Publications by authors named "Chia-Tung Shun"

203 Publications

Recurrence Outcomes Less Favorable in T1 Rectal Cancer than in T1 Colon Cancer.

Oncologist 2021 May 6. Epub 2021 May 6.

Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.

Background: With the implementation of screening programs worldwide, diagnosis of early-stage colorectal cancer steadily increased, including T1 cancer. Current T1 cancer treatment does not differ according to anatomic location. We therefore compared the disease-free survival of T1 cancer arising from the rectum versus the colon.

Methods: The hospital-based study included subjects with T1 cancer at National Taiwan University Hospital from 2005 to 2014. Clinical, colonoscopy, and histopathology were reviewed for patients with a mean follow-up time of 7.1 (0.7-12.9) years. We conducted Kaplan-Meier analysis to compare the risk of recurrence by cancer location and Cox regression analysis to identify risk factors for T1 cancer recurrence.

Results: The final cohort included a total of 343 subjects with T1 cancer (mean age, 64.9 ± 11.7 years; 56.1% male), of whom 25 underwent endoscopic resection alone. Of the subjects who underwent surgery, 50 had lymph node metastasis and 268 did not. Kaplan-Meier analysis showed that the risk of recurrence was higher in T1 rectal cancer than T1 colon cancer (p = .022). Rectal location and larger neoplasm size were independent risk factors for recurrence, with hazard ratios of 4.84 (95% confidence interval, 1.18-19.92), and 1.32 (95% confidence interval, 1.06-1.65), respectively. The occurrence of advanced histology did not differ between T1 rectal and colon cancers (p = .58).

Conclusion: T1 cancers arising from the rectum had less favorable recurrence outcomes than those arising from the colon. Further studies are needed to examine whether adjuvant radiotherapy or chemotherapy can reduce the risk of recurrence in T1 rectal cancer.

Implications For Practice: Current T1 colorectal cancer treatment and surveillance do not differ according to anatomic location. Clinical, colonoscopy, and histopathology were reviewed for 343 patients with T1 cancer with a mean follow-up time of 7.1 years. Kaplan-Meier analysis showed that the risk of recurrence was higher in T1 rectal cancer than T1 colon cancer. Moreover, the rectal location was an independent risk factor for recurrence. T1 cancers from the rectum had less favorable recurrence outcomes than those arising from the colon. It is critical to clarify whether adjuvant therapy or more close surveillance can reduce recurrence risk in T1 rectal cancer.
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http://dx.doi.org/10.1002/onco.13815DOI Listing
May 2021

Bismuth salts with versus without acid suppression for Helicobacter pylori infection: A transmission electron microscope study.

Helicobacter 2021 Jun 19;26(3):e12801. Epub 2021 Mar 19.

Department of Medicine, Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA.

Background: Bismuth oxychloride produced by interaction of bismuth compounds with gastric acid is believed to damage Helicobacter pylori. The effect of bismuth salts on H. pylori in the presence of strong acid suppression is unknown. This randomized trial aimed to determine effects of bismuth subcitrate on H. pylori with and without acid suppression.

Methods: H. pylori -positive participants were allocated (1:1:1) to receive (a) no treatment (control), (b) colloidal bismuth subcitrate (CBS, 125 mg/tab), or (c) CBS plus high-dose proton-pump inhibitor (PPI), esomeprazole 40 mg q.i.d. for 3 days. In the treatment groups, CBS was given: 1 dose, 1 hour before endoscopy, 1 dose, 4 hours before endoscopy, or q.i.d. 24 hours before endoscopy. The study end-points were evaluated using transmission electron microscopy to observe the morphological changes of H. pylori in antral and corpus biopsies.

Results: Twenty-seven H. pylori carriers were enrolled in this trial with qualitative end-points. In the no treatment group, active budding and replication of H. pylori were observed. In the CBS group, cellular swelling, vacuolization, structural degradation, and cell wall eruption of H. pylori were observed, with no apparent association with when the CBS was given. Among those receiving high-dose PPI-plus CBS or CBS only, there were no differences in number of H. pylori present or severity of bacterial damage whether CBS was given 1, 4, or 24 hours before endoscopy.

Conclusions: Based on direct morphological evaluation, the toxic effect of CBS treatment on H. pylori was demonstrated independent of acid suppression with PPI.
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http://dx.doi.org/10.1111/hel.12801DOI Listing
June 2021

Obesity alters ovarian folliculogenesis through disrupted angiogenesis from increased IL-10 production.

Mol Metab 2021 Feb 13;49:101189. Epub 2021 Feb 13.

Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei, Taiwan; Livia Shang Yu Wan Chair Professor of Obstetrics and Gynecology, College of Medicine, National Taiwan University, Taipei, Taiwan. Electronic address:

Objective: Obesity has been reported to have a modulatory effect on the ovulatory functions of patients with polycystic ovary syndrome. The role of adipokines in this obesity-associated ovulatory disturbance has not been extensively explored. In this study, the relationships between obesity, adipokine production from visceral fat, and ovarian folliculogenesis were explored in a mice model of induced obesity.

Methods: Obesity was induced in female C57BL/6 mice fed ad libitum with high-fat feed and fructose water for 4 weeks. Follicular developments in the ovaries were assessed by histopathology in these diet-induced obese mice. Changes in adipokine expression in the peri-ovarian adipose tissues were screened with an adipokine array. The adipokine with the most significant increase over time was identified. The functions of the adipokine in angiogenic processes were evaluated in a cell model of endothelial proliferation. The in vivo effects of neutralizing this adipokine using specific antibodies were assessed in the same obesity model.

Results: A high-fat and fructose diet induced an accumulation of early ovarian follicles and a reduction in mature follicles and corpus lutea. The number of microvessels in the early follicles also decreased. The adipokine protein array of the peri-ovarian adipose tissues identified a progressive increase in IL-10 expression with the duration of the obesogenic diet. In vitro experiments in the endothelial cell model confirmed IL-10 as a disrupter of VEGF-induced angiogenesis. Administration of anti-IL-10 antibodies prevented the histopathological changes induced by the obesogenic diet and further highlighted the role of IL-10 in disrupting folliculogenesis.

Conclusions: Obesity may disrupt normal folliculogenesis through increased production of IL-10 in visceral fats. This relationship may help clarify the reported association between obesity and ovulatory dysfunction, which has been found in patients with polycystic ovary syndrome. However, the duration of this study was short, which limited conclusions on the long-term reproductive outcomes.
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http://dx.doi.org/10.1016/j.molmet.2021.101189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933796PMC
February 2021

Metformin: a novel promising option for fertility preservation during cyclophosphamide-based chemotherapy.

Mol Hum Reprod 2021 01;27(1)

Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei 100, Taiwan.

Cyclophosphamide (CP) could cause severe gonadotoxicity via imbalanced activation of primordial follicles through PI3K/AKT/mTOR activation. Whether metformin, a widely prescribed anti-diabetes agent with mTOR inhibitory effect, could preserve ovarian function against CP toxicity is unknown. Female C57BL/6 mice were randomized into seven groups (n = 11), including control, CP-alone, CP + metformin, CP + sirolimus or everolimus, metformin-alone and sirolimus-alone groups. The duration of pharmaceutical treatment was 4 weeks. CP treatment significantly impaired ovarian function and fertility in mice. CP + metformin treatment significantly attenuated the gonadotoxicity comparing to CP-alone treatment (primordial follicle count: 17.6 ± 4.2 versus 10.3 ± 2.7 follicles/high-power field; P = 0.027). CP + metformin treatment also tended to increase antral follicular count (5.4 ± 1.1 versus 2.5 ± 1.6 follicles/section), serum AMH levels (4.6 ± 1.2 versus 2.0 ± 0.8 ng/ml) and the litter size (4.2 ± 1.3 versus 1.5 ± 1.0 mice per pregnancy), compared with CP-alone group. Expression of phospho-mTOR and the number of TUNEL-positive granulosa cells increased after CP treatment and decreased in the CP + metformin groups, suggesting the mTOR inhibitory and anti-apoptotic effects of metformin. In in-vitro granulosa cell experiments, the anti-apoptotic effect of metformin was blocked after inhibiting p53 or p21 function, and the expression of p53 mRNA was blocked with AMPK inhibitor, suggesting that the anti-apoptotic effect was AMPK/p53/p21-mediated. In conclusion, concurrent metformin treatment during CP therapy could significantly preserve ovarian function and fertility and could be a promising novel fertility preserving agent during chemotherapy. The relatively acceptable cost and well-established long-term safety profiles of this old drug might prompt its further clinical application at a faster pace.
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http://dx.doi.org/10.1093/molehr/gaaa084DOI Listing
January 2021

Additive Effects of Arsenic and Aristolochic Acid in Chemical Carcinogenesis of Upper Urinary Tract Urothelium.

Cancer Epidemiol Biomarkers Prev 2021 Feb 4;30(2):317-325. Epub 2020 Dec 4.

Department of Urology, National Taiwan University Hospital, Taipei, Taiwan.

Background: Aristolochic acids (AA) and arsenic are chemical carcinogens associated with urothelial carcinogenesis. Here we investigate the combined effects of AA and arsenic toward the risk of developing upper tract urothelial carcinoma (UTUC).

Methods: Hospital-based ( = 89) and population-based (2,921 cases and 11,684 controls) Taiwanese UTUC cohorts were used to investigate the association between exposure to AA and/or arsenic and the risk of developing UTUC. In the hospital cohort, AA exposure was evaluated by measuring aristolactam-DNA adducts in the renal cortex and by identifying A>T mutations in tumors. In the population cohort, AA exposure was determined from prescription health insurance records. Arsenic levels were graded from 0 to 3 based on concentrations in well water and the presence of arseniasis-related diseases.

Results: In the hospital cohort, 43, 26, and 20 patients resided in grade 0, 1+2, and 3 arseniasis-endemic areas, respectively. Aristolactam-DNA adducts were present in >90% of these patients, indicating widespread AA exposure. A>T mutations in were detected in 28%, 44%, and 22% of patients residing in grade 0, 1+2, and 3 arseniasis-endemic areas, respectively. Population studies revealed that individuals who consumed more AA-containing herbs had a higher risk of developing UTUC in both arseniasis-endemic and nonendemic areas. Logistic regression showed an additive effect of AA and arsenic exposure on the risk of developing UTUC.

Conclusions: Exposure to both AA and arsenic acts additively to increase the UTUC risk in Taiwan.

Impact: This is the first study to investigate the combined effect of AA and arsenic exposure on UTUC.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8083126PMC
February 2021

The possible role of sirtuin 5 in the pathogenesis of apical periodontitis.

Oral Dis 2020 Nov 15. Epub 2020 Nov 15.

Department of Dentistry, School of Dentistry, College of Medicine, National Taiwan University, Taipei, Taiwan.

Objectives: We investigated the relation between expression of sirtuin 5 (SIRT5) in osteoblastic cells and progression of apical periodontitis. The role of SIRT5 in hypoxia-induced reactive oxygen species (ROS) formation and osteoblast apoptosis was also examined.

Materials And Methods: Progression of rat apical periodontitis was monitored by conventional radiography and microcomputed tomography. SIRT5 and oxidative stress biomarker 8-OHdG in bone-lining cells were assessed by immunohistochemistry. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling was used to demonstrate apoptosis. In primary human osteoblasts cultured under hypoxia, Western blot was used to analyze SIRT5 expression and cleavage of pro-caspase 3 and poly(ADP-ribose) polymerase (PARP). SIRT5 was overexpressed through lentiviral technique. ROS formation and mitochondrial membrane potential changes were assessed by MitoSOX-Red and JC-1 fluorescence, respectively. Immunofluorescence microscope was used to evaluate mitochondrial release of cytochrome c.

Results: In rat apical periodontitis, disease progression was accompanied by decreased expression of SIRT5, increased oxidative stress, and enhanced apoptosis in bone-lining cells. SIRT5 was suppressed in cultured osteoblasts under hypoxia. SIRT5 overexpression ameliorated hypoxia-enhanced ROS formation, mitochondrial depolarization, cytochrome c leakage, activation of caspase-3, and PARP fragmentation.

Conclusions: SIRT5 is able to alleviate hypoxia-enhanced osteoblast apoptosis. SIRT5 augmentation may have therapeutic potential for apical periodontitis.
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http://dx.doi.org/10.1111/odi.13723DOI Listing
November 2020

Fibrin and Platelet-Rich Composition in Retrieved Thrombi Hallmarks Stroke With Active Cancer.

Stroke 2020 12 3;51(12):3723-3727. Epub 2020 Nov 3.

Department of Neurology (C.-H.F., C.-H.C., L.-K.T., S.-C.T., J.-S.J.), National Taiwan University Hospital, Taipei.

Background And Purpose: We aim to investigate whether histopathologic examination of thrombi retrieved from acute ischemic stroke patients undergoing endovascular treatment could distinguish cancer-related stroke from other etiologies.

Methods: Thrombi from patients undergoing endovascular treatment were analyzed. The etiology of stroke was divided into cardioembolism, large artery atherosclerosis, and active cancer groups. All selected thrombi were subjected to hematoxylin and eosin staining. The percentages of fibrin/platelets, red blood cells, and white blood cells within a thrombus were quantified.

Results: One-hundred fifty-two patients (active cancer, 19; cardioembolism, 107; large artery atherosclerosis, 26) were included. Thrombi from the active cancer group exhibited a higher fibrin/platelet composition than did those from the cardioembolism and large artery atherosclerosis groups (median, 85.7% versus 43.9% and 42.5%; <0.001). Fibrin/platelet composition was the only independent factor (odds ratio, 1.05 [95% CI, 1.02-1.08]) in differentiating cancer-related stroke from stroke caused by cardioembolism and large artery atherosclerosis. A fibrin/platelet proportion of ≥65% accurately predicted cancer-related stroke (area under the curve, 0.84; <0.001).

Conclusions: In thrombi retrieved from patients undergoing endovascular treatment, a high fibrin/platelet composition was a probable indicator of cancer-related stroke.
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http://dx.doi.org/10.1161/STROKEAHA.120.032069DOI Listing
December 2020

Comparison of the effect of clarithromycin triple therapy with or without -acetylcysteine in the eradication of : a randomized controlled trial.

Therap Adv Gastroenterol 2020 31;13:1756284820927306. Epub 2020 Jul 31.

Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, No. 7, Chung-Shan S. Road, Taipei Taiwan.

Background: Whether adjunctive -acetylcysteine (NAC) may improve the efficacy of triple therapy in the first-line treatment of infection remains unknown. Our aim was to compare the efficacy of 14-day triple therapy with or without NAC for the first-line treatment of .

Material And Methods: Between 1 January 2014 and 30 June 2018, 680 patients with infection naïve to treatment were enrolled in this multicenter, open-label, randomized trial. Patients were randomly assigned to receive triple therapy with NAC [NAC-T14, dexlansoprazole 60 mg four times daily (q.d.); amoxicillin 1 g twice daily (b.i.d.), clarithromycin 500 mg b.i.d., NAC 600 mg b.i.d.] for 14 days, or triple therapy alone (T14, dexlansoprazole 60 mg q.d.; amoxicillin 1 g b.i.d., clarithromycin 500 mg b.i.d.) for 14 days. Our primary outcome was the eradication rates by intention to treat (ITT). Antibiotic resistance and gene polymorphism were determined.

Results: The ITT analysis demonstrated eradication rates in NAC-T14 and T14 were 81.7% [276/338, 95% confidence interval (CI): 77.5-85.8%] and 84.3% (285/338, 95% CI 80.4-88.2%), respectively. In 646 participants who adhered to their assigned therapy, the eradication rates were 85.7% and 88.0% with NAC-T14 and T14 therapies, respectively. There were no differences in compliance or adverse effects. The eradication rates in subjects with clarithromycin-resistant, amoxicillin-resistant, or either clarithromycin/amoxicillin resistant strains were 45.2%, 57.9%, and 52.2%, respectively, for NAC-T14, and were 66.7%, 76.9%, and 70.0%, respectively, for T14. The efficacy of NAC-T14 and T14 was not affected by polymorphism.

Conclusion: Add-on NAC to triple therapy was not superior to triple therapy alone for first-line eradication [ClinicalTrials.gov identifier: NCT02249546].
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http://dx.doi.org/10.1177/1756284820927306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406927PMC
July 2020

Mass eradication of to reduce gastric cancer incidence and mortality: a long-term cohort study on Matsu Islands.

Gut 2021 Feb 13;70(2):243-250. Epub 2020 Aug 13.

Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan

Objective: Although mass eradication of has been proposed as a means to eliminate gastric cancer, its long-term effects remain unclear.

Design: Mass eradication of infection was launched in 2004 and continued until 2018 for a high-risk Taiwanese population aged 30 years or older dwelling on Matsu Islands with prevalent infection. Test positives for the C-urea breath test underwent eradication therapy. We evaluated the effectiveness of the mass eradication in reducing two main outcomes, incidence and mortality rates of gastric cancer, until the end of 2016 and 2018, respectively.

Results: After six rounds of mass screening and eradication, the coverage rate reached 85.5% (6512/7616). The referral rate for treatment was 93.5% (4286/4584). The prevalence rates of fell from 64.2% to 15.0% with reinfection rates of less than 1% per person-year. The presence and severity of atrophic gastritis and intestinal metaplasia also decreased with time. Compared with the historical control period from 1995 to 2003, the effectiveness in reducing gastric cancer incidence and mortality during the chemoprevention period was 53% (95% CI 30% to 69%, p<0.001) and 25% (95% CI -14% to 51%, p=0.18), respectively. No significant changes were noted in the incidence rates of other digestive tract cancers or the antibiotic resistance rate of .

Conclusion: Population-based eradication of has significantly reduced gastric cancer incidence with no increase in the likelihood of adverse consequences. A significant reduction in mortality is likely to be achieved with a longer follow-up period.

Trial Registration Number: NCT00155389.
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http://dx.doi.org/10.1136/gutjnl-2020-322200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815911PMC
February 2021

Risk stratification for gastric cancer after Helicobacter pylori eradication: A population-based study on Matsu Islands.

J Gastroenterol Hepatol 2021 Mar 24;36(3):671-679. Epub 2020 Jul 24.

Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.

Background And Aim: The reliable method to stratify the gastric cancer risk after Helicobacter pylori eradication remains an elusive goal.

Methods: Mass eradication of H. pylori began in 2004 in a high-risk population. After eradication, a screening program involving first-stage serological tests (pepsinogen-I, pepsinogen-II, H. pylori immunoglobin G, and gastrin-17) and second-stage endoscopic examination was launched in 2015-2018. Index lesions included gastric cancer or extensive premalignant lesions. We evaluated the performance of the serological tests to "rule in" and "rule out" the risk based on positive and negative likelihood ratios, respectively. The methylation levels of microRNA-124a-3 in the stomach were measured to indicate genetic damage.

Results: Among 6512 invited subjects, 3895 (59.6%) participated. Both gastrin-17 and pepsinogen tests were normal in 3560 (91.4%) subjects; 206 (5.3%) gastrin-17 and 129 (3.3%) pepsinogen tests were abnormal. Years after eradication, the severity of gastritis had fallen greatly, and extensive premalignant lesions or gastric cancer frequently occurred in newly non-atrophic-appearing mucosa. Pepsinogen testing could moderately predict atrophic gastritis (positive likelihood ratio: 4.11 [95% confidence interval: 2.92-5.77]; negative likelihood ratio: 0.14 [0.10-0.19]). Gastrin-17 was not useful (0.66 and 1.20, respectively). However, pepsinogen testing poorly predicted the index lesions (2.04 [1.21-3.42] and 0.57 [0.34-0.95]). DNA methylation levels in the post-eradication mucosa were more discriminative for predicting index lesions (3.89 [2.32-6.54] and 0.25 [0.15-0.42]).

Conclusions: After eradication, pepsinogen false-negative results become more frequent because histology is improved but genetic damage may persist. Direct testing for genetic damage offers better discrimination.
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http://dx.doi.org/10.1111/jgh.15187DOI Listing
March 2021

Copy Number Alterations of Depressed Colorectal Neoplasm Predict the Survival and Response to Oxaliplatin in Proximal Colon Cancer.

Cancers (Basel) 2020 Jun 10;12(6). Epub 2020 Jun 10.

Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan.

Depressed colorectal neoplasm exhibits high malignant potential and shows rapid invasiveness. We investigated the genomic profile of depressed neoplasms and clarified the survival outcome and treatment response of the cancers arising from them. We examined 20 depressed and 13 polypoid neoplasms by genome-wide copy number analysis. Subsequently, we validated the identified copy number alterations (CNAs) in an independent cohort of 37 depressed and 42 polypoid neoplasms. Finally, the CNAs were tested as biomarkers in 530 colorectal cancers (CRCs) to clarify the clinical outcome of depressed neoplasms. CNAs in , , and were significantly enriched in depressed neoplasms and designated as the D-marker panel. CRCs with a D-marker panel have significantly shorter progression-free survival compared with those without ( = 0.012), especially in stage I ( = 0.049), stages T ( = 0.027), and proximal cancers ( = 0.002). The positivity of the D-marker panel was an independent risk factor of cancer progression (hazard ratio (95% confidence interval) = 1.52 (1.09-2.11)). Furthermore, the proximal CRCs with D-marker panels had worse overall and progression-free survival when taking oxaliplatin as chemotherapy than those that did not. The D-marker panel may help to optimize treatment and surveillance in proximal CRC and develop a molecular test. However, the current result remains preliminary, and further validation in prospective trials is warranted in the future.
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http://dx.doi.org/10.3390/cancers12061527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352996PMC
June 2020

Higher risk of advanced histology in adenoma less than 10 mm in fecal immunochemical test screening: Implication for management.

J Gastroenterol Hepatol 2020 Oct 3;35(10):1738-1745. Epub 2020 Apr 3.

Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.

Background And Aim: Whether diminutive or small adenomas detected by fecal immunochemical tests (FITs) are associated with a higher risk of advanced histology remains unknown. We investigated the prevalence of advanced histology in diminutive and small adenomas detected by FIT and compared with that detected by colonoscopy screening.

Methods: We prospectively compared 1860 FIT-positive patients (FIT-positive cohort) and 6691 average-risk patients (screening colonoscopy cohort). Both groups underwent colonoscopies and were shown to have neoplastic lesions. The prevalence of advanced histology was determined, as was the associations with size and FIT positivity.

Results: We analyzed 3920 neoplastic lesions from the FIT-positive cohort and 9789 neoplastic lesions from the screening colonoscopy cohort. Eighty (4.3%) diminutive lesions in FIT-positive cohort had advanced histology but without any invasive cancer. Twenty-one patients in the FIT-positive cohort and 49 in the screening colonoscopy cohort with diminutive adenomas displayed advanced histology (3.5% vs 1.2%; adjusted odds ratio [aOR] = 2.99, 95% confidence interval [CI]: 1.77-5.06). Sixteen patients in the FIT-positive cohort (2.7%) with diminutive adenomas might have changed the surveillance interval if a resect-and-discard strategy was applied, with a higher likelihood compared with the screening colonoscopy cohort (aOR = 2.76, 95% CI: 1.53-4.99).

Conclusions: Fecal immunochemical test screening detected more diminutive and small adenomas with advanced histology compared with colonoscopy screening. Its impact on current management of diminutive polyp is limited.
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http://dx.doi.org/10.1111/jgh.15040DOI Listing
October 2020

A case with cytomegalovirus colitis and toxic megacolon initially diagnosed as Crohn's disease.

J Formos Med Assoc 2020 Sep 20;119(9):1442-1444. Epub 2020 Jan 20.

Division of Hepatology and Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; Inflammatory Bowel Disease Clinical and Study Integrated Center, National Taiwan University Hospital, Taipei, Taiwan; College of Medicine, National Taiwan University, Taipei, Taiwan. Electronic address:

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http://dx.doi.org/10.1016/j.jfma.2019.12.012DOI Listing
September 2020

B-Cell Activating Factor Enhances Hepatocyte-Driven Angiogenesis via B-Cell CLL/Lymphoma 10/Nuclear Factor-KappaB Signaling during Liver Regeneration.

Int J Mol Sci 2019 Oct 10;20(20). Epub 2019 Oct 10.

Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 10002, Taiwan.

B-cell activating factor (BAFF) is found to be associated with the histological severity of nonalcoholic steatohepatitis (NASH). BAFF was also found to have a protective role in hepatic steatosis via down regulating the expression of steatogenesis genes and enhancing steatosis in hepatocytes through BAFF-R. However, the roles of BAFF during liver regeneration are not well defined. In this study, C57/B6 mice with 70% partial hepatectomy were used as a liver regeneration model. BAFF expression was determined by enzyme immunoassay, and anti-BAFF-neutralizing antibodies were administered to confirm the effects of BAFF on liver regeneration. Western blotting, immunohistochemistry, and florescence staining determined the expression of B-cell CCL/lymphoma 10 (BCL10). The angiogenesis promoting capability was evaluated after the transfection of cells with siRNA targeting BCL10 expression, and the role of NF-κB was assessed. The results revealed that the BAFF and BCL10 levels were upregulated after partial hepatectomy. Treatment with anti-BAFF-neutralizing antibodies caused death in mice that were subjected to 70% partial hepatectomy within 72 h. In vitro, recombinant BAFF protein did not enhance hepatocyte proliferation; however, transfection with BCL10 siRNA arrested hepatocytes at the G2/M phase. Interestingly, conditioned medium from BAFF-treated hepatocytes enhanced angiogenesis and endothelial cell proliferation. Moreover, Matrix metalloproteinase-9 (MMP-9), Fibroblast growth factor 4 (FGF4), and Interleukin-8 (IL-8) proteins were upregulated by BAFF through BCL10/NF-κB signaling. In mice that were treated with anti-BAFF-neutralizing antibodies, the microvessel density (MVD) of the remaining liver tissues and liver regeneration were both reduced. Taken together, our study demonstrated that an increased expression of BAFF and activation of BCL10/NF-κB signaling were involved in hepatocyte-driven angiogenesis and survival during liver regeneration.
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http://dx.doi.org/10.3390/ijms20205022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829427PMC
October 2019

Mitochondrial Dysfunction Induced by High Estradiol Concentrations in Endometrial Epithelial Cells.

J Clin Endocrinol Metab 2020 01;105(1)

Department of Obstetrics and Gynecology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.

Context: A supraphysiological estradiol (E2) concentration after ovarian stimulation is known to result in lower embryo implantation rates in in vitro fertilization. Endometrial epithelial cell (EEC) apoptosis occurs after the stimulation with high E2 concentrations, and mitochondria play important roles in cell apoptosis.

Objective: To investigate the mitochondrial function in EECs after the stimulation with high E2 concentrations.

Materials And Methods: Human EECs were purified and cultured with different E2 concentrations (10-10, 10-9, 10-8, 10-7 M) in vitro, in which 10-7 M is supraphysiologically high. Eight-week-old female mouse endometrium was obtained 5.5 days after the injection of 1.25 IU or 20 IU equine chorionic gonadotropin, roughly during the embryo implantation window, to examine the in vivo effects of high E2 concentrations on mouse EECs.

Results: In vivo and in vitro experiments demonstrated decreased mitochondrial DNA contents and ATP formation after EECs were stimulated with supraphysiologically high E2 concentrations than those stimulated with a physiologic E2 concentration. Less prominent immunofluorescence mitochondrial staining, fewer mitochondria numbers under electron microscopy, lower 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolylcarbocyanine iodide aggregate/monomer ratio, and greater reactive oxygen species (ROS) production were found after EECs were stimulated with supraphysiologically high E2 concentrations. The high E2-induced ROS production was reduced when EECs were pretreated with N-acetyl-cysteine in vitro, but remained unchanged after the pretreatment with coenzyme Q10.

Conclusion: High E2 concentrations increase extramitochondrial ROS production in EECs and subsequently result in mitochondrial dysfunction.
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http://dx.doi.org/10.1210/clinem/dgz015DOI Listing
January 2020

Metabolic targeting of HIF-1α potentiates the therapeutic efficacy of oxaliplatin in colorectal cancer.

Oncogene 2020 01 2;39(2):414-427. Epub 2019 Sep 2.

Department of Pharmacology and Graduate Institute of Forensic Medicine, National Taiwan University College of Medicine, 100, Taipei, Taiwan.

Drug resistance is a major problem limiting the efficacy of chemotherapy in cancer treatment, and the hypoxia-induced stabilization of HIF-1α plays a role in this process. HIF-1α overexpression has been observed in a variety of human cancers, including colorectal cancer (CRC). Therefore, targeting HIF-1α is a promising strategy for overcoming chemoresistance to enhance the efficacy of chemotherapies in CRC. Here, we show that DNMT inhibitors can induce HIF-1α degradation to overcome oxaliplatin resistance and enhance anti-CRC therapy. We found that a low-toxicity DNMT inhibitor, zebularine, could downregulate HIF-1α expression and overcome hypoxia-induced oxaliplatin resistance in HCT116 cells and showed efficacy in HCT116 xenograft models and AOM/DSS-induced CRC mouse models. Zebularine could induce the degradation of HIF-1α protein through hydroxylation. LC-MS analysis showed a decrease in succinate in various CRC cells under hypoxia and in colon tissues of AOM/DSS-induced CRC mice. The decrease was reversed by zebularine. Tumor angiogenesis was also reduced by zebularine. Furthermore, zebularine potentiated the anticancer effect of oxaliplatin in AOM/DSS-induced CRC models. This finding provides a new strategy in which an increase in HIF-1α hydroxylation could overcome oxaliplatin resistance to enhance anti-CRC therapy.
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http://dx.doi.org/10.1038/s41388-019-0999-8DOI Listing
January 2020

Increased Expression of Programmed Death-Ligand 1 in Infiltrating Immune Cells in Hepatocellular Carcinoma Tissues after Sorafenib Treatment.

Liver Cancer 2019 Mar 15;8(2):110-120. Epub 2018 Jun 15.

Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.

Objective: Programmed death-ligand 1 (PD-L1) expression in the tumor microenvironment (TME) has been reported to be related to prognosis in patients with hepatocellular carcinoma (HCC) after hepatectomy. The impact of sorafenib on PD-L1 expression in the TME of advanced HCC is unclear.

Patients And Methods: Patients with HCC who received sorafenib for advanced disease at National Taiwan University Hospital, Taipei, Taiwan, and who had paired HCC tissues obtained before and after sorafenib treatment were included in the study group. HCC patients not treated with sorafenib who had paired primary and recurrent or metastatic tissues were identified as the reference group. The membrane PD-L1 staining, detected by immunohistochemistry (IHC) using SP142 antibody, was semiquantitatively scored in tumor cells (TCs) or tumor-infiltrating immune cells (ICs). Additional IHC assays were employed to characterize the PD-L1-expressing ICs.

Results: Twenty-three advanced HCC patients with pre- and post-sorafenib paired HCC tissues were included in the study group. The median duration of sorafenib treatment was 4.3 months (range: 1.3-18.7). PD-L1 expression in ICs was significantly higher in post-sorafenib HCC tissues than in pre-sorafenib HCC tissues (pre-sorafenib vs. post-sorafenib IHC 0/1/2/3: 11/5/5/2 vs. 5/5/2/11, = 0.016). However, PD-L1 expression in TCs was not significantly different between pre- and post-sorafenib tissues (IHC 0/1/2/3: 19/2/0/2 vs. 14/5/0/4, = 0.094). In the reference group of 44 patients not treated with sorafenib, PD-L1 expression in ICs and TCs was not significantly different between the paired primary and metastatic HCC tissues. By performing IHC double staining with PD-L1 and CD68, we found the PD-L1-expressing ICs were mainly CD68-positive macrophages. PD-L1 expression levels of pre- and post-sorafenib tissues were not associated with patients' overall survival or duration of sorafenib treatment.

Conclusions: PD-L1 expression in ICs was significantly increased in post-sorafenib HCC tissues. The mechanisms and clinical significance of this observation warrants further investigation.
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http://dx.doi.org/10.1159/000489021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6465685PMC
March 2019

Correction to: Trichostatin A, a histone deacetylase inhibitor, induces synergistic cytotoxicity with chemotherapy via suppression of Raf/MEK/ERK pathway in urothelial carcinoma.

J Mol Med (Berl) 2019 Mar;97(3):435-436

Department of Urology, College of Medicine, National Taiwan University, National Taiwan University Hospital, Taipei, Taiwan.

In Fig. 1b, upper part, the cell viability counts after treatment with cisplatin and TSA in T24 cells was by mistake a duplication of the image for NTUB1 on the left. In the corrected version of Fig. 1, the image was replaced appropriately.
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http://dx.doi.org/10.1007/s00109-019-01748-2DOI Listing
March 2019

Risk of delayed bleeding before and after implementation of cold snare polypectomy in a screening colonoscopy setting.

Endosc Int Open 2019 Feb 30;7(2):E232-E238. Epub 2019 Jan 30.

Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.

 Cold snare polypectomy (CSP) is considered to be effective in reducing risk of delayed bleeding but randomized trials fail to support this owing to the small sample size. The current study aimed to compare risk of delayed bleeding before and after implementation of CSP in a screening colonoscopy setting. This study retrospectively analyzed a prospectively maintained screening colonoscopy database in a university hospital in Taiwan. We compared the rate of delayed bleeding before and after implementation within similar periods (18 months and 15 months) and the respective number of polypectomies (1,304 and 1,255) performed to remove small and diminutive polyps. The main outcome measurement was delayed bleeding within the two periods. Multivariate analysis was performed to adjust for major confounders.  A total of 1,304 and 1,225 subjects received hot snare polypectomy (HSP) and CSP in two separate periods, respectively. Compared with the HSP, the CSP had a lower rate of delayed bleeding (0.1 % vs 1.1 %,  < 0.001), severe bleeding (0 % 0.7 %,  < 0.01), need for second-look colonoscopy (0 % 0.8 %,  < 0.01), and emergency service visits (0.1 % vs 1.0 %,  < 0.01). Total procedure time (12.60 ± 11.45 vs 16.48 ± 14.27 min/person,  < 0.01) and duration of hospital stay (1.18 ± 0.50 vs 1.53 ± 5.78 hour/person,  < 0.03) were also shorter after CSP implementation. Multivariate analysis showed that HSP was an independent risk factor for delayed bleeding after adjusting for age, gender, and number of polyps (adjusted odds ratio 14.4;95 % confidence interval = 1.88 - 110.6).  Implementation of CSP significantly reduces risk of delayed bleeding associated with removing small and diminutive polyps in screening colonoscopy.
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http://dx.doi.org/10.1055/a-0810-0439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353650PMC
February 2019

Trichostatin A, a histone deacetylase inhibitor, induces synergistic cytotoxicity with chemotherapy via suppression of Raf/MEK/ERK pathway in urothelial carcinoma.

J Mol Med (Berl) 2018 12 4;96(12):1307-1318. Epub 2018 Oct 4.

Department of Urology, College of Medicine, National Taiwan University, National Taiwan University Hospital, Taipei, Taiwan.

In this study, we aimed to investigate the antitumor effects of trichostatin A (TSA), an antifungal antibiotic that inhibits histone deacetylase (HDAC) family of enzymes, alone or in combination with anyone of the three chemotherapeutic agents (cisplatin, gemcitabine, and doxorubicin) for the treatment of human urothelial carcinoma (UC). Two high-grade human UC cell lines (T24 and NTUB1) were used. Cytotoxicity and apoptosis were assessed by MTT assay and flow cytometry, respectively. The expression of phospho-c-Raf, phospho-MEK1/2, and phospho-ERK1/2 was measured by western blotting. ERK siRNA knockdown and the specific MEK inhibitor U0126 were used to examine the role of Raf/MEK/ERK signaling pathway in combined cytotoxicity of TSA and chemotherapy. TSA co-treatment with any one of the three chemotherapeutic agents induced synergistic cytotoxicity (combination index < 1) and concomitantly suppressed chemotherapeutic drug-induced activation of Raf-MEK-ERK pathway. Combination of ERK siRNA knockdown and treatment with the specific MEK inhibitor (U0126) enhanced the cytotoxic effects of the chemotherapy on UC cells. These observations were confirmed in a xenograft nude mouse model. Moreover, activated Raf/MEK/ERK pathway was observed in human bladder UC specimens from patients with chemoresistant status. In conclusion, TSA elicits a synergistic cytotoxic response in combination with chemotherapy via targeting the Raf/MEK/ERK pathway. TSA elicits synergistic cytotoxic response in combination with three DNA-damaging drugs (cisplatin, gemcitabine, and doxorubicin). Activated Raf/MEK/ERK pathway is involved in chemoresistant mechanism of UC. Combining chemotherapeutic agents with HDAC inhibitor (TSA) or with targeting Raf/MEK/ERK pathway is promising to circumvent chemoresistance in UCs.
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http://dx.doi.org/10.1007/s00109-018-1697-7DOI Listing
December 2018

Risk factors for coexistence of cervical elongation in uterine prolapse.

Eur J Obstet Gynecol Reprod Biol 2018 Oct 8;229:94-97. Epub 2018 Aug 8.

Department of Obstetrics and Gynecology, Far Eastern Memorial Hospital, Banqiao, New Taipei, Taiwan; Department of Obstetrics and Gynecology, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan. Electronic address:

Objective: To identify factors predicting cervical elongation in women with uterine prolapse.

Study Design: The medical records of women with uterine prolapse who underwent vaginal hysterectomy were reviewed. Multivariable logistic regression analysis was performed to identify predictors of cervical elongation.

Results: Of 295 women with uterine prolapse, 136 (46.1%) patients had cervical elongation, according to Berger et al. Classification (i.e., cervical length >3.38 cm and/or cervix-to-corpus lengths ratio >0.79). Multivariable analysis revealed that lower parity (odds ratio = 0.85, 95% confidence interval [CI] = 0.73 to 0.99, P = 0.04) and advanced stage of uterine prolapse (odds ratio = 1.97, 95% CI = 1.35-2.88, P < 0.001) were predictors for cervical elongation. Based on a receiver operating characteristic curve (ROC) analysis, the following optimum cut-off values were determined for cervical elongation: (1) parity ≤3, ROC area = 0.60 (95% CI = 0.53 to 0.66); (2) stage of uterine prolapse ≥3, ROC area = 0.63 (95% CI = 0.56 to 0.69). Thus, the predicted logit(p) for a given parity (a) and stage of uterine prolapse (b) can be denoted by logit(p) = -1.26 - 0.16 x a + 0.68 x b. The optimum cut-off values of logit(p) ≥-0.18 to predict cervical elongation were determined using ROC analysis (area = 0.66, 95% CI = 0.59 to 0.73). For women with parity ≤6, we can use either (1) stage 2 uterine prolapse and parity ≤1, or (2) ≥ stage 3 uterine prolapse as criteria to predict cervical elongation.

Conclusions: Lower parity and advanced stage of uterine prolapse are predictors of cervical elongation in women with uterine prolapse. Thus, stage of uterine prolapse ≥3 or logit(p) ≥-0.18 may be useful for predicting cervical elongation.
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http://dx.doi.org/10.1016/j.ejogrb.2018.08.011DOI Listing
October 2018

CXCR4 Antagonist Reduced the Incidence of Acute Rejection and Controlled Cardiac Allograft Vasculopathy in a Swine Heart Transplant Model Receiving a Mycophenolate-based Immunosuppressive Regimen.

Transplantation 2018 12;102(12):2002-2011

Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.

Background: CXC motif chemokine receptor 4 (CXCR4) blockade is pursued as an alternative to mesenchymal stem cell treatment in transplantation based on our previous report that burixafor, through CXCR4 antagonism, mobilizes immunomodulatory mesenchymal stem cells. Here, we explored the efficacy of combining mycophenolate mofetil (MMF)-based immunosuppressants with repetitive burixafor administration.

Methods: Swine heterotopic cardiac allograft recipients received MMF and corticosteroids (control, n = 10) combined with burixafor as a 2-dose (burixafor2D, n = 7) or 2-dose plus booster injections (burixafor2D + B, n = 5) regimen. The efficacy endpoints were graft survival, freedom from first acute rejection, and the severity of intimal hyperplasia. Each specimen was sacrificed either at its first graft arrest or after 150 days.

Results: After 150 days, all specimens in the control group had died, but 28.5% of the burixafor2D group survived, and 60% of the burixafor2D + B group survived (P = 0.0088). Although the control group demonstrated acute rejection at a median of 33.5 days, the burixafor2D + B group survived without acute rejection for a median of 136 days (P = 0.0209). Burixafor administration significantly attenuated the incidence rate of acute rejection (P = 0.002) and the severity of intimal hyperplasia (P = 0.0097) at end point relative to the controls. These findings were associated with reduced cell infiltrates in the allografts, and modulation of C-reactive protein profiles in the circulation.

Conclusions: The augmentation of conventional MMF plus corticosteroids with a CXCR4 antagonist is potentially effective in improving outcomes after heart transplantation in minipigs. Future studies are warranted into optimizing the therapeutic regimens for humans.
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http://dx.doi.org/10.1097/TP.0000000000002404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6257103PMC
December 2018

Efficacies of Genotypic Resistance-Guided vs Empirical Therapy for Refractory Helicobacter pylori Infection.

Gastroenterology 2018 10 30;155(4):1109-1119. Epub 2018 Jun 30.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan. Electronic address:

Background & Aims: We aimed to compare the efficacy of genotypic resistance-guided therapy vs empirical therapy for eradication of refractory Helicobacter pylori infection in randomized controlled trials.

Methods: We performed 2 multicenter, open-label trials of patients with H pylori infection (20 years or older) failed by 2 or more previous treatment regimens, from October 2012 through September 2017 in Taiwan. The patients were randomly assigned to groups given genotypic resistance-guided therapy for 14 days (n = 21 in trial 1, n = 205 in trial 2) or empirical therapy according to medication history for 14 days (n = 20 in trial 1, n = 205 in trial 2). Patients received sequential therapy containing esomeprazole and amoxicillin for the first 7 days, followed by esomeprazole and metronidazole, with levofloxacin, clarithromycin, or tetracycline (doxycycline in trial 1, tetracycline in trial 2) for another 7 days (all given twice daily) based on genotype markers of resistance determined from gastric biopsy specimens (group A) or empirical therapy according to medication history. Resistance-associated mutations in 23S ribosomal RNA or gyrase A were identified by polymerase chain reaction with direct sequencing. Eradication status was determined by C-urea breath test. The primary outcome was eradication rate.

Results: H pylori infection was eradicated in 17 of 21 (81%) patients receiving genotype resistance-guided therapy and 12 of 20 (60%) patients receiving empirical therapy (P = .181) in trial 1. This trial was terminated ahead of schedule due to the low rate of eradication in patients given doxycycline sequential therapy (15 of 26 [57.7%]). In trial 2, H pylori infection was eradicated in 160 of 205 (78%) patients receiving genotype resistance-guided therapy and 148 of 205 (72.2%) patients receiving empirical therapy (P = .170), according to intent to treat analysis. The frequencies of adverse effects and compliance did not differ significantly between groups.

Conclusions: Properly designed empirical therapy, based on medication history, is an acceptable alternative to genotypic resistance-guided therapy for eradication of refractory H pylori infection after consideration of accessibility, cost, and patient preference. ClinicalTrials.gov ID: NCT01725906.
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http://dx.doi.org/10.1053/j.gastro.2018.06.047DOI Listing
October 2018

14 day sequential therapy versus 10 day bismuth quadruple therapy containing high-dose esomeprazole in the first-line and second-line treatment of Helicobacter pylori: a multicentre, non-inferiority, randomized trial.

J Antimicrob Chemother 2018 09;73(9):2510-2518

Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.

Background: Whether extending the treatment length and the use of high-dose esomeprazole may optimize the efficacy of Helicobacter pylori eradication remains unknown.

Objectives: To compare the efficacy and tolerability of optimized 14 day sequential therapy and 10 day bismuth quadruple therapy containing high-dose esomeprazole in first-line therapy.

Methods: We recruited 620 adult patients (≥20 years of age) with H. pylori infection naive to treatment in this multicentre, open-label, randomized trial. Patients were randomly assigned to receive 14 day sequential therapy or 10 day bismuth quadruple therapy, both containing esomeprazole 40 mg twice daily. Those who failed after 14 day sequential therapy received rescue therapy with 10 day bismuth quadruple therapy and vice versa. Our primary outcome was the eradication rate in the first-line therapy. Antibiotic susceptibility was determined. ClinicalTrials.gov: NCT03156855.

Results: The eradication rates of 14 day sequential therapy and 10 day bismuth quadruple therapy were 91.3% (283 of 310, 95% CI 87.4%-94.1%) and 91.6% (284 of 310, 95% CI 87.8%-94.3%) in the ITT analysis, respectively (difference -0.3%, 95% CI -4.7% to 4.4%, P = 0.886). However, the frequencies of adverse effects were significantly higher in patients treated with 10 day bismuth quadruple therapy than those treated with 14 day sequential therapy (74.4% versus 36.7% P < 0.0001). The eradication rate of 14 day sequential therapy in strains with and without 23S ribosomal RNA mutation was 80% (24 of 30) and 99% (193 of 195), respectively (P < 0.0001).

Conclusions: Optimized 14 day sequential therapy was non-inferior to, but better tolerated than 10 day bismuth quadruple therapy and both may be used in first-line treatment in populations with low to intermediate clarithromycin resistance.
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http://dx.doi.org/10.1093/jac/dky183DOI Listing
September 2018

Fulminant primary cardiac lymphoma with sudden cardiac death: A case report and brief review.

J Formos Med Assoc 2018 Oct 19;117(10):939-943. Epub 2018 Apr 19.

Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan. Electronic address:

Primary cardiac lymphoma (PCL) is very rare, with the variable clinical manifestations potentially leading to a delayed diagnosis. PCL is usually detected incidentally through image studies, whereas the diagnosis can be confirmed via analysis of pericardial effusion, endomyocardial biopsy tissue, or surgical specimens. Although no standard therapy has been established for PCL, without treatment, the prognosis is grave, with the estimated overall survival being approximately 1 year. We report a difficult diagnosis and complicated case of fulminant PCL, which is the first comprehensively reported case of PCL with secondary hemophagocytosis. A man presented with progressive dyspnea for 3 weeks, and then sudden cardiac death with ventricular fibrillation occurred. After resuscitation, echocardiography revealed a thickened left ventricular wall and severe mitral regurgitation, and computed tomography showed a right atrial mass with diffuse myocardial lesions. PCL was confirmed through a pathological analysis of specimens collected during mitral valvuloplasty, which also implied extensive myocardial involvement. Bone marrow biopsy demonstrated no evidence of lymphoma involvement, but secondary hemophagocytosis was noted. Despite aggressive chemotherapy, the patient died of sepsis with multiorgan failure 26 days after the operation.
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http://dx.doi.org/10.1016/j.jfma.2018.03.011DOI Listing
October 2018

Non-invasive detection of urothelial cancer through the analysis of driver gene mutations and aneuploidy.

Elife 2018 03 20;7. Epub 2018 Mar 20.

Masonic Cancer Center, University of Minnesota, Minneapolis, United States.

Current non-invasive approaches for detection of urothelial cancers are suboptimal. We developed a test to detect urothelial neoplasms using DNA recovered from cells shed into urine. UroSEEK incorporates massive parallel sequencing assays for mutations in 11 genes and copy number changes on 39 chromosome arms. In 570 patients at risk for bladder cancer (BC), UroSEEK was positive in 83% of those who developed BC. Combined with cytology, UroSEEK detected 95% of patients who developed BC. Of 56 patients with upper tract urothelial cancer, 75% tested positive by UroSEEK, including 79% of those with non-invasive tumors. UroSEEK detected genetic abnormalities in 68% of urines obtained from BC patients under surveillance who demonstrated clinical evidence of recurrence. The advantages of UroSEEK over cytology were evident in low-grade BCs; UroSEEK detected 67% of cases whereas cytology detected none. These results establish the foundation for a new non-invasive approach for detection of urothelial cancer.
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http://dx.doi.org/10.7554/eLife.32143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5860864PMC
March 2018

Serum Pepsinogen as a Predictor for Gastric Cancer Death: A 16-Year Community-based Cohort Study.

J Clin Gastroenterol 2019 May/Jun;53(5):e186-e193

Institute of Public Health, National Yang-Ming University, Taipei.

Goals: The purpose of this article is to validate the long-term association between initial serum pepsinogen (PG) measurements and subsequent gastric cancer-specific deaths from a long-term longitudinal cohort.

Background: Endoscopic surveillance can be effective and efficient in reducing gastric cancer mortality if a biomarker such as serum PG is available to identify high-risk individuals and if the biomarker also is specific to gastric cancer risk.

Study: Between 1995 and 1998, a gastric cancer-screening program was conducted in a high-risk population: The first stage involved PG testing, and the second stage involved upper endoscopy. The outcome was gastric cancer death, which was monitored until December 31, 2010; results were expressed as the hazard ratio (HR) and corresponding 95% confidence interval (CI) using the Cox proportional hazards regression model. Other causes of death were used as comparators.

Results: Among participants (n=3514) aged ≥30 years, 1682 (47.9%) were screened to determine serum PG levels. After 16 years of follow-up, 14 deaths from gastric cancer were documented. Multivariate analyses adjusted for age, sex, and Helicobacter pylori serological positivity showed that PG-I <30 μg/L and PG-I <30 μg/L or PG-I/II ratio <3 were significantly associated with the risk of gastric cancer death (HR, 3.27; 95% CI, 1.11-9.61 and HR, 3.45; 95% CI, 1.18-10.12, respectively). In contrast, there were no significant associations between PG and other causes of death, including neoplastic and non-neoplastic diseases.

Conclusion: This long-term cohort study shows the usefulness of PG measurement as a biomarker that is specific to the risk of gastric cancer death.
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http://dx.doi.org/10.1097/MCG.0000000000000992DOI Listing
August 2020