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Ian J Cohen

Publications and source records attributed to Ian J Cohen.

At least 19 recordsLinked to original sources
PubMed2005

Role of MRI in the management of children with diffuse pontine tumors: a study of 15 patients and review of the literature.

BACKGROUND: Pontine tumors carry the worst prognosis of all brain tumors. In most cases, the diagnosis is based solely on MR imaging, without biopsy. OBJECTIVE: To describe the MR findings of pontine tumors at diagnosis and during follow-up and correlate those with prognosis and to assess the value of MR imaging in patient management compared to clinical evaluation. MATERIALS AND METHODS: Ninety-one MR scans of 15 children with diffuse pontine tumors were reviewed at diagnosis and during follow-up. The parameters analyzed were as follows: tumor extent, area, and volume; encasement of the basilar artery; presence of exophytic component; necrosis; cysts; hydrocephalus; and intensity and enhancement. Findings were correlated to length of progression-free and overall survival. Trends of amelioration or worsening on imaging were compared with the clinical findings. RESULTS: Median length of progression-free survival was 10 months, and median survival was 20 months. Only hydrocephalus at presentation was associated with shorter progression-free survival (P=0.02). On the last examination of each patient, the craniocaudal diameter was significantly greater than at diagnosis (P=0.03). The concordance between the imaging and the clinical findings was good. CONCLUSION: MR is the mainstay for the diagnosis and management of pontine tumors. Cranial growth seems to be an ominous sign. However, the prognostic value of MR is limited. MR findings correlate well with the clinical examination.

Adolescent↗
PubMed2005

Task switching after cerebellar damage.

The authors of this study investigated task switching following cerebellar damage. The study group consisted of 7 children and adolescents (M age=13.8 years) who underwent surgical removal of a benign posterior fossa tumor. They were tested at a sufficient interval after surgery (M lag=6.13 years) for restoration of normal cognitive skills and intelligence. Although all showed normal learning of the task compared with control participants, when rapid behavioral changes were required (short preparation time), they exhibited behavioral rigidity manifested by enhanced switching cost. These results are in line with another study on serial reaction time with the same patients (A. Berger et al., in press). They have important implications for our understanding of the cognitive sequelae of early cerebellar damage as well as the involvement of the cerebellum in task switching.

Adolescent↗
PubMed2005

Prenatal imaging of fetal hepatoblastoma.

A detailed sonographic at 37 weeks of gestation performed due to non-reassuring fetal monitor of a breech presentation fetus detected a solid right lobe hepatic tumor. Prenatal gray scale and Doppler sonography suggested a diagnosis of hepatoblastoma which was confirmed postnatally. Differential ultrasonographic diagnosis of fetal hepatic tumors is discussed.

Adult↗
PubMed2005

Motor and non-motor sequence learning in children and adolescents with cerebellar damage.

Cerebellar involvement in motor and non-motor sequence learning was examined with serial reaction time tasks (SRT). Our sample consisted of 8 children and adolescents who had undergone surgical removal of a benign posterior fossa tumor (PFT) during childhood. None of them had undergone chemotherapy or cranial radiation therapy (CRT). Ages ranged from 1-11 years at surgery and 9-17 years at testing. The children were tested not earlier than 2.5 years after surgery (M = 5.9 years), enabling brain plasticity and recovery of functions. Their performance was compared with a matched control sample. The PFT group was not impaired in the implicit learning of sequences, as reflected in their performance in blocks with a repeated sequence, both before and after a random block. However, in the perceptual task, their performance deteriorated more than that of the control group when a random block was introduced, suggesting that it was more difficult for the patients to respond flexibly or change their response set when encountering changing task demands. These results are in line with another study by our group on task switching with the same patients.

Adolescent↗
PubMed2004

Prediction of high risk Ewing's sarcoma by gene expression profiling.

Ewing's sarcoma (ES) is the second most common primary malignant bone tumor in children and adolescents. Currently accepted clinical prognostic factors fail to classify ES patients' risk to relapse at diagnosis. We aimed to find a new strategy to distinguish between poor and good prognosis ES patients already at diagnosis. We analysed the gene expression profiles of 14 primary tumor specimens and six metastases from ES patients, using oligonucleotide microarray analysis. The over-expression of two genes was validated by quantitative PCR using the LightCycler system. We identified two distinct gene expression signatures distinguishing high-risk ES patients that are likely to progress from low-risk ES patients with a favorable prognosis of long-term progression-free survival. The microarray-based classification was superior to currently used prognostic parameters. Over-expressed genes in the poor prognosis patients included genes regulating the cell cycle and genes associated with invasion and metastasis, while among the downregulated genes were tumor suppressor genes and inducers of apoptosis. Our results indicate the existence of a specific gene expression signature of outcome in ES already at diagnosis, and provide a strategy to select patients who would benefit from risk-adapted improved therapy.

Adolescent↗
PubMed2004

High frequency of genomic instability in Ewing family of tumors.

We tested Ewing sarcoma tumors for microsatellite instability (MSI) and loss of heterozygosity (LOH) to investigate the role of genomic instability (GI) in this sarcoma. We detected a high frequency of GI (57%), mostly on 1p and 11p, 35% and 30%, respectively. Patients with GI compared to those with stable genome had a median progression-free survival (PFS) and overall survival (OS) of 24 months and 70 months, compared with 39 and 84 months, respectively. MSI was observed in 48% (11/23) of the tumor samples. Low-MSI (L-MSI) patients (with MSI presented at only one locus) tended to have a better prognosis, 70% PFS, compared with 25% in the high-MSI (H-MSI) group (P=0.13). LOH without MSI did not correlate with progression. H-GI (MSI and/or LOH in > or =30% of tested markers) tended to associate with an adverse prognosis (P=0.28), and correlated significantly with the pelvic site of the primary tumor (P=0.02). The instability of 1p was not associated with progression, while alterations at the 11p locus tended to correlate with a more aggressive disease (P=0.18). Our data suggest that GI may play a role in Ewing sarcoma clinical behavior and outcome.

Adolescent↗
PubMed2004

The predictive potential of molecular detection in the nonmetastatic Ewing family of tumors.

BACKGROUND: Tumors in the Ewing family (EFTs) are the second most common bone tumors in children and adolescents. Despite aggressive chemotherapy, one-third of patients with localized tumor still may develop recurrences. This implies that not all tumor cells are eradicated and that the patients may have a level of residual disease. EFTs are characterized by specific chromosomal translocations that result in chimeric transcripts that can be detected with reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. METHODS: The authors report the prognostic potential of the positive chimeric transcript (EWS/FLI1) in bone marrow (BM) and/or peripheral blood (PBL) in 26 patients with EFT during a long follow-up period (median, 61 months). RESULTS: At diagnosis, 43% of patients had positive RT-PCR BM results, with no correlation to tumor progression (P = 0.3). During follow-up, 58% of patients had positive RT-PCR results in their last sample analyzed (BM and/or PBL). A highly significant correlation between the presence of the chimeric transcript and disease progression was detected (P = 0.0028). In a multivariate analysis, the percentage of tumor necrosis (P = 0.007) and RT-PCR results during follow-up (P = 0.02) remained significant prognostic markers. In 10 of 11 patients who developed disease progression, BM and/or PBL samples were positive for the chimeric transcript before evidence of overt clinical recurrence. CONCLUSIONS: Occult tumor cells in BM and/or PBL samples during long follow-up are strong predictors of recurrent disease in patients with nonmetastatic EFTs.

Adolescent↗
PubMed2004

Germ-line ATM gene alterations are associated with susceptibility to sporadic T-cell acute lymphoblastic leukemia in children.

A major feature of ataxia-telangiectasia (A-T) is an increased risk of cancer, particularly of lymphoid malignancies. We studied ATM gene involvement in leukemic cells derived from 39 pediatric T-cell acute lymphoblastic leukemias (ALLs). Two types of sequence changes--truncating and missense--were identified in 8 T-cell ALL samples: 3 truncating changes, all previously identified in A-T (R35X, -30del215, 2284delCT), and 3 missense variants (V410A, F582L, F1463C) were found, none associated with loss of heterozygosity (LOH). In all patients studied, the mutation was present in the germ-line. A-T carriers, defined by the finding of truncating mutations, were found to be 12.9 times more frequent than in the normal population (P = 0.004). A normally ethnically matched population was screened for the 3 missense variants, and their frequency was significantly more prevalent (4.9-fold excess) than in the normal population (P = 0.03). Our data suggest there is some evidence of an association between missense alterations in the ATM gene and T-cell ALL. A significant difference in the mean age at diagnosis of T-cell ALL was noted between patients harboring an ATM sequence change and those with no change, 5.4 years and 9.7 years, respectively (P = 0.001). No ATM alterations were identified in relapse samples, indicating that ATM does not play a role in disease progression. The high prevalence of germ-line truncating and missense ATM gene alterations among children with sporadic T-cell ALL suggests an association with susceptibility to T-cell acute leukemia and supports the model of predisposition to cancer in A-T heterozygotes.

Ataxia Telangiectasia↗
PubMed2004

Defining the appropriate dosage of folinic acid after high-dose methotrexate for childhood acute lymphatic leukemia that will prevent neurotoxicity without rescuing malignant cells in the central nervous system.

Neurotoxicity after the administration of methotrexate continues to worry physicians. However, inadequate folinic acid rescue is often not considered as a cause of this complication. To clarify whether adequate folinic acid rescue prevents methotrexate-induced neurotoxicity without reducing the cure rate in childhood ALL, published evidence that supported or refuted this claim was investigated. A literature search was conducted and the authors of the relevant studies were contacted. The published data supported the contention that neurotoxicity can be prevented by adequate folinic acid rescue even after very high doses of methotrexate. The safe minimum dose of folinic acid can be defined in terms of the dose of methotrexate given; the time to start of rescue is probably less important. There was no evidence that higher doses of folinic acid, such as those used after methotrexate in the treatment of osteosarcoma, rescue leukemia cells. No change in cure rate was found in relation to changes in scheduling or clinically relevant doses of folinic acid rescue. The accumulation of folinic acid in the cerebrospinal fluid did not seem to be of clinical relevance. No studies indicate that doses of folinic acid after high-dose methotrexate administration interfere with the killing of leukemia cells, nor that delaying the start of rescue beyond a certain point increases the antileukemic effect; neurotoxicity will, however, be increased. Review of current protocols that use low-dose folinic acid rescue and are associated with neurotoxicity is highly recommended.

Central Nervous System Neoplasms↗
PubMed2004

Prenatal diagnosis in Li-Fraumeni syndrome.

PURPOSE: The hallmark of Li-Fraumeni syndrome (LFS), a familial cancer syndrome, is constitutional TP53 mutation. The authors addressed the complex question of predictive prenatal genetic testing for cancer risk associated with inheritance of TP53 mutation. METHODS: A classic LFS family including the proband (a 20-month-old boy with rhabdomyosarcoma), his 36-year-old father with osteosarcoma, and his 40-year-old paternal aunt with bilateral breast cancer were identified as carriers of a TP53 germline mutation, a novel 1 base pair deletion in exon 5. A few years later, the mother became pregnant twice, and the parents requested prenatal diagnosis on each occasion. Genetic counseling, psychological evaluation, and support were provided by a multidisciplinary team including a pediatric oncologist, a geneticist, a psychosocial worker, a prenatal care provider, and an ethical representative. After providing overall information on LFS, including the high risk of developing secondary multiple neoplasms in LFS survivors, the committee approved prenatal diagnosis at the request of the family. RESULTS: In the two pregnancies, the two fetuses were found to be carriers of the same mutation. Nine years from diagnosis of the first tumor, the proband, and a month later his father, developed second tumors, multifocal osteosarcoma and leiomyosarcoma, respectively. CONCLUSIONS: Children with primary tumors belonging to LFS should be considered for screening for germline mutations and genetic counseling by a multidisciplinary team. Whether family members are found to be positive or negative as carriers, such measures may provide, by reducing uncertainty, psychological benefit to high-risk families.

Adult↗
PubMed2004

Classical and molecular cytogenetic abnormalities and outcome of childhood acute myeloid leukaemia: report from a referral centre in Israel.

The incidence of cytogenetic abnormalities in childhood de novo acute myeloid leukaemia (AML) and its prognostic significance was assessed in an Israeli paediatric referral centre. Cytogenetic analysis was successful in 86 of 97 children (< 20 years of age) diagnosed between 1988 and 2002 with de novo AML. Fluorescence in situ hybridization analysis detected new information in 11 of them, leading to reassignment in cytogenetic group classification. The incidence of the various cytogenetic subgroups was as follows: normal - 9%; t(11q23) - 22%; t(8;21) - 13%; t(15;17) - 8%; inv(16) - 3.4%; abn(3q) - 4.6%; 7/7q-(sole or main) - 5.8%; del(9q)(sole) and +21(sole) - 4.6% each; t(8;16) - 2.3%; t(6;9), t(1;22), +8(sole) - 1.1% each; and miscellaneous - 18%. The overall survival (OS) and event-free survival (EFS) (4 years) for 94 patients treated with the modified Berlin-Frankfürt-Münster (BFM) AML protocols (non-irradiated) were 59.9% (SE = 5%) and 55.7% (SE = 5%), respectively, and for the favourable t(8;21), t(15;17) and inv(16), OS was 60% (SE = 15%), 83% (SE = 15%) and 100% respectively. For the normal group it was 62% (SE = 17%), miscellaneous 64% (SE = 12%), t(11q23) 44.6% (SE = 11%) and of the -7/7q-, del(9q)(sole) or t(6;9), none had survived at 4 years. The incidence of cytogenetic subgroups in the Israeli childhood AML population and their outcome were similar to other recently reported paediatric series. Cytogenetic abnormalities still carry clinical relevance for treatment stratification in the context of modern chemotherapy.

Acute Disease↗
PubMed2003

Pediatric non-neuronopathic Gaucher disease: presentation, diagnosis and assessment. Consensus statements.

UNLABELLED: Gaucher disease is caused by defective activity of glucocerebrosidase. The resulting accumulation of glucocerebroside in the lysosomes of visceral macrophages in various tissue and organ compartments leads to multiple manifestations, including hepatosplenomegaly, anemia, thrombocytopenia, growth retardation and skeletal disease. The most prevalent form of Gaucher disease is the non-neuronopathic (type 1) variant, which lacks primary involvement of the central nervous system. Traditionally, this has been referred to as the 'adult type'; however, 66% of individuals with symptomatic non-neuronopathic Gaucher disease manifest in childhood. Onset in childhood is usually predictive of a severe, rapidly progressive phenotype and children with non-neuronopathic Gaucher disease are at high risk for morbid complications. Enzyme therapy with recombinant human glucocerebrosidase in childhood can restore health in reversible manifestations and prevent the development of irreversible symptoms. A heightened focus on pediatric Gaucher disease is therefore needed. Although some correlation has been found between genotype and phenotype, mutation analysis is of limited value in disease prognosis. Management of pediatric Gaucher disease should be underpinned by a thorough assessment of the phenotype at baseline with regular monitoring thereafter. Excluding neuronopathic disease is recommended as the first step. Subsequently, baseline evaluation should focus on staging of different storage tissues, particularly the bone the involvement of which results in the greatest long-term morbidity. These organ assessments are recommended because bone disease severity may not correlate with disease severity in other organs and vice versa. In addition, different organs may respond differently to therapy. Initial assessment of each organ system can enable setting of realistic and individualized goals. CONCLUSION: A thorough approach to baseline assessment will improve the understanding of childhood Gaucher disease, optimizing management to minimize impairment of growth and development and prevent irreversible symptoms.

Adolescent↗
PubMed2003

Paediatric non-neuronopathic Gaucher disease: recommendations for treatment and monitoring.

UNLABELLED: In individuals with non-neuronopathic Gaucher disease, childhood manifestations are usually predictive of a more severe phenotype. Although children with Gaucher disease are at risk of irreversible disease complications, early intervention with an optimal dose of enzyme therapy can prevent the development of complications and ensure adequate, potentially normal, development through childhood and adolescence. Very few, if any, children diagnosed by signs and symptoms should go untreated. Evidence suggests that disease severity, disease progression and treatment response in different organs where glucocerebroside accumulates are often non-uniform in affected individuals. Therefore, serial monitoring of the affected compartments is important. This should include a thorough physical examination at 6- to 12-monthly intervals. Neurological assessment should be performed to rule out neurological involvement and should be undertaken periodically thereafter in children who are considered to have risk factors for developing neuronopathic disease. Haematological and biochemical markers, such as haemoglobin, platelet counts and chitotriosidase levels, should be assessed every 3 months initially, but when clinical goals have been met through treatment with enzyme therapy, the frequency can be reduced to every 12 to 24 months. Careful monitoring of bone disease is vitally important, as the resulting sequelae are associated with the greatest level of morbidity. By combining various imaging modalities, the skeletal complications of non-neuronopathic Gaucher disease can be effectively monitored so that irreversible skeletal pathology is avoided and pain due to bone involvement is diminished or eliminated. Monitoring must include regular psychosocial, functional status and quality-of-life evaluation, as well as consistent assessment of therapeutic goal attainment and necessary dosage adjustments based on the patient's progress. CONCLUSION: Through comprehensive and serial monitoring, ultimately, a therapeutic dose of enzyme therapy that achieves sustained benefits can be found for each child with non-neuronpathic Gaucher disease.

Bone Density↗
PubMed2003

Hair growth induction by the Tellurium immunomodulator AS101: association with delayed terminal differentiation of follicular keratinocytes and ras-dependent up-regulation of KGF expression.

The synthetic immunomodulator AS101[ammonium trichloro(dioxoethylene-o,o')tellurate] was previously found to protect cancer patients from chemotherapy-induced bone marrow toxicity and alopecia. Here we show that AS101 induces hair growth in nude and normal mice. AS101 possesses the dual ability to both induce anagen and retard spontaneous catagen in the C57BL/6 mouse model. Anagen induced by AS101 is mediated by keratinocyte growth factor (KGF), as it is abrogated both in nude mice co-treated with AS101 plus neutralizing anti KGF antibodies and in AS101-treated transgenic mice expressing a dominant-negative KGF receptor transgene in basal keratinocytes. AS101 up-regulates KGF expression by activating the ras signaling pathway in cultured fibroblasts. AS101-induced delayed catagen is associated with inhibition of terminal differentiation marker expression both in nude and C57BL/6 mice epidermal follicular keratinocytes and in cultures of primary mouse follicular keratinocytes induced to differentiate. This activity is associated with relatively sustained elevation of p21waf. Delayed expression of terminal differentiation markers was not induced by AS101 in follicular keratinocytes from p21waf knockout mice. Because similar results were obtained with cultures of primary human keratinocytes and fibroblasts, preliminary case report studies revealed substantial hair growth when AS101 was topically applied on three adolescents who had remained alopeciac 1-2 years after chemotherapy. The results emphasize the unique mode of action of AS101 and highlight its potential clinical use for treating certain types of alopecia.

Adjuvants, Immunologic↗
PubMed2003

ATM gene mutations are not involved in medulloblastoma in children.

Primitive neuroectodermal tumors (PNET)-medulloblastomas account for approximately 20% of all brain tumors in children. Ataxia-telangiectasia is an autosomal recessive neurological disorder with predisposition to cancer. The most common neoplasms are lymphoid malignancies and solid tumors, including central nervous system tumors, astrocytomas, and medulloblastomas. To investigate the potential role of the ATM gene in the pathogenesis of medulloblastoma, 13 tumors were screened for ATM mutations and 9 for loss of heterozygosity (LOH) of the ATM locus and flanking regions. In none of the tumors were mutations identified. In five of them, the well-known polymorphisms D1853N and F858L were identified and in all 22 tumors, the wild-type allele was preserved. The frequency of the polymorphisms was similar to that reported in our and other normal populations. The LOH of the 11q region (including the ATM gene), detected in 25% of informative cases, is consistent with the molecular and cytogenetic reports of deletion of chromosome 11 in 13%-41% of medulloblastomas. These results indicate that mutations in the ATM gene do not play a role in the pathogenesis of medulloblastoma in children. The LOH in the 11q region may suggest hidden unidentified tumor suppressor genes that may be involved in the malignant transformation.

Adolescent↗
PubMed2003

Epilepsy associated with pediatric brain tumors: the neuro-oncologic perspective.

The aim of the study was to correlate the onset of epilepsy with the disease stage in children with brain tumors through treatment and follow-up in the oncologic department. The study sample consisted of a heterogenous group of 219 children who were aged 6 months to 11 years, manifested brain tumors, and had been treated and monitored in the Department of Pediatric Oncology of the Schneider Children's Medical Center of Israel since 1991. The overall rate of epilepsy was 14.6%, which rose to 38% in those with cortical tumors. Two major causes of epilepsy were evident: tumor-related and treatment-related. The first group could be further divided into epilepsy starting at or before diagnosis of brain tumor, epilepsy associated with tumor progression, and epilepsy starting at end-stage disease. The second group could be divided into epilepsy caused by radiation damage to the brain and epilepsy related to another postoperative state. The data emphasize the significance of striving for complete tumor resection and the potential damage from the use of radiotherapy to the brain. The authors suggest that a change in local neurotransmitter balance may be the mechanism underlying tumor-related epilepsy.

Adolescent↗