The negative impact of being underweight and weight loss on survival of children with acute lymphoblastic leukemia

Body mass index and change in body mass index during treatment may influence treatment outcome of pediatric patients with acute lymphoblastic leukemia. However, previous studies in pediatric acute lymphoblastic leukemia reported contradictory results. We prospectively collected data on body composition from a cohort of newly diagnosed Dutch pediatric patients with acute lymphoblastic leukemia (n=762, age 2–17 years). Patients were treated from 1997–2004 and the median follow-up was 9 years (range, 0–10). Body mass index at diagnosis was expressed as age- and gender-matched standard deviation scores and on the basis of these scores the patients were categorized as being underweight, of normal weight or overweight. Multivariate analyses showed that patients who were underweight (8%) had a higher risk of relapse [hazard ratio: 1.88, 95% confidence interval (1.13–3.13)], but similar overall survival and event-free survival as patients who had a normal weight or who were overweight. Patients with loss of body mass index during the first 32 weeks of treatment had a similar risk of relapse and event-free survival, but decreased overall survival [hazard ratio: 2.10, 95% confidence interval (1.14–3.87)] compared to patients without a loss of body mass index. In addition, dual X-ray absorptiometry scans were performed in a nested, single-center cohort. Data from these scans revealed that a loss of body mass consisted mainly of a loss of lean body mass, while there was a gain in the percentage of fat. In conclusion, being underweight at diagnosis is a risk factor for relapse, and a decrease in body mass index early during treatment is associated with decreased survival. In addition, loss of body mass during treatment seems to consist mainly of a loss of lean body mass. This study was approved by the Medical Ethical Committee in 1996 (trial number NTR460/SNWLK-ALL-9).     

Recent advances in the understanding of iron overload in sideroblastic myelodysplastic syndrome

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal haematopoietic stem cell malignancies. A subgroup, the so‐called sideroblastic MDS, shows ring sideroblasts in the bone marrow aspirate that represent mitochondrial iron accumulation. Patients with sideroblastic MDS also develop systemic iron overload and generally have a low‐risk MDS. Therefore it is important to understand the mechanisms responsible for iron accumulation and the associated toxicity in these patients. Recently, low levels of the iron‐regulatory peptide hepcidin were found to contribute to body iron overload in β‐thalassaemia patients. A similar mechanism may account for systemic iron accumulation in sideroblastic MDS. Mitochondrial iron accumulation is observed in several subtypes of MDS, and predominantly in refractory anaemia with ring sideroblasts. The presence of ring sideroblasts is also the diagnostic hallmark in patients with inherited forms of sideroblastic anaemia. The ever‐increasing insights into the affected pathways in inherited sideroblastic anaemia may lead to a better comprehension of the pathogenesis of mitochondrial iron accumulation in MDS patients. Overall, an improved understanding of the mechanisms responsible for iron overload in MDS will lead to novel treatment strategies to reduce both systemic and mitochondrial iron overload, resulting in less tissue damage and more effective erythropoiesis.     

Enrichment Broth Improved Detection of Extended-Spectrum-Beta-Lactamase-Producing Bacteria in Throat and Rectal Surveillance Cultures of Samples from Patients in Intensive Care Units

We evaluated the use of a trypticase soy broth (TSB) for improving detection of extended-spectrum-beta-lactamase-producing (ESBL⁺) bacteria. Preenrichment of throat and rectal swabs in TSB prior to inoculation on solid medium doubled the number of ESBL⁺ bacteria detected in samples obtained from patients in our intensive care unit.Extended-spectrum beta-lactamases (ESBLs) are enzymes in gram-negative bacilli that confer resistance to the majority of β-lactam antibiotics up to the extended-spectrum cephalosporins. Their worldwide dissemination concerns clinicians, because infections with ESBL-producing (ESBL⁺) microorganisms are often not adequately covered with empirically started antibiotics. The proper choices of antibiotic therapy and infection control measures depend upon early and accurate ESBL detection; it is therefore pivotal to have a rapid and sensitive laboratory assay (4).The sensitivity of methicillin (meticillin)-resistant Staphylococcus aureus detection by culture is increased 9 to 25% by overnight enrichment of culture swabs in broth before inoculation on solid medium (2, 6). To the best of our knowledge, the effect of preenrichment on the sensitivity of detection of ESBL⁺ bacteria has not yet been determined. We have evaluated the effect of overnight enrichment in broth by culturing fecal samples that were spiked with genotypically characterized ESBL⁺ strains to see if normal flora of a fecal sample would interfere with detection of low numbers of ESBL-positive strains. The enrichment broth was also evaluated with clinical samples obtained from adult patients in two intensive care units (ICUs) of our hospital.For the spiking experiments, we used the Klebsiella pneumoniae K6 ATCC 700603 strain, which produces an SHV-18 ESBL (5), and two clinical isolates of Escherichia coli with a CTX-M-type ESBL. Bacterial suspensions of these strains with an optical density at a 0.5 McFarland standard were serially diluted in phosphate-buffered saline (PBS); nine 10-fold dilutions were made. To quantify the viable bacteria in each dilution step, a MacConkey agar was inoculated with 100 μl of a suspension and incubated overnight at 37°C; the number of grown colonies was counted the following day. Spiked samples were made by adding 100 μl of each dilution in PBS to 900 μl of a fecal suspension that was obtained by suspending 6 grams of fresh feces from healthy volunteers in 60 ml of antibiotic-free trypticase soy broth (TSB) with 0.5% sodium chloride (Becton Dickinson, Breda, The Netherlands). A fecal suspension without the addition of an ESBL⁺ strain was used as a negative control. Aliquots of 100 μl of the spiked samples were subcultured in 900 μl of TSB and onto beta-lactamase screening (BLSE) agar (Aes Chemunex, Bruz cedex, France). The BLSE agar is a commercially available double plate containing Drigalski medium supplemented with 1.5 μg per ml cefotaxime and MacConkey agar with 2 μg per ml ceftazidime. Gram-negative bacteria that are resistant to cephalosporins (including AmpC producers) can grow on this selective agar. Colonies of Pseudomonas aeruginosa can be discriminated from those of Enterobacteriaceae by observing colony morphology and color and by using an oxidase test. The samples in enrichment broth and BLSE plates were incubated for one night at 37°C. The following day, 100 μl of the enriched samples was subcultured onto BLSE as described above. Colonies on BLSE were counted after one night of incubation, and the recovery of the spiked strains was confirmed with the Vitek 2 system (Vitek ID and Vitek AST; BioMérieux, Marcy l''Etoile, France). All experiments were performed in triplicate.Surveillance cultures (throat and rectum) of samples from mechanically ventilated patients in the ICU of our hospital were performed one to two times per week and collected from 16 March to 17 May 2007. Specimens were obtained with an Amies swab (Copan, Brescia, Italy). On the day that the surveillance cultures were obtained, the patient''s swabs were first streaked on BLSE agar and then inserted into 5 ml of antibiotic-free TSB for overnight incubation at 37°C. The next day, the swabs in the TSB-enriched cultures were streaked on BLSE plates. The BLSE plates, both those inoculated with swabs before enrichment and those inoculated with swabs after overnight enrichment in TSB, were incubated for 2 days at 37°C. Gram-negative isolates growing on BLSE agars were identified by the Vitek 2 system and tested for ESBL production with three methods: by the double-disc synergy test with an amoxicillin (amoxicilline) clavulanate tablet in the center, surrounded by cefpodoxime, ceftazidime, and cefotaxime tablets; by the combined-disc diffusion test with cefepime and cefepime clavulanate tablets (all tablets from Rosco Diagnostica, Neo-Sensitabs, Taastrup, Denmark); and by an Etest with both cefepime and cefepime clavulanate (AB Biodisk, Solna, Sweden) (3). Patient characteristics and culture results were recorded; data were analyzed with SPSS (version 14.0).The suspensions of ESBL⁺ strains in PBS that were used to spike fecal samples yielded growth on MacConkey agars up to the seventh (E. coli, isolate 1) and eighth (K. pneumonia and E. coli, isolate 2) log dilutions. When cultured without TSB enrichment, spiked fecal suspensions showed numbers of colonies on BLSE agars that were similar to those in corresponding PBS dilutions of ESBL⁺ strains on MacConkey agars. After TSB enrichment, the cultures produced significantly more colonies on BLSE agars than they did without enrichment (P < 0.05; Wilcoxon signed-rank test). TSB enrichment of K. pneumoniae and E. coli (isolate 1) also yielded growth 1 log dilution further than the level observed without enrichment. Thus, for these strains and conditions, the spiking experiments demonstrate that the growth of ESBL⁺ strains in enrichment broth is not inhibited by fecal flora; enrichment in TSB can even improve the detection of ESBL⁺ bacilli.We also compared the yields of the clinical samples cultured with and without enrichment. During a 2-month period, we collected 500 surveillance specimens (throat and rectal swabs) from 88 mechanically ventilated ICU patients. The ICU patients in our hospital receive selective decontamination of the digestive tract (SDD) (an antibiotic cocktail containing polymyxin E, tobramycin, and amphotericin B, with cefotaxime intravenously administrated on the first 3 days) to reduce ventilator-associated infections (1). Surveillance cultures are routine in our ICUs and are performed to detect pathogens that are resistant to the SDD. With enrichment, twice the number of cultures yielded ESBL⁺ bacteria compared to the number of cultures without enrichment; this corresponded to nine patients detected as carriers of ESBL⁺ strains when culture with preenrichment was used, compared to five patients detected by conventional culture (Table ​(Table1).1). On the premise that differences in culture outcome were not affected by patient characteristics (with the null hypothesis not rejected by the goodness-of-fit test), we analyzed the two culture methods at the sample level with McNemar''s test, hypothesizing that both methods detect ESBL⁺ species equally well. The difference in detection between the two methods was statistically significant (P = 0.006); hence, we concluded that the enrichment step improved ESBL detection.

TABLE 1.

ESBL-positive clinical samples with and without enrichment^a

Bladder cancer diagnosis and recurrence prognosis: comparison of markers with emphasis on survivin

Expression of the anti-apoptotic protein survivin is hardly detectable or even absent in many differentiated adult tissues, but is upregulated in almost any type of cancer. Furthermore, high survivin mRNA or protein expression generally correlates with an adverse disease course. Both these important features of survivin expression have been investigated for diagnostic and prognostic purposes in many human cancers, including bladder cancer. In this review, the role of survivin in the detection of bladder tumors and the prediction of tumor recurrence in patients with superficial bladder cancer will be discussed and compared to that of other markers/tests. The most promising marker(s) will be outlined. Also, important requirements for a successful implementation of such markers in a hospital setting are discussed. Finally, future directions for the discovery of new diagnostic or prognostic candidate markers will be mentioned.     

Thyroid function and prevalence of anti-thyroperoxidase antibodies in a population with borderline sufficient iodine intake: influences of age and sex

BACKGROUND: We present a large European population-based study of thyroid function, performed in a population with longstanding borderline sufficient iodine intake. METHODS: The Nijmegen Biomedical Study is a population-based survey conducted in the eastern part of The Netherlands. Randomly selected inhabitants received a postal questionnaire on lifestyle and medical history, which was filled out by 9371 individuals (41.7%). We measured serum thyroid-stimulating hormone (TSH), free thyroxine (FT4), and anti-thyroperoxidase antibodies (TPOAbs) in 6434 responders. A reference population of 5167 individuals was selected by excluding those at risk for thyroid disease. RESULTS: Overt thyrotoxicosis was found in 0.4% of the total population and subclinical thyrotoxicosis in 0.8%. Overt hypothyroidism was found in 0.4% and subclinical hypothyroidism in 4.0%. In individuals older than 60 years, mean FT4 concentrations increased with age. Mean TSH decreased with age, from 1.46 mIU/L at 18-24 years to 1.07 mIU/L after 85 years. The mean TSH in the total population did not differ from the mean TSH in the reference population; the exclusion of those at risk for thyroid disease, however, lowered the upper limit of the TSH reference interval considerably. In the total population, 8.6% of males and 18.5% of females had positive TPOAbs. The presence of TPOAbs was associated with abnormally high and low TSH concentrations. CONCLUSION: In inhabitants of the eastern part of The Netherlands, serum TSH gradually decreases with age, whereas after age 60, serum FT4 increases, possibly because of the development of thyroid autonomy after longstanding borderline sufficient iodine intake.