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W G Sanger

Publications and source records attributed to W G Sanger.

At least 37 records · Page 2Linked to original sources
PubMed1997

Clinical variability of tetrasomy 12p.

We describe five patients with tetrasomy 12p (one previously reported). These patients exhibit a very wide range of phenotypic features from that of classic Pallister-Killian syndrome to only mild learning disabilities with pigmentary skin changes. As such, these cases highlight the fact that tetrasomy 12p [i(12p)] and Pallister-Killian syndrome are not synonymous, although this combination of genotype and phenotype is often seen. This information is especially important in prenatally ascertained i(12p). The full spectrum of phenotypic possibilities associated with this chromosome aneuploidy should be discussed in prenatal counseling.

Abnormalities, Multiple↗
PubMed1996

Occurrence of the t(2;5)(p23;q35) in non-Hodgkin's lymphoma.

Primary CD30(Ki-1)-positive anaplastic large-cell lymphoma (ALCL) is considered by some to be a distinct clinicopathologic entity associated with the t(2;5) (p23;q35). However, the specificity of t(2;5) for ALCL has not been carefully studied. Therefore, we performed a detailed analysis of all cases of ALCL with abnormal cytogenetics results in the Nebraska Lymphoma Study Group registry, as well as all other cases of non-Hodgkin's lymphoma with t(2;5) in the registry. We found the t(2;5) in only five of 10 cases of ALCL, four of whom were young patients. However, we also found the t(2;5) in 11 other cases of nonanaplastic lymphoma, including eight children with typical peripheral T-cell lymphomas of various types. The t(2;5) was also found in three older adults with B-cell lymphomas of various types. Thus, the t(2;5) was not specific for CD30+ ALCL. However, t(2;5) may define a clinicopathologic entity in children and young adults characterized by variable morphologies with a T-cell or indeterminate phenotype, CD30-positivity, nodal disease with frequent extranodal involvement, advanced stage, and an excellent response to therapy, including bone marrow transplantation for relapsed disease. The clinical relevance of the t(2;5) in older patients requires further study.

Adolescent↗
PubMed1995

Comparison of DNA content in non-Hodgkin's lymphoma as measured by flow cytometry and cytogenetics.

Specific cytogenetic changes such as t(14;18) and t(8;14) are associated with specific histologic subtypes of non-Hodgkin's lymphoma (NHL) and may predict disease outcome. Nonspecific cytogenetic changes include other structural rearrangements or numerical changes such as monosomies and trisomies, which may cause changes in total cellular DNA content. In many solid tumors, the presence of abnormal DNA content may be predictive of clinical behavior. NHL biopsies, however, contain normal (diploid) as well as abnormal cells, and DNA changes in the peridiploid range are detectable by cytogenetic analysis, but not consistently by flow cytometry. In the present study, we performed flow cytometric and cytogenetic analysis of DNA on biopsies from 129 patients with non-Hodgkin's lymphoma (NHL). Cytogenetic studies were successful on 88 (68%) of the samples. There was 55% concordance between flow cytometric and cytogenetic techniques in detecting aneuploid DNA content, with the majority of discrepancies occurring in the peridiploid range. We also detected six samples which were aneuploid by flow cytometry, but diploid by cytogenetics. We suggest that a reasonable approach to determine DNA content, as it relates to prediction of outcome in NHL, would be to combine data from both of these techniques and analyze the results in terms of ranges of DNA rather than by categorizing as diploid versus aneuploid.

Aneuploidy↗
PubMed1995

Effects of BCR-ABL antisense oligonucleotides (AS-ODN) on human chronic myeloid leukemic cells: AS-ODN as effective purging agents.

We examined phosphorothioate oligodeoxyribonucleotides (ODNs) directed against bcr in exon 3 or exon 2, which are rearranged with exon 2 of abl (B3A2 and B2A2) at t(9;22) of chronic myelogenous leukemia (CML). Since these ODNs are designed to be CML cell specific, we studied their effects on the human CML cell line K562, which is known to have B3A2 rearrangement, and leukemic cells from patients, as well as normal hematopoietic stem cells in vitro. In vitro experiments were performed to determine a potential role of these two ODNs as ex vivo purging agents. Incubation of B3A2 antisense at 40, 80, and 120 micrograms/ml with K562 CML cells for 72 hours at 37 degrees C resulted in 44%, 56%, and 63% reduction of CFU-L as compared to controls. In contrast, B3A2 sense and B2A2 antisense had no significant growth inhibitory effect on K562 cells. Incubation of B3A2 and B2A2 antisense ODNs at concentration of 80 micrograms/ml at 37 degrees C for 36 hours with normal peripheral blood stem/progenitor cells (PBSC) resulted in 124% and 98% CFU-GM formation as compared to untreated controls, respectively. However, incubation of PBSC with B3A2 and B2A2 sense-ODNs resulted in a 22% and 44% reduction in CFU-GM, respectively. In order to determine the ex vivo purging effects of bcr-abl ODNs, the K562 cells were mixed with PBSC from normal donors at a ratio of 1:20 (CML:PBSC). The mixture of cells was then incubated with B3A2 antisense at 80 micrograms/ml for 36 hrs at 37 degrees C. After incubation, no CML cells were detected by fluorescence in situ hybridization (FISH) as compared to untreated controls. These results were confirmed by RT-PCR using bcr-abl primers and mRNA isolated from the mixture of cells. Further, these results support the hypothesis that bcr-abl antisense ODNs are potentially effective agents for ex vivo purging of autologous stem cells before transplantation to eliminate/reduce the burden of leukemic cells. No significant toxicity to normal hematopoietic stem/progenitor cell population by the bcr-abl antisense ODNs was observed. Although unanticipated reductions in normal hematopoietic progenitor cells (CFU-GM) were observed with sense ODNs, no reduction in CFU-GM was observed with unrelated phosphorothioate ODN controls.

Base Sequence↗
PubMed1995

Proliferative fraction and DNA content are lower in B-cell non-Hodgkin's lymphomas with the t(14;18).

The t(14;18), which juxtaposes the immunoglobulin enhancer region from chromosome 14 to the bcl-2 gene on chromosome 18, is a recurrent cytogenetic abnormality in the majority of follicular lymphomas (FL). This translocation results in overexpression of bcl-2, which increases cellular life span of the mutated cells by decreasing apoptosis. The t(14;18) also occurs in a subgroup of diffuse large cell lymphomas (DLCL), and current thought is that the majority of these represent transformation of FL. Low grade FL are characterized by low proliferation, and diploid/peridiploid DNA content. In this study, we compared proliferative activity (PF) and DNA content (DI) in FL containing the t(14;18) to DLCL with and without the t(14;18). The mean PF and DI were lower in the NHL containing t(14;18) irregardless of histologic subtype. We conclude that increased life span due to the presence of t(14;18) provides the conditions for accumulation of a different set of mutations as compared to those NHL developing from mutations in more rapidly proliferating precursors. This has implications for prognosis of patients with DLCL depending upon the presence or absence of t(14;18).

Cell Division↗
PubMed1994

Mutation analysis for cystic fibrosis to determine carrier status in 167 sperm donors from the Nebraska Genetic Semen Bank.

Cystic fibrosis is the most common autosomal recessive disorder in Caucasian populations, with an approximate frequency of 1/2500 live births and a carrier frequency of 1/25. Due to the high rate of predicted carriers (> 63,000) in the Nebraska population (1990 U.S. Census = 1,578,358), we analyzed sperm DNA obtained from semen donors at the University of Nebraska Genetic Semen Bank for eight of the more common mutations to determine the frequency and diversity in our population. The subjects included 167 semen donors (31 normal healthy donors, 56 infertility patients, 21 prevasectomy patients, and 59 prechemotherapy or preradiation cancer patients). The mutations analyzed included delta F508, R117H, G542X, S549R/N, G551D, R553X, R560T, and W1282X. Analyses were performed using PCR amplified products that were analyzed using polyacrylamide gel electrophoresis, slot blot, and restriction endonuclease digestion. These results were correlated with results from the clinical semen analyses and selected clinical parameters. Results for the total donor population studied showed that the delta F508 mutation was present in 8/167 (4.8%) donors, the R117H mutation was present in 4/167 (2.4%) donors and the G542X mutation was present in 1/167 (0.6%) donors. The observed number of carriers from this population, 13/167 (7.8%), was significantly greater (P = 0.02) than that expected assuming a carrier frequency of 1/25. The excess of carriers was restricted to the subgroup of infertility patients. This suggests that CF carriers may be at higher risk for infertility than the general population.

Cystic Fibrosis↗
PubMed1994

Incidence and characterization of secondary myelodysplastic syndrome and acute myelogenous leukemia following high-dose chemoradiotherapy and autologous stem-cell transplantation for lymphoid malignancies.

PURPOSE: To analyze the risk of developing myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) following autologous bone marrow transplantation (ABMT) or peripheral stem-cell transplantation (PSCT) and to determine the impact on failure-free survival (FFS). PATIENTS AND METHODS: Patients underwent ABMT or PSCT for the treatment of Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) at the University of Nebraska Medical Center. For those patients who went on to develop MDS/AML, controls were selected and a case-control-within-a-cohort study undertaken. RESULTS: Twelve patients developed MDS or AML a median of 44 months following ABMT/PSCT. The cumulative incidence (P = .42) and the conditional probability (P = .32) of MDS/AML were not statistically different between HD and NHL patients. Age greater than 40 years at the time of transplant (P = .05) and receipt of a total-body irradiation (TBI)-containing regimen (P = .06) were predictive for developing MDS/AML in patients with NHL. CONCLUSION: There is an increased risk of MDS/AML following ABMT/PSCT for lymphoid malignancies. NHL patients age > or = 40 years at the time of transplant and who received TBI are at greatest risk.

Adult↗
PubMed1994

Peripheral T-cell lymphoma in children and adolescents: role of bone marrow transplantation.

Although PTCL in children, as in adults, has a spectrum of clinical, morphologic, cytogenetic and immunologic features, there are several significant differences in these features between children and adults. Our data show that CD30 expression is much more common in pediatric PTCL than is reported in adult PTCL. Furthermore, the majority of children with CD30-positive PTCL do not have tumors with anaplastic large cell histology. Our data also suggest that the t(2;5) is not a specific marker of anaplastic large cell lymphoma in childhood. The likelihood of cure for children with PTCL is unclear, predominantly because of the lack of large numbers of pediatric patients with this less common entity. As with other NHL, we expect that treatment with conventional dose chemotherapy following relapse will be unsuccessful in most cases. Although the data are preliminary, it appears that high dose chemoradiotherapy followed by hematopoietic stem cell transplantation is an effective therapy in these patients. We have been particularly successful with a regimen based on thioTEPA, VP-16 and total body irradiation, but other regimens may also be efficacious. Further studies of this interesting group of tumors are clearly needed.

Adolescent↗
PubMed1994

Cytogenetic abnormalities in B-immunoblastic lymphoma.

We have considered the cytogenetic abnormalities present in 27 unpublished cases of B-immunoblastic lymphoma. Among these 27 patients, the chromosome changes were heterogeneous and complex. The chromosomes most commonly gained were 3 (44% of cases), 18 (44%), 6 (30%) and 11 (30%). The most common structural abnormalities involved band 14q32 (26%), band 18q21 (15%) and bands 6q16-21 (19%). Study of these 27 immunoblastic lymphomas did not allow us to tentatively identify a common primary cytogenetic abnormality unique to B-immunoblastic lymphoma, however, a translocation at 14q32 may be the primary cytogenetic lesion in some of the cases. Rather, we have added to the number of abnormalities reported in immunoblastic lymphoma and in non-Hodgkin's lymphoma in general.

Adolescent↗
PubMed1993

Peripheral T-cell lymphoma in childhood and adolescence. A clinicopathologic study of 22 patients.

BACKGROUND: Peripheral T-cell lymphoma (PTCL), although the most common T-cell lymphoma in adults, is relatively rare in childhood, and only small series have been reported. METHODS/RESULTS: Twenty-two cases of PTCL were studied that occurred in patients 18 months to 20 years of age. Nine were seen when the condition was diagnosed, and the other 13 were referred after they had relapses. The stage at diagnosis was I or II (45%), III (41%), and IV (14%). Patients with Stage IV disease were younger than those with Stage I or II disease (2.5 versus 14.8 years, P = 0.04). Twelve patients had extranodal disease when the diagnosis was made; the skin was the most common site. Ten tumors were classified as diffuse large cell type; five, as diffuse anaplastic large cell type; and seven, as diffuse mixed cell type. Twenty of the 21 tumors tested were CD30 (Ki-1 or Ber-H2) antigen positive. Of the nine patients seen when the diagnosis was made and treated by the authors, three had a relapse (median, 12 months), a 2-year relapse-free survival (RFS) rate of 61%. For the total group, the RFS was longer for patients older than 12 years of age compared with those who were younger (20 versus 12 months, P = 0.05). Overall, six patients remained in their first complete remission. Sixteen patients had a relapse, and 13 of these underwent bone marrow transplantation (BMT). Six of these remained in complete remission (median, 18 months after BMT). Overall, only 6 of 22 patients died (median survival, > 60 months). CONCLUSION: It was concluded that aggressive therapy, including BMT for relapses, can provide prolonged disease control in most children with PTCL.

Adolescent↗
PubMed1993

Clinical features and prognosis of follicular large-cell lymphoma: a report from the Nebraska Lymphoma Study Group.

PURPOSE: Our purpose was to describe the treatment outcome of patients with follicular large-cell lymphoma (FLCL) and to identify prognostic factors that affect the treatment outcome. PATIENTS AND METHODS: Between 1980 and 1991, 107 newly diagnosed, previously untreated patients with FLCL were prospectively treated using treatment plans of the Nebraska Lymphoma Study Group (NLSG). Most stage I/II patients received two to three cycles of one of four closely related six-drug combination chemotherapy regimens (cyclophosphamide, doxorubicin or mitoxantrone, and procarbazine, plus bleomycin, vincristine, and prednisone or dexamethasone [CAP/BOP I-IV]) plus involved-field radiotherapy; 10 patients received involved-field irradiation only. Stage III/IV patients received six to eight cycles of CAP/BOP. RESULTS: Forty-four percent of patients had stage I/II disease. Stage I/II patients were older and more often female than stage III/IV patients. Cytogenetic studies were available on 35 patients: seven were normal; the most common abnormality was a translocation involving 14q32. Abnormalities of 1p or 1q were also common, often secondary to a 14q32 abnormality. The median follow-up of surviving patients is 2 years. The complete response rates observed were stage I/II, 88%; stage III/IV, 49%. Complete response rates were affected by both age and tumor bulk. Failure-free survival (FFS; time to first occurrence of progression, relapse after response, or death from any cause) at 3 years was estimated to be 61% for stage I/II patients and 34% for stage III/IV patients. Survival at 3 years was estimated to be 76% and 61%, respectively. FFS of stage III/IV patients was poorer for stage IV patients and those with composite lymphomas. Significantly poorer survival was only seen in patients older than 70 years of age. CONCLUSION: A proportion of stage I/II FLCL patients may obtain long-term disease control with combination chemotherapy plus radiotherapy. Results for patients with stage III/IV FLCL are similar to those seen for other follicular lymphomas.

Aged↗
PubMed1993

Oncogene rearrangement in non-Hodgkin's lymphoma with a 14q+ chromosome of unknown origin.

Southern blot analysis was performed with a panel of DNA probes to detect rearrangements of c-myc, bcl-1, bcl-2 and bcl-3 in 14 cases of B-cell non-Hodgkin's lymphoma (NHL) with a clonal cytogenetic rearrangement involving the chromosome 14q32 locus and no known donor chromosome [t(14;?)(q32;?)]. In our experience, 21% of all chromosomal abnormalities involving the 14q32 locus in B-cell NHL are of this type. We found oncogene rearrangements in five of the 14 cases: bcl-1 rearrangement on one mantle zone lymphoma, bcl-2 rearrangements in two follicular lymphomas, and c-myc rearrangements in two small noncleaved cell lymphomas. We conclude that a 14q32+ abnormality of unknown origin is a relatively frequent karyotypic finding in B-cell NHL. In one third of the cases, known oncogenes that have been previously described in reciprocal translocations involving the immunoglobulin heavy chain locus were shown to be involved in the 14q32+ abnormality. The translocations in the other cases are likely to have involved one of the above oncogenes with breakpoints not revealed by the probes employed, other known oncogenes, or oncogenes that have not yet been identified.

Adolescent↗
PubMed1993

Characterization of clonality of Epstein-Barr virus-induced human B lymphoproliferative disease in mice with severe combined immunodeficiency.

To improve the diagnostic accuracy and understanding of the pathogenesis of lymphoproliferative diseases (LPDs) occurring in immunosuppressed transplant recipients (post-transplantation LPD), clonality of Epstein-Barr virus-induced human LPDs in mice with severe combined immunodeficiency was examined by analyzing: 1) human immunoglobulin genes and their products, 2) the clonality of Epstein-Barr virus DNA, and 3) genetic alteration of c-myc or bcl-2 genes. A spectrum of clonality was found in the LPDs comparable with that reported for post-transplantation LPDs, although rearrangements of c-myc or bcl-2 genes were not detected. It is confirmed that this system is useful in terms of clonality for understanding the early phases in the pathogenesis of post-transplantation LPD or LPD in immune deficient patients.

Animals↗
PubMed1992

Bone marrow transplantation for peripheral T-cell lymphoma in children and adolescents.

We report nine children with relapsed (n = 8) or high-risk (n = 1) peripheral T-cell lymphoma (PTCL) who underwent autologous (n = 6) or allogeneic (n = 3) bone marrow transplantation (BMT). These children received transplants as part of a prospective phase I/II study of thioTEPA (TT) and total body irradiation (TBI) with escalating doses of VP-16. The median age of these patients at time of BMT was 6.5 years (range 2.5 years to 14 years). Three were transplanted with active disease after failing salvage chemotherapy. Of the other six, one was transplanted in first complete remission (CR) and five in second or subsequent CR. Of these nine patients, eight are free of disease a median of 25 months after BMT (range, 6 to 48 months), with an estimated 2-year relapse-free survival (RFS) of 89%. Six of these eight patients have been followed for 12 or more months after BMT, and in each their current remission exceeds their longest previous remission duration. The toxicity of the TT/TBI +/- VP-16 regimens was significant but manageable, predominantly consisting of severe mucositis. For a comparison, we reviewed retrospective data on the six additional children and adolescents with PTCL who underwent BMT during the 3-year period preceding this phase I/II study. The median age at BMT of these six patients was 19 years (range 15.5 years to 20 years). These patients were prepared for BMT with a variety of other regimens. One had no response to BMT and the other five relapsed at 1.5 to 5 months after BMT (median, 3 months) with an RFS of 0%. Our data suggest that thioTEPA plus TBI, with or without VP-16, is an effective preparative regimen for BMT for young patients with relapsed or high-stage PTCL and leads to prolonged RFS.

Adolescent↗
PubMed1992

Recurrent abnormalities of chromosome bands 10q23-25 in non-Hodgkin's lymphoma.

Many nonrandom chromosome abnormalities have been associated with non-Hodgkin's lymphomas (NHL). Some of these are nonspecific changes seen in many different histologic subtypes. We describe a series of abnormalities of chromosome bands 10q23-25 seen in 159 consecutive NHL patients with abnormal cytogenetic findings. The proportion of karyotypes with abnormalities of 10q varied from 3% among the immunoblastic lymphomas to 67% in the diffuse large cleaved cell lymphomas. Seventeen (10.7%) had abnormalities of 10q23-25. All but one of these were B-cell tumors. The abnormalities consisted of six deletions and 11 translocations. Sixteen of the 17 patients had the 10q abnormality when cells were first karyotyped. The remaining patient acquired the 10q abnormality in the third of a series of biopsies. In the follicular histologic subtypes [follicular small cleaved cell (FSC), follicular mixed small cleaved and large cell (FM), and follicular large cell noncleaved (FL-NC)], abnormalities of 10q were found in nine patients, all in association with abnormalities of 14q32. Seven of these were associated with the t(14;18)(q32;q21). Overall, 10q23-25 abnormalities were observed in 11.9% (8/67) of low-grade [small lymphocytic (SL), FSC, and FM] lymphoma cases. DNA was available from five patients with abnormalities of 10q and was probed for rearrangements with the HOXII (TCL3) oncogene probe. As expected, we did not find such rearrangements in these five patients with B-cell tumors. Abnormalities of 10q23-25 have been reported previously in NHL but not at this frequency.

Blotting, Southern↗
PubMed1992

Immunophenotypic and genotypic characterization of lymphomatoid papulosis.

BACKGROUND: Lymphomatoid papulosis (LyP) is a chronic dermatosis that histologically resembles malignant lymphoma. Thus far, only a few cases of LyP have been characterized in detail with regard to immunophenotype, genotype, and karyotype. OBJECTIVE: Our purpose was to study seven patients with LyP and compare the results to those reported in the literature. METHODS: Skin biopsy specimens were analyzed by frozen section immunohistochemical and molecular biologic techniques. Cytogenetic analysis was also performed in three cases. RESULTS: The atypical lymphoid cells consisted of activated helper T cells; four of the seven patients had lesions with a detectable clonal T-cell population. A peripheral T-cell lymphoma developed in one patient before the emergence of a genotypically different LyP T-cell clone. Cytogenetic studies were abnormal in one case of LyP and normal in another, whereas the karyotype of the lymphoma was abnormal. CONCLUSION: LyP is a preneoplastic proliferation of activated helper T cells, which is often clonal and may regress and expand with the development of new LyP clones or lymphoma.

Adolescent↗
PubMed1992

Semen cryobanking for men with cancer--criteria change.

OBJECTIVE: To summarize pregnancies and births after the use of pretherapy cryobanked semen from men with cancer and to reassess the clinical role of semen cryobanking for these patients. DESIGN: Survey of pregnancies and births that have occurred after the use of cryobanked semen from pretherapy cancer patients. SETTING: Survey of the literature and of nine semen banks. PATIENTS: Men with testicular cancer, Hodgkin's diseases, non-Hodgkin's lymphoma, and other types of cancer who cryobanked their semen specimens before therapy. OUTCOME MEASURES: Pregnancies and births resulting from the use of cryobanked semen after artificial insemination by husband (AIH) or other assisted reproductive technology (ART) procedures. RESULTS: The use of AIH and other ART procedures have resulted in 117 documented pregnancies and 115 livebirths. CONCLUSIONS: Cryobanking of semen should be offered to all men diagnosed with cancer because such a procedure provides the only reasonable chance of establishing a pregnancy after therapy that is detrimental to fertility potential. Existing criteria for pretherapy semen cryobanking, therefore, should be revised in view of successful pregnancies even with the use of semen with low spermatozoal densities and motilities, as well as other realized clinical efficacies of ART. Conceptions have occurred after in vitro fertilization (IVF) with < 1 x 10(6) motile spermatozoa. Semen cryobanking should be offered by the attending physician as a viable option for any pretherapy male patient who has any motile sperm and considers the future possibility of having children.

Cryopreservation↗