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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).The study concerns survivors of childhood and adolescence primary neoplasms (PN) treated with chemotherapy, with or without radiotherapy and surgery, subsequently diagnosed with SOS.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.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.

The chances of patients with relapsing pediatric non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) being cured are limited. This retrospective single-institutional study examines the potential role of routine surveillance imaging for detecting recurrent tumor, and its impact on post-relapse survival.The analysis concerned 86 patientslt; 21 years old with relapsing NRSTS treated from 1985 to 2020. Clinical findings, treatment modalities and survival were analyzed, comparing patients whose relapse was first suspected from symptoms (symptomatic group) with those whose relapse was detected by radiological surveillance (imaging group).Tumor relapses were identified from clinical symptoms in 49 cases and on routine imaging in 37. Time to relapse was similar in the two groups. Routine imaging detected 6/32 local relapses and 31/48 distant relapses (and 79% of the cases of lung metastases). Overall survival (OS) at 5 years was 34.3% for the symptomatic group, and 24.0% for the imaging group (p-value 0.270). In patients with lung metastases at relapse, the 5-year OS was statistically better for the imaging group, that is, 25.8% versus 0% for the symptomatic group (p-value 0.044).This is the first study to explore the role of surveillance imaging in pediatric NRSTS. Judging from our findings, the value of routine scanning of primary sites seems limited, while radiological surveillance may help to detect lung metastases, improving survival for this patient category. The potentially negative effects of periodic radiological exams should be considered in deciding the optimal follow-up for patients off therapy.

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.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.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.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.

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 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. Patients were 25, median age 11.4 years, 8 had metastases, three LCA histotype. According to 2016-2021 WHO-classification, 14 had SHH subgroup tumors(6 TP53 mutated,1 + MYC and 1 + NMYC amplification), 11 non-WNT/non-SHH (2 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 9, distant-DR in 14, LR+DR in two) was 26 months. Fourteen patients were re-operated, in 5 excising single DR-sites, thereafter 3 received CT, two after re-RT; out of 11 not re-operated patients, 4 had re-RT as first treatment and 7 after CT. Re-RT was administered at median 32 months after first RT: focally in 20 cases, CSI in 5, never resulting in radionecrosis. Median post-relapse-PFS/after re-RT were 16.7/8.2 months, while overall survival-OS were 35.1/23.9 months, respectively. Metastatic status both at diagnosis/relapse negatively affected outcome and re-surgery was prognostically favorable.MYC,MYCN,P53 status and molecular subgroups, RT extension/fractionation, gender and age were not statistically prognostic; in the multivariable model, OSs were positively influenced by longer intervals before re-RT, re-surgery and not-SHH subgroups (P=0.019 from recurrence and 0.004 from second RT). Conclusions. Re-surgery+reRT can prolong survival; a substantial fraction of patients with worse outcome belongs to SHH-subgroup.

Introduction: Cervicomedullary gliomas (CMGs) are usually low-grade tumors often found in the pediatric age. Histological findings, treatments, and classification have been much the same for 40 years, although histological and molecular classifications have largely been developed for other pediatric CNS tumors. The management and treatment of pediatric CMG are still conducted by many authors according to their anatomical location and characteristics, independently from histology. Methods: We conducted a literature review in PubMed (Medline) to identify relevant contributions about pediatric CMG published until December 31, 2021. We also analyzed a series of 10 patients with CMG treated from 2006 to 2021 at IRCCS Istituto Nazionale dei Tumori. The aim of the present review was to see whether and how the diagnosis, treatment, and classification of CMGs in children have developed over time, especially in the context of molecular advancements, and to analyze our single-center experience in the last 15 years. Results: Thirty articles have been included in the review. Articles have been divided into two historical periods (1981–2000 and 2001–2021) and data from different series were analyzed to see how much the management and treatment of pediatric CMG have changed during years. Analysis of our series of 10 patients affected by CMG was also performed to compare it with the literature. Discussion: Management and classification of CMG in children have not dramatically changed during years. However, new insight from molecular diagnostics and target therapies and the development of radiological, neurophysiological, and radiotherapy techniques have updated treatment modalities in the last 20 years. Treatment modalities and their innovations have been reviewed and discussed. Further studies are needed to standardize and customize treatment protocols for these tumors.

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.The analysis concerned 79 patients21 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).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).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.

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.The analysis concerned 105 patients21 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.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.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.

Rhabdomyosarcoma (RMS), an aggressive soft tissue sarcoma of the skeletal muscle generally affecting children and adolescents, shows extensive heterogeneity in histology, site and age of onset, clinical course, and prognosis. Tumorigenesis of RMS is multifactorial and genetic predisposition together with the family history of cancer may provide critical information to enhance the current knowledge and foster genetic counseling and testing. In our study, we evaluated the possible correlation of oncological family history with clinical outcomes in a cohort of RMS 512 patients and treated at the Pediatric Oncology Unit of our Institute. Family history was retrospectively collected from the specific ad hoc form available in medical records and filled in through an interview with the patients’ parents at the time of RMS diagnosis. While our series did not show a specific association between oncological family history and clinical variables, we observed an association with survival probabilities: among patients with a history of cancer-affected first-degree relatives at the time of the diagnosis, all children with alveolar RMS (ARMS) died of disease. Our study not only reports an interesting and not previously described association between a poor clinical outcome and ARMS in patients with young cancer-affected relatives, but also stimulates the discussion on oncological family history in RMS, to improve the clinical management of these young patients and their families.

Early-stage non-Hodgkin’s lymphomas (ES-NHL) are associated with high survival rates. To minimize the risk of long-term sequelae, the duration and intensity of chemotherapy have been progressively reduced. Between 1988 and 2018, children with ES-NHL were treated at a single institute with two subsequent protocols. Protocol I consisted of a 7-week induction phase followed by a maintenance phase alternating 6-mercaptopurine plus MTX, a brief reinduction, and thioguanine plus cytosine arabinoside, for a total duration of 8 months. The subsequent protocol II (applied since 1997) was modified adding etoposide plus a further dose of HD-MTX and omitting maintenance in all histological subtypes except T-lymphoblastic lymphoma (T-LBL), for a total duration of 9 weeks. Intrathecal prophylaxis was not provided in either protocol. With a median follow-up of 98.4 months, the 5-year event-free survival (EFS) rates in protocol I (n = 21) and II (n = 25) were 76.2% and 96%, respectively, and the 5-year overall survival (OS) rates were 90.5% and 96%, respectively. None of the patients experienced disease progression or relapse within the central nervous system (CNS). Acute toxicity was manageable in both protocols, except for a case of presumed acute cardiotoxic death; no chronic sequelae were evident. Low-intensity chemotherapy for 9 weeks without intrathecal prophylaxis was sufficient for curing children with ES-NHL, without jeopardizing the excellent survival rate of this disease.

Background The WHO Classification of Tumors of the Central Nervous System has undergone major restructuring. Molecularly defined diagnostic criteria were introduced in 2016 (revised 4th edition) and expanded in 2021 (5th edition) to incorporate further essential diagnostic molecular parameters. We investigated potential differences between specialists in perception of these molecularly defined subtypes for pediatric high-grade gliomas (pedHGG). Methods We designed a 22-question survey studying the impact of the revised 4th edition of the WHO classification on pedHGG. Data were collected and statistically analyzed to examine the spectrum of viewpoints and possible differences between neuro-oncologists and neuropathologists. Results 465 participants from 53 countries were included; 187 pediatric neuro-oncologists (40%), 160 neuropathologists (34%), and 118 additional experts (26%). Neuro-oncologists reported issues with the introduction of molecularly defined tumor types, as well as the abolishment or renaming of established tumor entities, while neuropathologists did not to the same extent. Both groups indicated less relevant or insufficient diagnostic definitions were available in 2016. Reported issues were classified and assessed in the 2021 WHO classification and a substantial improvement was perceived. However, issues of high clinical relevance remain to be addressed, including the definition of clinical phenotypes for diffuse intrinsic pontine glioma and gliomatosis cerebri. Conclusions Within the WHO classification of pediatric brain tumors, such as pedHGG, rapid changes in molecular characterization have been introduced. This study highlights the ongoing need for cross talk between pathologist and oncologist to advance the classification of pedHGG subtypes and ensure biological relevance and clinical impact.

PurposeThe aim of this study is to investigate the spectrum of neurological triad improvement in patients with diffuse intrinsic pontine glioma (DIPG) treated by re-irradiation (re-RT) at first progression.MethodsWe carried out a re-analysis of the SIOP-E retrospective DIPG cohort by investigating the clinical benefits after re-RT with a focus on the neurological triad (cranial nerve deficits, ataxia, and long tract signs). Patients were categorized as “responding” or “non-responding” to re-RT. To assess the interdependence between patients’ characteristics and clinical benefits, we used a chi-square or Fisher’s exact test. Survival according to clinical response to re-RT was calculated by the Kaplan–Meier method.ResultsAs earlier reported, 77% (n = 24/31) of patients had any clinical benefit after re-RT. Among 25/31 well-documented patients, 44% (n = 11/25) had improvement in cranial nerve palsies, 40% (n = 10/25) had improvement in long-tract signs, and 44% (11/25) had improvement in cerebellar signs. Clinical benefits were observed in at least 1, 2, or 3 out of 3 symptoms of the DIPG triad, in 64%, 40%, and 24%, respectively. Patients irradiated with a dose ≥20 Gy versus p-value = 0.028). The survival from the start of re-RT to death was not different between responding and non-responding DIPG patients (p-value = 0.871).ConclusionA median re-irradiation dose of 20 Gy provides a neurological benefit in two-thirds of patients with an improvement of at least one symptom of the triad. DIPG patients receiving ≥20 Gy appear to improve slightly better with regard to ataxia; however, we need more data to determine whether dose escalation up to 30 Gy provides additional benefits.

Peripheral precocious puberty (PPP) may be a paraneoplastic manifestation, associated with beta human chorionic gonadotropin (β-hCG)–secreting tumors. We describe 2 young children with β-hCG-secreting tumors presenting with signs of pubertal activation. In the first patient, a 16-month-old boy with hepatoblastoma, only initial signs of PPP at presentation were identifiable, with concomitant high levels of β-hCG. Although the tumor had good response to therapy, β-hCG levels were fluctuant until the tumor was resected surgically. The second patient, an 18-month-old boy with intracranial germ cell tumor, presented with clear signs of pubertal activation and genitalia enlargement with no initial alteration of sex hormones. In both cases, the oncologic response to therapy was good. In the first case, full remission of the pubertal signs was observed; in the second, pubertal signs were still visible 20 months after the end of treatment.

Purpose: There is no consensus in the literature about the impact of hydrocephalus on clinical course and overall survival of diffuse intrinsic pontine gliomas (DIPG) patients as well as about its specific treatment. Authors reviewed a series of DIPG patients to investigate factors related to the onset of hydrocephalus, its treatment, and its impact on clinical course and prognosis. Methods: A retrospective observational study was performed enrolling pediatric patients affected by DIPG from 2008 to 2018. Clinical and radiological charts were reviewed to find patients’ demographic, pathologic and radiologic features in hydrocephalic and non-hydrocephalic patients. In the hydrocephalus cohort, treatment strategy and its effectiveness and complications were analyzed. Results: Ninety-four pediatric patients were enrolled in the study. Patients who developed hydrocephalus showed significantly lesser maximum axial tumor areas than patients without hydrocephalus (respectively 6.5cm2 vs 16.45cm2, p< 0.005). Hydrocephalus developed in 33 patients (35%) with an onset interval of 5.24 ± 1.21months (range 3.2–7.3). The majority of hydrocephalic patients (28 cases, 90%) were treated by ventriculoperitoneal shunt, the remaining 3 patients being treated by endoscopic third ventriculostomy. Mean overall survival was 16.6months ± 20months without significative difference between the groups. Conclusion: The onset of hydrocephalus occurs in the first moths of the disease story and found a negative correlation with tumor maximal axial diameter. Early treatment of hydrocephalus presents a very low complications rate with satisfying clinical outcome, as it allows the patients to continue the neurooncological therapies being a part of the treatment armamentarium instead of a palliative solution.

Recurrence incidence for paediatric/adolescent high-grade glioma (HGG) exceeds 80%. Reirradiation (reRT) palliates symptoms and delays further progression. Strategies for reRT are scarce: we retrospectively analysed our series to develop rational future approaches.We re-evaluated MRI + RT plans of 21 relapsed HGG-patients, accrued 2010-2021, aged under 18 years. All underwent surgery and RT + chemotherapy at diagnosis. Pathologic/molecular re-evaluation allowed classification based on WHO 2021 criteria in 20/21 patients. Survival analyses and association with clinical parameters were performed.Relapse after 1st RT was local in 12 (7 marginal), 4 disseminated, 5 local + disseminated. Re-RT obtained 8 SD, 1 PR, 1PsPD, 1 mixed response, 10 PD; neurological signs/symptoms improved in 8. Local reRT was given to 12, followed again by 6 local (2 marginal) and 4 local + disseminated second relapses in 10/12 re-evaluated. The 4 with dissemination had 1 whole brain, 2 craniospinal irradiation (CSI), 1 spine reRT and further relapsed with dissemination and local + dissemination in 3/four assessed. Five local + disseminated tumours had 3 CSI, 1 spine reRT, further progressing locally (2), disseminated (1), n.a. (1). Three had a third RT; three were alive at 19.4, 29, 50.3 months after diagnosis. Median times to progression/survival after re-RT were 3.7 months (0.6-16.2 months)/6.9 months (0.6-17.9 months), improved for longer interval between 1st RT and re-RT (P = 0.017) and for non-PD after reRT (P 0.001). First marginal relapse showed potential association with dissemination after re-RT (P = 0.081).This is the biggest series of re-RT in paediatric HGG. Considering the dissemination observed at relapse, our results could prompt the investigation of different first RT fields in a randomized trial.

Objectives: Although transfusion support is commonly used in oncological palliative care, there is still a paucity of literature. We examined the transfusion support provided in the terminal stage of the disease and compared the approach at a pediatric oncology unit and a pediatric hospice. Case description This case series analyzed patients treated at the Fondazione IRCCS Istituto Nazionale dei Tumori di Milano (INT)’s pediatric oncology unit who died between January 2018 and April 2022. We compared these with those who died at the VIDAS hospice and analyzed the number of complete blood counts taken in a patient’s last 14 days of life, and the number of transfusions performed in the same period. We analyzed 44 patients (22 in pediatric oncology unit; 22 in hospice) in total. Twenty-eight complete blood counts were performed (7/22 patients at the hospice; 21/22 patients at the pediatric oncology unit). Nine patients were given transfusions, three at the hospice, six at our pediatric oncology unit (24 transfusions in total): 20 transfusions at the pediatric oncology unit, four at the hospice. In total 17/44 patients were given active therapies in the last 14 days of life: 13 at the pediatric oncology unit, four at the pediatric hospice. Ongoing cancer treatments did not correlate with a greater likelihood of receiving a transfusion (p=0.91). Conclusions: The hospice’s approach was more conservative than the pediatric oncology one. In the in-hospital setting, the need for a transfusion cannot always be decided on by a combination of numerical values and parameters alone. The family’s emotional-relational response must be considered too.

Each year approximately 35,000 children and adolescents are diagnosed with cancer in Europe. Five-year survival rates have improved and now reach 80% in most European countries, thanks to a combination of chemotherapy, radiotherapy, and surgery. To date, there are more than 44,000 Italians still living several years after being diagnosed with cancer in developmental age. The risk of premature morbidity and mortality for cancer survivors is well known and documented. Approximately 60% of survivors of cancer in childhood and adolescence have at least one chronic health condition in later life, and more than one in four develop severe or life-threatening disorders. Among the various long-term iatrogenic sequelae of cancer treatments, the most worrisome are second malignant neoplasms. We reported on our mono-institutional experiences of screening and treating secondary breast cancer, secondary thyroid cancer and secondary osteosarcoma. Recommendations on the surveillance needed for cancer survivors because of the risk of late effects of their disease or its treatment suggest that discussing the potential problems early on can be crucial to a patient’s future health. These considerations and our consolidated experience strengthen our conviction that survivors of cancer in childhood and adolescence who develop second malignant neoplasms should be treated at highly-specialized centers. Multidisciplinary care requires close communications and high levels of up-to-date professional expertise. This challenging area of health care is also changing rapidly because cancer survivorship is a work in progress, but we cannot wait for definitive conclusions on many aspects because this will take decades, especially for pediatric patients.

During the coronavirus disease 2019 (COVID-19) pandemic, oncologists have managed patients at higher risk of having a severe course of this infection. This raises new questions about their correct management, as well as the difficulty of distinguishing tumor/treatments complications from those related to COVID-19. We report a case of an 11-year-old boy undergoing treatment for T-cell lymphoblastic lymphoma who experienced a prolonged COVID-19 course. Oncologic therapy was continued without significant changes compared to the initially planned treatment. No relevant complications occurred. COVID-19 convalescent plasma was administered, resulting in a positive antibody titer after 24 days.

Extraosseous Ewing sarcoma is a rare entity and less is known about its clinical behavior and optimal treatment than for its counterpart in bone. This study is a retrospective analysis on a cohort of patients21 years treated according to a "soft tissue sarcoma approach."The "extraosseous" origin of the tumor was established on radiological findings, based on the lack of any bone involvement. Patients were treated using a multimodality approach including surgery, radiotherapy, and chemotherapy. All patients received chemotherapy with alkylating agents and anthracyclines for 25 weeks (nine courses). Radiotherapy (45-54.8 Gy) was required for all cases except those who had an initial R0 resection of tumors smaller than 5 cm.Fifty-seven patients (age 2-20 years, median 14) were treated from 1990 to 2020. Ten-year event-free survival (EFS) and overall survival (OS) were 77.5% and 85.5% in patients with localized disease, and 11.1% and 29.6% in those with metastatic disease (p .001) (follow-up 5-349 months, median 107 months). In patients with localized disease, the most recent IVADo-IVE regimen achieved excellent survivals, that is, 10-year EFS 95.5%.Our study showed that satisfactory results were achieved in patients with localized extraosseous Ewing sarcoma treated with a tailored approach derived from soft tissue sarcoma protocols, which was less intensive and shorter as compared to the standards utilized for the management of bone Ewing sarcoma. Our study suggests that the extraskeletal site might be considered as a variable to stratify patients and modulate treatment intensity accordingly in Ewing sarcoma protocol.

Background. Methotrexate is renally excreted. HDMTX (high dose-methotrexate)-induced acute kidney injury (AKI) is a non-oliguric decrease in glomerular filtration rate (GFR) heralded by an acute rise in serum creatinine. Moreover, AKI is also a frequent complication of COVID-19. Among our patients treated with HDMTX, some of these developed AKI during SARS-CoV-2 infection. Therefore, we wondered whether our patients’ kidney failure might have been triggered by their underlying SARS-CoV-2 positivity. Methods. Data were collected from the database at the Pediatric Oncology Unit of the Istituto Nazionale dei Tumori in Milan (Italy) regarding patients who matched the following selective criteria: (a) treatment with HDMTX during the pandemic period; (b) SARS-CoV-2 infection during the treatment; (c) development of AKI during HDMTX treatment and SARS-CoV-2 infection. Results. From March 2020 to March 2022, a total of 23 patients were treated with HDMTX; 3 patients were treated with HDMTX during SARS-CoV-2 infection and all 3 developed AKI. Conclusions. Clinical manifestations associated with this virus are many, so we are not yet able to lower our guard and rule out this infection as a cause of clinical manifestations with any certainty.

BACKGROUND: The purposes of this trial were to evaluate the feasibility, response, PFS/OS of a randomized study comparing two different RT schedules for DIPG while administering the same systemic treatment. METHODS: Patients: 2-21 years-old with a not-pretreated radiologically verified DIPG (MRI blindly reviewed at diagnosis and every 12 weeks thereafter) and symptoms duration below 6 months. Biopsy was required if suggested by atypical imaging. Vinorelbine 20 mg/m2+nimotuzumab 150 mg/m2 were administered weekly for 12 weeks; thereafter every other week until tumor progression or for up to 2 years. Standard(ST) arm included focal RT at total dose of 54Gy (1.8Gy/day); for local progression re-irradiation was proposed at 19.8Gy, in case of dissemination craniospinal irradiation(CSI) at 36Gy was adopted. Experimental(SP) arm included three elective courses of RT at defined timepoints at 36Gy, 19.8Gy and 19.8Gy with possible reirradiation for relapse at 9 Gy. Incidences of local(L) and distant(D) progression were assessed in a competing risk setting. RESULTS: Aggregated preliminary results are given for 4 Italian centers. 54 pts were screened and 51 included, 27 in ST, 28 males, median age 7 years (range 3-17). Median time of observation was 17.9 months. Twelve patients needed a shunt, 10 during treatment; 20 were biopsied, in 18 cases according local protocols. 19/20 tumors had H3.3 K27 mutation. 41 relapsed, 28 locally, 13 with a component of dissemination. 36 died, one for tracheotomy bleeding. SP irradiation was feasible and never produced significant radionecrosis. Median EFS/OS were 7.3/12.9 months, respectively; EFS/OS at 1 year were 19.0%/57.3%, not differing between patients with local vs. disseminated relapses. Patients submitted to biopsies had more dissemination (P=0.04) and less local progression (P=0.077). CONCLUSIONS: Treatment was feasible and OS confirmed previous results obtained in a single center. Randomization results will be later reported.

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: 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

This study reports a case series of patients with upper limb neuromotor deficits following pediatric central nervous system tumor and treated with rehabilitative therapy according to action observation therapy (AOT). AOT is based on the “mirror neurons” system and had positive results in various non-oncologic neurologic pathologies. This study is the first experience in the oncology field, and included 6 patients, 4 of whom were fully evaluated at 6-month follow-up. In all patients, therapy showed improvement in all assessment tests. These promising results lead to further studies to confirm their effectiveness.

Objective: Pediatric oncology patients are more likely to develop venous thromboembolic events related to central venous catheter (CVC). Study aim was to determine the incidence of catheter related thrombosis (CRT) in a cohort of pediatric oncology patients using vascular ultrasound (US). Methods: Consecutive children of a single cancer referral center, requiring medium to long term CVC implantation, were screened for CRT, using serial ultrasound exams. Measurements and main results: US examinations were taken 15, 30 and 90 days after CVC implantation. A total of 113 catheters were studied in 103 patients (median age 10.5 years old). Ultrasound screening was completed in 80.5% patients. Apart from three subjects, US investigations were well tolerated. Patients were followed for a median of 87 days. No symptomatic CRT was recorded throughout. Three cases of asymptomatic thrombosis were identified with early US screening; incidence of CRT events for 1000 catheter-days was 0.11. The presence of previous catheter-related infection and an history of one or more previous CVC placement were identified as risk factors. Conclusions: In our pediatric patients the incidence of CRT is low. Ultrasound monitoring is well tolerated and allows detecting asymptomatic CRT. Patients with previous CVC infection or insertion seem to have a higher risk of CRT (p =0.003 and p = 0.043 respectively). Keywords: Central venous catheters, Venous thrombosis, Vascular ultrasound, Vascular catheter infections, Children

Meningiomas are uncommon in children and usually arise in the context of tumor-predisposing syndromes. Recently, YAP1-fusions have been identified for the first time as potential NF2-independent oncogenic drivers in the development of meningiomas in pediatric patients. We report a case of a YAP1-fusion-positive atypical meningioma in a young child and compare it with the previous ones reported. Extending the clinico-pathological features of YAP1-fused meningiomas, we suggest additional clues for diagnosis and emphasize the urgent need for an integrated multilayered diagnostic approach, combining data from histological and molecular analyses, neuroradiology, and clinical findings.

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.

Introduction: The H3K27M-mutant diffuse midline glioma (DMG) was first included in the World Health Organization (WHO) Classification of central nervous system (CNS) tumors in 2016, and confirmed in its fifth edition. The biological behavior and dismal prognosis of this tumor resemble diffuse intrinsic pontine gliomas (DIPG). Homogeneously-treated series are rarely reported. Methods: From 2016 onwards, we treated patients with DMG with radiotherapy and concomitant/adjuvant nimotuzumab/vinorelbine, plus re-irradiation at relapse, as already done for DIPG. Results: We treated nine patients, seven females, with a median age at diagnosis of 13 years. Tumor sites were: thalamic in five cases, pontocerebellar in two, pineal in one, and paratrigonal with nodular/leptomeningeal dissemination in one. Three patients were biopsied, and six had partial tumor resections. Central pathological review was always performed. The median time to local progression was 12.7 months, and the median overall survival was 17.8 months. Six patients died of tumor progression, one of cerebral bleeding at progression. Two were alive, one in continuous remission, the other after relapsing, at 38.6 and 46.3 months after diagnosis. Progression-free survival was 33.3% at one year. Overall survival was 88.9%, 33.3% and 22.2% at 1, 2 and 3 years, respectively. Conclusions: This is a small series of homogeneously-treated DMG patients. The results obtained are comparable with those of DIPG patients. Given the phenotypically- and molecularly-defined setting of DMG and severe outcome in this orphan population, they should be treated and included in registries and protocols of DIPG.

BACKGROUND: The WHO Classification of Tumors of the Central Nervous System has undergone major restructuring following rapid advances in brain tumor genomics and epigenomics. The most significant changes resulted from the introduction of molecularly defined diagnostic criteria in 2016 (revised 4th edition). In 2021 (5th edition), further essential molecular criteria were incorporated. In the present study, we sought to investigate potential differences between specialists in perception of these newly defined molecular subtypes of pediatric high-grade gliomas (pedHGG). METHODS: We designed a 22-question survey studying the impact of the revised 4th edition of the WHO classification on pedHGG. Data were collected and statistically analyzed to capture the spectrum of viewpoints and possible differences among neuro-oncologists and neuropathologists. RESULTS: 465 participants from 53 countries responded, of which 187 pediatric neuro-oncologists (40%), 160 neuropathologists (34%) and 118 experts in other related fields (neurosurgeons, radiotherapists, neuroradiologists and others; 26%). Neuro-oncologists reported having issues with the introduction of new molecular entities, such as the abolishment and renaming of established tumor entities. Neuropathologists did not define these problems to the same extent. However, both groups felt that in the 2016 version, less relevant or insufficient diagnostic definitions were available for pedHGG. Within the 2021 WHO classification, a substantial improvement was perceived regarding the definition of pedHGG entities. However, some issues of high clinical relevance, like the definition of clinical phenotypes such as diffuse intrinsic pontine glioma (DIPG) and gliomatosis cerebri, are yet to be addressed. CONCLUSIONS: Within the WHO classification of pediatric brain tumors, such as high-grade gliomas, rapid changes in nomenclature have been introduced because of substantial improvement in molecular characterization. This study highlights that ongoing cross-talk between advancing classification of pedHGG subtypes and its biological relevance and clinical impact is essential.

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.

BACKGROUND: Diffuse intrinsic pontine glioma (DIPG), can cause hydrocephalus and if symptomatic, leads to rapid changes in consciousness requiring surgical intervention. The effect of cerebrospinal fluid (CSF) diversion on overall survival and the clinical factors influencing outcome remain unclear. The aim of this study was to evaluate the impact of the treatment of hydrocephalus on survival in DIPG patients. METHODS: The study was retrospective in design using data from the SIOPE-European Society of Pediatric Oncology DIPG Registry. Hydrocephalus was determined based on a centrally reviewed diagnostic MRI. The Kaplan-Meier method was used for survival statistics. Clinical prognostic factors including: duration of symptoms, age and cranial nerve palsy at diagnosis were evaluated for confounding and effect modification. The effect of hydrocephalus treatment (CSF diversion) on survival was examined using Cox regression. RESULTS: Among 582 patients from the SIOPE-DIPG Registry, 86 (14%) had hydrocephalus at diagnosis. Median OS for hydrocephalus patients treated with CSF diversion (n=43) was 13 months (95% CI, 10.2-17.7) and 9 months (95% CI, 7.4-10.6) for hydrocephalus patients without a CSF diversion (n=43). Survival rates were not significantly different (p=.41). On adjusted Cox regression, correcting for duration of symptoms, hydrocephalus patients with signs of cranial nerve palsy at diagnosis and a CSF diversion had a hazard ratio 0.476 (p=0.004). CONCLUSION: Survival among DIPG patients presenting with hydrocephalus at diagnosis was not influenced by CSF diversion. Hydrocephalus patients with signs of cranial nerve palsy at diagnosis, had a significantly reduced risk after undergoing CSF diversion. There is an indication this subgroup of DIPG patients may benefit more from CSF diversion, although the relationship between hydrocephalus and cranial nerve palsy requires further investigation.

OBJECTIVE: Diffuse intrinsic pontine glioma (DIPG) is a rare childhood brain tumour with poor prognosis. Radiotherapy (RT) remains the only palliative intervention. In this scenario, it is essential to investigate tumor and patient microinvironment. Microbiota plays a critical role in human health and a functional link between the central nervous system and gut microbiota has been reported: the microbiota-gut-brain axis. With these premises, we have investigated the gut microbiota in DIPG. METHODS: A cohort of 18 patients was enrolled and we collected stool specimens at diagnosis (pre-RT) and after radiotherapy. Microbiota content was analysed through 16S rRNA sequencing on IONS5xl; base calling and demultiplexing were performed by Torrent Suite (ThermoFisher). Association to progression free survival (PFS) and overall survival (OS) were assessed by cox-regression univariate analyses and differential abundance (DA) analyses identified differences following RT. RESULTS: The Firmicutes/Bacteroidetes (F/B) ratio in pre-RT specimens has a median of 0.757 (range= 0.243-1.19). Having PFS as endpoint and at family classification level, an increased risk of disease progression was disclosed for Flavobacteriaceae and Bacillales with HR of 1.57 (p=0.00913) and 1.57 (p=0.215), respectively. The anaerobic bacteria Synergistaceae is found related to a decreased risk of progression with HR 0.662 (p=0.00718). These findings were also confirmed with OS as endpoint. DA analyses pointed out a number of families belonging to Firmicutes and Bacteroidetes phyla highly differentiated (log2|fold-change|>2) between pre- and post-RT. CONCLUSIONS: This study represents the first report of the microbiota-gut-brain axis role in DIPG patients. The F/B ratio, a parameter of normal intestinal homeostasis, show the presence of inflammatory patterns and some family members are associated to increased disease progression. These preliminary findings needs further validations. However, 16S microbiota has the potential ability to stratify patients and probiotic administration could restore a normal F/B ratio.

BACKGROUND: The purposes of this trial were evaluating the feasibility, response and PFS/OS of patients receiving upfront radiotherapy and reirradiation at progression with concomitant nimotuzumab/vinorelbine chemotherapy as the standard arm of the ongoing protocol for DIPG. METHODS: Patients aged 2-21 years with not-pretreated DMG (evidence of H3.3K27M mutation at immunohistochemistry) received vinorelbine 20 mg/m2+nimotuzumab 150 mg/m2 weekly for 12 weeks; thereafter every other week until tumor progression or for up to 2 years. Focal photons irradiation was delivered within the 3rd week after first nimotuzumab+vinorelbine administration with a total dose of 54 Gy in 1.8 Gy daily fractions. For local progression re-irradiation was proposed at 19.8 Gy; in case of dissemination craniospinal-irradiation at 36 Gy was adopted. MRI were blindly centrally reviewed at diagnosis and every 12 weeks thereafter. RESULTS: Aggregated preliminary results are available for 20 patients from 4 Italian centers: 12 males, median age 11 years (range 3-17). Median time of observation was 12.5 months; 8 had thalamic/basal ganglia disease, in 5 pons was involved (2 pontobulbar, 3 pontomesencephalic), 6 spinal, 2 cerebellar. 13 patients had only biopsy, the others partial or near-total resection.14 relapsed: 5 locally, 4 with dissemination, 5 with both; 12 died, one was lost at follow-up. Two patients received reirradiation, one of them was irradiated three times without evidence of radionecrosis, still alive at 26 months from diagnosis. Median EFS/OS were 8.3/10.2 months, respectively; EFS/OS at 1 year were 25.8/36.7%. Survival curves between spinal and cerebral locations showed no difference. Patients after partial/near-total resection vs biopsied seemed to have earlier relapses (P 0.017) with EFS at 6 months of 34.3/75.0% respectively. CONCLUSIONS: This is one of the first series of DMG homogeneously and prospectively treated; treatment was feasible. A potential role of reirradiation emerge as in DIPGs.

PURPOSE: To investigate the spectrum of neurological triad improvement in patients with diffuse intrinsic pontine glioma (DIPG) treated by re-irradiation (re-RT) at first progression. METHODS: Re-analysis of the SIOP-E retrospective DIPG cohort by investigating clinical benefits after re-RT with focus on the neurological triad. Patients were divided as "responding" or "non-responding" to re-RT. To assess the interdependence between patients’ characteristics and clinical benefits we used a Chi-Square or Fisher’s Exact test. Survival according to clinical response to re-RT was calculated by the Kaplan-Meier method. RESULTS: As earlier reported, 77% (n = 24/31) of patients had any clinical benefit after re-RT. Among 25/31 well documented patients, 44% (n=11/25) had improvement in cranial nerve palsies, 40% (n=10/25) in long-tract signs, 44% (11/25) in cerebellar signs. Clinical benefits were observed in at least 1, 2 or 3 out of 3 symptoms of the DIPG triad, in 64%, 40% and 24% respectively. Patients irradiated with a dose ≥ 20 Gy versus < 20 Gy may improve slightly better with regards of ataxia (67% versus 23%; P-value = 0.028). The survival from the start of re-RT to death was not different between responding and non-responding DIPG patients (P-value = 0.871). CONCLUSION: A median re-irradiation dose of 20 Gy provides a neurological benefit in two-third of patients with an improvement of at least one symptom of the triad. DIPG patients receiving ≥20 Gy appear to improve slightly better with regards of ataxia, however we need more data to determine whether dose escalation up to 30 Gy provides additional benefit.

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.

INTRODUCTION: For terminally-ill children with brain tumors care focuses on quality of life, and patient management fundamentally affects grieving families. We describe our experience of palliative sedation (PS) for children with refractory symptoms caused by solid tumors, focusing on BT (brain tumor). METHODS: Retrospective data on all children treated for cancer who died between 1/2016-12/2020 in our Institution were collected. RESULTS: Of the 29 patients eligible for the study, M/F 17/12, the median duration of disease was 12.5 months(range 3-51) and the median age at death was 8.5 years(range 1-22). Fifteen had BT (5 DIPG, 2 Ependymoma, 8 high-grade-glioma). The reasons for starting PS in BT were: seizures(5), central respiratory failure(6), locked-in-syndrome(1), decerebration(1). Midazolam was combined in 16 cases with other drugs (neuroleptics, alpha-2 agonists, antihistamines) to achieve adequate sedation. Ten/15 with BT received antiepileptic therapy, apart midazolam. BT patients received oral benzodiazepins before PS less frequently than those with other cancers (p = 0.0033). Throughout the period of PS and on the day of death, patients with BT were given lower doses of midazolam and morphine. Mean dose of midazolam was 0.027 mg/kg/h (range 0.0069-0.06) for patients with BT, 0.055 mg/kg/h (range 0.01-0.38) for the others, while the mean morphine doses were 0.048 mg/kg/h (range 0-0.08) and 0.09 mg/kg/h (range 0.013-0.13), respectively. CONCLUSIONS: BT patients require less intensive analgesic-sedative therapies because their already impaired state of consciousness. Optimizing pharmacological treatments demands a medical team that knows how drugs (even developed for other indications) work. Emotional-relational aspects are important too, any action to lower a patient’s consciousness should be explained to the family. Guidelines on PS in pediatrics could help, providing they acknowledge that any child’s death is always a unique case.

Background: Cancer diagnosis and related treatment can limit young patients’ privacy. Their need for private physical and psychological spaces can be impeded by limited freedom, e.g., sharing hospital rooms with others and exposing their body to their parents and doctors. Methods: We conducted a survey among young patients of our center to investigate how their perception of privacy changed after being diagnosed with cancer and their need for hospital dedicated physical spaces and time for patients to enjoy their privacy. A questionnaire with 16 items was developed by the staff involving psychologists and physicians. The relevance of changes before and after the cancer diagnosis was assessed by calculating two scores indicating the situation before and after diagnosis for each answer, as well as a delta score. Results: Between May and June 2020, the questionnaire was completed by 60 patients aged 16–24 years. The median delta scores describing the changes before and after diagnosis were −8 points for perception of privacy, indicating a significant decrement of the level of privacy perceived. A major issue was the constant presence of parents being perceived as intrusive. Concerning hospital dedicated physical spaces and time for patients to enjoy their privacy, respondents requested dedicated spaces (50% of patients) and opportunities to have private interviews with medical personnel (88%). Conclusions: Our study offers a snapshot of how young people with cancer perceive the impact of the disease and its treatment on their privacy with the restrictions imposed on their individual freedom. Patients’ personal needs must be taken into consideration to adopt appropriate measures and better organize wards.

Introduction Mutations of the APC (adenomatous polyposis coli) gene correlate mainly with familial adenomatous polyposis (FAP), but can occasionally be pathogenic for medulloblastoma (MBL) wingless-related integration site (WNT) subtype, the course of which has only recently been described. Methods We retrieved all patients with documented germline APC mutations and a diagnosis of MBL to examine their outcome, late effects of treatment, and further oncological events. Results Between 2007 and 2016, we treated six patients, all with a pathogenic APC variant mutation and all with MBL, classic histotype. None had metastatic disease. All patients were in complete remission a median 65 months after treatment with craniospinal irradiation at 23.4 Gy, plus a boost on the posterior fossa/tumor bed up to 54 Gy, followed by cisplatin/carboplatin, lomustine, and vincristine for a maximum of eight courses. Five of six diagnostic revised MRI were suggestive of the WNT molecular subgroup typical aspects. Methylation profile score (in two cases) and copy number variation analysis (chromosome 6 deletion in two cases) performed on four of six retrieved samples confirmed WNT molecular subgroup. Four out of six patients had a positive family history of FAP, while gastrointestinal symptoms prompted its identification in the other two cases. Four patients developed other tumors (desmoid, MELTUMP, melanoma, pancreatoblastoma, thyroid Tir3) from 5 to 7 years after MBL. Discussion Our data confirm a good prognosis for patients with MBL associated with FAP. Patients' secondary tumors may or may not be related to their syndrome or treatment, but warrant adequate attention when planning shared guidelines for these patients.

Introduction. Mutations of the APC (adenomatous polyposis coli) gene correlate mainly with familial adenomatous polyposis (FAP), but can occasionally be pathogenic for medulloblastoma (MBL) WNT subtype as well, the course of which has only recently been described. Methods. We retrospectively retrieved all patients with documented germline APC mutations and a centrally-reviewed diagnosis of MBL to examine the outcome of their MBL, late effects of its treatment, and further oncological events. Results. Between 2007-2016 we diagnosed and treated 6 patients, all with a pathogenic APC variant mutation, who all had MBL, classic histotype. None had metastatic disease. All patients were in complete remission a median 65 months after treatment with craniospinal irradiation at 23.4 Gy, plus a boost on the posterior fossa/tumor bed up to 54 Gy, followed by cisplatin/carboplatin, lomustine and vincristine for a maximum of 8 courses. Five of 6 diagnostic revised MRI were suggestive of the WNT molecular subgroup typical aspects. Four of 6 patients had a positive family history of FAP, while gastrointestinal symptoms prompted its identification in the other 2 cases. Four patients had developed other tumors (desmoid, MELTUMP, melanoma, pancreatoblastoma, thyroid Tir3) from 5 to 7 years after MBL. Discussion. Our data confirm a good prognosis for patients with MBL associated with FAP. Patients’ secondary tumors may or may not be related to their syndrome or treatment, but warrant adequate attention when planning shared guidelines for these patients.

Introduction: Medulloblastoma is the most common malignant brain tumor in children, but accounts for only 1% of brain cancers in adults. For standard-risk pediatric medulloblastoma, current therapy includes craniospinal irradiation (CSI) at reduced doses (23.4Gy) associated with chemotherapy. Whereas most same-stage adult patients are still given CSI at 36Gy, with or without chemotherapy, we report here on our use of reduced-dose CSI associated with chemotherapy for older patients. Methods: We gathered non-metastatic patients over 18years old (median age 28years, range 18–48) with minimal or no residual disease after surgery, no negative histological subtypes, treated between 1996–2018 at the Centre Léon Bérard (Lyon) and the INT (Milano). A series of 54 children with similar tumors treated in Milano was used for comparison. Results: Forty-four adults were considered (median follow-up 101months): 36 had 23.4Gy of CSI, and 8 had 30.6Gy, plus a boost to the posterior fossa/tumor bed; 43 had chemotherapy as all 54 children, who had a median 83-month follow-up. The PFS and OS were 82.2 ± 6.1% and 89 ± 5.2% at 5 years, and 78.5 ± 6.9% and 75.2 ± 7.8% at ten, not significantly different from those of the children. CSI doses higher than 23.4Gy did not influence PFS. Female adult patients tended to have a better outcome than males. Conclusion: The results obtained in our combined series are comparable with, or even better than those obtained after high CSI doses, underscoring the need to reconsider this treatment in adults.

The rapid spread of coronavirus disease 2019 epidemic in Italy, in particular in the Milan focal point, required drastic measures and led to panic in the population. While in our center we did not change our approach to the treatment of our young patients with cancer, we developed a qualitative survey to assess their perception of the risk and level of stress. The survey showed that a relatively large proportion of young patients felt personally at risk of severe complications. We believe that we need to adequately inform our patients, focusing on hygienic measures and personal protection and prompt reporting of any suspicious symptoms.

Despite improvements in survival, cancer remains the leading cause of non-accidental death in children and adolescents, who risk receiving high-intensity end-of-life (HI-EOL) care.ObjectiveTo analyse treatments for relapses (particularly in the last weeks of life), assess their impact on the EOL, identify patients most likely to receive HI-EOL care and examine whether palliative care services can contain the intensity of EOL care.MethodsThis retrospective study involved patients treated at the paediatric oncology unit of the Istituto Nazionale Tumori in Milan who died between 2018 and 2020. The primary outcome was HI-EOL care, defined as: ≥1 session of intravenous chemotherapy ResultsThe study concerned 68 patients, and 17 had HI-EOL care. Patients given specific in-hospital treatments in the last 14 days of their life more frequently died in hospital. Those given aggressive EOL care were less likely to die at home or in the hospice. Patients with central nervous system (CNS) tumours were more likely to have treatments requiring hospitalisation, and to receive HI-EOL care.ConclusionThese results underscore the importance of considering specific treatments at the EOL with caution. Treatments should be administered at home whenever possible.The early activation of palliative care, especially for fragile and complicated patients like those with CNS cancers, could help families cope with the many problems they face.

Introduction: It is well known that, with advances in the treatment of cancer patients achieving a 5-year overall survival of over 75% nowadays, pediatric neuro-oncologists are worried about long-term sequelae that frequently demand lifelong care and multiple specialist skills.Areas covered: This review aims to discuss the main issues concerning cancer survivors’ disabilities and rehabilitation, including cognitive and neuropsychological aspects, language and social skills, the return to school, starting or returning to work, endocrinological impairments, and supportive measures. The review also covers some experimental rehabilitation pathways based on advanced tools or techniques to provide an overview of the currently-available options for improving patients’ quality of life. We have included our findings deriving from a lengthy experience (2000–2015) of assessing brain tumor patients and managing their intensive tailored rehabilitation.A case report on a patient’s coping with childhood cancer i...

BACKGROUND: Case reports have portrayed spinal cord atypical teratoid/rhabdoid tumor (spATRT) as an aggressive form of ATRT. We conducted a retrospective European survey to collect data on clinical characteristics, molecular biology, treatment, and outcome of children with intramedullary spATRT. METHODS: Scrutinizing a French national series and the European Rhabdoid Registry database, we identified 13 patients (median age 32 months; metastatic disease at diagnosis, n = 6). Systemic postoperative chemotherapy was administered to all patients; three received intrathecal therapy and six were irradiated (craniospinal, n = 3; local, n = 3). RESULTS: Median observation time was 8 (range, 1-93) months. Progression-free and overall survival rates at 1 and (2 years) were 35.2% ± 13.9% (26.4% ± 12.9%) and 38.5% ± 13.5% (23.1% ± 11.7%). Four patients (ATRT-SHH, n = 2; ATRT-MYC, n = 1; DNA methylation subgroup not available, n = 1) achieved complete remission (CR); two of them are alive in CR 69 and 72 months from diagnosis. One patient relapsed after CR and is alive with progressive disease (PD) and one died of the disease. Three patients (ATRT-MYC, n = 2; subgroup not available, n = 1) died after 7 to 22 months due to PD after having achieved a partial remission (n = 1) or stabilization (n = 2). Five patients (ATRT-MYC, n = 2; subgroup not available, n = 3) developed early PD and died. One patient (ATRT-MYC) died of intracerebral hemorrhage prior to response evaluation. CONCLUSIONS: Long-term survival is achievable in selected patients with spATRT using aggressive multimodality treatment. Larger case series and detailed molecular analyses are needed to understand differences between spATRT and their inracranial counterparts and the group of extradural malignant rhabdoid tumors.

Wilms tumor (or nephroblastoma), rhabdomyosarcoma, and medulloblastoma, common embryonal tumors in children, can occasionally occur in adults, for whom survival is significantly inferior than pediatric patients. Available data on adults with Wilms tumor consist of case or case series reports. Among other factors, the unfamiliarity of adult oncologists and pathologists with nephroblastoma and consequent delays in initiating the appropriate risk-adapted chemotherapy may negatively influence outcomes. The survival decrement in adults with rhabdomyosarcoma has been attributed to the lack of centralized care, the inconsistent use of standard protocol-driven multimodal therapy, and lower chemotherapy tolerance in adult patients. In children with medulloblastoma, evidence from randomized clinical trials has led to risk-tailored therapies tuned on histology, extent of initial disease, and biological features. Such refinements are still missing for adults due to the lack of similar trials and studies that might provide the same or a different understanding regarding patients' individual prognosis, treatment morbidity, and quality of life. Recent experiences have suggested that applying or adjusting pediatric protocols to adult patients with these tumors is feasible and can improve survival. Here, we provide an evaluation of the current evidence for the management of Wilms tumor, rhabdomyosarcoma, and medulloblastoma arising in adults. This review aims to promote the referral of adolescents and adults with pediatric tumors to pediatric centers for inclusion into pediatric protocols, or into protocols and studies specifically designed for that age group with the cooperation between pediatric and adult oncologists.

The diagnosis of diffuse intrinsic pontine glioma (DIPG) is based largely on a combination of clinical and radiological findings due to the difficulty of obtaining a biopsy. An accurate evaluation of magnetic resonance imaging (MRI) scans is consequently essential. Recent analyses on the genomic landscape of DIPG revealed recurrent mutations in the H3F3A and HIST1H3B histone genes. We reviewed cases with available tumor tissue from institutional DIPG series to ascertain the consistency between their histo-molecular findings and clinical-radiological features. We conducted a radiological and pathological central review of 22 cases enrolled in institutional DIPG trials. We performed immunohistochemical analyses to detect H3F3A/HIST1H3B K27M mutations, histone trimethylation, and EZH2 expression. Mutational analysis was performed for ACVR1, H3F3A, and HIST1H3B genes. Patients’ median age at diagnosis was 8 years, and their median overall survival was 11 months. Nineteen/22 cases (86%) showed evidence of K27M mutation on immunohistochemistry and/or mutation analysis. Histone trimethylation expression was low or lacking in these mutated cases. Sequence analysis revealed 13 cases with H3F3A and 1 case with HIST1H3B K27M mutation. There was no significant difference in EZH2 expression between the K27M mutant and wild-type DIPGs. Upon external, blinded MRI re-evaluation one lesion not consistent with DIPG showed no evidence of K27M mutation and retained histone trimethylation expression. In conclusion, our study demonstrates a high frequency of histone K27M mutations in DIPG when MRI features are carefully assessed, thus confirming the consistency of imaging with biological markers in our institutional series of DIPG.

The aim of this study was to investigate MRI-derived diffusion weighted imaging (DWI),We retrospectively analyzed 22 pediatric patients with DMG histologically proved and molecularly classified as H3K27M-mutant (12 subjects) and wild-type (10 subjects) who underwent DWI,The highest degrees of correlation among different techniques were found between T/S, rADC min and Cho/NAA ratio (p 0.01), and between rCBF max and rADC min (p 0.01). Significant differences between histologically classified low- and high-grade DMG, independently of H3K27M-mutation, were found among all imaging techniques (p ≤ 0.02). Significant differences in terms of rCBF max, rADC min, Cho/NAA andAdvanced MRI and

Background The potential impact of diagnostic delays on patients’ outcomes is a debated issue in pediatric oncology and discordant results have been published so far. We attempted to tackle this issue by analyzing a prospective series of 351 consecutive children and adolescents with solid malignancies using innovative statistical tools. Methods To address the nonlinear complexity of the association between symptom interval and overall survival (OS), a regression tree algorithm was constructed with sequential binary splitting rules and used to identify homogeneous patient groups vis-a-vis functional relationship between diagnostic delay and OS. Results Three different groups were identified: group A, with localized disease and good prognosis (5-year OS 85.4%); group B, with locally or regionally advanced, or metastatic disease and intermediate prognosis (5-year OS 72.9%), including neuroblastoma, Wilms tumor, nonrhabdomyosarcoma soft tissue sarcoma, and germ cell tumor; and group C, with locally or regionally advanced, or metastatic disease and poor prognosis (5-year OS 45%), including brain tumors, rhabdomyosarcoma, and bone sarcoma. The functional relationship between symptom interval and mortality risk differed between the three subgroups, there being no association in group A (hazard ratio [HR]: 0.96), a positive linear association in group B (HR: 1.48), and a negative linear association in group C (HR: 0.61). Conclusions Our analysis suggests that at least a subset of patients can benefit from an earlier diagnosis in terms of survival. For others, intrinsic aggressiveness may mask the potential effect of diagnostic delays. Based on these findings, early diagnosis should remain a goal for pediatric cancer patients.