Biomedical subjects
Publications and source records attributed to Giorgio Perilongo.
Over the last 15 years, various oncology groups throughout the world have used the PRETEXT system for staging malignant primary liver tumours of childhood. This paper, written by members of the radiology and surgery committees of the International Childhood Liver Tumor Strategy Group (SIOPEL), presents various clarifications and revisions to the original PRETEXT system.
A national cooperative project on rare paediatric tumours (the TREP project) was launched in 2000 in Italy, with a view to improving the clinical management and the basic research on these 'orphan' tumours, defined as those childhood solid malignancies characterised by an annual incidence <2/million and not considered in other clinical trials. This paper describes the process that the group developed and the problems it had to face, and aims to stimulate a debate on the rationale, scientific relevance and feasibility of running scientific research programs on rare childhood neoplasms. In the first phase of its activity, the project developed diagnostic and therapeutic recommendations for each rare tumour and established a collaborative network between 'experts' dedicated to each histotype and other specialists (i.e. adult oncologists, surgeons) involved in the management of these tumours. From 2000 to 2005, 297 patients have been registered from 35 Italian centres. This experience demonstrates the feasibility of a national multidisciplinary cooperation on rare paediatric malignancies and suggests that international studies could be realised.
PURPOSE: To discuss the results obtained by giving adjuvant treatment for childhood ependymoma (EPD) at relapse after complete surgery only. METHODS AND MATERIALS: Between 1993 and 2002, 63 children older than 3 years old entered the first Italian Association for Pediatric Hematology and Oncology protocol for EPD (group A), and another 14 patients were referred after relapsing after more tumor excisions only (group B). Prognostic factors were homogeneously matched in the two groups. We report on the outcome of group B. RESULTS: Mean time to first local progression in group B had been 14 months. Tumors originated in the posterior fossa (PF) in 10 children and were supratentorial (ST) in 4; 11 had first been completely excised (NED) and 3 had residual disease (ED). Diagnoses were classic EPD in 9 patients, anaplastic in 5. Eight children were referred NED and 6 ED after two or more operations, 5 had cranial nerve palsy, 1 had recurrent meningitis, and 2 had persistent hydrocephalus. All received radiotherapy (RT) to tumor bed and 5 also had pre-RT chemotherapy. Six of 14 patients (6/10 with PF tumors) had a further relapse a mean 6 months after the last surgery; 4 of 6 died: progression-free survival and overall survival at 4 years after referral were 54.4% and 77%, respectively. Considering only PF tumors and setting time 0 as at the last surgery for group B, progression-free survival and overall survival were 32% and 50% for group B and 52% (p < 0.20)/70% (p < 0.29) for the 46 patients in group A with PF tumors. Local control was 32% in group B and 70.5% in group A (p = 0.02). CONCLUSIONS: Relapsers after surgery only, especially if with PF-EPD, do worse than those treated after first diagnosis; subsequent surgery for tumor relapse has severe neurologic sequelae.
A systematic literature review was carried out to evaluate best existing evidence on prognostic factors for progression of childhood optic pathway glioma. Databases were searched for relevant articles and articles selected independently by two authors. Information about study design, population, treatment, outcome and prognostic analysis were abstracted and the quality of each article was assessed. A total of 23 articles met the inclusion criteria. Many studies had important methodological limitations, regarding external and internal validity. Eleven studies evaluated possible prognostic factors in a multivariate analysis. Three high-quality studies indicated age<1 year as an independent prognostic factor for a worse progression-free survival. Three studies with multivariate analysis, including one high-quality study, found that children with neurofibromatosis type 1 (NF-1) have a better progression-free survival than those without NF-1. Two studies with multivariate analysis found tumour site to be a prognostic factor, both with some methodological limitations. In conclusion, this systematic review demonstrates that only a few of the prognostic factors proposed have been proven to be clinically relevant. Age<1 year is a clear and independent prognostic factor for progression-free survival. Other prognostic factors, such as NF-1, tumour site and others, are suggested, but are still without solid evidence and need further high-quality studies to be clearly proven.
BACKGROUND: This study is a pilot experience aiming to investigate the compliance of an institutional cohort of Italian children treated for a malignant disease and their families in completing the health utilities index2, (HUI2) and the effectiveness of this measured in terms of their health status (HS) and health-related quality of life (HRQL). It specifically, it aimed to compare the HS and the HRQL, as expressed by the HUI2 global utility score, in cohorts of patients who had brain tumors, extra-cerebral solid tumors, or leukemia/lymphoma. PROCEDURE: Fifty survivors of brain tumors, between 8 and 30 years at the time of the assessment ("self") and/or their parents ("proxy"), attending the Pediatric Oncology Out Patient clinic of Padua, Italy, completed the HUI2 questionnaire. Eighty-nine children with acute leukemia/lymphoma and 74 with extra-cerebral solid tumors and/or their parents were also assessed. RESULTS: The mean "self" and "proxy" HUI2 global utility scores in the brain tumor patients were 0.87 and 0.84, respectively, while in the cohorts of children with other solid tumors and leukemia/lymphoma, there were 0.94, 0.91, 0.96, and 0.92, respectively. The differences between the HUI2 global utility scores in the "self" and "proxy" assessment within each cohort of children were not statistically significant. In decreasing order of frequency, the attributes affected most commonly were: "emotion," "pain," "sensation," and "cognition" both by "self" and "proxy" assessment. CONCLUSIONS: In this Italian population of childhood cancer survivors the HUI2 questionnaire proved to be a user-friendly tool, which provided information regarding HS and HRQL. A larger cohort of cancer children is needed to confirm the efficacy of the HUI2 questionnaire in distinguishing groups of children on this basis by disease category.
The treatment of hepatoblastoma is an example of the great advances made in paediatric oncology over the past few decades. Formerly a disease with a dreadful prognosis, children now have a 5-year survival rate of over 70%. This has been achieved by advances in surgical techniques and the use of chemotherapy. In future, we hope to be able to improve survival for children with high-risk tumours, and decrease the morbidity associated with treatment in the others.
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CASE REPORT: A case of a non-anaplastic pleomorphic xanthoastrocytoma (PXA) presenting with leptomeningeal dissemination (LMD) affecting a 9-year-old girl is presented. DISCUSSION: The neoplasia in this young girl had the otherwise classical clinical features of PXA: the relatively advanced paediatric age of the patient, the seizures as presenting sign; the primary site in the temporal lobe; and the MRI findings of the partially solid and cystic superficial lesion. Only the tumour involvement of the chiasma and the infundibulus was a relatively unusual finding. In a 5-year period, the tumour underwent malignant transformation, bringing the child to death because of the primary tumour progression. However, the leptomeningeal deposits remained unchanged throughout the clinical course. CONCLUSION: To our knowledge, this is the first case of a non-anaplastic PXA presenting with disseminated disease. Thus, it was thought important to describe this case in order to add further information regarding the spectrum of the presenting clinical features of this rare neoplasm and the phenomenon of LMD of non-malignant glioma.
PURPOSE: Preoperative staging (pretreatment extent of disease [PRETEXT]) was developed for the first prospective liver tumor study by the International Society of Pediatric Oncology (SIOPEL-1 study; preoperative chemotherapy and delayed surgery). Study aims were to analyze the accuracy and interobserver agreement of PRETEXT and to compare the predictive impact of three currently used staging systems. PATIENTS AND METHODS: Hepatoblastoma (HB) patients younger than 16 years who underwent surgical resection (128 of 154 patients) were analyzed. The centrally reviewed preoperative staging was compared with postoperative pathology (accuracy) in 91 patients (81%), and the local center staging was compared with the central review (interobserver agreement) in 97 patients (86%), using the agreement beyond change method (weighted kappa). The predictive values of the three staging systems were compared in 110 patients (97%) using survival curves and Cox proportional hazard ratio estimates. RESULTS: Preoperative PRETEXT staging compared with pathology was correct in 51%, overstaged in 37%, and understaged in 12% of patients (weighted kappa = 0.44; 95% CI, 0.26 to 0.62). The weighted kappa value of the interobserver agreement was 0.76 (95% CI, 0.64 to 0.88). The Children's Cancer Study Group/Pediatric Oncology Group-based staging system showed no predictive value for survival (P = .516), but the tumor-node-metastasis-based system and PRETEXT system showed good predictive values (P = .0021 and P = .0006, respectively). PRETEXT seemed to be superior in the statistical fit. CONCLUSION: PRETEXT has moderate accuracy with a tendency to overstage patients, shows good interobserver agreement (reproducibility), shows superior predictive value for survival, offers the opportunity to monitor the effect of preoperative therapy, and can also be applied in patients who have not had operations. For comparability reasons, we recommend that all HB patients included in trials also be staged according to PRETEXT.
Severe, life-threatening toxicity may be caused by errors in chemotherapy administration. To contribute with some useful information on drug-induced toxic effects and salvage therapy, we report a case of vinblastine (VBL) overdose (25 mg/m(2)) in a 12-year-old child affected by an end-stage metastatic primitive neuroectodermal tumor. Early signs of toxicity were acute, severe musculoskeletal pain and fever. This was followed by intestinal hypotonia, severe esophagitis, and peripheral neuropathy. Two consecutive plasma exchange procedures were performed at 4 and 18 hr after the administration of the overdose of VBL. The overall toxicity this child experienced was much less severe than expected; this finding, in combination with the known pharmacokinectis data of VBL in children, made us hypothesize that plasma exchange might have had a role in lowering the side effects of drug over dosage.
The treatment of childhood low grade glioma (LGG), if not amenable to complete resection, quite often is a relevant clinical challenge. LGG in many instances are indeed slow growing tumors, which, if not controlled, can cause severe morbidity and ultimately jeopardize life. Most of the time children bearing an unresectable LGG can be considered affected by a chronic disease, deserving protracted cures. The treatment philosophy, which has dictated the treatment of malignant cancers, has also inspired the therapeutic concepts for managing childhood LGG. However, it is getting more and more evident that different strategies are needed for them. LGG represent a highly heterogeneous group of neoplasm and comprehensive treatment concepts rarely meet the individual patient's needs. After more than 20 years of clinical research it can be stated with confidence that for unresectable, progressive LGG, chemotherapy (CT) represents an effective treatment modality. It delays tumor growth and postpones the use of radiotherapy (RT), thus sparing the deleterious effects of irradiation on a developing brain. However, CT rarely cures LGG and definitively obviates the need of RT or aggressive surgery. Furthermore, little is known on the actual impact of CT on patients' overall health status. Recent progresses in RT delivering techniques, which allow reducing the safety margins, are tempering the concerns related to the use of this treatment modality in children. This manuscript reviews and expands these data, trying to combine them in a coherent picture that it is hoped can help in directing future research in this field.
Cisplatin-containing chemotherapy and complete surgical resection are both crucial in the cure of hepatoblastoma. Radical resection can be obtained either conventionally by partial hepatectomy or with orthotopic liver transplant, but the surgical approach to hepatoblastoma differs considerably across the world. Our main aim in this paper is to present the surgical recommendations of the Childhood Liver Tumour Strategy Group of the International Society of Paediatric Oncology (SIOPEL), as well as to stimulate international debate on this issue. We discuss biopsy, verification of resectability, resection principles, indications and potential contraindications for orthotopic liver transplant, as well as thoracic surgery for pulmonary metastases. We suggest that heroic liver resections with a high probability of leaving residual tumour should be avoided whenever possible. In such cases primary orthotopic liver transplant should be considered. Superior survival rates in hepatoblastoma patients who have received a primary transplant after a good response to chemotherapy support the strategy of avoiding partial hepatectomy in cases where radical resection appears difficult and doubtful. We recommend early referral to a transplant surgeon in cases of: (i) multifocal or large solitary PRETEXT IV (PRE Treatment EXTent of disease scoring system) hepatoblastoma involving all four sectors of the liver and (ii) unifocal, centrally located tumours involving main hilar structures or main hepatic veins. Because complete tumour resection is a prerequisite for cure, any strategy leading to an increased resection rate will result in improved survival. We advise the more frequent use of orthotopic liver transplant, as well as the standardisation of techniques for partial liver resection. These guidelines should not be seen as final, but rather as a starting point for further discussion between the various national and international liver tumour study groups.
Several lines of evidence demonstrate that the biology, genetics and environment of childhood solid tumours (CSTs) sets them apart from adult solid tumours. The nature of the progenitor cells from which these tumours arise, and their immature tissue environment, allows CSTs to develop with fewer defects in cell regulatory processes than adult cancers. These differences could explain why CSTs are more susceptible to therapeutic intervention than adult tumours. How does the aetiology of these cancers differ from those occurring in adults and how might this affect the development of more effective therapies?
In this study the authors retrospectively evaluated the feasibility and effectiveness of prolonged oral etoposide therapy in children with recurrent ependymoma. Twelve ependymoma patients with documented recurrent or persistent disease were treated between May 1998 and October 2003. All patients were treated monthly with oral VP-16 administered at a dose of 50 mg/m2/d for 21 days, with a 7-day interval between cycles, for a planned minimum number of six cycles. Response (complete plus partial) after two cycles occurred in 5 of the 12 patients (41.6%). Response plus stable disease occurred in 10 of the 12 (83.3%), with a median duration of response or stable disease of 7 months (range 4-30). The median survival was 7 months; the 2-year progression-free survival was 16.7%. These results emphasize that oral etoposide is an attractive option for childhood recurrent ependymomas in terms of administration, tolerability, and neuroradiologic response.
PURPOSE: A postsurgical "stage-based" protocol for ependymoma was designed. METHODS AND MATERIALS: Children were given: (1) focal hyperfractionated radiotherapy (HFRT) if with no evidence of disease (NED), or (2) 4 courses with VEC followed by HFRT for residual disease (ED). HFRT dose was 70.4 Gy (1.1 Gy/fraction b.i.d.); VEC consisted of VCR 1.5 mg/m2 1/w, VP16 100 mg/m2/day x 3, CTX 3 g/m2 d 1. When feasible, second-look surgery was recommended. RESULTS: Sixty-three consecutive children were enrolled: 46 NED, 17 ED; the tumor was infratentorial in 47 and supratentorial in 16, with spinal metastasis in 1. Of NED patients, 35 of 46 have been treated with HFRT; 8 received conventionally fractionated radiotherapy, and 3 received no treatment. Of the 17 ED patients, 9 received VEC + HFRT; violations due to postsurgical morbidity were as follows: HFRT only (2), conventionally fractionated radiotherapy (3) + VEC (2), and no therapy (1). Objective responses to VEC were seen in 54%; objective responses to RT were seen in 75%. Overall survival and progression-free survival at 5 years for all 63 children were 75% and 56%, respectively; for the NED subgroup, 82% and 65%; and for the ED subgroup, 61% and 35%, respectively. All histologies were centrally reviewed. At multivariate analysis, grading, age, and site proved significant for prognosis. CONCLUSIONS: HFRT, despite the high total dose adopted, did not change the prognosis of childhood ependymoma as compared to historical series: New radiotherapeutic approaches are needed to improve local control. Future ependymoma strategies should consider grading when stratifying treatment indications.
The study sought to evaluate the response to cyclophosphamide (CPM) in hepatoblastoma (HB). Patients with a refractory or relapsing HB after first-line therapy as per SIOPEL 2 and 3 protocols were eligible. All patients were to receive two courses of CPM 2 g/m(2) on days 1 and 2 at 3-week intervals. Eighteen patients were included; 17 were evaluable for response. Prior treatment was cisplatinum alone (1 patient) or cisplatinum-carboplatin-doxorubicin (17 patients). The disease status at the beginning of CPM was: progressive during first-line treatment (10 patients), persistent unresectable disease at the end of the protocol (2 patients), relapse (6 patients). Tumour response was partial response (1 patient), stable disease (1 patient), progressive disease (15 patients) and not evaluable in one. All patients died, 17 of progressive disease and one of surgery complications. The low response rate (1/17) led the SIOPEL group to conclude that single-agent CPM is not effective for the treatment of relapsing or refractory HB.
DISCUSSION: The leptomeningeal dissemination (LMD) of low-grade gliomas (LGGs) is reported in clinical neuro-oncology practice more and more frequently. It is estimated that 5% of all childhood LGGs present LMD at diagnosis and 7-10% at the time of progression. LMD has been reported in association with almost all the known subtypes of LGGs. Furthermore, "unusual " LGGs can be encountered among slow-growing brain neoplasm capable of LMD, which cannot comfortably be included in the present WHO brain tumour classification. The biological, genetic and clinical characteristics that seem to favour LMD are far from being understood. Similarly, the clinical profile of those children with disseminated LGGs has not yet been firmly established. Young, non-neurofibromatosis type 1 boys with large hypothalamic-chiasmatic pilocytic astrocytomas seem to be at increased risk of LMD. The neuroradiological appearance of LMD in childhood LGGs is similar to that observed in malignant tumours, except for those cases characterised by multiple superficial non-enhancing cystic lesions, which seem to be almost exclusively associated with a type of slow-growing not yet fully identified brain stem or spinal tumour. No firm guidelines for the treatment of these diseases are yet available, mostly due to the rarity of this condition and the existing uncertainties regarding their natural clinical history. CONCLUSION: The evidence of LMD in children with LGGs does not seem to have a negative impact on patients' long-term outcome.
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