Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

We report on a case of a 70-year-old woman with an ocular melanoma, which was diagnosed and treated 14 years ago. The patient was referred to the hospital with a suspected lymphoma. Cytological examination of bone marrow proved a marked infiltration with melanoma cells. Because detection of isolated tumor cells in the bone marrow of patients with various types of tumors was shown to be of prognostic significance and since current tumor-staging techniques are unable to detect single disseminated tumor cells or small aggregates of tumor cells, which might be the seed for subsequent metastatic relapse, we therefore evaluated the feasibility of immunocytochemical screening of bone marrow aspirates of 36 melanoma patients in different clinical stages using three monoclonal antibodies against melanoma-associated antigens in comparison with 43 non-melanoma control patients. Two of these antibodies (HMB45 and NKI-beteb) are directed against the melanoma antigen gp100/pmel17, whereas the third one (TA99) recognizes gp75/Tyrosinase-related protein 1 (TRP-1). None of the patients demonstrated a macroscopic bone marrow infiltration as was present in our patient with metastatic ocular melanoma. Seven (20.6%) of the 34 eligible melanoma patients presented with cells in the bone marrow positive for one or more of the above-mentioned melanosomal markers. Four of the positive patients were clinically free of tumors by the time of puncture, whereas the remaining 3 patients showed overt metastases in the subcutaneous fat (2 patients) and the brain (1 patient). On the other hand, 20 (66%) of the 29 patients with negative bone marrow findings also presented with clinical advanced disease with overt metastasis in the skin, lymph node, spleen, liver, lung, bone and brain. In conclusion, immunocytochemical screening of bone marrow samples is a feasible procedure that allows the detection of micrometastatic tumor cells in a subset of melanoma patients. Massive invasion of bone marrow with melanoma cells is a rare event even in far-advanced metastatic stages and no clear correlation between tumor load and bone marrow infiltration could be established.
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PMID:Limitations of the immunocytochemical detection of isolated tumor cells in frozen samples of bone marrow obtained from melanoma patients. 1270 45

A 51-year-old male presented with a 5 cm left knee mass. Fine needle aspiration revealed large epithelioid cells with prominent nucleoli and abundant cytoplasmic pigment, consistent with malignant melanoma. Left inguinal lymphadenopathy was present, which was suspicious for metastatic disease by ultrasound examination. A dark perianal skin lesion was also identified, therefore raising the possibility of a primary melanoma. The knee and perianal lesions were resected and inguinal sentinel node biopsy was performed. In the specimen from the knee, there were clusters and fascicles of spindle and epithelioid cells with prominent nucleoli. Many of the cells displayed abundant, granular, brown, cytoplasmic pigment. The lymph node showed clusters of similar cells located in the subcapsular sinus. Immunohistochemical study showed that the cells expressed CD68, but failed to express S-100, MART-1, and gp100. The cytoplasmic pigment was positive for iron staining. The final diagnosis was pigmented villonodular synovitis. This case illustrates that pigmented villonodular synovitis may present with lymphadenopathy, mimicking a malignant process, including melanoma. Immunohistochemical studies may be essential for establishing the correct diagnosis.
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PMID:Extensive pigmented villonodular synovitis with markedly pigmented lymphadenopathy and its implication for differential diagnosis with malignant melanoma. 1271 34

Activation of CTL-mediated antitumor immunity to self-epitopes expressed by neoplastic cells is thought to be prevented, at any stage of tumor progression, by tolerance mechanisms. In contrast, in 74 American Joint Committee on Cancer stages I-IV melanoma patients, we found that development of lymph node metastases is a key event triggering CD8(+) T-cell-mediated immunity to self-epitopes encoded by melanocyte differentiation antigens. This was shown by the increased peripheral precursor frequency to Melan-A/Mart-1, gp100, and tyrosinase epitopes in stage III and IV compared with stage I and II patients, and by accumulation of functional memory T cells directed to Melan-A/Mart-1(26-35) in tumor-invaded lymph nodes. However, in tumor-invaded lymph nodes of most patients, CD8(+) T cells directed to melanocyte differentiation antigens or to tumor-restricted antigens (MAGE-3 and NY-ESO-1 epitopes), showed a CCR7(+) CD45RA(+) CD27(+) CD28(+) perforin(-) "precursor" phenotype. Only in 7 of 23 cases antigen-specific CD8(+) T cells in invaded lymph nodes showed a predominant CCR7(-) CD45RA(-) CD27(+) CD28(-) perforin(+) "preterminally differentiated" phenotype. In the latter subset of patients, by immunohistochemistry in lymph node lesions, we found that CD8(+) T lymphocytes intermingling with the neoplastic tissue expressed a CCR7(-) CD45RO(+)/RA(-) phenotype, whereas CD4(+) lymphocytes did not infiltrate the tumor. Furthermore, perforin and granzyme B were expressed on a higher fraction of the CD8(+) cells surrounding the invading tumor compared with the lymphocytes infiltrating the neoplastic tissue. In addition, no evidence for tumor regression was found in such metastatic lesions, as documented by absence of neoplastic cell necrosis or apoptosis. These data indicate that neoplastic cells in the lymph nodes and/or increased tumor burden in metastatic disease activate CD8(+) T-cell-mediated antitumor immunity to self-epitopes. However, the paucity of terminally differentiated CD8(+) T cells at tumor site suggests that immunotherapy strategies may require not only the boosting of tumor immunity, but also effective means to promote CD8(+) T-cell differentiation in the neoplastic tissue.
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PMID:Lack of terminally differentiated tumor-specific CD8+ T cells at tumor site in spite of antitumor immunity to self-antigens in human metastatic melanoma. 1275 Feb 77

Spontaneous histopathological regression of cancer has been reported. The involvement of the immune system in such regression has been advocated, leading to the theory of immunological surveillance against cancer. A prediction of this theory is that common tumour antigens can be recognized upon repeated exposure by cell-mediated immunity, which leads to tumour regression and the subsequent appearance of tumour antigen-loss variants. However, no direct evidence has been provided in non-viral-induced experimental animal models of primary malignancy or in human primary cancer. This study examined two groups of melanoma patients where histopathological regression of the primary tumour was observed. Many of the 23 patients with multiple (> or =3) primary melanomas showed significant regression of their last melanoma (median 33%, mean 40) compared with matched melanomas from patients with a single primary melanoma (median 0%, mean 12) (p=0.0080), or compared with their first primary melanoma (p=0.0013). Regression was consistent with an 'immunization effect' seen in murine tumour transplantation studies, where inoculation with > or =3 asynchronous tumours induces transplantation rejection on subsequent challenge. A significant decrease in the expression of the melanoma common tumour antigen MART-1 in the last primary tumour from multiple melanoma patients (median 8%, mean 24) versus matched single melanoma patients (median 79%, mean 68) (p=0.0041) and in the last versus first tumour in multiple primary patients was found (p=0.0083). Metastases from 17 patients whose primary skin melanomas had completely regressed (occult primary melanoma) also showed significant MART-1 loss (median 0%, mean 11) compared with matched metastases from patients with non-regressing primary melanoma (median 51%, mean 50) (p=0.0013). MART-1 antigen-loss variants observed in the multiple primary and occult primary patients correlated with the presence of peripheral blood MART-1-specific cytotoxic T lymphocytes (CTLs) (p=0.03). No similar effects were observed with two other melanoma antigens, gp100 and CD63. Thus, in two groups of human melanoma patients, evidence is provided for histopathological tumour regression associated with cancer immune surveillance.
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PMID:Autonomous histopathological regression of primary tumours associated with specific immune responses to cancer antigens. 1702 27

We describe a new phenotype of wide occurrence in human cancer: expression of coarse vesicles rich in beta1,6-branched oligosaccharides. beta1,6-branching, catalyzed by GNT-V, is associated with metastasis and predicts poor survival in primary human breast and colon carcinomas. Yet little is known on the histopathology of this phenomenon. We studied beta1,6-branching [determined by leukocytic phytohemagglutinin (LPHA) lectin-histochemistry] in 119 archival specimens of human melanomas and other neoplasms, including carcinomas of the lung, colon, breast, ovary, prostate, kidney, and Hodgkin's lymphoma. At least portions of most tumors (96%) stained to some extent with LPHA. Staining was always, but not exclusively, associated with coarse vesicles. In melanomas, LPHA staining colocalized with CD63 and gp100. In pigmented melanomas, the vesicles were melanized and are known as "coarse melanin." LPHA-positive, coarse melanin was a feature of both tumor cells and melanophages and accounted for the well-known hypermelanotic regions of primary melanomas. LPHA-positive tumor cells varied widely in primaries (melanoma and others), ranging from 0 to 100% for a given tumor, whereas metastases were far more homogeneous (P = 0.0080), with vesicular, LPHA-positive tumor cells comprising >75% of 15 of 16 metastatic melanomas and renal cell carcinomas. In studies by others, GNT-V elicited formation of autophagy-dependent, LPHA-positive vesicles in mink lung alveolar cells (Hariri et al., Mol. Biol. Cell, 11: 255-268, 2000), suggesting that the coarse vesicles in tumors reported here may have been induced by GNT-V. Expression of the phenotype was so common and pervasive that it appeared to be an integral component of the biology of tumor progression. The origin of this phenotype and its biological significance are as yet unclear and will require considerable further study.
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PMID:Beta1,6-branched oligosaccharides and coarse vesicles: a common, pervasive phenotype in melanoma and other human cancers. 1450 Mar 69

Interleukin (IL)-1 is a pleiotropic inflammatory cytokine that promotes angiogenesis and enhances tumor growth and metastases. We evaluated the effects of IL-1 receptor antagonist (IL-1ra) on tumor growth and metastases in human melanoma xenografts. We selected two human melanoma lines (SMEL and PMEL) with differential (high versus low, respectively) constitutive production of IL-1 by ELISA. The IL-1ra gene was isolated from monocyte RNA by PCR and retrovirally transduced into SMEL and PMEL. In vitro cell proliferation was evaluated using a WST-1 assay. Athymic nude mice received s.c. or i.v. injection with parental, vector-transduced, or IL-1ra-transduced melanoma cells, and tumor growth, lung metastases, and histology were characterized. IL-1 was produced by SMEL in vitro and ex vivo (117 and 67 pg/ml/10(6) cells/24 h, respectively), but not by PMEL (15 and 0 pg/ml/10(6) cells/24 h, respectively). Neither made IL-1ra natively. Gene-transduced cell lines secreted >1000 pg/ml/10(6) cells/24 h of IL-1ra by ELISA. In vitro proliferation of each parental cell line was comparable to the proliferation rate of each transduced cell line. IL-1ra-transduced SMEL (SMEL/IL-1ra) showed significantly slower tumor growth compared with null-transduced and parental cell lines (P < 0.001, ANOVA-Bonferroni/Dunn). There was no difference in growth rates between PMEL and IL-1ra-transduced PMEL (PMEL/IL-1ra). A mixing study of SMEL and SMEL/IL-1ra showed significant inhibition of tumor growth at various ratios (P < 0.001, ANOVA-Bonferroni/Dunn). There were significantly fewer lung metastases with SMEL/IL-1ra versus SMEL (P < 0.002). IL-1ra decreases in vivo growth and metastatic potential of a human melanoma xenograft that constitutively secretes IL-1. This effect may be exploitable using clinically available IL-1ra for the treatment of human cancers.
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PMID:Effect of interleukin 1 receptor antagonist gene transduction on human melanoma xenografts in nude mice. 1452 22

We performed a phase I/II clinical trial in metastatic melanoma patients with an ultraviolet (UV)-inactivated nonreplicating recombinant vaccinia virus enabling the expression, from a single construct, of endoplasmic reticulum-targeted HLA-A0201-restricted Melan-A/MART-1(27-35), gp100(280-288), and tyrosinase(1-9) epitopes, together with CD80 and CD86 costimulatory proteins. Corresponding soluble peptides were used to boost responses and granulocyte-macrophage colony-stimulating factor was used as systemic adjuvant. Safety and immunogenicity, as monitored with in vitro-restimulated peripheral blood mononuclear cells by cytotoxic T lymphocyte precursor (CTLp) frequency analysis and tetramer staining, were specifically addressed. Of 20 patients entering the protocol, 2 had to withdraw because of rapidly progressing disease. Immune responses were evaluated in 18 patients (stage III, n = 5; stage IV, n = 13) and increases in specific CTLp frequencies were observed in 15. In 16 patients responsiveness against all 3 antigens could be analyzed: 7 (43%), including all stage III cases, showed evidence of induction of CTLs specific for the three epitopes, and 2 (12%) and 4 (25%), respectively, showed reactivity against two or one tumor-associated antigen. In three stage IV patients no specific CTL reactivity could be induced. Increases in CTLp frequency were detected mostly after viral vaccine injections. However, in a majority of patients final CTLp levels were comparable to initial levels. Tetramer characterization of Melan-A/MART-1(27-35)-specific CTLs during the protocol also suggested preferential expansion after recombinant virus administration. Vector-specific humoral responses, frequently undetectable in stage IV patients, did not appear to prevent tumor-associated antigen-specific CTL induction. Aside from a single occurrence of transient grade 3 leukopenia, no major clinical toxicity was reported. Seventeen of 18 patients completed the 3-month trial (one patient died before the last delayed-type hypersensitivity test). Three displayed regression of individual metastases, seven had stable disease, and progressive disease was observed in seven patients. This is the first report on the administration of a UV-inactivated recombinant vaccinia virus coexpressing five transgenes in cancer patients. The results described here, in terms of safety and immunogenicity, support the use of this reagent in active specific immunotherapy.
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PMID:Phase I/II clinical trial of a nonreplicative vaccinia virus expressing multiple HLA-A0201-restricted tumor-associated epitopes and costimulatory molecules in metastatic melanoma patients. 1457 12

Fusion hybrids between normal macrophages and Cloudman S91 melanoma cells were shown earlier to have increased metastatic potential, along with high expression of beta1,6-N-acetylglucosaminyltransferase V and beta1,6-branched oligosaccharides. Curiously, hybrids, but not parental melanoma cells, also produced 'coarse melanin'- autophagic vesicles with multiple melanosomes. As beta1,6-branched oligosaccharides were known to be associated with metastasis, and coarse melanin had been described in invasive human melanomas, we looked for potential relationships between the two. Using lectin- and immunohistochemistry, we analyzed cell lines producing coarse melanin for beta1,6-branched oligosaccharides: gp100/pmel-17 (a melanosomal structural component) and CD63 (a late endosome/lysosome component associated with melanoma and certain other human cancers). Cell lines used in this study were (i) hybrid 94-H48, a highly metastatic, macrophage-melanoma experimental fusion hybrid; (ii) 6(neo) mouse melanoma cells, the weakly metastatic, parental fusion partner; and (iii) SKmel-23, a human melanoma cell line derived from a metastasis. Coarse melanin granules were prominent both in hybrids and in SKmel-23 cells, and co-localized with stains for beta1,6-branched oligosaccharides, gp100/pmel 17, and CD63. This is the first report of this phenotype being expressed in vitro, although co-expression of beta1,6-branched oligosaccharides and coarse melanin was recently shown to be a common and pervasive characteristic in archival specimens of human melanomas, and was most prominent in metastases. The results suggest that pathways of melanogenesis in melanoma may differ significantly from those in normal melanocytes. In vitro expression of this phenotype provides new biological systems for more detailed analyses of its genesis and regulation at the molecular genetic level.
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PMID:Co-localization of beta1,6-branched oligosaccharides and coarse melanin in macrophage-melanoma fusion hybrids and human melanoma cells in vitro. 1514 74

Previous studies in small groups of patients suggested that immunization of melanoma patients with peptide epitopes recognized by T cells could induce regression of melanoma. This approach was tested in 36 patients with stage IV melanoma. The (MHC class I-restricted) peptides were from gp100, MART-1, tyrosinase, and MAGE-3. The gp100 and MART-1 peptides had been modified to increase their immunogenicity. In half the patients (groups 3 and 4) the peptides were given in the adjuvant Montanide-ISA-720, and half the patients in both groups were given GM-CSF s.c. for 4 days following each injection. Treatment was well tolerated except for two severe erythematous responses to Montanide-ISA-720 and marked inflammatory responses at sites of GM-CSF administration in three patients. There were no objective clinical responses but stabilization of disease for periods from 3 to 12 months were seen in seven patients. Five of these were patients given the peptides in Montanide-ISA-720. Delayed-type hypersensitivity (DTH) skin test responses were also seen mainly in the patients given the peptides in Montanide-ISA-720. GM-CSF did not increase DTH responses in patients in the latter group but may have increased DTH responses in those not given peptides in Montanide-ISA-720. Inflammatory responses around s.c. metastases or regional lymph nodes were observed in two patients. These results suggest that the peptides are more effective when given in the adjuvant Montanide-ISA-720. Nevertheless, results from this study, together with those from a number of comparable studies, indicate that peptide vaccines are currently of minimal benefit to patients and support the need for ongoing development of new strategies in treatment of this disease.
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PMID:Phase I/II study of immunotherapy with T-cell peptide epitopes in patients with stage IV melanoma. 1544 35

After vaccination of melanoma patients with MAGE antigens, we observed that even in the few patients showing tumor regression, the frequency of anti-vaccine T cells in the blood was often either undetectable or <10(-5) of CD8 T cells. This frequency being arguably too low for these cells to be sole effectors of rejection, we reexamined the contribution of T cells recognizing other tumor antigens. The presence of such antitumor T cells in melanoma patients has been widely reported. To begin assessing their contribution to vaccine-induced rejection, we evaluated their blood frequency in five vaccinated patients. The antitumor cytotoxic T lymphocyte (CTL) precursors ranged from 10(-4) to 3 x 10(-3), which is 10-10,000 times higher than the anti-vaccine CTL in the same patient. High frequencies were also observed before vaccination. In a patient showing nearly complete regression after vaccination with a MAGE-3 antigen, we observed a remarkably focused antitumoral response. A majority of CTL precursors (CTLp's) recognized antigens encoded by MAGE-C2, another cancer-germline gene. Others recognized gp100 antigens. CTLp's recognizing MAGE-C2 and gp100 antigens were already present before vaccination, but new clonotypes appeared afterwards. These results suggest that a spontaneous antitumor T cell response, which has become ineffective, can be reawakened by vaccination and contribute to tumor rejection. This notion is reinforced by the frequencies of anti-vaccine and antitumor CTLs observed inside metastases, as presented by Lurquin et al. (Lurquin, C., B. Lethe, V. Corbiere, I. Theate, N. van Baren, P.G. Coulie, and T. Boon. 2004. J. Exp. Med. 201:249-257).
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PMID:High frequency of antitumor T cells in the blood of melanoma patients before and after vaccination with tumor antigens. 1565 93


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