Explore the vast range of titles available.

BackgroundThe concept of frailty becomes important for patients who undergo surgery in this recent aging society. The aim of this study is to investigate the frailty as a prognostic factor in elderly patients with hepatocellular carcinoma (HCC) who underwent hepatectomy.Patients and MethodsA total of 92 patients over 75 years old who underwent hepatectomy were enrolled in this study. Frailty was defined as clinical frailty scale (CFS) ≥ 4. Patients were divided into two groups, i.e., frailty group (n = 21) and no-frailty group (n = 71), and clinicopathological features were compared between them.ResultsThe frailty group showed significant higher PIVKA-II level and larger tumor diameter (p < 0.05). CRP level and modified Glasgow prognostic score were significantly higher in the frailty group (p < 0.05). The frailty group showed higher rate of postoperative complications of Clavien–Dindo III (p = 0.06) and longer postoperative stay (p = 0.08). Cancer-specific, overall, and disease-free survival rates were significantly worse in the frailty group (p < 0.05). Frailty was detected as an independent prognostic factor on multivariate analysis of cancer-specific survival.ConclusionFrailty can estimate the prognosis of HCC patients who underwent hepatectomy.

Cancer‐associated fibroblasts (CAF), derived from stroma of cancer tissues, interact with cancer cells and play an important role in cancer initiation, growth, and metastasis. Nab‐paclitaxel (nab‐PTX) is a 130 nm albumin‐binding paclitaxel and recommended for many types of cancer chemotherapy. The nab‐PTX stromal‐disrupting effect during pancreatic cancer treatment has been reported. The aim of the present study was to determine the role of nab‐PTX in cancer cells and CAF interaction. Cancer cells (MIA PaCa‐2 and Panc‐1) were cocultured with CAF or treated with CAF conditioned medium, after which their migration and invasion ability, epithelial‐mesenchymal transition (EMT)‐related marker expression and C‐X‐C motif chemokine 10 (CXCL10) expression and secretion were detected. Nab‐PTX treatment was carried out during the coculture system or during preparation of CAF conditioned medium. Then cancer cell migration and invasion ability, EMT‐related marker expression, CXCL10 expression and secretion, and interleukin‐6 (IL‐6) expression and secretion by CAF were checked After coculture with CAF, migration and invasion ability of cancer cells increased. CAF also downregulated E‐cadherin and upregulated N‐cadherin and vimentin expression in cancer cells. During coculture or stimulation with cancer cell‐cultured medium, CAF significantly increased IL‐6 expression and secretion. However, nab‐PTX in the coculture system canceled CAF‐induced migration and invasion promotion and EMT‐related gene changes. Moreover, nab‐PTX increased CXCL10 expression of cancer cells which blocked CAF IL‐6 expression and secretion. Nab‐PTX treatment could increase CXCL10 expression of cancer cells which blocks CAF cancer cell migration and invasion‐promoting effect by inhibiting IL‐6 expression. Pancreatic cancer cells increased IL‐6 expression of cancer‐associated fibroblasts (CAF) which could promote cancer cell metastasis. Nab‐paclitaxel could stimulate CXCL10 expression of pancreatic cancer cells, which could inhibit IL‐6 expression of CAF and decrease its cancer cell migration and invasion‐promoting ability.

Background The M2 phenotype of tumor-associated macrophages (TAM) inhibits the anti-tumor inflammation, increases angiogenesis and promotes tumor progression. The transcription factor Nuclear Factor (erythroid-derived 2)-Like 2 (Nrf2) not only modulates the angiogenesis but also plays the anti-inflammatory role through inhibiting pro-inflammatory cytokines expression; however, the role of Nrf2 in the cancer cell and macrophages interaction is not clear. Methods Hepatocellular carcinoma cells (Hep G2 and Huh 7) and pancreatic cancer cells (SUIT2 and Panc-1) were co-cultured with monocytes cells (THP-1) or peripheral blood monocytes derived macrophages, then the phenotype changes of macrophages and epithelial-mesenchymal transition of cancer cells were detected. Also, the role of Nrf2 in cancer cells and macrophages interaction were investigated. Results In this study, we found that cancer cells could induce an M2-like macrophage characterized by up-regulation of CD163 and Arg1, and down-regulation of IL-1b and IL-6 through Nrf2 activation. Also, Nrf2 activation of macrophages promoted VEGF expression. The Nrf2 activation of macrophages correlated with the reactive oxygen species induced by cancer cells derived lactate. Cancer cells educated macrophages could activate Nrf2 of the cancer cells, in turn, to increase cancer cells epithelial-mesenchymal transition (EMT) through paracrine VEGF. These findings suggested that Nrf2 played the important role in the cancer cells and macrophages interaction. Conclusions Macrophage Nrf2 activation by cancer cell-derived lactate skews macrophages polarization towards an M2-like phenotype and educated macrophages activate Nrf2 of the cancer cells to promote EMT of cancer cells. This study provides a new understanding of the role of Nrf2 in the cancer cell and TAM interaction and suggests a potential therapeutic target.

Tumor-associated macrophage (TAMs) are paramount for tumor progression and immune tolerance in the tumor microenvironment of various types of cancer, including liver cancer. The aim of the present study was to investigate the effect of vascular endothelial growth factor (VEGF) inhibition on TAM polarization and function during their interactions with macrophages and liver cancer cells. TAMs were induced by culturing M0 macrophages with cancer cell-conditioned medium. TAMs cultured with cancer cell-conditioned medium and vascular endothelial growth factor (VEGF) inhibitor were defined as modified TAMs, and the expression levels of TAM-associated markers and VEGF receptor 2 were evaluated using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The effects of TAMs and modified TAMs on cancer cell proliferation and migration were investigated using conditioned medium. Programmed death-ligand 1 (PD-L1) mRNA expression in modified TAMs and cancer cells cultured in modified TAM-conditioned medium (TAM-CM) for 48 h was examined using RT-qPCR. In order to investigate signaling pathways in macrophages, western blot analysis was performed. CD163 and CD206 and M2 macrophage marker expression was upregulated in TAMs and modified TAMs. Modified TAM-CM exhibited a decreased ability to promote cancer cell proliferation and migration in comparison with the use of TAM-CM. The VEGF concentration was significantly higher in the TAMs than in M0 macrophages; however, the modified TAMs displayed a significantly lower VEGF secretion than TAMs. PD-L1 expression was decreased in modified TAMs as compared with TAMs. Western blot analysis revealed that the Akt/mTOR signaling pathway was significantly suppressed in the modified TAMs compared with TAMs. It was observed that TAMs cultured in a VEGF-depleted environment displayed lower secretion levels of cytokines involved in tumor progression and a decreased immune tolerance-inducing ability. On the whole, the results of the present study suggested that VEGF inhibition in TAMs may be a potential therapeutic target for liver cancer.

Background Preoperative estimation of the liver functional reserve is important in liver surgery. We evaluated the role of dynamic magnetic resonance (MR) imaging with gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA), i.e., EOB-MRI, for determining liver functional reserve. Methods Fifty patients who underwent EOB-MRI to examine their liver tumors were included in this study. We first performed a pixel-by-pixel comparison of registered MR images and activity images with Tc-99m galactosyl human serum albumin (GSA) on each slice, and the correlation coefficient was calculated for 8 patients. We also determined the correlation coefficient between the relative signal intensity (SI) values of EOB-MRI and preoperative liver function, such as the GSA, indocyanine green dye retention at 15 min (ICGR15), and prothrombin time. Results The mean of the correlation coefficients for 512 × 512 matrices between the EOB-MRI and the GSA was 0.83 ± 0.05 (ranging from 0.73 to 0.87). The correlation coefficient between the relative SI of the EOB-MRI and the receptor index (LHL15) of GSA was 0.56 ( P  < 0.01). Better correlation coefficients were observed between the relative SI and the liver function test, including ICGR15 ( r  = −0.67, P  < 0.01) and prothrombin time ( r  = 0.59, P  < 0.01). In a patient with hilar cholangiocarcinoma whose right hepatic duct was obstructed, the relative SI in the right lobe (2.4 ± 0.3) was significantly lower than that in the left lobe (3.1 ± 0.1). Conclusion EOB-MRI represents a practical and reliable imaging technique that may be used to estimate regional liver functional reserve in the clinical setting.

The aim of this study was to investigate the characteristics of insulin producing cells (IPCs) differentiated from adipose-tissue derived stem cells (ADSCs) isolated from human subcutaneous and visceral adipose tissues and identify ADSCs suitable for differentiation into efficient and functional IPCs. Subcutaneous and visceral adipose tissues collected from four (4) patients who underwent digestive surgeries at The Tokushima University (000035546) were included in this study. The insulin secretion of the generated IPCs was investigated using surface markers by: fluorescence activated cell sorting (FACS) analysis; cytokine release; proliferation ability of ADSCs; in vitro (glucose-stimulated insulin secretion: (GSIS) test/ in vivo (transplantation into streptozotocin-induced diabetic nude mice). The less fat-related inflammatory cytokines secretions were observed ( P  < 0.05), and the proliferation ability was higher in the subcutaneous ADSCs ( P  < 0.05). Insulin expression and GISI were higher in the subcutaneous IPCs ( P  < 0.01 and P  < 0.05, respectively). The hyperglycaemic state of all mice that received IPCs from subcutaneous fat tissue converted into normo-glycaemia in thirty (30) days post-transplantation (4/4,100%). Transplanted IPCs were stained using anti-insulin and anti-human leukocyte antigen antibodies. The IPCs generated from the ADSCs freshly isolated from the human fat tissue had sufficient insulin secreting ability in vitro and in vivo .

The hepatic stellate cells (HSCs) have relationship to cancer progression. The aim of this study is to investigate the effect of HSCs and the role of IL-6/Stat3 pathway on hepatocellular carcinoma (HCC) progression. HCCs were co-cultured with HSCs. The viability and migration ability of cancer cells were detected. Epithelial-mesenchymal transition (EMT) marker (E-cadherin), stem cell marker (CD44) and p-signal transducer and activator of transcription 3 (p-STAT3) of cancer cells were evaluated. Finally, interleukin-6 (IL-6) neutralization was performed. Co-culture of HCCs with HSCs increased cancer cell viability and migration ability. EMT and stemness of cancer cells increased with HSCs. Following IL-6 neutralization, phospho-STAT3 activation, cancer cell viability and migration, as well as EMT, and stemness of cancer cells decreased. HSCs promoted HCC progression through the IL-6/STAT3 pathway.

BackgroundTumor-infiltrating lymphocytes (TILs) are a prognostic factor or an indicator of chemotherapy response for various malignancies. The aim of this study was to investigate the prognostic impact of TILs in resected intrahepatic cholangiocarcinoma (IHCC). We also investigated the usefulness of the apparent diffusion coefficient (ADC) in diffusion-weighted magnetic resonance imaging (DW-MRI) to predict TILs.MethodsWe enrolled 23 patients with IHCC who underwent initial hepatic resection in Tokushima University Hospital from 2006 to 2017. We evaluated stromal TILs in the tumor marginal area and central area in surgical specimens. Patients were divided into low vs high stromal TILs groups. We analyzed the patients’ clinicopathological factors, including prognosis, according to the degree of stromal TILs. We also analyzed the correlation between stromal TILs and the minimum ADC value.ResultsStromal TILs in the marginal area reflected overall survival more accurately than that in the central area. Additionally, marginal low TILs was significantly associated with lymph node metastasis and portal vein invasion. Both overall- and disease-free survival rates in the marginal low TILs group were significantly worse than those in the marginal high TILs group (P < 0.05). In the multivariate analysis, marginal low TILs were an independent prognostic factor for both overall- and disease-free survival (P < 0.05), and marginal low TILs were significantly associated with lower minimum ADC values (P < 0.02).ConclusionsStromal TILs, especially in the marginal area, might demonstrate prognostic impact in patients with IHCC. Moreover, the ADC values from MRI may predict TILs in IHCC tumor tissue.

Background and aim CD133 is one of the most important cancer-initiating (stem) cell markers and was confirmed to be expressed in solid cancers such as colon cancer. However, no one has investigated the role of CD133 in intrahepatic cholangiocarcinoma (IHCC). The aim of this study was to clarify the clinical role of CD133 expression in IHCC. Patients and methods Twenty-nine patients with IHCC who underwent hepatic resection at our institution were enrolled in this study. Expression of CD133 was examined using anti-CD133 antibody. Staining was observed in the cytoplasm of cancer cells and CD133-positive cells distributed in the whole tumor. The patients were divided into two groups: the CD133-positive group ( n  = 14) and CD133-negative group ( n  = 15), in which no staining of CD133 was observed. Clinicopathological factors including hypoxia-inducible factor-1α expression were compared between the two groups. The prognostic factors were investigated by multivariate analysis using Cox’s proportional hazard model. Results The 5-year survival rate in the CD133-positive group (8.0%) was worse than that in the CD133-negative group (57.0%). In the CD133-positive group, the incidence of intrahepatic metastasis and positive expression of hypoxia-inducible factor-1α tended to be higher than that in the CD133 negative group. The multivariate analysis revealed CD133 expression was an independent prognostic indicator in IHCC. Conclusions CD133 expression tended to be related to higher incidences of intrahepatic metastasis and positive expression of hypoxia-inducible factor-1α; furthermore, it was independently related to worse prognosis. Therefore, the CD133 expression is a potential prognostic indicator in IHCC.

Hepatocellular carcinoma (HCC) is an aggressive malignancy mainly due to tumor metastases or recurrence even after undergoing potentially curative treatment. There are two types of HCC recurrence. The early and late tumor recurrences appear in distinct biological contexts, and their clinical courses are quite different. Therefore, it is important to precisely and distinctly discriminate the risk of each type of HCC recurrence. Many researchers have used DNA microarray technology to reclassify HCC with respect to its malignant potential. Some of these studies successfully identified specific gene-expression signatures derived from the cancerous tissues of HCC for predicting the early recurrence due to intrahepatic metastasis. However, there are no well-defined predictors for late recurrence. Recently, a few studies have focused on the nontumorous portion of liver tissues to predict late recurrence, possibly due to de novo hepatocarcinogenesis based on the idea of “field cancerization.” This study reviewed the possible value of a gene-expression analysis of noncancerous liver tissue to clarify the risk for multicentric late recurrence of HCC. These findings may have important implications for chemopreventive strategies and tailored surveillance programs. Furthermore, this approach may also be applicable to other multifocal tumors, such as head and neck carcinoma.