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Abstract Background Elevated mammographic density (MD) for a woman’s age and body mass index (BMI) is an established breast cancer risk factor. The relationship of parity, age at first birth, and breastfeeding with MD is less clear. We examined the associations of these factors with MD within the International Consortium of Mammographic Density (ICMD). Methods ICMD is a consortium of 27 studies with pooled individual-level epidemiological and MD data from 11,755 women without breast cancer aged 35–85 years from 22 countries, capturing 40 country-& ethnicity-specific population groups. MD was measured using the area-based tool Cumulus. Meta-analyses across population groups and pooled analyses were used to examine linear regression associations of square-root (√) transformed MD measures (percent MD (PMD), dense area (DA), and non-dense area (NDA)) with parity, age at first birth, ever/never breastfed and lifetime breastfeeding duration. Models were adjusted for age at mammogram, age at menarche, BMI, menopausal status, use of hormone replacement therapy, calibration method, mammogram view and reader, and parity and age at first birth when not the association of interest. Results Among 10,988 women included in these analyses, 90.1% (n = 9,895) were parous, of whom 13% (n = 1,286) had ≥ five births. The mean age at first birth was 24.3 years (Standard deviation = 5.1). Increasing parity (per birth) was inversely associated with √PMD (β: − 0.05, 95% confidence interval (CI): − 0.07, − 0.03) and √DA (β: − 0.08, 95% CI: − 0.12, − 0.05) with this trend evident until at least nine births. Women who were older at first birth (per five-year increase) had higher √PMD (β:0.06, 95% CI:0.03, 0.10) and √DA (β:0.06, 95% CI:0.02, 0.10), and lower √NDA (β: − 0.06, 95% CI: − 0.11, − 0.01). In stratified analyses, this association was only evident in women who were post-menopausal at MD assessment. Among parous women, no associations were found between ever/never breastfed or lifetime breastfeeding duration (per six-month increase) and √MD. Conclusions Associations with higher parity and older age at first birth with √MD were consistent with the direction of their respective associations with breast cancer risk. Further research is needed to understand reproductive factor-related differences in the composition of breast tissue and their associations with breast cancer risk.

Abstract The prevalence and dynamics of circulating tumor DNA (ctDNA) in patients with breast cancer recurrence or de novo metastatic cancer were examined in a retrospective analysis of a prospective observational cohort. Twenty-three recurrent/metastatic breast cancer cases (8 locoregional, 15 distant metastasis) were enrolled, and sequential plasma samples were obtained. Anchor mutations were selected from the target sequencing of each patient’s primary and/or metastatic tumor. An in-house developed assay (UHS assay) was employed for a tumor-informed ctDNA assay during treatment and follow-up. A median of three (range 1–5) anchor mutations per case were applied for ctDNA detection. ctDNA was detected in 14 (63.6%, 14/22) cases at the time of enrollment and 18 (78.5%, 18/23) cases during follow-up. More anchor mutations and higher tumor burden were significantly related to higher ctDNA positive rates (p-value 0.036, 0.043, respectively). The mean enriched variant allele frequency (eVAF) at each time point was significantly higher for stable or progressive disease responses (ANOVA test p-value

Abstract Purpose This research aimed to clarify the impact of residual ductal carcinoma in situ(DCIS) in surgical specimens obtained after neoadjuvant chemotherapy(NAC) for breast cancer on the associated prognosis outcomes. Methods This retrospective study was performed on a cohort of 1,009 patients who achieved pCR following NAC for breast cancer and underwent subsequent breast surgery at a single institution between January 2008 and December 2019. Overall survival, local recurrence-free survival, distant metastasis-free survival, and disease-free survival of the residual and non-residual DCIS groups were the outcomes compared, with further subgroup analysis performed according to hormone receptor status. Results 260 individuals (25.8%) presented with residual DCIS. Based on a median follow-up of 54.0 months, no significant differences in outcomes were observed between the two groups. Patients with residual DCIS and hormone receptor-negative (HR-) breast cancer demonstrated a significant decrease in distant metastasis-free survival (p = 0.030) compared to those without residual DCIS. In the HR + cohort, no significant difference was observed between the two groups. Multivariate analysis of the HR- cohort demonstrated a significant association between residual DCIS and an elevated risk for distant recurrence (hazard ratio = 2.3, 95% confidence interval = 1.01–5.20, p = 0.047). Conclusions Residual DCIS following NAC may impact breast cancer outcomes, particularly with respect to the occurrence of distant metastasis in HR- patients. Therefore, clinicians must vigilantly monitor patients with residual DCIS after NAC, and further research is needed to expand our understanding of the clinical implications of residual DCIS.

Abstract High workload-induced cellular stress can cause pancreatic islet β cell death and dysfunction, or β cell failure, a hallmark of type 2 diabetes mellitus. Thus, activation of molecular chaperones and other stress-response genes prevents β cell failure. To this end, we have shown that deletion of the glucose-regulated protein 94 (GRP94) in Pdx1+ pancreatic progenitor cells led to pancreas hypoplasia and reduced β cell mass during pancreas development in mice. Here, we show that GRP94 was involved in β cell adaption and compensation (or failure) in islets from leptin receptor-deficient (db/db) mice in an age-dependent manner. GRP94-deficient cells were more susceptible to cell death induced by various diabetogenic stress conditions. We also identified a new client of GRP94, insulin-like growth factor-1 receptor (IGF-1R), a critical factor for β cell survival and function that may mediate the effect of GRP94 in the pathogenesis of diabetes. This study has identified essential functions of GRP94 in β cell failure related to diabetes.

IntroductionMale breast cancer (MBC) is a rare condition, and recent research has underscored notable distinctions between MBC and breast cancer in women. This study aimed to assess and contrast the long-term survival outcomes and disease patterns of MBC patients with those of their female counterparts.MethodsWe analyzed data from 113,845 patients diagnosed with breast cancer who had undergone curative surgery from the Korean Breast Cancer Registry (KBCR) between January 1990 and August 2014 in Seoul, Korea. The five-year overall survival was analyzed according to clinicopathological characteristics.ResultsAmong 113,845 patients with breast cancer, 473 MBC cases were included. The median duration of follow-up was 72 months. The median age at diagnosis was 60 and 48 years for MBC and female breast cancer, respectively. Most male patients (92.6%) underwent total mastectomy, while 50.4% of female patients underwent breast-conserving surgery. Among MBC, 63.2% received chemotherapy, and 83.9% of hormone receptor-positive male patients received endocrine therapy. In survival analysis, MBC demonstrated distinct 5-year overall survival patterns compared with female breast cancer, according to age at diagnosis. In women with breast cancer, the younger age group (≤40 years) demonstrated worse 5-year overall survival than did the older age group (>40 years) (91.3% vs 92.7%, p 40 years) (97.4% vs 86.4%, p

High-density polyethylene (HDPE) has emerged as a promising alternative to fiber-reinforced plastic (FRP) for small vessel manufacturing due to its durability, chemical resistance, lightweight properties, and recyclability. However, while thermoplastic polymers like HDPE have been extensively used in gas and water pipelines, their application in large, complex marine structures remains underexplored, particularly in terms of joining methods. Existing techniques, such as ultrasonic welding, laser welding, and friction stir welding, are unsuitable for large-scale HDPE components, where extrusion welding is more viable. This study focuses on evaluating the impact of key process parameters, such as the preheating temperature, hot air movement speed, and nozzle distance, on the welding performance of HDPE. By analyzing the influence of these variables on heat distribution during the extrusion welding process, we aim to conduct basic research to derive optimal conditions for achieving strong and reliable joints. The results highlight the critical importance of a uniform temperature distribution in preventing defects such as excessive melting or thermal degradation, which could compromise weld integrity. This research provides valuable insights into improving HDPE joining techniques, contributing to its broader adoption in the marine and manufacturing industries.

Aluminum hulls, which are preferred in the marine industry due to their durability, corrosion resistance, and lightweight properties, face serious challenges due to thermal deformation during welding. This study aims to predict and minimize transverse deformations due to welding sequences for a transverse model in the lower part of an aluminum hull. To predict deformations, heat source dimensions obtained from actual weld beads were used as simulation conditions, and various welding sequence conditions were simulated through the developed finite element method (FEM). The simulation results were compared with actual deformation measurements to verify their reliability, and the optimal welding sequence which minimized deformation was derived. The simulation results show that by changing the welding sequence conditions, the maximum displacement can be reduced from a maximum of 52.1% to a minimum of 39.1%, and the effective plastic strain can be reduced from a maximum of 19.6% to a minimum of 4.8%. These results show that adjusting the welding sequence conditions can significantly improve structural integrity by minimizing deformation. The results of this study suggest that the control of the welding sequence can be used to reduce the deformation of aluminum hulls and promote a more sustainable marine industry with improved quality.

The agr quorum-sensing system links Staphylococcus aureus metabolism to virulence, in part by increasing bacterial survival during exposure to lethal concentrations of H2O2, a crucial host defense against S. aureus. We now report that protection by agr surprisingly extends beyond post-exponential growth to the exit from stationary phase when the agr system is no longer turned on. Thus, agr can be considered a constitutive protective factor. Deletion of agr resulted in decreased ATP levels and growth, despite increased rates of respiration or fermentation at appropriate oxygen tensions, suggesting that Δagr cells undergo a shift towards a hyperactive metabolic state in response to diminished metabolic efficiency. As expected from increased respiratory gene expression, reactive oxygen species (ROS) accumulated more in the agr mutant than in wild-type cells, thereby explaining elevated susceptibility of Δagr strains to lethal H2O2 doses. Increased survival of wild-type agr cells during H2O2 exposure required sodA, which detoxifies superoxide. Additionally, pretreatment of S. aureus with respiration-reducing menadione protected Δagr cells from killing by H2O2. Thus, genetic deletion and pharmacologic experiments indicate that agr helps control endogenous ROS, thereby providing resilience against exogenous ROS. The long-lived ‘memory’ of agr-mediated protection, which is uncoupled from agr activation kinetics, increased hematogenous dissemination to certain tissues during sepsis in ROS-producing, wild-type mice but not ROS-deficient (Cybb−/−) mice. These results demonstrate the importance of protection that anticipates impending ROS-mediated immune attack. The ubiquity of quorum sensing suggests that it protects many bacterial species from oxidative damage.

Abstract Accumulation of α-synuclein into toxic oligomers or fibrils is implicated in dopaminergic neurodegeneration in Parkinson’s disease. Here we performed a high-throughput, proteome-wide peptide screen to identify protein-protein interaction inhibitors that reduce α-synuclein oligomer levels and their associated cytotoxicity. We find that the most potent peptide inhibitor disrupts the direct interaction between the C-terminal region of α-synuclein and CHarged Multivesicular body Protein 2B (CHMP2B), a component of the Endosomal Sorting Complex Required for Transport-III (ESCRT-III). We show that α-synuclein impedes endolysosomal activity via this interaction, thereby inhibiting its own degradation. Conversely, the peptide inhibitor restores endolysosomal function and thereby decreases α-synuclein levels in multiple models, including female and male human cells harboring disease-causing α-synuclein mutations. Furthermore, the peptide inhibitor protects dopaminergic neurons from α-synuclein-mediated degeneration in hermaphroditic C. elegans and preclinical Parkinson’s disease models using female rats. Thus, the α-synuclein-CHMP2B interaction is a potential therapeutic target for neurodegenerative disorders.

Abstract Our aim was to develop a tool to accurately predict the possibility of non-sentinel lymph node metastasis (NSLNM) during surgery so that a surgeon might decide the extent of further axillary lymph node dissection intraoperatively for patients with 1–3 positive sentinel lymph node(s) (SLN) after neoadjuvant chemotherapy. After retrospective analysis of Asan Medical Center (AMC) database, we included 558 patients’ records who were treated between 2005 and 2019. 13 factors were assessed for their utility to predict NSLNM with chi-square and logistic regression with a bootstrapped, backward elimination method. Based on the result of the univariate analysis for statistical significance, number of positive SLN(s), number of frozen nodes, Progesterone Receptor (PR) positivity, clinical N stage were selected for the multivariate analysis and were utilized to generate a nomogram for prediction of residual nodal disease. The resulting nomogram was tested for validation by using a patient group of more recent, different time window at AMC. We designed a nomogram to be predictive of the NSLNM which consisted of 4 components: number of SLN(s), number of frozen nodes, PR positivity, and clinical N stage before neoadjuvant chemotherapy. The Area under the receiver operating characteristics curve (AUC) value of this formula was 0.709 (95% CI, 0.658–0.761) for development set and 0.715 (95% CI, 0.634–0.796) for validation set, respectively. This newly created AMC nomogram may provide a useful information to a surgeon for intraoperative guidance to decide the extent of further axillary surgery.

Abstract Background MammaPrint (MMP) helps clinicians identify the ideal time for adjuvant treatment for patients with early HR+/HER2− breast cancer. We aimed to validate a nomogram designed to predict probability of low risk of MMP results and to evaluate the difference in survival outcome between two groups divided by nomogram score. Methods In this retrospective cohort study, we evaluated 172 patients from Asan Medical Center, Seoul, Korea, who underwent breast cancer surgery and MMP during 2020–2021. First, we validated the nomogram by calculating the area under the curve (AUC) and using calibration. Additionally, with the data of 1,835 T1-3N0-1M0 HR+/HER2− patients from Asan Medical Center during 2010–2013, we compared the disease-free survival (DFS), overall survival (OS), and breast cancer-specific survival (BCSS) rates by Kaplan−Meier analysis between the two groups divided by nomogram total point (TP) of 183. Results The AUC calculated by validation of 172 patients was 0.73 (95% confidence interval [CI], 0.66–0.81). The discrimination and calibration of the prediction model were satisfactory following additional validation of 1835 patients. The high-risk and low-risk groups had different 5-year OS (97.9% vs. 98.1%, p = 0.056), DFS (98.6% vs. 99.4%, p = 0.008), and BCSS rates (98.6% vs. 99.4%, p = 0.002). Conclusion For treatment decision-making among clinically high-risk patients with HR+/HER2− and node-positive disease, the nomogram showed satisfactory performance in predicting patients with low genomic risk. Survival outcome significantly differed between two groups divided by nomogram TP. More studies are needed to validate this model in international cohorts and large prospective cohorts from other institutions.

Staphylococcus aureus is an important pathogen that leads to significant disease through multiple routes of infection. We recently published a transposon sequencing (Tn-seq) screen in a mouse acute pneumonia model and identified a hypothetical gene (SAUSA300_1902, pgl) with similarity to a lactonase of Escherichia coli involved in the pentose phosphate pathway (PPP) that was conditionally essential. Limited studies have investigated the role of the PPP in physiology and pathogenesis of S. aureus. We show here that mutation of pgl significantly impacts ATP levels and respiration. RNA-seq analysis of the pgl mutant and parent strains identified compensatory changes in gene expression for glucose and gluconate as well as reductions in the pyrimidine biosynthesis locus. These differences were also evident through unbiased metabolomics studies and 13C labeling experiments that showed mutation of pgl led to reductions in pyrimidine metabolism including decreases in ribose-5P, UMP and GMP. These nucleotide reductions impacted the amount of extracellular DNA in biofilms and reduced biofilm formation. Mutation also limited the capacity of the strain to resist oxidant damage induced by hydrogen peroxide and paraquat and subsequent intracellular survival inside macrophages. Changes in wall teichoic acid impacted susceptibility to hydrogen peroxide. We demonstrated the importance of these changes on virulence in three different models of infection, covering respiratory, skin and septicemia, demonstrating the need for proper PPP function in all models. This work demonstrates the multifaceted role metabolism can play in multiple aspects of S. aureus pathogenesis.

Abstract Background Early age at menarche and tall stature are associated with increased breast cancer risk. We examined whether these associations were also positively associated with mammographic density, a strong marker of breast cancer risk. Methods Participants were 10,681 breast-cancer-free women from 22 countries in the International Consortium of Mammographic Density, each with centrally assessed mammographic density and a common set of epidemiologic data. Study periods for the 27 studies ranged from 1987 to 2014. Multi-level linear regression models estimated changes in square-root per cent density (√PD) and dense area (√DA) associated with age at menarche and adult height in pooled analyses and population-specific meta-analyses. Models were adjusted for age at mammogram, body mass index, menopausal status, hormone therapy use, mammography view and type, mammographic density assessor, parity and height/age at menarche. Results In pooled analyses, later age at menarche was associated with higher per cent density (β √PD = 0.023 SE = 0.008, P = 0.003) and larger dense area (β √DA = 0.032 SE = 0.010, P = 0.002). Taller women had larger dense area (β √DA = 0.069 SE = 0.028, P = 0.012) and higher per cent density (β √PD = 0.044, SE = 0.023, P = 0.054), although the observed effect on per cent density depended upon the adjustment used for body size. Similar overall effect estimates were observed in meta-analyses across population groups. Conclusions In one of the largest international studies to date, later age at menarche was positively associated with mammographic density. This is in contrast to its association with breast cancer risk, providing little evidence of mediation. Increased height was also positively associated with mammographic density, particularly dense area. These results suggest a complex relationship between growth and development, mammographic density and breast cancer risk. Future studies should evaluate the potential mediation of the breast cancer effects of taller stature through absolute breast density.

Abstract Salivary glands that produce and secrete saliva, which is essential for lubrication, digestion, immunity, and oral homeostasis, consist of diverse cells. The long-term maintenance of diverse salivary gland cells in organoids remains problematic. Here, we establish long-term murine and human salivary gland organoid cultures. Murine and human salivary gland organoids express gland-specific genes and proteins of acinar, myoepithelial, and duct cells, and exhibit gland functions when stimulated with neurotransmitters. Furthermore, human salivary gland organoids are established from isolated basal or luminal cells, retaining their characteristics. Single-cell RNA sequencing also indicates that human salivary gland organoids contain heterogeneous cell types and replicate glandular diversity. Our protocol also enables the generation of tumoroid cultures from benign and malignant salivary gland tumor types, in which tumor-specific gene signatures are well-conserved. In this study, we provide an experimental platform for the exploration of precision medicine in the era of tissue regeneration and anticancer treatment.

To gain a better insight of how Copper (Cu) ions toxify cells, metabolomic analyses were performed in S. aureus strains that lacks the described Cu ion detoxification systems (ΔcopBL ΔcopAZ; cop-). Exposure of the cop- strain to Cu(II) resulted in an increase in the concentrations of metabolites utilized to synthesize phosphoribosyl diphosphate (PRPP). PRPP is created using the enzyme phosphoribosylpyrophosphate synthetase (Prs) which catalyzes the interconversion of ATP and ribose 5-phosphate to PRPP and AMP. Supplementing growth medium with metabolites requiring PRPP for synthesis improved growth in the presence of Cu(II). A suppressor screen revealed that a strain with a lesion in the gene coding adenine phosphoribosyltransferase (apt) was more resistant to Cu. Apt catalyzes the conversion of adenine with PRPP to AMP. The apt mutant had an increased pool of adenine suggesting that the PRPP pool was being redirected. Over-production of apt, or alternate enzymes that utilize PRPP, increased sensitivity to Cu(II). Increasing or decreasing expression of prs resulted in decreased and increased sensitivity to growth in the presence of Cu(II), respectively. We demonstrate that Prs is inhibited by Cu ions in vivo and in vitro and that treatment of cells with Cu(II) results in decreased PRPP levels. Lastly, we establish that S. aureus that lacks the ability to remove Cu ions from the cytosol is defective in colonizing the airway in a murine model of acute pneumonia, as well as the skin. The data presented are consistent with a model wherein Cu ions inhibits pentose phosphate pathway function and are used by the immune system to prevent S. aureus infections.

Abstract Background Malignant adenomyoepithelioma of the breast is a rare tumor and most of relevant literature consists of individual case reports. This study objective was designed to evaluate clinicopathological features and treatment outcomes of 15 cases of malignant adenomyoepithelioma at a single institute. Methods A retrospective medical record review was performed for 15 subjects confirmed with malignant adenomyoepithelioma upon postoperative pathological diagnosis at the Asan Medical Center from January 2008 to June 2018. Data regarding age at diagnosis, preoperative biopsy results, operation methods, the status of hormone receptors and HER2, and clinical outcomes were collected. Results All cases were female patients diagnosed at median age of 50 years. Preoperative core needle biopsy results showed that 40% of the cases (6 out of 15) were benign which was in discordance with the final malignant pathology report. Thirteen cases underwent wide excision with or without sentinel lymph node biopsy (SLNB) and 2 cases had total mastectomy with SLNB. Five of 11 cases (45.5%) were triple negative. Ten of 15 cases underwent postoperative radiation therapy, 3 cases underwent chemotherapy, and 5 cases underwent endocrine therapy. During median follow-up of 55 months, the 5-year overall survival rate was 87.5% and the 5-year disease free survival rate was 91.7%. Two lung metastases developed. One case showed local recurrence 3 years after surgery and radiotherapy and subsequently developed lung metastasis 1 year late. Another case developed lung metastasis one and a half years after surgery in combination with endocrine therapy and neoadjuvant chemotherapy. Conclusion Preoperative core needle biopsy showed inaccurate results for diagnosing malignant adenomyoepithelioma. Malignant adenomyoepithelioma has a high rate of triple negative subtype but has a relatively good prognosis although there is a risk of local and systemic recurrence.

Acinetobacter baumannii is an opportunistic pathogen that has recently emerged as a global threat associated with high morbidity, mortality, and antibiotic resistance. We determined the role of type I interferon (IFN) signaling in A. baumannii infection. We report that A. baumannii can induce a type I IFN response that is dependent upon TLR4-TRIF-IRF3 and phagocytosis of the bacterium. Phase variants of A. baumannii that have a reduced capsule, lead to enhanced TLR4-dependent type I IFN induction. This was also observed in a capsule-deficient strain. However, we did not observe a role for this pathway in vivo. The enhanced signaling could be accounted for by increased phagocytosis in capsule-deficient strains that also lead to enhanced host cell-mediated killing. The increased cytokine response in the absence of the capsule was not exclusive to type I IFN signaling. Several cytokines, including the proinflammatory IL-6, were increased in cells stimulated with the capsule-deficient strain, also observed in vivo. After 4 h in our acute pneumonia model, the burden of a capsule-null strain was significantly reduced, yet we observed increases in innate immune cells and inflammatory markers compared to wild-type A. baumannii. This study underscores the role of phase variation in the modulation of host immune responses and indicates that the capsule of A. baumannii plays an important role in protection against host cell killing and evasion from activation of the innate immune response.

Abstract We aimed to develop a prediction MammaPrint (MMP) genomic risk assessment nomogram model for hormone-receptor positive (HR+) and human epidermal growth factor receptor-2 negative (HER2–) breast cancer and minimal axillary burden (N0-1) tumors using clinicopathological factors of patients who underwent an MMP test for decision making regarding adjuvant chemotherapy. A total of 409 T1-3 N0-1 M0 HR + and HER2– breast cancer patients whose MMP genomic risk results and clinicopathological factors were available from 2017 to 2020 were analyzed. With randomly selected 306 patients, we developed a nomogram for predicting a low-risk subgroup of MMP results and externally validated with remaining patients (n = 103). Multivariate analysis revealed that the age at diagnosis, progesterone receptor (PR) score, nuclear grade, and Ki-67 were significantly associated with MMP risk results. We developed an MMP low-risk predictive nomogram. With a cut off value at 5% and 95% probability of low-risk MMP, the nomogram accurately predicted the results with 100% positive predictive value (PPV) and negative predictive value respectively. When applied to cut-off value at 35%, the specificity and PPV was 95% and 86% respectively. The area under the receiver operating characteristic curve was 0.82 (95% confidence interval [CI] 0.77 to 0.87). When applied to the validation group, the nomogram was accurate with an area under the curve of 0.77 (95% CI 0.68 to 0.86). Our nomogram, which incorporates four traditional prognostic factors, i.e., age, PR, nuclear grade, and Ki-67, could predict the probability of obtaining a low MMP risk in a cohort of high clinical risk patients. This nomogram can aid the prompt selection of patients who does not need additional MMP testing.

Abstract Background Although few studies have shown that risk factors for Alzheimer’s disease (AD) are associated with cognitive decline in AD, not much is known whether the impact of risk factors differs between early-onset AD (EOAD, symptom onset

Abstract For residual N1 nodal disease following neoadjuvant chemotherapy (NAC) for patients with breast cancer, the optimal local therapy for axilla is an evolving area. We analyzed the long-term results of these patients according to axillary surgical methods using propensity score matching (PSM) to clarify whether omission of axillary lymph node dissection (ALND) is oncologically safe. This was a single institution retrospective study of patients with ypN1 from Asan Medical Center (AMC). We included 324 patients who had undergone axillary surgery with either sentinel lymph node biopsy (SLNB) only or ALND. The patients received NAC at AMC between 2008 and 2013. General indications for ALND included prominent nodes detected clinically before NAC, evident macrometastasis on multiple nodes during SLNB. Patients who had either micrometastasis or macrometastasis in 1 or 2 node(s) were included. SLNB was performed for patients with good responders to NAC with limited nodal burden. Patients were matched for baseline characteristics. After matching, we included 98 patients in each SLNB only group and ALND group respectively. We compared axillary recurrence-free survival (ARFS), distant metastasis-free survival (DMFS), overall survival (OS), and breast cancer-free survival (BCSS) according to the surgical method. The median follow-up period was 71 months. Univariate and multivariate analyses revealed no statistically significant differences between the two groups for ARFS, DMFS, OS, and BCSS. After the propensity score matching, no significant statistical differences were observed in 5-year ARFS, DMFS, OS, and BCSS between the SLNB only group and ALND group. SLNB might be a possible option for ALND in patients with breast cancer who have limited axillary node metastasis after NAC without compromising survival outcomes.

Abstract We used 3D printed-breast surgical guides (3DP-BSG) to designate the original tumor area from the pre-treatment magnetic resonance imaging (MRI) during breast-conserving surgery (BCS) in breast cancer patients who received neoadjuvant systemic therapy (NST). Targeting the original tumor area in such patients using conventional localization techniques is difficult. For precise BCS, a method that marks the tumor area found on MRI directly to the breast is needed. In this prospective study, patients were enrolled for BCS after receiving NST. Partial resection was performed using a prone/supine MRI-based 3DP-BSG. Frozen biopsies were analyzed to confirm clear tumor margins. The tumor characteristics, pathologic results, resection margins, and the distance between the tumor and margin were analyzed. Thirty-nine patients were enrolled with 3DP-BSG for BCS. The median nearest distance between the tumor and the resection margin was 3.9 cm (range 1.2–7.8 cm). Frozen sections showed positive margins in 4/39 (10.3%) patients. Three had invasive cancers, and one had carcinoma in situ; all underwent additional resection. Final pathology revealed clear margins. After 3-year surveillance, 3/39 patients had recurrent breast cancer. With 3DP-BSG for BCS in breast cancer patients receiving NST, the original tumor area can be identified and marked directly on the breast, which is useful for surgery. Trial Registration: Clinical Research Information Service (CRIS) Identifier Number: KCT0002272. First registration number and date: No. 1 (27/04/2016).

Abstract Background Prostaglandin is one of the key metabolites for inflammation-related carcinogenesis. Despite the microRNA-155 is implicated in various types of cancers, it’s function in prostaglandin metabolism is largely unknown. Methods A targeted profiling of eicosanoids including prostaglandin, leukotriene and thromboxanes was performed in miR-155 deficient breast tumors and cancer cells. The molecular mechanism of miR-155-mediated prostaglandin reprogramming was investigated in primary and cancer cell lines, by analyzing key enzymes responsible for the prostaglandin production. Results We found miR-155-deficient breast tumors, plasma of tumor-bearing mouse and cancer cells show altered prostaglandin level, especially for the prostaglandin E2 (PGE2) and prostaglandin D2 (PGD2). Subsequent analysis in primary cancer cells, 20 triple-negative breast cancer (TNBC) specimens and breast cancer cell lines with miR-155 knockdown consistently showed a positive correlation between miR-155 level and PGE2/PGD2 ratio. Mechanistically, we reveal the miR-155 reprograms the prostaglandin metabolism by up-regulating PGE2-producing enzymes PTGES/PTGES2 while down-regulating PGD2-producing enzyme PTGDS. Further, we show the up-regulation of PTGES2 is driven by miR-155-cMYC axis, whereas PTGES is transactivated by miR-155-KLF4. Thus, miR-155 hires dual-regulatory mode for the metabolic enzyme expression to reprogram the PGE2/PGD2 balance. Lastly, we show the miR-155-driven cellular proliferation is restored by the siRNA of PTGES1/2, of which expression also significantly correlates with breast cancer patients’ survival. Conclusions Considering clinical trials targeting PGE2 production largely have focused on the inhibition of Cox1 or Cox2 that showed cardiac toxicity, our data suggest an alternative way for suppressing PGE2 production via the inhibition of miR-155. As the antagomiR of miR-155 (MRG-106) underwent a phase-1 clinical trial, its effect should be considered and analyzed in prostaglandin metabolism in tumor.

Abstract To facilitate precise tumor resection at the time of breast-conserving surgery (BCS), we developed and implemented a magnetic resonance imaging (MRI)-based three-dimensional-printed (3DP) breast surgical guide (BSG). This prospective cohort study was conducted at a single institution from July 2017 to February 2019 on women with breast cancer who underwent partial breast resection using patient-specific 3DP BSGs. Eighty-eight patients with invasive cancer were enrolled, of whom 1 patient had bilateral breast cancer. The mean size of the tumor long-axis on MRI before surgery was 2.8 ± 0.9 cm, and multiple tumors were observed in 34 patients. In 16 cases (18.0%), the resection margin was tumor-positive according to intraoperative frozen biopsy; all of these tumors were ductal carcinoma in situ and were re-excised intraoperatively. In 93.3% of the cases, the resection margin was tumor-free in the permanent pathology. The mean pathological tumor size was 1.7 ± 1.0 cm, and the mean distance from the tumor to the border was 1.5 ± 1.0 cm. This exploratory study showed that the tumor area on the MRI could be directly displayed on the breast when using a 3DP BSG for BCS, thereby allowing precise surgery and safe tumor removal. Trial Registration Clinical Research Information Service (CRIS) Identifier (No. KCT0002375, KCT0003043).

Rationale: Exposure to fine particulate matter has adverse effects on mental health outcomes. However, no empirical study has yet been conducted on mechanisms of how and why exposure to fine particulate matter can affect mental health outcomes, especially focusing on children. In addition, children living in poverty may be more vulnerable to fine particulate matter. Objective: This study aims to examine whether physical activity can explain the impact of ambient fine particulate matter on depressive symptoms among Korean children and whether family poverty moderates the associations between fine particulate matter, physical activity, and children’s depressive symptoms. Methods: Children and their primary caregiver data were drawn from the Children’s Happiness Life Time Survey data collected by Child Fund Korea, and fine particulate matter data were derived from Air Korea, collected by the Korea Environment Corporation. Individual-level data were linked to a nationwide neighborhood-level data on air quality. Multilevel structural equation modeling was used to consider the hierarchical data structure. The analytical sample consisted of 4,161 children living in 79 neighborhoods. Results: The findings suggest that living in neighborhoods with higher levels of fine particulate matter is associated with a decrease in physical activity, which in turn increases children’s depressive symptoms. Physical activity fully mediates the association between fine particulate matter and children’s depressive symptoms. However, family poverty does not have a significant moderating role for the associations between fine particulate matter, physical activity, and children’s depressive symptoms. Conclusions: The results of this study indicate the importance of physical activity in relation to fine particulate matter and children’s depressive symptoms.

Purpose To evaluate the clinical course and long-term outcomes of patients with ipsilateral breast tumor recurrence (IBTR) after breast-conserving surgery (BCS) and identify independent prognostic factors for further recurrence. Methods In this retrospective study, we reviewed the records of 327 patients who experienced IBTR after undergoing BCS for breast cancer at Asan Medical Center during 1990–2013. Overall survival (OS) after IBTR and cumulative incidence rates of recurrences after IBTR were calculated. The association of clinicopathological factors with survival and the development of further recurrence after IBTR was determined in multivariate analysis. Results At a median follow-up of 127.7 months, 97 patients experienced recurrence after IBTR. The 5-year and 10-year cumulative incidence rates of recurrence after IBTR were 32% and 41%, respectively. The 5-year and 10-year OS rates after IBTR were 86.6% and 70.3%, respectively. In multivariate analysis, hormone receptor negativity was associated with decreases in OS after IBTR (hazard ratio [HR] 2.83, 95% confidence interval [CI] 1.18–6.78). Patients with longer disease-free interval (DFI) had decreased risks of second recurrence (HR .99, 95% CI .99–1.00), and second locoregional recurrence (LRR) (HR .98, 95% CI .97–.99). Lymphovascular invasion (LVI) of IBTR was associated with increased recurrence rates (second recurrence-free survival, HR 3.58, 95% CI 2.16–5.94; second LRR free survival, HR 5.21, 95% CI 2.77–9.78; second distant metastasis-free survival, 2.11, 95% CI 1.04–4.30) and lower survival rates (OS after IBTR, HR 4.64, 95% CI 2.23–9.67). Conclusions Despite subsequent recurrences during long-term follow-up, the survival rates after IBTR remained high. Patients with hormone receptor-negative tumors, shorter DFI, and tumors that present LVI of IBTR had higher risks for recurrence and poor survival rates after IBTR. The study findings may help in understanding the course and prognosis of IBTR patients and identifying high-risk IBTR to establish management strategies.

With the rapid diffusion of smartphones as well as the technical advances in mobile platform technologies, application domains supported by smartphones have dramatically increased. Unlike traditional computer systems, however, the context of applications may be lost in a smartphone as mobile OS usually kills applications without user's approval when free memory space is exhausted. This was not a serious issue when a smartphone was a personal entertainment device, but it is now significant as a lot of official works are also performed by a smartphone. Instead of killing a process, the context of an application can be backed up to swap storage, but smartphones do not accept it as swap incurs excessively heavy I/O traffic. However, our findings show that the overhead of swap is not serious in recent smartphone devices and it can also be eliminated by judicious software management. This article proposes a selective swap scheme that classifies applications based on their context-saving characteristics, and controls the number of processes involved in swap by monitoring system situations and application characteristics. That is, we maintain the context of applications selectively by swap or application's own state-saving. We implement and measure the effectiveness of our scheme on a real Android device, showing that it provides the context-savings of applications without additional overhead.

Virtualization is widely used in modern computer systems ranging from personal computers to cloud servers as it provides various heterogeneous platforms at low cost. However, due to its nested software structure in host and guest machines that are difficult to harmonize, it is challenging to manage resources efficiently in virtualized systems. In this article, we anatomize the overhead of virtualization associated with file system journaling and discover the excessively frequent commits that take place in virtualized systems. This is because the host triggers commit on every write request from all guest machines. This also generates unnecessary write traffic to storage. To remedy these problems, we propose the VM-separated commit, and implement it on QEMU-KVM and Ext4. Specifically, we devise a data structure that manages modified file blocks from each guest as a separate list and split the running transaction list into two sub-transactions based on this data structure upon a commit request from a guest. Measurement studies with Filebench and IOzone benchmarks show that the proposed policy improves the I/O throughput by 19.5% on average and up to 64.2% over existing systems. It also reduces the variability in performance.

Purpose Head rotation is thought to have an effect on obstructive sleep apnea (OSA) severity. However, keeping the head rotated fully during sleep is difficult to maintain, and the effect of head rotation is not the same in all OSA patients. Thus, this study aimed to identify whether less head rotation has an effect on airway patency and determine the responder characteristics to the head rotation maneuver (HRM). Methods We recruited 221 patients who underwent overnight polysomnography and drug-induced sleep endoscopy (DISE) in a tertiary hospital from June 2019 to July 2020. Airway patency and the site of airway collapse were determined in the supine position with the head at 0, 30, and 60 degrees of rotation (HRM0°, HRM30°, and HRM60°, respectively) during DISE. The site of collapse was determined using the VOTE classification system: the velum (palate), oropharyngeal lateral walls, tongue base, and epiglottis. Each structure was labeled as 0, 1, or 2 (patent, partially obstructed, and completely obstructed, respectively). Airway response to the HRM30° and 60° and the clinical characteristics associated with airway opening were analyzed. Results The study population had a median age of 52 (25–61) years, a body mass index of 26.7(24.6–29.4) kg/m2, and the apnea-hypopnea index (AHI) of 28.2(13.7–71.9) events/h. HRM influenced airway patency positively not only with HRM60° (pConclusion Head rotation improved airway obstruction in OSA patients, even with a small degree of rotation, and should be further explored as a potential form of therapy in appropriately selected patients.

Purpose The aim of this study was to evaluate the chronological changes over 14 years in the survival of Korean patients with breast cancer. We also sought to investigate the factors that may have influenced the changes in survival rate. Materials and methods We retrospectively analyzed 17,776 breast cancer patients who were treated at Asan Medical Center between January 2000 and December 2013. Patient information was collected from the Asan database, including age at diagnosis, clinical manifestation, pathology report, types of treatment and modality, types of recurrence, and follow-up period. We classified the patients into two cohorts according to the year of their surgery (P1: 2000–2007 and P2: 2008–2013) and compared survival and recurrence between both cohorts. Results We observed that patients treated more recently had better survival outcomes. The 5-year breast cancer-specific survival increased from 94.0% in P1 to 96.6% in P2 (pConclusion This study showed improvement in breast cancer survival over the succeeding years, which is consistent with the advancement in systemic therapy.

The East Asian summer monsoon (EASM) is an influential monsoon system that provides two-thirds of the annual precipitation in the Asian region. Therefore, considerable attention has been paid to the changes in future climate. Thus far, studies on EASM characteristics have not been conducted considering specific global warming level (GWL) using Coupled Model Inter-comparison Project 6 (CMIP6) simulations. We analyze the EASM characteristics in present-day (PD) and the changes in EASM corresponding to the projections at 1.5, 2.0, and 3.0°C GWLs. The newly released 30 CMIP6 models effectively captured the migration of the monsoon in PD with a pattern correlation coefficient of 0.91, which is an improvement over that reported in previous studies. As a result of the separate analysis of the P1 (first primary peak; 33–41 pentad) and P2 (from P1 to the withdrawal; 42–50 pentad) periods, a higher frequency of weak to moderate precipitation in P2 and a smaller amount of moderate to extreme precipitation in P1 are mainly occurred. The CMIP6 models project increasing precipitation of approximately 5.7%°C−1, 4.0%°C−1, and 3.9%°C−1 for the three GWLs, respectively, with longer durations (earlier onset and delayed termination). Under the three GWLs, the projected precipitation frequency decreases below 6 mm d−1 (76th percentile) and significant increases above 29 mm d−1 (97th percentile). These changes in precipitation frequency are associated with an increasing distribution of precipitation amount above 97th percentile. Additionally, these tendencies in P1 and P2 are similar to that of the total period, while the maximum changes occur in 3.0°C GWL. In particular, future changes in EASM accelerate with continuous warming and are mainly affected by enhanced extreme precipitation (above 97th percentile). Our findings are expected to provide information for the implementation of sustainable water management programs as a part of national climate policy.

Analysis of the dependency of the trabecular structure on loading conditions is essential for understanding and predicting bone structure formation. Although previous studies have investigated the relationship between loads and structural adaptations, there is a need for an in-depth analysis of this relationship based on the bone region and load specifics. In this study, the load dependency of the trabecular bone microstructure for twelve regions of interest (ROIs) in the synthetic proximal femur was quantitatively analyzed to understand the spatial characteristics under seven different loading conditions. To investigate the load dependency, a quantitative measure, called the load dependency score (LDS), was established based on the statistics of the strain energy density (SED) distribution. The results showed that for the global model and epiphysis ROIs, bone microstructures relied on the multiple-loading condition, whereas the structures in the metaphysis depended on single or double loads. These results demonstrate that a given ROI is predominantly dependent on a particular loading condition. The results confirm that the dependency analysis of the load effects for ROIs should be performed both qualitatively and quantitatively.

Age-associated persistent ER stress is the result of declining chaperone systems of the ER that reduces cellular functions, induces apoptosis, and leads to age-related diseases. This study investigated the previously unknown regulatory mechanism of TMBIM6 during age-associated hepatic abnormalities. Wild-type (WT) and the TMBIM6 knockout (TMBIM6−/−) mice liver, human liver samples from different age groups were used to demonstrate the effect of physiological aging on liver. For TMBIM6 rescue experiments, TMBIM6−/− old mice and stable human hepatic cell lines expressing TMBIM 6 were used to study the functional role of TMBIM6 on aging-associated steatosis and its associated mechanisms. In aging humans and mice, we observed declined expression of TMBIM6 and aberrant UPR expression, which were associated with high hepatic lipid accumulation. During aging, TMBIM6-deficient mice had increased senescence than their WT counterparts. We identified redox-mediated posttranslational modifications of IRE1α such as S-nitrosylation and sulfonation were higher in TMBIM6-deficient aging mice and humans, which impaired the ER stress response signaling. Sulfonation of IRE1α enhanced regulated IRE1α-dependent decay (RIDD) activity inducing TMBIM6 decay, whereas S-nitrosylation of IRE1α inhibited XBP1 splicing enhancing the cell death. Moreover, the degradation of miR-338-3p by strong IRE1α cleavage activity enhanced the expression of PTP1B, resulting in diminishing phosphorylation of PERK. The re-expression of TMBIM6 reduced IRE1α modifications, preserved ER homeostasis, reduced senescence and senescence-associated lipid accumulation in human hepatic cells and TMBIM6-depleted mice. S-nitrosylation or sulfonation of IRE1α and its controller, the TMBIM6, might be the potential therapeutic targets for maintaining ER homeostasis in aging and aging-associated liver diseases.

Topology optimization is currently the only way to provide bone microstructure information by enhancing a 600 μm low-resolution image into a 50 μm high-resolution image. Particularly, the recently proposed localized reconstruction method for the region of interest has received much attention because it has a high possibility to overcome inefficiency such as iterative large-scale problems of the conventional reconstruction. Despite the great potential, the localized method should be thoroughly validated for clinical application. This study aims to quantitatively validate the topology optimization-based localized bone microstructure reconstruction method in terms of accuracy and efficiency by comparing the conventional method. For this purpose, this study re-constructed bone microstructure for three regions of interest in the proximal femur by localized and conventional methods, respectively. In the comparison, the dramatically reduced total progress time by at least 88.2% (20.1 h) as well as computational resources by more than 95.9% (54.0 gigabytes) were found. Moreover, very high reconstruction accuracy in the trabecular alignment (up to 99.6%) and morphometric indices (up to 2.71%) was also found. These results indicated that the localized method could reconstruct bone microstructure, much more effectively preserving the originality of the conventional method.

Lumen formation of salivary glands has been investigated using in vivo or ex vivo rudiment culture models. In this study, we used a three-dimensional (3D) salivary gland organoid culture system and demonstrated that lumen formation could be recapitulated in mouse SMG organoids. In our organoid culture system, lumen formation was induced by vasoactive intestinal peptide and accelerated by treatment with RA. Furthermore, lumen formation was observed in branching duct-like structure when cultured in combination of fibroblast growth factors (FGF) in the presence of retinoic acid (RA). We suggest RA signaling-mediated regulation of VIPR1 and KRT7 as the underlying mechanism for lumen formation, rather than apoptosis in the organoid culture system. Collectively, our results support a fundamental role for RA in lumen formation and demonstrate the feasibility of 3D organoid culture as a tool for studying salivary gland morphogenesis.

BackgroundFew data are available on the risk factors of locoregional recurrence (LRR) after neoadjuvant chemotherapy (NACT) and immediate breast reconstruction (IBR) in breast cancer. Herein, we evaluated the factors predicting LRR in a large series of patients who underwent either nipple- (NSM) or skin-sparing mastectomy (SSM) with IBR after NACT.MethodsWe retrospectively analyzed 609 breast cancer patients who underwent NACT and NSM/SSM with IBR between February 2010 and June 2017. Factors associated with an increased risk of LRR were analyzed by univariate (chi-square or Fisher’s exact test) and multivariate (Cox proportional hazard regression model) analyses.ResultsDuring a median follow-up of 63 months, LRR as the first event occurred in 73 patients, and the 5-year cumulative LRR rate was 10.8%. Multivariate analysis revealed post-NACT Ki67 ≥ 10% [hazard ratio (HR), 2.208; 95% confidence interval (CI), 1.295-3.765; P = 0.004], high tumor grade (HR, 1.738; 95% CI, 1.038-2.908; P = 0.035), and presence of lymphovascular invasion (LVI) (HR, 1.725; 95% CI, 1.039-2.864; P = 0.035) as independently associated with increased LRR risk. The 10-year LRR rate was 8.5% for patients with none of the three associated risk factors, 11.6% with one factor, 25.1% with two factors, and 33.7% with all three factors (P < 0.001).ConclusionsPost-NACT Ki67 ≥ 10%, high tumor grade, and presence of LVI are independently associated with an increased risk of developing LRR after NACT and NSM/SSM with IBR. Future prospective trials are warranted to decrease the risk of LRR in patients with associated risk factors.

Eosinophilic esophagitis is a rare disease in Asian countries, but its incidence is growing rapidly in Western countries. The main pathophysiology of eosinophilic esophagitis is esophageal epithelial barrier dysfunction; disruption of the esophageal epithelial barrier easily induces antigen sensitization to foods and aeroallergens, which leads to subsequent esophageal inflammation as a result of eosinophil recruitment. Here we report a case of an 11-year-old Korean boy who suffered from fever, odynophagia, dysphagia, and chest pain. His upper endoscopic findings showed longitudinal ulcers with a volcano-like appearance at the distal esophagus. Polymerase chain reaction test results and biopsy specimens were positive for herpes simplex virus type 1. He was treated with acyclovir and a proton pump inhibitor, but his follow-up endoscopy showed typical patterns of eosinophilic esophagitis, and the biopsy specimens were compatible with the diagnostic criteria for eosinophilic esophagitis. Therefore, we report a very rare case of eosinophilic esophagitis after herpes esophagitis in a Korean child with normal immunity.

Summary: Background/Objective: The prognosis of hormone receptor-positive and HER2-negative breast cancer is better than that of other subtypes. Current guidelines recommend chemotherapy for N1 breast cancer patients. However, this has the possibility to be over-treatment. Methods: This was a retrospective study of 18,549 patients who were surgically treated for invasive breast cancer, at a single center in South Korea, between January 1993 and December 2012. N1 stage breast cancer patients who were hormone receptor-positive and HER2-negative were enrolled, and propensity score matching was performed to compare patients treated with anti-hormonal therapy alone (N = 83) and those treated with chemotherapy followed by anti-hormonal therapy (N = 85). Results: In survival analysis, the survival parameters of the endocrine therapy-only group and the chemotherapy with endocrine therapy group were respectively 96.1% and 94.0% for 5-year recurrence free survival (RFS), 89.6% and 94.0% for 10-year RFS, 97.4% and 94.0% for 5-year distant metastasis-free survival (DMFS), 93.2% and 94.0% for 10-year DMFS, 98.7% and 98.8% for 10-year breast cancer-specific survival (BCSS), and 98.7% and 98.8% for 10-year overall survival (OS). There were no significant differences in RFS (p = 0.871), DMFS (p = 0.491), BCSS (p = 0.569) and OS (p = 0.731) between the two groups. Conclusion: Several patients with clinicopathologic features like hormone receptor positivity and HER2 negativity can avoid chemotherapy even with lymph node metastasis. Future studies with a long-term follow-up and a larger number of patients are required for validating our results. Keywords: Adjuvant endocrine therapy, Breast neoplasms, Luminal A breast cancer, Node-positive breast cancer, Prognosis

Due to the recent advances in mobile platform technologies, people are increasingly working with their smartphones. For example, digital healthcare, automotive navigation, and stock trading are also performed by a smartphone as well as phone calls. However, there are some technical hurdles for executing reliable software in a smartphone. Specifically, current smartphones kill applications without using swap when free memory space is exhausted. Although supporting swap in a smartphone is not impossible, our observation shows that swap in Android increases storage accesses significantly, leading to thrashing conditions. To resolve this, we further analyze Android swap I/O traces and make two prominent observations. The first is the existence of hot 15% data, which account for 80% of total swap I/O, and the second is the existence of cold 50% data that are never used again after entering the swap area. Based on these observations, we present a new architecture that adopts non-volatile memory at the Android swap layer. Specifically, as Android swap has bimodal data access characteristics, we identify and manage hot and cold data efficiently by making use of precise admission control and replacement algorithms. This is possible as our swap architecture can access the full information of request time and frequency, which is different from the main memory layer with restricted information. Experimental results show that our architecture supports Android swap without performance degradations.

Nipple-spring mastectomy (NSM) with immediate breast reconstruction is being increasingly used in the treatment of breast cancer [1]. However, there are limited available data on the prognostic implications of locoregional recurrence (LRR) following this surgical procedure. This article is a supplementary resource of the original research article by Wu ZY et al. entitled “Locoregional Recurrence Following Nipple-Sparing Mastectomy with Immediate Breast Reconstruction: Patterns and Prognostic Significance” [2] and presents data regarding the subsequent distant metastasis following the first LRR, as well as the prognoses for isolated local recurrences according to the site of recurrence after NSM and immediate breast reconstruction for primary breast cancer. Data from a total of 1,696 patients with primary breast cancer who underwent NSM with immediate reconstruction from March 2003 to December 2016 at the Asan Medical Center, Seoul, Korea, were retrospectively reviewed. An LRR as the first event was found to have developed in 172 patients. Among these, 117 cases (6.9%) involved isolated local recurrence, including 52 cases (3.1%) of nipple-areola complex recurrence, 41 cases (2.4%) of skin/subcutaneous recurrence, and 24 cases (1.4%) of chest wall recurrence. Kaplan-Meier survival analysis and the log-rank test were performed to compare the subgroups of local recurrence. In 172 patients with LRR, subsequent distant metastases were observed in 30 cases (17.4%). Our data may be helpful for conducting further in-depth investigations on salvage treatment options in patients with LRR following NSM and immediate breast reconstruction.

BackgroundIn patients with hormone receptor-positive (HR+)/premenopausal breast cancer, luteinizing hormone-releasing hormone analogs (LHRHas) are used as standard endocrine treatment. Based on previous clinical studies, 1-month formulations are recommended in most breast cancer treatment guidelines, but long-acting formulations facilitate reductions in side effects and patient discomfort caused by frequent administration. However, few efficacy studies have been conducted on 6-month formulations. Therefore, this study aimed to evaluate the efficacy of 6-month formulations of LHRHas.MethodsThis retrospective study was conducted from January 2018 to December 2019 and involved premenopausal patients with HR+ breast cancer administered 6-month LHRHas as adjuvant treatment after surgery, and those previously administered chemotherapy or other LHRHa types were excluded. Patients’ estradiol (E2) and follicle-stimulating hormone (FSH) levels were measured before surgery, and their E2 levels were also measured at 3, 6, 12, 18, and 24 months at periodic postsurgical examinations.ResultsA total of 228 patients were included, and the median patient age was 44 (range, 25–54) years. The mean serum E2 and FSH levels before surgery were 69.7 (range, 4–683) pg/mL and 7.3 (range, 0.4–88.9) mIU/mL, respectively, whereas the mean serum E2 level monitored at intervals during the 6-month LHRHa administration was 5.5 (range, 4.0–52) pg/mL. No women menstruated during the follow-up period after the LHRHas administration, and the E2 levels were less than 30 pg/mL in all patients except one.ConclusionsThe 6-month LHRHa formulation adequately suppressed ovarian function in premenopausal patients with HR+ breast cancer. This indicates that long-acting LHRHas can be effectively used for patient convenience and that there is high compliance with long-term use.

This study aimed to evaluate the prognosis of breast cancer patients who received neoadjuvant chemotherapy and underwent sentinel lymph node biopsy (SLNB) alone as axillary surgery regardless of their clinical and pathological lymph node status. We reviewed the records of 1,795 patients from Asan Medical Center who were diagnosed with stage I-III breast cancer and received neoadjuvant chemotherapy during 2003-2014. We selected 760 patients who underwent SLNB alone as axillary surgery and divided these patients into four groups according to their clinical lymph node (cN) and pathological lymph node (pN) status: cN(-)pN(-) (n = 377), cN(-)pN(+) (n = 33), cN(+)pN(-) (n = 242), and cN(+)pN(+) (n = 108). We then compared axillary lymph node recurrence, locoregional recurrence (LRR), distant metastasis-free survival (DMFS), and overall survival (OS) among the four groups using Kaplan-Meier analysis. We compared prognosis between the cN(-)pN(-) and cN(+)pN(-) groups to determine whether SLNB alone is an adequate treatment modality even in patients with cN positive pathology before neoadjuvant therapy but SLNB-negative pathology after NAC. The 5-year axillary recurrence rates in the cN(-)pN(-) and cN(+)pN(-) groups were 1.4% and 2.9%, respectively, and there was no significant difference between the two groups (p = 0.152). The axillary recurrence and LRR rates were significantly different among the four groups, with the pN-negative groups (cN[-]pN[-], cN[+]pN[-]) showing lower recurrence rates. DMFS and OS were also significantly different among the four groups, with the cN negative groups (cN[-]pN[-], cN[-]pN[+]) showing improved survival rates. Our study findings suggest that SLNB alone was associated with lower LRR rates even in patients with cN positive pathology before neoadjuvant therapy but cN negative pathology after SLNB. Moreover, recurrence and survival rates differ significantly according to clinical and pathological lymph node status.

Background: Although international guidelines recommend bone screening for premenopausal breast cancer patients taking adjuvant tamoxifen, the effects of tamoxifen on osteoporosis and related risks remain controversial. The objective of this study was to investigate the incidence of and risk factors for osteoporosis and osteoporotic fractures in younger breast cancer patients.Methods: A nationwide retrospective cohort study was conducted using South Korea Health Insurance Review and Assessment Service claims data. The rates of osteoporosis and osteoporotic fracture were calculated as incident cases per person-year and disease-free probability rates were analyzed with the Kaplan-Meier method. To identify risk factors for osteoporosis and osteoporotic fracture, a multivariable Cox proportional hazard regression model was applied.Results: From January 2009 to December 2014, a total of 47,649 breast cancer patients were included. The incidence rates of osteoporosis and osteoporotic fracture were 23.59 and 2.40 per 1,000 person-years, respectively. In the overall population, tamoxifen was significantly associated with a decreased risk of osteoporosis and osteoporotic fractures 0.76). However, tamoxifen was not associated with the risk of osteoporosis (HR 1.24, CI 0.85–1.82) and osteoporotic fracture (HR 8.15, CI 0.36–186.70) in patients under age 40. In the 40–49 years subgroup, tamoxifen significantly decreased the risk of osteoporosis (HR 0.74, CI 0.65–0.84) and osteoporotic fracture (HR 0.49, CI 0.31–0.76).Conclusions: Tamoxifen is not associated with an increased risk of osteoporosis and osteoporotic fracture in premenopausal breast cancer patients. Tailored screening strategies for breast cancer survivors with different osteoporosis risks are needed.Precis: Tamoxifen is not associated with an increased risk of osteoporosis and osteoporotic fracture in premenopausal breast cancer patients. Tailored screening strategies for breast cancer survivors who are at different risks of developing osteoporosis are needed.

Blood and serum N-glycans can be used as markers for cancer diagnosis, as alterations in protein glycosylation are associated with cancer pathogenesis and progression. We aimed to develop a platform for breast cancer (BrC) diagnosis based on serum N-glycan profiles using MALDI-TOF mass spectroscopy. Serum N-glycans from BrC patients and healthy volunteers were evaluated using NosQuest's software "NosIDsys." BrC-associated "NosID" N-glycan biomarkers were selected based on abundance and NosIDsys analysis, and their diagnostic potential was determined using NosIDsys and receiver operating characteristic curves. Results showed an efficient pattern recognition of invasive ductal carcinoma patients, with very high diagnostic performance [area under the curve (AUC): 0.93 and 95% confidence interval (CI): 0.917-0.947]. We achieved effective stage-specific differentiation of BrC patients from healthy controls with 82.3% specificity, 84.1% sensitivity, and 82.8% accuracy for stage 1 BrC and recognized hormone receptor-2 and lymph node invasion subtypes based on N-glycan profiles. Our novel technique supplements conventional diagnostic strategies for BrC detection and can be developed as an independent platform for BrC screening.

PurposeRestricted shoulder mobility is a major upper extremity dysfunction associated with lower quality of life and disability after breast cancer surgery. We hypothesized that a poloxamer and sodium alginate mixture (Guardix-SG®) applied after axillary lymph node dissection (ALND) would significantly improve shoulder range of motion (ROM) in patients with breast cancer.MethodsWe conducted a double-blind, randomized, prospective study to evaluate the clinical efficacy and safety of Guardix-SG® for the prevention of upper extremity dysfunction after ALND. The primary outcome measure was shoulder ROM at baseline (T0) and 3 (T1), 6 (T2), and 12 months (T3) after surgery. Secondary outcome measures were the Disabilities of the Arm, Shoulder, and Hand score(DASH), pain associated with movement, which was assessed using a numeric rating scale, and lymphedema assessed using body composition analyzer.ResultsA total of 83 women with breast cancer were randomly assigned to either the Guardix-SG® group or the control group. In the Guardix-SG® group (n = 37), Guardix-SG® was applied to the axillary region after ALND. In the control group (n = 46), ALND was performed without using Guardix-SG®. Comparing ROM for shoulder flexion before surgery (178.2°) and 12 months after surgery (172.3°), that was restored 12 months after surgery in the Guardix-SG® group, and there was no statistically significant difference between that at before surgery and 12 months after surgery (p = 0.182). No adverse effect was observed in either group.ConclusionsThe results of this study have shown that Guardix-SG® help improve shoulder ROM without causing adverse effects in patients who underwent breast cancer surgery. However, there was no statistically significant difference from the control group. A further large-scale study is needed to obtain a more conclusive conclusion.Trial registrationCRISKCT0003386; https://cris.nih.go.kr (20181207).

Estimating future sea level rise (SLR) projections is important for assessing coastal risks and planning of climate-resilient infrastructure. Therefore, in this study, we estimated the future projections of SLR from Coupled Model Intercomparison Project phase 6 (CMIP6) models for three climate targets (1.5 °C (T15), 2.0 °C (T20), and 3.0 °C (T30)) described by the Paris Agreement. The global SLR projections are 60, 140, and 320 mm for T15, T20, and T30, respectively, relative to the present-day levels. Similarly, around the Korean Peninsula, SLR projections become more intense with continuous global warming (20 mm (T15), 110 mm (T20), and 270 mm (T30)). Ocean variables show a slow response to climate change. Therefore, we developed the Emergence of Climate Change (EoC) index for determining the time when the variable is not following the present climate trend. The EoC of SLR appears after the EoC of sea-ice melting near the time of T15 warming. Moreover, the EoC of thermal expansion appears around the 2040s, which is similar to the time of the maximum of the T15 warming period and the median of the T20 warming period. Overall, our analysis suggests that the T15 warming may act as a trigger and SLR will accelerate after the T15 warming.

As a result of strengthened sulfur content standards for ship fuel oil in IMO regulations, major domestic and foreign carriers have a high and growing demand for liquefied natural gas (LNG) powered ships and related equipment. For LNG operation in a cryogenic environment, a storage tank and fuel supply system that uses steel with excellent brittleness and fatigue strength is required. Ships that use LNG have a high vulnerability to explosion and fire. For this reason, 9% Ni is typically used, since a ship requires high quality products with special materials and structural technologies that guarantee operability at cryogenic temperatures. However, there is an urgent need for research to derive a uniform welding quality, since high process difficulty and differences in welding quality related to a welder’s skills can cause a deterioration of the weld quality in the 9% Ni steel welding process. For 9% Ni steel, the higher the dilution ratio of the base metal, the lower the strength. In order to secure the required strength, excessive dilution of the base metal should be avoided, and the relationship between dilution ratio and strength should be investigated. According to previous research, if it exceeds 25% it may be lower than the API standard of 363 MPa for hardening welds. Therefore, in this study, the flux cored arc welding process is performed by establishing criteria that can be evaluated based on the SVM method in order to determine the structure of the weld to be cured according to the dilution rate of the base metal. We would like to propose a multipurpose optimization algorithm to ensure uniform quality of 9% Ni steel.

The demand for LNG-powered ships and related equipment is rapidly increasing among major domestic and foreign carriers due to the strengthened IMO regulations on the sulfur content of ship fuel oil. LNG operation in a cryogenic environment requires a storage tank and fuel supply system that uses steel with excellent brittleness and fatigue strength. A ship using LNG is very sensitive to explosion and fire. For this reason, 9% Ni is often used, because ships require high quality products with special materials and structural technologies that ensure operability at cryogenic temperatures. However, research to derive uniform welding quality is urgent because the deterioration of weld quality in the 9% Ni steel welding process is caused by high process difficulty and differences in welding quality depending on a welder’s skill set. This study proposes a method to guarantee a uniform quality of 9% Ni steel in a fiber laser welding process by categorizing weld joint hardness according to the dilution ratio of a base material and establishing a standard for quantitative evaluation.