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BACKGROUND/AIM Thyroid lobectomy may cause post-lobectomy hypothyroidism. We investigated the difference in levothyroxine (LT4) supplementation and cessation between patients with benign disease and those with papillary thyroid carcinoma (PTC) and found that the rate of LT4 cessation could be decreased after thyroid-stimulating hormone (TSH) suppression in PTC. PATIENTS AND METHODS We retrospectively reviewed 88 patients with benign tumor and 463 patients with PTC and investigated the risk factors for LT4 supplementation after thyroid lobectomy. RESULTS During the median follow-up of 73.0 months, 207 (37.6%) patients maintained the euthyroid state, while 344 (62.4%) patients continued LT4 supplementation for LT4 replacement or TSH suppression. In patients with benign tumors, only high pre-TSH level (>1.98 mIU/l) was a significant risk factor (odds ratio [OR]=10.09). However, in patients with PTC, pre-TSH level ≥1.98 mIU/l (OR=3.28), pregnancy planning (OR=2.97), and age ≥42.5 years (OR=1.94) were significant risk factors. Moreover, the most potent risk factor was tumor aggressiveness (OR=4.00), which was found to be more significant than high pre-TSH. The overall rate of LT4 cessation in all patients was 37.6%; however, in the 303 patients who underwent the LT4-Off trial, there was no difference in the rate in the benign tumor, low-risk PTC, and intermediate-risk PTC groups (66.2%, 68.8%, and 70.8%, respectively; p=0.886). CONCLUSION When post-lobectomy TSH levels were adequate and the risk of recurrence was reduced, LT4 cessation in PTC could be achieved at the same rate as that in benign tumors, regardless of the duration of TSH suppression.

Phyllodes tumors of the breast are relatively rare fibroepithelial tumors that account for less than 1% of primary breast neoplasms. Phyllodes tumors have epithelial and stromal components and they originate from the periductal stroma. They are classified as benign, borderline, or malignant. Carcinomatous differentiation of the epithelial components of phyllodes tumors is rare, and their imaging features have not been accurately described. Herein, we report a rare case of invasive ductal carcinoma originating from a borderline phyllodes tumor in a 21-yearold female with radiologic and pathologic findings.

Background: Triple-negative breast cancer (TNBC) is a heterogeneous group of cancer with dismal prognosis. B7 families can be promising targets for cancer immunotherapy in TNBC. Previously we have found increased expression of B7-H3 and B7-H4 mRNA and protein in breast cancer including TNBC. In an effort to discover therapeutic targets, TNBC has been further stratified into molecular subtypes. However, little is known about the clinical impact and value of B7-H3 and B7-H4 in TNBC subtypes. The purpose of this study was to evaluate the clinicopathologic characteristics of the B7-H3 and B7-H4 mRNA and protein expression according to the TNBC subset. Materials and methods: A tissue microarray was constructed from 186 patients with TNBC. B7-H3 and B7-H4 mRNA and protein expression were assessed by the RNAscope in situ hybridization (ISH) and immunohistochemistry. Immunohistochemistry for the TNBC molecular subtype-surrogate markers [cytokeratin 5/6 (CK5/6), CK14, epidermal growth factor receptor (EGFR), and androgen receptor (AR)], CD3, and CD8 was also performed. TNBC subtypes were classified into three subtypes: basal-like (BL), luminal AR (LAR), and unclassifiable type (UN). Results: Based on the immunohistochemical results, 186 TNBCs were classified into BL (n=120, 64.5%), LAR (n=10, 10.8%), and UN (n=46, 24.7%) subtypes. BL and UN subtypes were associated with younger age than the LAR subtype. B7-H3 mRNA and protein expressions were expressed in the tumor and stromal cells of the TNBCs. On the contrary, B7-H4 mRNA and protein expressions were only observed in the tumor cells. High tumor mRNA and protein expression of B7-H3 and B7-H4 were found in 49 of 175 (28.0%) and 121 of 176 (68.8) cases, and 92 of 174 (52.9%) and 66 of 176 (37.5%) cases, respectively. High stromal B7-H3 mRNA and protein expression were observed in 22 of 175 (12.6%) and 43 of 176 (24.4%) cases. High stromal B7-H4 mRNA and protein expression were not observed. B7-H3 and B7-H4 protein expression were closely correlated with their mRNA expression according to the tumor compartment. Tumor B7-H4 mRNA expression was associated with younger age at the initial diagnosis and molecular TNBC subtypes. Expression of B7-H3 mRNA and protein in the tumor cells negatively correlated with CD3+ and CD8+ T cell infiltration density in the tumor and/or stromal compartment of the TNBCs and its subtypes. High stromal B7-H3 mRNA expression was associated with poor disease-free and overall survival in the TNBCs and overall survival in the UN subtype. Stromal B7-H3 mRNA expression was independently associated with overall survival in the TNBCs and disease-free survival in the BL subtype. Conclusions: As prognostic factors, our results point to the importance of the expression of B7-H3 mRNA by the stromal cells in the TNBCs and the BL subtype. The inverse relationship between B7-H3 expression and CD3+ and CD8+ T lymphocyte infiltration may represent a promising target in the immunotherapy of the TNBCs, irrespective of its molecular subtypes. Citation Format: Ji Shin Lee, Nah Ihm Kim, Min Ho Park. B7-H3 and B7-H4 expression in triple-negative breast cancer subtypes detected by RNA in situ hybridization and immunohistochemistry: Association with clinicopathological features and T-cell infiltration [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-35.

Triple-negative breast cancer (TNBC) is relatively more aggressive than other subtypes of breast cancer. Lymphovascular invasion (LVI) is a well-known predictive factor of worse survival outcomes; however, the role of LVI in TNBC remains unclear. This study aimed to evaluate the significance of LVI and examine clinical outcomes in patients with TNBC. We reviewed the medical records of 417 patients with pathology results negative for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2 (immunohistochemical stain score 0, 1, or 2 with negative for fluorescence (or silver) in situ hybridization). Cox proportional hazards analysis was used to investigate the relationship between clinicopathological variables and survival outcomes. During a median follow-up of 93.8 months (range, 7.1−193.8), 65 (15.6%) patients had recurrence, and 37 (8.9%) patients died from cancer progression. In multivariate analyses of survival outcomes, the N1–3 stage (vs. N0 stage; hazard ratio [HR], 2.127; 95% confidence interval [CI], 1.237−3.659; p = 0.006), and LVI (vs. no LVI; HR, 2.053; 95% CI, 1.199−3.515; p = 0.009) were associated with worse recurrence-free survival. The N1–3 stage (vs. N0 stage; HR, 4.386; 95% CI, 2.140−8.988; p < 0.001) was associated with worse disease-specific survival. LVI in TNBC is an important predictive factor for recurrence than cancer-related death after adjustment for other prognostic factors. We suggest that patients with TNBC with LVI should receive short-term follow-up with imaging studies for detecting loco-regional and distant recurrence.

Purpose Approval of eribulin for metastatic breast cancer was based on data primarily from Western patients, and there is a paucity of data on the effectiveness and safety of eribulin for Asian patients. To determine the effectiveness and safety of eribulin in Korean women with breast cancer in a real-world setting, we conducted a nationwide, multicenter, retrospective study. Methods Patients with locally advanced or metastatic breast cancer who were treated with eribulin in 14 centers throughout Korea were included in this study. Eribulin was generally administered at a dose of 1.23 mg/m2 (equivalent to 1.4 mg/m2 eribulin mesylate) by intravenous infusion for 2–5 min, or as a diluted solution, on Days 1 and 8 of every 21-day cycle. The primary endpoint was progression-free survival (PFS) rate at 6 months. Secondary endpoints included median PFS, overall survival (OS), time-to-treatment failure (TTF), tumor response rate, and incidence of hematologic treatment-emergent adverse events (TEAEs). Results The safety and full analysis populations included 398 and 360 (38 had no efficacy data) patients, respectively. The PFS rate at 6 months was 37.8%. Median PFS, OS, and TTF were 134, 631, and 120 days, respectively. Objective response rate, clinical benefit rate, and disease control rate were 18.1%, 50.6%, and 49.4%, respectively. Hematologic TEAEs were reported in 65.1% of patients; neutropenia (56.8%) and anemia (11.3%) were most common. Conclusion Real-world effectiveness and safety of eribulin in Korean breast cancer patients were consistent with previous reports; no new safety concerns were identified., Graphical abstract Image 1, Highlights • Metastatic breast cancer patients were treated with eribulin (1.23 mg/m2, IV). • Progression-free survival rate at 6 months was 37.8% in eribulin-treated patients. • Median progression-free and overall survivals were 134 and 631 days, respectively. • Hematologic treatment-emergent adverse events were reported in 65.1% of patients. • Effectiveness and safety of eribulin were consistent with previous reports.

Genome-wide screening of transcriptional changes among normal, cancer, and nodal metastases provides insights into the molecular basis of breast cancer (BC) progression and metastasis. To identify transcriptional changes and differentially expressed genes (DEGs) in the metastatic progression of BC and to determine the prognostic role of these DEGs in clinical outcome, we compared transcriptome profiling in matched normal, cancer, and lymph node metastatic tissues of 7 patients with estrogen receptor–positive, HER2-negative BC by using massive parallel RNA sequencing. The global profiles of gene expression in cancer and nodal metastases were highly correlated (r=0.962, P

ObjectiveThis study was conducted in order to investigate the feasibility of using radiomics analysis (RA) with machine learning algorithms based on breast magnetic resonance (MR) images for discriminating malignant from benign MR-detected additional lesions in patients with primary breast cancer.Materials and MethodsOne hundred seventy-four MR-detected additional lesions (benign, n = 86; malignancy, n = 88) from 158 patients with ipsilateral primary breast cancer from a tertiary medical center were included in this retrospective study. The entire data were randomly split to training (80%) and independent test sets (20%). In addition, 25 patients (benign, n = 21; malignancy, n = 15) from another tertiary medical center were included for the external test. Radiomics features that were extracted from three regions-of-interest (ROIs; intratumor, peritumor, combined) using fat-saturated T1-weighted images obtained by subtracting pre- from postcontrast images (SUB) and T2-weighted image (T2) were utilized to train the support vector machine for the binary classification. A decision tree method was utilized to build a classifier model using clinical imaging interpretation (CII) features assessed by radiologists. Area under the receiver operating characteristic curve (AUROC), accuracy, sensitivity, and specificity were used to compare the diagnostic performance.ResultsThe RA models trained using radiomics features from the intratumor-ROI showed comparable performance to the CII model (accuracy, AUROC: 73.3%, 69.6% for the SUB RA model; 70.0%, 75.1% for the T2 RA model; 73.3%, 72.0% for the CII model). The diagnostic performance increased when the radiomics and CII features were combined to build a fusion model. The fusion model that combines the CII features and radiomics features from multiparametric MRI data demonstrated the highest performance with an accuracy of 86.7% and an AUROC of 91.1%. The external test showed a similar pattern where the fusion models demonstrated higher levels of performance compared with the RA- or CII-only models. The accuracy and AUROC of the SUB+T2 RA+CII model in the external test were 80.6% and 91.4%, respectively.ConclusionOur study demonstrated the feasibility of using RA with machine learning approach based on multiparametric MRI for quantitatively characterizing MR-detected additional lesions. The fusion model demonstrated an improved diagnostic performance over the models trained with either RA or CII alone.

ImportancePolygenic risk scores (PRSs) have shown promises in breast cancer risk prediction; however, limited studies have been conducted among Asian women.ObjectiveTo develop breast cancer risk prediction models for Asian women incorporating PRSs and nongenetic risk factors.DesignPRSs were developed using data from genome-wide association studies (GWAS) of breast cancer conducted among 123 041 Asian-ancestry women (including 18 650 cases) using three approaches (1) reported PRS for European-ancestry women; (2) breast cancer-associated single-nucleotide polymorphisms (SNPs) identified by fine-mapping of GWAS-identified risk loci; (3) genome-wide risk prediction algorithms. A nongenetic risk score (NgRS) was built including six well-established nongenetic risk factors using data from 1974 Asian women. Integrated risk scores (IRSs) were constructed using PRSs and the NgRS. PRSs were initially validated in an independent dataset including 1426 cases and 1323 controls and further evaluated, along with the NgRS and IRSs, in the second dataset including 368 cases and 736 controls nested withing a prospective cohort study.SettingCase-control and prospective cohort studies.Participants20 444 breast cancer cases and 106 450 controls from the Asia Breast Cancer Consortium.Main Outcomes and MeasuresLogistic regression was used to examine associations of risk scores with breast cancer risk to estimate odds ratios (ORs) with 95% confidence intervals (CIs) and area under the receiver operating characteristic curve (AUC).ResultsIn the prospective cohort, PRS111, a PRS with 111 SNPs, developed using the fine-mapping approach showed a prediction performance comparable to a genome-wide PRS including over 855,000 SNPs. The OR per standard deviation increase of PRS111 was 1.67 (95% CI=1.46-1.92) with an AUC of 0.639 (95% CI=0.604-0.674). The NgRS had a limited predictive ability (AUC=0.565; 95% CI=0.529-0.601); while IRS111, the combination of PRS111 and NgRS, achieved the highest prediction accuracy (AUC=0.650; 95% CI=0.616-0.685). Compared with the average risk group (40th-60th percentile), women in the top 5% of PRS111 and IRS111 were at a 3.84-folded (95% CI=2.30-6.46) and 4.25-folded (95% CI=2.57-7.11) elevated risk of breast cancer, respectively.Conclusions and RelevancePRSs derived using breast cancer-associated risk SNPs have similar prediction performance in Asian and European descendants. Including nongenetic risk factors in models further improved prediction accuracy. Our findings support the utility of these models in developing personalized screening and prevention strategies.Key PointsQuestionWhat is the performance of breast cancer risk prediction models for Asian women incorporating polygenic risk scores (PRSs) and nongenetic risk factors?FindingsA 111-genetic-variant PRS developed using data of 125 790 Asian women was significantly associated with breast cancer risk in an independent case-control study nested within a prospective cohort, with an odd ratio (OR) per standard deviation increase of 1.67 (95% confidence interval [CI]=1.46-1.92) and an area under the receiver operating characteristic curve (AUC) of 0.639 (95% CI=0.604-0.674). The prediction model including this PRS and six nongenetic risk factors improved the AUC to 0.650 (95% CI=0.616-0.685).MeaningOur study provides strong supports for the utility of prediction models in identifying Asian women at high risk of breast cancer.

The combination of near-infrared (NIR) fluorophores and photothermal therapy (PTT) provides a new opportunity for safe and effective cancer treatment. However, the precise molecular design of functional NIR fluorophores with desired properties, such as high tumor targetability and low nonspecific uptake, remains challenging. In this study, a renal-clearable NIR fluorophore conjugate with high tumor targetability was developed for efficient photothermal cancer therapy. The isoniazid (INH)–ZW800-1 conjugate (INH–ZW) was synthesized by conjugating an antibiotic drug, INH, with a well-known zwitterionic NIR fluorophore, ZW800-1, to improve in vivo performance and fluorescence-guided cancer phototherapy. INH–ZW not only showed rapid tumor accumulation without nonspecific tissue/organ uptake within 1 h after the injection but also generated thermal energy to induce cancer cell death under NIR laser irradiation. Compared with previously reported ZW800-1 conjugates, INH–ZW preserved the ideal biodistribution of ZW800-1 and facilitated improved tumor targeting and PTT. Together, these results demonstrate that the INH–ZW conjugate has great potential to serve as an effective PTT agent capable of rapid tumor targeting and high renal clearance, with excellent photothermal efficacy.

B7-H3 and B7-H4 play an inhibitory role in T-cell function by limiting proliferation and cytokine production. Information about B7-H3 and B7-H4 expression in ductal carcinoma in situ (DCIS) remains uncertain. The objective of this study was to evaluate the expression levels of B7-H3 and B7-H4 in DCIS and their associations with clinicopathologic features and T-cell infiltration. B7-H3 and B7-H4 mRNA and protein expression levels in 8 pairs of DCIS tissues and matched normal adjacent tissues were examined by RNAscope in situ hybridization and immunohistochemistry analysis. Immunohistochemical staining of B7-H3, B7-H4, CD3, and CD8 was performed for 79 DCIS samples using tissue microarray. RNAscope in situ hybridization and immunohistochemistry analysis revealed that expression levels of B7-H3 and B7-H4 in DCIS tissues were higher than those in corresponding normal tissues. B7-H3 and B7-H4 mRNA and protein appeared to be mainly expressed in DCIS carcinoma cells. High B7-H3 and B7-H4 expression was observed in 58 (73.4%) and 62 (78.5%) cases with DCIS, respectively. High B7-H3 expression was significantly associated with high-nuclear grade and presence of comedo-type necrosis (both P

Introduction Meniscal extrusion is a typical finding of medial meniscus posterior root tear, and it causes loss of the chondroprotective function of the meniscus as well as progression of osteoarthritis; it is therefore associated with poor clinical outcomes. The purpose of this study was to investigate factors associated with meniscal extrusion in degenerative medial meniscus posterior root tear. It was hypothesized that larger displacement from the posterior root insertion was associated with larger meniscal extrusion. Materials and methods One hundred and nine knees with degenerative medial meniscus posterior root tears were retrospectively reviewed. Multiple regression analysis was used to determine whether factors such as age, weight, body mass index, chondral wear at surgery, Kellgren-Lawrence (KL) grade, alignment, tibial slope, and tear gap on performing magnetic resonance imaging (MRI) were associated with meniscal extrusion. Subjects were divided based on the amount of displacement (displaced group: tear gap ≥ 1 mm, non-displaced group: tear gap Results The mean age of the patients was 58.14 ± 9.64 years, the mean absolute extrusion was 4.02 ± 1.22 mm, the mean relative percentage of extrusion was 44.53 ± 13.09%, and the mean tear gap was 2.39 ± 2.42 mm. Multiple regression analysis showed that absolute extrusion was only associated with tear gap on MRI (B = 0.242, p = 0.001) and that the relative percentage of extrusion was associated with tear gap (B = 1.894, p = 0.001) and the K-L grade (B = 4.492, p = 0.024). Absolute extrusion was significantly higher in the displaced group than in the non-displaced group (4.29 ± 1.04 mm vs. 3.01 ± 1.35 mm, p = 0.001). Relative percentage of extrusion was also significantly higher in the displaced group than in the non-displaced group (47.70 ± 11.44% vs. 36.17 ± 13.65%, p = 0.001). The proportion of chondral wear (Outerbridge grade III and IV) on the medial femoral condyle and K-L grade III and IV were significantly greater in the displaced group than in the non-displaced group (76% vs. 53.3%, p = 0.023 and 13.9% vs. 0%, p = 0.001, respectively). Discussion Greater tear gap is significantly associated with increasing meniscal extrusion in medial meniscus posterior root tear. Additionally, severity of arthritis is significantly associated with increasing relative percentage of extrusion. Chondral wear and severity of arthritis tended to be significantly worse in the displaced group than in the non-displaced group. Level of evidence III, comparative retrospective study.

Objective: Interval breast cancer (IC) is a limitation of breast cancer screening. We investigated data from a large scaled breast cancer dataset of patients with breast cancer who underwent breast cancer screening in order to recapitulate the overall survival (OS) of patients with ICs compared to those with non-ICs. Methods: A total of 27,141 patients in the Korean breast cancer registry with breast cancer who had ever participated in biannual national breast cancer screening programs between 2009 and 2013 were enrolled. We compared the social, pregnancy-associated, and pathologic characteristics between the IC and non-IC groups and identified the significant prognostic factors for OS. Results: The proportion of ICs was 1.3% (370/27,141) in this study population. ICs were correlated with age 45-55 years at diagnosis, higher levels of education, early menopause (

Background Cigarette smoking is a major health risk, particularly in male South Koreans. Smoking cessation can benefit health; however, the process of quitting smoking is difficult to some smokers and shows its relationship to their stress level. The hypothesis of this study is that who has failed attempts to stop smoking induce more stress than habitual smoking. Methods To test this, the analysis on the association between smoking cessation attempts and stress levels in smokers was performed. The Korean Community Health Survey (2011–2016) data with the total of 488,417 participants’ data were used for this study. Survey data were analyzed using the chi-square test and logistic regression. As the dependent variable, self-reported level of stress was selected. Results Of the subject population, 78.3% (63.3% males, 81.4% females) felt stressed. Among participants who successfully stopped smoking, 73.0% (72.6% males, 78.1% females) reported feeling stressed. In contrast, of those who failed to stop smoking, 83.3% (83.6% males, 86.3% females) reported high stress levels. Among those who did not attempt smoking cessation, 81.1% (81.2% males, 80.3% females) responded that they experienced stress. Those who failed to stop smoking had higher odds of stress than those who did not attempt smoking cessation [odds ratio (OR) 1.11, 95% confidence interval (CI) 1.09–1.14, p

Background: Arthroscopic meniscectomy has been commonly performed for persistent pain caused by degenerative medial meniscal posterior root tears (MMPRTs). However, risk factors that affect long-term outcomes and joint survivorship after meniscectomy are unclear. Purpose: To identify the risk factors associated with end-stage osteoarthritis after arthroscopic meniscectomy for degenerative MMPRT for middle-aged or elderly patients and to determine the joint survivorship according to the identified risk factors. Study Design: Case-control study; Level of evidence, 3. Methods: Data from 288 patients (24 male and 264 female), followed for at least 5 years after arthroscopic meniscectomy for degenerative MMPRTs performed between 1999 and 2010, were examined retrospectively. The modified Lysholm score was used for clinical evaluation. Cox proportional hazards regression analysis was used to assess factors that affect joint survivorship when conversion to total knee arthroplasty (TKA) was taken as the endpoint; these factors were age, sex, body mass index (BMI), preoperative tibiofemoral alignment (varus [Results: Mean age at the time of surgery was 58.9 years (range, 43-78 years). Sixty (20.8%) patients underwent TKA at 7.0 ± 3.6 years (range, 1.1-14.4 years) postoperatively. The mean follow-up time for those who did not undergo TKA was 8.9 ± 2.9 years (range, 4.5-16.5 years). The overall modified Lysholm score improved from 64.4 to 81.3 ( P < .001), but progression of radiographic arthritis was noted in 156 (61.9%) patients ( P < .001) at 2 years postoperatively. Age (hazard ratio [HR] = 1.049), BMI (HR = 1.092), varus alignment (HR = 2.283), and Kellgren-Lawrence grade 2 or higher (HR = 2.960) were significant risk factors for end-stage arthritis requiring TKA. Well-aligned nonarthritic knees (n = 131, 45.5%) survived significantly longer before requiring TKA than did knees with varus alignment or radiographic arthritis ( P < .05). The 5- and 10-year survival rates in these low-risk groups were 97.7% (95% CI, 95.2%-100.2%) and 89.1% (95% CI, 82.4%-95.8%), respectively. Conclusion: Arthroscopic meniscectomy is an effective treatment for degenerative MMPRTs, with favorable long-term survival in well-aligned nonarthritic knees. However, meniscectomy should be undertaken cautiously in patients with varus alignment and preoperative radiographic osteoarthritis.

Among several anti-cancer therapies, chemotherapy can be used regardless of the stage of the disease. However, development of anti-cancer agents from potential chemicals must be executed very cautiously because of several problems, such as safety, drug resistance, and continuous administration. Most chemotherapeutics selectively cause cancer cells to undergo apoptosis. In this study, we tested the effects of a novel chemical, the benzothiazole derivative N-[2-[(3,5-dimethyl-1,2-oxazol-4-yl)methylsulfanyl]-1,3-benzothiazol-6-yl]-4-oxocyclohexane-1-carboxamide (PB11) on the human cell lines U87 (glioblastoma), and HeLa (cervix cancer). It was observed that this chemical was highly cytotoxic for these cells (IC50s < 50 nM). In addition, even 40 nM PB11 induced the classical apoptotic symptoms of DNA fragmentation and nuclear condensation. The increase of caspase-3 and -9 activities also indicated an increased rate of apoptosis, which was further confirmed via Western blotting analysis of apoptosis-associated proteins. Accordingly, PB11 treatment up-regulated the cellular levels of caspase-3 and cytochrome-c, whereas it down-regulated PI3K and AKT. These results suggest that PB11 induces cytotoxicity and apoptosis in cancer cells by suppressing the PI3K/AKT signaling pathways and, thus, may serve as an anti-cancer therapeutic.

Sulfasalazine (SAS), an anti-inflammatory drug with potent cysteine/glutamate antiporter system xc-(SXC) inhibition has recently shown beneficial effects in brain-related diseases. Despite many reports related to central nervous system (CNS) effect of SAS, pharmacokinetics (PK) and metabolite identification studies in the brain for SAS were quite limited. The aim of this study was to investigate the pharmacokinetics and metabolite identification of SAS and their distributions in mouse brain. Using in vivo brain exposure studies (neuro PK), the PK parameters of SAS was calculated for plasma as well as brain following intravenous and oral administration at 10 mg/kg and 50 mg/kg in mouse, respectively. In addition, in vivo metabolite identification (MetID) studies of SAS in plasma and brain were also conducted. The concentration of SAS in brain was much lower than that in plasma and only 1.26% of SAS was detected in mouse brain when compared to the SAS concentration in plasma (brain to plasma ratio (%): 1.26). In the MetID study, sulfapyridine (SP), hydroxy-sulfapyridine (SP-OH), and N-acetyl sulfapyridine (Ac-SP) were identified in plasma, whereas only SP and Ac-SP were identified as significant metabolites in brain. As a conclusion, our results suggest that the metabolites of SAS such as SP and Ac-SP might be responsible for the pharmacological effect in brain, not the SAS itself.

We prepared a drug carrier which consisted of injectable methacrylated glycol chitosan (MGC) hydrogel, and a conjugate of 6-monodeoxy-6-monoamino-&beta, cyclodextrin&sdot, hydrochloride (6-NH2-&beta, CD&sdot, HCl), polyethylene glycol (PEG), and folic acid (FA) for the local delivery and improved cellular uptake of paclitaxel (PTX) (MGC/CDPF-ic-PTX). CDPF refers to a conjugate of 6-NH2-&beta, HCl, PEG, and FA. The anti-cancer effect was investigated using a xenograft mouse model. As controls, the animal study on MGC/PTX and MGC/CD-ic-PTX was performed. The swelling ratio of all samples was analyzed for 7 days, and it showed a gradual increase for 3 days and a maintained state afterward. From the release result, the MGC-based samples have an initial burst for 1 day and a sustained release for 7 days. Results of cytotoxicity and animal study showed the biocompatibility and superior anti-cancer effect of MGC/CDPF-ic-PTX against breast cancer. Furthermore, histological results showed the anti-cancer capacity of MGC/CDPF-ic-PTX against breast cancer. These findings suggest that MGC/CDPF-ic-PTX has clinical potential for breast cancer therapy.

A feasible and biocompatible supramolecular complex self-assembled from indocyanine green (ICG) and methyl-&beta, cyclodextrin (M&beta, CD) was developed for targeted cancer imaging, which enhanced fluorescence-guided photothermal cancer therapy. This study confirmed that the formation of an inclusion complex of the heterocyclic ICG moiety and M&beta, CD inner cavity could result in improved tumor targetability compared with free ICG. The ICG-CD complex could be used as a bifunctional phototherapeutic agent for targeted cancer phototherapy due to the high tumor targetability of the M&beta, CD moiety and effective photothermal performance of the near-infrared (NIR) ICG moiety. Upon NIR laser irradiation, the photothermal effect exerted by the ICG-CD complex significantly enhanced the temperature at the tumor site by 56.2 &deg, C within 5 min. Targeting HT-29 tumors using the ICG-CD complex resulted in an apparent reduction in tumor volumes over the 9 days after photothermal treatment. Moreover, no tumor recurrence or body weight loss were observed after administering a single dose of ICG-CD complex with NIR laser irradiation. Therefore, the administration of the biocompatible ICG-CD complex in combination with NIR laser treatment can be safely explored as a potential strategy for future clinical applications.

Differentially expressed genes (DEGs) have been previously identified using massive parallel RNA sequencing in matched normal, breast cancer (BC) and nodal metastatic tissues. Squalene epoxidase (SQLE), one of these DEGs, is a key enzyme in cholesterol synthesis. The aim of the present study was to investigate the potential involvement of SQLE in the tumorigenic process of BC and to determine its association with the clinical outcome of BC. SQLE mRNA expression was measured using reverse transcription-quantitative PCR in 10 pairs of ductal carcinoma in situ (DCIS) and BC tissues and their adjacent normal tissues. Immunohistochemical staining of SQLE on tissue microarray was performed in 26 normal breast, 79 DCIS and 198 BC samples. The role of SQLE as a prognostic biomarker in patients with BC has been verified using BreastMark. SQLE mRNA expression was significantly increased in DCIS and BC tissues compared with that in their adjacent normal tissues. High SQLE expression was detected in 0, 48.1 and 40.4% of normal breast, DCIS and BC tissues, respectively. SQLE expression in DCIS and BC tissues was significantly higher than that in normal breast tissues. High SQLE expression was observed in DCIS with higher nuclear grade, comedo-type necrosis and HER2 positivity. High SQLE expression in BC was associated with larger tumor size, nodal metastases, higher stage, HER2 subtype and distant metastatic relapse. High SQLE expression was associated with poor disease-free and overall survival, and independently predicted poor disease-free survival in patients with BC. Following BreastMark analysis, high SQLE mRNA expression in BC was significantly associated with a poor prognosis in the 'all', lymph node negative, lymph node positive, luminal A subtype and luminal B subtype groups. Therefore, SQLE expression may be upregulated during the tumorigenic process of BC, and high SQLE expression may be a useful biomarker for predicting a poor prognosis in patients with BC.

OBJECTIVE To evaluate whether androgen receptor expression in triple-negative breast cancer (TNBC) is associated with F-fluorodeoxyglucose (FDG) uptake and to identify predictive factors of F-FDG uptake in TNBC. METHODS We retrospectively assessed data of 156 surgically resected primary TNBC in 156 consecutive patients who underwent F-FDG PET/computed tomography between July 2013 and May 2017. Clinicopathologic features, including androgen receptor expression, were categorized and the distribution of maximum standardized uptake value (SUVmax) was compared between the groups. We also evaluated the correlations between the predictive factors and SUVmax. RESULTS Median SUVmax was higher in the androgen receptor-negative group than in the androgen receptor-positive group (8.8 vs. 7.1, P = 0.026) with negative correlation between androgen receptor and SUVmax (P = 0.041, correlation coefficient (r) = -0.163). On multivariate regression analysis, tumor size (>20 mm), histological grade, Ki-67 (≥14%), and the presence of ductal carcinoma in situ (DCIS) were significantly associated with SUVmax (P

Carisbamate is an antiepileptic drug and it also has broad neuroprotective activity and anticonvulsant reaction. In this study, a liquid chromatography-quadrupole time-of-flight mass spectrometric (LC-qTOF-MS) method was developed and applied for the determination of carisbamate in rat plasma to support in vitro and in vivo studies. A quadratic regression (weighted 1/concentration2), with an equation y = ax2 + bx + c, was used to fit calibration curves over the concentration range from 9.05 to 6,600 ng/mL for carisbamate in rat plasma. Preclinical in vitro and in vivo studies of carisbamate have been studied through the developed bioanalytical method. Based on these study results, human pharmacokinetic (PK) profile has been predicted using physiologically based pharmacokinetic (PBPK) modeling. The PBPK model was optimized and validated by using the in vitro and in vivo data. The human PK of carisbamate after oral dosing of 750 mg was simulated by using this validated PBPK model. The human PK parameters and profiles predicted from the validated PBPK model were similar to the clinical data. This PBPK model developed from the preclinical data for carisbamate would be useful for predicting the PK of carisbamate in various clinical settings.

Background/aim Many cases of bone damage are due to trauma and metabolic diseases. This study aimed to evaluate bone regeneration into a porous hydroxyapatite (HA) scaffold using dexamethasone (DM)-loaded polymeric microspheres. Materials and methods Four adult dogs were used to evaluate the in vivo performance of DM-loaded microspheres immobilized on the surfaces of porous HA scaffolds. Two 5-mm drill holes were created in both the left and right femurs of each dog. The experimental groups included a control group (drill holes filled with HA scaffold alone), a DM 20 group (holes filled with DM-loaded HA scaffold with 20 mg DM per scaffold), and a DM 100 group (hole filled with DM-loaded HA scaffold with 100 mg DM per scaffold). Resulting bone volume percentages and bone mineral densities were calculated by examing micro-computed tomographic (CT) images. Results The DM-loaded HA scaffold groups showed a gradual periosteal reaction two weeks after insertion of the HA scaffold into the femoral drill holes. Four weeks after HA scaffold insertion, the periosteal reaction in the femoral drill holes became denser. Eight weeks after insertion of DM-loaded HA scaffolds, clear images of the scaffold were observed in micro-CT images of the femoral drill hole. The DM 100 group had better bone healing tendencies (bone mineral density, bone mass, trabecular volume, bone surface, and trabecular thickness) than the DM 20 group. Conclusion DM-loaded HA scaffolds are suitable platforms for distributing bioactive molecules during osteogenesis in femoral drill holes.

Precise photothermal cancer therapy still relies on the development of multifunctional theranostic agents to integrate tumor-specific targeting, imaging, and therapy. In this study, we identified the zwitterionic near-infrared (NIR) fluorophore ZW800-Cl, an analog of the well-known ZW800-1, and found that it preferentially accumulated in tumors in various xenograft models. We have demonstrated that the optical and physicochemical properties of ZW800-Cl are similar to those of ZW800-1, but it has a unique tumor targetability. Since ZW800-Cl showed binding selectivity to cancer cells in vitro, it could be specifically targeted to xenograft models of multiple tumor types, including MCF-7, NCI-H460, and HT-29. The in vivo results of photothermal cancer therapy indicated that the xenograft tumors could be effectively ablated by the combination of ZW800-Cl and an 808 nm laser irradiation. In this regard, our finding may provide a new approach for developing multifunctional cancer theranostic agents, setting them apart from conventional nanoparticles based on inorganic and polymeric materials. Therefore, ZW800-Cl may hold promise as a multifunctional theranostic agent for tumor-targeted imaging and effective photothermal cancer therapy.

Parkinson&rsquo, s disease is one of the most common neurodegenerative diseases. Adenosine regulates the response to other neurotransmitters in the brain regions related to motor function. In the several subtypes of adenosine receptors, especially, adenosine 2A receptors (A2ARs) are involved in neurodegenerative conditions. ZM241385 is one of the selective non-xanthine A2AR antagonists with high affinity in the nanomolar range. This study describes the in vitro and in vivo pharmacokinetic properties of ZM241385 in rats. A liquid chromatography-quadrupole time-of-flight mass spectrometric (LC-qToF MS) method was developed for the determination of ZM241385 in rat plasma. In vivo IV administration studies showed that ZM241385 was rapidly eliminated in rats. However, the result of in vitro metabolic stability studies showed that ZM241385 had moderate clearance, suggesting that there is an extra clearance pathway in addition to hepatic clearance. In addition, in vivo PO administration studies demonstrated that ZM241385 had low exposure in rats. The results of semi-mass balance studies and the in silico PBPK modeling studies suggested that the low bioavailability of ZM241385 after oral administration in rats was due to the metabolism and by liver, kidney, and gut.

Objective To investigate changes of cardiac and muscle damage markers in exercise-induced hypertension (EIH) runners before running (pre-race), immediately after completing a 100-km ultramarathon race, and during the recovery period (24, 72, and 120 hours post-race). Methods In this observational study, volunteers were divided into EIH group (n=11) whose maximum systolic blood pressure was ≥210 mmHg in graded exercise testing and normal exercise blood pressure response (NEBPR) group (n=11). Their blood samples were collected at pre-race, immediately after race, and at 24, 72, and 120 hours post-race. Results Creatine kinase (CK) and cardiac troponin I (cTnI) levels were significantly higher in EIH group than those in the NEBPR group immediately after race and at 24 hours post-race (all p

Background Patients with severe preoperative varus deformity have been reported to have high rates of loosening after total knee arthroplasty (TKA), primarily on the tibial side. This study investigated whether a short extension stem for the tibial component in severely varus knees would reduce the failure rate due to loosening on the tibial side. Methods Patients who underwent TKA, performed by a single surgeon using a single implant between November 1998 and January 2009, were retrospectively evaluated. Patients diagnosed with primary osteoarthritis, having a hip-knee-ankle axis greater than varus 8° on preoperative long-film radiographs, and postoperatively followed up for more than 2 years were included. Patients were divided into “stem” and “nonstem” groups, followed by 1:1 propensity score matching according to age, gender, body mass index, preoperative mechanical axis, and postoperative alignment. Tibial loosening rates in the 2 groups were compared. Results The study cohort included 602 patients, divided into “stem” and “nonstem” groups. Propensity score matching yielded 88 pairs of patients. Mean follow-up duration was similar in the stem and nonstem groups (109.22 vs 103.81 months, P = .451). None of the patients in the stem group, compared with 5 in the nonstem group, experienced aseptic loosening. The overall implant survival rate was significantly higher in the stem group than in the nonstem group (P = .0201). Conclusion Using a short extension stem for the tibial component in primary TKA in patients with severe varus deformity greater than 8° may reduce the rate of loosening of the tibial side and increase the longevity of the implant. Level of evidence Level III.

Systemic inflammation in breast cancer correlates with poor prognosis, but the molecular underpinnings of this connection are not well understood. In this study, we explored the relationship between HER2 overexpression, inflammation, and expansion of the mammary stem/progenitor and cancer stem–like cell (CSC) population in breast cancer. HER2-positive epithelial cells initiated and sustained an inflammatory milieu needed to promote tumorigenesis. HER2 induced a feedforward activation loop of IL1α and IL6 that stimulated NFκB and STAT3 pathways for generation and maintenance of breast CSC. In mice, Il1a genetic deficiency delayed MMTV-Her2–induced tumorigenesis and reduced inflammatory cytokine expression as well as CSC in primary tumors. In clinical specimens of human breast tumor tissues, tissue microarray analysis revealed a strong positive correlation between IL1α/IL6 expression and CSC-positive phenotype. Pharmacologic blockade of IL1α signaling reduced the CSC population and improved chemotherapeutic efficacy. Our findings suggest new therapeutic or prevention strategies for HER2-positive breast cancers. Significance: IL1α signaling driven by HER2 promotes chronic inflammation needed to support cancer stem-like cell maintenance in HER2-positive breast cancers. Cancer Res; 78(8); 2040–51. ©2018 AACR.

Purpose Breast cancer is one of the most common malignancies worldwide and the second most common cancer among Korean women. The prognosis of breast cancer is poor in patients with other primary cancers. However, there have been few clinical studies regarding this issue. Therefore, we analyzed the characteristics and prognosis of patients with breast cancer with multiple primary cancers (MPCs). Methods Data from the Korean Breast Cancer Society Registry were analyzed. Data from enrolled patients who underwent surgery for breast cancer were analyzed for differences in prognosis dependent on the presence of MPCs, and which MPC characteristics affected their prognosis. Results Among the 41,841 patients analyzed, 913 patients were found to have MPCs, accounting for 950 total MPCs. There was a significant difference in survival rates between the breast cancer only group and the MPC group. The 5-year survival rates were 93.6% and 86.7% and the 10-year survival rates were 87.5% and 70.4%, respectively. Among the 913 patients with MPCs, patients with two or more MPCs had significantly worse prognoses than patients with a single MPC. With respect to the time interval between breast cancer and MPC occurrence, patients with a 5-year or greater interval had significantly better prognoses than patients with less than 1 year between occurrences. Among MPCs, thyroid cancer was the most common primary cancer. However, this type was not related to the prognosis of breast cancer. Gynecologic cancer, colorectal cancer, upper gastrointestinal cancer, and lung cancer were related to breast cancer prognosis. Conclusion MPCs were a poor prognostic factor for patients with breast cancer. Two or more MPCs and a shorter time interval between occurrences were worse prognostic factors. Although MPCs were a poor prognostic factor, thyroid cancer did not affect the prognosis of patients with breast cancer.

Background/Aim: The purpose of this study was to explore the effect of platelet-rich plasma (PRP) on enhancing healing of trachea allotransplantation and confirm the effect via parallel histological and tracheoscopic examinations in seven adult New Zealand White rabbits. Materials and Methods: Harvested trachea was inserted into recipients with end-to-end anastomosis by a simple interrupted suture. PRP-treated rabbits were treated with 0.5 ml of PRP at the trachea grafts, while control rabbit allografts were treated with 0.5 ml of saline. Results: Tracheoscopy of tracheal allografts treated with PRP revealed that the trachea was well healed with no stenosis. The healing effect in the PRP-treated rabbits increased tracheal activity and produced faster trachea regeneration compared to that in control rabbits. There was a good correlation between the subjective symptom of noisy breathing and the objective grading of tracheal stenosis. The tracheal allografts with suture materials appeared slightly pale and looked more like mucosa erosion than normal mucosa at four weeks post-surgery. Contact of trachea-to-transplanted grafts in PRP-treated rabbits was intimate with the surface of the transplanted region and showed high-density epithelialization. After 8 weeks, blood vessels were observed in the transplanted graft in PRP-treated rabbits. Normal epithelium was present in grafts at 8 weeks after allotransplantation. No CD20(+) cells were detected in grafts but a few CD3(+) cells were observed under the epithelium. Conclusion: The results of this study show that it is possible to perform tracheal reconstruction in rabbits treated with PRP after tracheal transplantation

Trastuzumab emtansine (T-DM1, brand name: Kadcyla®) is the first FDA-approved antibody-drug conjugate (ADC) for metastatic human epidermal growth factor receptor 2 positive (HER2+) breast cancer. It consists of three components: trastuzumab, an anti-HER2 monoclonal antibody, maytansinoid (DM1) as a cytotoxic drug, and maleimidomethyl cyclohexane-1-carboxylate (MCC) as a linker. In particular, the MCC linker is known as a non-cleavable linker and has a feature of being conjugated to DM1 by a covalent thioether bond. In this study, we developed an immuno-affinity capture liquid chromatography-mass spectrometric (LC-MS/MS) assay for quantifying the antibody-conjugated drug (acDrug) component of T-DM1. To quantify acDrug, desulfurated DM1 was prepared using a chemical desulfuration pretreatment and quantified as an acDrug. A quadratic regression (weighted 1/concentration), with equation y = ax2 + bx + c, was used to fit the calibration curves over the concentration range of 17.09~1709.44 ng/mL for the acDrug of T-DM1. The quantification run met the in-house acceptance criteria of ±25% accuracy and precision values for the quality control (QC) samples. In conclusion, an immuno-affinity capture LC-MS/MS assay was successfully developed to quantify acDrug of T-DM1 and applied to evaluate in vitro plasma linker stability and preclinical pharmacokinetic (PK) study in rats. This assay could be helpful when applied to other ADCs with the same linker-cytotoxic drug platform.

Excessive free fatty acids (FFAs) causes reactive oxygen species (ROS) generation and non-alcoholic fatty liver disease (NAFLD) development. Garcinia cambogia (G. cambogia) is used as an anti-obesity supplement, and its protective potential against NAFLD has been investigated. This study aims to present the therapeutic effects of G. cambogia on NAFLD and reveal underlying mechanisms. High-fat diet (HFD)-fed mice were administered G. cambogia for eight weeks, and steatosis, apoptosis, and biochemical parameters were examined in vivo. FFA-induced HepG2 cells were treated with G. cambogia, and lipid accumulation, apoptosis, ROS level, and signal alterations were examined. The results showed that G. cambogia inhibited HFD-induced steatosis and apoptosis and abrogated abnormalities in serum chemistry. G. cambogia increased in NRF2 nuclear expression and activated antioxidant responsive element (ARE), causing induction of antioxidant gene expression. NRF2 activation inhibited FFA-induced ROS production, which suppressed lipogenic transcription factors, C/EBPα and PPARγ. Moreover, the ability of G. cambogia to inhibit ROS production suppressed apoptosis by normalizing the Bcl-2/BAX ratio and PARP cleavage. Lastly, these therapeutic effects of G. cambogia were due to hydroxycitric acid (HCA). These findings provide new insight into the mechanism by which G. cambogia regulates NAFLD progression.

Biomechanical remodeling of stroma by cancer-associated fibroblasts (CAF) in early stages of cancer is critical for cancer progression, and mechanical cues such as extracellular matrix stiffness control cell differentiation and malignant progression. However, the mechanism by which CAF activation occurs in low stiffness stroma in early stages of cancer is unclear. Here, we investigated the molecular mechanism underlying CAF regulation by SPIN90 and microtubule acetylation under conditions of mechanically soft matrices corresponding to normal stromal rigidity. SPIN90 was downregulated in breast cancer stroma but not tumor, and this low stromal expression correlated with decreased survival in breast cancer patients. Spin90 deficiency facilitated recruitment of mDia2 and APC complex to microtubules, resulting in increased microtubule acetylation. This increased acetylation promoted nuclear localization of YAP, which upregulated expression of myofibroblast marker genes on soft matrices. Spin90 depletion enhanced tumor progression, and blockade of microtubule acetylation in CAF significantly inhibited tumor growth in mice. Together, our data demonstrate that loss of SPIN90-mediated microtubule acetylation is a key step in CAF activation in low stiffness stroma. Moreover, correlation among these factors in human breast cancer tissue supports the clinical relevance of SPIN90 and microtubule acetylation in tumor development. Cancer Res; 77(17); 4710–22. ©2017 AACR.

To study the late cardiac toxicity of breast radiation therapy (RT) in Asian women. Female breast cancer patients in Korea who underwent breast conservation surgery followed by RT from 1990–2012 were identified from two large registries at institution and population levels. Cumulative incidences of acute coronary events (ACE) or cardiac mortality were estimated in relation to the laterality of breast cancer using a competing risks analysis. In an analysis of 2577 women from a single institution, 3.7% were obese (body mass index ≥30), and 3.4% were ever-smokers. Patients with a history of hypertension, diabetes, or coronary artery disease were 17.5, 5.7, and 2.8%, respectively. The mean heart doses were 6.2 and 1.5 Gy for left- and right-sided tumors, respectively. With a median follow-up of 7 (range 1–23) years, the overall and breast cancer-specific survivals at 10 years were 94.9 and 96.5%, respectively. The 10-year cumulative incidence of ACE was 2.96%. The mean time to ACE was 5.2 ± 3.9 years (range 1–17). There was no clinically relevant difference in rates of ACE between left-sided and right-sided patients, with an adjusted hazard ratio of 1.16 (CI 0.59–2.29). An analysis of 24,235 women in a nationwide registry validated these negative findings with respect to cardiac mortality, with an adjusted hazard ratio of 1.52 (CI 0.37–6.25). Increasing age, a higher body mass index, and a history of hypertension or ischemic heart disease were identified as risk factors. Our findings reassure that excess risk from breast RT may be small in healthy women, most of who not smoke, weigh less, and have fewer risk factors. A validation using a larger data set of National Health Insurance Corporation is ongoing.

Microglandular adenosis (MGA) of the breast is a rare, benign proliferative lesion but with a significant rate of associated carcinoma. Herein, we report an unusual case of metaplastic carcinoma with chondroid differentiation associated with typical MGA. Histologically, MGA showed a direct transition to metaplastic carcinoma without an intervening atypical MGA or ductal carcinoma in situ component. The immunohistochemical profile of the metaplastic carcinoma was mostly similar to that of MGA. In both areas, all the epithelial cells were positive for S-100 protein, but negative for estrogen receptor, progesterone receptor, HER2/neu, and epidermal growth factor receptor. An increase in the Ki-67 and p53 labelling index was observed from MGA to invasive carcinoma. To the best of our knowledge, this is the first case of metaplastic carcinoma with chondroid differentiation arising in MGA in Korea. This case supports the hypothesis that a subset of MGA may be a non-obligate morphologic precursor of breast carcinoma, especially the triple-negative subtype.

Gab-jin Park,1 Soo Hyeon Bae,1 Wan-Su Park,1 Seunghoon Han,1 Min-Ho Park,2 Seok-Ho Shin,2 Young G Shin,2 Dong-Seok Yim1,2 1Department of Clinical Pharmacology and Therapeutics, Seoul St Mary’s Hospital, PIPET (Pharmacometrics Institute for Practical Education and Training), College of Medicine, Catholic University of Korea, Seoul, South Korea; 2College of Pharmacy, Chungnam National University, Daejeon, South Korea Purpose: A microdose drug–drug interaction (DDI) study may be a valuable tool for anticipating drug interaction at therapeutic doses. This study aimed to compare the magnitude of DDIs at microdoses and regular doses to explore the applicability of a microdose DDI study. Patients and methods: Six healthy male volunteer subjects were enrolled into each DDI study of omeprazole (victim) and known perpetrators: fluconazole (inhibitor) and rifampin (inducer). For both studies, the microdose (100 µg, cold compound) and the regular dose (20 mg) of omeprazole were given at days 0 and 1, respectively. On days 2–9, the inhibitor or inducer was given daily, and the microdose and regular dose of omeprazole were repeated at days 8 and 9, respectively. Full omeprazole pharmacokinetic samplings were performed at days0, 1, 8, and 9 of both studies for noncompartmental analysis. Results: The magnitude of the DDI, the geometric mean ratios (with perpetrator/omeprazole only) of maximum concentration (Cmax) and area under the curve to the last measurement (AUCt) of the microdose and the regular dose were compared. The geometric mean ratios in the inhibition study were: 2.17 (micro) and 2.68 (regular) for Cmax, and 4.07 (micro), 4.33 (regular) for AUCt. For the induction study, they were 0.26 (micro) and 0.21 (regular) for Cmax, and 0.16 (micro) and 0.15 (regular) for AUCt. There were no significant statistical differences in the magnitudes of DDIs between microdose and regular-dose conditions, regardless of induction or inhibition. Conclusion: Our results may be used as partial evidence that microdose DDI studies may replace regular-dose studies, or at least be used for DDI-screening purposes. Keywords: drug–drug interaction, microdose, CYP2C19

Purpose This study investigated the role of the education level (EL) as a prognostic factor for breast cancer and analyzed the relationship between the EL and various confounding factors. Materials and Methods The data for 64,129 primary breast cancer patients from the Korean Breast Cancer Registry were analyzed. The EL was classified into two groups according to the education period; the high EL group (≥ 12 years) and low EL group (< 12 years). Survival analyses were performed with respect to the overall survival between the two groups. Results A high EL conferred a superior prognosis compared to a low EL in the subgroup aged > 50 years (hazard ratio, 0.626; 95% confidence interval [CI], 0.577 to 0.678) but not in the subgroup aged ≤ 50 years (hazard ratio, 0.941; 95% CI, 0.865 to 1.024). The EL was a significant independent factor in the subgroup aged > 50 years according to multivariate analyses. The high EL group showed more favorable clinicopathologic features and a higher proportion of patients in this group received lumpectomy, radiation therapy, and endocrine therapy. In the high EL group, a higher proportion of patients received chemotherapy in the subgroups with unfavorable clinicopathologic features. The EL was a significant prognosticator across all molecular subtypes of breast cancer. Conclusion The EL is a strong independent prognostic factor for breast cancer in the subgroup aged > 50 years regardless of the molecular subtype, but not in the subgroup aged ≤ 50 years. Favorable clinicopathologic features and active treatments can explain the main causality of the superior prognosis in the high EL group.

A lot of polymeric oral dosage forms have been invented for suitable drug delivery and compliance of patient. Oral dissolving film (ODF) offers a comfortable way to enable drug administration. The purpose of this study was to develop an ODF using lidocaine, with moderate mechanical strength and thickness, fast disintegration time and local anesthetic effect. Hydroxypropyl methyl cellulose, sodium alginate, glycerin, sodium lauryl sulfate, polyvinylpyrrolidone and citric acid were used to build the polymeric film base of the ODF. The optimal composition was determined by changing the ratio of individual excipients. The thickness was insignificantly varied in the range of 0.04 ± 0.01 to 0.06 ± 0.01 mm. On the other hand, the tensile strength was 1.23 ± 0.20 to 1.83 ± 0.30 N/cm2. Drug content in the films was evaluated and the values were 16 mg of lidocaine per each ODF (40 mg/strip). Lidocaine ODF formulation showed the release of 91.7% of lidocaine within 1 min and 96.3% of lidocaine in 5 min. These results suggested that lidocaine ODF was well prepared and showed the fast release of lidocaine.

Background aims Few studies have examined the migration pattern of natural killer (NK) cells, especially after radiation treatment for cancer. We investigated whether irradiation can modulate the expression of chemokines in cancer cells and the migration of NK cells to irradiated tumor cells. Methods The expression of chemokine receptors (CXCR3, CXCR4 and CXCR6) on interleukin-2 (IL-2)/IL-15–activated NK cells was assessed using flow cytometry. Related chemokine ligands (CXCL11, CXCL12 and CXCL16) in human breast cancer cell lines (MCF7, SKBR3 and MDA-MB231) irradiated at various doses were assessed using reverse transcription–polymerase chain reaction (RT-PCR), fluorescence-activated cell sorting (FACS) and enzyme-linked immunosorbent assay (ELISA). The cell-free culture supernatant was collected 96 h after irradiation of breast cancer cell lines for migration and blocking assays. Results The activated NK cells expressed CXCR6. Expression of the CXCR6 ligand CXCL16 increased in a time- and dose-dependent manner in all analyzed cancer cell lines. CXCL16 expression was statistically significantly enhanced in all breast cancer cell lines on day 3 after 20 Gy irradiation. Activated NK cells migration correlated with CXCL16 concentration ( R 2 = 0.91; P 0.0001). Significantly enhanced migration of NK cells to irradiated cancer cells was observed for a dose of 20 Gy in MCF7 ( P = 0.043) and SKBR3 ( P = 0.043) cells, but not in MDA-MB231 ( P = 0.225) cells. A blocking assay using a CXCR6 antibody showed a significant decrease in the migration of activated NK cells in all cancer cell lines. Conclusions Our data indicate that irradiation induces CXCL16 chemokine expression in cancer cells and enhances the migration of activated NK cells expressing CXCR6 to irradiated breast cancer cells. These results suggest that radiation would improve the anti-tumor effect of NK cells through enhanced migration of NK cells to tumor site for the treatment of patients with breast cancer.

Objectives: B7-H3 and B7-H4 proteins are expressed in breast cancer tissues, but their relationships with respect to tumor immune surveillance and outcomes in breast cancer are not conclusive. Methods: We first examined B7-H3 and B7-H4 mRNA expression in the Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) datasets. Next, mRNA and protein expression were assessed by RNAscope in situ hybridization (ISH) and immunohistochemistry in 10 pairs of breast cancer and matched normal tissues. Immunohistochemical staining of B7-H3, B7-H4, CD3, and CD8 was performed in tissue microarray slides containing 198 breast cancer samples. Association of B7-H3 and B7-H4 expression with survival was verified using the publicly accessible BreastMark tool. Results: B7-H3 and B7-H4 mRNA expression were significantly higher in breast cancer samples in the TCGA dataset than in normal breast tissues in the GTEx dataset. RNAscope ISH and immunohistochemistry showed that B7-H3 and B7-H4 mRNA and protein appeared to be mainly expressed in cancer cells. Expression of B7-H3 and B7-H4 tended to be associated with low-density scores of stromal tumor-infiltrating lymphocytes (TILs) as well as molecular subtypes. Expressions of B7-H3 and B7-H4 were negatively correlated with stromal CD3+ and CD8+ T cell infiltration density. B7-H3 and B7-H4 expression was not associated with survival, which was verified by BreastMark analysis. Conclusion: Expression levels of B7-H3 and B7-H4 were independent of clinical outcomes of breast cancer. There was an inverse relationship between the expression of B7-H3 and B7-H4 in breast cancer and the density of stromal TILs and CD8+ T lymphocytes. This inverse relationship may represent a promising target in the field of breast cancer immunotherapy.

Purpose Sentinel lymph node biopsy (SLNB) is the standard axillary procedure in early breast cancer patients. In a randomized trial, the survival rates were not different when axillary lymph node dissection (ALND) was omitted in patients with 1 or 2 lymph node metastases who underwent breast conserving surgery. This study aimed to compare the outcomes in patients who underwent total mastectomy (TM) with 1 or 2 metastatic nodes according to the types of axillary surgery. Methods In total, 79,058 patients registered in the Korean Breast Cancer Society database who underwent TM were included in the analysis. The inclusion criteria were history of TM and SLNB, pathologic T stage 1 or 2, clinically negative axillary lymph nodes, 1 or 2 metastatic axillary lymph nodes, no radiation therapy, and no neoadjuvant therapy. We divided the patients into the SLNB only and SLNB + ALND groups. The groups were matched by propensity scores. We retrospectively analyzed the differences in the overall survival (OS) between the 2 groups. Results A total of 883 patients were matched in a 1:4 ratio for the SLNB only and SLNB + ALND groups in the cohort from 1999 to 2014. There were no significant differences in OS between the 2 groups (P = 0.413). Subgroup analysis revealed a significant survival benefit in the SLNB + ALND group in the T2 subgroup (P = 0.013). Conclusion OS did not differ between the 2 groups in early breast cancer patients with 1 or 2 metastatic axillary lymph nodes who underwent TM. Omission of ALND may be considered in selected patients.

Common genetic variants in 183 loci have been identified in relation to breast cancer risk in genome-wide association studies (GWAS). These risk variants combined explain only a relatively small proportion of breast cancer heritability, particularly in Asian populations. To search for additional genetic susceptibility loci for breast cancer, we performed a meta-analysis of data from GWAS conducted in Asians (24,206 cases and 24,775 controls). Variants showing an association with breast cancer risk at P < 0.01 were evaluated in GWAS conducted in European women including 122,977 cases and 105,974 controls. In the combined analysis of data from both Asian and European women, the lead variant in 28 loci not previously reported showed an association with breast cancer risk at P < 5 ×10−8. In the meta-analysis of all GWAS data from Asian and European descendants, we identified SNPs in three additional loci in association with breast cancer risk at P < 5 ×10−8. The associations for 10 of these loci were replicated in an independent sample of 16,787 cases and 16,680 controls of Asian women (P < 0.05). Expression quantitative trait locus (eQTL) and gene-based analyses provided evidence for the possible involvement of the YBEY, MAN2C1, SNUPN, TBX1, SEMA4A, STC1, MUTYH, LOXL2, and LINC00886 genes underlying the associations observed in eight of these 28 newly identified risk loci. In addition, we replicated the association for 78 of the 166 previously reported risk variants at P < 0.05 in women of Asian descent using GWAS data. These findings improve our understanding of breast cancer genetics and etiology and extend to Asian populations previous findings from studies of European women.