Hematopoietic growth factors in bone marrow transplantation for hematologic malignancies.
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Bone Marrow Diseases↗
Biomedical subjects
H M Lazarus
Publications and source records attributed to H M Lazarus.
Percutaneous placement of femoral central venous catheter in patients undergoing transplantation of bone marrow.
Five patients undergoing transplantation of autologous bone marrow underwent percutaneous placement of a double lumen central venous catheter into the inferior vena cava by way of the femoral vein. All had conditions that precluded access to the superior vena cava or other sites in the upper part of the torso. Patients ranged in age from 18 to 59 years. The double lumen central venous catheter was inserted using aseptic technique in the operating room, and the catheter exit site was dressed using sterile technique every 48 hours afterward. Patients received all irradiated blood product transfusions, intravenous fluids, intravenous antibiotics, parenteral alimentation and autologous bone marrow reinfusion through the catheter. The duration of severe neutropenia (less than 500 neutrophils per microliter) and severe thrombocytopenia (less than 20,000 platelets per microliter) ranged from zero to 24 days (median of 22 days) and five to 20 days (median of 15 days), respectively. Catheters remained in the groin area 23 to 45 days (median of 35 days). Complications included one catheter-related Streptococcus species infection and one Escherichi coli bacteremia. These infections resolved with the catheter in place after appropriate institution of antibiotics. No episodes of thrombosis, kinking, migration, extravasation of drugs or local infection were noted. Central venous catheters can be safely inserted and maintained in the groin area even in severely immunocompromised patients receiving bone marrow transplants.
Adolescent↗
Granulocyte transfusions: have we learned anything?
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Adult↗
A cholangiographic clamp as an aid in the performance of operative cholangiography.
A multipurpose clamp has been developed that will facilitate the placement, securing and removal of a cholangiographic catheter during an operative cholangiogram. This technique will decrease the time taken for the cholangiography and encourage routine use of cholangiography during cholecystectomy.
Cholangiography↗
High-dose cytosine arabinoside and daunorubicin as primary therapy in elderly patients with acute myelogenous leukemia. A phase I-II study of the Southeastern Cancer Study Group.
We undertook a phase I-II trial in elderly (age greater than or equal to 60 years) untreated acute myelogenous leukemia (AML) patients using brief, intensive therapy to improve induction rates and overall survival in older AML patients. Twenty-one patients ranging in age from 60 to 81 years (median, 66 years) were treated using either a 4- or 5-day course of high-dose cytosine arabinoside, 3 g/m2 intravenously (IV) every 12 hours; followed by daunorubicin, 45 mg/m2/d IV bolus for 3 consecutive days. Thirteen patients were entered at the first dose level (a 4-day course or eight doses of cytosine arabinoside), whereas eight patients underwent therapy at the second dose level (a 5-day course or ten doses). Patients who achieved a complete remission received a repeat course of high-dose cytosine arabinoside and daunorubicin within 4 weeks of attaining remission. Seven patients had an antecedant history of a myelodysplastic syndrome. Infection was the major complication experienced by this elderly patient group, and included ten episodes of bacteremia or fungemia (four of which were fatal) and five cases of pneumonia (one fatality). Nine of the 21 patients (three of 13 at the first dose level and six of eight at the second dose level) achieved a complete remission. Median remission duration was 9 months (range, 4-19+ months). Although high-dose cytosine arabinoside plus daunorubicin was an effective antileukemic therapy, it is too toxic to recommend for most elderly leukemic patients.
Aged↗
Prospective evaluation of a Candida antigen detection test for invasive candidiasis in immunocompromised adult patients with cancer.
PURPOSE: Serologic tests to detect invasive candidiasis generally have been unreliable. We prospectively evaluated the clinical utility of a new, promising commercial latex particle agglutination test (i.e., Cand-Tec, Ramco Laboratories, Inc., Houston, Texas). This assay detects Candida antigens in serum. PATIENTS AND METHODS: We examined the reliability of Cand-Tec to diagnose invasive candidiasis in 142 consecutive in-patients intensively treated with chemo-radiation therapy. Serum samples were collected at admission and then weekly, until the patients' death or hospital discharge. Evaluation for clinical utility was done using various reference titers. Twenty-nine patients had invasive candidiasis whereas 113 patients did not have documented invasive candidal infections. RESULTS: At a titer of 1:8, the Cand-Tec test had sensitivity of 38%, specificity of 90%, positive predictive value of 50%, and negative predictive value of 85%. Weekly use of the Cand-Tec test did not improve early detection of invasive candidiasis, providing only a mean interval of 0.4 day from the first positive Cand-Tec result to a definitive diagnosis of invasive candidiasis by blood culture, tissue biopsy, or autopsy. In addition, surveillance cultures from the oropharynx or stool were not helpful in identifying those patients who would develop an invasive fungal infection. CONCLUSION: In the context of current clinical management strategies for suspected fungal infection, the Candida antigen detection assay (Cand-Tec) is not a reliable method for diagnosis of deep candidiasis in neutropenic patients. Until better methods of early detection are available, patients at high risk for the development of invasive candidiasis should continue to receive empiric antifungal agent therapy.
Adolescent↗
High-dose melphalan, misonidazole, and autologous bone marrow transplantation for the treatment of metastatic colorectal carcinoma. A phase I study.
To augment the antitumor effect of high-dose melphalan and determine pharmacokinetics we conducted a phase I trial of escalating doses of high-dose IV melphalan with the chemosensitizer misonidazole for patients with advanced colorectal carcinoma. Fourteen patients with modified Dukes D adenocarcinoma of the colorectum were treated with a single course of melphalan (40-60 mg/m2 i.v. bolus q.d. X 3 days) and misonidazole (1-3 g/m2 p.o. q.d. X 3 days) followed by autologous bone marrow transplantation. Toxicity consisted of severe myelosuppression, moderate nausea and vomiting, and mild mucositis and diarrhea. One patient developed unexplained renal tubular acidosis, and a diffuse encephalopathy occurred in another patient. Three patients died within the first 30 days after the start of treatment, two due to tumor progression and one due to sepsis and disseminated intravascular coagulation-induced intracerebral hemorrhage. Six of 14 patients achieved a partial response, and the median response duration was 4 months (range 3-10 months). Analysis of misonidazole serum concentrations showed similar pharmacokinetics to those previously reported, suggesting no significant drug interaction with intravenous melphalan. Mean peak serum concentrations ranged from 81.8 micrograms/ml to 115.2 micrograms/ml at the second and third misonidazole dose levels, which approximate those known to provide effective chemosensitization with melphalan in animal models. In this phase I study, we showed that maximally tolerated doses of intravenous melphalan can safely be combined with oral misonidazole. In view of the large volumes of oral misonidazole required at the highest dose level, subsequent studies to determine the maximally tolerated dose of misonidazole should employ the intravenous form.
Adenocarcinoma↗
High-dose chemotherapy and autologous marrow transplantation for esthesioneuroblastoma and sinonasal undifferentiated carcinoma.
Eight patients with recurrent esthesioneuroblastoma or sinonasal undifferentiated carcinoma of the nasal or sinus cavities were treated with high-dose chemotherapy and autologous bone marrow transplantation. All patients had stage C disease initially and had received extensive prior conventional treatment with surgery, radiotherapy, and chemotherapy. Two patients achieved prolonged relapse-free survival for 18+ and 60 months. The latter patient relapsed at 60 months, but died of progressive disease after a second transplant. Two additional patients remain alive without disease progression at 17+ and 31+ months posttransplant. No deaths occurred secondary to toxicity. Progression of tumor accounted for failure in five patients. High-dose chemotherapy and autologous bone marrow transplantation should be considered as a salvage regimen for selected patients who fail conventional therapy for these diseases.
Adult↗
Extracellular adenosine triphosphate activates calcium mobilization in human phagocytic leukocytes and neutrophil/monocyte progenitor cells.
We have examined the ability of extracellular ATP to elicit intracellular Ca2+ mobilization in a broad range of human leukocytes at particular stages of hematopoietic differentiation. The average cytosolic [Ca2+] in various leukocyte populations was measured in Fura 2-loaded cell suspensions while the cytosolic [Ca2+] in individual, Indo 1-loaded leukocytes was assayed by flow cytometric methods. Utilizing normal blood- and marrow-derived cells, human leukemic cell lines, and mononuclear cell fractions derived from the blood of patients with various leukemias, we have found that ATP-induced Ca2+ mobilization appears restricted to leukocytes of neutrophil/monocyte ontogeny. Significant ATP-induced increases in cytosolic [Ca2+] were observed in neutrophils, monocytes, and myeloid progenitor cells as immature as myeloblasts, but not in lymphocytes. Extensive characterization of the ATP-induced changes in [Ca2+] observed in the HL-60 promyelocytic cell line have indicated these Ca2+-mobilizing effects of ATP can be correlated with an activation of inositol phospholipid breakdown via the occupation of P2-purinergic receptors Significantly, of the various agonists (FMLP, platelet-activating factor, LTB4, and ATP) which elicit equivalent and maximal Ca2+ mobilization in mature neutrophils and monocytes, ATP was the most efficacious stimulant of Ca2+ mobilization in immature neutrophil/monocyte precursors. Thus, expression of putative P2-purinergic receptors for ATP appears to precede expression of other receptor types known to activate the inositol phospholipid signaling cascades in terminally differentiated phagocytes.
Adenosine Triphosphate↗
High-dose cytarabine and daunorubicin as consolidation therapy for acute myeloid leukemia in first remission: long-term follow-up and results.
In an effort to increase the proportion of patients with acute myeloid leukemia (AML) remaining in continued complete remission (CCR), we administered intensive postremission consolidation therapy with high-dose cytarabine (Ara-C) and daunorubicin. Eighty-seven patients, with a median age of 38 years (range, 7 to 71), received consolidation therapy after first complete remission was obtained with standard induction chemotherapy that included conventional doses of Ara-C. Consolidation therapy consisted of from one to three cycles of high-dose Ara-C (3 g/m2 intravenously [IV] over 1 hour every 12 hours for 12 doses) followed by daunorubicin (30 mg/m2/d IV bolus for 3 days). After completion of the high-dose Ara-C and daunorubicin, no further therapy was administered. Myelosuppression encountered with consolidation resulted in a median duration of neutropenia and thrombocytopenia of 3 weeks. Four patients (5%) died during consolidation due to infection and/or hemorrhage; 59% of patients experienced severe but nonfatal infectious or extramedullary organ toxicity. With a median follow-up of more than 3.5 years from diagnosis, the proportion of patients, by Kaplan-Meier product-limit estimate, remaining in CCR is 49% (95% confidence limits, 37% to 61%). In a Cox multivariate analysis, only age significantly (P less than .001) influenced the probability of remaining in CCR. The probability of remaining in CCR was 83%, 50%, and 23% for age groups of 25 or less, 26 to 45, and more than 45 years, respectively. These survival curves all have stable long-term plateaus, suggesting cure. In this study, the administration of brief, intensive nonmarrow ablative chemotherapy resulted in a large proportion of patients with AML remaining in CCR, results similar to those reported with allogeneic bone marrow transplantation. Relapse of acute leukemia was still the major reason for therapy failure, suggesting that more effective or additional postremission therapy will be required to further improve the likelihood of cure especially for older patients.
Adolescent↗
An in vitro analysis of aminoglycoside corneal epithelial toxicity.
We evaluated the cytotoxicity of four aminoglycoside agents (neomycin, gentamicin, tobramycin, and amikacin) using an in vitro confluent rabbit corneal epithelial cell culture model. Primary corneal epithelial cell cultures were established and cells replated at 2 x 10(4) cells/2 cm2 well. After 48 hours either vehicle or an antibiotic was added at varying concentrations, each for 5, 30, or 60 minutes. 3H-thymidine was added immediately after drug removal and incorporation was measured 8 hours after drug or vehicle exposure. Comparisons of each drug to vehicle were expressed as % inhibition of control culture values. At the 5-minute exposure time tobramycin and amikacin showed no significant inhibition at any concentration, whereas neomycin and gentamicin showed significant inhibition at 6 mg/ml and 3.5 mg/ml or greater concentrations, respectively (p less than 0.05). At 30- and 60-minute exposure times all agents demonstrated significant inhibition at all tested concentrations in a non-dose dependent fashion (p less than 0.05). These in vitro data corroborate the animal and limited clinical data available for the aminoglycosides. Based on these toxicity profiles, tobramycin appears to be the topical agent of choice in the treatment of susceptible bacterial keratitis.
Aminoglycosides↗
An in vitro method which assesses corneal epithelial toxicity due to antineoplastic, preservative and antimicrobial agents.
We developed an in vitro model for studying the cytotoxicity of pharmacologic agents on corneal epithelium employing 3H-thymidine incorporation. Primary rabbit corneal epithelial cell cultures were established, and the cells plated prior to each experiment. 3H-thymidine incorporation was measured after the addition of drug or vehicle to these confluent cells, and dose-response curves were generated. Marked inhibition of 3H-thymidine incorporation was reached at chemotherapeutic concentrations achieved clinically for cytosine arabinoside (10(-7) M), methotrexate (10(-3) M), and 5-fluorouracil (10(-6) M). A 10(-4) M concentration of 2-deoxycytidine, a naturally occurring competitive inhibitor of cytosine arabinoside, protected cells up to a concentration of 10(-5) M. We utilized these data to undertake an in vivo prophylaxis study in 13 leukemia patients receiving high-dose iv cytosine arabinoside. Topical deoxycytidine 10(-4) M and 1% prednisolone phosphate, given 12 hours prior to the start of antileukemic therapy, were effective in reducing symptoms and signs of keratitis; both were better than historical placebo-treated eyes. Ophthalmic preservatives were studied in vitro at concentrations used clinically: benzalkonium chloride (BAC) (0.004-0.02%) was the most toxic, thimerosal (TMS) (0.001-0.004%) intermediate, and chlorobutanol (CHB) (0.2-0.5%) the least toxic. Antiviral agents (final concentration) included: trifluridine (TFT) (1.0%), ethyldeoxuridine (EDU) (2.0%), and idoxuridine (IDU) (0.1%). Dose but not time-dependent concentrations of these 3 agents were noted to cause toxicity; however, (E)-5(2-bromovinyl)-2'-deoxyuridine (BVDU) (0.1%) was non-toxic. Similarly, tobramycin and amikacin were significantly less toxic than gentamicin and neomycin in this system. These in vitro cytotoxicity data correlate well with previous in vivo and pre-clinical corneal epithelial toxicity studies. Our model may be useful in the toxicologic study of future topical ophthalmic agents.
Adult↗
Treatment of progressive Hodgkin's disease with intensive chemoradiotherapy and autologous bone marrow transplantation.
Twenty-six patients with progressive Hodgkin's disease after conventional chemotherapy received intensive chemoradiotherapy and autologous bone marrow transplantation (ABMT); 19 also received additional involved-field radiotherapy. Twenty-one patients [81%, 95% confidence intervals (CI) 61% to 94%] attained complete (n = 18) or partial responses. Ten patients (38%, 95% CI 20% to 59%) are disease-free a median of 4.5 years later (range 3.5 to 7.0 years), including seven patients with continuous complete responses. The likelihood of overall response was not significantly influenced by any clinical or treatment variable examined. However, there was a trend favoring patients with higher Karnofsky scores, and higher scores were associated with attainment of complete responses (P = .06 and P = .02, respectively, Mann-Whitney U test). Both higher Karnofsky scores and shorter durations of disease before transplantation were associated with improved survival in a stepwise Cox multivariate analysis. The chief cause of failure was progression at sites previously involved with Hodgkin's disease. No patient relapsed in the marrow, and two of three patients with a history of marrow involvement with Hodgkin's disease achieved durable complete responses after transplantation. These data suggest that inadequate pretransplant conditioning, and not the reinoculation of occult tumor cells in the autologous marrow, caused most relapses. Fatal treatment-related toxicity occurred in six patients. Three patients died of idiopathic interstitial pneumonitis; each had previously received local mediastinal irradiation before intensive chemoradiotherapy. Intensive chemoradiotherapy and ABMT produces durable responses in some patients with Hodgkin's disease incurable with conventional therapy. Use of such therapies at the first sign of failure with conventional chemotherapy and development of more effective conditioning regimens should further improve results.
Adolescent↗
Hematopoietic emergencies.
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Bone Marrow Diseases↗
Infectious emergencies in oncology patients.
The development of neutropenia in a patient undergoing therapy for cancer represents a serious medical problem that rapidly escalates if fever develops. A diligent history and physical examination cannot be overemphasized, since this maneuver may direct the medical person to quickly identify the source of the infection and initiate appropriate therapy. No time should be wasted, but every attempt should be made to quickly obtain body fluids or tissue for microbiologic culture purposes. Appropriate therapy should then be instituted in an empiric manner. The antibacterial agents that are chosen as initial therapy should be selected based on a knowledge of the current local ecology and the antibiotic resistances of endemic strains of bacteria. The empiric therapy should continue until the patient has evidence of recovery of bone marrow function. In those patients who have developed obvious tissue infection, such as pneumonia or bloodstream infection, the therapy should be continued until the infection is eradicated. In patients who have persistent fever despite broad-spectrum antibacterial agents, a painstaking search for the source and type of infection should continue, including repeated blood cultures and other tests. Additional antibiotic or fungal agents should be administered as the need arises. Such an approach to this group of patients has resulted in a significantly better outcome for cancer patients. With the advent of recombinant hematopoietic growth factors, which may allow for a more rapid marrow and immunologic recovery, the therapy for the neutropenic patient should continue to improve.
Agranulocytosis↗
Rapid infusion amphotericin B: effective and well-tolerated therapy for neutropenic fever.
A retrospective analysis was carried out of the results of 115 intensively-treated cancer inpatients receiving 91 treatment courses of amphotericin B given in an empirical fashion. Amphotericin B was administered over 1.5 to 2 hours at a dose of 0.6 to 0.7 mg/kg/day. Median duration of neutropenic fever before amphotericin B administration was 5 days (range 1 to 32 days) and median total amphotericin B dose was 480 mg (range 10 to 2450 mg). In 56 (61%) of 91 amphotericin B courses, neutropenic fevers resolved; this occurred a median of 3 days (range 1 to 15 days) after amphotericin B was begun and at a median dose of 120 mg (range 10 to 850 mg). Response to amphotericin was independent of positive cultures for fungus or sites of positive culture. Adverse reactions to amphotericin B included rigors (89% of courses), fever (23%), bronchospasm (9%), and transient hypotension (9%). Median increase above baseline serum creatinine in patients given amphotericin B was 0.5 mg/dl (range 0 to 2.6 mg/dl) compared to a median of 0.1 mg/dl (range 0 to 2.9 mg/dl) in a similar group of intensively-treated cancer patients who did not receive amphotericin B. Amphotericin B was well tolerated when given by rapid infusion and was associated with prompt resolution of neutropenic fever in the majority of patients.
Adolescent↗
Treatment of myelodysplastic syndromes with low-dose oral 6-thioguanine.
Several cytotoxic agents when used in vitro in very low concentrations have been shown to induce differentiation of leukemic cells. We treated 18 patients with myelodysplastic syndromes with low-dose oral 6-thioguanine (6-TG; 20 to 60 mg daily). Four patients demonstrated significant improvement in peripheral blood counts. An additional three patients had significant reductions in the percentage of leukemic myeloblasts in the marrow without a corresponding improvement in peripheral counts. With the exception of a fall in the peripheral neutrophil count in four patients requiring dose reductions, no toxicity was observed. Low-dose oral 6-TG gives a response rate in myelodysplastic syndromes similar to that of parenteral agents such as cytosine arabinoside. Given the ease of administration and lack of toxicity, oral 6-TG may be a useful treatment modality for these syndromes either alone or in combination with other differentiation-enhancing agents.
Administration, Oral↗
An in vitro study of ophthalmic antiviral agent toxicity on rabbit corneal epithelium.
Using an in vitro system we measured the corneal epithelial cytotoxicity and the antiviral activity of the antiviral agents idoxuridine (IDU), trifluridine (TFT), ethyldeoxyuridine (EDU), and (E)-5-(2-Bromovinyl)-2'-deoxyuridine (BVDU). Confluent rabbit corneal epithelial cell cultures were established, and the antiviral agents were added for 5, 30, or 60 min at a range of concentrations including that used clinically (IDU 0.1%, TFT 1.0%, BVDU 0.1%, EDU 2.0%). Twelve hour [3H]thymidine incorporation then was measured and expressed as % inhibition of control cultures. In separate experiments confluent corneal epithelial cell monolayers were inoculated with 10(4) plaque forming units (PFU) of HSV type 1 (McKrae strain) for 1 h, and IDU 0.1%, TFT 1.0%, and BVDU 0.1% were added to the culture for determination of PFU inhibition. Significant dose-, but not time-dependent, toxicity was observed at the clinical concentrations of IDU, TFT, and EDU. Toxicity was absent for BVDU. TFT and IDU were the most toxic, and EDU was of intermediate toxicity. IDU, TFT, and BVDU showed significant antiviral activity in this corneal epithelial cell culture system (TFT greater than BVDU greater than IDU). The results of this in vitro study paralleled the findings of previous in vivo corneal epithelial toxicity studies of IDU, TFT, and BVDU. Our data, however, suggest that EDU has a potential for clinical toxicity and further studies are recommended. Our model may be useful in the future toxicologic study of new antiviral agents.
Animals↗