a glioneuronal neoplasm of the left temporal lobe and a cerebellar pilocytic astrocytoma. Molecular characterization of the glioneuronal tumor allowed to detect high levels of phosphorylated MTOR (pMTOR); therefore, a therapeutic approach based on an mTOR inhibitor (everolimus) was elected. The treatment was well tolerated and proved to be effective, leading to a stabilization of the tumor, which was surgical removed. The positive outcome of the present case suggests considering this approach for patients with RASopathies and brain tumors with hyperactivated MTOR signaling.

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No abstract available.

BACKGROUND: Neonatal acute liver failure (ALF) is a severe condition with a mortality rate up to 70%. Human enterovirus (HEV) infections are associated with serious diseases in newborns, including myocarditis, meningoencephalitis and, more rarely, ALF with a fulminant course. METHODS: Cases of neonatal-onset ALF were identified using the institutional clinical database. The history and clinical data of infants with HEV infection were collected by medical record revision. Viral testing by nested real- time PCR (nRT-PCR) was performed by the Bambino Gesù Children's Hospital Clinical Laboratory and by National Institute of Public Health in Rome. RESULTS: Among ten infants referred to our Institution with neonatal-onset ALF in the 2004-2018 period, we identified five cases due to HEV. In three of these, the mother reported an episode of mild fever and diarrhea during the last trimester of gestation, suggesting fetal-maternal transmission. All were late preterm infants (32-36 weeks). Two infants died as a result of ALF; the other three survived with full normalization of liver function. In four, the causing agents were coxsackie B serotypes 3 (n = 1), 4 (n = 1) and 5 (n = 2), in the fifth case we identified echovirus serotype 11. CONCLUSIONS: Human enterovirus (HEV) are a rare but relevant cause of ALF in neonates. HEV testing should be systematically performed in cases of neonatal ALF for diagnostic and management purposes.

Cystinosis is an autosomal recessive lysosomal storage disorder characterized by the defective transport of the amino acid cystine out of the lysosome due to a deficiency of cystinosin, the lysosomal cystine transporter. Patients have lysosomal cystine accumulation in various tissues, leading to cellular stress and damage, particularly in the kidney, cornea, and other extrarenal tissues. Cysteamine, a cystine-depleting agent, improves survival and delays the progression of disease, but it does not prevent the development of either renal failure or extrarenal complications. Furthermore, the drug has severe adverse effects that significantly reduce patient compliance. Allogeneic hematopoietic stem cell transplantation (HSCT) is currently established as a therapeutic option for many inborn errors of metabolism, where the main pathologic driving factor is an enzyme deficiency. Recent studies in the cystinosis mouse-model suggested that HSCT could be a curative treatment alternative to cysteamine therapy. We treated a 16-year-old boy who had infantile cystinosis and side effects of cysteamine therapy with HSCT. We were able to demonstrate successful transfer of the wild-type cystinosin protein and CTNS mRNA to nonhematological epithelial cells in the recipient, as well as a decrease in the tissue cystine-crystal burden. This is the first report of allogeneic HSCT in a patient with cystinosis, the prototype of lysosomal membrane-transporter disorders. ispartof: AMERICAN JOURNAL OF TRANSPLANTATION vol:18 issue:11 pages:2823-2828 ispartof: location:United States status: published

Kidney transplantation is the best treatment for children with end-stage kidney disease. Early results have improved, but late graft loss is still a major problem. Non-invasive, fully reliable early biomarkers of acute rejection are currently missing. Our aim was to evaluate the efficacy of protocol biopsies (PBXs) in a pediatric population. During 11 years, 209 renal transplantations were performed in 204 pediatric patients. Biopsies were performed 3–6 months, 1 year, and 5 years after transplantation. Procedure-related complications were systematically looked for by means of ultrasound scans. Unexpected findings (mainly subclinical rejections) requiring therapeutic intervention were found in 19.3% biopsies performed at 3–6 months, in 18.4% in 12-month biopsies and in none of those performed after 5 years. The 13.6% patients at 12-month biopsies and 23.6% at 5-year biopsies showed calcineurin inhibitor (CNI) toxicity. Interstitial fibrosis and tubular atrophy (IF/TA) was found in 17.6 and 83.6% of patients at 12-month and 5-year biopsies, respectively. Complications of the PBX were infrequent. Five-year estimated glomerular filtration rate (GFR) was not significantly different in patients who received treatment for any cause and patients with normal histology. Although we do not have a control group, we may speculate that patients who received treatment returned to a “standard” condition possibly improving final outcome. Protocol biopsies are a powerful diagnostic tool for the management of pediatric renal transplant recipients. In view of the lack of evidence that biopsies taken 5 years after transplantation lead to any therapeutic change, their use should be reconsidered.

BACKGROUND Medulloblastoma is the most frequent malignant brain tumor in children, still resulting fatal in about one third of affected patients. An accurate diagnosis is essential for correct therapeutic stratification. The DNA methylation profile (DMP) is a combination of changes in DNA methylation and genetic features that reflect the cell of tumor origin. DMP contributed to classify Medulloblastoma into four subgroups: WNT, SHH, Group 3/4 (the latter recently further subdivided into 8 subclasses). Each Methylation is associated with different genetic, demographic and clinical characteristics. We report our experience on Medulloblastoma molecular classification based on DMP. MATERIALS AND METHODS 54 Medulloblastoma patients (28 males, 26 females) were selected. The DMP analysis was carried out via IlluminaEPICarrays. The results were obtained using the brain tumor classifier (Capper, 2018). RESULTS In all cases the DMP allowed to classify the neoplasm, with an optimal score, in a defined methylation class. 10 WNTs, 15 SHHs, 10 Group 3, 19 Group 4 were found. Groups 3/4 were further refined based on the new consensus (Sharma 2019) in group I (n = 1); group II (n = 5); group III (n = 2); group IV (n = 4); group V (n = 3); group VI (n = 2); group VII (n = 6); group VIII (n = 7). CONCLUSIONS This study carried out the first classification of Medulloblastomas diagnosed in Italy through DMP, demonstrating its high reproducibility, precision and accuracy. The molecular classification improves diagnostic accuracy and provides further information that can guide personalized treatment.

INTRODUCTION Hematopoietic stem cell transplantation (HSCT) is increasingly used in the treatment of acute leukemias (AL), non-Hodgkin lymphomas and other primary malignancies. However, a growing number of neoplasms secondary to HSCT are reported. The combination of total body irradiation (TBI) and high dose chemotherapy (HD-CT) as conditioning regimen is considered a risk factor. We present four children who survived AL, treated with HSCT and conditioning regimens including TBI/HD-CT. These patients developed a high-grade-brain tumor. We analyzed histological and molecular characteristics of neoplasms. METHODS Histologically, tumors were assessed for: presence of mitosis, necrosis and vascular proliferation; expression of ki67; expression of neuronal and glial markers, p53 and therapeutic targets. We analyzed the DNA methylation profile (DMP) of all tumors using IlluminaEPICarrays and compared it to the brain tumor classifier which allowed to generate the CNVs. RESULTS Morphologically two cases were defined as anaplastic astrocytoma, two cases as glioblastoma. Based on the DMP, all cases were found to belong to the methylation class “glioblastoma, IDH wildtype, subclass midline”, hypermutants, with gain of chromosome 1q and loss of 1p. Two cases showed PDGFRA amplification. All patients were treated with Temozolomide combination therapy +/- Bevacizumab and radiation therapy. At progression three patients were treated with checkpoint inhibitors. CONCLUSIONS The improvement of the precision medicine is fundamental in the therapeutic decision of brain tumors and even more in neoplasms secondary to antiblastic treatments. DMP and CNV have proven to be useful tools to complement the histological characterization of the reported cases.

PURPOSE Medulloblastoma (MB) is a complex pathology. Four molecular subgroups have been unveiled (Wingless-WNT, Sonic Hedgehog-SHH, Group 3-G3 and Group 4-G4), characterized by significant differences in patient clinical outcome. We investigated the utility of a radiomic analysis to predict molecular subgroups in patients with MB. MATERIALS AND METHODS We retrospectively evaluated 42 patients with histological diagnosis of MB, known molecular subgroup, and diagnostic MRI scan performed in our Institution on a 3 Tesla magnet. For each patient, FLAIR, ADC, T2 and contrast-enhanced MPRAGE sequences were analysed. Solid tumor volumes were segmented semiautomatically. 107 features were extracted for each sequence (Pyradiomics, Python). Features were tested for stability against labelling variations, selecting those presenting Intraclass Correlation Coefficient (ICC)>0.9 across all labelling variations and all sequences. Among the remaining features, relevant features were selected with an all-relevant wrapper algorithm (Boruta, R). Remaining features were used to predict MB subgroup with a Random Forest algorithm(R). The most relevant features were ranked based on Gini index (R). RESULTS 83/107 features presented ICC >0.9 for all sequences. Boruta selected 10 features. Classification analysis yielded an out-of-bag (OOB) error rate of 0.6%, (99.4% accuracy). The most relevant features for classification were “simple” first-order features such as volume, major axis or shape. CONCLUSION This radiomic study yielded robust features, which showed high accuracy in predicting the molecular MB subgroups. Random forest algorithms are ideal for multiclass classification (eg. MB subgroups) and are intrinsically suited against overfitting. The most relevant for molecular classification were first-order features.

Brain tumors are the most common solid neoplasms of childhood, but they are very rarely reported in children with Down Syndrome (DS), who develop more commonly different types of malignancies. In particular, we hereby report the case of an 8-years-old child with DS that presented to our attention for neurological and endocrinological issues. Brain imaging revealed the presence of a mass that was partially resected revealing a histological diagnosis of Pleomorphic Xanthoastrocytoma (PXA), a rare WHO grade II tumor extending from the diencephalic region into the surrounding brain tissue. These tumors can harbor the BRAF mutation p.V600E, targetable by the specific inhibitor Vemurafenib. After confirming the presence of the mutation in the tumor, the patient was treated with Vemurafenib. The treatment proved to be effective, leading to a partial response and a stabilization of the disease. Usually, in patients with DS a reduction of the dose of chemotherapeutic drugs is necessary. Vemurafenib was instead well-tolerated as the only observed adverse effect was grade I skin toxicity. This is, to our knowledge, the first case of a PXA reported in a child with DS and the first DS patient treated with Vemurafenib.

Solid tumours are characterized by a high structural complexity that is difficult to reproduce with common bidimensional (2D) systems. We developed an innovative fibrin-based hydrogel 3D model and tested it as platform to establish primary LGG cultures, otherwise difficult to maintain owing to the activation of senescence pathways. To date, 37 samples were cultured in both 2D and 3D platforms (19 astrocytomas and 18 gangliogliomas), with an average culture duration of 177+13 days, showing that the 3D-culture enables the stabilization of LGG. Whereas in the 2D-culture the cells showed overtime a significant reduction in the average culture days between each passage (average P1-P3:35+6 days; P3-P6: 29+5; >P6: 17+5), suggesting the selection of a peculiar clone, in the 3D-setting, we observed a more regular growth (average P1-P3:44+5 days; P3-P6: 64+20;>P6: 48+16). Cell lines identity was confirmed by short tandem repeats (STRs) and the immunohistochemical characterization (H&E, Ki67, tumour and differentiation markers) in 3D cultures revealed phenotype, cellular organization and proliferative rates closer to those observed in the onset samples, as compared to the 2D. We then analyzed the methylation profile and preliminary results suggest that the 2D lines evolve towards different lineages. The analysis of cell senescence using ß-galactosidase assay revealed a lower senescence in the 3D cultures (3D:12,28%+4,3% of the cells vs 2D:50,69%+18,46%; p=0,008). Lastly, we evaluated the responses to radiotherapy by MTS assay, and showed that 2D-cultured cells are more sensitive to treatment than 3D (2D: untreated, 0,0232+0,023, 160 Gy 0,089+0,025; 3D: untreated 0,235+0,09, 160 Gy 0,169+0,08), suggesting an overestimation of the efficacy of such treatment by the 2D-setting, therefore reducing the predictive power. The response to chemotherapy and more innovative approaches (i.e. Oncolytic Adenovirus) is currently under evaluation, the preliminary results confirming a similar finding. Overall, the 3D-culture offers an innovative platform for biological and therapeutic studies.

Glanular venous malformations are uncommon in pediatric patients. The diagnosis can be easily achieved by observation, even if color Doppler ultrasound is useful for a better characterization. Abdomino-pelvic MRI is necessary to assess the extension of complex lesions and check for associated anomalies. Several therapeutic options are reported in literature. We report 3 paediatric cases successfully treated by surgery with no complications and functional sequelae. Cosmetic results were satisfactory, with minimal surgical scarring. In our opinion, surgery for small glanular venous malformations is indicated within puberty to prevent traumatic bleeding and psychological impact.

Astroblastoma is a rare tumor of the central nervous system (CNS) with uncertain clinical behavior. Recently, DNA methylation profiling has been shown to provide a highly robust and reproducible approach for the classification of all CNS tumors across different age groups. By using DNA methylation profiling, a subset of CNS high-grade tumors with astroblastoma-like morphology characterized by the meningioma 1 gene (MN1) rearrangements, has been identified; they were termed "CNS high-grade neuroepithelial tumors with MN1 alteration" (CNS-HGNET-MN1). Here, we describe a case of CNS-HGNET-MN1 diagnosed by DNA methylation profiling, using Illumina Infinium HumanMethylationEPIC BeadChip (EPIC), that offers the opportunity to conduct a brief literature review. The patient presented with an episode of partial seizures involving the right hemisoma. A gross total resection was performed. No other treatment was proposed in light of the histological and molecular findings. After 21 months, the patient is disease-free in good clinical conditions. Also in view of this case, we recommend DNA-methylation profiling as an important tool for diagnosis and more effective patient stratification and management.

Rosette-forming glioneuronal tumors (RGNTs) are rare, grade I, central nervous system (CNS) tumors typically localized to the fourth ventricle. We describe a 9-year-old girl with dizziness and occipital headache. A magnetic resonance imaging (MRI) revealed a large hypodense posterior fossa mass lesion in relation to the vermis, with cystic component. Surgical resection of the tumor was performed. A RGNT diagnosis was made at the histopathological examination. During follow-up, the patient experienced a first relapse, which was again surgically removed. Eight months after, MRI documented a second recurrence at the local level. She was a candidate for the proton beam therapy (PBT) program. Three years after the end of PBT, the patient had no evidence of disease recurrence. This report underlines that, although RGNTs are commonly associated with an indolent course, they may have the potential for aggressive behavior, suggesting the need for treatment in addition to surgery. Controversy exists in the literature regarding effective management of RGNTs. Chemotherapy and radiation are used as adjuvant therapy, but their efficacy management has not been adequately described in the literature. This is the first case report published in which PBT was proposed for adjuvant therapy in place of chemotherapy in RGNT relapse.

BACKGROUND Neurofibromatosis type 1 (NF1) is autosomal dominant neurogenetic disorder characterized by progressive cutaneous, neurologic, skeletal, and neoplastic manifestations. Plexiform neurofibromas (PN) are one of the different types of neurofibromas that occur in these patients. Complete surgical resection is difficult due to the tumor infiltrative behavior. We evaluated pegylated interferon- α-2b (PI) in patients with unresectable progressive or symptomatic PN. METHODS Pediatric patients (1–21 years old) affected by unresectable PN, followed at Bambino Gesù Hospital, were treated with PI. We administered PI as a weekly subcutaneous injection at a beginning dose of 1.0 mcg/kg/wk, increased to 3.0 mcg/kg/wk if well tolerated. Paracetamol (15mg/kg) was given 30 minutes prior the dose of PI and then every 4–6 hours as needed. Patients were evaluated with Magnetic Resonance Imaging (MRI) every 12 months after treatment start in case of stable disease. RESULTS 10 patients (3 females, 7 males) were enrolled. Median age was 12 years old. The median duration of treatment was 12,6 months. Grade 3 neutropenia (30%) and increased liver transaminases level (20%) were the most common toxicity. 6/10 patients experienced an improvement about pain. 7/10 patients showed clinical response. 1/10 patient had a radiological response at MRI, 1/10 experienced progression disease and 8/10 showed a stable disease at MRI evaluation. CONCLUSIONS Our study demonstrated that PI could be a suitable treatment for unresectable PN in terms of stabilization of the tumour size due to its antitumor activity although clinical response does not correlate with radiographic changes.

Hemolytic uremic syndrome (HUS) is defined by the simultaneous occurrence of hemolytic anemia, thrombocytopenia, and acute kidney injury due to thrombotic microangiopathy (TMA) mainly occurring in renal and cerebral microvessels. Although the most common cause of HUS in children is Shiga toxin-producing Escherichia coli, atypical forms in which Shiga toxin is not the trigger may occur. Research over the last few years has shown that complement dysregulation secondary to mutations of genes coding for proteins involved in the regulation of the alternative pathway of complement account for most forms of atypical HUS (aHUS). Among these, thrombomodulin (THBD) gene mutations, representing 3–5% of all alternative pathway complement component abnormalities, correlate with early disease onset and rapid evolution to end-stage renal failure. aHUS onset is generally sudden, but occasionally the only manifestations of renal TMA are arterial hypertension, proteinuria, and a progressive increase in serum creatinine. Nephrotic syndrome at disease onset is exceptional. We describe the case of an adolescent female who presented with peripheral edema due to nephrotic-range proteinuria with bioptic evidence of TMA. Study of the alternative complement pathway showed a heterozygous missense THBD gene mutation (P501L variant) consistent with aHUS diagnosis. One year later she developed clinical signs of hemolytic anemia. Eculizumab, an anti-C5 monoclonal antibody, was started with rapid improvement. This case report highlights the phenotypic variability in aHUS due to THBD gene mutation. Early diagnosis by renal biopsy followed by genetic screening is required to optimize management in such a rare disease with a severe prognosis.

Background: Several cases of severe antibody-mediated rejection (AMR) secondary to antibodies against the angiotensin II type 1 receptor (AT1R-Ab) have been described with variable outcome. Case-Diagnosis/Treatment: We report the case of a 13-year-old boy whose first kidney transplant failed due to steroid-resistant acute cellular rejection, with the subsequent development of sensitization. He received a second kidney transplant which was complicated by early humoral rejection, with weakly positive staining for the complement degradation product C4d. Test results were negative for donor-specific antibodies against human leukocyte antigens (HLA-DSA) and MHC class I-related chain A (MICA) but positive for AT1R-Ab. Retrospective testing of the sera collected during the first kidney transplant was also positive for AT1R-Ab. We therefore hypothesized that the failure of the first transplant was secondary to the same cause. Losartan was immediately introduced into the therapeutic regimen, and the patient showed an excellent clinical and histological recovery. Conclusions: Testing for AT1R-Ab in any hypertensive patient with acute rejection who tests negative or weakly positive for C4d and negative for HLA-DSA and who is refractory to therapy is highly advisable. Pre-transplant AT1R-Ab may be indicative of the outcome in patients whose first transplant failed. Prompt initiation of treatment with losartan--immediately after transplantation in patients with pre-existing AT1R-Ab--should be encouraged.

Transient infantile hypertriglyceridemia (HTGT1; OMIM #614480) is a rare autosomal recessive disorder, which manifests in early infancy with transient hypertriglyceridemia, hepatomegaly, elevated liver enzymes, persistent fatty liver and hepatic fibrosis. This rare clinical entity is caused by inactivating mutations in the GPD1 gene, which encodes the cytosolic isoform of glycerol-3-phosphate dehydrogenase. Here we report on four patients from three unrelated families of diverse ethnic origins, who presented with hepatomegaly, liver steatosis, hypertriglyceridemia, with or without fasting ketotic hypoglycemia. Whole exome sequencing revealed the affected individuals to harbor deleterious biallelic mutations in the GPD1 gene, including the previously undescribed c.806G > A (p.Arg269Gln) and c.640T > C (p.Cys214Arg) mutations. The clinical features in three of our patients showed several differences compared to the original reports. One subject presented with recurrent episodes of fasting hypoglycemia along with hepatomegaly, hypetriglyceridemia, and elevated liver enzymes; the second showed a severe liver disease, with intrahepatic cholestasis associated with kidney involvement; finally, the third presented persistent hypertriglyceridemia at the age of 30 years. These findings expand the current knowledge of this rare disorder, both with regard to the phenotype and molecular basis. The enlarged phenotypic spectrum of glycerol-3-phosphate dehydrogenase 1 deficiency can mimic other inborn errors of metabolism with liver involvement and should alert clinicians to recognize this entity by considering GPD1 mutations in appropriate clinical settings.

Medulloblastoma is the most common pediatric brain tumor. We describe a child with tuberous sclerosis complex that developed a Group 3, myc overexpressed, metastatic medulloblastoma (MB). Considering the high risk of treatment-induced malignancies, a tailored therapy, omitting radiation, was given. Based on the evidence of mammalian target of rapamycin mTORC, mTOR Complex; RAS, Rat sarcoma; RAF, rapidly accelerated fibrosarcoma (mTOR) pathway activation in the tumor, targeted therapy was applied resulting in complete remission of disease. Although the PI3K/AKT/mTOR signaling pathway plays a role in MB, we did not find TSC1/TSC2 (TSC, tuberous sclerosis complex) mutation in our patient. We speculate that a different pathway resulting in mTOR activation is the basis of both TSC and MB in this child; HE Gd, gadolinium.

Low-grade gliomas (LGG) are the most common central nervous system tumors in children. Prognosis depends on complete surgical resection. For patients not amenable of gross total resection (GTR) new approaches are needed. The BRAF mutation V600E is critical for the pathogenesis of pediatric gliomas and specific inhibitors of the mutated protein, such as Vemurafenib, are available. We investigated the safety and efficacy of Vemurafenib as single agent in pediatric patients with V600E+ LGG. From November 2013 to May 2018, 7 patients have been treated in our Institution; treatment was well-tolerated, the main concern being dermatological toxicity. The best responses to treatment were: 1 complete response, 3 partial responses, 1 stable disease, only one patient progressed; in one patient, the follow-up is too short to establish the clinical response. Two patients discontinued treatment, and, in both cases, immediate progression of the disease was observed. In one case the treatment was discontinued due to toxicity, in the other one the previously assessed BRAF V600E mutation was not confirmed by further investigation. Two patients, after obtaining a response, progressed during treatment, suggesting the occurrence of resistance mechanisms. Clinical response, with improvement of the neurologic function, was observed in all patients a few weeks after the therapy was started. Despite the limitations inherent to a small and heterogeneous cohort, this experience, suggests that Vemurafenib represents a treatment option in pediatric patients affected by LGG and carrying BRAF mutation V600E.

We present 47 consecutive patients operated at our Center for medulloblastoma in the last 5 years. Twenty five were males and mean age was 7 years. Eleven patients were infants. Surgery aimed at maximal safe resection in all cases. Molecular subgroup showed 7 WNT, 11 SHH, 14 Group 3, 15 Group 4. We tested a possible correlation between clinical variables relevant for surgery and molecular subgroup (Chi square test, significance = p

Extraventricular neurocytoma (EVN) is an extremely rare tumor of neuroglial origin with a tendency toward ganglionic or glial differentiation. In the 2016 World Health Organization Classification, EVN was classified as a grade II tumor and described as a neoplasm with good outcome. However, the presence of cellular atypia is an important unfavorable prognostic factor. Here, we describe the first case of a patient with a congenital EVN localized in the brainstem. After a sub-total resection, his disease rapidly progressed despite several chemotherapies, including molecular targeting approaches. He died 13 months after diagnosis. In conclusion, we report an atypical case of EVN presenting an extremely aggressive behavior, despite the absence of cellular atypia. The brainstem origin and the age of the patient may have represented two important prognostic factors for our patient.

Extraventricular neurocytoma (EVN) is a rare primary brain tumor occurring in brain parenchyma outside the ventricular system. Histopathological characteristics resemble those of central neurocytoma but exhibit a wider morphologic spectrum. Accurate diagnosis of these histologically heterogeneous tumors is often challenging because of the overlapping morphological features and the lack of defining molecular markers. Here, we explored the molecular landscape of 40 tumors diagnosed histologically as EVN by investigating copy number profiles and DNA methylation array data. DNA methylation profiles were compared with those of relevant differential diagnoses of EVN and with a broader spectrum of diverse brain tumor entities. Based on this, our tumor cohort segregated into different groups. While a large fraction (n = 22) formed a separate epigenetic group clearly distinct from established DNA methylation profiles of other entities, a subset (n = 14) of histologically diagnosed EVN grouped with clusters of other defined entities. Three cases formed a small group close to but separated from the epigenetically distinct EVN cases, and one sample clustered with non-neoplastic brain tissue. Four additional samples originally diagnosed otherwise were found to molecularly resemble EVN. Thus, our results highlight a distinct DNA methylation pattern for the majority of tumors diagnosed as EVN, but also indicate that approximately onethird of morphological diagnoses of EVN epigenetically correspond to other brain tumor entities. Copy number analysis and confirmation through RNA sequencing revealed FGFR1–TACC1 fusion as a distinctive, recurrent feature within the EVN methylation group (60%), in addition to a small number of other FGFR rearrangements (13%). In conclusion, our data demonstrate a specific epigenetic signature of EVN suitable for characterization of these tumors as a molecularly distinct entity, and reveal a high frequency of potentially druggable FGFR pathway activation in this tumor group.

Granular cell tumors (GCTs) or Abrikossoff's tumors are rare, soft tissue tumors of neural origin with a generally benign behavior. They can occur anywhere in the body (with up to 7%–16% situated in the vulva) and can occur in patients of any age, being considered rare in children. A 6 year-old girl presented with a clitoral mass, surgically removed. Pathology revealed GCT of clitoris. To our knowledge this is the first case of GCT of the clitoris in the pediatric (prepubertal) age group reported in English literature. Although rare in pediatric age, GCT has to be suspected as a cause of vulvar mass. Surgical treatment and clinical follow-up must consider the possibility of recurrence, multiple location and malignancy with time.

A two year-old male was seen to our Emergency Department for acute abdominal pain, urinary retention and worsening constipation. A first level diagnostic imaging showed a pelvic cystic mass between bladder and rectum. Left kidney was absent. Further workup with MRI and endoscopy demonstrated the cyst to be of urogenital origin. Rapid increase in size and clinical symptoms prompted surgery. Pathology and surgical specimen showed the mass to be a left seminal vesicle cyst secondary to a malformation of the eiaculatory duct and embriologically related to ipsilateral renal agenesis. Such findings were consistent with the diagnosis of Zinner’s syndrome (a clinical triad consisting of seminal vesicle cyst, ejaculatory duct obstruction and ipsilateral renal agenesis). Since the symptoms related to the seminal vesicle cyst coincide with the onset of a sexually active life, the majority of cases are generally observed and treated in the second and third decade. To our knowledge, this is the first case description in pediatric age.

High-grade gliomas of the spinal cord represent a rare entity in children. Their biology, behavior, and controversial treatment options have been discussed in a few pediatric cases. These tumors are associated with severe disability and poor prognosis. We report a case of a 4-year-old child diagnosed with an isolated glioblastoma multiforme of the conus medullaris. The patient underwent subtotal surgical excision, followed by adjuvant radiotherapy and oral chemotherapy. He is alive with mild neurologic deficits at 52 months after diagnosis. We describe the peculiar characteristics of this rare condition in pediatric oncology. We also provide an overview of current multidisciplinary therapeutic approaches and prognostic factors for this disease.

Background Medulloblastoma is the most common malignant brain tumor in children. To date only few cases of medulloblastoma with hemorrhages have been reported in the literature. Although some studies speculate on the pathogenesis of this anomalous increased vascularization in medulloblastoma, the specific mechanism is still far from clearly understood. A correlation between molecular medulloblastoma subgroups and hemorrhagic features has not been reported, although recent preliminary studies described that WNT-subtype tumors display increased vascularization and hemorrhaging. Case presentation Herein, we describe a child with a Wnt-medulloblastoma presenting as cerebellar-vermian hemorrhagic lesion. Brain magnetic resonance imaging (MRI) showed the presence of a midline posterior fossa mass with a cystic hemorrhagic component. The differential diagnosis based on imaging included cavernous hemangioma, arteriovenous malformation and traumatic lesion. At surgery, the tumor appeared richly vascularized as documented by the preoperative angiography. Conclusions The case we present showed that Wnt medulloblastoma may be associated with anomalous vascularization. Further studies are needed to elucidate if there is a link between the hypervascularization and the Wnt/β-catenin signaling activation and if this abnormal vasculature might influence drug penetration contributing to good prognosis of this medulloblastoma subgroup.

Objective To report 2 pediatric urology referral centers' experience on transitional cell carcinoma of the bladder (TCCB) in patients younger than 30 years, focusing on age-related prognostic factors. Materials and Methods Patients younger than 30 years affected by TCCB from January 1999 to December 2011 were investigated. Spearman's rank test and Kruskal-Wallis test were adopted for statistical analysis. Results Eighteen patients were identified (8 females, 10 males) and stratified by age at presentation: 5 in group A (12 years old and younger), 7 in group B (13-19 years), and 6 in group C (20-29 years). Females were predominant in groups A and B, whereas males were predominant in group C. Pathological grading revealed low-grade papillary urothelial carcinoma in 7, papillary urothelial neoplasm of low malignant potential in 7, and high-grade urothelial papillary carcinoma in 4 patients. At a mean follow-up of 6.5 years, recurrence was observed in 2 cases. Statistical analysis showed a positive correlation between age and grading. There was no statistical significance based on gender. Staging was significant between the age groups; older patients had more advanced tumors. Conclusion TCCB is rarely observed in the first 3 decades of life. The prognosis is good in early-age presentation. Sex distribution, pathological grading, and prognosis were found different according to age. Patients younger than 19 years behave in a more favorable manner than those older, and should be followed up like adults.

Medulloblastoma (MB) is the most common malignant brain tumor in children. Despite therapeutic advancements, high-risk groups still present significant mortality. A deeper knowledge of the signaling pathways contributing to MB formation and aggressiveness would help develop new successful therapies. The target of rapamycin, mTOR signaling, is known to be involved in MB and is already targetable in the clinical setting. Furthermore, mTOR is a master metabolic regulator able to control cell growth versus autophagy decisions in conditions of amino-acid deprivation that can be due to IDO1 enzymatic activity. IDO1 has been also implicated in the regulation of inflammation, as well as of T cell-mediated immune responses, in a variety of pathological conditions, including brain tumors. In particular, IDO1 induces expansion of regulatory T-cells (Treg), preventing immune response against tumor cells. Analysis of 27 MB tissue specimens for the expression of both mTOR and IDO1 showed their widespread expression in all samples. Testing their cooperation in vitro, a significant involvement of IDO1 in mTOR immunogenic pathway was found, able to counteract the aim of rapamycin treatment. In MB cell lines, inhibition of mTOR strongly induced IDO1 expression and activity, corroborating its ability to recruit Treg cells in the tumor microenvironment. The mTOR/IDO1 cross talk was found to be strictly specific of MB cells. We demonstrated that mTOR pathway cross talks with IDO1 pathway to promote MB immune escape, possibly contributing to failure of mTOR- targeted therapy.

The patient is an 18-month-old boy from Romania, whose parents are healthy and non-consanguineous. In October 2005, periorbital and lower extremities edema were first noted while the child was in general good conditions and without any sign of acute infectious problem. For generalized edema, he was admitted at a pediatric nephrology unit where heavy proteinuria (>10g day -1 ), with serum high cholesterol levels (>500mg per 100ml) and hypoalbuminemia (

Background: Esophageal diseases are common in infants and children, and may present with several clinical and pathological aspects. Eosinophilic esophagitis (EE) is characterized by inflammatory, predominantly eosinophilic infiltrate (≧15 eosinophils per high-power field (HPF)) that is not responsive to acid suppression therapy. An immunoallergic pathogenesis has been hypothesized, likely related to food allergy. Barrett’s esophagus (BE) is due to chronic gastroesophageal reflux. The pathological consequence is the replacement of normal stratified squamous epithelium by columnar mucosa with goblet cells. Methods: We present 2 children with a history of food allergy. Endoscopy revealed linear furrows and yellow plaques in the mid-distal esophagus. Results: In both patients histology showed a high number of eosinophils (>30 at HPF) in the mid-distal esophagus and intestinal metaplasia with goblet cells in distal esophagus. Diagnosis of EE associated to BE was made. Restriction diet was administered to treat EE whereas, in 1 case, laparoscopic fundoplication was performed to treat BE. Follow-up showed a remission of endoscopic and histological aspects. Conclusions: The unusual, possibly fortuitous association of EE and BE, two conditions differing in etiopathogenesis, clinical and pathological features, calls for a correct diagnosis to offer suitable treatment and prognosis.