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)

Adhesion molecules involved in leukocyte recruitment and lymphocyte recirculation impact on several aspects of tumor biology--the primary host response, the delivery of effective adoptive immunotherapy and the hematogenous spread of malignant cells. Common to all three processes are receptor-mediated adhesive interactions between circulating cells and the vessel wall. Recruitment of circulating lymphocytes, monocytes and natural killer cells is essential for an effective host response or successful adoptive immunotherapy. Thus poor induction or blockade of leukocyte binding sites on the microvasculature of tumor implants may help malignancies evade natural defenses. In addition, perturbation of adhesion receptor function during ex vivo expansion may alter the behavior of infused cells in adoptive immunotherapy protocols. Finally, circulating malignant cells may utilize receptors normally involved in recruitment and recirculation. This paper reviews the function and regulation of adhesion molecules involved in normal leukocyte trafficking. The evidence implicating specific adhesion receptors in the spread of lymphoid malignancies through the bloodstream is then discussed.
Invasion Metastasis 1992
PMID:Adhesion molecules involved in the trafficking of normal and malignant leukocytes. 139 99

When 5 million cells of the solid form 13762 rat mammary carcinoma are implanted into the footpad of syngeneic rats there is consistent (approximately 100%) metastasis to the draining popliteal node and thence up the lymphatic chain to the lungs. With the transmission electron microscope tumor cells are seen to penetrate gaps in the lymphatic endothelium, probably but not certainly, between endothelial cells. There is neither widespread patency nor significant destruction of lymphatic endothelium. The tumor cells penetrate in groups and lie in the lymphatic in groups with some evidence of acinar differentiation. Tumor cells lodge in groups in the subcapsular sinus and progressively pass down the radial sinusoids and destroy the node; as they grow there is extensive differentiation into adenocarcinoma. The draining lymph obtained by cannulation does not contain an increase in total cells. A few tumor cells are present mostly in clumps. Recruitment is continuous but not progressively increasing. Any theories on neoplastic invasion and metastasis must take into consideration possible aggregation of some tumor cell types in groups. The literature on experimental lymphatic metastasis is reviewed briefly.
Invasion Metastasis 1981
PMID:Lymphatic metastasis of mammary adenocarcinoma. An experimental study in the rat with a brief review of the literature. 676 47

Melanoma is the main cause of death in patients with skin cancer. Cytotoxic T lymphocytes (CTLs) attack melanoma cells in an HLA-restricted and tumor antigen-specific manner. Several melanoma-associated tumor antigens have been identified. These antigens are suitable candidates for a vaccination therapy of melanoma. Dendritic cells (DCs) are antigen-presenting cells (APCs) specialized for the induction of a primary T-cell response. Mouse studies have demonstrated the potent capacity of DCs to induce antitumor immunity. In the present clinical pilot study, DCs were generated in the presence of granulocyte/macrophage-colony stimulating factor (GM-CSF) and interleukin 4 (IL-4) and were pulsed with tumor lysate or a cocktail of peptides known to be recognized by CTLs, depending on the patient's HLA haplotype. Keyhole limpet hemocyanin (KLH) was added as a CD4 helper antigen and immunological tracer molecule. Sixteen patients with advanced melanoma were immunized on an outpatient basis. Vaccination was well tolerated. No physical sign of autoimmunity was detected in any of the patients. DC vaccination induced delayed-type hypersensitivity (DTH) reactivity toward KLH in all patients, as well as a positive DTH reaction to peptide-pulsed DCs in 11 patients. Recruitment of peptide-specific CTLs to the DTH challenge site was also demonstrated. Therefore, antigen-specific immunity was induced during DC vaccination. Objective responses were evident in 5 out of 16 evaluated patients (two complete responses, three partial responses) with regression of metastases in various organs (skin, soft tissue, lung, pancreas) and one additional minor response. These data indicate that vaccination with autologous DCs generated from peripheral blood is a safe and promising approach in the treatment of metastatic melanoma. Further studies are necessary to demonstrate clinical effectiveness and impact on the survival of melanoma patients.
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PMID:Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells. 950 May 93

In axillary node-negative primary breast cancer, 70% of the patients will be cured by locoregional treatment alone. Therefore, adjuvant systemic therapy is only needed for those 30% of node-negative patients who will relapse after primary therapy and eventually die of metastases. Traditional histomorphological and clinical factors do not provide sufficient information to allow accurate risk group assessment in order to identify node-negative patients who might benefit from adjuvant systemic therapy. In the last decade various groups have reported a strong and statistically independent prognostic impact of the serine protease uPA (urokinase-type plasminogen activator) and its inhibitor PAI-1 (plasminogen activator inhibitor type 1) in node-negative breast cancer patients. Based on these data, a prospective multicenter therapy trial in node-negative breast cancer patients was started in Germany in June 1993, supported by the German Research Association (DFG). Axillary node-negative breast cancer patients with high levels of either or both proteolytic factors in the tumor tissue were randomized to adjuvant CMF chemotherapy versus observation only. Recruitment was continued until the end of 1998, by which time 684 patients had been enrolled. Since then, patients have been followed up in order to assess the value of uPA and PAI-1 determination as an adequate selection criterion for adjuvant chemotherapy in node-negative breast cancer patients. This paper reports on the rationale and design of this prospective multicenter clinical trial, which may have an impact on future policies in prognosis-oriented treatment strategies.
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PMID:Tumor-biological factors uPA and PAI-1 as stratification criteria of a multicenter adjuvant chemotherapy trial in node-negative breast cancer. 1076 45

During recent years it has become evident that protein kinase B (PKB)/Akt plays an important role in oncogenic transformation. The gene for PKB/Akt has been found to be overexpressed in certain human tumours and a viral fusion protein gains transforming capacity. Recruitment to the plasma membrane is mandatory for the physiological activation of PKB/Akt; this shift from cytoplasm to the membrane is achieved by the N-terminal pleckstrin homology (PH) domain. We attempted to find out whether mutations of this domain were present in human malignant melanoma. RNA from 18 primary melanoma lesions of different sizes and histological subtypes and two melanoma metastases from 20 Caucasian patients were used for reverse transcription and subsequent polymerase chain reaction (PCR) amplification of the PH domain of PKB/Akt alpha. Cycle sequencing of the purified PCR products showed that mutations of the PH domain of PKB/Akt were absent in all 20 melanoma specimens. In virtual Northern hybridizations PKB/Akt showed a low expression in both melanomas and acquired melanocytic naevi; however, no overexpression of PKB/Akt was detected. Thus in human melanoma PH domain mutations of PKB/Akt do not play a major role in melanoma carcinogenesis.
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PMID:Absence of mutations in the pleckstrin homology (PH) domain of protein kinase B (PKB/Akt) in malignant melanoma. 1182 57

Vinorelbine (VNR) is a semi-synthetic vinca alkaloid (5'nor-anhydro-vinblastine) that differs from other vinca alkaloids by a modification of the catharantine moiety of the molecule. VNR binds to tubulin and inhibits tubulin assembly and microtubule formation. It has less activity than other vinca alkaloids against axonal microtubules and this may account for its reduced neurotoxicity in clinical use. In gastrointestinal tumours, VNR did not show significant activity in advanced pancreatic adenocarcinomas. Two phase II studies in metastatic colorectal cancer resulted in conflicting results: no activity in first-line therapy on lung metastases, but encouraging results in 5-fluorouracil (5-FU)-resistant metastases. Conversely, significant antitumoural effect in oesophageal squamous cell carcinoma has been demonstrated. The first study was performed in 46 patients with metastatic disease. Six of 30 patients (20%) without prior chemotherapy achieved a partial response (95% confidence interval (CI), 8-39%). One of 16 (6%) with prior chemotherapy responded. Grade (gr) 3 or 4 granulocytopaenia occurred in 59% of patients and peripheral neurotoxicity was minor (26% gr 1). These results were confirmed by another group. A phase I study was performed using VNR and concurrent radiation (64 Gy) in previously untreated patients with inoperable locally advanced oesophageal cancer ineligible for cisplatin-5-FU-based chemoradiation. Twenty-four patients entered the study. The maximal tolerated dose has been reached at 25 mg/m(2)/week, the dose-limiting toxicities being febrile neutropaenia and infection. Major objective tumour response was observed at each dose level except the first one. Recruitment is ongoing to confirm the recommended dose of VNR (20 mg/m(2)/week). A phase II study of a VNR-cisplatin combination in metastatic oesophageal squamous cell carcinoma was recently completed. Seventy-one eligible patients were included. Main toxicities were haematological (gr 3-4 granulocytopaenia, 41%), infection, vomiting and fatigue. The response rate was 37% (95% CI, 26-49%) with a median duration of response of 7.7 months. This 2-day regimen appears at least as active and less toxic than the standard 5-day 5-FU and cisplatin regimen.
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PMID:Activity of vinorelbine in gastrointestinal cancers. 1200 75

Adhesion of inflammatory cells to vascular endothelium is mediated by specific cell adhesion receptors on both leukocytes and endothelial cells. One of the adhesion molecules on the endothelium is P-selectin. Decreased vascular P-selectin expression has been associated with tumor progression in melanoma patients. We now report on the expression of endothelial P-selectin in colorectal cancer (CRC). We studied a colorectal tissue specimen series ranging from normal colorectal tissue via unmetastasized primary tumors to tumors with the same depth of invasion at the primary site but with liver metastases. Moreover, P-selectin expression levels in liver metastases were determined. The number of P-selectin positive vessels as a fraction of the total number of vessels, both intra- and peritumorally, was determined by staining for CD62P and CD34, respectively. Furthermore, by immunostaining for leukocytes (CD45) and macrophages (CD68), it was evaluated whether levels of P-selectin expression influenced infiltrate density and composition. The results showed that levels of peritumoral P-selectin expression were reciprocal to the degree of progression in CRC. This relation was even more pronounced intratumorally: in metastasized primary tumors and in the metastatic lesions, P-selectin expression was virtually absent. This distribution pattern was reflected in the numbers of leukocytes that accumulated in the various tissues, since in the primary tumors with metastases, and in the metastatic lesions, hardly any infiltrating cells were observed. In these lesions, leukocytes were present in the peritumoral zone, but seemed unable to enter the tumor tissue. In primary tumors without metastasis, the intratumoral leukocyte infiltration density was significantly higher. Recruitment levels of macrophages remained constant throughout the different tissues. We suggest that downregulation of endothelial P-selectin expression is a mechanism by which CRC lesions evade inflammatory regression and, thereby, progress to a more advanced stage of malignancy.
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PMID:Progressive loss of endothelial P-selectin expression with increasing malignancy in colorectal cancer. 1564 Aug 34

Recruitment of patients into drug trials is essential in order to evaluate new treatments. Knowing why patients enter drug trials and their fears regarding them can be used in future research to ensure good recruitment and provide a supportive atmosphere for patients. Forty patients with colorectal cancer and 30 patients with colorectal liver metastases were asked to participate in a drug trial involving the oral consumption of a diet-derived agent of unknown therapeutic action. All patients agreeing or refusing to participate were asked to complete a short questionnaire with a series of options detailing the reasons behind their decision. Patients with colorectal hepatic metastases were motivated by altruism in entering the trial (e.g. helping others, helping the investigator) and displayed a realistic expectation that the drug would give little direct benefit to them. Patients with primary colorectal tumours were motivated by more 'selfish' reasons such as helping themselves and displayed an unrealistic expectation concerning any therapeutic benefit from the trial drug. Over 90% of all patients polled stated that their decision was made after reading the patient information leaflet. Patients with different stages of the same disease have very different fears and anticipations of drug trials, which need to be addressed specifically. The importance of the initial contact is demonstrated. Unrealistic expectations regarding the trial drug are common despite clear information to the contrary.
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PMID:Differences in attitudes between patients with primary colorectal cancer and patients with secondary colorectal cancer: is it reflected in their willingness to participate in drug trials? 1584 66

Epithelial ovarian cancer cells metastasize by implanting onto the peritoneal mesothelial surface of the abdominal cavity. Adhesive molecules that lead to this implantation remain unclear. The aim of our study was to focus on the role of vitronectin (Vn) and its receptors, alpha(v) integrins and urokinase plasminogen activator receptor (uPAR), in the interactions of ovarian adenocarcinoma cells (IGROV1 and SKOV3 cell lines) with mesothelial cells (MeT-5A cell line and primary cultures). For all cell lines, immunofluorescence staining disclosed the presence of Vn over the whole cell surface and in thin continuous deposits underlining the cell periphery. Recruitment of Vn receptors to cell-cell contact sites was also revealed. We developed two distinct methods for the evaluation of in vitro cell-cell adhesion using cocultures of the tumor and mesothelial cells. Both adhesion assays revealed a strong ability of ovarian cancer cells to adhere preferentially to mesothelial intercellular junctions. Adhesion of ovarian carcinoma cells to mesothelial cells was significantly inhibited using anti-Vn-, -alpha(v)-integrin- and -uPAR-blocking antibodies or cyclic peptide cRGDfV. These results evidence the ability of ovarian carcinoma cells to bind to peritoneal mesothelium in vitro and strongly suggest that Vn and its receptors contribute to this crucial event.
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PMID:Vitronectin and its receptors partly mediate adhesion of ovarian cancer cells to peritoneal mesothelium in vitro. 1878 Oct 95

Ewing sarcoma is a rare connective tissue tumor characterized by the translocation of the EWS gene, mainly between chromosome 11 and 22, giving rise to gene re-arrangements between the EWS gene and various members of the ETS gene family. Multi-agent chemotherapy has improved the outcome for patients with localized Ewing sarcoma, but survival of patients with recurrent/metastatic disease remains poor. An exploratory two-stage, single-arm Phase II multicenter trial of the synthetic alkaloid, PM00104, was conducted in patients with recurrent Ewing sarcoma. The primary end point of the trial was objective response rate. PM00104 was administered at a dose of 2 mg/m(2) on Days 1, 8 and 15 of a 4 week cycle. Seventeen patients were recruited. No objective responses were reported in the 16 patients evaluable for efficacy. Recruitment was closed without proceeding to the second stage of the trial. Four patients achieved stable disease as best response, and in two of these patients the stabilization was longer than 4 months. The median progression-free survival was 1.8 months (95 % CI, 0.9-3.5 months) and median overall survival was not reached (95%CI, 56.2 % at censored data). Pharmacokinetics in patients with Ewing sarcoma was similar to that previously reported in other patient populations. PM00104 showed modest activity in Ewing sarcoma at 2 mg/m(2) on a weekly schedule. There remains an unmet need for effective therapies for patients with advanced/metastatic Ewing sarcoma.
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PMID:A Phase II multicenter, open-label, clinical and pharmokinetic trial of PM00104 in patients with advanced Ewing Family of Tumors. 2417 65


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