Publications by authors named "Jan Janssen"

22 Publications

  • Page 1 of 1

Performance evaluation of fifth-generation ultra-high-resolution SPECT system with two stationary detectors and multi-pinhole imaging.

EJNMMI Phys 2020 Nov 2;7(1):64. Epub 2020 Nov 2.

Department of Nuclear Medicine, University Hospital Würzburg, Oberdürrbacher Strasse 6, 97080, Würzburg, Germany.

Background: Small-animal single-photon emission computed tomography (SPECT) systems with multi-pinhole collimation and large stationary detectors have advantages compared to systems with moving small detectors. These systems benefit from less labour-intensive maintenance and quality control as fewer prone parts are moving, higher accuracy for focused scans and maintaining high resolution with increased sensitivity due to focused pinholes on the field of view. This study aims to investigate the performance of a novel ultra-high-resolution scanner with two-detector configuration (U-SPECT5-E) and to compare its image quality to a conventional micro-SPECT system with three stationary detectors (U-SPECT).

Methods: The new U-SPECT5-E with two stationary detectors was used for acquiring data with Tc-filled point source, hot-rod and uniformity phantoms to analyse sensitivity, spatial resolution, uniformity and contrast-to-noise ratio (CNR). Three dedicated multi-pinhole mouse collimators with 75 pinholes each and 0.25-, 0.60- and 1.00-mm pinholes for extra ultra-high resolution (XUHR-M), general-purpose (GP-M) and ultra-high sensitivity (UHS-M) imaging were examined. For CNR analysis, four different activity ranges representing low- and high-count settings were investigated for all three collimators. The experiments for the performance assessment were repeated with the same GP-M collimator in the three-detector U-SPECT for comparison.

Results: Peak sensitivity was 237 cps/MBq (XUHR-M), 847 cps/MBq (GP-M), 2054 cps/MBq (UHS-M) for U-SPECT5-E and 1710 cps/MBq (GP-M) for U-SPECT. In the visually analysed sections of the reconstructed mini Derenzo phantoms, rods as small as 0.35 mm (XUHR-M), 0.50 mm (GP-M) for the two-detector as well as the three-detector SPECT and 0.75 mm (UHS-M) were resolved. Uniformity for maximum resolution recorded 40.7% (XUHR-M), 29.1% (GP-M, U-SPECT5-E), 16.3% (GP-M, U-SPECT) and 23.0% (UHS-M), respectively. UHS-M reached highest CNR values for low-count images; for rods smaller than 0.45 mm, acceptable CNR was only achieved by XUHR-M. GP-M was superior for imaging rods sized from 0.60 to 1.50 mm for intermediate activity concentrations. U-SPECT5-E and U-SPECT both provided comparable CNR.

Conclusions: While uniformity and sensitivity are negatively affected by the absence of a third detector, the investigated U-SPECT5-E system with two stationary detectors delivers excellent spatial resolution and CNR comparable to the performance of an established three-detector-setup.
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http://dx.doi.org/10.1186/s40658-020-00335-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606439PMC
November 2020

Capabilities of multi-pinhole SPECT with two stationary detectors for in vivo rat imaging.

Sci Rep 2020 10 29;10(1):18616. Epub 2020 Oct 29.

Department of Nuclear Medicine, University Hospital Würzburg, Oberdürrbacher Strasse 6, 97080, Würzburg, Germany.

We aimed to investigate the image quality of the U-SPECT5/CT E-Class a micro single-photon emission computed tomography (SPECT) system with two large stationary detectors for visualization of rat hearts and bones using clinically available Tc-labelled tracers. Sensitivity, spatial resolution, uniformity and contrast-to-noise ratio (CNR) of the small-animal SPECT scanner were investigated in phantom studies using an ultra-high-resolution rat and mouse multi-pinhole collimator (UHR-RM). Point source, hot-rod, and uniform phantoms with Tc-solution were scanned for high-count performance assessment and count levels equal to animal scans, respectively. Reconstruction was performed using the similarity-regulated ordered-subsets expectation maximization (SROSEM) algorithm with Gaussian smoothing. Rats were injected with ~ 100 MBq [Tc]Tc-MIBI or ~ 150 MBq [Tc]Tc-HMDP and received multi-frame micro-SPECT imaging after tracer distribution. Animal scans were reconstructed for three different acquisition times and post-processed with different sized Gaussian filters. Following reconstruction, CNR was calculated and image quality evaluated by three independent readers on a five-point scale from 1 = "very poor" to 5 = "very good". Point source sensitivity was 567 cps/MBq and radioactive rods as small as 1.2 mm were resolved with the UHR-RM collimator. Collimator-dependent uniformity was 55.5%. Phantom CNR improved with increasing rod size, filter size and activity concentration. Left ventricle and bone structures were successfully visualized in rat experiments. Image quality was strongly affected by the extent of post-filtering, whereas scan time did not have substantial influence on visual assessment. Good image quality was achieved for resolution range greater than 1.8 mm in bone and 2.8 mm in heart. The recently introduced small animal SPECT system with two stationary detectors and UHR-RM collimator is capable to provide excellent image quality in heart and bone scans in a rat using standardized reconstruction parameters and appropriate post-filtering. However, there are still challenges in achieving maximum system resolution in the sub-millimeter range with in vivo settings under limited injection dose and acquisition time.
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http://dx.doi.org/10.1038/s41598-020-75696-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596477PMC
October 2020

Structural and Functional Maturation of Rat Primary Motor Cortex Layer V Neurons.

Int J Mol Sci 2020 Aug 24;21(17). Epub 2020 Aug 24.

Institute of Neuroanatomy, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany.

Rodent neocortical neurons undergo prominent postnatal development and maturation. The process is associated with structural and functional maturation of the axon initial segment (AIS), the site of action potential initiation. In this regard, cell size and optimal AIS length are interconnected. In sensory cortices, developmental onset of sensory input and consequent changes in network activity cause phasic AIS plasticity that can also control functional output. In non-sensory cortices, network input driving phasic events should be less prominent. We, therefore, explored the relationship between postnatal functional maturation and AIS maturation in principal neurons of the primary motor cortex layer V (M1LV), a non-sensory area of the rat brain. We hypothesized that a rather continuous process of AIS maturation and elongation would reflect cell growth, accompanied by progressive refinement of functional output properties. We found that, in the first two postnatal weeks, cell growth prompted substantial decline of neuronal input resistance, such that older neurons needed larger input current to reach rheobase and fire action potentials. In the same period, we observed the most prominent AIS elongation and significant maturation of functional output properties. Alternating phases of AIS plasticity did not occur, and changes in functional output properties were largely justified by AIS elongation. From the third postnatal week up to five months of age, cell growth, AIS elongation, and functional output maturation were marginal. Thus, AIS maturation in M1LV is a continuous process that attunes the functional output of pyramidal neurons and associates with early postnatal development to counterbalance increasing electrical leakage due to cell growth.
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http://dx.doi.org/10.3390/ijms21176101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7503395PMC
August 2020

Phase II Study of the ALK5 Inhibitor Galunisertib in Very Low-, Low-, and Intermediate-Risk Myelodysplastic Syndromes.

Clin Cancer Res 2019 12 3;25(23):6976-6985. Epub 2019 Sep 3.

Department of Medicine, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York.

Purpose: Overactivation of TGF-β signaling is observed in myelodysplastic syndromes (MDS) and is associated with dysplastic hematopoietic differentiation. Galunisertib, a first-in-class oral inhibitor of the TGF-β receptor type 1 kinase (ALK5) has shown effectiveness in preclinical models of MDS and acceptable toxicity in phase I studies of solid malignancies.

Patients And Methods: A phase II multicenter study of galunisertib was conducted in patients with very low-, low-, or intermediate-risk MDS by the Revised International Prognostic Scoring System criteria with hemoglobin ≤ 10.0 g/dL. Patients received oral galunisertib 150 mg twice daily for 14 days on/14 days off.

Results: Ten of 41 evaluable patients (24.4%; 95% confidence interval, 12.4-40.3) achieved hematologic improvement erythroid response by International Working Group (IWG) 2006 criteria. A total of 18 of 41 patients (43.9%) achieved erythroid response as per IWG 2000 criteria. Nine of 28 (32.1%) of transfusion-dependent patients had hematologic improvement. A total of 18 of 41 (44%) patients had a significant reduction in fatigue. Overall median duration of response was 90 days in all patients. Rigorous stem and progenitor flow cytometry showed that patients with an early stem cell differentiation block were more likely to respond to galunisertib. The most common treatment-emergent adverse events were grade 1 or 2 in 20 (49%) of 41 patients, including any-grade fatigue (8/41, 20%), diarrhea (7/41, 17%), pyrexia (5/41, 12%), and vomiting (5/41, 12%).

Conclusions: In summary, galunisertib treatment has an acceptable safety profile and was associated with hematologic improvements in lower- and intermediate-risk MDS, with responses in heavily transfusion-dependent patients and in those with signs of an early stem cell differentiation block.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1338DOI Listing
December 2019

Dynamic Regulation of Synaptopodin and the Axon Initial Segment in Retinal Ganglion Cells During Postnatal Development.

Front Cell Neurosci 2019 30;13:318. Epub 2019 Jul 30.

Institute of Neuroanatomy, Center for Biomedical Research and Medical Technology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

A key component allowing a neuron to function properly within its dynamic environment is the axon initial segment (AIS), the site of action potential generation. In visual cortex, AIS of pyramidal neurons undergo periods of activity-dependent structural plasticity during development. However, it remains unknown how AIS morphology is organized during development for downstream cells in the visual pathway (retinal ganglion cells; RGCs) and whether AIS retain the ability to dynamically adjust to changes in network state. Here, we investigated the maturation of AIS in RGCs during mouse retinal development, and tested putative activity-dependent mechanisms by applying visual deprivation with a focus on the AIS-specific cisternal organelle (CO), a presumed Ca-store. Whole-mount retinae from wildtype and Thy1-GFP transgenic mice were processed for multi-channel immunofluorescence using antibodies against AIS scaffolding proteins ankyrin-G, βIV-spectrin and the CO marker synaptopodin (synpo). Confocal microscopy in combination with morphometrical analysis of AIS length and position as well as synpo cluster size was performed. Data indicated that a subset of RGC AIS contains synpo clusters and that these show significant dynamic regulation in size during development as well as after visual deprivation. Using super resolution microscopy, we addressed the subcellular localization of synpo in RGC axons. Similar to cortical neurons, RGCs show a periodic distribution of AIS scaffolding proteins. A previously reported scaffold-deficient nanodomain correlating with synpo localization is not evident in all RGC AIS. In summary, our work demonstrates a dynamic regulation of both the AIS and synpo in RGCs during retinal development and after visual deprivation, providing first evidence that the AIS and CO in RGCs can undergo structural plasticity in response to changes in network activity.
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http://dx.doi.org/10.3389/fncel.2019.00318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682679PMC
July 2019

Restrictive strategy versus usual care for cholecystectomy in patients with gallstones and abdominal pain (SECURE): a multicentre, randomised, parallel-arm, non-inferiority trial.

Lancet 2019 06 27;393(10188):2322-2330. Epub 2019 Apr 27.

Department of Surgery, Radboud University Medical Centre, Nijmegen, Netherlands.

Background: International guidelines advise laparoscopic cholecystectomy to treat symptomatic, uncomplicated gallstones. Usual care regarding cholecystectomy is associated with practice variation and persistent post-cholecystectomy pain in 10-41% of patients. We aimed to compare the non-inferiority of a restrictive strategy with stepwise selection with usual care to assess (in)efficient use of cholecystectomy.

Methods: We did a multicentre, randomised, parallel-arm, non-inferiority study in 24 academic and non-academic hospitals in the Netherlands. We enrolled patients aged 18-95 years with abdominal pain and ultrasound-proven gallstones or sludge. Patients were randomly assigned (1:1) to either usual care in which selection for cholecystectomy was left to the discretion of the surgeon, or a restrictive strategy with stepwise selection for cholecystectomy. For the restrictive strategy, cholecystectomy was advised for patients who fulfilled all five pre-specified criteria of the triage instrument: 1) severe pain attacks, 2) pain lasting 15-30 min or longer, 3) pain located in epigastrium or right upper quadrant, 4) pain radiating to the back, and 5) a positive pain response to simple analgesics. Randomisation was done with an online program, implemented into a web-based application using blocks of variable sizes, and stratified for centre (academic versus non-academic and a high vs low number of patients), sex, and body-mass index. Physicians and patients were masked for study-arm allocation until after completion of the triage instrument. The primary, non-inferiority, patient-reported endpoint was the proportion of patients who were pain-free at 12 months' follow-up, analysed by intention to treat and per protocol. A 5% non-inferiority margin was chosen, based on the estimated clinically relevant difference. Safety analyses were also done in the intention-to treat population. This trial is registered at the Netherlands National Trial Register, number NTR4022.

Findings: Between Feb 5, 2014, and April 25, 2017, we included 1067 patients for analysis: 537 assigned to usual care and 530 to the restrictive strategy. At 12 months' follow-up 298 patients (56%; 95% CI, 52·0-60·4) were pain-free in the restrictive strategy group, compared with 321 patients (60%, 55·6-63·8) in usual care. Non-inferiority was not shown (difference 3·6%; one-sided 95% lower CI -8·6%; p=0·316). According to a secondary endpoint analysis, the restrictive strategy resulted in significantly fewer cholecystectomies than usual care (358 [68%] of 529 vs 404 [75%] of 536; p=0·01). There were no between-group differences in trial-related gallstone complications (40 patients [8%] of 529 in usual care vs 38 [7%] of 536 in restrictive strategy; p=0·16) and surgical complications (74 [21%] of 358 vs 88 [22%] of 404, p=0·77), or in non-trial-related serious adverse events (27 [5%] of 529 vs 29 [5%] of 526).

Interpretation: Suboptimal pain reduction in patients with gallstones and abdominal pain was noted with both usual care and following a restrictive strategy for selection for cholecystectomy. However, the restrictive strategy was associated with fewer cholecystectomies. The findings should encourage physicians involved in the care of patients with gallstones to rethink cholecystectomy, and to be more careful in advising a surgical approach in patients with gallstones and abdominal symptoms.

Funding: The Netherlands Organization for Health Research and Development, and CZ healthcare insurance.
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http://dx.doi.org/10.1016/S0140-6736(19)30941-9DOI Listing
June 2019

Rapid infusions of human normal immunoglobulin 50g/l are safe and well tolerated in immunodeficiencies and immune thrombocytopenia.

Int Immunopharmacol 2017 Mar 7;44:38-42. Epub 2017 Jan 7.

Department of Molecular Medicine, "Sapienza" University of Rome, Italy.

Intravenous immunoglobulin (IVIg) is accepted as an effective and well-tolerated treatment for primary and secondary immunodeficiencies (ID) and immune thrombocytopenia (ITP). Adverse reactions of IVIg are usually mild, comprising transient flu-like symptoms, change in blood pressure and tachycardia. However IVIg therapy can be burdensome for both patients and healthcare facilities, since the infusion may take up to 4h to administer. The objective of our multicentre, prospective, open-label phase III trial was to evaluate the tolerability and safety of human normal immunoglobulin 50g/l (Ig VENA) at high intravenous infusion rates in adult patients with ID and ITP who had previously tolerated IVIg treatment, by progressively increasing infusion rate up to 8ml/kg/hr. 39 ID patients received three infusions, 5 ITP patients received up to a maximum of 5 infusions for a maximum of 5days. Overall 55 adverse events were reported in 18 patients, and all were mild and self-limiting. Two serious adverse events occurred in ID patients and 1 in an ITP patient; none was fatal or treatment-related. No clinically significant changes or abnormalities were observed in vital signs, laboratory results and HRQoL. In summary, in this study, more rapid IVIg infusions were well tolerated by ID and ITP patients, while maintaining their quality of life, helping to minimise the time spent in outpatient hospital visiting to potentially optimise adherence to treatment.
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http://dx.doi.org/10.1016/j.intimp.2016.12.030DOI Listing
March 2017

Systemic therapy in metastatic renal cell carcinoma.

World J Urol 2017 Feb 9;35(2):179-188. Epub 2016 Jun 9.

Department of Urology, Charité Universitaetsmedizin Berlin, Berlin, Germany.

Purpose: Current systemic treatment of targeted therapies, namely the vascular endothelial growth factor-antibody (VEGF-AB), VEGF receptor tyrosine kinase inhibitor (TKI) and mammalian target of rapamycin (mTOR) inhibitors, have improved progression-free survival and replaced non-specific immunotherapy with cytokines in metastatic renal cell carcinoma (mRCC).

Methods: A panel of experts convened to review currently available phase 3 data for mRCC treatment of approved agents, in addition to available EAU guideline data for a collaborative review as the plurality of substances offers different options of first-, second- and third-line treatment with potential sequencing.

Results: Sunitinib and pazopanib are approved treatments in first-line therapy for patients with favorable- or intermediate-risk clear cell RCC (ccRCC). Temsirolimus has proven benefit over interferon-alfa (IFN-α) in patients with non-clear cell RCC (non-ccRCC). In the second-line treatment TKIs or mTOR inhibitors are treatment choices. Therapy options after TKI failure consist of everolimus and axitinib. Available third-line options consist of everolimus and sorafenib. Recently, nivolumab, a programmed death-1 (PD1) checkpoint inhibitor, improved overall survival benefit compared to everolimus after failure of one or two VEGFR-targeted therapies, which is likely to become the first established checkpoint inhibitor in mRCC. Data for the sequencing of agents remain limited.

Conclusions: Despite the high level of evidence for first and second-line treatment in mRCC, data for third-line therapy are limited. Possible sequences include TKI-mTOR-TKI or TKI-TKI-mTOR with the upcoming checkpoint inhibitors in perspective, which might settle a new standard of care after previous TKI therapy.
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http://dx.doi.org/10.1007/s00345-016-1868-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5272893PMC
February 2017

Everolimus in metastatic renal cell carcinoma after failure of initial anti-VEGF therapy: final results of a noninterventional study.

BMC Cancer 2015 Apr 18;15:303. Epub 2015 Apr 18.

Department of Urology, University Hospital Munich-Grosshadern, Marchioninistrasse, 15, 81377, Germany.

Background: Data are limited regarding routine use of everolimus after initial vascular endothelial growth factor (VEGF)-targeted therapy. The aim of this prospective, noninterventional, observational study was to assess efficacy and safety of everolimus after initial VEGF-targeted treatment in patients with metastatic renal cell carcinoma (mRCC) in routine clinical settings.

Methods: Everolimus was administered per routine clinical practice. Patients with mRCC of any histology from 116 active sites in Germany were included. The main objective was to determine everolimus efficacy in time to progression (TTP). Progression-free survival (PFS), treatment duration, tumor response, adherence to everolimus regimen, treatment after everolimus, and safety were also assessed.

Results: In the total population (N = 334), median follow-up was 5.2 months (range, 0-32 months). Median treatment duration (safety population, n = 318) was 6.5 months (95% confidence interval [CI], 5-8 months). Median TTP and median PFS were similar in populations investigated. In patients who received everolimus as second-line treatment (n = 211), median (95% CI) TTP was 7.1 months (5-9 months) and median PFS was 6.9 months (5-9 months). Commonly reported adverse events (safety population, n = 318) were dyspnea (17%), anemia (15%), and fatigue (12%). Limitations of the noninterventional design should be considered.

Conclusions: This study reflects routine clinical use of everolimus in a large sample of patients with mRCC. Favorable efficacy and safety were seen for everolimus after previous therapy with one VEGF-targeted agent. Results of this study confirm everolimus as one of the standard options in second-line therapy for patients with mRCC. Novartis study code, CRAD001LD27: VFA registry for noninterventional studies ( http://www.vfa.de/de/forschung/nisdb/).
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http://dx.doi.org/10.1186/s12885-015-1309-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4413536PMC
April 2015

Percutaneous balloon dilatation and long-term drainage as treatment of anastomotic and nonanastomotic benign biliary strictures.

Cardiovasc Intervent Radiol 2014 Dec 23;37(6):1559-67. Epub 2014 Jan 23.

Department of Radiology, Room G1-212, Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands,

Purpose: This study was designed to determine the effectiveness of percutaneous balloon dilation and long-term drainage of postoperative benign biliary strictures.

Methods: Medical records of patients with postoperative benign biliary strictures, in whom percutaneous transhepatic biliary drainage (PTBD) and balloon dilation was performed between January 1999 and December 2011, were retrospectively reviewed. PTBD and balloon dilation (4-10 mm) were followed by placement of internal-external biliary drainage catheters (8.5-12 F). Patients were scheduled for elective tube changes, if necessary combined with repeated balloon dilation of the stenosis, at 3-week intervals up to a minimum of 3 months.

Results: Ninety-eight patients received a total of 134 treatments. The treatment was considered technically successful in 98.5%. Drainage catheters were left in with a median duration of 14 weeks. Complications occurred in 11 patients. In 13 patients, percutaneous treatment was converted to surgical intervention. Of 85 patients in whom percutaneous treatment was completed, 11.8% developed clinically relevant restenosis. Median follow-up was 35 months. Probability of patency at 1, 2, 5, and 10 years was 0.95, 0.92, 0.88, and 0.72, respectively. Overall, 76.5% had successful management with PTBD. Restenosis and treatment failure occurred more often in patients who underwent multiple treatments. Treatments failed more often in patients with multiple strictures. All blood markers of liver function significantly decreased to normal values.

Conclusions: Percutaneous balloon dilation and long-term drainage demonstrate good short- and long-term effectiveness as treatment for postoperative benign biliary strictures with an acceptably low complication rate and therefore are indicated as treatment of choice.
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http://dx.doi.org/10.1007/s00270-014-0836-yDOI Listing
December 2014

Everolimus in metastatic renal cell carcinoma after failure of initial vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy: results of an interim analysis of a non-interventional study.

Onkologie 2013 25;36(3):95-100. Epub 2013 Feb 25.

University Hospital Frankfurt, Medical Clinic II, Frankfurt/Main, Germany.

Background: Everolimus is approved for treatment of anti-vascular endothelial growth factor (VEGF)-refractory patients with metastatic renal cell carcinoma (mRCC). Clinical trials rarely mirror treatment reality. Thus, a broader evaluation of everolimus is valuable for routine use.

Patients And Methods: A German multicenter non-interventional study documented mRCC patients starting everolimus after failure of initial VEGF-targeted therapy. Primary endpoint was effectiveness, defined as time to progression (TTP) according to investigator assessment (time from first dose to progression).

Results: Of 382 documented patients, 196 were included in this interim analysis. In the efficacy population (n = 165), median TTP was 7.0 months (95% confidence interval (CI) 5.1-9.0). Among patients with < or ≥ 6 months of previous VEGF-targeted therapy, median TTP was 6.6 months (95% CI 3.8-not estimable) and 7.4 months (95% CI 4.6-9.6), respectively. Most common adverse events were anemia (13%) and dyspnea (14%). Physicians assessed high tolerance and documented high adherence to everolimus therapy (approximately 97%).

Conclusion: In routine clinical practice, everolimus is effective, as measured by median TTP (longer than median progression-free survival in RECORD-1 trial), and well tolerated. Our results support everolimus use in anti-VEGF-refractory patients with mRCC.
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http://dx.doi.org/10.1159/000348522DOI Listing
September 2013

Efficacy of an artificial neural network-based approach to endoscopic ultrasound elastography in diagnosis of focal pancreatic masses.

Clin Gastroenterol Hepatol 2012 Jan 1;10(1):84-90.e1. Epub 2011 Oct 1.

Gastroenterology Department, University of Medicine and Pharmacy, Craiova, Romania.

Background & Aims: By using strain assessment, real-time endoscopic ultrasound (EUS) elastography provides additional information about a lesion's characteristics in the pancreas. We assessed the accuracy of real-time EUS elastography in focal pancreatic lesions using computer-aided diagnosis by artificial neural network analysis.

Methods: We performed a prospective, blinded, multicentric study at of 258 patients (774 recordings from EUS elastography) who were diagnosed with chronic pancreatitis (n = 47) or pancreatic adenocarcinoma (n = 211) from 13 tertiary academic medical centers in Europe (the European EUS Elastography Multicentric Study Group). We used postprocessing software analysis to compute individual frames of elastography movies recorded by retrieving hue histogram data from a dynamic sequence of EUS elastography into a numeric matrix. The data then were analyzed in an extended neural network analysis, to automatically differentiate benign from malignant patterns.

Results: The neural computing approach had 91.14% training accuracy (95% confidence interval [CI], 89.87%-92.42%) and 84.27% testing accuracy (95% CI, 83.09%-85.44%). These results were obtained using the 10-fold cross-validation technique. The statistical analysis of the classification process showed a sensitivity of 87.59%, a specificity of 82.94%, a positive predictive value of 96.25%, and a negative predictive value of 57.22%. Moreover, the corresponding area under the receiver operating characteristic curve was 0.94 (95% CI, 0.91%-0.97%), which was significantly higher than the values obtained by simple mean hue histogram analysis, for which the area under the receiver operating characteristic was 0.85.

Conclusions: Use of the artificial intelligence methodology via artificial neural networks supports the medical decision process, providing fast and accurate diagnoses.
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http://dx.doi.org/10.1016/j.cgh.2011.09.014DOI Listing
January 2012

Test performance of immunologic fecal occult blood testing and sigmoidoscopy compared with primary colonoscopy screening for colorectal advanced adenomas.

Cancer Prev Res (Phila) 2011 Oct 12;4(10):1563-71. Epub 2011 Jul 12.

Division of Gastroenterology-Hepatology, Department of Internal Medicine, Maastricht University Medical Center, the Netherlands.

Given the current increase in colorectal cancer screening, information on performance of screening tests is needed, especially in groups with a presumed lower test performance. We compared test performance of immunologic fecal occult blood testing (FIT) and pseudosigmoidoscopy with colonoscopy for detection of advanced adenomas in an average risk screening population. In addition, we explored the influence of gender, age, and location on test performance. FIT was collected prior to colonoscopy with a 50 ng/mL cutoff point. FIT results and complete colonoscopy findings were available from 329 subjects (mean age: 54.6 ± 3.7 years, 58.4% women). Advanced adenomas were detected in 38 (11.6%) of 329 subjects. Sensitivity for advanced adenomas of FIT and sigmoidoscopy were 15.8% (95% CI: 6.0-31.3) and 73.7% (95% CI: 56.9-86.6), respectively. No sensitivity improvement was obtained using the combination of sigmoidoscopy and FIT. Mean fecal hemoglobin in FIT positives was significantly lower for participants with only proximal adenomas versus those with distal ones (P = 0.008), for women versus men (P = 0.023), and for younger (<55 years) versus older (≥55 years) subjects (P = 0.029). Sensitivities of FIT were 0.0% (95% CI: 0.0-30.9) in subjects with only proximal versus 21.4% (95% CI: 8.3-41.0) in those with distal nonadvanced adenomas; 5.3% (95% CI: 0.0-26.0) in women versus 26.3% (95% CI: 9.2-51.2) in men; 9.5% (95% CI: 1.2-30.4) in younger versus 23.5% (95% CI: 6.8-49.9) in older subjects. Sigmoidoscopy had a significantly higher sensitivity for advanced adenomas than FIT. A single FIT showed very low sensitivity, especially in subjects with only proximal nonadvanced adenomas, in women, and in younger subjects. This points to the existence of "low" FIT performance in subgroups and the need for more tailored screening strategies.
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http://dx.doi.org/10.1158/1940-6207.CAPR-11-0076DOI Listing
October 2011

Limiting esophageal temperature in radiofrequency ablation of left atrial tachyarrhythmias results in low incidence of thermal esophageal lesions.

BMC Cardiovasc Disord 2010 Oct 26;10:52. Epub 2010 Oct 26.

HELIOS Klinikum Wuppertal, Department of Cardiology, Wuppertal, Germany.

Background: Atrio-esophageal fistula formation following radiofrequency ablation of left atrial tachyarrhythmias is a rare but devastating complication. Esophageal injuries are believed to be precursors of fistula formation and reported to occur in up to 47% of patients. This study investigates the incidence of esophageal lesions when real time esophageal temperature monitoring and temperature limitation is used.

Methods: 184 consecutive patients underwent open irrigated radiofrequency ablation of left atrial tachyarrhythmias. An esophageal temperature probe consisting of three independent thermocouples was used for temperature monitoring. A temperature limit of 40°C was defined to interrupt energy delivery. All patients underwent esophageal endoscopy the next day.

Results: Endoscopy revealed ulcer formation in 3/184 patients (1.6%). No patient developed atrio-esophageal fistula. Patient and disease characteristics had no influence on ulcer formation. The temperature threshold of 40°C was reached in 157/184 patients. A temperature overshoot after cessation of energy delivery was observed frequently. The mean maximal temperature was 40.8°C. Using a multiple regression analysis creating a box lesion that implies superior- and inferior lines at the posterior wall connecting the right and left encircling was an independent predictor of temperature. Six month follow-up showed an overall success rate of 78% documented as sinus rhythm in seven-day holter ECG.

Conclusion: Limitation of esophageal temperature to 40°C is associated with the lowest incidence of esophageal lesion formation published so far. This approach may contribute to increase the safety profile of radiofrequency ablation in the left atrium.
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http://dx.doi.org/10.1186/1471-2261-10-52DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2987899PMC
October 2010

The impact of EUS in primary gastric lymphoma.

Authors:
Jan Janssen

Best Pract Res Clin Gastroenterol 2009 ;23(5):671-8

Medical Clinic, HELIOS Klinikum Wuppertal, University of Witten/Herdecke, Germany.

Gastric lymphoma is the most frequent site of gastrointestinal lymphoma and is accessible for endosonographic evaluation. Most primary gastric lymphomas are classified as mucosa-associated lymphoid tissue (MALT)-type lymphomas that develop in the course of chronic Helicobacter pylori infection. Endoscopic ultrasonography (EUS) is regarded to be the most accurate method for the local staging of gastric lymphoma, although scientific evidence is limited. In stage uEI1 low-grade lymphoma, EUS is able to predict a high chance for cure by H. pylori eradication. The significance of EUS elastography or EUS-guided fine-needle aspiration biopsy to diagnose nodal involvement has not been investigated in prospective series yet. Since high-grade lymphoma is always treated as a systemic disease, the impact of endosonographic staging is lower than in low-grade lymphoma. After treatment of primary gastric lymphoma, EUS produces conflicting results that are not as accurate as endoscopy with biopsy. Therefore, EUS is not mandatory during follow-up.
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http://dx.doi.org/10.1016/j.bpg.2009.05.008DOI Listing
December 2009

Weekly vinorelbine versus docetaxel for metastatic breast cancer after failing anthracycline treatment.

Onkologie 2008 Sep 12;31(8-9):447-53. Epub 2008 Aug 12.

Klinikum Bremen-Mitte, Bremen, Germany.

Background: Vinorelbine and docetaxel are active in anthracycline-pretreated, metastatic breast cancer. We compared their efficacy.

Patients And Methods: Patients were randomized to receive weekly vinorelbine (VIN) or weekly docetaxel (DOC), 6 weekly doses per 8-week cycle, with optional crossover (X-DOC vs. X-VIN. The primary end point was time to progression (TTP) on initial treatment. Remission induction, survival, and quality of life were secondary end points.

Results: Among 122 poor risk patients, a non-significant trend for better TTP was seen for DOC, both on initial and on crossover treatment. Responses were seen on either treatment, but progression was more common with VIN than with DOC, while more patients had a response with X-DOC than with X-VIN. Survival was identical in those receiving only the initial VIN vs. DOC and in the subgroups receiving crossover treatments. Grade 3-4 toxicity, especially hematological toxicity resulting in treatment delay, was more common with VIN. Non-graded toxicity contributed to abandoning DOC. Quality of life scores reflected worse results in patients crossing treatment arms, in either direction.

Conclusions: DOC showed marginally better activity but did not improve TTP or other endpoints over VIN in this poor risk population.
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http://dx.doi.org/10.1159/000140453DOI Listing
September 2008

Comments on new technology--Endoscopic ultrasonography (EUS) routine method and new applications.

Ultraschall Med 2008 Aug;29(4):435-6

Medizinische Klinik 2, HELIOS Klinikum Wuppertal.

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http://dx.doi.org/10.1055/s-0028-1082168DOI Listing
August 2008

EUS accurately predicts the need for therapeutic ERCP in patients with a low probability of biliary obstruction.

Gastrointest Endosc 2008 Sep 11;68(3):470-6. Epub 2008 Jun 11.

Second Department of Medicine, HELIOS Klinikum Wuppertal, University of Witten/Herdecke, Wuppertal, Germany.

Background: Because of its inherent risks, ERCP should only be performed for purposes of treatment. EUS and MRCP have emerged as diagnostic alternatives before therapeutic ERCP.

Objective: Our purpose was to test the accuracy of EUS in predicting the need for therapeutic ERCP in low-risk patients.

Design: Prospective, unblinded, single-center study.

Setting: Academic center of the University of Witten/Herdecke.

Patients: Fifty patients with clinical, laboratory, or transabdominal US findings suggestive of biliary obstruction were included.

Interventions: After clinical assessment and US, all patients underwent EUS. If EUS was conclusive, either ERCP with sphincterotomy (EST) was performed or the patients were followed up for 1 year. If EUS was inconclusive, MRCP was performed, followed by ERCP or a 1-year follow-up. After each diagnostic step, the examiner decided whether any biliary conditon was present and whether therapeutic ERCP was necessary. The decicions were compared with the results of ERCP with EST or the outcome after the 1-year follow-up.

Main Outcome Measurements: Accuracy of EUS in predicting the need for therapeutic ERCP.

Results: Nine patients had ERCP with EST. The final assessment classified 2 of these interventions as having been unnecessary. EUS was conclusive in 49 cases. After EUS, the accuracy of the decision on the presence of a biliary condition increased from 82% to 96% and on the need for therapeutic ERCP from 86% to 96%.

Limitation: Single-center experience.

Conclusion: EUS accurately predicts the need for therapeutic ERCP in patients at low risk for biliary obstruction.
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http://dx.doi.org/10.1016/j.gie.2008.02.051DOI Listing
September 2008

EUS elastography of the pancreas: feasibility and pattern description of the normal pancreas, chronic pancreatitis, and focal pancreatic lesions.

Gastrointest Endosc 2007 Jun;65(7):971-8

Medical Clinic 2, Institute for Pathology, HELIOS Klinikum Wuppertal, University of Witten/Herdecke, Wuppertal, Germany.

Background: Initial clinical applications have shown that US elastography might be able to distinguish tissues because of their specific consistency.

Objective: (1) To investigate the feasibility of EUS elastography of the pancreas and (2) to describe elastographic patterns of the normal pancreas and the pancreas affected by inflammatory or focal disease.

Design: Prospective single-center study.

Setting: Academic center of the University of Witten/Herdecke.

Patients: Twenty patients with normal pancreas, 20 patients with chronic pancreatitis, and 33 patients with focal pancreatic lesion, histologically later proven in 32 of these 33 cases.

Interventions: Commercially available US equipment was used. The elasticity of tissue was reconstructed in real time within a sample area and was translated into a color scale imaging relative tissue elasticity within this area. Representative loops of at least 20 seconds were recorded regarding each region of interest.

Results: Adequate elastographic recordings could be obtained in all 73 patients. Patients with hypoechoic and intermediately echogenic normal pancreas revealed a relatively homogeneous elastographic pattern. Thirty-one focal lesions, including 30 neoplasms and most of the chronically inflamed pancreata had a honeycomb pattern dominated by hard strands. This pattern showed analogies to the histologic structure of 10 resected tumors. Other patients with chronic pancreatitis and those with hyperechoic healthy pancreas had miscellaneous elastographic appearances.

Conclusions: EUS elastography of the pancreas is feasible and produces plausible results. The examination of homogeneous tissue is impaired by the relative scale used. Chronic pancreatitis and hard tumors cannot be distinguished by elastography, probably because of their similar fibrous structure.
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http://dx.doi.org/10.1016/j.gie.2006.12.057DOI Listing
June 2007

[Menthol in the adjuvant treatment of gallbladder stones fragmented by ESWL as an option for reducing doses of urso- and chenodeoxycholic acid].

Med Klin (Munich) 2004 Jun;99(6):279-84

Medizinische Klinik A, Klinikum Wuppertal, Universität Witten/Herdecke, Witten/Herdecke.

Background: Assessments of the litholytic activity of terpenes in the conservative treatment of gallstone disease vary. Achievement of a stone-free state through dissolution of residual fragments after extracorporeal shock wave lithotripsy (ESWL) is a suitable model for investigating the litholytic activity of menthol.

Patients And Methods: After ESWL in patients with symptomatic gallbladder stones, the litholytic efficacy of the standard therapy of 125 mg urso-/chenodeoxycholic acid (UDC/CDC) per 25 kg body weight (UDC + CDC) was compared with that of 62.5 mg UDC/CDC plus 125 mg menthol (M) per 25 kg body weight (M + UDC + CDC). 70 patients were treated with M + UDC + CDC (n = 36) or UDC + CDC (n = 34) in a double-blind design.

Results: 19 of 34 patients (55.9%) in the UDC + CDC group became stonefree in an average period of 5.9 months, compared with 17 out of 36 patients (47.2%) in the M + UDC + CDC group in 8.8 months. Although the patients on UDC + CDC became stone-free significantly more quickly (p = max [p1,p2] = 0.4717), there was no relevant statistical difference in the total number of stone-free patients between the two treatment groups. After subtraction of the patients who terminated the study prematurely, significantly larger numbers of stone-free patients under the standard therapy were found at 9 and 12 months (16 : 9 and 19 : 12, respectively), while at the other time points no significant difference was found. Before ESWL, seven of 25 patients in the menthol group had two or more stones, while in the group treated with the standard therapy this was only the case in two patients. Five patients had mild calcification on admission to the study, four of whom received M + UDC + CDC.

Conclusion: Overall, patients become stone-free more quickly on the standard UDC + CDC therapy. However, after subtraction of the patients who discontinued the study prematurely it can be seen that this results from significantly higher numbers of stone-free patients at 9 and 12 months, so that over the entire observation period-and in consideration of the less favorable stone parameters in the menthol group-there is no substantial statistically relevant difference in the efficacy of the two treatments.
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http://dx.doi.org/10.1007/s00063-004-1041-6DOI Listing
June 2004

Frequency of bacteremia after linear EUS of the upper GI tract with and without FNA.

Gastrointest Endosc 2004 Mar;59(3):339-44

Department of Medicine 2 and the Institute for Microbiology and Immunology, HELIOS Klinikum Wuppertal, University of Witten/Herdecke, Wuppertal, Germany.

Background: Few data are available concerning the frequency of bacteremia after diagnostic EUS or EUS-guided FNA. This study was undertaken to provide these data and to determine whether present guidelines for prophylactic administration of antibiotics to prevent endocarditis during upper endoscopy are applicable to EUS and EUS-guided FNA.

Methods: A total of 100 patients who were to undergo diagnostic EUS of the upper-GI tract and 50 who were to have upper-GI EUS-guided FNA were enrolled in this prospective study. Blood cultures were obtained before and within 5 minutes after the conclusion of the procedure. In case of bacterial growth, patients were observed for at least 3 days for signs of infection.

Results: After diagnostic EUS, significant bacteremia was found in two patients with esophageal carcinoma (2%: 95% CI[0%, 4.8%]) and after EUS-guided FNA in two patients (4%: 95% CI[0%, 9.6%]). The difference was not statistically significant. None of these patients developed clinical signs of infection. Risk factors predisposing to bacteremia could not be identified.

Conclusion: The frequency of bacteremia after EUS, with and without FNA, is within the range of that for diagnostic upper endoscopy. Therefore, the same recommendations for prophylactic administration of antibiotics to prevent endocarditis may be applied in patients undergoing EUS and EUS-guided FNA. The role of esophageal cancer as a predisposing factor to EUS-associated infection remains uncertain.
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http://dx.doi.org/10.1016/s0016-5107(03)02707-xDOI Listing
March 2004