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Assessment of endothelial dysfunction in cancer survivors may have a role in the early identification of non-communicable diseases and cardiovascular late effects. Oncological therapies may impair endothelial function. Therefore, in patients such as childhood cancer survivors who could benefit from early cardioprotective pharmacological interventions, it is essential to monitor endothelial function, even if the optimal methodology for investigating the multifaceted aspects of endothelial dysfunction is still under debate. Biochemical markers, as well as invasive and non-invasive tools with and without pharmacological stimuli have been studied. Human clinical studies that have examined lifestyle or cancer treatment protocols have yielded evidence showing the involvement of lipid and lipoprotein levels, glycemic control, blood pressure, adiposity, inflammation, and oxidative stress markers on the state of endothelial health and its role as an early indicator of cardiometabolic risk. However, with regards to pharmacological interventions, cautious interpretation of the result attained whilst monitoring the endothelial function is warranted due to methodological limitations and substantial heterogeneity of the results reported in the published studies. In this narrative review, an overview of evidence from human clinical trials examining the effects of cancer therapies on endothelial disease is provided together with a discussion of endothelial function assessment using the different non-invasive techniques available for researchers and clinicians, in recent years.

A 13-year-old female patient was admitted for acute psychotic symptoms after two months of non-periodic mild fever and progressive behavioral changes. Hallucinations, delirium, disinhibition, coprolalia, and defiant behavior required admission to the Psychiatric Unit. Neurological examination and EEG werenormal. An extensive lesion involving the right frontal lobe was depicted in brain MRI. Psychiatric symptoms completely resolved after surgery. Histological diagnosis was of an Oligodendroglioma grade II, IDH mutant, and 1p/19q co-deleted. Presentation of a brain tumor with isolated psychiatric symptoms is exceptional in pediatric ages. Since acute psychotic symptoms may be misdiagnosed with a purely psychiatric disorder, the possibility of an underlying cerebral lesion must be kept in mind whatever the patient's age.

Purpose Our aim was to determine the main risk factors related to the occurrence of permanent alopecia in adult survivors of childhood medulloblastoma (MB) to improve their quality of life. Methods We retrospectively analysed the clinical features of all consecutive survivors of MBtreated at our Institute. We divided the patients into 3 groups depending on the craniospinal irradiation (CSI) dose received and defined permanent alopecia first in terms of the skin region affected (whole skin and nape region) then on the basis of the toxicity degree (G). Any relationship between alopecia and other characteristics was investigated by a univariate and multivariate analysis and Odds ratio (OR) with confidence interval (CI) was reported. Results We analysed data from 41 patients with a 10-year follow-up. High dose of CSI was found to be the independent factor leading to permanent hair loss in both groups: alopecia of the whole skin (G1 p-value 0.030, G2 p-value 0.003) and of the nape region (G1 p value 0.038, G2 p value 0.006). The posterior cranial fossa (PCF) boost volume and dose were not significant at multivariate analysis neither in permanent hair loss of the whole skin nor only in the nuchal region. Conclusion In paediatric patients with MB, the development of permanent alopecia seems to depend only on the CSI dose exceeding 36 Gy. Acute damage to the hair follicle is dose dependent, but in terms of late side effects, constant and homogeneous daily irradiation of a large volume may have a stronger effect than a higher but focal dose of radiotherapy.

Paediatric diffuse high-grade gliomas (PDHGG) are rare central nervous system neoplasms lacking effective therapeutic options. Molecular imaging of tumour metabolism might identify novel diagnostic/therapeutic targets. In this study, we evaluated the distribution and the dosimetry aspects of [Paediatric patients with PDHGG were prospectively recruited. [Ten patients were enrolled (median age 9, range 6-16 years, 6 females). Diagnoses were diffuse midline gliomas (n = 8, 5 of which with H3K27 alterations) and diffuse hemispheric gliomas (n = 2). Six patients had visible tracer uptake (SUV: 1.0 ± 0.6 TBR: 5 ± 3.1). [[

Two distinct genetically defined entities of ependymoma arising in the supratentorial compartment are characterized by the presence of either a C11orf95-RELA or a YAP-MAMLD1 fusion, respectively. There is growing evidence that supratentorial ependymomas without these genetic features exist. In this study, we report on 18 pediatric non-RELA/non-YAP supratentorial ependymomas that were systematically characterized by means of their histology, immunophenotype, genetics, and epigenomics. Comprehensive molecular analyses included high-resolution copy number analysis, methylation profiling, analysis of fusion transcripts by Nanostring technology, and RNA sequencing. Based upon histological and immunohistochemical features two main patterns were identified—RELA-like (n = 9) and tanycytic ependymomas (n = 6). In the RELA-like group histologically assigned to WHO grade III and resembling RELA-fused ependymomas, tumors lacked nuclear expression of p65-RelA as a surrogate marker for a pathological activation of the NF-κB pathway. Three tumors showed alternative C11orf95 fusions to MAML2 or NCOA1. A methylation-based brain tumor classifier assigned two RELA-like tumors to the methylation class “EP, RELA-fusion”; the others demonstrated no significant similarity score. Of the tanycytic group, 5/6 tumors were assigned a WHO grade II. No gene fusions were detected. Methylation profiling did not show any association with an established methylation class. We additionally identified two astroblastoma-like tumors that both presented with chromothripsis of chromosome 22 but lacked MN1 breaks according to FISH analysis. They revealed novel fusion events involving genes in chromosome 22. One further tumor with polyploid cytogenetics was interpreted as PFB ependymoma by the brain tumor methylation classifier but had no relation to the posterior fossa. Clinical follow-up was available for 16/18 patients. Patients with tanycytic and astroblastoma-like tumors had no relapse, while 2 patients with RELA-like ependymomas died. Our data indicate that in addition to ependymomas discovered so far, at least two more supratentorial ependymoma types (RELA-like and tanycytic) exist.

Background A prospective 2002–2014 study stratified 160 patients by resection extent and histological grade, reporting results in 2016. We re-analyzed the series after a median of 119 months, adding retrospectively patients’ molecular features. Methods Follow-up of all patients was updated. DNA copy number analysis and gene-fusion detection could be completed for 94/160 patients, methylation classification for 68. Results Progression-free survival (PFS) and overall survival (OS) at 5/10 years were 66/58%, and 80/73%. Ten patients had late relapses (range 66–126 mo), surviving after relapse no longer than those relapsing earlier (0–5 y). On multivariable analysis a better PFS was associated with grade II tumor and complete surgery at diagnosis and/or at radiotherapy; female sex and complete resection showed a positive association with OS. Posterior fossa (PF) tumors scoring ≥0.80 on DNA methylation analysis were classified as PFA (n = 41) and PFB (n = 9). PFB patients had better PFS and OS. Eighteen/32 supratentorial tumors were classified as RELA, and 3 as other molecular entities (anaplastic PXA, LGG MYB, HGNET). RELA had no prognostic impact. Patients with 1q gain or cyclin-dependent kinase inhibitor 2A (CDKN2A) loss had worse outcomes, included significantly more patients >3 years old (P = 0.050) and cases of dissemination at relapse (P = 0.007). Conclusions Previously described prognostic factors were confirmed at 10-year follow-up. Late relapses occurred in 6.2% of patients. Specific molecular features may affect outcome: PFB patients had a very good prognosis; 1q gain and CDKN2A loss were associated with dissemination. To draw reliable conclusions, modern ependymoma trials need to combine diagnostics with molecular risk stratification and long-term follow-up.

Purpose This study aims at defining the frequency and severity of late effects in a series of 288 long-term survivors of childhood cancer treated from 1962 to 1982 at the Giannina Gaslini Children's Research Hospital of Genoa, Italy. Patients and methods All cases with a diagnosis of malignancy in childhood and a minimum of 2.5 years from discontinuation of treatment were considered eligible. For all cases the study included physical, endocrinological, and psychological examination. Groups of patients selected according to treatment underwent cardiac, pulmonary, orthopedic, and ophthalmologic evaluation. The sequelae observed were scored according to a grading system in which asymptomatic subclinical defects are distinguished from those that are sufficiently symptomatic to require some type of corrective measure. Results Overall, 200 of 288 cases (69.4%) presented with some kind of abnormality. Symptomatic changes were present in 92 cases (42%); in these, severe and life-threatening late toxicity was reported in 61 (21.2%) and 12 cases (4.2%), respectively. The major risk factors appeared to be irradiation, type of tumor, and whether the patient had received therapy before 1974. Conclusions In our experience, this study demonstrates that there was a true excess of morbidity caused by the disease and its treatment in long-term survivors from almost any kind of childhood cancer. It also sheds light on how to prevent, diagnose, and adequately treat these patients and proposes specific criteria for the evaluation of the severity of delayed toxicity in long-term survivors of cancer in childhood.

Little is known about risks associated with germlineTo study tumour risks, we have analysed data of a large cohort of 45 unpublished patients with a germlineOverall, 117/172 (68%)Germline

Background More than 40% of patients with intracranial ependymoma need a salvage treatment within 5 years after diagnosis, and no standard treatment is available as yet. We report the outcome after first relapse of 64 patients treated within the 2nd AIEOP protocol. Methods We considered relapse sites and treatments, that is, various combinations of complete/incomplete surgery, if followed by standard or hypofractionated radiotherapy (RT) ± chemotherapy (CT). Molecular analyses were available for 38/64 samples obtained at first diagnosis. Of the 64 cases, 55 were suitable for subsequent analyses. Results The median follow-up was 147 months after diagnosis, 84 months after first relapse, 5-year EFS/OS were 26.2%/30.8% (median EFS/OS 13/32 months) after relapse. For patients with a local relapse (LR), the 5-year cumulative incidence of second LRs was 51.6%, with a 5-year event-specific probability of being LR-free of 40.0%. Tumor site/grade, need for shunting, age above/below 3 years, molecular subgroup at diagnosis, had no influence on outcomes. Due to variation in the RT dose/fractionation used and the subgroup sizes, it was not possible to assess the impact of the different RT modalities. Multivariable analyses identified completion of surgery, the absence of symptoms at relapse, and female sex as prognostically favorable. Tumors with a 1q gain carried a higher cumulative incidence of dissemination after first relapse. Conclusions Survival after recurrence was significantly influenced by symptoms and completeness of surgery. Only a homogeneous protocol with well-posed, randomized questions could clarify the numerous issues, orient salvage treatment, and ameliorate prognosis for this group of patients.

BackgroundLittle is known about risks associated with germlineSUFUpathogenic variants (PVs) known as a cancer predisposition syndrome.MethodsTo study tumour risks, we have analysed data of a large cohort of 45 unpublished patients with a germlineSUFUPV completed with 127 previously published patients. To reduce the ascertainment bias due to index patient selection, the risk of tumours was evaluated in relatives withSUFUPV (89 patients) using the Nelson-Aalen estimator.ResultsOverall, 117/172 (68%)SUFUPV carriers developed at least one tumour: medulloblastoma (MB) (86 patients), basal cell carcinoma (BCC) (25 patients), meningioma (20 patients) and gonadal tumours (11 patients). Thirty-three of them (28%) had multiple tumours. Median age at diagnosis of MB, gonadal tumour, first BCC and first meningioma were 1.5, 14, 40 and 44 years, respectively. Follow-up data were available for 160 patients (137 remained alive and 23 died). The cumulative incidence of tumours in relatives was 14.4% (95% CI 6.8 to 21.4), 18.2% (95% CI 9.7 to 25.9) and 44.1% (95% CI 29.7 to 55.5) at the age of 5, 20 and 50 years, respectively. The cumulative risk of an MB, gonadal tumour, BCC and meningioma at age 50 years was: 13.3% (95% CI 6 to 20.1), 4.6% (95% CI 0 to 9.7), 28.5% (95% CI 13.4 to 40.9) and 5.2% (95% CI 0 to 12), respectively. Sixty-four different PVs were reported across the entireSUFUgene and inherited in 73% of cases in which inheritance could be evaluated.ConclusionGermlineSUFUPV carriers have a life-long increased risk of tumours with a spectrum dominated by MB before the age of 5, gonadal tumours during adolescence and BCC and meningioma in adulthood, justifying fine-tuned surveillance programmes.

We report two cases of malignant mesothelioma (MM) in childhood brain tumor survivors. A 40-year-old man, who was treated at the age of ten with chemotherapy and craniospinal radiotherapy (up to 54.5 Gy) for a pineal secreting non-germinomatous germ cell tumor, had persistent fever, fatigue, and weight loss. A total body CT scan revealed several pulmonary and abdominal wall nodularities. The histological examination on a biopsy diagnosed a biphasic MM. The karyotype and array-CGH of peripheral blood were normal; a FISH of tumor cells showed a breakage of locus EWSR1 (22q12.2). In this case, environmental exposure was identified (asbestos in public water tanks). His MM followed an aggressive course and resulted in death after three months. A twelve-year-old boy affected by severe neurofibromatosis type 2 (NF2) already treated with several neurosurgical exeresis and chemotherapy lines (hydroxycarbamide, bevacizumab, sirolimus), developed multiple abdominal lesions, associated with pleural effusion and weight loss. The CT scan showed the thickening of the left pleura and multiple peritoneal nodules. The cytological examination on thoracentesis diagnosed an epithelioid MM. The karyotype on paracentesis-obtained cells revealed monosomy of chromosomes 14 and 22, loss of Y, and trisomy of 6, 10, 11, 16, and 20. NGS is currently ongoing to exclude germline or somatic second hits. Importantly, no exposure to asbestos was found. Less than 2% of MMs occur below 45 years of age; it is a rare secondary tumor in cancer survivors and environmental or genetic contributing causes are often detectable on a careful investigation. Variants in NF2 are considered to be the second most common after those in BAP1. To our knowledge, this is the first child with NF2 and concurrent MM reported to date. Compared to the expected prognosis, his MM has followed a mild course, and one year after diagnosis he is still alive.

AIMS: We report a cohort of YCMB cases homogeneously treated with HDCT in two Italian institutions, and the prognostic impact of histology and genetics retrospectively evaluated. METHODS: All YCMB (aged≤3 years) treated with upfront HDCT in the period 1998-2019 were included, reclassified according to the WHO2021 classification of CNS tumours. Mutational status ofPTCH1, SUFU, and TP53 was analysed in selected cases. Histology and genetics were correlated with survival, secondary tumours(STs), and cancer predisposition syndromes(CPSs). RESULTS: Fifty-three patients were enrolled (62.3% male), median age 2.2 years. 21 had classic(CMB), 15 desmoplastic/nodular(DMB), 11 MBEN and 6 large-cell/anaplastic(AMB/LCMB) medulloblastoma. Metastases were present in 18. Genomic pattern showed SHH-TP53wt in 29 cases, non-WNT/non-SHH in 22; 2 were SHH-TP53mut. Induction chemotherapy (VCR/HDMTX, HDVP16, VCR/HDCTX and HDCARBO) was followed by 2-3 HDCT courses; irradiation reserved to cases with metastatic disease and/or residual tumours. 22 patients never received irradiation. SHH-TP53wt cases had significantly less metastasis (p=0.002), while non-WNT/non-SHH received more often irradiation (p

BACKGROUND: Permanent alopecia in adult survivors of childhood cancer is a late effect that has a negative impact on vitality and social function, and it is not clear if it is only associated with radiotherapy or also with high-dose chemotherapy. In this study, we analysed a cohort of medulloblastoma survivors treated with craniospinal irradiation (CSI) with long follow-up looking for radiotherapy parameters associated with permanent hair loss. METHODS: We retrospectively analysed 42 patients with medulloblastoma with median follow up of 10 years. In 27 pts, Eclipse subgroup, the scalp was accurately re-contoured and were estimated specifics dosimetric parameters. Any relationship between presence of alopecia and other characteristics was investigated by univariate and multivariate analysis, in both groups. For each significant predictor variable, a Receiver Operating Characteristic curve was drawn for calculating the Area Under the Curve and identifying the optimal dose discriminatory cut-off value for prediction of alopecia. RESULTS: The best predictor for the occurrence of permanent alopecia was the dose of CSI (OR: 1.002; 95%CI: 1.001-1.003; p=0.003), with a cut-off value of 30.9 Gy. In Eclipse subgroup median Dose hair skin was statistically significant, (OR: 1.216; 95%CI: 1.030-1.435; p=0.021), with a cut-off value of 28.7 Gy. If the median dose of each Gy unit of D median is exceeded, the probability of alopecia increases by 21.6% (3.0% - 43.5%), with a specificity of 90.9%. None of the other variables was statistically significant. CONCLUSIONS: Pediatric Medulloblastoma survivors have a high risk of developing permanent alopecia.Our study supports the finding that permanent hair loss is dose-dependent and identified a threshold dose, the median dose of 28.7 Gy, to prevent the occurrence of permanent alopecia in paediatric patients undergoing radiotherapy. Therefore, we suggest that this dosimetric parameter should be evaluated when planning radiation treatment, especially when planning CSI in low- and standard-risk medulloblastoma.

BRAF inhibitors (iBRAF) are under investigations in ongoing clinical trials for pediatric brain tumor treatment. Preliminary data regarding the pediatric population report pyrexia, hematological, dermatological, cardiac, and ophthalmic toxicities among the most common adverse events. Acute kidney injury (AKI), mainly due to tubular interstitial injury, has been reported in the adult population. With our study we want to contribute to a more comprehensive knowledge of the short- and long-term nephrological adverse effects of iBRAF in a pediatric population. We collected and reviewed clinical and laboratory data of all patients treated with iBRAF for pediatric central nervous system tumors at our Institution and available for publication. AKI was monitored through serial creatinine measurements, kidney function with estimated glomerular filtration rate (eGFR) and kidney injury with creatinuria/proteinuria ratio. Tubular injury was evaluated with fractional excretion of sodium, potassium and magnesium and with glycosuria. Moreover, urine was examined to detect presence and morphology of erythrocytes. Eight patients were identified, 3 females; median age at treatment start was 9 years (range 2,75 – 18,75). Six patients with BRAFV600E–mutated pediatric Low-Grade Glioma were treated with Vemurafenib, 1 patient with BRAFV600E-mutated pediatric High-Grade Glioma was treated with Vemurafenib and 1 patient with BRAFV600E-mutated Langerhans Cell Histiocytoses was treated with Dabrafenib. Seven patients were considered for analysis. After a median follow up of 3,83 years (range 2,25 – 6,58) no AKI was reported and all patients but two retained normal eGFR at last follow up. No tubular and glomerular injury laboratory findings were detected, and erythrocytes in the urine resulted always below the upper limit of normality. CONCLUSIONS: iBRAF were not associated with AKI and tubular injury. Nevertheless, some data, namely significative decrease of eGFR in two out of seven patients, warrants further investigations.

A 2,5-year-old girl presented vomiting episodes associated with severe motor delay, macrocephaly, and distal hypotonia. Brain MRI showed hydrocephalus and a non-metastatic lesion in the posterior fossa. A pre-operative ECG showed isodifasic T waves in leads V4R and V1, follow-up was recommended. Histology after gross total resection was consistent with Desmoplastic/Nodular Medulloblastoma. At chest X-rays a bifid rib was noted, leading to the diagnosis of Gorlin syndrome (GS; c.3306 + 1G>T in PTCH1). During chemotherapy, ventricular tachycardia (VT) occurred, requiring synchronized electrical cardioversion. An echocardiogram revealed an echogenic mass of the left ventricle free wall, but normal coronaries and ventricular function. Cardiac MRI (CMR) confirmed a 21x40x38mm mass, with eccentric development and intense homogeneous enhancement, indicative of cardiac fibroma (CF). A computed tomography excluded local calcifications. Therapy with amiodarone and beta-blocker was initiated. TREATMENT STRATEGY: priority to chemotherapy vs cardiac surgery; full-dose chemotherapy, preferring drugs with minor cardiotoxicity; administration in ICU under continuous vital parameters and ECG-monitoring. Other three VTs occurred during treatment or anesthesia, resolved after electrical cardioversion (unsuccessful attempts with i.v. adenosine and amiodarone). Lacking specific guidelines concerning CF in GS, a wait-and-see approach was preferred with close tumor follow-up and regular cardiological assessment (ECG, stress-test, Holter monitoring, CMR). No further arrhythmias were recorded in a 10-year-long follow-up and CMR confirmed CF stability. Medulloblastoma has never recurred. PTCH1 variants are rarely associated with medulloblastoma (

BACKGROUND: Gliomatosis cerebri (GC), a radiologically defined diffusely infiltrating glioma, is no longer considered a distinct entity since the 2016 WHO classification for tumors of the CNS. Due to its rarity and dismal prognosis treatment recommendations in children remain ambiguous. Using central neuroradiological review, we performed a multi-institutional, retrospective study of GC providing comprehensive radiological, clinical, and (epi)genetic characterization. RESULTS: We included 104 patients between 1-19 years. Within a median follow-up of 15.5 months (range, 2.3-138.8), 93 patients (89.4 %) had died, 4 (3.8 %) were lost to follow-up and 7 (6.8 %) were alive with stable/progressive disease. Median progression-free- (PFS) and overall survival (OS) were 8.6 months (interquartile range, 4.3-14.0) and 15.5 months (10.9-27.7), respectively. Former WHO grading correlated significantly with median OS: WHO °II: 47.8 months (25.2-55.7); WHO °III: 15.9 months (11.4-26.3); WHO °IV: 10.4 months (8.8-14.4) (p

IntroductionTreatment of recurrent primary pediatric brain tumors remains a major challenge, with most children succumbing to their disease. We conducted a prospective phase 2 study investigating the safety and efficacy of pomalidomide (POM) in children and young adults with recurrent and progressive primary brain tumors.MethodsPatients with recurrent and progressive high-grade glioma (HGG), diffuse intrinsic pontine glioma (DIPG), ependymoma, or medulloblastoma received POM 2.6 mg/m2/day (the recommended phase 2 dose [RP2D]) on days 1-21 of a 28-day cycle. A Simon’s Optimal 2-stage design was used to determine efficacy. Primary endpoints included objective response (OR) and long-term stable disease (LTSD) rates. Secondary endpoints included duration of response, progression-free survival (PFS), overall survival (OS), and safety.Results46 patients were evaluable for response (HGG, n = 19; DIPG, ependymoma, and medulloblastoma, n = 9 each). Two patients with HGG achieved OR or LTSD (10.5% [95% CI, 1.3%-33.1%]; 1 partial response and 1 LTSD) and 1 patient with ependymoma had LTSD (11.1% [95% CI, 0.3%-48.2%]). There were no ORs or LTSD in the DIPG or medulloblastoma cohorts. The median PFS for patients with HGG, DIPG, ependymoma, and medulloblastoma was 7.86, 11.29, 8.43, and 8.43 weeks, respectively. Median OS was 5.06, 3.78, 12.02, and 11.60 months, respectively. Neutropenia was the most common grade 3/4 adverse event.ConclusionsTreatment with POM monotherapy did not meet the primary measure of success in any cohort. Future studies are needed to evaluate if POM would show efficacy in tumors with specific molecular signatures or in combination with other anticancer agents.Clinical Trial RegistrationClinicalTrials.gov, identifier NCT03257631; EudraCT, identifier 2016-002903-25.

We investigated the association between the molecular profile and telomere length in a infant medulloblastoma (iMB) cohort, retrospectively studied. Activation of telomeres maintenance mechanisms was analyzed to determine whether the senescence escape triggered by telomere-elongation mechanisms could explain the aggressivity of some iMB belonging to the same molecular subgroup. Interestingly, several telomerase- and ALT-targeted therapies have recently been tested on pediatric cancers and might represent a promising strategy for the future treatment of aggressive telomerase- or ALT-positive iMB. We analyzed a cohort of 50 FFPE tissues from young MB patients (age ≤ 3); IHC, FISH, and an Illumina 850K methylation profile were used to identify molecular subgroups. Telomere length was measured using Telo-quantitative FISH, and image analysis was performed using TFL-Telo software. Three distinct telomere intensity categories (low (L), medium (M), and high (H)) were identified by comparing neoplastic- to endothelial-cell signals in each sample. ATRX loss and TERTp mutation/methylation were investigated using IHC and Sanger sequencing/methylation-specific PCR. SHH-MBs accounted for 59% of our cohort, while Group3/4-MBs accounted for 41%; no WNT-MBs were detected. ALT was found to be activated in 10% of iMBs and was not exclusive to any molecular subgroup, implying that it could be a potential mechanism associated with aggressive behaviour in a subset of iMBs. Promising results have been found in the telomere length distribution among the iMB molecular subgroups: SHH iMBs had a higher frequency of High (H) telomeres length (85%) than NON-SHH/NON-WNT iMBs (p=0.046), which were more frequently associated with Medium (M) telomeres length. CONCLUSIONS: ALT activation in infant MBs (10%) could be a novel target for risk-stratification and personalized therapy. It may be useful to examine ALT as a potential predictor of aggressive behaviour and as a promising novel therapeutic approach for a subset of these tumors in the diagnostic workup.

High-dose chemotherapy is a therapeutic option in selected cases of pediatric high-grade brain tumor (pHGBT). Following high-dose chemotherapy, bone marrow is reconstituted by means of CD34+ peripheral blood stem cell (PBSC) infusion. Intravenously injected PBSCs have been reported to migrate to the Central Nervous System (CNS) and to persist for weeks. We report two cases of pHGBT in which, following PBSC infusion, we observed peculiar brain MRI signal alterations suggestive of clumps of CD34+ cells. A 15-month-old female underwent surgery and chemotherapy for an infratentorial, non-disseminated, Atypical Teratoid Rhabdoid Tumor. Following the second course of high-dose chemotherapy, MRI excluded residual disease, but revealed two contrast-enhancing nodules in the supratentorial ventricular system, with no evidence of diffusion restriction, unlike the primary tumor. Cerebrospinal fluid was collected by means of lumbar puncture and centrifuged: no neoplastic cells were found, while a few cells were positive when immunostained with anti-CD34 antibody. As no disease progression was documented, the patient completed her treatment with focal radiotherapy. Three months after the end of therapy, MRI showed new enhancing nodules with restricted diffusion, in keeping with leptomeningeal spread of disease; these progressively increased in size, despite subsequent lines of treatment, while the above-mentioned ventricular nodules shrank. Similar transient alterations were detected in a 4-year-old boy who had received treatment for high-risk Medulloblastoma, including high-dose chemotherapy. CONCLUSIONS: In the setting of new enhancing brain and spine findings with atypical MRI features, after high-dose chemotherapy to treat pHGBT, the hypothesis of CNS homing of CD34+ hematopoietic stem cells should be considered in the differential diagnosis.

We report two cases of pediatric low-grade glioma (pLGG) treated with vemurafenib, an oral BRAF-inhibitor: a 12-year-old girl with involvement of basal ganglia, hypothalamus, and diencephalic junction; a 3-year-old boy, with an optic pathway/hypothalamic glioma extending along the left optic tract and basal ganglia. Both received a biopsy and molecular analysis was performed in the girl’s tumor, showing BRAF V600E mutation. Therefore, instead of surgical removal planned by neurosurgeons, first-line treatment with vemurafenib was started: after one month 45% reduction of the mass according to RANO criteria was found, as well as better balance control and strong reduction of the right arm paresis; five months later, a 70% shrinkage was detected, stabilized to 76% after a year. The young boy first started chemotherapy with vincristine and carboplatin, but at the end of the induction phase the tumor had increased and ascites, hydrocephalus, and visual impairment occurred. Molecular testing showing BRAF V600E mutation on the initial tumor biopsy was obtained; therefore, the surgical option was postponed and therapy with vemurafenib started. After only three days, visual acuity and muscle tone improved; brain MRI showed a 34% reduction of the mass after one week, increased up to 65% after six months. Therefore, no ulterior surgery was necessary. In pLGG, the neurosurgical biopsy is essential to let an early and rapid molecular diagnosis of BRAF mutations and guide subsequent targeted therapies. Our cases demonstrate how a prompt radiological response to vemurafenib and the related clinical improvement can influence both therapeutic and surgical decisions, hopefully reducing the occurrence of second neurosurgery with associated risks of neurological sequelae. To our knowledge, this is the first report assessing such a quick shrinkage in pLGG treated with vemurafenib, highlighting the importance of an early investigation of BRAF status in all cases of LGG in children.

PURPOSE: The aim of the study was to describe neurocognitive and psychological outcomes among adolescents and young adults (AYA) survivors of paediatric brain tumour (BT). METHODS: neurocognitive and psychological assessment of 45 AYA (M = 30; F = 15), treated for paediatric BT at our institution between 1978 and 2018, were retrospectively collected. Survivors received psychological and neurocognitive assessment at a mean age of 21.4 years (range 15.11-39.4) after a median of 120 months from diagnosis. The assessment was carried out using the following self-report questionnaires: Beck Depression Inventory, State-Trait Anxiety Inventory, Body Uneasiness Test, Multidimensional Fatigue Inventory, European Organization for the Research and Treatment of Cancer Quality of LifeQuestionnaire. Neurocognitive evaluation was carried out using Wechsler Adult Intelligence Scale. RESULTS: 18/45 survivors had received a diagnosis of germ cell tumor, 12 of low grades glioma, 10 of embryonal tumor, 3 of high-grade glioma, 2 of meninges and mesenchymal tumor. Thirty-four patients received neurosurgery, 34 patients chemotherapy, 44 patients cranial radiotherapy. Fatigue was reported in 56% of the patients, 15% of them also showed low level of QoL. The psychological assessment showed clinical levels of anxiety in 56% of AYA, depression in 41% and body image problems in 29%. Neurocognitive assessment showed that 73% has an average tIQ (tIQ ≥ 80). CONCLUSIONS: The psychological evaluation showed that 77% of our cohort had at least one clinically significant distress symptom as fatigue, depressive symptoms, anxiety and body image problems, compared to 23% who did not report any problem. Further analysis is needed to identify any possible psychopathological risk factors. It is essential to provide an accurate and comprehensive assessment and effective psychological support to these patients, to help them better manage the late effects of cancer and therapies at different levels: physical, psychological and neurocognitive.

PURPOSE: to describe how often behavioral and emotional changes occur at diagnosis in children with DIPG, or precede it. METHODS: the anamnesis, clinical history, psychological evaluation, and onset symptoms of all cases of DIPG diagnosed at Gaslini Institute between January 2010 and December 2020 were reviewed. RESULTS: 20 DIPGs were diagnosed, 7 males, with a median age of 7,6 years (range 2,4-16,2). All patients presented typical neurological symptoms: 16 had cranial nerves palsy, 12 ataxia, 8 dysarthria, 5 dysphagia, 5 hemiparesis, 5 headache, and 2 obstructive hydrocephalus. Behavioral disorders were found in 14 cases, with several manifestations and in various association: irritability and aggressive behavior in 6, ideomotor slowdown and apathy in 5, emotional dysregulation in 4, mood deflection in 3, sleep disturbances (i.e. nightmares, insomnia, and somniloquy) in 3, marked behavioral changes, school phobia and separation anxiety in 2, depersonalization crisis and phobia of waterdrops in the eyes in 2 patients each. In 6 cases behavioral disturbances were the presenting symptom, appearing one to twelve months earlier than the classic neurological deficits. In all patients, behavioral symptoms improved during Radiotherapy. CONCLUSIONS: behavioral disturbances, although well-known and described in the literature, are not commonly reported among the onset symptoms of DIPG, thus being probably underestimated. Their pathogenesis can be explained by neurophysiology: the brainstem contains reciprocal cerebro-ponto-cerebellar connections whose disruption compromises their modulatory function on affective and cognitive behavior. Furthermore, the reticular formation contains aggregates of neurons regulating several complex functions including the state of alertness (e.g. sleep and wakefulness), the perception of pain, and cognitive functions (e.g. attention, mood, and memory). A careful anamnestic and medical history together with a detailed psychological assessment should be always performed in all DIPGs at diagnosis, in order to bring out those underlying behavioral disorders which could benefit from early neuropsycological support.

BACKGROUND: Central hypothyroidism is a well-known late effect of radiotherapy in children treated for brain tumours. AIM: To determine the risk of central hypothyroidism (CH) and the radiation dose-volume predictors of its onset. METHODS: We retrospectively analyzed 64 patients who received radiotherapy for brain tumours, with at least a 2-year-long serological follow-up, determined CH incidence and radiation predictive factors of its onset. To estimate the risk of CH according to the site of the tumour inside the central nervous system (CNS) we considered the sellar-suprasellar region, anterior cranial region, and others. For the same purpose, a further analysis was conducted comparing craniospinal radiotherapy (CSI) versus involved-field radiotherapy (IF-RT). Dose constraints for CH were determined using the Receiver Operating Characteristic to identify the pituitary mean dose cut-off and the probability of CH over time was assessed with the Cox model. RESULTS: 18 cases were excluded due to the presence of CH before RT; 17 of remaining 46 (37%) patients presented CH during follow-up: 14 of 17 (82%) patients received CSI, 3 (18%) IF-RT sellar-suprasellar region and anterior cranial region. A median dose higher than 30.5 Gy to the pituitary gland results in a 4-fold increased risk of central hypothyroidism (HR=3.9; 95% CI 1.1, 13.4; p=0.03). Almost 90% of events occurred within 5 years after treatment ended. 29 of 46 (63%) patients did not manifest CH and were in the "other regions”. However, 14 of these (48%) underwent CSI. CONCLUSIONS: Our data confirm the relationship between central hypothyroidism and mean pituitary radiation dose, and suggest a minimum of 5 years follow up in children brain tumor survivors. Tumours outside the sellar-suprasellar region, treated with radiotherapy, are not associated with CH onset. A significant association between CSI and risk of CH, highlighted with our analysis, warrants further investigations and a longer follow up

BRAF inhibitors (iBRAF) are a therapeutical option for pediatric Low-Grade-Gliomas (pLGG), but their chronic use may be needed to prevent tumor regrowth. Growth hormone (GH) replacement in children with GH deficiency (GHD) and on oncological treatment is under debate. We report on our experience of recombinant human GH (rhGH) replacement in two children (1 Female, 1 Male) which started Vemurafenib therapy, at 5 (F) and 9,25 (M) years of age, for recurrent/progressive chiasmatic-hypothalamic pLGG, with partial response (RANO criteria) and subsequent stable disease. A diagnosis of GHD was established at 9,2 (F) and 11,2 (M) years of age (GH peaks to stimulation tests

Neurofibromatosis type 1 (NF1) is a proteiform genetic condition caused by pathogenic variants in NF1 and characterized by a heterogeneous phenotypic presentation. Relevant genotype–phenotype correlations have recently emerged, but only few pertinent studies are available. We retrospectively reviewed clinical, instrumental, and genetic data from a cohort of 583 individuals meeting at least 1 diagnostic National Institutes of Health (NIH) criterion for NF1. Of these, 365 subjects fulfilled ≥2 NIH criteria, including 235 pediatric patients. Genetic testing was performed through cDNA-based sequencing, Next Generation Sequencing (NGS), and Multiplex Ligation-dependent Probe Amplification (MLPA). Uni- and multivariate statistical analysis was used to investigate genotype–phenotype correlations. Among patients fulfilling ≥ 2 NIH criteria, causative single nucleotide variants (SNVs) and copy number variations (CNVs) were detected in 267/365 (73.2%) and 20/365 (5.5%) cases. Missense variants negatively correlated with neurofibromas (p = 0.005). Skeletal abnormalities were associated with whole gene deletions (p = 0.05) and frameshift variants (p = 0.006). The c.3721C&gt, T, p.(R1241*) variant positively correlated with structural brain alterations (p = 0.031), whereas Lisch nodules (p = 0.05) and endocrinological disorders (p = 0.043) were associated with the c.6855C&gt, A, p.(Y2285*) variant. We identified novel NF1 genotype–phenotype correlations and provided an overview of known associations, supporting their potential relevance in the implementation of patient management.

Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. We identify alterations within the cAMP dependent pathway (GNAS, PRKAR1A) which converge on GLI2 activity and show that 18% of tumors have a genetic event that directly targets the abundance and/or stability of MYCN. Furthermore, we discover an extensive network of fusions in focally amplified regions encompassing GLI2, and several loss-of-function fusions in tumor suppressor genes PTCH1, SUFU and NCOR1. Molecular convergence on a subset of genes by nucleotide variants, copy number aberrations, and gene fusions highlight the key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma and open up opportunities for therapeutic intervention., Sonic Hedgehog medulloblastoma (Shh-MB) comprises four subtypes each with distinct clinical traits. Here the authors characterize the genome, transcriptome, and methylome of Shh-MB subtypes, revealing a complex fusion landscape and the molecular convergence of MYCN and cAMP signaling pathways.

This chapter presents an overview of late complications of therapy for childhood cancer with a focus on organ systems at risk. First comes an introductory overview of previous and current studies on late complications of treatment for childhood cancer, followed by data on epidemiology. Serious late complications such as late mortality (i.e. premature death), second malignant neoplasms, and cardiac disease, as well as neurological and neuropsychological toxicities, are described in more detail. Endocrine problems (both gonadal and non-gonadal) are presented, including information on the metabolic syndrome. Toxicities of other organ systems follow (i.e. lung, kidney, vision, hearing, face and teeth, gut and liver, skin, skeleton, and the immune system), as does specific information on survivors of haematopoietic stem-cell transplantation (HSCT) and central nervous system (CNS) tumours, as well as surgical complications. Finally, the chapter presents information on psychosocial outcomes regarding long-term follow-up care, with an outlook to the future and recommendations for further reading.

To evaluate the contribution of 18F-dihydroxyphenylalanine (DOPA) PET in association with conventional MRI in predicting treatment response and survival outcome of pediatric patients with diffuse intrinsic pontine gliomas (DIPGs). Methods: We retrospectively analyzed 19 children with newly diagnosed DIPGs who underwent 18F-DOPA PET/CT and conventional MRI within one week of each other at admission and subsequent MRI follow-up. Following co-registration and fusion of PET and MRI, 18F-DOPA uptake avidity and extent (PET tumor volume and uniformity) at admission, along with MRI indices including presence of ring contrast-enhancement, tumor volume at admission and at maximum response following first-line treatment, were evaluated and correlated with overall survival (OS). The association between 18F-DOPA uptake tumor volume at admission and MRI tumor volume following treatment was evaluated. Statistics included Wilcoxon signed-rank and Mann-Whitney U tests, Kaplan-Meier OS curve and Cox analysis. Results: DIPGs with a 18F-DOPA uptake Tumor/Striatum (T/S) ratio >1 presented an OS ≤ 12 months and lower degree of tumor volume reduction following treatment (p = 0.001). On multivariate analysis, T/S (p = 0.001), ring enhancement (p = 0.01) and the degree of MRI tumor volume reduction (p = 0.01) independently correlated with OS. In all patients, areas of increased 18F-DOPA uptake overlapped with regions demonstrating more prominent residual components/lack of response following treatment. Conclusions: 18F-DOPA PET provides useful information for evaluating the metabolism of DIPGs. T/S ratio is an independent predictor of outcome. 18F-DOPA uptake extent delineates tumoral regions with a more aggressive biological behaviour, less sensitive to first line treatment.

Brain tumors are the most common solid tumors in childhood. There is the need for biomarkers of residual disease, therapy response and recurrence. Cerebrospinal fluid (CSF) is a source of brain tumor biomarkers. We analyzed the proteome of waste CSF from extraventricular drainage (EVD) from 29 children bearing different brain tumors and 17 controls needing EVD insertion for unrelated causes. 1598 and 1526 proteins were identified by liquid chromatography-coupled tandem mass spectrometry proteomics in CSF control and brain tumor patients, respectively, 263 and 191 proteins being exclusive of either condition. Bioinformatic analysis revealed promising protein biomarkers for the discrimination between control and tumor (TATA-binding protein-associated factor 15 and S100 protein B). Moreover, Thymosin beta-4 (TMSB4X) and CD109, and 14.3.3 and HSP90 alpha could discriminate among other brain tumors and low-grade gliomas plus glyoneuronal tumors/pilocytic astrocytoma, or embryonal tumors/medulloblastoma. Biomarkers were validated by ELISA assay. Our method was able to distinguish among brain tumor vs non-tumor/hemorrhagic conditions (controls) and to differentiate two large classes of brain tumors. Further prospective studies may assess whether the biomarkers proposed by our discovery approach can be identified in other bodily fluids, therefore less invasively, and are useful to guide therapy and predict recurrences.

PURPOSE Children with pediatric gliomas harboring a BRAF V600E mutation have poor outcomes with current chemoradiotherapy strategies. Our aim was to study the role of targeted BRAF inhibition in these tumors. PATIENTS AND METHODS We collected clinical, imaging, molecular, and outcome information from patients with BRAF V600E–mutated glioma treated with BRAF inhibition across 29 centers from multiple countries. RESULTS Sixty-seven patients were treated with BRAF inhibition (pediatric low-grade gliomas [PLGGs], n = 56; pediatric high-grade gliomas [PHGGs], n = 11) for up to 5.6 years. Objective responses were observed in 80% of PLGGs, compared with 28% observed with conventional chemotherapy ( P < .001). These responses were rapid (median, 4 months) and sustained in 86% of tumors up to 5 years while receiving therapy. After discontinuation of BRAF inhibition, 76.5% (13 of 17) of patients with PLGG experienced rapid progression (median, 2.3 months). However, upon rechallenge with BRAF inhibition, 90% achieved an objective response. Poor prognostic factors in conventional therapies, such as concomitant homozygous deletion of CDKN2A, were not associated with lack of response to BRAF inhibition. In contrast, only 36% of those with PHGG responded to BRAF inhibition, with all but one tumor progressing within 18 months. In PLGG, responses translated to 3-year progression-free survival of 49.6% (95% CI, 35.3% to 69.5%) versus 29.8% (95% CI, 20% to 44.4%) for BRAF inhibition versus chemotherapy, respectively ( P = .02). CONCLUSION Use of BRAF inhibition results in robust and durable responses in BRAF V600E–mutated PLGG. Prospective studies are required to determine long-term survival and functional outcomes with BRAF inhibitor therapy in childhood gliomas.

To evaluate the contribution of 18F-dihydroxyphenylalanine (DOPA) PET in association with conventional MRI in predicting treatment response and survival outcome of pediatric patients with diffuse intrinsic pontine gliomas (DIPGs). Methods: We retrospectively analyzed 19 children with newly diagnosed DIPGs who underwent 18F-DOPA PET/CT and conventional MRI within one week of each other at admission and subsequent MRI follow-up. Following co-registration and fusion of PET and MRI, 18F-DOPA uptake avidity and extent (PET tumor volume and uniformity) at admission, along with MRI indices including presence of ring contrast-enhancement, tumor volume at admission and at maximum response following first-line treatment, were evaluated and correlated with overall survival (OS). The association between 18F-DOPA uptake tumor volume at admission and MRI tumor volume following treatment was evaluated. Statistics included Wilcoxon signed-rank and Mann-Whitney U tests, Kaplan-Meier OS curve and Cox analysis. Results: DIPGs with a 18F-DOPA uptake Tumor/Striatum (T/S) ratio >1 presented an OS ≤ 12 months and lower degree of tumor volume reduction following treatment (p = 0.001). On multivariate analysis, T/S (p = 0.001), ring enhancement (p = 0.01) and the degree of MRI tumor volume reduction (p = 0.01) independently correlated with OS. In all patients, areas of increased 18F-DOPA uptake overlapped with regions demonstrating more prominent residual components/lack of response following treatment. Conclusions: 18F-DOPA PET provides useful information for evaluating the metabolism of DIPGs. T/S ratio is an independent predictor of outcome. 18F-DOPA uptake extent delineates tumoral regions with a more aggressive biological behaviour, less sensitive to first line treatment.

BACKGROUND This 2002–2014 Italian prospective study stratified 160 patients by surgical resection (complete=NED/incomplete=ED) and centrally-reviewed grade. Grade2/NED patients received focal radiotherapy (RT) up to 59.4Gy, Grade3/NED received 4 courses of VEC(vincristine,etoposide,cyclophosphamide) after RT.ED patients received 1–4 VEC courses, second-look surgery, 59.4 Gy+8Gy boost on measurable residue. METHODS We re-analyzed data at 115 months follow-up including methylation profile on available samples. RESULTS Global PFS/OS at 5/10 years were 66/59% and 80/74%, respectively. Of the 64 relapsers at median 20 months, 53 died at median 37/18 months after diagnosis/relapse, respectively.10/64 relapsed after 5 years (66–126 months); 4 died, relapse was local in 8/10, metastatic 1, combined 1;5/10 patients were below age 3, 5 females, 8 PF tumors. Their survival post-relapse was not longer than earlier relapsers’. At univariable analysis, age over 3 years, female sex, complete surgery, grade 2, no shunt confirmed better PFS/OS. 66/95 analyzed tumors received a score >0.80 through the DNA methylation-based central nervous system tumor classifier: 41/8 as PFA/PFB, respectively,14/17 ST as RELA-positive (3 scored for other molecular entities i.e. anaplastic PXA, LGG MYB, HGNET). Prognostic factors were equally distributed among PFA/PFB groups,1 only group B patient relapsed locally at 96 months. CONCLUSIONS Already published prognostic factors remained at long-term follow-up;6.2% patients had late relapses. OS after relapse was not better in late relapsers. Group B confirmed better prognosis but all patients had received «at least» adjuvant RT. Modern ependymoma trials need long follow-up to draw firm conclusions.

PURPOSE: The aim of this study was to compare arterial spin labeling (ASL) and dynamic susceptibility contrast (DSC) MRI perfusion with respect to diagnostic performance in tumor grading in pediatric patients with low- and high-grade astrocytic tumors (AT). METHODS: We retrospectively analyzed 37 children with histologically proven treatment naive low- and high-grade AT who underwent concomitant pre-operative ASL and DSC MRI perfusion. Studies were performed on a 1.5 T scanner, and a pulsed technique was used for ASL. DSC data were post-processed with a leakage correction software. Normalization of tumor perfusion parameters was performed with contralateral normal appearing gray matter. Normalized cerebral blood volume (nCBV) values in the most perfused area of each neoplasm were compared with normalized DSC-derived cerebral blood flow (nDSC-CBF) and ASL-derived cerebral blood flow (nASL-CBF) data, and correlated with WHO tumor grade. Statistics included Pearson's chi-square and Mann-Whitney U tests, Spearman's rank correlation, and receiver operating characteristic (ROC) analysis. RESULTS: A significant correlation was demonstrated between DSC and ASL data (p

Purpose To evaluate neuroendocrine late effects in paediatric patients with low grade glioma (LGG) who underwent radiotherapy. Methods and material We performed a retrospective evaluation of 40 children with LGG treated from July 2002 to January 2015 with external radiotherapy. Tumour locations were cerebral hemisphere ( n = 2); posterior fossa ( n = 15); hypothalamic–pituitary axis (HPA, n = 15); spine ( n = 5). Three patients presented a diffuse disease. We looked for a correlation between endocrine toxicity and tumour and treatment parameters. The impact of some clinical and demographic factors on endocrinal and neuro toxicity was evaluated using the log-rank test. Results The median follow-up was 52 months (range: 2–151). Median age at irradiation was 6. The dose to the HPA was significantly associated with endocrine toxicity ( P value = 0.0190). Patients who received chemotherapy before radiotherapy and younger patients, showed worse performance status and lower IQ. The 5-year overall survival (OS) and progression free survival (PFS) rates were 94% and 73.7%, respectively. Conclusion Radiotherapy showed excellent OS and PFS rates and acceptable late neuroendocrine toxicity profile in this population of LGG patients treated over a period of 13 years. In our experience, the dose to the HPA was predictive of the risk of late endocrine toxicity.

Analysis of CNS MMGCT with AFP >1000 ng/ml (serum and/or CSF) at diagnosis, treated on trial in SIOP-CNS-GCT-96, revealed an inferior prognosis (32% 5-year progression-free survival) compared with AFP 1000 ng/ml at diagnosis. 41 patients were evaluable with a median observation time of 2.4 years; 6/41 received chemotherapy alone. Primary site, histological components (if available), metastatic status and outcome were evaluated. Primary site was pineal in 29/41, suprasellar in 6/41, bifocal 1/41 and other in 5/41 patients. 10/41 patients were metastatic at diagnosis. Four to five courses of standard PEI and radiotherapy (RT) or 2 standard and two intensified PEI (as for SIOP CNS GCT II) were administered in 32 patients. Two received less then 4x PEI and RT, 6 patients

// Giovanni Morana 1, * , Cesar Augusto Alves 1, 2, * , Domenico Tortora 1 , Mariasavina Severino 1 , Paolo Nozza 3 , Armando Cama 4 , Marcello Ravegnani 4 , Gabriella D’Apolito 5 , Alessandro Raso 4 , Claudia Milanaccio 6 , Claudia da Costa Leite 2 , Maria Luisa Garre 6 and Andrea Rossi 1 1 Neuroradiology Unit, Istituto Giannina Gaslini, Genova, Italy 2 Radiology Institute, Hospital das Clinicas, Sao Paulo, Brazil 3 Pathology Unit, Istituto Giannina Gaslini, Genova, Italy 4 Neurosurgery Unit, Istituto Giannina Gaslini, Genova, Italy 5 Neuroradiology Unit, Ospedale M. Bufalini, Cesena, Italy 6 Neuro-Oncology Unit, Istituto Giannina Gaslini, Genova, Italy * co-first authorship Correspondence to: Giovanni Morana, email: giovannimorana@gaslini.org Keywords: DWI, CNS embryonal tumors, medulloblastoma, ATRT, relapse Received: February 17, 2017 Accepted: June 16, 2017 Published: July 25, 2017 ABSTRACT Diffusion weighted imaging (DWI) has an established role in primary CNS embryonal tumor (ET) characterization; however, its diagnostic utility in detecting relapse has never been determined. We aimed to compare DWI and conventional MRI sensitivity in CNS ET recurrence detection, and to evaluate the DWI properties of contrast-enhancing radiation induced lesions (RIL). Fifty-six patients with CNS ET (25 with disease relapse, 6 with RIL and 25 with neither disease relapse nor RIL) were retrospectively evaluated with DWI, conventional MRI (including both T2/FLAIR and post-contrast images), or contrast-enhanced MR imaging (CE-MRI) alone. MRI studies were independently reviewed by two neuroradiologists for detection and localization of potential brain relapses. Sensitivity for focal relapse detection was calculated for each image set on a lesion-by-lesion basis. A descriptive per subject analysis was also performed. Evaluation of follow-up MRI studies served as standard of reference. Focal recurrence detection sensitivity of DWI (96%) was significantly higher than conventional MRI (77%) and CE-MRI alone (51%) (p=0.0003 and p

Background Following promising results to increase survival and reduce treatment burden in intracranial non-germinomatous germ cell tumors (NGGCTs), we conducted a European study using dose-intense chemotherapy followed by risk-adapted radiotherapy. Methods All patients received 4 courses of cisplatin/etoposide/ifosfamide. Non-metastatic patients then received focal radiotherapy only (54 Gy); metastatic patients received 30 Gy craniospinal radiotherapy with 24 Gy boost to primary tumor and macroscopic metastatic sites. Results Patients with localized malignant NGGCT (n = 116) demonstrated 5-year progression-free survival (PFS) and overall survival (OS) of 0.72 ± 0.04 and 0.82 ± 0.04, respectively. Primary tumor sites were: 67 pineal, 35 suprasellar, 5 bifocal, 9 others. One patient died postsurgery in clinical remission; 3 patients progressed during treatment and 27 (23%) relapsed afterward. Fourteen were local, 6 combined, and 7 distant relapses (outside radiation field). Seventeen of the 27 relapsed patients died of disease. Patients with metastatic disease (n = 33) demonstrated 5-year PFS and OS of 0.68 ± 0.09 and 0.75 ± 0.08, respectively; 1 patient died following progression on treatment and 9 (27%) relapsed afterward (5 local, 1 combined, 3 distant). Only one metastatic patient with recurrence was salvaged. Multivariate analysis identified diagnostic alpha-fetoprotein level (serum and/or cerebrospinal fluid level >1000 ng/mL, 19/149 patients, of whom 11 relapsed; P < 0.0003) and residual disease following treatment, including after second-look surgery (n = 52/145 evaluable patients, 26 relapsed; P = 0.0002) as significant prognostic indicators in this cohort. Conclusion In localized malignant NGGCT, craniospinal radiotherapy could be avoided without increased relapses outside the radiotherapy field. Chemotherapy and craniospinal radiotherapy remain the gold standard for metastatic disease.