Publications by authors named "Ta-Sen Yeh"

219 Publications

The optimal timing of interval laparoscopic cholecystectomy following percutaneous cholecystostomy based on pathological findings and the incidence of biliary events.

J Hepatobiliary Pancreat Sci 2021 Jun 15. Epub 2021 Jun 15.

Division of General Surgery, Chang Gung Memorial Hospital, Taoyuan City, Taiwan.

Background: The incidence of biliary events (BE) following percutaneous cholecystostomy (PC) in acute cholecystitis (AC) patients is high. Therefore, definitive laparoscopic cholecystectomy (LC) is recommended. We aimed to investigate the optimal timing of LC following PC with regard to the clinical course and pathological findings.

Methods: All 744 AC patients with PC were included. The incidence and median number of BE were investigated with the concept of competing risks. The 344 patients with interval LC were divided into two groups based on the pathological findings of resected gallbladders: the acute/acute-and-chronic group (AANC group) (n=221) and the chronic group (n=123). A comparative analysis of the demographic data and perioperative outcomes was performed.

Results: Among the 744 AC patients with PC, 142 patients experienced recurrent BE. The cumulative incidence of BE was 26.6%, and the median time to recurrence was 67.5 days. The PC-to-LC days of the chronic group were longer than those of the AANC group (73.51 vs. 63.00, p<0.001). The multivariate analysis indicated that the operation time was longer in the AANC group than in the chronic group (p=0.040).

Conclusion: In terms of the clinical course and sequential pathological changes in the gallbladder, a 9- to 10-week interval after PC is the optimal timing for LC.
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http://dx.doi.org/10.1002/jhbp.1012DOI Listing
June 2021

Metabolism of Proteins and Amino Acids in Critical Illness: From Physiological Alterations to Relevant Clinical Practice.

J Multidiscip Healthc 2021 14;14:1107-1117. Epub 2021 May 14.

Division of General Surgery, Chang Gung Memorial Hospital, Taoyuan, 333, Taiwan.

The clinical impact of nutrition therapy in critically ill patients has been known for years, and relevant guidelines regarding nutrition therapy have emphasized the importance of proteins. During critical illness, such as sepsis or the state following major surgery, major trauma, or major burn injury, patients suffer from a high degree of stress/inflammation, and during this time, metabolism deviates from homeostasis. The increased degradation of endogenous proteins in response to stress hormones is among the most important events in the acute phase of critical illness. Currently published evidence suggests that adequate protein supplementation might improve the clinical outcomes of critically ill patients. The role of sufficient protein supplementation may even surpass that of caloric supplementation. In this review, we focus on relevant physiological alterations in critical illness, the effects of critical illness on protein metabolism, nutrition therapy in clinical practice, and the function of specific amino acids.
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http://dx.doi.org/10.2147/JMDH.S306350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131070PMC
May 2021

Cytoreductive Surgery may be beneficial for highly selected patients with Metastatic Gastrointestinal Stromal Tumors receiving Regorafenib facing Local Progression: A Case Controlled Study.

J Cancer 2021 12;12(11):3335-3343. Epub 2021 Apr 12.

GIST Team, Department of Surgery, Chang Gung Memorial Hospital, Linkou; Chang Gung University, Taiwan.

Current evidence have shown surgery may provide progression-free survival (PFS) benefit for selected patients with metastatic gastrointestinal stromal tumor (GIST) who received first line imatinib and second line sunitinib. However, impact of cytoreductive surgery for GIST patients receiving third line regorafenib facing progression is not yet reported. Between 2014 and 2019, 41 patients with metastatic GIST received regorafenib and 37 of them facing progression. 37 of 41 (90.2%) pre-treated GIST patients receiving regorafenib who experienced progression of disease after a median follow-up of 12.42 months after regorafenib use and 15 out of 37 (40.5%) patients with local progression underwent cytoreductive surgery (local progression and operation, LPOP). All the patients facing local progression (LP) were significantly younger with more exon 17 mutation than diffuse progression (DP). The complication rate for cytoreductive surgery was 33.3% (5/15). Cytoreductive surgery provided PFS prolongation of 5.52 months. Patients underwent cytoreductive surgery, compared with control group (local progression and no operation (LPNOP) and DP), may gain a significant PFS (12.91 versus 2.33 versus 5.29 months, = 0.0001) and overall survival (OS) benefit (32.33 versus 5.26 versus 12.42 months, = 0.004). Cytoreductive surgery might be feasible in highly selected patients with pre-treated GIST who are being treated with regorafenib experiencing LP.
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http://dx.doi.org/10.7150/jca.50324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100794PMC
April 2021

Visceral-to-subcutaneous fat ratio independently predicts the prognosis of locally advanced gastric cancer----- highlighting the role of adiponectin receptors and PPARα, β/ δ, ɤ.

Eur J Surg Oncol 2021 Apr 26. Epub 2021 Apr 26.

Department of Surgery, Chang Gung Memorial Hospital, Linkou & Chang Gung University, Taiwan. Electronic address:

Background: Results of computed tomography body composition (CTBC) predicting long-term outcomes of gastric cancer have been mixed and the plausible mechanism remains elusive.

Methods: We retrospectively enrolled a cohort of stage III gastric cancer who had undergone curative-intent gastrectomy. Clinicopathological variables, preoperative CTBC including abdominal muscle, subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT), and nutritional and inflammatory index were taken together to construct prognostic analysis. In vitro tests using co-culture system of gastric cancer cell lines and visceral adipocytes were conducted.

Results: A total of 191 eligible patients were enrolled. By multivariate analysis, SAT and VAT/ SAT ratio were prognostic factors of disease-free survival, while sarcopenia was not. SAT remained as a prognostic factor of overall survival. SAT index was positively correlated with prognostic nutritional index, while VAT HU was positively correlated with platelet-to-lymphocyte ratio. Expression of adiponectin receptor 1 and 2 (AdipoR1, R2), and peroxisome proliferator-activated receptor (PPAR) α, β/δ, ɤ of patients with higher VAT/SAT ratio were decreased as compared to those with lower VAT/SAT ratio. Proliferation of gastric cancer cells co-cultured with adipocytes was increased by 50-100% and accompanied by down-regulation of mRNAs of AdipoR1, 2, PPARα, β/δ, ɤ, and pro-apoptotic genes, as compared to their controls.

Conclusion: SAT and VAT played exactly opposite prognostic roles of locally advanced gastric cancers, which might work through modulation of AdipoR1, 2 and PPARα, β/δ, ɤ. Preoperative CTBC, supplementary to classic TNM system, helps clinicians tailor individualized adjuvant therapy and/or nutritional support.
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http://dx.doi.org/10.1016/j.ejso.2021.04.028DOI Listing
April 2021

Management of Patients With Acute Cholecystitis After Percutaneous Cholecystostomy: From the Acute Stage to Definitive Surgical Treatment.

Front Surg 2021 15;8:616320. Epub 2021 Apr 15.

Division of General Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan.

Percutaneous cholecystostomy (PC) has become an important procedure for the treatment of acute cholecystitis (AC). PC is currently applied for patients who cannot undergo immediate laparoscopic cholecystectomy. However, the management following PC has not been well-reviewed. The efficacy of PC tubes has already been indicated, and compared to complications of other invasive biliary procedures, complications related to PC are rare. Following the resolution of AC, patients who can tolerate anesthesia and the surgical risk should undergo interval cholecystectomy to reduce the recurrence of biliary events. For patients unfit for surgery, whether owing to comorbidities, anesthesia risks, or surgical risks, expectant management may be applied; however, a high incidence of recurrence has been noted. In addition, several interesting issues, such as the indications for cholangiography via the PC tube, removal or maintenance of the PC catheter before definitive treatment, and timing of elective surgery, are all discussed in this review, and a relevant decision-making flowchart is proposed. PC is an effective and safe intervention, whether as expectant treatment or bridge therapy to definitive surgery. High-level evidence of post-PC care is still necessary to modify current practices.
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http://dx.doi.org/10.3389/fsurg.2021.616320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8083985PMC
April 2021

Everolimus Related Fulminant Hepatitis in Pancreatic Neuroendocrine Tumor With Liver Metastases: A Case Report and Literature Review.

Front Endocrinol (Lausanne) 2021 1;12:639967. Epub 2021 Apr 1.

Department of General Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan.

Background: Everolimus, an immunosuppressant, is approved for the treatment of advanced renal cell carcinoma, metastatic hormone receptor-positive breast cancer, and pancreatic neuroendocrine tumors (P-NETs) but has been reported to be related to hepatitis B reactivation. Here, we present the first case of fatal fulminant hepatitis B reactivation in a man with P-NET accompanied by multiple liver metastases who received everolimus and octreotide long-acting repeatable (LAR).

Case Presentation: A 45-year-old male had a history of chronic hepatitis B infection. He was found to have a complicated liver cyst incidentally, and then he underwent biopsy, which disclosed a grade 2 neuroendocrine tumor (NET). Subsequent MRI of the abdomen and PET revealed a solid mass at the pancreatic tail with numerous liver tumors favoring metastases and peripancreatic lymph node metastases. Transarterial chemoembolization (TACE) of the right lobe of the liver was performed, and he started to take 5 mg everolimus twice a day and 20 mg octreotide LAR every month 8 days after the 1 TACE. No hepatitis B virus (HBV) prophylaxis treatment was administered. He then underwent laparoscopic distal pancreatectomy and splenectomy three and half months after the initial treatment of everolimus. He continued everolimus 5 mg twice a day and octreotide 20 mg every month after the operation. Three months later, hepatic failure occurred due to acute hepatitis B flare-up-related fulminant hepatic failure since other possible causes of hepatic failure were excluded. Five days after hepatic failure presented, hepatic failure was apparent, and pulseless ventricular tachycardia occurred. The patient expired after failed resuscitation.

Conclusion: A literature review of everolimus-related hepatitis B reactivation was conducted. In P-NET patients with chronic hepatitis B who will undergo everolimus treatment, HBV prophylaxis should be considered since fatal hepatitis B reactivation might occur under rare conditions.
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http://dx.doi.org/10.3389/fendo.2021.639967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047461PMC
April 2021

Impact of Pancreatic Resection on Survival in Locally Advanced Resectable Gastric Cancer.

Cancers (Basel) 2021 Mar 14;13(6). Epub 2021 Mar 14.

Department of General Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan 333, Taiwan.

Whether gastric adenocarcinoma (GC) patients with adjacent organ invasion (T4b) benefit from aggressive surgery involving pancreatic resection (PR) remains unclear. This study aimed to clarify the impact of PR on survival in patients with locally advanced resectable GC. Between 1995 and 2017, patients with locally advanced GC undergoing radical-intent gastrectomy with and without PR were enrolled and stratified into four groups: group 1 (G1), pT4b without pancreatic resection (PR); group 2 (G2), pT4b with PR; group 3 (G3), positive duodenal margins without Whipple's operation; and group 4 (G4), cT4b with Whipple's operation. Demographics, clinicopathological features, and outcomes were compared between G1 and G2 and G3 and G4. G2 patients were more likely to have perineural invasion than G1 patients (80.6% vs. 50%, < 0.001). G4 patients had higher lymph node yield (40.8 vs. 31.3, = 0.002), lower nodal status ( = 0.029), lower lymph node ratios (0.20 vs. 0.48, < 0.0001) and higher complication rates (45.2% vs. 26.3%, = 0.047) than G3 patients. The 5-year disease-free survival (DFS) and overall survival (OS) rates were significantly longer in G1 than in G2 (28.1% vs. 9.3%, = 0.003; 32% vs. 13%, = 0.004, respectively). The 5-year survival rates did not differ between G4 and G3 (DFS: 14% vs. 14.4%, = 0.384; OS: 12.6% vs. 16.4%, = 0.321, respectively). In conclusion, patients with T4b lesion who underwent PR had poorer survival than those who underwent resection of other adjacent organs. Further Whipple's operation did not improve survival in pT3-pT4 GC with positive duodenal margins.
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http://dx.doi.org/10.3390/cancers13061289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001184PMC
March 2021

The clinicopathological significance of SWI/SNF alterations in gastric cancer is associated with the molecular subtypes.

PLoS One 2021 22;16(1):e0245356. Epub 2021 Jan 22.

Department of Anatomic Pathology, Linkou Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Taoyuan, Taiwan.

The clinicopathological significance of altered SWI/SNF complex has not been well evaluated in gastric cancer (GC). We examined SMARCA2, SMARCA4, SMARCB1 and ARID1A expression by immunohistochemistry in 1224 surgically resected GCs with subtyping into Epstein-Barr virus (EBV), microsatellite instability (MSI) and non-EBV/MSI Lauren histotypes. SWI/SNF mutations were investigated using the GC dataset of the TCGA Pan-Cancer Atlas. Clinicopathological association was assessed by statistical analysis. There were 427 cases (35%) of SWI/SNF-attenuated GC, including 344 SMARCA2 (28%), 28 SMARCA4 (2%), 11 SMARCB1 (1%) and 197 ARID1A (16%) cases. Simultaneous alterations of multiple subunits were observed. Compared to SWI/SNF-retained cases, SWI/SNF-attenuated GC exhibited a significant predilection to older ages, EBV and MSI genotypes, higher lymphatic invasion and less hematogenous recurrence (P < 0.05). SWI/SNF attenuation was an independent risk factor for short overall survival (P = 0.001, hazard ratio 1.360, 95% confidence interval 1.138-1.625). The survival impact stemmed from SMARCA2-attenuated GCs in stage III and non-EBV/MSI diffuse/mixed subtypes (P = 0.019 and < 0.001, respectively). ARID1A-lost/heterogeneous GCs were more aggressive in the EBV genotype (P = 0.016). SMARCB1 or SMARCA4 loss was not restricted to rhabdoid/undifferentiated carcinoma. In the TCGA dataset, 223 of 434 GCs (52%) harbored deleterious SWI/SNF mutations, including ARID1A (27%), SMARCA2 (9%), ARID2 (9%), ARID1B (8%), PBRM1 (7%), and SMARCA4 (7%). SWI/SNF-mutated GCs displayed a favorable outcome owing to the high percentage with the MSI genotype. In conclusion, SWI/SNF-altered GCs are common and the clinicopathological significance is related to the genotype.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245356PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822341PMC
June 2021

Non-small cell lung cancer with gastric metastasis and repeated gastrointestinal bleeding: A rare case report and literature review.

Thorac Cancer 2021 02 5;12(4):560-563. Epub 2021 Jan 5.

Departments of General Surgery, Chang Gung Memorial Hospital at Linkou and Chang Gung University, Taoyuan, Taiwan.

The occurrence of gastrointestinal metastasis from lung carcinoma is rare. Compared with non-small cell lung cancer (NSCLC), small cell lung cancer more commonly results in this sort of metastasis. Here, we report an unusual case of NSCLC initially without evidence of distant metastasis that developed into gastric metastasis five months after the initial diagnosis, despite the primary lung cancer having a partial response to radiotherapy and chemotherapy. Serial radiological examinations and endoscopic biopsies of the gastric tumor confirmed that it was a metastatic carcinoma originating from the lung. The patient received a total gastrectomy for gastric metastasis due to repeated gastrointestinal bleeding.
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http://dx.doi.org/10.1111/1759-7714.13815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882379PMC
February 2021

Alternative application of percutaneous cholecystostomy in patients with biliary obstruction.

Abdom Radiol (NY) 2021 06 2;46(6):2891-2899. Epub 2021 Jan 2.

Division of General Surgery, Chang Gung Memorial Hospital, No. 5, Fuxing St., Guishan Dist., Taoyuan, 333, Taiwan.

Purpose: Percutaneous cholecystostomy (PC) is an important modality for acute cholecystitis and has been applied for other clinical scenarios as well. In the present study, we aimed to investigate an alternative use of PC for obstructive jaundice.

Methods: From January 2012 to December 2018, eligible subjects were selected from patients undergoing PC in our institute. The characteristics, spectrum of underlying disease, indication for PC performance, details of the procedure, and treatment effect were all investigated.

Results: During the study period, 1364 patients underwent PC. Seventy patients fulfilled the defined inclusion criteria. While 47 patients were diagnosed with malignant biliary obstruction with or without cholangitis, 23 patients were diagnosed with nonmalignant biliary obstruction and acute cholangitis. There were 63 patients (90%) diagnosed with acute cholangitis. Pancreatic cancer (n = 24, 51%) and advanced malignancy (n = 28, 59%) were noted mostly in the group with malignant biliary obstruction. Treatment effects were proven by laboratory data, including the white blood cell count, C-reactive protein level, and hepatic function.

Conclusion: PC can temporize definitive therapies and serve as an alternative treatment for patients with nonmalignant conditions. For patients with advanced malignancy, PC can serve as a palliative procedure that has a high success rate and low complication rate and effectively relieves biliary obstruction.
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http://dx.doi.org/10.1007/s00261-020-02898-5DOI Listing
June 2021

Hemi-hepatectomy for E4 major bile duct injury following laparoscopic cholecystectomy.

Asian J Surg 2020 Dec 2;43(12):1212-1213. Epub 2020 Nov 2.

Departments of Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan. Electronic address:

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http://dx.doi.org/10.1016/j.asjsur.2020.09.018DOI Listing
December 2020

Targeting the histone demethylase PHF8-mediated PKCα-Src-PTEN axis in HER2-negative gastric cancer.

Proc Natl Acad Sci U S A 2020 10 21;117(40):24859-24866. Epub 2020 Sep 21.

Institute of Molecular and Cellular Biology and Department of Life Science, National Tsing-Hua University, Hsinchu 300, Taiwan;

Targeted treatments for advanced gastric cancer (GC) are needed, particularly for HER2-negative GC, which represents the majority of cases (80 to 88%). In this study, in silico analyses of the lysine histone demethylases (KDMs) involved in diverse biological processes and diseases revealed that PHD finger protein 8 (PHF8, KDM7B) was significantly associated with poor clinical outcome in HER2-negative GC. The depletion of PHF8 significantly reduced cancer progression in GC cells and in mouse xenografts. PHF8 regulated genes involved in cell migration/motility based on a microarray analysis. Of note, PHF8 interacted with c-Jun on the promoter of which encodes PKCα. The depletion of PHF8 or PKCα greatly up-regulated PTEN expression, which could be rescued by ectopic expression of a PKCα expression vector or an active Src. These suggest that PTEN destabilization occurs mainly via the PKCα-Src axis. GC cells treated with midostaurin or bosutinib significantly suppressed migration in vitro and in zebrafish models. Immunohistochemical analyses of PHF8, PKCα, and PTEN showed a positive correlation between PHF8 and PKCα but negative correlations between PHF8 and PTEN and between PKCα and PTEN. Moreover, high PHF8-PKCα expression was significantly correlated with worse prognosis. Together, our results suggest that the PKCα-Src-PTEN pathway regulated by PHF8/c-Jun is a potential prognostic/therapeutic target in HER2-negative advanced GC.
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http://dx.doi.org/10.1073/pnas.1919766117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547212PMC
October 2020

Regorafenib treatment outcome for Taiwanese patients with metastatic gastrointestinal stromal tumors after failure of imatinib and sunitinib: A prospective, non-randomized, single-center study.

Oncol Lett 2020 Sep 19;20(3):2131-2142. Epub 2020 Jun 19.

Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Kwei-Shan, Taoyuan 333, Taiwan.

The present study aimed to conduct a prognosis analysis of Taiwanese patients with metastatic gastrointestinal stromal tumors (GISTs), who are resistant to or were unable to tolerate imatinib or sunitinib, and were subsequently treated with regorafenib. The study considered the survival, potential prognostic factors and safety of these Taiwanese patients. A total of 28 patients with pre-treated metastatic GIST, receiving regorafenib treatment, were analyzed between April 2014 and December 2017. Data were collected prospectively, and patients were followed up for a median of 14.8 months. It was reported that 50% (10/20) of male patients and 50% (4/8) of female patients demonstrated response and clinical benefit to regorafenib. The median progression-free survival (PFS) and overall survival (OS) time in all patients receiving regorafenib were 4.4 and 29.3 months, respectively. Good performance status and disease control mediated by regorafenib were independently associated with a more favorable PFS time. Good performance status, higher pre-treated albumin level, lower neutrophil:lymphocyte ratio (NLR) and lower platelet:lymphocyte ratio (PLR) were independent favorable predictors of OS time. Overall, poor performance status and poor disease control predicted a less favorable PFS time in Taiwanese patients with GISTs, who were pre-treated with regorafenib. Meanwhile poor performance status, high NLR, PLR and low albumin level predicted a less favorable OS time.
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http://dx.doi.org/10.3892/ol.2020.11756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400021PMC
September 2020

Surgical options for submucosal tumors near the esophagogastric junction: does size or location matter?

BMC Surg 2020 Aug 6;20(1):179. Epub 2020 Aug 6.

Department of General Surgery, Chang Gung Memorial Hospital, Linkou branch, No.5, Fu-Xing Street, Kweishan District, Taoyuan City, 333, Taiwan.

Background: Submucosal tumors (SMTs) of different etiologies exist from esophagus to rectum. Esophagogastric junction (EGJ) is one of the known difficult locations for tumor resection. Although minimally invasive surgery (MIS) is a well-established approach for gastrointestinal surgery, there is no consensus that MIS for resection of SMTs around EGJ is superior to laparotomy. We tried to clarify the factors that determine the surgeons' choices between these two approaches.

Methods: From January 2002 to June 2016, 909 patients with SMTs underwent resection in our department. Among them, 119 patients (13%) had SMTs around EGJ were enrolled by retrospective review. The clinicopathological features and tumor-related parameters were reviewed and analyzed.

Results: The cohort was stratified into three groups according to the extent of gastrectomy and surgical approaches. The three groups are as following: major gastrectomy (n = 13), minor gastrectomy by laparotomy (n = 51), and minor gastrectomy with MIS (n = 55). The average tumor size was significantly larger in the major gastrectomy group than in the two minor gastrectomy groups; however, there was no difference between the two minor gastrectomy groups (5.33 cm, 4.07 cm, and 3.69 cm, respectively). The minor gastrectomy with MIS required least hospital stay and operation duration also. We re-stratify the two minor gastrectomy groups (n = 106) according to the orientation of SMTs around the EGJ into 4 zones. Most of SMTs located on the greater curvature side of the EGJ were resected with MIS (82% versus 18%), whereas SMTs in the other zones were resected more often by laparotomy (59% versus 41%). There was no surgical mortality within the cohort, while minor gastrectomy with MIS yielded least number of leakages among the three groups.

Conclusions: For SMTs around the EGJ, larger tumors (diameter of more than 5 cm) are more likely to be resected with major gastrectomy. To resect SMTs around the EGJ in a wedge-like (minor gastrectomy) fashion, tumors located other than the greater curvature side were more often resected by laparotomy. However, MIS yielded acceptable safety and surgical outcomes compared to conventional laparotomy for SMTs around the EGJ of the same size.
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http://dx.doi.org/10.1186/s12893-020-00840-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430816PMC
August 2020

Impact of Metformin Use on Survival in Patients with Gastric Cancer and Diabetes Mellitus Following Gastrectomy.

Cancers (Basel) 2020 Jul 23;12(8). Epub 2020 Jul 23.

Department of General Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan 33305, Taiwan.

Studies have shown the anticancer effects of metformin in vitro. However, whether metformin can prevent cancer recurrence or prolong survival in patients with gastric cancer (GC) and diabetes mellitus (DM) post-gastrectomy remains unknown. We evaluated the beneficial effects of metformin in patients with GC and DM post-gastrectomy. We recruited 2400 patients with GC (1749 without DM, 651 with DM) who underwent surgery between 1997 and 2010. Patients with DM were stratified into metformin (group 1) and non-metformin (group 2) users. Their clinicopathological data were recorded prospectively, and demographics, recurrence-free survival (RFS), and cancer-specific survival (CSS) were compared. Tumour recurrence risk and cause of death were analysed between groups 1 and 2 among patients with DM stratified by tumour stage. We also compared RFS and overall survival among patients with and without DM. Tumour recurrence occurred in 201 patients with GC: 57 (25%) in group 1 and 144 (37%) in group 2. After adjusting for confounders, metformin significantly prolonged CSS (hazard ratio (HR) = 0.54, 95% confidence interval (CI) = 0.38-0.77) in patients with stage I-III GC and DM. In subgroup analysis, metformin users with stage III GC and DM had significantly prolonged CSS compared to non-metformin users (HR = 0.45, 95% CI = 0.30-0.68), with an insignificant difference in patients with stage I-II GC. Adjusted HRs for RFS and CSS were significantly lower in patients with stage I-III GC and DM than those in patients without DM (0.67 (95% CI = 0.54-0.92) and 0.62 (95% CI = 0.50-0.77), respectively), with an insignificant difference in patients with stage I GC. Metformin significantly reduces tumour recurrence risk and improves CSS in patients with stage III GC and DM post-gastrectomy. Further prospective studies may confirm the efficacy of metformin as an adjunctive treatment for advanced GC postoperatively.
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http://dx.doi.org/10.3390/cancers12082013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465508PMC
July 2020

FTO variants are associated with ANGPTL4 abundances and correlated with body weight reduction after bariatric surgery.

Obes Res Clin Pract 2020 May - Jun;14(3):257-263. Epub 2020 Jun 3.

Department of General Surgery, Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Taiwan.

Background: The FTO (fat mass- and obesity-associated) gene variant is an established obesity-susceptibility locus. FTO protein is a nucleic acid demethylase and FTO genetic variants form long-range functional connections with IRX3, which regulates fat mass and metabolism in humans. From our previous results, we found FTO regulates the metabolism of triglyceride in adipocytes through demethylating Angptl4 (angiopoietin-like protein 4) mRNA in mice. We hypothesized that the FTO genetic variants regulate ANGPTL4 abundances in human adipose tissues and affect the outcome after bariatric surgery.

Methods And Results: We recruited 188 obesity subjects with body mass indices (BMI)>35kg/m and 102 non-obese subjects with BMI<30kg/m from the OCEAN registry between 2011 and 2014. The distribution of FTO variants rs9939609 among participates was 73.79% TT, 23.79% AT, and 2.41% AA. The subjects with FTO variants AA or AT were correlated with higher BMI than those with FTO variants TT. The serum ANGPTL4 levels were significantly higher in obese subjects and positively correlated with the presence of FTO AA or AT haplotype. Of these participates, 84 obese subjects underwent bariatric surgery and adipose Angptl4 expressions were analyzed. The adipose Angptl4 mRNA levels and protein abundances were correlated with FTO AA or AT haplotype. The magnitude of excess body weight reduction 2 years after bariatric surgery was correlated with the adipose ANGPTL4 protein levels.

Conclusion: Adipose ANGPTL4 abundances were affected by the presence of FTO obesity risk haplotype and correlated with excess weight loss percentage after bariatric surgery. These data signify the critical role of FTO variants and adipose ANGPTL4 in fatty acid metabolism and bariatric outcomes in humans.
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http://dx.doi.org/10.1016/j.orcp.2020.05.002DOI Listing
April 2021

The clinicopathological and molecular analysis of gastric cancer with altered SMARCA4 expression.

Histopathology 2020 Aug 2;77(2):250-261. Epub 2020 Jul 2.

Department of Anatomic Pathology, College of Medicine, Linkou Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan.

Aims: In this study, we examine the clinicopathological and molecular features of gastric cancer (GC) with SMARCA4 alterations.

Methods And Results: We screened SMARCA4 alterations using immunohistochemistry on 1199 surgically resected GCs with information on Epstein-Barr virus (EBV), microsatellite instability (MSI) and other SWI/SNF subunits. SMARCA4, SMARCA2 and ARID1A mutations were investigated by targeted sequencing. The clinicopathological significance was determined by statistical analysis. Twenty-seven cases (2%) with altered SMARCA4 expression were identified, exhibiting completely lost (six), reduced (nine) or heterogeneous (12) patterns. Frequent concomitant alterations of other SWI/SNF subunits were noted with an unusual discordant spatial heterogeneity. In comparison with SMARCA4-retained GCs, SMARCA4-lost GCs were observed more frequently in the non-EBV/MSI subgroup (five of six) and reduced or heterogeneous SMARCA4 expression mainly occurred in EBV- or MSI-associated cases (six of nine and six of 12, respectively; P < 0.001). Histologically, SMARCA4-altered GC, irrespective of expression pattern, demonstrated divergent histomorphology, spanning tubular, poorly cohesive or mixed, neuroendocrine to solid and undifferentiated carcinoma, with a predilection to the latter two (P < 0.001). De-differentiation-like transition and rhabdoid features were noted in a minority of cases. For overall survival, altered SMARCA4 expression was an unfavourable prognostic factor in stage III, EBV-associated GC and non-EBV/MSI intestinal subtype (P ≤ 0.001). SMARCA4 or ARID1A mutations were detected mainly in SMARCA4-lost or reduced GC, respectively.

Conclusions: SMARCA4-altered GCs are rare and have intratumoral heterogeneity, histomorphological diversity, conditional prognostic significance and various genetic drivers. SMARCA4-lost GC may represent a genuine SMARCA4-deficient neoplasm, but most SMARCA4-reduced/heterogeneous cases are secondary to ARID1A collapse or associated with different genotypes.
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http://dx.doi.org/10.1111/his.14117DOI Listing
August 2020

Surgical outcomes of patients with maintained or removed percutaneous cholecystostomy before intended laparoscopic cholecystectomy.

J Hepatobiliary Pancreat Sci 2020 Aug 1;27(8):461-469. Epub 2020 May 1.

Division of General Surgery, Chang Gung Memorial Hospital, Taoyuan, Taiwan.

Background: Percutaneous cholecystostomy (PC) followed by definitive cholecystectomy is an alternative treatment for acute cholecystitis (AC). We retrospectively investigated the impact of PC tube removal before definitive cholecystectomy on surgical outcomes.

Methods: From 2012 to 2017, 942 AC patients underwent PC at a single institute. Eligible patients were selected according to inclusion criteria. Demographic data, clinical and laboratory parameters, and treatment outcomes were extracted from medical records. Categorization of patients and subsequent subgroup analysis were based on cholangiography.

Results: The rate of emergent cholecystectomy in the PC tube removal group was higher than that in the PC tube preserved group (OR = 2.969, 95% CI 1.334-6.612, P = 0.008). In subgroup analysis of patients with patent bile flow under cholangiography, the rate of emergent cholecystectomy was higher in the PC tube removal group (OR = 3.173, 95% CI 1.182-8.523, P = 0.022), though the incidence of complications was higher in the PC tube preserved group (P = 0.012). In addition, routine preoperative cholangiography had no clinical impact on surgical outcome.

Conclusion: Percutaneous cholecystostomy tube can be removed before subsequent LC to avoid postoperative complications, though removal of the PC tube is associated with an increased likelihood of emergent cholecystectomy.
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http://dx.doi.org/10.1002/jhbp.740DOI Listing
August 2020

Endothelial Nitric Oxide Mediates the Anti-Atherosclerotic Action of Lindley var. Yamazaki.

Int J Mol Sci 2020 Feb 24;21(4). Epub 2020 Feb 24.

Graduate Institute and Department of Physiology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.

Lindley var. Yamazaki ethanolic extract (TCEE) is reported to have anti-inflammatory and anti-obesity properties. However, the effects of TCEE and its underlying mechanisms in the activation of endothelial nitric oxide synthase (eNOS) have not yet been investigated. Increasing the endothelium-derived nitric oxide (NO) production has been known to be beneficial against the development of cardiovascular diseases. In this study, we investigated the effect of TCEE on eNOS activation and NO-related endothelial function and inflammation by using an in vitro system. In endothelial cells (ECs), TCEE increased NO production in a concentration-dependent manner without affecting the expression of eNOS. In addition, TCEE increased the phosphorylation of eNOS at serine 635 residue (Ser635) and Ser1179, Akt at Ser473, calmodulin kinase II (CaMKII) at threonine residue 286 (Thr286), and AMP-activated protein kinase (AMPK) at Thr172. Moreover, TCEE-induced NO production, and EC proliferation, migration, and tube formation were diminished by pretreatment with LY294002 (an Akt inhibitor), KN62 (a CaMKII inhibitor), and compound C (an AMPK inhibitor). Additionally, TCEE attenuated the tumor necrosis factor-α-induced inflammatory response as evidenced by the expression of adhesion molecules in ECs and monocyte adhesion onto ECs. These inflammatory effects of TCEE were abolished by L-NG-nitroarginine methyl ester (an NOS inhibitor). Moreover, chronic treatment with TCEE attenuated hyperlipidemia, systemic and aortic inflammatory response, and the atherosclerotic lesions in apolipoprotein E-deficient mice. Collectively, our findings suggest that TCEE may confer protection from atherosclerosis by preventing endothelial dysfunction.
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http://dx.doi.org/10.3390/ijms21041532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073175PMC
February 2020

Is Adjuvant Chemotherapy Necessary for Patients with Deficient Mismatch Repair Gastric Cancer?-Autophagy Inhibition Matches the Mismatched.

Oncologist 2020 07 14;25(7):e1021-e1030. Epub 2020 Feb 14.

Department of Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan.

Purpose: The use of microsatellite instability (MSI) and mismatch repair (MMR) as predictive biomarkers for fluorouracil-based adjuvant chemotherapy in colorectal cancer has been a paradigm shift. However, whether this applies to gastric cancer is questionable. Furthermore, we herein investigated whether and how autophagy plays a role in MSI-relevant chemoresistance.

Materials And Methods: A total of 929 patients with deficient MMR (dMMR) and proficient MMR (pMMR) gastric cancers who underwent curative-intent gastrectomy were enrolled. We compared clinicopathological variables and survival among dMMR and pMMR cohorts and tested the responses of MSI-high and microsatellite stable (MSS) gastric cancer cell lines to 5-fluorouracil (5-FU) with or without chloroquine, an autophagy inhibitor.

Results: We identified an 8.9% prevalence of dMMR cases (83 out of 929) in our cohort. This was associated with old age, tumor site at the distal stomach, an intestinal phenotype, fewer nodal metastasis, and early pathological stages. MMR was an independent prognostic factor after multivariate adjustment. Overall survival (OS) of dMMR patients was better than that of the pMMR patients but was only applicable to stage III patients. There was no difference in OS between dMMR patients treated with or without adjuvant chemotherapy, although the latter showed more medical morbidities. The MSI-high gastric cancer cell lines, versus the MSS counterparts, displayed increased resistance to 5-FU and increased autophagy. Interestingly, autophagy inhibition abrogated the chemoresistance.

Conclusion: Our data show that fluorouracil-based adjuvant chemotherapy does not work for dMMR cases, if not worse. Autophagy inhibition and/or immune checkpoint inhibition might be promising alternative strategies for gastric cancer treatment.

Implications For Practice: The use of microsatellite instability (MSI) and mismatch repair (MMR) as predictive biomarkers for adjuvant chemotherapy in colorectal cancer has caused a paradigm shift in cancer therapy, although its implications in gastric cancer are still questionable. The data obtained in the current study indicate that MSI-MMR is an independent prognostic factor for gastric cancer. Standard fluorouracil-based adjuvant chemotherapy did not work for deficient MMR cases, and was likely worse. Instead, strategies like autophagy inhibition and/or immune checkpoint inhibition should be taken into consideration in the future.
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http://dx.doi.org/10.1634/theoncologist.2019-0419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356708PMC
July 2020

Impact of Platelet Counts, Surgical Methods, and Preoperative Platelet Transfusion on the Outcome of Splenectomy for Immune Thrombocytopenia.

Acta Haematol 2020 7;143(5):465-471. Epub 2020 Jan 7.

School of Medicine, Chang Gung University, Taoyuan, Taiwan.

Introduction: Splenectomy is an important and potentially curative treatment for immune thrombocytopenia (ITP). Laparoscopic splenectomy (LS) has replaced open splenectomy (OS) as the standard approach. The prognostic role of platelet count and the clinical indication of preoperative platelet transfusion are not entirely clear.

Methods: We designed a study to explore the prognostic impact of surgical methods, platelet count, and platelet transfusion in a large, single-institute, long-term cohort of ITP patients.

Result: In 118 ITP patients, there was no difference between OS and LS in response and surgical complications. The overall response rate was 77% and the complete response (CR) rate was 70%. Patients with a CR had a trend towards a higher baseline platelet count. A stable platelet count 14-28 days after splenectomy was associated with a sustained long-term response. Patients requiring preoperative platelet transfusion had a lower preoperative platelet count and were more likely to need postoperative transfusion of red blood cells and platelets. They also had a lower postoperative platelet count than the nontransfusion group. Relapse-free survival did not differ.

Conclusions: Baseline and postoperative platelet counts are apparently associated with the treatment response to splenectomy but the difference did not reach statistical significance. Preoperative platelet transfusion did not overcome the disadvantage of thrombocytopenia and was not recommended when other preparative measures are available.
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http://dx.doi.org/10.1159/000505011DOI Listing
October 2020

Video Coaching Improving Contemporary Technical and Nontechnical Ability in Laparoscopic Education.

J Surg Educ 2020 May - Jun;77(3):652-660. Epub 2019 Dec 16.

Department of Traumatology and Emergency Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan. Electronic address:

Objective: A video coaching (VC) system has been developed in surgical education. This study compares the educational effect on technical and nontechnical skills of the VC method for teaching laparoscopic surgery.

Design: We conducted a prospectively randomized study of an education program to teach laparoscopic procedures.

Setting: The study was performed at the Chang Gung Memorial Hospital, a university hospital in Taiwan.

Participants: We enrolled sixteen first- or second-year surgical residents.The participants were randomized into VC and conventional teaching (CT) groups, and their surgical skills were judged by the Global Operation Assessment of Laparoscopic Skills (GOALS) and the Objective Structured Assessment of Technical Skills (OSATS). Nontechnical skills were evaluated by the Non-Technical Skills for Surgeons (NOTSS) assessment and self-efficacy questionnaires (SEQs). After the program, posttraining scores were compared to assess improvements.

Results: The 16 enrolled participants finished the entire course and completed all the videos during the study period. Comparing the VC and CT groups, we found that the pretraining GOALS, OSATS, NOTSS and SEQ scores were similar between both groups. However, after training, the OSATS score gain was higher in the VC groupthan in the CT group (9.25 ± 2.05 vs. 6.50 ± 1.51, p=0.009). Regarding nontechnical skills, the NOTSS score improved more in the VC group than in the CT group (5.50 ± 0.93 vs. 4.25 ± 0.89, p=0.015). The SEQ score was also higher in the VC group (32.13 ± 2.10) than in the CT group (29.50 ± 1.77), with a significant difference (p=0.018).

Conclusion: VC can help surgeons build their expertise using a more accessible method. Additionally, VC can shorten the learning curve and improve self-efficacy, thereby contributing to surgeons' education.
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http://dx.doi.org/10.1016/j.jsurg.2019.11.012DOI Listing
June 2021

Acute Tumor Transition Angle on Computed Tomography Predicts Chromosomal Instability Status of Primary Gastric Cancer: Radiogenomics Analysis from TCGA and Independent Validation.

Cancers (Basel) 2019 May 9;11(5). Epub 2019 May 9.

Department of Diagnostic Radiology, University of Hong Kong, Hong Kong 999077, China.

Chromosomal instability (CIN) of gastric cancer is correlated with distinct outcomes. This study aimed to investigate the role of computed tomography (CT) imaging traits in predicting the CIN status of gastric cancer. We screened 443 patients in the Cancer Genome Atlas gastric cancer cohort to filter 40 patients with complete CT imaging and genomic data as the training cohort. CT imaging traits were subjected to logistic regression to select independent predictors for the CIN status. For the validation cohort, we prospectively enrolled 18 gastric cancer patients for CT and tumor genomic analysis. The imaging predictors were tested in the validation cohort using receiver operating characteristic curve (ROC) analysis. Thirty patients (75%) in the training cohort and 9 patients (50%) in the validation cohort had CIN subtype gastric cancers. Smaller tumor diameter ( = 0.017) and acute tumor transition angle ( = 0.045) independently predict CIN status in the training cohort. In the validation cohort, acute tumor transition angle demonstrated the highest accuracy, sensitivity, and specificity of 88.9%, 88.9%, and 88.9%, respectively, and areas under ROC curve of 0.89. In conclusion, this pilot study showed acute tumor transition angle on CT images may predict the CIN status of gastric cancer.
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http://dx.doi.org/10.3390/cancers11050641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562475PMC
May 2019

Natural Course of Acute Cholecystitis in Patients Treated With Percutaneous Transhepatic Gallbladder Drainage Without Elective Cholecystectomy.

J Gastrointest Surg 2020 04 3;24(4):772-779. Epub 2019 Apr 3.

Division of Trauma and Emergency Surgery, General Surgery, Chang Gung Memorial Hospital, No. 5, Fuxing St., Guishan Dist., Taoyuan, 333, Republic of China.

Background: Percutaneous transhepatic gallbladder drainage (PTGBD) is an alternative treatment for acute cholecystitis (AC). We aimed to understand the natural course of AC in patients treated with PTGBD but without later definitive treatments, such as laparoscopic cholecystectomy.

Methods: This was a retrospective study of the period from June 2010 to December 2016, during which time 2371 patients were diagnosed with AC and 625 received PTGBD treatment. Among the 625 patients, 237 received no definitive treatment. A biliary event after the initial AC episode was the outcome of interest. In addition, the competing risk of death unrelated to biliary causes was present in the cohort. Therefore, a competing risk model was applied for analysis.

Results: The cumulative incidence of biliary events was 29.8% with a median of 4.27 months, while the competing event, i.e., death unrelated to a biliary event, was noted in 14.9% of patients with a median 23.54 months. The risk factors of biliary events were prolonged PTGBD indwelling and an abnormal PTGBD cholangiogram. The risk factors of death unrelated to a biliary event included a high Charlson comorbidity index and the initial AC severity.

Conclusions: Definitive cholecystectomy is still recommended for patients undergoing PTGBD treatment due to the high incidence of later biliary events. A thorough preoperative evaluation is necessary for those patients before elective cholecystectomy because of the inferior life expectancy and physical status.
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http://dx.doi.org/10.1007/s11605-019-04213-0DOI Listing
April 2020

Prospective Evaluation of Neoadjuvant Imatinib Use in Locally Advanced Gastrointestinal Stromal Tumors: Emphasis on the Optimal Duration of Neoadjuvant Imatinib Use, Safety, and Oncological Outcome.

Cancers (Basel) 2019 Mar 25;11(3). Epub 2019 Mar 25.

GIST Team, Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan.

Background: Neoadjuvant imatinib therapy has been proposed for routine practice with favorable long-term results for patients with locally advanced gastrointestinal stromal tumors (GISTs). However, clarification of the optimal duration, safety, and oncological outcomes of neoadjuvant imatinib use before surgical intervention remains necessary.

Methods: We prospectively analyzed the treatment outcomes of 51 patients with locally advanced, nonmetastatic GISTs treated with neoadjuvant imatinib followed by surgery. The optimal duration was defined as the timepoint when there was a <10% change in the treatment response or a size decrease of less than 5 mm between two consecutive computed tomography scans.

Results: Primary tumors were located in the stomach (23/51; 45%), followed by the rectum (17/51; 33%), ileum/jejunum (9/51; 18%), and esophagus (2/51; 4%). The median maximal shrinkage time was 6.1 months, beyond which further treatment may not be beneficial. However, the maximal shrinkage time was 4.3 months for the stomach, 8.6 months for the small bowel and 6.9 months for the rectum. The R0 tumor resection rate in 27 patients after neoadjuvant imatinib and surgery was 81.5%, and 70.4% of resection procedures succeeded in organ preservation. However, 10 of 51 patients (19.6%) had complications following neoadjuvant imatinib use (six from imatinib and four from surgery).

Conclusion: Our analysis supports treating GIST patients with neoadjuvant imatinib, which demonstrated favorable long-term results of combined therapy. However, careful monitoring of complications is necessary. The optimal duration of neoadjuvant imatinib use before surgical intervention is, on average, 6.1 months.
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http://dx.doi.org/10.3390/cancers11030424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468640PMC
March 2019

Glycerophospholipids pathways and chromosomal instability in gastric cancer: Global lipidomics analysis.

World J Gastrointest Oncol 2019 Mar;11(3):181-194

Clinical Metabolomics Core Lab, Chang Gung Memorial Hospital at Linkou and Chang Gung University, Taoyuan 333, Taiwan.

Background: Based on the breakthrough of genomics analysis, The Cancer Genome Atlas Research Group recently proposed an integrative genomic analysis, dividing gastric cancer (GC) into four subtypes, characterized by the chromosomal instability (CIN) status. However, the CIN status of GC is still vaguely characterized and lacking the valuable easy-to-use CIN markers to diagnosis in molecular and histological detection.

Aim: To explore the associations of CIN with downstream lipidomics profiles.

Methods: We collected cancerous and noncancerous tissue samples from 18 patients with GC; the samples were divided into CIN and non-CIN types based on the system of The Cancer Genome Atlas Research Group and 409 sequenced oncogenes and tumor suppressor genes. We identified the lipidomics profiles of the GC samples and samples of their adjacent noncancerous tissues by using liquid chromatography-mass spectrometry. Furthermore, we selected leading metabolites based on variable importance in projection scores of > 1.0 and < 0.05.

Results: Twelve men and six women participated in this study; the participants had a median age of 67.5 years (range, 52-87 years) and were divided into CIN ( = 9) and non-CIN ( = 9) groups. The GC samples exhibited distinct profiles of lysophosphocholine, phosphocholine, phosphatidylethanolamine, phosphatidylinositol, phosphoserine, sphingomyelin, ceramide, and triglycerides compared with their adjacent noncancerous tissues. The glycerophospholipid levels (phosphocholine, phosphatidylethanolamine, and phosphatidylinositol) were 1.4- to 2.3-times higher in the CIN group compared with the non-CIN group ( < 0.05). Alterations in the glycerolipid and glycerophospholipid pathways indicated progression of GC toward CIN.

Conclusion: The lipidomics profiles of GC samples were distinct from those of their adjacent noncancerous tissues. CIN status of GC is primarily associated with downstream lipidomics in the glycerophospholipid pathway.
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http://dx.doi.org/10.4251/wjgo.v11.i3.181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425327PMC
March 2019

Is there a sex difference in postoperative prognosis of hepatocellular carcinoma?

BMC Cancer 2019 Mar 20;19(1):250. Epub 2019 Mar 20.

Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan.

Background: Although men carry a higher risk of hepatocellular carcinoma (HCC) than women, it is still controversial whether men also have a poorer postoperative prognosis. A retrospective study was conducted to evaluate the postoperative prognostic predictors of HCC focusing on sex differences.

Methods: We enrolled 516 consecutive adult patients with HCC (118 women, 398 men), who received surgical resection between January 2000 and December 2007, and were followed-up for >10 years. Clinical and laboratory data together with postoperative outcomes were reviewed.

Results: At baseline, female patients had a higher anti-hepatitis C virus antibody prevalence (P = 0.002); lower hepatitis B virus surface antigen prevalence (P = 0.006); less microvascular invasion (P = 0.019); and lower alpha-fetoprotein (P = 0.023), bilirubin (P = 0.002), and alanine transaminase (P = 0.001) levels. Overall, there were no significant sex differences in terms of intrahepatic recurrence-free survival (RFS), distant metastasis-free survival (MFS), and overall survival (OS). However, subgroup analysis showed that women had favorable RFS (P = 0.019) and MFS (P = 0.034) in patients with alpha-fetoprotein ≤ 35 ng/mL, independent of other clinical variables (adjusted P = 0.008 and 0.043, respectively). Additionally, men had favorable OS in patients with prothrombin time (international normalized ratio [INR]) <1.1 (P = 0.033), independent of other clinical variables (adjusted P = 0.042).

Conclusions: Female sex is independently associated with favorable postoperative RFS and MFS in patients with alpha-fetoprotein ≤35 ng/mL, while male sex is independently associated with favorable OS in patients with prothrombin time INR <1.1.
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http://dx.doi.org/10.1186/s12885-019-5453-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425676PMC
March 2019

Interferon α-inducible protein 27 is an oncogene and highly expressed in cholangiocarcinoma patients with poor survival.

Cancer Manag Res 2019 28;11:1893-1905. Epub 2019 Feb 28.

Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Kwei-Shan, Taoyuan, Taiwan, ROC,

Objective: Cholangiocarcinoma (CCA) is a devastating disease. Interferon α-inducible protein 27 (IFI27), originally known to involve in innate immunity, is later found to intervene in cell proliferation, leading to inventive studies regarding the role of IFI27 in cancer treatment. We aimed to investigate the role of IFI27 in CCA.

Materials And Methods: Cell proliferation, migration, and invasion assays, Western blot, gene transfection and knockdown, immunofluorescent and immunohistochemical stains, and xenograft animal model were applied.

Results: IFI27 knockdown in CCA cells induced cell cycle arrest in S phase, resulting in lower cell proliferative rate in vitro and in vivo. IFI27 knockdown attenuated CCA cell migration and invasion through inhibition of epithelial-mesenchymal transition, which was supported by increased E-cadherin and decreased N-cadherin and fibronectin. Filamentous actin level was also reduced. IFI27 knockdown further repressed expression and secretion of vascular endothelial growth factor (VEGF-A), a strong stimulator of angiogenesis, through downregulation of c-jun and c-fos, which was supported in vitro by the finding that human vascular endothelial cells grew more slowly in conditioned medium of IFI27 knockdown on CCA cells and in vivo by the lower erythropoietin concentration found in the xenografted tumors derived from IFI27 knockdown on CCA cells. In addition, anti-VEGF-A antibody treatment was able to repress CCA cell growth. To the contrary, IFI27 overexpression could increase CCA cell proliferation, migration, and invasion. Clinically, higher IFI27 expression was linked to inferior overall survival of CCA patients.

Conclusion: Our data strongly suggest that IFI27 could be deemed as a potential target for CCA treatment.
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http://dx.doi.org/10.2147/CMAR.S196485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6400119PMC
February 2019

Subtraction of Epstein-Barr virus and microsatellite instability genotypes from the Lauren histotypes: Combined molecular and histologic subtyping with clinicopathological and prognostic significance validated in a cohort of 1,248 cases.

Int J Cancer 2019 12 1;145(12):3218-3230. Epub 2019 Mar 1.

Department of Anatomic Pathology, Linkou Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Taoyuan, Taiwan.

Limited studies investigated clinicopathological and prognostic significance of histologic and molecular subgroups of gastric cancer concurrently. We retrospectively enrolled 1,248 patients with gastric cancer who received radical gastrectomy with lymphadenectomy and classified these cases into the Epstein-Barr virus (EBV)-associated and microsatellite instability (MSI)-associated subtypes by EBV-encoded small RNA in situ hybridization and immunohistochemical stains for DNA mismatch repair proteins, respectively. The remaining cases were categorized as the Lauren intestinal and diffuse/mixed subtypes. The clinicopathological and prognostic significance of the subtypes was examined by statistical analysis. In total, 65 (5.2%), 116 (9.3%), 496 (39.7%), 431 (34.5%) and 140 (11.2%) cases were identified as EBV-associated, MSI-associated, intestinal, diffuse and mixed subtypes, respectively. The EBV-associated, MSI-associated, intestinal and diffuse/mixed subtypes exhibited distinctive clinicopathological characteristics, including differences in age, gender, stump cancer, gastric location, tumor size, TNM stage, margin involvement, lymphatic/perineural invasion, HER2 status and recurrence pattern. The log-rank test showed survival discrimination (p < 0.001), and the multivariate analysis identified EBV-associated and MSI-associated cases demonstrated better outcomes than the diffuse/mixed subtype (EBV, HR 0.464, 95% CI 0.296-0.727, p = 0.001; MSI, HR 0.590, 95% CI 0.407-0.856, p = 0.005). EBV-associated lymphoepithelioma-like carcinoma cases had the most favorable outcome (HR 0.138, 95% CI 0.033-0.565, p = 0.006). In different clinical groups, the subtypes exhibited survival discrepancies. The EBV-associated and diffuse/mixed cases exhibited more favorable response to chemotherapy. In conclusion, this combined classification, in parallel with the molecular subtypes specified in the Cancer Genome Atlas study, has implications for the clinical management of gastric cancer.
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http://dx.doi.org/10.1002/ijc.32215DOI Listing
December 2019

Optimal Timing for Postsurgical Adjuvant Therapy in Patients with Gastric Cancer: A Propensity Score Matching Study.

J Cancer 2019 1;10(2):332-340. Epub 2019 Jan 1.

Department of Radiation Oncology, Proton and radiation therapy center, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan.

In clinical trials, adjuvant therapy (AT) has been shown to improve the prognosis in patients with gastric adenocarcinoma who undergo curative gastrectomy and adequate lymph node dissection. However, the optimal timing for initiating AT is still unclear. We collected data from 538 patients with stage II-III gastric cancer who underwent curative gastrectomy and AT in two tertiary hospitals from 2006 to 2013. Patients were divided into the early group (≤8 weeks, n=393) and the late group (>8 weeks, n=145), based on the interval between gastrectomy and initiation of AT. Propensity score matching was applied according to baseline characteristics. After 1:1 propensity score matching, an even distribution of characteristics in both groups (143:143) was achieved. The 5-year overall survival (OS) rates were 56.6% and 40.2% in the matched early and late groups, respectively (=0.062), while the corresponding 5-year recurrence-free survival (RFS) rates were 57.6% and 46.4%, respectively (=0.028). The time to AT initiation was correlated with RFS and had a positive association with OS. The 5-year distant metastasis-free survival was also significantly better (HR 0.682, 95% CI 0.472-0.985, =0.040), suggesting an early AT results in a better outcome in patients. We observed that initiation of AT within 8 weeks of curative gastrectomy produces better disease control and may contribute to better overall survival.
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http://dx.doi.org/10.7150/jca.27753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360315PMC
January 2019