Priming with r-metHuSCF and filgrastim or chemotherapy and filgrastim in patients with malignant lymphomas: a randomized phase II pilot study of mobilization and engraftment.

SCF has been shown to synergize with G-CSF to mobilize CD34(+) PBPCs. In this study we report results from this combination after a phase II trial of 32 patients with malignant lymphoma randomized to receive recombinant methionyl human SCF (ancestim, r-metHuSCF) in combination with recombinant methionyl human G-CSF (filgrastim, r-metHuG-CSF) (experimental arm A) or routine chemotherapy plus filgrastim (conventional arm B). The primary objective was to evaluate the side effects and toxicity during priming and mobilization. The secondary objectives were efficacy by the level of blood-circulating PBPCs, the number of harvest days and the time to three-lineage engraftment after autografting. First, during priming 5 patients had 8 serious events, 4 in each arm. A summary of all adverse events revealed 30 (94%) patients suffering from 132 events of all grading. Second, neutropenia and thrombocytopenia was documented in arm B. Third, 9/14 (64%) patients in arm A reached the target of 5 million CD34(+) cells/kg body weight (bw) compared with 13/15 (87%) in arm B. The results represent the first randomized trial of growth factor plus chemotherapy priming and indicate that a formal phase III trial very unlikely may challenge chemotherapy plus r-metHuG-CSF priming in candidates for high-dose therapy.

Detection of candidaemia in patients with and without underlying haematological disease.

Diagnosing candidaemia remains difficult despite the development of new diagnostics. We report a direct comparison of three different blood-culture systems and four indirect tests. One hundred and fourteen episodes either with haematological disease and fever despite antibacterials, or with documented invasive candidiasis, were enrolled prospectively. Clinical, para-clinical information and surveillance cultures were obtained. Blood culture was performed using conventional blood-culture bottles, mycosis bottles, and the Isolator 10 lysis centrifugation system. Serum D-arabinitol/L-arabinitol (DA/LA) ratios were determined by gas chromatography mass spectrometry. Antigen, mannan-antigen (Ag) and anti-mannan antibody (Ab) were detected by CandTec, Platelia Candida Ag ELISA and Candida AB/AC/AK kits, respectively. Episodes were classified as proven (n = 24), probable (n = 14), possible (n = 52) or unlikely (n = 24) invasive candidiasis. Candidaemia involved C. albicans (17), C. albicans + C. glabrata (3), C. tropicalis (1) and yeast (1). Mycosis bottles yielded two additional positives and the conventional blood culture yielded one positive not identified by other blood-culture methods. Considering proven and unlikely episodes, respectively, sensitivity and specificity were as follows: mannan-Ag and/or anti-mannan Ab: 83.3%, 78.3%; DA/LA ratio: 41.7%, 86.4%; and CandTec Candida Ag: 66.6%, 70.8%. Lowering the cut-off values to mannan-Ag 0.10 ng/mL and anti-mannan Ab 4 AU/mL, the values were: 100%, 73.9%. Applying the DA/LA ratio to only patients with haematological neutropenia the values were: 75%, 90.5%. Fungal blood culture allowed slightly improved detection of candidaemia. The best indirect test performance was obtained from combined mannan-Ag and anti-mannan Ab detection, especially with lower cut-offs. DA/LA ratio appears to be useful in the context of haematological neutropenia.

A case of lymphoblastoid natural killer (NK)-cell lymphoma: association with the NK-cell receptor complex CD94/NKG2 and TP53 intragenic deletion.

The clinical, histological, phenotypic and genotypic features of a lymphoblastoid natural killer (NK)-cell lymphoma presenting in the skin in a young caucasian woman are described. The disease behaved aggressively, but long-lasting remission was obtained by combination chemotherapy followed by autologous bone marrow transplantation. The blastoid cells were positive for terminal deoxynucleotidyl transferase, CD34, CD56 and CD4. Furthermore, the NK-cell receptor complex CD94/NKG2 was strongly expressed, as shown by examination with reverse transcription-polymerase chain reaction. The T-cell receptor (TCR)-gamma genes were in germline, and with the exception of CD4 all T-cell antigens were negative, including CD3, TCR-beta, TCR-delta, TIA-1, granzyme B and perforin. Epstein-Barr virus was negative, and no expression was seen of myeloid cell-associated markers. Molecular analysis showed no abnormalities of the CDKN2A (p16), CDKN2B (p15) or TNFRSF6 (Fas) genes. By contrast, a 34-bp deletion in exon 7 of the TP53 (p53) gene was detected. It is suggested that lymphoblastoid NK-cell lymphoma, which is a rare but distinctive disease, originates from NK cell precursors and may be associated with and possibly caused by alterations in the TP53 gene. Experience is too limited to warrant therapeutic suggestions. However, stem cell transplantation may be a useful option in younger patients.

[Acute hemolytic anemia in Clostridium perfringens infection]. / Akut haemolytisk anaemi ved Clostridium perfringens-infektion.

Haemolytic anaemia caused by Clostridium perfringens is a rare complication in patients with neoplastic diseases. According to the literature, our patient seems to be the first patient with underlying malignancy (multiple myeloma) who has survived C. perfringens septicaemia complicated with acute haemolysis and acute anuria. It is concluded that treatment with penicillin should be considered in case of acute haemolytic anaemia, if the patient is febrile and no other obvious cause of the haemolytic condition can be found.

Early infections after autologous transplantation for haematological malignancies.

The purpose of this study was to evaluate the early infectious complications following autologous transplantation in haematological patients. Sixty-one patients who underwent either autologous bone marrow (BM; 28 patients) or peripheral blood stem cell (PBSC; 33 patients) transplantation for haematological malignancies were reviewed retrospectively. Engraftment happened significantly faster and the length of hospital stay was shorter in the PBSC group compared with the BM group. All patients in the study developed fever and all but two experienced temperatures > or = 38.5 degrees C. Overall, 57 patients had signs of oral mucositis, 23 with ulceration. Twenty patients had bacteraemia, 12 developed pneumonia, 6 systemic fungal infection. No major differences were found between the two groups in distribution or incidence of infections. This study indicates that the use of peripheral blood stem cells results in faster engraftment and shorter hospital stay, whereas the effect on the incidence of early infections seems to be unaffected.

Acyclovir prophylaxis and fever during remission-induction therapy of patients with acute myeloid leukemia: a randomized, double-blind, placebo-controlled trial.

PURPOSE: A randomized, double-blind, placebo-controlled trial was performed to estimate the preventive effect of the antiherpetic drug acyclovir on fever, incidence of bacteremia, use of antibiotics, and presentation of infections in patients with acute myeloid leukemia (AML). PATIENTS AND METHODS: Ninety herpes simplex virus (HSV)-seropositive patients aged 18 to 84 years were included. Forty-five patients received acyclovir (800 mg by mouth daily) and 45 placebo. The patients were examined daily for 28 days from the initiation of remission-induction chemotherapy. RESULTS: Fever developed in all patients in both groups. Acyclovir prophylaxis postponed the development of an oral temperature > or = 38.0 degrees C by 3 days (95% confidence interval [CI], 1 to 4 days; P = .03) and the initiation of antibacterial treatment by 3 days (95% CI, 1 to 5 days; P = .008). The duration of fever, use of antibacterial treatment, incidence of bacteremia, and need for systemic antifungal therapy were not affected by acyclovir prophylaxis. At fever development, acyclovir prophylaxis affected the incidence and localization pattern of oral ulcers. Thus, in the acyclovir group, the number of nonfungal oral infections was reduced (relative risk, 0.45 [95% CI, 0.24 to 0.85]) and mainly located on the soft palate (relative risk, 2.49 [95% CI, 1.19 to 5.22]). CONCLUSION: Acyclovir prophylaxis has an impact on fever development, but not on the duration of fever or the need for antibiotics. It does not reduce the incidence of bacteremia, but the presentation of acute oral infections is changed.

Anal and cervical abnormality in women--prediction by human papillomavirus tests.

A total of 151 women at risk of human immunodeficiency virus infection were investigated, to study the strength of the association between cervix and anus regarding the presence of HPV and cytological abnormality. An equal percentage of women had abnormal cervical (12.2%) and anal (12.1%) Papanicolaou smears. HPV measured by PCR was detected in 93.3% of cervical squamous intraepithelial lesions (SIL) compared to 49.1% of normal cervical cytologies, and in 100% of anal SIL and 67.4% of normal anal cytologies, respectively. After controlling for HPV-PCR status, immunodeficiency, as measured by a low CD4+ count and HIV positivity, increased the detection of cervical and to some extent anal squamous intraepithelial lesions (SIL). We evaluated how precisely an HPV test could predict cervical disease and found that the HPV-PCR test was slightly more sensitive than the HPV-hybrid capture (HC) test (PCR: 93.3% vs. HC: 88.9%), whereas the HC test was significantly more specific (83.6% vs. 50.9%), and with a much higher positive predictive value (43.2% vs. 20.6%). Similar results were obtained for anal SIL. HIV positivity increased sensitivity, lowered specificity and increased the positive predictive value of the tests. A diagnosis of cervical SIL was associated with a more than 3-fold increased risk of a simultaneous abnormal anal smear (p < 0.05). In conclusion, cervical and anal disease were significantly associated and almost exclusively seen in the presence of HPV. Immunodeficiency and HIV positivity increased the risk of disease in HPV-positive subjects. Hybrid capture, which requires a higher viral load than PCR to detect HPV, was clearly superior in predicting cervical and anal disease. Altogether, these findings suggest that a high level of HPV infection may be important for the development of SIL in the population studied.

The demonstration of candidal pseudohyphae in salivary smears as a method of early diagnosis of oral candidiasis in patients with acute myeloid leukemia.

To investigate the oral coloniation of candidal pseudohyphae, a salivary smear method was tested against the use of mucosal smears in 10 patients with acute myeloid leukemia. The salivary smears showed to be reproducible and more sensitive than mucosal smears for the demonstration of Candida organisms. The salivary smear method was applied to another group of 10 patients with acute myeloid leukemia during a 28-day period. According to swab cultures, 8 patients were colonized with Candida spp. on day 0, whereas 2 patients were unclonized on day 0, and remained so. All colonized patients developed acute oral candidiasis. According to the salivary smear method, 5 patients were colonized with pseudohyphae as early as on day 0, whereas 3 patients became colonized with pseudohyphae within the first 7 days. Pseudohyphae were detected with a median of 4 days prior to the emergence of acute oral candidiasis, and the detection of acute oral candidiasis was associated with an increase in the quantity of pseudohyphoae. The study suggests that the demonstration of candidal pseudohyphae in salivary smears is an early indicator of subsequent development of acute oral candidiasis. Further studies are neded to clairfy whether early treatment based on this finding will reduce the occurrence of acute oral candidiasis and disseminated candidiasis in these patients.

Acyclovir given as prophylaxis against oral ulcers in acute myeloid leukaemia: randomised, double blind, placebo controlled trial.

OBJECTIVES: To evaluate (a) the prophylactic effect of the antiherpetic drug acyclovir on oral ulcers in patients with acute myeloid leukaemia receiving remission induction chemotherapy and thus (b), indirectly, the role of herpes simplex virus in the aetiology of these ulcers. DESIGN: Randomised, double blind, placebo controlled trial. SUBJECTS: 74 herpes simplex virus seropositive patients aged 18-84. Thirty seven patients received acyclovir (800 mg by mouth daily) and 37 placebo. The patients were examined daily for 28 days. MAIN OUTCOME MEASURES: Occurrence of herpes labialis, intraoral ulcers, and acute necrotising ulcerative gingivitis. RESULTS: The two populations were comparable in age, sex, type of antineoplastic treatment, and history of herpes labialis. Acute oral infections occurred in 25 of the acyclovir treated patients and 36 of the placebo treated patients (relative risk 0.69 (95% confidence interval 0.55 to 0.87)). This difference was due to a reduction in the incidence of herpes labialis (one case versus eight cases; relative risk 0.13 (0.02 to 0.95)), intraoral ulcers excluding the soft palate (one case versus 13 cases; relative risk 0.08 (0.01 to 0.56)), and acute necrotising ulcerative gingivitis (one case versus eight cases; relative risk 0.13 (0.02 to 0.95)). However, ulcers on the soft palate were diagnosed with similar frequency in the two groups. Isolation of herpes simplex virus type 1 in saliva was reduced from 15 cases in the placebo group to one case in the acyclovir group (relative risk 0.07 (0.01 to 0.48)). CONCLUSION: Intraoral ulcers excluding the soft palate are most often due to infection with herpes simplex virus, whereas ulcers on the soft palate have a non-herpetic aetiology. The findings suggest that acute necrotising ulcerative gingivitis may also be due to herpes simplex virus. Prophylaxis with acyclovir should be considered for patients with acute myeloid leukaemia during remission induction therapy.

Gingival status during chemical plaque control with or without prior mechanical plaque removal in patients with acute myeloid leukaemia.

The purpose of the study was to evaluate the effect of a mouthrinse regimen comprising both chemical plaque control and mechanical plaque removal. 20 adult patients with acute myeloid leukaemia were assigned to one of the following 2 regimens: (1) (group 1) mouthrinse twice daily with a 0.1% chlorhexidine solution; or (2) (group 2) the same regimen, but preceded by mechanical removal of plaque and calculus on day 1. All patients were followed for 28 days from the initiation of remission-induction therapy. In group 2, the plaque scores remained lower than those of group 1 throughout the study, although only 3 patients remained completely free of plaque after 28 days. Gingival inflammation as judged by bleeding scores remained unchanged in group 1, whereas in group 2, the degree of inflammation was reduced from 52% (median value) on day 1 to 31% (median value) on day 28. The bleeding scores were also lower in group 2 (31%) than in group 1 (60%) on day 28. No differences were found between the 2 groups with respect to the occurrence of other oral infections. It is concluded that chemical plaque control with chlorhexidine should be preceded by mechanical removal of plaque and calculus, when used in patients with acute myeloid leukaemia and thrombocytopenia.

Alterations in oral microflora and pathogenesis of acute oral infections during remission-induction therapy in patients with acute myeloid leukaemia.

To investigate changes in the aerobic and facultatively anaerobic oral microflora during remission-induction chemotherapy in patients with acute myeloid leukaemia, 10 consecutive patients were studied during a period of 28 days. During antineoplastic treatment, the concentration of microorganisms in saliva doubled from day 0 to day 2, presumably as a result of a concurrent 64% decrease in the salivary flow rate. No changes in the relative proportion of individual microorganisms or acquisition of new microorganisms occurred during antineoplastic treatment. During antibacterial treatment, which was subsequently initiated in all patients, a 100-fold decline occurred in the median salivary concentration of microorganisms within the first 7 days. During this period, members of the normal flora became undetectable in 5 patients, and Enterobacteriaceae, Enterococcus faecalis or Candida spp. became parts of the quantitatively predominant oral microflora in 7 patients. Apart from Candida spp., these potentially pathogenic microorganisms were acquired only after the initiation of the antibacterial treatment. After termination of the antibacterial treatment, the median concentration of microorganisms increased again to the original level and normal flora became reestablished within a period of 8 days. Clinically, 10/20 acute oral infections emerged before day 8, i.e. within the period with increased concentrations of microorganisms in saliva. Specifically, the clinical diagnosis of acute oral candidiasis was associated with a rise in the concentration of Candida spp. above a critical value of 1,000 CFU/ml. Herpes simplex virus (HSV) type 1 was detected in 4/9 HSV-seropositive patients on days 14 and 21, and HSV-1 was in all 4 cases isolated simultaneously with the emergence of an intraoral ulcer. The results suggest that chemotherapy-induced xerostomia plays a significant role in the pathogenesis of acute oral infections and transmission of potentially pathogenic microorganisms is of importance mainly after initiated antibiotic treatment in these patients.

Humoral immunity of the oral cavity during remission-induction therapy in patients with acute myeloid leukaemia.

To evaluate whether local oral humoral immunity changes during remission-induction therapy of newly diagnosed acute myeloid leukaemia, 10 consecutive adult patients were investigated during 4 weeks. The concentrations of the oral secretory immunoglobulins A and M were increased during the first 7 days but, when corrected for changes in the salivary flow rate, the secretion rates of S-IgA and S-IgM remained unchanged, relative to the values before chemotherapy. In comparison, the concentrations of the serum immunoglobulins A, G and M were decreased, like the leukocyte and thrombocyte counts, during the first 14 d. It is concluded that the chemotherapeutic agents appear to act differently upon the local plasma cells associated with oral secretory glands and plasma cells in the bone marrow, and that the secretion rate of oral immunoglobulins remains constant during remission-induction therapy.

Herpes simplex virus and intraoral ulcers in immunocompromised patients with haematologic malignancies.

Possible factors predisposing to the development of intraoral ulcers in immunocompromised patients with haematologic malignancies were investigated. Among 46 patients undergoing antineoplastic treatment, 18 developed an intraoral ulcer during the prospective study. Patients with or without ulcers were comparable with respect to underlying disease, presence of teeth, the qualitative composition of the aerobic and facultatively anaerobic oral microflora, herpes simplex virus (HSV) titer positivity, a past history of herpes labialis, leukocyte and thrombocyte counts, and duration of fever. Viral cultures from saliva revealed an association between the presence of HSV in saliva and the presence of intraoral ulcers. HSV was not isolated from the saliva of any patient without ulcers. Viral cultures from the ulcers revealed growth of HSV in 11 (61%) of the 18 patients with ulcers. HSV-positive ulcers were located more often on the alveolar process than elsewhere in the oral cavity. Ulcers on the lateral borders of the tongue and on the buccal mucosa were found only in dentate patients. Development of intraoral ulcers was not associated with an increase of the HSV titer in serum in any patient. It is concluded that some intraoral ulcers, especially when located on the alveolar process, are associated with and probably caused by HSV, while mechanical trauma during mastication seems likely to be involved in the pathogenesis of ulcers elsewhere in the oral cavity.

Acute oral candidiasis during febrile episodes in immunocompromised patients with haematologic malignancies.

To estimate clinical, pathogenic and serological aspects of acute oral candidiasis (AOC) during febril episodes in patients with haematologic malignancies, 23 consecutive patients who developed AOC within 7 days from start of fever were compared with 23 consecutive patients who did not develop AOC. The duration of fever and severe granulocytopenia (less than 0.5 x 10(9)/l) was significantly longer in patients with AOC than in patients without AOC, the median differences between the patients with and without AOC being 4 and 3 days, respectively. Development of AOC could not be correlated to a change in the qualitative composition of the oral microflora. The thrombocyte count was lower in patients with AOC on day 4, whereas no differences were found in leukocyte counts. The prevalences of Candida albicans agglutinin titres greater than or equal to 5 were similar in patients with (24%) and without AOC (33%), and in controls (29%). Seroconversion or a significant increase in the agglutinin titre occurred in 4 patients with AOC and long-lasting fever, who became afebrile after systemic antifungal therapy. It is concluded that AOC is associated with long-lasting fever and decreased bone marrow function as judged by low thrombocyte counts, but not related to specific bacteria in the oral cavity or to an increased occurrence of C. albicans antibodies in the serum.

Complement and immunoglobulin studies in 15 cases of chronic meningococcemia: properdin deficiency and hypoimmunoglobulinemia.

The purpose of this study was to investigate whether patients with chronic meningococcemia have abnormalities in their humoral immune system. The alternative and classical complement system, the levels of IgA, IgG and IgM, as well as IgG subclasses were studied in 15 individuals who had recovered from chronic meningococcemia. We found one individual with complete deficiency of properdin, a component of the alternative complement pathway. In the other patients, the complement system was normal. The mean plasma IgG concentration was significantly below normal in the patient group, while the mean values of IgA, IgM and the IgG subclasses were normal. Two individuals, however, had low IgG2 and IgG4 levels. We conclude that properdin deficiency and reduced plasma IgG levels may predispose to chronic meningococcal disease, but that the majority of patients with chronic meningococcemia have a normal humoral immune system.

[Accumulated microbiological data. Surveillance of infection/antibiotic policy]. / Akkumulerede mikrobiologiske data. Infektionsovervågning/antibiotikapolitik.

Database reviews of the findings in bacteriological specimens from a period of six years from patients in a department of haematology are employed as a model of how cumulative data about the microorganisms isolated may be employed for surveillance of accumulated infections and in the organization of the antibiotic policy of a department. During the period of observation, the standard treatment with antibiotics for febrile episodes in granulocytopenic patients was altered to piperacillin and netilimicin on the basis of the frequent occurrence of Gram-negative rods including Pseudomonas aeruginosa in blood cultures. It is concluded that accumulated microbiological data is of value for a clinical department and that analysis of the data does not constitute an increased work-load provided that the microbiological reports are routinely registered in a database.

Acute myeloid and lymphoblastic leukemia in adults. The course of the disease in 315 patients from one region, during a ten-year period.

In a ten-year retrospective singlecenter study of a nonselected patient population, we describe our experience with an unchanged chemotherapy regimen for 264 patients with acute myeloid leukemia (AML) and 51 patients with acute lymphoblastic leukemia (ALL). In the AML group, 85 patients could not receive specific antileukemic treatment because of uncontrollable bleeding, infection or organ failure, but 179 were fit for remission-induction therapy with cytarabine and daunorubicin, resulting in complete remission in 79 patients. During treatment, 54 patients died of resistant disease or complications. The median duration of survival of the patients in complete remission was 18-24 months (n = 79) compared with 1-2 months for patients in partial or no remission (n = 100). As maintenance chemotherapy, thioguanine, cytarabine and daunorubicin were given for one year. In the ALL group 50 of 51 patients received remission-induction therapy with vincristine, prednisone and Adriablastin, resulting in complete remission in 39 of the patients. The median duration of survival of the patients in complete remission was nine months (n = 39) compared with 2-3 months for patients not in remission (n = 12). Central nervous system prophylaxis with intraspinal methotrexate and cranial irradiation was given, followed by methotrexate and Purinetol for three years as maintenance chemotherapy. The remission rate for AML and adult ALL was 44% and 78%, respectively. The major Cause of death after first complete remission was leukemic relapse in boths groups, with a median survival time after relapse of 3-4 months for 48 AML and six months for 30 ALL patients.(ABSTRACT TRUNCATED AT 250 WORDS)