Cross-cutting view of current challenges in paediatric solid organ and haematopoietic stem cell transplantation in Europe: the European Reference Network TransplantChild.

The low prevalence of European paediatric transplanted patients and scarcity of resources and expertise led to the need for a multidisciplinary network able to improve the quality of life of paediatric patients and families requiring a solid organ or haematopoietic stem cell transplantation. The European Reference Network (ERN) TransplantChild is one of the 24 ERNs established in a European legal framework to improve the care of patients with rare diseases. ERN TransplantChild is the only ERN focused on both solid organ and haematopoietic stem cell paediatric transplantation, based on the understanding of paediatric transplantation as a complex and highly specialised process where specific complications appear regardless the organ involved, thus linking the skills and knowledge of different organ disciplines. Gathering European centres of expertise in paediatric transplantation will give access to a correct and timely diagnosis, share expertise and knowledge and collect a critical mass of patients and data that increases the speed and value of clinical research outcomes. Therefore, the ERN TransplantChild aims for a paediatric Pan-European, Pan-transplant approach.

The quality of life in extracorporeal life support survivors: single-center experience of a long-term follow-up.

OBJECTIVE: To evaluate the health-related quality of life on a very long-term follow-up in patients treated with extracorporeal membrane oxygenation (ECMO) during neonatal and pediatric age. DESIGN: Prospective follow-up study. SETTING: Pediatric Intensive Care Unit of a tertiary-care University-Hospital. PATIENTS: Out of 20 neonates and 21 children treated with ECMO in our center, 24 patients underwent short-term neurological follow-up. Twenty of them underwent long-term neurological follow-up. INTERVENTION: Short-term follow-up was performed at 18 months and consisted in clinical evaluation, electroencephalography, and neuroimaging. Long-term follow-up was performed in 2017, at the mean period 19.72 years from ECMO (median 20.75, range 11.50-24.08) and consisted in a standardized questionnaires self-evaluation (PedsQL 4.0 Generic Core Scale) of health-related quality of life and an interviewed about the presence of organ morbidity, school level, or work position. MEASUREMENTS AND MAIN RESULTS: Sixty-one percent (25/41) of the patients survived within 30 days after ECMO treatment. Short-term follow-up was performed in 24 patients (1 patient but died before the evaluation): 21 patients (87%) showed a normal neurological status, and 3 developed severe disability. Long-term follow-up was performed in 20 long-term survivors (3 patients were not possible to be contacted and considered lost to follow-up): mean age of patients at long-term follow-up was 21.23 (median 20.96, range 13.33-35.58) years; 90% (18/20) of them have no disability with a complete normal quality of life and 95% have no cognitive impairment. CONCLUSIONS: ECMO represents a life-saving treatment for infants and children with respiratory and/or heart failure; survivors show a good quality of life comparable to healthy peers.

Mucociliary clearance techniques for treating non-cystic fibrosis bronchiectasis: Is there evidence?

Non-cystic fibrosis bronchiectasis (nCFb) is an acquired condition of variable etiology. An impaired mucociliary clearance seems to be one of the mechanisms behind nCFb, and treatment involves antibiotics, mucoactive agents, and airway clearance techniques (ACTs). Traditional ACTs have four components: postural drainage, percussion, vibration of the chest wall, and coughing. Reviewing the international medical literature on the use of ACTs for patients with nCFb from 1989 to the present day, we retrieved 93 articles, of which 35 met our selection criteria for this analysis. We reviewed active cycle of breathing techniques (ACBT), forced expiration techniques (FET), autogenic drainage, postural drainage, oscillating positive expiratory pressure (OPep), high frequency chest wall oscillation (HFCWO), and exercise or pulmonary rehabilitation. Overall, ACTs appear to be safe for individuals (adults and children) with stable bronchiectasis; where there may be improvements in sputum expectoration, selected measures of lung function, and health-related quality of life. Unfortunately, there is a lack of RCTs in nCFb patients, especially in children. Moreover, none of the studies describes long-term effects of ACTs. It should be noted that a single intervention might not reflect the longer-term outcome and there is no evidence to recommend or contest any type of ACTs in nCFb management. Multicenter RCTs are necessary to evaluate the different techniques of ACTs especially in children with nCFb.

Fibrolamellar variant of hepatocellular carcinoma does not have a better survival than conventional hepatocellular carcinoma--results and treatment recommendations from the Childhood Liver Tumour Strategy Group (SIOPEL) experience.

PURPOSE: Fibrolamellar hepatocellular carcinoma (FL-HCC) and conventional hepatocellular carcinoma (HCC) cases in two consecutive paediatric HCC trials were analysed to compare outcome and derive treatment implications. PATIENTS AND METHODS: Data of 24 FL-HCC (24% PRETEXT IV) and 38 HCC (42% PRETEXT IV) cases from SIOPEL-2 and -3 (1995-1998, 1998-2006) were analysed. Patients were treated according to SIOPEL-2 and -3 high-risk protocol (carboplatin+doxorubicin alternating with cisplatin; seven preoperative, three postoperative cycles) or with primary surgery followed by chemotherapy as indicated. RESULTS: Thirteen of 24 FL-HCC (54%) and 32/38 HCC (84%) were initially treated with chemotherapy. Eight FL-HCC (33%) and five HCC patients (13%) had primary surgery. Partial response was observed in 31% of FL-HCC versus 53% of HCC patients (p=0.17). Complete resection was achieved in ten FL-HCC and seven HCC patients (p=0.08). Three-year event free survival (EFS) was 22% for FL-HCC versus 28% for HCC. Overall survival (OS) was not significantly different at 3 years follow up (42% for FL-HCC versus 33% for HCC, p=0.24). EFS/OS Kaplan-Meier curves did not differ significantly, with median follow up of 43 (FL-HCC) and 60 (HCC) months. No significant correlation was found between potential prognostic factors and OS. In the entire cohort nine out of 23 (39%) patients with complete resection or orthotopic liver transplantation versus 34/39 (87%) without successful surgical treatment, died. CONCLUSIONS: Long-term OS in FL-HCC and HCC is similar. With low response rates, complete resection remains the treatment of choice.

Relapses in hepatoblastoma patients: clinical characteristics and outcome--experience of the International Childhood Liver Tumour Strategy Group (SIOPEL).

PURPOSE: To analyse the clinical characteristics and outcome of hepatoblastoma (HB) patients who relapsed after enrolment on SIOPEL studies 1-3. PATIENTS AND METHODS: Analysis of clinical data of all 59 patients (pts) registered in SIOPEL 1-3 studies, who relapsed after achieving complete remission (CR). RESULTS: The median time from the initial diagnosis to relapse was 12 months (4-115 m). The site of relapse was lung N=27, liver N=21, both liver and lung N=5 and other N=5 (missing data-MD: 1 patient). All but 9 pts had an alpha-fetoprotein level >10 ng/mL at the time of relapse. Treatment of the relapse included chemotherapy and surgery N=25, chemotherapy alone N=21, surgery alone N=7 and only palliative treatment N=5 (MD: 1 pt). Overall, 31 pts (52%) achieved a second CR. With a median follow-up of 83 months, 23 pts are alive, (18 in 2nd CR, 5 after a second relapse) and 36 pts have died (35 from disease and 1 from complications). Three-year event-free survival and overall survival are 34% and 43% respectively (95% confidence interval [CI] 0.28-0.69). The main factors associated with a good outcome were PRETEXT group I-III at diagnosis, a high AFP level at relapse and relapse treatment including both chemotherapy and surgery. CONCLUSION: Relapses in HB are rare events occurring in less than 12% of pts after CR. Combined treatment with chemotherapy and surgical removal of the tumour is essential for long-term survival.

Diffuse leptomeningeal glioneuronal tumours: clinico-pathological follow-up.

Glioneuronal tumours are a group of primary brain neoplasms of relatively recent acquisition in the World Health Organization (WHO) Classification of the Central Nervous System tumours. In diagnostic practice it is still possible to encounter glioneuronal tumours that cannot be placed into any of the well-defined WHO categories despite a growing list of entities. We have recently published four paediatric cases of diffuse leptomeningeal tumours that cannot be easily classified in the currently used CNS WHO classification, but which have histological and immunohistochemical criteria to be considered as glioneuronal tumours. The clinical, neuroradiological and pathological long-term follow-up of an unusual diffuse leptomeningeal glioneuronal tumour is presented herein.

Hydrocephalus in infants less than six months of age: effectiveness of endoscopic third ventriculostomy.

OBJECTIVE: Although endoscopic third ventriculostomy (ETV) is a well established procedure for the treatment of congenital and acquired hydrocephalus, there is still a controversy with regard to the higher risk of failure in younger infants compared to older children after such a procedure. The aim of this article is to define the effectiveness of third ventriculostomy for hydrocephalus in infants less than 6 months of age better and to determine possible positive predictive factors. MATERIALS AND METHODS: In a series of 126 consecutive patients who underwent ETV between January 2000 and December 2002, 21 procedures were performed on infants ranging in age from 23 to 180 days, and without a previous history of shunting. The follow-up period was 49 to 82 months. RESULTS: The overall success rate of ETV was 67% (14/21). All failures occurred in the early postoperative period (average 38 days, range 25-88 days). The success rate varied with the etiology of the patient's hydrocephalus. The best results were obtained in patients with acqueductal stenosis, Dandy-Walker malformation and myelomeningocele. The least favorable results (50% failure rate) occurred in infants treated for post-hemorrhagic and post-meningitic hydrocephalus. CONCLUSION: This study does not demonstrate a correlation between the age of the infants and the ETV success rate. The specific etiology of hydrocephalus is the most relevant prognostic factor in infants under six months of age.

Distinctive clinical features of pediatric systemic lupus erythematosus in three different age classes.

It is estimated that around 20% of patients with systemic lupus erythematosus (SLE) have their onset in childhood but there have been conflicting data about the prevalence and severity of the clinical features in different age classes. We conducted this study to analyse the clinical features of patients with pediatric SLE (pSLE) with onset in infancy, prepubertal and postpubertal age. The charts of patients followed at the Department of Pediatrics, University of Padua, who met the criteria for SLE diagnosis, were reviewed. Patients were divided into three groups based on age at disease onset: group A, patients < or =2 years old, group B patients aged between 2 and 10 years, group C patients between 11 and 16 years of age. The clinical and laboratory characteristics of each group were compared. Forty-two patients with pSLE entered the study: 2 were diagnosed before the age of 2 years, 11 between 2 and 10 years and 29 between 10 and 16 years. Eleven more patients with infantile (onset <2 years) SLE (iSLE) were found by a systematic literature search on PubMed and EmBASE and added for analysis to the group A. The female preponderance was significant only in postpubertal patients (F:M = 6.3: 1) whereas the other two groups presented a similar F:M ratio (1.2: 1). In comparison with the other two groups, iSLE showed a significantly higher prevalence of cardiovascular and pulmonary involvement, anemia and thrombocytopenia and a shorter disease duration at time of diagnosis. The postpubertal group showed a higher frequency of musculoskeletal involvement and leukopenia. In prepubertal patients there was no female preponderance and the frequency of clinical features was intermediate between infantile and postpubertal patients. Complement fractions level, antinuclear antibodies (ANA), anti-dsDNA, anti-cardiolipin antibodies and lupus anti-coagulant autoantibodies were not significantly different in the three groups. In general, the prevalence of internal organs involvement in pSLE seems to decrease with age. In infants, SLE is more severe than in the following ages. Postpubertal patients have a strong female preponderance and more specific signs of disease at onset. Prepubertal patients have an intermediate disease severity and no gender predilection.

Germinoma with synchronous involvement of midline and off-midline structures associated with progressive hemiparesis and hemiatrophy in a young adult.

INTRODUCTION: Cerebral germinomas, the most common and least malignant intracranial germ cell tumors, usually arise in the pineal or suprasellar region and have characteristic clinical and radiological features. Germinomas more rarely occur in the thalamus, basal ganglia, and internal capsule, causing sometimes cerebral hemiatrophy and hemiparesis. More rarely, other clinical features can be fever of unknown origin, visual disturbance, and neuropsychiatric symptoms. Cerebral hemiatrophy can precede the imaging depiction of the off-midline mass. CASE: The authors present the first case of cerebral germinoma with synchronous involvement of the midline and off-midline structures, with unusual clinical and radiological presentation. DISCUSSION: The literature is reviewed, and the pathogenesis, the clinical findings, the imaging, and the therapy are discussed.

Acute and late morbidity after limited resection and focal radiation therapy in craniopharyngiomas.

Aggressive surgery of craniopharyngioma can cause severe, life-long hypothalamic and pituitary dysfunctions and possibly further impair visual function; conventional radiation therapy (RT) can affect intellectual functioning and cause secondary tumours. Because of the severe morbidity associated with aggressive surgery, many authors nowadays recommend a less radical approach followed by RT. This combined approach allows achieving 70-83% 10-year local control rates which are comparable to that achieved with aggressive surgery. The main morbidity of this conservative combined approach is represented by pituitary dysfunction secondary to RT, however, sparing severe hypothalamic disturbances. The interval between treatment and onset of the disorder is much longer than in the case of aggressive surgery and this can have a beneficial impact on quality of life, especially in children. This alternative therapeutic approach has become more appealing now that modern RT techniques allow safer delivery of the RT, particularly in childhood.

Embryonal tumor with abundant neuropil and true rosettes. A new entity or only variations of a parent neoplasms (PNETs)? This is the dilemma.

A rare embryonal brain tumor has been diagnosed in a 4-year-old boy. The mass, located at the pons and mesencephalon, has been histologically classified as an embryonal tumor containing abundant neuropil and true rosettes. After surgical complete removal of the neoplasia, the child received intensive combined chemotherapy and radiotherapy. He is alive and free of disease at 34 months from surgery. Difficulties in histological definition, possible suggestions for treatment proposals are discussed.

Risk-adapted treatment for childhood hepatoblastoma. final report of the second study of the International Society of Paediatric Oncology--SIOPEL 2.

SIOPEL 2 was a pilot study designed to test the efficacy and toxicity of two chemotherapy (CT) regimens, one for patients with hepatoblastoma (HB) confined to the liver and involving no more than three hepatic sectors ('standard-risk (SR) HB'), and one for those with HB extending into all four sectors and/or with lung metastases or intra-abdominal extra hepatic spread 'high-risk (HR) HB'. SR-HB patients were treated with four courses of cisplatin (CDDP), at a dose of 80 mg/m(2) every 14 days, delayed surgery, and then two more similar CDDP courses. HR-HB patients were given CDDP alternating every 14 days with carboplatin (CARBO), 500 mg/m(2), and doxorubicin (DOXO), 60 mg/m(2). Two courses of CARBO/DOXO and one of CDDP were given postoperatively. Between October 1995 and May 1998, 77 SR-HB (10 of whom were actually treated with the HR protocol) and 58 HR-HB patients were registered and all 135 could be evaluated. Response rates for the entire SR-HB and HR-HB groups were 90% (95% CI 80-96%) and 78% (95% CI 65-87%), and resection rates were 97% (95% CI 87-99%) and 67% (95% CI 54-79%) including several children undergoing liver transplantation. For SR-HB patients, 3-year overall and progression-free survivals were 91% (+/-7%) and 89% (+/-7%) and for the HR-HB group 53% (+/-13%) and 48% (+/-13%), respectively. The short-term toxicity of these regimens was acceptable, with no toxic deaths. A treatment strategy based on CDDP monotherapy and surgery thus appears effective in SR-HB but, despite CT intensification, only half of the HR-HB patients are long-term survivors. For SR-HB patients, the efficacy of CDDP monotherapy and the CDDP/DOXO ('PLADO') combination are now being compared in a prospective randomised trial (SIOPEL 3).

Liver transplantation for hepatoblastoma: results from the International Society of Pediatric Oncology (SIOP) study SIOPEL-1 and review of the world experience.

BACKGROUND: For hepatoblastoma (HB) that remains unresectable by partial hepatectomy after chemotherapy, total hepatectomy with orthotopic liver transplantation (LTX) has been advocated as the best treatment option. The role of LTX in the overall management of HB is still, however, unclear. PROCEDURE: The results of LTX from the first study of HB by the International Society of Pediatric Oncology, SIOPEL-1, were analyzed. In addition, the world experience of LTX for HB was extensively reviewed. Twelve patients in the SIOPEL-1 study underwent a LTX. Median (range) follow-up at Dec. 31, 2001 was 117 months (52-125) since LTX. RESULTS: Overall survival at 10 years post-LTX was 85% for the seven children who received a "primary LTX" and 40% for the 5 children who underwent a "rescue LTX" after previous partial hepatectomy. In the world experience (147 cases), the overall survival rate at 6 year post-LTX was 82% for 106 patients who received a "primary LTX" and 30% for 41 patients who underwent a "rescue LTX." Multivariate analysis of patients undergoing primary LTX showed that only macroscopic venous invasion had a significant impact (P-value: 0.045 with a hazard ratio of 2.96) on overall survival. CONCLUSIONS: Orthotopic LTX has added a new dimension to the treatment of HB unresectable by partial hepatectomy. Because of the rarity of the disease and to optimize results, children with extensive HB should be treated in centers with surgical expertise in pediatric major liver resection and LTX, in close collaboration with pediatric oncologists, radiologists, and histopathologists.

Liver transplantation for the management of hepatoblastoma.

INTRODUCTION: Hepatoblastoma (HEP) is the most frequent liver malignancy occurring in childhood. Surgical resection currently represents the gold standard for treatment. In patients with initially unresectable tumors, chemotherapy may induce remarkable reductions in size. In nonresponder patients, liver transplantation (OLTx) may offer a chance of cure. MATERIALS AND METHODS: From 1990 to 2003, a total of 400 OLTx (31 pediatric transplants) have been performed at Padua University. Seven patients (4 males and 3 females) underwent OLTx for hepatoblastoma. All patients presented with bilobar liver involvement and had received chemotherapy according to the SIOPEL-1. In all patients preoperative staging was negative for extrahepatic involvement. RESULTS: The mean age of the pts was 8.2 years (range 6.4 months to 34 years). Mean follow-up after OLTx was 41.4 months (median 36, range 3 to 108 months). Actuarial patient survival rates after OLTx for hepatoblastoma are 83.3%, 83.3%, and 56% at 1, 3, and 5 years, respectively. Five of seven subjects with HEP are alive after transplant at 3, 12, 36, 65, and 108 months. Two patients died owing to recurrent disease after 6 and 60 months, respectively, from transplantation. Another subject, primarily treated with surgical resection, shows HEP recurrence at 40 months after OLTx. The remaining 4 patients are alive and well at a mean follow-up of 28 months (median 24, range 3 to 65 months). CONCLUSIONS: Liver transplantation may represent a valid therapeutic option for patients with unresectable HEP, but it is contraindicated in cases of recurrence following previous resection surgery. Neo-adjuvant chemotherapy is of paramount importance to obtain good long-term results.

Ifosfamide in pediatric solid tumors.

Phase II studies conducted in Europe and the USA on pediatric solid tumors have shown that ifosfamide, as a single agent, is an active drug against a variety of neoplasms - rhabdomyosarcoma (RMS), some non-RMS soft tissue sarcomas, Wilms' tumor, bone sarcomas and neuroblastoma. Furthermore, an increase in tumor response rate has been observed when ifosfamide has been used in combination with other drugs. The usual dose of ifosfamide varies from 1.8 to 3 g/m(2)/day for 2-5 days according to the different regimens. Some controversies still exist on the modality of drug administration and more precisely on the time of infusion, however in pediatric practice, short infusion (e.g. 3 h) is usually preferred because of the reduced neurotoxicity in comparison to lengthier administration (e.g. 24 h). Ifosfamide is currently included in the standard therapy of pediatric bone and soft tissue sarcomas. It is also used in a selected high-risk group of patients with Wilms' tumor, neuroblastoma and germ cell tumors.

Fluorescent in situ hybridization (FISH) reveals frequent and recurrent numerical and structural abnormalities in hepatoblastoma with no informative karyotype.

BACKGROUND: Hepatoblastoma (HB) is the most frequent malignant liver tumor in children. The few cytogenetic studies available indicate that HB is associated with recurring trisomies of chromosomes 2, 8, and 20; recurrent t(1;4) (q12;q34) has been reported in few cases. The abnormalities of chromosome 1q are relatively frequent and usually lead to overexpression of 1q material. A cluster of breakpoints is located at the level of bands 1q12 and 1q21. More work is needed to clarify their real incidence and prognostic significance. Cytogenetic analysis is limited by the requirement of suitable cells in metaphase. A different method that increases analysis sensitivity is fluorescent in situ hybridization (FISH). PROCEDURE: We studied 10 cases of HB with no informative karyotype (normal karyotype or no metaphases). FISH was performed by the standard method, using cytospins and imprints obtained from frozen or cytogenetic samples of direct cultures. Alpha-satellite probes for centromeric DNA were used for chromosomes 2, 8, and 20 analysis; rearrangement of region 1q12-21 was detected with BAC (bacterial artificial chromosome) probe bA79E5. RESULTS: We detected at least one trisomic clone in 5/10 of these cases. Trisomy 20 was the most frequently detected abnormality, followed by trisomy of the chromosomes 2 and 8. Analysis of 1q12 band revealed that the rearrangement of 1q usually is in pericentromeric heterochromatin, it was present in 5/10 of studied cases. CONCLUSION: FISH analysis is recommended in all cases of HB with no informative karyotype to gain more information regarding the frequent trisomies encountered and their significance.

Hepatocellular carcinoma in children: results of the first prospective study of the International Society of Pediatric Oncology group.

PURPOSE: To improve survival and reduce operative morbidity and mortality in children with primary epithelial liver tumors by using preoperative chemotherapy, as well as to collect information on the epidemiology, natural history, and prognostic factors. PATIENTS AND METHODS: Forty children with hepatocellular carcinoma (HCC) were registered onto the Group for Epithelial Liver Tumors International Society of Pediatric Oncology's first study from January 1990 to February 1994. The outcome could be analyzed in 39 of those patients. Disease was often advanced at the time of diagnosis; metastases were identified in 31% of the children and extrahepatic tumor extension, vascular invasion, or both in 39%. Multifocal tumors were common (56%). Thirty-three percent of tumors were associated with hepatic cirrhosis. All but two patients received preoperative chemotherapy (cisplatin and doxorubicin). RESULTS: Partial response was observed in 18 (49%) of 37 patients; there was no response or progression in the remainder. Complete tumor resection was achieved in 14 patients (36%). Twenty patients (51%) never became operable. Overall survival at 5 years was 28%, and event-free survival was 17%. Most deaths resulted from tumor progression (26 of 28). Presence of metastases and pretreatment extent of disease system grouping at diagnosis had an adverse influence on overall survival in multivariate analysis. CONCLUSION: Survival for pediatric HCC patients is significantly inferior to that for children with hepatoblastoma. Complete tumor excision remains the only realistic chance of cure, although it is often prevented by advanced disease. The presence of metastases is the most potent predictor of poor prognosis. A prospective worldwide cooperation in the field of pediatric HCC should be encouraged to look for novel therapeutic concepts.

Fluorescence in situ hybridization improves cytogenetic results in the analysis of hepatoblastoma.

Hepatoblastoma (HB) is the most frequent malignant liver tumor in children. Cytogenetic data indicate the presence of recurring trisomies of the chromosomes 2, 8, and 20, but more work is needed to clarify their incidence and prognostic significance. Cytogenetic analysis is limited by the requirement of suitable cells in metaphase. A different method that increases analysis sensitivity is fluorescence in situ hybridization (FISH). We studied 20 cases of hepatoblastoma; FISH analysis obtained results in 10 cases of HB with no informative karyotype. In 5 of 10 of these cases at least one trisomic clone was detected, which always coexisted with a population of diploid cells. These results confirm that trisomy 20 and/or 2 and 8 coexisting with diploid cells is a frequent finding in hepatoblastoma and provide further support to the clonal evolution theory: indeed, trisomy 20 was the most frequently detected abnormality, followed by trisomy of chromosomes 2 and 8. In view of the high incidence of recurrent trisomies, FISH analysis should be recommended in all the cases of HB with no informative karyotype.

An unusual cystic appearance of disseminated low-grade gliomas.

We report five cases of pediatric disseminated low-grade gliomas of the brainstem or spinal cord that exhibited an unusual, cystic pattern. Leptomeningeal disease was present in three of these at diagnosis, and was detected shortly afterwards in the other two. Four patients are alive up to 5 years later, following minimal to no intervention, while one is dead.