Protective effects of statins on the incidence of NAFLD-related decompensated cirrhosis in T2DM.

BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome and poses a significant threat to patients with type 2 diabetes mellitus (T2DM) and metabolic dysregulation. Statins exert anti-inflammatory, antioxidative and antithrombotic effects that target mechanisms underlying NAFLD. However, the protective effects of the different doses, intensities and types of statins on the incidence of NAFLD-related decompensated liver cirrhosis (DLC) in patients with T2DM remain unclear. METHODS: This study used the data of patients with T2DM who were non-HBV and non-HCV carriers from a national population database to examine the protective effects of statin use on DLC incidence through propensity score matching. The incidence rate (IR) and incidence rate ratios (IRRs) of DLC in patients with T2DM with or without statin use were calculated. RESULTS: A higher cumulative dose and specific types of statins, namely rosuvastatin, pravastatin, atorvastatin, simvastatin and fluvastatin, reduced the risk of DLC in patients with T2DM. Statin use was associated with a significant reduction in the risk of DLC (HR: .65, 95% CI: .61-.70). The optimal daily intensity of statin use with the lowest risk of DLC was .88 defined daily dose (DDD). CONCLUSIONS: The results revealed the protective effects of specific types of statins on DLC risk in patients with T2DM and indicated a dose-response relationship. Additional studies are warranted to understand the specific mechanisms of action of different types of statins and their effect on DLC risk in patients with T2DM.

A simple and effective technique for laparoscopic gastrorrhaphy: modified Graham's patch with barbed suture.

INTRODUCTION: Peptic ulcers are caused by unbalanced acid production, and proton pump inhibitors (PPIs) in recent decades have helped to treat peptic ulcers effectively. Meanwhile, the incidence of perforated peptic ulcer (PPU) persists and has a high mortality rate if there is no adequate management. Primary closure with a modified Graham's patch was well performed in early detected PPU with a small size < 2 cm. A laparoscopic approach for PPU was prescribed for decades with proven feasibility and safety. We introduced an effective technique combined with barbed suture and modified Graham's patch, which can significantly reduce the surgical time without significantly increasing morbidity and mortality compared with traditional interrupted suture. PATIENTS AND METHOD: We retrospectively collected data from January 2014 to December 2020 in Keelung Change Gung Memorial Hospital, and a total of 154 patients receiving laparoscopic repair of PPU were included. There were 59 patients in the V-loc group (V group) and 95 patients in the laparoscopic primary repair group (P group). RESULTS: The V group had a significantly shorter operation time than the P group (96.93 ± 22.14 min vs. 123.97 ± 42.14, P < 0.001). Ten patients suffered from morbidity greater than the Clavien‒Dindo classification 4 (5 from V group, and 5 from P group). Three patients with leakage were reported. Two patients were in the V group, and one patient was in the P group (p = 0.432). CONCLUSION: Laparoscopic repair with barbed suture and modified Graham's patch provides a simple and effective technique in the management of acute abdomen. This technique can be easily performed by experienced surgeons and trainees in minimally invasive surgery without affecting patient safety.

Should we change the treatment plan in early hepatocellular carcinoma with chronic kidney disease?

BACKGROUND: Chronic kidney disease (CKD) has been considered to be a poor prognostic factor for hepatocellular carcinoma (HCC). However, few studies have focused on early HCC and the impact of CKD on survival, which should be considered in curative treatment for early HCC. MATERIALS AND METHODS: Patients with BCLC stage 0/A were enrolled from 2009 to 2019. A total of 383 patients were divided into Control group and CKD group, based on estimated glomerular filtration rate. Overall survival (OS) and disease-free survival (DFS) of different treatments were determined using the Kaplan-Meier method. RESULTS: The Control group had a significantly better OS than the CKD group (72.6 months vs. 56.7 months; p = 0.003). DFS was similar between the groups (62.2 months vs. 63.8 months, p = 0.717). In the Control group, the surgically treated (OP) group had significantly superior OS (65.0 months vs. 80.0 months, p = 0.014) and DFS (50.9 months vs. 70.2 months, p = 0.020) than the radiofrequency ablation-treated group. In the CKD group, the OP group showed a survival advantage in OS (70.6 months vs. 49.2 months, p = 0.004), while DFS was similar between treatment groups (56.0 months vs. 62.2 months, p = 0.097). CONCLUSION: CKD should not be considered to be a poor prognostic factor in early HCC patients. Moreover, hepatectomy should be carried out in CKD patient with early HCC for better prognosis if feasible.

Bis-benzylidine Piperidone RA190 treatment of hepatocellular carcinoma via binding RPN13 and inhibiting NF-κB signaling.

BACKGROUND: According to GLOBOSCAN, hepatocellular carcinoma (HCC) claimed 782,000 lives in 2018. The tyrosine kinase inhibitor sofafenib is used to treat HCC, but new anticancer agents targeting different pathways are urgently needed to improve outcomes for patients with advanced disease. The aberrant metabolism and aggressive growth of cancer cells can render them particularly susceptible to proteasome inhibition, as demonstrated by bortezomib treatment of multiple myeloma. However, resistance does emerge, and this 20S proteasome inhibitor has not proven active against HCC. The bis-benzylidine piperidone RA190 represents a novel class of proteasome inhibitor that covalently binds to cysteine 88 of RPN13, an ubiquitin receptor subunit of the proteasome's 19S regulatory particle. RA190 treatment inhibits proteasome function, causing rapid accumulation of polyubiquitinated proteins. Considerable evidence suggests that nuclear factor κB (NF-κB) signaling, which is dependent upon the proteasome, is a major driver of inflammation-associated cancers, including HCC. METHODS: Human HCC cell lines were treated with titrations of RA190. The time course of endoplasmic reticulum stress and NF-κB-related mechanisms by which RA190 may trigger apoptosis were assessed. The therapeutic activity of RA190 was also determined in an orthotopic HCC xenograft mouse model. RESULTS: RA190 is toxic to HCC cells and synergizes with sofafenib. RA190 triggers rapid accumulation of polyubiquitinated proteins, unresolved endoplasmic reticulum stress, and cell death via apoptosis. RA190 blocks proteasomal degradation of IκBα and consequent release of NF-κB into the nuclei of HCC cells. Treatment of mice bearing an orthotopic HCC model with RA190 significantly reduced tumor growth. CONCLUSIONS: RA190 has therapeutic activity in a xenograft model, and with sorafenib exhibited synergetic killing of HCC cells in vitro, suggesting further exploration of such a combination treatment of HCC is warranted.

Prognostic impact and risk factors of low body mass index in patients undergoing liver transplantation.

We aimed to investigate the effect of body mass index (BMI) on the overall survival rates and to identify the risk factors associated with adverse outcomes. A total of 381 adult-to-adult living donor liver transplantations performed were retrospectively analyzed. These patients were classified according to the BMI categories established by the World Health Organization: The underweight group (BMI<18.5 kg/m2 ) and the non-underweight group (BMI≥18.5 kg/m2 ). The underweight group had significantly worse outcomes, compared with that of the non-underweight group (5-year overall survival: 45.6% vs 74.6%, P<.001). Underweight patients with CD4/CD8 ratio <1.4 had a significant worse prognosis, compared with those with CD4/CD8 ratio ≥1.4. (The 1-, 3-, and 5-year overall patient survival rates in both groups were 71.0% vs 20%, 58.9% vs 0%, and 53.6% vs 0%, respectively, P=.002.) In the multivariate analysis, only CD4/CD8 ratio <1.4 was an independent poor prognostic factor (hazard ratio=7.063, 95% confidence interval=1.329-37.547, P=.022). CONCLUSIONS: Pre-operative CD4/CD8 ratio <1.4 is an independent poor prognostic indicator for underweight patients undergoing liver transplantation. Early intervention in replenishing the nutrient deficit and cautious use of immunosuppressive regimens are essential to prepare this high-risk population for a more successful liver transplantation.

Unraveling Postoperative Bleeding Dynamics in Laparoscopic Roux-en-Y Gastric Bypass: Insights from a Single-Center Tranexamic Acid Study.

BACKGROUND: The efficacy of postoperative tranexamic acid (TXA) administration in mitigating bleeding after primary laparoscopic Roux-en-Y gastric bypass (RYGB), a prevalent complication associated with significant morbidities and mortality, and the use of sequential laboratory parameter changes in bleeding screening and TXA impact tracking were investigated. METHODS: This retrospective analysis included RYGB patients (aged 18-65 years, with a body mass index of 35-50 kg/m2) over 5 years who were categorized into three groups by evolving treatment regimens: Group A (n = 42) received standard pre- and postoperative enoxaparin (30 mg) every 12 h; Group B (n = 160) received enoxaparin and postoperative TXA (250 mg every 6 h); and Group C (n = 73) received TXA alone. Postoperative bleeding-related adverse events, vital signs, and laboratory changes were compared. RESULTS: Postoperative hemorrhage occurred in 3.6% (10/275) of patients, with no significant intergroup differences. Patients who experienced bleeding had greater decreases in hemoglobin (∆Hb) (2.1 vs. 1.4; p = 0.003), greater ∆Hb > 2 (50% vs. 15%; p = 0.013), and greater use of staples than did those who did not experience bleeding (8 vs. 7; p = 0.001). The ∆Hb values were lower in Groups B (1.4) and C (1.3) than in Group A (1.7, p = 0.011). No significant difference was noted between Groups C and B. CONCLUSION: This study emphasizes the potential of TXA to mitigate postoperative bleeding after RYGB, with no added benefit from excluding enoxaparin. Monitoring patients with a ∆Hb > 2 mg/dl and increased stapler usage is crucial. Further research is needed to validate routine TXA use across different procedures.

Feasibility of split liver transplantation for 2 adults in the model of end-stage liver disease era.

OBJECTIVE: To examine the results of split liver transplantation for 2 adults in the model of end-stage liver disease (MELD) era. BACKGROUND: In the MELD era, liver allografts are first allocated to recipients with the highest MELD scores. However, the application of split liver transplantation for 2 adults in urgent condition has doubled and has become a matter of concern. METHODS: Twenty-one deceased liver grafts were split into full right and full left lobes for 42 adult recipients. One of the hemiliver grafts was allocated to the recipient with the highest MELD score in the waiting list. The results of split liver transplantation were examined and compared with those of living donor liver transplantation. RESULTS: Among 42 recipients, 24 (57.1%) had MELD scores higher than 20. The median (interquartile) MELD score for the recipients with split liver transplantation was 22 (15-30), which was higher than that for the recipients with living donor liver transplantation (P < 0.001). The 1-, 3-, and 5-year survival rates for split liver transplantation were comparable with those of living donor transplantation (P = 0.489). Nevertheless, 10 of 42 split liver recipients died within 3 months after transplantation. By receiver operating characteristic curve analysis, the safe graft-recipient weight ratio was better more than 1% to avoid early patient death for split liver transplantation. CONCLUSIONS: Although most of the recipients with split liver transplantation had high MELD scores, the results were comparable with those of living donor liver transplantation. Split liver transplantation for 2 adults is still feasible in the MELD era.

Intratumoral injection of therapeutic HPV vaccinia vaccine following cisplatin enhances HPV-specific antitumor effects.

Despite the conventional treatments of radiation therapy and chemotherapy, the 5-year survival rates for patients with advanced-stage cervical cancers remain low. Cancer immunotherapy has emerged as an alternative, innovative therapy that may improve survival. Here, we utilize a preclinical HPV-16 E6/E7-expressing tumor model, TC-1, and employ the chemotherapeutic agent cisplatin to generate an accumulation of CD11c+ dendritic cells in tumor loci making it an ideal location for the administration of therapeutic vaccines. Following cisplatin treatment, we tested different routes of administration of a therapeutic HPV vaccinia vaccine encoding HPV-16 E7 antigen (CRT/E7-VV). We found that TC-1 tumor-bearing C57BL/6 mice treated with cisplatin and intratumoral injection of CRT/E7-VV significantly increased E7-specific CD8+ T cells in the blood and generated potent local and systemic antitumor immune responses compared to mice receiving cisplatin and CRT/E7-VV intraperitoneally or mice treated with cisplatin alone. We further extended our study using a clinical grade recombinant vaccinia vaccine encoding HPV-16/18 E6/E7 antigens (TA-HPV). We found that intratumoral injection with TA-HPV following cisplatin treatment also led to increased E7-specific CD8+ T cells in the blood as well as significantly decreased tumor size compared to intratumoral injection with wild type vaccinia virus. Our study has strong implications for future clinical translation using intratumoral injection of TA-HPV in conjunction with the current treatment strategies for patients with advanced cervical cancer.

Effects of H1-Antihistamines on hepatocellular carcinoma risk in patients with type 2 diabetes mellitus.

PURPOSE: H1-antihistamines (AHs) may exert protective effects against cancer. We investigated the association of AH use with hepatocellular carcinoma (HCC) risk in type 2 diabetes mellitus (T2DM) patients without hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. METHODS: The data of patients with T2DM enrolled from Taiwan's National Health Insurance Research Database were examined for the period of January 1, 2008, to December 31, 2018. We used the Kaplan-Meier method and Cox proportional hazards regression to evaluate the AH use-HCC risk association. RESULTS: After 1:1 propensity score matching was performed, the two cohorts were each divided into AH users (n = 47,990) and nonusers (n = 47,990). The risk of HCC was significantly lower in AH users than in AH nonusers (adjusted hazard ratio [aHR]: 0.55 95% confidence interval [95% CI], 0.46 to 0.67; IRR: 0.70; 95% CI, 0.60 to 0.84), respectively. The dose-response relationship between AH use and HCC risk was also observed (aHRs: 0.58, 0.56, 0.50, and 0.41 for 28-35, 36-49, 50-77, and >77 cumulative defined daily doses of AH, respectively). CONCLUSION: AH use can reduce HCC risk in T2DM patients without HBV or HCV infection in a dose-dependent manner.

The influence of the Pringle maneuver in laparoscopic hepatectomy: continuous monitor of hemodynamic change can predict the perioperatively physiological reservation.

Importance: This is the first study to investigate the correlation between intra-operative hemodynamic changes and postoperative physiological status. Design settings and participants: Patients receiving laparoscopic hepatectomy were routinely monitored using FloTract for goal-directed fluid management. The Pringle maneuver was routinely performed during parenchymal dissection and the hemodynamic changes were prospectively recorded. We retrospectively analyzed the continuous hemodynamic data from FloTrac to compare with postoperative physiological outcomes. Exposure: The Pringle maneuver during laparoscopic hepatectomy. Results: Stroke volume variation that did not recover from the relief of the Pringle maneuver during the last application of Pringle maneuver predicted elevated postoperative MELD-Na scores. Conclusions and relevance: The complexity of the hemodynamic data recorded by the FloTrac system during the Pringle Maneuver in laparoscopic hepatectomy can be effectively analyzed using the growth mixture modeling (GMM) method. The results can potentially predict the risk of short-term liver function deterioration.

A late recurring and easily forgotten tumor: ovarian granulosa cell tumor.

Ovarian granulosa cell tumor (GCT) is a malignant tumor with slow progression. The recurrence of granulosa cell tumor often happens after 5 years, leading to a 'forgotten tumor' by the patient. We present the case of a 64-year-old woman with a presentation of left flank pain. An initial computed tomography scan revealed a single tumor with multiple adjacent organ invasions. Surgical intervention was prescribed and the pathological results revealed a metastatic granulosa cell tumor. We also review the literature for the follow-up and further management of this tumor.

Sac transection versus sac reduction during laparoscopic herniorrhaphy: A systematic review and meta-analysis.

Hernia repair techniques have evolved recently; however sac handling remains a critical step. Transection of the herniated sac as opposed to total sac reduction may simplify the procedure. However, residual sac tissue may increase the risk for seroma formation. We performed a systemic review and meta-analysis to evaluate the safety and feasibility of transecting the hernia sac during laparoscopic herniorrhaphy. Relevant literature search was performed in PubMed, EMBASE, SCORPUS, and the Cochrane Library databases. Relevant studies that compared total reduction with transection of the herniated sac during laparoscopic herniorrhaphy were included. The primary outcome measure was the incidence of seromas. We also analyzed secondary outcomes including operative duration, postoperative pain scores, complications, and hernia recurrence rate. Of the 330 studies identified, four studies published between 2002 and 2020, with sample sizes ranging from 70 to 520 patients, met the inclusion criteria. Overall, 848 hernias were evaluated. We observed a high incidence of seroma formation in the sac transection group compared to that in the sac reduction group (OR 2.41; 95% CI 1.39 to 4.17, P = 0.002), but the groups did not differ significantly with respect to factor such as operative duration, postoperative complications, and pain score. Herniated sac transection during laparoscopic herniorrhaphy might be associated with a higher risk of seroma formation than that observed with sac reduction. The former approach did not show any significant benefits compared to the latter approach with respect to operative duration and postoperative complications.

A Novel Predictive Scoring System for 90-Day Mortality among Patients with Hepatocellular Cell Carcinoma Receiving Major Hepatectomy.

PURPOSE: Hepatocellular carcinoma (HCC) is a major malignancy and the common cause of cancer-related deaths. Surgical intervention provides superior long-term survival outcomes; however, perioperative mortality is a major concern for clinicians while making treatment decisions, especially for major hepatectomy. Scoring systems for predicting 90-day mortality in patients with HCC undergoing major hepatectomy are not available. METHODS: This study used the Taiwan Cancer Registry Database that is linked to the National Health Insurance Research Database to analyze data of 60,250 patients with HCC who underwent major hepatectomy and determine risk factors to establish a novel predictive scoring system. By using the stepwise selection of the multivariate Cox proportional hazards model, we divided the patients with HCC undergoing major hepatectomy into four risk groups. RESULTS: The Chang Gung-PohAi predictive scoring system exhibited significant differences in the 90-day mortality rate among the four risk groups (very low risk: 2.42%, low risk: 4.09%, intermittent risk: 17.1%, and high risk: 43.6%). CONCLUSION: The Chang Gung-PohAi predictive scoring system is a promising tool for predicting 90-day perioperative mortality in patients with HCC undergoing major hepatectomy.

Partial Versus Total Omentectomy in Patients with Gastric Cancer: A Systemic Review and Meta-Analysis.

Background: Surgical treatment is the key to cure localized gastric cancer. There is no strong evidence that supports the value of omentectomy. Thus, a meta-analysis was conducted to compare the safety and efficiency of partial and total omentectomy in patients with gastric cancer. Methods: PubMed, Embase, and Cochrane Library databases were searched. All studies that compared total and partial omentectomy as treatments for gastric cancer were included. The primary outcomes were patients' overall survival and disease-free survival, while the secondary outcomes were perioperative outcome and postoperative complications. Results: A total of nine studies were examined, wherein 1043 patients were included in the partial omentectomy group, and 1995 in the total omentectomy group. The partial omentectomy group was associated with better overall survival (hazard ratio: 0.80, 95% CI: 0.66 to 0.98, p = 0.04, I2 = 0%), shorter operative time, and lesser blood loss than the total omentectomy group. In addition, no statistically significant difference was observed in the number of dissected lymph nodes, length of hospital stays, complication rate, and disease-free survival. Conclusions: Our results show that, compared with total omentectomy in gastric cancer surgery, partial omentectomy had non-inferior oncological outcomes and comparable safety outcomes.

Predicting Short-term Survival after Liver Transplantation using Machine Learning.

Liver transplantation is one of the most effective treatments for end-stage liver disease, but the demand for livers is much higher than the available donor livers. Model for End-stage Liver Disease (MELD) score is a commonly used approach to prioritize patients, but previous studies have indicated that MELD score may fail to predict well for the postoperative patients. This work proposes to use data-driven approach to devise a predictive model to predict postoperative survival within 30 days based on patient's preoperative physiological measurement values. We use random forest (RF) to select important features, including clinically used features and new features discovered from physiological measurement values. Moreover, we propose a new imputation method to deal with the problem of missing values and the results show that it outperforms the other alternatives. In the predictive model, we use patients' blood test data within 1-9 days before surgery to construct the model to predict postoperative patients' survival. The experimental results on a real data set indicate that RF outperforms the other alternatives. The experimental results on the temporal validation set show that our proposed model achieves area under the curve (AUC) of 0.771 and specificity of 0.815, showing superior discrimination power in predicting postoperative survival.

Structure-function analyses of candidate small molecule RPN13 inhibitors with antitumor properties.

We sought to design ubiquitin-proteasome system inhibitors active against solid cancers by targeting ubiquitin receptor RPN13 within the proteasome's 19S regulatory particle. The prototypic bis-benzylidine piperidone-based inhibitor RA190 is a michael acceptor that adducts Cysteine 88 of RPN13. In probing the pharmacophore, we showed the benefit of the central nitrogen-bearing piperidone ring moiety compared to a cyclohexanone, the importance of the span of the aromatic wings from the central enone-piperidone ring, the contribution of both wings, and that substituents with stronger electron withdrawing groups were more cytotoxic. Potency was further enhanced by coupling of a second warhead to the central nitrogen-bearing piperidone as RA375 exhibited ten-fold greater activity against cancer lines than RA190, reflecting its nitro ring substituents and the addition of a chloroacetamide warhead. Treatment with RA375 caused a rapid and profound accumulation of high molecular weight polyubiquitinated proteins and reduced intracellular glutathione levels, which produce endoplasmic reticulum and oxidative stress, and trigger apoptosis. RA375 was highly active against cell lines of multiple myeloma and diverse solid cancers, and demonstrated a wide therapeutic window against normal cells. For cervical and head and neck cancer cell lines, those associated with human papillomavirus were significantly more sensitive to RA375. While ARID1A-deficiency also enhanced sensitivity 4-fold, RA375 was active against all ovarian cancer cell lines tested. RA375 inhibited proteasome function in muscle for >72h after single i.p. administration to mice, and treatment reduced tumor burden and extended survival in mice carrying an orthotopic human xenograft derived from a clear cell ovarian carcinoma.

A novel spontaneous hepatocellular carcinoma mouse model for studying T-cell exhaustion in the tumor microenvironment.

Immunotherapy has ushered in a new era of cancer therapy, and this is also applicable to therapy of hepatocellular carcinoma (HCC). In this context, effective development of therapeutic strategies requires an HCC mouse model with known tumor-associated antigens (TAAs) and an HCC growth reporter. We created such a model using hydrodynamic injection and a transposon system to introduce AKT and NRAS and open reading frames (ORFs) encoding surrogate tumor antigens and luciferase into chromosomes of hepatocytes to induce nodular and diffuse tumors in the liver. TAA-specific CD8+ T cells were detected during HCC progression; however, these showed exhausted-like phenotypes and were unable to control tumor growth. Myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAM) from the tumor microenvironment were found to contribute to the suppression of the CD8+ T-cell response. The transposon-based Akt/N-Ras-induced HCC mouse model we developed enables researchers to monitor tumor growth non-invasively and to quantify and characterize endogenous or adoptively transferred TAA-specific CD8+ T-cell responses. These features make it a suitable preclinical model for exploration and evaluation of immune checkpoint inhibitors and cell-based immunotherapies for HCC treatment.

Covalent Rpn13-Binding Inhibitors for the Treatment of Ovarian Cancer.

Substitution of the m,p-chloro groups of bis-benzylidinepiperidone RA190 for p-nitro, generating RA183, enhanced covalent drug binding to Cys88 of RPN13. Treatment of cancer cell lines with RA183 inhibited ubiquitin-mediated protein degradation, resulting in rapid accumulation of high-molecular-weight polyubiquitinated proteins, blockade of NFκB signaling, endoplasmic reticulum stress, an unfolded protein response, production of reactive oxygen species, and apoptotic cell death. High-grade ovarian cancer, triple-negative breast cancer, and multiple myeloma cell lines were particularly vulnerable to RA183. RA183 stabilized a tetraubiquitin-linked firefly luciferase reporter protein in cancer cell lines and mice, demonstrating in vitro and in vivo proteasomal inhibition, respectively. However, RA183 was rapidly cleared from plasma, likely reflecting its rapid degradation to the active compound RA9, as seen in human liver microsomes. Intraperitoneal administration of RA183 inhibited proteasome function and orthotopic tumor growth in mice bearing human ovarian cancer model ES2-luc ascites or syngeneic ID8-luc tumor.