葛谷 貞二

The new Kyoto guidelines for the management of intraductal papillary mucinous neoplasm (IPMN) provide evidence-based recommendations for the diagnosis and treatment of IPMN. Endoscopic ultrasonography (EUS) is a diagnostic modality with a high spatial resolution that allows detailed observation and obtaining cyst fluid or tissue samples via EUS-guided fine needle aspiration (EUS-FNA). Currently, EUS is an indispensable examination method for the diagnosis of pancreatic diseases. On the other hand, there have been concerns that EUS imaging tends to be highly operator-dependent, and may lack objectivity. Previous guidelines have assigned EUS as an option for patients with worrisome features. However, recent reports indicate that the sensitivity of EUS for the diagnosis of mural nodules (MNs) is more than 90%, comparable or superior to that of contrast-enhanced computed tomography or magnetic resonance cholangiopancreatography. The specific advantages of EUS in the diagnosis of IPMN are: (1) high spatial resolution imaging for the diagnosis of MNs, (2) contrast-enhanced EUS for differentiation of intra-cystic MNs from mucous clots, and (3) pathological diagnosis using EUS-FNA and differential diagnosis of a pancreatic cystic tumor by cystic fluid analysis. In order to utilize EUS in the diagnosis of IPMN, endoscopists are required to have the skills to provide sufficiently objective imaging findings.

AIM: To investigate the characteristics and prognosis of patients with advanced hepatocellular carcinoma (HCC) treated with atezolizumab and bevacizumab (Atz/Bev) who achieved a complete response (CR) according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST). METHODS: A total of 120 patients with Eastern Cooperative Oncology Group performance status (PS) 0 or 1 and Child-Pugh A at the start of Atz/Bev treatment were included. Barcelona Clinic Liver Cancer stage C was recorded in 59 patients. RESULTS: The CR rate with Atz/Bev alone was 15.0%. The median time to CR was 3.4 months, and the median duration of CR was 15.6 months. A significant factor associated with achieving CR with Atz/Bev alone was an AFP ratio of 0.34 or less at 3 weeks. Adding transarterial chemoembolization (TACE) in the six patients who achieved a partial response increased the overall CR rate to 20%. Among the 24 patients who achieved CR, the median progression-free survival was 19.3 months, the median overall survival was not reached, and 14 patients (58.3%) were able to discontinue Atz/Bev and achieve a drug-free status. Twelve of these patients developed progressive disease (PD), but eleven successfully received post-PD treatments and responded well. CONCLUSIONS: Achieving CR by mRECIST using Atz/Bev alone or with additional TACE can be expected to offer an extremely favorable prognosis.

Introduction. Hepatocellular carcinoma (HCC) is one of the deadliest cancers worldwide.Gap statement. Monitoring of HCC and predicting its immunotherapy responses are challenging.Aim. This study explored the potential of the gut microbiome for HCC monitoring and predicting HCC immunotherapy responses.Methods. DNA samples were collected from the faeces of 22 patients with HCC treated with atezolizumab/bevacizumab (Atz/Bev) and 85 healthy controls. The gut microbiome was analysed using 16S rRNA next-generation sequencing and quantitative PCR (qPCR).Results. The microbiomes of patients with HCC demonstrated significant enrichment of Lactobacillus, particularly Lactobacillus fermentum, and Streptococcus, notably Streptococcus anginosus. Comparative analysis between Atz/Bev responders (R) and non-responders (NR) revealed a higher abundance of Bacteroides stercoris in the NR group and Bacteroides coprocola in the R group. Using qPCR analysis, we observed elevated levels of S. anginosus and reduced levels of 5α-reductase genes, essential for the synthesis of isoallolithocholic acid, in HCC patients compared to controls. Additionally, the analysis confirmed a significantly lower abundance of B. stercoris in the Atz/Bev R group relative to the NR group.Conclusions. The gut microbiome analysis and specific gene quantification via qPCR could provide a rapid, less invasive, and cost-effective approach for assessing the increased risk of HCC, monitoring patient status, and predicting immunotherapy responses.

Less than half of all patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) respond to chemotherapy, and the prognosis of PDAC is poor, which may be mediated by the gut microbiota. We investigated the clinical improvement effects of 1-kestose, a fructooligosaccharide, on PDAC chemotherapy in this single-center, randomized, controlled pilot trial conducted at Fujita Health University Hospital, which enrolled patients with PDAC. The trial included 1-kestose administration and non-administration groups. The 1-kestose group received 9 g of 1-kestose daily for 12 weeks, and their blood markers, imaging studies, physical findings, and gut microbiota were evaluated. In the 1-kestose administration group, the cancer marker CA19-9 significantly decreased, and there was a reduction in the neutrophil-to-lymphocyte ratio (NLR). There was also suppression of the reduction of albumin levels and of an increase in C-reactive protein. Additionally, Escherichia coli, which typically increases in PDAC, significantly decreased in the 1-kestose group. Thus, 1-kestose altered the gut microbiota and improved the prognostic factors for PDAC. Large-scale, long-term trials of 1-kestose interventions for PDAC are thus warranted to improve the prognosis of PDAC.

The relationship between antitumor response and tumor marker changes was evaluated in patients with advanced hepatocellular carcinoma treated with durvalumab plus tremelimumab (Dur/Tre). Forty patients were enrolled in this retrospective evaluation of treatment outcomes. According to the Response Evaluation Criteria for Solid Tumors version 1.1 at 8 weeks, the objective response (OR) rate was 25% and the disease control (DC) rate was 57.5%. The median alpha-fetoprotein (AFP) ratio at 4 weeks was 0.39 in patients who achieved OR at 8 weeks (8W-OR group), significantly lower than the 1.08 in the non-8W-OR group (p = 0.0068); however, it was 1.22 in patients who did not achieve DC at 8 weeks (non-8W-DC group), significantly higher than the 0.53 in the 8W-DC group (p = 0.0006). Similarly, the median des-γ-carboxy-prothrombin (DCP) ratio at 4 weeks was 0.15 in the 8W-OR group, significantly lower than the 1.46 in the non-8W-OR group (p < 0.0001); however, it was 1.23 in the non-8W-DC group, significantly higher than the 0.49 in the 8W-DC group (p = 0.0215). Early changes in tumor markers after Dur/Tre initiation were associated with antitumor response. In particular, changes in AFP and DCP at 4 weeks may offer useful biomarkers for early prediction of both response and progressive disease following Dur/Tre.

This study aimed to complement the results of the REACH-2 study by prospectively evaluating the safety and efficacy of ramucirumab in advanced hepatocellular carcinoma (HCC) in a real-world setting. This was an open-label, nonrandomized, multicenter, prospective study conducted at 13 institutions in Japan (jRCTs031190236). The study included Child-Pugh Class A patients with advanced HCC who had received pretreatment with atezolizumab plus bevacizumab (Atez/Bev) or lenvatinib. Ramucirumab was introduced as a second-line treatment after Atez/Bev or lenvatinib and as a third-line treatment after Atez/Bev and lenvatinib. Between May 2020 and July 2022, we enrolled 19 patients, including 17 who received ramucirumab. Additionally, seven patients received lenvatinib, another seven patients received Atez/Bev, and three patients received Atez/Bev followed by lenvatinib as prior treatment. The primary endpoint was a 6-month progression-free survival (PFS) rate, which was 14.3%. The median PFS and overall survival were 3.7 and 12.0 months, respectively. The most common grade ≥ 3 adverse events (AEs) were hypertension (23.5%), proteinuria (17.6%), and neutropenia (11.8%). The discontinuation rate due to AEs was 29.4%. Six patients progressed from Child-Pugh A to B after treatment with ramucirumab. Thirteen patients were eligible for post-ramucirumab treatment, including systemic therapy. Despite the limited number of patients, the efficacy of ramucirumab was comparable to that observed in the REACH-2 study when used after lenvatinib and Atez/Bev. However, the incidence of AEs was higher than that in the REACH-2 study.

はじめに:進行肝細胞癌患者に対してアテゾリズマブ+ベバシズマブ治療を行う際に,尿蛋白定性検査と尿蛋白/クレアチニン比(UPCR)を同時に測定すると結果が解離する症例にしばしば遭遇する。本研究では,アテゾリズマブ+ベバシズマブ治療中の進行肝細胞癌患者における尿蛋白定性検査とUPCRとの関係を調べ,UPCRを尿蛋白のモニタリング時に追加することで,ベバシズマブの不必要な休薬を防ぐことができるかどうかを評価した。対象と方法:2020年10月1日～2021年8月31日までに当院でアテゾリズマブ+ベバシズマブ治療を受けた進行肝細胞癌の61例から採取した延べ298尿検体を対象とした。本研究ではUPCRを1日尿蛋白排泄量と同等として評価し,ベバシズマブの休薬基準をUPCR2.0以上とした。結果:UPCR2.0を超えた検体は尿蛋白定性2+で1/41(2.4%),3+で24/44(54.5%)であった。仮に尿蛋白定性2+で休薬と判断した場合,40/41検体(97.6%)もの場合でベバシズマブの投与を継続することができ,尿蛋白定性3+で休薬を判断した場合でも20/44検体(45.5%)とほぼ半数近くの場合でベバシズマブの投与を継続することができると考えられた。結論:実臨床において,進行肝細胞癌患者に対するアテゾリズマブ+ベバシズマブ治療を行う際に,尿蛋白定性検査にUPCRを追加することはベバシズマブの不必要な休薬を防ぐことができ,尿蛋白定性検査のみを使用する場合に比べて,より多くの臨床的ベネフィットを得ることにつながる可能性があると考えられた。(著者抄録)

はじめに:進行肝細胞癌患者に対してアテゾリズマブ+ベバシズマブ治療を行う際に,尿蛋白定性検査と尿蛋白/クレアチニン比(UPCR)を同時に測定すると結果が解離する症例にしばしば遭遇する。本研究では,アテゾリズマブ+ベバシズマブ治療中の進行肝細胞癌患者における尿蛋白定性検査とUPCRとの関係を調べ,UPCRを尿蛋白のモニタリング時に追加することで,ベバシズマブの不必要な休薬を防ぐことができるかどうかを評価した。対象と方法:2020年10月1日～2021年8月31日までに当院でアテゾリズマブ+ベバシズマブ治療を受けた進行肝細胞癌の61例から採取した延べ298尿検体を対象とした。本研究ではUPCRを1日尿蛋白排泄量と同等として評価し,ベバシズマブの休薬基準をUPCR2.0以上とした。結果:UPCR2.0を超えた検体は尿蛋白定性2+で1/41(2.4%),3+で24/44(54.5%)であった。仮に尿蛋白定性2+で休薬と判断した場合,40/41検体(97.6%)もの場合でベバシズマブの投与を継続することができ,尿蛋白定性3+で休薬を判断した場合でも20/44検体(45.5%)とほぼ半数近くの場合でベバシズマブの投与を継続することができると考えられた。結論:実臨床において,進行肝細胞癌患者に対するアテゾリズマブ+ベバシズマブ治療を行う際に,尿蛋白定性検査にUPCRを追加することはベバシズマブの不必要な休薬を防ぐことができ,尿蛋白定性検査のみを使用する場合に比べて,より多くの臨床的ベネフィットを得ることにつながる可能性があると考えられた。(著者抄録)

＜文献概要＞HIMALAYA試験(第III相臨床試験)のpositiveな結果に基づき,デュルバルマブ(抗PD-L1抗体)とトレメリムマブ(抗CTLA-4抗体)の併用療法(STRIDEレジメン)は,アテゾリズマブ+ベバシズマブと共に,切除不能肝細胞癌に対する薬物療法の第一選択薬となった.STRIDE群の3年生存率は30.7%と高く,奏効例の奏効期間は22.3ヵ月と長かった.一方,imAE発現率は35.8%,高用量ステロイドが必要な頻度は20.1%であり,imAEに対する早期発見やマネジメントが重要である.VEGF阻害作用をもたないデュルバルマブ+トレメリムマブの登場により進行HCCのさらなる予後延長が期待される.

Endoscopic ultrasonography (EUS) provides high spatial resolution and more detailed images than other diagnostic modalities. Furthermore, EUS-guided tissue acquisition (EUS-TA), such as EUS-guided fine needle aspiration or biopsy (EUS-FNA/FNB), is an indispensable tool in pancreaticobiliary disease diagnostics, supporting a conclusive pathological diagnosis. In this review, we evaluate the current status and the usefulness of EUS-TA for the diagnostics of the following biliary tract diseases: (A) biliary stricture diagnostics, (B) biliary tract cancer (BTC) itself, and (C) staging of advanced BTC. Previous reports have shown that EUS-FNA for biliary lesions is a safe procedure that is useful in differentiating biliary cancer from benign lesions and in the staging of BTC. On the other hand, the diagnostic performance of EUS-TA for bile duct lesions is reported to be similar to that of transpapillary biopsy. Overall, EUS-TA for biliary lesions may be a safe and effective method, but it should be performed with an understanding of the risk of serious adverse events such as bile leakage and peritoneal dissemination of cancer. It is recommended for distal biliary stricture lesions for which endoscopic retrograde cholangiopancreatography cannot confirm the diagnosis or gallbladder lesions if they do not require the needle to pass through the biliary lumen.

Endoscopic ultrasonography (EUS) provides high spatial and contrast resolution and is a useful tool for evaluating the pancreato-biliary regions. Recently, contrast-enhanced harmonic EUS (CH-EUS) has been used to evaluate lesion vascularity, especially for the diagnosis of pancreatic tumors. CH-EUS adds two major advantages when diagnosing pancreatic cystic lesions (PCL). First, it can differentiate between mural nodules and mucous clots, thereby improving the accurate classification of PCL. Second, it helps with evaluation of the malignant potential of PCL, especially of intraductal papillary mucinous neoplasms by revealing the vascularity in the mural nodules and solid components. This review discusses the use and limitations of CH-EUS for the diagnosis of PCL.

BACKGROUND/AIM: The combination of atezolizumab plus bevacizumab (Atz/Bev) has become widely used as a first-line therapy for advanced hepatocellular carcinoma (HCC). However, for post-Atz/Bev therapy, evidence on the outcomes of molecular targeted agents, such as lenvatinib, is limited. The present study aimed to assess the clinical effectiveness of lenvatinib on advanced HCC in patients who had previously undergone Atz/Bev treatment. PATIENTS AND METHODS: Twenty patients with HCC, who received lenvatinib after Atz/Bev treatment, were enrolled in the study. In particular, we examined the impact of adverse events (AEs), such as anorexia and general fatigue. During the treatment, lenvatinib dosages were adjusted or temporarily discontinued in response to AEs. Treatment outcomes were retrospectively evaluated. RESULTS: The objective response rate (ORR) and disease control rate (DCR) for lenvatinib treatment were 25.0% and 95.0%, respectively, according to the Response Evaluation Criteria in Solid Tumors. The median progression-free survival (PFS) was 6.0 months, and the median overall survival (OS) was 10.5 months. Eleven patients experienced anorexia or fatigue, leading to a reduction in the dose of lenvatinib but not to a significant difference in the time to drug discontinuation. Importantly, there were no significant differences between the 11 anorexia/fatigue-suffering patients and the nine other patients with regard to PFS and OS. CONCLUSION: Lenvatinib can be efficacious and safe for treating advanced HCC patients previously treated with Atz/Bev, and AEs such as anorexia and general fatigue can be effectively managed without losing lenvatinib's therapeutic benefits.

ラムシルマブ(RAM)は,日本では2019年6月に,「がん化学療法後に増悪した血清alpha-fetoprotein(AFP)値が400ng/mL以上の切除不能な肝細胞癌(HCC)」を適応として承認され,2021年改訂の肝癌診療ガイドラインでは,ソラフェニブでの治療後に画像進行または副作用のため中止し,Child-Pugh分類A,血清AFP値が400ng/mL以上の患者に対する二次以降の薬物療法として推奨されている。本稿では,日本の実臨床下での切除不能進行HCC患者に対するRAM治療の有効性・安全性を確認する目的で,RAMがHCCの適応を取得した2019年以降に公表された原著論文から,日本の実臨床下でのRAMのエビデンスを要約した。併せて,切除不能進行HCC患者で,ソラフェニブ治療後の二次薬物療法としてRAMが投与された国際共同第3相の2試験(REACH試験とREACH-2試験)の併合解析,ならびにソラフェニブ以外の全身療法後にRAMを投与したREACH-2試験拡大コホートの結果を紹介する。(著者抄録)

Background:Transarterial chemoembolization (TACE) is the standard treatment for unresectable intermediate-stage hepatocellular carcinoma (HCC), but recurrence after TACE is common. The present phase II, prospective, multicenter, single-arm trial, the TACTICS-L trial, investigated the efficacy and safety of TACE plus lenvatinib (LEN), a drug that more strongly promotes vascular normalization and has a better ORR than sorafenib (jRCTs031180074). Patients and Methods:Participants were patients with HCC who had not previously received systemic therapy, hepatic arterial infusion chemotherapy, or immunotherapy, and who were ineligible for resection or percutaneous ablation therapy. LEN was to be administered 14-21 days before the first TACE, stopped 2 days before TACE, and resumed 3 days after TACE. Key inclusion criteria were unresectable HCC, Child-Pugh A liver function, 0-2 prior TACE sessions, tumor size <= 10 cm, number of tumors <= 10, and ECOG performance status 0-1. Key exclusion criteria were vascular invasion and extrahepatic spread. The primary endpoint was PFS by RECICL, and secondary endpoints were time to untreatable progression, objective response rate (ORR), OS, and safety. Results:A total of 62 HCC patients were enrolled in this trial. The median age was 72 years, 77.4% of patients were men, and 95.2% had PS 0. The primary endpoint of median PFS was 28.0 months (95% CI 25.1-31.0) after a minimum 24 months of follow-up. The secondary endpoint of median OS was not reached (95% CI 35.5 months-NR). LEN-TACE achieved a high response rate and high CR rate (4 weeks after the first TACE: ORR 79.0%, CR rate 53.2%; best response: ORR 88.7%, CR rate 67.7%) by RECICL. Exploratory subgroup analyses showed that the characteristics of responders/nonresponders (ORR and CR) were similar, and that LEN-TACE would be effective in all subgroups, including the population in whom TACE alone would be less likely to be curative (e.g., patients with the nonsimple nodular type or a high tumor burden). The relative dose intensity of LEN before the first TACE was important for achieving higher CR/ORR by LEN-TACE. No new safety concerns were observed. Conclusion:The results of this trial provide encouraging evidence supporting the efficacy and favorable safety profile of LEN-TACE in patients who are ineligible for locoregional therapy.

(1) Background: This study aimed to investigate clinical outcomes for cabozantinib in clinical practice in patients with advanced hepatocellular carcinoma (HCC) previously treated with atezolizumab plus bevacizumab (Atz/Bev), with a focus on whether patients met criteria of Child-Pugh Class A and Eastern Cooperative Oncology Group performance status (ECOG-PS) score 0/1 at baseline. (2) Methods: Eleven patients (57.9%) met the criteria of both Child-Pugh class A and ECOG-PS score 0/1 (CP-A+PS-0/1 group) and eight patients (42.1%) did not (Non-CP-A+PS-0/1 group); efficacy and safety were retrospectively evaluated. (3) Results: Disease control rate was significantly higher in the CP-A+PS-0/1 group (81.1%) than in the non-CP-A+PS-0/1 group (12.5%). Median progression-free survival, overall survival and duration of cabozantinib treatment were significantly longer in the CP-A+PS-0/1 group (3.9 months, 13.4 months, and 8.3 months, respectively) than in the Non-CP-A+PS-0/1 group (1.2 months, 1.7 months, and 0.8 months, respectively). Median daily dose of cabozantinib was significantly higher in the CP-A+PS-0/1 group (22.9 mg/day) than in the non-CP-A+PS-0/1 group (16.9 mg/day). (4) Conclusions: Cabozantinib in patients previously treated with Atz/Bev has potential therapeutic efficacy and safety if patients have good liver function (Child-Pugh A) and are in good general condition (ECOG-PS 0/1).

BACKGROUND: Proteinuria is a common adverse event in systemic therapy for hepatocellular carcinoma (HCC). However, whether the presence of pretreatment proteinuria affects the clinical course is still unclear. METHOD: From 2011 to 2022, 321 patients with unresectable HCC who were treated with systemic therapy as first-line treatment were enrolled in this study. We retrospectively analyzed the presence of pretreatment proteinuria and the treatment course of systemic therapy. RESULTS: In the cohort, 190 patients were tested for proteinuria qualitatively within 3 months before systemic therapy; 75 were treated with sorafenib, 72 were treated with lenvatinib, and 43 were treated with atezolizumab plus bevacizumab. Overall survival tended to be longer for patients treated with lenvatinib and significantly longer with atezolizumab plus bevacizumab in patients without pretreatment proteinuria but not for those treated with sorafenib. Further analysis was performed in 111 patients treated with lenvatinib or atezolizumab plus bevacizumab who had proteinuria measured quantitatively. Multivariate analysis including proteinuria, liver function, and HCC stage revealed that the severity of proteinuria was an independent predictor of prognosis. CONCLUSION: Pretreatment proteinuria predicts a poorer prognosis in patients with unresectable HCC treated with lenvatinib or atezolizumab plus bevacizumab but not in those treated with sorafenib.

Inflammatory myofibroblastic tumor (IMT) is a rare tumor composed of myofibroblasts with inflammatory blood cell infiltration. It commonly occurs in the lungs and rarely in the esophagus. We herein report a valuable case of IMT originating in the esophagus. A 60-year-old Japanese woman with dysphagia had a large subepithelial lesion (SEL) in the cervical esophagus, which was 15 cm in length. Surgical resection was performed to confirm the pathological diagnosis and improve the symptoms. The postoperative diagnosis was IMT composed of multiple nodules. There was no recurrence or metastasis within one year after surgery.

The combination therapy of atezolizumab, an anti-programmed cell death ligand-1 antibody, plus bevacizumab (Atz/Bev) is widely used to treat patients with advanced hepatocellular carcinoma (HCC). The development of polymyalgia rheumatica (PMR) during immune checkpoint inhibitor therapy for patients with HCC has not been reported to date. Two patients who developed PMR during Atz/Bev therapy for advanced HCC are reported. Both patients developed fever, bilateral symmetrical shoulder pain, morning stiffness, and an elevated C-reactive protein level. Their symptoms improved rapidly with prednisolone (PSL) 15-20 mg/d, and their C-reactive protein levels decreased. In PMR, long-term low-dose PSL should be administered. In the present patients who developed PMR as immune-related adverse events, starting with a small dose of PSL resulted in rapid improvement of symptoms.

The diagnosis of bile duct tumors can be difficult at times. A transpapillary bile duct biopsy findings with endoscopic retrograde cholangiopancreatography sometimes contradict diagnostic imaging findings. In bile duct tumors, inflammatory polyps in the extrahepatic bile duct are relatively rare with extrahepatic cholangitis. The disease's clinical relevance, including its natural history and prognosis, is not always clear. We show here a rare case of an inflammatory polyp in the common bile duct. A 69-year-old woman with abdominal pain was diagnosed with cholangitis. The findings of contrast-enhanced computed tomography and magnetic resonance cholangiopancreatography suggested that she had extrahepatic cholangiocarcinoma. The examination and therapy of cholangitis were performed by endoscopic retrograde cholangiopancreatography. The cholangiography revealed a suspected tumor in the hilar bile duct with some common bile duct stones. Then, after endoscopic sphincterotomy to remove tiny common bile duct stones, further detailed examinations were performed at the same time using an oral cholangioscope revealed a papillary raised lesion with a somewhat white surface in the bile duct; a biopsy was conducted on the same spot, and epithelial cells with mild atypia appeared in the shape of a papilla. Since the malignant tumor or the intraductal papillary neoplasm of the bile duct could not be ruled out, extrahepatic bile duct resection was conducted with the patient's informed consent. Bile duct inflammatory polyp was the histopathological diagnosis.

Pancreatic ductal adenocarcinoma (PDAC) can be treated with surgery, chemotherapy, and radiotherapy. Despite medical progress in each field in recent years, it is still insufficient for managing PDAC, and at present, the only curative treatment is surgery. A typical pancreatic cancer is relatively easy to diagnose with imaging. However, it is often not recommended for surgical treatment at the time of diagnosis due to metastatic spread beyond the pancreas. Even if it is operable, it often recurs during postoperative follow-up. In the case of PDAC with a diameter of 10 mm or less, the 5-year survival rate is as good as 80% or more, and the best index for curative treatment is tumor size. The early detection of pancreatic cancer with a diameter of less than 10 mm or carcinoma in situ is critical. Here, we provide an overview of the current status of diagnostic imaging features and genetic tests for the accurate diagnosis of early-stage PDAC.

Patients with nonalcoholic fatty liver disease (NAFLD) have illness uncertainty. The purpose of this longitudinal study was to investigate the effect of the degree of illness uncertainty in patients with NAFLD on liver function values. We conducted a questionnaire survey and collected blood samples from outpatients with NAFLD. The items in the questionnaire were measured for illness uncertainty using the Japanese version of the Mishel Uncertainty in Illness Scale-Community (MUIS-C). Blood samples were collected at baseline and after 1 year. We divided the patients into two groups: one with high illness uncertainty and the other with low illness uncertainty. We then compared changes in alanine transaminase (ALT) and aspartate aminotransferase (AST) levels over time from baseline using multiple regression analysis. This study analyzed 148 patients with NAFLD; 75 were male and 73 were female, with a mean age of 58.4 +/- 12.3 years. The group with higher illness uncertainty had significantly higher ALT and AST levels at 1 year (b = .185 and .183, respectively) than the group with lower illness uncertainty. High illness uncertainty in patients with NAFLD can lead to higher ALT and AST levels. Healthcare providers must focus on reducing illness uncertainty in patients with NAFLD.

BACKGROUND: Systemic treatments are recommended for advanced hepatocellular carcinoma (HCC) in preserved liver function. However, their effects are unsatisfactory in some tumor conditions, particularly macrovascular invasion (MVI) including major portal vein tumor thrombus (PVTT). We compared the efficacy of hepatic arterial infusion chemotherapy (HAIC) regimens New-FP and sorafenib for various tumor conditions in preserved liver function. METHODS: We retrospectively collected the data of 1709 patients with HCC who were treated with New-FP or sorafenib. Survival was assessed after propensity score matching. Subgroup analyses were conducted: cohort 1 (no MVI or extrahepatic spread (EHS)), cohort 2 (MVI only), cohort 3 (EHS only), cohort 4 (MVI and EHS), and cohort 5 (major PVTT). RESULTS: The New-FP group had a longer median survival time (MST) than the sorafenib in the whole analysis (18 vs. 9 months; p &lt; 0.0001). New-FP demonstrated a longer MST compared with sorafenib in cohort 2 and cohort 4. In cohort 5, the MST of the New-FP group was 16 months, while that of sorafenib was 6 months (p &lt; 0.0001). For major PVTT-HCC, the response rate of New-FP was 73.0%. The MST of patients who achieved complete response with New-FP was 59 months. CONCLUSIONS: HAIC using New-FP is promising for patients with MVI- and major PVTT-HCC in preserved liver function.

Introduction: Several clinical trials comparing the efficacy and safety of transarterial chemoembolization (TACE) plus molecular-targeted agents versus TACE alone revealed no clinical benefits in progression-free survival (PFS) or overall survival (OS). Here, we report the final OS analysis from the TACTICS trial, which previously demonstrated significant improvement in PFS with TACE plus sorafenib in patients with unresectable hepatocellular carcinoma (HCC) (NCT01217034). Methods: Patients with unresectable HCC were randomized to a TACE plus sorafenib group (N = 80) or a TACE alone group (N = 76). Patients in the combination treatment group received sorafenib 400 mg once daily for 2-3 weeks before TACE, followed by 800 mg once daily during on-demand conventional TACE sessions until time to untreatable progression. In this trial, TACE-specific PFS was used. TACE-specific PFS is defined as the time from randomization to progressive disease (PD) or death from any cause, and PD was defined as untreatable progression, caused by the inability of a patient to further receive or benefit from TACE for reasons that include intrahepatic tumor progression (25% increase vs. baseline) according to response evaluation criteria in cancer of the liver, the detection of extrahepatic spread, vascular invasion, or transient deterioration of liver function to Child-Pugh C after TACE. Results: At the cut-off date of July 31, 2020, 131 OS events were observed. The median OS was 36.2 months with TACE plus sorafenib and 30.8 months with TACE alone (hazard ratio [HR] = 0.861; 95% confidence interval [CI], 0.607-1.223; p = 0.40, ΔOS, 5.4 months). The updated PFS was 22.8 months with TACE plus sorafenib and 13.5 months with TACE alone (HR = 0.661; 95% CI, 0.466-0.938; p = 0.02). Post-trial treatments with active procedures/agents were received by 47 (58.8%) patients in the TACE plus sorafenib group and 58 (76.3%) in the TACE alone group (p = 0.01). In post hoc analysis, PFS and OS benefit were shown in HCC patients with tumor burden beyond up-to-7 criteria. Conclusions: In TACTICS trial, TACE plus sorafenib did not show significant OS benefit over TACE alone; however, clinical meaningful OS prolongation and significantly improved PFS was observed. Thus, the TACE plus sorafenib can be considered a choice of treatment in intermediate-stage HCC, especially in patients with high tumor burden. Trial Registration: NCT01217034.

Small intestinal tumors (adenoma and adenocarcinoma, SIT) are rare, and their microRNA (miRNA) expression profiles have not been established. Previously, we reported a relationship between miRNA expression profiles and the development, growth, morphology, and anticancer drug resistance of colorectal tumors. Here, we demonstrate that the miRNA expression profile of SIT is significantly different from those of tumors of the colon. We compared the onco-related miRNA expression profiles of SIT and colorectal tumors and found them to be different from each other. The expressions of miR-143 and miR-145 were frequently downregulated in SIT and colorectal tumors but not in sessile serrated adenoma/polyp tumors. The profiles of SIT and colorectal carcinomas of miR-7, miR-21, and miR-34a were considerably different. Upregulation of miR-31 expression was not found in any SIT cases. Our data suggested that miR-143 and miR-145 might act as anti-oncomirs common to adenocarcinoma of the small intestine, similar to those of colorectal adenoma and other cancers. However, the expression profiles of the other miRNAs of SIT were significantly different from those of colorectal tumors. These findings contribute useful insights into the tumor development and diagnosis of SIT.

AIM: The present study evaluated the efficacy and safety of ramucirumab (RAM) in clinical practice as post-treatment, following atezolizumab plus bevacizumab (Atz/Bev) for advanced hepatocellular carcinoma (HCC) with alpha-fetoprotein (AFP) levels of ≥400 ng/ml. PATIENTS AND METHODS: Of the 77 patients treated with Atz/Bev at our institution, 13 patients for whom RAM was introduced as post-treatment following Atz/Bev were enrolled in this retrospective study. There were 9 patients (69.2%) with Child-Pugh A and 11 patients (84.6%) for whom RAM was initiated as 3rd- or later-line therapy. The median AFP level was 2259 ng/ml. RESULTS: The objective response rate by Response Evaluation Criteria in Solid Tumours at 6 weeks was 15.4%, and the disease control rate was 69.2%. The median time to progression was 3.0 months; AFP level decreased at 2 weeks in 11 patients (84.6%) and at 6 weeks in seven patients (53.8%). The most common adverse events (AEs) within 6 weeks were ascites, peripheral oedema, and proteinuria, while grade 3 AEs occurred in six patients (46.2%). Albumin-bilirubin scores at both 4 and 6 weeks were significantly worse than those at baseline. CONCLUSION: In HCC patients with AFP levels of ≥400 ng/mL, RAM after Atz/Bev is expected to be an effective treatment option. Careful attention should be paid to the development of AEs and deterioration of liver function, especially when RAM is used as 3rd- or later-line therapy. Additional studies are needed to confirm the efficacy and safety of RAM as 2nd-line treatment after Atz/Bev in Child-Pugh A patients.

AIM: Changes in body composition parameters are important prognostic factors in hepatocellular carcinoma (HCC) treatment. This study aimed to assess the clinical impact of early changes in body composition during lenvatinib (LEN) treatment on its time to treatment failure (TTF) for patients with advanced HCC. METHODS: In this retrospective study, we enrolled 65 patients who were administered LEN as the first-line treatment for unresectable HCC and evaluated the body composition change using computed tomography. We focused on the body composition change after 2 weeks of LEN treatment and assessed its impact on TTF and prognosis. RESULTS: Significant changes in body composition were observed during 14 weeks of LEN treatment. Among these changes, mean-skeletal muscle attenuation (SMA) decreased significantly within 2 weeks (P = 0.004) without symptoms or changes in the other parameters. In multivariate analysis, this early change in mean-SMA after LEN treatment was a significant predictor of time to treatment failure (HR: 2.67, 95%CI: 1.338-5.081, P = 0.005) in patients with HCC. CONCLUSIONS: This study revealed that LEN treatment induces a change in the skeletal muscle asymptomatically for a short period, and evaluation of this change may help to predict the TTF of LEN treatment in patients with HCC. Supplemental data for this article is available online at https://doi.org/10.1080/01635581.2022.2049322 .

There are various types of pancreatic neoplasms, and their prognosis and treatment methods are different. Therefore, accurate diagnosis is important to determine the best treatment strategy. Transabdominal ultrasonography is frequently used as a screening examination for diagnostic imaging of pancreatic neoplasms. In this review, we have focused on the characteristics of ultrasonic findings for relatively rare pancreatic neoplasms.

Pancreatic neuroendocrine neoplasms (PNENs) are relatively rare with a reported incidence of 1-2/100,000 and generally thought to originate from the precursor of the neuroendocrine cells including the islet and the pancreatic duct cells. About 65% of PNENs are non-functional. While insulinomas and gastrinomas are the most common functional PNENs, ACTH-producing PNENs are extremely rare. We herein present an extremely rare case of a patient with Cushing's syndrome caused by PNEN. A 46-year-old woman with edema in bilateral lower extremities and moon face was admitted with a suspicious pancreatic tumor. Enhanced computed tomography and endoscopic ultrasonography revealed a pancreatic tumor. The final diagnosis of ACTH-producing PNEN with Cushing's syndrome was based on clinical and biochemical test results and endocrinological studies. The symptoms associated Cushing's syndrome improved after pancreaticoduodenectomy for PNEN.

The gut microbiota interacts with infectious diseases and affects host immunity. Liver disease is also reportedly associated with changes in the gut microbiota. To elucidate the changes in the gut microbiota before and after hepatitis C virus (HCV) eradication through direct-acting antiviral (DAA) treatment in patients with chronic hepatitis C (CHC), we investigated 42 samples from 14 patients who received DAA therapy for HCV. Fecal samples were obtained before treatment (Pre), when treatment ended (EOT), and 24 weeks after treatment ended (Post24). The target V3-4 region of the 16S rRNA gene from fecal samples was amplified using the Illumina Miseq sequencing platform. The diversity of the gut microbiota did not significantly differ between Pre, EOT, and Post24. Principal coordinates analysis showed that for each patient, the values at Pre, EOT, and Post24 were concentrated within a small area. The linear discriminant analysis of effect size showed that the relative abundances of Faecalibacterium and Bacillus increased at EOT, further increased at Post24, and were significantly increased at Post24 compared to Pre. These suggest that changes in the gut microbiota should be considered as among the various effects observed on living organisms after HCV eradication.

INTRODUCTION: The aim of this study was to investigate the early changes in alpha-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP) levels in patients with advanced hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab and to evaluate the relationship between changes in these tumor markers and treatment efficacy. METHODS: Of 58 consecutive patients who started atezolizumab plus bevacizumab at our institution, 50 patients with information on antitumor response obtained at 6 weeks after therapy were enrolled in this study and their treatment outcomes were retrospectively evaluated. RESULTS: According to the Response Evaluation Criteria in Solid Tumors at 6 weeks, the objective response (OR) rate was 22.0% and the disease control (DC) rate was 78.0%. In patients who achieved OR at 6 weeks, median AFP and DCP ratios at weeks 1, 2, 3, and 6 were significantly lower than those in patients who did not achieve OR. AFP ratios in patients who did not achieve DC at 6 weeks (Non-6W-DC group) were significantly higher than in those who achieved DC at week 6 (6W-DC group). Median overall survival in the Non-6W-DC group was significantly shorter than in the 6W-DC group (156 days vs. not reached, p = 0.0008). An AFP ratio of 1.4 or higher at 3 weeks had a specificity of 88.0% and a sensitivity of 88.9% for predicting Non-6W-DC. Median progression-free survival was significantly shorter in patients with an AFP ratio of 1.4 or higher at 3 weeks than in those with an AFP ratio of <1.4 (42 days vs. 210 days, p = 0.0003). CONCLUSION: Early changes in AFP might be useful for predicting the antitumor efficacy of atezolizumab plus bevacizumab in patients with advanced HCC. An AFP ratio of 1.4 or higher at 3 weeks might be an early predictor of refractoriness to atezolizumab plus bevacizumab therapy.

Gallbladder (GB) diseases represent various lesions including gallstones, cholesterol polyps, adenomyomatosis, and GB carcinoma. This review aims to summarize the role of endoscopic ultrasound (EUS) in the diagnosis of GB lesions. EUS provides high-resolution images that can improve the diagnosis of GB polypoid lesions, GB wall thickness, and GB carcinoma staging. Contrast-enhancing agents may be useful for the differential diagnosis of GB lesions, but the evidence of their effectiveness is still limited. Thus, further studies are required in this area to establish its usefulness. EUS combined with fine-needle aspiration has played an increasing role in providing a histological diagnosis of GB tumors in addition to GB wall thickness.

ABSTRACT: Real-world clinical cases of molecularly targeted agent (MTA) administration to patients with advanced hepatocellular carcinoma (HCC) with ≥50% liver occupation have been reported, but treatment outcomes have rarely been described. We have encountered several cases in which albumin-bilirubin (ALBI) scores deteriorated markedly and C-reactive protein (CRP) levels elevated in the early post-dose period. The present study therefore investigated early clinical changes in ALBI score and CRP levels after initiating MTA in advanced HCC patients with ≥50% liver occupation, focusing on antitumor response at 6 weeks.This retrospective study included 46 HCC patients with liver occupation ≥50% and 191 patients with <50%, Child-Pugh score ≤7, and Eastern Cooperative Oncology Group Performance Status scores of 0 or 1, who were treated with sorafenib or lenvatinib as first-line systemic therapy at our hospital between June 2011 and January 2020. We analyzed their medical records up to March 2020 and investigated the outcomes and changes in CRP and ALBI scores classified according to antitumor response at 6 weeks.Overall survival was significantly longer in patients with partial response (PR) + stable disease (SD) (13.7 months) than in patients with progressive disease (PD) (1.7 months, P < .001) in the ≥50% group. Patients with antitumor response of PR + SD at 6 weeks in the ≥50% group showed more marked deterioration of ALBI score at 2 weeks than those in the <50% group. These significant differences between groups had again disappeared at 4 and 6 weeks. Focusing on patients with PD at 6 weeks, ALBI score deteriorated over time in both groups. Regarding CRP, on 6-week PR + SD patients, a significant increase in CRP levels at 1 and 2 weeks was evident in the >50% group compared to the <50% group. These significant differences between groups had again disappeared at 4 and 6 weeks. In PD patients, no difference between groups in CRP elevation occurred at 1 and 2 weeks.In MTA treatment for patients with ≥50% liver occupation, to obtain an antitumor response of PR + SD, adequate management might be important considering transient deteriorated ALBI scores and elevated CRP levels.

BACKGROUND & AIMS: To provide an adequate treatment strategy for chronic hepatitis B, it is essential to know which patients are expected to have a good prognosis and which patients do not require therapeutic intervention. Previously, we identified the substitution of isoleucine to leucine at amino acid 97 (I97L) in the hepatitis B core region as a key predictor among patients with stable hepatitis. In this study, we attempted to identify the point at which I97L affects the hepatitis B virus (HBV) life cycle and to elucidate the underlying mechanisms governing the stabilization of hepatitis. METHODS: To confirm the clinical features of I97L, we used a cohort of hepatitis B e antigen-negative patients with chronic hepatitis B infected with HBV-I97 wild-type (wt) or HBV-I97L. The effects of I97L on viral characteristics were evaluated by in vitro HBV production and infection systems with the HBV reporter virus and cell culture-generated HBV. RESULTS: The ratios of reduction in hepatitis B surface antigen and HBV DNA were higher in patients with HBV-I97L than in those with HBV-I97wt. HBV-I97L exhibited lower infectivity than HBV-I97wt in both infection systems with reporter HBV and cell culture-generated HBV. HBV-I97L virions exhibiting low infectivity primarily contained a single-stranded HBV genome. The lower efficiency of cccDNA synthesis was demonstrated after infection of HBV-I97L or transfection of the molecular clone of HBV-I97L. CONCLUSIONS: The I97L substitution reduces the level of cccDNA through the generation of immature virions with single-stranded genomes. This I97L-associated low efficiency of cccDNA synthesis may be involved in the stabilization of hepatitis.

BACKGROUND: Endoscopic papillectomy of duodenal papillary tumors (PT) is indicated for adenomas or well-differentiated adenocarcinomas that do not involve the sphincter of Oddi. However, there is currently no reliable pre-operative method to diagnose the infiltration in the sphincter of Oddi.' Insulin-like growth factor 2 mRNA protein 3 (IMP3) staining is reportedly associated with advanced disease stage and clinical outcomes in many carcinomas. The aim of this retrospective study was to investigate the ability of diagnosing sphincter of Oddi involvement in PT and predicting the prognoses using IMP3 immunohistochemistry. METHODS: Twenty-five resected specimens from patients with PT and 24 biopsy specimens from the same patients excluding one were immunostained for IMP3. The percentage of positive cells in the tumor was evaluated and compared with the final pathological diagnosis and prognosis. RESULTS: The final pathological diagnoses were adenoma in 5 patients and adenocarcinoma in 20 patients (no sphincter of Oddi involvement in 5 and involvement in 15). The ability to diagnose sphincter of Oddi involvement based on the percentage of IMP3-positive cells in resected specimens and tissue biopsies was the area under the curve 0.8 and 0.78, respectively, of the receiver operating characteristic curve, and the accuracies were 80.0% and 75.0% (cutoff value: 10%), respectively. Moreover, patients with an IMP3-positive cell rate of ≥ 10% had a significantly worse prognosis (log-rank test P = 0.01). CONCLUSION: IMP3 immunostaining of resected and biopsy specimens from PT patients enables the diagnosis of sphincter of Oddi involvement objectively and is also effective in predicting the prognosis.

Background/Aim: The aim of this study was to investigate the outcomes of atezolizumab plus bevacizumab in patients with advanced hepatocellular carcinoma (HCC), including those with disease refractory to lenvatinib, in clinical practice. Patients and Methods: Of 34 patients treated with atezolizumab plus bevacizumab, a total of 23, including 16 with lenvatinib failure, were enrolled in this retrospective study. The adverse events, changes in liver function and antitumor responses at 6 weeks after starting therapy were evaluated. Results: The incidence of grade 3 adverse events was low, at 13.0%. Albumin–bilirubin scores did not worsen at 3 and 6 weeks compared to baseline. The objective response rate and disease control rate at 6 weeks were 17.4% and 78.3% according to Response Evaluation Criteria in Solid Tumors (RECIST), and 30.4% and 78.3% according to modified RECIST, respectively. Conclusion: Our results suggest that atezolizumab plus bevacizumab might have potential therapeutic safety and efficacy in patients with advanced HCC, including those with disease refractory to lenvatinib. Further studies are needed to confirm the outcomes of atezolizumab plus bevacizumab after lenvatinib failure.

BACKGROUND & AIMS: Hepatocellular carcinoma in nonalcoholic steatohepatitis is caused by the complex factors of inflammation, fibrosis and microbiomes. We used network analysis to examine the interrelationships of these factors. METHODS: C57Bl/6 mice were categorized into groups: choline-sufficient high-fat (CSHF, n = 8), choline-deficient high-fat (CDHF, n = 9), and CDHF+ diethylnitrosamine (DEN, n = 8). All mice were fed CSHF or CDHF for 20 weeks starting at week 8, and mice in the CDHF + DEN group received one injection of DEN at 3 weeks of age. Bacterial gene was isolated from feces and analyzed using Miseq. RESULTS: The CSHF group had less fibrosis than the other groups. Tumors were found in 22.2% and 87.5% of the CDHF group and CDHF + DEN groups, respectively. Gene expression in the liver of Cdkn1a (p21: tumor-suppressor) and c-jun was highest in the CDHF group. Bacteroides, Roseburia, Odoribacter, and Clostridium correlated with fibrosis. Streptococcus and Dorea correlated with inflammation and tumors. Akkermansia and Bilophila were inversely correlated with fibrosis and Bifidobacterium was inversely correlated with tumors. CONCLUSIONS: DEN suppressed the overexpression of p21 caused by CDHF. Some bacteria formed a relationship networking associated with their progression and inhibition for tumors and fibrosis.

AIM: Patients with nonalcoholic fatty liver disease (NAFLD) have a low quality of life (QOL) and illness uncertainty. This study examined the structure of QOL and associated factors, including illness uncertainty, among individuals with NAFLD. METHODS: A cross-sectional survey was conducted using a self-administered questionnaire for outpatients with NAFLD. QOL was measured using the Short Form-8. Dietary habits, physical activity level, illness uncertainty, health locus of control, and knowledge of NAFLD were assessed. Path analysis was used to study the associated factors of QOL and their structure, including uncertainty of disease. RESULTS: Path analysis of 168 NAFLD patients indicated that a high Physical Component Summary score on the Short Form-8-representing physical QOL-was predicted by a body mass index <25 kg/m2 and high educational level. A high Mental Component Summary score-representing mental QOL-was predicted by being male, good dietary habits, low illness uncertainty, and presence of consultants. The model showed satisfactory goodness-of-fit without being rejected by the chi-square test (goodness-of-fit index = .947, adjusted goodness-of-fit index = .917, comparative fit index = .967, root mean square error of approximation = 0.023). CONCLUSIONS: Nurses need to work closely with NAFLD patients as consultants, providing adequate information about the causes, treatments, and dietary habits, and focusing on the individual's perception of health. This could reduce illness uncertainty and contribute to the improvement of QOL.

BACKGROUND: Bacteria of oral origin (BO) in the gut are associated with prognosis in patients with cirrhosis. The Greengenes database (gg_13_8) is widely used in microbiome analysis, but the expanded Human Oral Microbiome Database (eHOMD), a specialized database for BO, can add more detailed information. We used each database to evaluate the relationship between the albumin-bilirubin grade (ALBI) and the microbiome in patients with hepatitis C. METHODS: Eighty patients were classified into the low ALBI group (LA; n = 34) or high ALBI group (HA; n = 46). Isolated DNA from stool was amplified to target the V3-4 regions of 16S rRNA. The microbiomes of the two groups were compared using gg_13_8 or eHOMD. We evaluated the associations between microbiomes and prognoses using Cox proportional hazards models. RESULTS: At the genus level, the two groups differed significantly regarding 6 (gg_13_8) and 7 (eHOMD) types of bacteria. All types except Akkermansia are classified as BO. Both databases showed an increase in Streptococcus and Veillonella. eHOMD showed a decrease in Fusobacterium and an increase in Fretibacterium; both produce various types of short-chain fatty acids. At the species level, the two groups demonstrated significant differences in 2 (gg_13_8) and 6 (eHOMD) bacterial types. Selenomonas noxia and Streptococcus salivarius were related to poor prognosis in univariate analysis. CONCLUSION: The HA group demonstrated increased BO, most of which produce lactic acid or acetic acid. The correlation between the microbiome and metabolism might be related to prognosis. eHOMD was a useful database for analyzing BO.

PURPOSE: This study aimed to evaluate the usefulness of a coaxial double balloon catheter for simplification of the balloon-occluded retrograde transcatheter obliteration (BRTO) procedure compared with a single-balloon catheter. MATERIALS AND METHODS: Thirty-three patients who underwent BRTO with a single-balloon catheter (Single-balloon group, n = 15) or a coaxial double balloon catheter (Coaxial group, n = 18) were included, retrospectively. The frequency of additional procedures for stagnation of sclerosant including ethanol injection, coil embolization, and additional balloon occlusion for collateral draining veins; the dose of ethanolamine oleate (EO); and the complication rate and the success rate of sclerosant stagnation were evaluated. RESULTS: Additional procedures were needed in four patients in the Coaxial group, which was significantly lower than that in the Single-balloon group (nine patients, P = 0.038). The dose of EO in the Coaxial group (11.2 ± 6.6 g) was lower, but not significantly different than that in the Single-balloon group (14.4 g ± 6.1 g, P = 0.184). The complication rate and the success rate of sclerosant stagnation were not different between the two groups. CONCLUSION: The use of a coaxial double balloon catheter can simplify the BRTO procedure compared with a single-balloon catheter.

BACKROUND: Not all patients with hepatocellular carcinoma (HCC) benefit from treatment with molecular targeted agents such as sorafenib. We investigated whether New-FP (fine-powder cisplatin and 5-fluorouracil), a hepatic arterial infusion chemotherapy regimen, is more favorable than sorafenib as an initial treatment for locally progressed HCC. METHODS: To avoid selection bias, we corrected the data from different facilities that did or did not perform New-FP therapy. In total, 1709 consecutive patients with HCC initially treated with New-FP or sorafenib; 1624 (New-FP, n = 644; sorafenib n = 980) were assessed. After propensity score matching (PSM), overall survival (OS) and prognostic factors were assessed (n = 344 each). Additionally, the patients were categorized into four groups: cohort-1 [(without macrovascular invasion (MVI) and extrahepatic spread (EHS)], cohort-2 (with MVI), cohort-3 (with EHS), and cohort-4 (with MVI and EHS) to clarify the efficacy of each treatment. RESULTS: New-FP prolonged OS than sorafenib after PSM (New-FP, 12 months; sorafenib, 7.9 months; p < 0.001). Sorafenib treatment, and severe MVI and EHS were poor prognostic factors. In the subgroup analyses, the OS was significantly longer the New-FP group in cohort-2. CONCLUSIONS: Local treatment using New-FP is a potentially superior initial treatment compared with sorafenib as a multidisciplinary treatment in locally progressed HCC without EHS.

BACKGROUND: Endoscopic variceal ligation (EVL) is a widely accepted treatment for esophagogastric varices in patients with portal hypertension. It is used for urgent treatment and prophylactic treatment of esophagogastric varices not only in adults, but also in pediatric patients. However, major life-threatening adverse events such as early rebleeding can occur. Although early rebleeding after EVL among children and adolescents has been reported, the risk factors remain obscure. This study evaluated the risk factors for early rebleeding after EVL in children and adolescents. METHODS: Subjects were children and adolescents with portal hypertension aged less than 18 years who underwent EVL for esophagogastric varices. Early rebleeding was defined as hematemesis, active bleeding or blood retention in the stomach, confirmed by esophagogastroduodenoscopy from 2 hours to 5 days after EVL. RESULTS: A total of 50 EVL sessions on 22 patients were eligible for this study. There were 4 episodes of early rebleeding. No other major adverse events have occurred. Multivariate analysis showed that EVL implemented at cardiac varices just below the esophagogastric junction (EGJ); within 5mm from the EGJ, is the independent factor of higher risk of early rebleeding: odds ratio 18.2 (95% Confidence interval: 1.40-237.0), p=0.02. CONCLUSIONS: Children and adolescents who undergo EVL for cardiac varices just below the EGJ have a higher risk of early rebleeding than those who do not.

BACKGROUND/AIM: The purpose of this study was to determine changes in the hepatic arteries after treatment with a molecular targeted agent (MTA), and evaluate the safety and efficacy of transarterial chemoembolization (TACE) as a post-MTA treatment in patients with hepatocellular carcinoma (HCC). PATIENTS AND METHODS: The cases of 33 patients with intermediate HCC treated with MTA and TACE were studied retrospectively. The hepatic arteries, and the safety and efficacy of TACE were evaluated before and after MTA treatment. RESULTS: Following long-term MTA treatment, the diameters of hepatic arteries decreased significantly, while there was no difference in the diameters of the splenic artery or the portal vein. No significant adverse events were observed due to TACE after MTA; however, the therapeutic effect of TACE was limited after MTA treatment. CONCLUSION: This study demonstrated that the diameters of hepatic arteries were significantly smaller than those before MTA induction, suggesting ischemic effects and tumor vessel "normalization" by MTA treatment. Although TACE can be performed as a post-MTA treatment without lowering the hepatic reserve or causing serious complications, its therapeutic effect is limited.

A 10-month-old boy with biliary atresia who had undergone the Kasai procedure, was admitted to our hospital due to tarry stool. We performed emergency esophagogastroduodenoscopy and found severe esophagogastric varices. There was a spurting bleeding site at the lower esophagus. We implemented endoscopic injection sclerotherapy (EIS) for esophagogastric variceal bleeding, since it was impossible to insert the scope through the esophagus with an endoscopic variceal ligation device attached. After performing four sessions of EIS, the patient developed esophageal ulcers and stricture related to EIS, leading to poor oral intake and body weight loss. We were able to manage these adverse events with conservative treatment. After healing of the esophageal ulcers and stricture, two additional sessions of EIS were performed. The patient's esophagogastric varices disappeared completely. Intra-variceal EIS followed by para-variceal EIS by polidocanol was reported to be effective and relatively safe for the treatment of esophageal varices in adult patients. The aim of paravariceal EIS is to form ulcers at the injection sites, resulting in the development of fibrosis of the mucosa during the healing process. This mucosal fibrosis is considered important for preventing recurrence of varices. There is little evidence for the safety and efficacy of intra-variceal EIS followed by para-variceal EIS in pediatric patients. Although we should be cautious of EIS-related stricture due to esophageal ulcer, especially in children who have a narrower esophageal lumen than adults, we have experienced a successful case of EIS for esophageal varices in an infant with biliary atresia.

Introduction: The ALBI score is acknowledged as the gold standard for the assessment of liver function in patients with hepatocellular carcinoma (HCC). Unlike the Child-Pugh score, the ALBI score uses only objective parameters, albumin (Alb) and total bilirubin (T.Bil), enabling a better evaluation. However, the complex calculation of the ALBI score limits its applicability. Therefore, we developed a simplified ALBI score, based on data from a large-scale HCC database. We used the data of 5,249 naïve HCC cases registered in eight collaborating hospitals. Methods: We developed a new score, the EZ (Easy)-ALBI score, based on regression coefficients of Alb and T.Bil for survival risk in a multivariate Cox proportional hazard model. We also developed the EZ-ALBI grade and EZ-ALBI-T grade as alternative options for the ALBI grade and ALBI-T grade and evaluated their stratifying ability. Results: The equation used to calculate the EZ-ALBI score was simple {[T.Bil (mg/dL)] - [9 × Alb (g/dL)]}; this value highly correlated with the ALBI score (correlation coefficient, 0.981; p < 0.0001). The correlation was preserved across different Barcelona clinic liver cancer grade scores (regression coefficient, 0.93-0.98) and across different hospitals (regression coefficient, 0.98-0.99), indicating good generalizability. Although a good agreement was observed between ALBI and EZ-ALBI, discrepancies were observed in patients with poor liver function (T.Bil, ≥3 mg/dL; regression coefficient, 0.877). The stratifying ability of EZ-ALBI grade and EZ-ALBI-T grade were good and their Akaike's information criterion values (35,897 and 34,812, respectively) were comparable with those of ALBI grade and ALBI-T grade (35,914 and 34,816, respectively). Conclusions: The EZ-ALBI score, EZ-ALBI grade, and EZ-ALBI-T grade are useful, simple scores, which might replace the conventional ALBI score in the future.