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Background: Several studies have shown that the intensity of treatment in Ewing sarcoma has an impact on outcome. The present trial tested the non-inferiority of intensive, shorter, induction chemotherapy (25 weeks total treatment time) compared to the standard treatment (37 weeks) in non-metastatic Ewing sarcoma (ES) at onset., Procedure: This national, multicenter, parallel, randomized, controlled, open-label, non-inferiority, phase III trial was conducted in 14 specialized hospitals in Italy. Patients aged 2-40 years with newly diagnosed localized ES were randomized to receive four courses of induction therapy (one every 21 days) either with a standard arm (Arm A) or with an intensive arm (Arm B). For consolidation therapy, good responders (GRs) in Arm A received nine courses (37 weeks), while Arm B patients received five courses (25 weeks). Poor responders for both arms received four courses followed by high-dose busulfan/melphalan + autologous stem cell rescue. Follow-up was 5 years., Results: In the study period 2009-2018, 274 patients with ES at onset were screened, 248 were eligible, 15 refused randomization, and 233 were randomized (Arm A: 113; Arm B: 120). Median age was 14 years. Arm B was not inferior to Arm A: 5-year EFS was 77.5% and 71.6%, respectively (HR vs. Arm A: 0.74, 90% CI: 0.49-1.14). GRs were 54.9% in Arm A and 62.5% in Arm B. Hematological, gastrointestinal, and cardiovascular Grade ≥3 toxicities had higher frequencies in Arm B., Conclusions: Intensive induction therapy showed non-inferiority in 5-year EFS when compared with the standard induction therapy. Higher toxicity was reported in Arm B with similar outcome, counterbalanced in GRs with a shorter treatment plan., Clinicaltrials: gov Identifier: NCT02063022., (© 2025 The Author(s). Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

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., Objective: To 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., Methods: This 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 <14 days before death; ≥1 hospitalisation in intensive care in the last 30 days of life and ≥1 emergency room admission in the last 30 days of life., Results: The 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., Conclusion: These 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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ Group.)

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., (© 2024 The Author(s). Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

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., (© 2024 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

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., (© 2024 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Objectives: Cancer remains the leading cause of mortality by disease in childhood in high-income countries. For terminally ill children, care focuses on quality of life, and patient management fundamentally affects grieving families. This paper describes our experience of palliative sedation (PS) for children with refractory symptoms caused by solid tumours, focusing on the drugs involved., Methods: We retrospectively collected data on all children treated for cancer who died at the pediatric oncology unit of the Fondazione IRCCS Istituto Nazionale dei Tumori between January 2016 and December 2020., Results: Of the 29 patients eligible for the study, all but 4 received PS. Midazolam was always used, combined in 16 cases with other drugs (mainly classic neuroleptics, alpha-2 agonists and antihistamines). Throughout the period of PS and on the day of death, patients with sarcoma were given higher doses of midazolam and morphine, and more often received combinations of drugs than patients with brain tumours. Sarcoma causes significant symptoms, while brain tumours require less intensive analgesic-sedative therapies because they already impair a patient's state of consciousness., Conclusions: Optimising pharmacological treatments demands a medical team that knows how drugs (often developed for other indications) work. Emotional and relational aspects are important too, and any action to lower a patient's consciousness should be explained to the family and justified. Parents should not feel like helpless witnesses. Guidelines on PS in paediatrics could help, providing they acknowledge that a child's death is always a unique case., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

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., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Bats are important natural reservoir hosts of a diverse range of viruses that can be transmitted to humans and have been suggested to play an important role in the Zika virus (ZIKV) transmission cycle. However, the exact role of these animals as reservoirs for flaviviruses is still controversial. To further expand our understanding of the role of bats in the ZIKV transmission cycle in Latin America, we carried out an experimental infection in wild-caught Artibeus lituratus bats and sampled several free-living neotropical bats across three countries of the region. Experimental ZIKV infection was performed in wild-caught adult bats (4 females and 5 males). The most relevant findings were hemorrhages in the bladder, stomach and patagium. Significant histological findings included inflammatory infiltrate consisting of a predominance of neutrophils and lymphocytes, in addition to degeneration in the reproductive tract of males and females. This suggests that bat reproduction might be at some level affected by ZIKV. Leukopenia was also observed in some inoculated animals. Hemorrhages, genital alterations, and leukopenia are suggested to be caused by ZIKV; however, since these were wild-caught bats, we cannot exclude other agents. Detection of ZIKV by qPCR was observed at low concentrations in only two urine samples in two inoculated animals. All other animals and tissues tested were negative. Finally, no virus-neutralizing antibodies were found in any animal. To determine ZIKV infection in nature, the blood of a total of 2056 bats was sampled for ZIKV detection by qPCR. Most of the sampled individuals belonged to the genus Pteronotus sp. (23%), followed by the species Carollia sp. (17%), Anoura sp. (14%), and Molossus sp. (13.7%). No sample of any tested species was positive for ZIKV by qPCR. These results together suggest that bats are not efficient amplifiers or reservoirs of ZIKV and may not have an important role in ZIKV transmission dynamics., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Aguilar-Setién et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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: 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., (© 2022 Wiley Periodicals LLC.)

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., (© 2022. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

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., (© 2022 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

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.

Purpose: 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., Methods: The analysis concerned 86 patients &lt; 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)., Results: 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)., Conclusion: 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., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: The prognosis for patients with metastatic rhabdomyosarcoma (RMS) remains largely unsatisfactory despite the adoption of intensive multimodal therapy. To assess the role of different treatments adopted over the years, we retrospectively analyzed a cohort of patients &lt;21 years old with metastatic RMS, treated from 1990 to 2020 at a referral center for pediatric sarcomas., Methods: Patients were treated using a multimodal approach that included surgery, radiotherapy, and chemotherapy (both high-dose chemotherapy and maintenance therapy in some cases). The type of radiotherapy administered was categorized as radical (to all sites of disease); partial (to at least one, but not all sites of disease); or none. A landmark analysis was used to examine the impact of radiotherapy on survival, that is, patients who had an event before day 221 were excluded from the analysis., Results: The series included 80 patients. Event-free survival (EFS) and overall survival (OS) rates at 5 years were 17.3% and 21.3%, respectively. Survival was significantly associated with radiotherapy to metastatic sites, and with the radiotherapy category. In particular, 5-year EFS and OS rates were 70.6% and 76.0% for patients given radical radiotherapy, and 4.8% and 10.7%, respectively, for those given partial radiotherapy or none. Using the Cox multivariable analysis, OS correlated significantly with radiotherapy category., Conclusions: While confirming the poor overall outcome of patients with metastatic RMS, this study identified radiotherapy-when given to all sites of disease (including metastases)-as the main variable influencing survival., (© 2022 Wiley Periodicals LLC.)

Purpose: 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., Methods: 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., Results: 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)., Conclusions: 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., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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.

Purpose: Though the prognosis for patients with pediatric non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) is generally good, the chances of being cured after relapse are limited. This report describes a series of relapsing NRSTS patients treated at a referral center for pediatric sarcoma, investigating the pattern of relapse, salvage rates, and factors correlating with the final outcome., Methods: The analysis concerned 103 patients <21 years old with relapsing adult-type NRSTS treated from 1985 to 2020. For risk-adapted stratification purposes, the patient outcome was 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: The first relapse occurred within 2-102 months (median 14 months) after patients' first diagnosis and was local in 47%, metastatic in 34%, and both in 19%. Treatment at relapse included chemotherapy in 72 patients, radiotherapy in 38, and surgery in 55. The median overall survival (OS) was 20 months. Post-relapse OS was 56.1%, 25.8%, and 19.1% at 1, 5, and 10 years, respectively. Cox's multivariable regression analysis showed that OS was significantly better for patients with local and late relapses (occurring more than 12 months after their first diagnosis) and for those achieving secondary remission., Conclusion: The outcome of patients with recurrent NRSTS is poor. The above-mentioned variables (type and time of relapse and achievement of secondary remission) were combined in a risk-adapted model to develop a tool for estimating the chance of salvage and deciding the best second-line treatment approach., Competing Interests: Conflict of interest statement The authors declare that there is no conflict of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: 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 patients <21 years treated according to a "soft tissue sarcoma approach.", Methods: 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., Results: 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%., Conclusions: 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., (© 2021 Wiley Periodicals LLC.)

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., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)