Publications by authors named "Chun-Nan Yeh"

230 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

A Nomogram Predicting Progression Free Survival in Patients with Gastrointestinal Stromal Tumor Receiving Sunitinib: Incorporating Pre-Treatment and Post-Treatment Parameters.

Cancers (Basel) 2021 May 25;13(11). Epub 2021 May 25.

Department of Surgery and GIST Team, Chang Gung Memorial Hospital at Linkou, ChangGung University College of Medicine, Taoyuan 33305, Taiwan.

The present study aimed to construct a prognostic nomogram incorporating pre-treatment and post-treatment factors to predict progression-free survival (PFS) after use of sunitinib in patients with metastatic gastrointestinal stromal tumors (GISTs) following imatinib intolerance or failure. From 2007 to 2018, 109 metastatic GIST patients receiving sunitinib at Chang Gung Memorial Hospital, Taiwan, were enrolled. A prognostic nomogram to predict PFS was developed. Sixty-three male and forty-six female metastatic GIST patients, with a median age of 61 years (range: 15-91 years), received sunitinib. The median PFS for 109 patients is 9.93 months. For pre-treatment factors, male gender, body mass index more than 18.5 kg/m, no sarcopenia status, higher lymphocyte count, lower platelet/lymphocyte ratio, good performance status, higher sunitinib dose, and non-liver metastasis were significantly associated with favorable PFS. For post-treatment factors, adverse events with hypertension, hand-foot skin reaction, and diarrhea were significantly associated with favorable PFS. However, only eight clinicopathological independent factors for PFS prediction were selected for prognostic nomogram establishment. The calibration curve for probability of PFS revealed good agreement between the nomogram prediction and actual observation. High risk patients will experience the lowest PFS. A prognostic nomogram integrating eight clinicopathological factors was constructed to assist prognostic prediction for individual patients with advanced GIST after sunitinib use.
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http://dx.doi.org/10.3390/cancers13112587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197516PMC
May 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

ARHGAP25 Inhibits Pancreatic Adenocarcinoma Growth by Suppressing Glycolysis via AKT/mTOR Pathway.

Int J Biol Sci 2021 24;17(7):1808-1820. Epub 2021 Apr 24.

Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-17177 Stockholm, Sweden.

Increasing evidence reveals that the Rho GTPase-activating protein is a crucial negative regulator of Rho family GTPase involved in tumorigenesis. The Rho GTPase-activating protein 25 (ARHGAP25) has been shown to specifically inactivate the Rho family GTPase Rac1, which plays an important role in pancreatic adenocarcinoma (PAAD) progression. Therefore, here we aimed to clarify the expression and functional role of ARHGAP25 in PAAD. The ARHGAP25 expression was lower in PAAD tissues than that in normal pancreatic tissues based on bioinformatics analysis and immunohistochemistry staining. Overexpression of ARHGAP25 inhibited cell growth of AsPC-1 human pancreatic cancer cells in vitro, while opposite results were observed in BxPC-3 human pancreatic cancer cells with ARHGAP25 knockdown. Consistently, in vivo tumorigenicity assays also confirmed that ARHGAP25 overexpression suppressed tumor growth. Mechanically, overexpression of ARHGAP25 inactivated AKT/mTOR signaling pathway by regulating Rac1/PAK1 signaling, which was in line with the results from the Gene set enrichment analysis on The Cancer Genome Atlas dataset. Furthermore, we found that ARHGAP25 reduced HIF-1α-mediated glycolysis in PAAD cells. Treatment with PF-04691502, a dual PI3K/mTOR inhibitor, hampered the increased cell growth and glycolysis due to ARHGAP25 knockdown in PAAD cells. Altogether, these results conclude that ARHGAP25 acts as a tumor suppressor by inhibiting the AKT/mTOR signaling pathway, which might provide a therapeutic target for PAAD.
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http://dx.doi.org/10.7150/ijbs.55919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120455PMC
April 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

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

Proteomics-based identification of TMED9 is linked to vascular invasion and poor prognoses in patients with hepatocellular carcinoma.

J Biomed Sci 2021 Apr 22;28(1):29. Epub 2021 Apr 22.

Genomics Research Center, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei, 11529, Taiwan.

Background: Due to the difficulties in early diagnosing and treating hepatocellular carcinoma (HCC), prognoses for patients remained poor in the past decade. In this study, we established a screening model to discover novel prognostic biomarkers in HCC patients.

Methods: Candidate biomarkers were screened by liquid chromatography with tandem mass spectrometry (LC-MS/MS) analyses of five HCC normal (N)/tumor (T) paired tissues and preliminarily verified them through several in silico database analyses. Expression levels and functional roles of candidate biomarkers were respectively evaluated by immunohistochemical staining in N/T paired tissue (n = 120) and MTS, colony formation, and transwell migration/invasion assays in HCC cell lines. Associations of clinicopathological features and prognoses with candidate biomarkers in HCC patients were analyzed from GEO and TCGA datasets and our recruited cohort.

Results: We found that the transmembrane P24 trafficking protein 9 (TMED9) protein was elevated in HCC tissues according to a global proteomic analysis. Higher messenger (m)RNA and protein levels of TMED9 were observed in HCC tissues compared to normal liver tissues or pre-neoplastic lesions. The TMED9 mRNA expression level was significantly associated with an advanced stage and a poor prognosis of overall survival (OS, p = 0.00084) in HCC patients. Moreover, the TMED9 protein expression level was positively correlated with vascular invasion (p = 0.026), OS (p = 0.044), and disease-free survival (p = 0.015) in our recruited Taiwanese cohort. In vitro, manipulation of TMED9 expression in HCC cells significantly affected cell migratory, invasive, proliferative, and colony-forming abilities.

Conclusions: Ours is the first work to identify an oncogenic role of TMED9 in HCC cells and may provide insights into the application of TMED9 as a novel predictor of clinical outcomes and a potential therapeutic target in patients with HCC.
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http://dx.doi.org/10.1186/s12929-021-00727-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063382PMC
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 highest drain fluid amylase levels on surgical outcomes and postoperative interventions in patients undergoing pancreaticoduodenectomy.

Asian J Surg 2021 Mar 2. Epub 2021 Mar 2.

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

Objectives: The clinical significance of the highest drain fluid amylase (DFA) level beyond pancreaticoduodenectomy (PD) postoperative day three (POD 3) remains unclear. This study investigated the impact of highest DFA level beyond POD 3 on postoperative pancreatic fistula (POPF) severity and outcomes of patients undergoing PD with POPF.

Methods: Patient demographics of biochemical POPF and clinically relevant POPF (CR-POPF) were compared. Predictive factors were assessed using binary logistic regression. Receiver operating characteristic curve analysis was performed to determine the optimal cutoff value of highest DFA (beyond POD 3). We compared length of hospital stay, surgical mortality rates, and need for postoperative interventions by highest DFA level.

Results: Patients with CR-POPF had an older age (p = 0.039), required intraoperative blood transfusion (p = 0.006), and had greater highest DFA levels (p = 0.001) than those with biochemical POPF. The optimal highest DFA cutoff was 2014.5 U/L. Multivariate analysis showed that percentage of patients with intraoperative blood transfusion (p = 0.011; odds ratio, 3.716) and a highest DFA > 2014.5 U/L beyond POD 3 (p = 0.001; odds ratio, 5.722) was predictive of CR-POPF.

Conclusion: Highest DFA > 2014.5 U/L beyond POD 3 is an independent predictor for CR-POPF. At a highest DFA >2014.5 U/L, 30-day surgical mortality rate, length of stay, and need for postoperative interventions did not differ.
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http://dx.doi.org/10.1016/j.asjsur.2021.01.041DOI Listing
March 2021

A scalable physician-level deep learning algorithm detects universal trauma on pelvic radiographs.

Nat Commun 2021 02 16;12(1):1066. Epub 2021 Feb 16.

PAII Inc, Bethesda, MD, USA.

Pelvic radiograph (PXR) is essential for detecting proximal femur and pelvis injuries in trauma patients, which is also the key component for trauma survey. None of the currently available algorithms can accurately detect all kinds of trauma-related radiographic findings on PXRs. Here, we show a universal algorithm can detect most types of trauma-related radiographic findings on PXRs. We develop a multiscale deep learning algorithm called PelviXNet trained with 5204 PXRs with weakly supervised point annotation. PelviXNet yields an area under the receiver operating characteristic curve (AUROC) of 0.973 (95% CI, 0.960-0.983) and an area under the precision-recall curve (AUPRC) of 0.963 (95% CI, 0.948-0.974) in the clinical population test set of 1888 PXRs. The accuracy, sensitivity, and specificity at the cutoff value are 0.924 (95% CI, 0.912-0.936), 0.908 (95% CI, 0.885-0.908), and 0.932 (95% CI, 0.919-0.946), respectively. PelviXNet demonstrates comparable performance with radiologists and orthopedics in detecting pelvic and hip fractures.
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http://dx.doi.org/10.1038/s41467-021-21311-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887334PMC
February 2021

Development of Possible Next Line of Systemic Therapies for Gemcitabine-Resistant Biliary Tract Cancers: A Perspective from Clinical Trials.

Biomolecules 2021 01 13;11(1). Epub 2021 Jan 13.

Center for Immuno-Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei 112, Taiwan.

Biliary tract cancer (BTC) compromises a heterogenous group of tumors with poor prognoses. Curative surgery remains the first choice for localized disease; however, most BTC patients have had unresectable or metastatic disease. The gold standard therapy for these patients is chemotherapy with gemcitabine and cisplatin. There are no consensus guidelines for standard treatment in a second-line setting, although the data of the ABC-06 trial showed a slight survival benefit from oxaliplatin and 5-fluorouracil combination chemotherapy. Recent progress in comprehensive genomic profiling for advanced BTC (ABTC) has helped to clarify tumorigenesis and facilitate the coming era of precision medicine. Generally, targeted agents fail to show significant clinical benefits in unselected populations. Only fibroblast growth factor receptor 2 () fusion and isocitrate dehydrogenase ()- and mutation-enriched populations have survival benefits from the corresponding inhibitors. Several interesting targeted agents for monotherapies or combination therapies with other compounds are currently ongoing or recruiting. Here, we review the published data from clinical trials of second-line therapies after the failure of gemcitabine-based chemotherapy in ABTC. The results were stratified by different genetic alternations, as well as by chemotherapy, targeted therapy and immunotherapy.
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http://dx.doi.org/10.3390/biom11010097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828560PMC
January 2021

Purely laparoscopic feeding jejunostomy: a procedure which deserves more attention.

BMC Surg 2021 Jan 13;21(1):37. Epub 2021 Jan 13.

College of Medicine, Chang Gung University, Guishan, Taoyuan, Taiwan, Republic of China.

Background: Laparoscopic procedure has inherent merits of smaller incisions, better cosmesis, less postoperative pain, and earlier recovery. In the current study, we presented our method of purely laparoscopic feeding jejunostomy and compared its results with that of conventional open approach.

Methods: We retrospectively reviewed our patients from 2012 to 2019 who had received either laparoscopic jejunostomy (LJ, n = 29) or open ones (OJ, n = 94) in Chang Gung Memorial Hospital, Linkou. Peri-operative data and postoperative outcomes were analyzed.

Results: In the current study, we employed 3-0 Vicryl, instead of V-loc barbed sutures, for laparoscopic jejunostomy. The mean operative duration of LJ group was about 30 min longer than the OJ group (159 ± 57.2 mins vs 128 ± 34.6 mins; P = 0.001). There were no intraoperative complications reported in both groups. The patients in the LJ group suffered significantly less postoperative pain than in the OJ group (mean NRS 2.03 ± 0.9 vs. 2.79 ± 1.2; P = 0.002). The majority of patients in both groups received early enteral nutrition (< 48 h) after the operation (86.2% vs. 74.5%; P = 0.143).

Conclusions: Our study demonstrated that purely laparoscopic feeding jejunostomy is a safe and feasible procedure with less postoperative pain and excellent postoperative outcome. It also provides surgeons opportunities to enhance intracorporeal suture techniques.
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http://dx.doi.org/10.1186/s12893-021-01050-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805100PMC
January 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

Therapeutic inhibition of polo-like kinases in anaplastic thyroid cancer.

Cancer Sci 2021 Feb 2;112(2):803-814. Epub 2021 Jan 2.

Head and Neck Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

Polo-like kinases (PLKs) are potent regulators of cell proliferation and cell survival. Polo-like kinases are potential targets in the treatment of anaplastic thyroid cancer (ATC), a rare but deadly disease. The therapeutic effects of volasertib, a PLK inhibitor, was evaluated for the treatment of ATC either alone or in combination with sorafenib. Volasertib decreased cell viability in three ATC cell lines (8505C, 8305C, and KAT18) in a dose-dependent manner. Volasertib caused ATC cells to accumulate in G /M phase, activated caspase-3 activity, and induced apoptosis. Combination therapy using volasertib and sorafenib in ATC cells showed mostly synergistic effects. In vivo studies revealed that combination therapy of volasertib and sorafenib was effective in the treatment of 8505C xenografts. Single-agent volasertib treatment was sufficient to retard 8305C tumor growth. No substantial morbidity was observed in animals that received either single-agent or combination treatment. These preclinical findings suggest that volasertib could be an effective drug in treating ATC.
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http://dx.doi.org/10.1111/cas.14769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893987PMC
February 2021

Comprehensive Evaluation of Immune-Checkpoint DNA Cancer Vaccines in a Rat Cholangiocarcinoma Model.

Vaccines (Basel) 2020 Nov 24;8(4). Epub 2020 Nov 24.

Department of General Surgery and Liver Research Center, Chang Gung Memorial Hospital, Linkou Branch, Chang Gung University, Taoyuan 333, Taiwan.

Cholangiocarcinoma (CCA) is a malignant tumor with aggressive biological behavior. Immune checkpoints such as cytotoxic T-lymphocyte antigen 4 (CTLA4) and antiprogrammed death 1 (PD-1) are critical immune-checkpoint molecules that repress T-cell activation. The DNA against CTLA4 and PD-1 in CCA is unknown. We used a thioacetamide (TAA)-induced intrahepatic (iCCA) rat model to investigate the DNA vaccine potential against CTLA4, PD-1, and PD-L1. We detected PD-L1 expression in CCA and CD8 T-cell infiltration during CCA progression in rats. We validated antibody production, carcinogenesis, and CD8 T-cell infiltration in rats receiving DNA vaccination against PD-1, PD-L1, or CTLA4. In our TAA-induced iCCA rat model, the expression of PD-L1 and the infiltration of CD8 T cells increased as in rat CCA tumorigenesis. PD-1 antibodies in rats were not increased after receiving PD-1 DNA vaccination, and CCA tumor growth was not suppressed. However, in rats receiving PD-L1-CTLA4 DNA vaccination, CCA tumor growth was inhibited, and the antibodies of PD-L1 and CTLA4 were produced. Furthermore, the number of CD8 T cells was enhanced after PD-L1-CTLA4 DNA vaccination. DNA vaccination targeting CTLA4-PD-L1 triggered the production of specific antibodies and suppressed tumor growth in TAA-induced iCCA rats.
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http://dx.doi.org/10.3390/vaccines8040703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7712087PMC
November 2020

A Human-Algorithm Integration System for Hip Fracture Detection on Plain Radiography: System Development and Validation Study.

JMIR Med Inform 2020 Nov 27;8(11):e19416. Epub 2020 Nov 27.

Department of Trauma and Emergency Surgery, Linkou Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan.

Background: Hip fracture is the most common type of fracture in elderly individuals. Numerous deep learning (DL) algorithms for plain pelvic radiographs (PXRs) have been applied to improve the accuracy of hip fracture diagnosis. However, their efficacy is still undetermined.

Objective: The objective of this study is to develop and validate a human-algorithm integration (HAI) system to improve the accuracy of hip fracture diagnosis in a real clinical environment.

Methods: The HAI system with hip fracture detection ability was developed using a deep learning algorithm trained on trauma registry data and 3605 PXRs from August 2008 to December 2016. To compare their diagnostic performance before and after HAI system assistance using an independent testing dataset, 34 physicians were recruited. We analyzed the physicians' accuracy, sensitivity, specificity, and agreement with the algorithm; we also performed subgroup analyses according to physician specialty and experience. Furthermore, we applied the HAI system in the emergency departments of different hospitals to validate its value in the real world.

Results: With the support of the algorithm, which achieved 91% accuracy, the diagnostic performance of physicians was significantly improved in the independent testing dataset, as was revealed by the sensitivity (physician alone, median 95%; HAI, median 99%; P<.001), specificity (physician alone, median 90%; HAI, median 95%; P<.001), accuracy (physician alone, median 90%; HAI, median 96%; P<.001), and human-algorithm agreement [physician alone κ, median 0.69 (IQR 0.63-0.74); HAI κ, median 0.80 (IQR 0.76-0.82); P<.001. With the help of the HAI system, the primary physicians showed significant improvement in their diagnostic performance to levels comparable to those of consulting physicians, and both the experienced and less-experienced physicians benefited from the HAI system. After the HAI system had been applied in 3 departments for 5 months, 587 images were examined. The sensitivity, specificity, and accuracy of the HAI system for detecting hip fractures were 97%, 95.7%, and 96.08%, respectively.

Conclusions: HAI currently impacts health care, and integrating this technology into emergency departments is feasible. The developed HAI system can enhance physicians' hip fracture diagnostic performance.
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http://dx.doi.org/10.2196/19416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732715PMC
November 2020

ATM Inhibitor Suppresses Gemcitabine-Resistant BTC Growth in a Polymerase θ Deficiency-Dependent Manner.

Biomolecules 2020 11 9;10(11). Epub 2020 Nov 9.

Department of General Surgery and Liver Research Center, Chang Gung Memorial Hospital, Linkou branch, Chang Gung University, Taoyuan 333, Taiwan.

Patients with advanced biliary tract cancer (BTC) inevitably experience progression after first-line, gemcitabine-based chemotherapy, due to chemo-resistance. The genetic alterations of DNA damage repair (DDR) genes are usually determined in BTC tumors. In this study, we found that the mRNA levels are downregulated and the ataxia-telangiectasia mutated (ATM) inhibitor AZD0156 was more sensitive in gemcitabine-resistant BTC sublines than in the parental cell lines. The knockdown of DNA polymerase θ does not affect cell proliferation, but its combination with the ATM inhibitor facilitated cell death in gemcitabine-resistant and gemcitabine-intensive BTC cells. Moreover, in the DNA damage caused by photon, hydrogen peroxide, or chemotherapy drugs, synthetic lethal interactions were found in combination with ATM inhibition by AZD0156 and DNA polymerase θ depletion, resulting in increased DNA damage accumulation and micronucleus formation, as well as reduced cell survival and colony formation. Collectively, our results reveal that ATM acts as a potential target in gemcitabine-resistant and DNA polymerase θ-deficient BTC.
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http://dx.doi.org/10.3390/biom10111529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697425PMC
November 2020

Predicting cholecystocholedochal fistulas in patients with Mirizzi syndrome undergoing endoscopic retrograde cholangiopancreatography.

World J Gastroenterol 2020 Oct;26(40):6241-6249

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

Background: Mirizzi syndrome (MS) is defined as an extrinsic compression of the extrahepatic biliary system by an impacted stone in the gallbladder or the cystic duct leading to obstructive jaundice. Endoscopic retrograde cholangiopancreatography (ERCP) could serve diagnostic and therapeutic purposes in patients with MS in addition to revealing the relationships between the cystic duct, the gallbladder, and the common bile duct (CBD). Cholecystectomy is a challenging procedure for a laparoscopic surgeon in patients with MS, and the presence of a cholecystocholedochal fistula renders preoperative diagnosis important during ERCP.

Aim: To evaluate cholecystocholedochal fistulas in patients with MS during ERCP before cholecystectomy.

Methods: From 2004 to 2018, all patients diagnosed with MS during ERCP were enrolled in this study. Patients with associated malignancy or those who had already undergone cholecystectomy before ERCP were excluded. In total, 117 patients with MS diagnosed by ERCP were enrolled in this study. Among them, 21 patients with MS had cholecystocholedochal fistulas. MS was further confirmed during cholecystectomy to check if cholecystocholedochal fistulas were present. The clinical data, cholangiography, and endoscopic findings during ERCP were recorded and analyzed.

Results: Gallbladder opacification on cholangiography is more frequent in patients with MS complicated by cholecystocholedochal fistulas ( < 0.001). Pus in the CBD and stricture length of the CBD longer than 2 cm were two additional independent factors associated with MS, as demonstrated by multivariate analysis (odds ratio 5.82, = 0.002; 0.12, = 0.008, respectively).

Conclusion: Gall bladder opacification is commonly seen in patients with MS with cholecystocholedochal fistulas during pre-operative ERCP. Additional findings such as pus in the CBD and stricture length of the CBD longer than 2 cm may aid the diagnosis of MS with cholecystocholedochal fistulas.
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http://dx.doi.org/10.3748/wjg.v26.i40.6241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596637PMC
October 2020

Chromosomal Instability May Not Be a Predictor for Immune Checkpoint Inhibitors from a Comprehensive Bioinformatics Analysis.

Life (Basel) 2020 Nov 8;10(11). Epub 2020 Nov 8.

Department of General Surgery and Liver Research Center, Chang Gung Memorial Hospital, Linkou branch, Chang Gung University, Taoyuan 333, Taiwan.

Immune checkpoint inhibitors (ICIs) have become the standard of care in various cancers, although their predictive tools have not yet completely developed. Here, we aimed to exam the role of 70-gene chromosomal instability signature (CIN70) in cancers, and its association with previous predictors, tumor mutation burden (TMB), and microsatellite instability (MSI), for patients undergoing ICIs, as well as the possible predictive value for ICIs. We examined the association of CIN70 with TMB and MSI, as well as the impact of these biomarkers on the survival of 33 cancer cohorts from The Cancer Genome Atlas (TCGA) databank. The predictive value of the ICIs of CIN70 in previously published reports was also validated. Using the TCGA dataset, CIN70 scores were frequently (either positively or negatively) associated with TMB, but were only significantly associated with MSI status in three types of cancer. In addition, our current study showed that all TMB, MSI, and CIN70 had their own prognostic values for survival in patients with various cancers, and that they could be cancer type-specific. In two validation cohorts (melanoma by Hugo et al. and urothelial cancer by Snyder et al.), no significant difference of CIN70 scores was found between responders and non-responders (-value = 0.226 and 0.108, respectively). In addition, no overall survival difference was noted between patients with a high CIN70 and those with a low CIN70 (-value = 0.106 and 0.222, respectively). In conclusion, the current study, through a comprehensive bioinformatics analysis, demonstrated a correlation between CIN70 and TMB, but CIN70 is not the predictor for cancer patients undergoing ICIs. Future prospective studies are warranted to validate these findings.
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http://dx.doi.org/10.3390/life10110276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695172PMC
November 2020

Targeting P53 as a Future Strategy to Overcome Gemcitabine Resistance in Biliary Tract Cancers.

Biomolecules 2020 10 23;10(11). Epub 2020 Oct 23.

Newcastle University Cancer Centre, Bioscience Institute, Medical Faculty, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.

Gemcitabine-based chemotherapy is the current standard treatment for biliary tract cancers (BTCs) and resistance to gemcitabine remains the clinical challenge. mutation has been shown to be associated with poor clinicopathologic characteristics and survival in patients with BTCs, indicating that p53 plays an important role in the treatment of these cancers. Herein, we comprehensively reviewed previous BTC preclinical research and early clinical trials in terms of p53, as well as novel p53-targeted treatment, alone or in combination with either chemotherapy or other targeted therapies in BTCs. Preclinical studies have demonstrated that p53 mutations in BTCs are associated with enhanced gemcitabine resistance, therefore targeting p53 may be a novel therapeutic strategy for treatment of BTCs. Directly targeting mutant p53 by p53 activators, or indirectly by targeting cell cycle checkpoint proteins (Chk1, ataxia telangiectasia related (ATR), and Wee1) leading to synthetic lethality, may be potential future strategies for gemcitabine-resistant p53 mutated BTCs. In contrast, for wild-type p53 BTCs, activation of p53 by inhibition of its negative regulators (MDM2 and wild-type p53-induced phosphatase 1 (WIP1)) may be alternative options. Combination therapies consisting of standard cytotoxic drugs and novel small molecules targeting p53 and related signaling pathways may be the future key standard approach to beat cancer.
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http://dx.doi.org/10.3390/biom10111474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690712PMC
October 2020

The Emerging Role of MicroRNAs in Regulating the Drug Response of Cholangiocarcinoma.

Biomolecules 2020 09 30;10(10). Epub 2020 Sep 30.

Department of Surgery and Liver Research Center, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan 333, Taiwan.

Cholangiocarcinoma (CCA) is the most common biliary malignancy, and has a poor prognosis. The median overall survival with the standard-of-care chemotherapy (Gemcitabine and cisplatin) in patients with advanced-stage CCA is less than one year. The limited efficacy of chemotherapy or targeted therapy remains a major obstacle to improving survival. The mechanisms involved in drug resistance are complex. Research efforts focusing on the distinct molecular mechanisms underlying drug resistance should prompt the development of treatment strategies that overcome chemoresistance or targeted drug resistance. MicroRNAs (miRNAs) are a class of evolutionarily conserved, short noncoding RNAs regulating gene expression at the post-transcriptional level. Dysregulated miRNAs have been shown to participate in almost all CCA hallmarks, including cell proliferation, migration and invasion, apoptosis, and the epithelial-to-mesenchymal transition. Emerging evidence demonstrates that miRNAs play a role in regulating responses to chemotherapy and targeted therapy. Herein, we present an overview of the current knowledge on the miRNA-mediated regulatory mechanisms underlying drug resistance among CCA. We also discuss the application of miRNA-based therapeutics to CCA, providing the basis for innovative treatment approaches.
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http://dx.doi.org/10.3390/biom10101396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600158PMC
September 2020

Omics-Based Platforms: Current Status and Potential Use for Cholangiocarcinoma.

Biomolecules 2020 09 28;10(10). Epub 2020 Sep 28.

Genomics Research Center, Academia Sinica, 128 Academia Rd., Sec. 2, Nankang-Dist., Taipei 115, Taiwan.

Cholangiocarcinoma (CCA) has been identified as a highly malignant cancer that can be transformed from epithelial cells of the bile duct, including intrahepatic, perihilar and extrahepatic. High-resolution imaging tools (abdominal ultrasound, computed tomography and percutaneous transhepatic cholangial drainage) are recruited for diagnosis. However, the lack of early diagnostic biomarkers and treatment evaluation can lead to serious outcomes and poor prognosis (i.e., CA19-9, MUC5AC). In recent years, scientists have established a large number of omics profiles to reveal underlying mechanisms and networks (i.e., IL-6/STAT3, NOTCH). With these results, we achieved several genomic alteration events (i.e., TP53 KRAS) and epigenetic modifications (i.e., DNA methylation, histone modification) in CCA cells and clinical patients. Moreover, we reviewed candidate gene (such as NF-kB, YAP1) that drive gene transcription factors and canonical pathways through transcriptomics profiles (including microarrays and next-generation sequencing). In addition, the proteomics database also indicates which molecules and their directly binding status could trigger dysfunction signatures in tumorigenesis (carbohydrate antigen 19-9, mucins). Most importantly, we collected metabolomics datasets and pivotal metabolites. These results reflect the pharmacotherapeutic options and evaluate pharmacokinetic/pharmacodynamics in vitro and in vivo. We reversed the panels and selected many potentially small compounds from the connectivity map and L1000CDS system. In this paper, we summarize the prognostic value of each candidate gene and correlate this information with clinical events in CCA. This review can serve as a reference for further research to clearly investigate the complex characteristics of CCA, which may lead to better prognosis, drug repurposing and treatment strategies.
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http://dx.doi.org/10.3390/biom10101377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600697PMC
September 2020

Management of Gallstones and Acute Cholecystitis in Patients with Liver Cirrhosis: What Should We Consider When Performing Surgery?

Gut Liver 2020 Sep 15. Epub 2020 Sep 15.

Department of General Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan.

Acute cholecystitis and several gallbladder stone-related conditions, such as impacted common bile duct stones, cholangitis, and biliary pancreatitis, are common medical conditions in daily practice. An early cholecystectomy or drainage procedure with delayed cholecystectomy is the current standard of treatment based on published clinical guidelines. Cirrhosis is not only a condition of chronically impaired hepatic function but also has systemic effects in patients. In cirrhotic individuals, several predisposing factors, including changes in the bile acid composition, increased nucleation of bile, and decreased motility of the gallbladder, contribute to the formation of biliary stones and the possibility of symptomatic cholelithiasis, which is an indication for surgical treatment. In addition to these predisposing factors for cholelithiasis, systemic effects and local anatomic consequences related to cirrhosis lead to anesthesiologic risks and perioperative complications in cirrhotic patients. Therefore, the treatment of the aforementioned biliary conditions in cirrhotic patients has become a challenging issue. In this review, we focus on cholecystectomy for cirrhotic patients and summarize the surgical indications, risk stratification, surgical procedures, and surgical outcomes specific to cirrhotic patients with symptomatic cholelithiasis.
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http://dx.doi.org/10.5009/gnl20052DOI Listing
September 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

Establishment of a novel gene panel as a biomarker of immune checkpoint inhibitor response.

Clin Transl Immunology 2020 30;9(7):e1145. Epub 2020 Jun 30.

Department of General Surgery and Liver Research Center, Chang Gung Memorial Hospital, Linkou Branch Chang Gung University Taoyuan Taiwan.

Objective: Immune checkpoint inhibitors (ICIs) have become the standard of care in various cancers, although the predictive tool is still unknown.

Methods: This study aimed to develop a novel gene panel by selecting DNA damage response (DDR) genes from the Catalogue of Somatic Mutations in Cancer (COSMIC) databank and validating them in previously reported cohorts. This association between DDR gene mutations and tumor mutation burden or microsatellite status was analysed from The Cancer Genome Atlas (TCGA) databank. Furthermore, we made the gene panel clinically accessible and predicted the response in clinical patients receiving ICIs by using cell-free DNA.

Results: The top 20 mutated DDR genes in various cancers (total 37 genes) were taken from the COSMIC databank, and the DDR genes found to individually predict a response rate > 50% in Van Allen's cohort were selected (, , 2015 and 207). Eighteen DDR genes were selected as the gene panel. The prevalence and predicted response rate were validated in the other three reported cohorts. Tumor mutational burden-high was positively associated with mutations of the 18 DDR genes for most cancers. We used cell-free DNA to test the DDR gene panel and validated by our patients receiving ICIs. This DDR gene panel accounted for approximately 30% of various cancers, achieving a predicted response rate of approximately 60% in patients with a mutated gene panel receiving ICIs.

Conclusion: This gene panel is a novel and reliable tool for predicting the response to ICIs in cancer patients and guides the appropriate administration of ICIs in clinical practice.
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http://dx.doi.org/10.1002/cti2.1145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326616PMC
June 2020

A bubble bursting-mediated oral drug delivery system that enables concurrent delivery of lipophilic and hydrophilic chemotherapeutics for treating pancreatic tumors in rats.

Biomaterials 2020 10 3;255:120157. Epub 2020 Jun 3.

Department of Chemical Engineering/Institute of Biomedical Engineering and Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu, Taiwan. Electronic address:

The therapeutic outcome of pancreatic cancer remains unsatisfactory, despite many attempts to improve it. To address this challenge, an oral drug delivery system that spontaneously initiates an effervescent reaction to form gas-bubble carriers is proposed. These carriers concurrently deliver lipophilic paclitaxel (PTX) and hydrophilic gemcitabine (GEM) in the small intestine. The bursting of the bubbles promotes the intestinal absorption of the drugs. The antitumor efficacy of this proposed oral drug delivery system is evaluated in rats with experimentally created orthotopic pancreatic tumors. The combined administration of equivalent amounts of PTX and GEM via the intravenous (i.v.) route, which is clinically used for treating pancreatic cancer, serves as a control. Following oral administration, the lipophilic PTX is initially absorbed through the intestinal lymphatic system and then enters systemic circulation, whereas the hydrophilic GEM is directly taken up into the blood circulation, ultimately accumulating in the tumorous pancreatic tissues. A pharmacokinetic study reveals that the orally delivered formulation has none of the toxic side-effects that are associated with the i.v. injected formulation; changes the pharmacokinetic profiles of the drugs; and increases the bioavailability of PTX. The oral formulation has a greater impact than the i.v. formulation on tumor-specific stromal depletion, resulting in greater inhibition of tumor growth with no evidence of metastatic spread. As well as enhancing the therapeutic efficacy, this unique approach of oral chemotherapy has potential for use on outpatients, greatly improving their quality of life.
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http://dx.doi.org/10.1016/j.biomaterials.2020.120157DOI Listing
October 2020

Heterogeneity of Metabolic Vulnerability in Imatinib -Resistant Gastrointestinal Stromal Tumor.

Cells 2020 05 26;9(6). Epub 2020 May 26.

Department of Oncology-Pathology, Karolinska Institutet, BioClinicum J6:20, Karolinska University Hospital, SE-17164 Solna, Sweden.

Metabolic reprogramming is a hallmark of cancer cells in response to targeted therapy. Decreased glycolytic activity with enhanced mitochondrial respiration secondary to imatinib has been shown in imatinib-sensitive gastrointestional stromal tumors (GIST). However, the role of energy metabolism in imatinib-resistant GIST remains poorly characterized. Here, we investigated the effect of imatinib treatment on glycolysis and oxidative phosphorylation (OXPHOS), as well as the effect of inhibition of these energy metabolisms on cell viability in imatinib-resistant and -sensitive GIST cell lines. We observed that imatinib treatment increased OXPHOS in imatinib-sensitive, but not imatinib-resistant, GIST cells. Imatinib also reduced the expression of mitochondrial biogenesis activators (peroxisome proliferator-activated receptor coactivator-1 alpha (PGC1α), nuclear respiratory factor 2 (NRF2), and mitochondrial transcription factor A (TFAM)) and mitochondrial mass in imatinib-sensitive GIST cells. Lower TFAM levels were also observed in imatinib-sensitive GISTs than in tumors from untreated patients. Using the Seahorse system, we observed bioenergetics diversity among the GIST cell lines. One of the acquired resistant cell lines (GIST 882R) displayed a highly metabolically active phenotype with higher glycolysis and OXPHOS levels compared with the parental GIST 882, while the other resistant cell line (GIST T1R) had a similar basal glycolytic activity but lower mitochondrial respiration than the parental GIST T1. Further functional assays demonstrated that GIST 882R was more vulnerable to glycolysis inhibition than GIST 882, while GIST T1R was more resistant to OXPHOS inhibition than GIST T1. These findings highlight the diverse energy metabolic adaptations in GIST cells that allow them to survive upon imatinib treatment and reveal the potential of targeting the metabolism for GIST therapy.
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http://dx.doi.org/10.3390/cells9061333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348861PMC
May 2020

Prognostic and predictive factors for Taiwanese patients with advanced biliary tract cancer undergoing frontline chemotherapy with gemcitabine and cisplatin: a real-world experience.

BMC Cancer 2020 May 14;20(1):422. Epub 2020 May 14.

Division of Haematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, 5, Fu-Hsing Street, Kwei-Shan, Taoyuan, Taiwan.

Background: Chemotherapy with gemcitabine and cisplatin has been the standard of care in first-line chemotherapy for advanced biliary tract cancer (BTC) since the trial ABC-02 was published in 2010. We aimed to investigate the prognostic and predictive factors of this regimen in a cohort of Taiwanese patients with advanced BTC.

Methods: A total of 118 patients with histologically confirmed BTC treated at Chang Gung Memorial Hospital at Linkou from 2012 to 2017 were retrospectively reviewed.

Results: The median progression-free survival (PFS) and overall survival (OS) were 3.6 months and 8.4 months, respectively. In the multivariate analysis, neutrophil to lymphocyte ratio (NLR) > 7.45, biliary drainage requiring both percutaneous transhepatic cholangiography drainage (PTCD) and internal stenting, and tumor responses with progressive diseases and not assessed were independent poor prognostic factors for PFS. Male sex, NLR > 7.45, alkaline phosphatase> 94 U/L, biliary drainage requiring both PTCD and internal stenting, and tumor responses with stable disease, progressive diseases and not assessed were independent poor prognostic factors for OS. Monocyte to lymphocyte ratio (MLR) ≤ 0.28 was the only significant predictive factor for the tumor response. Patients with complete response/partial response had significantly lower MLR than patients with other tumor responses.

Conclusion: We identified three important prognostic factors, namely tumor response, NLR, and biliary drainage requiring both PTCD and internal stenting for both PFS and OS. MLR was the only significant predictive factor for the tumor response. These findings could provide physicians with more information to justify the clinical outcomes in patients with advanced BTC in real-world practice.
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http://dx.doi.org/10.1186/s12885-020-06914-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227306PMC
May 2020