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Biomedical subjects

A D Ho

Publications and source records attributed to A D Ho.

At least 55 records · Page 3Linked to original sources
PubMed2002

Stable mixed chimerism after T cell-depleted allogeneic hematopoietic stem cell transplantation using conditioning with low-dose total body irradiation and fludarabine.

Although reduced intensity conditioning (RIC) before allografting is associated with low treatment-related morbidity and mortality, graft-versus-host disease (GVHD) remains a significant complication of hematopoietic stem cell transplantation (HSCT). T cell depletion (TCD) has been successfully used in conventional allotransplantation to reduce the incidence of GVHD, but was associated with an increased rate of engraftment failure. In a small cohort of six patients at high risk of developing GVHD we have determined whether sustained engraftment could be achieved using reduced intensity conditioning and T cell depletion in combination. All patients engrafted and 5/6 developed high levels (i.e. > or =95%) of donor chimerism, even though mismatched related or matched unrelated donors were used. Only one patient developed acute GVHD, as he received donor lymphocyte infusions (DLI) for relapse. In summary, TCD might be a useful prophylactic tool in RIC allogeneic HSCT. Although TCD after RIC might be associated with high relapse rate, as 5/6 patients are not in remission, this combined strategy might be appropriate for patients with less aggressive malignant or non-malignant diseases in which high transplant-related morbidity and mortality is not acceptable.

Adult↗
PubMed2002

Long-term outcome in acute myelogenous leukemia autografted with mafosfamide-purged marrow in a single institution: adverse events and incidence of secondary myelodysplasia.

We have analyzed the long-term outcome and toxicities in 98 patients with high-risk acute myelogenous leukemia (AML) who were treated with autologous bone marrow transplantation (ABMT) and monitored for a median observation period of 11.67 years. Between 1983 and 1994, 98 patients in our institution in first or second and higher complete remission (CR) underwent total body irradiation and high-dose cyclophosphamide prior to ABMT purged with mafosfamide. Twenty-seven out of the 90 evaluable patients (30%) were alive and in continuous CR for a median of 11.67 years (range, 6.39-15.53) after ABMT and could be considered as 'cured'. Among the 90 patients, 39 were transplanted at first CR and had a significantly higher survival rate than those transplanted at > or = 2 CR. Younger patients (<40 years) had a better prognosis and patients with FAB M1-4 had a more favorable outcome than those with M5. Long-term complications included four patients with cardiac complications, two with renal insufficiency. Five developed HCV infections, four myelodysplastic syndrome. The incidence of cataract among the long-term survivors was 44.4%. Therefore, a significant number of adult patients with AML in first CR derived long-term benefit from ABMT, despite the risks of a few long-term complications and of MDS (4.4%).

Adolescent↗
PubMed2002

Continuous infusion of ceftazidime for patients with breast cancer and multiple myeloma receiving high-dose chemotherapy and peripheral blood stem cell transplantation.

This prospective study was performed to examine the safety and efficacy of a continuous infusion of ceftazidime in patients who developed febrile neutropenia after high-dose chemotherapy (HDCT) and autologous peripheral blood stem cell transplantation (PBSCT) and to determine if the underlying disease represents a risk factor for infectious complications. From September 1995 to May 2000, 55 patients with breast cancer (BC, group I, 54 females, one male) and 32 patients with multiple myeloma (MM, group II, 10 female, 22 male) were included in this study. The febrile patients received a 2 g intravenous bolus of ceftazidime, followed by a 4 g continuous infusion over 24 h using a portable infusion pump. If the fever persisted for 72 h a glycopeptide antibiotic was added. The median age was 42 years (range 22-59) in group I and 52 years (range 35-63) in group II. Thirty-five BC patients (64%) and 20 MM patients (63%) responded to the monotherapy with ceftazidime. After addition of a glycopeptide antibiotic, an additional 11 BC patients vs 10 MM patients became afebrile. The causes of fever in group I were fever of unknown origin (FUO) in 49 patients, microbiologically documented infection (MDI) in five patients, and clinically documented infection (CDI) in one patient. The causes of fever in group II were FUO in 22 patients, MDI in eight patients and CDI in two patients. Forty-one febrile episodes in BC patients (75%) and 22 episodes in the MM patients (69%) were successfully managed by out-patient treatment, resulting in a saving of an average of 20 days of inpatient care. Significantly more episodes of MDI and CDI occurred in patients with MM (P = 0.05). The results indicate that BC and MM patients with febrile neutropenia after HDCT and PBSCT can be treated as outpatients with close monitoring to ensure safety. This approach represents a better use of health care resources.

Adult↗
PubMed2002

Less intense conditioning with fludarabine, cyclophosphamide, idarubicin and etoposide (FCIE) followed by allogeneic unselected peripheral blood stem cell transplantation in elderly patients with leukemia.

The objective of this study was to assess toxicity and feasibility of achieving engraftment of allogeneic blood progenitor cells following nonmyeloablative conditioning according to the FCIE protocol (fludarabine 25 mg/m(2)/day, days -7 to -3; cyclophosphamide 200 mg/m(2)/day, days -7 to -3; idarubicin 12 mg/m(2)/day, days -7 to -5; etoposide 250 mg/m(2)/day, days -4 to -3) in elderly patients with leukemia. Eleven patients were included in the study: six patients with acute myeloid leukemia (AML) in complete remission (CR); three patients with refractory or relapsed AML; one patient with chronic myeloid leukemia; one patient with acute lymphoblastic leukemia. The median age of the patients was 62 years. All patients received blood progenitor cells from an HLA-identical sibling with 8.8 x 10(6) CD34(+) cells/kg (median; range 4.7 to 26.2 x 10(6)/kg) and 5.5 x 10(8) CD3(+)cells/kg (median; range 4.5 to 7.9 x 10(8)/kg). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and three courses of methotrexate. The median duration of white blood cell counts <1 x 10(9)/l was 17 days and of platelet counts <50 x 10(9)/l 20 days. In two patients acute GVHD grade I occurred. Nine of 10 patients analyzed developed mixed chimerism. Of seven patients transplanted in CR, three remained in CR 19 to 31 months after transplantation. Three patients with refractory leukemia did not achieve CR, while the patient with relapsed AML achieved a 3rd CR. After a median follow-up time of 22 months, chronic GVHD was mild and limited. The data from this pilot study in elderly patients with leukemia show that the combination of primarily immunosuppressive (FC) and antileukemic (IE) drugs for nonmyeloablative conditioning has moderate nonhematological toxicity and allows engraftment of allogeneic blood progenitor cells.

Adult↗
PubMed2002

Centrosome replication, genomic instability and cancer.

Karyotypic alterations, including whole chromosome loss or gain, ploidy changes, and a variety of chromosome aberrations are common in cancer cells. If proliferating cells fail to coordinate centrosome duplication with DNA replication, this will inevitably lead to a change in ploidy, and the formation of monopolar or multipolar spindles will generally provoke abnormal segregation of chromosomes. Indeed, it has long been recognized that errors in the centrosome duplication cycle may be an important cause of aneuploidy and thus contribute to cancer formation. This view has recently received fresh impetus with the description of supernumerary centrosomes in almost all solid human tumors. As the primary microtubule organizing center of most eukaryotic cells, the centrosome assures symmetry and bipolarity of the cell division process, a function that is essential for accurate chromosome segregation. In addition, a growing body of evidence indicates that centrosomes might be important for initiating S phase and completing cytokinesis. Centrosomes undergo duplication precisely once before cell division. Recent reports have revealed that this process is linked to the cell division cycle via cyclin-dependent kinase (cdk) 2 activity that couples centriole duplication to the onset of DNA replication at the G(1)/S phase transition. Alterations in G(1)/S phase regulating proteins like the retinoblastoma protein, cyclins D and E, cdk4 and 6, cdk inhibitors p16(INK4A) and p15(INK4B), and p53 are among the most frequent aberrations observed in human malignancies. These alterations might not only lead to unrestrained proliferation, but also cause karyotypic instability by uncontrolled centrosome replication. Since several excellent reports on cell cycle regulation and cancer have been published, this review will focus on the role of centrosomes in cell cycle progression, as well as causes and consequences of aberrant centrosome replication in human neoplasias.

Aneuploidy↗
PubMed2002

Alterations of the cyclin D1/pRb/p16(INK4A) pathway in multiple myeloma.

The retinoblastoma protein (pRb), p16(INK4A), D-type cyclins, and their partners cyclin-dependent kinase (CDK) 4 and 6 constitute a G(1) regulatory pathway commonly targeted in tumorigenesis. Several malignancies show a reciprocal correlation between genetic alterations of single members of the pRb pathway. Therefore, we determined the frequency of Rb deletions and cyclin D1 alterations by fluorescence in situ hybridization as well as 5' CpG island hypermethylation of the p16(INK4A)gene using methylation-specific polymerase chain reaction in bone marrow mononuclear cells from 82 individuals with plasma cell disorders. Alterations in at least one of the components of the pathway were found in 75%. Cyclin D1 translocations or amplifications were detected in 14/82 (17.1%), Rb deletions at 13q14 in 23/82 (28%) of the cases, including three (3.6%) homozygous deletions. p16(INK4A) was hypermethylated in 33/57 (57.9%) of the samples. Further analysis revealed a highly significant correlation between cyclin D1 alterations and extramedullar or leukemic myeloma manifestations (P = 0.014; Fisher's test). Whereas Rb deletions seemed to occur alternatively to cyclin D1 alterations, no reciprocal correlation was found between p16(INK4A) hypermethylations and cyclin D1 or Rb locus aberrations. Cyclin D1 locus alterations and Rb deletions were associated with a significantly worse prognosis whereas p16(INK4A) hypermethylation had no impact on survival. We conclude that cyclin D1 and Rb aberrations seem to occur as alternative events in plasma cell malignancies and contribute to clinical course and prognosis. In contrast, although p16(INK4A) hypermethylation is frequent, inactivation of p16(INK4A) seems not to be involved in the pathogenesis of plasma cell disorders.

Chromosome Aberrations↗
PubMed2002

Nonmyeloablative stem cell transplantation in adults with high-risk ALL may be effective in early but not in advanced disease.

The feasibility of nonmyeloablative stem cell transplantation (NST) was evaluated in 22 adults with high-risk ALL. 16/22 patients had advanced disease and 11/22 had Ph+ ALL. Eleven patients received NST as first stem cell transplantation (SCT). Eleven patients had relapses after allogeneic or autologous SCT and underwent a salvage NST. 18/22 patients (82%) engrafted after NST. 13/16 patients (81%) with active disease reached complete remission (CR). 11 of 13 patients developed GVHD. After first NST 10/11 patients (91%) engrafted. Six of seven patients with active disease reached CR. Three of five relapsing patients reached subsequent CR after donor lymphocyte infusions, termination of immunosuppression or imatinib. Three of 11 patients (27%) are alive in CR 5 to 30 months after NST. Eight of 11 patients have died, 3/8 from leukemia and 5/8 from transplant-related causes. After salvage NST, 8/11 patients (73%) engrafted. Seven of nine patients with active disease reached CR. Only one of 11 patients transplanted, who was in CR before undergoing salvage NST is alive 19 months after NST. Five of 11 have died from leukemia, one of 11 after graft failure and four of 11 from transplant-related causes. Four of 22 patients (18%) are alive in CR 5, 14, 19 and 30 months after NST. NST is feasible in adults with high risk ALL. However, transplant-related mortality remains high and only patients transplanted in CR seem to have long-term disease-free survival.

Adult↗
PubMed2002

Quality of life and rehabilitation in social and professional life after autologous stem cell transplantation.

BACKGROUND: In this study, we report on quality of life (QOL) in long-term survivors after high-dose chemotherapy and autologous stem cell transplantation (ASCT) with special emphasis on rehabilitation in social and professional life. PATIENTS AND METHODS: The European Organization of Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 questionnaire was sent by mail to 391 patients 1 to 12 years (median 31 months) after ASCT. The procedure was performed at our institution alone. Of the questionnaires 78% were returned and evaluated. RESULTS: Of the 238 patients who had an occupation and were employed, 132 (55%) have returned full time (68%) or part time (32%) to their previous occupation. A total of 139 patients (46%) received a 3- to 4-week inpatient rehabilitation treatment in specialised institutions following ASCT. Employment status post-transplantation and QOL were similar in these patients as compared with those who did not participate in rehabilitation programmes. Of the 304 evaluable patients, 39% reported physical problems that reduced their satisfaction with sex and intimacy. The general QOL was significantly reduced in the first year, improved with interval to transplant, and reached the level of the general population after 4 years. CONCLUSIONS: Our retrospective data showed that ASCT has a significant, unfavourable impact on QOL, including reintegration into social and professional life. Most symptoms and scores returned to normal after 3 to 6 years. Employment status and QOL were similar in patients who participated in a rehabilitation programme and those who did not.

Adolescent↗
PubMed2002

Characteristics associated with long-term progression-free survival following high-dose chemotherapy in metastatic breast cancer and influence of chemotherapy dose.

BACKGROUND: The purpose of this study was to characterize long-term progression-free survivors (LTPFS) of metastatic breast cancer (MBC) following high-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) and to assess the influence of chemotherapy dose in order to identify patients who derive major benefit from this approach. PATIENTS AND METHODS: We compared patient and tumor characteristics of 16 LTPFS with the characteristics of 118 MBC patients who received HDCT with ASCT at our institution between 1992 and 2000. To estimate the cumulative dose of chemotherapy received, the summation dose intensity product (SDIP) of the different chemotherapy regimens was calculated as recently described by Hryniuk et al. The SDIP of the induction regimens was added to that of the HDCT regimens to yield the total SDIP of the chemotherapy received. Multivariate analysis was performed to describe the influence of the total SDIP and other prognostic factors on progression-free survival (PFS). RESULTS: LTPFS were mostly < or = 50 years of age and had limited, chemotherapy-sensitive, hormone-responsive MBC. Due to an apparent dose-survival relationship, an increase by 10 units (U) in the SDIP increased the PFS time by 3 months. Independent predictors of an improved PFS were positive estrogen receptors (P = 0.001), positive combined hormone receptors (P = 0.020), and a complete remission/no evidence of disease status after HDCT (P < 0.001). In patients who had a disease-free interval (DFI) >24 months after primary surgery, an SDIP of >55 U was independently associated with a longer PFS [hazard ratio (HR) = 2.73; 95% confidence interval 1.29-5.81; P = 0.009]. CONCLUSION: HDCT can achieve long-term PFS in young MBC patients with limited, hormone-responsive and chemotherapy-sensitive disease. After a DFI >24 months, a longer PFS is associated with a higher chemotherapy dose as measured by SDIP. These retrospective analyses suggest SDIP might be a tool for studying cumulative dose as a determinant of outcome of MBC chemotherapy. Thus far, however, we cannot clearly identify any subgroup of MBC patients in whom HDCT with ASCT is of particular benefit.

Adult↗
PubMed2002

Functional characterization of podia formation in normal and malignant hematopoietic cells.

Hematopoietic cells extend multiple podia of yet unknown function. Our morphological studies using scanning electron microscopy and functional studies using time-lapse video microscopy suggest that podia formed by CD34+ hematopoietic stem cells (HSC) on the bone marrow stroma component fibronectin are characteristic of lamellipodia at the leading edge and uropodia at the trailing edge, cytoskeletal structures that have previously been shown to be responsible for cell locomotion of lymphocytes. In the leukemic cells studied here, stroma-derived factor-1alpha (SDF-1alpha) led to a significant eightfold increase in transmigration (BCR-ABL-positive BV173 leukemia cell line; P<0.05) and podia formation in all BCR-ABL-positive leukemic cell lines studied (BV173, K562, 32Dp210) and in two of three BCR-ABL-negative lines (HL60, 32D, not KG1a). We could show that SDF-1alpha exposure led to a down-regulation of the gene expression of the chemokine receptors CCR4, CXCR4, and CXCR5, which are associated with cell motility and podia formation, indicating a negative feedback control. In BCR-ABL-positive leukemic cells, the effects of SDF-1alpha on podia formation and cell migration were independent of BCR-ABL-tyrosine kinase activity. Our data are compatible with the hypothesis that formation of specific podia by hematopoietic cells is associated with egression of these cells from the bone marrow.

Cell Movement↗
PubMed2002

Reduced non-relapse mortality after reduced intensity conditioning in advanced chronic lymphocytic leukemia.

We studied in 30 patients with progressive or relapsing chronic lymphocytic leukemia (CLL) if hematopoietic stem cell transplantation (HSCT) after conditioning with fludarabine, busulfan and ATG is effective and if treatment related mortality can be reduced compared to myeloablative conditioning regimens. Patients had 15 matched related and 15 matched unrelated donors. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine alone or a combination with "short course" methotrexate or mycophenolate mofetil. The median follow-up is 24 months. At last follow up 11 patients were in complete and 13 in partial remission. Six patients had stable or progressive disease. Late complete remissions occurred up to one year after transplantation and the number of patients with CR is still increasing. Four patients died due to treatment related complications resulting in a probability of treatment-related mortality of 15% (CI 95%, 1% to 29%) at 2 years. The probability of overall survival and progression free survival at two years was 79% and 61%, respectively. In conclusion, HSCT after reduced conditioning may lower the treatment-related toxicity and has the capacity to induce complete remissions.

Busulfan↗
PubMed2001

Anti-CD20 antibody as consolidation therapy in a patient with primary plasma cell leukemia after high-dose therapy and autologous stem cell transplantation.

In multiple myeloma (MM), circulating malignant B cells are proposed as the proliferative compartment of the disease. In view of the close relationship between multiple myeloma and primary plasma cell leukemia (PCL), an anti-CD20 antibody treatment might also be considered as consolidation for patients with PCL. A 55-year-old patient diagnosed with PCL achieved complete remission after autologous transplantation. A total of four weekly courses of rituximab (375 mg/m(2)) were administered. Prior to antibody therapy, CD20+ cells comprised 22.6% of the mononuclear cells in peripheral blood (PB) assessed by flow cytometry and were enriched by magnetic activated cell sorting (MACS). In the enriched CD20+ fraction, 0.093% clonotypic cells were detected using a quantitative polymerase chain reaction (PCR) assay based on limiting dilutions. The proportion of clonotypic cells was 0.034% in PB and 0.032% in bone marrow (BM). Rituximab depleted CD20+ cells completely in PB and BM. Tumor load in PB and BM at day 40 and in PB at day 70 did not change in comparison to prior to therapy (0.037% in PB, 0.026% in BM). At day 90, the tumor load increased to 0.066% in PB. At day 120, the patient relapsed with 0.65% CD38++/CD138+/CD20- plasma cells and furthermore no CD20+ B cells in PB. The expansion of plasma cells was accompanied by an increase in the tumor load in both compartments (PB: 0.65%, BM: 1.8%). The accumulation of plasma cells during disease progression without the reappearance of CD20+ cells did not sustain the role of circulating clonotypic B cells as proliferative compartment in our patient. However, it cannot be excluded that rituximab was not able to eradicate malignant B cells, which subsequently contributed to relapse.

Antibodies, Monoclonal↗
PubMed2001

Salvage therapy for multiple myeloma with thalidomide and CED chemotherapy.

The feasibility and efficacy of a combination of thalidomide, cyclophosphamide, etoposide, and dexamethasone were studied in 56 patients with poor-prognosis multiple myeloma. Of 50 patients evaluable for response, 4% achieved complete response (CR), 64% partial response (PR), 18% minimal response (MR), 6% stable disease (SD), and 8% progressive disease (PD), resulting in an objective response rate (> or = MR) of 86.0% (76.7% overall objective response rate in intent-to-treat analysis; n = 56). Subsequent to successful remission induction, 18 patients received autologous or allogeneic stem cell transplantation. The median progression-free survival in all patients was 16 months. The median overall survival time could not be calculated, since the last observed death occurred after 16 months of follow-up (median follow-up of 14 months) with a corresponding estimated survival probability of 55%. Severe adverse effects (World Health Organization III/IV) included infectious complications (35.7%) and cardiovascular events (7.1%). The data suggest that Thal improves antitumor activity of salvage chemotherapy regimens in poor-prognosis multiple myeloma.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

Angiogenesis in hematologic malignancies.

Angiogenesis, defined as the blood vessel generation from preexisting blood vessels, was found to play an important role in the progression of solid tumors. In addition, bone marrow-derived endothelial precursor cells may contribute to tumor angiogenesis. Recently angiogenesis induction was described in several hematologic neoplasms as leukemia, lymphoma, myelodysplastic syndrome and multiple myeloma (MM). Clinical angiogenesis research also termed as angiodiagnosis has established the prognostic relevance of markers of angiogenesis e.g., microvessel density and circulating levels of angiogenic peptides. Development of antiangiogenic treatment for hematologic neoplasms has recently been sparked by the success of Thalidomide (Thal) which has antiangiogenic properties in MM. Antiangiogenic treatment strategies are now being tested in clinical trials on several types of hematologic neoplasms.

Angiogenesis Inhibitors↗
PubMed2001

Rituximab therapy of patients with B-cell chronic lymphocytic leukemia.

Rituximab (IDEC-C2B8) is a chimeric antibody that binds to the B-cell surface antigen CD20. Rituximab has significant activity in follicular non-Hodgkin lymphomas. Much less is known about the effects in chronic lymphocytic leukemia (CLL). We have initiated a phase II trial to evaluate the efficacy and safety of rituximab in patients with CD20+ pretreated CLL. To avoid the rituximab-associated toxicity, we restricted the tumor cell load, as measured by the number of circulating lymphocytes and the spleen size, in the first 2 cohorts of patients included in the study. Patients received 4 intravenous infusions of 375 mg/m2 once a week over a period of 1 month. Of the 28 patients evaluable for response, 7 patients showed a partial remission (National Cancer Institute criteria) lasting for a median of 20 weeks, with 1 patient still in remission after 71 weeks. Based on lymphocyte counts only, we found at least a 50% reduction of lymphocyte counts lasting for at least 4 weeks in 13 (45%) of 29 patients. Fifteen patients from 3 institutions were monitored for the immunophenotype profile of lymphocyte subsets. The number of CD5+CD20+ cells decreased significantly and remained low until day 28 after therapy. T-cell counts were not affected. With the exception of one rituximab-related death, adverse events in the remaining patients were mild. The results suggest that rituximab has clinical activity in pretreated patients with B-CLL. Toxicity is tolerable. Response duration after withdrawal of rituximab is rather short. Therefore, other modes of application and the combination with other agents need to be tested.

Adolescent↗