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Introduction The value of a sural nerve biopsy for the diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is controversial. Evidence-based recommendations for its implementation are lacking. We investigated factors leading to biopsy and analyzed biopsy outcomes and consequences, assessed the predictability of biopsy outcomes through clinical parameters to avoid unnecessary biopsies, and compared results with electrophysiological and clinical severity to determine their prognostic value. Methods 190 sural nerve biopsies were analyzed in two cohorts. One consisted of 163 biopsies and the second of 72 biopsies from the prospective Immune-mediated Neuropathies Biomaterial and Data registry (INHIBIT). Both have an intersection of 45 patients. 75 data sets from patients without biopsy were used. Analysis of nerve conduction studies, treatment, overall disability sum score (ODSS), biopsy outcomes, and diagnosis was performed. Results 51% of biopsied patients received the diagnosis CIDP (77% fulfilled EFNS/PNS criteria), 21% were not CIDP typical, and 27% were unspecific. Biopsied patients responded less frequently to immunotherapies at time of biopsy than non-biopsied patients ( p  = 0.003). Immunotherapy was initiated more frequently after biopsy ( p  < 0.001) and more often with intravenous immunoglobulins ( p  < 0.0001). 76% of all biopsied patients met the electrophysiological criteria for CIDP. Sensory nerve action potential amplitudes of 0 µV still provide 73% of histological diagnostic value. Histologic signs of degeneration predicted ODSS worsening after 1 year ( p  = 0.028) but disease severity did not correlate with histological damage severity. Discussion The main indication for nerve biopsy was the treatment of refractory cases of autoimmune neuropathies with the therapeutic consequence of treatment initiation or escalation. Sural biopsy also provided prognostic information. Even with extinguished sural SNAP, the biopsy can still have diagnostic value.

This review encompasses the most important advances in liver functions and hepatotoxicity and analyzes which mechanisms can be studied in vitro. In a complex architecture of nested, zonated lobules, the liver consists of approximately 80 % hepatocytes and 20 % non-parenchymal cells, the latter being involved in a secondary phase that may dramatically aggravate the initial damage. Hepatotoxicity, as well as hepatic metabolism, is controlled by a set of nuclear receptors (including PXR, CAR, HNF-4α, FXR, LXR, SHP, VDR and PPAR) and signaling pathways. When isolating liver cells, some pathways are activated, e.g., the RAS/MEK/ERK pathway, whereas others are silenced (e.g. HNF-4α), resulting in up- and downregulation of hundreds of genes. An understanding of these changes is crucial for a correct interpretation of in vitro data. The possibilities and limitations of the most useful liver in vitro systems are summarized, including three-dimensional culture techniques, co-cultures with non-parenchymal cells, hepatospheres, precision cut liver slices and the isolated perfused liver. Also discussed is how closely hepatoma, stem cell and iPS cell–derived hepatocyte-like-cells resemble real hepatocytes. Finally, a summary is given of the state of the art of liver in vitro and mathematical modeling systems that are currently used in the pharmaceutical industry with an emphasis on drug metabolism, prediction of clearance, drug interaction, transporter studies and hepatotoxicity. One key message is that despite our enthusiasm for in vitro systems, we must never lose sight of the in vivo situation. Although hepatocytes have been isolated for decades, the hunt for relevant alternative systems has only just begun.

Infantile myofibromatosis (IM), which is typically diagnosed in young children, comprises a wide clinical spectrum ranging from inconspicuous solitary soft tissue nodules to multiple disseminated tumors resulting in life-threatening complications. Familial IM follows an autosomal dominant mode of inheritance and is linked to PDGFRB germline variants. Somatic PDGFRB variants were also detected in solitary and multifocal IM lesions. PDGFRB variants associated with IM constitutively activate PDGFRB kinase activity in the absence of its ligand. Germline variants have lower activating capabilities than somatic variants and, thus, require a second cis-acting hit for full receptor activation. Typically, these mutant receptors remain sensitive to tyrosine kinase inhibitors such as imatinib. The SIOPE Host Genome Working Group, consisting of pediatric oncologists, clinical geneticists and scientists, met in January 2020 to discuss recommendations for genetic testing and surveillance for patients who are diagnosed with IM or have a family history of IM/PDGFRB germline variants. This report provides a brief review of the clinical manifestations and genetics of IM and summarizes our interdisciplinary recommendations.

Background The clinical phenotype associated with germline SMARCB1 mutations has as yet not been fully documented. It is known that germline SMARCB1 mutations may cause rhabdoid tumor predisposition syndrome (RTPS1) or schwannomatosis. However, the co‐occurrence of rhabdoid tumor and schwannomas in the same patient has not so far been reported. Methods We investigated a family with members harboring a germline SMARCB1 deletion by means of whole‐body MRI as well as high‐resolution microstructural magnetic resonance neurography (MRN). Breakpoint‐spanning PCRs were performed to characterize the SMARCB1 deletion and its segregation in the family. Results The index patient of this family was in complete continuous remission for an atypical teratoid/rhabdoid tumor (AT/RT) treated at the age of 2 years. However, at the age of 21 years, she exhibited paraparesis of her legs and MRI investigations revealed multiple intrathoracic and spinal schwannomas. Breakpoint‐spanning PCRs indicated that the germline deletion segregating in the family encompasses 6.4‐kb and includes parts of SMARCB1 intron 7, exons 8–9 and 3.3‐kb located telomeric to exon 9 including the SMARCB1 3′ UTR. The analysis of sequences at the deletion breakpoints showed that the deletion has been caused by replication errors including template‐switching. The patient had inherited the deletion from her 56‐year‐old healthy mother who did not exhibit schwannomas or other tumors as determined by whole‐body MRI. However, MRN of the peripheral nerves of the mother's extremities revealed multiple fascicular microlesions which have been previously identified as indicative of schwannomatosis‐associated subclinical peripheral nerve pathology. Conclusion The occurrence of schwannomatosis‐associated clinical symptoms independent of the AT/RT as the primary disease should be considered in long‐term survivors of AT/RT. Furthermore, our investigations indicate that germline SMARCB1 mutation carriers not presenting RTs or schwannomatosis‐associated clinical symptoms may nevertheless exhibit peripheral nerve pathology as revealed by MRN. Our findings indicate that long‐term survivors of AT/RT harboring germline SMARCB1 mutations should be surveilled for the occurrence of schwannomatosis‐associated clinical symptoms which are independent of the AT/RT as the primary disease. Furthermore, our investigations indicate that germline SMARCB1 mutation carriers not presenting rhabdoid tumors or schwannomatosis‐associated clinical symptoms may nevertheless exhibit peripheral nerve pathology as revealed by MRN.