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Josephine Issakov

Publications and source records attributed to Josephine Issakov.

At least 19 recordsLinked to original sources
PubMed2006

Novel genes implicated in embryonal, alveolar, and pleomorphic rhabdomyosarcoma: a cytogenetic and molecular analysis of primary tumors.

Rhabdomyosarcoma, the most common pediatric soft tissue sarcoma, likely results from deregulation of the skeletal myogenesis program. Although associations between PAX3, PAX7, FOXO1A, and RMS tumorigenesis are well recognized, the entire spectrum of genetic factors underlying RMS development and progression is unclear. Using a combined approach of spectral karyotyping, array-based comparative genomic hybridization (CGH), and expression analysis, we examined 10 primary RMS tumors, including embryonal, alveolar, and the rare adult pleomorphic variant, to explore the involvement of different genes and genetic pathways in RMS tumorigenesis. A complete karyotype established for each tumor revealed a high aneuploidy level, mostly tetraploidy, with double minutes and additional structural aberrations. Quantitative expression analysis detected the overexpression of the AURKA gene in all tumors tested, suggesting a role for this mitotic regulator in the aneuploidy and chromosomal instability observed in RMS. Array-based CGH analysis in primary RMS tumors detected copy number changes of genes involved in multiple genetic pathways, including transcription factors such as MYC-related gene from lung cancer and the cytoskeleton and cell adhesion-encoding genes laminin gamma-2 and p21-activated kinase-1. Our data suggest the involvement of genes encoding cell adhesion, cytoskeletal signaling, and transcriptional and cell cycle components in RMS tumorigenesis.

Adolescent↗
PubMed2005

Limb sparing approach: adjuvant radiation therapy in adults with intermediate or high-grade limb soft tissue sarcoma.

BACKGROUND: Limb soft tissue sarcomas (STS) are currently treated with limb sparing surgery (LSS) followed by radiation therapy (RT). PATIENTS AND METHODS: Between October 1994 and October 2002, 133 adult patients with intermediate or high-grade limb STS were approached by LSS+RT. RESULTS: RT related toxicity was manageable, with a low rate of severe effects. At 4-year median follow-up, there were 48 recurrences of any type, 23 of isolated local failure, and 35 of systemic spread w/o local failure. DFS and OS were influenced by disease stage II vs I, primary site in the upper limb vs lower limb, MPNST vs other types, induction therapy vs no induction, adequate resection vs marginal resection or involved margins, and good response to induction therapy vs bad response. DFS and OS were Patient's age and sex, tumor depth, acute or late toxicity of RT, or the interval of time between the date of definitive surgery and the start of RT did not affect DFS and or OS. CONCLUSIONS: The RT protocol is applicable in the era of complicated, expensive and time-consuming 3D therapy. Our results of LSS+RT in adults with limb HG STS are satisfactory.

Adolescent↗
PubMed2005

A single-team experience of limb sparing approach in adults with high-grade malignant fibrous histiocytoma.

Malignant fibrous histiocytoma (MFH) is the most common subtype of soft-tissue sarcoma (STS). When located in a limb, MFH, is currently treated with limb sparing surgery (LSS) followed by radiation therapy (RT). During 8 years, 42 adult patients with high-grade limb MFH were approached by LSS and RT. Our results reflect a single-team experience and point to several important conclusions. High grade MFH, treated by conservative approach, lead to a 10-year relapse-free survival of 62% and a 10-year overall survival rate of 80%. Recurrences of MFH tend to occur during the first 2 years. Relapse-free survival was affected mainly by location in the lower limb vs. the upper limb, irrespective of the tumor size. Patients who had their diagnostic biopsies in another medical center had a greater tendency to local and systemic relapse. It seems that the most important clues for disease-free survival are the team experience and cooperation. All other factors are tumor-biology dependent, and thus far are beyond our control.

Adult↗
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

Radiotherapy for spinal cord compression in patients with soft-tissue sarcoma.

PURPOSE: Spinal metastases of soft-tissue sarcoma (STS) occur rarely and pose a therapeutic problem. Although wide resection is warranted for best local control, it is rarely feasible. A radiotherapy (RT) dose of 70 Gy is usually needed to treat limb STS, but only 45 Gy can be given to the spine. In the present series, we report our experience using RT to treat spinal cord compression (SpCC) associated with STS. METHODS AND MATERIALS: The medical files of 19 adult patients with STS and SpCC were reviewed. RT was considered in all the cases, together with steroids and analgesics. The prescribed dose was 30 Gy in 10 fractions within 12 days. The effect of treatment was evaluated on a clinical basis. RESULTS: Twenty-three events of SpCC were found. The prevailing symptom was pain. The Karnofsky performance status was 40-70% at presentation. RT was given in all but 1 patient and surgical decompression in 3. Small, but important, improvements in signs and Karnofsky performance status were noted in 14 of 23 cases of SpCC, expressed mainly by pain alleviation and restoration of independence. The median survival after the diagnosis of SpCC was 5 months. CONCLUSION: Radiotherapy is an important tool in palliating SpCC in patients with STS.

Adult↗
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↗
PubMed2003

Presacral tumors: a practical classification and treatment of a unique and heterogeneous group of diseases.

BACKGROUND: Presacral tumors are a rare and diverse group of diseases that originate from the different tissues that comprise the potential presacral space. Because of their relative rarity, confusion exists regarding their clinical presentation, natural history, and treatment. The aim of this study is to describe a single institution's experience with the management of presacral tumors and to suggest a practical method of classification. METHODS: Records of all patients who underwent operation for presacral tumors from the years 1991 to 2001 were reviewed. Clinical, pathologic, treatment, and outcome variables were evaluated. RESULTS: Forty-two patients were included in the study and were divided into 4 groups according to lesion pathology: benign congenital (n = 12), malignant congenital (n = 9), benign acquired (n = 9), and malignant acquired (n = 12). Symptoms were nonspecific, and 26% of the cases were completely asymptomatic. Diagnosis was made with rectal examination and confirmed with pelvic computerized tomographic scan. Surgical approach varied among the different groups, with the posterior approach used mainly for congenital tumors and the anterior approach for acquired. Complete surgical resection of the tumor was obtained in all cases of benign tumors and in 76% of malignant tumors. No postoperative mortality was seen, and complications occurred in 36% (15/42); most were reversible. None of the patients with benign tumors had recurrences, and all are alive at this time. The survival rate of patients with malignant tumors was significantly improved when complete resection was possible. CONCLUSION: Classification of presacral tumors into congenital versus acquired and benign versus malignant is simple and efficient. Treatment is complete surgical resection, which can be performed safely with low morbidity and no mortality.

Adult↗
PubMed2003

Atypical mycobacterial granulomatous epiphyseal osteomyelitis in an immunocompetent child.

Osteomyelitis caused by atypical mycobacteria is rare in children. The majority of affected patients have had some kind of predisposing factor, namely a penetrating injury or surgery, or were immune-compromised. Our experience shows that this diagnosis should be considered in apparently healthy children as well. The use of polymerase chain reaction has now made it possible to identify the pathogen in cases that were previously diagnosed as granulomatous osteomyelitis. We present a case of atypical mycobacterial osteomyelitis affecting the distal femoral epiphysis in an immunocompetent 10-year-old child. The diagnosis in this case was made by the use of the polymerase chain reaction assay.

Antitubercular Agents↗
PubMed2003

Computed tomography-guided core needle biopsy for bone and soft tissue tumors.

BACKGROUND: Imaging-guided core needle biopsy is a well-established technique for the diagnosis of bone and soft tissue tumors and tumor-like lesions in specialized orthopedic oncology centers. OBJECTIVE: To present our results of computed tomography-guided core needle biopsy with assessment of the accuracy of the technique. METHODS: Between July 1998 and October 2000, 215 CT-guided core needle biopsies were performed and histologically examined in the Unit of Bone and Soft Tissue Pathology, Tel Aviv Sourasky Medical Center. There were 80 soft tissue and 135 bony lesions. All biopsies were performed by the same radiologist and the histologic examination by the same pathologist. To assess the accuracy of the procedure, we compared the diagnosis at biopsy with the diagnosis after definitive surgery (when available). RESULTS: Bone core needle biopsy (n = 135) showed malignancy in 89 cases (primary or recurrent bone sarcoma, lymphoma, myeloma, metastatic carcinoma or melanoma). There were 29 benign lesions. In 17 cases the result was inconclusive and an open incisional biopsy was performed. Of the 80 soft tissue biopsies, 35 were malignant (25 soft tissue sarcomas, 6 lymphomas, 4 metastatic carcinomas); 40 were benign (myositis ossificans, neurofibroma, desmoid tumor, schwannoma, hematoma and others), and 5 were inconclusive and followed by an open incisional biopsy. The core needle biopsy histologic diagnosis was compared with that of the definitive surgery and the diagnostic accuracy was 90%. Only three samples initially diagnosed as benign turned out to be malignant. No significant complications occurred during the procedures. CONCLUSIONS: CT-guided CNB of musculoskeletal lesions is a safe and effective procedure that assures sufficient and proper material for histologic examination. The accuracy of this method in our center was 90%. Tumor sampling is extremely important, especially in soft tissue sarcomas, and cores should be taken in different directions, including areas of necrosis. The processing is quick, especially for bone CNB, and diagnosis can be achieved within 24 hours. The material undergoes excellent fixation and the immunostains are reliable.

Biopsy, Needle↗
PubMed2003

Gestation-related malignant musculoskeletal tumors.

BACKGROUND: The incidence of malignant musculoskeletal tumors during pregnancy is very low. The paucity of data precludes the drawing of solid conclusions regarding a standard approach. OBJECTIVES: To summarize our experience treating 13 pregnant women with malignant soft tissue or bone tumors. METHODS: We conducted a retrospective analysis of 13 cases of patients with either soft tissue or bone sarcoma that developed or progressed during pregnancy or immediately after delivery. RESULTS: The clinical presentation of the tumors was a growing mass and/or increasing pain and disability. Most of the masses were located in the lower part of the body and were of considerable size. Treatment given during gestation was limited to wide excision of the mass in the 28th week of gestation in one patient. All the patients reported disease progression during gestation. Vaginal delivery was possible in eight patients with no complications, cesarean section was carried out in three women, spontaneous miscarriage occurred in one and termination of pregnancy was performed in one patient. CONCLUSIONS: The diagnostic and therapeutic approaches should be tailored specifically in every pregnant woman in whom sarcoma is suspected.

Adult↗
PubMed2002

Aggressive resection of retroperitoneal sarcoma is superior to simple excision: an animal study using a novel model for retroperitoneal sarcoma.

BACKGROUND AND OBJECTIVES: Retroperitoneal sarcomas constitute a difficult management problem. The need for, and extent of, aggressive surgery continues to be debated. The aim of our study was to compare the impact of radical en bloc resection of retroperitoneal sarcoma with complete resection of the tumor alone in a rat model. METHODS: Under laparoscopic guidance, a fibrosarcoma cell line suspension was injected into the left paranephric space of a rat, resulting in the development of a macroscopic retroperitoneal tumor. Ten days after inoculation, 50 rats were randomized into three groups: (1) local resection, (2) radical resection, and (3) follow-up only. Groups 1 and 2 were further randomized for sacrifice 1 month after surgery or were followed up for 2 months. RESULTS: Local recurrence: 46% of group 1, while none in group 2 developed local recurrence during the same follow-up period (P = 0.02). Survival: 33% of group 1 were alive after 2 months, as compared with 54.5% of group 2. (P = 0.04). All rats in the control group died within <25 days. CONCLUSIONS: Our results suggest that aggressive en bloc resection of retroperitoneal sarcomas with adjacent viscera, even when macroscopically uninvolved with disease, has an advantage over complete local resection alone.

Animals↗
PubMed2002

Expression of p53 gene product and cell proliferation marker Ki-67 in Ewing's sarcoma: correlation with clinical outcome.

Overexpression of tumor suppressor gene p53, cell proliferation nuclear antigen Ki-67, and proto-oncogene HER-2/neu are associated with poor prognosis in some tumors. We studied p53, Ki-67, and HER-2/neu immunohistochemical expression in archival biopsies of 37 patients with Ewing's sarcoma (ES). Patients with ES were treated at four Israeli hospitals between 1982 and 2000. Formalin-fixed paraffin-embedded tissue sections were stained by immunohistochemistry for p53, Ki-67, and HER-2/neu. More than 300 cells were counted on each slide, and the percentage of positively stained nuclei was computed. p53 overexpression was defined as nuclear staining of >2.3% of cells, Ki-67 overexpression as nuclear staining of >8.3% malignant cells. HER-2/neu staining was scored semiquantitatively on a scale of 0 to 4+. Twenty-two of 37 patients are alive and well, with mean follow-up time of 38 months. There was overexpression of p53 in 16 patients (43%) and of Ki-67 in 21 patients (57%). The correlation between p53 and Ki-67 overexpressions was 0.61. We found no overexpression of HER-2/neu. Median relapse-free survival (RFS) was statistically significantly shorter for patients with p53 overexpression (25 months) than for patients with negative staining (>92 months). The prognostic value of p53 overexpression was also significant after adjusting for tumor location and age. Median RFS was shorter for patients with positive Ki-67 staining (40 months) than for patients with negative staining (80 months) but did not reach statistical significance. Our study suggests that p53 is a predictor of RFS in patients with ES. More patients must be studied to assess the validity of this observation.

Adolescent↗
PubMed2002

Lack of ErbB-2 oncogene product overexpression in soft tissue sarcomas.

The c-erbB-2 gene and its products (also designated HER-2 and c-neu) encode for a 185-kd transmembrane glycoprotein with intracellular tyrosine kinase activity. c-erbB-2 belongs to the epidermal growth factor receptor family, of which there are four known members, and has molecular homology to the epidermal growth factor receptor. It seems that this family is critical in control of growth, differentiation, and mobility of many normal and transformed epithelial cell types. We have looked for overexpression of c-erbB-2 gene product in paraffin-embedded material from 230 cases of soft tissue sarcoma, in order to establish a possible new prognostic marker and a potentially new treatment option. In all the cases, irrespective of the sarcoma histological type, the immunostaining for erbB-2 was negative. Applications of erbB-2 for prognostication as well as the option of receptor targeting by trastuzumab monoclonal antibodies were aborted.

Adolescent↗
PubMed2001

Localization of a specific germ cell marker, DAZL1, in testicular germ cell neoplasias.

DAZ-like 1( DAZL1) is a germ cell-specific protein expressed in both male and female gonads. The DAZL1 gene, which maps to chromosome 3 in humans, is an autosomal homologue to the Deleted in AZoospermia ( DAZ) gene(s) located on the Y chromosome. We studied the expression of DAZL1 by means of immunohistochemistry in order to determine its distribution among testicular germ cell neoplasias and among the intratubular lesions in their vicinity. Our results demonstrated that expression of DAZL1 protein was consistently observed in scattered cells in all intratubular germ cell neoplasias (IGCN) of the unclassified type, as well as in some of the intratubular seminomas. Foci of DAZL1 immunopositive cells were detected in pure seminomas, while single immunopositive cells were dispersed in the seminomatous component of mixed germ cell neoplasias. All the nonseminomatous components were negative for DAZL1 expression. These findings demonstrate an antigenic heterogeneity of seminoma cells. The localization of a specific germ cell protein, DAZL1, in the putative ontogenic progenitor, IGCN, and in their putative derivative, seminoma, provides further support for the hypothesis that IGCN is the precursor of germ cell neoplasias.

Adult↗
PubMedDate not supplied

Sarcoma and thyroid disorders: a common etiology?

We have recently observed that many of our sarcoma patients presented also with thyroid disorders. Literature data are almost unavailable on this topic. The relationship between the sarcoma and thyroid disorders is examined. Retrospective analysis of files of patients with sarcoma and clinically overt thyroid disorders was carried out. Of the 375 patients with soft tissue sarcomas (STS) and 235 with bone sarcoma (BS) including small blue round cell tumors (SBRC), 28 patients (4.6%) had an associated significant thyroid disorder. The types of sarcoma were mainly liposarcoma followed by malignant fibrous histiocytoma, leiomyosarcoma and bone sarcoma. The primary sites were mainly limb and trunk. The interval between the diagnosis of the thyroid disorder and the sarcoma varied between -14 years (thyroid first) and +16.5 years (thyroid later) with a median of -0.2 years. Thyroid disorders included goiter, thyroiditis and carcinoma. There are both basic-science and clinical evidence to a possible common pathway that leads to the association between overt thyroid disorders and sarcomas of bone or soft tissues. Oncogene erbA activity is related to thyroid receptors to T3 and to development of sarcoma. Cross talk of the sarcoma oncogene and the erbA might contribute to the development of sarcoma. The thyroid hormone receptor and the highly related viral oncoprotein v-erbA are found exclusively in the nucleus as stable constituents of chromatin. It has been shown that v-erbA can block the spontaneous differentiation in erythroid cells transformed by various retroviral oncogenes. V-erbA can alter the spectrum of neoplasia induced by the v-src oncogene, which causes predominantly sarcomas and erythroblastosis in chicks. The erbA can cooperate with other oncogenes such as v-erbB or with v-fms, v-ras, and c-kit. Cooperation with v-myc may play a role in the development of rhabdomyosarcoma especially in thyroid hormone deficiency state. The possible clinical implications are the need to screen patients with sarcoma to thyroid disorders, and patients with thyroid disorders for malignant diseases.

Adult↗