Faculty Bibliography

The seventh leading cause of cancer-related death globally, pancreatic ductal adenocarcinoma (PDAC) involves the exocrine pancreas and constitutes greater than 90% of all pancreatic cancers. Surgical resection in combination with systemic chemotherapy with or without radiation remains the mainstay of treatment and the only potentially curative treatment option. While there has been improvement in systemic chemotherapy, long-term survival among patients with PDAC remains poor. Improvement in the understanding of tumorigenesis, genetic mutations, the tumor microenvironment (TME), immunotherapies, as well as targeted therapies continued to drive advances in PDAC treatment. We herein review the TME, genetic landscape, as well as various metabolic pathways associated with PDAC tumorigenesis relative to emerging therapies.

BACKGROUND:Neoadjuvant therapy (NT) has increasingly been utilized for patients with localized pancreatic ductal adenocarcinoma (PDAC). It is the recommended approach for borderline resectable (BR) and locally advanced (LA) cancers and an increasingly utilized option for potentially resectable (PR) disease. Despite its increased use, little research has focused on patient-centered metrics among patients undergoing NT, including patient experiences, preferences, and recommendations. A better understanding of all aspects of the patient experience during NT may identify opportunities to design interventions aimed at improving quality of life; it may also facilitate the completion of NT and receipt of surgery, ultimately optimizing long-term outcomes. AIM/OBJECTIVE:To understand the experience of patients initiating and receiving NT to identify opportunities to improve neoadjuvant cancer care delivery. METHODS:Semi-structured interviews of patients with localized PDAC during NT were conducted to explore their experience initiating and receiving NT. Interviews took place between August 2020 and October 2021. Due to the descriptive nature of the research, questions were open ended. Interviews were conducted over the phone, audio recorded and then transcribed. All interviews were coded by two independent researchers using NVivo 12, iteratively identifying themes until thematic saturation was achieved. An integrative approach to qualitative analysis was used, utilizing both inductive and deductive methods. RESULTS:= 5). CONCLUSION/CONCLUSIONS:This study provides a framework to allow for a better understanding of the PDAC patient experience during NT and highlights opportunities to improve quality and quantity of life outcomes.

INTRODUCTION/UNASSIGNED:Hepatocellular carcinoma (HCC) is a major health problem worldwide with limited systemic therapy options. Since the approval of sorafenib in 2008, no systemic therapy has provided a sustained/robust/survival benefit for patients with advanced HCC until recently. Many initially promising therapies have been trialed, but survival outcomes remained stagnant. Knowledge concerning previous treatment failures may help inform future therapeutic approaches. AREA COVERED/UNASSIGNED:This article reviews recent advances in the treatment of HCC. Despite some recent success, many systemic and locoregional therapies have failed to produce significant improvements in outcome. These treatment failures are examined and insight into pathways for future success are discussed. EXPERT OPINION/UNASSIGNED:Combination atezolizumab and bevacizumab has changed the landscape of systemic treatment for patients with HCC when it became the first therapy after demonstrating improve outcomes over sorafenib. Clinical trials in patients with advanced HCC have inherent difficulty with challenges to determine if a patient's declining liver function is secondary to disease progression, worsening cirrhosis, or drug toxicity, which may skew results. As we gain more knowledge of underlying genetic alterations behind the pathophysiology of the development of HCC, molecular markers may be identified to assist in predicting which patients would respond to a specific therapy.

Cholangiocarcinoma (CCA) represents nearly 15% of all primary liver cancers and 2% of all cancer-related deaths worldwide. Perihilar cholangiocarcinoma (pCCA) accounts for 50-60% of all CCA. First described in 1965, pCCAs arise between the second-order bile ducts and the insertion of the cystic duct into the common bile duct. CCA typically has an insidious onset and commonly presents with advanced, unresectable disease. Complete surgical resection is technically challenging, as tumor proximity to the structures of the central liver often necessitates an extended hepatectomy to achieve negative margins. Intraoperative frozen section can aid in assuring negative margins and complete resection. Portal lymphadenectomy provides important prognostic and staging information. In specialized centers, vascular resection and reconstruction can be performed to achieve negative margins in appropriately selected patients. In addition, minimally invasive surgical techniques (e.g., robotic surgery) are safe, feasible, and provide equivalent short-term oncologic outcomes. Neoadjuvant chemoradiation therapy followed by liver transplantation provides a potentially curative option for patients with unresectable disease. New trials are needed to investigate novel chemotherapies, immunotherapies, and targeted therapies to better control systemic disease in the adjuvant setting and, potentially, downstage disease in the neoadjuvant setting.

Hepatocellular carcinoma (HCC) is a major cause of mortality worldwide with an increasing incidence due to escalating rates of obesity and non-alcoholic fatty liver disease. Unfortunately, a majority of patients with HCC present with advanced disease. The immune checkpoint inhibitor atezolizumab, a PD-L1 inhibitor, in combination with bevacizumab, anti-VEGF, has become the new standard of care for patients with advanced HCC after demonstrating improved overall and progression free survival over sorafenib. In this review, we discuss the evolving role of immune checkpoint inhibitors in the treatment of HCC and their safety, efficacy, and tolerability.

BACKGROUND:Hepatic adenomas (HA), or hepatocellular adenomas, are benign, solid liver lesions that develop in otherwise normal livers, often in the setting of increased estrogen levels. While considered a benign tumor, there is a risk for substantial complications such as hemorrhage and malignant transformation. We review the diagnosis, classification, and potential therapeutic management options for patients with HA. METHODS:A scoping narrative review was conducted based on recent literature regarding classification, diagnosis, and management of HA. RESULTS:While HAs are typically considered benign, complications such as hemorrhage and malignant transformation may occur in approximately 25% and 5% of patients, respectively. Recent advances in imaging and molecular profiling have allowed for the classification of HAs into subtypes allowing for patient risk stratification that helps guide management. Surgical resection should be considered in asymptomatic patients who are male, have an adenoma ≥5 cm in diameter, or have the β-catenin-activated subtype due to an increased risk of hemorrhage and/or malignant transformation. CONCLUSION:Molecular profiling has aided in the stratification of patients relative to the risk of complications to predict better the potential behavior of HAs.

INTRODUCTION/BACKGROUND:Unfortunately, some hepatocellular carcinoma (HCC) patients do not qualify for curative-intent treatments such as surgical resection or transplantation. Hence, locoregional treatments such as transarterial chemoembolization (TACE) remain instrumental in the treatment of HCC. Systemic therapy has improved over the past decade with the introduction of combination atezolizumab and bevacizumab as the new standard of care for advanced disease. These new therapies are currently under investigation in combination with TACE. AREA COVERED/METHODS:Combination therapies with TACE including systemic therapies, locoregional therapies, and immunotherapies are reviewed. EXPERT OPINION/CONCLUSIONS:There has been limited progress in the management of advanced and intermediate HCC. Recent advances in the management of advanced disease with systemic therapy could be beneficial in combination with TACE for the treatment of intermediate stage disease. Immune based therapies are potentially beneficial in combination with TACE because TACE may produce increased antigen release and immune recognition.

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer behind hepatocellular carcinoma (HCC) and carries a dismal prognosis. Improved genetic analysis has paved the way for a better understanding of the distinct somatic genomic landscapes of ICC. The use of next generation sequencing has paved the way for more personalized medicine through identifying unique mutations which may prove to be therapeutic targets. The ability to identify biomarkers specific to ICC will assist in establishing a diagnosis, monitoring response to therapy, as well as assist in identifying novel therapies and personalized medicine. Herein, we discuss potential biomarkers for ICC and how these markers can assist in diagnosis, monitor response to therapy, and potentially identify novel interventions for the treatment of ICC.

INTRODUCTION/BACKGROUND:HCC comprises roughly 60 to 80% of all primary liver cancers and exhibits wide geographical variability. Appropriate treatment allocation needs to include both patient and tumor characteristics. AREAS COVERED/METHODS:Current HCC classification systems to guide therapy are either liver function-centric and evaluate physiologic liver function to guide therapy or prognostic stratification classification systems broadly based on tumor morphologic parameters, patient performance status, and liver reserve assessment. This review focuses on different classification systems for HCC, their strengths, and weaknesses, as well as the use of artificial intelligence in improving prognostication in HCC. EXPERT OPINION/CONCLUSIONS:Future HCC classification systems will need to incorporate clinic-pathologic data from a multitude of sources and emerging therapies to develop patient-specific treatment plans targeting a patient's unique tumor profile.

INTRODUCTION/BACKGROUND:Cholangiocarcinomas (CCA) are rare, highly invasive tumors often diagnosed at an advanced disease stage with an associated poor prognosis. Surgery represents the only chance for curative-intent treatment, but recurrence rates remain high. Neoadjuvant or adjuvant chemotherapy are options for patients with resectable CCA to increase recurrence-free survival and overall survival, while palliative chemotherapy represents the treatment for unresectable disease. Global efforts are currently focused on the development of novel more effective therapies. AREAS COVERED/METHODS:A review was conducted in August 2021 using the PubMed database with the following keywords: 'cholangiocarcinoma,' 'chemotherapy,' and 'therapy.' Manuscripts reporting on first- and second-line chemotherapy, neoadjuvant and adjuvant treatment regimens, and targeted therapies currently being tested or employed in the management of CCA were examined. EXPERT OPINION/CONCLUSIONS:The prognosis of CCA is negatively affected by several factors including a lack of reliable biomarkers leading to delayed diagnoses, high inter- and intra-tumoral heterogeneity, and few effective chemotherapy regimens. In pursuit of more effective therapies, ongoing trials are testing both conventional and targeted drugs.