Healthcare migration in Italian paediatric haematology-oncology centres belonging to AIEOP.

BACKGROUND: In Italy, there is a network of centres headed by the Italian Association of Pediatric Hematology and Oncology (AIEOP) for the diagnosis and treatment of paediatric cancers on almost the entire national territory. Nevertheless, migration of patients in a hospital located in a region different from that of residence is a widespread habit, sometimes motivated by several reasons. The aim of this paper is to assess the impact of migration of children with cancer to AIEOP centres in order to verify their optimal distribution throughout the national territory. METHODS: To this purpose, we used information on 41,205 registered cancer cases in the database of Mod.1.01 Registry from AIEOP centres, with age of less than 20 years old at diagnosis, diagnosed from 1988 to 2017. Patients' characteristics were analysed and compared using the X2 or Fisher's exact test or Mann-Whitney test, when appropriate. Survival distributions were estimated using the method of Kaplan and Meier, and the log-rank test was used to examine differences among subgroups. RESULTS: Extra-regional migration involved overall 19.5% of cases, ranging from 23.3% (1988-1997) to 16.4% (2008-2017) (p < 0.001). In leukaemias and lymphomas we observed a mean migration of 8.8% overall, lower in the North (1.2%) and Centre (7.8%) compared to the South & Isles (32.3%). In the case of solid tumours, overall migration was 25.7%, with 4.2% in the North, 17.2% in the Centre and 59.6% in the South & Isles. For regions with overall levels of migration higher than the national average, most migration cases opted for AIEOP centres of close or even neighbouring regions. Overall survival at 10 years from diagnosis results 69.9% in migrants vs 78.3% in no migrants (p < 0.001). CONCLUSIONS: There is still a certain amount of domestic migration, the causes of which can be easily identified: migration motivated by a search for high specialization, migration due to lack of local facilities, or regions in which no AIEOP centres are present, which makes migration obligatory. Better coordination between AIEOP centres could help to reduce so-called avoidable migration, but technical and political choices will have to be considered, with the active participation of sector technicians.

Correction: Bailey et al. Clinical Trials in High-Risk Medulloblastoma: Evolution of the SIOP-Europe HR-MB Trial. Cancers 2022, 14, 374.

In the original publication [...].

Local treatment in initially unresected non-rhabdomyosarcoma soft-tissue sarcomas of children and adolescents: A retrospective single-center experience.

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.

Exoscopic microneurosurgery in pediatric brain tumors: an ideal tool for complex and peculiar anatomo-topographic scenarios?

PURPOSE: Since its introduction in the 1950s, the microsurgical paradigm has revolutionized neurosurgery. New technologies have been introduced over the years trying to overcome limits of the classical operating microscope. The recently developed 3D exoscopes represent a potential new paradigm for micro-neurosurgery. We analyzed our own experience with a 4 K-3D exoscope in a series of pediatric brain tumors to verify its advantages and limitations in comparison to the operating microscope and in light of the literature. METHODS: Twenty-five pediatric patients with brain tumors underwent surgery at our Institute; the population has been analyzed and described. A score to evaluate the exoscopes and compare it to the operating microscope was considered and postoperatively applied to each single case. RESULTS: The exoscope appears to be at least comparable to the operating microscope (OM) in all analyzed aspects. In the case of deep-seated or fourth ventricle tumors, the exoscope seems to be superior to the microscope. A surgeon-dependent learning curve is necessary for neurosurgeons to be confident with the exoscope. CONCLUSION: Exoscopes appear to be as safe and effective as operating microscopes in pediatric neuro-oncological surgery. They have some advantages that make them superior to microscopes, particularly regarding surgeon ergonomics and fatigue, visual field qualities, and higher choice of intraoperative viewing angles.

I was only sixteen.

This short piece describes a new project developed by the adolescent patients with cancer involved in the Youth Project at the Istituto Nazionale dei Tumori in Milan, Italy. This is a scheme dedicated to young cancer patients with the dual aim of optimizing medical aspects of their care and promoting a holistic approach to their needs. "I was only sixteen" is a ballad, written in English by the patients, that became a song with the help of professional musicians (and among them international star Tony Hadley, former frontman of Spandau Ballet). This song sounds like hymn to life for teenagers with cancer in the world. It emphasizes again the value of giving young patients novel creative ways to express themselves.

Clinical Insight on Proton Therapy for Paediatric Rhabdomyosarcoma.

This paper offers an insight into the use of Proton Beam Therapy (PBT) in paediatric patients with rhabdomyosarcoma (RMS). This paper provides a comprehensive analysis of the literature, investigating comparative photon-proton dosimetry, outcome, and toxicity. In the complex and multimodal scenario of the treatment of RMS, clear evidence of the therapeutic superiority of PBT compared to other modern photon techniques has not yet been demonstrated; however, PBT can be considered an excellent treatment option, in particular for young children and patients with specific primary sites, such as the head and neck area (and especially the parameningeal regions), genito-urinary, pelvic, and paravertebral regions. The unique depth-dose characteristics of protons can be exploited to achieve significant reductions in normal tissue doses and may allow an escalation of tumour doses and greater sparing of normal tissues, thus potentially improving local control while at the same time reducing toxicity and improving quality of life. However, access of children with RMS (and more in general with solid tumors) to PBT remains a challenge, due to the limited number of available proton therapy installations.

Pediatric cancer care management during the COVID-19 pandemic: a review of the literature and a single-centre real-life experience of an Italian pediatric oncology unit.

INTRODUCTION: The severe acute respiratory syndrome coronavirus-2 pandemic significantly affected clinical practice, also in pediatric oncology units. Cancer patients needed to be treated with an adequate dose density despite the SARS-CoV-2 infection, balancing risks of developing severe COVID-19 disease. AREAS COVERED: Although the pandemic spread worldwide, the prevalence of affected children was low. The percentage of children with severe illness was approximately 1-6%. Pediatric cancer patients represent a prototype of a previously healthy immune system that is hampered by the tumor itself and treatments, such as chemotherapy and steroids. Through a review of the literature, we reported the immunological basis of the response to SARS-CoV-2 infection, the existing antiviral treatments used in pediatric cancer patients, and the importance of vaccination. In conclusion, we reported the real-life experience of our pediatric oncology unit during the pandemic period. EXPERT OPINION: Starting from the data available in literature, and our experience, showing the rarity of severe COVID-19 disease in pediatric patients with solid tumors, we recommend carefully tailoring all the oncological treatments (chemotherapy/targeted therapy/stem cell transplantation/radiotherapy). The aim is the preservation of the treatment's timing, balanced with an evaluation of possible severe COVID-19 disease.

Extra-neural metastases in pediatric diffuse midline gliomas, H3 K27-altered: presentation of two cases and literature review.

Introduction: Pediatric diffuse midline gliomas (DMG), H3 K27- altered, are the most aggressive pediatric central nervous system (CNS) malignancies. Disease outcome is dismal with a median survival of less than one year. Extra-neural metastases are an unusual occurrence in DMG and have been rarely described. Methods and results: Here, we report on two pediatric patients affected by DMG with extra-neural dissemination. Their clinical, imaging, and molecular characteristics are reported here. An 11-year-old male 5 months after the diagnosis of diffuse intrinsic pontine glioma (DIPG) developed metastatic osseous lesions confirmed with computed tomography (CT) guided biopsy of the left iliac bone. The patient died one month after the evidence of metastatic progression. Another 11-year-old female was diagnosed with a cerebellar H3K27- altered DMG. After six months, she developed diffuse sclerotic osseous lesions. A CT-guided biopsy of the right iliac bone was non-diagnostic. She further developed multifocal chest and abdominal lymphadenopathy and pleural effusions. Droplet digital polymerase chain reaction (ddPCR) on pleural effusion revealed the presence of H3.3A mutation (c.83A>T, p.K28M). The patient died 24 months after the diagnosis of DMG and 3 months after the evidence of metastatic pleural effusion. Discussion: Extra-neural metastasis of DMG is a rare event and no standard therapy exists. An accurate and early diagnosis is necessary in order to develop a personalized plan of treatment. Further research is needed to gain further insights into the molecular pathology of DMG, H3K27- altered and improve the quality of life and the final outcome of patients with this deadly disease.

Optimizing reirradiation for relapsed medulloblastoma: identifying the ideal patient and tumor profiles.

BACKGROUND: First-line therapies for medulloblastoma(MBL) are obtaining higher survival-rates while decreasing late-effects, but treatment at relapse is not standardized. We report here the experience with MBL re-irradiation(re-RT), its timing and outcome in different clinical settings and tumor groups. METHODS: Patient's staging/treatment at diagnosis, histotypes/molecular subgroups, relapse site/s, re-treatments outcome are reported. RESULTS: 25 patients were included, with a median age of 11.4 years; 8 had metastases. According to 2016-2021 WHO-classification, 14 had SHH subgroup tumors(six TP53 mutated,one + MYC,one + NMYC amplification), 11 non-WNT/non-SHH (two with MYC/MYCN amplification).Thirteen had received HART-CSI, 11 standard-CSI, one HFRT; all post-radiation chemotherapy(CT), 16 also pre-RT. Median time to relapse (local-LR in nine, distant-DR in 14, LR + DR in two) was 26 months. Fourteen patients were re-operated, in five cases excising single DR-sites, thereafter three received CT, two after re-RT; out of 11 patients not re-operated, four had re-RT as first treatment and seven after CT. Re-RT was administered at median 32 months after first RT: focally in 20 cases, craniospinal-CSI in five. Median post-relapse-PFS/after re-RT was 16.7/8.2 months, while overall survival-OS was 35.1/23.9 months, respectively. Metastatic status both at diagnosis/relapse negatively affected outcome and re-surgery was prognostically favorable. PD after re-RT was however significantly more frequent in SHH (with a suggestive association with TP53 mutation, p = 0.050). We did not observe any influence of biological subgroups on PFS from recurrence while SHH showed apparently worse OS compared to non-WNT/non-SHH group. CONCLUSIONS: Re-surgery + reRT can prolong survival; a substantial fraction of patients with worse outcome belongs to the SHH-subgroup.

A pilot exome sequencing study suggests that germline variants influence methotrexate-induced toxicities in pediatric patients with localized osteosarcoma.

INTRODUCTION: Osteosarcoma (OS) is a rare pediatric cancer for which therapeutic approaches, including chemotherapy and surgery, show a wide interindividual variability in patient response, both in terms of adverse events and therapy efficacy. There is growing evidence that this individual variable response to therapies is also influenced by inherited genetic variations. However, the results obtained to date in these pediatric cancers have been contradictory and often lack validation in independent series. Additionally, these studies frequently focused only on a limited number of polymorphisms in candidate genes. METHODS: In order to identify germline coding variations associated with individual differences in adverse events occurrence in pediatric patients affected by localized OS, we carried out an exome-wide association study in 24 OS patients treated with methotrexate, cisplatin, and doxorubicin, using the SNP-Set (Sequence) Kernel Association Test (SKAT), optimized for small sample size. RESULTS: Gene sets significantly associated (FDR < .05) with neutropenia and hepatotoxicity induced by methotrexate were identified. Some of the identified genes map in loci previously associated with similar phenotypes (e.g., leukocyte count, alkaline phosphatase levels). CONCLUSION: Further studies in larger series and with functional characterization of the identified associations are needed; nonetheless, this pilot study prompts the relevance of broadly investigating variants along the whole genome, to identify new potential pharmacogenes, beyond drug metabolism, transport, and receptor candidate genes.

End-of-Life transfusion support at hospice and pediatric oncology unit: Bridging the gap between benefits and therapeutic alliance.

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.

Optimizing biomarkers for accurate ependymoma diagnosis, prognostication, and stratification within International Clinical Trials: A BIOMECA study.

BACKGROUND: Accurate identification of brain tumor molecular subgroups is increasingly important. We aimed to establish the most accurate and reproducible ependymoma subgroup biomarker detection techniques, across 147 cases from International Society of Pediatric Oncology (SIOP) Ependymoma II trial participants, enrolled in the pan-European "Biomarkers of Ependymoma in Children and Adolescents (BIOMECA)" study. METHODS: Across 6 European BIOMECA laboratories, we evaluated epigenetic profiling (DNA methylation array); immunohistochemistry (IHC) for nuclear p65-RELA, H3K27me3, and Tenascin-C; copy number analysis via fluorescent in situ hybridization (FISH) and MLPA (1q, CDKN2A), and MIP and DNA methylation array (genome-wide copy number evaluation); analysis of ZFTA- and YAP1-fusions by RT-PCR and sequencing, Nanostring and break-apart FISH. RESULTS: DNA Methylation profiling classified 65.3% (n = 96/147) of cases as EPN-PFA and 15% (n = 22/147) as ST-ZFTA fusion-positive. Immunohistochemical loss of H3K27me3 was a reproducible and accurate surrogate marker for EPN-PFA (sensitivity 99%-100% across 3 centers). IHC for p65-RELA, FISH, and RNA-based analyses effectively identified ZFTA- and YAP-fused supratentorial ependymomas. Detection of 1q gain using FISH exhibited only 57% inter-center concordance and low sensitivity and specificity while MIP, MLPA, and DNA methylation-based approaches demonstrated greater accuracy. CONCLUSIONS: We confirm, in a prospective trial cohort, that H3K27me3 immunohistochemistry is a robust EPN-PFA biomarker. Tenascin-C should be abandoned as a PFA marker. DNA methylation and MIP arrays are effective tools for copy number analysis of 1q gain, 6q, and CDKN2A loss while FISH is inadequate. Fusion detection was successful, but rare novel fusions need more extensive technologies. Finally, we propose test sets to guide future diagnostic approaches.

Treating secondary malignant neoplasms: A burden of childhood cancer survivors.

Each year approximately 35,000 children and adolescents are diagnosed with cancer in Europe. Five-year survival rates have improved and now reach 80% in most European countries, thanks to a combination of chemotherapy, radiotherapy, and surgery. To date, there are more than 44,000 Italians still living several years after being diagnosed with cancer in developmental age. The risk of premature morbidity and mortality for cancer survivors is well known and documented. Approximately 60% of survivors of cancer in childhood and adolescence have at least one chronic health condition in later life, and more than one in four develop severe or life-threatening disorders. Among the various long-term iatrogenic sequelae of cancer treatments, the most worrisome are second malignant neoplasms. We reported on our mono-institutional experiences of screening and treating secondary breast cancer, secondary thyroid cancer and secondary osteosarcoma. Recommendations on the surveillance needed for cancer survivors because of the risk of late effects of their disease or its treatment suggest that discussing the potential problems early on can be crucial to a patient's future health. These considerations and our consolidated experience strengthen our conviction that survivors of cancer in childhood and adolescence who develop second malignant neoplasms should be treated at highly-specialized centers. Multidisciplinary care requires close communications and high levels of up-to-date professional expertise. This challenging area of health care is also changing rapidly because cancer survivorship is a work in progress, but we cannot wait for definitive conclusions on many aspects because this will take decades, especially for pediatric patients.

Acute Kidney Injury with SARS-CoV-2 Infection in Pediatric Patients Receiving High-Dose Methotrexate Chemotherapy: A Report of Three Cases.

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.

Science and pseudo science: racist eugenics in Italy.

In the present article we briefly discuss the historical premises of eugenics. Differences and some analogies between the Latin and the German way of eugenics in the 20th century are presented, until the tragic antisemitic turn. The fate of some children in the South Tyrol border region is also discussed, as well as the role of several anatomo-pathologists as willing executors of autopsies on the victims of the eugenic project of eliminating mentally and physically disabled people.

Establishment of 6 pediatric rhabdomyosarcoma patient's derived xenograft models closely recapitulating patients' tumor characteristics.

INTRODUCTION: The prognosis for patients with metastatic and recurrent pediatric rhabdomyosarcoma (RMS) remains poor. The availability of preclinical models is essential to identify promising treatments We established a series of pediatric RMS patient derived xenografts (PDXs), all faithfully mirroring primary tumor characteristics and representing a unique tool for clarifying the biological processes underlying RMS progression and relapse. METHODS: Fresh tumor samples from 12 RMS patients were implanted subcutaneously in both flanks of immunocompromised mice. PDXs were considered as grafted after accomplishing three passages in mice. Characterization of tumor tissues and models was performed by comparing both morphology and immunoistochemical and fluorescence in situ hybridization (FISH) characteristics. RESULTS: Six PDXs were established, with a successful take rate of 50%. All models closely mirrored parental tumor characteristics. An increased grafting rate for tumors derived from patients with worse outcome (p = 0.006) was detected. For 50% PDXs grafting occurred when the corresponding patient was still alive. CONCLUSION: Our findings increase the number of available RMS PDX models and strengthen the role of PDXs as useful preclinical tools for patients with unmet medical needs and to develop personalized therapies.

Trabectedin-irinotecan, a potentially promising combination in relapsed desmoplastic small round cell tumor: report of two cases.

Effective new drugs are urgently needed for desmoplastic small round cell tumor (DSRCT), an extremely rare and aggressive disease with a generally poor prognosis. We describe two heavily-pretreated young patients with advanced-stage DSRCT given third-line treatment with a combination of trabectedin and irinotecan, based on our preclinical data demonstrating its effect on patient-derived xenografts. This trabectedin-irinotecan treatment showed a limited toxicity. One patient had a mixed response (overall stable disease), the other a complete tumor remission. This is the first report of preliminary findings to suggest that combining trabectedin and irinotecan is worth further investigating as a potentially valuable chemotherapy for DSRCT.

Lung metastasectomy for osteosarcoma in children, adolescents, and young adults: proof of permanent cure.

INTRODUCTION: Surgical resection of pulmonary metastases has been associated with increased survival at 5 years for osteosarcoma, but limited information is available on long-term outcome, role of repeated metastasectomies, and surgical sequelae in a pediatric population. We analyzed a consecutive series of children, adolescents, and young adults (AYA) treated by repeated lung metastasectomies during a period >40 years to estimate the clinical benefit and potential cure rate of salvage surgery. METHODS: All patients who underwent lung metastasectomy for osteosarcoma at the IRCCS Istituto Ortopedico Rizzoli of Bologna, University of Modena, and IRCCS Istituto Nazionale Tumori of Milan from May 1973 to January 2014 were included. Overall survival (OS) at 20 years from the first metastasectomy was calculated. RESULTS: A total of 463 consecutive children and AYA were analyzed. Median age was 15.9 years (range 0.2-23.2 years) and median follow-up 18.6 years. The 5- and 20-year OS were 34.0% and 29.7% (95% CI 25.5-34.0%). Among the 138 (29.8%) alive patients, 42 (30.4%) had disease recurrence cured by repeated metastasectomies. Disease-free interval from primary tumor, number of metastases, and complete resection were the most relevant survival predictors at multivariable model analysis. DISCUSSION: The extended follow-up of this consecutive series shows that repeated lung metastasectomy can achieve a permanent cure when offered to properly selected patients with metastases from osteosarcoma.