Endoscopic submucosal dissection for tumors involving the ileocecal valve with extension into the terminal ileum: a multicenter study from the Hiroshima GI Endoscopy Research Group.

BACKGROUND: The efficacy and safety of endoscopic submucosal dissection (ESD) for tumors extending into the terminal ileum remain obscure. We aimed to evaluate the outcomes of ESD for tumors involving the ileocecal valve (ICV) with extension into the terminal ileum. METHODS: Sixty-eight patients (40 men; mean age, 67 years) with 68 tumors involving the ICV that were resected by ESD between December 2013 and December 2018 were included and classified into Group A (21 tumors with extension into the terminal ileum) and Group B (47 tumors without extension). ESD outcomes were compared between groups. RESULTS: The clinical features of the patients and tumors were not significantly different between the groups. There were no significant differences in en bloc resection rate (95% and 94%, respectively; p = 0.79), R0 resection rate (90% and 89%, respectively; p = 0.89), procedure time (95 ± 54 min and 94 ± 69 min, respectively; p = 0.64), postoperative bleeding rate (5% and 3%, respectively; p = 0.79), intraoperative perforation rate (0% and 4%, respectively; p = 0.34), delayed perforation rate (0% and 0%, respectively), or postoperative symptomatic stenosis rate (0% and 0%, respectively) between Groups A and B. No specific factors related to the outcomes of ESD were found by subgroup analysis according to the dominance and degree of circumference of the ICV. Local recurrence was observed in 1 patient in Group A who was retreated using ESD. CONCLUSIONS: ESD for tumors involving the ICV with extension into the terminal ileum is safe and effective.

Acute necrotic disorder of the small intestine post-coronavirus disease-2019 vaccination.

The Pfizer-BioNTech coronavirus disease 2019 (COVID-19) vaccine is extensively used worldwide, and its safety has been proven. Herein, we report a case of an acute necrotic disorder in the small intestine post-COVID-19 vaccination. The patient developed severe abdominal pain the day after the first vaccination. Contrast-enhanced computed tomography showed extensive ileum wall thickening and ascites. Colonoscopy revealed a ring-shaped ulcer and stricture in the terminal ileum. Ileocecal resection was performed, and the patient did not have further episodes of a necrotic disorder in the small intestine. Although it is unknown if this event is associated with vaccination, and this occurrence also does not outweigh the efficacy and safety of the Pfizer-BioNTech COVID-19 vaccine, gastroenterologists need to be aware of this rare case, given its noteworthy timing.

[A Case of Resected Esophageal Endocrine Cell Carcinoma That Responded to Combination Therapy Comprising Irinotecan and Cisplatin].

We report a case of resected esophagealcancer that responded wellto first-line combination therapy comprising irinotecan and cisplatin. The patient was a 71-year-old woman being treated for liver cirrhosis. She was admitted to our hospital in April 2015 because of dysphasia. Endoscopic examination revealed a tumor in the mid-thoracic esophagus, which was diagnosed as an endocrine cell carcinoma following pathological examination. Contrast-enhanced computed tomography and positron emission tomography did not show lymph node or distant metastases. She was treated with irinotecan and cisplatin combination therapy. After 6 courses of treatment, the tumor size had remarkably reduced. Subsequently, we performed subtotal esophagectomy and gastric tube reconstruction through the retroposterior mediastinalroute and the histologicaleffect was reported as a partial response. No viable tumor cells were observed in the extracted lymph nodes. However, bone metastasis and lymph node swelling occurred after 4 months. She received other therapeutic regimens, such as etoposide and carboplatin combination therapy. However, the tumor gradually progressed, and she died 18 months after the first treatment. Irinotecan and cisplatin combination therapy is a possible option for the management of esophageal endocrine cell carcinoma as a first-line treatment.

Laparoscopic operation after pre-operative reduction of an intussusception-induced inflammatory fibroid polyp.

Intussusception occurs mainly in children but rarely in adults. About 80-90% of adult cases of intussusception are due to benign or malignant neoplasms as a lead point. One of the causes is an inflammatory fibroid polyp (IFP), a rare, benign entity that occurs more frequently in the stomach than the ileum. We describe an uncommon case of a patient who presented with intussusception-induced IFP of the ileum. A 35-year-old woman presented with a 2-day history of abdominal pain. A computed tomography scan demonstrated ileocolic intussusception. During colonoscopy, reduction by pressured air easily released intussusception, and we suspected a submucosal tumour of the ileum. Successful pre-operative colonoscopic reduction was helpful for performing laparoscopic ileocecal resection 2 days later. Results of the histopathological examination confirmed a large IFP. The patient's post-operative course was uneventful. Pre-operative reduction by colonoscopy is effective for the diagnosis and treatment of intussusception-induced IFP.

[A Case of Effective Chemoradiotherapy Using mFOLFOX6 for Locally Advanced Rectal Cancer].

We report a case of locally advanced rectal cancer, treated effectively with chemotherapy consisting of mFOLFOX6 combined with radiotherapy. A 63-year-old man was admitted to our hospital in March 2012 for diarrhea and anal and perineal pain. Advanced rectal cancer with invasion ofthe right perineum was diagnosed based on computer tomography(CT) findings. Surgery was performed; however, the rectal cancer was unresectable. A sigmoid colostomy was performed, and a central venous port was implanted. In April 2012, the patient was treated with chemotherapy using 3 courses ofmFOLFOX6 and concurrent radiotherapy. Radiotherapy at 2 Gy/day was administered 25 times(total dose, 50 Gy). After chemoradiotherapy, the patient underwent 3 courses ofmFOLFOX6 as an additional therapy. By June 2012, CT showed resolution ofthe tumor in the right perineum and a marked decrease in the size ofthe primary rectal cancer. Because the patient refused surgery, we started treatment with combination chemotherapy using oral S-1 and intravenous CPT-11 in August 2012. After 18 courses, the treatment was changed to oral administration ofS -1 alone, which was continued for 1 year. The patient remained well without recurrence for 54 months since the original diagnosis. Therefore, chemoradiotherapy with mFOLFOX6 is a possible option for the management of advanced rectal cancer.

[A Case of Resected Advanced Esophageal Cancer That Responded to Combination Therapy Comprising Docetaxel, Cisplatin, and 5-Fluorouracil].

We report a case of resected advanced esophagealcancer that responded wellto first-line combination therapy with docetaxel, cisplatin, and 5-fluorouracil(DCF therapy). A 72-year-old man was admitted to our hospital in January 2013 because of dysphagia. On the basis of the computed tomography(CT)and gastroendoscopy findings, he was diagnosed with advanced esophagealcancer with lymph node metastasis. The patient was treated with DCF therapy. After 2 courses of treatment, the primary tumor and lymph node metastasis were reduced on CT. After 3 courses of treatment, we performed subtotalesophagectomy and gastric tube reconstruction through the retroposterior mediastinalroute. No residualcancer cells were found in the esophagus or lymph nodes. The patient subsequently received oral administration of tegafur-uracilal one for 24 months. The post-operative course was uneventful, and there was no detectable lymph node metastasis 42 months after the originaldiagnosis. Therefore, DCF therapy is a possible option for the management of advanced esophagealcancer.

[A Case of HER2-Positive Advanced Gastric Cancer with Multiple Liver Metastases Effectively Treated with Trastuzumab, Capecitabine, and Cisplatin Combination Therapy].

We reported a case of human epidermal growth factor receptor 2(HER2)-positive advanced gastric cancer with multiple liver metastases that responded well to a combination of trastuzumab, capecitabine, and cisplatin(T-XP therapy)as first-line chemotherapy. A 73-year-old man was admitted to our hospital in December 2012 for liver dysfunction. Based on computed tomography(CT)and gastroendoscopy findings, he was diagnosed with advanced gastric cancer with multiple liver metastases. Because HER2 protein overexpression was observed in the primary tumor, he was treated with T-XP therapy. After 5 courses of treatment, the sizes of the primary tumor and multiple liver metastases were reduced on CT scans. In March 2013, a Billroth I distal gastrectomy with D2 lymph node dissection was performed. Liver metastasis was not detected. No residual cancer cells were found in the stomach or lymph nodes. The patient subsequently received oral administration of S-1 alone for 2 weeks followed by a 2-week rest period as 1 course. This was repeated for 19 courses. The postoperative course was uneventful, and there was no detectable liver metastasis 36 months after the original diagnosis. Therefore, T-XP therapy is an option for the management of HER2-positive advanced gastric cancer with liver metastasis.

[A case of advanced gastric cancer with carcinomatous pericarditis effectively treated by S-1/CDDP combined therapy].

The patient was a 48-year-old woman, admitted for pleural effusion detected on chest X-ray in July 2005. Computer tomography(CT)scan showed massive pericardial and pleural effusion. We performed pericardial drainage, and the cytological diagnosis of the pericardial effusion was class V. Because endoscopic examination revealed advanced gastric cancer, we diagnosed it as gastric cancer complicated with carcinomatous pericarditis. The serum tissue polypeptide antigen(TPA) level was markedly elevated. In August 2005, we started combination chemotherapy using oral S-1(100mg/body/day; day 1- 21)and intravenous CDDP(100mg/body/day; day 8)for 5 weeks. After 2 courses, TPA was reduced and pericardial effusion disappeared. However, after 3 courses, pericardial effusion recurred. We changed treatment to weekly docetaxel. After 2 courses, we changed it to paclitaxel/CDDP. However, TPA was increased and pleural effusion and dyspnea occurred. There- fore, we changed to a course of combination chemotherapy using oral S-1(100mg/body/day; day 1-14)and intravenous CPT-11(100mg/body/day; day 1 and 8)for 4 weeks from March 2006. After 10 courses, we were unable to control pleural effusion, and dyspnea recurred. She died in December 2006. Gastric cancer complicated with carcinomatous pericarditis has a poor prognosis, but systemic chemotherapy mainly with S-1 was effective.

Evaluation of individual risk in nonvariceal gastrointestinal bleeding patients with NSAID administration: a multicenter study in Japan.

BACKGROUNDS: Gastrointestinal (GI) toxicity is an undesirable effect of nonsteroidal anti-inflammatory drugs (NSAIDs). We conducted a multicenter study in Japan to clarify the GI risk grade in patients with NSAID-induced GI bleeding. METHODS: Patients with emergent endoscopic hemostasis by nonvariceal bleeding were registered from 36 hospitals in Hiroshima. In cases with NSAID use, the GI risk grade (low, moderate, or high) was evaluated, and concomitant drugs were investigated. We asked 79 gastroenterologists and 234 orthopedists what concomitant drugs they would prescribe to 3 simulated patients. RESULTS: A total of 1,350 patients were registered. NSAIDs were used in 278 cases (21%). Concerning the risk grade in each patient, the largest group was the moderate-risk group (203 patients; 73%), while the high-risk group comprised 10% of all NSAID users with bleeding. A proton pump inhibitor (PPI) or misoprostol was administrated to only 20 patients (7%). A small number of the gastroenterologists and orthopedists who responded to the questionnaire would prescribe PPI or misoprostol to simulated patients with short-term loxoprofen use. CONCLUSIONS: In NSAID users with GI bleeding, the moderate-risk group was the largest group for GI toxicity in Japan. In these cases, PPI or misoprostol was not commonly medicated in clinical practice.

Plaunotol induces a comparative increase of acidic mucin fraction in gastric juice.

BACKGROUND/AIMS: Gastric mucus protects the gastric mucosa. Plaunotol, a gastroprotective agent, has been shown to increase mucus production in animal models. However, it is unclear whether plaunotol benefits human gastric mucus secretion. METHODOLOGY: Twenty-five patients with atrophic gastritis were studied. All patients underwent gastroendoscopy and gastric juice was collected before and after plaunotol treatment for 3 months. Gastric juice mucin was examined by gel filtration as well as anion-exchange chromatography. The identification of each fraction was examined by enzyme-linked immunosorbent assay (ELISA) with the use of HGM75 and HIK1083, antibodies against mucin from surface mucus cells and from gastric glandular mucus cells, respectively. RESULTS: Plaunotol significantly increased the total gastric juice volume (7.8mL before vs. 10.7mL, after administration; p=0.03). By anion exchange chromatography, we detected three mucin fractions (Fr I-III). Fr I strongly reacted with HGM75 but did not react with HIK1083. The other fractions (Fr II, III) reacted with HIK1083 but weakly reacted with HGM75. After administration of plaunotol, a significant increase in Fr III (acidic mucin) was observed (p=0.02). CONCLUSIONS: Long-term administration of plaunotol changes the composition of gastric juice mucin, including a significant increase in the proportion of acidic mucin fraction.

Amino acid substitutions in core and NS5A regions of the HCV genome can predict virological decrease with pegylated interferon plus ribavirin therapy.

BACKGROUND: The current standard therapy for chronic hepatitis C is pegylated interferon (PEG-IFN) plus ribavirin (RBV) combination therapy. Recently, it has been reported that amino acid (aa) substitutions in the core region, as well as the IFN-sensitivity-determining region (ISDR), were predictive of non-virological response (NVR), sustained virological response (SVR) and early virological response. Despite the importance of these two predictive factors for combination therapy, their interaction is poorly understood. METHODS: A total of 117 patients who were treated with PEG-IFN-α2b plus RBV combination therapy were selected for participation in this study. We determined the aa sequences in the core region and ISDR by direct sequencing and analysed them along with clinical data to identify predictive factors for therapeutic response. RESULTS: The aa sequences in the core region and γ-glutamyl transpeptidase (GTP) levels were associated with SVR and NVR, but aa sequences in the ISDR were not. However, substitutions at both aa 70 and aa 91 in the core region without substitutions in the ISDR and higher levels of γ-GTP were independent predictive factors for NVR. Wild-type aa 70 and aa 91 in the core region, higher platelet counts and lower levels of γ-GTP were independent predictive factors for SVR. CONCLUSIONS: These results indicate that analyses of aa substitutions in both the core region and the ISDR are useful for predicting the effectiveness of combination therapy, and could help to avoid therapy exposure for patients who have a low probability of SVR.

Importance of serum concentration of adefovir for Lamivudine-adefovir combination therapy in patients with lamivudine-resistant chronic hepatitis B.

Lamivudine (LMV)-adefovir pivoxil (ADV) combination therapy suppresses the replication of LMV-resistant hepatitis B virus (HBV), although its efficacy in suppressing HBV varies among patients. This study analyzed the clinical, virological, and pharmaceutical factors that influence the effect of the combination therapy. Patients negative for hepatitis B virus e antigen (HBeAg) and with low HBV DNA titers immediately prior to the combination therapy effectively cleared serum HBV DNA (P=0.0348 and P=0.0310, respectively). The maximum concentration of ADV in serum (ADV Cmax) was higher in patients who showed HBV DNA clearance (P=0.0392), and the cumulative clearance rates of HBV DNA were significantly higher in patients with ADV Cmax equal to or greater than 24 ng/ml (P=0.0284). HBeAg negativity and lower HBV DNA at the start of the combination therapy and higher ADV Cmax were found to be independent factors for serum HBV DNA clearance. Serum creatinine increased significantly during the combination therapy, and the ADV Cmax was higher in patients with low creatinine clearance rates. In conclusion, higher serum concentrations of ADV are associated with a good response to therapy based on clearance of HBV DNA in serum. However, care should be taken to prevent worsening of renal function due to high ADV serum concentrations.

HBx protein is indispensable for development of viraemia in human hepatocyte chimeric mice.

The non-structural X protein, HBx, of hepatitis B virus (HBV) is assumed to play an important role in HBV replication. Woodchuck hepatitis virus X protein is indispensable for virus replication, but the duck hepatitis B virus X protein is not. In this study, we investigated whether the HBx protein is indispensable for HBV replication in vivo using human hepatocyte chimeric mice. HBx-deficient (HBx-def) HBV was generated in HepG2 cells by transfection with an overlength HBV genome. Human hepatocyte chimeric mice were infected with HBx-def HBV with or without hepatic HBx expression by hydrodynamic injection of HBx expression plasmids. Serum virus levels and HBV sequences were determined with mice sera. The generated HBx-def HBV peaked in the sucrose density gradient at points equivalent to the generated HBV wild type and the virus in a patient's serum. HBx-def HBV-injected mice developed measurable viraemia only in continuously HBx-expressed liver. HBV DNA in the mouse serum increased up to 9 log(10) copies ml(-1) and the viraemia persisted for more than 2 months. Strikingly, all revertant viruses had nucleotide substitutions that enabled the virus to produce the HBx protein. It was concluded that the HBx protein is indispensable for HBV replication and could be a target for antiviral therapy.

G to A hypermutation of TT virus.

APOBEC3 proteins function as part of innate antiviral immunity and induce G to A hypermutation in retroviruses and hepatitis B virus (HBV) genomes. Whether APOBEC3 proteins affect viruses that replicate without a reverse transcription step is unknown. TT virus (TTV), known to present in serum of healthy individuals and HBV carriers, has a single-stranded circular DNA genome and replicates without reverse transcription. In this study, we examined 67 blood samples obtained from healthy individuals and HBV carriers and observed G to A hypermutation of genomes of TTV in both healthy individuals and HBV carriers. During ALT flare-up in HBV carriers, G to A hypermutation of HBV increased, but TTV genomes significantly decreased in number and hypermutated TTV genomes became undetectable. Our results show that hypermutated TTV exist in healthy individuals and HBV carriers and that TTV genomes were susceptible to immune reaction directed to HBV by interacting with APOBEC3 proteins.

Effects of structural variations of APOBEC3A and APOBEC3B genes in chronic hepatitis B virus infection.

AIM: Human APOBEC3 deaminases induce G to A hypermutation in nascent DNA strand of hepatitis B virus (HBV) genomes and seem to operate as part of the innate antiviral immune system. We analyzed the importance of APOBEC3A (A3A) and APOBEC3B (A3B) proteins, which are potent inhibitors of adeno-associated-virus and long terminal repeat (LTR)-retrotransposons, in chronic HBV infection. METHODS: We focused on the common deletion polymorphism that spans from the 3' part of A3A gene to the 3' portion of A3B gene. An association study was carried out in 724 HBV carriers and 469 healthy control subjects. We also analyzed hypermutated genomes detected in deletion and insertion (non-deletion) homozygous patients to determine the effect of APOBEC3 gene deletion. Further, we performed functional analysis of A3A gene by transient transfection experiments. RESULTS: The association study showed no significant association between deletion polymorphism and chronic HBV carrier state. Context analysis also showed a negligible effect for the deletion. Rather, mild liver fibrosis was associated with APOBEC gene deletion homozygosity, suggesting that A3B deletion is not responsible for chronic HBV infection. Functional analysis of A3A showed that overexpression of A3A induced hypermutation in HBV genome, although the levels of hypermutants were less than those introduced by A3G. However, overexpression of A3A did not decrease replicative intermediates of HBV. CONCLUSION: These results suggest that A3A and A3B play little role in HBV elimination through anti-viral defense mechanisms. The significance of hypermutation induced by A3A should be investigated further.

Absence of viral interference and different susceptibility to interferon between hepatitis B virus and hepatitis C virus in human hepatocyte chimeric mice.

BACKGROUND/AIMS: Both hepatitis B virus (HBV) and hepatitis C virus (HCV) replicate in the liver and show resistance against innate immunity and interferon (IFN) treatment. Whether there is interference between these two viruses is still controversial. We investigated the interference between these two viruses and the mode of resistance against IFN. METHODS: We performed infection experiments with either or both of the two hepatitis viruses in human hepatocyte chimeric mice. Huh7 cell lines with stable production of HBV were also established and transfected with HCV JFH1 clone. Mice and cell lines were treated with IFN. The viral levels in mice sera and culture supernatants and messenger RNA levels of IFN-stimulated genes were measured. RESULTS: No apparent interference between the two viruses was seen in vivo. Only a small (0.3 log) reduction in serum HBV and a rapid reduction in HCV were observed after IFN treatment, regardless of infection with the other virus. In in vitro studies, no interference between the two viruses was observed. The effect of IFN on each virus was not affected by the presence of the other virus. IFN-induced reductions of viruses in culture supernatants were similar to those in in vivo study. CONCLUSIONS: No interference between the two hepatitis viruses exists in the liver in the absence of hepatitis. The mechanisms of IFN resistance of the two viruses target different areas of the IFN system.

Little necessity of acid inhibition against proton pump inhibitor rebound effects and prior helicobacter pylori eradication therapy in gastric ulcer patients: a randomized prospective study.

BACKGROUND/AIMS: Helicobacter pylori (H. pylori) eradication therapy increases acid secretion and promotes the development of gastroesophageal reflux disease (GERD) and reflux esophagitis (RE). Rebound acid hypersecretion develops after the use of proton pump inhibitors (PPI). We examined the clinical necessity of acid inhibitors to prevent GERD or RE caused by PPI rebound phenomenon and prior H. pylori eradication therapy. METHODOLOGY: We enrolled 39 patients who underwent successful H. pylori eradication therapy prior to endoscopic mucosal resection of gastric cancer. After 8-week rabeprazole treatment for iatrogenic ulcer, they were randomly divided into two groups (who took nizatidine (group N) and sofalcone (group S)), and took each for 16 weeks, we compared RE/GERD symptoms with the baseline by endoscopy and QUEST score. RESULTS: All patients had corpus atrophy in which there was no difference between the two groups. Only 1 patient in group S (5.9%) developed symptomatic GERD, and 1 patient in group N (4.5%) developed RE. CONCLUSIONS: In severe atrophic gastritis patients, there is little clinical necessity of acid inhibitors to prevent GERD/RE caused by PPI rebound and prior H. pylori eradication therapy.

Clinical prevention of gastric cancer by Helicobacter pylori eradication therapy: a systematic review.

Helicobacter pylori (H. pylori) infection plays an important role in gastric carcinogenesis. We conducted a systematic review concerning gastric cancer development after H. pylori eradication therapy. In total 15 papers matched our criteria, the results were reviewed. The H. pylori eradication therapy statistically diminished the prevalence of clinical gastric cancer by approximately one-third. The studies from Japan supported this conclusion; however, studies from overseas reported conflicting results. The differences in these conclusions lie in the diagnostic ability of endoscopic examination, since the clinical stage was quite different between these studies. Gastric cancer that developed after eradication revealed a mainly intestinal type histology and depressed-type appearance. The following are possible reasons for reduced gastric cancer: (1) eradication therapy inhibits the new occurrence of gastric cancer, (2) eradication regresses or inhibits the growth of gastric cancer, and (3) eradication interferes with the discovery of gastric cancer. Considering the biological nature of cancer cell proliferation, a sufficiently long-term follow-up may clarify the effect of eradication therapy on inhibition of the development (not discovery) of gastric cancer and reduction of gastric cancer-related mortality.