High dose craniospinal irradiation as independent risk factor of permanent alopecia in childhood medulloblastoma survivors: cohort study and literature review.

PURPOSE: Our aim was to determine the main risk factors related to the occurrence of permanent alopecia in childhood medulloblastoma (MB) survivors. METHODS: We retrospectively analyzed the clinical features of all consecutive MB survivors treated at our institute. We divided the patients into 3 groups depending on the craniospinal irradiation (CSI) dose received and defined permanent alopecia first in terms of the skin region affected (whole scalp and nape region), then on the basis of the toxicity degree (G). Any relationship between permanent alopecia and other characteristics was investigated by a univariate and multivariate analysis and Odds ratio (OR) with confidence interval (CI) was reported. RESULTS: We included 41 patients with a mean10-year follow-up. High dose CSI resulted as an independent factor leading to permanent hair loss in both groups: alopecia of the whole scalp (G1 p-value 0.030, G2 p-value 0.003) and of the nape region (G1 p-value 0.038, G2 p-value 0.006). The posterior cranial fossa (PCF) boost volume and dose were not significant factors at multivariate analysis neither in permanent hair loss of the whole scalp nor only in the nuchal region. CONCLUSION: In pediatric patients with MB, the development of permanent alopecia seems to depend only on the CSI dose ≥ 36 Gy. Acute damage to the hair follicle is dose dependent, but in terms of late side effects, constant and homogeneous daily irradiation of a large volume may have a stronger effect than a higher but focal dose of radiotherapy.

Pineal germinoma in a child with interferon-γ receptor 1 deficiency. case report and literature review.

Interferon-γ receptor 1 (IFN-γR1) deficiency is one of the primary immunodeficiencies conferring Mendelian Susceptibility to Mycobacterial Disease (MSMD). Some cases of neoplasms have been recently reported in patients with MSMD, underlying the already known link between immunodeficiency and carcinogenesis. We report the first case of intracranial tumour, i.e. pineal germinoma, in a 11-year-old patient with complete IFN-γR1 deficiency. The first clinical presentation of the genetic immunodeficiency dates back to when the child was aged 2 y and 10 mo, when he presented a multi-focal osteomyelitis caused by Mycobacterium scrofulaceum. The diagnosis of IFN-γR1 deficiency (523delT/523delT in IFNGR1 gene) was subsequently made. The child responded to antibiotic therapy and remained in stable clinical condition until the age of 11 years, when he started complaining of frontal, chronic headache. MRI revealed a solid pineal region mass lesion measuring 20 × 29 × 36 mm. Histological findings revealed a diagnosis of pineal germinoma. The patient received chemotherapy followed by local whole ventricular irradiation with boost on pineal site, experiencing complete remission, and to date he is tumor-free at four years follow-up. Four other cases of tumors have been reported in patients affected by MSMD in our knowledge: a case of Kaposi sarcoma, a case of B-cell lymphoma, a case of cutaneous squamous cell carcinoma and a case of oesophageal squamous cell carcinoma. In conclusion, in patients with MSMD, not only the surveillance of infectious diseases, but also that of tumors is important.

TCERG1L allelic variation is associated with cisplatin-induced hearing loss in childhood cancer, a PanCareLIFE study.

In children with cancer, the heterogeneity in ototoxicity occurrence after similar treatment suggests a role for genetic susceptibility. Using a genome-wide association study (GWAS) approach, we identified a genetic variant in TCERG1L (rs893507) to be associated with hearing loss in 390 non-cranial irradiated, cisplatin-treated children with cancer. These results were replicated in two independent, similarly treated cohorts (n = 192 and 188, respectively) (combined cohort: P = 5.3 × 10-10, OR 3.11, 95% CI 2.2-4.5). Modulating TCERG1L expression in cultured human cells revealed significantly altered cellular responses to cisplatin-induced cytokine secretion and toxicity. These results contribute to insights into the genetic and pathophysiological basis of cisplatin-induced ototoxicity.

Identification of a SUFU germline mutation in a family with Gorlin syndrome.

Gorlin syndrome (GS) is inherited in an autosomal dominant pattern with high-penetrance and is characterized by a range of developmental anomalies and increased risk of developing basal cell carcinoma and medulloblastoma. Between 50% and 85% of patients with GS harbor germ line mutations in the only susceptibility gene identified to date, PTCH1, a key component in the Sonic Hedgehog signaling pathway. Another component in this pathway, SUFU, is known to be involved in susceptibility to medulloblastoma but has never been reported in GS patients to date. We have identified the known c.1022 + 1G>A SUFU germ line splicing mutation in a family that was PTCH1-negative and who had signs and symptoms of GS, including medulloblastoma. This is the first report of a germ line SUFU mutation associated with GS.

Successful isolation and long-term establishment of a cell line with stem cell-like features from an anaplastic medulloblastoma.

AIMS: Herein we report on the successful isolation and establishment of a novel, long-term, primary, neurosphere-like cell line called 1603-MED from a 5-year-old boy affected by a highly aggressive anaplastic medulloblastoma. METHODS: Elaboration of the new protocol for neurosphere assay is extensively discussed, together with a complete immuno-histochemical and cytogenetic characterization of 1603-MED. RESULTS: Clinical course and histopathology are briefly discussed. The 1603-MED possesses a high capacity for proliferation, CD133 expression, self-renewal and differentiation, thus indicating that anaplastic medulloblastoma contains a subpopulation of cancer stem cells as observed in classic medulloblastoma. CONCLUSIONS: 1603-MED provides us with the first in vitro model of anaplastic medulloblastoma that may be suitable for studying both tumour progression and the genetic mechanisms related to therapy resistance, and may lead to the development and testing of chemosensitivity and new therapeutic targets.

Evolving role of myeloablative chemotherapy in the treatment of childhood brain tumours.

Primary brain tumours, a heterogeneous group of cancer that constitute the second most common cancer in childhood, were historically treated with neurosurgical resection and radiation therapy. Chemotherapy has proven to be beneficial for some histological types, which has since led to exploration of the role of high-dose chemotherapy and haematopoietic stem cell rescue. Patients with high-grade glial tumours, primitive neuroectodermal tumours and high-risk medulloblastoma usually fare poorly. The indicators of bad prognosis are metastatic status, extent of resection and age. Children <3 years at diagnosis carry worse prognosis. Rare cancers such as ependymoblastoma, atypical teratoid rhabdoid tumour and choroid plexus carcinoma have a dismal prognosis regardless of the above-mentioned indicators. The use of myeloablative therapy (MAT) has been investigated to improve the rate of long-term DFS, as well as to reduce and delay in the youngest children the use of the craniospinal irradiation associated with unacceptable late effects. We will overview the literature regarding patients with 'good and uncertain indications' to MAT. Ependymoma and brain stem tumours, for which the available data discourage the use of MAT, are excluded. Finally, we will summarize a single Institution experience (Giannina Gaslini Children's Hospital, Genoa) with MAT in the period 1997-2003.

Expression of histone H3 cell cycle-related gene, vimentin and MYC genes in pediatric brain tumors. A preliminary analysis showing the different malignant cell growth potential.

Eleven pediatric brain tumors were studied for the histone H3, Vimentin and MYC gene expression. H3, an S phase cell cycle-related gene (ccr), was found prevalently expressed in tumors with a high mitotic index (MI). Vimentin gene, which contributes to maintaining the cell structure but is also demonstrated to be an early responder gene to growth stimulation was found variously expressed. The different expression of Vimentin gene in the examined samples suggests the active proliferation of the tumor cells. Analysis of MYC gene expression was found increased only in a mesenchymal chondrosarcoma while in other samples MYC mRNA was undetectable. Medulloblastoma, chondrosarcoma, and choroid plexus carcinoma have high S phase H3 gene expression associated with a high MI. Differently an astrocytoma shows a low MI associated with high H3 gene expression. This first preliminary report of H3, Vimentin and MYC gene expression in brain tumors demonstrates that malignant cells are characterized by a different gene expression and different growth potentials.

ins(6;1) in a patient with congenital leukemia.

Q- and C-banded karyotypes of leukemic cells of a patient with congenital acute lymphoblastic leukemia showed the karyotype: 46,XX,ins(6;1)(p21;p13p36). This rearrangement is unusual, and the breakpoints on chromosome 1 are interestingly close to known cellular oncogenes (N-ras, fgr, src-2) and to a putative antioncogene.

Secondary acute promyelocytic leukemia with t(8;21) and t(9;22) at onset and loss of the Philadelphia chromosome at relapse.

The translocation (8;21) is a typical marker of the M2 subtype of acute nonlymphocytic leukemia, whereas the Philadelphia (Ph) chromosome is predominantly associated with chronic myelogenous leukemia, and seldom with immature acute leukemias, either lymphoblastic or nonlymphoblastic. Furthermore, the association between t(8;21) and a Ph in the same cell is extremely rare. We present a case of secondary acute promyelocytic leukemia with a karyotype 46,XY,t(8;21), t(9;22) at onset. At relapse the patient lost the Ph, while maintaining the t(8;21). This apparently paradoxical pattern of cytogenetic features and evolution is discussed.

Medulloblastoma with extensive nodularity: a variant with favorable prognosis.

OBJECT: Some medulloblastomas (MBs) are characterized by extreme nodularity and intranodular nuclear uniformity in a fine fibrillary background. These lesions have also been designated as "cerebellar neuroblastoma." Although numerous reports have been published in which their morphological features have been investigated, only a few studies have been focused on their neuroradiological appearance, biological behavior, and response to therapy. The goal of this study was to gather more information about these lesions. METHODS: The authors present 11 cases of MB with extensive nodularity. Five patients were boys and six were girls; all but one were 24 months of age or younger at diagnosis. Magnetic resonance imaging disclosed a peculiar grapelike architecture in eight cases. Surgical tumor removal was complete in nine cases and partial in one. In the other case a biopsy sample of the tumor was obtained after a preoperative course of chemotherapy. After surgery, two children were treated with radiotherapy alone and one with craniospinal irradiation followed by systemic chemotherapy. Eight patients were treated with chemotherapy only. All the patients in the study are presently alive with a median follow up of 66 months. Eight patients (73%) are in complete remission at 35 to 156 months. Three patients treated with chemotherapy alone postsurgery relapsed; however, all underwent successful retreatment (two with craniospinal irradiation and one with further surgery plus high-dose chemotherapy) and are in complete remission. A review of the literature revealed that patients in 11 of 12 reported cases were younger than 3 years of age and that seven of eight in whom follow-up information was available were alive and well, with survival times ranging from 6 to 84 months. CONCLUSIONS: Medulloblastomas with extensive nodularity represent a variant that is characterized by: 1) occurrence in very young children; 2) a peculiar grapelike appearance on neuroimaging; and 3) an apparently favorable outcome.

Very high dose cis-platinum (450 mg/sq m) in an infant with rhabdomyosarcoma.

The toxic effects of CDDP, erroneously given at 450 mg/sq m, are described. Life threatening gastrointestinal and myelotoxicity was observed as well as prolonged severe renal tubular acidosis without renal failure. No significant oto (brain-stem evoked responses) or neurotoxicity (EEG, neurologic examination and nerve conduction velocity) was detected indicating major age-related differences in the toxicity of this drug.

Growth hormone treatment in irradiated children with brain tumors.

We assessed the efficacy of GH treatment in 25 GH deficient patients irradiated for brain tumors (eight with glioma cranio-irradiated, eleven with medulloblastoma and six with ependymoma craniospinal-irradiated). We administered GH at doses of 0.6-0.9 IU/kg/week for one to three years at least two years after diagnosis of the tumor. We assessed the efficacy of the treatment each year by comparing the values of height velocity over bone age and change in the ratios progression of chronological age/progression of bone age and progression of statural age/progression of bone age. The treatment promoted satisfactory growth; better results were obtained in patients with glioma, who received cranial irradiation only, than in those with medulloblastoma or ependymoma, who received spinal irradiation as well. Moreover, the growth prognosis improved, especially in the cranio-irradiated patients. In our series of patients four presented tumor recurrence; these results did not differ significantly from those in irradiated patients with cerebral tumors who were not treated with GH.

[Wilms' tumor, polycythemia, ichthyosis and ear malformations: a new syndrome?]. / Tumore di Wilms, poliglobulia, ittiosi e malformazioni auricolari: una nuova sindrome?

Wilms' tumor (WT) is frequently associated to congenital malformations, i.e. aniridia (0.8%), hemihypertrophy (2.5%), and genitourinary malformations. Ear malformations have been suggested to be a sign of genitourinary malformations. On the other hand WT cases associated to ichthyosis has never been reported. The authors present a case of Wilms' tumor (WT) associated to ear malformations, ichthyosis and polycythemia, and suggest that such a malformation pattern might represent a new syndrome.

[Ewing's sarcoma in preschool children. Description of 6 cases]. / Sarcoma di Ewing in età prescolare. Descrizione di 6 casi.

Ewing's sarcoma (ES) is rarely diagnosed in the pre-school age; these few cases however present a number of difficult diagnostic and therapeutic problems. The Authors describe a series of six such cases aged less than 4 years diagnosed in the period 1974-1987. Standard treatment was modified with the purpose to reduce acute toxicity and late sequelae. These modifications are described in details. Four/6 patients are presently alive disease-free from 29 to 87 months from diagnosis (median, 34 months). Two patients died from acute toxicity. The Authors suggest that young children with ES may be treated successfully with proper adjustments of current protocols. Increased aggressiveness of chemotherapy regimens may compensate for reduced radiotherapy; however, the high susceptibility to infection of youngsters has to be taken into account and makes mandatory a careful monitoring during phases of profound myelodepression.

[2 cases of osteomyelitis in acute leukemia in the induction phase of treatment]. / Due casi di osteomielite in fase di induzione di leucemia acuta.

Whereas children with Acute Leukemia are highly susceptible to infectious complications, the occurrence of acute osteomyelitis is extremely rare in these patients. The authors describe two such cases in children at onset of an acute lymphoblastic and of a myelomonocytic leukemia, respectively. In the former case, the clinical course has been characterized by the progressive involvement of several joints and bones. A citrobacter Freundii was isolated in the synovial fluid of an involved knee. This complication was successfully treated with proper antimicrobic agents and surgical toilet, while the patient was vigorously treated for her leukemia, achieving a complete remission. The latter case developed a right humerus osteomyelitis from an Enterobacter. The patient failed to respond to antibiotics, and his leukemia also turned refractory to antiblastic therapy. The difficulty in the differential diagnosis among the X-graphic aspects of leukemic, inflammatory and degenerative disease of bones are discussed by the authors. Some pathogenetic hypothesis of leukemic osteomyelitis are also presented.

[Fungal infections in pediatric oncology]. / Infezioni fungine in oncologia pediatrica.

The clinical charts of cancer patients with documented fungal infections hospitalized at G. Gaslini Children's Hospital, Italy, from 1980 to 1990 were reviewed. Thirty-seven episodes developing in 37 patients were identified, based on microbiological and/or histological documentation. Patients' age ranged from 3 months to 18 years (median 7 years). Twenty patients were treated for hematological malignancy and 17 had solid tumor. Seven patients (3 with leukemia and 4 with solid tumours), developed mycosis after bone marrow transplantation procedure. A history of neutropenia in the month preceding the documentation of fungal infection was present in 76% of cases (28 of 37). However, only 16 of 28 (55%) of these patients were still neutropenic at time of diagnosis. In 40% of the cases the fungal infection developed as primary infection not preceded by any febrile and/or infectious episode. Fungemias without evident organ localization accounted for the 40% of episodes with a mortality rate of 20%. The other 22 cases (60%) were classified as invasive mycoses; 9 of these patients died (41%). Mortality was higher among patients with mold infection (5 of 7, 72%), than in those with yeast infection (7 of 29.24%). Molds infections and invasive mycoses were virtually absent in the first part of our period of observation (1980-84), but emerged in the second period (1985-90) when also the incidence rate of fungal disease increased (from 2.67/10,000 person/day to 5.93), probably in relation with extensive construction works and with the implementation of a bone marrow transplantation program.

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.