Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We assessed diagnostic criteria among 38 spindle cell tumors of the urinary bladder and obtained follow-up in 36 patients. Patients comprised 28 males and 10 females aged 2.5 months to 87 years. Hematuria was the commonest presenting symptom (27 patients). After review and immunohistochemical workup, 17 patients had inflammatory pseudotumor (myofibroblastic tumor), 4 postoperative spindle cell nodule, 1 leiomyoma, 13 sarcoma (7 low-grade; 6 high-grade), and 3 carcinoma. Mean age was 38 years for pseudotumor (range 15 to 74), 65 for postoperative spindle cell nodule, 51 for sarcoma, and 76 for carcinoma. Size of pseudotumor averaged 4.4 +/- 0.7 cm (range 1.5 to 13.0), similar to sarcoma, 4.0 +/- 0.6 cm (range 0.5 to 7.0). Similar proportions of benign tumors and sarcomas had muscularis propria invasion. The criteria that best differentiated sarcoma from inflammatory pseudotumor were presence of necrosis at the tumor-detrusor muscle interface in muscle-invasive cases, and nuclear atypia. Sarcoma also had less prominent microvasculature, less variable cellularity, consistently > or =1 mitotic figure per 10 high-power fields, and predominant acute inflammation without plasma cells. p53 protein nuclear immunostaining was moderate, unlike the rare to absent staining in pseudotumors. Because all 12 sarcomas were desmin-negative, we did not call them leiomyosarcoma; they overlapped with benign tumor in epithelial, mesenchymal, and actin immunostaining. Among 12 sarcoma patients, 2 died of tumor (at 3 months). Two of four experienced tumor recurrence after partial cystectomy (2 and 26 months). No pseudotumors recurred after transurethral resection or partial cystectomy, although one patient, 5 months after transurethral resection, had histologically identical pseudotumor that the surgeon considered residual. Another patient with pseudotumor, not a candidate for tumor ablation after transurethral resection, had continued tumor growth and he died of urosepsis. In conclusion, inflammatory pseudotumor, although overlapping with sarcoma in presentation, age range, and size, does not metastasize and remains histologically distinct from low-grade sarcoma.
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PMID:Inflammatory pseudotumor and sarcoma of urinary bladder: differential diagnosis and outcome in thirty-eight spindle cell neoplasms. 1159 76

ONYX-015 is a provisionally replication competent adenovirus with oncolytic activity in cells with malfunctioning p53. Sarcomas represent a rational target for this approach given the high frequency of p53 mutations (40-75%) and MDM-2 amplification (10-30%). We, therefore, undertook a phase I/II study of ONYX-015, days 1-5 every month administered intratumorally under radiographic guidance, in combination with MAP (mitomycin-C, doxorubicin, cisplatin) chemotherapy in patients with advanced sarcoma. Six patients were treated. Injected lesions included liver metastases in four patients and chest wall metastases in two patients. Sarcoma histologies were gastrointestinal stromal tumors (GIST, two patients), leiomyosarcoma (two patients), liposarcoma (one patient), and malignant peripheral nerve sheath tumor (1 patient). Dose escalation was performed from 10(9) plaque forming units (PFU)/dose (total dose of 5 x 10(9) PFU/cycle) to 10(10) PFU/dose (total dose of 5 x 10(10) PFU/cycle) without dose-limiting toxicity being encountered. Immunohistochemistry of the metastatic lesions prior to treatment showed that five out of six patients were positive for p53, while two patients also had mdm-2 overexpression. Adenoviral replication was detected in two out of six patient biopsies on day 5 of the first cycle, by in situ hybridization (ISH). Both patients were treated at the highest dose level. ONYX-015 viral DNA was detected by quantitative PCR in the plasma of 5/6 patients on day 5 of the first cycle, and up to day 12 (7 days after the last viral dose) in one patient who had extended sampling for viral kinetics performed, suggesting viral replication in sarcoma tissue. One patient with p53 mutation and MDM-2 amplification achieved a partial response to treatment that lasted 11 months. In conclusion, intratumoral administration of ONYX-015 in combination with MAP chemotherapy is well tolerated with no significant toxicity due to ONYX-015 being encountered. Detection of viral DNA in post treatment tumor specimens by ISH and detection of the ONYX-015 genome in the peripheral blood by quantitative PCR, up to 7 days after the last viral dose provide evidence for adenoviral replication. There was evidence of antitumor activity in one out of six patients. Further investigation of this approach in patients with recurrent sarcomas is warranted.
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PMID:Phase I-II trial of ONYX-015 in combination with MAP chemotherapy in patients with advanced sarcomas. 1564 67

Purpose. MDM2 is an oncogene whose protein product may promote tumorigenesis by blocking wild-type p53 tumor suppressor mediated G (0)/G(1) cell cycle arrest, thereby inhibiting repair of damaged DNA prior to cell division. While MDM2 DNA amplification is frequently observed in human sarcoma, the mechanisms linking this amplification to MDM2 oncoprotein over-production as well as its functional significance have not been well characterized in patients with soft tissue sarcoma.Methods. A tissue bank of resected soft tissue sarcomas and autologous normal tissues was assembled; all specimens were snap frozen within 15 min of resection. DNA and RNA were extracted from tissues using isoamyl alcohol and phenol chloroform extraction methods, respectively; cell lysates were prepared using PBSTDS lysis buffer. DNA and mRNA were confirmed as being non-degraded and were then examined for MDM2 DNA amplification (Southern blots) and mRNA over-expression (Northern blots) using actin (DNA) and glyceraldehyde-3-phosphate dehydrogenase (mRNA) as loading controls. The MDM2 protein was examined on Western blots using the MDM2-specific monoclonal antibody IF2 (Oncogene Science, Inc). The presence of p53 DNA and expression of p53 mRNA was examined by rehybridizing the Southern and Northern filters using a p53-specific cDNA probe.Results. Soft tissue sarcomas and autologous normal tissues were screened for MDM2 DNA amplification, which was detected in 10 of 30 tumors screened. After screening, there was sufficient biomaterials from six specimens for subsequent Northern and Western analysis to see whether MDM2 gene amplification correlated with over-expression of MDM2 mRNA and MDM2 protein. In addition, we examined whether other mechanisms may lead to over-expression of the MDM2 oncoprotein. Several possible mechanisms of MDM2 oncoprotein over-expression were identified. These most commonly included MDM2 DNA amplification, MDM2 mRNA over-expression and MDM2 oncoprotein over-expression. However, some soft tissue sarcoma patient specimens had no evidence of MDM2 mRNA over-expression yet had MDM2 oncoprotein over-production in the tumor relative to autologous normal tissue, implying possible post-transcriptional regulation. Of functional relevance, MDM2 oncoprotein over-production by tumors was associated with large decreases in the percentage of cells in the (0)/G(1) cell cycle interface compared with autologous normal tissue cells.Discussion. It is likely that there are multiple mechanisms underlying human soft tissue sarcoma MDM2 oncoprotein over-production. Consequently, strategies that decrease MDM2 over-production, such as transcriptional repression to inhibit MDM2 promoter activity or RNA antisense approaches, may ultimately offer the best therapeutic efficacy.
Sarcoma 1997
PMID:Enhanced MDM2 Oncoprotein Expression in Soft Tissue Sarcoma: Several Possible Regulatory Mechanisms. 1852 Nov 97

Purpose. The prognosis, treatment principles and prediction of clinical outcome of patients with chondrosarcoma currently rest on histologic grading which is somewhat ambiguous due to difficulty in pathologic interpretation of this neoplasm. Immunohistochemistry, flow cytometry and oncogene/tumor suppressor gene expression have been examined as alternative indices to predict the biologic behavior of these tumors. Because of partial successes obtained with flow cytometry and because of the improvement in predicting recurrence offered by examining the S-phase fraction, we undertook the current study to determine if expression of specific regulators of the cell cycle would act as prognostic indicators for these patients.Subjects/methods. We examined archival pathologic specimens from 39 patients with at least 2 years' clinical follow-up for the presence of p53, Rb, src and MIB-1 by immunohistochemistry and correlated this with clinical histories and incidence of recurrence.Results. While Rb, p53 and src gene products were identified to a variable extent in these specimens, there was no prognostic significance to their expression. In contrast, MIB-1, an epitope expressed only during semiconservative replication and an accepted marker of cell proliferation, served as a significant prognostic indicator. MIB-1 staining was present in 14.5% of tumor cells in all specimens (range 0-59%). When MIB-1 staining was examined with respect to disease recurrence, there was a statistically significant association between staining and histologic grade (p < 0.05) as well as event-free survival (p < 0.02). Comparing survival curves stratified by MIB-1 expression, there was a significant decrease in event-free survival associated with increasing MIB-1 indices (p < 0.003). Covariates that were associated with event-free survival include histologic grade (p = 0.025) and stage (Musculoskeletal Tumor Society) (p = 0.014). There was no statistical association with patient age (p = 0.15), tumor size (p = 0.47), tumor histology (p = 0.62) or anatomic location (p = 0.316).Discussion. These results indicate that determination of the proliferation index by MIB-1 immunostaining may serve as a useful adjunct to current histopathologic classification. Patients with a high proliferation index may benefit from established adjuvant therapies or experimental approaches including immunotherapy or biologic modulation.
Sarcoma 1997
PMID:Prognostic markers in chondrosarcoma: evaluation of cell proliferation and of regulators of the cell cycle. 1852 Dec 6

Purpose. In a previous series of 25 human osteosarcoma samples studied for MYC gene amplification, we found amplification in two cases (8%), including one arising in association with Paget's disease (pagetic osteosarcoma). Based on this observation, we further investigated the prevalence of MYC gene amplification in pagetic osteosarcomas.Methods. MYC gene amplification was assessed by Southern blot analysis using frozen tissue samples in five cases of pagetic osteosarcoma and 53 cases of primary (non-pagetic) osteosarcoma. Amplification was considered present if the MYC copy number was six or greater.Results. Three out of five patients (60%) with pagetic osteosarcoma showed MYC gene amplification, whereas it was present in only 5/53 patients (9.4%) with primary osteosarcoma. The incidence of MYC amplification in pagetic osteosarcoma was thus significantly higher than that in primary osteosarcoma (p = 0.016).Discussion. The finding that MYC gene amplification may be more common in pagetic than primary osteosarcoma warrants further study and suggests pathogenetic differences between primary osteosarcomas and those arising in the setting of Paget's disease. Three of the four pagetic osteosarcomas from the present study were previously shown to be immunoreactive for p53, suggesting that p53 mutation may also be a frequent genetic lesion in these tumors.
Sarcoma 1997
PMID:Amplification of the MYC Gene in Osteosarcoma Secondary to Paget's Disease of Bone. 1852 Dec 14

Purpose/Results. Although surgical, chemo- and radiotherapeutic treatment regimens in patients with soft tissue sarcomas have constantly been refined over the past two decades, the survival rate for these patients is rather low.Discussion. There is a great need to investigate the mechanisms for oncogenesis and to identify the factors involved in malignant transformation in sarcomas. Among these factors, IGFs are thought to play a pivotal role as progression factors in various types of sarcomas. The dysregulation of the IGF-II synthesis, e.g. by loss of imprinting which occurs in most types of sarcomas, is a permissive effect through the suppression of cell death. In addition, cells that overexpress the type I IGF receptors are more susceptible to transformation by oncogenes. As TP53 suppresses the activity of IGF-II P3 and P4, as well as the type I IGF receptor promoter, mutations of TP53 in sarcomas may alternatively lead to the activation of these factors. Finally, the phenomenon of non-islet cell tumour hypoglycaemia that occurs in patients with sarcomas, and which is related to the secretion of IGF-II prohormones, is discussed. Future therapeutic strategies may be based upon the application of antibodies or antisense oligonucleotides directed against the type I IGF receptors, with the common goal of inducing apoptosis in sarcoma cells. Ultimately, these and other therapeutic approaches may lead to a better outcome in patients suffering from sarcoma.
Sarcoma 1998
PMID:The role of insulin-like growth factor system in soft tissue sarcomas: from physiopathology to targeted therapeutic approaches. 1852 Dec 37

We describe a patient who underwent thoracic radiation therapy for biopsy-proven pulmonary spindle cell sarcoma in the left lower lobe, 15 months after birth. At the age of 37 she developed shoulder pain, fatigue, and progressive exertion dyspnoea. Chest X-ray revealed a pulmonary mass in the left lower lobe due to a cytology-proven malignant tumour.The patient underwent left pneumonectomy. Histology revealed a myosarcoma of the lung, similar to the previous sarcoma. Furthermore, the patient was diagnosed to have Turner syndrome mosaic and chromosomal analysis revealed a translocation t(1;13) in 3/50 metaphases. However a germline mutation of the p53 tumour suppressor gene was excluded. After 2 years of follow-up the patient is stable and there are no signs of recurrence of the tumour.We conclude a re-occurrence of this very rare malignant disorder of the lung after a 36-year interval in a patient with Turner syndrome mosaic. Following initial curative radiation therapy, with a remission over 36 years, lung resection was now successfully performed.
Sarcoma 2002
PMID:Successful resection of a re-occurred pulmonary myosarcoma in a patient with turner syndrome mosaic. 1852 51

Phyllodes tumours and angiosarcoma are both rare mesenchymal tumours. There are no reports of their coexistence in the literature except in families with germline p53 mutations. Here we report a case of an elderly woman who developed an extensive angiosarcoma of the scalp nearly 4 years after surgical removal of a borderline malignant phyllodes tumour of the breast. The scalp lesion was initially thought more likely to be a metastasis of her first rare tumour than a second equally rare primary tumour, but histologically this was not the case. The case and the literature are discussed.
Sarcoma 2003
PMID:Angiosarcoma of the scalp presenting in association with borderline malignant phyllodes tumour of the breast. 1852 83

Malignant peripheral nerve sheath tumours (MPNSTs) are highly malignant and resistant. Transformation might implicate up regulation of epidermal growth factor receptor (EGFR). Fifty-two MPNST samples were studied for EGFR, Ki-67, p53, and survivin expression by immunohistochemistry and for EGFR amplification by in situ hybridization. Results were correlated with clinical data. EGFR RNA was also quantified by RT-PCR in 20 other MPNSTs and 14 dermal neurofibromas. Half of the patients had a neurofibromatosis type 1 (NF1). EGFR expression, detected in 86% of MPNSTs, was more frequent in NF1 specimens and closely associated with high-grade and p53-positive areas. MPNSTs expressed more EGFR transcripts than neurofibromas. No amplification of EGFR locus was observed. NF1 status was the only prognostic factor in multivariate analysis, with median survivals of 18 and 43 months for patients with or without NF1. Finally, EGFR might become a new target for MPNSTs treatment, especially in NF1-associated MPNSTs.
Sarcoma 2008
PMID:Frequent EGFR Positivity and Overexpression in High-Grade Areas of Human MPNSTs. 1876 52

Purpose. To investigate angiogenesis, multiple drug resistance (MDR) and proliferative activity as prognostic variables in patients suffering from osteosarcoma. Methods. Histologic biopsies from 117 patients treated in the period from 1972 through 1999 were immunohistologically investigated regarding angiogenesis (CD34), proliferative activity (MIB-1), and the expression of p53 and MDR (P-glycoprotein (Pgp); clones JSB-1, C494, and MRK16). Quantitative and semiquantitative scores of immunoreactive cells were analyzed statistically along with retrospectively obtained clinicopathologic variables. Results. Chemotherapy reduced the rate of amputations (P = .00002). The Pgp was overexpressed (score >/=2) in 48% of the primary, diagnostic biopsies, and high Pgp correlated with high Pgp in postsurgical specimens (P = .003). In contrast, no such associations were disclosed for estimates of angiogenesis (P = .64) and p53 (P > .32), whereas the MIB-1 index was reduced in the post-chemotherapy specimens (P = .02). The overall, disease-specific survival was 47%, increasing to 54% in patients receiving pre-operative chemotherapy. Statistical analyses showed prognostic impact exclusively by patient age and type of osteosarcoma. Discussion. The studied series of patients documented already prior to the chemotherapy era, a rather excellent survival and estimates of angiogenesis, proliferation, p53, and Pgp expressions, did not demonstrate sufficient power to serve as predictors of treatment response or survival.
Sarcoma 2008
PMID:Immunohistochemical Estimates of Angiogenesis, Proliferative Activity, p53 Expression, and Multiple Drug Resistance Have No Prognostic Impact in Osteosarcoma: A Comparative Clinicopathological Investigation. 1926 50


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