Absence of Survival Impact from Hepatitis During Immunotherapy in 193 Patients with Advanced Hepatocellular Carcinoma - An Observational Study from Taiwan.

Background: Hepatitis often occurs after initiating immune checkpoint inhibitor (ICI) treatment. The time and grade of hepatitis after ICI starts and the prognostic role of immune-related hepatitis in patients with advanced hepatocellular carcinoma (aHCC) remain unclear. Methods: In this real-world analysis, we enrolled aHCC patients receiving ICIs, documented the highest level of liver enzymes during/after ICIs, and analyzed the survival impact of different hepatitis patterns. Results: One hundred and ninety-three aHCC patients receiving ICIs were recruited. During ICIs, 88.6% of patients experienced aspartate transaminase (AST) elevations (Grade III/IV: 7.8%). For alanine transaminase (ALT), 81.3% had elevated levels (Grade III/IV: 3.6%), and 41.5% of patients had elevated bilirubin levels (Grade 3/4: 6.7%). The median AST, ALT, and total bilirubin values significantly increased after ICI treatment initiated (all p < 0.001) and, similarly, after excluding progressive disease (p = 0.014, p = 0.002, p < 0.001). The median time of hepatitis occurrence is from the 4.0th to 15.9th weeks. Multivariable analysis showed that patterns of liver enzyme change of AST and total bilirubin in patients receiving ICIs significantly correlate to overall survival (OS, p = 0.009 and 0.001, respectively). After ICI termination, patients with elevated bilirubin (p = 0.003) and AST (p = 0.005) would indicate poor survival, with adjustment of viral hepatitis and ICI responses. Conclusion: Hepatitis emerges between the 4th and 20th weeks post-ICI initiation. Changes in liver enzymes during ICI therapy do not directly affect OS, implying the safety of ICI use when corticosteroids are promptly administered if clinically indicated.

Do low skeletal muscle bulk and disturbed body fat mass impact tumor recurrence in stage I/II HCC undergoing surgery? An observational cohort study.

INTRODUCTION: The influence of deranged body composition on stage I/II HCC after surgery remains undetermined. The current study aimed to investigate the impact of low skeletal muscle bulk and disturbed body fat mass on the recurrence outcome of stage I/II HCC patients undergoing liver resection. The associated metabolomic alterations were also assessed. METHODS: From 2012 to 2021, stage I and II HCC patients who underwent liver resection at our institute were retrospectively reviewed. Their preoperative body composition including skeletal muscle mass and body fat volume was measured by computed tomography (CT). The recurrence outcome was recorded and analyzed. The preoperative serum was collected and subjected to metabolomic analysis. RESULTS: A total of 450 stage I and II HCC patients were included in the current study. Among them, 76% were male and around 60% had HBV infection. After stratified by normal cutoff values obtained from a healthy cohort, 6.4% of stage I/II HCC patients were found to have a low psoas muscle index (PMI), 17.8% a high subcutaneous adipose tissue (SAT) index, and 27.8% a high visceral adipose tissue (VAT) index. Cox regression multivariate analysis further demonstrated that low PMI and high SAT index were independent prognostic factors for time-to-recurrence (TTR) after surgery. Metabolomic analysis discovered that free fatty acid ß-oxidation was enhanced in with low PMI or high SAT index. CONCLUSION: The current study demonstrated that reduced psoas muscle mass may impair while elevated SAT may prolong the TTR of stage I/II HCC patients undergoing liver resections. VAT, on the other hand, was not associated with recurrence outcome after surgery. Further studies are warranted to validate our findings.

Lonicera japonica Thunb. Ethanol Extract Exerts a Protective Effect on Normal Human Gastric Epithelial Cells by Modulating the Activity of Tumor-Necrosis-Factor-α-Induced Inflammatory Cyclooxygenase 2/Prostaglandin E2 and Matrix Metalloproteinase 9.

Gastric inflammation-related disorders are commonly observed digestive system illnesses characterized by the activation of proinflammatory cytokines, particularly tumor necrosis factor-α (TNF-α). This results in the induction of cyclooxygenase-2 (COX-2)/prostaglandin E2 (PEG2) and matrix metallopeptidase-9 (MMP-9). These factors contribute to the pathogenesis of gastric inflammation disorders. We examined the preventive effects of Lonicera japonica Thunb. ethanol extract (Lj-EtOH) on gastric inflammation induced by TNF-α in normal human gastric mucosa epithelial cells (GES-1). The GES-1 cell line was used to establish a model that simulated the overexpression of COX-2/PGE2 and MMP-9 proteins induced by TNF-α to examine the anti-inflammatory properties of Lj extracts. The results indicated that Lj-EtOH exhibits significant inhibitory effects on COX-2/PEG2 and MMP-9 activity, attenuates cell migration, and provides protection against TNF-α-induced gastric inflammation. The protective effects of Lj-EtOH are associated with the modulation of COX-2/PEG2 and MMP-9 through the activation of TNFR-ERK 1/2 signaling pathways as well as the involvement of c-Fos and nuclear factor kappa B (NF-κB) signaling pathways. Based on our findings, Lj-EtOH exhibits a preventive effect on human gastric epithelial cells. Consequently, it may represent a novel treatment for the management of gastric inflammation.

Does autoimmune disease impair the survival of hepatocellular carcinoma patients undergoing liver resection? A multi-institutional observational study.

BACKGROUND: Patients with autoimmune diseases (AD) generally carry an increased risk of developing cancer. However, the effect of AD in hepatocellular carcinoma (HCC) patients receiving surgical treatment is uncertain. The present study aimed to investigate the potential influence of AD on the survival of HCC patients undergoing hepatectomies. METHODS: Operated HCC patients were identified from the Chang Gung Research Database, and the survival outcomes of HCC patients with or without AD were analyzed ad compared. Cox regression model was performed to identify significant risk factors associated with disease recurrence and mortality. RESULTS: From 2002 to 2018, a total of 5532 patients underwent hepatectomy for their HCC. Among them, 229 patients were identified to have AD and 5303 were not. After excluding cases who died within 30 days of surgery, the estimated median overall survival (OS) was 43.8 months in the AD (+) group and 47.4 months in the AD (-) group (P = 0.367). The median liver-specific survival and disease-free survival (DFS) were also comparable between the two groups. After Cox regression multivariate analysis, the presence of AD did not lead to a higher risk of all-cause mortality, liver-specific mortality, or disease recurrence. CONCLUSION: Our study demonstrated that autoimmune disease does not impair the OS and DFS of HCC patients undergoing liver resections. AD itself is not a risk factor for tumor recurrence after surgery. Patients eligible for liver resections, as a result, should be considered for surgery irrespective of the presence of AD. Further studies are mandatory to validate our findings.

Altered microbiome of serum exosomes in patients with acute and chronic cholecystitis.

BACKGROUND: This study aimed to investigate the differences in the microbiota composition of serum exosomes from patients with acute and chronic cholecystitis. METHOD: Exosomes were isolated from the serum of cholecystitis patients through centrifugation and identified and characterized using transmission electron microscopy and nano-flow cytometry. Microbiota analysis was performed using 16S rRNA sequencing. RESULTS: Compared to patients with chronic cholecystitis, those with acute cholecystitis exhibited lower richness and diversity. Beta diversity analysis revealed significant differences in the microbiota composition between patients with acute and chronic cholecystitis. The relative abundance of Proteobacteria was significantly higher in exosomes from patients with acute cholecystitis, whereas Actinobacteria, Bacteroidetes, and Firmicutes were significantly more abundant in exosomes from patients with chronic cholecystitis. Furthermore, functional predictions of microbial communities using Tax4Fun analysis revealed significant differences in metabolic pathways such as amino acid metabolism, carbohydrate metabolism, and membrane transport between the two patient groups. CONCLUSIONS: This study confirmed the differences in the microbiota composition within serum exosomes of patients with acute and chronic cholecystitis. Serum exosomes could serve as diagnostic indicators for distinguishing acute and chronic cholecystitis.

Recurrence Pattern Is an Independent Surgical Prognostic Factor for Long-Term Oncological Outcomes in Patients with Hepatocellular Carcinoma.

BACKGROUND: The perioperative outcomes of a partial hepatectomy for hepatocellular carcinoma (HCC) have improved. However, high recurrence rates after a curative hepatectomy for HCC is still an issue. This study aimed to analyze the difference between various recurrence patterns. METHODS: We retrospectively reviewed 754 patients with HCC who underwent a curative hepatectomy between January 2012 and March 2021. Patients with recurrent events were categorized into three types: regional recurrence (type I), multiple intrahepatic recurrence (type II), or presence of any distant metastasis (type III). RESULTS: The median follow-up period was 51.2 months. Regarding recurrence, 375 (49.7%) patients developed recurrence, with 244 (32.4%), 51 (6.8%), and 80 (10.6%) patients having type I, II, and III recurrence, respectively. Type III recurrence appeared to be more common in male patients and those with major liver resection, vascular invasion, a large tumor size (>5 cm), a higher tumor grade, and higher levels of AST and AFP (p < 0.05). Patients who had distant metastasis at recurrence had the shortest recurrence time and the worst overall survival (p < 0.001 and p < 0.001). CONCLUSIONS: our study demonstrated that recurrence with distant metastasis occurred earliest and had the worst outcome compared to regional or multiple intrahepatic recurrences.

Integrative multiomics enhancer activity profiling identifies therapeutic vulnerabilities in cholangiocarcinoma of different etiologies.

OBJECTIVES: Cholangiocarcinoma (CCA) is a heterogeneous malignancy with high mortality and dismal prognosis, and an urgent clinical need for new therapies. Knowledge of the CCA epigenome is largely limited to aberrant DNA methylation. Dysregulation of enhancer activities has been identified to affect carcinogenesis and leveraged for new therapies but is uninvestigated in CCA. Our aim is to identify potential therapeutic targets in different subtypes of CCA through enhancer profiling. DESIGN: Integrative multiomics enhancer activity profiling of diverse CCA was performed. A panel of diverse CCA cell lines, patient-derived and cell line-derived xenografts were used to study identified enriched pathways and vulnerabilities. NanoString, multiplex immunohistochemistry staining and single-cell spatial transcriptomics were used to explore the immunogenicity of diverse CCA. RESULTS: We identified three distinct groups, associated with different etiologies and unique pathways. Drug inhibitors of identified pathways reduced tumour growth in in vitro and in vivo models. The first group (ESTRO), with mostly fluke-positive CCAs, displayed activation in estrogen signalling and were sensitive to MTOR inhibitors. Another group (OXPHO), with mostly BAP1 and IDH-mutant CCAs, displayed activated oxidative phosphorylation pathways, and were sensitive to oxidative phosphorylation inhibitors. Immune-related pathways were activated in the final group (IMMUN), made up of an immunogenic CCA subtype and CCA with aristolochic acid (AA) mutational signatures. Intratumour differences in AA mutation load were correlated to intratumour variation of different immune cell populations. CONCLUSION: Our study elucidates the mechanisms underlying enhancer dysregulation and deepens understanding of different tumourigenesis processes in distinct CCA subtypes, with potential significant therapeutics and clinical benefits.

The Extended Surgical Concepts for Hepatocellular Carcinoma in the Era of Immune Checkpoint Inhibitors.

Surgical resection remains one of the most effective curative therapies for HCC. However, the majority of patients have advanced unresectable diseases upon presentation. It is of paramount importance to raise the resectability of patients with HCC. The remarkable objective response rate reported by Phase III IMbrave150 trial has led to the concept of "Atezo/Bev followed by curative conversion (ABC conversion)" for initially unresectable HCC. With this revolutionary treatment strategy, the concept of surgical resection for HCC should be amended. The current opinion illustrated three extended surgical concepts, which could be integrated into clinical practice in the era of immune checkpoint inhibitors (ICI).

Daily Aspirin Reduced the Incidence of Hepatocellular Carcinoma and Overall Mortality in Patients with Cirrhosis.

BACKGROUND: Cirrhosis is the primary risk factor for hepatocellular carcinoma (HCC) and gastrointestinal bleeding (GI). We aimed to assess the efficacy and safety of daily aspirin on HCC occurrence, overall survival, and GI bleeding in cirrhotic patients. METHODS: A total of 35,898 eligible cases were enrolled for analyses from an initial 40,603 cirrhotic patients without tumor history. Patients continuously treated with aspirin for at least 84 days were in the therapy group, whereas those without treatment were controls. A 1:2 propensity score matching by age, sex, comorbidities, drugs, and significant clinical laboratory tests with covariate assessment was used. RESULTS: Multivariable regression analyses revealed that daily aspirin use was independently associated with a reduced risk of HCC (three-year HR 0.57; 95% CI 0.37-0.87; p = 0.0091; five-year HR 0.63, 95% CI 0.45-0.88; p = 0.0072) inversely correlated with the treatment duration [3-12 months: HR 0.88 (95% CI 0.58-1.34); 12-36 months: HR 0.56 (0.31-0.99); and ≥ 36 months: HR 0.37 (0.18-0.76)]. Overall mortality rates were significantly lower among aspirin users compared with untreated controls [three-year HR 0.43 (0.33-0.57); five-year HR 0.51 (0.42-0.63)]. Consistent results were obtained when the laboratory data were included in the propensity score for matching. CONCLUSIONS: Long-term aspirin use significantly reduced the incidence of HCC and overall mortality without increasing gastrointestinal bleeding in cirrhotic patients.

A novel technique of sutureless omentopexy during dual-incision laparoscopic peritoneal dialysis catheter insertion to prevent catheter dysfunction due to omental wrapping.

BACKGROUND: Omental wrapping (OW) is the leading cause of obstruction of the peritoneal dialysis (PD) catheter, which interferes with dialysis treatment. Routinely or selectively performing omentopexy during laparoscopic PD catheter placement has been suggested to prevent OW. However, most of the published techniques for performing this adjunctive procedure require additional incisions and suturing. Herein, we aimed to report our experience in performing omentopexy with a sutureless technique during dual-incision PD catheter insertion. We also performed a comparative analysis to assess the benefit/risk profile of routine omentopexy in these patients. METHODS: This retrospective study enrolled 469 patients who underwent laparoscopic PD catheter insertion. Their demographic characteristics and operative details were collected from the database of our institution. Omentopexy was performed by fixing the inferior edge of the omentum to the round ligament of the liver using titanium clips. For analysis, the patients were divided into the omentopexy group and the non-omentopexy group. We also reviewed the salvage management and outcomes of patients who experienced OW. RESULTS: The patients were categorized into the omentopexy (n = 81) and non-omentopexy (n = 388) groups. The patients in the non-omentopexy group had a higher incidence of OW, whereas no patient in the omentopexy group experienced this complication (5.2% vs. 0.0%, p = 0.033). The median operative time was 27 min longer in patients who underwent omentopexy than in those who did not [100 (82-118) min vs. 73 (63-84) min, p < 0.001]. One patient had an intra-abdominal hematoma after omentopexy and required salvage surgery to restore catheter function. The complication rate of omentopexy was 1.2% (1/81). CONCLUSION: Sutureless omentopexy during laparoscopic PD catheter insertion is a safe and reliable technique that does not require additional incisions and suturing. Routinely performing omentopexy provides clinical benefits by reducing the risk of catheter dysfunction due to OW.

Laparoscopic liver resection is associated with less significant muscle loss than the conventional open approach.

BACKGROUND: Laparoscopic liver resections (LLR) have been shown a treatment approach comparable to open liver resections (OLR) in hepatocellular carcinoma (HCC). However, the influence of procedural type on body composition has not been investigated. The aim of the current study was to compare the degree of skeletal muscle loss between LLR and OLR for HCC. METHODS: By using propensity score matching (PSM) analysis, 64 pairs of patients were enrolled. The change of psoas muscle index (PMI) after the operation was compared between the matched patients in the LLR and OLR. Risk factors for significant muscle loss (defined as change in PMI > mean change minus one standard deviation) were further investigated by multivariate analysis. RESULTS: Among patients enrolled, there was no significant difference in baseline characteristics between the two groups. The PMI was significantly decreased in the OLR group (P = 0.003). There were also more patients in the OLR group who developed significant muscle loss after the operations (P = 0.008). Multivariate analysis revealed OLR (P = 0.023), type 2 diabetes mellitus, indocyanine green retention rate at 15 min (ICG-15) > 10%, and cancer stage ≧ 3 were independent risk factors for significant muscle loss. In addition, significant muscle loss was associated with early HCC recurrence (P = 0.006). Metabolomic analysis demonstrated that the urea cycle may be decreased in patients with significant muscle loss. CONCLUSION: LLR for HCC was associated with less significant muscle loss than OLR. Since significant muscle loss was a predictive factor for early tumor recurrence and associated with impaired liver metabolism, LLR may subsequently result in a more favorable outcome.

The Vessels That Encapsulate Tumor Clusters (VETC) Pattern Is a Poor Prognosis Factor in Patients with Hepatocellular Carcinoma: An Analysis of Microvessel Density.

The outcomes of patients with hepatocellular carcinoma (HCC) are unsatisfactory because of its high recurrence rate. The Vessels that encapsulate tumor clusters (VETC) pattern is a unique vascular structure. In this study, we investigated the clinical−pathological features of HCC patients with the VETC pattern. We retrospectively reviewed patients with HCC who underwent curative hepatectomy at Chang Gung Memorial Hospital between 2007 and 2013. The form of the VETC pattern was established using an anti-CD31 stain. The results were classified into positive (VETC+) and negative (VETC−) patterns. We investigated and compared demographic data between these two groups. Overall, 174 patients were classified into either the VETC+ or VETC− groups. The median followed-up period was 80.5 months. There were significant differences in the number of hepatitis B carriers, the occurrence of vascular invasion, tumor size, TNM staging, microvessel density, and recurrence (all p < 0.05). Regarding the prediction of disease-free survival, after COX regression multivariate analysis, VETC+ remained independently associated with recurrent episodes (p = 0.003). The intra-tumoral microvessel density, demonstrated by CD-31, was the only clinical−pathological feature independently associated with VETC+. Our study demonstrated that the VETC pattern is an independent factor of poor prognosis for DFS. Higher intra-tumoral microvessel density was significantly associated with the VETC pattern. Further studies are needed to validate our findings.

A Retrospective Comparison of Three Patient-Controlled Analgesic Strategies: Intravenous Opioid Analgesia Plus Abdominal Wall Nerve Blocks versus Epidural Analgesia versus Intravenous Opioid Analgesia Alone in Open Liver Surgery.

Background: Adequate pain control is of crucial importance to patient recovery and satisfaction following abdominal surgeries. The optimal analgesia regimen remains controversial in liver resections. Methods: Three groups of patients undergoing open hepatectomies were retrospectively analyzed, reviewing intravenous patient-controlled analgesia (IV-PCA) versus IV-PCA in addition to bilateral rectus sheath and subcostal transversus abdominis plane nerve blocks (IV-PCA + NBs) versus patient-controlled thoracic epidural analgesia (TEA). Patient-reported pain scores and clinical data were extracted and correlated with the method of analgesia. Outcomes included total morphine consumption and numerical rating scale (NRS) at rest and on movement over the first three postoperative days, time to remove the nasogastric tube and urinary catheter, time to commence on fluid and soft diet, and length of hospital stay. Results: The TEA group required less morphine over the first three postoperative days than IV-PCA and IV-PCA + NBs groups (9.21 ± 4.91 mg, 83.53 ± 49.51 mg, and 64.17 ± 31.96 mg, respectively, p < 0.001). Even though no statistical difference was demonstrated in NRS scores on the first three postoperative days at rest and on movement, the IV-PCA group showed delayed removal of urinary catheter (removal on postoperative day 4.93 ± 5.08, 3.87 ± 1.31, and 3.70 ± 1.30, respectively) and prolonged length of hospital stay (discharged on postoperative day 12.71 ± 7.26, 11.79 ± 5.71, and 10.02 ± 4.52, respectively) as compared to IV-PCA + NBs and TEA groups. Conclusions: For postoperative pain management, it is expected that the TEA group required the least amount of opioid; however, IV-PCA + NBs and TEA demonstrated comparable postoperative outcomes, namely, the time to remove nasogastric tube/urinary catheter, to start the diet, and the length of hospital stay. IV-PCA with NBs could thus be a reliable analgesic modality for patients undergoing open liver resections.

The combination of sarcopenia and biochemical factors can predict the survival of hepatocellular carcinoma patients receiving transarterial chemoembolization.

Background: Transarterial chemoembolization(TACE) is the suggested treatment for hepatocellular carcinoma (HCC) not amenable to curative treatments. We investigated the role of sarcopenia on overall survival in HCC patients receiving TACE and proposed a new prognostic scoring system incorporating sarcopenia. Materials and methods: We retrospectively analyzed 260 HCC patients who received TACE between 2010 and 2015. Total psoas muscle was measured on a cross-sectional CT image before the first TACE session. Sarcopenia was defined by the pre-determined sex-specific cutoff value. We assessed the impact of sarcopenia and other biochemical factors on the overall survival and compared the new scoring system with other prognostic scoring systems. Results: One hundred and thirty patients (50%) were classified as sarcopenia before the first TACE. They were older with a higher male tendency and a significantly lower body mass index (BMI). Cox regression multivariate analysis demonstrated that sarcopenia, multiple tumors, maximal tumor diameter≥ 5cm, major venous thrombosis, sarcopenia, AFP ≥ 200 ng/ml, and albumin<3.5mg/dL were independent poor prognostic factors for overall survival in HCC patients receiving TACE. Our scoring system comprising these factors outperformed other major scoring systems in terms of predicting survival after TACE. Conclusion: The current study demonstrated that sarcopenia was an independent prognostic factor for HCC undergoing TACE therapy. Our newly developed scoring system could effectively predict patient survival after TACE. Physicians could, based on the current score model, carefully select candidate patients for TACE treatment in order to optimize their survival. Further studies are warranted to validate our findings.

Differential Response to Sorafenib Administration for Advanced Hepatocellular Carcinoma.

Sorafenib has been used to treat advanced hepatocellular carcinoma (aHCC). However, there is no evidence for a response of different target lesions to sorafenib administration. Therefore, we aimed to evaluate the effect of sorafenib on various aHCC target lesions. The outcomes of sorafenib treatment on aHCC, i.e., treatment response for all Child A status patients receiving the drug, were analyzed. Of 377 aHCC patients, 73 (19.3%) had complete/partial response to sorafenib, while 134 (35.4%) and 171 (45.2) had a stable or progressive disease, respectively, in the first six months. Of the evaluated metastatic lesions, 149 (39.4%), 48 (12.7%), 123 (32.5%), 98 (25.9%), 83 (22.0%), and 45 (11.9%) were present in liver, bone, lung, portal/hepatic vein thrombus, lymph nodes, and peritoneum, respectively. The overall survival and duration of treatment were 16.9 ± 18.3 and 8.1 ± 10.5 months (with median times of 11.4 and 4.6, respectively). Our analysis showed poor outcomes in macroscopic venous thrombus and bone, higher AFP, and multiple target lesions. ALBI grade A had a better outcome. Sorafenib administration showed good treatment outcomes in selected situations. PD patients with thrombus or multiple metastases should be considered for sorafenib second-line treatment. The ALBI liver function test should be selected as a treatment criterion.

A proposal for T1 subclassification in hepatocellular carcinoma: reappraisal of the AJCC 8th edition.

BACKGROUND: In the 8th edition of American Joint Committee on Cancer (AJCC) staging system for hepatocellular carcinoma (HCC), tumor size is not considered in T1 stage. The present study aimed to find out the optimal cutoff for tumor size to further stratify patients with T1 HCC. METHODS: Operated HCC patients were identified from the Chang Gung Research Database (CGRD), and the patients with T1bN0M0 tumors were further divided into two groups based on the tumor size. The resulting subgroups were denoted as T1b (≤ cutoff) and T1c (> cutoff). The survivals were compared between T1a/b and T1c as well as T1c and T2. RESULTS: From 2002 to 2018, a total of 2893 patients who underwent surgery for T1N0M0 HCC were identified from the CGRD. After excluding cases who died within 30 days of surgery, Kaplan-Meier survival analysis discovered that T1 tumors > 65 mm (T1c) had survivals similar to those of T2N0M0 tumors. Cox regression multivariate analysis further demonstrated that tumor size > 6.5 cm was an independent poor prognostic indicator for T1 HCC. Sensitivity tests also confirmed that tumors lager than 6.5 cm were significantly more likely to develop both tumor recurrence and liver-specific death after surgery. CONCLUSIONS: Our study demonstrated that tumor size would significantly impact the survival outcome of T1 HCC after surgery. Due to significantly worse survival, we proposed a subclassification within T1 HCC, T1c: solitary tumor > 6.5 cm without vascular invasion, to further stratify those patients at risk. Further studies are mandatory to validate our findings.

Reappraisal of the Role of Alkaline Phosphatase in Hepatocellular Carcinoma.

Background: Alkaline phosphatase (ALP) is a marker of liver function and is associated with biliary tract disease. It was reported as a prognostic factor for hepatocellular carcinoma (HCC). The genetic expression in tumor-tissue microarrays and the perioperative serologic changes in ALP have never been studied for their correlation with HCC prognosis. Methods: The genetic expression of ALP isoforms (placental (ALPP), intestinal (ALPI) and bone/kidney/liver (ALPL)) was analyzed in tumor and non-cancerous areas in 38 patients with HCC after partial hepatectomy. The perioperative change in ALP was further analyzed in a cohort containing 525 patients with HCC to correlate it with oncologic outcomes. A total of 43 HCC patients were enrolled for a volumetry study after major and minor hepatectomy. Results: The genetic expression of the bone/kidney/liver isoform was specifically and significantly higher in non-cancerous areas than in tumors. Patients with HCC with a higher ALP (>81 U/dL) had significantly more major hepatectomies, vascular invasion, and recurrence. Cox regression analysis showed that gender, major hepatectomies, the presence of satellite lesions, higher grades (III or IV) and perioperative changes in liver function tests were independent prognostic factors for recurrence-free survival, and a postoperative increase in the ALP ratio at postoperative day (POD) 7 vs. POD 0 > 1.46 should be emphasized. A liver regeneration rate more than 1.8 and correlation analysis revealed that the ALP level at POD 7 and 30 was significantly higher and correlated with remnant liver growth. Conclusions: This study demonstrated that the perioperative ALP change was an independent prognostic factor for HCC after partial hepatectomies, and the elevation of ALP represented a functional biomarker for the liver but not an HCC biomarker. The higher regeneration capacity was possibly associated with the elevation of ALP after operation.

Quercetin exerts anti-inflammatory effects via inhibiting tumor necrosis factor-α-induced matrix metalloproteinase-9 expression in normal human gastric epithelial cells.

BACKGROUND: Gastric injury is the most common digestive system disease worldwide and involves inflammation, which can lead to gastric ulcer or gastric cancer (GC). Matrix metallopeptidase-9 [MMP-9 (gelatinase-B)] plays an important role in inflammation and GC progression. Quercetin and quercetin-rich diets represent potential food supplements and a source of medications for treating gastric injury given their anti-inflammatory activities. However, the effects and mechanisms of action of quercetin on human chronic gastritis and whether quercetin can relieve symptoms remain unclear. AIM: To assess whether tumor necrosis factor-α (TNF-α)-induced MMP-9 expression mediates the anti-inflammatory effects of quercetin in normal human gastric mucosal epithelial cells. METHODS: The normal human gastric mucosa epithelial cell line GES-1 was used to establish a normal human gastric epithelial cell model of TNF-α-induced MMP-9 protein overexpression to evaluate the anti-inflammatory effects of quercetin. The cell counting Kit-8 assay was used to evaluate the effects of varying quercetin doses on cell viability in the normal GES-1 cell line. Cell migration was measured using Transwell assay. The expression of proto-oncogene tyrosine-protein kinase Src (c-Src), phospho (p)-c-Src, extracellular-signal-regulated kinase 2 (ERK2), p-ERK1/2, c-Fos, p-c-Fos, nuclear factor kappa B (NF-κB/p65), and p-p65 and the effects of their inhibitors were examined using Western blot analysis and measurement of luciferase activity. p65 expression was detected by immunofluorescence. MMP-9 mRNA and protein levels were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and gelatin zymography, respectively. RESULTS: qRT-PCR and gelatin zymography showed that TNF-α induced MMP-9 mRNA and protein expression in a dose- and time-dependent manner. These effects were reduced by the pretreatment of GES-1 cells with quercetin or a TNF-α antagonist (TNFR inhibitor) in a dose- and time-dependent manner. Quercetin and TNF-α antagonists decreased the TNF-α-induced phosphorylation of c-Src, ERK1/2, c-Fos, and p65 in a dose- and time-dependent manner. Quercetin, TNF-α antagonist, PP1, U0126, and tanshinone IIA (TSIIA) reduced TNF-α-induced c-Fos phosphorylation and AP-1-Luciferase (Luc) activity in a dose- and time-dependent manner. Pretreatment with quercetin, TNF-α antagonist, PP1, U0126, or Bay 11-7082 reduced TNF-α-induced p65 phosphorylation and translocation and p65-Luc activity in a dose- and time-dependent manner. TNF-α significantly increased GES-1 cell migration, and these results were reduced by pretreatment with quercetin or a TNF-α antagonist. CONCLUSION: Quercetin significantly downregulates TNF-α-induced MMP-9 expression in GES-1 cells via the TNFR-c-Src-ERK1/2 and c-Fos or NF-κB pathways.

Neutrophil-to-lymphocyte-ratio-based perioperative prognosis prediction model on early mortality after cytoreductive surgery with hyperthermic intraperitoneal chemotherapy.

BACKGROUND: Combined cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) to treat peritoneal surface malignancy (PSM) has gained a positive result compared with palliative chemotherapy alone in several cancer types. However, its postoperative care could be challenging. We aimed to develop a predicting model on early mortality. METHODS: We retrospectively reviewed 132 PSM patients who had received CRS-HIPEC. The optimal cut-off value of the neutrophil-to-lymphocyte ratio (NLR) was determined as 4.4 by using the receiver operating characteristic curve analysis with an area under the curve (AUC) of 0.75. The impact of NLR on survival was elucidated by comparing the pre-operative low (NLR≤ 4.4, n = 101) and high (NLR> 4.4, n = 31) groups using the Kaplan-Meier method. The significant variables selected in multivariate analysis on early mortality were used in prediction model development. RESULTS: Multivariate analysis showed that incomplete CRS, major postoperative complications, higher pre-operative NLR, and dynamic NLR changes were significant predictors of early mortality. Our perioperative prediction of prognosis (triple P) model contained four independent risks, and the AUC after classification was 0.860 (95% confidence interval [CI]: 0.773-0.947). External validation confirmed positive discrimination ability (AUC: 0.808, 95% CI: 0.666-0.950). CONCLUSION: In conclusion, our triple P model provides great determination in outcomes prediction and it is easily obtained, reliable, and applicable in routine practice.

Molecular mechanism of therapeutic approaches for human gastric cancer stem cells.

Gastric cancer (GC) is a primary cause of cancer-related mortality worldwide, and even after therapeutic gastrectomy, survival rates remain poor. The presence of gastric cancer stem cells (GCSCs) is thought to be the major reason for resistance to anticancer treatment (chemotherapy or radiotherapy), and for the development of tumor recurrence, epithelial-mesenchymal transition, and metastases. Additionally, GCSCs have the capacity for self-renewal, differentiation, and tumor initiation. They also synthesize antiapoptotic factors, demonstrate higher performance of drug efflux pumps, and display cell plasticity abilities. Moreover, the tumor microenvironment (TME; tumor niche) that surrounds GCSCs contains secreted growth factors and supports angiogenesis and is thus responsible for the maintenance of the growing tumor. However, the genesis of GCSCs is unclear and exploration of the source of GCSCs is essential. In this review, we provide up-to-date information about GCSC-surface/intracellular markers and GCSC-mediated pathways and their role in tumor development. This information will support improved diagnosis, novel therapeutic approaches, and better prognosis using GCSC-targeting agents as a potentially effective treatment choice following surgical resection or in combination with chemotherapy and radiotherapy. To date, most anti-GCSC blockers when used alone have been reported as unsatisfactory anticancer agents. However, when used in combination with adjuvant therapy, treatment can improve. By providing insights into the molecular mechanisms of GCSCs associated with tumors in GC, the aim is to optimize anti-GCSCs molecular approaches for GC therapy in combination with chemotherapy, radiotherapy, or other adjuvant treatment.