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)

The pigment epithelium of the retina (RPE) is derived from the optic cup and is essential for function and development of the eye. We produced a transgenic mouse line that expresses simian virus (SV40) transforming sequences under control of the 1.4 kb tyrosinase-related protein 1 (TRP-1) promoter, targeting expression of T antigen (Tag) to the RPE. In transgenic embryos, RPE cells proliferated in the anterior part of the eye and near the optic nerve. This resulted in formation of tumors, which were pigmented and of epithelial origin. In 3 months-old mice, pigmented cells were detected in spleen and inguinal lymph nodes. In spleen, tyrosinase, TRP-1 and SV40 Tag were expressed and tyrosinase was enzymatically active. Pigmented regions were positive for an epithelial marker, cytokeratin. Cell lines were established from tumor and metastases and kept in culture for more than 2 months. These were pigmented, and maintained expression of tyrosinase, TRP-1, cytokeratin and SV40 Tag. This demonstrates that RPE tumor cells metastasize to lymph node and spleen. In conclusion, the metastasis from TRP-1/Tag RPE tumors towards spleen and lymph nodes serves as potential tool to investigate biology and metastasis of tumors derived from the pigment epithelium.
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PMID:Tumors of the retinal pigment epithelium metastasize to inguinal lymph nodes and spleen in tyrosinase-related protein 1/SV40 T antigen transgenic mice. 984 Sep 23

There is ample evidence for spontaneous antimelanoma immune reactivity mediated by melanocyte-differentiation-antigens (MDAs). Our aim was to determine whether MDA immunoreactivity is associated with increased tumour-infiltrating lymphocytes (TIL) and macrophages (TIM). A retrospective study was conducted in 30 medium and high grade primary cutaneous melanomas (PCM) as identified by CART-analysis. All of the cases had developed clinical evidence for metastasis within 3 years following surgical excision of the PCM. We used immunohistochemistry and computerized image analysis to quantify MDAs positive cells (Melan A/MART-1, gp100/Pmel 17/HMB45, tyrosinase), CD45R0-positive TIL and LI-protein-positive TIM. A stochastic relationship was present between the MDA immuno-reactivities and the densities in TIL and TIM. An inverse relationship was yielded between TIL and TIM. No specific pattern of PCM immunoreactivity for MDAs, TIL and TIM was found to predict metastases.
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PMID:Patterns of the immunohistochemical expression of melanoma-associated antigens and density of CD45R0+ activated T lymphocytes and L1-protein positive macrophages in primary cutaneous melanomas. 985 Jul 42

Determination of blood tyrosinase mRNA by RT-PCR and markers of tyrosinase activity (L-DOPA/L-tyrosine ratio) by HPLC have been proposed as biological tools for the detection of metastases in melanoma patients. We prospectively evaluated their significance and clinical value in a group of 30 stage III (n = 10) and IV (n = 20) melanoma patients and one with melanosis of Dubreuilh. L-DOPA/L-tyrosine ratio was elevated in 30% of stage III, 41% of stage IV patients (range: 7.5-261.0 x 10(5)) and in melanosis of Dubreuilh (184.8) (reference values: 6-16 X 10(5)). One stage III and four stage IV melanoma patients were positive for tyrosinase mRNA. In stage IV patients, tyrosinase mRNA positivity was associated with disease progression (P<0.01). The presence of tyrosinase mRNA in blood is more related to clinical status than level of melanin precursors, which probably reflects tumor burden.
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PMID:Simultaneous analysis of tyrosinase mRNA and markers of tyrosinase activity in the blood of patients with metastatic melanoma. 1034 Apr 38

Recent reports suggest that as a marker of progression of malignant melanoma, the detection of tyrosinase mRNA in blood is of limited value. In the present study, we investigated whether the detection of tyrosinase mRNA by reverse transcription-polymerase chain reaction (RT-PCR) in bone marrow samples might be a more useful method for the detection of micrometastatic melanoma. The presence of tyrosinase mRNA was analysed in blood and in bone marrow samples from 20 melanoma patients with widespread clinical metastases. Of these 20 patients, 12 were negative for tyrosinase mRNA in both blood and bone marrow. The remaining eight patients had tyrosinase mRNA in either blood or bone marrow: six in bone marrow and blood, one in bone marrow but not blood, and one in blood but not bone marrow. The sensitivity of tyrosinase mRNA detection by RT-PCR in bone marrow samples apparently does not exceed that in blood samples from metastatic melanoma patients. This seems to be independent of prior chemotherapy or immunotherapy. In contrast to different solid tumours, in melanoma, bone marrow seems not to be a significant reservoir for micrometastatic tumour cells.
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PMID:The detection of tyrosinase-specific mRNA in bone marrow is not more sensitive than in blood for the demonstration of micrometastatic melanoma. 1035 71

Physical examination and ultrasound B-scan screening are important follow-up procedures in melanoma patients with regional disease. However, they do not allow definite diagnosis of suspicious lesions. Fine-needle aspiration cytology (FNAC) enhances the diagnostic accuracy in such patients but, unfortunately, reaches its technical limits, particularly when very small or necrotic lesions are examined. We therefore tested whether tyrosinase reverse transcription polymerase chain reaction (RT-PCR) of fine-needle aspirates (FNA-PCR) could help to increase diagnostic sensitivity. With clinical follow-up in 69 melanoma patients 81 regional lymph nodes were detected by ultrasound B-scan examination, nine of whom appeared to be palpable. Technically, FNAC was successful in all 81 lymph nodes, while FNA-PCR failed to obtain RNA at detectable levels in two lymph nodes of two patients. Of 79 lesions which have been completely evaluated by B-scan, FNAC and FNA-PCR, 44 proved to be melanoma metastases by histopathology, while the remaining 35 lesions were finally classified as non-specific lymph nodes. Of the 44 melanoma metastases 80% (n = 35) have been detected by B-scan, 90% (n = 39) by FNAC and 100% (n = 44) by FNA-PCR (P < 0.05 vs FNAC, P < 0.005 vs B-scan). In the subclass of lesions with diameters below 10 mm the sensitivities were 72% (n = 13), 78% (n = 14) and 100% (n = 18) respectively. In 35 regional lymph nodes classified as benign lesions, FNAC was always negative while FNA-PCR produced one positive result. Neither of these methods did produce false positive results in 15 control lymph nodes of non-melanoma patients. We conclude, that FNA-PCR might have superior sensitivity as compared to FNAC or ultrasound B-scan, particularly in melanoma lesions with diameters below 10 mm.
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PMID:Detection of regional melanoma metastases by ultrasound B-scan, cytology or tyrosinase RT-PCR of fine-needle aspirates. 1040 17

In advanced stages of malignant melanoma (MM), metastases to the CNS are frequently observed. Few results are available on trophic factors and immunological features involved in the process of invasion and adhesion of circulating metastatic cells into the CNS. A direct comparison of remote metastases found in different locations of the same patient might help to identify such properties. For this purpose, we screened a panel of MM cell cultures, which had been established from patients with surgically removed MM lesions of the CNS, for expression and regulation of immunorelevant molecules. The results were compared with standard controls and cultures established from non-CNS metastatic lesions of the same patients. No significant differences were observed for expression of HLA-I, HLA-II, ICAM-1 and the melanoma-associated antigens Mage-3, MelanA and tyrosinase. Constitutive expression of the neuronal cell adhesion molecule (NCAM) was found in all CNS-derived samples and in fewer than 50% of non-CNS derived cultures. IFN-gamma was found to have a weak up-regulating effect in all non-CNS-derived cultures, except normal melanocytes. However, in 6/7 CNS-derived cultures, pre-treatment with IFN-gamma reduced expression of NCAM to 28% to 77% of the level in untreated cultures. The presence and regulation of NCAM differs between MM cells derived from CNS metastases and non-CNS-derived melanocytic cells. Thus, NCAM might be a candidate immunoregulating molecule involved in the formation of CNS metastases of MM.
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PMID:Inverse regulation of neuronal cellular adhesion molecule (NCAM) by IFN-gamma in melanoma cell cultures established from CNS lesions. 1044 20

Humoral immune responses against the "Cancer-Testis" (CT) antigen NY-ESO-1 are frequently observed in patients with NY-ESO-1 expressing tumors. This is in contrast to other known tumor antigens (TA) defined by antibody or cytotoxic T cell (CTL) reactivity, i.e., MAGE-1, MAGE-3, SSX2, Melan A, and tyrosinase. No NY-ESO-1 antibody has been detected in healthy controls and patients with NY-ESO-1 negative tumors. In this study, we have assessed the NY-ESO-1 serum antibody response in patients with NY-ESO-1 positive tumors of different histological types and stages using Western blotting and an ELISA. Of the 12 patients analyzed, 10 had demonstrable NY-ESO-1 antibodies at the start of the study. All patients were followed for changes in NY-ESO-1 antibody titers during the course of tumor treatment and clinical evolution. In 4 patients, an increase of NY-ESO-1 antibody titer was observed with progression of disease or extensive tumor necrosis under treatment. One patient showed a stable NY-ESO-1 antibody titer over 3 years along with gradual regression of a large tumor mass. In 5 patients, a decrease of NY-ESO-1 antibody was detected: in 1 patient after curative tumor resection, in 3 patients with partial regression of metastatic disease under chemo- and immunotherapy, and in another patient with a NY-ESO-1 negative tumor relapse. Our results indicate that the induction and maintenance of NY-ESO-1 antibody is dependent on the presence of NY-ESO-1 expressing tumors. Furthermore, changes in NY-ESO-1 antibody titers correlate with the evolution of NY-ESO-1 positive disease.
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PMID:Humoral immune responses of cancer patients against "Cancer-Testis" antigen NY-ESO-1: correlation with clinical events. 1050 28

Detection of melanoma cells in the peripheral blood has been facilitated by the reverse transcriptase-polymerase chain reaction (RT-PCR), but their presence is of uncertain importance in the evolution of the disease. We studied the detection of melanoma cells using RT-PCR in the peripheral blood of 21 patients, four with regional lymph node metastases (American Joint Committee on Cancer [AJCC] stage III) and 17 with disseminated disease (AJCC stage IV). RNA was extracted from 10 ml of heparinized blood following density gradient centrifugation and converted into cDNA for PCR analysis. Assay sensitivity of 10 cells in 10(7) mononuclear cells and granulocytes obtained from 10 ml of peripheral blood was achieved using the G361 and C32 melanoma cell lines. Tyrosinase mRNA was not detected in control samples from healthy volunteers or patients with non-malignant disease. Six patients (one stage III, five stage IV) tested positive for tyrosinase mRNA (28.6%); with one exception, all patients were receiving chemotherapy at the time of sampling. Of the six positive results, three were from patients who initially tested negative but were subsequently positive after a 3-4 week interval. The low detection rates of melanoma cells in the peripheral blood of patients with widely disseminated disease is consistent with recent reports and correlates poorly with the clinical stage of melanoma. This may be partly explained by the clinically observed intermittent and random evolution of melanoma metastases.
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PMID:Detection of tyrosinase mRNA by RT-PCR in the peripheral blood of patients with advanced metastatic melanoma. 1050 59

To examine the distribution of occult micrometastases that could be potential sources of recurrence, complete maps of microscopic and submicroscopic metastases in entire inguinal lymph node basins were generated in 13 melanoma patients who had undergone elective or therapeutic lymphadenectomy. Occult micrometastases were analysed immunohistochemically for the pigment cell-specific antigen HMB-45 in all 155 nodes and using a reverse transcriptase-polymerase chain reaction (RT-PCR) assay to detect tyrosinase mRNA in 35 nodes. Five patients were determined to be node-negative by routine histopathology; three of these subjects were also negative by RT-PCR and/or immunohistochemistry. However, the remaining two patients had occult metastases, which were confined to a possibly sentinel node in one and were detected in multiple nodes in the other. Eight patients had histological evidence of lymph node metastasis. Three of these patients had no additional detectable submicroscopic disease, and one had occult metastasis in one node adjacent to the histologically positive node. In contrast, the other four patients had occult micrometastases in multiple non-sentinel, higher level nodes. The two patients who relapsed belonged to this group. The results show considerable variation in the distribution pattern of occult metastases in the regional lymph nodes, and have significant implications for the role of regional lymph node dissection, including sentinel node mapping with selective lymphadenectomy, in the management of melanoma patients.
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PMID:Mapping of occult melanoma micrometastases in the inguinal lymph node basin by immunohistochemistry and RT-PCR. 1050 60

The aim of our study was to investigate the metastatic pathways of melanoma cells in sentinel and other regional lymph nodes. The term "sentinel lymph node" means that the first lymph node of the draining site of a primary tumor is never bypassed in malignant melanoma. In this case lymph node dissection would be necessary only when melanoma cells are detected in the sentinel node. Tyrosinase reverse transcriptase-polymerase chain reaction was applied to search for metastatic melanoma in the sentinel lymph node and in further lymph nodes of a complete lymph node basin in patients who underwent lymph node dissection. In 24 patients with malignant melanoma the draining site of the tumor was marked by lymphoscintigraphy and by intraoperative injection of patent blue V in the area around the primary tumor. The lymph nodes of the affected basin were excised and prepared for histopathologic, immunohistochemical, and molecular biologic examinations. Regarding the sentinel lymph node, 10 of 24 patients showed morphologic evidence for metastases, three additional patients showed only tyrosinase transcripts. In 11 of these 13 cases we found one or more nonsentinel lymph nodes with morphologically detectable melanoma cells and/or tyrosinase mRNA. Interestingly, in seven of 24 patients a positive tyrosinase reverse transcriptase-polymerase chain reaction was received in nonsentinel lymph nodes, whereas the sentinel lymph node was negative, not only for all histologic examinations but also by tyrosinase reverse transcriptase-polymerase chain reaction. In five of seven patients of the latter group, gp100 reverse transcriptase-polymerase chain reaction was carried out, showing also gp100 mRNA in nonsentinel lymph nodes only. Our data indicate that the concept of the sentinel lymph node may miss micrometastases. Whether such micrometastases cause a recurrence or a metastasis of malignant melanoma, or can be destroyed by the immune system, remains to be clarified.
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PMID:Detection of melanoma micrometastases in the sentinel lymph node and in nonsentinel nodes by tyrosinase polymerase chain reaction. 1050 40


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