Publications by authors named "Ying-Jui Chao"

25 Publications

  • Page 1 of 1

Local ablation of gastric cancer by reconstituted apolipoprotein B lipoparticles carrying epigenetic drugs.

Nanomedicine 2021 Jul 29;37:102450. Epub 2021 Jul 29.

Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Electronic address:

Epigenetic inhibitors have shown anticancer effects. Combination chemotherapy with epigenetic inhibitors has shown high effectiveness in gastric cancer clinical trials, but severe side effect and local progression are the causes of treatment failure. Therefore, we sought to develop an acidity-sensitive drug delivery system to release drugs locally to diminish unfavorable outcome of gastric cancer. In this study, we showed that, as compared with single agents, combination treatment with the demethylating agent 5'-aza-2'-deoxycytidine and HDAC inhibitors Trichostatin A or LBH589 decreased cell survival, blocked cell cycle by reducing number of S-phase cells and expression of cyclins, increased cell apoptosis by inducing expression of Bim and cleaved Caspase 3, and reexpressed tumor suppressor genes more effectively in MGCC3I cells. As a carrier, reconstituted apolipoprotein B lipoparticles (rABLs) could release drugs in acidic environments. Orally administrated embedded drugs not only showed inhibitory effects on gastric tumor growth in a syngeneic orthotopic mouse model, but also reduced the hepatic and renal toxicity. In conclusion, we have established rABL-based nanoparticles embedded epigenetic inhibitors for local treatment of gastric cancer, which have good therapeutic effects but do not cause severe side effects.
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http://dx.doi.org/10.1016/j.nano.2021.102450DOI Listing
July 2021

No association between alcohol consumption and pancreatic cancer even among individuals genetically susceptible to the carcinogenicity of alcohol.

Sci Rep 2021 Jul 15;11(1):14567. Epub 2021 Jul 15.

National Institute of Cancer Research, National Health Research Institutes, 1F No 367, Sheng-Li Road, Tainan, 70456, Taiwan.

Inconsistent results have been reported for the association between alcohol use and pancreatic cancer, particularly at low levels of alcohol consumption. Individuals genetically susceptible to the carcinogenic effect of alcohol might have higher pancreatic cancer risk after drinking alcohol. The current study investigated the association between alcohol use and pancreatic cancer with 419 pancreatic cancer cases and 963 controls recruited by a hospital-based case-control study in Taiwan. Gene-environment interaction between alcohol use and polymorphisms of two ethanol-metabolizing genes, ADH1B and ALDH2, on pancreatic risk was evaluated. Our results showed no significant association between alcohol drinking and an increased pancreatic cancer risk, even at high levels of alcohol consumption. Even among those genetically susceptible to the carcinogenic effect of alcohol (carriers of ADH1B*2/*2(fast activity) combined with ALDH2*1/*2(slow activity) or ALDH2*2/*2(almost non-functional)), no significant association between alcohol use and pancreatic cancer was observed. Overall, our results suggested that alcohol drinking is not a significant contributor to the occurrence of pancreatic cancer in Taiwan.
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http://dx.doi.org/10.1038/s41598-021-94111-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282609PMC
July 2021

Surgery alone, adjuvant tegafur/gimeracil/octeracil (S-1), or platinum-based chemotherapies for resectable gastric cancer: real-world experience and a propensity score matching analysis.

BMC Cancer 2021 Jul 9;21(1):796. Epub 2021 Jul 9.

Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, No. 138, Sheng-Li Road, Tainan, 70403, Taiwan.

Background: Adjuvant chemotherapy has changed the paradigm in resectable gastric cancer. S-1 is an oral chemotherapeutic with promising efficacy in Asia. However, comparisons with close observation or platinum-based doublets post D2 gastrectomy have been less reported, notably on real-world experiences.

Methods: We retrospectively evaluated patients with D2-dissected stage IB-III gastric cancer who received S-1 (S-1, n = 67), platinum-based doublets (P, n = 145) and surgery with close observation (OBS, n = 221) from Jan 2008 to Oct 2018. A propensity score matching was used to compare for recurrence-free (RFS) and overall survivals (OS) in patients who had a locally-advanced disease (T3-4 or lymph node-positive). Adverse reactions, dosage, and associated factors for S-1 are also discussed.

Results: In a median follow-up time of 51.9 months, adjuvant S-1 monotherapy was associated with an intermediate survival as compared with P and OBS (median RFS/OS: S-1 vs. P, 20.9/35.8 vs. 31.2/50.5 months, HR = 1.76/2.14, p = 0.021/0.008; S-1 vs. OBS, 24.4/40.2 vs. 20.7/27.0 months, HR = 0.62/0.55, p = 0.041/0.024). The survival differences were more prominent in patients with N2-3 diseases. S-1 was well-tolerated with a relative dose intensity of 73.6%, a median duration of 8.3 months and associated with less adverse reactions as compared with P. S-1 monotherapy was selected by physicians based on age, lymph node stage, serum carcinoembryonic antigen and disease stage.

Conclusions: Adjuvant S-1 correlated with intermediate survival outcomes between OBS and P but conferred fewer adverse reactions as compared with P. Patients with a moderate risk of recurrence had comparable survivals when treated with S-1 while platinum-based doublets were favored in advanced cases. The study provides additional information about adjuvant S-1 in patients with selected risk of recurrence.
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http://dx.doi.org/10.1186/s12885-021-08487-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268293PMC
July 2021

Impact of body mass index on the early experience of robotic pancreaticoduodenectomy.

Updates Surg 2021 Jun 19;73(3):929-937. Epub 2021 May 19.

Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, 138, Sheng-Li Road, Tainan, 70428, Taiwan.

Obesity increases surgical morbidity and mortality in open pancreaticoduodenectomy (OPD). Its influence on robotic pancreaticoduodenectomy (RPD) remains uncertain. This study aimed to investigate the impact of body mass index (BMI) on the early experience of RPD. Between June 2015 and April 2020, 68 consecutive RPDs were performed at the National Cheng Kung University Hospital. The patients were categorized as normal-weight (BMI < 23 kg/m), overweight (BMI = 23-27.5 kg/m), and obese (BMI > 27.5 kg/m) according to the definition of obesity in Asian people from the World Health Organization expert consultation. Preoperative characteristics, operative details, and postoperative outcomes were prospectively collected. The cumulative sum was used to assess the learning curves. The average age of the patients was 64.8 ± 11.7 years with an average BMI of 24.6 ± 3.7 kg/m (23 normal-weight, 29 overweight, and 16 obese patients). Eighteen patients were required to overcome the learning curve. The overall complication rate was 51.5%, and the major complication rate (Clavien grade ≥ III) was 19.1%. The normal-weight group showed the most favorable outcomes. The blood loss, major complication rate, peripancreatic fluid collection rate, and conversion rate were higher in the obese group than in the non-obese group. There were no differences in the operative time, clinically relevant postoperative pancreatic fistula, postoperative hemorrhage, delayed gastric emptying, bile leak, wound infection, reoperation, hospital stay, and readmission rate between the obese and non-obese groups. Multivariate analysis showed obesity as the only independent factor for major complications (OR: 5.983, CI: 1.394-25.682, p = 0.001), indicating that obesity should be considered as a surgical risk factor during the implementation of RPD.
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http://dx.doi.org/10.1007/s13304-021-01065-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184700PMC
June 2021

Upregulation of peroxisome proliferator-activated receptor-α and the lipid metabolism pathway promotes carcinogenesis of ampullary cancer.

Int J Med Sci 2021 1;18(1):256-269. Epub 2021 Jan 1.

Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan.

Ampullary cancer is a rare periampullary cancer currently with no targeted therapeutic agent. It is important to develop a deeper understanding of the carcinogenesis of ampullary cancer. We attempted to explore the characteristics of ampullary cancer in our dataset and a public database, followed by a search for potential drugs. We used a bioinformatics pipeline to analyze complementary (c)DNA microarray data of ampullary cancer and surrounding normal duodenal tissues from five patients. A public database from the National Center for Biotechnology Information Gene Expression Omnibus (NCBI GEO) was applied for external validation. Bioinformatics tools used included the Gene Set Enrichment Analysis (GSEA), Database for Annotation, Visualization and Integrated Discovery (DAVID), MetaCore, Kyoto Encyclopedia of Genes and Genomes (KEGG), Hallmark, BioCarta, Reactome, and Connectivity Map (CMap). In total, 9097 genes were upregulated in the five ampullary cancer samples compared to normal duodenal tissues. From the MetaCore analysis, genes of peroxisome proliferator-activated receptor alpha () and retinoid X receptor ()-regulated lipid metabolism were overexpressed in ampullary cancer tissues. Further a GSEA of the KEGG, Hallmark, Reactome, and Gene Ontology databases revealed that and lipid metabolism-related genes were enriched in our specimens of ampullary cancer and in the NCBI GSE39409 database. Expressions of messenger (m)RNA and the PPAR-α protein were higher in clinical samples and cell lines of ampullary cancer. US Food and Drug Administration (FDA)-approved drugs, including alvespimycin, trichostatin A (a histone deacetylase inhibitor), and cytochalasin B, may have novel therapeutic effects in ampullary cancer patients as predicted by the CMap analysis. Trichostatin A was the most potent agent for ampullary cancer with a half maximal inhibitory concentration of < 0.3 μM. According to our results, upregulation of and lipid metabolism-related genes are potential pathways in the carcinogenesis and development of ampullary cancer. Results from the CMap analysis suggested potential drugs for patients with ampullary cancer.
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http://dx.doi.org/10.7150/ijms.48123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738964PMC
September 2021

Cancer-Derived Transforming Growth Factor-β Modulates Tumor-Associated Macrophages in Ampullary Cancer.

Onco Targets Ther 2020 3;13:7503-7516. Epub 2020 Aug 3.

Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan.

Purpose: Tumor-associated macrophages (TAMs) originate from monocytes and differentiate into mature macrophages. The interaction between cancer cells and TAMs promotes tumor growth and suppresses immunosurveillance. However, this phenomenon has seldom been observed in ampullary cancer.

Patients And Methods: TAMs in ampullary cancer were investigated using immunohistochemical (IHC) staining of cancer tissues. Bioinformatic analysis of data from the Gene Expression Omnibus (GEO) database revealed transforming growth factor-beta (TGF-β) signaling in ampullary cancer. The complementary DNA microarray of cancer was compared with adjacent normal duodenum and enzyme-linked immunosorbent assay of serum was used to verify TGF-β signaling in patients. The THP-1 cell line was activated to imitate M2 TAMs. ClueGo and CluePedia software were operated to simulate TGF-β-related networks in ampullary cancer.

Results: The IHC study revealed that the majority of TAMs inside ampullary cancer were cluster of differentiation (CD)163 cells and that the expression of mature CD68 macrophages was correlated with advanced cancer stage. Bioinformatics analysis revealed that TGF-β and its downstream signaling were significantly upregulated. To verify our bioinformatics-derived predictions, we performed several experiments and demonstrated that increased TGF-β expression was detected in the cDNA microarray. Higher serum levels of TGF-β were correlated with fewer CD68 and more inducible nitric oxide synthase macrophages in ampullary cancer. Treatment with TGF-β induced modulation of THP-1-derived macrophages.

Conclusion: The present study demonstrates that TGF-β modulates macrophage activity in ampullary cancer. Targeting TGF-β could be an approach to activating immunosurveillance.
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http://dx.doi.org/10.2147/OTT.S246714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423398PMC
August 2020

Increased expression of secreted frizzled related protein 1 (SFRP1) predicts ampullary adenocarcinoma recurrence.

Sci Rep 2020 08 6;10(1):13255. Epub 2020 Aug 6.

Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Ampullary adenocarcinoma is a rare gastrointestinal cancer in which WNT signalling dysregulation has been previously reported. Secreted frizzled related protein 1 (SFRP1) is one of the extracellular ligands of WNT signalling. We performed bioinformatics analyses of SFRP1 expression in human cancer. Microarray analysis of SFRP1 in periampullary adenocarcinoma was obtained from the Gene Expression Omnibus GSE39409 dataset. SFRP1 expression in ampullary adenocarcinoma was detected by immunohistochemistry staining and correlated with patients' clinical outcomes. Our results showed that SFRP1 expression had different clinical applications in all types of human cancer. No detected alteration of SFPR1 gene and SFRP1 expression in ampullary adenocarcinoma was lower than that in other periampullary adenocarcinomas. However, high expression levels of SFRP1 protein were correlated with cancer recurrence, peritoneal carcinomatosis and poor patient prognosis. Gene set enrichment analysis showed downregulation of multiple WNT-related genes in primary culture cells from ampullary adenocarcinoma, but SFRP1 expression was increased. We found an interaction between WNT, bone morphogenetic protein and hedgehog signalling with SFRP1. Furthermore, a high expression of SFRP1 predicted poor prognosis for ampullary adenocarcinoma patients. Because it is a multifunctional protein, SFRP1 targeting serves as a potential therapy for ampullary adenocarcinoma patients.
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http://dx.doi.org/10.1038/s41598-020-69899-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413269PMC
August 2020

Validation of genome-wide association study-identified single nucleotide polymorphisms in a case-control study of pancreatic cancer from Taiwan.

J Biomed Sci 2020 May 26;27(1):69. Epub 2020 May 26.

National Institute of Cancer Research, National Health Research Institutes, 1F No 367, Sheng-Li Road, Tainan, 70456, Taiwan.

Background: Due to differences in genetic background, it is unclear whether the genetic loci identified by the previous genome-wide association studies (GWAS) of pancreatic cancer also play significant roles in the development of pancreatic cancer among the Taiwanese population.

Methods: This study aimed to validate the 25 pancreatic cancer GWAS-identified single nucleotide polymorphisms (SNPs) in a case-control study (278 cases and 658 controls) of pancreatic cancer conducted in Taiwan. Statistical analyses were conducted to determine the associations between the GWAS-identified SNPs and pancreatic cancer risk. Gene-environment interaction analysis was conducted to evaluate the interactions between SNPs and environmental factors on pancreatic cancer risk.

Results: Among the 25 GWAS-identified SNPs, 7 (rs2816938 (~ 11 kb upstream of NR5A2), rs10094872 (~ 28 kb upstream of MYC), rs9581943 (200 bp upstream of PDX1) and 4 chromosome 13q22.1 SNPs: rs4885093, rs9573163, rs9543325, rs9573166) showed a statistically significant association with pancreatic cancer risk in the current study. Additional analyses showed two significant gene-environment interactions (between poor oral hygiene and NR5A2 rs2816938 and between obesity and PDX1 rs9581943) on the risk of pancreatic cancer.

Conclusions: The current study confirmed the associations between 7 of the 25 GWAS-identified SNPs and pancreatic risk among the Taiwanese population. Furthermore, pancreatic cancer was jointly influenced by lifestyle and medical factors, genetic polymorphisms, and gene-environment interaction. Additional GWAS is needed to determine the genetic polymorphisms that are more relevant to the pancreatic cancer cases occurring in Taiwan.
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http://dx.doi.org/10.1186/s12929-020-00664-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251895PMC
May 2020

Laparoscopic Splenic Vessels and Spleen Preservation Distal Pancreatectomy Via Inferior-Posterior Splenic Vein Approach.

Surg Laparosc Endosc Percutan Tech 2020 Oct;30(5):424-429

Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University.

Background: Preservation of splenic vessels can minimize the risks of splenic infarction and gastric varices in laparoscopic spleen preserving distal pancreatectomy. A well-established procedure would provide high splenic vessels and spleen preservation rate. This study evaluated the outcomes and depending factors of laparoscopic splenic vessels and spleen preservation distal pancreatectomy (LsvspDP) via inferior-posterior splenic vein approach.

Materials And Methods: This retrospective study enrolled patients who underwent LsvspDP via inferior-posterior splenic vein approach in National Cheng-Kung University Hospital from February 2009 to June 2019. The clinic-pathologic data were collected and analyzed. The primary outcome of this study was the learning curve based on the cumulative sum analysis. The secondary outcomes were to evaluate the critical factors for the failure of splenic vessels and spleen preservation.

Results: During the study period, a total of 64 patients received LsvspDP attempt. Splenic vessels were successfully preserved in 49 patients and the overall spleen preservation rate was 76.6%. According to cumulative sum analysis, the learning curve of LsvspDP was the 33rd case and several plateaus were observed during the learning curve phase. Old age (P=0.001), tail location (P=0.038), and large tumor (P=0.01) were independent risk factors of failed splenic vessels preservation, whereas the cut-off point of tumor size for prediction of spleen preservation was 5.4 cm. The complication rates were 7.8%, 7.8%, and 12.5% for Clavien grade I, II, and III, respectively, and 0% for Clavien grade IV or V. The rate of postoperative pancreatic fistula-grade B was 14.8%, among which the tail location was lower than the nontail location (0% vs. 24.3%; P=0.008). The mean value of operative time, blood loss, and hospital stay were 198±67 minutes, 139±242 mL, and 8.5±5.6 days, respectively.

Conclusions: In LsvspDP, the inferior-posterior splenic vein approach resulted in high splenic vessels and spleen preservation rate. Thirty-three patients were required to overcome the learning curve. Old age, tail location, and large tumor size were independent factors for the failure of splenic vessels preservation, whereas the cut-off value for tumor size was 5.4 cm to predict splenic vessels preservation.
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http://dx.doi.org/10.1097/SLE.0000000000000804DOI Listing
October 2020

Pancreatic stellate cells activated by mutant KRAS-mediated PAI-1 upregulation foster pancreatic cancer progression via IL-8.

Theranostics 2019 23;9(24):7168-7183. Epub 2019 Sep 23.

Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

The dense fibrotic stroma enveloping pancreatic tumors is a major cause of drug resistance. Pancreatic stellate cells (PSCs) in the stroma can be activated to induce intra-tumor fibrosis and worsen patient survival; however, the molecular basics for the regulation of PSC activation remains unclear. The coculture system was used to study cancer cell-PSC interactions. Atomic force microscopy was used to measure the stiffness of tumor tissues and coculture gels. Cytokine arrays, qPCR, and Western blotting were performed to identify the potential factors involved in PSC activation and to elucidate underlying pathways. PSC activation characterized by α-SMA expression was associated with increased pancreatic tumor stiffness and poor prognosis. Coculture with cancer cells induced PSC activation, which increased organotypic coculture gel stiffness and cancer cell invasion. Cancer cells-derived PAI-1 identified from coculture medium could activate PSCs, consistent with pancreatic cancer tissue microarray analysis showing a strong positive correlation between PAI-1 and α-SMA expression. Suppression by knocking down PAI-1 in cancer cells demonstrated the requirement of PAI-1 for coculture-induced PSC activation and gel stiffness. PAI-1 could be upregulated by KRAS in pancreatic cancer cells through ERK. In PSCs, inhibition of LRP-1, ERK, and c-JUN neutralized the effect of PAI-1, suggesting the contribution of LRP-1/ERK/c-JUN signaling. Furthermore, activated PSCs might exacerbate malignant behavior of cancer cells via IL-8 because suppression of IL-8 signaling reduced pancreatic tumor growth and fibrosis . KRAS-mutant pancreatic cancer cells can activate PSCs through PAI-1/LRP-1 signaling to promote fibrosis and cancer progression.
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http://dx.doi.org/10.7150/thno.36830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831292PMC
September 2020

Percutaneous Computed Tomography-Guided Coaxial Core Biopsy for the Diagnosis of Pancreatic Tumors.

J Clin Med 2019 Oct 5;8(10). Epub 2019 Oct 5.

Department of Diagnostic Radiology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan.

Endoscopic, ultrasound-guided tissue acquisition (EUS-TA) with rapid on-site evaluation is recommended as a first choice in the diagnosis of pancreatic lesions. Since EUS facilities and rapid on-site evaluation are not widely available, even in medical centers, an alternative for precise diagnoses of pancreatic tumor is warranted. The percutaneous computed tomography-guided, core needle biopsy (CT-CNB) is a commonly applicable method for biopsies. Our institute has developed a fat-transversing approach for pancreatic biopsies which is able to approach most tumors in the pancreas without penetrating organs or vessels. Herein, we report a 15-year experiment of pancreatic tumor coaxial CT-CNB in 420 patients. The success rate of tissue yielding by the technique was 99.3%. The overall sensitivity, specificity, and accuracy were 93.2%, 100%, and 93.4%, respectively. The diagnostic accuracy could be increased to 96.4% in 2016-2018 (after the learning curve period). The overall complication rate was 8.6%. Neither life-threatening major complications, nor seeding through the biopsy tract, were observed. Our study supported the hypothesis that CT-CNB could be a complementary option for diagnostic tissue acquisition in patients with unresectable or metastatic pancreatic tumors when EUS-TA is either unsuitable or unavailable.
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http://dx.doi.org/10.3390/jcm8101633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832146PMC
October 2019

Low CD8⁺ T Cell Infiltration and High PD-L1 Expression Are Associated with Level of CD44⁺/CD133⁺ Cancer Stem Cells and Predict an Unfavorable Prognosis in Pancreatic Cancer.

Cancers (Basel) 2019 Apr 15;11(4). Epub 2019 Apr 15.

Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan.

Cancer immunotherapy targeting immune checkpoints has exhibited promising clinical outcomes in many cancers, but it offers only limited benefits for pancreatic cancer (PC). Cancer stem cells (CSCs), a minor subpopulation of cancer cells, play important roles in tumor initiation, progression, and drug resistance. Accumulating evidence suggests that CSCs employ immunosuppressive effects to evade immune system recognition. However, the clinical implications of the associations among CD8⁺ T cells infiltration, programmed death receptor ligand-1 (PD-L1) expression, and CSCs existence are poorly understood in PC. Immunostaining and quantitative analysis were performed to assess CD8⁺ T cells infiltration, PD-L1 expression, and their relationship with CD44⁺/CD133⁺ CSCs and disease progression in PC. CD8⁺ T cells infiltration was associated with better survival while PD-L1 expression was correlated with PC recurrence. Both the low CD8⁺ T cells infiltration/high PD-L1 expression group and the high CD8⁺ T cells infiltration/high PD-L1 expression group show high levels of CD44⁺/CD133⁺ CSCs, but patients with low CD8⁺ T cells infiltration/high PD-L1 expression had worse survival and higher recurrence risk than those with high CD8⁺ T cells infiltration/high PD-L1 expression. Moreover, high infiltration of CD8⁺ T cells could reduce unfavorable prognostic effect of high co-expression of PD-L1 and CD44/CD133. Our study highlights an interaction among CD8⁺ T cells infiltration, PD-L1 expression, and CD44⁺/CD133⁺ CSCs existence, which contributes to PC progression and immune evasion.
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http://dx.doi.org/10.3390/cancers11040541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520688PMC
April 2019

A Simple Method of Intracorporeal "W-shaped" Liver Retraction Technique for Minimally Invasive Gastric Cancer Surgery.

Surg Laparosc Endosc Percutan Tech 2019 Jun;29(3):e24-e28

Department of Surgery, National Cheng Kung University Hospital.

Background: Minimally invasive gastric cancer surgery requires an extended liver retraction in order to provide optimal operative view, working space for lymph node dissection, and esophageojejunal reconstruction. Ideally, it should avoid reposition of the retractor, additional skin incision or puncture, and liver parenchyma injury. Herein, we introduced an intracorporeal W-shaped liver retraction technique (W-LRT) for minimally invasive gastric cancer surgery without an additional incision or abodminal puncture.

Methods: Between October 2013 and October 2016, the W-LRT was applied in 80 patients undergoing minimally invasive gastric cancer surgery. The W-LRT was performed using one 75 cm 3-0 monocryl suture with its end fixed to one hemoclip. The perioperative outcome was recorded.

Results: The W-LRT was applied in 80 gastric cancer patients using either laparoscopic approach (N=69) or robotic approach (N=11). The mean age was 62.7±14 years and the mean body mass index (BMI) was 24.1±3.6 kg/m. The time required for W-LRT was 5.6±5.2 minutes in laparoscopic approach and 6.2±4.7 minutes in robotic approach. This technique was successfully applied in all procedures and no other technique or additional instrument was required. Major complications developed in 7 patients (8.8%), classified as greater than Clavien-Dindo classification II; however, there was neither any intraoperative nor postoperative major complication related to W-LRT. The length of hospital stay was 9.1±4.4 days.

Conclusions: In laparoscopic or robotic gastric cancer surgery, the W-LRT can provide excellent operative view during lymph node dissection and reconstruction of esophagojejunostomy and eliminate an additional skin incision or abdominal puncture.
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http://dx.doi.org/10.1097/SLE.0000000000000648DOI Listing
June 2019

Elevated Serum Interleukin-8 Level Correlates with Cancer-Related Cachexia and Sarcopenia: An Indicator for Pancreatic Cancer Outcomes.

J Clin Med 2018 Dec 1;7(12). Epub 2018 Dec 1.

Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan.

Cancer cachexia (CC), characterized by body weight loss and sarcopenia, contributes to over 20% of all cancer-related death. Approximately 80% of pancreatic cancer (PC) patients develop CC during disease progression. Pro-inflammatory cytokines, including interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor (TNF)-α, have been correlated with CC; however, its prognostic significance remains unclear. In this study, serum levels of the CC-related cytokines were determined in normal donors and PC patients. IL-8 expression was assessed in PC tissue microarrays. The correlation of levels of each cytokine with disease progression, weight loss, and sarcopenia was calculated. The relationships among the baseline variables, CC, and IL-8 expression with disease progression were examined using univariate and multivariate analyses. Of these mentioned cytokines, only serum IL-8 level was elevated in the locally advanced group ( = 55) compared with the normal ( = 17) and resected groups ( = 55). Serum IL-8 level was positively correlated with CC status, weight loss, sarcopenia, but was negatively correlated with total psoas area (TPA). IL-8 expression in tissue samples was also positively associated with weight loss. Furthermore, serum IL-8 level was an independent predictor of survival. In conclusion, elevated serum IL-8 level significantly correlates with CC and sarcopenia and can be used as a prognostic indicator in PC.
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http://dx.doi.org/10.3390/jcm7120502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6306800PMC
December 2018

Laparoscopic surgery for large left lateral liver tumors: safety and oncologic outcomes.

Surg Endosc 2018 10 29;32(10):4314-4320. Epub 2018 Jun 29.

Division of Trauma and Acute Care Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medical College, National Cheng Kung University, Tainan, Taiwan.

Background: Although laparoscopic hepatectomy has been proven to be safe and reliable, the influence of tumor size on the feasibility of laparoscopic left lateral segmentectomy (LLLS) is unclear. We retrospectively reviewed our surgical results focusing on hepatic tumor located in the left lateral segment.

Methods: From January 2003 to June 2016, patients who underwent left lateral segmentectomy were retrospectively reviewed, and data were collected on patient characteristics, peri-operative outcomes, and pathologic results. Patients with intrahepatic stone, cystic lesion, or unmeasurable tumor size were excluded. The continuous variables were compared using the Mann-Whitney U test and categorical variables using the Chi square or Fisher's exact test. The overall and disease-free survival rates were computed using the Kaplan-Meier method and compared using the log-rank test.

Results: A total of 103 patients were enrolled for analysis. Among the patients with tumors larger than 5 cm in the left lateral segment, those who underwent laparoscopic surgery had significantly shorter hospital stay and larger resection margin than those who underwent open surgery. The surgical results of the patients who underwent LLLS were not significantly different from those of the patients with tumors larger than 5 cm. Specifically, the 5-year overall survival and disease-free survival rates of the patients with hepatocellular carcinoma (HCC) larger than 5 cm who underwent LLLS were comparable to those of the patients who underwent open left lateral segmentectomy.

Conclusions: LLLS is safe and also feasible for hepatic tumors larger than 5 cm. For HCCs larger than 5 cm, the laparoscopic approach yields satisfying oncologic outcomes as the open approach.
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http://dx.doi.org/10.1007/s00464-018-6287-9DOI Listing
October 2018

KIT Exon 11 Codons 557-558 Deletion Mutation Promotes Liver Metastasis Through the CXCL12/CXCR4 Axis in Gastrointestinal Stromal Tumors.

Clin Cancer Res 2016 07 2;22(14):3477-87. Epub 2016 Mar 2.

Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Department of Surgery, National Cheng Kung University Hospital, Tainan, Taiwan.

Purpose: KIT mutations, the most prevalent genetic event in gastrointestinal stromal tumors (GIST), are associated with malignant features and poor prognosis. Aggressive GISTs possess a high propensity to spread to the liver. This study aimed to explore the role of KIT mutations in GIST liver metastasis.

Experimental Design: A total of 170 GISTs were used to determine the association between KIT mutations and liver metastasis. Immunohistochemistry was performed to assess the correlation of KIT mutations with CXCR4 and ETV1 expression. Genetic and pharmacologic methods were used to study the regulation of CXCR4 and ETV1 by KIT mutations.

Results: Codons 557 and 558 in KIT exon 11 were deletion hot spots in GISTs. KIT exon 11 deletions involving codons 557-558 were highly associated with liver metastasis. Overexpression of mutant KIT with exon 11 codons 557-558 deletion (KIT Δ557-558) increased GIST cell motility and liver metastasis. Mechanistically, overexpression of KIT Δ557-558 in GIST cells increased ETV1 and CXCR4 expression. CXCR4 knockdown counteracted KIT Δ557-558-mediated cell migration. Moreover, KIT Δ557-558-induced CXCR4 expression could be abolished by silencing ETV1. The chromatin immunoprecipitation assay showed that ETV1 directly bound to the CXCR4 promoter. After ERK inhibitor PD325901 treatment, the upregulation of ETV1 by KIT Δ557-558 was prevented. In addition, KIT exon 11 codons 557-558 deletion enhanced CXCL12-mediated GIST cell migration and invasion.

Conclusions: KIT exon 11 557-558 deletion upregulates CXCR4 through increased binding of ETV1 to the CXCR4 promoter in GIST cells, which thus promotes liver metastasis. These findings highlighted the potential therapeutic targets for metastatic GISTs. Clin Cancer Res; 22(14); 3477-87. ©2016 AACR.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-2748DOI Listing
July 2016

Dual role of CD44 isoforms in ampullary adenocarcinoma: CD44s predicts poor prognosis in early cancer and CD44ν is an indicator for recurrence in advanced cancer.

BMC Cancer 2015 Nov 16;15:903. Epub 2015 Nov 16.

Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Background: Although postoperative adjuvant chemoradiotherapies prevent recurrence for some patients with ampullary cancer, the recurrence rate is as high as 29% in patients with stage I cancer. In an effort to identify predictors of recurrence in patients with ampullary adenocarcinoma, we investigated the clinical value of assessing standard and variant forms of CD44.

Methods: Immunohistochemistry staining and reverse-transcription polymerase chain reaction (RT-PCR) was used to detect standard and variant forms of CD44 in samples of ampullary adenocarcinoma. The cDNA microarray analysis comparing tumors with or without pancreatic invasion was undertaken and analyzed by Ingenuity Pathway Analysis.

Results: The standard CD44 (CD44s) isoform was detected in 76 of 98 patients with ampullary adenocarcinoma, and the negative or weak expression of CD44s was correlated with pancreatic invasion, lymphovascular invasion, advanced stage and bone metastasis. Moderate to dense expression of CD44s was correlated with shorter overall survival in patients with localized cancer (T1 or T2 disease, P=0.0268). The patients with advanced cancer (T3 or T4 disease) and moderate or dense CD44s expression had a trend toward better survival. Alternative splicing of CD44 was confirmed using RT-PCR, which revealed that the CD44ν3-10 isoform was only expressed in patients with cancer recurrence. Fold change of CD44ν6-10 was also increased. In addition, networks containing CD44, vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR), transforming growth factor-β (TGF-β), matrix metalloproteinase 2 (MMP2), AKT, extracellular signal-regulated protein kinase 1 and 2 (ERK1/2), p38 MAPK, activated protein 1 (AP1)' and CTNNB1 were constructed after comparing microarray data from patients with and without pancreatic invasion.

Conclusions: Whereas CD44s functions as tumor-promoting oncoprotein in early localized ampullary adenocarcinoma, CD44 variants are expressed in advanced cancer and patients with recurrence. Regional invasiveness and distant metastasis of ampullary cancer is controlled by a complex interacting network.
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http://dx.doi.org/10.1186/s12885-015-1924-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4647323PMC
November 2015

Hemostasis Plug for an Electromagnetic Thermotherapy and Its Application for Liver Laceration.

Ann Biomed Eng 2016 Apr 3;44(4):1310-20. Epub 2015 Jul 3.

Department of Power Mechanical Engineering, National Tsing Hua University, Hsinchu, 300, Taiwan.

Accident-induced liver trauma is a significant human health concern, as this organ is readily injured during periods at which the abdominal region is compromised. In this work, electromagnetic thermotherapy was successfully developed and employed in vitro and in vivo to treat livers that had been lacerated. Briefly, a new hemostasis plug was integrated with an electromagnetic thermotherapy system (ETS) to perform surgery on lacerated livers. The high-frequency, alternating electromagnetic field (EMF) was generated by the ETS and was shown to induce a pre-set temperature increase within the hemostasis plug embedded in the target tissue. In order to prevent overheating and maintain a constant hemostasis temperature, a temperature feedback control system was utilized. The effect of the intensity of the EMF on the heating capacity of the ETS-hemostasis system was first explored. Furthermore, the relationship between the coagulation zone and operating temperature were investigated in vitro. By utilizing the temperature feedback control system, the hemostasis plug could be heated to a specific temperature for efficient hemostasis. With this approach, the optimal treatment temperature and time were investigated for liver laceration. Lacerated livers from New Zealand white rabbits were successfully treated with the hemostasis plug and ETS within a short period of time. When compared with the traditional perihepatic packing approach, the volume of blood loss from liver laceration surgeries treated by ETS has been dramatically reduced by 83%, suggesting a high therapeutic potential for this system.
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http://dx.doi.org/10.1007/s10439-015-1365-9DOI Listing
April 2016

The significance of the co-existence of osteopontin and tumor-associated macrophages in gastric cancer progression.

BMC Cancer 2015 Mar 15;15:128. Epub 2015 Mar 15.

Background: Osteopontin (OPN) can recruit macrophages to the site of inflammation and promote tumorigenesis. M2 tumor-associated macrophages (M2-TAMs) also play an important role in cancer progression. This study aimed to clarify the role of OPN and M2-TAMs co-existence in gastric cancer.

Methods: The levels of OPN and M2-TAMs were evaluated by immunohistochemical staining in 170 resected gastric cancer specimens that were collected from 1998 to 2012. M2-TAMs were identified by staining for an M2 marker, CD204. The prognostic significance and correlation between OPN and CD204 expression were analyzed. A co-culture system of OPN+-AGS and U937 cells was designed to study the effect of OPN on the skewing of macrophages toward M2-TAMs for gastric cancer progression in vitro and in vivo.

Results: Patients with high expression (>50%) of OPN or CD204 exhibited poor 5-year overall survival rates (48.61%, p = 0.0055, and 52.14%, p = 0.0498, respectively). A positive correlation was observed between OPN and CD204 expression and high co-expression of OPN and CD204 demonstrated poor 5-year overall survival rates (48.90%, p = 0.0131). In the co-culture study, OPN was able to attract U937 cells and skew them toward M2-TAMs through paracrine action. The M2-TAMs could increase the invasiveness of OPN+-AGS cells and the growth rate of xenograft of a mixture of co-cultured OPN+-AGS and U937 cells.

Conclusion: OPN can skew macrophages toward M2-TAMs during gastric cancer progression. The co-existence of OPN and infiltrating M2-TAMs correlates with disease progression and poor survival and thus can serve as a prognostic marker in gastric cancer.
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http://dx.doi.org/10.1186/s12885-015-1114-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4384326PMC
March 2015

Predictors for resectability and survival in locally advanced pancreatic cancer after gemcitabine-based neoadjuvant therapy.

BMC Surg 2014 Sep 25;14:72. Epub 2014 Sep 25.

Division of General Surgery, Department of Surgery, National Cheng Kung University Hospital, Tainan, Taiwan.

Background: To evaluate the predictors for resectability and survival of patients with locally advanced pancreatic cancer (LAPC) treated with gemcitabine-based neoadjuvant therapy (GBNAT).

Methods: Between May 2003 and Dec 2009, 41 tissue-proved LAPC were treated with GBNAT. The location of pancreatic cancer in the head, body and tail was 17, 18 and 6 patients respectively. The treatment response was evaluated by RECIST criteria. Surgical exploration was based on the response and the clear plan between tumor and celiac artery/superior mesentery artery. Kaplan-Meier analysis and Cox Model were used to calculate the resectability and survival rates.

Results: Finally, 25 patients received chemotherapy (CT) and 16 patients received concurrent chemoradiation therapy (CRT). The response rate was 51% (21 patients), 2 CR (1 in CT and 1 in CRT) and 19 PR (10 in CT and 9 in CRT). 20 patients (48.8%) were assessed as surgically resectable, in which 17 (41.5%) underwent successful resection with a 17.6% positive-margin rate and 3 failed explorations were pancreatic head cancer for dense adhesion. Two pancreatic neck cancer turned fibrosis only. Patients with surgical intervention had significant actuarial overall survival. Tumor location and post-GBNAT CA199 < 152 were predictors for resectability. Post-GBNAT CA-199 < 152 and post-GBNAT CA-125 < 32.8 were predictors for longer disease progression-free survival. Pre-GBNAT CA-199 < 294, post-GBNAT CA-125 < 32.8, and post-op CEA < 6 were predictors for longer overall survival.

Conclusion: Tumor location and post-GBNAT CA199 < 152 are predictors for resectability while pre-GBNAT CA-199 < 294, post-GBNAT CA-125 < 32.8, post-GBNAT CA-199 < 152 and post-op CEA < 6 are survival predictors in LAPC patients with GBNAT.
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http://dx.doi.org/10.1186/1471-2482-14-72DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4182443PMC
September 2014

Coexpression of CD44-positive/CD133-positive cancer stem cells and CD204-positive tumor-associated macrophages is a predictor of survival in pancreatic ductal adenocarcinoma.

Cancer 2014 Sep 19;120(17):2766-77. Epub 2014 May 19.

Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Background: The interactions between cancer stem cells (CSCs) and tumor-associated macrophages (TAMs) can promote tumor progression, maintain the CSCs population, and reduce therapeutic effects. The objective of this study was to investigate the coexpression of CSCs and TAMs and its clinical significance in pancreatic ductal adenocarcinoma (PDAC).

Methods: Ninety-six patients with PDAC were included in this study. Tissue microarrays were constructed for immunostaining of the CSCs markers CD44 and CD133 and the TAMs marker CD204. Correlations between the expression of CSCs and TAMs markers and clinicopathologic characteristics or disease progression were analyzed.

Results: Expression levels of CD44/CD133 and CD204 were significantly higher in tumor tissues than in normal tissues (P < .0001). The variables associated with survival were high coexpression of CD44/CD133 (P = .000), high expression of CD204 (P = .011), and tumor grade (P = .014). There was a positive correlation between CD44/CD133 and CD204 expression (r = 0.294; P = .004). Survival analysis indicated that high coexpression of CD44/CD133 and CD204 was associated significantly with shorter overall survival (P = .000) and disease-free survival (P = .003). Multivariate analysis revealed that high CD44/CD133 expression was an independent prognostic factor for disease-free survival, whereas high CD204 expression was an independent predictor for both overall and disease-free survival.

Conclusions: Coexpression of CD44/CD133 and CD204 is a useful survival prediction marker for patients with PDAC.
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http://dx.doi.org/10.1002/cncr.28774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4232049PMC
September 2014

Successfully seal pancreatic end after thermal distal pancreatectomy using needle arrays in alternating electromagnetic fields.

Surg Innov 2013 Apr 1;20(2):150-7. Epub 2012 May 1.

National Cheng Kung University, Tainan, Taiwan.

Background: Pancreatic fistula is still the major postoperative morbidity after distal pancreatectomy (DP). An inductive heat technology via needle arrays in a system of alternating magnetic fields (AMFs) was designed to seal off the pancreatic end.

Methods: Twenty Lanyu pigs were divided into 2 groups for DP: the conventional group had hand-sewn closure of the pancreatic end (n = 10), and the AMF group received thermal DP by AMF (n = 10). Pathological examinations of the resected and remnant pancreas were studied immediately after resection and on the 14th postoperative day (POD), respectively. The severity and the incidence of pancreatic abscess were compared.

Results: The incidence and severity of pancreatic abscess were significantly decreased in the AMF group than those in the conventional group (P = .009). In the immediate postoperative period, microscopic examination of the pancreatic resected end showed prominent coagulative necrosis, loss of NADPH-diaphorase activity, and significant apoptosis at the resected pancreas in the AMF group compared with the control group. Fourteen days after AMF ablation, the pancreatic stump end was covered with thick fibrosis, and histological study of the remnant pancreas showed that the parenchyma had well recovered with positive NADPH-diaphorase activity, and the pancreatic duct was sealed off successfully by prominent periductal fibrosis and intraductal plug. The body weight gain on the 14th POD was significantly increased in the AMF group (from 23.8 ± 1.8 kg to 25.4 ± 5.5 kg) compared with the conventional group (from 25.3 ± 2.1 to 25.4 ± 6.0 kg; P = .003).

Conclusions: Inductive heats by the AMF system via needle array can be performed easily and can seal the pancreatic cut surface well during DP.
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http://dx.doi.org/10.1177/1553350612445640DOI Listing
April 2013

Technical notes: a self-designed, simple, secure, and safe six-loop intracorporeal Pringle's maneuver for laparoscopic liver resection.

Surg Endosc 2012 Sep 22;26(9):2681-6. Epub 2012 Mar 22.

Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138, Sheng-Li Road, Tainan 70428, Taiwan.

Background: The aim of this study is to design a simple, secure, and safe technique of intracorporeal Pringle's maneuver to facilitate safer laparoscopic liver resection.

Methods: A self-designed six-loop catheter was made using 20-French T-tube and 10-French nelaton urethral catheter. The cross head and stem of the T-tube were trimmed to 1 cm, respectively. The nelaton was shortened to 12-cm-long tube from the round tip, and the cut end was inserted and sutured to the stem of the T-tube. After establishment of pneumoperitoneum, the T-tube with nelaton was placed into the abdomen. The round end of the nelaton was inserted into the lesser sac and pulled through the foramen of Winslow, and the end of nelaton was then inserted into one end of the T-tube and pulled through the other end, forming a six-loop. The nelaton was pulled to occlude the hepatic inflow and temporarily fixed with 1-0 Vicryl on a curved round needle on the other end of the T-tube. The protocol of Pringle's maneuver was 15-min clamp and 5-min release periods. The liver parenchymal transection was performed using Harmonic scalpel.

Results: From November 2009 to August 2011, 20 patients received laparoscopic liver resection using the six-loop Pringle's maneuver. During operation, 17 patients were positioned supine, 2 patients in left decubitus, and 1 patient in supine followed by left decubitus position. There were 9 anatomical resections and 11 nonanatomical resections (18 patients for single lesion, 1 for two lesions, and 1 for three lesions). The average times of liver resection and Pringle's maneuver were 33.1 and 36.2 min, respectively. Mean blood loss was 102.5 ml. The postoperative course was uneventful, and average hospital stay was 4.4 days.

Conclusion: Our self-designed six-loop intracorporeal Pringle's maneuver can facilitate safer laparoscopic liver resection.
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http://dx.doi.org/10.1007/s00464-012-2210-yDOI Listing
September 2012

Dual-row needle arrays under an electromagnetic thermotherapy system for bloodless liver resection surgery.

IEEE Trans Biomed Eng 2012 Mar 19;59(3):824-31. Epub 2011 Dec 19.

Department of Power Mechanical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan.

Electromagnetic thermotherapy has been extensively investigated recently and may become a new surgical modality for a variety of medical applications. It applies a high-frequency alternating magnetic field to heat up magnetic materials inserted within the human body to generate tissue coagulation or cell apoptosis. Using a new procedure with dual-row needle arrays under an electromagnetic thermotherapy system with a feedback temperature control system, this study demonstrates bloodless porcine liver resection, which is challenging using existing methods. In vitro experiments showed that hollowed, stainless-steel needles could be heated up to more than 300 °C within 30 s when centered under the induction coils of the electromagnetic thermotherapy system. In order to generate a wide ablation zone and to prevent the dual-row needle arrays from sticking to the tissue after heating, a constant temperature of 120 °C was applied using a specific treatment protocol. The temperature distribution in the porcine livers was also measured to explore the effective coagulation area. Liver resection was then performed in Lan-Yu pigs. Experimental results showed that seven pigs underwent liver resection without bleeding during surgery and no complications afterward. The dual-row needle arrays combined with the electromagnetic thermotherapy system are thus shown to be promising for bloodless tissue resection.
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http://dx.doi.org/10.1109/TBME.2011.2180381DOI Listing
March 2012
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