Publications by authors named "Mariëtte E G Kranendonk"

11 Publications

  • Page 1 of 1

Testis Sparing Surgery in Pediatric Testicular Tumors.

Cancers (Basel) 2020 Oct 6;12(10). Epub 2020 Oct 6.

Princess Máxima Center for Pediatric Oncology, 3584 Utrecht, The Netherlands.

Objective: The purpose of this review is to evaluate the outcomes of testis sparing surgery (TSS) and to investigate under which circumstances TSS can be considered a safe treatment option in pediatric patients with testicular tumors.

Methods: A database search was performed in Cochrane, Pubmed, and Embase for studies that focused on TSS as treatment for testicular tumors in the pediatric population, excluding reviews and single case reports.

Results: Twenty studies, describing the surgical treatment of 777 patients with testicular tumors, were included in the analysis. The majority of pediatric patients with benign germ cell tumors (GCTs) (mean age: 3.7 years) and sex cord-stromal tumors (SCSTs) (mean age: 6.6 years) were treated with TSS, 61.9% and 61.2%, respectively. No cases of testicular atrophy occurred. Four of the benign GCTs, i.e., three teratomas and one epidermoid cyst, recurred. No cases of recurrence were reported in patients with SCSTs. Of the 243 malignant GCTs (mean age: 4.2 years), only one patient had TSS (0.4%).

Conclusion: TSS is a safe treatment option for prepubertal patients less than 12 years of age with benign GCTs and low grade SCSTs.
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http://dx.doi.org/10.3390/cancers12102867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600997PMC
October 2020

The decisive role of molecular pathology in presumed somatic metastases of type II testicular germ cell tumors: report of 2 cases.

Diagn Pathol 2020 Jul 25;15(1):99. Epub 2020 Jul 25.

Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.

Background: Molecular diagnostics can be decisive in the differential diagnosis between a somatic metastasis of type II testicular germ cell tumor (TGCT) or a second primary carcinoma. This is in line with recent recommendations from the International Society of Urological Pathology, based on an international survey which showed that molecular testing is currently only performed by a minority of urological pathologists.

Case Presentations: This case report illustrates the necessity of molecular testing in two patients with a history of type II TGCT and a metastatic (retro) peritoneal carcinoma years later. The genetic hallmark of type II TGCT, chromosome 12p gain, was studied by fluorescence in situ hybridization and whole genome methylation profiling in case 1, and by single nucleotide polymorphism (SNP)-array in case 2. Next generation sequencing (NGS) was used to further explore clonality between the primary TGCT and peritoneal metastasis in case 2. In case 1, chromosome 12p gain was found in the primary type II TGCT and in the acinar cell carcinoma of the metastatic malignancy. In case 2, SNP array showed 12p gain in the epithelial component of the primary teratomatous TGCT but not in the peritoneal adenocarcinoma. Furthermore, NGS showed no mutations in the primary teratomatous TGCT but a KRAS and GNAS mutation in the peritoneal adenocarcinoma, suggestive of an appendicular origin.

Conclusions: Without the molecular data, both cases would have been regarded as a metastatic TGCT with development of somatic-type malignancy, which appeared a wrong diagnosis for case 2. These cases demonstrate the importance of molecular methods as an adjunct in today's pathology practice.
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http://dx.doi.org/10.1186/s13000-020-01011-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382836PMC
July 2020

Tumor-Specific Uptake of Fluorescent Bevacizumab-IRDye800CW Microdosing in Patients with Primary Breast Cancer: A Phase I Feasibility Study.

Clin Cancer Res 2017 Jun 9;23(11):2730-2741. Epub 2016 Nov 9.

Department of Surgery, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

To provide proof of principle of safety, breast tumor-specific uptake, and positive tumor margin assessment of the systemically administered near-infrared fluorescent tracer bevacizumab-IRDye800CW targeting VEGF-A in patients with breast cancer. Twenty patients with primary invasive breast cancer eligible for primary surgery received 4.5 mg bevacizumab-IRDye800CW as intravenous bolus injection. Safety aspects were assessed as well as tracer uptake and tumor delineation during surgery and in surgical specimens using an optical imaging system. multiplexed histopathology analyses were performed for evaluation of biodistribution of tracer uptake and coregistration of tumor tissue and healthy tissue. None of the patients experienced adverse events. Tracer levels in primary tumor tissue were higher compared with those in the tumor margin ( < 0.05) and healthy tissue ( < 0.0001). VEGF-A tumor levels also correlated with tracer levels ( = 0.63, < 0.0002). All but one tumor showed specific tracer uptake. Two of 20 surgically excised lumps contained microscopic positive margins detected by fluorescent macro- and microscopy and confirmed at the cellular level. Our study shows that systemic administration of the bevacizumab-IRDye800CW tracer is safe for breast cancer guidance and confirms tumor and tumor margin uptake as evaluated by a systematic validation methodology. The findings are a step toward a phase II dose-finding study aimed at margin assessment and point to a novel drug assessment tool that provides a detailed picture of drug distribution in the tumor tissue. .
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http://dx.doi.org/10.1158/1078-0432.CCR-16-0437DOI Listing
June 2017

Threshold Analysis and Biodistribution of Fluorescently Labeled Bevacizumab in Human Breast Cancer.

Cancer Res 2017 02 22;77(3):623-631. Epub 2016 Nov 22.

Chair for Biological Imaging, Technical University of Munich, München, Germany.

In vivo tumor labeling with fluorescent agents may assist endoscopic and surgical guidance for cancer therapy as well as create opportunities to directly observe cancer biology in patients. However, malignant and nonmalignant tissues are usually distinguished on fluorescence images by applying empirically determined fluorescence intensity thresholds. Here, we report the development of fSTREAM, a set of analytic methods designed to streamline the analysis of surgically excised breast tissues by collecting and statistically processing hybrid multiscale fluorescence, color, and histology readouts toward precision fluorescence imaging. fSTREAM addresses core questions of how to relate fluorescence intensity to tumor tissue and how to quantitatively assign a normalized threshold that sufficiently differentiates tumor tissue from healthy tissue. Using fSTREAM we assessed human breast tumors stained in vivo with fluorescent bevacizumab at microdose levels. Showing that detection of such levels is achievable, we validated fSTREAM for high-resolution mapping of the spatial pattern of labeled antibody and its relation to the underlying cancer pathophysiology and tumor border on a per patient basis. We demonstrated a 98% sensitivity and 79% specificity when using labeled bevacizumab to outline the tumor mass. Overall, our results illustrate a quantitative approach to relate fluorescence signals to malignant tissues and improve the theranostic application of fluorescence molecular imaging. Cancer Res; 77(3); 623-31. ©2016 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-16-1773DOI Listing
February 2017

Inflammatory characteristics of distinct abdominal adipose tissue depots relate differently to metabolic risk factors for cardiovascular disease: distinct fat depots and vascular risk factors.

Atherosclerosis 2015 Apr 2;239(2):419-27. Epub 2015 Feb 2.

Department of Vascular Medicine, University Medical Center Utrecht (UMC Utrecht), Utrecht, The Netherlands. Electronic address:

Objective: Abdominal obesity is associated with insulin resistance and metabolic syndrome. However, specific contributions of distinct adipose tissue (AT) depots to metabolic complications of obesity are still unclear. In this study, the inflammatory profile of four distinct abdominal AT-depots and the relation between AT-characteristics and obesity-induced metabolic complications was evaluated.

Methods: In 28 men undergoing abdominal aortic surgery, biopsies were collected from subcutaneous fat (SAT), and 3 visceral AT-depots: mesenteric (MAT), omental (OAT) and periaortic (PAT). The AT biopsies were characterized morphologically (adipocyte size, capillary density, CD68 + macrophages and crown-like-structures (CLS)) and the ex vivo adipokine secretion profile was determined by multiplex-immunoassay. The relation between depot-specific inflammatory characteristics and clinical parameters (waist circumference, insulin resistance and metabolic syndrome) was assessed by multivariable linear regression analysis.

Results: PAT contained the smallest adipocytes, highest capillary density and secreted abundant amounts of adipokines. SAT contained the lowest amount of macrophages and adipokines, while MAT and OAT displayed a similar inflammatory profile. In contrast to the other depots, MAT inflammation was most strongly related to metabolic complications of obesity, as adipocyte size and CLS were related to insulin resistance (β2.0; 95%CI1.15-2.85 and β0.24; 95%CI0.06-0.43) and MAT adipocyte size was associated with 79% higher odds of having metabolic syndrome (OR1.79; 95% CI1.13-2.89).

Conclusions: There are significant differences in the inflammatory profile of distinct abdominal fat depots, of which MAT characteristics were mostly associated with metabolic complications of obesity. These findings suggest a differential contribution of AT-depots to systemic metabolic dysfunction which precedes type 2 diabetes and vascular diseases.
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http://dx.doi.org/10.1016/j.atherosclerosis.2015.01.035DOI Listing
April 2015

Effect of extracellular vesicles of human adipose tissue on insulin signaling in liver and muscle cells.

Obesity (Silver Spring) 2014 Oct 17;22(10):2216-23. Epub 2014 Jul 17.

Department of Vascular Medicine, University Medical Center Utrecht (UMC Utrecht), Utrecht, The Netherlands; Molecular Cancer Research, Center for Molecular Medicine, UMC Utrecht, Utrecht, The Netherlands.

Objective: Insulin resistance (IR) is a key mechanism in obesity-induced cardiovascular disease. To unravel mechanisms whereby human adipose tissue (AT) contributes to systemic IR, the effect of human AT-extracellular vesicles (EVs) on insulin signaling in liver and muscle cells was determined.

Methods: EVs released from human subcutaneous (SAT) and omental AT (OAT)-explants ex vivo were used for stimulation of hepatocytes and myotubes in vitro. Subsequently, insulin-induced Akt phosphorylation and expression of gluconeogenic genes (G6P, PEPCK) was determined. AT-EV adipokine levels were measured by multiplex immunoassay, and AT-EVs were quantified by high-resolution flow cytometry.

Results: In hepatocytes, AT-EVs from the majority of patients inhibited insulin-induced Akt phosphorylation, while EVs from some patients stimulated insulin-induced Akt phosphorylation. In myotubes AT-EVs exerted an ambiguous effect on insulin signaling. Hepatic Akt phosphorylation related negatively to G6P-expression by both SAT-EVs (r = -0.60, P = 0.01) and OAT-EVs (r = -0.74, P = 0.001). MCP-1, IL-6, and MIF concentrations were higher in OAT-EVs compared to SAT-EVs and differently related to lower Akt phosphorylation in hepatocytes. Finally, the number of OAT-EVs correlated positively with liver enzymes indicative for liver dysfunction.

Conclusions: Human AT-EVs can stimulate or inhibit insulin signaling in hepatocytes- possibly depending on their adipokine content- and may thereby contribute to systemic IR.
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http://dx.doi.org/10.1002/oby.20847DOI Listing
October 2014

Extracellular vesicle markers in relation to obesity and metabolic complications in patients with manifest cardiovascular disease.

Cardiovasc Diabetol 2014 Feb 5;13:37. Epub 2014 Feb 5.

Department of Vascular Medicine, University Medical Centre Utrecht (UMCU), F02,126, Heidelberglaan 100, Utrecht 3584 CX, The Netherlands.

Background: Alterations in extracellular vesicles (EVs), including exosomes and microparticles, contribute to cardiovascular disease. We hypothesized that obesity could favour enhanced release of EVs from adipose tissue, and thereby contribute to cardiovascular risk via obesity-induced metabolic complications. The objectives of this study were: 1) to investigate the relation between the quantity, distribution and (dys) function of adipose tissue and plasma concentrations of atherothrombotic EV-markers; 2) to determine the relation between these EV-markers and the prevalence of the metabolic syndrome; and 3) to assess the contribution of EV markers to the risk of incident type 2 diabetes.

Methods: In 1012 patients with clinically manifest vascular disease, subcutaneous and visceral fat thickness was measured ultrasonographically. Plasma EVs were isolated and levels of cystatin C, serpin G1, serpin F2 and CD14 were measured, as well as fasting metabolic parameters, hsCRP and adiponectin. The association between adiposity, EV-markers, and metabolic syndrome was tested by multivariable linear and logistic regression analyses. As sex influences body fat distribution, sex-stratified analyses between adipose tissue distribution and EV-markers were performed. The relation between EV-markers and type 2 diabetes was assessed with Cox regression analyses.

Results: Higher levels of hsCRP (β 5.59; 95% CI 3.00-8.18) and lower HDL-cholesterol levels (β-11.26; 95% CI -18.39 - -4.13) were related to increased EV-cystatin C levels, and EV-cystatin C levels were associated with a 57% higher odds of having the metabolic syndrome (OR 1.57; 95% CI 1.19-2.27). HDL-cholesterol levels were positively related to EV-CD14 levels (β 5.04; 95% CI 0.07-10.0), and EV-CD14 levels were associated with a relative risk reduction of 16% for development of type 2 diabetes (HR 0.84, 95% CI 0.75-0.94), during a median follow up of 6.5 years in which 42 patients developed type 2 diabetes.

Conclusions: In patients with clinically manifest vascular disease, EV-cystatin C levels were positively related, and EV-CD14 levels were negatively related to metabolic complications of obesity.
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http://dx.doi.org/10.1186/1475-2840-13-37DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3918107PMC
February 2014

An oral mixed fat load is followed by a modest anti-inflammatory adipocytokine response in overweight patients with metabolic syndrome.

Lipids 2014 Mar 21;49(3):247-54. Epub 2014 Jan 21.

Department of Vascular Medicine, University Medical Center Utrecht, PO Box 85500, 3508 GA, Utrecht, The Netherlands,

We investigated the postprandial changes in plasma levels of adipocytokines in overweight patients with metabolic syndrome after an oral fat load. After an oral fat load and during a prolonged fast, blood was drawn at 0, 2, 3, 4 and 8 h for measurement of adiponectin, adipsin, cathepsin S, chemerin, hepatic growth factor, interferon-γ-inducible protein-10, leptin, macrophage chemoattractant protein-1, macrophage migration inhibitory factor, nerve growth factor, retinol binding protein-4, resistin, serum amyloid A1, tissue inhibitor of metalloproteinase-1 and thrombopoietin using a microbead-based Luminex assay. Area under the curves (AUC) were calculated and compared. Plasma adiponectin levels were higher after an oral fat load compared to fasting at t = 2 h (950 ± 513 vs. -1,881 ± 713 ng/ml) while the plasma levels for adipsin (-9 ± 5 vs. 16 ± 5 ng/ml), chemerin (-122 ± 35 vs. 13 ± 21 ng/ml), SAA-1 (-391 ± 213 vs. 522 ± 173 ng/ml) and TPO (-335 ± 144 vs. 622 ± 216 ng/ml) were lower after an oral fat load compared to fasting. The baseline corrected AUC for IP-10 was higher after fat load compared to fasting (median -116 pg h/ml; IQR -270 to 10 vs. -21 pg h/ml; IQR -136 to 418 (p = 0.047). In conclusion, in overweight male subjects with the metabolic syndrome, an oral fat load is accompanied with a modest anti-inflammatory response of adipose tissue-derived adipocytokines.
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http://dx.doi.org/10.1007/s11745-014-3877-8DOI Listing
March 2014

Human adipocyte extracellular vesicles in reciprocal signaling between adipocytes and macrophages.

Obesity (Silver Spring) 2014 May 9;22(5):1296-308. Epub 2014 Jan 9.

Department of Vascular Medicine, University Medical Center Utrecht (UMC Utrecht), Utrecht, The Netherlands; Section Metabolic Diseases, Molecular Cancer Research, UMC Utrecht, Utrecht, The Netherlands.

Objective: Extracellular vesicles (EVs) released by human adipocytes or adipose tissue (AT)-explants play a role in the paracrine interaction between adipocytes and macrophages, a key mechanism in AT inflammation, leading to metabolic complications like insulin resistance (IR) were determined.

Methods: EVs released from in vitro differentiated adipocytes and AT-explants ex vivo were characterized by electron microscopy, Western blot, multiplex adipokine-profiling, and quantified by flow cytometry. Primary monocytes were stimulated with EVs from adipocytes, subcutaneous (SCAT) or omental-derived AT (OAT), and phenotyped. Macrophage supernatant was subsequently used to assess the effect on insulin signaling in adipocytes.

Results: Adipocyte and AT-derived EVs differentiated monocytes into macrophages characteristic of human adipose tissue macrophages (ATM), defined by release of both pro- and anti-inflammatory cytokines. The adiponectin-positive subset of AT-derived EVs, presumably representing adipocyte-derived EVs, induced a more pronounced ATM-phenotype than the adiponectin-negative AT-EVs. This effect was more evident for OAT-EVs versus SCAT-EVs. Furthermore, supernatant of macrophages pre-stimulated with AT-EVs interfered with insulin signaling in human adipocytes. Finally, the number of OAT-derived EVs correlated positively with patients HOMA-IR.

Conclusions: A possible role for human AT-EVs in a reciprocal pro-inflammatory loop between adipocytes and macrophages, with the potential to aggravate local and systemic IR was demonstrated.
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http://dx.doi.org/10.1002/oby.20679DOI Listing
May 2014

Mouse telomerase reverse transcriptase (mTert) expression marks slowly cycling intestinal stem cells.

Proc Natl Acad Sci U S A 2011 Jan 20;108(1):179-84. Epub 2010 Dec 20.

Division of Gastroenterology, Children's Hospital Boston, Boston, MA 02115, USA.

The intestinal epithelium is maintained by a population of rapidly cycling (Lgr5(+)) intestinal stem cells (ISCs). It has been postulated, however, that slowly cycling ISCs must also be present in the intestine to protect the genome from accumulating deleterious mutations and to allow for a response to tissue injury. Here, we identify a subpopulation of slowly cycling ISCs marked by mouse telomerase reverse transcriptase (mTert) expression that can give rise to Lgr5(+) cells. mTert-expressing cells distribute in a pattern along the crypt-villus axis similar to long-term label-retaining cells (LRCs) and are resistant to tissue injury. Lineage-tracing studies demonstrate that mTert(+) cells give rise to all differentiated intestinal cell types, persist long term, and contribute to the regenerative response following injury. Consistent with other highly regenerative tissues, our results demonstrate that a slowly cycling stem cell population exists within the intestine.
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http://dx.doi.org/10.1073/pnas.1013004108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3017192PMC
January 2011

Dynamics of human respiratory virus-specific CD8+ T cell responses in blood and airways during episodes of common cold.

J Immunol 2008 Oct;181(8):5551-9

Division of Paediatrics, Wilhelmina Children's Hospital, Utrecht, The Netherlands.

We determined the dynamics of CD8(+) T cells specific for influenza virus and respiratory syncytial virus in blood and tracheostoma aspirates of children during the course of respiratory infections. We showed that during localized respiratory infections the ratio of activated effector CD8(+) T cells to resting memory/naive CD8(+) T cells in peripheral blood increased significantly. Furthermore, the number of effector/memory T cells specific for respiratory viruses declined in blood and increased in the airways, suggesting that these T cells redistributed from blood to airways. T cells specific for the infecting virus were present in the airways for longer periods at increased levels than nonspecifically recruited bystander T cells. After clearance of the infection, the ratio of resting memory and naive CD8(+) T cells normalized in peripheral blood and also memory T cell numbers specific for unrelated viruses that declined during the infection due to bystander recruitment were restored. Taken together, these results showed a significant systemic T cell response during relatively mild secondary infections and extensive dynamics of virus-specific and nonspecific Ag-experienced T cells.
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http://dx.doi.org/10.4049/jimmunol.181.8.5551DOI Listing
October 2008