Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase predominantly expressed in the developing nervous system. Recently, mutated ALK has been identified as a major oncogene associated with familial and sporadic neuroblastomas (NBL). Yet, a direct correlation between endogenous expression level of the ALK protein, oncogenic potential, and clinical outcome has not been established. We investigated ALK genetic mutations, protein expression/ phosphorylation, and functional inhibition both in NBLderived cell lines and in 34 localized and 48 advanced/ metastatic NBL patients. ALK constitutive phosphorylation/ activation was observed in high-ALK expressing cells, harboring either a mutated or a wild-type receptor. No activation was found in cell lines with low expression of wild-type ALK. After 72 hours of treatments, small molecule ALK inhibitor CEP-14083 (60 nmol/L) induced growth arrest and cell death in NBL cells overexpressing wild-type (viability: ALK high 12.8%, ALK low 73%, P = 0.0035; cell death: ALK high 56.4%, ALK low 16.2%, P = 0.0001) or mutated ALK. ALK protein expression was significantly up-regulated in advanced/metastatic compared with localized NBLs (ALK overexpressing patients: stage 1-2, 23.5%; stage 3-4, 77%; P < 0.0001). Interestingly, protein levels did not always correlate with ALK genetic alterations and/or mRNA abundance. Both mutated and wild-type ALK receptor can exert oncogenic activity in NBL cells. However, wild-type ALK receptor requires a critical threshold of expression to achieve oncogenic activation. Overexpression of either mutated or wild-type ALK defines poor prognosis patients. Alternative mechanisms other than direct mutations and/or gene amplification regulate the ALK level of expression in NBL cells. Wild-type ALK is a potential therapeutic target for advanced/metastatic NBLs.

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

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BACKGROUNDA Phase II trial in children with advanced neuroblastoma was carried out in five Italian institutions to evaluate the antitumor activity and tolerability of topotecan followed by vincristine and doxorubicin.METHODSChildren older than age 1 year with Stage III or Stage IV neuroblastoma, all of whom had been treated previously with chemotherapy and were diagnosed with either refractory or recurrent disease, were treated with topotecan at an intravenous dose of 1.5 mg/m2 (the dose was 0.75 mg/m2 for patients who were treated within 1 year of previous megatherapy) per day for 5 days followed by 48‐hour intravenous infusions of 2 mg/m2 vincristine and 45 mg/m2 doxorubicin. Cycles of therapy were repeated every 3 weeks.RESULTSTwenty‐five patients (2 with Stage III disease and 23 with Stage IV disease; 19 with refractory disease and 6 with recurrent disease) were treated with a total of 115 cycles. Four patients had complete responses, 12 patients had partial responses, 4 patients had minor responses or stable disease, and 5 patients had tumor progression. The overall response rate (including complete and partial responses) was 64% (95% confidence interval, 43–82%). Fifteen patients were alive at the time of the current report and were progression free at 4–16 months (median, 9 months) after the first course of this treatment. Toxicity generally was limited to the hematopoietic system. Dose‐limiting toxicity was observed in only 1 patient (Grade 4 liver toxicity). There were no deaths due to infectious or toxic causes.CONCLUSIONSThe topotecan‐vincristine‐doxorubicin combination was active and well tolerated in previously treated patients with advanced neuroblastoma. Cancer 2003. © 2003 American Cancer Society.

Radiotherapy is the only treatment definitely indicated for diffuse pontine gliomas (DIPG). Findings on the role of EGFR signaling in the onset of childhood DIPG prompted the use of nimotuzumab, an anti-EGFR monoclonal antibody. Assuming a potential synergy with both radiotherapy and vinorelbine, a pilot phase 2 protocol was launched that combined nimotuzumab with concomitant radiation and vinorelbine. An amendment in July 2011 introduced re-irradiation at relapse. The primary endpoint for first-line treatment was objective response rate (CR + PR + SD) according to the RECIST. This report concerns the outcome of this strategy as a whole. Vinorelbine 20 mg/m(2) was administered weekly, with nimotuzumab 150 mg/m(2) in the first 12 weeks of treatment; radiotherapy was delivered from weeks 3 to 9, for a total dose of 54 Gy. Vinorelbine 25 mg/m(2) and nimotuzumab were given every other week thereafter until the tumor progressed or for up to 2 years. Re-irradiation consisted of 19.8 Gy, fractionated over 11 days. Baseline and latest MRIs were assessed blindly by an outside neuroradiologist. Twenty five children (mean age 7.4 years) were enrolled as of August 2009 (median follow-up 29 months). A response was observed in 24/25 patients (96 %). The nimotuzumab/vinorelbine combination was very well tolerated, with no acute side-effects. Eleven of 16 locally-relapsing patients were re-irradiated. One-year PFS and OS rates were 30 ± 10 % and 76 ± 9 %, respectively; 2-year OS was 27 ± 9 %; the median PFS and OS were 8.5 and 15 months, respectively. This strategy generated interesting results and warrants further investigation.

In our analysis, initial tumor size and tumor response were significant prognostic factors in rhabdomyosarcoma, regardless of whether tumor diameter or volume was considered. Three-dimensional tumor assessment was of no greater prognostic value than one-dimensional assessment, neither initially nor after induction treatment.

The paper describes the key issues of the Youth Project launched in 2011 at the pediatric oncology unit of the Istituto Nazionale Tumori in Milan dedicated to adolescents (over 15 years old) and young adults (up to 25 years old) with solid tumors. The Youth Project was developed within the pediatric oncology unit in the conviction that adolescent patients may benefit from the multidisciplinary team typical of the pediatric oncology setting, as well as the expertise in treating pediatric-type malignancies and enrolling patients in clinical trials. The project was an offshoot of existing activities, making no major changes to the hospital's organization and posing no major demands on the institution's administration and board. Patients are managed by the pediatric oncology staff, but they have access to particular services (e.g., regarding their psychosocial support, fertility preserving measures, access to care after completing therapy); dedicated, adequately equipped multifunctional rooms have been provided. The location of the pediatric unit within a cancer referral center and the cooperation with divisions dedicated to adults have played an important role in the project's creation.