Explaining survival differences between two consecutive studies with allogeneic stem cell transplantation in patients with chronic myeloid leukemia

Purpose

In the two consecutive German studies III and IIIA on chronic myeloid leukemia, between 1995 and 2004, 781 patients were randomized to receive either allogeneic hematopoietic stem cell transplantation with a related donor or continued drug treatment. Despite comparable transplantation protocols and most centers participating in both studies, the post-transplant survival probabilities for patients transplanted in first chronic phase were significantly higher in study IIIA (144 patients) than in study III (113 patients). Prior to the decision on a combined analysis of both studies, reasons for this discrepancy had to be investigated.

Methods

The Cox proportional hazard cure model was used to identify prognostic factors for post-transplant survival.

Results

Donor–recipient matching for human leukocyte antigen, patient age, time between diagnosis and transplantation, and calendar time showed a significant influence on survival and/or the incidence of cure. Added as a further factor, affiliation to study IIIA had no significant impact any longer.

Conclusions

Discrepancies in influential prognostic factors explained the different post-transplant survival probabilities between the studies. The significance of calendar time suggests a lack of consistency of transplantation practice over time. Accordingly, the prerequisite for a common assessment of overall survival in the two randomized transplantation arms was not met. Moreover, our analyses provide an independent validation of established prognostic factors and their cutoffs. The statistical approach in investigating and modeling potential prognostic factors for survival sets an example for the examination of studies with unexpected outcome differences in concurrent treatment arms.     

Role of lon, an ATP-dependent protease homolog, in resistance of Pseudomonas aeruginosa to ciprofloxacin

With few novel antimicrobials in the pharmaceutical pipeline, resistance to the current selection of antibiotics represents a significant therapeutic challenge. Microbial persistence in subinhibitory antibiotic environments has been proposed to contribute to the development of resistance. Pseudomonas aeruginosa cultures pretreated with subinhibitory concentrations of ciprofloxacin were found to exhibit an adaptive resistance phenotype when cultures were subsequently exposed to suprainhibitory ciprofloxacin concentrations. Microarray experiments revealed candidate genes involved in such adaptive resistance. Screening of 10,000 Tn5-luxCDABE mutants identified several mutants with increased or decreased ciprofloxacin susceptibilities, including mutants in PA1803, a close homolog of the ATP-dependent lon protease, which were found to exhibit > or = 4-fold-increased susceptibilities to ciprofloxacin and other fluoroquinolones, but not to gentamicin or imipenem, as well as a characteristic elongated morphology. Complementation of the lon mutant restored wild-type antibiotic susceptibility and cell morphology. Expression of the lon mutant, as monitored through a luciferase reporter fusion, was found to increase over time in the presence of subinhibitory ciprofloxacin concentrations. The data are consistent with the hypothesis that the induction of Lon by ciprofloxacin is involved in adaptive resistance.     

The role of facemasks and hand hygiene in the prevention of influenza transmission in households: results from a cluster randomised trial; Berlin, Germany, 2009-2011

Background

Previous controlled studies on the effect of non-pharmaceutical interventions (NPI) - namely the use of facemasks and intensified hand hygiene - in preventing household transmission of influenza have not produced definitive results. We aimed to investigate efficacy, acceptability, and tolerability of NPI in households with influenza index patients.

Methods

We conducted a cluster randomized controlled trial during the pandemic season 2009/10 and the ensuing influenza season 2010/11. We included households with an influenza positive index case in the absence of further respiratory illness within the preceding 14 days. Study arms were wearing a facemask and practicing intensified hand hygiene (MH group), wearing facemasks only (M group) and none of the two (control group). Main outcome measure was laboratory confirmed influenza infection in a household contact. We used daily questionnaires to examine adherence and tolerability of the interventions.

Results

We recruited 84 households (30 control, 26 M and 28 MH households) with 82, 69 and 67 household contacts, respectively. In 2009/10 all 41 index cases had a influenza A (H1N1) pdm09 infection, in 2010/11 24 had an A (H1N1) pdm09 and 20 had a B infection. The total secondary attack rate was 16% (35/218). In intention-to-treat analysis there was no statistically significant effect of the M and MH interventions on secondary infections. When analysing only households where intervention was implemented within 36 h after symptom onset of the index case, secondary infection in the pooled M and MH groups was significantly lower compared to the control group (adjusted odds ratio 0.16, 95% CI, 0.03-0.92). In a per-protocol analysis odds ratios were significantly reduced among participants of the M group (adjusted odds ratio, 0.30, 95% CI, 0.10-0.94). With the exception of MH index cases in 2010/11 adherence was good for adults and children, contacts and index cases.

Conclusions

Results suggest that household transmission of influenza can be reduced by the use of NPI, such as facemasks and intensified hand hygiene, when implemented early and used diligently. Concerns about acceptability and tolerability of the interventions should not be a reason against their recommendation.

Trial registration

The study was registered with ClinicalTrials.gov (Identifier NCT00833885).     

Interleukin-31: The “itchy” cytokine in inflammation and therapy

The cytokine interleukin-31 has been implicated in the pathophysiology of multiple atopic disorders such as atopic dermatitis (AD), allergic rhinitis, and airway hyper-reactivity. In AD, IL-31 has been identified as one of the main “drivers” of its cardinal symptom, pruritus. Here, we summarize the mechanisms by which IL-31 modulates inflammatory and allergic diseases. T_H2 cells play a central role in AD and release high levels of T_H2-associated cytokines including IL-31, thereby mediating inflammatory responses, initiating immunoregulatory circuits, stimulating itch, and neuronal outgrowth through activation of the heterodimeric receptor IL-31 receptor A (IL31RA)/Oncostatin M receptor (OSMRβ). IL31RA expression is found on human and murine dorsal root ganglia neurons, epithelial cells including keratinocytes and various innate immune cells. IL-31 is a critical cytokine involved in neuroimmune communication, which opens new avenues for cytokine modulation in neuroinflammatory diseases including AD/pruritus, as validated by recent clinical trials using an anti-IL-31 antibody. Accordingly, inhibition of IL-31-downstream signaling may be a beneficial approach for various inflammatory diseases including prurigo. However, as to whether downstream JAK inhibitors directly block IL-31-mediated-signaling needs to be clarified. Targeting the IL-31/IL31RA/OSMRβ axis appears to be a promising approach for inflammatory, neuroinflammatory, and pruritic disorders in the future.     

Navigator respiratory‐triggered diffusion‐weighted imaging in the follow‐up after hepatic radiofrequency ablation—initial results

Purpose

To evaluate diffusion alterations after hepatic radiofrequency (RF) ablation using a navigator respiratory‐triggered diffusion‐weighted imaging (NRT‐DWI) sequence with regard to potential diagnostic information for detection of local tumor progression (LTP).

Materials and Methods

One hundred forty‐eight consecutive follow‐up magnetic resonance (MR) examinations of 54 patients after hepatic RF ablation were reviewed. Apparent diffusion coefficient (ADC) values of ablation zones and liver parenchyma were assessed using a single‐shot echoplanar imaging sequence with the NRT technique. ADC values of ablation zones and adjacent signal alterations identified in NRT‐DWI were analyzed with regard to LTP.

Results

Mean ADC values of ablation zones (119.9 ± 30.5 × 10^?5 mm²/sec) and liver (106.3 ± 21.2 × 10^?5 mm²/sec) differed significantly (P = 0.0003). No evident changes in ablations' ADC values over time could be identified. ADC values obtained from the entire ablation zone did not significantly differ regarding the presence of LTP. In 58 examinations, hyperintense areas in the periphery of the ablation zone were detected on the NRT‐DWI. Corresponding ADC values were significantly lower in patients with LTP (102.1 ± 22.4 versus 130.8 ± 47.6 × 10^?5 mm²/sec; P = 0.0124).

Conclusion

NRT‐DWI is useful in the follow‐up imaging after RF ablation. ADC‐based evaluation of signal alterations adjacent to the ablation zone may contribute to the identification of LTP and nontumoral posttreatment tissue changes. J. Magn. Reson. Imaging 2009. © 2009 Wiley‐Liss, Inc.

     

Serial O-(2-[18F]fluoroethyl)-L-tyrosine PET for monitoring the effects of intracavitary radioimmunotherapy in patients with malignant glioma

Purpose Intracavitary radioimmunotherapy (RIT) offers an effective adjuvant therapeutic approach in patients with malignant gliomas. Since differentiation between recurrence and reactive changes following RIT has a critical impact on patient management, the aim of this study was to analyse the value of serial O-(2-[¹⁸F]fluoroethyl)-l-tyrosine (FET) PET scans in monitoring the effects of this locoregional treatment. Methods Following conventional therapy, 24 glioma patients (5 WHO III, 19 WHO IV) underwent one to five RIT cycles with either ¹³¹I-labelled (n=19) or ¹⁸⁸Re-labelled (n=5) anti-tenascin antibodies. Patients were monitored with serial FET PET scans (2–12 scans). For semiquantitative evaluation, maximal tumoural uptake (TU_max) was evaluated and the ratio to background (BG) was calculated. Results of PET were correlated with histopathological findings (n=9) and long-term clinical follow-up for up to 87 months. Results In seven tumour-free patients, PET revealed slightly increasing but homogeneous FET uptake surrounding the resection cavity with a peak up to 18 months following RIT (TU_max/BG 2.07±0.25) but stable or decreasing values during further follow-up (last follow-up: TU_max/BG 1.63±0.22). Seventeen patients developed regrowth of residual tumour/tumour recurrence showing additional nodular FET uptake (TU_max/BG 2.79±0.53). A threshold value of 2.4 (TU_max/BG) allowed best differentiation between recurrence and reactive changes (sensitivity 82%, specificity 100%). Conclusion FET PET is a sensitive tool for monitoring the effects of locoregional RIT. Homogeneous, slightly increasing FET uptake around the tumour cavity with a peak up to 18 months after RIT, followed by stable or decreasing uptake, points to benign, therapy-related changes. In contrast, nodular uptake is a reliable indicator of recurrence.     

Reproductive function and risk for PCOS in women treated for bipolar disorder

INTRODUCTION: This study examined the reproductive function and prevalence of polycystic ovary syndrome (PCOS) in women with bipolar disorder taking antimanic medications. METHOD: Women aged 18-45 treated for bipolar disorder and not taking steroid contraceptives were recruited to complete questionnaires about their menstrual cycle and to provide blood samples for measurement of a range of reproductive endocrine and metabolic hormone levels. Eighty women participated in completing the questionnaires and 72 of them provided blood samples. RESULTS: Fifty-two of the 80 women (65%) reported current menstrual abnormalities, 40 of which (50%) reported one or more menstrual abnormalities that preceded the diagnosis of bipolar disorder. Fifteen women (38%) reported developing menstrual abnormalities since treatment for bipolar disorder, 14 of which developed abnormalities since treatment with valproate (p = 0.04). Of the 15 patients reporting menstrual abnormalities since starting medication, 12 (80%) reported changes in menstrual flow (heavy or prolonged bleeding) and five (33%) reported changes in cycle frequency. No significant differences were observed between women receiving or not receiving valproate in mean levels of free or total serum testosterone levels. This was true for the total sample and for the sub-group without preexisting menstrual problems. However, within the valproate group, duration of use was significantly correlated with free testosterone levels (r = 0.33, p = 0.02). Three of the 50 women (6%) taking VPA, and 0% of the 22 taking other antimanic medications, met criteria for PCOS (p = 0.20). Other reproductive and metabolic values outside the normal range across treatment groups included elevated 17 alpha-OH progesterone levels, luteinizing hormone: follicle-stimulating hormone ratios, homeostatic model assessment (HOMA) values, and low estrogen and dehydroepiandrosterone sulfate (DHEAS) levels. Preexisting menstrual abnormalities predicted higher levels of 17 alpha-OH progesterone, free testosterone, and estrone as well as development of new menstrual abnormalities. Body mass index (BMI) was significantly positively correlated with free testosterone levels and insulin resistance (HOMA) across all subjects, regardless of medication used. CONCLUSIONS: Rates of menstrual disturbances are high in women with bipolar disorder and, in many cases, precede the diagnosis and treatment for the disorder. Treatment with valproate additionally contributes significantly to the development of menstrual abnormalities and an increase in testosterone levels over time. A number of bipolar women, regardless of type of medication treatment received, have reproductive and metabolic hormonal abnormalities, yet the etiology of such abnormalities requires further study. Women with preexisting menstrual abnormalities may represent a group at risk for development of reproductive dysfunction while being treated for bipolar disorder.     

Oscillatory MEG gamma band activity dissociates perceptual and conceptual aspects of visual object processing: a combined repetition/conceptual priming study

We used a combined repetition/conceptual priming task to investigate attenuations of induced gamma-band activity (iGBA) due to prior experience. We hypothesized that distinguishable iGBA suppression effects can be related to the processing of (a) perceptual aspects, and (b) conceptual aspects of cortical object representations. Participants were asked to perform a semantic classification task with pictures of real world objects and their semantically corresponding words, using a design that isolated distinct levels of the neural suppression effect. By means of volumetric source analysis we located stimulus domain-specific iGBA repetition suppression effects (60-90 Hz) in temporal, parietal, and occipital areas of the human cortex. In contrast, domain-unspecific iGBA repetition suppression, corresponding to conceptual priming, was restricted to left temporal brain regions. We propose that the selective involvement of left temporal areas points to the activation of conceptual representations, whereas more posterior temporal, parietal, and occipital areas probably reflect perceptual aspects of higher-order visual object processing.