川部 直人

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.

Background/Objective: Recently, there has been an increasing need to implement the diagnosis of the presence of covert hepatic encephalopathy (CHE) in patients with cirrhosis. The aim of this study was to identify novel factors associated with CHE in clinical practice. Methods: This retrospective study enrolled a total of 402 patients with cirrhosis at 17 institutions. The Stroop test was performed to diagnose CHE at each center. Results: The patients comprised 233 males and 169 females, with a median age of 69 (IQR, 61–75) years. The median albumin and 25(OH)D3 levels were 3.9 (3.5–4.3) g/dL and 15.4 (11.0–21.0) ng/mL, respectively. This cohort included 181 patients with esophageal varices (EV). Multivariate analysis revealed that low 25(OH)D3 (p < 0.05) and EV (p < 0.05) were independent risk factors for CHE. When limited to only laboratory factors, low albumin (p < 0.01) and low 25(OH)D3 (p < 0.05) were independent factors for CHE. The optimal cut-off values of albumin and 25(OH)D3 for predicting CHE were 3.7 g/dL and 16.5 ng/mL, respectively. The prevalence of CHE was 59.2% for 25(OH)D3 < 16.5 ng/mL and EV, 53.8% for albumin < 3.7 g/dL and 25(OH)D3 < 16.5 ng/mL, and 66.7% for albumin < 3.7 g/dL, EV, and 25(OH)D3 < 16.5 ng/mL. Conclusions: Low 25(OH)D3 and albumin levels, and the EV were positively associated with CHE in patients with cirrhosis. Specifically, the prevalence of CHE increased with a decrease in 25(OH)D3 levels. Patients with such risk factors should be actively and carefully examined for the presence of CHE.

Background/Objectives: Rifaximin is a therapeutic agent for patients with hepatic encephalopathy (HE); however, there is little data on the effects of its long-term (>1 year) administration in Japanese patients with cirrhosis. The effects and safety of 3-year rifaximin treatment on HE was investigated in Japan. Methods: A total of 190 Japanese patients with cirrhosis who were continuously administered rifaximin for more than 1 year suffered overt or covert HE, which was diagnosed by a physician. Laboratory data were collected at baseline, 3, 6, 12, 18, 24, 30, and 36 months following rifaximin administration. We examined the cumulative overt HE incidences, overall survival rates, and hepatic functional reserves following rifaximin treatment. The occurrence of adverse events was also assessed. Results: The levels of ammonia improved significantly after 3 months of rifaximin administration, which continued for 3 years. Serum albumin and prothrombin activity also significantly improved 3 years after initiation of rifaximin treatment. Cumulative overt HE incidences were 12.1%, 19.7%, and 24.9% at 1, 2, and 3 years, respectively. The survival rates following rifaximin treatment were 100%, 88.9%, and 77.8% at 1, 2, and 3 years, respectively. In contrast, renal function and electrolytes did not change following rifaximin administration. Only three (1.6%) patients discontinued rifaximin therapy because of severe diarrhea after 1 year of rifaximin administration. No other serious adverse events were observed. Conclusions: Three years of continuous rifaximin (RFX) treatment was both effective and safe for patients with hepatic encephalopathy. Liver function improved and did not worsen during treatment.

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.

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.

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)

INTRODUCTION: When we administer atezolizumab plus bevacizumab treatment to patients with advanced hepatocellular carcinoma, we often encounter inconsistent results between the qualitative dipstick urinalysis and the urine protein/creatinine ratio(UPCR)measurements. In this study, we investigated the relationship between qualitative dipstick urinalysis and UPCR in these patients, and assessed whether incorporating UPCR into the testing protocol could prevent unnecessary interruptions during bevacizumab treatment. SUBJECTS AND METHODS: This study analyzed 298 urine samples collected from 61 patients of advanced hepatocellular carcinoma, who were treated with atezolizumab plus bevacizumab at our institution between October 1, 2020, and August 31, 2021. We used UPCR as an alternative test to the 24-hour urine protein and set the discontinuation criteria for bevacizumab at a UPCR of 2.0 or higher. RESULTS: Among the 41 samples that tested positive for 2+ on the dipstick test, only one(2.4%)had a UPCR exceeding 2.0. Additionally, among the 44 samples that showed a 3+ result, 24 samples(54.5%)had a UPCR higher than 2.0. If our decision to discontinue bevacizumab had been based on a dipstick urinalysis result of 2+, we could have continued administering bevacizumab in 97.6%(40/41)of the cases. Even if the decision had been based on a dipstick urinalysis result of 3+, we could have continued administering bevacizumab in almost half of the cases(45.5%, 20/44). CONCLUSIONS: Our findings suggest that the addition of UPCR to the qualitative dipstick urinalysis during atezolizumab plus bevacizumab treatment for patients with advanced hepatocellular carcinoma could help prevent unnecessary interruptions of bevacizumab and offer more clinical benefits in real-world practice, compared to using qualitative dipstick urinalysis alone.

＜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.

膵癌(pancreatic ductal adenocarcinoma:PDAC)は極めて予後不良な疾患であり,10mm程度の病変が発見され外科切除がなされない場合,多くは5年生存率10%に到達しない。多くの癌腫において有効性が示されている免疫チェックポイント阻害薬(immune check-point inhibitor:ICI)もPDACに対しては現時点では全く無力と言わざるを得ない。ICIが有効性を発揮するためには,腫瘍局所と腫瘍を取り巻く免疫環境を改変する必要がある。具体的には,CD8陽性T細胞の集積である。CD8陽性T細胞の集積がなければ理論的にICIは無効である。われわれは15症例の切除不能局所進行膵癌(UR-LA)に対してゲムシタビン(gemcitabine:GEM)投与と未熟樹状細胞のEUSガイド下腫瘍内局注の臨床試験を実施した。有効性を認めた群では腫瘍局所にCD8陽性T細胞の集積を認めた。GEM単剤との組み合わせではなく,GEM/nab-PTXやFOLFIRINOXとの組み合わせにICIを上乗せすることでPDACに対する有効性が認められる可能性がある。(著者抄録)

膵腫瘍には様々な種類が存在し,予後と治療法は異なる.そのため,最善の治療計画を決定するには正確な診断が重要である.経腹的超音波検査は,膵腫瘍の画像診断のためのスクリーニング検査としてよく用いられる.本論説では,比較的稀な膵腫瘍の超音波所見の特徴に焦点を当てて解説する.(著者抄録)

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.