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Biomedical subjects

S O'Brien

Publications and source records attributed to S O'Brien.

At least 109 records · Page 6Linked to original sources
PubMed1998

Transplant-lite: induction of graft-versus-malignancy using fludarabine-based nonablative chemotherapy and allogeneic blood progenitor-cell transplantation as treatment for lymphoid malignancies.

PURPOSE: To investigate the use of a nonmyeloablative fludarabine-based preparative regimen to produce sufficient immunosuppression to allow engraftment of allogeneic stem cells and induction of graft-versus-leukemia/lymphoma (GVL) as the primary treatment modality for patients with chronic lymphocytic leukemia (CLL) and lymphoma. PATIENTS AND METHODS: Fifteen patients were studied. Six patients were in advanced refractory relapse, and induction therapy had failed in two patients. Patients with CLL or low-grade lymphoma received fludarabine 90 to 150 mg/m2 and cyclophosphamide 900 to 2,000 mg/m2. Patients with intermediate-grade lymphoma or in Richter's transformation received cisplatin 25 mg/m2 daily for 4 days; fludarabine 30 mg/m2; and cytarabine 500 mg/m2 daily for 2 days. Chemotherapy was followed by allogeneic stem-cell infusion from HLA-identical siblings. Patients with residual malignant cells or mixed chimerism could receive a donor lymphocyte infusion of 0.5 to 2 x 10(8) mononuclear cells/kg 2 to 3 months posttransplantation if graft-versus-host disease (GVHD) was not present. RESULTS: Eleven patients had engraftment of donor cells, and the remaining four patients promptly recovered autologous hematopoiesis. Eight of 11 patients achieved a complete response (CR). Five of six patients (83.3%) with chemosensitive disease continue to be alive compared with two of nine patients (22.2%) who had refractory or untested disease at the time of study entry (P = .04). CONCLUSION: These findings indicate the feasibility of allogeneic hematopoietic transplantation with a nonablative preparative regimen to produce engraftment and GVL against lymphoid malignancies. The ability to induce remissions with donor lymphocyte infusion in patients with CLL, Richter's, and low-grade and intermediate-grade lymphoma is direct evidence of GVL activity against these diseases. This approach appears to be most promising in patients with chemotherapy-responsive disease and low tumor burden.

Aged↗
PubMed1998

Activity of oral and intravenous 9-aminocamptothecin in SCID mice engrafted with human leukemia.

The intravenous (i.v.) injection of the human acute myelogenous leukemia cell line KBM-3 into severe combined immune deficient (SCID) mice results in disseminated multi-organ human disease involvement in these animals which leads to their death over a defined period of time. We utilized this model of human leukemia to investigate the in vivo therapeutic efficacy of the topoisomerase I inhibitor 9-aminocamptothecin (9-AC) given by two different routes. Mice injected with KBM-3 were divided into five groups. Group 1 received only diluent and served as control. The four remaining groups were treated with 9-AC four days a week for three consecutive weeks as follows: group 2 received 1.33 mg/kg/dose, i.v.; group 3, 1.33 mg/kg/dose, orally (p.o.); group 4, 2.0 mg/kg/dose i.v. and group 5, 2.0 mg/kg/dose p.o.. All animals in the control group died from disseminated human leukemia by day 64 from grafting, with a median survival of 59 days. Eleven out of 20 treated mice survived with no evidence of disease and were sacrificed at the termination of the experiment on day 128. PCR-assisted tissue analysis for the presence of human DNA showed no evidence of human leukemia. In conclusion, 9-AC is an active agent in SCID mice engrafted with human myelogenous leukemia and should be explored in phase I-II trials. Oral and intravenous routes are equally effective.

Acute Disease↗
PubMed1998

CECA-cyclophosphamide, etoposide, carboplatin and cytosine arabinoside--a new salvage regimen for relapsed or refractory acute myelogenous leukemia.

In an effort to develop more effective therapy for patients with refractory or relapsed acute myelogenous leukemia (R-AML) we combined three drugs with proven activity in AML, that are not typically used in induction regimens, with cytosine arabinoside (ara-C). Twenty-five patients (3 primary refractory, 22 relapsed) were treated. Patients received 3 days of "CECA" therapy as follows: cyclophosphamide (CTX) 1 g/m2 i.v. over 2 hrs., etoposide (VP-16) 200 mg/m2 i.v. over 3 hr, carboplatin (CBP) 150 mg/m2 i.v. over 24 hours and ara-C 1 g/m2 over 2 hr. Peripheral circulating blasts cleared in 24 cases (96%), and marrow aplasia was achieved in 19 (76%). There were 3 complete remissions (CR), 1 patient died before day 14, 5 died aplastic 14 or more days from the start of therapy, 5 had primary resistant disease, and 10 had secondary resistance i.e., leukemia reappearing after developing aplasia and 1 was lost to follow up 6 weeks into therapy. Two of the patients achieving CR received allogeneic BMT in CR (at 18 and 22 weeks): one died of fungal infection on day 50 and the other, who had CNS involvement at relapse, is alive 24 months post transplant. Toxicity was tolerable: one patient each developed grade III diarrhea and mucositis, another had grade III cardiac toxicity, a fourth developed a grade IV bilirubin elevation. Single, 2, and 3 or more infectious episodes occurred in 10, 5 and 4 patients respectively. This regimen showed definite anti-leukemic activity: the 3 patients achieving CR were among 23 patients with a 1%, 10% or 20% expectation for second CR attainment. The CECA regimen should be investigated in better prognosis salvage groups.

Adolescent↗
PubMed1998

Chronic lymphocytic leukemia in the young patient.

Chronic lymphocytic leukemia is customarily considered a disease of the elderly. However, 10% of patients reported in a variety of clinical trials are less than 50 years of age. Because of the new approaches to treatment with purine analogs, bone marrow transplantations, and monoclonal antibodies, the time is appropriate for reconsideration to the approach to treatment of younger patients. It is now established that the characteristics which predict for prognosis in young patients are similar to those of patients who are older. However, the survival of patients younger than 55 years of age is significantly greater than those older than 55 years of age. The sex distribution appears to be similar in younger patients as with older patients. The response to treatment with purine analogs has enabled the development of procedures for autologous stem cell transplantation. Allogeneic transplantation is being used increasingly with full dose ablative approaches or modified, less intensive regimens. The new approaches to therapy hold promise for improved survival in this subset of patients. Increasingly these patients are being diagnosed at an earlier stage in association with routine physical examinations or laboratory tests for other procedures.

Adult↗
PubMed1998

Selective inhibition of cell proliferation and BCR-ABL phosphorylation in acute lymphoblastic leukemia cells expressing Mr 190,000 BCR-ABL protein by a tyrosine kinase inhibitor (CGP-57148).

The excessive proliferation of the myeloid marrow compartment in Philadelphia chromosome (Ph)-positive acute and chronic leukemias has been largely attributed to a hyperactive and autonomously acting hybrid tyrosine kinase BCR-ABL, a product of the fusion between the second exon of the c-ABL proto-oncogene and 5' portions of the BCR gene on chromosome 22. This specific molecular event, amenable to attack with specifically designed inhibitors, has recently been successfully influenced by the drug CGP-57148 in mammalian cells transfected with full-length BCR-ABL gene and expressing full-length p210Bcr-Abl protein, as well as in primary human leukemic cells expressing p210Bcr-Abl fusion protein. In view of the heterogeneity of BCR-ABL transcripts associated with various phenotypes, we investigated the effect of CGP-57148 on p190Bcr-Abl- and p210Bcr-Abl-expressing, patient-derived cell lines and primary intact blast cells. In particular, we were interested in whether the variations in molecular events and/or the phenotype of Ph-positive cells would affect their susceptibility to the specific tyrosine kinase inhibitor CGP-57148. We have demonstrated that the sensitivity of human cells with lymphoblastic immunophenotype expressing p190Bcr-Abl protein is comparable to that for leukemic myeloid cells expressing p210Bcr-Abl protein. After documenting profound and phenotype-independent suppression of both autophosphorylation and cell growth, we explored the importance of time and dose of exposure on the manifestation and stability of the induced events. Although there were variations between target cells, in vitro exposure for 24-48 h induced extensive and apparently irreversible apoptosis in BCR-ABL-expressing but not other normal or BCR-ABL-negative leukemic cells. These findings support the potential use of CGP-57148 to purge Ph-positive cells from autologous bone marrow in vitro. Another important finding was the comparable suppressive effect of temporary CGP-57148 exposure on both clonogenic KBM-5 cells and the whole cell population. Exposure time and dose appeared to be important variables among various cell types. Moreover, effective doses appeared uniformly harmless to cells lacking BCR-ABL protein functioning as tyrosine kinase. Thus, the continuous exposure of target cells, at least during the initial period of 24-48 h, may prove to be an important variable in the design of in vitro and in vivo therapy using tyrosine kinase inhibitors.

Apoptosis↗
PubMed1998

Premenstrual syndrome: diagnosis and intervention.

Premenstrual syndrome (PMS) is a recurrent disorder that occurs in the luteal phase of the menstrual cycle. It is characterized by intense physical, psychologic, and behavioral changes that interrupt interpersonal relationships and disrupt the lives of affected women. Up to 40% of women of childbearing age have some form of PMS, and up to 10% have severe signs and symptoms. There are at least four types of PMS, each with its own constellation of signs and symptoms. Related illnesses or illnesses that need to be ruled out include diabetes mellitus, thyroid dysfunction, hypoglycemia, and primary and secondary dysmenorrhea. Difficulty in identifying the exact etiology of the disorder is documented. Diagnostic issues include confusion over exact signs and symptoms, differential diagnoses, pertinent laboratory data, careful history taking, and the importance of women recording a menstrual cycle history on a calendar. Recommended first-line treatments include a diet low in salt, fat, caffeine, and sugar; an aerobic exercise regimen; and stress reduction via changes in lifestyle.

Adolescent↗
PubMed1997

Implications of potential cure in acute myelogenous leukemia: development of subsequent cancer and return to work.

Chemotherapy produces extended remissions, and potential cures, in a small minority of patients with acute myeloid leukemia (AML). We explored whether potentially cured patients were at increased risk of subsequent invasive cancer and were able to return to work. Potentially cured patients were defined as those in first or second complete remission (CR) for at least 3 years based on hazard rates for recurrence or death in CR, which declined sharply after this time. Patients who received allogeneic marrow transplant were excluded. We used questionnaires, phone contact, and chart review to obtain information about subsequent cancer and work status. The number of patients who developed invasive cancer was compared with the number expected based on age, gender, and years of follow-up using the Connecticut Tumor Registry. A total of 215 patients met our criteria for potential cure: 203 in first CR and 12 in second CR (of 1,663 treated between 1965 and December, 1992). At a median of 9.2 years from first or second CR, 163 (76%) remain alive in CR. Fifteen patients developed 18 invasive cancers (expected number of patients, 8.8; observed/expected, 1.70; 95% CI, 0.96 to 2.84; P = . 06). Patients initially treated between 1973 to 1979, patients above the potentially cured cohort's median age of 40 years, and those who presented with abnormalities of chromosomes 5 and/or 7 were more likely to develop subsequent cancer, whereas the observed/expected ratio for younger patients was 1.05 (95% CI, 0.13 to 3.80; P = .56). Seventy-four percent of the patients who were working full-time and who were under age 50 at time of treatment for AML have been working full-time in the last 6 months. Only 17 of 56 patients who are currently not working cited physical limitation as the reason. Patients with potentially cured AML are likely to be able to return to work, and at least if younger do not, on average, have an increased risk of invasive cancer.

Age Factors↗
PubMed1997

Thiotepa for the treatment of thrombocythemia in patients with Philadelphia chromosome positive chronic myelogenous leukemia.

BACKGROUND: Patients with chronic myelogenous leukemia (CML) occasionally experience persistent thrombocythemia despite having adequate white blood cell (WBC) counts. Trimethylenethiophosphoramide (thiotepa) is an alkylating agent that significantly inhibits platelet production. METHODS: The authors studied the effects of thiotepa in eight patients with CML with persistent thrombocythemia. All patients had adequate WBC counts while receiving therapy for leukemia. The median age of the patients was 58 years, and all had received at least 2 prior therapy regimens for CML. Thiotepa was administered by intravenous infusion at a dose of 75 mg/m2 once every 2 to 3 weeks; doses were adjusted according to hematologic response. RESULTS: Seven patients were evaluable for response to thiotepa. Their pretreatment median platelet count was 1215 x 10(9)/L. After receiving the first dose, 6 patients (86%) had favorable responses as the median platelet count dropped to 348 x 10(9)/L (P = 0.02). However, all the patients' platelet counts returned to near baseline values after the first course. Patients required a median of three courses to achieve stable platelet counts near the normal range. In 4 patients (57%), administration of thiotepa was discontinued because of a stable normal platelet count after a median of 7.5 courses; 1 patient was still receiving treatment at last follow-up (18 courses) and 2 patients stopped receiving treatment after their disease progressed to the blastic phase. Toxicity was mostly hematologic, with neutropenia (< or = 1 x 10(9)/L) occurring during 5 of the 64 courses (8%) administered but only 1 patient's course was complicated by fever. CONCLUSIONS: The authors conclude that thiotepa is useful in controlling thrombocythemia in CML patients who have elevated platelet counts despite having adequate WBC counts.

Adult↗
PubMed1997

Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy.

The immune-mediated graft-versus-leukemia effect is important to prevent relapse after allogeneic progenitor cell transplantation. This process requires engraftment of donor immuno-competent cells. The objective of this study was to assess the feasibility of achieving engraftment of allogeneic peripheral blood or bone marrow progenitor cell after purine analog containing nonmyeloablative chemotherapy. Patients with advanced leukemia or myelodysplastic syndromes (MDS) who were not candidates for a conventional myeloablative therapy because of older age or organ dysfunction were eligible. All patients had an HLA-identical or one-antigen-mismatched related donor. Fifteen patients were treated (13 with acute myeloid leukemia and 2 with MDS). The median age was 59 years (range, 27 to 71 years). Twelve patients were either refractory to therapy or beyond first relapse. Eight patients received fludarabine at 30 mg/m2/d for 4 days with idarubicin at 12 mg/m2/d for 3 days and ara-c at 2 g/m2/d for 4 days (n = 7) or melphalan at 140 mg/m2/d (n = 1). Seven patients received 2-chloro-deoxyadenosine at 12 mg/m2/d for 5 days and ara-C 1 at g/m2/d for 5 days. Thirteen patients received allogeneic peripheral blood stem cells and 1 received bone marrow after chemotherapy. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and methyl-prednisolone. Treatment was generally well tolerated, with only 1 death from multiorgan failure before receiving stem cells. Thirteen patients achieved a neutrophil count of greater than 0.5 x 10(9)/L a median of 10 days postinfusion (range, 8 to 17 days). Ten patients achieved platelet counts of 20 x 10(9)/L a median of 13 days after progenitor cell infusion (range, 7 to 78 days). Eight patients achieved complete remissions (bone marrow blasts were < 5% with neutrophil recovery and platelet transfusion independence) that lasted a median of 60 days posttransplantation (range, 34 to 170+ days). Acute GVHD grade > or = 2 occurred in 3 patients. Chimerism analysis of bone marrow cells in 6 of 8 patients achieving remission showed > or = 90% donor cells between 14 and 30 days postinfusion, and 3 of 4 patients remaining in remission between 60 and 90 days continued to have > or = 80% donor cells. We conclude that purine analog-containing nonmyeloablative regimens allow engraftment of HLA-compatible hematopoietic progenitor cells. This approach permits us to explore the graft-versus-leukemia effect without the toxicity of myeloablative therapy and warrants further study in patients with leukemia who are ineligible for conventional transplantation with myeloablative regimens either because of age or concurrent medical conditions.

Acute Disease↗
PubMed1997

Clinical and economic outcomes of expanded criteria donors in renal transplantation.

Although graft and patient survival rates were similar between recipients of kidneys from ECDs and non-ECDs, transplantation with organs from ECDs was significantly more expensive. Multivariate analysis using stepwise linear regression demonstrated length of stay to be a strong proxy for total hospital costs. Inherent tensions between the overall good clinical outcomes associated with the use of ECDs in terms of graft survival and the markedly increased costs seen with these organs are evident.

Age Factors↗
PubMed1997

ED use by older victims of family violence.

STUDY OBJECTIVE: To determine the nature and frequency of ED use by victims of physical elder abuse. METHODS: Community-dwelling victims of abuse were identified through a state elderly protective service program independent of the health care system in a geographic area served by two EDs. ED records were reviewed and abstracted to determine if and how victims used emergency services. RESULTS: During a 7-year period, 182 elderly victims of physical abuse were identified in the catchment area of the study, and 114 (62.6%) had been seen in one or both EDs at least once during a 5-year "window" surrounding the initial identification of abuse. These 114 individuals accounted for 628 visits (median 3, range 1-46); 30.6% of visits resulted in a hospital admission. An ordinal system was used that assigned a probability of any single ED visit being referable to abuse; 37.8% of subjects had at least one visit categorized as being of high probability, and 66% of subjects had at least one visit that resulted in an injury-related chief symptom or ICD-9 discharge diagnosis. CONCLUSION: Elder abuse victims have substantial interactions with EDs and these visits frequently result in admission. Strategies that identify elder abuse in less acute settings and effectively address the needs of victims would improve quality of life and likely result in substantial savings in health care expenditures.

Aged↗
PubMed1997

Cytogenetics of chronic myelogenous leukaemia.

The Philadelphia (Ph) chromosome is present in the leukaemic cells of most patients with chronic myelogenous leukaemia. Variant translocations occur in 10% of patients but breakpoints on chromosomes 9 and 22 remain the same, so prognosis of these patients is unchanged. Clonal evolution is infrequent in chronic phase and its significance depends on the specific chromosome involved, the number of metaphases affected and the timing in the chronic phase. The majority of patients in blastic phase demonstrate clonal evolution; three specific abnormalities (+Ph, +8 and isochromosome 17q) are present in 70% of patients. Loss of the Ph chromosome on therapy is associated with prolonged survival. For monitoring these events conventional G-band cytogenetics (CG) is essential at presentation to characterize the Disease cytogenetically, while fluorescence in situ hybridization (FISH) on hypermetaphase preparations (hypermetaphase FISH (HMF)) is important for establishing the specific frequency of Ph+ cells. During treatment FISH on interphase cells (I-FISH) can monitor the level of Ph+ cells in circulation, while CG may be used to identify any suspected clonal evolution. Where I-FISH is negative, HMF is essential to evaluate minimal residual disease.

Chromosomes, Human, Pair 12↗
PubMed1997

Cognitive-motor learning in Parkinson's disease.

Procedural learning deficits are common in Parkinson's disease (PD), but contradictory results have been reported in rotary pursuit learning. This article compared rotary pursuit learning in 2 nondemented PD groups and 2 normal control (NC) groups, using a between-subjects group design in which 3 rotation speeds were presented either randomly or in blocks. The pattern of learning differed between the randomized and the blocked conditions in the NC, but not in the PD groups. Learning was impaired in the PD group in the random condition only. Memory, visuospatial, or executive skills were not associated with the PD group's poorer learning in the randomized context. Results show that procedural learning deficits are not universal with basal ganglia abnormalities but rather depend on the specific cognitive requirements of the learning context.

Aged↗