Marcel P Stokkel

Netherlands Cancer Institute, Amsterdamo, North Holland, Netherlands

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Publications (53)264.87 Total impact

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    Linda De Wit - van der Veen · Marcel Stokkel
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    ABSTRACT: Advances in the oncological sciences have led to the development of agents that are designed to affect specific molecular pathways. However, many of these immunotherapeutic agents do not successfully pass phase 2 trials due to concerns with efficacy, toxicity or side effects. The generalized endpoints that traditionally have been used in these trials, such as maximum tolerated dose and overall response, may be less optimal for immunotherapeutic agents. The addition of in vivo nuclear imaging in these early trials can aid in patient stratification, evaluation of drug biodistribution, pharmacodynamic effects and tumor heterogeneity. This review discusses the advantages of nuclear imaging, and outlines the first application of these imaging biomarkers in clinical trials.
    Full-text · Article · Aug 2015
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    ABSTRACT: To determine the lymphatic drainage pattern using SPECT/CT in clinically node-negative (cN0) patients with vulvar cancer, and to evaluate the possible implications for the extent of inguinal lymph node dissection. A total of 83 patients with vulvar cancer scheduled for sentinel node (SN) biopsy were injected peritumorally with radioactive nanocolloid particles followed by lymphoscintigraphy and SPECT/CT for anatomical localization. The SN and higher-echelon nodes on SPECT/CT were located in different zones in the groin and pelvic region. The groin was divided into five zones according to Daseler et al.: four zones obtained by drawing two perpendicular lines over the saphenofemoral junction and one zone directly overlying this junction. The nodes in the pelvic region were classified into three zones: external iliac/obturator, the common iliac and the paraaortic zones. A total of 217 SNs and 202 higher-echelon nodes were localized on SPECT/CT. All SNs were located in the five zones according to Daseler et al.: 149 (69 %) in the medial superior region, 31 (14 %) in the medial inferior region, 22 (10 %) in the central region, 14 (6.5 %) in the lateral superior region and only 1 (0.5 %) in the lateral inferior region. The higher-echelon nodes were located both in the groin (15 %) and in the pelvic region (85 %). In patients with cN0 vulvar cancer, lymphatic drainage occurs predominantly to the medial regions of the groin. Drainage to the lateral inferior region of the groin is only incidental and in SN-positive patients this zone might be spared in subsequent extended lymph node dissection. This may lead to a decrease in the morbidity associated with this procedure. SPECT/CT is able to personalize lymphatic mapping, providing detailed information about the number and anatomical location of SNs for adequate surgical planning in the groin.
    Full-text · Article · Jul 2015 · European Journal of Nuclear Medicine
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    ABSTRACT: El propósito del estudio es evaluar el valor añadido de la SPECT-TC en la valoración preoperatoria de los ganglios centinelas de las regiones presacral y pararrectal, los cuales se localizan fuera del área estándar de la linfadenectomía extendida utilizada para la estadificación de la pelvis en cáncer de próstata. La SPECT-TC puede servir de guía para la escisión de estos ganglios mediante linfadenectomía por cirugía abierta o laparoscopia.
    No preview · Article · Oct 2014 · Revista Española de Medicina Nuclear e Imagen Molecular
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    ABSTRACT: This study has aimed to evaluate the added value of SPECT-CT scan in the preoperative assessment of sentinel nodes of the presacral and pararectal regions localized outside the standard area of extended pelvic lymphadenectomy for the staging of the pelvis in prostate cancer. SPECT-CT scan can serve as a guide for the excision of these nodes by lymphadenectomy by open surgery or laparoscopy. We evaluated 4 patients with prostate cancer presenting sentinel nodes in the pararectal and presacral regions on SPECT-CT scan performed in addition to lymphoscintigraphy. These patients underwent lymphadenectomy with robot-assisted laparoscopy together with prostatectomy. All of the excised lymph nodes were sent for histopathology study. An average of 6 sentinel nodes per patient were found on SPECT-CT scan with a mean of 2 sentinel nodes in presacral/pararectal región. Lymphadenectomy including these areas was performed. Pararectal/presacral sentinel nodes of all patients depicted by SPECT-CT scan were tumor free on histopathology study. Sentinel nodes (no pararectal/presacral) were positive for malignancy in only one patient. Preoperative SPECT-CT scan is a useful tool to localize the sentinel nodes in pararectal/presacral regions. It can be an anatomic guide for new modalities of laparoscopic surgery such as robot-assisted procedures that can access the pelvic areas visualized with SPECT-CT scan, making excision of these nodes possible. Copyright © 2014 Elsevier España, S.L.U. y SEMNIM. All rights reserved.
    No preview · Article · Oct 2014 · Revista Española de Medicina Nuclear e Imagen Molecular
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    ABSTRACT: Wire-guided localization is the most commonly used technique for intraoperative localization of non-palpable breast cancer. Radioactive seed localization (RSL) is becoming more popular and seems to be a reliable alternative for intraoperative lesion localization. The purpose of the present meta-analysis was to evaluate the use of RSL. Primary study outcomes were irradicality and re-excision rates. In total 3168 patients were included. The clinical adaptation shows growing confidence in RSL and further growth is expected. J. Surg. Oncol. © 2014 Wiley Periodicals, Inc.
    No preview · Article · Sep 2014 · Journal of Surgical Oncology
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    ABSTRACT: Introduction: Cardiotoxicity related to trastuzumab anticancer treatment poses a diagnostic challenge at early stages. The aim of the present pilot study was to assess the value of iodine-123-metaiodobenzylguanidine (I-123-MIBG) scintigraphy in breast cancer patients treated with trastuzumab who showed a decrease in their cardiac function. Materials and methods: I-123-MIBG scintigraphy was performed in nine patients with decreased or significantly decreasing left ventricular ejection fraction (LVEF) during trastuzumab therapy. On the basis of planar images, 4 h heart-to-mediastinum (HMR) ratio and washout percentages (WR) were calculated. Results: I-123-MIBG scintigraphy revealed abnormal 4 h HMR and increased WR in three patients. LVEF recovery was observed in none of these patients during 3, 6, and 13 months of follow-up. In two of five patients with normal 4 h HMR the washout rates were also normal, whereas in three patients slightly increased washout rates were found. All five patients demonstrated a recovery of their LVEF value during follow-up. One patient with a normal 4 h HMR and normal WR initially showed a significant decrease in LVEF, which decreased further during follow-up. However, the LVEF value remained at 53%, which was within normal limits, after trastuzumab administration. Conclusion: In this pilot study we have explored the role of I-123-MIBG scintigraphy in the assessment of trastuzumab-related cardiotoxicity and suggest that, in patients with a persistently decreasing LVEF, I-123-MIBG scintigraphy might indicate whether recovery will occur and, consequently, whether retreatment may be initiated.
    No preview · Article · Oct 2012 · Nuclear Medicine Communications
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    ABSTRACT: The aim of this study was to systematically review literature, exploring the role of radioguided surgery with iodine-labeled metaiodobenzylguanidine (MIBG) in resection of neuroendocrine tumors. PubMed, EMBASE, Web of Science, COCHRANE, CINAHL, Academic Search Premier, ScienceDirect, Wiley, and references of key articles were searched to identify potentially relevant studies. Twenty studies were included. A total of 130 procedures in 120 patients were performed. Ninety percent of included studies concerned case reports or case series. It is described that radioguided surgery with iodine-labeled MIBG can improve the quality of macroscopic resection of neuroendocrine tumors in selected cases, ie, in cases where the tumor is small, nonpalpable, difficult to visualize on conventional imaging studies, or located in an area with adhesional scar tissue from previous surgery. However, in a substantial number of cases the gamma probe failed due to technical problems. Since there is limited evidence that radioguided surgery contributes substantially in resection of neuroendocrine tumors, we cannot advocate its use in general. However, we can conclude that it can seemingly improve the quality of resection in selected cases. When radioguided surgery is performed in neuroendocrine tumors, we advocate the use of I to label MIBG.
    No preview · Article · Sep 2012 · Clinical nuclear medicine
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    ABSTRACT: Radioactive MIBG can be used in radioguided surgery for neuroendocrine tumors. We report the case of a man with a mutation in the succinate dehydrogenase subunit B (SDHB) gene, in which an abdominal MRI scan identified two 5-mm left para-aortic nodules, suspect for paragangliomas. Subsequent SPECT revealed increased uptake of tracer. 123I MIBG probe-guided resection was scheduled. During surgery, 2 small nodules with elevated activity in between the superior mesenteric artery and the left adrenal gland were identified by the detection probe and were resected. Histopathologic examination revealed mature ganglioneuromas.
    No preview · Article · Aug 2012 · Clinical nuclear medicine
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    ABSTRACT: The canonical Wnt pathway plays a key regulatory role in osteoblastogenesis and bone mass acquisition through its main effector, β-catenin. Adenomatous polyposis coli (APC) represents the key intracellular gatekeeper of β-catenin turnover, and heterozygous germ-line mutations in the APC gene cause familial adenomatous polyposis (FAP). Whether APC mutations affect bone mass has not been previously investigated. We conducted a cross-sectional study evaluating skeletal status in FAP patients with a documented APC mutation. Twenty-two FAP patients with a mean age of 42 years (54.5% women) were included in this study. Mean bone mineral density (BMD) Z-scores were significantly increased above normal at all measured sites: lumbar spine (p < .01), total hip (p < .01), femoral neck (p < .05), and trochanter (p < .01). Z-scores were +1 or greater in 14 patients (63.6%) and +2 or greater in 5 (22.7%). Mean values of bone turnover markers were within normal ranges. There was a significant positive correlation between procollagen type I N-terminal propeptide (P1NP) and β-crosslaps (β-CTX) (r = 0.70, p < .001) and between these markers and sclerostin and BMD measurements. We demonstrate that FAP patients display a significantly higher than normal mean BMD compared with age- and sex-matched healthy controls in the presence of a balanced bone turnover. Our data suggest a state of "controlled" activation of the Wnt signaling pathway in heterozygous carriers of APC mutations, most likely owing to upregulation of cytoplasmic β-catenin levels.
    Full-text · Article · Dec 2010 · Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research
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    ABSTRACT: previous studies have shown that the presence of stenosis alone on multislice computed tomography (MSCT) has a limited positive predictive value for the presence of ischemia on myocardial perfusion imaging (MPI). The purpose of this study was to assess which variables of atherosclerosis on MSCT angiography are related to ischemia on MPI. both MSCT and MPI were performed in 514 patients. On MSCT, the calcium score, degree of stenosis (≥ 50% and ≥ 70% stenosis), and plaque extent and location were determined. Plaque composition was classified as noncalcified, mixed, or calcified. Ischemia was defined as a summed difference score (≥ 2 on a per-patient basis. Ischemia was observed in 137 patients (27%). On a per-patient basis, multivariate analysis showed that the degree of stenosis (presence of (≥ 70% stenosis, odds ratio=3.5), plaque extent and composition (mixed plaques (≥3, odds ratio=1.7; calcified plaques ≥ 3, odds ratio=2.0), and location (atherosclerotic disease in the left main coronary artery and/or proximal left anterior descending coronary artery, odds ratio=1.6) were independent predictors for ischemia on MPI. In addition, MSCT variables of atherosclerosis, such as plaque extent, composition, and location, had significant incremental value for the prediction of ischemia over the presence of ≥70% stenosis. in addition to the degree of stenosis, MSCT variables of atherosclerosis describing plaque extent, composition, and location are predictive of the presence of ischemia on MPI.
    Preview · Article · Nov 2010 · Circulation Cardiovascular Imaging
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    ABSTRACT: Timing of acquisition is a factor that may influence the subdiaphragmatic activity in myocardial perfusion scintigraphy (MPS). According to the instructions of tetrofosmin, scintigraphy may already be started 15 minutes postinjection. The aim of the present study was to compare the image quality and the functional parameters between early and late scanning. Eventually, 49 consecutive patients underwent a 2-day MPS protocol in which 15 and 45 minutes after the injection of 500 MBq of technetium-99m-tetrofosmin scintigraphy both at stress and rest were performed. The amount of subdiaphragmatic tracer activity was scored from "no tracer activity" to "severe." Moderate and severe subdiaphragmatic tracer activity was considered relevant for the interpretation of the myocardial perfusion scan. Two-thirds of the patients (64%) showed a considerable amount of subdiaphragmatic activity on the 15 minutes rest images, whereas only 9 patients (18%) had considerable subdiaphragmatic activity on the late images. Stress imaging showed comparable results, however, subdiaphragmatic activity was generally less frequent and less prominent following stress. The value of the ejection fraction was significantly lower during early imaging comparing with late imaging. Lower ejection fraction was exclusively noticed in imaging with moderate and severe subdiaphragmatic tracer activity related wrong border estimation. Acquisition 15 minutes after the injection of Tetrofosmin shows a significant and clinically relevant subdiaphragmatic activity in most myocardial perfusion scans leading to poorer image quality and to an erroneous measurement of the ejection fraction. Therefore, early acquisition in MPS is not recommended in clinical practice.
    No preview · Article · Oct 2010 · Clinical nuclear medicine
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    ABSTRACT: The purpose of this study was to evaluate the prevalence of cardiac autonomic neuropathy (CAN) in a cohort of patients with type 2 diabetes, truly asymptomatic for coronary artery disease (CAD), using heart rate variability (HRV) and (123)I-metaiodobenzylguanidine ((123)I-mIBG) myocardial scintigraphy. The study group comprised 88 patients with type 2 diabetes prospectively recruited from an outpatient diabetes clinic. In all patients myocardial perfusion scintigraphy, CAN by HRV and (123)I-mIBG myocardial scintigraphy were performed. Two or more abnormal tests were defined as CAN-positive (ECG-based CAN) and one or fewer as CAN-negative. CAN assessed by (123)I-mIBG scintigraphy was defined as abnormal if the heart-to-mediastinum ratio was <1.8, the washout rate was >25%, or the total defect score was >13. The prevalence of CAN in patients asymptomatic for CAD with type 2 diabetes and normal myocardial perfusion assessed by HRV and (123)I-mIBG scintigraphy was respectively, 27% and 58%. Furthermore, in almost half of patients with normal HRV, (123)I-mIBG scintigraphy showed CAN. The current study revealed a high prevalence of CAN in patients with type 2 diabetes. Secondly, disagreement between HRV and (123)I-mIBG scintigraphy for the assessment of CAN was observed.
    Full-text · Article · Aug 2010 · European Journal of Nuclear Medicine
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    ABSTRACT: The purpose of this study was to evaluate whether 123-iodine metaiodobenzylguanidine (123-I MIBG) imaging predicts ventricular arrhythmias causing appropriate implantable cardioverter-defibrillator (ICD) therapy (primary end point) and the composite of appropriate ICD therapy or cardiac death (secondary end point). Although cardiac sympathetic denervation is associated with ventricular arrhythmias, limited data are available on the predictive value of sympathetic nerve imaging with 123-I MIBG on the occurrence of arrhythmias. Before ICD implantation, patients underwent 123-I MIBG and myocardial perfusion imaging. Early and late 123-I MIBG (planar and single-photon emission computed tomography [SPECT]) imaging was performed to assess cardiac innervation (heart-to-mediastinum ratio, cardiac washout rate, and 123-I MIBG SPECT defect score). Stress-rest myocardial perfusion imaging was performed to assess myocardial infarction and perfusion abnormalities (perfusion defect scores). During follow-up, appropriate ICD therapy and cardiac death were documented. One-hundred sixteen heart failure patients referred for ICD therapy were enrolled. During a mean follow-up of 23 +/- 15 months, appropriate ICD therapy (primary end point) was documented in 24 (21%) patients and appropriate ICD therapy or cardiac death (secondary end point) in 32 (28%) patients. Late 123-I MIBG SPECT defect score was an independent predictor for both end points. Patients with a large late 123-I MIBG SPECT defect (summed score >26) showed significantly more appropriate ICD therapy (52% vs. 5%, p < 0.01) and appropriate ICD therapy or cardiac death (57% vs. 10%, p < 0.01) than patients with a small defect (summed score </=26) at 3-year follow-up. Cardiac sympathetic denervation predicts ventricular arrhythmias causing appropriate ICD therapy as well as the composite of appropriate ICD therapy or cardiac death.
    Full-text · Article · Jun 2010 · Journal of the American College of Cardiology
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    Full-text · Article · Mar 2010 · Journal of the American College of Cardiology
  • Linda van der Veen · Arthur Scholte · Marcel Stokkel
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    ABSTRACT: (123)I-meta-iodobenzyl-guanidine ((123)I-MIBG) scintigraphy is used to visualize and quantify the sympathetic nerve activity. Although it has been used since 1980 to identify myocardial innervation, it is not yet regarded a routine sympathetic imaging agent in this respect. The lack of large multicentre studies and the presence of variations in the protocols that are used for planar MIBG acquisition confines the comparability of study results and application of normal values. Therefore, the aim of this study was to assess the variations in mathematical methods that are currently used to quantify the heart-to-mediastinum ratio and washout rate (WOR). In addition, normal values were evaluated in concordance with these methods. A systematic literature search yielded 169 unique manuscripts, of which 30 contained a complete description of the acquisition protocol for planar MIBG acquisition, image analysis and quantification of the parameters. The results indicate not only large variations in mathematical methods, but also in various aspects of the protocols that are used during acquisition. In many manuscripts method-specific normal values were used; however, these values were generally generated from small, single-centre studies. This study stresses the need to produce guidelines to achieve a standardized method for MIBG acquisition, image analysis and methods to quantify parameters.
    No preview · Article · Mar 2010 · Nuclear Medicine Communications
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    Preview · Article · Mar 2010 · Journal of the American College of Cardiology
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    ABSTRACT: In patients with diabetes mellitus, myocardial perfusion defects are often observed in the absence of obstructive epicardial coronary artery disease (CAD), thereby presenting a diagnostic problem. We hypothesized that these perfusion abnormalities may be explained by endothelial dysfunction or occult coronary atherosclerosis. Prospectively, 130 asymptomatic patients with diabetes mellitus underwent cardiovascular screening by coronary artery calcium (CAC) scoring, multislice CT coronary angiography, and myocardial perfusion imaging by SPECT. Multislice CT images were evaluated for the presence of obstructive epicardial CAD (>or=50% luminal narrowing). To quantify abnormal myocardial perfusion on SPECT images, we determined the summed stress score for each patient. The presence of abnormal myocardial perfusion was defined as a summed stress score of 3 or more. In addition, flow-mediated dilatation of the brachial artery, a marker of endothelial function, was determined using ultrasonography. In 35 patients (27%), obstructive epicardial CAD was observed on multislice CT, and these patients were excluded from further analysis. In the remaining 95 patients, abnormal myocardial perfusion was observed in 30 (32%) of patients. Flow-mediated dilatation was significantly lower in patients with abnormal myocardial perfusion (3.6% +/- 2.4%) than in those with normal myocardial perfusion (6.4% +/- 2.6%) (P < 0.001). Importantly, flow-mediated dilatation remained a significant predictor of the extent of abnormal myocardial perfusion after correction for cardiovascular risk factors and CAC score (P < 0.001). In contrast, no association was observed between nonobstructive plaque burden as reflected by CAC scores and extent of abnormal myocardial perfusion. In patients with diabetes mellitus, myocardial perfusion abnormalities in the absence of obstructive epicardial CAD are associated with endothelial dysfunction.
    Preview · Article · Nov 2009 · Journal of Nuclear Medicine
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    ABSTRACT: Identification of asymptomatic patients with type 2 diabetes at increased risk for coronary artery disease (CAD) remains a challenge. We evaluated the potential of carotid intima-media thickness (CIMT) for prediction of abnormal myocardial perfusion in this population. CIMT and SPECT myocardial perfusion imaging were assessed in 98 asymptomatic patients with type 2 diabetes. An increased CIMT was defined as > or =75th percentile of reference values. RESULTS Increased CIMT was an independent predictor of the extent of abnormal perfusion (P < 0.001). In patients with increased CIMT as compared with patients with normal CIMT, abnormal perfusion (75 vs. 9%) and severely abnormal perfusion (28 vs. 3%) were observed more frequently. Increased CIMT was significantly related to the presence and extent of abnormal myocardial perfusion. Assessment of CIMT may be useful to identify asymptomatic patients with type 2 diabetes at higher risk for CAD.
    Preview · Article · Nov 2009 · Diabetes care
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    ABSTRACT: The aim of the study was to evaluate the current role of (123)I-MIBG scintigraphy in the detection and follow-up of patients with paragangliomas. 117 patients were referred for diagnostic (123)I-MIBG scintigraphy based on a strong clinical suspicion, positive familial history and genetic testing, or for follow-up of paragangliomas.(123)I-MIBG images were analyzed and correlated with (111)In-octreotide scintigraphy, CT or MRI results. Accuracy of the imaging method was calculated per patient and per tumor per site. A total of 117 patients were referred for (123)I-MIBG diagnostic imaging; 80 patients were diagnosed with paraganglioma; 66 patients had a single neuroendocrine tumor and 14 patients multiple tumors. The total number of all lesions in these patients was 172. (123)I-MIBG scintigraphy demonstrated 65 lesions in 56 patients (overall sensitivity: 56.3%, specificity: 84%). Lesion-per-site analysis revealed that sensitivity and specificity significantly varied per tumor site (lowest sensitivity for the head and neck: 17.5% and lowest specificity for the abdomen: 87.5%). Hormones were elevated in 85 patients: 55 (123)I-MIBG tumors were positive and 35 tumors were negative. In 16 patients (13.7%) with a genetic burden and a single neuroendocrine tumor, (123)I-MIBG whole-body imaging was successful at detecting a second tumor. In 2 patients (1.7%) with paragangliomas, (123)I-MIBG unexpectedly detected metastases, so the restaging was properly done. (123)I-MIBG scintigraphy remains important in pheochromocytoma and functioning neuroendocrine tumors. The value of (123)I-MIBG scintigraphy is high in familial syndromes with multiple neuroendocrine tumors at different sites, multifocal tumors, and relapsing and metastatic disease.
    No preview · Article · Sep 2009 · Neuroendocrinology
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    ABSTRACT: Treatment options for patients with radioactive iodine (RaI) refractory metastases of differentiated thyroid carcinoma (DTC) are limited. We studied the effects of the multitarget tyrosine kinase inhibitor sorafenib on the reinduction of RaI uptake and tumor progression. Open, single center, single arm 26-week prospective phase II study with open-ended extension. We treated 31 patients with progressive metastatic or locally advanced RaI refractory DTC with sorafenib 400 mg b.i.d. The primary endpoint was reinduction of RaI uptake at 26 weeks. Additional endpoints were the radiological response and the influence of bone metastases. At 26 weeks of sorafenib therapy, no reinduction of RaI uptake at metastatic sites was observed, but 19 patients (59%) had a clinical beneficial response, eight of whom had a partial response (25%) and 11 had stable disease (34%). Seven patients had progressive disease (22%). Sorafenib was significantly less effective in patients with bone metastases. The estimated median progression free survival was 58 weeks (95% confidence interval, CI, 47-68). In general, thyroglobulin (Tg) response (both unstimulated and TSH stimulated) reflected radiological responses. The median time of the nadir of Tg levels was 3 months. Responses were not influenced by histological subtype, mutational status or other variables. No unusual side effects were observed. Sorafenib has a beneficial effect on tumor progression in patients with metastatic DTC, but was less effective in patients with bone metastases. Diagnostic whole body scintigraphy did not reveal an effect of sorafenib on the reinduction of RaI uptake.
    Preview · Article · Sep 2009 · European Journal of Endocrinology

Publication Stats

2k Citations
264.87 Total Impact Points

Institutions

  • 2012-2015
    • Netherlands Cancer Institute
      • Department of Nuclear Medicine
      Amsterdamo, North Holland, Netherlands
  • 2007-2010
    • Leiden University
      Leyden, South Holland, Netherlands
  • 1997-2010
    • Leiden University Medical Centre
      • • Department of Cardiology
      • • Department of Clinical Epidemiology
      Leyden, South Holland, Netherlands
  • 2008
    • University Medical Center Utrecht
      • Department of Image Processing
      Utrecht, Utrecht, Netherlands