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Poikiloderma with neutropenia (PN) is a very rare genetic disorder mainly characterized by poikiloderma and congenital neutropenia, which explains the recurrence of respiratory infections and risk of developing bronchiectasis. Patients are also prone to develop hematological and skin cancers. Here, we present the case of a patient, the only child of apparently unrelated Serbian parents, affected by PN resulting from the homozygous mutation NM_024598.3:c.243G>A (p.Trp81Ter) of USB1; early onset of poikiloderma (1 year of age) was associated with cutaneous mastocytosis. We also provide a review of the literature on this uncommon condition with a focus on dermatological findings.

Background Among factors influencing the higher risk of developing unknown or rare adverse drug reactions (ADRs) among children and adolescents, there is the frequent off-label use of drugs that seems to be very common in pediatric oncological patients. Our study aim to collect and evaluate data on the safety profile of antineoplastic drugs and their off-label use in the pediatrics population using real life data. Methods We retrieved Individual Case Safety Reports (ICSRs) with an anticancer agent as suspected drug among those reported through the Campania spontaneous reporting system from 1 January 2013 to 30 September 2019. We classified ICSRs into four off-label categories: “age,” “route of administration,” “weight,” and “therapeutic indication.” We defined an ICSR as an off-label case if it met at least one of the aforementioned categories for at least one of the reported suspected antineoplastic drugs. Results A total of 18 ICSRs (7.6%) out of 236 were classified as off-label cases. The median age of patients was 13 years (interquartile range, IQR: 6–16), with 94.4% of cases occurring in male patients. In the classification of the off-label category, 16 ICSRs were categorized according to the “therapeutic indication” and two for the “age.” No case was categorized for the off-label categories “route of administration” and “weight.” The two off-label cases categorized as “age” were both related to the use of brentuximab vedotin for Hodgkin’s lymphoma in patients aged 16 years. Twenty-nine ADRs (1.6 suspected adverse drug reactions per ICSR) were identified among off-label cases. Among ADRs, those reported more than one were diarrhea (N = 3), neutropenia (N = 3), nausea (N = 2), pyrexia (N = 2), and vomit (N = 2). Conclusions Our findings showed a low number of ICSRs classified as off-label. The majority of off-label ICSRs were categorized for the “therapeutic indication.” This low number of off-label ICSRs might be largely due to the underreporting phenomenon, which is a major limit in pharmacovigilance. Therefore, we believe that spreading pharmacovigilance knowledge and awareness might improve this aspect.

Actually, there is still no consensus related to diagnostic and management algorithms in case of head and neck lymphadenopathy in children. The aim of our study was to analyze the causes of head and neck lymphadenopathy in children to determine a systematic diagnostic approach. We enrolled all cases of head and neck lymphadenopathy in children under the age of 18 diagnosed at the Unit of Hemato-Oncology, Pediatric Department of University "Luigi Vanvitelli," Naples, over a 15-year period (January 2003-December 2017). In total, 405 patients (271 males) were enrolled in the study. Thirteen cases due to other causes, were left off the study. Therefore, the study was performed on 392 cases. A total of 220 patients (56.1%) had a history of infection, 66 cases (16.8%) a diagnosis of neoplasia, and 101 (24.9%) cases a diagnosis of reactive inflammatory changes of nonspecific origin. We have observed the following from our study: (1) the acute infections are the most common causes of head and neck lymphadenopathy in the pediatric population; (2) in about a quarter of patients, the lymphadenopathy resulted by nonspecific origin; (3) the supraclavicular nodes should be regarded with a high index of suspicion of malignancy.

Osteosarcoma (OS) is the most severe bone malignant tumor, responsible for altered osteoid deposition and with a high rate of metastasis. It is characterized by heterogeneity, chemoresistance and its interaction with bone microenvironment. The 5-year survival rate is about 67% for patients with localized OS, while it remains at 20% in case of metastases. The standard therapy for OS patients is represented by neoadjuvant chemotherapy, surgical resection, and adjuvant chemotherapy. The most used chemotherapy regimen for children is the combination of high-dose methotrexate, doxorubicin, and cisplatin. Considered that the necessary administration of high-dose chemotherapy is responsible for a lot of acute and chronic side effects, the identification of novel therapeutic strategies to ameliorate OS outcome and the patients’ life expectancy is necessary. In this review we provide an overview on new possible innovative therapeutic strategies in OS.

Background: Mucoepidermoid carcinoma (MEC) is the most common malignant salivary gland tumour in paediatric population, accounting for 16% of all cases. Patients affected by a previous solid or leukaemic neoplasm during their childhood may develop a second different tumour during the follow-up. In this setting, salivary gland MEC is relatively frequent, accounting for 6% of the second neoplasms in paediatric patients. Consequently, the occurrence of salivary gland nodules in paediatric patients with a previous neoplasm should be considered an event with a high risk of malignancy that poses peculiar diagnostic challenges. Summary: This study was designed to define clinical and instrumental findings and morphological features of MEC on fine-needle aspiration cytology (FNAC) samples in paediatric patients with and without a previous neoplasm. Five patients under 19 years are included in this series. FNAC was performed in all patients on a parotid nodule. We have identified 2 groups of patients: (a) 2 cases with previous history of malignancy (acute lymphoblastic leukaemia and Hodgkin lymphoma) and (b) 3 cases without previous malignant neoplasms. In all cases, a final diagnosis of MEC was rendered. Key Messages: MEC may occur as a second malignancy in paediatric patients. FNAC is certainly a valid and accurate diagnostic tool for this type of neoplasm, even in the paediatric age, allowing the correct management of the patients.

Highlights • Hemipelvectomy with immediate reconstruction with prosthetic devices for the surgical treatment of malignant tumors is an invasive procedure. • The treatment of an exposed hip implant in these cluster of patient is extremely challenging and the literature shows how negative pressure wound therapy and myocutaneous, both pedicled and free, flaps are workhorses in these situations. • The literature shows that the gold standard in the coverage of exposed prosthetic devices and in the treatment of infected non healing wounds is represented by muscular or myocutaneous flap. • In this paper we report a successful coverage of exposed prosthetic hip implant with a local fasciocutaneous flap in a patient in which any other kind of reconstruction was not feasible., Introduction Hemipelvectomy with immediate reconstruction with prosthetic devices for the surgical treatment of malignant tumors is an invasive procedure with many possible complications such as wound breakdown, seroma, hematoma and infection. The treatment of an exposed hip implant in these cluster of patient is extremely challenging and the literature shows how negative pressure wound therapy and myocutaneous, both pedicled and free, flaps are workhorses in these situations. Case report In this paper we report a successful coverage of exposed prosthetic hip implant with a local fasciocutaneous flap in a patient in which any other kind of reconstruction was not feasible. Discussion Fasciocutaneous flaps can be considered as an easily performed and minimally invasive surgical procedure, particularly reliable even in patients in poor general conditions, with preservation of future flap options.

The prognosis for children with recurrent or refractory neuroblastoma remains a significant clinical challenge, and currently there are no known curative salvage regimens. In this paper we investigated the effect of imatinib with rapamycin and the chemotherapeutic agents temozolomide and irinotecan. We treated two children with recurrent neuroblastoma with this so called RIST protocol. Both patients, off therapy for 15 and 31 months, respectively are well, and developing normally, without any complications. These findings suggest that a combination regimen of RIST may provide a therapeutic benefit with a favorable toxicity profile to a unfortunate subset of patients with neuroblastoma.

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.

Acute leukemia (AL) in children can mimic several orthopedic pathologies at presentation, with a variable delay in the correct diagnosis. This is a major problem, which may result in fractures, loss of mobility, and deformity, with resultant adverse effects on quality of life. Here, we studied the clinical and radiological musculoskeletal manifestations in children with AL. We reviewed 328 children [208 boys (62%), median age 7.2 years] with acute lymphoblastic (279, 85%) or myeloid (49, 15%) leukemia, treated between January 1982 and December 2003 by the Paediatric Oncology Service, Second University of Naples. The group was further divided into two groups: group 1 included 255 patients (78%, 163 boys) without skeletal morbidity at diagnosis, and group 2 included 73 patients (22%, 41 boys) with musculoskeletal symptoms. This group was further subdivided into group 2A (56 patients), which included children with symptoms related to the appendicular skeleton, and group 2B (17 patients), which included children with symptoms related to the axial skeleton. Moreover, we also reported the long-term complications of therapy, such as osteonecrosis of the weight-bearing joints. In group 2A, 44 children presented only pain, seven septic arthritis-type symptoms, and five osteomyelitis-type symptoms. Joint compression was in the tibia-tarsus (21 patients), knee (16), coxofemoral (12), and elbow (seven). In group 2B, 11 patients presented with vertebral collapses. The remaining six patients complained of localized pain in the lumbar-sacral area, with limited flexor and extensor muscle capacity. Fifty-five (75.3%) patients showed radiographic abnormalities: osteoporosis in 22 patients (40%), pathological fractures in 11 (20%), osteolysis in 10 (18.1%), osteosclerosis in five (9%), periosteal reactions in four (7.2%), and metaphyseal bands in three (5.4%). Four (1.2%) patients in total showed avascular necrosis (4.3% when only high-risk patients were considered). At presentation, 22% of our children had at least one musculoskeletal manifestation and 75.3% showed one radiographic change. Our study highlights the importance of including AL in the differential diagnosis of musculoskeletal manifestations. Four cases of avascular necrosis confirm the need for regular check-ups, both orthopedic and nonorthopedic, particularly in adolescent girls, to prevent permanent disability.

Background Children with Wilms’ tumor (WT) aged under 24 months (infants) have a better prognosis than older patients. Our aim was to study the epidemiology of this age group, with focus on the modality of diagnosis, tumor size, and association with malformations/syndromes, seeking to understand if any of these factors might be related to prognosis. Patients and methods Infants diagnosed with WT between 2003 and February 2010 were evaluated. A query form was used to collect data on the modality of WT diagnosis (symptomatic or incidental), tumor volume, maximum diameter, site, and stage. Results Data were collected for 117 of 124 WT infants registered. Twenty-four cases had an incidental diagnosis (ID) of renal mass, usually arising from an abdominal ultrasound performed for other reasons, and 93 had been diagnosed based on clinical signs/symptoms. The incidental cohort displayed unifocal disease, mean tumor diameter 5.52 cm, mean tumor volume 84.30 ml, and 14 patients showed associated malformations. Symptomatic patients had mean maximum tumor diameter of 10.18 cm, mean tumor volume of 451.18 ml, and six had associated malformations. Conclusions Our study showed that 20% of the infants had an ID of WT; they had a relatively smaller nonmetastatic tumor and a higher rate of malformations than infants of the symptomatically diagnosed group, but we did not detect any difference in age at diagnosis between the two groups. Conversely, we found a significant difference in the 5-year event-free survival rate (P = 0.018) between infants under 1 year (96%), more frequently associated with congenital malformations, and infants 1–2 years (80%).

Background: Cornelia de Lange syndrome is the prototype for cohesinopathy disorders, which are characterized by defects in chromosome segregation. Kidney malformations, including nephrogenic rests, are common in Cornelia de Lange syndrome. Only one post-mortem case report has described an association between Wilms tumor and Cornelia de Lange syndrome. Here, we describe the first case of a living child with both diseases. Case presentation: Non-anaplastic triphasic nephroblastoma was diagnosed in a patient carrying a not yet reported mutation in NIPBL (c.4920 G > A). The patient had the typical facial appearance and intellectual disability associated with Cornelia de Lange syndrome in absence of limb involvement. The child's kidneys were examined by ultrasound at 2 years of age to exclude kidney abnormalities associated with the syndrome. She underwent pre-operative chemotherapy and nephrectomy. Seven months later she was healthy and without residual detectable disease. Conclusion: The previous report of such co-occurrence, together with our report and previous reports of nephrogenic rests, led us to wonder if there may be any causal relationship between these two rare entities. The wingless/integrated (Wnt) pathway, which is implicated in kidney development, is constitutively activated in approximately 15-20 % of all non-anaplastic Wilms tumors. Interestingly, the Wnt pathway was recently found to be perturbed in a zebrafish model of Cornelia de Lange syndrome. Mutations in cohesin complex genes and regulators have also been identified in several types of cancers. On the other hand, there is no clear evidence of an increased risk of cancer in Cornelia de Lange syndrome, and no other similar cases have been published since the fist one reported by Cohen, and this prompts to think Wilms tumor and Cornelia de Lange syndrome occurred together in our patient by chance.

Kaposiform hemangioendothelioma (KHE) is a rare, locally aggressive, vascular spindle-cell proliferation, with resemblance to Kaposi sarcoma. Usually, this tumor occurs in the skin and the retroperitoneum. We described a girl with a kidney localization and extension into the inferior vena cava and even into the right atrium. The case presented here is unique in 2 ways. First, kidney involvement of KHE has never been described in the literature until now. Second, and most remarkably, extensive tumor thrombosis suggests surgical excision even with cardiopulmonary bypass. The KHE of the kidney is a rare tumor but should be taken into account in the differential diagnosis with other pediatric renal neoplasms.

Background One of the most important adverse prognostic factors for adult renal cell carcinoma (RCC) is the retroperitoneal lymph node involvement. The aim of this article is to study the prognostic significance of local lymph node involvement in pediatric RCC and the role of retroperitoneal lymph node dissection (RLND) at diagnosis. Procedure The series included 16 patients with RCC and lymph nodes involvement registered in the Italian Rare Tumors Pediatric Age (TREP) project, accounting for 26.2% of 61 pediatric RCC observed at AIEOP centers. Results A radical nephrectomy was performed in all cases: at diagnosis in 12 cases, after preoperative chemotherapy (CT) in 4 cases. As a part of the same procedure 9 patients underwent RLND, and 7 received a more limited lymph nodes resection. Five (31.2%) developed disease recurrence 2–34 months after diagnosis (median, 6 months) plus 1 developed progression; 6 patients died, 1 of them from secondary leukemia. Among the nine patients receiving RLND, eight are alive and disease free. This compares with only one patient surviving among the seven receiving a more limited lymph nodes resection. The estimated 25-year PFS and OS rates for all patients were 61.4% (95% CI 33.2–80.5) and 50.8% (95% CI 16.5–77.5), respectively. Conclusions Lymph node involvement is an unfavorable prognostic factor in children with RCC. RLND appears to be a critical factor to improve the outcome. However, when compared to similar adult patients, the outcome in children appears to be better, suggesting that pediatric RCC, or the host, may be critical differences. Pediatr Blood Cancer 2008;51:475–478. © 2008 Wiley-Liss, Inc.

Background Childhood cancer is relatively uncommon and the European age-standardized rate was 164 new case per million per year among children 0 to 14 years of age (95 % CI 158-170). Aims of our study are to evaluate the cases of these malignant diseases observed between 0 and 15 years of age in the Campania region between 1990 and 2014, the ration between observed and expected cases by disease and province of residence. Also we studied the percentage of extra-regional migration over the time by disease and province of residence. Methods In this study we reported the patients with malignant disease observed in 25 years (1990–2014) based on the specialized registry, the Mod. 1.01 of the AIEOP (Association Italian Pediatric Hematology-Oncology). The size of the monitored population also allowed us to systematically examine five time trends: 1990–94: 1995–99; 2000–04; 2005–09; and 2010–14. Results Between 1990 and 2014 a total of 3655 malignant neoplasms were reported: Napoli province (2059 cases), Salerno province (625), Caserta province (589), Avellino province (229), and Benevento province (153). Epidemiological data suggested that about 4100 cases could be expected in Campania region during the same period. The overall ratio between observed (O) and expected (E) numbers of cases in the five periods considered rose gradually from 0.69 in the first period to 0.76, then 0.82, 0.91, and 0.94, in the other periods considered. The extra-regional migration involved 1029 cases (28.1 %), showing a reduction from 33.7 % of the first period to 20.3 % of the last period considered. Considering single province of residence we observed the lowest rate of migration in Napoli and Caserta province, whereas higher levels were observed in the other provinces. For all provinces, except Salerno, the extra-regional migration declined significantly over time. Conclusions The present findings showed an increase over time of O/E ratio, probably due to improvement in the organization of centers and greater trust of families in local centers. It is possible to further improve the efficiency of healthcare system of Campania region and migration can be reduced with a more rational use of hospitals throughout region.

Background Pediatric nonrhabdomyosarcoma soft tissue sarcomas (NRSTS) may rarely occur in visceral tissues, and little is known about their clinical history. The present study retrospectively analyzed a group of patients prospectively registered in Italian pediatric protocols conducted between 1979 and 2004. Methods Inclusion criteria for the study were as follows: a pathological diagnosis of “adult-type NRSTS,” arising at visceral sites (lung-pleurae, liver, kidney, and mesentery-bowel); age under 18 years; no previous treatment except for primary surgery; available clinical data; and written consent. Results Thirty cases with visceral NRSTS were collected and analyzed. Sites of origin were as follows: mesentery-bowel in 12 cases, lung-pleurae in 11, liver in 5, and kidney in 2. According to the Intergroup Rhabdomyosarcoma Study (IRS) surgical grouping system, patients were classified as follows: nine IRS group I, three group II, 12 group III, and six group IV. Patients were treated with a multimodal approach including surgery, radiotherapy, and/or chemotherapy, according to their characteristics. For the series as a whole, the 5-year event-free and overall survival rates were 33.3% and 40.0%, respectively. The IRS group (reflecting the feasibility of initial complete resection) emerged as the main prognostic factor. Survival rates also correlated with tumor size and local invasiveness, histological subtype, and tumor sites (the worst outcome was seen for tumors arising in the lung and pleurae). Conclusions This study confirmed that visceral NRSTS are aggressive tumors carrying a worse prognosis than pediatric NRSTS arising in soft tissues of the extremities. Local treatment remains the main challenge for these tumors.

High-dose methotrexate (MTX) is a key component of most treatment protocols for childhood and adolescent non-Hodgkin lymphoma (NHL). Recent studies have suggested that the toxicity of antifolate drugs, such as MTX, is affected by inherited single nucleotide polymorphisms (SNPs) in folate metabolizing genes. The aim of our study was to investigate the potential influence of the C677T and A1298C genetic variants of the methylenetetrahydrofolate reductase (MTHFR) gene on the clinical toxicity and efficacy of MTX in pediatric patients with NHL (n = 95) treated with therapeutic protocols Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) LNH-97 and EURO LB-02. We demonstrated that patients with the 677T genotype had an approximately six-fold greater risk of developing hematological toxicity compared with wild-type carriers, especially in the 1 g/m(2) treatment group (p = 0.01). Moreover, we identified a correlation between the risk of relapse and the T genotype: T carriers had reduced disease-free survival compared with wild-type patients (67% vs. 100%). Our data suggest a pharmacogenetic influence on the adverse effects of high-dose MTX in the 1 g/m(2) treatment group.

Purpose To evaluate the prognostic factors in a series of children affected by pleuropulmonary blastoma (PPB). Patients and Methods Clinicopathological findings, treatment, and outcome of 22 PPB cases observed in 13 Italian Associations for Pediatric Hematology and Oncology centers are reported. Clinical data, surgical notes, pathologic findings, and summaries of treatment were taken from the charts and correlated with outcome by standard statistical methods. Results The series included 22 patients (14 males) with a median age of 30.5 months followed up for a median of 22 months (range 2–176 months). In nine patients the PPB developed with lung involvement only. Congenital lung cysts were recorded in five cases. Nine patients had recurrences. Gender, side, tumor size, pre-existing lung cysts, and extent of surgical resection at diagnosis did not significantly affect survival by univariate analysis. Achieving total resection of the tumor at any time of treatment resulted in a significantly better prognosis (P = 0.01), whereas extrapulmonary involvement at diagnosis resulted in a significantly worse prognosis (P = 0.01). Estimated 15-year event-free and overall survival rates were 44 and 49% for all patients, respectively. Conclusions PPB is an aggressive neoplasm. Total resection of PPB performed at any time of treatment appears to provide a better outcome, whereas extrapulmonary involvement at diagnosis worsens the prognosis. Pediatr Blood Cancer 2007;48:318–323. © 2006 Wiley-Liss, Inc.