Recent studies have revealed that decline in cellular nicotinamide adenine dinucleotide (NAD+) levels causes aging-related disorders and therapeutic approaches increasing cellular NAD+ prevent these ...disorders in animal models. The administration of nicotinamide mononucleotide (NMN) has been shown to mitigate aging-related dysfunctions. However, the safety of NMN in humans have remained unclear. We, therefore, conducted a clinical trial to investigate the safety of single NMN administration in 10 healthy men. A single-arm non-randomized intervention was conducted by single oral administration of 100, 250, and 500 mg NMN. Clinical findings and parameters, and the pharmacokinetics of NMN metabolites were investigated for 5 h after each intervention. Ophthalmic examination and sleep quality assessment were also conducted before and after the intervention. The single oral administrations of NMN did not cause any significant clinical symptoms or changes in heart rate, blood pressure, oxygen saturation, and body temperature. Laboratory analysis results did not show significant changes, except for increases in serum bilirubin levels and decreases in serum creatinine, chloride, and blood glucose levels within the normal ranges, independent of the dose of NMN. Results of ophthalmic examination and sleep quality score showed no differences before and after the intervention. Plasma concentrations of N-methyl-2-pyridone-5-carboxamide and N-methyl-4-pyridone-5-carboxamide were significantly increased dose-dependently by NMN administration. The single oral administration of NMN was safe and effectively metabolized in healthy men without causing any significant deleterious effects. Thus, the oral administration of NMN was found to be feasible, implicating a potential therapeutic strategy to mitigate aging-related disorders in humans.
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.
Background
The number of cancer patients with impairment of activities of daily living (ADLs) has increased. This study aimed to examine associations of perioperative Barthel index score, a validated ...measure of ADLs, with survival outcomes following hepatectomy for hepatocellular carcinoma (HCC).
Methods
We analyzed data of 492 consecutive patients who underwent hepatectomy for HCC between 2010 and 2018. Pre‐ and postoperative ADLs were assessed using the Barthel index (range, 0–100; higher scores indicate greater independence). Preoperative Barthel index score ≤85 or postoperative Barthel index score ≤85 was defined as impairment of perioperative ADLs. Cox proportional hazards regression was used to calculate hazard ratios (HRs) after adjusting for potential confounders.
Results
Among the 492 patients, 26 (5.2%) had a preoperative Barthel index score ≤85 and 95 (19%) had a postoperative Barthel index score ≤85. Impairment of perioperative ADLs was independently associated with shorter overall survival (multivariable HR: 1.75, 95% confidence interval CI: 1.06–2.81, p = 0.028). The association of impairment of perioperative ADLs with recurrence‐free survival was not statistically significant.
Conclusion
Impairment of perioperative ADLs is associated with poor prognosis following hepatectomy for HCC. Maintenance and improvement of perioperative ADLs would be important to provide favorable long‐term outcomes in patients with HCC.
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/Purpose
The aim of this study was to identify risk factors for bile leakage in hepatic resections without biliary reconstructions using the large Japanese national clinical database (NCD).
...Methods
A total of 10 102 patients who had undergone hepatic resection involving more than one segment without biliary reconstructions for hepatocellular carcinoma during 2015‐2017 were enrolled. Risk factors for bile leakage, with special reference to the type of hepatic resection, were identified by multivariable logistic regression analysis.
Results
Bile leakage occurred in 726 patients (7.2%). Risk factors for bile leakage were as follows: male sex (odds ratio OR 1.28, 95% confidence interval CI 1.04‐1.58), diabetes mellitus (+) (OR 1.19, 95% CI 1.01‐1.39), hemoglobin <10 g/dL (OR 1.4, 95% CI 1.02‐1.93), albumin <3.5 g/dL (OR 1.3, 95% CI 1.03‐1.63), central bisectionectomy (OR 3.8, 95% CI 2.81‐5.13), left trisectionectomy (OR 3.6, 95% CI 2.10‐6.15), right anterior sectionectomy (OR 2.07, 95% CI 1.58‐2.72), and S5 or S8 segmentectomy (OR 1.33, 95% CI 1.00‐1.77).
Conclusion
Central bisectionectomy, left trisectionectomy, and right anterior sectionectomy are high‐risk types of hepatic resection for bile leakage.
Highlight
Using the Japanese National Clinical Database, Yamashita and colleagues identified the following risk factors for bile leakage in 10,102 patients who had undergone hepatic resection without biliary reconstruction for hepatocellular carcinoma: central bisectionectomy (OR 3.8), left trisectionectomy (OR 3.6), right anterior sectionectomy (OR 2.07), and S5 or S8 segmentectomy (OR 1.33).
This study aimed to clarify the prognostic value of various inflammation-based prognostic scores (IBPSs) in patients who underwent radical surgery for colorectal cancer (CRC) and to develop a novel ...prognostic index using IBPSs and other predictive factors.
Data of 1157 patients who underwent radical surgery for CRC were reviewed. The predictive value of various IBPSs in determining the CRC prognosis was compared. A novel index score based on the IBPSs and other parameters that were associated with survival in patients with CRC was established, and its usefulness was evaluated.
The patients were randomly divided into the training (n = 694) and validation (n = 463) sets. Male sex (P = 0.0001), age ≥ 75 years (P < 0.0001), a carcinoembryonic antigen (CEA) level of > 5 (P = 0.0009), a C-reactive protein/albumin ratio (CAR) of ≥ 0.04 (P = 0.0033), and a prognostic nutritional index (PNI) of < 43.1 (P = 0.0004) were poor independent prognostic factors of overall survival. The novel index score was calculated based on the scores of these five prognostic factors. The Kaplan-Meier survival curves showed that the CRC patients with higher novel index scores in the training and validation datasets had poorer overall survival.
CAR and PNI were superior to other IBPSs for predicting the prognosis of CRC patients. The novel index score established based on sex, age, CEA level, CAR, and PNI can predict the prognosis of CRC with more precise and clearer stratification than the individual parameters alone.
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.
PDF
