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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this issue, Molecular Cancer Therapeutics inaugurates a new feature-The Cutting Edge: Spotlight on Clinical Response-whose objective is the rapid publication of breaking discoveries regarding target- or mechanism-based clinical responses in cancer. Targeted molecules are poised to alter the landscape of clinical cancer treatment. For example, because they can distinguish cancer cells from their normal counterparts, agents such as imatinib mesylate, a Bcr-Abl and Kit kinase inhibitor, can result in remarkable responses with minimal host toxicity in patients suffering from diseases characterized by abnormalities in the targeted kinases. Indeed, studies of imatinib mesylate in early-stage chronic myelogenous leukemia, whose hallmark is the aberrant Bcr-Abl, show response rates of more than 90%. Furthermore, gastrointestinal stromal tumors (GIST), a notoriously chemotherapy-refractory sarcoma, characterized by activating Kit kinase mutations, can show dramatic metabolic responses within days after initiation of treatment. With the wealth of new knowledge in this field, and numerous novel targeted molecules entering clinical trials, the above examples are likely to represent the tip of the iceberg. Indeed, in this issue, a paper by Senzer et al. documents, for the first time, successful use of adenoviral p53 therapy to treat a tumor in a patient with Li Fraumeni Syndrome, a hereditary cancer syndrome caused by the mutation of the p53 tumor suppressor gene. Some of the features of this response, such as the early disappearance of metabolic activity on fluorodeoxyglucose-positron emission tomography scans, are reminiscent of those of GIST responses to imatinib. These findings have important implications for patients with this syndrome, who are prone to develop numerous tumors and often succumb at a young age. In addition, because mutations in p53 are one of the more common aberrations in cancer in general, identification of these mutations and exploration of this approach is warranted in patients with sporadic cancers. In summary, the era of "molecular cancer therapeutics" has begun. Even so, results in the laboratory and in animals often do not translate into salutary effects in patients. However, when they do, it is important that the information be made quickly available to the investigative community. Molecular Cancer Therapeutics believes that providing a forum for the rapid dissemination of cutting-edge findings of successful, albeit early, clinical research should stimulate further study and will ultimately benefit patients with cancer.
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PMID:Studies in target-based treatment. 1748 34

One of the least commonly encountered spindle cell tumors seen on prostatic needle biopsy or transurethral resection (TUR) of the prostate is solitary fibrous tumor (SFT). We studied 13 cases of SFTs identified on either prostate needle biopsy (n=9) or TUR of the prostate (n=4). Mean patient age at diagnosis was 63 years (range: 46 to 75 y; median: 65 y). Twelve men presented with urinary tract symptoms and 1 patient was biopsied during work-up of bone metastases. Ten cases were SFTs originating in the prostate, 2 cases arose between the prostate and rectum extending into the prostate (n=2), and 1 case was a pelvic mass without infiltration of the prostate. In 9 cases, a complete tumor resection was attempted by cystoprostatectomy (n=2), radical prostatectomy (n=4), pelvic exenteration (n=2), or pelvic tumor resection (n=1). Enucleation (n=1) and TUR (n=1) were performed in 2 other cases. Tumor sizes ranged from 8.5 to 15 cm in 7 radically resected cases. Mitotic rates were 3 to 5 per 10 high power fields in 5 cases, with the remaining cases having either rare (n=4) or no mitoses (n=4). Seven cases demonstrated areas of necrosis. Based on a combination of increased cellularity, mitotic activity, necrosis, nuclear pleomorphism, and infiltrativeness, 4 prostatic SFTs were malignant, 4 were benign, and 2 were borderline. Of the 3 non-prostatic SFTs, 1 was malignant and 2 were borderline. All tumors but 1 were immunoreactive for CD34 (n=12). Material for additional immunohistochemistry was available for the majority of cases with positive stains for Bcl-2 (11/11), CD99 (7/10), beta-catenin (5/10), and c-kit (0/11). Three SFTs demonstrated >or=10% p53 immunoreactivity including 1 tumor with 50% positivity; and 3 cases had Ki-67 rates of >or=20%. Although all SFTs were initially clinically considered to be of prostatic origin, some of the cases arose in the pelvis with secondary involvement of the prostate. Approximately 50% of prostatic SFTs were malignant. Even in the prostatic and nonprostatic SFTs with no overt malignant features, sometimes it was necessary to remove the prostate and in some instances the adjacent organs because of the large size of the tumors. SFTs must be differentiated from other spindle cell neoplasms of the prostate especially from gastrointestinal stromal tumors that may arise from the rectal wall with invasion of the prostate or from the region between the rectum and the prostate.
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PMID:Solitary fibrous tumor on needle biopsy and transurethral resection of the prostate: a clinicopathologic study of 13 cases. 1752 73

Gastrointestinal stromal tumors (GISTs) have unique immunohistochemical and molecular genetic features that set them apart from leiomyomas, leiomyosarcomas, and schwannomas. Although recurrence of GIST usually tends to develop locally or in the liver, rectal GIST reoccur predominantly at the original site of the tumor. We describe a rare case of rectal GIST with multiple liver metastases. We carried out immunohistochemical staining for p53 protein, proliferating cell nuclear antigen (PCNA), integrins, and interleukin-1 receptor type I (IL-1RI) in order to investigate the degree of malignancy of this neoplasm in addition to the immunohistochemical analyses that were necessary for diagnosing GIST. Histologically, the rectal tumor was classified as an uncommitted type of rectal GIST with multiple liver metastases. Positive immunostaining for PCNA, alpha6 integrin subunit, and IL-1RI was found in both the rectal and hepatic tumors. The patients with a rectal GIST may have an increased risk of liver metastasis and a poor prognosis independent of the size of the tumor.
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PMID:Gastrointestinal stromal tumor of the rectum with liver metastasis: report of a case. 1762 50

To elucidate the prognostic role and relationship of the p53/p21/PCNA pathway in gastrointestinal stromal tumors (GISTs), a total of 167 resected gastric and small intestinal CD117-positive stromal tumor specimens were collected from January 1987 to December 2000. Immunohistochemical studies were performed on the paraffin sections with antibodies of p53, p21/WAF1, proliferating cell nuclear antigen (PCNA) and Ki-67. The immunoreactivity of four markers was recorded by labeling index (LI, %) for clinicopathologic and survival correlation. The labeling index was 0-83% for p53, 0-81% for p21/WAF1, 0-33% for Ki-67 and 12-92% for PCNA. Completely negative immunostaining (LI<1%) was found in 54.5% of p53, 25.8% of p21/WAF1 and 44.3% of Ki-67. The LI of four markers strongly correlate with each other (p<0.05). Furthermore, the LI of all four markers positively correlate to microscopic tumor mitotic counts (p<0.05). Only the LI of p53 and PCNA positively correlate to tumor sizes. Tumors with non-spindle cell type (versus spindle cell) and high cellular pleomorphism (versus low) exhibited a higher p53, p21/WAF1 and PCNA LI (p<0.05). Increased NIH risk significantly correlates to increased p53, PCNA and Ki-67 (p<0.05) LI. Survival analysis indicated that a large tumor size (> or =5 cm, p=0.003), increased tumor mitosis (> or =5/50 HPF, p<0.001), high NIH risk (p<0.001), non-spindle cell type (p=0.024), high p53 LI (p<0.001), high p21/WAF1 LI (p=0.007), high Ki-67 LI (p<0.001) and high PCNA LI (p<0.001) were prognostic factors for poor disease-free survival. Independent factors are tumor size, NIH risk, p53 and p21/WAF1 LI. We demonstrated the first evidence of the linear relationship and prognostic role of the p53/p21/PCNA pathway in gastrointestinal stromal tumors. Abnormalities of the p53/p21WAF1 pathway lead to increased proliferating states, thereby triggering the progression of GISTs.
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PMID:The abnormalities in the p53/p21WAF1 pathway have a significant role in the pathogenesis and progression of gastrointestinal stromal tumors. 1809 75

The aim of the present study was to evaluate the clinicopathological, immunohistochemical, and molecular genetic features of gastrointestinal stromal tumors in Brazil and compare them with cases from other countries. Five hundred and thirteen cases were retrospectively analyzed. HE-stained sections and clinical information were reviewed and the immunohistochemical expression of CD117, CD34, smooth-muscle actin, S-100 protein, desmin, CD44v3 adhesion molecule, p53 protein, epidermal growth factor receptor, and Ki-67 antigen was studied using tissue microarrays. Mutation analysis of KIT and platelet-derived growth factor receptor-alpha genes was also performed. There was a slight female predominance (50.3%) and the median age at diagnosis was 59 years. The tumors were mainly located in the stomach (38.4%). Immunohistochemistry showed that CD117 was expressed in 95.7% of cases. Epidermal growth factor receptor expression was observed in 84.4% of tumors. p53 protein expression was found only in 2.6% of cases but all belonged to the high-risk group for aggressive behavior according to the National Institutes of Health consensus approach. No CD44v3 adhesion molecule expression was detected. KIT exon 11 mutations were the most frequent (62.2%). The present data confirm that gastrointestinal stromal tumors in Brazilian patients do not differ from tumors occurring in other countries.
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PMID:Gastrointestinal stromal tumor in Brazil: clinicopathology, immunohistochemistry, and molecular genetics of 513 cases. 1847 13

The author reports a very rare case of sporadic primary multiple extragastrointestinal stromal tumors (EGISTs) of the omentum associated with different mutations of the exon 11 of the c-kit gene in a 75-year-old man with gastric cancer. During an operation for the cancer, two solid tumors (10 mm and 8 mm) were found in the omentum. Both tumors consisted of cellular spindle cells. Mitotic figures were two and three per 50 high power fields. The tumor cells were positive for KIT, CD34 and vimentin, but negative for desmin, S100 protein, alpha-smooth muscle actin and p53 protein. Ki67 labeling was 2% and 3%. The larger EGIST showed a deletion of codons 552-558 of exon 11 of the c-kit gene, while the smaller EGIST had a point mutation at codon 559 (GTT-->GAT) in exon 11 of the c-kit gene. Exons 9, 13, and 17 of the c-kit gene, and exons 12 and 18 of the platelet derived growth factor receptor alpha genes showed no mutations. The case shows that sporadic multiple EGISTs can occur in the omentum.
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PMID:Primary multiple extragastrointestinal stromal tumors of the omentum with different mutations of c-kit gene. 1908 44

Sarcomas are mesenchymal cancers consisting of tumors with various clinical and pathological features. Some of them compel affected individuals to lose important musculoskeletal functions, and some of them are highly malignant and life-threatening. A great amount of genetic information for sarcomas has accumulated during the past two decades, contributing diagnoses and treatments. From the standpoint of molecular genetics, sarcomas are classified into two groups: those with defined genetic alterations and those with various genetic alterations. The genetic alterations in the first group include reciprocal translocations resulting in fusion oncoproteins and oncogenic mutations of defined genes such as those of the c-kit gene in gastrointestinal stromal tumors. The function of fusion proteins includes transcription regulator, signal transducer, chromatic remodeling factor, and growth factor, some of which are suitable targets for the molecular therapy. In tumors belonging to the second group, the number of which is far larger than those of the first group, considerable genetic heterogeneity was found even among tumors with same pathological diagnosis. The disruption of the RB and p53 pathways was frequently found, resulting in the dysregulation of cell cycle and the genomic instability. The application of molecular target therapy for tumors in this group requires novel strategies to overcome cross talk between different signal pathways. Recent evidence from in vitro and in vivo experiments has indicated that the cells of origin of sarcomas are tissue stem cells such as mesenchymal stem cells, and the application of stem cell biology holds the promise of novel treatment options.
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PMID:Molecular genetics of sarcomas: applications to diagnoses and therapy. 1955 93

Sarcomas are a group of heterogeneous tumors that arise from mesenchymal tissue and account for approximately 1% of all adult solid malignancies diagnosed, although its incidence approaches 20% in pediatric cancers. Characterization of molecular abnormalities in patients with sarcomas, in particular the up-regulation of the receptor tyrosine kinase and the PI3K-AKT-mTOR pathway, loss or deletions of retinoblastoma (Rb) and p53 gene, increased VEGF expression and angiogenesis, dysregulation of apoptosis through Bcl-2 overexpression, along with oncogene mutations and activations, such as c-KIT in Gastrointestinal stromal tumors (GISTs), makes treatment with novel biological therapies a promising option. This review focuses on the molecular heterogeneity of soft tissue and bone sarcomas, novel biological therapies currently in clinical trials to target the various molecular pathways, and the potential biological agents in pre-clinical and early clinical development.
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PMID:Targeting sarcomas: novel biological agents and future perspectives. 1986 Jun 42

The aim of the present study was to compare the efficiency of tissue microarray (TMA) results using immunohistochemistry markers applied to a variety of core sizes and full sections of gastrointestinal stromal tumors (GIST) using performance measures such as core loss rate and concordance rate. Six primary antibody markers (c-Kit, CD34, smooth muscle actin (SMA), S-100, p53, and Ki-67) were used with the TMA technique to analyze 0.6 mm, 2 mm, and 3 mm punch cores of GIST samples from 67 patients. No statistical association was found between core size and loss rate (P= 0.512). TMA results for the 0.6 mm, 2 mm, and 3 mm core showed that all core sizes could statistically significantly reflect full sections with regard to c-Kit, SMA, and S-100 antibodies, but that the 3 mm core section was the most representative except for CD34. With regard to p53 and Ki-67 staining, the 0.6 mm core section was not representative, but the 2 mm and 3 mm core sections could statistically significantly represent full section results. Among them, the 3 mm core section was more accurate than the 2 mm core section. Use of a single 3 mm core size in TMA is suitable for evaluating large numbers of protein and nuclear stains with regard to immunohistochemistry for GIST.
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PMID:Comparison of tissue microarray and full section in immunohistochemistry of gastrointestinal stromal tumors. 2002 9

Here, we report the Ki-67 Labeling Index, the expression of c-kit, p53, bcl-2, and apoptosis in 11 gastrointestinal stromal tumors (GISTs). The Ki-67 Labeling Index in the malignant GIST group was higher than that in the benign group. The Ki-67 Labeling Index in the p53-positive cases was higher than that in the p53-negative cases. The Ki-67 Labeling Index in the C-kit-positive group was higher than that in the C-kit-negative group. The bcl-2 expression was not correlated with potential malignancy. The apoptotic count in the bcl-2-positive cases was higher than that in the bcl-2-negative cases. The Ki-67 Labeling Index, the p53 overexpression, and the C-kit expression were useful in predicting the potential malignancy.
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PMID:Malignant potential of gastrointestinal stromal tumor of the stomach. 2009 18


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