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Publications (10 of 36) Show all publications
Crona, J. & Beuschlein, F. (2019). Adrenocortical carcinoma: towards genomics guided clinical care. Nature Reviews Endocrinology, 15(9), 548-560
Open this publication in new window or tab >>Adrenocortical carcinoma: towards genomics guided clinical care
2019 (English)In: Nature Reviews Endocrinology, ISSN 1759-5029, E-ISSN 1759-5037, Vol. 15, no 9, p. 548-560Article, review/survey (Refereed) Published
Abstract [en]

Adrenocortical carcinoma (ACC) is an aggressive and rare neoplasm that originates in the cortex of the adrenal gland. The disease is associated with heterogeneous but mostly poor outcomes and lacks effective pharmaceutical treatment options. Multi-omics studies have defined the landscape of molecular alterations in ACC. Specific molecular signatures can be detected in body fluids, potentially enabling improved diagnostic applications for patients with adrenal tumours. Importantly, pan-molecular data sets further reveal a spectrum within ACC, with three major subgroups that have different disease outcomes. These new subgroups have value as prognostic biomarkers. Research has revealed that the p53-RB and the WNT-beta-catenin pathways are common disease drivers in ACC. However, these pathways remain difficult to target by therapeutic interventions. Instead, a unique characteristic of ACC is steroidogenic differentiation, which has emerged as a potential treatment target, with several agents undergoing preclinical or clinical investigations. Finally, a large proportion of ACC tumours have genetic profiles that are associated with promising therapeutic responsiveness in other cancers. All these opportunities now await translation from the laboratory into the clinical setting, thereby offering a real potential of improved survival outcomes and increased quality of life for patients with this serious condition.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-393685 (URN)10.1038/s41574-019-0221-7 (DOI)000480419200011 ()31147626 (PubMedID)
Funder
Swedish Cancer SocietyGerman Research Foundation (DFG), CRC/Transregio 205/1Wallenberg FoundationsTore Nilsons Stiftelse för medicinsk forskning
Available from: 2019-09-25 Created: 2019-09-25 Last updated: 2019-09-25Bibliographically approved
Vyakaranam, A. R., Crona, J., Norlén, O., Hellman, P. & Sundin, A. (2019). C-11-hydroxy-ephedrine-PET/CT in the Diagnosis of Pheochromocytoma and Paraganglioma. Cancers, 11(6), Article ID 847.
Open this publication in new window or tab >>C-11-hydroxy-ephedrine-PET/CT in the Diagnosis of Pheochromocytoma and Paraganglioma
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2019 (English)In: Cancers, ISSN 2072-6694, Vol. 11, no 6, article id 847Article in journal (Refereed) Published
Abstract [en]

Pheochromocytomas (PCC) and paragangliomas (PGL) may be difficult to diagnose because of vague and uncharacteristic symptoms and equivocal biochemical and radiological findings. This was a retrospective cohort study in 102 patients undergoing C-11-hydroxy-ephedrine (C-11-HED)-PET/CT because of symptoms and/or biochemistry suspicious for PCC/PGL and/or with radiologically equivocal adrenal incidentalomas. Correlations utilized CT/MRI, clinical, biochemical, surgical, histopathological and follow-up data. C-11-HED-PET/CT correctly identified 19 patients with PCC and six with PGL, missed one PCC, attained one false positive result (nodular hyperplasia) and correctly excluded PCC/PGL in 75 patients. Sensitivity, specificity, positive and negative predictive values of C-11-HED-PET/CT for PCC/PGL diagnosis was 96%, 99%, 96% and 99%, respectively. In 41 patients who underwent surgical resection and for whom correlation to histopathology was available, the corresponding figures were 96%, 93%, 96% and 93%, respectively. Tumor C-11-HED-uptake measurements (standardized uptake value, tumor-to-normal-adrenal ratio) were unrelated to symptoms of catecholamine excess (p > 0.05) and to systolic blood pressure (p > 0.05). In PCC/PGL patients, norepinephrine and systolic blood pressure increased in parallel (R-2 = 0.22, p = 0.016). C-11-HED-PET/CT was found to be an accurate tool to diagnose and rule out PCC/PGL in complex clinical scenarios and for the characterization of equivocal adrenal incidentalomas. PET measurements of tumor C-11-HED uptake were not helpful for tumor characterization.

Place, publisher, year, edition, pages
MDPI, 2019
Keywords
pheochromocytoma, paraganglioma, PET-CT, C-11-hydroxy-ephedrine, adrenal incidentaloma
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:uu:diva-390633 (URN)10.3390/cancers11060847 (DOI)000475351200111 ()31248124 (PubMedID)
Available from: 2019-08-21 Created: 2019-08-21 Last updated: 2019-09-10Bibliographically approved
Vyakaranam, A. R., Crona, J., Norlén, O., Granberg, D., Garske-Román, U., Sandström, M., . . . Sundin, A. (2019). Favorable Outcome in Patients with Pheochromocytoma and Paraganglioma Treated with 177Lu-DOTATATE.. Cancers, 11(7), Article ID 909.
Open this publication in new window or tab >>Favorable Outcome in Patients with Pheochromocytoma and Paraganglioma Treated with 177Lu-DOTATATE.
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2019 (English)In: Cancers, ISSN 2072-6694, Vol. 11, no 7, article id 909Article in journal (Refereed) Published
Abstract [en]

Peptide receptor radiotherapy (PRRT) with 177Lu-DOTATATE has emerged as a promising therapy for neuroendocrine tumors (NETs). This retrospective cohort study aimed to assess the outcome of PRRT for 22 patients with histopathologically confirmed pheochromocytoma (PCC) and paraganglioma (PGL), of which two were localized and 20 metastatic. Radiological response utilized response evaluation criteria in solid tumors 1.1 and toxicity was graded according to common terminology criteria for adverse events version 4. Median 4 (range 3-11) 7.4 GBq cycles of 177Lu-DOTATATE were administered as first-line therapy (n = 13) or because of progressive disease (n = 9). Partial response (PR) was achieved in two and stable disease (SD) in 20 patients. The median overall survival (OS) was 49.6 (range 8.2-139) months and median progression-free survival (PFS) was 21.6 (range 6.7-138) months. Scintigraphic response >50% was achieved in 9/19 (47%) patients. Biochemical response (>50% decrease) of chromogranin A was found in 6/15 (40%) patients and of catecholamines in 3/12 (25%) patients. Subgroup analysis showed Ki-67 <15% associated with longer OS (p = 0.013) and PFS (p = 0.005). PRRT as first-line therapy was associated with increased OS (p = 0.041). No hematological or kidney toxicity grade 3-4 was registered. 177Lu-DOTATATE therapy was associated with favorable outcome and low toxicity. High Ki-67 (≥15%) and PRRT received because of progression on previous therapy could constitute negative predictive factors for OS.

Keywords
pheochromocytoma, paraganglioma, Lu-177-DOTATATE, peptide receptor radiotherapy, PRRT, neuroendocrine tumor, NET, PCC, PGL
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-392835 (URN)10.3390/cancers11070909 (DOI)000479322800020 ()31261748 (PubMedID)
Available from: 2019-09-10 Created: 2019-09-10 Last updated: 2019-10-30Bibliographically approved
Muth, A., Crona, J., Gimm, O., Elmgren, A., Filipsson, K., Askmalm, M. S., . . . Tham, E. (2019). Genetic testing and surveillance guidelines in hereditary pheochromocytoma and paraganglioma. Journal of Internal Medicine, 285(2), 187-204
Open this publication in new window or tab >>Genetic testing and surveillance guidelines in hereditary pheochromocytoma and paraganglioma
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2019 (English)In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 285, no 2, p. 187-204Article, review/survey (Refereed) Published
Abstract [en]

Pheochromocytoma and paraganglioma (PPGL) are rare tumours and at least 30% are part of hereditary syndromes. Approximately 20% of hereditary PPGL are caused by pathogenic germ line variants in genes of the succinate dehydrogenase complex (SDHx), TMEM127 or MAX. Herein we present guidelines regarding genetic testing of family members and their surveillance based on a thorough literature review. All cases of PPGL are recommended genetic testing for germ line variants regardless of patient and family characteristics. At minimum, FH, NF1, RET, SDHB, SDHD and VHL should be tested. In addition, testing of MEN1, SDHA, SDHAF2, SDHC, TMEM127 and MAX is recommended. Healthy first-degree relatives (and second-degree relatives in the case of SDHD and SDHAF2 which are maternally imprinted) should be offered carrier testing. Carriers of pathogenic variants should be offered surveillance with annual biochemical measurements of methoxy-catecholamines and bi-annual rapid whole-body magnetic resonance imaging and clinical examination. Surveillance should start 5 years before the earliest age of onset in the family and thus only children eligible for surveillance should be offered pre-symptomatic genetic testing. The surveillance of children younger than 15 years needs to be individually designed. Our guidelines will provide a framework for patient management with the possibility to follow outcome via national registries and/or follow-up studies. Together with improved insights into the disease, this may enable optimisation of the surveillance scheme in order to minimise both anxiety and medical complications while ensuring early disease detection.

Place, publisher, year, edition, pages
John Wiley & Sons, 2019
Keywords
molecular genetics, neuroendocrine tumours, pheochromocytoma
National Category
Medical Genetics Surgery
Identifiers
urn:nbn:se:uu:diva-379423 (URN)10.1111/joim.12869 (DOI)000459577200004 ()30536464 (PubMedID)
Available from: 2019-03-19 Created: 2019-03-19 Last updated: 2019-10-30Bibliographically approved
Crona, J., Lamarca, A., Ghosal, S., Welin, S., Skogseid, B. & Pacak, K. (2019). Genotype-phenotype correlations in pheochromocytoma and paraganglioma: a systematic review and individual patient meta-analysis. Endocrine-Related Cancer, 26(5), 539-550
Open this publication in new window or tab >>Genotype-phenotype correlations in pheochromocytoma and paraganglioma: a systematic review and individual patient meta-analysis
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2019 (English)In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 26, no 5, p. 539-550Article, review/survey (Refereed) Published
Abstract [en]

Pheochromocytoma and paraganglioma (PPGL) can be divided into at least four molecular subgroups. Whether such categorizations are independent factors for prognosis or metastatic disease is unknown. We performed a systematic review and individual patient meta-analysis aiming to estimate if driver mutation status can predict metastatic disease and survival. Driver mutations were used to categorize patients according to three different molecular systems: two subgroups (SDHB mutated or wild type), three subgroups (pseudohypoxia, kinase signaling or Wnt/unknown) and four subgroups (tricarboxylic acid cycle, VHL/EPAS1, kinase signaling or Wnt/unknown). Twenty-one studies and 703 patients were analyzed. Multivariate models for association with metastasis showed correlation with SDHB mutation (OR 5.68 (95% CI 1.79-18.06)) as well as norepinephrine (OR 3.01 (95% CI 1.02-8.79)) and dopa mine (OR 6.39 (95% CI 1.62-25.24)) but not to PPGL location. Other molecular systems were not associated with metastasis. In multivariate models for association with survival, age (HR 1.04 (95% CI 1.02-1.06)) and metastases (HR 6.13 (95% CI 2.86-13.13)) but neither paraganglioma nor SDHB mutation remained significant. Other molecular subgroups did not correlate with survival. We conclude that molecular categorization accordingly to SDHB provided independent information on the risk of metastasis. Driver mutations status did not correlate independently with survival. These data may ultimately be used to guide current and future risk stratification of PPGL.

Place, publisher, year, edition, pages
BIOSCIENTIFICA LTD, 2019
Keywords
pheochromocytoma, paraganglioma, molecular genetics, driver mutations, meta-analysis
National Category
Cancer and Oncology Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-383282 (URN)10.1530/ERC-19-0024 (DOI)000465198700009 ()30893643 (PubMedID)
Available from: 2019-05-14 Created: 2019-05-14 Last updated: 2019-10-30Bibliographically approved
Lamarca, A., Crona, J., Ronot, M., Opalinska, M., Lopez Lopez, C., Pezzutti, D., . . . Dromain, C. (2019). Value of Tumor Growth Rate (TGR) as an Early Biomarker Predictor of Patients' Outcome in Neuroendocrine Tumors (NET): The GREPONET Study. The Oncologist, 24(11), E1082-E1090
Open this publication in new window or tab >>Value of Tumor Growth Rate (TGR) as an Early Biomarker Predictor of Patients' Outcome in Neuroendocrine Tumors (NET): The GREPONET Study
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2019 (English)In: The Oncologist, ISSN 1083-7159, E-ISSN 1549-490X, Vol. 24, no 11, p. E1082-E1090Article in journal (Refereed) Published
Abstract [en]

INTRODUCTION: Tumor growth rate (TGR; percent size change per month [%/m]) is postulated to be an early radiological biomarker to overcome limitations of RECIST. This study aimed to assess the impact of TGR in neuroendocrine tumors (NETs) and potential clinical and therapeutic applications.

MATERIALS AND METHODS: Patients (pts) with advanced grade (G) 1/2 NETs from the pancreas or small bowel initiating systemic treatment (ST) or watch and wait (WW) were eligible. Baseline and follow-up scans were retrospectively reviewed to calculate TGR at pretreatment (TGR0), first follow-up (TGRfirst), and 3(±1) months of study entry (TGR3m).

RESULTS: Out of 905 pts screened, 222 were eligible. Best TGRfirst (222 pts) cutoff was 0.8 (area under the curve, 0.74). When applied to TGR3m (103 pts), pts with TGR3m <0.8 (66.9%) versus TGR3m ≥ 0.8 (33.1%) had longer median progression-free survival (PFS; 26.3 m; 95% confidence interval [CI] 19.5-32.4 vs. 9.3 m; 95% CI, 6.1-22.9) and lower progression rate at 12 months (7.3% vs. 56.8%; p = .001). WW (vs. ST) and TGR3m ≥ 0.8 (hazard ratio [HR], 3.75; 95% CI, 2.21-6.34; p < .001) were retained as factors associated with a shorter PFS in multivariable Cox regression. TGR3m (HR, 3.62; 95% CI, 1.97-6.64; p < .001) was also an independent factor related to shorter PFS when analysis was limited to pts with stable disease (81 pts). Out of the 60 pts with TGR0 data available, 60% of pts had TGR0 < 4%/month. TGR0 ≥ 4 %/month (HR, 2.22; 95% CI, 1.15-4.31; p = .018) was also an independent factor related to shorter PFS.

CONCLUSION: TGR is an early radiological biomarker able to predict PFS and to identify patients with advanced NETs who may require closer radiological follow-up.

IMPLICATIONS FOR PRACTICE: Tumor growth rate at 3 months (TGR3m) is an early radiological biomarker able to predict progression-free survival and to identify patients with advanced neuroendocrine tumors who may require closer radiological follow-up. It is feasible to calculate TGR3m in clinical practice and it could be a useful tool for guiding patient management. This biomarker could also be implemented in future clinical trials to assess response to therapy.

Keywords
NET, Neuroendocrine tumor, Progression‐free survival, TGR, Tumor growth rate
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-382950 (URN)10.1634/theoncologist.2018-0672 (DOI)000496040200007 ()30910869 (PubMedID)
Available from: 2019-05-07 Created: 2019-05-07 Last updated: 2019-12-04Bibliographically approved
Crona, J., Beuschlein, F., Pacak, K. & Skogseid, B. (2018). Advances in adrenal tumors 2018. Endocrine-Related Cancer, 25(7), R405-R420
Open this publication in new window or tab >>Advances in adrenal tumors 2018
2018 (English)In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 25, no 7, p. R405-R420Article, review/survey (Refereed) Published
Abstract [en]

This review aims to provide clinicians and researchers with a condensed update on the most important studies in the field during 2017. We present the academic output measured by active clinical trials and peer-reviewed published manuscripts. The most important and contributory manuscripts were summarized for each diagnostic entity, with a particular focus on manuscripts that describe translational research that have the potential to improve clinical care. Finally, we highlight the importance of collaborations in adrenal tumor research, which allowed for these recent advances and provide structures for future success in this scientific field.

Keywords
adrenal tumor, adrenocortical adenoma, adrenocortical carcinoma, paraganglioma, pheochromocytoma
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-363615 (URN)10.1530/ERC-18-0138 (DOI)000438079000002 ()29794126 (PubMedID)
Available from: 2018-10-18 Created: 2018-10-18 Last updated: 2019-10-30Bibliographically approved
Barbolosi, D., Crona, J., Serre, R., Pacak, K. & Taieb, D. (2018). Mathematical modeling of disease dynamics in SDHB- and SDHD-related paraganglioma: Further step in understanding hereditary tumor differences and future therapeutic strategies.. PLoS ONE, 13(8), Article ID e0201303.
Open this publication in new window or tab >>Mathematical modeling of disease dynamics in SDHB- and SDHD-related paraganglioma: Further step in understanding hereditary tumor differences and future therapeutic strategies.
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2018 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 8, article id e0201303Article in journal (Refereed) Published
Abstract [en]

Succinate dehydrogenase subunit B and D (SDHB and SDHD) mutations represent the most frequent cause of hereditary pheochromocytoma and paraganglioma (PPGL). Although truncation of the succinate dehydrogenase complex is thought to be the disease causing mechanism in both disorders, SDHB and SDHD patients exihibit different phenotypes. These phenotypic differences are currently unexplained by molecular genetics. The aim of this study is to compare disease dynamics in these two conditions via a Markov chain model based on 4 clinically-defined steady states. Our model corroborates at the population level phenotypic observations in SDHB and SDHD carriers and suggests potential explanations associated with the probabilities of disease maintenance and regression. In SDHB-related syndrome, PPGL maintenance seems to be reduced compared to SDHD (p = 0.04 vs 0.95) due to higher probability of tumor cell regression in SDHB vs SDHD (p = 0.87 vs 0.00). However, when SDHB-tumors give rise to metastases, metastatic cells are able to thrive with decreased probability of regression compared with SDHD counterparts (p = 0.17 vs 0.89). By constrast, almost all SDHD patients develop PGL (mainly head and neck) that persist throughout their lifetime. However, compared to SDHB, maintenance of metastatic lesions seems to be less effective for SDHD (p = 0.83 vs 0.11). These findings align with data suggesting that SDHD-related PPGL require less genetic events for tumor initiation and maintenance compared to those related to SDHB, but fail to initiate biology that promotes metastatic spread and metastatic cell survival in host tissues. By contrast, the higher number of genetic abnormalities required for tumor initiation and maintenance in SDHB PPGL result in a lower penetrance of PGL, but when cells give rise to metastases they are assumed to be better adapted to sustain survival. These proposed differences in disease progression dynamics between SDHB and SDHD diseases provide new cues for future exploration of SDHx PPGL behavior, offering considerations for future specific therapeutic and prevention strategies.

National Category
Surgery
Identifiers
urn:nbn:se:uu:diva-363617 (URN)10.1371/journal.pone.0201303 (DOI)000441662800006 ()30106970 (PubMedID)
Available from: 2018-10-18 Created: 2018-10-18 Last updated: 2019-10-30Bibliographically approved
Crona, J., Lamarca, A., Ronot, M., Opalinska, M., Lopez Lopez, C., Pezzutti, D., . . . Dromain, C. (2018). Pre-Treatment Tumor Growth Rate (TGR0) in Patients Diagnosed with Well-Differentiated Neuroendocrine Tumors (NETs) Treated with Systemic Therapies: Subgroup Analysis of the GREPONET Study. Paper presented at 15th Annual ENETS Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, MAR 07-09, 2018, Barcelona, SPAIN. Neuroendocrinology, 106(Supplement: 1), 171-171
Open this publication in new window or tab >>Pre-Treatment Tumor Growth Rate (TGR0) in Patients Diagnosed with Well-Differentiated Neuroendocrine Tumors (NETs) Treated with Systemic Therapies: Subgroup Analysis of the GREPONET Study
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2018 (English)In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 106, no Supplement: 1, p. 171-171Article in journal, Meeting abstract (Other academic) Published
Keywords
tumor growth rate, tgr, recist, neuroendocrine tumor
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-355842 (URN)10.1159/000487699 (DOI)000427285300169 ()
Conference
15th Annual ENETS Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, MAR 07-09, 2018, Barcelona, SPAIN
Note

Meeting Abstract: G05

Available from: 2018-07-13 Created: 2018-07-13 Last updated: 2019-10-30Bibliographically approved
Crona, J., Backman, S., Welin, S., Taieb, D., Hellman, P., Stålberg, P., . . . Pacak, K. (2018). RNA-Sequencing Analysis of Adrenocortical Carcinoma, Pheochromocytoma and Paraganglioma from a Pan-Cancer Perspective. Cancers, 10(12), Article ID 518.
Open this publication in new window or tab >>RNA-Sequencing Analysis of Adrenocortical Carcinoma, Pheochromocytoma and Paraganglioma from a Pan-Cancer Perspective
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2018 (English)In: Cancers, ISSN 2072-6694, Vol. 10, no 12, article id 518Article in journal (Refereed) Published
Abstract [en]

Adrenocortical carcinoma (ACC) and pheochromocytoma and paraganglioma (PPGL) are defined by clinicopathological criteria and can be further sub-divided based on different molecular features. Whether differences between these molecular subgroups are significant enough to re-challenge their current clinicopathological classification is currently unknown. It is also not fully understood to which other cancers ACC and PPGL show similarity to. To address these questions, we included recent RNA-Seq data from the Cancer Genome Atlas (TCGA) and Therapeutically Applicable Research to Generate Effective Treatments (TARGET) datasets. Two bioinformatics pipelines were used for unsupervised clustering and principal components analysis. Results were validated using consensus clustering model and interpreted according to previous pan-cancer experiments. Two datasets consisting of 3319 tumors from 35 disease categories were studied. Consistent with the current classification, ACCs clustered as a homogenous group in a pan-cancer context. It also clustered close to neural crest derived tumors, including gliomas, neuroblastomas, pancreatic neuroendocrine tumors, and PPGLs. Contrary, some PPGLs mixed with pancreatic neuroendocrine tumors or neuroblastomas. Thus, our unbiased gene-expression analysis of PPGL did not overlap with their current clinicopathological classification. These results emphasize some importances of the shared embryological origin of these tumors, all either related or close to neural crest tumors, and opens for investigation of a complementary categorization based on gene-expression features.

Place, publisher, year, edition, pages
MDPI, 2018
Keywords
pheochromocytoma, paraganglioma, adrenocortical carcinoma, adrenal tumor, pan-cancer analysis, neural crest, neuroendocrine
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-375237 (URN)10.3390/cancers10120518 (DOI)000455199200056 ()30558313 (PubMedID)
Available from: 2019-01-29 Created: 2019-01-29 Last updated: 2019-01-29Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0003-0677-4894

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