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Abstract Allostatic load (AL) is a biological measure of cumulative exposure to socioenvironmental stressors (e.g., poverty). This study aims to examine the association between allostatic load (AL) and postoperative complications (POC) among patients with breast cancer. Females ages 18+ with stage I-III breast cancer who received surgical management between 01/01/2012-12/31/2020 were identified in the Ohio State Cancer registry. The composite AL measure included biomarkers from the cardiovascular, metabolic, immune, and renal systems. High AL was defined as composite scores greater than the cohort’s median (2.0). POC within 30 days of surgery were examined. Univariable and multivariable regression analysis examined the association between AL and POC. Among 4459 patients, 8.2% had POC. A higher percentage of patients with POC were unpartnered (POC 44.7% vs no POC 35.5%), government-insured (POC 48.2% vs no POC 38.3%) and had multiple comorbidities (POC 32% vs no POC 20%). Patients who developed POC were more likely to have undergone sentinel lymph node biopsy followed by axillary lymph node dissection (POC 51.2% vs no POC 44.6%). High AL was associated with 29% higher odds of POC (aOR 1.29, 95% CI 1.01–1.63). A one-point increase in AL was associated with 8% higher odds of POC (aOR 1.08, 95% CI 1.02-1.16) and a quartile increase in AL was associated with 13% increased odds of POC (aOR 1.13, 95% CI 1.01–1.26). Among patients undergoing breast cancer surgery, increased exposure to adverse socioenvironmental stressors, operationalized as AL, was associated with higher odds of postoperative complications.

Abstract Background The addition of radiation therapy (RT) to surgery in retroperitoneal sarcoma (RPS) remains controversial. We examined practice patterns in the use of RT for patients with RPS over time in a large, national cohort. Methods Patients in the National Cancer Database (2004–2017) who underwent resection of RPS were included. Trends over time for proportions were calculated using contingency tables with Cochran-Armitage Trend test. Results Of 7,485 patients who underwent resection, 1,821 (24.3%) received RT (adjuvant: 59.9%, neoadjuvant: 40.1%). The use of RT decreased annually by 10 cm (OR 2.009, p = 0.001) were associated with neoadjuvant RT. In contrast liposarcomas (OR 0.574, p = 0.001) were associated with adjuvant RT. There was no statistically significant difference in overall survival between patients treated with surgery alone versus surgery and RT (p = 0.07). Conclusion In the United States, the use of RT for RPS has decreased over time, with a shift towards neoadjuvant RT. However, a large percentage of patients are still receiving adjuvant RT and this mostly occurs at low-volume hospitals.

Background: The association of social vulnerability (SV) and cardiac transplant survival remains poorly defined, particularly related to long-term outcomes. The purpose of this study was to define the impact of SV on survival among heart transplant recipients with at least 1 year of survival post-transplant. Methods: Heart transplant recipients were identified using the United Network for Organ Sharing database between June 1, 2006, and December 31, 2020. The Center for Disease Control’s Social Vulnerability Index (SVI) database was used to stratify patients based on SVI into 3 groups: low:

Colorectal cancer (CRC) represents a significant global healthcare burden, with a particularly concerning rising incidence among younger adults. This trend may highlight potential links between diet, gut microbiome, and CRC risk. Novel therapeutic options have been increasingly based on the understanding of molecular mechanisms and pathways. The PI3K/AKT/mTOR pathway, a crucial cell growth regulator, offers a promising target for CRC therapy. mTOR, a key component within this pathway, controls cell growth, survival, and metabolism. Understanding the specific roles of defensins, particularly human β-Defensin 1 (HBD-1), in CRC is crucial. HBD-1 exhibits potent antimicrobial activity and may influence CRC development. Deciphering defensin expression patterns in CRC holds the promise of improved understanding of tumorigenesis, which may pave the way for improved diagnostics and therapies. This article reviews recent advances in understanding regarding how HBD-1 influences CRC initiation and progression, highlighting the molecular mechanisms by which it impacts CRC. Further, we describe the interaction between defensins and mTOR pathway in CRC.

Surgical resection and liver transplant remain the only curative therapies for most patients with hepatocellular carcinoma (HCC). Systemic therapy options have typically been ineffective, but recent advances, such as the combination of immune checkpoint inhibitors and targeted therapies, have shown great promise. Neoadjuvant systemic therapy in resectable or locally advanced HCC is under active investigation with encouraging results in small, early-phase trials. Many of these completed and ongoing trials include combinations of systemic therapy (e.g. immune checkpoint inhibitors, tyrosine kinase inhibitors), transarterial therapies, and radiation. Despite early successes, larger trials with evaluation of long-term oncologic outcomes are needed to determine the role of neoadjuvant systemic therapy in patients with HCC who may be eligible for curative intent surgery or transplant.

Background & aimsThe effectiveness of adjuvant immunotherapy to diminish recurrence and improve long-term prognosis following curative-intent surgical resection for hepatocellular carcinoma (HCC) is of increased interest, especially among individuals at high risk of recurrence. The objective of the current study was to investigate the impact of adjuvant immunotherapy on long-term recurrence and survival after curative resection among patients with intermediate/advanced HCC.MethodsUsing a prospectively-collected multicenter database, patients who underwent curative-intent resection for Barcelona Clinic Liver Cancer (BCLC) stage B/C HCC were identified. Propensity score matching (PSM) analysis was used to compare recurrence-free survival (RFS) and overall survival (OS) between patients treated with and without adjuvant immune checkpoint inhibitors (ICIs). Multivariate Cox-regression analysis further identified independent factors of RFS and OS.ResultsAmong the 627 enrolled patients, 109 patients (23.3%) received adjuvant immunotherapy. Most ICI-related adverse reactions were grading I-II. PSM analysis created 99 matched pairs of patients with comparable baseline characteristics between patients treated with and without adjuvant immunotherapy. In the PSM cohort, the median RFS (29.6 vs. 19.3 months, P=0.031) and OS (35.1 vs. 27.8 months, P=0.036) were better among patients who received adjuvant immunotherapy versus patients who did not. After adjustment for other confounding factors on multivariable analyzes, adjuvant immunotherapy remained independently associated with favorable RFS (HR: 0.630; 95% CI: 0.435-0.914; P=0.015) and OS (HR: 0.601; 95% CI: 0.401-0.898; P=0.013). Subgroup analyzes identified potentially prognostic benefits of adjuvant immunotherapy among patients with intermediate-stage and advanced-stage HCC.ConclusionThis real-world observational study demonstrated that adjuvant immunotherapy was associated with improved RFS and OS following curative-intent resection of intermediate/advanced HCC. Future randomized controlled trials are warranted to establish definitive evidence for this specific population at high risks of recurrence.

The Centers for Medicare & Medicaid Services have mandated that hospitals implement measures to screen social determinants of health (SDoH). We sought to report on available SDoH screening tools. PubMed, Scopus, Web of Science, as well as the grey literature were searched (1980 to November 2023). The included studies were US-based, written in English, and examined a screening tool to assess SDoH. Thirty studies were included in the analytic cohort. The number of questions in any given SDoH assessment tool varied considerably and ranged from 5 to 50 (mean: 16.6). A total of 19 SDoH domains were examined. Housing (n = 23, 92%) and safety/violence (n = 21, 84%) were the domains assessed most frequently. Food/nutrition (n = 17, 68%), income/financial (n = 16, 64%), transportation (n = 15, 60%), family/social support (n = 14, 56%), utilities (n = 13, 52%), and education/literacy (n = 13, 52%) were also commonly included domains in most screening tools. Eighteen studies proposed specific interventions to address SDoH. SDoH screening tools are critical to identify various social needs and vulnerabilities to help develop interventions to address patient needs. Moreover, there is marked heterogeneity of SDoH screening tools, as well as the significant variability in the SDoH domains assessed by currently available screening tools.

Intrahepatic cholangiocarcinoma (ICCA) is a rare and aggressive malignant tumor that arises from the biliary tracts in the liver. Upfront surgery with adjuvant capecitabine in patients with resectable disease is often the standard treatment. Unfortunately, only 20% of patients present with resectable disease and many individuals will develop recurrence or metastatic disease after curative-intent resection. Patients with advanced or metastatic ICCA often require multidisciplinary care with a combination of cytotoxic chemotherapy, targeted therapy, and/or locoregional therapies. Gemcitabine plus cisplatin is currently first line therapy for advanced or metastatic ICCA. In recent years, efforts have been focused to develop more effective targeted therapy, most commonly with FGFR and IDH inhibitors for ICCA. Despite these efforts, ICCA still carries a poor prognosis. We herein review the current clinical management of ICCA focusing on surgical technique and systemic therapies.

In 2022, colorectal cancer (CRC) was the third most prevalent malignancy worldwide. The therapeutic approach for CRC typically involves a multimodal regimen. The human gut microbiota comprises over 35,000 bacterial species. The composition of the gut microbiota is influenced by dietary intake, which plays a crucial role in food absorption, nutrient extraction, and the development of low-grade inflammation. Dysbiosis in the gut microbiota is a key driver of inflammation and is strongly associated with CRC development. While the gut microbiome influences CRC initiation and progression, emerging evidence suggests a role for the gut microbiome in modulating the efficacy and toxicity of cancer treatments. Therapeutic strategies targeting the gut microbiome, such as probiotics, hold promise as effective interventions in the modern therapeutical approach to CRC. For example, Microbiota Implementation to Reduce Anastomotic Colorectal Leaks (MIRACLe) implementation has resulted in improvements in clinical outcomes, including reduced incidence of anastomotic leakage (AL), surgical site infections (SSIs), reoperation, as well as shorter recovery times and hospital stays compared with the control group. Therefore, this review aims to describe the current state of knowledge regarding the involvement of the gut microbiota in CRC pathogenesis and its potential therapeutic implications to treat CRC.

The incidence of gastric cancer (GC) is expected to increase to 1.77 million cases by 2040. To improve treatment outcomes, GC patients are increasingly treated with neoadjuvant chemotherapy (NAC) prior to curative-intent resection. Although NAC enhances locoregional control and comprehensive patient care, survival rates remain poor, and further investigations should establish outcomes assessment of current clinical pathways. Individually assessed parameters have served as benchmarks for treatment quality in the past decades. The Outcome4Medicine Consensus Conference underscores the inadequacy of isolated metrics, leading to increased recognition and adoption of composite measures. One of the most simple and comprehensive is the “All or None” method, which refers to an approach where a specific set of criteria must be fulfilled for an individual to achieve the overall measure. This narrative review aims to present the rationale for the implementation of a novel composite measure, Textbook Neoadjuvant Outcome (TNO). TNO integrates five objective and well-established components: Treatment Toxicity, Laboratory Tests, Imaging, Time to Surgery, and Nutrition. It represents a desired, multidisciplinary care and hospitalization of GC patients undergoing NAC to identify the treatment- and patient-related data required to establish high-quality oncological care further. A key strength of this narrative review is the clinical feasibility and research background supporting the implementation of the first and novel composite measure representing the “ideal” and holistic care among patients with locally advanced esophago-gastric junction (EGJ) and GC in the preoperative period after NAC. Further analysis will correlate clinical outcomes with the prognostic factors evaluated within the TNO framework.

The liver maintains a balance between immune tolerance and activation in its role as a filtration system. Chronic inflammation disrupts this immune microenvironment, thereby allowing for the rise and progression of cancer. Hepatocellular carcinoma (HCC) is a liver tumor generally diagnosed in the setting of chronic liver disease. When diagnosed early, the primary treatment is surgical resection, liver transplantation, or liver directed therapies. Unfortunately, patients with HCC often present at an advanced stage or with poor liver function, thereby limiting options. To further complicate matters, most systemic therapies are relatively limited and ineffective among patients with advanced disease. Recently, the IMbrave150 trial demonstrated that the combination of atezolizumab and bevacizumab was associated with better survival compared to sorafenib among patients with advanced HCC. As such, atezolizumab and bevacizumab is now recommended first-line therapy for these patients. Tumor cells work to create an immunotolerant environment by preventing the activation of stimulatory immunoreceptors and upregulating expression of proteins that bind inhibitory immunoreceptors. ICIs work to block these interactions and bolster the anti-tumor function of the immune system. We herein provide an overview of the use of ICIs in the treatment of HCC.

Pancreatic adenocarcinoma (PDAC) is disease with a 5-year survival of only 12%. Many patients with PDAC present with late-stage disease and even early-stage disease can often be characterized by an aggressive tumor biology. Standard therapy for metastatic PDAC consists mainly of chemotherapy regimens like FOLFIRINOX, FOLFOX, or gemcitabine and nab-paclitaxel. Research has focused on sequencing PDAC tumors to understand better the mutational landscape and transcriptomics of PDAC with the goal to develop targeted therapies. Targeted therapies may potentially minimize the toxic risks of chemotherapy and provide a long-term survival benefit. We herein review the underlying molecular pathogenesis of PDAC, as well as the classification schema created from current sequencing data, and recent updates related to targeted therapy for PDAC.

The 5th edition of the World Health Organization (WHO) classification of tumors of the digestive system distinguishes four categories of appendiceal tumors (ATs): serrated lesions and polyps, mucinous neoplasms, adenocarcinomas, and neuroendocrine neoplasms (NENs). The differential diagnosis of ATs can be challenging in medical practice, due to their rarity and lack of data from randomized controlled trials on a large, diverse group of patients. ATs are usually noted in specimens obtained during appendectomies due to clinical acute appendicitis. In the European population, most ATs (65%) occur over the age of 50 and among women (56.8%). According to histological type, 54.6% are neuroendocrine tumors (NETs); 26.8% cystic, mucinous, and serous neoplasms; and 18.6% adenocarcinoma not otherwise specified (NOS). On pathologic analysis, most AT findings are benign lesions or small NENs that do not require further therapeutic measures. The presence of appendiceal mucinous neoplasm (AMN) can lead to pseudomyxoma peritonei (PMP). While the multimodal treatment for abdominal malignancies has evolved over the past several decades, the clinical workup and treatment of ATs remain a challenge. Therefore, this review aims to describe the diagnostic possibilities, molecular-based diagnosis, staging, differences in the treatment process, and prognostic factors associated with ATs.

Since increasing evidence underlines the prominent role of systemic inflammation in carcinogenesis, the inflammation burden index (IBI) has emerged as a promising biomarker to estimate survival outcomes among cancer patients. The IBI has only been validated in Eastern gastric cancer (GC) patients; therefore, the aim of this study was to evaluate the IBI as a prognostic biomarker in Central European GC patients undergoing multimodal treatment. Ninety-three patients with histologically confirmed GC who underwent multimodal treatment between 2013 and 2021 were included. Patient recruitment started with the standardization of neoadjuvant chemotherapy (NAC). Blood samples were obtained one day prior to surgical treatment. The textbook outcome (TO) served as the measure of surgical quality, and tumor responses to NAC were evaluated according to Becker’s system tumor regression grade (TRG). A high IBI was associated with an increased risk of postoperative complications (OR 2.95, 95% CI 1.13–7.72). In multivariate analysis, a high IBI (HR = 2.56, 95% CI 1.28–5.13) and a high neutrophil-to-lymphocyte ratio (NLR, HR = 2.55, 95% CI 1.32–4.94) were associated with an increased risk of death, while NAC administration (HR = 0.40, 95% CI 0.18–0.90) and TO achievement (HR = 0.42, 95% CI 0.22–0.81) were associated with a lower risk of death. The IBI was associated with postoperative complications and mortality among GC patients undergoing multimodal treatment.

Metastatic colorectal cancer remains a deadly malignancy and is the third leading cause of cancer-related death. The mainstay of treatment for metastatic colorectal cancer is chemotherapy, but unfortunately, even with recent progress, overall survival is still poor. Colorectal cancer is a heterogeneous disease, and the underlying genetic differences among tumors can define the behavior and prognosis of the disease. Given the limitations of cytotoxic chemotherapy, research has focused on developing targeted therapy based on molecular subtyping. Since the early 2000s, multiple targeted therapies have demonstrated efficacy in treating metastatic colorectal cancer and have received FDA approval. The epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and DNA mismatch repair pathways have demonstrated promising results for targeted therapies. As new gene mutations and proteins involved in the oncogenesis of metastatic colorectal cancer are identified, new targets will continue to emerge. We herein provide a summary of the updated literature regarding targeted therapies for patients with mCRC.

Cachexia is a condition characterized by substantial loss of body weight resulting from the depletion of skeletal muscle and adipose tissue. A considerable fraction of patients with advanced cancer, particularly those who have been diagnosed with pancreatic or gastric cancer, lung cancer, prostate cancer, colon cancer, breast cancer, or leukemias, are impacted by this condition. This syndrome manifests at all stages of cancer and is associated with an unfavorable prognosis. It heightens the susceptibility to surgical complications, chemotherapy toxicity, functional impairments, breathing difficulties, and fatigue. The early detection of patients with cancer cachexia has the potential to enhance both their quality of life and overall survival rates. Regarding this matter, blood biomarkers, although helpful, possess certain limitations and do not exhibit universal application. Additionally, the available treatment options for cachexia are currently limited, and there is a lack of comprehensive understanding of the underlying molecular pathways associated with this condition. Thus, this review aims to provide an overview of molecular mechanisms associated with cachexia and potential therapeutic targets for the development of effective treatments for this devastating condition.

Patients who undergo resection for non-invasive IPMN are at risk for long-term recurrence. Further evidence is needed to identify evidence-based surveillance strategies based on the risk of recurrence. We performed a systematic review of the current literature regarding recurrence patterns following resection of non-invasive IPMN to summarize evidence-based recommendations for surveillance. Among the 61 studies reviewed, a total of 8779 patients underwent resection for non-invasive IPMN. The pooled overall median follow-up time was 49.5 months (IQR: 38.5–57.7) and ranged between 14.1 months and 114 months. The overall median recurrence rate for patients with resected non-invasive IPMN was 8.8% (IQR: 5.0, 15.6) and ranged from 0% to 27.6%. Among the 33 studies reporting the time to recurrence, the overall median time to recurrence was 24 months (IQR: 17, 46). Existing literature on recurrence rates and post-resection surveillance strategies for patients with resected non-invasive IPMN varies greatly. Patients with resected non-invasive IPMN appear to be at risk for long-term recurrence and should undergo routine surveillance.

Shortages of psychiatrists can lead to disparities in access to mental healthcare. We examined block-level access to psychiatric services via geospatial analysis of locations registered with National Provider Identifier numbers accounting for travel time. Among 718 counties from 12 states, 208 (29%) counties had less than half of their population within 30-min travel time, while only 51 (6%) provided their entire population convenient access to psychiatrists. A considerable amount of the population resides in areas underserved by psychiatry services with varied disparities by rurality and state. Improving access to care could improve mental health outcomes in vulnerable populations.

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.

Hepatocellular Carcinoma (HCC) is one of the most common cancers and a leading cause of cancer related death worldwide. Until recently, systemic therapy for advanced HCC, defined as Barcelona Clinic Liver Cancer (BCLC) stage B or C, was limited and ineffective in terms of long-term survival. However, over the past decade, immune check point inhibitors (ICI) combinations have emerged as a potential therapeutic option for patients with nonresectable disease. ICI modulate the tumor microenvironment to prevent progression of the tumor. Radiotherapy is a crucial tool in treating unresectable HCC and may enhance the efficacy of ICI by manipulating the tumor microenvironment and decreasing tumor resistance to certain therapies. We herein review developments in the field of ICI combined with radiotherapy for the treatment of HCC, as well as look at challenges associated with these treatment modalities, and review future directions of combination therapy.

Cholangiocarcinoma (CCA) is a rare malignancy of the intrahepatic and extrahepatic biliary ducts. CCA is primarily defined by its anatomic location: intrahepatic cholangiocarcinoma versus extrahepatic cholangiocarcinoma. Hilar cholangiocarcinoma (HC) is a subtype of extrahepatic cholangiocarcinoma that arises from the common hepatic bile duct and can extend to the right and/or left hepatic bile ducts. Upfront surgery with adjuvant capecitabine is the standard of care for patients who present with early disease and the only curative therapy. Unfortunately, most patients present with locally advanced or metastatic disease and must rely on systemic therapy as their primary treatment. However, even with current systemic therapy, survival is still poor. As such, research is focused on developing targeted therapies and multimodal strategies to improve overall prognosis. This review discusses the work-up and management of HC focused on the most up-to-date literature and ongoing clinical trials.

Introduction: The role of surgery in stage IV gastric cancer with peritoneal metastasis (PM) remains unclear. The objective of the current single-center study was to define the impact of gastrectomy with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) on outcomes among Central European GC patients with limited peritoneal disease progression after neoadjuvant chemotherapy (NAC). Methods: Patients with histologically confirmed GC who underwent curative-intent multimodal treatment between 2013 and 2023 were included. Patients without adenocarcinoma, who did not undergo gastrectomy, had early (cT1) or metastatic GC at the time of initial diagnosis, who underwent multivisceral resection, incomplete cytoreduction or palliative care, died before planned curative-intent treatment, or had incomplete clinical or pathological missing information were excluded. Results: A total of 74 patients who underwent curative-intent treatment for GC with PM were included in the final analytic cohort. Patients who underwent gastrectomy with CRS+HIPEC were less likely to achieve TOO (CRS+HIPEC: 28% vs. CRS: 57.1%, p = 0.033) compared with individuals after CRS alone. Specifically, patients who underwent gastrectomy with CRS+HIPEC had a higher likelihood of postoperative complications (CRS+HIPEC: 48% vs. CRS: 20.4%, p = 0.018) and longer hospital LOS (median, CRS+HIPEC: 12 vs. CRS: 10, p = 0.019). While administration of HIPEC did not impact long-term survival (median OS, CRS+HIPEC: 16 months vs. CRS: 12 months, p = 0.55), postoperative complications (median OS, CCI < 30:16 months vs. CCI > 30:5 months, p = 0.024) and ICU stay (median OS, no ICU stay: 16 months vs. ICU stay: 5 months, p = 0.008) were associated with worsened long-term survival among GC patients with PM. Conclusions: Data from the current study demonstrated a lack of survival benefit among advanced GC patients with PM undergoing gastrectomy with CRS+HIPEC when compared with individuals after gastrectomy with CRS alone. Administration of perioperative chemotherapy and achievement of TO failed to withstand the peritoneal disease progression during NAC.

Thermal ablation, including microwave ablation, has become increasingly important in the management of many solid tumors, including primary and metastatic tumors of the liver, kidney, and lung. However, its adoption to treat pancreatic lesions has been slowed due to concerns about potential adverse events. The success of radiofrequency ablation (RFA) in inoperable pancreatic cancers paved the way for its use in pancreatic neuroendocrine tumors and pancreatic cystic neoplasms (PCLs). In the last decade, other thermal ablation techniques, like microwave ablation, have emerged as alternatives to RFA. Microwaves, with frequencies ranging from 900 to 2450 MHz, generate heat by rapidly oscillating water molecules. Microwave ablation’s advantage lies in its ability to achieve higher intra-lesion temperatures and uniform heating compared with RFA. Microwave ablation’s application in pancreatic cancer and pancreatic neuroendocrine tumors has demonstrated promise with similar technical success to RFA. Yet, concern for peri-procedure complications, as well as a dearth of studies comparing RFA and microwave ablation, emphasize the need for further research. No studies have evaluated microwave ablation in PCLs. We herein review thermal ablation’s potential to treat pancreatic lesions.

Hepatocellular carcinoma (HCC) is the fourth most common malignancy worldwide and exhibits a universal burden as the incidence of the disease continues to rise. In addition to curative-intent therapies such as liver resection and transplantation, locoregional and systemic therapy options also exist. However, existing treatments carry a dismal prognosis, often plagued with high recurrence and mortality. For this reason, understanding the tumor microenvironment and mutational pathophysiology has become the center of investigation for disease control. The use of precision medicine and genetic analysis can supplement current treatment modalities to promote individualized management of HCC. In the search for personalized medicine, tools such as next-generation sequencing have been used to identify unique tumor mutations and improve targeted therapies. Furthermore, investigations are underway for specific HCC biomarkers to augment the diagnosis of malignancy, the prediction of whether the tumor environment is amenable to available therapies, the surveillance of treatment response, the monitoring for disease recurrence, and even the identification of novel therapeutic opportunities. Understanding the mutational landscape and biomarkers of the disease is imperative for tailored management of the malignancy. In this review, we summarize the molecular targets of HCC and discuss the current role of precision medicine in the treatment of HCC.

Transplant oncology is a relatively new field in which transplantation is used to treat patients who would otherwise be unresectable. New anticancer treatment paradigms using tumor and transplant immunology and cancer immunogenomics are emerging. In turn, liver transplantation (LT) has become a potential therapy for certain patients with colorectal cancer (CRC) with liver metastasis, hepatocellular (HCC), cholangiocarcinoma (CCA), and metastatic neuroendocrine tumor (NET) of the liver. Although there are established criteria for LT in HCC, evidence regarding LT as a treatment modality for certain gastrointestinal malignancies is still debated. The aim of this review is to highlight updates in the role of LT for certain malignancies, including HCC, metastatic CRC, hilar CCA, and neuroendocrine tumor (NET), as well as contextualize LT use and discuss controversies in transplant oncology.

Colorectal cancer (CRC) is the second most common cause of cancer-related mortality in the United States. Among newly diagnosed patients with CRC, 20% will present with metastatic disease and another 25% will develop metastases. The surgical resection of the primary tumor and metastatic disease sites confers the best chance at long-term survival. Unfortunately, many patients will recur after resection or present with unresectable disease. As such, metastatic CRC is commonly treated with a combination of surgery, systemic therapy, and/or liver-directed therapies. Despite best efforts, 5-year survival for unresectable metastatic CRC is only about 20%. CRC is a heterogeneous disease and the underlying genetic differences inform behavior, treatment strategy, and prognosis. Given the limitations of cytotoxic chemotherapy and the growing role of molecular profiling, research has focused on identifying and developing targeted therapies. We herein review how genetic profiling informs prognosis, crucial cell-signaling pathways that play a role in CRC carcinogenesis, and currently approved targeted therapies for metastatic CRC.

Abstract Background and aims Although adjuvant transcatheter arterial chemoembolization (TACE) for resected hepatocellular carcinoma (HCC) may improve survival for some patients, identifying which patients can benefit remains challenging. The present study aimed to construct a survival prediction calculator for individualized estimating the net survival benefit of adjuvant TACE for patients with resected HCC. Methods From a multicenter database, consecutive patients undergoing curative resection for HCC were enrolled and divided into the developing and validation cohorts. Using the independent survival predictors in the developing cohort, two nomogram models were constructed for patients with and without adjuvant TACE, respectively, which predictive performance was validated internally and externally by measuring concordance index (C-index) and calibration. The difference between two estimates of the prediction models was the expected survival benefit of adjuvant TACE. Results A total of 2514 patients met the inclusion criteria for the study. The nomogram prediction models for patients with and without adjuvant TACE were, respectively, built by incorporating the same eight independent survival predictors, including portal hypertension, Child–Pugh score, alpha-fetoprotein level, tumor size and number, macrovascular and microvascular invasion, and resection margin. These two prediction models demonstrated good calibration and discrimination, with all the C-indexes of greater than 0.75 in the developing and validation cohorts. A browser-based calculator was generated for individualized estimating the net survival benefit of adjuvant TACE. Conclusions Based on large-scale real-world data, an easy-to-use online calculator can be adopted as a decision aid to predict which patients with resected HCC can benefit from adjuvant TACE.

BackgroundPrior studies attempting to identify disparities in the care of patients with appendiceal (AC) or colorectal cancer (CRC) with peritoneal metastasis (PM) are limited to single-institution, highly selected patient populations. This observational cohort study sought to identify factors associated with specialty care for Medicare beneficiaries with AC/CRC-PM.Materials and methodsPatients >65 years old in the United States diagnosed with AC/CRC and isolated PM were identified within the Medicare Standard Analytic File (2013-2017). Mixed-effects analyses assessed patient factors associated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) and outpatient consultation with a peritoneal surface malignancy (PSM) surgeon, and Cox proportional-hazards analysis compared 3-year overall survival (OS) between patients receiving CRS/HIPEC versus systemic therapy alone.ResultsAmong 7,653 patients, only 250 (3.3%) underwent CRS/HIPEC. Among those individuals who did not undergo CRS/HIPEC (N=7,403), only 475 (6.4%) had outpatient consultation with a PSM surgeon. Patient factors independently associated with lower odds of CRS/HIPEC and PSM surgery consultation included older age, greater comorbidity burden, higher social vulnerability index, and further distance from a PSM center (p

Abstract Background Cancer cells develop resistance to chemotherapeutic intervention by excessive formation of stress granules (SGs), which are modulated by an oncogenic protein G3BP2. Selective control of G3BP2/SG signaling is a potential means to treat non-small cell lung cancer (NSCLC). Methods Co-immunoprecipitation was conducted to identify the interaction of MG53 and G3BP2. Immunohistochemistry and live cell imaging were performed to visualize the subcellular expression or co-localization. We used shRNA to knock-down the expression MG53 or G3BP2 to test the cell migration and colony formation. The expression level of MG53 and G3BP2 in human NSCLC tissues was tested by western blot analysis. The ATO-induced oxidative stress model was used to examine the effect of rhMG53 on SG formation. Moue NSCLC allograft experiments were performed on wild type and transgenic mice with either knockout of MG53, or overexpression of MG53. Human NSCLC xenograft model in mice was used to evaluate the effect of MG53 overexpression on tumorigenesis. Results We show that MG53, a member of the TRIM protein family (TRIM72), modulates G3BP2 activity to control lung cancer progression. Loss of MG53 results in the progressive development of lung cancer in mg53 -/- mice. Transgenic mice with sustained elevation of MG53 in the bloodstream demonstrate reduced tumor growth following allograft transplantation of mouse NSCLC cells. Biochemical assay reveals physical interaction between G3BP2 and MG53 through the TRIM domain of MG53. Knockdown of MG53 enhances proliferation and migration of NSCLC cells, whereas reduced tumorigenicity is seen in NSCLC cells with knockdown of G3BP2 expression. The recombinant human MG53 (rhMG53) protein can enter the NSCLC cells to induce nuclear translation of G3BP2 and block arsenic trioxide-induced SG formation. The anti-proliferative effect of rhMG53 on NSCLC cells was abolished with knockout of G3BP2. rhMG53 can enhance sensitivity of NSCLC cells to undergo cell death upon treatment with cisplatin. Tailored induction of MG53 expression in NSCLC cells suppresses lung cancer growth via reduced SG formation in a xenograft model. Conclusion Overall, these findings support the notion that MG53 functions as a tumor suppressor by targeting G3BP2/SG activity in NSCLCs.

BackgroundThe GALAD and ASAP scores are two well-recognized algorithms to estimate the risk of hepatocellular carcinoma (HCC) based on gender, age, alpha-fetoprotein (AFP), protein induced by vitamin K absence or Antagonist-II (PIVKA-II) and AFP-L3 (included in the GALAD score but not in the ASAP score). The current study sought to compare the diagnostic performance of each score to detect HCC among patients infected with hepatitis C virus (HCV).MethodsA multicenter case-control study was undertaken in which blood samples were collected from HCVinfected patients with and without HCC. Using the area under the receiver operating characteristic curve (AUROC), ASAP and GALAD scores were compared relative to diagnostic performance to detect any stage HCV-HCC and early-stage HCV-HCC.ResultsThe analytic cohort included 168 HCV-HCC patients and a control group of 193 HCV-infected patients. The ASAP score had a higher AUROC to detect any stage HCV-HCC versus the GALAD score, both in the overall group (0.917 vs. 0.894, P=0.057) and in the cirrhosis subgroup (0.909 vs. 0.889, P=0.132). Similar results were noted relative to the detection of early-stage HCV-HCC, whether defined by BCLC staging (stage 0-A: 0.898 vs. 0.860, P=0.026) or 8th TNM staging (stage I: 0.899 vs. 0.870, P=0.070). In subgroup analysis to detect AFP-negative HCV-HCC, the ASAP score also demonstrated a higher AUROC than the GALAD score to detect any stage HCV-HCC in the AFP-negative subgroup (0.815 vs. 0.764, P=0.063).ConclusionsThe ASAP score had better diagnostic performance for early detection of HCV-HCC compared with the GALAD score. The ASAP score may be preferrable to the GALAD score for HCC screening and surveillance among HCV-infected patients.

Although hepatocellular carcinoma is increasingly common, debate exists surrounding the management of patients with unresectable disease comparing transarterial embolisation (TAE) or transarterial chemoembolisation (TACE). This study aimed to compare the outcomes of patients receiving TAE and TACE. A systematic review was performed using PubMed, Medline, Embase, and Cochrane databases to identify randomised controlled trials (RCTs) until August 2021. The primary outcome was overall survival (OS) and the secondary outcomes were progression-free survival (PFS) and adverse events. Five studies with 609 patients were included in the analysis. There was no statistically significant difference in the OS (p = 0.36) and PFS (p = 0.81). There was no difference in OS among patients treated with a single TACE/TAE versus repeat treatments. Post-procedural adverse effects were higher in the TACE group but were not statistically significant. TACE has comparable long-term survival and complications profile to TAE for patients with HCC. However, the low-to-moderate quality of current RCTs warrants high-quality RCTs are necessary to provide enough evidence to give a definitive answer and inform treatment plans for the future.

The liver is the most frequently target for metastasis among patients with colorectal cancer mainly because of the portal vein circulation that directly connects the colon and rectum with the liver. The liver tumor microenvironment consists of different cell types each with unique characteristics and functions that modulate the antigen recognition and immune system activation. Primary tumors from other sites “prime” the liver prior to the seeding of cancer cells, creating a pre-metastatic niche. Following invasion into the liver, four different phases are key to the development of liver metastases: a microvascular phase in which cancer cells infiltrate and become trapped in sinusoidal vessels; an extravascular, pre-angiogenic phase; an angiogenic phase that supplies oxygen and nutrients to cancer cells; and a growth phase in which metastatic cells multiply and enlarge to form detectable tumors. Exosomes carry proteins, lipids, as well as genetic information that can create a pre-metastatic niche in distant sites, including the liver. The complexity of angiogenic mechanisms and the exploitation of the vasculature in situ by cancer cells have limited the efficacy of currently available anti-angiogenic therapies. Delineating the molecular mechanisms implicated in colorectal liver metastases is crucial to understand and predict tumor progression; the development of distant metastases; and resistance to chemotherapy, immunotherapy, and targeted treatment.

Background: Although surgery is the mainstay of curative-intent treatment for extrahepatic biliary tract cancer (EBTC), recurrence following surgery can be high and prognosis poor. The impact of neoadjuvant therapy (NAT) relative to upfront surgery (US) among patients with EBTC remains unclear. Methods: The Surveillance, Epidemiology, and End Results (SEER) databases was utilized to identify patients who underwent surgery from 2006 to 2017 for EBTC, including gallbladder cancer (GBC) and extrahepatic cholangiocarcinoma (ECC). Trends in NAT utilization were investigated, and the impact of NAT on prognosis was compared with US using a propensity score-matched (PSM) analysis. Results: Among 6582 EBTC patients (GBC, n = 4467, ECC, n = 2215), 1.6% received NAT; the utilization of NAT for EBTC increased over time (Ptrend = 0.03). Among patients with lymph node metastasis, the lymph node ratio was lower among patients with NAT (0.18 vs. 0.40, p < 0.01). After PSM, there was no difference in overall survival (OS) and cancer-specific survival (CSS) among patients treated with NAT versus US (5-year OS: 24.0% vs. 24.6%, p = 0.14, 5-year CSS: 38.0% vs. 36.1%, p = 0.21). A subgroup analysis revealed that NAT was associated with improved OS and CSS among patients with stages III–IVA of the disease (OS: HR 0.65, 95%CI 0.46–0.92, p = 0.02, CSS: HR 0.62, 95%CI 0.41–0.92, p = 0.01). Conclusions: While NAT did not provide an overall benefit to patients undergoing surgery for EBTC, individuals with advanced-stage disease had improved OS and CSS with NAT. An individualized approach to NAT use among patients with EBTC may provide a survival benefit.

Background. Quality in liver transplantation (LT) is currently measured using 1-y patient and graft survival. Because patient and graft survival rates now exceed 90%, more informative metrics are needed. Textbook outcomes (TOs) describe ideal patient outcomes after surgery. This study critically evaluates TO as a quality metric in LT. Methods. United Network for Organ Sharing data for 25 887 adult LT recipients were used to define TO as patient and graft survival >1 y, length of stay ≤10 d, 0 readmissions within 6 mo, absence of rejection, and bilirubin

Introduction: Over the past 4 decades, the management of hepatocellular carcinoma (HCC) has changed dramatically. The publications that have had the most significant impact on HCC management have not been quantitatively analyzed. In this article, we analyzed the 100 most influential articles over the past 4 decades using bibliometric citation analysis to characterize the evolution in HCC treatment. Methods: The top-cited publications were identified and analyzed from the Clarivate Analytics Web of Science Core Collection database. Results: The 100 most cited articles were identified with an average of 738 citations (range: 349–6,799). There was an increase in the number of influential articles in the late 1990s, which was paralleled by an increase in reports focused on locoregional treatment of HCC. Most top 100 articles came from the USA (n = 35), followed by Italy (n = 28), mainland China (n = 26), and Japan (n = 24). The surgical management was the most studied topic (n = 33). The Annals of Surgery published the highest number of papers (n = 26) with 13,978 citations. While other 3 topics (surgical management, locoregional treatment, and outcome prediction) declined among publications beginning in the 2000s, there was an emergence of highly cited papers on targeted drugs and immune checkpoint inhibitors with a concomitant increase in the number of publications on systemic therapy. Conclusions: Based on bibliometric analysis of the literature over the last 40 years, a comprehensive analysis of the most historically significant HCC management articles highlighted the key contributions made to the evolution and advancement of this specialist field. The data should provide clinicians and researchers insight into future directions relative to the advancement of HCC management.

Background and Objectives: Liver transplantation (LT) is the best strategy for curing several primary and secondary hepatic malignancies. In recent years, growing interest has been observed in the enlargement of the transplant oncology indications. This paper aims to review the most recent developments in the setting of LT oncology, with particular attention to LT for unresectable colorectal liver metastases (CRLM) and cholangiocellular carcinoma (CCA). Materials and Methods: A review of the recently published literature was conducted. Results: Growing evidence exists on the efficacy of LT in curing CRLM and peri-hilar and intrahepatic CCA in well-selected patients when integrating this strategy with (neo)-adjuvant chemotherapy, radiotherapy, or locoregional treatments. Conclusion: For unresectable CCA and CRLM management, several prospective protocols are forthcoming to elucidate LT’s impact relative to alternative therapies. Advances in diagnosis, treatment protocols, and donor-to-recipient matching are needed to better define the oncological indications for transplantation. Prospective, multicenter trials studying these advances and their impact on outcomes are still required.

Colorectal cancer is the third most common cause of cancer-related death in the United States, with 20% of patients presenting with metastatic disease at the time of diagnosis. Metastatic colon cancer is often treated with a combination of surgery, systemic therapy (chemotherapy, biologic therapy, immunotherapy), and/or regional therapy (hepatic artery infusion pumps). Utilizing the molecular and pathologic features of the primary tumor to tailor treatment for patients may improve overall survival. Rather than a “one size fits all” approach, a more nuanced treatment plan guided by the unique features of a patient’s tumor and the tumor’s microenvironment can more effectively treat the disease. Basic science work to elucidate new drug targets, understand mechanisms of evasion, and develop drugs and drug combinations is critical to inform clinical trials and identify novel, effective therapies for metastatic colorectal cancer. Through the lens of key targets for metastatic colorectal cancer, this review discusses how work in the basic science lab translates into clinical trials.

Recurrence following curative-intent hepatectomy for colorectal cancer liver metastasis, hepatocellular carcinoma, or cholangiocarcinoma is unfortunately common with a reported incidence as high as 75%. Various treatment modalities can improve survival following disease recurrence. A review of the literature was performed using PubMed. In addition to systemic therapy, liver-directed treatment options for recurrent liver disease include repeat hepatectomy, salvage liver transplantation, radiofrequency or microwave ablation, intra-arterial therapy, and stereotactic body radiation therapy. Repeat resection can be consider for patients with limited recurrent disease that meets resection criteria, as this therapeutic approach can provide a survival benefit and is potentially curative in a subset of patients. Salvage liver transplantation for recurrent hepatocellular carcinoma is another option, which has been associated with a 5-year survival of 50%. Salvage transplantation may be an option in particular for patients who are not candidates for resection due to underlying liver dysfunction but meet criteria for transplantation. Ablation is another modality to treat patients who recur with smaller tumors and are not surgical candidates due to comorbidity, liver dysfunction, or tumor location. For patients with inoperable disease, transarterial chemoembolization, or radioembolization with Yttrium-90 are liver-directed intra-arterial therapy modalities with relatively low risks that can be utilized. Stereotactic body radiation therapy is another palliative treatment option that can provide a response and local tumor control for smaller tumors.

ObjectivesInvestigate long-term effects of repeated transarterial chemoembolization (TACE) on portal venous pressure (PVP) using non-invasive surrogate markers of portal hypertension.MethodsRetrospective, Institutional Review Board-approved study. 99 patients [hepatocellular carcinoma (HCC) group (n=57); liver metastasis group (n=42)] who underwent 279TACEs and had longitudinal pre-/post-therapy contrast-enhanced-MRI (n=388) and complete blood work were included. Outcomes of interest were platelet count (PC), spleen volume, ascites and portosystemic collaterals. Variables included TACE type/number, tumor type, microcatheter location, Child-Pugh, baseline tumor burden (tumor number/total/largest size), vessel invasion, alpha-fetoprotein, Eastern Cooperative Oncology Group (ECOG) performance status, and Model for End-Stage Liver Disease (MELD) score. Generalized Estimating Equations assessed the associations between TACE and outcomes. Power analysis determined the sample size was sufficient.ResultsNo significant change in PC over time was observed in either groups, regardless of liver function (P>0.05). Baseline spleen volume was 226 cm3 for metastatic group, and was larger by 204 cm3 for HCC group (P

Cancer of the hepatobiliary system can be divided into primary liver cancer and biliary tract cancer (BTC), which includes hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and gallbladder cancer (GBC). These aggressive cancers often present at an advanced stage or among patients with poorly preserved liver function. The primary treatment for HCC and BTC when diagnosed early is surgical resection, but given the high rate of recurrence and often advanced stage at diagnosis, many patients will require systemic therapy. Unfortunately, even with systemic therapy, long-term survival is poor. The immune system plays an important role in preventing cancer progression. The unique immune environment of the liver and subsequent alterations to the immune microenvironment by tumor cells to create a favorable microenvironment plays a key role in the progression of HCC and BTC. Due to the paucity of effective systemic therapies and distinctive immune environment of the liver, research and clinical trials are investigating the use of immunotherapy in HCC and BTC. This review will focus on current immunotherapies and emerging data for the treatment of HCC and BTC.

Hepatocellular carcinoma (HCC) is the most common primary hepatic malignancy and a leading cause of cancer-related death in both the developed and developing world. Recurrent HCC (rHCC) develops in a significant proportion of patients even following curative-intent resection. In the absence of a structured treatment algorithm, a number of treatment options including repeat hepatectomy (RH) and radiofrequency ablation (RFA) have been utilized in select patients with rHCC. The aim of this systematic review and meta-analysis was to compare short- and long-term outcomes of patients undergoing RHR versus RFA for rHCC. Four electronic databases were screened until September 2022. A total of 17 studies were included in the meta-analysis. Overall and disease-free survival were comparable among the two groups. Patients undergoing RH were less likely to develop a second recurrence (RR 0.89, 95% C.I. 0.81 to 0.98, p = 0.02). Overall and major morbidity were significantly increased in the RH group (RR 3.01, 95% C.I. 1.98 to 4.56, p < 0.001 and RR 3.65, 95% C.I. 2.07 to 6.43, p < 0.001, respectively), while mortality was similar between RFA and RH. The data demonstrated that RFA is a safe and efficient alternative to RH for selected patients with rHCC. Nevertheless, despite higher morbidity associated with RH, repeat resection remains the preferred treatment option whenever feasible, as it allows for better local disease control.

Aging is associated with chronic oxidative stress and inflammation that affect tissue repair and regeneration capacity. MG53 is a TRIM family protein that facilitates repair of cell membrane injury in a redox-dependent manner. Here, we demonstrate that the expression of MG53 was reduced in failing human hearts and aged mouse hearts, concomitant with elevated NF-κB activation. We evaluated the safety and efficacy of longitudinal, systemic administration of recombinant human MG53 (rhMG53) protein in aged mice. Echocardiography and pressure-volume loop measurements revealed beneficial effects of rhMG53 treatment in improving heart function of aged mice. Biochemical and histological studies demonstrated that the cardioprotective effects of rhMG53 are linked to suppression of NF-κB–mediated inflammation, reducing apoptotic cell death and oxidative stress in the aged heart. Repetitive administration of rhMG53 in aged mice did not have adverse effects on major vital organ functions. These findings support the therapeutic value of rhMG53 in treating age-related decline in cardiac function.

BackgroundHepatocellular carcinoma (HCC) is one of the most serious consequences of chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. This study sought to investigate long-term outcomes after liver resection for HCC among patients with HBV/HCV co-infection (HBV/HCV-HCC) compared with patients with HBV infection (HBV-HCC).MethodsPatients who underwent curative-intent liver resection for HCC were identified from a multicenter Chinese database. Using propensity score matching (PSM), patients with HBV/HCV-HCC were matched one-to-one to patients with HBV-HCC. Overall survival (OS) and recurrence-free survival (RFS) were compared between the two groups before and after PSM.ResultsAmong 2,467 patients identified, 93 (3.8%) and 2,374 (96.2%) patients had HBV/HCV-HCC and HBV-HCC, respectively. Compared with patients with HBV-HCC, patients with HBV/HCV-HCC were older, have poorer liver-related characteristics but better tumor-related characteristics. PSM created 88 pairs of patients with comparable liver- and tumor-related characteristics (all P > 0.2). In the PSM cohort, the 3- and 5-year RFS rates in patients with HBV/HCV-HCC were 48.3% and 38.9%, which were significantly poorer than patients with HBV-HCC (61.8% and 49.2%, P = 0.037). Meanwhile, the 3- and 5-year OS rates in patients with HBV/HCV-HCC were also poorer than patients with HBV-HCC (65.4% and 51.1% vs. 73.7% and 63.0%), with a difference close to be significant between them (P = 0.081).ConclusionComparing to patients with HBV-HCC, liver resection resulted in relatively poorer long-term surgical outcomes in patients with HBV/HCV-HCC.

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.

Tumor mutational analysis has been incorporated into the management of patients with CRLM since it can provide valuable prognostic information as well as guide peri-operative systemic treatment. Unlike tumor biopsy, liquid biopsy has emerged as a promising, non-invasive alternative that can detect cell-derived markers from a variety of body fluids and might better characterize all subclones present at a specific time point and allow sequential monitoring of disease evolution. Although not currently considered standard of care, an increasing number of cancer centers are nowadays routinely using liquid biopsies in the treatment of CRLM patients with promising results. The current review provides an overview of liquid biopsies in cancer therapeutics and focuses on the application of this relatively new approach on patients with CRLM.

Background and Aim: Alpha-fetoprotein (AFP), a lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), is a protein that is induced by vitamin K deficiency or antagonist-II (PIVKA-II) that has been clinically used as a serum biomarker for early detection and diagnosis of hepatocellular carcinoma (HCC). Diagnostic performance of each serum biomarker alone, or their combinations for the detection of hepatitis C virus (HCV)-associated HCC were compared. Methods: Serum AFP, AFP-L3, and PIVKA-II levels were evaluated in patients with HCV-associated HCC, and those with chronic HCV infection without HCC (HCV-controls). The areas under the curve (AUC), sensitivity, and specificity were compared to identify the diagnostic performance of each serum HCC biomarker alone or in combination. Results: Overall, 172 HCV controls and 105 patients with HCV-associated HCC were enrolled. The AFP, AFP-L3, and PIVKA-II levels were significantly increased among patients with HCV-associated HCC when compared with HCV patients without HCC (p < 0.001). When these biomarkers were analyzed individually, PIVKA-II revealed the best predictive performance (AUC: PIVKA-II 0.90 vs. AFP 0.80 vs. AFP-L3 0.69, p < 0.001). In evaluating the combinations of any two biomarkers, the best predictive performance was found in PIVKA-II + AFP (0.93 vs. AFP + AFP-L3 0.78, p = 0.001; and PIVKA-II + AFP-L3 0.89, p < 0.001), which had no difference compared to the predictive performance of the combination of all three serum biomarkers (AFP + AFP-L3 + PIVKA-II 0.93, p = 0.277). Similar results were identified in the subgroups of patients with HCV-induced cirrhosis, and among patients with early-stage HCC defined by BCLC and TNM staging. Conclusions: The addition of the PIVKA-II test to routine AFP test maybe provide a more suitable biomarker approach to detect HCV-induced HCC in patients with HCV infection undergoing HCC surveillance.

Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy, and there is a need for effective systemic therapies. Gene expression profile-based analyses may allow for efficient screening of potential drug candidates to serve as novel therapeutics for patients with ICC. The RNA expression profile of ICC and normal biliary epithelial cells were downloaded from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Function annotation and enrichment pathway analyses of the differentially expressed genes (DEGs) were finished using the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. A weighted gene co-expression network (WGCN) was constructed by WGCN analysis (WGCNA). Key genes from the DEGs and co-expression gene modules were analyzed to generate a protein–protein interaction (PPI) network. The association between the top 10 screened hub genes and the overall and disease-free survival of ICC patients was examined. The Connectivity Map (cMap) analysis was performed to identify possible drugs for ICC using hub genes. A total of 151 key genes were selected from the overlapping genes of 1287 GSE-DEGs, 8183 TCGA-DEGs and 1226 genes in the mixed modules. A total of 10 hub genes of interest (CTNNB1, SPP1, COL1A2, COL3A1, SMAD3, SRC, VCAN, PKLR, GART, MRPS5) were found analyzing protein–protein interaction. Using the cMap, candidate drugs screened with potential efficacy for ICC included three tyrosine kinase inhibitors (dasatinib, NVP-BHG712, tivantinib), two cannabinoid receptor agonists (palmitoylethanolamide, arachidonamide), two antibiotics (moxifloxacin, amoxicillin), one estrogen receptor agonist (levonorgestrel), one serine/threonine protein kinase inhibitor (MK-2206) and other small molecules. Key genes from network and PPI analysis allowed us to identify potential drugs for ICC. The identification of novel gene expression profiles and related drug screening may accelerate the identification of potential novel drug therapies for ICC.

Hereditary pancreatic cancer, which includes patients with familial pancreatic cancer (FPC) and hereditary pancreatic cancer syndromes, accounts for about 10% of all pancreatic cancer diagnoses. The early detection of pre-cancerous pancreatic cysts has increasingly become a focus of interest in recent years as a potential avenue to lower pancreatic cancer incidence and mortality. Intraductal papillary mucinous cystic neoplasms (IPMNs) are recognized precursor lesions of pancreatic cancer. IPMNs have high prevalence in patients with hereditary pancreatic cancer and their relatives. While various somatic mutations have been identified in IPMNs, certain germline mutations associated with hereditary cancer syndromes have also been identified in IPMNs, suggesting a role in their formation. While the significance for the higher prevalence of IPMNs or similar germline mutations in these high-risk patients remain unclear, IPMNs do represent pre-malignant lesions that need close surveillance. This review summarizes the available literature on the incidence and prevalence of IPMNs in inherited genetic predisposition syndromes and FPC and speculates if IPMN and pancreatic cancer surveillance in these high-risk individuals needs to change.

Hepatocellular carcinoma (HCC) is the most frequent primary liver tumor. As a result of advanced disease being often present at diagnosis, only a small percentage of patients are amenable to curative-intent treatment options such as surgical resection and liver transplantation. Systemic therapy consisting of tyrosine kinase inhibitors such as sorafenib had been used for over a decade with limited efficacy. More recently, treatment with immune checkpoint inhibitors has revolutionized the treatment landscape of various malignant tumors. With this shifting paradigm, recent data have demonstrated encouraging outcomes among patients with HCC. In particular, several trials have investigated the safety and efficacy of various immune checkpoint inhibitors (ICI) either as monotherapy or in the form of combined treatments. We sought to provide an overview of recent clinical trials among patients with advanced HCC as well as to highlight predictors of response and immune-related adverse events and to review the evidence on perioperative administration of ICI in patients with resectable HCC.

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.