Role of heat shock factor 1 expression in the microenvironment of intrahepatic cholangiocarcinomas.

Heat shock factor 1 (HSF1), a master regulator of heat shock response, has been shown to play a multifaceted role in cancer progression. However, the clinical significance and biological effect of HSF1 expression in intrahepatic cholangiocarcinoma (IHCC) remain unknown. Forty-nine patients with IHCC who underwent hepatic resection were enrolled in this study. HSF1 expression in tumor tissue was determined by immunohistochemistry, and patients were divided into two groups, those with high (n = 20) and low (n = 29) HSF1 expression. Clinicopathological factors including prognosis were compared in these two groups. HSF1 expression was significantly higher in tumors than in normal tissue. The overall survival rate was significantly lower in patients with high than low HSF1. Multivariate analysis showed that high HSF1 expression was a factor independently prognostic of patient survival. High HSF1 expression in tumor tissues may be a prognostic biomarker in patients with IHCC.

Journal of Gastroenterology and Hepatology


Potential predictive factors for microvascular invasion in hepatocellular carcinoma classified within the Milan criteria.

Microvascular invasion (mvi) is an important risk factor for recurrent hepatocellular carcinoma (HCC), even after curative liver resection or orthotopic liver transplantation. However, mvi is difficult to detect preoperatively. The aim of this study was to clarify the risk factors of postoperative recurrence and investigate predictive factors of mvi before hepatectomy for HCC classified within the Milan criteria. One hundred fifty-nine patients with hepatocellular carcinoma (HCC) classified within the Milan criteria, who underwent hepatectomy, were enrolled in this study. We investigated the risk factors of recurrence. In addition, we divided them into two groups: mvi-negative group and mvi-positive group, based on pathological findings after surgery. We compared the clinicopathological factors between the two groups and determined the risk factors for mvi. Overall survival rate at 1, 3, and 5 years were 91.6%, 80.5%, and 74.9%, and the recurrence-free survival rate at 1, 3, and 5-years were 72.3%, 51.6%, and 37.2%. Risk factor analysis for tumor recurrence revealed that total bilirubin, albumin, ICGR15, AFP-L3, tumor number, mvi, and tumor stage had a significant predictive value. Multivariate analysis revealed that tumor number and mvi were significant independent risk factors for tumor recurrence. Predictive analysis for risk factors of mvi revealed that multiple tumors and AFP-L3 > 10% were significant independent risk factors for mvi in HCC classified within the Milan criteria. The mvi was one of the independent risk factors for tumor recurrence in HCC classified within the Milan criteria. Multiple tumors and high AFP-L3 value were independent predictive factors for mvi.

International Journal of Clinical Oncology


The Outcome of Sorafenib Therapy on Unresectable Hepatocellular Carcinoma: Experience of Conversion and Salvage Hepatectomy.

We report the outcomes of sorafenib therapy for advanced hepatocellular carcinoma (HCC) in our Department. Thirty-eight patients with unresectable HCC who were administrated sorafenib from 2009 to 2015 were investigated retrospectively. The 1-year overall survival rate was 59.3%. The macroscopic vascular invasion and response rate were independent prognostic factors of survival. Surgical resection after sorafenib achieved long-term survival in two cases. Case 1: A patient with locally unresectable HCC showed significant response induced by sorafenib, which allowed complete surgical resection. This tumor tested positive for FGF4. Case 2: A patient with a history of hepatectomy for HCC had multiple distant metastases. Most lesions were reduced in size after sorafenib therapy and new lesions in the remnant liver and residual lung metastases were resected. The sorafenib-resistant lesions were negative for FGF4. Sorafenib combined with surgical resection is a feasible option in advanced HCC patients, if sorafenib has been effective.


Evaluation of malignancy in gallbladder tumors using the apparent diffusion coefficient obtained by diffusion-weighted MRI.

The utility of the apparent diffusion coefficient (ADC) of diffusion-weighted image (DWI) magnetic resonance imaging was examined for evaluating malignancy and prognosis in gallbladder tumors. A total of 63 patients (benign tumors, n=33; cancer, n=30) were included after surgical resection for gallbladder tumors, and their mean ADC values by DWI were obtained. Cases of advanced gallbladder cancer (n=25) were divided into ADC and ADC groups, and clinicopathological factors were compared. In 63 cases, ADC values in advanced gallbladder cancer were significantly lower compared with benign tumors and non-advanced gallbladder cancer (P<0.05), and ADC values in early gallbladder cancer were also significantly lower compared with benign tumors (P<0.05). In 25 advanced gallbladder cancer cases, the ADC group tended to have a higher rate of advanced stage disease (P=0.09). Disease-free survival and overall survival (OS) of the ADC group were worse compared with the ADC group (P<0.01). In the multivariate analysis of OS, poor differentiation and low ADC value were independent prognostic factors. ADC values may be useful for evaluating tumor malignancies in gallbladder tumors.


Lenvatinib-resistant hepatocellular carcinoma promotes malignant potential of tumor-associated macrophages via exosomal miR-301a-3p.

The interactions between cancer cells and tumor-associated macrophages (TAMs) via microRNAs (miRNAs) play crucial roles in malignant potential and drug resistance. However, it remains unclear how lenvatinib-resistant hepatocellular carcinoma (LR HCC) promotes TAM tumor biology. Here we investigated the crosstalk between LR HCC cells and TAMs for cancer progression and lenvatinib resistance, focusing on an exosomal miRNA. We used two bioinformatics software programs to identify miRNAs that target PTEN in gastrointestinal cancers, then investigated exosomal miRNA expression in LR HCC conditioned medium (CM). After modifying TAMs with LR HCC CM (LR TAM), macrophage phenotype and PTEN-Nrf2 signaling pathway component expression were analyzed in LR TAMs. The malignant potential and drug resistance were investigated in naïve HCC cells cultured with LR TAM CM. LR HCC cells highly induced M2-like properties in macrophages compared with naïve HCC cells. Exosomal miR-301a-3p expression was increased in LR HCC CM, with higher activation of the PTEN/PI3K/GSK3β/Nrf2 signaling pathway in LR TAMs. Naïve HCC cells were educated with LR TAM CM to promote malignant potential and lenvatinib resistance. Inhibition of exosomal miR-301a-3p prevented the malignant potential of LR TAMs. Activation of Nrf2 signaling by LR HCC cell-derived exosomal miR-301a-3p skewed the transformation of macrophages to the M2 phenotype. Our study provides new findings on the role of miR-301a-3p, suggesting it is a promising therapeutic target to improve HCC lenvatinib resistance.


Generation of Highly Functional Hepatocyte-like Organoids from Human Adipose-Derived Mesenchymal Stem Cells Cultured with Endothelial Cells.

Previously, we successfully established a highly functional, three-dimensional hepatocyte-like cell (3D-HLC) model from adipose-derived mesenchymal stem cells (ADSCs) via a three-step differentiation protocol. The aim of the present study was to investigate whether generating hepatocyte-like organoids (H-organoids) by adding endothelial cells further improved the liver-like functionality of 3D-HLCs and to assess H-organoids' immunogenicity properties. Genes representing liver maturation and function were detected by quantitative reverse transcription-PCR analysis. The expression of hepatic maturation proteins was measured using immunofluorescence staining. Cytochrome P (CYP)450 metabolism activity and ammonia metabolism tests were used to assess liver function. H-organoids were successfully established by adding human umbilical vein endothelial cells at the beginning of the definitive endoderm stage in our 3D differentiation protocol. The gene expression of alpha-1 antitrypsin, carbamoyl-phosphate synthase 1, and apolipoprotein E, which represent liver maturation state and function, was higher in H-organoids than non-organoid 3D-HLCs. H-organoids possessed higher CYP3A4 metabolism activity and comparable ammonia metabolism capacity than 3D-HLCs. Moreover, although H-organoids expressed human leukocyte antigen class I, they expressed little human leukocyte antigen class II, cluster of differentiation (CD)40, CD80, CD86, and programmed cell death ligand 1, suggesting their immunogenicity properties were not significantly upregulated during differentiation from ADSCs. In conclusion, we successfully established an H-organoid model with higher liver-like functionality than previously established 3D-HLCs and comparable immunogenicity to ADSCs.


Pancreatoduodenectomy combined with intestinal de-rotation as a complete artery-first approach for inexperienced surgeons.

Recent technical advances have reduced the incidence of intraoperative complications associated with pancreatoduodenectomy (PD). We aimed to determine whether inexperienced surgeons (ISs) would be as successful as experienced surgeons (ESs) when performing the complete artery-first approach using the intestinal de-rotation method of PD. Seventy patients who underwent PD using the intestinal de-rotation method in Tokushima University Hospital were enrolled in the present study. Intra- and post-operative parameters were compared between patients operated on by ESs (n=20) or ISs (n=50). The surgical procedure lasted longer in the IS group (ES : 402 }68 min vs. IS : 483 }51 min, p<0.0001), but the volume of blood loss was similar (p=0.7304). There was no mortality in either group, and the incidences of postoperative complications with a Clavien-Dindo grade of>III did not differ between the groups. Grade B postoperative pancreatic fistulae developed in 20.0% of patients in the ES group and 22.0% in the IS group (p=0.9569). Finally, the postoperative hospital stay of the IS group (32 }33 days) was equivarent to that of the ES group (33 }16 days) (p=0.9256). ISs were able to perform similarly successful PDs using the intestinal de-rotation method to ESs. J. Med. Invest. 71 : 75-81, February, 2024.

The Journal of Medical Investigation : JMI


Association between high expression of intratumoral fibroblast activation protein and survival in patients with intrahepatic cholangiocarcinoma.

Cancer-associated fibroblasts (CAFs) have been reported to exhibit protumorigenic effects. Among the well-known CAF markers such as smooth muscle actin (SMA) and fibroblast activation protein (FAP), high expression of SMA in the peritumoral stroma has been reported to be a prognostic factor in various cancers. However, the effect of high FAP expression in intrahepatic cholangiocarcinoma (IHCC) has not been fully clarified. We evaluated the expression of CAF markers, focusing on FAP expression in the peripheral and intratumoral regions, to clarify the association with survival in patients with IHCC. The study cohort comprised 37 patients who underwent curative resection for IHCC. The FAP expressions were evaluated in the peripheral and intratumoral regions of the resected tissues. Clinicopathological factors and survival outcomes were investigated between patients with high versus low FAP expression. Uni- and multivariate analyses were performed to identify the prognostic factors for overall survival and relapse-free survival. The median area percentages of FAP expression in the peripheral and intratumoral regions were 15.5% and 17.8%, respectively. High FAP expression in the intratumoral region was significantly associated with worse overall survival and disease-free survival than low FAP expression in the intratumoral region. Multivariate analysis identified high intratumoral FAP expression as a risk factor for worse overall survival (hazard ratio, 2.450; p = 0.049) and relapse-free survival (hazard ratio, 2.743; p = 0.034). High intratumoral FAP expression was associated with worse survival, suggesting that intratumoral FAP expression represents malignant progression in patients with IHCC.


Effects of green light-emitting diode irradiation on hepatic differentiation of hepatocyte-like cells generated from human adipose-derived mesenchymal cells.

Light-emitting diode (LED) irradiation has been used in the differentiation of mesenchymal stem cells into a variety of cell types. This study investigated the effect of green LED (GLED) irradiation on the differentiation of adipocyte-derived mesenchymal cells into hepatocyte-like cells (HLCs) and the mechanism of its action. HLCs in the hepatocyte maturation phase were irradiated with GLED (520 nm, 21 W/m, 5 min/day for 10 days). The cells were then assessed for expression of hepatocyte maturity genes and opsin 3 (OPN3), hepatocyte function, viability, apoptosis, and levels of reactive oxygen species (ROS), intracellular adenosine triphosphate (ATP) and calcium ions (Ca). GLED irradiation increased Alpha-1 antitrypsin and Ornithine transcarbamylase gene expression, promoted Cytochrome P450 3A4 activity and urea synthesis, and elevated intracellular ROS, ATP and Ca levels. OPN3 expression was significantly more upregulated in GLED-irradiated HLCs than in the non-irradiated HLCs. No significant difference in cell viability or apoptosis was observed between GLED-irradiated and non-irradiated HLCs. GLED irradiation can promote hepatocyte maturation and functions through OPN3. GLED irradiation also stimulated mitochondrial function via Ca/ATP/ROS activation. GLED irradiation has potential to support cell-based transplantation in patients.


Preoperative Weight Loss Program for Hepatocellular Carcinoma Patients with High Body Mass Index in Hepatectomy.

This study aimed to investigate the usefulness of a weight-loss program (WLP) in patients with a high body mass index (BMI) prior to liver resection (Hx) for hepatocellular carcinoma (HCC). Among 445 patients with HCC who underwent initial Hx between 2000 and 2020, 19 with a high BMI (≥25.0) were enrolled in our WLP since 2014. For calorie restriction, the amount of energy consumed was calculated as the standard body weight (SBW) kg × 20-25 kcal/day. Protein mass was calculated as SBW kg × 1.0-1.2 g/day to maintain skeletal muscle mass. Patients also performed both aerobic and resistance exercises. The before-and-after changes were compared, and the effect of WLP on the short- and long-term results was investigated. The average length of WLP was 21 days, and weight loss was successfully achieved in all patients. Body fat mass was reduced during the program, while skeletal muscle mass was maintained. WLP led to improvements in liver function and fibrotic markers, without tumor progression. There were no postoperative complications (≥Clavien-Dindo [CD] III). A retrospective comparison between with and without WLP using propensity score-matching analysis revealed that WLP group showed better NLR value, however, there were no significant differences in both short and long-term outcomes after Hx based on participation in the WLP. WLP with multidisciplinary intervention improved immune-nutrition status and liver function of obese patients. WLP had not affected both short and long-term outcomes after Hx.


患者は50代女性.検診の腹部超音波検査で肝S3に16×14mm大の腫瘤を指摘され精査加療目的に当科紹介となった.既往歴・生肉食歴なし.術前の血液検査で異常なく,末梢好酸球も正常.造影CTの動脈・門脈相では辺縁に造影効果を認めるが,平衡相では造影されず,MRI T1強調像で低信号,T2強調像で低∼等信号,拡散強調像でやや高信号であった.PET-CTで肝臓への集積は認めなった.悪性腫瘍の可能性を完全に否定できず,腹腔鏡下肝部分切除を施行した.病理組織学的には腫瘤全体に凝固壊死像が見られ,辺縁に線維増生を伴い,組織球が柵状に配列したpalisading granulomaであった.原因特定のために複数の染色を行ったが,病原体は同定できなかった.palisading granulomaは術前診断が困難であり,診断的治療として腹腔鏡下肝切除術は有用であると考えられた.(著者抄録)


Clinical impact of myosteatosis measured by magnetic resonance imaging on long-term outcomes of hepatocellular carcinoma after radical hepatectomy.

A variety of factors have been reported to affect long-term outcomes after radical resection of hepatocellular carcinoma (HCC). However, the indicators remain controversial. The purpose of this study was to evaluate the relationship between myosteatosis of the multifidus muscle and long-term outcomes after radical surgery for HCC. We retrospectively analyzed clinicopathological data for 187 patients with HCC who underwent radical surgery at Tokushima University between January 2009 and December 2020 and measured the density of fat in the multifidus muscle at L3 on their preoperative magnetic resonance images (MRI). Associations of myosteatosis and clinicopathological factors with long-term outcomes were evaluated. The patients were divided into a myosteatosis-negative group (n = 122) and a myosteatosis-positive group (n = 65). The cancer-specific survival rate after hepatectomy was significantly worse in the myosteatosis-positive group than in the myosteatosis-negative group (p = 0.03). Univariate analysis identified multiple tumors, stage III/IV disease, an alfa-fetoprotein level ≥ 10 ng/ml, PIVKA-II ≥ 400 AU/ml, vp(+) status, and myosteatosis to be prognostic factors for cancer-specific survival. Multivariate analysis revealed multiple tumors, an alfa-fetoprotein level ≥ 10 ng/ml, and myosteatosis to be independent prognostic factors. Myosteatosis measured by MRI is a simple and useful predictor of the long-term outcome after radical surgery for HCC.


TU-100 Antagonizes the M2 Polarization Phenotype of Macrophages in the Tumor Microenvironment by Suppressing the TLR4/NF-B/STAT3 Axis.

Macrophages are the most abundant immune cells in the tumor stroma, and their polarization states within the tumor microenvironment (TME) exert critical roles in tumorigenesis. TU-100 (Daikenchuto) is a commonly prescribed Japanese herbal medicine that has shown anti-cancer effects by regulating cancer-associated fibroblasts (CAFs) in the TME. However, its effects on tumor-associated macrophages (TAMs) remain unclear. TAMs were generated by macrophage exposure to tumor-conditioned medium (CM), and their polarization states were evaluated after TU-100 treatment. The underlying mechanism was further studied. TU-100 exhibited little cytotoxicity over a range of doses in M0 macrophages and TAMs. However, it could antagonize the M2-like polarization of macrophages evoked by tumor-CM exposure. These effects might be caused by the inhibition of TLR4/NF-B/STAT3 signaling in the M2-like phenotype of macrophages. Interestingly, TU-100 antagonized the malignancy promoting effects of M2 macrophages on hepatocellular carcinoma cell lines in vitro. Mechanistically, the administration of TU-100 restrained the high expression of MMP-2, COX-2, and VEGF in TAMs. TU-100 may alleviate the progression of cancer by regulating the M2 polarization of macrophages within the TME, suggesting a viable therapeutic approach.


術前に肝細胞癌との鑑別が困難であった筋腫型肝血管筋脂肪腫の1例

術前に肝細胞癌との鑑別が困難であった筋腫型肝血管筋脂肪腫の1例

患者は40代女性.検診で肝から突出する15cmの巨大腫瘤を指摘され,精査加療目的に当科紹介となった.既往歴や背景肝に特記事項なく,腫瘍マーカーは正常であったが,造影CTの動脈・門脈相で肝右葉に15cm大の早期濃染と遅延相でwashoutを認めた.EOB-MRI肝細胞相ではdefectとして描出され肝細胞癌が疑われた.破裂の危険性を考慮し,まずTACEを行い,その後拡大肝右葉切除を施行した.病理組織学的には腫瘍の大半が平滑筋様細胞で構成されており,脂肪細胞は認めず,免疫組織化学染色にてVimentin,αSMA,HMB-45,melan Aが陽性であり,Perivascular epithelioid cell tumor(PEComa)として包括される腫瘍群の中の筋腫型の肝血管筋脂肪腫(Angiomyolipoma;AML)と診断した.今回我々は,術前に肝細胞癌との鑑別が困難であった,若年女性に発生した肝原発筋腫型AMLを経験したため報告する.(著者抄録)


Curcumin-Mediated Resistance to Lenvatinib via EGFR Signaling Pathway in Hepatocellular Carcinoma.

Lenvatinib is a multi-kinase inhibitor approved as a first-line treatment for patients with unresectable advanced hepatocellular carcinoma (HCC). However, its response rate is unsatisfactory, primarily due to the acquisition of resistance, which limits its clinical significance for treating patients with HCC. Recent evidence suggests that epidermal growth factor receptor (EGFR) activation can trigger Lenvatinib-resistance; and is considered an important therapeutic target in HCC. Curcumin, one of the most studied naturally occurring botanicals with robust anti-cancer activity, is also reported to be a potent tyrosine kinase inhibitor. In this study, we hypothesized that the anti-EGFR potential of Curcumin might help overcome Lenvatinib resistance in HCC. We established two Lenvatinib-resistant cells and discovered that a combination of Curcumin and Lenvatinib exhibited a synergistic anti-tumor efficacy in the resistant HCC cell lines. In line with previous reports, Lenvatinib-resistant cell lines revealed significant activation of the EGFR, and genomewide transcriptomic profiling analysis identified that the PI3K-AKT pathway was associated with Lenvatinib resistance. The combination treatment with Curcumin and Lenvatinib dramatically suppressed gene and protein expression of the EGFR-PI3K-AKT pathway, suggesting Curcumin overcomes Lenvatinib resistance via inhibition of EGFR. We further validated these findings in tumor spheroids derived from resistant cell lines. In conclusion, we, for the first time, report that Curcumin reverses Lenvatinib resistance in HCC, and that their combination has clinical application potential for adjunctive treatment in HCC.


Multiplication of tumor maximum diameter and number as a new surgical indicator for Barcelona Clinic Liver Cancer intermediate-stage hepatocellular carcinoma.

Recent advances in treatment modalities have been made, limiting the indication of hepatic resection in the treatment strategy for hepatocellular carcinoma (HCC) patients. This retrospective study investigated the significance of multiplication of tumor maximum diameter and number (MDN) as a surgical indicator for Barcelona Clinic Liver Cancer intermediate-stage HCC. A total of 49 patients with Barcelona Clinic Liver Cancer intermediate-stage HCC who underwent curative hepatic resection between 2000 and 2020 were enrolled in this study. Prognostic factors of overall survival and disease-free survival, including the product of MDN, were analyzed. Patients with MDN >12 experienced significantly worse prognosis compared with those with MDN ≤12 (p = 0.0395), and 5-year overall survival rates after hepatic resection were 60.0% and 23.4%, respectively. Furthermore, the disease-free survival rate of patients with MDN >12 was significantly worse compared with those with MDN ≤12 (p = 0.0049), and all patients with MDN >12 experienced recurrence within 3 years after hepatic resection. In the multivariate analysis, MDN >12 was identified as the only independent prognostic factor of both overall survival and disease-free survival. In addition, patients with MDN >12 suffered from uncontrollable recurrence by locoregional treatment, such as more than four intrahepatic and extrahepatic recurrences, after hepatic resection. MDN index might be a new surgical indicator for Barcelona Clinic Liver Cancer intermediate-stage HCC, and influence clinical decision-making for individual treatment strategies.


Impact of apparent diffusion coefficient on prognosis of early hepatocellular carcinoma: a case control study.

We investigated the usefulness of apparent diffusion coefficients (ADC) from diffusion-weighted images (DWI) obtained using magnetic resonance imaging (MRI) for prognosis of early hepatocellular carcinoma (HCC): Barcelona Clinic Liver Cancer (BCLC) stage 0 and A. We enrolled 102 patients who had undergone surgical resection for early HCC: BCLC stage 0 and A, and calculated their minimum ADC using DWI-MRI. We divided patients into ADC (n = 72) and ADC (n = 30) groups, and compared clinicopathological factors between the two groups. The ADC group showed higher protein induced by vitamin K absence-II (PIVKA-II) levels (p = 0.02) compared with the ADC group. In overall survival, the ADC group showed significantly worse prognosis than the ADC group (p < 0.01). Univariate analysis identified multiple tumors, infiltrative growth, high PIVKA-II, and low ADC value as prognostic factors. Multivariate analysis identified infiltrative growth and low ADC value as an independent prognostic factor. ADC values can be used to estimate the prognosis of early HCC.


Fontan associated liver disease(FALD)関連肝癌に対しての腹腔鏡肝切除の1例 Fontan循環における肝離断対策

30代男性,3歳時に単心房・単心室症を背景にFontan手術を受けた.Fontan associated liver disease(FALD)として肝臓内科にフォローを開始されて以来3年後にFALD関連肝癌を疑われ,腹腔鏡肝切除を施行した.肝離断中は,Central venous pressure(CVP)圧を下げるため,positive end expiratory pressureをオフし,最小限の輸液量,利尿剤併用しながらの麻酔管理を行うも,Fontan循環の影響でCVPコントロールは不良で,静脈性出血が継続したままの肝離断となった.本症例は,術後合併症なく経過したものの,FALD関連肝癌症例は,Fontan循環による高CVP下での肝離断を余儀なくされるため,そのジレンマを解決する必要があり,その対策に関して考察を加え報告する.(著者抄録)


Impact of pancreatic resection in patients with liver cirrhosis.

Several reports have shown a high mortality rate in patients with liver cirrhosis (LC) who undergo pancreaticoduodenectomy, however, there are few reports on its long-term prognosis. Twelve patients with LC who had undergone pancreatic resection were enrolled. To compare clinicopathological variables, 159 non-LC patients who had undergone resection for pancreatic cancer were enrolled. Pancreaticoduodenectomy (PD) was performed in 5 LC patients and distal pancreatectomy (DP) was performed in 7 LC patients. Patients in the LC group had more co-morbidities, lower platelet counts and higher Fib4 index than the non-LC group. The postoperative complication rate was higher in the LC group (83.3% vs 47.8%). While the postoperative hospital stay and 30-day mortality rate were not different, the 90-day mortality rate was higher in the LC group (25.0% vs 2.5% ; p<0.01). Comparison by operative procedure showed no significant differences of postoperative outcomes in DP cases. However, in PD cases, postoperative complications were more frequent (100% vs 42.3%) and 90-day mortality was higher (40.0% vs 2.9% ; p<0.01) in the LC group. PD resulted in higher postoperative morbidity and mortality rates in patients with LC compared with non-LC patients. DP could be tolerated in the LC patients. J. Med. Invest. 70 : 189-194, February, 2023.

The Journal of Medical Investigation : JMI


Impact of L-type amino acid transporter 1 on intrahepatic cholangiocarcinoma.

Amino acid transporters, such as L-type amino acid transporter 1 (LAT1), have an effect on tumor growth, metastasis, and survival of various solid tumors. However, the role of LAT1 in patients with intrahepatic cholangiocarcinoma (IHCC) remains unknown. Forty-six patients who had undergone initial hepatic resection for IHCC at Tokushima University Hospital were enrolled in this study. Immunohistochemical analysis of LAT1 and phosphorylated Akt (p-AKT) was performed using resected specimens. Clinicopathological factors, including prognosis, were analyzed between LAT1-high and LAT1-low groups. The LAT1-high group showed a higher proportion of periductal infiltrating type and higher carcinoembryonic antigen/carbohydrate antigen 19-9 levels compared with the LAT1-low group. Multivariate analysis revealed that LAT1-high expression was an independent prognostic factor for disease-free survival. Furthermore, the proportion of p-AKT positivity was higher in the LAT1-high group than in the LAT1-low group. LAT1 expression was associated with poor prognosis of IHCC and higher p-Akt expression. J. Med. Invest. 70 : 160-165, February, 2023.


Short- and long-term outcomes of pancreatectomy in patients with hemodialysis.

Several reports have shown the high mortality rate of pancreatic resection in patients with hemodialysis (HD), however, its long-term outcome remains unclear. In this study, we examined cases of pancreatic resection in patients with HD and conducted a literature review. Four patients with HD who underwent pancreatic resection from 2004 to 2019 were enrolled. To compare the clinicopathological variables of HD and non-HD patients, 161 non-HD patients who had undergone surgical resection for pancreatic cancer were enrolled. Among four cases of pancreatic resection with HD, three cases were malignant diseases. All patients with HD had some co-morbidities (100% in HD group, 45.3% in the non-HD group) and postoperative complications (100% in the HD group, vs 46.6% in the non-HD group). Although one patient had severe postoperative complications and length of postoperative hospital stay was longer, the 30- and 90-day mortality rates were both 0% in patients with HD. However, three cases in the HD group (75%) died approximately 6 months after surgery, including one cancer-related death. Pancreatic surgery in patients with HD should be carefully indicated, especially pancreaticoduodenectomy or total pancreatectomy, because of the poor prognosis induced by non-cancer-related causes of death. J. Med. Invest. 70 : 105-109, February, 2023.


【胆膵疾患と最新テクノロジーの融合】胆膵疾患における最新の術前術中手術支援システム

胆膵手術における術前シミュレーションは,腫瘍進展範囲あるいは主要脈管解剖をいかに正確にイメージできるかが,ポイントとなる．空間認識力という意味で,extended realityは有用である．また,術中ナビゲーションに関しては,ICG蛍光法がゴールドスタンダードとなるが,人工知能を駆使した最新の知見,ならびに自験例も踏まえて,本稿で紹介する．(著者抄録)


Impact of L-type amino acid transporter 3 on the prognosis of hepatocellular carcinoma.

The aim of the present study was to investigate the impact of L-type amino acid transporter 3 (LAT3) expression on the prognosis of hepatocellular carcinoma (HCC). A total of 135 patients who had undergone initial hepatic resection for HCC at Tokushima University Hospital (Tokushima, Japan) were enrolled in the present study. Immunohistochemical analysis of LAT3 and phosphorylated AKT (p-AKT) was performed using resected specimens. Clinicopathological factors, including prognosis, were compared between the LAT3-high and -low expression groups. The results demonstrated that the LAT3-high group showed significantly higher protein induced by vitamin K absence-II levels (P=0.01) compared with the LAT3-low group. The LAT3-high group showed significantly worse prognosis compared with the LAT3-low group regarding cancer-specific survival and disease-free survival (P<0.05). Multivariate analysis revealed that high LAT3 expression and multiple tumors were independent prognostic factors for cancer-specific survival. Furthermore, the rate of p-AKT-positive cases was higher in the LAT3-high group than in the LAT3-low group. Overall, these findings suggested that LAT3 expression was associated with poor prognosis of HCC and high p-AKT expression.


Inhibition of the VEGF signaling pathway attenuates tumor-associated macrophage activity in liver cancer.

Tumor-associated macrophage (TAMs) are paramount for tumor progression and immune tolerance in the tumor microenvironment of various types of cancer, including liver cancer. The aim of the present study was to investigate the effect of vascular endothelial growth factor (VEGF) inhibition on TAM polarization and function during their interactions with macrophages and liver cancer cells. TAMs were induced by culturing M0 macrophages with cancer cell-conditioned medium. TAMs cultured with cancer cell-conditioned medium and vascular endothelial growth factor (VEGF) inhibitor were defined as modified TAMs, and the expression levels of TAM-associated markers and VEGF receptor 2 were evaluated using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The effects of TAMs and modified TAMs on cancer cell proliferation and migration were investigated using conditioned medium. Programmed death-ligand 1 (PD-L1) mRNA expression in modified TAMs and cancer cells cultured in modified TAM-conditioned medium (TAM-CM) for 48 h was examined using RT-qPCR. In order to investigate signaling pathways in macrophages, western blot analysis was performed. CD163 and CD206 and M2 macrophage marker expression was upregulated in TAMs and modified TAMs. Modified TAM-CM exhibited a decreased ability to promote cancer cell proliferation and migration in comparison with the use of TAM-CM. The VEGF concentration was significantly higher in the TAMs than in M0 macrophages; however, the modified TAMs displayed a significantly lower VEGF secretion than TAMs. PD-L1 expression was decreased in modified TAMs as compared with TAMs. Western blot analysis revealed that the Akt/mTOR signaling pathway was significantly suppressed in the modified TAMs compared with TAMs. It was observed that TAMs cultured in a VEGF-depleted environment displayed lower secretion levels of cytokines involved in tumor progression and a decreased immune tolerance-inducing ability. On the whole, the results of the present study suggested that VEGF inhibition in TAMs may be a potential therapeutic target for liver cancer.


Role of Central Hypo-enhancement in the Hepatic Arterial Phase of Dynamic Computed Tomography in Patients with Mass-Forming Intrahepatic Cholangiocarcinoma.

The enhancement pattern in the hepatic arterial phase (HAP) of dynamic computed tomography (CT) is reportedly a prognostic marker in patients with intrahepatic cholangiocarcinoma (IHCC). This study was performed to clarify the significance of central hypo-enhancement in the HAP in patients with mass-forming IHCC. Forty patients who had undergone initial surgical resection for mass-forming IHCC were enrolled. The dynamic CT was scanned 40 s after contrast agent injection as the HAP. A radiologist classified the patients into three groups based on the vascular pattern: the hyper-enhancement group (Hyper group), rim-enhancement group (Rim group), and hypo-enhancement group (Hypo group). The surgical specimens were immunohistochemically stained for hypoxia-inducible factor 1 (HIF-1). The correlation with clinicopathological findings and HIF-1 expression was investigated. The Hyper, Rim, and Hypo groups comprised 8, 7, and 25 patients, respectively. There were no significant correlations between the groups and clinicopathological factors. Overall survival (OS) was significantly worse in the Hypo than in the Hyper group (p = 0.03). OS was also significantly worse in the Rim +ypo group (i.e., hypo-enhancement in the central tumor) than in the Hyper group (p = 0.04). Furthermore, inclusion in the Rim +ypo group was a prognostic factor for OS (hazard ratio 6.68). High HIF-1 expression in the central part of the tumor was correlated with central hypo-enhancement (Hyper group: 25% and Rim +ypo group: 72%). Central hypo-enhancement was a prognostic factor in patients with IHCC. The high malignant potential of tumors with central hypo-enhancement might be associated with HIF-1 upregulation.


A new formula to calculate the resection limit in hepatectomy based on Gd-EOB-DTPA-enhanced magnetic resonance imaging.

Dynamic magnetic resonance imaging with gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (EOB-MRI) can be used not only to detect liver tumors but also to estimate liver function. The aim of this study was to establish a new EOB-MRI-based formula to determine the resection limit in patients undergoing hepatectomy. Twenty-eight patients with a normal liver (NL group) and five with an unresectable cirrhotic liver (UL group) who underwent EOB-MRI were included. Standardized liver function (SLF) was calculated based on the signal intensity (SI), the volume of each subsegment (S1-S8), and body surface area. A formula defining the resection limit was devised based on the difference in the SLF values of patients in the NL and UL groups. The formula was validated in 50 patients who underwent EOB-MRI and hepatectomy. The average SLF value in the NL and UL groups was 2038 and 962 FV/m2, respectively. The difference (1076 FV/m2) was consistent with a 70% in resection volume. Thus, the resection limit for hepatectomy was calculated as a proportion of 70%: 70 (SLF-962)/1076 (%). The one patient who underwent hepatectomy over the resection limit died due to liver failure. In other 49 patients, in whom the resection volume was less than the resection limit, procedures were safely performed. Our formula for resection limit based on EOB-MRI can improve the safety of hepatectomy.


Maximum Diameter and Number of Tumors as a New Prognostic Indicator of Colorectal Liver Metastases.

Surgical resection is currently considered the only potentially curative option as a treatment strategy of colorectal liver metastases (CRLM). However, the criteria for selection of resectable CRLM are not clear. The aim of this study was to confirm a new prognostic indicator of CRLM after hepatic resection. One hundred thirty nine patients who underwent initial surgical resection from 1994 to 2015 were investigated retrospectively. Prognostic factors of overall survival including the product of maximum diameter and number of metastases (MDN) were analyzed. Primary tumor differentiation, vessel invasion, lymph node (LN) metastasis, non-optimally resectable metastases, H score, grade of liver metastases, resection with non-curative intent and MDN were found to be prognostic factors of overall survival (OS). In multivariate analyses of clinicopathological features associated with OS, MDN and non-curative intent were independent prognostic factors. Patients with MDN ·30 had shown significantly poorer prognosis than patients with MDN <30 in OS and relapse-free survival (RFS). MDN ·30 is an independent prognostic factor of survival in patients with CRLM and optimal surgical criterion of hepatectomy for CRLM.


Elevated Preoperative Serum CEA Level Is Associated with Poor Prognosis in Patients with Hepatocellular Carcinoma Through the Epithelial-Mesenchymal Transition.

Serum carcinoembryonic antigen (CEA) is used as an indicator of tumor progression in a variety of carcinomas. A subset of patients with hepatocellular carcinoma (HCC) exhibit increased serum CEA level, but the significance of this is unclear. In this study, we investigated the prognosis of patients with HCC with increased serum CEA, and explored the correlations with expression of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) and epithelial-mesenchymal transition (EMT) and tumor angiogenesis. One hundred and twenty-three patients with HCC who underwent radical resection were divided into two groups according to a cut-off value of 5.0 ng/ml for serum CEA: high (n=24) and normal (n=99) groups. We compared the clinicopathological factors with serum CEA levels and its correlations with CEACAM1 expression, EMT-related factors and microvessel density (MVD) of tumor tissues by immunohistochemistry. In the high CEA group, the disease-free survival (DFS) rate was significantly worse than in the normal CEA group. Multivariate analysis revealed that a high CEA level was an independent factor predictive of recurrence. Furthermore, increased serum CEA levels were positively correlated with CEACAM1 expression. Moreover, CEACAM1 expression was positively correlated with expression of EMT-related factors and MVD of tumor tissues. Increased serum CEA level reflected CEACAM1 expression and was an independent factor predictive of recurrence in HCC through EMT and tumor angiogenesis.


Loss of Secreted Frizzled-Related Protein-1 expression is associated with poor prognosis in intrahepatic cholangiocarcinoma.

Secreted Frizzled-Related Protein-1 (SFRP1) is a well-known negative regulator of the wingless type (Wnt)- -catenin pathway and its inactivation plays an important role in the development and progression of many cancers. In this study, we aimed to determine the clinical significance of SFRP1 expression in intrahepatic cholangiocarcinoma (IHCC) and to define the relationship to Wnt- -catenin pathway. Fifty IHCC patients who had liver resection were enrolled in this study. SFRP1 protein expression was examined by immunohistochemistry in tumor tissues. The patients were divided into two groups: SFRP1 positive (n = 30) and negative (n = 20). Clinicopathological characteristics were analyzed. SFRP1 significantly correlated with curability (Cur A, B vs. C, p = 0.029); and recurrent pattern (intrahepatic vs. extrahepatic, p = 0.010). The negative SFRP1 group had significantly poorer prognosis, and 5-year survival rates were 8.1% of the negative SFRP1 group and 44.6% of the positive SFRP1 group, respectively. Moreover, the disease-free survival rate in the negative SFRP1 group was significantly poorer (p < 0.001). Multivariate analysis revealed that loss of SFRP1served as an independent prognostic factor in IHCC for both overall (HR, 2.923; 95% CI, 1.30-6.56; p = 0.009) and disease-free (HR, 2.631; 95% CI, 1.31-5.27; p = 0.006) survival. In addition, SFRP1 expression negatively correlated to -catenin expression (p = 0.005). Those results suggested that the loss of SFRP1 could be a poor prognostic factor for IHCC, through the Wnt- -catenin pathway.

EJSO - European Journal of Surgical Oncology