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Biomedical subjects

W Sanger

Publications and source records attributed to W Sanger.

At least 19 recordsLinked to original sources
PubMed2000

Anaplastic large cell lymphoma arising in bone: report of a case of the monomorphic variant with the t(2;5)(p23;q35) translocation.

Anaplastic large cell lymphoma (ALCL) represents approximately 2% of all non-Hodgkin lymphomas according to the recent Non-Hodgkin Lymphoma Classification Project. As defined in the revised European-American classification of lymphoid neoplasms (REAL), ALCL is a neoplasm of T-cell or null-cell lineage; 20% to 60% of cases are associated with the t(2;5)(p23;q35) translocation. ALCL commonly involves nodal as well as a wide variety of extranodal sites, although primary or secondary involvement of bone is rare. We describe the case of a 71-year-old man with stage IE T-cell ALCL, monomorphic variant, arising in the left anterior fifth rib and involving adjacent soft tissue without other sites of disease. The monomorphic histologic features hindered the initial recognition of this neoplasm as ALCL. However, strong uniform CD30 antigen expression and subsequent demonstration of the t(2;5)(p23;q35) translocation and anaplastic lymphoma kinase (ALK) immunoreactivity led to the correct diagnosis. We identified only 5 reported cases of T-cell and null-cell ALCL arising in bone and only 2 of these cases involved a single bone site. All 5 previously reported cases were ALCL of the classic type. We report a case of ALCL that is unique to our knowledge. This case of monomorphic ALCL was localized to bone and tumor cells contained the t(2;5)(p23;q35) translocation.

Aged↗
PubMed1999

Induction of adenocarcinoma from hamster pancreatic islet cells treated with N-nitrosobis(2-oxopropyl)amine in vitro.

Our previous studies in the hamster pancreatic cancer model have indicated that pancreatic ductal adenocarcinomas derive not only from ductal/ductular cells but also from islets. To verify the presence of carcinogen-responsive cells within islets, we tested the effect of the pancreatic carcinogen N-nitrosobis(2-oxopropyl)amine (BOP) on recently established continuous hamster pancreatic islet culture. Isolated pure pancreatic islets of hamsters were treated in vitro with BOP at a concentration of 0.25 mM three times a week for 19 weeks. Each treatment week was designed as a stage. The growth of these cells, designated KL5B, was compared with untreated cultured islets, designated KL5N. As in our previous study, between 14 and 21 days of culture, exocrine and intermediary cells developed within both KL5N and KL5B islets, which were then replaced by undifferentiated cells. No differences were found in the growth patterns of KL5N and KL5B until stage 4, when KL5B cells showed accelerated cell growth and cell pleomorphism, which increased gradually at later stages of treatment. Anchorage-independent and in vivo growth did not appear until stage 19. Mutation of c-Ki-ras at codon 12 (GGT-->GAT) was detected in KL5B cells but not in KL5N cells. In vivo KL5B cells formed anaplastic invasive cancer with areas of glandular formation, overexpressed TGF-alpha and EGFR, expressed cytokeratin, vimentin, laminin and alpha-1 antitrypsin and reacted strongly with L-phytohemagglutinin and tomato lectin. Some cells within islets are responsive to the carcinogenic effects of BOP. Whether these cells represent islet cell precursors (stem cells) or malignant transdifferentiated islet cells remains to be seen.

Adenoma, Islet Cell↗
PubMed1997

In vitro pancreatic ductal cell carcinogenesis.

Our experiments were designed to identify initial biochemical and biological changes that occur during pancreatic carcinogenesis. TAKA-1, an immortal hamster pancreatic ductal cell line, was treated in vitro for up to 11 weeks with the pancreatic carcinogen N-nitorosobis(2-oxopropyl)amine (BOP). These treated cells were designated TAKA-1 + BOP. The growth of TAKA-1 and TAKA-1 + BOP cell lines was investigated in soft agar and in hamsters intradermally. The resulting tumor from TAKA-1 + BOP was re-cultured in vitro and designated TAKA-1 + BOP-T. Mutation of c-K-ras and p53 oncogenes, chromosomal changes, expression of transforming growth factor alpha (TGF-alpha) and epidermal growth factor (EGF) receptor and several biochemical markers were examined in all cell lines. TAKA-1 + BOP but not TAKA-1 cells grew in soft agar and produced an invasive tumor in vivo. However, there were no differences in cell growth rate, DNA flow cytometry, or immunohistochemical findings between the non-transformed and transformed cells. TAKA-1, TAKA-1 + BOP and TAKA-1 + BOP-T cells all expressed mRNA of TGF-alpha and EGF receptor in a comparable pattern. DNA sequence analysis following polymerase chain reaction showed that neither TAKA-1 nor TAKA-1 + BOP cells has a mutation of c-K-ras or p53. Karyotype analysis demonstrated that TAKA-1 + BOP cells had more chromosomal abnormalities compared with TAKA-1 cells. Mutation of c-K-ras and p53 was not essential for carcinogenesis in hamster pancreatic ductal cells in vitro. In conclusion, immortality of the TAKA-1 cells caused expression of TGF-alpha to the same extent as in malignant cells. Chromosomal and ultrastructural patterns were the only differences detected between the non-transformed and BOP-transformed cells.

Amino Acid Sequence↗
PubMed1997

Experimental evidence for the origin of ductal-type adenocarcinoma from the islets of Langerhans.

To investigate the role of the islets of Langerhans in pancreatic carcinogenesis, freshly isolated islets from male Syrian hamsters were transplanted into the right submandibular glands of 50 female hamsters that were or were not pre-treated with streptozotocin. Thyroid gland fragments, cellulose powder, and immortal hamster pancreatic ductal cells were injected into the left submandibular gland of the same hamsters. All recipient hamsters were then treated with the potent pancreatic carcinogen N-nitrosobis(2-oxopropyl)amine weekly at a dose of 40 mg/kg of body weight for 3 weeks. Between 3 and 8 weeks later, 18 of 75 (24%) hamsters developed large ductal-type adenocarcinomas in the submandibular gland region, where islets were transplanted, but none developed tumors in the left submandibular gland. In 9 of 18 hamsters, tumors were multiple so that a total of 31 cancers were found. Eleven of these carcinomas were in the vicinity of transplanted islets, eight of which showed intra-insular ductular or cyst formation as seen in the pancreas of hamsters during pancreatic carcinogenesis. The formation of ductular structures within islets was also demonstrated in vitro. Some tumor cells in the vicinity of these islets were reactive with anti-insulin. Y chromosome message was found by polymerase chain reaction analysis in one of the three tumors examined. Also, like the induced pancreatic tumors, all three submandibular gland tumors that were examined had the mutation of the c-Ki-ras oncogene at codon 12 and all tumors expressed blood group A antigen. These and other findings strongly suggest that some components of islets, most probably stem cells, are the origin of ductal-type adenocarcinomas in this model.

Adenocarcinoma↗
PubMed1995

Transcripts of the npm-alk fusion gene in anaplastic large cell lymphoma, Hodgkin's disease, and reactive lymphoid lesions.

Anaplastic large cell lymphoma (ALCL) and Hodgkin's disease (HD) have some pathologic and immunohistochemical similarities, and a histogenetic relationship between them has been suggested by some investigators. By cytogenetic study, the t(2;5)(p23;q35) translocation appears to be unique for ALCL. The breakpoints of the t(2;5)(p23;q35) have recently been cloned and are reported to involve a novel tyrosine kinase gene, anaplastic lymphoma kinase (alk), on chromosome 2 and the nucleophosmin gene (npm) on chromosome 5. Therefore, we studied the frequency of npm-alk translocation in ALCL using a reverse transcriptase-polymerase chain reaction (RT-PCR) assay. We also studied HD and a variety of reactive lymphoid lesions since there is contradictory information in the literature on the occurrence of the npm-alk rearrangement in HD. We detected npm-alk hybrid mRNA in 8 of 22 cases of ALCL (36%), but none of the 21 cases of HD or the 11 cases with reactive lesions contained amplifiable template. All positive ALCL had the T or indeterminate phenotype and occurred in young adults or children. There was very good correlation between a cytogenetically detectable t(2;5) and a positive signal by RT-PCR. Our results indicate a selective but relatively infrequent association between the t(2;5) and ALCL of T or indeterminate phenotype, not shared with HD or reactive hyperplasia.

Adolescent↗
PubMed1995

Familial inverted duplication 7p.

A 10-month-old female with developmental delay and failure to thrive was referred for genetic evaluation as part of an adoption assessment. Physical exam showed a mildly beaked nose and clinodactyly, but otherwise nothing remarkable. Chromosome analysis showed an inverted duplication of the p12.2-->p13 portion of chromosome 7[(46,XX, dup(7)(p13p12.2)]. The proposita's older brother, mother, and grandmother were cognitively delayed and had the same chromosome 7 duplication. A review of the literature showed no other cases involving this exact duplication.

Chromosome Inversion↗
PubMed1995

Establishment and characterization of a new, spontaneously immortalized, pancreatic ductal cell line from the Syrian golden hamster.

Spontaneously immortal pancreatic cell lines are not available. By use of a defined culture medium, such a line (TAKA-1) was established from the Syrian golden hamster. Cytological, cytogenetic, molecular biological, enzymatic and receptor patterns as well as antigenicity were studied and were compared with those of the normal hamster pancreatic ductal cells in vivo. TAKA-1 cells grew exponentially in a monolayer on collagen gel in a defined medium but did not proliferate in soft agar. Ultrastructurally, the cells closely resembled the normal hamster pancreatic ductal cells. Similarities and dissimilarities were found between the normal ductal cells and TAKA-1 cells. Similarities included the presence of cytokeratin, carbonic anhydrase and some tumor-associated antigens. However, unlike the normal ductal cells, TAKA-1 cells expressed blood group A antigen and anti-vimentin, showed affinity to selected lectins, and an abnormality of chromosome 3, which is suggested to be associated with immortality. Moreover, unlike the hamster pancreatic ductal cancer cells but like the normal hamster pancreatic ductal cells, TAKA-1 cells did not have a c-Ki-ras mutation. EGF, TGF-alpha and secretin, but not CCK or GRP, bound to the TAKA-1 cells. TAKA-1 cells produced TGF-alpha, and their growth was stimulated by exogenous EGF in serum-free medium. This cell line presents a suitable model for biologic and pathologic study of the hamster pancreatic ductal cells in vitro.

Animals↗
PubMed1995

Differences in molecular biological, biological and growth characteristics between the immortal and malignant hamster pancreatic cells.

We compared morphological, biological and molecular biological patterns of a newly established, spontaneously immortalized pancreatic ductal cell line, TAKA-1, with a hamster pancreatic ductal adenocarcinoma cell line, PC-1. PC-1 cells grew in a monolayer on plastic tissue culture flasks, whereas TAKA-1 cells required type I collagen gel matrix to propagate. The growth rate and argyrophilic nuclear organizer region (Ag-NOR) counts were greater in PC-1 cells than in TAKA-1 cells. More TAKA-1 cells were in G0/G1 and less were in the S cell cycle phase than PC-1 cells. Karyotypically, the consistent change in TAKA-1 cells was an abnormal no. 3 chromosome, whereas additional chromosomal abnormalities were found in PC-1 cells. Ultrastructurally, TAKA-1 cells formed ductal structures and were composed of two types of cells, as in the normal hamster pancreatic ducts, whereas PC-1 cells were pleomorphic, showed evidence for loss of differentiation and contained intracytoplasmic lumens. Unlike the PC-1, TAKA-1 cells did not show a point mutation at codon 12 in the c-Ki-ras oncogene and did not grow in soft agar. Receptor binding assay showed specific epidermal growth factor binding to both cell lines, but secretin binding only to TAKA-1 cells. Both cells produced and released transforming growth factor-alpha in serum-free medium. Both cell lines expressed blood group A antigen, carbonic anhydrase, coexpressed cytokeratin and vimentin, and reacted with tomato and Phaseolus vulgaris leucoagglutinin (L-PHA) lectins. The results demonstrate that chromosomal abnormalities, cell cycle patterns, expression of cytokeratin 18, lectin bindings and the c-Ki-ras mutation are the features that distinguish the benign from the malignant pancreatic ductal cells in Syrian hamster.

Adenocarcinoma↗
PubMed1992

Evolution of clonality and invasive behavior of Epstein-Barr virus immortalized lymphoblastoid cell lines in SCID mice brains.

BACKGROUND: Recently established Epstein-Barr virus immortalized lymphoblastoid cell lines express polyclonal immunoglobulins, are diploid, and grow into invasive tumors when injected intracerebrally into mice with severe combined immunodeficiency (SCID). It is unclear whether clonal selection of neurotropic cell lines occurs during long-term growth in the brain and the effect of this selection on brain invasiveness. EXPERIMENTAL DESIGN: Epstein-Barr immortalized lymphoblastoid cell lines from a normal Epstein-Barr negative donor were serially passaged seven times intracerebrally within groups of SCID/SCID CB 17 mice. Each cell line was injected into five or more animals during each passage. Clonality of the rescued cell lines, genotype, and brain invasiveness were examined. RESULTS: All mice developed extensive intracerebral lymphoproliferative disease within 10-18 days after injection. Intracerebral, subarachnoid, intraventricular, and perivascular lymphoid lesions were noted. Infiltrates were similar in all animals studied regardless of the passage number. Clonal B cell populations were detectable in lesions after the first passage by Southern blot hybridization using JH probe. Immunohistochemically, polyclonal tumors were seen initially, but after the fourth passage, monoclonal cytoplasmic immunoglobulin was predominantly expressed by all tumors. Minor bands seen in the early passages disappeared subsequently. Random chromosomal abnormalities appeared in the rescued cell lines after the third passage; however, after the sixth passage, the abnormalities became more consistent. Clonability in agarose was very low initially in both cell lines and increased significantly after the sixth passage. CONCLUSIONS: These experiments demonstrate that within the immunoprivileged conditions of the SCID mouse brain, the evolution of Epstein-Barr immortalized lymphocytes from polyclonal to oligo- and monoclonal cell lines with chromosomal abnormalities occurs very early. This evolution is not paralleled by increased invasiveness in vivo.

Animals↗
PubMed1991

SCID/human mouse model of central nervous system lymphoproliferative disease.

Epstein-Barr virus (EBV) carrying malignant lymphomas of the central nervous system are increasing owing to the increasing numbers of immunodeficient patients. To further understand the pathogenesis of these tumors, we studied the invasiveness of four EBV-immortalized lymphoblastoid cell lines in the brains of immunodeficient mice and the expression of adhesion molecules during this process. We injected four EBV-infected human lymphoblastoid cell lines intracerebrally into nude as well as SCID/SCID CB17 mice. Within 13 to 14 days, lethal brain lymphoproliferative lesions resulted in SCID mice, whereas similar lesions developed in 21 to 24 days in nude mice. Atypical large lymphoid cells aggressively infiltrated brain parenchyma, ventricular, and subarachnoid spaces. No difference in invasiveness was found between the monoclonal lymphoblastoid cell lines grown in long-term culture and polyclonal lymphoblastoid cell lines grown for a shorter duration. Tumors retained the same human immunoglobulin expression and activation antigen profile as the original cell lines. Furthermore, tumors expressed human LFA-1/ICAM-1 and the tumor blood vessels strongly expressed murine ICAM-1, but not MECA 79. Mice injected intracerebrally with peripheral blood leukocytes or normal bone marrow cells from an EBV seronegative individual failed to form tumors confirming the pivotal role for EBV in this process. SCID mice offer advantages for studying central nervous system lymphoproliferative disease.

Animals↗
PubMed1989

Lymphomatoid papulosis and progression to T cell lymphoma: an immunophenotypic and genotypic analysis.

A 37-year-old white man had untreated lymphomatoid papulosis for 12 years before a submandibular T cell immunoblastic lymphoma developed. A genetic abnormality, composed of extra chromosomal material attached to the short arm of chromosome 9, was detected in the lymphoma tissue but not in the skin. The lymphomatoid papulosis skin lesions did not manifest clonal T cell receptor gene rearrangements, but the submandibular lymphoma tissue was clonal and of T cell lineage. The patient's lymphoma responded well to combination chemotherapy, but the lymphomatoid papulosis remains active.

Adult↗
PubMed1988

Acute myelogenous leukemia with eosinophilic differentiation and trisomy-1.

A 50-year-old woman presented with anemia and eosinophilia. Her bone marrow biopsy, peripheral blood, and clinical features were consistent with a diagnosis of an evolving acute myelogenous leukemia. Striking dysplastic eosinophilic differentiation associated with trisomy-1 was evident, and eosinophil granule major basic protein was detected in involved tissue. Trisomy-1 has not been previously reported in association with acute myelogenous leukemia showing eosinophilic differentiation. Intensive cytotoxic chemotherapy produced a short-lived clinical and cytogenetic remission. At autopsy multiple tumor nodules composed of dysplastic eosinophil precursors and myeloblasts were evident in multiple organs.

Bone Marrow↗
PubMed1987

Early leukemic recurrence of non-Hodgkin lymphoma after high-dose anti-neoplastic therapy with autologous marrow rescue.

Five patients with recurrent non-Hodgkin lymphoma treated with high-dose salvage anti-neoplastic therapy supported by unpurged histologically uninvolved autologous bone marrow reinfusion have suffered relapse in the blood and bone marrow within a few weeks of the marrow reinfusion. Four of these patients had the small non-cleaved (Burkitt) sub-type of malignant lymphoma. Additional risk factors for such 'leukemic relapse' appear to include a rapid clinical course prior to the salvage therapy and the presence of karyotypic subclones within the malignant cell population. It seems likely that these relapses occurred as a result of reinfusion of small numbers of viable 'marrow homing' malignant cells with the autologous bone marrow. This pattern of recurrence is rare in patients with other lymphoma sub-types receiving unpurged marrow. These data may permit exclusion of patients at high risk for this devastating relapse pattern from clinical trials of unpurged autologous marrow transplantation and the selection of patients for trials of marrow purging.

Adolescent↗
PubMed1986

Cystic fibrosis complicated by acute leukemia.

During a 3-month period, two men ages 20 and 25 years, respectively, with cystic fibrosis developed acute lymphocytic and nonlymphocytic leukemias, respectively. These two patients were among 120 patients who attended our cystic fibrosis clinic during the last 3 years. Thirty-five of the 120 patients have survived beyond the second decade. The authors ask whether acute leukemia will be recognized with increasing frequency in cystic fibrosis patients who achieve prolonged survival.

Adult↗