Clinical Significance of Venous Thromboembolism in Patients with Advanced Cholangiocarcinoma.

Background/Aims: Patients with active cancer frequently develop venous thromboembolism (VTE). However, there is little data about VTE in patients with advanced cholangiocarcinoma (CCA). Therefore, we investigated the clinical significance of VTE in patients with advanced CCA. Methods: We analyzed the data of a total of 332 unresectable CCA patients diagnosed between 2010 and 2020 in this retrospective study. We investigated the incidence and risk factors for VTE, and its effect on survival in patients with advanced CCA. Results: During a median follow-up of 11.6 months, 118 patients (35.5%) developed VTE. The cumulative incidence of VTE was 22.4% (95% confidence interval [CI], 0.18 to 0.27) at 3 months and 32.8% (95% CI, 0.27 to 0.38) at 12 months. Major vessel invasion was an independent risk factor for VTE (hazard ratio, 2.88; 95% CI, 1.92 to 4.31; p<0.001). Patients who developed VTE during follow-up had shorter overall survival than patients who did not (11.50 months vs 15.83 months, p=0.005). In multivariable analysis, VTE (hazard ratio, 1.58; 95% CI, 1.23 to 2.02; p<0.001) was associated with poor overall survival. Conclusions: Major vessel invasion is related to the occurrence of VTE in advanced CCA. The development of VTE significantly decreases the overall survival and is an important unfavorable prognostic factor for survival.

A prospective randomized noninferiority trial comparing conventional smears and SurePathTM liquid-based cytology in endoscopic ultrasound-guided sampling of esophageal, gastric, and duodenal lesions.

BACKGROUND: Several liquid-based cytology (LBC) methods are currently used, but the diagnostic accuracy of each method is not well known. We aimed to compare the diagnostic performance of SurePathTM LBC and conventional smear (CS) cytology in endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) samples of esophageal, gastric, and duodenal lesions. METHODS: As a prospective randomized noninferiority study, patients who needed EUS-FNA due to subepithelial mass in the upper gastrointestinal tract were randomly assigned 1:1 to the LBC and CS groups. Cytologic preparation was carried out using a crossover design where 1 method was used for the first needle-pass sample and another method was used for the second needle-pass sample. The primary outcome was to compare the diagnostic performance between LBC and CS using the final diagnosis as the gold standard. RESULTS: A total of 87 patients were randomized and 60 patients were analyzed. There were no differences between LBC and CS in diagnostic accuracy (91.7% vs 86.7%, P = .380), sensitivity (97.7% vs 90.7%, P = .169), specificity (76.5% vs 76.5%, P > .99), negative predictive value (92.9% vs 76.5%, P = .225), or positive predictive value (91.3% vs 90.7%, P = .921). The background of LBC was less bloody than that of CSs (5.0% vs 53.3%, P < .001) and the sample preparation time of LBC was shorter than that of CSs (29 ±â€…7 seconds vs 90 ±â€…17 seconds, P < .001). CONCLUSION: In the EUS-FNA of a subepithelial mass in the upper gastrointestinal tract, the diagnostic performance of LBC was not inferior to that of CS. The field of view was better in LBC, because the background was less bloody and necrotic. As LBC is more convenient to perform and takes shorter time, it is expected that it can replace the CS method for EUS-FNA samples.

Association between glycemic status and the risk of acute pancreatitis: a nationwide population-based study.

BACKGROUND: Although diabetes is reportedly associated with the occurrence of acute pancreatitis (AP), the risk of AP according to the duration and severity of diabetes is not yet clear. We aimed to investigate the risk of AP based on glycemic status and the presence of comorbidities using a nationwide population-based study. METHODS: We enrolled 3,912,496 adults who underwent health examinations under the National Health Insurance Service in 2009. All participants were categorized by glycemic status as normoglycemic, impaired fasting glucose (IFG), or diabetes. Baseline characteristics and the presence of comorbidities at the time of health check-up were investigated, and the occurrence of AP was followed up until 31 December 2018. We estimated the adjusted hazard ratios (aHRs) for AP occurrence according to the glycemic status, duration of diabetes (new-onset, duration < 5 years, or ≥ 5 years), type and number of anti-diabetic medications, and presence of comorbidities. RESULTS: During the observation period of 32,116,716.93 person-years, 8,933 cases of AP occurred. Compared with normoglycemia, the aHRs (95% confidence interval) were 1.153 (1.097-1.212) in IFG, 1.389 (1.260-1.531) in new-onset diabetes, 1.634 (1.496-1.785) in known diabetes < 5 years, and 1.656 (1.513-1.813) in patients with known diabetes aged ≥ 5 years. The presence of comorbidities associated with diabetes severity had a synergistic effect on the relationship between diabetes and AP occurrence. CONCLUSION: As glycemic status worsens, the risk of AP increases, and there is a synergistic effect when comorbidities coexist. To reduce the risk of AP, active control of factors that can cause AP should be considered in patients with long-standing diabetes and comorbidities.

Development of novel biliary metal stent with coil-spring structure and its application in vivo swine biliary stricture model.

Background: As of date, endoscopic biliary stenting with plastic stent (PS) and self-expandable metal stent (SEMS) have been widely used for the palliation of biliary tract strictures. However, these two stents have several limitations regarding the management of biliary strictures caused by intrahepatic and hilar cholangiocarcinoma. PS has short patency and also risks bile duct injury and bowel perforation. SEMS is difficult to revise when occluded by tumor overgrowth. To compensate for such shortcomings, we developed a novel biliary metal stent with coil-spring structure. The aim of this study was to investigate the feasibility and efficacy of the novel stent in a swine model. Methods: The biliary stricture model was prepared in six mini-pigs using endobiliary radiofrequency ablation. Conventional PS (n=2) and novel stents (n=4) were deployed endoscopically. Technical success was defined as successful stent placement and clinical success was defined as >50% reduction of serum bilirubin level. Adverse events, stent migration, and endoscopic removability for one month after stenting were also assessed. Results: The biliary stricture was successfully created in all animals. The technical success rate was 100 %, and the clinical success rate was 50% in the PS group and 75% in the novel stent group. In the novel stent group, the median pre- and post-treatment serum bilirubin levels were 3.94 and 0.3 mg/dL. Stent migration occurred in two pigs and two stents were removed by endoscopy. There was no stent-related mortality. Conclusions: The newly designed biliary metal stent was feasible and effective in a swine biliary stricture model. Further studies are needed to verify the usefulness of the novel stent in the management of biliary strictures.

A population-based cohort study on risk factors for acute pancreatitis: A comparison by age group.

BACKGROUND: /objectives: Acute pancreatitis (AP) is an acute inflammatory disorder that can occur in all age groups. The risk of AP has been shown to increase with age. However, no study has compared risk factors for AP according to age group yet. Thus, the aim of this study was to perform such comparison. METHODS: Clinical data from individuals 20 years of age and older who received a health examination arranged by the Korean national health insurance program in 2009 (n = 4,238,822) were used. First-attack AP was identified using claims data from baseline to December 2018. Incidence and risk factors of AP were analyzed for young (20-39 years old), middle-aged (40-64 years old), and old (over 65 years old) groups. RESULTS: Incidences of AP in young, middle-aged, and old groups were 16.30, 27.85, and 57.19 per 100,000 person-years, respectively. Smoking, alcohol drinking, diabetes, gallstone, and chronic pancreatitis were associated with increased risk of AP in all age groups. Meanwhile, male, older age, and higher waist circumference were associated with increased risk of AP in middle-aged and old groups. In young and middle-aged groups, risk of AP was increased in the presence of hypertension and dyslipidemia. However, high income was associated with decreased risk of AP in these groups. CONCLUSIONS: In this population-based cohort study, incidences and risk factors for AP differed according to age group. Thus, a tailored strategy might be needed to prevent AP according to age group.

Efficacy and safety of novel hemostatic gel in endoscopic sphincterotomy or endoscopic papillectomy: A multicenter, randomized controlled clinical trial.

BACKGROUND: Endoscopists often experience obstacles with traditional hemostasis using the side-viewing duodenoscope for bleeding after endoscopic sphincterotomy (EST) or endoscopic papillectomy (EP). AIMS: In this randomized controlled trial, we evaluated the efficacy and safety of a novel hemostatic gel for post-EST or post-EP bleeding. METHODS: A randomized trial was conducted from November 2020 to December 2021 at two tertiary centers in South Korea. Patients who experienced bleeding immediately after EST or EP were enrolled in the study, and primary hemostasis was achieved with either the novel hemostatic gel or epinephrine spray. RESULTS: A total of 84 patients were enrolled in this study, and 41 patients were finally analyzed in each group. Hemostatic gel was significantly superior to epinephrine spray for successful primary hemostasis (100% vs. 85.4%; P = 0.026). ). In terms of delayed bleeding, no significant difference was observed between the hemostatic gel and epinephrine spray (2.4% vs. 7.3%; P = 0.329). The mean procedural time was significantly higher for the hemostatic gel than epinephrine spray (3.23 ± 1.94 vs. 1.76 ± 0.99 min; P < 0.001), and no differences were observed in the adverse events. CONCLUSIONS: The novel hemostatic gel is expected to achieve satisfactory results with easier hemostasis for immediate bleeding after EST or EP. (Registered in Clinical Research Information Service: KCT0005607).

In-stent radiofrequency ablation with uncovered metal stent placement for tumor ingrowth/overgrowth causing self-expandable metal stent occlusion in distal malignant biliary obstruction: multicenter propensity score-matched study.

BACKGROUND AND AIMS: In patients with unresectable malignant biliary obstruction (MBO), endoscopic drainage with a self-expandable metal stent (SEMS) is a well-established treatment, but stent patency is limited. This study aimed to evaluate the efficacy of in-stent radiofrequency ablation (IS-RFA) followed by uncovered SEMS placement for the management of occluded SEMSs. METHODS: From 2016 to 2020, 48 patients with recurrent biliary obstruction due to tumor ingrowth or overgrowth after SEMS placement for pancreatobiliary cancer in 3 tertiary hospitals were analyzed. For distal MBO, patients in the RFA group were treated with IS-RFA and uncovered SEMS placement, and those in the control group were treated with uncovered SEMS placement alone. Patients in both groups were matched on the basis of propensity scores in a 1:1 ratio. RESULTS: The median time to recurrent biliary obstruction (TRBO) was 117 days in the RFA group and 82.5 days in the control group (P = .029). No significant differences in median overall survival were detected between the 2 groups (170 days vs 72 days; P = .902). No significant adverse events were reported after the second SEMS placement in either group, but 2 cases of mild cholangitis were reported in the control group. Ablation was interrupted in 5 patients (35.7%) of the RFA group owing to in-stent contact, but sufficient ablative energy was delivered in the majority of the patients (92.9%) after IS-RFA was repeated in the same session. CONCLUSIONS: IS-RFA followed by an uncovered SEMS is safe and feasible and may improve TRBO as a stent revision for occluded SEMSs in pancreatobiliary cancer.

Combinatorial Effect of Prophylactic Interventions for Post-ERCP Pancreatitis among Patients with Risk Factors: A Network Meta-Analysis.

Background/Aims: The combinatorial effects of prophylactic methods for postendoscopic retrograde cholangiopancreatography pancreatitis (PEP) in patients with risk factors remain unclear. In this network meta-analysis, we compared the efficacy of various prophylactic strategies to decrease the risk of PEP among patients with risk factors. Methods: A systematic review was performed to identify randomized controlled trials from PubMed, Embase, and the Cochrane Library through July 2021. We used frequentist network meta-analysis to compare the rates of PEP among patients who received prophylactic treatments as follows: class A, rectal nonsteroidal anti-inflammatory drugs; class B, prophylactic pancreatic stent; class C, aggressive hydration; or control, no prophylaxis or active control. We selected those studies that included patients with risk factors for PEP. Results: We identified 19 trials, comprising 4,328 participants. Class ABC (odds ratio [OR], 0.08; 95% confidence interval [CI], 0.03 to 0.24), class AC (OR, 0.10; 95% CI, 0.02 to 0.47), class AB (OR, 0.12; 95% CI, 0.05 to 0.26), class BC (OR, 0.13; 95% CI, 0.04 to 0.41), class A (OR, 0.16; 95% CI, 0.05 to 0.50), and class B (OR, 0.26; 95% CI, 0.14 to 0.46), were associated with a reduced risk of PEP as compared to that of the control. The most effective prophylaxis was ABC (0.87), followed by AC (0.68), AB (0.65), BC (0.56), A (0.49), and B (0.24) according to P-score. Conclusions: The results of this network meta-analysis suggest that the more prophylactic methods are employed, the better the outcomes. It appears that for patients with risk factors, we need to prevent PEP through the use of these well proven combination strategies.

The association between smoking, changes in smoking behavior, and acute pancreatitis: A population-based cohort study in Korea.

BACKGROUND AND AIMS: In the Asian population, existing studies regarding the association between smoking and acute pancreatitis are few in number. The aim of this study was to investigate the incidence of acute pancreatitis according to smoking habits and smoking habit changes of the Korean population. METHODS: We used clinical data from individuals (aged 20 years or older) who received health examinations arranged by the Korean National Health Insurance Service in 2009 (n = 4 238 822) or in 2009 and 2011 (n = 2 617 306). The incidence of acute pancreatitis was analyzed according to smoking status or smoking habit change reported by individuals during their health examination. Newly diagnosed acute pancreatitis was identified using claims data from baseline to the date of diagnosis or until December 31, 2018. RESULTS: The risk of acute pancreatitis was significantly higher in current smokers compared with never-smokers regardless of age or sex. The adjusted hazard ratio (HR) of acute pancreatitis in current smokers increased according to the amount of smoking (HR 1.28; 95% confidence interval [CI], 1.12-1.45 in <10 cigarettes/day, HR 1.4; CI, 1.3-1.52 in 10-19 cigarettes/day, HR 1.66; CI, 1.55-1.78 in ≥20 cigarettes/day). The adjusted HR of acute pancreatitis in continuous smokers was 1.66 (CI, 1.53-1.8) compared with never-smokers and was higher than smokers who quit smoking (HR 1.34; CI, 1.17-1.54). CONCLUSIONS: In this Korean population-based cohort study, smoking increased the incidence of acute pancreatitis in a dose-dependent manner, and smoking cessation helped decrease the incidence of acute pancreatitis.

Proper adjuvant therapy in patients with borderline resectable and locally advanced pancreatic cancer who had received neoadjuvant FOLFIRINOX.

Background: The complete resection rate of pancreatic cancer has increased because of the advent of efficacious first-line treatments for unresectable pancreatic cancer. Still, strategies regarding adjuvant therapy after neoadjuvant FOLFIRINOX treatment remain to be established. Methods: Data on 144 patients with borderline resectable and locally advanced pancreatic cancer who underwent resection after neoadjuvant FOLFIRINOX between January 2013 and April 2021 were retrospectively reviewed. Results: Among the study patients, 113 patients (78.5%) were diagnosed with borderline resectable pancreatic cancer and 31 patients (21.5%) were diagnosed with locally advanced pancreatic cancer. Seventy-five patients (52.1%) received radiotherapy before surgery. After radical resection, 84 patients (58.3%) received 5-fluorouracil-based adjuvant therapy and 60 patients (41.7%) received non-5-fluorouracil-based adjuvant therapy. Adjuvant therapy with 5-fluorouracil-based regimen [hazard ratio (HR), 0.43 (95% CI, 0.21-0.87); p = 0.019], preoperative assessment as locally advanced pancreatic cancer [HR, 2.87 (95% CI, 1.08-7.64); p = 0.035], positive resection margin [HR, 3.91 (95% CI, 1.71-8.94); p = 0.001], and presence of pathologic lymph node involvement [HR, 2.31 (95% CI, 1.00-5.33), p = 0.050] were associated with decreased recurrence-free survival. Adjuvant therapy with 5-fluorouracil-based regimen [HR, 0.35 (95% CI, 0.15-0.84); p = 0.018], positive resection margin [HR, 4.14 (95% CI, 1.75-9.78); p = 0.001], presence of pathologic lymph node involvement [HR, 3.36 (95% CI, 1.23-9.15); p = 0.018], poor differentiation [HR, 5.69 (95% CI, 1.76-18.36); p = 0.004], and dose reduction during adjuvant therapy [HR, 1.78 (95% CI, 1.24-24.37); p = 0.025] were associated with decreased overall survival. Conclusions: The 5-fluorouracil-based adjuvant therapy seems to be the proper adjuvant therapy for patients who received neoadjuvant FOLFIRINOX for borderline resectable and locally advanced pancreatic cancer.

A real-world analysis of nanoliposomal-irinotecan with 5-fluorouracil and folinic acid as third- or later-line therapy in patients with metastatic pancreatic adenocarcinoma.

Background: Nanoliposomal encapsulation of irinotecan (nal-IRI) with 5-fluorouracil and leucovorin (5-FU/LV) has shown a survival benefit for gemcitabine-pretreated patients with metastatic pancreatic adenocarcinoma (mPAC). The aim of this study was to evaluate the effectiveness and safety of nal-IRI with 5-FU/LV for use beyond second-line treatment after standard frontline therapy for mPAC. Method: This multicenter, retrospective, non-comparative observational study included mPAC patients who received nal-IRI plus 5-FU/LV as third- or later-line therapy after disease progression on first-line FOLFIRINOX (FFX) or gemcitabine plus nab-paclitaxel. Results: In all, 128 patients who received nal-IRI plus 5-FU/LV beyond second-line treatment between October 2017 and July 2021 were analyzed. Most patients (82%) received nal-IRI plus 5-FU/LV as a third-line treatment. The median overall survival (OS) was 4.9 months and the median progression-free survival (PFS) was 2.4 months. Patients with better Eastern Cooperative Oncology Group (ECOG) performance status experienced significantly longer OS (ECOG 0, 8.7 months; ECOG 1, 4.8 months; ECOG 2, 2.9 months; p < 0.001) and PFS (3.9 months; 2.1 months; 1.5 months; p = 0.019). Patients who had not been previously treated with FFX or had a time to progression of 7 months or more on FFX experienced longer OS and PFS than those who did not (6.1 months and 5.6 versus 4.1 months, p = 0.053; 3.6 months and 2.4 versus 2.1 months, p = 0.002). The most common adverse events were neutropenia (56%) and anemia (51%). Conclusion: Our real-world data indicated that nal-IRI plus 5-FU/LV can be effective not only as second-line therapy, but also as third-line or later-line treatment in selected patients. Nal-IRI plus 5-FU/LV may be particularly beneficial for the survival of patients that maintain good general condition or those with favorable prior experience to irinotecan.

The effect of nafamostat mesilate infusion after ERCP for post-ERCP pancreatitis.

BACKGROUND: Nafamostat mesilate decreases the incidence of pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP). However, no studies have administered nafamostat mesilate after ERCP. So we investigated if the infusion of nafamostat mesilate after ERCP can affect the post-ERCP pancreatitis (PEP) in high-risk patients. METHODS: In a tertiary hospital, 350 high-risk patients of PEP were reviewed retrospectively. Among them, 201 patients received nafamostat mesilate after ERCP. Patient-related and procedure-related risk factors for PEP were collected. We performed a propensity score matching to adjust for the significant different baseline characteristics. The incidence and severity of PEP were evaluated according to the infusion of nafamostat mesilate. The risk factors of PEP were also analyzed by multivariate logistic regression. RESULTS: The baseline characteristics were not different after the matching. The PEP rate (17.4% vs. 10.3%, P = 0.141) was insignificant. Among the PEP patients, mild PEP was significantly higher in the nafamostat mesilate group (85.7% vs. 45.5%, P = 0.021). Only one patient in the nafamostat mesilate group developed severe PEP. Although young age (odds ratio [OR] 3.60, 95% CI 1.09-11.85, P = 0.035) was a risk factor, nafamostat mesilate (odds ratio [OR] 0.30, 95% CI 0.09-0.98, P = 0.047) was a protective factor for moderate to severe PEP. CONCLUSIONS: The administration of nafamostat mesilate after ERCP in high-risk patients was not effective in preventing PEP, but may attenuate the severity of PEP.

Acetylsalicylic acid for metal stent in malignant distal common bile duct obstruction: A randomized controlled trial.

BACKGROUND: Endoscopic biliary drainage is the treatment of choice for patients with malignant distal common bile duct obstruction. Self-expandable metal stents have clinical advantages including an increased duration of patency that may be prolonged by acetylsalicylic acid (ASA) use. The aim of this study was to investigate whether ASA had a positive effect on the patency of self-expandable metal stents compared with placebo. METHODS: This prospective, multicenter, double-blinded, and randomized placebo-controlled trial was conducted from October 2017 to May 2020 in Korea. Patients who underwent palliative endoscopic biliary drainage with self-expandable metal stents for malignant distal bile duct obstruction were enrolled, and allocated to ASA treatment or placebo. The study outcomes were the rate of stent dysfunction at 6 months, duration of stent patency, risk factors for stent dysfunction, and any adverse events. RESULTS: Interim analysis included 24 and 28 patients in the ASA and placebo groups, respectively. There was no significant difference between the ASA and placebo groups in stent dysfunction (25.0% vs. 20.7%, P = 0.761) or the duration of stent patency (150.97 ± 10.55 vs. 158.07 ± 8.70 days, P = 0.497). Six patients experienced suspected ASA-related adverse events, and there was one lethal case. CONCLUSIONS: ASA did not prolong stent patency. This study was terminated early because of the possibility of serious adverse events related to ASA treatment of these patients receiving palliative care.

Comparison between FOLFIRINOX and gemcitabine plus nab-paclitaxel including sequential treatment for metastatic pancreatic cancer: a propensity score matching approach.

BACKGROUND: FOLFIRINOX (FFX) and Gemcitabine plus nab-paclitaxel (GnP) have been recommended as the first-line chemotherapy for metastatic pancreatic cancer (mPC). However, the evidence is lacking comparing not only two regimens, but also sequential treatment (FFX-GnP vs. GnP-FFX). METHODS: Data of 528 patients (FFX, n = 371; GnP, n = 157) with mPC were collected retrospectively. Propensity score matching was conducted to alleviate imbalance of the two groups. Overall survival (OS), progression free survival (PFS), and toxicity of patients were analyzed. RESULTS: In the whole population, OS (12.5 months vs. 10.3 months, P = 0.05) and PFS (7.1 months vs. 5.8 months, P = 0.02) were longer in the FFX group before matching and after matching (OS: 11.8 months vs. 10.3 months, P = 0.02; PFS: 7.2 months vs. 5.8 months, P <  0.01). For sequential treatment, OS and PFS showed no significant difference. Interruptions of chemotherapy due to toxicities were more frequent (6.8 vs. 29.3%, P <  0.001) in the GnP group, and cessation of chemotherapy showed a significant association with mortality (z = - 1.94, P = 0.03). CONCLUSIONS: FFX achieved a longer overall survival than GnP in mPC, but not in the comparison for sequential treatment. More frequent adverse events followed by treatment interruptions during GnP might lead to a poor survival outcome. Therefore, FFX would be a better first-line treatment option than GnP for mPC.

Optimal timing of endoscopic retrograde cholangiopancreatography for acute cholangitis associated with distal malignant biliary obstruction.

BACKGROUND: There is a lack of studies regarding the optimal timing for endoscopic retrograde cholangiopancreatography (ERCP) in patients with cholangitis caused by distal malignant biliary obstruction (MBO). This study aims to investigate the optimal timing of ERCP in patients with acute cholangitis associated with distal MBO with a naïve papilla. METHODS: A total of 421 patients with acute cholangitis, associated with distal MBO, were enrolled for this study. An urgent ERCP was defined as being an ERCP performed within 24 h following emergency room (ER) arrival, and early ERCP was defined as an ERCP performed between 24 and 48 h following ER arrival. We evaluated both 30-day and 180-day mortality as primary outcomes, according to the timing of the ERCP. RESULTS: The urgent ERCP group showed the lowest 30-day mortality rate (2.2%), as compared to the early and delayed ERCP groups (4.3% and 13.5%) (P < 0.001). The 180-day mortality rate was lowest in the urgent ERCP group, followed by early ERCP and delayed ERCP groups (39.4%, 44.8%, 60.8%; P = 0.006). A subgroup analysis showed that in both the primary distal MBO group, as well as in the moderate-to-severe cholangitis group, the urgent ERCP had significantly improved in both 30-day and 180-day mortality rates. However, in the secondary MBO and mild cholangitis groups, the difference in mortality rate between urgent, early, and delayed ERCP groups was not significant. CONCLUSIONS: In patients with acute cholangitis associated with distal MBO, urgent ERCP might be helpful in improving the prognosis, especially in patients with primary distal MBO or moderate-to-severe cholangitis.

High platelet-to-lymphocyte ratio is associated with poor prognosis in patients with unresectable intrahepatic cholangiocarcinoma receiving gemcitabine plus cisplatin.

BACKGROUND: Several systemic inflammatory response (SIR) markers, including platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and albumin-to-globulin ratio (AGR), have emerged as prognostic markers in various cancers. The aim of this study was to explore the impact of SIR markers on the survival outcomes of unresectable intrahepatic cholangiocarcinoma (IHC) patients. METHODS: Patients with histologically confirmed, unresectable IHC treated with gemcitabine plus cisplatin (GP) chemotherapy in a single tertiary hospital from 2012 to 2016 were retrospectively reviewed. Progression-free survival (PFS) and overall survival (OS) were determined using unadjusted Kaplan-Meier and adjusted Cox-proportional-hazards analysis. Time-dependent receiver operating characteristic (ROC) analysis was performed to compare the performance of the SIR markers in predicting OS. RESULTS: A total of 137 patients received a median of six cycles (interquartile range [IQR], 3-11) of GP chemotherapy with a median observation time of 9.9 months (range, 1.8-54.7 months). The median PFS and OS of all patients were 7.8 months and 9.9 months, respectively. Among the SIR markers, high PLR (> 148) and high NLR (> 5) were associated with a short PFS (Hazard ratio [HR] 1.828, P = 0.006; HR 1.738, P = 0.030, respectively) and short OS (HR 2.332, P < 0.001; HR 2.273, P < 0.001, respectively). Low LMR (< 3.5) and low AGR (< 1.2) were associated with a short OS (HR 2.423, P < 0.001; HR 1.768, P = 0.002, respectively). In multivariable cox-regression analysis, high PLR (HR 1.766, P = 0.009) and distant lymph node (LN) metastasis (HR 2.085, P = 0.001) were associated with a short PFS. High PLR (HR 1.856, P = 0.002) was an independent predictor of a short OS, along with distant LN metastasis (HR 1.929; P < 0.001), low LMR (HR 1.691; P = 0.041), and low level of serum albumin (< 3.5 g/dL) (HR 1.632; P = 0.043). Time-dependent ROC analysis revealed that the area under the curve of PLR for predicting overall survival was greater than that of NLR, LMR, and AGR at most time points. CONCLUSIONS: High PLR was an independent prognostic factor of a short PFS and OS in patients with unresectable IHC receiving GP chemotherapy.

Inhibition of sphingolipid metabolism enhances resveratrol chemotherapy in human gastric cancer cells.

Resveratrol, a chemopreventive agent, is rapidly metabolized in the intestine and liver via glucuronidation. Thus, the pharmacokinetics of resveratrol limits its efficacy. To improve efficacy, the activity of resveratrol was investigated in the context of sphingolipid metabolism in human gastric cancer cells. Diverse sphingolipid metabolites, including dihydroceramides (DHCer), were tested for their ability to induce resveratrol cytotoxicity. Exposure to resveratrol (100 µM) for 24 hr induced cell death and cell cycle arrest in gastric cancer cells. Exposure to the combination of resveratrol and dimethylsphingosine (DMS) increased cytotoxicity, demonstrating that sphingolipid metabolites intensify resveratrol activity. Specifically, DHCer accumulated in a resveratrol concentration-dependent manner in SNU-1 and HT-29 cells, but not in SNU-668 cells. LC-MS/MS analysis showed that specific DHCer species containing C24:0, C16:0, C24:1, and C22:0 fatty acids chain were increased by up to 30-fold by resveratrol, indicating that resveratrol may partially inhibit DHCer desaturase. Indeed, resveratrol mildly inhibited DHCer desaturase activity compared to the specific inhibitor GT-11 or to retinamide (4-HPR); however, in SNU-1 cells resveratrol alone exhibited a typical cell cycle arrest pattern, which GT-11 did not alter, indicating that inhibition of DHCer desaturase is not essential to the cytotoxicity induced by the combination of resveratrol and sphingolipid metabolites. Resveratrol-induced p53 expression strongly correlated with the enhancement of cytotoxicity observed upon combination of resveratrol with DMS or 4-HPR. Taken together, these results show that DHCer accumulation is a novel lipid biomarker of resveratrol-induced cytotoxicity in human gastric cancer cells.