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.

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.

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.

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.

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.

A disease-based comparison of liver transplantation outcomes.

An increasing demand for transplant donor organs has made optimal allocation of resources a priority. Our objective was to evaluate outcomes for orthotopic liver transplantation (OLT) performed in the United States. A query of the United Network for Organ Sharing registry between 1988 and 2007 was performed for patients who underwent OLT for all etiologies. Patients were stratified by pathology necessitating OLT and clinical and pathologic factors were compared. Multivariate Cox-regression analysis was used to assess the association of pathology with survival. Of 61,823 patients, 33 per cent (n = 20,305) of OLTs were secondary to hepatitis C virus, 21 per cent autoimmune disease, 17 per cent alcohol-induced injury, 11 per cent cryptogenic cirrhosis, 8 per cent hepatocellular carcinoma (HCC), 6 per cent hepatitis B virus, and 4 per cent metabolic disease. Patients with autoimmune disease and HCC demonstrated the best and worst survival, respectively, after OLT (median survival 16.0 vs 6.4 yrs, respectively, P < 0.001). By multivariate analysis, OLT for HCC was significantly associated with poorer overall survival (hazard ratio [HR] 2.19, 95% confidence interval [CI]: 2.02-2.37, P < 0.001). Our results indicate that outcomes for liver transplantation vary by primary hepatic pathology with HCC patients having the poorest overall survival. To optimize organ allocation for all patients with end-stage liver disease, a better understanding of poor survival for HCC is necessary.

Pancreatic neuroendocrine tumors: presentation, management, and outcomes.

Pancreatic neuroendocrine tumors (pNETs) are an uncommon pancreatic neoplasm. We reviewed the presentation, management, and outcome of patients with pNETs treated at a single center by a multidisciplinary approach between 2004 and 2008. Over this time period, 154 patients with carcinoid and neuroendocrine tumors were treated, which included 46 patients (30% of total) with pNETs. The most common presentations included abdominal pain (20 of 46 [43%]), systemic symptoms such as hypoglycemia (15 of 46 [33%]), and incidental mass (7 of 46 [15%]). Fourteen patients had functional tumors. At the time of diagnosis, 22 patients (48%) presented without metastases and 24 (52%) had metastatic disease. Median follow up for the entire group was 42 months. All patients with nonmetastatic pNET underwent pancreatic resection with 95 per cent postoperative survival. Overall survival in this group at 3 years was 86 per cent and disease-free survival was 81 per cent. In patients presenting with metastatic pNET, multiple treatment modalities were used, including liver resection or ablation (n = 15), hepatic chemoembolization (n = 17), pancreatic resection (n = 12), and systemic treatments (n = 7). Three-year survival was 70 per cent. Pancreatic resection results in greater than 80 per cent 3-year survival in nonmetastatic pNET. In patients presenting with metastatic pNET, excellent survival rates are also achievable using a multidisciplinary multimodal approach.

Alemtuzumab and liver transplantation: a review.

PURPOSE OF REVIEW: Liver transplantation has always been fraught with conflict. The ongoing shortage of organs for transplantation has led to sicker recipients and the pressure to utilize more marginal grafts. At the same time, increasing public scrutiny and regulatory oversight have emphasized lower costs and better outcomes. This environment exaggerates the importance of the most fundamental conflict: that between preventing allograft rejection and avoiding the toxicities of immunosuppressive agents and the risks of infection. Resolving this struggle requires skillful balancing and a need to keep abreast of the latest developments. Alemtuzumab is a still-new agent with relatively little clinical experience that, therefore, deserves a review and an update of current knowledge in the setting of liver transplantation. RECENT FINDINGS: The use of alemtuzumab in liver transplant recipients has shown promise with little information to support concerns over significantly increased risks of infectious complications. However, there have been very few studies overall and fewer still in the last 2-3 years. Much of what is known must still be extrapolated from experience in kidney transplant recipients. SUMMARY: Alemtuzumab appears to be a drug with significant potential advantages for liver transplant recipients. Improved renal function may be the largest potential advantage. However, the advantages may be offset in some groups. Defining subgroups will be critical to the definition of the optimal role of alemtuzumab in liver transplant recipients.

Pancreaticoduodenectomy after neoadjuvant therapy in a Jehovah's witness with locally advanced pancreatic cancer: case report and approach to avoid transfusion.

Although the morbidity and mortality rates associated with pancreaticoduodenectomy (PD) have been improving over the past several decades, perioperative transfusions are often needed. Here, we review the preoperative planning and overall management of a Jehovah's Witness patient with locally advanced pancreatic cancer who would not accept blood transfusion. Management of this case is reviewed, along with the relevant literature regarding major surgery in the Jehovah's Witness population. The use of neoadjuvant chemoradiation was used successfully in locally advanced disease, allowing surgical resection. In addition, we outline a cogent strategy using pre-, intra-, and postoperative techniques to minimize blood loss and maintain hemoglobin at acceptable levels thereby preventing the need for transfusion. These strategies, once in place, may be able to reduce transfusions in all patients having major resections for malignancy.

Morbidity in live liver donors: standards-based adverse event reporting further refined.

HYPOTHESIS: The true extent of morbidity among live liver donors remains poorly understood. In this unique and often high-profile area of surgery, the development of standards for defining and reporting complications would foster a better understanding of the incidence and magnitude of such adverse events (AEs). DESIGN: Retrospective review of AEs among live liver donors. SETTING: University-affiliated teaching hospital. PATIENTS AND METHODS: Of 202 individuals undergoing evaluation for live liver donation, 42 (20.8%) proceeded to surgery. Thirty-four underwent a right lobectomy without the middle hepatic vein; 3, a left lateral segmentectomy. Any event causing a deviation from a patient's ideal course was considered an AE and subsequently classified according to a derived framework. Morbidity was defined as 1 or more AEs. MAIN OUTCOME MEASURES: Incidence, timing, type, severity, and impact of AEs. RESULTS: No deaths or significant hepatic dysfunction occurred. In 5 (12%) of the 42 donors, the hepatectomy was aborted for anatomic reasons before parenchymal transection. Eight (22%) of the remaining 37 experienced 11 AEs, of which 10 completely resolved, whereas 1 AE (3%) resulted in a permanent disability (brachial plexopathy). The overall incidence of AEs was 0.30 per case. Ten (91%) of the 11 AEs presented within the first postoperative month. CONCLUSIONS: Most live liver donations are uncomplicated or do not lead to permanent consequence. The adoption of a standards-based classification framework for AEs in live liver donors would allow for an inclusive, consistent, and universally applicable method to collect, analyze, and report donor morbidity.

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.

Endoscopically placed nasogastrojejunal feeding tubes: a safe route for enteral nutrition in patients with hepatic encephalopathy.

Patients with hepatic encephalopathy are at particular risk for aspiration when given oral or gastric feedings. An ideal strategy might combine distal enteral feeding with proximal gastric decompression, which is offered by a nasogastrojejunal (NGJ) feeding tube. One objective was to determine the efficacy and safety of endoscopically placed NGJ feeding tubes in patients with hepatic encephalopathy. Charts of patients who underwent NGJ tube placements between April 1997 and January 2000 were retrospectively reviewed. Two endoscopic techniques ("push" and "pull") were used. Eighteen patients (nine male and nine female) underwent 32 procedures. Twelve patients had undergone liver transplantation, four had decompensated cirrhosis, and two had fulminant hepatic failure. Twenty procedures used the push technique and 12 required the pull technique. The insertion time was shorter for the push technique compared with the pull technique (21.8 vs 39.6 min, P < 0.05). Enteral feedings were begun at an average of 5.2 hours after tube placement. The tubes remained in place for an average of 13.9 days. Complications related to the NGJ tubes included self-removal in eight, tube clogging in five, proximal migration in four, and intraduodenal migration of the gastric port in one. No aspiration episodes occurred. We conclude that NGJ feeding tubes may be placed endoscopically as a bedside procedure for patients with hepatic encephalopathy and provide a safe, efficacious, and rapid route for enteral nutrition in these patients.

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.

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.

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.

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.