PubMed Health⌕ Search

Biomedical subjects

A Keating

Publications and source records attributed to A Keating.

At least 55 records · Page 3Linked to original sources
PubMed1999

High treatment-related mortality in cardiac amyloid patients undergoing autologous stem cell transplant.

Dose-intensive chemotherapy with PBSC support was recently reported to be feasible in cardiac amyloidosis with some patients achieving post-transplant improvement in performance status. At our center, 11 patients with symptomatic primary systemic amyloidosis and predominant cardiac involvement confirmed by biopsy or increased wall thickness on echocardiogram were evaluated for high-dose therapy. The average time from diagnosis to referral was 11 months (4-26 months). Of the 11 patients, two were not candidates for high-dose therapy, based on poor performance status. The remaining nine patients proceeded to PBSC collection. Three patients died during the mobilization period: two of rapid atrial fibrillation, and the third secondary to progressive heart failure. Six patients proceeded to transplantation. However, one died of sudden cardiac arrest the day of melphalan administration, one following hypotension related to stem cell infusion, and one of hypotensive shock the day following stem cell infusion. Three patients recovered and left the hospital, but one died of a cardiorespiratory event at home within 6 weeks of discharge. Both surviving patients demonstrate objective improvement. A decision to use high-dose therapy and stem cell support in cardiac amyloidosis must balance the substantial morbidity of the procedure with the potential benefits. Transplant regimens should avoid cardiotoxic agents such as cyclophosphamide and DMSO and patients should receive anti-arrythmic therapy.

Amyloidosis↗
PubMed1999

Intensification of the stem cell transplant induction regimen results in increased treatment-related mortality without improved outcome in multiple myeloma.

Randomized trials conducted by the Intergroupe Française du Myelome (IFM) demonstrate that the use of high-dose chemotherapy (HDCT) and stem cell transplantation (SCT) improves event-free (EFS) and overall survival (OS) in younger patients with multiple myeloma (MM). Nevertheless, current HDCT regimens remain inadequate as all patients ultimately relapse following SCT. In an attempt to improve the OS of MM patients post-SCT we used an escalated HDCT regimen incorporating both intensified melphalan (160 mg/m2) and fractionated total body irradiation (12 Gy) to maximize the dose response of myeloma cells to these agents and included infusional etoposide 60 mg/kg in an attempt to eradicate clonal B cells potentially contributing to the myeloma clone. One hundred patients with MM received this intensified SCT regimen. The 100-day treatment-related mortality was 12% predominantly reflecting the development of interstitial pneumonitis (IP) in 28% of patients of whom 7/28 (25%) died. The predicted 5-year OS and EFS following the diagnosis of MM were 60% and 35%, respectively. The median OS from the time of transplant is 41 months and the median EFS is 28 months. More than two prior chemotherapy regimens, previous radiation therapy (RT) and the presence of an abnormal karyotype involving chromosomes 11 or 13 were significantly predictive of poor outcome. Interferon maintenance was not associated with improved outcome. Intensification of the HDCT regimen utilizing etoposide together with escalated melphalan and TBI increases morbidity and mortality without increasing OS beyond that reported with less toxic regimens.

Adult↗
PubMed1999

Autotransplants for Hodgkin's disease in patients never achieving remission: a report from the Autologous Blood and Marrow Transplant Registry.

PURPOSE: Hodgkin's disease patients who never achieve complete remission with conventional chemotherapy (i.e., those with primary induction failure) have a poor prognosis. Some subjects who receive high-dose therapy with autologous hematopoietic progenitor-cell infusion experience prolonged progression-free survival. PATIENTS AND METHODS: Detailed records from the Autologous Blood and Marrow Transplant Registry (ABMTR) on 122 Hodgkin's disease patients who failed to achieve complete remission after one or more conventional therapy regimens and subsequently received an autotransplant between 1989 and 1995 were reviewed. RESULTS: Median age was 27 years (range, 7 to 57 years). Median time from diagnosis to transplantation was 14 months (range, 5 to 38 months). Most patients received high-dose chemotherapy without radiation for pretransplantation conditioning (n = 107). The regimen most frequently used was cyclophosphamide, carmustine, and etoposide (n = 47). Fifteen patients received total-body irradiation (n = 15). The graft consisted of bone marrow (n = 86), blood stem cells (n = 25), or both (n = 11). The 100-day mortality was 12% (95% confidence interval, 7% to 19%). Sixty patients (50%) were considered to have achieved complete remission after autotransplantation; 37 of these had negative imaging studies, whereas scan abnormalities of unknown significance persisted in 23 patients. Twenty-seven patients (22%) had no response or progressive disease after transplantation. Probabilities of progression-free and overall survival at 3 years were 38% (95% confidence interval, 28% to 48%) and 50% (95% confidence interval, 39% to 60%), respectively. In multivariate analysis, "B" symptoms at diagnosis and poor performance score at transplantation were adverse prognostic factors for outcome. CONCLUSION: Autotransplants should be considered for patients with Hodgkin's disease who do not achieve complete remission with conventional therapy.

Adolescent↗
PubMed1998

A multicenter study of platelet recovery and utilization in patients after myeloablative therapy and hematopoietic stem cell transplantation.

An observational study was conducted at 18 transplant centers in the United States and Canada to characterize the platelet recovery of patients receiving myeloablative therapy and stem cell transplantation and to determine the clinical variables influencing recovery, determine platelet utilization and cost, and incidence of hemorrhagic events. The study included 789 evaluable patients transplanted in 1995. Clinical, laboratory, and outcome data were obtained from the medical records. Variables associated with accelerated recovery in multivariate models included (1) higher CD34 count; (2) higher platelet count at the start of myeloablative therapy; (3) graft from an HLA-identical sibling donor; and (4) prior stem cell transplant. Variables associated with delayed recovery were (1) prior radiation therapy; (2) posttransplant fever; (3) hepatic veno-occlusive disease; and (4) use of posttransplant growth factors. Disease type also influenced recovery. Recipients of peripheral blood stem cells (PBSC) had faster recovery and fewer platelet transfusion days than recipients of bone marrow (BM). The estimated average 60-day platelet transfusion cost per patient was $4,000 for autologous PBSC and $11,000 for allogeneic BM transplants. It was found that 11% of all patients had a significant hemorrhagic event during the first 60 days posttransplant, contributing to death in 2% of patients. In conclusion, clinical variables influencing platelet recovery should be considered in the design and interpretation of clinical strategies to accelerate recovery. Enhancing platelet recovery is not likely to have a significant impact on 60-day mortality but could significantly decrease health care costs and potentially improve patient quality of life.

Antigens, CD34↗
PubMed1998

High level engraftment of NOD/SCID mice by primitive normal and leukemic hematopoietic cells from patients with chronic myeloid leukemia in chronic phase.

We have previously shown that intravenously injected peripheral blood (PB) or bone marrow (BM) cells from newly diagnosed chronic myeloid leukemia (CML) patients can engraft the BM of sublethally irradiated severe combined immunodeficient (SCID) mice. We now report engraftment results for chronic phase CML cells in nonobese diabetic (NOD)/SCID recipients which show the superiority of this latter model. Transplantation of NOD/SCID mice with 7 to 10 x 10(7) patient PB or BM cells resulted in the continuing presence of human cells in the BM of the mice for up to 7 months, and primitive human CD34+ cells, including those detectable as colony-forming cells (CFC), as long-term culture-initiating cells, or by their coexpression of Thy-1, were found in a higher proportion of the NOD/SCID recipients analyzed, and at higher levels than were seen previously in SCID recipients. The human CFC and total human cells present in the BM of the NOD/SCID mice transplanted with CML cells also contained higher proportions of leukemic cells than were obtained in the SCID model, and NOD/SCID mice could be repopulated with transplants of enriched CD34+ cells from patients with CML. These results suggest that the NOD/SCID mouse may allow greater engraftment and amplification of both normal and leukemic (Ph+) cells sufficient for the quantitation and characterization of the normal and leukemic stem cells present in patients with CML. In addition, this model should make practical the investigation of mechanisms underlying progression of the disease and the development of more effective in vivo therapies.

Adult↗
PubMed1998

Delphi-panel analysis of appropriateness of high-dose therapy and bone marrow transplants in adults with acute lymphoblastic leukemia in first remission.

BACKGROUND: There is controversy over whether high-dose therapy and a bone marrow transplant is better than conventional-dose chemotherapy in adults with acute lymphoblastic leukemia (ALL) in first remission. This decision may depend on which type of donor is available: an HLA-identical sibling, an alternative donor transplant (HLA-matched related or unrelated people other than HLA-identical siblings), or autotransplant. OBJECTIVE: To determine the appropriate use of high-dose therapy and bone marrow transplants in ALL in first remission. Develop a treatment algorithm. PANELISTS: Nine leukemia experts from diverse geographic sites and practice settings. EVIDENCE: Boolean MEDLINE searches of acute lymphoblastic leukemia and chemotherapy and/or transplants. CONSENSUS PROCESS: We used a modified Delphi-panel group judgment process. Age, white blood cell (WBC) count, cytogenetics and immune type were permuted to define 48 clinical settings. Each panelist rated appropriateness of high-dose therapy and a transplant versus conventional-dose chemotherapy on a 9-point ordinal scale (1, most inappropriate; 9, most appropriate) considering three types of donors: (1) HLA-identical siblings; (2) alternative donors; and (3) autotransplants. An appropriateness index was developed based on median rating and amount of disagreement. Relationship of appropriateness indices to the permuted clinical variables was considered by analysis of variance and recursive partitioning. Preference between donor types was analyzed by comparing mean appropriateness indices of comparable settings and a treatment algorithm was developed. CONCLUSIONS: In people with an HLA-identical sibling donor, transplants were rated appropriate in those with unfavorable cytogenetics and uncertain in all other settings. An HLA-identical sibling donor was always preferred to an alternative donor or autotransplant. In people without an HLA-identical sibling but with an alternative donor, this type of transplant was rated appropriate in those with unfavorable cytogenetics. However, an autotransplant was preferred over an alternative donor transplant in all other settings where a transplant was rated uncertain. In people without an HLA-identical sibling or alternative donor, autotransplants were rated uncertain in all settings except in those with not unfavorable cytogenetics, WBC < 100 x 10(9) l(-1) and T- or pre-B-cell type where they were rated inappropriate.

Adolescent↗
PubMed1998

Granulocyte-macrophage colony-stimulating factor-associated histiocytosis and capillary-leak syndrome following autologous bone marrow transplantation: two case reports and a review of the literature.

Bone marrow (BM) histiocystosis in association with the administration of granulocyte-macrophage colony-stimulating factor (GM-CSF) is a rare phenomenon with few published cases. We report two cases of BM histiocystosis in patients with Hodgkin's disease treated with GM-CSF after autologous bone marrow transplantation. Both patients also developed clinical features of capillary leak syndrome, another rare complication of GM-CSF administration. GM-CSF-induced histiocystosis should now be considered in the differential diagnosis of delayed engraftment post-autotransplant.

Adult↗
PubMed1998

New clonal karyotypic abnormalities acquired following autologous bone marrow transplantation for acute myeloid leukemia do not appear to confer an adverse prognosis.

We undertook a retrospective review of all 76 patients with AML transplanted between August 1986 and March 1995 at our center. All patients received melphalan (140-160 mg/m2), etoposide (60 mg/kg) and total body irradiation. All patients had bone marrow cytogenetic analysis at regular intervals following ABMT. The primary study end point was the development of the new cytogenetic abnormalities. Secondary end points were the development of myelodysplasia (MDS) or AML. Sixty-two of 77 patients were alive at least 6 months post transplant. Cytogenetic abnormalities developed in 7/62 patients (11%) following ABMT. No patients demonstrated MDS or AML. At a median of 30 months after development of the cytogenetic abnormality, only one patient developed features suggestive but not diagnostic of MDS. All seven patients remain alive and leukemia-free up to 70 months after detection of the abnormal clone. There was no increased incidence of cytogenetic abnormalities developing in patients receiving a purged autograft. New cytogenetic abnormalities are frequent following ABMT for AML but do not appear to predict development of myelodysplasia or acute myeloid leukemia. These abnormalities may relate to use of total body radiation as part of the high-dose therapy.

Adolescent↗
PubMed1998

Safety of therapeutic anticoagulation in patients with multiple myeloma receiving autologous stem cell transplantation.

The use of autologous stem cell transplantation (ASCT) for the treatment of multiple myeloma is increasing. Anticoagulation may be required during ASCT for conditions such as Hickman line thrombosis. The safety of anticoagulation in patients receiving ASCT is unknown. We report a retrospective case-control study of the safety of therapeutic anticoagulation in patients with multiple myeloma receiving ASCT. We identified 10 patients who received therapeutic anticoagulation during ASCT. For each of the 10 cases identified, two matched controls were selected. As a primary endpoint, bleeding complications were assessed. Secondary endpoints included survival, length of hospital stay, transfusion requirements, grade 4 toxicity, and days to platelet engraftment. Bleeding complications were not significantly different between patients receiving anticoagulation and controls (P = 0.3). Three of 10 anticoagulated patients and two of 20 controls had a bleeding complication. Mortality during admission was similar (P = 1.0); one anticoagulated patient and one control died of sepsis. A trend towards increased median number of platelet transfusions in the heparinized patients was seen (27 vs 12 units, P = 0.055), reflecting the higher transfusion threshold chosen for the anticoagulated patients. The other secondary endpoints did not differ between patients and controls. In this case control study, bleeding was not significantly increased in the group receiving anticoagulation during ASCT. This group electively received more units of platelets than controls. Thus, therapeutic anticoagulation can be managed with minimal increased toxicity during ASCT.

Adult↗
PubMed1998

Expression of p210 and p190 BCR-ABL due to alternative splicing in chronic myelogenous leukaemia.

The hallmark of chronic myelogenous leukaemia (CML) is the presence of the Philadelphia chromosome and its resultant fusion message, BCR-ABL, and fusion protein, p210. Patients with CML in blast crisis, or with Philadelphia positive acute lymphoblastic leukaemia (ALL), can have a smaller BCR-ABL fusion transcript possessing only the first exon of BCR fused to ABL. This smaller transcript encodes a 190 kD protein which is more strongly transforming than the p210 protein derived from the larger CML-associated transcript. We performed RT-PCR on samples from CML patients in chronic phase to determine the frequency and mechanism of p190 and p210 co-expression and to see if this correlated with clinical indices. We examined the peripheral blood or marrow of 67 patients with CML and found that 35 of them expressed both transcripts whereas the remainder expressed the p210-encoding transcript exclusively. Additional PCR products of an intermediate size were also frequently detected and have been isolated and sequenced. Data from two of these products indicate that they are the result of alternative splicing and include variable combinations of BCR exons. We believe that the expression of the p190-encoding transcript in the chronic phase of CML is also due to alternative splicing. A comparison of patients co-expressing the p190- and p210-encoding transcripts with those patients who expressed only the p210-encoding transcript detected significantly higher white blood cell (WBC) counts and blast cell counts at time of testing as well as significantly higher white blood cell counts at diagnosis.

Adolescent↗
PubMed1998

Ovarian function after autologous bone marrow transplantation.

PURPOSE: To determine the frequency of return of ovarian function after autologous bone marrow transplantation (ABMT), and the major factors that predict recovery. PATIENTS AND METHODS: Records of 200 consecutive women who underwent ABMT at the University of Toronto Autologous Blood and Marrow Program (Toronto, Canada) were reviewed. Seventeen patients met the inclusion criteria, which were (1) alive at the time of evaluation, (2) disease-free at least 18 months after transplantation, (3) age younger than 50 years at transplantation, and (4) premenopausal before transplantation. Recovery of ovarian function was determined by pregnancy or regular menses, with no menopausal symptoms and an estradiol level greater than 20 pmol/L off hormonal therapy. RESULTS: All 17 patients became menopausal immediately after ABMT. Five patients (29%) recovered ovarian function a median of 24 months post-ABMT (range, 6 to 48 months). The median age at transplantation of women with restored ovarian function was 19 years (range, 19 to 28 years) versus 30 years (range, 22 to 48 years) for those who did not regain function. Younger age at transplantation predicted ovarian recovery (P = .03) by means of a log-rank test. Only one of five women who regained ovarian function received total-body irradiation (TBI) compared with five of 12 women who did not. Univariate analysis suggested a trend for TBI to predict a sustained loss of ovarian function (P = .067). The number of regimens of induction or salvage chemotherapy that contained an alkylating agent ranged from none to five and was not predictive (P = .45). CONCLUSION: All women became menopausal after ABMT but 29% recovered ovarian function. Younger age at transplantation predicted return of ovarian function, whereas TBI may have had a negative effect.

Actuarial Analysis↗
PubMed1997

Salvage chemotherapy with mini-BEAM for relapsed or refractory non-Hodgkin's lymphoma prior to autologous bone marrow transplantation.

BACKGROUND: The role of intensive chemotherapy with autologous blood and marrow transplantation (ABMT) for patients with relapsed or refractory intermediate grade non-Hodgkin's lymphoma has recently been established. However, conventional dose salvage chemotherapy is frequently used to determine chemotherapy sensitivity and reduce tumor bulk prior to intensive therapy. Different salvage regimens have been proposed but none appears significantly superior. The purpose of this study was to determine the efficacy of mini-BEAM salvage chemotherapy in patients referred for AMBT and to define prognostic factors of response. PATIENTS AND METHODS: One hundred four patients referred for consideration of AMBT after failure of primary anthracycline-based chemotherapy received BCNU 60 mg/m2 day 1, etoposide 75 mg/m2 day 2-5, ara-C 100 mg/m2 q12 h day 2-5, melphalan 30 mg/m2 day 6 (mini-BEAM) until maximum tumor reduction. Median age was 52 (range 18-65), 57% had failed to achieve a complete response (CR) to doxorubicin-based chemotherapy at diagnosis and only 13% had a previous CR lasting > 12 months. Seventy-six received mini-BEAM as first salvage chemotherapy. RESULTS: The overall response rate (RR) was 37% (95% confidence interval (CI) 28-46%) with 12 patients achieving CR and 25 achieving PR. The response rate among patients treated as first salvage was 43% compared to 20% for patients who had failed to respond to a previous salvage regimen. Only 15% of patients who failed to respond to mini-BEAM responded to another conventional dose salvage regimen. Thirty-eight of 104 patients ultimately demonstrated sufficient response to proceed to ABMT. Actuarial survival at four years is 22% for all 104 patients, and 36% for those who went on to AMBT. For those who were not transplanted, four-year survival was 18%. B symptoms and tumor burden at relapse were significant predictors of response to mini-BEAM in multivariate analysis, and identified a poor prognosis group of patients unlikely to be cured by the approach. CONCLUSIONS: Mini-BEAM does not appear to be a superior salvage regimen in this high-risk group of relapsed or refractory NHL patients for whom ABMT was the ultimate treatment intention. Only one-third of patients referred for ABMT ultimately proceed to transplant; alternative treatment strategies should be developed for those with a low likelihood of cure by this approach.

Adolescent↗
PubMed1997

Granulocyte-macrophage colony-stimulating factor/interleukin-3 fusion protein versus granulocyte-macrophage colony-stimulating factor after autologous bone marrow transplantation for non-Hodgkin's lymphoma: results of a randomized double-blind trial.

PURPOSE: A phase III trial to compare PIXY321 with granulocyte-macrophage colony-stimulating factor (GM-CSF) following high-dose therapy and autologous bone marrow transplant (ABMT) was conducted to evaluate the time to hematopoietic recovery. PATIENTS AND METHODS: One hundred seventy-seven patients with non-Hodgkin's lymphoma (NHL) receiving ABMT were randomized to receive either PIXY321 750 micrograms/m2/d divided into two subcutaneous (SC) doses or GM-CSF 250 micrograms/m2/d as a 2-hour intravenous (IV) infusion starting on day 0 post-ABMT for a maximum of 28 days. RESULTS: The median time to reach an absolute neutrophil count (ANC) > or = 500/microL in the PIXY321 group was 17 days versus 19 days in the GM-CSF group (P = .07) and the median time to reach platelet transfusion independence in the PIXY321 group was 25 days versus 23 days in the GM-CSF group (P = .30). The toxicity profiles of the two agents appeared to be equivalent with the exception of more patients in the PIXY321 group with a rash (64%) compared with the GM-CSF group (48%) (P = .028). A logistic regression model identified the use of a non-total-body irradiation (TBI) regimen and/or receipt of unpurged marrow and a body-surface area greater than 2.0 m2 as predictive of faster neutrophil engraftment, and those three factors, as well as the receipt of < or = two prior chemotherapy regimens as predictive for rapid platelet engraftment. CONCLUSION: There was a trend toward a slight improvement in neutrophil engraftment post-ABMT with the PIXY321 administered by an SC route compared with GM-CSF administered by an IV route. However, no differences could be identified between the two agents with respect to the time to platelet transfusion independence. Patient, regimen, and graft characteristics were most predictive of the engraftment tempo.

Adolescent↗
PubMed1997

Human gene therapy.

Human gene therapy and its application for the treatment of human genetic disorders, such as cystic fibrosis, cancer, and other diseases, are discussed. Gene therapy is a technique in which a functioning gene is inserted into a human cell to correct a genetic error or to introduce a new function to the cell. Many methods, including retroviral vectors and non-viral vectors, have been developed for both ex vivo and in vivo gene transfer into cells. Vectors need to be developed that efficiently transfer genes to target cells, and promoter systems are required that regulate gene expression according to physiologic needs of the host cell. There are several safety and ethical issues related to manipulating the human genome that need to be resolved. Current gene therapy efforts focus on gene insertion into somatic cells only. Gene therapy has potential for the effective treatment of genetic disorders, and gene transfer techniques are being used for basic research, for example, in cancer, to examine the underlying mechanism of disease. There are still many technical obstacles to be overcome before human gene therapy can become a routine procedure. The current human genome project provides the sequences of a vast number of human genes, leading to the identification, characterization, and understanding of genes that are responsible for many human diseases.

Genetic Diseases, Inborn↗
PubMed1997

A phase I study of interleukin-6 after autologous bone marrow transplantation for patients with poor prognosis Hodgkin's disease.

We performed a pilot study of human recombinant IL-6 (SDZ ILs 969) in 6 patients with poor prognosis Hodgkin's disease following autologous bone marrow transplantation (ABMT) to determine its safety and tolerability. IL-6 was administered the day following bone marrow infusion by subcutaneous injection once daily at a dose of 1 micro/kg/day to 3 patients and 2.5 microg/kg/day to 3 patients and was continued for 6 weeks or until platelet engraftment (>50 x 10(9)/L independent of transfusion). No severe or life threatening toxicities were seen at either dose level. A reversible elevation in alkaline phosphatase occurred in 4 patients and all patients complained of headache, myalgias, and fever. Gastrointestinal toxicity was low, grade 3-4 mucositis occured less frequently than in similarly-treated historical controls receiving GM-CSF. Serum concentrations of other cytokines such as IL-3 and G-CSF after ABMT differed from results obtained in transplant recipients given GM-CSF. The median time to an ANC >0.5 x 10(9)/L was 25.5 days and to a platelet count of >20 x 10(9)/L independat of transfusion was 35.5 days. Engraftment was no different from controls. Five patients relapsed at a median of 5 months post-ABMT and four remain alive at a median of 12 months post-ABMT. We conclude that IL-6 administration is safe and well tolerated in patients following ABMT. Further efforts to evaluate its effect on hematopietic recovery as well as relapse following transplantation in a larger patient series are warranted.

Adult↗