Faculty Bibliography

BACKGROUND:Choledochal cysts (CCs) are rare cystic dilatations of the intrahepatic and/or extrahepatic bile ducts. We review the pathophysiology, diagnosis, and management of CCs. METHODS:MEDLINE/PubMed and Web of Science databases were queried for "choledochal cyst", "bile duct cyst", "choledochocele", and "Caroli disease". Data were synthesized and systematically reviewed. RESULTS:Classified according to the Todani Classification, CCs are generally believed to arise secondary to reflux of pancreatic enzymes into the biliary tree due to anomalous pancreaticobiliary duct union. Complications of CCs include abdominal pain, jaundice, cystolithiasis, cholecystitis, pancreatitis, liver abscess, liver cirrhosis and malignant transformation (3-7.5%). Radiological and endoscopic imaging is the cornerstone of CC diagnosis and full delineation of cyst anatomy is imperative for proper management. Management is generally guided by cyst classification with complete cyst excision necessary for CCs with high potential of malignant transformation such as types I and IV. 5-year overall survival after choledochal cyst excision is 95.5%. CONCLUSION:Most CCs should undergo surgical intervention to mitigate the risk of cyst related complications such as cholangitis and malignant transformation.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the fourth leading cause of cancer-related death worldwide. HCC often occurs in the setting of chronic liver disease or cirrhosis. Recent evidence has highlighted the importance of the immune microenvironment in the development and progression of HCC, as well as its role in the potential response to therapy. Liver disease such as viral hepatitis, alcohol induced liver disease, and non-alcoholic fatty liver disease is a major risk factor for the development of HCC and has been demonstrated to alter the immune microenvironment. Alterations in the immune microenvironment may markedly influence the response to different therapeutic strategies. As such, research has focused on understanding the complex relationship among tumor cells, immune cells, and the surrounding liver parenchyma to treat HCC more effectively. We herein review the immune microenvironment, as well as the relative effect of liver disease on the immune microenvironment. In addition, we review how changes in the immune microenvironment can lead to therapeutic resistance, as well as highlight future strategies aimed at developing the next-generation of therapies for HCC.

BACKGROUND:Neoadjuvant therapy is increasingly being used before surgery for localized pancreatic cancer. Given the importance of completing multimodal therapy, the aim of this study was to characterize surgical resection rates after neoadjuvant therapy as well as the reasons for, and long-term prognostic impact of, not undergoing resection. METHODS:A systematic review and meta-analysis of prospective trials and high-quality retrospective studies since 2010 was performed to calculate pooled resection rates using a generalized random-effects model for potentially resectable, borderline resectable, and locally advanced pancreatic cancer. Median survival times were calculated using random-effects models for patients who did and did not undergo resection. RESULTS:In 125 studies that met the inclusion criteria, neoadjuvant therapy consisted of chemotherapy (36.8 per cent), chemoradiation (15.2 per cent), or chemotherapy and radiation (48.0 per cent). Among 11 713 patients, the pooled resection rates were 77.4 (95 per cent c.i. 71.3 to 82.5), 60.6 (54.8 to 66.1), and 22.2 (16.7 to 29.0) per cent for potentially resectable, borderline resectable, and locally advanced pancreatic cancer respectively. The most common reasons for not undergoing resection were distant progression for resectable and borderline resectable cancers, and local unresectability for locally advanced disease. Among 42 studies with survival data available, achieving surgical resection after neoadjuvant therapy was associated with improved survival for patients with potentially resectable (median 38.5 versus 13.3 months), borderline resectable (32.3 versus 13.9 months), and locally advanced (30.0 versus 14.6 months) pancreatic cancer (P < 0.001 for all). CONCLUSION:Although rates of surgical resection after neoadjuvant therapy vary based on anatomical stage, surgery is associated with improved survival for all patients with localized pancreatic cancer. These pooled resection and survival rates may inform patient-provider decision-making and serve as important benchmarks for future prospective trials.

Pancreatic ductal adenocarcinoma is an aggressive malignancy that carries a poor prognosis because the majority of patients present with locally advanced or metastatic disease. However, even patients who are fortunate enough to present with resectable disease are often plagued by high recurrence rates. While adjuvant chemotherapy has been shown to decrease the risk of recurrence after surgery, post operative complications and poor performance status after surgery prevent up to 50% of patients from receiving it. Given the benefits of neoadjuvant therapy in patients with borderline resectable disease, it is understandable that neoadjuvant therapy has been steadily increasing in patients with resectable cancers as well. In this review paper, we highlight the rational and existing evidence of using neoadjuvant therapy in all patients with resectable pancreatic adenocarcinoma.

Surgical management combined with improved systemic therapies have extended 5-year overall survival beyond 50% among patients with colorectal liver metastases (CRLM). Furthermore, a multitude of liver-directed therapies has improved local disease control for patients with unresectable CRLM. Unfortunately, a significant portion of patients treated with curative-intent hepatectomy develops disease recurrence. Traditional markers fail to risk-stratify and prognosticate patients with CRLM appropriately. Over the last few decades, advances in molecular sequencing technology have greatly expanded our knowledge of the pathophysiology and tumor microenvironment characteristics of CRLM. These investigations have revealed biomarkers with the potential to better inform management decisions in patients with CRLM. Actionable biomarkers such as RAS and BRAF mutations, microsatellite instability/mismatch repair status, and tumor mutational burden have been incorporated into national and societal guidelines. Other biomarkers, including circulating tumor DNA and radiomic features, are under active investigation to evaluate their clinical utility. Given the plethora of therapeutic modalities and lack of evidence on timing and sequence, reliable biomarkers are needed to assist clinicians with the development of patient-tailored management plans. In this review, we discuss the current evidence regarding biomarkers for patients with CRLM.

Platelets, the often-overlooked component of the immune system, have been shown to promote tumor growth. Non-alcoholic fatty liver disease (NAFLD) is a common disease in the Western world and rising risk for hepatocellular carcinoma (HCC). Unexpectedly, we observed that platelets can inhibit the growth of established HCC in NAFLD mice. Through pharmacological inhibition and genetic depletion of P2Y12 as well as in vivo transfusion of wild-type (WT) or CD40L^-/- platelets, we demonstrate that the anti-tumor function of platelets is mediated through P2Y12-dependent CD40L release, which leads to CD8⁺ T cell activation by the CD40 receptor. Unlike P2Y12 inhibition, blocking platelets with aspirin does not prevent platelet CD40L release nor accelerate HCC in NAFLD mice. Similar findings were observed in liver metastasis models. All together, our study reveals a complex role of platelets in tumor regulation. Anti-platelet treatment without inhibiting CD40L release could be considered for liver cancer patients with NAFLD.

Regardless of anatomic origin, cholangiocarcinoma is generally an aggressive malignancy with a relatively high case fatality. Surgical resection with curative intent remains the best opportunity to achieve meaningful long-term survival. Most patients present, however, with advanced disease and less than 20% of patients are candidates for surgical resection. Unfortunately, even patients who undergo resection have a 5-year survival that ranges from 20 to 40%. Biomarkers are indicators of normal, pathologic, or biologic responses to an intervention and can range from a characteristic (i.e., blood pressure reading which can detect hypertension) to specific genetic mutations or proteins (i.e., carcinoembryonic antigen level). Novel biomarkers and improved molecular diagnostics represent an attractive opportunity to improve detection as well as to identify novel therapeutic targets for patients with cholangiocarcinoma. We herein review the latest advances in molecular diagnostics and biomarkers related to the early detection and treatment of patients with cholangiocarcinoma.

Hepatic, pancreatic, and biliary (HPB) cancers, including hepatocellular carcinoma (HCC), pancreatic ductal adenocarcinoma (PDAC), and cholangiocarcinoma (CCA) cause a disproportionate amount of the global cancer-related mortality. Despite advances in surgical technique and improved systemic therapies, overall 5-year survival remains dismal, especially for patients with pancreatic and biliary cancer. Historically, systemic therapies for patients with HPB cancers were administered in a "one-size-fits-all" approach due to limited reliable data on efficacy for specific patient populations. However, recent advances in genetic testing techniques have greatly improved our understanding of HPB oncogenesis, shedding light on specific genetic mutations responsible for progression from physiologic cellular regulation to uninhibited cellular replication and invasive cancer. Investigations into the oncogenesis of HPB cancers have revealed multiple actionable genetic variants, as well as increased susceptibilities to currently available systemic therapies. For example, patients with PDAC and a known BRCA mutation are more likely to benefit from FOLFIRINOX or gemcitabine plus cisplatin. While patients with CCA and a IDH1 mutation may benefit from ivosidenib. As a result, many national and societal guidelines now recommend some form of genetic testing in the workup of patients with HPB cancers. We herein review the role of genetic testing in these aggressive cancers including DNA sequencing techniques, clinically relevant mutations, therapeutic implications, and current clinical recommendations.

BACKGROUND:Hepatic hemangiomas (HHs) are benign liver lesions often discovered incidentally on imaging for various unrelated pathologies. We herein review the etiology, classification, diagnostic imaging, and management of HHs. METHODS:A comprehensive systematic review was performed utilizing MEDLINE/PubMed and Web of Science databases, with the end of search date being March 1, 2022, regarding HH diagnosis, imaging, and management. RESULTS:HHs can be broadly classified as capillary hemangiomas or cavernous hemangiomas. While the exact pathophysiology related to the development of HHs remains largely unknown, hormone exposure has been postulated to cause HH growth. HHs appear homogenously hyperechoic on US with distinct margins and posterior acoustic enhancement. While cavernous hemangiomas appear as well-defined hypodense lesions on pre-contrast CT images with the same density as the vasculature, one of the most reliable imaging features for diagnosing cavernous hemangiomas is high signal intensity on T2 weighted images. While most HHs are asymptomatic, some patients can present with pain or compressive symptoms with bleeding/rupture being very rare. Kasabach-Merritt syndrome is a rare but life-threatening condition associated with thrombocytopenia and microangiopathic hemolytic anemia. When HHs are symptomatic or in the setting of Kasabach Merritt syndrome, surgery is indicated. Enucleation is an attractive surgical option for HH as it spares normal liver tissue. Most patients experience symptom relief following surgical resection. CONCLUSION:HHs are very common benign liver lesions. High-quality imaging is imperative to distinguish HHs from other liver lesions. Surgery is generally reserved for patients who present with symptoms such as pain, obstruction, or rarely Kasabach-Merritt syndrome. Surgery can involve either formal resection or, in most instances, simple enucleation. Patients generally have good outcomes following surgery with resolution of their symptoms.