Multifocal Hepatocellular Carcinoma Research Articles

Macrophage hitchhiking for systematic suppression in postablative multifocal hepatocellular carcinoma.

Hepatocellular carcinoma (HCC), particularly the multifocal HCC, features aggressive invasion and dismal prognosis. Locoregional treatments were often refractory to eliminate tumor tissue, resulting in residual tumor cells persisting and subsequent progression. Owing to problematic delivery to the tumor tissue, systemic therapies, such as lenvatinib (LEN) therapy, show limited clinical benefit in preventing residual tumor progression. Therefore, more advanced strategies for postablative multifocal HCC are urgently needed. Motivated by the chemotaxis in tumor penetration of macrophages, we report a strategy named microinvasive ablation-guided macrophage hitchhiking (MAMH) for the targeted therapy toward HCC. In this study, the strategy leverages the natural inflammatory gradient induced by ablation to guide LEN-loaded macrophages toward tumor targeting, which increased by ~10-fold the delivery efficiency of LEN in postablative HCC in vivo. MAMH has demonstrated significant antitumor activity in various HCC models, including the hydrodynamic tail vein injection multifocal HCC mouse model and the orthotopic xenograft HCC rabbit model, systematically inhibiting residual tumor progression after ablation and prolonging the median survival of tumor-bearing mice. The potential antitumor mechanism was explored using techniques such as flow cytometry, enzyme-linked immunosorbent assay, and immunohistochemistry. We found that the strategy significantly suppressed tumor cell proliferation and neovascularization, and such enhanced delivery of LEN stimulated systemic immune responses and induced durable immune memory. The macrophage hitchhiking strategy demonstrates exceptional therapeutic efficacy and biosafety across various species, offering promising prospects for clinical translation in controlling residual tumor progression and improving outcomes following HCC ablation.

Transarterial chemoembolization with 125I seed insertion for multifocal hepatocellular carcinoma.

A common treatment strategy for individuals with multifocal hepatocellular carcinoma (HCC) who are not candidates for surgical resection is transarterial chemoembolization (TACE). Combining TACE with 125I seed insertion (ISI) may offer a means of enhancing therapeutic efficacy. The purpose of this study was to compare the therapeutic efficacy of TACE administered with and without ISI for the treatment of multifocal HCC. The data from the two centers were analyzed retrospectively. The present study involved 85 consecutive patients with multifocal HCC who underwent TACE between January 2018 and December 2021. Of these patients, 43 were in the combined group, receiving TACE with ISI, and 42 were in the TACE-only group, receiving TACE without ISI. Comparisons of treatment outcomes were made between these groups. No significant differences in baseline data were observed between these groups of patients. Higher rates of complete (60.5% vs. 33.3%, P = 0.016) and total (93.0% vs. 61.9%, P = 0.001) responses were evident in the combined group compared to the TACE-only group. Median progression-free survival (PFS, 13 vs. 10 months, P = 0.014) and overall survival (OS, 22 vs. 17 months, P = 0.035) were also significantly longer in the combined group than in the TACE-only group. Using a Cox regression analysis, risk variables associated with shorter PFS and OS included Child-Pugh B status (P = 0.027 and 0.004) and only TACE treatment (P = 0.011 and 0.022). In summary, these findings suggest that, as compared to TACE alone, combining TACE and ISI can enhance HCC patients' treatment outcomes and survival.

Liver transplant versus liver resection in patients with multifocal hepatocellular carcinoma

BackgroundThe optimal surgical option in patients with multifocal hepatocellular carcinoma (MHCC) is an area of active research. The preference varies based on geographic variations and institutional policies. We sought to determine long-term outcomes in patients with MHCC based on surgical treatment—liver transplant (LT) vs resection (LR). MethodsWe performed a retrospective analysis of the National Cancer Database (2004–2015) and identified patients with MHCC within Milan criteria. Patients with α-fetoprotein ≥ 1000 ng/mL and those who underwent ablation were excluded. The primary outcome measure was long-term survival in patients undergoing LT vs LR. The secondary aim of our study was to determine clinicodemographic factors associated with the receipt of LT and LR. ResultsA total of 1546 patients were included, of whom 1211 received LT and 335 underwent LR. Patients who were non-Hispanic White (70.8% vs 54.9%; P < .01), privately insured (53.7% vs 36.7%; P < .01), and treated at academic centers (85.4% vs 71.6%; P < .01) were more likely to receive an LT. Multivariable Cox analysis revealed LT was associated with improved survival compared with LR (hazard ratio, 0.34; 95% CI, 0.28–0.42). ConclusionWe described clinical and sociodemographic differences in LT and LR patients and found LT to be associated with a decreased mortality risk compared with LR. The study’s findings should be interpreted in the context of several limitations, including the selection of MHCC criteria within Milan criteria.

Transesophageal Echocardiography: Timely Resolution of an Urgent Right Atrial Mass/ Hepatocellular Carcinoma Thrombosis

Advanced hepatocellular carcinoma (HCC) with metastasis is linked to a bleak diagnostic prognosis. Common sites of dissemination involve the lungs, portal vein, and portal lymph nodes. This report presents a rare case of a 57-year-old man with a right atrial mass, a thrombus of an undiagnosed multifocal HCC. This case demonstrates the crucial role that transoesophageal echocardiography (TEE) has in promptly confirming the diagnosis with more details, as well as monitoring the surgery. The transthoracic and, in particular, the TEE were valuable in this patient’s case in providing a timely resolution of an urgent right atrial mass/HCC thrombosis.

Liver resection is superior to tumor ablation in patients with multifocal hepatocellular carcinoma.

The management of T2 multifocal hepatocellular carcinoma (MHCC) is controversial, and the comparative impact of liver resection (LR) versus tumor ablation (TA) on survival continues to be debated. The aim of our study was to examine short- and long-term survival for LR and TA in a nationally representative cohort. We hypothesized that patients who underwent LR would have improved survival. We utilized the National Cancer Database (2004-2015) to identify patients diagnosed with non-metastatic T2 MHCC. Kaplan-Meier survival curves were generated to compare 10-year overall survival (OS) between LR and TA patients. Kaplan-Meier analysis with stratification was also performed based on lymphovascular invasion, resection margin status, and Charlson-Deyo score. Cox proportional hazard models were used in multivariable analyses. A total of 1225 patients met the inclusion criteria. 991 patients received LR, and 234 received TA. The majority of patients were male, White, and older than ≥60 years old. Clinicodemographic characteristics were generally similar between LR and TA patients. Among patients who underwent LR, 84% had negative margins, and 17% had lymphovascular invasion. Mortality at 30 days was significantly higher among LR patients compared to TA patients (5.4% vs 0.0%, p < 0.001), with those having a Charlson-Deyo score ≥2 facing the highest risk at 7.3%. Nevertheless, 10-year OS for the LR cohort was 27.5% (95% confidence interval [CI]: 24.4%-30.8%) versus 14.7% (95% CI: 9.8%-20.7%, p < 0.001) for TA patients. In stratified analysis, survival benefit was statistically significant only among those with negative resection margin, no lymphovascular invasion, and Charlson-Deyo score ≤1. In multivariable Cox analysis, LR was independently associated with improved survival compared to TA (hazard ratio: 0.80; 95% CI = 0.67-0.95). LR poses a higher long-term survival benefit than TA. Prospective studies are warranted to confirm these findings. Although our study patients are a highly selected group of multifocal T2 patients, it gives us a good insight into the fact that LR provides better outcomes if a transplant option is unavailable.

Downstaging and laparoscopic hepatectomy plus intraoperative radiofrequency ablation for the treatment of initially unresectable multifocal hepatocellular carcinomas.

Using TKIs plus anti-PD-1 antibodies combined with TACE in the treatment of patients with initially unresectable multiple HCCs has a high tumour response rate, and using laparoscopic hepatectomy (LH) combined with intraoperative RFA for radical treatment of multiple HCCs after successful downstaging treatment has not been reported. Consecutive patients with multiple HCCs (≤4 lesions) who were downstaged with TKIs plus anti-PD-1 antibodies combined with TACE were analysed. Imaging examinations were performed monthly, and RECIST v1.1 criteria were used to evaluate treatment effect and resectability. Forty-five consecutive patients with multiple HCCs who met the inclusion criteria received downstaging treatment with TKIs plus anti-PD-1 antibodies combined with TACE. Nine patients were successfully downstaged and met the R0 resection criteria, and 8 patients underwent surgery. Among the patients, 5 patients had BCLC stage C, and 3 patients had BCLC stage B. There were 2 lesions in 5 patients, 3 lesions in 2 patients, and 4 lesions in 1 patient. The average size of the main HCC was 8.5 cm (range: 5.4-9.1 cm), and the diameter of the remaining HCCs was 1.6 cm (range: 0.8-2.9 cm). The average time from the start of downstaging therapy to surgery was 81 days (range: 60-210 days). All 8 patients underwent LH of the main HCC, and the remaining HCCs were targeted with RFA. The mean operation time was 220 min (range 150-370 min), the average intraoperative blood loss was 260 ml (range 100-750 ml), there was no case conversion to laparotomy, and the average postoperative hospital stay was 9 days (range 7-25 days). The incidence of postoperative complications was 37.5% and there were no deaths. The average follow-up time was 18.2 months (range 6.1-22.4 months), 5 patients survived tumour-free, 2 patients had tumour recurrence, and 1 patient died. After successful downstaging of multiple HCCs by treatment with TKIs plus anti-PD-1 antibodies and TACE, LH combined with RFA for radical surgery is safe and feasible, and the treatment effect is satisfactory. It is worthy of clinical reference, and its long-term effects require further research for confirmation.

Multifocal hepatocellular carcinoma: a narrative review assessing treatment options from the interventional radiologist’s perspective.

It is estimated that 35-40% of hepatocellular carcinoma (HCC) patients present with multiple nodules at the time of diagnosis. Treating multifocal disease is difficult given patient population heterogeneity. Multiple interventional radiological (IR) options, including ablation, transarterial chemoembolization (TACE), and transarterial radioembolization (TARE), are available, each with its own merits and limitations. Our aim is to explore the current state of the literature to identify where each of these options is best applied to multifocal HCC management. A narrative literature review of 107 papers was performed in PubMed. Articles from 2010 and newer were used for clinical data and for classification/scoring system details. The majority of the keywords for searches include the treatment modality name alongside terms such as "HCC", "multifocal", or "multinodular". Ablation is a curative option for Barcelona Clinic Liver Cancer (BCLC) A disease and is appropriate when liver transplantation (LT) is impractical. It is ideal in disease with ?3 nodules (each <3 cm) preferably confined to one segment. TACE [conventional TACE (cTACE), drug-eluting bead TACE (DEB-TACE), balloon-occluded TACE (B-TACE), and less so hepatic arterial infusion chemotherapy (HAIC)] is the major workhorse for multifocal BCLC B disease, in pre-transplant downstaging, and in advanced disease palliation. The Kinki BCLC B subclassification can guide TACE subtype selection. TACE response can be assessed over 2-3 sessions per modified Response Evaluation Criteria in Solid Tumors (mRECIST) and patient session tolerance. TARE is an option for BCLC C disease, with BCLC A/B applications limited by radiation induced liver disease (RILD). Pseudo-ablative techniques like sub-selective TARE (sTARE) are promising but are unproven and less useful in multinodular disease. Finally, combination therapies [TACE + ablation, liver resection (LR) + ablation/TACE] are an exciting option but warrant further study. Multifocal HCC remains challenging to manage. While BCLC is a useful starting point, the patient's tumor imaging characteristics and clinical circumstances must be considered when selecting the appropriate treatment modality.

H - 40 The Role of Neuropsychology in Solid Organ Transplantation Candidacy in a Patient with a Diverse Linguistic and Sociocultural Background.

Candidates for transplantation with end stage organ failure (ESOF) undergo extensive pre-surgical medical and psychosocial evaluations, however neuropsychology is rarely required. This is concerning, as patients with ESOF often have cognitive deficits that may impact their ability to safely manage post-transplant care and are at increased risk for morbidity/mortality. This case highlights the novel perspective a comprehensive neuropsychological evaluation provides, especially in patients of diverse sociocultural backgrounds. The patient is a 37-year-old monolingual Spanish-speaking woman referred for evaluation in the context of liver transplant candidacy due to apparent inability to follow medical guidance, medication adherence, and continued alcohol consumption. Medical history includes autoimmune hepatitis, multifocal hepatocellular carcinoma, and diabetes. The patient reported problems with remembering information from providers even with compensatory strategies. Her family assists heavily with scheduling and transportation. When asked about alcohol use, she reported recent use of a few beers due to very hot weather, limited access to clean water, and the death of a family member despite providers urging her to remain abstinent. She was not aware of the hazard that even minimal alcohol use presented to her candidacy. She did not meet criteria for a neurocognitive disorder. The etiology of her noncompliance was secondary to poor social support, limited coping skills, and feeling overwhelmed by team instructions. Conducting a culturally informed evaluation in the patient's native language provided clear evidence of intact cognition and a nuanced understanding of her limitations that would not be appreciated in a more limited evaluation.

SAT170 Paraneoplastic Hypoglycemia Secondary To Hepatocellular Carcinoma

Abstract Disclosure: S. Dejhansathit: None. N. Sheung: None. A. Akofu: None. A. Uddin: None. F. marium: None. N.G. Akabogu: None. W. Salam, MD: None. Introduction: Hypoglycemia is a known but rare Paraneoplastic manifestation of hepatocellular carcinoma and can lead to significant morbidity and mortality. Even though HCC-related hypoglycemia is a known entity, knowledge about prevention and treatment is limited. Case Description: We report a 36-year-old male with no significant past medical history presenting initially to emergency room for abdominal pain and distension for 2 months. He reported associated 10 pounds unintentional weight loss, fatigue, night sweat and loss of appetite in the past 3 months. The patient noted to have hypoglycemia with blood glucose of 20 mg/dl on admission. He was given 2 ampoules of 50% dextrose and started on 5% dextrose solution intravenously. A CT abdomen and pelvis showed enlarged heterogenous liver with numerous hepatic lesions, concerning for multifocal hepatocellular carcinoma. A liver biopsy was done and confirmed hepatocellular carcinoma. Labs showed alpha fetoprotein level over 60500 ng/mL (0-8.3 ng/mL). Hepatitis B surface antigen was reactive with positive hepatitis B DNA, confirming the diagnosis of chronic hepatitis B infection. Gastroenterology, Oncology and Surgical Oncology were consulted. Patient was felt not to be a good surgical or transarterial chemo-embolization. Endocrinology was consulted when patient develops scrotal and legs swelling after receiving high rate of dextrose fluid since admission to maintain blood glucose. Prednisone 20 mg twice a day was initiated and later increased to 30 mg twice day after 2 days without significant improvement. Prednisone was then switched to dexamethasone 4 mg four times a day for longer half-life. 10% dextrose was slowly decreased from 200cc/hr to100cc/hr but resulted in rebound hypoglycemia. Somatropin 4 mg daily was also added with a goal to further decrease fluid rate in order to help with his discomfort from swelling. 10% dextrose was eventually decreased to 75 cc/hr. Patient subsequently opted for hospice care and passed away within 24 hours. Discussion: The paraneoplastic hypoglycemia associated with HCC can be classified into two categories. Type A hypoglycemia is usually found in the late-stage HCC when tumor burden is high. Type B hypoglycemia is caused by an increase in pro-IGF-2 level that is incompletely processed by the tumor cells, stimulating insulin receptors. It is likely our patient had type A hypoglycemia due to the extensive tumor burden. Overall, paraneoplastic hypoglycemia associated with HCC has very poor prognosis and high mortality rate. There is no single effective management and combination of steroids and Somatropin may provide palliative improvement as seen in our patient. Presentation: Saturday, June 17, 2023

Clinical outcome of surgical resection for multifocal T2-T3 hepatocellular carcinoma up to 3 nodules: a comparative analysis with a single nodule.

Although the Barcelona Clinic Liver Cancer staging system seems to underestimate the impact of curative-intent surgical resection for multifocal hepatocellular carcinoma (HCC), recent studies have indicated favorable results for the surgical resection of multiple HCC. This study aimed to assess clinical outcomes and feasibility of surgical resection for multifocal HCC with up to three nodules compared with single tumor cases. Patients who underwent surgical resection for HCC with up to three nodules between 2009 and 2020 were included, and those with the American Joint Committee on Cancer (AJCC) 8th edition, T1 and T4 stages were excluded to reduce differences in disease distribution and severity. Finally, 81 and 52 patients were included in the single and multiple treatment groups, respectively. Short- and long-term outcomes including recurrence-free survival (RFS) and overall survival (OS), were evaluated. All patients were classified as Child-Pugh class A. RFS and OS were not significantly different between the two groups (P=0.176 and P=0.966, respectively). Multivariate analysis revealed that transfusion and intrahepatic metastasis were significantly associated with recurrence (P=0.046 and P=0.005, respectively). Additionally, intrahepatic metastasis was significantly associated with OS (hazard ratio, 1.989; 95% confidence interval, 1.040-3.802; P=0.038). Since there was no significant difference in survival between the single and multiple groups among patients with AJCC 8th stage T2 and T3, surgical resection with curative intent could be considered with acceptable long-term survival for selected patients with multiple HCC of up to three nodules.

The number of hepatocellular carcinoma foci as predictor of poor response to tumor-directed therapies in patients awaiting liver transplantation: a prospective cohort study.

Tumor-directed therapies (TDTs) are a constitutive part of hepatocellular carcinoma (HCC) treatment in patients awaiting liver transplantation (LT). While most patients benefit from TDTs as a bridge to LT, some patients drop out from the waiting list due to tumor progression. The study aimed to determine the risk factors for poor treatment outcome following TDTs among patients with HCC awaiting LT. A total of 123 patients with HCC were evaluated with 92 patients meeting Milan Criteria enrolled in the prospective cohort study. Tumor response was evaluated using the modified Response Evaluation Criteria for Solid Tumors for HCC 1 month after the procedure. The risk factors for progressive disease (PD) and dropout were evaluated. After TDT, 55 patients (59.8%) achieved complete or partial response (44.6% and 15.2% respectively), 17 patients (18.5%) had stable disease, and 20 patients (21.7%) were assessed as PD. Multivariate analysis revealed a significant and independent association between the number of HCC foci and PD ( P = 0.03, OR = 2.68). There was no statistically significant association between treatment response and demographics, MELDNa score, pre-and post-treatment alpha-fetoprotein (AFP), cumulative tumor burden the largest tumor size, or TDT modality. PD was the major cause of dropout in our cohort. Pre-treatment AFP levels ≥200 ng/ml had a strong association with dropout after TDTs ( P = 0.0005). This study demonstrated the presence of multifocal HCC is the sole prognostic factor for PD following TDTs in HCC patients awaiting LT. We recommend prioritizing patients with multifocal HCC within Milan criteria by exception points for LT to improve the dropout rate.

Combining Crocin and Sorafenib Improves Their Tumor-Inhibiting Effects in a Rat Model of Diethylnitrosamine-Induced Cirrhotic-Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies, with continuously increasing cases and fatalities. Diagnosis often occurs in the advanced stages, confining patients to systemic therapies such as sorafenib. Sorafenib (SB), a multi-kinase inhibitor, has not yet demonstrated sufficient efficacy against advanced HCC. There is a strong argument in favor of studying its use in combination with other medications to optimize the therapeutic results. According to our earlier work, crocin (CR), a key bioactive component of saffron, hinders HCC development and liver cancer stemness. In this study, we investigated the therapeutic use of CR or its combination with SB in a cirrhotic rat model of HCC and evaluated how effectively SB and CR inhibited tumor growth in this model. Diethylnitrosamine (DEN) was administered intraperitoneally to rats once a week for 15 weeks, leading to cirrhosis, and then 19 weeks later, leading to multifocal HCC. After 16 weeks of cancer induction, CR (200 mg/kg daily) and SB (10 mg/kg daily) were given orally to rats for three weeks, either separately or in combination. Consistently, the combination treatment considerably decreased the incidence of dyschromatic nodules, nodule multiplicity, and dysplastic nodules when compared to the HCC group of single therapies. Combined therapy also caused the highest degree of apoptosis, along with decreased proliferating and β-catenin levels in the tumor tissues. Additionally, when rats received combined therapy with CR, it showed anti-inflammatory characteristics where nuclear factor kappa B (NF-κB) and cyclooxygenase-2 (Cox-2) were considerably and additively lowered. As a result, CR potentiates the suppressive effects of SB on tumor growth and provides the opportunity to strengthen the therapeutic effects of SB in the treatment of HCC.

Molecular evolution in different subtypes ofmultifocal hepatocellular carcinoma.

Multifocal hepatocellular carcinoma (MF-HCC) accounts for > 40% of HCCs, exhibiting a poor prognosis than single primary HCCs. Characterizing molecular features including dynamic changes of mutational signature along with clonal evolution, intrahepatic metastatic timing, and genetic footprint in the preneoplastic stage underlying different subtypes of MF-HCC are important for understanding their molecular evolution and developing a precision management strategy. We conducted whole-exome sequencing in 74 tumor samples from spatially distinct regions in 35 resected lesions and adjacent noncancerous tissues from 11 patients, 15 histologically confirmed preneoplastic lesions, and six samples from peripheral blood mononuclear cells. A previously published MF-HCC cohort (n = 9) was included as an independent validation dataset. We combined well-established approaches to investigate tumor heterogeneity, intrahepatic metastatic timing, and molecular footprints in different subtypes of MF-HCCs. We classified MF-HCCs patients into three subtypes, including intrahepatic metastasis, multicentric occurrence, and mixed intrahepatic metastasis and multicentric occurrence. The dynamic changes in mutational signatures between tumor subclonal expansions demonstrated varied etiologies (e.g., aristolochic acid exposure) underlying the clonal progression in different MF-HCC subtypes. Furthermore, the clonal evolution in intrahepatic metastasis exhibited an early metastatic seeding at 10-4-0.01cm3 in primary tumor volume (below the limits of clinical detection), further validated in an independent cohort. In addition, mutational footprints in the preneoplastic lesions for multicentric occurrence patients revealed common preneoplastic arising clones, evidently being ancestors of different tumor lesions. Our study comprehensively characterized the varied tumor clonal evolutionary history underlying different subtypes of MF-HCC and provided important implications for optimizing personalized clinical management for MF-HCC.

Large, multifocal or portal vein-invading hepatocellular carcinoma (HCC) downstaged by Y90 using personalized dosimetry: safety, pathological results and outcomes after surgery.

Transarterial radioembolization (TARE) has recently been recognized as a bridging/downstaging therapy to surgery for early hepatocellular carcinomas (HCCs) with high rates of complete pathological necrosis (CPN) on liver explants. In patients with portal vein tumoral thrombus (PVTT), multifocal or large tumors, TARE has mainly a palliative role and surgery remains controversial in this poor-prognosis population. Personalized dosimetry recently proved to outperform standard dosimetry used in prior negative Y90 randomized-controlled trials. In this retrospective study, we evaluated safety, radiological and pathological response and outcomes in HCC patients with PVTT, multifocal or large tumors, who underwent surgery after downstaging using TARE with Y90-loaded glass microspheres with personalized dosimetry. Between December 2015 and October 2021, 18 unresectable patients (14/18 with PVTT) had surgery (16 resections, 2 liver transplantations) 6.2 months (range, 2-14.6 months) after a single Y90 treatment. No 90-day mortality was reported. Objective modified response criteria in solid tumors (mRECIST) response were noted in all but one patient. Complete and extensive (50-99%) necrosis was observed in 36% and 45% of tumors, respectively. The post-treatment tumor-absorbed dose significantly differed depending on the extent of pathological necrosis (P=0.045). Median overall survival and progression-free survival (PFS) were respectively of 61.8 months [95% CI: 31.4 months-not reached (NR)] and 49.3 months (95% CI: 14 months-NR). PFS was longer in patients with complete imaging response [median NR (none recurred or died) vs. 21.5 months (95% CI: 10.1 months-NR), P<0.001] and in those with complete pathological response [median NR vs. 22.5 months (95% CI: 10.1 months-NR), P<0.001]. Y90 TARE using personalized dosimetry can provide high rates of imaging and pathological response in patients with PVTT, large or multifocal HCC. Subsequent surgery is safe and leads to outcomes far exceeding expectations in an otherwise poor prognosis population with no chance for cure. Clinical trial number: NCT05045573.

Synergistic effects of combined immunotherapy strategies in a model of multifocal hepatocellular carcinoma

Immune checkpoint-inhibitor combinations are the best therapeutic option for advanced hepatocellular carcinoma (HCC) patients, but improvements in efficacy are needed to improve response rates. We develop a multifocal HCC model to test immunotherapies by introducing c-myc using hydrodynamic gene transfer along with CRISPR-Cas9-mediated disruption of p53 in mouse hepatocytes. Additionally, induced co-expression of luciferase, EGFP, and the melanosomal antigen gp100 facilitates studies on the underlying immunological mechanisms. We show that treatment of the mice with a combination of anti-CTLA-4+ anti-PD1 mAbs results in partial clearance of the tumor with an improvement in survival. However, the addition of either recombinant IL-2 or an anti-CD137 mAb markedly improves both outcomes in these mice. Combining tumor-specific adoptive Tcell therapy to the aCTLA-4/aPD1/rIL2 or aCTLA-4/aPD1/aCD137 regimens enhances efficacy in a synergistic manner. As shown by multiplex tissue immunofluorescence and intravital microscopy, combined immunotherapy treatments enhance Tcell infiltration and the intratumoral performance of T lymphocytes.

Preoperative Predictors of Early Recurrence After Liver Resection for Multifocal Hepatocellular Carcinoma

BackgroundLiver transplantation remains the optimal treatment for multifocal hepatocellular carcinoma (HCC). However, due to resource constrains, other therapeutic modalities such as liver resection (LR), are frequently utilized. LR, however, has to be balanced against potential morbidity and mortality along with the risks of early recurrence leading to futile surgery. In this study, we evaluated preoperative factors, including inflammatory indices, in predicting early (< 1 year) recurrence in patients who underwent LR for multifocal HCC. MethodsThis was a post hoc analysis of 250 consecutive patients with multifocal HCC who underwent LR. ResultsAfter exclusion of 10 patients with 30-day/in-hospital mortality, 240 were included of which 134 (55.8%) developed early recurrence. Hepatitis B/C aetiology, 3/ > more hepatic nodules and elevated alpha-fetoprotein (AFP) ≥ 200 ng/ml were significant independent preoperative predictors of early recurrence. The early recurrence rate was 72.1% when 2 out of 3 significant predictive factors were present. The conglomerate of all 3 factors predicted early recurrence of 100% with a statistically significant association between number of predictive factors and early recurrence (p < 0.001). ConclusionBetter patient selection via the use of preoperative predictive factors of early recurrence such as hepatitis B/C aetiology, ≥ 3 nodules and elevated AFP ≥ 200 ng/ml may assist in identifying patients in whom LR is deemed futile and improve resource allocation.

Metastatic yolk sac tumor masquerading as multifocal hepatocellular carcinoma in a young adult: A case report

Primary yolk sac tumor of the liver is very rare and can present as multifocal liver lesions. Multifocal nature may mimic other diagnoses such as hepatocellular carcinoma. Early recognition and therapeutic intervention are important as the prognosis of metastatic yolk sac tumors is poor. We present a case of a young adolescent who presented with bleeding per rectum abdominal pain and multiple liver lesions.

Repeat hepatic resection combined with intraoperative radiofrequency ablation versus repeat hepatic resection alone for recurrent and multiple hepatocellular carcinoma patients meeting the Barcelona Clinic Liver Cancer stage A: A propensity score-matched analysis.

The surgical indications and therapeutic strategies for early-stage multifocal and recurrent hepatocellular carcinoma (rHCC) remain controversial. This study compared the long-term outcome of patients with recurrent and multifocal HCC meeting the Barcelona Clinic Liver Cancer (BCLC) stage A with repeat hepatectomy (RH) and RH combined with intraoperative radiofrequency ablation (RFA). A total of 109 consecutive patients with intrahepatic early-stage multifocal rHCC within BCLC stage A following RH or RH + RFA were retrospectively collected from April 2010 to May 2020. Propensity score matching, subgroup analysis, and univariate and multivariate analyses were performed. Overall survival after recurrence (rOS) and recurrence-free survival after recurrence (rRFS) were calculated by Kaplan-Meier analysis. The 1-, 3-, and 5-year rOS and rRFS of the combination group and the RH group were similar (p=.699; p=.587, respectively). The similar results also appeared in matched population. Subgroup analyses indicated that there was no significant difference between patients with two tumors and three tumors, but the RH group was associated with better rRFS than the combination group for patients whose tumors were located in the same lobe (p=.045). Multivariate analysis revealed that time to recurrence (TTR) ≤ 2 years and intrahepatic metastasis (IM) pathologically were independent risk factors. For multifocal rHCC patients meeting the BCLC stage A, tumor which is difficult to be surgically resected could be treated by RFA in order to avoid complications or bleeding. Tumors which were located in the same lobe may be more suitable to be treated by RH alone.

Locoregional treatment approaches for hepatocellular carcinoma – a case report

A hepatocellular carcinoma (HCC) is a primary liver malignancy, often arising in the setting of chronic liver disease. Incidence of this carcinoma is increasing at a great rate. Disease often manifests asymptomatically and to make the final diagnosis is often challenging. Screening of patients at risk is based on ultrasound (US) examinations, which in the setting of suspicion lesion findings often converts to multiphasic computed tomography (CT) and magnetic resonance imaging (MRI) procedures for advanced disease evaluation. The selection of treatment modality depends on tumor size and location, extrahepatic spread and subsequent liver disease. For years the first line of treatment was liver resection and transplantation. Locoregional therapy is a novel approach to diverse stages of HCC with good response and higher overall survival rates, especially in early stages. Transarterial chemoembolization (TACE) is the method of choice in patients with multifocal HCC and maintained liver function, unsuitable for surgical treatment. We present a patient with HCC in the setting of hepatitis C virus (HCV) infection, treated with combined methods of locoregional therapy.

Laparoscopic versus open hepatectomy for large hepatocellular carcinoma: a single center propensity-score-matching comparative analysis of perioperative outcomes and long-term survival.

Although the benefits of laparoscopic hepatectomy (LH) for hepatocellular carcinoma (HCC) in most circumstances are evident, the benefits for large HCC are contentious. This study aimed to compare the perioperative outcomes and survival after LH versus open hepatectomy (OH) in large HCC patients. An analysis of prospectively maintained database included 215 hepatectomies for large HCC (diameter ≥ 5cm). The operative and survival outcomes were compared between the LH group (n = 109) and the OH group (n = 106). Propensity score matching (PSM) 1:1 included 70 patients in each group. The entire cohort multivariable analyses were performed to identify the factors associated with surgical complications and suboptimal recurrence-free survival (RFS). After PSM, baseline characteristics and the extent of liver resection were similar in both groups. The LH group had a shorter hospital stay than the OH group (7 vs 9.5days, p = 0.001). The R0 resection rate, complication rate, overall survival, and RFS were similar between the groups. The multivariate analyses revealed two independent factors predicting surgical complication (major resection; p < 0.001 and large volume blood loss; p = 0.042), and 3 independent factors predicting suboptimal RFS including R1 resection (p = 0.011), multifocal HCC (p = 0.005), and microvascular invasion (p = 0.001). LH was not associated with surgical complication and suboptimal RFS. Our study highlights the benefits of LH by improving the perioperative outcomes, without long-term survival inferiority in selected large HCC patients compared with conventional OH. LH can be an attractive option for large HCC treatment.