Differences in epidemiology of candidaemia in the Nordic countries - what is to blame?

National data from Denmark, Finland, Norway and Sweden demonstrate remarkable differences in candidaemia epidemiology. Only Denmark has reported a high incidence of 10 per 100 000 inhabitants and a species shift towards increased C. glabrata candidaemias. The reasons for this development remain unclear. The aim of this study was to explore possible contributing factors for the differences in Candida epidemiology in the Nordic countries. We used public data from 2011 from Denmark, Finland, Norway and Sweden on epidemiology, demographics, health facilities, predisposing risk factors, consumption of antimicrobial drugs and fungicides in agricultural industry. Only the prevalence of haematological malignancies (P < 0.001) was significantly higher in Denmark compared to the other Nordic countries. The antibacterial drug use of metronidazole, piperacillin-tazobactam, ciprofloxacin, colistin and carbapenems, and antifungal use of fluconazole in humans (P < 0.001), were significantly higher in Denmark compared to the other Nordic countries (all P < 0.001). Our findings suggest haematological malignancy, the use of certain antibacterial drugs and azoles in humans as possible contributing factors for the differences in Candida epidemiology. However, our results should be interpreted with caution due to the lack of long-term, case-specific data. Further studies are needed.

Cost-effectiveness of First-line Chronic Lymphocytic Leukemia Treatments When Full-dose Fludarabine Is Unsuitable.

PURPOSE: The cost-effectiveness of first-line chronic lymphocytic leukemia treatments was assessed among patients unsuitable for full doses of fludarabine. METHODS: The study's key outcome was the life-time incremental cost-effectiveness ratio (ICER) (euro/quality-adjusted life-year [QALY] gained) with an annual 3% discounting. A probabilistic Markov model with 3 health states (progression-free, progression, and death) was developed. Survival time was modeled based on age-matched clinical data by using appropriate survival distributions. Each health state was assigned an EuroQoL-5D-3L quality-of-life estimate and Finnish payer costs according to treatment received, and Binet stage of disease; severe adverse events and treatment inconvenience were also included. Six approaches considered the risk and value of key outcomes: cost-effectiveness efficiency frontiers; Bayesian treatment ranking (BTR) rated the lowest ICERs and best QALY gains; the cost-effectiveness acceptability frontier demonstrated optimal treatment; expected value of perfect information; and the cost-benefit assessment (CBA), a type of clinical value analysis, increased the clinical interpretation and appeal of modeled outcomes by including both relative and absolute (impact investment [benefit obtained with a fixed limited budget]) benefit assessments. FINDINGS: The ICERs compared with chlorambucil varied from €29,334 with obinutuzumab + chlorambucil to €82,159 with ofatumumab + chlorambucil. Based on the BTR of ICERs versus chlorambucil, obinutuzumab + chlorambucil was the most cost-effective with 93% probability; rituximab + chlorambucil was the second most cost-effective (73%); and rituximab + bendamustine was the third most cost-effective (65%). The ICERs of obinutuzumab + chlorambucil were €20,038, €11,556, and €15,586 compared with rituximab + chlorambucil, rituximab + bendamustine, and ofatumumab + chlorambucil. Obinutuzumab + chlorambucil was the most cost-effective treatment, with 54% and 99% probability at €30,000 and €50,000/QALY gained, respectively. The corresponding expected values of perfect information were €1438 and €44 per patient. Based on the BTR of QALYs gained, obinutuzumab + chlorambucil was the most effective, with 100% probability; rituximab + chlorambucil was the second most effective (56%); and rituximab + bendamustine was the third most effective treatment (81%). Results were robust in sensitivity analyses. For obinutuzumab + chlorambucil, the CBA demonstrated the best clinical value-to-cost-effectiveness relation and the longest time progression-free with a limited budget. IMPLICATIONS: The mean results were sensitive to large changes in time horizon, indirect comparison hazard ratios, survival distributions, and discounting; however, obinutuzumab + chlorambucil provided considerable effectiveness and best value for money among chronic lymphocytic leukemia patients unsuitable to receive full doses of fludarabine. In this case, CBA concurred with the key outcome of the study. However, the CBA cannot fully substitute the key outcome, and further cost-effectiveness studies with different cancer types are needed to assess the validity of a limited CBA.

Nitrous oxide analgesia for bone marrow aspiration and biopsy - A randomized, controlled and patient blinded study.

Background and aims Bone marrow aspiration and/or biopsy (BMAB), performed under local anaesthesia in adults, is a common and often painful procedure. Anxiety is known to intensify pain during the procedure. Nitrous oxide (N2O), known for its sedative and analgesic benefit in various short medical procedures and labour pain, could be advantageous also for pain relief during bone marrow examination. N2O acts rapidly and is eliminated in a couple of minutes once the inhalation is stopped, and occasional side effects (e.g. dizziness and nausea) are mild. The aim of this study was to compare the analgesic effects of inhaled 50% mixture of nitrous oxide and oxygen to 50% oxygen during bone marrow examination. Methods In this randomized, controlled, patient and observer blinded study patients received either 50% mixture of nitrous oxide and oxygen or 50% mixture of oxygen in air during bone marrow examination, in addition to local analgesia. Both patient groups comprised 35 adult patients. Pre-procedural anxiety and procedural pain were rated on the Numeral Rating Scale (NRS 0‒10). Cognitive function was measured before and 30 min after the procedure. Possible side effects were recorded. A telephone interview was performed 24 h later. Results There were no statistically significant differences in pain scores of the procedural steps (median NRS ranging 3.0‒4.0) between the study groups. High pain scores of 8‒10 comprised 0% vs. 8.6% of the scores during infiltration, 2.9% vs. 5.7% during puncture, 11.4% vs. 14.3% during aspiration and 2.9% vs. 2.9% during biopsy in N2O and 50% O2 groups, respectively (NS). Pre-procedural anxiety (median NRS 3.5 in both groups), measured in the outpatient clinic just prior to procedure, correlated with pain intensity during bone marrow aspiration (P = 0.045). There were no significant differences between side effects. During the BMAB four patients (3 in N2O group, 1 in 50% O2 group) reported dizziness and one patient in the N2O group reported nausea. Gas inhalation did not affect the cognitive function of the participants. In both groups the majority (>80%) of the patients was satisfied with the inhalation technique. During the 24 h interview, most of the participants were pain free and they did not report any serious adverse effects. Conclusions In spite of similar moderate to strong procedural pain in both groups and no benefit of N2O, most patients were satisfied with the inhalational techniques. We assume that the bedside presence of an anaesthesiologist and the distraction caused by the inhalational arrangements introduced positive context-sensitive therapeutic effect independent of the gas used. Pre-procedural anxiety predicted pain associated with bone marrow aspiration. Implications Inhaled 50% nitrous oxide was not an effective analgesic during bone marrow examination in our unselected outpatient population. Further studies should concentrate on its use with patients predicted to be at increased risk of suffering intense pain during the procedure, such as very anxious patients or those who have a painful history of previous bone marrow examinations.

Prolonged immunochemotherapy with rituximab, cytarabine and fludarabine added to cyclophosphamide, doxorubicin, vincristine and prednisolone and followed by rituximab maintenance in untreated elderly patients with mantle cell lymphoma: a prospective study by the Finnish Lymphoma Group.

There is no consensus on treatment strategies for elderly patients with mantle cell lymphoma (MCL). In this prospective phase II study we investigated whether the poor outcome could be improved, with reasonable toxicity, by prolonging the immunochemotherapy. Ten cycles of alternating cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP)/cytarabine (AraC) with eight doses of rituximab (R) were given as induction. The potential synergism of intermediate-dose AraC and fludarabine was tested in cycles 6-8. Induction was followed by bimonthly rituximab maintenance for 2 years. The median age of the 60 included patients was 74 years, and the Mantle Cell Lymphoma International Prognostic Index (MIPI) was intermediate or high risk in 98% of the patients. The overall response rate was 95% (complete response/complete response unconfirmed 87%). The response of 11 patients improved with cycles 6-8 (R-fludarabine-AraC). Progression-free survival was 70% and overall survival 72% at 4 years, respectively. Treatment related mortality was 2%. Severe infections were rare, with only one grade 4 infection. More dose reductions were needed during fludarabine-containing courses as compared to R-AraC. In 20 patients a transient grade 4 neutropenia without severe infections was recorded during maintenance. In conclusion, elderly patients with MCL can be treated relatively intensively with acceptable toxicity.

Secular trend in candidemia and the use of fluconazole in Finland, 2004-2007.

BACKGROUND: In a previous study we observed an increasing trend in candidemia in Finland in the 1990s. Our aim was now to investigate further population-based secular trends, as well as outcome, and evaluate the association of fluconazole consumption and prophylaxis policy with the observed findings. METHODS: We analyzed laboratory-based surveillance data on candidemia from the National Infectious Diseases Register during 2004-2007 in Finland. Data on fluconazole consumption, expressed as defined daily doses, DDDs, was obtained from the National Agency for Medicines, and regional prophylaxis policies were assessed by a telephone survey. RESULTS: A total of 603 candidemia cases were identified. The average annual incidence rate was 2.86 cases per 100,000 population (range by year, 2.59-3.09; range by region, 2.37-3.85). The highest incidence was detected in males aged >65 years (12.23 per 100,000 population). Candida albicans accounted for 67% of cases, and C. glabrata ranked the second (19%), both without any significant change in proportions. C. parapsilosis accounted for 5% of cases and C. krusei 3% of cases. The one-month case-fatality varied between 28-32% during the study period. Fluconazole consumption increased from 19.57 DDDs per 100,000 population in 2000 to 25.09 in 2007. Systematic fluconazole prophylaxis was implemented for premature neonates, patients with acute leukemias and liver transplant patients. CONCLUSION: The dominant proportion of C. albicans remained stable, but C. glabrata was the most frequent non-albicans species. The proportion of C. glabrata had increased from our previous study period in the presence of increasing use of fluconazole. The rate of candidemia in Finland is still low but mortality high like in other countries.

Nosocomial candidaemia in a Finnish tertiary care centre during 1987-2004.

We studied the epidemiology of nosocomial candidaemia by assessing the incidence and outcome of illness and causative species in a large Finnish tertiary care centre during 1987-2004. A total of 364 episodes were observed; annual incidence varied between 0.26 per 10,000 patient-d in 2000 and 0.59 in 1989. The most common species were C. albicans (65%), C. parapsilosis (13%), and C. glabrata (9%). The proportion of C. albicans decreased from 71% during 1987-1992 to 58% during 1999-2004, and C. glabrata increased from 3% to 14%, respectively. The proportion of intensive care patients increased from 27% during 1987-1992 to 44% by 1999-2004, associated with neonates and surgical patients. The 1-month case fatality ranged from 30% to 33%. Nosocomial candidaemias did not increase, but the distribution of Candida spp. changed. Mortality remained high. The observed changes may reflect differences in prevention strategies that need to be explored for further improvements in prevention.

Valproic acid combined with 13-cis retinoic acid and 1,25-dihydroxyvitamin D3 in the treatment of patients with myelodysplastic syndromes.

Valproic acid (VPA), an inhibitor of histone deacetylases, inhibits the growth of leukemia cells and induces their differentiation in vitro. In the present study, VPA in combination with two differentiating agents, 13-cis retinoic acid and 1,25-dihydroxyvitamin D3, was given to 19 previously untreated patients with MDS or CMML. Eight patients had to discontinue treatment before week 16 due to toxicity. According to international working group criteria, three patients (16%) responded to treatment. No correlation between VPA serum level, histone acetylation or clinical response was observed.

Candidemia in Finland, 1995-1999.

We analyzed laboratory-based surveillance candidemia data from the National Infectious Disease Register in Finland and reviewed cases of candidemia from one tertiary-care hospital from 1995 to 1999. A total of 479 candidemia cases were reported to the Register. The annual incidence rose from 1.7 per 100,000 population in 1995 to 2.2 in 1999. Species other than Candida albicans accounted for 30% of cases without change in the proportion. A total of 79 cases of candidemia were identified at the hospital; the rate varied from 0.03 to 0.05 per 1,000 patient-days by year. Predisposing factors included indwelling catheters (81%), gastrointestinal surgery (27%), hematologic malignancy (25%), other types of surgery (21%), and solid malignancies (20%). Crude 7-day and 30-day case-fatality ratios were 15% and 35%, respectively. The rate of candidemia increased in Finland but is still substantially lower than in the United States. No shift to non-C. albicans species could be detected.