Comprehensive targeted next-generation sequencing approach in the molecular diagnosis of gastrointestinal stromal tumor.

Mutational analysis guides therapeutic decision making in patients with advanced-stage gastrointestinal stromal tumors (GISTs). We evaluated three targeted next-generation sequencing (NGS) assays, consecutively used over 4 years in our laboratory for mutational analysis of 162 primary GISTs: Agilent GIST MASTR, Illumina TruSight 26 and an in-house developed 96 gene panels. In addition, we investigated the feasibility of a more comprehensive approach by adding targeted RNA sequencing (Archer FusionPlex, 11 genes) in an attempt to reduce the number of Wild Type GISTs. We found KIT or PDGFRA mutations in 149 out of 162 GISTs (92.0%). Challenging KIT exon 11 alterations were initially missed by different assays in seven GISTs and typically represented deletions at the KIT intron 10-exon 11 boundary or large insertions/deletions (>24 base pairs). Comprehensive analysis led to the additional identification of driver alterations in 8/162 GISTs (4.9%): apart from BRAF and SDHA mutations (one case each), we found five GISTs harboring somatic neurofibromatosis type 1 (NF1) alterations (3.1%) and one case with an in-frame TRIM4-BRAF fusion not reported in GIST before. Eventually, no driver alteration was found in two out of 162 GISTs (1.2%) and three samples (1.9%) failed analysis. Our study shows that a comprehensive targeted NGS approach is feasible for routine mutational analysis of GIST, thereby substantially reducing the number of Wild Type GISTs, and highlights the need to optimize assays for challenging KIT exon 11 alterations.

Roux-en-y gastric bypass attenuates hepatic mitochondrial dysfunction in mice with non-alcoholic steatohepatitis.

OBJECTIVE: No therapy for non-alcoholic steatohepatitis (NASH) has been approved so far. Roux-en-y gastric bypass (RYGB) is emerging as a therapeutic option, although its effect on NASH and related hepatic molecular pathways is unclear from human studies. We studied the effect of RYGB on pre-existent NASH and hepatic mitochondrial dysfunction-a key player in NASH pathogenesis-in a novel diet-induced mouse model nicely mimicking human disease. DESIGN: C57BL/6J mice were fed a high-fat high-sucrose diet (HF-HSD). RESULTS: HF-HSD led to early obesity, insulin resistance and hypercholesterolaemia. HF-HSD consistently induced NASH (steatosis, hepatocyte ballooning and inflammation) with fibrosis already after 12-week feeding. NASH was accompanied by hepatic mitochondrial dysfunction, characterised by decreased mitochondrial respiratory chain (MRC) complex I and IV activity, ATP depletion, ultrastructural abnormalities, together with higher 4-hydroxynonenal (HNE) levels, increased uncoupling protein 2 (UCP2) and tumour necrosis factor-α (TNF-α) mRNA and free cholesterol accumulation. In our model of NASH and acquired mitochondrial dysfunction, RYGB induced sustained weight loss, improved insulin resistance and inhibited progression of NASH, with a marked reversal of fibrosis. In parallel, RYGB preserved hepatic MRC complex I activity, restored ATP levels, limited HNE production and decreased TNF-α mRNA. CONCLUSIONS: Progression of NASH and NASH-related hepatic mitochondrial dysfunction can be prevented by RYGB. RYGB preserves respiratory chain complex activity, thereby restoring energy output, probably by limiting the amount of oxidative stress and TNF-α. These data suggest that modulation of hepatic mitochondrial function contributes to the favourable effect of RYBG on established NASH.

Peritoneal Surface Malignancies Originating From Urachal Carcinoma: Case Reports and Review of the Literature.

Urachal carcinoma (UC) is a rare and aggressive tumor arising from the urachal remnants, with the potential for peritoneal dissemination. Patients diagnosed with UC often have a poor prognosis. To date, there is no standardized treatment. Our objective is to present two cases of patients with peritoneal carcinomatosis (PC) secondary to an UC, who were treated with cytoreductive surgery (CRS) and hyperthermic peroperative intraperitoneal chemotherapy (HIPEC). A review of the literature on CRS and HIPEC in UC suggests CRS and HIPEC to be a safe and viable treatment option. Two patients with PC of UC underwent CRS and HIPEC in our institution. All available data were gathered and reported on. A literary search was carried out to find all available cases of patients with PC secondary to UC treated with CRS and HIPEC. Both patients underwent CRS and HIPEC and are currently free of recurrence. Literature research revealed nine other publications adding up to a total of 68 additional cases. CRS and HIPEC can provide satisfactory long-term oncological outcome with acceptable morbidity and mortality rates in patients with PC of urachal origin. It should be considered as a safe and feasible treatment option with curative potential.

Glioblastoma with extracranial parotid, lymph node, and pulmonary metastases: a case report.

We present a rare case of an isocitrate dehydrogenase-wildtype glioblastoma with histologically proven parotid, cervical lymph node, and lung metastases. While recent therapy advances are likely to increase glioblastoma mid- and long-term survival, this will also increase the time window for extraneural glioblastoma spread. Radiologists should be aware of this risk, so they can accurately detect and interpret metastatic glioblastoma disease.