Targeting MFAP5 in cancer-associated fibroblasts sensitizes pancreatic cancer to PD-L1-based immunochemotherapy via remodeling the matrix.

Highly desmoplastic and immunosuppressive tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDAC) contributes to tumor progression and resistance to current therapies. Clues targeting the notorious stromal environment have offered hope for improving therapeutic response whereas the underlying mechanism remains unclear. Here, we find that prognostic microfibril associated protein 5 (MFAP5) is involved in activation of cancer-associated fibroblasts (CAFs). Inhibition of MFAP5highCAFs shows synergistic effect with gemcitabine-based chemotherapy and PD-L1-based immunotherapy. Mechanistically, MFAP5 deficiency in CAFs downregulates HAS2 and CXCL10 via MFAP5/RCN2/ERK/STAT1 axis, leading to angiogenesis, hyaluronic acid (HA) and collagens deposition reduction, cytotoxic T cells infiltration, and tumor cells apoptosis. Additionally, in vivo blockade of CXCL10 with AMG487 could partially reverse the pro-tumor effect from MFAP5 overexpression in CAFs and synergize with anti-PD-L1 antibody to enhance the immunotherapeutic effect. Therefore, targeting MFAP5highCAFs might be a potential adjuvant therapy to enhance the immunochemotherapy effect in PDAC via remodeling the desmoplastic and immunosuppressive microenvironment.

Sorafenib enhances effects of transarterial chemoembolization for hepatocellular carcinoma: a systematic review and meta-analysis.

BACKGROUND AND AIM: Combination therapy of sorafenib and transarterial chemoembolization (TACE) showed benefits for hepatocellular carcinoma (HCC). This systematic review aims for evaluation of efficacy and safety between sorafenib plus TACE and TACE alone for HCC. METHODS: We systematically searched multi-databases to identify eligible studies. Studies comparing sorafenib combined with TACE and TACE alone for HCC were included. RESULTS: Nine studies with 900 patients (sorafenib + TACE = 446, TACE = 454) were finally included. Sorafenib combined with TACE significantly reduced 6-month mortality [OR 0.24, 95 % confidential interval (CI) 0.09-0.68, P = 0.007] and 1-year mortality (OR 0.35, 95 % CI 0.21-0.56, P < 0.0001), but did not decrease 2-year mortality (OR 0.58, 95 % CI 0.14-2.46, P = 0.46). Although combination therapy tend to reduce 3-month (OR 0.76, 95 % CI 0.52-1.10, P = 0.15) and 6-month progression free rate (OR 0.27, 95 % CI 0.07-1.05, P = 0.06), the changes were not significant. Additionally, objective response ratio (OR 0.39, 95 % CI 0.19-0.78, P = 0.008) and clinical benefit ratio (OR 0.27, 95 % CI 0.15-0.50, P < 0.0001) also favored for combination therapy, which, however, caused higher morbidity, especially hand-foot skin reaction (OR 53.71, 95 % CI 28.86-99.93, P < 0.00001), hematological events (OR 14.8, 95 % CI 6.07-36.07, P < 0.00001), diarrhea (OR 6.62, 95 % CI 3.82-11.45, P < 0.00001), hypertension (OR 5.03, 95 % CI 3.02-8.38, P < 0.00001), rash/desquamation (OR 5.67, 95 % CI 3.58-8.99, P < 0.00001), and fatigue (OR 2.5, 95 % CI 1.09-5.72, P = 0.03). CONCLUSION: Combination of sorafenib and TACE showed survival and clinical benefits in patients with HCC, though enhanced morbidity.

Expression of MMP-9 in hepatic sinusoidal obstruction syndrome induced by Gynura segetum.

BACKGROUND AND OBJECTIVE: Hepatic sinusoidal obstruction syndrome (HSOS) is characterized by painful hepatomegaly, ascites, increased body weight, and jaundice. Gynura segetum (Compositae), a plant widely used in Chinese traditional medicine, often leads to the development of HSOS. However, the mechanism is unclear. The aim was to study the role of matrix metalloproteinase-9 (MMP-9) in the onset of HSOS induced by Gynura segetum. METHODS: Twenty-five male Sprague-Dawley rats were randomly divided into two groups. Twenty were exposed to 600 mg/kg daily Gynura segetum extract solution for three weeks; five control rats were exposed to tap water alone. Liver sections were evaluated by light microscopy with a modified scoring system. Routine transmission electron microscopy (TEM) methods were used to evaluate the ultrastructual features of fixed liver tissue, and blood samples were collected to determine liver enzyme concentrations. MMP-9 expression was assessed by both immunohistochemical staining and enzyme-linked immunosorbent assay (ELISA) methods. RESULTS: A stable and reproducible rat model of HSOS was achieved by long-term exposure to Gynura segetum extract. The treated rats presented clinical symptoms and the histopathological manifestation of HSOS, including abnormal liver enzyme concentrations (alanine aminotransferase (ALT): (84.8±13.62) vs. (167.0±72.63) U/L, P<0.05; aspartate aminotransferase (AST): (27.6±6.31) vs. (232.8±108.58) U/L, P<0.05). Hematoxylin and eosin (H&E) staining and TEM together revealed deposition of red blood cells, the damage and destruction of hepatic sinusoidal endothelial cells, collapse of hepatic sinusoids, hemorrhage of subendothelial cells, atrophy and destruction of hepatocytes, etc. Compared with controls, the expression of MMP-9 in the blood sample, the lung and liver tissues of HSOS rats was increased. CONCLUSIONS: MMP-9 may have an important role in early pathological changes of HSOS, and thus the onset of the disease.

Intraoperative blood salvage and leukocyte depletion during liver transplantation with bacterial contamination.

BACKGROUND: Bacterial contamination is considered to be a contraindication for intraoperative blood salvage (IBS) during OLT. The aims of this study were to evaluate the efficiency of the autotransfusion device with an additional leukocyte depletion filter (LDF) for eliminating bacterial contaminations, and its clinical outcomes in terms of post-operative infections during OLT. METHODS: Forty-five patients with end-stage liver disease and cirrhotic ascites were enrolled in this study. The blood from the surgical field was collected and processed by an autotransfusion device (Cell Saver 5) and a LDF for bacteriological analysis. Among them, 12 patients with chronic severe hepatitis B received autologous transfusion for analysis of the effect on post-operative infections. RESULTS: Spontaneous bacterial peritonitis (SBP) (p < 0.05, OR = 20.1) and a long duration of operation (p < 0.01, OR = 8.3) were found to be critical risk factors for contamination. Autotransfusion devices with an additional LDF significantly eliminated bacterial contaminants from shed blood (p < 0.05). About 33% (4/12) of the patients who received autologous transfusion with salvaged and filtered erythrocytes got post-operative bacterial infection. CONCLUSIONS: Autotransfusion devices with an additional LDF could significantly eliminate bacterial contaminants of shed blood during OLT. The new mode of IBS might be a good option in reducing post-operative infections, and deserves a large-scale clinical trial.

Intraoperative blood salvage during liver transplantation in patients with hepatocellular carcinoma: efficiency of leukocyte depletion filters in the removal of tumor cells.

BACKGROUND: Intraoperative blood salvage (IBS) reduces homologous transfusion in orthotopic liver transplantation (OLT), but may carry with it the risk of reinfusing tumor cells in patients with hepatocellular carcinoma (HCC). The use of leukocyte depletion filters (LDFs) for the removal of tumor cells is rarely reported in clinical OLT. The aims of this study were to evaluate the frequency of tumor cell contamination in surgical field during OLT for HCC recipients and to investigate the efficiency of additional LDFs for eliminating tumor cells from IBS. METHODS: Thirty-two HCC patients with preoperatively elevated serum alpha-fetoprotein (AFP) underwent OLT. The blood from the surgical field was collected and processed by an autotransfusion device (Cell Saver 5), followed by 2 consecutive LDF filtrations. The HCC cells in IBS samples and filtered samples were determined using a nested RT-PCR technique to detect the AFP mRNA. RESULTS: The shed blood samples from 20 (62.5%) of the 32 HCC patients were contaminated with HCC cells and 15 of them remained positive after Cell Saver processing. Patients within the Milan or UCSF criteria were less likely to have HCC cell contamination and the contaminated HCC cells were more likely to be removed by the Cell Saver in these patients as compared to other patients (P<0.01). After filtration through an additional LDF, most cases (13/15) became negative except for those with ruptured tumors (P<0.05). CONCLUSIONS: Our results suggest that blood filtration with the LDF can efficiently remove tumor cells and the use of an additional LDF after use of the Cell Saver could markedly reduce the risk of tumor cell reintroduction during the OLT in HCC recipients with nonruptured tumors.