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Abstract Background The prognosis of patients with Relapsed/Refractory Osteosarcoma (R/R OS) remains dismal without an agreement on systemic therapy. The use of High-Dose Ifosfamide (14 g/sqm) with an external pump in outpatient setting (14-IFO) in R/R OS patients is limited. This study represents the first retrospective cohort analysis focused on evaluating the activity and toxicity of 14-IFO in this setting. Patients and methods The study investigated 14-IFO activity, in terms of tumour response according to RECIST 1.1 criteria, as well as survival rates and toxicity, according to CTCAE v.5. Results The trial enrolled 26 patients with R/R OS. The Overall Response Rate (ORR) and Disease Control Rate (DCR) obtained was 23% and 57.5%, respectively. Patients with relapsed OS showed a higher ORR (45%) and DCR (82%) compared to refractory patients, irrespective of the number of prior treatment lines received. The achievement of disease control with 14-IFO administration enabled 27% of patients to undergo new local treatment. Four-month Progression-Free Survival (PFS) was 54% for all patients and 82% for the relapsed OS sub-group. Median Overall Survival (OSurv) was 13.7 months, with 1-year OSurv of 51% for all patients and 71% for relapsed patients. Age over 18 years and the presence of refractory disease were identified as negative prognostic factors for this patient cohort. A total of 101 cycles were evaluated for toxic assessment, demonstrating a tolerable profile without grade 3–4 non-haematological toxicities. Conclusions 14-IFO should be considered a viable treatment option for R/R OS, particularly due to its well tolerated toxicity profile and the potential for home-administration, which can improve patient quality of life without compromising efficacy.

The Bosniak classification of renal cysts aims to provide a probabilistic risk assessment indicating the likelihood of malignancy from imaging findings. Originally designed to classify adult renal cysts based on computed tomography findings, the Bosniak classification has been extended to pediatric patients, with some adjustments made with the aim of accommodating magnetic resonance imaging (MRI) and ultrasonography (US). Bosniak IV lesions are rare in adolescents, indicating localized renal cell carcinoma and requiring surgical intervention. In contrast, Bosniak III lesions can be treated conservatively, although there is a lack of specific guidelines on their management. We present a case of a 14-year-old boy with a Bosniak III lesion, which was incidentally detected during the US evaluation of a left varicocele. After a 12-month follow-up, MRI revealed progression to a Bosniak IV cyst. Robot-assisted tumor enucleation was performed with selective artery clamping when the patient was 15. Histopathology showed tubulocystic renal cell carcinoma without adverse features. Immunocytochemistry supported a favorable prognosis of this rare tumor (

Summary: Few studies investigated the genetics of relapsed Wilms tumor (WT), suggesting the SIX1 gene, the microRNA processing genes, and the MYCN network as possibly involved in a relevant percentage of relapses. We investigated 28 relapsing WT patients (10 new cases and 18 cases in which the involvement of SIX and miRNAPG had been excluded) with a panel of ∼5000 genes. We identified variants affecting genes involved in DNA damage prevention and repair in 12/28 relapsing patients (42.9%), and affecting genes involved in chromatin modification and regulation in 6/28 relapsing patients (21.4%), widening the spectrum of anomalies detected in relapsed tumors. The disclosure of molecular pathways possibly underlying tumor progression might allow to use molecularly targeted therapies at relapse. Surprisingly, germline anomalies, mostly affecting DNA damage prevention and repair genes, were identified in 13/28 patients (46.4%), raising the issue of performing a genetic testing to all children presenting with a WT.

IntroductionThis study examined the efficacy of eye movement desensitisation and reprocessing (EMDR) therapy compared with standard psychotherapy (SP) in treating post-traumatic stress disorder (PTSD) in paediatric oncology patients and their families in the early stage of cancer treatment. The secondary aim of this study was to assess whether EMDR therapy has a different impact on post-traumatic growth compared to SP.MethodsForty patients were randomly assigned to EMDR or SP groups. The Impact of Event Scale – Revised (IES-R) and the Distress Thermometer (DT) were used to assess PTSD symptoms at pre-treatment (at cancer diagnosis) and in the post-treatment stages (after 8 sessions). The Post-traumatic Growth Inventory-PTGI was administered in the post-treatment stage in order to evaluate positive changes.ResultsBoth EMDR and SP are effective in reducing PTSD, but EMDR was significantly more effective than the SP in reducing scores on the IES-R, especially regarding the intrusive symptom subscale. Also, in the EMDR group there were higher scores of PTGI than in the standard group.ConclusionEMDR thus represents a promising treatment in the paediatric psycho-oncology setting.

IntroductionChildhood cancer is rare, but it is the most frequent serious event with a high risk of traumatization for children, adolescents, parents and siblings. EMDR is widely studied as clinical intervention that addressed cancer-related stressors among cancer adult population, but to our knowledge, no researches have been conducted among children and adolescent with cancer.MethodsThe purpose of this case study is to describe for the first time the application of the EMDR protocol in a pediatric hospital setting with a 17-years-old Italian adolescent who received a diagnosis of leukemia. He accessed the psychological support service complaining of feelings of anxiety and general discomfort. EMDR protocol started after the diagnosis and ended after the usual eight phases. The Impact of Event Scale—Revised (IES-R) was used to assess stress disorders symptoms as outcome at the baseline (before the First Phase) and at the end of the EMDR protocol (after the Eight Phase).ResultsBy using EMDR protocol the patient reported a decrease of emotional activation after a few EMDR sessions.ConclusionEMDR protocol may be effective for pediatric cancer patients in treating stress disorders symptoms and it can be proposed immediately after diagnosis as a standard care also in pediatric hospital setting.

Background: Wilms tumor (WT) is the most frequent renal tumor in children. The SIOP-UMBRELLA Guidelines allow for nephron-sparing surgery (NSS) in syndromic patients, as well as in cases of small (

IntroductionMulibrey nanism (MUL) is a rare disorder caused by TRIM37 gene variants characterized by growth failure, dysmorphic features, congestive heart failure (CHF), and an increased risk of Wilms’ tumor. Although immune system impairment has been documented in MUL, the underlying mechanisms remain poorly understood.MethodsWe present a case of MUL with progressive lymphopenia and review similar cases from the literature.ResultsOur patient presented with prenatal onset growth restriction, characteristic dysmorphic features, and Wilms’ tumor. She developed progressive lymphopenia starting at 10 years of age, leading to the initiation of intravenous immunoglobulin (IVIG) replacement therapy and infection prophylaxis. Genetic analysis detected a likely pathogenic variant on the maternal allele and copy number loss on the paternal allele in TRIM37. Subsequently a cardiac magnetic resonance imaging was conducted revealing signs of pericardial constriction raising concerns for intestinal lymphatic losses. The cessation of IVIG therapy did not coincide with any increase in the rate of infections. The patient exhibited a distinct immunological profile, characterized by hypogammaglobulinemia, impaired antibody responses, and skewed T-cell subsets with an altered CD4+/CD8+ ratio, consistent with previous reports. Normal thymocyte development assessed by artificial thymic organoid platform ruled out an early hematopoietic intrinsic defect of T-cell development.DiscussionThe immunological profile of MUL patients reported so far shares similarities with that described in protein-losing enteropathy secondary to CHF in Fontan circulation and primary intestinal lymphangiectasia. These similarities include hypogammaglobulinemia, significant T-cell deficiency with decreased CD4+ and CD8+ counts, altered CD4+/CD8+ ratios, and significantly modified CD4+ and CD8+ T-cell phenotypes toward effector and terminal differentiated T cells, accompanied by a loss of naïve CD45RA+ T lymphocytes. In MUL, CHF is a cardinal feature, occurring in a significant proportion of patients and influencing prognosis. Signs of CHF or constrictive pericarditis have been evident in the case reported here and in all cases of MUL with documented immune dysfunction reported so far. These observations raise intriguing connections between these conditions. However, further investigation is warranted to in-depth define the immunological defect, providing valuable insights into the pathophysiology and treatment strategies for this condition.

Background: The pandemic of coronavirus disease 2019 (COVID-19) was undoubtedly a stressful experience for everyone. General opinion believed that children with acute or chronic illness could experience additional burden, but this is not confirmed. The aim of this study is to understand how children and adolescents already suffering from acute or chronic illness (e.g., cancer, cystic fibrosis, neuropsychiatric disorders) feel about the COVID-19 pandemic, and if the experience is significantly different between these children and children without illness. Methods: Children and adolescents affected by acute or chronic illness (named the “fragile group”) treated at the Regina Margherita Children Hospital in Italy, were enrolled in the study by filling a questionnaire about their pandemic experiences. Also, a group of children and adolescents without acute or chronic illness (named the “low-risk group”) recruited in the emergency department of the hospital, participated in the study in order to compare experiences. Results: The study group was composed of 166 children and adolescents (Median age = 12 yrs; 78% fragile group, 22% low-risk group). Participants experienced a general state of fear of the virus and of a potential infection for both themselves and their families, while feelings and thoughts that interfere with daily functioning were less frequent. The fragile group seems to be more resilient towards the pandemic situation than low-risk group and some differences on the basis of the type of illness were found in the fragile group. Conclusions: Dedicated psychosocial intervention must be proposed in order to support fragile children and adolescents’ well-being during the pandemic, also on the basis of their clinical and mental history.

Intestinal graft-versus-host disease (I-GvHD) represents a life-threatening complication in allogeneic stem cell transplantation (SCT). Unfortunately, non-invasive validated diagnostic tools to diagnose I-GvHD, evaluate treatment response, and guide the duration of immunosuppression are still lacking. We employed standard ultrasound and power Doppler to diagnose and follow up on pediatric intestinal GvHD. We herein report on three patients, prospectively evaluated among 24 pediatric patients referred to our center for allogeneic SCT. These three patients presented abdominal pain and diarrhea within the first 200 days after transplantation. In the reported cases, we performed small- and large-intestine ultrasound (US) at clinical onset of lower-intestinal symptoms and, when intestinal GvHD was confirmed, at GvHD flares, if any, and at follow-up. US constantly (3/3 patients) revealed increased bowel wall thickening (BWT) with different bowel segments’ involvement from patient to patient. Further, a moderate or strong increased Doppler signaling was seen in 2 out of 3 patients, according to clinical GVHD staging (e.g., the more the increase, the more the staging). Standard sonography corroborated GvHD diagnosis in all patients considered and was able to detect GvHD progression or complete normalization of findings, thus simplifying ensuing clinical decisions. Our report highlights the need to design clinical trials for the validation of non-invasive radiologic tools for diagnosis and follow-up of GvHD, especially in pediatric patients.

Children and adolescents affected by brain tumors are at risk for neuropsychological sequelae that need to be evaluated in order to plan adequate rehabilitation programs, and to support their development and recovery. This work aims to describe an innovative prospective observational study protocol for the early evaluation and monitoring over time of neuropsychological outcomes in this pediatric population. Pediatric patients aged 3–17 with a brain tumor diagnosis will be assessed through the use of a battery of Italian standardized neuropsychological tests, with good psychometric properties and age-appropiate, at three different time points of their clinical course: at diagnosis and before surgery (T0), after surgical removal and before the start of potential adjuvant therapies (T1), and at the one-year follow-up after potential adjuvant therapies (T2). This study will allow clinicians to support the neuropsychological development of these children by promoting appropriate and timely rehabilitation and educational programs from the early phases of their clinical course.

Beckwith–Wiedemann Syndrome (BWS) is a pediatric overgrowth disorder involving a predisposition to embryonal tumors. Most of the tumors associated with BWS occur in the first 8–10 years of life, and the most common is Wilms tumor (WT). BWS clinical heterogeneity includes subtle overgrowth features or even silent phenotypes, and WT may be the presenting symptom of BWS. WT in BWS individuals exhibit distinct characteristics from those of sporadic WT, and the management of these patients needs a peculiar approach. The most important feature is a higher risk of developing bilateral disease at some time in the course of the illness (synchronous bilateral disease at diagnosis or metachronous recurrence after initial presentation with unilateral disease). Accordingly, neoadjuvant chemotherapy is the recommended approach also for BWS patients with unilateral WT to facilitate nephron-sparing surgical approaches. This review emphasizes the importance of early BWS recognition, particularly if a WT has already occurred, as this will result in an urgent consideration of first-line cancer therapy.

The restrictive measures adopted worldwide against SARS-CoV-2 produced a drastic reduction in respiratory pathogens, including RSV, but a dramatic rebound was thereafter reported. In this multicenter retrospective observational study in 15 Pediatric Emergency Departments, all children

Objective The objective of this study was to assess the potential of the use of asynchronous tele-expertise (ASTE) to provide prenatal diagnosis from a medical and economic point of view. Population Patients screened by a midwife at a primary center. Methods A technical and clinical evaluation was conducted retrospectively, and a cost minimization study compared asynchronous tele-expertise to face-to-face consultations that would have been performed without ASTE. Main outcome measures In our study we assessed the feasibility of ASTE, what were the origins of the requests for expertise, whether patients need to be moved and the reasons for doing so, and the costs of tele-expertise and conventional consultation. Results In this retrospective analysis 322 advices from 260 patients were interpreted remotely via a platform. The results revealed a 90.68% feasibility of transmitting in a satisfactory and interpretable way ultrasound images and videos via the tele-expertise platform (292/322 files). In our series, asynchronous analysis allowed the required physician to make an accurate diagnosis and identify 74 (28.5%, 95% CI [23% –33.9%]) pregnancies associated with malformations and rule out abnormalities in 186 (71.5%, 95% CI [66.1% –77%]) of the cases. The ASTE was not associated with face-to-face consultations for 72.7% (189/260) of the patients, who without moving, were able to have access to a precise diagnosis by ruling out the presence of anomalies in 163/189 of these patients and confirming them in 26/189 patients. The practice of ASTE would result from a societal point of view, an average saving of 61.8% (€ 120.57) per patient compared to a face-to-face consultation. Conclusion The use of asynchronous tele-expertise (ASTE) using fetal ultrasound, is feasible and may contribute to increased diagnostic accuracy while generating a significant reduction in costs for society.

ObjectiveThe objective of this study was to assess the potential of the use of asynchronous tele-expertise (ASTE) to provide prenatal diagnosis from a medical and economic point of view.PopulationPatients screened by a midwife at a primary center.MethodsA technical and clinical evaluation was conducted retrospectively, and a cost minimization study compared asynchronous tele-expertise to face-to-face consultations that would have been performed without ASTE.Main outcome measuresIn our study we assessed the feasibility of ASTE, what were the origins of the requests for expertise, whether patients need to be moved and the reasons for doing so, and the costs of tele-expertise and conventional consultation.ResultsIn this retrospective analysis 322 advices from 260 patients were interpreted remotely via a platform. The results revealed a 90.68% feasibility of transmitting in a satisfactory and interpretable way ultrasound images and videos via the tele-expertise platform (292/322 files). In our series, asynchronous analysis allowed the required physician to make an accurate diagnosis and identify 74 (28.5%, 95% CI [23% -33.9%]) pregnancies associated with malformations and rule out abnormalities in 186 (71.5%, 95% CI [66.1% -77%]) of the cases. The ASTE was not associated with face-to-face consultations for 72.7% (189/260) of the patients, who without moving, were able to have access to a precise diagnosis by ruling out the presence of anomalies in 163/189 of these patients and confirming them in 26/189 patients. The practice of ASTE would result from a societal point of view, an average saving of 61.8% (€ 120.57) per patient compared to a face-to-face consultation.ConclusionThe use of asynchronous tele-expertise (ASTE) using fetal ultrasound, is feasible and may contribute to increased diagnostic accuracy while generating a significant reduction in costs for society.

Homogenization is an important and crucial step to improve the usage of observational data for climate analysis. This work is motivated by the analysis of long series of GNSS Integrated Water Vapour (IWV) data, which have not yet been used in this context. This paper proposes a novel segmentation method called segfunc that integrates a periodic bias and a heterogeneous, monthly varying, variance. The method consists in estimating first the variance using a robust estimator and then estimating the segmentation and periodic bias iteratively. This strategy allows for the use of the dynamic programming algorithm, which is the most efficient exact algorithm to estimate the change point positions. The performance of the method is assessed through numerical simulation experiments. It is implemented in the R package GNSSseg, which is available on the CRAN. This paper presents the application of the method to a real data set from a global network of 120 GNSS stations. A hit rate of 32% is achieved with respect to available metadata. The final segmentation is made in a semi-automatic way, where the change points detected by three different penalty criteria are manually selected. In this case, the hit rate reaches 60% with respect to the metadata.

Patient input is critical for all aspects of value-based healthcare design. This contribution describes the following: the specifics of communications with doctors regarding the disease in adolescents and young adults with cancer; the patients’ thoughts, emotions and changes in self-perception; “other meanings” taking shape along the treatment pathway; and reacting modes to the disease and treatments. Thirty-five Italian AYA patients in follow-up (age 18–24) were involved in a plenary interview on the cited aspects of their oncological experience. The answers were analyzed by MADIT (Analysis Methodology of Computerized Textual Data) with the software SPAD. MADIT allowed us to perform text analysis, describe the graphical outcomes and discuss the results. Respondents took a first-person perspective and their personal narrative recall had objective and unequivocal connotations. Experience was narrated mainly by maintenance repertoires that fix the reality of disease, its treatments and personal identity. The account focused on the tumor and on an agreed approach to it. The time “after” was described as a distressing space that defines them. Making sense of the events was considered a significant help. Professionals need to focus on the discursive repertoires of communication with which the inner and outer reality are built. Lastly, these patients required a two-way dialogue throughout the entire caring process.

Background & aim Screening for genital infection (GI) such as bacterial vaginosis (BV) and yeast infection, for sexually transmitted infection (STI), and for asymptomatic carriage of group B streptococcus (GBS) in pregnant women are common reason for medical appointments. The diagnosis and control of GIs, STIs, and GBS are major issues, for fertility and overall well-being of affected women. Conventional testing is performed using vaginal/cervical classical sampling (VCS); this procedure requires pelvic examination performed by health care professionals which raises concerns among women. Vaginal-self-sampling (VSS), as an alternative to VCS, might capture more women. The aim was first to show non-inferiority of VSS compared with VCS to screen for GIs, STIs, and GBS; second to determine the feasibility of VSS. Methods VSS and VCS from 1027 women were collected by health care professionals and simultaneously carried out on each patient. GIs, STIs, and GBS were systematically screened in both paired VSS and VCS samples. Non-inferiority of VSS compared with VCS was assessed using z statistic for binomial proportions. Results Prevalence of GIs were 39.7% using VSS and 38.1% using VCS (p = 0.0016). Prevalence of STIs was 8.5% (VSS) vs 8.1% (VCS) (p = 0.0087). Prevalence of GBS was 13.4% (VSS) and 11.5% (VCS) (p = 0.0001). Most participants (84%) recommended the use of VSS. Conclusions This study shows that VSS was not inferior to VCS for the detection of GIs, STIs, and GBS. This study provides evidence that VSS can be used as a universal specimen for detection of lower genital tract infections in women. Study identification number ID-RCB 2014-A01250-4.

Abstract We assess the performance of different break detection methods on three sets of benchmark data sets, each consisting of 120 daily time series of integrated water vapor differences. These differences are generated from the Global Positioning System (GPS) measurements at 120 sites worldwide, and the numerical weather prediction reanalysis (ERA‐Interim) integrated water vapor output, which serves as the reference series here. The benchmark includes homogeneous and inhomogeneous sections with added nonclimatic shifts (breaks) in the latter. Three different variants of the benchmark time series are produced, with increasing complexity, by adding autoregressive noise of the first order to the white noise model and the periodic behavior and consecutively by adding gaps and allowing nonclimatic trends. The purpose of this “complex experiment” is to examine the performance of break detection methods in a more realistic case when the reference series are not homogeneous. We evaluate the performance of break detection methods with skill scores, centered root mean square errors (CRMSE), and trend differences relative to the trends of the homogeneous series. We found that most methods underestimate the number of breaks and have a significant number of false detections. Despite this, the degree of CRMSE reduction is significant (roughly between 40% and 80%) in the easy to moderate experiments, with the ratio of trend bias reduction is even exceeding the 90% of the raw data error. For the complex experiment, the improvement ranges between 15% and 35% with respect to the raw data, both in terms of RMSE and trend estimations.

Diamond Blackfan anemia (DBA) is predominantly an autosomal dominant inherited red cell aplasia primarily caused by pathogenic germline variants in ribosomal protein genes. DBA due to pathogenic RPL35A variants has been associated with large 3q29 deletions and phenotypes not common in DBA. We conducted a multi-institutional genotype-phenotype study of 45 patients with DBA associated with pathogenic RPL35A germline variants and curated the variant data on 21 additional cases from the literature. Genotype-phenotype analyses were conducted comparing patients with large deletions versus all other pathogenic variants in RPL35A. Twenty-two of the 45 cases had large deletions in RPL35A. After adjusting for multiple tests, a statistically significant association was observed between patients with a large deletion and steroid-resistant anemia, neutropenia, craniofacial abnormalities, chronic gastrointestinal problems, and intellectual disabilities (p

This study investigates the sensitivity of the GNSSseg segmentation method to change in: GNSS data processing method, length of time series (17 to 25 years), auxiliary data used in the integrated water vapor (IWV) conversion, and reference time series used in the segmentation (ERA-Interim versus ERA5). Two GNSS data sets (IGS repro1 and CODE REPRO2015), representative of the first and second IGS reprocessing, were compared. Significant differences were found in the number and positions of detected change-points due to different a priori ZHD models, antenna/radome calibrations, and mapping functions. The more recent models used in the CODE solution have reduced noise and allow the segmentation to detect smaller offsets. Similarly, the more recent reanalysis ERA5 has reduced representativeness errors, improved quality compared to ERA-Interim, and achieves higher sensitivity of the segmentation. Only 45–50% of the detected change-points are similar between the two GNSS data sets or between the two reanalyses, compared to 70–80% when the length of the time series or the auxiliary data are changed. About 35% of the change-points are validated with respect to metadata. The uncertainty in the homogenized trends is estimated to be around 0.01–0.02 kg m−2 year−1.

Forthcoming.

The excavations of terramara S. Rosa of Poviglio (RE), of the Middle-Late Bronze Age, arrived at the XXX campaign, have gained a large knowledge of the site, thanks to the contribution of many collaborators with different academic background. Multidisciplinarity of the research and attention at publishing and promotion of the area arise as essential elements of the project. It is worth to mention also the close-knit and competent team and the logistic organization well strengthened in time.

Diamond-Blackfan Anaemia (DBA) is a rare inherited anaemia caused by heterozygous mutations in one of 13 ribosomal protein genes. Erythroid progenitors (BFU-E and CFU-E) in bone marrow (BM) show a proapoptotic phenotype. Suspicion of DBA is reached after exclusion of other forms of BM failure syndromes. To improve DBA diagnosis, which is confirmed by mutation analysis, we tested a new approach based on the study of extracellular vesicles (EVs) isolated from plasma by differential centrifugations and analysed by flow cytometry. We chose CD34, CD71 and CD235a markers to study erythroid EVs. We characterised the EVs immunophentoypic profiles of 13 DBA patients, 22 healthy controls and 16 patients with other haematological diseases. Among the three EVs clusters we found, only the CD34+/CD71low population showed statistically significant differences between DBA patients and controls (p< 0.05). The absence of this cluster is in agreement with the low levels of BFU-E found in DBA patients. The assessment of ROC curves demonstrated the potential diagnostic value of this population. We suggest that this assay may be useful to improve DBA diagnosis as a quicker and less invasive alternative to BM BFU-E culture analysis.

Children with high-risk acute lymphoblastic leukemia in first complete remission can benefit from allogeneic hematopoietic stem cell transplantation. We analyzed the outcome of 211 children with high-risk acute lymphoblastic leukemia in first complete remission who were given an allogeneic transplant between 1990 and 2008; the outcome of patients who, despite having an indication for transplantation and a suitable donor, did not receive the allograft for different reasons in the same time period was not analyzed. Sixty-nine patients (33%) were transplanted between 1990 and 1999, 58 (27%) between 2000 and 2005, and 84 (40%) between 2005 and 2008. A matched family donor was employed in 138 patients (65%) and an unrelated donor in 73 (35%). The 10-year probabilities of overall and disease-free survival were 63.4% and 61%, respectively. The 10-year cumulative incidences of transplantation-related mortality and relapse were 15% and 24%, respectively. After 1999, no differences in either disease-free survival or transplant-related mortality were observed in patients transplanted from unrelated or matched family donors. In multivariate analysis, grade IV acute graft-versus-host disease was an independent factor associated with worse disease-free survival. By contrast, grade I acute graft-versus-host disease and age at diagnosis between 1 and 9 years were favorable prognostic variables. Our study, not intended to evaluate whether transplantation is superior to chemotherapy for children with acute lymphoblastic leukemia in first complete remission and high-risk features, shows that the allograft cured more than 60% of these patients; in the most recent period, the outcome of recipients of grafts from matched family and unrelated donors was comparable.

Diamond-Blackfan anemia is an autosomal dominant disease due to mutations in nine ribosomal protein encoding genes. Because most mutations are loss of function and detected by direct sequencing of coding exons, we reasoned that part of the approximately 50% mutation negative patients may have carried a copy number variant of ribosomal protein genes. As a proof of concept, we designed a multiplex ligation-dependent probe amplification assay targeted to screen the six genes that are most frequently mutated in Diamond-Blackfan anemia patients: RPS17, RPS19, RPS26, RPL5, RPL11, and RPL35A. Using this assay we showed that deletions represent approximately 20% of all mutations. The combination of sequencing and multiplex ligation-dependent probe amplification analysis of these six genes allows the genetic characterization of approximately 65% of patients, showing that Diamond-Blackfan anemia is indisputably a ribosomopathy.

The Authors present data about the breeding of the Golden Eagle in Campania (Southern Italy) from 2004 to 2007. One of the 4 pairs resident in Campania is located on the border of the Basilicata Region. In the years considered, productivity varied between 0 and 0.75 fledglings per pair, with a cyclical course in alternate years. Only one fledgling was ever raised by the successful breeding pairs.

Diamond Blackfan anemia typically presents in infants and is often associated with many kinds of malformations. Severity of anemia often needs transfusional support in the first months of life. We describe here a patient with Diamond Blackfan anemia related to a RPL5 mutation. The patient had no physical abnormalities and experienced a very late onset of transfusion dependency.

Background Diamond-Blackfan anemia is a rare, pure red blood cell aplasia of childhood due to an intrinsic defect in erythropoietic progenitors. About 40% of patients display various malformations. Anemia is corrected by steroid treatment in more than 50% of cases; non-responders need chronic transfusions or stem cell transplantation. Defects in the RPS19 gene, encoding the ribosomal protein S19, are the main known cause of Diamond-Blackfan anemia and account for more than 25% of cases. Mutations in RPS24, RPS17, and RPL35A described in a minority of patients show that Diamond-Blackfan anemia is a disorder of ribosome biogenesis. Two new genes (RPL5, RPL11), encoding for ribosomal proteins of the large subunit, have been reported to be involved in a considerable percentage of patients.Design and Methods In this genotype-phenotype analysis we screened the coding sequence and intron-exon boundaries of RPS14, RPS16, RPS24, RPL5, RPL11, and RPL35A in 92 Italian patients with Diamond-Blackfan anemia who were negative for RPS19 mutations.Results About 20% of the patients screened had mutations in RPL5 or RPL11, and only 1.6% in RPS24. All but three mutations that we report here are new mutations. No mutations were found in RPS14, RPS16, or RPL35A. Remarkably, we observed a higher percentage of somatic malformations in patients with RPL5 and RPL11 mutations. A close association was evident between RPL5 mutations and craniofacial malformations, and between hand malformations and RPL11 mutations.Conclusions Mutations in four ribosomal proteins account for around 50% of all cases of Diamond-Blackfan anemia in Italian patients. Genotype-phenotype data suggest that mutation screening should begin with RPL5 and RPL11 in patients with Diamond-Blackfan anemia with malformations.