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Biomedical subjects

M Keating

Publications and source records attributed to M Keating.

At least 91 records · Page 5Linked to original sources
PubMed1997

A buccal mucosal harvesting technique for urethral reconstruction.

PURPOSE: A step-by-step harvesting technique for buccal mucosa is described that maximizes graft yield while minimizing potential donor site morbidity in urethral reconstruction. MATERIALS AND METHODS: A specialized oral retractor was used to expose and retract the buccal mucosal lining of the oral cavity for graft harvesting in 12 patients. RESULTS: Adequate buccal mucosal graft size was obtained for each reconstruction. There were no oral donor site or urethral recipient site complications. CONCLUSIONS: This harvesting technique offers a simple and effective method for optimizing buccal mucosal graft harvests.

Adult↗
PubMed1997

Tallimustine, an effective antileukemic agent in a severe combined immunodeficient mouse model of adult myelogenous leukemia, induces remissions in a phase I study.

Despite progress in leukemia therapy, only 20-30% of patients with acute myelogenous leukemia (AML) are cured. 1-beta-D-arabinofuranosylcytosine- and topoisomerase II-reactive drugs are the primary therapeutic agents used. The aim of this study was to evaluate the potential activity of tallimustine in leukemia. In this study, we first investigated the efficacy and toxic effects of tallimustine, a distamycin-A derivative, in a human leukemia model in severe combined immunodeficient (SCID) mice. On the basis of its dramatic activity in this preclinical study, a Phase I study of tallimustine at a starting dose of 300 microgram/m2/day for 3 days every 3-4 weeks was conducted in patients with refractory or relapsed leukemia. In SCID mice grafted with a human myelomonocytic leukemia cell line, tallimustine resulted in complete remission of disease in most mice at tolerable dosages ranging from 0.86 to 3.0 mg/kg/day for 3 days and was combined effectively and safely with a 2-day schedule of high-dose ara-C. In the Phase I study, 26 patients with refractory or relapsed leukemia were treated. The maximum tolerated dose was 900 microgram/m2/day for 3 days every 3-4 weeks. This dose was 3 times higher than the maximum tolerated dose in solid tumors and was limited by severe mucositis. Magnesium and potassium wasting were also observed, but other side effects (fatigue and gastrointestinal) were minor. Two (8%) patients with AML achieved complete remission and two achieved hematological improvement with persistent thrombocytopenia. The results of this study indicate that tallimustine has promising activity in AML. Future studies may combine tallimustine with other agents known to be active against AML, and investigate its activity in other hematological malignancies. The recommended Phase II single-agent dose of tallimustine is 750-900 microgram/m2/day for 3 days, and combination studies may start at 50-66% of this dose schedule. The SCID mouse model of human leukemia may be promising in the preclinical evaluation and selection of potential antileukemic agents.

Adolescent↗
PubMed1996

Topotecan, a topoisomerase I inhibitor, is active in the treatment of myelodysplastic syndrome and chronic myelomonocytic leukemia.

The aim of this study was to evaluate the activity of topotecan in patients with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML). Forty-seven patients with a diagnosis of MDS (n = 22) or CMML (n = 25) were treated. The median age was 66 years. Chromosomal abnormalities were present in 70% and thrombocytopenia less than 50 x 10(3)/microL in 51%. Evaluation of outcome and of differences among subgroups was performed according to standard methods; the criteria for response were those used for acute leukemia. Topotecan was administered as 2 mg/ m2 by continuous infusion over 24 hours daily for 5 days (10 mg/m2 per course) every 3 to 4 weeks until remission, then once every month for a maximum of 12 courses. Thirteen patients (28%) achieved a complete response (CR) and six (13%) had hematologic improvement. A CR was achieved in six of 22 patients with MDS (27%) and in seven of 25 with CMML (28%). All eight patients who presented with cytogenetic abnormalities (five chromosome 5 or 7 abnormalities) who achieved CR were cytogenetically normal in CR. Characteristics for which there was evidence of association with a higher response rate were lack of prior chemotherapy, less than 10% marrow monocytes, and absence of RAS oncogene mutations. In contrast, CR rates were similar in patients with or without abnormal karyotypes. Mucositis occurred in 64% of patients (severe in 19%) and diarrhea in 32% (severe in 13%). Febrile episodes occurred in 85% of patients and documented infections in 47%. With a median follow-up duration of 8 months, the 12-month survival rate was 38%, median survival time 10.5 months, and median remission duration 7.5 months. We conclude that topotecan has significant activity in MDS and CMML, with acceptable side effects. Future studies will investigate topotecan combined with topoisomerase II reactive agents, cytarabine, or hypomethylating agents (azacytidine and decitabine).

Adult↗
PubMed1996

Apoptosis sensitivity in chronic lymphocytic leukemia is determined by endogenous endonuclease content and relative expression of BCL-2 and BAX.

Therapeutic agents used in the treatment of chronic lymphocytic leukemia (CLL) are capable of inducing apoptosis in some (but not all) patient isolates. It is not yet clear whether cells that are resistant to one agent will also be resistant to others, and the mechanisms contributing to differential apoptosis sensitivity are not known. Here we report that glucocorticoid hormone and a clinically relevant chemotherapy combination (fludarabine plus mitoxantrone) fail to induce apoptosis in four of 24 CLL patient isolates. Apoptosis resistance was associated with elevated BCL-2 and BAX expression. Interestingly, incubation in vitro led to down-regulation of BCL-2 expression in both apoptosis-sensitive and apoptosis-resistant cells, whereas parallel down-regulation of BAX occurred only in the resistant samples. Evaluation of nuclear endonuclease content indicated that all of the apoptosis-sensitive samples contained appreciable levels of activity, whereas the endonuclease was not detected in the four populations of resistant cells. Our results indicate that nuclear endonuclease activity represents an excellent prognostic indicator of CLL apoptosis sensitivity that may be controlled by differential BCL-2 family polypeptide expression and signals from the in vivo microenvironment.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1996

Acute lymphoblastic leukemia with myeloperoxidase activity.

The French-American-British (FAB) classification of acute leukemias is based on the light microscopic detection of myeloperoxidase (MPO) activity in blast cells. Cells with MPO activity in > 3% of cells are classified as acute myeloid leukemia (AML) and usually express myeloid cell surface antigens. We describe a case of acute leukemia in which the blast cells have lymphoid morphology, ultrastructure, immunophenotype, and molecular rearrangements, but express significant amounts of MPO. We discuss the incidence, features, and outcome of MPO-positive acute lymphoblastic leukemia (ALL).

Adult↗
PubMed1996

Fludarabine, mitoxantrone, and dexamethasone: an effective new regimen for indolent lymphoma.

PURPOSE: Although most patients with indolent lymphomas respond to initial therapy, virtually all experience relapse. Secondary therapy is often beneficial, but responses are rarely, if ever, durable. We conducted this phase II trail to evaluate the therapeutic efficacy and toxicity of fludarabine, mitoxantrone, and dexamethasone (FND) in patients with relapsed indolent lymphoma. PATIENTS AND METHODS: Fifty-one patients with recurrent or refractory indolent lymphoma were treated with a regimen of fludarabine 25 mg/m2/d intravenously (IV) on days 1 to 3, mitoxantrone 10 mg/m2 IV on day 1, and dexamethasone 20 mg/d IV or orally on days 1 to 5. Treatment was repeated at 4-week intervals for a maximum of eight courses. Late in the course of this trial, trimethoprim-sulfamethoxazole (TMP-SMX) was incorporated for Pneumocystis carinii (PCP) prophylaxis. RESULTS: Responses were complete (CR) in 24 patients (47%) and partial (PR) in 24 (47%). The median failure-free survival time was 21 months for CR patients and 9 months for PR patients. Notable activity of FND was seen even in the elderly, in those with high serum lactate dehydrogenase (LDH) or beta2-microglobulin levels, and in those with multiple prior treatment regimens. The predominant toxic effects were myelosuppression and infections; other toxic effects were modest. Infections occurred in 12% of courses. Almost half of the infections were proven or suspected opportunistic infections, including six cases of dermatomal herpes zoster and two cases of proven PCP pneumonia. CONCLUSION: The FND combination is highly active in patients with recurrent or relapsed indolent lymphoma and results in a high percentage of CRs. Because of the risk of opportunistic infections, we currently recommend prophylaxis with TMP-SMX and advise deletion of corticosteroids for patients who develop opportunistic infections.

Aged↗
PubMed1996

Disseminated intravascular coagulation in adult acute lymphoblastic leukemia: frequent complications with fibrinogen levels less than 100 mg/dl.

In order to establish the frequency and clinical complications of DIC during remission induction of untreated adults with acute lymphoblastic leukemia, we retrospectively reviewed the records of 125 consecutive patients treated with vincristine, doxorubicin, and dexamethasone but without L-asparaginase. DIC, defined as hypofibrinogenemia in the presence of elevated fibrin-fibrinogen degradation products, was detected at presentation in 10% of 99 and during remission induction in 67% of 58 patients who were screened for DIC. Elevated levels of D-dimers (DD) were seen in all eight patients with DIC in whom they were measured. All cases of DIC were diagnosed by the ninth day of induction and were associated with infection in 15 of 39 patients. DIC did not cause any deaths but was temporally associated with two thromboses and four hemorrhages in six of the 16 patients with fibrinogen levels < 100 mg/dl but with only one hemorrhage among 23 patients (4%) with fibrinogen levels > 100 mg/dl (P < 0.01). Heparin was not administered to any patient, whereas platelets were administered to all to maintain platelet counts > 20 x 10(9)/l. Fresh frozen plasma (FFP) and/or cryoprecipitate were administered 26 patients resulting in a contemporaneous correction of the coagulopathy and in control of hemorrhages and thromboses. We conclude that DIC is rare at presentation but common during induction of adult ALL and is frequently associated with clinical complications when fibrinogen levels are < 100 mg/dl. We recommend daily testing of fibrinogen, PT, and DD during the first 10 days of induction, and for the patients with DIC platelet transfusions to maintain counts > 20 x 10(9)/l, and when fibrinogen levels fall below 100 mg/dl transfusions of FFP and/or cryoprecipitate. Additional studies are needed to determine the optimal management of the DIC during remission induction of adult acute lymphoblastic leukemia.

Adult↗
PubMed1996

Secondary acute promyelocytic leukemia. Characteristics and prognosis of 14 patients from a single institution.

The aims of this study were to analyze the characteristics and outcome of patients with secondary acute promyelocytic leukemia (APL) and compare them to those with primary APL. One hundred and thirteen patients referred to our service with a diagnosis of APL were reviewed. Fourteen were classified as secondary APL. Nine were induced with chemotherapy, and five with all-trans retinoic acid plus chemotherapy. Pretreatment characteristics, response to therapy and outcome of primary vs secondary APL were compared by standard statistical methods. Secondary APL constituted 12% of all APL cases. Patients with secondary APL were significantly older (median age 56 vs 36 years; P < 0.01) and had a lower incidence of hypofibrinogenemia (P < 0.01) than those with primary APL. The complete response (CR) rates were similar with secondary vs primary APL (CR rates 79 vs 69%), as were CR duration and survival. The CR rates at 5 years were 57 and 45%, respectively(P not significant), and the survival rates 37 and 35%, respectively (P not significant). The incidence of secondary APL within APL disease (12%) was similar to the incidence of secondary acute myeloid leukemia (AML) in karyotypes not known to be therapy-related (diploid, t(8;21), inversion 16: incidences 9 to 12%), but was significantly lower than in karyotypes known to be therapy-related (chromosome 5 or 7 abnormalities, 11q; incidences 30 and 33%). We conclude that secondary APL has general characteristics and outcome similar to primary APL. it is more likely a second primary rather than therapy-related AML, and should be treated in a manner similar to primary APL.

Adult↗
PubMed1996

Engraftment of chronic prolymphocytic and T cell leukemia in SCID mice.

Engraftment of human acute leukemia cells in immunocompromised (SCID) mice has resulted in in vivo models for exploration of human tumor biology. Attempts at engraftment of chronic leukemia cells have been generally unsuccessful. We have engrafted cells from three human chronic leukemias in SCID mice. Cell populations were from two patients with chronic lymphocytic leukemia (CLL) and either increased proolymphocytes (CLL-Pro; patient 1), or prolymphocytic transformation (PLL; patient 2) and from a third patient with newly diagnosed T cell CLL. Both fresh and cryopreserved cells were used and were injected intravenously, intraperitoneally, or both, after conditioning with cyclophosphamide. In addition, cells derived from a mouse spleen engrafted with human leukemia were passaged into another mouse. The animals were observed daily for signs of disease or appearance of tumors and sacrificed when terminally ill. At intervals blood samples were obtained and analyzed for the presence of human cells or DNA. Human leukemic cells were demonstrated by polymerase chain reaction (PCR) analysis of the human DQalpha gene or positive staining for human leukocyte common antigen (LCA). The presence of Epstein-Barr virus (EBV)-positive cells was also investigated by PCR analysis. Disseminated tumors developed in most mice inoculated with cells from the first patient, and this was associated with shortened survival times. The methods of administration, use of fresh or frozen samples, or the size of the inoculum had no effect on the development of leukemia. Survival of the mouse receiving passaged cells was similar to mice inoculated with fresh cells. Extensive histologic, immunophenotypic, and DNA studies were performed on organs from mice engrafting with cells from patient 1. PCR analysis for EBV sequences was negative in the mice engrafting from all three cases. The successful engraftment of human CLL-Pro PLL and T cell CLL in SCID mice, and the reproducibility of this effect using frozen cells, will provide a model for exploration of disease biology and for investigations of new drugs or combinations that may be useful in the treatment of CLL.

Aged↗
PubMed1995

Myeloid markers in adult acute lymphocytic leukemia. Correlations with patient and disease characteristics and with prognosis.

BACKGROUND: The expression of myeloid markers on lymphoblasts has been associated with adverse outcome in acute lymphocytic leukemia (ALL). The purpose of the study was to analyze the experience with adults treated at the University of Texas M. D. Anderson Cancer Center with myeloid marker- (MY) positive ALL in relation to patient and disease characteristics, response to therapy, and prognosis. METHODS: Since 1988, 64 of 162 adults (40%) with newly diagnosed ALL referred to our service had MY-positive ALL. Their characteristics and outcomes were compared with the 98 patients with MY-negative ALL. Patients were treated with the vincristine-doxorubicin-dexamethasone (VAD) regimens. RESULTS: Patients with MY-positive ALL were significantly older (median ages, 47 years vs. 33 years; P = 0.03), had a higher incidence of CD34 antigen expression (59% vs. 36%; P < 0.01), and a lower incidence of common acute leukemia antigen expression (50% vs. 71%; P < 0.01), serum alkaline phosphatase elevation (58% vs. 83%; P < 0.01), and thrombocytopenia at diagnosis (49% vs. 69%; P = 0.02). Myeloid marker positivity, as expected, was significantly higher in null cell ALL (82%), and significantly lower in mature B-cell ALL (17%) (P < 0.01). Forty-one of 64 MY-positive patients achieved complete remission (CR) after induction therapy compared with 76 of 98 patients MY-negative disease (CR rate 64% vs. 78%; P = 0.06). With a median follow-up of 45 months, no statistical differences were observed in remission duration or survival between MY-positive and MY-negative patients, overall, and within immunophenotypic subsets (T-cell vs. others), or among subgroups with single marker (CD13, CD14, CD33, CD34) positivity. The 3-year remission duration rates were 32% for MY-negative and 40% for MY-positive patients (P not significant), and 3-year survival rates were 26% and 31%, respectively (P not significant). CONCLUSIONS: With VAD therapy, myeloid marker positivity is not associated with significant differences in prognosis in adult ALL.

Adolescent↗
PubMed1995

Homoharringtonine therapy induces responses in patients with chronic myelogenous leukemia in late chronic phase.

Homoharringtonine (HHT) is a plant alkaloid with potent myelosuppressive activity and little toxicity when used in a continuous infusion schedule. The antileukemic efficacy of HHT has been shown in acute myeloid leukemia, but has not been investigated in chronic myelogenous leukemia (CML). Seventy-one patients with Philadelphia chromosome-positive (Ph+) CML in late chronic phase (time from diagnosis to therapy longer than 12 months) were treated with a continuous infusion of HHT at a daily dose of 2.5 mg/m2 for 14 days for remission induction and for 7 days every month for maintenance. The median number of courses given was 6 (range, 1 to 35) and 21 patients (30%) continue on treatment. Forty-two of 58 patients (72%) evaluable for hematologic response achieved a complete hematologic remission, and 9 (16%) had a partial hematologic remission. Twenty-two of 71 patients (31%) developed a cytogenetic response; it was major (Ph+ cells less than 35%) in 11 (15%) and complete (Ph+ cells 0%) in 5 (7%). Significant myelosuppression occurred in 39% of induction courses and 9% of maintenance courses. Fever or documented infection was present in 26% of induction courses and in only 8% of maintenance courses. Nonmyelosuppressive toxicity was minimal. Homoharringtonine produced hematologic remissions in the majority of patients with advanced chronic-phase CML. Cytogenetic response occurred in some patients without an association with myelosuppression, and these responses may be prolonged. Future studies investigating homoharringtonine in combination with other active agents in CML, such as interferon, are warranted.

Adult↗
PubMed1995

The breakpoint cluster region site in patients with Philadelphia chromosome-positive chronic myelogenous leukemia. Clinical, laboratory, and prognostic correlations.

BACKGROUND: The breakpoint site of the breakpoint cluster region (bcr) has been correlated with patient characteristics, with the disease phase, and with the prognosis of patients with chronic myelogenous leukemia (CML), but the findings remain controversial. METHODS: Appropriate restriction enzymes and the 3' and universal probes were used to map the breakpoint site by Southern blot analysis into 5' and 3' breakpoints and a breakpoint in zone 3 (or fragment 2) in 362 patients in different phases of CML (238 in early chronic phase, 69 in late chronic phase, 31 in accelerated phase, and 24 in blastic phase). Standard statistical methods were used to evaluate differences in characteristics and in prognosis by the breakpoint site. RESULTS: No correlation was noted between CML phases and breakpoint site. Among patients in the early chronic phase, thrombocytosis was significantly associated with the 3' breakpoint site (P = 0.02), whereas peripheral basophilia occurred more frequently with the 5' breakpoint site (P = 0.05). Other patient and disease characteristics were similar in frequency among the breakpoint-site subgroups. There was no difference in response to alpha-interferon therapy (186 patients treated) by the breakpoint site. Survival, dated from either referral to the authors' institution or from diagnosis, was not significantly different among patients with early chronic phase CML by the breakpoint site. However, patients with a 3' deletion tended to have a shorter survival. CONCLUSION: Determination of the breakpoint site by Southern blot analysis does not help to predict prognosis of patients with CML.

Chromosomes, Human, Pair 22↗
PubMed1995

Topotecan in chronic lymphocytic leukemia.

BACKGROUND: Topotecan is one of a new class of agents that targets topoisomerase I (Topo I) and stabilizes the DNA-topo1 complex, ultimately resulting in cell death. The rationale for the use of topotecan in chronic lymphocytic leukemia (CLL) is based on the finding that levels of Topo I are elevated in the lymphocytes of patients with this disease. METHODS: Twelve patients with CLL were treated with topotecan to assess its clinical efficacy; in addition, DNA-protein cross-linking was measured after exposure of the cells to topotecan, in an attempt to correlate potential anti-CLL effects with this parameter. The median age of the patients was 63 years; all had received prior therapy with fludarabine and four (33%) were resistant to fludarabine. Four patients (33%) had also received therapy with chlorambucil, and three of them were resistant to this agent. Seven patients (58%) were Rai stage I-II and five (42%) were Rai stage III-IV. Topotecan was given as a 30-minute infusion at a daily dose of 2 mg/m2 for 5 days, and courses were repeated monthly. Cells were obtained from the patients before treatment and exposed to 2 microM topotecan or control in vitro. In addition, cells were obtained from patients after they received the first dose of topotecan and protein-bound DNA was measured with the same technique. RESULTS: No patient responded to therapy with topotecan (95% confidence interval, 0-27%). Nonhematologic toxicity was mild and thrombocytopenia occurred in four of eight patients whose conditions could be evaluated. One patients died of myocardial infarction and another died of fungal pneumonia. DNA-protein cross-linking was detected in all nine patients whose cells were assessed in vitro, with levels of cleavable complex ranging from twofold to 7.5-fold that of the control cells. Only two of eight patients with evaluable conditions had increased cross-linking detectable in circulating cells after the first dose of topotecan, which was consistent with the drug's lack of effect in vivo. CONCLUSIONS: Although exposure of cells from patients with CLL to topotecan in vitro at 2 microM resulted in detectable protein-DNA cross-linking, this effect was not seen in patients who received a bolus dose of 2 mg/m2, and no remissions were noted in 12 patients.

Adult↗
PubMed1995

Advances in the biology and treatment of B-cell chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in the western hemisphere. Diagnosis and staging of CLL are usually straightforward, but predicting an individual patient's prognosis is still a challenge. Cytogenetic abnormalities provide important prognostic information in CLL and may show its molecular heterogeneity. A search for oncogene abnormalities continues, although no consistent defects have been identified. New agents such as fludarabine produce high complete remission rates and have generated interest in earlier treatment as a first step in a potential cure. Fludarabine also makes autologous bone marrow transplant feasible as a consolidation therapy. Immunologic abnormalities and minimal residual disease persist in most patients in remission. Combining fludarabine with other active agents and devising effective postremission strategies may change the natural history of CLL.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

A new form of long QT syndrome associated with syndactyly.

OBJECTIVES: The purpose of this study was to characterize a possible association between long QT syndrome and syndactyly. BACKGROUND: Long QT syndrome causes syncope and sudden death from ventricular arrhythmias. Syndactyly is a developmental disorder that causes webbing of the hands and feet. Both disorders can be inherited as isolated, autosomal dominant traits, but an association between them has not been established. METHODS: We identified three children with long QT syndrome, atrioventricular (AV) block and simple syndactyly. Phenotypic and laboratory data were obtained from families, attending physicians and medical records. RESULTS: All patients had bilateral cutaneous syndactyly and were diagnosed with long QT syndrome within the 1st 2 years of life. Structural heart disease, particularly a patent ductus arteriosus, was present in all three patients. Analysis of electrocardiograms showed marked prolongation of the QT intervals with rate-corrected QT intervals of 633, 628 and 680 ms, respectively. Transient AV block was also noted. Two of the three children died suddenly despite treatment with beta-adrenergic blocking agents and permanent pacing. CONCLUSIONS: We postulate that these children have a new form of long QT syndrome associated with syndactyly and a high risk of sudden death. The association of syndactyly with long QT syndrome may provide insight into the mechanisms underlying both disorders. Patients with syndactyly should be evaluated for the presence of long QT syndrome, and if it is found, aggressive treatment may be warranted.

Child, Preschool↗