Metastatic Uveal Melanoma: An Ocular Melanoma Associated Antigen in the Serum of Patients with Metastatic Disease

Abstract

Two monoclonal antibodies, MAb8-1H and ME491, which bind to different determinants of the same highly glycosylated melanoma-associated antigen, were used to determine melanoma-associated antigen levels in serum samples from patients treated for primary choroidal or ciliary body melanoma and who subsequently developed systemic metastasis. An immunoassay was developed in which ME491 was absorbed to polystyrene beads in order to bind the melanoma-associated antigen present in serum. ¹²⁵I-MAb8-1H was used to detect the bound antigen. This double-determinant immunoassay is both sensitive and reproducible. Supernatant fluids of tissue cultured melanoma cell lines served as positive standards for the calculation of melanoma-associated antigen units. The mean serum levels of melanoma-associated antigen were 7.7 units for patients with benign ocular conditions, 9.51 units for patients with choroidal melanoma without documented metastatic disease, and 48.3 units for patients with choroidal melanoma and documented systemic metastasis. The clinical implications of using this test as a screening method for the detection of metastatic disease is discussed.     

Multinodular Goiter and Primary Hyperparathyroidism: A Circuitous Route to Diagnosing Metastatic Uveal Melanoma

Uveal melanoma spreads exclusively via a hematogenous route and is notable for its latency. Liver metastases are common; however, metastatic spread to unusual sites has been encountered. We report the case of metastatic uveal melanoma in a woman with multinodular goiter and primary hyperparathyroidism. The patient presented with hypercalcemia and an elevated intact parathyroid hormone level, in conjunction with a follicular neoplasm in the setting of goiter. She underwent an uneventful total thyroidectomy and parathyroidectomy. Postoperatively, she became normocalcemic. Histopathologic analyses revealed metastatic uveal melanoma cells within both the multinodular goiter and parathyroid adenoma. At present, she is enrolled in a phase II trial for disseminated uveal melanoma. This is a report of uveal melanoma metastatic to both a parathyroid adenoma and a nodular hyperplastic thyroid. Additionally, this case serves to display the unusual metastatic potential of uveal melanoma.     

Ultrastructural Organization of Uveal Melanoma Stromal Cells

Bulletin of Experimental Biology and Medicine - Typical blood capillaries and vessels in uveal melanoma were shown and different types of uveal melanoma stromal cells were determined by electron...     

Metastatic Melanoma: The Spectrum of Ultrastructural Morphology

The fine structure of 26 metastatic melanomas, including 13 pigmented and 13 amelanotic tumors, was studied to define ultrastructural criteria for diagnosis. Several important features in addition to melanosome granules were identified. Dendritic cytoplasmic processes were seen in 25 of the 26 cases, cell clusters formed by concentric aggregates of several cells and their processes were present in 18, and microvilli were found on cell surfaces in all cases. The cytoplasm was complex, containing numerous mitochondria, Golgi systems, endoplasmic reticulum, nonspecific filaments, and microtubules. Nuclear morphology was variable. Basement membranes and cell junctions including desmosomes were often encountered, and some melanomas shared features with Schwann cells, including complex membrane interdigitations. All tumors contained melanosomes, although the classic forms were frequently difficult to identify and abnormal variant forms often predominated. Knowledge of the variant melanosome morphology and an understanding of the other fine structural features of malignant melanocytes can help identify those cases that lack classic premelanosome granules.     

Metastatic Melanoma: The Spectrum of Ultrastructural Morphology

The fine structure of 26 metastatic melanomas, including 13 pigmented and 13 amelanotic tumors, was studied to define ultrastructural criteria for diagnosis. Several important features in addition to melanosome granules were identified. Dendritic cytoplasmic processes were seen in 25 of the 26 cases, cell clusters formed by concentric aggregates of several cells and their processes were present in 18, and microvilli were found on cell surfaces in all cases. The cytoplasm was complex, containing numerous mitochondria, Golgi systems, endoplasmic reticulum, nonspecific filaments, and microtubules. Nuclear morphology was variable. Basement membranes and cell junctions including desmosomes were often encountered, and some melanomas shared features with Schwann cells, including complex membrane interdigitations. All tumors contained melanosomes, although the classic forms were frequently difficult to identify and abnormal variant forms often predominated. Knowledge of the variant melanosome morphology and an understanding of the other fine structural features of malignant melanocytes can help identify those cases that lack classic premelanosome granules.     

Talimogene Laherparepvec: A Review in Unresectable Metastatic Melanoma

Talimogene laherparepvec (Imlygic?) is a first-in-class oncolytic viral immunotherapy derived from herpes simplex virus type 1, which has been genetically modified to increase tumour selectivity and stimulate antitumour immune response. This article reviews the pharmacological properties of intralesional talimogene laherparepvec and its clinical efficacy and tolerability in patients with unresectable metastatic melanoma. In the phase III OPTiM trial, talimogene laherparepvec was more effective than subcutaneous human granulocyte-macrophage colony-stimulating factor (GM-CSF), both in patients with stage IIIB–IV melanoma [intention-to-treat (ITT) population] and in those with stage IIIB–IVM1a disease (in an exploratory subgroup analysis). Durable response rate (DRR) was significantly higher with talimogene laherparepvec in the ITT population; beneficial results in DRR were also observed in talimogene laherparepvec recipients in patients with stage IIIB–IVM1a disease. Talimogene laherparepvec was generally well tolerated in clinical trials. In conclusion, talimogene laherparepvec is a novel, effective and well tolerated option for the treatment of patients with unresectable metastatic melanoma.     

Establishment and Characterization of Orthotopic Mouse Models for Human Uveal Melanoma Hepatic Colonization

Uveal melanoma (UM) is a rare type of melanoma, although it is the most common primary ocular malignant tumor in adults. Nearly one-half the patients with primary UM subsequently develop systemic metastasis, preferentially to the liver. Currently, no treatment is effective for UM hepatic metastasis, and the prognosis is universally poor. The main challenge in designing a treatment strategy for UM hepatic metastasis is the lack of suitable animal models. We developed two orthotopic mouse models for human UM hepatic metastases: direct hepatic implantation model (intrahepatic dissemination model) and splenic-implantation model (hematogenous dissemination model) and investigated the tumorgenesis in the liver. A human UM cell line, established from a hepatic metastasis and nonobese diabetic severe combined immunodeficient γ mice, were used for development of in vivo tumor models. In the direct hepatic implantation model, a localized tumor developed in the liver in all cases and intrahepatic dissemination was subsequently seen in about one-half of cases. However, in the splenic implantation model, multiple hepatic metastases were observed after splenic implantation. Hepatic tumors subsequently seeded intra-abdominal metastasis; however, lung metastases were not seen. These findings are consistent with those observed in human UM hepatic metastases. These orthotopic mouse models offer useful tools to investigate the biological behavior of human UM cells in the liver.Uveal melanoma (UM) is a rare form of melanoma but remains the most common primary ocular malignant tumor in adults. The annual incidence of the disease is 6.3 per million among whites, 0.9 among Hispanics, and 0.24 among blacks.¹ In North America, the incidence has been stable, and approximately 1500 cases per year are newly diagnosed.² Although the diagnostic modalities and the local treatments have improved over the past decades, with increased use of nonsurgical methods such as radiation for preservation of the eye, the mortality has remained unchanged because of the lack of effective treatments for metastatic disease. The eye lacks lymphatics, and metastatic spread exclusively occurs by the hematogenous route, especially to the liver. Up to 50% of patients with UM develop systematic metastasis after initial diagnosis and the treatment of the primary site. In patients that develop metastatic disease, the liver is the site of dissemination in 70% to 90% of cases.^{3, 4, 5} The site of metastasis affects length of survival. The median survival of the patients with only extrahepatic metastasis is approximately 19 to 28 months with a 1-year survival rate of approximately 76%.^{4, 6, 7} In contrast, the median survival of patients with hepatic metastasis is approximately 4 to 6 months with a 1-year survival rate of approximately 10% to 15%.^{8, 9} Currently, no standard treatment is able to prolong the survival of the patients with hepatic metastases; therefore, investigation on the pathogenesis of hepatic metastasis and the development of effective treatments for metastatic lesions in the liver are urgently needed to improve the prognosis of patients having this disease. In vivo models for human UM hepatic metastasis are essential to investigate its biological behavior and to test therapeutic strategies. Current models are limited by the use of cell lines derived from primary UM lesions and their growth in the subcutaneous tissue. Considering the hepatic tropism of UM, an orthotopic hepatic tumor model is essential to investigate the tumor progression and to test treatment efficacies in the liver microenvironment.^{10, 11} The evolution of UM hepatic metastasis consists of two phases: hematogenous spread of UM cells to the liver and intrahepatic growth and subsequent dissemination of the UM cells. In this study, we have developed two orthotopic mouse models of human UM hepatic metastasis with the use of a human UM cell line established from a hepatic metastasis (TJU-UM001) injected into nonobese diabetic severe combined immunodeficient γ (NSG) mice. The resulting lesions were characterized by macroscopic and histologic examinations. Moreover, we have generated a td-Tomato fluorescent protein-expressed UM cell line to permit noninvasive, quantitative, and temporal analysis of UM tumor colonization in the liver.     

Metastatic Melanoma with Balloon Cell Changes: An Electron Microscopic Study

A case of metastatic balloon cell melanoma is presented. The balloon cells are ultrastructurally characterized by the presence of numerous cytoplasmic vacuoles and abnormal melanosomes, which confirm their melanocytic origin. The study supports the concept that the cytoplasmic vacuoles represent grossly dilated melanosomes. The value of electron microscopic examination is emphasized in order to distinguish these lesions from other malignant clear cell tumors.     

Metastatic Melanoma with Balloon Cell Changes: An Electron Microscopic Study

A case of metastatic balloon cell melanoma is presented. The balloon cells are ultrastructurally characterized by the presence of numerous cytoplasmic vacuoles and abnormal melanosomes, which confirm their melanocytic origin. The study supports the concept that the cytoplasmic vacuoles represent grossly dilated melanosomes. The value of electron microscopic examination is emphasized in order to distinguish these lesions from other malignant clear cell tumors.     

Metastatic Spindle Cell Malignant Melanoma with Prominent Microvilli

A metastatic spindle cell malignant melanoma with positive immunoreactivity for S-100 protein and HMB-45 antigen and the presence of premelanosomes is described in a lymph node of the neck 11 years after removal of a superficial spreading malignant melanoma from the arm. Ultrastructurally, long, slender microvilli created a pattern with great similarity to an anemone cell tumor. A more solid pattern without microvilli was also present. Despite the abundance of microvilli in the anemone part of the tumor, intracytoplasmic lumina were not observed. In addition, crystalline structures within enlarged mitochondria and intracisternal tubules were noted.     

Metastatic Spindle Cell Malignant Melanoma with Prominent Microvilli

A metastatic spindle cell malignant melanoma with positive immunoreactivity for S-100 protein and HMB-45 antigen and the presence of premelanosomes is described in a lymph node of the neck 11 years after removal of a superficial spreading malignant melanoma from the arm. Ultrastructurally, long, slender microvilli created a pattern with great similarity to an anemone cell tumor. A more solid pattern without microvilli was also present. Despite the abundance of microvilli in the anemone part of the tumor, intracytoplasmic lumina were not observed. In addition, crystalline structures within enlarged mitochondria and intracisternal tubules were noted.     

Involvement of HIF-1 in Invasion of Mum2B Uveal Melanoma Cells

The propensity of uveal melanoma cells for invasion and metastasis is critical factor for the clinical outcome of this form of cancer, and the essential biology of its aggressiveness is not completely understood. In the present study we investigated the involvement of hypoxia-inducible factor 1 (HIF-1) in uveal melanoma migration, invasion and adhesion, the hallmarks of aggressive behavior of cancer cells. We demonstrate that exposure to hypoxia increased migration, invasion and adhesion of uveal melanoma cells in in vitro assays. The “silencing” of HIF-1α, the oxygen-regulated subunit of HIF-1, using RNA interference technology resulted in a marked decrease of the uveal melanoma cell migration, invasion and adhesion. GeneChip microarray analysis revealed that a number of genes which regulate cancer invasion and metabolism such as CXCR4, angiopoietin-related protein, pyruvate dehydrogenase kinase 1 (PDK1) are also activated by hypoxia in a HIF-1-dependent manner in Mum2B uveal melanoma cells. We further demonstrate that serum deprivation resulted in HIF-1 and CXCR4 activation, suggesting specific metabolic regulation of HIF-1 in these cells. Microarray analysis of serum-deprived cells identified among the upregulated genes a number of cancer invasion-related genes, some of them being known HIF-1-regulated targets. Taken together, these results suggest that the involvement of HIF-1 in uveal melanoma tumorigenesis is significant and complex, and that metabolic regulation of HIF-1 activation in Mum2B uveal melanoma cells has its specificities.     

转移性激素敏感性前列腺癌研究进展

在过去的七十多年,转移性激素敏感性前列腺癌（mHSPC）的标准治疗一直都是单独使用雄激素剥夺治疗（ADT）。直到近几年研究显示,多西他赛（DOC）联合ADT可显著提高mHSPC患者的生存率,引起了mHSPC治疗标准的改变。近期研究证实,ADT结合醋酸阿比特龙（AA）和泼尼松（P）同样可以改善mHSPC的生存率。因此,本文将结合近期临床试验,综述mHSPC治疗的新进展。     

Immunohistochemical Markers for Distinguishing Metastatic Breast Carcinoma from Other Common Malignancies: Update and Revisit

Due to the high prevalence of breast cancer in the female, a metastasis from primary breast cancer is usually considered in the differential diagnosis of metastatic carcinoma in the female patient, even for those without a history of breast cancer, as some breast cancers are first diagnosed as metastases. Immunohistochemical analysis for breast cancer markers is the most common way to determine breast cancer origin besides clinical history and histology. In this review, we (1) summarize the commonly used and the newly identified breast cancer markers, including GCDFP-15, mammaglobin, GATA3, SOX10, and TRPS1; (2) point out the strengths and weaknesses of using these markers for breast cancers with luminal/epithelial or basal/myoepithelial differentiation; and (3) recommend diagnostic panels to differentiate breast carcinoma from carcinoma with similar morphology of other origins.     

Quantified Visual Scoring of Metastatic Melanoma Patient Treatment Response Using Computed Tomography: Improving on the Current Standard

To assess whether quantitative visual scoring (QVS) is a better early predictor of progression-free survival (PFS) in patients on chemotherapy for metastatic melanoma using CT than the currently used Response Evaluation Criteria in Solid Tumors (RECIST) standard. Retrospective evaluation of 65 consecutive patients with metastatic melanoma on treatment who had a baseline and follow-up CT after two cycles of therapy. QVS was used to code imaging findings on the radiology reports considering size change, brain metastases, new lesions, mixed lesion response, and the number of organ systems involved. RECIST 1.1 criteria placed patients in the progressive disease, stable disease, or partial response groups. Multiple regression analysis was used to correlate the various independent variables with PFS. The Cox hazard proportions ratio, median survival, and Kaplan–Meier curves of the different prognostic groups were calculated. QVS of size change was found more sensitive in detecting patients deteriorating (57.1% versus 37.5%) or improving (23.8% versus 10.7%), more correlated with the median PFS for the deteriorating (1.8 versus 1.7 months), stable (5.6 versus 4.0 month), and improving (8.3 versus 5.5 months) categories and more predictive of PFS (Cox hazard proportion ratio of 3.070 versus 1.860) than RECIST 1.1 categorization. Multiple regression analysis demonstrated QVS of lesion size correlated most closely with PFS among the variables assessed (r = 0.519, p < 0.0001). QVS in this study was superior to standard RECIST categorization in terms of discriminating treated metastatic melanoma patients likely to have longer PFS.     

Malignant Melanoma Metastatic to the Testis: A Report of Three Cases with Clinically Significant Manifestations

Three cases of malignant melanoma metastatic to the testis, each of which was a challenge in pathologic interpretation, are reported. The patients were 43, 55, and 80 years of age, respectively. A history of malignant melanoma was not known to the initial examining pathologist in two of the cases. The testicular tumors were all unilateral. One took the form of multiple nodules, but the others were discrete solitary masses. On microscopic examination diffuse, nested, follicular, and fascicular patterns, usually in combination, were seen. The tumor cells had moderate to abundant eosinophilic cytoplasm in two cases, but scanty cytoplasm in a third. In one case there was also a component of cells with copious foamy cytoplasm. Rare areas of melanin pigment were identified in two tumors. Immunohistochemistry for S-100 and HMB-45 was positive in the two cases in which it was performed. In the third case electron microscopy revealed aberrant melanosomes within the tumor cells. The differential diagnosis in these and rare other cases of malignant melanoma involving the testis during life is broad and includes seminoma, malignant lymphoma, and Leydig cell tumor. When the diagnosis is entertained, a search for melanin pigment, immunohistochemical stains for S-100 protein and HMB 45, and further inquiry into the clinical history are often crucial. Int J Surg Pathol 8(1):49-57 2000     

血管内生物可吸收支架现状与挑战

尽管目前介入用血管支架各类药物涂层技术较从前已经获得长足的进步,涂层支架的临床使用数量也远远超过裸支架,但远期疗效仍有待继续验证。无论何种药物涂层支架,当其被植入生物体内一段时间后,表面携带的功能药物涂层都会被生物体逐渐吸收而最终露出裸支架,带来晚期再狭窄及血栓的问题。因此,生物可吸收支架应运而生。由于其具有独特的可降解性,随着植入时间的延长而逐渐在生物体内被完全降解、吸收,最终代谢出体外;同时,血管自有的部分原始功能也得到一定恢复,如同从未被植入过支架一般。重点介绍国内外高分子聚合物、镁合金、纯铁、锌合金等几种不同材质的生物可吸收血管支架研究现状,并分析各材质可吸收支架现存的主要问题,希望对血管介入用生物可吸收支架的了解起到一定的作用。     

De Novo Meningitis Caused by Propionibacterium acnes in a Patient with Metastatic Melanoma

Propionibacterium acnes is a known cause of postneurosurgical meningitis; however, it is rarely implicated in de novo meningitis. Herein we report a case of a 49-year-old male with de novo meningitis caused by P. acnes with metastatic melanoma as the only identified risk factor for his infection.