A Hematogenous Route for Medulloblastoma Leptomeningeal Metastases.

While the preponderance of morbidity and mortality in medulloblastoma patients are due to metastatic disease, most research focuses on the primary tumor due to a dearth of metastatic tissue samples and model systems. Medulloblastoma metastases are found almost exclusively on the leptomeningeal surface of the brain and spinal cord; dissemination is therefore thought to occur through shedding of primary tumor cells into the cerebrospinal fluid followed by distal re-implantation on the leptomeninges. We present evidence for medulloblastoma circulating tumor cells (CTCs) in therapy-naive patients and demonstrate in vivo, through flank xenografting and parabiosis, that medulloblastoma CTCs can spread through the blood to the leptomeningeal space to form leptomeningeal metastases. Medulloblastoma leptomeningeal metastases express high levels of the chemokine CCL2, and expression of CCL2 in medulloblastoma in vivo is sufficient to drive leptomeningeal dissemination. Hematogenous dissemination of medulloblastoma offers a new opportunity to diagnose and treat lethal disseminated medulloblastoma.

Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma.

In cancer, recurrent somatic single-nucleotide variants-which are rare in most paediatric cancers-are confined largely to protein-coding genes1-3. Here we report highly recurrent hotspot mutations (r.3A>G) of U1 spliceosomal small nuclear RNAs (snRNAs) in about 50% of Sonic hedgehog (SHH) medulloblastomas. These mutations were not present across other subgroups of medulloblastoma, and we identified these hotspot mutations in U1 snRNA in only <0.1% of 2,442 cancers, across 36 other tumour types. The mutations occur in 97% of adults (subtype SHHδ) and 25% of adolescents (subtype SHHα) with SHH medulloblastoma, but are largely absent from SHH medulloblastoma in infants. The U1 snRNA mutations occur in the 5' splice-site binding region, and snRNA-mutant tumours have significantly disrupted RNA splicing and an excess of 5' cryptic splicing events. Alternative splicing mediated by mutant U1 snRNA inactivates tumour-suppressor genes (PTCH1) and activates oncogenes (GLI2 and CCND2), and represents a target for therapy. These U1 snRNA mutations provide an example of highly recurrent and tissue-specific mutations of a non-protein-coding gene in cancer.

Being diagnosed with a rhabdomyosarcoma in the era of artificial intelligence: Whom can we trust?

In the era of big data, young patients may be overwhelmed by artificial intelligence-based tools, like chatbots. Five clinical experts were asked to evaluate the performance of the most currently used chatbots in providing information on a rare cancer affecting young people, like rhabdomyosarcoma. Generally speaking, despite their high performance in giving general information about the disease, these chatbots were considered by the experts to be inadequate in providing suggestions on cancer treatments and specialized centers, and also lacking in "sensitivity." Efforts are planned by the pediatric oncology community to improve the quality of data used to train these tools.

Local treatment in initially unresected non-rhabdomyosarcoma soft-tissue sarcomas of children and adolescents: A retrospective single-center experience.

BACKGROUND: Pediatric non-rhabdomyosarcoma soft-tissue sarcomas (NRSTS) are a heterogeneous group of aggressive tumors. Patients with locally advanced/initially unresected disease represent a subset of patients with unsatisfactory outcome: limited data are available on the best treatment approach, in particular regarding local therapy. METHODS: This retrospective analysis concerned 71 patients < 21 years old with nonmetastatic, initially unresected adult-type NRSTS, treated at a referral center for pediatric sarcomas from 1990 to 2021. Patients were treated using a multimodal approach, based on the protocols adopted at the time of their diagnosis. RESULTS: The series included a selected group of patients with unfavorable clinical characteristics, i.e., most cases had high-grade and large tumors, arising from axial sites in 61% of cases. All patients received neoadjuvant chemotherapy, 58 (82%) had delayed surgery (R0 in 45 cases), and 50 (70%) had radiotherapy. Partial response to chemotherapy was observed in 46% of cases. With a median follow-up of 152 months (range, 18-233), 5-year event-free survival (EFS) and overall survival (OS) were 39.9% and 56.5%, respectively. Survival was significantly better for patients who responded to chemotherapy, and those who had a delayed R0 resection. Local relapse at 5 years was 7.7% for patients who did not undergo delayed surgery. CONCLUSIONS: Our series underscores the unsatisfactory outcome of initially unresected NRSTS patients. Improving the outcome of this patient category requires therapeutic strategies able to combine novel effective systemic therapies with a better-defined local treatment approach to offer patients the best chances to have R0 surgery.

Caring for children with cancer evacuated from Ukraine: The patients' perception.

BACKGROUND AND AIMS: Since the beginning of the war in Ukraine on February 24, 2022, many pediatric oncology centers welcomed evacuated patients. To better understanding the needs of patients and families arriving at two Lombardy hospitals in the period March to November 2022, an anonymous questionnaire investigated the families' backgrounds, feelings, and impressions about hospitality and care. METHODS: Twenty questions investigated how patients had reached Italy, from whom they had received help (logistically/financially); the emotions regarding their status as war refugees; the knowledge, expectations, and opinions about Italy and Italians; the quality of medical care received and the relationships with the healthcare staff; lastly, suggestions to improve assistance. RESULTS: The questionnaires were completed by 19/32 patients/parents in November 2022 in two different pediatric-oncology centers. Most families had reached Italy (58%) and received medical care (95%) with the help of charities and the Italian Public Health Care System. A significant majority (69%) expressed satisfaction with the assistance provided. The Italian population demonstrated remarkable warmth, for 95% exhibiting friendliness and for 58% generosity. An improvement in their stay could be linked with the positive outcome of their children's cancer (15%), achieving complete family reunification (15%), the cessation of the conflict (10%), and the overcoming of language barriers (10%). CONCLUSIONS: Providing care for children from another country, not only grappling with the trauma of fleeing their homeland but also battling cancer, is an immense undertaking. It demands a diverse range of efforts and resources to ensure a positive and fulfilling outcome for this experience.

Foreign patients and multicultural challenges in pediatric oncology: The experience of the Istituto Nazionale dei Tumori in Milan.

This paper describes the complexity of the clinical management of foreign minors suffering from cancer, through the clinical experience of an Italian referral center. The study includes 50 patients less than 18 years (22% of the patients admitted to the unit in 2023), 32 foreigners who were Italian resident and 18 who had come to Italy specifically to receive cancer treatment. Patients who migrate for healthcare reasons often arrive at the referral center with advanced disease or relapse. Numerous socio-cultural issues were reported. To address them, specific strategies were implemented to ensure equal and high-quality care for all patients, respecting their needs.

Exoscopic microneurosurgery in pediatric brain tumors: an ideal tool for complex and peculiar anatomo-topographic scenarios?

PURPOSE: Since its introduction in the 1950s, the microsurgical paradigm has revolutionized neurosurgery. New technologies have been introduced over the years trying to overcome limits of the classical operating microscope. The recently developed 3D exoscopes represent a potential new paradigm for micro-neurosurgery. We analyzed our own experience with a 4 K-3D exoscope in a series of pediatric brain tumors to verify its advantages and limitations in comparison to the operating microscope and in light of the literature. METHODS: Twenty-five pediatric patients with brain tumors underwent surgery at our Institute; the population has been analyzed and described. A score to evaluate the exoscopes and compare it to the operating microscope was considered and postoperatively applied to each single case. RESULTS: The exoscope appears to be at least comparable to the operating microscope (OM) in all analyzed aspects. In the case of deep-seated or fourth ventricle tumors, the exoscope seems to be superior to the microscope. A surgeon-dependent learning curve is necessary for neurosurgeons to be confident with the exoscope. CONCLUSION: Exoscopes appear to be as safe and effective as operating microscopes in pediatric neuro-oncological surgery. They have some advantages that make them superior to microscopes, particularly regarding surgeon ergonomics and fatigue, visual field qualities, and higher choice of intraoperative viewing angles.

Antonio Grossich, the doctor and the irredentist.

The routine use of iodine tincture in medicine represents a turning point in the history of surgical procedures. It was the Istrian doctor Antonio Grossich (1849-1926) who first defined and applied the best formula and demonstrated to the world its superiority over other antiseptics. Although his was a life guided by medicine and the steadfast translation of his political ideals into practice, Grossich's achievements were somewhat obscured by his active involvement in the Istrian irredentism of the first decades of the wentieth century.

Optimizing reirradiation for relapsed medulloblastoma: identifying the ideal patient and tumor profiles.

BACKGROUND: First-line therapies for medulloblastoma(MBL) are obtaining higher survival-rates while decreasing late-effects, but treatment at relapse is not standardized. We report here the experience with MBL re-irradiation(re-RT), its timing and outcome in different clinical settings and tumor groups. METHODS: Patient's staging/treatment at diagnosis, histotypes/molecular subgroups, relapse site/s, re-treatments outcome are reported. RESULTS: 25 patients were included, with a median age of 11.4 years; 8 had metastases. According to 2016-2021 WHO-classification, 14 had SHH subgroup tumors(six TP53 mutated,one + MYC,one + NMYC amplification), 11 non-WNT/non-SHH (two with MYC/MYCN amplification).Thirteen had received HART-CSI, 11 standard-CSI, one HFRT; all post-radiation chemotherapy(CT), 16 also pre-RT. Median time to relapse (local-LR in nine, distant-DR in 14, LR + DR in two) was 26 months. Fourteen patients were re-operated, in five cases excising single DR-sites, thereafter three received CT, two after re-RT; out of 11 patients not re-operated, four had re-RT as first treatment and seven after CT. Re-RT was administered at median 32 months after first RT: focally in 20 cases, craniospinal-CSI in five. Median post-relapse-PFS/after re-RT was 16.7/8.2 months, while overall survival-OS was 35.1/23.9 months, respectively. Metastatic status both at diagnosis/relapse negatively affected outcome and re-surgery was prognostically favorable. PD after re-RT was however significantly more frequent in SHH (with a suggestive association with TP53 mutation, p = 0.050). We did not observe any influence of biological subgroups on PFS from recurrence while SHH showed apparently worse OS compared to non-WNT/non-SHH group. CONCLUSIONS: Re-surgery + reRT can prolong survival; a substantial fraction of patients with worse outcome belongs to the SHH-subgroup.

A pilot exome sequencing study suggests that germline variants influence methotrexate-induced toxicities in pediatric patients with localized osteosarcoma.

INTRODUCTION: Osteosarcoma (OS) is a rare pediatric cancer for which therapeutic approaches, including chemotherapy and surgery, show a wide interindividual variability in patient response, both in terms of adverse events and therapy efficacy. There is growing evidence that this individual variable response to therapies is also influenced by inherited genetic variations. However, the results obtained to date in these pediatric cancers have been contradictory and often lack validation in independent series. Additionally, these studies frequently focused only on a limited number of polymorphisms in candidate genes. METHODS: In order to identify germline coding variations associated with individual differences in adverse events occurrence in pediatric patients affected by localized OS, we carried out an exome-wide association study in 24 OS patients treated with methotrexate, cisplatin, and doxorubicin, using the SNP-Set (Sequence) Kernel Association Test (SKAT), optimized for small sample size. RESULTS: Gene sets significantly associated (FDR < .05) with neutropenia and hepatotoxicity induced by methotrexate were identified. Some of the identified genes map in loci previously associated with similar phenotypes (e.g., leukocyte count, alkaline phosphatase levels). CONCLUSION: Further studies in larger series and with functional characterization of the identified associations are needed; nonetheless, this pilot study prompts the relevance of broadly investigating variants along the whole genome, to identify new potential pharmacogenes, beyond drug metabolism, transport, and receptor candidate genes.

Relapse after non-metastatic rhabdomyosarcoma: The impact of routine surveillance imaging on early detection and post-relapse survival.

BACKGROUND: Patients with rhabdomyosarcoma (RMS) whose disease relapses have little chance of being cured, so front-line treatments are usually followed up with surveillance imaging in an effort to detect any recurrences as early as possible, and thereby improve post-relapse outcomes. The real benefit of such routine surveillance imaging in RMS remains to be demonstrated, however. This retrospective, single-center study examines how well surveillance imaging identifies recurrent tumors and its impact on post-relapse survival. METHODS: The analysis concerned 79 patients <21 years old treated between 1985 and 2020 whose initially localized RMS relapsed. Clinical findings, treatment modalities, and survival were analyzed, comparing patients whose relapse was first suspected from symptoms they developed (clinical symptoms group) with those whose relapse was identified by radiological surveillance (routine imaging group). RESULTS: Tumor relapses came to light because of clinical symptoms in 42 cases, and on routine imaging in 37. The time to relapse was much the same in the two groups. The median overall survival (OS) and 5-year OS rate were, respectively, 10 months and 12.6% in the clinical symptoms group, and 11 months and 27.5% in the routine imaging group (p-value .327). Among patients with favorable prognostic scores, survival was better for those in the routine imaging group (5-year OS 75.0% vs. 33.0%, p-value .047). CONCLUSION: It remains doubtful whether surveillance imaging has any real impact on RMS relapse detection and patients' post-relapse survival. Further studies are needed to establish the most appropriate follow-up recommendations, taking the potentially negative effects of regular radiological exams into account.

Relapse after nonmetastatic rhabdomyosarcoma: Salvage rates and prognostic variables.

BACKGROUND: Patients with relapsing rhabdomyosarcoma (RMS) pose a therapeutic challenge, and the survival rate is reportedly poor. We describe a retrospective series of relapsing RMS patients treated at a referral center for pediatric sarcoma, investigating the pattern of relapse, salvage rates, and factors correlating with final outcomes. METHODS: The analysis concerned 105 patients <21 years old treated from 1985 to 2020 with initially localized RMS at first relapse. For risk-adapted stratification purposes, patient outcomes were examined using univariable and multivariable analyses based on patients' clinical features at first diagnosis, first-line treatments, clinical findings at first relapse, and second-line treatments. RESULTS: First relapses occurred 0.08-4.8 years (median 1 year) following initial diagnosis and were local/locoregional in 59% of cases. Treatment at first relapse included chemotherapy in all but two cases, radiotherapy in 38, and surgery in 21. Median event-free survival (EFS) after first relapse was 4 months, while 5-year EFS was 16.3%; median overall survival (OS) was 9 months, while 5-year OS was 16.7%. Several variables influenced survival rates. Considering only clinical findings and treatment at relapse, Cox's multivariable analysis showed that OS correlated significantly with time to relapse, radiotherapy administered at relapse, response to chemotherapy, and whether a second remission was achieved. CONCLUSION: Survival following first relapse of patients with localized RMS at initial diagnosis is poor. The variables found to influence survival can be utilized in a risk-adapted model to estimate the chances of salvage to guide decisions for second-line treatments.

Secondary osteosarcoma: a challenge indeed.

BACKGROUND: The risk of survivors developing a secondary bone sarcoma after being treated for pediatric cancers is well established. The aim of this study was to examine the clinical characteristics and outcomes of patients with secondary osteosarcoma (SOS). METHODS: The study concerns survivors of childhood and adolescence primary neoplasms (PN) treated with chemotherapy, with or without radiotherapy and surgery, subsequently diagnosed with SOS. RESULTS: We identified 26 patients (13 females, 13 males) who developed SOS a median 7.3 years after being diagnosed with a PN (5/7 of these patients tested for Li-Fraumeni and found positive for the syndrome). The sample's median age was 8.0 and 15.0 years when their PN and SOS were diagnosed, respectively. To treat their PN, 24 out of 26 patients had been given radiotherapy, and 19 had received chemotherapy including doxorubicin. A considerable number of SOS occurred at unfavorable sites (nine hip bone, six skull). All but one patient received chemotherapy with tailored schedules, omitting doxorubicin in 19 cases. Eighteen of the 26 patients underwent surgery. The 5- and 10-year overall survival and probabilities after the diagnosis of SOS (95% confidence interval) were 50% (32.7-76.5%) and 38.9% (22.4-67.4%); 5- and 10-year progression-free survival was 47% (29.9-73.7%) and 35.2% (19.3-64.4%), respectively. CONCLUSIONS: The survival rates after SOS are lower than in patients with primary osteosarcoma, but not negligible. It is therefore mandatory to discuss the best choice of treatment for such patients at a referral center, in terms of their chances of cure and quality of life.

Science and pseudo science: racist eugenics in Italy.

In the present article we briefly discuss the historical premises of eugenics. Differences and some analogies between the Latin and the German way of eugenics in the 20th century are presented, until the tragic antisemitic turn. The fate of some children in the South Tyrol border region is also discussed, as well as the role of several anatomo-pathologists as willing executors of autopsies on the victims of the eugenic project of eliminating mentally and physically disabled people.

Response assessment in paediatric intracranial ependymoma: recommendations from the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group.

Response criteria for paediatric intracranial ependymoma vary historically and across different international cooperative groups. The Response Assessment in the Pediatric Neuro-Oncology (RAPNO) working group, consisting of an international panel of paediatric and adult neuro-oncologists, neuro-radiologists, radiation oncologists, and neurosurgeons, was established to address both the issues and the unique challenges in assessing the response in children with CNS tumours. We established a subcommittee to develop response assessment criteria for paediatric ependymoma. Current practice and literature were reviewed to identify major challenges in assessing the response of paediatric ependymoma to clinical trial therapy. For areas in which data were scarce or unavailable, consensus was reached through an iterative process. RAPNO response assessment recommendations include assessing disease response on the basis of changes in tumour volume, and using event-free survival as a study endpoint for patients entering clinical trials without bulky disease. Our recommendations for response assessment include the use of brain and spine MRI, cerebral spinal fluid cytology, neurological examination, and steroid use. Baseline postoperative imaging to assess for residual tumour should be obtained 24-48 h after surgery. Our consensus recommendations and response definitions should be prospectively validated in clinical trials.

MRI and Molecular Characterization of Pediatric High-Grade Midline Thalamic Gliomas: The HERBY Phase II Trial.

Background Diffuse midline gliomas (DMG) are characterized by a high incidence of H3 K27 mutations and poorer outcome. The HERBY trial has provided one of the largest cohorts of pediatric DMGs with available radiologic, histologic-genotypic, and survival data. Purpose To define MRI and molecular characteristics of DMG. Materials and Methods This study is a secondary analysis of a prospective trial (HERBY; ClinicalTrials.gov identifier, NCT01390948) undertaken between October 2011 and February 2016. Among 121 HERBY participants, 50 had midline nonpontine-based tumors. Midline high-grade gliomas were reclassified into DMG H3 K27 mutant, H3 wild type with enhancer of zest homologs inhibitory protein overexpression, epidermal growth factor receptormutant, or not otherwise stated. The epicenter of each tumor and other radiologic characteristics were ascertained from MRI and correlated with the new subtype classification, histopathologic characteristics, surgical extent, and outcome parameters. Kaplan-Meier curves and log-rank tests were applied to determine and describe survival differences between groups. Results There were 42 participants (mean age, 12 years ± 4 [SD]; 23 girls) with radiologically evaluable thalamic-based DMG. Eighteen had partial thalamic involvement (12 thalamopulvinar, six anteromedial), 10 involved a whole thalamus, nine had unithalamic tumors with diffuse contiguous extension, and five had bithalamic tumors (two symmetric, three partial). Twenty-eight participants had DMG H3 K27 mutant tumors; there were no differences in outcome compared with other DMGs (n = 4). Participants who underwent major debulking or total or near-total resection had longer overall survival (OS): 18.5 months vs 11.4 months (P = .02). Enrolled participants who developed leptomeningeal metastatic dissemination before starting treatment had worse outcomes (event-free survival, 2.9 months vs 8.0 months [P = .02]; OS, 11.4 months vs 18.5 months [P = .004]). Conclusion Thalamic involvement of diffuse midline gliomas ranged from localized partial thalamic to holo- or bithalamic with diffuse contiguous spread and had poor outcomes, irrespective of H3 K27 subtype alterations. Leptomeningeal dissemination and less than 50% surgical resection were adverse risk factors for survival. Clinical trial registration no. NCT01390948 © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Widjaja in this issue.

Langerhans cell histiocytosis in adults: a retrospective, single-center case series.

Langerhans cell histiocytosis is rare in adults, and most of what we know about its diagnosis and treatment comes from pediatric studies. We report clinical findings and results of treatment in a retrospective series of 63 consecutive adult patients (18-76 years old), treated at our pediatric unit from 1990 to 2020 using the same approach as for children. Patients were classified as having single-system disease (SS-LCH) in 41 cases, which was unifocal in 34 of them and multifocal in 7, or multisystem disease (MS-LCH) in 17 and primary pulmonary (pLCH) in 5. Twenty patients also had diabetes insipidus. A "wait and see" strategy was recommended after biopsy/surgery for patients with unifocal SS-LCH. Systemic treatment was proposed for cases of SS-LCH involving "special sites" or with multifocal disease, and in cases of MS-LCH. EFS and OS for the cohort as a whole were 62.2% and 100%, respectively, at 5 years and 52.5% and 97.6% at 10 years. Three patients died due to the damage caused by the multiple therapies administered. The rate of disease reactivation was high (affecting 40% of cases), with several reactivations over the years despite multiple lines of treatment. Though clinical history of LCH may differ between adults and children, in the absence of specific, tailored protocols, clinical approach to adult cases may draw on pediatric experience. Patients with limited disease have a good prognosis without any need for systemic therapy. Potentially greater toxicity in adults of systemic treatments generally used in pediatric setting should be borne in mind.

Atypical teratoid/rhabdoid tumor in adults: a systematic review of the literature with meta-analysis and additional reports of 4 cases.

INTRODUCTION: Atypical teratoid/rhabdoid tumor (AT/RT) is a highly aggressive embryonal CNS neoplasm, characterized by inactivation of SMARCB1 (INI1) or rarely of SMARCA4 (BRG1). While it is predominantly a childhood tumor, AT/RT is rare in adults. METHODS: We provide a comprehensive systematic review of literature with meta-analysis; 92 adult cases were found from 74 articles. We additionally present 4 cases of adult AT/RTs (age ranging from 19 to 29 years), located to cerebellum in 2 cases, to ponto-cerebellar angle in 1 case and to spinal cord in the remaining case. RESULTS: Microscopic features of our 4 cases showed a highly cellular tumor with rhabdoid morphology and high mitotic activity. All tumor cells lacked nuclear SMARCB1/INI1 protein expression. In case no. 3 we also performed methylation profiling which clustered the tumor with pediatric AT/RT-MYC subgroup. Prognosis remains poor in both pediatric and adult population with a median overall survival of 11 months. Our review demonstrated median overall survival of 15 months among the adult populations. However, consistent with a recent review, adult AT/RT seems to have highly variable prognosis and some patients reach long term survival with 22.9% of 5-year survival without evidence of disease and mean follow up time of 35.9 months (SD = 36.5). 27.1% of dissemination was also reported among the adult population. CONCLUSIONS: Adult AT/RTs predominantly arise in female patients and in supratentorial location. Midline structures, including the sellar region, are the most affected sites, especially among females aged > 40 years. Male gender is more prevalent between the age of 18 and 40 years and more frequently associated with non-midline tumors. Factors significantly associated with better prognosis are patient's age (< 40 years), combined radio-chemotherapy adjuvant approach and Ki-67 score < 40%.

Posterior fossa syndrome in a population of children and young adults with medulloblastoma: a retrospective, multicenter Italian study on incidence and pathophysiology in a histologically homogeneous and consecutive series of 136 patients.

INTRODUCTION: Posterior fossa syndrome (PFS) is a set of debilitating complications that can occur after surgery for posterior fossa tumors. This study aimed to assess the preoperative radiological and surgical risk factors for the onset of PFS in a histologically homogeneous population of children with medulloblastoma and compare it to a similar population of young adults. METHODS: Included patients underwent posterior fossa surgery for medulloblastoma at 11 Italian neurosurgical wards (2003-2019) and were referred to Fondazione IRCCS Istituto Nazionale dei Tumori in Milan (INT) for postoperative treatments. We collected patients' pre- and post-operative clinical, surgical and radiological data from the INT charts. To compare the distribution of variables, we used the Mann-Whitney and Fisher tests for continuous and categorical variables, respectively. RESULTS: 136 patients (109 children and 27 young adults) were included in the study. Among children, 29 (27%) developed PFS, and all of them had tumors at midline site with invasion of the fourth ventricle. Radiological evidence of involvement of the right superior (39% versus 12%; p = 0.011) or middle cerebellar peduncles (52% versus 18%; p = 0.002) seemed more common in children who developed PFS. Young adults showed an expected lower incidence of PFS (4 out of 27; 15%), that may be due to anatomical, physiological and oncological elements. CONCLUSIONS: This study confirmed some factors known to be associated with PFS onset and shed light on other debated issues. Our findings enhance an already hypothesized role of cerebellar language lateralization. The analysis of a population of young adults may shed more light on the often-neglected existence of PFS in non-pediatric patients.