Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0278883 (metastatic melanoma)
 6,224 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We performed immunohistochemical analysis for KIT in 365 soft tissue sarcomas. Most tumors evaluated were completely negative for KIT, including all cases of leiomyosarcoma, rhabdomyosarcoma, myxofibrosarcoma, liposarcoma, solitary fibrous tumor, synovial sarcoma, dermatofibrosarcoma protuberans, schwannoma, malignant peripheral nerve sheath tumor, clear cell sarcoma, low-grade endometrial stromal sarcoma, and follicular dendritic cell sarcoma. Tumors showing occasional immunoreactivity for KIT included extraskeletal myxoid chondrosarcoma (2/20), Ewing sarcoma/malignant primitive peripheral neuroectodermal tumor (4/20), melanotic schwannoma (3/5), metastatic melanoma (4/20), and angiosarcoma (5/20). In most cases, staining for KIT was focal. Rare tumor cells showing KIT positivity were identified in a small number of other tumors. This study demonstrates very limited expression of KIT in soft tissue tumors other than gastrointestinal stromal tumors and underscores the discriminatory value of KIT immunohistochemical analysis for differential diagnosis. As some of these findings differ markedly from previous reports, it is evident again that variations in immunohistochemical technique can lead to major discrepancies in positive staining. Since treatment eligibility for selective tyrosine kinase inhibitors such as STI571 hinges on positive immunostaining, standardization and reproducibility of meaningful results are critically important.
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PMID:Immunohistochemical staining for KIT (CD117) in soft tissue sarcomas is very limited in distribution. 1221 91

EphA2 (Eck) is a tyrosine kinase receptor that is overexpressed in several human cancers such as breast, colon, lung, prostate, gastric carcinoma, and metastatic melanoma but not in nonmalignant counterparts. To validate EphA2 as a tumor antigen recognized by CD8+ T lymphocytes, we used reverse immunology approach to identify HLA-A*0201-restricted epitopes. Peptides bearing the HLA-A*0201-specific anchor motifs were analyzed for their capacity to bind and stabilize the HLA-A*0201 molecules. Two peptides, EphA2(58) and EphA2(550), with a high affinity for HLA-A*0201 were selected. Both peptides were immunogenic in the HLA-A*0201-transgenic HHD mice. Interestingly, peptide-specific murine CTLs cell lines responded to COS-7 cells coexpressing HLA-A*0201 and EphA2 and to EphA2-positive human tumor cells of various origin (renal cell, lung, and colon carcinoma and sarcoma). This demonstrates that EphA2(58) and EphA2(550) are naturally processed from endogenous EphA2. In addition, EphA2(58) and EphA2(550) stimulated specific CD8(+) T cells from healthy donor peripheral blood mononuclear cells. These T cells recognized EphA2-positive human tumor cells in an HLA-A*0201-restricted manner. Interestingly, EphA2-specific CD8+ T cells were detected in the peripheral blood mononuclear cells of prostate cancer patients. These results show for the first time that EphA2 is a tumor rejection antigen and lead us to propose EphA2(58) and EphA2(550) peptides for a broad-spectrum-tumor immunotherapy.
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PMID:EphA2 as target of anticancer immunotherapy: identification of HLA-A*0201-restricted epitopes. 1467 12

The v-raf murine sarcoma viral homolog B1 (BRAF) gene, one of the human isoforms of RAF, is activated by Ras, leading to cooperative effects in cells responsive to growth factor signals. Recently, somatic missense mutations of the BRAF gene have been detected in more than 66% of malignant melanomas of the skin. We analyzed 42 malignant melanomas of the uvea, 3 corresponding liver metastases, and 10 cutaneous melanomas for possible BRAF mutations: after microdissection, mutation analysis of BRAF and KRAS was performed. The expression of extracellular-regulated kinase 1 and 2 (ERK1/2), an important downstream point of convergence in the Ras-RAF-MEK-Erk pathway, was analyzed immunohistochemically. Interestingly, we failed to detect activating BRAF mutations in uvea melanomas and their corresponding liver metastases. There were no mutations of BRAF in corresponding non-neoplastic uvea specimens, although we detected three BRAF mutations in sporadic cutaneous melanoma that led to a substitution of valine by glutamic acid at position 599 (V599E). KRAS mutations were detected in 1 of 10 cutaneous melanoma but not in uveal or metastatic melanoma. Despite the lack of activating mutations in the BRAF gene, we identified constitutively activated ERK in almost all (86%) uveal melanoma tissues tested but not in corresponding normal retina or uveal cells. Our data indicate that BRAF gene mutations are rare to absent events in uveal melanoma. The finding of activated Erk suggests a causative role for MAPK activation in uveal melanoma independent of activating BRAF or RAS mutations.
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PMID:Absence of mutations of the BRAF gene and constitutive activation of extracellular-regulated kinase in malignant melanomas of the uvea. 1469 Dec 95

A patient initially presented in 1988 with a solitary axillary mass, diagnosed as a high-grade neuroendocrine spindle-cell neoplasm; there was no history of a primary cutaneous malignancy. After subsequent development of a pulmonary nodule in 2001 (14-years post initial diagnosis), the case was reviewed and the possibility of metastatic melanoma was raised. The histopathologic and immunohistochemical profile of this melanocytic neoplasm was diagnostic of clear cell sarcoma (CCS) of tendons and aponeuroses, although the differential diagnosis included malignant melanoma, follicular dendritic and interdigitating cell tumors, malignant peripheral nerve sheath tumor, and a category of so-called PEComas. It is the role of pathologists, particularly dermatopathologists, to distinguish CCS from malignant melanoma, and to alert the clinician, because proper diagnosis ultimately influences treatment. We discuss the immunophenotype, differential diagnosis, and molecular signatures of these neoplasms, and review the pertinent literature on these entities.
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PMID:A 71-year-old man with spindle-cell neoplasm of unknown origin: a difficult-to-diagnose clear-cell sarcoma. 1534 90

A 40-yr-old woman with an asymptomatic sinonasal rhabdomyosarcoma (RMS) initially presented with submental nodal metastasis. The fine-needle aspiration (FNA) and the subsequent biopsy of the nodal metastasis were misinterpreted as metastatic carcinoma because the primary tumor was occult, the tumor cells were exclusively round cells with a nested arrangement, and rhabdomyoblasts were absent. The correct diagnosis of metastatic RMS became apparent when the primary sinonasal tumor, detected in a CT, was biopsy proven to be an alveolar RMS. Retrospectively, there were helpful clues to the correct diagnosis in the nodal FNA and biopsy. When FNA cytology or biopsy histology of a lymph node suggests metastatic carcinoma but the tumor cells are nonimmunoreactive to carcinoma markers, the differential diagnosis should be expanded to include not only metastatic melanoma but also metastatic sarcoma and lymphoma. Cytologically, the presence of multinucleated giant tumor cells, including the rosette forms, in the FNA smears should alert the cytopathologist to the possibilities of sarcoma and anaplastic large cell lymphoma.
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PMID:Rhabdomyosarcoma in an adult presenting with nodal metastasis: a pitfall in fine-needle aspiration cytology of lymph nodes. 1583 Mar 59

The senior author of this comprehensive review observed and reported in 1969 that his lymphocytes killed allogeneic tumor cells in vitro. Some of his research associates and technicians and other healthy individuals also yielded such killer lymphocytes. The team considered pre-immunization to cancer occurring in individuals after in-family or professional exposure to patients with cancer (in an era when the concept of viral etiology of cancer was receiving major support); or that lymphocytes can acquire through blastic transformation immune reactivity to allogeneic cells anew in vitro. The phenomenon was eventually referred to as 'lymphocytes practicing Burnet's immunosurveillance.' Project site visitors of the USA NCI first viewed these observations as a matter of 'in vitro artifacts' being in opposition to strong tumor- specific cytotoxicity of tumor-bearing patients' lymphocytes recognized in the vast majority of other assays. After NCI funds were released for intramural studies on the phenomenon of non-specific cytotoxicity by lymphocytes, recipients (other than the senior author) of these NCI funds later characterized (1973-1975) the 'indiscriminately' cytotoxic lymphocyte populations as those of 'natural killer (NK) cells.' In this article, the original observations made in 1969-1971 are reviewed based on genuine material preserved by the senior author and are explained in view of recent discoveries that were not available at the time of the original observations. NK cells display a fascinating history arising first in urochordates during the cambrian explosion. At that level, NK cells protected their hosts from incompatible cell colony fusions and against intracellular, especially viral, pathogens. Since then, viruses evolved evasive maneuvers to escape NK cell attack on the infected cells. NK cells persisted after the evolution of adaptive immunity in cartilaginous fish fitting seamlessly into the new system. In mammals, NK cells assumed the role of chief arbitrators between the fetal trophoblast and maternal immune reactions to the semi-allograft fetus. Tumors induce in NK cells the same (inactivating; mediating Th2-type immunity) reactions the fetal trophoblast engenders in utero, but NK cells may overcome the host's tolerance to its tumor and kill tumor cells, especially when converted into lymphokine-activated killer (LAK) cells by molecular mediators of Th1-type immunity. The authors prepare and utilize LAK cells and IL-2 for adoptive immunotherapy of patients with metastatic melanoma and kidney carcinoma. A patient with malignant ascites due to ovarian carcinoma entered remission on LAK cell therapy. Just as dendritic cells, the major antigen presentors, may undergo malignant transformation, NK cells are also subject to transformation into FasL-producer virulent lymphoma-leukemia cells. The senior author reported in 1970 a patient with 'lymphosarcoma cell leukemia' whose circulating lymphoma cells killed indiscriminately human sarcoma and carcinoma cells. The exemplary case history of another patient with NK cell lymphoma-leukemia treated by the authors is presented.
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PMID:Human natural killer cells: a comprehensive review. 1594 42

This study was designed to consider the cytomorphological spectrum, differential diagnosis, and the role of ancillary studies in small-cell tumors of the liver. Three independent pathologists reviewed cytological slides from 91 cases of small-cell tumors of the liver. The results were compared with the findings of three recently published studies (Cytopathology 11 (2000) 262-267; Diagn Cytopathol 19 (1998) 29-32; and Acta Cytol 40 (1996) 937-947). The role of immunohistochemistry in reaching timely and specific diagnoses was also examined. The diagnostic categories included 44 cases of metastatic small-cell undifferentiated carcinoma, 15 cases of metastatic neuroendocrine carcinoma, 10 cases of metastatic adenocarcinoma, 7 cases of malignant lymphoma, 4 cases of hepatocellular carcinoma with small-cell features, 2 cases of cholangiocarcinoma, 1 case of poorly differentiated carcinoma, and 8 cases of rare tumors including granulosa cell tumor (2 cases), sarcoma (4 cases), malignant melanoma with small-cell features (1 case), and meningioma with small-cell features (1 case). Metastatic granulosa cell-tumor, metastatic melanoma, and metastatic meningioma should be included in the differential diagnoses of small-cell malignancies found in the liver.
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PMID:Small-cell tumors of the liver: a cytological study of 91 cases and a review of the literature. 1594 87

In 2005, melanoma is estimated to affect 55,000 Americans. Of these, 7700 are estimated to die from the disease. Immunological approaches have yielded the only newly FDA-approved agents for melanoma in 30 years, which includes high-dose bolus IL-2, based on durable responses in some patients with metastatic melanoma. A survival advantage was shown in two of three randomised clinical trials with high-dose IFN-alpha2b in the high-risk adjuvant setting. However, both agents are associated with high cost and toxicity rates. A number of novel therapeutic agents are undergoing active clinical investigation. The more promising of these will be discussed in this review, including bcl-2 antisense therapy, v-raf murine sarcoma viral oncogene homologue B1 inhibition, heat-shock proteins, anti-alphavbeta3 integrin monoclonal antibody, thalidomide and newer immunomodulatory drugs, and anti-cytotoxic T lymphocyte-associated protein-4 monoclonal antibody.
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PMID:Novel agents in development for the treatment of melanoma. 1602 77

Melanoma is a highly malignant disease that may initially present as a poorly differentiated metastatic tumor. Therefore, the S100 immunostain, immunoreactive in 96% to 99% of melanoma, is used to evaluate poorly differentiated malignant tumors. To develop criteria for correctly diagnosing S100-negative melanomas, we studied the immunohistochemical profile of 1553 patients enrolled in ongoing National Cancer Institute clinical trials for melanoma. Seventeen patients (1%) had metastatic melanoma specimens that were negative for S100. Of the 17 S100-negative lesions, 10 (59%) were immunoreactive for both GP100 and MART-1. Of the 17 S100-negative cases, 13 had a documented primary melanoma. Twenty-four percent of the S100-negative cases had an ocular primary, whereas only 6% of all melanomas had an ocular origin. In 11 of the 17 cases with previous surgical specimens, a prior documented S100-immunoreactive specimen was identified in 9 cases (82%). The time interval for loss of S100 immunoreactivity ranged from 3 weeks to 3 years (average, 13.5 months). There was no association between S100-negative status and histological appearance or site of metastasis. We conclude that all S100-negative melanomas could be correctly identified by negative workup for carcinoma, lymphoma, and sarcoma plus (1) GP100/MART-1 immunoreactivity and/or (2) prior documentation of melanoma.
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PMID:Loss of S100 antigenicity in metastatic melanoma. 1615 66

Clear cell sarcoma is a high-grade sarcoma with morphological features resembling those of malignant melanoma. An osteoclast-rich tumor of the gastrointestinal tract with features resembling those of clear cell sarcomas of soft parts is very rare. Herein, we report an unusual stomach tumor with microscopic and immunohistochemical characteristics of an osteoclast-rich tumor of the gastrointestinal tract with features resembling those of clear cell sarcomas of soft parts. The tumor cells were predominantly oval, admixed with some round and spindle elements arranged in nests and fascicles, and admixed with scattered osteoclast-like multinucleated giant cells. Neoplastic cells were positive for S-100 protein, and osteoclast-like multinucleated giant cells were immunoreactive to CD68. The unusual morphology of the tumor caused significant diagnostic difficulties. The differential diagnosis included gastrointestinal stromal tumor, primary or metastatic melanoma, and epithelioid malignant peripheral nerve sheath tumor. To the best of our knowledge, this is possibly the second description of an osteoclast-rich tumor of the gastrointestinal tract with features resembling those of clear cell sarcomas of soft parts.
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PMID:Osteoclast-rich tumor of the gastrointestinal tract with features resembling those of clear cell sarcoma of soft parts. 1622 Feb 98


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