Prognostic value of preoperative geriatric nutritional risk index in intrahepatic cholangiocarcinoma after hepatectomy: a single­center retrospective cohort study.

AIM: Patients with malignant tumors are prone to develop nutritional disorders. The Geriatric Nutritional Risk Index (GNRI) is a new prognostic indicator for assessing the nutritional status. This study was performed to evaluate whether the preoperative GNRI can serve as a prognostic factor in patients with intrahepatic cholangiocarcinoma (ICC) undergoing curative surgery. METHODS: This study included 123 consecutive patients with ICC who were treated with curative surgery. Kaplan-Meier analysis was performed to calculate the recurrence-free survival (RFS) and overall survival (OS), and Cox regression analysis was used to evaluate prognostic factors. RESULTS: Of the 123 patients, 82 were male and 41 were female. The median age of the patients was 70 years, and the median follow-up period was 37.0 months (interquartile range, 16.2-71.7 months). The patients were classified by the median GNRI into a low GNRI group (GNRI < 105) and high GNRI group (GNRI ≥ 105). The patients in the low GNRI group had a significantly poorer prognosis in terms of RFS and OS than the patients in the high GNRI group (RFS, p = 0.0201; OS, p < 0.0001). Lymph node metastasis [hazard ratio (HR), 4.66; 95% confidence interval (CI), 2.46-8.85], postoperative complications (HR, 2.38; 95% CI, 1.32-4.31), and a low GNRI (HR, 2.53; 95% CI, 1.42-4.50) were independent poor prognostic factors for OS. CONCLUSION: The GNRI may be a useful prognostic indicator in patients with ICC undergoing curative hepatectomy.

Perioperative disabilities in activities of daily living are associated with worse prognosis after hepatectomy for colorectal liver metastasis.

BACKGROUND: The number of vulnerable patients with colorectal liver metastasis (CRLM) has increased. This study aimed to clarify the relationship between perioperative activities of daily living (ADL) and clinical outcomes after hepatectomy for CRLM. METHODS: Consecutive patients undergoing resection of CRLM from 2004 to 2020 were included. Pre- or postoperative ADL was evaluated according to Barthel index (BI) scores, which range from 0 to 100. Higher scores represent greater level of independence in ADL. Pre- or postoperative BI scores of ≤85 were defined as perioperative disabilities in ADL. Multivariable Cox proportional hazard regression models were utilised to estimate adjusted hazard ratios (HRs) and confidence interval (CI). RESULTS: A total of 218 patients were included, 16 (7.3%) revealed preoperative BI scores of ≤85, and 32 (15%) revealed postoperative BI scores of ≤85. In multivariate analyses, the perioperative disabilities in ADL were independently associated with shorter overall survival (HR, 1.96; 95% CI, 1.10-3.31; P = 0.023) and cancer-specific survival (HR, 2.31; 95% CI, 1.29-3.92; P = 0.006). CONCLUSION: Perioperative disabilities in ADL were associated with poor prognosis following hepatectomy for CRLM. Improving preoperative vulnerability and preventing functional decline after surgery may provide a favourable prognosis for patients with CRLM.

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.

RAS mutation status in combination with the JSHBPS nomogram may be useful for preoperative identification of colorectal liver metastases with high risk of recurrence and mortality after hepatectomy.

PURPOSE: To investigate the prognostic impact of RAS mutations on the Japanese Society of Hepatobiliary and Pancreatic Surgeons (JSHBPS) nomogram score in patients with colorectal cancer liver metastasis (CRLM) following hepatectomy. METHODS: We included 218 consecutive patients undergoing hepatectomy for CRLM between 2004 and 2020. The JSHBPS nomogram score was calculated using six preoperative clinical factors. The score ranged from 0 to 25, and higher scores indicated greater tumor burden. Associations of RAS mutations with disease-free survival (DFS) and overall survival (OS) by the JSHBPS nomogram score were examined. Multivariable Cox proportional hazard regression models were used to estimate adjusted hazard ratios (HRs) and confidence intervals (CIs). RESULTS: RAS mutations were detected in 72 (33%) of the 218 patients. Multivariate analyses revealed that RAS mutations were independently associated with poor DFS (HR, 1.93; 95% CI: 1.20-3.10; p = .007) and OS (HR, 2.65; 95% CI: 1.59-4.71; p = .001) compared with wild-type RAS with JSHBPS nomogram scores ≤ 10. However, in patients with scores ≥ 11, the association of RAS mutations with DFS or OS was not statistically significant (p > .08). CONCLUSION: RAS mutation status in combination with the JSHBPS nomogram may be useful for preoperatively identifying CRLM with high risk of recurrence and mortality after hepatectomy.

The Prognostic Role of Serine Racemase in Patients With Pancreatic Cancer: A New Marker in Cancer Metabolism.

OBJECTIVES: Serine racemase (SRR) participates in serine metabolism in central nervous systems. Serine racemase is only studied in colorectal cancer, and its role in pancreatic cancer (PC) is unknown. This study aims to investigate the role of SRR in PC. METHODS: Totally 182 patients with PC were enrolled in this study. Slices from patients were stained for SRR and CD8+ T cells. Kaplan-Meier methods were used to do survival analysis according to SRR expression from immunohistochemical staining. Univariate and multivariate Cox regression analysis was performed to clarify the independent prognostic value of SRR. Bioinformatic tools were used to explore and validate the expression, prognostic value, possible mechanism, and immune interaction of SRR in PC. RESULTS: The expression of SRR was lower in tumor tissue than normal tissue, also potentially decreased with the increasing tumor grade. Low SRR expression was an independent risk factor for overall survival (hazards ratio, 1.875; 95% confidence interval, 1.175-2.990; P = 0.008) in patients with PC. Serine racemase was positively correlated with CD8+ T cells infiltration and possibly associated with CCL14 and CXCL12 expression. CONCLUSIONS: Serine racemase plays a prognostic role in PC and may be a potentially therapeutic target.

Statins exert anti-growth effects by suppressing YAP/TAZ expressions via JNK signal activation and eliminate the immune suppression by downregulating PD-L1 expression in pancreatic cancer.

Statins are cholesterol-lowering agents that act as inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzymeA (HMG CoA) reductase. Recently, statins have received a lot of attention, especially regarding how statins act on the immune system. Here, the clinical impact of statin intake was examined in patients with resected pancreatic cancer, and the underlying mechanisms were investigated in vitro and in vivo. We found that statin intake was associated with favorable prognostic outcomes in patients with resectable pancreatic cancer. Statins, especially lipophilic statins, exert anti-proliferative effects on pancreatic cancer cells in vitro (simvastatin > fluvastatin > atorvastatin > rosuvastatin > pravastatin). Simvastatin had an anti-proliferative effect on pancreatic cancer cells with decreased the yes-associated protein (YAP)/PDZ-binding motif (TAZ) expression by activating the JNK pathway, and simvastatin treatment with oxaliplatin revealed additive anti-growth effects. Furthermore, lipophilic and hydrophilic statins suppressed programmed cell death ligand 1 (PD-L1) expression by downregulating TAZ. Simvastatin treatment with an anti-PD-1 drug (BP0273) provided immediate anti-growth effects compared to controls, such as anti-PD-1 only and simvastatin only, and suppressed progressive disease during the early period of anti-PD-1 treatment in vivo. In conclusion, Statins display two distinct anti-cancer effects (direct anti-growth effect and elimination of immune suppression by downregulating PD-L1 expression) by targeting YAP/TAZ expression.

Distinct approaches (antecolic and retrocolic) according to tumor location in laparoscopic and endoscopic cooperative surgery for non-ampullary duodenum tumors.

AIM: Laparoscopic and endoscopic cooperative surgery for early non-ampullary duodenum tumors (D-LECS) is now noted because of its safety and lower invasiveness. Here, we introduce two distinct approaches (antecolic and retrocolic) according to the tumor location during D-LECS. METHODS: From October 2018 to March 2022, 24 patients (25 lesions) underwent D-LECS. Two (8%), two (8%), 16 (64%), and five (20%) lesions were located in the first portion, in the second portion to Vater's papilla, around the inferior duodenum flexure, and in the third portion of the duodenum, respectively. The median preoperative tumor diameter was 22.5 mm. RESULTS: Antecolic and retrocolic approaches were employed in 16 (67%) and 8 (33%) cases, respectively. LECS procedures, such as two-layer suturing after full-thickness dissection and laparoscopic reinforcement by seromuscular suturing after endoscopic submucosal dissection (ESD), were performed in five and 19 cases, respectively. Median operative time and blood loss were 303 min and 5 g, respectively. Intraoperative duodenal perforations occurred in three of 19 cases during ESD; however, they were successfully laparoscopically repaired. Median times until start diet and postoperative hospital stay were 4.5 and 8 days, respectively. Histological examination of the tumors revealed nine adenomas, 12 adenocarcinomas, and four GISTs. Curative resection (R0) was achieved in 21 cases (87.5%). In a comparison of the surgical short outcomes between antecolic and retrocolic approaches, there was no significant difference. CONCLUSION: D-LECS can be a safe and minimally invasive treatment option for non-ampullary early duodenal tumors, and two distinct approaches according to the tumor location are feasible.

Frailty and surgical outcomes in gastrointestinal cancer: Integration of geriatric assessment and prehabilitation into surgical practice for vulnerable patients.

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.

Hyperglycaemia induces metabolic reprogramming into a glycolytic phenotype and promotes epithelial-mesenchymal transitions via YAP/TAZ-Hedgehog signalling axis in pancreatic cancer.

BACKGROUND: Hyperglycaemia is a well-known initial symptom in patients with pancreatic ductal adenocarcinoma (PDAC). Metabolic reprogramming in cancer, described as the Warburg effect, can induce epithelial-mesenchymal transition (EMT). METHODS: The biological impact of hyperglycaemia on malignant behaviour in PDAC was examined by in vitro and in vivo experiments. RESULTS: Hyperglycaemia promoted EMT by inducing metabolic reprogramming into a glycolytic phenotype via yes-associated protein (YAP)/PDZ-binding motif (TAZ) overexpression, accompanied by GLUT1 overexpression and enhanced phosphorylation Akt in PDAC. In addition, hyperglycaemia enhanced chemoresistance by upregulating ABCB1 expression and triggered PDAC switch into pure basal-like subtype with activated Hedgehog pathway (GLI1 high, GATA6 low expression) through YAP/TAZ overexpression. PDAC is characterised by abundant stroma that harbours tumour-promoting properties and chemoresistance. Hyperglycaemia promotes the production of collagen fibre-related proteins (fibronectin, fibroblast activation protein, COL1A1 and COL11A1) by stimulating YAP/TAZ expression in cancer-associated fibroblasts (CAFs). Knockdown of YAP and/or TAZ or treatment with YAP/TAZ inhibitor (K975) abolished EMT, chemoresistance and a favourable tumour microenvironment even under hyperglycemic conditions in vitro and in vivo. CONCLUSION: Hyperglycaemia induces metabolic reprogramming into glycolytic phenotype and promotes EMT via YAP/TAZ-Hedgehog signalling axis, and YAP/TAZ could be a novel therapeutic target in PDAC.

Disability in perioperative activities of daily living is associated with worse survival outcomes following hepatic resection in patients with intrahepatic cholangiocarcinoma.

AIM: Intrahepatic cholangiocarcinoma (ICC) is a rare disease; however, its incidence and mortality are increasing worldwide. The rapid aging of populations around the world is leading to an increased number of patients with cancer who develop disability in activities of daily living (ADL). This study was conducted to investigate the associations of perioperative ADL with patient survival after hepatic resection for ICC. METHODS: We included 70 consecutive patients who underwent hepatectomy for ICC from 2010 to 2021 in the current study. Preoperative and postoperative ADL were evaluated based on the Barthel index, which yields a score of 0-100 points, with higher scores indicating greater independence. A preoperative or postoperative Barthel index score of <100 was defined as disability in perioperative ADL. Cox proportional hazards regression was used to calculate hazard ratios after adjusting for potential confounders. RESULTS: Among the 70 patients, seven (10%) had a preoperative Barthel index score of <100, and 23 (33%) showed a postoperative Barthel index score of <100. Multivariate analyses revealed that disability in perioperative ADL was associated with shorter recurrence-free survival (multivariable hazard ratios 2.38, 95% confidence interval 1.22-4.57; p = 0.011) and overall survival (multivariable hazard ratio 2.49, 95% confidence interval 1.09-5.70; p = 0.031). CONCLUSIONS: Disability in perioperative ADL is associated with shorter recurrence-free and overall survival after hepatic resection for ICC. Upon validation, perioperative measurement of ADL may improve risk assessment, and improvement of perioperative ADL may lead to favorable clinical outcomes in patients with ICC.

[The Usefulness of RFA as a Conversion Therapy after Molecular Targeted Therapy for Advanced Hepatocellular Carcinoma-A Case of Long-Term Survival with Multidisciplinary Treatment].

In this study, we report a case in which molecular-targeted agents have been shown to be effective in the treatment of unresectable hepatocellular carcinoma(HCC), which has enabled a radical treatment, conversion therapy, and long-term survival with multimodality treatment including RFA. Case: A 61-year-old male, abdominal ultrasonography revealed a large liver tumor and multiple lesions mainly in the right lobe of the liver. He was diagnosed as having unresectable HCC, and treatment with sorafenib was initiated. After treatment, the tumor was clearly reduced in size and the lung metastases disappeared. Five years later, recurrence was observed at the treated site of S7/8, and RFA was performed again after TACE. The patient has survived for 8 years without recurrence.

Thrombospondin-1 overexpression stimulates loss of Smad4 and accelerates malignant behavior via TGF-ß signal activation in pancreatic ductal adenocarcinoma.

INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma and cancer-associated fibroblasts (CAFs) provide a favorable tumor microenvironment. Smad4 is known as tumor suppressor in several types of cancers including PDAC, and loss of Smad4 triggers accelerated cell invasiveness and metastatic potential. The thrombospondin-1 (TSP-1) can act as a major activator of latent transforming growth factor-ß (TGF-ß) in vivo. However, the roles of TSP-1 and the mediator of Smad4 loss and TGF-ß signal activation during PDAC progression have not yet been addressed. The aim is to elucidate the biological role of TSP-1 in PDAC progression. METHODS AND RESULTS: High substrate stiffness stimulated TSP-1 expression in CAFs, and TSP-1 knockdown inhibited cell proliferation with suppressed profibrogenic and activated stroma-related gene expressions in CAFs. Paracrine TSP-1 treatment for PDAC cells promoted cell proliferation and epithelial mesenchymal transition (EMT) with activated TGF-ß signals such as phosphorylated Akt and Smad2/3 expressions. Surprisingly, knockdown of DPC4 (Smad4 gene) induced TSP-1 overexpression with TGF-ß signal activation in PDAC cells. Interestingly, TSP-1 overexpression also induced downregulation of Smad4 expression and enhanced cell proliferation in vitro and in vivo. Treatment with LSKL peptide, which antagonizes TSP-1-mediated latent TGF-ß activation, attenuated cell proliferation, migration and chemoresistance with enhanced apoptosis in PDAC cells. CONCLUSIONS: TSP-1 derived from CAFs stimulates loss of Smad4 expression in cancer cells and accelerates malignant behavior by TGF-ß signal activation in PDAC. TSP-1 could be a novel therapeutic target, not only for CAFs in stiff stroma, but also for cancer cells in the PDAC microenvironment.

Risk factors for lymph node metastasis in patients with pancreatic neuroendocrine neoplasms.

BACKGROUND: Although PNENs generally have a better prognosis than pancreatic cancers, some PNENs display malignant behavior including lymph node (LN) metastasis. Complete tumor resection can be the only potentially curative treatment for patients with resectable PNENs. However, the indications for LN dissection are still controversial. Over the last decade, minimally invasive surgery such as laparoscopic pancreatic surgery (LPS) has been increasingly performed for pancreatic tumors including PNENs. AIM: To investigate the risk factors for LN metastasis in PNENs and to select appropriate patients for limited surgery by LPS. METHODS: From April 2001 to December 2019, 92 patients underwent pancreatic resection for PNENs at Kumamoto University Hospital. Finally, 82 patients were enrolled in this study. Using perioperative factors, we examined the predictive factors for LN metastasis in PNENs. RESULTS: Among the 82 patients, the percentage of LN metastasis according to the pathological findings was 12% (10/82 cases). The median tumor size was 12 mm (range: 5-90 mm). The median tumor size in the LN-positive group (37 mm) was significantly larger than that in the LN-negative group (12 mm) (P = 0.0001). Multivariate analyses revealed that larger tumor size (≥ 20 mm) was an independent risk factor for LN metastasis (odds ratio 16.8, P = 0.0062). In patients with small tumors (≤ 10 mm), LN metastasis was not found. CONCLUSION: Larger tumor size (≥ 20 mm) is an independent risk factor for LN metastasis in PNENs. In smaller PNENs (≤ 10 mm), we may be able to choose limited surgery without LN dissection.

Multimodal therapy with aggressive hepatectomy, everolimus, and octreotide for metastatic pancreatic neuroendocrine neoplasm enables 10-year survival.

The presence of neuroendocrine liver metastases is one of the poorest prognostic factors in patients with pancreatic neuroendocrine neoplasms, and surgical resection of neuroendocrine liver metastases is the only curable treatment. A 38-year-old man had a pancreatic neuroendocrine neoplasm with synchronous multiple liver metastases, and two surgeries and continuous everolimus and octreotide achieved R0 resection. However, multiple neuroendocrine liver metastases developed twice after more than 5 years of recurrence-free survival. Aggressive repeat hepatectomy was performed and he has survived for more than 10 years after the initial surgery. This report highlights that patients with pancreatic neuroendocrine neoplasms have a potential risk of recurrence even after 5 years of recurrence-free survival. In addition, combined aggressive hepatectomy and continuous medication can contribute dramatically to long-term survival even for late-stage recurrence of liver metastases.

Impairment of perioperative activities of daily living is associated with poor prognosis following hepatectomy for hepatocellular carcinoma.

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.

Molecular signatures of long-term hepatocellular carcinoma risk in nonalcoholic fatty liver disease.

Prediction of hepatocellular carcinoma (HCC) risk is an urgent unmet need in patients with nonalcoholic fatty liver disease (NAFLD). In cohorts of 409 patients with NAFLD from multiple global regions, we defined and validated hepatic transcriptome and serum secretome signatures predictive of long-term HCC risk in patients with NAFLD. A 133-gene signature, prognostic liver signature (PLS)-NAFLD, predicted incident HCC over up to 15 years of longitudinal observation. High-risk PLS-NAFLD was associated with IDO1+ dendritic cells and dysfunctional CD8+ T cells in fibrotic portal tracts along with impaired metabolic regulators. PLS-NAFLD was validated in independent cohorts of patients with NAFLD who were HCC naïve (HCC incidence rates at 15 years were 22.7 and 0% in high- and low-risk patients, respectively) or HCC experienced (de novo HCC recurrence rates at 5 years were 71.8 and 42.9% in high- and low-risk patients, respectively). PLS-NAFLD was bioinformatically translated into a four-protein secretome signature, PLSec-NAFLD, which was validated in an independent cohort of HCC-naïve patients with NAFLD and cirrhosis (HCC incidence rates at 15 years were 37.6 and 0% in high- and low-risk patients, respectively). Combination of PLSec-NAFLD with our previously defined etiology-agnostic PLSec-AFP yielded improved HCC risk stratification. PLS-NAFLD was modified by bariatric surgery, lipophilic statin, and IDO1 inhibitor, suggesting that the signature can be used for drug discovery and as a surrogate end point in HCC chemoprevention clinical trials. Collectively, PLS/PLSec-NAFLD may enable NAFLD-specific HCC risk prediction and facilitate clinical translation of NAFLD-directed HCC chemoprevention.

High Expression of Bloom Syndrome Helicase is a Key Factor for Poor Prognosis and Advanced Malignancy in Patients with Pancreatic Cancer: A Retrospective Study.

BACKGROUND: Bloom syndrome helicase (BLM) is overexpressed in multiple types of cancers and its overexpression may induce genomic instability. This study aimed to determine the function of BLM expression in pancreatic cancer. METHODS: BLM messenger RNA (mRNA) expression was analyzed using public datasets to determine its relationship with pancreatic cancer prognosis. Overall, 182 patients with pancreatic cancer who underwent radical resection at our institution were enrolled. BLM expression was evaluated by immunohistochemistry (IHC). We explored the effect of BLM on the proliferation, invasion, migration, and chemoresistance of pancreatic cancer cells via small-interfering RNAs and performed pathway analysis using gene set enrichment analysis. RESULTS: BLM mRNA expression was higher in tumor tissue than in normal tissue and had a prognostic effect on overall survival (OS) and recurrence-free survival. The same results were validated by IHC. Multivariate analysis showed that high BLM expression was an independent poor prognostic factor for OS (hazard ratio [HR] 1.678, p = 0.029). In subgroup analysis, the effect of high BLM expression was more significant on OS in patients with younger age (HR 2.27, p = 0.006), male sex (HR 2.39, p = 0.002), high cancer antigen 19-9 level (HR 2.44, p = 0.001), advanced tumor stage (HR 2.25, p = 0.001), lymph node metastasis (HR 2.51, p = 0.001), nerve invasion (HR 2.07, p = 0.002), and adjuvant chemotherapy (HR 2.66, p < 0.001). In vitro, BLM suppression resulted in reduced tumor proliferation, invasion, migration, and chemoresistance. Mechanistically, BLM expression may be associated with E2F1 and E2F2. CONCLUSION: BLM expression is a prognostic factor for patients with pancreatic cancer, especially in those with advanced malignancies and receiving chemotherapy.

Pan-immune-inflammation Value and Prognosis in Patients With Esophageal Cancer.

Mini-abstract: The pan-immune-inflammation value was associated with clinical outcomes and tumor-infiltrating lymphocytes in 866 esophageal cancers. Systemic immune competence may influence patient prognosis through local immune response. Objective: To examine the relationship between the pan-immune-inflammation value (PIV), tumor immunity, and clinical outcomes in 866 patients with esophageal cancer. Background: The PIV, calculated from all immune-inflammatory cells in the peripheral blood count, is a recently proposed marker for clinical outcomes in some types of cancers. Nonetheless, the prognostic significance of PIV in esophageal cancer remains unclear. Methods: In the derivation cohort (n = 433), we set the optimal cutoff value using a time-dependent receiver operating characteristic (ROC) curve. In the validation cohort (n = 433), the relationships between the PIV, tumor-infiltrating lymphocytes (TILs), CD8 expression by immunohistochemical staining, and patient prognosis were examined. Results: The area under the ROC curve for the PIV at 5 years was 0.631 in the derivation cohort. The validation cohort, divided into PIV-low cases (n = 223) and PIV-high cases (n = 210), showed significantly worse overall survival (log-rank P = 0.0065; hazard ratio [HR]: 1.48; 95% confidence interval [CI]: 1.12-1.98; P < 0.001; multivariate HR: 1.41; 95% CI: 1.05-1.90; P = 0.023). The prognostic effect of the PIV was not significantly modified by any clinical characteristics (P for interaction > 0.05). The PIV-high cases were significantly associated with a low TIL status (P < 0.001) and low CD8-positive cell counts (P = 0.011). Conclusions: The PIV was associated with clinical outcomes in esophageal cancer, supporting its role as a prognostic biomarker. Considering the relationship between the PIV and TILs, systemic immune competence may influence patient prognosis through a local immune response.

Molecular Signature Predictive of Long-Term Liver Fibrosis Progression to Inform Antifibrotic Drug Development.

BACKGROUND & AIMS: There is a major unmet need to assess the prognostic impact of antifibrotics in clinical trials because of the slow rate of liver fibrosis progression. We aimed to develop a surrogate biomarker to predict future fibrosis progression. METHODS: A fibrosis progression signature (FPS) was defined to predict fibrosis progression within 5 years in patients with hepatitis C virus and nonalcoholic fatty liver disease (NAFLD) with no to minimal fibrosis at baseline (n = 421) and was validated in an independent NAFLD cohort (n = 78). The FPS was used to assess response to 13 candidate antifibrotics in organotypic ex vivo cultures of clinical fibrotic liver tissues (n = 78) and cenicriviroc in patients with nonalcoholic steatohepatitis enrolled in a clinical trial (n = 19, NCT02217475). A serum protein-based surrogate FPS was developed and tested in a cohort of compensated cirrhosis patients (n = 122). RESULTS: A 20-gene FPS was defined and validated in an independent NAFLD cohort (adjusted odds ratio, 10.93; area under the receiver operating characteristic curve, 0.86). Among computationally inferred fibrosis-driving FPS genes, BCL2 was confirmed as a potential pharmacologic target using clinical liver tissues. Systematic ex vivo evaluation of 13 candidate antifibrotics identified rational combination therapies based on epigallocatechin gallate, which were validated for enhanced antifibrotic effect in ex vivo culture of clinical liver tissues. In patients with nonalcoholic steatohepatitis treated with cenicriviroc, FPS modulation was associated with 1-year fibrosis improvement accompanied by suppression of the E2F pathway. Induction of the PPARα pathway was absent in patients without fibrosis improvement, suggesting a benefit of combining PPARα agonism to improve the antifibrotic efficacy of cenicriviroc. A 7-protein serum protein-based surrogate FPS was associated with the development of decompensation in cirrhosis patients. CONCLUSION: The FPS predicts long-term fibrosis progression in an etiology-agnostic manner, which can inform antifibrotic drug development.

A human liver cell-based system modeling a clinical prognostic liver signature for therapeutic discovery.

Chronic liver disease and hepatocellular carcinoma (HCC) are life-threatening diseases with limited treatment options. The lack of clinically relevant/tractable experimental models hampers therapeutic discovery. Here, we develop a simple and robust human liver cell-based system modeling a clinical prognostic liver signature (PLS) predicting long-term liver disease progression toward HCC. Using the PLS as a readout, followed by validation in nonalcoholic steatohepatitis/fibrosis/HCC animal models and patient-derived liver spheroids, we identify nizatidine, a histamine receptor H2 (HRH2) blocker, for treatment of advanced liver disease and HCC chemoprevention. Moreover, perturbation studies combined with single cell RNA-Seq analyses of patient liver tissues uncover hepatocytes and HRH2+, CLEC5Ahigh, MARCOlow liver macrophages as potential nizatidine targets. The PLS model combined with single cell RNA-Seq of patient tissues enables discovery of urgently needed targets and therapeutics for treatment of advanced liver disease and cancer prevention.