Publications by authors named "Tomoka Nakamura"

27 Publications

  • Page 1 of 1

Feasibility of balloon endoscope-assisted endoscopic retrograde cholangiopancreatography for the elderly.

Endosc Int Open 2020 Sep 31;8(9):E1202-E1211. Epub 2020 Aug 31.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Endoscopic retrograde cholangiopancreatography (ERCP) for patients with surgically altered anatomy is challenging. Recently, balloon endoscopy has been shown to facilitate ERCP for this population with a high technical success rate, but adverse events (AEs) are not uncommon. Compared to non-elderly patients, elderly patients may be at higher risk of AEs due to underlying comorbidities. The current study aimed to evaluate the feasibility of balloon endoscope-assisted ERCP (BE-ERCP) for the elderly. We retrospectively identified patients who underwent BE-ERCP between January 2010 and September 2019. For patients who underwent multiple procedures during the study period, the first session was analyzed. Early AEs associated with BE-ERCP were compared between elderly (≥ 75 years) and non-elderly patients. A total of 1,363 BE-ERCP procedures were performed, and 568 patients (211 elderly and 357 non-elderly) were included for the analyses. Technical success rates were high in both the elderly and non-elderly groups (80 % vs. 80 %, respectively). The rates of early AEs were similar between the groups (12 % vs. 9.0 % in the elderly and non-elderly group, respectively;  = 0.31). The mltivariable-adjusted odds ratio for early AEs comparing elderly to non-elderly patients was 1.36 (95 % confidence interval, 0.74-2.51;  = 0.32). Specifically, we did not observe between-group differences in rates of gastrointestinal perforation (2.4 % vs. 2.8 % in elderly and non-elderly groups, respectively;  = 0.99) and aspiration pneumonia (1.9 % vs. 0.6 %,  = 0.20). BE-ERCP is a feasible procedure for elderly individuals with surgically altered anatomy.
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http://dx.doi.org/10.1055/a-1216-1363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458759PMC
September 2020

Maturity-Onset diabetes of the young type 5 treated with the glucagon-like peptide-1 receptor agonist: A case report.

Medicine (Baltimore) 2020 Aug;99(35):e21939

Department of Diabetes, Endocrinology and Metabolism, Center Hospital, National Center for Global Health and Medicine, Tokyo.

Rationale: Maturity-onset diabetes of the young type 5 (MODY 5) is a form of monogenic diabetes that is often accompanied by pancreatic dysfunction. To date, no cases of MODY 5 treated with glucagon-like peptide-1 receptor agonist (GLP-1RA) have been reported. We present the first case of MODY 5 treated with GLP-1RA.

Patient Concerns: A 17-year-old woman, with a history of being operated for congenital ileal atresia at birth, was admitted to our hospital due to hyperglycemia. She had been clinically diagnosed with type 1 diabetes 1 month prior, and administered 14 units of insulin glargine 300 U/mL per day.

Diagnosis: She had hypopotassemia, hypomagnesaemia, pancreatic body, and tail defects, multiple renal cysts, and a family history of diabetes, and urogenital anomaly. Genetic testing revealed heterozygous deletion of hepatocyte nuclear transcription factor-1 beta, leading to the diagnosis of MODY 5.

Interventions: The patient was treated with multiple daily insulin injections for 9 days (22 units/d) before administration of GLP-1RA, and then liraglutide was initiated.

Outcomes: Liraglutide treatment (0.6 mg/d) alone maintained the patient's glycated hemoglobin level below 7.0% for at least 12 months after discharge. A higher dose, 0.9 mg/d, of liraglutide was not tolerated by the patient due to nausea. Serum levels of C-peptide immunoreactivity were 1.15 ng/mL and 1.91 ng/mL, respectively, after 6 and 12 months of liraglutide therapy.

Lessons: GLP-1RA might be effective at regulating glucose metabolism by utilizing residual pancreatic endocrine function in patients with MODY 5. Imaging and genetic screening were helpful in the diagnosis of MODY 5.
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http://dx.doi.org/10.1097/MD.0000000000021939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458169PMC
August 2020

Endoscopic Ultrasound-Guided Tissue Acquisition by 22-Gauge Franseen and Standard Needles for Solid Pancreatic Lesions.

Gut Liver 2020 11;14(6):817-825

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Japan.

Background/aims: Recently, a three-plane symmetric needle with Franseen geometry was developed for endoscopic ultrasound-guided fine needle biopsy (EUS-FNB). In this retrospective study, tissue acquisition per pass was compared between 22-gauge Franseen FNB and standard fine needle aspiration (FNA) needles in patients with solid pancreatic lesions.

Methods: Consecutive patients who underwent EUSFNA or EUS-FNB for solid pancreatic lesions between October 2014 and March 2018 were retrospectively studied. The tissue acquisition rate and the diagnostic performance per session, per pass, and at first pass were compared.

Results: A total of 663 passes (300 by the FNB needle and 363 by the standard FNA needle) were performed in 154 patients (71 FNB and 83 FNA). The tissue acquisition rate per session and at first pass in the FNB and FNA groups was 100% and 95% (p=0.13) and 87% and 69% (p=0.007), respectively. The multivariate analysis revealed that among the patients, EUS-FNB (odds ratio, 3.07; p=0.01) was associated with a higher first-pass tissue acquisition rate. While the tissue acquisition rate reached a plateau after the 4th pass with FNA, it reached a plateau after the 2nd pass with FNB. Among the 129 malignant cases, the histological tissue acquisition rate per session was similar (100% and 94%), but the sensitivity by histology alone per session was higher for FNB than for FNA (93% and 73%, p<0.01).

Conclusions: The results of our retrospective analysis indicated that compared with a standard FNA needle, a 22-gauge Franseen FNB needle was associated with a higher first-pass tissue acquisition rate.
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http://dx.doi.org/10.5009/gnl19171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667934PMC
November 2020

Lenvatinib-induced acute acalculous cholecystitis in a patient with hepatocellular carcinoma.

Clin J Gastroenterol 2020 Aug 2;13(4):568-571. Epub 2020 Apr 2.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

The patient was a 67-year-old man with advanced hepatocellular carcinoma (HCC) due to chronic hepatitis B. Due to refractoriness to radiofrequency ablation and transcatheter arterial chemoembolization, lenvatinib, a new oral mutikinase inhibitor, was started with a daily dose of 12 mg. However, on day 6 the patient developed acute-onset, right upper quadrant pain associated with fever; laboratory tests revealed leukocytosis and liver dysfunction. CT scan showed the swollen gallbladder with wall thickening with no evidence of gallstones, and the diagnosis of acute acalculous cholecystitis was made. After the resolution of cholecystitis by antibiotics and endoscopic nasogallbladder drainage placement, lenvatinib was resumed at a reduced daily dose of 4 mg. However, acute acalculous cholecystitis recurred, supporting lenvatinib as a cause of acute acalculous cholecystitis. Using the Naranjo adverse drug reaction probability scale, a score of 6 was derived, which indicates that this adverse event was probably caused by lenvatinib. In summary, we present a patient with advanced HCC who underwent repeated episodes of acute acalculous cholecystitis as a rare adverse event associated with lenvatinib.
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http://dx.doi.org/10.1007/s12328-020-01116-5DOI Listing
August 2020

Regular Statin Use and Incidence of Postendoscopic Retrograde Cholangiopancreatography Pancreatitis.

J Clin Gastroenterol 2020 Nov/Dec;54(10):905-910

Department of Gastroenterology, Graduate School of Medicine.

Goals And Background: Endoscopic retrograde cholangiopancreatography is widely utilized to diagnose and treat various pancreaticobiliary diseases, but postendoscopic retrograde cholangiopancreatography pancreatitis (PEP) can be a fatal adverse event. Evidence suggests that statins may exhibit suppressive effects on inflammation in the pancreas. We carried out an observational cohort study to examine the protective effect of statins on PEP.

Study: We retrospectively identified consecutive patients who underwent endoscopic retrograde cholangiopancreatography at a tertiary care center in Japan between January 2010 and January 2019. The incidences of PEP were compared between regular and nonregular statin users. Using the multivariable logistic regression model, we examined the association of regular statin use with the incidence of PEP controlling for potential risk factors for PEP.

Results: We included 2664 patients (328 regular statin users and 2336 nonregular users). The incidence of PEP did not differ by statin use status (P=0.52): 8.8% in regular statin users and 7.9% in nonregular users. The multivariable-adjusted odds ratio for PEP comparing regular statin use with nonregular use was 1.08 (95% confidence interval, 0.67-1.72; P=0.76). When we examined specific statin types (hydrophilic and lipophilic statins), we consistently observed the null association: 6.8% of 132 hydrophilic statin users and 10% of 196 lipophilic statin users (P=0.74 and 0.27, respectively, compared with nonregular users).

Conclusions: Regular statin use was not shown to be protective against PEP. A further investigation is warranted before this medication is tested in prospective randomized trials.
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http://dx.doi.org/10.1097/MCG.0000000000001312DOI Listing
January 2020

Effects of storage temperature, storage time, and Cary-Blair transport medium on the stability of the gut microbiota.

Drug Discov Ther 2019 Nov 11;13(5):256-260. Epub 2019 Oct 11.

RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.

How long fecal samples can withstand a period of refrigeration or room temperature, and the appropriate preservative, are largely unknown. Cary-Blair transport medium has been used for many years because it is inexpensive and prevents bacterial overgrowth. However, its effectiveness for metagenomic analyses has never been tested. We found that the microbial compositions using a 16S rRNA sequence of samples left at 4°C for 3 or 7 days or at 25°C for 1, 3, or 7 days differed significantly from samples stored at -80°C in no-preservative method. Whereas samples stored in Cary-Blair medium remained unchanged for longer periods. The relative abundances of phylum Bacteroidetes and Actinobacteria, changed significantly at 25°C, whereas Cary-Blair medium inhibited the reduction in Bacteroidetes and the increase in Actinobacteria. The bacterial survival counts were significantly lower in the RNAlater samples than in the Cary-Blair samples under aerobic and anaerobic culture conditions. In conclusion, storage time and storage temperature significantly affect the gut microbial composition in fecal samples. Given the low cost, inhibitory effect on bacterial changes, and potential utility in bacterial isolation, Cary-Blair medium containers are suitable for large-scale or hospital-based microbiome studies, especially if direct freezing at -80°C is unavailable.
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http://dx.doi.org/10.5582/ddt.2019.01071DOI Listing
November 2019

Insulin secretion improvement during steroid therapy for autoimmune pancreatitis according to the onset of diabetes mellitus.

J Gastroenterol 2020 Feb 30;55(2):198-204. Epub 2019 Aug 30.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Background: Autoimmune pancreatitis (AIP) is frequently complicated by diabetes mellitus (DM), but DM associated with AIP is reported to improve after steroid therapy. The aim of this study is to investigate glucose intolerance during steroid therapy according to the onset of DM.

Methods: Sixty-one patients who underwent steroid therapy for AIP were included into this study. We evaluated C peptide index (CPI), homeostasis model assessment for insulin resistance (HOMA-R), and the pancreatic diameter at AIP diagnosis and after 4 weeks, 1 year, and 2 years of steroid therapy. Patients were categorized into three groups according to DM onset: Pre-existing DM (pDM), concurrent DM (cDM), and non-DM (nDM).

Results: Forty-three patients (71%) had DM: 15 pDM and 28 cDM. At AIP diagnosis, CPI was lower in patients with pDM (0.7, P = 0.007) and cDM (0.9, P = 0.018) than nDM (1.3). After 4 weeks of steroid therapy, CPI improved in cDM (P < 0.001) and in nDM (P = 0.021). After 2 years of steroid therapy, HOMA-R increased (2.1-3.0, P = 0.007) but CPI gradually improved (1.0-2.1, P = 0.004). DM improved in 23% of cDM, and 55% of insulin users in cDM discontinued using insulin. Pancreatic atrophy was seen in 30%, and was associated with DM.

Conclusion: DM in patients with AIP was associated with impaired insulin secretion rather than insulin resistance. Insulin secretion improved during steroid therapy for AIP in patients with concurrent DM. Thus, glucose intolerance can be an indication for AIP treatment.
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http://dx.doi.org/10.1007/s00535-019-01615-4DOI Listing
February 2020

Poorly controlled type 2 diabetes with no progression of diabetes-related complications and low levels of advanced glycation end products: A Case report.

Medicine (Baltimore) 2019 Jul;98(30):e16573

Department of Diabetes, Endocrinology, and Metabolism, Center Hospital.

Rationale: Previous studies have suggested that increased levels of advanced glycation end products (AGEs) and soluble receptor for AGE (sRAGE) are associated with diabetes-related complications. However, there is little evidence on the association between long-term levels of AGEs and sRAGE and progression of diabetes-related complications.

Patient Concerns: A 64-year-old man had poorly controlled type 2 diabetes, obesity, smoking, hypertension, and dyslipidemia. He had many risk factors for diabetes-related complications.

Diagnosis: Despite poor glycemic control over 15 years, the patient did not exhibit diabetes-related complications.

Interventions: We examined serum AGEs (CEL and MG-H1) and sRAGE levels in this patient over the past 10 years.

Outcomes: The patient maintained low serum AGEs and sRAGE levels.

Lessons: AGEs and sRAGE levels may be associated with long-term development of diabetes-related complications.
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http://dx.doi.org/10.1097/MD.0000000000016573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6709306PMC
July 2019

Global impact of rotavirus vaccine introduction on rotavirus hospitalisations among children under 5 years of age, 2008-16: findings from the Global Rotavirus Surveillance Network.

Lancet Glob Health 2019 07;7(7):e893-e903

Expanded Program on Immunization, World Health Organization, Geneva, Switzerland.

Background: Rotavirus vaccine use in national immunisation programmes has led to declines in hospital admissions for rotavirus gastroenteritis among children; however, the global impact of rotavirus vaccine introduction has not been described using primary data. We describe the impact of rotavirus vaccine introduction on admissions for acute rotavirus gastroenteritis in primarily low-income and middle-income countries, using 9 years of data from the WHO-coordinated Global Rotavirus Surveillance Network (GRSN).

Methods: Between Jan 1, 2008, and Dec 31, 2016, children younger than 5 years of age who were admitted to hospital with acute gastroenteritis were prospectively enrolled in GRSN sites. We included sites that enrolled children and collected stool specimens monthly and tested at least 100 specimens annually in the impact analysis, with a separate analysis taking into account site continuity. We compared proportions of acute gastroenteritis cases positive for rotavirus in the pre-vaccine and post-vaccine periods and calculated mean proportion changes for WHO regions, with 95% CIs; these findings were then compared with interrupted time series analyses. We did further sensitivity analyses to account for rotavirus vaccination coverage levels and sites that collected specimens for at least 11 months per year and tested at least 80 specimens per year. We also analysed the age distribution of rotavirus-positive cases before and after vaccine introduction.

Findings: 403 140 children younger than 5 years of age admitted to hospital with acute gastroenteritis from 349 sites in 82 countries were enrolled over the study period, of whom 132 736 (32·9%) were positive for rotavirus. We included 305 789 children from 198 sites in 69 countries in the impact analysis. In countries that had not introduced rotavirus vaccine in their national immunisation programmes, rotavirus was detected in 38·0% (95% CI 4·8-73·4) of admissions for acute gastroenteritis annually whereas in those that have introduced the vaccine, rotavirus was detected in 23·0% (0·7-57·7) of admissions for acute gastroenteritis, showing a 39·6% (35·4-43·8) relative decline following introduction. Interrupted time series analyses confirmed these findings. Reductions by WHO regions ranged from 26·4% (15·0-37·8) in the Eastern Mediterranean Region to 55·2% (43·0-67·4) in the European Region and were sustained in nine countries (contributing up to 31 sites) for 6-10 years. The age distribution of children with rotavirus gastroenteritis shifted towards older children after rotavirus vaccine introduction.

Interpretation: A significant and sustained reduction in the proportion of hospital admissions for acute gastroenteritis due to rotavirus was seen among children younger than 5 years in GRSN sites following rotavirus vaccine introduction. These findings highlight the need to incorporate rotavirus vaccines into immunisation programmes in countries that have not yet introduced them and underline the importance of high-quality surveillance.

Funding: The GRSN receives funding from Gavi, the Vaccine Alliance and the US Centers for Disease Control and Prevention. No specific funding was provided for this Article.
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http://dx.doi.org/10.1016/S2214-109X(19)30207-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336990PMC
July 2019

Significance of biopsy with ERCP for diagnosis of bile duct invasion of DLBCL.

Int J Hematol 2019 Sep 15;110(3):381-384. Epub 2019 May 15.

Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-City, Tokyo, 113-8655, Japan.

Obstructive jaundice is an initial symptom in 1-2% of diffuse large B cell lymphoma (DLBCL) cases. The major cause of bile duct obstruction in patients with DLBCL is extrinsic compression by enlarged lymph nodes. In such cases, the existence of bile duct invasion of lymphoma is rarely mentioned or observed pathologically, so the ratio of bile duct invasion to the total cases of obstructive jaundice, and its significance remains unknown. We report two cases of DLBCL presenting as an obstructive jaundice, in which we demonstrated bile duct invasion pathologically by biopsy from the wall of common bile duct with endoscopic retrograde cholangiopancreatography (ERCP). Endoscopic stent placement is a minimally invasive procedure to relieve cholestasis and is effective for diagnosing bile duct invasion. This procedure should thus be performed in all cases of obstructive jaundice caused by lymphoma to evaluate for bile duct invasion. Our cases suggest that ERCP may be useful as a diagnostic procedure for bile duct invasion.
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http://dx.doi.org/10.1007/s12185-019-02661-7DOI Listing
September 2019

Effects of bowel preparation on the human gut microbiome and metabolome.

Sci Rep 2019 03 11;9(1):4042. Epub 2019 Mar 11.

Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, Japan.

Large bowel preparation may cause a substantial change in the gut microbiota and metabolites. Here, we included a bowel prep group and a no-procedure control group and evaluated the effects of bowel prep on the stability of the gut microbiome and metabolome as well as on recovery. Gut microbiota and metabolome compositions were analyzed by 16S rRNA sequencing and capillary electrophoresis time-of-flight mass spectrometry, respectively. Analysis of coefficients at the genus and species level and weighted UniFrac distance showed that, compared with controls, microbiota composition was significantly reduced immediately after the prep but not at 14 days after it. For the gut metabolome profiles, correlation coefficients between before and immediately after the prep were significantly lower than those between before and 14 days after prep and were not significantly different compared with those for between-subject differences. Thirty-two metabolites were significantly changed before and immediately after the prep, but these metabolites recovered within 14 days. In conclusion, bowel preparation has a profound effect on the gut microbiome and metabolome, but the overall composition recovers to baseline within 14 days. To properly conduct studies of the human gut microbiome and metabolome, fecal sampling should be avoided immediately after bowel prep.
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http://dx.doi.org/10.1038/s41598-019-40182-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6411954PMC
March 2019

Cholangitis complicated by infection of a simple hepatic cyst.

Clin J Gastroenterol 2018 Dec 8;11(6):493-496. Epub 2018 Jun 8.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

An 87-year-old man was admitted to our hospital due to fever and elevated liver enzymes. Computed tomography (CT) scan revealed bile duct stones with a dilated biliary system, which confirmed the diagnosis of cholangitis. A 12-cm simple hepatic cyst was also seen in the right liver, which had been detected on CT scan 5 years before, and did not change in size. Fever did not subside even after endoscopic biliary drainage and a repeated CT scan showed an enlarged cyst up to 14 cm, suggesting cyst infection. An enlarged hepatic cyst collapsed after percutaneous transhepatic drainage, along with resolution of fever. Simple hepatic cysts are common and most of them are asymptomatic. Infection of simple hepatic cysts is a rare condition and the major entry route is considered as the biliary tract as communication between the biliary tract and cysts is reportedly observed in those cases. However, in our case, no communication was seen on cholangiogram or cystogram on fluoroscopy and bilirubin level of the cyst aspirate was low. Given the fact that patients with cholangitis are rarely complicated by hepatic cyst infection, other routes of bacterial entry to simple hepatic cysts should also be considered.
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http://dx.doi.org/10.1007/s12328-018-0874-0DOI Listing
December 2018

Diarrhea among hospitalized children under five: A call for inclusion of rotavirus vaccine to the national immunization program in Indonesia.

Vaccine 2018 12 1;36(51):7826-7831. Epub 2018 Jun 1.

Department of Child Health, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada/Dr. Sardjito Hospital, Yogyakarta, Indonesia; Pediatric Research Office, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada/Dr. Sardjito Hospital, Yogyakarta, Indonesia.

Context: Rotavirus diarrhea is a common disease worldwide which mostly affects children under five years old. Rotavirus infection causes severe diarrhea and leads to substantial health care costs. In Indonesia the rotavirus vaccine has been available since 2011, however it has not been included into the National Immunization Program. This study aims to describe the proportion of rotavirus in children under 5 in Indonesia, the clinical characteristics of rotavirus infections, and the rotavirus strains circulating in the country during 2010-2015.

Methods: Children under five years of age with acute watery diarrhea were prospectively identified and enrolled through the active diarrhea surveillance system in 5 sites in four provinces in Indonesia during 2010-2015. The rotavirus specimens were tested using Enzyme Immunoassay. Bivariate logistic regression tests were performed to compare rotavirus positive and negative results with respect to the collected demographic and clinical variables.

Results: From January 2010 to December 2015, the average annual rotavirus prevalence among children hospitalized with acute watery diarrhea in four provinces in Indonesia was 47.5%. Rotavirus diarrhea occurred mostly in children under 2 years of age. Of all age groups, children aged 6-11 and 12-23 months had the highest prevalence of rotavirus diarrhea in all years (54.2% and 50.6%, respectively). This study found that the most prevalent of G and P genotypes were G1P8 in 2010 (63.2%), 2011 (64.1%) and 2012 (74.6%) and G3P8 in 2013 (49.7%), 2014 (82.5%) and 2015 (84.4%) CONCLUSIONS: This study demonstrates that rotavirus is a major cause of diarrhea in hospitalized children in Indonesia. These findings highlight the need for inclusion of the rotavirus vaccine to the National Immunization Program in Indonesia.
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http://dx.doi.org/10.1016/j.vaccine.2018.05.031DOI Listing
December 2018

CA19-9 kinetics during systemic chemotherapy in patients with advanced or recurrent biliary tract cancer.

Cancer Chemother Pharmacol 2017 Dec 16;80(6):1105-1112. Epub 2017 Oct 16.

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

Purpose: The role of carbohydrate antigen 19-9 (CA19-9) kinetics in patients with biliary tract cancer (BTC) receiving chemotherapy remains to be elucidated.

Methods: A total of 185 advanced or recurrent BTC patients receiving a first line chemotherapy between January 2006 and March 2016, were retrospectively studied. Serum CA19-9 was measured at baseline and after two cycles of chemotherapy, and patients were categorized based on CA19-9 response: CA19-9 decrease group (≥ 30% decrease), stable group (< 30% decrease and < 20% increase) and increase group (≥ 20% increase). The associations of CA19-9 response with radiological tumor response, progression-free survival (PFS) and overall survival (OS) were investigated.

Results: There was a statistically significant association between CA19-9 response and radiological tumor responses (p < 0.001). The median PFS and OS were significantly different among three groups according to CA19-9 response: PFS of 8.0, 5.7 and 3.5 months in CA19-9 decrease, stable and increase groups (p < 0.001) and OS of 18.8, 16.0 and 7.5 months in CA19-9 decrease, stable and increase groups, respectively (p < 0.001). Multivariate analyses showed that CA19-9 response was prognostic both of OS and PFS in addition, to CA19-9 at baseline, and performance status.

Conclusion: CA19-9 kinetics after the first two cycles of a first line chemotherapy was a prognostic factor for OS and PFS in patients with advanced and recurrent BTC.
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http://dx.doi.org/10.1007/s00280-017-3456-9DOI Listing
December 2017

Postprandial Glucose Surges after Extremely Low Carbohydrate Diet in Healthy Adults.

Tohoku J Exp Med 2017 09;243(1):35-39

Department of Endocrinology and Diabetes, Saitama Medical University.

Carbohydrate-restricted diets are prevalent not only in obese people but also in the general population to maintain appropriate body weight. Here, we report that extreme carbohydrate restriction for one day affects the subsequent blood glucose levels in healthy adults. Ten subjects (median age 30.5 years, BMI 21.1 kg/m, and HbA1c 5.5%), wearing with a continuous glucose monitoring device, were given isoenergetic test meals for 4 consecutive days. On day 1, day 2 (D2), and day 4 (D4), they consumed normal-carbohydrate (63-66% carbohydrate) diet, while on day 3, they took low-carbohydrate/high-fat (5% carbohydrate) diet. The daily energy intake was 2,200 kcal for males and 1,700 kcal for females. On D2 and D4, we calculated the mean 24-hr blood glucose level (MEAN/24h) and its standard deviation (SD/24h), the area under the curve (AUC) for glucose over 140 mg/dL within 4 hours after each meal (AUC/4h/140), the mean amplitude of the glycemic excursions (MAGE), the incremental AUC of 24-hr blood glucose level above the mean plus one standard deviation (iAUC/MEAN+SD). Indexes for glucose fluctuation on D4 were significantly greater than those on D2 (SD/24h; p = 0.009, MAGE; p = 0.013, AUC/4h/140 after breakfast and dinner; p = 0.006 and 0.005, and iAUC/MEAN+SD; p = 0.007). The value of MEAN/24h and AUC/4h/140 after lunch on D4 were greater than those on D2, but those differences were not statistically significant. In conclusion, consumption of low-carbohydrate/high-fat diet appears to cause higher postprandial blood glucose on subsequent normal-carbohydrate diet particularly after breakfast and dinner in healthy adults.
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http://dx.doi.org/10.1620/tjem.243.35DOI Listing
September 2017

Performance of a High-Sensitivity Rapid Diagnostic Test for Malaria in Asymptomatic Individuals from Uganda and Myanmar and Naive Human Challenge Infections.

Am J Trop Med Hyg 2017 Nov 18;97(5):1540-1550. Epub 2017 Aug 18.

Diagnostics Program, PATH, Seattle, Washington.

Sensitive field-deployable diagnostic tests can assist malaria programs in achieving elimination. The performance of a new Alere™ Malaria Ag P.f Ultra Sensitive rapid diagnostic test (uRDT) was compared with the currently available SD Bioline Malaria Ag P.f RDT in blood specimens from asymptomatic individuals in Nagongera, Uganda, and in a Karen Village, Myanmar, representative of high- and low-transmission areas, respectively, as well as in pretreatment specimens from study participants from four -induced blood-stage malaria (IBSM) studies. A quantitative reverse transcription PCR (qRT-PCR) and a highly sensitive enzyme-linked immunosorbent assay (ELISA) test for histidine-rich protein II (HRP2) were used as reference assays. The uRDT showed a greater than 10-fold lower limit of detection for HRP2 compared with the RDT. The sensitivity of the uRDT was 84% and 44% against qRT-PCR in Uganda and Myanmar, respectively, and that of the RDT was 62% and 0% for the same two sites. The specificities of the uRDT were 92% and 99.8% against qRT-PCR for Uganda and Myanmar, respectively, and 99% and 99.8% against the HRP2 reference ELISA. The RDT had specificities of 95% and 100% against qRT-PCR for Uganda and Myanmar, respectively, and 96% and 100% against the HRP2 reference ELISA. The uRDT detected new infections in IBSM study participants 1.5 days sooner than the RDT. The uRDT has the same workflow as currently available RDTs, but improved performance characteristics to identify asymptomatic malaria infections. The uRDT may be a useful tool for malaria elimination strategies.
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http://dx.doi.org/10.4269/ajtmh.17-0245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5817764PMC
November 2017

A novel "hitch-and-ride" deep biliary cannulation method during rendezvous endoscopic ultrasound-guided ERCP technique.

Endoscopy 2017 Oct 21;49(10):983-988. Epub 2017 Jul 21.

Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

Endoscopic ultrasound-guided rendezvous (EUS-RV) is increasingly reported as a treatment option after failed endoscopic retrograde cholangiopancreatography. We developed a novel "hitch-and-ride" catheter for biliary cannulation to reduce the risk of guidewire loss during EUS-RV. We retrospectively evaluated safety and technical success of EUS-RV between June 2011 and May 2016. Biliary cannulation during EUS-RV using three methods - over-the-wire, along-the-wire, and hitch-and-ride - were compared. A total of 30 EUS-RVs were attempted and the technical success rate was 93.3 %, with two failures (one bile duct puncture and one guidewire insertion). After 28 cases of successful guidewire passage, cannulation was attempted by the over-the-wire (n = 13), along-the-wire (n = 4) or hitch-and-ride (n = 11) method. Only the hitch-and-ride method achieved biliary cannulation without guidewire loss or conversion to the other methods. Time to cannulation was shorter with the hitch-and-ride method (4 minutes) than with over-the-wire and along-the-wire methods (9 and 13 minutes, respectively). The adverse event rate of EUS-RV was 23.3 %. A novel hitch-and-ride catheter was feasible for biliary cannulation after EUS-RV.
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http://dx.doi.org/10.1055/s-0043-113444DOI Listing
October 2017

The eIF2-alpha kinase HRI is a novel therapeutic target in multiple myeloma.

Leuk Res 2017 04 12;55:23-32. Epub 2017 Jan 12.

Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, WA, USA; Department of Pediatric Hematology/Oncology, Seattle Children's Hospital, 4800 Sand Point Way, Seattle, WA, USA; Department of Pediatrics, University of Washington, 1959 NE Pacific St., Seattle, WA, USA.

Dexamethasone (dex) induces apoptosis in multiple myeloma (MM) cells and is a frontline treatment for this disease. However resistance to dex remains a major challenge and novel treatment approaches are needed. We hypothesized that dex utilizes translational pathways to promote apoptosis in MM and that specific targeting of these pathways could overcome dex-resistance. Global unbiased profiling of mRNA translational profiles in MM cells treated with or without dex revealed that dex significantly repressed eIF2 signaling, an important pathway for regulating ternary complex formation and protein synthesis. We demonstrate that dex induces the phosphorylation of eIF2α resulting in the translational upregulation of ATF4, a known eIF2 regulated mRNA. Pharmacologic induction of eIF2α phosphorylation via activation of the heme-regulated eIF2α kinase (HRI) induced apoptosis in MM cell lines and in primary MM cells from patients with dex-resistant disease. In addition, co-culture with marrow stroma failed to protect MM cells from apoptosis induced by targeting the eIF2 pathway. Combination therapy with rapamycin, an mTOR inhibitor, and BTdCPU, an activator of HRI, demonstrated additive effects on apoptosis in dex-resistant cells. Thus, specific activation of the eIF2α kinase HRI is a novel therapeutic target in MM that can augment current treatment strategies.
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http://dx.doi.org/10.1016/j.leukres.2017.01.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5354961PMC
April 2017

H/ACA small RNA dysfunctions in disease reveal key roles for noncoding RNA modifications in hematopoietic stem cell differentiation.

Cell Rep 2013 May 23;3(5):1493-502. Epub 2013 May 23.

School of Medicine and Department of Urology, UCSF Helen Diller Comprehensive Cancer Center, San Francisco, CA 94115, USA.

Noncoding RNAs control critical cellular processes, although their contribution to disease remains largely unexplored. Dyskerin associates with hundreds of H/ACA small RNAs to generate a multitude of functionally distinct ribonucleoproteins (RNPs). The DKC1 gene, encoding dyskerin, is mutated in the multisystem disorder X-linked dyskeratosis congenita (X-DC). A central question is whether DKC1 mutations affect the stability of H/ACA RNPs, including those modifying ribosomal RNA (rRNA). We carried out comprehensive profiling of dyskerin-associated H/ACA RNPs, revealing remarkable heterogeneity in the expression and function of subsets of H/ACA small RNAs in X-DC patient cells. Using a mass spectrometry approach, we uncovered single-nucleotide perturbations in dyskerin-guided rRNA modifications, providing functional readouts of small RNA dysfunction in X-DC. In addition, we identified that, strikingly, the catalytic activity of dyskerin is required for accurate hematopoietic stem cell differentiation. Altogether, these findings reveal that small noncoding RNA dysfunctions may contribute to the pleiotropic manifestation of human disease.
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http://dx.doi.org/10.1016/j.celrep.2013.04.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3857015PMC
May 2013

Pluripotent stem cell models of Shwachman-Diamond syndrome reveal a common mechanism for pancreatic and hematopoietic dysfunction.

Cell Stem Cell 2013 Jun 18;12(6):727-36. Epub 2013 Apr 18.

Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Dana-Farber Cancer Institute, Boston, MA 02115, USA.

Shwachman-Diamond syndrome (SDS), a rare autosomal-recessive disorder characterized by exocrine pancreatic insufficiency and hematopoietic dysfunction, is caused by mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene. We created human pluripotent stem cell models of SDS through knockdown of SBDS in human embryonic stem cells (hESCs) and generation of induced pluripotent stem cell (iPSC) lines from two patients with SDS. SBDS-deficient hESCs and iPSCs manifest deficits in exocrine pancreatic and hematopoietic differentiation in vitro, enhanced apoptosis, and elevated protease levels in culture supernatants, which could be reversed by restoring SBDS protein expression through transgene rescue or by supplementing culture media with protease inhibitors. Protease-mediated autodigestion provides a mechanistic link between the pancreatic and hematopoietic phenotypes in SDS, highlighting the utility of hESCs and iPSCs in obtaining novel insights into human disease.
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http://dx.doi.org/10.1016/j.stem.2013.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3755012PMC
June 2013

Impaired ribosomal subunit association in Shwachman-Diamond syndrome.

Blood 2012 Dec 31;120(26):5143-52. Epub 2012 Oct 31.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.

Shwachman-Diamond syndrome (SDS) is an autosomal-recessive marrow failure syndrome with a predisposition to leukemia. SDS patients harbor biallelic mutations in the SBDS gene, resulting in low levels of SBDS protein. Data from nonhuman models demonstrate that the SBDS protein facilitates the release of eIF6, a factor that prevents ribosome joining. The complete abrogation of Sbds expression in these models results in severe cellular and lethal physiologic abnormalities that differ from the human disease phenotype. Because human SDS cells are characterized by partial rather than complete loss of SBDS expression, we interrogated SDS patient cells for defects in ribosomal assembly. SDS patient cells exhibit altered ribosomal profiles and impaired association of the 40S and 60S subunits. Introduction of a wild-type SBDS cDNA into SDS patient cells corrected the ribosomal association defect, while patient-derived SBDS point mutants only partially improved subunit association. Knockdown of eIF6 expression improved ribosomal subunit association but did not correct the hematopoietic defect of SBDS-deficient cells. In summary, we demonstrate an SBDS-dependent ribosome maturation defect in SDS patient cells. The role of ribosomal subunit joining in marrow failure warrants further investigation.
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http://dx.doi.org/10.1182/blood-2012-04-420166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3537309PMC
December 2012

Functional screen of human MCM2-7 variant alleles for disease-causing potential.

Mutat Res 2009 Jun 27;666(1-2):74-8. Epub 2009 Mar 27.

Department of Genetics, Cell Biology and Development, College of Biological Sciences,Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, United States.

Origin licensing builds a fundamental basis for genome stability in DNA replication. Recent studies reported that deregulation of origin licensing is associated with replication stress in precancerous lesions. The heterohexameric complex of minichromosome maintenance proteins (MCM2-7 complex) plays an essential role in origin licensing. Previously, we reported the recovery of the first viable Mcm mutant allele (named Mcm4(Chaos3)) in mice. The Mcm4(Chaos3) allele destabilizes the MCM2-7 complex, leading to chromosome instability and the formation of spontaneous tumors in Mcm4(Chaos3) homozygous mice. Supporting our finding, a recent study reported that mice with reduced expression of MCM2 die with lymphomas within the first few months after birth. These data strongly suggest that mutant Mcm2-7 genes are cancer-causing genes with nearly complete penetrance in mice. This could be the case for humans as well. Nevertheless, related investigations have not been undertaken due to the essential nature of the MCM2-7 genes. To circumvent this problem, we focused on the variant alleles of human MCM2-7 genes derived from single nucleotide polymorphisms. We created a total of 14 variant alleles in the corresponding genes in Saccharomyces cerevisiae. The phenotypic consequence was assayed for minichromosome loss, a surrogate phenotype for genome instability and cancer susceptibility. This screen identified a MCM5 variant allele with pathogenic potential. This allele deserves further investigations on its effect on cancer development in human populations.
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http://dx.doi.org/10.1016/j.mrfmmm.2009.03.006DOI Listing
June 2009

[Anesthetic management for repair of Ebstein's anomaly with WPW syndrome].

Masui 2009 Apr;58(4):438-41

Department of Anesthesiology, Tokushima University Medical and Dental Hospital, Tokushima 770-8503.

Ebstein's anomaly is a rare congenital malformation of the tricuspid valve, often associated with Wolff-Parkinson-White (WPW) syndrome. We report the perioperative management of 3 patients (a 34-year-old man, a 5-month-old boy and a 5-year-old girl) with Ebstein's anomaly associated with WPW syndrome. Anesthetic managements for valvuloplasty of the tricuspid valve and ablation of accessory pathway in 3 patients were successfully accomplished with a combination of fentanyl, sevoflurane, and midazolam. The management of Ebstein's anomaly is based on its severity. The major concerns with anesthesia for children with Ebstein's anomaly include decreased cardiac output, right-to-left atrial level shunting with cyanosis, and the propensity for atrial tachyarrhythmias. We conclude that perioperative management of arrhythmia and evaluation of residual tricuspid regurgitation using transesophageal echocardiography are essential.
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April 2009

Argon gas embolism in the application of laparoscopic microwave coagulation therapy.

J Hepatobiliary Pancreat Surg 2009 11;16(3):394-8. Epub 2009 Feb 11.

Department of Surgery, The University of Tokushima, 3-18-15, Kuramoto-cho, Tokushima, 770-8503, Japan.

Background: A major concern in the use of the argon beam coagulator system is the potential risk of argon gas embolism.

Methods: Seven cases with argon gas embolism in the English literature were reviewed along with the current case. The latter case was a 77-year-old female having laparoscopic hepatectomy after application of the microwave coagulation system on the cutting planes.

Results: Immediately following shots of an argon beam to control local bleeding at the needle hole in the liver caused by microwave coagulation, the end-tidal carbon disappeared, followed by cardiovascular collapse. After 18 min of cardiovascular resuscitation, the tumors were resected under laparotomy.

Conclusions: After reviewing the cases, pneumoperitoneum (57.1%), hepatic needle punctures (42.8%) and direct application of the argon beam to the liver (28.6%) can be considered as risky processes in such events. Caution is necessary in the use of an argon beam in liver surgery to avoid life-threatening gas embolism.
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http://dx.doi.org/10.1007/s00534-008-0039-5DOI Listing
August 2009

Taltirelin improves motor ataxia independently of monoamine levels in rolling mouse nagoya, a model of spinocerebellar atrophy.

Biol Pharm Bull 2005 Dec;28(12):2244-7

Laboratory of CNS Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Japan.

To examine the relationship between motor ataxia and monoamine levels in the central nervous system, the contents and concentrations of noradrenaline (NA), dopamine (DA) and serotonin (5-HT) in the cerebellum, brain stem and spinal cord were measured in rolling mouse Nagoya (RMN), a murine model of spinocerebellar atrophy. The tissue weight of the cerebellum and spinal cord, but not that of the brain stem was significantly lower in RMN than in the control group. In RMN, the NA content of the brain stem and spinal cord, but not the cerebellum were decreased relative to the control, and the concentration of NA in the spinal cord was also lower, but not significant. The DA and 5-HT contents in each tissue did not differ from those of the control, but the concentrations of monoamines, except for DA, were elevated in the brain stem and spinal cord in RMN. In particular, the concentrations of NA, DA and 5-HT in the cerebellum were significantly increased in RMN. Repeated administration of tartilerin hydrate, an analog of thyrotropin-releasing hormone, improved the ataxia of RMN, and elicited no obvious changes in either monoamine content or concentration of cerebellum, brain stem and spinal cord. These results indicate that the concentration of DA, as well as NA and 5-HT, increased in the RMN cerebellum, and that tartilerin improves the motor function of these mice via mechanisms other than changes in the levels of NA, DA and 5-HT in the central nervous system.
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http://dx.doi.org/10.1248/bpb.28.2244DOI Listing
December 2005