Expression of Wnt5a and ROR2, Components of the Noncanonical Wnt-Signaling Pathway, is Associated with Tumor Differentiation in Hepatocellular Carcinoma.

BACKGROUND: Wnt5a is the key ligand of the noncanonical Wnt pathway, and receptor tyrosine kinase-like orphan receptor 2 (ROR2) is a receptor associated with Wnt5a. The association between the noncanonical Wnt-signaling pathway and carcinogenesis in hepatocellular carcinoma (HCC) is unclear. This study investigated the significance of ROR2 expression in HCC. METHODS: The study examined ROR2 expression in liver cancer cell lines. Immunohistochemical staining of ROR2 was performed on 243 resected HCC specimens. The study investigated ROR2 expression and its association with clinicopathologic factors and prognosis. RESULTS: Findings showed that ROR2 was expressed in well-differentiated Huh7 and HepG2 cells, but not in poorly differentiated HLE and HLF cells. Expression of ROR2 was positive in 147 (60.5%) and negative in 96 (39.5%) HCC specimens. A significant association was shown between ROR2 negativity and high alpha-fetoprotein (AFP) level (P = 0.006), poor differentiation (P = 0.015), and Wnt5a negativity (P = 0.024). The 5-year overall survival (OS) rate for the ROR2-negative group (64.2 %) tended to be worse than for the ROR2-positive group (73.8%), but the difference was not significant (P = 0.312). The 5-year OS rate was 78.7% for the ROR2+Wnt5a+ group, 71.3 % for the ROR2+Wnt5a- group, 80.8% for the ROR2-Wnt5a+ group, and 60.5 % for the ROR2-Wnt5a- group. The OS in the ROR2-Wnt5a- group was significantly poorer than in the ROR2+Wnt5a+ group (P = 0.030). The multivariate analysis showed that Wnt5a-ROR2- was an independent prognostic factor (hazard ratio, 2.058; 95% confidence interval, 1.013-4.180; P = 0.045). CONCLUSIONS: The combination of ROR2 and Wnt5a may be a prognostic indicator for HCC. The Wnt5a/ROR2 signal pathway may be involved in the differentiation of HCC. This pathway may be a new therapeutic target for HCC.

An intraoperative artificial intelligence system identifying anatomical landmarks for laparoscopic cholecystectomy: a prospective clinical feasibility trial (J-SUMMIT-C-01).

BACKGROUND: We have implemented Smart Endoscopic Surgery (SES), a surgical system that uses artificial intelligence (AI) to detect the anatomical landmarks that expert surgeons base on to perform certain surgical maneuvers. No report has verified the use of AI-based support systems for surgery in clinical practice, and no evaluation method has been established. To evaluate the detection performance of SES, we have developed and established a new evaluation method by conducting a clinical feasibility trial. METHODS: A single-center prospective clinical feasibility trial was conducted on 10 cases of LC performed at Oita University hospital. Subsequently, an external evaluation committee (EEC) evaluated the AI detection accuracy for each landmark using five-grade rubric evaluation and DICE coefficient. We defined LM-CBD as the expert surgeon's "judge" of the cystic bile duct in endoscopic images. RESULTS: The average detection accuracy on the rubric by the EEC was 4.2 ± 0.8 for the LM-CBD. The DICE coefficient between the AI detection area of the LM-CBD and the EEC members' evaluation was similar to the mean value of the DICE coefficient between the EEC members. The DICE coefficient was high score for the case that was highly evaluated by the EEC on a five-grade scale. CONCLUSION: This is the first feasible clinical trial of an AI system designed for intraoperative use and to evaluate the AI system using an EEC. In the future, this concept of evaluation for the AI system would contribute to the development of new AI navigation systems for surgery.

Development of a cross-artificial intelligence system for identifying intraoperative anatomical landmarks and surgical phases during laparoscopic cholecystectomy.

BACKGROUND: Attention to anatomical landmarks in the appropriate surgical phase is important to prevent bile duct injury (BDI) during laparoscopic cholecystectomy (LC). Therefore, we created a cross-AI system that works with two different AI algorithms simultaneously, landmark detection and phase recognition. We assessed whether landmark detection was activated in the appropriate phase by phase recognition during LC and the potential contribution of the cross-AI system in preventing BDI through a clinical feasibility study (J-SUMMIT-C-02). METHODS: A prototype was designed to display landmarks during the preparation phase and Calot's triangle dissection. A prospective clinical feasibility study using the cross-AI system was performed in 20 LC cases. The primary endpoint of this study was the appropriateness of the detection timing of landmarks, which was assessed by an external evaluation committee (EEC). The secondary endpoint was the correctness of landmark detection and the contribution of cross-AI in preventing BDI, which were assessed based on the annotation and 4-point rubric questionnaire. RESULTS: Cross-AI-detected landmarks in 92% of the phases where the EEC considered landmarks necessary. In the questionnaire, each landmark detected by AI had high accuracy, especially the landmarks of the common bile duct and cystic duct, which were assessed at 3.78 and 3.67, respectively. In addition, the contribution to preventing BDI was relatively high at 3.65. CONCLUSIONS: The cross-AI system provided landmark detection at appropriate situations. The surgeons who previewed the model suggested that the landmark information provided by the cross-AI system may be effective in preventing BDI. Therefore, it is suggested that our system could help prevent BDI in practice. Trial registration University Hospital Medical Information Network Research Center Clinical Trial Registration System (UMIN000045731).

Lymphaticovenous anastomosis for treatment of refractory chylous ascites: A case report.

Chylous ascites, the leakage of lymphatic fluid into the abdominal cavity caused by lymphatic fluid stasis or lymphatic vessel damage, can be treated by lymphaticovenous anastomosis (LVA). We report rarely performed abdominal LVA to treat a case of refractory ascites possibly caused by ligation of the thoracic duct and pleurodesis in a man aged 60 years requiring weekly ascites drainage. Ligation was abandoned because the leakage site was not determined. The greater omentum (GO) was generally edematous and showed lymphatic effusion by gross appearance, and was considered suitable for LVA. We performed once LVA in the lymphatic vessels and veins of the GO using common microsurgical instrumentation and lateral anastomosis. Lymphatic vessels in the omentum were dilated to 2-3 mm, and LVA was simple. After LVA, GO edema improved. Postoperatively, the patient developed paralytic ileus, which improved within a few days, and the patient was discharged without any increase in ascites after starting to diet. One year post-surgery, there was no recurrence of ascites. LVA at the GO may be effective for the treatment of refractory chylous ascites because of its absorptive lymphatic draining capabilities and large transverse vessels.

Hepatectomy is Beneficial in Select Patients with Multiple Hepatocellular Carcinomas.

BACKGROUND: A single hepatocellular carcinoma (HCC) is a good indication for hepatic resection regardless of tumor size, but the surgical indications for cases with multiple HCCs remain unclear. METHODS: We retrospectively reviewed the outcomes of hepatectomies for Barcelona Clinic Liver Cancer (BCLC) stage 0, A, and B HCCs. We further subclassified stage A and B into A1 (single nodule <5 cm, or three or fewer nodules ≤3 cm), A2 (single nodule 5-10 cm), A3 (single nodule ≥10 cm), B1 (two to three nodules >3 cm), and B2 (four or more nodules). RESULTS: A total of 1088 patients were enrolled, comprising 88 stage 0, 750 stage A (A1: 485; A2: 190; A3: 75), and 250 stage B (B1: 166; B2: 84) cases. The 5-year overall survival (OS) rates for stage 0, A1, A2, A3, B1, and B2 patients were 70.4%, 74.2%, 63.8%, 47.7%, 47.5%, and 31.9%, respectively (p < 0.0001). Significant differences in OS were found between stages A1 and A2 (p = 0.0118), A2 and A3 (p = 0.0013), and B1 and B2 (p = 0.0050), but not between stages A3 and B1 (p = 0.4742). In stage B1 patients, multivariate analysis indicated that Child-Pugh B cirrhosis was the only independent prognostic factor for the OS outcome. CONCLUSIONS: A hepatectomy should be considered for multiple HCCs if the number of tumors is three or fewer, especially in patients with no cirrhosis or in Child-Pugh A cases, because the long-term results are equivalent to those for a single HCC.

Versican Secreted by Cancer-Associated Fibroblasts is a Poor Prognostic Factor in Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is highly recurrent. Cancer-associated fibroblasts (CAFs), a major component of the tumor microenvironment, promote malignancy; however, the mechanisms underlying their actions are obscure. We aimed to identify CAF-specific proteins in HCC and determine whether they could be potential therapeutic targets. METHODS: Using comprehensive proteomic analysis of CAFs and noncancerous fibroblasts (NFs) primary-cultured from resected HCC specimens from the same patients, CAF-specific proteins were identified. Immunohistochemistry for versican (VCAN) was performed on cancerous tissues obtained from 239 patients with HCC. Conditioned medium from CAFs transfected with siRNA for VCAN was analyzed in vitro. RESULTS: CAFs significantly promoted HCC cell proliferation, migration, and invasion (p < 0.01, 0.01, and 0.01, respectively) compared with NFs. VCAN was upregulated in CAFs, and its stromal level correlated with poor differentiation (p = 0.009) and positive vascular invasion (p = 0.003). Stromal VCAN level was also associated with significantly lower overall (p = 0.002) and relapse-free (p < 0.001) survival rates. It also independently predicted prognosis and recurrence. VCAN-knockdown CAFs significantly suppressed HCC cell migration and invasion compared with negative control. CONCLUSIONS: VCAN secreted from CAFs promoted malignant transformation of HCC cells and has potential as a new therapeutic target in HCC.

Artificial intelligence software available for medical devices: surgical phase recognition in laparoscopic cholecystectomy.

BACKGROUND: Surgical process modeling automatically identifies surgical phases, and further improvement in recognition accuracy is expected with deep learning. Surgical tool or time series information has been used to improve the recognition accuracy of a model. However, it is difficult to collect this information continuously intraoperatively. The present study aimed to develop a deep convolution neural network (CNN) model that correctly identifies the surgical phase during laparoscopic cholecystectomy (LC). METHODS: We divided LC into six surgical phases (P1-P6) and one redundant phase (P0). We prepared 115 LC videos and converted them to image frames at 3 fps. Three experienced doctors labeled the surgical phases in all image frames. Our deep CNN model was trained with 106 of the 115 annotation datasets and was evaluated with the remaining datasets. By depending on both the prediction probability and frequency for a certain period, we aimed for highly accurate surgical phase recognition in the operation room. RESULTS: Nine full LC videos were converted into image frames and were fed to our deep CNN model. The average accuracy, precision, and recall were 0.970, 0.855, and 0.863, respectively. CONCLUSION: The deep learning CNN model in this study successfully identified both the six surgical phases and the redundant phase, P0, which may increase the versatility of the surgical process recognition model for clinical use. We believe that this model can be used in artificial intelligence for medical devices. The degree of recognition accuracy is expected to improve with developments in advanced deep learning algorithms.

Serum fatty acid-binding protein 5 is a significant factor in hepatocellular carcinoma progression independent of tissue expression level.

Fatty acid-binding protein 5 (FABP5) is highly expressed in hepatocellular carcinoma (HCC) tissues and is related to HCC progression. In this study, we analyzed the potential of serum FABP5 (sFABP5) as a tumor marker in HCC and its clinical significance in HCC progression. We compared the sFABP5 concentration in patients with HCC (HCC group) with that of patients with hepatitis without HCC (hepatitis group). Moreover, we measured the FABP5 expression levels in resected HCC tissues (tFABP5) and analyzed their relationship with sFABP5. We also performed cell-based assays using FABP5 knockout and overexpressing HCC cell lines to analyze the effect of extrinsic FABP5 (exFABP5) on HCC cells. We showed that sFABP5 was not a useful tumor marker for HCC, as HCC and sFABP5 were not correlated. However, sFABP5 and tFABP5 significantly correlated with survival after surgery for HCC, while sFABP5 and tFABP5 were independent of each other. In cell-based assays, exFABP5 was taken up by HCC cell lines and positively affected cell survival under glucose-depleted conditions by complementing the endogenous FABP5 function. In conclusion, sFABP5 had a significant impact on HCC progression irrespective of tFABP5 by augmenting cell viability under glucose-depleted conditions. As tFABP5 and sFABP5 are important factors that are independent of each other in HCC progression, both of them should be considered independently in improving the prognosis of patients with HCC.

Central Hepatectomy Versus Major Hepatectomy for Centrally Located Hepatocellular Carcinoma: A Propensity Score Matching Study.

BACKGROUND: In terms of anatomical liver sectionectomy approaches, both a central hepatectomy (CH) and major hepatectomy (MH) are feasible options for a centrally located hepatocellular carcinoma (HCC). METHODS: We retrospectively reviewed the surgical outcomes of central HCC patients who underwent CH or MH. MH includes hemihepatectomy or trisectionectomy, whereas CH involves a left medial sectionectomy, right anterior sectionectomy, or central bisectionectomy. The surgical outcomes were compared before and after propensity score matching (PSM). RESULTS: A total of 233 patients were enrolled, including 132 in the CH group and 101 in the MH group. The MH group cases were pathologically more advanced and had poorer overall survival rates than the CH group. After PSM, 68 patients were selected into each group, both of which showed similar overall and recurrence-free survival outcomes. The CH group showed a tendency for a longer operation time; however, other perioperative outcomes were similar between the two groups. Multivariate analyses of our matched HCC patients revealed that the type of surgery (CH or MH) was not an independent prognostic factor. More patients in the matched CH group experienced a repeat hepatectomy for recurrence and no patients in this group underwent a preoperative portal vein embolization. CONCLUSIONS: The short- and long-term surgical outcomes of CH and MH for a centrally located HCC are similar under a matched clinicopathological background. CH has the advantage of not requiring a preoperative portal vein embolization and increased chances of conducting a repeat hepatectomy for recurrence.

Treatment outcomes of stereotactic body radiation therapy using a real-time tumor-tracking radiotherapy system for hepatocellular carcinomas.

AIM: To report the outcomes of stereotactic body radiotherapy using a real-time tumor-tracking radiotherapy system for hepatocellular carcinoma patients. METHODS: From January 2005 to July 2018, 63 patients with 74 lesions with a maximum diameter ≤52 mm were treated by stereotactic body radiotherapy using a real-time tumor-tracking radiotherapy system. No patient with a Child-Pugh Score ≥9 was included, and 85.6% had a score of 5 or 6. Using the biological effective dose (BED) with an α/ß ratio of 10 (BED10 ), the median dose in BED10 at the reference point was 76.8 Gy (range 60-122.5 Gy). Overall survival (OS) and local control rates were assessed using the Kaplan-Meier method. RESULTS: With a median follow-up period of 24.6 months (range 0.9-118.4 months), the 1-year and 2-year OS rates were 86.8% (95% confidence interval [95% CI] 75.8-93.3) and 71.1% (57.8-81.6), respectively. The 2-year OS was 89.6% in patients with the baseline modified albumin-bilirubin (mALBI) grade =1, and 61.7% in patients with grade ≥2a. In the multivariate analysis, the mALBI grade (=1 vs. ≥2a) was a significant factor for OS (p = 0.028, 95% CI 1.11-6.18). The 1-year and 2-year local control rates were 100% (100-100%) and 92.0% (77.5-97.5%). The local control rates were significantly higher in the BED10 ≥100 Gy group than in the BED10 <100 Gy group (2-year 100% vs. 86.5%, p = 0.049) at the reference point. CONCLUSION: This retrospective study of stereotactic body radiotherapy using real-time tumor-tracking radiotherapy for hepatocellular carcinoma showed favorable outcomes with lower incidence of toxicities, especially in patients treated with BED10 ≥100 Gy to the reference point.

Development of an artificial intelligence system using deep learning to indicate anatomical landmarks during laparoscopic cholecystectomy.

BACKGROUND: The occurrence of bile duct injury (BDI) during laparoscopic cholecystectomy (LC) is an important medical issue. Expert surgeons prevent intraoperative BDI by identifying four landmarks. The present study aimed to develop a system that outlines these landmarks on endoscopic images in real time. METHODS: An intraoperative landmark indication system was constructed using YOLOv3, which is an algorithm for object detection based on deep learning. The training datasets comprised approximately 2000 endoscopic images of the region of Calot's triangle in the gallbladder neck obtained from 76 videos of LC. The YOLOv3 learning model with the training datasets was applied to 23 videos of LC that were not used in training, to evaluate the estimation accuracy of the system to identify four landmarks: the cystic duct, common bile duct, lower edge of the left medial liver segment, and Rouviere's sulcus. Additionally, we constructed a prototype and used it in a verification experiment in an operation for a patient with cholelithiasis. RESULTS: The YOLOv3 learning model was quantitatively and subjectively evaluated in this study. The average precision values for each landmark were as follows: common bile duct: 0.320, cystic duct: 0.074, lower edge of the left medial liver segment: 0.314, and Rouviere's sulcus: 0.101. The two expert surgeons involved in the annotation confirmed consensus regarding valid indications for each landmark in 22 of the 23 LC videos. In the verification experiment, the use of the intraoperative landmark indication system made the surgical team more aware of the landmarks. CONCLUSIONS: Intraoperative landmark indication successfully identified four landmarks during LC, which may help to reduce the incidence of BDI, and thus, increase the safety of LC. The novel system proposed in the present study may prevent BDI during LC in clinical practice.

Current role of intraoperative ultrasonography in hepatectomy.

Hepatectomy had a high mortality rate in the previous decade because of inadequate techniques, intraoperative blood loss, liver function reserve misdiagnoses, and accompanying postoperative complications. However, the development of several modalities, including intraoperative ultrasonography (IOUS), has made hepatectomy safer. IOUS can provide real-time information regarding the tumor position and vascular anatomy of the portal and hepatic veins. Systematic subsegmentectomy, which leads to improved patient outcomes, can be performed by IOUS in open and laparoscopic hepatectomy. Although three-dimensional (3D) computed tomography and gadoxetic acid-enhanced magnetic resonance imaging have been widely used, IOUS and contrast-enhanced IOUS are important modalities for risk analyses and making decisions regarding resectability and operative procedures because of the vital anatomical information provided and high sensitivity for liver tumors, including "disappearing" liver metastases. Intraoperative color Doppler ultrasonography can be used to delineate the vascular anatomy and evaluate the blood flow volume and velocity in hepatectomy patients and recipients of deceased- and living-donor liver transplantation after vessel reconstruction and liver positioning. For liver surgeons, IOUS is an essential technique to perform highly curative hepatectomy safely, although recent advances have also been made in virtual modalities, such as real-time virtual sonography with 3D visualization.

Diagnostic timing dependent characteristics of acute kidney injury following hepatectomy: a retrospective historical cohort analysis.

BACKGROUND: The timing of diagnosis of post-hepatectomy acute kidney injury (AKI) has rarely been investigated. The aim of this retrospective study was to reveal the differences between AKI subtypes following hepatectomy, as classified by timing of diagnosis. METHOD: Post-hepatectomy AKI was classified as very transient AKI (vtAKI; criteria satisfied by the serum creatinine value immediately after surgery) or non-transient AKI (ntAKI; all other AKI types except for vtAKI). Multivariate logistic regression analyses for both AKI types were performed separately to identify differences in known perioperative AKI risk factors. The impacts of each AKI subtype on postoperative complications, hospital stay and renal outcome at discharge were also evaluated. RESULTS: AKI was diagnosed in 135 of 750 patients (18.0%); 82 and 53 patients were classified as vtAKI and ntAKI, respectively. In multivariate analysis, even among the perioperative factors associated with whole AKI, there were distinct relationships depending on vtAKI or ntAKI. Furthermore, only ntAKI was associated with postoperative complications, longer hospital stays and impaired renal function at discharge. CONCLUSIONS: Based on the results of this study, future post-hepatectomy AKI studies should only include ntAKI and exclude vtAKI, as vtAKI has minimal clinical impact despite accounting for a significant proportion of AKI patients. CLINICAL TRIAL REGISTRATIONS: None.

Impaired O-Glycosylation at Consecutive Threonine TTX Motifs in Mucins Generates Conformationally Restricted Cancer Neoepitopes.

Autoantibody signatures of circulating mucin fragments stem from cancer tissues, and microenvironments are promising biomarkers for cancer diagnosis and therapy. This study highlights dynamic epitopes generated by aberrantly truncated immature O-glycosylation at consecutive threonine motifs (TTX) found in mucins and intrinsically disordered proteins (IDPs). NMR analysis of synthetic mucin models having glycosylated TTX motifs and colonic MUC2 tandem repeats (TRs) containing TTP and TTL moieties unveils a general principle that O-glycosylation at TTX motifs generates a highly extended and rigid conformation in IDPs. We demonstrate that the specific conformation of glycosylated TTX motifs in MUC2 TRs is rationally rearranged by concerted motions of multiple dihedral angles and noncovalent interactions between the carbohydrate and peptide region. Importantly, this canonical conformation of glycosylated TTX motifs minimizes steric crowding of glycans attached to threonine residues, in which O-glycans possess restricted orientations permitting further sugar extension. An antiadhesive microarray displaying synthetic MUC2 derivatives elicited the presence of natural autoantibodies to MUC2 with impaired O-glycosylation at TTX motifs in sera of healthy volunteers and patients diagnosed with early stage colorectal cancer (CRC). Interestingly, autoantibody levels in sera of the late stage CRC patients were distinctly lower than those of early stage CRC and normal individuals, indicating that the anti-MUC2 humoral response to MUC2 neoepitopes correlates inversely with the CRC stage of patients. Our results uncovered the structural basis of the creation of dynamic epitopes by immature O-glycosylation at TTX motifs in mucins that facilitates the identification of high-potential targets for cancer diagnosis and therapy.

Hepatectomy Combined with Diaphragmatic Resection for Hepatocellular Carcinoma with Diaphragmatic Involvement: A Propensity Score-Matched Analysis.

PURPOSE: We evaluated the short- and long-term surgical outcomes of hepatectomy combined with diaphragmatic resection for hepatocellular carcinoma (HCC) with diaphragmatic involvement. METHODS: We retrospectively reviewed the surgical outcomes of HCC patients with diaphragmatic resection (DR group) and HCC patients without diaphragmatic resection (non-DR group). We applied 1:1 propensity score matching (PSM) to these subjects. RESULTS: The study included 46 patients in DR group and 828 patients in non-DR group. The DR group cases were pathologically more advanced, and both overall and relapse-free survival among the patients in this group with pathological diaphragmatic invasion were similar to cases with pathological diaphragmatic fibrous adhesion. There were 40 patients from each group subjected to PSM. In these matched cohorts, there was no statistically significant difference between the two groups regarding perioperative outcomes, overall survival, and relapse-free survival. Multivariate analyses of our matched HCC patients revealed that alpha-fetoprotein expression and tumor size were independent prognostic factors for overall survival and poor differentiation for relapse-free survival, whereas neither diaphragmatic invasion nor diaphragmatic resection were prognostic indicators. The most frequent site of recurrence in non-DR group was the liver, whereas the most frequent site of recurrence in DR group was the lung before and after PSM. CONCLUSIONS: The short- and long-term surgical outcomes of DR HCC cases are equivalent to their non-DR counterparts under a matched clinicopathological background. Hepatectomy combined with DR is an acceptable treatment for HCC with either diaphragmatic fibrous adhesion or diaphragmatic invasion.

Long-term prognostic factors of patients with hepatocellular carcinoma who survive over 10 years after hepatectomy.

BACKGROUND AND OBJECTIVES: The aim was to evaluate long-term prognostic factors in hepatocellular carcinoma (HCC) patients who survived over 10 years after hepatectomy and compare prognostic factors between patients with recurrence who died and survived 10 years after initial hepatectomy. METHODS: We analyzed the HCC patients without recurrence over 10 years after hepatectomy (n = 35), those with recurrence who survived over 10 years (n = 48), and those who died within 10 years (n = 132). RESULTS: The rate of recurrence was 16.3%, 10-year overall survival rate was 38.6%, and the 10-year recurrence-free survival (RFS) rate was 16.7%. Nonviral, solitary tumor, well differentiation, and without severe fibrosis were independent favorable factors for long-term RFS. High cholinesterase levels, small tumors and without portal vein invasion were independent favorable factors for long-term survival among patients with recurrence. Long-term survivors with recurrence showed significantly low early recurrence, extrahepatic recurrence, multiple intrahepatic recurrences. CONCLUSION: Important factors for long-term prognoses in HCC patients were a solitary tumor, small tumors, and no advanced fibrosis. A treatment for nonviral hepatitis is needed to achieve long-term RFS. Even patients who relapse might survive long term if they have a late or solitary intrahepatic recurrence, nonsevere cirrhosis, and curative treatment at recurrence.

CD133 and epithelial cell adhesion molecule expressions in the cholangiocarcinoma component are prognostic factors for combined hepatocellular cholangiocarcinoma.

AIM: A new classification of combined hepatocellular cholangiocarcinoma (CHC) was recently reported. Cancer stem cells have been associated with CHC carcinogenesis. This study examined the association of cancer stem cell marker expression and prognosis in CHC classified using the new classification. METHODS: We enrolled 26 CHC patients and classified them according to the new classification. We evaluated the expression of cancer stem cell markers (CD56, CD133, and epithelial cell adhesion molecule [EpCAM]) by immunohistochemical staining in each component. We analyzed the association between expressions and prognosis. RESULTS: Seven cases were hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) (cHCC-CCA), 12 were HCC and intermediate cell carcinoma (HCC-INT), and seven were intermediate cell carcinoma (INT). The CD133-positive rate tended to be higher in the CCA (42.9%) and INT component (50.0%) than the HCC component (14.3%) in cHCC-CCA. In HCC-INT, the CD133-positive rate in the INT component (83.3%) was significantly higher than the HCC component (8.3%; P = 0.001). For EpCAM, the positive rate in the CCA component (71.4%) and INT component (50.0%) tended to be higher than the HCC component (14.3%) in cHCC-CCA. Overall survival and disease-free survival were significantly worse in cases with CD133-positive (P = 0.048 and P = 0.048, respectively) or EpCAM-positive (P = 0.041 and P = 0.041, respectively) CCA component in cHCC-CCA. CONCLUSIONS: INT and CCA components showed higher expression rates of cancer stem cell markers than the HCC component. CD133 or EpCAM expression in the CCA component was associated with poor prognosis in cHCC-CCA.

Lenvatinib in patients with unresectable hepatocellular carcinoma who do not meet the REFLECT trial eligibility criteria.

AIM: This study aimed to determine the efficacy and safety of lenvatinib for patients with unresectable hepatocellular carcinoma (HCC) who did not meet REFLECT eligibility criteria (phase 3 clinical trial). METHODS: In this multicenter retrospective study, patients with unresectable HCC treated with lenvatinib between 2018 and 2019 and had adequate clinical data were included. Objective response rate, progression-free-survival (PFS) and safety were evaluated according to meeting or not meeting the REFLECT eligibility criteria and according to the criteria of the REFLECT trial. RESULTS: Of the 105 patients included, 61% (64 of 105) did not meet the REFLECT eligibility criteria. Safety and median PFS of lenvatinib were similar between the patients who did and those who did not meet the criteria. Among the patients who did not meet the criteria, 28, 27, 14, six, seven and five had a history of tyrosine kinase inhibitor (TKI) treatment, Child-Pugh score B, HCC in ≥50% of the liver, reduced platelet count, bile duct invasion and main portal vein invasion, respectively. The efficacy and safety of lenvatinib for patients with or without Child-Pugh-score B or HCC in ≥50% of the liver were similar. Although treatment outcome was not significantly different, patients with TKI treatment history tended to have longer median PFS, whereas those with main portal vein invasion tended to have shorter median PFS. CONCLUSION: Lenvatinib was effective for patients who did not meet the REFLECT inclusion criteria. However, the treatment outcome may vary according to several factors, such as a history of TKI treatment and tumor invasion.

Prognoses, outcomes, and clinicopathological characteristics of very elderly patients with hepatocellular carcinoma who underwent hepatectomy.

OBJECTIVES: The aim was to evaluate the prognostic factors, clinicopathological characteristics, and surgical outcomes after hepatectomy in very elderly patients with hepatocellular carcinoma (HCC). METHODS: We analyzed 796 patients with HCC from 2000 to 2017. Patients aged 80 years or older were classified into the very elderly group (group VE; n = 49); patients younger than 80 years old and aged 65 years or older were classified into the elderly group (group E; n = 363), and patients younger than 65 years old were classified into the young group (group Y; n = 384). We investigated the prognoses, clinicopathological characteristics, and surgical outcomes after hepatectomy. RESULTS: The number of surgical procedures and outcomes, including morbidities, was not significantly different. Groups VE, E, and Y showed similar prognoses in terms of both survival and recurrence. In group VE, prothrombin activity (PA) < 80% and PIVKA-II ≥ 400 mAU/ml were unfavorable factors for survival, and PIVKA-II ≥ 400 mAU/ml and the presence of portal venous invasion (PVI), hepatic venous invasion, and fibrosis were unfavorable factors for recurrence. In group E, ChE < 180 IU/l, AFP ≥ 20 ng/ml, tumor size ≥ 10 cm, and the presence of multiple tumors, PVI, and hepatic venous invasion (HVI) were unfavorable factors for survival, and ChE < 180 IU/l, tumor size ≥ 10 cm, and the presence of multiple tumors, PVI, and HVI were unfavorable factors for recurrence. In group Y, AFP ≥ 20 ng/ml, the presence of multiple tumors, poor differentiation, PVI, HVI, and blood loss ≥ 400 ml were unfavorable factors for survival, and PA < 80%, albumin < 3.5 g/dl, AFP ≥ 20 ng/ml, tumor size ≥ 10 cm, and the presence of multiple tumors, poor differentiation, and PVI were unfavorable factors for recurrence. CONCLUSIONS: Tumor factors might have limited influence on the prognosis of very elderly patients, and liver function reserve might be important for the long-term survival of very elderly patients. Hepatectomy can be performed safely, even in very elderly patients. Hepatectomy should not be avoided in very elderly patients with HCC if patients have a good general status because these patients have the same prognoses as nonelderly individuals.

Recent advances in surgical strategies for alveolar echinococcosis of the liver.

Liver resection is the safest intervention for alveolar echinococcosis (AE), because the only potentially curative treatment is complete removal of the lesion. In combination with medical anthelmintic treatment, a safe distance of at least 1 mm is permissible in this procedure. Even when liver resection does not cure AE, good long-term survival outcomes can be achieved if most of the lesion has been removed and the disease is controlled with lifelong benzimidazole treatment. If the residual lesion is comparatively small and does not contain a closed space that may adhere to the surrounding tissue and form an abscess, complications such as sepsis arising from an abscess on the cut surface can be prevented and the required biliary drainage might be relatively simple. Larger AE lesions that invade the inferior vena cava can be treated effectively with the recent advances in reduction surgical techniques. An effective concentration of albendazole (ABZ) is found only in the periphery of AE lesions, because this drug penetrates the lesions passively. Liver transplantation, with adjuvant ABZ and the administration of appropriate immunosuppressive agents such as cyclosporin A, is indicated for patients with end-stage AE.