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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.

Cystinosis is a rare autosomal recessive disorder caused by mutations in the CTNS gene that encodes cystinosin, a ubiquitous lysosomal cystine/H+ antiporter. The hallmark of the disease is progressive accumulation of cystine and cystine crystals in virtually all tissues. At the kidney level, human cystinosis is characterized by the development of renal Fanconi syndrome and progressive glomerular and interstitial damage leading to end-stage kidney disease in the second or third decade of life. The exact molecular mechanisms involved in the pathogenesis of renal disease in cystinosis are incompletely elucidated. We have previously shown upregulation of NLRP2 in human cystinotic proximal tubular epithelial cells and its role in promoting inflammatory and profibrotic responses. Herein, we have investigated the role of NLRP2 in vivo using a mouse model of cystinosis in which we have confirmed upregulation of Nlrp2 in the renal parenchyma. Our studies show that double knock out Ctns-/- Nlrp2-/- animals exhibit delayed development of Fanconi syndrome and kidney tissue damage. Specifically, we observed at 4-6 months of age that animals had less glucosuria and calciuria and markedly preserved renal tissue, as assessed by significantly lower levels of inflammatory cell infiltration, tubular atrophy, and interstitial fibrosis. Also, the mRNA expression of some inflammatory mediators (Cxcl1 and Saa1) and the rate of apoptosis were significantly decreased in 4-6-month old kidneys harvested from Ctns-/- Nlrp2-/- mice compared to those obtained from Ctns-/-mice. At 12-14 months of age, renal histological was markedly altered in both genetic models, although double KO animals had lower degree of polyuria and low molecular weight proteinuria and decreased mRNA expression levels of Il6 and Mcp1. Altogether, these data indicate that Nlrp2 is a potential pharmacological target for delaying progression of kidney disease in cystinosis.

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.

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.

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.

Background: Diffuse intrinsic pontine glioma (DIPG) has a dismal prognosis. Magnetic resonance imaging (MRI) remains the gold standard for non-invasive DIPG diagnosis. MRI features have been tested as surrogate biomarkers. We investigated the direct involvement of cranial nerve V (CN V) in DIPG at diagnosis and its utility as predictor of poor overall survival.Materials and Methods: We examined MRI scans of 35 consecutive patients with radiological diagnosis of DIPG. Direct involvement of CN V was assessed on the diagnostic scans. Differences in overall survival (OS) and time to progression (TTP) were analyzed for involvement of CN V, sex, age, tumor size, ring enhancement, and treatment regimen. Correlations between involvement of CN V and disease dissemination, magnet strength and slice thickness were analyzed. Statistical analyses included Kaplan-Meier curves, log-rank test and Spearman's Rho.Results: After excluding six long-term survivors, 29 patients were examined (15 M, 14 F). Four patients presented direct involvement of CN V. Histological data were available in 12 patients. Median OS was 11 months (range 3–23 months). Significant differences in OS were found for direct involvement of CN V (median OS: 7 months, 95% CI 1.1–12.9 months for involvement of CN V vs. 13 months, 95% CI 10.2–15.7 for lack of involvement of CN V, respectively, p < 0.049). Significant differences in TTP were found for the two treatment regimens (median TTP: 4 months, 95% CI 2.6–5.3 vs. 7 months, 95% CI 5.9–8.1, respectively, p < 0.027). No significant correlation was found between involvement of CN V and magnet strength or slice thickness (r = −0.201; p = NS). A trend toward positive correlation was found between direct involvement of CN V at diagnosis and dissemination of disease at follow-up (r = 0.347; p < 0.065).Conclusions: In our cohort, direct involvement of CN V correlated with poor prognosis. Based on our data, we suggest that in DIPG direct involvement of CN V should be routinely evaluated on diagnostic scans.

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.

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.