SARS-CoV-2 Infection in the Pediatric Oncology Population: The Definitive Comprehensive Report of the Infectious Diseases Working Group of AIEOP.

OBJECTIVE: The objective of this study was to assess the clinical impact and outcome of the SARS-CoV-2 infection on children with cancer or those who received a hematopoietic stem cell transplantation. METHODS: AIEOP (Italian Association of Pediatric Hematology and Oncology) performed a nationwide multicenter observational cohort study, including consecutive patients between April 2020 and November 2022. RESULTS: Twenty-five Italian centers participated and 455 patients were enrolled. We reported a significant increasing trend of symptomatic cases over the years, while the number of nonmild infections remained stable. Early infection after oncologic diagnosis (<60 days) and severe neutropenia were identified as independent risk factors for developing moderate, severe, or critical infections. The percentage of patients who were asymptomatic and mildly symptomatic and who stopped chemotherapy reduced over the years of the pandemic. Nine patients died, but no death was attributed to SARS-CoV-2 infection. CONCLUSIONS: SARS-CoV-2 infection presented a self-limiting benign course in the Italian pediatric oncohematology population during the pandemic, and its main consequence has been the discontinuation of cancer-directed therapies. The rate of patients who were asymptomatic and stopped chemotherapy reduced over the years, suggesting that the continuation of chemotherapy is a feasible option.

Therapeutic Targeting of ALK in Neuroblastoma: Experience of Italian Precision Medicine in Pediatric Oncology.

Neuroblastoma (NB) is the most common extracranial solid tumor in childhood. Patients with relapsed/refractory disease have a poor prognosis, and additional therapeutic options are needed. Mutations and amplifications in the ALK (Anaplastic Lymphoma Kinase) gene constitute a key target for treatment. Our goal, within the Italian project of PeRsonalizEdMEdicine (PREME), was to evaluate the genomic status of patients with relapsed/refractory NB and to implement targeted therapies in those with targetable mutations. From November 2018 to November 2021, we performed Whole Exome Sequencing or Targeted Gene Panel Sequencing in relapsed/refractory NB patients in order to identify druggable variants. Activating mutations of ALK were identified in 8(28.57%) of 28 relapsed/refractory NB patients. The mutation p.F1174L was found in six patients, whereas p.R1275Q was found in one and the unknown mutation p.S104R in another. Three patients died before treatment could be started, while five patients received crizotinib: two in monotherapy (one with p.F1174L and the other with p.S104R) and three (with p.F1174L variant) in combination with chemotherapy. All treated patients showed a clinical improvement, and one had complete remission after two cycles of combined treatment. The most common treatment-related toxicities were hematological. ALK inhibitors may play an important role in the treatment of ALK-mutated NB patients.

Phosphoproteomic Analysis Reveals a Different Proteomic Profile in Pediatric Patients With T-Cell Lymphoblastic Lymphoma or T-Cell Acute Lymphoblastic Leukemia.

T-cell lymphoblastic lymphoma (T-LBL) and lymphoblastic leukemia (T-ALL) arise from the transformation of precursor T-cells sharing common morphological and immunophenotypic features. Despite this, T-LBL and T-ALL show different genomic/transcriptomic profiles and whether they represent two distinct disease entities or variant manifestations of the same disease is still a matter of debate. In this work, we performed a Reverse Phase Protein Array study on T-LBL and T-ALL samples and demonstrated that they are characterized by a different phosphoproteomic profile. Indeed, T-LBLs showed the hyperactivation of FAK/ERK1/2 and AKT/mTOR pathways, whereas JAK/STAT pathway was significantly hyperphosphorylated in T-ALLs. Moreover, since the only criteria for discriminating T-LBL from T-ALL is blasts' infiltration below 25% in the bone marrow and lymphoma patients can present with a percentage of blasts close to this cut-off, a biomarker that could help distinguishing the two diseases would be of great help for the clinical diagnosis and treatment decision. Pursuing this aim, we identified a proteomic signature of six proteins whose expression/activation was able to discriminate stage IV T-LBL from T-ALL. Moreover, we demonstrated that AKT hyperphosphorylation alone was able to distinguish stage IV T-LBL from both T-ALL and stage III T-LBL. Concluding, these data demonstrate that T-ALL and T-LBL bear different phosphoproteomic profiles, further sustaining the hypothesis of the two disease as different entities and paving the way for the identification of new biomarkers able to distinguish stage IV T-LBL from T-ALL disease, so far based only on BM involvement criteria.

Outcome of Children and Adolescents with Recurrent Classical Hodgkin Lymphoma: The Italian Experience.

The objective of this study was to identify prognostic factors for children and adolescents with relapsed or progressive classical Hodgkin's lymphoma (cHL) to design salvage therapy tailored to them. We analyzed a homogeneous pediatric population, diagnosed with progressive/relapsed cHL previously enrolled in two subsequent protocols of the Italian Association of Pediatric Hematology and Oncology in the period 1996−2016. There were 272 eligible patients, 17.5% of treated patients with cHL. Overall survival (OS) and event-free survival (EFS) after a 10-year follow-up were 65.3% and 53.3%, respectively. Patients with progressive disease (PD), advanced stage at recurrence, and ≥5 involved sites showed a significantly worse OS. PD, advanced stage, and extra-nodal involvement at recurrence were significantly associated with a poorer EFS. Multivariable analysis identified three categories for OS based on the type of recurrence and number of localizations: PD and ≥5 sites: OS 34%; PD and <5 sites: OS 56.5%; relapses: OS 73.6%. Four categories were obtained for EFS based on the type of recurrence and stage: PD and stage 3−4: EFS 25.5%; PD and stage 1−2: EFS 43%; relapse and stage 3−4: EFS 55.4%; relapse and stage 1−2: EFS 72.1%. Patients with PD, in advanced stage, or with ≥5 involved sites had a very poor survival and they should be considered refractory to first- and second-line standard chemotherapy. Probably, they should be considered for more innovative approaches since the first progression. Conversely, patients who relapsed later with localized disease had a better prognosis, and they could be considered for a conservative approach.

Bilateral adrenal primary tumor in Stage 4S neuroblastoma: The Italian experience and review of the literature.

Bilateral adrenal neuroblastoma (NB) is rare and is mainly stage 4S. Its incidence, presenting features, management, and outcome have not been fully defined yet. We searched the Italian NB Registry (RINB) for stage 4S NB infants with bilateral adrenal primary tumor to compare them with stage 4S NB with unilateral tumor. Between 1979 and 2016, the RINB enrolled 3731 NB patients aged 0-18 years including 317 infants (8.5%) diagnosed with stage 4S NB. Eleven/317 (3.5%) had a bilateral adrenal primary tumor (Group 1) and 190/317 (59.9%) had a unilateral tumor (Group 2). Group 1 infants were significantly younger (51 vs. 89 days) but were comparable with Group 2 for any other presenting features. In the absence of specific protocols, upfront treatment was based on symptoms, size of adrenal tumors, and biology, and consisted of observation in 5 cases, radiotherapy in one, chemotherapy in 2, and surgery in 3. Five/11 developed progression and 2 of them, both with MYCN amplification, died. The 5-year EFS rates of Group 1 and 2 were 54.5% vs. 73.3% (P=.14) and 5-year OSs were 81.8% and 89.4%, respectively (P=.44). Our data support the hypothesis that 4S NB infants with bilateral adrenal tumors can have favorable outcome with personalized therapeutic approach. The three patients with MYCN amplified tumor benefited from upfront aggressive chemotherapy, in accordance with current protocols. Because of the rarity of this intriguing form of neuroblastoma, collaborative prospective studies are warranted, especially in view of gaining a better insight on its biological and genetic features.

Malignant sacrococcygeal germ cell tumors in childhood: The Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) experience.

PURPOSE: To evaluate clinical features at diagnosis, prognostic factors, and outcomes of malignant sacrococcygeal germ cell tumors (SC-GCTs) in patients enrolled in the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) TCG 2004 protocol. PATIENTS AND METHODS: A prospective analysis was conducted on all consecutive patients diagnosed with malignant SC-GCTs between January 2004 and May 2017. Patients with stage I underwent surgery and subsequent surveillance, the others received pediatric cisplatinum-etoposide-bleomycin (pPEB) regimen and eventual deferred surgery. RESULTS: Of 45 patients, 35 were females. Age at diagnosis ranged from 1 day to 3.6 years (median 1.6 years); 26 were stage IV. Of 38 patients who underwent surgery, pathology revealed yolk sac tumor (YST) in 27 and teratoma + YST/embryonal carcinoma in 11, while seven patients were diagnosed based on imaging and elevated levels of alpha-fetoprotein (AFP). Of six patients approached with surgery, only one relapsed and was rescued with first-line chemotherapy. Overall, 38 out of 45 achieved complete remission, three a partial remission, and four were resistant. Ten out of 41 patients who entered remission later relapsed and nine were rescued with a second-line treatment. We observed a global failure percentage of 31% and a 5-year overall survival (OS) and event-free survival (EFS) of 95% and 69%, respectively. CONCLUSIONS: Chemotherapyis generally effective in malignant SC-GCTs, even though almost one-third of our patients experienced events salvageable with second-line treatment. Most of the relapses occurred within 1 year from diagnosis. A close follow up with serial AFP level monitoring should be done for at least 2 years after diagnosis.

Clinical Characteristics and Outcome of Severe Acute Respiratory Syndrome Coronavirus 2 Infection in Italian Pediatric Oncology Patients: A Study From the Infectious Diseases Working Group of the Associazione Italiana di Oncologia e Ematologia Pediatrica.

BACKGROUND: Little is known as yet about the outcome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children being treated for cancer. METHODS: We collected information on the clinical characteristics and outcomes of a cohort of 29 children (16 female and 13 male; median age, 7 years [range, 0-16 years]) diagnosed with SARS-CoV-2 infection while on chemotherapy/immunotherapy (n = 26), or after stem cell transplantation (n = 3) during the peak of the epidemic in Italy. These patients suffered from leukemia (n = 16), lymphoma (n = 3), solid tumors (n = 10), and Langerhans cell histiocytosis (n = 1). RESULTS: The course of the disease was mild in all cases, with only 12 children developing symptoms (pneumonia in 3 cases), and none needing intensive care. Fifteen patients were hospitalized, including 7 asymptomatic patients. Nine patients (including 5 with no symptoms) were given hydroxychloroquine, and 3 of them were also given lopinavir/ritonavir. Among the 26 patients on chemotherapy/immunotherapy, the treatment was suspended in 16 cases for a median of 26 days (range, 15-68 days), whereas 8 patients continued their chemotherapy and 2 had minor modifications to their treatment regimen. CONCLUSIONS: SARS-CoV-2 infection seems to take a milder clinical course in children than in adults with cancer. Specific SARS-CoV-2 treatment seems unnecessary for most children. In light of our findings, and albeit with the necessary caution, we suggest avoiding major changes to planned anticancer treatments in pediatric patients acquiring COVID-19.

Comparison of Hodgkin's Lymphoma in Children and Adolescents. A Twenty Year Experience with MH'96 and LH2004 AIEOP (Italian Association of Pediatric Hematology and Oncology) Protocols.

Adolescents and young adults (AYAs) represent a distinct group of patients. The objectives of this study were: To compare adolescent prognosis to that of younger children; to compare the results achieved with the two consecutive protocols in both age groups; to analyze clinical characteristics of children and adolescents. Between 1996 and 2017, 1759 patients aged <18 years were evaluable for the study. Five hundred and sixty patients were treated with the MH'96 protocol and 1199 with the LH2004 protocol. Four hundred and eighty-two were adolescents aged ≥15 years. Patients in both age groups showed very favorable prognoses. In particular, OS improved with the LH2004 protocol, especially in the adolescent group and in the low risk group, where radiation therapy was spared. Adolescent characteristics differed significantly from the children's according to sex, histology, and the presence of symptoms. Remarkable is the decrease both in mixed cellularity in the children and in low stages in both age groups in the LH2004 protocol with respect to MH'96 protocol. Based on our experience, adopting pediatric protocols for AYA does not compromise patient outcomes.

Flash survey on severe acute respiratory syndrome coronavirus-2 infections in paediatric patients on anticancer treatment.

INTRODUCTION: Since the beginning of COVID-19 pandemic, it is known that the severe course of the disease occurs mostly among the elderly, whereas it is rare among children and young adults. Comorbidities, in particular, diabetes and hypertension, clearly associated with age, besides obesity and smoke, are strongly associated with the need for intensive treatment and a dismal outcome. A weaker immunity of the elderly has been proposed as a possible explanation of this uneven age distribution. Thus, there is concern that children treated for cancer may allso be at risk for an unfavourable course of infection. Along the same line, anecdotal information from Wuhan, China, mentioned a severe course of COVID-19 in a child treated for leukaemia. AIM AND METHODS: We made a flash survey on COVID-19 incidence and severity among children on anticancer treatment. Respondents were asked by email to fill in a short Web-based survey. RESULTS: We received reports from 25 countries, where approximately 10,000 patients at risk are followed up. At the time of the survey, more than 200 of these children were tested, nine of whom were positive for COVID-19. Eight of the nine cases had asymptomatic to mild disease, and one was just diagnosed with COVID-19. We also discuss preventive measures that are in place or should be taken and treatment options in immunocompromised children with COVID-19. CONCLUSION: Thus, even children receiving anticancer chemotherapy may have a mild or asymptomatic course of COVID-19. While we should not underestimate the risk of developing a more severe course of COVID-19 than that observed here, the intensity of preventive measures should not cause delays or obstructions in oncological treatment.

A Review of Infants With Localized Neuroblastoma That Evolve to Stage 4s Disease.

The authors describe a newborn diagnosed with localized neuroblastoma that evolved to stage 4s at the age of 5 months. Peculiar features of the case included a bilateral adrenal primary, the skin as the only metastatic site, and the development of a muscular lesion late in the clinical course. The patient underwent left adrenalectomy and all other lesions regressed without further therapy. The case prompted a search for similar cases both in the Italian Neuroblastoma Registry and in the literature. All patients identified, although variously treated, survived with the exception of the 2 with MYCN gene amplification. We conclude that infants with neuroblastoma who undergo a transition from a localized to stage 4s disease could be less rare than expected. In the absence of unfavorable biology, a wait-and-see policy with strict follow-up could be adopted for these patients, avoiding potentially damaging systemic therapy.

A Child with Early-Onset Gorham-Stout Disease Complicated by Chylothorax: Near-Complete Regression of Bone Lesions with Interferon and Bisphosphonate Treatment.

We report a case of Gorham-Stout disease (GSD) complicated by chylothorax and treated with a combination therapy with interferon and bisphosphonates. This treatment may be helpful in improving the usually unfavorable prognosis of GSD beginning with a chylothorax before 1 year of age, and in reducing bone lesions. Moreover, the use of bisphosphonates appears to be useful in treating pain.

Classical pediatric Hodgkin lymphoma in very young patients: the Italian experience.

Many studies have reported a more favorable outcome in younger patients with Hodgkin lymphoma (HL). The aims of this study were to find an appropriate age cutoff able to identify low-risk children and to describe the natural history of 135 very young patients affected by classic HL (cHL). The best age cutoff was identified at 7 years of age. EFS (p = .0451) and PFS (p = .00921) were significantly better in the group of younger patients. The OS rate at 10 years was 97.0% in the younger group and 92.5% in the older one (p = .0448). However, age was not found to be an independent prognostic factor in multivariate analysis and the better prognosis in younger patients seems to be related to more favorable disease characteristics at presentation.

Biliary tract rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Associazione Italiana Ematologia Oncologia Pediatrica.

INTRODUCTION: Rhabdomyosarcoma is a soft tissue malignant musculoskeletal tumor frequent in children. Biliary duct localization is extremely rare, but it is the most common cause of malignant obstructive jaundice in pediatric patients. METHODS: This report describes a series of 10 patients under 18 years of age with biliary tract rhabdomyosarcoma who were enrolled, from 1979 to 2004, in 3 consecutive Italian pediatric cooperative protocols that had been drawn up by the Soft Tissue Sarcoma Committee of the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP). RESULTS: Considering initial and delayed surgery, tumor resection was achieved in 7 cases, 3 complete with free margins (2 liver transplants) and 4 with microscopic residual disease. Chemotherapy was given to all patients and radiotherapy to 3. At present, 5 patients survive in complete remission 90-200 months after diagnosis while 4 died of disease progression or relapse and 1 of liver transplant-related complications. CONCLUSIONS: Better outcomes in this series were associated with the feasibility of conservative surgery due to the favorable location of the tumor, in particular in the common bile duct. Chemotherapy and radiotherapy might obviate the need for demolitive surgery or liver transplant, which were linked to worse outcomes in our series.

Results of the Third AIEOP Cooperative Protocol on Wilms Tumor (TW2003) and Related Considerations.

PURPOSE: TW2003, the third Italian prospective study on Wilms tumor, aimed to improve survival in patients with stage III-IV tumors, de-escalate therapy for stage I-II nonanaplastic tumors, refine the risk stratification of therapy, and develop a national infrastructure for biobanking and central pathology review. MATERIALS AND METHODS: TW2003 recruited children 18 years old or younger with primary intrarenal tumors. Local physicians chose nephrectomy with or without preoperative chemotherapy as the initial treatment based on the risk of unsafe and/or incomplete immediate surgery. The main drivers for adjuvant therapy were tumor stage and diffuse anaplasia. A new risk stratification schema was investigated, incorporating patient age, reason for stage III designation and completeness of lung nodule response in stage IV disease. RESULTS: We report on 453 patients with unilateral Wilms tumor. Preoperative chemotherapy was administered to 42% of patients. The 5-year event-free survival and overall survival rates were 89.1% (95% CI 83.6-94.9) and 97.0% (93.7-100) for stage I; 85.1% (79.6-91.1) and 94.0% (90.1-98.1) for stage II (160); 82.7% (75.3-90.8) and 90.9% (85.0-97.1) for stage III (101); and 72.1% (61.9-84.0) and 82.5% (73.1-93.1) for stage IV (69), respectively. On multivariable analysis only anaplasia was significant for event-free survival (HR 2.68, 95% CI 1.48-4.86, p=0.001; bias corrected c-index 0.580) and overall survival (HR 5.29, 95% CI 2.52-11.12, p <0.001; bias corrected c-index 0.697). CONCLUSIONS: The survival rates achieved and the proposed risk stratification schema provide a basis for future comparisons of Wilms tumor treatment burden and patient outcome.

The prognostic value of biological markers in paediatric Hodgkin lymphoma.

BACKGROUND: Many biological and inflammatory markers have been proposed as having a prognostic value at diagnosis of Hodgkin lymphoma (HL), but very few have been validated in paediatric patients. We explored the significance of these markers in a large population of 769 affected children. PATIENTS AND METHODS: By using the database of patients enrolled in A.I.E.O.P. (Associazione Italiana di Emato-Oncologia Pediatrica) trial LH2004 for paediatric HL, we identified 769 consecutive patients treated with curative intent from 1st June 2004 to 1st April 2014 with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), or hybrid COPP/ABV (cyclophosphamide, vincristine, prednisone, procarbazine, doxorubicin, bleomycin and vinblastine) regimens. RESULTS: On multivariate analysis with categorical forms, the 5-year freedom from progression survival was significantly lower in patients with stage IV or elevated value of platelets, eosinophils and ferritin at diagnosis. Furthermore, stage IV and eosinophils seem to maintain their predictive value independently of interim (after IV cycles of chemotherapy) positron emission tomography. CONCLUSION: Using the combination of four simple markers such as stage IV and elevated levels of platelets, ferritin and eosinophils, it is possible to classify the patients into subgroups with very different outcomes.

Risk-adapted Treatment for Severe B-Lineage Posttransplant Lymphoproliferative Disease After Solid Organ Transplantation in Children.

BACKGROUND: Optimal management of posttransplant lymphoproliferative disease (PTLD) remains to be defined due to heterogeneity of this condition and lack of predictors of the outcome. Here we report our experience with pediatric PTLD nonresponsive to immunosuppression (IS) withdrawal, managed after stratification into high and low risk according to the presenting features. METHODS: This is a single-center retrospective review of prospectively enrolled patients. From 2001 to 2011, 17 children were diagnosed with severe B-lineage, CD20+, PTLD after a median of 37 months (range, 5-93) from liver (12), heart (4), or multiorgan (1) transplantation. Treatment was tailored on 2 risk groups: (1) standard-risk (SR) patients received IS reduction and rituximab; (2) high-risk (HR) patients received IS discontinuation, rituximab and polychemotherapy. RESULTS: The cumulative incidence of rejection at 1 and 5 years after the diagnosis of PTLD was 35% (95% confidence interval [95% CI], 18-69%) and 53% (33-85%), respectively, whereas the disease-free survival at 1 and 5 years was 94% (95% CI, 65-99%) and 75% (45-90%), respectively. Three children died, PTLD-free, from different transplant-related complications: primary nonfunction after retransplantation (liver), cytomegalovirus disease 21 months after PTLD treatment (liver), graft dysfunction 25 months after PTLD (heart). CONCLUSIONS: Severe B-lineage PTLD after solid organ transplantation may be classified as SR or HR and treated accordingly with a tailored protocol obtaining a satisfactory long-term outcome. This approach accomplishes the control of lymphoproliferation in severe forms as well as the minimization of toxicity in milder PTLDs.

Percutaneous transhepatic biliary drainage in an infant with obstructive jaundice caused by neuroblastoma.

Neuroblastoma presenting with obstructive jaundice is a rare event. Management of this condition includes surgery, chemotherapy, radiotherapy, temporary cholecystostomy tube, endoscopic retrograde cholangiopancreatography (ERCP), and internal biliary drainage (IBD). We herein describe our experience with one infant affected by neuroblastoma presenting with jaundice, who successfully underwent percutaneous transhepatic biliary drainage (PTBD). This report introduces PTBD as a viable treatment option for neuroblastoma and obstructive jaundice and provides a review of the pertinent literature.