橋本 千樹

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.

症例は72歳,男性。年に1度の人間ドックで施行した血液検査にてCA19-9が62.2U/mLと高値であったため,CT検査を行ったところ膵頭部に腫瘍を指摘され,精査加療目的で当院紹介受診となった。腹部造影CT検査で膵頭部に21mm大の乏血性腫瘍を認め膵癌が疑われた。同部位に対して超音波内視鏡下穿刺吸引生検法を施行し,腺癌と病理診断された。以上から膵頭部癌と診断し,手術前化学療法施行後,幽門輪温存膵頭十二指腸切除術を施行した。手術検体の病理組織学的所見では,Hematoxylin Eosin染色で低分化型腺癌成分に加え,小型円形核,淡明な胞体を有する異型に乏しい細胞が蜂巣状に増生しており,免疫染色でsynaptophysin染色,chromogranin染色が共に陽性であったことから,充実胞巣状構造の成分はneuroendocrine neoplasmと診断した。腺癌およびneuroendocrine neoplasmがそれぞれ30%以上存在していたことから膵頭部原発Mixed neuroendocrine-non-neuroendocrine neoplasmと最終診断された。(著者抄録)

エネルギー産生栄養素とは,たんぱく質,脂質,炭水化物に分類される宿主のエネルギーとして利用される成分である。エネルギー産生栄養素には,体に必要な筋肉,内臓,血管などさまざまな組織の構成成分を供給するとともに,脳をはじめとして生体活動を維持するために日々使用するエネルギーを供給する役割を担っている。さらに,炭水化物の一部は,食物繊維という消化酵素で分解されることなく,大腸に存在する腸内細菌の栄養素として利用される成分を含む。本稿では,エネルギー産生栄養素の代謝の代表的なプロセスを紹介するとともに食物繊維に関し最新の研究動向を紹介する。(著者抄録)

ビタミンとは,三大栄養素などのエネルギー産生栄養素に比べ微量ではあるものの,人体の機能を正常に保つため必要な有機化合物である。ヒトは,三大栄養素を代謝してエネルギー貯蔵分子であるATPに変換する生体内酵素反応において,特定のビタミン(B群,C)やミネラル(鉄,マグネシウム)を必要とする。さらに,ヒトは自ら消化酵素をもたない食物繊維やポリフェノールの代謝を腸内細菌叢に依存し,それが生産するビタミンや短鎖脂肪酸などの低分子代謝物をヒトの代謝に利用している。われわれは,バランスのよい食生活を通じ,自分達の代謝に必要な三大栄養素,ビタミン,ミネラルなどを摂取することはもちろん,腸内細菌の代謝に必要な食物繊維などのプレバイオティクスも摂取する必要がある。(著者抄録)

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.

肝門部領域胆管癌においては肝葉切除術以上の広範肝切除術を要する症例が多い。広範肝切除術を施行する場合は術後合併症による死亡率が5%前後と高率であり,主な死因が肝不全であることから,高度黄疸例には術前胆道ドレナージを行うことが推奨される。一方で,肝門部領域胆管癌の黄疸を認める肝葉切除術であっても(1)黄疸が軽度であり,(2)全身状態および肝予備能が比較的良好で,(3)肝切除量が少なく,待機期間の短い例においては,術前胆道ドレナージの必要がないとも報告されている。これまでのエビデンスから,肝門部領域胆管癌の術前ドレナージ術は(1)残存予定側の肝領域に対して,(2)経乳頭的なドレナージ術が行われることが推奨されている。ドレナージ方法としては本邦ではENBDが推奨される傾向にあるが,感染のコントロールや術前診断が十分になされている症例に対してはEBSも許容されると考えられる。近年では胆管内留置のインサイド型プラスチックステントや細径のfully covered metallic stentを用いた術前ドレナージ術の試みも報告されている。本稿では肝門部領域胆管癌に対する手術前ドレナージについて最近の動向を踏まえて解説する。(著者抄録)

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.

次世代シークエンサーをはじめとする難培養性の細菌を解析する研究技術の発展により,腸内細菌叢と疾患の関連性を示す研究が爆発的進歩を遂げている。消化器癌においても例外ではなくそれぞれの癌に特徴的な細菌との関連性が数多く報告されている。本稿では,腸内細菌を研究するうえでの基礎的な研究方法を紹介するとともに消化器癌における腸内細菌叢の影響に関し包括的に述べる。(著者抄録)

次世代シークエンサーをはじめとする難培養性の細菌を解析する研究技術の発展により,腸内細菌叢と疾患の関連性を示す研究が爆発的進歩を遂げている。消化器癌においても例外ではなくそれぞれの癌に特徴的な細菌との関連性が数多く報告されている。本稿では,腸内細菌を研究するうえでの基礎的な研究方法を紹介するとともに消化器癌における腸内細菌叢の影響に関し包括的に述べる。(著者抄録)

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.

BACKGROUND AND AIM: In colorectal endoscopic submucosal dissection (ESD), post-ESD electrocoagulation syndrome (PECS) has been recognized as one of the major complications. There are no reports on the relationships between ESD findings and PECS. This study aims to evaluate the risk factors for PECS, including ESD findings such as muscularis propria exposure. METHODS: We performed a retrospective cohort study of patients who underwent colorectal ESD between January 2017 and December 2021 in Japan. The grade of injury to the muscle layer caused by ESD was categorized as follows: Grade 0, no exposure of muscularis propria; Grade 1, muscularis propria exposure; Grade 2, torn muscularis propria; and Grade 3, colon perforation. The risk factors for PECS, including injury to the muscle layer, were analyzed by univariate and multivariate analyses. RESULTS: Out of 314 patients who underwent colorectal ESD, PECS occurred in 28 patients (8.9%). The multivariate analysis showed that female sex (odds ratio [OR] 3.233; 95% confidence interval [95% CI]: 1.264-8.265, P = 0.014), large specimen size (≥ 40 mm) (OR 6.138; 95% CI: 1.317-28.596, P = 0.021), long procedure time (≥ 90 min) (OR 2.664; 95% CI: 1.053-6.742, P = 0.039), and Grade 1 or 2 injury to the muscle layer (OR 3.850; 95% CI: 1.090-13.61, P = 0.036) were independent risk factors for PECS. CONCLUSIONS: Injury to the muscle layer, such as exposure or tear, was identified as a novel independent risk factor for PECS. We should perform colorectal ESD carefully to avoid injuring the muscle layers.

In inflammatory bowel disease, including Crohn's disease and ulcerative colitis, an excessive immune response due primarily to T-cell lymphocytes causes inflammation in the gastrointestinal tract. Lesions in Crohn's disease can occur anywhere in the gastrointestinal tract, i.e., from the oral cavity to the anus. Endoscopically, aphthoid lesions/ulcers believed to be initial lesions progress to discrete ulcers, which coalesce to form a longitudinal array and progress to longitudinal ulcers with a cobblestone appearance, which is a typical endoscopic finding. Before long, complications such as strictures, fistulas, and abscesses form. Lesions in ulcerative colitis generally extend continuously from the rectum and diffusely from a portion of the colon to the entire colon. Endoscopically, lack of vascular pattern, fine granular mucosa, erythema, aphthae, and small yellowish spots are seen in mild cases; coarse mucosa, erosions, small ulcers, bleeding (contact bleeding), and adhesion of mucous, bloody, and purulent discharge in moderate cases; and widespread ulcers and marked spontaneous bleeding in severe cases.

Background: The relationship between pancreatic ductal adenocarcinoma (PDAC) and the intestinal environment is not fully understood. The purpose of this study was to elucidate the characteristics of the intestinal environment in PDAC. Methods: We performed a case-control study of 5 Japanese patients with unresectable PDAC located in the body or tail (PDAC-bt). The number of patients analyzed was limited for this preliminary study. We included 68 healthy subjects, herein control, of pre-printed study in the preliminary study. 16S rRNA amplicon sequencing and metabolomic analysis were performed using fecal samples from the subjects. Results: There was no difference in the Shannon index and Principal Coordinate Analysis between PDAC-bt and the control. However, a significant increase in oral-associated bacteria (Actinomyces, Streptococcus, Veillonella, Lactobacillus) was observed. A significant decrease of Anaerostipes was demonstrated in the feces of PDAC-bt compared with the control. The intestinal propionic acid and deoxycholic acid were significantly lower in PDAC-bt compared with the control. Conclusions: We showed that the intestinal environment of PDAC-bt is characterized by an increase in oral-associated bacteria and an imbalance of metabolites but without changes in alpha and beta diversity of the gut microbiota profiles.Clinical Trial Registration: www.umin.ac.jp, UMIN 000041974, 000023675, 000023970.

BACKGROUND: The management of bleeding during endoscopic submucosal dissection (ESD) is critical and related to the procedure time. We collaborated on a new image enhancement algorithm with parameter optimization for clinical use being developed by FUJIFILM Co. and processed white light image data offline to evaluate the effectiveness of this technology. This study aims to evaluate the clinical usefulness of this technology. METHODS: Eighteen video scenes of bleeding points from 5 gastric ESDs were selected and processed by the new image enhancement algorithm. The time until a bleeding point was found, visibility of a bleeding point and color abnormality of the submucosal layer were evaluated by ESD experts, ESD trainees, and endoscopy trainees. The color differences between the bleeding point and the surroundings in CIE- L*a*b* color space were calculated in the original and enhanced images. RESULTS: The time until a bleeding point was found in the enhanced videos was significantly shorter than that in the original videos (11.10 seconds vs. 13.85 seconds) (P=0.017). On a 5-point (-2 to +2) Likert scale of visibility, the enhanced image was slightly superior to the original (+0.45), and the appearance of the submucosa was comparable between images (+0.14). The color difference among the bleeding areas on the enhanced images were significantly larger than that on the original images (10.93 vs. 8.36). CONCLUSION: This novel image enhancement algorithm emphasizes the color difference between a bleeding point and the surrounding area, which would help find bleeding points faster during ESD for the less experienced endoscopists.

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.

The following are some common features of ulcerative colitis (UC) and Crohn's disease (CD) on transabdominal ultrasonography (TUS). UC, which consists primarily of mucosal inflammation, is seen on TUS as wall thickening with preserved layer structure continuing from the rectum in the active phase of UC. Inflammation confined to the mucosa is seen as thickening of the mucosal/submucosal layers. When the inflammation becomes severe, the echogenicity of the submucosal layer decreases and the layer structure becomes indistinct. CD, which consists primarily of discontinuous transmural inflammation, shows more pronounced hypoechoic wall thickening than UC at the transmural inflammation. On TUS, the layer structure becomes indistinct and gradually disappears due to the depth of the myriad inflammation during the active phase of CD. It is important to evaluate the changes in wall thickening and layer structure when diagnosing UC and CD with TUS. In addition, diagnostic techniques such as color Doppler and contrast-enhanced ultrasonography, which can be used to assess blood flow, and elastography, which can be used to evaluate stiffness, are also used. Thus, TUS is a noninvasive and convenient modality that shows promise as a useful examination for diagnosis of UC and CD.

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.

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.