http://repub.eur.nl/res/aut/30820/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/33275/ 2011-10-01T00:00:00Z Context: Anticancer treatment with the tyrosine kinase inhibitor sunitinib causes thyroid dysfunction. Objective: Our objective was to investigate the time course and underlying mechanisms of sunitinib-induced thyroid dysfunction. Design: Thyroid function tests of 83 patients on sunitinib were collected retrospectively for their total treatment duration between January 2006 and November 2009 and prospectively in 15 patients on sunitinib for 10 wk. Additionally, thyroid function and histology were assessed in rats on sunitinib (8 d; n = 10) and after sunitinib withdrawal (11 d; n = 7) and compared with controls (n = 7). Setting: Patients were seen at a university outpatient oncology clinic. Patients and Animals: Patients with metastatic renal cell carcinoma or gastrointestinal stromal tumors participated in the clinical study and Wistar Kyoto rats were used in the rat study. Intervention: Sunitinib was taken according to a 4 wk "on," 2 wk "off" treatment regimen. Blood samples for measurement of thyroid function were collected at baseline and at wk 4 and 10. In rats, blood, liver, and thyroid were collected to assess thyroid hormones, deiodinase activity, and thyroid histology. Main Outcome Measures: TSH and free T4levels, deiodinase activity, and thyroid histology were assessed. Results: Forty-two percent of patients in the retrospective study developed elevated TSH levels. Prospective analysis showed increased TSH levels within 10 wk of treatment, accompanied by a decreased T3/rT3ratio. In rats, serum T4and T3decreased, hepatic type 3 deiodinase activity increased, andthyroid histology showed marked capillary regression, which all but thyroid hormones reversed after sunitinib withdrawal. Conclusion: Sunitinib induces hypothyroidism due to alterations in T4/T3metabolism as well as thyroid capillary regression. Copyright http://repub.eur.nl/res/pub/31460/ 2011-08-01T00:00:00Z Objective: Over 90% of all cervical adenocarcinoma are caused by a transforming infection with a high-risk type human papillomavirus (hrHPV). Previous studies demonstrated that the association between hrHPV positivity and cervical clear-cell adenocarcinoma (CCAC) varies between 0% and 100%. As approximately 60% of all CCAC are associated with intra-uterine diethylstilbestrol (DES) exposure, we determined in a cohort of both DES-exposed and DES-unexposed women the prevalence of hrHPV infections, and the potential etiological role of hrHPV by additional analysis of p16INK4a and p53 expression. Methods: Representative slides of 28 women diagnosed with CCAC were tested for hrHPV by two PCR methods (the clinically validated GP5+/6+ PCR and the very sensitive SPF10PCR/LiPA25). Fifteen women were DES-exposed, 10 unexposed and of 3 women DES-exposure was unknown. Twenty-one cases with sufficient material were immuno-histochemically stained for p16INK4a and p53. Results: Seven tumors, of which four DES-exposed and two unexposed tested positive for hrHPV with GP5+/6+ PCR. Thirteen tumors, of which five DES-exposed and seven unexposed, tested positive with SPF10PCR/ LiPA25. In one women with unknown exposure, a CCAC tested positive in both assays. Only three cases, none in DES-exposed women, and all positive with both hrHPV assays, revealed diffuse p16INK4a immuno-staining and weak p53 staining as well, supporting indisputable hrHPV involvement. Conclusions: Although the prevalence of hrHPV was high, only two DES-unrelated CCAC (25%) and one tumor in a woman with unknown exposure could be attributed to hrHPV. http://repub.eur.nl/res/pub/33641/ 2011-08-01T00:00:00Z Angiogenesis inhibition is an established treatment for several tumor types. Unfortunately, this therapy is associated with adverse effects, including hypertension and renal toxicity, referred to as "preeclampsia." Recently, we demonstrated in patients and in rats that the multitarget tyrosine kinase inhibitor sunitinib induces a rise in blood pressure (BP), renal dysfunction, and proteinuria associated with activation of the endothelin system. In the current study we investigated the effects of sunitinib on rat renal histology, including the resemblance with preeclampsia, as well as the roles of endothelin 1, decreased nitric oxide (NO) bioavailability, and increased oxidative stress in the development of sunitinib-induced hypertension and renal toxicity. In rats on sunitinib, light and electron microscopic examination revealed marked glomerular endotheliosis, a characteristic histological feature of preeclampsia, which was partly reversible after sunitinib discontinuation. The histological abnormalities were accompanied by an increase in urinary excretion of endothelin 1 and diminished NO metabolite excretion. In rats on sunitinib alone, BP increased (ΔBP: 31.6±0.9 mm Hg). This rise could largely be prevented with the endothelin receptor antagonist macitentan (ΔBP: 12.3±1.5 mm Hg) and only mildly with Tempol, a superoxide dismutase mimetic (ΔBP: 25.9±2.3 mm Hg). Both compounds could not prevent the sunitinib-induced rise in serum creatinine or renal histological abnormalities and had no effect on urine nitrates but decreased proteinuria and urinary endothelin 1 excretion. Our findings indicate that both the endothelin system and oxidative stress play important roles in the development of sunitinib-induced proteinuria and that the endothelin system rather than oxidative stress is important for the development of sunitinib-induced hypertension. http://repub.eur.nl/res/pub/28328/ 2010-12-01T00:00:00Z Background: Our aim was to evaluate the diagnostic accuracy of fine-needle aspiration cytology (FNAC) for Warthin tumors of the parotid gland. Methods All cytologic diagnoses of Warthin tumor between 1990 and 2007 were correlated with available histology. In addition, our results were compared to current literature. Results In 310 cases, Warthin tumor was diagnosed by FNAC. In 133 cases, (43%) both cytology and histology were available. In 127 of these 133 cases (95.5%), the diagnosis Warthin tumor was confirmed by histology. In 4 cases (3%), a benign lesion was diagnosed and 2 (1.5%) revealed a malignant lesion. On review, those cytologic diagnoses were not certain. In the literature, 11 missed malignancies (5.4%) in 202 cases were reported. Conclusion The diagnostic accuracy of FNAC for the diagnosis of Warthin tumor is high and the percentage of missed malignant tumors is very low. Our results imply that a cytologic diagnosis of Warthin tumor may justify conservative treatment. http://repub.eur.nl/res/pub/24453/ 2009-12-01T00:00:00Z Purpose: Computerized tomography and ultrasound are usually sufficient for preoperative evaluation of renal masses greater than 5 cm. For renal masses less than 5 cm additional histological evaluation could improve diagnosis and treatment decisions. We investigated the concordance between an improved agar microbiopsy technique and conventional cytology for diagnosing renal tumors. Materials and Methods: We performed fine needle aspiration in 40 renal masses after nephrectomy using a 22 gauge needle, obtaining multiple blind aspirations from the tumor surrounded by Gerota's fascia. Four conventional smears were prepared from each aspiration. An alcohol Carbowax™ solution was drawn up in the syringe and expelled in a vial. The fluid in the vial was processed according to our modified agar microbiopsy method using an additional cycle of centrifuging the hot sediment mixed in agar. Histological sections were prepared for light microscopy and immunohistochemistry. Cytology smears and agar microbiopsy sections were evaluated by 2 pathologists blinded to the definitive histological diagnosis. Results: The series consisted of 28 renal cell carcinomas, including 25 clear cell, 2 chromophobe and 1 papillary lesions, 7 urothelial cell carcinomas, 3 oncocytomas, 1 angiomyolipoma and 1 unclassified malignant tumor. Agar microbiopsy was concordant with the final histological diagnosis in 39 of 40 cases (correlation 0.98). Classic cytology was concordant with definitive histology in 21 of 40 cases (correlation 0.52). In 5 of 40 cases cytology identified malignancy but did not subtype the tumor correctly. Of the aspirates 15% contained too few diagnostic cells. Conclusions: Ex vivo fine needle aspiration using an improved agar microbiopsy block technique is highly concordant (98%) with the final diagnosis and subclassification of renal masses. Future validation using an in vivo pretreatment setting is needed to determine its clinical value.