KIT in ovarian carcinoma: disillusion about a potential therapeutic target.
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Antineoplastic Agents↗
Biomedical subjects
Stephan Dirnhofer
Publications and source records attributed to Stephan Dirnhofer.
Edrecolomab in the adjuvant treatment of colorectal carcinoma.
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Antibodies, Monoclonal↗
High-throughput tissue microarray analysis of G1-cyclin alterations in classical Hodgkin's lymphoma indicates overexpression of cyclin E1.
Deregulation of G1-cyclins (CCN) plays a key role in the pathogenesis of many human malignancies, including non-Hodgkin's lymphomas (NHLs). In contrast to NHL, little is known about phenotypic and genotypic changes in the regulation of the cell cycle in classical Hodgkin's lymphoma (cHL). To facilitate analysis of aberrant gene expression in cHL, a lymphoma tissue microarray (TMA) containing 752 cores of 330 different cHL samples was constructed. Direct comparison of Epstein-Barr virus (EBV) latent membrane protein 1 (LMP-1) expression in Hodgkin's and Reed-Sternberg (HRS) cells on conventional full sections with the corresponding duplicate/triplicate tumour cores on the TMA showed a concordance of 100%, indicating that cHL-TMA is a reliable and representative method for evaluating gene expression profiles in situ. Using TMA technology, protein expression and gene amplification of different G1-CCNs in cHL were analysed. Among the G1-CCNs analysed, cyclin E (CCNE) was expressed in 212/253 cases (84%). In most of the individual tumours, over 75% of the HRS cells stained positive for CCNE, suggesting that CCNE is overexpressed in cHL. This overexpression was not due to CCNE gene amplification, as judged by fluorescence in situ hybridization, and did not correlate with EBV infection, as assessed by the expression of LMP-1. Thus, the overexpression of CCNE could be caused by profound changes in HRS cell-cycle regulation that could contribute to the malignant phenotype.
Cyclin E↗
Rituximab effective in a patient with refractory autoimmune haemolytic anaemia and CD20-negative multiple myeloma.
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Anemia, Hemolytic, Autoimmune↗
Longer failure-free survival interval of Epstein-Barr virus-associated classical Hodgkin's lymphoma: a single-institution study.
We analyzed Epstein-Barr virus association in classical Hodgkin's lymphoma from a single center in Austria with special emphasis on the latent membrane protein1 gene configuration and clinical outcome. All 119 (65 male, 54 female) patients were treated from 1974 to 1999 in the Division of Hematology and Oncology at the Department of Internal Medicine, University of Innsbruck, Austria. The mean follow-up time was 122 months (range, 3-333 mo). Epstein-Barr virus was examined by latent membrane protein1 immunohistochemistry and by in situ hybridization for Epstein-Barr virus-encoded early ribonuclein acid transcripts. For assessment of the Epstein-Barr virus subtype (A/B) and latent membrane protein1 gene configuration, the polymerase chain reaction was employed. Fifty-four reactive tonsils were used as the control population. These results as well as clinical parameters such as age, gender, tumor stage, risk factors, and B symptoms were correlated with failure-free and overall survival. Latent membrane protein1 was detected in 31/119 (26%) classical Hodgkin's lymphoma, and Epstein-Barr virus subtyping was successful in 19 of the 31 virus-infected classical Hodgkin's lymphoma cases, as well as in 28 of 54 reactive tonsils. Subtype A was observed in all classical Hodgkin's lymphoma patients and in 26/28 (93%) tonsils. The 30-base pair latent membrane protein1 gene deletion was found in only 4/31 (13%) Epstein-Barr virus-associated classical Hodgkin's lymphoma as well as in 20/54 (37%) reactive tonsils. Patients with Epstein-Barr virus-associated classical Hodgkin's lymphoma showed a significantly longer mean time to first relapse of 99 months, as compared with 49 months for the Epstein-Barr virus-negative cases (P <.02), and were more frequent in those aged >45 years (P <.04). Epstein-Barr virus-associated classical Hodgkin's lymphoma were predominantly of the mixed-cellularity subtype and occurred more frequently in male patients, in patients with Stage III and IV, and in patients with B symptoms as well as risk factors. However, overall survival did not correlate with Epstein-Barr virus association. The 30-base pair latent membrane protein1 gene deletion had no influence on overall survival and failure-free survival time. Although the number of patients with this specific mutation was low, it further shows that an increased oncogenic potential of the latent membrane protein1 deletion variant is unlikely. This large single-center study demonstrates a low prevalence of Epstein-Barr virus positivity in classical Hodgkin's lymphoma in western Europe. In accordance with results of similar studies, the presence of Epstein-Barr virus has a beneficial effect on the length of failure-free survival despite the higher frequency of risk factors such as higher tumor stage or advanced age.
Adolescent↗
Expression of B-cell markers in classical hodgkin lymphoma: a tissue microarray analysis of 330 cases.
Hodgkin and Reed-Sternberg cells of classical Hodgkin lymphoma arise from B-lymphocytes. However, classical markers of the B-cell phenotype, such as CD20, are present only in about 25% of the cases. The aim of the present study was to assess expression of the B-cell-related antigens CD20, CD79a, and CD138 in classical Hodgkin lymphoma using a tissue microarray consisting of 330 classical Hodgkin lymphoma cases. Expression of CD15, CD20, CD30, CD79a, CD138, and latent membrane protein 1 of Epstein-Barr virus was assessed by immunohistochemistry, and the methodology was validated by direct comparison of CD20 expression on the tissue microarray cores with corresponding large sections. The influence of the number of arrayed sample cores on the obtained expression levels of CD20 was analyzed by comparing the results from single, duplicate, and triplicate cores. Two-hundred fifty-three (77%) of the 330 cases were morphologically representative. CD20 was expressed in 84 cases (33%), CD79a in 26 (10%), and CD138 in 2 (1%), respectively. CD20 and CD79a were co-expressed in 16 cases (P <.005), and expression of CD20 correlated inversely with CD15 (P <.01). Comparing the tissue microarray results with those from conventional sections for expression of CD20 yielded a concordance of 94% (63/67). Examining one, two, and three cores from individual cases revealed positivity for CD20 at 24% (61/253), 32% (82/253), and 33% (84/253), respectively. We conclude that B-cell markers are expressed in 38% of classical Hodgkin lymphoma in the following rank order: CD20>CD79a>>CD138. The use of two cores per tissue sample renders the tissue microarray technology effectively representative and thus very useful for high-throughput evaluation of heterogeneously expressed markers in classical Hodgkin lymphoma.
Antigens, CD↗
Prognostic significance of CD20 expression in classical Hodgkin lymphoma: a clinicopathological study of 119 cases.
PURPOSE: Recent evidence has demonstrated that classical Hodgkin lymphoma (cHL) originates from mature germinal center B cells. However, only approximately 25% of cHLs express the classical B-cell marker CD20. There is very little, and controversial, information on the prognostic significance of CD20 expression in cHL with regard to failure-free (FFS) and overall survival (OS). EXPERIMENTAL DESIGN: CD20 expression was investigated in a series of 119 cases of cHL treated at a single institution where complete clinical follow-up was available. The results were correlated to FFS and OS by the Kaplan-Maier method and uni- and multivariate analyses. RESULTS: Hodgkin and Reed-Sternberg cells expressed CD20 in 20% (24 of 119) of the cases based on a cutoff of 10% positivity. Within a mean follow-up period of 12 years, univariate analysis revealed a significantly higher frequency of disease relapses in the CD20-negative group (30 of 95; 32%) compared with CD20-positive tumors (2 of 24; 8%; P = 0.022). Compared by the log-rank test, the mean FFS in CD20-negative cases (202 months) was considerably shorter than in the CD20-positive cases (286 months; P = 0.0195). In a multivariate analysis, CD20 expression was an independent positive prognostic factor for FFS in cHL patients treated from 1974 to 1980 (P = 0.035). This effect disappeared in the period from 1981 to 1999 (P = 0.266). CONCLUSION: CD20-positive cHL shows a trend for better FFS and OS. However, improved treatment modalities seem to abolish these differences.
Adolescent↗
Characterisation and predictive value of epidermal growth factor receptor status using quantitative real-time PCR combined with immunohistochemistry on non-small cell lung cancer specimens.
The frequency of increased EGFR-mRNA expression was determined in 57 patients suffering from NSCLC by applying quantitative real-time PCR. The findings were correlated with clinical parameters and the immunohistochemical (IHC) markers EGFR, c-erbB-2, c-erbB-3, Ki-67 and p53 on cryostat sections. Of the patients 46% showed increased EGFR-mRNA, 35% revealed an increased IHC-EGFR expression; 16% of the patients showed a combined positivity and 35% a combined negativity when applying both methods, and 17 (30%) of the cases revealed increased EGFR-mRNA without IHC-EGFR expression. This subgroup was characterised by p53 coexpression and the highest frequency of deaths (35% vs. 20%) indicating a more aggressive tumour type. In contrast to IHC - where positivity was seen predominantly in squamous cell carcinomas (48% vs. 27%) - EGFR-mRNA expression was observed equally in both histological subtypes (48% vs. 43%). PCR-EGFR and IHC-EGFR tumour typing identifies different tumour characteristics with different clinical courses. Whether this combined typing could help to identify patients who respond to anti-EGFR therapies is worth further testing.
Carcinoma, Non-Small-Cell Lung↗
Automated real-time PCR to determine K-ras codon 12 mutations in non-small cell lung cancer: comparison with immunohistochemistry and clinico-pathological features.
A real-time PCR technique with automated computerized analysis (TaqMan ) was tested to detect K-ras mutations in 66 patients suffering from NSCLC. This technology is characterized by high reproducibility of data and a time-saving analysis procedure. In 11% (7/66) of the tumour specimens and 2% (1/58) of adjacent tumour-free lung specimens a K-ras codon 12 mutation was detected. In adenocarcinomas containing > or =40% tumour cells, however, K-ras mutations were seen in 25% of the cases. The point mutations detected in tumours were GGT right curved arrow TGT in five cases and GGT right curved arrow GTT in two cases. As compared with immunohistochemical parameters, the K-ras mutated group was characterized by a c-erbB-2 negativity (p=0.04) and a smaller number of c-erbB-3 (p=0.02) positive cases. EGFR, bcl-2, p53, Ki-67 and p120 expression did not differ significantly. Determination of the K-ras point mutations by automated TaqMan PCR in NSCLC tumour specimens is feasable and highly specific. Due to its high throughput capacity this method represents a valuable tool for routine screening.
Carcinoma, Non-Small-Cell Lung↗
Primary gastric follicular lymphoma with parafollicular monocytoid B-cells and lymphoepithelial lesions, mimicking extranodal marginal zone lymphoma of MALT.
The incidence of B-cell non-Hodgkin lymphomas (B-NHL) at nodal and extranodal sites is fairly different. Follicular lymphomas (FL) occur predominantly at nodal sites and rarely in the gastrointestinal tract, while marginal zone lymphomas (MZL) of the mucosa-associated lymphatic tissue (MALT) type predominate in the digestive organs and especially in the stomach. We report a 72-year-old female patient admitted for gastroscopy because of epigastric pain. The antral biopsies showed dense lymphocytic infiltrates, partially forming follicles with widened marginal zones and monocytoid cells. Multiple lymphoepithelial lesions (LEL) were also observed. A MZL of the MALT type was suspected morphologically. Immunohistochemical analysis revealed the lymphatic infiltrates to be CD20, bcl-2, bcl-6 and CD10 positive, and negative for CD43, CD5 and cyclin D1. PCR-based analysis showed a JH/bcl-2 rearrangement, corresponding to the translocation t(14;18). An extranodal FL mimicking MZL was diagnosed. The present case is remarkable, as it demonstrates that the detection of LEL and monocytoid B-cells, although suggestive for MZL, is not entirely specific and can also be observed in FL. Pathologists should be aware of this diagnostic pitfall in classifying gastric B-NHL. In equivocal cases, a careful morphological examination, supported by specific immunohistochemical and molecular findings, should lead to the correct diagnosis.
Aged↗
Hepatosplenic gammadelta-T-cell lymphoma with leukemic course after renal transplantation.
Hepatosplenic gammadelta-T-cell lymphoma (HSTCL) is a rare extranodal T-cell non-Hodgkin's lymphoma (T-NHL) with only 46 well-documented cases in medical literature. Notably, a relatively high number of these case reports (15%) describe the occurrence of HSTCL after solid organ transplantation. We describe the case of a 45-year-old man who developed a leukemic HSTCL 5 years after renal transplantation and continous immunosuppression with cyclosporine A and prednisolone. After a rapid clinical course, the patient died and autopsy was performed. The malignant lymphocytes showed a natural killer-like gammadelta-T-cell phenotype (CD2(+), CD3(+), CD7(+), TCR gammadelta(+), CD56(+), TIA-1(+), CD4(-), CD8(-), and TCR alphabeta(-)) and infiltrated the sinusoids of liver and the red pulp of the spleen. Cytogenetically, an isochromosome 7q, trisomy 8, Y-loss, and a translocation t(1;4) was detectable. This case shows the difficulties of recognizing HSTCL early in the clinical course and underlines that all types of T-NHL, nodal as well as extranodal, have to be considered in the differential diagnosis of posttransplantation lymphoproliferative disorders. Moreover, HSTCL seems to occur as a specific late complication of solid organ transplantation.
Antineoplastic Combined Chemotherapy Protocols↗
Idiopathic myelofibrosis with nodal, serosal and parenchymatous infiltration. Case report and review of the literature.
Idiopathic myelofibrosis (IMF) is a breakpoint cluster region rearrangement-negative chronic myeloproliferative disease with progressive bone marrow fibrosis. We report a female patient (65 years old) who was admitted to our hospital in 1996. Trephine bone marrow biopsy revealed diffuse fibrosis with atypical multilobulated megakaryocytes. A cellular phase of IMF was diagnosed. Three years later, despite being at intermediate risk, the patient developed generalized lymphadenopathy and multiple sclerosing tumors throughout the peritoneum and retroperitoneum. Biopsy specimens from these tumors revealed sclerosing hematopoietic infiltrates. The present case demonstrates that IMF not only can progress to acute leukemia but can also spread uncontrollably, or 'metastasize' with extensive sclerosing hematopoietic tumors throughout the body.
Aged↗
Serum tryptase levels in patients with mastocytosis: correlation with mast cell burden and implication for defining the category of disease.
BACKGROUND: The serum tryptase level is used as a diagnostic marker in mastocytosis and is considered to reflect the burden of (neoplastic) mast cells (MC). METHODS: In the present study, serum tryptase levels were measured in patients with mastocytosis by fluoroenzyme immunoassay and compared with the extent of infiltration of the bone marrow (BM) by neoplastic MC, determined by tryptase immunohistochemistry. Sixteen patients with cutaneous mastocytosis (CM) and 43 patients with systemic mastocytosis (SM) were examined. RESULTS: In most patients with CM (defined by the absence of dense compact MC infiltrates in tryptase-stained BM sections), normal or near-normal serum tryptase levels (median 10 ng/ml, range 2-23 ng/ml) were measured. By contrast, in the vast majority of patients with SM, elevated serum tryptase levels (median 67 ng/ml) were found. In addition, there was a significant correlation between the grade of infiltration of the BM by neoplastic MC and tryptase levels in patients with SM (r = 0.8). Moreover, enzyme levels differed significantly among the groups of patients with different types of SM. The highest levels (>900 ng/ml) were detected in the patient with MC leukemia, 2 patients with slowly progressing SM and high MC burden (smoldering SM) and 1 patient with indolent SM. In contrast, in all 3 patients with isolated BM mastocytosis (no skin lesions and no signs of multiorgan involvement), serum tryptase levels were <20 ng/ml. CONCLUSIONS: In summary, our data suggest that the measurement of serum tryptase is a reliable noninvasive diagnostic approach to estimate the burden of MC in patients with mastocytosis and to distinguish between categories of disease.
Adolescent↗
Human lipocalin-1, a physiological scavenger of lipophilic compounds, is produced by corticotrophs of the pituitary gland.
Lipocalin-1 (Lcn-1), a member of the lipocalin superfamily that binds a broad array of different chemical classes of lipophilic ligands, is believed to act as a physiological scavenger of potentially harmful lipophilic molecules. Thus far, it was thought to be produced exclusively by a number of exocrine glands and tissues, including lachrymal and lingual glands, prostate, secretory glands of the tracheobronchial tract, and sweat glands. Using Northern blotting analysis, we were able to demonstrate Lcn-1 expression by the human pituitary gland. Moreover, double immunolabeling with antibodies against Lcn-1 and pituitary gland hormones and detection with fluorophore-conjugated secondary antibodies revealed that Lcn-1 is specifically produced by corticotrophs, clearly indicating that its distribution is not restricted to exocrine tissues.
Acute-Phase Proteins↗
Identification of cyclin D1 mRNA overexpression in B-cell neoplasias by real-time reverse transcription-PCR of microdissected paraffin sections.
PURPOSE: Overexpression of cyclin D1 mRNA and protein as a result of the chromosomal translocation t(11;14)(q13;q32) is a highly specific molecular marker of mantle cell lymphoma, but cyclin D1 dysregulation can also be found in other B-cell neoplasias. The aim of the study was to develop a precise and reliable tool for quantitation of cyclin D1 mRNA suitable for archival clinical specimens. EXPERIMENTAL DESIGN: A real-time reverse transcription-PCR (RT-PCR) assay was used to quantitate cyclin D1 mRNA copy numbers. Using 2000 microdissected cells as template, 104 formalin-fixed, paraffin-embedded lymph node, spleen, and decalcified bone marrow biopsies from a panel of 95 cases of B-cell non-Hodgkin's lymphomas (B-NHLs) were analyzed. In addition, cyclin D1 protein expression was assessed by immunohistochemistry. RESULTS: Strong cyclin D1 mRNA overexpression was detected in mantle cell lymphomas (23 of 23), hairy cell leukemias (5 of 19), and multiple myelomas (7 of 23) with particularly high levels in 2 of the latter cases. Intermediate transcript levels were found in 5 of 23 multiple myelomas and 7 of 19 hairy cell leukemias. B-cell chronic lymphocytic leukemias (10 of 10), follicular lymphomas (9 of 9), mucosa-associated lymphoid tissue lymphomas (5 of 5) and reactive lymphoid tissues with the exception of normal spleen had no or very low cyclin D1 expression. In comparison with real-time RT-PCR, immunohistochemistry showed a lower level of sensitivity, more variability, and did not allow accurate quantitation. CONCLUSIONS: Real-time RT-PCR for cyclin D1 mRNA is an excellent tool for the differential diagnosis of B-NHLs and, in combination with microdissection, a powerful approach for retrospective trials using archival clinical specimens as tissue source. Furthermore, real-time RT-PCR may help to identify subgroups of B-NHLs according to cyclin D1 mRNA copy numbers and to investigate the possible influence of different chromosomal breakpoints on cyclin D1 expression.
Chromosomes, Human, Pair 11↗
Tissue microarray technology: principles, pitfalls and perspectives--lessons learned from hematological malignancies.
Detection, validation and incorporation into clinical use of new diagnostic, prognostic and therapeutic molecular targets in modern medical science should be time- and cost-efficient. Here, we discuss the principles, advantages, disadvantages and possible pitfalls of tissue microarray (TMA) technology, a powerful tool for high throughput large-scale morphological in situ analysis of molecular targets. Based on recent observations from molecular profiling of hematological malignancies, we review potential TMA applications assessing molecular targets in large collectives of tissue specimens.
Animals↗
Comparison of automated cellular imaging system and manual microscopy for immunohistochemically stained cryostat sections of lung cancer specimens applying p53, ki-67 and p120.
Seventy-one frozen lung tissue specimens from 52 patients suffering from non-small cell lung cancer (NSCLC) were analysed in this study. Cryostat sections were stained with monoclonal antibodies against p53, ki-67 and p120, all of which are of prognostic value in NSCLC. Slides were evaluated by standard manual microscopy (MM) and using a new Automated Cellular Imaging System (ACIS). The results obtained with ACIS correlated significantly with MM examination (p<0.001). However, ACIS showed a higher sensitivity, especially for specimens with a low infiltration volume. In 15 (6.8%) MM negative cases singular positive cells were identified with ACIS. In cases with a high infiltration volume subjective (MM) quantitation tended to overestimate the number of infiltrating cells. ACIS guaranteed a high reproducibility of data. We conclude that ACIS-assisted analysis is a valid means of investigating the p53, ki-67 and p120 antibody expression in cryostat sections of lung cancer specimens. ACIS can complement conventional manual microscopy due to its higher accuracy, sensitivity and better reproducibility of data.
Adenocarcinoma↗