Conversion surgery for hepatocellular carcinoma after tyrosine kinase inhibitor treatment.

Background and Aim: Conversion surgery (CS), which aims to cure after systematic therapy, is only scarcely reported in the field of hepatocellular carcinoma (HCC). However, advancements in systemic therapy for HCC are expected to increase the candidates eligible for CS because of the higher response rate. The aim of this study was to clarify the characteristics of patients who underwent CS after tyrosine kinase inhibitor (TKI) therapy. Methods: In all, 364 patients who were treated with first-line sorafenib (SOR; n = 292) and lenvatinib (LEN; n = 72) from July 2009 to October 2020 were retrospectively enrolled. The endpoint of this analysis was overall survival (OS), and factors associated with CS are revealed. Results: Six patients underwent CS after TKI therapy, and of these four (1.4%) and two (2.7%) patients received SOR and LEN, respectively. At baseline, patients who underwent CS were significantly younger (median 52 [range, 46-83] years of age, P = 0.019), and their etiology included viral hepatitis, especially hepatitis B virus (HBV) (P = 0.049). Improvements or maintenance of preoperative modified albumin-bilirubin grade from baseline were observed in five (83.3%) patients, and partial radiologic response was observed in four (66.7%) patients. The median OS and 3-year survival rate of patients treated with CS were "not reached" and 80.0%, respectively. Conclusion: The patients who underwent CS after TKI therapy for HCC experienced long survival, were relatively young, and exhibited radiologic response to TKIs, and their liver function was either maintained or improved. Therefore, CS may lead to a better prognosis in patients with advanced HCC.

Prognosis of intrahepatic cholangiocarcinoma stratified by albumin-bilirubin grade.

AIM: Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive malignancy. However, the characteristics and prognosis of ICC is not well known. This study aims to reveal the relationship between liver function and prognosis of ICC. METHODS: A total of 83 ICC patients were recruited retrospectively from March 2009 to August 2020. Child-Pugh (CP) and albumin-bilirubin (ALBI) scores were used to assess liver function. The extent of portal vein tumor thrombosis (PVTT) was classified from Vp0 to Vp4. The end-point for this analysis was overall survival (OS). RESULTS: The median age was 72 (44-88) years, 48 patients were male (57.8%), and 70 patients were classified as CP grade A (84.3%). At baseline, chronic liver disease (hepatitis B, 9.6%; hepatitis C, 15.7%; alcoholic liver disease, 9.6%; and nonalcoholic fatty liver disease, 4.8%) were diagnosed. The median OS of all ICC patients was 21.2 months. A total of 27 patients underwent surgical resection; these patients showed a longer median OS compared to those who did not undergo surgery (50.8 months vs. 5.5 months, p < 0.001). The prognosis of patients with ICC can be stratified by ALBI grade (grade 1, 54.3 months; grade 2a, 8.4 months; grade 2b, 3.9 months; and grade 3, 1.4 months; p < 0.001) and the extent of PVTT (Vp0, 54.3 months; Vp1/2, 8.4 months; and Vp3/4, 3.9 months; p = 0.0039). CONCLUSION: In this study, viral hepatitis (25.3%) was identified as the most prevalent background liver disease of ICC. Assessing liver function using ALBI grade is useful for stratifying the prognosis of patients with ICC.

Methotrexate-associated lymphoproliferative disorder complicated by severe acute respiratory failure and ileal perforation:a case report.

Lymphoproliferative disorder (LPD) is a potentially severe adverse effect of methotrexate (MTX) administration in patients with rheumatoid arthritis (RA). We report a case of MTX-associated LPD (MTX-LPD) in a patient with RA who developed severe pulmonary failure complicated by perforation of the terminal ileum. A 61-year-old woman with RA receiving MTX complained of dyspnea and abdominal pain. She was diagnosed with intestinal perforation and peritonitis, and underwent immediate abdominal surgery. Pathological examinations of the specimen obtained from the resected ileum and a bone marrow aspirate revealed diffuse large B-cell lymphoma. Steroid therapy failed to improve her respiratory failure, but her condition improved after abdominal surgery and suspension of MTX. MTX-LPD can result in multiple life-threatening conditions; however, the symptoms are highly variable. RA patients receiving MTX should thus be monitored carefully, and MTX administration should be stopped immediately on suspicion of MTX-LPD.

[Neoadjuvant Chemoradiotherapy for Locally Advanced Carcinoma Associated with Anal Fistula].

The patient was a 59-year-old man. He was admitted to our hospital because of increasing anal pain with induration of the perianal region. There were large secondary orifices with mucous discharge on the left side of the perineal resion and buttock. We diagnosed adenocarcinoma on analysis of a biopsy specimen from induration of the perianal region. Pelvic CT and MRI showed that the tumor spreaded within the pelvis, with invasion of the prostate and sacrum. We performed neoadjuvant chemoradiotherapy preoperatively. After chemoradiotherapy, the tumor reduced in size greatly. We performed abdominoperineal resection and massive resection of skin of the perianal region. The defect of the pelvic floor and perianal skin was repaired using skin flap. The surgical margin was tumor free. Neoadjuvant chemoradiotherapy was considered effective for locally advanced carcinoma associated with anal fistula.

[Malignant Pleural Mesothelioma with Excessive Inflammation and High Level of Interleukin 6 - A Case Report].

Malignant mesothelioma is a rare aggressive solid tumor that is invariably incurable. A 23-year-old female patient with ascites, anemia, and high levels of ferritin and CRP was diagnosed with pleural mesothelioma by exploratory laparotomy. She remained asymptomatic, but 7 years later, she developed intractable diarrhea and fever. Systematic chemotherapy with both cisplatin and pemetrexed was administered. However, the treatment was discontinued due to side effects, after which time the diarrhea, ascites, and fever became progressively more severe. Hepatomegaly and hepatic siderosis also developed. At the same time, the patient's serum interleukin 6(IL-6)levels were abnormally high. Although there was a temporary symptomatic improvement after intraperitoneal injection of cisplatin, the intractable mesothelioma-associated symptoms returned a few days later. The patient died of liver failure 1 week later. The poor prognosis in this case was due to symptoms associated with the high IL-6 level. There are limited medically proven treatments, and it is important to develop new treatments. Therefore, "anti-IL-6 therapy" may have to be tested as a potential treatment for symptoms associated with high IL-6 levels.

Prognostic role of Child-Pugh score 5 and 6 in hepatocellular carcinoma patients who underwent curative hepatic resection.

BACKGROUND: It is unclear whether Child-Pugh score discriminates a prognosis of the Child-Pugh A patients who underwent hepatic resection for hepatocellular carcinoma. METHODS: Between April 2000 and March 2011, 361 patients with Child-Pugh A who underwent curative hepatectomy were divided into 2 groups: Child-Pugh score 5 points group (CPS5) and Child-Pugh score 6 points group (CPS6); both CPS5 (n = 274) and CPS6 (n = 87) groups were compared. RESULTS: Overall survival rates (1/2/5 years of the CPS5 and CPS6 groups were 90.9%/82.5%/62.4% and 80.6%/68.0%/47.6%, respectively) and disease-free survival rates (67.6%/51.8%/30.1% and 36.9%/16.0%/5.9%, respectively) showed that the CPS5 group was significantly better than the CPS6 group. Multivariate analysis revealed that Child-Pugh score at overall survival (P = .0125) and disease-free survival (P = .0103) was a significant prognostic factor. CONCLUSIONS: The overall survival and disease-free survival in Child-Pugh A showed quite a difference between the CPS5 and CPS6 groups. However, CPS5 and CPS6 may be a useful prognostic marker of hepatocellular carcinoma patients with hepatic resection.

A novel therapeutic combination sequentially targeting aurora B and Bcl-xL in hepatocellular carcinoma.

BACKGROUND: Effective therapeutic combinations targeting the oncogenic pathway still are unknown in human hepatocellular carcinoma (HCC). The authors previously identified aberrant expression of aurora B kinase as the independent predictor for the lethal recurrence of HCC, showing that AZD1152 induced in vitro and in vivo apoptosis with polyploidy in human HCC cells. In this preclinical study, the combined effects of molecular-targeted therapies were evaluated based on the cellular response of aurora B inhibition. METHODS: This study analyzed the expression of Bcl-2 family proteins in polyploidization induced by AZD1152 and the in vitro synergistic effects of AZD1152 with control of the Bcl-2 family pathway in human HCC cells. The in vivo effects of the combination therapy targeting the specific molecules were evaluated using subcutaneous tumor xenograft models. RESULTS: The findings showed that Bcl-xL was specifically overexpressed in AZD1152-induced polyploid HCC cells. The combination of AZD1152 followed by Bcl-xL/2 inhibitor ABT263 induced synergistically cellular apoptosis (p < 0.001) and growth inhibition (p < 0.0001). Interestingly, the reverse sequential administration of AZD1152 combined with pretreatment of ABT263 was less effective than the original one. In vivo studies using tumor xenografts of human HCC cells showed that combination therapy of ABT263 after AZD1152 pretreatment induced significant intratumoral apoptosis (p < 0.05) and remarkable anti-tumor effects (p < 0.05) without a severe adverse effect compared with the monotherapy. CONCLUSION: Based on Bcl-xL overexpression in polyploidy induced by aurora B inhibition, the rationale for therapeutic combinations targeting aurora B and Bcl-xL was demonstrated in the authors' preclinical studies, leading to a promising novel approach for the mechanism-based treatment of human HCC.

Advances in reduced port laparoscopic liver resection.

Reduced port surgery has been attracting attention in the field of minimally invasive surgery. Although the use of SILS is becoming widespread, technical difficulty has delayed its adoption for laparoscopic liver resection. Recently, advances in laparoscopic liver resection have been made in tandem with advances in surgical skill and devices. The main driver in conventional laparoscopic liver resection's evolution to become less surgically invasive seems to be single-incision laparoscopic liver resection (SILLR). To date, most reports on SILLR have been single case reports or case series. Only a few cohort studies on conventional laparoscopic surgery and SILLR have been conducted. Recent reports have described the use of SILLR for well-localized lesions and solitary tumors located in the anterolateral segments of the liver or left liver lobe, but its application remains limited to partial resection and left lateral sectionectomy. The feasibility and safety of SILLR have been demonstrated, but additional work is needed for standardization of the procedure.

Age-related clinicopathologic and molecular features of patients receiving curative hepatectomy for hepatocellular carcinoma.

BACKGROUND: Age-related differences of clinicopathologic features, outcomes, and molecular properties of hepatocellular carcinoma remain unclarified. METHODS: We classified patients who underwent hepatectomy for hepatocellular carcinoma into 3 groups by age bracket; younger group (<50 years), middle-aged group (50 to 79 years), and elderly group (≥80 years) and compared age-related features. RESULTS: Hepatitis viral infection was dominant in the younger group (hepatitis B virus [HBV]; 67%) and middle-aged group (hepatitis C virus [HCV]; 56%), whereas the elderly group showed a significantly higher rate without hepatitis virus infection (absence of HBV and HCV infection, 66%; P = .0001). There was a significantly greater proportion of age-associated pre-existing comorbidity in the elderly group (89%; P = .0004). Liver cirrhosis in the elderly group (24%) was significantly lower than other groups (younger, 67%; middle-aged, 50%; P = .0058). There was no significant difference in perioperative and postoperative outcomes among these groups. Microarray analysis revealed age-related upregulation of androgen and phosphatidylinositol 3-kinase pathways in the tumor tissue and downregulation of the fibrosis-related pathways in the noncancerous liver tissue. CONCLUSIONS: Based on increased correlation with the absence of HBV and HCV infection and pre-existing comorbidity, the age-related carcinogenic pathways might play a critical role in elderly hepatocarcinogenesis.

Does the preoperative alpha-fetoprotein predict the recurrence and mortality after hepatectomy for hepatocellular carcinoma without macrovascular invasion in patients with normal liver function?

AIM: It has been highly controversial whether elevated serum α-fetoprotein (AFP) level before hepatectomy predicts recurrence and mortality of patients with hepatocellular carcinoma (HCC) or not. This study is to identify whether the index predicts recurrence and mortality after hepatectomy in HCC. METHODS: Of 568 consecutive patients, 342 with normal liver function (Child-Pugh score, 5) and no macrovascular invasion were enrolled between April 2000 and March 2013. Multivariate analysis was performed to identify risk factors for disease-free survival (DFS) and overall survival (OS). RESULTS: In multivariate analysis, the elevated serum AFP level was an independent risk factor for DFS (hazard ratio [HR], 1.9; P < 0.0001) and OS (HR, 2.0; P < 0.0001). Histological hepatic venous tumor thrombus was also an independent risk factor for DFS (HR, 2.6; P < 0.0001) and OS (HR, 2.5; P = 0.001). Anatomical resection decreases the risk factor for recurrence after hepatectomy (HR, 0.6; P = 0.003), though it did not decrease the risk for OS (P = 0.3). At 5 years, DFS rates were 42% and 21% (P < 0.0001) and OS rates were 75% and 46% among patients with low and high AFP levels, respectively (P < 0.0001). The area under the receiver-operator curves (AUROC) of serum AFP and des-γ-carboxy prothrombin were 0.65 and 0.58 for DFS and 0.65 and 0.57 for OS, respectively. Tumor size was the best predictor of microvascular invasion (AUROC, 0.70, P < 0.0001). CONCLUSION: Serum AFP was a highly reliable index for DFS and OS.

[Curative resection of stage IV advanced gallbladder cancer following combined treatment with gemcitabine and CDDP].

A 74-year-old woman was referred to our hospital following the diagnosis of advanced gallbladder cancer with para-aortic lymph node metastasis. Combination treatment involving gemcitabine(1,000mg/m / 2 body surface area)and CDDP(50mg/ m2 body surface area)was initiated and repeated for 4 courses; gemcitabine was administrated on day 1 and day 8, whereas CDDP was administrated on day 8, followed by 1 week of no treatment. After 4 courses, abdominal computed tomography (CT)indicated a reduction in size of the main lesion and disappearance of para -aortic lymph nodes. The remarkable response to the chemotherapy, which resulted in tumor downstaging, enabled us to perform the curative surgery procedure. Thus, cholecystectomy with resection of the hepatic bed and lymph node dissection were performed. The resected specimens indicated papillary adenocarcinoma of the gallbladder infiltrating the muscular wall of the gallbladder. In addition, the resected para-aortic lymph nodes indicated hyalinization and fibrosis as a result of the chemotherapy. Moreover, the pericholedocal lymph nodes were necrotic and no viable tumor was noted, thus indicating the excellent response to the chemotherapy.

Mixed adenoneuroendocrine carcinoma of the colon progressed rapidly after hepatic rupture: report of a case.

The rupture of a metastatic mixed adenoneuroendocrine carcinoma (MANEC) has not been previously reported, although the neuroendocrine cell carcinoma is often associated with a high incidence of hepatic metastases. The patient was a 39-year-old male who presented with upper abdominal pain over 3 months. Computed tomography showed multiple tumors in both hepatic lobes, while lower gastrointestinal endoscopy revealed a tumor in the transverse colon. Histopathologic examination of the tumor revealed it to be a neuroendocrine cell carcinoma. After the resection of the primary tumor, hepatic metastases rapidly increased, and one of them in the left lateral segment was ruptured with significant hemorrhage. The rupture led us to undertake the emergency operation to stop the bleeding. Histology showed a high-grade large-cell neuroendocrine carcinoma associated with moderately differentiated tubular adenocarcinoma. The Ki-67 labeling index was 80% (G3). The diagnosis was mixed adenoneuroendocrine carcinoma according to the 2010 World Health Organization guidelines. Hepatic arterial infusion chemotherapy, systemic chemotherapy, and transcatheter arterial chemoembolization did not decrease the tumor progress, and the patient died on postoperative day 110. Reporting this highly malignant case, I hope all doctors can be interested in MANEC.

EpCAM-targeted therapy for human hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most lethal malignancies and the identification of new effective therapies for HCC is urgently needed. We have previously identified EpCAM, one of the hepatic stem/progenitor markers, as a prognostic predictor of patients who received curative hepatectomy for HCC. In this preclinical study, the effects of VB4-845, an immunotoxin targeting EpCAM, were evaluated in HCC. METHODS: In vitro effects of VB4-845 on human HCC cells, the cytotoxic activity, sphere-forming ability, and expression of hepatic stem/progenitor markers were analyzed. In vivo effects of VB4-845 were evaluated using subcutaneous and orthotopic liver xenograft models. RESULTS: In all HCC cell lines expressing EpCAM, VB4-845 showed potent cytotoxicity and was significantly effective in combination with 5-FU (p < 0.05). Although 5-FU did not affect the sphere-forming ability and increased the populations expressing other stem/progenitor markers CD133 and CD13 (p < 0.05), VB4-845 strongly suppressed the sphere-formation and decreased the population expressing CD133 and CD13 (p < 0.0005, <0.01, respectively). In subcutaneous xenograft models, the combination of VB4-845 plus 5-FU showed significant regression of tumors compared with the control (p = 0.016). Moreover, in orthotopic liver xenograft models, the combination therapy dramatically decreased the tumor volume compared with the control (p = 0.0011). CONCLUSIONS: Our preclinical investigation suggests that EpCAM-targeted therapy may offer a promising and novel approach for the treatment of HCC with a poorer prognosis.

Alcohol consumption and recurrence of non-B or non-C hepatocellular carcinoma after hepatectomy: a propensity score analysis.

BACKGROUND: The aim of this study was to identify factors related to the recurrence of non-B or non-C (NBNC) hepatocellular carcinoma (HCC). STUDY DESIGN: Between April 2000 and March 2012, out of 621 consecutive HCC patients at our institution, 543 who underwent initial hepatectomy and had no extrahepatic metastases were enrolled in the study. Multivariate analysis were performed to identify risk factors for poor disease-free survival (DFS). RESULTS: The 5-year DFS rate of NBNC (34 %) was better than that of hepatitis virus B (30 %, P = 0.011) and hepatitis virus C (21 %, P < 0.0001), significantly. Multivariate analysis revealed NBNC [hazard ratio (HR), 0.5; 95 % CI, 0.4-0.8; P < 0.0001)] to be an independent factor for DFS rate. We constructed a propensity score matching model with the 543 patients, and the 5-year DFS rates with and without severe alcohol liver disease (ALD) were 31.6 and 47.5 %, respectively (P = 0.013). In the 163 NBNC patients, severe ALD, mild ALD, and no ALD were seen in 35, 56, and 72 patients, respectively. Multivariate analysis revealed a vascular invasion into the hepatic vein (HR, 3.3; 95 % CI, 1.7-6.3; P < 0.0001) and severe ALD (HR, 2.0; 95 % CI, 1.1-3.6; P = 0.020) to be independent risk factors for poor DFS. By propensity score matching between mild and severe ALD, the 5-year DFS rates with severe and mild ALD were 26 and 50 %, respectively (P = 0.035). CONCLUSIONS: The prognoses of NBNC patients were better than those of patients with viral infections. Among the NBNC patients, preoperative excessive alcohol intake decreased DFS rate of HCC occurrence after surgery.

Anatomic resection reduces the recurrence of solitary hepatocellular carcinoma ≤5 cm without macrovascular invasion.

BACKGROUND: In patients with solitary hepatocellular carcinoma ≤5 cm without macrovascular invasion, it is unknown whether the initial anatomic resection improves the long-term survival. METHODS: Among 545 initial hepatectomies for hepatocellular carcinoma between 2000 and 2012, the 233 patients with the aforementioned criteria of hepatocellular carcinoma were enrolled. RESULTS: The mean observation time was 1,125 days. Disease-free 5-year survival rates with and without anatomic resection were 46% and 23%, respectively (P = .009). Multivariate analyses for disease-free survival rates revealed the risk factors to be α-fetoprotein (odds ratio, 1.6; P = .028) and anatomic resection (odds ratio, .7; P = .048), while increased Child-Pugh score (>5) was the only independent risk factor for overall survival (odds ratio, 1.8; P = .043). The 5-year overall survival rates with and without Child-Pugh score 5 were 74% and 40%, respectively (P < .0001, log-rank test). CONCLUSIONS: Initial anatomic resection for small solitary hepatocellular carcinoma without macrovascular invasion improved disease-free survival rates remarkably.

Severe postoperative hemorrhage caused by antibody-mediated coagulation factor deficiencies: report of two cases.

Antibody-mediated coagulation factor deficiencies constitute a rare disorder that may develop in elderly patients without any history of a bleeding diathesis. Patients may present with severe and sometimes catastrophic bleeding. We report two cases of postoperative hemorrhage caused by a coagulation factor deficiency. In Case 1, massive intraabdominal bleeding occurred on day 3 after pancreaticoduodenectomy for bile duct cancer, and was caused by an acquired inhibitor of coagulation factor VIII. Hemostasis was achieved and the factor VIII inhibitor titer decreased to zero with activated prothrombin complex concentrates, prednisolone, and cyclophosphamide. In Case 2, intraabdominal bleeding occurred on day 7 after hepatectomy for hepatocellular carcinoma, and was caused by an acquired inhibitor against factors II (prothrombin) and V. This patient was treated with hemostatic agents containing bovine thrombin during surgery and also with prednisolone. We report these cases to highlight that antibody-mediated coagulation factor deficiencies should be considered when an elderly patient suffers sudden postoperative hemorrhage and to stress the importance of prompt diagnosis because of the risk of potentially life-threatening hemorrhage.

Mitochondrial metabolism in the noncancerous liver determine the occurrence of hepatocellular carcinoma: a prospective study.

BACKGROUND: Recurrence determines the postoperative prognosis with hepatocellular carcinoma (HCC). It is unknown how the liver dysfunction involving organic anion transporter failure causes the occurrence of HCCs. This study was designed to elucidate the link between liver dysfunction and multicentric occurrence (MO) after radical hepatectomy. METHODS: Forty-nine samples of noncancerous liver tissue from HCC patients within the Milan criteria who were treated at our institution between January 2004 and August 2008 were examined as a training set by using genome-wide gene expression analysis. Using the independent 2-institutional cohort of 134 patients between September 2008 and December 2009, we performed a validation study using tissue microarray analysis. Cox proportional hazard regression analyses for MFS were performed to estimate the risk factors. RESULTS: In the Gene Ontology database (GO:0015711), SLC22A7 expression was the best predictor of MO-free survival [MFS] (Fold, 0.726; P = 0.001). High SLC22A7 gene expression prevented the occurrence of HCC after hepatectomy (odds ratio [OR], 0.2; P = 0.004). Multivariate analyses identified SLC22A7 expression as an independent risk factor (OR, 0.3; P = 0.043). In the validation study, multivariate analyses of MFS identified SLC22A7 expression as an independent risk factor (OR, 0.5; P = 0.012). As judged by gene set enrichment analysis, SLC22A7 down regulation was associated with mitochondrion (P = 0.008) and oxidoreductase activity (P = 0.006). Sirtuin 3 as a regulator of mitochondrial metabolism also determined MFS (P = 0.018). CONCLUSIONS: The mitochondrial pathways may affect SLC 22A7 function to promote the occurrence of HCC. (Word count: 246).

A Simple Index to Predict Liver Functional Reserve after Hepatectomy.

BACKGROUND/AIMS: It is difficult to estimate the functional reserve of the liver required for safe hepatectomy in patients with severe chronic liver disease The aim of this study was to retrospectively construct simple model based on routine laboratory data to predict both early liver failure (ELF) and mortality from recurrence-free liver failure (MLF) as an index for late liver failure after hepatectomy. METHODOLOGY: Between 2000 and 2004, 196 consecutive patients underwent curative hepatectomy, and data from 127 minor hepatectomies were included in this study. RESULTS: Mean survival time was [mean (SD)] 1252 (670) days after hepatectomy. ELF and MLF were observed in 29 and 13 patients, respectively. PT%, TB, and direct bilirubin (DB) were the best predictors in patients with both ELF and MLF. PT% alone was the best predictor of ELF and MLF with area under ROC curves of 0.70 and 0.81, respectively. By using a preoperative PT% of ≤ 70, we could accurately predict ELF and MLF in 77% and 87% of patients, respectively. ICG-R15 could not accurately predict both ELF and MLF for any cut-off values. CONCLUSIONS: Unlike ICG-R15, PT% is a simple noninvasive index for estimating liver functional reserve to predict both ELF and MLF.

[A case ectopic hepatocellular carcinoma with peritoneal dissemination].

An 83-year-old man was admitted to our hospital for further investigation of liver dysfunction. Laboratory examination revealed serum alpha-fetoprotein (AFP) levels of 4205ng/ml, an AFP/AFP-L3 ratio of 32.3%, an indocyanine green retention rate at 15 minutes of 25.9%, and negative serology for viral hepatitis. Ultrasonography, contrast-enhanced computed tomography, and magnetic resonance imaging revealed an early enhanced tumor measuring approximately 3cm at its maximal dimension. The tumor contacted segment 6 of the liver, and there was no other specific space-occupying lesion in the liver. Detailed angiography revealed that the tumor received its blood supply from the gastroduodenal artery. A diagnosis of ectopic hepatocellular carcinoma was made and laparoscopy with partial liver resection was performed. Intraoperative findings revealed a small amount of bloody ascites and peritoneal dissemination. The tumor, which was attached to the liver, was resected. Histopathologically, the tumor was a moderately differentiated hepatocellular carcinoma without connection to the liver parenchyma. A final diagnosis of ectopic hepatocellular carcinoma accompanied by peritoneal dissemination was thus confirmed.

Visualization of stem cell features in human hepatocellular carcinoma reveals in vivo significance of tumor-host interaction and clinical course.

UNLABELLED: Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies because of recurrence and/or metastasis even after curative resection. Emerging evidence suggests that tumor metastasis and recurrence might be driven by a small subpopulation of stemness cells, so-called cancer stem cells (CSCs). Previous investigations have revealed that glioma and breast CSCs exhibit intrinsically low proteasome activity and that breast CSCs also reportedly contain a lower reactive oxygen species (ROS) level than corresponding nontumorigenic cells. Here we visualized two stem cell features, low proteasome activity and low intracellular ROS, in HCC cells using two-color fluorescence activated cell sorting to isolate cells with stem cell features. These cells were then analyzed for their division behavior in normoxia and hypoxia, expression of stem cell markers, tumorigenicity, metastatic potential, specific gene expression signatures, and their clinical implications. A visualized small subpopulation of HCC cells demonstrated asymmetric divisions. Their remarkable tumorigenicity in nonobese diabetic/severe combined immunodeficient mice suggested the cancer initiation potential of these HCC CSCs. Comprehensive gene expression analysis revealed that chemokine-related genes were up-regulated in the CSCs subpopulation. Our identified HCC CSCs facilitated the migration of macrophages in vitro and demonstrated metastatic potential by way of recruitment of macrophages in vivo. In patients who undergo curative operation for HCC, the CSC-specific gene signature in the liver microenvironment significantly correlates with recurrence. CONCLUSION: Based on these findings, the stem cell feature monitoring system proposed here is a promising tool to analyze the in vivo significance of CSC microenvironments in human HCCs.