Positive Impact of [18F]FDG-PET/CT on Mortality in Patients With Staphylococcus aureus Bacteremia Explained by Immortal Time Bias.

BACKGROUND: Several studies have suggested that in patients with Staphylococcus aureus bacteremia (SAB) [18F] fluorodeoxyglucose positron emission tomography/computed tomography ([18F]FDG-PET/CT) improves outcome. However, these studies often ignored possible immortal time bias. METHODS: Prospective multicenter cohort study in 2 university and 5 non-university hospitals, including all patients with SAB. [18F]FDG-PET/CT was performed on clinical indication as part of usual care. Primary outcome was 90-day all-cause mortality. Effect of [18F]FDG-PET/CT was modeled with a Cox proportional hazards model using [18F]FDG-PET/CT as a time-varying variable and corrected for confounders for mortality (age, Charlson score, positive follow-up cultures, septic shock, and endocarditis). Secondary outcome was 90-day infection-related mortality (assessed by adjudication committee) using the same analysis. In a subgroup-analysis, we determined the effect of [18F]FDG-PET/CT in patients with high risk of metastatic infection. RESULTS: Of 476 patients, 178 (37%) underwent [18F]FDG-PET/CT. Day-90 all-cause mortality was 31% (147 patients), and infection-related mortality was 17% (83 patients). The confounder adjusted hazard ratio (aHR) for all-cause mortality was 0.50 (95% confidence interval [CI]: .34-.74) in patients that underwent [18F]FDG-PET/CT. Adjustment for immortal time bias changed the aHR to 1.00 (95% CI .68-1.48). Likewise, after correction for immortal time bias, [18F]FDG-PET/CT had no effect on infection-related mortality (cause specific aHR 1.30 [95% CI .77-2.21]), on all-cause mortality in patients with high-risk SAB (aHR 1.07 (95% CI .63-1.83) or on infection-related mortality in high-risk SAB (aHR for 1.24 [95% CI .67-2.28]). CONCLUSIONS: After adjustment for immortal time bias [18F]FDG-PET/CT was not associated with day-90 all-cause or infection-related mortality in patients with SAB.

[Peritoneal tuberculosis in a postmenopausal woman with progressive ascites]. / Peritoneale tuberculose.

BACKGROUND: The non-specific symptomatology in peritoneal tuberculosis often results in a delay in the diagnosis. Due to clinical overlap symptoms may be confused with metastatic ovarian carcinoma. This can lead to delayed treatment, unnecessary surgical interventions and a deteriorated prognosis. CASE DESCRIPTION: A 75-year-old female of Moroccan descent was referred to the gastroenterology department with increasing ascites and weight loss. Based on the clinical picture metastatic ovarian cancer was suspected. However, repeatedly no malignant cells were found in both ascitic fluid and tissue biopsies. Peritoneal tuberculosis was considered and ovarian malignancy could not be excluded. A diagnostic laparoscopyand biopsy was considered necessary. The laparoscopic view was pathognomic for tuberculosis after which antituberculosis treatment was started with good result. CONCLUSION: Peritoneal tuberculosis should be included in the differential diagnosis in women from endemic areas with symptoms of abdominal pain, ascites, weight loss and/or increased CA-125. Laparoscopy should be considered if less invasive tests are inconclusive about the diagnosis.

Deep Learning for Real-time, Automatic, and Scanner-adapted Prostate (Zone) Segmentation of Transrectal Ultrasound, for Example, Magnetic Resonance Imaging-transrectal Ultrasound Fusion Prostate Biopsy.

BACKGROUND: Although recent advances in multiparametric magnetic resonance imaging (MRI) led to an increase in MRI-transrectal ultrasound (TRUS) fusion prostate biopsies, these are time consuming, laborious, and costly. Introduction of deep-learning approach would improve prostate segmentation. OBJECTIVE: To exploit deep learning to perform automatic, real-time prostate (zone) segmentation on TRUS images from different scanners. DESIGN, SETTING, AND PARTICIPANTS: Three datasets with TRUS images were collected at different institutions, using an iU22 (Philips Healthcare, Bothell, WA, USA), a Pro Focus 2202a (BK Medical), and an Aixplorer (SuperSonic Imagine, Aix-en-Provence, France) ultrasound scanner. The datasets contained 436 images from 181 men. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Manual delineations from an expert panel were used as ground truth. The (zonal) segmentation performance was evaluated in terms of the pixel-wise accuracy, Jaccard index, and Hausdorff distance. RESULTS AND LIMITATIONS: The developed deep-learning approach was demonstrated to significantly improve prostate segmentation compared with a conventional automated technique, reaching median accuracy of 98% (95% confidence interval 95-99%), a Jaccard index of 0.93 (0.80-0.96), and a Hausdorff distance of 3.0 (1.3-8.7) mm. Zonal segmentation yielded pixel-wise accuracy of 97% (95-99%) and 98% (96-99%) for the peripheral and transition zones, respectively. Supervised domain adaptation resulted in retainment of high performance when applied to images from different ultrasound scanners (p > 0.05). Moreover, the algorithm's assessment of its own segmentation performance showed a strong correlation with the actual segmentation performance (Pearson's correlation 0.72, p < 0.001), indicating that possible incorrect segmentations can be identified swiftly. CONCLUSIONS: Fusion-guided prostate biopsies, targeting suspicious lesions on MRI using TRUS are increasingly performed. The requirement for (semi)manual prostate delineation places a substantial burden on clinicians. Deep learning provides a means for fast and accurate (zonal) prostate segmentation of TRUS images that translates to different scanners. PATIENT SUMMARY: Artificial intelligence for automatic delineation of the prostate on ultrasound was shown to be reliable and applicable to different scanners. This method can, for example, be applied to speed up, and possibly improve, guided prostate biopsies using magnetic resonance imaging-transrectal ultrasound fusion.

Detection of clinically significant prostate cancer in biopsy-naïve men: direct comparison of systematic biopsy, multiparametric MRI- and contrast-ultrasound-dispersion imaging-targeted biopsy.

OBJECTIVES: To compare and evaluate a multiparametric magnetic resonance imaging (mpMRI)-targeted biopsy (TBx) strategy, contrast-ultrasound-dispersion imaging (CUDI)-TBx strategy and systematic biopsy (SBx) strategy for the detection of clinically significant prostate cancer (csPCa) in biopsy-naïve men. PATIENTS AND METHODS: A prospective, single-centre paired diagnostic study included 150 biopsy-naïve men, from November 2015 to November 2018. All men underwent pre-biopsy mpMRI and CUDI followed by a 12-core SBx taken by an operator blinded from the imaging results. Men with suspicious lesions on mpMRI and/or CUDI also underwent MRI-TRUS fusion-TBx and/or cognitive CUDI-TBx after SBx by a second operator. A non-inferiority analysis of the mpMRI- and CUDI-TBx strategies in comparison with SBx for International Society of Urological Pathology Grade Group [GG] ≥2 PCa in any core with a non-inferiority margin of 1 percentage point was performed. Additional analyses for GG ≥2 PCa with cribriform growth pattern and/or intraductal carcinoma (CR/IDC), and GG ≥3 PCa were performed. Differences in detection rates were tested using McNemar's test with adjusted Wald confidence intervals. RESULTS: After enrolment of 150 men, an interim analysis was performed. Both the mpMRI- and CUDI-TBx strategies were inferior to SBx for GG ≥2 PCa detection and the study was stopped. SBx found significantly more GG ≥2 PCa: 39% (56/142), as compared with 29% (41/142) and 28% (40/142) for mpMRI-TBx and CUDI-TBx, respectively (P < 0.05). SBx found significantly more GG = 1 PCa: 14% (20/142) compared to 1% (two of 142) and 3% (four of 142) with mpMRI-TBx and CUDI-TBx, respectively (P < 0.05). Detection of GG ≥2 PCa with CR/IDC and GG ≥3 PCa did not differ significantly between the strategies. The mpMRI- and CUDI-TBx strategies were comparable in detection but the mpMRI-TBx strategy had less false-positive findings (18% vs 53%). CONCLUSIONS: In our study in biopsy-naïve men, the mpMRI- and CUDI-TBx strategies had comparable PCa detection rates, but the mpMRI-TBX strategy had the least false-positive findings. Both strategies were inferior to SBx for the detection of GG ≥2 PCa, despite reduced detection of insignificant GG = 1 PCa. Both strategies did not significantly differ from SBx for the detection of GG ≥2 PCa with CR/IDC and GG ≥3 PCa.

Contrast-enhanced ultrasound with dispersion analysis for the localization of prostate cancer: correlation with radical prostatectomy specimens.

PURPOSE: To determine the value of two-dimensional (2D) contrast-enhanced ultrasound (CEUS) imaging and the additional value of contrast ultrasound dispersion imaging (CUDI) for the localization of clinically significant prostate cancer (csPCa). METHODS: In this multicentre study, subjects scheduled for a radical prostatectomy underwent 2D CEUS imaging preoperatively. CUDI maps were generated from the CEUS recordings. Both CEUS recordings and CUDI maps were scored on the likelihood of presenting csPCa (any Gleason ≥ 4 + 3 and Gleason 3 + 4 larger than 0.5 mL) by five observers and compared to radical prostatectomy histopathology. An automated three-dimensional (3D) fusion protocol was used to match imaging with histopathology. Receiver operator curve (ROC) analysis was performed per observer and imaging modality. RESULTS: 133 of 216 (62%) patients were included in the final analysis. Average area under the ROC for all five readers for CEUS, CUDI and the combination was 0.78, 0.79 and 0.78, respectively. This yields a sensitivity and specificity of 81 and 64% for CEUS, 83 and 56% for CUDI and 83 and 55% for the combination. Interobserver agreement for CEUS, CUDI and the combination showed kappa values of 0.20, 0.18 and 0.18 respectively. CONCLUSION: The sensitivity and specificity of 2D CEUS and CUDI for csPCa localization are moderate. Despite compressing CEUS in one image, CUDI showed a similar performance to 2D CEUS. With a sensitivity of 83% at cutoff point 3, it could become a useful imaging procedure, especially with 4D acquisition, improved quantification and combination with other US imaging techniques such as elastography.

Artificial intelligence in multiparametric prostate cancer imaging with focus on deep-learning methods.

Prostate cancer represents today the most typical example of a pathology whose diagnosis requires multiparametric imaging, a strategy where multiple imaging techniques are combined to reach an acceptable diagnostic performance. However, the reviewing, weighing and coupling of multiple images not only places additional burden on the radiologist, it also complicates the reviewing process. Prostate cancer imaging has therefore been an important target for the development of computer-aided diagnostic (CAD) tools. In this survey, we discuss the advances in CAD for prostate cancer over the last decades with special attention to the deep-learning techniques that have been designed in the last few years. Moreover, we elaborate and compare the methods employed to deliver the CAD output to the operator for further medical decision making.

Automated multiparametric localization of prostate cancer based on B-mode, shear-wave elastography, and contrast-enhanced ultrasound radiomics.

OBJECTIVES: The aim of this study was to assess the potential of machine learning based on B-mode, shear-wave elastography (SWE), and dynamic contrast-enhanced ultrasound (DCE-US) radiomics for the localization of prostate cancer (PCa) lesions using transrectal ultrasound. METHODS: This study was approved by the institutional review board and comprised 50 men with biopsy-confirmed PCa that were referred for radical prostatectomy. Prior to surgery, patients received transrectal ultrasound (TRUS), SWE, and DCE-US for three imaging planes. The images were automatically segmented and registered. First, model-based features related to contrast perfusion and dispersion were extracted from the DCE-US videos. Subsequently, radiomics were retrieved from all modalities. Machine learning was applied through a random forest classification algorithm, using the co-registered histopathology from the radical prostatectomy specimens as a reference to draw benign and malignant regions of interest. To avoid overfitting, the performance of the multiparametric classifier was assessed through leave-one-patient-out cross-validation. RESULTS: The multiparametric classifier reached a region-wise area under the receiver operating characteristics curve (ROC-AUC) of 0.75 and 0.90 for PCa and Gleason > 3 + 4 significant PCa, respectively, thereby outperforming the best-performing single parameter (i.e., contrast velocity) yielding ROC-AUCs of 0.69 and 0.76, respectively. Machine learning revealed that combinations between perfusion-, dispersion-, and elasticity-related features were favored. CONCLUSIONS: In this paper, technical feasibility of multiparametric machine learning to improve upon single US modalities for the localization of PCa has been demonstrated. Extended datasets for training and testing may establish the clinical value of automatic multiparametric US classification in the early diagnosis of PCa. KEY POINTS: • Combination of B-mode ultrasound, shear-wave elastography, and contrast ultrasound radiomics through machine learning is technically feasible. • Multiparametric ultrasound demonstrated a higher prostate cancer localization ability than single ultrasound modalities. • Computer-aided multiparametric ultrasound could help clinicians in biopsy targeting.

3-D Multi-parametric Contrast-Enhanced Ultrasound for the Prediction of Prostate Cancer.

Trans-rectal ultrasound-guided 12-core systematic biopsy (SBx) is the standard diagnostic pathway for prostate cancer (PCa) because of a lack of sufficiently accurate imaging. Quantification of 3-D dynamic contrast-enhanced ultrasound (US) might open the way for a targeted procedure in which biopsies are directed at lesions suspicious on imaging. This work describes the expansion of contrast US dispersion imaging algorithms to 3-D and compares its performance against malignant and benign disease. Furthermore, we examined the feasibility of a multi-parametric approach to predict SBx-core outcomes using machine learning. An area under the receiver operating characteristic (ROC) curve of 0.76 and 0.81 was obtained for all PCa and significant PCa, respectively, an improvement over previous US methods. We found that prostatitis, in particular, was a source of false-positive readings.

Multiparametric Ultrasound for Prostate Cancer Detection and Localization: Correlation of B-mode, Shear Wave Elastography and Contrast Enhanced Ultrasound with Radical Prostatectomy Specimens.

PURPOSE: Similar to multiparametric magnetic resonance imaging, multiparametric ultrasound represents a promising approach to prostate cancer imaging. We determined the diagnostic performance of B-mode, shear wave elastography and contrast enhanced ultrasound with quantification software as well as the combination, multiparametric ultrasound, for clinically significant prostate cancer localization using radical prostatectomy histopathology as the reference standard. MATERIALS AND METHODS: From May 2017 to July 2017, 50 men with biopsy proven prostate cancer underwent multiparametric ultrasound before radical prostatectomy at 1 center. Three readers independently evaluated 12 anatomical regions of interest for the likelihood of clinically significant prostate cancer on a 5-point Likert scale for all separate ultrasound modalities and multiparametric ultrasound. A logistic linear mixed model was used to estimate diagnostic performance for the localization of clinically significant prostate cancer (any tumor with Gleason score 3 + 4 = 7 or greater, tumor volume 0.5 ml or greater, extraprostatic extension or stage pN1) using a Likert score of 3 or greater and 4 or greater as the threshold. To detect the index lesion the readers selected the 2 most suspicious regions of interest. RESULTS: A total of 48 men were included in the final analysis. The region of interest specific sensitivity of multiparametric ultrasound (Likert 3 or greater) for clinically significant prostate cancer was 74% (95% CI 67-80) compared to 55% (95% CI 47-63), 55% (95% CI 47-63) and 59% (95% CI 51-67) for B-mode, shear wave elastography and contrast enhanced ultrasound, respectively. Multiparametric ultrasound sensitivity was significantly higher for Likert thresholds and all different clinically significant prostate cancer definitions (all p <0.05). Multiparametric ultrasound improved the detection of index lesion prostate cancer. CONCLUSIONS: Multiparametric ultrasound of the prostate, consisting of B-mode, shear wave elastography and contrast enhanced ultrasound with parametric maps, improved localization and index lesion detection of clinically significant prostate cancer compared to single ultrasound modalities, yielding good sensitivity.

Multiparametric ultrasound: evaluation of greyscale, shear wave elastography and contrast-enhanced ultrasound for prostate cancer detection and localization in correlation to radical prostatectomy specimens.

BACKGROUND: The diagnostic pathway for prostate cancer (PCa) is advancing towards an imaging-driven approach. Multiparametric magnetic resonance imaging, although increasingly used, has not shown sufficient accuracy to replace biopsy for now. The introduction of new ultrasound (US) modalities, such as quantitative contrast-enhanced US (CEUS) and shear wave elastography (SWE), shows promise but is not evidenced by sufficient high quality studies, especially for the combination of different US modalities. The primary objective of this study is to determine the individual and complementary diagnostic performance of greyscale US (GS), SWE, CEUS and their combination, multiparametric ultrasound (mpUS), for the detection and localization of PCa by comparison with corresponding histopathology. METHODS/DESIGN: In this prospective clinical trial, US imaging consisting of GS, SWE and CEUS with quantitative mapping on 3 prostate imaging planes (base, mid and apex) will be performed in 50 patients with biopsy-proven PCa before planned radical prostatectomy using a clinical ultrasound scanner. All US imaging will be evaluated by US readers, scoring the four quadrants of each imaging plane for the likelihood of significant PCa based on a 1 to 5 Likert Scale. Following resection, PCa tumour foci will be identified, graded and attributed to the imaging-derived quadrants in each prostate plane for all prostatectomy specimens. Primary outcome measure will be the sensitivity, specificity, negative predictive value and positive predictive value of each US modality and mpUS to detect and localize significant PCa evaluated for different Likert Scale thresholds using receiver operating characteristics curve analyses. DISCUSSION: In the evaluation of new PCa imaging modalities, a structured comparison with gold standard radical prostatectomy specimens is essential as first step. This trial is the first to combine the most promising ultrasound modalities into mpUS. It complies with the IDEAL stage 2b recommendations and will be an important step towards the evaluation of mpUS as a possible option for accurate detection and localization of PCa. TRIAL REGISTRATION: The study protocol for multiparametric ultrasound was prospectively registered on Clinicaltrials.gov on 14 March 2017 with the registry name 'Multiparametric Ultrasound-Study for the Detection of Prostate Cancer' and trial registration number NCT03091231.

Accurate validation of ultrasound imaging of prostate cancer: a review of challenges in registration of imaging and histopathology.

As the development of modalities for prostate cancer (PCa) imaging advances, the challenge of accurate registration between images and histopathologic ground truth becomes more pressing. Localization of PCa, rather than detection, requires a pixel-to-pixel validation of imaging based on histopathology after radical prostatectomy. Such a registration procedure is challenging for ultrasound modalities; not only the deformations of the prostate after resection have to be taken into account, but also the deformation due to the employed transrectal probe and the mismatch in orientation between imaging planes and pathology slices. In this work, we review the latest techniques to facilitate accurate validation of PCa localization in ultrasound imaging studies and extrapolate a general strategy for implementation of a registration procedure.

Viscoelasticity Mapping by Identification of Local Shear Wave Dynamics.

Estimation of soft tissue elasticity is of interest in several clinical applications. For instance, tumors and fibrotic lesions are notoriously stiff compared with benign tissue. A fully quantitative measure of lesion stiffness can be obtained by shear wave (SW) elastography. This method uses an acoustic radiation force to produce laterally propagating SWs that can be tracked to obtain the velocity, which in turn is related to Young's modulus. However, not only elasticity, but also viscosity plays an important role in the propagation process of SWs. In fact, viscosity itself is a parameter of diagnostic value for the detection and characterization of malignant lesions. In this paper, we describe a new method that enables imaging viscosity from SW elastography by local model-based system identification. By testing the method on simulated data sets and performing in vitro experiments, we show that the ability of the proposed technique to generate parametric maps of the viscoelastic material properties from SW measurements, opening up new possibilities for noninvasive tissue characterization.

The efficacy of Internet-based cognitive behavioral therapy for severely fatigued survivors of breast cancer compared with care as usual: A randomized controlled trial.

BACKGROUND: Severe fatigue is a common and distressing symptom affecting approximately one in four survivors of breast cancer. The current study examined the efficacy of Internet-based cognitive behavioral therapy (ICBT) for severe fatigue in survivors of breast cancer compared with care as usual (CAU). METHODS: The authors conducted a parallel-group randomized controlled trial. Severely fatigued, disease-free survivors of breast cancer who had completed cancer treatment at least 3 months previously were eligible. Participants were randomly allocated to ICBT or CAU using computer-generated stratified block randomization. The primary outcome of fatigue severity was assessed at baseline and after 6 months, as were the secondary outcomes of functional impairment, psychological distress, and quality of life. Statistical effects were tested with analyses of covariance (intention-to-treat analysis). RESULTS: Participants were recruited between January 2014 and March 2016 and assigned to ICBT (66 patients) or CAU (66 patients). Compared with the participants who had received CAU, those who had received ICBT reported lower fatigue scores at 6 months (mean difference [Δ], 11.5; 95% confidence interval [95% CI], 7.7-15.3) and a large effect size (Cohen d = 1.0), with the majority of patients (73%) demonstrating clinically significant improvement. ICBT also was found to lead to lower functional impairment (Δ, 297.8; 95% CI, 145.5-450.1) and psychological distress scores (Δ, 5.7; 95% CI, 3.4-7.9) and higher quality-of-life scores (Δ, 11.7; 95% CI, 5.8-17.7) compared with CAU, with medium to large effect sizes (Cohen d = 0.6-0.8). CONCLUSIONS: ICBT appears to be effective in reducing severe fatigue and related symptoms and meets the current need for easy accessible and more efficient evidence-based treatment options for severely fatigued survivors of breast cancer. Cancer 2017;123:3825-34. © 2017 American Cancer Society.

Multiparametric dynamic contrast-enhanced ultrasound imaging of prostate cancer.

OBJECTIVES: The aim of this study is to improve the accuracy of dynamic contrast-enhanced ultrasound (DCE-US) for prostate cancer (PCa) localization by means of a multiparametric approach. MATERIALS AND METHODS: Thirteen different parameters related to either perfusion or dispersion were extracted pixel-by-pixel from 45 DCE-US recordings in 19 patients referred for radical prostatectomy. Multiparametric maps were retrospectively produced using a Gaussian mixture model algorithm. These were subsequently evaluated on their pixel-wise performance in classifying 43 benign and 42 malignant histopathologically confirmed regions of interest, using a prostate-based leave-one-out procedure. RESULTS: The combination of the spatiotemporal correlation (r), mean transit time (µ), curve skewness (κ), and peak time (PT) yielded an accuracy of 81% ± 11%, which was higher than the best performing single parameters: r (73%), µ (72%), and wash-in time (72%). The negative predictive value increased to 83% ± 16% from 70%, 69% and 67%, respectively. Pixel inclusion based on the confidence level boosted these measures to 90% with half of the pixels excluded, but without disregarding any prostate or region. CONCLUSIONS: Our results suggest multiparametric DCE-US analysis might be a useful diagnostic tool for PCa, possibly supporting future targeting of biopsies or therapy. Application in other types of cancer can also be foreseen. KEY POINTS: • DCE-US can be used to extract both perfusion and dispersion-related parameters. • Multiparametric DCE-US performs better in detecting PCa than single-parametric DCE-US. • Multiparametric DCE-US might become a useful tool for PCa localization.

Exploring genetic and non-genetic risk factors for delayed graft function, acute and subclinical rejection in renal transplant recipients.

AIMS: This study aimed at identifying pharmacological factors such as pharmacogenetics and drug exposure as new predictive biomarkers for delayed graft function (DGF), acute rejection (AR) and/or subclinical rejection (SCR). METHODS: Adult renal transplant recipients (n = 361) on cyclosporine-based immunosuppression were followed for the first 6 months after transplantation. The incidence of DGF and AR were documented as well as the prevalence of SCR at 6 months in surveillance biopsies. Demographic, transplant-related factors, pharmacological and pharmacogenetic factors (ABCB1, CYP3A5, CYP3A4, CYP2C8, NR1I2, PPP3CA and PPP3CB) were analysed in a combined approach in relation to the occurrence of DGF, AR and prevalence of SCR at month 6 using a proportional odds model and time to event model. RESULTS: Fourteen per cent of the patients experienced at least one clinical rejection episode and only DGF showed a significant effect on the time to AR. The incidence of DGF correlated with a deceased donor kidney transplant (27% vs. 0.6% of living donors). Pharmacogenetic factors were not associated with risk for DGF, AR or SCR. A deceased donor kidney and acute rejection history were the most important determinants for SCR, resulting in a 52% risk of SCR at 6 months (vs. 11% average). In a sub-analysis of the patients with AR, those treated with rejection treatment including ATG, significantly less frequent SCR was found in the 6-month biopsy (13% vs. 50%). CONCLUSIONS: Transplant-related factors remain the most important determinants of DGF, AR and SCR. Furthermore, rejection treatment with depleting antibodies effectively prevented SCR in 6-month surveillance biopsies.

Hookworm with hypereosinophilia: atypical presentation of a typical disease.

We describe a 55-year-old man returning from the Philippines infected with a hookworm, the novel bacterium Laribacter hongkongensis, and a Blastocystis hominis and presenting with both gastrointestinal and neurological symptoms. The high eosinophilia caused by the hookworm infection resulted in both gastrointestinal and neurological symptoms, resembling a hypereosinophilic syndrome.

Febrile neutropenia: significance of elaborated screening for respiratory viruses, and the comparison of different sampling methods, in neutropenic patients with hematological malignancies.

BACKGROUND: During febrile neutropenia in only 30 to 60 percent an infectious agent is identified. This diagnostic gap could hypothetically be reduced with the broad implementation of molecular detection techniques like PCR, which has revolutionized the detection of infectious diseases during the last two decades. FINDINGS: We performed a longitudinal prospective study (N = 81) of neutropenic patients to assess the role of respiratory viruses in neutropenic fever and to determine the clinical relevance of blind screening for these viruses. Respiratory viruses were recovered in 14% of the patients prior to neutropenia. In 13% of neutropenic patients without fever and in 19% of those with fever, a respiratory virus was detected. Comparing different sample types; nasal swabs performed significantly better (16/117 = 43%), than throat swabs (6/106 = 6%). Throat gurgles did not show significant differences from the latter sample types. CONCLUSIONS: Blind diagnostic screening for respiratory viruses before or during neutropenia is not useful. Nasal swabs are sensitive and practical option for screening on respiratory viruses.

Population pharmacokinetics and pharmacogenetics of everolimus in renal transplant patients.

BACKGROUND AND OBJECTIVE: Everolimus is a novel macrolide immunosuppressant used in the prevention of acute and chronic rejection of solid organ transplants. Everolimus is being actively investigated worldwide as a non-nephrotoxic alternative for calcineurin inhibitors. Its highly variable pharmacokinetics and narrow therapeutic window make it difficult to maintain an adequate exposure to prevent serious adverse effects. The primary objective of this study was to improve prediction of everolimus systemic exposure in renal transplant patients by describing the pharmacokinetics of everolimus and identifying the influence of demographic factors and a selection of polymorphisms in genes coding for ABCB1, CYP3A5, CYP2C8 and PXR. The secondary objective of this study was to develop a limited sampling strategy to enable prediction of everolimus exposure in an efficient way and to compare it with the widely used trough blood concentration (C(trough)) monitoring. METHODS: A total of 783 blood samples were obtained from 53 renal transplant patients who had been switched from a triple therapy of ciclosporin, mycophenolate mofetil and prednisolone to a calcineurin inhibitor-free dual therapy of everolimus (twice daily) and prednisolone. Everolimus blood concentrations were analysed in whole blood using liquid chromatography-tandem mass spectrometry during routine therapeutic drug monitoring targeting an area under the blood concentration-time curve from time zero to 12 hours (AUC(12)) of 120 µg · h/L. A population pharmacokinetic model was developed and demographic factors and genetic polymorphisms in genes coding for ABCB1, CYP3A5, CYP2C8 and PXR were included as covariates. In addition, a limited sampling strategy was developed. RESULTS: Maintaining everolimus systemic exposure at an AUC(12) of 120 µg · h/L resulted in low rejection rates but considerable numbers of adverse events and toxicity. Everolimus pharmacokinetics were best described by a two-compartment model with lag-time (oral clearance = 17.9 L/h; volume of distribution of the central compartment after oral administration [V(1)/F] = 148 L and first-order absorption rate constant [k(a)] = 7.36 h-1). Ideal body weight was significantly related to V(1)/F. None of the selected polymorphisms in genes coding for enzymes involved in distribution and metabolism of everolimus had a significant influence on everolimus pharmacokinetics. The pharmacokinetic limited sampling model (C(trough) and whole blood drug concentration at 2 hours postdose [C(2)]) resulted in a significantly improved prediction of everolimus exposure compared with the widely used C(trough) monitoring. CONCLUSION: A two-compartment pharmacokinetic model with lag-time describing the concentration-time profile of oral everolimus in renal transplant patients has been developed using pharmacokinetic modelling. Ideal body weight significantly influenced V(1)/F of everolimus; however, the selected polymorphisms in genes coding for ABCB1, CYP3A5, CYP2C8 and PXR had no clinically relevant effect on everolimus pharmacokinetics. Everolimus C(trough) and C(2) as a limited sampling model can be used to accurately estimate everolimus systemic exposure, an improvement over the widely used C(trough) monitoring.

Minimization of maintenance immunosuppression early after renal transplantation: an interim analysis.

INTRODUCTION: Chronic allograft nephropathy is the main cause of long-term renal transplant failure. Chronic use of calcineurin inhibitors contributes to its pathogenesis. Here, we report on a multicenter randomized trial to study the effects of withdrawal of cyclosporine A (CsA) from a triple immunosuppressive regimen containing CsA, prednisolone (P), and mycophenolate sodium (MPS) early after transplantation. METHODS: Patients continued on P/CsA, P/MPS, or P and everolimus (EVL). Before withdrawal, a transplant biopsy was performed ensuring no subclinical rejection was present. Drug levels were closely monitored. The primary outcome was interstitial graft fibrosis and hyalinosis. Secondary outcome was among others graft rejection. RESULTS: According to trial regulations, an interim analysis was performed after enrollment of half of the intended number of patients (n=113). Mean follow-up was 14+/-5 months from transplantation and 8+/-5 months from conversion. After conversion, acute rejection percentages were 3% in the P/CsA group, 22% in the P/MPS group, and 0% in the P/EVL group (P<0.009). CONCLUSIONS: We conclude that switching immunosuppressive therapy from P/CsA/MPS to therapy with P/CsA or P/EVL at 6 months after renal transplantation is effective in preventing rejection. Double therapy with P/MPS after withdrawal of P/CsA resulted in an increase in severe acute rejection episodes. These results were the immediate reason to halt the P/MPS arm. Serum creatinine values at the latest follow-up (8+/-5 months after conversion and 14+/-5 months after transplantation) in the P/EVL group were lower than in the P/CsA group.