Programmed Death Ligand 1 Expression in Circulating Tumor Cells as a Predictor and Monitor of Response to Atezolizumab plus Bevacizumab Treatment in Patients with Hepatocellular Carcinoma.

There remains no reliable biomarker of therapeutic efficacy in hepatocellular carcinoma (HCC) for the PD-L1 inhibitor atezolizumab and bevacizumab (Atezo/Bev). Circulating tumor cells (CTCs) enable the serial collection of living tumor cells. Pre-treatment and serial CTC gene expression changes and tumor histology were evaluated to identify predictors of response to Atezo/Bev. Peripheral blood from 22 patients with HCC treated with Atezo/Bev and 24 patients treated with lenvatinib was serially collected. The RNA expression in CTCs was analyzed using qRT-PCR. Higher PD-L1 expression in pre-treatment CTCs was associated with response and improved prognosis with Atezo/Bev treatment, but not with lenvatinib. There was no correlation between PD-L1 expression in CTCs and that in liver tumor biopsy specimens scored using imaging software. Furthermore, PD-L1 RNA expression in CTCs was dynamically altered by Atezo/Bev, decreasing during effective response and increasing upon progression. CTC-derived RNA collected during Atezo/Bev indicates that patients with higher PD-L1 expression in CTCs at baseline were 3.9 times more responsive to treatment. Therefore, PD-L1 RNA levels in CTCs are an accurate response predictor and may be a monitorable biomarker that changes dynamically to reflect the response during Atezo/Bev treatment.

Isolation of mucosa-associated microbiota dysbiosis in the ascending colon in hepatitis C virus post-sustained virologic response cirrhotic patients.

Background: Achieving sustained virologic response (SVR) in patients infected with hepatitis C virus (HCV) reduces all-cause mortality. However, the mechanisms and risk factors for liver fibrosis and portal hypertension post-SVR remain incompletely understood. In the gut-liver axis, mucosa-associated microbiota (MAM) substantially influence immune and metabolic functions, displaying spatial heterogeneity at the anatomical intestinal site. We analyzed MAM composition and function to isolate the locoregional MAM involved in chronic liver disease progression in HCV post-SVR patients. Methods: We collected MAM samples from three intestinal sites (terminal ileum, ascending colon, and sigmoid colon) via brushing during colonoscopy in 23 HCV post-SVR patients and 25 individuals without liver disease (controls). The 16S rRNA of bacterial DNA in specimens collected with a brush and in feces was sequenced. The molecular expression of intestinal tissues and hepatic tissues were evaluated by quantitative real-time PCR. Results: In the post-SVR group, the microbial ß-diversity of MAM, especially in the ascending colon, differed from the control group and was associated with liver fibrosis progression. In PICRUSt analysis, MAM in the ascending colon in the liver cirrhosis (LC) group showed compromised functions associated with the intestinal barrier and bile acid production, and FGF19 expression was markedly decreased in the terminal ileum biopsy tissue in the LC group. At the genus level, six short-chain fatty acid (SCFA)-producing bacterial genera, Blautia, Alistipes, Roseburia, Agathobaculum, Dorea, and Pseudoflavonifractor were reduced in the ascending colon of post-SVR LC patients. Conclusion: In patients of HCV post-SVR, we identified the association between the degree of liver fibrosis and dysbiosis of mucosa-associated SCFA-producing bacterial genera that may be related to intestinal barrier and bile acid production in the ascending colon.

High correlation of hepatic shear wave velocity with esophageal varices complication rate in patients with chronic liver diseases.

BACKGROUND: Histological evaluation by liver biopsy is considered the gold standard for assessing liver disease; however, it is highly invasive. Non-invasive liver stiffness measurement by shear wave elastography (SWE) is effective for evaluating the hepatic fibrosis stage and related diseases. In this study, we investigated the correlations of liver stiffness with hepatic inflammation/fibrosis, functional hepatic reserve, and related diseases in patients with chronic liver disease (CLD). METHODS: Shear wave velocity (Vs) values were measured using point SWE in 71 patients with liver disease from 2017 to 2019. Liver biopsy specimens and serum biomarkers were collected at the same time, and splenic volume was measured using computed tomography images with the software Ziostation2. Esophageal varices (EV) were evaluated by upper gastrointestinal endoscopy. RESULTS: Among CLD-related function and complications, Vs values were highly correlated with liver fibrosis and EV complication rates. The median Vs values for liver fibrosis grades F0, F1, F2, F3, and F4 were 1.18, 1.34, 1.39, 1.80, and 2.12 m/s, respectively. Comparison of receiver operating characteristic (ROC) curves to predict cirrhosis showed that area under the ROC (AUROC) curve for Vs values was 0.902, which was not significantly different from the AUROCs for the FIB-4 index, platelet count, hyaluronic acid, or type IV collagen 7S, while it was significantly different from the AUROC for mac-2 binding protein glycosylation isomer (M2BPGi) (P < 0.01). Comparison of ROC curves to predict EV showed that the AUROC for Vs values was 0.901, which was significantly higher than the AUROCs for FIB-4 index (P < 0.05), platelet count (P < 0.05), M2BPGi (P < 0.01), hyaluronic acid (P < 0.05), and splenic volume (P < 0.05). In patients with advanced liver fibrosis (F3 + F4), there was no difference in blood markers and splenic volume, while Vs value was significantly higher in patients with EV (P < 0.01). CONCLUSIONS: Hepatic shear wave velocity was highly correlated with EV complication rates in chronic liver diseases as compared to blood markers and splenic volume. In advanced CLD patients, Vs values of SWE are suggested to be effective in predicting the appearance of EV noninvasively.

Longer Survival and Preserved Liver Function after Proton Beam Therapy for Patients with Unresectable Hepatocellular Carcinoma.

BACKGROUND: Proton beam therapy (PBT) has been recently reported to achieve excellent tumor control with minimal toxicity in patients with unresectable hepatocellular carcinoma (HCC). Radiofrequency ablation (RFA) combined with transcatheter arterial chemoembolization (TACE) was investigated for larger HCC. This study was designed to evaluate the therapeutic effect of PBT on unresectable HCC in comparison with TACE combined with RFA. METHODS: We retrospectively analyzed 70 patients with HCC which was difficult to control by surgical resection or RFA monotherapy, 24 patients treated with PBT and 46 patients with TACE plus RFA. The therapeutic effects were assessed as local progression-free survival (PFS) and overall survival (OS). RESULTS: The local PFS was more than 65% in 60 months for PBT and TACE plus RFA. The patients treated with PBT showed 82% OS at 60 months post-treatment. In contrast, those treated with TACE plus RFA showed 28% OS. When comparing the changes of ALBI scores in patients with different severities of chronic liver disease, the scores of PBT-treated patients were maintained at the baseline; however, those of TACE plus RFA-treated patients worsened after the treatments. CONCLUSIONS: The results indicated that PBT may show better benefits than TACE plus RFA therapy in terms of OS in patients with unresectable HCC by sparing the non-tumor liver tissues.

Clinical Usefulness of [18F]-Fluoro-2-Deoxy-d-Glucose-Positron Emission Tomography/Computed Tomography for Distinguishing Between Autoimmune Pancreatitis and Pancreatic Cancer.

OBJECTIVES: We investigated the [18F]-fluoro-2-deoxy-d-glucose (FDG)-positron emission tomography (PET)/computed tomography (CT) findings of pancreatic and extrapancreatic lesions in patients with autoimmune pancreatitis (AIP) and pancreatic cancer (PC) and evaluated the usefulness of 18F-FDG-PET/CT for differentiating between AIP and PC. METHODS: Eighty-five patients, 19 with AIP and 66 with PC, who underwent 18F-FDG-PET/CT were studied retrospectively. We evaluated the maximum standardized uptake value (SUVmax), patterns and distributions of FDG activity in pancreatic lesions, as well as FDG uptake in extrapancreatic lesions. RESULTS: The levels of SUVmax of pancreatic lesions in PC patients were significantly higher than those in AIP patients (P < 0.05). Focal/segmental distribution of FDG activity was found in 61.1% of the AIP patients and 98.4% of the PC patients. Heterogeneous FDG activity patterns were found in 61.1% of the AIP patients and 18.7% of the PC patients. Activities of FDG in pancreatic lesions were significantly different between AIP and PC. Extrapancreatic activities of salivary glands, extraperitoneal lymph nodes, prostate, retroperitoneum, and kidneys in the AIP patients were significantly higher than those in the PC patients (P < 0.05). Multivariate analysis revealed that SUVmax (>7.08) and focal/segmental FDG distribution were independent predictors of PC (P < 0.05). CONCLUSIONS: The 18F-FDG-PET/CT findings are useful for differentiating between AIP and PC.

Severe necrotizing pancreatitis immediately after non-abdominal surgery under general anesthesia with propofol.

Postoperative pancreatitis is a relatively rare disease and is poorly recognized. Herein, we present a case of necrotizing pancreatitis that developed immediately after non-abdominal surgery under general anesthesia. In this report, 4 h after thyroidectomy under general anesthesia using propofol, the patient developed upper abdominal pain and was diagnosed with severe acute pancreatitis with extensive pancreatic necrosis. Immediately after the diagnosis, the patient received appropriate treatment, and acute pancreatitis was improved. Subsequently, the patient has the formation of non-infectious giant walled-off necrosis and remained in good condition without additional treatment for 1.5 years after pancreatitis onset. In this case report, our detailed causative search suggested that propofol administration could be the cause of this pancreatitis. Propofol-induced pancreatitis is extremely rare but develops often severely, resulting in fatality. In this case, the patient developed severe acute pancreatitis within a very short time after surgery but was able to survive by immediate intervention of treatment. We suggest that clinicians should consider acute pancreatitis as a life-threatening adverse event under general anesthesia with propofol and perform thorough postoperative management.

Bipolar-current needle-knife with a water jet function (Jet B-knife) shortens the procedure time of endoscopic submucosal dissection for colorectal tumors.

BACKGROUND: Endoscopic submucosal dissection (ESD) is a technically difficult and time-consuming procedure for the treatment of large colorectal tumors. In Japan, the ball-tip bipolar-current needle-knife (BB-knife) has been used in ESD as a safe device that minimizes the damage to deeper tissues of colorectal neoplasms. In May 2012, a BB-knife combined with a water jet function (Jet B-knife) was newly developed. METHODS: This retrospective study was aimed at examining the effectiveness and safety of the Jet B-knife. The BB-knife was used in 276 lesions (BB-knife group), while the Jet B-knife was used in 245 lesions (Jet B-knife group). We evaluated tumor characteristics and the results of the ESD procedures, including the size of the resected tumor, histological diagnosis, time required for resection, frequency of using other electrical devices, en bloc resection rate, and incidence rate of associated complications. Then, the data obtained were compared between the two groups. RESULTS: The histological evaluation of the resected tumors revealed that the incidence of cancer was not significantly different between the two groups. The median time required for resection was 103 min (45-255) in the BB-knife group and 51 min (28-210) in the Jet B-knife group. The difference was statistically significant (p < 0.05). Furthermore, the median tumor diameters were 23.1 mm (18-50) and 26.2 mm (20-60) in the BB-knife and Jet B-knife groups, respectively, demonstrating a statistically significant difference (p < 0.05). Multivariate logistic regression analysis revealed that short resection time (p < 0.001) and reduced use of hemostatic devices (p < 0.01) were independent favorable features of Jet B-knife. The en bloc resection rate and the perforation rate were not statistically significant between the two groups. CONCLUSIONS: Use of the Jet B-knife may contribute to the development of a time-saving, cost-effective, and safe procedure for ESD of colorectal tumors.

Daily Usage of Proton Pump Inhibitors May Reduce the Severity of Critical Upper Gastrointestinal Bleeding in Elderly Patients.

INTRODUCTION: We retrospectively examined the relationship between daily proton pump inhibitor (PPI) use and severity of upper gastrointestinal bleeding (UGIB), mainly in the elderly. METHODS: We included 97 patients with nonvariceal UGIB diagnosed at our hospital from January 2012 to October 2017. Bleeding severity was assessed using the shock index (SI) and estimated bleeding volume; 49 patients met the criterion for the mild group and 48 for the moderate/severe group. The effect of PPI use on bleeding severity was compared between the groups. The relationships of PPI use and dose with the clinical symptoms of UGIB were also analyzed. RESULTS: Among the 97 patients, 17 (17.5%) habitually used PPIs. The rate of habitual PPI use was significantly higher in the mild group, indicating as an independent factor contributing to a reduction in the severity of UGIB in a multiple logistic regression analysis (30.6% vs. 4.2%; OR 10.147; 95% CI 2.174-47.358, P < 0.01). When analyzing data for a subgroup of patients older than 75 years, we found the protective PPI effect to be even higher in the mild UGIB group than in the moderate/severe group (37.0% vs. 5.6%; OR 10.000; 95% CI 1.150-86.951, P < 0.05). Conversely, we found no association between PPI prescription and UGIB symptoms in patients younger than 75 years. The mean estimated bleeding volume and SI in the 17 habitual PPI users were both significantly less than those among the 80 nonhabitual users, respectively (P < 0.05). The proportion of patients with mild UGIB was similar between the low- and high-dose PPI users. CONCLUSIONS: Particularly in elderly patients with nonvariceal UGIB, habitual PPI use can alleviate the clinical symptoms of UGIB by suppressing the volume of bleeding, regardless of the adapted dose of PPIs.

Batch-Learning Self-Organizing Map Identifies Horizontal Gene Transfer Candidates and Their Origins in Entire Genomes.

Horizontal gene transfer (HGT) has been widely suggested to play a critical role in the environmental adaptation of microbes; however, the number and origin of the genes in microbial genomes obtained through HGT remain unknown as the frequency of detected HGT events is generally underestimated, particularly in the absence of information on donor sequences. As an alternative to phylogeny-based methods that rely on sequence alignments, we have developed an alignment-free clustering method on the basis of an unsupervised neural network "Batch-Learning Self-Organizing Map (BLSOM)" in which sequence fragments are clustered based solely on oligonucleotide similarity without taxonomical information, to detect HGT candidates and their origin in entire genomes. By mapping the microbial genomic sequences on large-scale BLSOMs constructed with nearly all prokaryotic genomes, HGT candidates can be identified, and their origin assigned comprehensively, even for microbial genomes that exhibit high novelty. By focusing on two types of Alphaproteobacteria, specifically psychrotolerant Sphingomonas strains from an Antarctic lake, we detected HGT candidates using BLSOM and found higher proportions of HGT candidates from organisms belonging to Betaproteobacteria in the genomes of these two Antarctic strains compared with those of continental strains. Further, an origin difference was noted in the HGT candidates found in the two Antarctic strains. Although their origins were highly diversified, gene functions related to the cell wall or membrane biogenesis were shared among the HGT candidates. Moreover, analyses of amino acid frequency suggested that housekeeping genes and some HGT candidates of the Antarctic strains exhibited different characteristics to other continental strains. Lys, Ser, Thr, and Val were the amino acids found to be increased in the Antarctic strains, whereas Ala, Arg, Glu, and Leu were decreased. Our findings strongly suggest a low-temperature adaptation process for microbes that may have arisen convergently as an independent evolutionary strategy in each Antarctic strain. Hence, BLSOM analysis could serve as a powerful tool in not only detecting HGT candidates and their origins in entire genomes, but also in providing novel perspectives into the environmental adaptations of microbes.

Efficacy of immunotherapy targeting the neoantigen derived from epidermal growth factor receptor T790M/C797S mutation in non-small cell lung cancer.

Lung cancer is the leading cause of cancer-related deaths worldwide. Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) often have good clinical activity against non-small cell lung cancer (NSCLC) with activating EGFR mutations. Osimertinib, which is a third-generation EGFR-TKI, has a clinical effect even on NSCLC harboring the threonine to methionine change at codon 790 of EGFR (EGFR T790M) mutation that causes TKI resistance. However, most NSCLC patients develop acquired resistance to osimertinib within approximately 1 year, and 40% of these patients have the EGFR T790M and cysteine to serine change at codon 797 (C797S) mutations. Therefore, there is an urgent need for the development of novel treatment strategies for NSCLC patients with the EGFR T790M/C797S mutation. In this study, we identified the EGFR T790M/C797S mutation-derived peptide (790-799) (MQLMPFGSLL) that binds the human leukocyte antigen (HLA)-A*02:01, and successfully established EGFR T790M/C797S-peptide-specific CTL clones from human PBMC of HLA-A2 healthy donors. One established CTL clone demonstrated adequate cytotoxicity against T2 cells pulsed with the EGFR T790M/C797S peptide. This CTL clone also had high reactivity against cancer cells that expressed an endogenous EGFR T790M/C797S peptide using an interferon-γ (IFN-γ) enzyme-linked immunospot (ELISPOT) assay. In addition, we demonstrated using a mouse model that EGFR T790M/C797S peptide-specific CTL were induced by EGFR T790M/C797S peptide vaccine in vivo. These findings suggest that an immunotherapy targeting a neoantigen derived from EGFR T790M/C797S mutation could be a useful novel therapeutic strategy for NSCLC patients with EGFR-TKI resistance, especially those resistant to osimertinib.

Efficacy of the NCCV Cocktail-1 vaccine for refractory pediatric solid tumors: A phase I clinical trial.

Pediatric refractory solid tumors are aggressive malignant diseases, resulting in an extremely poor prognosis. KOC1, FOXM1, and KIF20A are cancer antigens that could be ideal targets for anticancer immunotherapy against pediatric refractory solid tumors with positive expression for these antigens. This nonrandomized, open-label, phase I clinical trial evaluated the safety and efficacy of the NCCV Cocktail-1 vaccine, which is a cocktail of cancer peptides derived from KOC1, FOXM1, and KIF20A, in patients with pediatric refractory solid tumors. Twelve patients with refractory pediatric solid tumors underwent NCCV Cocktail-1 vaccination weekly by intradermal injections. The primary endpoint was the safety of the NCCV Cocktail-1 vaccination, and the secondary endpoints were the immune response, as measured by interferon-r enzyme-linked immunospot assay, and the clinical outcomes including tumor response and progression-free survival. The NCCV Cocktail-1 vaccine was well tolerated. The clinical response of this trial showed that 4 patients had stable disease after 8 weeks and 2 patients maintained remission for >11 months. In 4, 8, and 5 patients, the NCCV Cocktail-1 vaccine induced the sufficient number of peptide-specific CTLs for KOC1, FOXM1, and KIF20A, respectively. Patients with high peptide-specific CTL frequencies for KOC1, FOXM1, and KIF20A had better progression-free survival than those with low frequencies. The findings of this clinical trial showed that the NCCV Cocktail-1 vaccine could be a novel therapeutic strategy, with adequate effects against pediatric refractory solid tumors. Future large-scale trials should evaluate the efficacy of the NCCV Cocktail-1 vaccination.

Usefulness of serum microRNA as a predictive marker of recurrence and prognosis in biliary tract cancer after radical surgery.

Biliary tract cancer (BTC) is an aggressive type of malignant tumour. Even after radical resection, the risk of recurrence is still high, resulting in a poor prognosis. Here, we investigated the usefulness of serum miRNAs as predictive markers of recurrence and prognosis for patients with BTC after radical surgery using 66 serum samples that were collected at three time points from 22 patients with BTC who underwent radical surgery. Using microarray analysis, we successfully identified six specific miRNAs (miR-1225-3p, miR-1234-3p, miR1260b, miR-1470, miR-6834-3p, and miR-6875-5p) associated with recurrence and prognosis of BTC after radical surgery. In addition, using a combination of these miRNAs, we developed a recurrence predictive index to predict recurrence in patients with BTC after operation with high accuracy. Patients having higher index scores (≥ cut-off) had significantly worse recurrence-free survival (RFS) and overall survival (OS) than those with lower index scores (

Higher human lymphocyte antigen class I expression in early-stage cancer cells leads to high sensitivity for cytotoxic T lymphocytes.

Human lymphocyte antigen (HLA) class I molecules play a central role in cytotoxic T lymphocytes (CTL)-based antitumor immunity. However, the expression rate of HLA class I in cancer cells remains a topic of discussion. We compared HLA class I expression levels between cancer cells and surrounding non-tumorous hepatocytes in 20 early-stage hepatocellular carcinoma (HCC) patients by immunohistochemistry using EMR 8-5. The expression levels of HLA class I were classified as negative, incomplete positive or complete positive. Similarly, for various types of solid cancers, HLA class I expression was examined. For the HLA class I expression in cancer cells, among 20 HCC patients, 13 were complete positive, 3 were incomplete positive, and 4 were negative. In addition, 15 (75.0%) had higher expression levels of HLA class I in cancer cells compared with that in surrounding non-tumorous hepatocytes. An interferon-γ (IFN-γ) enzyme-linked immunospot (ELISPOT) assay indicated that cancer cells with positive expression of HLA class I had strong sensitivity to antigen-specific CTL. We suggested that HLA class I expression in cancer cells could be involved in the clinical prognosis of HCC patients. Similarly, 66.7%, 100.0%, 66.7% and 62.5% of patients with early-stage pancreatic, gallbladder, esophageal and breast cancers, respectively, had higher expression levels of HLA class I in cancer cells than in surrounding normal tissue cells. We suggest that in several early-stage solid cancers, including HCC, HLA class I expression levels in cancer cells are higher than that in surrounding normal tissue cells, which could result in the anti-tumor effect of CTL-based cancer immunotherapy.

Reactivation of intraabdominal tuberculous lymphadenopathy after drug-eluting beads transcatheter arterial chemoembolization in a patient with hepatocellular carcinoma.

Owing to effective treatments and sanitary improvements, the incidence of latent tuberculosis infection (LTBI) has decreased. However, approximately one-quarter of the world's population is thought to have LTBI, and the reactivation of tuberculosis (TB) sometimes occurs in immunocompromised hosts. A 54-year-old man presented with a fever. The patient had past histories of alcoholic and hepatitis C virus-related cirrhosis and hepatocellular carcinoma (HCC). He was treated with drug-eluting beads transarterial chemoembolization (DEB-TACE) for HCC three times, beginning 10 months before his current visit. A computed tomography scan showed enlarged intraabdominal lymph nodes with calcification, and the interferon-gamma release assay for TB infection was positive. The patient was diagnosed with tuberculous reactivation. Anti-TB therapy was administered to the patient, after which we restarted TACE and the TB infection remains controlled. In this case, we presumed that DEB-TACE is associated with the reactivation of TB infection and that anthracycline increases the risk of reactivating TB infection. In summary, we experienced a case of TB reactivation during the clinical course of a patient with HCC who was treated with DEB-TACE. When patients with HCC are treated with TACE, their symptoms, laboratory data, and imaging results should be monitored when latent TB infections are suspected.

Long-term prognosis after biliary stenting for common bile duct stones in high-risk elderly patients.

OBJECTIVE: To evaluate the long-term outcomes of complete common bile duct (CBD) stone removal and biliary stenting in elderly patients (≥85 years) with CBD stones. METHODS: We retrospectively examined 65 patients who underwent complete CBD stone removal (the duct clearance group) and 40 patients who underwent biliary stenting (the biliary stenting group) between July 2006 and March 2016. To reduce selection bias, we also conducted a propensity score matching analysis and generated 30 pairs of patients. Cholangitis recurrence-free survival and overall survival were compared between the two groups and independent prognostic factors of survival were identified by univariate and multivariate analyses. RESULTS: Cholangitis recurrence-free survival was significantly better in the duct clearance group than in the biliary stenting group (P < 0.001). Their overall survival did not significantly differ after propensity score matching (P = 0.388). In all cohorts, univariate analysis demonstrated that poor performance status and biliary stenting were factors of poor prognosis, and in multivariate analysis only performance status remained associated with poor prognosis for survival. Similarly, in the propensity score-matched cohort, only performance status independently predicted poorer survival (hazard ratio [HR] 2.726, 95% confidence interval [CI] 1.105-6.675, P = 0.029). The choice of endoscopic treatment was not a significant factor associated with prognosis (HR 1.354, 95% CI 0.678-2.701, P = 0.391). CONCLUSIONS: Biliary stenting was similar to complete stone removal in terms of prognosis for long-term survival. Biliary stenting for CBD stones could be an effective therapeutic tool in high-risk elderly patients.

Duplication cyst of the ileum presenting with severe anemia detected by double-balloon endoscopy.

Background and study aims Duplication cysts of the ileum are rare and present with non-specific clinical manifestations such as abdominal pain, vomiting, melena, and intussusception. Therefore, preoperative diagnosis is difficult. Here, we report a case of duplication cyst of the small intestine that was diagnosed preoperatively using double-balloon enteroscopy. A 19-year-old man presented with severe iron deficiency anemia, abdominal pain, and exertional dyspnea. Gastroscopy and colonoscopy revealed no remarkable findings. Abdominal computed tomography revealed a cystic structure in the ileum. Therefore, we performed double-balloon enteroscopy via the anal route. The intestinal tract was bifurcated, with one segment ending in a blind sac containing normal villi and an ulceration. Tc-99 m pertechnetate scintigraphy showed no accumulation in the lesion. Accordingly, we diagnosed a duplication cyst and suspected that this was the cause of severe anemia. Following small bowel resection with cyst excision and anastomosis, the anemia and presenting symptoms resolved. This report highlights the usefulness of double-balloon enteroscopy of the small intestine for preoperative diagnosis of the obscure gastrointestinal bleeding, including duplication cysts .

[Enhancement of Cytotoxic T Lymphocytes(CTLs)Infiltration into the Cancer Tissues].

Recently, with the rapid development of elucidating the tumor immunological status, it has become clear that various lymphocytes, which are infiltrating tumor, are deeply involved in not only tumor growth but also its elimination. The interest and importance of cytotoxic T cells(CTLs)for cancer immunotherapy has been further increased, since CTLs play an important role in eliminating cancer cells by having high cytotoxic activity and high proliferation ability. To achieve potent antitumor effects, in addition to the anti-tumor immune response induced by various methods such as cancer peptide vaccine and immune checkpoint inhibitor, it is thought to be essential that CTLs should migrate and invade into localized cancer tissues. In this article, we will introduce the latest immunotherapies related to CTLs infiltration, and various methods to enhancement of CTLs infiltration into the cancer tissues.

Genetic polymorphism and decreased expression of HLA class II DP genes are associated with HBV reactivation in patients treated with immunomodulatory agents.

Hepatitis B virus (HBV) reactivation can be triggered by immunosuppressive chemotherapy. HLA class II molecules may play a role in HBV reactivation. Genetic polymorphism and mRNA expression of HLA class II were examined in patients with latent HBV infection treated with immunosuppressive therapies. Subjects with resolved HBV infection who had undergone treatment with immunosuppressive chemotherapies were retrospectively enrolled (n = 42) and divided into reactivated (n = 9) and non-reactivated groups (n = 33). Patients were genotyped for 17 single nucleotide polymorphisms (SNPs) within HLA class II DPA1, and DPB1, and mRNA expression levels of HLA class II genes were assessed. The frequency of the AA genotype of rs872956, a SNP in HLA-DPB1, was significantly higher in the reactivated group than in the non-reactivated group (55.6% vs 12.1%, P < 0.05). The frequencies of the T allele and non-AA genotypes (AT/TT) of rs3116996 (located in DPB1) were significantly higher in the reactivated group (T allele frequency: 16.7% vs 0.0% [P < 0.01], non-AA genotype frequency: 22.2% vs 0.0% [P < 0.05]). Multivariate logistic regression identified the AA genotype of rs872956 as an independent protective factor against HBV reactivation (odds ratio [OR] = 18.1, 95% confidence interval [CI] = 2.6-126.7, P < 0.01). mRNA expression of HLA-DPB1 was lower in the HBV reactivated group than in the non-reactivated group (median 276.1 ± 165.6/ß-actin vs 371.4 ± 407.5/ß-actin [P < 0.05]). These results suggest the involvement of HLA class II molecules in HBV reactivation after treatment with immunomodulatory agents.

Preoperative diagnosis of cavernous hemangioma presenting with melena using wireless capsule endoscopy of the small intestine.

BACKGROUND AND STUDY AIMS: Primary neoplasms of the small intestine are relatively rare in all age groups, accounting for about 5 % of all gastrointestinal tumors 1. Cavernous hemangiomas of the small intestine are also rare, can cause gastrointestinal bleeding, and are extremely difficult to diagnose preoperatively 2. We present a patient who presented with melena and iron deficiency anemia, for whom wireless capsule endoscopy and single-balloon enteroscopy facilitated the diagnosis of cavernous hemangioma.