Mechanisms of venoocclusive disease resulting from the combination of cyclophosphamide and roxithromycin

BACKGROUND: High doses (>or=500 mg/m) of cyclophosphamide are known to cause venoocclusive disease (VOD). The authors recently observed a patient treated with immunosuppressive cyclophosphamide doses (100 mg/day) and roxithromycin who developed VOD. Because roxithromycin inhibits cytochrome P450 (CYP) 3A4 and P-glycoprotein, the patient may have been exposed to higher cyclophosphamide and/or cyclophosphamide metabolite concentrations. METHODS: The effect of roxithromycin on the metabolism and toxicity of cyclophosphamide was studied using human hepatic microsomes and a human endothelial cell line. RESULTS: Cyclophosphamide or roxithromycin at concentrations from 0.05 to 500 micromol/L were not toxic to endothelial cells as assessed by lactate dehydrogenase (LDH) leakage assay. However, the combination of roxithromycin (500 micromol/L) and cyclophosphamide was toxic for all the tested cyclophosphamide concentrations (0.05 to 500 micromol/L) without clear concentration dependence (LDH ratio 38.3 +/- 11.0 [mean +/- SEM] for the combination with cyclophosphamide 0.05 micromol/L and 50.2 +/- 10.2 for the combination with cyclophosphamide 500 micromol/L; P 相似文献   

Learning to dislike alcohol: conditioning negative implicit attitudes toward alcohol and its effect on drinking behavior

Rationale  

Since implicit attitudes toward alcohol play an important role in drinking behavior, a possible way to obtain a behavioral change is changing these implicit attitudes.     

Training inhibitory control. A recipe for resisting sweet temptations

When inhibitory control is lacking, people are more prone to indulge in high calorie food. This research examined whether training to inhibit food-related responses renders one less susceptible to temptations of high calorie food. Trait chocolate lovers were divided into three conditions: participants either consistently inhibited responding to chocolate stimuli (chocolate/no-go condition), consistently responded to chocolate stimuli (chocolate/go condition), or responded to chocolate stimuli only during half the trials (control condition). Chocolate consumption was measured following the manipulation with a taste test. Chocolate consumption did not differ between the control condition and the chocolate/go condition, and increased as a function of dietary restraint in both conditions. In the chocolate/no-go condition, however, chocolate consumption was significantly reduced, and higher levels of dietary restraint were associated with decreased chocolate intake. These findings demonstrate that repeatedly practicing inhibitory control over food-related responses can help people regain control over the consumption of high calorie food.     

Making implicit measures of associations with snack foods more negative through evaluative conditioning

The present study examined whether implicit measures of associations with snack foods and food consumer behaviour could be changed through a picture–picture evaluative conditioning procedure. In the experimental condition (n = 41), female participants completed a conditioning procedure in which pictures of snack foods were paired with images of negatively valenced female body shapes, and pictures of fruits were paired with images of positively valenced body shapes. In a control condition (n = 44), snack and fruit stimuli were randomly paired with positively and negatively valenced body shapes. Implicit measures of associations with high-fat snack foods were obtained by using a positive and a negative unipolar single category Implicit Association Test (sc-IAT). A virtual supermarket task was used to assess food consumer behaviour. Results indicated that participants in the experimental condition held a less positive association with high-fat foods on the positive sc-IAT and a more negative association with these foods on the negative sc-IAT as compared to control participants. Opposed to our hypothesis, no behavioural differences were found between the groups. These results imply that this form of associative learning can produce shifts in implicit measures of food evaluations, though behavioural effects were absent.     

Feasibility of whole-body diffusion-weighted MRI for detection of primary tumour,nodal and distant metastases in women with cancer during pregnancy: a pilot study

Objectives

To evaluate the feasibility of whole-body diffusion-weighted MRI (WB-DWI/MRI) for detecting primary tumour, nodal and distant metastases in pregnant women with cancer.

Methods

Twenty pregnant patients underwent WB-DWI/MRI in additional to conventional imaging. Reproducibility of WB-DWI/MRI between two readers was evaluated using Cohen’s κ statistics and accuracy was compared to conventional imaging for assessing primary tumour site, nodal and visceral metastases.

Results

Both WB-DWI/MRI readers showed good–very good agreement for lesion detection (primary lesions: κ=1; lymph nodes: κ=0.89; distant metastases: κ=0.61). Eight (40 %) patients were upstaged after WB-DWI/MRI. For nodal metastases, WB-DWI/MRI showed 100 % (95 % CI: 83.2–100) sensitivity for both readers with specificity of 99.4 % (96.9–100) and 100 % (80.5–100) for readers 1 and 2, respectively. For distant metastases, WB-DWI/MRI showed 66.7 % (9.4–99.2) and 100 % (29.2–100) sensitivity and specificity of 94.1 % (71.3–99.9) and 100 % (80.5–100) for readers 1 and 2, respectively. Conventional imaging showed sensitivity of 50 % (27.2-72.8) and 33.3 % (0.8–90.6); specificity of 100 % (98–100) and 100 % (80.5–100), for nodal and distant metastases respectively.

Conclusions

WB-DWI/MRI is feasible for single-step non-invasive staging of cancer during pregnancy with additional value for conventional imaging procedures.

Key points

? In our study, WB-DWI/MRI was more accurate than conventional imaging during pregnancy. ? WB-DWI/MRI improves diagnostic assessment of patients with cancer during pregnancy. ? Accurate imaging and oncologic staging improves treatment and outcome.

     

Reasons for revision are associated with rerevised total knee arthroplasties: an analysis of 8,978 index revisions in the Dutch Arthroplasty Register

Background and purpose — From previous studies, we know that clinical outcomes of revision total knee arthroplasty (rTKA) differ among reasons for revision. Whether the prevalence of repeat rTKAs is different depending on the reason for index rTKA is unclear. Therefore, we (1) compared the repeat revision rates between the different reasons for index rTKA, and (2) evaluated whether the reason for repeat rTKA was the same as the reason for the index revision.Patients and methods — Patients (n = 8,978) who underwent an index rTKA between 2010 and 2018 as registered in the Dutch Arthroplasty Register were included. Reasons for revision, as reported by the surgeon, were categorized as: infection, loosening, malposition, instability, stiffness, patellar problems, and other. Competing risk analyses were performed to determine the cumulative repeat revision rates after an index rTKA for each reason for revision.Results — Overall, the cumulative repeat revision rate was 19% within 8 years after index rTKA. Patients revised for infection had the highest cumulative repeat revision rate (28%, 95% CI 25–32) within 8 years after index rTKA. The recurrence of the reason was more common than other reasons after index rTKA for infection (18%), instability (8%), stiffness (7%), and loosening (5%).Interpretation — Poorest outcomes were found for rTKA for infection: over 1 out of 4 infection rTKAs required another surgical intervention, mostly due to infection. Recurrence of other reasons for revision (instability, stiffness, and loosening) was also considerable. Our findings also emphasize the importance of a clear diagnosis before doing rTKA to avert second revision surgeries.

The number of revision total knee arthroplasties (rTKA) has increased over the past years, and projections predict further increases in the coming decades (Kurtz et al. 2007, Patel et al. 2015, LROI 2019). The outcome of these rTKAs is in general inferior compared with the outcome of the primary total knee arthroplasty (Greidanus et al. 2011, Baker et al. 2012, Nichols and Vose 2016). Evidence suggests that one of the determinants for outcome of rTKA is the indication for the revision. To illustrate, several studies have shown a poor prognosis when the rTKA is performed for infection or stiffness compared with revisions for aseptic loosening (Sheng et al. 2006, Pun and Ries 2008, Baker et al. 2012, Van Kempen et al. 2013, Leta et al. 2015). Poor results were reported in terms of complication rates, patient satisfaction, and survival of the prosthesis. However, the majority of these studies based their findings on small samples, and single-center cohorts.A repeat revision indicates that either the initial problem was not resolved despite the index revision, or that another problem occurred. Several reasons for a failed index rTKA can be: inaccurate diagnosis, the decision to choose operative versus nonoperative treatment, surgical failure, the occurrence of complications, or insufficient rehabilitation protocols. Insight into whether the reason for index rTKA is related to the same reason for the repeat rTKA might provide a base for improvement of treatment choices in these revision surgeries.Therefore, we (1) compared the repeat revision rates among the different reasons for index rTKA, and (2) evaluated how often the reason for repeat rTKA was the same as the reason for the index revision.     

Implicitly positive about alcohol? Implicit positive associations predict drinking behavior

Research using unipolar Implicit Association Tests (IATs) demonstrated that positive but not negative implicit alcohol associations are related to drinking behavior. However, the relative nature of the IAT with respect to target concepts (i.e., alcohol vs. soft drinks) obscures the interpretation of IAT scores and their relationship to behavior. Here, results with unipolar alcohol vs. soft drinks IATs were compared to results with unipolar Single Target IATs (ST-IAT) for alcohol alone. As expected, positive implicit alcohol associations assessed with both the alcohol-soft drinks IAT and the alcohol ST-IAT were related to alcohol use. In contrast, negative implicit associations with alcohol, whether they were assessed with alcohol-soft drinks IAT or the alcohol ST-IAT, showed no relationship with drinking behavior. Importantly, the alcohol-soft drinks IAT also predicted alcohol use above the variance explained by explicit alcohol-related cognitions, demonstrating that positive implicit associations with alcohol predict unique variance in drinking behavior.     

Absorption,distribution, metabolism and excretion (ADME) of the ALK inhibitor alectinib: results from an absolute bioavailability and mass balance study in healthy subjects

1.?Alectinib is a highly selective, central nervous system-active small molecule anaplastic lymphoma kinase inhibitor.

2.?The absolute bioavailability, metabolism, excretion and pharmacokinetics of alectinib were studied in a two-period single-sequence crossover study. A 50?μg radiolabelled intravenous microdose of alectinib was co-administered with a single 600?mg oral dose of alectinib in the first period, and a single 600?mg/67?μCi oral dose of radiolabelled alectinib was administered in the second period to six healthy male subjects.

3.?The absolute bioavailability of alectinib was moderate at 36.9%. Geometric mean clearance was 34.5?L/h, volume of distribution was 475?L and the hepatic extraction ratio was low (0.14).

4.?Near-complete recovery of administered radioactivity was achieved within 168?h post-dose (98.2%) with excretion predominantly in faeces (97.8%) and negligible excretion in urine (0.456%). Alectinib and its major active metabolite, M4, were the main components in plasma, accounting for 76% of total plasma radioactivity. In faeces, 84% of dose was excreted as unchanged alectinib with metabolites M4, M1a/b and M6 contributing to 5.8%, 7.2% and 0.2% of dose, respectively.

5.?This novel study design characterised the full absorption, distribution, metabolism and excretion properties in each subject, providing insight into alectinib absorption and disposition in humans.