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Biomedical subjects

A Goy

Publications and source records attributed to A Goy.

18 recordsLinked to original sources
PubMed2005

Reduced-intensity allogeneic stem cell transplantation in relapsed and refractory Hodgkin's disease: low transplant-related mortality and impact of intensity of conditioning regimen.

A total of 40 patients with relapsed/refractory Hodgkin's disease (HD) underwent reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (allo-SCT) from an HLA-identical sibling (n=20) or a matched unrelated donor (n=20). The median age was 31 years (range 18-58). Disease status at allo-SCT was refractory relapse (n=14) or sensitive relapse (n=26). The conditioning regimens were fludarabine-cyclophosphamide+/-antithymocyte globulin (n=14), a less intensive regimen, and fludarabine-melphalan (FM) (n=26), a more intensive one. The two groups had similar prognostic factors. The median time to neutrophil recovery (ie absolute neutrophil count >/=500/microl) was 12 days (range 10-24). The median time to platelet recovery (ie platelet count >/=20 000/microl) was 17 days (range 7-132). Day 100 and cumulative (18-month) transplant-related mortalities (TRMs) were 5 and 22%. Twenty-four patients (60%) are alive (14 in complete remission or complete remission, unconfirmed/uncertain) with a median follow-up of 13 months (4-78). In all, 16 patients expired (TRM n=8, disease progression n=8). FM patients had better overall survival (73 vs 39% at 18 months; P=0.03), and a trend towards better progression-free survival (37 vs 21% at 18 months; P=0.2). RIC allo-SCT is feasible in relapsed/refractory HD patients with a low TRM. The intensity of the preparative regimen affects survival.

Adolescent↗
PubMed2002

Irinotecan in relapsed or refractory non-Hodgkin's lymphomas. Indications of activity in a phase II trial.

Because irinotecan (CPT-11, Camptosar) is a topoisomerase I inhibitor with a broad spectrum of antitumor clinical activity, we investigated its activity in relapsed or refractory non-Hodgkin's lymphomas (NHLs). Irinotecan at 300 mg/m2 i.v. was administered every 21 days with intensive loperamide management of diarrhea. Responders received up to six treatment cycles. Of 44 registered patients, 32 are evaluable for response. Seventeen patients had received one previous regimen, and 15 patients had received two. Disease was refractory to the regimen preceding irinotecan in 12 patients. At baseline, serum lactate dehydrogenase levels were high in 47% (14/30), and beta-2-microglobulin levels were higher than 3.0 mg/L in 29% (8/28) of patients. Responses were seen in 12 of 32 (38%) patients (95% confidence interval [CI] = 21%-56%). Response rates were 43% for seven indolent (95% CI = 10%-82%), 0% for three mantle cell (95% CI = 0%-71%), 44% for 18 relapsed aggressive (95% CI = 22%-69%), and 20% for five refractory aggressive NHLs (95% CI = 1%-72%). Grade 3/4 toxicities included myelosuppression, neutropenic fever, and diarrhea. Irinotecan appears active and relatively well tolerated in patients with relapsed aggressive or indolent NHL. Accrual to this study is continuing for better determination of response rates in all histologic subtypes of NHL.

Adult↗
PubMed2001

Fludeoxyglucose positron emission tomography in the diagnosis of giant cell arteritis.

We describe a case in which fludeoxyglucose F 18 positron emission tomography (PET) led directly to the diagnosis of giant cell arteritis in an elderly woman with a fever of unknown origin. The patient presented with a 3-month history of fatigue, fever, headache, visual disturbance, jaw claudication, and anemia. A computed tomographic scan showed an anterior mediastinal mass that was suspected of being malignant. A fludeoxyglucose F 18 PET scan performed for preoperative evaluation identified striking uptake of fludeoxyglucose F 18 in the walls of the entire aorta, left main coronary artery, and subclavian, carotid, and common iliac arteries bilaterally, suggestive of an arteritis, a diagnosis subsequently confirmed by the findings of an arterial biopsy. Her erythrocyte sedimentation rate was 129 mm/h. There was normalizaton of the PET scan 2 weeks following treatment with prednisolone. This case suggests that fludeoxyglucose F 18 PET contributes to the noninvasive diagnosis of giant cell arteritis, as well as to the evaluation of the extent of disease, response to therapy, and disease recurrence.

Aged↗
PubMed2001

A 2-step comprehensive high-dose chemoradiotherapy second-line program for relapsed and refractory Hodgkin disease: analysis by intent to treat and development of a prognostic model.

Salvage of patients with relapsed and refractory Hodgkin disease (HD) with high-dose chemoradiotherapy (HDT) and autologous stem cell transplantation (ASCT) results in event-free survival (EFS) rates from 30% to 50%. Unfortunately, the reduction in toxicity associated with modern supportive care has improved EFS by only 5% to 10% and has not reduced the relapse rate. Results of a comprehensive 2-step protocol encompassing dose-dense and dose-intense second-line chemotherapy, followed by HDT and ASCT, are reported. Sixty-five consecutive patients, 22 with primary refractory HD and 43 with relapsed HD, were treated with 2 biweekly cycles of ifosfamide, carboplatin, and etoposide (ICE). Peripheral blood progenitor cells from responding patients were collected, and the patients were given accelerated fractionation involved field radiotherapy (IFRT) followed by cyclophosphamide-etoposide and either intensive accelerated fractionation total lymphoid irradiation or carmustine and ASCT. The EFS rate at a median follow-up of 43 months, as analyzed by intent to treat, was 58%. The response rate to ICE was 88%, and the EFS rate for patients who underwent transplantation was 68%. Cox regression analysis identified 3 factors before the initiation of ICE that predicted for outcome: B symptoms, extranodal disease, and complete remission duration of less than 1 year. EFS rates were 83% for patients with 0 to 1 adverse factors, 27% for patients with 2 factors, and 10% for patients with 3 factors (P <.001). These results compare favorably with other series and document the feasibility and efficacy of giving uniform dose-dense and dose-intense cytoreductive chemotherapy and integrating accelerated fractionation radiotherapy into an ASCT treatment program. This prognostic model provides a basis for risk-adapted HDT.

Adolescent↗
PubMed2001

Establishment of a human cell line (SKI-DLCL-1) with a t(1;14)(q21;q32) translocation from the ascites of a patient with diffuse large cell lymphoma.

Cytogenetic abnormalities at chromosome 1q21 are among the most common second genetic events observed in Non-Hodgkin's Lymphomas and have prognostic significance. Recently, BCL9 has been cloned from a pre-B-cell lymphoblastic leukemia cell line, which carried a t(1:14)(q21;q32). However, among a panel of 39 B-cell malignancies with 1q21 translocation, only two cases showed rearrangement for the BCL9 gene. We report the establishment of a new lymphoma cell line from a patient with relapsed diffuse large cell lymphoma. This cell line SKI-DLCL-1 showed cell surface antigens identical to the original tumor and demonstrated the profile of a mature B-cell phenotype: CD19 and CD20 positive, CD5 and C10 negative. It carried a t(1;14)(q21;q32) translocation identical to the original tumor. Although the clinical presentation was an isolated effusion lymphoma, studies for HIV-1, HHV8 and EBV were all negative. Southern blot analysis demonstrated that BCL9 was not rearranged in the SKI-DLCL-1 cell line. In addition, the BCL9 gene was not over-expressed in SKI-DLCL-1 cell line. The identification of a new locus at 1q21 will help clarify the pathogenesis of B-cell malignancies with a translocation involving this locus.

Aged↗
PubMed2000

Cloning and characterization of a Golgin-related gene from the large-scale polymorphism linked to the PML gene.

Megabase-scale mapping of the PML gene locus revealed the presence of a large-scale insertion-deletion polymorphism located 25 kb downstream of the PML gene. The polymorphism is organized as a head-to-tail tandem 25-kb repeat containing one to five units. Characterization of the first repeat unit downstream of PML revealed the presence of a gene with strong homology to a family of Golgin-related proteins. The gene, designated GLP (for Golgin linked to PML), is strongly expressed as a 6-kb transcript in normal human testis. In situ hybridization of normal human testis demonstrated that the expression of GLP was restricted to late meiotic germ cells. There was weak expression in late pachytene spermatocytes and strong expression in spermatids. GLP is 50% homologous to other Golgin-related proteins including the vesicle docking protein GM130. Southern blot hybridization of genomic DNA with a GLP probe demonstrated numerous homologous bands outside the PML locus. Three of these loci have been mapped by fluorescence in situ hybridization to chromosome loci 9q34.1, 15q11-q13, and 15q22-q24. Hybridization of a GLP cDNA probe to a zoo blot demonstrated multiple signals in nonhuman primates but not in other species and suggested the duplication of an ancestral locus around 20 million years ago.

Amino Acid Sequence↗
PubMed2000

MUC1 dysregulation as the consequence of a t(1;14)(q21;q32) translocation in an extranodal lymphoma.

Cytogenetic abnormalities at chromosome 1q21 are among the most common lesions in diffuse large-cell lymphoma and have been associated with a poor prognosis. A novel cell line, SKI-DLCL-1, was established from ascitic fluid that carries a t(1;14)(q21;q32) chromosomal translocation. Using pulsed-field gel electrophoresis, the breakpoint on the IgH locus mapped to a gamma locus between Calpha(1) and Calpha(2). A cosmid library was prepared from SKI-DLCL-1, and Cgamma-positive clones spanning the breakpoint were identified by screening with fluorescence in situ hybridization. The breakpoint occurs 860 bp downstream of the 3' UTR of the MUC1 gene. The break appears to be a staggered double-strand break consistent with an error in immunoglobulin class switching. The MUC1 gene is highly transcribed and translated, and the protein is highly glycosylated. It is postulated that MUC1 expression is brought under the control of the 3'Ealpha enhancer. MUC1 lies in a region of chromosome 1 characterized by an unusually high density of genes, with 7 known genes in a region of approximately 85 kb. To determine whether there was a pleiotropic effect of the expression of genes in the region as a consequence of the translocation, the expression of 6 additional genes was assessed. None of the other genes in this region (CLK2, propin, COTE1, GBA, metaxin, and thrombospondin 3) are overexpressed in SKI-DLCL-1. Thus, the translocation t(1;14)(q21;q32) seen in both the primary tumor and the derived cell line results in the marked overexpression of MUC1 without affecting the expression of other genes in the region. (Blood. 2000;95:2930-2936)

Ascites↗
PubMed2000

A novel gene STORP (STOmatin-Related Protein) is localized 2 kb upstream of the promyelocytic gene on chromosome 15q22.

We generated a 100-kb map of the region 5' of the PML (promyelocytic leukemia) gene on human chromosome 15q22 and identified a new gene provisionally named STORP for stomatin-related protein. The STORP gene is positioned 2 kb upstream of the PML gene in a head-to-head configuration, and contains 7 exons spanning a genomic region of about 11 kb. There is an open reading frame of 398 amino acids, which would encode a protein of 45 kD. Northern blot analysis demonstrated that the STORP gene has a ubiquitous pattern of expression similar to that of the PML gene. Hybridization of STORP cDNA probe to genomic DNA from other species demonstrated that the STORP gene is conserved among mammalian vertebrates and that the physical linkage with PML is conserved in mice. Unlike PML, the STORP gene is not induced by interferon alpha (IFNalpha), and thus can be distinctly regulated from the PML gene. STORP is homologous to the EPB72 gene coding for the erythrocyte band 7 integral membrane protein or stomatin, which is deficient in a certain form of hereditary stomatocytosis. The function of STORP is unknown. Further study will focus on studying its potential role in red cell function and disorders.

Amino Acid Sequence↗
PubMed2000

Physical linkage of the lysyl oxidase-like (LOXL1) gene to the PML gene on human chromosome 15q22.

A contig was constructed centered on the PML (promyelocytic leukemia) gene. Using an exon-trapping approach to identify potential genes from a pool of cosmids located 5' of the PML gene, four exons were identified that showed 100% sequence homology with the previously cloned lysyl oxidase-like (LOXL1) gene. An exon probe identified a single transcript of 2.4 kb on a multitissue Northern blot with a pattern identical to the one reported for the LOXL1 gene. Pulsed-field gel electrophoresis showed comigrating bands for both the PML cDNA and LOXL1 probes, demonstrating a physical linkage between these two genes. These data provide physical mapping information to complement the previous cytogenetic localization of LOXL1.

Blotting, Southern↗
PubMed1999

Ifosfamide, carboplatin, and etoposide: a highly effective cytoreduction and peripheral-blood progenitor-cell mobilization regimen for transplant-eligible patients with non-Hodgkin's lymphoma.

PURPOSE: To evaluate a chemotherapy regimen that consisted of ifosfamide administered as an infusion with bolus carboplatin, and etoposide (ICE) supported by granulocyte colony-stimulating factor (G-CSF) for cytoreduction and stem-cell mobilization in transplant-eligible patients with primary refractory or relapsed non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: One hundred sixty-three transplant-eligible patients with relapsed or primary refractory NHL were treated from October 1993 to December 1997 with ICE chemotherapy at Memorial Sloan-Kettering Cancer Center. Administration of three cycles of ICE chemotherapy was planned at 2-week intervals. Peripheral-blood progenitor cells were collected after cycle 3, and all patients who achieved a partial response (PR) or complete response (CR) to ICE chemotherapy were eligible to proceed to transplantation. Event-free and overall survival, ICE-related toxicity, and the number of CD34(+) cells collected after treatment with ICE and G-CSF were evaluated. RESULTS: All 163 patients were assessable for response, and there was no treatment-related mortality. A major response (CR/PR) was evident in 108 patients (66.3%); 89% of the responding patients underwent successful transplantation. Patient who underwent transplantation and achieved a CR to ICE had a superior overall survival to that of patients who achieved a PR (65% v 30%; P =.003). The median number of CD34(+) cells/kg collected was 8.4 x 10(6). The dose-limiting toxicity of ICE was hematologic, with 29.4% of patients developing grade 3/4 thrombocytopenia. There were minimal nonhematologic side effects. CONCLUSION: ICE chemotherapy, with ifosfamide administered as a 24-hour infusion to decrease CNS side effects, and the substitution of carboplatin for cisplatin to minimize nephrotoxicity, is a very effective cytoreduction and mobilization regimen in patients with NHL. Furthermore, the quality of the clinical response to ICE predicts for posttransplant outcome.

Adolescent↗
PubMed1995

The PML gene is linked to a megabase-scale insertion/deletion restriction fragment length polymorphism.

The PML gene located on chromosome band 15q22 is involved with the RAR alpha locus (17q21) in a balanced reciprocal translocation uniquely observed in acute promyelocytic leukemia. Physical mapping studies by pulsed-field gel electrophoresis revealed that the PML gene is flanked by two CpG islands that are separated by a variable distance in normal individuals. Several lines of evidence demonstrate that this is the consequence of a large insertion/deletion polymorphism linked to the PML locus: (1) overlapping fragments obtained with a variety of rare-cutting restriction enzymes demonstrated the same variability in distance between the flanking CpG islands; (2) mapping with restriction enzymes insensitive to CpG methylation confirmed that the findings were not a consequence of variable methylation of CpG dinucleotides; (3) the polymorphism followed a Mendelian inheritance pattern. This polymorphism is localized 3' to the PML locus. There are five common alleles, described on the basis of BssHII fragments, ranging from 220 to 350 kb with increments of approximately 30 kb between alleles. Both heterozygous (61%) and homozygous (39%) patterns were observed in normal individuals. Megabase-scale insertion/deletion restriction fragment length polymorphisms are very rare and have been described initially in the context of multigene families. Such structures have been also reported as likely regions of genetic instability. High-resolution restriction mapping of this particular structure linked to the PML locus is underway.

Alleles↗
PubMed1995

Clinical and molecular characterization of a rare syndrome of acute promyelocytic leukemia associated with translocation (11;17).

Analysis of a variant translocation t(11;17) in a case of acute promyelocytic leukemia (APL) led to discovery of a novel zinc finger gene, PLZF, fused to the retinoic acid receptor-alpha (RAR alpha) gene. We reviewed the clinical and molecular features of five additional patients with t(11;17)-associated APL. The clinical course of three patients was characterized by early death and three experienced disseminated intravascular coagulation. Morphologically all of the patients fell in a unusual morphologic spectrum of APL, with features intermediate between M2 and M3 AML. All six patients had PLZF-RAR alpha gene fusion as detected by reverse transcription/polymerase chain reaction assay, Southern blotting, or pulsed-field gel electrophoresis. Five of the six patients failed to achieve complete remission after initial chemotherapy or differentiation therapy with all-trans retinoic acid (ATRA). A sixth patient responded to initial chemotherapy, but on relapse failed to respond to ATRA. When tested in vitro, cultured cells from three of the patients failed to differentiate in response to ATRA. APL associated with t(11;17) and fusion of the PLZF and RAR alpha genes is a discrete clinico-pathologic syndrome with a distinctly worse prognosis than t(15;17) APL.

Adult↗
PubMed1993

High doses of intravenous recombinant erythropoietin for the treatment of anaemia in myelodysplastic syndrome.

We studied the efficacy of high doses (100,000 IU intravenously (IV)/twice a week) of human recombinant erythropoietin (rHuEpo) in patients with transfusion dependent myelodysplastic syndromes (MDS). Rationale for such dose of IV Epo was the poor in vitro response of MDS erythroid progenitors (CFU-E) to physiological concentrations of Epo, and the usual high endogenous serum Epo levels of MDS patients. Seventeen patients (nine males, eight females) were included, five refractory anaemia (RA), six RA with blasts excess (RAEB), five RA with ringed sideroblasts (RARS). Tolerance was good, except in three patients who experienced severe flu-like syndrome after Epo injection. None of the patients showed hypertension or developed anti rHuEpo antibodies. Three patients (17.6%) with RAEB had 35-60% reduction of transfusion requirements. No progression of disease occurred. Percentage of erythroblasts, endogenous baseline Epo level and in vitro cultures of erythroid progenitors did not correlate with response to Epo treatment. This study shows that very high IV doses induce only seldom and partial improvement in the status of transfusion dependent MDS. This rate of response, not higher than described with lower dosage, probably represents the maximum expectable response to rHuEpo in this category of patients.

Adult↗
PubMed1992

Cyclic AMP upregulates mRNA and surface expression of IL-2R alpha p55(Tac) in normal human NK cell clones.

The effects of cAMP upon cell proliferation, cytotoxic activity, and regulation of IL-2R expression was investigated in normal human, IL-2-dependent natural killer (NK) cell clones. We report here that addition to the cultures of Bt2cAMP, a cell permeant analogue of cAMP, results in inhibition of IL-2-dependent proliferation, as assessed by [3H]Thymidine incorporation, in both NK and T cell clones. In addition, Bt2cAMP was shown to block the cytotoxic activity of NK cell clones at the level of the lytic phase. Contrasting with these inhibitory effects, cAMP induces an upregulation of the membrane expression of the IL-2R alpha chain (p55, Tac) in normal NK cell clones, which correlates with an accumulation of Tac mRNA. This is clearly at variance with T cell clones in which no such effect of cAMP alone is observed. In both cell types however, cAMP appears to synergize with IL-2 to increase IL-2R alpha mRNA expression. In addition, we demonstrate, using a cDNA probe to the IL-2R beta, that expression of this second component of the high affinity IL-2R, does not appear to be co-regulated together with IL-2R alpha in response to cAMP or/and IL-2 in cultured NK cells. Thus the effects of cAMP on human NK cell clones are complex. cAMP is inhibitory of proliferation and cytolytic function, whereas it is stimulatory of IL-2R alpha expression in these cells.

Blotting, Northern↗
PubMed1992

High-dose recombinant human erythropoietin administered intravenously for the treatment of anaemia in myelodysplastic syndromes.

As the importance of recombinant human erythropoietin (r-HuEPO) therapy has been clearly demonstrated in anaemic patients with chronic renal failure (CRF), we carried out an open, non-randomized, non-placebo-controlled trial of high-dose intravenous (i.v.) r-HuEPO (100,000 U twice weekly) therapy in 14 anaemic, transfusion-dependent patients. Clinical response was defined by a rise in haemoglobin concentration to 9-11 g/dl and/or a reduction in the transfusion requirement during the treatment period compared with the 12 weeks before treatment. Eight patients completed the 12-week treatment and 4 were still under treatment, 1 at 10 weeks, 2 at 8 weeks and 1 at 4 weeks. Only those patients completing treatment were included in the efficacy evaluation. After treatment there was no significant change in haemoglobin concentrations, reticulocyte counts, or transfusion requirements. However, the number of patients included is too low to allow any definitive conclusion to be made.

Adult↗
PubMed1992

Peripheral blood stem cell collection and autografting in high risk lymphomas.

Peripheral blood stem cells (PBSC) were collected from 29 patients with high risk Hodgkin's disease (n = 3) or non-Hodgkin's lymphoma (n = 26) in partial remission or first sensitive relapse. Patients had either bone marrow involvement or hypoplastic bone marrow. The conditioning regimen prior PBSC collection included amsacrine and cytosine arabinoside (Ara-C) or Ara-C alone. PBSC collection was performed after leukocyte counts reached 1 x 10(9)/1. A good yield was obtained in 23 patients, whereas sufficient numbers of CFU-GM were not obtained in six cases. Twenty-one patients have been transplanted. All patients except one achieved bone marrow engraftment. Eight patients are in complete remission (mean duration 15 months). The estimated 2 years survival rate is 46.4% (CI 25-68%). This procedure would seems a good alternative in poor prognosis lymphomas.

Adult↗
PubMed1990

[Immunotherapy of cancer using cytokinins. Use and perspectives in lung oncology].

Progress in genetics now enables the synthesis of molecules acting on the regulation of the immune system which are called cytokines. Currently there are several cytokines, Interferon (IFN), Interleukin 2 (IL2), tumour necrosis factor (TNF) as well as haematopoietic growth factors and these are the object of study in clinical trials. Interferon has already been used in the therapy of hairy cell leukaemia, Kaposi sarcoma associated with AIDS(SIDA) and metastasis of malignant melanoma. Interleukin 2 allows for an increase in the cytotoxic activity of NK cells in producing LAK cells, the lymphocyte infiltrating the tumour (TIL). Therapeutic combinations combining IL2 associated with LAK or of TIL have been evaluated in some private studies. These treatments have shown some interesting response levels on those tumours which are usually resistant, such as malignant melanoma or carcinoma of the kidney. TNF is active in vitro on human tumours; its potential toxicity is important; it is the object of a phase 1 clinical trial. Haematopoietic growth factors, G-CSF and GM-CSF, stimulate the production of leucocytes which will be valuable to correct toxic affects on the marrow during chemotherapy. This will enable chemotherapy to be given at a high dose.

Colony-Stimulating Factors↗