Biomedical subjects

Alfred C Feller

Publications and source records attributed to Alfred C Feller.

33 records · Page 2Linked to original sources

PubMed2002

HER2 overexpression in muscle-invasive urothelial carcinoma of the bladder: prognostic implications.

The HER2 (c-erbB-2) receptor is overexpressed in a variety of human malignant tumors and, in breast carcinoma, has been identified as a target for anti-HER2-directed therapy with the monoclonal antibody (MAb) trastuzumab. The aim of this retrospective study was to evaluate immunohistochemic HER2 expression in a large cohort of muscle-invasive urothelial cell carcinomas of the urinary bladder and to compare the results to pathologic characteristics and survival. Paraffin-embedded tumor specimens from 138 patients undergoing radical cystectomy for muscle-invasive bladder carcinoma were studied immunohistochemically with the Food and Drug Administration (FDA)-approved HercepTest (Dako, Glostrup, Denmark). HER2 overexpression was observed in 57 of 138 tumors (41%) and occurred more frequently in high-grade carcinomas than in low-grade carcinomas (p = 0.036). No significant relationship with HER2 overexpression was registered for tumor staging and lymph node status. Kaplan-Meier curves showed a significantly worse disease-related survival (p = 0.034) in patients with HER2-overexpressing tumors compared to those without HER2 overexpression. In addition to lymph node status (p = 0.0001; relative risk [RR] = 2.93), HER2 status (p = 0.020; RR = 2.22) was identified as an independent predictor for disease-related survival in a multivariate analysis. These results suggest that HER2 expression might provide additional prognostic information in patients with muscle-invasive bladder carcinomas. Because many of these patients harbor HER2-overexpressing tumors, clinical trials evaluating the efficacy of trastuzumab in bladder carcinoma are warranted.

Adult↗

PubMed2002

Heterogeneity of CD4 and CD8+ memory T cells in localized and generalized Wegener's granulomatosis.

Memory T cells display phenotypic heterogeneity. Surface antigens previously regarded as exclusive markers of naive T cells, such as L-selectin (CD62L), can also be detected on some memory T cells. Moreover, a fraction of CD45RO+ (positive for the short human isoform of CD45) memory T cells reverts to the CD45RA+ (positive for the long human isoform of CD45) phenotype. We analyzed patients with biopsy-proven localized Wegener's granulomatosis (WG) (n = 5), generalized WG (n = 16) and age- and sex-matched healthy controls (n = 13) to further characterize memory T cells in WG. The cell-surface expression of CD45RO, CD45RA, CD62L, CCR3, CCR5 and CXCR3 was determined on blood-derived T cells by four-color flow cytometric analysis. The fractions of CCR5+ and CCR3+ cells within the CD4+CD45RO+ and CD8+CD45RO+ memory T cell populations were significantly expanded in localized and generalized WG. The mean percentage of Th1-type CCR5 expression was higher in localized WG. Upregulated CCR5 and CCR3 expression could also be detected on a fraction of CD45RA+ T cells. CD62L expression was seen on approximately half of the memory T cell populations expressing chemokine receptors. This study demonstrates for the first time that expression of the inducible inflammatory chemokine receptors CCR5 and CCR3 on CD45RO+ memory T cells, as well as on CD45RA+ T cells ('revertants'), contributes to phenotypic heterogeneity in an autoimmune disease, namely WG. Upregulated CCR5 and CCR3 expression suggests that the cells belong to the effector memory T cell population. CCR5 and CCR3 expression on CD4+ and CD8+ memory T cells indicates a potential to respond to chemotactic gradients and might be important in T cell migration contributing to granuloma formation and vasculitis in WG.

CD4-Positive T-Lymphocytes↗

PubMed2002

[Aleukemic mast cell leukemia (formerly: "malignant mastocytosis"): an extremely rare form of leukemia. A case report and simultaneously a contribution to revised classification of mastocytosis].

The term mastocytosis denotes a heterogeneous group of rare hematological disorders characterized by abnormal accumulation of mast cells. While cutaneous mastocytosis is relatively frequent mast cell leukemia belongs to the rarest forms of human leukemia. In the following we present the case of an aleukemic mast cell leukemia and shall discuss the revised classification of mastocytosis based on the "Year 2000 Working Conference on Mastocytosis" held in Vienna, Austria. A 48 year-old caucasian man presented with a four-week history of diarrhea, obstipation, vomiting, rash, and mild fever. Clinical inspection revealed a disseminated itching rash and a mild hepatomegaly. Red and white blood cell counts were within the normal range. Levels of the alkaline phosphatase and serum histamine were significantly increased. There was no splenomegaly or lymphadenopathy. Cytologic and histologic investigation of the bone marrow revealed a marked increase in atypical mast cells. Since only a few circulating mast cells could be detected in a cytospin preparation of the blood, the diagnosis of an aleukemic mast cell leukemia was established. About four weeks after the diagnosis had been established, the patient died with signs of a hemorrhagic shock due to a massive gastrointestinal bleeding. Autopsy revealed widespread mast cell infiltration of bone marrow, spleen, liver and lungs, but also a small, deeply penetrating, non-specific duodenal ulcer. In conclusion, despite of presentation with signs of a primary gastrointestinal disorder, the patient was found to suffer from an exceedingly rare aleukemic mast cell leukemia ("malignant mastocytosis") and died after a total duration of the disease of only about three months.

Alkaline Phosphatase↗

PubMed2002

Fibrosarcoma associated with a benign cystic teratoma of the ovary.

OBJECTIVE: A case of ovarian fibrosarcoma associated with a benign cystic teratoma is described. METHODS: A 32-year-old patient with an ovarian tumor detected by routine gynecological examination was referred to our hospital. In addition to histopathological examination of the resected tumor, immunohistochemical studies as well as a cytogenetic analysis by comparative genomic hybridization were carried out. RESULTS: The 7-cm-sized tumor consisted of two different components: a fibrosarcoma and a benign cystic teratoma. The teratoma contained elements of all three germ layers and lacked any focus of immature teratoma. A fibrosarcoma was immediately connected to the teratoma. The sarcoma cells showed eight mitoses per 10 high-power fields on average and exhibited immunohistochemical reactivity for vimentin only. Cytogenetic analysis of the fibrosarcoma using comparative genomic hybridization revealed imbalances of chromosomes 9, 12, and 16. After a 1-year follow-up, there were no signs of tumor recurrence or systemic disease. CONCLUSION: To the authors' knowledge, this is the second report of an association of ovarian fibrosarcoma and benign cystic teratoma, and the first including a cytogenetic analysis.

Adult↗

PubMed2002

Expression of angiopoietin-1 and its receptor TEK in hematopoietic cells from patients with myeloid leukemia.

Apart from endothelial cells, the receptor tyrosine kinase TEK/Tie-2 is also expressed by primitive hematopoietic stem cells. While the role of this receptor and its ligand angiopoietin-1 (ang-1) during angiogenesis has been intensively studied before, little is known about their function in normal or malignant hematopoiesis. Recently several studies suggested that TEK plays an important role in the proliferation of primitive hematopoietic cells. We, therefore, analyzed blood cells of healthy donors and leukemia patients for expression of TEK and ang-1 by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and Northern blotting. We found an increased expression of the receptor and its ligand in 11 of 17 cases of acute and chronic myeloid leukemia (CML) but not in four lymphocytic leukemias or five myeloid leukemias in remission. Abundant ang-1 message could also be detected in 4/6 myeloid and 1/9 cell lines of lymphocytic origin, but only one cell line co-expressed the TEK receptor, suggesting that ang-1 and TEK were probably expressed by different subsets of cells in the leukemic samples. Recently, several studies have indicated that angiogenic factors like ang-1 and vascular endothelial growth factor can enhance the proliferation of normal and malignant hematopoietic cells. The expression of both the TEK receptor and its ligand in acute myeloid leukemia (AML) and CML patients might, therefore, suggest an involvement of these genes in the pathogenesis of myeloproliferative disorders.

Acute Disease↗

PubMed2002

cDNA arrays: gene expression profiles of Hodgkin's disease and anaplastic large cell lymphoma cell lines.

cDNA arrays are a powerful tool for the identification of differentially expressed genes in malignant tumors. We used this technique to study the gene expression profiles of anaplastic large cell lymphoma (ALCL) and Hodgkin's disease (HD). Gene expression of 11 lymphoma cell lines was analyzed covering 1176 cDNA sequences. Comparing these data to the expression profiles of B- and T-lymphocytes, we identified 27 genes that were deregulated in all cell lines or in a particular entity. For the establishment of gene expression profiles the 27 genes were assigned to four groups composed of genes deregulated in (i) all lymphoma cell lines, (ii) ALCL and HD, (iii) only HD, and (iv) ALCL exclusively. Our results indicate that ALCL and HD share the differential expression of at least five genes. In addition, both entities are characterized by the differentially deregulated expression of four genes in HD and seven genes in ALCL. Because the expression profiling was performed on cell lines, further studies are needed to clarify the biological significance of the differentially expressed genes.

B-Lymphocytes↗

PubMed2002

Characterization of a novel human anaplastic large cell lymphoma cell line tumorigenic in SCID mice.

L82, a novel anaplastic large cell lymphoma (ALCL) cell line was established from the pleural effusion of a 24-year-old patient with recurrent ALCL. L82 cells showed the typical morphologic features of ALCL cells with irregular, often indented, nuclear profiles, prominent nucleoli, and abundant cytoplasm. The immunoprofile of L82 corresponds to that seen typically in primary ALCL cells, with positivity for CD30, EMA, CD3, CD4, CD25, CD71, TIA1, and granzyme B; the cells were negative for EBV-related antigens. Cytogenetic analysis showed a complex, near triploid karyotype with 72-77 chromosomes, including the ALCL specific translocation t(2;5)(p23;q35). Chromosomal analysis revealed a number of secondary structural alterations including amplification of 7q21-31, 1q, and 6p, and gain of chromosomal material in 8q (affecting the c-myc gene). The rearrangement of the T-cell receptor-gamma locus shows that L82 is clonally derived from T-lineage lymphoid cells. mRNAs for interleukin 7 (IL-7), IL-8, IL-9, IL-10, TNF-beta, and for the IL-7 and IL-9 receptor were found. These data show that the T-helper cell (Th)1/Th2 balance was polarized to Th2. L82 were inoculated intraperitoneally into 4 week-old SCID mice and produced a disseminated tumor within 4-6 weeks. Morphological, immunohistochemical, and molecular genetic investigation confirmed that the xenograft and the original ALCL tumor were identical. SCID mice xenografted with the human ALCL cell line, L82, provide a useful model system for the investigation of the biology of ALCL and of new therapeutic approaches, such as specific immunotherapy.

Adult↗

PubMed2002

Gene profiling in anaplastic large-cell lymphoma-derived cell lines with cDNA expression arrays.

Comparative hybridization of cDNA arrays is a powerful high-throughput tool for the measurement of gene expression between two or more tissues. Moreover, cDNA array technology permits detection of genes involved in carcinogenesis and prospective targets for diagnosis or therapy in the future. We used this technique in cell lines to discover genes possibly involved in the pathogenesis of the large-cell anaplastic lymphoma (ALCL). CD30(+) lymphoma cells are characteristic for this lymphoma entity and were first described 16 years ago. Still, little is known about the biology of this aggressive lymphoma. Identical arrays covering 1176 genes (Clontech Human Cancer 1.2) were hybridized with labeled first-strand cDNA from five ALCL cell lines and stimulated T cells. We found overlapping gene expression patterns in the five cell lines. Three genes, tissue inhibitor of metalloproteinases 1 (TIMP-1), nm23-H4, and interferon-induced 56K protein (IFI-56K) were strongly overexpressed in all ALCL cell lines compared with stimulated T cells. Whereas interleukin-2 precursor, interleukin-9 precursor, interferon-gamma precursor, T cell surface glycoprotein CD3 epsilon subunit, 40S ribosomal protein SA, and protein-tyrosine phosphate 1C were underexpressed, Reverse transcription polymerase chain reaction and Northern blot analysis were employed to confirm the expression patterns of the genes identified by Atlas hybridization.

DNA Fingerprinting↗

PubMed2002

Cutaneous lymphomas with prominent granulomatous reaction: a potential pitfall in the histopathologic diagnosis of cutaneous T- and B-cell lymphomas.

The presence of a granulomatous reaction in lesions of cutaneous lymphomas has been described in the past in several cases. Especially in mycosis fungoides, a "granulomatous" variant of the disease has been well characterized. We studied the clinicopathologic features of cutaneous lymphomas with prominent granulomatous reaction, including both cutaneous T-cell lymphomas and B-cell lymphomas (primary cutaneous lymphoma 22, secondary cutaneous lymphoma one). Biopsies of 23 patients with histopathologic features of cutaneous T-cell lymphoma or cutaneous B-cell lymphoma with prominent granulomatous reaction were included in this study. A prominent granulomatous reaction was defined as the presence of a granulomatous component exceeding 25% of the dermal infiltrate. There were 14 cases of mycosis fungoides, two of subcutaneous panniculitis-like T-cell lymphoma, four of small/medium pleomorphic T-cell lymphoma, one of follicle center cell lymphoma, one of large B-cell lymphoma, and one of secondary cutaneous peripheral T-cell lymphoma. Altogether, a prominent granulomatous reaction could be observed in 1.8% of all patients with cutaneous lymphoma (primary or secondary) registered in the files of the Department of Dermatology of the University of Graz (Graz, Austria), demonstrating that there is a distinct, albeit small, proportion of cases revealing this peculiar reaction pattern. In seven cases a misdiagnosis of granulomatous dermatitis preceded the correct diagnosis for a period of 1-216 months, suggesting that sequential biopsies and complete phenotypic and molecular genetic analyses should be carried out in cases of "unusual" granulomatous dermatitis.

Adult↗

PubMed2002

Human beta-defensin 2 but not beta-defensin 1 is expressed preferentially in colonic mucosa of inflammatory bowel disease.

OBJECTIVE: Various antimicrobial peptides such as defensins are part of innate immunity and contribute to the intestinal barrier that may be defective in inflammatory bowel disease (IBD). This study investigated beta-defensin mRNA and peptide expression in the colon from controls and patients with Crohn's disease, ulcerative colitis or unspecific colitis as inflammatory controls. METHODS: Mucosal mRNA expression was measured by multiplex reverse transcriptase-polymerase chain reaction (RT-PCR) with primers for human beta-defensin 1 (HBD-1) and human beta-defensin 2 (HBD-2) in CaCo-2 cells and in biopsies from 103 patients (33 controls, 24 Crohn's disease patients, 36 ulcerative colitis patients, 10 unspecific colitis patients). Paraffin-embedded tissue from colonic resections was tested for HBD-1 and HBD-2 peptides by immunohistochemistry. RESULTS: HBD-1 mRNA was expressed constitutively whereas HBD-2 was induced by pro-inflammatory cytokines in CaCo-2 cells. HBD-1 mRNA was detectable in 61% of control and Crohn's disease biopsies and 53% of ulcerative colitis biopsies. HBD-2 transcript was expressed differentially, with 18% of control biopsies positive as opposed to 34% in Crohn's disease and 53% in ulcerative colitis. HBD-2 mRNA but not HBD-1 mRNA was expressed preferentially in inflamed areas. Immunohistochemical investigation demonstrated the presence of defensin peptides in colonic epithelium as well as the differential induction in IBD. CONCLUSIONS: HBD-1 is expressed constitutively in colonic tissue irrespective of inflammation. HBD-2 is barely present in uninflamed colon but it is induced in inflammation. The lower expression of HBD-2 in Crohn's disease compared with ulcerative colitis indicates different responses of the mucosal innate defence. Defensins may play a crucial role in controlling pathogen invasion in IBD, although the functional significance remains to be established.

Cells, Cultured↗

PubMed2002

Overexpression of c-erbB-2 oncoprotein in muscle-invasive bladder carcinoma: relationship with gene amplification, clinicopathological parameters and prognostic outcome.

Amplification of the c-erbB-2 oncogene and protein overexpression are well-known in breast cancer and a basis for therapy with the monoclonal antibody trastuzumab, which binds to the receptor encoded by c-erbB-2. Regarding bladder carcinoma, several studies have examined c-erbB-2 expression, but their results are quite heterogeneous. In the present study, we evaluated the expression of this oncoprotein immunohistochemically in 203 muscle-invasive urothelial bladder carcinomas using the HercepTest. Additionally, 42 cases were studied for gene amplification by fluorescence in situ hybridization (FISH) using the PathVysion kit. Follow-up was known in 147 patients. The results were compared with pathologic characteristics and disease-related survival. Immunohistochemical c-erbB-2 overexpression was observed in 37% of the tumors (76/203). However, only 5% (2/42) showed amplification of the oncogene, indicating that predominantly other mechanisms than gene amplification may cause protein overexpression in bladder cancer. C-erbB-2 protein overexpression was significantly associated with high tumor grade (p=0.004) and infiltrative growth pattern (p=0.0001), and tendentiously associated with the presence of lymph node metastases (p=0.077). Regarding tumor stage, sex and age, no significant correlation was registered. Kaplan-Meier curves showed a significantly worse disease-related survival for patients with c-erbB-2 overexpressing tumors (p=0.0346 by log-rank test). Multivariate analysis revealed that, besides nodal status (p=0.0001) and tumor stage (p=0.028), c-erbB-2 overexpression was an independent predictor of disease-related survival (p=0.030). Thus, our results suggest that immunohistochemical c-erbB-2 detection might represent an additional tool in determining bladder cancer prognosis. Clinical trials evaluating the efficacy of trastuzumab therapy in bladder cancer patients are warranted.

Adult↗

PubMedDate not supplied

Primary malignant melanoma of the small bowel: a case report and review of the literature.

Although small bowel involvement by malignant melanoma is most frequently metastatic, a primary origin at this site has been reported in rare cases. The biological and clinical features of these cases have not yet been summarized. Here, another case of small bowel melanoma is described, and a review of the existing literature is given. An 81-year-old man presented with anemia and gastrointestinal bleeding. A tumor of the ileum was detected by video capsule endoscopy and removed by segment resection. Histological examination revealed a malignant melanoma of the ileum. Another primary site could be excluded by clinical and radiographic examination. The patient felt well five months after surgery. Only 18 cases of primary small bowel melanoma (including the present one) have been reported to date. A literature review reveals that this rare neoplasm is associated with a slight predilection for the male gender, a predilection for the ileum and a poor prognosis.

Aged↗

PubMedDate not supplied

EMMPRIN (CD 147) is expressed in Hodgkin's lymphoma and anaplastic large cell lymphoma. An immunohistochemical study of 60 cases.

BACKGROUND: Matrix metalloproteinases are involved in tumor invasion and metastatic spread. Expression of metalloproteinases is induced by the extracellular matrix metalloproteinase inducer (EMMPRIN). Their activity can be inhibited by several tissue inhibitors of metalloproteinases (TIMP1-to-4). Whereas TIMP-1 expression is described for high-grade malignant lymphomas and seems to be correlated with unfavourable prognosis, there are no data on the expression of EMMPRIN in malignant lymphoma. MATERIALS AND METHODS: We investigated 60 cases of Hodgkin's lymphoma and anaplastic large cell lymphoma for TIMP-1 and EMMPRIN expression using immunohistochemistry. RESULTS: EMMPRIN was expressed in all but four cases. EMMPRIN and TIMP-1 were co-expressed in two-thirds of the Hodgkin's lymphomas and anaplastic large cell lymphomas. CONCLUSION: This is the first report on the expression of EMMPRIN in malignant lymphoma. We speculate that EMMPRIN and TIMP-1 may be important in the pathogenesis of anaplastic large cell lymphoma and Hodgkin's disease.

Antigens, CD↗

PubMedDate not supplied

Whole cell ELISA for measuring anti-tumour effects of immunotherapies in a mouse tumour model of ALCL.

The use of whole cell vaccines to augment anti-tumour immunity has been explored throughout the last century. Using the recently established TS1G6 ALCL mouse model, we compared the ability of whole cell vaccines with different combinations of CpG oligodeoxynucleotides, Diphteria-, Pertussis- and Tetanus-vaccine (DPT) to enhance the immunogenicity of tumour cells. We have therefore developed a whole cell ELISA that detects the systemic anti-tumor-cell antibody response. CpG oligodeoxy-nucleotides can induce production of different TH1-cytokines and stimulate immune effector cells. Diphteria-, Pertusis- and Tetanusvaccine, injected together with irradiated tumor cells into Diphteria-, Pertussis- and Tetanus-preimmunized mice were used to serve as a target for the host's existing memory response and thus enhance the immunogenicity of the tumour cells by induction of a local inflammation. The combined application of oligodeoxynucleotides, the vaccines and irradiated tumor cells into preimmunized mice quickly induced very high titers of tumour cell-specific antibody response. We conclude that this therapy may be a new attractive part of a tumour immunization strategy.

Adjuvants, Immunologic↗

PubMedDate not supplied

Protein expression and gene copy number analysis of topoisomerase 2alpha, HER2 and P53 in minimally invasive urothelial carcinoma of the urinary bladder--a multitissue array study with prognostic implications.

BACKGROUND: Due to their variable clinical course, there is a need for new prognostic parameters in minimally invasive (stage T1) bladder carcinomas. MATERIALS AND METHODS: Using multitissue arrays, protein expression and gene copy numbers of topoisomerase (TOP2alpha), HER2 and p53 were investigated by immunohistochemistry and by fluorescence in situ hybridization (FISH) in 73 T1 tumors. The results were compared with tumor recurrence and progression. RESULTS: The median TOP2alpha and p53 index was 21% (range, 3-59%) and 7% (range, 0-93%), respectively. HER2 overexpression (score 3+) was detected in 9 cases (12%). High TOP2alpha and p53 indices and HER2 overexpression were significantly associated with earlier tumor recurrence, but not with earlier tumor progression. While TOP2alpha and p53 gene amplification was detected in no case, 5 cases (8%) showed HER2 gene amplification, which was related to HER2 3+ score in 4 cases. Loss of TOP2alpha, HER2 and p53 gene was observed in 4 (8%), 8 (13%) and 6 cases (12%), respectively. By univariate analysis, TOP2alpha index (p=0.0267), HER2 score (p =0.028) and p53 index (p=0.0188) were significantly and loss of TOP2alpha gene (p=0.0575) tendentially correlated with tumor recurrence, while loss of HER2 gene (p=0.069) and loss of p53 gene (p=0.0587) were tendentially correlated with tumor progression. In a multivariate analysis, which also included tumor grade and T1 substage, TOP2alpha index (p=0.043) and p53 index (p=0.02) were identified as independent predictors of tumor recurrence and loss of p53 gene (p=0.012) and T1 substage (p=0.029) as independent predictors of tumor progression. CONCLUSION: Immuno-histochemical TOP2alpha and p53 staining as well as FISH analysis of p53 gene copy numbers and T1 substaging are helpful means of providing additional information on the biological behavior of T1 transitional cell carcinomas.

Adult↗