The abscopal effect is a rare phenomenon characterized by disease regression in distant sites after tumoral locoregional therapy. Locoregional therapy, such as cryoablation, can induce an antitumor immunological response, potentially improving outcomes in cancer patients receiving immunotherapy. This report describes a patient with multifocal hepatocellular carcinoma who progressed through multiple locoregional therapies, was initially unresponsive to immunotherapy, and later achieved rapid and sustained disease regression with a combination cryoablation and immunotherapy. A 5-year sustained complete tumor response successfully bridged to liver transplantation.

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy, and liver transplantation is usually curative. HCC recurrences are rare after curative treatment options, although they are prevalent depending on various risk factors. We present a 71-year-old female patient with an unusual pattern of disease progression following a curative liver transplant with a metastatic presentation in the absence of alpha-fetoprotein elevation after 3 years of disease-free clinical presentation. We present this case to emphasize the importance of intermittent cross-sectional imaging in addition to ultrasound screening in HCC surveillance.

Organ transplantation represents the optimal therapeutic tool for patients with end-stage organ failure. Hematopoietic stem cell transplantation (HSCT) is likewise an effective therapy for a wide range of malignant and non-malignant diseases. Better understanding of transplantation immunology and the use of multi-modal immunosuppression protocols, can decrease the risk of graft failure and graft-versus-host disease (GVHD) after HSCT. Nevertheless, a major challenge of modern transplantology still seems to be finding non-invasive biomarkers for recipients selection, monitoring of allograft function, and diagnosis of rejection. Since proinflammatory cytokine osteopontin (OPN) is closely involved in regulating both adaptive and innate immune responses, as well as the pathogenesis of inflammatory and autoimmune diseases, it is likely to play an important role in organ and HSC transplantation. This review is to summarize recent advances in our knowledge about OPN function in the kidney, heart, liver, lung, and HSC transplantation. Most studies found that elevated OPN is associated with poorer graft function in kidney, heart, liver and lung recipients. Moreover, some reports suggested that this protein can play role in GVHD pathogenesis. However, due to relatively small number of similar studies, as well as some inconclusive results, future investigation in this field is needed to verify if OPN can serve as a biomarker of organ and HSC transplantation. The knowledge about such markers will promote our understanding of the mechanisms underlying graft dysfunction and posttransplant mortality. In addition, such knowledge may be helpful in the development of new treatment strategies and identification of recipients with increased risk of allograft failure.

Currently, no surveillance guidelines for hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) exist. In this retrospective, multicenter study, we have investigated the role of surveillance imaging on postrecurrence outcomes.

Patients with recurrent HCC after LT from 2002 to 2016 were reviewed from 3 transplant centers (University of California San Francisco, Mayo Clinic Florida, and University of Toronto). For this study, we proposed the term cumulative exposure to surveillance (CETS) as a way to define the cumulative sum of all the protected intervals that each surveillance test provides. In our analysis, CETS has been treated as a continuous variable in months.

Two hundred twenty-three patients from 3 centers had recurrent HCC post-LT. The median follow-up was 31.3 months, and median time to recurrence was 13.3 months. Increasing CETS was associated with improved postrecurrence survival (hazard ratio, 0.94; P < 0.01) as was treatment of recurrence with resection or ablation (hazard ratio, 0.31; P < 0.001). An receiver operating characteristic curve (area under the curve, 0.64) for CETS covariate showed that 252 days of coverage (or 3 surveillance scans) within the first 24 months provided the highest probability for aggressive postrecurrence treatment.

In this review of 223 patients with post-LT HCC recurrence, we found that increasing CETS does lead to improved postrecurrence survival as well as a higher probability for aggressive recurrence treatment. We found that 252 days of monitoring (ie, 3 surveillance scans) in the first 24 months was associated with the ability to offer potentially curative treatment.

Background: Hepatocellular carcinoma (HCC) has high morbidity and mortality, but current therapeutic methods cannot effectively improve patient's prognosis. FOXD3-AS1, a new identified long noncoding RNA, is dysregulated in several cancers and functions as a carcinogenic or tumor-suppressor factor. However, the function of FOXD3-AS1 in HCC has not been reported. Materials and Methods: Quantitative real time-polymerase chain reaction was applied to evaluate the expression of FOXD3-AS1 in HCC tissues and cell lines. miRDB and TargetScan websites were utilized to predict the interaction network of FOXD3-AS1 as a competing endogenous RNA. The interaction was confirmed by luciferase reporter assay and RNA binding protein immunoprecipitation (RIP) assay. The effect of FOXD3-AS1 on HCC cells (Huh6) were measured by cell counting kit (CCK)-8, BrdU cell proliferation assay, Transwell invasion assay, and wound healing assay. Results: FOXD3-AS1 was overexpressed in HCC, and HCC patients with the high level of FOXD3-AS1 had a poor prognosis. In addition, FOXD3-AS1 knockdown considerably inhibited the proliferation, migration, and invasion of Huh6 cells. Besides, FOXD3-AS1 functioned as a sponge of miR-335, and RICTOR was a direct target gene of miR-335. Furthermore, FOXD3-AS1 could enhance the level of RICTOR through sponging miR-335. Moreover, the knockdown of FOXD3-AS1 could competitively bind with miR-335 to suppress RICTOR expression, thereby inhibiting the growth of Huh6 cells through the deactivation of AKT signaling pathway. Conclusions: FOXD3-AS1 is crucial for the tumorigenesis and progression of HCC. The interaction among FOXD3-AS1, miR-335, and RICTOR provides a novel insight for understanding the molecular mechanism of HCC, and FOXD3-AS1, miR-335, and RICTOR can be regarded as the potential targets for HCC treatment.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. The Brazilian Society of Hepatology (SBH) published in 2015 its first recommendations about the management of HCC. Since then, new data have emerged in the literature, prompting the governing board of SBH to sponsor a single-topic meeting in August 2018 in São Paulo. All the invited experts were asked to make a systematic review of the literature reviewing the management of HCC in subjects with cirrhosis. After the meeting, all panelists gathered together for the discussion of the topics and the elaboration of updated recommendations. The text was subsequently submitted for suggestions and approval of all members of the Brazilian Society of Hepatology through its homepage. The present manuscript is the final version of the reviewed manuscript containing the recommendations of SBH.

For individuals with hepatocellular carcinoma (HCC), type of insurance may be an important prognostic factor because of its impact on access to care. This study investigates the relationship between insurance type at diagnosis and stage-specific survival.

This retrospective cohort analysis used data from 18 Surveillance, Epidemiology, and End Results Program cancer registries. Individuals ages 20 to 64 years, diagnosed with primary HCC between 2010 and 2015, with either private, Medicaid, or no insurance were eligible for cohort inclusion. Adjusted Cox proportional-hazards regression models were used to generate HRs and 95% confidence intervals (CI) for associations between insurance type at diagnosis and overall survival. All models were stratified by stage at diagnosis.

This analysis included 14,655 cases. Compared with privately insured individuals with the same stage of disease, those with Medicaid had a 43% (HR = 1.43; 95% CI, 1.13-1.32), 22% (HR = 1.22; 95% CI, 1.13-1.32), and 7% higher risk of death for localized, regional, and distant stage, respectively. Uninsured individuals had an 88% (HR = 1.88; 95% CI, 1.65-2.14), 59% (HR = 1.59; 95% CI, 1.41-1.80), and 35% (HR = 1.35; 95% CI, 1.18-1.55) higher risk of death for localized, regional, and distant stage, respectively, compared with privately insured individuals.

Disparities in survival exist by the type of insurance that individuals with HCC have at the time of diagnosis.

These findings support the need for additional research on access to and quality of cancer care for Medicaid and uninsured patients.

Hepatocellular carcinoma (HCC) is a morbid condition for which surgical and ablative therapy are the only options for cure. Nonetheless, over half of patients treated with an R0 resection will develop recurrence. Early recurrences within 2 years after resection are thought to be due to the presence of residual microscopic disease, while late recurrences > 2 years after resection are thought to be de novo metachronous HCCs arising in chronically injured liver tissue. Microvascular invasion (MVI) is defined as the presence of micrometastatic HCC emboli within the vessels of the liver, and is a critical determinant of early recurrence and survival. In this review, we summarize the pathogenesis and clinical relevance of MVI, which correlates with adverse biological features, including high grade, large tumor size, and epithelial-mesenchymal transition. Multiple classification schemas have been proposed to capture the heterogeneous features of MVI that are associated with prognosis. However, currently, MVI can only be determined based on surgical specimens, limiting its clinical applicability. Going forward, advances in axial imaging technologies, molecular characterization of biopsy tissue, and novel serum biomarkers hold promise as future methods for non-invasive MVI detection. Ultimately, MVI status may be used to help clinicians determine treatment plans, particularly with respect to surgical intervention, and to provide more accurate prognostication.

Hepatocellular carcinoma (HCC) is a global health issue with increasing incidence and high mortality rate. Depending on the tumor load and extent of underlying liver cirrhosis, aggressive surgical treatment by hepatectomy or liver transplantation (LT) may lead to cure, whereas different modalities of liver-directed locoregional or systemic tumor treatments are currently available for a noncurative approach. Apart from tumor burden and grade of liver dysfunction, assessment of prognostic relevant biological tumor aggressiveness is vitally important for establishing a promising multimodal therapeutic strategy and improving the individual treatment-related risk/benefit ratio. In recent years, an increasing body of clinical evidence has been presented that ¹⁸F-fludeoxyglucose (¹⁸F-FDG) positron emission tomography (PET), which is a standard nuclear imaging device in oncology, may serve as a powerful surrogate for tumor invasiveness and prognosis in HCC patients and, thereby, impact individual decision making on most appropriate therapy concept. This review describes the currently available data on the prognostic value of ¹⁸F-FDG PET in patients with early and advanced HCC stages and the resulting implications for treatment strategy.

Liver transplantation (LT) is a curative treatment for hepatocellular carcinoma (HCC) and the underlying primary liver disease; however, tumor recurrence is still a major issue. Therefore, the aim of this study was to assess predictors and risk factors for HCC recurrence after LT in patients within and outside the Milan criteria with a special focus on the impact of different bridging strategies.

All patients who underwent LT for HCC between 07/2002 and 09/2016 at the University Hospital of Muenster were consecutively included in this retrospective study. Database research was performed and a multivariable regression analysis was conducted to explore potential risk factors for HCC recurrence.

A total of 82 patients were eligible for the statistical analysis. Independent of bridging strategy, achieving complete remission (CR) was significantly associated with a lower risk for tumor recurrence (p = 0.029; OR = 0.426, 95% CI 0.198-0.918). A maximal diameter of lesion < 3 cm was also associated with lower recurrence rates (p = 0.040; OR = 0.140, 95% CI 0.022-0.914). Vascular invasion proved to be an independent risk factor for HCC recurrence (p = 0.004; OR = 11.357, 95% CI 2.142-60.199).

Achieving CR prior to LT results in a significant risk reduction of HCC recurrence after LT independent of the treatment modalities applied.

Hepatocellular carcinoma represents the most frequent primary liver tumor; curative options are only surgical resection and liver transplantation. From 1996, Milan Criteria are applied in consideration of patients with cirrhosis and hepatocellular for liver transplantation; nonetheless, more recently, Milan Criteria have been criticized because they appear over conservative. Apart from number and size of lesions and biomarker levels, which already have been associated with poorer prognosis, overall survival and recurrence rates after transplantation are affected also by the presence of vascular invasion. Microvascular invasion suggests a poor prognosis but it is often hard to detect before transplant. Diagnostic imaging and tumor markers may play an important role and become the main tools to define microvascular invasion. In particular, a possible role could be found for computed tomography, magnetic resonance imaging, and positron emission tomography. In this paper, we analyze the possible role of positron emission tomography as a preoperative imaging biomarker capable of predicting microvascular invasion in patients with hepatocellular carcinoma and thus selecting optimal candidates for liver transplantation.

Tumor-infiltrating lymphocytes (TILs) represent the host immune response to a tumor. In this study, we investigated the prognostic value of tumor-infiltrating lymphocytes (TILs) in liver transplant candidates with hepatocellular carcinoma (HCC) and established an improved prognostic model for predicting clinical outcome. CD3⁺, CD4⁺, CD8⁺, and FoxP3⁺ TILs were assessed by immunohistochemistry in tumor tissue from 153 patients who had undergone liver transplantation for HCC. Prognostic effects of these TIL subsets and other clinicopathologic factors were evaluated by Kaplan-Meier and Cox regression analysis. The area under the curve (AUC) and net reclassification improvement (NRI) were calculated to determine if the new model improved risk prediction. We found that the prevalence of intra-tumoral FoxP3⁺ Tregs among CD4⁺ TILs, but not the density of intra-tumoral FoxP3⁺ Tregs, was an independent predictor for disease-free (DFS) and overall survival (OS) (P<0.05). A Cox model combining the prevalence of intra-tumoral FoxP3⁺ Tregs with Hangzhou criteria was highly predictive of tumor recurrence and death. The AUCs of the Cox model for recurrence (0.733; 95% CI, 0.656-0.802) and survival (0.765; 95% CI, 0.690-0.830) were significantly increased when compared with those of Hangzhou criteria (P<0.001). Net reclassification improvement showed that predictability of the Cox models for both recurrence and survival was superior to Hangzhou criteria (P<0.05). Our results collectively showed that the prevalence of intra-tumoral FoxP3⁺ Tregs is a promising prognostic predictor for HCC patients after OLT. Inclusion of FoxP3⁺ Tregs into Hangzhou criteria could improveme risk prediction.

Organ shortage requires policies and guidelines to aid organ allocation along the principles of urgency or utility. Identifying patients with significant benefit and withholding liver transplantation (LT) from patients too sick for transplantation are ongoing challenges, in particular in patients with malignancies. An arbitrary threshold of >50% 5-year overall survival (OS) is broadly considered a minimum standard for LT. In patients transplanted for intrahepatic cholangiocarcinoma (iCC), this was only achieved in select cases and when the tumor had a diameter of <2 cm. In patients with extrahepatic and hilar cholangiocarcinoma (CCC), strict selection criteria and combined preoperative radiotherapy/chemotherapy according to the Mayo protocol showed that acceptable longterm results can be achieved in a single high-volume center but are difficult to repeat elsewhere. Furthermore, only rigorously selected patients with neuroendocrine tumors (NETs) meeting the NET Milan criteria adopted by United Network for Organ Sharing can also have >50% 5-year OS. A prospective study in patients with unresectable colorectal cancer metastases in the liver has shown promising OS rates, but further prospective trials are warranted. Current evidence shows that none of the proposed expanded malignant criteria justify deviation of scarce donor organs to patients with hilar CCC, iCC > 2 cm, metastatic NET beyond NET Milan criteria, or metastatic colorectal cancer (CRC) outside clinical trials. Liver Transplantation 24 104-111 2018 AASLD.

Cellular senescence is a fundamental cell fate caused by several cellular injuries which results in irreversible cell cycle arrest yet remaining metabolically active across all species. Cellular senescence not only can prevent tumor occurrence by inhibiting the proliferation of injured cells, but also can affect the surrounding cells through the senescence-associated secretory phenotype (SASP). Attractively, accumulating evidence shows that cellular senescence is closely related to various liver diseases. Therapeutic opportunities based on targeting senescent cells and the SASP are considered to be potential strategy for liver diseases. However, although research on cell senescence has attracted widespread attention, the overview on detailed mechanism and biological function of cell senescence in liver disease is still largely unknown. The present review summarizes the specific role of cell senescence in various liver diseases, and updates the molecular mechanisms underlying cell senescence. Moreover, the review also explores new strategies for prevention and treatment of liver disease through promoting senescence or counteracting excessive pathological senescence.