[Show abstract][Hide abstract] ABSTRACT: CV9103 is a prostate-cancer vaccine containing self-adjuvanted mRNA (RNActive®) encoding the antigens PSA, PSCA, PSMA, and STEAP1. This phase I/IIa study evaluated safety and immunogenicity of CV9103 in patients with advanced castration-resistant prostate-cancer.
44 Patients received up to 5 intra-dermal vaccinations. Three dose levels of total mRNA were tested in Phase I in cohorts of 3-6 patients to determine a recommended dose. In phase II, 32 additional patients were treated at the recommended dose. The primary endpoint was safety and tolerability, the secondary endpoint was induction of antigen specific immune responses monitored at baseline and at weeks 5, 9 and 17.
The most frequent adverse events were grade 1/2 injection site erythema, injection site reactions, fatigue, pyrexia, chills and influenza-like illness. Possibly treatment related urinary retention occurred in 3 patients. The recommended dose was 1280 μg. A total of 26/33 evaluable patients treated at 1280 μg developed an immune response, directed against multiple antigens in 15 out of 33 patients. One patient showed a confirmed PSA response. In the subgroup of 36 metastatic patients, the Kaplan-Meier estimate of median overall survival was 31.4 months [95 % CI: 21.2; n.a].
The self-adjuvanted RNActive® vaccine CV9103 was well tolerated and immunogenic. The technology is a versatile, fast and cost-effective platform allowing for creation of vaccines. The follow-up vaccine CV9104 including the additional antigens prostatic acid phosphatase (PAP) and Muc1 is currently being tested in a randomized phase IIb trial to assess the clinical benefit induced by this new vaccination approach.
EU Clinical Trials Register: EudraCT number 2008-003967-37, registered 27 Jan 2009.
[Show abstract][Hide abstract] ABSTRACT: To develop a microRNA (miRNA)-based predictive model for prostate cancer patients of 1) time to biochemical recurrence after radical prostatectomy and 2) biochemical recurrence after salvage radiation therapy following documented biochemical disease progression post-radical prostatectomy.
Forty three patients who had undergone salvage radiation therapy following biochemical failure after radical prostatectomy with greater than 4 years of follow-up data were identified. Formalin-fixed, paraffin-embedded tissue blocks were collected for all patients and total RNA was isolated from 1mm cores enriched for tumor (>70%). Eight hundred miRNAs were analyzed simultaneously using the nCounter human miRNA v2 assay (NanoString Technologies; Seattle, WA). Univariate and multivariate Cox proportion hazards regression models as well as receiver operating characteristics were used to identify statistically significant miRNAs that were predictive of biochemical recurrence.
Eighty eight miRNAs were identified to be significantly (p<0.05) associated with biochemical failure post-prostatectomy by multivariate analysis and clustered into two groups that correlated with early (≤ 36 months) versus late recurrence (>36 months). Nine miRNAs were identified to be significantly (p<0.05) associated by multivariate analysis with biochemical failure after salvage radiation therapy. A new predictive model for biochemical recurrence after salvage radiation therapy was developed; this model consisted of miR-4516 and miR-601 together with, Gleason score, and lymph node status. The area under the ROC curve (AUC) was improved to 0.83 compared to that of 0.66 for Gleason score and lymph node status alone.
miRNA signatures can distinguish patients who fail soon after radical prostatectomy versus late failures, giving insight into which patients may need adjuvant therapy. Notably, two novel miRNAs (miR-4516 and miR-601) were identified that significantly improve prediction of biochemical failure post-salvage radiation therapy compared to clinico-histopathological factors, supporting the use of miRNAs within clinically used predictive models. Both findings warrant further validation studies.
PLoS ONE 03/2015; 10(3):e0118745. DOI:10.1371/journal.pone.0118745 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A lack of cell surface markers for the specific identification, isolation and subsequent analysis of living prostate tumor cells hampers progress in the field. Specific characterization of tumor cells and their microenvironment in a multi-parameter molecular assay could significantly improve prognostic accuracy for the heterogeneous prostate tumor tissue. Novel functionalized gold-nano particles allow fluorescence-based detection of absolute mRNA expression levels in living cells by fluorescent activated flow cytometry (FACS). We use of this technique to separate prostate tumor and benign cells in human prostate needle biopsies based on the expression levels of the tumor marker alpha-methylacyl-CoA racemase (AMACR). We combined RNA and protein detection of living cells by FACS to gate for epithelial cell adhesion molecule (EPCAM) positive tumor and benign cells, EPCAM/CD45 double negative mesenchymal cells and CD45 positive infiltrating lymphocytes. EPCAM positive epithelial cells were further sub-gated into AMACR high and low expressing cells. Two hundred cells from each population and several biopsies from the same patient were analyzed using a multiplexed gene expression profile to generate a cell type resolved profile of the specimen. This technique provides the basis for the clinical evaluation of cell type resolved gene expression profiles as pre-therapeutic prognostic markers for prostate cancer.
[Show abstract][Hide abstract] ABSTRACT: Background
Nodal pelvic/retroperitoneal recurrent prostate cancer (PCa) after primary therapy can be treated with salvage lymph node dissection (salvage-LND) in order to delay disease progression and offer cure for a subset of patients. Whether adjuvant radiotherapy (ART) in affected regions improves the outcome by elimination of residual tumour burden remains unclear.
A total of 93 patients with exclusively nodal PCa relapse underwent choline-positron-emission tomography-computed-tomography-directed pelvic/retroperitoneal salvage-LND; 46 patients had surgery only and 47 patients received ART in regions with proven lymph node metastases. In case of subsequent prostate specific antigen (PSA) progression, different imaging modalities were performed to confirm next relapse within or outside the treated region (TR). Mean follow-up was 3.2 years.
Lymphatic tumour burden was balanced between the two groups. Additional ART resulted in delayed relapse within TR (5-year relapse-free rate 70.7 %) versus surgery only (5-year relapse-free rate 26.3 %, p
Strahlentherapie und Onkologie 10/2014; 191(4). DOI:10.1007/s00066-014-0763-5 · 2.91 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Anterior gradient 2 (AGR2) is a gene predominantly expressed in mucus-secreting tissues or in endocrine cells. Its expression is drastically increased in tumors including prostate cancer. Here we investigated whether AGR2 transcript levels can be used as a biomarker to detect prostate cancer (PCa). Using a PCR-based approach, we could show that in addition to the wild-type (AGRwt long and short) transcripts, five other AGR2 splice variants (SV) (referred to as AGR2 SV-C, -E, -F, -G and -H) were present in cancer cell lines. In tissue biopsies, SV-H and AGR2wt (short) distinguished between benign and PCa (p ≤ 0.05 n = 32). In urine exosomes, AGR2 SV-G and SV-H outperformed serum PSA. Receiver operating characteristic (ROC) curves showed the highest discriminatory power of SV-G and SV-H in predicting PCa. AGR2 SV-G and SV-H are potential diagnostic biomarkers for the non-invasive detection of PCa using urine exosomes.
[Show abstract][Hide abstract] ABSTRACT: Background
In a previous study we demonstrated that, based on 11C/18 F-choline positron emission tomography-computerized-tomography as a diagnostic tool, salvage lymph node dissection (LND) plus adjuvant radiotherapy (ART) is feasible for treatment of pelvic/retroperitoneal nodal recurrence of prostate cancer (PCa). However, the toxicity of this combined treatment strategy has not been systematically investigated before. The aim of the current study was to evaluate the acute and late toxicity and quality of life of ART after LND in pelvic/retroperitoneal nodal recurrent PCa.
Material and methods
43 patients with nodal recurrent PCa were treated with 46 LND followed by ART (mean 49.6 Gy total dose) at the sites of nodal recurrence. Toxicity of ART was analysed by physically examination (31/43, 72.1%), by requesting 15 frequent items of adverse events from the Common-Terminology-Criteria for Adverse Events Version 4.0-catalogue and by review of medical records. QLQ-C30 (EORTC quality of life assessment) and PR25 (prostate cancer module) questionnaires were used to investigate quality of life. Toxicity was evaluated before starting of ART, during ART (acute toxicity), after ART (mean 2.3 months) and at end of follow up (mean 3.2 years after end of ART) reflecting late toxicity.
71.7% (33/46) of 46 ART were treatment of pelvic, 10.9% (5/46) of retroperitoneal only and 28.3% (13/46) of pelvic and retroperitoneal regions. Overall 52 symptoms representing toxicities were observed before ART, 107 during ART, 88 after end of ART and 52 at latest follow up. Leading toxicities during ART were diarrhoea (19%, 20/107), urinary incontinence (16%, 17/107) and fatigue (16%, 17/107). The spectrum of late toxicities was almost equal to those before beginning of ART. No grade 3 adverse events or chronic lymphedema at extremities were observed. We observed no clear correlation between localisation of treated regions, technique of ART and frequency or severity of toxicities. Mean quality of life at final evaluation was 74%.
ART after extended LND in PCa relapse is justifiable with respect to adverse effects and toxicity. The side effects were circumscribed and well tolerated. The spectrum of adverse events at latest follow up was almost equal to those before start of ART.
[Show abstract][Hide abstract] ABSTRACT: Purpose:
To evaluate the diagnostic accuracy of choline-PET/CT for nodal relapse of prostate cancer (PCA) according to topographical location and the size of tumor infiltration in lymph nodes (LN).
72 patients with nodal PCA-relapse after primary therapy underwent pelvic and/or retroperitoneal salvage lymph node dissection (salvage-LND) after a whole body PET/CT with 11C-Choline or 18F-Fluoroethylcholine showing PET-positive LN but no other detectable metastases. Diagnostic accuracy was evaluated for 160 dissected LN-regions (pelvic left/right, retroperitoneal), 498 subregions (common,-external,-internal-iliac, obturatoria, presacral, aortic-bifurcation, aortal, caval, interaortocaval) and 2122 LNs.
Lymph node metastases (LNM) were present in 32% of the resected LN (681/2122) resulting in 238 positive subregions and 111 positive regions. PET/CT was positive for 110 regions and 209 subregions. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy were: region-based 91.9%, 83.7%, 92.7%, 82.0% and 89.4%, subregion-based 80.7%, 93.5%, 91.9%, 84.1% and 87.3%, lesion-based 57.0%, 98.4%, 94.5%, 82.6% and 84.9%. 70.7% (278/393) of true positive LNM detected by PET/CT were located in LN with a short axis diameter <10mm. Sensitivity of choline-PET/CT was 13.3%, 57.4% and 82.8% for depth of tumor infiltration of ≥2-<3mm, ≥5-<6mm and ≥10-<11mm, respectively. Location of LNM and radiotracer (11C-choline/18F-fluoroethylcholine) had no substantial impact on diagnostic accuracy.
Choline-PET/CT detects affected LN-regions (left/right pelvic, retroperitoneal) in PCA-relapse with high accuracy and seems helpful for guiding salvage-LND. Sensitivity of choline-PET/CT decreases with the size of metastatic infiltration in LNs. Choline-PET/CT detects metastases in a significant fraction of LNs that are not pathologically enlarged on CT.
The Journal of urology 07/2014; DOI:10.1016/j.juro.2013.12.054 · 4.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose:
(18)F-Fluoroethylcholine ((18)F-FECh) is excreted via the urinary system with high activity accumulation in the urinary bladder. Furosemide and oral hydration can be administered concomitantly to reduce urinary activity to provide better detectability of retroperitoneal and pelvic lesions. Currently it is unknown if there is any effect of furosemide on (18)F-FECh uptake in organs, tissues and tumour lesions and the extent to which image quality along the urinary tract may be improved by furosemide.
We retrospectively analysed 217 (18)F-FECh PET/CT examinations from 213 patients with known prostate cancer (PCa), performed either with oral hydration (109) or furosemide 20 mg together with oral hydration (108). Maximum (18)F-FECh uptake in different organs, tissues, lymph nodes and osseous metastases was quantified in terms of standardized uptake value (SUV) in a volume of interest and compared between the two groups. To characterize the impact of furosemide on lesion detectability a three-point rating scale was used to assess the presence of focal activity spots in the ureters and of perivesicular artefacts.
Patient characteristics and distribution of tumour lesions were well balanced between the two groups. Overall, SUVmax values from normal organs were increased after furosemide compared to the values in patients scanned without furosemide. Significant changes were observed in the salivary glands, liver, spleen, pancreas, kidneys, gluteus muscle and perirenal fat. SUVmax values were significantly decreased after furosemide in lymph node metastases (SUVmax 4.81 ± 2.68 vs. 6.48 ± 4.22, p = 0.0006), but not in osseous metastases. Evaluation of image quality along the urinary tract revealed significantly better depiction of the perivesicular space and significantly less focal tracer accumulation in the ureters in patients receiving furosemide, but the number of detected lymph nodes was not significantly different.
Furosemide administration reduced choline uptake in tumour lesions, especially significant in pelvic lymph node metastases. Although furosemide administration improved image quality, optimal image quality may also be obtained by adequate hydration without the risk of diminishing choline uptake in PCa lesions. Therefore a controlled hydration protocol seems more appropriate than administration of furosemide.
European journal of nuclear medicine and molecular imaging 06/2014; 41(11). DOI:10.1007/s00259-014-2829-0 · 5.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Ex vivo studies have shown that the gastrin releasing peptide receptor (GRPr) is overexpressed on almost all primary prostate cancers, making it a promising target for prostate cancer imaging and targeted radiotherapy.Methods: Biodistribution, dosimetry and tumor uptake of the GRPr antagonist 64Cu-CB-TE2A-AR06 [(64Cu-4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo(6.6.2)hexadecane)-PEG4-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-LeuNH2] were studied by PET/CT in four patients with newly diagnosed prostate cancer (T1c-T2b, Gleason 6-7).Results: No adverse events were observed after injection of 64Cu-CB-TE2A-AR06. Three of four tumors were visualized with high contrast [tumor-to-prostate ratio > 4 at 4 hours (h) post injection (p.i.)], one small tumor (T1c, < 5% tumor on biopsy specimens) showed moderate contrast (tumor-to-prostate ratio at 4 h: 1.9). Radioactivity was cleared by the kidneys and only the pancreas demonstrated significant accumulation of radioactivity, which rapidly decreased over time.Conclusion:
64Cu-CB-TE2A-AR06 shows very favorable characteristics for imaging prostate cancer. Future studies evaluating 64Cu-CB-TE2A-AR06 PET/CT for prostate cancer detection, staging, active surveillance, and radiation treatment planning are necessary.
[Show abstract][Hide abstract] ABSTRACT: Background:
The role of autosomal dominant polycystic kidney disease (ADPKD) as a risk factor for renal cell carcinoma (RCC) is still under discussion. Data on prevalence of RCC in ADPKD are limited, especially on a large population scale. The aim of this study was to analyze the prevalence of RCC in ADPKD kidneys and characterize the clinical features of this coincidence.
Based on our histopathological registry for ADPKD and the Else Kröner-Fresenius Registry, we retrospectively reviewed malignant and benign renal lesions in patients with ADPKD who had undergone renal surgery from 1988 to 2011.
240 ADPKD patients underwent 301 renal surgeries. Mean age at surgery was 54 years. Overall, 16 malignant and 11 benign lesions were analyzed in 301 kidneys (5.3%; 3.7%), meaning that 12/240 (5%; 1:20) patients presented with malignant renal lesions. 66.7% (8/12) of these patients had undergone dialysis prior to surgery. We found 10/16 (63%) papillary RCC, 5/16 (31%) clear cell RCC, and 1/16 (6%) papillary noninvasive urothelial cancer. Regarding all renal lesions, 6/17 (35.3%) patients had more than one histological finding in their kidneys. In 2 cases, metachronous metastases were removed. Mean follow-up was 66.7 months.
Kidney-related prevalence of RCC in ADPKD kidneys was surprisingly high. Whether or not this is due to chronic dialysis or due to the underlying disease is still speculative. Like other cystic renal diseases with an increased risk for RCC, the attending physician should be aware of the malignant potential of ADPKD, especially with concomitant dialysis.
Nephron Clinical Practice 06/2013; 123(1-2):13-21. DOI:10.1159/000351049 · 1.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose
To evaluate the value of dynamic contrast enhanced Magnetic Resonance Imaging (DCE-MRI) without endorectal coil (EC) in the detection of local recurrent prostate cancer (PC) after radical prostatectomy (RP).
Material and methods
Thirty-three patients with recurrent PC underwent DCE-MRI without EC before salvage radiotherapy (RT). At median 15 (mean 16±4.9, range 12–27) months after completion of RT all patients showed complete biochemical response. Additional follow up post RT DCE-MRI scans were available. Prostate specific antigen (PSA) levels at the time of imaging were correlated to the imaging findings.
In 22/33 patients (67%) early contrast enhancing nodules were detected in the post-prostatectomy fossa on pre-RT DCE-MRI images. The average pre-RT PSA level of the 22 patients with positive pre-RT DCE-MRI findings was significantly higher (mean, 0.74±0.64 ng/mL) compared to the pre-RT PSA level of the 11 patients with negative pre-RT DCE-MRI (mean, 0.24±0.13 ng/mL) (p<0.001). All post-RT DCE-MRI images showed complete resolution of initial suspicious lesions. A pre-RT PSA cut-off value of ≥0.54 ng/ml readily predicted a positive DCE-MRI finding.
This is the first study that shows that DCE-MRI without EC can detect local recurrent PC with an estimated accuracy of 83% at low PSA levels. All false negative DCE-MRI scans were detected using a PSA cut-off of ≥0.54 ng/mL.
[Show abstract][Hide abstract] ABSTRACT: Purpose:
We evaluated the impact of salvage lymph node dissection with adjuvant radiotherapy in patients with nodal recurrence of prostate cancer. By default, nodal recurrence of prostate cancer is treated with palliative antihormonal therapy, which causes serious side effects and invariably leads to the development of hormone refractory disease.
Materials and methods:
A total of 47 patients with nodal recurrence of prostate cancer based on evidence of (11)C-choline/(18)F-choline ((18)F-fluorethylcholine) positron emission tomography-computerized tomography underwent primary (2 of 52), secondary (45 of 52), tertiary (4 of 52) and quaternary (1 of 52) salvage lymph node dissection with histological confirmation. Of 52 salvage lymph node dissections 27 were followed by radiotherapy. Biochemical response was defined as a prostate specific antigen less than 0.2 ng/ml after salvage therapy. The Kaplan-Meier method, binary logistic regression and Cox regression were used to analyze survival as well as predictors of biochemical response and clinical progression.
Mean prostate specific antigen at salvage lymph node dissection was 11.1 ng/ml. A mean of 23.3 lymph nodes were removed per salvage lymph node dissection. Median followup was 35.5 months. Of 52 salvage lymph node dissections 24 resulted in complete biochemical response followed by 1-year biochemical recurrence-free survival of 71.8%. Gleason 6 or less (OR 7.58, p = 0.026), Gleason 7a/b (OR 5.91, p = 0.042) and N0 status at primary therapy (OR 8.01, p = 0.011) were identified as independent predictors of biochemical response. Gleason 8-10 (HR 3.5, p = 0.039) as a preoperative variable, retroperitoneal positive lymph nodes (HR 3.76, p = 0.021) and incomplete biochemical response (HR 4.0, p = 0.031) were identified as postoperative predictors of clinical progression. Clinical progression-free survival was 25.6% and cancer specific survival was 77.7% at 5 years.
Based on (11)C/(18)F-choline positron emission tomography-computerized tomography as a diagnostic tool, salvage lymph node dissection is feasible for the treatment of nodal recurrence of prostate cancer. Most patients experience biochemical recurrence after salvage lymph node dissection. However, a specific population has a lasting complete prostate specific antigen response.
The Journal of urology 10/2012; 188(6). DOI:10.1016/j.juro.2012.08.041 · 4.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Approximately 30% of patients with renal cell cancer (RCC) develop bone metastasis causing skeletal-related events (SRE): pathologic fracture, spinal cord compression, surgery to bone and radiotherapy. Zoledronic acid demonstrated significant clinical benefit in RCC patients in a retrospective analysis. Primary objective of this prospective study was the proportion of patients experiencing ≥ 1 SRE during 12 months of zoledronic acid treatment and to verify the retrospective data.
Fifty patients with histologically confirmed RCC and evidence of ≥ 1 cancer-related bone lesion and ≤ 3 prior bisphosphonate applications were enrolled in 19 German centers between 2004 and 2007. The patients received 4 mg zoledronic acid every 3 weeks for 12 months followed by a follow up period for overall survival of 12 months. Bone lesions were diagnosed by bone scan or MRI-quickscan. Greater and equal to 1 lesion had to be confirmed by x-ray, CT or MRI scan. Additional bone scans were performed after completion of study treatment and if clinically indicated. In case of suspicion or evidence of a SRE it had to be confirmed radiologically.
In total, 49 of the 50 enrolled patients were treated. Only 11 of them (22.4%) experienced any SRE until month 12. Patients with > 6 lesions and higher baseline MSKCC (Memorial Sloan-Kettering Cancer Center) score had a higher risk for SREs. Zoledronic acid was generally well tolerated and its known safety profile was affirmed.
This prospective study confirms the results of prior data about the efficacy of zoledronic acid in patients with metastatic (m)RCC, supporting its beneficial use in these patients.
The Canadian Journal of Urology 06/2012; 19(3):6261-7. · 0.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We evaluated the clinicopathological outcome of von Hippel-Lindau (VHL)-patients who had mainly undergone nephron sparing surgery (NSS) for renal cell carcinoma (RCC) when the tumour diameter has reached 4.0 cm. Multiple, bilateral RCC with high recurrence rates and subsequent repeated interventions, followed by increasing risk for end-stage renal failure and metastases is characteristic for VHL. NSS is widely used for VHL-associated RCC at 3.0 cm cut-off. 54 VHL patients underwent NSS, nephrectomy or thermal ablation for RCC. We analysed time to second treatment, overall and cancer specific survival, intra- and post-operative data as well as tumour characteristics. We also examined the effects of delaying removal of RCC to 4.0 cm cut-off. Median follow-up was 67 months. 54 patients underwent 97 kidney treatments. 96 % of first and 67 % of second interventions comprised of NSS. 0 % metastases were observed in the group with largest tumour size ≤4 cm. The probability for second surgery was 21 %, at 5 years and 42 % at 10 years. Median time to second NSS was 149.6 months. The overall and cancer specific survival rate was 96.5 and 100 % at 5-year follow-up, and 82.5 and 90.5 % respectively at 10-year follow-up. Median delay to second NSS at 4.0 cm cut-off versus 3.0 cm was 27.8 months. NSS was both successfully used in first and second surgery and to some extent even in third surgery. By following a strict surveillance protocol it is possible to support a 4.0 cm-threshold strategy for NSS, based on the assumption that delaying time to second NSS prevents patients from premature renal failure.
Familial Cancer 03/2012; 11(3). DOI:10.1007/s10689-012-9525-7 · 1.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To evaluate the growth kinetics of renal cell carcinoma (RCC) in von Hippel-Lindau (VHL) disease in a large trial by CT/MRI scan. VHL disease is a multisystemic disorder predisposing to renal cysts and cancer. There is a general assumption that VHL-associated RCC presents slower growth rates than sporadic RCC.
We describe growth kinetics of 96 renal tumours in 64 VHL patients with analysed germline mutation (54/64 treated, 10/64 active surveillance) over a mean follow-up of 54.9 months. We calculated tumour volume, growth rate, multiplication of tumour volume per year and overall, as well as tumour volume doubling time.
The mean growth rate of 96 tumours was 4.4 mm/year (SD 3.2, median 4.1 mm/year), mean volume doubling time was 25.7 months (SD 20.2, median 22.2 months). We saw a median 1.4-fold increase in tumour volume per year. At treatment time point, VHL kidneys comprised 39% tumour and 15.7% cyst volume fraction. We saw no correlation between tumour size and growth parameters.
VHL-associated RCC show large variances in tumour growth behaviour. Compared to the literature, in our study the growth rates (mm/year) of RCC in VHL disease did not differ from those of sporadic RCC. Fast tumour growth increases the risk for metastases.
Urologia Internationalis 12/2011; 88(1):71-8. DOI:10.1159/000333348 · 1.43 Impact Factor