Inflammatory and immune cells in the tumor microenvironment are reported to be associated with tumor progression in several cancers. In total, 225 patients who underwent initial and curative ...hepatectomy for hepatocellular carcinoma (HCC) from 2004 to 2013 were enrolled in this study. Tumor‐associated neutrophils (TANs), M2 macrophages (TAMs; tumor‐associated macrophages), CD8+ T cells, and regulatory T cells (Tregs) were evaluated by immunohistochemistry (IHC), and their relationships with patient clinicopathological characteristics and prognosis were evaluated. IHC was performed focusing on TANs first. We could not find a relationship between intratumoral and peritumoral TANs and clinicopathological features except for the fibrous capsule and infiltration of tumors into capsule. Next, TAMs, CD8+ cells and Tregs were evaluated by IHC. At the peritumoral area, TANs and TAMs (r = 0.36, p = 0.001) or Tregs (r = 0.16, p = 0.008) showed a positive correlation, whereas TANs and CD8+ cells showed a negative correlation (r = −0.16, p = 0.02). As for survival outcomes, at the peritumoral area, high TANs (p = 0.0398), low CD8+ cells (p = 0.0275), and high TAMs (p = 0.001) were significantly associated with worse overall survival (OS). In addition, high TANs (p = 0.010), and high TAMs (p = 0.00125) were significantly associated with worse disease‐free survival (DFS). Finally, we established a risk signature model by combining the expression patterns of these cells. The high‐risk signature group had significantly worse OS (p = 0.0277) and DFS (p = 0.0219) compared with those in the low‐risk signature group. Our risk signature based on immune cells at the peritumoral area of the HCC can predict patient prognosis of HCC after curative hepatectomy.
In this study, we showed that infiltration of inflammatory and immune cells at peri‐tumoral site of HCC showed a significant association with patients’ prognosis. We also made risk signature evaluated by the infiltration of immune cells at peri‐tumoral site of HCC, and it might to be a new prognostic marker of patients with HCC after curative hepatectomy.
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•Heparin functionalized PCL/gelatin co-spun nanofibrous dressings were synthesized.•Fabricated dressings showed improved mechanical and degradation properties.•Fabricated dressings ...showed exogenous and endogenous GFs sequestration ability.•In-vivo, synergistic effect of exogenous and endogenous GFs promoted tissue regeneration.
Growth factors (GFs) are signaling molecules that are principle mediators in tissue regeneration. Biomaterial scaffolds employed as wound dressings are often hampered by their limitations to deliver GFs exogenously due to their instability and low half-life. The key to overcome this challenge lies in the better organization and use of endogenous pro-regenerative GFs released at regenerative site, with an aim to minimize the sole dependency on exogenous factors. Considering such challenges, this research utilizes the exogenous and endogenous GFs sequestering capability of heparin functionalized PCL/gelatin co-spun nanofabrics to mediate synergistically driven tissue regeneration by utilizing combined therapeutic effect of exogenous and endogenous GFs, and thereby minimizing the sole dependency on exogenous GFs for tissue regeneration. Basic fibroblast growth factor (bFGF) was chosen as GF for exogenous loading whereas vascular endothelial growth factor (VEGF) was chosen as a representative example to demonstrate the endogenous pro-regenerative GF sequestration capability of fabricated nanofabrics. From our results, the fabricated nanofabrics showed loading efficiency of 80% for exogenous bFGF and can sequester 15-fold more amount of endogenous VEGF compared to non-heparin functionalized nanofibrous dressings. When applied as wound dressings, heparin functionalized nanofibers showed better therapeutic capability compared to control groups that were treated using patches without heparin functionalization, indicating endogenously driven tissue regeneration. This was indicated by significant higher number of newly formed skin appendages, lesser scarring and lower inflammatory levels in newly formed granulation. Additionally, further improvements in therapeutic effect was observed when exogenous bFGF was employed indicating effectiveness of synergistically mediated tissue regeneration.
Aim
Combined hepatocellular cholangiocarcinoma (cHCC‐CCA) is a very rare subtype of primary liver carcinoma; therefore, its clinicopathological characteristics have not yet been elucidated in detail. ...The aim of the study was to reveal the clinicopathological characteristics and prognostic factors of cHCC‐CCA after hepatic resection (HR)
Methods
A total of 124 patients who underwent curative HR for cHCC‐CCA between 2000 and 2016 were enrolled in this multi‐institutional study conducted by the Kyushu Study Group of Liver Surgery. Clinicopathological analysis was performed from the viewpoint of patient prognosis.
Results
A total of 62 patients (50%) had early recurrence within 1.5 years after HR, including 36 patients (58%) with extrahepatic recurrence. In contrast, just four patients (3%) had late recurrence occurring >3 years after HR. The independent predictors of early recurrence were as follows: des‐gamma carboxyprothrombin >40 mAU/mL (odds ratio 26.2, P = 0.0117), carbohydrate antigen 19–9>37 IU/l (odds ratio 18.0, P = 0.0200), and poorly differentiated HCC or CCA (odds ratio 11.2, P = 0.0259).
Conclusions
Half of the patients with cHCC‐CCA had early recurrence after HR. Preoperative elevation of des‐gamma carboxyprothrombin or carbohydrate antigen 19–9 and the existence of poorly differentiated components of HCC or CCA in resected specimens are predictors of its early recurrence.
Background
The prediction of prognostic outcomes can provide the most suitable strategy for patients with pancreatic ductal adenocarcinoma (PDAC). This study aimed to evaluate the clinical value of ...the preoperative tumor marker index (pre-TI) in predicting prognostic outcomes after resection for PDAC.
Methods
For 183 patients who underwent pancreatic resection of PDAC, adjusted carbohydrate antigen 19-9 (CA19-9), carcinoembryonic antigen (CEA), pancreatic cancer-associated antigen-2 (DUpan-2), and s-pancreas-1 antigen (SPan-1) were retrospectively evaluated, and the positive number of these markers was scored as the pre-TI.
Results
A high pre-TI (≥ 2) was significantly associated with a larger tumor and lymph node metastases, and the patients with a high pre-TI had worse prognostic outcomes in terms of both relapse-free survival (RFS) (
P
< 0.0001, log-rank) and overall survival (OS) (
P
< 0.0001, Λlog-rank) than the patients with a low pre-TI. The pre-TI was one of the independent factors of a poor prognosis for RFS (hazard ratio HR, 2.36;
P
< 0.0001) and OS (HR, 2.27;
P
< 0.0001). In addition, even for the patients with normal adjusted CA19-9 values (
n
= 74, 40.4%), those with the high pre-TI had a significantly poorer prognosis than those with a low pre-TI (RFS:
P
= 0.002, log-rank; OS:
P
= 0.031, log-rank).
Conclusions
The pre-TI could be a potent predictive marker of prognostic outcomes for patients with resections for PDAC. Patients with a high pre-TI may need additional strategies to improve their prognosis.
In this study, we propose a microfluidic cell culture device mimicking the microscopic structure in liver tissue called hepatic cords. The cell culture area of the device was designed to align ...hepatocytes in two lines in a similar way to hepatic cords. Thanks to the structural design together with a cell seeding procedure, rat primary hepatocytes were successfully aligned in two lines and cultured under perfusion condition. It is shown that aligned hepatocytes gradually self-organize and form bile canaliculi along the hepatic cord-like structure. The present technique to culture hepatocytes with functional bile canaliculi could be used as an alternative to animal testing in the field of drug discovery and toxicological studies, and also be beneficial to tissue engineering applications.
Background
With population aging, the number of frail patients with pancreatic cancer has increased. The Clinical Frailty Scale (CFS) is a simple and validated tool to assess frailty, and higher ...scores predict worse clinical outcomes after cardiovascular surgery. In this retrospective study, we aimed to examine the association of preoperative frailty with prognosis after resection for pancreatic cancer.
Methods
We retrospectively analyzed data from 142 consecutive patients undergoing resection for pancreatic cancer between April 2010 and December 2018. We used the CFS: 1 (very fit) to 9 (terminally ill) to assess frailty and examined associations of the CFS scores with recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). Multivariable Cox proportional hazards models were used to calculate hazard ratios (HRs), controlling for potential confounders.
Results
Of the 142 patients, 113 (80%) had CFS scores of ≤ 3, 13 (9.2%) scores of 4, and 16 (11%) scores of ≥ 5. Scores of ≥ 5 on the CFS were associated with worse CSS (univariable HR: 2.62, 95% confidence interval CI: 1.19–5.18,
P
= 0.019; multivariable HR: 2.49, 95% CI 1.05–5.34,
P
= 0.039) and OS (univariable HR: 2.42, 95% CI 1.19–4.46,
P
= 0.016; multivariable HR: 2.25, 95% CI 1.05–4.43,
P
= 0.038). The association between CFS scores and RFS was not significant in multivariable analysis (univariable HR: 2.11, 95% CI 1.08–3.79,
P
= 0.030; multivariable HR: 1.47, 95% CI 0.71–2.83,
P
= 0.29).
Conclusion
Higher scores on the CFS are associated with worse CSS and OS after resection for pancreatic cancer. Preoperative measurement of frailty may improve risk assessment among patients with pancreatic cancer.
The predictive significance of programmed death ligand 1 (PD-L1) for programmed death 1 (PD-1) inhibitors remains unclear in gastric cancer (GC) due to the dynamic alteration by treatments. We aimed ...to elucidate the effects of trastuzumab (Tmab) on PD-L1 expression in GC.
PD-L1 expression was evaluated by multicolour flow cytometry analysis after co-culturing GG cell lines and immune cells with Tmab. IFN-γ in the co-culture experiments was quantified. Immunohistochemistry (IHC) for PD-L1 expression using clinical samples was also performed to confirm PD-L1 alteration by Tmab.
PD-L1 expression was significantly upregulated by Tmab in HER2-amplified GC cell lines co-cultured with peripheral blood mononuclear cells (PBMCs). PD-L1 upregulation by Tmab was also observed in the GC cells co-cultured with NK cells in time-dependent manner, but not with monocytes. IFN-γ concentration in conditioned media from co-cultured PBMCs and NK cells with Tmab was significantly higher and anti-IFN-γ significantly suppress the Tmab-induced PD-L1 upregulation. IHC also suggested PD-L1 upregulation after Tmab treatment.
Tmab can upregulate PD-L1 expression on GC cells through interaction with NK cells. These results suggest clinical implications in the assessment of the predictive significance of PD-L1 expression for PD-1 inhibitors.
Cancer cells craftily adapt their energy metabolism to their microenvironment. Nutrient deprivation due to hypovascularity and fibrosis is a major characteristic of pancreatic ductal adenocarcinoma ...(PDAC); thus, PDAC cells must produce energy intrinsically. However, the enhancement of energy production via activating Kras mutations is insufficient to explain the metabolic rewiring of PDAC cells. Here, we investigated the molecular mechanism underlying the metabolic shift in PDAC cells under serine starvation. Amino acid analysis revealed that the concentrations of all essential amino acids and most nonessential amino acids were decreased in the blood of PDAC patients. In addition, the plasma serine concentration was significantly higher in PDAC patients with PHGDH-high tumors than in those with PHGDH-low tumors. Although the growth and tumorigenesis of PK-59 cells with PHGDH promoter hypermethylation were significantly decreased by serine starvation, these activities were maintained in PDAC cell lines with PHGDH promoter hypomethylation by serine biosynthesis through PHGDH induction. In fact, DNA methylation analysis by pyrosequencing revealed that the methylation status of the PHGDH promoter was inversely correlated with the PHGDH expression level in human PDAC tissues. In addition to PHGDH induction by serine starvation, PDAC cells showed enhanced serine biosynthesis under serine starvation through 3-PG accumulation via PGAM1 knockdown, resulting in enhanced PDAC cell growth and tumor growth. However, PHGDH knockdown efficiently suppressed PDAC cell growth and tumor growth under serine starvation. These findings provide evidence that targeting the serine biosynthesis pathway by inhibiting PHGDH is a potent therapeutic approach to eliminate PDAC cells in nutrient-deprived microenvironments.
•High PHGDH expression is significantly correlated with a high serum serine concentration and poor prognosis in PDAC patients.•DNA hypomethylation in CpG islands of the PHGDH gene locus has a strong impact on PHGDH induction under serine deprivation.•3-PG accumulation via PGAM1 downregulation enhances serine biosynthesis and tumor growth under serine deprivation.•PHGDH inhibition shows a significant suppressive effect on tumor growth under serine deprivation.
Background
MicroRNA (miRNA) expression abnormalities are implicated in tumor progression. Previous reports have indicated that microRNA-25 (miR-25) acts as a tumor suppressor or oncogene in diverse ...cancers. However, its molecular mechanisms in hepatocellular carcinoma (HCC) are still unclear. F-box and WD repeat domain 7 (Fbxw7) is a critical tumor suppressor and is one of the most important deregulated proteins of the ubiquitin–proteasome system in cancer. Our objective was to elucidate the role of miR-25 and Fbxw7 in HCC and to clarify the mechanism by which Fbxw7 is regulated.
Methods
Fbxw7 expression was estimated in 210 fixed paraffin-embedded HCC samples by immunohistochemistry, and miR-25 expression was evaluated in 142 frozen HCC tissue samples by quantitative real-time PCR. Oncogenic functions of miR-25 and its role in the regulation of Fbxw7 expression were assayed in vitro.
Results
miR-25 was overexpressed in HCC tissue compared with adjacent normal tissue and significantly correlated with a poorer prognosis. Moreover, it was inversely correlated with Fbxw7 expression in HCC tissues. Furthermore, miR-25 inhibition significantly reduced the proliferation, migration, and invasion of HCC cells in vitro.
Conclusion
miR-25 may promote tumor progression in HCC patients by repression of Fbxw7 and could serve as a promising molecular target for HCC treatment.
Background
Pancreatic cancer has an extremely poor prognosis, even after curative resection. Treatment options for pancreatic cancer remain limited, therefore new therapeutic targets are urgently ...needed. We searched for genes predictive of poor prognosis in pancreatic cancer using a public database and validated the survival impact of the selected gene in a patient cohort.
Methods
We used a public database to search for genes associated with early pancreatic cancer recurrence. As a validation cohort, 201 patients who underwent radical resection in our institution were enrolled. Expression of the target gene was evaluated using immunohistochemistry (IHC). We evaluated growth and invasiveness using small interfering RNAs, then performed pathway analysis using gene set enrichment analysis.
Results
We extracted ARHGEF2 from GSE21501 as a gene with a high hazard ratio (HR) for early recurrence within 1 year. The high ARHGEF2 expression group had significantly poorer recurrence-free survival (RFS) and poorer overall survival (OS) than the low ARHGEF2 expression group. Multivariate analysis demonstrated that high ARHGEF2 expression was an independent poor prognostic factor for RFS (HR 1.92) and OS (HR 1.63). In vitro, ARHGEF2 suppression resulted in reduced cell growth and invasiveness. Bioinformatic analysis revealed that ARHGEF2 expression was associated with MYC, G2M, E2F, and CDC25A expression, suggesting that c-Myc and cell cycle genes are associated with high ARHGEF2 expression. IHC revealed a positive correlation between ARHGEF2 and c-Myc expression.
Conclusions
High ARHGEF2 expression is associated with cell cycle progression, and predicts early recurrence and poor survival in patients with pancreatic cancer.
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