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Janneke E Witteveen, Job Kievit, Hans Morreau, Johannes A Romijn and Neveen A T Hamdy

Objective

Cure rate for primary hyperparathyroidism (PHPT) is reported to be 94–100% 1 year after surgery, but recent data suggest recurrence in 4% of the patients 1–5 years post-operatively. The aim of our study was to establish the cure rate and its maintenance in the long-term after parathyroidectomy (PTx) in patients with sporadic PHPT.

Design

Evaluation of recurrence in patients with sporadic hyperparathyroidism who underwent PTx 1–24 years prior to the study.

Patients and methods

We identified 111 patients who underwent initial PTx between 1984 and 2008, and had no MEN-1, MEN-2, or CaR mutation; parathyroid carcinoma; a history of lithium use; or renal failure. Thirty-eight patients were lost to follow-up or were unwilling or unable to participate in the study. Cure was defined as maintenance of normal serum calcium and parathyroid hormone concentrations 6 months after PTx.

Results

Cure was achieved in 68 of 73 patients studied (93%) and was sustained in all for 6±5 years.

Conclusion

The cure rate of sporadic PHPT after initial surgery is 93%. When cure is achieved, this is sustained in 100% of the patients for up to 24 years post-operatively. Our data suggest that closer early follow-up is advocated in all patients undergoing PTx to definitively establish cure and to provide a safety net for those with residual gland pathology. The data do not support the need for long-term follow-up when cure is established 6 months after PTx.

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Ying Y Liu, Hans Morreau, Job Kievit, Johannes A Romijn, Nancy Carrasco and Johannes W Smit

Objectives

The microscopic distinction between benign and malignant thyroid lesions in clinical practice is still largely based on conventional histology. This study was performed to evaluate the diagnostic value of galectin-3 (Gal-3), Hector Battifora mesothelial-1 (HBME-1), cytokeratin (CK)-19, CBP P300-interacting transactivator with glutamic acid E- and aspartic acid D-rich C-terminal domain (CITED-1), fibronectin (FN)-1, peroxisome proliferator-activated receptor (PPAR)-γ, and intracellular sodium/iodide symporter (iNIS) immunostaining in a large panel of thyroid neoplasms. Our study differed from earlier ones with regard to the identification of optimal semiquantitative cut-off levels using receiver operator curve (ROC) analysis and hierarchical cluster analysis.

Methods

We used tissue arrays containing 177 thyroid tissues: 100 benign tissues (including normal thyroid, Graves disease, multinodular goiter, and follicular adenoma (FA)) and 77 thyroid carcinomas (including papillary thyroid carcinoma (PTC), follicular thyroid carcinoma, and follicular variant of PTC (FVPTC)). Antibody staining was scored semiquantitatively based on the ROC analyses and with hierarchical cluster analysis.

Results

In general, we found overexpression of FN-1, CITED-1, Gal-3, CK-19, HBME-1, and iNIS in malignant thyroid lesions. Gal-3, FN-1, and iNIS had the highest accuracy in the differential diagnosis of follicular lesions. A panel of Gal-3, FN-1, and iNIS, identified by hierarchical cluster analysis, had a 98% accuracy to differentiate between FA and malignant thyroid lesions. In addition, HBME-1 was found to be useful in the differentiation between FA and FVPTC (accuracy 88%).

Conclusion

We conclude that identifying optimal antibody panels with cluster analysis increases the diagnostic value in the differential diagnosis of thyroid neoplasms, the combination of FN-1, Gal-3, and iNIS having the best accuracy (98%).

Free access

Janneke E Witteveen, Job Kievit, Arian R van Erkel, Hans Morreau, Johannes A Romijn and Neveen A T Hamdy

Introduction

Localization studies are mandatory prior to revision surgery in patients with persistent hyperparathyroidism in order to improve surgical outcome and reduce the risk of lengthy explorations. However, in this case, noninvasive localization studies are reported to have a poor sensitivity. The aim of our study is to determine the accuracy of selective venous sampling (SVS) for parathyroid hormone (PTH) in localizing residual hyperactive parathyroid glands in patients with persistent or recurrent hyperparathyroidism.

Patients and methods

We retrospectively evaluated the localizing accuracy of 20 PTH SVS performed prior to revision surgery in 18 patients with persistent or recurrent primary hyperparathyroidism (n=11) or autonomous (tertiary) hyperparathyroidism (n=7). Tc99m-methoxy-isobutyle-isonitrile (MIBI)-single photon emission computed tomography (SPECT) was also performed in all patients prior to revision surgery. Operative and pathological data were obtained from hospital records.

Results

The SVS was able to accurately localize 15 of the 20 pathological glands removed at revision surgery, representing a sensitivity of 75%. This sensitivity is significantly higher than that of Tc99m-MIBI-SPECT, which was only 30% (P=0.012).

Conclusion

Our findings demonstrate that SVS is a valuable localization study in patients with persistent or recurrent hyperparathyroidism, with a sensitivity significantly higher than that of Tc99m-MIBI-SPECT. Our data suggest that SVS represents a useful addition to the preoperative workup of these patients prior to revision surgery.

Free access

Hendrieke C Hoftijzer, Ying Y Liu, Hans Morreau, Ton van Wezel, Alberto M Pereira, Eleonora P M Corssmit, Johannes A Romijn and Johannes W A Smit

Background

Although differential expression of retinoic acid receptor (RAR) subtypes between benign and malignant thyroid tissues has been described, their diagnostic value has not been reported.

Aim

To investigate the diagnostic accuracy of RAR and retinoid X receptor (RXR) subtype protein expression for the differential diagnosis of thyroid neoplasms.

Methods

We used a tissue array containing 93 benign thyroid tissues (normal thyroid, multinodular goiter, and follicular adenoma (FA)) and 77 thyroid carcinomas (papillary thyroid carcinoma (PTC), follicular thyroid carcinoma, and follicular variant of PTC (FVPTC)). Immunostaining was done for RAR and RXR subtypes. Staining was analyzed semiquantitatively based on receiver operating curve analyses and using hierarchical cluster analysis.

Results

We found increased expression of cytoplasmic (c) RARA, cRARG, cRXRB and decreased expression of nuclear (n) RARB, nRARG, and nRXRA in thyroid carcinomas compared with benign tissues. We found three proteins differently expressed between FA and FTC and five proteins differentially expressed between FA and FVPTC, with high diagnostic accuracies. Using cluster analysis, the combination of negative staining of membranous RXRB and positive staining for cRXRB had a high positive predictive value (98%) for malignant thyroid disease, whereas the combination of positive nRXRA and negative cRXRB staining had a high predictive value (91%) for benign thyroid lesions.

Conclusion

We conclude that differences in RAR and RXR subtype protein expression may be valuable for the differential diagnosis of thyroid neoplasms. The results of this study and especially the value of cluster analysis have to be confirmed in subsequent studies.

Free access

Ying Y Liu, Marcel P Stokkel, Alberto M Pereira, Eleonora P Corssmit, Hans A Morreau, Johannes A Romijn and Johannes W A Smit

Objective: Treatment options for metastases of differentiated thyroid carcinoma (DTC) are limited due to decreased uptake of radioiodide (I-131). Therefore, strategies to improve I-131 uptake are mandatory. It has been suggested that retinoids have beneficial effects on iodide uptake in vitro and in humans. However, to date, only studies with 13-cis-retinoic acid have been performed in humans. We therefore decided to study the effects of 6 weeks of treatment with the retinoid X receptor activator bexarotene on I-131 uptake in patients with metastatic DTC.

Design: Open prospective intervention study.

Methods: Twelve patients with metastases of DTC, with insufficient uptake of I-131, received 6 weeks of treatment with 300 mg bexarotene/day. Prior to, and after this intervention, I-131 uptake was measured by whole-body scintigraphy and single photon emission tomography (SPECT) 3 days after 185 MBq I-131. Diagnostic imaging was preceded by two consecutive injections of recombinant human TSH.

Results: Bexarotene treatment induced I-131 uptake in metastases of 8 out of 11 patients (one patient died for reasons not related to the study). However, uptake was only discernable at SPECT and had incomplete matching with metastases as visualized by CT scanning.

Conclusions: Bexarotene partially restores I-131 uptake in metastases of DTC. The clinical relevance of this observation may be limited due to the differential responses of the different metastases within each patient and the low intensity of I-131 uptake.

Free access

Hendrieke Hoftijzer, Karen A Heemstra, Hans Morreau, Marcel P Stokkel, Eleonora P Corssmit, Hans Gelderblom, Karin Weijers, Alberto M Pereira, Maya Huijberts, Ellen Kapiteijn, Johannes A Romijn and Johannes W Smit

Objective

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.

Design

Open, single center, single arm 26-week prospective phase II study with open-ended extension.

Methods

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.

Results

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.

Conclusions

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.

Restricted access

Karin van der Tuin, Marina Ventayol, Willem Corver, Midia Khalifa, Dina Ruano, E P Corssmit, Frederik J Hes, Thera P Links, Jan Smit, Theo S. Plantinga, E Kapiteijn, Ton Van Wezel and Hans Morreau

OBJECTIVE: Gene alterations leading to activation of the MAPK pathway are of interest for targeted therapy in patients with advanced radioactive iodine-refractory (RAI-R) thyroid carcinoma. Due to technical reasons gene fusion analysis in RNA isolated from formalin-fixed tumor tissues has till now been limited. The objective of the present study was to identify targetable gene rearrangements in RNA isolated from formalin-fixed RAI-R thyroid carcinomas.

DESIGN: Retrospective study in 132 patients with RAI-R thyroid carcinoma (59 papillary-, 24 follicular-, 35 Hürthle cell-, and 14 anaplastic thyroid carcinoma).

METHODS: Total nucleic acid (undivided DNA and RNA) was isolated from formalin-fixed tissue. Extensive gene fusion analysis was performed in all samples that tested negative for pathogenic BRAF, NRAS, HRAS and KRAS variants.

RESULTS: Seven targetable gene fusions were identified in the remaining 60 samples without known DNA variants. This includes frequently reported gene fusions such as CCDC6/RET [PTC1], PRKAR1A/RET [PTC2] and ETV6/NTRK3 (n=2), and gene fusions that are less common in thyroid cancer (TPM3/NTRK1, EML4/ALK and EML4/NTRK3). Of note, most gene fusions were detected in papillary thyroid carcinoma and MAPK-associated alterations in Hürthle cell carcinomas are rare (2/35).

CONCLUSION: Targetable gene fusions were found in 12% of RAI-R thyroid carcinoma without DNA variants, and can be effectively identified in formalin-fixed tissue. These gene fusionsmight provide a preclinical rationale to include specific kinase inhibitors in the treatment regimen for these patients. The latter intends to restore iodine transport and/or take advantage of the direct effect on tumor cell vitality once progressive disease is seen.

Free access

Ilse G C Hermsen, Harm R Haak, Ronald R de Krijger, Thomas M A Kerkhofs, Richard A Feelders, Wouter W de Herder, Hanneke Wilmink, Jan W A Smit, Hans Gelderblom, Noel F C C de Miranda, Ronald van Eijk, Tom van Wezel and Hans Morreau

Background

Adrenocortical carcinoma (ACC) is a rare disease with a poor prognosis and limited therapeutic options. Mitotane is considered the standard first-line therapy with only 30% of the patients showing objective tumour response. Defining predictive factors for response is therefore of clinical importance.

 The epidermal growth factor receptor (EGFR) has been implicated in the development of one-third of all malignancies. EGFR pathway members in ACC have been investigated, however, without available clinical data and relation to survival.

Methods

In this study, mutation status of EGFR and downstream signalling pathways was evaluated in 47 ACC patients on mitotane using direct sequencing, a TaqMan allele-specific assay and immunohistochemistry. Archival formalin-fixed paraffin-embedded tumour tissue was used for all analyses. Patient data were obtained anonymously, after coupling with the collected tumour tissue.

Results

One BRAF, two EGFR TK domain (c.2590G>A, p.864A>T) and 11 T P53, but no PIK3CA or KRAS, mutations were found. No relationship was found between mutation status, immunostaining and mitotane response or survival.

Conclusion

In conclusion, our data suggest that the role of EGFR tyrosine kinase inhibitors in ACC is limited. Treatment with EGFR monoclonal antibodies on the other hand might be beneficial for a larger group of patients. The possible efficacy of this therapy in ACC should be evaluated in future trials.

Free access

Thomas G Papathomas, Jose Gaal, Eleonora P M Corssmit, Lindsey Oudijk, Esther Korpershoek, Ketil Heimdal, Jean-Pierre Bayley, Hans Morreau, Marieke van Dooren, Konstantinos Papaspyrou, Thomas Schreiner, Torsten Hansen, Per Arne Andresen, David F Restuccia, Ingrid van Kessel, Geert J L H van Leenders, Johan M Kros, Leendert H J Looijenga, Leo J Hofland, Wolf Mann, Francien H van Nederveen, Ozgur Mete, Sylvia L Asa, Ronald R de Krijger and Winand N M Dinjens

Objective

Although the succinate dehydrogenase (SDH)-related tumor spectrum has been recently expanded, there are only rare reports of non-pheochromocytoma/paraganglioma tumors in SDHx-mutated patients. Therefore, questions still remain unresolved concerning the aforementioned tumors with regard to their pathogenesis, clinicopathological phenotype, and even causal relatedness to SDHx mutations. Absence of SDHB expression in tumors derived from tissues susceptible to SDH deficiency is not fully elucidated.

Design and methods

Three unrelated SDHD patients, two with pituitary adenoma (PA) and one with papillary thyroid carcinoma (PTC), and three SDHB patients affected by renal cell carcinomas (RCCs) were identified from four European centers. SDHA/SDHB immunohistochemistry (IHC), SDHx mutation analysis, and loss of heterozygosity analysis of the involved SDHx gene were performed on all tumors. A cohort of 348 tumors of unknown SDHx mutational status, including renal tumors, PTCs, PAs, neuroblastic tumors, seminomas, and adenomatoid tumors, was investigated by SDHB IHC.

Results

Of the six index patients, all RCCs and one PA displayed SDHB immunonegativity in contrast to the other PA and PTC. All immunonegative tumors demonstrated loss of the WT allele, indicating bi-allelic inactivation of the germline mutated gene. Of 348 tumors, one clear cell RCC exhibited partial loss of SDHB expression.

Conclusions

These findings strengthen the etiological association of SDHx genes with pituitary neoplasia and provide evidence against a link between PTC and SDHx mutations. Somatic deletions seem to constitute the second hit in SDHB-related renal neoplasia, while SDH x alterations do not appear to be primary drivers in sporadic tumorigenesis from tissues affected by SDH deficiency.