Hepatocellular carcinoma immunotherapy: The impact of epigenetic drugs and the gut microbiome.

The incidence of hepatocellular carcinoma (HCC) has been increasing for decades. This disease has now risen to become the sixth most common malignancy overall, while ranking as the third most frequent cause of cancer mortality. While several surgical interventions and loco-regional treatment options are available, up to 80% of patients present with advanced disease not amenable to standard therapies. Indeed, traditional cytotoxic chemotherapeutic agents are notoriously ineffective and essentially play no role in the management of affected patients. This has led to an enormous need for more effective systemic therapeutic options. In recent years, immunotherapy has emerged as a potentially viable and exciting new alternative for the treatment of HCC. Although the current immunotherapeutic options remain imperfect, various strategies can be employed to further improve their efficacy. New findings have revealed epigenetic modulation can be effective as a new approach for improving HCC immunotherapy. Studying the gut microbiome (gut-liver axis) can also be an interesting subject in this regard. Here, we explore the latest insights into the role of immunotherapy treatmenting HCC, both mono and in combination with other agents. We also focus on the impact of epigenetic drugs and the microbiome in the overall effectiveness of HCC immunotherapy.

Overexpression of Galectin-1 and Galectin-3 in hepatocellular carcinoma.

Galectins (Gals) are evolutionarily conserved proteins that bind to ß-galactoside containing glycans. Abnormal expression of Gals is associated with the development, progression, and metastasis of different types of cancer. Among the 11 Gals identified in humans, the roles of Gal-1 and Gal-3 have been extensively investigated in various tumors. Here, we summarize the roles of overly expressed Gal-1 and Gal-3 in the pathogenesis of hepatocellular carcinoma (HCC). The overexpression of Gal-1 and Gal-3 correlates with tumor growth, HCC cell migration and invasion, tumor aggressiveness, metastasis, and poor prognosis. A potentially promising future treatment strategy for HCC may include the combination of immunotherapy with Gal-1 inhibition. Additional research is warranted to investigate targeting Gal-1 and Gal-3 for HCC treatment.

Extracorporeal cellular therapy (ELAD) in severe alcoholic hepatitis: A multinational, prospective, controlled, randomized trial.

Severe alcoholic hepatitis (sAH) is associated with a poor prognosis. There is no proven effective treatment for sAH, which is why early transplantation has been increasingly discussed. Hepatoblastoma-derived C3A cells express anti-inflammatory proteins and growth factors and were tested in an extracorporeal cellular therapy (ELAD) study to establish their effect on survival for subjects with sAH. Adults with sAH, bilirubin ≥8 mg/dL, Maddrey's discriminant function ≥ 32, and Model for End-Stage Liver Disease (MELD) score ≤ 35 were randomized to receive standard of care (SOC) only or 3-5 days of continuous ELAD treatment plus SOC. After a minimum follow-up of 91 days, overall survival (OS) was assessed by using a Kaplan-Meier survival analysis. A total of 203 subjects were enrolled (96 ELAD and 107 SOC) at 40 sites worldwide. Comparison of baseline characteristics showed no significant differences between groups and within subgroups. There was no significant difference in serious adverse events between the 2 groups. In an analysis of the intent-to-treat population, there was no difference in OS (51.0% versus 49.5%). The study failed its primary and secondary end point in a population with sAH and with a MELD ranging from 18 to 35 and no upper age limit. In the prespecified analysis of subjects with MELD < 28 (n = 120), ELAD was associated with a trend toward higher OS at 91 days (68.6% versus 53.6%; P = .08). Regression analysis identified high creatinine and international normalized ratio, but not bilirubin, as the MELD components predicting negative outcomes with ELAD. A new trial investigating a potential benefit of ELAD in younger subjects with sufficient renal function and less severe coagulopathy has been initiated. Liver Transplantation 24 380-393 2018 AASLD.

MicroRNA-93 activates c-Met/PI3K/Akt pathway activity in hepatocellular carcinoma by directly inhibiting PTEN and CDKN1A.

To assess the role of microRNAs (miR) in hepatocellular carcinoma (HCC), we performed comprehensive microRNA expression profiling using HCC cell lines and identified miR-93 as a novel target associated with HCC. We further verified miR-93 expression levels in advanced HCC tumors (n=47) by a direct PCR assay and found that elevated miR-93 expression level is significantly correlated with poor prognosis. Elevated miR-93 expression significantly stimulated in vitro cell proliferation, migration and invasion, and additionally inhibited apoptosis. We confirmed that miR-93 directly bound with the 3' untranslated regions of the tumor-suppressor genes PTEN and CDKN1A, respectively,and inhibited their expression. As a result of this inhibition, the c-Met/PI3K/Akt pathway activity was enhanced. IHC analysis of HCC tumors showed significant correlation between c-Met protein expression levels and miR-93 expression levels. Knockdown of c-Met inhibited the activation of the c-Met/PI3K/Akt pathway regardless of hepatocyte growth factor (HGF) treatment, and furthermore reduced the expression of miR-93 in these HCC cells. miR-93 also rendered cells to be more sensitive to sorafenib and tivantinib treatment. We concluded that miR-93 stimulated cell proliferation, migration, and invasion through the oncogenic c-Met/PI3K/Akt pathway and also inhibited apoptosis by directly inhibiting PTEN and CDKN1A expression in human HCC.

Increasing age and survival after orthotopic liver transplantation for patients with hepatocellular cancer.

BACKGROUND: Orthotopic liver transplantation (OLT) is the gold standard treatment for patients with early hepatocellular carcinoma (HCC). There are concerns about the efficacy of OLT for HCC in older patients, who we hypothesized might have poorer outcomes. Therefore, we sought to examine advanced age and its impact on OLT outcomes. STUDY DESIGN: The United Network for Organ Sharing database was queried for patients who underwent OLT for HCC from 1987 to 2009. Patients were divided into 3 age groups: 35 to 49 years old, 50 to 64 years old, and 65 years or older, and patient characteristics were compared. Univariate and multivariate analyses were performed to assess the impact of age on OLT outcomes. RESULTS: Of 10,238 patients with OLT for HCC, 16.5% (n = 1,688) of patients were 35 to 49 years old, 67.8% (n = 6,937) were 35 to 49 years old, and 15.8% (n = 1,613) were 65 years and older. By Kaplan-Meier method, the 50- to 64-year-old age group had the highest overall survival, despite having one of the highest rates of hepatitis C positivity (70%), but this group also had the lowest rate of diabetes mellitus (8.7%). The lowest overall survival was observed in the 65-year or older age group (p < 0.001). Finally, there was no difference in disease-specific survival among the age groups (p = 0.858), and patients aged 65 years and older had the highest rate of death from nonhepatic causes (17.5%). CONCLUSIONS: Although OS was prolonged in younger patients who underwent OLT for HCC, there was no observed difference in disease-specific survival among the age groups. Our results suggest that carefully selected patients 65 years of age and older can derive equal benefit from OLT for HCC when compared with their younger counterparts.

Hepaticojejunostomy using short-limb Roux-en-Y reconstruction.

IMPORTANCE: When performing biliary reconstruction, one of the long-standing tenets of surgery is that Roux-en-Y (RY) reconstruction should use a long hepatic limb to decrease the risk for postoperative cholangitis. However, this practice is not well supported and may also make postoperative biliary endoscopy difficult. While some authors recommend Roux limbs of up to 75 cm, we have routinely used a Roux length of 20 cm to facilitate possible postoperative endoscopic access. OBJECTIVE: To review our experience with short-limb RY hepaticojejunostomy (HJ) and examine the short-term and long-term outcomes following this procedure, as well as the success of future biliary interventions. DESIGN: Retrospective medical record review of all patients who underwent short-limb RYHJ by 2 surgeons (N.N.N. and S.D.C.). SETTING: Tertiary care, university-affiliated teaching hospital. PARTICIPANTS: One hundred patients who underwent RYHJ were identified, with 30 of those patients being excluded owing to creation of an RYHJ to intrahepatic bile ducts with concomitant liver resection. MAIN OUTCOMES AND MEASURES: Patient records were reviewed to determine the incidence of postoperative cholangitis and biliary stricture. Secondary outcomes were the need for postoperative biliary endoscopy and success rates for endoscopic biliary interventions. RESULTS Seventy patients underwent short-limb RYHJ over an 11-year period (2001-2012). Indications included benign stricture (n = 18), malignant stricture (n = 12), choledochal cyst (n = 5), choledocholithiasis (n = 3), idiopathic cholangitis (n = 2), and deceased donor or live donor liver transplant (n = 30). Seven patients, including 4 liver transplant patients, developed clinical or radiographic evidence of postoperative biliary stricture, and all patients underwent successful endoscopic cholangiography. Four of these patients required dilation and/or stone extraction, which were accomplished endoscopically in all cases. CONCLUSIONS AND RELEVANCE: Short-limb RYHJ is safe and associated with a low incidence of postoperative complications. In addition, biliary intervention, when indicated, can be performed endoscopically with a high degree of success. In the absence of any evidence demonstrating longer limbs to be superior, we recommend using short-limb RY reconstruction for HJ.

Mixed acinar-endocrine carcinoma of the pancreas: new clinical and pathological features in a contemporary series.

OBJECTIVE: The objective of this study was to characterize the novel clinical and pathological features of mixed acinar-endocrine carcinoma of the pancreas. METHODS: This was a retrospective review of medical records and surgical pathology specimens of patients with a diagnosis of mixed acinar-endocrine carcinoma of the pancreas at Cedars-Sinai Medical Center between 2005 and 2011. Additional immunohistochemistry was performed on the specimens of some patients. RESULTS: Five patients were identified. The median age at presentation was 74 years (range, 59-89 years), and all patients were male. The presenting symptoms were all related to tumor mass effects. The median size of the tumor was 10 cm (range, 3.9-16 cm). Preoperative clinical diagnosis aided by fine-needle aspiration biopsy was incorrect in all 5 cases. Most tumors (3/5) exhibited predominantly endocrine differentiation without hormonal production. Only 10% to 30% of cells were truly amphicrine, whereas most were differentiated into either endocrine or acinar phenotype. The clinical behavior ranged from moderate to aggressive with postoperative survival from 2.5 months to more than 3 years. Four patients received neoadjuvant or adjuvant chemotherapy with variable responses. CONCLUSIONS: Mixed acinar-endocrine carcinoma of the pancreas appears to be not uncommon in men, may harbor predominantly endocrine component, is often misdiagnosed by cytology, and exhibits variable clinical behavior. Mixed acinar-endocrine carcinoma of the pancreas should be considered in older patients with sizable pancreatic mass and may warrant aggressive surgical resection and chemotherapy.

Universal multifunctional HD video system for minimally invasive, [corrected] open and microsurgery.

BACKGROUND: Laparoscopy has familiarized most surgeons with the benefits of a surgical video system, including the ability to magnify fine structures, to display the operative field on a monitor for improved intraoperative communication, and to capture video footage for documentation and education. Use of intraoperative video systems during open surgery is far less common and the potential benefits of this have not been well explored. In this report we describe a simple video system that is applicable to both laparoscopic and open surgery. METHODS: We employed a standard laparoscopic HD camera (1080p) and telescope for initial laparoscopy. In cases requiring laparotomy, a mechanical arm is attached to the operating table and the camera is mounted without the telescope; this provides video display of the open surgical field. In cases requiring dissection or anastomosis of minute structures, a prototype telescope made for open cases is attached to the same camera; this provides improved magnification and illumination for the surgeon. Microsurgical components can then proceed with the surgeon working off the video monitor at a more convenient posture and with the benefits of video display. RESULTS: This multifunctional HD video system for open abdominal surgery has been utilized in 98 complex hepatopancreaticobiliary surgeries. Clear benefits include (1) improved intraoperative communication, (2) improved teaching of bystanders, (3) improved visualization of minute structures, and (4) improved capture and utilization of surgical video and images for education. In an analysis of patients who underwent pancreaticoduodenectomy (PD) with this system, there was a trend toward fewer pancreatic leaks and shorter length of stay but slightly longer operative time compared to PD prior to implementation of this system. CONCLUSIONS: This system can be employed with little added cost over a standard laparoscopy setup and has the potential to be widely utilized in surgical education programs.

Primary hepatocellular carcinoma ("hepatoid" carcinoma) of the pancreas: a case report and review of the literature.

KEY CLINICAL MESSAGE: We present a case of hepatocellular carcinoma located within the pancreas. These tumors occur in the body and tail of the pancreas, with a male predominance, and at a younger age. Tumors with pure hepatocellular histopathology have better survival and recurrence rates and should be offered surgical therapy if possible.

Milan Criteria and UCSF Criteria: A Preliminary Comparative Study of Liver Transplantation Outcomes in the United States.

The application of orthotopic liver transplantation (OLT) for patients with hepatocellular cancer (HCC) necessitates highly selective criteria to maximize survival and to optimize allocation of a scarce resource. The objective of this study was to compare the outcomes of OLT for HCC in patients transplanted under Milan and UCSF criteria. The United Network of Organ Sharing (UNOS) database was queried for patients who had undergone OLT for HCC from 2002 to 2007, and 1,972 patients (Milan criteria, n = 1, 913; UCSF criteria, n = 59) were identified. Patients were stratified by pretransplant criteria (Milan versus UCSF), and clinical and pathologic factors and overall survival were compared. There were no differences in age, gender, diabetes mellitus, body mass index, and hepatitis B, or C status between the two groups. Overall survival was similar between the Milan and UCSF cohorts (1-, 2-, 3-, and 4-year survival rates: 88%, 81%, 76%, and 72% versus 91%, 80%, 68% and 51%, respectively, P = 0.21). Although the number of patients within UCSF criteria was small, our results nevertheless suggest that patients with HCC may have equivalent survival when transplanted under Milan and UCSF criteria. Long-term followup may better determine whether UCSF criteria should be widely adopted.

Ki-67 proliferative index predicts progression-free survival of patients with well-differentiated ileal neuroendocrine tumors.

Ki-67 proliferative index (Ki-67 index) is suggested to be an important prognostic variable and is included as one of the grading parameters for neuroendocrine tumors. The present study was undertaken to determine the usefulness of the Ki-67 index and the corresponding tumor grade in predicting progression-free survival (PFS) of patients with ileal well-differentiated neuroendocrine tumors (wNETs). Tumors from 57 patients with ileal wNETs were studied. Immunohistochemical staining for Ki-67 was performed on the primary as well as selected metastatic tumors and quantitated by computer-assisted image analysis using the Ariol system. The tumors were graded based on mitotic activity and Ki-67 index. Clinical and pathological variables affecting the PFS were analyzed. There were 29 women and 28 men, with a mean age of 59 years. At the time of initial presentation, 8 patients (14%) had localized disease (stages I and II), 29 patients (51%) had regional (nodal/mesenteric) spread (stage III), and 20 patients (35%) had distant metastasis (stage IV). Twelve patients experienced disease progression during subsequent follow-up. Patients with initial stage IV disease were more likely to experience disease progression (P = .005). Additionally, higher histological grade (as determined by Ki-67 index >2%) was associated with a decreased PFS (P = .001). Ki-67 index greater than 2% at either the primary site or the metastatic site was found to be the only significant predictor of PFS after consideration of all other variables in an adjusted analysis. In conclusion, the Ki-67 index predicts PFS of patients with ileal wNETs.

Recurrent hepatocellular carcinoma after liver transplant: identifying the high-risk patient.

BACKGROUND: Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) is rarely curable. However, in view of the advent of new treatments, it is critical that patients at high risk for recurrence are identified. METHODS: Patients undergoing LT for HCC at a single centre between 2002 and 2010 were reviewed and data on clinical parameters and explant pathology were analysed to determine factors associated with HCC recurrence. All necrotic and viable tumour nodules were included in explant staging. All patients underwent LT according to the United Network for Organ Sharing (UNOS) Model for End-stage Liver Disease (MELD) tumour exception policies. RESULTS: Liver transplantation was performed in 122 patients with HCC during this period. Rates of recurrence-free survival in the entire cohort at 1 year and 3 years were 95% and 89%, respectively. Thirteen patients developed HCC recurrence at a median of 14 months post-LT. In univariate analysis the factors associated with HCC recurrence were bilobar tumours, vascular invasion, and stage exceeding either Milan or University of California San Francisco (UCSF) Criteria. Multivariate analysis showed pathology outside UCSF Criteria was the major predictor of recurrence; when pathology outside UCSF Criteria was found in combination with vascular invasion, the predicted 3-year recurrence-free survival was only 26%. CONCLUSIONS: Explant pathology can be used to predict the risk for recurrent HCC after LT, which may allow for improved adjuvant and management strategies.

Evaluation of absolute serum α-fetoprotein levels in liver transplant for hepatocellular cancer.

HYPOTHESIS: An elevated serum α-fetoprotein (AFP) level before orthotopic liver transplant (OLT) is predictive of mortality after OLT for hepatocellular carcinoma (HCC). DESIGN: Retrospective analysis of a population-based cohort. SETTING: United Network for Organ Sharing registry (2003-2008). PATIENTS: We identified 2253 patients who underwent OLT for HCC with available pre-OLT serum AFP values. METHODS: Patients were stratified by AFP levels into low (<20 ng/mL), medium (20-399 ng/mL), or high (≥400 ng/mL) groups. Clinical and pathological characteristics were compared among groups. Survival curves were constructed by the Kaplan-Meier method, and univariate and multivariate Cox-regression analysis was performed. RESULTS: Of the 2253 patients, 1210 (53.7%), 805 (35.7%), and 238 (10.6%) were in the low, medium, and high AFP groups, respectively. On univariate analysis, the low AFP group demonstrated the best 4-year survival (76%) compared with the medium (65%; P = .001) and high (57%; P < .001) AFP groups. When AFP levels in patients with only stage II HCC underwent assessment, improved survival in the low AFP group was still observed (P < .001). On multivariate analysis, the medium and high AFP groups were associated with higher mortality (hazard ratios, 1.50 [95% confidence interval, 1.19-1.89; P = .001] and 2.11 [1.55-2.88; P < .001], respectively). CONCLUSIONS: Serum AFP level is an independent prognostic predictor of outcome after OLT for HCC. The association between serum AFP value and post-OLT survival warrants further investigation to potentially better allocate donor allografts for HCC.

Current surgical management of infected pancreatic necrosis.

Infected pancreatic necrosis (IPN) continues to be a challenging problem for the surgeon. We reviewed the experience on a hepatobiliary surgical service with patients who required operative intervention for IPN with emphasis on surgical approach, timing of surgery, and complications. Between 2002 and 2008, 21 patients underwent surgery for IPN. The initial surgical approach in these 21 patients included either direct pancreatic débridement (DPD, n=13) or transgastric débridement using cyst-gastrostomy (CG, n=8). Fifteen patients (71%) required only a single procedure, whereas three (14%) required two procedures and three (14%) required three procedures. The mean time from onset of pancreatitis to operation was 77 days. Patients requiring a single intervention had a longer interval from onset of pancreatitis to surgery compared with those requiring multiple interventions. When comparing CG and DPD groups, there was a longer interval from onset of pancreatitis to débridement, a lower chance of needing multiple débridements, and fewer pancreatic fistulae in the CG group. Overall survival was 95 per cent. Our results demonstrate that CG can be successfully used in select patients with IPN. Patients undergoing CG are less likely to require repeat surgical debridement and to develop pancreatic fistulae compared with patients undergoing DPD.

Race, ethnicity, and socioeconomic status influence the survival of patients with hepatocellular carcinoma in the United States.

BACKGROUND: Racial, ethnic, and socioeconomic disparities in the survival of patients with hepatocellular carcinoma (HCC) continue to exist. The authors of this report hypothesized that these differences result from inequities in access to care and in response to therapy. METHODS: Patients with HCC (n = 20,920) were identified from the Surveillance, Epidemiology, and End Results (SEER) database, and patients who underwent liver transplantation for HCC (n = 4735) were identified from the United Network for Organ Sharing (UNOS) database. Clinical and pathologic factors were compared after patients were stratified by race and ethnicity. RESULTS: The survival of patients with HCC improved over time for all racial, ethnic, and income groups (P < .001). Black and low income individuals had the poorest long-term survival (P < .001). On multivariate analysis, black race was predictive of the poorest survival (hazard ratio [HR], 1.15; 95% confidence interval [CI], 1.09-1.22; P < .001), whereas Asian race was associated with the best survival (HR, 0.87; 95% CI, 0.83-0.91; P < .001). After liver transplantation, black patients had the worst graft survival and overall survival (median survival [MS], 30.5 months and 39.7 months, respectively; P < .001), whereas Hispanics had the best survival (MS, 83.4 months and 86.6 months, respectively; P < .001). In a multivariate analysis of transplantation patients, race and ethnicity were associated significantly with outcome. CONCLUSIONS: Significant racial and ethnic disparities in the outcome of patients with HCC persist despite the receipt of comparable treatment. The authors concluded that further investigations are warranted to identify the reasons for the stark disparity in outcomes between black patients and Hispanic patients after liver transplantation for HCC.