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Trynke van der Boom, Esther N Klein Hesselink, Hilde A M Kooistra, Karina Meijer, Anouk N A van der Horst-Schrivers, Joop D Lefrandt and Thera P Links

Although cancer in general is a strong risk factor for developing venous thromboembolism (VTE), the risk factors for venous thromboembolic events in patients with differentiated thyroid carcinoma (DTC) have never been assessed. This is remarkable, as several parts of the treatment comprise a hypercoagulable state that could in subgroups of DTC patients lead to an increased risk of VTE. The aim of this study was to assess which risk factors could cause DTC patients to develop VTE. We performed a nested case–control study, involving cases of DTC patients treated between 1980 and 2014 with confirmed VTE after diagnosis of DTC. Controls were defined as DTC patients without VTE. In all subjects, we collected information about thyroid cancer characteristics, treatment characteristics, traditional risk factors for VTE and additional clinical data, and we performed univariable and multivariable regression analyses. We included 28 cases and 56 controls matched for age at DTC diagnosis, sex and date of DTC diagnosis. In the univariable regression analysis, histology, distant metastases, DTC risk classification, recent surgery and other active malignancy were associated with VTE. In the multivariable analysis, distant metastases (odds ratio 7.9) and recent surgery (odds ratio 6.1) were independently associated with VTE. In conclusion, surgery and presence of distant metastases are independent risk factors for developing VTE in DTC patients. The risk factors identified in this study could be considered when making decisions regarding thromboprophylaxis for patients with thyroid cancer.

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Roeliene C Kruizinga, Wim J Sluiter, Elisabeth G E de Vries, Bernard A Zonnenberg, Cornelis J Lips, Anouk N A van der Horst-Schrivers, Annemiek M E Walenkamp and Thera P Links

von Hippel–Lindau (VHL) mutation carriers develop benign and malignant tumors, requiring regular surveillance. The aim of this study was to calculate the optimal organ-specific age to initiate surveillance and optimal intervals to detect initial and subsequent VHL-related manifestations. In this study, we compare these results with the current VHL surveillance guidelines. We collected data from 82 VHL mutation carriers in the Dutch VHL surveillance program. The cumulative proportion of carriers diagnosed with a first VHL-related manifestation was estimated by the Kaplan–Meier method. The Poisson distribution model was used to calculate average time to detection of the first VHL-related manifestation and subsequent manifestations. We used this to calculate the optimal organ-specific age to initiate surveillance and the surveillance interval that results in a detection probability of 5%. The calculated organ-specific ages to initiate surveillance were 0 years (birth) for adrenal glands, 7 years for the retina, 14 years for the cerebellum, 15 years for the spinal cord, 16 years for pancreas, and 18 years for the kidneys. The calculated surveillance intervals were 4 years for the adrenal glands, biennially for the retina and pancreas, and annually for the cerebellum, spinal cord, and kidneys. Compared with current VHL guidelines, the calculated starting age of surveillance was 6 years later for the retina and 5 years earlier for adrenal glands. The surveillance intervals were two times longer for the retina and four times longer for the adrenal glands. To attain a 5% detection probability rate per organ, our mathematical model indicates that several modifications of current VHL surveillance guidelines should be considered.

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Hartmut P Neumann, William F Young Jr, Tobias Krauss, Jean-Pierre Bayley, Francesca Schiavi, Giuseppe Opocher, Carsten C Boedeker, Amit Tirosh, Frederic Castinetti, Juri Ruf, Dmitry Beltsevich, Martin Walz, Harald-Thomas Groeben, Ernst von Dobschuetz, Oliver Gimm, Nelson Wohllk, Marija Pfeifer, Delmar M Lourenço Jr, Mariola Peczkowska, Attila Patocs, Joanne Ngeow, Özer Makay, Nalini S Shah, Arthur Tischler, Helena Leijon, Gianmaria Pennelli, Karina Villar Gómez de las Heras, Thera P Links, Birke Bausch and Charis Eng

Although the authors of the present review have contributed to genetic discoveries in the field of pheochromocytoma research, we can legitimately ask whether these advances have led to improvements in the diagnosis and management of patients with pheochromocytoma. The answer to this question is an emphatic Yes! In the field of molecular genetics, the well-established axiom that familial (genetic) pheochromocytoma represents 10% of all cases has been overturned, with >35% of cases now attributable to germline disease-causing mutations. Furthermore, genetic pheochromocytoma can now be grouped into five different clinical presentation types in the context of the ten known susceptibility genes for pheochromocytoma-associated syndromes. We now have the tools to diagnose patients with genetic pheochromocytoma, identify germline mutation carriers and to offer gene-informed medical management including enhanced surveillance and prevention. Clinically, we now treat an entire family of tumors of the paraganglia, with the exact phenotype varying by specific gene. In terms of detection and classification, simultaneous advances in biochemical detection and imaging localization have taken place, and the histopathology of the paraganglioma tumor family has been revised by immunohistochemical-genetic classification by gene-specific antibody immunohistochemistry. Treatment options have also been substantially enriched by the application of minimally invasive and adrenal-sparing surgery. Finally and most importantly, it is now widely recognized that patients with genetic pheochromocytoma/paraganglioma syndromes should be treated in specialized centers dedicated to the diagnosis, treatment and surveillance of this rare neoplasm.

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Ioana N Milos, Karin Frank-Raue, Nelson Wohllk, Ana Luiza Maia, Eduardo Pusiol, Attila Patocs, Mercedes Robledo, Josefina Biarnes, Marta Barontini, Thera P Links, Jan Willem de Groot, Sarka Dvorakova, Mariola Peczkowska, Lisa A Rybicki, Maren Sullivan, Friedhelm Raue, Ioana Zosin, Charis Eng and Hartmut P H Neumann

RET testing in multiple endocrine neoplasia type 2 for molecular diagnosis is the paradigm for the practice of clinical cancer genetics. However, precise data for distinct mutation-based risk profiles are not available. Here, we survey the clinical profile for one specific genotype as a model, TGC to TGG in codon 634 (C634W). By international efforts, we ascertained all available carriers of the RET C634W mutation. Age at diagnosis, penetrance, and clinical complications were analyzed for medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism (HPT), as well as overall survival. Our series comprises 92 carriers from 20 unrelated families worldwide. Sixty-eight subjects had MTC diagnosed at age 3–72 years (mean 29). Lymph node metastases were observed in 16 subjects aged 20–72 and distant metastases in 4 subjects aged 28–69. Forty-one subjects had pheochromocytoma detected at age 18–67 (mean 36). Amongst the 28 subjects with MTC and pheochromocytoma, six developed pheochromocytoma before MTC. Six subjects had HPT diagnosed at age 26–52 (mean 39). Eighteen subjects died; of the 16 with known causes of death, 8 died of pheochromocytoma and 4 of MTC. Penetrance for MTC is 52% by age 30 and 83% by age 50, for pheochromocytoma penetrance is 20% by age 30 and 67% by age 50, and for HPT penetrance is 3% by age 30 and 21% by age 50. These data provide, for the first time, RET C634W-specific neoplastic risk and age-related penetrance profiles. The data may facilitate risk assessment and genetic counseling.

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Frederic Castinetti, Ana Luiza Maia, Mariola Peczkowska, Marta Barontini, Kornelia Hasse-Lazar, Thera P Links, Rodrigo A Toledo, Sarka Dvorakova, Caterina Mian, Maria Joao Bugalho, Stefania Zovato, Maria Alevizaki, Andrei Kvachenyuk, Birke Bausch, Paola Loli, Simona R Bergmann, Attila Patocs, Marija Pfeifer, Josefina Biarnes Costa, Ernst von Dobschuetz, Claudio Letizia, Gerlof Valk, Marcin Barczynski, Malgorzata Czetwertynska, John T M Plukker, Paola Sartorato, Tomas Zelinka, Petr Vlcek, Svetlana Yaremchuk, Georges Weryha, Letizia Canu, Nelson Wohllk, Frederic Sebag, Martin K Walz, Charis Eng and Hartmut P H Neumann

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Tobias Krauss, Alfonso Massimiliano Ferrara, Thera P Links, Ulrich Wellner, Irina Bancos, Andrey Kvachenyuk, Karina Villar Gómez de las Heras, Marina Y Yukina, Roman Petrov, Garrett Bullivant, Laura von Duecker, Swati Jadhav, Ursula Ploeckinger, Staffan Welin, Camilla Schalin-Jäntti, Oliver Gimm, Marija Pfeifer, Joanne Ngeow, Kornelia Hasse-Lazar, Gabriela Sansó, Xiaoping Qi, M Umit Ugurlu, Rene E Diaz, Nelson Wohllk, Mariola Peczkowska, Jens Aberle, Delmar M Lourenço Jr, Maria A A Pereira, Maria C B V Fragoso, Ana O Hoff, Madson Q Almeida, Alice H D Violante, Ana R P Quidute, Zhewei Zhang, Mònica Recasens, Luis Robles Díaz, Tada Kunavisarut, Taweesak Wannachalee, Sirinart Sirinvaravong, Eric Jonasch, Simona Grozinsky-Glasberg, Merav Fraenkel, Dmitry Beltsevich, Viacheslav I Egorov, Dirk Bausch, Matthias Schott, Nikolaus Tiling, Gianmaria Pennelli, Stefan Zschiedrich, Roland Därr, Juri Ruf, Timm Denecke, Karl-Heinrich Link, Stefania Zovato, Ernst von Dobschuetz, Svetlana Yaremchuk, Holger Amthauer, Özer Makay, Attila Patocs, Martin K Walz, Tobias B Huber, Jochen Seufert, Per Hellman, Raymond H Kim, Ekaterina Kuchinskaya, Francesca Schiavi, Angelica Malinoc, Nicole Reisch, Barbara Jarzab, Marta Barontini, Andrzej Januszewicz, Nalini Shah, William F Young Jr, Giuseppe Opocher, Charis Eng, Hartmut P H Neumann and Birke Bausch

Pancreatic neuroendocrine tumors (PanNETs) are rare in von Hippel–Lindau disease (VHL) but cause serious morbidity and mortality. Management guidelines for VHL-PanNETs continue to be based on limited evidence, and survival data to guide surgical management are lacking. We established the European-American-Asian-VHL-PanNET-Registry to assess data for risks for metastases, survival and long-term outcomes to provide best management recommendations. Of 2330 VHL patients, 273 had a total of 484 PanNETs. Median age at diagnosis of PanNET was 35 years (range 10–75). Fifty-five (20%) patients had metastatic PanNETs. Metastatic PanNETs were significantly larger (median size 5 vs 2 cm; P < 0.001) and tumor volume doubling time (TVDT) was faster (22 vs 126 months; P = 0.001). All metastatic tumors were ≥2.8 cm. Codons 161 and 167 were hotspots for VHL germline mutations with enhanced risk for metastatic PanNETs. Multivariate prediction modeling disclosed maximum tumor diameter and TVDT as significant predictors for metastatic disease (positive and negative predictive values of 51% and 100% for diameter cut-off ≥2.8 cm, 44% and 91% for TVDT cut-off of ≤24 months). In 117 of 273 patients, PanNETs >1.5 cm in diameter were operated. Ten-year survival was significantly longer in operated vs non-operated patients, in particular for PanNETs <2.8 cm vs ≥2.8 cm (94% vs 85% by 10 years; P = 0.020; 80% vs 50% at 10 years; P = 0.030). This study demonstrates that patients with PanNET approaching the cut-off diameter of 2.8 cm should be operated. Mutations in exon 3, especially of codons 161/167 are at enhanced risk for metastatic PanNETs. Survival is significantly longer in operated non-metastatic VHL-PanNETs.