Quality of life gains in frail and intermediate-fit patients with multiple Myeloma: Findings from the prospective HOVON123 clinical trial.

BACKGROUND: Frailty in newly-diagnosed multiple myeloma (NDMM) patients is associated with treatment-related toxicity, which negatively affects health-related quality of life (HRQoL). Currently, data on changes in HRQoL of frail and intermediate-fit MM patients during active treatment and post-treatment follow-up are absent. METHODS: The HOVON123 study (NTR4244) was a phase II trial in which NDMM patients ≥ 75 years were treated with nine dose-adjusted cycles of Melphalan-Prednisone-Bortezomib (MPV). Two HRQoL instruments (EORTC QLQ-C30 and -MY20) were obtained before start of treatment, after 3 and 9 months of treatment and 6 and 12 months after treatment for patients who did not yet start second-line treatment. HRQoL changes and/or differences in frail and intermediate-fit patients (IMWG frailty score) were reported only when both statistically significant (p < 0.005) and clinically relevant (>MID). RESULTS: 137 frail and 71 intermediate-fit patients were included in the analysis. Compliance was high and comparable in both groups. At baseline, frail patients reported lower global health status, lower physical functioning scores and more fatigue and pain compared to intermediate-fit patients. Both groups improved in global health status and future perspective; polyneuropathy complaints worsened over time. Frail patients improved over time in physical functioning, fatigue and pain. Improvement in global health status occurred earlier than in intermediate-fit patients. CONCLUSION: HRQoL improved during anti-myeloma treatment in both intermediate-fit and frail MM patients. In frail patients, improvement occurred faster and, in more domains, which was retained during follow-up. This implies that physicians should not withhold safe and effective therapies from frail patients in fear of HRQoL deterioration.

Guideline adherence for empirical treatment of pneumonia and patient outcome. Treating pneumonia in the Netherlands.

INTRODUCTION: According to the Dutch guidelines, severity of community acquired pneumonia (CAP) (mild, moderate-severe, severe) should be based on either PSI, CURB65 or a 'pragmatic' classification. In the last mentioned, the type of ward of admission, as decided by the treating physician, is used as classifier: no hospital admission is mild, admission to a general ward is moderate-severe and admission to an intensive care unit (ICU) is severe CAP. Empiric antibiotic recommendations for each severity class are uniform. We investigated, in 23 hospitals, which of the three classification systems empirical treatment of CAP best adhered to, and whether a too narrow spectrum coverage (according to each of the systems) was associated with a poor patient outcome (in-hospital mortality or need for ICU admission). PATIENTS AND METHODS: Prospective observational study in 23 hospitals. RESULTS: 271 (26%) of 1047 patients with CAP confirmed by X-ray were categorised in the same severity class with all three classification methods. Proportions of patients receiving guideline-adherent antibiotics were 62.9% (95% CI 60.0-65.8%) for the pragmatic, 43.1% (95% CI 40.1-46.1%) for PSI and 30.5% (95% CI 27.8-33.3%) for CURB65 classification. 'Under-treatment' based on the pragmatic classification was associated with a trend towards poor clinical outcome, but no such trend was apparent for the other two scoring systems. CONCLUSIONS: Concordance between three CAP severity classification systems was low, implying large heterogeneity in antibiotic treatment for CAP patients. Empirical treatment appeared most adherent to the pragmatic classification. Non-adherence to treatment recommendations based on the PSI and CURB65 was not associated with a poor clinical outcome.

[Systematic diagnosis of erythrocytosis]. / Systematische diagnostiek van erytrocytose.

Erythrocytosis is a phenomenon with life-threatening complications and a broad differential diagnosis. Erythrocytosis is usually secondary to a cardiopulmonary condition leading to a low arterial oxygen tension. A probable diagnosis can often be made on the basis of the history, physical examination, a measurement of the peripheral oxygen saturation, and simple laboratory tests. The differential diagnosis can be narrowed down by a determination of the erythropoietin concentration and the JAK2 mutation. If the erythrocytosis is found to be non-physiological, then reduction of the haematocrit via bloodletting and, depending on the diagnosis, treatment with acetylsalicylic acid are indicated.

Two patients with recurrent melioidosis after prolonged antibiotic therapy.

Melioidosis is a tropical infectious disease caused by Burkholderia (Pseudomonas) pseudomalleï. Clinically manifest melioidosis occurs mostly in people with underlying disorders. Melioidosis is a disease with protein manifestations and a high rate of relapse. Two patients with infection due to Burkholderia pseudomalleï after a visit to Thailand are described. Both patients presented with sepsis and appropriate therapy was initiated and continued for several months. Despite such long-term antimicrobial treatment, both patients had a relapse after cessation of therapy. It is unclear if recurrent melioidosis can be prevented by prolonging the treatment even further.

[A patient with acute leukemia and meningitis caused by Staphylococcus epidermidis treated with fosfomycin]. / Een patiënt met acute leukemie en meningitis door Staphylococcus epidermidis behandeld met fosfomycine.

In a 17-year-old male patient with acute lymphoblastic leukaemia, who was being treated with chemotherapy, a Staphylococcus epidermidis infection with several septicaemias developed during a period of protracted neutropenia. The patient was treated with vancomycin and fusidic acid, but blood cultures remained positive. The patient also developed staphylococcal meningitis. After the antibiotic regimen was supplemented by fosfomycin, the blood cultures became sterile. Combination treatment with vancomycin and fosfomycin was continued for two months without apparent toxicity. In individual cases of infection with multiresistant S. epidermidis fosfomycin may be included in the antibiotic regimen. This is the first report of parenteral use of fosfomycin in the Netherlands.

[The phenomenon of the delayed initial attack of tertian malaria]. / Het fenomeen van de uitgestelde eerste aanval van malaria tertiana.

From 1986 to 1990 we have treated 215 patients with falciparum malaria. In 8 patients (4%) who had not returned to any malarial area, malaria attacks recurred after 6-20 weeks. Curiously these were now caused by different species: Plasmodium vivax (4 patients) and P. ovale (4 patients). After proper management of malignant tertian malaria caused by P. falciparum, patients are considered cured, provided the treatment has been in accordance with the resistance pattern of the parasite in the country of origin. Yet, in a small number of patients attacks of malaria recur after different time intervals. The explanation of this seemingly paradoxical phenomenon is that these were delayed primary attacks of benign tertian malaria rather than recrudescences of malignant tertian malaria. Consequently the patients must have been infected by two different species of malaria at a time. In P. vivax and P. ovale hypnozoites occur (notably absent in P. falciparum), dormant stages in the liver that are not susceptible to the antimalarials in use for the eradication or prophylaxis of the blood stages which cause the acute attacks of malaria. After a variable amount of time the blood is then (re)invaded and the patient suffers a delayed primary attack or a relapse. Physicians should be aware that definite cure of malignant tertian malaria does not prevent future attacks of benign tertian malaria. They should inform their patients accordingly.

Combination therapy of ACNU and ifosfamide in tumor bearing mice with M2661 breast cancer, B16 malignant melanoma or C38 colon cancer.

Three murine tumor lines, B16 melanoma, C38 colon cancer and M2661 breast cancer, were used to evaluate the therapeutic efficacy of the drug combination ACNU and ifosfamide. For each tumor type five treatment groups of 12 mice each were studied, which respectively received 16.5 mg/kg ACNU, 150 mg/kg ifosfamide, 33 mg/kg ACNU, 300 mg/kg ifosfamide or 16.5 mg/kg ACNU + 150 mg/kg ifosfamide. One group served as controls. Growth delay was measured as the endpoint. In the B16 and C38 tumor lines both drugs were active and showed additive antitumor effects. However, no synergism was observed. Neither ACNU or ifosfamide or the combination of both had any activity against the M2661 tumor line.

Effects of cyclosporin A and verapamil on the intracellular daunorubicin accumulation in Chinese hamster ovary cells with increasing levels of drug-resistance.

Multidrug-resistance (MDR) is characterized by the presence of a 170 kDa glycoprotein (P-glycoprotein) in the plasma membrane. P-glycoprotein is thought to act as an efflux pump, leading to reduced drug accumulation in MDR cells. This defect in drug accumulation can be overcome by membrane transport modulating agents (MTMAs). We determined the concentration of MTMA needed for maximal restoration of daunorubicin content in 4 Chinese hamster ovary cell lines with increasing levels of drug-resistance using flow cytometry. Stimulation of daunorubicin accumulation occurred in a dose-dependent manner. The required level of MTMA needed for maximal drug accumulation increased with the level of drug-resistance. CHrA3 cells, which have a level of resistance comparable to clinical samples, needed relatively low concentrations of MTMA for maximal restoration of drug accumulation. This indicates that, in trial combining drugs and MTMAs, low dosages of MTMAs could be sufficient for optimal potentiation of cytotoxicity.