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PURPOSE: Rituximab was recently approved for use in relapsed, low-grade non-Hodgkin's lymphoma; however, few data exist regarding the safety of this agent in patients with a high number of tumor cells in the blood. METHODS AND RESULTS: After the observation at our institution of a rapid reduction of peripheral-blood tumor cells with associated severe pulmonary infusion-related toxicity in two patients with refractory hematologic malignancies, data on three additional cases were collected from physician-submitted reports of adverse events related to rituximab treatment. Five patients with hematologic malignancies possessing a high number of blood tumor cells were treated with rituximab and developed rapid tumor clearance. The median age was 68 years (range, 26 to 78 years). Patients were diagnosed with B-cell prolymphocytic leukemia (n = 2), chronic lymphocytic leukemia (n = 2), or transformed non-Hodgkin's lymphoma (n = 1). All of these patients had bulky adenopathy or organomegaly. All five patients developed a unique syndrome of severe infusion-related reactions, thrombocytopenia, rapid decrement in circulating tumor cell load, and mild electrolyte evidence of tumor lysis, and all required hospitalization. In addition, one patient developed ascites. These events resolved, and four patients were subsequently treated with rituximab without significant complications. CONCLUSION: Rituximab administration in patients who have a high number of tumor cells in the blood may have an increased likelihood of severe initial infusion-related reactions. These data also suggest that rituximab may have activity in a variety of other lymphoid neoplasms, such as chronic lymphocytic leukemia and B-cell prolymphocytic leukemia.

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The Department of Defense (DoD) military health system has responsibility for providing medical care for more than 8 million beneficiaries. This article discusses initiatives related to both the providing and purchasing of oncology services. A description of health care coverage under TRICARE, the Department's managed care program, which utilizes military treatment facilities and civilian health care providers, is provided. Participation in clinical trials by the DoD beneficiaries, oncology services in military treatment facilities, quality management programs, cancer research, and the development of new technologies to enhance early cancer detection are presented. Access to research trials and new technologies is necessary for a comprehensive approach to cancer care. Clinical trials have been the vehicle by which the oncology community developed most of its formal clinical evidence for the efficacy of various treatment approaches. The Department participates in clinical trials through cooperative group membership or affiliation. Through an interagency agreement with the National Cancer Institute, DoD beneficiaries have available the option of participating in NCI-sponsored clinical trials through the direct military care system or through civilian care with reimbursement for approved protocols nationwide. The DoD has been actively involved in breast cancer research since 1992 and prostate and ovarian cancer research since 1997. The goals of the cancer research programs are to expedite and facilitate breakthroughs in research, support innovative, and exploratory ideas with a vision to foster new directions, address neglected issues, and bring new investigators into the research arena. The program incorporates the consumer perspective by involving consumers in the decision-making process. The DoD health care system trains experts in the management of cancer patients and provides a multidisciplinary approach to care through the direct military health care system or through network providers as part of the TRICARE system. Although cost containment is key, the delivery of high quality health care that is easily accessible is a primary goal of the military health system. Provision of a comprehensive benefits package that includes a spectrum of care and employing outcomes measurements to evaluate care that is appropriate for the patient's disease is essential.

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BACKGROUND: Methotrexate is a chemotherapeutic agent frequently utilized for the treatment of malignant, rheumatic, and pulmonary diseases. Although this agent has been extensively used for more than 45 years, there are few reports of immediate systemic hypersensitivity reactions. The reported immediate reactions include anaphylaxis, urticaria, and hepatitis. However, these reactions have been reported to occur only after some prior exposure to methotrexate. No immediate hypersensitivity reactions to methotrexate have been reported during the initial exposure. We describe two patients who developed immediate systemic hypersensitivity reactions during the initial administration of methotrexate. METHODS: The clinical outcomes of two patients treated by the Hematology/Oncology department at a tertiary care military medical center are described. The National Library of Medicine in Bethesda, Maryland, was electronically searched for the literature review. RESULTS: Patient 1, a 30-year-old male with localized high grade osteosarcoma of the left distal femur, developed generalized pruritus, urticaria, angioedema, and pharyngeal edema within 10 minutes of receiving the initial administration of intravenous high-dose methotrexate. No other pharmaceutical agents, such as antiemetics, were found to cause symptoms on rechallenge. The severity of this reaction precluded continuation of methotrexate therapy. Patient 2, a 23-year-old male with localized high grade osteosarcoma of the right distal tibia, developed pruritus and urticaria within 30 minutes of receiving the initial administration of intravenous high dose methotrexate. This patient, like most patients with immediate hypersensitivity reactions to methotrexate, developed recurrent symptoms during rechallenge of this agent despite prophylactic premedication. CONCLUSIONS: Unlike prior reports in our literature, our cases demonstrate that anaphylactoid reactions can occur during the initial exposure to methotrexate. Clinicians must be prepared to treat potentially life-threatening reactions with both the initial and subsequent doses of methotrexate.

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Antibodies to mature blood neutrophils and to bone marrow myeloid cells have been described in the sera of some patients with apparent autoimmune neutropenia. To further explore the prevalence and specificities of antibodies to myeloid precursor cells, we evaluated sera from 148 patients with suspected autoimmune neutropenia for the presence of antibodies to neutrophils, to cultured myeloid cell lines, and to highly purified bone marrow myeloid progenitor cells. Using an immunofluorescence flow cytometric assay, we identified IgG antibodies in 42 (28%) of these sera that bound specifically to K562 cells, a multilineage cell line originally derived from a patient with chronic myelogenous leukemia. Twenty-two (15%) of the sera also contained IgG antibodies that bound specifically to the primitive myelomonocytic leukemia cell line KG1a. Twenty-five (17%) of the sera had IgG antibodies to myeloid cell lines in the absence of antibodies to mature neutrophils. There was a trend toward more severe neutropenia in patients with antibodies to K562 cells, without antineutrophil antibodies. In further studies, antibodies from 12 sera bound to mononuclear CD34+ cells that had been purified from normal human bone marrow by an immunomagnetic separation procedure. Moreover, two of these sera suppressed the growth of granulocyte-macrophage colony-forming units (CFU-GM) in methylcellulose cultures. The presence of antibodies to primitive hematopoietic cells in the sera of some patients with suspected immune neutropenia suggests that these antibodies may have a role in the pathogenesis of the neutropenia observed.

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Hexamethylene bisacetamide (HMBA) is a potent in vitro differentiating agent that has clinical potential as an anticancer drug both as a single agent and as a component of combination therapy. A sensitive and efficient GC method for the isolation, derivatization, and measurement of both HMBA and its two major metabolites in plasma and urine in a single analysis is described. In situ carbamylation of the biological sample with diethylpyrocarbonate forms the urethane derivative of the basic N-acetyl diaminohexane metabolite and allows analyte isolation and concentration by solid-phase extraction. Subsequent formation of the n-butyl ester of 6-acetamidohexanoic acid, the major metabolite, provides a derivatized biological extract that can be rapidly analyzed by temperature-programmed GC. The quantitative extraction and the efficient derivatization steps provide a limit of quantitation of 0.05 mM (10 micrograms/ml) for all analytes with a precision better than 8% for the range of in vitro activity (0.1-2.0 mM). This method is amenable to automation and is well-suited for the analysis of clinical samples.

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A Phase I clinical trial and pharmacological study of nasogastrically administered hexamethylene bisacetamide, a polar-planar compound with in vitro differentiating activity, was conducted in 14 adult patients with refractory cancer. Hexamethylene bisacetamide was administered as a 5% (w/v) solution via a nasogastric or gastrostomy tube every 4 h for 5 days, followed in 21 days by a 5-day continuous i.v. infusion at the same daily dose. Parenteral drug administration was then continued at the same interval in the absence of disease progression or unacceptable toxicity. Three patients each were treated at doses of 12 and 24 g/m2/day, while eight patients received a dose of 30 g/m2/day. Toxicity was comparable for both routes of drug administration at the above doses. Nasogastrically administered hexamethylene bisacetamide was well tolerated at the lower doses, whereas neurotoxicity and nausea and vomiting were the major, but manageable, toxicities at 30 g/m2/day. Metabolic acidosis, renal dysfunction, mucositis, and thrombocytopenia were the other commonly observed drug toxicities at this dose. No objective tumor responses were observed. Hexamethylene bisacetamide was rapidly absorbed from the gastrointestinal tract with a mean measured bioavailability of 99 +/- 15%. Pharmacokinetic parameters for hexamethylene bisacetamide and plasma concentrations of the two major metabolites, N-acetyl-1,6-diaminohexane and 6-acetamidohexanoic acid, were similar for either route of administration in individual patients. Hexamethylene bisacetamide exhibited apparent monoexponential plasma elimination after either nasogastric or parenteral administration with 27 to 60% of the administered dose being excreted in the urine as parent compound. Based on its demonstrated complete bioavailability and tolerability, nasogastric administration of hexamethylene bisacetamide can be directly and safely substituted for the comparable i.v. dose.

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Data are limited on the localization of Ga-67 in primary or metastatic adrenal cortical carcinoma. We report the localization of Ga-67 to pathologically confirmed adrenal cortical carcinoma metastatic to the lung. A review of the literature revealed four patients have previously been reported to have metastatic adrenal cortical carcinoma detected on Ga-67 scan. Gallium imaging may be useful in the evaluation of patients with adrenal cortical carcinoma. SPECT imaging should further improve lesion resolution and localization.

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Our patient had stage IIIAI Hodgkin's disease with synchronous myelofibrosis and myeloid metaplasia. A slowly progressive myeloproliferative disease developed over 9 1/2 years and terminated in a painful osteolytic bone disease, spinal extradural granulocytic sarcoma and acute megakaryocytic leukemia. It is likely that this was a result of the myeloproliferative disease rather than a late complication from combination chemotherapy. Our case demonstrates the importance of a curative approach to Hodgkin's disease even in the face of a coexistent disease with a long or unknown natural history.

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Shared haplotypes have been documented in three of the four previously reported families with familial hairy cell leukemia (HCL). Human leukocyte antigen (HLA) typing was done on a four-member sibship in which two siblings had hairy cell leukemia. The two affected siblings share the haplotype A2; Bw6, Bw62(15); Cw1; DR4, DRw53; DQw3. No one HLA antigen or haplotype is common among the five families reported at this time. These limited data suggest HCL is not associated with a specific HLA antigen. HLA typing of a larger collection of cases of familial HCL may help better define what role, if any, inheritance plays in the occurrence of this rare disorder among numerous first degree relatives.

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