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J A Van Unnik

Publications and source records attributed to J A Van Unnik.

At least 19 recordsLinked to original sources
PubMed1995

[Consensus soft tissue tumors. Dutch Workgroup Soft-Tissue Tumors].

Soft-tissue sarcomas constitute a rare group of malignant tumours with histopathological features of connective, muscular, fatty or peripheral nervous tissue. The prognosis at manifestation depends on only two factors: the spread, both local and remote, and the biological behaviour of the tumour. The latter factor cannot be influenced but the former can: by inexpert manipulation. Consequently, tumours suspected of being soft-tissue sarcomas require multidisciplinary management from the beginning, with the team members familiar with each other's diagnostic and therapeutic skills. Imaging diagnostic methods should precede invasive methods for collection of material for pathological examination. The number of mitotic figures observed at microscopical examination of the tissue is an important prognostic feature. Surgical resection is the treatment of first choice. Radiotherapy is indicated in grade 3 tumours, after recurrence surgery, and when radical resection would involve too much mutilation. Chemotherapy is only given in the context of clinical trials. Surgical treatment of lung metastases may be indicated in selected patients. Regional isolated perfusion with tumour necrosis factor may be an alternative for limb amputation.

Biopsy↗
PubMed1993

Detection of calcitonin and calcitonin gene-related peptide mRNA in human medullary thyroid carcinoma. A retrospective study.

In situ hybridization finds many applications in modern pathology. In many cases, special attention is paid to the processing of the tissues prior to in situ hybridization. In order to investigate the value of RNA in situ hybridization (RISH) in retrospective studies, we performed RISH for calcitonin and calcitonin gene-related peptide (CGRP)-I and -II mRNA in eight medullary thyroid carcinomas processed in 1981-1983. RISH was successful with radioactive calcitonin and CGRP-I probes. With biotinylated probes, only calcitonin-specific probes gave adequate results. The concentrations of CGRP mRNA were probably too low to be detected by non-radioactive RISH. The results of RISH were correlated with the immunohistochemical localization of the polypeptides. The results matched in all cases except one, where hybridization for calcitonin mRNA was found, but no immunoreactive calcitonin polypeptide. We conclude that RISH can be successfully used for retrospective analysis, even after long storage of tissue embedded in paraffin.

Calcitonin↗
PubMed1991

Two cell lines with epithelial cell-like characteristics established from malignant fibrous histiocytomas.

Two malignant fibrous histiocytoma (MFH) cell lines were established: one from a storiform-pleomorph subtype and the other from a myxoid one (codes, MFH-3 and MFH-4). Light microscopic examination revealed large rounded cells, growing mostly separately, in both cell lines. Their ultrastructure was different in various aspects. The MFH-3 cells showed abundant lysosomal activity, a well-developed Golgi apparatus, and a few desmosome-like cell contacts. The MFH-4 cells had a well-developed rough endoplasmic reticulum, delicate bundles of tonofilaments, the formation of pseudoacini, and the presence of small completely developed desmosomes. Based on immunostaining and immunoblotting assays of cultured cells, both cell lines expressed immunoreactivity for vimentin; cytokeratins 7, 8, and 18; desmin; and laminin, but they lacked reactivity for cytokeratins 10 and 19, neurofilament, alpha-smooth muscle actin, S-100 protein, collagen type IV, carcinoembryonic antigen, and antigens specific for macrophages. Fibronectin and, to a variable extent, glial fibrillary acid protein and epithelial membrane antigen (EMA) were detectable in MFH-3 cells only. Furthermore, a 60-kilodalton band was present in both cell lines which was reactive for cytokeratins 8 and 18. The MFH-3 cells had the capacity to grow as xenografts with a carcinoma-like pattern. The cells retained their immunoreactivity for vimentin and cytokeratin 8 and showed the presence of desmosomes. Several of these immunophenotypic features also were noticed in established sarcoma cell lines and in short-term cultures of fibroblasts, smooth muscle cells, and endothelial cells. However, experimental data on the two MFH cell lines show that the MFH cell line may express some immunophenotypic and ultrastructural features considered to be specific for epithelial cells. The MFH cells may originate from multipotential mesenchymal cells with a capacity to differentiate to fibroblast-like cells, and less frequently, to epithelial cells, smooth muscle cells, and Schwannian cells. Such a differentiation became evident when these cells were adapted to culture conditions or grew in nude mice.

Aged↗
PubMed1991

Hybridohistochemical demonstration of alternative splicing of the CALC-I gene.

Precursor RNA is processed to mature mRNA by excision of the noncoding introns. This process is called splicing and usually is studied by in vitro transcription experiments and by Northern blotting. The pre-mRNA of the first calcitonin gene (CALC-I) can be spliced alternatively into two different mRNAs encoding either for calcitonin or for calcitonin gene-related peptide (alpha-CGRP). The expression of CALC-I was studied by in situ hybridization in the nervous system of the rat with calcitonin-specific and CGRP-specific probes. We found evidence for alternative splicing of the pre-mRNA of CALC-I in the motor neurons of the spinal cord. alpha-CGRP mRNA was found in the nuclei and the cytoplasm of the spinal motor neurons, whereas hybridization with a calcitonin-specific probe was located strictly in the nuclei. Because no calcitonin RNA and protein was detected in the cytoplasm of the cells, we concluded that the hybridization obtained in the nucleus was the pre-mRNA encoding for alpha-CGRP.

Animals↗
PubMed1990

Insulin-like growth factor gene expression in human smooth muscle tumors.

A role for insulin-like growth factors (IGF) in autocrine or paracrine growth stimulation of tumor cells has been proposed for tumors of different origins. We have studied IGF gene expression in human uterus smooth muscle (myometrium) and in a panel of benign (leiomyoma) and malignant (leiomyosarcoma) smooth muscle tumors. Using RNA transfer blot analysis we could demonstrate that in smooth muscle tissue and tumors IGF genes are differentially expressed. The mRNA species detected had the same size as reported for IGF mRNAs from other tissues. However, the abundance of the IGF gene transcripts varied from tissue to tissue. The amounts of IGF mRNAs detected in smooth muscle tumors were compared to the levels found in normal smooth muscle. The IGF-I gene was expressed at high levels in normal myometrium and in leiomyomas but appears to be repressed in leiomyosarcomas. Also the IGF-I peptide was detected in myometrium and in leiomyomas, but in leiomyosarcomas the level was substantially lower. The IGF-II gene was expressed at low levels in normal myometrium and leiomyomas but is activated in leiomyosarcomas. With increasing malignancy from the two major IGF-II mRNA species, 6.0 and 4.8 kilobases, in particular the 6.0-kilobase mRNA is produced at higher levels. In conclusion, these data suggest that for IGF-I a role in tumor cell growth is not likely, but probably IGF-II is involved in malignant smooth muscle tumor growth progression.

Female↗
PubMed1990

The relevance of the DNA index and proliferation rate in the grading of benign and malignant soft tissue tumors.

The relevance of the DNA index (DI) to malignancy grading and the relationships between mitotic score, Ki-67 score, and the proportion of cells in the G1-phase (G1PF) of the cell cycle, as proliferative indicators, were investigated in benign (n = 8) and malignant (n = 46) soft tissue sarcomas. Although DI was not found to be related to the histology of the sarcomas, it was associated with malignancy grade, i.e., 14%, 25%, 42%, and 86% of benign, Grade 1, Grade 2, and Grade 3, respectively had a DI greater than 1. The relevance of aneuploidy in benign tumors is discussed and the literature reviewed. A subgroup of the malignant tumors (n = 13) had both a low mitotic score and a low Ki-67 value. However, a distinct correlation between Ki-67 and the mitotic score could not be shown. For malignant tumours G1PF was related to DI, i.e., low G1PF occurred in tumors with diploid DNA content. Low Ki-67 scores were observed in 59% of diploid tumors and in 20% of aneuploid tumors. However, it appeared that G1PF and Ki-67 were not correlated. In conclusion, (1) benign and Grade 1 tumors were predominantly diploid with high G1PF and low Ki-67 values, (2) most of Grade 3 tumors were aneuploid (86%) with low G1PF and high Ki-67 values, and (3) the group of Grade 2 tumors could be divided into two subgroups either with the characteristics displayed by benign and Grade 1 tumors (DI = 1, low Ki-67 scores, and high G1PF) or with the characteristics exhibited by Grade 3 tumors (DI greater than 1, high Ki-67 scores, and low G1PF). Hence, supplementary to the grading of soft tissue tumors, DI, G1PF, and Ki-67 score could be useful as prognostic parameters in soft tissue tumors.

Alkaline Phosphatase↗
PubMed1990

Expression of insulin-like growth factor 1 in sarcomas.

The expression of insulin-like growth factor-1 (IGF-1) was studied in normal tissues, in eight benign lesions and in 50 sarcomas. In palmar fibromatosis the spindle cells in cell-dense areas exhibited a strong immunoreactivity. IGF-1 was variably found in leiomyosarcomas (7/8), malignant schwannomas (7/9), synovial sarcomas (2/3), liposarcomas (3/6), fibrosarcomas (1/3), malignant fibrous histiocytomas (10/18) and in one angiosarcoma. Two rhabdomyosarcomas failed to express IGF-1 and only the spindle cell component of synovial sarcomas was positive. Immunoreactivity for IGF-1 in 10 malignant filrous histiocytomas (MFH) appeared to be related to co-expression of smooth muscle actin. These findings imply that MFHs can be subdivided into a group of tumours which are devoid of morphological and immunophenotypic evidence of differentiation and a group which manifest immunophenotypic differentiation.

Actins↗
PubMed1990

Detection of calcitonin-encoding mRNA by radioactive and non-radioactive in situ hybridization: improved colorimetric detection and cellular localization of mRNA in thyroid sections.

The localization of mRNA encoding calcitonin was studied by in situ hybridization using 35S-labeled RNA probes and biotin-labeled DNA probes. Radiolabeled probes were detected by autoradiography and biotin-labeled probes by streptavidin-biotin-peroxidase. To intensify the colorimetric signal, the indirect avidin-biotin complex (ABC) method was performed. However, the results were often variable. To improve the sensitivity, the peroxidase reaction signal was enhanced with a gold-silver deposit intensification reaction. To shorten the incubation times and to enhance the colorimetric reaction, several reaction steps were performed in a microwave oven. The localization of calcitonin mRNA in thyroid tissue, as detected with in situ hybridization, was confirmed by immunohistochemical localization of the calcitonin polypeptide. The results of in situ hybridization using biotinylated probes were compared to in situ hybridization using radioactive probes. Our data show that the results of in situ hybridization applied on frozen and paraffin-embedded sections using biotinylated DNA probes, detected with an indirect streptavidin-biotin-peroxidase reaction and intensified by silver-gold enhancement, were comparable to those obtained with radioactive probes. The localization of calcitonin encoding mRNA was in agreement with the localization of the calcitonin polypeptide.

Affinity Labels↗
PubMed1988

Immunologic marker analysis of normal and malignant histiocytes. A comparative study of monoclonal antibodies for diagnostic purposes.

The authors investigated the phenotype of "monocyte-derived histiocytes/macrophages" on frozen sections of various human tissues, in 12 histiocytic tumors, and in 15 large cell non-Hodgkin's lymphomas. The monoclonal antibodies (MAbs) considered specifically directed against antigens associated with monocytes/histiocytes included the following: Leu-M1, Leu-M3, Leu-M5, My4, My7, My8, My9, anti-Monocyte 1, anti-Monocyte 2, RFD-7, RFD-9, OKM1, and FMC17. The histiocytes in normal tissues and the tumor cells of the histiocytic malignancies expressed these antigens in various degrees. They were not reactive with MAbs specific for lymphocytes, myeloid cells, or Reed-Sternberg cells (Ki-1 antigen). Out of these 13 MAbs, only the labeling by MAb Leu-M3, Leu-M5, anti-Monocyte 1, and RFD-7 was restricted to normal and malignant monocytes/histiocytes. In combination with their broad labeling of different types of monocytes/macrophages, these MAbs are of value in differential diagnostic purposes to distinguish histiocytic malignancies from large cell lymphomas. However, none of the 13 MAbs can be considered as pan-histiocytic reagents because they did not recognize all cell types belonging to the mononuclear/phagocytic system.

Adolescent↗
PubMed1988

Characterization of human soft tissue sarcomas in nude mice. Evidence for histogenic properties of malignant fibrous histiocytomas.

Twenty-two human sarcomas were grafted subcutaneously into nude mice. Twelve tumors grew successfully. Nine of these 12 tumors had an aneuploid DNA content, whereas only 1 of 10 nonsuccessful tumors was aneuploid. The 12 sarcomas included two leiomyosarcomas, two malignant schwannomas, one synovial sarcoma, and seven malignant fibrous histiocytomas (MFHs). With light and electron microscopic and immunolabeling studies the original and xenografted tumors (the latter for at least two generations) were histopathologically compared. The xenografted leiomyosarcomas showed ultrastructurally a more pronounced leiomyodifferentiation, and one of the malignant schwannomas a more pronounced schwannian differentiation. The second malignant schwannoma and the synovial sarcoma, however, remained unchanged. Five storiform pleomorphic MFHs expressed features that were not observed in the original tumors. Tumor cells of three of these xenografted sarcomas showed leiomyogenic differentiation (filamentous densities, pinocytotic vescicles, and desmin immunoreactivity), whereas cells of the two others demonstrated schwannian differentiation (long cytoplasmic processes, basal lamina). A xenografted myxoid MFH and a pleomorphic MFH gave rise to pleomorphic sarcomas composed of undifferentiated cells. It appeared that under transplantation conditions tumor cells of storiform pleomorphic MFH can differentiate into various directions.

Animals↗
PubMed1988

Immunophenotyping of non-Hodgkin's lymphoma. Correlation with relapse-free survival.

In a retrospective analysis the authors studied the relation between the immunologic phenotype of B-cell non-Hodgkin's lymphoma (NHL) and disease-free survival. The phenotype included immunoglobulin isotypes; B-cell maturation/differentiation antigens of clusters of differentiation CD9, CD10, CD19-24, CD37, CD38; T-lymphocyte antigens in CD5-7; HLA-DR; peanut agglutinin binding capacity; terminal deoxynucleotidyl transferase; the activation marker CD25 (interleukin-2 receptor); and the proliferation marker transferrin receptor. The phenotype and clinical data were available for 109 patients. Two patients underwent bone marrow transplantation, and 15 patients (with low or intermediate grade NHL) did not receive treatment intended to achieve complete remission. These 17 cases were excluded from the analysis. For individual markers, CD23 expression was associated with a longer actuarial disease-free survival (50% survival in CD23-positive cases was 40 months; and in CD23-negative cases, 16 months; P = 0.01). Among the total study population of 92 patients, this finding applied in particular to those with a low-grade malignancy according to the Kiel classification (P = 0.03). In high-grade NHL (Kiel classification) the absence of CD38 or presence of CD24 on tumor cells correlated with a higher degree of disease-free survival (P values 0.009 and 0.04, respectively). For a combination of five CD markers associated with stages in physiologic B-lymphocyte maturation/differentiation (CD9, CD10, CD21-23), the lowest measure of disease-free survival was observed where NHLs were at an immature stage, and the greatest extent of survival where NHLs were associated with a resting B-cell stage (P = 0.006). These statistical significances aside, the detailed immunologic phenotyping has relatively little prognostic value when compared with that of the malignancy grade assessed by conventional histopathology.

Antigens, Neoplasm↗
PubMed1987

Cellular composition of follicles of follicle centre cell lymphomas in relation to germinal centres of reactive lymph nodes. A morphometrical electromicroscopical study.

The cell spectrum of neoplastic and benign reactive germinal centres was determined ultrastructurally. The degree in which the cell composition found in reactive germinal centres is maintained in analogous structures of follicular lymphomas was investigated by pattern recognition methods and discriminant analysis based on the frequencies of the various lymphoid and non-lymphoid cell types. The follicular lymphomas included lymphomas with predominantly centrocytes (FCCL, Cb-cc) and lymphomas with predominantly centroblasts (FCCL, Cb). Pattern analysis of FCCL Cb, FCCL Cb-cc and reactive germinal centres indicates that FCCL Cb follicles resemble reactive germinal centres in more aspects than follicles of FCCL Cb-cc. Clear statistical differences were encountered between the frequencies of the lymphoid cell types and of the follicular dendritic and histiocytic reticulum cells in follicles of FCCL Cb-cc and FCCL Cb and reactive germinal centres. Application of a discriminant analysis using a combination of the frequency of centrocytes and follicular dendritic cells demonstrated that both types of neoplastic follicles and reactive germinal centres were correctly classified on the basis of their cell spectrum. For the three groups the most potent discriminator was the centrocyte, whereas the small and large centroblast were of less value. For discrimination between Cb-cc follicles and reactive germinal centres again the centrocyte was the most potent discriminator. Discrimination between FCCL Cb follicles and reactive germinal centres of FCCL Cb-cc follicles can be easily achieved using the frequencies of small centroblasts or centrocytes on their own. These findings indicate that (1) follicles of both FCCL Cb and FCCl Cb-cc differ greatly in the cellular composition and not only with respect to their content of centroblasts but also in their content of follicular dendritic cells and (2) they may be considered as neoplasms representing different developmental phases of germinal centres.

Castleman Disease↗
PubMed1987

Glycolytic enzymes in breast cancer, benign breast disease and normal breast tissue.

The activities of hexokinase, phosphofructokinase, aldolase, enolase and pyruvate kinase were studied in breast cancer tissues, in comparison to benign breast disease and normal breast tissues. The enzyme activities in breast cancer were significantly increased compared to normal and benign breast tissues (p less than 0.001). Also the increase in activity in benign disease compared to normal was statistically significant (p less than 0.001). Within the group of benign diseases, fibroadenomas could be distinguished from fibrocystic disease, the former generally showing higher activities compared to the latter (p less than or equal to 0.05). Carcinoma subgroups, classified according to their histology, could not be recognized enzymologically. In addition, isozyme composition of pyruvate kinase and enolase was studied. We did not find a significant shift towards K type pyruvate kinase expression in benign disease compared to normal breast tissues. Also fibroadenomas did not differ from fibrocystic disease. However, the amount of K type pyruvate kinase in carcinomas proved to be significantly higher in comparison to benign disease and normal breast tissues (p less than 0.001). Expression of alpha gamma-enolase in normal breast tissue was virtually absent. In benign disease only a minority of specimens did show the hybrid alpha gamma-enolase. Nearly all carcinomas had alpha gamma-enolase expression and in 20% of the carcinomas gamma gamma-enolase could be detected (so-called neuron-specific enolase). By discriminant analysis, the function giving the best discrimination compared to the histological data was based on natural logarithm aldolase and the total of gamma-enolase subunits. Contrary to expectation, the regulator enzymes of glycolysis; i.e., hexokinase, phosphofructokinase and pyruvate kinase were not included in this discriminant function. The best fit produced a 90% correct classification in both benign and malignant disease. If these findings are confirmed to a larger series, the discrimination is sufficiently strong to form the basis of a clinically useful tool.

Biomarkers, Tumor↗
PubMed1987

Tumor cell growth fraction in Hodgkin's disease.

The growth fraction of tumor cells was studied in 45 cases of Hodgkin's disease by means of a recently developed double immunostaining technique using monoclonal antibody Ki-1, which reacts selectively with Hodgkin and Reed-Sternberg cells in tissues affected by Hodgkin's disease, and antibody Ki-67, which recognizes a cell proliferation-associated nuclear antigen. The medians of the growth fractions of the tumor cells in all histologic subtypes of Hodgkin's disease varied between 78% and 83%. In none of the cases investigated did we find a growth fraction below 50%. Furthermore, mononucleated Hodgkin cells as well as multi-nucleated Reed-Sternberg cells showed a similar Ki-67 labeling index, indicating that both tumor cell types belong to the proliferating pool of this malignancy.

Antibodies, Monoclonal↗
PubMed1986

Characterization of two cell lines, derived from two malignant fibrous histiocytomas.

We have investigated the phenotype and ultrastructure of tumour cells from two cell lines each derived from a malignant fibrous histiocytoma (MFH) as a means of studying the histogenesis of this group of tumours. The first MFH (MFH-I) was of the pleomorphic subtype, with a predominantly histiocytic appearance, the second was of the pleomorphic subtype associated with myxoid and storiform areas (MFH-II). In vitro tumour cells from both neoplasms showed aberrant growth properties. Xenografts in nude mice from both neoplasms showed a similar histology to that of the original tumour. Both tumours showed hyaluronidase sensitive alcian blue staining. Phenotypic studies of the two cell lines and of the tumour tissues demonstrated that the cells differed in the presence of collagen types I and III. They did not show evidence of histiocytic, endothelial, leiomyoblastic, rhabdomyoblastic, lipoblastic of schwannian origin. Ultrastructurally, the two cell lines were found to be different. In vitro and in xenografts the cell type of MFH-I resembled a primitive mesenchymal cell. Whereas that of MFH-II resembled a fibroblast-like cell. We concluded that the group of MFH is heterogeneous and is probably derived from more than one progenitor cell.

Aged↗
PubMed1985

Determination and characterization of hexokinase in thyroid cancer and benign neoplasms.

Hexokinase (ADP: D-hexose-6-phosphotransferase, EC 2.7.1.1) was studied in human thyroid carcinomas (n = 11), follicular adenomas (n = 32), and normal thyroid tissue (n = 21). The specific activity was significantly increased in carcinoma (0.163 +/- 0.083 U/mg protein) compared with normal tissue (0.030 +/- 0.010 U/mg protein) (P less than 0.001). Specific activities of follicular adenomas are rather heterogeneous, but when subdivided into three groups according to histopathologic criteria, a significant difference was found between follicular adenomas group I and II and follicular adenomas group III. A lesser cellular differentiation of adenomas is indicated by the lower degree or even absence of colloid production and follicle formation. A higher proliferation rate may be assumed on the grounds of the irregularities in outline, the often defective pseudocapsule, and signs of compression of the surrounding tissue. The highest specific activity in adenomas was found in the group with the highest proliferative activity, i.e., group III, whereas the lowest specific activities were found in adenomas with the lowest grade of proliferation, i.e., group I; the former was comparable with values found in carcinomas and the latter was comparable with values found in normal thyroid tissue. An interesting difference was found when the compartmentation of hexokinase was compared in carcinomas of different degree of differentiation. In papillary carcinomas a significantly lower proportion of hexokinase (HK) is present in the cytosol in comparison to follicular and undifferentiated carcinomas. In carcinomas more HK II and less HK I was found in comparison with normal thyroid tissue. In contrast hexokinase isozyme composition and compartmentation in adenomas were not different from normal thyroid tissue.

Adenoma↗
PubMed1985

Characterization of tumour cells in malignant fibrous histiocytomas and other soft tissue tumours in comparison with malignant histiocytes. I. Immunohistochemical study on paraffin sections.

We have studied the possible origin of histiocytic cells, present in fibrous histiocytomas (MFH) by using immunohistochemistry to demonstrate lysozyme, alpha 1-antitrypsin, alpha 1-antichymotrypsin and receptors for peanut and soy bean agglutinin in tumour cells of MFH compared with their presence in tumour cells of malignant histiocytosis (MH) ('true' histiocytic lymphoma, 'true' histiocytic sarcoma). We included in this study a number of other soft tissue tumours (STT). Lysozyme was detected in half of the cases of malignant histiocytosis (n = 16) but in only two out of 77 MFH. alpha 1-Antitrypsin and alpha 1-antichymotrypsin usually occurred together although the latter was seen in more cases. Both markers were present in majority of cases of MH whereas they were detected in a minority of cases of MFH. MFH cases of the storiform subtype were less frequently stained than the pleomorphic or giant cell subtypes. Receptors for peanut or soy bean agglutinin were detected in nearly all MH cases, whereas their presence was only detected in a small number of MFH. Lysozyme was not detectable in other STT. alpha 1-Antitrypsin and alpha 1-antichymotrypsin were uncommonly present in other STT, except in osteosarcoma and rhabdomyosarcoma. These markers therefore have a limited value as indicators of a possible histiocytic origin of MFH. Lectins showed weak affinity for other STT. In accordance with others, we therefore conclude that the progenitor cell of MFH has to be sought within the undifferentiated mesenchymal cells and that histiocytes themselves probably do not give rise to MFH.

Chymotrypsin↗