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.

Diencephalic Syndrome: Misleading Clinical Onset of Low-Grade Glioma.

BACKGROUND: Diencephalic Syndrome is an atypical early manifestation of low-grade gliomas; so, it is important to detect it in patients that experience a failure to thrive despite adequate length growth and food intake. The purpose of this article is to focus attention on this rare but potentially dangerous cause of poor weight gain or stunting in childhood. MATERIALS AND METHODS: We describe four patients with Diencephalic Syndrome and low-grade gliomas who were evaluated in our institution from January 2017 to December 2021. CASE DESCRIPTION AND RESULTS: two patients presented with suspected malabsorption, and two presented with a suspected eating disorder. In all cases, neurological symptoms appeared late, explaining the reason for the diagnostic delay, which impacts negatively on prognosis and on quality of life. Currently, patients 1 and 2 have stable disease in second-line therapy, patient 3 has stable disease post end of second-line therapy, and patient 4 has stable disease in first-line therapy. Everyone is in psychophysical rehabilitation. CONCLUSIONS: A multidisciplinary evaluation is essential in order to make an early diagnosis and improve prognosis and quality of life.

The Role of Ultrasound in the Diagnosis of Pulmonary Infection Caused by Intracellular, Fungal Pathogens and Mycobacteria: A Systematic Review.

BACKGROUND: Lung ultrasound (LUS) is a widely available technique allowing rapid bedside detection of different respiratory disorders. Its reliability in the diagnosis of community-acquired lung infection has been confirmed. However, its usefulness in identifying infections caused by specific and less common pathogens (e.g., in immunocompromised patients) is still uncertain. METHODS: This systematic review aimed to explore the most common LUS patterns in infections caused by intracellular, fungal pathogens or mycobacteria. RESULTS: We included 17 studies, reporting a total of 274 patients with M. pneumoniae, 30 with fungal infection and 213 with pulmonary tuberculosis (TB). Most of the studies on M. pneumoniae in children found a specific LUS pattern, mainly consolidated areas associated with diffuse B lines. The typical LUS pattern in TB consisted of consolidation and small subpleural nodes. Only one study on fungal disease reported LUS specific patterns (e.g., indicating "halo sign" or "reverse halo sign"). CONCLUSIONS: Considering the preliminary data, LUS appears to be a promising point-of-care tool, showing patterns of atypical pneumonia and TB which seem different from patterns characterizing common bacterial infection. The role of LUS in the diagnosis of fungal disease is still at an early stage of exploration. Large trials to investigate sonography in these lung infections are granted.

Favorable outcome of SARS-CoV-2 infection in pediatric hematology oncology patients during the second and third pandemic waves in Italy: a multicenter analysis from the Infectious Diseases Working Group of the Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP).

COVID-19 has a mild clinical course with low mortality rate in general pediatric population, while variable outcomes have been described in children with cancer. Infectious diseases working party of the AIEOP collected data on the clinical characteristics and outcomes of SARS-CoV-2 infections in pediatric oncology/hematology patients from April 2020 to May 2021, including the second and the third waves of the pandemic in Italy. Factors potentially associated with moderate, severe, or critical COVID-19 were analyzed. Of the 153 SARS-Cov2 infections recorded, 100 were asymptomatic and 53 symptomatic. The course of COVID-19 was mild in 41, moderate in 2, severe in 5, and critical in 5 children. A total of 40.5% of patients were hospitalized, ten requiring oxygen support and 5 admitted to the intensive care unit. Antibiotics and steroids were the most used therapies. No patient died due to SARS-CoV-2 infection. Infections occurring early (< 60 days) after the diagnosis of the underlying disease or after SCT were associated to moderate, severe, and critical disease compared to infections occurring late (> 60 days) or during maintenance therapy. In the patients on active chemotherapy, 59% withdrew the treatment for a median of 15 days. SARS-CoV-2 presented a favorable outcome in children with cancer in Italy during the pandemic. Modification of therapy represents a major concern in this population. Our findings suggest considering regular chemotherapy continuation, particularly in patients on maintenance therapy or infected late after the diagnosis.

New Insights into Iron Deficiency Anemia in Children: A Practical Review.

Iron deficiency anemia (IDA) is the most frequent hematological disorder in children, with an incidence in industrialized countries of 20.1% between 0 and 4 years of age and 5.9% between 5 and 14 years (39 and 48.1% in developing countries). Although IDA has been recognized for a long time, there are still uncovered issues and room for improving the management of this condition. New frontiers regarding its diagnosis and therapeutic options emerge every day; recently, innovative formulations of iron have been launched, both for oral and parenteral administration, with the aim of offering treatment schedules with higher efficacy and lower toxicity. As a matter of fact, glycinate and liposomal preparations, while maintaining a satisfying efficacy profile, have significantly fewer side effects, in comparison to the traditional elemental iron salts; parenteral iron, usually considered a second-choice therapy reserved to selected cases, may evolve further, as a consequence of the production of molecules with an interesting clinical profile such as ferrocarboxymaltose, which is already available for adolescents aged >14 years. The present article reports the clinically relevant latest insights regarding IDA in children and offers a practical guide to help pediatricians, particularly to choose the most appropriate prevention and therapy strategies.

Consensus on COVID-19 Vaccination in Pediatric Oncohematological Patients, on Behalf of Infectious Working Group of Italian Association of Pediatric Hematology Oncology.

Vaccines represent the best tool to prevent the severity course and fatal consequences of the pandemic by the new Coronavirus 2019 infection (SARS-CoV-2). Considering the limited data on vaccination of pediatric oncohematological patients, we developed a Consensus document to support the Italian pediatric hematological oncological (AIEOP) centers in a scientifically correct communication with families and patients and to promote vaccination. The topics of the Consensus were: SARS-CoV-2 infection and disease (COVID-19) in the pediatric subjects; COVID-19 vaccines (type, schedule); who and when to vaccinate; contraindications and risk of serious adverse events; rare adverse events; third dose and vaccination after COVID-19; and other general prevention measures. Using the Delphi methodology for Consensus, 21 statements and their corresponding rationale were elaborated and discussed with the representatives of 31 centers, followed by voting. A high grade of Consensus was obtained on topics such as the potential risk of severe COVID-19 outcome in pediatric oncohematological patients, the need for vaccination as a preventative measure, the type, schedule and booster dose of vaccine, the eligibility of the patients for vaccination, and the timing, definition, and management of contraindications and serious adverse events, and other general prevention measures. All 21 of the statements were approved. This consensus document highlights that children and adolescents affected by hematological and oncological diseases are a fragile category. Vaccination plays an important role to prevent COVID-19, to permit the regular administration of chemotherapy or other treatments, to perform control visits and hospital admissions, and to prevent treatment delays.

Pleuro-pulmonary ultrasound in the diagnosis and follow-up of lung infections in children with cancer: a pilot study.

PURPOSE: Febrile neutropenia and lung infections are common and potential fatal complications of pediatric cancer patients during chemotherapy. Lung ultrasound (LUS) has a good accuracy in the diagnosis of pneumonia in childhood, but there is no data concerning its use in the diagnosis and follow-up of pulmonary infection in children with cancer. The goal of this pilot study is to verify the feasibility of lung ultrasonography for the diagnosis and follow up of pneumonia in children and adolescents with cancer. MATERIAL AND METHODS: This is a prospective observational case-control monocentric study conducted in the Pediatric Hematology and Oncology Department of University Hospital of Catania in patients aged < 18 years with cancer. Attending Physician used ultrasonography to detect pneumonia in cancer children with fever. As control group, cancer patients with no infection suspicion were also tested. LUS results were compared to chest X-ray (CXR) and/or chest CT scan, when these imaging techniques were performed, according to clinical indication. RESULTS: Thirty-eight patients were studied. All underwent LUS, 16 underwent CXR, 3 chest CT. Statistical analysis showed LUS specificity of 93% (95% CI 84-100%), and sensitivity of 100%; CXR, instead, showed a specificity of 83% (95% CI 62-100%) and a sensitivity of 50% (95% CI 1-99%). CONCLUSION: This study shows for the first time that LUS allows physicians to diagnose pneumonia in children and young adults with cancer, with high specificity and sensitivity.

Ecthyma Gangrenosum in Children With Cancer: Diagnosis at a Glance: A Retrospective Study From the Infection Working Group of Italian Pediatric Hematology Oncology Association.

BACKGROUND: To depict ecthyma gangrenosum (EG) clinical presentation and evolution in a large multicenter pediatric retrospective collection of children with malignancies or bone marrow failure syndromes, to facilitate early diagnosis. METHODS: EG episodes diagnosed in the period 2009-2019 were identified by a retrospective review of clinical charts at centers belonging to the Italian Pediatric Hematology Oncology Association. RESULTS: Thirty-eight cases of EG occurring in children (male/female 16/22; median age 5.2 years) with hematologic malignancy (29), allogeneic stem cell transplantation (2) or relapsed/refractory solid tumor (3) were collected. The involved sites were: perineal region (19), limbs (10), trunk (6), head and the iliac crest (3). Bacteremia was present in 22 patients. Overall, the germs isolated were Pseudomonas aeruginosa (30), Stenotrophomonas maltophilia (3) and Escherichia coli (1); 31% of them were multidrug-resistant. All patients received antibacterial treatment, while surgery was performed in 24 patients (63.1%). Predisposing underlying conditions for EG were severe neutropenia (97.3%), corticosteroid treatment (71%) and iatrogenic diabetes (23.7%). All patients recovered, but EG recurred in 5 patients. Nine patients (24%) showed sequelae (deep scars, with muscle atrophy in 2). Four patients (10.5%) died, 1 due to relapse of EG with Carbapenem-resistant Enterobacteriaceae co-infection and 3 due to the progression of the underlying disease. CONCLUSIONS: EG requires early recognition and a proper and timely treatment to obtain the recovery and to avoid larger necrotic lesions, eventually evolving in scarring sequelae.

Risk of Benign and Malignant Thyroid Disorders in Subjects Treated for Paediatric/Adolescent Neoplasia: Role of Morphological and Functional Screening.

BACKGROUND: Patients treated for paediatric/adolescent (P/A) neoplasia have a high incidence of both benign and malignant thyroid diseases. Given the high incidence of sequelae, literature data show a clinical benefit of morpho-functional thyroid screening in paediatric/adolescent cancer survivors and a careful lifetime follow-up. PATIENTS AND METHODS: The incidence of thyroid alterations was evaluated in a consecutive series of 343 patients treated with chemotherapy (CHE) and radiotherapy (RTE) or only with CHE for P/A tumours between 1976 and 2018 (mean age at time of primary paediatric malignancy 7.8 ± 4.7 years). All patients underwent thyroidal morpho-functional evaluation between 2000 and 2019. RESULTS: 178 patients (51.9%) were treated only with CHE and 165 (48.1%) with CHE+RTE. A functional and/or structural thyroid disease was diagnosed in 147 (42.5%; 24.2% in CHE and 62.4% in CHE+RTE group; p = 0.0001). Of note, 71 (20.7%) patients with no evidence of disease at first evaluation developed a thyroid alteration during the follow-up. Primitive hypothyroidism was diagnosed in 54 patients (15.7%; 11.2% in CHE vs. 20.6% in CHE+RTE group; p = 0.01) and hyperthyroidism in 4. Sixty-three patients developed thyroid nodules (18.4%; 4.0% in CHE and 14.1% in CHE+RTE group; p < 0.001); thyroid cancer was diagnosed in 30 patients (8.7%; 4.5% in CHE and 12.4% in CHE + RTE group; p = 0.007). CONCLUSIONS: In patients treated with CHE+RTE, the prevalence of hypothyroidism and nodular pathology, both malignant and benign, were significantly greater than in patients treated with CHE. However, also in the CHE group, the frequency of thyroid disease is not negligible and the pathogenetic mechanisms remain to be clarified. Our data suggest the clinical benefit of morpho-functional thyroid screening in P/A cancer survivors.

Spinal cord compression as tumor onset: an unusual case report of Hodgkin lymphoma in a teenager.

BACKGROUND: Spinal cord compression (SCC) is an uncommon, severe complication of Hodgkin lymphoma (HL), occurring in 0.2% of cases at the onset and in 6% during disease progression. We present a teenager with SCC with clinical onset of HL; her pre-existing neurological abnormalities covered the presence of an epidural mass, which could have misled us. CASE PRESENTATION: A 13-year-old girl presented with a three-month history of lower back pain and degrading ability to walk. She suffered from a chronic gait disorder due to her preterm birth. A magnetic resonance imaging of the spine revealed an epidural mass causing collapse of twelfth thoracic vertebra and thus compression and displacement of the spinal cord. Histological examination with immunohistochemical analysis of the epidural mass demonstrated a classic-type Hodgkin lymphoma. Early pathology-specific treatment allowed to avoid urgent surgery, achieve survival and restore of neurological function. CONCLUSIONS: Children and adolescents with back pain and neurological abnormalities should be prioritized to avoid diagnostic delay resulting in potential loss of neurological function. SCC requires a prompt radiological assessment and an expert multidisciplinary management.

Prophylaxis With Trimethoprim/Sulfamethoxazole Is Not Necessary in Children With Solid Tumors Treated With Low-medium Intensity Chemotherapy.

Prophylaxis of Pneumocystis jiroveci pneumonia (PJP) with trimethoprim/sulfamethoxazole is a standard of care for children with hematologic malignancies, while its use in solid tumor patients is still debated. A retrospective study focusing on the use of PJP prophylaxis in patients with solid tumors was performed among 16 AIEOP centers: 1046/2863 patients did not receive prophylaxis and no cases of PJP were reported.

General anesthesia, conscious sedation, or nothing: Decision-making by children during painful procedures.

BACKGROUND: Following diagnosis, children with cancer suddenly find themselves in an unknown world where unfamiliar adults make all the important decisions. Children typically experience increasing levels of anxiety with repeated invasive procedures and do not adapt to the discomfort. The aim of the present study is to explore the possibility of asking children directly about their medical support preferences during invasive procedures. PROCEDURE: Each patient was offered a choice of medical support on the day of the procedure, specifically general anesthesia (GA), conscious sedation (CS), or nothing. An ad hoc assessment tool was prepared in order to measure child discomfort before, during, and after each procedure, and caregiver adequacy was measured. Both instruments were completed at each procedure by the attending psychologist. RESULTS: We monitored 247 consecutive invasive procedures in 85 children and found that children in the 4 to 7 year age group showed significantly higher distress levels. GA was chosen 66 times (26.7%), CS was chosen 97 times (39.3%), and nothing was chosen 5 times and exclusively by adolescents. The child did not choose in 79 procedures (32%). The selection of medical support differed between age groups and distress level was reduced at succeeding procedures. CONCLUSIONS: Offering children the choice of medical support during invasive procedures allows for tailored support based on individual needs and is an effective modality to return active control to young patients, limiting the emotional trauma of cancer and treatment.

Pediatric intracranial ependymoma: correlating signs and symptoms at recurrence with outcome in the second prospective AIEOP protocol follow-up.

PURPOSE: The aims of patients' radiological surveillance are to: ascertain relapse; apply second-line therapy; accrue patients in phase 1/2 protocols if second-line therapy is not standardized/curative; and assess/treat iatrogenic effects. To lessen the emotional and socioeconomic burdens for patients and families, we ideally need to establish whether scheduled radiological surveillance gives patients a better outcome than waiting for symptoms and signs to appear. METHODS: We analyzed a prospective series of 160 newly-diagnosed and treated pediatric/adolescent patients with intracranial ependymoma, comparing patients with recurrent disease identified on scheduled MRI (the RECPT group; 34 cases) with those showing signs/symptoms of recurrent disease (the SYMPPT group; 16 cases). The median follow-up was 67 months. RESULTS: No significant differences emerged between the two groups in terms of gender, age, tumor grade/site, shunting, residual disease, or type of relapse (local, distant, or concomitant). The time to relapse (median 19 months; range 5-104) and the MRI follow-up intervals did not differ between the SYMPPT and RECPT groups. The presence of signs/symptoms was an unfavorable factor for overall survival (OS) after recurrence (5-year OS: 8% vs. 37%, p = 0.001). On multivariable analysis, an adjusted model confirmed a significantly worse OS in the SYMPPT than in the RECPT patients. CONCLUSIONS: Symptomatic relapses carried a significantly worse survival for ependymoma patients than recurrences detected by MRI alone. It would therefore be desirable to identify recurrences before symptoms develop. Radiological follow-up should be retained in ependymoma patient surveillance because there is a chance of salvage treatment for relapses found on MRI.

Triptorelin for Fertility Preservation in Adolescents Treated With Chemotherapy for Cancer.

BACKGROUND: Triptorelin, a gonadotropin releasing hormone analogue, can be administered to postpubertal female individuals with cancer who receive chemotherapy to obtain menstrual suppression and decrease the risk of hemorrhage caused by thrombocytopenia. Our goal was to assess whether triptorelin also has a protective role against the gonadotoxicity of chemotherapy. PATIENTS AND METHODS: This retrospective observational study includes all postmenarchal female patients who presented to our Unit from 2000 to 2015 and received chemotherapy for cancer. They were administered depot triptorelin. We evaluated long-term ovarian function in order to detect clinical signs of ovarian damage, miscarriages, and pregnancies. Laboratory follow-up consisted in dosing serum follicle stimulating hormone, luteinizing hormone, prolactin, estradiol, and progesterone. Ultrasound of the ovaries was performed as well. RESULTS: Of 36 evaluable patients, 9 received hematopoietic stem cell transplantation (HSCT). The remaining 27 patients maintained normal ovarian function at clinical, laboratory, and ultrasound assessment. Five of them achieved spontaneous physiological pregnancy. Four of the 9 patients who underwent HSCT developed premature ovarian failure. CONCLUSION: Our study suggests that gonadotropin releasing hormone-a administered during chemotherapy can prevent premature ovarian failure in patients treated without HSCT and that it is not enough to preserve the ovarian function during HSCT. Hence, a prospective randomized trial with a larger population would be recommended.

Bilateral adrenal neuroblastoma in the infant: Is it an image-defined risk factor?

The treatment of neuroblastoma is based on the International Neuroblastoma Risk Group stratification considering life-threatening symptoms, image-defined risk factors (IDRFs), presence and site of metastases, biology, and histopathology. The authors present an infant with bilateral nonmetastatic adrenal neuroblastoma with favorable biology. Both tumors were resectable and without IDRFs, but bilateral resection was considered mutilating, so it was decided to operate one side only. The authors suggest considering bilaterality among IDRFs.

Final results of the second prospective AIEOP protocol for pediatric intracranial ependymoma.

BACKGROUND: This prospective study stratified patients by surgical resection (complete = NED vs incomplete = ED) and centrally reviewed histology (World Health Organization [WHO] grade II vs III). METHODS: WHO grade II/NED patients received focal radiotherapy (RT) up to 59.4 Gy with 1.8 Gy/day. Grade III/NED received 4 courses of VEC (vincristine, etoposide, cyclophosphamide) after RT. ED patients received 1-4 VEC courses, second-look surgery, and 59.4 Gy followed by an 8-Gy boost in 2 fractions on still measurable residue. NED children aged 1-3 years with grade II tumors could receive 6 VEC courses alone. RESULTS: From January 2002 to December 2014, one hundred sixty consecutive children entered the protocol (median age, 4.9 y; males, 100). Follow-up was a median of 67 months. An infratentorial origin was identified in 110 cases. After surgery, 110 patients were NED, and 84 had grade III disease. Multiple resections were performed in 46/160 children (28.8%). A boost was given to 24/40 ED patients achieving progression-free survival (PFS) and overall survival (OS) rates of 58.1% and 68.7%, respectively, in this poor prognosis subgroup. For the whole series, 5-year PFS and OS rates were 65.4% and 81.1%, with no toxic deaths. On multivariable analysis, NED status and grade II were favorable for OS, and for PFS grade II remained favorable. CONCLUSIONS: In a multicenter collaboration, this trial accrued the highest number of patients published so far, and results are comparable to the best single-institution series. The RT boost, when feasible, seemed effective in improving prognosis. Even after multiple procedures, complete resection confirmed its prognostic strength, along with tumor grade. Biological parameters emerging in this series will be the object of future correlatives and reports.

Vulvar Melanoma Associated with Lichen Sclerosus in a Child: Case Report and Literature Review.

The authors describe the sixth pediatric case to date of primary vulvar melanoma associated with lichen sclerosus and propose a practical management for such a rare cancer.

A difficult diagnosis of Hodgkin lymphoma due to immune thrombocytopenia.

We report a rare clinical presentation of childhood Hodgkin lymphoma with immune thrombocytopenia. Diagnostic biopsy of the abdominal mass was performed after administration of intravenous immunoglobulins, steroids, and platelet transfusion. Concomitant thrombocytopenia complicated the whole diagnosis work up and the initial management of neoplasia.

Hepatoblastoma presenting as precocious puberty: a case report.

Hepatoblastoma (HB), a primary liver tumor in childhood, is often accompanied by alpha-fetoprotein (AFP) secretion, and sometimes by ß-human chorionic gonadotropin hormone (ß-hCG) secretion, and this can cause peripheral precocious puberty (PPP). We describe a case of PPP associated with HB. Laboratory tests showed an increase in AFP, ß-hCG and testosterone values, and suppression of follicle-stimulating hormone and luteinizing hormone levels. After chemotherapy and surgery, AFP, ß-hCG and testosterone levels normalized and signs of virilization did not progress further. The child did not show evidence for tumor recurrence after 16 months of follow-up. New therapeutic approaches and early diagnosis may ensure a better prognosis of virilizing HB, than reported in the past. Assessment of PPP should always take into account the possibility of a tumoral source.

CNS-PNETs with C19MC amplification and/or LIN28 expression comprise a distinct histogenetic diagnostic and therapeutic entity.

Amplification of the C19MC oncogenic miRNA cluster and high LIN28 expression has been linked to a distinctly aggressive group of cerebral CNS-PNETs (group 1 CNS-PNETs) arising in young children. In this study, we sought to evaluate the diagnostic specificity of C19MC and LIN28, and the clinical and biological spectra of C19MC amplified and/or LIN28+ CNS-PNETs. We interrogated 450 pediatric brain tumors using FISH and IHC analyses and demonstrate that C19MC alteration is restricted to a sub-group of CNS-PNETs with high LIN28 expression; however, LIN28 immunopositivity was not exclusive to CNS-PNETs but was also detected in a proportion of other malignant pediatric brain tumors including rhabdoid brain tumors and malignant gliomas. C19MC amplified/LIN28+ group 1 CNS-PNETs arose predominantly in children <4 years old; a majority arose in the cerebrum but 24 % (13/54) of tumors had extra-cerebral origins. Notably, group 1 CNS-PNETs encompassed several histologic classes including embryonal tumor with abundant neuropil and true rosettes (ETANTR), medulloepithelioma, ependymoblastoma and CNS-PNETs with variable differentiation. Strikingly, gene expression and methylation profiling analyses revealed a common molecular signature enriched for primitive neural features, high LIN28/LIN28B and DNMT3B expression for all group 1 CNS-PNETs regardless of location or tumor histology. Our collective findings suggest that current known histologic categories of CNS-PNETs which include ETANTRs, medulloepitheliomas, ependymoblastomas in various CNS locations, comprise a common molecular and diagnostic entity and identify inhibitors of the LIN28/let7/PI3K/mTOR axis and DNMT3B as promising therapeutics for this distinct histogenetic entity.