Impairment of perioperative activities of daily living is associated with poor prognosis following pancreatectomy for pancreatic cancer.

PURPOSE: It has reported that the prevalence of frailty in patients with pancreatic cancer is 45%. The number of patients with pancreatic cancer is increasing, and within this cohort, patients often suffer from impaired activities of daily living (ADLs). This study aimed to examine the association between perioperative Barthel Index (BI) scores, a validated measure of ADLs, and survival outcomes after pancreatectomy for pancreatic cancer. METHODS: We analyzed the data of 201 patients who underwent pancreatectomy for pancreatic cancer between 2010 and 2020. Preoperative and postoperative ADLs were assessed using the BI (range: 0-100; higher scores indicated greater independence). A preoperative or postoperative BI score ≤ 85 was defined as an impairment of perioperative ADLs. Cox proportional hazards regression was used to calculate the hazard ratios (HRs) after adjusting for potential confounders. RESULTS: Among the 201 patients, 14 (7.0%) had a preoperative BI score ≤ 85 and 50 (25%) had a postoperative BI score ≤ 85. Impairment of perioperative ADLs was independently associated with shorter overall survival (multivariable HR: 2.66, 95% confidence interval [95%CI]: 1.75-4.03, P < 0.001), cancer-specific survival (multivariable HR: 2.64, 95%CI: 1.15-4.25, P < 0.001), and recurrence-free survival (multivariable HR: 1.94, 95%CI: 1.08-3.50, P = 0.021). CONCLUSION: Impairment of perioperative ADLs is associated with poor prognosis following pancreatectomy for pancreatic cancer. The maintenance and improvement of perioperative ADLs could play an important role in providing favorable long-term outcomes in patients with pancreatic cancer.

Patient vulnerability is associated with poor prognosis following upfront hepatectomy for colorectal liver metastasis.

BACKGROUND: With the rapid aging of populations worldwide, the number of vulnerable patients with liver metastasis from colorectal cancer has increased. This study aimed to examine the association between vulnerability and clinical outcomes in patients with colorectal liver metastasis (CRLM). METHODS: Consecutive 101 patients undergoing upfront hepatectomy for CRLM between 2004 and 2020 were included. The preoperative vulnerability was assessed using the Clinical Frailty Scale (CFS) score ranging from one (very fit) to nine (terminally ill), and frailty was defined as a CFS score of ≥ 4. A multivariable Cox proportional hazard regression model was utilized to investigate associations of frailty with disease-free survival (DFS), overall survival (OS), and cancer-specific survival (CSS). RESULTS: Of the 101 patients, 12 (12%) had frailty. Associations between frailty and surgical outcomes, namely, the incidence of 90-day mortality and postoperative complications, were not statistically significant (P > 0.05). In the multivariable analyses, after adjusting for clinical risk scores calculated using six factors (timing of liver metastasis, primary tumor lymph node status, number of liver tumors, size of the largest tumor, extrahepatic metastatic disease, and carbohydrate antigen 19-9 level) to predict recurrence following hepatectomy for CRLM, preoperative frailty was found to be an independent risk factor for DFS (hazard ratio [HR]:2.37, 95% confidence interval [CI] 1.06-4.72, P = 0.036), OS (HR:4.17, 95% CI 1.43-10.89, P = 0.011), and CSS (HR:3.49, 95% CI 1.09-9.60, P = 0.036). CONCLUSION: Preoperative frailty was associated with worse DFS, OS, and CSS after upfront hepatectomy for CRLM. Assessment and improvement of patient vulnerability may provide a favorable prognosis for patients with CRLM.

Prognostic impact of aspirin in patients with hepatocellular carcinoma after liver resection: propensity-score-matched analysis.

BACKGROUND: The association between aspirin and hepatocellular carcinoma (HCC) has been reported to prevent carcinogenesis caused by hepatitis B or C virus infection. The objective of this study was to investigate the prognostic impact of aspirin in patients who underwent liver resection for HCC. METHODS: Data for 1032 patients who underwent primary resection for HCC between 2000 and 2019 were reviewed. There were 87 patients (8.4%) who took aspirin (aspirin group) and 945 (91.6%) who did not (non-aspirin group). Short-term outcomes, recurrence-free survival (RFS), and overall survival (OS) were compared between two groups in the matched cohort using propensity-score matching. RESULTS: The median patient follow-up was 42.6 months (95% confidence interval 3.12-136.8 months). There was no significant difference in short-term outcomes, including bleeding events. RFS and OS after liver resection in the aspirin group were significantly better than those in the non-aspirin group in the unmatched cohort [5-year RFS rate: 50.3% vs 31.4%, hazard ratio (HR) 0.55, P = 0.0002; 5-year OS rate: 82.9% vs 70.2%, HR 0.46, P = 0.002]. In the matched cohort, RFS and OS after liver resection in the aspirin group were also significantly better than those in the non-aspirin group (5-year RFS rate: 50.3% vs 32.0%, HR 0.60, P = 0.003; 5-year OS rate: 82.9% vs 74.6%, HR 0.56, P = 0.03). CONCLUSION: Use of aspirin was associated with better prognosis for patients who underwent primary resection for HCC.

IL-1ß derived from mixed-polarized macrophages activates fibroblasts and synergistically forms a cancer-promoting microenvironment.

BACKGROUND: Remodeling the tumor microenvironment (TME) to benefit cancer cells is crucial for tumor progression. Although diffuse-type gastric cancer (DGC) preferentially interacts with the TME, the precise mechanism of the complicated network remains unknown. This study aimed to investigate the mutual activation mechanism underlying DGC progression. METHODS: Mass cytometry analysis of co-cultured macrophages, noncancerous fibroblasts (NFs), and DGC cells was performed. RNA sequencing was applied to examine gene expression in fibroblasts. DGC cells were treated with cytokines to examine their effect on characteristic changes. The TCGA and Kumamoto University cohorts were used to evaluate the clinical relevance of the in vitro findings. RESULTS: Cohort analysis revealed that DGC patients had a poor prognosis. The fibroblasts and macrophages interacted with DGC cells to form a cell cluster in the invasive front of DGC tissue. The original 3D triple co-culture system determined the promotional effects of nonmalignant cells on DGC invasive growth. We notably identified a mixed-polarized macrophage cell type with M1/M2 cell surface markers in a triple co-culture system. IL-1ß from mixed-polarized macrophages induced the conversion of NFs to cancer-associated fibroblast-like (CAF-like) cells, promoting the malignant phenotype of DGC cells by inducing the secretion of IL-6, IL-24, and leukemia inhibitory factor (LIF). Moreover, IL-6 and colony stimulating factor 2 (GM-CSF) cooperated to maintain the stable state of mixed-polarized macrophages. Finally, we found that mixed-polarized macrophages were frequently detected in DGC tissues. CONCLUSION: These findings demonstrated that mixed-polarized macrophages exist as a novel subtype through the reciprocal interaction between DGC cells and nonmalignant cells.

Survival impact of immune cells infiltrating peritumoral area of hepatocellular carcinoma.

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.

Tumor microenvironmental 15-PGDH depletion promotes fibrotic tumor formation and angiogenesis in pancreatic cancer.

The arachidonic acid cascade is a major inflammatory pathway that produces prostaglandin E2 (PGE2). Although inhibition of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is reported to lead to PGE2 accumulation, the role of 15-PGDH expression in the tumor microenvironment remains unclear. We utilized Panc02 murine pancreatic cancer cells for orthotopic transplantation into wild-type and 15-pgdh+/- mice and found that 15-pgdh depletion in the tumor microenvironment leads to enhanced tumorigenesis accompanied by an increase in cancer-associated fibroblasts (CAFs) and the promotion of fibrosis. The fibrotic tumor microenvironment is widely considered to be hypovascular; however, we found that the angiogenesis level is maintained in 15-pgdh+/- mice, and these changes were also observed in a genetically engineered PDAC mouse model. Further confirmation revealed that fibroblast growth factor 1 (FGF1) is secreted by pancreatic cancer cells after PGE2 stimulation, consequently promoting CAF proliferation and vascular endothelial growth factor A (VEGFA) expression in the tumor microenvironment. Finally, in 15-pgdh+/- Acta2-TK mice, depletion of fibroblasts inhibited angiogenesis and cancer cell viability in orthotopically transplanted tumors. These findings highlighted the role of 15-pgdh downregulation in enhancing PGE2 accumulation in the pancreatic tumor microenvironment and in subsequently maintaining the angiogenesis level in fibrotic tumors along with CAF expansion.

What are the factors predictive of postoperative complications in patients with colorectal cancer undergoing stenting as a bridge to surgery?

OBJECTIVE: Using a self-expanding metal stent as a bridge to surgery (BTS) is considered a reasonable strategy for patients with acute malignant large bowel obstruction. Since postoperative complications have a negative impact on patient survival, we aim to clarify the predictors of complications in patients undergoing BTS using a self-expanding metal stent. METHODS: We conducted a retrospective review of 61 patients with colorectal cancer (CRC) who underwent stenting as a BTS at our institution. We analyzed the association of postoperative complications with clinicopathologic, surgical, and patient factors, and with the prestenting or preoperative laboratory data. RESULTS: Both postoperative complications in general and severe complications were significantly associated with a longer stenotic-section length (p = 0.007 and p = 0.003), lower preoperative hemoglobin levels (p < 0.001 and p = 0.081), and lower prestenting hemoglobin levels (p = 0.006 and p = 0.042). Multivariate logistic regression analysis showed that lower prestenting (<13.0 g/dl) and preoperative (<11.5 g/dl) hemoglobin levels were independent predictive factors for postoperative complications (odds ratio [OR]: 4.15; 95% confidence interval [CI]: 1.07-18.90; p = 0.040; and OR: 4.93; 95% CI: 1.35-20.28; p = 0.016). A stenotic-section length of 5.0 cm or greater was predictive of severe complications (OR: 25.67; 95% CI: 1.95-1185.00; p = 0.011). CONCLUSIONS: Our data suggest that lower hemoglobin levels before stenting and a longer length of the stenotic section of bowel might predict postoperative complications in patients with CRC undergoing BTS for obstruction.

[Safety of Pancreaticoduodenectomy in Patients of Advanced Age and Our Efforts to Prevent Postoperative Pneumonia].

With the aging of society, surgical patients are becoming older. The same trend can be seen in patients undergoing highly invasive operations, such as pancreaticoduodenectomy(PD). The risk of postoperative complications is reportedly higher in patients of advanced age, and postoperative pneumonia occurs at particularly high frequency. We investigated the safety of PD in patients of advanced age with a focus on the prevention of postoperative pneumonia. In total, 223 patients underwent PD at our department from January 2015 to December 2020. We compared various parameters between older patients(≥80 years of age, n=32)and younger patients(<80 years of age, n=191). Although older patients had lower nutrition scores, there was no significant difference in the incidence of postoperative complications between the two groups. Three older patients who were undergoing swallowing rehabilitation by a speech-language therapist did not develop postoperative pneumonia. However, one patient who did not receive swallowing rehabilitation developed postoperative pneumonia. Based on these findings, we plan to incorporate swallowing evaluation before postoperative oral intake into the clinical pathway and introduce speech-language therapy intervention in patients of advanced age.

MicroRNA-25 Exerts an Oncogenic Function by Regulating the Ubiquitin Ligase Fbxw7 in Hepatocellular Carcinoma.

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.

Prognostic Value of the Preoperative Tumor Marker Index in Resected Pancreatic Ductal Adenocarcinoma: A Retrospective Single-Institution Study.

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.

High ARHGEF2 (GEF-H1) Expression is Associated with Poor Prognosis Via Cell Cycle Regulation in Patients with Pancreatic Cancer.

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.

Frailty is associated with poor prognosis after resection for pancreatic cancer.

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.

Clinical Significance of PD-L1 Expression in Both Cancer and Stroma Cells of Cholangiocarcinoma Patients.

BACKGROUND: The clinical significance of programmed death 1 and its ligand (PD-L1) as therapeutic targets has been reported previously. This study aimed to investigate the clinical impact of PD-L1 expression in cancer and stroma cells in cholangiocarcinoma (CCA). METHODS: The study enrolled 177 consecutive CCA patients who underwent curative resection between 2005 and 2014. Expression of PD-L1 in CCA and stroma cells was assayed by immunohistochemistry, and their relationships with patient clinicopathologic characteristics and prognoses were evaluated. Tumor-infiltrating immune cells (CD66b+ neutrophils [TANs] and CD163+ M2 macrophages [TAMs]) also were assayed by immunohistochemistry, and their relationship with PD-L1 expression in cancer and stroma cells was evaluated. RESULTS: Among the 177 analyzed CCA cases, PD-L1 expression was identified in cancer cells in 54 cases (30.5%) and in stroma cells in 77 cases (43.5%). The patients with positive PD-L1 expression in cancer and stroma cells had worse overall survival rates than those negative for PD-L1 (cancer cells: hazard ratio [HR] 2.08; P = 0.0004; stroma cells: HR 1.84; P = 0.003). Moreover, the patients with PD-L1-positive cancer cells had higher rates of PD-L1 expression in stroma cells (P < 0.0001) and higher numbers of TANs (P = 0.0003) and TAMs (P = 0.004) than those with low PD-L1 expression. In the multivariate analysis, PD-L1 expression in both cancer and stroma cells (HR 2.20; P = 0.002) was an independent predictor of poor overall survival. CONCLUSIONS: The study showed PD-L1 expressed in both CCA and stromal cells and demonstrated that its expression may affect numbers of TANs and TAMs and play a pivotal role in CCA outcomes.

The pivotal predictor of severe postoperative complications of pancreatoduodenectomy: complex links of bacterial contamination from preoperative biliary drainage.

PURPOSE: Preoperative biliary drainage (PBD) prior to pancreatoduodenectomy (PD) is controversial. The aim of this study was to clarify how PBD leads to postoperative complications of PD. METHODS: The subjects of this retrospective study were 230 patients who underwent PD between January, 2008 and January, 2018. We analyzed how PBD was associated with severe postoperative complications (Clavien-Dindo ≥ IIIB) with special reference to its links with bacterial contamination. RESULTS: Preoperative biliary drainage (PBD) was correlated with the contamination of both bile juice collected at surgery (p < 0.001) and ascites collected from the intraperitoneal drain on postoperative day (POD) 3 (p < 0.001). Receiver operating characteristic curve analysis revealed that PBD for longer than 28 days was significantly associated with the contamination of bile juice. Multivariate regression analysis revealed that the contamination of ascites on POD3 was independently associated with severe postoperative complications (Clavien-Dindo ≥ IIIB) (odds ratio 3.52, p = 0.03), although PBD and the contaminated bile juice at surgery were not. CONCLUSIONS: PBD was associated with the contamination of biliary tract and ascites after surgery. The current study revealed that contaminated ascites on POD 3, not PBD by itself, was independently associated with severe postoperative complications after PD.

Postoperative nonalcoholic fatty liver disease is correlated with malnutrition leading to an unpreferable clinical course for pancreatic cancer patients undergoing pancreaticoduodenectomy.

PURPOSES: This study aimed to clarify the impact of postoperative nonalcoholic fatty liver disease (NAFLD) on the clinical course of patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: One hundred and eight patients with pancreatic cancer undergoing pancreaticoduodenectomy (PD) with curative intent in between 2005 and 2016 were enrolled in this study. Post-PD NAFLD was assessed by computed tomography (CT), which was routinely performed at 3 months, 6 months, and 1 year after surgery. The clinical impact of post-PD NAFLD was examined from an oncological perspective. RESULTS: There were 50 (46.2%) post-PD NAFLD patients. The NAFLD group showed significantly lower CT values at 3 months, 6 months, and 1 year after surgery than those without NAFLD. Patients with NAFLD showed significant body weight loss and a decrease in serum albumin level after surgery compared with those without NAFLD. Consequently, the 70% completion rate of adjuvant chemotherapy with gemcitabine, but not S1, was significantly lower in the NAFLD group than in the non-NAFLD group. The 5-year overall survival and disease-free survival rates were comparable between the two groups. CONCLUSION: Post-PD NAFLD was associated with malnutrition in patients with PDAC, reducing their tolerance to gemcitabine-based adjuvant chemotherapy. Post-PD NAFLD needs to be emphasized and requires special nutritional intervention in patients with PDAC.

Clinical role of serum programmed death ligand 1 in patients with hepatocellular carcinoma: Where does it come from?

PURPOSES: Programmed death ligand 1 (PD-L1) is a key target for the treatment of several malignancies. The present study was conducted to clarify the role of serum PD-L1 in hepatocellular carcinoma (HCC). METHODS: Serum PD-L1 (sPD-L1) was examined by an enzyme-linked immunosorbent assay in 153 patients with HCC who underwent curative hepatectomy at Kumamoto University in 2011-2016. The expression of PD-L1 in tissue (tPD-L1) was investigated by immunohistochemistry. The clinical roles of the PD-L1 expression in both serum and tissue were examined. RESULTS: The sPD-L1 was significantly elevated in HCC patients compared to patients without any malignant or inflammatory disease (234 vs. 93 pg/mL, p < 0.0001). The percentage of the tPD-L1-positive area (%tPD-L1) in the background liver was significantly higher than in the tumor (1.52% vs. 0.48%, p < 0.0001). The %tPD-L1 in the background liver but not in the tumor was significantly correlated with the sPD-L1 level (p = 0.0079). The sPD-L1, %tPD-L1 in the tumor, and %tPD-L1 in the background liver were not correlated with the overall survival after surgery. CONCLUSION: PD-L1-expressing cells in the background liver, but not in the tumor tissue, appeared to contribute to the sPD-L1 level. The sPD-L1 level may thus not indicate the tumor burden in patients with HCC.

Perioperative Allogeneic Blood Transfusion Does not Influence Patient Survival After Hepatectomy for Hepatocellular Carcinoma: A Propensity Score Matching Analysis.

BACKGROUND: Whether perioperative allogeneic blood transfusion (PABT) negatively influences patient survival after hepatectomy (HR) for hepatocellular carcinoma (HCC) remains controversial. METHODS: Five hundred two patients who underwent HR for initial HCC between 1994 and 2015 were enrolled in this study. All patients were divided into two groups: the PABT group and the non-PABT group. Differences of clinicopathological factors, overall survival (OS), recurrence-free survival (RFS), and the recurrence pattern between the two groups were evaluated. Using propensity score matching for tumor-related factors, liver functions, and surgical factors (total 11 factors), the survival impact of PABT was also analyzed. RESULTS: In the entire cohort, 78 patients (15.5%) received PABT such as red cell concentrate, fresh-frozen plasma, or platelets. OS (5-year OS: 55% vs. 76%; p = 0.0005) and RFS (2-year RFS: 47% vs. 56%; p = 0.0131) were significantly worse in the PABT group. The extrahepatic recurrence happened more frequently in the PABT group (15% vs. 5.4%; p = 0.0039). There were many significant clinicopathological differences between the two groups: more advanced tumor stage (tumor diameter, stage III or IV, microvascular invasion), worse liver functions (albumin, indocyanine green retention rate at 15 min), and more surgical stress (blood loss, operation time) in the PABT group. After propensity score matching, 43 pairs of patients were extracted. In this matched cohort, the survival curves of the PABT and non-PABT groups almost completely overlapped both in OS (5-year OS: 62% vs. 62%; p = 0.4384) and in RFS (2-year RFS: 49% vs. 47%; p = 0.8195). The significant difference of the extrahepatic recurrence rate disappeared in the matched cohort (p = 0.5789). CONCLUSION: Using propensity score matching, we found that PABT does not influence patient survival after HR for HCC.

Clinical role of fludeoxyglucose (18F) positron emission tomography/computed tomography (18F-FDG PET/CT) in patients with pancreatic neuroendocrine tumors.

PURPOSES: Clinical predictive markers for the malignant potential of pancreatic neuroendocrine tumors (PNETs) are limited without histological investigation. We reported previously that a loss of the regular enhancement pattern in preoperative computed tomography (CT) was correlated with the malignant tumor phenotype. This study aimed to establish whether the metabolic aspect of the tumor evaluated by fludeoxyglucose (18F) positron emission tomography/computed tomography 18F-FDG PET/CT is associated with the tumor imaging characteristics and postoperative oncological outcome. METHODS: Among 77 patients who underwent surgery with curative intent for a PNET at our institution between 2001 and 2017, 24 who received 18F-FDG PET/CT before surgery were enrolled in this study. The clinical importance of the standardized uptake value (SUVmax) was investigated with regard to tumor progression and prognosis after curative surgery. RESULTS: There were four (16%) patients with insulinoma. The mean tumor size was 17 mm and when the median value of the SUVmax (= 2.0) was measured as the cut-off value, the SUVmax ≥ 2.0 group (n = 12) was associated with large tumor size (p = 0.021), high tumor grade (p = 0.015), and irregular pattern on CT (p = 0.0055). The SUVmax was not correlated with age, gender, whether the tumor was functioning or non-functioning, or lymph node metastasis. The SUVmax ≥ 2.0 group had significantly poorer disease-free survival (median, 3.5 vs 16.2 months; p = 0.023) and poorer overall survival (median, 8.8 vs 16.2 months; p = 0.042). CONCLUSION: An SUVmax ≥ 2.0 on 18F-FDG PET/CT might be associated with higher malignant potential of PNETs.

Implication of primary tumor location for the indication of preoperative chemotherapy in patients with colorectal liver metastases.

BACKGROUND: The benefit of preoperative chemotherapy for colorectal liver metastases (CRLM) remains uncertain. The aim was to clarify the effect of preoperative chemotherapy on CRLM according to the primary tumor location. METHODS: Among a total cohort of 163 patients who underwent curative hepatectomy for CRLM, 36 patients had a right-sided and 127 had a left-sided primary tumor. According to the performance of preoperative chemotherapy, survival analysis was conducted and prognostic factors were identified. RESULTS: Preoperative chemotherapy was administered to 17 patients (47.2%) with a right-sided and 74 (58.3%) with a left-sided primary tumor (P = 0.24). Among the patients who received preoperative chemotherapy, overall survival (OS) and disease-free survival (DFS) were similar between patients with right- and left-sided primary tumors (P = 0.36 and P = 0.44, respectively). Among the patients who underwent upfront hepatectomy, the OS and DFS of patients with a right-sided primary tumor were worse than those with a left-sided primary tumor (P = 0.02 and P = 0.025, respectively). Among the patients who underwent upfront surgery, the right-sided primary tumor was identified as an independent poor prognostic factor for OS (hazard ratio 3.44, P = 0.021). CONCLUSION: The existence of a right-sided primary tumor may be an indication of preoperative chemotherapy for patients with CRLM.

Downregulation of 15-hydroxyprostaglandin dehydrogenase by interleukin-1ß from activated macrophages leads to poor prognosis in pancreatic cancer.

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-1ß (IL-1ß), a pro-inflammatory cytokine, downregulates 15-PGDH expression in PDAC cells, and that IL-1ß expression was inversely correlated with 15-PGDH levels in frozen PDAC tissues. We also found that activated macrophages produced IL-1ß 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-1ß derived from TAMs suppresses 15-PGDH expression in PDAC cells, resulting in poor prognosis of PDAC patients.