No Improvement in Intention-to-treat Survival and Increasing Liver Nonutilization Rate During the MELD Era.

BACKGROUND: Although post liver transplant survival rates have significantly improved during the past 2-3 decades, the trend in intention-to-treat (ITT) survival (survival from waitlist addition) has not been well studied. METHODS: We conducted a retrospective analysis of Scientific Registry of Transplant Recipients data to determine the trend in ITT survival in liver transplant candidates. Adult (age ≧ 18 y) patients who were on the waitlist between the time period of March 1, 2002, to December 31, 2019 (n = 200 816) and deceased liver donors that were registered between the same time period (n = 152 593) were analyzed. RESULTS: We found a constant increase in posttransplant survival rates; however, the ITT survival rates showed no statistically significant improvement through the study period. We observed significant linear increase in waitlist dropout rates over time. We also observed linear increase in liver nonutilization rate in both entire cases and brain-dead cases. Donor risk index increased significantly over the years; however, it was mostly driven by increase in donation after circulatory death cases; without donation after circulatory death cases, donor risk index was stable throughout the 17 y we observed. CONCLUSIONS: The reason of the increased liver nonutilization rate is unclear; however, it is possible that reluctance to use high-risk organ to maintain better posttransplant outcomes contributed to this increase, which also could have led to increase in waitlist dropout rates and no improvements in ITT survival. Further investigation is warranted on the increased nonutilization rates to improve over all contribution of liver transplant to patient care.

Emerging Therapies in Management of Cholangiocarcinoma.

Cholangiocarcinoma is a heterogeneous group of biliary tract cancers that has a poor prognosis and globally increasing incidence and mortality. While surgical resection remains the only curative option for the treatment of cholangiocarcinoma, the majority of cancers are unresectable at the time of diagnosis. Additionally, the prognosis of cholangiocarcinoma remains poor even with the current first-line systemic therapy regimens, highlighting the difficulty of treating locally advanced, metastatic, or unresectable cholangiocarcinoma. Through recent developments, targetable oncogenic driver mutations have been identified in the pathogenesis of cholangiocarcinoma, leading to the utilization of molecular targeted therapeutics. In this review, we comprehensively discuss the latest molecular therapeutics for the treatment of cholangiocarcinoma, including emerging immunotherapies, highlighting promising developments and strategies.

The Immunology of Hepatocellular Carcinoma.

Liver cancer is the third leading cause of cancer death worldwide. Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver. Liver resection or transplantation offer the only potentially curative options for HCC; however, many patients are not candidates for surgical resection, either due to presentation at advanced stages or poor liver function and portal hypertension. Liver transplantation is also limited to patients with certain characteristics, such as those that meet the Milan criteria (one tumor ≤ 5 cm, or up to three tumors no larger than 3 cm, along with the absence of gross vascular invasion or extrahepatic spread). Locoregional therapies, such as ablation (radiofrequency, ethanol, cryoablation, microwave), trans-arterial therapies like chemoembolization (TACE) or radioembolization (TARE), and external beam radiation therapy, have been used mainly as palliative measures with poor prognosis. Therefore, emerging novel systemic treatments, such as immunotherapy, have increasingly become popular. HCC is immunogenic, containing infiltrating tumor-specific T-cell lymphocytes and other immune cells. Immunotherapy may provide a more effective and discriminatory targeting of tumor cells through induction of a tumor-specific immune response in cancer cells and can improve post-surgical recurrence-free survival in HCC. We herein review evidence supporting different immunomodulating cell-based technology relative to cancer therapy in vaccines and targeted therapies, such as immune checkpoint inhibitors, in the management of hepatocellular carcinoma among patients with advanced disease.

Potential experimental immune checkpoint inhibitors for the treatment of cancer of the liver.

Introduction: Traditional systemic therapies offer limited benefit for advanced cancers of the liver. Immune checkpoints are inhibitory regulators of the immune system and the success of immune checkpoint inhibitors (ICIs) in the treatment of other cancers has led to clinical trials investigating the use of ICIs alone or in combination with other therapies for liver cancers.Area covered: Clinical trials involving ICIs for the treatment of liver cancer were broadly reviewed. Hepatocellular carcinoma and intrahepatic cholangiocarcinoma were examined. Phase I/II trials were prioritized, and relevant phase III trials were discussed. MEDLINE, PubMed, ASCO meeting library, and Web of Science databases were searched with the keywords 'immune checkpoint inhibitor' or 'targeted therapy' in combination with 'hepatocellular carcinoma,' or 'intrahepatic cholangiocarcinoma'. Major outcomes were safety and efficacy defined by response rate, progression-free survival, or overall survival.Expert opinion: ICIs can improve progression-free and overall survival among patients with advanced disease with an acceptable safety profile. Given the heterogeneity of liver disease, ideal strategies will likely include a combination of ICIs with additional therapies to achieve the most robust and durable response. Additional biomarkers will be needed to guide combination therapy to personalize treatment regimen for patients with primary liver cancers.

Cholangiocarcinoma: shedding light on the most promising drugs in clinical development.

Introduction: Cholangiocarcinoma (CCA) is a diverse group of fatal malignancies arising from the biliary tract. Surgical resection with negative margin offers the only potentially curative option. The majority of patients present at locally advanced or metastatic stages, when surgical resection is not feasible, highlighting the significance of systemic therapy. Given the limited effectiveness of traditional chemotherapy regimens in CCA, many investigators have focused on developing novel molecular therapies targeting key aberrant signaling pathways.Areas covered: We present the main genomic aberrations known to play a key role in cholangiocarcinogenesis and discuss promising targeted therapies in clinical development.In October of 2020, a review of the English literature was performed utilizing PubMed and Web of Science databases for the keywords of 'cholangiocarcinoma', 'biliary tract cancer', and 'targeted therapy'.Expert opinion: Unfortunately, despite encouraging results in preclinical studies, the outcome of clinical trials with established targeted therapies like anti-EGFR medications have been discouraging. Currently, agents targeting FGFR2 fusion and IDH1/2 mutations hold great promise for improving the management of CCA. Future studies focused on enhancing our understanding of key aberrant signaling pathways of cholangiocarcinogenesis and the design of homogeneous and biomarker-driven cohorts are key elements of establishing precision medicine in CCA.

Donor CMV Reactivation as a Novel Risk Factor for CMV Replication in Seropositive Liver Transplant Recipients.

Risk factors for cytomegalovirus (CMV) viremia in CMV seropositive liver transplant recipients are incompletely defined and have focused primarily on recipient factors. We hypothesized that active CMV replication (CMV viremia) in seropositive donors might increase the risk for CMV viremia in recipients, as reported for other viruses in organ transplantation. METHODS: From January 3, 2009, to July 27, 2015, stored plasma from consecutive CMV seropositive liver donors was retrospectively tested for CMV viremia by PCR. From April 20, 2012, to July 27, 2015, CMV seropositive recipients of a liver transplant from the donors during this time period received preemptive therapy for CMV prevention (valganciclovir therapy for CMV viremia ≥250 IU/mL). The association of recipient factors and donor CMV viremia with viremia in recipients was assessed. RESULTS: Among 317 CMV-seropositive donors, CMV viremia was detected in 11 (3.5%) and was associated with longer time to collection after admission and bacteremia. Among 115 CMV-seropositive liver recipients, 5 (4.3%) received an organ from a donor with CMV viremia. Donor CMV viremia was independently associated with higher incidence of CMV viremia ≥250 IU/mL and shorter time to onset of CMV viremia ≥250 IU/mL in recipients: 4 (80%) versus 26 (23.6%), P = 0.02, and hazard ratio 8.55 (2.60-28.10), P = 0.003, respectively. CONCLUSION: Donor CMV reactivation is associated with CMV viremia in seropositive orthotopic liver transplant recipients receiving preemptive therapy, identifying a novel potential risk factor for CMV infection in seropositive liver transplant recipients. Future studies should independently validate and assess these findings in other organ transplant settings.

Surgical Management of Breast Cancer Liver Metastasis.

Hepatic resection for patients with isolated breast cancer liver metastases (BCLM) is associated with prolonged disease-free interval and better overall survival in highly selected patients. Patients with limited disease who are not candidates for surgery benefit from ablative therapies for isolated breast cancer metastasis in addition to systemic chemotherapy. In the era of modern effective systemic chemotherapy for BCLM, local regional therapies are warranted, yet only in well-selected patients following discussion in a multidisciplinary setting. This article reviews data related to hepatic resection and ablative therapies of BCLM, as well as long-term outcomes of women treated with these approaches.

Emerging pathways for precision medicine in management of cholangiocarcinoma.

Cholangiocarcinoma (CCA) is the second most common biliary tract malignancy with a dismal prognosis. Surgical resection with a negative microscopic margin offers the only hope for long-term survival. However, the majority of patients present with advanced disease not amenable to curative resection, mainly due to late presentation and aggressive nature of the disease. Unfortunately, due to the heterogeneous nature of CCA as well as limitations of available chemotherapy medications, traditional chemotherapy regimens offer limited survival benefit. Recent advances in genomic studies and next-generation sequencing techniques have assisted in better understanding of cholangiocarcinogenesis and identification of potential aberrant signaling pathways. Targeting the specific genomic abnormalities via novel molecular therapies has opened a new avenue in management of CCA with encouraging results in preclinical studies and early clinical trials. In this review, we present emerging therapies for precision medicine in CCA.

Current Advances in Minimally Invasive Surgical Management of Perihilar Cholangiocarcinoma.

BACKGROUND: While the safety of minimally invasive surgery (MIS) has been reported for several liver malignancies, the role of MIS in the management of perihilar cholangiocarcinoma (pCCA) has been poorly defined. METHODS: A systematic review of the literature was performed utilizing MEDLINE/PubMed and Web of Science databases up to January 2020 to assess the safety and feasibility of MIS in the management of patients with pCCA. RESULTS: Limited data exist on the MIS approach to treat pCCA. Staging laparoscopy carries a low diagnostic yield and typically is used only in select patients with high suspicion of metastatic disease. Data on the use of MIS approach for resection of pCCA have largely been limited to case reports or small case series. A MIS approach to pCCA resection has been demonstrated to be feasible and safe, yet in most series the surgeon failed to include resection of the caudate lobe. Given that caudate lobe involvement occurs in 31-98% of patients with pCCA, incomplete resection of the caudate lobe may be associated with higher local recurrence. More recently, several surgeons have reported complete R0 surgical with removal of the caudate lobe using a MIS approach. While patients may have a shorter length-of-stay, the true benefit of the MIS approach for pCCA needs to be better defined. CONCLUSIONS: MIS may be a safe and feasible approach at high-volume centers with robust expertise in the management of patients with pCCA. Further studies with larger number of patients are required prior to universal application of MIS for pCCA.

National Underutilization of Neoadjuvant Chemotherapy for Gastric Cancer.

BACKGROUND: Since the publication of the landmark MAGIC trial in 2006, neoadjuvant chemotherapy has become the standard of care for stage II/III gastric cancer. Nevertheless, many patients still do not begin their treatment with neoadjuvant chemotherapy. The objective of our study was to identify factors associated with underutilization of neoadjuvant chemotherapy for stage II/III gastric cancer. METHODS: Patients with pathological stage II and III primary gastric cancer between 2004 and 2015 were identified from the American College of Surgeons National Cancer Database. Patients who received neoadjuvant chemotherapy were compared with those who underwent surgery only or surgery followed by chemotherapy. Predictors of receipt of neoadjuvant chemotherapy were identified using multivariable logistic regression model. Median survival was calculated for each treatment strategy. RESULTS: We included 15,947 patients with pathological stage II/III gastric cancer. The proportion of patients receiving neoadjuvant chemotherapy increased from less than 5% before 2006 to 27.5% in 2015. On multivariable analysis, factors associated with no receipt of neoadjuvant therapy included treatment year before 2006 and age greater than 80. Treatment at high-volume centers, academic research programs, or integrated network cancer programs and undergoing total/subtotal or en bloc gastrectomy predicted receipt of neoadjuvant chemotherapy. CONCLUSIONS: Ten years after the publication of the MAGIC trial, fewer than 1/3 of patients with stage II/III gastric cancer are receiving neoadjuvant chemotherapy, which has been shown to improve disease-specific survival. Further studies are needed to understand these disparities and ensure both patients and providers are having evidence-based discussions about multimodal therapy for gastric cancer.

Correction to: Current Approaches in the Management of Hepatic Adenomas.

The following reference in this paper refers to a paper that has been since retracted.

Molecular pathways and potential biomarkers in gallbladder cancer: A comprehensive review.

The most common malignancy of the biliary tract, gallbladder cancer (GBC) often has a dismal prognosis. The aggressive nature of the tumor, delayed diagnosis at advanced stages of the disease, and lack of effective treatment options are some of the factors that contribute to a poor outcome. Early detection and accurate assessment of disease burden is critical to optimize management and improve long-term survival, as well as identify patients for adjuvant therapy and clinical trials. With recent advances in the understanding of the molecular pathogenesis of GBC, several specific diagnostic and biomarkers have been proposed as being of diagnostic and prognostic importance. Indeed, identification of novel diagnostic and prognostic markers has an important role in early diagnosis and development of targeted therapies among patients with GBC. Next-generation sequencing technology and genomewide data analysis have provided novel insight into understanding the molecular pathogenesis of biliary tract cancers, thereby identifying potential biomarkers for clinical use. We herein review available GBC biomarkers and the potential clinical implications in the management of GBC.

Current Approaches in the Management of Hepatic Adenomas.

INTRODUCTION: Hepatic adenomas (HAs) are a benign and relatively rare type of liver neoplasms. We review the diagnosis, evaluation, and potential therapeutic management options for patients with HA. METHODS: A comprehensive review of the English literature was performed utilizing MEDLINE/PubMed and Web of Science databases with end of search date the 30th April of 2018. In PubMed, the terms "hepatocellular," "hepatic," "liver," and "adenoma," "adenomatosis" were searched in the title and/or abstract. RESULTS: Recent advances in molecular classification of HA have determined distinct subtypes with specific clinical, pathological, and imaging characteristics. In general, cessation of exogenous hormonal administration or weight loss may lead to HA regression. Surgical resection, either open or laparoscopic, should be considered in patients with symptoms and risk factors for hemorrhage or malignant transformation. These risk factors include tumor diameter greater than 5 cm, ß-catenin activated subtype, and/or male gender. The management of acute hemorrhage should primarily aim at achieving hemodynamic stability via angioembolization followed by elective resection, whereas malignant transformation is treated according to oncologic resection principles. Although pregnancy is one of the known risk factors for tumor growth and associated complications, the presence of an HA per se should not be considered a contradiction to pregnancy. CONCLUSION: Future genomic-based multicenter studies are required to provide a strong basis for formulating an evidence-based risk-adapted model that guides individualized management strategies for patients with HA.

Role of associating liver partition and portal vein ligation in staged hepatectomy (ALPPS)-strategy for colorectal liver metastases.

Colorectal carcinoma (CRC) is the third leading cause of cancer-related death in the United States. The liver is the most frequent site of metastasis and a key determinant of survival in patients with isolated colorectal liver metastasis (CRLM). Surgical resection remains the only hope for prolonged survival in patients with CRLM. However, most patients are deemed to be unresectable at presentation due to a small future liver remnant (FLR) and fear of post-hepatectomy liver failure. Procedures such as portal vein ligation or embolization (PVL/PVE) followed by hepatectomy have been established as standard methods to increase FLR volume, but have limitations dependent upon extent of disease and patient's ability to grow the liver remnant. Recently, associating liver partition and portal vein ligation in staged hepatectomy (ALPPS) has been introduced as a technique to induce liver hypertrophy over a shorter time period. Being a complex two-stage surgical procedure, initial reports of higher ALPPS-associated complications and mortality limited its worldwide adoption by hepatobiliary surgeons. However, recent studies have showed ALPPS superiority over conventional procedures in terms of feasibility and inducing liver hypertrophy, with comparable morbidity and mortality. We herein review the role of ALPPS in management of patients with CRLM.

Update on Liver Failure Following Hepatic Resection: Strategies for Prediction and Avoidance of Post-operative Liver Insufficiency.

Liver resection is increasingly used for a variety of benign and malignant conditions. Despite advances in preoperative selection, surgical technique and perioperative management, posthepatectomy liver failure (PHLF) is still a leading cause of morbidity and mortality following liver resection. Given the devastating physiological consequences of PHLF and the lack of effective treatment options, identifying risk factors and preventative strategies for PHLF is paramount. In the past, a major limitation to conducting high quality research on risk factors and prevention strategies for PHLF has been the absence of a standardized definition. In this article, we describe relevant definitions for PHLF, discuss risk factors and prediction models, and review advances in liver assessment tools and PHLF prevention strategies.

Updates and Critical Insights on Glissonian Approach in Liver Surgery.

Recent advances in surgical techniques have broadened the indications of surgical management of liver malignancies. Intraoperative bleeding is one of the known predictors of postoperative outcomes following liver surgery, signifying the importance of vascular control during liver resection. Furthermore, preservation of future liver remnant plays a critical role in prevention of post-hepatectomy liver failure as one of the main causes of postoperative morbidity and mortality. Glissonian approach liver resection offers an effective method for vascular inflow control while protecting future liver remnant from ischemia-reperfusion injury. Several studies have demonstrated the feasibility of Glisson's pedicle resection technique in modern liver surgery with an acceptable safety profile. Moreover, with increasing popularity of minimally invasive surgery, laparoscopic liver resection via Glissonian approach has been shown to be superior to standard laparoscopic hepatectomy. Herein, we systematically review the role of Glissonian approach hepatectomy in current practice of liver surgery, highlighting its advantages and disadvantaged over other methods of vascular control.

Ex vivo excision of retroperitoneal soft tissue tumors: A case report.

Ganglioneuromas are slow growing, clinically silent benign tumors for which surgery is considered to be the standard treatment. However, surgical excision in cases where surrounding structures are involved can be challenging. The present study reports a novel technique of ex vivo excision for the management of a retroperitoneal ganglioneuroma in a 21-year old patient, that appeared to be inoperable using standard surgical resection. Preoperative investigations revealed a large tumor with encasement of the origins of the superior mesenteric artery (SMA) and bilateral renal arteries. Initially, to prevent the need to explant the liver, the distal SMA (with takeoff of the replaced common hepatic artery) was anastomosed to the splenic artery. The bulk of the tumor along with the bilateral kidneys was mobilized from the retroperitoneum, and the aorta and inferior vena cava (IVC) were cross-clamped above and below the tumor and divided. The two kidneys were dissected free of the tumor at the back-table and were auto-transplanted in a standard technique following the reconstruction of the aorta and IVC. The patient tolerated surgery well and a one-year postoperative follow-up did not show any sign of tumor recurrence. Although technically demanding, ex vivo resection and auto-transplantation of the involved organs can be introduced as a final option for the treatment of tumors that are un-resectable using standard surgical techniques.

Program death-1 immune checkpoint and tumor microenvironment in malignant liver tumors.

Hepatic malignancies are one of the leading causes of cancer death globally. Considering the limited efficacy of current standard treatments in management of patients with advanced liver cancers, there has been a growing interest in identifying novel therapies. Despite achieving promising results in initial clinical trials, the therapeutic benefit of immunotherapy is limited due to strong immune-tolerogenic characteristics of liver tumors. Therapeutic regimens that impede tumor immunosuppressive mechanisms or elaborate tumor-specific immunity may improve clinical outcomes of patients with liver malignancies. Programmed cell death 1 (PD-1), an inhibitory checkpoint molecule, and its ligands (PD-L1 and -L2) are the main mediators of immunosuppression within the tumor microenvironment. The expression level of PD-1/PD-L1 may act as a biomarker to predict disease progression, as well as long-term survival. Furthermore, early trials have demonstrated the efficacy and safety of targeting PD-1/PD-L1 as an emerging field in the management of patients with advanced hepatocellular carcinoma. We herein review the role of PD-1/PD-L1 in the pathogenesis of liver malignancies, as well as its potential diagnostic and therapeutic implications.

Postoperative Abdominal Adhesions: Clinical Significance and Advances in Prevention and Management.

Postoperative adhesions remain one of the more challenging issues in surgical practice. Although peritoneal adhesions occur after every abdominal operation, the density, time interval to develop symptoms, and clinical presentation are highly variable with no predictable patterns. Numerous studies have investigated the pathophysiology of postoperative adhesions both in vitro and in vivo. Factors such as type and location of adhesions, as well as timing and recurrence of adhesive obstruction remain unpredictable and poorly understood. Although the majority of postoperative adhesions are clinically silent, the consequences of adhesion formation can represent a lifelong problem including chronic abdominal pain, recurrent intestinal obstruction requiring multiple hospitalizations, and infertility. Moreover, adhesive disease can become a chronic medical condition with significant morbidity and no effective therapy. Despite recent advances in surgical techniques, there is no reliable strategy to manage postoperative adhesions. We herein review the pathophysiology and clinical significance of postoperative adhesions while highlighting current techniques of prevention and treatment.

Current Management of Perihilar Cholangiocarcinoma and Future Perspectives.

Perihilar cholangiocarcinoma is the most common type of biliary tract cancer and is associated with a high mortality, usually due to late presentation. High-resolution cross-sectional imaging modalities are necessary for diagnosis and preoperative planning. Although surgical resection with negative margins offers the only hope for cure, only a small subset of patients are amenable for surgery at the time of diagnosis. Portal vein embolization and biliary tract decompression are important in some patients prior to surgical resection. Liver transplantation in combination with neoadjuvant therapy has resulted in excellent 5-year recurrence-free survival rates in highly selected patients with inoperable disease. Gemcitabine plus cisplatin constitute the backbone of chemotherapy in patients with inoperable metastatic perihilar cholangiocarcinoma. Recent advances in understanding the molecular pathogenesis of CCA have created a growing interest in identifying novel therapies targeting key molecular pathways. Herein, we provide an overview of the most current principles of management of patients with perihilar cholangiocarcinoma.