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Worldwide, the coronavirus 19 disease pandemic caused a worse chance of a timely diagnosis for cancer patients. We conducted a retrospective analysis of new diagnoses registered in the national pediatric oncology database, comparing the first lockdown period (March-May 2020) with the same period of 2015-2019. The total number of cases (0-19 years) dropped by 20.8% (from 441 between 2015 and 2019 to 349 in 2020). A major reduction was observed for adolescents (15-19 years) (-32.9%) and for adolescents with solid tumors (-56.4%, p = 0.03). Our data suggest that the enforced lockdown reduced the possibility for these already vulnerable patients to access the referral centers.

Purpose: To describe how the provision of services for adolescents with cancer has evolved in Italy, the study evaluated access to pediatric oncology centers affiliated to the national cooperative ...

Purpose: Adolescents (15–19 years) with soft tissue sarcomas (STS) have worse survival than children. One reason is the former's limited access to expert centers. We investigated where adolescents ...

Background: The association between inflammatory bowel disease (IBD) and immune thrombocytopenia (ITP) is still uncertain. In this multicenter retrospective study, the coexistence of both diseases was investigated in children diagnosed from 1 January 2000 to 31 December 2019. Methods: Clinical characteristics of both IBD and ITP, onset of disorders, and patient’s response to treatment were collected through a structured form sent to 55 Italian pediatric referring centers for hematological disorders. Result: Centers responded to the survey and reported the coexistence of IBD and ITP in 14 children. The first diagnosis was ITP in 57.1% and IBD in 35.7% of patients: it was simultaneous in 7.1%. IBD was classified as ulcerative colitis (57.1%), Crohn disease (35.7%), and unclassified (7.1%). No therapy for IBD other than steroids had any effect on ITP course. Colectomy resulted in recovery from ITP in 1 of the 2 patients surgically treated. ITP was always mild but turned to be chronic in half of patients. Conclusions: In all patients, ITP was mild without any evident impact on IBD severity, but the incidence of chronic ITP seems to be higher than what is usually observed in the pediatric age group. Colectomy had unpredictable effects on ITP.

Brain tumors in infants including those diagnosed in fetal age, newborns and under a year old represent less than 10% of pediatric nervous system tumors and present differently when compared with older children in terms of clinical traits, location and histology. The most frequent clinical finding is a macrocephaly but non-specific symptoms can also be associated. The prognosis is usually poor and depends on several factors. Surgery continues to be the main option in terms of therapeutic strategies whereas the role of chemotherapy is not yet well defined and radiotherapy is exceptionally undertaken. In view of this situation, a molecular characterization could assist in providing therapeutic options for these tumors. This review highlights the recent advances in the diagnosis and treatment of brain tumors in infants with a particular focus on the molecular landscape and future clinical applications.

Summary Background Presenting symptoms of childhood cancers might mimic those of rheumatic diseases. However, the evidence available to guide differential diagnosis remains scarce. Preventing wrong or delayed diagnosis is therefore important to avoid incorrect administration of glucocorticoid or immunosuppressive therapy and worsening of prognosis. As such, we aimed to assess the prevalence and characteristics of presenting musculoskeletal manifestations in patients at cancer onset and to identify the factors that differentiate childhood malignancies with arthropathy from juvenile idiopathic arthritis. Methods We did a multicentre, cross-sectional study at 25 paediatric haemato-oncology centres and 22 paediatric rheumatology centres in Italy. We prospectively recruited patients who were younger than 16 years that were newly diagnosed with cancer or juvenile idiopathic arthritis. We excluded patients with glucocorticoid pre-treatment (>1 mg/kg per day of oral prednisone or equivalent for ≥2 consecutive weeks). We collected data for patients with a new diagnosis of cancer or juvenile idiopathic arthritis using an electronic case report form on a web-based platform powered by the Cineca Interuniversity Consortium. The primary outcome was to describe the frequency and characteristics of musculoskeletal manifestations at cancer onset; and the secondary outcome was to identify factors that could discriminate malignancies presenting with arthropathy, with or without other musculoskeletal symptoms, from juvenile idiopathic arthritis using multivariable logistic regression analysis. Findings Between May 1, 2015, and May 31, 2018, 1957 patients were eligible, of which 1277 (65%) had cancer and 680 (35%) had juvenile idiopathic arthritis. Musculoskeletal symptoms occurred in 324 (25% [95% CI 23·0–27·8]) of 1277 patients with cancer, of whom 207 had arthropathy. Patients with malignant bone tumours had the highest frequency of musculoskeletal symptoms (53 [80%] of 66), followed by patients with Langerhans histiocytosis (16 [47%] of 34), leukaemia (189 [32%] of 582), soft-tissue sarcomas (16 [24%] of 68), and neuroblastoma (21 [19%] of 109). In the 324 patients with cancer and musculoskeletal symptoms, the most common complaints were joint pain (199 [61%]), followed by limb bone pain (112 [35%]). Joint involvement had a prevalent monoarticular pattern (100 [48%] of 207) and oligoarticular pattern (86 [42%] had 2–4 joints involved and 20 [10%] had >4 joints involved), with the most frequently involved joints being the hip (88 [43%] of 207) and knee (81 [39%]). On multivariable analysis, limb bone pain was the independent variable most strongly associated with cancer (odds ratio [OR] 87·80 [95% CI 18·89–408·12]), followed by weight loss (59·88 [6·34–565·53]), thrombocytopenia (12·67 [2·40–66·92]), monoarticular involvement (11·30 [4·09–31·19]), hip involvement (3·30 [1·13–9·61]), and male sex (2·40 [1·03–5·58]). Factors independently associated with juvenile idiopathic arthritis were morning stiffness (OR 0·04 [95% CI 0·01–0·20]), joint swelling (0·03 [0·01–0·09]), and involvement of the small hand joints (0·02 [0–1·05]). Interpretation Our study provides detailed information about presenting musculoskeletal manifestations of childhood cancers and highlights the clinical and laboratory features that are most helpful in the differential diagnosis with juvenile idiopathic arthritis. Funding Associazione Lorenzo Risolo.

Background: Patients with hematologic malignancies appear to have a greater risk of SARS-CoV-2 infection and severe disease due to myelosuppression;furthermore, delays in treatment of patients with hematologic malignancies, especially those with acute leukemia planned for chemotherapy or transplantation, are associated with a risk of disease progression. To date, some societies recommend that chemotherapy should generally not be started until COVID-19 symptoms have completely resolved and viral testing becomes negative. However, implications of the aforementioned recommendations remain uncertain in routine clinical practice, and data on COVID-19 in patients with hematologic malignancies are still limited. Aims: We carried out a single-center analysis of acute leukemia inpatients who developed COVID-19 during the last year. Methods: Since February 2020 to February 2021, a total of 310 Hospitalizations,63 adult patients were admitted in our Center for treatment of hematologic malignancies. The indication for admission was acute myeloid leukemia (AML) in 50 (30%) patients, acute lymphoblastic leukemia (ALL) in4 (8%), lymphoma in 54 (33%), myeloma in4 (8%), other 31 (19%). Diagnosis of SARS-CoV-2 infection was based on virus detection by real-time polymerase chain reaction (SARS-CoV-2 E-gene RT-PCR) in respiratory tract specimens. Standard preventive measures for SARS-CoV-2 infection control were applied to all patients care, accordance with National disease control and prevention guidelines. Results: Ten (6%) patients tested positive for SARS-CoV-2 via PCR in a unique Covid-19 outbreak during hospitalization stay, and they were immediately transferred to Covid Infectious Unit. All these patients, were affected by Acute Leukemia (8 pts AML, 2 pts ALL ph negative), the majority of them was in peak of cytopenia at the Covid-19 infection time. Nine patients had been treated with intensive chemotherapy before SARS-CoV-2 confirmation. At SARS-CoV-2 diagnosis, only one patient had untreated, newly diagnosed AML;3 patients had refractory/relapsed AML. One patient was in complete remission with incomplete hematologic recovery (CRi). Deep vein thrombosis complicated by pulmonary embolism and interstitial pneumonia was observed in a patients despite anticoagulation and in thrombocytopenia. After SARS-CoV-2 infection, no leukemia-specific treatment was adjusted. Three patients (30%) died due to severe acute respiratory distress syndrome (ARDS) despite extracorporeal membrane oxygenation (ECMO) in deep aplasia, all of them was in refractory disease. Seven patients delayed in chemotherapy treatment for a media of 34 days;chemotherapy started until COVID-19 symptoms have completely resolved and two viral testing becomes negative. However, these patients are still alive and maintained their complete remission, remaining for long-time negative for SARS-CoV-2. One patient underwent to bone marrow transplantation Summary/Conclusion: Our findings support the vulnerability of patients with hematologic malignancies in the COVID-19 pandemic, and we reported a high COVID-19 infection mortality of 30%, in accordance with other hematological case series. However, deaths owing to Covid-19 were observed in patients in disease leukemia progression;furthermore, our recovered COVID-19 leukemia patients remained negative for SARSCoV- 2 after delivery of chemotherapy, and underwent to their following chemotherapy and allo-BMT program without any other complications.

The association between celiac disease (CD) and immune thrombocytopenia (ITP) is still uncertain. The aim of this study was to characterize the coexistence of these two diseases in Italian children.This is a retrospective multicenter study investigating the occurrence of CD in 28 children with ITP diagnosed from January 1, 2000, to December 31, 2019.The first diagnosis was ITP in 57.1% and CD in 32.1% of patients. In 3 patients (10.7%), the two diagnoses were simultaneous. All the potential and silent cases of CD in our cohort were diagnosed in the groups of “ITP first” and “simultaneous diagnosis”. In all children ITP was mild, and in 2 out of 8 not recovered from ITP at the time of CD diagnosis a normalization of platelet counts (100,000/μL) occurred 3 and 5 months after starting a gluten-free diet, respectively.We think that screening for CD should be considered in children with ITP regardless of the presence of gastrointestinal symptoms. Furthermore, some patients may recover from ITP after starting a gluten-free diet.İmmün trombositopeni (İTP) ve çölyak hastalığı (ÇH) arasındaki ilişki hala belirsizliğini korumaktadır. Bu çalışmanın amacı İtalyan çocuklarında bu iki hastalık arasındaki ilişkiyi ortaya koymaktır.Bu çalışma, 1 Ocak 2000’den 31 Aralık 2019’a kadar İTP tanısına ek olarak ÇH tanısı alan 28 çocuğun araştırıldığı geriye dönük çok merkezli bir çalışmadır.Hastaların %57,1’inde ilk tanı İTP ve %32,1’inde ÇH idi. Üç hastada (%10,7) iki tanı aynı anda konulmuştu. Kohortumuzdaki tüm potansiyel ve sessiz ÇH olguları “önce İTP” ve “eşzamanlı tanı” gruplarında teşhis edildi. Tüm çocuklarda İTP hafifti ve ÇH tanısı sırasında trombositopenisi devam eden 8 çocuktan 2’sinde, glutensiz diyete başladıktan sonra sırasıyla 3 ve 5 ayda trombosit sayılarında normalleşme (100.000/μL) görüldü.Bu çalışma İTP’li çocuklarda gastrointestinal semptomların varlığına bakılmaksızın ÇH taramasının yapılması gerektiğini düşündürmektedir. Bazı hastalarda trombosit sayılarının glutensiz bir diyete başladıktan sonra düzelebileceği akılda bulundurulmalıdır.

Adolescents with cancer face unique medical and psychosocial challenges and it is important for their doctors to understand the psychological manifestations of cancer diagnosis and treatment in this age group. Using patient dialogues, we describe how simultaneous participation of physicians and patients could help to give voice to patient needs, in particular concerning communication.

Ectopic ACTH syndrome is rare in pediatric age. Sarcomas that cause Ectopic ACTH Syndrome (EAS) are even more uncommon. Currently, only three cases of EAS caused by Ewing' sarcoma have been reported. We detail a 10-year-old boy with Cushing's syndrome symptoms caused by ectopic ACTH production by a metastatic Ewing's sarcoma of the right ischio-pubic and ileo-pubic branches. The rapid appearance of cushingoid symptoms, with significant weight gain, acne, hirsutism, and hypercortisolism were implications of ectopic ACTH production as paraneoplastic Cushing's Syndrome. The very high levels of ACTH and non-suppression at the high dose dexamethasone test confirmed the clinical suspicion. We underline the possibility EAS was caused by an ACTH-secreting tumor, including soft tissue sarcomas.

Brain tumors in infants account for less than 10% of all pediatric nervous system tumors. They include tumors diagnosed in fetal age, neonatal age and in the first years of life. Among these, high-grade gliomas (HGGs) are a specific entity with a paradoxical clinical course that sets them apart from their pediatric and adult counterparts. Currently, surgery represents the main therapeutic strategy in the management of these tumors. Chemotherapy does not have a well-defined role whilst radiotherapy is rarely performed, considering its late effects. Information about molecular characterization is still limited, but it could represent a new fundamental tool in the therapeutic perspective of these tumors. Chimeric proteins derived from the fusion of several genes with neurotrophic tyrosine receptor kinase mutations have been described in high-grade gliomas in infants as well as in neonatal age and the recent discovery of targeted drugs may change the long-term prognosis of these tumors, along with other target-driven therapies. The aim of this mini review is to highlight the recent advances in the diagnosis and treatment of high-grade gliomas in infants with a particular focus on the molecular landscape of these neoplasms and future clinical applications.

Introduction Asplenic patients are at high risk of potentially fatal invasive infections, such as sepsis, meningitis, and pneumonia. It has been shown that infection from influenza viruses can precede or increase the risk of bacterial infection and of serious complications of the underlying disease. International and national guidelines recommend annual influenza vaccination in asplenic subjects. Following the Covid-19 pandemic, the major government and medical-scientific institutions in the US and in Europe have been planning how to contain infection during the 2020-2021 influenza season. Extending influenza vaccination is the safest and most effective way to reduce the circulation of influenza virus and to promote the correct diagnosis and management of suspected cases of SARS-CoV-2. Influenza vaccination also reduces complications associated with the underlying disease and visits to Emergency Units. Our study aims to evaluate influenza vaccination in a large population of asplenic patients and explore the main causes for non-vaccination to identify critical areas for improvement in the vaccination programme in these at-risk patients for the 2020-2021 influenza season. Methods The Italian Network of Asplenia (INA) is made up of 88 doctors working in 50 clinical centers in 27 cities and 16 of the 20 regions of Italy. It aims to build a large, prospective cohort of asplenic patients throughout Italy through which to study the interaction between asplenia and its associated underlying conditions, collecting precise, accurate data also in cases of rarer diseases. The study also aims to improve the quality of healthcare for this at-risk population. The number of patients enrolled in the Network who had had at least one dose of influenza vaccine at the time of diagnosis of asplenia was retrieved from the INA database. All participating centers were asked to answer a questionnaire to report the main obstacles for influenza vaccination. Results At 1st August 2020, 1,670 patients had been enrolled in the INA (783 females; 887 males). All underlying causes of asplenia are shown in Table 1. Only 466 (28%) patients had had at least one influenza vaccination, while 1,204 (72%) had never been vaccinated since diagnosis of asplenia. Thirty-five (70%) of the 50 centers answered the questionnaire. Main causes of non-vaccination were physicians' ambivalence concerning vaccination and patients' inadequate awareness or logistical problems. Conclusions These data show very low seasonal influenza vaccination cover even though asplenic patients are considered at-risk of complications associated with infection from influenza viruses. Since the 2020-2021 influenza season could see influenza viruses in circulation with SARS-CoV-2, influenza vaccination must be expanded as widely as possible, in particular to subjects of all ages at high risk. These results reveal important areas of concern in the management of asplenic patients and the need to improve the quality of information to physicians and patients alike. The INA co-ordinating center will launch a campaign to provide information and organize ad hoc meetings to widen influenza vaccination coverage in asplenic patients and reduce the pressure on the national health service during the next influenza season. Disclosures Forni: Novartis: Membership on an entity's Board of Directors or advisory committees. Colombatti:Addmedica: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Giona:Sanofi Genzyme: Research Funding, Speakers Bureau; Takeda: Speakers Bureau; Novartis: Research Funding. Ferrero:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Research Funding, Speakers Bureau; Servier: Speakers Bureau. Perrotta:Novartis: Consultancy, Research Funding, Speakers Bureau. Casale:Novartis: Membership on an entity's Board of Directors or advisory committees.

BACKGROUND: Everolimus, an mTOR inhibitor, in combination with exemestane is approved for hormone receptor (HR) positive advanced breast cancer (ABC), after failure of treatment with non-steroidal aromatase inhibitor (NSAI). We assessed the toxicity of the combination and the correlation between dose intensity and response to therapy, in a real world population of ABC from 11 Italian centers. Moreover, we evaluated OS of the whole population, RR and PFS according to line of treatment (from 1rd to 3th and from 4th on). METHODS: 154 pts were treated with combination of everolimus 10 mg and exemestane 25 mg daily from 05/2011 today. Median age was 62 (47-82). Median time to metastatic disease was 49 months (0-269). Median number of metastatic sites was 2 (55.2% of pts visceral versus 44.8% non visceral disease). N=117 (75.9%) pretreated with HT as adjuvant; N=126 pts (81.8%) treated with HT for advanced disease prior to EVE/EXE, with a median of one line (0-5). N=102 pts (66.2%) treated with chemotherapy for metastatic disease, with a median of one line (0-6) before everolimus treatment. RESULTS: Sixteen pts received EVE/EXE as 1st line (10.4%), 39 as 2nd (25.3%), 37 as 3rd (24%), 62 as 4th or more (40,3%). Response was evaluable in 127 out of 154 pts; CR/PR/SD respectively 5/27/56 pts. RR according to line (from 1st to 3rd vs ≥ 4th) was respectively 22.8% vs 26.4% (p=0,864). The median PFS for all population (150 pts) was 38 weeks (95% CI: 33-42). The PFS according to line (1st- 3rd vs ≥ 4th) was 38 wks in both subgroups, p=0.73. OS (126/154 pts) was 28 mths (95% CI: 31-38). The most frequent adverse events were collected in the table. Adverse eventsOverall %Grade 3-4 %Stomatitis55.810.4Hypercholesterolemia47.40.0Asthenia42.95.2Hyperglycemia36.45.8Hypertriglyceridemia29.20.6Anemia28.63.9Peripheral edema24.71.3Rash23.40.6Increased ALT/AST/GGT21.46.5Thrombocytopenia19.53.9Diarrhea18.81.9Weight loss18.21.3Dysgeusia17.50.6Pneumonitis15.61.9Cutaneous toxicity14.90.6Infection14.33.2Neutropenia11.71.9Nausea11.70.0Anorexia (without stomatitis)10.41.3Electrolyte alterations9.71.3Urea/creatinine increase6.51.3Vomiting6.50.0Uric acid increase4.50.0 Median duration of treatment with everolimus 10 mg and 5 mg was respectively 180 (9-854) and 129 days (3-738). Fifty-eight pts (37,6%) never stopped treatment with everolimus 10 mg; 16 pts (10,4%) definitively stopped everolimus for toxicity; 80 pts (52,0%) temporarily interrupted the treatment, resuming at dose level 10 mg (31 pts) or reducing at 5 mg (49 pts). Main reason for discontinuation/interruption was stomatitis G2-G3. RR and PFS evaluated according to dose intensity, 10 mg vs 5 mg, were respectively 25.9% vs 30% p=0.779, 38 wks (27-44) vs 40 wks (31-48) P=0.614 CONCLUSIONS: efficacy in terms of RR and PFS of the combination EVE/EXE is not related to dose intensity (10 mg vs 5 mg), the discontinuation of the treatment is high with the starting dose of 10 mg, the toxicity is consistent with previous phase II-III studies although we collected some different toxicities. Citation Format: Forcignanò R, Petrucelli L, Cazzaniga ME, Lupo LI, Chiuri VE, Cairo G, De Matteis E, Febbraro A, Giordano G, Campidoglio S, Fabi A, Giampaglia M, Bilancia D, La Verde N, Maiello E, Morritti M, Giotta F, Lorusso V, Scavelli C, Romito S, Cusmai A, Palmiotti G, Tornesello A, Ciccarese M. Dose intensity and efficacy of the combination of everolimus and exemestane (EVE/EXE) in a real world population of hormone receptor positive advanced breast cancer: A multicenter Italian experience. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-13-15.

Medulloblastoma is the most common pediatric brain tumor. We describe a child with tuberous sclerosis complex that developed a Group 3, myc overexpressed, metastatic medulloblastoma (MB). Considering the high risk of treatment-induced malignancies, a tailored therapy, omitting radiation, was given. Based on the evidence of mammalian target of rapamycin mTORC, mTOR Complex; RAS, Rat sarcoma; RAF, rapidly accelerated fibrosarcoma (mTOR) pathway activation in the tumor, targeted therapy was applied resulting in complete remission of disease. Although the PI3K/AKT/mTOR signaling pathway plays a role in MB, we did not find TSC1/TSC2 (TSC, tuberous sclerosis complex) mutation in our patient. We speculate that a different pathway resulting in mTOR activation is the basis of both TSC and MB in this child; HE Gd, gadolinium.

Purpose: The aims of patients’ radiological surveillance are to: ascertain relapse; apply second-line therapy; accrue patients in phase 1/2 protocols if second-line therapy is not standardized/curative; and assess/treat iatrogenic effects. To lessen the emotional and socioeconomic burdens for patients and families, we ideally need to establish whether scheduled radiological surveillance gives patients a better outcome than waiting for symptoms and signs to appear. Methods: We analyzed a prospective series of 160 newly-diagnosed and treated pediatric/adolescent patients with intracranial ependymoma, comparing patients with recurrent disease identified on scheduled MRI (the RECPT group; 34 cases) with those showing signs/symptoms of recurrent disease (the SYMPPT group; 16 cases). The median follow-up was 67 months. Results: No significant differences emerged between the two groups in terms of gender, age, tumor grade/site, shunting, residual disease, or type of relapse (local, distant, or concomitant). The time to relapse (median 19 months; range 5–104) and the MRI follow-up intervals did not differ between the SYMPPT and RECPT groups. The presence of signs/symptoms was an unfavorable factor for overall survival (OS) after recurrence (5-year OS: 8% vs. 37%, p = 0.001). On multivariable analysis, an adjusted model confirmed a significantly worse OS in the SYMPPT than in the RECPT patients. Conclusions: Symptomatic relapses carried a significantly worse survival for ependymoma patients than recurrences detected by MRI alone. It would therefore be desirable to identify recurrences before symptoms develop. Radiological follow-up should be retained in ependymoma patient surveillance because there is a chance of salvage treatment for relapses found on MRI

Introduction Treatment of pediatric malignancies is becoming progressively more complex, implying the adoption of multimodal therapies. A reliable, long-lasting venous access represents one of the critical requirements for the success of those treatments. Recent technical innovations—such as minimally invasive procedures for placement, new devices and novel materials—have rapidly spread for clinical use in adult patients, but are still not consistently used in the pediatric population. Methods The Supportive Therapy Working Group of Italian Association of Hematology and Oncology (AIEOP) reviewed medical literature focusing on new aspects of central venous access devices (VADs) in pediatric patients affected by oncohematological diseases. Results Appropriate recommendations for clinical use in these patients have been discussed and formulated. Conclusions The importance of the correct choice, management and use of VADs in pediatric oncohematological patients is a necessary prerequisite for an adequate standard of care, also considering the increased chances of cure and the longer life expectancy of those patients with modern therapies.

Aims of patient follow-up are: discovering relapse to apply second-line therapy for possible cure, accruing patients in phase 1/2 protocols if second-line therapy is not standardized/curative, evaluating/treating iatrogenic effects. To lessen the patient/family emotional and social economic burdens, we should ideally understand if scheduled radiological follow-up has a better rationale/outcome than the symptomatic relapse. We analyzed the Italian series of 2016 (doi:10.1093/neuonc/now108) comprehending 160 newly diagnosed pediatric/adolescent patients with intracranial ependymoma (EPD) according to relapse status (recurrence at scheduled exam [RECPT]/sign-symptomatic recurring [SYMPPT]). RECPT and SYMPPT were assessed in Cox model as time-dependent variables for overall survival (OS). Differences in characteristics between RECPT and SYMPPT subgroups were assessed by Wilcoxon-Mann-Whitney or Fisher Exact tests. Kaplan-Meier curves depicted event-free survival (EFS) and OS after recurrence according to signs/symptoms. There were 16 SYMPPT /34 RECPT, at a median follow-up of 55 months. No significant differences were found between SYMPPT/RECPT for gender, age, tumor grade/site, shunt, residual disease, radiation boost, type of relapse (local/distant/combined). Time-to-relapse (median:19 months, range 5–104) and treatment adoption did not differ between SYMPPT/RECPT while signs/symptoms depicted an unfavorable factor for OS after relapse (5-year OS: 8% vs 37%). Adjusted model in multivariate analysis confirmed that presence of signs/symptoms was prognostically unfavorable. In order to improve the OS in symptomatic patients, their early identification-in the first two/three years after diagnosis- would be desirable. Perhaps, this could be obtained paying attention to “heuristically detected” subgroup of patients, not just describing general prognostic variables but discovering possible biology differences according to signs/symptoms.

Background: Immune Thrombocytopenia (ITP) is one of the most common conditions encoutered by the pediatric hematologist. Current first-line therapy includes: observation without drug therapy, corticosteroids and intravenous immune globulin. A minority of patients are refractory to first-line approaches. Second-line treatment options are: immunosuppressive agents and thrombopoietin receptor agonists (TPO-RA). Eltrombopag and Romiplostin are TPO-RA licensed for clinical use. Eltrombopag is, actually, the only TPO-RA approved in Italy (since two years ago) for children, over one year old, with a chronic and/or refractory ITP. Real life data of Eltrombopag are limited. Methods: We performed an Italian multicenter retrospective survey to study the clinical on-label use of TPO-RA, focus on Eltrombopag, in pediatric ITP. Our aims were, primarily, to bring out the prevalence of the use in clinical practice and secondarily to collect data on efficacy and toxicity. Results: We enrolled 69 pediatric ITP subjects from 15 Italian treatment centers (TC). 4 patients received Romiplostin as TPO-RA and were excluded by the analysis. 36/65 patients weer female (55%). Median age at ITP diagnosis: 6 years + 6 months (min 1 y + 2 m; max 16 y + 7 m). Median age at first Eltrombopag assumption: 11 years + 5 months (min 2 y + 0 m; max 17 y + 8 m). Accounting in 344 the total number of chronic ITP subjects treated by TC in the same observation period (July 2016-June 2018), we observed an Eltrombopag clinical use prevalence of 0.19 (95% CI 0.15 to 0.26). We underlined a "no response" to Eltrombopag (platelet count persistently less than 30000 per microliter) in 16/65 (25%); a "partial response" (platelet count between 30000 and 100000 per microliter) in 14/65 (21%) and a "complete response" (platelet count persistently up than 100000 per microliter) in 35/65 (54%). The overall response (partial or complete) was described in 49/65 (75%) children. During the follow up was seen in 16/49 (33%) subjects with initial response a platelet rise that waned to no response. There was no evidence of significant adverse events (clinicians are obliged, to monthly surveillance, by Italian drug agency for hypertransaminasemia and peripheral smear cell abnormalities). Conclusions: Our results demonstrate that Eltrombopag is a therapeutic option quite considered by Italian clinicians. Moreover, according with the percentages of clinical trials, Eltrombopag is safe and effective to rise platelet count. Further studies need to emphasize how factors favor a complete response and to know the incidence of long-term adverse effects. A prospective study designed and driven by Italian Association of Pediatric Hematology Oncology (AIEOP) Coagulation Disorders Working Group is, already, in progress. Disclosures No relevant conflicts of interest to declare.

Aberrant signal transduction contributes substantially to leukemogenesis. The Janus kinase 1 (JAK1) gene encodes a cytoplasmic tyrosine kinase that noncovalently associates with a variety of cytokine receptors and plays a nonredundant role in lymphoid cell precursor proliferation, survival, and differentiation. We report that somatic mutations in JAK1 occur in individuals with acute lymphoblastic leukemia (ALL). JAK1 mutations were more prevalent among adult subjects with the T cell precursor ALL, where they accounted for 18% of cases, and were associated with advanced age at diagnosis, poor response to therapy, and overall prognosis. All mutations were missense, and some were predicted to destabilize interdomain interactions controlling the activity of the kinase. Three mutations that were studied promoted JAK1 gain of function and conferred interleukin (IL)-3–independent growth in Ba/F3 cells and/or IL-9–independent resistance to dexamethasone-induced apoptosis in T cell lymphoma BW5147 cells. Such effects were associated with variably enhanced activation of multiple downstream signaling pathways. Leukemic cells with mutated JAK1 alleles shared a gene expression signature characterized by transcriptional up-regulation of genes positively controlled by JAK signaling. Our findings implicate dysregulated JAK1 function in ALL, particularly of T cell origin, and point to this kinase as a target for the development of novel antileukemic drugs.

Pearson syndrome (PS) is a very rare and often fatal multisystemic mitochondrial disorder involving the liver, kidney, pancreas, and hematopoietic and central nervous system. It is characterized principally by a transfusion-dependent anemia that usually improves over time, a tendency to develop severe infections, and a high mortality rate. We describe a group of 11 PS patients diagnosed in Italy in the period 1993-2014. The analysis of this reasonably sized cohort of patients contributes to the clinical profile of the disease and highlights a rough incidence of 1 case/million newborns. Furthermore, it seems that some biochemical parameters like increased serum alanine and urinary fumaric acid can help to address an early diagnosis.

Biological and clinical observations suggest that initial marked reduction of resistant clones may be critical in any attempt to improve long-term results in advanced neuroblastoma (NB). The aim of this pilot study is to determine short-term toxicity and efficacy of a new therapeutic model based on the simultaneous use of multiple drug chemotherapy and specific irradiation using 131-I-MIBG. The study population consisted of 21 patients, from 1 to 8 years of age with good 131-I-MIBG uptake. 16 extensively pre-treated patients with refractory or relapsed disease were divided into 2 groups. In Group 1 (9 patients) the basic chemotherapy regimen consisted in cisplatin at the dose of 20 mg/m2i.v. per day infused over 2 h, for 4 consecutive days; on day 4 Cy 2 g/m2i.v. was administered over 2 h followed by Mesna. Group 2 (7 patients) was treated with basic chemotherapeutic regimen plus VP16 and Vincristine. VP16 at the dose of 50 mg/m2i.v. per day was administered as a 24 h infusion on days 1–3; Vincristine 1.5 mg/m2i.v. was administered on days 1 and 6. On day 10 a single dose of 131-I-MIBG (200 mCi) with a high specific activity (>1.1 GBq/mg) was administered to both Groups by i.v. infusion over 4–6 hours. A further 5 patients were treated at diagnosis: 2 with the same regimen as Group 1 and 3 with the same as Group 2. The severity of toxicity was graded according to World Health Organization (WHO) criteria. Assessment of tumour response was monitored 4–6 weeks after the beginning of combined therapy (CO-TH). Response was defined according to INSS (International Neuroblastoma Staging System) criteria. No extra-medullary toxicity was observed in any patient. Haematological toxicity was the only toxicity observed and seemed mainly related to chemotherapy. Myelosuppression was mild in the 5 patients treated at diagnosis. No serious infections or significant bleeding problems were observed. In the 16 resistant patients, 12 PR, 1 mixed response and 3 SD were obtained. In the 5 patients treated at diagnosis 2 PR, 1 CR and 2 VGPR were observed. No alteration in 131-I-MIBG uptake was observed after the chemotherapy preceding radio-metabolic treatment. The therapeutic results of this pilot regimen of CO-TH resulted in a high percentage of major response after only a single course in both resistant patients and patients treated at diagnosis. Because of the minimal toxicity observed in patients studied at diagnosis so far, there is room for gradual intensification of the treatment. It is to be hoped that this suggested novel approach may represent an important route of investigation to improve final outcome in patients with advanced NB. © 2001 Cancer Research Campaign http://www.bjcancer.com

The overall prognosis in children with medulloblastoma/PNET has not significantly improved over the past decade. Intensive neoadjuvant chemotherapy has not yet adequately explored. We evaluated the short-term clinical results of an intensive chemotherapy regimen in high risk children with newly diagnosed MB/PNET, after surgery and before radiation. Twelve previously untreated patients with high-risk medulloblastoma/PNET, according to Chang's classification, were treated with the following chemotherapy regimen: high dose carboplatin 600 mg/m2/day on days 1 and 2; the same course was administered 4 weeks later. One month later, high dose cyclophosphamide 2 g/m2/day on days 1 and 2, followed by an identical course 4 weeks later. Vincristine 1,5 mg/m2 iv was given on the first day of each course. Systemic evaluation of the disease included imaging of the entire neuraxis, including MRI of the entire spine. Out of 12 enrolled, 7 patients were able to be evaluated for a residual disease after surgery. After two cycles of high dose carboplatin, we noted I CR, 4 PR and 2 MR. After the subsequent two cycles of high dose cyclophosphamide we observed an additional response in 4 cases. On the other hand, 4 patients clearly showed evidence of PD immediately after the first course of cyclophosphamide (2 cases) or following the second course. Three of the 4 patients had shown respectively 1 CR and 2 PR after the second course of carboplatin. Whereas it was confirmed that 2 courses of high dose carboplatin is effective in high risk MB/PNET children, we observed an unacceptable number of PD during the subsequent high dose cyclophosphamide therapy. A review from the literature also suggests that, in general, the longer radiotherapy is delayed, the higher the incidence of PD. In the search for the optimal drug combination in “sandwich chemotherapy” for children with high risk MB/PNET, PD must be reduced to an acceptable incidence, since a high number of PD may significantly lower the probability of long-term survival.

Background. Standard chemo-radiotherapy methods for the treatment of children with advanced neuroblastoma (NBL) including bone marrow transplant approaches have been disappointing. These poor results can be ascribed to the evolution of residual drug-resistant cell populations. Curative attempts should therefore be directed to their elimination during induction treatment. This can best be accomplished through the use of multiple, non-cross-resistant agents early in therapy. 131 -Metaiodobenzyl-guanidine ( 131 -MIBG) provides a mechanism for the delivery of high doses of radiation to NBL lesions. Experience reported from several institutions indicates an approximate 50% response rate in previously treated children with advanced NBL. Conclusions. A better strategy is to employ 131 -MIBG together with intensive chemotherapy at the time of diagnosis. A pilot study adopting these principles and supported by laboratory data has been designed and is underway.

Background. With the exception of a single study the cytogenetic aspects of leukemic cells in the central nervous system (CNS) have not been investigated. Patients and Results. During the course of a work-in-progress on the chromosomal constitution both of the spinal fluid and of bone marrow (BM) in children with acute myeloblastic leukemia (AML), we have observed a unique case of AML and CNS leukemia (CNSL) at diagnosis. The patient showed the simultaneous presence at diagnosis of a 46 cytogenetic line in the spinal fluid and a 47 (+8) cell line in the BM, present in the great majority of the metaphases examined. Discussion. This observation allows hypotheses on the relationship between BM and CNS disease in AML. Regardless of the pathogenetic mechanism, the cytogenetic findings of the present case clearly suggest that the leukemic population in the CNS compartment represents a less malignant cell process compared to the BM leukemic population. This easily fits in with the usually less malignant course of CNSL in AML. Conclusion. The foregoing findings may have critical pathogenetic and therapeutic implications.

Neuroblastoma (NB), a childhood radiosensitive tumor, is very aggressive and malignant; in its disseminated form, despite very intensive chemotherapy, prognosis continues to be dismal. Owing to its capacity to concentrate in NB lesions, large doses of 131-I-MIBG, have given very encouraging therapeutic results in patients resistant to conventional therapy as well as at diagnosis.We recently reported the first attempt in combination therapy (CO-TH) using 131-I-MIBG and cisplatin. This new form of CO-TH appears very effective in obtaining a rapid and excellent response in relapsed patients.In this report, we describe the results of further experience with CO-TH in disseminated NB. We have attempted to verify to what extent interaction between the effects of the two agents may produce therapeutic benefit, and we have sought the optimization of CO-TH use.Three stage IV NB patients were treated with CO-TH. The following treatment schedule, was planned: day 1, cisplatin 50 mg/m2 i.v. over 6 h; day 2, 131-I-MIBG 100—130 mCi at high specific activity (- 1.1 Gbq/mg) i.v. over 6 h followed, a week later, by the same treatment combination.The therapeutic results were encouraging. However, hematological toxicity continued to represent a major limiting factor. In view of the overall effectiveness of CO-TH, at the price of lasting hematological toxicity, it may be indicated as a consolidationregimen some time before conditioning chemotherapy for autologous bone marrow transplantation.

We developed an animal model to evaluate the 125-I-metaiodobenzylguanidine (125-I-mIBG) biodistribution in tumor bearing mice. Six weeks old nude-atimic mice were subcutaneously injected with 30 x 10(6) cells of the human neuroblastoma (NB) cell line SH-SY5Y. TE-671, a rhabdomyosarcoma cell line, was used as a control tumor without a specific mIBG uptake mechanism. In order to prevent possible tumor rejection mediated by NK activity the anti asialo GM1 antiserum was administered intraperitoneally once a week for 4 weeks. The maximum anti asialo mediated effect was obtained by administering the first dose the same day as the cell implant. In this group of animals by 9 weeks 98% of mice had a measurable tumor. We have utilized this model to evaluate the biodistribution of 125-I-mIBG given as two different formulations: standard preparation with a specific activity of 84 mCi/mg and the no carrier added (n.c.a) formulation with a specific activity of approximately 8,000 mCi/mg. Our preliminary results indicate that the biodistribution of the two different formulations in the various organs are similar. Therefore it appears that n.c.a. mIBG should not cause an increased toxicity in possible normal target organs such as heart or adrenals. Additional experiments will be performed in this model to ascertain if there is a potential advantage of the clinical use of n.c.a. mIBG over the standard preparation.

In the last 30 years, the use of long-term central venous catheters (CVC) is increased especially for children with hemato-oncological disorders. However, the use of CVC is associated to complications, as mechanical accidents, thrombosis, and infections that can determine a prolongation of hospital stay, an increase of costs, and sometimes life-threatening conditions that require urgent systemic treatment or CVC removal. CVC removal may be troublesome especially in neonates, infants, or any other “highly needed CVC patients”; in these selected cases, the prevention and treatment of CVC-related complications play a pivotal role and specific surveillance programs are crucial. While extensive literature is focused on CVC management in adults, no guidelines are available for children. To this aim, the first recommendations for the management of CVC infectious complication in pediatric age have been written after pediatric and adult literature review and collegial discussion among members of Supportive Therapy working group of Italian Association of Pediatric Hematology and Oncology. Compared to the adult age, the necessity of peripheral vein cultures for the diagnosis of CVC-related infection remains controversial in children because of the poorer venous asset and a conservative, pharmacologically focused management through CVC remains mandatory, with CVC removal to be performed only in selected cases.

Background Streptococcus intermedius belongs to the Streptococcus anginosus group. It is part of the normal flora of the human mouth, but it can be etiologically associated with deep-site infections. Case presentation We present a case of deep neck infection complicating Streptococcus intermedius lymphadenitis, which developed in an immunocompetent 14-year-old boy with a history of recent dental work. The infection was ultimately eradicated by a combined medical and surgical approach. Conclusion Our report suggests that combined medical and surgical therapy is essential for the complete resolution of deep infections caused by Streptococcus intermedius. Molecular biological techniques can be useful in guiding the diagnostic investigation and providing insight into the possibility of occult abscesses, which are particularly common with Streptococcus intermedius infections.

Aim: ABC remains an incurable disease although the introduction of targeted agents and newest drugs has significantly improved the overall outcome. Nevertheless, the degree of the benefit provided by CT beyond the 3rd line is controversial. Methods: Data of consecutive ABC patients (pts) were retrospectively gathered, according to pathological subtype (Ki67 Results: The characteristics of 485 pts from 3 different institutions were: median age: 60 years (29-91); median time from primary: 29 months (0-721), median number of sites: 2 (1-6); visceral/bone only disease: 300 (62%)/125 (26%); Luminal A/B/HER2-positive/triple-negative/non-evaluable: 92 (19%)/124 (25%)/117 (24%)/41 (9%)/111 (23%); median number of CT lines: 2 (1-12); overall OS: 45 months (95% CI 34-56). Age (HR 1.01, 95% CI 1.01-1.03, p = 0.04), Conclusions: These data suggest that CT beyond 3rd line may potentially have a significant impact upon survival. The correlation between OS and both PPS and PFS is consistently maintained across all treatment lines. Disclosure: All authors have declared no conflicts of interest.

Veno-occlusive disease of the liver (VOD) is an important complication in children with Wilms' tumour. Although in most patients this complication resolves uneventfully, fatal cases have been reported. Several observations strongly suggest that actinomycin-D is the likeliest cause of VOD in Wilms' tumour, but VOD seems to be rather uncommon in other malignancies treated with chemotherapy including actinomycin-D. The present case of VOD and the review of the literature stress the pathogenetic and clinical implications of VOD in the presence of a Wilms' tumour treated with actinomycin-D, originating in the right kidney. Greater awareness of this 'predisposing factor' may alert paediatricians to the presence of minimal signs of the syndrome.

Few studies have been carried out regarding preoperative chemotherapy utilized in the treatment of primitive neuroectodermal tumors/medulloblastomas (PNET/MB). In this paper, the authors report 3 cases of children under three years of age, with a presumed diagnosis of PNET/MB, who were preoperatively treated with chemotherapy consisting of high doses of carboplatin alone. The treatment improved the childrens' clinical condition prior to surgery and facilitated tumor removal, resulting in partial regression of the tumor. The preoperative single-drug therapy did not affect the histological diagnosis or prevent the presence of an effective degree of tumor sensitivity to the drug. All three children are still disease-free, after a mean follow-up period of 42 months.

A diagnosis of myelodysplastic syndrome was made in an 18-year-old patient with Warkany syndrome due to constitutional trisomy 8 mosaicism. The possible causal role of this particular chromosome constitution with respect to myelodysplasia and embryonal childhood tumors is discussed.

Sixteen patients with high risk MB/PNET at diagnosis were included in a pilot study employing carboplatin (CBDCA) as a single drug prior to conventional therapy. The main goal of the study was to identify in a short-term trial a significant response that would predict further response to CBDCA in the single patient. Exploration of CBDCA activity was focused on response after the first course as compared to the response following the second course. A course consisted of CBDCA 600 mg/m2 on days 1 and 2 administered in a 1 h infusion to be repeated 3–4 weeks later. After two cycles we observed 1 CR and 9 PR, that is a 62% response rate. The first course resulted in 5 PR, 5 MR, 5 SD, and 1 PD; after the subsequent course in all responding patients, response persisted or improved whereas in no patient with SD any improvement was observed. The correlation of response to the first course with response to the second course was statistically significant (P = 0.0009). The main toxicity of the single course was hematologic and consisted of rapidly reversible grade 3–4 neutropenia and thrombocytopenia in 94% of patients. Pharmacokinetic studies showed a very limited interpatient variability of both Cmax (57.6 ± 9.9 μg/ml) and AUC (15.3 ± 1.5 mg/ml · min) of free CBDCA, which eliminates an important variable in the evaluation of response. In conclusion, this “in vivo test” appears effective, reasonably safe, and reproducible in identifying patients likely to benefit from CBCDA: after a period of time as short as 3–4 weeks following the first course, multidrug chemotherapy including CBDCA may be employed in the responding patients, whereas an alternative regimen would be indicated in the non-responding patients. © 1995 Wi1ey-Liss Inc.