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Neoplastic Cells (neoplastic + cell)
Terms modified by Neoplastic Cells Selected AbstractsIn Vitro Cyclooxygenase-2 Protein Expression and Enzymatic Activity in Neoplastic CellsJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 5 2007David A. Heller Background: Cyclooxygenase-2 (COX-2) and its principle enzymatic metabolite, prostaglandin E2 (PGE2), are implicated in cancer progression. Based upon immunohistochemical (IHC) evidence that several tumor types in animals overexpress COX-2 protein, COX-2 inhibitors are used as anticancer agents in dogs and cats. Hypothesis: IHC is inaccurate for assessing tumor-associated COX-2 protein and enzymatic activity. Methods: Five mammalian cell lines were assessed for COX-2 protein expression by IHC and Western blot analysis (WB), and functional COX-2 activity was based upon PGE2 production. Results: Detection of COX-2 protein by IHC and WB were in agreement in 4 of 5 cell lines. In 1 cell line that lacked COX-2 gene transcription because of promoter hypermethylation (HCT-116), IHC produced false-positive staining for COX-2 protein expression. Functional COX-2 enzymatic activity was dissociated from relative IHC-based COX-2 protein expression in 2 cell lines (RPMI 2650 and SCCF1). The RPMI 2650 cell line demonstrated strong COX-2 protein expression but minimal PGE2 production. Conclusions and Clinical Importance: Western blot is more accurate than IHC for the detection of COX-2 protein in the cell lines studied. Furthermore, the semiquantitative identification of COX-2 protein by IHC or WB does not necessarily correlate with enzymatic activity. Based upon the potential inaccuracy of IHC and dissociation of COX-2 protein expression from enzymatic activity, the practice of instituting treatment of tumors with COX-2 inhibitors based solely on IHC results should be reconsidered. [source] Role of ancillary techniques in diagnosing and subclassifying non-Hodgkin's lymphomas on fine needle aspiration cytologyCYTOPATHOLOGY, Issue 5 2006P. DeyArticle first published online: 8 SEP 200 Non-Hodgkin's lymphomas (NHL) are tumours of the lymphoid cells. During the process of development of lymphoid cells, neoplasia may evolve at any point. Neoplastic cells usually carry the imprint of cell of origin at the stage of origin. Various types of NHL may have similar morphology with wide variation in origin, immunophenotype and other biological features. Different ancillary laboratory techniques may help to overcome the limitations of morphology in this aspect. The commonly used ancillary techniques in lymphomas are immunocytochemistry (IC), flow cytometry, Southern blot (SB) technique, polymerase chain reaction (PCR) and fluorescent in situ hybridization (FISH). In addition, laser scanning cytometry (LSC) and DNA microarray technologies are in the research phase. Various laboratory techniques are used for immunophenotyping, demonstration of monoclonality, identification of chromosomal translocation, assessment of cell kinetics and expression of mRNA in the tumour cells. Flow cytometry helps in rapid immunophenotying of NHL and it has an added advantage over IC in recognizing the co-expression of CD markers. Fine needle aspiration cytology (FNAC) combined with flow immunophenotyping may help us to diagnose and subclassify certain NHLs, such as follicular lymphoma and mantle cell lymphoma, which were previously recognized as pure morphological entities. Loss of morphology is one of the important limitations of flow cytometry. LSC can overcome this limitation by studying morphology along with the immunophenotyping pattern of individual cells. Chromosomal changes in NHL can be identified by SB, PCR and FISH. Molecular diagnosis of NHL helps in diagnosis, subclassification, prognostic assessment and even in planning of therapy. DNA microarray is a relatively newer and promising technology. It gives information about the expression of several thousands of genes in a tumour in a single experiment. In the near future, FNAC combined with ancillary techniques may play a major role in diagnosis, subclassification and management of lymphomas. [source] S-100-negative atypical granular cell tumor: report of a caseINTERNATIONAL JOURNAL OF DERMATOLOGY, Issue 3 2002Mi-Woo Lee MD A 38-year-old man presented with a solitary, round, 1.2 × 1.2 cm, bluish-colored, dome-shaped, hard nodule on the left side of the neck, which had grown over 2 months (Fig. 1). The nodule was nontender and nonmovable. Light microscopy revealed that the neoplasm was situated in the reticular dermis with extension into the papillary dermis. The tumor showed expansile growth with smooth and round borders, and was made up of sheets of cells arranged in nests or lobules separated by thin delicate connective tissue septa. The tumor cells were round, oval, or polygonal in shape with distinct cellular borders. The cells had abundant eosinophilic granular cytoplasm, and considerable variation of cellular and nuclear size was noted (Fig. 2a). The tumor cell nuclei were vesicular and some had pleomorphism (Fig. 2b). Sometimes multiple nucleoli were seen. Mitoses and necrosis were virtually absent. Immunohistochemical staining revealed that some of the cytoplasmic granules stained positively with periodic acid,Schiff (PAS) after diastase treatment. Tumor cells showed strong reactivity for CD68 and neuron-specific enolase, and negative results for S-100, factor XIIIa, cytokeratin, desmin, CD34, and smooth muscle actin. Electron microscopy revealed that the tumor was composed of polygonal cells with round to irregular nuclei, and the cytoplasm contained numerous secondary lysosomes. The tumor was completely excised. Figure 1. A solitary, round, 1.2 × 1.2 cm, bluish-colored, dome-shaped, hard nodule on the left side of the neck Figure 2. (a) Tumor cells contain granular cytoplasm and show atypical cytologic features (b) Neoplastic cells show variation of cell size and nuclear pleomorphism [source] Cutaneous composite hemangioendothelioma with satellitosis and lymph node metastasesJOURNAL OF CUTANEOUS PATHOLOGY, Issue 2 2008Luis Requena The term hemangioendothelioma has been used in recent years to name a heterogeneous group of vascular neoplasms, intermediate in both biological behavior and histopathologic appearance between benign tumors (hemangiomas) and frankly malignant tumors (angiosarcomas). Thus, within the spectrum of hemangioendothelioma have been successively included epithelioid hemangioendothelioma, spindle cell hemangioendothelioma, retiform hemangioendothelioma, kaposiform hemangioendothelioma, polymorphous hemagioendothelioma of the lymph nodes, papillary intralymphatic angioendothelioma (PILA) and composite hemangioendothelioma. The latter is a vascular neoplasm showing varying combinations of benign, low-grade malignant and malignant vascular components. We herein report a case of composite hemangioendothelioma showing a combination of retiform hemangioendothelioma, epithelioid hemangioendothelioma, spindle cell hemangioma and PILA. The neoplasm showed a more aggressive behavior than other reported cases of composite hemangioendothelioma and it developed satellitosis and metastases to the inguinal lymph nodes. Neoplastic cells expressed immunoreactivity for Prox-1, supporting a lymphatic line of differentiation. [source] Epithelioid blue nevus: a rare variant of blue nevus not always associated with the Carney complexJOURNAL OF CUTANEOUS PATHOLOGY, Issue 5 2000Carmen Moreno Epithelioid blue nevus is a rare variant of blue nevus that has been recently described in patients with Carney complex. Some of the patients with Carney complex have multiple epithelioid blue nevi and a familial history of similar lesions is often recorded. Epithelioid blue nevus consists of an intradermal melanocytic nevus composed of polygonal epithelioid cells laden with melanin. Neoplastic cells show no maturation at the base of the lesion and, in contrast with the usual stromal changes in blue nevi, epithelioid blue nevus exhibits no fibrosis of the dermis. We have studied three cases of epithelioid blue nevus in three patients with no evidence of Carney complex. The lesions were solitary and there was no family history of similar lesions. Therefore, epithelioid blue nevus is a distinctive variant of blue nevus that may also appear as a sporadic lesion and is not always associated with Carney complex. [source] AML with bilateral retinal detachmentACTA OPHTHALMOLOGICA, Issue 2007E SARKADY Purpose: To present a case of thrombotic ocular and CNS involvement complicating acute myeloid leukaemia (AML). Methods: A 42 year old woman developed blurred vision shortly after diagnosis and treatment of M6 AML. Investigations showed anterior orbital infiltration, retinal detachment and panuveitis. Iris biopsy and vitreous aspirate were negative. She developed right temporal lobe infarction and died following further CNS infarction two months after initial diagnosis. Results: Post mortem examination showed cerebral oedema, multiple cerebral infarctions and hepatosplenomegaly; both eyes contained vitreous exudates, retinal detachment and uveal thickening. Microscopy showed exudative and haemorrhagic retinal detachment, without inflammatory or neoplastic infiltrate, and bilateral uveal leukaemic infiltration with infarction. Neoplastic cells infiltrated the leptomeninges and brain parenchyma with focal vascular occlusion. Lung vessels were occluded by neoplastic cells. The spleen and bone marrow were heavily infiltrated. Partial immunophenotyping suggested a diagnosis of acute promyelocytic leukaemia (APL). Conclusions: Acute leukaemia involves the eye occurs in 39-53% cases. Visual loss is uncommon. Retinal involvement most frequently occurs in the form of superficial haemorrhages, detachment is uncommon. Acute lymphoblastic leukaemia (ALL) treated with L-asparaginase, acute promyelocytic leukaemia (APL) and non-M3 AML may present with a prothrombotic state which may be catastrophic, as occurred in this fatal case. [source] Overexpression of CD7 in classical Hodgkin lymphoma-infiltrating T lymphocytes,CYTOMETRY, Issue 3 2009Adam C. Seegmiller Abstract Background: Diagnosis of Hodgkin lymphoma (HL) is sometimes complicated by the scarcity of neoplastic cells in a reactive inflammatory background. Immunophenotyping by flow cytometry (FC) has not played a significant role in HL diagnosis because of its consistent failure to identify these neoplastic cells. However, HL-infiltrating T cells have been shown to play a role in HL pathogenesis. This study characterizes the FC immunophenotype of these T lymphocytes to determine whether they can be used to assist in the diagnosis of HL. Methods: Cell suspensions from 76 lymph nodes involved by HL and 156 lymph nodes with reactive lymphadenopathy (LAD) were analyzed by flow cytometry to assess the expression of T-cell antigens. Results: The CD4:CD8 ratio and CD7 expression in both CD4(+) and CD8(+) T cells are increased in HL compared with reactive lymph nodes and there are significant differences between these features in different subtypes of HL. However, only the expression of CD7 in CD4(+) T cells distinguishes between HL and reactive LAD. This is especially true for classical HL in younger patients. Using a CD7 mean fluorescence intensity (MFI) cutoff value generated by this data, 37/47 FNA specimens were correctly diagnosed. Conclusions: There are significant differences in the immunophenotypes of HL-infiltrating T cells. Of these, the CD7 expression in CD4(+) T cells discriminates between HL and reactive LAD, suggesting that this could be a useful and practical adjunctive tool in the diagnosis of HL. It may also further our understanding of the pathophysiology of this disease. © 2008 Clinical Cytometry Society [source] Locoregional Cutaneous Metastases of Malignant Melanoma and their ManagementDERMATOLOGIC SURGERY, Issue 2004Ingrid H. Wolf MD The correct classification of locoregional metastases of malignant melanoma to skin is central to the planning of treatment. Local recurrence means persistence of neoplastic cells at the local site by virtue of incomplete excision of the primary melanoma. Standard treatment is excisional surgery. In contrast, locoregional metastases of malignant melanoma (satellites, in-transit metastases) are metastases around a primary melanoma or between a primary melanoma and regional lymph nodes. They represent intralymphatic or hematogenous spread of neoplastic cells. We present a variety of available treatment options and discuss especially topical imiquimod as a novel approach for the palliative treatment of locoregional cutaneous melanoma metastases in selected patients. [source] Cytopathological diagnosis of adult retinoblastoma in a vitrectomy specimen,DIAGNOSTIC CYTOPATHOLOGY, Issue 1 2010Maria E. Orellana M.D. Abstract Retinoblastoma (RB) is extremely rare in adults. We describe a case of RB diagnosed by cytology in a vitrectomy specimen of a 23-year-old patient who presented with diminished visual acuity and retinal detachment in the absence of a clinically-visible mass. Cytological examination of the vitreous fluid showed clusters of loosely cohesive atypical cells with high nuclear to cytoplasmic ratio and "salt and pepper" chromatin pattern in a background of normal neuronal retinal cells. Nuclear molding was present as well as numerous apoptotic bodies. The cells were focally positive for epithelial markers and showed strong and diffuse positivity for neuroendocrine markers. Ki-67 stained 90% of the "atypical cells" nuclei, in contrast to nonneoplastic retinal neuronal cells, which were negative for the marker. A diagnosis of RB was rendered, and subsequently was confirmed in the enucleation specimen. The cytological differential diagnosis is discussed as well as the role that cytology and immunohistochemistry can play in differentiating neoplastic cells from normal retinal cellular elements in vitreous fluid specimens. Diagn. Cytopathol. 2010. © 2009 Wiley-Liss, Inc. [source] Papillary thyroid carcinoma with metastasis to the frontal skullDIAGNOSTIC CYTOPATHOLOGY, Issue 7 2009Dian Feng M.D., Ph.D. Abstract Papillary thyroid carcinoma with metastasis to the frontal skull is extremely rare. We report a case of unsuspected papillary thyroid carcinoma with frontal skull metastasis. The patient was a 62-year-old African American woman with presentation of a 4-cm firm, painless, immobile, ill-defined mass at the right forehead. Ultrasound and computer tonography detected a hypervascular and osteolytic tumor involving the skull and overlying skin. Fine-needle aspiration was performed followed by surgical biopsy. Cytologic examination revealed the presence of hypercellular and bloody material. The neoplasm showed glandular features and was composed of clusters of round to oval cells with pinkish squamoid cytoplasm, oval nuclei and inconspicuous nucleoli on smears and sections of cell block. With immunocytochemical stain, the neoplastic cells were positive for pancytokeratin and vimentin and focally positive for EMA, while they were negative for S100, HMB45, Melan-A, CD34, GFAP, CD10, LCA, RCC and CD138. The diagnosis was a metastatic carcinoma. Clinical follow up with surgical biopsy was recommended. Surgical biopsy demonstrated histological and cytological features of papillary thyroid carcinoma including prominent papillae, nuclear overlapping, grooves, and intranuclear pseudoinclusions. Thus, a diagnosis of metastatic papillary thyroid carcinoma was rendered. Though skull metastasis of thyroid carcinoma is rare, it should be considered in the differential diagnosis when a skull mass lesion is encountered. Diagn. Cytopathol. 2009. © 2009 Wiley-Liss, Inc. [source] Mass-forming extramedullary hematopoiesis diagnosed by fine-needle aspiration cytologyDIAGNOSTIC CYTOPATHOLOGY, Issue 12 2006Maria Luisa C. Policarpio-Nicolas M.D. Abstract Extramedullary hematopoiesis (EMH) is usually a microscopic finding. However, it may present as a mass-forming lesion making it amenable to fine-needle aspiration biopsy (FNAB). When mass-forming EMH occurs, it can simulate a neoplasm clinically and radiologically. Additionally, the megakaryocytes can mimic malignant neoplastic cells, particularly if EMH is not a considered diagnosis. We report six cases of mass-forming EMH diagnosed by FNAB and evaluate the utility of FNAB in diagnosing EMH. Four patients had prior diagnoses of hematologic disorders, one patient had malignant mastocytosis who presented with lymphadenopathy and one patient had a history of carcinoma. The patients' ages ranged from 46 to 78 yr with an equal sex distribution. Aspirate smears showed trilineage hematopoiesis. The cytomorphologic differential diagnosis included metastatic carcinoma, Hodgkin lymphoma and myeloid sarcoma. No special stains were necessary due to the classic cytologic findings and prior hematologic history. Diagn. Cytopathol. 2006; 34:807,811. © 2006 Wiley-Liss, Inc. [source] Fine needle aspiration biopsy of epithelioid hemangioendothelioma of the oral cavity: Report of one case and review of literatureDIAGNOSTIC CYTOPATHOLOGY, Issue 3 2006Guo-Xia Tong M.D., Ph.D. Abstract Epithelioid hemangioendothelioma (EHE) is an uncommon vascular tumor with biological behavior intermediate between hemangioma and angiosarcoma. It rarely occurs in the oral cavity. We report a case of an 81-yr-old woman with a 2-mo history of a 2 × 2 cm2 submucosal buccal mass. Fine needle aspiration (FNA) smears were paucicellular and showed mainly single atypical large epithelioid cells in a bloody background. The atypical cells had abundant dense cytoplasm, some with fine vacuoles. Occasionally, cells with large cytoplasmic lumina were seen. Cytology preparations from fresh tissue received for frozen section revealed numerous neoplastic cells with large intracytoplasmic lumina, some of which contained red blood cells. In addition, cells with distinct intranuclear inclusions were present. Histologic sections and immunohistochemical stains confirmed the diagnosis of EHE. Although the histologic features of EHE are well recognized, reports of FNA cytology findings are sparsely existent in the literature as several case reports. The characteristic cytological features of EHE are reviewed in this report. We believe that the diagnosis of this rare tumor can be suggested when an adequate FNA specimen is obtained. Diagn. Cytopathol. 2006;34:218,223. © 2006 Wiley-Liss, Inc. [source] Intracytoplasmic lumina in invasive micropapillary carcinoma of the lungDIAGNOSTIC CYTOPATHOLOGY, Issue 3 2006Naoto Kuroda M.D. Abstract Micropapillary carcinoma of the lung is a rare neoplasm, and several reports on micropapillary carcinoma of the lung have been presented to date. We present a case of micropapillary carcinoma of the lung here. A 75-yr-old Japanese man received the medical checkup and his chest X-ray disclosed the abnormal shadow of the lower lobe of the left lung. The histological examination of resected lung and extirpated lymph node showed the finding of micropapillary carcinoma. Some neoplastic cells of primary site contained intracytoplasmic lumina positive for Alcian blue and PAS stains. Pleural effusion appeared 9-mo after the operation. The cytology of pleural effusion showed cohesive clusters of neoplastic cells consisting of 3,20 cells without fibrovascular core. Additionally, intracytoplasmic lumina were observed in some neoplastic cells. Finally, carcinoma cells with micropapillary morphology may possess the intracytoplasmic lumina in the cytoplasm of metastatic site as well as primary site. Diagn. Cytopathol. 2006;34:224,226. © 2006 Wiley-Liss, Inc. [source] Cytologic comparison of a primary parathyroid cancer and its metastatic lesions: A case reportDIAGNOSTIC CYTOPATHOLOGY, Issue 1 2006I.A.C., Katsuhide Ikeda C.T. Abstract We describe the fine-needle aspiration cytology features of a primary parathyroid cancer and of the local recurrent and distant metastatic lesions. The presence of prognostic factors Ki-67 and proliferating cell nuclear antigen (PCNA) was compared immunohistochemically between primary parathyroid carcinoma and related metastatic and recurrent foci. Flow cytometric DNA analysis was also performed to investigate any chromosomal abnormality of the parathyroid carcinoma. Cytologic examination of the endocrine tumor showed that it comprised a loose cohesive cluster and tumor cells with granular cytoplasm and mild nuclear atypia, but for purposes of cytodiagnosis, it is difficult to determine whether such a neoplasm is malignant on the basis of morphology alone. Immunohistochemical analysis showed that Ki-67 and PCNA labeling indices were higher in the recurrent and metastasized carcinomas than in the primary cancer, suggesting that neoplastic cells become more malignant in the recurrent and metastasized foci. To our knowledge, this is the first report describing not only cytopathologic but also immunocytologic differences between primary parathyroid cancer and the metastatic lesion. Diagn. Cytopathol. 2006;34:50-55. © 2005 Wiley-Liss, Inc. [source] Intranuclear cytoplasmic inclusions in fine-needle aspiration smears of papillary thyroid carcinoma: A study of its morphological forms, association with nuclear grooves, and mode of formationDIAGNOSTIC CYTOPATHOLOGY, Issue 5 2005D.SC., Dilip K. Das M.B.B.S., Ph.D. Abstract Intranuclear cytoplasmic inclusion (INCI) and nuclear grooves in fine-needle aspiration (FNA) smears of papillary thyroid carcinoma (PTC) represent cytoplasmic invaginations into the nucleus. Although formation of INCIs is linked to nuclear grooves, they seldom exist together. This study was undertaken to find out the various morphological forms of INCIs, their relation to nuclear grooves, and mode of formation. FNA smears of 54 PTC cases were studied for various forms of INCI, nuclear chromatin pattern, nuclear grooves, and nuclear notches. A differential count of INCIs was made in 19 cases having ,10 INCIs per 200 neoplastic cells. INCIs were present in 48 (88.9%) of 54 PTC cases. Round INCIs were present in 46 (85.2%) cases, followed by oval (48.1%), tear drop/flask-shaped (18.5%), irregular (14.8%), planoconvex/semicircular (13%), rectangular (9.3%), spindle-shaped (3.7%), and bilobed (3.7%). A differential count of INCIs also showed that the round form was the commonest (76.3%). The oval and other forms constituted 19.5 and 4.2%, respectively. INCIs and nuclear grooves were present together in a cell in 15 (27.8%) cases. The formation of INCIs as a cytoplasmic invagination into the nucleus was shown cytomorphologically in rare cells. For the first time in this study, the various morphological forms of INCIs, and the extent of their coexistence with nuclear grooves, (have been highlighted) and showed their mode of formation shown at a light microscopic level. Diagn. Cytopathol. 2005;32:264,268. © 2005 Wiley-Liss, Inc. [source] Fine-needle aspiration cytology of metastatic nasopharyngeal carcinomaDIAGNOSTIC CYTOPATHOLOGY, Issue 4 2005José M. Viguer M.D. Abstract Cytological features of nasopharyngeal carcinoma (NPC) were reviewed in an attempt to select cytological criteria that permit a specific recognition of metastases. For this purpose, 54 fine-needle aspiration (FNA) procedures from 43 patients with NPC were analyzed. Thirty-two (59.3%) procedures were performed before the histological diagnosis. In 25 (46.3%) procedures, smears showed many neoplastic single cells, clusters, and abundant lymphoid cells (mixed pattern). A dissociated (single cell) pattern consisting of individual neoplastic and lymphoid cells was seen in 18 (33.3%) cases. Finally, 11 (20.4%) cases showed cohesive epithelial clusters (cohesive pattern) without relevant cellular dissociation or lymphoid cells. Squamous-cell differentiation was seen in three of these cases. Most single neoplastic cells presented as large, pleomorphic naked nuclei. Other interesting findings were granulomas (n = 3), prominent eosinophilic infiltrates (n = 4), and suppurative changes (n = 5). In most smears with mixed and dissociated patterns, a nasopharyngeal origin could be suggested. On the contrary, those smears with a cohesive pattern were indistinguishable from other head and neck carcinomas. The presence (on cervical lymph nodes) of a dissociated or mixed (single cells and groups) architectural pattern of large, anaplastic cells and naked nuclei accompanied by an abundant lymphoid component is highly suggestive of undifferentiated NPC. Cytology offers a rapid diagnosis, establishes the necessity of a complete cavum examination, and helps in avoiding unnecessary and harmful biopsies. Diagn. Cytopathol. 2005;32:233,237. © 2005 Wiley-Liss, Inc. [source] Changes in antioxidant defense status in response to cisplatin and 5-FU in esophageal carcinomaDISEASES OF THE ESOPHAGUS, Issue 2 2008T. Kaur SUMMARY., The ability of reactive oxygen species to induce cellular damage and to cause cell death opens the possibility of exploiting this property in the treatment of esophageal cancer through a free radical mediated mechanism. The present study was carried out with the aim of evaluating the changes in the antioxidant defense status in esophageal cancer patients treated without and with neoadjuvant therapy (NAT). Forty surgically resected tissue specimens from tumors, tissue adjoining the tumors and paired macroscopically normal mucosa were obtained from esophageal cancer patients treated with or without chemo-radiotherapy. An evaluation of antioxidant defense system in the normal, adjoining and tumor esophageal tissues in response to NAT revealed decreased catalase activity in tumor and adjoining tissues as compared to their respective normal tissue levels. Similarly, decreased superoxide dismutase activity was observed in tumor tissue in response to NAT. In both the treatment groups (with and without NAT), no significant change was observed in the enzyme activity of glutathione reductase in the normal, adjoining and tumor tissues. Enhanced glutathione peroxidase activity was found in tumor tissue, as compared to the adjoining and paired normal tissue of patients after NAT. Estimation of reduced glutathione (GSH) levels showed a significant decline in GSH levels in esophageal tumors after NAT. Depletion of GSH, an endogenous antioxidant, would elevate drug sensitivity and might predispose neoplastic cells to apoptosis in response to NAT. The antioxidant enzymes in the esophageal carcinoma thus may play an important role in influencing the final outcome upon NAT course. [source] Proteomic analysis of liver cancer cells treated with 5-Aza-2,-deoxycytidine (AZA),DRUG DEVELOPMENT RESEARCH, Issue 1 2009Shujun Bai Abstract 5-Aza-2,-deoxycytidine (AZA) is a potent inhibitor of DNA methylation that exhibits anti-tumor activity in a variety of tumor cells via reactivation of tumor suppressor genes. However, few studies have been done on the biological and clinical significance of AZA in human hepatocellular carcinoma. To identify potential genes that may be aberrantly methylated and confer growth advantage to neoplastic cells and to better understand the molecular mechanism(s) underlying AZA anti-tumor activity, a proteomics approach was used to annotate global gene expression changes of HepG2 cell line pre- and post-treatment with AZA. A total of 56 differentially expressed proteins were identified by 2D gel analysis, 48 of which were up-regulated while the remaining 8 were down regulated. Among the identified proteins, eight of these showed marked changed proteins, including seven up-regulated proteins: glutathione S-transferase P, protein DJ-1, peroxiredoxin-2, UMP-CMP kinase, cytochrome c-type heme lyase, enhancer of rudimentary homolog, profilin-1, and one down-regulated protein, heat-shock protein ,,1. The possible implication of these proteins in hepatocarcinogenesis is discussed. We tested two up-regulated proteins, glutathione S-transferase P and peroxiredoxin-2, using RT-PCR and their expression was consistent with the results obtained in the protein level. Both of these genes were methylated when methylation-specific PCR was used against their promoter regions. Following treatment with AZA, the gene promoter regions were found to be unmethylated, concomitant with overexpression of the proteins compared to HepG2 cells without treatment. These data provide useful information in evaluating the therapeutic potential of AZA for the treatment of HCC. Drug Dev Res 69, 2009. © 2009 Wiley-Liss, Inc. [source] Elevated tryptase levels selectively cluster in myeloid neoplasms: a novel diagnostic approach and screen marker in clinical haematologyEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 10 2009W. R. Sperr Abstract Background, Recent data suggest that tryptase, a mast cell enzyme, is expressed in neoplastic cells in myeloid leukaemias. In several of these patients, increased serum tryptase levels are detectable. Materials and methods, We have determined serum tryptase levels in 914 patients with haematological malignancies, including myeloproliferative disorders (n = 156), myelodysplastic syndromes (MDS, n = 241), acute myeloid leukaemia (AML, n = 317), systemic mastocytosis (SM, n = 81), non-Hodgkin,s lymphoma (n = 59) and acute lymphoblastic leukaemia (n = 26). Moreover, tryptase was measured in 136 patients with non-neoplastic haematological disorders, 102 with non-haematological disorders and 164 healthy subjects. Results, In healthy subjects, the median serum tryptase was 5·2 ng mL,1. Elevated serum tryptase levels were found to cluster in myeloid neoplasm, whereas almost all patients with lymphoid neoplasms exhibited normal tryptase. Among myeloid neoplasms, elevated tryptase levels (> 15 ng mL,1) were recorded in > 90% of patients with SM, 38% with AML, 34% with CML and 25% with MDS. The highest tryptase levels, often > 1000 ng mL,1, were found in advanced SM and core-binding-factor leukaemias. In most patients with non-neoplastic haematological disorders and non-haematological disorders analysed in our study, tryptase levels were normal, the exception being a few patients with end-stage kidney disease and helminth infections, in whom a slightly elevated tryptase was found. Conclusions, In summary, tryptase is a new diagnostic marker of myeloid neoplasms and a useful test in clinical haematology. [source] Treatment responses to cladribine and dasatinib in rapidly progressing aggressive mastocytosisEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 11 2008K. J. Aichberger ABSTRACT Background, Systemic mastocytosis (SM) is a mast cell neoplasm in which neoplastic cells usually display the D816V-mutated variant of KIT. Cladribine (2CdA) and dasatinib are two drugs that counteract the in vitro growth of neoplastic mast cells in SM. However, only little is known about the in vivo effects of these drugs in SM. Patient and methods, We report on a patient with highly aggressive interferon-alpha-resistant SM who was treated with 2CdA and dasatinib. In vitro pretesting revealed a response of neoplastic mast cells to both compounds with reasonable IC50 values. Results, The patient was treated with six cycles of 2CdA (0·13 mg kg,1 intravenously daily on 5 consecutive days). Despite a short-lived major clinical response and a decrease in serum tryptase, the patient progressed to mast cell leukaemia after the sixth cycle of 2CdA. The patient then received two further courses of 2CdA followed by treatment with dasatinib (100 mg per os daily). However, no major response was obtained and the patient died from disease progression after 2 months. Conclusions, In a patient with rapidly progressing aggressive SM, neither 2CdA nor dasatinib produced a long-lasting response in vivo, despite encouraging in vitro results. For such patients, alternative treatment strategies have to be developed. [source] High levels of serum prostate-specific antigen due to PSA producing follicular non-Hodgkin's lymphomaEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 2 2007Jan Jelrik Oosterheert Abstract Objective:, Both carcinoma of the prostate and non-Hodgkin's lymphoma are common in elderly patients. Measurement of serum prostate-specific antigen (PSA) is a frequently used tool to diagnose and monitor prostate carcinoma and is generally specific for diseases of the prostate. Case:, We describe a 68-yr-old patient with voiding difficulties and high PSA levels, but without inflammatory or malignant changes upon multiple transrectal ultrasound guided prostate biopsies. Digital rectal examination was normal. Laboratory showed a strongly elevated PSA level (62 ,g/L, Immulight 2000®; DPC, USA). A CT-scan showed a retroperitoneal process with mass in the right pelvis and infiltration of the bladder wall, suggestive for metastatic prostate carcinoma. Surgical excision of an axillary lymph node set the diagnosis at a stage IV follicular lymphoma, Berard grade I to II in which the majority of neoplastic cells expressed PSA. After lymphoma-specific treatment, there was a positron emission tomography (PET) confirmed complete remission with normal PSA levels (6 ,g/L), which still persists. Conclusion:, Although rare, high PSA levels can be due to the presence of non-Hodgkin's lymphoma. Such a diagnosis should be considered when patients present with lymphadenopathy other than regional prostatic lymphadenopathy. [source] Enhanced immunogenicity of CTL antigens through mutation of the CD8 binding MHC class,I invariant regionEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 5 2007Linda Wooldridge Abstract CD8+ cytotoxic T,lymphocytes (CTL) are key determinants of immunity to intracellular pathogens and neoplastic cells. Recognition of specific antigens in the form of peptide-MHC class,I complexes (pMHCI) presented on the target cell surface is mediated by T cell receptor (TCR) engagement. The CD8 coreceptor binds to invariant domains of pMHCI and facilitates antigen recognition. Here, we investigate the biological effects of a Q115E substitution in the ,2,domain of human leukocyte antigen (HLA)-A*0201 that enhances CD8 binding by,,50% without altering TCR/pMHCI interactions. Soluble and cell surface-expressed forms of Q115E HLA-A*0201 exhibit enhanced recognition by CTL without loss of specificity. These CD8-enhanced antigens induce greater CD3 ,,chain phosphorylation in cognate CTL leading to substantial increases in cytokine production, proliferation and priming of naive T cells. This effect provides a fundamental new mechanism with which to enhance cellular immunity to specific T cell antigens. [source] Genomic instability in giant cell tumor of bone.GENES, CHROMOSOMES AND CANCER, Issue 6 2009A study of 52 cases using DNA ploidy, array-CGH analysis, relocalization FISH Genetic instability in relation to clinical behavior was studied in 52 cases of giant cell tumor of bone (GCTB). Ploidy was determined in the mononuclear cell population by using native cell smears and image cytometry. A relocalization technique allowed fluorescent in situ hybridization (FISH) analysis of CD68-negative neoplastic cells for numerical changes of chromosomes X, 3, 4, 6, 11, and telomeric association on 11p. Genome-wide alterations were tested using array comparative genomic hybridization (array-CGH) on magnetically separated CD68-negative tumor cells. CTNNB1, TP53, and BCL2 protein expression was also analyzed in formol-paraffin sections to see if their pathways are involved in the development of chromosomal instability. CD68-positive histiocytes showed no significant numerical chromosome and telomeric alterations. Based on ploidy values and clinical outcome, we could distinguish five groups as follows: diploid nonrecurrent (n = 20), tetraploid nonrecurrent (n = 6), diploid recurrent (n = 5), tetraploid and/or aneuploid recurrent (n = 14), and malignant cases (n = 7). Random individual-cell aneusomy was significantly (P < 0.001) more frequent in the recurrent groups (36.01 ± 11.94%) than in the benign nonrecurrent cases (10.65 ± 3.66%). The diploid recurrent group showed significantly (P < 0.001) increased balanced aneusomy compared with the diploid nonrecurrent group and the tetraploid nonrecurrent group represented eusomic polysomy. Array-CGH and FISH showed clonal aberrations almost exclusively in the malignant group. None of the protein markers tested showed significant correlation with elevated aneuploidy/polysomy (P = 0.56). Our results show that ploidy determination combined with FISH analysis may help predicting recurrence potential of GCTB and suggest that chromosomal abnormalities superimposed on telomeric associations could be responsible for an aggressive clinical course. © 2009 Wiley-Liss,Inc. [source] The noncoding RNA, miR-126, suppresses the growth of neoplastic cells by targeting phosphatidylinositol 3-kinase signaling and is frequently lost in colon cancersGENES, CHROMOSOMES AND CANCER, Issue 11 2008Chunguang Guo MicroRNAs (miRNA/miR) are a class of small noncoding RNAs implicated in the pathogenesis of various malignancies. In the current study, using micro(RNA) arrays, we found a ubiquitous loss of miR-126 expression in colon cancer lines when compared to normal human colon epithelia. Reconstitution of miR-126 in colon cancer cells resulted in a significant growth reduction as evidenced in clonogenic assays. A search for miR-126 gene targets revealed p85,, a regulatory subunit involved in stabilizing and propagating the phosphatidylinositol 3-kinase (PI3K) signal, as one of the potential substrates. Restoration of miR-126 in cancer cells induced a ,3-fold reduction in p85, protein levels, with no concomitant change in p85,, a gene that is functionally related to p85, but not a supposed target of miR-126. Additionally, using reporter constructs, we show that the p85,-3, untranslated region is directly targeted by miR-126. Furthermore, this miR-126 mediated reduction of p85, was accompanied by a substantial reduction in phosphorylated AKT levels in the cancer cells, suggesting an impairment in PI3K signaling. Finally, in a panel of matched normal colon and primary colon tumors, each of the tumors demonstrated miR-126 down-regulation together with an increase in the p85, protein level. Taken together, we propose that miR-126 regulates PI3K signaling partly by targeting p85,, and that the loss of miR-126 may provide a selective growth advantage during colon carcinogenesis. © 2008 Wiley-Liss, Inc. [source] The Influence of Lactobacillus brevis on Ornithine Decarboxylase Activity and Polyamine Profiles in Helicobacter pylori -Infected Gastric MucosaHELICOBACTER, Issue 2 2004Michele Linsalata ABSTRACT Background., Functional probiotics may prevent Helicobacter pylori infection, and some evidence suggests that they also possess antitumor properties. Lactobacillus brevis (CD2) is a functional Lactobacillus strain with peculiar biochemical features, essentially related to the activity of arginine deiminase. This enzyme catalyzes the catabolism of arginine and affects the biosynthesis of polyamines (putrescine, spermidine, and spermine). Polyamines are polycations found in high concentrations in both normal and neoplastic cells. Our aims were: 1, to assess whether oral administration of L. brevis (CD2) affects H. pylori survival in the human gastric mucosa; 2, to evaluate the effects of L. brevis (CD2) on polyamine biosynthesis in gastric biopsies from H. pylori- positive patients. Materials and Methods., For 3 weeks before endoscopy, 22 H. pylori- positive dyspeptic patients randomly received (ratio 1 : 1) high oral doses of L. brevis (CD2) or placebo. Before and after treatment, H. pylori infection was determined by urea breath test (UBT). In gastric biopsies, ornithine decarboxylase activity and polyamine levels were, respectively, evaluated by a radiometric technique and high-pressure liquid chromatography (HPLC). Results.,L. brevis (CD2) treatment did not eradicate H. pylori. However, a reduction in the UBT delta values occurred, suggesting a decrease in intragastric bacterial load. Significantly, L. brevis (CD2) induced a decrease in gastric ornithine decarboxylase activity and polyamine levels. Conclusions., Our data support the hypothesis that L. brevis (CD2) treatment decreases H. pylori colonization, thus reducing polyamine biosynthesis. Alternatively, the arginine deiminase activity following L. brevis (CD2) administration might cause arginine deficiency, preventing polyamine generation from gastric cells. [source] Expression, regulation, and function of ,V integrins in hepatocellular carcinoma: An in vivo and in vitro studyHEPATOLOGY, Issue 2 2002Mimoun Nejjari The expression of ,V integrins by neoplastic cells contributes to the promotion of local invasion and metastasis. The most characteristic extracellular ligands of ,V integrins are vitronectin and fibronectin. Hepatocytes are the main source of vitronectin, and the capacity to synthesize and secrete vitronectin is usually retained in hepatocellular carcinoma. The aim of this study was to explore the expression, regulation, and functional role of ,V integrins in hepatocellular carcinoma. We first analyzed the expression of ,V integrins and their ligands fibronectin and vitronectin in 80 cases of hepatocellular carcinoma. ,V integrin chain was detected in 44 cases and vitronectin in 50. Twenty-four of the 44 ,V-positive tumors contained large amounts of vitronectin. These cases presented more frequently with adverse histoprognostic factors, including infiltrative growth pattern (62.5%), lack of capsule (71%), presence of capsular invasion (57%), and satellite nodules (50%). We then used HepG2 and Hep3B cell lines as in vitro models to study ,V integrin regulation and function. HepG2 and Hep3B cells expressed ,V integrin chain and used ,V,1 and ,V,5 for adhesion and migration on vitronectin. Tumor necrosis factor (TNF) , and transforming growth factor (TGF) , significantly increased the expression levels of ,V integrins and stimulated the adhesion and migration of both HepG2 and Hep3B cell lines on vitronectin. The effects of growth factors on cell adhesion and migration were reproduced by incubation with conditioned medium from rat liver myofibroblasts. In conclusion, our results support the existence of an ,V integrin/vitronectin connection in hepatocellular carcinoma and suggest that this connection may be an adverse prognostic factor. [source] Nuclear survivin is associated with disease recurrence and poor survival in patients with cutaneous malignant melanomaHISTOPATHOLOGY, Issue 7 2007F Piras Aims:, Survivin is expressed in neoplastic cells and appears to be associated with resistance to therapy and shorter survival in various types of tumours. The aim of the present study was to determine whether nuclear or cytoplasmic expression of survivin is related to disease recurrence and overall survival of patients with Stage I and II melanoma according to the American Joint Committee on Cancer (AJCC) staging system. Methods and results:, Immunohistochemistry was performed on formalin-fixed paraffin-embedded sections of primary cutaneous melanoma from 50 patients. Survival rates were estimated using the Kaplan,Meier method and compared using the log rank test. Association of clinical variables (gender, age, tumour location, thickness, Clark level and AJCC stage) with survivin expression was analysed by Fisher's exact test. Patients with nuclear immunoreactivity for survivin had an increased risk of disease recurrence during the first three postoperative years (P < 0.05) and of death (P < 0.05). Cytoplasmic immunoreactivity was not correlated with either survival or clinical variables. Conclusions:, Nuclear presence of survivin may be an independent biomarker for disease recurrence and overall survival in patients with Stage I and II melanoma. [source] DNA mismatch repair protein expression and microsatellite instability in primary mucosal melanomas of the head and neckHISTOPATHOLOGY, Issue 6 2007C Marani Aims:, To examine the expression of DNA mismatch repair (MMR) proteins and the presence of microsatellite instability (MSI) in seven primary mucosal melanomas of the head and neck (MMHN). Methods and results:, Haematoxylin and eosin staining and immunohistochemical analysis for routine diagnostic markers and for MMR proteins were performed. Six cases were examined for MSI. Four cases were monomorphous and three cases were pleomorphic type MMHN. Melanocytic markers were positive in all cases. Immunoreactivity for MMR proteins was weak in normal epithelium. The neoplastic tissue in six cases showed positivity for all MMR proteins with different percentages. One case showed weak positivity for hMSH2 and hMSH6 and no immunoreactivity for hMLH1 or hPMS2. Staining intensity was higher in tumour cells than in matched normal mucosa in three cases for hMSH2 and hMLH1 and in two cases for hPMS2. None of the examined cases showed MSI. Conclusions:, Expression of hMSH2 and hMLH1 proteins was up-regulated in three cases, whereas in two cases that of hPMS2 was increased. hMSH6 expression was comparable to that of normal cells in all cases. The percentage of positive neoplastic cells and the intensity of staining seemed to be greater in pleomorphic melanomas. Six cases were MMR-proficient and microsatellite stable. [source] Neuropilin-1 expression identifies a subset of regulatory T cells in human lymph nodes that is modulated by preoperative chemoradiation therapy in cervical cancerIMMUNOLOGY, Issue 1 2008Alessandra Battaglia Summary We examined the phenotype and function of CD4+ T cells expressing the semaphorin III receptor neuropilin-1 (Nrp1) in human lymph nodes and peripheral blood. In lymph nodes, Nrp1 identified a small regulatory CD4+ CD25high T-cell subpopulation (Nrp1+ Treg) that expressed higher levels of Forkhead box P3 (Foxp3) message and protein than Nrp1, Treg, and various molecular markers of activated Treg, i.e. CD45RO, human leucocyte antigen (HLA)-DR and glucocorticoid-induced tumour necrosis factor receptor (GITR). Similarly to conventional Treg, Nrp1+ Treg proliferated poorly in vitro, and exerted contact-dependent in vitro suppression of T-cell proliferation and cytokine secretion. However, Nrp1+ Treg were more efficient than Nrp1, Treg at inducing suppression. Nrp1 was also expressed on a small subpopulation of CD25int and CD25, CD4+ T cells that expressed more Foxp3, CD45RO, HLA-DR and GITR than their Nrp1, counterparts. In contrast, in peripheral blood Nrp1 identified a minor CD4+ T-cell subset that did not display the phenotypic features of Treg lacking Foxp3 expression and marginally expressing CD25. Hence, the function of Nrp1+ CD4+ T cells seemingly depends on their anatomical location. In a previous report, we proposed that Treg may curb the anti-tumour T-cell response in cervical cancer. We show here that Treg and Nrp1+ Treg levels dropped in the tumour-draining lymph nodes of patients with cervical cancer following preoperative chemoradiotherapy in a direct relationship with the reduction of tumour mass, suggesting that suppressor cell elimination facilitated the generation of T cells mediating the destruction of the neoplastic cells left behind after cytotoxic therapy. [source] Expression of RANTES and MCP-1 in epithelial cells is regulated via LMP1 and CD40INTERNATIONAL JOURNAL OF CANCER, Issue 12 2007Maike Buettner Abstract Epstein-Barr virus (EBV)-associated undifferentiated nasopharyngeal carcinoma (NPC) is characterized by a prominent nonneoplastic lymphoid stroma. The functional role of these inflammatory cells and the mechanism of their recruitment are not fully understood. In B-cells, the EBV-encoded latent membrane protein 1 (LMP1) can induce the expression of chemokines in an NF-,B dependent manner. We now show that LMP1 can induce the expression of RANTES and MCP-1 in an epithelial cell line, and that this effect is partially reversible by an inhibitor of NF-,B. Since tumor cells of virtually all NPCs show CD40 expression while many cases are LMP1-negative at the protein level, we also investigated the effect of CD40 signaling and demonstrate that CD40 stimulation can transiently induce RANTES and MCP-1 expression in LMP1-negative epithelial cells. In in situ hybridization only rare tumor cells showed expression of these chemokines unrelated to LMP1 expression, a pattern consistent with transient induction through CD40 signaling. Since RANTES and MCP-1 were also detected in the neoplastic cells of oral squamous cell carcinomas lacking a lymphoid stroma it remains uncertain to what extent these CC chemokines contribute to the attraction of inflammatory cells into the NPC microenvironment. © 2007 Wiley-Liss, Inc. [source] | |||||||||||||||||||||||||||||||||||||||||||