Sorafenib for the treatment of advanced hepatocellular cancer – a UK audit

Aims: Sorafenib is the current standard treatment for advanced hepatocellular carcinoma. We carried out a national audit of UK patients treated with sorafenib as standard-of-care and those treated with systemic therapy in first-line trials. Materials and methods: Sorafenib-treated and trial-treated patients were identified via the Cancer Drugs Fund and local databases. Data were collected retrospectively from medical records according to a standard case report form. The primary outcome measure was overall survival, estimated by the Kaplan–Meier method. Results: Data were obtained for 448 sorafenib-treated patients from 15 hospitals. The median age was 68 years (range 17–89) and 75% had performance status ≤ 1. At baseline, 77% were Child-Pugh A and 16.1% Child-Pugh B; 38% were albumin–bilirubin grade 1 (ALBI-1) and 48% ALBI-2; 23% were Barcelona Clinic Liver Classification B (BCLC-B) and 72% BCLC-C. The median time on sorafenib was 3.6 months, with a mean daily dose of 590 mg. The median overall survival for 448 evaluable sorafenib-treated patients was 8.5 months. There were significant differences in overall survival comparing Child-Pugh A versus Child-Pugh B (9.5 versus 4.6 months), ALBI-1 versus ALBI-2 (12.9 versus 5.9 months) and BCLC-B versus BCLC-C (13.0 versus 8.3 months). For trial-treated patients (n = 109), the median overall survival was 8.1 months and this was not significantly different from the sorafenib-treated patients. Conclusion: For Child-Pugh A patients with good performance status, survival outcomes were similar to those reported in global randomised controlled trials. Patients with ALBI grade > 1, Child-Pugh B or poor performance status seem to derive limited benefit from sorafenib treatment

High salt reduces the activation of IL-4- and IL-13-stimulated macrophages

A high intake of dietary salt (NaCl) has been implicated in the development of hypertension, chronic inflammation, and autoimmune diseases. We have recently shown that salt has a proinflammatory effect and boosts the activation of Th17 cells and the activation of classical, LPS-induced macrophages (M1). Here, we examined how the activation of alternative (M2) macrophages is affected by salt. In stark contrast to Th17 cells and M1 macrophages, high salt blunted the alternative activation of BM-derived mouse macrophages stimulated with IL-4 and IL-13, M(IL-4+IL-13) macrophages. Salt-induced reduction of M(IL-4+IL-13) activation was not associated with increased polarization toward a proinflammatory M1 phenotype. In vitro, high salt decreased the ability of M(IL-4+IL-13) macrophages to suppress effector T cell proliferation. Moreover, mice fed a high salt diet exhibited reduced M2 activation following chitin injection and delayed wound healing compared with control animals. We further identified a high salt-induced reduction in glycolysis and mitochondrial metabolic output, coupled with blunted AKT and mTOR signaling, which indicates a mechanism by which NaCl inhibits full M2 macrophage activation. Collectively, this study provides evidence that high salt reduces noninflammatory innate immune cell activation and may thus lead to an overall imbalance in immune homeostasis

The amyloid precursor protein controls PIKfyve function

While the Amyloid Precursor Protein (APP) plays a central role in Alzheimer's disease, its cellular function still remains largely unclear. It was our goal to establish APP function which will provide insights into APP's implication in Alzheimer's disease. Using our recently developed proteo-liposome assay we established the interactome of APP's intracellular domain (known as AICD), thereby identifying novel APP interactors that provide mechanistic insights into APP function. By combining biochemical, cell biological and genetic approaches we validated the functional significance of one of these novel interactors. Here we show that APP binds the PIKfyve complex, an essential kinase for the synthesis of the endosomal phosphoinositide phosphatidylinositol-3,5-bisphosphate. This signalling lipid plays a crucial role in endosomal homeostasis and receptor sorting. Loss of PIKfyve function by mutation causes profound neurodegeneration in mammals. Using C. elegans genetics we demonstrate that APP functionally cooperates with PIKfyve in vivo. This regulation is required for maintaining endosomal and neuronal function. Our findings establish an unexpected role for APP in the regulation of endosomal phosphoinositide metabolism with dramatic consequences for endosomal biology and important implications for our understanding of Alzheimer's disease

Carcinoid syndrome: Patient outcomes from a European Neuroendocrine Tumour Society (ENETs) centre of excellence

Background: Carcinoid syndrome (CS), characterised by flushing, diarrhoea, wheeze and fibrotic valvulopathy, arises in patients (pts) with advanced NETs due to serotonin and kallikrein secretion.Methods: Sequential pts with advanced well-differentiated gastroenteropancreatic NETs (GEP-NETs) treated at The Christie (1998-2017) with ≥1 carcinoid symptom(s) and raised serum/urinary 5-hydroxyindoleacetic acid (5-HIAA) were identified. Ratio of 5-HIAA/upper limit normal (ULN) was calculated. Progression-free (PFS) and overall survival (OS) were estimated (Kaplan-Meier method) and prognostic factors identified (Cox proportional hazards model).Results: Of 882 pts, 139 (16%) had CS: median (med) age 64 yrs, 55% male, 80% performance status (PS) 0-1, 13% PS 2; 65% had small bowel primary, 10% large bowel, 4% pancreas, 0.7% gastric, 21% unknown primary (consistent with GEP-NET origin). Tumour grade (G) was 1 in 45%; G2 in 29%; symptoms included diarrhoea (91%), flushing (89%), wheeze (22%), and carcinoid heart disease (CHD; 35%). Fifty-seven (41%) had primary resection, and 121 (87%) had liver metastases. In first line, 66% received a somatostatin analogue (SSA), 20% debulking surgery, 14% other. Med baseline 5-HIAA levels were 8.45 x ULN (urinary: 10.56 x ULN, serum: 6.07 x ULN). Med follow-up was 45.7 months (mo). Med PFS and OS were 27.0 (95%CI 17.2-33.9) and 65.4 (95%CI 50.4-76.4) mo. On univariate analysis, small bowel primary (P = 0.045), liver metastases (P = 0.03), Ki-67 (P < 0.01) and 5-HIAA baseline ratio (P < 0.001) were prognostic for PFS; and age (P < 0.01), PS (P < 0.01), primary in situ (P < 0.001), CHD (P = 0.03), Ki-67 (P = 0.03), baseline 5-HIAA ratio (P < 0.001) and use of SSA vs surgery (P = 0.02) were prognostic for OS. On multivariable analysis, high Ki-67 (HR 1.06, 95%CI 1.00-1.12, P = 0.049) and baseline 5-HIAA ratio (HR 1.03, 95%CI 1.01-1.05, P = 0.001) were prognostic for worse PFS. Primary in situ (HR 2.23, 95%CI 1.09-4.54, P = 0.03) and high baseline 5-HIAA ratio (HR 1.02, 95%CI 1.00-1.04, P = 0.04) were prognostic for worse OS. Change in 5-HIAA at 6 mo was not prognostic for PFS (P = 0.42) or OS (P = 0.60).Conclusions: Baseline 5-HIAA ratio, but not change from baseline to 6 months, was prognostic for PFS and OS. Treatment optimisation is pivotal

HOXB4 can enhance the differentiation of embryonic stem cells by modulating the haematopoietic niche

Haematopoietic differentiation of embryonic stem (ES) cells in vitro has been used as a model to study early haematopoietic development and it is well documented that haematopoietic differentiation can be enhanced by over-expression of HOXB4. HOXB4 is expressed in haematopoietic progenitor cells (HPC) where it promotes self-renewal, but it is also expressed in the primitive streak of the gastrulating embryo. This led us to hypothesise that HOXB4 might modulate gene expression in pre-haematopoietic mesoderm and that this property might contribute to its pro-haematopoietic effect in differentiating ES cells. To test our hypothesis we developed a conditionally activated HOXB4 expression system using the mutant oestrogen receptor (ER(T2)) and showed that a pulse of HOXB4 prior to HPC emergence in differentiating ES cells led to an increase in haematopoietic differentiation. Expression profiling revealed an increase in the expression of genes associated with paraxial mesoderm that gives rise to the haematopoietic niche. We therefore considered that HOXB4 might modulate the formation of the haematopoietic niche as well as the production of haematopoietic cells per se. Cell mixing experiments supported this hypothesis demonstrating that HOXB4 activation can generate a paracrine as well as a cell autonomous effect on haematopoietic differentiation. We provide evidence to demonstrate that this activity is partly mediated by the secreted protein FRZB