M.R. de Boer

Docetaxel (Taxotere): an active agent in metastatic urothelial cancer; results of a phase II study in non-chemotherapy-pretreated patients.

The semisynthetic taxoid docetaxel was investigated in a phase II study in non-chemotherapy pretreated patients with metastatic urothelial cell cancer. Thirty patients (median age 61, range 45-72) were treated with docetaxel 100 mg m(-2) administered as a 1-h infusion every 3 weeks. Of 29 evaluable patients, four achieved a complete response and five a partial response, for an overall response rate of 31%. The median duration of response was 6 months (range 4-51+). A total of 104 cycles were administered. The median number of cycles given was three (range 1-9). Toxic effects of docetaxel mainly consisted of neutropenia, which, however, rarely caused infectious complications (5%). Fluid retention or neuropathy necessitated treatment cessation in two patients. We conclude that docetaxel is an effective agent in urothelial cell cancer, and should be further tested in combination chemotherapy.

Transcriptional regulation of the Saccharomyces cerevisiae amino acid permease gene BAP2.

Abstract. Uptake of branched-chain amino acids by Saccharomyces cerevisiae from media containing a preferred nitrogen source is mediated by the permeases encoded by BAP2, BAP3, and VAP1/TAT1. The transcriptional activity of the BAP2 promoter is affected by a number of genes, including SSY1, which encodes an amino acid permease homologue that is necessary for transcription of BAP2. Other genes that control BAP2 encode known (Leu3p, Tup1p) and putative (Stp1p, Stp2p) transcription factors. We present evidence that the zinc-finger proteins Stp1p and Stp2p bind directly to the BAP2 promoter. Binding of Stp1p to the BAP2 promoter in vivo and in vitro indicates that the STP gene family indeed encodes transcription factors. The presence of a Leu3p binding site in the BAP2 promoter is required for full promoter activity on synthetic complete medium. The capacity of Leu3p to activate BAP2 transcription correlates with conditions that affect the level of α-isopropyl malate. The effect of a tup1 deletion on BAP2 transcription depends on SSY1. In an ssy1 strain, the phenotype of tup1 conforms to the well-established role of Tup1p as part of a repressor complex, but in the SSY1 strain deletion of TUP1 causes a decrease in transcription, indicating that Tup1p may also have an activating role at the BAP2 promoter. Our results thus suggest a complex interplay between several transcription factors in the expression of BAP2.

Cancer mortality in long-term survivors of retinoblastoma.

This study examined long-term cause-specific mortality among 998 Dutch retinoblastoma survivors, diagnosed from 1862 to 2005, according to follow-up time, treatment and heredity. After a median follow-up of 30.8 years, only cause-specific mortality for second malignancies among hereditary retinoblastoma survivors was statistically significantly increased with 12.8-fold. Risk of death from second malignancies among non-hereditary survivors was not increased. Mortality rates of second malignancy among hereditary patients were non-significantly elevated with 1.6-fold for treated with radiotherapy, compared to those treated otherwise. Standardised mortality ratios (SMRs) for second malignancy among hereditary patients increased during the first three decades after retinoblastoma diagnosis. Whereas these risks decreased after three decades, the absolute excess risk (AER) increased significantly, up to 23.2 excess cases per 1000 patients/year after five decades of follow-up. Fifty years after retinoblastoma diagnosis the cumulative mortality from any second malignancy was 17.3% for hereditary patients. Very long-term follow-up of retinoblastoma patients revealed an emerging excess risk of mortality in hereditary retinoblastoma survivors. This implies that lifelong follow-up is needed, whereas at the same time, patients and their physicians must be alerted to the increased second malignancy risks.

Early hepatic regeneration index and completeness of regeneration at 6 months after partial hepatectomy

The liver is known to regenerate following partial hepatectomy (PH), but little is known about the timing and completeness of regeneration relative to the resected volume. This study examined whether liver volume regeneration following PH and its completeness 6 months after surgery is related to the resected volume.

Risk of third malignancies and death after a second malignancy in retinoblastoma survivors

Retinoblastoma patients have a strongly increased risk of second malignancies, and survivors with a third or subsequent malignancy are increasingly observed. However, it has not been examined whether survivors who developed a second malignancy have a greater risk of a subsequent malignancy. On the basis of the Dutch retinoblastoma registry, the risk of a third malignancy was compared with cancer risk in the Dutch population. Cox model analysis with a time-dependent covariate was used to compare the subsequent malignancy risk and survival among patients with and without a second malignancy. Risk of a third malignancy was increased 8-fold compared with the general population. The hazard ratio (HR) of a third malignancy after a second malignancy was more than 7-fold increased compared to the risk of a second malignancy after retinoblastoma. Radiotherapy increased the risk 3-fold. A third malignancy was associated with worse survival compared with survival of patients only diagnosed with a second malignancy (HR=5.0). Survivors of retinoblastoma who already developed a second primary malignancy have an even higher risk of subsequent primary malignancies than retinoblastoma survivors without a second malignancy. Treating physicians and patients should be aware of this higher risk.

Development and validation of the Diagnostic Interview Adjustment Disorder (DIAD)

Adjustment disorders (ADs) are under‐researched due to the absence of a reliable and valid diagnostic tool. This paper describes the development and content/construct validation of a fully structured interview for the diagnosis of AD, the Diagnostic Interview Adjustment Disorder (DIAD). We developed the DIAD by partly adjusting and operationalizing DSM‐IV criteria. Eleven experts were consulted on the content of the DIAD. In addition, the DIAD was administered by trained lay interviewers to a representative sample of disability claimants (n = 323). To assess construct validity of the DIAD, we explored the associations between the AD classification by the DIAD and summary scores of the Kessler Psychological Distress 10‐item Scale (K10) and the World Health Organization Disability Assessment Schedule (WHODAS) by linear regression. Expert agreement on content of the DIAD was moderate to good. The prevalence of AD using the DIAD with revised criteria for the diagnosis AD was 7.4%. The associations of AD by the DIAD with average sum scores on the K10 and the WHODAS supported construct validity of the DIAD. The results provide a first indication that the DIAD is a valid instrument to diagnose AD. Further studies on reliability and on other aspects of validity are needed. Copyright

Reproducibility of measurements of mid-upper arm circumference in older persons

BACKGROUND Mid-upper arm circumference (MUAC) is used as an alternative measure for body mass index to determine thinness in older persons. However, there are limited data on the reproducibility of this measurement in an older population. The present study examined the reproducibility of MUAC measurements in older persons, as well as the influence of different body positions and clothing. METHODS A cross-sectional reproducibility study was performed in a nursing home (n = 43; age 65-96 years) and swimming pool facilities (n = 107; age 65-88 years). A different pair of observers independently measured the MUAC of each participant in the upright position on two occasions within 1 week. In the nursing home, measurements were also performed for each participant in the laying position and with clothes covering the upper arm. RESULTS Mean differences and the 95% limit of agreement for inter-observer reproducibility of MUAC were 0.0 cm (-2.6 to 2.5 cm) for the swimming pool facilities and 0.3 cm (-0.6 to 1.3 cm) for the nursing home. Intra-class correlation coefficients (ICCs) were 0.89 and 0.92, respectively. Mean differences between laying and upright positions were 0.1 cm (-2.0 to 2.2 cm) and 0.0 cm (-1.9 to 2.0 cm) for each observer, respectively (ICC 0.96-0.97). Mean differences between clothes versus bare upper arm were -2.7 cm (-6.2 to 0.7) and -2.4 (-5.6 to 0.9 cm) (ICC 0.75 and 0.78). CONCLUSIONS The reproducibility of the MUAC measurement in older persons is acceptable for group comparisons and, although borderline for the swimming pool facilities, remains acceptable for clinical purposes. The measurement can also be performed in the laying position but not with clothes covering the upper arm.

Different methods to analyze stepped wedge trial designs revealed different aspects of intervention effects.

OBJECTIVES Within epidemiology, a stepped wedge trial design (i.e., a one-way crossover trial in which several arms start the intervention at different time points) is increasingly popular as an alternative to a classical cluster randomized controlled trial. Despite this increasing popularity, there is a huge variation in the methods used to analyze data from a stepped wedge trial design. STUDY DESIGN AND SETTING Four linear mixed models were used to analyze data from a stepped wedge trial design on two example data sets. The four methods were chosen because they have been (frequently) used in practice. Method 1 compares all the intervention measurements with the control measurements. Method 2 treats the intervention variable as a time-independent categorical variable comparing the different arms with each other. In method 3, the intervention variable is a time-dependent categorical variable comparing groups with different number of intervention measurements, whereas in method 4, the changes in the outcome variable between subsequent measurements are analyzed. RESULTS Regarding the results in the first example data set, methods 1 and 3 showed a strong positive intervention effect, which disappeared after adjusting for time. Method 2 showed an inverse intervention effect, whereas method 4 did not show a significant effect at all. In the second example data set, the results were the opposite. Both methods 2 and 4 showed significant intervention effects, whereas the other two methods did not. For method 4, the intervention effect attenuated after adjustment for time. CONCLUSION Different methods to analyze data from a stepped wedge trial design reveal different aspects of a possible intervention effect. The choice of a method partly depends on the type of the intervention and the possible time-dependent effect of the intervention. Furthermore, it is advised to combine the results of the different methods to obtain an interpretable overall result.

Possible lack of full cross-resistance of 5HT3 antagonists; a pilot study

We investigated the potential of cross-over to the serotonin receptor (5HT3) antagonist ondansetron after protection failure with tropisetron. Several cases of complete protection were observed. These limited data suggest that there is an indication for retreatment with a different 5HT3 antagonist after an initial failure to another and also stress the need and relevance for comparative studies between 5HT3 antagonists.

Examining courses of sleep quality and sleepiness in full 2 weeks on/2 weeks off offshore day shift rotations

ABSTRACT To better understand sleep quality and sleepiness problems offshore, we examined courses of sleep quality and sleepiness in full 2-weeks on/2-weeks off offshore day shift rotations by comparing pre-offshore (1 week), offshore (2 weeks) and post-offshore (1 week) work periods. A longitudinal observational study was conducted among N=42 offshore workers. Sleep quality was measured subjectively with two daily questions and objectively with actigraphy, measuring: time in bed (TIB), total sleep time (TST), sleep latency (SL) and sleep efficiency percentage (SE%). Sleepiness was measured twice a day (morning and evening) with the Karolinska Sleepiness Scale. Changes in sleep and sleepiness parameters during the pre/post and offshore work periods were investigated using (generalized) linear mixed models. In the pre-offshore work period, courses of SE% significantly decreased (p=.038). During offshore work periods, the courses of evening sleepiness scores significantly increased (p<.001) and significantly decreased during post-offshore work periods (p=.004). During offshore work periods, TIB (p<.001) and TST (p<.001) were significantly shorter, SE% was significantly higher (p=.002), perceived sleep quality was significantly lower (p<.001) and level of rest after wake was significantly worse (p<.001) than during the pre- and post-offshore work periods. Morning sleepiness was significantly higher during offshore work periods (p=.015) and evening sleepiness was significantly higher in the post-offshore work period (p=.005) compared to the other periods. No significant changes in SL were observed. Courses of sleep quality and sleepiness parameters significantly changed during full 2-weeks on/2-weeks off offshore day shift rotation periods. These changes should be considered in offshore fatigue risk management programmes.