TY  - JOUR
A1  - Koehler, Viktoria Florentine
A1  - Adam, Pia
A1  - Fuss, Carmina Teresa
A1  - Jiang, Linmiao
A1  - Berg, Elke
A1  - Frank-Raue, Karin
A1  - Raue, Friedhelm
A1  - Hoster, Eva
A1  - Knösel, Thomas
A1  - Schildhaus, Hans-Ulrich
A1  - Negele, Thomas
A1  - Siebolts, Udo
A1  - Lorenz, Kerstin
A1  - Allelein, Stephanie
A1  - Schott, Matthias
A1  - Spitzweg, Christine
A1  - Kroiss, Matthias
T1  - Treatment of RET-positive advanced medullary thyroid cancer with multi-tyrosine kinase inhibitors — a retrospective multi-center registry analysis
JF  - Cancers
N2  - Background: RET (rearranged during transfection) variants are the most prevalent oncogenic events in medullary thyroid cancer (MTC). In advanced disease, multi-tyrosine kinase inhibitors (MKIs) cabozantinib and vandetanib are the approved standard treatment irrespective of RET status. The actual outcome of patients with RET-positive MTC treated with MKIs is ill described. Methods: We here retrospectively determined the RET oncogene variant status with a targeted DNA Custom Panel in a prospectively collected cohort of 48 patients with advanced MTC treated with vandetanib and/or cabozantinib at four German referral centers. Progression-free survival (PFS) and overall survival (OS) probabilities were estimated using the Kaplan-Meier method. Results: In total, 44/48 (92%) patients had germline or somatic RET variants. The M918T variant was found in 29/44 (66%) cases. In total, 2/32 (6%) patients with a somatic RET variant had further somatic variants, while in 1/32 (3%) patient with a germline RET variant, additional variants were found. Only 1/48 (2%) patient had a pathogenic HRAS variant, and no variants were found in 3 cases. In first-line treatment, the median OS was 53 (95% CI (95% confidence interval), 32–NR (not reached); n = 36), and the median PFS was 21 months (12–39; n = 33) in RET-positive MTC patients. In second-line treatment, the median OS was 18 (13–79; n = 22), and the median PFS was 3.5 months (2–14; n = 22) in RET-positive cases. Conclusions: RET variants were highly prevalent in patients with advanced MTC. The treatment results in RET-positive cases were similar to those reported in unselected cohorts.
KW  - medullary thyroid cancer
KW  - rearranged during transfection
KW  - variant
KW  - multi-tyrosine kinase inhibitor
KW  - survival
KW  - treatment outcome
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-281776
SN  - 2072-6694
VL  - 14
IS  - 14
ER  - 
TY  - JOUR
A1  - Lau, Kolja
A1  - Üçeyler, Nurcan
A1  - Cairns, Tereza
A1  - Lorenz, Lora
A1  - Sommer, Claudia
A1  - Schindehütte, Magnus
A1  - Amann, Kerstin
A1  - Wanner, Christoph
A1  - Nordbeck, Peter
T1  - Gene variants of unknown significance in Fabry disease: Clinical characteristics of c.376AG (p.Ser126Gly)
JF  - Molecular Genetics & Genomic Medicine
N2  - Background
Anderson–Fabry disease (FD) is an X-linked lysosomal storage disorder with varying organ involvement and symptoms, depending on the underlying mutation in the alpha-galactosidase A gene (HGNC: GLA). With genetic testing becoming more readily available, it is crucial to precisely evaluate pathogenicity of each genetic variant, in order to determine whether there is or might be not a need for FD-specific therapy in affected patients and relatives at the time point of presentation or in the future.

Methods
This case series investigates the clinical impact of the specific GLA gene variant c.376A>G (p.Ser126Gly) in five (one heterozygous and one homozygous female, three males) individuals from different families, who visited our center between 2009 and 2021. Comprehensive neurological, nephrological and cardiac examinations were performed in all cases. One patient received a follow-up examination after 12 years.

Results
Index events leading to suspicion of FD were mainly unspecific neurological symptoms. However, FD-specific biomarkers, imaging examinations (i.e., brain MRI, heart MRI), and tissue-specific diagnostics, including kidney and skin biopsies, did not reveal evidence for FD-specific symptoms or organ involvement but showed normal results in all cases. This includes findings from 12-year follow-up in one patient with renal biopsy.

Conclusion
These findings suggest that p.Ser126Gly represents a benign GLA gene variant which per se does not cause FD. Precise clinical evaluation in individuals diagnosed with genetic variations of unknown significance should be performed to distinguish common symptoms broadly prevalent in the general population from those secondary to FD.
KW  - diagnosis in Fabry disease
KW  - Fabry disease
KW  - gene variant
KW  - genotype/phenotype correlation
KW  - lysosomal storage disease
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-312817
VL  - 10
IS  - 5
ER  -