A NOVEL ORALLY BIOAVAILABLE SMALL MOLECULE COMPOUND HJC0416 INHIBITS LIVER FIBROGENESIS THROUGH THE HSP90/NF-κB PATHWAY

Background: The majority of HCC patients within Milan criteria, compete with cirrhosis patients with high MELD for liver transplantation based on an exceptional score which is the calculated MELD at registration, 28 after six months of waiting, 31 after 1 year and thereafter capped at 34 after one and a half years. In competitive UNOS regions, HCC patients may have to wait for more than a year before they receive a transplant. This prolonged waiting can lead to progression of their cancer and/or cirrhosis and loss of candidature for transplantation while may have been acceptable resection candidates at the beginning of their waiting period. In such regions, survival may be better with hepatectomy as it obviates the waiting.

Aim: To compare the survival of HCC patients with single tumor and low Child’s class after liver transplantation or hepatectomy.

Material and Methods: We used the UNOS and NCDB databases to make the comparison. Between 2004 to 2013, 13, 519 patients with HCC were registered for liver transplantation in the US. Of them 5, 338 were of Child’s class A; sufficient tumor details were available for 2,726 cases allowing us to select cases with single tumor of up to 5 cm size and within Milan criteria were included in the study. The NCDB database does not record preoperative staging information. Therefore, we selected patients with single tumor of up to 5 cm in size at the time of diagnosis and without major vascular invasion at pathologic staging after partial hepatectomy. 2, 507 patients were included. We assumed that these patients were Child’s class A or early B as the NCDB does not record CPT score . AKaplan-Meier survival analysis was performed. We used intention to treat principles and included all patients registered for transplantation whether or not they were transplanted. Survival analysis was was initiated at the time of listing for transplant. Reasons for removal from waiting list were summarized.

Results: The mean age was 58.8 years (std. dev. 7.3) and 77% were male in the transplant (UNOS) arm. The mean age was 62.4 years (std. dev. 11) and 71.8% were male in the hepatectomy (NCDB) arm. Kaplan-Meier survival estimates show that for the first 700 days patients have similar chances of survival. However, as time goes by, patients in the UNOS group experience better survival rates. The Log-rank test for equality of survivor functions, suggests that UNOS patients have better survival rates compared with NCBD (Chi-sq(1) = 83.8, p < 0.001).

Conclusion: In cirrhotic patients with HCC, survival after partial hepatectomy was non-inferior to that after transplantation for the first two years for low Child’s class liver disease. Resection should be strongly considered in eligible patients and this strategy could improve organ allocation.

Introduction
Unplanned care (readmission and emergency room (ER) visits) is a Center for Medicare Services measure of quality of care. Patients who undergo major gastrointestinal (GI) surgery are at high risk for postoperative complications which lead to unplanned care. We implemented a pilot program of postoperative outpatient monitoring using an FDA-approved wearable biometric monitoring device (BMD) to identify patients who suffered setbacks to mitigate severity of significant complications and to facilitate intervention for minor setbacks so as to prevent unplanned care.

Methods
Adult patients who underwent high-risk GI operations from the colorectal and hepatopancreatobiliary services were prospectively enrolled in a quality improvement remote monitoring project from discharge until 30 days after surgery. The BMD relayed biometric data (temperature, heart rate, respiratory rate, and activity) to a cloud-based monitoring dashboard. Patients with abnormal data (alerts) were contacted and, if necessary, care was escalated to their clinical team. In-hospital death and a home-monitoring period of less than 7 days were exclusion criteria. The primary outcome was rate of avoidance of unplanned care. Secondary outcomes were 30-day ER visit rates, readmission rates, and their associated monitoring device-detection rate.

Results
A total of 129 patients were enrolled but 25 (19.4%) patients were excluded from analysis due to death (n=2) and monitoring <7 days (n=23). Of the 104 patients included in analysis, the average age was 60±13.4 year and 40 (38.5%) patients were female. We contacted 78 (75.0%) patients at least once in response to 192 alerts. In 17 (8.9%) of 192 cases, the setback was managed in the outpatient setting successfully avoiding unplanned care. In 145 (75.5%) cases, escalation was not required and in 37 (19.3%) cases, the patients could not be reached. There were a total of 22 ER visits by 18 (17.3%) patients. Nineteen patients (18.3%) had a total of 24 readmissions of which 5 (20.8%) were direct and not via the ER. BMD alerts resulted in 8 patient (7.7%) escalations that translated to ER visits and/or readmission. In 7 instances (6.7%) gaps in biometric data interfered with our ability to detect setbacks that resulted in unplanned care.

Conclusion
Patients who undergo major gastrointestinal operations can be safely monitored remotely. The technological and logistic complexity of monitoring outpatients are significant and require further optimization. Biometric findings that merit clinical alerts in the postoperative setting require refinement. However, this pilot data suggests remote monitoring has the potential to both reduce unplanned care and assist in detection of clinical deterioration.

Introduction. Chronic inflammation leads to liver fibrosis and, potentially, cirrhosis. Hepatic stellate cell (HSC) activation represents the initial step of liver fibrogenesis since the HSC is the major producer of extracellular matrix (ECM). Understanding the mechanism of inflammation and fibrogenesis is critically important to developing treatments for liver fibrosis. NF-ΚB is a key inflammatory signaling pathway, and the survival of activated HSC was found to be NF-KB dependent. Using a fragment-based drug design approach, our team previously designed and synthesized a group of small molecule compounds for cancer therapy. After screening these molecules in cancer cells and activated HSC In vivo and In vitro, HJC0416 was identified to be a novel, orally bioavailable molecules with potent anti-cancer, anti-inflammatory and anti-fibrotic effects. For example, HJC0416 induced activated HSC cell cycle arrest and apoptosis, inhibited endogenous and TGFβ-stimulated ECM expression. However, the molecular mechanisms of HJC0416’s anti-fibrogenetic effects in HSC remain largely unknown. In this study, we examined the effects of HJC0416 on NF-KB and its associate factor HSP90 in HSC in vitro.
Methods. Activated human HSC line LX-2 was treated with either JHC0416 or 17-AAG, then exposed to TNFα or TGFβ as indicated. Nuclear and cytosolic proteins were isolated for Western blots or immunofluorescence assay.
Results. HJC0416 treatment significantly attenuated TNFα–induced IκBα phosphorylation, NF-KBp65 nuclear translocation and DNA binding activity. Endogenous and TNFα–induced p65 phosphorylation of Ser536 was suppressed by HJC0416. Notably, HJC0416 treatment dose-dependently down-regulated the expression of IKKβ, RIP1 and AKT, FAK, CDK9, all of which are HSP90 interacting proteins, suggesting that HSP90 may be involved in HJC0416 regulated-NF-KB signaling and fibrogenesis in HSC. Our results confirmed that HSP90 specific inhibitor 17-AAG prevented TNFα-induced IκBα phosphorylation and degradation, p65 nuclear translocation and DNA binding. Similar with previous HJC0416 data, 17-AAG inhibited endogenous and TGFβ-stimulated fibrosis markers collagen type I and fibronectin. Conclusion. The anti-fibrogenetic effect of orally bioavailable compound HJC0416 is through the HSP90/NF-KB pathway. HJC0416 may be a promising drug candidate for liver fibrosis treatment.