Fulminant Hepatic Failure Caused by Diffuse Liver Metastases following Gastrointestinal Stromal Tumor Resection

Metastatic tumors to the liver resulting in fulminant hepatic failure are a rare occurrence and have not been previously described in patients with gastrointestinal stromal tumor (GIST). A 70 year-old man was referred to hospital with postprandial discomfort. On examination a 19.5 cm large epithelioid GIST of the stomach was diagnosed. The mass exhibited unfavorable prognostic features: mitotic index 18/50 high-power fields, large primary tumor size and male sex. Complete tumor resection with negative margins was achieved and metastases were not detected. The patient presented six months later with jaundice, asterixis and elevated liver enzymes. Computerized tomography showed multiple liver hypodense lesions representing metastases. Treatment with imatinib mesylate was of no avail and the patient died 3 days later as the result of hepatic failure. Massive liver metastases can, even though rarely, be responsible for fulminant hepatic failure. Clinical and radiological follow-up are crucial in patients with GIST even after surgical resection

Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes

Adoptive transfer of chimeric antigen receptor (CAR)-redirected T lymphocytes (CAR-T cells) has had less striking effects in solid tumors(1–3) than in lymphoid malignancies(4, 5). Although active tumor-mediated immunosuppression may play a role in limiting efficacy(6), functional changes in T lymphocytes following their ex vivo manipulation may also account for cultured CAR-T cells’ reduced ability to penetrate stroma-rich solid tumors. We therefore studied the capacity of human in vitro-cultured CAR-T cells to degrade components of the extracellular matrix (ECM). In contrast to freshly isolated T lymphocytes, we found that in vitro-cultured T lymphocytes lack expression of the enzyme heparanase (HPSE) that degrades heparan sulphate proteoglycans, which are main components of ECM. We found that HPSE mRNA is down regulated in in vitro-expanded T cells, which may be a consequence of p53 binding to the HPSE gene promoter. We therefore engineered CAR-T cells to express HPSE and showed improved capacity to degrade ECM, which promoted tumor T-cell infiltration and antitumor activity. Employing this strategy may enhance the activity of CAR-T cells in individuals with stroma-rich solid tumors

Sequence variation in PPP1R13L results in a novel form of cardio‐cutaneous syndrome

Dilated cardiomyopathy (DCM) is a life‐threatening disorder whose genetic basis is heterogeneous and mostly unknown. Five Arab Christian infants, aged 4–30 months from four families, were diagnosed with DCM associated with mild skin, teeth, and hair abnormalities. All passed away before age 3. A homozygous sequence variation creating a premature stop codon at PPP1R13L encoding the iASPP protein was identified in three infants and in the mother of the other two. Patients’ fibroblasts and PPP1R13L‐knocked down human fibroblasts presented higher expression levels of pro‐inflammatory cytokine genes in response to lipopolysaccharide, as well as Ppp1r13l‐knocked down murine cardiomyocytes and hearts of Ppp1r13l‐deficient mice. The hypersensitivity to lipopolysaccharide was NF‐κB‐dependent, and its inducible binding activity to promoters of pro‐inflammatory cytokine genes was elevated in patients’ fibroblasts. RNA sequencing of Ppp1r13l‐knocked down murine cardiomyocytes and of hearts derived from different stages of DCM development in Ppp1r13l‐deficient mice revealed the crucial role of iASPP in dampening cardiac inflammatory response. Our results determined PPP1R13L as the gene underlying a novel autosomal‐recessive cardio‐cutaneous syndrome in humans and strongly suggest that the fatal DCM during infancy is a consequence of failure to regulate transcriptional pathways necessary for tuning cardiac threshold response to common inflammatory stressors