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Amir Sara,1 Samantha M Ruff,2 Anne M Noonan,1 Timothy M Pawlik2 1Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA; 2Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USACorrespondence: Timothy M Pawlik, Department of Surgery, The Urban Meyer III and Shelley Meyer Chair for Cancer Research, Professor of Surgery, Oncology, Health Services Management and Policy, The Ohio State University, Wexner Medical Center, 395 W. 12th Ave., Suite 670, Columbus, OH, 43210, USA, Tel +1 614 293-8701, Fax +1 614 293-4063, Email Tim.Pawlik@osumc.eduAbstract: Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related mortality worldwide and accounts for 90% of all primary liver cancers. Chronic inflammation is the hallmark across most prevalent etiologies among which HBV is the leading cause worldwide (33%), followed by alcohol (30%), HCV (21%), other factors like non-alcoholic steatohepatitis linked to insulin resistance/metabolic syndrome, and obesity associated inflammation (16%). Deregulation of the tightly controlled immunological network leads to liver disease, including chronic infection, autoimmunity, and tumor development. While inflammation drives oncogenesis in the liver, HCC also recruits ICOS+ FOXP3+ Tregs and MDSCs and upregulates immune checkpoints to induce a state of immunosuppression in the tumor microenvironment. As such, research is focused on targeting and modulating the immune system to treat HCC. The Checkmate 040 and Keynote 224 studies established the role of immunotherapy in the treatment of patients with HCC. In Phase I and II trials, nivolumab and pembrolizumab demonstrated durable response rates of 15– 20% and were subsequently approved as second-line agents after sorafenib. Due to the success of the IMbrave 150 and HIMALAYA trials, which examined the combination of atezolizumab/bevacizumab and tremelimumab/durvalumab, respectively, the FDA approved these regimens as first-time treatment options for patients with advanced HCC. The encouraging results of immunotherapy in the management of HCC has led researchers to evaluate if combination with locoregional therapies may result in a synergistic effect. Real-world studies represent an invaluable tool to assess and verify the applicability of clinical trials in the bedside setting with a more varied patient population. We herein review current real-life use of ICIs in the management of HCC and highlight some of the ongoing clinical trials that are expected to change current recommended first-line treatment in the near future.Keywords: hepatocellular carcinoma, immunotherapy, real-world data, immunotherapy biomarkers, liver microenvironment

Alexander H Shannon, Samantha M Ruff, Timothy M Pawlik Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, USACorrespondence: Timothy M Pawlik, Department of Surgery, The Urban Meyer III and Shelley Meyer Chair for Cancer Research, Professor of Surgery, Oncology, Health Services Management and Policy, The Ohio State University, Wexner Medical Center, 395 W. 12th Ave., Suite 670, Columbus, OH, USA, Tel +1 614 293 8701, Fax +1 614 293 4063, Email Tim.Pawlik@osumc.eduAbstract: Hepatocellular carcinoma (HCC) is a primary liver tumor that typically occurs in the setting of chronic liver disease/cirrhosis. Treatment modalities for HCC have evolved and given the variety of treatment options, a multi-disciplinary approach requiring input from surgical, medical, and radiation oncology, hepatology, and interventional radiology is necessary. Multiple advances have been made over the last decade regarding treatment of HCC, especially advanced disease. Resection and transplantation remain as cornerstone curative-intent treatment options. For patients who are not candidates for curative-intent therapy, exciting progress has been made in molecular and cellular approaches to systemic therapy for HCC including immunotherapies and tyrosine kinase inhibitors. Although the prognosis for advanced HCC remains poor, the armamentarium of therapies has increased, and valuable years of life can be gained with these therapies. While the main therapeutic modality for early-stage disease remains resection, multimodal immunotherapy has emerged as first-line treatment for advanced disease. We herein review different clinical and molecular treatment modalities related to the treatment of HCC, as well as provide insights into future directions for HCC treatment. We highlight how research and progress are needed to move into a new era of molecular and cellular treatments.Keywords: hepatocellular carcinoma, current treatments

Dimitrios Papaconstantinou,1 Diamantis I Tsilimigras,2 Timothy M Pawlik2 1Third Department of Surgery, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece; 2Department of Surgery, Division of Surgical Oncology, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, Ohio, USACorrespondence: Timothy M Pawlik, Department of Surgery, The Urban Meyer III and Shelley Meyer Chair for Cancer Research, The Ohio State University, Wexner Medical Center, 395 W. 12th Ave., Suite 670, Columbus, OH, USA, Tel +1 614 293 8701, Fax +1 614 293 4063, Email tim.pawlik@osumc.eduAbstract: Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide with the incidence of recurrence being as high as 88% even among patients who have undergone curative-intent treatment. Despite improvements in overall survival, recurrence remains a challenge necessitating accurate reappraisal of patient and disease status. To that end, accurate staging of recurrent HCC is a necessity to provide better care for these patients. Risk factors for poor survival after HCC recurrence have been identified and include characteristics of the primary disease, such as tumor multifocality, large size (≥ 5 cm), macroscopic vascular or microscopic lymphovascular invasion, preoperative a-fetoprotein (AFP) levels, R0 resection, and the presence of impaired liver function. Close surveillance with imaging is warranted following curative-intent therapy, with magnetic resonance imaging (MRI) being the preferred approach to identify small, early recurrent HCCs. Treatment decisions at the time of recurrence involve ruling out extrahepatic disease and identifying candidates for potentially curative-intent repeat treatment options. Patients with recurrent disease are, however, very diverse in terms of tumor morphology and biologic behavior, as well as residual hepatic functional reserve. Patients with preserved liver function may benefit from repeat liver resection or ablation. Patients with recurrence within the Milan criteria may even be candidates for salvage liver transplantation, while multimodality treatment with combination of liver-directed therapies appears to enhance oncologic outcomes for individuals with advanced recurrent disease. A “one-size-fits-all” approach in staging recurrent HCC does not exist. Rather, individualized and evidence-based decision-making is necessary in order to optimize outcomes for patients with recurrent HCC.Keywords: hepatocellular carcinoma, recurrence, staging, treatment, classification

Nikolaos Serifis,1 Diamantis I Tsilimigras,2 Daniel J Cloonan,3 Timothy M Pawlik2 1Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA, USA; 2Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA; 3Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA, USACorrespondence: Diamantis I TsilimigrasDepartment of Surgery, The Ohio State University, Wexner Medical Center, 410 W 10th Avenue, Columbus, OH, 43210, USATel +1 215 987 9177Email diamantis.tsilimigras@osumc.eduAbstract: Intrahepatic cholangiocarcinoma (ICC) is one of the rarest and most aggressive types of cancer. The symptoms of ICC patients can be vague, leading to late diagnosis and dismal prognosis. In this review, we investigated the treatment options for ICC, as well as ways to overcome challenges in identifying and treating this disease. Imaging remains the gold standard to diagnose ICC. Patients are staged based on the tumor, nodes and metastases (TNM) staging system. Patients eligible for surgical resection should undergo surgery with curative intent with the goal of microscopically disease-free margins (R0 resection) along with lymphadenectomy. Minimal invasive surgery (MIS) and liver transplantation have recently been offered as possible ways to improve disease outcomes. ICC recurrence is relatively common and, thus, most patients will need to be treated with systemic therapy. Several clinical trials have recently investigated the use of neoadjuvant (NT) and adjuvant therapies for ICC. NT may offer an opportunity to downsize larger tumors and provide patients, initially ineligible for surgery, with an opportunity for resection. NT may also treat occult micro-metastatic disease, as well as define tumor biology prior to surgical resection, thereby decreasing the risk for early postoperative recurrence. Adjuvant systemic therapy may improve outcomes of patients with ICC following surgery. Ongoing clinical trials are investigating new targeted therapies that hold the hope of improving long-term outcomes of patients with ICC.Keywords: liver, intrahepatic cholangiocarcinoma, resection, outcomes

Lei Liang,1,2,* Ming-Da Wang,3,* Yao-Ming Zhang,4 Wan-Guang Zhang,5 Cheng-Wu Zhang,1 Wan Yee Lau,3,6 Feng Shen,3 Timothy M Pawlik,7 Dong-Sheng Huang,1,2,8 Tian Yang1– 3,8 1Department of Hepatobiliary, Pancreatic and Minimal Invasive Surgery, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Zhejiang, People’s Republic of China; 2School of Clinical Medicine, Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of China; 3Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai, People’s Republic of China; 4The 2nd Department of Hepatobiliary Surgery, Meizhou People’s Hospital, Guangdong, People’s Republic of China; 5Department of Hepatic Surgery, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 6Faculty of Medicine, The Chinese University of Hong Kong, New Territories, Hong Kong, China; 7Department of Surgery, Ohio State University, Wexner Medical Center, Columbus, OH, USA; 8The Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People’ s Hospital (People’ s Hospital of Hangzhou Medical College), Hangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Tian YangDepartment of Hepatobiliary, Pancreatic and Minimal Invasive Surgery, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, No. 158, Shangtang Road, Hangzhou, Zhejiang, 310014, People’s Republic of ChinaEmail yangtiandfgd@hotmail.comDong-Sheng HuangDepartment of Hepatobiliary, Pancreatic and Minimal Invasive Surgery, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, No. 158, Shangtang Road, Hangzhou, Zhejiang, 310014, People’s Republic of ChinaEmail Huangdongshengsj@hotmail.comBackground: High alpha-fetoprotein (AFP) expressions (> 400 ng/mL) are associated with poor oncological characteristics for hepatocellular carcinoma (HCC). However, prognosis after liver resection for high-AFP HCC is poorly studied. To investigate long-term recurrence and survival after hepatectomy for high-AFP HCC, and to identify the predictive value of postoperative incomplete biomarker response (IBR) on overall survival (OS) and recurrence-free survival (RFS).Methods: Patients undergoing curative resection for high-AFP HCC were analyzed. According to the decline magnitude of serum AFP as measured at first follow-up (4∼ 6 weeks after surgery), all patients were divided into the complete biomarker response (CBR) and IBR groups. Characteristics, recurrence, and survival rates were compared. Univariate and Multivariate Cox-regression analyses were performed to identify independent predictors associated with poorer OS and RFS after liver resection for high-AFP HCC.Results: Among 549 patients, the overall and early recurrence rates in patients with IBR were significantly higher than patients with CBR (97.8%vs.56.4%, and 92.5%vs.33.3%, both P< 0.001). On multivariate analysis, postoperative IBR was the strongest risk factor with the highest hazard ratio in predicting poor OS (HR 2.97; 95% CI 2.49∼ 3.45; P< 0.001) and RFS (HR 4.29; 95% CI 3.31∼ 5.55; P< 0.001).Conclusion: Postoperative biomarker response of serum AFP can be used in predicting recurrence and survival for high-AFP HCC patients. Once postoperative IBR was identified at first follow-up, subsequent enhanced recurrence surveillance and available treatments against recurrence should actively be considered.Keywords: hepatocellular carcinoma, alpha-fetoprotein, hepatectomy, survival, recurrence

Kelly J Lafaro,1 Timothy M Pawlik2 1Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, 2Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD, USA Abstract: Fibrolamellar carcinoma (FLC) is a variant of hepatocellular carcinoma (HCC), which comprises ~1%–9% of all HCCs. Although FLC is a variant of HCC, it is distinct from HCC in that it most often affects younger patients (10–35 years of age) with no underlying liver disease. FLC often presents with vague abdominal pain, nausea, abdominal fullness, malaise, and weight loss. Surgery is the current mainstay of treatment for FLC and remains the only potentially curative option. While FLCs are considered less responsive to chemotherapy than their classic HCC counterparts, there have been suggestions that multimodality treatments may be effective, especially in advanced cases. Further research is necessary to determine effective systemic therapies as an adjunct to surgery for FLC. Keywords: hepatocellular carcinoma, fibrolamellar, hepatocyte paraffin I, locoregional therapy

Vicente Valero III,1 Timothy M Pawlik,1 Robert A Anders21Department of Surgery, Division of Surgical Oncology, 2Department of Pathology, Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USAAbstract: Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third most common cause of cancer-related mortality worldwide. Due to the poor prognosis and limited therapeutic options, there is great interest in further understanding better the molecular underpinnings and potential molecular targets associated with HCC. The Hippo (Hpo) signaling pathway and YAP, its principal downstream effector, represent an innovative area of research in HCC. Pioneered in Drosophila melanogaster, the Hpo cascade controls tissue homeostasis including organ size, cell proliferation, apoptosis, as well as cell-cycle regulation and differentiation. This conserved kinase cascade in mammals depends on central control by the tumor suppressor mammalian sterile 20-like kinase 1/2 (Mst1/2). The Mst1/2 commences the downstream kinase cascade, ultimately activating the oncoprotein YAP and allowing its physical association with downstream targets to enhance the gene expression signatures that are involved in proliferation and survival. Alterations in YAP expression and defective regulation of other key Hpo pathway members, such as Mst1/2, Salvador, neurofibromatosis and Mer (Nf2/mer), large tumor suppressor homolog 1/2 (Lats1/2), and Mps one binder kinase activator-like 1A and 1B (Mob1) drive carcinogenesis in animal models. The dysregulation of the Hpo pathway – resulting in an unchecked activation of YAP – culminates in the development of a broad range of human tumor types, including HCC. The abrogation of Mst1/2-mediated YAP phosphorylation permits YAP entry into the nucleus in murine models and functions similarly in human HCCs. Chemoresistance mechanisms displayed by HCC tumors occur in a YAP-dependent manner. The HCC specimens exhibit YAP overexpression, and YAP serves as an independent prognostic marker for disease-free survival and overall survival in patients with HCC. Recently, the small molecule inhibitor, verteporfin has been shown to attenuate YAP activity in murine models, perhaps offering a novel therapeutic approach for patients with advanced HCC.Keywords: hepatocellular carcinoma, yes-associated-protein, Hippo signaling, liver cancer, hepatic malignancy

Hepatic metastatic disease affects more than half of the patients with colorectal cancer and neuroendocrine cancer. Hepatic resection remains the gold standard for liver metastasis from colorectal and neuroendocrine primaries. Thermal ablative technologies, however, are increasingly being used either alone or in combination with resection to treat this group of patients. Radiofrequency ablation is the most common modality used in the United States, whereas microwave ablation has been more widely used in the East. In addition to being adjuncts to hepatic resection, ablation has gained an increased popularity in the management of patients who are not operative candidates or have unresectable colorectal or neuroendocrine hepatic metastasis. Although radiofrequency ablation seems to have a higher local recurrence than resection, ablation remains an important therapeutic option for many patients with hepatic metastasis. [ABSTRACT FROM AUTHOR]

Objective: Despite earlier diagnosis and advancements in treatment, cancer remains a leading cause of death in the world (13% of all deaths according to the World Health Organization) among men and women. Cancer accounts for approximately 20% of the deaths in the USA every year. Here, we report the findings from a cross-sectional survey of psychosocial factors in lung and gastrointestinal cancer patients. The aim of the study was to explore the associations among transitoriness, uncertainty, and locus of control (LOC) with quality of life. Transitoriness is defined as a person's confrontation with life's finitude due to a cancer diagnosis.Methods: A total of 126 patients with lung or gastrointestinal cancer completed eight self-reporting questionnaires addressing demographics, spiritual perspective, symptom burden, transitoriness, uncertainty, LOC, and quality of life.Results: Transitoriness, uncertainty, and LOC were significantly associated with one another (r = 0.3267, p = 0.0002/r = 0.1994, p = 0.0252, respectively). LOC/belief in chance has a significant inverse relationship with patients' quality of life (r = -0.2505, p = 0.0047). Transitoriness, uncertainty, and LOC were found to have a significant inverse relationship with patients' quality of life (transitoriness state: r = -0.5363, p = 0.0000/trait: r = -0.4629, p = 0.0000/uncertainty: r = -0.4929, p = 0.0000/internal LOC: r = 0.1759, p = 0.0489/chance LOC: r = -0.2505, p = 0.0047).Conclusion: Transitoriness, uncertainty, and LOC are important concepts as they adversely influence patients' quality of life. Incorporating this finding into the care of cancer patients may provide them with the support they need to cope with treatment and maintenance of a positive quality of life. [ABSTRACT FROM AUTHOR]