Biomedical subjects

M J Keating

Publications and source records attributed to M J Keating.

At least 199 records · Page 11Linked to original sources

PubMed1992

A comparison of imipenem to ceftazidime with or without amikacin as empiric therapy in febrile neutropenic patients.

BACKGROUND: Neutropenic patients with cancer are traditionally treated with empiric antibiotic combinations when they become febrile. The availability of broad-spectrum antibiotics such as ceftazidime and imipenem has made it possible to initiate therapy with a single agent (monotherapy). The objectives of this trial were to compare ceftazidime and imipenem as single agents for the therapy of febrile episodes in neutropenic patients and to ascertain whether the addition of an aminoglycoside (amikacin) to either of these agents would provide an advantage. METHODS: A prospective clinical trial was conducted in which eligible neutropenic patients with cancer were randomized to one of four treatment arms: ceftazidime alone; imipenem alone; ceftazidime plus amikacin; and imipenem plus amikacin. Efficacy analysis was done for 750 assessable episodes. A multivariate logistic-regression analysis was also performed to examine the unique contribution of various prognostic factors. RESULTS: The overall response rates were 76% with imipenem plus amikacin, 72% with imipenem, 71% with ceftazidime plus amikacin, and 59% with ceftazidime alone. Single-organism gram-positive infections occurred in 101 of 750 episodes. Without a change in antibiotics, the response rates were 50% with imipenem, 40% with imipenem plus amikacin, 39% with ceftazidime plus amikacin, and 38% with ceftazidime. Most responded to vancomycin or other antibiotics, and the mortality associated with gram-positive infections was only 5%. Regardless of the antibiotic regimen, the majority of uncomplicated gram-negative infections responded to therapy and the majority of complicated gram-negative infections failed to respond. Multivariate logistic-regression analysis showed that recovery of the neutrophil count was the most favorable prognostic factor in a patient's response to infection, whereas the presence of gram-positive infection, acute leukemia, pulmonary or enteric infection, and therapy with ceftazidime were unfavorable factors. CONCLUSIONS: Single-agent therapy with imipenem is as effective as more conventional combination antibiotic therapy for the empirical treatment of febrile episodes in neutropenic patients with cancer.

Adolescent↗

PubMed1991

Significance of the P210 versus P190 molecular abnormalities in adults with Philadelphia chromosome-positive acute leukemia.

We investigated the significance of p210 and p190 molecular abnormalities in 32 adults with Philadelphia chromosome (Ph)-positive acute leukemia. p210 was detected in 15 patients (47%), p190 in 16 (50%), and both in one (3%). p210 was noted in 11 of 24 patients (46%) with acute lymphocytic leukemia, and in four of eight patients (50%) with acute myelogenous or undifferentiated leukemia. Among 29 patients with untreated disease (p210, 14 patients; p190, 15 patients), no significant differences in the two molecularly distinct groups were observed by pretreatment characteristics including age, degree of organomegaly, anemia, leukocytosis, thrombocytopenia, occurrence of karyotypic abnormalities in addition to Ph, or residual diploid metaphases. Complete response (CR) rates were also similar. Although the remission duration tended to be longer with p190 (P = .08), the differences were minor (median duration 29 v 20 weeks) and not paralleled by differences in survival rate. In 10 patients studied by karyotypic analysis in remission, two of four patients with p190 and two of six patients with p210 showed 100% normal metaphases. One of the seven patients (14%) with p210 who achieved CR manifested a morphologic picture of second chronic-phase chronic myelogenous leukemia lasting for 1 month. We conclude that the molecular studies in Ph-positive acute leukemia are not associated with significantly different clinico-laboratory, karyotypic, or prognostic implications.

Adult↗

PubMed1991

Intensive chemotherapy induction followed by interferon-alpha maintenance in patients with Philadelphia chromosome-positive chronic myelogenous leukemia.

In a pilot study, 32 patients with Philadelphia chromosome-positive chronic myelogenous leukemia were treated with intensive chemotherapy induction followed by interferon-alpha (IFN-A) maintenance. Intensive chemotherapy consisted of three cycles of daunorubicin 120 mg/m2 on day 1, cytarabine 80 mg/m2 daily for 10 days, vincristine 2 mg on day 1, and prednisone 100 mg daily for 5 days (DOAP). Maintenance therapy with IFN-A at a doses of 3 x 10(6) to 5 x 10(6) units/m2 daily was adjusted according to counts and toxicity. The outcome of patients was compared with a matched historic population of 64 patients treated with IFN-A alone. Overall, 60% of patients had a cytogenetic response (partial or complete) with induction chemotherapy, but only eight (25%) had a sustained cytogenetic response with IFN-A maintenance. After a median follow-up of 67 months, the 6-year survival rate of the 32 patients was 58%, compared with 36% for the matched historic group (P = 0.084). The incidence of lymphoid blastic transformation in the two groups was 25% and 48%, respectively (P = 0.10) and durable cytogenetic responses, 25% and 19%, respectively (P = 0.48). In summary, the addition of intensive chemotherapy induction to IFN-A maintenance does not improve the survival rate, incidence of lymphoid blastic transformation, or incidence of durable cytogenetic response compared with the results achieved with IFN-A therapy alone.

Adolescent↗

PubMed1991

The normal emergence of the superior collicular map of auditory space in the guinea pig following developmental removal of visual cortex.

The normal development of the superior collicular map of auditory space in the guinea pig requires visual experience (Eur. J. Neurosci., 2 (1990) 682-692). The possible role of the visual cortex in this process was assessed by unilateral removal of the cortex prior to the crucial period during which visual experience is needed (Neurosci. Lett., 116 (190) 280-286). This removal did not affect the normal emergence of an ordered auditory space map in the superior colliculus. The cortico-tectal pathway does not appear, therefore, to play an essential role in the developmental dependence of the collicular auditory map upon visual experience.

Acoustic Stimulation↗

PubMed1991

Exposure histories in acute nonlymphocytic leukemia patients with a prior preleukemic condition.

A subset of patients with acute nonlymphocytic leukemia (ANLL) have evidence of a myelodysplastic syndrome (MDS), low infiltrate leukemia, or other preleukemic condition that may be present for several months before onset of disease. The hypothesis that these conditions act as markers for environmentally induced cancer was examined in 270 ANLL patients, 46 with a preleukemic phase and 224 with an acute onset. Although the effects of previously identified risk factors (male sex, age older than 50 years, prior cytotoxic therapy) were demonstrated, no associations with common environmental conditions (cigarette smoking, alcohol use, occupations with exposure to chemicals or radiation) were present with the exception of hobbies involving potential chemical exposure, odds ratio (OR) and 95% confidence intervals = 4.2 (1.4 to 12.3) and self-reported exposure to pesticides, OR = 10.2 (1.8 to 63.1). These may be chance associations although a previous case-control study of MDS reported similar findings.

Age Factors↗

PubMed1991

Fludarabine therapy in hairy cell leukemia.

This study evaluated the efficacy of fludarabine, a new adenine nucleoside analogue, in typical and variant forms of hairy cell leukemia (HCL). Two patients with HCL and one patient with a variant form of HCL (HCL-variant) with resistant or progressive disease with prior treatments were studied. Fludarabine (30 mg/m2) was administered intravenously over 30 minutes daily for 5 days every month. Two patients (one with HCL and one with HCL-variant) achieved partial responses; the third patient had a minor response. This is the first report of encouraging activity of fludarabine in typical and variant forms of HCL. Further experience with fludarabine in these disorders is indicated.

Adult↗

PubMed1991

Effect of antileukemia chemotherapy on marrow, blood, and oral granulocyte counts.

This study was designed to elicit the effects of antileukemia chemotherapy on marrow production, blood carriage, and oral extravasation of granulocytes, and on the phagocytic activity of those harvested from the mouth. Fifteen adult patients with various morphologic forms of acute leukemia were followed through one to four courses of chemotherapy. Oral saline rinse samples were obtained thrice weekly and prepared for enumeration in a hemocytometer. The oral granulocyte counts were compared with concurrent counts in the bone marrow and peripheral blood. Phagocytic activity of the oral granulocytes was measured by the method of Smith and Rommel. The 15 patients were followed through 30 courses of chemotherapy and recovery. During each, there was a drug-induced decrease in marrow, blood, and oral granulocytes that was reversed when therapy was discontinued and bone marrow activity was restored. Phagocytic activity of the oral granulocytes was not perceptibly affected by the antileukemic drugs. Oral granulocyte counts provide a noninvasive method for monitoring the onset and recovery of chemotherapy-induced myelosuppression and granulocytopenia in patients with leukemia.

Acute Disease↗

PubMed1991

Effects of low doses of recombinant human granulocyte-macrophage colony stimulating factor (GM-CSF) in patients with myelodysplastic syndromes.

There has been no previously published experience with granulocyte-macrophage colony stimulating factor (GM-CSF) doses less than 12 micrograms/m2 daily in patients with myelodysplastic syndromes, and most observations have been made at doses greater than or equal to 120 micrograms/m2 daily. We administered 5 micrograms/m2 daily by subcutaneous injection to 29 such patients increasing the dose in patients who did not show a haematologic response. Doses of 5 or 10 micrograms/m2 ('low-dose GM-CSF') produced an increase in neutrophils in 14/29 patients. Response was significantly (P = 0.03) more frequent in patients who had a higher pre-treatment neutrophil count (e.g. 11/16 in patients with greater than or equal to 0.5 x 10(9)/l). A rise in blasts followed administration of low-dose GM-CSF in five patients, all with either refractory anaemia with excess blasts (RAEB) or refractory anaemia with excess blasts in transformation (RAEBT). Platelets decreased in five patients, four of whom had no change in blasts, reverting to baseline when GM-CSF was discontinued. We and others have previously observed similar rises in blasts or decreases in platelets at doses of 120 micrograms/m2 daily. Low-dose GM-CSF produced no constitutional side effects. Our results suggest that low doses of GM-CSF might be initially employed in neutropenic patients with myelodysplastic syndromes who present with pretreatment neutrophil counts greater than 0.5 x 10(9)/l. Increasing the dose, and hence the risk of extramedullary toxicity, only in patients who do not respond to the low dose. Patients who present with lower pre-treatment neutrophil counts might begin treatment at doses above 10 micrograms/m2, but below the 120 micrograms/m2 commonly employed, which may be necessary in relatively few patients.

Aged↗

PubMed1991

Fludarabine: a new agent with marked cytoreductive activity in untreated chronic lymphocytic leukemia.

Thirty-three patients with chronic lymphocytic leukemia (CLL) with advanced Rai stage (III-IV) or progressive Rai stage (0-II) disease were treated with fludarabine as a single agent. Eleven patients (33%) obtained a complete remission (CR), 13 (39%) a clinical CR with residual nodules as the only evidence of disease (nodular partial remission [PR]), and two patients (6%) achieved a PR for a total response rate of 79%. Response was rapid, usually occurring after three to six courses of treatment. The major morbidity was infection. Febrile episodes occurred in 13% of the courses (pneumonia 6%, minor infection 4%, and transient fever of undocumented cause 3%). Fludarabine appears to be the most cytoreductive single agent so far studied in CLL.

Adult↗

PubMed1991

Therapeutic approaches to chronic lymphocytic leukemia.

Chronic lymphocytic leukemia is the most common leukemia in the Western Hemisphere and will increase in prevalence as the population continues to age. Partly because of the advanced age of patients and the often prolonged indolent course of disease, therapy has changed little over the past several decades. The clinical course is highly variable and several clinical features have prognostic value. Until recently, therapeutic approaches have ranged from watchful observation to palliative treatment with an alkylating agent alone or combined with a corticosteroid; however, a number of new chemotherapeutic agents (eg, fludarabine, deoxycoformycin, and chloride-oxyadenosine) have been shown to act effectively against the disease. The availability of effective new agents combined with a better understanding of the biology and prognostic determinants in this disease have sparked recent interest in the optimal management of patients with this increasingly common malignancy.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1991

Efficacy of fludarabine, a new adenine nucleoside analogue, in patients with prolymphocytic leukemia and the prolymphocytoid variant of chronic lymphocytic leukemia.

PURPOSE: To describe the results of fludarabine therapy in patients with prolymphocytic leukemia (PLL) and the prolymphocytoid variant of chronic lymphocytic leukemia (CLL-Pro). PATIENTS AND METHODS: Seventeen patients with a diagnosis of PLL or CLL-Pro received fludarabine 30 mg/m2 over 30 minutes daily for 5 days every 4 weeks alone (12 patients), or with prednisone (five patients). Previously defined criteria for response were used. Differences in response rates according to various characteristics were evaluated by chi-square test. RESULTS: Three patients (18%) achieved complete remission, and three (18%) had a partial remission, for an overall response rate of 35%. Responses were durable and occurred in all involved organ sites. Lower response rates were observed in patients with anemia, thrombocytopenia, advanced Rai stages, and primary resistance to prior therapy. Toxicities were minimal except for febrile episodes associated with therapy. CONCLUSION: Fludarabine has shown encouraging results in these patients and deserves further investigation in combination with other active agents, and in the setting of front-line therapy.

Aged↗

PubMed1990

Pharmacologically directed design of the dose rate and schedule of 2',2'-difluorodeoxycytidine (Gemcitabine) administration in leukemia.

The objective of this study was to determine the dose rate of 2',2'-difluorodeoxycytidine (dFdC) that maximizes the accumulation of the active 5'-triphosphate (dFdCTP) in circulating leukemia cells during therapy. The investigational approach was to evaluate the relationship between plasma dFdC and the accumulation of dFdCTP by circulating leukemia cells during infusion of different dFdC dose rates in the same individuals. Four patients with relapsed leukemia were treated weekly with two or three consecutive infusions of 800 mg/m2, the first administered over 1 h, the second over 2 h, and the third over 3 h. Two patients, one with acute myelogenous leukemia and one with acute lymphocytic leukemia, received all three infusions, but thrombocytopenia prohibited infusion of the third dose to two patients with chronic lymphocytic leukemia. The average steady-state plasma dFdC levels, achieved within 15 min after the infusion began, were 43.8 microM during infusion of 800 mg/m2/h, 9.4 microM during infusion of 400 mg/m2/h, and 5.6 microM at 267 mg/m2/h. The median area under the concentration times time curve of dFdCTP in leukemia cells during infusion was increased 2.3- and 5.1-fold for the 2- and 3-h infusions, respectively. In vitro incubations of leukemia cells from the four patients with 2.5-100 microM dFdC for 1 h showed that the maximum cellular accumulation of dFdCTP was produced by 15-20 microM dFdC. We conclude that a dose rate of greater than 400 mg/m2/h was required to achieve plasma dFdC levels that supported the maximum rate of dFdCTP accumulation in leukemia cells.

Adult↗

PubMed1990

A four-day period of bimodality auditory and visual experience is sufficient to permit normal emergence of the map of auditory space in the guinea pig superior colliculus.

Previous work has shown that if guinea pigs are deprived of simultaneous visual and auditory experience during a 4-day period 26-30 days after birth (DAB), this prevents the normal emergence of an auditory space map in the superior colliculus. The present work reports that if this 4-day period is the only developmental period in which the animals have simultaneous bimodality experience, the auditory space map appears at the normal time. Apart from this time-window animals were deprived of either visual experience (by dark-rearing) or of normal auditory experience (by rearing in an environment of omnidirectional masking noise). We conclude that the period 26-30 DAB is a crucial developmental period during which coincident auditory and visual experience is utilized in the initial formation of the collicular map of auditory space.

Animals↗

PubMed1990

Fludarabine therapy in macroglobulinemic lymphoma.

Fludarabine, a fluorinated analogue of adenine, was given to 11 patients with macroglobulinemic lymphoma, all but one having failed prior standard chemotherapy. Five patients (45%) responded with more than a 50% reduction of immunoglobulin M (IgM) tumor mass for a projected median duration of longer than 1 year. The onset of remission was usually slow, with a median tumor halving time of 5.2 months in responding patients, emphasizing the importance of repeated courses of treatment. Fludarabine is an important new agent effective against macroglobulinemic lymphoma, and should be evaluated further in combination with other active modalities.

Adult↗

PubMed1990

Treatment of poor-prognosis, newly diagnosed acute myeloid leukemia with ara-C and recombinant human granulocyte-macrophage colony-stimulating factor.

We administered recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) (120 micrograms/m2/d by continuous intravenous [IV] infusion) to 12 patients with newly diagnosed acute myeloid leukemia (AML) at relatively high risk of early death during remission induction. GM-CSF began 3 days after completion of induction chemotherapy (ara-C 1.5 g/m2 d x 4 days by continuous IV infusion after a 3 g/m2 bolus). Rates of fatal infection (42%), pneumonia and/or sepsis (83%), and CR (50%) did not differ significantly (P less than .05) from those observed after administration of the identical chemotherapy without GM-CSF to 53 historical controls with newly diagnosed AML at similarly high risk of early death. There were no significant differences between the GM-CSF-treated and the historical groups in the time required to reach neutrophil counts of 500 or 1,000/microL after administration of chemotherapy. Four patients died of infection before they could have benefited from the earliest recovery of neutrophil count observed in patients who entered CR. Growth of leukemia after GM-CSF administration was observed in only 1 of the 8 patients who survived long enough for response to induction therapy to be fully evaluated. This observation suggests that it might be safe to undertake larger, randomized studies, perhaps using earlier administration of GM-CSF, to definitively determine the role of GM-CSF added to chemotherapy in patients with newly diagnosed AML.

Adult↗

PubMed1990

Fatal pulmonary failure complicating high-dose cytosine arabinoside therapy in acute leukemia.

One hundred three relapsed leukemia patients were treated with high-dose cytosine arabinoside (Ara-C); 3 g/m2 intravenously over 2 hours every 6 to 12 hours for a total of nine to 12 doses or 3 g/m2 intravenously over 2 hours for two doses 12 hours apart followed by a continuous infusion of 1.5 g/m2 over 24 hours daily for 3 to 4 days. Thirteen of them developed adult respiratory distress syndrome (ARDS) without having any recognized reason for the development of pulmonary edema. This problem showed no correlation with age or prior chemotherapy. Four of the patients recovered, but in nine this complication was fatal. The authors have reviewed the clinical course of these 13 patients and the postmortem findings of the seven patients who had an autopsy performed. The pulmonary tissue from six patients showed massive edema and one had diffuse alveolar damage. Histologic examination revealed a highly proteinaceous intraalveolar infiltrate without any inflammatory reaction in all cases. Intestinal tissue from all patients revealed changes compatible with cytotoxic damage, and pleura and/or pericardium from six of the seven patients showed an extensive fibrinous exudate suggestive of capillary leakage. The time sequence of the clinical events and the histologic findings indicate that high-dose Ara-C treatment in leukemia may cause a capillary leakage syndrome with ARDS that may progress to fatal respiratory failure.

Acute Disease↗

PubMed1990

The developmental emergence of a map of auditory space in the superior colliculus of the guinea pig.

We describe the developmental emergence of a topographically ordered map of auditory space in the deep layers of the guinea pig superior colliculus. The central auditory system of this precocial mammal is functional in utero. A map of auditory space in the superior colliculus is not, however, electrophysiologically demonstrable until 32 days after birth (DAB). The map develops in 4 postnatal phases. In very young animals (1-15 DAB) vigorous responses to auditory stimuli were recordable from collicular sites. Apart from a preference for stimuli orginating in the contralateral hemifield of auditory space, the responses in these young animals, however, showed little evidence of directional tuning. In animals aged between 16 and 30 DAB, an increasing proportion of responses displayed directional tuning but such responses were not arranged so as to constitute a topographic map. A relatively short third developmental phase (31-32 DAB) involved the ordering of individually tuned responses so as to form a topographic map of the contralateral auditory hemifield. As the animals further mature the individual responses display a higher degree of spatial tuning reflecting an ongoing process of refinement.

Acoustic Stimulation↗

PubMed1990

Mitoxantrone and high-dose cytosine arabinoside for the treatment of refractory acute lymphocytic leukemia.

Twenty-five adult patients with refractory acute lymphocytic leukemia received salvage therapy with mitoxantrone 5 mg/m2 intravenously over 1 hour daily for 5 days and cytosine arabinoside 3 g/m2 intravenously over 2 hours every 12 hours for six doses. Overall, nine patients (36%) achieved complete remission, eight (32%) died during induction, and eight (32%) had resistant disease. No significant associations were found between pretreatment patient characteristics and remission. Remission durations toxic effects were related to myelosuppression. Febrile episodes requiring hospitalization occurred in 23 patients (92%), including five episodes of fever of unknown origin (20%) and 18 episodes of documented infections (72%). The authors conclude that the combination of mitoxantrone and high-dose cytosine arabinoside has significant activity in adults with refractory acute lymphocytic leukemia. The addition of colony-stimulating growth factors to the intensive chemotherapy, and the use of the combination regimen as part of front-line maintenance intensification therapy may further improve the prognosis in these patients.

Adolescent↗