Comments on economic evaluation of chemotherapy.
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Antineoplastic Agents↗
Biomedical subjects
M M Hansen
Publications and source records attributed to M M Hansen.
Subcutaneous lesions and bacteraemia due to Stenotrophomonas maltophilia in three leukaemic patients with neutropenia.
Subcutaneous lesions were seen in three of 13 neutropenia patients who had Stenotrophomonas (Xanthomonas) maltophilia bacteraemia. The characteristic clinical presentation resembled leukaemic infiltrates, and were different from deep ulcers or subcutaneous nodules caused by Pseudomonas aeruginosa. The three patients had acute leukaemia and were treated with intensive combination chemotherapy. All had previously been treated with broad-spectrum antibiotics, and each patient recovered after proper combination antibiotic treatment given according to sensitivity testing.
Adult↗
[Medical treatment of cancer].
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Antineoplastic Agents↗
[Chronic lymphatic leukemia. Peroral cladribine as primary treatment].
Ten patients with newly diagnosed B-chronic lymphocytic leukaemia were treated with cladribin orally for five days every four weeks with a median of four series. This is the first reported clinical study where a purine analogue is administered orally. The tumour reducing effect was fast. Eight out of 10 patients responded with a partial or clinical complete remission. Two of these were in molecular biological complete remission. With an observation time of 22 months we have seen no serious side effects so far. A randomized study (including a long term follow up) between chlorambucil, fludarabin and cladribin is needed to clarify the future role of cladribin in B-CLL treatment.
Aged↗
[Autologous stem cell transplantation. From bone marrow to selected blood stem cells: 100 consecutive procedures at a single center].
One hundred consecutive autologous stem cell transplants are reported: Non-Hodgkin's lymphoma 51 cases, Hodgkin's disease 27 cases, acute leukaemia 14 cases, multiple myeloma seven cases and chronic myeloid leukaemia one case. Most patients were in their second or later remission. The overall three-year survival for all patients was 60% and the three-year disease-free survival was 50% for lymphoma patients and 30% for acute leukaemia patients. The dominant source of stem cells was bone marrow during 1993, but from 1994 it has been peripheral blood, now totalling 33 cases. There were 12 toxic deaths, all among patients who were heavily treated before bone marrow harvest and transplantation. The patients transplanted with blood stem cells had significantly shorter duration of pancytopenia, and hospital stay, but their disease-free survival was not longer than that of a comparable group of bone marrow transplanted patients. Six patients were transplanted with purified CD34+ cells (selected by avidity column (Ceprate (R)), and had duration of thrombocytopenia and hospital stay similar to the patients transplanted with unmanipulated blood stem cells, but slightly longer duration of neutropenia. We conclude that high-dose therapy with autologous stem cell transplantation in not too heavily pretreated patients is a safe procedure irrespective of the source of stem cells.
Adolescent↗
The bone-marrow infiltration pattern in B-cell chronic lymphocytic leukemia is not an important prognostic factor. Danish CLL Study Group.
In a multicentre study of 635 consecutive newly diagnosed patients with B-CLL, the histological bone marrow (BM) specimens were reviewed independently by each of 3 pathologists and found evaluable for BM infiltration pattern in 575 patients, 404 of whom had a CD5+, mainly FMC7-, faint surface-membrane immunoglobulin (SIg) fluorescence-intensity ppenotype. In these 404 patients the following BM infiltration patterns were found: mixed nodular-interstitial (30%), moderate interstitial (44%), heavy interstitial (20%) and diffuse packed (6%). In univariate survival analysis, significant differences were found according to BM pattern (p < 0.05), the presence of nodules being a favorable prognostic sign. In multivariate survival analysis in a model including age, clinical stage, BM pattern, BM lymphocytosis, WBC and sex, only age and stage but not BM pattern or BM lymphocytosis had independent prognostic significance. In stage A, progression-free survival was significantly longer in patients with nodular than in patients with non-nodular bone-marrow pattern. The overall survival of these patients, however, did not differ, possibly owing to the prompt and prolonged treatment given to most patients at the time of progression to stage B or C. We conclude that in CD5+, SIg(faint), mainly FMC7-B-CLL, bone-marrow histology may predict unstable disease in early clinical stage but is not important for treatment decisions, when these are based on clinical stage.
Age Factors↗
Oral cladribine as primary therapy for patients with B-cell chronic lymphocytic leukemia.
PURPOSE: Purine analogs have wide potential indications in the treatment of hematologic malignancies, but intravenous administration has been required. We previously established that the oral bioavailability of cladribine is 50%. Our aim was to evaluate the efficacy and toxicity of oral cladribine to previously untreated patients with chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS: Sixty-three patients with symptomatic but previously untreated CLL received cladribine solution 10 mg/m2/d orally for 5 consecutive days in monthly courses. RESULTS: Complete remission (CR) was achieved in 24 patients (38%), and 23 patients (37%) had a partial response (PR). Most patients, including those in whom there was no remission (NR) achieved normal blood lymphocyte counts. Failure to meet response criteria was mostly due to thrombocytopenia. The median response duration was not reached at 2 years. The median survival time among 13 deceased patients was 322 days, whereas the median observation time of surviving patients is 760 days. The overall survival rate at 2 years is 82%. Response rate was associated with clinical stage. Grade III to IV infectious toxicity occurred in one third of patients. CONCLUSION: Orally administered cladribine is an effective and feasible therapy for CLL, and produces durable remissions in three quarters of the patients. However, significant toxicity may occur and further studies are required to assess long-term effects and quality-of-life aspects.
Administration, Oral↗
Salvage therapy with fludarabine in patients with progressive B-chronic lymphocytic leukemia.
Thirty patients with B-chronic lymphocytic leukemia, aged 45-82 years, were treated with fludarabine. CLL was diagnosed 8-120 months earlier. The patients had been exposed to a median of 3 different regimens before treatment with fludarabine, and all had progressive disease when they entered the study. Among the 30 patients, 1 had a metastatic carcinoma and 7 patients with WHO performance status 3 died before the second cycle of fludarabine treatment could be given. The remaining 22 patients were considered eligible for response evaluation. The response rate was 32% with 1 complete response and 6 partial responses. However, seven patients achieved stable disease and 8 progressed. The median survival for responders was 24 months and for non-responders 9 months. Response to treatment was correlated with low tumor burden and performance status. In a total of 94 treatment courses, 17 febrile episodes were registered in 10 patients. We conclude that treatment with fludarabine can be useful in patients with progressive and refractory disease.
Aged↗
Multiple autoimmune manifestations in monoclonal gammopathy of undetermined significance and chronic lymphocytic leukemia.
In 18 cases of monoclonal gammopathy of undetermined significance, MGUS (monoclonal gammopathy of undetermined significance), admitted for diagnosed or suspected peripheral neuropathy, 11 patients showed other co-existing autoimmune manifestations. Two had POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-component, and skin symptoms), the others mainly endocrinopathy and polyclonal pseudolymphoma. There were 13 cases of sensorimotor neuropathy, two cases of neuritis, while neuropathy could not be confirmed in three cases. Compared with a retrospective review of autoimmunity in a randomly selected CLL (chronic lymphocytic leukemia) cohort of 115 patients, 13 out of 42 patients with clinical and/or laboratory features of autoimmunity showed co-expression of autoimmune signs, the dominating traits being Coombs positive AIHA (auto-immune hemolytic anemia), platelet autoantibodies, endocrinopathy mainly associated with the thyroid gland, serological and/or rheumatological symptoms, but only one case of sensorimotor neuropathy. Viewed from a current model of acquired autoimmunity it is perhaps not surprising that such autoimmunity is seen predominantly in patients with monoclonal gammopathy. Thus, a high concentration of cross-reacting polyreactive autoantibodies related to the M-component might be present in these patients. Furthermore, quantitative defects of the immunoglobulins including the hypogammaglobulinemia associated with M-components can presumably give rise to a defect of the anti-idiotypic network's regulation of natural autoantibodies and autoimmune manifestations in vivo. Such autoimmune manifestations, which are easily overlooked in CLL may call for additional treatment with immunosuppression and/or intravenous, polyclonal IgG.
Adult↗
[Quality of cryopreserved ejaculate in Hodgkin disease].
Each year approximately 70 males are diagnosed with Hodgkin's disease (HD) in Denmark. Most of these are less than 50 years of age. Since chemotherapy and radiotherapy may induce infertility in about 80% of patients, it has become routine to offer cryopreservation of semen prior to initiation of treatment. In 41 men aged 17-42 years at diagnosis we evaluated the quality of semen (according to the WHO criteria) prior to cryopreservation and after thawing. The median sperm concentration at the time of diagnosis was 33 x 10(6)/ml (range: 0.3-458 x 10(6)/ml) and positively correlated to age (rs = 0.36 p = 0.02) and to the histopathological classification (highest for patients with nodular sclerosis (p = 0.04) but not to semen volume, stage or presence of B-symptoms. The percentage of motile spermatozoa (range: 0-90%, median value 72%) was correlated to the sperm concentration; but not to any of the other parameters studied. Prior to freezing, 19 of 41 patients had normal semen quality according to the WHO criteria, whereas following thawing this was the case for only 14 semen samples. Ten of 23 patients with nodular sclerosis HD had normal semen quality (according to the WHO criteria) after thawing whereas this was the case for only 2 of 15 patients with mixed cellularity HD (p = 0.05). Cryopreservation of semen may secure the possibility of fathering children for patients with HD following therapy, and is to be recommended.
Adolescent↗
Pharmacoeconomic aspects in the treatment of curable and incurable cancer.
Assessments of the direct and indirect costs of cancer treatment have demonstrated the extreme complexity of these costs. Expenditure on cancer treatment is high, often reaching 3 to 6% of the gross national product in industrialised countries. In this article, we propose that the health outcomes associated with this high expenditure should be analysed in relation to concepts such as total cytoreduction (leading to disease-free survival and cure) and cytostabilisation with acceptable quality of life (in incurable cancer patients). Outcomes appear to be more variable among incurable compared with curable patients, so that cure and survival (which apply to only about 50% of all patients) are not the sole outcome parameters. For the 50% of patients in industrialised countries in whom cure is not possible, outcomes (in the form of cytostabilisation and an ongoing obligation to seek curative cytoreduction) will require further pharmacoeconomic assessment.
Antineoplastic Agents↗
Improved vaccination response during ranitidine treatment, and increased plasma histamine concentrations, in patients with B cell chronic lymphocytic leukemia.
Patients with B cell chronic lymphocytic leukemia (B-CLL) have decreased capacity to mount relevant antibody responses upon immunization, and development of hypogammaglobulinemia is part of the natural history of the disease. We investigated the influence of histamine type-2 (H2) receptor blockade by ranitidine on the in vivo antibody production in B-CLL patients following vaccination. Anti-polysaccharide antibodies in B-CLL patients, vaccinated with a tetanus-toxoid conjugated vaccine against Haemophilus influenzae type-B (Hib), reached long-term protective levels in more than 90% of B-CLL patients randomized to ranitidine treatment, as compared to 43% of the untreated patients (P = 0.024). No difference in the response to vaccination against influenza virus types A and B protein could be detected between the two groups. Plasma histamine levels were 2-fold to 20-fold higher in 23 out of 31 B-CLL patients, compared to normal controls, and these levels showed a significant positive correlation to disease duration. These findings indicate the possibility of improving in vivo antibody production against a highly relevant pathogen in B-CLL patients by histamine type-2 receptor blockade, and the combined finding of an immune-stimulatory effect of ranitidine and increased plasma histamine levels, strongly suggests the involvement of histamine in the pathogenesis of B-CLL immunodeficiency.
Adjuvants, Immunologic↗
Treatment of hypogammaglobulinaemia in chronic lymphocytic leukaemia by low-dose intravenous gammaglobulin.
Intravenous immunoglobulin replacement therapy reduces the number of bacterial infections in B-cell chronic lymphocytic leukaemia (B-CLL) patients. However, due to the complexity of immunodeficiency in B-CLL and the cost-effectiveness of replacement therapy, it is important to identify patients who are likely to benefit from the treatment and to investigate which dose should be used. 15 patients with hypogammaglobulinaemia and a history of recurrent infections received a fixed dose of 10 grams of gammaglobulin intravenously every 3 weeks. Serum IgG levels were significantly higher after three doses (p = 0.0002), and stabilized just above lower reference value after 11 doses. The total number of infection-related events during 168 months before therapy was compared to the total number of infection-related events in 169 months during therapy. The number of antibiotic prescriptions was reduced from 78 to 54 (N.S.), the number of admissions to hospital due to infections was reduced from 16 to 5 (p = 0.047) and the number of febrile episodes was reduced from 63 to 31 (p = 0.004). We conclude that a fixed low dose of gammaglobulin intravenously can restore normal serum IgG levels in hypogammaglobulinaemic B-CLL patients, and leads to a decreased number of febrile episodes and admissions to hospital due infections.
Agammaglobulinemia↗
Effects of stair-stepping exercise direction and cadence on EMG activity of selected lower extremity muscle groups.
Step ergometry has become a popular treatment mode in cardiovascular fitness and knee rehabilitation programs. The following study describes the effects of forward stair stepping at 35 and 95 steps/minute and forward and retrograde stair stepping at 60 steps/minute on the mean electromyographic (EMG) activity of the gluteus maximus, rectus femoris, vastus medialis, semimembranosus/semitendinosus, and gastrocnemius muscles. Thirty-three subjects without prior lower extremity pathology participated in the study. Analysis of variance was used to compare mean EMG activity during the knee extension phase of the different stepping conditions. Significant differences (p < 0.05) in mean EMGs of gluteus maximus, rectus femoris, vastus medialis, and gastrocnemius were noted across all cadences. The semimembranosus/semitendinosus EMG activity displayed a single significant difference between the cadences of 35 and 95. The comparison between forward and retrograde stepping identified only one significant difference in mean EMG (semimembranosus/semitendinosus). The effects of cadence on EMG activity should be considered when developing conditioning or rehabilitation programs for the lower extremity. Faster cadences result in increased peak activity of shorter duration for the gluteus maximus, quadriceps, and gastrocnemius. There is no apparent difference in EMG activity of the hamstrings due to cadence. Also, noting the minimal activation that occurs, stair-stepping exercise would not be recommended for strengthening of the hamstrings musculature.
Adolescent↗
Changing etiology of bacteremia in patients with hematological malignancies in Denmark.
To ascertain whether the microbiological etiology of bacteremia among patients with hematological malignancies has changed in Denmark, the species distribution of clinically relevant blood culture isolates from the Hematological Department at Rigshospitalet, Copenhagen in 1990 was compared with 2 previous studies (1970-72; 1981-85). In addition, time trends of the etiology of bacteremia among hematological patients in Copenhagen (eastern Denmark) and in Arhus (western Denmark) were compared. In contrast to many other studies, a significant increase in the proportion of Gram-negative aerobes was observed in Copenhagen (from 43% in 1981-85 to 55% in 1990; p < 0.05), whereas in Arhus the proportion of Gram-positive aerobes increased steadily during the 1980s (from 34% to 51%; p < 0.05). In Copenhagen, non-hemolytic streptococci and Xanthomonas maltophilia increased significantly and accounted for 10% (p < 0.01) and 5% (p < 0.05) respectively, of all isolates in 1990, whereas Staphylococcus aureus during the 2 decades studied decreased from 25% to 8% (p < 0.001). In both regions, a decrease was observed in the proportion of Pseudomonas aeruginosa which accounted for only about 5% of all isolates in 1990. No changes were observed in the rates of anaerobes and yeasts. Several factors may contribute to the reported differences in the etiology of bacteremia among hematological patients, e.g. criteria used to assign the clinical significance of the isolate, blood culture system used, practice of using indwelling intravenous catheters, different policies with respect to antimicrobial treatment, and the degree of immunosuppression. A local surveillance of blood culture isolates is mandatory if changes in etiology and resistance development are to be detected.
Bacteremia↗
Xanthomonas maltophilia bacteremia in immunocompromised hematological patients.
Epidemiological, microbiological and clinical characteristics of 14 episodes of Xanthomonas maltophilia bacteremia in 12 seriously immunocompromised hematological patients, admitted to Rigshospitalet in Copenhagen over the 3-year period 1989-91, were evaluated. The results were compared with a randomly selected control group of 25 patients with Escherichia coli bacteremia. Hospital acquired bacteremia was more common among the patients with X. maltophilia bacteremia (p < 0.01). Treatment with broad-spectrum antibiotics before the bacteremic episode was markedly more common among the patients with X. maltophilia bacteremia (p < 0.001). The presence of a central venous catheter and previous treatment with corticosteroids were more frequent in patients with X. maltophilia bacteremia (p < 0.05). The X. maltophilia blood culture isolates were generally resistant to aminoglycosides and most beta-lactams. The mortality rates related to bacteremia caused by X. maltophilia and E. coli were 14% and 20%, respectively.
Adolescent↗
Multiple myeloma treated with mitoxantrone in combination with vincristine and prednisolone (NOP regimen) versus melphalan and prednisolone: a phase III study. Nordic Myeloma Study Group (NMSG).
One-hundred-and-fifty-one patients with previously untreated multiple myeloma were allocated to treatment with either NOP regimen (mitoxantrone 16 mg/m2 and vincristine 2 mg day 1 and prednisolone 250 mg day 1-4 and 17-20) or M+P regimen (melphalan 0.25 mg/kg and prednisolone 100-200 mg/day day 1-4). Both regimens were repeated every 4 weeks and were scheduled for 1 year. Seventy-seven patients were treated with NOP and 74 patients with M+P. No major clinical differences were recorded between the groups before treatment. Sixty percent of the patients responded (CR+PR) to NOP versus 64% to M+P (NS). The time to progression was 16 months (95% C.L. 14-51) in the NOP group versus 21 months (95% C.L. 15-27) in the M+P group (NS). The median survival was 14 months (7-21) in the NOP group and 31 months (21-43) in the M+P group (p = 0.02). NOP was significantly more toxic than M+P. Seven patients treated with NOP died due to infection and neutropenia and 1 patient died of cardiac toxicity, in contrast to 1 death due to infection and neutropenia in the M+P group. Gastrointestinal toxicity was acceptable in both groups. In conclusion, NOP was inferior to M+P as primary treatment of multiple myeloma.
Adult↗
Mouse erythrocyte rosette formation with malignant human B-lymphocytes re-evaluated: still a useful marker for differentiating mature B-cell malignancies.
We have re-evaluated mouse rosette formation (MRF) as a marker for B-CLL by estimating the fraction of mouse rosette forming B-lymphocytes (identified by CD20 monoclonal antibodies) in normal donors and malignant CD20+ cell proliferations (ALL, AML, B-NHL, B-HCL and B-CLL). Whereas this ratio was increased in B-CLL, all other CD20 positive malignancies showed mean ratios of less than 0.1. As part of a Danish multi-centre study, we furthermore prospectively analysed 86 patients and found that the mouse/CD20 ratio divided the 78 patients with monoclonal B-cell populations suspected of B-CLL in two distinct groups. In the low ratio group, three patients were categorized as leukaemized B-NHL and one as PLL. The remaining three patients with low ratio were clinically and immunologically (by SmIg density and CD5 expression) B-CLL patients suggesting a frequency of MR-negative B-CLLs of approximately 5%. In the high ratio group two of 70 patients were diagnosed as B-NHLs. Thirdly, MRF was a valuable parameter in patients, where transformation of disease is suspected, since it preceded clinical changes by several months. Thus, MRF is still a useful marker in the age of monoclonal antibodies.
Adult↗