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Showing complete radiological response of lung metastases

Dose escalation flow chart. DLT - dose limiting toxicity, MTD - maximum tolerated dose

Trial Protocol

A) CT and MRI of patient with prolonged partial response with MTL-CEBPA treatment B) IFN-gamma, NFkB and IL6 trend at days 1, 8 and 15 following treatment and C) AFP change at from baseline to 4, 8 and 16 weeks on treatment

Supplementary Legends

Supplementary Table 1 CEBPA-51 PK parameters Supplementary Table 2 RECIST 1.1 response observed overall and per cohorts in HCC patients at cut-off (12 Sep 2018) presented as n (%)

Purpose:Transcription factor C/EBP-α (CCAAT/enhancer-binding protein alpha) acts as a master regulator of hepatic and myeloid functions and multiple oncogenic processes. MTL-CEBPA is a first-in-class small activating RNA oligonucleotide drug that upregulates C/EBP-α.Patients and Methods:We conducted a phase I, open-label, dose-escalation trial of MTL-CEBPA in adults with advanced hepatocellular carcinoma (HCC) with cirrhosis, or resulting from nonalcoholic steatohepatitis or with liver metastases. Patients received intravenous MTL-CEBPA once a week for 3 weeks followed by a rest period of 1 week per treatment cycle in the dose-escalation phase (3+3 design).Results:Thirty-eight participants have been treated across six dose levels (28–160 mg/m2) and three dosing schedules. Thirty-four patients were evaluable for safety endpoints at 28 days. MTL-CEBPA treatment–related adverse events were not associated with dose, and no maximum dose was reached across the three schedules evaluated. Grade 3 treatment-related adverse events occurred in nine (24%) patients. In 24 patients with HCC evaluable for efficacy, an objective tumor response was achieved in one patient [4%; partial response (PR) for over 2 years] and stable disease (SD) in 12 (50%). After discontinuation of MTL-CEBPA, seven patients were treated with tyrosine kinase inhibitors (TKIs); three patients had a complete response with one further PR and two with SD.Conclusions:MTL-CEBPA is the first saRNA in clinical trials and demonstrates an acceptable safety profile and potential synergistic efficacy with TKIs in HCC. These encouraging phase I data validate targeting of C/EBP-α and have prompted MTL-CEBPA + sorafenib combination studies in HCC.

Longitudinal changes in WBC mRNA expression of CEBPA, adenosine, PD-1 & CXCR4 at screening, day2, 8 and 15 of a single patient treated in the 130mg/m2 cohort

qPCR of CEBPA mRNA levels at days 2, 8 and 15 following treatment

Metabolic syndrome (MetS) is a pathological condition characterized by abdominal obesity, insulin resistance, hypertension, and hyperlipidemia. Sirtuin 1 (SIRT1), a highly conserved histone deacetylase, is characterized as a key metabolic regulator and protector against aging-associated pathologies, including MetS. In this study, we investigate the therapeutic potential of activating SIRT1 using small activating RNAs (saRNA), thereby reducing inflammatory-like responses and re-establishing normal lipid metabolism. SIRT1 saRNA significantly increased SIRT1 messenger RNA (mRNA) and protein levels in both lipopolysaccharide-stimulated and nonstimulated macrophages. SIRT1 saRNA significantly decreased inflammatory-like responses, by reducing mRNA levels of key inflammatory cytokines, such as Tumor Necrosis Factor alpha, Interleukin 1 beta (IL-1β), Interleukin 6 (IL-6), and chemokines Monocyte Chemoattractant Protein-1 and keratinocyte chemoattractant. SIRT1 overexpression also significantly reduced phosphorylation of nuclear factor-κB and c-Jun N-terminal kinase, both key signaling molecules for the inflammatory pathway. To investigate the therapeutic effect of SIRT1 upregulation, we treated a high-fat diet model with SIRT1 saRNA conjugated to a transferrin receptor aptamer for delivery to the liver and cellular internalization. Animals in the SIRT1 saRNA treatment arm demonstrated significantly decreased weight gain with a significant reduction in white adipose tissue, triglycerides, fasting glucose levels, and intracellular lipid accumulation. These suggest treatment-induced changes to lipid and glucose metabolism in the animals. The results of this study demonstrate that targeted activation of SIRT1 by saRNAs is a potential strategy to reverse MetS.

A crystal phase is a key factor to determine the physical and chemical properties of crystalline materials. As a new class of nanoscale structures, heterophase nanoparticles, which assemble conventional and unconventional phases, exhibit exceptional properties in comparison with their single-phase counterparts. In this work, we explored the thermodynamic stability of Au, Co, and AuCo heterophase nanoparticles with fcc and hcp phases by using molecular dynamics simulations. These heterostructured nanoparticles were continuously heated to examine their thermally activated structural evolutions. Au and Co single-phase nanoparticles were also considered for comparison. The results show that the phase transition between fcc and hcp is absent in these heterophase nanoparticles despite the existence of an unconventional phase. Although the melting of Au and Co heterophase nanoparticles is homogeneous, AuCo heterophase nanoparticles show heterogeneous melting

Despite significant advances in outcomes with immunotherapy, most cancer patients do not benefit from currently approved immune checkpoint inhibitors (ICI). The reasons for ICI resistance are multi-faceted and suggest that additional immunomodulation is required to improve outcomes. MTL-CEBPA is a novel immunotherapy based on RNA activation that upregulates expression of a master myeloid transcription factor, CEBPA. The small activating RNA for CEBPA is encapsulated within a NOV340 liposome that targets the myeloid cell lineage. MTL-CEBPA has shown favorable safety and promising clinical activity in combination with tyrosine kinase inhibitors (Sorafenib) in hepatocellular carcinoma (NCT-02716012) [Hashimoto et al, CCR 2021; Sarker et al, CCR 2020]. We recently reported preliminary clinical data from the ongoing multi-center phase 1 TIMEPOINT study (NCT-04105335) evaluating the safety, pharmacokinetics, immunomodulation, and clinical activity of MTL-CEBPA in combination with pembrolizumab in patients with solid tumors who have exhausted standard therapy. This demonstrated a favorable safety profile and initial clinical activity [Plummer et al, JITC 2021]. Here we report the findings from a biomarker pharmacodynamic analysis of paired baseline and cycle 2 tumor sample biopsies in 23 patients from the TIMEPOINT trial. Brightplex® IHC and digital pathology analyses of the samples for myeloid and T cell panels were undertaken, alongside gene expression (Nanostring I/O 360). Prior to study treatment, nine patients out of 23 had an immune cold tumor microenvironment (TME) at baseline as measured by the Immunosign®21 score. Following the combination of MTL-CEBPA with pembrolizumab, seven of these patients converted to an inflamed TME by Immunosign®21 (P=0.008). This change in the TME was associated with infiltration of CD8 and cytotoxic T cells (CD8+, GrzB+, Ki-67+) (P=0.1). GSEA analysis indicated that a Tstem-like signature was enriched post-treatment. A Brightplex® IHC analysis of myeloid cells in these patients indicated that, post treatment, there was a significant influx of HLA-DR+ myeloid cells into the TME (P=0.04). We also observed a significant increase in the expression of CXCL9, 10, and 11. The remaining 14 patients had an inflamed TME at baseline. Here, we also observed an increase in HLA-DR+ cells, T cells, and chemokines, though to a lesser extent. Further, however, in these inflamed tumors—which have significantly greater infiltration of myeloid-derived suppressor cells (MDSCs) than desert tumors—we observed a reduction in 8/10 patients with detectable PMN-MDSCs (P=0.1) post treatment, consistent with the mechanism of action of CEBPA. An expression signature based on 18 genes significantly enriched for clinical response across all patients. Collectively, these data suggest a positive immunomodulatory TME effect of the combination of MTL-CEBPA with pembrolizumab. In both hot and cold TME tumors, the combination drives directed differentiation of progenitor monocytes into HLA-DR+ myeloid cells secreting chemokines that stimulate the ingress of T cells into the TME. We observe a significant positive correlation between the change in cytotoxic T cells and HLA-DR+ myeloid cells post treatment (P=0.004). These effects are most pronounced in cold tumors. Citation Format: Ruth Plummer, Mikael Sodergren, Brid Ryan, Ilian Tchakov, Nina Raulf, Rose Hodgson, CP Tan, Joanna P. Nicholls, Alison Adderkin, N Vasileiadou, Vikash Reebye, Tim Meyer, David J. Pinato, Debashis Sarker, Bristi Basu, Sarah Blagden, Natalie Cook, Jeff Evans, Jeffrey Yachnin, Cheng Ean Chee, Dan Li, Anthony El-Khoueiry, Maria Diab, Kai-Wen Huang, Marcus S. Noel, Bridget Keenan, Devalingam Mahalingam, Melanie Grosso, Denis Arnaud, Aurelie Auguste, Jan Storkholm, Iain McNeish, Robert Habib, John J. Rossi, Nagy Habib. MTL-CEBPA in combination with pembrolizumab converts an immune desert to an inflamed TME in solid tumors resistant to checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB192.

Taiwan has witnessed a surge in the incidence of colorectal cancer (CRC), of which 40–60% metastasize. Continuous updating of cytoreductive strategies in metastatic CRC (mCRC) has contributed to median overall survival reaching 40 months. In this changing scenario, to standardize the approaches across Taiwan, a group of experts from the Taiwan Society of Colon and Rectal Surgeons (TSCRS) convened to establish evidence- and opinion-based recommendations for defining the criteria of “resectability” in mCRC. Over the course of one-on-one consultations, lasting 30–40 min each, with 30 medical specialists (19 colorectal surgeons, 4 general surgeons, and 7 medical oncologists) from 16 hospitals in Taiwan followed by a 2-h meeting with 8 physician experts (3 general surgeons, 4 colorectal surgeons, and 1 thoracic surgeon), 12 key questions on cytoreduction were addressed. This was further contextualized based on published literature. The final consensus includes eight recommendations regarding the criteria for metastasis resection, role of local control treatment in liver potentially resectable patients, management of synchronous liver metastases, approach for peritoneal metastasis, place for resection in multiple-organ metastasis, and general criteria for resectability. mCRC patients undergoing R0 resection have the greatest survival advantage following surgery. Our role as a multidisciplinary team (MDT) should be to treat potentially resectable mCRC patients as rapidly and safely as possible, and achieve R0 resection as far as possible and for as long as possible (continuum of care). This TSCRS consensus statement aims to help build clinical capacity within the MDTs, while making better use of existing healthcare resources.

Irreversible electroporation (IRE) is a modality that utilizes high electric voltage to cause cell apoptosis. IRE has been used to treat locally advanced pancreatic cancer (LAPC). However, studies of IRE via surgical approaches for LAPC are limited. This study aims to analyse the outcomes and related prognostic factors of IRE for Asian patients with LAPC.From 2012 to 2017, this prospective trial for using IRE through surgical approaches for LAPC was conducted in 11 medical centres in Asia. All related and treatment outcomes were analysed from a prospective database.Seventy-four patients were enrolled. Thirty complications occurred in thirteen (17.6%) patients without mortality. The electrode placement direction (anteroposterior vs. craniocaudal, HR = 14.2, p 0.01) and gastrointestinal invasion (HR = 15.7, p 0.01) were significant factors for complications. The progression-free survival (PFS) rate in one year, three years, and five years were 69.1%, 48.7%, and 28.8%, and the overall survival (OS) rate in one year, three years, and five years were 97.2%, 53%, and 31.2%. In univariate analysis, the chemotherapy regimen, local tumour recurrence, axial tumour length, tumour volume, and serum carbohydrate antigen 19-9 levels were all significantly associated with PFS and OS. In multivariate analysis, the chemotherapy regimen was the only significant factor associated with PFS and OS. TS-1 (Tegafur, gimeracil, and oteracil) group has superior survival outcome than gemcitabine group.This study showed that combined induction chemotherapy and surgical IRE for LAPC is safe. For well-selected patients, IRE can achieve encouraging survival outcomes.

Purpose: To evaluate the mechanisms of how therapeutic upregulation of the transcription factor, CCAAT/enhancer-binding protein alpha (C/EBPα), prevents tumor progression in patients with advanced hepatocellular carcinoma (HCC) and in different mouse tumor models. Experimental Design: We conducted a phase I trial in 36 patients with HCC (NCT02716012) who received sorafenib as part of their standard care, and were given therapeutic C/EBPα small activating RNA (saRNA; MTL-CEBPA) as either neoadjuvant or adjuvant treatment. In the preclinical setting, the effects of MTL-CEBPA were assessed in several mouse models, including BNL-1ME liver cancer, Lewis lung carcinoma (LLC), and colon adenocarcinoma (MC38). Results: MTL-CEBPA treatment caused radiologic regression of tumors in 26.7% of HCC patients with an underlying viral etiology with 3 complete responders. MTL-CEBPA treatment in those patients caused a marked decrease in peripheral blood monocytic myeloid-derived suppressor cell (M-MDSC) numbers and an overall reduction in the numbers of protumoral M2 tumor-associated macrophages (TAM). Gene and protein analysis of patient leukocytes following treatment showed CEBPA activation affected regulation of factors involved in immune-suppressive activity. To corroborate this observation, treatment of all the mouse tumor models with MTL-CEBPA led to a reversal in the suppressive activity of M-MDSCs and TAMs, but not polymorphonuclear MDSCs (PMN-MDSC). The antitumor effects of MTL-CEBPA in these tumor models showed dependency on T cells. This was accentuated when MTL-CEBPA was combined with checkpoint inhibitors or with PMN-MDSC–targeted immunotherapy. Conclusions: This report demonstrates that therapeutic upregulation of the transcription factor C/EBPα causes inactivation of immune-suppressive myeloid cells with potent antitumor responses across different tumor models and in cancer patients. MTL-CEBPA is currently being investigated in combination with pembrolizumab in a phase I/Ib multicenter clinical study (NCT04105335).

The transcription factor CEBPA is a master regulator of liver homeostasis, myeloid cell differentiation and is downregulated in several oncogenic diseases. MTL-CEBPA is a small activating RNA drug which upregulates gene expression of CEBPA for treatment of hepatocellular carcinoma (HCC). We investigate whether MTL-CEBPA has immune modulatory effects by combining MTL-CEBPA with an anti-PD-1 checkpoint inhibitor (CPI) and/or radiofrequency ablation (RFA) in two preclinical models. First, mice with two flanks of HCC tumors (BNL) were treated with combinations of RFA (right flank), anti-PD-1 or MTL-CEBPA. The reduction of the left flank tumors was most pronounced in the group treated with RFA+anti-PD1+MTL-CEBPA and 7/8 animals responded. This was the only group with a significant increase in CD8+ and CD49b+/CD45+ tumor infiltrating lymphocytes (TIL). Second, a combination of anti-PD-1+MTL-CEBPA was tested in a CT26 colon cancer model and this treatment significantly reduced tumor size, modulated the tumor immune microenvironment and increased TILs. These data suggest a clinical role for combination treatment with CPIs, RFA and MTL-CEBPA through synergistic priming of the immune tumor response, enabling RFA and CPIs to have a pronounced anti-tumor effect including activity in non-treated tumors in the case of RFA.

The outcome of radiofrequency ablation (RFA) for liver metastases from colorectal cancer (CRLM) has been thought to be inferior to metastasectomy. However, the recent development of multielectrode RFA (multi-RFA) systems has made the ablation zone larger and more complete. Thus, we assessed the survival benefits of this modality in cases of metachronous CRLM. This retrospective study assessed patients diagnosed with resectable metachronous CRLM between 2013 and 2016, 132 patients were categorized by treatment for liver metastases: multi-RFA (n = 68), hepatectomy (n = 34), or systemic treatment only (n = 30). Therapeutic effectiveness, outcomes, and intervention-related complications were compared between groups. Median overall survival (OS), recurrence-free survival (RFS), and intrahepatic recurrence-free survival (IHRFS) were 69.8, 85.2, and 59.7 months for the hepatectomy group, 53.4, 41.3, and 32.3 months for the multi-RFA group, and 19.1, 7.1, and 7.1 months for the systemic treatment group. No significant differences were observed between the multi-RFA and hepatectomy groups after a median follow-up of 59.8 months. This study demonstrated that multi-RFA and hepatectomy provide similar survival benefits for patients with resectable CRLM. Multi-RFA may represent a reliable treatment option for the management of resectable liver metastases.

Excessive or inappropriate inflammatory responses can cause serious and even fatal diseases. The CCAAT/enhancer-binding protein alpha (CEBPA) gene encodes C/EBPα, a transcription factor that plays a fundamental role in controlling maturation of the myeloid lineage and is also expressed during the late phase of inflammatory responses when signs of inflammation are decreasing. MTL-CEBPA, a small activating RNA targeting for upregulation of C/EBPα, is currently being evaluated in a phase 1b trial for treatment of hepatocellular carcinoma. After dosing, subjects had reduced levels of pro-inflammatory cytokines, and we therefore hypothesized that MTL-CEBPA has anti-inflammatory potential. The current study was conducted to determine the effects of C/EBPα saRNA - CEBPA-51 - on inflammation in vitro and in vivo after endotoxin challenge. CEBPA-51 led to increased expression of the C/EBPα gene and inhibition of pro-inflammatory cytokines in THP-1 monocytes previously stimulated by E. coli-derived lipopolysaccharide (LPS). Treatment with MTL-CEBPA in an LPS-challenged humanized mouse model upregulated C/EBPα mRNA, increased neutrophils, and attenuated production of several key pro-inflammatory cytokines, including TNF-α, IL-6, IL-1β, and IFN-γ. In addition, a Luminex analysis of mouse serum revealed that MTL-CEBPA reduced pro-inflammatory cytokines and increased the anti-inflammatory cytokine IL-10. Collectively, the data support further investigation of MTL-CEBPA in acute and chronic inflammatory diseases where this mechanism has pathogenic importance., MTL-CEBPA is a small activating RNA that targets the upregulation of transcription factor C/EBPα, currently being evaluated in a phase 1b trial for treatment of hepatocellular carcinoma. Zhou et al. demonstrate that MTL-CEBPA increases the expression of C/EBPα and displays anti-inflammatory effects in a tissue culture system and a humanized mouse model.

Hepatocellular carcinoma (HCC) is generally accompanied by high mortality and low cure rate. CCAAT enhancer-binding proteins (CEBPs) are transcriptional regulators that play a key role in maintaining liver function. Altered expression of C/EBPα and C/EBPβ occurs in many tumours including HCC. saRNAs are small double-stranded RNAs that enhance target gene expression at the transcriptional level. In this report, we activate CEPBA with saRNAs and suppress CEBPB with siRNAs in cells that represent three different degrees of HCC. We performed functional assays to investigate the effects of enhancing C/EBPα and its downstream targets, p21 and albumin across these lines. We also used Mass-spectrometry (MS) subsequent to a ChIP pull-down assay to characterise the components of the protein complex involved in regulating saRNA function. Putative saRNA interacting protein candidates that were identified by MS were knocked-down with siRNAs to investigate its impact on saRNA activity. We confirmed CEBPA-saRNA decreased proliferation and migration in the differentiated lines (HepG3/Hep3B). The undifferentiated line (PLCPRF5) showed saRNA-induced increase in CEBPA but with no loss in proliferation. This effect was reversed when CEBPB was suppressed with CEBPB-siRNA. When interrogating saRNA mode of action; three saRNA interacting proteins, CTR9, HnRNPA2/B1 and DDX5 were identified by MS. Targeted knock-down of these two proteins (by siRNA) abrogated saRNA activity. This study provides insight into how different HCC lines are affected by CEBPA-saRNAs and that endogenous abundance of CEBPB and saRNA accessory proteins may dictate efficacy of CEBPA-saRNA when used in a therapeutic context.

Background Radiofrequency (RF)-assisted devices are widely used for hemostasis during liver resection. This study compared the use of dual switching (DS) versus single switching (SS) control modes for RF-based liver resections in a pig model. Methods The RF-based system comprised a 200-W generator and three electrodes with 4-cm tips arranged in a linear configuration using an adaptor. Eight Lanyu pigs were used to assess ablation outcomes with electrode spacing of 2 or 3 cm, and ablation durations of 1.5, 2 or 3 min. All combinations were tested in DS and SS modes. Procedures were performed on left lateral, caudal and right anterior liver lobes, and after which transections were performed using a scalpel. Blood loss, complete ablation rate and ablation speed were compared. Results DS mode was shown to induce significantly less blood loss than SS mode when the electrode spacing was set at 2 cm and the ablation duration was 2 min or 3 min (p=.010 and .012, respectively). Extended ablation duration and narrow electrode spacing tended to induce less blood loss, regardless of operating mode. Bloodless resection was achieved using DS mode with electrode spacing of 2 cm and ablation duration of 2–3 min. The highest rate of complete ablation (11.3 cm2/min) was achieved using DS mode with electrode spacing of 2 cm and ablation duration of 1.5 min. Conclusion RF-based hepatic resection using DS mode is safe and feasible, resulting in less blood loss than SS mode with a higher rate of complete ablation (i.e., superior ablation efficiency).

Background Second harmonic generation (SHG)/two-photon excited fluorescence (TPEF) microscopy is commonly used for the quantitative assessment of liver fibrosis; however, the accuracy is susceptible to sampling error and count error due to disturbances induced by some forms of collagen in liver specimens. In this study, we sought to improve the accuracy of quantitative assessments by removing the effects of this disturbing collagen and optimizing the sampling protocol. Methods Large liver resection samples from 111 patients with chronic hepatitis B were scanned using SHG/TPEF microscopy with multiple adjacent images. During the quantitative assessment, we then removed SHG signals associated with three types of extraneous physiological collagen: large patches of collagen near the boundary of the capsule, collagen around tubular structures, and collagen associated with distorted vessel walls. The optimal sampling protocol was identified by comparing scans from regions of interest of various sizes (3×3 tiles and 5×5 tiles) with full scans of the same tissue. Results The proposed auto-correction algorithm detected 88 of 97 (90.7%) disturbing collagen on the images from the validation set. Removing these signals of disturbing collagen improved the correlation between Metavir stage and quantification of all 41 proposed collagen features. Through optimal sampling, five scans of 5×5 tiles or ten scans of 3×3 tiles were sufficient to minimize the mean error rate to around 2% of collagen percentage quantification and to achieve similar correlations around 0.27 with Metavir stage as using full tissue scans. Conclusions Our results demonstrate that the quantitative assessments of liver fibrosis can be greatly enhanced in terms of accuracy and efficiency through optimal sampling and the automated removal of disturbing collagen signals. These types of image processing could be integrated in next-generation SHG/TPEF microscopic systems.

Using in vivo multiphoton fluorescent dosimetry, we demonstrate that the clearance dynamics of Indocyanine Green (ICG) in the blood can quickly reveal liver function reserve. In normal rats, the ICG retention rate was below 10% at the 15-minute post-administration; While in the rat with severe hepatocellular carcinoma (HCC), the 15-minute retention rate is over 40% due to poor liver metabolism. With a 785 nm CW laser, the fluorescence dosimeter can evaluate the liver function reserve at a 1/10 clinical dosage of ICG without any blood sampling. In the future, this low-dosage ICG 15-minute retention dosimetry can be applied for the preoperative assessment of hepatectomy or timely perioperative examination.

Irreversible electroporation (IRE) is a non-thermal ablation modality that has been shown to be safe and effective in its application to tumors that are close to risky areas. This study aims to assess the safety and efficacy of IRE for unresectable hilar cholangiocarcinoma. Nine patients from two medical centers in Asia received IRE treatment between June 2015 and July 2017. Before IRE treatment, percutaneous biliary decompressions had been performed on eight patients, and internal stenting had been performed on one patient. All patients tolerated the procedure well without high-grade complications. The ablated tumors had constant size without contrast enhancement for more than three months in eight patients and the level of CA19-9 decreased significantly in all patients. The percutaneous biliary drainage tube was removed from two patients with recanalization of the bile duct. The internal stent in one patient was removed without further stenting. The median overall survival period was 26 months, and the progression-free survival was 18 months. Bile ducts remained narrow in the majority (2/3) of the treated patients. Nevertheless, IRE ablation of unresectable hilar cholangiocarcinoma involving vital structures is a safe and feasible primary treatment for local tumor control and is effective in prolonging survival.

Taiwan has witnessed a surge in the incidence of colorectal cancer (CRC), of which 40-60% metastasize. Continuous updating of cytoreductive strategies in metastatic CRC (mCRC) has contributed to median overall survival reaching 40 months. In this changing scenario, to standardize the approaches across Taiwan, a group of experts from the Taiwan Society of Colon and Rectal Surgeons (TSCRS) convened to establish evidence- and opinion-based recommendations for defining the criteria of "resectability" in mCRC.Over the course of one-on-one consultations, lasting 30-40 min each, with 30 medical specialists (19 colorectal surgeons, 4 general surgeons, and 7 medical oncologists) from 16 hospitals in Taiwan followed by a 2-h meeting with 8 physician experts (3 general surgeons, 4 colorectal surgeons, and 1 thoracic surgeon), 12 key questions on cytoreduction were addressed. This was further contextualized based on published literature.The final consensus includes eight recommendations regarding the criteria for metastasis resection, role of local control treatment in liver potentially resectable patients, management of synchronous liver metastases, approach for peritoneal metastasis, place for resection in multiple-organ metastasis, and general criteria for resectability.mCRC patients undergoing R0 resection have the greatest survival advantage following surgery. Our role as a multidisciplinary team (MDT) should be to treat potentially resectable mCRC patients as rapidly and safely as possible, and achieve R0 resection as far as possible and for as long as possible (continuum of care). This TSCRS consensus statement aims to help build clinical capacity within the MDTs, while making better use of existing healthcare resources.

International audience; Non-alcoholic fatty liver disease (NAFLD) culminates in insulin resistance and metabolic syndrome. Because there are no approved pharmacological treatment agents for non-alcoholic steatohepatitis (NASH) and NAFLD, different signaling pathways are under investigation for drug development with the focus on metabolic pathways. Hepatocyte nuclear factor 4-alpha (HNF4A) is at the center of a complex transcriptional network where its disruption is directly linked to glucose and lipid metabolism. Resetting HNF4A expression in NAFLD is therefore crucial for re-establishing normal liver function. Here, small activating RNA (saRNA) specific for upregulating HNF4A was injected into rats fed a high-fat diet for 16 weeks. Intravenous delivery was carried out using 5-(G 5)-triethanolamine-core pol-yamidoamine (PAMAM) dendrimers. We observed a significant reduction in liver triglyceride, increased high-density lipopro-tein/low-density lipoprotein (HDL/LDL) ratio, and decreased white adipose tissue/body weight ratio, all parameters to suggest that HNF4A-saRNA treatment induced a favorable metabolic profile. Proteomic analysis showed significant regulation of genes involved in sphingolipid metabolism, fatty acid b-oxidation , ketogenesis, detoxification of reactive oxygen species, and lipid transport. We demonstrate that HNF4A activation by oligonucleotide therapy may represent a novel single agent for the treatment of NAFLD and insulin resistance.