Publications by authors named "In Kyu Park"

300 Publications

Clinical Characteristics According to Age and Duration of Symptoms to Be Considered for Rapid Diagnosis of Pediatric Intussusception.

Front Pediatr 2021 31;9:651297. Epub 2021 Mar 31.

Department of Surgery, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, South Korea.

The purpose of this study was to evaluate whether clinical findings in children with ileocolic intussusception differ based on age and duration of symptoms and to assess the clinical characteristics of diagnosed and undiagnosed patients to determine which symptoms make diagnosis more difficult. We reviewed 536 medical records of <15-year-old children diagnosed with ileocolic intussusception between 2008 and 2019. We divided the children into three categories according to age (<1 year, 1-2 years, and ≥2 years). The children were also divided into two groups based on whether symptoms lasted for more or <6 h. Diagnosed and undiagnosed children were assessed separately during for the initial evaluation. Following analysis of the three age groups, bloody stool, post-enema bloody stool, diarrhea, vomiting, poor oral intake, and lethargy were more frequent in children aged <1 year. In children aged ≥2 years, non-specific abdominal pain was more frequent and the undiagnosed rate was higher. Following analysis of the duration of symptoms, paroxysmal pain was significantly more frequent in the early group (<6 h), and bloody stool and fever were significantly more frequent in the late group (≥6 h). Nonspecific abdominal pain was more frequent and the door-to-diagnosis time was significantly longer in the undiagnosed group than in the diagnosed group. Clinical findings of ileocolic intussusception vary depending on the age and duration of symptoms. Younger children with paroxysmal pain, vomiting, bloody stool, poor oral intake, or lethargy should be suspected of having intussusception. In older children, non-specific abdominal pain without bloody stool may be a symptom of intussusception. Glycerin enema is helpful in diagnosing intussusception in children with no typical symptoms.
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http://dx.doi.org/10.3389/fped.2021.651297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044523PMC
March 2021

Glycol chitosan-based tacrolimus-loaded nanomicelle therapy ameliorates lupus nephritis.

J Nanobiotechnology 2021 Apr 17;19(1):109. Epub 2021 Apr 17.

Department of Internal Medicine, Chonnam National University Medical School, 160, Baekseo-ro, Dong-gu, Gwangju, 61496, Republic of Korea.

Background: Recently, we developed hydrophobically modified glycol chitosan (HGC) nanomicelles loaded with tacrolimus (TAC) (HGC-TAC) for the targeted renal delivery of TAC. Herein, we determined whether the administration of the HGC-TAC nanomicelles decreases kidney injury in a model of lupus nephritis. Lupus-prone female MRL/lpr mice were randomly assigned into three groups that received intravenous administration of either vehicle control, an equivalent dose of TAC, or HGC-TAC (0.5 mg/kg TAC) weekly for 8 weeks. Age-matched MRL/MpJ mice without Fas mutation were also treated with HGC vehicle and used as healthy controls.

Results: Weekly intravenous treatment with HGC-TAC significantly reduced genetically attributable lupus activity in lupus nephritis-positive mice. In addition, HGC-TAC treatment mitigated renal dysfunction, proteinuria, and histological injury, including glomerular proliferative lesions and tubulointerstitial infiltration. Furthermore, HGC-TAC treatment reduced renal inflammation and inflammatory gene expression and ameliorated increased apoptosis and glomerular fibrosis. Moreover, HGC-TAC administration regulated renal injury via the TGF-β1/MAPK/NF-κB signaling pathway. These renoprotective effects of HGC-TAC treatment were more potent in lupus mice compared to those of TAC treatment alone.

Conclusion: Our study indicates that weekly treatment with the HGC-TAC nanomicelles reduces kidney injury resulting from lupus nephritis by preventing inflammation, fibrosis, and apoptosis. This advantage of a new therapeutic modality using kidney-targeted HGC-TAC nanocarriers may improve drug adherence and provide treatment efficacy in lupus nephritis mice.
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http://dx.doi.org/10.1186/s12951-021-00857-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052756PMC
April 2021

Kidney-accumulating olmesartan-loaded nanomicelles ameliorate the organ damage in a murine model of Alport syndrome.

Int J Pharm 2021 May 19;600:120497. Epub 2021 Mar 19.

Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea. Electronic address:

ACE inhibitors or angiotensin II receptor blockers (ACEi/ARBs) have been a cornerstone of the management in kidney disease, but their use is often limited by undesired systemic effects, such as symptomatic hypotension. To minimize the extra-renal effects of ACEi/ARBs, we formulated hydrophobically modified glycol chitosan (HGC) nanomicelles releasing olmesartan (HGC-Olm) that specifically accumulated in the kidney, and investigated whether kidney-specific delivery of olmesartan by HGC nanomicelles could ameliorate organ damage in Col4a3 mouse, a murine model of progressive chronic kidney disease mimicking human Alport syndrome. Ex vivo tracing demonstrated that intravenously injected HGC-Olm nanomicelles were specifically delivered to the kidney, with sustained release of olmesartan for more than 48 h. Contrary to the conventional delivery of olmesartan via oral route, injection of HGC-Olm nanomicelles did not alter blood pressure in Col4a3 mice. Immunohistochemistry revealed that HGC nanomicelles were diffusely distributed from the cortex and glomeruli to the outer medulla, sparing the inner medulla. Phenotypic analysis showed that the attenuation of kidney fibrosis in the kidney of Col4a3 mice by HGC-Olm nanomicelles was comparable to that noted with conventionally delivered olmesartan. Therefore, our results suggest that HGC-Olm nanomicelles could be a safe and effective alternative drug delivery system for kidney diseases.
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http://dx.doi.org/10.1016/j.ijpharm.2021.120497DOI Listing
May 2021

Stereotactic ablative radiotherapy versus surgery in older patients with stage I lung cancer.

Eur J Cardiothorac Surg 2021 Feb 28. Epub 2021 Feb 28.

Department of Thoracic and Cardiovascular Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.

Objectives: Surgical resection is the best option for the treatment of early-stage lung cancer. However, older patients are less likely to receive curative treatment. Therefore, we compared long-term survival rates between surgical resection and stereotactic ablative radiotherapy (SABR) for the treatment of early-stage lung cancer in older patients.

Methods: From 2013 to 2016, 272 patients aged ≥75 years with clinical stage I lung cancer underwent surgical resection (n = 191) or SABR (n = 81). A propensity score-matched analysis was performed. Overall survival, cumulative incidence of cancer-related death and recurrence were compared between the 2 groups.

Results: In the matched cohort, 48 well-balanced pairs were extracted. An overall survival benefit was associated with surgery (surgery vs SABR = 65.9% vs 40.3%; P = 0.034); however, there was no significant difference in the cumulative incidence of cancer-related death (P = 0.089) or recurrence (P = 0.111) between the 2 groups. Systemic dissemination was the dominant pattern of progression in both groups. The 3-year cumulative incidence of regional recurrence was significantly higher in the SABR group compared to the surgery group (surgery vs SABR = 0% vs 11.4%, P = 0.046).

Conclusions: Surgical resection with mediastinal lymph node dissection provides better long-term survival compared to SABR in older patients with stage I lung cancer. Surgery should be considered for older patients aged ≥75 years who are appropriate candidates for surgery. SABR remains an alternative treatment with comparable cancer-related death and recurrence for patients unsuitable for surgery.
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http://dx.doi.org/10.1093/ejcts/ezab045DOI Listing
February 2021

Development and Validation of Machine Learning-based Model for the Prediction of Malignancy in Multiple Pulmonary Nodules: Analysis from Multicentric Cohorts.

Clin Cancer Res 2021 Apr 24;27(8):2255-2265. Epub 2021 Feb 24.

Department of Thoracic Surgery, Peking University People's Hospital, Beijing, China.

Purpose: Nodule evaluation is challenging and critical to diagnose multiple pulmonary nodules (MPNs). We aimed to develop and validate a machine learning-based model to estimate the malignant probability of MPNs to guide decision-making.

Experimental Design: A boosted ensemble algorithm (XGBoost) was used to predict malignancy using the clinicoradiologic variables of 1,739 nodules from 520 patients with MPNs at a Chinese center. The model (PKU-M model) was trained using 10-fold cross-validation in which hyperparameters were selected and fine-tuned. The model was validated and compared with solitary pulmonary nodule (SPN) models, clinicians, and a computer-aided diagnosis (CADx) system in an independent transnational cohort and a prospective multicentric cohort.

Results: The PKU-M model showed excellent discrimination [area under the curve; AUC (95% confidence interval (95% CI)), 0.909 (0.854-0.946)] and calibration (Brier score, 0.122) in the development cohort. External validation (583 nodules) revealed that the AUC of the PKU-M model was 0.890 (0.859-0.916), higher than those of the Brock model [0.806 (0.771-0.838)], PKU model [0.780 (0.743-0.817)], Mayo model [0.739 (0.697-0.776)], and VA model [0.682 (0.640-0.722)]. Prospective comparison (200 nodules) showed that the AUC of the PKU-M model [0.871 (0.815-0.915)] was higher than that of surgeons [0.790 (0.711-0.852), 0.741 (0.662-0.804), and 0.727 (0.650-0.788)], radiologist [0.748 (0.671-0.814)], and the CADx system [0.757 (0.682-0.818)]. Furthermore, the model outperformed the clinicians with an increase of 14.3% in sensitivity and 7.8% in specificity.

Conclusions: After its development using machine learning algorithms, validation using transnational multicentric cohorts, and prospective comparison with clinicians and the CADx system, this novel prediction model for MPNs presented solid performance as a convenient reference to help decision-making.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4007DOI Listing
April 2021

External and Internal Stimuli-Responsive Metallic Nanotherapeutics for Enhanced Anticancer Therapy.

Front Mol Biosci 2020 11;7:597634. Epub 2021 Jan 11.

Department of Biomedical Sciences, Chonnam National University Medical School, Jeollanam-do, South Korea.

Therapeutic, diagnostic, and imaging approaches based on nanotechnology offer distinct advantages in cancer treatment. Various nanotherapeutics have been presented as potential alternatives to traditional anticancer therapies such as chemotherapy, radiotherapy, and surgical intervention. Notably, the advantage of nanotherapeutics is mainly attributable to their accumulation and targeting ability toward cancer cells, multiple drug-carrying abilities, combined therapies, and imaging approaches. To date, numerous nanoparticle formulations have been developed for anticancer therapy and among them, metallic nanotherapeutics reportedly demonstrate promising cancer therapeutic and diagnostic efficiencies owing to their dense surface functionalization ability, uniform size distribution, and shape-dependent optical responses, easy and cost-effective synthesis procedure, and multiple anti-cancer effects. Metallic nanotherapeutics can remodel the tumor microenvironment by changing unfavorable therapeutic conditions into therapeutically accessible ones with the help of different stimuli, including light, heat, ultrasound, an alternative magnetic field, redox, and reactive oxygen species. The combination of metallic nanotherapeutics with both external and internal stimuli can be used to trigger the on-demand release of therapeutic molecules, augmenting the therapeutic efficacies of anticancer therapies such as photothermal therapy, photodynamic therapy, magnetic hyperthermia, sonodynamic therapy, chemodynamic therapy, and immunotherapy. In this review, we have summarized the role of different metallic nanotherapeutics in anti-cancer therapy, as well as their combinational effects with multiple stimuli for enhanced anticancer therapy.
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http://dx.doi.org/10.3389/fmolb.2020.597634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831291PMC
January 2021

Pulmonary Metastasectomy in Colorectal Cancer: A Population-Based Retrospective Cohort Study Using the Korean National Health Insurance Database.

Cancer Res Treat 2021 Jan 15. Epub 2021 Jan 15.

Department of Thoracic and Cardiovascular Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.

Purpose: The study aimed to investigate the current status and prognostic factors for overall survival in patients who had undergone pulmonary metastasectomy for colorectal cancer.

Materials And Methods: The data of 2,573 patients who had undergone pulmonary metastasectomy after surgery for colorectal cancer between January 2009 and December 2014 were extracted from the Korean National Health Insurance Service claims database. Patient-, colorectal cancer-, pulmonary metastasis-, and hospital-related factors were analyzed using the Kaplan-Meier method, log-rank test, and Cox proportional hazards analysis to identify prognostic factors for overall survival after pulmonary metastasectomy.

Results: The mean age of the patients was 60.910.5 years; 66.2% and 79.1% of the participants were male and had distally located colorectal cancer, respectively. Wedge resection (71.7%) was the most frequent extent of pulmonary resection; 21.8% of the patients underwent repeated pulmonary metastasectomies; 73% of pulmonary metastasectomy cases were performed in tertiary hospitals; 53.9% of patients were treated in Seoul area; 82% of patients received chemotherapy in conjunction with pulmonary metastasectomy. The median survival duration was 51.8 months. The 3- and 5-year overall survival rates were 67.7% and 39.4%, respectively. In multivariate analysis, female sex, distally located colorectal cancer, pulmonary metastasectomy-only treatment, and high hospital volume (>10 pulmonary metastasectomy cases/year) were positive prognostic factors for survival.

Conclusion: Pulmonary metastasectomy seemed to provide long-term survival of patients with colorectal cancer. The female sex, presence of distally located colorectal cancer, and performance of pulmonary metastasectomy in high-volume centers were positive prognostic factors for survival.
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http://dx.doi.org/10.4143/crt.2020.1213DOI Listing
January 2021

Tumor Microenvironment-Regulating Immunosenescence-Independent Nanostimulant Synergizing with Near-Infrared Light Irradiation for Antitumor Immunity.

ACS Appl Mater Interfaces 2021 Feb 24;13(4):4844-4852. Epub 2021 Jan 24.

Department of Biomedical Sciences, Chonnam National University Medical School, 160 Baekseo-ro, Gwangju 58128, Republic of Korea.

The combination of photothermal therapy (PTT) and toll-like receptor (TLR)-mediated immunotherapy can elicit antitumor immunity and modulate the immunosuppressive tumor microenvironment (TME). Unlike other TLRs, TLR-5 is a promising target for immune activation, as its expression is well-maintained even during immunosenescence. Here, we developed a unique tumor microenvironment-regulating immunosenescence-independent nanostimulant consisting of TLR-5 adjuvant flagellin B (FlaB) conjugated onto the surface to an IR 780-loaded hyaluronic acid-stearylamine (HIF) micelles. These HIF micelles induced immune-mediated cell death PTT when irradiated with a near-infrared laser. In comparison with PTT alone, the combination of -generated tumor-associated antigens produced during PTT and the immune adjuvant FlaB demonstrated enhanced vaccine-like properties and modulated the TME by suppressing immune-suppressive regulatory cells (Tregs) and increasing the fraction of CD103 migratory dendritic cells, which are responsible for trafficking tumor antigens to draining lymph nodes (DLNs). This combinatorial strategy (, applying a TLR-5 adjuvant targeted to immunosenescence-independent TLR-5 and the photothermal generation of tumor-associated antigens) is a robust system for next-generation immunotherapy and could even be applied in elderly patients, thus broadening the clinical scope of immunotherapy strategies.
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http://dx.doi.org/10.1021/acsami.0c20063DOI Listing
February 2021

Current Limitations and Recent Progress in Nanomedicine for Clinically Available Photodynamic Therapy.

Biomedicines 2021 Jan 16;9(1). Epub 2021 Jan 16.

College of Pharmacy, Chosun University, Gwangju 61452, Korea.

Photodynamic therapy (PDT) using oxygen, light, and photosensitizers has been receiving great attention, because it has potential for making up for the weakness of the existing therapies such as surgery, radiation therapy, and chemotherapy. It has been mainly used to treat cancer, and clinical tests for second-generation photosensitizers with improved physicochemical properties, pharmacokinetic profiles, or singlet oxygen quantum yield have been conducted. Progress is also being made in cancer theranostics by using fluorescent signals generated by photosensitizers. In order to obtain the effective cytotoxic effects on the target cells and prevent off-target side effects, photosensitizers need to be localized to the target tissue. The use of nanocarriers combined with photosensitizers can enhance accumulation of photosensitizers in the tumor site, owing to preferential extravasation of nanoparticles into the tumor vasculature by the enhanced permeability and retention effect. Self-assembly of amphiphilic polymers provide good loading efficiency and sustained release of hydrophobic photosensitizers. In addition, prodrug nanomedicines for PDT can be activated by stimuli in the tumor site. In this review, we introduce current limitations and recent progress in nanomedicine for PDT and discuss the expected future direction of research.
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http://dx.doi.org/10.3390/biomedicines9010085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830249PMC
January 2021

Multistimuli-Responsive Polymeric Vesicles for Accelerated Drug Release in Chemo-photothermal Therapy.

ACS Biomater Sci Eng 2020 09 25;6(9):5012-5023. Epub 2020 Aug 25.

BK21 PLUS Center for Advanced Chemical Technology, Department of Polymer Science and Engineering, Pusan National University, Busan 609-735, Republic of Korea.

Multistimuli-responsive nanomedicines present great potential for cancer therapy, as they can be featured as simple, selective, and smart carriers that can release their payload on-demand. In this study, we prepared a multifunctional polymeric vesicular nanocarrier (PVN) based on robust and triple stimuli-responsive micelles that could encapsulate chemotherapeutic drugs (doxorubicin (DOX)) and photothermal agents (IR780 iodide) for combined chemo-photothermal therapy. The size of the PVNs was stable and uniform (∼100 nm), and its DOX and IR780 loading were high: 26.5 and 16.4 wt %, respectively. Further investigations suggested that the DOX/IR780 coloaded PVNs presented controlled drug release kinetics upon costimulation with specific endogenous stimuli. Upon laser irradiation, DOX/IR780 coloaded PVNs exhibited prominent photothermal cytotoxicity toward murine colon cancer (CT-26) cells. Intracellular uptake assays indicated that DOX/IR780 coloaded PVNs could be readily uptaken by CT-26 cells, resulting in the release of DOX within the cytoplasm of the cells in response to laser irradiation.
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http://dx.doi.org/10.1021/acsbiomaterials.0c00585DOI Listing
September 2020

Trends in Extracorporeal Membrane Oxygenation Application and Outcomes in Korea.

ASAIO J 2021 02;67(2):177-184

Department of Thoracic and Cardiovascular Surgery, Seoul National University Hospital and Seoul National University College of Medicine, Jongro-gu, Seoul, Korea.

The use of extracorporeal membrane oxygenation (ECMO) is increasing despite the limited evidence in survival benefit. This study aimed to analyze the changes of in-hospital mortality, medical costs, and other outcomes in ECMO therapy. We used 2004-2017 data from a nationwide healthcare administrative claims database in Korea. Overall, 14,775 ECMO procedures were performed in 14,689 patients at 112 hospitals. We found a 170-fold and a 334-fold increase in the number of ECMO procedures and related costs, respectively. For indications, the performance of ECMO for heart or lung transplantation and respiratory failure increased, whereas that for cardiovascular surgery decreased. The duration of ECMO increased from a median of 3 days (IQR, 2-5 days) in 2004 to 4 days (IQR, 2-9 days) in 2017. The overall in-hospital mortality rate was 68.6%, and this improved over time, especially for lung transplantation and respiratory failure patients. Bleeding-related complications and the transfusion amount also decreased. Hospitals with higher case volume showed better survival outcomes. The median cost per procedure and per day was 26,538 USD (IQR, 14,646-47,862 USD) and 1,560 USD (IQR, 903-2,929 USD), respectively, and increased with time. A trend toward greater resource use and better outcomes requires additional cost-effective analysis based on indications.
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http://dx.doi.org/10.1097/MAT.0000000000001331DOI Listing
February 2021

Intravitreal Injection of Liposomes Loaded with a Histone Deacetylase Inhibitor Promotes Retinal Ganglion Cell Survival in a Mouse Model of Optic Nerve Crush.

Int J Mol Sci 2020 Dec 6;21(23). Epub 2020 Dec 6.

Department of Ophthalmology, Chonnam National University Medical School and Hospital, Gwangju 61469, Korea.

Various neuroprotective agents have been studied for the treatment of retinal ganglion cell (RGC) diseases, but issues concerning the side effects of systemically administered drugs and the short retention time of intravitreally injected drugs limit their clinical applications. The current study aimed to evaluate the neuroprotective effects of intravitreally injected trichostatin A (TSA)-loaded liposomes in a mouse model of optic nerve crush (ONC) and determine whether TSA-loaded liposomes have therapeutic potential in RGC diseases. The histone deacetylase inhibitor, TSA, was incorporated into polyethylene glycolylated liposomes. C57BL/6J mice were treated with an intravitreal injection of TSA-loaded liposomes and liposomes loaded with a lipophilic fluorescent dye for tracking, immediately after ONC injury. The expression of macroglial and microglial cell markers (glial fibrillary acidic protein and ionized calcium binding adaptor molecule-1), RGC survival, and apoptosis were assessed. We found that the liposomes reached the inner retina. Their fluorescence was detected for up to 10 days after the intravitreal injection, with peak intensity at 3 days postinjection. Intravitreally administered TSA-loaded liposomes significantly decreased reactive gliosis and RGC apoptosis and increased RGC survival in a mouse model of ONC. Our results suggest that TSA-loaded liposomes may help in the treatment of various RGC diseases.
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http://dx.doi.org/10.3390/ijms21239297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7730870PMC
December 2020

The role of postoperative radiotherapy in stage II and III thymoma: a Korean multicenter database study.

J Thorac Dis 2020 Nov;12(11):6680-6689

Department of Thoracic and Cardiovascular Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.

Background: Complete resection is a standard treatment for patients with Masaoka-Koga stages II and III thymoma, however the role of postoperative radiotherapy (PORT) is controversial. We analyzed data collected from 4 Korean hospitals to determine the effectiveness of PORT in stage II and III thymoma patients.

Methods: Between January 2000 and December 2013, 1,663 patients underwent surgery for thymic tumors at the 4 hospitals. Among them, 668 patients (527 with stage II and 141 with stage III) were investigated, among whom, 443 received PORT (335 with stage II and 108 with stage III). Propensity score matching (PSM) was performed, and 404 patients (346 with stage II and 58 with stage III) were selected.

Results: Perioperative characteristics were similar in the PORT and non-PORT groups after PSM. On survival analysis of stage II patients, the PORT and non-PORT groups showed no difference in either 5-year recurrence-free survival (RFS) (96.3% 96.6%, P=0.622) or 5-year overall survival (OS) (94.6% 93.8%, P=0.839). However, among stage III patients, the PORT group showed significantly better 5-year RFS (75.7% 50.1%, P=0.040) and 5-year OS (86.5% 54.7%, P=0.001). On multivariate Cox regression analysis, PORT was a significant positive prognostic factor in terms of both RFS (P=0.005) and OS (P=0.004) in patients with stage III thymomas, but not in those with stage II disease (P=0.987 and 0.968, respectively).

Conclusions: PORT improved the RFS and OS in stage III thymoma patients, but showed no survival benefit in stage II patients.
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http://dx.doi.org/10.21037/jtd-20-1713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711424PMC
November 2020

Self-assembled heptamethine cyanine dye dimer as a novel theranostic drug delivery carrier for effective image-guided chemo-photothermal cancer therapy.

J Control Release 2021 Jan 28;329:50-62. Epub 2020 Nov 28.

Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Republic of Korea. Electronic address:

Near-infrared (NIR)-induced dye-based theranostic drug delivery carriers are used for critical image-guided chemo-photothermal cancer therapy. However, most carriers fail to deliver sufficient heat and fluorescence efficiently due to direct π-π stacking of the aromatic rings of the NIR dye and drug. In the work reported herein, we examined a self-assembled heptamethine cyanine dye dimer (CyD) with improved heat and fluorescence delivery that was developed by manipulating the unique structural and optical properties of the dimer. The H-aggregation of CyD in an aqueous solution generated a great amount of heat by transforming the energy of the excited electrons into non-radiative energy. Moreover, the disulfide bond of CyD assisted nanoparticles with a drug by minimizing the interaction between the NIR dye and drug, and also by releasing the drug in a redox environment. As a result, DOX encapsulated within CyD (CyD/DOX) showed strong heat generation and fluorescence imaging in tumor-bearing mice, allowing detection of the tumor site and inhibition of tumor growth by chemo-photothermal therapy. The multiplicity of features supplied by the newly developed CyD demonstrated the potential of CyD/DOX as an NIR dye-based theranostic drug-delivery carrier for effective chemo-photothermal cancer therapy.
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http://dx.doi.org/10.1016/j.jconrel.2020.11.046DOI Listing
January 2021

Combination of Photodynamic Therapy and a Flagellin-Adjuvanted Cancer Vaccine Potentiated the Anti-PD-1-Mediated Melanoma Suppression.

Cells 2020 11 7;9(11). Epub 2020 Nov 7.

Department of Microbiology, Chonnam National University Medical School, Hwasun-gun, Jeonnam 58128, Korea.

Immune checkpoint inhibitors become a standard therapy for malignant melanoma. As immune checkpoint inhibitor monotherapies proved to have limited efficacy in significant portion of patients, it is envisaged that combination with other therapeutic modalities may improve clinical outcomes. We investigated the effect of combining photodynamic therapy (PDT) and TLR5 agonist flagellin-adjuvanted tumor-specific peptide vaccination (FlaB-Vax) on the promotion of PD-1 blockade-mediated melanoma suppression using a mouse B16-F10 implantation model. Using a bilateral mouse melanoma cancer model, we evaluated the potentiation of PD-1 blockade by the combination of peritumoral FlaB-Vax delivery and PDT tumor ablation. A photosensitizing agent, pheophorbide A (PhA), was used for laser-triggered photodynamic destruction of the primary tumor. The effect of combination therapy in conjunction with PD-1 blockade was evaluated for tumor growth and survival. The effector cytokines that promote the activation of CD8 T cells and antigen-presenting cells in tumor tissue and tumor-draining lymph nodes (TDLNs) were also assayed. PDT and FlaB-Vax combination therapy induced efficacious systemic antitumor immune responses for local and abscopal tumor control, with a significant increase in tumor-infiltrating effector memory CD8 T cells and systemic IFNγ secretion. The combination of PDT and FlaB-Vax also enhanced the infiltration of tumor antigen-reactive CD8 T cells and the accumulation of migratory CXCL10-secreting CD103 dendritic cells (DCs) presumably contributing to tumor antigen cross-presentation in the tumor microenvironment (TME). The CD8 T-cell-dependent therapeutic benefits of PDT combined with FlaB-Vax was significantly enhanced by a PD-1-targeting checkpoint inhibitor therapy. Conclusively, the combination of FlaB-Vax with PDT-mediated tumor ablation would serve a safe and feasible combinatorial therapy for enhancing PD-1 blockade treatment of malignant melanoma.
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http://dx.doi.org/10.3390/cells9112432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694978PMC
November 2020

Volume and Mass Doubling Time of Lung Adenocarcinoma according to WHO Histologic Classification.

Korean J Radiol 2021 03 30;22(3):464-475. Epub 2020 Oct 30.

Department of Radiology, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea.

Objective: This study aimed to evaluate the tumor doubling time of invasive lung adenocarcinoma according to the International Association of the Study for Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) histologic classification.

Materials And Methods: Among the 2905 patients with surgically resected lung adenocarcinoma, we retrospectively included 172 patients (mean age, 65.6 ± 9.0 years) who had paired thin-section non-contrast chest computed tomography (CT) scans at least 84 days apart with the same CT parameters, along with 10 patients with squamous cell carcinoma (mean age, 70.9 ± 7.4 years) for comparison. Three-dimensional semiautomatic segmentation of nodules was performed to calculate the volume doubling time (VDT), mass doubling time (MDT), and specific growth rate (SGR) of volume and mass. Multivariate linear regression, one-way analysis of variance, and receiver operating characteristic curve analyses were performed.

Results: The median VDT and MDT of lung cancers were as follows: acinar, 603.2 and 639.5 days; lepidic, 1140.6 and 970.1 days; solid/micropapillary, 232.7 and 221.8 days; papillary, 599.0 and 624.3 days; invasive mucinous, 440.7 and 438.2 days; and squamous cell carcinoma, 149.1 and 146.1 days, respectively. The adjusted SGR of volume and mass of the solid-/micropapillary-predominant subtypes were significantly shorter than those of the acinar-, lepidic-, and papillary-predominant subtypes. The histologic subtype was independently associated with tumor doubling time. A VDT of 465.2 days and an MDT of 437.5 days yielded areas under the curve of 0.791 and 0.795, respectively, for distinguishing solid-/micropapillary-predominant subtypes from other subtypes of lung adenocarcinoma.

Conclusion: The tumor doubling time of invasive lung adenocarcinoma differed according to the IASCL/ATS/ERS histologic classification.
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http://dx.doi.org/10.3348/kjr.2020.0592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909861PMC
March 2021

Long-Term Outcomes of Robotic Thymectomy in Patients With Thymic Epithelial Tumors.

Ann Thorac Surg 2020 Oct 29. Epub 2020 Oct 29.

Department of Thoracic and Cardiovascular Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.

Background: The long-term outcomes of robotic thymectomy for thymic epithelial tumors (TETs) are not well known, even though the early postoperative outcomes have improved. This study aimed to report the long-term survival and recurrence in patients with TETs who underwent robotic thymectomies.

Methods: A total of 158 patients who underwent robotic thymectomy for TET and who were followed-up for more than 1 year were included in the study. The median follow-up time was 43 (interquartile range, 40) months, and 156 (98%) patients were followed completely until the end of the study period.

Results: The mean age of the patients was 55.7 ± 12.7 years, and the mean size of the tumor was 4.6 ± 2.1 cm. There was no postoperative mortality and postoperative complications occurred in 7 (4.4%) patients. The median length of the postoperative hospital stay was 2 (interquartile range, 1-20) days. Thymoma was the most common cell type (n = 132, 84%), and thymic carcinoma (n = 24, 15%) and neuroendocrine tumors (n = 2, 1%) were the next most common types. Advanced stages more than stage III were identified in 15 patients (stage IIIA: n = 7, 4%; stage IVA: n = 5, 3%; and stage IVB: n = 3, 2%). The 5-year disease-specific survival was 100% in thymoma and 95% in thymic carcinoma. The 5-year recurrence-free survival was 94% in thymoma and 79% in thymic carcinoma.

Conclusions: Robotic thymectomy could achieve favorable long-term survival and recurrence rates, comparable to open or thoracoscopic thymectomy.
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http://dx.doi.org/10.1016/j.athoracsur.2020.09.018DOI Listing
October 2020

The Biological Function and Therapeutic Potential of Exosomes in Cancer: Exosomes as Efficient Nanocommunicators for Cancer Therapy.

Int J Mol Sci 2020 Oct 5;21(19). Epub 2020 Oct 5.

College of Pharmacy, Chosun University, 309 Pilmun-daero, Dong-gu, Gwangju 61452, Korea.

Cancer therapeutics must be delivered to their targets for improving efficacy and reducing toxicity, though they encounter physiological barriers in the tumor microenvironment. They also face limitations associated with genetic instability and dynamic changes of surface proteins in cancer cells. Nanosized exosomes generated from the endosomal compartment, however, transfer their cargo to the recipient cells and mediate the intercellular communication, which affects malignancy progression, tumor immunity, and chemoresistance. In this review, we give an overview of exosomes' biological aspects and therapeutic potential as diagnostic biomarkers and drug delivery vehicles for oncotherapy. Furthermore, we discuss whether exosomes could contribute to personalized cancer immunotherapy drug design as efficient nanocommunicators.
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http://dx.doi.org/10.3390/ijms21197363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582692PMC
October 2020

Utilization of Polymer-Lipid Hybrid Nanoparticles for Targeted Anti-Cancer Therapy.

Molecules 2020 Sep 23;25(19). Epub 2020 Sep 23.

Department of Biomedical Sciences, Chonnam National University Medical School, 264, Seoyang-ro, Jeollanam-do 58128, Korea.

Cancer represents one of the most dangerous diseases, with 1.8 million deaths worldwide. Despite remarkable advances in conventional therapies, these treatments are not effective to completely eradicate cancer. Nanotechnology offers potential cancer treatment based on formulations of several nanoparticles (NPs). Liposomes and polymeric nanoparticle are the most investigated and effective drug delivery systems (DDS) for cancer treatment. Liposomes represent potential DDS due to their distinct properties, including high-drug entrapment efficacy, biocompatibility, low cost, and scalability. However, their use is restricted by susceptibility to lipid peroxidation, instability, burst release of drugs, and the limited surface modification. Similarly, polymeric nanoparticles show several chemical modifications with polymers, good stability, and controlled release, but their drawbacks for biological applications include limited drug loading, polymer toxicity, and difficulties in scaling up. Therefore, polymeric nanoparticles and liposomes are combined to form polymer-lipid hybrid nanoparticles (PLHNPs), with the positive attributes of both components such as high biocompatibility and stability, improved drug payload, controlled drug release, longer circulation time, and superior in vivo efficacy. In this review, we have focused on the prominent strategies used to develop tumor targeting PLHNPs and discuss their advantages and unique properties contributing to an ideal DDS.
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http://dx.doi.org/10.3390/molecules25194377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582728PMC
September 2020

Corrigendum to "Glycol chitosan-based renal docking biopolymeric nanomicelles for site specific delivery of the immunosuppressant" [Carbohydr. Polym. 241 (2020) 116255].

Carbohydr Polym 2020 12 10;249:116814. Epub 2020 Aug 10.

Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju, Republic of Korea. Electronic address:

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http://dx.doi.org/10.1016/j.carbpol.2020.116814DOI Listing
December 2020

Tumor immune profiles noninvasively estimated by FDG PET with deep learning correlate with immunotherapy response in lung adenocarcinoma.

Theranostics 2020 29;10(23):10838-10848. Epub 2020 Aug 29.

Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.

The clinical application of biomarkers reflecting tumor immune microenvironment is hurdled by the invasiveness of obtaining tissues despite its importance in immunotherapy. We developed a deep learning-based biomarker which noninvasively estimates a tumor immune profile with fluorodeoxyglucose positron emission tomography (FDG-PET) in lung adenocarcinoma (LUAD). A deep learning model to predict cytolytic activity score (CytAct) using semi-automatically segmented tumors on FDG-PET trained by a publicly available dataset paired with tissue RNA sequencing (n = 93). This model was validated in two independent cohorts of LUAD: SNUH (n = 43) and The Cancer Genome Atlas (TCGA) cohort (n = 16). The model was applied to the immune checkpoint blockade (ICB) cohort, which consists of patients with metastatic LUAD who underwent ICB treatment (n = 29). The predicted CytAct showed a positive correlation with CytAct of RNA sequencing in validation cohorts (Spearman rho = 0.32, 0.04 in SNUH cohort; spearman rho = 0.47, 0.07 in TCGA cohort). In ICB cohort, the higher predicted CytAct of individual lesion was associated with more decrement in tumor size after ICB treatment (Spearman rho = -0.54, 0.001). Higher minimum predicted CytAct in each patient associated with significantly prolonged progression free survival and overall survival (Hazard ratio 0.25, 0.001 and 0.18, 0.004, respectively). In patients with multiple lesions, ICB responders had significantly lower variance of predicted CytActs ( 0.005). The deep learning model that predicts CytAct using FDG-PET of LUAD was validated in independent cohorts. Our approach may be used to noninvasively assess an immune profile and predict outcomes of LUAD patients treated with ICB.
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http://dx.doi.org/10.7150/thno.50283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482798PMC
August 2020

Comparison between lung perfusion scan and single-photon emission computed tomography/computed tomography for predicting postoperative lung function after pulmonary resection in patients with borderline lung function.

Eur J Cardiothorac Surg 2020 12;58(6):1228-1235

Department of Thoracic and Cardiovascular Surgery, Seoul National University Hospital, Seoul National College of Medicine, Seoul, Korea.

Objectives: We compared the usefulness of single-photon emission computed tomography/computed tomography (SPECT/CT) and lung perfusion scintigraphy (LPS) for predicting postoperative lung function by comparing patients with borderline lung function.

Methods: A total of 274 patients who underwent simultaneous LPS and SPECT/CT and had a forced expiratory volume in 1 s (FEV1) or diffusing capacity for carbon monoxide (DLCO) under 80% were included. The % uptake by LPS was calculated by the posterior-oblique method. The concordance and difference of the % uptake, predicted postoperative (ppo) FEV1 and ppoDLCO as determined by 2 methods were evaluated. The association between ppo values and actual postoperative FEV1 and DLCO was examined. Subgroup analysis was conducted in redo-operation cases.

Results: The % uptake of each lobe, except the right middle lobe, showed fair concordance (concordance correlation coefficients for right upper, middle, lower, left upper and lower lobe = 0.61, 0.37, 0.71, 0.66 and 0.69, respectively). ppoFEV1 and ppoDLCO also revealed high concordance between both methods (concordance correlation coefficient = 0.93 for ppoFEV1 and concordance correlation coefficient = 0.92 for ppoDLCO) without a significant difference (P = 0.42 for ppoFEV1; P = 0.31 for ppoDLCO). Both ppoFEV1 and ppoDLCO showed a significantly high correlation with the actual FEV1 (r = 0.77, P < 0.01 for LPS, r = 0.77, P < 0.01 for SPECT/CT) and DLCO (r = 0.62, P < 0.01 for LPS, r = 0.62, P < 0.01 for SPECT/CT). High concordance of % uptake, ppoFEV1 and ppoDLCO was present in redo-operation patients.

Conclusions: Both LPS and SPECT/CT showed high predictability for actual postoperative lung function, and LPS showed good performance to estimate ppoFEV1 and ppoDLCO with reference to SPECT/CT, even in redo-operation cases.
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http://dx.doi.org/10.1093/ejcts/ezaa211DOI Listing
December 2020

Reciprocal change in Glucose metabolism of Cancer and Immune Cells mediated by different Glucose Transporters predicts Immunotherapy response.

Theranostics 2020 25;10(21):9579-9590. Epub 2020 Jul 25.

Department of Thoracic and Cardiovascular Surgery, Seoul National University Hospital, Seoul, Republic of Korea.

The metabolic properties of tumor microenvironment (TME) are dynamically dysregulated to achieve immune escape and promote cancer cell survival. However, properties of glucose metabolism in cancer and immune cells are poorly understood and their clinical application to development of a biomarker reflecting immune functionality is still lacking. We analyzed RNA-seq and fluorodeoxyglucose (FDG) positron emission tomography profiles of 63 lung squamous cell carcinoma (LUSC) specimens to correlate FDG uptake, expression of glucose transporters (GLUT) by RNA-seq and immune cell enrichment score (ImmuneScore). Single cell RNA-seq analysis in five lung cancer specimens was performed. We tested the GLUT3/GLUT1 ratio, the GLUT-ratio, as a surrogate representing immune metabolic functionality by investigating the association with immunotherapy response in two melanoma cohorts. ImmuneScore showed a negative correlation with GLUT1 ( = -0.70, < 0.01) and a positive correlation with GLUT3 ( = 0.39, < 0.01) in LUSC. Single-cell RNA-seq showed GLUT1 and GLUT3 were mostly expressed in cancer and immune cells, respectively. In immune-poor LUSC, FDG uptake was positively correlated with GLUT1 ( = 0.27, = 0.04) and negatively correlated with ImmuneScore ( = -0.28, = 0.04). In immune-rich LUSC, FDG uptake was positively correlated with both GLUT3 ( = 0.78, = 0.01) and ImmuneScore ( = 0.58, = 0.10). The GLUT-ratio was higher in anti-PD1 responders than nonresponders ( = 0.08 for baseline; = 0.02 for on-treatment) and associated with a progression-free survival in melanoma patients who treated with anti-CTLA4 ( = 0.04). Competitive uptake of glucose by cancer and immune cells in TME could be mediated by differential GLUT expression in these cells.
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http://dx.doi.org/10.7150/thno.48954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449929PMC
July 2020

Efficacy and Cost-effectiveness of Surgical Biopsy for Histologic Diagnosis of Indeterminate Nodules Suspected for Early Stage Lung Cancer: Comparison with Percutaneous Needle Biopsy.

J Korean Med Sci 2020 Jul 20;35(28):e261. Epub 2020 Jul 20.

Department of Thoracic and Cardiovascular Surgery, Seoul National University Hospital, Seoul, Korea.

Background: Indeterminate pulmonary nodules (IPN) suspected for early stage lung cancer mandate accurate diagnosis. Both percutaneous needle biopsy (PCNB) and surgical biopsy (SB) are valuable options. The present study aimed to compare the efficacy and cost-effectiveness between PCNB and SB for IPN suspected for early stage lung cancer.

Methods: During January-November 2018, patients who underwent operation for IPN suspected for early stage lung cancer (SB group, n = 245) or operation after PCNB (PCNB group, n = 113) were included. Patient-level cost data were extracted from medical bills from the institution. Propensity score matching was performed between the two groups from a retrospectively-collected database.

Results: Fifteen patients (11.5%) had complications after PCNB; thirteen (11.5%) were not confirmed to have lung cancer through PCNB but underwent operation for IPN. In SB group, 172 (70.2%) and 7 (2.9%) patients underwent wedge resection and segmentectomy for SB, respectively; 66 patients (26.9%) underwent direct lobectomy without SB. After propensity score matching, 58 paired samples were produced. Most patients in PCNB group were admitted twice (n = 55, 94.8%). The average hospital stay was longer in PCNB group (12.9 ± 5.3 vs. 7.3 ± 3.0, < 0.001). Though the cost of the operation was comparable (USD 12,509 ± 2,909 vs. 12,669 ± 3,334; = 0.782), the total cost was higher for PCNB group (USD 14,403 ± 3,085 vs. 12,669 ± 3,334; = 0.006). The average subcategory cost, which increases proportional to hospital stay, was higher in PCNB group, whereas the cost of operation and surgical materials were comparable between the two groups.

Conclusion: Lung cancer operation following SB for IPN was associated with lesser cost, shorter hospital stays, and lesser admission time than lung cancer operation after PCNB. The increased cost and longer hospital stay appear largely related to the admission for PCNB.
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http://dx.doi.org/10.3346/jkms.2020.35.e261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371454PMC
July 2020

Photo- and pH-Responsive Polycarbonate Block Copolymer Prodrug Nanomicelles for Controlled Release of Doxorubicin.

Macromol Biosci 2020 08 22;20(8):e2000118. Epub 2020 Jun 22.

BK21 PLUS Centre for Advanced Chemical Technology, Department of Polymer Science and Engineering, Pusan National University, Busan, 46241, Republic of Korea.

Photo/pH dual-responsive amphiphilic diblock copolymers with alkyne functionalized pendant o-nitrobenzyl ester group are synthesized using poly(ethylene glycol) as a macroinitiator. The pendant alkynes are functionalized as aldehyde groups by the azide-alkyne Huisgen cycloaddition. The anticancer drug doxorubicin (DOX) molecules are then covalently conjugated through acid-sensitive Schiff-base linkage. The resultant prodrug copolymers self-assemble into nanomicelles in aqueous solution. The prodrug nanomicelles have a well-defined morphology with an average size of 20-40 nm. The dual-stimuli are applied individually or simultaneously to study the release behavior of DOX. Under UV light irradiation, nanomicelles are disassembled due to the ONB ester photocleavage. The light-controlled DOX release behavior is demonstrated using fluorescence spectroscopy. Due to the pH-sensitive imine linkage the DOX molecules are released rapidly from the nanomicelles at the acidic pH of 5.0, whereas only minimal amount of DOX molecules is released at the pH of 7.4. The DOX release rate is tunable by applying the dual-stimuli simultaneously. In vitro studies against colon cancer cells demonstrate that the nanomicelles show the efficient cellular uptake and the intracellular DOX release, indicating that the newly designed copolymers with dual-stimuli-response have significant potential applications as a smart nanomedicine against cancer.
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http://dx.doi.org/10.1002/mabi.202000118DOI Listing
August 2020

The Role of Primary Tumor Resection in Patients with Pleural Metastasis Encountered at the Time of Surgery.

Korean J Thorac Cardiovasc Surg 2020 Jun;53(3):114-120

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

Background: Evidence is lacking on whether the resection of lung parenchymal cancer improves the survival of patients with unexpected pleural metastasis encountered during surgery. We conducted a single-center retrospective study to determine the role of lung resection in the long-term survival of these patients.

Methods: Among 4683 patients who underwent lung surgery between 1995 and 2014, 132 (2.8%) had pleural metastasis. After excluding 2 patients who had incomplete medical records, 130 patients' data were collected. Only a diagnostic pleural and/or lung biopsy was performed in 90 patients, while the lung parenchymal mass was resected in 40 patients.

Results: The mean follow-up duration was 29.8 months. The 5-year survival rate of the resection group (34.7%±9.4%) was superior to that of the biopsy group (15.9%±4.3%, p=0.016). Multivariate Cox regression analysis demonstrated that primary tumor resection (p=0.041), systemic treatment (p<0.001), lower clinical N stage (p=0.018), and adenocarcinoma histology (p=0.009) were significant predictors of a favorable outcome. Interestingly, primary tumor resection only played a significant prognostic role in patients who received systemic treatment.

Conclusion: When pleural metastasis is unexpectedly encountered during surgical exploration, resection in conjunction with systemic treatment may improve long-term survival, especially in adenocarcinoma patients without lymph node metastasis.
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http://dx.doi.org/10.5090/kjtcs.2020.53.3.114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287219PMC
June 2020

Non-steroidal anti-inflammatory drug-induced enteropathy as a major risk factor for small bowel bleeding: a retrospective study.

BMC Gastroenterol 2020 Jun 8;20(1):178. Epub 2020 Jun 8.

Department of Internal Medicine, Kosin University College of Medicine, Kosin University Gospel Hospital, Busan, South Korea.

Background: Small bowel (SB) bleeding accounts for 5% of all gastrointestinal (GI) bleeding cases and 80% of obscure GI bleeding cases. Although angioectasia is the common etiology of SB bleeding, nonsteroidal anti-inflammatory drug (NSAID)-induced SB lesions are also reported as a major cause in studies from Eastern countries. Herein, we assessed the frequency of occurrence of NSAID-induced SB lesions in Korean patients with obscure GI bleeding.

Methods: We retrospectively analyzed medical records of all consecutive patients aged ≥18 years who underwent capsule endoscopy from March 2018 to February 2019 at Ulsan University Hospital and Kosin University Gospel Hospital.

Results: Of the 83 subjects (all Korean; mean age ± standard deviation: 59 ± 18 years; age range: 18-84 years; men: n = 52; women: n = 31), 55 (66.2%) had stool with clear blood and 28 (33.8%) had normal stool with iron deficiency anemia. The detection rate of SB bleeding and lesions using capsule endoscopy was 72.3% (60 of 83 patients). A significantly higher frequency (40 of 51) of ulcerative/erosive lesions than other causes was observed in patients with inactive bleeding but visible SB lesions. As a result, NSAID-induced enteropathy accounted for 30.1% of 83 patients with obscure GI bleeding (25 of the all 60 SB bleeding cases).

Conclusions: Contrary to what is reported for patients in Western countries, this study in Korean patients showed an improved diagnostic yield of capsule endoscopy for obscure GI bleeding and that NSAID-induced enteropathy was the most common etiology of SB bleeding. Aggressive small intestine examination is required for patients with unexplained GI bleeding.
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http://dx.doi.org/10.1186/s12876-020-01329-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282042PMC
June 2020

Glycol chitosan-based renal docking biopolymeric nanomicelles for site-specific delivery of the immunosuppressant.

Carbohydr Polym 2020 Aug 30;241:116255. Epub 2020 Apr 30.

Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju, Republic of Korea. Electronic address:

In this study, we propose the use of glycol chitosan for the targeted delivery of hydrophobic drugs such as tacrolimus (TAC) towards the kidney. We synthesized a hydrophobically modified glycol chitosan (HGC) polymeric nanomicelle followed by loading TAC resulting in TAC loaded HGC nanomicelles (HGC-TAC). The HGC-TAC nanomicelles displayed spherical morphology with superior drug loading content and encapsulation efficiency. in vitro and in vivo evaluations demonstrated that HGC-TAC nanomicelles are non toxic and delivered TAC preferentially to kidney while lowering the plasma concentrations. The therapeutic effects of HGC-TAC and unencapsulated ("bare") TAC on the kidneys showed that a single intravenous administration of HGC-TAC achieved a therapeutic efficacy comparable to that obtained from daily intraperitoneal injections of TAC for 14 days without any systemic side effects. Thus, HGC-TAC nanomicelles could be effectively used for delivery of TAC towards the kidney, highlighting its potential as a safe modality for renal-targeted delivery of therapeutics.
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http://dx.doi.org/10.1016/j.carbpol.2020.116255DOI Listing
August 2020

Self-Quenched Polysaccharide Nanoparticles with a Reactive Oxygen Species-Sensitive Cascade for Enhanced Photodynamic Therapy.

ACS Appl Mater Interfaces 2020 Jun 16;12(25):28004-28013. Epub 2020 Jun 16.

Department of Biomedical Science, BK21 PLUS Center for Creative Biomedical Scientists, Chonnam National University Medical School, 160 Baekseo-ro, Gwangju 61469, Republic of Korea.

Tumor microenvironment (TME)-responsive nanocarrier systems that keep the photosensitizer (PS) inactive during systemic circulation and then efficiently release or activate the PS in response to unique TME conditions have attracted much attention. Herein, we report novel TME-responsive, self-quenched polysaccharide nanoparticles (NPs) with a reactive oxygen species (ROS)-sensitive cascade. The PS, pheophorbide A (PhA), was conjugated to a water-soluble glycol chitosan (GC) through an ROS-sensitive thioketal (TK) linker. The amphiphilic GC-TK-PhA conjugates could arrange themselves into NPs and remain photoinactive due to their self-quenching effects. Upon reaching the ROS-rich hypoxic core of the tumor tissue, the NPs release the PS in a photoactive form by efficient, ROS-sensitive TK bond cleavage, thus generating potent phototoxic effects. Following near-infrared irradiation, the increase in locoregional ROS levels further accelerates the release and activation of PS. These cascade reactions caused a significant reduction in the tumor volume, demonstrating good antitumor potential.
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http://dx.doi.org/10.1021/acsami.0c06311DOI Listing
June 2020