Prolonged 14-day continuous infusion of high-dose ifosfamide for patients with relapsed and refractory high-grade osteosarcoma: a retrospective multicentre cohort study.

BACKGROUND: The prognosis of patients with Relapsed/Refractory Osteosarcoma (R/R OS) remains dismal without an agreement on systemic therapy. The use of High-Dose Ifosfamide (14 g/sqm) with an external pump in outpatient setting (14-IFO) in R/R OS patients is limited. This study represents the first retrospective cohort analysis focused on evaluating the activity and toxicity of 14-IFO in this setting. PATIENTS AND METHODS: The study investigated 14-IFO activity, in terms of tumour response according to RECIST 1.1 criteria, as well as survival rates and toxicity, according to CTCAE v.5. RESULTS: The trial enrolled 26 patients with R/R OS. The Overall Response Rate (ORR) and Disease Control Rate (DCR) obtained was 23% and 57.5%, respectively. Patients with relapsed OS showed a higher ORR (45%) and DCR (82%) compared to refractory patients, irrespective of the number of prior treatment lines received. The achievement of disease control with 14-IFO administration enabled 27% of patients to undergo new local treatment. Four-month Progression-Free Survival (PFS) was 54% for all patients and 82% for the relapsed OS sub-group. Median Overall Survival (OSurv) was 13.7 months, with 1-year OSurv of 51% for all patients and 71% for relapsed patients. Age over 18 years and the presence of refractory disease were identified as negative prognostic factors for this patient cohort. A total of 101 cycles were evaluated for toxic assessment, demonstrating a tolerable profile without grade 3-4 non-haematological toxicities. CONCLUSIONS: 14-IFO should be considered a viable treatment option for R/R OS, particularly due to its well tolerated toxicity profile and the potential for home-administration, which can improve patient quality of life without compromising efficacy.

Off-label and compassionate use of targeted anticancer therapies: The experience of an Italian pediatric cancer center.

INTRODUCTION: In Europe, despite recent advances in clinical development, most of the drugs currently used to treat childhood cancers are adult medicines, prescribed outside of the authorized indication. In this context, a monocentric retrospective cohort analysis was conducted, evaluating pediatric, adolescent, and young adult patients affected by onco-hematologic disease, treated with targeted therapies used off-label or as compassionate use. METHODS: The analysis was conducted on 45 patients aged less than or equal to 30 years with cancer, having received at least one targeted therapy prescribed as off-label or compassionate use at a large Italian pediatric center between January 1, 2016 and June 30, 2021. Data collected included information on the patient and tumor, data on off-label/compassionate treatment, and data on safety and efficacy. RESULTS: Total 25 out of 45 patients treated with off-label or compassionate targeted therapies were affected by onco-hematological diseases. Overall, 22 out of the 52 agents (42%) were prescribed in patients with relapsed neoplasm and 39% (20/52) in patients with refractory diseases. Complete response was observed in more than half (27/52) of treatments. At least one adverse reaction occurred in 76% (n = 22) of agents administered to patients with onco-hematological tumor and in 43% (n = 10) of agents prescribed to patients with solid tumor. CONCLUSION: This work aims to provide a snapshot of off-label and compassionate use prescriptions in a large Italian pediatric cancer center. This study confirms that targeted agents for unauthorized indications are often prescribed in pediatric patients with cancer, especially after disease relapse and that these treatments are mostly tolerable and effective.

Omic approaches to pediatric bone sarcomas.

Over the last decade, next-generation sequencing technologies have improved our ability to assess biological aspects, at genomic and transcriptomic levels, on a large scale- and have been increasingly used for the management of adult cancers. However, their efficacy and feasibility within pediatrics is still under investigation. "Omic" approaches represent an opportunity to understand the oncogenic mechanisms driving the onset and progression of bone sarcoma and improve the clinical management of young patients with bone sarcomas. This review focuses on the current genomic and transcriptomic characteristics of managing pediatric patients, affected by Ewing sarcoma and osteosarcoma.

Translation and cultural adaptation of the US National Cancer Institute's patient-reported outcome (PRO) version of the CTCAE for Italian pediatric oncology populations.

PURPOSE: This study intends to translate and make any necessary cultural adaptations of the Pediatric PRO-CTCAE version for Italian oncological patients aged 7-18 years and their caregivers. METHODS: The questionnaire has been forward/backward translated into Italian and subjected to detailed verification by fluent Italian speakers, children and their parents, for use in clinical trials in Italian populations. The Italian version includes 130 questions that assess 62 symptoms. To verify the patients' comprehension some interviews were completed with 24 oncological children and adolescents in different age groups and 24 parents (Mage = 41.2). Caregivers were interviewed independently. RESULTS: A final Italian version of the Pediatric PRO-CTCAE was produced. Across the age range, most patients and caregivers were able to understand and answer the questions. The 7-9 years old had greater challenges completing two terms which were retested in a second round of interviews. There were no comprehension differences on the basis of trials enrollment phase. CONCLUSIONS: The translation and adaptation of the Pediatric PRO-CTCAE confirms that this instrument is also suitable for assessing symptom toxicities among Italian cancer patients. Its rapid integration into care pathways is necessary to guarantee an early response to patient symptoms and to facilitate drug tolerability assessment.

Toxoplasma gondii Dense Granule Antigen 1 stimulates apoptosis of monocytes through autocrine TGF-ß signaling.

Monocyte/macrophages represent the first line of defense against protozoan parasites. Different mechanisms of monocyte suppression by Toxoplasma gondii that sustain parasite invasion and persistence have been described, including apoptosis. In the present study, we investigated the effect of microbial excretory­secretory polypeptides, namely the microneme protein MIC3 and the dense granule antigen GRA1, on apoptosis of monocytes from patients with congenital toxoplasmosis and healthy individuals. We found that GRA1 but not MIC3 could induce apoptosis of monocytes, observing the effect in samples from both Toxoplasma-infected and uninfected individuals, thus ruling out involvement of mechanisms of apoptosis linked to adaptive immunity or a cellular context related to infection. Selective inhibition of TGF-ß type I receptors reversed GRA1-induced apoptosis, indicating that this apoptosis involved canonical TGF-ß signaling. By using TGF-ß-neutralizing antibodies, we showed that monocyte apoptosis required endogenous TGF-ß and that GRA1 stimulation activated TGF-ß transcription and expression in monocytes but not lymphocytes, suggesting involvement of an autocrine TGF-ß-mediated mechanism in GRA1-induced apoptosis.