Clinical Guidelines for Diagnosis and Management of Cowden Syndrome/PTEN Hamartoma Tumor Syndrome in Children and Adults-Secondary Publication.

Cowden syndrome (CS)/ hamartoma tumor syndrome (PHTS) is a rare autosomal dominantly inherited condition caused by germline pathogenesis. It is associated with multiple hamartomatous lesions occurring in various organs and tissues, including the gastrointestinal tract, skin, mucous membranes, breast, thyroid, endometrium, and brain. Macrocephaly or multiple characteristic mucocutaneous lesions commonly develop in individuals in their 20s. This syndrome is occasionally diagnosed in childhood due to the occurrence of multiple gastrointestinal polyps, autism spectrum disorders, and intellectual disability. CS/PHTS can be diagnosed taking the opportunity of multigene panel testing in patients with cancer. Appropriate surveillance for early diagnosis of associated cancers is required because patients have a high risk of cancers including breast, thyroid, colorectal, endometrial, and renal cancers. Under these circumstances, there is growing concern regarding the management of CS/PHTS in Japan, but there are no available practice guidelines. To address this situation, the guideline committee, which included specialists from multiple academic societies, was organized by the Research Group on Rare and Intractable Diseases granted by the Ministry of Health, Labour, and Welfare, Japan. The present clinical guidelines explain the principles in the diagnosis and management of CS/PHTS, together with four clinical questions and the corresponding recommendations, incorporating the concept of the Grading of Recommendations Assessment, Development, and Evaluation system. Herein, we present an English version of the guideline, some of which have been updated, to promote seamless implementation of accurate diagnosis and appropriate management of pediatric, adolescent, and adult patients with CS/PHTS.


1,3a,6a-Triazapentalene derivatives as photo-induced cytotoxic small fluorescent dyes

1,3a,6a-Triazapentalene (TAP) is a compact fluorescent chromophore whose fluorescence properties vary greatly depending on the substituents on the TAP ring. This study investigated the photo-induced cytotoxicities of various TAP derivatives. Among the derivatives, 2-p-nitrophenyl-TAP showed significant cytotoxicity to HeLa cells under UV irradiation but no cytotoxicity without UV. In addition, the photo-induced cytotoxicity of 2-p-nitirophenyl-TAP was found to be cancer cell selective and effective against HeLa cells and HCT 116 cells. Under UV irradiation, 2-p-nitrophenyl-TAP generated reactive oxygen species (ROS) that induced an apoptosis and ferroptosis in cancer cells. Therefore, it was revealed that 2-p-nitrophenyl-TAP is the most compact dye that can generate ROS by photoirradiation.


Initial therapeutic results of atezolizumab plus bevacizumab for unresectable advanced hepatocellular carcinoma and the importance of hepatic functional reserve.

We analyzed the association between the modified albumin-bilirubin (mALBI) grade and therapeutic efficacy of atezolizumab plus bevacizumab (Atezo+Bev) for the treatment of unresectable hepatocellular carcinoma (u-HCC). In this retrospective observational study, we included 71 u-HCC patients treated with Atezo+Bev between September 2020 and September 2021. Patients were grouped corresponding to the mALBI grade at the start of treatment (mALBI 1+2a or mALBI 2b+3) and analyzed for therapeutic effect and the transition rate to secondary treatment. According to the Response Evaluation Criteria in Solid Tumors, the overall response rate was significantly higher for the mALBI 1+2a group, than for the mALBI 2b+3 group, with 26.2% and 3.4%, respectively. The progression-free survival (PFS) was significantly longer in the mALBI 1+2a group (10.5 months) than in the mALBI 2b+3 group (3.0 months). In the multivariate analysis, an mALBI of 1+2a was found to be an independent factor of PFS. The rate of second-line treatment with multi-targeted agents was also significantly higher in the mALBI 1+2a group. In real-world practice, Atezo+Bev treatment might have higher therapeutic efficacy in u-HCC patients with mALBI 1+2a.


Resveratrol inhibits development of colorectal adenoma via suppression of LEF1; comprehensive analysis with connectivity map.

Although many chemopreventive studies on colorectal tumors have been reported, no effective and safe preventive agent is currently available. We searched for candidate preventive compounds against colorectal tumor comprehensively from United States Food and Drug Administration (FDA)-approved compounds by using connectivity map (CMAP) analysis coupled with in vitro screening with colorectal adenoma (CRA) patient-derived organoids (PDOs). We generated CRA-specific gene signatures based on the DNA microarray analysis of CRA and normal epithelial specimens, applied them to CMAP analysis with 1309 FDA-approved compounds, and identified 121 candidate compounds that should cancel the gene signatures. We narrowed them down to 15 compounds, and evaluated their inhibitory effects on the growth of CRA-PDOs in vitro. We finally identified resveratrol, one of the polyphenolic phytochemicals, as a compound showing the strongest inhibitory effect on the growth of CRA-PDOs compared with normal epithelial PDOs. When resveratrol was administered to Apc mice at 15 or 30 mg/kg, the number of polyps (adenomas) was significantly reduced in both groups compared with control mice. Similarly, the number of polyps (adenomas) was significantly reduced in azoxymethane-injected rats treated with 10 or 100 mg/resveratrol compared with control rats. Microarray analysis of adenomas from resveratrol-treated rats revealed the highest change (downregulation) in expression of LEF1, a key molecule in the Wnt signaling pathway. Treatment with resveratrol significantly downregulated the Wnt-target gene (MYC) in CRA-PDOs. Our data demonstrated that resveratrol can be the most effective compound for chemoprevention of colorectal tumors, the efficacy of which is mediated through suppression of LEF1 expression in the Wnt signaling pathway.


Pulmonary Tumor Thrombotic Microangiopathy Due to Gastric Cancer Diagnosed Antemortem by a Cytological Examination of Aspirated Pulmonary Artery Blood.


Colorectal carcinoma occurring via the adenoma-carcinoma pathway in patients with serrated polyposis syndrome.

Although serrated polyposis syndrome (SPS) is associated with an increased colorectal cancer (CRC) risk, the carcinogenic mechanisms remain unknown. We investigated clinicopathological characteristics and genetic abnormalities in colorectal polyps and CRC to elucidate carcinogenic mechanisms in SPS. We retrospectively analyzed clinicopathological features of colorectal polyps in 44 SPS patients, and examined mutations of genes including APC, RAS, BRAF, and TP53, and microsatellite instability (MSI) in CRC tissues. Of the 44 patients, 25 (56%) fulfilled WHO criterion 1, 11 (25%) fulfilled criterion 2, and 8 (18%) fulfilled both. A total of 956 polyps were observed; 642 (67%) hyperplastic polyps (HP), 204 (21%) sessile serrated lesions (SSL), 10 (1%) traditional serrated adenoma (TSA), and 100 (11%) adenomas. The median numbers of polyps (/patient) were 10.5 (IQR 2.75-23) HPs, 4.0 (2.0-6.0) SSLs, 0 (0-0) TSA, and 1 (0-3.3) adenoma. SSL and HP located preferentially in the proximal and distal colon, respectively. Twenty-two CRCs were found in 18 patients. Based on the histological coexistence of SSL/TSA, BRAF mutation and MSI, 5 CRCs (26%) were classified as serrated-neoplasia pathway. Conversely, based on the coexistence of adenoma, APC/RAS and TP53 mutations, 11 CRCs (58%) were classified as adenoma-carcinoma pathway. The remaining three were unclassifiable. Most CRCs through adenoma-carcinoma pathway were located in the left-side colorectum and patients bearing those met criterion 2, characterized by many HP and advanced adenomas. Adenoma was a significant risk factor for CRC. Our results suggest that more than half of the CRCs, particularly those in the left-side colorectum, developed through the adenoma-carcinoma pathway in SPS patients. Adenoma was a risk factor for CRCs, suggesting its importance in colorectal carcinogenesis.


miR-144-3p/miR-451a promotes lymphovascular invasion through repression of PTEN/p19 in rectal neuroendocrine tumors.

Although rectal neuroendocrine tumor (NET-G1) have potential metastatic capability, even among small tumors, no predictive biomarker for invasion and metastasis has been reported. We analyzed microRNA (miRNA) expression profiles in rectal NET-G1 tissues with and without lymphovascular invasion (LVI). Moreover, we then investigated their target genes to clarify the mechanism of invasion/metastasis in NET-G1. miRNA array analysis was performed using seven rectal NET-G1 tissues with LVI and seven without LVI. miRNA expression was confirmed by quantitative real-time PCR. A NET cell line H727 was transfected with miRNA mimic or target gene small interfering RNA, and migration and invasion assays were performed. The expression levels of miR-144-3p and miR-451a were significantly higher in NET-G1 with LVI versus without LVI, as determined by miRNA array analysis and RT-qPCR. A significant correlation was observed between miR-144-3p and miR-451a expression levels, strongly suggesting miR144/451 cluster overexpression in NET-G1 with LVI. Bioinformatic analysis of target genes revealed that miR-144-3p and miR-451a directly interact with PTEN and p19 mRNA, respectively. Immunohistochemistry revealed significantly lower expression of PTEN and p19 in NET-G1 tissues with LVI than in those without LVI. The miR-144-3p and miR-451a mimic significantly increased cell migration/invasion capability, respectively. Knockdown of PTEN and p19 induced significant augmentation of cell invasion and migration capability, respectively. Our data suggest that overexpression of miR-144/miR-451 cluster promotes LVI via repression of PTEN and p19 in rectal NET-G1 cells. miR-144/451 cluster may be a novel biomarker for predicting invasion/metastasis in rectal NET-G1.

Journal of Gastroenterology and Hepatology


Cancer risk and genotype-phenotype correlation in Japanese patients with Cowden syndrome.

Cowden syndrome (CS) is an autosomal-dominant hereditary disorder caused by a germline PTEN variant and characterized by multiple hamartomas and a high risk of cancers. However, no detailed data on CS in Asian patients nor genotype-phenotype correlation have been reported. We performed the first Japanese nationwide questionnaire survey on CS and obtained questionnaire response data on 49 CS patients. Patients included 26 females (median age 48 years). The incidence of breast, thyroid, endometrium, and colorectal cancer was 32.7%, 12.2%, 19.2% (among females), and 6.1%, respectively. The incidence of any cancers was relatively high among all patients (46.9%, 23/49), and particularly female patients (73.1%, 19/26), compared with previous reports from Western countries. Gastrointestinal (GI) polyps were more frequently found throughout the GI tract compared with previous studies. PTEN variants were detected in 95.6% (22/23) of patients; 12 in the N-terminal region (11 in phosphatase domain) and 10 in the C-terminal (C2 domain) region. The incidence of cancer in the C2 domain group was significantly higher than in the N-terminal region (phosphatase) group. All female patients with C2 domain variant had breast cancer. Our data suggest that Japanese patients with CS, particularly female patients and patients with C2 domain variant may have a high risk of cancers.

International Journal of Clinical Oncology


Small Intestinal Involvement and Genotype-Phenotype Correlation in Familial Adenomatous Polyposis.

Techniques and Innovations in Gastrointestinal Endoscopy


Therapeutic efficacy of lenvatinib in nonviral unresectable hepatocellular carcinoma.


Long-Term Survival due to Chemotherapy including Paclitaxel in a Patient with Metastatic Primary Splenic Angiosarcoma.

A primary splenic angiosarcoma is a rare type of soft tissue sarcoma and is associated with an extremely poor prognosis. In this study, we describe the case of a patient who was diagnosed with metastatic primary splenic angiosarcoma and survived for about 2 years. A 62-year-old female was referred to us for the treatment of splenic angiosarcoma with disseminated intravascular coagulation (DIC) and multiple liver and bone metastases. Paclitaxel therapy resulted in recovery from DIC and enabled her to continue sequential treatment through to sixth-line chemotherapy. We reviewed all splenic angiosarcoma case reports which were described as stage IV to date and compared with our case. From these data, we found that the median overall survival was 105 days, and the prognosis of splenic angiosarcoma of stage IV was worse than conventional case series. Splenectomy was performed in more patients than chemotherapy as a treatment. Moreover, various chemotherapeutic regimens were used. These data suggest that administering chemotherapy including paclitaxel to patients with splenic angiosarcoma might improve their prognosis.


MiR-125b-5p is Involved in Sorafenib Resistance through Ataxin-1-Mediated Epithelial-Mesenchymal Transition in Hepatocellular Carcinoma.

The mechanism of resistance to sorafenib in hepatocellular carcinoma (HCC) remains unclear. We analyzed miRNA expression profiles in sorafenib-resistant HCC cell lines (PLC/PRF5-R1/R2) and parental cell lines (PLC/PRF5) to identify the miRNAs responsible for resistance. Drug sensitivity, migration/invasion capabilities, and epithelial-mesenchymal transition (EMT) properties were analyzed by biochemical methods. The clinical relevance of the target genes to survival in HCC patients were assessed using a public database. Four miRNAs were significantly upregulated in PLC/PRF5-R1/-R2 compared with PLC/PRF5. Among them, miR-125b-5p mimic-transfected PLC/PRF5 cells (PLC/PRF5-miR125b) and showed a significantly higher IC50 for sorafenib compared with controls, while the other miRNA mimics did not. PLC/PRF5-miR125b showed lower E-cadherin and higher Snail and vimentin expression-findings similar to those for PLC/PRF5-R2-which suggests the induction of EMT in those cells. PLC/PRF5-miR125b exhibited significantly higher migration and invasion capabilities and induced sorafenib resistance in an in vivo mouse model. Bioinformatic analysis revealed ataxin-1 as a target gene of miR-125b-5p. PLC/PRF5 cells transfected with ataxin-1 siRNA showed a significantly higher IC50, higher migration/invasion capability, higher cancer stem cell population, and an EMT phenotype. Median overall survival in the low-ataxin-1 patient group was significantly shorter than in the high-ataxin-1 group. In conclusion, miR-125b-5p suppressed ataxin-1 and consequently induced Snail-mediated EMT and stemness, leading to a poor prognosis in HCC patients.


Clinicopathological characteristics of early gastric cancer associated with autoimmune gastritis.


Comparison of therapeutic outcomes of Sorafenib and Lenvatinib as primary treatments for hepatocellular carcinoma with a focus on molecular-targeted agent sequential therapy: A propensity score-matched analysis.

The optimal choice between sorafenib (SOR) or lenvatinib (LEN) as the first-line treatment for unresectable hepatocellular carcinoma (u-HCC) remains debatable. Using propensity score matching, this study compares the outcomes of SOR and LEN in the molecular-targeted agent (MTA) sequential treatment of u-HCC patients. This retrospective, multicenter, observational study recruited 137 u-HCC patients who underwent primary treatment with LEN (n = 52) or SOR (n = 85) between June 2017 and June 2020 after regorafenib was approved as the secondary treatment for u-HCC. Propensity score matching was used to reduce confounding, resulting in the selection of 104 patients (n = 52 for the SOR and LEN cohorts). The median overall survival was 21.8 months for LEN and 20.4 months for SOR. LEN exhibited significantly greater therapeutic efficacy as compared to SOR (objective response rate: 3.8% [SOR] vs. 42.3% [LEN], P <0.01; progression-free survival: 10 months [LEN] vs. 5.1 months [SOR], P <0.01). No significant intergroup differences were noted in the rate of transition to secondary MTA treatments (SOR: 58.7%; LEN: 48.4%), adverse events (SOR: 86%; LEN: 95%), and maintenance of the Child-Pugh (CP) score during treatment. Compared to non-MTA treatments, secondary MTA treatment achieved a greater improvement in survival ( 4.3 months vs. 2.8 months, P=0.0047). Multivariate analysis demonstrated that the CP score (P <0.01) and alpha-fetoprotein level (P <0.01) were independent prognostic factors. Both SOR and LEN treatments showed a clinically comparable therapeutic efficacy as the first-line treatments for u-HCC patients in an MTA sequential therapy.


An Adult Case of Congenital Extrahepatic Portosystemic Shunt Successfully Treated with Balloon-occluded Retrograde Transvenous Obliteration

A 42-year-old woman visited our hospital due to syncope. Contrast-enhanced CT revealed portosystemic shunt, portal vein hypoplasia, and multiple liver nodules. The histological examination of a liver biopsy specimen exhibited portal vein hypoplasia and revealed that the liver tumor was positive for glutamine synthetase. The patient was therefore diagnosed with congenital extrahepatic portosystemic shunt type II, and with focal nodular hyperplasia (FNH)-like nodules. She had the complication of severe portopulmonary hypertension and underwent complete shunt closure by balloon-occluded retrograde transvenous obliteration (B-RTO). The intrahepatic portal vein was well developed at 1 year after B-RTO, and multiple liver nodules completely regressed. Her pulmonary hypertension also improved.


S100P expression via DNA hypomethylation promotes cell growth in the sessile serrated adenoma/polyp-cancer sequence.

Sessile serrated adenomas/polyps (SSA/Ps) are a putative precursor lesion of colon cancer. Although the relevance of DNA hypermethylation in the SSA/P-cancer sequence is well documented, the role of DNA hypomethylation is unknown. We investigated the biological relevance of DNA hypomethylation in the SSA/P-cancer sequence by using 3-dimensional organoids of SSA/P. We first analyzed hypomethylated genes using datasets from our previous DNA methylation array analysis on 7 SSA/P and 2 cancer in SSA/P specimens. Expression levels of hypomethylated genes in SSA/P specimens were determined by RT-PCR and immunohistochemistry. We established 3-dimensional SSA/P organoids and performed knockdown experiments using a lentiviral shRNA vector. DNA hypomethylation at CpG sites of the gene was quantitated by MassARRAY analysis. The mean number of hypomethylated genes in SSA/P and cancer in SSA/P was 41.6 ± 27.5 and 214 ± 19.8, respectively, showing a stepwise increment in hypomethylation during the SSA/P-cancer sequence. S100P, S100α2, PKP3, and MUC2 were most commonly hypomethylated in SSA/P specimens. The mRNA and protein expression levels of S100P, S100α2, and MUC2 were significantly elevated in SSA/P compared with normal colon tissues, as revealed by RT-PCR and immunohistochemistry, respectively. Among these, mRNA and protein levels were highest for S100P. Knockdown of the S100P gene using a lentiviral shRNA vector in 3-dimensional SSA/P organoids inhibited cell growth by >50% (p < 0.01). The mean diameter of SSA/P organoids with S100P gene knockdown was significantly smaller compared with control organoids. MassARRAY analysis of DNA hypomethylation in the S100P gene revealed significant hypomethylation at specific CpG sites in intron 1, exon 1, and the 5'-flanking promoter region. These results suggest that DNA hypomethylation, including S100P hypomethylation, is supposedly associated with the SSA/P-cancer sequence. S100P overexpression via DNA hypomethylation plays an important role in promoting cell growth in the SSA/P-cancer sequence.


Lansoprazole Inhibits the Development of Sessile Serrated Lesions by Inducing G1 Arrest via Skp2/p27 Signaling Pathway.

Although the serrated-neoplasia pathway reportedly accounts for 15-30% of colorectal cancer (CRC), no studies on chemoprevention of sessile serrated lesions (SSLs) have been reported. We searched for effective compounds comprehensively from a large series of compounds by employing Connectivity Map (CMAP) analysis of SSL-specific gene expression profiles coupled with in vitro screening using SSL patient-derived organoids (PDOs), and validated their efficacy using a xenograft mouse model of SSL. We generated SSL-specific gene signatures based on DNA microarray data, and applied them to CMAP analysis with 1309 FDA-approved compounds to select candidate compounds. We evaluated their inhibitory effects on SSL-PDOs using a cell viability assay. SSL-PDOs were orthotopically transplanted into NOG mice for in vivo evaluation. The signal transduction pathway was evaluated by gene expression profile and protein expression analysis. We identified 221 compounds by employing CMAP analysis of SSL-specific signatures, which should cancel the gene signatures, and narrowed them down to 17 compounds. Cell viability assay using SSL-PDOs identified lansoprazole as having the lowest IC50 value (47 µM) among 17 compounds. When SSL-PDO was orthotopically transplanted into murine intestinal tract, the tumor grew gradually. Administration of lansoprazole to mice inhibited the growth of SSL xenograft whereas the tumor in control mice treated with vehicle alone grew gradually over time. The Ki67 index in xenograft lesions from the lansoprazole group was significantly lower compared with the control group. Cell cycle analysis of SSL-PDOs treated with lansoprazole exhibited a significant increase in G1 phase cell population. Microarray and protein analysis revealed that lansoprazole downregulated Skp2 expression and upregulated p27 expression in SSL-PDOs. Our data strongly suggest that lansoprazole is the most effective chemopreventive agent against SSL, and that lansoprazole induces G1 cell cycle arrest by downregulating Skp2 and upregulating p27 in SSL cells.


Clinical impact of primary tumour location, early tumour shrinkage, and depth of response in the treatment of metastatic colorectal cancer with first-line chemotherapy plus cetuximab or bevacizumab.

The primary tumour location is an important prognostic factor for previously untreated metastatic colorectal cancer (mCRC). However, the predictive efficacies of primary tumour location, early tumour shrinkage (ETS), and depth of response (DpR) on mCRC treatment has not been fully evaluated. This study aimed to investigate the predictive efficacies of these traits in mCRC patients treated with first-line 5-fluorouracil-based chemotherapy plus biologic agents, namely, cetuximab and bevacizumab. This was a retrospective analysis of the medical records of 110 patients with pathology-documented unresectable mCRC. Patients with left-sided mCRC receiving any first-line regimen showed better overall survival (OS) than those with right-sided mCRC [33.3 vs 16.3 months; hazard ratio (HR) 0.44; 95% confidence interval (CI) 0.27-0.74; p < 0.001]. In patients with left-sided tumours, treatment with chemotherapy plus cetuximab yielded longer OS than chemotherapy plus bevacizumab (50.6 vs 27.8 months, HR 0.55; 95% CI 0.32-0.97; p = 0.0378). mCRC patients with ETS and high DpR showed better OS than those lacking ETS and with low DpR (33.5 vs 19.6 months, HR 0.50, 95% CI 0.32-0.79, p = 0.023 and 38.3 vs 19.0 months, HR 0.43, 95% CI 0.28-0.68, p < 0.001, respectively). Moreover, ETS and/or high DpR achieved in patients with right-sided mCRC receiving chemotherapy plus cetuximab were associated with significantly better OS than in those lacking ETS and with low DpR (34.3 vs 10.4 months, HR 0.19, 95% CI 0.04-0.94, p = 0.025 and 34.3 vs 10.4 months, HR 0.19, 95% CI 0.04-0.94, p = 0.0257, respectively). Taken together, our study demonstrates that primary tumour location is not only a well-known prognostic factor but also a relevant predictive factor in patients with mCRC receiving chemotherapy plus cetuximab. Additionally, both ETS and DpR could predict treatment outcomes and also potentially guide cetuximab treatment even in right-sided mCRCs.


MicroRNA-296-5p Promotes Cell Invasion and Drug Resistance by Targeting Bcl2-Related Ovarian Killer, Leading to a Poor Prognosis in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by aggressive invasion, early metastasis, and resistance to chemotherapy, leading to a poor prognosis. To clarify the molecular mechanism of these malignant characteristics, we performed a genome-wide microRNA (miRNA) array analysis utilizing micro-cancer tissues from patients with unresectable PDAC (stage IV), obtained by endoscopic ultrasound-fine needle aspiration (EUS-FNA). The expression profiles of 2,042 miRNAs were determined using micro-cancer tissues from 13 patients with unresectable PDAC obtained by EUS-FNA. The relationship between individual miRNA levels and overall survival (OS) was analyzed. Possible target genes for miRNAs were bioinformatically analyzed using the online database miRDB. Pancreatic cancer cell lines PANC-1, MIA PaCa-2, and PK-8 were transfected with miRNA mimic or small interfering RNA, and cell invasion, epithelial-mesenchymal transition (EMT), and apoptosis markers were examined. miRNA and mRNA expressions were examined by quantitative polymerase chain reaction. Of 2,042 miRNAs, the 10 that exhibited the lowest correlation coefficient (p 0.005) between miRNA expression level and OS among the patients were identified. The miRDB and expression analysis in cancer cell lines for the 10 miRNAs identified miR-296-5p and miR-1207-5p as biomarkers predictive of shorter survival (p < 0.0005). Bioinformative target gene analysis and transfection experiments with miRNA mimics showed that Bcl2-related ovarian killer (BOK), a pro-apoptotic gene, is a target for miR296-5p in pancreatic cancer cells; transfection of miR-296-5p mimic into PANC-1, MIA PaCa-2, and PK-8 cells resulted in significant suppression of BOK mRNA and protein expression. These transfectants showed significantly higher invasion capability compared with control cells, and knock down of BOK in pancreatic cancer cells similarly enhanced invasion capability. Transfectants of miR-296-5p mimic also exhibited aberrant expression of EMT markers, including vimentin and N-cadherin. Moreover, these transfectants showed a significantly lower apoptosis rate in response to 5-fluorouracil and gemcitabine with a decrease of BOK expression, suggesting a role of miR-296-5p in drug resistance. These results suggest that miR-296-5p is a useful biomarker for a poor prognosis in patients with PDAC, and that the miR-296-5p/BOK signaling axis plays an important role in cell invasion, drug resistance, and EMT in PDACs.


Indocyanine green-labeled dasatinib as a new fluorescent probe for molecular imaging of gastrointestinal stromal tumors.

It is difficult to differentiate gastrointestinal stromal tumors (GISTs) from other subepithelial lesions under gastrointestinal endoscopy. Because most GISTs express tyrosine kinase receptor c-KIT, fluorescence-labeled c-KIT-specific tyrosine kinase inhibitors seem to be useful agents for molecular imaging of GIST. We aimed to develop a near-infrared fluorescent imaging technology for GIST targeting c-KIT using the novel fluorescent probe indocyanine green-labeled dasatinib (ICG-dasatinib) and to investigate the antitumor effect of ICG-dasatinib on GIST cells. Indocyanine green-labeled dasatinib was synthesized by labeling linker-induced dasatinib with ICG derivative 3-indocyanine-green-acyl-1,3-thiazolidine-2-thione. Human GIST cell lines GIST-T1 and GIST-882M were incubated with ICG-dasatinib and observed by fluorescent microscopy. GIST cells were incubated with ICG-dasatinib, unlabeled dasatinib, or imatinib, and cell viabilities were evaluated. Subcutaneous GIST model mice or orthotopic GIST model rats were intravenously injected with ICG-dasatinib and observed using an IVIS Spectrum. Strong fluorescent signals of ICG-dasatinib were observed in both GIST cell lines in vitro. IC50 values for ICG-dasatinib, unlabeled dasatinib, and imatinib were 13.9, 1.17, and 16.2 nM in GIST-T1 and 26.6, 3.63, and 47.6 nM in GIST-882M cells, respectively. ICG-dasatinib accumulated in subcutaneous xenografts in mice. Fluorescent signals were also observed in liver and gallbladder, indicating biliary excretion; however, fluorescence intensity of tumors was significantly higher than that of intestine after washing. Strong fluorescent signals were observed in orthotopic xenografts through the covering normal mucosa in rats. Indocyanine green-labeled dasatinib could visualize GIST cells and xenografted tumors. The antitumor effect of ICG-dasatinib was preserved to the same degree as imatinib.

Journal of Gastroenterology and Hepatology


Conversion therapy for unresectable hepatocellular carcinoma after lenvatinib Three case reports.

Lenvatinib (LEN) is a novel potent multi-tyrosine kinase inhibitor, approved as first-line treatment for unresectable hepatocellular carcinoma (HCC). Considering its high objective response rate, LEN therapy could be expected to achieve downstaging of tumors and lead to conversion therapy with hepatectomy or ablation. However, the feasibility of conversion therapy after LEN treatment in unresectable HCC remains largely unknown. Here, we reported 3 cases of unresectable HCC: case 1, a 69-year-old man diagnosed with ruptured HCC; case 2, a 72-year-old woman with nonalcoholic steatohepatitis-based HCC; and case 3, a 73-year-old man with a history of alcoholic cirrhosis-based HCC. In all cases, cirrhosis was classified as Child-Pugh 5 and modified albumin-bilirubin grade 1 or 2a. HCC was diagnosed as Barcelona Clinic Liver Cancer (BCLC) stage B. In all cases, LEN was initiated after conventional-transcatheter arterial embolization enforcement, while maintaining liver function. In all cases, the main tumor size decreased after 6 months of LEN treatment and no satellite nodes were detected, indicating downstaging of HCC to BCLC stage A. Subsequently, conversion hepatectomy or ablation was performed. After successful conversion therapy, the general condition of the patients was good, without tumor recurrence during the observation period (median 10 months). This study demonstrated that LEN enables downstaging of HCC and thus represents a bridge to successful surgery or ablation therapy. In particular, LEN treatment may facilitate the possibility for conversion therapy of initially unresectable HCC, while maintaining the hepatic functional reserve.


胃癌における免疫チェックポイント阻害薬の効果と免疫関連副作用(irAE) との関連性についての検討

Recently, immune checkpoint inhibitors(ICI)have been approved for use in advanced gastric cancer(AGC)based on the positive results of ATTRACTION‐2 trial in Japan. There has been accumulating evidence that the development of immune-related adverse events(irAE)may be associated with a response to ICI therapy, particularly in lung cancer, although little is known about these correlations in gastrointestinal cancer. To investigate the efficacy and irAE of ICI treatment and their correlation in AGC, we retrospectively examined 29 patients with AGC who received nivolumab therapy in our departments. Among them, 15 patients(52%)developed irAEs including 4 patients(14%)for grade 3 irAEs ; liver dysfunction(n＝2), type 1 diabetes mellitus(n＝2) and adrenal insufficiency(n＝1). The median overall survival was12．0months in the irAE group and 3．25 months in the non-irAE group(p＝0．164), which suggested the relationship between the effects and irAEs in ICI treatment of AGC. Further research is required to understand the implications of irAE characteristics on ICI response in GCA patients.


Assessment of accidental events in images during capsule endoscopy

当院における カプセル内視鏡検査の画像不良事例と対策について

Recently, there have been some reports of electromagnetic interference during capsule endoscopy(CE)in regards to other medical devices and facility environment. These accidental events have not been analyzed sufficiently although academic societies and related ministries are proposing guidelines with cautious attention. Based on this, detailed analyses and development of solution are required. In this study, we review our experience with cases of accidental events during CE and assessed the causes and preventive solutions. A total of149CE cases(male :89, female :60, mean age :56±18 8)from January 2017 until December 2019 were analyzed retrospectively. Four cases(2%)with defective images were noted. Detailed events were as follows ;1 disorder of the sensor array, 2 recorder freezes, and 1 electromagnetic interference. These mechanical and electromagnetic troubles should be assessed and shared among medical staffs and manufacturers to propose possible solutions and perform CE safely.


Sorafenib as second-line treatment option after failure of lenvatinib in patients with unresectable hepatocellular carcinoma

Abstract Background and Aim Currently, there is no molecular-targeted agent that has demonstrated evidence of efficacy in patients with unresectable hepatocellular carcinoma (u-HCC) who have developed resistance to treatment with lenvatinib (LEN). In this real-world study, we aimed to investigate the therapeutic effect and safety of sorafenib (SOR) in patients with u-HCC after progression on treatment with LEN. Methods (Patients) and Results A total of 13 patients with u-HCC (12 males and 1 female), who were treated with SOR after progression on LEN, were enrolled in this retrospective study. Therapeutic efficacy was evaluated via contrast-enhanced computerized tomography at 8 weeks after the initiation of SOR therapy according to modified response evaluation criteria in solid tumors (mRECIST) and RECIST. According to mRECIST, the objective response rate (ORR) and disease control rate (DCR) were 15.3


Cancer-associated Adipocytes Promote Pancreatic Cancer Progression Through SAA1 Expression

Although pancreatic cancer often invades into peripancreatic adipose tissue, little is known about the cancer-adipocyte interaction. We first investigated the ability of adipocytes to de-differentiate to cancer-associated adipocytes (CAAs) by co-culturing with pancreatic cancer cells. We then examined the effects of CAA-conditioned media (CAA-CM) on the malignant characteristics of cancer cells, the mechanism underlying those effects, and their clinical relevance in pancreatic cancer. When 3T3-L1 adipocytes were co-cultured with pancreatic cancer cells (PANC-1) using Transwell system, adipocytes lost their lipid droplets and morphologically changed to fibroblast-like cells (CAA). Adipocyte-specific marker mRNA levels significantly decreased but those of fibroblast-specific markers appeared, characteristic findings of CAA, as revealed by real-time PCR. When PANC-1 cells were cultured with CAA-CM, significantly higher migration/invasion capability, chemoresistance, and epithelial-mesenchymal transition (EMT) properties were observed compared with control cells. To investigate the mechanism underlying these effects, we performed microarray analysis of PANC-1 cells cultured with CAA-CM, and found 78.5-fold higher expression of SAA1 compared with control cells. When SAA1 gene in PANC-1 cells was knocked down with SAA1 siRNA, migration/invasion capability, chemoresistance, and EMT properties were significantly attenuated compared with control cells. Immunohistochemical analysis on human pancreatic cancer tissues revealed positive SAA1 expression in 46/61 (75.4%). Overall survival in the SAA1-positive group was significantly shorter than in the SAA1-negative group (p=0.013). In conclusion, we demonstrated that pancreatic cancer cells induced de-differentiation in adipocytes toward CAA, and CAA promoted malignant characteristics of pancreatic cancer via SAA1 expression, suggesting that SAA1 is a novel therapeutic target in pancreatic cancer.


Synergistic anti-tumor activity of miriplatin and radiation through PUMA-mediated apoptosis in hepatocellular carcinoma.

The prognosis for patients with unresectable advanced hepatocellular carcinoma (HCC) is poor. Miriplatin is a hydrophobic platinum compound that has a long retention time in lesions after transarterial chemoembolization (TACE). We investigated anti-tumor activity of miriplatin combined with irradiation on HCC cells, and its underlying mechanism of apoptosis. We also analyzed the effectiveness of miriplatin-TACE and radiotherapy for locally advanced HCC. Human HCC cell lines HepG2 and HuH-7 were treated with DPC (active form of miriplatin) and radiation, and synergy was evaluated using a combination index (CI). Apoptosis-related proteins and cell cycles were analyzed by western blotting and flowcytometry. We retrospectively analyzed treatment outcomes in 10 unresectable HCC patients with vascular/bile duct invasion treated with miriplatin-TACE and radiotherapy. DPC or X-ray irradiation decreased cell viability dose-dependently. DPC plus irradiation decreased cell viability synergistically in both cell lines (CI < 1, respectively). Cleaved PARP expression was induced much more strongly by DPC plus irradiation than by each treatment alone. Expression of p53 up-regulated modulator of apoptosis (PUMA) was significantly induced by the combination, and knockdown of PUMA with siRNA significantly decreased apoptosis in both cell lines. DPC plus irradiation caused sub-G1, G2/M, and S phase cell arrest in those cells. The combination of miriplatin-TACE and radiotherapy showed a high response rate for patients with locally advanced HCC despite small number of patients. Miriplatin plus irradiation had synergistic anti-tumor activity on HCC cells through PUMA-mediated apoptosis and cell cycle arrest. This combination may possibly be effective in treating locally advanced HCC.


Potential use of lenvatinib for patients with unresectable hepatocellular carcinoma including after treatment with sorafenib: Real-world evidence and in vitro assessment via protein phosphorylation array.

The efficacy and safety of lenvatinib (LEN) as a second/third-line treatment for unresectable hepatocellular carcinoma (HCC) after sorafenib (SOR) therapy remains unknown. We evaluated the outcomes of second/third-line LEN treatment, investigated the sensitivity of a SOR-resistant HCC cell line (PLC/PRF5-R2) to LEN, and assessed their signal transduction pathways by protein array analysis. We retrospectively enrolled 57 patients with unresectable HCC. Fifty-three radiologically evaluated patients comprised 34 molecular-targeted agent (MTA)-naive (first-line), nine intolerant to SOR (second-line), and 10 resistant to regorafenib (third-line). The objective response rates (ORRs) were 61.8% in first-line, 33.3% in second-line, and 20.0% in third-line groups. The overall survival (OS) in the first-line was significantly longer than that in the third-line group ( < 0.05). Patients with better liver functional reserves (child score, ALBI grade) exhibited higher ORR and longer OS. The IC of LEN against PLC/PRF5-R2 was significantly higher than that against PLC/PRF5. LEN significantly inhibited more LEN-related signal transduction pathways in PLC/PRF5 than in PLC/PRF5-R2 cells. This suggests that LEN is active and safe as a second/third-line treatment for unresectable HCC. LEN seems more effective for patients with HCC with better hepatic reserve functions or before MTA-resistance is acquired because of the partial cross-resistance to SOR.


JMJD2A sensitizes gastric cancer to chemotherapy by cooperating with CCDC8.

Jumonji domain-containing protein 2A (JMJD2A) of the JMJD2 family of histone lysine demethylases has been implicated in tumorigenesis. However, its expression and role in gastric cancer (GC) drug resistance remain unknown. Here, we investigated the role of JMJD2A in GC chemotherapeutic susceptibility and its clinical relevance in GC. We selected 12 relevant genes from previously identified gene signatures that can predict GC susceptibility to docetaxel, cisplatin, and S-1 (DCS) therapy. Each gene was knocked down using siRNA in GC cell lines, and cell viability assays were performed. JMJD2A expression in GC cell lines and tissues was assessed using qRT-PCR and immunohistochemistry, respectively. A JMJD2A downstream target related to drug susceptibility was examined using whole-gene expression array and immunoprecipitation. Among the 12 candidate genes, down-regulation of JMJD2A showed the maximum effect on GC susceptibility to anti-cancer drugs and increased the IC values for 5-FU, cisplatin, and docetaxel 15.3-, 2.7-, and 4.0-fold, respectively. JMJD2A was universally expressed in 12 GC cell lines, and its overexpression in GC tissue was positively correlated with tumor regression in 34 DCS-treated patients. A whole-gene expression array of JMJD2A-knockdown GC cells demonstrated a significant decrease in the expression of pro-apoptotic coiled-coil domain containing 8 (CCDC8), a downstream target of JMJD2A. Direct interaction between CCDC8 and JMJD2A was verified using immunoprecipitation. CCDC8 inhibition restored drug resistance to docetaxel, cisplatin, and S-1. Our results indicate that JMJD2A is a novel epigenetic factor affecting GC chemotherapeutic susceptibility, and JMJD2A/CCDC8 is a potential GC therapeutic target.


Epidermal growth factor receptortargeted molecular imaging of colorectal tumors: Detection and treatment evaluation of tumors in animal models.

To overcome the problem of overlooking colorectal tumors, a new and highly sensitive modality of colonoscopy is needed. Moreover, it is also important to establish a new modality to evaluate viable tumor volume in primary lesions of colorectal cancer (CRC) during chemotherapy. Therefore, we carried out molecular imaging of colorectal tumors targeting epidermal growth factor receptor (EGFR), which is highly expressed on tumor cells, for evaluating chemotherapeutic efficacy and for endoscopic detection of colorectal adenomas. We first attempted to image five CRC cell lines with various levels of EGFR expression using an Alexa Fluor-labeled anti-EGFR monoclonal antibody (AF-EGFR-Ab). A strong fluorescence signal was observed in the cells depending on the level of EGFR expression. When nude mice xenografted with LIM1215 CRC cells, which highly express EGFR, were i.v. injected with AF-EGFR-Ab, a strong fluorescence signal appeared in the tumor with a high signal to noise ratio, peaking at 48 hours after injection and then gradually decreasing, as shown using an IVIS Spectrum system. When the xenografted mice were treated with 5-fluorouracil, fluorescence intensity in the tumor decreased in proportion to the viable tumor cell volume. Moreover, when the colorectum of azoxymethane-treated rats was observed using a thin fluorescent endoscope with AF-EGFR-Ab, all 10 small colorectal adenomas (3 mm) were detected with a clear fluorescence signal. These preliminary results of animal experiments suggest that EGFR-targeted fluorescent molecular imaging may be useful for quantitatively evaluating cell viability in CRC during chemotherapy, and also for detecting small adenomas using a fluorescent endoscope.


Massive hemobilia following plastic stent removal in common bile duct cancer associated with primary sclerosing cholangitis (with video).

Hemobilia is defined as bleeding into the biliary tract. Herein, we report a very rare case of massive hemobilia following plastic stent (PS) removal in common bile duct (CBD) cancer. A 72-year-old man with primary sclerosing cholangitis had undergone repeated insertion of a PS into the CBD. Biliary tract biopsy was performed based on suspicion of combined CBD cancer. Biopsy revealed poorly differentiated adenocarcinoma of the CBD. One month after the biliary tract biopsy, he was admitted for acute cholangitis, and endoscopic retrograde cholangiography was performed for the exchange of the PS. When one of the two biliary PSs was removed, spurting bleeding from the major papilla began abruptly. The massive bleeding caused the patient to be in a pre-shock state. A retrieval balloon catheter was compressed against the papilla for hemostasis. Although he was treated conservatively, the patient developed a bloody discharge. Upper gastrointestinal endoscopy revealed that the pulsatile bleeding beside the PSs started immediately after the removal of the coagula. Emergent contrast-enhanced computed tomography showed right hepatic artery aneurysm across the CBD. Therefore, transarterial embolization was performed. The patient's post-therapeutic course was uneventful. He received chemotherapy, but died about a half year after hemobilia occurred.


A dose-escalation study of docetaxel, oxaliplatin, and S-1 (DOS) as a first-line therapy for patients with unresectable metastatic gastric cancer.

The aim of this study was to determine the recommended dose (RD) for a docetaxel/oxaliplatin/S-1 (DOS) regimen in patients with unresectable gastric cancer and to preliminarily evaluate its efficacy. Previously untreated patients with histologically proven unresectable metastatic gastric cancer were enrolled (n = 16). Docetaxel and oxaliplatin were administered intravenously on day 8 and S-1 was administered orally twice a day on days 1-14. Each cycle was repeated every 3 weeks. Dose-limiting toxicities (DLTs) were evaluated during the first treatment cycle. Three dose escalations of DOS were employed in this study: level 1 (50/100/80 mg/m), level 2 (50/130/80 mg/m), and level 3 (60/130/80 mg/m). According to the 3 + 3 dose-escalating schedule, we determined that the RD and maximum tolerated dose for this regimen were level 1 and level 2, respectively. The DLTs were grade 3 diarrhea and febrile neutropenia. The overall response rate was 78% (7/9) for patients with measurable lesions and consisted of two complete responses and five partial responses. Five patients underwent conversion surgery. The median follow-up time was 19 months with median survival time and progression-free survival being 19.6 months and 7.6 months, respectively. The results from this study demonstrated the safety and tolerability of DOS in unresectable metastatic gastric cancer patients and revealed promising preliminary efficacy with a high conversion rate. A phase II trial of DOS regimen using the identified RD is ongoing.


Detection of aberrant crypt foci with image-enhanced endoscopy.

Conventional detection of aberrant crypt foci (ACF) with dye-spraying and magnifying observation is labor- and skill-intensive. We performed a prospective non-inferiority study to investigate the utility of image-enhanced endoscopy (IEE) for detection of ACF. Patients with a history of colorectal neoplasm were eligible. The number of ACF in the lower rectum was counted first using IEE magnification with narrow-band imaging (NBI) or blue-laser imaging (BLI), and subsequently using the methylene blue method. The primary endpoint was the ACF detection rate with IEE, i. e., the number of ACF detected with IEE relative to the number of ACF detected with methylene blue. The secondary endpoints were bowel preparation time, ACF detection time, and the detection rate with NBI or BLI. A total of 40 patients were enrolled (NBI 20 and BLI 20). The overall detection rate for ACF with IEE was 81.7 % (503/616; 95 %CI 78.8 - 84.6 %), meeting the primary endpoint. The detection rate for ACF with BLI (84.9 %, 258/304) was significantly higher than with NBI (78.5 %, 245/312; < 0.05). Both bowel preparation time and ACF detection time were significantly shorter with IEE versus the methylene blue method ( < 0.01, respectively). The detection rates for dysplastic and non-dysplastic ACF with IEE were 84.4 % (27/32) and 80.3 % (469/584), respectively. IEE is able to detect ACF during colonoscopy with sensitivity non-inferior to that of the conventional methylene blue method. IEE is simpler than the methylene blue method and is therefore a potentially useful new tool for ACF detection.


First report of an Asian family with gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) revealed with the germline mutation of the APC exon 1B promoter region.

A 48-year-old Japanese female with left hypochondralgia presented at our hospital. Esophagogastroduodenoscopy (EGD) revealed gastric cancers and carpeting fundic gland polyposis (FGPs) without Helicobacter pylori infection. Computed tomography showed multiple liver metastases. Total colonoscopy revealed a colonic tubular adenoma but not polyposis. She was diagnosed as having advanced gastric cancer with liver metastasis and received chemotherapy. Her mother had died from gastric cancer, and her elderly brother and niece had FGPs as revealed by EGD. Thus, the pedigree was diagnosed as gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS). Germline mutation analysis exhibited a point mutation in exon1B of the APC gene (c.-191T > C). Adenocarcinoma showed a gastric mucinous phenotype and was positive for a somatic mutation of p53, suggesting that p53 mutation may play a role in FGPs carcinogenesis. This is the first family with GAPPS in Asia in whom germline mutation of APC exon 1B has been detected.


A Novel Theranostic Combination of Near-infrared Fluorescence Imaging and Laser Irradiation Targeting c-KIT for Gastrointestinal Stromal Tumors.

It is difficult to distinguish gastrointestinal stromal tumors (GISTs) from other types of submucosal tumors under conventional gastrointestinal endoscopy. We aimed to detect GISTs by molecular fluorescence imaging using a near-infrared (NIR) photosensitizer (IR700)-conjugated anti-c-KIT antibody and to treat GISTs by photoimmunotherapy with NIR irradiation as a non-invasive theranostic procedure. We also investigated the therapeutic mechanisms. Human GIST cell lines GIST-T1 and GIST-882M were incubated with IR700-conjugated anti-c-KIT antibody, IR700-12A8, and observed by confocal laser microscopy. Mice with GIST-T1 xenografts or rats with orthotopic xenografts were injected with IR700-12A8 or AF488-conjugated antibody, and observed under IVIS or autofluorescence imaging (AFI) endoscopy. GIST cells were treated with IR700-12A8 and NIR light and vivo, and cell viability, histology and apoptosis were evaluated. Strong red fluorescence of IR700-12A8 was observed on the cell membrane of GIST cells and was gradually internalized into the cytoplasm. Tumor-specific accumulation of IR700-12A8 was observed in GIST-T1 xenografts in mice. Under AFI endoscopy, a strong fluorescence signal was observed in orthotopic GIST xenografts in rats through the normal mucosa covering the tumor. The percentage of dead cells significantly increased in a light-dose-dependent manner and both acute necrotic and late apoptotic cell death was observed with annexin/PI staining. Cleaved PARP expression was significantly increased after IR700-12A8-mediated NIR irradiation, which was almost completely reversed by NaN. All xenograft tumors (7/7) immediately regressed and 4/7 tumors completely disappeared after IR700-12A8-mediated NIR irradiation. Histologic assessment and TUNEL staining revealed apoptosis in the tumors. NIR fluorescence imaging using IR700-12A8 and subsequent NIR irradiation could be a very effective theranostic technology for GIST, the underlying mechanism of which appears to involve acute necrosis and supposedly late apoptosis induced by singlet oxygen.


APOB codon 4311 polymorphism is associated with hepatitis C virus infection through altered lipid metabolism.

It has been reported that some single-nucleotide polymorphisms (SNPs) in lipid regulators such as apolipoproteins and cell surface molecules for hepatitis C virus (HCV) entry into hepatocytes are associated with HCV infection. However, it is unknown how HCV infection is affected by altered lipid metabolism resulting from the SNPs. We investigated the relationship between these SNPs and HCV infection status, and also analyzed the mechanism by which these SNPs mediate HCV infection via lipid metabolism alterations. Serum lipid and apolipoprotein profiles were tested in 158 HCV-positive and 220 HCV-negative subjects. We selected 22 SNPs in five lipid regulator genes which were related to HCV entry into hepatocytes and to lipid metabolism (APOA1, APOB, SR-B1, LDLR, and APOE), and their polymorphisms were analyzed using the PCR-sequence-specific oligonucleotide probe-Luminex method. An APOB N4311S (g.41553a > g) SNP, rs1042034, was significantly associated with HCV positivity; the HCV positivity rate for the minor allele AA genotype was significantly higher than for genotype AG + GG (P = 0.016). Other SNPs except for APOB P2712L SNP rs676210, which is in linkage disequilibrium with rs1042034, showed no significant difference in genotype distribution. The serum level of low density lipoprotein-cholesterol (LDL-C) in the genotype AA group was significantly lower than in the genotype non-AA group (P = 0.032), whereas the triglyceride (TG) level was significantly higher (P = 0.007). An APOB SNP, rs1042034, is closely associated with HCV infection through lipid metabolism alteration. The minor allele AA genotype might contribute to facilitating serum LDL uptake into hepatocytes via LDLR by modifying their affinity and interaction and may have an influence on HCV infection by their entry to the liver through the LDLR.


Linked color imaging enhances endoscopic detection of sessile serrated adenoma/polyps.

Although new image-enhanced endoscopy (IEE) technologies such as blue laser imaging (BLI), BLI-bright, and linked color imaging (LCI) have been developed, their utility for the detection of sessile serrated adenoma/polyps (SSA/Ps) is still unclear. This study aimed to evaluate the utility of BLI, BLI-bright, and LCI for SSA/P detection in still image examinations and in a prospective randomized controlled trial (RCT). A group of 6 expert and non-expert endoscopists read 200 endoscopic still images containing SSA/P lesions using white light image (WLI), BLI, BLI-bright, and LCI. Color differences were calculated using the color space method. A prospective RCT of tandem colonoscopy with WLI and LCI was performed. Patients with SSA/P and those with a history of SSA/P that had been endoscopically removed were enrolled and randomly allocated to WLI-LCI or LCI-WLI groups. Additional endoscopic detection rates for SSA/P were compared between the 2 groups. LCI showed the highest SSA/P detection rate among the 4 modes for both expert and non-expert endoscopists. The detection rate with LCI for the 6 expert endoscopists (mean 98.3 ± standard deviation 2.0 %) was significantly higher than that with WLI (86.7 ± 6.0 %, < 0.01). Likewise, the detection rate with LCI for the 6 non-expert endoscopists (92.3 ± 2.9 %) was significantly higher than that with WLI (72.7 ± 11.5 %, < 0.01). The color difference of SSA/P with LCI was the highest among the 4 modes, and was significantly higher than with WLI (median 15.9, (interquartile range 13.7 - 20.6) vs. 10.2, (7.6 - 14.2); < 0.0001). In the RCT, a total of 44 patients (WLI-LCI 22 vs. LCI-WLI 22) underwent colonoscopy. The additional detection rate for SSA/P in the second inspection in the WLI-LCI group (21.6 %, 8/37) was significantly higher than in the LCI-WLI group (3.2 %, 1/31; = 0.02). The small, flat, non-mucus and isochromatic SSA/Ps in the transverse colon were detected more frequently in the second inspection with LCI. LCI was the most sensitive mode for SSA/P detection among WLI, BLI, BLI-bright, and LCI in the still image examinations. Our RCT strongly suggests that LCI is superior to conventional WLI for SSA/P detection during colonoscopy. UMIN000017599.


A triplet combination with capecitabine/oxaliplatin/irinotecan (XELOXIRI) plus cetuximab as first-line therapy for patients with metastatic colorectal cancer: a dose escalation study.

The addition of cetuximab to triplet chemotherapy can increase treatment efficacy for patients with metastatic colorectal cancer (mCRC). We explored the dose-limiting toxicity and feasibility of a triweekly capecitabine, oxaliplatin, irinotecan, plus cetuximab (XELOXIRI plus cetuximab) regimen in patients with wild-type KRAS mCRC. Patients received oxaliplatin (100 mg/m, day 1), capecitabine (1700 mg/m per day from day 2 to 15), irinotecan (100, 120, and 150 mg/m for dose levels 1, 2, 3, respectively, on day 1), and cetuximab (400 mg/m, day 1 and, thereafter, 250 mg/m every week), repeated every 3 weeks. Dose-limiting toxicities (DLTs) were assessed in the first 2 treatment cycles to determine the maximum tolerated dose (MTD) and the recommended dose (RD). Twelve patients received a median of 7 cycles of therapy (range 2-10). The DLT was grade 4 neutropenia, observed in 1 of 6 patients at dose level 2. The MTD was not reached at dose level 3. Therefore, the RD of irinotecan was defined as 150 mg/m. Most common grade ≥ 3 toxicities were neutropenia (50%), diarrhea (17%), and febrile neutropenia (8%). The response rate was 83% (complete and partial response: 1 and 9 patient(s), respectively), including 4 conversion cases. The combination of XELOXIRI and cetuximab is feasible and has an acceptable toxicity profile; neutropenia was the DLT. The RD of irinotecan is 150 mg/m. The observed response rate was promising and warrants further investigation.


EGFR Down-regulation After anti-EGFR Therapy Predicts the Anti-tumor Effect in Colorectal Cancer.

Anti-EGFR mAb is reported to induce EGFR internalization in colorectal cancer cells. However, the biological relevance of EGFR internalization with anti-EGFR mAb is unknown. Therefore, the relevance of EGFR downregulation with anti-EGFR mAb to antitumor activity in colorectal cancer cells was investigated. Quantification of EGFR on the cell surface before cetuximab treatment was assessed by flow cytometry, and its growth-inhibitory effects were measured by Trypan blue exclusion, in 10 wild-type colorectal cancer cell lines, but there was no significant correlation between EGFR number and its growth-inhibitory effect. However, a significant correlation existed between the percentage decrease in the number of EGFRs after cetuximab treatment and its growth-inhibitory effect in those cell lines. Treatment with TGFα, a ligand for EGFR, induced EGFR internalization in colorectal cancer cells, but most EGFRs subsequently recycled to the cell surface, consistent with previous studies. While cetuximab treatment induced EGFR internalization, most receptors subsequently translocated into the late endosome, leading to lysosomal degradation, as revealed by immunoblotting and double immunofluorescence. Cetuximab-sensitive colorectal cancer cells showed greater EGFR internalization, stronger cell growth inhibition, and more augmented apoptotic signals than nonsensitive cells. IHC for EGFR, performed using an EGFR pharmDx Kit (mouse anti-human EGFR mAb clone 2-18C9), in clinical specimens before and after anti-EGFR mAb therapy in 13 colorectal cancer patients showed a significant correlation between the response to anti-EGFR mAb and decreased staining after therapy. This report clearly demonstrates that anti-EGFR mAb facilitates internalization and subsequent degradation of EGFRs in lysosomes, which is an important determinant of the efficacy of anti-EGFR mAb treatment for colorectal cancer. .


Clinicopathological Assessment of Gastric Xanthomas as Potential Predictive Markers of Gastric Cancer.

Gastric xanthomas are frequently observed in the stomach as small yellowish plaques or nodules. A close relationship among Helicobacter pylori infection, atrophic gastritis, and xanthomas has been reported. We assessed the clinicopathological features of gastric cancer with or without xanthomas. A total of 91 patients who were diagnosed as having early gastric cancer were enrolled. We evaluated the gastritis status using scores for gastritis and atrophy, positivity of H. pylori infection, the prevalence rate of xanthomas, and the clinicopathological features of gastric cancer. Gastric xanthomas were observed in 72.5% of early gastric cancer cases. Scores for gastritis and atrophy were significantly higher in the xanthoma-positive group than those in the xanthoma-negative group. A higher prevalence of differentiated-type adenocarcinoma was found in the xanthoma-positive group. Among the cases with multiple gastric xanthomas, the prevalence of males was significantly higher than that of females. A high prevalence rate of gastric xanthomas in gastric cancer cases was shown. Xanthomas were highly associated with age, the severities of gastritis and atrophy, and differentiated-type adenocarcinoma. Regardless of the eradication of H. pylori, xanthomas may be useful predictive markers for the development of differentiated-type adenocarcinoma.


Twin Rectal Tonsils Mimicking Carcinoid or Mucosa-Associated Lymphoid Tissue Lymphoma.

The rectal tonsil is a rare polypoid lesion exclusively found in the rectum and is considered a reactive proliferation of the lymphoid tissue. Although this lesion is benign, we recommend that it should be differentiated from carcinoid or polypoid type of mucosaassociated lymphoid tissue (MALT) lymphomas, based on gross findings. In this case report, we describe a case of rectal lesions with a unique appearance in a 41-year-old man. Colonoscopy revealed two 5-mm-sized nodules located opposite from each other on the left and right sides of the lower rectum. Endoscopic mucosal resection was conducted. Histopathologically, both lesions were mainly located in the submucosa and consisted of prominent lymphoid follicles with germinal centers of various sizes. No immunoreactivity of Bcl-2 was seen in the germinal centers. Immunohistochemical staining for kappa and lambda light chains revealed a polyclonal pattern. Therefore, these lesions were diagnosed as rectal tonsils.


Molecular imaging of aberrant crypt foci in the human colon targeting glutathione S-transferase P1-1.

Aberrant crypt foci (ACF), the earliest precursor lesion of colorectal cancers (CRCs), are a good surrogate marker for CRC risk stratification and chemoprevention. However, the conventional ACF detection method with dye-spraying by magnifying colonoscopy is labor- and skill-intensive. We sought to identify rat and human ACF using a fluorescent imaging technique that targets a molecule specific for ACF. We found that glutathione S-transferase (GST) P1-1 was overexpressed in ACF tissues in a screening experiment. We then synthesized the fluorogenic probe, DNAT-Me, which is fluorescently quenched but is activated by GSTP1-1. A CRC cell line incubated with DNAT-Me showed strong fluorescence in the cytosol. Fluorescence intensities correlated significantly with GST activities in cancer cell lines. When we sprayed DNAT-Me onto colorectal mucosa excised from azoxymethane-treated rats and surgically resected from CRC patients, ACF with strong fluorescent signals were clearly observed. The ACF number determined by postoperative DNAT-Me imaging was almost identical to that determined by preoperative methylene blue staining. The signal-to-noise ratio for ACF in DNAT-Me images was significantly higher than that in methylene blue staining. Thus, we sensitively visualized ACF on rat and human colorectal mucosa by using a GST-activated fluorogenic probe without dye-spraying and magnifying colonoscopy.


The differing influence of several factors on the development of fatty liver with elevation of liver enzymes between genders with metabolic syndrome: A cross-sectional study.

Nonalcoholic fatty liver disease (NAFLD) is known to be strongly associated with obesity, visceral fat, metabolic syndrome (MS), lifestyle, and lifestyle-related diseases in both males and females. However, the prevalence of NAFLD, MS, and clinical backgrounds is different between males and females. We conducted a cross-sectional study to examine the differing influence of lifestyle-related factors and visceral fat on fatty liver (FL) with elevation of liver enzymes between males and females with MS. We enrolled 42,134 persons who underwent a regular health check-up, and after excluding subjects who fulfilled excluding criteria, the remaining subjects were 2,110 persons with MS. We examined the differing influence of lifestyle-related factors and visceral fat on FL with elevation of alanine aminotransferase (ALT) (ALT elevation was defined as ALT level of ≥31 IU/l in the present study). The odds rations for FL with ALT elevation were as follows: WC, 1.83 (95% confidence interval (CI) 1.36-2.46); dyslipidemia, 1.89 (95% CI 1.34-2.68); hemoglobin A1c, 1.36 (95% CI 1.00-1.85); visceral fat type MS (V-type MS), 5.78 (95% CI 4.29-7.80); and light drinker, 0.56 (95% CI 0.41-0.78) in males with MS and BMI, 2.18 (95% CI 1.43-3.33); WC, 1.85 (95% CI 1.27-2.70); diastolic blood pressure, 1.69 (95% CI 1.16-2.45); triglyceride, 2.22 (95% CI 1.56-3.17); impaired glucose tolerance, 1.66 (95% CI 1.11-2.47); and V-type MS, 3.83 (95% CI 2.57-5.70) in females with MS. The prevalence of FL with ALT elevation and ALT was significantly higher in V-type MS than in the subcutaneous fat type MS in both males and females with MS (P < 0.001). Although V-type MS and WC is a common significant predictor of an increased prevalence of FL with ALT elevation in both males and females with MS, gender, lifestyle-related factors, and MS type in individuals with MS should be considered for the development of FL with ALT elevation.


Plasma brain natriuretic peptide levels are elevated in patients with cancer

Natriuretic peptides have been proposed as biomarkers of cardiovascular disease, especially heart failure. Brain natriuretic peptide (BNP) has also been shown to be upregulated at the transcriptional and translational levels by pro-inflammatory cytokines in cardiac myocytes. Although we often measure plasma BNP levels in cancer patients, it remains unknown whether cancer-related inflammation affects the plasma BNP levels. We investigated the relationship between the BNP and human cancers. We retrospectively studied 2,923 patients in whom the plasma BNP levels and serum C-reactive protein (CRP) were measured and echocardiography was performed. Patients with clinically evident heart failure (NYHA II or higher), heart disease requiring medical treatment or surgery, renal dysfunction, and inflammatory disease were excluded. There were 234 patients in the final analysis. Blood sampling was performed before surgery and chemotherapy. In addition, we evaluated the relationship between the inflammation and plasma BNP levels in mouse models of colon cancer. Of the 234 patients, 80 were diagnosed with cancer. Both the plasma BNP and serum CRP levels were significantly higher in cancer patients than those without. There were no significant differences in the echocardiographic parameters. There was a significant positive correlation between the plasma BNP and serum CRP levels in cancer patients (r = 0.360, P<0.01) but not in those without. In cancer patients, only the CRP correlated with the BNP independent of the age, creatinine level, hypertension, and body mass index. In addition, in nude mice with subcutaneous colon cancer, the plasma BNP level was elevated compared with that in non-cancer mice, and there was a significant relationship between the plasma BNP and serum levels of the inflammatory markers. In cancer patients, as well as colon cancer model mice, the plasma BNP levels were elevated, possibly due to cancer-related inflammation. The effect of cancer on the BNP levels should be considered when using BNP as an indicator of heart failure in cancer patients.


Paraneoplastic hypocalcemia developed in gastric cancer accompanied by osteoblastic metastasis

Paraneoplastic syndromes are generally defined as clinical disorders associated with malignant diseases, and hypocalcemia associated with cancer is a rare condition. A woman in her 60s was referred to our hospital for the further examination of massive ascites due to carcinoma of unknown primary origin. She complained of numbness around her lips, and marked hypocalcemia of 5.0 mg/dL was noted. After two courses of chemotherapy, computed tomography showed a decrease in the ascites, and her serum calcium level increased. Although hypocalcemia is a very rare condition in patients with gastric cancer, serum calcium values should be evaluated when neurological symptoms are observed.


Response Predictors of S-1, Cisplatin, and Docetaxel Combination Chemotherapy for Metastatic Gastric Cancer: Microarray Analysis of Whole Human Genes.

The aim of this study was to identify biomarkers for predicting the efficacy of docetaxel, cisplatin, and S-1 (DCS) therapy for advanced gastric cancer using microarrays of biopsy specimens before chemotherapy. Nineteen samples were taken from 19 patients with unresectable metastatic gastric cancer who received DCS as a first-line therapy. Laser capture microdissection was performed, and total cellular RNA was extracted from each microdissected sample. Whole-gene expression was analyzed by microarray, and the difference in mRNA expression observed with the microarrays was confirmed by quantitative real-time PCR. Immunohistochemical staining was performed using clinical tissue sections obtained by endoscopic biopsy. Eleven patients were identified as early responders and 8 patients as nonresponders to DCS therapy. Twenty-nine genes showed significant differences in relative expression ratios between tumor and normal tissues. A classifier set of 29 genes had high accuracy (94.7%) for distinguishing gene expression between 11 early responders and 8 nonresponders. Decreasing the size of the classifier set to 4 genes (PDGFB, PCGF3, CISH, and ANXA5) increased the accuracy to 100%. Expression levels by real-time PCR for validation were well correlated with those 4 genes in microarrays. The genes identified may serve as efficient biomarkers for personalized cancer-targeted therapy.


Efficacy of hybrid endoscopic submucosal dissection (ESD) as a rescue treatment in difficult colorectal ESD cases.

Endoscopic submucosal dissection (ESD), which provides a higher en bloc resection rate than conventional endoscopic mucosal resection (EMR), is considered to be a useful treatment option for large colorectal tumors. However, colorectal ESD is not widely used because of its technical difficulty, risk of complications and time required. To overcome these drawbacks, a simpler modified technique, ESD with snaring (hybrid ESD), has been developed. The aim of the present study was to retrospectively compare the safety and efficacy of hybrid ESD and conventional ESD for colorectal tumors. Between September 2008 and June 2016, ESD was carried out on 137 lesions and hybrid ESD on 27 lesions. All hybrid ESD cases were carried out as a rescue treatment in difficult ESD cases. We retrospectively investigated procedure time, and the rates of en bloc resection, perforation, bleeding, and local recurrence. In the hybrid ESD group, procedure time was shorter compared with the ESD group (108 ± 59.5 min vs 122 ± 72.2 min), but the en bloc resection rate was lower (66.7% vs 94.2%). However, there were no significant differences in procedure time, or in rates of en bloc resection, perforation and bleeding between the two groups. Local recurrence did not develop in any of our cases. Hybrid ESD as a rescue treatment in difficult ESD cases may be less effective for en bloc resection of large colorectal tumors. Indication for hybrid ESD may be limited to scheduled treatment from the outset and emergency cases with patients who present unstable vital signs during ESD.


Poly-(ADP-Ribose) Polymerase-1 Promotes Prothrombin Gene Transcription and Produces Des-Gamma-Carboxy Prothrombin in Hepatocellular Carcinoma.

Although des-gamma-carboxy prothrombin (DCP) is a well-known tumor marker for hepatocellular carcinoma (HCC), the mechanism of DCP production is unclear. This study aimed to investigate the mechanism how DCP is produced in HCC cells. Levels of mRNA and DCP were analyzed by real-time polymerase chain reaction and electro-chemiluminescence immunoassay respectively. Secreted alkaline phosphatase (SEAP) expression vectors including deletion mutants of the prothrombin gene promoter were constructed for reporter gene assay. The transcription factors bound to DNA fragments were analyzed by mass spectrometry. An electrophoretic mobility shift assay (EMSA) was performed using a biotin end-labeled DNA. The prothrombin mRNA levels in all 5 DCP producing cell lines were appreciably high. However, those in 2 DCP non-producing cell lines were below detectable levels. A SEAP vector with -2985 to +27 showed a very high transcription activity in DCP-producing Huh-1 cells. However, transcription abruptly decreased when the vector with -2955 to +27 was transfected, and then remained at the similar levels with larger deletion mutants, indicating the existence of a cis-element at -2985 to -2955 (31-bp). Mass spectrometry analysis identified the protein that bound to the 31-bp DNA as poly-(ADP-ribose) polymerase-1 (PARP-1). Knockdown of the PARP-1 gene by small interfering RNA in Huh-1 cells induced marked inhibition of prothrombin gene transcription. The EMSA clearly showed that PARP-1 specifically binds to the 31-bp DNA fragment in the prothrombin gene promoter. Our data suggest that PARP-1 activates prothrombin gene transcription and that the excessive prothrombin gene transcription induces DCP production in DCP-producing HCC cells.


Colon capsule endoscopy: toward the future.

Colon capsule endoscopy is a wireless and minimally invasive technique for visualization of the whole colon. With recent improvements of technical features in second-generation systems, a more important role for colon capsule endoscopy is rapidly emerging. Although several limitations and drawbacks are yet to be resolved, its usefulness as a tool for colorectal cancer screening and monitoring disease activity in inflammatory bowel diseases has become more apparent with increased use. Further investigations, including multicenter trials, are required to evaluate the substantial role of the colon capsule in managing colorectal diseases.


Hemosuccus pancreaticus caused by a mucinous cystic neoplasm of the pancreas.

Hemosuccus pancreaticus is a gastrointestinal hemorrhage through the main pancreatic duct. Here, we report a rare case of hemosuccus pancreaticus due to a mucinous cystic neoplasm of the pancreas. A 62-year-old woman who had been followed for a branch duct intraductal papillary mucinous neoplasm visited our emergency room due to severe abdominal pain and bloody discharge. Computed tomography revealed that the pancreatic cyst increased the tension of the wall and a high-density area indicative of bleeding into the cyst was observed. Endoscopy showed opening of and hemorrhaging from the papilla of Vater. The patient was diagnosed with hemosuccus pancreaticus caused by hemorrhaging into the cyst from the branch duct intraductal papillary mucinous neoplasm. Based on this diagnosis, elective distal pancreatectomy was performed. The histopathological diagnosis was a mucinous cystic neoplasm with intermediate-grade dysplasia based upon the pathological findings that fibrous ovarian-type stroma existed abundantly and the stroma cells were positive for progesterone receptor and inhibin. Hemosuccus pancreaticus caused by a mucinous cystic neoplasm is extremely rare and there has been only one case reported to date. In conclusion, it should be recognized that pancreatic cystic neoplasms including mucinous cystic neoplasms may cause hemosuccus pancreaticus.


Duodenal cancer in a young patient with Peuts-Jeghers syndrome harboring an entire deletion of the STK11 gene.


Downregulation of miR-100/miR-125b is associated with lymph node metastasis in early colorectal cancer with submucosal invasion.

A majority of early colorectal cancers (CRCs) with submucosal invasion undergo surgical operation, despite a very low incidence of lymph node metastasis. Our study aimed to identify microRNAs (miRNAs) specifically responsible for lymph node metastasis in submucosal CRCs. MicroRNA microarray analysis revealed that miR-100 and miR-125b expression levels were significantly lower in CRC tissues with lymph node metastases than in those without metastases. These results were validated by quantitative real-time PCR in a larger set of clinical samples. The transfection of a miR-100 or miR-125b inhibitor into colon cancer HCT116 cells significantly increased cell invasion, migration, and MMP activity. Conversely, overexpression of miR-100 or miR-125b mimics significantly attenuated all these activities but did not affect cell growth. To identify target mRNAs, we undertook a gene expression array analysis of miR-100-silenced HCT116 cells as well as negative control cells. The Ingenuity Pathway Analysis, TargetScan software analyses, and subsequent verification of mRNA expression by real-time PCR identified mammalian target of rapamycin (mTOR) and insulin-like growth factor 1 receptor (IGF1R) as direct, and Fas and X-linked inhibitor-of-apoptosis protein (XIAP) as indirect candidate targets for miR-100 involved in lymph node metastasis. Knockdown of each gene by siRNA significantly reduced the invasiveness of HCT116 cells. These data clearly show that downregulation of miR-100 and miR-125b is closely associated with lymph node metastasis in submucosal CRC through enhancement of invasion, motility, and MMP activity. In particular, miR-100 may promote metastasis by upregulating mTOR, IGF1R, Fas, and XIAP as targets. Thus, miR-100 and miR-125b may be novel biomarkers for lymph node metastasis of early CRCs with submucosal invasion.


Clinicopathological Characteristics of Serrated Polyps as Precursors to Colorectal Cancer: Current Status and Management.

Serrated polyps have long been thought to lack malignant potential in the human colorectum. However, identification of the serrated pathway to colorectal cancer based on molecular biology has improved our understanding of the pathogenesis of colorectal cancers. Accordingly, serrated polyps such as traditional serrated adenoma and sessile serrated adenoma/polyps (SSA/P) are now considered to be precursor lesions of the serrated pathway. Recently, serrated polyps were classified into three subtypes, consisting of hyperplastic polyp, SSA/P, and traditional serrated adenoma, according to the World Health Organization classification. It has been suggested that SSA/P in the proximal colon are a precursor lesion of pathogenesis of colorectal cancer and are characterized by BRAF mutation and a CpG island methylator phenotype with or without microsatellite instability. However, SSA/P is more challenging to detect by colonoscopy and is likely to account for some interval cancers, particularly in the proximal colon because it presents flat or sessile, isochroous appearance, and occasionally has a mucous cap. Furthermore, the possibility has been raised that pathologists misclassify SSA/P as hyperplastic polyp. It is important for gastroenterologists to recognize the endoscopic features of serrated polyps to facilitate their detection and removal and also to establish postpolypectomy surveillance guidelines. In this review, we discuss the recent classification of serrated polyps; the molecular characteristics of the serrated pathway; appropriate diagnostic methods using endoscopy, including a new image-enhanced endoscopic technique; and management of these lesions.

Journal of Gastroenterology and Hepatology


隆起を呈する病変 上皮性・非腫瘍性 胃黄色腫

隆起を呈する病変 上皮性・非腫瘍性 胃黄色腫


Neuroendocrine carcinoma of the pancreas with similar genetic alterations to invasive ductal adenocarcinoma.

Neuroendocrine carcinoma (NEC) of the pancreas is very rare, and its origin is not fully elucidated. Here, we present a case of a small-size NEC of the pancreas that is genetically similar to invasive ductal adenocarcinoma (IDA). A 65-year-old man was referred to our hospital due to obstructive jaundice and found to have a 12-mm solid tumor in the pancreas head. The tumor exhibited low vascularity on enhanced computed tomography, and endoscopic retrograde pancreatographic imaging revealed an irregular obstruction in a branch duct of the pancreas. The patient was thereby diagnosed with a pancreatic ductal cancer, and stomach-preserving pancreaticoduodenectomy with regional lymph node resection was performed. Histochemical analysis of the resected tumor showed that the neoplastic cells with scanty cytoplasm and hyperchromatic nuclei strongly expressed chromogranin A and synaptophysin. The Ki-67 index was 40 % in the most proliferative tumor regions, and the tumor was diagnosed as a NEC of the pancreas. However, in the analysis of genetic alterations of the tumor tissue, the neoplastic cells showed altered KRAS, TP53, and SMAD4/DPC4, suggesting that the NEC in our case is genetically related to IDA. Our data suggest that poorly differentiated IDAs may transform into NECs.


Panitumumab in combination with irinotecan plus S-1 (IRIS) as second-line therapy for metastatic colorectal cancer.


Influence of metabolic syndrome on upper gastrointestinal disease.

A recent increase in the rate of obesity as a result of insufficient physical exercise and excess food consumption has been seen in both developed and developing countries throughout the world. Additionally, the recent increased number of obese individuals with lifestyle-related diseases associated with abnormalities in glucose metabolism, dyslipidemia, and hypertension, defined as metabolic syndrome (MS), has been problematic. Although MS has been highlighted as a risk factor for ischemic heart disease and arteriosclerotic diseases, it was also recently shown to be associated with digestive system disorders, including upper gastrointestinal diseases. Unlike high body weight and high body mass index, abdominal obesity with visceral fat accumulation is implicated in the onset of various digestive system diseases because excessive visceral fat accumulation may cause an increase in intra-abdominal pressure, inducing the release of various bioactive substances, known as adipocytokines, including tumor necrosis factor-α, interleukin-6, resistin, leptin, and adiponectin. This review article focuses on upper gastrointestinal disorders and their association with MS, including obesity, visceral fat accumulation, and the major upper gastrointestinal diseases.


食生活を改善して大腸癌を予防する1次予防では，赤身肉，加工肉，アルコール，喫煙などの危険因子を回避(または減量)すること，野菜，線維，果物，牛乳，カルシウムなどを十分に摂取するとともに，適度な運動を行うように心がけるべきである．また，大腸癌を早期に発見する2次予防では，便潜血検査や大腸内視鏡検査を受けることが重要である．大腸内視鏡検査では，前癌病変である腺腫を摘除することも癌の予防に重要である．一方，現在種々の薬剤の発癌予防効果を調べる臨床試験が行われており，近い将来，有効な予防薬が開発されることが期待される．大腸癌の3次予防としては，異時性の大腸癌予防の観点から定期検査の受診が必要である．

The Japanese Journal of Gastro-enterology


Protein-losing enteropathy in a patient with familial adenomatous polyposis and advanced colon cancer.

A 29-year-old female visited a hospital because of increasingly severe lower leg edema. She was diagnosed as having multiple polyps in the stomach and colon by gastroscopy and sigmoidoscopy as well as multiple liver tumors by abdominal CT. She was referred to our hospital for further examination. Total colonoscopy revealed a type 2 tumor in the transverse colon and more than 200 polyps distributed throughout the colorectum. Biopsies of the tumor and polyps showed histological characteristics of adenocarcinoma and tubulovillous adenoma, respectively. Thus, she was diagnosed as having metastatic colon cancer derived from familial adenomatous polyposis (FAP). Laboratory tests showed a marked hypoalbuminemia of 1.1 g/dl. The fecal alpha-1 anti-trypsin test showed abnormal clearance (62.1 ml/day), and scintigraphy using 99mTc-human serum albumin revealed protein loss in the whole colon. Multiple ligation probe amplification analysis of the APC gene identified a germline duplication of exons 11-13. Direct sequencing of the reverse transcription PCR products of APC mRNA revealed a deletion of 25 base pairs and a tandem duplication of exons 11-13. This case was considered to be protein-losing enteropathy resulting from numerous colonic tubulovillous adenomas and advanced colon cancer in a FAP patient with unusual mutational events in APC.


Localized amyloidosis of the stomach mimicking a superficial gastric cancer.

A 73-year-old man was referred to our hospital for further examination of a depressed lesion in the stomach found by cancer screening gastroscopy. A barium upper gastrointestinal series showed an area of irregular mucosa measuring 15 mm on the anterior wall of the gastric body. Esophagogastroduodenoscopy revealed a 15 mm depressed lesion on the anterior wall of the lower gastric body. We suspected an undifferentiated adenocarcinoma from the appearance and took some biopsies. However, histology of the specimens revealed amyloidal deposits in the submucosal layer without malignant findings. Congo red staining was positive for amyloidal protein and green birefringence was observed under polarized light microscopy. Congo red staining with prior potassium permanganate incubation confirmed the light chain (AL) amyloid type. There were no amyloid deposits in the colon or duodenum. Computed tomography of the chest, abdomen, and pelvis showed no remarkable findings. Thus, this case was diagnosed as a localized gastric amyloidosis characterized by AL type amyloid deposition in the mucosal or submucosal layer. As the clinical outcome of gastric AL amyloidosis seems favorable, this case is scheduled for periodic examination to recognize potential disease progression and has been stable for 2 years.


Influence of light alcohol consumption on lifestyle-related diseases: a predictor of fatty liver with liver enzyme elevation in Japanese females with metabolic syndrome.

Although heavy drinking is known to lead to liver injury, some recent studies have reported that light alcohol consumption (LAC) may play a protective role against fatty liver in the general population, and may even play a protective role against non-alcoholic fatty liver disease (NAFLD) in males with metabolic syndrome (MS). However, the association between LAC and fatty liver with liver enzyme elevation in females with MS is unclear. Participants of this study were 20,853 females who underwent a regular health check-up between April 2008 and March 2012 at our hospital. Enrolled subjects were 1141 females with MS, who underwent all necessary tests and drank less than 20 g/day of alcohol. We investigated the presence of fatty liver with liver enzyme elevation, defined in this study as alanine aminotransferase (ALT) levels ≧31 IU/I, and the association between LAC and fatty liver with ALT elevation. There was no significant difference in the prevalence of fatty liver and ALT between light drinkers and non-drinkers. The prevalence of individuals receiving a treatment for dyslipidemia and impaired glucose tolerance (IGT) was significantly lower in light drinkers than in non-drinkers. Body mass index (BMI), waist circumference (WC), diastolic blood pressure (DBP), triglyceride (TG), uric acid (UA), IGT, and visceral fat type MS (V-type MS) were significant predictors of the prevalence of fatty liver with ALT elevation in logistic regression analysis. The odds ratio [OR] (95 % confidence interval [CI], p value) for fatty liver with ALT elevation were as follows: BMI, 2.181 (1.445-3.293, p <0.001); WC, 1.853 (1.280-2.684, p <0.01); DBP, 1.604 (1.120-2.298, p <0.05); TG, 2.202 (1.562-3.105, p <0.001); UA, 2.959 (1.537-5.698, p <0.01); IGT, 1.692 (1.143-2.506, p <0.01); and V-type MS, 3.708 (2.529-5.437, p <0.001). There was no significant difference in the prevalence of fatty liver with ALT elevation in females with MS between light drinkers and non-drinkers, suggesting that other factors such as BMI, WC, V-type MS, and lifestyle-related disease may be more important than LAC for the prevalence of fatty liver with ALT elevation.


MRP3 as a novel resistance factor for sorafenib in hepatocellular carcinoma

The mechanism of resistance of hepatocellular carcinoma (HCC) to sorafenib is unknown and no useful predictive biomarker for sorafenib treatment has been reported. Accordingly, we established sorafenib-resistant HCC cells and investigated the underlying mechanism of resistance to sorafenib. Sorafenib-resistant cell lines were established from the HCC cell line PLC/PRF5 by cultivation under continuous exposure to increasing concentration of sorafenib. The IC50 values of the 2 resistant clones PLC/PRF5-R1 and PLC-PRF5-R2 were 9.2±0.47 M (1.8-fold) and 25±5.1 M (4.6-fold) respectively, which were significantly higher than that of parental PLC/PRF5 cells (5.4±0.17 M) (p < 0.01 respectively), as determined by MTT assay. Western blot analysis of signal transduction-related proteins showed no significant differences in expression of AKT/pAKT, mTOR/pmTOR, or ERK/pERK between the 2 resistant clones versus parent cells, suggesting no activation of an alternative signal transduction pathway. Likewise, when expression of membrane transporter proteins was determined, there were no significant differences in expression levels of BSEP, MDR1, MRP2, BCRP, MRP4 and OCT1 between resistant clones and parent cells. However, the expression levels of MRP3 in the 2 resistant clones were significantly higher than that of parent cells. When MRP3 gene was knocked down by siRNA in PLC-PRF5-R2 cells, the sensitivity of the cells to sorafenib was restored. In the analysis of gene mutation, there was no mutation in the activation segment of Raf1 kinase in the resistant clones. Our data clearly demonstrate that the efflux transporter MRP3 plays an important role in resistance to sorafenib in HCC cells.


Serum diamine oxidase activity as a predictor of gastrointestinal toxicity and malnutrition due to anticancer drugs.

Objective evaluation of intestinal mucosal damage due to anticancer drugs is generally difficult. Serum diamine oxidase (DAO) activity is reported to reflect the integrity and maturity of the small intestinal mucosa. Therefore, we investigated whether serum DAO activity is an indicator of gastrointestinal toxicity or nutritional status in patients receiving chemotherapy. We prospectively enrolled 20 patients with unresectable metastatic gastric cancer who received oral S-1 (80 mg/m(2) ) on days 1-14, and intravenous cisplatin (60 mg/m(2) ) and docetaxel (50 mg/m(2) ) on day 8 every 3 weeks. Serum DAO activity was measured by colorimetry. Gastrointestinal toxicity was evaluated by CTCAE v4.0. Endoscopic examination and biopsy of duodenal mucosa assessed mucosal damage. Malnutrition was evaluated by measuring serum total protein and albumin levels. Serum DAO activity decreased step-by-step significantly during anticancer drug treatment and recovered after drug holidays. In all 14 patients who experienced diarrhea, serum DAO activity significantly decreased prior to diarrhea onset. Percent decrease in DAO activity was significantly correlated with severity of diarrhea. Significant correlation was observed between percent decrease in DAO activity and percent decrease in duodenal villus height or surface area from baseline. There were also significant correlations between percent decrease in serum DAO activity at day 14 and percent decrease in serum total protein or albumin levels at day 21 from baseline. Serum DAO activity sensitively indicates gastrointestinal damage prior to symptom onset and can be a useful predictor of intestinal mucosal damage and nutritional status in patients receiving chemotherapy.

Journal of Gastroenterology and Hepatology


A Phase I/II Study of Fixed-dose-rate Gemcitabine and S-1 with Concurrent Radiotherapy for Locally Advanced Pancreatic Cancer

This study was conducted to identify the maximum-tolerated dose (MTD) of fixed-dose-rate gemcitabine (FDR-gem) administered concurrently with S-1 and radical radiation for locally advanced pancreatic cancer (LAPC) and to provide efficacy and safety data. Patients with unrespectable pancreatic cancer confined to the pancreatic region were treated with FDR-gem (300-400 mg/m(2), 5 mg/m(2)/min) on days 1, 8, 22, and 29 and 60 mg/m(2) of S-1 orally on days 1-14, 22-35. A total radiation dose of 50.4 Gy (1.8 Gy/day, 28 fractions) was delivered concurrently. Twenty-five patients were enrolled; all were evaluable for toxicity assessment. In phase I, eight patients were treated in sequential cohorts of three to five patients per dose level. The MTD was reached at level 2, and dose-limiting toxicities were neutropenia and thrombocytopenia. The recommended doses were 300 mg/m(2) of gemcitabine and 60 mg/m(2) of S-1 daily. The overall response rate was 25% and disease control rate (partial response plus stable disease) was 92%. The progression-free survival was 11.0 months. The median overall survival and 1-year survival rates were 16.0 months and 73%, respectively. The combination of FDR-gem and S-1 with radiation is a feasible regimen that shows favorable antitumor activity with an acceptable safety profile in patients with LAPC.


Investigation of Gastroduodenal Mucosal Injury in Japanese Asymptomatic Antiplatelet Drug Users

Antiplatelet drugs are widely used for the prevention of cardiovascular disease and cerebral vascular disorders. Although there have been several studies on gastroduodenal mucosal injury with gastrointestinal (GI) symptoms such as GI bleeding, in antiplatelet drug users (including low-dose aspirin (LDA)), there have been few reports on the association between antiplatelet drug use and gastroduodenal mucosal injury in asymptomatic antiplatelet drug users. This study was a cross-sectional study elucidating the association between antiplatelet drug use and gastroduodenal mucosal injury in asymptomatic antiplatelet drug users.Subjects were 186 asymptomatic Japanese antiplatelet drug users who underwent a regular health checkup. Subjects were divided into those with and without gastroduodenal mucosal injury endoscopically, and the association between gastroduodenal mucosal injury and other data in asymptomatic antiplatelet drug users was investigated.The prevalence of males and drinkers were significantly higher in subjects with gastroduodenal mucosal injury than in those without. In addition, the prevalence of proton pump inhibitor (PPI) users was significantly lower in subjects with gastroduodenal mucosal injury than in subjects without gastroduodenal mucosal injury. Logistic regression analysis showed PPI (odds ratios: 0.116; 95% confidence intervals: 0.021-0.638; P < 0.05) was a significant predictor of a decreased prevalence of gastroduodenal mucosal injury and closed-type (C-type) atrophy (3.172; 1.322-7.609; P < 0.01) was a significant predictor of an increased prevalence of severe gastroduodenal mucosal injury in asymptomatic antiplatelet drug users.Gender and lifestyle, such as drinking, may have an impact on risk of gastroduodenal mucosal injury in asymptomatic subjects taking antiplatelet drugs. Although PPI is a significant predictor of a decreased prevalence of gastroduodenal mucosal injury, including in asymptomatic antiplatelet drug users, status of gastric atrophy should also be considered against severe gastroduodenal mucosal injury.


Endoscopic Management of Nonvariceal Upper Gastrointestinal Bleeding: State of the Art.

Nonvariceal upper gastrointestinal (GI) bleeding is one of the most common reasons for hospitalization and a major cause of morbidity and mortality worldwide. Recently developed endoscopic devices and supporting apparatuses can achieve endoscopic hemostasis with greater safety and efficiency. With these advancements in technology and technique, gastroenterologists should have no concerns regarding the management of acute upper GI bleeding, provided that they are well prepared and trained. However, when endoscopic hemostasis fails, endoscopy should not be continued. Rather, endoscopists should refer patients to radiologists and surgeons without any delay for evaluation regarding the appropriateness of emergency interventional radiology or surgery.


Epidermoid metaplasia of the esophagus with an unusual appearance on magnification.


Gastric inflammatory fibroid polyp morphologically changed by Helicobacter pylori eradication.

A 60-year-old male presented to our hospital for further investigation of abnormal findings on an upper gastrointestinal series. Esophagogastroduodenoscopy demonstrated atrophic gastritis and a submucosal tumor (SMT) at the anterior wall of the antrum. The patient was positive for serum anti-Helicobacter pylori (H. pylori) antibody and H. pylori eradication therapy was performed. Five months later, the SMT showed a remarkable morphological change in that an ulcer had developed on its apex, and partial gastrectomy was performed. Pathological examination suggested an inflammatory fibroid polyp (IFP), and genetic analysis revealed no mutation in the platelet-derived growth factor receptor alpha gene. This case suggests that H. pylori infection plays an important role in the etiology of IFPs.


Insulin-like growth factor II-producing metastatic colon cancer with recurrent hypoglycemia.

A 45-year-old man was referred to our hospital and found to have a tubular adenocarcinoma of the descending colon with multiple liver metastases. During hospitalization, the patient suffered recurrent hypoglycemic attacks that required intravenous 50% glucose infusion. He was diagnosed with non-islet cell tumor hypoglycemia (NICTH) because the colon cancer tissue obtained by biopsy was strongly stained for insulin-like growth factor-II (IGF-II) by immunohistochemistry. He received chemotherapy with oxaliplatin, 5-FU and leucovorin (FOLFOX) plus bevacizumab (Bmab), and showed a partial response. As the metastatic lesions decreased in size, the hypoglycemic attacks gradually disappeared. Subsequently, he received outpatient chemotherapy and maintained a high quality of life for about 10 months. Western blot analysis of IGF-II in serum at the time of admission showed a high-molecular-weight form of IGF-II, which was considered to have caused hypoglycemia. This patient presents a very rare case of colorectal cancer associated with NICTH syndrome due to production of high-molecular-weight IGF-II by cancer cells. It is important to investigate IGF-II expression in cancer tissues for establishing the diagnosis of NICTH in cases with intractable hypoglycemia complicated by advanced cancer.