Real-world effectiveness and safety of adalimumab in Korean patients with intestinal Behcet’s disease: a Korean Association for the Study of Intestinal Diseases (KASID) multicenter study

Background/Aims@#The short- and long-term effects of adalimumab (ADA) on Korean patients with intestinal Behcet’s disease (BD) for remain unclear. Therefore, a multicenter study was performed to evaluate the efficacy and safety of ADA in Korean patients with intestinal BD in a real-world setting. @*Methods@#The medical records of 67 patients with BD prescribed ADA between January 2012 and December 2020 at five referral centers in Korea were retrospectively analyzed and the safety and efficacy of ADA within 52 weeks were assessed. To evaluate the clinical efficacy of ADA, the Disease Activity Index for Intestinal BD (DAIBD) and representative blood biochemical markers were compared at 0, 12, 24, and 52 weeks of ADA treatment. @*Results@#During the follow-up period of 52 weeks, 46 patients continued ADA treatment. The cumulative drug survival rate was 83.5%. The DAIBD score decreased over the study period (p < 0.001). Moreover, the erythrocyte sedimentation rate, serum C-reactive protein levels, and serum albumin levels significantly improved at 12, 24, and 52 weeks of ADA treatment (all, p <0.05). @*Conclusions@#As ADA is effective for refractory intestinal BD with few safety concerns in real-world situations, it is a potential treatment option for Korean patients with intestinal BD.

Outcomes according to treatment modalities as a bridge to curative surgery for malignant obstruction of the proximal colon: stent versus stoma

Background/Aims@#The optimal treatment for acute malignant obstruction of the proximal colon (MOPC, proximal to the splenic flexure) remains challenging. Emergency resection, the traditional modality for MOPC, has shown significantly high mortality and morbidity rates, according to recent studies. This study aimed to investigate the clinical outcomes of stent vs stoma as a bridge to curative surgery for MOPC. @*Methods@#This retrospective cohort study included 72 patients who underwent endoscopic placement of a self-expanding metallic stent (SEMS) or loop ileostomy for MOPC at six referral centers between January 2011 and July 2021. Clinical and pathological characteristics, procedure-related complications, and long-term mortality rates after curative surgery were analyzed. @*Results@#During a mean follow-up period of 32 months, 30 patients (41.7%) underwent ileostomy preferentially for more proximal cancer, complete obstruction, and advanced tumor stage compared to the SEMS group. No difference was found in procedure-related complications, but five deaths were observed after ileostomy. Survival analysis for 5-year mortality after curative surgery showed no significant difference between the bridge modalities (log-rank p = 0.253). @*Conclusions@#In this study, SEMS as a bridge to surgery showed relatively safe results in terms of post-procedural mortality. However, these results should be considered when performing ileostomy in patients with more advanced malignant obstruction.

Low-level viremia and cirrhotic complications in patients with chronic hepatitis B according to adherence to entecavir

Background/Aims@#Low-level viremia (LLV) after nucleos(t)ide analog treatment was presented as a possible cause of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). However, detailed information on patients’ adherence in the real world was lacking. This study aimed to evaluate the effects of LLV on HCC development, mortality, and cirrhotic complications among patients according to their adherence to entecavir (ETV) treatment. @*Methods@#We performed a retrospective observational analysis of data from 894 consecutive adult patients with treatment-naïve CHB undergoing ETV treatment. LLV was defined according to either persistent or intermittent episodes of <2,000 IU/mL detectable hepatitis B virus DNA during the follow-up period. Good adherence to medication was defined as a cumulative adherence ≥90% per study period. @*Results@#Without considering adherence in the entire cohort (n=894), multivariate analysis of the HCC incidence showed that LLV was an independent prognostic factor in addition to other traditional risk factors in the entire cohort (P=0.031). Good adherence group comprised 617 patients (69.0%). No significant difference was found between maintained virologic response and LLV groups in terms of the incidence of liver-related death or transplantation, HCC, and hepatic decompensation in good adherence group, according to multivariate analyses. @*Conclusions@#In patients with treatment-naïve CHB and good adherence to ETV treatment in the real world, LLV during treatment is not a predictive factor for HCC and cirrhotic complications. It may be unnecessary to adjust their antiviral agent for patients with good adherence who experience LLV during ETV treatment.

Simple Maturation of Direct-Converted Hepatocytes Derived from Fibroblasts

Target cells differentiation techniques from stem cells are developed rapidly. Recently, direct conversion techniques are introduced in various categories. Unlike pluripotent stem cells, this technique enables direct differentiation into the other cell types such as neurons, cardiomyocytes, insulin-producing cells, and hepatocytes without going through the pluripotent stage. However, the function of these converted cells reserve an immature phenotype. Therefore, we modified the culture conditions of mouse direct converted hepatocytes (miHeps) to mature fetal characteristics, such as higher AFP and lower albumin (ALB) expression than primary hepatocytes. First, we generate miHeps from mouse embryonic fibroblasts (MEFs) with two transcription factors HNF4α and Foxa3. These cells indicate typical epithelial morphology and express hepatic proteins. To mature hepatic function, DMSO is treated during culture time for more than 7 days. After maturation, miHeps showed features of maturation such as exhibiting typical hepatocyte-like morphology, increased up-regulated ALB and CYP enzyme gene expression, down-regulated AFP expressions, and acquired hepatic function over time. Thus, our data provides a simple method to mature direct converted hepatocytes functionally and these cells enable them to move closer to generating functional hepatocytes.

Establishment of Hepatocellular Cancer Induced Pluripotent Stem Cells Using a Reprogramming Technique

BACKGROUND/AIMS: Cancer is known to be a disease by many factors. However, specific results of reprogramming by pluripotency-related transcription factors remain to be scarcely reported. Here, we verified potential effects of pluripotent-related genes in hepatocellular carcinoma cancer cells. METHODS: To better understand reprogramming of cancer cells in different genetic backgrounds, we used four liver cancer cell lines representing different states of p53 (HepG2, Hep3B, Huh7 and PLC). Retroviral-mediated introduction of reprogramming related genes (KLF4, Oct4, Sox2, and Myc) was used to induce the expression of proteins related to a pluripotent status in liver cancer cells. RESULTS: Hep3B cells (null p53) exhibited a higher efficiency of reprogramming in comparison to the other liver cancer cell lines. The reprogrammed Hep3B cells acquired similar characteristics to pluripotent stem cells. However, loss of stemness in Hep3B-iPCs was detected during continual passage. CONCLUSIONS: We demonstrated that reprogramming was achieved in tumor cells through retroviral induction of genes associated with reprogramming. Interestingly, the reprogrammed pluripotent cancer cells (iPCs) were very different from original cancer cells in terms of colony shape and expressed markers. The induction of pluripotency of liver cancer cells correlated with the status of p53, suggesting that different expression level of p53 in cancer cells may affect their reprogramming.

Induced Pluripotent Stem Cells: Next Generation Stem Cells to Clinical Applications / 한양의대학술지

Induced pluripotent stem cells (iPSC) are specially manipulated cells from somatic cells by the introduction of four factors that are reprogrammed. The properties of iPSC are similar to embryonic stem cells (ESC) characteristic of self-renewal and pluripotency. The technology of reprogramming somatic cells to iPSC enables the generation of patient-specific cells that can be used as powerful tools for drug screening, in vitro models for human disease and autologous transplantation. The iPSC technology provides a priceless resource for regenerative medicine but there are still changing obstacles over the safety of iPSC in avoiding induction of tumorigenicity and maintaining high purity of re-differentiated cells from iPSC to produce more functional cells for cell therapy. A variety of methods to overcome the limitation of iPSC application applied in the clinical setting have been developed. In this review, we summarize the recent progress in iPSC generation and differentiation techniques to facilitate clinical application of iPSC with future potential in regenerative medicine.

Liver Stem Cells / 한양의대학술지

Liver transplantation has been regarded as the definitive curative approach for pathologic liver conditions from the acute stage to the chronic end stage for decades. Recently, translational research has been focused on liver stem cell transplantation, using various cell therapies, due to the potential benefit of natural host liver regeneration. Many studies are ongoing utilizing and evaluating the use of either fetal-liver-derived stem cells or oval cells, however many obstacles still remain. Extensive research identifying and characterizimg stem/progenitor cells for potential application to in vitro cell therapy, whereas many questions remain concerning the isolation and identification of adult liver stem cells with adequate capacity for proliferation and the regeneration of injured liver. Recent approaches to liver regeneration include the production of hepatocyte-like cells from other stem cell sources such as mesenchymal stem cells and embryonic stems cells. Another major target for liver regeneration studies include the generation of liver stem cells from induced pluripotent stem cells (IPSC) We review the current data concerning characterization of stem cells and progenitor cells for their capacity to support their potential for re-population and regeneration of normal adult liver from liver damaged due to injury and/or disease.

A Full-Thickness Macular Hole in a Female Adult with Bilateral Retinal Capillary Hemangiomas

PURPOSE: We report a case of a full-thickness macular hole treated in a female adult with bilateral retinal capillary hemangiomas. CASE SUMMARY: A 20-year-old woman with bilateral retinal capilliary hemangiomas presented with blurred vision in her right eye. A thin epiretinal membrane and impending macular hole were found that did not appear to be related with a 2-disc-diameter-sized retinal angioma, telangiectactic vessels, and hard exudates in the lower retinal area of her right eye. Four months later, optical coherence tomography revealed a full-thickness macular hole in her right eye. A vitrectomy was performed, and the full-thickness macular hole was completely resolved.

Two Cases of Unusual Infectious Peritonitis Mimicking Peritoneal Carcinomatosis of Early Gastric Cancer / 대한소화기내시경학회지

Endoscopic mucosal resection is an organ-saving and minimally invasive treatment modality for early gastric cancer that is mucosa-confined, differentiated, and less than 2 cm in size. On pre-treatment cancer staging work-ups, unusual, benign, infiltrative peritoneal lesions can mimic metastasis of early gastric cancer, and thus lead to loss of an opportunity for the lesion to be properly treated by endoscopy. In the present cases, we report two unusual cases of infectious peritonitis, i.e., tuberculosis and paragonimiasis, which have been occurring sporadically in Korea. The two infectious lesions were confirmed by peritoneal biopsy and the gastric cancers were subsequently removed by endoscopic mucosectomy. These two cases remind us of 1) following indications for endoscopic mucosectomy, 2) the need for peritoneal biopsy for undetermined peritoneal lesions while avoiding laparoscopic gastrectomy, and 3) the coincidental occurrence of unusual infectious peritonitis with gastric cancer in our geographic region.

Investigation of bone formation using calcium phosphate glass cement in beagle dogs

PURPOSE: Among available biomaterials, bioceramics have drawn special interest due to their bioactivity and the possibility of tailoring their composition. The degradation rate and formulation of bioceramics can be altered to mimic the compositions of the mineral phase of bone. The aim of this study was to investigate the bone formation effect of amorphous calcium phosphate glass cement (CPGC) synthesized by a melting and quenching process. METHODS: In five male beagle dogs, 4 x 4 mm 1-wall intrabony defects were created bilaterally at the mesial or distal aspect of the mandibular second and fourth premolars. Each of the four defects was divided according to graft materials: CPGC with collagen membrane (CM), biphasic calcium phosphate (BCP) with CM, CM alone, or a surgical flap operation only. The dogs were sacrificed 8 weeks post-surgery, and block sections of the defects were collected for histologic and histometric analysis. RESULTS: There were significant differences in bone formation and cementum regeneration between the experimental and control groups. In particular, the CPGC and BCP groups showed greater bone formation than the CM and control groups. CONCLUSIONS: In conclusion, CPGC was replaced rapidly with an abundant volume of new bone; CPGC also contributed slightly to regeneration of the periodontal apparatus.

The clinical effects of Calcium Sulfate combined with Calcium Carbonate in treating intrabony defects / 대한치주과학회지

PURPOSE: If bone grafts and guided tissue regeneration are effective individually in treating osseous defects, then the question is, what would happen when they are combined. Bone grafts using Calcium Carbonate(Biocoral) and Guided Tissue Regeneration using Calcium Sulfate(CALMATRIX) will maximize their advantages and show the best clinical results in intrabony defects. This study was to compare the effects of a combination of CS and CC with control treated only with modified widman flap in a periodontal repair of intrabony defects. MATERIALS AND METHODS: 30 patients with chronic periodontitis were used in this study. 10 patients were treated with a combination of CS and CC as the experimental groupII and another 10 patients were treated with CC as the experimental groupI, and the remaining 10 patients, the control group were treated only with modified widman flap. Clinical parameters including probing depth, gingival recession, bone probing depth and loss of attachment were recorded 6 months later. RESULTS: The probing depth changes were 3.30+/-1.34 mm in the control group, 4.2+/-1.55 mm in the experimental groupI(CC) and 5.00+/-1.33 mm in the experimental groupII(CS+CC). They all showed a significant decrease 6 months after surgery(p <0.01). There was a significant difference(p <0.05) between the control and experimental group. However there were no significant difference(p <0.05) between the experimental groupIand II. The gingival recession changes w -1.30+/-1.25 mm in the control group, This is a significant difference(p <0.01). However, there was a -0.50+/-0.53 mm change in the experimental groupI(CC) and -0.60+/-0.97 mm in the experimental groupII(CS+CC). In addition, in terms of gingival recession, there was a no significance difference(p <0.05) among the groups. The clinical attachment level changes were 2.00+/-1.33 mm in the control group, 3.60+/-1.58 mm in the experimental groupI(CC) and 4.40+/-1.17 mm in the experimental groupII(CS+CC). They all showed a significant decrease 6 months after surgery(p <0.01). There was a significant difference(p <0.05) between the control and experimental group. However there was a no significance difference(p <0.05) between the experimental groupI andII. The bone probing depth changes were 0.60+/-0.52 mm in the control group, 3.20+/-1.48 mm in the experimental groupI (CC) and 4.60+/-1.43 mm in the experimental groupII(CS+CC). All of them showed a significant decrease 6 months after surgery(p <0.01), there was a significance difference(p <0.05) among the groups. CONCLUSION: Treatment using a combination of CS and CC have a potential to improve periodontal parameters in intrabony defects and More efficient clinical results can be expected in intrabony defects less than 2 walls grafted with CS and CC.

A study of the clinical effects of various bone graft materials / 대한치주과학회지

PURPOSE: Various bone graft materials are being used for periodontal tissue regeneration.Th materials are being developed continuously for ideal clinical effects. Therefore, it is necessary to identify the clinical characteristics of each bone graft material through comparing the various bone graft materials statistically and in doing so, proposing a more efficient bone graft material. In this study, the following results were attained through comparing the clinical effects among the bone graft materials, using the statistical method based on the clinical studies published at the department of periodontology of Yonsei hospital. MATERIALS AND METHOD: 6 selected studies of department of Periodontology at Yonsei University Hospital were based on clinical study of bone grafting in intrabony defects. It was compared the clinical parameters among the 6 clinical studies, using the statistical META analysis. RESULT: When comparing the probing depth reduction, there was a relatively great amount of decrease when using the xenograft, Anorganic Bovine Derived Hydroxapatite Bone Matrix/Cell Binding Peptide(ABM/P-15: PepGen P-15(R)) and the autogenous bone and absorbable membrane, d,l-alctide/glycolide copolymer(GC: Biomesh(R)). The allogfrafts showed a relatively low decrease in the probing depth and clinical attachment change. It also showed a slight decrease in the bone probing depth. The allografts showed various results according to different bone graft materials. When comparing the ABM/P-15 and bovine bone powder(BBP(R)), ABM/P-15 showed a relatively high clinical attachment level and the bovine bone powder showed a relatively high clinical attachment level. The probing depth change and gingival recession change showed a lower value than the mean value between the two bone graft materials. The synthetic bone showed a relatively high decrease in clinical attachment level and periodontal probing depth change. There was a relatively larger amount of gingival recession when using Bioactive Glass(BG) but a relatively low bone regeneration effect was seen. CONCLUSION: Good restorative results of the periodontal tissue can be attained by applying the various bone graft materials being used today after identifying the accurate clinical effects.

Ionizing radiation induces blockade of c-Jun N-terminal kinasedependent cell death pathway in amanner correlated with p21Cip/WAF1 induction in primary cultured normal human fibroblasts

During radiotherapy of cancer, neighboring normal cells may receive sub-lethal doses of radiation. To investigate whether such low levels of radiation modulate normal cell responses to death stimuli, primary cultured human fibroblasts were exposed to various doses of gamma-rays. Analysis of cell viability using an exclusion dye propidium iodide revealed that the irradiation up to 10 Gy killed the fibroblasts only to a minimal extent. In contrast, the cells efficiently lost their viability when exposed to 0.5-0.65 mM H2O2. This type of cell death was accompanied by JNK activation, and was reversed by the use of a JNK-specific inhibitor SP600125. Interestingly, H2O2 failed to kill the fibroblasts when these cells were pre-irradiated, 24 h before H2O2 treatment, with 0.25-0.5 Gy of gamma-rays. These cytoprotective doses of gamma-rays did not enhance cellular capacity to degrade H2O2, but elevated cellular levels of p21Cip/WAF1, a p53 target that can suppress H2O2-induced cell death by blocking JNK activation. Consistently, H2O2-induced JNK activation was dramatically suppressed in the pre-irradiated cells. The overall data suggests that ionizing radiation can impart normal fibroblasts with a survival advantage against oxidative stress by blocking the process leading to JNK activation.

A Case of Conjunctival Malignant Melanoma with Extensive Corneal Displacement

PURPOSE: To report a patient with malignant conjunctival melanoma with extensive corneal invasive growth. METHODS: A 63-year-old woman with 9 x 7 mm sized dark brown colored conjunctival mass with extensive corneal invasive growth over a 3-month history was seen. The mass was removed and biopsy was done. Fontana-Masson, S-100 protein, and HMB stainings were used to confirm the diagnosis of malignant melanoma. RESULTS: The tumor was easily separated from the corneal surface and adjacent conjunctiva was excised. Fontana-Masson, S-100 protein, and HMB stainings revealed corneally-displaced malignant conjunctival melanoma. There was no evidence of metastasis. CONCLUSIONS: Corneally displaced malignant conjunctival melanoma was very rare. A good surgical result was obtained with its removal.

Factors Associated with Visual Outcomes of Postoperative Endophthalmitis Following Cataract Surgery

PURPOSE: The most serious complication related to cataract surgery is endophthalmitis. Although its incidence is decreasing, it remains the great threat to the outcome of visual acuity in patients who received cataract surgery. METHODS: Retrospective analysis was performed on 18 patients who were diagnosed with endophthalmitis. The following factors were investigated: method of cataract extraction, performance of anterior vitrectomy, presence of posterior capsule rupture, results of bacterial culture, existence of systemic disease, and the duration of time from initial cataract surgery to diagnosis of endophthalmitis and then to subsequent posterior vitrectomy. In addition, the differences in final visual acuity due to variations in these factors were analyzed. RESULTS: Patients who were diagnosed with endophthalmitis and had been commenced on systemic antibiotics within a week of the cataract operation, showed better outcomes in final visual acuity (P=0.043). CONCLUSION: Occurrence of endophthalmitis and subsequent usage of systemic antibiotics within a one-week time frame of cataract surgery, led to statistically significant improvement in final visual acuity compared to cases in which these events occurred one week later.

Factors Associated with Visual Outcomes of Postoperative Endophthalmitis Following Cataract Surgery

PURPOSE: The most serious complication related to cataract surgery is endophthalmitis. Although its incidence is decreasing, it remains the great threat to the outcome of visual acuity in patients who received cataract surgery. METHODS: Retrospective analysis was performed on 18 patients who were diagnosed with endophthalmitis. The following factors were investigated: method of cataract extraction, performance of anterior vitrectomy, presence of posterior capsule rupture, results of bacterial culture, existence of systemic disease, and the duration of time from initial cataract surgery to diagnosis of endophthalmitis and then to subsequent posterior vitrectomy. In addition, the differences in final visual acuity due to variations in these factors were analyzed. RESULTS: Patients who were diagnosed with endophthalmitis and had been commenced on systemic antibiotics within a week of the cataract operation, showed better outcomes in final visual acuity (P=0.043). CONCLUSION: Occurrence of endophthalmitis and subsequent usage of systemic antibiotics within a one-week time frame of cataract surgery, led to statistically significant improvement in final visual acuity compared to cases in which these events occurred one week later.

Correlation between Infiltrations of Tumor-associated Macrophages, Mast Cells, and Dendritic Cells with Clinicopathologic Factors in Advanced Gastric Cancer

PURPOSE: Angiogenesis has a critical role in tumor proliferation, invasion, and metastasis. In gastric cancer, tumor- associated macrophages and mast cells produce angiogenic factors such as VEGF, that inhibit the functional maturation of dendritic cells. The aim of this study is to identify tumor-associated macrophages, mast cells, dendritic cell infiltrations, and microvessel densities (MVD) to investigate the relationship between them and the prognosis for gastric-cancer patients. MATERIALS AND METHODS: The subjects were 79 patients selected from those who had undergone a curative gastric resection for stomach cancer. With them, Immuno-histochemical staining was done using CD34 for the MVD, CD68 antigen for macrophages, and S-100 protein for dendritic cells, and toluidine blue staining was done for mast cells. RESULTS: Macrophage infiltration showed a statistically significant positive correlation with histologic differentiation and a negative correlation with invasion depth, nodal metastasis, and stage. S-100 (+) dendritic cells and mast cells had no significant correlations with histologic differentiation, invasion depth, nodal metastasis, distant metastasis, stage, and MVD. As survival, no statistically significant differences were seen between the variables. CONCLUSION: Tumor-associated macrophages should be evaluated as possible prognostic markers in gastric-cancer patients.

The Availability and Safety of the Microkeratome in LASIK

PURPOSE: To evaluate the reproducibility of the flap thickness in LASIK using Moria M2 microkeratome and to examine the safety and the complication rate intraoperatively and postoperatively. METHODS: 92-Ninety-two consecutive eyes of 50 patients that received LASIK using the Moria M2 microkeratome were reviewed. The mean of the predictable corneal flap thickness was compared with the mean of the created corneal flap thickness, and intraoperative and postoperative complication and safety were evaluated. RESULTS: The average corneal flap thicknesses were 140+/-15.16 micrometer with 130 micrometer head and 108.01+/-16.72 micrometer with 110 micrometer head. There was no statistically significant correlation between the predictable corneal flap thickness and the created corneal flap thickness with the 130 micrometer head (p=0.001, one-sample t-test), but there was a stastistically significant correlation with the 110 micrometer head (p=0.573, one-sample t-test). CONCLUSIONS: The M2 Moria microkeratome created a desirable thickness with the 110 micrometer head, and we can expect postoperative stability of the remaining corneal thickness. The complication rate both intraoperatively and postoperatively was very low.