Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

E-cadherin is a calcium 2+-dependent cell-adhesion molecule that determines epithelial development in the embryo and maintains adult differentiated epithelium and homeostasis. Aberrant or decreased expression has been reported to be associated with prostate carcinoma progression. The degree of E-cadherin expression in prostate cancer remains controversial. Some studies have reported decreased expression of E-cadherin as tumors advance and metastasize. Other studies have not demonstrated this relationship. To address these variations, we undertook a study to systematically evaluate E-cadherin expression in a broad range of prostate tissue. Benign prostate, clinically localized prostate cancer, and hormone-refractory metastatic prostate cancer were analyzed under uniform conditions using high-density tissue microarrays (TMA). Formalin-fixed, paraffin-embedded prostate carcinoma from men with clinically localized prostate carcinoma and autopsy material from men who died of widely metastatic, hormone-refractory prostate carcinoma were arrayed into 6 high-density TMA blocks. Benign and atrophic prostate tissue and high-grade prostatic intraepithelial neoplasia (PIN) were also included from the clinically localized cases. Immunohistochemistry was performed using the immunoglobulin G1 mouse monoclonal antibody (HECD-1; Zymed, San Francisco, CA). Membranous staining was recorded as low (aberrant) or high (normal). E-cadherin expression was considered aberrant if less than 70% of the cells had strong membranous staining. A total of 1,220 prostate TMA samples were analyzed. High (normal) E-cadherin expression was seen in 87% of 757 benign, 80% of 41 high-grade PIN, 82% of 325 prostate carcinoma and 90% of 97 hormone-refractory prostate carcinoma TMA samples. Mean E-cadherin expression was determined for each of the 128 clinically localized prostate cancer cases. Aberrant E-cadherin expression showed a statistical trend toward an association with positive surgical margins (P =.012), higher Gleason score (P =.18), and prostate-specific antigen (PSA) failure (Kaplan-Meier analysis, log-rank P =.09). There was a statistically significant association between aberrant E-cadherin expression and larger tumor size (P =.01). No significant associations were seen with extraprostatic extension and seminal vesicle invasion. The current study shows a broad-spectrum approach to evaluating E-cadherin protein expression in prostate carcinoma. Clinically localized prostate tumors, treated with surgery alone, show a high level of E-cadherin expression. Aberrant expression was identified in tumors with positive surgical margins, higher Gleason score, and a higher rate of PSA failure. However, these trends were not statistically significant. A statically significant association between aberrant E-cadherin expression and larger tumor size was identified. In the metastatic hormone-refractory prostate tumors, E-cadherin expression was vastly expressed, and only rare cases had aberrant expression. Therefore, the findings of this study are most consistent with a transient down-regulation of E-cadherin in localized prostate cancer. Metastatic prostate cancer shows strong E-cadherin expression as determined by anti-E-cadherin antibody HECD-1.
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PMID:E-cadherin expression in prostate cancer: a broad survey using high-density tissue microarray technology. 1148 67

Despite advances in screening procedures and the use of adjuvant therapy, approximately 50% of patients with colorectal cancer eventually will develop metastatic disease. Long-term disease-free survival can be achieved in 25% to 40% of selected patients who undergo resection of liver or lung metastases. For all other patients, treatment is palliative. For decades, 5-fluorouracil was the only available drug for colorectal cancer; hence, numerous trials were performed that used various administration schedules and modulating agents to improve therapeutic efficacy. The addition of leucovorin to 5-FU improves response but not survival. Infusion schedules alter the toxicity profile but have a negligible impact on survival. Irinotecan was the first new drug to demonstrate activity in colorectal cancer. It was used initially in the second-line setting, where it was shown to improve quality of life and survival over best supportive care or infusional 5-FU. Recently, irinotecan has been incorporated into the front-line treatment of metastatic colorectal cancer in combination with 5-FU and leucovorin; this combination improves survival by approximately 3 months. Careful patient selection and adherence to strict dose adjustments are essential to prevent significant toxicity when patients are treated on this regimen. The oral fluoropyrimidine capecitabine recently has been approved for the front-line treatment of patients with colorectal cancer who are not appropriate candidates for combination therapy. Oxaliplatin, a novel DACH (diaminocyclohexane) platinum with definite activity in colorectal cancer, is approved for this disease in Europe and is undergoing phase III clinical trials in the United States. Other drugs with potential activity in colorectal cancer include raltitrexed, pemetrexed disodium, and the epothilone analog BMS-247550 (Bristol-Myers Squibb, New York, NY). Novel cytostatics with promising activity in colorectal cancer are being evaluated in clinical trials, including epidermal growth factor receptor inhibitors, such as IMC-C225 (Imclone Systems, New York, NY) and ZD1839 (AstraZeneca, London, UK), angiogenesis inhibitors such as bevacizumab and SU5416 (Sugen, San Francisco, CA), and vaccines such as CEAVac (Titan Pharmaceuticals, San Francisco, CA). For those patients whose disease is localized to the liver, there also is an emerging role for local therapies, including cryosurgery, radiofrequency ablation, and hepatic artery infusional chemotherapy, and resection. The emergence of these new drugs and new interventional modalities has allowed physicians who treat colorectal cancer to move beyond 5-FU.
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PMID:Metastatic colorectal cancer. 1205 92

Neoplastic meningitis is recognized clinically in 4% to 7% of patients with extraneural cancer, but it remains dramatically under-diagnosed. The frequency of neoplastic meningitis is increasing because of heightened clinical suspicion, improved neuroimaging techniques, and longer survival in patients with extraneural cancer Longer survival allows residual tumor cells within central nervous system sanctuary sites time to become symptomatic. Affected patients may present with cerebral, cranial nerve, or spinal signs and symptoms, depending on the specific sites of central nervous system (CNS) involvement. Magnetic Resonance Imaging (MRI) seems to be sensitive for detecting metastatic deposits along the neuraxis. However, metastases at a microscopic level are below the resolution of MRI scanning. As a result, the standard diagnostic test for neoplastic meningitis remains the cytologic identification of malignant cells in cerebrospinal fluid (CSF). Although CSF cytology is useful, malignant cells are not detected in as many as one third of patients who have compelling clinical or radiographic evidence of neoplastic meningitis. Novel assays are being tested that may enhance the early identification of malignant cells in CSF. Currently, the diagnosis occurs generally after the onset of neurologic manifestations and heralds a rapidly fatal course for most patients. By the time symptoms appear, most tumors have disseminated widely within the CNS, due to cortical irritation, compression of nervous system structures, or obstruction of CSF flow. At this stage surgery, cranial irradiation, and chemotherapy are rarely, if ever, curative. The goals of treatment are to improve or to stabilize the neurologic status of patients and to prolong survival. A major problem in treating neoplastic meningitis is that the entire neuraxis must be treated. If only symptomatic areas are treated, reseeding of the neuraxis with tumor cells will occur. Therefore, intrathecal chemotherapy remains a mainstay of therapy. Currently, four therapeutic agents are available for intrathecal treatment: methotrexate, ara-C, sustained-release ara-C (DepoCyt; Chiron Therapeutics, San Francisco, CA), and thiotepa. Unfortunately, intrathecal chemotherapy does not treat bulky disease in the subarachnoid space, and often is slow to stabilize progressive neurologic deficits. For these reasons, radiation therapy to sites of symptomatic disease and sites of bulky disease on imaging studies is recommended. High dose intravenous methotrexate may be as effective as intrathecal methotrexate. Alternative approaches (which offer less toxicity, enhanced therapeutic effect, and prolonged survival) are being investigated.
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PMID:Neoplastic meningitis. 1205 97

Solid tumors consist of several components, including normal and stromal cells, extracellular matrix, and vasculature. To grow and metastasize, tumors must stimulate the development of new vasculature through a process known as angiogenesis. Unlike normal blood vessels, tumor blood vessels are chaotic, irregular, and leaky, which leads to uneven delivery of nutrients and therapeutic agents to the tumor. Conventional therapies target neoplastic cells within a tumor; however, tumor vasculature is emerging as an important target for anticancer therapy. Antiangiogenic therapy offers several potential advantages as an approach to cancer treatment, notably physical accessibility and genetic stability of target cells. Vascular endothelial growth factor (VEGF), a central mediator of angiogenesis, has emerged as an important target for antiangiogenic therapy. In preclinical studies, treatment of human tumor xenografts in immunodeficient mice with the anti-VEGF monoclonal antibody A4.6.1 led to reduced tumor vessel permeability and caused vascular regression. The reduced vascular permeability, resulting from inhibition of VEGF, led to increased delivery of oxygen and therapeutic agents to tumors. Anti-VEGF therapy was effectively combined with other treatment modalities, including radiation, antihormonal, antibody, and chemotherapies in multiple preclinical models. Currently, several phase 3 clinical trials in various cancer types are under way to establish the efficacy of antiangiogenic therapy with a recombinant humanized anti-VEGF monoclonal antibody, bevacizumab (Avastin, rhuMAb-VEGF; Genentech, South San Francisco, CA), in combination with chemotherapeutic agents.
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PMID:Tumor angiogenesis and accessibility: role of vascular endothelial growth factor. 1251 32

A free-ranging, adult, female offshore bottlenose dolphin (Tursiops truncatus) was found freshly dead in 1999 on Ocean Park Beach in San Juan, Puerto Rico. The left-lung and right-lung pleura had multiple white, firm-to-hard nodules with coagulative necrosis. Histologically, the neoplasms were characterized by multiple well-circumscribed, nonencapsulated expansile masses consisting mostly of polygonal cells with fewer circumferential flattened basaloid cells that compressed alveoli, bronchioles, and bronchi. Neoplastic cells stained positive for cytokeratin, with sporadic vimentin staining, and were negative for epithelial membrane antigen, thyroid transcription factor-1, calretinin, and human mesothelial cell antigen. A diagnosis of poorly differentiated pulmonary squamous cell carcinoma with lymph node and renal metastases was made on the basis of histomorphology and immunohistochemical staining. This is the first documentation of pulmonary squamous cell carcinoma in a dolphin.
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PMID:A poorly differentiated pulmonary squamous cell carcinoma in a free-ranging Atlantic bottlenose dolphin (Tursiops truncatus). 1266 27

Treatment of advanced renal cancer has made little progress in the past 30 yr. Most clinical efforts have incorporated cytokine-based therapy. The presumption has been that the cytokines may trigger a host immune response against the renal cancer. Only IFN-alpha and high-dose IL-2 seemed to have positive effects on patient outcomes. IFN has prolonged the lives of patients by a few months, and high-dose IL-2 is capable of inducing very prolonged remissions (>5 yr) for a small number of patients. Nephrectomy in the presence of metastatic disease has been established as an effective procedure for select patients, providing palliation and prolonging survival. Finally, enthusiasm has focused on the use of nonmyeloablative allogeneic stem cell transplantation and donor leukocyte infusion for the induction of graft versus tumor effects. Early results are both provocative and promising. A number of agents that target the critical gene products downstream from pVHL and hypoxia-inducible factor-1, such as vascular endothelial growth factor, PDGF, EGF receptor, and TGF-alpha, have recently become available. The new agents are capable of inhibiting specific cellular targets, and the biologic characteristics of clear cell carcinoma of the kidney support their application. If the correct targets are carefully selected for inhibition in tumors in which the targets are present (clear cell histologic features and loss of VHL expression), then results should resemble those others have observed with targeted therapy, such as the use of STI-571 (Gleevec; Novartis Pharmaceuticals, East Hanover, NJ) for treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors or anti-HER2/neu (Herceptin; Genentech, South San Francisco, CA) for treatment of breast cancer.
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PMID:Targeting of the VHL-hypoxia-inducible factor-hypoxia-induced gene pathway for renal cell carcinoma therapy. 1456 78

Expanding knowledge about basic biology and a detailed understanding of the signaling pathways that participate in the growth and metastasis of breast cancer have identified opportunities for diagnostic and therapeutic intervention. Endocrine therapy represents the first and most successful example of targeted therapy in breast cancer. Trastuzumab (Herceptin; Genentech, Inc, South San Francisco, CA) is now part of the management of metastatic disease and is under evaluation as adjuvant therapy. Other pathways have been targeted, and several candidate drugs are being developed. While these developments represent opportunities for better therapies, they have also identified limitations in identification of targets and development of targeted therapies. Validation of targets is critical, and it is also critical to determine whether the putative target can be identified in a consistent, practical, and inexpensive manner. Finally, it is imperative that targeted therapies are devoid of toxicities secondary to the ubiquitous nature of the target, and we must improve our understanding of interactions that provide specificity of signaling under physiologic conditions.
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PMID:Opportunities and challenges in the development of targeted therapies. 1505 40

Dual inhibition of ErbB-1 (EGFR) and ErbB-2 (HER-2) tyrosine kinases has been found to exert greater biologic effects in the inhibition of signaling pathways promoting cancer cell proliferation and survival than inhibition of either receptor alone. The novel dual EGFR/ErbB-2 tyrosine kinase inhibitor lapatinib (GlaxoSmithKline; Research Triangle Park, NC) has been shown to inhibit tumor cell growth in vitro and in xenograft models for a variety of human tumors. Preliminary findings in a phase I study of lapatinib in patients with solid tumors indicate doses up to 1,800 mg per day are well tolerated. No grade 4 toxicities were observed and only two of 43 patients had grade 3 toxicity (diarrhea). Clinical activity of lapatinib was observed in these patients; nine patients with a variety of tumors remained on study for > or =4 months, one with a complete response (head and neck cancer). In a phase IB study in pretreated metastatic cancer patients with disease that could be biopsied, grade 1 or 2 diarrhea and rash were the most common adverse events. Three patients with breast cancer refractory to trastuzumab (Herceptin; Genentech, Inc.; South San Francisco, CA) had partial responses and 12 patients with a variety of tumors had stable disease. Assessment of biologic correlates in these patients indicates that increased tumor cell apoptosis on the terminal deoxynucleotide transferase-mediated dUTP nick-end labeling assay correlates with clinical response. Lapatinib currently is being evaluated in phase II and phase III trials in patients with metastatic breast cancer.
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PMID:Dual kinase inhibition in the treatment of breast cancer: initial experience with the EGFR/ErbB-2 inhibitor lapatinib. 1516 42

Vascular endothelial growth factor (VEGF) has emerged as a key target for the treatment of cancer. As the ligand to the VEGF receptor, it plays a central role in promoting tumor angiogenesis. Overexpression of VEGF leads to poor outcomes in patients with breast cancer and other tumors. Preclinical studies have shown that the humanized monoclonal antibody to VEGF, bevacizumab (Avastin; Genentech, Inc., South San Francisco, CA), can reduce tumor angiogenesis and inhibit the growth of solid tumors, either alone or in combination with chemotherapy. As a single agent or added to vinorelbine, bevacizumab has produced encouraging results in phase II clinical trials in patients with refractory metastatic breast cancer. When added to capecitabine chemotherapy in a phase III trial, bevacizumab produced a greater response rate, but did not prolong progression-free survival. This may reflect the late disease stage and poor prognostic factors in the patient population. A large, ongoing, phase III, cooperative group trial is evaluating the effect of bevacizumab in combination with paclitaxel as first-line therapy for metastatic disease. The adverse effect profile of bevacizumab differs from that of cytotoxic chemotherapy and includes hypertension, proteinuria, thrombosis, and epistaxis.
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PMID:Bevacizumab in the treatment of breast cancer: rationale and current data. 1517 15

At the last congress of the American Urological Association (AUA), which took place in San Francisco from the 9th to the 12th May 2004, more than 200 abstracts on prostate cancer were presented as posters or as full communications. We present here the highlights of this congress and in particular the main subjects of news, controversies or innovations. Two major topics are particularly worthy of discussion: localized disease on the one hand and locally advanced or metastatic disease on the other. In the chapter on localized disease, we expound the most relevant data on epidemiology, screening, staging and prognosis. For the locally advanced disease we discuss quality of life, prognostic factors and recent advances in hormone therapy and chemotherapy.
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PMID:[Congress of the American Urological Association (AUA): update on prostate cancer]. 1567 79


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