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Neuroblastoma is the most common extracranial solid tumour in children, accounting for 15% of all paediatric cancer deaths. High-risk neuroblastoma is a particularly challenging-to-treat form of disease that requires multimodality treatment, consisting of chemotherapy, surgery, high-dose chemotherapy with autologous haematopoietic stem cell rescue, radiotherapy and differentiation therapy. However, despite intense multimodal treatment regimens, the prognosis for this patient population remains poor. In recent years, immunotherapy with anti-disialoganglioside 2 (anti-GD2) antibodies was found to improve survival rates for patients with high-risk neuroblastoma. Based on studies led by the SIOPEN (International Society of Paediatric Oncology European Neuroblastoma) group, the anti-GD2 antibody dinutuximab beta was approved for use in high-risk neuroblastoma by the European Medicines Agency and has been implemented into the standard of care in many countries across Europe. However, immunotherapy with dinutuximab beta is associated with a number of adverse events that may be challenging for clinicians, such as pain, fever, hypersensitivity reactions and capillary leak syndrome. While these adverse events are considered manageable, there are currently no formal guidelines to support clinicians with their management. The aim of this article is to discuss the management of the most common adverse events encountered in clinical practice and to provide practical guidance to assist clinicians in minimising toxicity associated with dinutuximab beta.

Background: According to retrospective osteosarcoma series, ABCB1/P-glycoprotein (Pgp) overexpression predicts for poor outcomes. A prospective trial to assess a risk-adapted treatment strategy using mifamurtide in Pgp+ patients was performed. Methods: This was a phase 2, multicenter, uncontrolled trial including patients 40 years old or younger with nonmetastatic extremity high-grade osteosarcoma stratified according to Pgp expression. All patients received high-dose methotrexate, doxorubicin, and cisplatin (MAP) preoperatively. In Pgp+ patients, mifamurtide was added postoperatively and combined with MAP for a good histologic response (necrosis ≥ 90%; good responders [GRs]) or with high-dose ifosfamide (HDIFO) at 3 g/m2/d on days 1 to 5 for a histologic response < 90% (poor responders [PRs]). Pgp– patients received MAP postoperatively. After an amendment, the cumulative dose of methotrexate was increased from 60 to 120 g/m2 (from 5 to 10 courses). The primary end point was event-free survival (EFS). A postamendment analysis was performed. Results: In all, 279 patients were recruited, and 194 were included in the postamendment analysis: 70 (36%) were Pgp–, and 124 (64%) were Pgp+. The median follow-up was 51 months. For Pgp+ patients, 5-year EFS after definitive surgery (null hypothesis, 40%) was 69.8% (90% confidence interval [CI], 62.2%-76.2%): 59.8% in PRs and 83.7% in GRs. For Pgp– patients, the 5-year EFS rate was 66.4% (90% CI, 55.6%-75.1%). Conclusions: This study showed that adjuvant mifamurtide, combined with HDIFO for a poor response to induction chemotherapy, could improve EFS in Pgp+ patients. Overall, the outcomes compared favorably with previous series. Mifamurtide and HDIFO as salvage chemotherapy are worth further study.

Simple Summary The prognosis of patients with primary disseminated multifocal Ewing sarcoma (PDMES) remains dismal. Previously, a combination of temozolomide and irinotecan (TEMIRI) was tested in patients with refractory or relapsed disease. The aim of our study was to evaluate the activity and tolerability of TEMIRI (two courses) as a front-line treatment in PDMES. With thirty-four patients enrolled, the Response Evaluation Criteria in Solid Tumors (RECIST), after TEMIRI, was acceptable with a manageable toxicity and a high percentage of patients showing an amelioration in their Eastern Cooperative Oncology Group (ECOG)/Lansky scores. TEMIRI in front-line therapy showed encouraging activity and deserves further evaluation combined with conventional treatments in non-metastatic patients; meanwhile, new treatment strategies for PDMES are urgently needed. Abstract Purpose: The main objective was to evaluate the activity and tolerability of TEMIRI as a front-line treatment in primary disseminated Ewing sarcoma (PDMES) using the RECIST 1.1 criteria. The secondary objectives included the assessment of toxicity and the performance status/symptom changes. Methods: Between 2012 and 2018, patients with PDMES received two courses of temozolomide 100 mg/sqm/day + irinotecan 50 mg/sqm/day for 5 days every 3 weeks as an amendment to the Italian Sarcoma Group/Associazione Italiana EmatoIogia ed Oncologia Pediatrica (ISG/AIEOP) EW-2 protocol (EUDRACT#2009-012353-37, Vers. 1.02). Results: Thirty-four patients were enrolled. The median age at diagnosis was 19 years (range 3–55). After TEMIRI, the RECIST response was as follows: a partial response in 20 (59%) patients, stable disease in 11 (32%), and disease progression in 3 (9%). The ECOG/Lansky score was improved in 25/34 (73.5%) cases, and a reduction or disappearance of pain was observed in 31/34 patients (91%). The incidence of grade 3–4 toxicity was 3%. The 3-year event-free survival (EFS) and overall survival (OS) were 21% (95% CI 6–35%) and 36% (95% CI: 18–54%), respectively. Conclusion: the smooth handling and encouraging activity demonstrated by up-front TEMIRI did not change the EFS in PDMES, so this result suggests the need for the further evaluation of the efficacy of TEMIRI in combination with conventional treatments in non-metastatic patients.

GD2-directed immunotherapies improve survival of high-risk neuroblastoma (NB) patients (pts). Treatment with chimeric anti-GD2 antibodies (Ab), such as ch14.18, can induce development of human anti-chimeric Ab (HACA). Here, we report HACA effects on ch14.18/CHO pharmacokinetics, pharmacodynamics and pain intensity in pts treated by long-term infusion (LTI) of ch14.18/CHO combined with IL-2. 124 pts received up to 5 cycles of ch14.18/CHO 10 days (d) infusion (10 mg/m2/d, d8&ndash, 18) combined with s.c. IL-2 (6 &times, 106 IU/m2/d, d1&ndash, 5, d8&ndash, 12). HACA, treatment toxicity, ch14.18/CHO levels, Ab-dependent cellular- (ADCC) and complement-dependent cytotoxicity (CDC) were assessed using respective validated assays. HACA-negative pts showed a steadily decreased pain in cycle 1 (74% pts without morphine by d5 of LTI) with further decrease in subsequent cycles. Ch14.18/CHO peak concentrations of 11.26 &plusmn, 0.50 &micro, g/mL found in cycle 1 were further elevated in subsequent cycles and resulted in robust GD2-specific CDC and ADCC. Development of HACA (21% of pts) resulted in strong reduction of ch14.18/CHO levels, abrogated CDC and ADCC. Surprisingly, no difference in pain toxicity between HACA-positive and -negative pts was found. In conclusion, ch14.18/CHO LTI combined with IL-2 results in strong activation of Ab effector functions. Importantly, HACA response abrogated CDC but did not affect pain intensity indicating CDC-independent pain induction.

The prognosis of children with metastatic neuroblastoma (NB) > 18 months at diagnosis is dismal. Since the immune status of the tumor microenvironment could play a role in the history of disease, we evaluated the expression ofCD45,CD14,ARG1,CD163,CD4,FOXP3,Perforin-1(PRF1),Granzyme B (GRMB), andIL-10mRNAs in primary tumors at diagnosis from children with metastatic NB and tested whether the transcript levels are significantly associated to event-free and overall survival (EFS and OS, resp.). Children with high expression ofCD14,ARG1andFOXP3mRNA in their primary tumors had significantly better EFS. Elevated expression ofCD14, andFOXP3mRNA was significantly associated to better OS.CD14mRNA expression levels significantly correlated to all markers, with the exception ofCD4. Strong positive correlations were found betweenPRF1andCD163, as well as betweenPFR1andFOXP3. It is worth noting that the combination of high levels ofCD14,FOXP3, andARG1mRNAs identified a small group of patients with excellent EFS and OS, whereas low levels ofCD14were sufficient to identify patients with dismal survival. Thus, the immune status of the primary tumors of high-risk NB patients may influence the natural history of this pediatric cancer.

We analyzed the outcome of 167 consecutive children with second CR acute lymphoblastic leukemia ( ALL), for whom an unrelated donor (UD) search was activated between 1989 and 1998 at a median time of 2 months after relapse. A suitable donor was identified for 70 patients at 1 year and 6.5 months before and after 1995 from search activation, respectively; a further leukemia relapse occurred during the search in 94 children at a median of 4 months after search activation, 36 of whom underwent UD ( 14) or other types of transplant ( 22), beyond second CR, while 58 died of progressive disease. Of 73 patients not experiencing a second relapse, 64 underwent UD ( 46) or other types of transplant ( 18), while nine proceeded with chemotherapy, and only four of them survived. The 3-year disease-free survival (DFS) from second CR for the 167 patients is 15.1%, whereas 3-year DFS after transplant for the 60 UD and 40 alternative donor transplanted children is 31.6 and 25.4%, respectively. In conclusion, a further relapse is the main factor adversely affecting outcome of children with second CR ALL. Thus, for these patients, the search should be activated early after relapse and either a UD or an alternative transplant should be performed as early as possible.

Background Ewing Sarcoma Family Tumours (ESFT) are rare in early childhood. The aim of this study was to report the clinical characteristics and outcome of children under 6 years of age affected by ESFT of the bone in Italy. Methods The records of all the children diagnosed with osseous ESFT in centres members of the Associazione Italiana di Ematologia ed Oncologia Pediatrica (AIEOP) from 1990 to 2008 were reviewed. The Kaplan–Meier method was used for estimating overall and progression-free survival (OS, PFS) curves; multivariate analyses were performed using Cox proportional hazards regression model. Results This study includes 62 patients. An axial primary localization was present in 66% of patients, with the primary site in the chest wall in 34%. Fourteen (23%) patients presented metastatic disease. The 5-year OS and PFS were 73% (95% confidence interval, CI, 58–83%) and 72% (95% CI 57–83%) for patients with localized disease and 38% (95% CI 17–60%) and 21% (95% CI 5–45%) for patients with metastatic disease. Metastatic spread, skull/pelvis/spine primary localization, progression during treatment and no surgery predicted worse survival (P

Wilms’ tumour (WT) is the most common primary genitourinary tumour of childhood with the annual incidence of approximately 8 per million children younger than 15 years of age. Genetic plays an important role in this cancer. WT1 located on chromosome 11p13, WT2 on 11p15, loci at 1p, 7p, 16q, 17p (the p53 tumor suppressor gene), and 19q (the putative familial WT gene FWT2) are believed to harbor genes involved in the biology of WT. The majority of these children are surviving into adult life and due to the combination of genetic susceptibility, irradiation and antineoplastic treatment, are at increased risk for second malignant neoplasms (SMNs). We report the case of a young man with a parotid carcinoma occurring thirteen years after diagnosis of WT. The patient was initially treated according to the SIOP 6 Nephroblastoma protocol, comprising a 4-week two-drug (Actinomycin D, Vincristine) presurgical treatment, nephrectomy and 22-week treatment with biweekly Actinomycin D and Vincristine. No radiation therapy was given. Nine months after the end of therapy he experienced an isolated hepatic relapse, treated with Peptichemio (450 mg/m2), two courses of Cisplatin (40 mg/m2/day for 5 days) and Etoposide (100 mg/m2/day for 5 days) and two cycles of the combination Ifosfamide (2 gr/m2/day for 5 days), Doxorubicin (40 mg/m2/day for 2 days), Vincristine (1.5 mg/m2). Resection of a complete necrotic lesion at the fourth hepatic segment was subsequently performed. Treatment was completed with high dose association of Melphalan (200 mg/M2) and Vincristine (4 mg/M2) followed by autologous bone marrow transplantation (BMT). After 13 years since WT diagnosis and 11 years after BMT the patient presented a right non tender, homogeneous and mobile parotideal mass. After the total parotidectomy the diagnosis was consistent with a low-grade mucoepidermoidal carcinoma. In the National WT Study Group review regarding 43 SMNs out of 5278 patients enrolled between 1969 and 1991 the relevant risk factor for developing a SMN were radiation therapy (RT), the association of Doxo-rubicin and RT and utilization of chemo-therapy for the treatment of the relapse. All these risk factors were present in the only reported case of parotideal carcinoma in these series. In the SIOP survey RT was related to secondary bone cancer and the use of epipodophyllotoxin with leukemia occurrence. On these basis in our patient a clear pathogenetic mechanism is lacking, then we can also attribute the secondary parotid carcinoma simply to the chance. Physician needto be aware that even unusual SMNs, can develop also in subjects that for their primary malignancy and related treatment are at low risk.

Unrelated donor bone marrow transplant (UD-BMT) has become an attractive alternative source of hematopoietic cells for patients lacking a matched sibling. The aim of this paper was to report on results of the 696 UD BMTs performed in 31 Italian institutions during the first 10 years of activity of the Italian Bone Marrow Donor Registry (IBMDR). In 1989 the Italian Bone Marrow Transplant Group (GITMO) established the IBMDR to facilitate donor search and marrow procurement for patients lacking an HLA identical sibling. By end of December 1999, 260,000 HLA-A, B typed volunteer donors had been cumulatively registered and 2,620 searches had been activated for Italian patients. At least one HLA-A, B, DRB1 matched donor was found for 54% of the patients and 696 UD BMTs were performed. In 50% of cases the donor was found in the IBMDR and in 50% in 15 other Registries. The average time from search activation to transplant was 6 months for disease other than CML. For CML it was 14 months. Actuarial 12-month transplant-related mortality (TRM) was 68% in patients grafted between 1979 and 1992 and 44% for patients grafted after 1993. Twenty-eight per cent of patients developed grade III or IV acute GvHD and 24% developed extensive chronic GvHD. The rate of disease free survival at three years was 57% for patients with 1st chronic phase CML, 37% for patients with 1st or 2nd CR ALL, 31% for AML or MDS patientsor = 18 years of age and 54% for patients with inborn errors. We conclude that the IBMDR has benefited a substantial number of patients lacking a matched sibling and has facilitated the recruitment of UDs into the international donor pool. The long time required for the search is the major obstacle to the success of this programme. This suggests that early transplant and a decrease in TRM could further improve these encouraging results.

To evaluate incidence, risk factors and outcome of SNE after BMT, we retrospectively evaluated 272 (169 M, 103 F) consecutive children that between June 1985 and January 2001 underwent BMT at the “G. Gaslini” Institute. Subjects with solid tumor were excluded. Their median age at transplant was 8 years (range 2 mos. – I 9 yr.), and the source of stem cells was autologous (A), related donor (RD)., and unrelated donor (UD) in 87, 115 and 70 subjects, respectively. 166 children received total body irradiation (TBI) as part of the conditioning regimen; 63 received Busulfan while 43 were treated with other drugs; finally, 54 children received cranial prophylactic irradiation (CPI) (1800 cGy) during front line treatment before BMT.A total of 41 SNE were observed in 37 children (18 M, 19 F); their median age at BMT was 10 years (range 2–16 yr.). Neurological symptoms occurred after a median time of 92 days (range 5–3203) The source of HSCT was UD-BM, RD-BM, and A-BM in 19, 16, and 2 cases respectively.). Ten of them received CPI before BMT. Neuralogical symptoms were: seizures (n=20), changes of mental status and coma (n=12), motor or sensitive defects (n=6), progressive loss of cognitive functions (n=3), clonus and myoclonus (n=2) and visual impairment (n=1). Causes of neurological symptoms were attributed to CSA toxicity (CSA-t) in 21 pt. (77%), to irradiation or chemotherapy injury (IC-i) in 7 (2.6%), to CNS infections (CNS-I) in 7 (2.6%), to CNS hemorrhages in 3 pt. (1.1%) and to immunomediated pathogenesis in the remaining 3 (1.1%). CSA-t occurred in 21 out of 185 patients receiving immunosuppressive therapy. Onset of symptoms was after a median of 96 days (range 20–370 days) after BMT. When CSA was discontinued, a complete resolution of SNE was observed in all cases. The 7 IC-i occurred between 1 month and 7 years after BMT. Mental deterioration and/or coma were observed in 5, clonus and dysarthria in one and visual impairment in another. CNS-I were observed in 7 pt. and were mostly of viral origin (2 cases of EBV, and 1 of CMV, HHV6 and adenovirus, respectively), whereas the 2 remaining cases had neuratoxoplasmosis and aspergillosis. The 3 CNS hemorrhages occurred 30, 50 and 250 days fram BMT, respectively. Finally the 3 immunomedia-ted SNE were due to a demyelinating leucoencephalopathy in the context of ex-tensive chranic GvHD in 2 cases; and to a Guillain-Barré syndrome in the remainning one.Preliminary analysis shows that type of BMT (p