From the identification of actionable molecular targets to the generation of faithful neuroblastoma patient-derived preclinical models.

BACKGROUND: Neuroblastoma (NB) represents the most frequent and aggressive form of extracranial solid tumor of infants. Although the overall survival of patients with NB has improved in the last years, more than 50% of high-risk patients still undergo a relapse. Thus, in the era of precision/personalized medicine, the need for high-risk NB patient-specific therapies is urgent. METHODS: Within the PeRsonalizEd Medicine (PREME) program, patient-derived NB tumors and bone marrow (BM)-infiltrating NB cells, derived from either iliac crests or tumor bone lesions, underwent to histological and to flow cytometry immunophenotyping, respectively. BM samples containing a NB cells infiltration from 1 to 50 percent, underwent to a subsequent NB cells enrichment using immune-magnetic manipulation. Then, NB samples were used for the identification of actionable targets and for the generation of 3D/tumor-spheres and Patient-Derived Xenografts (PDX) and Cell PDX (CPDX) preclinical models. RESULTS: Eighty-four percent of NB-patients showed potentially therapeutically targetable somatic alterations (including point mutations, copy number variations and mRNA over-expression). Sixty-six percent of samples showed alterations, graded as "very high priority", that are validated to be directly targetable by an approved drug or an investigational agent. A molecular targeted therapy was applied for four patients, while a genetic counseling was suggested to two patients having one pathogenic germline variant in known cancer predisposition genes. Out of eleven samples implanted in mice, five gave rise to (C)PDX, all preserved in a local PDX Bio-bank. Interestingly, comparing all molecular alterations and histological and immunophenotypic features among the original patient's tumors and PDX/CPDX up to second generation, a high grade of similarity was observed. Notably, also 3D models conserved immunophenotypic features and molecular alterations of the original tumors. CONCLUSIONS: PREME confirms the possibility of identifying targetable genomic alterations in NB, indeed, a molecular targeted therapy was applied to four NB patients. PREME paves the way to the creation of clinically relevant repositories of faithful patient-derived (C)PDX and 3D models, on which testing precision, NB standard-of-care and experimental medicines.

The real-life management of glucose homeostasis abnormalities in pediatric onco-hematological diseases: data from a national survey.

Glycemic abnormalities are a frequent finding in pediatric oncological patients, both during treatment and after its discontinuation. Moreover, impaired glucose tolerance (IGT), impaired fasting glycemia (IFG) and diabetes mellitus (DM) are not rarely diagnosed in non-oncological hematological diseases. To explore the current pediatric Italian approach to the diagnosis and the management of the glycemic alterations in this clinical setting and, thus, to identify and enforce current clinical needs, we submitted an online 23-items survey to all the Italian Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) centers, and surveys were descriptively analyzed. Thirty-nine AIEOP centers were involved in the study. In 2021, among 75278 children and adolescents affected by an oncological or a hematological disease, 1.2 and 0.65% developed DM, while IGT or IFG were widespread in 2.3 and 2.8%, respectively. The main causes of DM were the use of corticosteroids in patients with cancer and the iron overload in patients with thalassemia. Venous fasting plasma glycemia was the most used tool to detect glycemic abnormalities. The performance of oral glucose tolerance test (OGTT) was extremely limited, except when IFG occurred. Despite the diagnosis of DM, ∼45% of patients with cancer and 30% of patients with one hematological disease did not receive an appropriate treatment. In the other cases, insulin was the drug of first choice. Emerging technologies for diabetes care (glucose sensors and insulin pumps) are not largely used yet. The results of our study support the standardization of the care of the glycemic abnormalities during or after onco-hematologic diseases in the pediatric age. Despite the scarce data in pediatric literature, proper guidelines are needed.

Letermovir for Cytomegalovirus infection in pediatric patients undergoing allogenic hematopoietic stem cell transplantation: a real-life study by the Infectious Diseases Working Group of Italian Association of Pediatric Hematology-Oncology (AIEOP).

Letermovir prophylaxis revolutionized the approach to Cytomegalovirus infection in adult hematopoietic stem cell transplant (HCT), while data in pediatric setting are still lacking. We retrospectively analyzed 87 HCT children transplanted in 11 AIEOP centers receiving letermovir as off-label indication between January 2020 and November 2022. Letermovir was used as primary, secondary prophylaxis or CMV treatment in 39, 26 and 22 cases, respectively; no discontinuation due to toxicity was reported. Median duration was 100 days (14-256) for primary and 96 days (8-271) for secondary prophylaxis, respectively. None of the patients experienced CMV-clinically significant reactivation during Letermovir primary prophylaxis; one patient developed breakthrough infection during secondary prophylaxis, and 10 and 1 patient experienced asymptomatic CMV-reactivation and CMV-primary infection after drug discontinuation, respectively. Median duration of letermovir in CMV treatment was 40 days (7-134), with 4/22 patients suffering CMV-pneumonia, with an overall response rate of 86.4%. With a median follow-up of 10.7 months (8.2-11.8), estimated 1-year overall survival was 86%; no CMV-related deaths were reported in prophylaxis groups. This is the largest report on Letermovir use in pediatric HCT; real-life data confirm an excellent toxicity profile, with high efficacy as CMV prophylaxis; results in CMV-infection treatment should be investigated in larger, prospective trials.

Use of music therapy in pediatric oncology: an Italian AIEOP multicentric survey study in the era of COVID-19.

Music therapy (MT) is a complementary therapy offered to children, young adults, and their families in pediatric oncology and palliative care. We performed a survey to collect information about MT in pediatric oncology in Italy. The outbreak of COVID-19 unavoidably changed the scenario of MT, suggesting some considerations presented in this survey. 27/32 (84.4%) centers belonging to the Infections and Supportive Therapy Working Group of Association of Pediatric Hematology and Oncology (AEIOP) completed in 2 different time points (T1 and T2) an online survey on MT, before and after COVID-19 pandemia. Different kinds of music approach were used taking care of patients in 21/27 centers, while in 14/21 (66%), a specific project of MT conducted by a music therapist was present. In 6/14 centers, MT activities were delivered for < 3 h/week, in 3 centers for > 3 and < 10 h/week, and in the remaining 5 for > 3 h/week. MT sessions were in different areas, day hospital, or ward (patient rooms, operating rooms, waiting rooms), on an individual basis or by groups. Patients were invited to MT by psychologists, caring physician, or nurse, or on equipé decision. MT was evaluated with tools self-made by music therapist in 11/14 centers. After COVID-19, MT has been withdrawn in 3 centers, sessions in the waiting rooms were reduced, individual sessions were preferred, and enrollment by multidisciplinary teams increased. CONCLUSION: This survey represents the starting platform to compare and discuss different experience of MT in AIEOP centers, to implement MT in pediatric oncology for a more qualified assistance to patients, and to improve quality of care. WHAT IS KNOWN: • Music therapy in pediatric oncology and palliative care can be used for the management and prevention of various somatic and psychological symptoms of patients and often is provided to children together with their families. • In Italy the application of Music therapy in the AIEOP pediatric oncology centers is constantly increasing, but due to the outbreak of Covid-19 Pandemic, Italian pediatric oncology departments were obliged to adopt restrictive measures. WHAT IS NEW: • Although the majority of Centres did not abrogate MT interventions, judgment about limitation should be carefully taken since MT helps children and even more adolescents in their fight against cancer. • The best practice of Music therapy in pediatric oncology requires communication and collaboration among qualified music therapists and multidisciplinary care team, using a model of family-centered care that actively involves parents/ caregivers in assessment, treatment planning, and care delivery.

Italian Precision Medicine in Pediatric Oncology: Moving beyond Actionable Alterations.

Neuroblastoma (NB) is the most common extracranial solid tumor encountered in childhood. Although there has been significant improvement in the outcomes of patients with high-risk disease, the prognosis for patients with metastatic relapse or refractory disease is poor. Hence, the clinical integration of genome sequencing into standard clinical practice is necessary in order to develop personalized therapy for children with relapsed or refractory disease. The PeRsonalizEdMEdicine (PREME) project focuses on the design of innovative therapeutic strategies for patients suffering from relapsed NB. We performed whole exome sequencing (WES) of patient-matched tumor-normal samples to identify genetic variants amenable to precision medicine. Specifically, two patients were studied (First case: a three-year-old male with early relapsed NB; Second case: a 20-year-old male who relapsed 10 years after the first diagnosis of NB). Results were reviewed by a multi-disciplinary molecular tumor board (MTB) and clinical reports were issued to the ordering physician. WES revealed the mutation c.G320C in the CUL4A gene in case 1 and the mutation c.A484G in the PSMC2 gene in case 2. Both patients were treated according to these actionable alterations, with promising results. The effective treatment of NB is one of the main challenges in pediatric oncology. In the era of precision medicine, the need to design new therapeutic strategies for NB is fundamental. Our results demonstrate the feasibility of incorporating clinical WES into pediatric oncology practice.

Low miR-214-5p Expression Correlates With Aggressive Subtypes of Pediatric ALCL With Non-Common Histology.

The unsatisfactory cure rate of relapsing ALK-positive Anaplastic Large-Cell Lymphoma (ALCL) of childhood calls for the identification of new prognostic markers. Here, the small RNA landscape of pediatric ALK-positive ALCL was defined by RNA sequencing. Overall, 121 miRNAs were significantly dysregulated in ALCL compared to non-neoplastic lymph nodes. The most up-regulated miRNA was miR-21-5p, whereas miR-19a-3p and miR-214-5p were reduced in ALCL. Characterization of miRNA expression in cases that relapsed after first line therapy disclosed a significant association between miR-214-5p down-regulation and aggressive non-common histology. Our results suggest that miR-214-5p level may help to refine the prognostic stratification of pediatric ALK-positive ALCL.

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.

Musculoskeletal manifestations of childhood cancer and differential diagnosis with juvenile idiopathic arthritis (ONCOREUM): a multicentre, cross-sectional study.

BACKGROUND: Presenting symptoms of childhood cancers might mimic those of rheumatic diseases. However, the evidence available to guide differential diagnosis remains scarce. Preventing wrong or delayed diagnosis is therefore important to avoid incorrect administration of glucocorticoid or immunosuppressive therapy and worsening of prognosis. As such, we aimed to assess the prevalence and characteristics of presenting musculoskeletal manifestations in patients at cancer onset and to identify the factors that differentiate childhood malignancies with arthropathy from juvenile idiopathic arthritis. METHODS: We did a multicentre, cross-sectional study at 25 paediatric haemato-oncology centres and 22 paediatric rheumatology centres in Italy. We prospectively recruited patients who were younger than 16 years that were newly diagnosed with cancer or juvenile idiopathic arthritis. We excluded patients with glucocorticoid pre-treatment (>1 mg/kg per day of oral prednisone or equivalent for ≥2 consecutive weeks). We collected data for patients with a new diagnosis of cancer or juvenile idiopathic arthritis using an electronic case report form on a web-based platform powered by the Cineca Interuniversity Consortium. The primary outcome was to describe the frequency and characteristics of musculoskeletal manifestations at cancer onset; and the secondary outcome was to identify factors that could discriminate malignancies presenting with arthropathy, with or without other musculoskeletal symptoms, from juvenile idiopathic arthritis using multivariable logistic regression analysis. FINDINGS: Between May 1, 2015, and May 31, 2018, 1957 patients were eligible, of which 1277 (65%) had cancer and 680 (35%) had juvenile idiopathic arthritis. Musculoskeletal symptoms occurred in 324 (25% [95% CI 23·0-27·8]) of 1277 patients with cancer, of whom 207 had arthropathy. Patients with malignant bone tumours had the highest frequency of musculoskeletal symptoms (53 [80%] of 66), followed by patients with Langerhans histiocytosis (16 [47%] of 34), leukaemia (189 [32%] of 582), soft-tissue sarcomas (16 [24%] of 68), and neuroblastoma (21 [19%] of 109). In the 324 patients with cancer and musculoskeletal symptoms, the most common complaints were joint pain (199 [61%]), followed by limb bone pain (112 [35%]). Joint involvement had a prevalent monoarticular pattern (100 [48%] of 207) and oligoarticular pattern (86 [42%] had 2-4 joints involved and 20 [10%] had >4 joints involved), with the most frequently involved joints being the hip (88 [43%] of 207) and knee (81 [39%]). On multivariable analysis, limb bone pain was the independent variable most strongly associated with cancer (odds ratio [OR] 87·80 [95% CI 18·89-408·12]), followed by weight loss (59·88 [6·34-565·53]), thrombocytopenia (12·67 [2·40-66·92]), monoarticular involvement (11·30 [4·09-31·19]), hip involvement (3·30 [1·13-9·61]), and male sex (2·40 [1·03-5·58]). Factors independently associated with juvenile idiopathic arthritis were morning stiffness (OR 0·04 [95% CI 0·01-0·20]), joint swelling (0·03 [0·01-0·09]), and involvement of the small hand joints (0·02 [0-1·05]). INTERPRETATION: Our study provides detailed information about presenting musculoskeletal manifestations of childhood cancers and highlights the clinical and laboratory features that are most helpful in the differential diagnosis with juvenile idiopathic arthritis. FUNDING: Associazione Lorenzo Risolo.

Microarray expression studies on bone marrow of patients with Shwachman-Diamond syndrome in relation to deletion of the long arm of chromosome 20, other chromosome anomalies or normal karyotype.

BACKGROUND: Clonal chromosome changes are often found in the bone marrow (BM) of patients with Shwachman-Diamond syndrome (SDS). The most frequent ones include an isochromosome of the long arm of chromosome 7, i (7)(q10), and an interstitial deletion of the long arm of chromosome 20, del (20)(q). These two imbalances are mechanisms of somatic genetic rescue. The literature offers few expression studies on SDS. RESULTS: We report the expression analysis of bone marrow (BM) cells of patients with SDS in relation to normal karyotype or to the presence of clonal chromosome anomalies: del (20)(q) (five cases), i (7)(q10) (one case), and other anomalies (two cases). The study was performed using the microarray technique considering the whole transcriptome (WT) and three gene subsets selected as relevant in BM functions. The expression patterns of nine healthy controls and SDS patients with or without chromosome anomalies in the bone marrow showed clear differences. CONCLUSIONS: There is a significant difference between gene expression in the BM of SDS patients and healthy subjects, both at the WT level and in the selected gene sets. The deletion del (20)(q), with the EIF6 gene consistently lost, even in patients with the smallest losses of material, changes the transcription pattern: a low proportion of abnormal cells led to a pattern similar to SDS patients without acquired anomalies, whereas a high proportion yields a pattern similar to healthy subjects. Hence, the benign prognostic value of del (20)(q). The case of i (7)(q10) showed a transcription pattern similar to healthy subjects, paralleling the positive prognostic role of this anomaly as well.

Late mortality and causes of death among 5-year survivors of childhood cancer diagnosed in the period 1960-1999 and registered in the Italian Off-Therapy Registry.

INTRODUCTION: Advances in paediatric oncology led to the increase in long-term survival, revealing the burden of therapy-related long-term side effects. We evaluated overall and cause-specific mortality in a large cohort of Italian childhood cancer survivors (CCSs) and adolescent cancer survivors identified through the off-therapy registry. MATERIALS AND METHODS: CCSs alive 5 years after cancer diagnosis occurring between 1960 and 1999 were eligible; the last follow-up was between 2011 and 2014. Outcomes were reported as standardised mortality ratios (SMRs) and absolute excess risks (AERs). RESULTS: Among 12,214 CCSs, 1113 (9.1%) deaths occurred. Survival at 35 years since diagnosis was 87% (95% confidence interval [CI]: 86-88) and at 45 years was 81% (95% CI: 77-84). CCSs had an 11-fold increased risk of death (SMR 95% CI: 10.7-12), corresponding to an AER of 48 (95% CI: 45-51). Mortality decreased by 60% for survivors treated most recently (1990-1999). The most frequent causes of death were recurrence of the original cancer (56%), a subsequent neoplasm (19%) and cardiovascular diseases (5.8%). Among those who survived at least 15 years after diagnosis, a secondary malignancy was the leading cause of death. CONCLUSIONS: This study confirms the impact of recent advances in anticancer therapy in reducing mortality, mainly attributable to recurrence but also to other causes. However, overall mortality continues to be higher than in the general population. A long-term follow-up is needed to prevent late mortality due to secondary neoplasms and non-neoplastic causes in CCSs.

Detection of prognostic factors in children and adolescents with Burkitt and Diffuse Large B-Cell Lymphoma treated with the AIEOP LNH-97 protocol.

Burkitt lymphoma (BL) and Diffuse Large B-Cell Lymphoma (DLBCL) account for most cases of non-Hodgkin lymphoma (NHL) in childhood. We report the clinical characteristics, outcome and prognostic factors in children with BL or DLBCL treated according to the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) LNH-97 protocol. Patients aged up to 18 years that were newly diagnosed with BL/DLBCL were included in the study. Therapy consisted of pre-phase followed by 2-6 high-dose chemotherapy courses tailored according to lactate dehydrogenase (LDH) value and disease stage. A total of 442 patients (379 BL, 63 DLBCL) were enrolled between 1997 and 2014, of whom 18 failed to achieve remission, 6 experienced treatment-related death, 2 developed second malignancy and 20 relapsed. At a median follow-up time of 5 years, overall survival was 93% (±1%) and event-free survival was 90% (±1%). LDH value above the median value had an independently negative prognostic value (P < 0·0001). However, in the subgroup of 128 patients in which minimal disseminated disease (MDD) was analysed, MDD-positivity became the only unfavourable prognostic factor for progression-free survival. Tailored chemotherapy could be extremely effective with limited toxicity. Identification of MDD as a hallmark of a higher risk of treatment failure may provide a target population for treatment intensification by anti-CD20.

Non-Hodgkin lymphoma in children with an associated inherited condition: A retrospective analysis of the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP).

BACKGROUND: Inherited conditions affecting genetic aberration, viral oncogenesis, reduced immune surveillance, and long-lasting antigen stimulation may build the way to lymphomagenesis in humans. METHODS: We extracted from the database of 4 consecutive trials for pediatric non-Hodgkin lymphoma (NHL) all cases with an associated genetic disease. RESULTS: Among 1,430 patients, 34 (2.4%) had an associated inherited condition and a mature B-lineage (n = 28), anaplastic large cell lymphoma (n = 4), or T-lineage (n = 2) NHL. Their median age at the diagnosis was 9.3 years (range, 2.6-17.8 years). In 14 cases (41%) the underlying condition was considered to be a potential cause for undue toxicity if the expected therapy was applied. Thus, treatment modification had been planned in advance. The overall survival was 89% (standard error [SE] 1%), 73% (SE 10%), and 73% (SE 23%) at 3 years for registered patients with no inherited condition associated, with genetic abnormalities and with underlying condition causing an immune deficiency, respectively (P = 0.003). CONCLUSION: In our cohort, patients with NHL with an underlying constitutional condition represent the 2.4% of the cases. In the subset of patients with primary immune deficiency, which may have contributed to lymphomagenesis, allogeneic hematopoietic stem cell transplantation may be required. In the remaining patients, the association with lymphoma remains apparently unexplained and could be not causative. Detailed reporting of such cases may contribute to disclose even rare and fully unexpected association, which may have implications for research in the field of lymphomagenesis.

Long-term results of the AIEOP LNH-97 protocol for childhood lymphoblastic lymphoma.

BACKGROUND: Treatment intensification was considered a suitable strategy to increase the cure rate of lymphoblastic lymphoma (LBL) in children. PROCEDURE: The AIEOP LNH-97 trial was run between 1997 and 2007 for newly diagnosed LBL in patients aged less than 18 years. Treatment schedule was based on the previous, LSA2-L2 derived, AIEOP LNH-92 protocol. Modifications included: increased dose of upfront cyclophosphamide and methotrexate, use of l-Asparaginase during induction therapy, intensive block therapy for slow responders, and late intensification ("Reinduction") for patients with advanced stage disease. Total therapy duration was 12 months for stage I and II, and 24 months for stage III and IV. Central nervous system prophylaxis did not include cranial irradiation. RESULTS: 114 eligible patients were enrolled, 84 males and 30 females; median age was 9 years. Complete remission was obtained in 98% of patients. After a median follow-up time of seven years, 29 patients failed due to progression of disease (n = 2), relapse (n = 25), or second malignancy (n = 2). The 7-year overall survival was 82% (standard error [SE] 4%) and the 7-year event-free survival was 74% (SE 4%). No subgroup showed significantly different event free survival. None of the patients died of front line chemotherapy-related toxicity. CONCLUSIONS: Treatment intensification was associated with good outcome in children and adolescents with LBL, with limited toxicity. Prognosis after relapse was better for patients who underwent allogeneic hematopoietic stem cell transplantation. Measurements of biological markers and treatment response are necessary for achieving further improvement through more accurate identification and stratification of patients at risk of disease relapse.

Low PKCα expression within the MRD-HR stratum defines a new subgroup of childhood T-ALL with very poor outcome.

Pediatric T-cell Acute Lymphoblastic Leukemia (T-ALL) outcome has improved in the last decades, yet one patient in every four still relapses. Except treatment response and immunophenotype, few markers are reliably prognostic in pediatric T-ALL patients. Aiming to improve T-ALL risk stratification, we investigated a new candidate biomarker with potential prognostic relevance. A phosphoproteomic screening of 98 pediatric T-ALL samples at diagnosis had been performed using the high-throughput Reverse Phase Protein Arrays technique, which led to the identification of PKCαS657 as an activated protein with a broad variation among T-ALL samples. To evaluate PKCα potential as a prognostic biomarker, PKCα expression was analyzed using RQ-PCR in a cohort of 173 patients, representative of ALL2000-ALLR2006 AIEOP study. A threshold of PKCα expression with the highest discrimination for incidence of relapse was identified. Patients with PKCα down-regulation, compared to patients with PKCα levels above the threshold, presented a markedly increased cumulative incidence of relapse (43.8% vs. 10.9%, P<0.001), as well as a worse 4-year overall survival (66% vs. 87.9%, P=0.002) and event-free survival (53.1% vs. 85.2%, P=0.002). In particular, low PKCα expression identified cases with extremely poor outcome within the high-risk minimal residual disease (MRD) stratum, their incidence of relapse being of 69% vs. 15% in the high PKCα levels group. In a multivariate analysis adjusting for main prognostic features, PKCα proved to be an independent prognostic factor related to incidence of relapse. Very high risk patients within the high-risk MRD stratum, identified by PKCα expression, could be proposed for experimental therapeutic protocols.

Single-day trimethoprim/sulfamethoxazole prophylaxis for Pneumocystis pneumonia in children with cancer.

OBJECTIVE: To determine whether a simplified, 1-day/week regimen of trimethoprim/sulfamethoxazole is sufficient to prevent Pneumocystis (jirovecii [carinii]) pneumonia (PCP). Current recommended regimens for prophylaxis against PCP range from daily administration to 3 consecutive days per week dosing. STUDY DESIGN: A prospective survey of the regimens adopted for the PCP prophylaxis in all patients treated for childhood cancer at pediatric hematology-oncology centers of the Associazione Italiana Ematologia Oncologia Pediatrica. RESULTS: The 20 centers participating in the study reported a total of 2466 patients, including 1093 with solid tumor and 1373 with leukemia/lymphoma (or primary immunodeficiency; n = 2). Of these patients, 1371 (55.6%) received the 3-day/week prophylaxis regimen, 406 (16.5%) received the 2-day/week regimen, and 689 (27.9%), including 439 with leukemia/lymphoma, received the 1-day/week regimen. Overall, only 2 cases of PCP (0.08%) were reported, both in the 2-day/week group. By intention to treat, the cumulative incidence of PCP at 3 years was 0.09% overall (95% CI, 0.00-0.40%) and 0.51% for the 2-day/week group (95% CI, 0.10%-2.00%). Remarkably, both patients who failed had withdrawn from prophylaxis. CONCLUSION: A single-day course of prophylaxis with trimethoprim/sulfamethoxazole may be sufficient to prevent PCP in children with cancer undergoing intensive chemotherapy regimens. This simplified strategy might have implications for the emerging need for PCP prophylaxis in other patients subjected to the increased use of biological and nonbiological agents that induce higher levels of immune suppression, such as those with rheumatic diseases.

Image-enhanced endoscopy with I-scan technology for the evaluation of duodenal villous patterns.

BACKGROUND: I-scan technology is the newly developed endoscopic tool that works in real time and utilizes a digital contrast method to enhance endoscopic image. AIMS: We performed a feasibility study aimed to determine the diagnostic accuracy of i-scan technology for the evaluation of duodenal villous patterns, having histology as the reference standard. METHODS: In this prospective, single center, open study, patients undergoing upper endoscopy for an histological evaluation of duodenal mucosa were enrolled. All patients underwent upper endoscopy using high resolution view in association with i-scan technology. During endoscopy, duodenal villous patterns were evaluated and classified as normal, partial villous atrophy, or marked villous atrophy. Results were then compared with histology. RESULTS: One hundred fifteen subjects were recruited in this study. The endoscopist was able to find marked villous atrophy of the duodenum in 12 subjects, partial villous atrophy in 25, and normal villi in the remaining 78 individuals. The i-scan system was demonstrated to have great accuracy (100 %) in the detection of marked villous atrophy patterns. I-scan technology showed quite lower accuracy in determining partial villous atrophy or normal villous patterns (respectively, 90 % for both items). CONCLUSIONS: Image-enhancing endoscopic technology allows a clear visualization of villous patterns in the duodenum. By switching from the standard to the i-scan view, it is possible to optimize the accuracy of endoscopy in recognizing villous alteration in subjects undergoing endoscopic evaluation.

Breast metastases in children and adolescents with rhabdomyosarcoma: Experience of the Italian Soft Tissue Sarcoma Committee.

BACKGROUND: Breast metastasis from rhabdomyosarcoma (RMS) is an uncommon event but may be problematic in treatment decision-making. Aim of the study was to evaluate clinical characteristics, treatment, and subsequent outcome, of patients with RMS metastasis in the breast, enrolled in four consecutive Associazione Italiana di Ematologia ed Oncologia Pediatrica (AIEOP) Soft Tissue Sarcoma Committee protocols during the last 20 years, in order to obtain information to establish a more adequate diagnostic and therapeutic approach. PROCEDURES: Data were derived from the AIEOP STSC database and reviewed for the purpose of this study. RESULTS: From 1988 to 2008, among 189 patients with metastatic RMS, we identified 7 (3.7%) patients with RMS with breast involvement at diagnosis. All patients were females, aged 13-17 years with alveolar histology and multiple metastasis sites (2-5). The primary tumor was located in the extremities in 3/7 patients. In spite of intensive treatment no patient survived. The cause of treatment failure was distant relapse in six patients, including two on the mammary region. Treatment data analysis revealed that local measures to control breast lesions were used in only two patients. CONCLUSIONS: Our data suggest that investigations of the mammary region should be part of the usual diagnostic workup in adolescent girls with alveolar RMS, especially if the primary tumor arises in the extremities. New and more effective strategies are needed to improve the outcome of these patients including aggressive local measures to control breast disease.

Long-term results of AIEOP LNH-92 protocol for the treatment of pediatric lymphoblastic lymphoma: a report of the Italian Association of Pediatric Hematology and Oncology.

BACKGROUND: Lymphoblastic lymphoma (LBL) is the second most frequent lymphoma subtype in childhood. It is commonly treated according to therapy strategies for lymphoblastic leukemia. METHODS: The AIEOP LNH-92 protocol was a modified LSA2-L2 therapy used for both T- and B-cell precursor LBL and included Induction, Consolidation, and Maintenance treatment with a total duration of 11 and 24 months for stages I and II, stages III and IV disease, respectively. RESULTS: Fifty-five eligible patients were enrolled, 40 males and 15 females, with a median age of 8 years. Complete remission was achieved in 93% of the cases. With a median follow-up of 9 years the event-free survival (EFS) was 69% and overall survival 72%. EFS of localized disease was 100%. The most frequent grades III and IV toxicity was hematologic and hepatic (elevated transaminases) toxicity. No toxic death nor second tumor were observed. Outcome was comparable to most concomitant international protocols for LBL, but inferior to recent trials that included reinduction treatment or a higher intensity therapy for high stage disease. CONCLUSIONS: AIEOP LNH92 protocol demonstrated similar efficacy compared to contemporary regimens, with limited toxicity. Nevertheless, an intensified treatment is warranted for high stage disease.