Melanogenesis is the production of melanin from tyrosine by a series of enzyme-catalyzed reactions, in which tyrosinase and DOPA oxidase play key roles. The melanin content in the skin determines skin pigmentation. Abnormalities in skin pigmentation lead to various skin pigmentation disorders. Recent research has shown that the expression of EMP2 is much lower in melanoma than in normal melanocytes, but its role in melanogenesis has not yet been elucidated. Therefore, we investigated the role of EMP2 in the melanogenesis of MNT1 human melanoma cells. We examined TRP-1, TRP-2, and TYR expression levels during melanogenesis in MNT1 melanoma cells by gene silencing of EMP2. Western blot and RT-PCR results confirmed that the expression levels of TYR and TRP-2 were decreased when EMP2 expression was knocked down by EMP2 siRNA in MNT1 cells, and these changes were reversed when EMP2 was overexpressed. We verified the EMP2 gene was knocked out of the cell line (EMP2 CRISPR/Cas9) by using a CRISPR/Cas9 system and found that the expression levels of TRP-2 and TYR were significantly lower in the EMP2 CRISPR/Cas9 cell lines. Loss of EMP2 also reduced migration and invasion of MNT1 melanoma cells. In addition, the melanosome transfer from the melanocytes to keratinocytes in the EMP2 KO cells cocultured with keratinocytes was reduced compared to the cells in the control coculture group. In conclusion, these results suggest that EMP2 is involved in melanogenesis via the regulation of TRP-2 expression.

Advanced or metastatic breast cancer affects multiple organs and is a leading cause of cancer-related death. Cancer metastasis is associated with epithelial-mesenchymal metastasis (EMT). However, the specific signals that induce and regulate EMT in carcinoma cells remain unclear. PRR16/Largen is a cell size regulator that is independent of mTOR and Hippo signalling pathways. However, little is known about the role PRR16 plays in the EMT process. We found that the expression of PRR16 was increased in mesenchymal breast cancer cell lines. PRR16 overexpression induced EMT in MCF7 breast cancer cells and enhances migration and invasion. To determine how PRR16 induces EMT, the binding proteins for PRR16 were screened, revealing that PRR16 binds to Abl interactor 2 (ABI2). We then investigated whether ABI2 is involved in EMT. Gene silencing of ABI2 induces EMT, leading to enhanced migration and invasion. ABI2 is a gene that codes for a protein that interacts with ABL proto-oncogene 1 (ABL1) kinase. Therefore, we investigated whether the change in ABI2 expression affected the activation of ABL1 kinase. The knockdown of ABI2 and PRR16 overexpression increased the phosphorylation of Y412 in ABL1 kinase. Our results suggest that PRR16 may be involved in EMT by binding to ABI2 and interfering with its inhibition of ABL1 kinase. This indicates that ABL1 kinase inhibitors may be potential therapeutic agents for the treatment of PRR16-related breast cancer.

Purpose: This study was performed to evaluate the quality of life and genitourinary function after total mesorectal excision with lateral lymph node dissection compared to those after total mesorectal excision alone following neoadjuvant chemoradiotherapy for rectal cancer. Methods: Among patients who underwent rectal cancer surgery after completing neoadjuvant chemoradiotherapy between September 2011 and October 2018 at the National Cancer Center, Korea, patients who completed the validated questionnaires before initiation of neoadjuvant chemoradiotherapy and at 3 months and 1 year postoperatively were included in this study. The European Organization for Research and Treatment of Cancer (EORTC) core quality of life questionnaire (QLQ-C30), colorectal cancer-specific quality of life questionnaire (QLQ-CR38), and International Prostate Symptom Score (IPSS) questionnaire were used for collecting data. Results: The total mesorectal excision alone group and the total mesorectal excision with lateral lymph node dissection group included 52 and 38 patients, respectively. The second group included significantly younger patients (P = 0.024), had a higher incidence of clinical T4 stage disease (P = 0.033), estimated blood loss (P = 0.003), and longer operation time (P < 0.001). Significant differences were not observed between the groups with respect to the EORTC QLQ-C30, QLQ-CR38, and IPSS. Multivariable analysis showed that lateral lymph node dissection had no statistically significant association with postoperative urinary dysfunction (P = 0.953). Conclusion The overall quality of life and urinary function after total mesorectal excision does not differ significantly when lateral lymph node dissection is performed as well.

Purpose: The effect of transanal total mesorectal excision (TaTME) on patients’ quality of life and functional outcomes is not fully understood. This study aimed to compare the quality of life and bowel, anorectal, and urogenital functions after laparoscopic and TaTME. Methods: Laparoscopic or TaTME was performed for 202 propensity score-matched patient pairs with rectal cancer between January 2014 and December 2017 at the National Cancer Center, Korea. The outcomes for all patients were assessed using anorectal manometry, the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire (QLQ-C30) and Colorectal Cancer-Specific Quality of Life Questionnaire (QLQ-CR38), low anterior resection syndrome (LARS) score, Fecal Incontinence Severity Index, and International Prostate Symptom Score (IPSS). This retrospective comparative study included patients who completed anorectal manometry and the questionnaires before treatment and at 1 year after surgery. Results: The EORTC QLQ-C30 and QLQ-CR38 showed comparable outcomes regarding the quality of life in both groups. More patients experienced major LARS in the transanal group at 1 year postoperatively (31.0% vs. 6.8% in the laparoscopic group, P = 0.004). Multivariable analysis revealed no significant difference in the LARS score between the groups at 1 year postoperatively (odds ratio, 2.30; 95% confidence interval, 0.79–6.72; P = 0.127). Significant differences in the IPSS were not noted between the groups. Conclusion The quality of life and functional outcomes were comparable between the laparoscopic and transanal approaches; however, our findings suggest a higher rate of LARS after TaTME.

Purpose: The effect of transanal total mesorectal excision (TaTME) on patients’ quality of life and functional outcomes is not fully understood. This study aimed to compare the quality of life and bowel, anorectal, and urogenital functions after laparoscopic and TaTME. Methods: Laparoscopic or TaTME was performed for 202 propensity score-matched patient pairs with rectal cancer between January 2014 and December 2017 at the National Cancer Center, Korea. The outcomes for all patients were assessed using anorectal manometry, the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire (QLQ-C30) and Colorectal Cancer-Specific Quality of Life Questionnaire (QLQ-CR38), low anterior resection syndrome (LARS) score, Fecal Incontinence Severity Index, and International Prostate Symptom Score (IPSS). This retrospective comparative study included patients who completed anorectal manometry and the questionnaires before treatment and at 1 year after surgery. Results: The EORTC QLQ-C30 and QLQ-CR38 showed comparable outcomes regarding the quality of life in both groups. More patients experienced major LARS in the transanal group at 1 year postoperatively (31.0% vs. 6.8% in the laparoscopic group, P = 0.004). Multivariable analysis revealed no significant difference in the LARS score between the groups at 1 year postoperatively (odds ratio, 2.30; 95% confidence interval, 0.79–6.72; P = 0.127). Significant differences in the IPSS were not noted between the groups. Conclusion The quality of life and functional outcomes were comparable between the laparoscopic and transanal approaches; however, our findings suggest a higher rate of LARS after TaTME.

Purpose: The details of breast reconstruction and radiation therapy (RT) vary between institutions; therefore, we sought to investigate the practice patterns of radiation oncologists who specialize in breast cancer. Materials and Methods: We identified the practice patterns and inter-hospital variations from a multi-center cohort of women with breast cancer who underwent post-mastectomy RT (PMRT) to the reconstructed breast at 16 institutions between 2015 and 2016. The institutions were requested to contour the target volume and produce RT plans for one representative case with five different clinical scenarios and answer questionnaires which elicited infrastructural information. We assessed the inter-institutional variations in RT in terms of the target, normal organ delineation, and dose-volume histograms. Results: Three hundred fourteen patients were included; 99% of them underwent immediate reconstruction. The most irradiated material was tissue expander (36.9%) followed by transverse rectus abdominis musculocutaneous flap (23.9%) and silicone implant (12.1%). In prosthetic-based reconstruction with tissue expander, most patients received PMRT following partial deflation. Conventional fractionation and hypofractionation RT were used in 66.6% and 33.4% patients, respectively (commonest: 40.05 Gy in 15 fractions [17.5%]). Furthermore, 15.6% of the patients received boost RT and 53.5% were treated with bolus. Overall, 15 physicians responded to the questionnaires and six submitted their contours and RT plans. There was a significant variability in target delineations and RT plans between physicians, and between clinical scenarios. Conclusion Adjuvant RT following post-mastectomy reconstruction has become a common practice in Korea. The details vary significantly between institutions, which highlights an urgent need for standard protocol in this clinical setting.

Purpose: The details of breast reconstruction and radiation therapy (RT) vary between institutions; therefore, we sought to investigate the practice patterns of radiation oncologists who specialize in breast cancer. Materials and Methods: We identified the practice patterns and inter-hospital variations from a multi-center cohort of women with breast cancer who underwent post-mastectomy RT (PMRT) to the reconstructed breast at 16 institutions between 2015 and 2016. The institutions were requested to contour the target volume and produce RT plans for one representative case with five different clinical scenarios and answer questionnaires which elicited infrastructural information. We assessed the inter-institutional variations in RT in terms of the target, normal organ delineation, and dose-volume histograms. Results: Three hundred fourteen patients were included; 99% of them underwent immediate reconstruction. The most irradiated material was tissue expander (36.9%) followed by transverse rectus abdominis musculocutaneous flap (23.9%) and silicone implant (12.1%). In prosthetic-based reconstruction with tissue expander, most patients received PMRT following partial deflation. Conventional fractionation and hypofractionation RT were used in 66.6% and 33.4% patients, respectively (commonest: 40.05 Gy in 15 fractions [17.5%]). Furthermore, 15.6% of the patients received boost RT and 53.5% were treated with bolus. Overall, 15 physicians responded to the questionnaires and six submitted their contours and RT plans. There was a significant variability in target delineations and RT plans between physicians, and between clinical scenarios. Conclusion Adjuvant RT following post-mastectomy reconstruction has become a common practice in Korea. The details vary significantly between institutions, which highlights an urgent need for standard protocol in this clinical setting.

PURPOSE: With the emergence of next-generation sequencing (NGS) technology, profiling a wide range of genomic alterations has become a possibility resulting in improved implementation of targeted cancer therapy. In Asian populations, the prevalence and spectrum of clinically actionable genetic alterations has not yet been determined because of a lack of studies examining high-throughput cancer genomic data. MATERIALS AND METHODS: To address this issue, 1,071 tumor samples were collected from five major cancer institutes in Korea and analyzed using targeted NGS at a centralized laboratory. Samples were either fresh frozen or formalin-fixed, paraffin embedded (FFPE) and the quality and yield of extracted genomic DNA was assessed. In order to estimate the effect of sample condition on the quality of sequencing results, tissue preparation method, specimen type (resected or biopsied) and tissue storage time were compared. RESULTS: We detected 7,360 non-synonymous point mutations, 1,164 small insertions and deletions, 3,173 copy number alterations, and 462 structural variants. Fifty-four percent of tumors had one or more clinically relevant genetic mutation. The distribution of actionable variants was variable among different genes. Fresh frozen tissues, surgically resected specimens, and recently obtained specimens generated superior sequencing results over FFPE tissues, biopsied specimens, and tissues with long storage duration. CONCLUSION: In order to overcome, challenges involved in bringing NGS testing into routine clinical use, a centralized laboratory model was designed that could improve the NGS workflows, provide appropriate turnaround times and control costs with goal of enabling precision medicine.
Academies and Institutes ; Asian Continental Ancestry Group ; DNA ; Humans ; Korea ; Methods ; Paraffin ; Point Mutation ; Precision Medicine ; Prevalence

PURPOSE: The purpose of this study was to investigate the effect of hospital case volume on clinical outcomes in patients with nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: Data on 1,073 patients with cT1-4N0-3M0 NPC were collected from a multi-institutional retrospective database (KROG 11-06). All patients received definitive radiotherapy (RT) either with three-dimensional-conformal RT (3D-CRT) (n=576) or intensity-modulated RT (IMRT) (n=497). The patients were divided into two groups treated at high volume institution (HVI) (n=750) and low volume institution (LVI) (n=323), defined as patient volume ≥ 10 (median, 13; range, 10 to 18) and < 10 patients per year (median, 3; range, 2 to 6), respectively. Endpoints were overall survival (OS) and loco-regional progression-free survival (LRPFS). RESULTS: At a median follow-up of 56.7 months, the outcomes were significantly better in those treated at HVI than at LVI. For the 614 patients of propensity score-matched cohort, 5-year OS and LRPFS were consistently higher in the HVI group than in the LVI group (OS: 78.4% vs. 62.7%, p < 0.001; LRPFS: 86.2% vs. 65.8%, p < 0.001, respectively). According to RT modality, significant difference in 5-year OS was observed in patients receiving 3D-CRT (78.7% for HVI vs. 58.9% for LVI, p < 0.001) and not in those receiving IMRT (77.3% for HVI vs. 75.5% for LVI, p=0.170). CONCLUSION: A significant relationship was observed between HVI and LVI for the clinical outcomes of patients with NPC. However, the difference in outcome becomes insignificant in the IMRT era, probably due to the standardization of practice by education.
Cohort Studies ; Disease-Free Survival ; Education ; Follow-Up Studies ; Humans ; Nasopharyngeal Neoplasms ; Radiotherapy ; Radiotherapy, Intensity-Modulated ; Retrospective Studies* ; Treatment Outcome

PURPOSE: To investigate the clinical outcome of proton therapy (PT) in patients with chordoma. MATERIALS AND METHODS: Fifty-eight patients with chordoma treated with PT between June 2007 and December 2015 at the National Cancer Center, Korea, were retrospectively analyzed. The median total dose was 69.6 cobalt gray equivalent (CGE; range, 64.8 to 79.2 CGE). Local progression-free survival (LPFS), distant metastasis-free survival (DMFS), overall survival (OS), and diseasespecific survival (DSS) rates were calculated by the Kaplan–Meier method. RESULTS: With the median follow-up of 42.8 months (range, 4 to 174 months), the 5-year LPFS, DMFS, OS, and DSS rates were 87.9%, 86.7%, 88.3%, and 92.9%, respectively. The tumor location was associated with the patterns of failure: the LPFS rates were lower for cervical tumors (57.1%) than for non-cervical tumors (93.1%) (p = 0.02), and the DMFS rates were lower for sacral tumors (53.5%) than for non-sacral tumors (100%) (p = 0.001). The total dose was associated with both the LPFS rate and DMFS rate. The initial tumor size was associated with the DMFS rate, but was not associated with the LPFS rate. Three patients had grade 3 late toxicity with none ≥grade 4. CONCLUSION: PT is an effective and safe treatment in patients with chordomas. The tumor location was associated with the patterns of failure: local failure was common in cervical tumors, and distant failure was common in sacral tumors. Further refinement of PT, such as the utilization of intensity modulated PT for cervical tumors, is warranted to improve the outcome.
Chordoma ; Cobalt ; Disease-Free Survival ; Follow-Up Studies ; Humans ; Korea ; Methods ; Proton Therapy ; Protons ; Retrospective Studies ; Treatment Outcome