21-Gene Assay to Inform Chemotherapy Benefit in Node-Positive Breast Cancer.

BACKGROUND: The recurrence score based on the 21-gene breast-cancer assay has been clinically useful in predicting a chemotherapy benefit in hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, axillary lymph-node-negative breast cancer. In women with positive lymph-node disease, the role of the recurrence score with respect to predicting a benefit of adjuvant chemotherapy is unclear. METHODS: In a prospective trial, we randomly assigned women with hormone-receptor-positive, HER2-negative breast cancer, one to three positive axillary lymph nodes, and a recurrence score of 25 or lower (scores range from 0 to 100, with higher scores indicating a worse prognosis) to endocrine therapy only or to chemotherapy plus endocrine (chemoendocrine) therapy. The primary objective was to determine the effect of chemotherapy on invasive disease-free survival and whether the effect was influenced by the recurrence score. Secondary end points included distant relapse-free survival. RESULTS: A total of 5083 women (33.2% premenopausal and 66.8% postmenopausal) underwent randomization, and 5018 participated in the trial. At the prespecified third interim analysis, the chemotherapy benefit with respect to increasing invasive disease-free survival differed according to menopausal status (P = 0.008 for the comparison of chemotherapy benefit in premenopausal and postmenopausal participants), and separate prespecified analyses were conducted. Among postmenopausal women, invasive disease-free survival at 5 years was 91.9% in the endocrine-only group and 91.3% in the chemoendocrine group, with no chemotherapy benefit (hazard ratio for invasive disease recurrence, new primary cancer [breast cancer or another type], or death, 1.02; 95% confidence interval [CI], 0.82 to 1.26; P = 0.89). Among premenopausal women, invasive disease-free survival at 5 years was 89.0% with endocrine-only therapy and 93.9% with chemoendocrine therapy (hazard ratio, 0.60; 95% CI, 0.43 to 0.83; P = 0.002), with a similar increase in distant relapse-free survival (hazard ratio, 0.58; 95% CI, 0.39 to 0.87; P = 0.009). The relative chemotherapy benefit did not increase as the recurrence score increased. CONCLUSIONS: Among premenopausal women with one to three positive lymph nodes and a recurrence score of 25 or lower, those who received chemoendocrine therapy had longer invasive disease-free survival and distant relapse-free survival than those who received endocrine-only therapy, whereas postmenopausal women with similar characteristics did not benefit from adjuvant chemotherapy. (Funded by the National Cancer Institute and others; RxPONDER ClinicalTrials.gov number, NCT01272037.).

Dietary Isoflavone Intake and Breast Cancer Prognosis: A Prospective Analysis and Meta-Analysis.

We aimed to examine the association between dietary isoflavone intake and the risk of breast cancer recurrence and summarize evidence on the role of dietary isoflavone intake in breast cancer prognosis. This prospective study included 592 breast cancer survivors who completed a dietary assessment. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. Of the studies published until May 31, 2023, that were searched in PUBMED and EMBASE databases, 14 studies were selected. Adjusted HRs were combined using fixed- or random-effects models. During the median follow-up of 4.3 years, 47 recurrences were identified. The HR (95% CI) for recurrence comparing the highest versus the lowest tertile of isoflavones intake was 1.29 (0.60-2.78). In a meta-analysis of previously published data and ours, dietary isoflavone intake was associated with a better breast cancer prognosis. The combined HRs (95% CIs) comparing the extreme categories were 0.81 (0.67-0.98) for recurrence and 0.85 (0.76-0.96) for all-cause mortality. A nonlinear inverse association was observed between isoflavone intake and the risk of recurrence and all-cause mortality. Our study suggests that dietary isoflavone intake is associated with a favorable prognosis in breast cancer survivors and warrants further investigation.

Determining the Factors Predicting the Response to Anti-HER2 Therapy in HER2-Positive Breast Cancer Patients.

PURPOSE: We aimed to identify the differently expressed genes or related pathways associated with good responses to anti-HER2 therapy and to suggest a model for predicting drug response in neoadjuvant systemic therapy with trastuzumab in HER2-positive breast cancer patients. METHODS: This study was retrospectively analyzed from consecutively collected patient data. We recruited 64 women with breast cancer and categorized them into 3 groups: complete response (CR), partial response (PR), and drug resistance (DR). The final number of patients in the study was 20. RNA from 20 core needle biopsy paraffin-embedded tissues and 4 cultured cell lines (SKBR3 and BT474 breast cancer parent cells and cultured resistant cells) was extracted, reverse transcribed, and subjected to GeneChip array analysis. The obtained data were analyzed using Gene Ontology, Kyoto Gene and Genome Encyclopedia, Database for Annotation, Visualization and Integrated Discovery. RESULTS: In total, 6,656 genes differentially expressed between trastuzumab-susceptible and trastuzumab-resistant cell lines were identified. Among these, 3,224 were upregulated and 3,432 were downregulated. Expression changes in 34 genes in several pathways were found to be related to the response to trastuzumab-containing treatment in HER2-type breast cancer, interfering with adhesion to other cells or tissues (focal adhesion) and regulating extracellular matrix interactions and phagosome action. Thus, decreased tumor invasiveness and enhanced drug effects might be the mechanisms explaining the better drug response in the CR group. CONCLUSIONS: This multigene assay-based study provides insights into breast cancer signaling and possible predictions of therapeutic response to targeted therapies such as trastuzumab.

Therapeutic Targeting of DNA Damage Response in Cancer.

DNA damage response (DDR) is critical to ensure genome stability, and defects in this signaling pathway are highly associated with carcinogenesis and tumor progression. Nevertheless, this also provides therapeutic opportunities, as cells with defective DDR signaling are directed to rely on compensatory survival pathways, and these vulnerabilities have been exploited for anticancer treatments. Following the impressive success of PARP inhibitors in the treatment of BRCA-mutated breast and ovarian cancers, extensive research has been conducted toward the development of pharmacologic inhibitors of the key components of the DDR signaling pathway. In this review, we discuss the key elements of the DDR pathway and how these molecular components may serve as anticancer treatment targets. We also summarize the recent promising developments in the field of DDR pathway inhibitors, focusing on novel agents beyond PARP inhibitors. Furthermore, we discuss biomarker studies to identify target patients expected to derive maximal clinical benefits as well as combination strategies with other classes of anticancer agents to synergize and optimize the clinical benefits.

Analysis of the tumor characteristics in young age breast cancer patients using collaborative stage data of the Korea Central Cancer Registry.

PURPOSE: This study aimed to evaluate tumor characteristics in young age (20-39 years old) breast cancer (YABC) patients in Korea. MATERIALS AND METHODS: We identified 10,897 breast cancer patients from 2010 to 2015. The data were collected through 10% systematic sampling of the Korea National Cancer Incidence Database (KNCI DB). Tumor size, lymph node status, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status were collected according to the Collaborative Stage version 2 (CSv2) Data Collection System. RESULTS: Of the 10,897 patients, 1245 (11.4%) were YABC patients. They were found to have larger tumors (T2: 41.6% in 20-39 age group vs 36.4% in 40-49 age group vs 36.5% in 50-59 age group vs 38.4% in ≥ 60 age group; T3: 10.1% vs 7.3% vs 6.5% vs 6.2%, P < .0001), greater rates of lymph node involvement (41.2% vs 32.7% vs 35.7% vs 32.5%, P < .0001), higher tumor grade (High grade: 26.8% vs 19.4% vs 23.5% vs 22.1%, P < .0001), and a larger proportion of triple-negative subtype (18.2% vs 11.0% vs 12.2% vs 13.5%, P < .0001). Compared to the 40-49 age group, breast cancer-related survival (BCRS) rates were worse (91.74% vs 95.04%, P < .0001), and the characteristics of YABC patients were associated with higher risk of death from breast cancer. CONCLUSION: YABC patients have more aggressive tumor characteristics and worse survival rates. Therefore, we need to identify high-risk groups among YABC patients and support active surveillance in them. These findings from a national cohort provide important information for establishing a national cancer care strategy to manage YABC patients.

Survival of Breast-Conserving Surgery Plus Radiotherapy versus Total Mastectomy in Early Breast Cancer.

BACKGROUND: Breast-conserving surgery (BCS) has been reported to have better survival rates when compared with total mastectomy (TM) in early breast cancer. We evaluated the long-term outcomes of Korean women with early breast cancer who underwent either BCS plus radiotherapy (RT) or TM. METHODS: In this population-based study, we evaluated 45,770 patients from the Korean Breast Cancer Registry (KBCR) who were diagnosed with early breast cancer, and divided them into the BCS + RT and TM groups. To minimize bias caused by factors other than the surgical method, we used exact match pairing of prognostic factors. We compared the 10-year overall survival (OS) and breast cancer-specific survival (BCSS) before and after exact matching. As the KBCR is a multicenter, online-based registry program, we used the Asan Medical Center (AMC) database, a single-center database, to validate the results from the KBCR database. RESULTS: In both the KBCR and AMC cohorts, the BCS + RT group showed better OS and BCSS than the TM group, before and after exact matching. For the KBCR cohort after exact matching, the hazard ratios for OS and BCSS were 1.541 (95% confidence interval [CI] 1.392-1.707, p < 0.001) and 1.405 (95% CI 1.183-1.668, p < 0.001), respectively, favoring the BCS + RT group. For the AMC cohort after exact matching, the hazard ratios for OS and BCSS were 1.854 (95% CI 1.476-2.328, p < 0.001) and 1.807 (95% CI 1.186-2.752, p = 0.006), respectively. CONCLUSIONS: Our results suggest that BCS + RT is at least equivalent to TM in terms of OS and may affect treatment decisions in early breast cancer patients.

Regulation of adipocyte differentiation by clusterin-mediated Krüppel-like factor 5 stabilization.

Clusterin (CLU) is a heterodimeric glycoprotein involved in a range of biological processes. We investigated the function of CLU as a novel regulator of adipogenesis. CLU expression increased during 3T3-L1 preadipocyte differentiation. CLU overexpression promoted adipogenic differentiation of preadipocytes and increased the mRNA levels of adipogenic markers including peroxisome proliferator-activated receptor γ (Pparg) and CCAAT enhancer-binding protein α (Cebpa). Conversely, knockdown of CLU attenuated adipogenesis and reduced transcript levels of Pparg and Cebpa. However, the promoter activities of both the Pparg and the Cebpa gene were not affected by alteration of CLU expression on its own. Additionally, the protein level of Krüppel-like factor 5 (KLF5), an upstream transcription factor of Pparg and Cebpa involved in adipogenic differentiation, was upregulated by CLU overexpression, although the mRNA level of Klf5 was not altered by changes in the expression level of CLU. Cycloheximide chase assay showed that the increased level of KLF5 by CLU overexpression was due to decreased degradation of KLF5 protein. Interestingly, CLU increased the stability of KLF5 by decreasing KLF5 ubiquitination. CLU inhibited the interaction between KLF5 and F-box/WD repeat-containing protein 7, which is an E3 ubiquitin ligase that targets KLF5. The adipogenic role of CLU was also addressed in mesenchymal stem cells (MSCs) and Clu-/- mouse embryonic fibroblasts (MEFs). Furthermore, CLU enhanced KLF5-mediated transcriptional activation of both the Cebpa and the Pparg promoter. Taken together, these results suggest that CLU is a novel regulator of adipocyte differentiation by modulating the protein stability of the adipogenic transcription factor KLF5.

Efficacy of neoadjuvant endocrine therapy compared with neoadjuvant chemotherapy in pre-menopausal patients with oestrogen receptor-positive and HER2-negative, lymph node-positive breast cancer.

INTRODUCTION: Neoadjuvant endocrine therapy (NET) has demonstrated efficacy in post-menopausal patients with hormone-responsive breast cancer. This trial was designed to compare the efficacy of neoadjuvant chemotherapy (NCT) with NET in pre-menopausal breast cancer. PATIENTS AND METHODS: In this prospective, randomised, phase III study, oestrogen receptor (ER)-positive, HER2-negative, and lymph node-positive pre-menopausal breast cancer patients were recruited from 7 hospitals in South Korea. Enrolled patients were randomly assigned (1:1) to receive 24 weeks of either NCT or NET with goserelin and tamoxifen. The primary purpose was to evaluate the non-inferiority of NET compared to NCT using clinical response, assessed by MRI. Besides, pathological complete response rate (pCR), changes in Ki-67 expression, breast conservation surgery (BCS) rate, and quality of life were included as secondary endpoints. RESULTS: A total of 187 patients were assigned to receive NCT (n = 95) or NET (n = 92), and 87 patients in each group completed treatments. More NCT patients had complete response or partial response than NET patients using MRI (NCT 83.7% vs. NET 52.9%, 95% CI 17.6-44.0, p < 0.001) and callipers (NCT 83.9% vs. NET 71.3%, 95% CI 0.4-24.9, p = 0.046). Three NCT patients (3.4%) and one NET patient (1.2%) showed pCR (p < 0.005). No difference existed in the conversion rate of BCS (13.8% for NCT vs. 11.5% for NET, p = 0.531) and Ki-67 change (p = 0.114) between the two groups. Nineteen NCT patients had treatment-related grade 3 or worse events compared with none in the NET group. CONCLUSIONS: Better clinical responses were observed in pre-menopausal patients after 24 weeks of NCT compared to those observed after NET. TRIAL REGISTRATION: Clinicaltrials.gov, NCT01622361. Registration June 19, 2012.

Exon splicing analysis of intronic variants in multigene cancer panel testing for hereditary breast/ovarian cancer.

The use of multigene panel testing for patients with a predisposition to breast/ovarian cancer is increasing as the identification of variants is useful for diagnosis and disease management. We identified pathogenic and likely pathogenic (P/LP) variants of high-and moderate-risk genes using a 23-gene germline cancer panel in 518 patients with hereditary breast and ovarian cancers (HBOC). The frequency of P/LP variants was 12.4% (64/518) for high- and moderate-penetrant genes, namely, BRCA2 (5.6%), BRCA1 (3.3%), CHEK2 (1.2%), MUTYH (0.8%), PALB2 (0.8%), MLH1 (0.4%), ATM (0.4%), BRIP1 (0.4%), TP53 (0.2%), and PMS2 (0.2%). Five patients possessed two P/LP variants in BRCA1/2 and other genes. We also compared the results from in silico splicing predictive tools and exon splicing patterns from patient samples by analyzing RT-PCR product sequences in six P/LP intronic variants and two intronic variants of unknown significance (VUS). Altered transcriptional fragments were detected for P/LP intronic variants in BRCA1, BRIP1, CHEK2, PARB2, and PMS2. Notably, we identified an in-frame deletion of the BRCA1 C-terminal (BRCT) domain by exon skipping in BRCA1 c.5152+6T>C-as known VUS-indicating a risk for HBOC. Thus, exon splicing analysis can improve the identification of veiled intronic variants that would aid decision making and determination of hereditary cancer risk.

Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy.

BACKGROUND: Patients who have residual invasive carcinoma after the receipt of neoadjuvant chemotherapy for human epidermal growth factor receptor 2 (HER2)-negative breast cancer have poor prognoses. The benefit of adjuvant chemotherapy in these patients remains unclear. METHODS: We randomly assigned 910 patients with HER2-negative residual invasive breast cancer after neoadjuvant chemotherapy (containing anthracycline, taxane, or both) to receive standard postsurgical treatment either with capecitabine or without (control). The primary end point was disease-free survival. Secondary end points included overall survival. RESULTS: The result of the prespecified interim analysis met the primary end point, so this trial was terminated early. The final analysis showed that disease-free survival was longer in the capecitabine group than in the control group (74.1% vs. 67.6% of the patients were alive and free from recurrence or second cancer at 5 years; hazard ratio for recurrence, second cancer, or death, 0.70; 95% confidence interval [CI], 0.53 to 0.92; P=0.01). Overall survival was longer in the capecitabine group than in the control group (89.2% vs. 83.6% of the patients were alive at 5 years; hazard ratio for death, 0.59; 95% CI, 0.39 to 0.90; P=0.01). Among patients with triple-negative disease, the rate of disease-free survival was 69.8% in the capecitabine group versus 56.1% in the control group (hazard ratio for recurrence, second cancer, or death, 0.58; 95% CI, 0.39 to 0.87), and the overall survival rate was 78.8% versus 70.3% (hazard ratio for death, 0.52; 95% CI, 0.30 to 0.90). The hand-foot syndrome, the most common adverse reaction to capecitabine, occurred in 73.4% of the patients in the capecitabine group. CONCLUSIONS: After standard neoadjuvant chemotherapy containing anthracycline, taxane, or both, the addition of adjuvant capecitabine therapy was safe and effective in prolonging disease-free survival and overall survival among patients with HER2-negative breast cancer who had residual invasive disease on pathological testing. (Funded by the Advanced Clinical Research Organization and the Japan Breast Cancer Research Group; CREATE-X UMIN Clinical Trials Registry number, UMIN000000843 .).

Use of Gadoxetic Acid-enhanced Liver MRI and Mortality in More than 30 000 Patients with Hepatocellular Carcinoma: A Nationwide Analysis.

Background The impact on survival of gadoxetic acid-enhanced MRI in addition to multiphase contrast material-enhanced CT for initial staging in patients with hepatocellular carcinoma (HCC) is unknown. Purpose To compare all-cause mortality in patients with HCC who underwent CT only, CT plus non-gadoxetic acid-enhanced MRI, or CT plus gadoxetic acid-enhanced MRI as part of their initial diagnostic work-up. Materials and Methods The authors performed a nationwide retrospective cohort study of patients diagnosed with HCC in South Korea between January 2008 and December 2010. Follow-up extended through December 2014. The primary outcome was all-cause mortality. Cox proportional hazards regression model with adjustment of confounding factors was used to estimate hazard ratios (HRs) for all-cause mortality. Results Among 30 023 patients with HCC (mean age ± standard deviation, 58.5 years ± 10.7, 23 978 men), the proportions of patients in whom HCC was diagnosed using CT only, CT plus non-gadoxetic acid-enhanced MRI, and CT plus gadoxetic acid-enhanced MRI were 56.1%, 12.9%, and 31.0%, respectively. In adjusted analysis using CT only as the reference category, the HR for mortality for CT plus gadoxetic acid-enhanced MRI was 0.64 (95% confidence interval [CI]: 0.62, 0.67; P < .001), and the HR for CT plus non-gadoxetic acid-enhanced MRI was 0.71 (95% CI: 0.68, 0.75; P < .001). Use of CT plus gadoxetic acid-enhanced MRI was associated with lower mortality compared with CT plus non-gadoxetic acid-enhanced MRI (adjusted HR, 0.90; 95% CI: 0.85, 0.95; P < .001), but this survival advantage was restricted to patients with localized disease. Conclusion In patients with hepatocellular carcinoma, additional use of contrast-enhanced MRI was associated with lower mortality. Furthermore, CT plus gadoxetic acid-enhanced MRI was associated with better survival than CT plus non-gadoxetic acid-enhanced MRI but only in patients with localized disease. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Kim in this issue.

Efficacy of health coaching and a web-based program on physical activity, weight, and distress management among cancer survivors: A multi-centered randomised controlled trial.

OBJECTIVES: To investigate the efficacy of health coaching and a web-based program on survivor physical activity (PA), weight, and distress management among stomach, colon, lung and breast cancer patients. METHODS: This randomised, controlled, 1-year trial conducted in five hospitals recruited cancer survivors within 2 months of completing primary cancer treatment who had not met ≥1 of these behavioural goals: (i) conducting moderate PA for at least 150 minutes/week or strenuous exercise for over 75 minutes per week or, in the case of lung cancer patients, low or moderate intensity exercise for over 12.5 MET per week, (ii) maintaining normal weight, and (iii) attaining a score >72 in the Post Traumatic Growth Inventory (PTGI). Participants were randomly assigned to one of three groups: the control group, a web-only group, or a health coaching + web group. The primary endpoint was based on a composite of PA, weight, and PTGI score at 12 months. RESULTS: Patients in the health coaching + web group (difference = 6.6%, P = .010) and the web-only group (difference = 5.9%, P = .031) had greater overall improvements across the three-outcome composite than the control group. The health coaching + web group had greater overall improvement in PTGI (difference = 12.6%; P < .001) than the control group, but not in PA and weight. CONCLUSION: The web-based program, with or without health coaching, may improve health behaviours including PA, weight, and distress management among cancer survivors within 2 months of completing primary cancer treatment. The web-based program with health coaching was mainly effective for reducing psychological distress.

Integrative molecular profiling identifies a novel cluster of estrogen receptor-positive breast cancer in very young women.

Very young breast cancer patients are more common in Asian countries than Western countries and are thought to have worse prognosis than older patients. The aim of the current study was to identify molecular characteristics of young patients with estrogen receptor (ER)-positive breast cancer by analyzing mutations and copy number variants (CNV), and by applying expression profiling. The whole exome and transcriptome of 47 Korean young breast cancer (KYBR) patients (age <35) were analyzed. Genomic profiles were constructed using mutations, CNV and differential gene expression from sequencing data. Pathway analyses were also performed using gene sets to identify biological processes. Our data were compared with young ER+ breast cancer patients in The Cancer Genome Atlas (TCGA) dataset. TP53, PIK3CA and GATA3 were highly recurrent somatic mutation genes. APOBEC-associated mutation signature was more frequent in KYBR compared with young TCGA patients. Integrative profiling was used to classify our patients into 3 subgroups based on molecular characteristics. Group A showed luminal A-like subtype and IGF1R signal dysregulation. Luminal B patients were classified into groups B and C, which showed chromosomal instability and enrichment for APOBEC3A/B deletions, respectively. Group B was characterized by 11q13 (CCND1) amplification and activation of the ubiquitin-mediated proteolysis pathway. Group C showed 17q12 (ERBB2) amplification and lower ER and progesterone receptor expression. Group C was also distinguished by immune activation and lower epithelial-mesenchyme transition (EMT) degree compared with group B. This study showed that integrative genomic profiling could classify very young patients with breast cancer into molecular subgroups that are potentially linked to different clinical characteristics.

Retrospectively validating the results of the ACOSOG Z0011 trial in a large Asian Z0011-eligible cohort.

PURPOSE: The Z0011 trial demonstrated that axillary dissection (ALND) could be omitted during breast-conserving therapy for cT1-2N0 breast cancers with 1-2 metastatic SLNs. However, that result has not been validated in a larger cohort and the significance of the small number of SLNs remains unclear. This study aimed to validate the Z0011 results within an Asian Z0011-eligible cohort and determine whether the number of sentinel lymph nodes (SLNs) influenced the Z0011-based outcomes. METHODS: Data from Asian patients who fulfilled the Z0011 criteria were collected from five hospitals. Disease recurrence (DR) was compared between patients who underwent ALND or SLN dissection (SLND) alone. Propensity-score matching was performed to reduce the effects of potential selection biases. RESULTS: During 2010-2016, 1750 Asian patients had 1-2 SLN metastases and fulfilled the Z0011 criteria. These patients included 707 cases treated using SLND alone (40%) and 967 patients with ≤ 2 SLNs (55%). Ninety-five patients (5.4%) experienced DR at a median interval of 50 months, although the rates of DR were similar in the ALND and SLND groups. The adjusted hazard ratios for DR after ALND omission were 0.95 (95% CI 0.55-1.64) among the entire cohort and 0.83 (95% CI 0.34-2.03) among patients with ≤ 2 SLNs. CONCLUSIONS: In this Asian Z0011-eligible cohort, ALND omission did not increase risk of DR, even among patients with ≤ 2 SLNs. Therefore, the Z0011 strategy might be safely applied in Asia, and a small number of SLNs did not significantly influence this strategy.

Effect of Antihypertensive Medications on Sepsis-Related Outcomes: A Population-Based Cohort Study.

OBJECTIVES: Although the effect of antihypertensive agents on sepsis has been studied, evidence for survival benefit was limited in the literature. We investigated differences in sepsis-related outcomes depending on the antihypertensive drugs given prior to sepsis in patients with hypertension. DESIGN: Population-based cohort study. SETTING: Sample cohort Database of the National Health Insurance Service from 2003 to 2013 in South Korea. PATIENTS: Patients over 30 years old who were diagnosed with sepsis after receiving hypertension treatment. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Primary outcomes, 30-day and 90-day mortality rates, were analyzed for differences among three representative antihypertensive medications: angiotensin- converting enzyme inhibitors or angiotensin II receptor blockers, calcium channel blockers, and thiazides. In total, 4,549 patients diagnosed with hypertension prior to hospitalization for sepsis were identified. The 30-day mortality was significantly higher among patients who did not receive any medications within 1 month before sepsis (36.8%) than among patients who did (32.0%; p < 0.001). The risk for 90-days mortality was significantly lower in prior angiotensin-converting enzyme inhibitors or angiotensin II receptor blocker users (reference) than in other drug users (odds ratio, 1.27; 95% CI, 1.07-1.52). There was no difference in the risk for 30-day and 90-day mortality depending on whether calcium channel blockers or thiazides were used. Use of calcium channel blockers was associated with a decreased risk for inotropic agent administration, compared with those of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (odds ratio, 1.23; 95% CI, 1.05-1.44) and thiazides (odds ratio, 1.33; 95% CI, 1.12-1.58). CONCLUSIONS: In patients with sepsis, lower mortality rate was associated with prior use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers not with use of calcium channel blockers or thiazides. The requirement of inotropic agents was significantly lower in prior use of calcium channel blockers, although the survival benefits were not prominent.

The Sentinel Lymph Node Biopsy Using Indocyanine Green Fluorescence Plus Radioisotope Method Compared With the Radioisotope-Only Method for Breast Cancer Patients After Neoadjuvant Chemotherapy: A Prospective, Randomized, Open-Label, Single-Center Phase 2 Trial.

BACKGROUND: This study aimed to compare the sentinel lymph node (SLN) identification rates for breast cancer patients after neoadjuvant chemotherapy (NAC) between the dual method (DM) of indocyanine green fluorescence (ICG-F) plus a radioisotope (RI) and RI alone. METHODS: This randomized study enrolled 130 patients who received NAC for breast cancer and 122 patients who received SLN biopsy (SLNB) using either DM (n = 58) or RI only (n = 64). The study compared the identification rate, number of SLNs, and detection time of SLNB. RESULTS: Among the 122 patients, 113 (92.6%) were clinically node-positive before NAC. The SLN identification rate was 98.3% in the DM group and 93.8% in the RI group (p = 0.14). The DM group and the RI group were similar in the average number of SLNs (2.2 ± 1.13 vs. 1.9 ± 1.33; p = 0.26) and the time to detection of the first SLN (8.7 ± 4.98 vs. 8.3 ± 4.31 min; p = 0.30). In the DM group, transcutaneous lymphatic drainage was visualized by fluorescence imaging for 65.5% (38 of 58) of the patients. The SLN identification rate was 94.7% using ICG-F and 93% using RI (p = 0.79). During and after the operation, no complications, including allergic reactions or skin necrosis, occurred. CONCLUSIONS: This study is the first randomized trial to use ICG-F for SLNB in breast cancer patients after NAC. The DM including ICG-F could be a feasible and safe method for SLNB in initially node-positive breast cancer patients with NAC.

Factors associated with physical activity of breast cancer patients participating in exercise intervention.

PURPOSE: Physical activity has been known to improve survival and quality of life of patients with breast cancer. To find factors associated with physical activity, we analyzed the dataset of the multicenter controlled trial of exercise intervention. METHODS: Three hundred fifty-six participants were assigned to two groups: "Smart After-Care" (smartphone application and pedometer were provided) or exercise education only. Physical activity was measured by International Physical Activity Questionnaire-Short Form (IPAQ-SF) at baseline and after 12 weeks. The association between physical activity and other clinical characteristics was analyzed. RESULTS: At baseline, physical activity amount was 2315.5 ± 3513.2 MET min/week: 33.0% inactive, 49.6% minimally active, and 17.4% health-enhancing physical activity (HEPA) active. Factors associated with HEPA include cancer stage and grip strength. A significantly lower proportion was HEPA active among those with advanced stage than among those with stage 0. After intervention, physical activity was increased to 3466.2 ± 4712.5 MET min/week: 15.3% inactive, 50.4% minimally active, and 34.2% HEPA active. Physical activity was increased in 63.4% of the participants. Factors associated with physical activity increase include cancer stage, diarrhea, and type of exercise intervention. Participants with advanced stage have a 3.3 times higher chance of increasing physical activity. Participants who received "Smart After-Care" have a 64% higher chance of increasing physical activity. CONCLUSION: Before the intervention, participants with advanced stage are less likely to be HEPA active. Exercise intervention was more beneficial for those with advanced stage or physical symptoms. "Smart After-Care" was more effective than education only in increasing physical activity.

Direct isolation and characterization of circulating exosomes from biological samples using magnetic nanowires.

BACKGROUND: Tumor-derived exosomes are gaining attention as important factors that facilitate communication between neighboring cells and manipulate cellular processes associated with cancer development or progression. The conventional techniques for the isolation and detection of exosomes face several limitations, restricting their clinical applications. Hence, a highly efficient technique for the isolation and identification of exosomes from biological samples may provide critical information about exosomes as biomarkers and improve our understanding of their unique role in cancer research. Here, we describe the use of antibody cocktail-conjugated magnetic nanowires to isolate exosomes from plasma of breast and lung cancer patients. METHODS: The isolated exosomes were characterized based on size and concentration using nanoparticle tracking analysis. Levels of exosomal proteins were measured by bicinchoninic acid assay and enzyme-linked immunosorbent assay. Morphology was visualized by transmission electron microscopy. Immunoblotting (Western blotting) was used to detect the presence of exosomal markers. RESULTS: The use of antibody cocktail-conjugated magnetic nanowires resulted in approximately threefold greater yield when compared to the conventional methods. The elongated feature of nanowires significantly improved the efficiency of exosome isolation, suggesting its potential to be translated in diverse clinical applications, including cancer diagnosis and treatment. CONCLUSIONS: The nanowire-based method allows rapid isolation of homogeneous population of exosomes with relatively high yield and purity from even small amounts of sample. These results suggest that this method has the potential for clinical applications requiring highly purified exosomes for the analysis of protein, lipid, mRNA, and miRNA.

Clinical subtypes and prognosis of pregnancy-associated breast cancer: results from the Korean Breast Cancer Society Registry database.

PURPOSE: We analyzed the clinicopathologic characteristics and prognosis of pregnancy-associated breast cancer (PABC) according to clinical subtypes to better understand the characteristics of PABC. METHODS: A total of 83,792 female patients between the ages of 20 and 49 were enrolled in the Korean Breast Cancer Society Registry database from January 1, 1996 to December 31, 2015. 'PABC' is defined as breast cancer diagnosed during pregnancy or within 1 year after delivery. Other patients were defined as 'non-PABC' patients. RESULTS: In non-PABC patients, luminal A subtype was the most common (50.2%). In PABC patients, TNBC was the most common (40.4%) subtype, while luminal A comprised 21.2% and HER2 subtype comprised 17.3%. There was a significant difference in overall survival (OS). In non-PABC patients, TNBC had the highest HR (HR 2.3, 95% CI 2.1-2.6). In PABC patients, the luminal B subtype (HR+ HER2-high Ki67) had the highest HR at 7.0 (95% CI 1.7-29.1). In multivariate analysis of OS by subtypes, PABC patients had significantly higher HR than non-PABC patients in the HER2 subtype (HR 2.0, 95% CI 1.1-3.7) and luminal B subtype (HR+ HER2-high Ki67) (HR 4.4, 95% CI 1.6-12.3). CONCLUSION: PABC showed different biologic features than non-PABC. PABC had a particularly poor prognosis in the luminal B (HR+ HER2-highKi67) and HER2 subtypes. To improve the prognosis of PABC, treatment should be considered according to subtype. Development of drugs that can be used during pregnancy is needed.

Tamoxifen therapy improves overall survival in luminal A subtype of ductal carcinoma in situ: a study based on nationwide Korean Breast Cancer Registry database.

PURPOSE: To determine the prognostic role of tamoxifen therapy for patients with ductal carcinoma in situ (DCIS) according to molecular subtypes. METHODS: Data of 14,944 patients with DCIS were analyzed. Molecular subtypes were classified into four categories based on expression of estrogen receptor (ER)/progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). Kaplan-Meier estimator was used for overall survival analysis while Cox proportional hazards model was used for univariate and multivariate analyses. RESULTS: Luminal A subtype (ER/PR+, HER2-) showed higher (P = .009) survival rate than triple-negative (TN) subtype. Tamoxifen therapy group showed superior (P < .001) survival than no-tamoxifen therapy group. It had survival benefit only for luminal A subtype (P = .001). Tamoxifen therapy resulted in higher survival rate in subgroups with positive ER (P = .006), positive PR (P = .009), and negative HER2 (P < .001). In luminal A subtype, tamoxifen therapy showed lower hazard ratio (HR) compared to no-tamoxifen therapy (HR, 0.420; 95% CI 0.250-0.705; P = .001). Tamoxifen therapy was a significant independent factor by multivariate analysis (HR, 0.538; 95% CI 0.306-0.946; P = .031) as well as univariate analysis. CONCLUSION: Tamoxifen therapy group showed superior prognosis than the no-tamoxifen therapy group. Its prognostic influence was only effective for luminal A subtype. Patients with luminal A subtype showed higher survival rate than those with TN subtype. Active tamoxifen therapy is recommended for DCIS patients with luminal A subtype, and routine tests for ER, PR, and HER2 should be considered for DCIS.