Molecular profiling of platinum resistant ovarian cancer

The aim of this study is to discover a gene set that can predict resistance to platinum-based chemotherapy in ovarian cancer. The study was performed on 96 primary ovarian adenocarcinoma specimens from 2 hospitals all treated with platinum-based chemotherapy. In our search for genes, 24 specimens of the discovery set (5 nonresponders and 19 responders) were profiled in duplicate with 18K cDNA microarrays. Confirmation was done using quantitative RT-PCR on 72 independent specimens (9 nonresponders and 63 responders). Sixty-nine genes were differentially expressed between the nonresponders (n=5) and the responders (n=19) in the discovery phase. An algorithm was constructed to identify predictive genes in this discovery set. This resulted in 9 genes (FN1, TOP2A, LBR, ASS, COL3A1, STK6, SGPP1, ITGAE, PCNA), which were confirmed with qRT-PCR. This gene set predicted platinum resistance in an independent validation set of 72 tumours with a sensitivity of 89% (95% CI: 0.68-1.09) and a specificity of 59% (95% CI: 0.47-0.71)(OR=0.09, p=0.026). Multivariable analysis including patient and tumour characteristics demonstrated that this set of 9 genes is independent for the prediction of resistance (p<0.01). The findings of this study are the discovery of a gene signature that classifies the tumours, according to their response, and a 9-gene set that determines resistance in an independent validation set that outperforms patient and tumour characteristics. A larger independent multicentre study should further confirm whether this 9-gene set can identify the patients who will not respond to platinum-based chemotherapy and could benefit from other therapies.     

Gleason score, age and screening: modeling dedifferentiation in prostate cancer

Tumor differentiation as measured by the Gleason score is highly predictive of the course of prostatic cancer after diagnosis. Since the introduction of the prostate‐specific antigen (PSA) test tumors are diagnosed with a favorable tumor stage and differentiation grade. Does screening with PSA just detect more tumors with favorable characteristics or is dedifferentiation actually being prevented by early detection and consequent treatment? The latter option implies that tumors dedifferentiate in the preclinical screen‐detectable phase. To model the natural history of prostate cancer, we analyzed the age‐specific distribution of clinical stage and Gleason score of 2,204 tumors diagnosed in the ERSPC‐Rotterdam trial. We fitted 2 MISCAN simulation models to the observed data: Model I where tumors dedifferentiate before becoming screen‐detectable and Model II where dedifferentiation occurs during the screen‐detectable preclinical phase. The hypothesis of dedifferentiation during the screen‐detectable phase was tested by a goodness of fit test of both models. In ERSPC‐Rotterdam, we observed a significantly more favorable distribution of Gleason scores in screen‐detected cancers compared to cancers found in the control arm, and in cancers detected in the second round compared to cancers detected in the first round of screening. Also, a significant association between Gleason score and age at diagnosis was found, most notably in cancers detected in the first round of screening. These findings were reproduced by Model II and less so by Model I, with a significant difference in goodness of fit between the 2 models (p < 0.001). This study provides epidemiological evidence of dedifferentiation as a major mechanism of progression in prostate cancer. Tumors dedifferentiate during the screen‐detectable phase and consequently screening with PSA and early treatment can possibly prevent dedifferentiation. © 2006 Wiley‐Liss, Inc.     

The MISCAN-Fadia continuous tumor growth model for breast cancer

The MISCAN-Fadia model was used to analyze the impact of screening and adjuvant treatment on U.S. breast cancer mortality between 1975 and 2000. MISCAN-Fadia uses the concept of "fatal diameter" to model survival and screening benefit and is based on continuous tumor growth. It consists of four major components: population, natural history, screening, and treatment. Population parameters were quantified using U.S. population data. Most natural history and screening parameters were fitted to the Swedish Two County screening trial data; some were based on Surveillance, Epidemiology, and End Results data. Adjuvant treatment parameters were quantified using data from the Early Breast Cancer Trialists' Collaborative Group's meta-analysis. The simulated trend in incidence matches the observed trend reasonably well; the simulated mortality is equal to the observed in 1975 but becomes increasingly too high in 2000. We estimate that screening leads to a 15% and adjuvant treatment to a 21% mortality reduction in the year 2000.     

Development of antiinfliximab antibodies and relationship to clinical response in patients with rheumatoid arthritis

OBJECTIVE: Treatment of patients with infliximab, a chimeric monoclonal IgG1 antibody against tumor necrosis factor, may result in the formation of infliximab-specific IgG antibodies. This study evaluated the clinical significance of these antibodies in patients with rheumatoid arthritis (RA). METHODS: Antiinfliximab antibodies were measured using a newly developed radioimmunoassay in a cohort of 51 consecutive patients with RA treated with infliximab, with a followup of 1 year. In addition, serum infliximab levels were determined by enzyme-linked immunosorbent assay. The results were analyzed in relation to the clinical response to treatment according to the European League Against Rheumatism criteria. RESULTS: Antibodies against infliximab were detected in 22 patients (43%). Patients without detectable antiinfliximab antibodies (n = 29 [57%]) were significantly more often classified as responders (20 of 29 [69%]) compared with patients with detectable antiinfliximab antibodies (8 of 22 [36%]; P = 0.04). Three patients had an infusion-related allergic reaction, all of whom had detectable antiinfliximab antibodies. CONCLUSION: In this study, nearly half of the RA patients treated with infliximab developed antiinfliximab antibodies within the first year of treatment. This seems to be clinically relevant, since development of antiinfliximab antibodies is associated with a reduced response to treatment.     

Age dependence of adenovirus-specific neutralizing antibody titers in individuals from sub-Saharan Africa

We assessed neutralizing antibody titers to adenovirus serotype 5 (Ad5) and six rare adenovirus serotypes, serotypes 11, 35, 50, 26, 48, and 49, in pediatric populations in sub-Saharan Africa. We observed a clear age dependence of Ad5-specific neutralizing antibody titers. These data will help to guide the development of Ad vector-based vaccines for human immunodeficiency virus type 1 and other pathogens.     

Spiritual issues in palliative care consultations in the Netherlands

INTRODUCTION: In the Netherlands, healthcare professionals are able to consult Palliative Care Consultation (PCC) teams about individual patients, for information, support and advice. This study aims to understand which spiritual issues are discussed in these consultations and to determine which factors influence whether they are raised or not. METHODS: The national register of the consultations of the PCC teams was analysed for a two-year period. RESULTS: Spiritual issues played a role in 8.4% of palliative care consultations, of which 4.1% were by phone and 18.3% were bedside consultations. Often spiritual issues were raised by the consultant during the exploration of the request from the caregiver; the discipline of the consultant rather than the discipline of the requesting professional or the patient characteristics determined whether or not such issues were raised. The main support given by the consultant was in coaching the professional caregiver on how to address these issues. DISCUSSION: This study demonstrates the important role of PCC team consultants in exploring and identifying the spiritual needs of patients about whom they are consulted. Although continued education in spiritual care for palliative care professionals is essential, PCC team consultants will play an important role in drawing the attention of healthcare professionals to the need to recognize and address the spiritual needs of their patients.     

Quality management systems and clinical outcomes in Dutch nursing homes

The objective of the article is to explore the impact quality management systems and quality assurance activities in nursing homes have on clinical outcomes. The results are based on a cross-sectional study in 65 Dutch nursing homes. The management of the nursing homes as well as the residents (N = 12,377) participated in the study. Primary survey-data about the implementation of quality management systems and quality assurance activities were collected in 1994/1995 and in 1998, and were combined with information on resident characteristics and the prevalence of undesirable clinical outcomes. The results demonstrate that there are differences between nursing homes in the prevalence of undesirable clinical outcomes. In the nursing homes with the lowest scores, undesirable outcomes occur approximately 10 times less often than in nursing homes with the highest scores. The multi-level analysis has demonstrated that the differences in outcomes are mainly caused by differences between residents and, to some extent, also by differences between nursing homes. Resident characteristics explain 48% of the differences between residents and 72% of the differences between nursing homes. The size of the nursing home, the involvement of a client council and the implementation of a quality management system could explain a small part of the remaining variation in the number of undesirable outcomes. It seems that the implementation of a quality management system and the involvement of a client council had significant influence on the number of undesirable outcomes. Approximately 50% of the undesirable outcomes cannot be explained by the selected resident characteristics, the size of the nursing home and the implementation of quality management systems or quality assurance activities.     

Influence of Cremophor El on the bioavailability of intraperitoneal paclitaxel.

It has been hypothesized that the paclitaxel vehicle Cremophor EL (CrEL) is responsible for nonlinear drug disposition by micellar entrapment. To gain further insight into the role of CrEL in taxane pharmacology, we studied the pharmacokinetics of paclitaxel in the presence and absence of CrEL after i.p. and i.v. dosing. Patients received an i.p. tracer dose of [G-(3)H]paclitaxel in ethanol without CrEL (100 microCi diluted further in isotonic saline) on day 1, i.p. paclitaxel formulated in CrEL (Taxol; 125 mg/m(2)) on day 4, an i.v. tracer of [G-(3)H]paclitaxel on day 22, and i.v. Taxol (175 mg/m(2)) on day 24. Four patients (age range, 54-74 years) were studied, and serial plasma samples up to 72 h were obtained and analyzed for total radioactivity, paclitaxel, and CrEL. In the presence of CrEL, i.v. paclitaxel clearance was 10.2 +/- 3.76 liters/h/m(2) (mean +/- SD), consistent with previous findings. The terminal disposition half-life was substantially prolonged after i.p. dosing (17.0 +/- 11.3 versus 28.7 +/- 8.72 h), as was the mean residence time (7.28 +/- 2.76 versus 40.7 +/- 13.8 h). The bioavailability of paclitaxel was 31.4 +/- 5.18%, indicating insignificant systemic concentrations after i.p. treatment. CrEL levels were undetectable after i.p. dosing (<0.05 microl/ml), whereas after i.v. dosing, the mean clearance was 159 +/- 58.4 ml/h/m(2), in line with earlier observations. In the absence of CrEL, the bioavailability and systemic concentrations of i.p. paclitaxel were significantly increased. This finding is consistent with the postulated concept that CrEL is largely responsible for the pharmacokinetic advantage for peritoneal cavity exposure to total paclitaxel compared with systemic delivery.     

Design of a retrospective patient record study on the occurrence of adverse events among patients in Dutch hospitals

Background  

Various international studies have shown that a substantial number of patients suffer from injuries or even die as a result of care delivered in hospitals. The occurrence of injuries among patients caused by health care management in Dutch hospitals has never been studied systematically. Therefore, an epidemiological study was initiated to determine the incidence, type and impact of adverse events among discharged and deceased patients in Dutch hospitals.