Benefit and Harm of Aspirin on Mortality From Gastrointestinal Cancers Vs Bleeding in Helicobacter pylori-Eradicated Patients.

BACKGROUND & AIMS: We investigated the benefit-risk profile of aspirin on mortality reduction from chemoprevention of gastrointestinal (GI) cancer vs excess mortality from bleeding among Helicobacter pylori-eradicated patients, and its interaction with proton pump inhibitors (PPIs). METHODS: H pylori-eradicated patients (between 2003 and 2016), identified from a territory-wide database, were observed from the date of H pylori therapy until death or the end of the study (July 2020). Primary exposure was aspirin use as time-varying variable. The primary outcome was GI cancer-related (gastrointestinal, hepatobiliary, or pancreatic cancer) death and the secondary outcome was bleeding-related (gastrointestinal bleeding or intracranial bleeding) death. The adjusted hazard ratio (aHR) of outcomes was calculated by multivariable Cox model after adjusting for age, sex, comorbidities, and concomitant medications. The benefit-risk profile was expressed as the adjusted absolute risk difference of cancer-related deaths and bleeding-related deaths between aspirin users and nonusers. RESULTS: A total of 87,967 subjects were followed up for a median of 10.1 years, with 1294 (1.5%) GI cancer-related deaths and 304 (0.3%) bleeding-related deaths. Aspirin was associated with lower GI cancer-related mortality (aHR, 0.51; 95% CI, 0.42-0.61), but higher bleeding-related mortality (aHR, 1.52; 95% CI, 1.11-2.08). Among PPI users, the aHR of bleeding-related mortality with aspirin was 1.06 (95% CI, 0.70-1.63). For the whole cohort, the adjusted absolute risk difference between aspirin users and nonusers was 7 (95% CI, 5-8) fewer cancer-related and 1 (95% CI, 0.3-3) more bleeding-related death per 10,000 person-years. Among concomitant PPI-aspirin use, there were 9 (95% CI, 8-10) fewer cancer-related deaths per 10,000 person-years without an increase in bleeding-related deaths. CONCLUSIONS: GI cancer mortality benefit from aspirin outweighs bleeding-related mortality in H pylori-eradicated subjects, which is enhanced further by PPI use.

Risk of hospitalization for upper gastrointestinal bleeding in Helicobacter pylori eradicated patients newly started on warfarin or direct oral anticoagulants: A population-based cohort study.

BACKGROUND: To investigate risks of hospitalization for upper gastrointestinal bleeding (UGIB) in H. pylori-eradicated patients newly started on warfarin or direct oral anti-coagulants (DOACs). METHODS: We identified all patients who had previously received H. pylori eradication therapy or were found to have no H. pylori on endoscopy and were then newly started on warfarin or DOACs from a population-based electronic healthcare database. Primary analysis was the risk of UGIB between warfarin and DOACs users in H. pylori-eradicated patients. Secondary analysis included the UGIB risk between H. pylori-eradicated and H. pylori-negative patients who were newly started on warfarin or DOACs. The hazard ratio (HR) of UGIB was approximated by pooled logistic regression model incorporating the inverse propensity of treatment weightings with time-varying covariables. RESULTS: Among H. pylori-eradicated patients, DOACs had a significantly lower risk of UGIB (HR: 0.26, 95% CI 0.09-0.71) compared with warfarin. In particular, lower UGIB risks with DOACs were observed among older (≥65 years) patients, female, those without a history of UGIB or peptic ulcer, or ischemic heart disease, and non-users of acid-suppressive agents or aspirin. Secondary analysis showed no significant difference in UGIB risk between H. pylori-eradicated and H. pylori-negative patients newly started on warfarin (HR: 0.63,95% CI 0.33-1.19) or DOACs (HR: 1.37, 95% CI 0.45-4.22). CONCLUSIONS: In H. pylori-eradicated patients, new users of DOACs had a significantly lower risk of UGIB than new warfarin users. Furthermore, the risk of UGIB in new warfarin or DOACs users was comparable between H. pylori-eradicated and H. pylori-negative patients.

Minimally Invasive Thymectomy Could Be Attempted for Locally Advanced Thymic Malignancies: A Real-World Study With Propensity Score-Matched Analysis.

INTRODUCTION: Increasing evidence supports minimally invasive thymectomy (MIT) for early stage thymic malignancies than open median sternotomy thymectomy (MST). Nevertheless, whether MIT could be attempted for locally advanced disease remains unclear. METHODS: The clinical data of consecutive patients with stage T2-3NxM0 (eighth edition TNM staging) thymic malignancies who underwent MIT or MST were identified from a prospectively maintained database. The co-resected structures were rated with a resection index to evaluate surgical difficulty. The impact of surgical approach on treatment outcomes was investigated through propensity score-matched analysis and multivariable analysis. RESULTS: From January 2008 to December 2019, a total of 128 patients were included; MIT was initially attempted in 58 (45.3%) cases, and eight (13.8%) were converted to MST during surgery. The conversion group had similar perioperative outcomes to the MST group, except for a longer operation time. After propensity score matching, the resection index scores were similar between the MIT and MST groups (3.5 versus 3.7, p = 0.773). The MIT group had considerably less blood loss (p < 0.001), fewer postoperative complications (p = 0.048), a shorter duration of chest drainage (p < 0.001), and a shorter hospitalization duration (p < 0.001) than the MST group. The 5-year freedom from recurrence rate was not different between the two groups (78.2% versus 78.5%, p = 0.942). In multivariable analysis, surgical approach was not associated with freedom from recurrence (p = 0.727). CONCLUSIONS: MIT could be safely attempted in carefully selected patients with locally advanced thymic tumors. Conversion did not compromise the surgical outcomes. Patients may benefit from the less traumatic procedure and thus better recovery, with comparable long-term oncologic outcomes.

Statins associate with lower risk of biliary tract cancers: A systematic review and meta-analysis.

BACKGROUND: Biliary tract cancers (BTCs), encompassing cholangiocarcinoma (CCA), gallbladder (GBC), and ampulla of Vater cancers (AVC), are common hepatobiliary cancer after hepatocellular carcinoma with a high mortality rate. As there is no effective chemopreventive agent to prevent BTCs, this study aimed to explore the role of statins on the risk of BTCs. METHODS: PubMed, Embase, and Cochrane Library from inception until 24 April 2020 were searched according to the Meta-Analyses of Observational Studies in Epidemiology (MOOSE) guidelines. The adjusted risk ratios (aRRs) of BTCs and individual cancer were pooled using a random-effects model. RESULTS: Eight observational studies (3 cohort and 5 case-control studies) were included with 10,485,231 patients. The median age was 68.0 years (IQR: 67.0-71.5) and 48.3% were male. Statins were associated with a lower risk of all BTCs (aRR: 0.67; 95% CI: 0.51-0.87). The pooled aRR for CCA was 0.60 (95% CI: 0.38-0.94) and GBC was 0.78 (95% CI: 0.68-0.90). There was only one study on AVC with aRR of 0.96 (95% CI: 0.66-1.41). The pooled aRR for lipophilic and hydrophilic statins was 0.78 (95% CI: 0.69-0.88) and 0.70 (95% CI: 0.61-0.80), respectively. The effects were attenuated in studies that adjusted for aspirin and/or non-steroidal anti-inflammatory drugs (aRR: 0.80, 95% CI: 0.72-0.89) and metformin (aRR: 0.80, 95% CI: 0.72-0.90). CONCLUSIONS: Statins, both lipophilic and hydrophobic, were associated with a lower risk of BTCs, particularly CCA and GBC.

Age of eradication and failure rates of clarithromycin-containing triple therapy for Helicobacter pylori: A 15-year population-based study.

BACKGROUND: Failure rates of clarithromycin-containing triple therapy for H. pylori are rising. To determine the trend of failure rates of clarithromycin-containing triple therapy in different age groups in Hong Kong over the past 15 years. MATERIALS AND METHODS: This is a population-based retrospective age-period-cohort study involving all adult H. pylori-infected patients who had received the first course of clarithromycin-containing triple therapy in 2003-2017. Failed eradication was identified by the need of retreatment within 2 years of eradication. Logistic regression model was used to characterize the risk of retreatment. RESULTS: 113,526 H. pylori-infected patients were included. The overall failure rate increased from 4.83% in 2003 to 10.2% in 2016 (p for linear trend <0.001). When stratified by age of eradication, patients 75 years or above had the lowest retreatment rate of 5.11%, which progressively increased in younger patients (60-74 years: OR 1.26, 95% CI 1.15-1.38; 45-59 years: OR 1.36, 95% CI 1.24-1.48; 18-44 years: OR 1.55, 95% CI 1.41-1.69). The results remained consistent when stratified by year of birth, and period of eradication. Other risk factors for retreatment included female (OR 1.24, 95% CI 1.18-1.30), triple therapy containing metronidazole (OR 2.30, 95% CI 2.12-2.50), and shorter duration of therapy (10 days: OR 0.88, 95% CI 0.79-0.97; 14 days: OR 0.67, 95% CI 0.58-0.77 vs 7 days). CONCLUSIONS: While failure rates of clarithromycin-containing triple therapy progressively increased over the past 15 years, the failure rate was particularly high among younger patients, which could undermine the potential benefits of early H. pylori eradication.

Timing of prior exposure to antibiotics and failure of Helicobacter pylori eradication: a population-based study.

BACKGROUND: The success rate of conventional Helicobacter pylori eradication therapy is declining, due to rising antibiotic resistance. OBJECTIVES: To determine the temporal effects of prior antibiotic exposure on eradication outcome. PATIENTS AND METHODS: This is a retrospective cohort study including all H. pylori-infected patients who received their first course of clarithromycin-containing triple therapy in 2003-18. Prior antibiotic exposures before H. pylori eradication therapy (up to 180 days, 1 year or 3 years) were retrieved. A logistic regression model was used to evaluate the association between different timings of previous antibiotic exposure, recent (within 30/60 days) or distant period, and the need for retreatment for H. pylori. RESULTS: A total of 120 787 H. pylori-infected patients were included. Prior exposure to any antibiotics within 180 days was associated with a higher risk of retreatment (OR 1.18, 95% CI 1.13-1.24) and the risk progressively increased with longer duration of antibiotic use. The results were consistent for prior exposure up to 1 year (OR 1.26, 95% CI 1.20-1.31) or 3 years (OR 1.30, 95% CI 1.25-1.35). However, when compared with those without prior antibiotic exposure, recent exposure (within 30 days) did not increase the risk of retreatment, which was consistent for analysis with prior antibiotic exposure up to 3 years. Notably, recent use of cephalosporins within 30/60 days and nitroimidazole within 30 days had significantly lower risks of retreatment. CONCLUSIONS: Any prior antibiotic exposure increased the risk of treatment failure of clarithromycin-containing triple therapy. Recent exposures to some classes of antibiotics may paradoxically increase treatment success.

Reduced hepatic steatosis is associated with higher risk of hepatocellular carcinoma in chronic hepatitis B infection.

BACKGROUND: Concomitant chronic hepatitis B infection (CHB) and non-alcoholic fatty liver disease (NAFLD) is common, but the implications of NAFLD on clinical outcomes of CHB, including hepatocellular carcinoma (HCC), are not well-investigated. METHODS: CHB patients were recruited for transient elastography assessment for liver stiffness (LS), and controlled attenuation parameter (CAP), a non-invasive quantification of hepatic steatosis, and were prospectively followed up for development of HCC. Steatosis and severe steatosis were diagnosed by CAP ≥ 248 dB/m and ≥ 280 dB/m respectively, and advanced fibrosis/cirrhosis was diagnosed by LS ≥ 9 kPa. The independent effect of hepatic steatosis on HCC was examined via propensity score matching (PSM) of LS and other significant clinical variables. RESULTS: Forty-eight patients developed HCC among 2403 CHB patients (55.6% male, median age 55.6 years, 57.1% antiviral-treated, median ALT 26 U/L) during a median follow-up of 46.4 months. Multivariate Cox regression analysis showed age (HR 1.063), male (HR 2.032), Albumin-Bilirubin score (HR 2.393) and CAP (HR 0.993) were associated with HCC development. The cumulative probability of HCC was 2.88%, 1.56% and 0.71%, respectively for patients with no steatosis, mild-to-moderate steatosis, and severe steatosis, respectively (p = 0.01). The risk of HCC increased from 1.56 to 8.89% in patients without severe steatosis if advanced fibrosis/cirrhosis was present (p < 0.001). PSM yielded 957 pairs of CHB patients and hepatic steatosis was independently associated with HCC (HR 0.41). CONCLUSION: Reduced hepatic steatosis was significantly associated with a higher risk of incident HCC in CHB infection. Routine CAP and LS measurements are important for risk stratification.

Divergent trends of hospitalizations for upper and lower gastrointestinal bleeding based on population prescriptions of aspirin, proton pump inhibitors and Helicobacter pylori eradication therapy: Trends of upper and lower gastrointestinal bleeding.

BACKGROUND: With the increasing use of medications that alter the risk of gastrointestinal bleeding (GIB), comprising aspirin, proton pump inhibitors (PPIs), and Helicobacter pylori eradication therapies, the trends of GIB are evolving. OBJECTIVE: The aim of this study is to determine and predict the trends of GIB and to evaluate the effects of population prescriptions of these medications on GIB incidences. METHODS: We retrieved patients hospitalized for GIB in all public hospitals in Hong Kong between 2009 and 2019. Monthly age- and sex-standardized GIB data were fitted and predicted, based on population prescriptions of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), anticoagulants, other antiplatelet drugs, PPIs, and H. pylori therapies, using autoregressive integrated moving average model for time series analysis. RESULTS: The incidence of upper GIB (UGIB) showed a clear declining trend while lower GIB (LGIB) decreased slightly. Older population (>80 years) had the greatest decline in UGIB but was associated with an increase in LGIB. Prescriptions of PPIs and aspirin increased significantly with time. PPIs prescriptions were negatively associated with UGIB incidence (coefficient log(PPIs) -4.58; 95% confidence interval [CI]: -5.69, -3.47). H. pylori eradication in the previous month showed a nonsignificant trend on UGIB (coefficient -0.14; 95% CI: -0.30, 0.02). In contrast, aspirin increased the incidences of UGIB (coefficient 0.06; 95% CI: 0.04, 0.07) and LGIB (coefficient 0.04; 95% CI: 0.03, 0.05). NSAIDs, anticoagulants, and other antiplatelet drugs were not significantly associated with the trend of either UGIB or LGIB. UGIB is predicted to decline continuously but LGIB is projected to rise, particularly with increasing use of aspirin. CONCLUSIONS: UGIB incidences were decreasing and had been surpassed by LGIB. Based on population prescriptions of aspirin and PPIs, divergent trends of upper and lower GIB are expected, especially in elderly.

Nonaspirin nonsteroidal anti-inflammatory drugs and gastric cancer risk after Helicobacter pylori eradication: A territory-wide study.

BACKGROUND: Despite Helicobacter pylori (HP) eradication, individuals can still develop gastric cancer (GC). Prior studies have demonstrated that nonaspirin nonsteroidal anti-inflammatory drugs (NA-NSAIDs) reduce the risk of GC, but this may be caused by immortal time bias and failure to adjust for HP status. The objective of this study was to investigate whether NA-NSAIDs reduced the risk of GC in patients who undergo H. pylori eradication. METHODS: Adult patients who had received clarithromycin-based triple therapy between 2003 and 2016 were identified from a territory-wide health care database. Exclusion criteria included prior GC or GC diagnosed <6 months after HP eradication, prior gastrectomy, gastric ulcer after HP eradication, and failure of triple therapy. Covariates included age, sex, prior peptic ulcer disease, other comorbidities, and concurrent medications (aspirin, proton pump inhibitors, statins, and metformin). To avoid immortal time bias, NA-NSAID use (≥90 days) was treated as a time-dependent variable in a multivariable Cox model (time-dependent analysis). Time-independent analysis was also performed. RESULTS: During a median follow-up of 8.9 years (interquartile range, 5.4-12.6 years), 364 of 92,017 patients (0.4%) who underwent HP eradication developed GC. NA-NSAID use was associated with a significant reduction in the risk of GC in time-fixed analysis (adjusted hazard ratio [aHR], 0.65; 95% CI, 0.47-0.90), but not in time-dependent multivariable analysis (aHR, 1.35; 95% CI, 0.97-1.87). Time-dependent subgroup analyses also did not indicate any significant association between NA-NSAID use and either cardia GC (aHR, 0.75; 95% CI, 0.27-2.06) or noncardia GC (aHR, 1.28; 95% CI, 0.83-1.98). CONCLUSIONS: NA-NSAID use was not associated with a reduced risk of GC among patients who underwent HP eradication. The chemopreventive effect of NA-NSAIDs observed in prior studies may have been confounded by immortal time bias.

Applications of machine learning models in the prediction of gastric cancer risk in patients after Helicobacter pylori eradication.

BACKGROUND: The risk of gastric cancer after Helicobacter pylori (H. pylori) eradication remains unknown. AIM: To evaluate the performances of seven different machine learning models in predicting gastric cancer risk after H. pylori eradication. METHODS: We identified H. pylori-infected patients who had received clarithromycin-based triple therapy between 2003 and 2014 in Hong Kong. Patients were divided into training (n = 64 238) and validation sets (n = 25 330), according to period of eradication therapy. The data were used to construct seven machine learning models to predict risk of gastric cancer development within 5 years after H. pylori eradication. A total of 26 clinical variables were input into these models. The performances were measured by the area under receiver operating characteristic curve (AUC) analysis. RESULTS: During a mean follow-up of 4.7 years, 0.21% of H. pylori-eradicated patients developed gastric cancer. Of the seven machine learning models, extreme gradient boosting (XGBoost) had the best performance in predicting cancer development (AUC 0.97, 95%CI 0.96-0.98), and was superior to conventional logistic regression (AUC 0.90, 95% CI 0.84-0.92). With the XGBoost model, the number of patients considered at high risk of gastric cancer was 6.6%, with miss rate of 1.9%. Patient age, presence of intestinal metaplasia, and gastric ulcer were the heavily weighted factors used by the XGBoost. CONCLUSION: Based on simple baseline patient information, machine learning model can accurately predict the risk of post-eradication gastric cancer. This model could substantially reduce the number of patients who require endoscopic surveillance.

Calcium channel blockers are associated with lower gastric cancer risk: A territory-wide study with propensity score analysis.

Prior studies showed that calcium channel blockers (CCBs) could modify cancer risk, but data on gastric cancer (GC) are limited. We aimed to investigate whether CCBs could modify GC risk in Helicobacter pylori-eradicated patients. H pylori-infected patients with hypertension who are aged ≥50 and had received clarithromycin-based triple therapy between 2003 and 2016 were identified from a territory-wide healthcare database. Patients with eradication failure, GC diagnosed within 6 months after HP eradication, and gastric ulcer were excluded. Time-fixed Cox model with one-to-one propensity score matching was used to calculate hazard ratio (HR) of GC with CCBs. Sensitivity analysis using time-dependent multivariable Cox model in which CCB use was treated as time-varying covariate was also performed to address immortal time bias. 17 622 (29.6%) H pylori-eradicated patients with hypertension were included. During a median follow-up of 8.6 years, 105 (0.6%) developed GC. After PS matching, CCBs were associated with a lower GC risk (HR: 0.56; 95% CI: 0.32-0.97). Time-dependent analysis showed consistent result (aHR: 0.50; 95% CI: 0.33-0.75). A longer duration of CCB use was associated with even lower GC risk (adjusted HR [aHR]: 0.69; 95% CI: 0.61-0.79 for every 1-year increase in use). Long-acting CCBs (aHR: 0.47; 95% CI: 0.29-0.76) and dihydropyridines (aHR: 0.49; 95% CI: 0.32-0.73) conferred greater benefit than short-acting ones (aHR: 0.60; 95% CI: 0.36-1.03) and nondihydropyridines (aHR: 0.76; 95% CI: 0.24-2.48). The aHR was 0.57 (95% CI: 0.34-0.97) for noncardia and 0.59 (95% CI: 0.27-1.31) for cardia cancer. Use of CCBs was associated with lower risk of GC development in H pylori-eradicated patients, in a duration- and dose-response manner.

Comparison of laparoscopic versus open gastrectomy for gastric cancer.

BACKGROUND: This study aimed to compare the short-term and long-term outcomes of laparoscopic gastrectomy (LG) and open gastrectomy (OG) for gastric cancer in a tertiary referral center in Hong Kong. METHODS: Two hundred and ninety-four consecutive patients with gastric cancer who underwent radical gastrectomy with curative intent between January 2008 and December 2015 were analyzed. Data was prospectively collected and reviewed. Propensity score matching was applied at a ratio of 1:1 to compare the OG and LG groups. RESULTS: After propensity score matching, operation duration (294.7 vs 231.8min, P < 0.01) was significantly longer while estimated blood loss (191.6 vs 351.0 ml, P = 0.01) was significantly less in LG group compared with OG. There were no significant differences in postoperative complications and mortality between LG and OG groups (postoperative complication rate, 35.2% vs 40.7%, P = 0.69; 90-day mortality rate, 1.9% vs 3.7%, P = 1.00). Three-year OS and 3-yr DFS of patients who underwent LG was not inferior to that of patients who had OG (P = 0.34; P = 0.51). However, there were significantly more peritoneal recurrences among the OG group than LG group (P < 0.01). CONCLUSIONS: LG has comparable outcomes for gastric cancer, even in advanced tumors. We could appropriately increase the proportion of laparoscopic gastrectomy for gastric cancer.

Impact of Extracapsular Extension of Lymph Node in Adenocarcinoma of the Stomach.

BACKGROUND: Extracapsular extension (ECE) of lymph node may have important prognostic impact for patients with adenocarcinoma of the stomach, but it generally is ignored in staging systems and prognostic models. This study aimed to examine the impact that ECE of lymph node has on prognosis for patients with adenocarcinoma of the stomach. METHODS: The study analyzed 321 consecutive patients with gastric cancer who underwent radical gastrectomy between January 2008 and December 2015. None of these patients had distant metastases. Lymph node metastases were found in 187 patients. The ECE grade was evaluated according to the previously described system used in head and neck cancers. Deposits of cancer cells in sub-serosal fat without a recognizable lymph node were classified as ECE grade 4. Survival outcomes were compared using Kaplan-Meier and Cox regression analyses. A nomogram was constructed using identified significant prognostic factors. The predictive accuracy and model performance were measured by the concordance index (C-index). RESULTS: Patients with ECE(+) showed significantly worse 3-year overall survival (OS) and disease-free survival (DFS) than those without ECE. In the sensitivity analysis, ECE had independent prognostic value for both 3-year OS and 3-year DFS, whereas ECE grading showed little impact on mortality trend or disease progression trend. The ECE-based nomogram showed a significantly higher C-index than the pathological tumor and node staging (pTN) staging system. CONCLUSIONS: The adverse prognostic impact of ECE was validated. Sub-serosal tumor deposits without recognizable lymph node tissue are recommended for inclusion in the ECE definition. A nomogram involving ECE could provide better individual prediction of survival for patients with lymph node-positive gastric cancer.

Effects and mechanism of Lanthanum Citrate on the proliferation and apoptosis of hepatocellular carcinoma cell line SMMC-7721.

BACKGROUND/AIMS: To investigate the effect and the possible mechanism of lanthanum citrate on the proliferation and apoptosis of human hepatocellular carcinoma (HCC) cell line SMMC-7721 through the Hedgehog (Hh) signaling pathway. MATERIALS AND METHODS: Different concentrations of lanthanum citrate and KAAD-cyclopamine (the Hh signaling pathway representative inhibitor) were used to treat SMMC-7721 cells. Cell proliferation was detected using Methylthiazolyldiphenyl-tetrazolium bromide (MTT) assays. Cell apoptosis was detected using flow cytometry analysis of Annexin V-FITC/ propidium iodide (PI). The protein expressions of regulatory genes, such as cell cycle protein D1 (CyclinD1), cyclin-dependent kinase inhibitor 1 (p21), cysteinyl aspartate specific proteinase 3 (Caspase-3), B-cell lymphoma-2 (Bcl-2), glioma-associated oncogene homolog 1 (Gli1), and sonic hedgehog (Shh) were quantified using Western blot assays. The mRNA expressions of Gli1 and Shh were tested using quantitative real-time polymerase chain reaction (qRT-PCR) assays and the protein expressions of Gli1 and Shh were determined using immunofluorescence assays. RESULTS: The Annexin V-FITC and PI double staining results revealed that the 0.1 mM lanthanum citrate group and the 15 µM KAAD-cyclopamine group had both increased the apoptosis rate of SMMC-7721 cells. Both lanthanum citrate and KAAD-cyclopamine downregulated the protein expressions of CyclinD1, Bcl-2, Gli1, and Shh and upregulated the protein expressions of p21 and Caspase-3. Additionally, the immunofluorescence results revealed that the protein expressions of Gli1 and Shh were significantly decreased in both the lanthanum citrate group and the KAAD-cyclopamine group compared to the control group. CONCLUSION: Lanthanum citrate inhibits proliferation and promotes apoptosis in HCC SMMC-7721 cells by suppressing the Hh signaling pathway.

The expressions of Hedgehog and PI3K-AKT pathway components correlate with invasion and metastasis in hepatocellular carcinoma.

OBJECTIVE: To investigate the expression and clinical significance of Shh, Gli1, FAK, p-FAK and p-AKT in HCC. METHODS: Immunohistochemistry was used to measure Shh, Gli1, FAK, p-FAK, and p-AKT expressions in 50 cases of HCC and paracancerous tissues. The Shh, Gli1, and FAK mRNA levels were determined by qRT-PCR in 20 HCCs. The correlations between the expressions of these target genes and the clinicopathological factors were analyzed in HCC. RESULTS: The immunohistochemical results showed that the expressions of Shh, Gli1, FAK, p-FAK, and p-AKT in 50 HCC tissues were significantly higher than those of the paracancerous tissues (P < 0.05). Shh and p-FAK expressions were associated with portal vein invasion, capsular integrity, and distant metastasis (P < 0.05). Gli1, FAK, and p-AKT expressions were closely related to tumor diameter, tumor differentiation, portal vein invasion, capsular integrity, TNM stage and distant metastasis (P < 0.05). Shh was related to Gli1 and p-FAK (r = 0.67, 0.30; P = 0.00, 0.03), Gli1 was positively related to p-FAK and p-AKT (r = 0.52, 0.49; P = 0.00, 0.00), and there was a positive correlation between p-FAK and p-AKT (r = 0.36, P = 0.00). Furthermore, the Shh, Gli1, and FAK mRNA levels in the HCC tissues were significantly higher than those in the paracancerous tissues (P < 0.0001), and the high TNM stages (III and IV) or distant metastasis were significantly higher than those in the low TNM stages (I and II) (P < 0.05) or without distant metastasis (P < 0.05). CONCLUSION: In HCC, the Hh and PI3K-AKT signaling pathways are both abnormally activated, and Shh, Gli1, FAK, p-FAK and p-AKT can serve as indicators to predict the prognosis of liver cancer.

Time-Varying Effects of Marital Status on Gastric Cancer: A Population-Based Study.

BACKGROUND: Although prior studies have shown that marital status affects the prognosis of patients with gastric cancer, its time-varying effects are not well understood. We aimed to investigate the changes in marital status' impact over a 10-year follow-up time among patients with gastric cancer (GC) in the United States. MATERIALS AND METHODS: All patients with gastric cancer diagnosed between 2004 and 2008 in the Surveillance, Epidemiology, and End Results (SEER) database were retrieved. Married patients and unmarried patients (single, separated, divorced or widowed) with complete survival time were selected for comparisons. A total of 14,545 patients who had clinical data and follow-up information available were enrolled. We used Kaplan-Meier analyses and time-dependent flexible parametric models to estimate time-varying hazard ratios (HRs). RESULTS: Unmarried GC patients had worse overall and cancer-specific survival compared with married patients (log-rank test: P < 0.001 and P < 0.001, respectively). The time-varying analysis found that unmarried patients had a significantly higher risk of overall mortality during the 10-year follow-up time, with the lowest adjusted hazard ratio (HR) at 12 months after diagnosis (HR at 12 months, 1.08; 95% CI, 1.03-1.15). For cancer-specific mortality, the time-varying adjusted HR of unmarried patients was significantly higher initially (HR at 12 months, 1.08; 95% CI, 1.02-1.14) but decreased to null after 20 months (HR at 24 months = 1.04; 95% CI = 0.99-1.11). CONCLUSION: Unmarried patients had a higher risk of cancer-specific mortality during the 20 months after gastric cancer diagnosis, which may be an appropriate time frame for intervention.

Long-term outcomes of laparoscopic versus open D2 gastrectomy for advanced gastric cancer.

BACKGROUND: Technical safety and short-term surgical outcomes of laparoscopy-assisted gastrectomy (LAG) for advanced gastric cancer (AGC) have been investigated in many clinical trials. However, studies with large sample size and sufficient follow-up comparing LAG and open gastrectomy (OG) for AGC have seldom been reported. The purpose of this study was to compare the long-term outcomes of LAG versus open OG for AGC using a propensity score matching analysis. METHODS: We retrospectively evaluated 459 and 856 patients who underwent LG or OG with D2 lymph node dissection, respectively, for AGC between June 2007 and June 2012. One-to-one propensity score matching was performed to compensate for heterogeneity between groups. We compared long-term outcomes between the two groups after propensity score matching. RESULTS: In the propensity score-matched cohort, no significant differences were observed in 5-year overall survival (OS) (52.0% vs. 53.4%; P = 0.805) and disease-free survival (DFS) (46.8% vs. 47.3%; P = 0.963) between the LAG group and OG group. Stratified analysis showed that the 5-year OS and DFS rates were comparable between the two groups in each tumor stage (P > 0.05). Multivariate analysis revealed that the operation method was not an independent prognostic factor for OS or DFS. Further analysis showed that the recurrence pattern was similar between the LAG group the OG group (P > 0.05). CONCLUSION: LAG is a feasible surgical procedure for AGC in terms of long-term prognosis, although the results should be confirmed by the ongoing randomized controlled trials.

Robotic versus laparoscopic gastrectomy with D2 lymph node dissection for advanced gastric cancer: a propensity score-matched analysis.

BACKGROUND: Robotic gastrectomy (RG) is a new surgical method alternative for gastric cancer. However, few studies have evaluated the outcomes of RG for advanced gastric cancer (AGC). Thus, the aim of this study was to compare the short-and long-term outcomes of RG and laparoscopic gastrectomy (LG) with D2 lymph node dissection for AGC. PATIENTS AND METHODS: We retrospectively evaluated 454 patients with AGC who underwent RG or LG with D2 lymph node dissection for AGC between August 2013 and March 2017. The short-and long-term outcomes were compared between the propensity score-matched groups. RESULTS: The RG group was associated with longer operation time, less intraoperative blood loss, and higher hospital cost. Additionally, there was a tendency favoring RG in terms of number of harvested lymph nodes, time to first flatus, time to first start diet, and postoperative hospital stay, although the differences were not statistically significant. The overall postoperative complication rate was 13.4% and 11.6% in the RG and LG groups, respectively, with no significant difference (P=0.686). The 3-year overall survival and recurrence rates of the RG and LG groups were also comparable (78.6% vs 74.1%, P=0.483; 18.8% vs 21.4%, P=0.617; respectively). CONCLUSION: RG with D2 lymph node dissection is safe and feasible for AGC in terms of both short- and long-term outcomes. High-volume randomized controlled trials with sufficient follow-up are needed to confirm this rationale.

[Effect of lymphatic vascular invasion on the prognosis of stage I( gastric cancer patients after radical gastrectomy].

OBJECTIVE: To investigate the prognostic value of lymphatic vascular invasion (LVI) for stage I( gastric cancer patients after radical gastrectomy. METHODS: Clinicopathological and intact follow-up data of 469 stage I( gastric cancer patients who underwent radical gastrectomy with R0 resection and were pathologically proven as gastric adenocarcinoma without other malignancy at the Department of Digestive Surgery, The First Affiliated Hospital, The Fourth Military Medical University between February 2009 and December 2012 were retrospectively collected. Chi square test was used to examine the relationship between LVI and clinicopathological data; Log-rank test was used for survival analysis; Cox proportional hazards model was used for univariate and multivariate analysis to explore the prognostic influence of LVI on stage I( gastric cancer patients. RESULTS: A total of 469 patients were enrolled, including 360 male (76.8%) and 109 female patients (23.2%). Median age was 58(25-82) years. There were 114 T1a cases (24.3%), 195 T1b cases (41.6%), and 160 T2 cases (34.1%). There were 439 (93.6%) cases without lymph node metastasis and 30 cases with lymph node metastasis. Presence of LVI was found in 52 patients (11.1%). LVI was closely associated with tumor grade, depth of invasion and status of lymph node metastasis (all P<0.05), rather than gender, age, tumor location and tumor diameter (all P>0.05). LVI detection rate was higher in poorly differentiated and undifferentiated group (14.3%, 32/223) than that in moderately and well differentiated group (8.1%, 20/246) (χ2=4.590, P=0.032). LVI detection rate was higher in T2 (14.4%, 23/160) and T1b (13.3%, 26/195) group than that in T1a group (2.6%,3/114)(χ2=11.020, P=0.004). LVI detection rate was higher in patients with lymph node metastasis (30.0%, 9/30) compared to those without lymph node metastasis (9.8%, 43/439) (χ2=11.629, P=0.001). Median follow-up time was 63(3-74) months. There were totally 46 deaths (9.8%). The 5-year overall survival rate was 90.2%. The 5-year overall survival rate was 82.7% in patients with LVI and 91.1% without LVI, which was significantly different (P=0.039). Univariate analysis showed that age (P=0.012), AJCC T stage (8th edition) (P=0.011), and LVI (P=0.043) were closely associated with the prognosis of gastric cancer patients, while gender, tumor location, tumor diameter, tumor grade, lymph node metastasis or postoperative chemotherapy were not associated to the prognosis (all P>0.05). Multivariate analysis revealed that only age(HR=2.038, 95%CI:1.126 to 3.686, P=0.019) and advanced T stage (T1b: HR=1.427, 95%CI:0.554 to 3.678; T2: HR=2.926, 95%CI:1.199 to 7.140; P=0.017) were independent prognostic factors of stage I( gastric cancer patients (both P<0.05). CONCLUSIONS: LVI is not an independent prognostic factor of stage I( gastric cancer patients. In clinical practice, we should consider adjuvant chemotherapy prudently for stage I( gastric cancer patients with LVI.