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PubMed1995

MIC2 detection in tumors of bone and adjacent soft tissues.

The diagnosis of Ewing's sarcoma has been based classically in large part on the exclusion of other similar small round-cell tumors by light microscopic and histochemical criteria. This study was undertaken to explore the use of a recently developed immunohistochemical stain directed against the glycoprotein p30/32MIC2 antigen (the gene product of MIC2), as a diagnostic tool and as a probe for the examination of potential interrelationships among the putative members of the family of peripheral primitive neuroectodermal tumors. Fifty-six small round-cell tumors of bone were selected for study from the files of the Armed Forces Institute of Pathology and Rhode Island Hospital; all tissues had been formalin fixed and paraffin embedded. Nine of 10 Ewing's sarcomas were MIC2 positive, as were 2 of 3 atypical Ewing's sarcomas (small round-cell tumors that diverged from the classic pattern of Ewing's sarcoma by exhibiting a greater degree of cytologic atypia and pleomorphism), and 7 of 8 Askin tumors of the thoracopulmonary region. Ten of 11 mesenchymal chondrosarcomas, 1 primitive neuroectodermal tumor of bone, 10 small cell osteosarcomas, 10 malignant lymphomas, and 3 sarcomas of bone (not additionally subclassified) were negative. The finding of MIC2 positivity in the majority of Ewing's sarcomas and Askin tumors provides additional support for earlier proposals (based on a shared cytogenetic abnormality, among other criteria) that these lesions be considered members of the same family, the peripheral primitive neuroectodermal tumors. The present study, drawing on archival and current case material (including decalcified and undecalcified specimens), indicates that neither the specimen age nor the application of any of a variety of decalcification solutions appears to adversely influence MIC2 staining of paraffin-embedded tissues. This suggests that this antibody has use in retrospective and prospective studies. The rare occurrence of false negative (in the case of Ewing's sarcoma) and positive results in tumors other than peripheral primitive neuroectodermal tumors (as in 1 of the mesenchymal chondrosarcomas) suggests that MIC2 staining should not be relied on as the sole criterion for identification or exclusion of Ewing's sarcomas and related tumors.

12E7 Antigen↗
PubMed1996

Intraoperative consultation in ovarian lesions: a comparison between cytology and frozen section.

Little information is available on the relative value of intraoperative cytology (IOC) and frozen section (FS) in evaluation of ovarian lesions. We compared the two methods in 63 histologically proven cases of resected ovaries studied by imprints (40 cases), FNAs (38 cases), and scrapes (5 cases). Diagnoses were: 10 nonneoplastic cysts, 46 neoplasms (benign, 19; borderline, 8; and malignant, 19) and 7 tumors comprised of small blue cells (SBC): granulosa cell (3), lymphoma (1), small cell carcinoma (1), and sarcoma (2). There were no false-positive diagnoses by IOC or FS among the benign and borderline conditions. Five benign lesions, however, had FS deferred because of architectural complexity, this in contrast to only one case reported as atypical by IOC. Borderline tumors were recognized as such in 3 cases examined by FS, but no such diagnosis was possible by IOC due to the inability to assess invasion. The diagnosis in borderline neoplasms of surface epithelial origin was deferred in 4 cases by FS and reported as atypical in 5 cases examined by IOC due to the spectrum of architectural and nuclear atypia in borderline tumors. Of the 19 malignant cases, five were deferred because of uncertainty of invasion by FS, whereas two were called atypical by IOC. Five of 7 SBC tumors were recognized as such by FS and 6 of 7 by IOC, but none could be unequivocally subclassified by either method. Intraoperative FNAs and scrapes were superior to imprints, which tended to be bloodier and thicker. In contrast to FNAs, scrapes were easier to direct and yielded greater cellularity, although both methods were comparable in diagnostic accuracy. Even though the diagnostic yield of IOC was only slightly better than that of FS, it provided much better cytologic detail, and afforded a more representative sampling.

Biopsy, Needle↗
PubMed1996

Cytotoxic activity of calcein acetoxymethyl ester (Calcein/AM) on primary cultures of human haematological and solid tumours.

The aim of this study was to determine the in vitro cytotoxicity of calcein acetoxymethyl ester (Calcein/AM) on primary cultures derived from solid and haematological human tumours. Calcein/AM is a fluorescent dye that localises intracellularly after esterase-dependent cellular trapping and which has shown cytotoxic activity against various established human tumour cell lines at relatively low concentrations. The semi-automated fluorometric microculture cytotoxicity assay, based on the measurement of fluorescence generated from cellular hydrolysis of fluorescein diacetate to fluorescein, in microtitre plates was used for the evaluation of Calcein/AM activity in tumour cell suspensions from patients. The cytotoxicity was measured as a survival index (SI), defined as the fluorescence as a percentage of control cultures. A total of 163 evaluable samples from various tumours were tested with continuous drug exposure. The activity of Calcein/AM was compared with representatives of six major classes of standard chemotherapeutic drugs. Calcein/AM was found to induce concentration-dependent decreases in the SI of both haematological and solid tumour cells. The ratio of solid over haematological tumour activity increased at a rate that was concentration dependent. Although it was relatively less active than cisplatin against solid tumours, Calcein/AM showed higher solid tumour activity compared to leukaemic specific agents (cytarabine and amsacrine), vincristine and doxorubicin (Dox). Among the solid tumours tested, childhood tumours, non-small cell lung cancer and sarcomas were the most sensitive to Calcein/AM. The best correlation between SI values was seen between Calcein/AM and Dox, with weaker correlations to representatives of antimetabolites, platinum compounds, topoisomerase II inhibitors, tubulin interactive agents and alkylators. Non-cytotoxic concentrations of cyclosporin A significantly potentiated calcein-induced cytotoxicity. The results show that Calcein/AM is differentially active against haematological tumours, but with substantial activity against solid tumours. The drug may represent a new class of anticancer compound with a unique means of drug delivery.

Antineoplastic Agents↗
PubMed1984

Phase II evaluation of Lonidamine in patients with advanced malignancy.

Lonidamine, a substituted indazole carboxylic acid with unique effects on cellular respiration, was studied in 27 patients with advanced malignancies. Of the 18 evaluable patients, 5 had small-cell lung cancer, 3 had non-small-cell lung cancer, 3 sarcoma, 2 breast cancer, and 5 other tumour types. All but 1 had had extensive prior treatment. A partial response was seen in 1 patient with metastatic synovial sarcoma, and tumour growth inhibition was demonstrated in 2 other cases. The major toxicity encountered was myalgia (66.6%) which was incompletely ameliorated by prednisone and required dose reduction in 2 patients and cessation of drug in 3. Other toxicities included auditory changes, anorexia, nausea and vomiting, diarrhoea, skin sensitivity, and conjunctivitis. No added toxicity was seen, when Lonidamine was combined with other chemotherapeutic agents. No correlation between Lonidamine dose and serum lactate levels was seen, although 4 patients showed a progressive increase in lactate levels over time, thought to be related to their increasing tumour burden. 5 patients demonstrated a dramatic fall in serum testosterone levels 4-8 weeks after starting Lonidamine which was accompanied by an increase in luteinizing hormone levels in 3 patients. In summary, modest antitumour activity was demonstrated in 3 patients; moderate toxicity was seen in most patients, but was usually tolerable. Further studies of Lonidamine are warranted in less heavily treated patients, alone or in combination with other chemotherapeutic agents.

Adult↗
PubMed2004

Cancer-directed surgery for localized disease: decreased use in the elderly.

BACKGROUND: Previous studies report underuse of radiation and chemotherapy in the elderly, yet few have examined the rates of use (or underuse) of surgery. Using national data, we examined rates of surgical resection for patients with local-stage cancers. METHODS: By using the Surveillance, Epidemiology, and End RESULTS database (1988-1997), patients (> or =40 years) were identified with localized adenocarcinoma of the breast, esophagus, stomach, pancreas, colon, or rectum; non-small-cell lung carcinoma; and sarcoma (n = 200,360). Rates of cancer-directed surgery (CDS) were compared across age groups (at 5-year intervals). Multivariate regression was used to identify predictors of receipt of CDS in each tumor group. RESULTS: Rates of CDS declined steadily with increasing age for all nine localized tumors. Most striking were the low rates of CDS for patients >70 years with esophagus, stomach, pancreas, and lung cancers (range, 0%-83%). However, CDS rates were >90% for breast and colon and >84% for rectal cancer in all age groups. Multivariate regression found lower odds of CDS for elderly patients for all cancers except colon. For example, age significantly decreased the odds of receiving CDS beginning at 60 years for lung cancer (odds ratio [OR], .550; P = .03), at 70 years for liver cancer (OR, .109; P = .003), and at 80 years for pancreatic cancer (OR, .120; P < .05). CONCLUSIONS: Although CDS for localized disease is being performed regularly in the elderly for some cancers (e.g. breast, colon, and rectum), this analysis shows that elderly patients are not receiving surgery for many potentially curable cancers. Whether these rates are appropriate or too low requires further evaluation. This is particularly essential because our population is aging.

Adult↗
PubMed1997

The status of immunohistochemical studies in lymphoma diagnosis.

Immunohistochemical studies of formalin fixed paraffin embedded sections today constitute an essential component of the diagnostic process for malignant lymphoma. Lineage related markers are of value in distinguishing various lymphomas from anaplastic large and small cell carcinomas, and from sarcomas. Other more recently available markers are of value in establishing prognosis and, on occasion, in differentiating between neoplastic and reactive proliferations. Meticulous attention to reagent control and technical procedures is essential to all such studies.

Algorithms↗
PubMed2005

Cdk inhibition in human cells compromises chk1 function and activates a DNA damage response.

Cyclin-dependent kinases (Cdk) promote cell proliferation, are often deregulated in human cancers, and are targets of ongoing cancer chemotherapy trials. We show here that Cdk activity is also required in human cells to maintain function of the Chk1 pathway, a key component of the response to DNA damage or stalled replication. Chk1 expression was markedly reduced in primary fibroblasts and U2OS osteogenic sarcoma cells by treatment with small molecule Cdk inhibitors or induction of a dominant-negative mutant of Cdk2. The findings of decreased Chk1 activity and accumulation of Cdc25A, a protein targeted for degradation by Chk1, confirmed that Chk1 function was impaired. Furthermore, Cdk inhibition triggered a DNA damage response, characterized by the accumulation of activated forms of ATM and Chk2 as well as nuclear foci containing phosphorylated substrates of ATM/ATR, including histone H2AX (gammaH2AX). Time course experiments showed that the bulk of ATM activation followed Chk1 down-regulation. Chk1 RNA interference combined with partial inhibition of DNA replication was sufficient to evoke the DNA damage response. Conversely, ectopic expression of Chk1 blunted induction of gammaH2AX foci by Cdk inhibitors, indicating that Chk1 down-regulation was necessary to elicit the full phenotype. Finally, both Cdk and Chk1 inhibitors enhanced the cytotoxity of etoposide, a DNA-damaging agent. These results define a pathway through which Cdk inhibition can mediate DNA damage and potentially enhance the efficacy of extant cancer chemotherapies.

Ataxia Telangiectasia Mutated Proteins↗
PubMed1991

Histiocytic medullary reticulosis occurring with small cell lung carcinoma.

Haematophagocytic activity is a salient feature of malignant histiocytic medullary reticulosis. This potency has also been observed as an aberrant property of non-histiocytic malignant cells or as a benign histiocytic process in response to infections or malignancies. We report the case of a patient who presented simultaneously with a limited stage small cell lung carcinoma and a fatal reactive form of histiocytosis. We conclude that such a haematophagocytic syndrome may occur in the setting of small cell lung carcinoma s previously described in other malignancies.

Aged↗
PubMed1989

"Undifferentiated" neoplasms of the sinonasal region: differential diagnosis based on clinical, light microscopic, immunohistochemical, and ultrastructural features.

Sinonasal neoplasms and neoplasm-like proliferations composed of light microscopically poorly differentiated or undifferentiated, small- to medium-sized cells cause considerable diagnostic confusion. Lesions in this category include lymphoepithelioma (undifferentiated carcinoma), olfactory neuroblastoma, small-cell undifferentiated (oat cell) carcinoma, sinonasal undifferentiated carcinoma, malignant melanoma, pituitary adenoma, lymphoid hyperplasia, malignant lymphoma, plasmacytoma, lymphomatoid granulomatosis, rhabdomyosarcoma, mesenchymal chondrosarcoma, small cell osteosarcoma, Ewing's sarcoma, and synovial sarcoma. Many of these lesions can be definitively diagnosed based on light microscopic features alone, but, in some instances, additional techniques such as immunohistochemistry are of value. The authors review the pertinent clinicopathologic features of the above lesions, with emphasis on light microscopic, immunohistochemical, and ultrastructural features of particular utility in differential diagnosis.

Carcinoma, Squamous Cell↗
PubMed1977

[Radiation therapy and treatment results in carcinoma of the esophagus (author's transl)].

Results from radiotherapeutic treatment of 200 patients with malignant tumors of the esophagus are reported. The principal part is represented by squamous cell carcinomas with 88%, followed by adenocarcinomas with 4.5%, by more or less differentiated solid carcinomas with 4%, and small cell carcinomas with 1.5%. Sarcoma was found in three cases, one of them a myosarcoma, another a reticulosarcoma. An ectopic carcinoma of the gastric glands was present in one case. The staging was performed according to the TNM system. A focal dose of 6000 to 6500 rd within 6 or 8 weeks was tried for, using 60Co-gamma-rays. The one-year and five-year survival rates in stage T2N0M0 amounted to 80% and to 17%; no survival was obtained in stage T3N0M0. Out of the total of stage T2-3N0M0 cases 24% obtained one-year survival, and 2% five-year survival. In stages T3N2-3M0 and T3Nx-3M1 after one year 9% and 7% of the patients were alive. The mean survival time of stage T2N0M0 cases was 30.5 months; of T3N0M0, 7.3 months; of T3N1-3M0, 5.2 months; of T3Nx-3M1, 3.8 months. The one-year and five-year survival rates, being related to the irradiation dose administered, amounted to 28% and to 2% after a minimum dose of 5000 rd to the focus. With less than 5000 rd, none of the patients survived two years. The bad results of treatment demand new therapeutic pathways. Short-term pre-irradiation followed by surgical treatment is discussed as well as a combined radiation therapy with cobalt-60 and neutrons or a combined radio-chemotherapy using cytostatics.

Adenocarcinoma↗
PubMed2003

Newly established Askin tumor cell line and overexpression of focal adhesion kinase in Ewing sarcoma family of tumors cell lines.

Askin tumor is a malignant small round cell tumor that originates from the thoracopulmonary region and is a member of Ewing sarcoma family of tumors (ESFT). Only a few Askin tumor cell lines have been established. An Askin tumor cell line, designated MP-ASKIN-SA, was established from the left thoracic tumor of a 13-year-old Japanese boy. ESFT is known to have a high rate of distant metastases at diagnosis. The genes controlling the spread of ESFT cells, however, have not been elucidated. G-banding chromosome analysis revealed that the MP-ASKIN-SA cell line has complex chromosomal abnormalities including trisomy 8. The EWS/FLI1 chimeric transcript and c-myc overexpression were revealed by the reverse transcriptase-polymerase chain reaction and Northern blot analysis. Furthermore, we investigated the expression of the focal adhesion kinase (FAK) gene in the ESFT cell lines using Northern blot analysis. In addition to the MP-ASKIN-SA cell line, six Ewing sarcoma cell lines, one peripheral nerve sheath tumor cell line, and two Askin tumor cell lines were analyzed. All ESFT cell lines, including MP-ASKIN-SA, expressed five- to twenty-eight-fold-increased values of FAK, as compared with fibroblasts obtained from the bone marrow of a healthy volunteer. These results raise the possibility that the overexpression of c-myc and FAK are involved in the poor prognosis of ESFT.

Adolescent↗
PubMed1980

Extraskeletal Ewing's sarcoma: prolonged survival with recurrence after operation.

Unlike the osseous variety, extraskeletal small cell tumors histologically identical to Ewing's sarcoma of bone frequently respond to radical surgical excision. The relative infrequence of this tumor, compounded by the comprehensive eponym "Ewing's sarcoma," may deter surgical intervention in this group of patients. This patient's course demonstrates the value of surgery alone, but emphasizes the role of combined surgery, irradiation, and chemotherapy as the best management for extraskeletal Ewing's sarcoma.

Adult↗
PubMed1994

Ewing's sarcoma--routine diagnostic utilization of MIC2 analysis: a Pediatric Oncology Group/Children's Cancer Group Intergroup Study.

Ewing's sarcoma and peripheral neuroectodermal tumor (PNET) are small blue cell tumors with no reliable positive diagnostic markers. However, Ewing's sarcoma and PNET recently have been shown to strongly express an antigen determined by the MIC2 gene, whereas other blue cell tumors of childhood for the most part do not. MIC2 analysis therefore offers a distinctive addition to the panel of immunohistochemical stains used to differentiate among small blue cell tumors of childhood, since it represents the first positive marker for Ewing's sarcoma and PNET. This study addresses the reliability of MIC2 analysis using the monoclonal antibody 12E7 on tumors registered in the current Intergroup Ewing's Sarcoma protocol. Of 244 tumors, 221 (91%) showed a diffuse strong membranous pattern. The antibody appears to withstand all the fixation variables inherent in a multi-institutional study. We conclude that MIC2 expression is highly reliable as a positive marker for the Ewing's sarcoma/PNET family of tumors when the results are interpreted in the total context with clinical and pathologic parameters.

12E7 Antigen↗
PubMed1989

Immunocytochemical study of small round cell tumors in routinely processed specimens.

Fourteen commercially available monoclonal antibodies were used to examine, by the indirect immunoperoxidase technique, 20 formaldehyde solution-fixed, routinely processed bone marrow biopsy and surgical biopsy specimens from a group of small round cell tumors with bone marrow involvement, including 6 neuroblastomas, 4 rhabdomyosarcomas, 3 Ewing's sarcomas, 3 Burkitt's lymphomas, and 4 small-cell carcinomas of the lung. Eight of 14 monoclonal antibodies worked well on the routinely processed sections. Antidesmin (D33) (Dako Corp, Santa Barbara, Calif) and anti-muscle actin (HHF35) showed specific immunostaining in all 4 rhabdomyosarcomas included in this study. Anti-epithelial membrane antigen immunoreactivity was positive in all small-cell carcinomas of the lung. Anti-leukocyte common antigen (Dako) showed positive immunostaining in lymphomas and did not immunoreact with nonhematopoietic tumors. However, it was important to be aware that some lymphomas may not have been labeled with anti-leukocyte common antigen. All 6 neuroblastomas showed a positive immunoreactivity with anti-chromogranin A (LK2H10) and a weak reaction with antisynaptophysin (SY38). Panels of commercially available monoclonal antibodies, including anti-leukocyte common antigen, anti-epithelial membrane antigen, antidesmin (Dako), anti-muscle actin, and anti-chromogranin A, appear to be most useful in the differential diagnosis and staging of small round cell tumors on routinely processed biopsy specimens.

Actins↗
PubMed2005

Extended pulmonary resections of advanced thoracic malignancies with support of cardiopulmonary bypass.

OBJECTIVE: Complete resection of advanced pulmonary malignancies infiltrating the heart or the great vessels may require the application of cardiopulmonary bypass (CPB). Extracorporal circulation, however, is known to cause lung injury and may be harmful especially in pneumonectomies. METHODS: Over a period of 10 years extended pulmonary resections requiring cardiopulmonary bypass were analyzed in a retrospective study. RESULTS: From August 1993 to August 2003, 13 patients underwent an extended pulmonary resection for curative indications, requiring support by CPB. Underlying diseases were sarcomas (n=8), non-small cell lung carcinomas (n=3), and others (n=2). Pneumonectomies were performed in nine and lobectomies in four cases. In the majority of cases, several cardiac structures, predominantly the left atrium (n=9), were affected. In four patients (31%), the indication for a CPB-supported procedure was not electively planned, but made intraoperatively. Complete en-bloc resection (R0) was achieved in 12 of 13 cases (92%). The 30-day mortality rate was 15% (n=2). Major complications observed were acute lung injury (n=4), right heart failure (n=1), and multi-organ failure (n=1). The cumulative survival at 1, 3, and 5 years in patients presenting with sarcomas was 62.5% compared to 33%, 0%, and 0%, respectively, in patients with non-small cell carcinoma (n=3). CONCLUSIONS: Our results encourage the application of CPB in extended pulmonary resections to achieve complete resections. In carefully selected patients, especially those with sarcomas, the radical surgical procedure associated with increased pulmonary complications allows for significantly prolonged survival and quality of life.

Adult↗
PubMed2004

Desmoplastic small cell tumor in the pancreas.

Desmoplastic small cell tumor (DSCT) is a distinct type of small blue cell tumors and is characterized by the unique karyotypic aberration involving the fusion of the Ewing's sarcoma (EWS) gene and Wilms' tumor (WT1) gene. Typically, it grows along serosal surfaces; however, in some cases, the tumor presents as a dominant mass in an internal organ. Examples of DSCT forming a primary mass in ovary, testes, and brain have been described, but its presentation as a primary pancreatic mass has not been reported previously. The case reported here is a 31-year-old woman who presented with a 14-cm mass in the pancreas. There were smaller nodules on the peritoneal surfaces that were regarded clinically as metastasis from a primary pancreatic tumor. During the frozen section, the diagnosis of a poorly differentiated endocrine carcinoma of pancreatic origin was rendered and patient underwent subtotal pancreatectomy. On microscopic examination, the tumor was composed of large nests and broad bands of small blue cells, separated by fibrous stroma. Immunohistochemical stains showed positivity of the tumor cells for cytokeratins (AE1:AE3 and CAM5.2), neuron specific enolase, desmin and WT1, whereas chromogranin, S-100, and CD99 were negative. Since this immunoprofile is characteristic of DSCT, molecular analysis was performed which revealed the presence of EWS-WT1 gene fusion characteristic of DSCT. This case shows that in addition to primary pancreatic tumors characterized by prominent cellularity such as solid pseudopapillary tumors, acinar cell carcinoma, pancreatoblastoma, endocrine tumors, and other small blue cell tumors, the differential diagnosis of cellular, stroma-poor neoplasia in the pancreas also includes DSCT. This case is also another demonstrative example of how DSCT may form a dominant mass in intraabdominal organs.

12E7 Antigen↗
PubMed1999

Immunohistochemical evaluation of small round cell tumors of childhood.

OBJECTIVE: This study was done to evaluate the pediatric undifferentiated small round cell tumors with immunohistochemical staining. SETTING: The present study included consecutive cases of small round cell tumors which were diagnosed in children (< 15 years) in the section of Histopathology at the Aga Khan University Hospital, Karachi during the period of two years. METHODS: The group of undifferentiated small round cell tumors were evaluated immunohistochemically by using a panel of antibodies on sections from routinely processed, formalin fixed, paraffin embedded tissue blocks. RESULTS: The category of undifferentiated small round cell tumors included rhabdomyosarcoma (23.2%), primitive neuroectodermal tumor (17.9%), non-Hodgkin's lymphoma (16.1%), neuroblastoma (14.2%), Ewing's sarcoma (10.7%) in order of frequency. Osteosarcoma (Small cell variant), retinoblastoma and medulloblastoma comprised 1.8% each. In seven cases (12.5%), the immunohistochemical analysis was inconclusive. CONCLUSION: Immunohistochemistry is a very valuable diagnostic tool which helps in distinguishing the undifferentiated tumors especially small round cell tumors. The immunohistochemical staining needs to be performed routinely for undifferentiated tumors in diagnostic histopathology.

Adolescent↗