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Biomedical subjects

I J Cohen

Publications and source records attributed to I J Cohen.

At least 19 recordsLinked to original sources
PubMed1999

Anaphylactoid reaction to imiglucerase, but not to alglucerase, in a type I Gaucher patient.

Imiglucerase, the recombinantly produced enzyme, is gradually replacing the human placental derived alglucerase in the treatment of gaucher patients. We describe the first case, to the best of our knowledge, of an anaphylactoid reaction to imiglucerase in a patient who tolerated alglucerase. The patient was diagnosed at the age of 2 4/12 years with anemia and hepatosplenomegaly. Over the years he had suffered from marked splenomegaly, thrombocytopenia and recurrent bleeding episodes. At the age of 24 he started treatment with imiglucerase. After 3 months of treatment, immediately after starting an infusion, he experienced flushing, cough, tachycardia, palpitation, chest pain and excessive sweating, which reoccurred on a consecutive administration. Substitution with alglucerase was tolerated well, with only mild rash when he was premedicated with benadryl. Immediate skin tests to alglucerase, imiglucerase and gelatin were negative. IgG against alglucerase was undetectable. The in vitro mast cell degranulation test was positive for alglucerase, imiglucerase heamaccel (a gelatin based plasma substitute, which is a component of imiglucerase). This sensitivity to imiglucerase but not to alglucerase, raises the question of future treatment for this patient, since the production of alglucerase may cease, once imiglucerase production will cover the need for replacement enzyme.

Adult↗
PubMed1999

Involvement of the foot and ankle in patients with Gaucher disease.

Of 48 children with type I Gaucher disease treated at our hospital, 11 had involvement of the foot and ankle that first appeared in adolescence. Follow-up ranged from 3 to 27 years (average, 10 years). We reviewed their clinical and radiographic histories. Patients presented with four types of pain: six (7 events of pain) complained of dull pain defined as nonspecific; seven (11 events) had severe pain caused by bone crisis; two (2 events) had moderate progressive pain caused by pathological fractures; and one had painful swollen ankles caused by degenerative arthritis. Greater awareness of these complications in patients with Gaucher disease will prevent misdiagnosis and lead to early treatment.

Adolescent↗
PubMed1999

Prognostic factors in non-metastatic limb osteosarcoma: A 20-year experience of one center.

The purpose of this study was to evaluate the prognostic significance of variables in osteosarcoma. We performed a retrospective analysis of 35 patients with non-metastatic limb osteosarcoma that were treated between 1973 and 1994. The following variables were evaluated: age, sex, ethnic group, tumor histology and primary site, alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) levels at diagnosis, treatment regimen, and the histologic response to treatment. Three variables showed significant correlation with prognosis: i) histologic response to preoperative treatment. Disease-free survival (DFS) was 89% in patients with grade III-IV histologic response after a median follow-up (MFU) of 64 months, 67% in patients with grade II after an MFU of 64 months, the patients with grade I response died within 15 months (p<0.0001); ii) treatment regimen. DFS was 83% after an MFU of 42 months, 62% after an MFU of 82 months, and 30% after an MFU of 177 months in patients treated by the 90's, 80's, and 70's protocols, respectively (p<0.05); iii) corrected ALP (cALP) levels at diagnosis. DFS was 78% after an MFU of 88 months in patients with cALP levels <200, and 32% after an MFU of 56 months in patients with cALP levels >200 (p=0.01). Low ALP levels, good histologic response to preoperative chemotherapy, and the new therapeutic regimen correlated with good prognosis in patients with osteosarcoma.

Adolescent↗
PubMed1998

Mutations of the adenomatous polyposis coli and p53 genes in a child with Turcot's syndrome.

Turcot's syndrome is a rare heritable complex that is characterized by an association between a primary neuroepithelial tumor of the central nervous system and multiple colonic polyps. The aim of this study was to analyze genetic alterations in a case of Turcot's syndrome in a 10.5-year-old boy in whom a colorectal tumor developed 3.5 years following astrocytoma. An APC germline non-sense mutation at codon 1284 leading to a truncated protein was identified, as was a somatic p53 mutation in the colorectal carcinoma in exon 7, codon 244. The latter was not identified in the primary astrocytoma. However, immunohistochemistry revealed high p53 protein expression in both tumors, suggesting an additional p53 mutation in the primary astrocytic tumor. The diverse p53 mutations observed in this unique syndrome in two different sites and stages of the disease may shed light on the multistep progression of the malignant events.

Adenomatous Polyposis Coli↗
PubMed1998

Linkage disequilibrium of common Gaucher disease mutations with a polymorphic site in the pyruvate kinase (PKLR) gene.

Gaucher disease (GD), caused by a deficiency of the lysosomal enzyme glucocerebrosidase (GBA), is the most common human glycolipid storage disease. The incidence of the disease is particularly high in the Ashkenazi Jewish population, with a carrier frequency of 0.068. The 1226A-->G and 84GG mutations are the two predominant disease-causing alleles. We investigated the association of various mutations in the GBA gene with different alleles of a highly polymorphic site in the adjacent pyruvate kinase (PKLR) gene. Ninety-seven unrelated type I GD patients of various genotypes were studied to determine their genotype for the PKLR gene trinucleotide repeat polymorphism. One hundred out of 104 (96%) alleles carrying the 1226G mutation also carried the A1 allele of the PKLR gene, which is present in only 6.7% of the control population. The calculated linkage disequilibrium between 1226G and the A1 allele of the PKLR gene is 0.957. Mutation 84GG was found to be uniquely associated with the PKLR A6 allele, with a linkage disequilibrium of 1.00. The association of several less frequent GD mutations with PKLR alleles was also studied. These results support the hypothesis that the 1226G and 84GG mutations in the Ashkenazi Jewish population each originated in a single founder. Further studies of the association of the 1226G and 84GG mutations with PKLR alleles in European non-Jewish GD patients could help in the study of the chronological order of these mutations and may shed light on the history of the Ashkenazi Jews in the past two millennia.

Alleles↗
PubMed1998

Low-dose high-frequency enzyme replacement therapy prevents fractures without complete suppression of painful bone crises in patients with severe juvenile onset type I Gaucher disease.

Patients with type I Gaucher disease often present as adults with a mild disease and with less severe genetic mutations, especially 1226G/1226G (N370S/N370S). Patients presenting as children have an excess of compound heterozygotes of N370S and other mutations, such as 84GG, 1448C (L444P) and IVS2 + 1 in whom bone disease is common. We report our experience with low-dose high-frequency enzyme replacement therapy in such severely affected children. Ten patients (with severe juvenile onset type I Gaucher disease) were treated. Alglucerase (Ceredase) was infused at 30 units/kg/month in 13 fractions/month for more than one year. Bone disease was used as the main criterion for evaluating treatment results. No fractures occurred in spite of the fact that bone crises occurred in four patients after 12 to 24 months of treatment, in two during the third year, and in one during the fifth year. Nonosseous manifestations improved with treatment. The ability of low-dose high frequency alglucerase to prevent fractures in the presence of continuing bone crises was demonstrated.

Adolescent↗
PubMed1998

Splenic "regeneration" after partial splenectomy for Gaucher disease: histological features.

Partial splenectomy for Gaucher disease is often followed by reenlargement of the splenic remnant. It remains unclear if this process is due to tissue regeneration or to continued deposition of glucocerebroside in the reticuloendothelial system or both. We compared the splenic architecture before and after reenlargement in three cases of failed repeated partial splenectomy after two, six and five years. Using the number of lymphoid follicles per hundred low power fields (LF/LPF) as an arbitrary index, we found that prior to the first operation 18, 20 and 27 lymphoid follicles were present per one hundred low power fields, while at the second operation, the corresponding rates were 11, 15 and 17; in control spleens, an average of 712.5 lymphoid follicles were present in one hundred low power fields. The difference in the LF/LPF ratio before and after reenlargement, led us to speculate that splenic re-enlargement in Gaucher disease is mainly the result of the continued deposition of the glucocerebroside in the reticuloendothelial system of the splenic remnant, though some degree of true regeneration as well cannot be completely ruled out. These findings are compared with animal studies and results for partial splenectomy on humans, performed for trauma. Further studies in patients with Gaucher disease are warranted to better define the underlying mechanism of splenic reenlargement.

Adolescent↗
PubMed1998

Diffuse brain stem gliomas. Are we improving outcome?

We reviewed our experience with diffuse brain stem glioma (dBSG) to evaluate whether any improvement of outcome had occurred in our patients over the years. Of the 24 children referred to our department with suspected dBSG from 1981 to 1997, 5 had a different final diagnosis based on the clinical course. Mean survival in the remainder was 16+/-9.8 months from diagnosis. Survival increased with a longer interval from onset of symptoms to diagnosis (12.9+/-9.0 months with an interval of 1-4 weeks; 19.50+/-10.8 months with a longer interval). Visual symptoms at presentation were associated with a poorer prognosis. Survival was better in the 3- to 5-year age group (at diagnosis). Overall, a trend toward a slight improvement in survival was seen over the years, which we presumptively attribute to the introduction of intensive chemotherapy for these patients. We suggest that chemotherapy may be important in the management of dBSG until a better modality is found.

Adolescent↗
PubMed1998

Molecular analysis of childhood acute lymphoblastic leukemia in Israel.

Ninety-two Israeli children with acute lymphoblastic leukemia (ALL) (67 B-lineage and 25 T-lineage) were analyzed for the immunological antigen receptor gene configuration. Thirty-nine of the patients (27 B-lineage and 12 T-lineage) relapsed. The incidence of the identified rearrangements within the immunoglobulin heavy chain (IgH) and T-cell receptor (TCR)beta, gamma and delta genes, at diagnosis, was in accordance with previous studies from other countries. Furthermore, the clinical relevance of bi/oligoclonal status, at diagnosis, and clonal selection was determined in this long-term follow-up study (median 112 months). A similar relapse rate was observed among the B-lineage patients with bi/oligoclonal and monoclonal patterns indicated by IgH gene rearrangement. Based on our results, we suggest that bi/oligoclonality has no prognostic significance (P=0.8533). Clonal variations between diagnosis and subsequent relapses were detected in 60% (12/20) of the patients; 64% (7/11) B-lineage and 55% (5/9) T-lineage. Clonal selection significantly correlated with shorter duration of remission and earlier recurrence (P=0.0025).

Adolescent↗
PubMed1998

A novel germ-line mutation in the noncoding region of the p53 gene in a Li-Fraumeni family.

We identified a novel germ-line p53 mutation in the noncoding, nonsplicing regions of a Li-Fraumeni family. Patients belonging to this family included pediatric medulloblastoma and rhabdomyosarcoma patients and a breast carcinoma patient. Three positions in the p53 gene were analyzed for loss of heterozygosity (LOH). One of the three loci retained heterozygosity, whereas the other two exhibited LOH. Sequence analysis of the third locus identified a change of 5'-CCGGGTGA-3' to 5'-CCAGGTTGGA-3', 63 bp downstream of exon 6. The mutation was identified in the germ line of the two pediatric patients and in each of the related parents. We excluded any additional mutation in the entire coding region of the p53 gene, including splice-site intronic sequences. Strong positive nuclear staining of the p53 protein was detected in both normal and tumor paraffin-embedded tissues. Eighty-five normal persons were negative for this alteration, which thus supports it as a mutation. These results may indicate that genetic changes within the noncoding region of the p53 gene may serve as an alternative mechanism of activating this gene. Mutations in the noncoding region of this gene should be further studied.

Adolescent↗
PubMed1998

Metastatic brain involvement in Ewing family of tumors in children.

OBJECTIVE: To evaluate the incidence and clinical characteristics of CNS involvement in Ewing family of tumors (EF) in children. METHODS: Chart reviews of children with EF treated in our center from 1972 to 1997. Clinical and imaging data regarding possible CNS involvement were collected. RESULTS: During this 25-year period, 80 children with EF were treated. Intracranial involvement was found in eight (10%) children: the brain was involved in seven children (8.8%) and a retro-orbital metastasis without parenchymal brain involvement was noted in one child. Metastases were localized intrahemispherically, or in the cerebellum or the basal ganglia. Intracranial spread was hematogenous in five children and by contiguous spread from the skull in three children. Intracranial involvement was diagnosed 1.3 to 11 years from initial presentation. Seizures and hemiparesis were the main neurologic complications. CONCLUSIONS: The rate of parenchymal brain involvement in our patients with EF was 8.8%. Spread was mainly hematogenous. Substantial morbidity was associated with CNS disease, which appeared in most patients late in the course of disease.

Adolescent↗
PubMed1997

p53 mutation as the second event in juvenile chronic myelogenous leukemia in a patient with neurofibromatosis type 1.

BACKGROUND: Young patients with neurofibromatosis type 1 (NF1) are at increased risk of developing various malignancies, most of which are myeloid disorders. The observed loss of NF1 allele in the myeloid malignancies of NF1 patients suggests a role of NF1 as a tumor suppressor gene. Loss of 17p was found to be quite frequent in neural crest tumors from patients with NF1, raising the possibility of p53 tumor suppressor gene involvement in other NF1-related tumors. METHODS: The authors studied mutations in the NF1 and p53 genes, using loss of heterozygosity, single strand conformation polymorphism, heteroduplex and sequencing analyses. RESULTS: An NF1 germline mutation was identified in exon 31 of a child who developed juvenile chronic myelogenous leukemia (JCML). The mutation was segregated within the proband's family. A 14bp deletion at exon 6 of the p53 gene was observed when JCML was diagnosed, and the wild-type p53 allele was lost during progression of the disease. No loss of the normal NF1 allele could be detected. CONCLUSIONS: A germline mutation in the NF1 gene and sequential inactivation of p53 alleles in the malignant clone of JCML raise the possibility of a correlation between NF1 and p53 genes in the tumorigenesis of JCML.

Child, Preschool↗
PubMed1997

A novel germ line p53 mutation in intron 6 in diverse childhood malignancies.

Screening for p53 mutations in exons 5 to 8 in 124 pediatric malignancies identified 18 abnormal shifts using single strand conformation polymorphism: 12 were missense mutations and in 6, no mutation was detected in the exon or in the splice donor acceptor sequences. Sequencing was then performed in the adjacent introns, revealing a G to A base substitution at 39 base pairs upstream to exon 7. This mutation was identified in the germ line of five of the patients, and also in the father of one, whose parents were available. For comparison, of the 184 normal controls similarly screened, only one had this mutation (P=0.036). Positive staining of p53 protein was observed in three of the paraffin embedded tissues that were available: brain tumor, rhabdomyosarcoma, and lymphocytes from a normal lymph node from the rhabdomyosarcoma patient. All tumors with the identified intron mutation were Li-Fraumeni syndrome tumors. Sequencing of all exons including splice sites was performed and revealed no mutation. We suggest that this mutation in intron 6 of the p53 gene stabilizes the wild type p53 protein, resulting in its abnormal accumulation. Mutations in the noncoding region of p53 should be further studied.

Brain Neoplasms↗
PubMed1997

Cure of recurrent medulloblastoma: the contribution of surgical resection at relapse.

BACKGROUND: Recurrent medulloblastoma has long been considered universally fatal. In spite of attempts to improve its treatment, only rarely have long term survivors been documented in the world's medical literature. Although the treatment of primary medulloblastoma is well established and includes surgical excision, postsurgical irradiation, and, more recently, chemotherapy, there is no established treatment for its recurrence. Current guidelines dictate the experimental use of chemotherapy, and there have been some encouraging results; yet no increase in long term survival has been documented. METHODS: This article presents a case of cured recurrent medulloblastoma in which the only intervention at the time of recurrence was surgical excision. In addition, a review of the literature is presented, which evaluates chemotherapeutic trials involving cases of recurrent medulloblastoma. RESULTS: The authors were surprised to find that the longest survivors of multiple trials had undergone reoperation at the time of recurrence. The authors' case, as well as cases described in the literature, point to a valid treatment alternative largely ignored in the management of recurrent medulloblastoma. CONCLUSIONS: Reoperation of recurrent brain tumors has received surprisingly little attention in the medical literature. Yet, as this case and a review of the literature demonstrate, this is a useful intervention.

Antineoplastic Combined Chemotherapy Protocols↗