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Background: It is important to have precise image guidance throughout proton therapy in order to take advantage of the therapy's physical selectivity., Purpose: We evaluated the effectiveness of computed tomography (CT)-image guidance in proton therapy for patients with hepatocellular carcinoma (HCC) by assessing daily proton dose distributions. The importance of daily CT image-guided registration and daily proton dose monitoring for tumors and organs at risk (OARs) was investigated., Methods: A retrospective analysis was conducted using 570 sets of daily CT (dCT) images throughout whole treatment fractions for 38 HCC patients who underwent passive scattering proton therapy with either a 66 cobalt gray equivalent (GyE)/10 fractions (n = 19) or 76 GyE/20 fractions (n = 19) protocol. The actual daily delivered dose distributions were estimated by forward calculation using the dCT sets, their corresponding treatment plans, and the recorded daily couch correction information. We then evaluated the daily changes of the dose indices D 99% , V 30GyE , and D max for the tumor volumes, non-tumorous liver, and other OARs, that is, stomach, esophagus, duodenum, colon, respectively. Contours were created for all dCT sets. We validated the efficacy of the dCT-based tumor registrations (hereafter, "tumor registration") by comparing them with the bone registration and diaphragm registration as a simulation of the treatment based on the positioning using the conventional kV X-ray imaging. The dose distributions and the indices of three registrations were obtained by simulation using the same dCT sets., Results: In the 66 GyE/10 fractions, the daily D 99% value in both the tumor and diaphragm registrations agreed with the planned value with 3%-6% (SD), and the V 30GyE value for the liver agreed within ±3%; the indices in the bone registration showed greater deterioration. Nevertheless, tumor-dose deterioration occurred in all registration methods for two cases due to daily changes of body shape and respiratory condition. In the 76 GyE/20 fractions, in particular for such a treatment that the dose constraints for the OARs have to be cared in the original planning, the daily D 99% in the tumor registration was superior to that in the other registration (p < 0.001), indicating the effectiveness of the tumor registration. The dose constraints, set in the plan as the maximum dose for OARs (i.e., duodenum, stomach, colon, and esophagus) were maintained for 16 patients including seven treated with re-planning. For three patients, the daily D max increased gradually or changed randomly, resulting in an inter-fractional averaged D max higher than the constraints. The dose distribution would have been improved if re-planning had been conducted. The results of these retrospective analyses indicate the importance of daily dose monitoring followed by adaptive re-planning when needed., Conclusions: The tumor registration in proton treatment for HCC was effective to maintain the daily dose to the tumor and the dose constraints of OARs, particularly in the treatment where the maintenance for the dose constraints needs to be considered throughout the treatment. Nevertheless daily proton dose monitoring with daily CT imaging is important for more reliable and safer treatment., (© 2023 American Association of Physicists in Medicine.)

Fucosylated proteins are widely used as biomarkers of cancer and inflammation. Fucosylated alpha-fetoprotein (AFP-L3) is a specific biomarker for hepatocellular carcinoma. We previously showed that increases in serum AFP-L3 levels depend on increased expression of fucosylation-regulatory genes and abnormal transport of fucosylated proteins in cancer cells. In normal hepatocytes, fucosylated proteins are selectively secreted in the bile duct but not blood. In cases of cancer cells without cellular polarity, this selective secretion system is destroyed. Here, we aimed to identify cargo proteins involved in the selective secretion of fucosylated proteins, such as AFP-L3, into bile duct-like structures in HepG2 hepatoma cells, which have cellular polarity like, in part, normal hepatocytes. α1-6 Fucosyltransferase (FUT8) is a key enzyme to synthesize core fucose and produce AFP-L3. Firstly, we knocked out the FUT8 gene in HepG2 cells and investigated the effects on the secretion of AFP-L3. AFP-L3 accumulated in bile duct-like structures in HepG2 cells, and this phenomenon was diminished by FUT8 knockout, suggesting that HepG2 cells have cargo proteins for AFP-L3. To identify cargo proteins involved in the secretion of fucosylated proteins in HepG2 cells, immunoprecipitation and the proteomic Strep-tag system experiments followed by mass spectrometry analyses were performed. As a result of proteomic analysis, seven kinds of lectin-like molecules were identified, and we selected vesicular integral membrane protein gene VIP36 as a candidate of the cargo protein that interacts with the α1-6 fucosylation (core fucose) on N -glycan according to bibliographical consideration. Expectedly, the knockout of the VIP36 gene in HepG2 cells suppressed the secretion of AFP-L3 and other fucosylated proteins, such as fucosylated alpha-1 antitrypsin, into bile duct-like structures. We propose that VIP36 could be a cargo protein involved in the apical secretion of fucosylated proteins in HepG2 cells.

Recent advances in highly conformal radiotherapies greatly extend the indications for radiotherapy of liver tumors. However, because of poor tolerance to hepatic radiation, estimation of the intensity of irradiation of the liver is important, particularly for a cirrhotic liver. Knowledge of radiation-induced hepatitis is important for understanding how to optimize hepatic radiation therapy. Pathological changes of the irradiated liver, which include perivenular fibrosis, sinusoidal obstruction, and damage to Kupffer cells and hepatocytes, can be visualized using clinical imaging techniques. This review article discusses and illustrates the pathological and radiological changes of hepatic tumors and the surrounding parenchyma of the irradiated liver.

Background: Proton beam therapy (PBT) achieves good local control for hepatocellular carcinoma (HCC), and toxicity tends to be lower than for photon radiotherapy. Focal liver parenchymal damage in radiotherapy is described as the focal liver reaction (FLR); the threshold doses (TDs) for FLR in the background liver have been analyzed in stereotactic ablative body radiotherapy and brachytherapy. To develop a safer approach for PBT, both TD and liver volume changes are considered clinically important in predicting the extent of damage before treatment, and subsequently in reducing background liver damage. We investigated appearance time, TDs and volume changes regarding FLR after PBT for HCC., Material and Methods: Patients who were treated using PBT and were followed up using gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (Gd-EOB-DTPA MRI) after PBT were enrolled. Sixty-eight lesions in 58 patients were eligible for analysis. MRI was acquired at the end of treatment, and at 1, 2, 3 and 6 months after PBT. We defined the FLR as a clearly depicted hypointense area on the hepatobiliary phase of Gd-EOB-DTPA MRI, and we monitored TDs and volume changes in the FLR area and the residual liver outside of the FLR area., Results: FLR was depicted in all lesions at 3 months after PBT. In FLR expressed as the 2-Gy equivalent dose (α/β = 3 Gy), TDs did not differ significantly (27.0±6.4 CGE [10 fractions [Fr] vs. 30.5±7.3 CGE [20 Fr]). There were also no correlations between the TDs and clinical factors, and no significant differences between Child-Pugh A and B scores. The volume of the FLR area decreased and the residual liver volume increased, particularly during the initial 3 months., Conclusion: This study established the FLR dose for liver with HCC, which might be useful in the prediction of remnant liver volume for PBT., Competing Interests: The authors declare that they have no competing interests.

Background: Fucosylation is one of the most important glycosylation events involved in cancer and inflammation. We previously developed a lectin antibody ELISA kit to measure fucosylated haptoglobin (Fuc-Hpt), which we identified as a novel cancer biomarker. In this study, we investigated Fuc-Hpt as a biomarker in chronic liver diseases, especially in hepatocellular carcinoma (HCC)., Methods: We measured serum Fuc-Hpt levels using our ELISA kit in 318 patients with chronic liver diseases, including 145 chronic hepatitis (CH) patients, 81 liver cirrhosis (LC) patients, and 92 HCC patients. During a long-term follow-up period of 7 years (1996-2003), Fuc-Hpt levels were measured at three different time points in 19 HCC patients. Serum Fuc-Hpt levels were also examined with a short-term follow-up period of 3 years (2009-2012) in 13 HCC patients., Results: Fuc-Hpt levels increased with liver disease progression. Patients with LC and HCC showed significantly increased Fuc-Hpt levels in comparison to CH patients or healthy volunteers. Fuc-Hpt levels tended to be higher in HCC patients than in LC patients. Fuc-Hpt was better than α-fetoprotein (AFP) and AFP-L3 for predicting HCC [diagnosed by computed tomography (CT) or ultrasound] in LC patients with long-term follow-up. More than 80% of LC patients with long-term follow-up showed increased Fuc-Hpt during hepatocarcinogenesis, and 38% of early-stage HCC patients with short-term follow-up showed a gradual increase in Fuc-Hpt before imaging diagnosis., Conclusions: These results suggest that Fuc-Hpt is a novel and potentially useful biomarker for predicting liver disease progression and HCC development.

Sialylation is one of the most important types of glycosylation involved in carcinogenesis and establishment of cancer stemness. We previously showed that increased sialylation is a characteristic glycan change in cancer stem cells (CSCs) from hepatocellular carcinoma. However, the identities of glycoproteins targeted for sialylation remain unknown. In the present study, we identified glycoproteins targeted for sialylation in doxorubicin (DXR)-treated hepatocarcinoma cell line, Huh7, using glycoproteomic analyses. Since CSCs constitute a small subset of cells within carcinoma cell lines, it is difficult to identify sialylated proteins using general glycoproteomic strategies. It is known that treatment with anticancer drug can condense CSCs, we used DXR to concentrate CSCs. In DXR-treated Huh7 cells, isobaric tag for relative and absolute quantitation (iTRAQ) analysis identified 17 sialylated glycoproteins. Most of the identified glycoproteins were cancer-associated proteins. Furthermore, two proteins of approximately 70 kDa were detected using Sambucus sieboldoana agglutinin (SSA) blot analysis and identified as beta-galactosidase and alpha-2-HS-glycoprotein (fetuin-A) by SSA precipitation followed by liquid chromatography-tandem mass spectrometry analyses. Sialylation levels of fetuin-A were increased in DXR-treated Huh7 cell lysates. These changes in sialylation of glycoproteins might be involved in the establishment of cancer stemness.

Background/aims: We investigated a relationship between the risk factors for metabolic syndrome, such as obesity, diabetes mellitus, hypertension, and hyperlipidemia, and the pathogenesis and outcome of hepatocellular carcinoma (HCC)., Methodology: One hundred twenty four patients who underwent curative resections for HCC were classified into 3 groups: those patients who were positive for hepatitis B surface antigen (group B), those positive for antibody to hepatitis C virus (group C), and those negative for both of them (non-B non-C) (group NBNC). The preoperative laboratory data, risk factors for metabolic syndrome, history of alcohol abuse, and outcome after surgery were investigated. The presence of non-alcoholic steatohepatitis (NASH) was also evaluated., Results: The incidence of diabetes mellitus, hyperlipidemia, and alcohol abuse, and the serum level of triglyceride were significantly higher in group NBNC than in groups B or C. The risk factors for metabolic syndrome tended to lower the survival rates in group B and C, but not in group NBNC. Three of the 37 non-B non-C patients were associated with NASH., Conclusions: It is suggested that the pathogenesis of non-B non-C HCC may be more closely associated with the risk factors for metabolic syndrome than that of hepatitis virus related HCC.

Purpose: To retrospectively evaluate the arterial blood supply to the posterior aspect of segment IV of the liver with computed tomography (CT) after transcatheter arterial chemoembolization (TACE) with iodized oil through the caudate arterial branch of the liver for treatment of hepatocellular carcinoma (HCC)., Materials and Methods: Institutional review board approval and patient informed consent were not required for this retrospective study. Twenty-four patients (11 men and 13 women; mean age, 68 years) with HCC originating in the caudate lobe (n = 23) or posterior aspect of segment IV (n = 1) were selected. TACE of the caudate arterial branch was performed in all patients, including one patient with HCC in the posterior aspect of segment IV who underwent TACE of the caudate arterial branch after CT helped confirm that iodized oil was not distributed in the tumor after TACE of the medial segmental artery. The distribution of iodized oil in the posterior aspect of segment IV was analyzed with CT 1 week after TACE. The number and origin of all arteries supplying the caudate lobe and the number of arteries embolized were determined., Results: Thirty-three caudate arterial branches were embolized. Twenty-nine branches were derived from the right hepatic artery and four were derived from the left hepatic artery. A single branch was seen in 17 patients, two branches were seen in five, and three branches were seen in two. Eight patients simultaneously underwent additional TACE of branches of the right hepatic artery (n = 6) or right inferior phrenic artery (n = 2). At CT, iodized oil was seen to be distributed entirely (n = 19) or partially (n = 5) in the caudate lobe. Distribution of iodized oil at the posterior aspect of segment IV was observed in 16 patients (67%), including 13 (54%) whose caudate arterial branches were derived entirely from the right hepatic artery., Conclusion: The results of this study suggest that the caudate arterial branch, which is mainly derived from the right hepatic artery, frequently supplies the posterior aspect of segment IV. This knowledge is important for managing HCC in the posterior aspect of segment IV by means of TACE., (RSNA, 2005)

Background: Laparoscopic/thoracoscopic intervention has been recently developed for hepatocellular carcinoma (HCC). However, no precise evaluation regarding this type of surgery has been performed., Patients and Methods: A total of 33 laparoscopic and thoracoscopic treatments were performed on HCC patients, laparoscopic or thoracoscopic liver resection (LTR) in 15 patients and laparoscopic or thoracoscopic thermal ablation (LTA) in 18 patients., Results: Postoperative hospital stay was 12.7 days after resection and 14.8 days after ablation. The 1- and 3- year actuarial survival rate were 100% and 80%, respectively, after LTR and 95% and 75%, respectively, after LTA. The 1- and 3- year disease-free survival rates were 75% and 40%, respectively, after LTR, and 60% and 28%, respectively, after LTA., Conclusion: LTR has the advantages of the curability of open surgery and less invasiveness of laparoscopic surgery. LTA is useful for tumors that cannot be percutaneously detected by ultrasound. Laparoscopic/thoracoscopic intervention is therefore considered an alternative means of treatment for selected HCC patients.

Purpose: To evaluate reconstructed patterns of occluded inferior phrenic artery (IPA) and determine the technical success rate and complications of transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) fed by the occluded IPA through the anastomosing branch., Materials and Methods: In 19 patients, 24 IPAs, including two that had been previously embolized, were demonstrated through collateral pathways. The incidence of each collateral circulation was evaluated. Thirteen IPAs in 12 patients fed the tumor and TACE was attempted. TACE was performed only if the catheter could be advanced into the anastomosing branch so that the nontarget branches were avoided., Results: A reconstructed unilateral IPA was observed in 14 patients (11 right IPAs and three left IPAs) and two reconstructed IPAs were observed in five. The IPA was demonstrated through the dorsal pancreatic artery (n = 13), inferior or middle adrenal artery (n = 7), left gastric artery (n = 2), contralateral IPA (n = 2), lumbar artery (n = 1), and small branch derived from the celiac trunk (n = 1). Five IPAs (21%) were demonstrated through more than two separate arteries, including two demonstrated through both dorsal pancreatic arteries arising from the celiac and superior mesenteric artery. The IPA opacified through the lumbar artery had been previously embolized. TACE of the reconstructed IPA was possible in 10 of 13 IPAs (77%). Complications related to the procedure were a small amount of pleural effusion (n = 4) and basal atelectasis (n = 2)., Conclusion: The IPA is reconstructed mainly through the retroperitoneal anastomosing branch in the upper abdomen. TACE of the reconstructed IPA can be performed with a high success rate without major complications.

Several trials have been reported examining laparoscopic liver resections for the treatment of various kinds of liver tumors. However, there are no detailed reports on the use of laparoscopic (LH) and thoracoscopic (TH) hepatectomy for the treatment of hepatocellular carcinoma (HCC). Eleven laparoscopic and thoracoscopic partial liver resections were attempted for treating HCC. The indications for performing a laparoscopic or thoracoscopic partial hepatectomy were as follows: (1) the tumor was located on the surface of the liver; (2) the tumor was less than 3 cm in diameter; and (3) the tumor was not located adjacent to any large vessels. A TH was performed if the tumor was located in segment 8; an LH was performed if the tumor was located in segment 3, 4, or 5. Hand-assisted operations were performed in two patients. The mean operating time was 186.1 +/- 44.0 minutes (range 130-310 minutes). The operative blood loss was 218.3 +/- 197.6 ml (range 20-650 ml). The mean postoperative hospital stay was 11.3 +/- 5.7 days (range 7-26 days). Two patients experienced postoperative complications (wound infection and ascites). No local recurrences have occurred to date. The overall 5-year survival rate and disease-free 5-year survival rate were 75.0% and 38.2%, respectively. Laparoscopic and thoracoscopic hepatic resections are less invasive than conventional surgical techniques and are useful for treating HCC in select patients.

Background: Resection of the IVC is required when a liver tumor invading the IVC is completely removed. The purpose of this study was to evaluate the clinical significance of hepatectomy combined with IVC resection and reconstruction with an ePTFE graft for treatment of invasive liver tumors and to discuss the validity of this surgery., Study Design: Eleven selected patients with liver tumors underwent various types of hepatectomy with retrohepatic IVC resection, followed by IVC reconstruction. The postoperative courses, clinicopathologic features of the tumors, operative procedures, and outcomes of the patients were studied., Results: Ten of 11 patients did not require an active ventriculovenous bypass using a biopump. Invasion to the IVC was histologically proved in 9 of the 11 patients. After reconstruction, all artificial vessel grafts maintained patency throughout the observation period. Four patients are still alive with cancer-free status ranging from approximately 11 years to 5 months. One-year, 3-year, and 5-year survival rates were 63.6%, 38.2%, and 25.5%, respectively, with a 50% survival of 29 months., Conclusions: IVC resection and its reconstruction with ePTFE for treatment of liver tumors was safely performed on 11 selected patients with a 50% survival of 29 months. Patency of the graft was maintained for the longterm without infectious complications. This surgical procedure is indicated in some select patients in whom IVC invasion is extensive.

Background: There have been no effective treatments for intra-abdominal lymph node metastasis. One of the main reasons is that we cannot deliver chemotherapeutic agents directly. We evaluated percutaneous transhepatic lymphography (PTL) as a drug delivery system., Methods: PTL was performed 16 times in 13 patients. PTL was performed by puncture of the intrahepatic periportal area. Immediately after injection of contrast medium, lymphatic flow through the hepatoduodenal ligament to the intra-abdominal lymph nodes was visualized. The chemotherapeutic agent was delivered to the metastatic intra-abdominal lymph nodes by this route., Results: In 10 of 13 patients, intrahepatic and extrahepatic lymphatic vessels and lymph nodes were visualized by PTL. Computed tomography after PTL showed retention of lipiodol in the lymphatic system around the portal vein and in the enlarged metastatic lymph nodes located in the pancreatic and celiac lymph nodes. According to the Response Evaluation Criteria in Solid Tumors, there were 8 patients with progressive disease and 5 with stable disease., Conclusions: The present study showed that PTL can be used as a drug delivery system specific for intra-abdominal lymph nodes as well as for identification of the lymph tracts.

Percutaneous local treatment for hepatocellular carcinoma is minimally invasive. Moreover, since local radical cure may be possible, the procedure has become widely performed. Percutaneous radiofrequency ablation (PRFA) was recently introduced in Japan. Excellent results are expected. PRFA was conducted on 244 tumor nodules found in 177 cases of hepatocellular carcinoma (a total of 349 procedures), and the usefulness was examined. 1. Tumor markers significantly decreased after PRFA and a favorable necrotic effect was obtained on CT images. 2. Mild post-operative inflammatory reaction and exacerbation of liver dysfunction was noted, but recovery was achieved in one week. There were no major complications. 3. The cumulative local recurrence in 1 year was 5.4%, which is lower than that with percutaneous microwave coagulation therapy. 4. PRFA is a safe and handy procedure for hepatocellular carcinoma, which promises the favorable effect of coagulation necrosis. PRFA will likely become a key method among local ablation therapies.

The human hepatoma cell line, HepG2, secreted an activity that degrades platelet-activating factor (PAF) by the hydrolysis of the sn-2 acetyl group. This activity was Ca++ independent, inhibited by diisopropylfluorophosphate but not by p-bromophenacyl bromide, and resistant to treatment with trypsin or pronase. Separation of HepG2-conditioned medium by gel filtration disclosed that the activity was associated with lipoproteins. An antiserum against PAF acetylhydrolase immunoprecipitated this activity. It was not recognized by an antibody against lecithin:cholesterol acyltransferase (LCAT), which also is secreted by HepG2 cells. Therefore the phospholipase A2 activity of LCAT was excluded as a source of the observed activity. PAF added to the culture medium stimulated the secretion of the PAF-degrading activity by HepG2 cells, while lyso-PAF was inactive. Maximal stimulation was observed with 5 ng/ml PAF, which induced a fivefold increase. The presence of 5 ng/ml PAF, enhanced the secretion of [35S]methionine-labeled PAF acetylhydrolase and cycloheximide inhibited both the basal and PAF-stimulated secretion of the labeled enzyme. We conclude that HepG2 cells produce PAF acetylhydrolase. The liver may be a major source of plasma PAF acetylhydrolase, and PAF may induce the production of its inactivating enzyme by the liver.