Search for other papers by Arnaud Lagarde in
Google Scholar
PubMed
Search for other papers by Grégory Mougel in
Google Scholar
PubMed
Search for other papers by Lucie Coppin in
Google Scholar
PubMed
Search for other papers by Magalie Haissaguerre in
Google Scholar
PubMed
Inserm/CNRS UMR 1283/8199, Pasteur Institute of Lille, EGID, Lille, France
Search for other papers by Lauriane Le Collen in
Google Scholar
PubMed
Search for other papers by Amira Mohamed in
Google Scholar
PubMed
Search for other papers by Marc Klein in
Google Scholar
PubMed
Univ. Lille, Inserm, CHU Lille, U1286 – Infinite – Institute for Translational Research in Inflammation, Lille, France
Search for other papers by Marie-Françoise Odou in
Google Scholar
PubMed
Search for other papers by Antoine Tabarin in
Google Scholar
PubMed
Search for other papers by Hedia Brixi in
Google Scholar
PubMed
Search for other papers by Thomas Cuny in
Google Scholar
PubMed
Search for other papers by Brigitte Delemer in
Google Scholar
PubMed
Search for other papers by Anne Barlier in
Google Scholar
PubMed
Search for other papers by Pauline Romanet in
Google Scholar
PubMed
Purpose
Mosaicism is a feature of several inherited tumor syndromes. Only a few cases of mosaicism have been described in multiple endocrine neoplasia type 1 (MEN1). Next-generation sequencing (NGS) offers new possibilities for detecting mosaicism. Here, we report the first study to systematically look for MEN1 mosaicism, using blood DNA, in MEN1-suspected patients but without MEN1 pathogenic variants (PV) in a heterozygous state.
Methods
Digital targeted NGS, including unique molecular identifiers (UMIs), was performed in routine practice, and the analytic performance of this method was verified.
Results
Among a cohort of 119 patients harboring from 2 to 5 MEN1 lesions, we identified 3 patients with MEN1 mosaic PVs. The allele frequencies ranged from 2.3 to 9.5%. The detection rate of MEN1 mosaicism in patients bearing at least 3 MEN1 lesions was 17% (3/18). No cases were detected in patients with two lesions.
Conclusion
We report here three new cases with MEN1 mosaicism. This study examined the performance of UMI in the diagnosis of MEN1 mosaicism in routine practice, and our results underline that the frequency of mosaicism is probably underestimated in patients with suspected MEN1.
Center for Neuroendocrine Tumors, ENETS Center of Excellence, Netherlands Cancer Institute, University Medical Center Utrecht, Utrecht, The Netherlands
Search for other papers by Mark J C van Treijen in
Google Scholar
PubMed
Department of Clinical Chemistry, The Netherlands Cancer Institute, Amsterdam, The Netherlands
Search for other papers by Catharina M Korse in
Google Scholar
PubMed
Department of Gastroenterology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
Search for other papers by Wieke H Verbeek in
Google Scholar
PubMed
Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
Search for other papers by Margot E T Tesselaar in
Google Scholar
PubMed
Center for Neuroendocrine Tumors, ENETS Center of Excellence, Netherlands Cancer Institute, University Medical Center Utrecht, Utrecht, The Netherlands
Search for other papers by Gerlof D Valk in
Google Scholar
PubMed
Objective
Up to now, serial NETest measurements in individuals assessing the disease course of gastroenteropancreatic neuroendocrine tumors (GEPNETs) at long-term follow-up and treatment response were not studied.
Design
The study was a longitudinal validation study of serial NETest measurements – a blood-based gene expression signature – in 132 patients with GEPNETs on therapy or watch-and-wait strategy.
Methods
Serial samples were collected during 46 (range: 6–71) months of follow-up. NETest scores were compared with Response Evaluation Criteria in Solid Tumors version 1.1-defined treatment response (e.g. no evidence of disease (NED), stable disease (SD) or progressive disease (PD)).
Results
Consecutive NETest scores fluctuated substantially (range: 0–100) over time in individuals with SD (n = 28) and NED (n = 30). Follow-up samples were significantly higher in SD (samples 3–5) and NED subgroups (samples 2–5) compared with baseline results, without changes in imaging. In 82% of untreated patients with PD, consecutive NETest scores consistently remained high. In patients undergoing systemic treatment, the median pre-treatment NETest score in treatment-responders was 76.5 (n = 22) vs 33 (n = 12) in non-responders (P = 0.001). Patients with low pre-treatment scores had 21 months reduced progression-free survival (10 vs 31 months; P = 0.01). The accuracy of the NETest for treatment response prediction was 0.73 (P = 0.009).
Conclusion
In patients not undergoing treatment, consecutive low NETest scores are associated with indolent behavior. Patients who develop PD exhibit elevated scores. Elevated results have important predictive value for treatment responsiveness and could be used for individualizing decisions on systemic therapy. The clinical value of follow-up NETest scores for patients who choose to watch and wait requires further study.
Search for other papers by J Gebauer in
Google Scholar
PubMed
Search for other papers by R Skinner in
Google Scholar
PubMed
Search for other papers by R Haupt in
Google Scholar
PubMed
Amsterdam UMC, Emma’s Children’s Hospital, Amsterdam, The Netherlands
Search for other papers by L Kremer in
Google Scholar
PubMed
Search for other papers by H van der Pal in
Google Scholar
PubMed
Search for other papers by G Michel in
Google Scholar
PubMed
Search for other papers by G T Armstrong in
Google Scholar
PubMed
Search for other papers by M M Hudson in
Google Scholar
PubMed
Search for other papers by L Hjorth in
Google Scholar
PubMed
Search for other papers by H Lehnert in
Google Scholar
PubMed
Search for other papers by T Langer in
Google Scholar
PubMed
Many long-term childhood cancer survivors suffer from treatment-related late effects, which may occur in any organ and include a wide spectrum of conditions. Long-term follow-up (LTFU) is recommended to facilitate early diagnosis and to ensure better health outcomes. Due to the heterogeneity of these sequelae, different specialists work together in the diagnosis and treatment of these conditions. Experts from both pediatric and internal medicine are involved in age-appropriate care by providing a transition process. Hence, LTFU of childhood cancer survivors is a prototypic example of multidisciplinary care for patients with complex needs treated in a specialized setting. International collaborations of healthcare professionals and scientists involved in LTFU of childhood cancer survivors, such as the International Guideline Harmonization Group, compile surveillance recommendations that can be clinically adopted all over the world. These global networks of clinicians and researchers make a joint effort to address gaps in knowledge, increase visibility and awareness of cancer survivorship and provide an excellent example of how progress in clinical care and scientific research may be achieved by international and multidisciplinary collaboration.
Search for other papers by Judith Gebauer in
Google Scholar
PubMed
Search for other papers by Claire E Higham in
Google Scholar
PubMed
Search for other papers by Malgorzata Fuksiewicz in
Google Scholar
PubMed
Search for other papers by Maria Kowalska in
Google Scholar
PubMed
Search for other papers by Agnieszka Kolasinska-Cwikla in
Google Scholar
PubMed
Search for other papers by Beata Kotowicz in
Google Scholar
PubMed
The aim of this study was to assess the usefulness of neuron-specific enolase (NSE) concentrations as a prognostic factor in patients with neuroendocrine neoplasms and to determine the relationship between NSE and clinicopathological features. Serum NSE levels were measured in 179 NEN patients before treatment. It was found that NSE levels in patients with a primary pancreatic location were higher compared to patients with a small intestine lesion (P = 0.015). NSE levels were significantly higher in patients with primary pancreatic location with histological grade G2 compared with the group with low-grade G1 (P = 0.047). Patients with initial liver involvement showed significantly higher NSE levels compared to patients with tumour location in the pancreas (P = 0.009). Statistical analysis confirmed that higher NSE levels were associated with disease progression (P = 0.001) in both the overall study group and in patients with tumours in the pancreas and small intestine. During treatment monitoring, an increase in median NSE concentrations was observed in patients with persistent progression with subsequent blood draws, and a decrease in NSE concentrations was observed in patients with disease stabilisation. We showed that NSE concentrations have prognostic value for progression-free survival in addition to primary liver involvement. In conclusion, the most important results of the study include the demonstration of an association between NSE concentrations and clinical status, which confirms its usefulness in patient monitoring and as a potential predictive indicator for progression-free survival in patients with NENs.
Search for other papers by Matteo Scopel in
Google Scholar
PubMed
Search for other papers by Eugenio De Carlo in
Google Scholar
PubMed
Search for other papers by Francesca Bergamo in
Google Scholar
PubMed
Search for other papers by Sabina Murgioni in
Google Scholar
PubMed
Search for other papers by Riccardo Carandina in
Google Scholar
PubMed
Search for other papers by Anna Rita Cervino in
Google Scholar
PubMed
Search for other papers by Marta Burei in
Google Scholar
PubMed
Search for other papers by Federica Vianello in
Google Scholar
PubMed
Search for other papers by Vittorina Zagonel in
Google Scholar
PubMed
Search for other papers by Matteo Fassan in
Google Scholar
PubMed
Search for other papers by Roberto Vettor in
Google Scholar
PubMed
We considered 351 patients affected by neuroendocrine tumors (NETs), followed at the University Hospital of Padua and at the Veneto Oncological Institute. Of these, 72 (20.5%) suffered from bone metastases. The sample was divided according to the timing of presentation of bone metastases into synchronous (within 6 months of diagnosis of primary tumor) and metachronous (after 6 months). We collected data on the type and grading of the primary tumor and on the features of bone metastases. Our analysis shows that the group of synchronous metastases generally presents primary tumors with a higher degree of malignancy rather than the ones of the metachronous group. This is supported by the finding of a Ki-67 level in GEP-NETs, at the diagnosis of bone metastases, significantly higher in the synchronous group. Moreover, in low-grade NETs, chromogranin A values are higher in the patients with synchronous metastases, indicating a more burden of disease. The parameters of phospho-calcium metabolism are within the normal range, and we do not find significant differences between the groups. Serious bone complications are not frequent and are not correlated with the site of origin of the primary tumor. From the analysis of the survival curves of the total sample, a cumulative survival rate of 33% at 10 years emerges. The average survival is 80 months, higher than what is reported in the literature, while the median is 84 months. In our observation period, synchronous patients tend to have a worse prognosis than metachronous ones with 52-months survival rates of 58 and 86%.
Search for other papers by Eleftherios E Deiktakis in
Google Scholar
PubMed
Search for other papers by Eleftheria Ieronymaki in
Google Scholar
PubMed
Search for other papers by Peter Zarén in
Google Scholar
PubMed
Search for other papers by Agnes Hagsund in
Google Scholar
PubMed
Search for other papers by Elin Wirestrand in
Google Scholar
PubMed
Search for other papers by Johan Malm in
Google Scholar
PubMed
Search for other papers by Christos Tsatsanis in
Google Scholar
PubMed
Imperial College London, Institute of Reproductive and Developmental Biology, London, UK
Search for other papers by Ilpo T Huhtaniemi in
Google Scholar
PubMed
Malmö University Hospital, Reproductive Medicine Center, Malmö, Sweden
Search for other papers by Aleksander Giwercman in
Google Scholar
PubMed
Search for other papers by Yvonne Lundberg Giwercman in
Google Scholar
PubMed
Objective
During androgen ablation in prostate cancer by the standard gonadotropin-releasing hormone (GnRH) agonist treatment, only luteinizing hormone (LH) is permanently suppressed while circulating follicle-stimulating hormone (FSH) rebounds. We explored direct prostatic effects of add-back FSH, after androgen ablation with GnRH antagonist, permanently suppressing both gonadotropins.
Methods
The effects of recombinant human (rFSH) were examined in mice treated with vehicle (controls), GnRH antagonist degarelix (dgx), dgx + rFSH, dgx + flutamide, or dgx + rFSH + flutamide for 4 weeks. Prostates and testes size and expression of prostate-specific and/or androgen-responsive genes were measured. Additionally, 33 young men underwent dgx-treatment. Seventeen were supplemented with rFSH (weeks 1–5), and all with testosterone (weeks 4–5). Testosterone, gondotropins, prostate-specific antigen (PSA), and inhibin B were measured.
Results
In dgx and dgx + flutamide treated mice, prostate weight/body weight was 91% lower than in controls, but 41 and 11%, respectively, was regained by rFSH treatment (P = 0.02). The levels of seminal vesicle secretion 6, Pbsn, Nkx3.1, beta-microseminoprotein, and inhibin b were elevated in dgx + rFSH-treated animals compared with only dgx treated (all P < 0.05). In men, serum inhibin B rose after dgx treatment but was subsequently suppressed by testosterone. rFSH add-back had no effect on PSA levels.
Conclusions
These data provide novel evidence for the direct effects of FSH on prostate size and gene expression in chemically castrated mice. However, in chemically castrated men, FSH had no effect on PSA production. Whether FSH effects on the prostate in humans also require suppression of the residual adrenal-derived androgens and/or a longer period of rFSH stimulation, remains to be explored.
Search for other papers by Carole Morin in
Google Scholar
PubMed
Search for other papers by Keo-Morakort Benedetto in
Google Scholar
PubMed
Centre de Recherche en Cancérologie de Lyon, UMR Inserm 1052 CNRS 5286, Lyon Cedex 08, France
Search for other papers by Agathe Deville in
Google Scholar
PubMed
University of Lyon, Université Lyon 1, France
Search for other papers by Laurent Milot in
Google Scholar
PubMed
Search for other papers by Aurélie Theillaumas in
Google Scholar
PubMed
University of Lyon, Université Lyon 1, France
Hospices Civils de Lyon, Institut de Pathologie Est, Bron Cedex, France
Search for other papers by Valérie Hervieu in
Google Scholar
PubMed
Hospices Civils de Lyon, Hôpital Edouard Herriot, Gastroentérologie, Lyon Cedex 03, France
Search for other papers by Mathieu Pioche in
Google Scholar
PubMed
University of Lyon, Université Lyon 1, France
Hospices Civils de Lyon, Hôpital Edouard Herriot, Chirurgie Digestive, Lyon Cedex 03, France
Search for other papers by Gilles Poncet in
Google Scholar
PubMed
Search for other papers by Julien Forestier in
Google Scholar
PubMed
Search for other papers by Laurent François in
Google Scholar
PubMed
Hospices Civils de Lyon, Hôpital Louis Pradel, Endocrinologie, Bron Cedex, France
Search for other papers by Francoise Borson-Chazot in
Google Scholar
PubMed
Hospices Civils de Lyon, Hôpital Edouard Herriot, Chirurgie Digestive, Lyon Cedex 03, France
Search for other papers by Mustapha Adham in
Google Scholar
PubMed
Search for other papers by Catherine Lombard-Bohas in
Google Scholar
PubMed
Centre de Recherche en Cancérologie de Lyon, UMR Inserm 1052 CNRS 5286, Lyon Cedex 08, France
University of Lyon, Université Lyon 1, France
Search for other papers by Thomas Walter in
Google Scholar
PubMed
Purpose
To improve neuroendocrine neoplasm (NEN) management, the European Neuroendocrine Tumor Society (ENETS) recognised 62 Centers of Excellence (CoE). This retrospective study compares conformity of patients’ initial management within vs outside an ENETS CoE with clinical practice guidelines (CPGs).
Methods
Patients diagnosed with a NEN between August 2018 and July 2020 and presented in the Lyon-CoE Multidisciplinary Tumour Board (MDT) were included. Factors potentially associated with the conformity of initial management (work-up and first treatment) to CPG underwent univariate and multivariate analyses.
Results
Among the 615 included patients, 170 (27.6%) were initially managed in the CoE and 445 (72.4%) were only presented at the CoE-MDT. Patients in the CoE group more often had intestinal or pancreatic primaries, metastatic disease (61.8% vs 33%), hereditary syndrome, and a functioning tumour. Work-up conformity was 37.1% in the CoE (vs 29.9%, P = 0.09); this was 95.8% for the first treatment (vs 88.7%, P = 0.01). After multivariate analysis, CPG conformity was significantly higher for patients managed in the CoE, for younger patients, for those having a grade 1–2 tumour, and a genetic syndrome. Pancreatic and small intestinal (SI) NET surgeries performed in the CoE had a higher splenic preservation rate during left pancreatectomy, better detection of multiple tumours in SI surgeries, and higher number of resected lymph nodes.
Conclusions
Given the widespread observance of CPG, not all patients require management in the CoE. Referral should be considered for more complex cases such as metastatic diseases, G2 tumours, or carcinoid syndromes. Finally, we should encourage the centralization of NET surgery.
Search for other papers by Anela Blažević in
Google Scholar
PubMed
Search for other papers by Anand M Iyer in
Google Scholar
PubMed
Search for other papers by Marie-Louise F van Velthuysen in
Google Scholar
PubMed
Search for other papers by Johannes Hofland in
Google Scholar
PubMed
Search for other papers by Peter M van Koestveld in
Google Scholar
PubMed
Search for other papers by Gaston J H Franssen in
Google Scholar
PubMed
Search for other papers by Richard A Feelders in
Google Scholar
PubMed
Search for other papers by Marina Zajec in
Google Scholar
PubMed
Search for other papers by Theo M Luider in
Google Scholar
PubMed
Search for other papers by Wouter W de Herder in
Google Scholar
PubMed
Search for other papers by Leo J Hofland in
Google Scholar
PubMed
Background
Increased levels of serotonin secretion are associated with mesenteric fibrosis (MF) in small intestinal neuroendocrine tumors (SI-NETs). However, the profibrotic potential of serotonin differs between patients, and in this study, we aimed to gain an understanding of the mechanisms underlying this variability. To this end, we analyzed the proteins involved in tryptophan metabolism in SI-NETs.
Methods
Proteomes of tumor and stroma from primary SI-NETs and paired mesenteric metastases of patients with MF (n = 6) and without MF (n = 6) were identified by liquid chromatography–mass spectrometry (LC-MS). The differential expression of proteins involved in tryptophan metabolism between patients with and without MF was analyzed. Concurrently, monoamine oxidase A (MAO-A) expression was analyzed in the tumor and stromal compartment by immunohistochemistry (IHC) and reported as intensity over area (I/A).
Results
Of the 42 proteins involved in tryptophan metabolism, 20 were detected by LC-MS. Lower abundance of ten proteins was found in mesenteric metastases stroma in patients with MF. No differential expression was found in primary SI-NETs. In patients with MF, IHC showed lower MAO-A expression in the stroma of the primary SI-NETs (median 4.2 I/A vs 6.5 I/A in patients without MF, P = 0.003) and mesenteric metastases (median 2.1 I/A vs 2.8 I/A in patients without MF, P= 0.019).
Conclusion
We found a decreased expression of tryptophan and serotonin-metabolizing enzymes in the stroma in patients with MF, most notably in the mesenteric stroma. This might account for the increased profibrotic potential of serotonin and explain the variability in the development of SI-NET-associated fibrotic complications.
European Institute for Molecular Imaging (EIMI), University of Münster, Münster, Germany
Search for other papers by Daniel Alexander Hescheler in
Google Scholar
PubMed
Search for other papers by Milan Janis Michael Hartmann in
Google Scholar
PubMed
Search for other papers by Burkhard Riemann in
Google Scholar
PubMed
Search for other papers by Maximilian Michel in
Google Scholar
PubMed
Search for other papers by Christiane Josephine Bruns in
Google Scholar
PubMed
Search for other papers by Hakan Alakus in
Google Scholar
PubMed
Search for other papers by Costanza Chiapponi in
Google Scholar
PubMed
Objective
Anaplastic thyroid cancer (ATC) is one of the most lethal human cancers with meager treatment options. We aimed to identify the targeted drugs already approved by the Food and Drug Administration (FDA) for solid cancer in general, which could be effective in ATC.
Design
Database mining.
Methods
FDA-approved drugs for targeted therapy were identified by screening the databases of MyCancerGenome and the National Cancer Institute. Drugs were linked to the target genes by querying Drugbank. Subsequently, MyCancerGenome, CIViC, TARGET and OncoKB were mined for genetic alterations which are predicted to lead to drug sensitivity or resistance. We searched the Cancer Genome Atlas database (TCGA) for patients with ATC and probed their sequencing data for genetic alterations which predict a drug response.
Results
In the study,155 FDA-approved drugs with 136 potentially targetable genes were identified. Seventeen (52%) of 33 patients found in TCGA had at least one genetic alteration in targetable genes. The point mutation BRAF V600E was seen in 45% of patients. PIK3CA occurred in 18% of cases. Amplifications of ALK and SRC were detected in 3% of cases, respectively. Fifteen percent of the patients displayed a co-mutation of BRAF and PIK3CA. Besides BRAF-inhibitors, the PIK3CA-inhibitor copanlisib showed a genetically predicted response. The 146 (94%) remaining drugs showed no or low (under 4% cases) genetically predicted drug response.
Conclusions
While ATC carrying BRAF mutations can benefit from BRAF inhibitors and this effect might be enhanced by a combined strategy including PIK3CA inhibitors in some of the patients, alterations in BRAFWT ATC are not directly targeted by currently FDA-approved options.
