Diagnosis and management of acquired aplastic anemia in childhood. Guidelines from the Marrow Failure Study Group of the Pediatric Haemato-Oncology Italian Association (AIEOP).

Acquired aplastic anemia (AA) is a rare heterogeneous disorder characterized by pancytopenia and hypoplastic bone marrow. The incidence is 2-3 per million population per year in the Western world, but 3 times higher in East Asia. Survival in severe aplastic anemia (SAA) has improved significantly due to advances in hematopoietic stem cell transplantation (HSCT), immunosuppressive therapy, biologic agents, and supportive care. In SAA, HSCT from a matched sibling donor (MSD) is the first-line treatment. If a MSD is not available, options include immunosuppressive therapy (IST), matched unrelated donor, or haploidentical HSCT. The purpose of this guideline is to provide health care professionals with clear guidance on the diagnosis and management of pediatric patients with AA. A preliminary evidence-based document prepared by a group of pediatric hematologists of the Bone Marrow Failure Study Group of the Italian Association of Pediatric Hemato-Oncology (AIEOP) was discussed, modified and approved during a series of consensus conferences that started online during COVID 19 and continued in the following years, according to procedures previously validated by the AIEOP Board of Directors.

Late-onset and long-lasting neutropenias in the young: A new entity anticipating immune-dysregulation disorders.

This study identifies a new chronic form of immune neutropenia in the young with or without detectable indirect anti-neutrophil antibodies, characterized by mild/moderate neutropenia low risk of severe infection (14%), tendency to develop autoimmune phenomena over the course of the disease (cumulative incidence of 58.6% after 20 years of disease duration), leukopenia, progressive reduction of absolute lymphocyte count and a T- and B-cell profile similar to autoimmune disorders like Sjogren syndrome, rheumatoid arthritis, and systemic lupus erythematosus (increased HLADR+ and CD3 + TCRγδ cells, reduced T regulatory cells, increased double-negative B and a tendency to reduced B memory cells). In a minority of patients, P/LP variants related to primary immuno-regulatory disorders were found. This new form may fit the group of "Likely acquired neutropenia," a provisional category included in the recent International Guidelines on Diagnosis and Management of Neutropenia of EHA and EUNET INNOCHRON ACTION 18233. The early recognition of this form of neutropenia would help clinicians to delineate better specific monitoring plans, genetic counseling, and potentially targeted therapies.

Non-anaplastic peripheral T cell lymphoma in children and adolescents-an international review of 143 cases.

Peripheral T cell lymphomas (PTCL) are rare in children and adolescents, and data about outcome and treatment results are scarce. The present study is a joint, international, retrospective analysis of 143 reported cases of non-anaplastic PTCL in patients <19 years of age, with a focus on treatment and outcome features. One hundred forty-three patients, between 0.3 and 18.7 years old, diagnosed between 2000 and 2015 were included in the study. PTCL not otherwise specified was the largest subgroup, followed by extranodal NK/T cell lymphoma, hepatosplenic T cell lymphoma (HS TCL), and subcutaneous panniculitis-like T cell lymphoma (SP TCL). Probability of overall survival (pOS) at 5 years for the whole group was 0.56 ± 0.05, and probability of event-free survival was (pEFS) 0.45 ± 0.05. Patients with SP TCL had a good outcome with 5-year pOS of 0.78 ± 0.1 while patients with HS TCL were reported with 5-year pOS of only 0.13 ± 0.12. Twenty-five percent of the patients were reported to have a pre-existing condition, and this group had a dismal outcome with 5-year pOS of 0.29 ± 0.09. The distribution of non-anaplastic PTCL subtypes in pediatric and adolescent patients differs from what is reported in adult patients. Overall outcome depends on the subtype with some doing better than others. Pre-existing conditions are frequent and associated with poor outcomes. There is a clear need for subtype-based treatment recommendations for children and adolescents with PTCL.

[Review of clinical experience for a new preputioplasty technique as circumcision alternative]. / Retour d'expérience d'une nouvelle technique de préputioplastie comme alternative à la circoncision.

Surgery is required for phimosis with a contracted fibrous ring or when the medical treatment with steroids has been unsuccessful. Surgical teams often opt for circumcision when a conservative technique can be used. This surgery could have some psychologic consequences, and when the circumcision in not according to religious convictions, it cannot be live well for the patient and his family. Furthermore, some surgery procedures for prepuce conservation seem to give some unaesthesics aspects with cutaneous excess. The objective of this study was to evaluate our new preputioplasty technique according to the initial diagnosis (phimosis with scarred foreskin or long and narrow foreskin), in situation where circumcision is required currently. Outcome evaluated was: easy and painless foreskin retraction, absence of postoperative phimosis as well as cosmetic aspects of the penis. In this study, 90 children benefited from this technique and subsequent follow-up. The mean age was 7.9 years for the 32 children in the sclerotic phimosis group and 6.8 years for the 58 children in the long and narrow foreskin group. We observed complete foreskin retraction without any recurrence in 100% of children with a phimosis resistant to medical treatment which consisted of progressive foreskin retraction and application of topical steroids, with a mean postoperative follow-up of 1.4 years. Results showed an excellent cosmetic aspect of the penis with absence of enlarged foreskin in all our subjects. This study underlines the relevance of this surgical technique.

X-ray beam monitor made by thin-film CVD single-crystal diamond.

A novel beam position monitor, operated at zero bias voltage, based on high-quality chemical-vapor-deposition single-crystal Schottky diamond for use under intense synchrotron X-ray beams was fabricated and tested. The total thickness of the diamond thin-film beam monitor is about 60 µm. The diamond beam monitor was inserted in the B16 beamline of the Diamond Light Source synchrotron in Harwell (UK). The device was characterized under monochromatic high-flux X-ray beams from 6 to 20 keV and a micro-focused 10 keV beam with a spot size of approximately 2 µm × 3 µm square. Time response, linearity and position sensitivity were investigated. Device response uniformity was measured by a raster scan of the diamond surface with the micro-focused beam. Transmissivity and spectral responsivity versus beam energy were also measured, showing excellent performance of the new thin-film single-crystal diamond beam monitor.

Use of cutaneous flap for continent cystostomy (daoud technique).

PURPOSE: We present the results of a new technique using a pedicled cutaneous flap for continent cystostomy. MATERIALS AND METHODS: A total of 15 boys and 8 girls (mean +/- SD age 13.4 +/- 6.4 years) underwent continent cystostomy for neurogenic bladder (20), bladder exstrophy (2) and sequelae of hypospadias (1) between 1999 and 2008. In this procedure a rectangular pedicled flap is surgically elevated from a hairless area on the abdomen. The flap is tubularized and passed through the anterior abdominal wall directly into the bladder. A submucosal detrusor incision is made to expose the bladder mucosa, and the distal part of the flap is anastomosed to the bladder mucosa in a circular manner. The tube is positioned along the incised detrusor, which is closed over. Viability of the flap, self-catheterization management and continence status are then evaluated. RESULTS: Mean +/- SD followup was 4.5 +/- 3.1 years. There was 1 case of distal necrosis of the flap, which required a secondary surgery using the Mitrofanoff technique. The 22 remaining flaps were initially viable, although 2 patients were eventually lost to followup and 3 subsequently presented with false-passage incidents requiring a few days of calibration using a balloon catheter. Dryness was achieved immediately in 73% of the cases. After adding a complementary bulking agent the dryness rate reached 77%. CONCLUSIONS: We present a novel approach to continent cystostomy that is safe and easy to perform. This technique is a less invasive and more efficient alternative to other commonly used approaches.

A prospective study of BK-virus-associated haemorrhagic cystitis in paediatric patients undergoing allogeneic haematopoietic stem cell transplantation.

We investigated the incidence, risk factors and outcome of haemorrhagic cystitis (HC) in paediatric patients undergoing HSCT and the predictive value of BK viruria and viraemia for developing HC. Over a period of 54 months, 74 patients were recruited. The cumulative incidence of HC was 22%. Among 15 patients prospectively monitored for BK viruria and viraemia, four patients developed HC of grade > or =II. This group, which had two consecutive BK positive samples, showed a sensitivity of 100%, a specificity of 82%, a positive predictive value of 67%, and negative predictive value of 100% for developing HC. Analysed by a receiver-operator characteristic curve (ROC), a urine BK load >9 x 10(6) genomic copies/ml had a sensitivity of 95% and specificity of 90%; while a blood BK load >1 x 10(3) genomic copies/ml had a sensitivity of 40% and a specificity of 93% for HC, respectively. In univariate analysis, BK positivity was the only factor significantly associated with HC. After a median follow-up of 1.8 years, patients with HC showed a lower overall survival, 40 vs 65%, P 0.01, and a lower event-free survival, 42 vs 62%, P 0.03, compared to patients without HC. We conclude that BK detection in urine and/or plasma is a specific predictor for developing HC.

Treatment of pediatric non-Hodgkin lymphomas in a country with limited resources: results of the first national protocol in Nicaragua.

We report the results of a protocol for the diagnosis and treatment of pediatric non-Hodgkin lymphomas (NHL) conducted in Nicaragua in the context of an international collaborative program. Fifty-three children with NHL treated between 1996 and 2003 were retrospectively evaluated. Therapy was designed based on local drug availability and affordability with dose and schedule adaptations for Burkitt and lymphoblastic lymphomas. With a median follow-up of 3 years, the projected 9-year overall survival was 63% and event-free survival 53%. The treatment was efficacious, feasible, and well tolerated in spite of the local socio-economical conditions.

99mTc by 99Mo produced at the ENEA-FNG facility of 14MeV neutrons.

A severe supply crisis of 99Mo, precursor of 99mTc a diagnostic radionuclide largely used in Nuclear Medicine, occurred in 2008-2009 due to repeated shut-down of the two main (aged) fission reactors. An alternative route for producing 99Mo by 100Mo(n,2n)99Mo reaction was investigated at ENEA. The experiment, designed according to Monte Carlo simulations performed with the Fluka code, produced 99Mo by irradiating a natural Molybdenum powdered target with 14MeV neutrons produced at the Frascati Neutron Generator. The 99Mo specific activity was measured at metrological level by γ-ray spectrometry.

OVERVIEW OF NEUTRON MEASUREMENTS IN JET FUSION DEVICE.

The design and operation of ITER experimental fusion reactor requires the development of neutron measurement techniques and numerical tools to derive the fusion power and the radiation field in the device and in the surrounding areas. Nuclear analyses provide essential input to the conceptual design, optimisation, engineering and safety case in ITER and power plant studies. The required radiation transport calculations are extremely challenging because of the large physical extent of the reactor plant, the complexity of the geometry, and the combination of deep penetration and streaming paths. This article reports the experimental activities which are carried-out at JET to validate the neutronics measurements methods and numerical tools used in ITER and power plant design. A new deuterium-tritium campaign is proposed in 2019 at JET: the unique 14 MeV neutron yields produced will be exploited as much as possible to validate measurement techniques, codes, procedures and data currently used in ITER design thus reducing the related uncertainties and the associated risks in the machine operation.

Impact of cumulative anthracycline dose, preparative regimen and chronic graft-versus-host disease on pulmonary and cardiac function in children 5 years after allogeneic hematopoietic stem cell transplantation: a prospective evaluation on behalf of the EBMT Pediatric Diseases and Late Effects Working Parties.

This prospective study focused on risk factors and clinical outcome of pulmonary and cardiac late effects after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We prospectively evaluated 162 children by pulmonary function tests (PFTs) and cardiac shortening fraction (SF) before allo-HSCT and yearly up to the 5th year of follow-up. The 5-year cumulative incidence of lung and cardiac impairment was 35 (hazard rate=0.03) and 26% (hazard rate=0.06), respectively. Patients presenting abnormal PFTs and SF at last follow-up were 19 and 13%, respectively, with a median Lansky performance status of 90% (70-100). Chronic graft-versus-host disease (c-GVHD) was the major risk factor for reduced lung function in univariate (P=0.02) and multivariate analysis (P=0.02). Total body irradiation (TBI) alone and TBI together with pre-transplant anthracycline administration were significant risk factors for reduced cardiac function in univariate analysis, only (P=0.04 and 0.004, respectively). In conclusion, our prospective study demonstrates an asymptomatic post-allo-HSCT deterioration of pulmonary and cardiac function in some long-term survivors, who had been transplanted in childhood, and thus emphasizes the need for lifelong cardiopulmonary monitoring and the development of new strategies both to reduce pre-transplant cardiotoxic regimens and to treat more efficiently c-GVHD.

The role of survivin expression in the differential diagnosis of laryngeal (glottic) verrucous squamous cell carcinoma.

AIMS: Laryngeal verrucous squamous cell carcinoma (VSCC) is a highly differentiated carcinoma (SCC) whose histological diagnosis has many pitfalls in particular considering small biopsies: multiple glottic biopsies may be necessary to conclude for a malignant or benign lesion (papillary hyperplasia). Survivin is a member of the inhibitor of apoptosis protein family. Survivin over-expression has been demonstrated in laryngeal SCCs. The aims of the present study have been to evaluate for the first time survivin expression in glottic VSCC and investigate the potential role of survivin expression in the differential diagnosis of laryngeal VSCC. METHODS: Survivin expression was determined in 11 consecutive cases of glottic VSCC, in 24 cases of glottic papillary hyperplasia, and in 23 cases of SCC. RESULTS: Nuclear survivin reaction predominated in laryngeal VSCCs, papillary hyperplasias, and SCCs. Mean survivin expressions in the VSCC basal layer, hyper-proliferative areas of laryngeal papillary hyperplasia, and SCC were 62.7%, 68.3%, and 70.0%, respectively. Mean survivin expression was 15.6% in VSCC parakeratosis and 1.5% in papillary hyperplasia parakeratosis (p<0.001). CONCLUSIONS: Survivin expression was significantly higher in parakeratosis areas of laryngeal VSCC than in parakeratosis areas of laryngeal papillary hyperplasia. Immunohistochemical determination of survivin expression in parakeratosis areas may be a promising tool to substantiate differential diagnosis between glottic VSCC and papillary hyperplasia.

[Secondary megaureter: A rare complication of Deflux® endoscopic management of vesicoureteral reflux in children]. / Le méga-uretère secondaire : une complication rare du traitement endoscopique du reflux vésico-urétéral par Deflux® chez l'enfant.

Endoscopic management is the gold standard for symptomatic low-grade vesicoureteral reflux (VUR) in children. Deflux® (hyaluronic acid/dextranomer) injection is highly effective and has very few complications. We report on two cases of secondary megaureter after Deflux® injections. In the first case, a boy presented with Grade 4 VUR. He received a bilateral Deflux® injection with a total of three syringes. The postoperative ultrasound was normal. However, a check-up ultrasound 3 years later showed a significant ureteropyelocalyceal dilatation, with stasis and decreased renal function on scintigraphy, the reason why antireflux surgery (Cohen procedure) was performed. In the second case, a girl diagnosed with bilateral VUR at birth received bilateral injections with one syringe on each side at the age of 12 months. One month later, the ultrasound showed a dilation of the distal ureters (diameter of the right ureter, up to 10mm; left ureter, up to 6.7mm). The child underwent surgery 8 months later (Cohen procedure) because of iterative pyelonephritis and persistent ureter dilatation. Only one previous case has been described in the literature. In our experience, this complication has occurred only twice in 452 injections (4‰). In conclusion, endoscopic treatment with hyaluronic acid/dextranomer injection is a minimally invasive procedure that improves the situation in cases of VUR. It has few complications. Other than failure, there is a low risk of secondary expansion requiring, in our opinion, ultrasound verification over the long term.

Fertility preservation practices in pediatric and adolescent cancer patients undergoing HSCT in Europe: a population-based survey.

Chemotherapy and irradiation can affect the gonads, leading to impairment of pubertal development and/or infertility. Fertility preservation (FP) is therefore a crucial endeavor in hematopoietic stem cell transplantation (HSCT) because of the severe impact of infertility on the quality of life of long-term survivors. Despite the existence of different international guidelines, FP counseling and procedures are not routinely implemented as part of patient care. We present herein a survey conducted by the Pediatric Working Party of the European Society for Blood and Marrow Transplantation (EBMT), which aims to analyze and compare different FP practices for children and adolescents across EBMT centers in 2013. A total of 177 pediatric centers reporting to the EBMT were contacted; of this number, 38 centers (21%) located in 16 different countries responded. These centers reported 834 patients receiving HSCT in 2013 (73% prepubertal), corresponding to 22% of all children (n=3789) undergoing HSCT in EBMT reporting centers. Overall, 39% of the reported patients received counseling and 29% received an FP procedure. The increased need for FP programs, extended education for patient-care teams, and more personal resources and funding emerged from this survey as pivotal factors necessary to support and implement such programs.

Prevalence and clinical implications of bone marrow involvement in pediatric anaplastic large cell lymphoma.

Anaplastic large cell lymphoma (ALCL) harbors the reciprocal chromosomal translocation t(2;5)(p23;q35) in approximately 80% of the cases. The genes involved are nucleophosmin (NPM) and anaplastic lymphoma kinase (ALK) and the resulting chimeric NPM-ALK protein is thought to play a key role in the pathogenesis of t(2;5) positive ALCL. Few data on bone marrow (BM) involvement in ALCL have been published and they mostly rely on morphological examination of BM smears. We studied 52 ALCL for NPM-ALK expression by RT-PCR: 47/52 biopsies were positive. In 41 of the 47 cases we obtained the BM at diagnosis and investigated the prevalence of minimal BM infiltration by RT-PCR and real-time PCR. Minimal disseminated disease was positive in 25/41 patients (61%), of whom six had morphologically infiltrated BM. Survival analysis demonstrated a 5-year progression-free survival of 41 +/- 11% for patients with molecularly positive BM vs 100% for patients with negative BM (P = 0.001). These results suggest that minimal BM involvement at diagnosis is a common event in pediatric ALCL and that minimal BM disease monitoring could identify patients at risk of relapse.

Neutron detection and dosimetry using polycrystalline CVD diamond detectors with high collection efficiency.

Polycrystalline chemical vapour deposited (CVD) diamond film is an interesting material for neutron detection and dosimetry. However, the use of CVD diamond detectors is still limited by the low-level signal pulse produced because of the high energy required to produce an electron-hole pair in diamond (13.2 eV) and by the reduced charge collection efficiency owing to several types of traps for electrons and holes in CVD films. A new type of CVD diamond detector with high gain (HG) contacts was produced as part of the collaboration between the ENEA Fusion Division and the Faculty of Engineering of Rome 'Tor Vergata' University. In this paper the performance of the HG CVD diamond detector is presented and possible applications of CVD diamond detectors to neutron dosimetry are also discussed.

The polymorphisms -318C>T in the promoter and 49A>G in exon 1 of CTLA4 and the risk of aplastic anemia in a Caucasian population.

Aplastic anemia (AA) is a rare disease with a major autoimmune pathogenetic component. CTLA4 is a T-lymphocyte surface molecule involved in the maintenance of immune tolerance. Some polymorphisms associated with a reduced expression of CTLA4, and thus presumably with increased tendency to autoimmunity, have been associated with various autoimmune diseases. In this study, we evaluated the distribution of the low expression polymorphisms -318C > T and 49A > G of CTLA4 in a population of 67 patients with acquired AA and in 100 normal controls. There was no difference in the distribution of the tested polymorphism between patients and controls and, within the patient group, between those who responded to immunosuppression vs those who did not respond. This study indicates that the polymorphisms -318C > T and 49A > G of CTLA4 do not affect the risk of developing AA and do not influence the response to immunosuppression.

Prospective analysis of minimal bone marrow infiltration in pediatric Burkitt's lymphomas by long-distance polymerase chain reaction for t(8;14)(q24;q32).

The chromosomal translocation t(8;14)(q24;q32) represents a characteristic marker for Burkitt's lymphoma (BL). This translocation involves the MYC oncogene on chromosome 8 and the immunoglobulin heavy-chain (IgH) locus on chromosome 14. Since the translocation does not produce a fusion gene, we established a long-distance polymerase chain reaction (LD-PCR) assay that can detect the t(8;14) at the genomic level. The sensitivity of the LD-PCR was 10(-4). We used the LD-PCR assay to prospectively study 78 BL patients and found a specific PCR product in 52 of them. Among the 52 positive patients, we could test both the tumor and the bone marrow (BM) at diagnosis in 33 and determined the prevalence of minimal disseminated disease (MDD) at diagnosis. In 12/33 patients, BM was positive by LD-PCR and in 10 of them we conducted a study of minimal residual disease (MRD). Eight out of 10 children showed a clearance of MRD after one cycle of chemotherapy. The only two patients who did not achieve a negative MRD status died of disease progression. The comparative analysis of sensitivity of BM aspirate, BM biopsy and LD-PCR in t(8;14)-positive patients demonstrated a superiority of the molecular method in the assessment of MDD. The LD-PCR for t(8;14) is an important tool to study minimal BM infiltration at diagnosis and to determine its response kinetics in BL.

Focal nodular hyperplasia of the liver: an emerging complication of hematopoietic SCT in children.

Hepatic focal nodular hyperplasia (FNH) is a nonmalignant condition rarely affecting children previously treated for cancer, especially those who received hematopoietic SCT (HSCT). Some aspects of its pathogenesis still remain unclear and a strong association with specific risk factors has not yet been identified. We report here a single institution's case series of 17 patients who underwent HSCT and were diagnosed with FNH, analyzing retrospectively their clinical features and the radiological appearance of their hepatic lesions. We aimed to compare the diagnostic accuracy of ultrasound (US) and magnetic resonance imaging (MRI) and to explore the role of transient elastography (FibroScan) to evaluate the degree of hepatic fibrosis in FNH patients. Our analysis showed an association of FNH with age at transplant ⩽12 years (hazard ratio (HR) 9.10); chronic GVHD (HR 2.99); hormone-replacement therapy (HR 4.02) and abdominal radiotherapy (HR 4.37). MRI proved to be a more accurate diagnostic tool compared with US. Nine out of 12 patients who underwent FibroScan showed hepatic fibrosis. Our study points out that FNH is an emerging complication of HSCT, which requires a lifelong surveillance to follow its course in cancer patients.

Outcome of children with high-risk acute myeloid leukemia given autologous or allogeneic hematopoietic cell transplantation in the aieop AML-2002/01 study.

We analyzed the outcome of 243 children with high-risk (HR) AML in first CR1 enrolled in the AIEOP-2002/01 protocol, who were given either allogeneic (ALLO; n=141) or autologous (AUTO; n=102) hematopoietic SCT (HSCT), depending on the availability of a HLA-compatible sibling. Infants, patients with AML-M7, or complex karyotype or those with FLT3-ITD, were eligible to be transplanted also from alternative donors. All patients received a myeloablative regimen combining busulfan, cyclophosphamide and melphalan; [corrected] AUTO-HSCT patients received BM cells in most cases, while in children given ALLO-HSCT stem cell source was BM in 96, peripheral blood in 19 and cord blood in 26. With a median follow-up of 57 months (range 12-130), the probability of disease-free survival (DFS) was 73% and 63% in patients given either ALLO- or AUTO-HSCT, respectively (P=NS). Although the cumulative incidence (CI) of relapse was lower in ALLO- than in AUTO-HSCT recipients (17% vs 28%, respectively; P=0.043), the CI of TRM was 7% in both groups. Patients transplanted with unrelated donor cord blood had a remarkable 92.3% 8-year DFS probability. Altogether, these data confirm that HSCT is a suitable option for preventing leukemia recurrence in HR children with CR1 AML.