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2. Druggable growth dependencies and tumor evolution analysis in patient-derived organoids of neuroendocrine neoplasms from multiple body sites

Author

Dayton, Talya L., Alcala, Nicolas, Moonen, Laura, den Hartigh, Lisanne, Geurts, Veerle, Mangiante, Lise, Lap, Lisa, Dost, Antonella F.M., Beumer, Joep, Levy, Sonja, van Leeuwaarde, Rachel S., Hackeng, Wenzel M., Samsom, Kris, Voegele, Catherine, Sexton-Oates, Alexandra, Begthel, Harry, Korving, Jeroen, Hillen, Lisa, Brosens, Lodewijk A.A., Lantuejoul, Sylvie, Jaksani, Sridevi, Kok, Niels F.M., Hartemink, Koen J., Klomp, Houke M., Borel Rinkes, Inne H.M., Dingemans, Anne-Marie, Valk, Gerlof D., Vriens, Menno R., Buikhuisen, Wieneke, van den Berg, José, Tesselaar, Margot, Derks, Jules, Speel, Ernst Jan, Foll, Matthieu, Fernández-Cuesta, Lynnette, and Clevers, Hans

Published
2023
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3. Primary Tumor Resection is Associated with Improved Disease-Specific Mortality in Patients with Stage IV Small Intestinal Neuroendocrine Tumors (NETs): A Comparison of Upfront Surgical Resection Versus a Watch and Wait Strategy in Two Specialist NET Centers

Author

Levy, Sonja, Arthur, James D., Banks, Melissa, Kok, Niels F. M., Fenwick, Stephen W., Diaz-Nieto, Rafael, van Leerdam, Monique E., Cuthbertson, Daniel J., Valk, Gerlof D., Kuhlmann, Koert F. D., and Tesselaar, Margot E. T.

Published
2022
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6. ASO Visual Abstract: Primary Tumour Resection is Associated with Improved Disease-Specific Mortality in Patients with Stage IV Small Intestinal Neuroendocrine Tumours (NET)—A Comparison of Upfront Surgical Resection versus a Watch-and-Wait Strategy in Two Specialist NET Centres

Author

Levy, Sonja, Arthur, James D., Banks, Melissa, Kok, Niels F. M., Fenwick, Stephen W., Diaz-Nieto, Rafael, van Leerdam, Monique E., Cuthbertson, Daniel J., Valk, Gerlof D., Kuhlmann, Koert F. D., and Tesselaar, Margot E. T.

Published
2022
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9. Druggable growth dependencies and tumor evolution analysis in patient-derived organoids of neuroendocrine neoplasms from multiple body sites

Author

Dayton, Talya L, Alcala, Nicolas, Moonen, Laura, den Hartigh, Lisanne, Geurts, Veerle, Mangiante, Lise, Lap, Lisa, Dost, Antonella F M, Beumer, Joep, Levy, Sonja, van Leeuwaarde, Rachel S, Hackeng, Wenzel M, Samsom, Kris, Voegele, Catherine, Sexton-Oates, Alexandra, Begthel, Harry, Korving, Jeroen, Hillen, Lisa, Brosens, Lodewijk A A, Lantuejoul, Sylvie, Jaksani, Sridevi, Kok, Niels F M, Hartemink, Koen J, Klomp, Houke M, Borel Rinkes, Inne H M, Dingemans, Anne-Marie, Valk, Gerlof D, Vriens, Menno R, Buikhuisen, Wieneke, van den Berg, José, Tesselaar, Margot, Derks, Jules, Speel, Ernst Jan, Foll, Matthieu, Fernández-Cuesta, Lynnette, Clevers, Hans, Dayton, Talya L, Alcala, Nicolas, Moonen, Laura, den Hartigh, Lisanne, Geurts, Veerle, Mangiante, Lise, Lap, Lisa, Dost, Antonella F M, Beumer, Joep, Levy, Sonja, van Leeuwaarde, Rachel S, Hackeng, Wenzel M, Samsom, Kris, Voegele, Catherine, Sexton-Oates, Alexandra, Begthel, Harry, Korving, Jeroen, Hillen, Lisa, Brosens, Lodewijk A A, Lantuejoul, Sylvie, Jaksani, Sridevi, Kok, Niels F M, Hartemink, Koen J, Klomp, Houke M, Borel Rinkes, Inne H M, Dingemans, Anne-Marie, Valk, Gerlof D, Vriens, Menno R, Buikhuisen, Wieneke, van den Berg, José, Tesselaar, Margot, Derks, Jules, Speel, Ernst Jan, Foll, Matthieu, Fernández-Cuesta, Lynnette, and Clevers, Hans

Abstract

Neuroendocrine neoplasms (NENs) comprise well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). Treatment options for patients with NENs are limited, in part due to lack of accurate models. We establish patient-derived tumor organoids (PDTOs) from pulmonary NETs and derive PDTOs from an understudied subtype of NEC, large cell neuroendocrine carcinoma (LCNEC), arising from multiple body sites. PDTOs maintain the gene expression patterns, intra-tumoral heterogeneity, and evolutionary processes of parental tumors. Through hypothesis-driven drug sensitivity analyses, we identify ASCL1 as a potential biomarker for response of LCNEC to treatment with BCL-2 inhibitors. Additionally, we discover a dependency on EGF in pulmonary NET PDTOs. Consistent with these findings, we find that, in an independent cohort, approximately 50% of pulmonary NETs express EGFR. This study identifies an actionable vulnerability for a subset of pulmonary NETs, emphasizing the utility of these PDTO models.

Published
2023

10. Druggable growth dependencies and tumor evolution analysis in patient-derived organoids of neuroendocrine neoplasms from multiple body sites

Author

CMM Groep Maurice, Cancer, MS Endocriene Oncologie, Pathologie Groep Brosens, Pathologie Pathologen staf, MS CGO, Regenerative Medicine and Stem Cells, Heelkunde Opleiding, CMM, Hubrecht Institute with UMC, Dayton, Talya L, Alcala, Nicolas, Moonen, Laura, den Hartigh, Lisanne, Geurts, Veerle, Mangiante, Lise, Lap, Lisa, Dost, Antonella F M, Beumer, Joep, Levy, Sonja, van Leeuwaarde, Rachel S, Hackeng, Wenzel M, Samsom, Kris, Voegele, Catherine, Sexton-Oates, Alexandra, Begthel, Harry, Korving, Jeroen, Hillen, Lisa, Brosens, Lodewijk A A, Lantuejoul, Sylvie, Jaksani, Sridevi, Kok, Niels F M, Hartemink, Koen J, Klomp, Houke M, Borel Rinkes, Inne H M, Dingemans, Anne-Marie, Valk, Gerlof D, Vriens, Menno R, Buikhuisen, Wieneke, van den Berg, José, Tesselaar, Margot, Derks, Jules, Speel, Ernst Jan, Foll, Matthieu, Fernández-Cuesta, Lynnette, Clevers, Hans, CMM Groep Maurice, Cancer, MS Endocriene Oncologie, Pathologie Groep Brosens, Pathologie Pathologen staf, MS CGO, Regenerative Medicine and Stem Cells, Heelkunde Opleiding, CMM, Hubrecht Institute with UMC, Dayton, Talya L, Alcala, Nicolas, Moonen, Laura, den Hartigh, Lisanne, Geurts, Veerle, Mangiante, Lise, Lap, Lisa, Dost, Antonella F M, Beumer, Joep, Levy, Sonja, van Leeuwaarde, Rachel S, Hackeng, Wenzel M, Samsom, Kris, Voegele, Catherine, Sexton-Oates, Alexandra, Begthel, Harry, Korving, Jeroen, Hillen, Lisa, Brosens, Lodewijk A A, Lantuejoul, Sylvie, Jaksani, Sridevi, Kok, Niels F M, Hartemink, Koen J, Klomp, Houke M, Borel Rinkes, Inne H M, Dingemans, Anne-Marie, Valk, Gerlof D, Vriens, Menno R, Buikhuisen, Wieneke, van den Berg, José, Tesselaar, Margot, Derks, Jules, Speel, Ernst Jan, Foll, Matthieu, Fernández-Cuesta, Lynnette, and Clevers, Hans

Published
2023

11. Avelumab treatment for patients with metastatic Merkel cell carcinoma can be safely stopped after 1 year and a PET/CT–confirmed complete response.

Author

Zijlker, Lisanne P., Levy, Sonja, Wolters, Wendy, van Thienen, Johannes V., van Akkooi, Alexander C. J., and Tesselaar, Margot E. T.

Abstract

Background: Immune checkpoint inhibitor treatment of patients with metastatic Merkel cell carcinoma (mMCC) has shown high response rates, ranging from 33% to 73%. The ideal duration of treatment, however, is currently unknown. The aim of this study was to evaluate if avelumab treatment for mMCC can be safely stopped after 1 year of treatment and a complete response (CR) confirmed by fluorodeoxyglucose positron emission tomography/computed tomography (FDG‐PET/CT) imaging. Methods: Patients who received more than one dose of avelumab treatment for mMCC between November 2017 and February 2022 were included in this study. Treatment was discontinued in case of a FDG‐PET/CT confirmed CR after 1 year (26 cycles) of avelumab or a CR and unacceptable toxicity earlier. The primary end point was recurrence‐free survival (RFS). Results: Sixty‐five patients were included: 25 (38%) had a FDG‐PET/CT–confirmed CR at discontinuation of avelumab. In those 25 patients, reasons for discontinuation of treatment were completion of 1 year of treatment in 13 (52%), toxicity in five (20%), and patient preference in seven (28%). Median duration of treatment in this group was 11 months (interquartile range, 6.1–11.7). Median follow‐up was 27 months (interquartile range, 15.8–33.8). The 12‐month RFS was 88% (95% CI, 0.74–1) and median RFS was not reached. Two patients (8%) had a recurrence at 4 and 7 months after discontinuation of treatment. Conclusions: Patients with mMCC who acquire a CR on PET/CT imaging appear to have durable responses after discontinuation of treatment after 1 year. The optimal duration of avelumab treatment for metastatic Merkel cell carcinoma is unknown. Here, we show that avelumab treatment can be safely stopped after 1 year and a positron emission tomography/computed tomography–confirmed complete response. [ABSTRACT FROM AUTHOR]

Published
2024
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12. Druggable Growth Dependencies and Tumor Evolution Analysis in Patient-Derived Organoids of Neuroendocrine Cancer

Author

Dayton, Talya L., primary, Alcala, Nicolas, additional, Moonen, Laura, additional, den Hartigh, Lisanne, additional, Mangiante, Lise, additional, Lap, Lisa, additional, Dost, Antonella F. M., additional, Beumer, Joep, additional, Levy, Sonja, additional, van Leeuwaarde, Rachel S., additional, Hackeng, Wenzel M., additional, Samsom, Kris, additional, Voegele, Catherine, additional, Sexton-Oates, Alexandra, additional, Begthel, Harry, additional, Korving, Jeroen, additional, Hillen, Lisa, additional, Brosens, Lodewijk A. A., additional, Lantuejoul, Sylvie, additional, Jaksani, Sridevi, additional, Kok, Niels F.M., additional, Hartemink, Koen J., additional, Klomp, Houke M., additional, Rinkes, Inne H.M. Borel, additional, Dingemans, Anne-Marie, additional, Valk, Gerlof D., additional, Vriens, Menno R., additional, Buikhuisen, Wieneke, additional, van den Berg, José, additional, Tesselaar, Margot, additional, Derks, Jules, additional, Speel, Ernst Jan, additional, Foll, Matthieu, additional, Fernández-Cuesta, Lynnette, additional, and Clevers, Hans, additional

Published
2022
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14. Postoperative radiotherapy in stage I-III Merkel cell carcinoma

Author

Levy, Sonja, primary, Blankenstein, Stephanie A., additional, Grünhagen, Dirk Jan, additional, Jalving, Mathilde, additional, Hamming-Vrieze, Olga, additional, Been, Lukas B., additional, Tans, Lisa, additional, van Akkooi, Alexander C.J., additional, and Tesselaar, Margot E.T., additional

Published
2022
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15. First-line everolimus and cisplatin in patients with advanced extrapulmonary neuroendocrine carcinoma:a nationwide phase 2 single-arm clinical trial

Author

Levy, Sonja, Verbeek, Wieke H.M., Eskens, Ferry A.L.M., van den Berg, José G., de Groot, Derk Jan A., van Leerdam, Monique E., Tesselaar, Margot E.T., Levy, Sonja, Verbeek, Wieke H.M., Eskens, Ferry A.L.M., van den Berg, José G., de Groot, Derk Jan A., van Leerdam, Monique E., and Tesselaar, Margot E.T.

Abstract

Background: Extrapulmonary neuroendocrine carcinoma (EP-NEC) are an aggressive subgroup of neuroendocrine neoplasms (NEN). Advanced EP-NEC is generally treated with platinum-based cytotoxic regimens, but progressive disease occurs rapidly, resulting in a poor prognosis. Genetic alterations in the mammalian target for rapamycin (mTOR) pathway have been identified in NEN, providing a rationale for treatment with the mTOR-inhibitor everolimus. Methods: A prospective phase 2 single-arm study included patients with advanced EP-NEC from three Dutch NEN expertise centres between March 2016 and January 2020. Treatment consisted of cisplatin 75 mg/m2 every 3 weeks in combination with daily everolimus 7.5 mg for a maximum of six cycles, followed by maintenance everolimus until disease progression. Primary endpoint was disease control rate (DCR), defined as the sum of overall response rate (ORR) plus the rate of stable disease according to RECIST 1.1, assessed at 9-week intervals. Toxicity was evaluated according to CTCAE version 5.0. Results: Thirty-nine patients, with a median age of 64 years (range: 28–74), of whom 20 (51%) were male, were enrolled. DCR was 82.1% (95% confidence interval (CI): 66.4–92.4), with an ORR of 58.9% (CI: 42.1–74.4). Median duration of response was 6.4 (CI: 5.8–7.0) months and median progression-free survival was 6.0 (CI: 4.3–7.8) months. Three patients (8%) had durable responses lasting > 12 months. Median overall survival was 8.7 (CI: 7.8–9.6) months. Most common grade 3/4 toxicities were haematological (36%) and renal (21%). Conclusion: Everolimus in combination with cisplatin is an effective first-line treatment option for advanced EP-NEC, especially in highly selected patients. Trial registration: Clinicaltrials.gov, NCT02695459, https://clinicaltrials.gov/ct2/show/NCT02695459.

Published
2022

16. ASO Visual Abstract: Primary Tumour Resection is Associated with Improved Disease-Specific Mortality in Patients with Stage IV Small Intestinal Neuroendocrine Tumours (NET)-A Comparison of Upfront Surgical Resection versus a Watch-and-Wait Strategy in Two Specialist NET Centres

Author

MS Endocriene Oncologie, Cancer, Levy, Sonja, Arthur, James D, Banks, Melissa, Kok, Niels F M, Fenwick, Stephen W, Diaz-Nieto, Rafael, van Leerdam, Monique E, Cuthbertson, Daniel J, Valk, Gerlof D, Kuhlmann, Koert F D, Tesselaar, Margot E T, MS Endocriene Oncologie, Cancer, Levy, Sonja, Arthur, James D, Banks, Melissa, Kok, Niels F M, Fenwick, Stephen W, Diaz-Nieto, Rafael, van Leerdam, Monique E, Cuthbertson, Daniel J, Valk, Gerlof D, Kuhlmann, Koert F D, and Tesselaar, Margot E T

Published
2022

17. Primary Tumor Resection is Associated with Improved Disease-Specific Mortality in Patients with Stage IV Small Intestinal Neuroendocrine Tumors (NETs): A Comparison of Upfront Surgical Resection Versus a Watch and Wait Strategy in Two Specialist NET Centers

Author

MS Endocriene Oncologie, Cancer, Levy, Sonja, Arthur, James D, Banks, Melissa, Kok, Niels F M, Fenwick, Stephen W, Diaz-Nieto, Rafael, van Leerdam, Monique E, Cuthbertson, Daniel J, Valk, Gerlof D, Kuhlmann, Koert F D, Tesselaar, Margot E T, MS Endocriene Oncologie, Cancer, Levy, Sonja, Arthur, James D, Banks, Melissa, Kok, Niels F M, Fenwick, Stephen W, Diaz-Nieto, Rafael, van Leerdam, Monique E, Cuthbertson, Daniel J, Valk, Gerlof D, Kuhlmann, Koert F D, and Tesselaar, Margot E T

Published
2022

18. Four decades of experience with carcinoid heart disease: An analysis of 84 patients

Author

MS Endocriene Oncologie, CTC, Circulatory Health, Cancer, Levy, Sonja, Korse, Catherina E, de Groot, Andre C A, Meijer, Ronald C A, Tesselaar, Margot E T, Valk, Gerlof D, MS Endocriene Oncologie, CTC, Circulatory Health, Cancer, Levy, Sonja, Korse, Catherina E, de Groot, Andre C A, Meijer, Ronald C A, Tesselaar, Margot E T, and Valk, Gerlof D

Published
2022

19. Elevated Serotonin and NT-proBNP Levels Predict and Detect Carcinoid Heart Disease in a Large Validation Study

Author

Experimentele Afd. Cardiologie 2, Team Medisch, Circulatory Health, Onderzoek Cardiovasculair Reg. Med., Regenerative Medicine and Stem Cells, MS Endocriene Oncologie, Cancer, Levy, Sonja, Kilgallen, Aoife B, Korse, Catharina M, Oerlemans, Marish I F J, Sluijter, Joost P G, van Laake, Linda W, Valk, Gerlof D, Tesselaar, Margot E T, Experimentele Afd. Cardiologie 2, Team Medisch, Circulatory Health, Onderzoek Cardiovasculair Reg. Med., Regenerative Medicine and Stem Cells, MS Endocriene Oncologie, Cancer, Levy, Sonja, Kilgallen, Aoife B, Korse, Catharina M, Oerlemans, Marish I F J, Sluijter, Joost P G, van Laake, Linda W, Valk, Gerlof D, and Tesselaar, Margot E T

Published
2022

22. Well-Differentiated Bronchopulmonary Neuroendocrine Tumors: More Than One Entity

Author

van den Broek, Medard F.M., primary, Levy, Sonja, additional, Buikhuisen, Wieneke A., additional, Dijke, Kim, additional, Hartemink, Koen J., additional, van Leeuwaarde, Rachel S., additional, Vriens, Menno R., additional, Tesselaar, Margot E.T., additional, Valk, Gerlof D., additional, de Herder, Wouter, additional, Dekkers, Olaf, additional, van de Ven, Annenienke, additional, Havekes, Bas, additional, Drent, Madeleine, additional, Bisschop, Peter, additional, Zandee, Wouter, additional, and Valk, Gerlof, additional

Published
2021
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23. Driver mutations occur frequently in metastases of well-differentiated small intestine neuroendocrine tumours

Author

Team 2 Hemat, MS Endocriene Oncologie, Externen Med. Onco, Cancer, Samsom, Kris G., Levy, Sonja, van Veenendaal, Linde M., Roepman, Paul, Kodach, Liudmila L., Steeghs, Neeltje, Valk, Gerlof D., Wouter Dercksen, M., Kuhlmann, Koert F.D., Verbeek, Wieke H.M., Meijer, Gerrit A., Tesselaar, Margot E.T., van den Berg, José G., Team 2 Hemat, MS Endocriene Oncologie, Externen Med. Onco, Cancer, Samsom, Kris G., Levy, Sonja, van Veenendaal, Linde M., Roepman, Paul, Kodach, Liudmila L., Steeghs, Neeltje, Valk, Gerlof D., Wouter Dercksen, M., Kuhlmann, Koert F.D., Verbeek, Wieke H.M., Meijer, Gerrit A., Tesselaar, Margot E.T., and van den Berg, José G.

Published
2021

24. Postoperative radiotherapy in Merkel cell carcinoma (MCC).

Author

Levy, Sonja, primary, Blankenstein, Stephanie, additional, Grunhagen, Dirk J., additional, Jalving, Mathilde, additional, Hamming-Vrieze, Olga, additional, Been, Lukas B., additional, Tans, Lisa, additional, Van Akkooi, Alexander Christopher Jonathan, additional, and Tesselaar, Margot Et, additional

Published
2021
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25. Driver mutations occur frequently in metastases of well‐differentiated small intestine neuroendocrine tumours

Author

Samsom, Kris G, primary, Levy, Sonja, additional, Veenendaal, Linde M, additional, Roepman, Paul, additional, Kodach, Liudmila L, additional, Steeghs, Neeltje, additional, Valk, Gerlof D, additional, Wouter Dercksen, M, additional, Kuhlmann, Koert F D, additional, Verbeek, Wieke H M, additional, Meijer, Gerrit A, additional, Tesselaar, Margot E T, additional, and Berg, José G, additional

Published
2020
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27. Survival in Patients with Neuroendocrine Tumours of the Small Intestine: Nomogram Validation and Predictors of Survival

Author

Levy, Sonja, primary, van Veenendaal, Linde M., additional, Korse, Catharina M., additional, Breekveldt, Emilie C.H., additional, Verbeek, Wieke H.M., additional, Vriens, Menno R., additional, Kuhlmann, Koert F.D., additional, van den Berg, José G., additional, Valk, Gerlof D., additional, and Tesselaar, Margot E.T., additional

Published
2020
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28. Avelumab for advanced Merkel cell carcinoma in the Netherlands:a real-world cohort

Author

Levy, Sonja, Aarts, Maureen J B, Eskens, Ferry A L M, Keymeulen, Kristien B M I, Been, Lukas B, Grünhagen, Dirk, van Akkooi, Alexander, Jalving, Mathilde, Tesselaar, Margot E T, Levy, Sonja, Aarts, Maureen J B, Eskens, Ferry A L M, Keymeulen, Kristien B M I, Been, Lukas B, Grünhagen, Dirk, van Akkooi, Alexander, Jalving, Mathilde, and Tesselaar, Margot E T

Abstract

BACKGROUND: Merkel cell carcinoma (MCC) is associated with high recurrence rates and poor survival when metastatic disease is present. The immune checkpoint inhibitor avelumab has shown high response rates (RRs) and durable responses in patients with advanced MCC (aMCC) in clinical trials. To date, only results from clinical trials, patients treated in an expanded access program and very small numbers of patients have been reported. In this study, detailed real-world efficacy and toxicity data of avelumab in patients with aMCC are reported.METHODS: Patients with aMCC treated in four dedicated referral centers in the Netherlands were analyzed from February 2017 until December 2019. Patients were included if they had received at least one administration of avelumab, regardless of previous lines of therapy. Patient data were collected retrospectively from patient records. Primary endpoints were response rate (RR) and duration of response (DOR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity.RESULTS: Fifty-four patients received avelumab. Eight (15%) patients had locally advanced disease (laMCC). In 40 (74%) patients, avelumab was first-line treatment, these included all patients with laMCC. The median follow-up was 8.9 (range 0.5-35.9) months. RR was 57% (n=31) with 24% (n=13) of patients achieving a complete response. The median DOR was 8.4 (range 1.3-22.1) months and 23 (43%) patients had an ongoing response at the end of the study. The median PFS was 8.6 (95% CI 1.6-15.5) months, and the median OS was 25.8 (95% CI 9.1-42.4) months. Six (11%) patients experienced grade 3 toxicity. No grade 4-5 toxicity was seen.CONCLUSIONS: In this real-world cohort, clinical efficacy and toxicity outcomes in clinical practice were in line with results from clinical trials and showed relatively high RRs and durable responses in patients with aMCC.

Published
2020

29. Survival in patients with neuroendocrine tumours of the small intestine: Nomogram validation and predictors of survival

Author

MS Endocriene Oncologie, Heelkunde Opleiding, MS CGO, Cancer, Levy, Sonja, van Veenendaal, Linde M., Korse, Catharina M., Breekveldt, Emilie C.H., Verbeek, Wieke H.M., Vriens, Menno R., Kuhlmann, Koert F.D., van den Berg, José G., Valk, Gerlof D., Tesselaar, Margot E.T., MS Endocriene Oncologie, Heelkunde Opleiding, MS CGO, Cancer, Levy, Sonja, van Veenendaal, Linde M., Korse, Catharina M., Breekveldt, Emilie C.H., Verbeek, Wieke H.M., Vriens, Menno R., Kuhlmann, Koert F.D., van den Berg, José G., Valk, Gerlof D., and Tesselaar, Margot E.T.

Published
2020

31. Driver mutations occur frequently in metastases of well‐differentiated small intestine neuroendocrine tumours.

Author

Samsom, Kris G, Levy, Sonja, Veenendaal, Linde M, Roepman, Paul, Kodach, Liudmila L, Steeghs, Neeltje, Valk, Gerlof D, Wouter Dercksen, M, Kuhlmann, Koert F D, Verbeek, Wieke H M, Meijer, Gerrit A, Tesselaar, Margot E T, and Berg, José G

Subjects
*TUMOR suppressor genes, *SMALL intestine, *SOMATIC mutation, *GENES, *METASTASIS, *NUCLEOTIDE sequencing
Abstract

Aims: To investigate the clinicopathological significance of driver mutations in metastatic well‐differentiated small intestine neuroendocrine tumours (SI‐NETs). Methods and results: Whole genome sequencing (WGS) of 35 metastatic SI‐NETs and next‐generation sequencing (NGS) of eight metastatic SI‐NETs were performed. Biopsies were obtained between 2015 and 2019. Tumours were classified according to the 2019 World Health Organization classification. WGS included assessment of somatic mutations in all cancer‐related driver genes, the tumour mutational burden (TMB), and microsatellite status. NGS entailed a cancer hotspot panel of 58 genes. Our cohort consisted of 21% grade 1, 60% grade 2 and 19% grade 3 SI‐NETs. Driver mutations were identified in ~50% of SI‐NETs. In total, 27 driver mutations were identified, of which 74% were in tumour suppressor genes (e.g. TP53, RB1, and CDKN1B) and 22% were in proto‐oncogenes (e.g. KRAS, NRAS, and MET). Allelic loss of chromosome 18 (63%), complete loss of CDKN2A and CDKN1B (both 6%) and CDKN1B mutations (9%) were most common. Potential targetable genetic alterations were detected in 21% of metastasised SI‐NETs. All tumours were microsatellite‐stable and showed low TMBs (median 1.10; interquartile range 0.87–1.35). The Ki67 proliferation index was significantly associated with the presence of driver mutations (P = 0.015). Conclusion: Driver mutations occur in 50% of metastasised SI‐NETs, and their presence is associated with a high Ki67 proliferation index. The identification of targetable mutations make these patients potentially eligible for targeted therapy. [ABSTRACT FROM AUTHOR]

Published
2021
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32. Sudden cardiac death in families with premature cardiovascular disease.

Author

Bruikman, Caroline, de Ronde, Maurice W. J., Amin, Ahmed, Levy, Sonja, Lof, Pien, de Ruijter, Ursula, Hovingh, Kees, Tan, Hanno L., and Pinto-Sietsma, Sara-Joan

Subjects
CARDIAC arrest, BRUGADA syndrome, CARDIOVASCULAR diseases, EARLY death, ACADEMIC medical centers, FAMILIAL hypercholesterolemia
Abstract

Objective: Sudden cardiac death (SCD) in families with premature atherosclerosis (PAS) is generally attributed to lethal arrhythmias during myocardial infarction. Yet, such arrhythmias may also arise from non-ischaemic inherited susceptibility. We aimed to test the hypothesis that Brugada syndrome is prevalent among families with PAS in which SCD occurred.Methods: We investigated all patients who underwent Ajmaline testing to screen them for Brugada syndrome because of unexplained familial SCD in the Amsterdam University Medical Centers between 2004 and 2017. We divided the cohort into two groups based on a positive family history for PAS. All individuals with a positive Ajmaline test were screened for SCN5A-mutation.Results: In families with SCD and PAS, the prevalence of positive Ajmaline test was similar to families with SCD alone (22% vs 19%). The number of SCD cases in families with SCD and PAS was higher (2.34 vs 1.63, p<0.001) and SCD occurred at older age in families with SCD and PAS (42 years vs 36 years, p<0.001), while the prevalence of SCN5A mutations was lower (3% vs 18%, p<0.05).Conclusions: Brugada syndrome has a similar prevalence in families with SCD and PAS as in families with SCD alone, although SCD in families with SCD and PAS occurs in more family members and at older age, while SCN5A mutations in these families are rare. This suggests that the SCD occurring in families with PAS could be related to an underlying genetic predisposition of arrhythmias, with a different genetic origin. It could be considered to screen families with SCD and PAS for Brugada syndrome. [ABSTRACT FROM AUTHOR]

Published
2020
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