Publications by authors named "Song Cheol Kim"

246 Publications

A Serum Marker for Early Pancreatic Cancer with a Possible Link to Diabetes.

J Natl Cancer Inst 2021 Oct 6. Epub 2021 Oct 6.

Natural Product Research Institute, College of Pharmacy, Seoul National University, Seoul, Korea.

Background: Pancreatic cancer (PC) has a grim prognosis, and an early diagnostic biomarker has been highly desired. The molecular link between diabetes and PC has not been well-established.

Methods: Bioinformatics screening was performed for a serum PC marker. Experiments in cell lines (5 PC and 1 normal cell lines), mouse models, and human tissue staining (37 PC and 10 normal cases) were performed to test asprosin production from PC. Asprosin's diagnostic performance was tested with serums from multi-center cohorts (347 PC, 209 normal, and 55 additional diabetic subjects) and evaluated according to PC status, stages, and diabetic status, which was compared with that of CA19-9.

Results: Asprosin, a diabetes-related hormone, was found from the bioinformatics screening, and its production from PC was confirmed. Serum asprosin levels from multi-center cohorts yielded an age-adjusted diagnostic AUC of 0.987 (95% confidence interval [CI] = 0.961 to 0.997), superior to that of CA19-9 (AUC = 0.876, 95% CI = 0.847 to 0.905), and a cut-off of 7.18 ng/mL, at which the validation set exhibited a sensitivity of 0.957 and a specificity of 0.924. Importantly, the performance was maintained in early-stage and non-metastatic PC, consistent with the tissue staining. A slightly lower performance against additional diabetic patients (n = 55) was restored by combining asprosin and CA19-9 (AUC = 0.985, 95% CI = 0.975 to 0.995).

Conclusion: Asprosin is presented as an early-stage PC serum marker that may provide clues for PC-induced diabetes. Larger prospective clinical studies are warranted to solidify its utility.
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http://dx.doi.org/10.1093/jnci/djab191DOI Listing
October 2021

ASO Visual Abstract: Predictive Performance of Current Nodal Staging Systems in Various Categories of Pancreatic Cancer.

Ann Surg Oncol 2021 Aug 30. Epub 2021 Aug 30.

Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea.

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http://dx.doi.org/10.1245/s10434-021-10679-7DOI Listing
August 2021

Predictive Performance of Current Nodal Staging Systems in Various Categories of Pancreatic Cancer.

Ann Surg Oncol 2021 Aug 22. Epub 2021 Aug 22.

Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 05505, Republic of Korea.

Background: Nodal staging systems (NSS) for pancreatic ductal adenocarcinoma (PDAC) classify patients on the basis of number of metastatic lymph nodes (MLN), metastatic/retrieved lymph node ratio (LNR), and log odds of positive LN (LODDS). The relative prognostic performance of these NSS, however, remains unclear.

Patients And Methods: We identified 2584 patients who underwent surgery for PDAC between 2010 and 2019. Subgroups of each staging system were classified using K-adaptive partitioning method and assessed by comparing time-dependent areas under the curve (AUC) 5 years after surgery.

Results: Patients were subgrouped by MLN (0, 1-3, ≥ 4), LNR (0, 0-0.23, > 0.23), and LODDS (< - 3.5, - 3.5 to - 0.970, > - 0.97). All three NSS were independent prognostic factors for overall survival (OS) and recurrence-free survival (RFS). The AUCs for OS were comparable for the MLN (0.622), LNR (0.609), and LODDS (0.596) systems. Subgroup evaluation based on 12 retrieved lymph nodes (RLN), R1 resection, and extent of resection showed that the AUCs of the MLN and LNR NSS were comparable for OS and RFS regardless of the number of RLNs, R1 resection, and extent of resection. By contrast, the AUCs of the LODDS NSS were lower.

Conclusion: The NSS based on the number of MLN is the best prognostic indicator, with prognostic performance comparable to the other NSS and greater convenience for practical use. This NSS was applicable regardless of the numbers of RLN, R1 resection, and extent of resection.
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http://dx.doi.org/10.1245/s10434-021-10641-7DOI Listing
August 2021

Imaging Strategy that Achieves Ultrahigh Contrast by Utilizing Differential Esterase Activity in Organs: Application in Early Detection of Pancreatic Cancer.

ACS Nano 2021 Aug 18. Epub 2021 Aug 18.

Department of Molecular Medicine, Brain Korea 21 four KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea.

Most nanoparticles show much higher uptake in mononuclear phagocyte system (MPS) organs than in tumors, which has been a long-lasting dilemma in nanomedicine. Here, we report an imaging strategy that selectively decreases MPS organ uptakes by utilizing the differential esterase activity in tumors and other organs. When an esterase-labile radiotracer loaded liposome was injected into the body, radioactivity was rapidly excreted from the liver and spleen after breakage of the ester bond by esterase. However, the lipophilic radiotracer delivered to the tumor remained in the tumor with minimal bond cleavage. The underlying mechanism was fully characterized and in colon tumor models. As a proof of concept, the liposomal radiotracer was further optimized for the early detection of pancreatic cancer. The folate-coated liposomal radiotracer showed highly selective tumor uptake. At 4 h postinjection, a pancreatic tumor a few millimeters in size was unambiguously visualized in orthotopic tumor models by PET imaging. At 24 h, an exceptionally high tumor-to-background ratio was achieved, enabling the visualization of tumors alone with minimal background noise. More than 9% of the total radioactivity was found in the tumor. Utilizing our imaging strategy, various tumor imaging agents can be developed for sensitive detection with ultrahigh contrast.
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http://dx.doi.org/10.1021/acsnano.1c05165DOI Listing
August 2021

Comparison of perioperative outcomes in pancreatic head cancer patients following either a laparoscopic or open pancreaticoduodenectomy with a superior mesenteric artery first approach.

Ann Hepatobiliary Pancreat Surg 2021 Aug;25(3):358-365

Division of Hepato-Biliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Backgrounds/aims: A superior mesenteric artery first approach (SFA) technique can improve the complete resection rate. It can be used to determine whether an operation can be performed by invading the superior mesenteric artery before performing a pancreatic transection in patients with pancreatic ductal adenocarcinoma (PDAC). The aim of this study was to compare perioperative outcomes between laparoscopic and open SFA for PDAC.

Methods: Between January 2017 and August 2019, consecutive patients who underwent laparoscopic and open pancreaticoduodenectomy (PD) for PDAC using SFA procedures were included and compared between laparoscopic and open procedures.

Results: Fourteen and 83 patients underwent laparoscopic and open surgeries, respectively. In perioperative outcomes, there were no significant differences in the amount of intraoperative blood loss or transfusion rate between the two groups. In the laparoscopic group, the operation time was longer with less patients showing wound infection. R0 resection rate and the number of retrieved lymph nodes showed no significant difference. The average time to adjuvant chemotherapy was longer in the open group. There was no significant difference in the mean survival time or the recurrence free period.

Conclusions: Patients who underwent laparoscopic PD using SFA showed perioperative outcomes comparable compared to those of patients who underwent open procedures performed by experienced surgeons.
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http://dx.doi.org/10.14701/ahbps.2021.25.3.358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8382868PMC
August 2021

Surgical outcomes are hampered after endoscopic ultrasonography-guided ethanol lavage and/or Taxol injection in cystic lesions of the pancreas.

Ann Hepatobiliary Pancreat Surg 2021 Aug;25(3):342-348

Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Backgrounds/aims: Endoscopic ultrasonography-guided ethanol lavage and Taxol injection (EUS-ELTI) for pancreatic cystic lesions have been recently performed in some medical centers. The aim of this study was to optimize patient selection and analyze outcomes of patients who underwent surgeries after EUS-ELTI for pancreatic cystic lesions.

Methods: Among 310 patients who underwent EUS-ELTI between January 2007 and December 2014, 23 underwent surgeries after EUS-ELTI owing to incomplete treatment and/or adverse events. Surgical outcomes of patients who underwent surgeries after EUSELTI were evaluated. Clinical outcomes of patients who underwent surgeries after EUS-ELTI were then retrospectively compared with those of patients who underwent upfront surgery for left-sided pancreatic lesions without an EUS-ELTI procedure.

Results: The pathology revealed degenerated cysts in 12 patients, mucinous cyst neoplasms in five, neuroendocrine tumors in two, intraductal papillary mucinous neoplasm (IPMN) in one, solid pseudopapillary tumor in one, pancreatic ductal adenocarcinoma arising from an IPMN in one, and hepatoid carcinoma in one. Twelve patients underwent laparoscopic distal pancreatectomy and five patients underwent open distal pancreatectomy. When clinical outcomes were retrospectively compared between patients who underwent laparoscopic distal pancreatectomy after EUS-ELTI and those who did not receive an EUS-ELTI procedure, the spleen-preserving rate was 0% in the EUS-ELTI group and 61.7% (365/592) in the control group ( < 0.001).

Conclusions: Surgical outcomes are compromised after EUS-ELTI for cystic tumor of the pancreas. Further studies are needed to investigate the efficacy and safety of the EUS-ELTI procedure.
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http://dx.doi.org/10.14701/ahbps.2021.25.3.342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8382853PMC
August 2021

Clinical Outcomes Between a Minimally Invasive and Open Extended Cholecystectomy for T2 Gallbladder Cancer: A Propensity Score Matching Analysis.

J Laparoendosc Adv Surg Tech A 2021 Aug 11. Epub 2021 Aug 11.

Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.

Although a minimally invasive extended cholecystectomy (MIEC) for T2 gallbladder cancer (T2 GBC) has been performed in many experienced centers, no oncologic comparison with open extended cholecystectomy (OEC) has yet been reported. T2 GBC patients who underwent MIEC ( = 60) or OEC ( = 135) were enrolled. We used propensity score matching (PSM) using pre- and intraoperative variables. Short- and long-term outcomes were then compared before and after PSM. Before PSM, OEC patients more frequently showed completion of surgery after a simple cholecystectomy (standardized mean difference [SMD] = -0.551), and lymph node enlargement on preoperative computed tomography (SMD = -0.471). PSM was used to select 56 patients from each of the 2 patient groups. MIEC patients showed comparable complication rate (7.1% versus 12.5%,  = .365) and shorter hospital stay (5.7 days versus 9.8 days,  < .001). The median follow-up period was 26.2 months, and 5-year overall survival (OS) rate (96.8% versus 91.1%,  = .464) and 5-year recurrence free survival (RFS) (54.7% versus 44.4%,  = .580) outcomes were still comparable between MIEC and OEC groups. MIEC have advantages such as early recovery and comparable short-term outcomes compared with OEC. MIEC showed comparable OS and RFS outcomes compared with OEC. MIEC is a safe option without oncological compromise for T2 GBC.
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http://dx.doi.org/10.1089/lap.2021.0417DOI Listing
August 2021

Metabolic activity by FDG-PET/CT after neoadjuvant chemotherapy in borderline resectable and locally advanced pancreatic cancer and association with survival.

Br J Surg 2021 Aug 11. Epub 2021 Aug 11.

Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.

Background: The optimal prognostic markers for neoadjuvant chemotherapy in patients with borderline resectable or locally advanced pancreatic cancer are not yet established.

Method: Patients who received neoadjuvant chemotherapy prior to surgery and underwent FDG-PET/CT between July 2012 and December 2017 were included. Metabolic parameters including standardised uptake value (SUV), metabolic tumour volume (MTV), and total lesion glycolysis (TLG) on PET/CT, and response evaluations using PERCIST criteria, were investigated for its impact on survival and recurrence. Cox proportional hazards model was performed. Differences in risk were expressed as hazard ratio [HR] with 95% confidence interval [c.i.].

Results: The patients with borderline resectable (N = 106) or locally advanced pancreatic cancer (N = 82) were identified. The median survival was 33.6 months. Decreased metabolic parameters of PET/CT after neoadjuvant chemotherapy were associated with positive impacts on survival and recurrence such as SUVmax (HR 1.16, 95% c.i. 1.01 to 1.32, P = 0.025), SUVpeak (HR 1.26, 95% c.i. 1.05 to 1.51, P = 0.011), and MTV (HR 1.15, 95% c.i. 1.04 to 1.26, P = 0.005). Large delta values were related to a positive impact on recurrence such as SUVmax (HR 1.21, 95% c.i. 1.06 to 1.38, P = 0.005). Post-neoadjuvant chemotherapy SUVmax ≥3 (HR 3.46, 95% c.i. 1.21 to 9.91; P = 0.036) was an independent prognostic factor for negative impact on survival. Patients with post-neoadjuvant chemotherapy SUVmax <3 showed more chemotherapy cycles (8.7 versus 6.2, P = 0.001), more frequent complete metabolic response (25 vs 2.2%, P = 0.002), smaller tumour size (2.1 vs 3.1 cm, P = 0.002), and less frequent lymphovascular invasion (23.7 vs 51.1%, P = 0.020) than patients with SUVmax ≥3.

Conclusion: Reduction in metabolic tumour parameters of FDG- PET/CT after neoadjuvant chemotherapy indicates improved overall survival and recurrence-free survival.
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http://dx.doi.org/10.1093/bjs/znab229DOI Listing
August 2021

Longitudinal Changes in Body Composition of Long-Term Survivors of Pancreatic Head Cancer and Factors Affecting the Changes.

J Clin Med 2021 Aug 2;10(15). Epub 2021 Aug 2.

Department of Rehabilitation Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea.

Previous studies on changes in body composition of pancreatic cancer patients have only focused on short-term survivors. We studied longitudinal body composition changes and factors affecting them in long-term survivors by analyzing many abdominal computed tomography images using artificial intelligence technology. Of 302 patients who survived for >36 months after surgery were analyzed. Multivariate logistic regression analysis for factors affecting body composition changes and repeated-measures analysis of variance to observe differences in the course of change according to each factor were performed. In logistic analysis, preoperative sarcopenia and recurrence were the main factors influencing body composition changes at 1 and 3 years after surgery, respectively. In changes of longitudinal body composition, the decrease in body composition was the greatest at 3-6 months postoperatively, and the preoperative status did not recover even 3 years after surgery. Especially, males showed a greater reduction in skeletal muscle (SKM) after surgery than females ( < 0.01). In addition, SKM ( < 0.001) and subcutaneous adipose tissue ( < 0.05) mass rapidly decreased in case of recurrence. In conclusion, long-term survivors of pancreatic cancer did not recover their preoperative body composition status, and preoperative sarcopenia and recurrence influenced body composition changes.
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http://dx.doi.org/10.3390/jcm10153436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8348760PMC
August 2021

Perioperative and oncologic outcomes of right anterior sectionectomy for liver disease: A single-center experience with 415 patients.

ANZ J Surg 2021 09 27;91(9):1847-1853. Epub 2021 Jul 27.

Division of Hepato-biliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.

Background: Right anterior sectionectomy (RAS) is technically difficult and performed infrequently, so there are few published reports about experiences with this surgery. We describe 10 years' worth of clinicopathologic and oncologic outcomes associated with RAS.

Methods: We retrospectively reviewed the medical records of 415 patients treated with RAS for hepatic tumors located at segment five and/or eight between January 2008 and December 2017.

Results: All patients underwent RAS with the alternative Glissonean pedicle clamp and Kelly clamp-crushing methods for transection. The mean operative time was 165 min, and the mean transection time was 28 min. Major morbidity (≥grade III) occurred in 28 cases (6.7%). Bile leakage occurred in 63 patients (15.1%), but no patients required reoperation. Grade A, B, and C post-hepatectomy liver failure occurred in 39 (9.4%), 7 (1.7%), and 0 patients, respectively. There were no in-hospital deaths caused by postoperative complications. The mean hospital stay was 13.3 days. The mean tumor size was 3.8 cm. Among hepatocellular carcinoma (HCC) patients (n = 361, 87.0%), the 5- and 10-year overall survival rates were 78.3%, 64.4%, and the 5- and 10-year disease-free survival rates were 57.2%, 37.7%, respectively.

Conclusions: RAS was associated with acceptable procedure-related morbidity and mortality as well as appropriate oncologic outcomes for HCC patients.
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http://dx.doi.org/10.1111/ans.17098DOI Listing
September 2021

The clinicopathologic and operative characteristics of patients with small nonfunctioning pancreatic neuroendocrine tumors.

ANZ J Surg 2021 Jul 21;91(7-8):E484-E492. Epub 2021 Jul 21.

Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, University of Ulsan College of Medicine and Asan Medical Center, Seoul, South Korea.

Background: Incidentally detected, small nonfunctioning pancreatic neuroendocrine tumors (NF-PNETs) are increasingly diagnosed on imaging modalities. This retrospective investigation evaluated the clinicopathologic characteristics and perioperative and oncologic outcomes in patients with small NF-PNETs undergoing curative resection.

Methods: The medical records of 444 patients who underwent pancreatic resection for NF-PNETs at a single, large-volume institution between January 2000 and December 2018 were retrospectively reviewed. Patients were divided into those with small (≤2 cm) and large (>2 cm) tumors based on the largest tumor diameter on preoperative computed tomography (CT). Outcomes were also evaluated in subgroups of patients with small NF-PNET who did and did not undergo lymphadenectomy.

Results: Of the 444 patients with NF-PNETs, 195 (43.9%) had small (≤2 cm) and 249 (56.1%) had large (>2 cm) NF-PNETs. The rate of parenchyma-preserving surgery (14.4% vs. 7.2%, p = 0.014) and the ratio of spleen preservation for left-sided pancreatectomy (65.6% vs. 38.3%, p < 0.001) were higher in the small NF-PNET group. Size on CT >2 cm (p < 0.001, hazard ratio [HR]: 5.836, 95% confidence interval [CI]: 2.474-13.769), presence of perineural invasion (p < 0.001, HR: 3.025, 95% CI: 1.640-5.577), World Health Organization (WHO) Grade 2 (p = 0.007, HR: 2.861, 95% CI: 1.325-6.176), and WHO Grade 3 (p < 0.001, HR: 11.537, 95% CI: 5.282-25.199) were independent predictors of disease-free survival (DFS). DFS did not differ significantly in patients with small NF-PNETs who did and did not undergo lymphadenectomy (p = 0.886).

Conclusions: Assessment of long-term oncologic outcomes suggests that surgical resection may cure small NF-PNETs. Minimally invasive surgery and organ-preserving surgery are acceptable treatment options for select patients with small NF-PNETs. The effect on survival outcomes of lymph node dissection for small NF-PNETs remains unclear.
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http://dx.doi.org/10.1111/ans.17055DOI Listing
July 2021

The impact of preoperative EUS-FNA for distal resectable pancreatic cancer: Is it really effective enough to take risks?

Surg Endosc 2021 Jul 12. Epub 2021 Jul 12.

Division of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea.

Background And Aims: Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is frequently used for the preoperative histologic diagnosis of pancreatic cancer. However, debate continues regarding the clinical merits of preoperative EUS-FNA for the management of resectable pancreatic cancer. We aimed to evaluate the benefits and safety of preoperative EUS-FNA for resectable distal pancreatic cancer.

Methods: The medical records of 304 consecutive patients with suspected distal pancreatic cancer who underwent EUS-FNA were retrospectively reviewed to evaluate the clinical benefits of preoperative EUS-FNA. We also reviewed the medical records of 528 patients diagnosed with distal pancreatic cancer who underwent distal pancreatectomy with or without EUS-FNA. The recurrence rates and cancer-free survival periods of patients who did or did not undergo preoperative EUS-FNA were compared.

Results: The diagnostic accuracy of preoperative EUS-FNA was high (sensitivity, 87.5%; specificity, 100%; positive predictive value 100%; accuracy, 90.7%; negative predictive value, 73.8%). Among patients, 26.7% (79/304) avoided surgery based on the preoperative EUS-FNA findings. Of the 528 patients who underwent distal pancreatectomy, 193 patients received EUS-FNA and 335 did not. During follow-up (median 21.7 months), the recurrence rate was similar in the two groups (EUS-FNA, 72.7%; non-EUS-FNA, 75%; P = 0.58). The median cancer-free survival was also similar (P = 0.58); however, gastric wall recurrence was only encountered in the patients with EUS-FNA (n = 2).

Conclusion: Preoperative EUS-FNA is not associated with increased risks of cancer-specific or overall survival. However, clinicians must consider the potential risks of needle tract seeding, and care should be taken when selecting patients.
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http://dx.doi.org/10.1007/s00464-021-08627-3DOI Listing
July 2021

Transcriptomic Profiling Identifies an Exosomal microRNA Signature for Predicting Recurrence Following Surgery in Patients with Pancreatic Ductal Adenocarcinoma.

Ann Surg 2021 Jun 16. Epub 2021 Jun 16.

Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope Comprehensive Cancer Center, Duarte, CA, USA Department of Surgery, Nara Medical University, Nara, Japan Center for Gastrointestinal Research, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA Department of Biological Chemistry, University of California, Irvine, CA, USA Department of Convergence Medicine and Division of Hepato-Biliary and Pancreatic Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Institute for Life Sciences, AMIST, Asan Medical Center, Seoul, Korea Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan Department of Surgery and Science, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan Division of Hepato-Biliary Pancreatic Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea Pancreatic Cancer Program, Department of Surgery, The Medical College of Wisconsin, Milwaukee, WI, USA Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea Translational Genomics Research Institute, Phoenix, AZ, USA Division of Hepato-Biliary and Pancreatic Surgery, Department of Surgery, University of Ulsan College of Medicine, Asan Biomedical Engineering Research Center, AMIST, Asan Medical Center, Seoul, Korea.

Objective: We performed genome-wide expression profiling to develop an exosomal miRNA panel for predicting recurrence following surgery in patients with PDAC.

Summary Background Data: Pre-treatment risk stratification is essential for offering individualized treatments to patients with pancreatic ductal adenocarcinoma (PDAC), but predicting recurrence following surgery remains clinically challenging.

Methods: We analyzed 210 plasma and serum specimens from four cohorts of PDAC patients. Using a discovery cohort (n = 25), we performed genome-wide sequencing to identify candidate exosomal miRNAs (exo-miRNAs). Subsequently, we trained and validated the predictive performance of the exo-miRNAs in two clinical cohorts (training cohort: n = 82, validation cohort: n = 57) without neoadjuvant therapy (NAT), followed by a post-NAT clinical cohort (n = 46) as additional validation.

Results: We performed exo-miRNA expression profiling in plasma specimens obtained before any treatment in a discovery cohort. Subsequently we optimized and trained a 6-exo-miRNA risk-prediction model, which robustly discriminated patients with recurrence (AUC: 0.81, 95% CI: 0.70-0.89) and relapse-free survival (RFS, P < 0.01) in the training cohort. The identified exo-miRNA panel was successfully validated in an independent validation cohort (AUC: 0.78, 95% CI: 0.65-0.88, RFS: P < 0.01), where it exhibited comparable performance in the post-NAT cohort (AUC: 0.72, 95% CI: 0.57-0.85, RFS: P < 0.01) and emerged as an independent predictor for RFS (HR: 2.84, 95% CI: 1.30-6.20).

Conclusions: We identified a novel, non-invasive exosomal miRNA signature that robustly predicts recurrence following surgery in patients with PDAC; highlighting its potential clinical impact for optimized patient selection and improved individualized treatment strategies.
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http://dx.doi.org/10.1097/SLA.0000000000004993DOI Listing
June 2021

Acetazolamide-eluting biodegradable tubular stent prevents pancreaticojejunal anastomotic leakage.

J Control Release 2021 07 10;335:650-659. Epub 2021 Jun 10.

Biomedical Engineering Research Center, Asan Institute for Life Sciences, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea; Division of Hepatobiliary Pancreas Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea; Asan Medical Institute of Convergence Science and Technology (AMIST), Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea. Electronic address:

Postoperative pancreatic fistula at the early stage can lead to auto-digestion, which may delay the recovery of the pancreaticojejunal (PJ) anastomosis. The efficacy and safety of an acetazolamide-eluting biodegradable tubular stent (AZ-BTS) for the prevention of self-digestion and intra-abdominal inflammatory diseases caused by pancreatic juice leakage after PJ anastomosis in a porcine model were investigated. The AZ-BTS was successfully fabricated using a multiple dip-coating process. Then, the drug amount and release profile were analyzed. The therapeutic effects of AZ were examined in vitro using two kinds of pancreatic cancer cell lines, AsPC-1 and PANC-1. The efficacy of AZ-BTS was assessed in a porcine PJ leakage model, with animals were each assigned to a leakage group, a BTS group and an AZ-BTS group. The overall mortality rates in these three groups were 44.4%, 16.6%, and 0%, respectively. Mean α-amylase concentrations were significantly higher in the leakage and BTS groups than in the AZ-BTS group on day 2-5 (p < 0.05 each all). The luminal diameters and areas of the pancreatic duct were significantly larger in the leakage group than in the BTS and AZ-BTS groups (p < 0.05 each all). These findings indicate that AZ-BTS can significantly suppress intra-abdominal inflammatory diseases caused by pancreatic juice leakage and also prevent late stricture formation at the PJ anastomotic site in a porcine model.
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http://dx.doi.org/10.1016/j.jconrel.2021.06.010DOI Listing
July 2021

Multi-biomarker panel prediction model for diagnosis of pancreatic cancer.

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

Department of Surgery and Cancer Research Institute, College of Medicine, Seoul National University, Seoul, Korea.

Background/purpose: The current study aimed to develop a prediction model using a multi-marker panel as a diagnostic screening tool for pancreatic ductal adenocarcinoma.

Methods: Multi-center cohort of 1991 blood samples were collected from January 2011 to September 2019, of which 609 were normal, 145 were other cancer (colorectal, thyroid, and breast cancer), 314 were pancreatic benign disease, and 923 were pancreatic ductal adenocarcinoma. The automated multi-biomarker Enzyme-Linked Immunosorbent Assay kit was developed using three potential biomarkers: LRG1, TTR, and CA 19-9. Using a logistic regression model on a training data set, the predicted values for pancreatic ductal adenocarcinoma were obtained, and the result was classification into one of the three risk groups: low, intermediate, and high. The five covariates used to create the model were sex, age, and three biomarkers.

Results: Participants were categorized into four groups as normal (n = 609), other cancer (n = 145), pancreatic benign disease (n = 314), and pancreatic ductal adenocarcinoma (n = 923). The normal, other cancer, and pancreatic benign disease groups were clubbed into the non-pancreatic ductal adenocarcinoma group (n = 1068). The positive and negative predictive value, sensitivity, and specificity were 94.12, 90.40, 93.81, and 90.86, respectively.

Conclusions: This study demonstrates a significant diagnostic performance of the multi-marker panel in distinguishing pancreatic ductal adenocarcinoma from normal and benign pancreatic disease states, as well as patients with other cancers.
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http://dx.doi.org/10.1002/jhbp.986DOI Listing
May 2021

Minimally Invasive Versus Open Pancreatectomy for Right-Sided and Left-Sided G1/G2 Nonfunctioning Pancreatic Neuroendocrine Tumors: A Multicenter Matched Analysis with an Inverse Probability of Treatment-Weighting Method.

Ann Surg Oncol 2021 May 9. Epub 2021 May 9.

Department of Surgery, Seoul National University Bundang Hospital, Seongnam-si, Gyeonggi-do, Korea.

Background: Limited evidence exists for the safety and oncologic efficacy of minimally invasive surgery (MIS) for nonfunctioning pancreatic neuroendocrine tumors (NF-PNETs) according to tumor location. This study aimed to compare the surgical outcomes of MIS and open surgery (OS) for right- or left-sided NF-PNETs.

Methods: The study collected data on patients who underwent surgical resection (pancreatoduodenectomy, distal/total/central pancreatectomy, duodenum-preserving pancreas head resection, or enucleation) of a localized NF-PNET between January 2000 and July 2017 at 14 institutions. The inverse probability of treatment-weighting method with propensity scores was used for analysis.

Results: The study enrolled 859 patients: 478 OS and 381 MIS patients. A matched analysis by tumor location showed no differences in resection margin, intraoperative blood loss, or complications between MIS and OS. However, MIS was associated with a longer operation time for right-sided tumors (393.3 vs 316.7 min; P < 0.001) and a shorter postoperative hospital stay for left-sided tumors (8.9 vs 12.9 days; P < 0.01). The MIS group was associated with significantly higher survival rates than the OS group for right- and left-sided tumors, but survival did not differ for the patients divided by tumor grade and location. Multivariable analysis showed that MIS did not affect survival for any tumor location.

Conclusion: The short-term outcomes offered by MIS were comparable with those of OS except for a longer operation time for right-sided NF-PNETs. The oncologic outcomes were not compromised by MIS regardless of tumor location or grade. These findings suggest that MIS can be performed safely for selected patients with localized NF-PNETs.
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http://dx.doi.org/10.1245/s10434-021-10092-0DOI Listing
May 2021

Development, validation, and comparison of a nomogram based on radiologic findings for predicting malignancy in intraductal papillary mucinous neoplasms of the pancreas: An international multicenter study.

J Hepatobiliary Pancreat Sci 2021 Apr 2. Epub 2021 Apr 2.

Department of Surgery, Sungkyunkwan University School of Medicine, Seoul, South Korea.

Background: Although we previously proposed a nomogram to predict malignancy in intraductal papillary mucinous neoplasms (IPMN) and validated it in an external cohort, its application is challenging without data on tumor markers. Moreover, existing nomograms have not been compared. This study aimed to develop a nomogram based on radiologic findings and to compare its performance with previously proposed American and Korean/Japanese nomograms.

Methods: We recruited 3708 patients who underwent surgical resection at 31 tertiary institutions in eight countries, and patients with main pancreatic duct >10 mm were excluded. To construct the nomogram, 2606 patients were randomly allocated 1:1 into training and internal validation sets, and area under the receiver operating characteristics curve (AUC) was calculated using 10-fold cross validation by exhaustive search. This nomogram was then validated and compared to the American and Korean/Japanese nomograms using 1102 patients.

Results: Among the 2606 patients, 90 had main-duct type, 900 had branch-duct type, and 1616 had mixed-type IPMN. Pathologic results revealed 1628 low-grade dysplasia, 476 high-grade dysplasia, and 502 invasive carcinoma. Location, cyst size, duct dilatation, and mural nodule were selected to construct the nomogram. AUC of this nomogram was higher than the American nomogram (0.691 vs 0.664, P = .014) and comparable with the Korean/Japanese nomogram (0.659 vs 0.653, P = .255).

Conclusions: A novel nomogram based on radiologic findings of IPMN is competitive for predicting risk of malignancy. This nomogram would be clinically helpful in circumstances where tumor markers are not available. The nomogram is freely available at http://statgen.snu.ac.kr/software/nomogramIPMN.
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http://dx.doi.org/10.1002/jhbp.962DOI Listing
April 2021

Prognostic Impact of Perioperative CA19-9 Levels in Patients with Resected Perihilar Cholangiocarcinoma.

J Clin Med 2021 Mar 24;10(7). Epub 2021 Mar 24.

Department of Hepatobiliary and Pancreatic Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea.

We aimed to examine the predictive value of changes in perioperative carbohydrate antigen (CA) 19-9 levels for patients operated for perihilar cholangiocarcinoma (pCCA). A total of 322 patients who underwent curative resection for pCCA were divided into three groups: normal preoperative CA19-9 (CA19-9 ≤ 37 U/mL), normalization (preoperative CA19-9 > 37 U/mL, postoperative CA19-9 ≤ 37 U/mL), and non-normalization (pre- and postoperative CA19-9 > 37 U/mL) groups. The association of clinicopathological factors with overall survival (OS) was investigated. The non-normalization group ( = 82) demonstrated significantly worse OS than the normal CA19-9 ( = 114) and normalization ( = 126) groups (5-year OS, 16.9%, 29.4%, and 34.4%, respectively; both ≤ 0.001). The cutoff points of 300 U/mL for preoperative ( = 0.001) and 37 U/mL for postoperative ( < 0.001) CA19-9 levels showed the strongest prognostic values. In the non-normalization group, patients who underwent R1 resection displayed significantly worse OS than those who underwent R0 resection (median OS, 10.2 vs. 15.7 months; = 0.016). Multivariate analysis revealed that lymph node metastasis (hazard ratio (HR), 2.07; < 0.001), postoperative CA19-9 > 37 U/mL (HR, 1.94; < 0.001), transfusion (HR, 1.74; = 0.002), and T stage (T3,4) (HR, 1.67; = 0.006) were related to worse OS. Persistent high CA19-9 level after resection of pCCA and R1 resection, especially in the non-normalization group, was associated with poor OS. A high postoperative CA19-9 level was an independent prognostic factor in resected pCCA.
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http://dx.doi.org/10.3390/jcm10071345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036534PMC
March 2021

Lack of Association between Postoperative Pancreatitis and Other Postoperative Complications Following Pancreaticoduodenectomy.

J Clin Med 2021 Mar 11;10(6). Epub 2021 Mar 11.

Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea.

Background: Prediction of post-pancreaticoduodenectomy (PD) morbidity is difficult, especially in the early postoperative period when CT (Computed Tomography) scans are not available. Elevated serum amylase and lipase in postoperative day 0 or 1 may be used to define postoperative acute pancreatitis (POAP), but the existing literature does not agree on whether POAP is significantly associated with postoperative pancreatic fistula (POPF).

Methods: We analyzed the data obtained from a previously published randomized controlled trial. POAP was defined as elevations in serum amylase above 110 U/L on postoperative day 0 or 1. Clinically relevant POAP (CR-POAP) was defined as elevations in C-reactive protein level (CRP) on postoperative day 2 in those with POAP. Postoperative complications including severe complications (Clavien-Dindo ≥ IIIa), POPF, and clinically relevant POPF (CR-POPF) were analyzed.

Results: In 246 patients, POAP did not show significant associations with total postoperative complications (odds ratio (OR) 0.697; 95% CI, 0.360-1.313; = 0.271), severe complications (OR 0.647; 95% CI, 0.258-1.747; = 0.367), and CR-POPF (OR 0.998; 95% CI, 0.310-3.886; = 0.998) in multivariable analysis.

Conclusions: In patients undergoing PD, POAP was not significantly associated with postoperative complications including POPF. Caution should be taken when using POAP as a predictor of POPF.
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http://dx.doi.org/10.3390/jcm10061179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001526PMC
March 2021

Diagnostic model for pancreatic cancer using a multi-biomarker panel.

Ann Surg Treat Res 2021 Mar 26;100(3):144-153. Epub 2021 Feb 26.

Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.

Purpose: Diagnostic biomarkers of pancreatic ductal adenocarcinoma (PDAC) have been used for early detection to reduce its dismal survival rate. However, clinically feasible biomarkers are still rare. Therefore, in this study, we developed an automated multi-marker enzyme-linked immunosorbent assay (ELISA) kit using 3 biomarkers (leucine-rich alpha-2-glycoprotein [LRG1], transthyretin [TTR], and CA 19-9) that were previously discovered and proposed a diagnostic model for PDAC based on this kit for clinical usage.

Methods: Individual LRG1, TTR, and CA 19-9 panels were combined into a single automated ELISA panel and tested on 728 plasma samples, including PDAC (n = 381) and normal samples (n = 347). The consistency between individual panels of 3 biomarkers and the automated multi-panel ELISA kit were accessed by correlation. The diagnostic model was developed using logistic regression according to the automated ELISA kit to predict the risk of pancreatic cancer (high-, intermediate-, and low-risk groups).

Results: The Pearson correlation coefficient of predicted values between the triple-marker automated ELISA panel and the former individual ELISA was 0.865. The proposed model provided reliable prediction results with a positive predictive value of 92.05%, negative predictive value of 90.69%, specificity of 90.69%, and sensitivity of 92.05%, which all simultaneously exceed 90% cutoff value.

Conclusion: This diagnostic model based on the triple ELISA kit showed better diagnostic performance than previous markers for PDAC. In the future, it needs external validation to be used in the clinic.
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http://dx.doi.org/10.4174/astr.2021.100.3.144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943279PMC
March 2021

Pancreatic cancer induces muscle wasting by promoting the release of pancreatic adenocarcinoma upregulated factor.

Exp Mol Med 2021 Mar 17;53(3):432-445. Epub 2021 Mar 17.

Department of Health Sciences, The Graduate School of Dong-A University, Busan, 49315, Republic of Korea.

Cancer cachexia is a highly debilitating condition characterized by weight loss and muscle wasting that contributes significantly to the morbidity and mortality of pancreatic cancer. The factors that induce cachexia in pancreatic cancer are largely unknown. We previously showed that pancreatic adenocarcinoma upregulated factor (PAUF) secreted by pancreatic cancer cells is responsible for tumor growth and metastasis. Here, we analyzed the relation between pancreatic cancer-derived PAUF and cancer cachexia in mice and its clinical significance. Body weight loss and muscle weight loss were significantly higher in mice with Panc-1/PAUF tumors than in those with Panc-1/Mock tumors. Direct administration of rPAUF to muscle recapitulated tumor-induced atrophy, and a PAUF-neutralizing antibody abrogated tumor-induced muscle wasting in Panc-1/PAUF tumor-bearing mice. C2C12 myotubes treated with rPAUF exhibited rapid inactivation of Akt-Foxo3a signaling, resulting in Atrogin1/MAFbx upregulation, myosin heavy chain loss, and muscle atrophy. The neutrophil-to-lymphocyte ratio and body weight loss were significantly higher in pancreatic cancer patients with high PAUF expression than in those with low PAUF expression. Analysis of different pancreatic cancer datasets showed that PAUF expression was significantly higher in the pancreatic cancer group than in the nontumor group. Analysis of The Cancer Genome Atlas data found associations between high PAUF expression or a high DNA copy number and poor overall survival. Our data identified tumor-secreted circulating PAUF as a key factor of cachexia, causing muscle wasting in mice. Neutralizing PAUF may be a useful therapeutic strategy for the treatment of pancreatic cancer-induced cachexia.
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http://dx.doi.org/10.1038/s12276-021-00582-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080719PMC
March 2021

Tumour-derived Dilp8/INSL3 induces cancer anorexia by regulating feeding neuropeptides via Lgr3/8 in the brain.

Nat Cell Biol 2021 02 8;23(2):172-183. Epub 2021 Feb 8.

Metabolism and Neurophysiology Research Group, Disease Target Structure Research Center, KRIBB, Daejeon, Korea.

In patients with advanced-stage cancer, cancer-associated anorexia affects treatment success and patient survival. However, the underlying mechanism is poorly understood. Here, we show that Dilp8, a Drosophila homologue of mammalian insulin-like 3 peptide (INSL3), is secreted from tumour tissues and induces anorexia through the Lgr3 receptor in the brain. Activated Dilp8-Lgr3 signalling upregulated anorexigenic nucleobinding 1 (NUCB1) and downregulated orexigenic short neuropeptide F (sNPF) and NPF expression in the brain. In the cancer condition, the protein expression of Lgr3 and NUCB1 was significantly upregulated in neurons expressing sNPF and NPF. INSL3 levels were increased in tumour-implanted mice and INSL3-treated mouse hypothalamic cells showed Nucb2 upregulation and Npy downregulation. Food consumption was significantly reduced in intracerebrospinal INSL3-injected mice. In patients with pancreatic cancer, higher serum INSL3 levels increased anorexia. These results indicate that tumour-derived Dilp8/INSL3 induces cancer anorexia by regulating feeding hormones through the Lgr3/Lgr8 receptor in Drosophila and mammals.
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http://dx.doi.org/10.1038/s41556-020-00628-zDOI Listing
February 2021

Effectiveness of early endoscopic ultrasound-guided drainage for postoperative fluid collection.

Surg Endosc 2021 Jan 28. Epub 2021 Jan 28.

Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, Korea.

Background: Postoperative abdominal fluid collections (PAFCs) are a potentially fatal complication of pancreatobiliary surgery. Endoscopic ultrasound (EUS)-guided drainage has recently been shown to be effective in treating PAFCs of more than 4 weeks old. Little is currently known, however, regarding the EUS-guided drainage of PAFCs of less than 4 weeks. This study assessed the efficacy and safety of the early drainage (< 4 weeks) of PAFCs via EUS guidance.

Methods: The data of patients who had undergone EUS-guided PAFC drainage between July 2008 and January 2018 were retrospectively analyzed. Data of EUS-guided PAFC drainage were obtained from prospectively collected EUS database of our institute and reviewed of patients' clinical parameters based on electrical medical record.

Results: A total of 48 patients who had undergone EUS-guided PAFC drainage within 4 weeks of pancreatobiliary surgery were enrolled. The indications of procedure included abdominal pain (n = 27), fever (n = 18), leukocytosis (n = 2), and increased size of PAFC during external tube drainage (n = 1). Technical success was achieved in all cases, and the clinical success rate was 95.8% (46/48). Four patients underwent secondary procedures. The median period from surgery to EUS-guide drainage was 14 days (Interquartile range [IQR] 10-16), and median time to resolution was 23.5 days (IQR 8.5-33.8). Adverse events occurred in two cases that were developed intracystic bleeding and were successfully resolved by arterial coil embolization.

Conclusions: Early EUS-guided drainage is a technically feasible, effective, and safe method in patients who have developing PAFCs within 4 weeks of pancreatobiliary surgery.
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http://dx.doi.org/10.1007/s00464-020-08247-3DOI Listing
January 2021

Circulating tumour cells as an indicator of early and systemic recurrence after surgical resection in pancreatic ductal adenocarcinoma.

Sci Rep 2021 01 18;11(1):1644. Epub 2021 Jan 18.

Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Asan Medical Center, AMIST, University of Ulsan College of Medicine, Seoul, Republic of Korea.

Early recurrence in pancreatic ductal adenocarcinoma (PDAC) is a decisive factor in determining a patient's prognosis. We determined in our current study whether circulating tumour cells (CTCs) exist in the blood of PDAC patients and can be used as a predictor of recurrence patterns (i.e. time and site) after surgical resection. Between December 2017 and November 2018, the mononuclear cell layer was obtained from the peripheral blood of 36 patients diagnosed with PDAC. CTCs were then isolated using the CD-PRIME™ platform and detected via immunostaining. The patient records were analyzed to correlate these data with survival and recurrence patterns. Twelve patients were CTC-positive (33.3%) and showed a significantly frequent rate of systemic recurrence (distant metastases and peritoneal dissemination) (p = 0.025). On multi-variable logistic regression analysis, CTC positivity was an independent risk factor for early recurrence (p = 0.027) and for systemic recurrence (p = 0.033). In summary, the presence or absence of CTC in the blood of the patients with PDAC could help predict the recurrence pattern after surgery. PDAC patients with CTC positivity at tumour diagnosis should therefore undergo a comprehensive strategy for systemic therapy and active monitoring to detect possible early recurrence.
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http://dx.doi.org/10.1038/s41598-020-80383-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814057PMC
January 2021

Improvement of the therapeutic capacity of insulin-producing cells trans-differentiated from human liver cells using engineered cell sheet.

Stem Cell Res Ther 2021 01 6;12(1). Epub 2021 Jan 6.

Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

Background: Although pancreatic islet transplantation therapy is ideal for diabetes patients, several hurdles have prevented it from becoming a standard treatment, including donor shortage and low engraftment efficacy. In this study, we prepared insulin-producing cells trans-differentiated from adult human liver cells as a new islet source. Also, cell sheet formation could improve differentiation efficiency and graft survival.

Methods: Liver cells were expanded in vitro and trans-differentiated to IPCs using adenovirus vectors carrying human genes for PDX1, NEUROD1, and MAFA. IPCs were seeded on temperature-responsive culture dishes to form cell sheets. Differentiation efficiency was confirmed by ß cell-specific gene expression, insulin production, and immunohistochemistry. IPC suspension was injected by portal vein (PV), and IPC sheet was transplanted on the liver surface of the diabetic nude mouse. The therapeutic effect of IPC sheet was evaluated by comparing blood glucose control, weight gain, histological evaluation, and hepatotoxicity with IPC injection group. Also, cell biodistribution was assessed by in vivo/ex vivo fluorescence image tagging.

Results: Insulin gene expression and protein production were significantly increased on IPC sheets compared with those in IPCs cultured on conventional culture dishes. Transplanted IPC sheets displayed significantly higher engraftment efficiency and fewer transplanted cells in other organs than injected IPCs, and also lower liver toxicity, improved blood glucose levels, and weight gain. Immunohistochemical analyses of liver tissue revealed positive staining for PDX1 and insulin at 1, 2, and 4 weeks after IPC transplantation.

Conclusions: In conclusion, cell sheet formation enhanced the differentiation function and maturation of IPCs in vitro. Additionally, parameters for clinical application such as distribution, therapeutic efficacy, and toxicity were favorable. The cell sheet technique may be used with IPCs derived from various cell sources in clinical applications.
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http://dx.doi.org/10.1186/s13287-020-02080-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786992PMC
January 2021

Spheroid Fabrication Using Concave Microwells Enhances the Differentiation Efficacy and Function of Insulin-Producing Cells via Cytoskeletal Changes.

Cells 2020 11 27;9(12). Epub 2020 Nov 27.

Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea.

Pancreatic islet transplantation is the fundamental treatment for insulin-dependent diabetes; however, donor shortage is a major hurdle in its use as a standard treatment. Accordingly, differentiated insulin-producing cells (DIPCs) are being developed as a new islet source. Differentiation efficiency could be enhanced if the spheroid structure of the natural islets could be recapitulated. Here, we fabricated DIPC spheroids using concave microwells, which enabled large-scale production of spheroids of the desired size. We prepared DIPCs from human liver cells by trans-differentiation using transcription factor gene transduction. Islet-related gene expression and insulin secretion levels were higher in spheroids compared to those in single-cell DIPCs, whereas actin-myosin interactions significantly decreased. We verified actin-myosin-dependent insulin expression in single-cell DIPCs by using actin-myosin interaction inhibitors. Upon transplanting cells into the kidney capsule of diabetic mouse, blood glucose levels decreased to 200 mg/dL in spheroid-transplanted mice but not in single cell-transplanted mice. Spheroid-transplanted mice showed high engraftment efficiency in in vivo fluorescence imaging. These results demonstrated that spheroids fabricated using concave microwells enhanced the engraftment and functions of DIPCs via actin-myosin-mediated cytoskeletal changes. Our strategy potentially extends the clinical application of DIPCs for improved differentiation, glycemic control, and transplantation efficiency of islets.
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http://dx.doi.org/10.3390/cells9122551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768489PMC
November 2020

Risk prediction for malignant intraductal papillary mucinous neoplasm of the pancreas: logistic regression versus machine learning.

Sci Rep 2020 11 18;10(1):20140. Epub 2020 Nov 18.

Pancreatic Surgery Unit, Division of Surgery, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institute At Center for Digestive Diseases, Karolinska University Hospital, Stockholm, Sweden.

Most models for predicting malignant pancreatic intraductal papillary mucinous neoplasms were developed based on logistic regression (LR) analysis. Our study aimed to develop risk prediction models using machine learning (ML) and LR techniques and compare their performances. This was a multinational, multi-institutional, retrospective study. Clinical variables including age, sex, main duct diameter, cyst size, mural nodule, and tumour location were factors considered for model development (MD). After the division into a MD set and a test set (2:1), the best ML and LR models were developed by training with the MD set using a tenfold cross validation. The test area under the receiver operating curves (AUCs) of the two models were calculated using an independent test set. A total of 3,708 patients were included. The stacked ensemble algorithm in the ML model and variable combinations containing all variables in the LR model were the most chosen during 200 repetitions. After 200 repetitions, the mean AUCs of the ML and LR models were comparable (0.725 vs. 0.725). The performances of the ML and LR models were comparable. The LR model was more practical than ML counterpart, because of its convenience in clinical use and simple interpretability.
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http://dx.doi.org/10.1038/s41598-020-76974-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676251PMC
November 2020

Putative positive role of inflammatory genes in fat deposition supported by altered gene expression in purified human adipocytes and preadipocytes from lean and obese adipose tissues.

J Transl Med 2020 11 12;18(1):433. Epub 2020 Nov 12.

Division of Biomedical Convergence, College of Biomedical Science, Institute of Bioscience & Biotechnology, Kangwon National University, Chuncheon, Gangwon-do, 24341, Korea.

Background: Obesity is a chronic low-grade inflammatory disease that is generally characterized by enhanced inflammation in obese adipose tissue (AT). Here, we investigated alterations in gene expression between lean and obese conditions using mRNA-Seq data derived from human purified adipocytes (ACs) and preadipocytes (preACs).

Results: Total mRNA-seq data were generated with 27 AC and 21 preAC samples purified from human visceral AT collected during resection surgery in cancer patients, where the samples were classified into lean and obese categories by BMI > 25 kg/m. We defined four classes of differentially expressed genes (DEGs) by comparing gene expression between (1) lean and obese ACs, (2) lean and obese preACs, (3) lean ACs and lean preACs, and 4) obese ACs and obese preACs. Based on an analysis of comparison 1, numerous canonical obesity-related genes, particularly inflammatory genes including IL-6, TNF-α and IL-1β, i.e., the genes that are expected to be upregulated in obesity conditions, were found to be expressed at significantly lower levels in obese ACs than in lean ACs. In contrast, some inflammatory genes were found to be expressed at higher levels in obese preACs than lean preACs in the analysis of comparison 2. The analysis of comparisons 3 and 4 showed that inflammatory gene classes were expressed at higher levels in differentiated ACs than undifferentiated preACs under both lean and obese conditions; however, the degree of upregulation was significantly greater for lean than for obese conditions. We validated our observations using previously published microarray transcriptome data deposited in the GEO database (GSE80654).

Conclusions: Taken together, our analyses suggest that inflammatory genes are expressed at lower levels in obese ACs than in lean ACs because lean adipogenesis involves even greater enhancement of inflammatory responses than does obese adipogenesis.
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http://dx.doi.org/10.1186/s12967-020-02611-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664034PMC
November 2020

Adjuvant Chemotherapy for Resected Ampulla of Vater Carcinoma: Retrospective Analysis of 646 Patients.

Cancer Res Treat 2021 Apr 9;53(2):424-435. Epub 2020 Nov 9.

Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Purpose: This study evaluated the efficacy of adjuvant chemotherapy (AC) in patients with resected ampulla of Vater (AoV) carcinoma.

Materials And Methods: Data from 646 patients who underwent surgical resection at Asan Medical Center between 2000 and 2017 were retrospectively reviewed.

Results: The median age of the patients was 62 years, and 54.2% were male. Patients were classified into AC group (n=165, 25.5%) and no AC group (n=481, 74.5%). With a median follow-up duration of 88 months, in patients with stage I, II, III, median recurrence-free survival (RFS) was not reached, 44 months, and 15 months, respectively, and the median overall survival (OS) were not reached, 88 months and 35 months, respectively. Despite no statistical significance, RFS and OS were better in stage II patients with AC than in those without AC (median RFS, 151 months vs. 38 months; p=0.156 and median OS, 153 months vs. 74 months; p=0.299). In multivariate analysis for RFS and OS, TNM stage, R1 resection status, presence of lymphovascular invasion, and perineural invasion remained significant factors, whereas AC (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.54 to 1.00; p=0.052) was marginally related with RFS. After propensity score matching in only stage II/III patients, RFS and OS with AC were numerically longer than those without AC (HR, 0.80; 95% CI, 0.60 to 1.06; p=0.116 and HR, 0.77; 95% CI, 0.56 to 1.06; p=0.111).

Conclusion: AC with fluoropyrimidine did not improve survival of patients with resected AoV carcinoma. However, multivariate analysis with prognostic factors showed a marginally significant survival benefit with AC.
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http://dx.doi.org/10.4143/crt.2020.953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053873PMC
April 2021
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