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Fusobacterium nucleatum has been detected in 8%‐13% of human colorectal cancer, and shown to inhibit immune responses against primary colorectal tumors in animal models. Thus, we hypothesized that the presence of F. nucleatum might be associated with reduced T cell density in colorectal cancer liver metastases (CRLM). We quantified F. nucleatum DNA in 181 CRLM specimens using quantitative PCR assay. The densities of CD8+ T cells, CD33+ cells (marker for myeloid‐derived suppressor cells [MDSCs]), and CD163+ cells (marker for tumor‐associated macrophages [TAMs]) in CRLM tissue were determined by immunohistochemical staining. Fusobacterium nucleatum was detected in eight (4.4%) of 181 CRLM specimens. Compared with F. nucleatum‐negative CRLM, F. nucleatum‐positive CRLM showed significantly lower density of CD8+ T cells (P = .033) and higher density of MDSCs (P = .001). The association of F. nucleatum with the density of TAMs was not statistically significant (P = .70). The presence of F. nucleatum is associated with a lower density of CD8+ T cells and a higher density of MDSCs in CRLM tissue. Upon validation, our findings could provide insights to develop strategies that involve targeting microbiota and immune cells for the prevention and treatment of CRLM. Fusobacterium nucleatum was detected in eight (4.4%) of 181 colorectal cancer liver metastasis tissue. We found that the presence of F. nucleatum was associated with lower CD8+ T cell density and greater densities of both myeloid‐derived suppressor cells and tumor‐associated macrophages.

Immunotherapy using anti‐PD‐1/PD‐L1 antibodies for several types of cancer has received considerable attention in recent decades. However, the molecular mechanism underlying PD‐L1 expression in pancreatic ductal adenocarcinoma (PDAC) cells has not been clearly elucidated. We investigated the clinical significance and regulatory mechanism of PD‐L1 expression in PDAC cells. Among the various cytokines tested, tumor necrosis factor (TNF)‐α upregulated PD‐L1 expression in PDAC cells through NF‐κB signaling. The induction of PD‐L1 expression was also caused by co‐culture with activated macrophages, and the upregulation was inhibited by neutralization with anti‐TNF‐α antibody after co‐culture with activated macrophages. PD‐L1 expression in PDAC cells was positively correlated with macrophage infiltration in tumor stroma of human PDAC tissues. In addition, survival analysis revealed that high PD‐L1 expression was significantly associated with poor prognosis in 235 PDAC patients and especially in patients harboring high CD8‐positive T‐cell infiltration. These findings indicate that tumor‐infiltrating macrophage‐derived TNF‐α could be a potential therapeutic target for PDAC. Survival analysis revealed that PD‐L1 expression was significantly associated with poor prognosis in PDAC patients and especially in patients harboring high CD8‐positive T‐cell infiltration. The induction of PD‐L1 expression was caused by co‐culture with activated macrophages, and the upregulation was inhibited by neutralization with anti‐TNF‐α antibody after co‐culture with activated macrophages.

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.

Hepatocellular carcinoma (HCC) has high recurrence rates even after curative hepatectomy. Drug therapy for recurrence of HCC is still limited; therefore, identifying new therapeutic targets is urgently needed. We searched for genes that would predict HCC recurrence from intrahepatic metastasis in an exhaustive DNA microarray database by searching genes associated with high early recurrence rate and having higher expression in the tumor area compared to background liver. We detected lysyl oxidase (LOX) and validated the clinical significance of LOX in 358 patients who underwent hepatectomy. Expression of LOX was evaluated by qRT‐ PCR, and immunohistochemical (IHC) staining. High LOX expression group had a significantly higher recurrence rate than the low LOX expression group (2‐year recurrence rate was 64.0% vs 24.2%, P < .0001 for IHC) and poorer survival rate (5‐year rate was 60.1% vs 86.2%, P < .0001 for IHC). Multivariate analysis showed that high LOX expression was an independent risk factor for early recurrence (IHC: HR, 2.52; P < .0001). Bioinformatic analysis showed that LOX expression was associated with hypoxia‐inducible factor‐1α (HIF‐1α) and the hypoxia cascade, suggesting that HIF‐1α or hypoxia regulates LOX expression and induces epithelial‐mesenchymal transition (EMT). In vitro, LOX and HIF‐1α were involved in migration and invasion capability. High LOX expression is associated with EMT markers and predicts early recurrence and poor survival in patients with HCC. These findings indicate that lysyl oxidase could be a potential therapeutic target for early recurrence of HCC. Lysyl oxidase (LOX) expression induces EMT‐related genes, and promotes invasion and migration capability in hepatocellular carcinoma (HCC). High LOX expression predicts early recurrence and poor survival in patients with HCC.

Background Several studies have examined controlling nutritional status (CONUT), which is one of the useful biomarkers for predicting patients’ prognosis following cancer treatment. The aim of this study was to evaluate the value of CONUT as a postoperative prognostic marker in patients with intrahepatic cholangiocarcinoma (ICC) following curative hepatectomy. Methods We retrospectively analyzed 71 patients who underwent curative hepatectomy for ICC between May 2002 and November 2016. Patients were divided into two groups according to their preoperative CONUT score (i.e., CONUT ≧ 2 or CONUT < 2). Results The number of patients assigned to the normal, mild, moderate, or severe malnutrition groups was 40, 28, two, and one, respectively. The high CONUT group (CONUT ≧ 2) consisted of 31 patients (43.7%) and had a poor prognosis with regard to overall survival (OS) ( p  = 0.0149). A high CONUT score is also identified as one of the independent predictors of poor prognosis in OS (hazard ratio 3.02; 95% confidence interval 1.4–6.8; p  = 0.007). However, in the current study, a high CONUT score was not associated with postoperative complications (Clavien–Dindo classification ≧ III or more). Conclusions CONUT may be useful for the preoperative assessment of prognosis in patients with ICC who have undergone curative hepatectomy.

Chronic inflammation has a crucial role in cancer development and the progression of various tumors, including pancreatic ductal adenocarcinoma (PDAC). The arachidonate cascade is a major inflammatory pathway that produces several metabolites, such as prostaglandin E2. The enzyme 15‐hydroxyprostaglandin dehydrogenase (15‐PGDH) degrades prostaglandin and is frequently decreased in several types of cancer; however, the molecular mechanisms of 15‐PGDH suppression are unclear. The current study was carried out to elucidate the molecular mechanisms and clinical significance of 15‐PGDH suppression in PDAC. Here, we showed that interleukin‐1β (IL‐1β), a pro‐inflammatory cytokine, downregulates 15‐PGDH expression in PDAC cells, and that IL‐1β expression was inversely correlated with 15‐PGDH levels in frozen PDAC tissues. We also found that activated macrophages produced IL‐1β and reduced 15‐PGDH expression in PDAC cells. Furthermore, the number of CD163‐positive tumor‐associated macrophages was shown to be inversely correlated with 15‐PGDH levels in PDAC cells by immunohistochemical staining of 107 PDAC samples. Finally, we found that low 15‐PGDH expression was significantly associated with advanced tumors, presence of lymph node metastasis and nerve invasion, and poor prognosis in PDAC patients. Our results indicate that IL‐1β derived from TAMs suppresses 15‐PGDH expression in PDAC cells, resulting in poor prognosis of PDAC patients. IL‐1β derived from activated macrophages down‐regulates 15‐PGDH expression in PDAC cells. Down‐regulation of 15‐PGDH promotes PDAC cell growth and leads to poor prognosis in PDAC patients.

Intrahepatic cholangiocarcinoma is a rare malignant biliary neoplasm that causes a poor prognosis even after curative hepatectomy. Liver metastasis is the major recurrence pattern of intrahepatic cholangiocarcinoma; therefore, the prevention of liver metastasis is a desirable objective. The aim of this study is to identify gene(s) related to liver metastasis of intrahepatic cholangiocarcinoma and to examine the inhibitory effects on metastasis of intrahepatic cholangiocarcinoma by controlling such gene(s). We collected 3 pairs of intrahepatic cholangiocarcinoma frozen samples, and 36 pairs (primary and metastatic lesions) of intrahepatic cholangiocarcinoma formalin‐fixed paraffin‐embedded samples, from patients who underwent surgical resection at hospitals related to the Kyushu Study Group of Liver Surgery between 2002 and 2016. We carried out cDNA microarray analyses and immunohistochemistry to identify candidate genes, and evaluated one of them as a therapeutic target using human cholangiocarcinoma cell lines. We identified 4 genes related to liver metastasis using cDNA microarray, and found that CXCL12 was the only gene whose expression was significantly higher in liver metastasis than in primary intrahepatic cholangiocarcinoma by immunohistochemistry (P = .003). In prognosis, patients in the high CXCL12 group showed a significantly poor prognosis in disease‐free (P < .0001) and overall survival (P = .0004). By knockdown of CXCL12, we could significantly suppress the invasive and migratory capabilities of 2 human cholangiocarcinoma cell lines. Therefore, CXCL12 might be associated with metastasis and poor prognosis in intrahepatic cholangiocarcinoma. CXCL12 was significantly more highly expressed in liver metastasis than in primary intrahepatic cholangiocarcinoma. In terms of prognosis, patients in the high CXCL12 group showed a significantly poorer prognosis in disease‐free and overall survival than those in the low CXCL12 group. CXCL12 might be associated with metastasis and poor prognosis in intrahepatic cholangiocarcinoma.

As life expectancy increases, the older population continues to grow rapidly, resulting in increased requirement for surgery for older patients with gastrointestinal cancer. Older individuals represent a heterogeneous group in terms of physiological reserves, co‐morbidity, cognitive impairment, and disability. Owing to the lack of treatment guidelines for vulnerable patients with gastrointestinal cancer, these patients are more likely to be at risk of undertreatment or overtreatment. Hence, the identification of frail patients with gastrointestinal cancer would improve cancer treatment outcomes. Although there is no standardized geriatric assessment tool, a growing body of research has shown associations of frailty with adverse postoperative outcomes and poor prognosis after resection of gastrointestinal tract and hepatobiliary‐pancreatic cancers. Emerging evidence suggests that prehabilitation, which includes exercise and nutritional support, can improve preoperative functional capacity, postoperative recovery, and surgical outcomes, particularly in frail patients with gastrointestinal cancer. We reviewed major geriatric assessment tools for identification of frail patients and summarized clinical studies on frailty and surgical outcomes, as well as prehabilitation or rehabilitation in gastrointestinal tract and hepatobiliary‐pancreatic cancers. The integration of preoperative geriatric assessment and prehabilitation of frail patients in clinical practice may improve surgical outcomes. In addition, improving preoperative vulnerability and preventing functional decline after surgery is important in providing favorable long‐term survival in patients with gastrointestinal cancer. Further clinical trials are needed to examine the effects of minimally invasive surgery, and chemotherapy in frail patients with gastrointestinal cancer. Accumulating evidence demonstrates that the integration of preoperative geriatric assessment and prehabilitation for frail patients into clinical practice may improve perioperative and long‐term outcomes in patients with gastrointestinal cancer. We proposed an example for the integration of older patients‐specific care into treatment strategies for gastrointestinal cancer.

BackgroundCaveolin-1 (CAV1) in cancer-associated fibroblasts (CAFs) has pro- or anti-tumourigenic effect depending on the cancer type. However, its effect in intrahepatic carcinoma (ICC) remains unknown. Therefore, this study aimed to investigate the relationship between CAV1 in CAFs and tumour-infiltrating lymphocyte (TIL) numbers or PD-L1 levels in ICC patients.MethodsConsecutive ICC patients (n = 158) were enrolled in this study. The levels of CAV1 in CAFs, CD8 + TILs, Foxp3+ TILs and PD-L1 in cancer cells were analysed using immunohistochemistry. Their association with the clinicopathological factors and prognosis were evaluated. The correlation between these factors was evaluated.ResultsCAV1 upregulation in CAFs was associated with a poor overall survival (OS) (P < 0.001) and recurrence-free survival (P = 0.008). Clinicopathological factors were associated with high CA19-9 levels (P < 0.001), advanced tumour stage (P = 0.046) and lymph node metastasis (P = 0.004). CAV1 level was positively correlated with Foxp3+ TIL numbers (P = 0.01). There were no significant correlations between CAV1 levels and CD8 + TIL numbers (P = 0.80) and PD-L1 levels (P = 0.97). An increased CD8 + TIL number and decreased Foxp3+ TIL number were associated with an increased OS. In multivariate analysis, positive CAV1 expression in CAFs (P = 0.013) and decreased CD8 + TIL numbers (P = 0.021) were independent poor prognostic factors.ConclusionCellular senescence, represented by CAV1 levels, may be a marker of CAFs and a prognostic indicator of ICC through Foxp3+ TIL regulation. CAV1 expression in CAFs can be a therapeutic target for ICC.

Background A decrease in skeletal muscle mass and function, defined as sarcopenia, is associated with poor postoperative outcome in patients with cancers. Although systemic or local immune status impacts cancer progression, the relationship between sarcopenia and these statuses remains unclear. The aim of this study is to investigate the clinical impact of sarcopenia and its relationship to immune systems in patients with extrahepatic cholangiocarcinoma (ECC). Methods A total of 110 consecutive ECC patients with curative resection between 2005 and 2014 were enrolled. Sarcopenia was determined from skeletal muscle index, assessed by a L3 skeletal muscle mass on axial computed tomography images, and their relationships with patients’ clinicopathological characteristics and survival were evaluated. Systemic immune status was calculated using preoperative laboratory data, and tumor-infiltrating (TI) immune cells (CD8 + T cells, CD66b + neutrophils, CD163 + M2 macrophages) assayed by immunohistochemistry, and their relationship to sarcopenia were evaluated. Results Sarcopenia was present in 31 patients (28.2%). Patients with sarcopenia had a worse recurrence-free survival (HR 1.87, p  = 0.009) and overall survival (OS) (HR 2.47, p  = 0.0004) than patients without sarcopenia. Moreover, patients with sarcopenia had a higher level of platelet–lymphocyte ratio (159 vs. 119; p  = 0.003) and lower number of TI CD8 + T cells (47 vs. 66 cells/spot; p  = 0.03) than patients without sarcopenia. On multivariate analysis, the presence of sarcopenia (HR 2.60, p  = 0.0008) was an independent predictor of poor OS. Conclusions Our data showed that sarcopenia and systemic or local immune cells may interact with each other and play a pivotal role in clinical outcomes of patients with ECC.