Factors associated with successful mobilization of peripheral blood progenitor cells in 200 patients with lymphoid malignancies

To examine the repertoire of Pneumocystis carinii antigens recognized by antibody-secreting B cells from tracheobronchial lymph nodes isolated immediately following recovery from P. carinii pneumonia, monoclonal antibodies (MAbs) were produced from these cells. In contrast to previous studies of systemic immunity, P. carinii gpA was not the immunodominant antigen recognized by these B cells. Forty-nine (91%) of 54 P. carinii-specific hybridoma culture supernatants reacted with P. carinii antigens other than gpA. Many of the resulting MAbs recognized a previously uncharacterized antigen expressed on the surface of both cysts and trophozoites. Western blotting using one of the cloned MAbs revealed reactivity with a broad range of antigenic material, with the most intense reactivity in the 50- to 65-kDa region of the blot. The antigens identified by these MAbs merit further investigation regarding protective immunity to P. carinii because they were recognized by B cells in the context of recovery from P. carinii pneumonia.     

Growth of cultured cells from patients with ataxia-telangiectasia

Fibroblast cultures derived from skin biopsies of patients with ataxia-telangiectasia had doubling times (mean of five lines: 29.9 +/- 0.6 hours) significantly longer than normal controls (mean of ten lines: 22.4 +/- 0.5 hours).     

Urate oxidase in prevention and treatment of hyperuricemia associated with lymphoid malignancies

Standard prophylaxis and treatment of malignancy-associated hyperuricemia in the USA has been allopurinol with vigorous hydration, urinary alkalinization and osmotic diuresis. Urate oxidase, the enzyme that converts uric acid to allantoin (a readily excreted metabolite that has 5- to 10-fold higher solubility than uric acid), is an alternative therapy; however, few published findings support this practice. Between February 1994 and December 1996, we administered non-recombinant urate oxidase (Uricozyme) to 126 children with newly diagnosed non-B cell acute lymphoblastic leukemia (ALL) during the first 5 days of chemotherapy with methotrexate, 6-mercaptopurine or both. Their blood levels of uric acid and other indicators of tumor lysis were measured at diagnosis and during treatment and then compared with findings in 129 similarly treated historical controls who had received allopurinol to control hyperuricemia. Clinical responses to urate oxidase were also determined in eight patients with newly diagnosed B cell ALL or advanced-stage non-Hodgkin lymphoma. Patients treated with urate oxidase had rapid and significantly greater decreases in their blood uric acid levels than did the historical controls (median maximal level during treatment, 2.3 vs 3.9 mg/dl, P < 0.001). They also had lower creatinine (0.6 vs 0.7 mg/dl, P = 0.01) and blood urea nitrogen (11 vs 24 mg/dl, P < 0.001) levels. Similar findings were made in the eight cases of B cell ALL or non-Hodgkin lymphoma. None of the patients required dialysis for acute renal failure. Six (4.5%) of the 134 children given urate oxidase had allergic reactions, manifested primarily by urticaria, bronchospasm and hypoxemia. Thus, non-recombinant urate oxidase is a more effective uricolytic agent than allopurinol but is associated with acute hypersensitivity reactions, even in patients without a history of allergy.     

Xenotransplantation of human lymphoid malignancies is optimized in mice with multiple immunologic defects

While it is known that mice with genetic immune defects are useful for establishing durable engraftment of human tumor xenografts, the relative role of components of host innate and adoptive immunity in engraftment has not been determined. We directly compared the ability of four strains of genetically immunodeficient mice (NOD/SCID, SCID, Nude and Rag-1-deficient) to successfully engraft and support the human cell lines Daudi, Raji, Namalwa and Molt-4 as subcutaneous tumors. We additionally examined the effect of further immunosuppression of the mice by whole body irradiation at a dose of 600 cGy for Nude and Rag-1 and 300 cGy for SCID mice and by administration of anti-natural killer (asialo-GM1) antibody on tumor growth. Mice with each of the defects supported xenografts to varying degrees. We found differences in growth characteristics in the cell lines tested, with Namalwa consistently producing the largest tumors. With all cell lines studied, optimal growth was achieved using NOD/SCID mice. Overall, tumor growth was somewhat enhanced by pretreatment with radiation with little additional benefit from the addition of anti-asialo-GM1 antibody. The importance of multiple components of the innate and adoptive immune system in xenotransplantation were best demonstrated when results in untreated NOD/SCID mice were compared to SCID, nude and RAG-1-deficient mice. The NOD/SCID mouse with or without additional immunosuppression provides the optimal model for the study of the biology and treatment of human leukemias and lymphomas.     

Seroprevalence study of HTLV-1 and HIV infection in blood donors and patients with lymphoid malignancies in Lagos, Nigeria

OBJECTIVE: To document the seroprevalence of HTLV-1 and HIV in blood donors and in patients with lymphoma and leukaemia in Lagos metropolis. DESIGN: Cross sectional. SETTING: The Lagos University Teaching Hospital (LUTH) and General Hospital, Lagos (GH). SUBJECTS: 406 apparently healthy voluntary blood donors from the LUTH and GH and 30 patients [20 patients with histological diagnosis of Non-Hodgkin's Lymphoma (NHL) and 10 patients with diagnosis of Chronic Lymphocytic Leukaemia (CLL)] were recruited at LUTH. MAIN OUTCOME MEASURES: HTLV-1 and HIV-1 seroprevalence. RESULTS: Out of 406 donors, three (0.7%) were positive for HTLV-1 and 20 (4.9%) were positive for HIV-1. None of the 30 patients with NHL or CLL were positive for HTLV-1. Five of NHL patients were positive for HIV-1. CONCLUSION: HTLV-1 seroprevalence is low among Lagos donors. Routine screening of donors for this virus will not be cost effective. NHL is one of the AIDS related malignancies which has been documented in this study.     

Neurological and cytogenetic study in early-onset ataxia-telangiectasia patients

The clinical diagnosis of ataxia-telangiectasia (AT) is difficult before the age of 4 years. We report clinical and cytogenetic data on three early-onset, early-diagnosed AT patients at the age of 12, 18 and 22 months, respectively. Postural instability of the trunk, characterized by motor impersistence, was the earliest neurological sign detected as early as 1 year of life. Dystonic movements and postures of arms and trunk and a subtle disorder of eye movement (blinking before gaze changing, increased latency and dysmetry of saccades) were observed during the 2nd year of life. All patients exhibited an unusual temper tantrum. We also observed an increased bleomycin-induced chromosomal instability in patient's cells in the early stages of the disease before all the clinical hallmarks were apparent. Our data suggest that detection of clinical indications, leading to early laboratory confirmation of AT, can reduce the age at diagnosis.     

CD30 ligand is frequently expressed in human hematopoietic malignancies of myeloid and lymphoid origin

CD30 ligand (CD30L) is a type-II membrane glycoprotein capable of transducing signals leading to either cell death or proliferation through its specific counterstructure CD30. Although several lines of evidence indicate that CD30L plays a key role as a paracrine- or autocrine-acting surface molecule in the deregulated cytokine cascade of Hodgkin's disease, little is known regarding its distribution and biologic significance in other human hematopoietic malignancies. By analyzing tumor cells from 181 patients with RNA studies and immunostaining by the anti-CD30L monoclonal antibody M80, we were able to show that human hematopoietic malignancies of different lineage and maturation stage display a frequent and broad expression of the ligand. CD30L mRNA and surface protein were detected in 60% of acute myeloid leukemias (AMLs), 54% of B-lineage acute lymphoblastic leukemias (ALLs), and in a consistent fraction (68%) of B-cell lymphoproliferative disorders. In this latter group, hairy cell leukemia and high-grade B-cell non-Hodgkin's lymphoma (B-NHL) expressed a higher surface density of CD30L as compared with B-cell chronic lymphocytic leukemia and low-grade B-NHL. Purified plasmacells from a fraction of multiple myeloma patients also displayed CD30L mRNA and protein. A more restricted expression of CD30L was found in T-cell tumors that was mainly confined to neoplasms with an activated peripheral T-cell phenotype, such as T-cell prolymphocytic leukemia, peripheral T-NHL, and adult T-cell leukemia/lymphoma. In contrast, none of the T-lineage ALLs analyzed expressed the ligand. In AML, a high cellular density of CD30L was detected in French-American-British M3, M4, and M5 phenotypes, which are directly associated with the presence on tumor cells of certain surface structures, including the p55 interleukin-2 receptor alpha-chain, the alpha(M) (CD11b) chain of beta2 integrins, and the intercellular adhesion molecule-1 (CD54). Analysis of normal hematopoietic cells evidenced that, in addition to circulating and tonsil B cells, a fraction of bone marrow myeloid precursors, erythroblasts, and subsets of megakaryocytes also express CD30L. Finally, we have shown that native CD30L expressed on primary leukemic cells is functionally active by triggering both mitogenic and antiproliferative signals on CD30+ target cells. As opposed to CD30L, only 10 of 181 primary tumors expressed CD30 mRNA or protein, rendering therefore unlikely a CD30-CD30L autocrine loop in human hematopoietic neoplasms. Taken together, our data indicate that CD30L is widely expressed from early to late stages of human hematopoiesis and suggest a regulatory role for this molecule in the interactions of normal and malignant hematopoietic cells with CD30+ immune effectors and/or microenvironmental accessory cells.     

2-Chlorodeoxyadenosine: a newer purine analog active in the treatment of indolent lymphoid malignancies

OBJECTIVE: To review the structure, mechanism of action, pharmacologic features, and clinical trial results of the newer purine analog, 2-chlorodeoxyadenosine (2-CdA). DATA SOURCES AND STUDY SELECTION: English-language medical literature review of more than 70 articles. DATA SYNTHESIS: 2-Chlorodeoxyadenosine is unique compared with traditional antimetabolite drugs in that it is equally active against dividing and resting lymphocytes, which may be especially important in indolent lymphoid malignancies, such as chronic lymphocytic leukemia, because most cells in these disorders are in the resting phase. In patients with alkylator-refractory chronic lymphocytic leukemia who were treated with 2-CdA, 44% achieved a response (4% complete responses, 40% partial responses), and 54%, scored as nonresponders, had a sustained reduction in their peripheral lymphocytosis. Patients with untreated chronic lymphocytic leukemia had an 85% response rate (25% complete responses, 60% partial responses). Patients with previously treated low-grade lymphoma achieved an overall response rate of 43%. The most striking clinical effects of this drug have been seen in hairy cell leukemia, in which a single course of therapy induces complete remissions in 85% of partial remissions in 12%. Activity has also been shown in cutaneous T-cell lymphoma and the myeloid leukemias. CONCLUSIONS: 2-Chlorodeoxyadenosine is a newer purine analog with potent activity in the treatment of indolent lymphoproliferative diseases and illustrates the model for rational drug development.     

Insulin-resistant diabetes mellitus in a black woman with ataxia-telangiectasia

A 24-year-old woman with ataxia-telangiectasia had traumatic arthritis, elevated serum transaminase values, polyuria, polydipsia, and a serum glucose level of 575 mg/dL. A relatively high daily dose of insulin (2.8 U/kg) was required to achieve near normoglycemia. The fasting insulin concentration was elevated. During an insulin-modified frequently sampled intravenous glucose tolerance test, the first phase of insulin release in response to the administration of glucose was blunted. The insulin sensitivity was similar to that found in individuals with non-insulin-dependent diabetes mellitus. Insulin receptor antibodies were not detected in the serum. We conclude that insulin resistance and islet beta-cell dysfunction are characteristics of diabetes mellitus in ataxia-telangiectasia. Contrary to a previous report, our findings do not support a cause-and-effect relationship between insulin receptor antibodies and insulin resistance in this disorder.     

Piperacillin-tazobactam as empiric monotherapy in febrile neutropenic patients with haematological malignancies

To examine the relationship between apolipoprotein E (apoE) phenotype and life span, we measured the frequently of the apoE phenotype and allele in 54 Japanese centenarians who lived in the Tokyo metropolitan area in 1994, 1995, and 1996. The control group consisted of 973 subjects, 883 healthy volunteers who were described previously and 90 healthy people who came to the Keio health consulting center. The apoE phenotypes in the centenarians was 2 E2/E2 (3.7%), 5 E2/E3 (9.3%), 38 E3/E3 (70.4%), and 9 3E/E4 (16.7%). No other phenotype was observed. In the control group, the phenotypes were 2 E2/E2 (0.2%), 57 E2/E3 (5.9%) 712 E3/E3 (73.2%), and 179 E3/E4 (18.4%). The frequency of E2 was higher in the centenarians. The frequencies of the apoE allele in the centenarians and the control subjects were epsilon 2 8.3% vs. 3.5%, epsilon 3 83.3% vs. 85.4%, and epsilon 4 8.3% vs. 10.9%. The frequency of the apoE allele differed significantly between centenarians and control subjects (chi 2 = 6.84, p = 0.033). Levels of serum cholesterol and apolipoprotein B were significantly lower in the E2/E2 + E2/E3 centenarians. Studies of the frequency of the apoE allele in Japanese, French, and Finnish subjects showed that epsilon 2 is more frequent and epsilon 4 is less frequent in centenarians. These data show the apoE phenotype may affect life span: epsilon 2 is positively and epsilon 4 is negatively associated with longevity.     

Treatment of mucosa-associated lymphoid tissue lymphoma of the stomach with radiation alone

PURPOSE: Mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach (MLS) has recently been defined as a distinct clinicopathologic entity, often associated with Helicobacter pylori infection. Many regard antibiotic therapy as the primary treatment of MLS, but in the absence of H pylori infection, or when salvage of antibiotic failures is required, gastrectomy and/or chemotherapy have frequently been used. This study evaluates the efficacy of low-dose radiotherapy alone as an alternative to surgery. PATIENTS AND METHODS: Seventeen patients with stage I to II(2) low-grade MLS without evidence of H pylori infection or with persistent lymphoma after antibiotic therapy of associated H pylori infection were included in this series. Median age was 69 years (range, 39 to 84). Median total radiation dose was 30 Gy (range, 28.5 to 43.5 Gy) delivered in 1.5-Gy fractions within 4 weeks to the stomach and adjacent lymph nodes. Following treatment, all patients underwent endoscopic evaluation and biopsy at a median of 4 months, at 6-month intervals to 2 years, and annually thereafter. RESULTS: All obtained a biopsy-confirmed complete response. At a median follow-up time of 27 months (range, 11 to 68) from completion of radiotherapy, event-free survival was 100%. Treatment was well tolerated, with no significant acute side effects. All remained asymptomatic at last follow-up. CONCLUSION: These results suggest that effective treatment of MLS with low-dose radiation therapy alone is feasible and safe, and allows stomach preservation. Longer follow-up evaluation is required to determine the long-term efficacy of this treatment approach and its side effects. Further studies should clarify the indications for radiotherapy in H pylori-negative or antibiotic-resistant cases of MLS.     

Management of infective complications in patients with advanced hematologic malignancies in home care

A home care service has been implemented at our center with the aim of offering domiciliary assistance to patients with hematologic malignancies in advanced phase. We report our experience concerning the home management of these patients in the setting of infective complications. Of 151 patients in home care, 70 (46%) developed a total of 109 febrile episodes, performance status and neutrophil count significantly affecting the incidence of infections. Fever was of unknown origin in 51% of cases and microbiologically and clinically documented infections accounted for 26 and 23% of the cases, respectively. Oral ciprofloxacin in patients not neutropenic and intravenous ceftriaxone plus amikacin in neutropenic patients was shown to be effective and suitable for empiric home antibacterial treatment; in fact, 65% of febrile episodes responded to the initial antibacterial therapy with a further 16% after modification. Overall, 19.3% of the infective episodes were fatal, the prognosis appearing to be similar to that usually observed in the same category of patients in an inpatient setting. Our experience appears to show that a home care program could be the option of choice for patients with advanced cancer even in the setting of infective complications. It could improve the quality of life of patients and of their families, and it could save these subjects the risk of developing infections by resistant nosocomial isolates.     

Renal masses simulating primary renal cell carcinoma in patients with advanced malignancies

Most patients who present with a large solid renal mass and evidence of advanced malignancy will have primary renal cell carcinoma but a small subset with similar features have different and more treatable malignancies. We identified 7 patients with clinical and radiological findings suggestive of metastatic renal cell carcinoma who were ultimately diagnosed as have non-Hodgkin's lymphoma (5), germ cell tumor (1) or transitional cell carcinoma (1). Two of these patients presented with abdominal pain, gross hematuria and a flank mass. Computerized tomography was interpreted as showing renal cell carcinoma in all patients, although lymphoma and sarcoma were included in the differential diagnoses in 2. With the correct diagnosis and appropriate therapy, 4 of the 7 patients are currently disease-free. We emphasize the need for histological documentation in such patients in view of curative therapy available for possible underlying neoplasms simulating renal cell carcinoma.     

Treatment-related parameters predicting efficacy of Lym-1 radioimmunotherapy in patients with B-lymphocytic malignancies

The aim of this study was to evaluate the in vivo stability of ECD brain SPECT. METHODS: Twenty normal volunteers (35.4 +/- 9.1 yr) each had six ECD scans at 30, 60, 120, 240, 360 and 480 min postinjection. Each scan was acquired for 24 min using a triple-head SPECT system. Average counts per pixel were measured from frontal, temporal, parietal, occipital, cerebellum, basal ganglia, thalamus and white matter regions. ECD clearance rates were calculated by fitting regional time activity data to a monoexponential equation. Regional gray-to-white matter (G/W) and gray-to-cerebellum (G/C) ratios were calculated for each scan. Analysis of variance was used to compare regional ECD clearance and ratio measurements. RESULTS: The average ECD clearance was 4.3%/hr. There was a significant regional variation in the ECD clearance, being higher for occipital (6.34%/hr) but lower for both white matter (2.39%/hr) and thalamus (2.45%/hr). Both G/W and G/C ratios showed a significant regional variation with time. The overall G/W ratio was 2.13 at 30 min and became progressively lower after 2 hr, reaching 1.78 at 8 hr. All regional G/W ratios declined with time except for thalamus where it remained constant at 2.15. The overall G/C ratio was 0.984 at 30 min but it declined after 4 hr, reaching 0.955 at 8 hr. All regional G/C ratios declined with time except for thalamus where it increased progressively from 0.955 to 1.120 at 8 hr. CONCLUSION: ECD clears from normal brain slowly and shows a significant regional variation. As a result, G/W contrast begins to decrease after 2 hr and the gray-matter activity pattern becomes significantly different after 4 hr. Therefore, the optimal imaging time may be between 30-120 min. However, images obtained up to 4 hr still maintain the initial gray-matter activity pattern.     

Red blood cell glutathione status in patients with gastrointestinal malignancies treated with 5-fluorouracil

As an alternative to surgical splenectomy, partial splenic embolization was performed in seven children for hypersplenism manifested by splenomegaly, thrombocytopenia, leukopenia, and erythrocyte hemolysis. Within a few days, platelet and leukocyte counts rose significantly in all patients and were maintained in six of seven patients during a follow-up period of 9 to 69 months. Spleen size and abdominal distention also decreased significantly in all children. There were no infectious complications.     

Coagulation system in patients with blood malignancies treated with estrogens in the course of cytostatic therapy

Hospital managers initiate a nurse orientation program modeled after critical pathways. The structure allows them to assess nurses' competency while providing experience.