Pilot study of 13cis-retinoic acid+dexamethasone+alpha interferon as maintenance therapy following high-dose chemotherapy and autologous stem cell transplant for multiple myeloma.

Interleukin 6 (IL-6) is a major growth factor for myeloma cells and retinoids have been shown to inhibit expression of the interleukin 6 receptor (IL-6R). We performed a pilot study to assess the efficacy and tolerability of 13cis retinoic acid (13cRA) and dexamethasone (Dex), when added to interferon alpha (IFNalpha) as maintenance therapy post autologous stem cell transplantation. Between 90 and 120 days post stem cell transplantation, 33 patients were started on 13cRA 1 mg/kg p.o. daily for 14 days and Dex 40 mg p.o daily for 5 days every month. 13cRA was dose escalated by 0.5 mg/kg/month to 2 mg/kg. Seventeen patients had a persistent paraprotein post transplant. Overall, a response to therapy was observed in 11/17 (64%), with a complete response in 4/17 (23.5%) and a partial response (>/=50% paraprotein decline) in 7/17 (41%). With a median follow-up of 34.8 months, 22/33 (66%) demonstrated disease progression and 11/33 (33%) died. The median progression-free survival from diagnosis was 34.7 months. Although a decline in paraprotein was frequently observed on triple therapy, many patients discontinued therapy due to the side-effects of the IFNalpha. Future trials should be designed using 13cRA and Dex alone.

Persistently positive culture results in a patient with community-acquired pneumonia due to Legionella pneumophila.

We describe a patient with community-acquired pneumonia due to Legionella pneumophila serogroup 6. This patient was found to have bronchoalveolar carcinoma of the lung by means of cytologic testing in 1 of 2 bronchoalveolar lavage samples, but no lesions were visible on bronchoscopy. Despite intravenous administration of azithromycin to the patient, repeat culture and polymerase chain reaction showed persistence of Legionella; the isolates remained susceptible to azithromycin. The patient did not respond to 14 doses of daily intravenously administered azithromycin. The poor outcome may have been partially due to the suspected underlying lung malignancy, as shown by cytologic examination, and by a delay in seeking medical attention.

Does early treatment with high-dose methylprednisolone alter the course of hepatic regimen-related toxicity?

Hepatic regimen-related toxicity (RRT) is a serious complication of stem cell transplantation. Cytokine activation may be involved in the pathogenesis. Corticosteroids are potent inhibitors of cytokine production, and, therefore could play a role in the treatment of hepatic RRT. Between January 1994 and June 1998, 28 of 782 consecutive transplant patients (3.6%) developed hepatic RRT (20 veno-occlusive disease (VOD) and eight liver dysfunction of uncertain etiology (LDUE) as defined by Seattle criteria), and were treated with high-dose methylprednisolone (MP, 500 mg/m2 i.v. every 12 h for six doses), initiated upon increase in serum total bilirubin to > or =4 mg/dl. Other causes of liver dysfunction were excluded. Response to therapy with high-dose MP was defined as reduction in total bilirubin by 50% within 10 days of initiation of MP. Overall, 17 patients (61%) responded to treatment (12 patients with VOD, five patients with LDUE). The bilirubin in responding patients decreased from a mean of 8.6 mg/dl (range, 4-17.9) at the start of MP to 4.1 mg/dl (range, 0.5-17.9) 10 days later. There were no statistically significant differences between responders and non-responders in the day treatment with high-dose MP was initiated (P = 0.38), total serum bilirubin (P = 0.17) and percent weight gain at the time high-dose MP was started (P = 0.10) or the calculated probability of fatal outcome from VOD (18% for responders, 23% for non-responders; P = 0.30). A lower pre-transplant DLCOc was observed among non-responders (P = 0.04). At 100 days post-transplant, hepatic RRT resolved in all 13 survivors who responded to high-dose MP, and in one non-responding patient. No serious toxicities due to high-dose MP were observed. We conclude that resolution of hepatic RRT occurred in the majority of patients treated with high-dose MP in this study; however, randomized controlled trials are required to determine the efficacy of high-dose MP for treatment of hepatic RRT.

Human herpesvirus 8 (KSHV) contamination of peripheral blood and autograft products from multiple myeloma patients.

Human herpesvirus 8 (HHV-8), also known as Kaposi's sarcoma-associated herpesvirus (KSHV), has recently been identified within the bone marrow dendritic cells of multiple myeloma (MM) patients. This virus contains homologues to human cytokines such as IL-6 that could potentially stimulate myeloma cell growth and contribute to disease pathogenesis. Since mobilization chemotherapy may increase circulating dendritic cell numbers, we searched for HHV-8 in peripheral blood mononuclear cells (PBMCs) before and after mobilization chemotherapy given to MM patients. Furthermore, we determined if autograft purging using the CEPRATE SC device would reduce the percentage of HHV-8 infected stem cell products. Only two of the 39 PBMC samples collected prior to mobilization chemotherapy contained PCR detectable virus, yet nine of 37 PBMCs collected on the first day of leukapheresis had detectable HHV-8 (P = 0.016). HHV-8 was more frequently identified in autograft products before vs after Ceprate SC selection (40% vs 15%, P = 0.016). Although the role HHV-8 plays in myeloma pathogenesis remains unclear, these results imply that mobilization chemotherapy increases the numbers of circulating HHV-8-infected dendritic cells within the peripheral blood. In addition, CD34 selection of autograft products in MM patients may reduce the reintroduction of virally infected cells following high-dose chemotherapy. Bone Marrow Transplantation (2000) 25, 153-160.

Leukodepleted-ABO-identical blood components in the treatment of hematologic malignancies: a cost analysis.

To assess the effect of ABO-identical, filtration leukodepleted transfusions on resource consumption and costs of care we performed a cohort study in consecutive adult patients admitted for induction therapy of acute myeloid or lymphoid leukemia during 1985-92 (n = 120) and consecutive adult patients admitted for autologous bone marrow transplantation for Hodgkin's or non-Hodgkin's lymphoma during 1989-1991 in our university hospital. Patients with acute leukemia received either ABO unmatched, unfiltered transfusions (1985-89), ABO identical, unfiltered transfusions (1987-90), or ABO identical, filtered transfusions (1990-92). Patients with lymphoma received either ABO unmatched, unfiltered transfusions (1989-90) or ABO identical, filtered transfusions (1990-91). Mean platelet transfusion requirements per patient decreased with ABO identical platelets and filtered transfusions: from 143 to 71 units in the transplant setting; from 146 to 83 in acute leukemia (P < 0.05). Mean hospital ancillary service charges in 1992 dollars decreased with ABO identical platelets and filtered transfusions approximately $14,000 per patient for acute leukemia and $26,000 for for lymphoma. Per patient actual costs for filters ($643 in transplantation for lymphoma and $875 in leukemia) were offset by savings in actual blood component purchase costs alone ($4,127 in lymphoma and $3,283 in leukemia). In our setting, introduction of ABO identical platelets and filtration leukodepletion were implemented with substantial decreases in costs.

Wide variability in Pseudomonas aeruginosa aminoglycoside results among seven susceptibility testing procedures.

Seven commonly used antimicrobial susceptibility testing methods were used to test the susceptibility of 150 isolates of Pseudomonas aeruginosa against gentamicin, tobramycin, amikacin, carbenicillin, and piperacillin. Results were compared with respect to the susceptibility characteristics of the population of isolates as defined by each method. Conventional methods included agar disk diffusion and agar dilution, carried out in accordance with current recommendations of the National Committee for Clinical Laboratory Standards, as well as broth microdilution testing with cation-supplemented Mueller-Hinton broth (CSMHB). Methods in which instrumentation was used for result determination included the Autobac I, Avantage, Sensititre Autoreader (using a breakpoint panel at 18 h of incubation), and Vitek (AMS-240, using the GNS susceptibility card). When necessary for comparison, MIC data were converted to categorical interpretations (susceptible, intermediate, and resistant). With respect to gentamicin, no significant differences were noted among the results of disk diffusion, broth microdilution, Sensititre Auto breakpoint, or Vitek methods which characterized 60 to 67% of isolates as susceptible, 16 to 22% as intermediate, and 13 to 17% as resistant. In contrast, agar dilution, Autobac, and Avantage, although yielding gentamicin results similar to those of one another, were each significantly different in result reporting from the other four methods above for gentamicin results, and they characterized the Pseudomonas population largely as susceptible (88 to 97%), with 0 to 6% intermediate and only 3% to 6% resistant. More isolates were characterized as being resistant to gentamicin in the Avantage test if an assay broth supplemented with increased amounts of calcium was used. Cation impregnation of Autobac disks did not appreciably change Autobac results. The geometric mean MIC of gentamicin was 4 micrograms/ml lower in the agar dilution method than in the CSMHB microdilution method, despite monitoring of the agar for cation content through performance disk diffusion testing with P. aeruginosa ATCC 27853. Tobramycin activity was greater than gentamicin activity, and susceptibility to tobramycin ranged from 89 to 97%, with few statistically significant differences noted among the seven methods studied. Differences in MIC distribution and geometric mean MIC between agar dilution and CSMHB microdilution testing were minimal and suggested less of a cation influence on tobramycin than gentamicin results. Although amikacin was also more active than gentamicin (83 to 99% of isolates were susceptible), differences in the amikacin results among methods tended to reflect the same trends in reporting as seen with gentamicin testing, with the exception that results of Avantage testing were similar to those of disk diffusion, CSMHB microdilution, Sensititre, and Vitek. A difference in geometric mean MIC of 5 micrograms/ml between CSMHB testing and agar dilution testing suggested the influence of divalent cations on amikacin results. Few highly significant differences were noted among methods when isolates were tested against carbenicillin and piperacillin, except that Avantage piperacillin results (66% susceptible) and Autobac piperacillin results (98% susceptible) were noticeably different from the percent piperacillin susceptibility (range, 85 to 92%) measured by the other methods. Method-dependent variability among aminoglycoside susceptibility results, particularly when testing gentamicin, prevents meaningful comparison of Pseudomonas susceptibility trends among hospitals when different methods are used and promotes confusion and frustration among clinical microbiologists and clinicians owing to the uncertainties of clinical meaning of these data.