Neuroendocrine tumor (NET) entities are rare malignancies. Higher awareness and improved diagnost... more Neuroendocrine tumor (NET) entities are rare malignancies. Higher awareness and improved diagnostic methods have led to an increasing incidence of these diseases, and most oncologists deal with such patients in their daily practice. The symposium on NETs that was held in Merano (Italy) in October 2009 was organized by the German-speaking European School of Oncology (dESO) and gathered specialists from different disciplines of transalpine countries to bring together experiences and observations regarding these tumors. The goal of the meeting and of this review was to illustrate both well- and poorly differentiated NETs and to encourage interdisciplinary approaches.
Die Diagnostik neuroendokriner Neoplasien des Pankreas (PanNEN) hat in den letzten Jahren v. a. i... more Die Diagnostik neuroendokriner Neoplasien des Pankreas (PanNEN) hat in den letzten Jahren v. a. im Bereich der WHO-Klassifikation, der TNM-Einteilung sowie der Gradierung Veränderungen erfahren. Zudem wurden einzelne neue diagnostische sowie prädiktive immunhistochemische Marker eingeführt. Die meisten Fortschritte wurden auf der Ebene der molekularen Pathogenese von PanNEN erzielt. Mittels „next generation sequencing“ wurden der „mammalian target of rapamycin (mTOR) pathway“, Hypoxie, aber auch epigenetische Veränderungen als wichtige tumorigene Mechanismen identifiziert. Im vorliegenden Artikel werden die wichtigsten Entwicklungen in der morphologischen und immunhistochemischen Diagnostik von PanNEN und deren molekularer Hintergrund beleuchtet. Abstract The diagnostics of pancreatic neuroendocrine tumors (PanNEN) have changed in recent years especially concerning the World Health Organization (WHO) classification, TNM staging and grading. Furthermore, some new prognostic and predi...
The Journal of Clinical Endocrinology & Metabolism, 2010
Through overexpression and aberrant activation in many human tumors, the IGF system plays a key r... more Through overexpression and aberrant activation in many human tumors, the IGF system plays a key role in tumor development and tumor cell proliferation. Different strategies targeting IGF-I receptor (IGFI-R) have been developed, and recent studies demonstrated that combined treatments with cytostatic drugs enhance the potency of anti-IGFI-R therapies. The objective of the study was to examine the IGFI-R expression status in neuroendocrine tumors of the gastroenteropancreatic system (GEP-NETs) in comparison with healthy tissues and use potential overexpression as a target for novel anti-IGFI-R immunoliposomes. A human tumor tissue array and samples from different normal tissues were investigated by immunohistochemistry. An IGFI-R antagonistic antibody (1H7) was coupled to the surface of sterically stabilized liposomes loaded with doxorubicin. Cell lines from different tumor entities were investigated for liposomal association studies in vitro. For in vivo experiments, neuroendocrine tumor xenografts were used for evaluation of pharmacokinetic and therapeutic properties of the novel compound. Immunohistochemistry revealed significant IGFI-R overexpression in all investigated GEP-NETs (n = 59; staining index, 229.1 +/- 3.1%) in comparison with normal tissues (115.7 +/- 3.7%). Furthermore, anti-IGFI-R immunoliposomes displayed specific tumor cell association (44.2 +/- 1.6% vs. IgG liposomes, 0.8 +/- 0.3%; P < 0.0001) and internalization in human neuroendocrine tumor cells in vitro and superior antitumor efficacy in vivo (life span 31.5 +/- 2.2 d vs. untreated control, 19 +/- 0.6, P = 0.008). IGFI-R overexpression seems to be a common characteristic of otherwise heterogenous NETs. Novel anti-IGFI-R immunoliposomes have been developed and successfully tested in a preclinical model for human GEP-NETs. Moreover in vitro experiments indicate that usage of this agent could also present a promising approach for other tumor entities.
mucosa. Gastrin and its derivates have been reported to regulate epithelial cell proliferation, m... more mucosa. Gastrin and its derivates have been reported to regulate epithelial cell proliferation, migration, and differentiation. Mutations in the epithelial cadherin (E-cadherin) gene have been shown to be associated with the occurrence of diffuse gastric carcinomas in af- fected families. Objective: In this study we investigated the histopathological and molecular findings in the gastrointestinal wall of a patient with mul-
The tall cell variant of papillary thyroid carcinoma (PTC) has an unfavorable prognosis. The diag... more The tall cell variant of papillary thyroid carcinoma (PTC) has an unfavorable prognosis. The diagnostic criteria remain inconsistent and the role of a minor tall cell (TC) component is unclear. Molecular diagnostic markers are not available; however, there are two potential candidates: BRAF V600E and TERT promoter mutations. Using a novel approach, we enriched a collective with PTC harboring an adverse outcome, overcoming the limited statistical power of most studies. This enabled us to review 125 PTC patients, 57 of them with an adverse outcome. The proportion of TC that constitute a poor prognosis was assessed. All tumors underwent sequencing for TERT promoter and BRAF V600E mutational status and were stained with an antibody detecting the BRAF V600E mutation. A 10% cut off for TC was significantly associated with advanced tumor stage and lymph node metastasis. Multivariate analysis showed that tall cells above 10% were the only significant factor for overall, tumor-specific and r...
Neuroendocrine tumor (NET) entities are rare malignancies. Higher awareness and improved diagnost... more Neuroendocrine tumor (NET) entities are rare malignancies. Higher awareness and improved diagnostic methods have led to an increasing incidence of these diseases, and most oncologists deal with such patients in their daily practice. The symposium on NETs that was held in Merano (Italy) in October 2009 was organized by the German-speaking European School of Oncology (dESO) and gathered specialists from different disciplines of transalpine countries to bring together experiences and observations regarding these tumors. The goal of the meeting and of this review was to illustrate both well- and poorly differentiated NETs and to encourage interdisciplinary approaches.
Die Diagnostik neuroendokriner Neoplasien des Pankreas (PanNEN) hat in den letzten Jahren v. a. i... more Die Diagnostik neuroendokriner Neoplasien des Pankreas (PanNEN) hat in den letzten Jahren v. a. im Bereich der WHO-Klassifikation, der TNM-Einteilung sowie der Gradierung Veränderungen erfahren. Zudem wurden einzelne neue diagnostische sowie prädiktive immunhistochemische Marker eingeführt. Die meisten Fortschritte wurden auf der Ebene der molekularen Pathogenese von PanNEN erzielt. Mittels „next generation sequencing“ wurden der „mammalian target of rapamycin (mTOR) pathway“, Hypoxie, aber auch epigenetische Veränderungen als wichtige tumorigene Mechanismen identifiziert. Im vorliegenden Artikel werden die wichtigsten Entwicklungen in der morphologischen und immunhistochemischen Diagnostik von PanNEN und deren molekularer Hintergrund beleuchtet. Abstract The diagnostics of pancreatic neuroendocrine tumors (PanNEN) have changed in recent years especially concerning the World Health Organization (WHO) classification, TNM staging and grading. Furthermore, some new prognostic and predi...
The Journal of Clinical Endocrinology & Metabolism, 2010
Through overexpression and aberrant activation in many human tumors, the IGF system plays a key r... more Through overexpression and aberrant activation in many human tumors, the IGF system plays a key role in tumor development and tumor cell proliferation. Different strategies targeting IGF-I receptor (IGFI-R) have been developed, and recent studies demonstrated that combined treatments with cytostatic drugs enhance the potency of anti-IGFI-R therapies. The objective of the study was to examine the IGFI-R expression status in neuroendocrine tumors of the gastroenteropancreatic system (GEP-NETs) in comparison with healthy tissues and use potential overexpression as a target for novel anti-IGFI-R immunoliposomes. A human tumor tissue array and samples from different normal tissues were investigated by immunohistochemistry. An IGFI-R antagonistic antibody (1H7) was coupled to the surface of sterically stabilized liposomes loaded with doxorubicin. Cell lines from different tumor entities were investigated for liposomal association studies in vitro. For in vivo experiments, neuroendocrine tumor xenografts were used for evaluation of pharmacokinetic and therapeutic properties of the novel compound. Immunohistochemistry revealed significant IGFI-R overexpression in all investigated GEP-NETs (n = 59; staining index, 229.1 +/- 3.1%) in comparison with normal tissues (115.7 +/- 3.7%). Furthermore, anti-IGFI-R immunoliposomes displayed specific tumor cell association (44.2 +/- 1.6% vs. IgG liposomes, 0.8 +/- 0.3%; P < 0.0001) and internalization in human neuroendocrine tumor cells in vitro and superior antitumor efficacy in vivo (life span 31.5 +/- 2.2 d vs. untreated control, 19 +/- 0.6, P = 0.008). IGFI-R overexpression seems to be a common characteristic of otherwise heterogenous NETs. Novel anti-IGFI-R immunoliposomes have been developed and successfully tested in a preclinical model for human GEP-NETs. Moreover in vitro experiments indicate that usage of this agent could also present a promising approach for other tumor entities.
mucosa. Gastrin and its derivates have been reported to regulate epithelial cell proliferation, m... more mucosa. Gastrin and its derivates have been reported to regulate epithelial cell proliferation, migration, and differentiation. Mutations in the epithelial cadherin (E-cadherin) gene have been shown to be associated with the occurrence of diffuse gastric carcinomas in af- fected families. Objective: In this study we investigated the histopathological and molecular findings in the gastrointestinal wall of a patient with mul-
The tall cell variant of papillary thyroid carcinoma (PTC) has an unfavorable prognosis. The diag... more The tall cell variant of papillary thyroid carcinoma (PTC) has an unfavorable prognosis. The diagnostic criteria remain inconsistent and the role of a minor tall cell (TC) component is unclear. Molecular diagnostic markers are not available; however, there are two potential candidates: BRAF V600E and TERT promoter mutations. Using a novel approach, we enriched a collective with PTC harboring an adverse outcome, overcoming the limited statistical power of most studies. This enabled us to review 125 PTC patients, 57 of them with an adverse outcome. The proportion of TC that constitute a poor prognosis was assessed. All tumors underwent sequencing for TERT promoter and BRAF V600E mutational status and were stained with an antibody detecting the BRAF V600E mutation. A 10% cut off for TC was significantly associated with advanced tumor stage and lymph node metastasis. Multivariate analysis showed that tall cells above 10% were the only significant factor for overall, tumor-specific and r...
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Papers by Aurel Perren