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

Sunitinib, a new vascular endothelial growth factor receptor inhibitor, has demonstrated high activity in renal cell carcinoma (RCC) and is now widely used for patients with metastatic disease. Although generally well tolerated and associated with a low incidence of common toxicity criteria grade 3 or 4 toxicities, sunitinib exhibits a distinct pattern of novel side effects that require monitoring and management. This article summarizes the most important side effects and proposes recommendations for their monitoring, prevention and treatment, based on the existing literature and on suggestions made by an expert group of Canadian oncologists. Fatigue, diarrhea, anorexia, oral changes, skin toxicity and hypertension seem to be the most clinically relevant toxicities of sunitinib. Fatigue may be partly related to the development of hypothyroidism during sunitinib therapy for which patients should be observed and, if necessary, treated. Hypertension can be treated with standard antihypertensive therapy and rarely requires treatment discontinuation. Neutropenia and thrombocytopenia usually do not require intervention, in particular no episodes of neutropenic fever have been reported to date. A decrease in left ventricular ejection fraction is a rare, but potentially life-threatening side effect. Because of its metabolism by cytochrome P450 3A4 a number of drugs can potentially interact with sunitinib. Clinical response and toxicity should be carefully observed when sunitinib is combined with either a cytochrome P450 3A4 inducer or inhibitor and doses adjusted as necessary. Knowledge about side effects, as well as the proactive assessment and consistent management of sunitinib-related side effects, is critical to ensure optimal benefit from sunitinib treatment.
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PMID:Sunitinib therapy for metastatic renal cell carcinoma: recommendations for management of side effects. 1854 84

Head and neck cancer is a challenging disease that is expected to account for greater than 500,000 new cases worldwide in 2008. Toxicity has impeded advances in chemotherapy and radiation for head and neck cancer, and the prognosis for patients with recurrent and/or metastatic disease remains poor. Over the past decade, clinical research in head and neck cancer has focused on improving the efficacy of current multimodal approaches by targeting cellular pathways associated with carcinogenesis. Blocking the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor receptor (VEGFR) have emerged as primary strategies that account for the success of current targeted therapies in cancer. Recent studies with cetuximab, a monoclonal antibody inhibitor of the EGFR, have demonstrated survival benefits across the range of treatment settings in advanced head and neck cancer, and it is the only targeted therapy approved for use in this malignancy. In this review, the authors present the current development status of targeted therapies, focusing on those that have potential to impact the management of head and neck cancer in the near-term future. Trials are ongoing in all stages of disease and with a variety of modalities and agents, and those trials should provide critical insight into the best way to use these agents to improve patient outcomes.
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PMID:Targeted therapies in squamous cell carcinoma of the head and neck. 1915 11

Tumor-educated macrophages facilitate tumor metastasis and angiogenesis. We discovered that granulocyte macrophage colony-stimulating factor (GM-CSF) blocked macrophages vascular endothelial growth factor (VEGF) activity by producing soluble VEGF receptor-1 (sVEGFR-1) and determined the effect on tumor-associated macrophage behavior and tumor growth. We show GM-CSF treatment of murine mammary tumors slowed tumor growth and slowed metastasis. These tumors had more macrophages, fewer blood vessels, and lower oxygen concentrations. This effect was sVEGFR-1 dependent. In situ hybridization and flow cytometry identified macrophages as the primary source of sVEGFR-1. These data suggest that GM-CSF can re-educate macrophages to reduce angiogenesis and metastases in murine breast cancer.
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PMID:Granulocyte macrophage colony-stimulating factor inhibits breast cancer growth and metastasis by invoking an anti-angiogenic program in tumor-educated macrophages. 1922 54

Recent studies suggest that vascular endothelial growth factor receptor (VEGFR) 1-positive hematopoietic progenitor cells precede the arrival of tumor cells and form clusters that may portend sites of future metastatic disease. The aim of the present study was to clarify whether VEGFR1 expression in pelvic lymph nodes predicts the risk of prostate cancer progression after radical prostatectomy. VEGFR1 expression in pelvic lymph nodes was examined by immunohistochemistry in 95 patients who underwent radical prostatectomy for prostate cancer. A cluster of VEGFR1-positive cells was considered positive. Expression of VEGFR1 in pelvic lymph nodes and biochemical recurrence after radical prostatectomy were examined by univariate survival analysis and multivariate Cox proportional hazards regression analysis. Thirty-seven of 79 lymph node-negative patients (46.8%) were found to have VEGFR1-positive cells in their pelvic lymph nodes, whereas 16 of 16 lymph node metastasis-positive patients (100%) had VEGFR1 clusters. There was a significant correlation between pathological stage and VEGFR1 staining (P = 0.002). Univariate analysis showed that pathological stage > or = pT3 and VEGFR1 expression in pelvic lymph nodes were each significantly associated with biochemical recurrence after radical prostatectomy. Multivariate analysis showed VEGFR1 expression to be an independent predictor of biochemical recurrence after radical prostatectomy (risk ratio = 5.715, P = 0.010), as was preoperative prostate-specific antigen (PSA) level > or = 10 ng/mL. Although larger validation studies are required, our results suggest that VEGFR1 expression in pelvic lymph nodes predicts the risk of biochemical PSA recurrence after radical prostatectomy.
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PMID:Vascular endothelial growth factor receptor 1 expression in pelvic lymph nodes predicts the risk of cancer progression after radical prostatectomy. 1938 72

Raf kinases and vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) tyrosine kinases are potential molecular targets for obtaining both anti-tumor cell progression and anti-angiogenesis effects in cancers, including hepatocellular carcinoma (HCC). Sorafenib is an oral multi-kinase inhibitor that mainly targets Raf kinases and receptor tyrosine kinases associated with angiogenesis (VEGFR-2/-3, PDGFR-beta). A global randomized controlled trial (RCT) of sorafenib versus placebo conducted in patients with advanced HCC demonstrated the beneficial effects of the drug on the time-to-progression and overall survival. Furthermore, a RCT with a similar design to that of the global trial conducted in the Asia-Pacific region also demonstrated the efficacy of the drug. The most common treatment-related adverse events of sorafenib were found to be diarrhea, fatigue, and skin toxicity, namely, hand-foot syndromes and rash. Based on the results of the RCTs, sorafenib has been established as a standard agent for systemic chemotherapy in HCC patients with metastatic disease or transcatheter arterial chemoembolization (TACE)-refractory disease who are not suitable candidates for local treatments. The efficacy and safety of sorafenib in patients with moderate liver dysfunction have not been confirmed to date and more data are needed. Development of new therapeutic methods is needed for the treatment of advanced HCC in the future; clinical trials of sorafenib-based combination therapy, second-line therapy after sorafenib failure, and adjuvant therapy after local treatments are warranted in HCC patients.
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PMID:Sorafenib for the treatment of unresectable hepatocellular carcinoma. 1970 58

The human vascular endothelial growth factor receptor-1 (VEGFR-1, or Flt-1) is widely expressed in normal and pathologic tissue and contributes to the pathogenesis of both neoplastic and inflammatory diseases. In human cancer, VEGFR-1 mediated signaling is responsible for both direct tumor activation and angiogenesis. VEGFR-1 mediated activation of nonmalignant supporting cells, particularly stromal, dendritic, hematopoietic cells, and macrophages, is also likely important for cancer pathogenesis. VEGFR-1 is also hypothesized to enable the development of cancer metastases by means of activation and premetastatic localization in distant organs of bone marrow-derived hematopoietic progenitor cells, which express VEGFR-1. IMC-18F1 is a fully human IgG(1) antibody that binds to VEGFR-1 and has been associated with the inhibition of cancer growth in multiple in vitro and human tumor xenograft models. The preliminary results of phase 1 investigations have also indicated a favorable safety profile for IMC-18F1 at doses that confer antibody concentrations that are associated with relevant antitumor activity in preclinical models.
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PMID:Vascular endothelial growth factor receptor-1 in human cancer: concise review and rationale for development of IMC-18F1 (Human antibody targeting vascular endothelial growth factor receptor-1). 2012 48

Differentiated thyroid cancer accounts for >90% of cases of thyroid cancer, with most patients having an excellent prognosis. Distant metastases occur in 10%-15% of patients, decreasing the overall 10-year survival rate in this group to 40%. Radioactive iodine has been the mainstay of treatment for distant metastases, with good results when lesions retain the ability to take up iodine. For patients with metastatic disease resistant to radioactive iodine, treatment options are few and survival is poor. Chemotherapy and external beam radiotherapy have been used in these patients, but with disappointing results. In recent years, our understanding of the molecular pathways involved in thyroid cancer has increased and a number of molecular targets have been identified. These targets include the proto-oncogenes BRAF and RET, known to be common mutations in thyroid cancer; vascular endothelial growth factor receptor and platelet-derived growth factor receptor, associated with angiogenesis; and the sodium-iodide symporter, with the aim of restoring its expression and hence radioactive iodine uptake. There are now multiple trials of tyrosine kinase inhibitors, angiogenesis inhibitors, and other novel agents available to patients with metastatic thyroid cancer. This review discusses both traditional and novel treatments for metastatic differentiated thyroid cancer with a particular focus on emerging treatments for patients with radioactive iodine-refractory disease.
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PMID:Standard and emerging therapies for metastatic differentiated thyroid cancer. 2014 32

Bilateral spontaneous pneumothorax is a rare occurrence in patients with both primary and metastatic lung cancer. Pneumothorax occurring as a complication of vascular endothelial growth factor receptor (VEGFR) inhibitor therapy has not been previously described in the medical literature. Sunitinib malate is a VEGFR inhibitor approved for the treatment of advanced renal cell carcinoma. We present a patient with metastatic renal cell carcinoma manifested as bilateral pulmonary nodules who developed a bilateral spontaneous pneumothorax 3 weeks after initiation of sunitinib therapy. We believe that sunitinib therapy resulted in necrosis of multiple pleural-based pulmonary nodules with central cavernization and ultimately rupture with bronchopleural fistula formation. Based on this experience, we advise that practitioners exercise caution when prescribing anti-VEGFR therapy in patients with pleural-based pulmonary metastases and recognize that the efficacy and toxicity of these agents may be closely linked.
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PMID:Spontaneous bilateral pneumothorax in metastatic renal cell carcinoma on sunitinib therapy. 2020 63

Hepatocellular carcinoma (HCC) is an intrinsically chemotherapy refractory malignancy. Development of effective therapeutic regimens would be facilitated by improved preclinical HCC models. Currently, most models consist of subcutaneous human tumor transplants in immunodeficient mice; however, these do not reproduce the extensive liver disease associated with HCC or metastasize. To address this deficiency, we developed an orthotopic model. Human HCC cells were transfected with the gene encoding secretable beta-subunit human choriogonadotropin (beta-hCG), which was used as a surrogate marker of tumor burden. The HCC cells were implanted into the left liver lobe of severe combined immunodeficient (SCID) mice, after which the efficacy of different therapies was evaluated on established, but liver-confined human Hep3B cell line HCC. Treatments included sorafenib or metronomic chemotherapy using cyclophosphamide (CTX), UFT, an oral 5-fluorouracil prodrug, or doxorubicin either alone or in various combinations, with or without an antiangiogenic agent, DC101, an anti-vascular endothelial growth factor receptor-2 antibody. Sorafenib inhibited tumor growth in a dose-dependent manner but caused severe weight loss in SCID mice, thus necessitating use of DC101 in subsequent experiments. Although less toxicity was observed using either single or doublet metronomic chemotherapy without any added antiangiogenic agent, none, provided survival benefit. In contrast, significantly improved overall survival was observed using various combinations of metronomic chemotherapy regimens such as UFT + CTX with DC101. In conclusion, using this model of liver-confined but advanced HCC suggests that the efficacy of a targeted antiangiogenic drug or metronomic chemotherapy can be mutually enhanced by concurrent combination treatment.
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PMID:Impact of metronomic UFT/cyclophosphamide chemotherapy and antiangiogenic drug assessed in a new preclinical model of locally advanced orthotopic hepatocellular carcinoma. 2023 20

Cervical cancer is known to metastasize primarily by the lymphatic system. Dissemination through lymphatic vessels represents an early step in regional tumor progression, and the presence of lymphatic metastasis is associated with a poor prognosis. In patients who have undergone a radical hysterectomy, lymphovascular space invasion (LVSI), assessed on hematoxylin and eosin-stained slides, is a major factor for adjuvant therapy in patients with cervical cancer. With the advent of a lymphatic endothelial cell-specific marker, such as D2-40, it is now possible to distinguish between blood and lymphatic space invasion (LSI). In this study, the utility of D2-40 was assessed for the detection of lymphatic vessel density (LVD) and identification of LSI. The expressions of vascular endothelial growth factor receptor-3 (VEGFR-3), VEGF-C, tyrosine receptor kinase-2, and angiopoietin-1 were assessed by immunohistochemical methods on 50 patients with squamous cell carcinoma of the cervix. Clinicopathologic characteristics, including pelvic lymph node metastasis, were correlated with the above histochemical findings. We found that lymphangiogenesis, measured by an increase in peritumoral LVD, was significantly associated with positive lymph node status (P < .005). VEGFR-3 expression was significantly associated with LVD (P < .05). D2-40 staining verified LSI (P = .03) and surpassed that of hematoxylin and eosin-identified LVSI (P = .54). In conclusion, lymphangiogenic markers, specifically LVD quantified by D2-40 and VEGFR-3, are independently associated with LSI and lymph node metastasis in patients with early squamous cell carcinoma of the cervix treated with radical hysterectomy and pelvic lymphadenectomy.
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PMID:Prognostic significance of peritumoral lymphatic vessel density and vascular endothelial growth factor receptor 3 in invasive squamous cell cervical cancer. 2056 58


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