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ILK (beta1-integrin-linked protein kinase): a novel immunohistochemical marker for Ewing's sarcoma and primitive neuroectodermal tumour.

ILK (beta1-integrin-linked protein kinase) is a recently identified 59-kDa serine/threonine protein kinase that interacts with the cytoplasmic domain of the beta1-integrin containing four ankyrin-like repeats. We have developed a polyclonal antibody against ILK and explored the ILK immunoreactivity in normal human cells and tissues. ILK was mainly expressed in cardiac muscle and skeletal muscles. Surprisingly, ILK expression was observed in Ewing's sarcoma (ES; 100%), primitive neuroectodermal tumour (PNET; 100%), medulloblastoma (100%), and neuroblastoma (33.3%), whereas other small round cell sarcomas were not stained by the anti-ILK antibody. These results suggest that ILK could be a novel marker for tumours with primitive neural differentiation. Our findings support the notion that ES is a tumour that is closely related to PNET and that both originate from the neuroectoderm. ILK may be a sensitive and specific immunohistochemical marker and useful for the positive identification of ES and PNET in formalin-fixed, paraffin-embedded tissue sections.

Adolescent↗

Immunohistochemical and pharmacokinetic characterization of site-specific immunoconjugate 15A8-glycyl-tyrosyl-(N-epsilon-diethylenetriamine pentaacetic acid)-lysine derived from anti-breast carcinoma monoclonal antibody 15A8.

In this study, the breast carcinoma-reactive monoclonal antibody 15A8 and a site-specific immunoconjugate of the antibody, 15A8-glycyl-tyrosyl-(N-epsilon-diethylenetriamine pentaacetic acid)-lysine (15A8-GYK-DTPA), were characterized by immunohistological methods for reactivity with normal and neoplastic human tissues and normal cynomolgus monkey tissues. In addition, 15A8-GYK-DTPA labeled with 111In was assessed by in vivo imaging and pharmacokinetic studies for localization to human tumor xenografts in nude mice. The native antibody and the site-specific immunoconjugate exhibited similar limited reactivity with normal human tissues. Specifically, epithelial structures, including normal breast epithelium, lung alveoli, bronchial epithelium and glands, liver bile ducts, pancreatic ducts, kidney distal and collecting tubules, epidermal and esophageal epithelium, endometrial glands, and thymic Hassall's corpuscles, were reactive. Normal monkey tissues stained with 15A8 exhibited a similar pattern of reactivities. Antibody 15A8 reacted broadly with epithelium-derived tumors; more than 60% of the cells in all of the breast, colon, non-small cell lung, ovarian, prostate, bladder, and renal carcinomas tested expressed the antigen. In contrast, a variety of nonepithelial neoplasms, including lymphomas, melanomas, sarcomas, and small cell lung carcinomas, were nonreactive. 15A8-GYK-DTPA-111In administered i.v. rapidly localized to and imaged both MX-1 and MCF-7 human breast carcinoma xenografts in nude mice, reaching maximal levels of about 20% of injected dose/g of tumor within 4 days. No unusual localization to any nontumor tissue or organ was seen; the level of radioactivity in the normal tissues and organs was at or below that seen in the blood. Furthermore, the immunoconjugate did not accumulate in xenografts of the antigen-negative breast carcinoma ZR-75-1, which indicates that tumor localization was antigen specific. Pharmacokinetic studies in cynomolgus monkeys suggested that significant amounts of 15A8-GYK-DTPA-111In did not localize to normal epithelia and demonstrated that the immunoconjugate was not toxic. These findings suggest that antibody 15A8 may be useful in the diagnosis and therapy of breast cancer and possibly other carcinomas.

Animals↗

Surgical treatment of malignant tumors of the right heart.

Seven patients with malignant cardiac tumors were treated surgically in the Department of Cardiothoracic Surgery of the University of Tokyo between 1981 and 2000. Their treatments and outcomes are summarized and discussed. The ages of the patients ranged from 21 to 70 years old (mean: 49.5+/-15) and there were three males and four females. The histopathological diagnoses were hepatocellular carcinoma (HCC), spindle cell sarcoma, round cell sarcoma, osteosarcoma, renal cell carcinoma, and leiomyosarcoma. In four of the cases, the tumor extended or metastasized from other organs, while in the other three cases it originated in the heart. Before the cardiac operation, an above-knee amputation, left nephrectomy, transarterial embolization, or extended right hepatic lobectomy had been performed to treat the primary site of the tumor. Tumor resection using cardiopulmonary bypass was performed in every case. The NYHA classification of heart failure was significantly improved (preop: 3.3+/-0.8, postop: 1.9+/-0.7 [P<0.001]). The mean survival period of the patients who died was 8.8+/-7.0 months. A patient with renal cell carcinoma is still alive after 87 months of follow-up. In summary, surgical treatment of malignant tumors of the right heart can improve the QOL in patients with cardiac failure. However, its effectiveness was temporary in all cases except one case of renal cell carcinoma.

Adult↗

Comparison of tumor density by CT scan based on histologic type in lung cancer patients.

AIM: To investigate the differences of tumor density of lung cancer by CT scan based on histopathologic type of cancer cell. METHODS: Subjects were lung cancer patients at Dr. Kariadi hospital Semarang between January 2002 and December 2003. Diagnosis was made based on clinical symptoms, histologic examination and lateral chest radiograph, and thorax CT scan. Density of tumor was measured within area which had most enhancements before and after contrast administration. Then, it was followed by transthoraxic fine needle aspiration (TNFNAB) and histopathologic examination. Study design was a cross sectional study. Inclusion criteria were primary lung cancer and exclusion criteria were non lung cancer, metastatic cancer, histopathologic non interpreted. Estimated number of samples was 41 patients. Density value before and after contrast were analyzed using Wilcoxon signed rank test. Difference of tumor density for each type of cancer cell was analyzed using chi-square test with significant level at p < 0.05 and confidence interval of 95%. RESULTS: Forty-one patients with lung cancer were enrolled in this study. There were 30 males (73.2%) and 11 females (26.8%). Histopathologic types of cell cancer were epidermoid in 17 patients (14.5%), adenocarcinoma 8 patients (19.5%), large cell 7 patients ( 17.1%), small cell 7 patients ( 17.1%) and undifferentiated cell 2 patients ( 4.5%). Mean of increasing HU before and after contrast in epidermoid carcinoma was 26.8 (10.4) HU, adenocarcinoma 17.2 (7.1) HU, large cell 8.7 (4.5) HU, small cell 9.9(4.1) HU and undifferentiated cell 23.5 (1.5) HU with overall increase of all cancer cell types was 17.3(9.2) HU, p < 0.001. Histopathologic type of non small cell lung carcinoma (NSCLC) with density < 60 HU was found in 30 patients (73.2%) and small cell lung carcinoma with density > 60 HU was found in 5 patient (12.2%), p=0.01. CONCLUSION: There was evident increase of density in all histopathologic type of cell cancer, p < 0.0001, with mean of density after contrast administration was 17.2 (7.1). There was significant difference between NSCLC and SCLC group and tumor density > 60 HU and < 60 HU, p=0.01.

Adenocarcinoma↗

Extraskeletal Ewing's sarcoma. A clinicopathologic and electron microscopic. Analysis of 8 cases.

This clinicopathologic study concerns 8 cases of extraskeletal Ewing's sarcoma, including electron-microscopic examination of one case. In three patients, autopsy was done. The age of the patients ranged from 12 to 31 years with a median of 16 years. The tumors mainly arose in the soft tissues of the trunk (4 cases) and the lower extremity (3 cases). Histologically, they were made up of closely packed uniform, small cells, arranged in sheets separated by strands of fibrovascular stroma. The tumor cells had round to oval nuclei with finely dispersed chromatin and scanty ill-defined cytoplasm almost invariably containing a fair amount of diastase-digested PAS-positive material. Ultrastructurally, the tumor cells were composed principally of undifferentiated mesenchymal cells, and contained prominent pools of glycogen in the cytoplasm. Aggregates of intermediate filaments were seen in a perinuclear location. These light- and electron-microscopic findings are indistinguishable from those of Ewing's sarcoma of the bone. Differential points from other soft-tissue small round cell sarcomas such as malignant neuroepithelioma (peripheral neuroblastoma), embryonal or alveolar rhabdomyosarcoma were briefly discussed.

Adolescent↗

Fine needle aspiration cytology of small cell variant of anaplastic large cell lymphoma. A case report.

BACKGROUND: Small cell variant of anaplastic large cell lymphoma (ALCL) is a rare and still underrecognized variant of ALCL. In contrast to the classic type of ALCL, which is sometimes mistaken for carcinoma or sarcoma, the small cell variant may be misdiagnosed as a reactive lesion without a high index of suspicion. CASE: We present a case of small cell variant of ALCL occurring in a 14-year-old female. It posed great difficulty in the fine needle aspiration (FNA) diagnosis due to the rarity of large, atypical cells. A subsequent lymph node biopsy demonstrated the typical histologic and immunophenotypic findings of the small cell variant of ALCL. CONCLUSION: This case indicates that small cell variant of ALCL should always be considered in the FNA diagnosis of unusual-looking, heterogeneous lymphoid proliferations dominated by atypical small or medium-sized lymphoid cells, particularly in young patients.

Adolescent↗

Analysis of incipient growth of Yoshida sarcoma in vivo after transplantation of a small number of tumor cells.

Incipient growth of Yoshida sarcoma in ascitic and solid forms was analyzed after transplantation of a small number of tumor cells varying from 1 to 10(6). Growth curves of the ascites tumors revealed that the duration of the incipient growth was much longer than the length of subsequent advanced stage and that the ascites tumor during its incipient stage appeared to grow exponentially and most rapidly in the entire course of the tumor development. Growth rate analyses of the ascites and solid tumors showed that, during their incipient stage, the population doubling time prolonged gradually as the inoculum size increased. This phenomenon was thought to suggest probable cell death on account of the transplantation procedure.

Animals↗

Interventional radiology cases from the royal hospital for sick children, glasgow: percutaneous metal biliary stent placement for palliation of intra-abdominal desmoplastic small round-cell tumour in a child.

Percutaneous placement of metal biliary stents for palliation of malignant processes affecting the porta hepatis is a well established technique in adults. We describe a case where the technique has been used successfully to treat obstructive jaundice in a ten-year-old boy suffering from intra-abdominal desmoplastic small round-cell tumour.

Abdomen↗

Cytogenetic and pathologic aspects of Ewing's sarcoma and neuroectodermal tumors.

Diagnostic classification of poorly differentiated, round cell, primitive neuroectodermal neoplasms, including Ewing's sarcoma, peripheral neuroepithelioma, Askin's tumor, and esthesioneuroblastoma, is challenging to the surgical pathologist using conventional histopathologic approaches because of very similar and overlapping morphologic and cytologic features. Furthermore, distinguishing these neoplasms from neuroblastoma, embryonal rhabdomyosarcoma, small cell osteogenic sarcoma, and non-Hodgkin's lymphoma can be difficult. This paper describes and reviews the cytogenetic and molecular genetic changes in these tumors and demonstrates how the ability to detect these changes has enabled a greater understanding of the histogenesis, classification, diagnosis, and prognosis of these neoplasms.

Cell Transformation, Neoplastic↗

Inactivation of the retinoblastoma susceptibility gene in non-small-cell lung cancer. The Lung Cancer Study Group.

Mutations that prevent the normal expression of the retinoblastoma susceptibility gene (RB) have been linked to the pathogenesis of several human malignancies. Mutational inactivation of this tumor-suppressor gene appears to initiate the development of retinoblastoma, and may also contribute to the pathogenesis of osteosarcomas, soft-tissue sarcomas, small-cell lung cancer and other malignancies. In cooperation with the Lung Cancer Study Group, we studied the structure and expression of the RB gene in a cohort of 219 primary non-small-cell lung cancers (NSCLCs). RB gene structure was studied at the DNA level by Southern blot and chromosome 13 restriction fragment length polymorphism analyses. Expression of the RB gene was evaluated by Northern analysis of the transcript and immunohistochemical analysis of the protein (p105RB). Immunohistochemistry of the RB protein proved to be the most sensitive method for the detection of Rb gene inactivation. Absent or abnormal RB protein staining was detected in 53/163 (32%) evaluable cases studied, while Northern analysis showed 22/219 cases to have an altered or absent RB transcript. Southern analysis revealed only two cases of structural alteration of the gene, but loss of heterozygosity from chromosome 13 was common in tumors that failed to express the protein. Analysis of the clinical outcomes of the patients whose tumors were studied did not show any correlation of RB inactivation with time to relapse or death. The data from this study indicate that the RB gene is inactivated in a significant number of NSCLCs. The role that these mutations may play in the development of NSCLC remains to be defined.

Base Sequence↗

Desmoplastic small round cell tumor.

Desmoplastic small round cell tumor is an undifferentiated tumor associated with serosal surfaces, especially the peritoneum. It is found predominantly in adolescents and young adults and is much more common in males than in females. The tumor has a characteristic histology, with extensive stromal tissue around islands of small and undifferentiated cells revealing the desmoplastic appearance. The coexpression of epithelial and mesenchymal antigens distinguishes this entity from other small round and blue cell tumors of this age group. Cytogenetic studies showed a t(11;22) translocation that differs from the Ewing's tumor translocation and seems to be specific to this entity. The involvement of the WT1 and EWS genes in the translocation makes this tumor an interesting subject for research on histogenesis and differentiation in small round and blue cell tumors.

Abdominal Neoplasms↗

An Epicurean learning approach to gene-expression data classification.

We investigate the use of perceptrons for classification of microarray data where we use two datasets that were published in [Nat. Med. 7 (6) (2001) 673] and [Science 286 (1999) 531]. The classification problem studied by Khan et al. is related to the diagnosis of small round blue cell tumours (SRBCT) of childhood which are difficult to classify both clinically and via routine histology. Golub et al. study acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). We used a simulated annealing-based method in learning a system of perceptrons, each obtained by resampling of the training set. Our results are comparable to those of Khan et al. and Golub et al., indicating that there is a role for perceptrons in the classification of tumours based on gene-expression data. We also show that it is critical to perform feature selection in this type of models, i.e. we propose a method for identifying genes that might be significant for the particular tumour types. For SRBCTs, zero error on test data has been obtained for only 13 out of 2308 genes; for the ALL/AML problem, we have zero error for 9 out of 7129 genes that are used for the classification procedure. Furthermore, we provide evidence that Epicurean-style learning and simulated annealing-based search are both essential for obtaining the best classification results.

Algorithms↗

Biphasic intra-abdominal desmoplastic small cell tumor in a patient with proximal spinal muscular atrophy.

A case is reported of intra-abdominal desmoplastic small cell tumor (IDSCT) with biphasic histologic features in a patient with proximal spinal muscular atrophy. The tumor was composed of small epithelial cell nests with spindle cell sarcomatous areas. Both areas were surrounded by a desmoplastic stroma. Immunohistochemical studies revealed reactivity for low molecular weight cytokeratin, epithelial membrane antigen, vimentin, desmin and Leu-7 in both areas. Electron microscopic examination demonstrated paranuclear aggregates of intermediate filaments, zonula adherens and basement membrane-like material in the epithelial cells, while spindle cells in the tumor had fewer intracytoplasmic organelles. However, intermediate or transitional forms of both types of tumor cells were frequently observed. Although IDSCT are known to express multi-phenotypes immunohistochemically, attention should be paid to the broad spectrum of cell morphology in these tumors.

Adult↗

Analyzing tumor gene expression profiles.

A brief introduction to high throughput technologies for measuring and analyzing gene expression is given. Various supervised and unsupervised data mining methods for analyzing the produced high-dimensional data are discussed. The main emphasis is on supervised machine learning methods for classification and prediction of tumor gene expression profiles. Furthermore, methods to rank the genes according to their importance for the classification are explored. The approaches are illustrated by exploratory studies using two examples of retrospective clinical data from routine tests; diagnostic prediction of small round blue cell tumors (SRBCT) of childhood and determining the estrogen receptor (ER) status of sporadic breast cancer. The classification performance is gauged using blind tests. These studies demonstrate the feasibility of machine learning-based molecular cancer classification.

Adult↗

New drug developments for patients with metastatic soft tissue sarcoma.

For the subgroup of patients with inoperable gastrointestinal stromal tumors, progress has been made by the rapid development and approval of the targeted therapy imatinib mesylate. Small round cell sarcomas (SRCT), such as Ewing/primitive neuroectodermal tumor, desmoplastic SRCT, and rhabdomyosarcoma, are chemotherapy-sensitive and potentially curable malignancies that are treated with multimodality dose-intensive neoadjuvant protocols regardless of size or overt metastatic disease. However, the number of effective cytotoxic agents for the treatment of patients with metastatic so-called adult soft tissue sarcoma is limited, especially when patients have failed anthracycline- and ifosfamide-based chemotherapy.

Antineoplastic Agents↗

The Ewing tumor family of peripheral primitive neuroectodermal tumors expresses human gastrin-releasing peptide.

The Ewing tumor family of peripheral primitive neuroectodermal tumors (pPNETs) are characterized by chromosomal translocations leading to EWS-ETS gene fusions. These hybrid genes express chimeric proteins that are thought to act as aberrant transcription factors. We therefore used differential display-PCR to compare gene expression patterns in pPNET cell lines with those of other small round cell tumors (SRCTs) of childhood. This technique detected differential expression of sequences corresponding to human gastrin-releasing peptide (GRP) in pPNET cell lines but not in other SRCT cell lines. Subsequent Northern and reverse transcription-PCR analysis of SRCT cell lines confirmed GRP positivity in all pPNET lines tested. Of primary tumors tested by reverse transcription-PCR, GRP expression was found in 7 (44%) of 16 pPNETs but in no other primary SRCTs examined. Expression of the GRP receptor gene was demonstrable in 55% of pPNET cell lines and 25% of primary pPNET tumors but also in several other SRCTs. Radioimmunoassays and immunohistochemistry confirmed expression of bioactive GRP peptide in pPNET cell lines and primary tumors, respectively. Moreover, in vitro growth of a pPNET cell line was slowed by treatment with a GRP receptor antagonist and accelerated by a GRP receptor agonist. GRP is a known autocrine growth factor in small cell lung cancer and other neuroendocrine tumors. Its expression in pPNETs provides further evidence for a neuroectodermal histogenesis of these tumors and suggests that autocrine growth of this family of tumors may be at least partially regulated by GRP.

Artificial Gene Fusion↗