The Significance of Histopathological Findings on Clinical Outcomes in Endoscopic Papillectomy with Endocut.

This study aimed to evaluate primary clinical outcomes in patients who underwent endoscopic papillectomy (EP) using the Endocut mode while examining the pathological characteristics of the margin of the resected specimen. To this end, 70 patients who underwent Endocut EP were included. Resection margins were classified according to pathological findings as "negative", "positive", or "uncertain (difficult pathological evaluation)". The effect of pathological resection margins on residual tumor recurrence rates was evaluated. The median follow-up was 47 months (range, 22-84). Eleven patients (15.7%) were diagnosed with residual tumors, ten of whom were diagnosed within 6 months after EP. The resection margins were pathologically negative in 27 patients, positive in 15, and uncertain in 28; residual tumors occurred in 5 patients (33.3%) in the positive group, 5 (17.9%) in the uncertain group, and 1 (3.7%) in the negative group. The patient in the negative group had familial adenomatous polyposis (FAP). Female sex, FAP, and uncertain or positive resection margins were significantly more common in residual patients (p = 0.009, 0.044, and 0.041, respectively). Pathological resection margins can be used to infer the residual tumor incidence, leading to early post-treatment of residual tumors.

Selenoneine Is Methylated in the Bodies of Mice and then Excreted in Urine as Se-Methylselenoneine.

Oral intake of purified selenoneine and seafoods has been reported to result in selenoneine accumulation in erythrocytes in mice and human. In addition, Se-methylselenoneine was suggested to be produced as a metabolite of selenoneine in the urine and whole blood of humans. In order to confirm the molecular mechanism of production of Se-methylselenoneine, a stable isotope (Se-76) labeled selenoneine was biosynthesized using genetically modified fission yeast and administered to mice. The Se-76-labeled Se-methylselenoneine was detected in urine but Se-78 and Se-80-labeled Se-methylselenoneine arising from natural isotopes of Se was hardly detected. These results suggest that Se-methylselenoneine was a metabolite and the excreted form of selenoneine. The methylation of selenoneine in mice administered selenoneine continuously was evaluated by the analyses of organs using an online liquid chromatograph system with an inductively coupled plasma mass spectrometer (LC-ICP-MS). These experiments indicate that selenoneine is methylated in the liver and (or) kidneys.

Distribution and Effects of Selenoneine by Ingestion of Extract from Mackerel Processing Residue in Mice.

Selenoneine is an organic selenium compound contained in blood and dark muscle of fish. It has a strong antioxidative capacity and is considered useful as a new functional food material. However, the distribution and effects of selenoneine in the mammalian body have not been thoroughly examined. In this study, a selenoneine-rich mackerel extract was developed and fed to mice at 0.07% in standard rodent chow (ME diet) for 32 days to examine its distribution in the body. Selenoneine was distributed in the liver, kidney, and spleen in mice fed with mackerel extract, but it was not distributed in the plasma or erythrocytes. Moreover, concentrations of the major selenium-containing protein were not affected by the mackerel extract. The results of this study suggest that selenoneine is absorbed in the body following ingestion of low doses in crude material and preferentially accumulates in organs and later distributes in erythrocytes. Biochemical analyses of plasma in male mice showed that the glucose level was significantly increased and LDL-cholesterol level was significantly decreased by ME diet feeding. The results indicate that male mice are sensitive to ME diet.

Utility of Covered Self-Expanding Metal Stents for Biliary Drainage during Neoadjuvant Chemotherapy in Patients with Borderline Resectable Pancreatic Cancer.

OBJECTIVES: We aimed to compare the utility of covered self-expanding metal stents (CSEMSs) with that of plastic stents (PSs) for biliary drainage during neoadjuvant chemotherapy in patients with borderline resectable pancreatic cancer. METHODS: Forty patients with borderline resectable pancreatic cancer underwent biliary stenting during neoadjuvant chemotherapy at Hiroshima University Hospital. PSs and CSEMSs were placed in 19 and 21 patients, respectively. Two gemcitabine-based regimens for chemotherapy were used. Treatment outcomes and postoperative complications were compared between both groups. RESULTS: The incidence of recurrent biliary obstruction was significantly lower in the CSEMS group (0% vs. 47.4%, p < 0.001), and the median time to recurrent biliary obstruction in the PS group was 47 days. There was no difference in the incidence of other complications such as non-occlusive cholangitis, pancreatitis, and cholecystitis between the two groups. Delays in the chemotherapy schedule due to stent-related complications were significantly frequent in the PS group (52.6% vs. 4.8%, p = 0.001). There was no significant difference in the incidence of postoperative complications between the two groups. CONCLUSIONS: CSEMSs may be the best choice for safely performing neoadjuvant chemotherapy for several months in patients with borderline resectable pancreatic cancer with bile duct stricture.

Relapse rate and predictors of relapse after cessation of glucocorticoid maintenance therapy in type 1 autoimmune pancreatitis: a multicenter retrospective study.

BACKGROUND: Type 1 autoimmune pancreatitis responds well to glucocorticoid therapy with a high remission rate. Moreover, glucocorticoid maintenance therapy can help prevent relapse. However, the relapse rate following cessation of long-term glucocorticoid therapy is unknown. The aim of this study was to clarify the relapse rate and predictors of relapse following long-term glucocorticoid therapy cessation. METHODS: We analyzed 94 patients who achieved remission after undergoing glucocorticoid therapy, discontinued treatment after at least 6 months of maintenance therapy, and were subsequently followed up for at least 6 months. The patients were divided into three groups based on treatment duration (< 18, 18-36, and ≥ 36 months), and their relapse rates were compared. Univariate and multivariate analyses of clinical factors were conducted to identify relapse predictors. RESULTS: After discontinuing glucocorticoid therapy, relapse was observed in 43 (45.7%) patients, with cumulative relapse rates of 28.2% at 1 year, 42.1% at 3 years, 47.0% at 5 years, and a plateau of 77.6% at 9 years. Of the 43 patients who relapsed, 25 (58.1%) relapsed within 1 year after after cessation of glucocorticoid therapy. Relapse and cumulative relapse rates did not differ significantly according to treatment duration. In the multivariate analysis, an elevated serum IgG4 level at the time of glucocorticoid cessation was found to be an independent predictor of relapse (hazard ratio, 4.511; p < 0.001). CONCLUSIONS: A high relapse rate occurred after cessation of glucocorticoid maintenance therapy, regardless of the duration of maintenance therapy, especially within the first year after cessation. However, the normalization of long-term serum IgG4 levels may be a factor in considering cessation.

A case of unresectable intrahepatic cholangiocarcinoma with a germline BRCA1 mutation.

Intrahepatic cholangiocarcinoma (ICC) is a malignant liver tumor with poor prognosis. Various mutations in cancer-predisposing genes have been reported in ICC, and germline BRCA1/2 mutations, which are the causative genes for hereditary breast and ovarian cancer syndrome (HBOC), have been reported in many patients with ICC. Here, we report a case of unresectable ICC with a germline BRCA1 mutation. A 73-year-old man was found to have a mass in the left lobe of the liver on abdominal ultrasonography during a medical check-up and was referred to our institution. Contrast-enhanced computed tomography revealed a 30-mm mass with a delayed enhancement pattern, tumor invasion into the major blood vessels, and enlarged regional lymph nodes. Ultrasound-guided percutaneous tumor biopsy revealed a well-differentiated adenocarcinoma, and the patient was diagnosed with clinical Stage IIIB ICC. Systemic chemotherapy with gemcitabine and cisplatin was initiated because of the unresectable nature of the disease. Regarding family history, his eldest daughter was diagnosed with HBOC with a germline BRCA1 mutation at the time of breast cancer surgery, and she developed pancreatic cancer seven years later. The patient underwent BRCA1 single-site analysis and was diagnosed with HBOC with a germline BRCA1 mutation.

Efficacy of vonoprazan 10 mg compared with 20 mg for the initial treatment in patients with erosive esophagitis: a randomized pilot study.

BACKGROUND: The study aimed to investigate the efficacy of vonoprazan 10 mg compared with 20 mg in patients with erosive esophagitis. METHOD: Seventy-three patients with erosive esophagitis were randomly divided into two groups either vonoprazan 20 mg (n = 37) or 10 mg (n = 36). They were administered each dose for 4 weeks as the initial treatment followed by maintenance treatment with 10 mg for 8 weeks. The primary endpoints were mucosal healing rate and symptom relief at 4 weeks. The secondary endpoint was symptom relief at 12 weeks after the maintenance treatment. Mucosal healing was assessed endoscopically, and symptom relief was assessed using the FSSG score. RESULTS: At 4 weeks, the endoscopic healing rates of the 20 mg and 10 mg groups were 94.6% and 94.4%, respectively. The FSSG scores of the 20 mg and 10 mg groups were significantly decreased in both treatment groups from 13 (4-39) to 4 (0-25) and 14 (4-40) to 3 (0-29), respectively. At 12 weeks, the scores further decreased to 2 (0-13) and 2 (0-26), respectively. The vonoprazan 10 mg group showed a similar therapeutic effect to the 20 mg group in mucosal healing at 4 weeks and in symptom relief throughout the study period. When stratified by esophagitis grading, these findings were still demonstrated in grade A/B patients but not in grade C/D patients. CONCLUSION: Our findings suggest that initial treatment with vonoprazan 10 mg might be useful especially in patients with mild erosive esophagitis. Large controlled studies are warranted to confirm our investigation.

[A Case of Long-Term Survival in a Patient with Advanced Rectal Cancer and Paraaortic and Lateral Lymph Node Metastases].

A 65-year-old woman was referred for further examination following positive results on a fecal occult blood test. Colonoscopy revealed type 0-Ⅱa cancer, with a lesion measuring 2 cm in diameter in the rectosigmoid colon, and type 5 cancer, with a lesion measuring 6 cm in diameter in the upper rectum. Computed tomography(CT)and positron emission tomography (PET)-CT revealed mesorectal lymph node metastases. Therefore, she was diagnosed with rectosigmoid colon cancer(Stage Ⅰ)and upper rectal cancer(Stage Ⅲa). However, PET-CT also revealed slight fluorodeoxyglucose uptake in the paraaortic and lateral lymph node lesions; hence, the possibility ofmetastasis could not be ruled out. Given that chemotherapy was restricted due to renal dysfunction, low anterior resection was performed as the first choice. Analysis of intraoperative frozen sections showed paraaortic and lateral lymph node metastases; thus, we performed lymph node dissection of these lesions. Pathological examination ofthe resected lymph nodes revealed that 21 of 37 lesions were cancer metastases. S-1 was administered as adjuvant chemotherapy for 5 months. Mediastinal lymph node metastases was suspected on chest CT 5 months and 3 years post-surgery; thus, panitumumab was administrated. These lymph nodes decreased in size immediately. Six years after the first surgery, the patient was well without any signs of recurrence.

Dietary Supplementation of Selenoneine-Containing Tuna Dark Muscle Extract Effectively Reduces Pathology of Experimental Colorectal Cancers in Mice.

Selenoneine is an ergothioneine analog with greater antioxidant activity and is the major form of organic selenium in the blood, muscles, and other tissues of tuna. The aim of this study was to determine whether a selenoneine-rich diet exerts antioxidant activities that can prevent carcinogenesis in two types of colorectal cancer model in mice. We administrated selenoneine-containing tuna dark muscle extract (STDME) to mice for one week and used azoxymethane (AOM) and dextran sodium sulfate (DSS) for inducing colorectal carcinogenesis. Next, we examined the incidence of macroscopic polyps and performed functional analysis of immune cells from the spleen. In the AOM/DSS-induced colitis-associated cancer (CAC) model, the oral administration of STDME significantly decreased tumor incidence and inhibited the accumulation of myeloid-derived suppressor cells (MDSCs) while also inhibiting the downregulation of interferon-γ (IFN-γ) production during carcinogenesis. These results suggest that dietary STDME may be an effective agent for reducing colorectal tumor progression.

Identification and determination of selenoneine, 2-selenyl-N α , N α , N α -trimethyl-L-histidine, as the major organic selenium in blood cells in a fish-eating population on remote Japanese Islands.

Selenoneine is the major selenium compound in fish muscles, and fish appears to be an important source of selenium in the fish-eating population. Selenoneine has strong antioxidant activity and a detoxifying function against methylmercury (MeHg) toxicity. Dietary intake, bioaccumulation, and metabolism of selenoneine have not been characterized in humans. A nutritional survey was conducted in remote islands of the Kagoshima Prefecture in Japan. To evaluate the potential risks and benefits of fish consumption for health, we measured concentrations of selenoneine, total selenium, MeHg, inorganic mercury, and polyunsaturated fatty acid (LC-PUFA) in the blood of a fish-eating human population. The erythrocyte, leukocyte, and platelet residues following removal of serum (cellular fraction) contained 0.510 µg Se/g, 0.212 µg selenoneine Se/g, and 0.262 µg Se-containing proteins Se/g, whereas the serum contained 0.174 µg total Se/g. Selenoneine was highly concentrated in the cellular fraction in a manner that was dependent on subjects' frequency of fish consumption. Concentrations of selenoneine were closely correlated with concentrations of MeHg in the cellular fraction. Selenoneine is the major chemical form of selenium in the blood cells of this fish-eating human population and may be an important biomarker for selenium redox status.

Selenoneine, a novel selenium-containing compound, mediates detoxification mechanisms against methylmercury accumulation and toxicity in zebrafish embryo.

The selenium (Se)-containing antioxidant selenoneine (2-selenyl-N α,N α,N α-trimethyl-L-histidine) has recently been discovered to be the predominant form of organic Se in tuna blood. Although dietary intake of fish Se has been suggested to reduce methylmercury (MeHg) toxicity, the molecular mechanism of MeHg detoxification by Se has not yet been determined. Here, we report evidence that selenoneine accelerates the excretion and demethylation of MeHg, mediated by a selenoneine-specific transporter, organic cations/carnitine transporter-1 (OCTN1). Selenoneine was incorporated into human embryonic kidney HEK293 cells transiently overexpressing OCTN1 and zebrafish blood cells by OCTN1. The K m for selenoneine uptake was 13.0 µM in OCTN1-overexpressing HEK293 cells and 9.5 µM in zebrafish blood cells, indicating high affinity of OCTN1 for selenoneine in human and zebrafish cells. When such OCTN1-expressing cells and embryos were exposed to MeHg-cysteine (MeHgCys), MeHg accumulation was decreased and the excretion and demethylation of MeHg were enhanced by selenoneine. In addition, exosomal secretion vesicles were detected in the culture water of embryos that had been microinjected with MeHgCys, suggesting that these may be responsible for MeHg excretion and demethylation. In contrast, OCTN1-deficient embryos accumulated MeHg, and MeHg excretion and demethylation were decreased. Furthermore, Hg accumulation was decreased in OCTN1-overexpressing HEK293 cells, but not in mock vector-transfected cells, indicating that selenoneine and OCTN1 can regulate MeHg detoxification in human cells. Thus, the selenoneine-mediated OCTN1 system regulates secretory lysosomal vesicle formation and MeHg demethylation.

Selenium content in seafood in Japan.

Selenium is an essential micronutrient for humans, and seafood is one of the major selenium sources, as well as red meat, grains, eggs, chicken, liver and garlic. A substantial proportion of the total amount of selenium is present as selenium containing imidazole compound, selenoneine, in the muscles of ocean fish. In order to characterize the selenium content in seafood, the total selenium levels were measured in the edible portions of commercially important fish and shellfish species. Among the tested edible portions, alfonsino muscle had the highest selenium levels (concentration of 1.27 mg/kg tissue). High levels of selenium (1.20-1.07 mg/kg) were also found in the salted ovary products of mullet and Pacific herring. In other fish muscles, the selenium levels ranged between 0.12 and 0.77 mg/kg tissue. The selenium levels were closely correlated with the mercury levels in the white and red muscles in alfonsino. The selenium content in spleen, blood, hepatopancreas, heart, red muscle, white muscle, brain, ovary and testis ranged between 1.10 and 24.8 mg/kg tissue in alfonsino.

Pegylated interferon-α2b and ribavirin combination therapy induces Hashitoxicosis followed by type 1 diabetes mellitus.

The combination of pegylated interferon-α2b (PEG-IFNα) and ribavirin (RBV) is a standard treatment for chronic hepatitis C. The case of a patient with chronic hepatitis C who developed Hashitoxicosis followed by type 1 diabetes mellitus (T1DM) with PEG-IFNα plus RBV combination therapy, but not IFNα alone, is presented.

Haploidentical hematopoietic stem cell transplantation to adults with hematologic malignancies: analysis of 66 cases at a single Japanese center.

Sixty-six adult patients with hematologic malignancies underwent haploidentical hematopoietic stem cell transplantation (haplo-HSCT) without T cell depletion. The patients were preconditioned with a reduced intensity regimen, and tacrolimus was used for graft-versus-host disease (GVHD) prophylaxis. Successful engraftment occurred in 60 patients (90.1%) and graft rejection in only 4 patients (6.1%). Among the 60 engrafted patients, only 5 developed severe (grade III or IV) acute GVHD. Twenty patients, including 19 relapse-free patients were alive at a median follow-up of 48 months (range 6-77 months). The overall survival (OS) at 6 years was 29.3%. The OS of 45 patients < 60 years of age was 43.6%, which was superior to that of 21 patients who were 60 years of age and older (9.5%) (P < 0.01). The OS of 11 patients from human leukocyte antigen (HLA) 1 locus-mismatched donors (63.6%) was higher than that of 28 patients from HLA 3 loci-mismatched donors (12.5%) (P < 0.01). Organ injury and infection were the main causes of mortality. Notably, immunosuppressive therapy could be successfully stopped in 9 patients transplanted from HLA 2 or 3 loci-mismatched donors with a median duration of 45 months (range 5-71 months). These data suggest that haplo-HSCT is a promising treatment for patients who need urgent allogeneic transplantation but lack HLA-identical family donors.

Identification of a novel selenium-containing compound, selenoneine, as the predominant chemical form of organic selenium in the blood of bluefin tuna.

A novel selenium-containing compound having a selenium atom in the imidazole ring, 2-selenyl-N(alpha),N(alpha),N(alpha)-trimethyl-L-histidine, 3-(2-hydroseleno-1H-imidazol-5-yl)-2-(trimethylammonio)propanoate, was identified from the blood and other tissues of the bluefin tuna, Thunnus orientalis. The selenium-containing compound was purified from the tuna blood in several chromatographic steps. High resolution mass spectrometry and nuclear magnetic resonance spectroscopy showed that the exact mass of the [M+H](+) ion of the compound was 533.0562 and the molecular formula was C(18)H(29)N(6)O(4)Se(2). Its gross structure was assigned as the oxidized dimeric form of an ergothioneine selenium analog in which the sulfur of ergothioneine is replaced by selenium. Therefore, we named this novel selenium-containing compound "selenoneine." By speciation analysis of organic selenium compounds using liquid chromatography inductively coupled plasma mass spectrometry, selenoneine was found widely distributed in various tissues of the tuna, with the highest concentration in blood; mackerel blood contained similar levels. Selenoneine was measurable at 2-4 orders of magnitude lower concentration in a limited set of tissues from squid, tilapia, pig, and chicken. Quantitatively, selenoneine is the predominant form of organic selenium in tuna tissues.

New feruloyl tyramine glycosides from Stephania hispidula YAMAMOTO.

Three new feruloyl tyramine glycosides, N-cis-feruloyl tyramine-4'''-O-beta-D-glucopyranoside (1), N-trans-ferloyl tyramine-4'''-O-beta-D-glucopyranoside (2), and N-trans-feruloyl tyramine-4'-O-beta-D-glucopyranoside (3), along with six known compounds, N-trans-feruloyl-3'''-methoxydopamine-4'-O-beta-D-glucopyranoside (4), haitinosporine (5), tubocurine (6), fuzitine (7), (+)-lyoniresinol-3alpha-O-beta-D-glucopyranoside (8), and (-)-lyoniresinol-2alpha-O-beta-D-glucopyranoside (9), were isolated from the stem of Stephania hispidula YAMAMOTO. The structures were elucidated by spectroscopic and chemical analysis.

Discovery of the strong antioxidant selenoneine in tuna and selenium redox metabolism.

A novel selenium-containing compound, selenoneine, has been isolated as the major form of organic selenium in the blood and tissues of tuna. Selenoneine harbors a selenium atom in the imidazole ring, 2-selenyl-N(α), N(α), N(α)-trimethyl-L-histidine, and is a selenium analog of ergothioneine. This selenium compound has strong antioxidant capacity and binds to heme proteins, such as hemoglobin and myoglobin, to protect them from iron auto-oxidation, and it reacts with radicals and methylmercury (MeHg). The organic cations/carnitine transporter OCTN1 transports selenoneine and MeHg, regulates Se-enhanced antioxidant activity, and decreases MeHg toxicity. Thus, the dietary intake of selenoneine, by consuming fish, might decrease the formation of reactive oxygen radicals that could oxidize nucleotides in DNA, and thereby inhibit carcinogenesis, chronic diseases, and aging.

Methylglyoxal induces prostaglandin E2 production in rat mesangial cells.

The formation of methylglyoxal (MG), a reactive dicarbonyl compound, is accelerated under hyperglycemia, presumably contributing to tissue injury in diabetes. On the other hand, prostaglandin E2 (PGE2) has been implicated in glomerular hyperfiltration, a characteristic change in the early stage of diabetic nephropathy. We therefore examined whether MG was capable of inducing PGE2 production in rat mesangial cells (RMC) to address a possible mechanism by which hyperglycemia-derived dicarbonyls accelerated the development of diabetic nephropathy. RMC were incubated with 0 - 200 microM of MG, followed by determination of secreted PGE2 by enzyme immunoassay (EIA). We further investigated the intracellular mechanisms mediating the MG-induced PGE2 synthesis, focusing particularly on cyclooxygenase-2 (COX-2) and the MAPK superfamily. Our results indicated that MG induced PGE2 production in a dose-dependent manner, accompanied by augmentation of COX-2 mRNA expression. This MG-induced PGE2 production was significantly suppressed by inhibiting either ERK1/2 or p38 MAPK, implicating involvement of the MAPK superfamily. Our results suggest a potential role of MG in the development of diabetic nephropathy through PGE2 production, and may serve as a novel insight into the therapeutic strategies for diabetic nephropathy.

Relationship between postmortem changes and browning of boiled, dried, and seasoned product made from Japanese common squid (Tedarodes pacificus) mantle muscle.

To clarify the process that possibly causes discoloration in boiled, dried, and seasoned squid products ("sakiika" or "ikakun" in Japanese), we investigated the relationship of squid freshness with the rate of browning using the boiled, freeze-dried, and ground squid product model. ATP and its related compounds in Japanese common squid (Tedarodes pacificus) decomposed gradually during storage, yielding hypoxanthine and ribose at 24 h postmortem. The browning rate of the model during preservation as revealed by the increase of the b* value showed a high coefficient in the linear regression against ribose content (R2 = 0.767). Only the model made from the squid stored for 24 h postmortem turned brown. These results strongly suggest that ribose produced during storage plays a major role in the browning of dried and seasoned squid products.

Relation between serum 3-deoxyglucosone and development of diabetic microangiopathy.

OBJECTIVE: 3-Deoxyglucosone (3-DG), a highly reactive intermediate of the glycation reaction, has been suggested to contribute to the development of diabetes complications. To verify this hypothesis, we assessed the relation between serum 3-DG concentrations and the severity of diabetic microangiopathy in diabetic patients. RESEARCH DESIGN AND METHODS: We conducted a high-performance liquid chromatography assay to determine the serum 3-DG concentrations of 110 diabetic patients with different degrees of severity of diabetic microangiopathy and 57 age-matched control subjects. RESULTS: The fasting serum 3-DG level in diabetic patients was significantly (P < 0.001) higher than that in control subjects (353 +/- 110 vs. 199 +/- 53 nmol/l). The 3-DG levels were significantly (P < 0.001) elevated even in the diabetic patients showing normoalbuminuria (n = 62, 322 +/- 79 nmol/l) compared with control subjects. The 3-DG levels were further elevated in the patients with microalbuminuria (n = 30, 383 +/- 146 nmol/l) and overt proteinuria (n = 18, 410 +/- 100 nmol/l) (P = 0.027 and P < 0.001 vs. normoalbuminuria group, respectively). This phenomenon was basically reproduced in a category of retinopathy. Furthermore, the diabetic patients with low nerve conduction velocity showed a tendency to display higher 3-DG levels. CONCLUSIONS: The present results show that the fasting serum 3-DG level is elevated in diabetic patients and that the patients with relatively higher 3-DG levels were prone to suffer from more severe complications, indicating a possible association of 3-DG with diabetic microangiopathy.