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Sclerosing stromal tumor (SST) is a rare ovarian tumor arising from the sex cord-stromal cells that occurs mainly in young adults during the second and third decades of life and rarely in pediatric and adolescent populations. The objective of this study is to report three illustrative cases of SST in young girls who had undergone surgery at our clinic in or after 2009, and to perform a literature review of this rare ovarian tumor. A retrospective chart review of female patients aged

Cysteamine is currently the only therapy for nephropathic cystinosis. It significantly improves life expectancy and delays progression to end-stage kidney disease; however, it cannot prevent it. Unfortunately, compliance to therapy is often weak, particularly during adolescence. Therefore, finding better treatments is a priority in the field of cystinosis. Previously, we found that genistein, an isoflavone particularly enriched in soy, can revert part of the cystinotic cellular phenotype that is not sensitive to cysteamine in vitro. To test the effects of genistein in vivo, we fed 2-month-old wild-type and Ctns−/− female mice with either a control diet, a genistein-containing diet or a cysteamine-containing diet for 14 months. Genistein (160 mg/kg/day) did not affect the growth of the mice or hepatic functionality. Compared with untreated mice at 16 months, Ctns−/− mice fed with genistein had lower cystine concentrations in their kidneys, reduced formation of cystine crystals, a smaller number of LAMP1-positive structures and an overall better-preserved parenchymal architecture. Cysteamine (400 mg/kg/day) was efficient in reverting the lysosomal phenotype and in preventing the development of renal lesions. These preclinical data indicate that genistein ameliorates kidney injury resulting from cystinosis with no side effects. Genistein therapy represents a potential treatment to improve the outcome for patients with cystinosis.

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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/438254885See related commentary by Szulzewsky and Cimino, p. 904.This article is highlighted in the In This Issue feature, p. 890

Median raphe cyst are uncommon malformations of male genitalia, in which are rarely described melanin pigments or melanocytes; less than ten cases have been reported in literature. The aim of our study is to describe a rare ormations, case of pigmented median raphe cyst of the scrotum, successfully treated in our hospital.A 6-years-old boy underwent surgical removal of a melanocytic lesion of the ventral surface of the scrotum in Day Surgery regimen. He reported no surgical complication or recurrence.Histology showed multiple cystic nodules, lined by squamous and pluri-stratified columnar epithelium, some of which contained melanic deposits and were anti-MART-positive.Even though the first case has been reported in 1985, the etiology of median raphe cysts remains unclear. Infrequently associated with trauma or infections, these lesions seem to origin from an abnormal development of the periurethral glands or atypical closure of the median raphe. Rarely melanin pigments or melanocytes are described in the histological examination, and the cause of the pigmentation is still unknown.Median raphe cysts present a non-negligible variety of clinical presentations and histological features. Pigmented ones represent the rarest form: further studies may be necessary to clarify their pathogenesis and describe their clinical evolution.Median raphs, Male genitalia, Malformations.Le cisti del rafe mediano rappresentano una rara malformazione dei genitali maschili; in pochissimi casi (meno di 10 riportati in letteratura) presente nella lesione una componente melanocitica o pigmenti di melanina. Lo scopo del nostro studio quello di descrivere un raro caso di cisti pigmentata del rafe mediano dello scroto, trattata con successo presso il nostro nosocomio.Il paziente, di 6 anni di et , presentava una lesione cistica e melanocitica della superficie ventrale dello scroto; stato sottoposto ad asportazione della cisti in regime di Day Surgery e non ha mostrato, con un follow-up di 5 anni, alcuna recidiva n complicanza chirurgica.L’analisi istologica della lesione ha mostrato multipli noduli cistici, caratterizzati da un epitelio squamoso pluristratificato, che conteneva depositi di melanina ed esprimeva positivit per anti-MART.Nonostante il primo caso sia stato descritto nel 1985, l’eziologia delle cisti del rafe mediano risulta ancora ignota. Raramente associati ad infezioni o trauma, tali lesioni sembrerebbero originale da un anomalo sviluppo delle ghiandole periuretrali o da una chiusura patologica del rafe mediano. Solo in pochi casi sono presenti melanociti o pigmenti di melanina all’esame istologico e la causa di tale pigmentazione non ancora chiara.Le cisti del rafe mediano mostrano un’ampia gamma di presentazioni cliniche e di aspetti istologici. Le forme pigmentate rappresentano una minima percentuale: ulteriori studi sono necessari per chiarirne la patogenesi e descriverne la naturale evoluzione clinica.

BackgroundDiffuse midline gliomas (DMG) H3K27M-mutant, including diffuse intrinsic pontine glioma (DIPG), are pediatric brain tumors associated with grim prognosis. Although GD2-CAR T-cells demonstrated significant anti-tumor activity against DMG H3K27M-mutant in vivo, a multimodal approach may be needed to more effectively treat patients. We investigated GD2 expression in DMG/DIPG and other pediatric high-grade gliomas (pHGG) and sought to identify chemical compounds that would enhance GD2-CAR T-cell anti-tumor efficacy.MethodsImmunohistochemistry in tumor tissue samples and immunofluorescence in primary patient-derived cell lines were performed to study GD2 expression. We developed a high-throughput cell-based assay to screen 42 kinase inhibitors in combination with GD2-CAR T-cells. Cell viability, western blots, flow-cytometry, real time PCR experiments, DIPG 3D culture models, and orthotopic xenograft model were applied to investigate the effect of selected compounds on DIPG cell death and CAR T-cell function.ResultsGD2 was heterogeneously, but widely, expressed in the tissue tested, while its expression was homogeneous and restricted to DMG/DIPG H3K27M-mutant cell lines. We identified dual IGF1R/IR antagonists, BMS-754807 and linsitinib, able to inhibit tumor cell viability at concentrations that do not affect CAR T-cells. Linsitinib, but not BMS-754807, decreases activation/exhaustion of GD2-CAR T-cells and increases their central memory profile. The enhanced anti-tumor activity of linsitinib/GD2-CAR T-cell combination was confirmed in DIPG models in vitro, ex vivo, and in vivo.ConclusionOur study supports the development of IGF1R/IR inhibitors to be used in combination with GD2-CAR T-cells for treating patients affected by DMG/DIPG and, potentially, by pHGG.

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.

Purpose: To develop a predictive grading model based on diffusion kurtosis imaging (DKI) metrics in children affected by gliomas, and to investigate the clinical impact of the predictive model by correlating with overall survival and progression-free survival. Materials and methods: 59 patients with a histological diagnosis of glioma were retrospectively studied (33 M, 26 F, median age 7.2 years). Patients were studied on a 3T scanner with a standardized MR protocol, including conventional and DKI sequences. Mean kurtosis (MK), axial kurtosis (AK), radial kurtosis (RK), fractional anisotropy (FA), and apparent diffusion coefficient (ADC) maps were obtained. Whole tumour volumes (VOIs) were segmented semi-automatically. Mean DKI values were calculated for each metric. The quantitative values from DKI-derived metrics were used to develop a predictive grading model to develop a probability prediction of a high-grade glioma (pHGG). Three models were tested: DTI-based, DKI-based, and combined (DTI and DKI). The grading accuracy of the resulting probabilities was tested with a receiver operating characteristics (ROC) analysis for each model. In order to account for dataset imbalances between pLGG and pHGG, we applied a random synthetic minority oversampling technique (SMOTE) analysis. Lastly, the most accurate model predictions were correlated with progression-free survival (PFS) and overall survival (OS) using the Kaplan–Meier method. Results: The cohort included 46 patients with pLGG and 13 patients with pHGG. The developed model predictions yielded an AUC of 0.859 (95%CI: 0.752–0.966) for the DTI model, of 0.939 (95%CI: 0.879–1) for the DKI model, and of 0.946 (95%CI: 0.890–1) for the combined model, including input from both DTI and DKI metrics, which resulted in the most accurate model. Sample estimation with the random SMOTE analysis yielded an AUC of 0.98 on the testing set. Model predictions from the combined model were significantly correlated with PFS (25.2 months for pHGG vs. 40.0 months for pLGG, p < 0.001) and OS (28.9 months for pHGG vs. 44.9 months for pLGG, p < 0.001). Conclusions: a DKI-based predictive model was highly accurate for pediatric glioma grading. The combined model, derived from both DTI and DKI metrics, proved that DKI-based model predictions of tumour grade were significantly correlated with progression-free survival and overall survival.

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.

Germline pathogenic variants in AMER1 cause osteopathia striata with cranial sclerosis (OSCS: OMIM 300373), an X-linked sclerosing bone disorder. Female heterozygotes exhibit metaphyseal striations in long bones, macrocephaly, cleft palate, and, occasionally, learning disability. Male hemizygotes typically manifest the condition as fetal or neonatal death. Somatically acquired variants in AMER1 are found in neoplastic tissue in 15-30% of patients with Wilms tumor; however, to date, only one individual with OSCS has been reported with a Wilms tumor. Here we present four cases of Wilms tumor in unrelated individuals with OSCS, including the single previously published case. We also report the first case of bilateral Wilms tumor in a patient with OSCS. Tumor tissue analysis showed no clear pattern of histological subtypes. In Beckwith-Wiedemann syndrome, which has a known predisposition to Wilms tumor development, clinical protocols have been developed for tumor surveillance. In the absence of further evidence, we propose a similar protocol for patients with OSCS to be instituted as an initial precautionary approach to tumor surveillance. Further evidence is needed to refine this protocol and to evaluate the possibility of development of other neoplasms later in life, in patients with OSCS.

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.

Cystic dysplasia of the rete testis (CDRT) is a rare cause of testicular masses in children. The pathogenesis of this malformation remains unclear. It is often associated with other genitourinary anomalies, commonly presenting as agenesis or dysplasia of the ipsilateral kidney. A case involving a 9-year-old boy with a testicular lesion and ipsilateral renal agenesis, who was diagnosed with CDRT after histological examination, is reported. In addition, a systematic review of the literature was performed to better understand this pathology to design the most appropriate treatment and follow-up strategy for patients with CDRT.

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

Astroblastomas are neuroepithelial tumours defined by the presence of MN1 rearrangement and are typically located in the cerebral hemispheres. Rare cases of astroblastoma-like tumours carrying an EWSR1-BEND2 fusion have been recently described in the brain stem and spinal cord. We report a paediatric case of neuroepithelial astroblastoma-like tumour occurring in the spine and carrying a novel MAMLD1-BEND2 fusion. We believe that our case aligns with the rare astroblastoma-like tumours with EWSR1-BEND2 fusion, in terms of non-hemispheric location, pathology, methylation profile and activation of BEND2 transcription. Whether they may represent a distinct entity or a variant of MN1-altered astroblastoma is not clear.

Nephropathic cystinosis is an inherited lysosomal storage disorder caused by pathogenic variants in the cystinosin (CTNS) gene and is characterized by the excessive shedding of proximal tubular epithelial cells (PTECs) and podocytes into urine, development of the renal Fanconi syndrome and end-stage kidney disease (ESKD). We hypothesized that in compensation for epithelial cell losses, cystinosis kidneys undertake a regenerative effort, and searched for the presence of kidney progenitor cells (KPCs) in the urine of cystinosis patients. Urine was cultured in a specific progenitor medium to isolate undifferentiated cells. Of these, clones were characterized by qPCR, subjected to a differentiation protocol to PTECs and podocytes and assessed by qPCR, Western blot, immunostainings and functional assays. Cystinosis patients voided high numbers of undifferentiated cells in urine, of which various clonal cell lines showed a high capacity for self-renewal and expressed kidney progenitor markers, which therefore were assigned as cystinosis urine-derived KPCs (Cys-uKPCs). Cys-uKPC clones showed the capacity to differentiate between functional PTECs and/or podocytes. Gene addition with wild-type CTNS using lentiviral vector technology resulted in significant reductions in cystine levels. We conclude that KPCs present in the urine of cystinosis patients can be isolated, differentiated and complemented with CTNS in vitro, serving as a novel tool for disease modeling. ispartof: CELLS vol:11 issue:7 ispartof: location:Switzerland status: published

As a relevant element of novelty, the fifth CNS WHO Classification highlights the distinctive pathobiology underlying gliomas arising primarily in children by recognizing for the first time the families of paediatric-type diffuse gliomas, both high-grade and low-grade. This review will focus on the family of paediatric-type diffuse high-grade gliomas, which includes four tumour types: 1) Diffuse midline glioma H3 K27-altered; 2) Diffuse hemispheric glioma H3 G34-mutant; 3) Diffuse paediatric-type high-grade glioma H3-wildtype and IDH-wildtype; and 4) Infant-type hemispheric glioma. The essential and desirable diagnostic criteria as well as the entities entering in the differential will be discussed for each tumour type. A special focus will be given on the issues encountered in the daily practice, especially regarding the diagnosis of the diffuse paediatric-type high-grade glioma H3-wildtype and IDH-wildtype. The advantages and the limits of the multiple molecular tests which may be utilised to define the entities of this tumour family will be evaluated in each diagnostic context.

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.

Medulloblastoma with extensive nodularity (MBEN) is one of the few central nervous system (CNS) tumor entities occurring in infants which is traditionally associated with good to excellent prognosis. Some MBEN, however, have been reported with an unfavorable clinical course. We performed an integrated DNA/RNA-based molecular analysis of a multi-institutional MBEN cohort (n = 41) to identify molecular events which might be responsible for variability in patients' clinical outcomes. RNA sequencing analysis of this MBEN cohort disclosed two clear transcriptome clusters (TCL) of these CNS tumors: "TCL1 MBEN" and "TCL2 MBEN" which were associated with various gene expression signatures, mutational landscapes and, importantly, prognosis. Thus, the clinically unfavorable "TCL1 MBEN" subset revealed transcriptome signatures composed of cancer-associated signaling pathways and disclosed a high frequency of clinically relevant germline PTCH1/SUFU alterations. In contrast, gene expression profiles of tumors from the clinically favorable "TCL2 MBEN" subgroup were associated with activation of various neurometabolic and neurotransmission signaling pathways, and germline SHH-pathway gene mutations were extremely rare in this transcriptome cluster. "TCL2 MBEN" also revealed strong and ubiquitous expression of VSNL1 (visinin-like protein 1) both at the mRNA and protein level, which was correlated with a favorable clinical course. Thus, combining mutational and epigenetic profiling with transcriptome analysis including VSNL1 immunohistochemistry, MBEN patients could be stratified into clinical risk groups of potential value for subsequent treatment planning.

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.

Paediatric-type diffuse high-grade gliomas (PDHGG) are aggressive brain tumors, affecting children and young adults, with no effective treatments. A main constraint to the development of effective treatment is associated with their highly heterogeneous nature. In order to further dissect their intra and inter tumor heterogeneity, we exploited the mass cytometry technology, an advanced -OMIC approach that, by using metal-tagged antibodies, allows the simultaneous measurement of more than 40 markers, at single-cell level. Here we characterized 8 primary cell lines derived from diffuse pediatric-type high-grade glioma H3-wildtype (DHGG-WT), Diffuse hemispheric glioma H3G34-mutant (DHG-G34) and Diffuse midline glioma H3K27-altered (DMG-K27) patients. The adopted antibody panel was set to recognize antigens expressed by brain and tumor cells, including H3K27M and H3.3G34R variants, and it highlighted important intra- and inter- tumor heterogeneity in the expression of the 16 considered markers. Of these, CD56, CD44, CD29 and NESTIN were more expressed in the hemispheric cell lines, while CD90 was more expressed in the pontine. Even if there was not always a concordance between CyTOF and mRNA expression data from cell lines and tumor samples (e.g. CD90 and GFAP), CyTOF data were in line with the immunohistochemistry analysis for GFAP, whose expression was significantly higher in H3.1K27 compared to H3.3K27. The UMAP analysis allowed us to identify 10 cell clusters, with very minimal overlap between hemispheric and pontine location subgroups and with a peculiar antigenic profile, whose abundance strongly varied according to the mutational subgroups. For example, while the G34 subgroup was enriched for cluster 9 (CD29/CD63/CD56/PDGRFa), the H3.1K27 was enriched for cluster 3 (H3K27M/CD90/CD63/CD56) and cluster 4 (H3K27M/CD63/CD90/CD56/GFAP). In conclusion, single-cell mass cytometry reveals a significant inter and intra-tumoral heterogeneity at protein level, dependent on the molecular alterations. This approach could contribute to the identification of new clinically relevant biomarkers for PDHGG.

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.

Purpose Our purpose was to better understand the pathogenesis of seizures associated with angiocentric glioma. Angiocentric glioma is an indolent and rare low-grade glioma. Its typical clinical presentation is with epileptic seizures. The pathogenesis of tumor-associated seizures is poorly understood. Among the possible pathomechanisms, the increased neurotoxic concentrations of the glutamate has been proposed. Glutamate transporters, pyruvate carboxylase and glutamine synthetase are involved in maintaining the physiological concentration of glutamate in the inter synaptic spaces. Methods We evaluated the immunohistochemical expression of EAAT2 (the most important glutamate transporter), pyruvate carboxylase and glutamine synthetase in 17 angiocentric gliomas. Results EAAT2 was never expressed (0%) in the neoplastic cells in none of the cases studied. Pyruvate carboxylase was expressed in the cytoplasm of the neoplastic cells in 16/17 cases (94 %). Glutamine synthetase was expressed in the cytoplasm of the neoplastic cells in 15/17 cases (88 %). Conclusion The net result of this enzymatic expression, in particular considering the loss of EAAT2, could be an increased glutamate concentration in the synaptic clef, which might increase local network excitability initially involving intratumoral neurons. The observation that the angiocentric glioma-associated epilepsy might be at least in part related to EAAT2 deficiency opens up interesting therapeutic perspectives.

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.

Medulloblastoma (MB) is a childhood malignant brain tumour comprising four main subgroups characterized by different genetic alterations and rate of mortality. Among MB subgroups, patients with enhanced levels of the c-MYC oncogene (MBGroup3) have the poorest prognosis. Here we identify a previously unrecognized role of the pro-autophagy factor AMBRA1 in regulating MB. We demonstrate that AMBRA1 expression depends on c-MYC levels and correlates with Group 3 patient poor prognosis; also, knockdown of AMBRA1 reduces MB stem potential, growth and migration of MBGroup3 stem cells. At a molecular level, AMBRA1 mediates these effects by suppressing SOCS3, an inhibitor of STAT3 activation. Importantly, pharmacological inhibition of autophagy profoundly affects both stem and invasion potential of MBGroup3 stem cells, and a combined anti-autophagy and anti-STAT3 approach impacts the MBGroup3 outcome. Taken together, our data support the c-MYC/AMBRA1/STAT3 axis as a strong oncogenic signalling pathway with significance for both patient stratification strategies and targeted treatments of MBGroup3.