Outcomes in Nonmetastatic Hormone Receptor-Positive HER2-Negative Pure Mucinous Breast Cancer: A Multicenter Cohort Study.

BACKGROUND: Although considered a favorable subtype, pure mucinous breast cancer (PMBC) can recur, and evidence for adjuvant therapy is limited. We aimed to compare outcomes of nonmetastatic PMBC with invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) to address these uncertainties. METHODS: Individual patient-level data from 6 centers on stage I-III hormone receptor-positive and HER2-negative PMBC, IDC, and ILC were used to analyze recurrence-free interval (RFI), recurrence-free survival (RFS), and overall survival (OS), and to identify prognostic factors for PMBC. RESULTS: Data from 20,684 IDC cases, 1,475 ILC cases, and 943 PMBC cases were used. Median follow-up was 6.6 years. Five-year RFI, RFS, and OS for PMBC were 96.1%, 94.9%, and 98.1%, respectively. On multivariable Cox regression, PMBC demonstrated superior RFI (hazard ratio [HR], 0.59; 95% CI, 0.43-0.80), RFS (HR, 0.70; 95% CI, 0.56-0.89), and OS (HR, 0.71; 95% CI, 0.53-0.96) compared with IDC. ILC showed comparable outcomes to IDC. Fewer than half (48.7%) of recurrences in PMBC were distant, which was a lower rate than for IDC (67.3%) and ILC (80.6%). In contrast to RFI, RFS events were driven more by non-breast cancer deaths in older patients. Significant prognostic factors for RFI among PMBC included positive lymph node(s) (HR, 2.42; 95% CI, 1.08-5.40), radiotherapy (HR, 0.44; 95% CI, 0.23-0.85), and endocrine therapy (HR, 0.25; 95% CI, 0.09-0.70). No differential chemotherapy associations with outcomes were detected across PMBC subgroups by nodal stage, tumor size, and age. A separate SEER database analysis also did not find any association of improved survival with adjuvant chemotherapy in these subgroups. CONCLUSIONS: Compared with IDC, PMBC demonstrated superior RFI, RFS, and OS. Lymph node negativity, adjuvant radiotherapy, and endocrine therapy were associated with superior RFI. Adjuvant chemotherapy was not associated with better outcomes.

Preliminary Attainability Assessment of Real-World Data for Answering Major Clinical Research Questions in Breast Cancer Brain Metastasis: Framework Development and Validation Study.

BACKGROUND: In recent decades, real-world evidence (RWE) in oncology has rapidly gained traction for its potential to answer clinical questions that cannot be directly addressed by randomized clinical trials. Integrating real-world data (RWD) into clinical research promises to contribute to more sustainable research designs, including extension, augmentation, enrichment, and pragmatic designs. Nevertheless, clinical research using RWD is still limited because of concerns regarding the shortage of best practices for extracting, harmonizing, and analyzing RWD. In particular, pragmatic screening methods to determine whether the content of a data source is sufficient to answer the research questions before conducting the research with RWD have not yet been established. OBJECTIVE: We examined the PAR (Preliminary Attainability Assessment of Real-World Data) framework and assessed its utility in breast cancer brain metastasis (BCBM), which has an unmet medical need for data attainability screening at the preliminary step of observational studies that use RWD. METHODS: The PAR framework was proposed to assess data attainability from a particular data source during the early research process. The PAR framework has four sequential stages, starting with clinical question clarification: (1) operational definition of variables, (2) data matching (structural/semantic), (3) data screening and extraction, and (4) data attainability diagramming. We identified 5 clinical questions to be used for PAR framework evaluation through interviews and validated them with a survey of breast cancer experts. We used the Samsung Medical Center Breast Cancer Registry, a hospital-based real-time registry implemented in March 2021, leveraging the institution's anonymized and deidentified clinical data warehouse platform. The number of breast cancer patients in the registry was 45,129; it covered the period from June 1995 to December 2021. The registry consists of 24 base data marts that represent disease-specific breast cancer characteristics and care pathways. The outcomes included screening results of the clinical questions via the PAR framework and a procedural diagram of data attainability for each research question. RESULTS: Data attainability was tested for study feasibility according to the PAR framework with 5 clinical questions for BCBM. We obtained data sets that were sufficient to conduct studies with 4 of 5 clinical questions. The research questions stratified into 3 types when we developed data fields for clearly defined research variables. In the first, only 1 question could be answered using direct data variables. In the second, the other 3 questions required surrogate definitions that combined data variables. In the third, the question turned out to be not feasible for conducting further analysis. CONCLUSIONS: The adoption of the PAR framework was associated with more efficient preliminary clinical research using RWD from BCBM. Furthermore, this framework helped accelerate RWE generation through clinical research by enhancing transparency and reproducibility and lowering the entry barrier for clinical researchers.

HER2 expression, copy number variation and survival outcomes in HER2-low non-metastatic breast cancer: an international multicentre cohort study and TCGA-METABRIC analysis.

BACKGROUND: HER2-low breast cancer (BC) is currently an area of active interest. This study evaluated the impact of low expression of HER2 on survival outcomes in HER2-negative non-metastatic breast cancer (BC). METHODS: Patients with HER2-negative non-metastatic BC from 6 centres within the Asian Breast Cancer Cooperative Group (ABCCG) (n = 28,280) were analysed. HER2-low was defined as immunohistochemistry (IHC) 1+ or 2+ and in situ hybridization non-amplified (ISH-) and HER2-zero as IHC 0. Relapse-free survival (RFS) and overall survival (OS) by hormone receptor status and HER2 IHC 0, 1+ and 2+ ISH- status were the main outcomes. A combined TCGA-BRCA and METABRIC cohort (n = 1967) was also analysed to explore the association between HER2 expression, ERBB2 copy number variation (CNV) status and RFS. RESULTS: ABCCG cohort median follow-up was 6.6 years; there were 12,260 (43.4%) HER2-low BC and 16,020 (56.6%) HER2-zero BC. The outcomes were better in HER2-low BC than in HER2-zero BC (RFS: centre-adjusted hazard ratio (HR) 0.88, 95% CI 0.82-0.93, P < 0.001; OS: centre-adjusted HR 0.82, 95% CI 0.76-0.89, P < 0.001). On multivariable analysis, HER2-low status was prognostic (RFS: HR 0.90, 95% CI 0.85-0.96, P = 0.002; OS: HR 0.86, 95% CI 0.79-0.93, P < 0.001). These differences remained significant in hormone receptor-positive tumours and for OS in hormone receptor-negative tumours. Superior outcomes were observed for HER2 IHC1+ BC versus HER2-zero BC (RFS: HR 0.89, 95% CI 0.83-0.96, P = 0.001; OS: HR 0.85, 95% CI 0.78-0.93, P = 0.001). No significant differences were seen between HER2 IHC2+ ISH- and HER2-zero BCs. In the TCGA-BRCA and METABRIC cohorts, ERBB2 CNV status was an independent RFS prognostic factor (neutral versus non-neutral HR 0.71, 95% CI 0.59-0.86, P < 0.001); no differences in RFS by ERBB2 mRNA expression levels were found. CONCLUSIONS: HER2-low BC had a superior prognosis compared to HER2-zero BC in the non-metastatic setting, though absolute differences were modest and driven by HER2 IHC 1+ BC. ERBB2 CNV merits further investigation in HER2-negative BC.

Prevalence, treatment patterns, and prognosis of low estrogen receptor-positive (1% to 10%) breast cancer: a single institution's experience in Korea.

PURPOSE: To determine prevalence, clinicopathological characteristics, initial treatments, and outcomes associated with low estrogen receptor (ER)-expressing invasive breast cancer. METHODS: This retrospective, non-interventional database study included patients undergoing surgery with curative intent for invasive ductal or lobular breast cancer. Patients were treated between January 2003-December 2012. Demographics, clinicopathological characteristics, initial treatments, and outcomes were abstracted from patient records. Patients were categorized using immunohistochemistry to determine ER, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) levels. ER-positive patients were subclassified as ER-low (1% to 10%) and ER-high (> 10%) according to the Allred Proportion Score. Disease-free survival (DFS) and overall survival (OS) were estimated by the Kaplan-Meier method and compared among groups by log-rank test. RESULTS: 5930 patients were included (median follow-up, 80.9 months). Of all patients included, 117 (2.0%) had ER-low tumors: 63 (53.8%) of whom had HER2- tumors and 54 (46.2%) HER2+ tumors. Five-year DFS and OS were highest in the ER-high/HER2- cohort (94.0% and 98.6%, respectively) and lowest in the triple-negative breast cancer (TNBC; 81.3% and 90.1%) and ER-low/HER2- (85.7% and 92.1%) cohorts. Menopausal status, elevated Ki-67, higher nuclear grade, higher tumor stage, presence of lymphovascular invasion, greater regional lymph node involvement, and larger tumor size were all potential prognostic factors for shorter DFS and OS. CONCLUSION: Patients with ER-low/HER2- breast cancer had similar clinicopathological characteristics, treatments, and outcomes as patients with TNBC irrespective of disease setting. Further research is needed to understand predictive and prognostic factors associated with ER-low/HER2- disease.

Current State-of-Practice: Transportation for Patients with End Stage Renal Disease.

Patients receiving care for the management of end stage renal disease require transport to nephrology practice settings and treatment centers for hemodialysis and peritoneal dialysis. This type of transportation, defined as non-emergency medical transportation, has long presented a challenge for patients, families, and healthcare providers. This article explores the current and projected statistics and trends for chronic kidney disease,transportation challenges faced by patients and nephrology healthcare providers, and examples of successful transportation services and programs. Implications for practice with a focus placed on the importance of an interprofessional approach are described.

Cranial irradiation regulates CREB-BDNF signaling and variant BDNF transcript levels in the mouse hippocampus.

The brain can be exposed to ionizing radiation in various ways, and such irradiation can trigger adverse effects, particularly on learning and memory. However, the precise mechanisms of cognitive impairments induced by cranial irradiation remain unknown. In the hippocampus, brain-derived neurotrophic factor (BDNF) plays roles in neurogenesis, neuronal survival, neuronal differentiation, and synaptic plasticity. The significance of BDNF transcript variants in these contexts is becoming clearer. In the present study, both object recognition memory and contextual fear conditioning task performance in adult C57BL/6 mice were assessed 1 month after a single exposure to cranial irradiation (10 Gy) to evaluate hippocampus-related behavioral dysfunction following such irradiation. Furthermore, changes in the levels of BDNF, the cAMP-response element binding protein (CREB) phosphorylation, and BDNF transcript variants were measured in the hippocampus 1 month after cranial irradiation. On object recognition memory and contextual fear conditioning tasks, mice evaluated 1 month after irradiation exhibited significant memory deficits compared to sham-irradiated controls, but no apparent change was evident in locomotor activity. Both phosphorylated CREB and BDNF protein levels were significantly downregulated after irradiation of the hippocampus. Moreover, the levels of mRNAs encoding common BDNF transcripts, and exons IIC, III, IV, VII, VIII, and IXA, were significantly downregulated after irradiation. The reductions in CREB phosphorylation and BDNF expression induced by differential regulation of BDNF hippocampal exon transcripts may be associated with the memory deficits evident in mice after cranial irradiation.

Evaluation of the adsorption performance and thermal treatment-associated regeneration of adsorbents for formaldehyde removal.

Indoor air pollution remains a major concern, with formaldehyde (HCHO) a primary contributor due to its long emission period and associated health risks, including skin allergies, coughing, and bronchitis. This study evaluated the adsorption performance and economic efficiency of various adsorbents (biochar, activated carbon, zeolites A, X, and Y) selected for HCHO removal. The impact of thermal treatment on adsorbent regeneration was also assessed. The experimental apparatus featured an adsorption column and HCHO concentration meter with an electrochemical sensor designed for adsorption analysis. Zeolite X exhibited the highest adsorption performance, followed by zeolite A, zeolite Y, activated carbon, and biochar. All adsorbents displayed increased HCHO removal rates with an extended length/diameter (L/D) ratio of the adsorption column. Zeolite A demonstrated the highest economic efficiency, followed by zeolite X, activated carbon, zeolite Y, and biochar. Higher L/D ratios improved economic efficiency and prolonged the replacement cycle (the optimal timing for adsorbent replacement to maintain high adsorption performance). Sensitivity analysis of adsorbent regeneration under varying thermal treatment conditions (150, 120, and 80°C) and durations (60, 45, and 30 min) revealed minimal changes in adsorption efficiency (±3%). The results indicated the potential of adsorbent regeneration under energy-efficient thermal treatment conditions (80°C, 30 min). In conclusion, this study underscores the importance of a comprehensive assessment, considering factors such as adsorption performance, replacement cycle, economic efficiency, and regeneration performance for the selection of optimal adsorbents for HCHO adsorption and removal.Implications: This study underscores the importance of adsorption technology for the removal of formaldehyde and similar volatile organic compounds (VOCs), highlighting the potential of alternative adsorbents, such as environmentally friendly biochar, in addition to traditional strategies, such as activated carbon and zeolites. Our findings demonstrate the feasibility of adsorbent regeneration under energy-efficient thermal treatment conditions. These results hold promise for improving indoor air quality, reducing environmental pollutants, and enhancing responses to air contaminants like fine dust and VOCs.

Impact of Social Support during Diagnosis and Treatment on Disease Progression in Young Patients with Breast Cancer: A Prospective Cohort Study.

PURPOSE: We evaluated the association between changes in social support after cancer treatment and recurrence-free survival (RFS) in such patients using a prospective cohort study. MATERIALS AND METHODS: Data were obtained from a prospective cohort study (NCT03131089) conducted at Samsung Medical Center (2013-2021). The primary outcome measure was RFS. Social support was measured using the social and family well-being (SFWB) domain of the Functional Assessment of Cancer Therapy-General. We calculated the changes in SFWB scores before and during treatment and the hazard ratio for RFS by comparing such changes. RESULTS: The mean±standard deviation (SD) age of the patients was 35±3.9 years, and 71.5% and 64.8% of the patients were married and had children, respectively. The mean±SD SFWB score at baseline was 20.5±5.0 out of 26. After cancer treatment, 35.9%, 10.3%, and 53.8% of the participants had increasing, unchanged, and decreasing SFWB scores, respectively. The decreasing SFWB score group had a higher risk of mortality or recurrence than the increasing group. Risk factors for the decreasing score were the presence of children during diagnosis. CONCLUSION: In this cohort, changes in social support after treatment were associated with RFS in young patients with breast cancer. Health professionals should develop family interventions to help them receive proper social support.

Comprehensive Young Age Breast Cancer registry from clinical, genomics, and patient-reported outcomes measured with 15 years follow-up: the CHARM cohort profile.

BACKGROUND: In recognition of the distinct clinical challenges and research gaps in young breast cancer (YBC) patients, we established the Comprehensive Young Age Breast Cancer (CHARM) registry to collect prospective data. METHODS: This prospective cohort included patients who were newly diagnosed with histologically confirmed breast cancer without prior treatment at the Samsung Medical Center (SMC) in April 2013. We included patients who were either 40 years old or younger at the time of diagnosis, pregnant at breast cancer diagnosis or diagnosed with breast cancer within 1 year of delivery. All data were collected using Medidata's Rave Electronic Data. Clinical data were obtained from electronic medical records. Two experienced pathologists reviewed the pathologic data. Bone mineral densitometry tests have been conducted annually. To obtain multi-omics data, tumor tissues and blood samples were prospectively collected from consenting patients in the registry during surgery. The fertility-related factor also collected collaborated with the Department of Obstetrics and Gynecology. Anti-Müllerian hormone, estradiol, follicle-stimulating hormone, and luteinizing hormone levels were measured using an additional blood sample from baseline to last follow-up. Patient-reported outcomes were assessed using mobile questionnaires. RESULTS: A total of 1868 participants were included in the SMC YBC study. The average (standard deviation) age was 35.57 (3.79) and 99.8% of the participants were premenopausal. Among them, 1062 participants completed the PRO questionnaires. CONCLUSIONS: The SMC YBC cohort serves as a comprehensive registry for YBC to optimize care and improve knowledge regarding the management of YBC.

Pretreatment endocrine symptoms and recurrence-free survival among young premenopausal patients with breast cancer: a prospective cohort study.

Background: Pretreatment endocrine symptoms in premenopausal patients might be considered as a potential marker of poor prognosis. We conducted a cohort study to evaluate the association between endocrine symptoms prior to treatment and recurrence-free survival (RFS) among premenopausal patients with breast cancer aged ⩽40 years. Methods: Data were obtained from a prospective cohort study (NCT03131089) conducted at the Samsung Medical Center from 2013 to 2021. We included patients aged ⩽40 years who had been diagnosed with breast cancer. The primary outcome measure was RFS. Endocrine symptoms were measured using the Functional Assessment of Cancer Therapy - Endocrine Symptoms (FACT-ES). We also calculated the hazard ratio (HR) for recurrence or all-cause mortality by comparing the tertiles of the FACT-ES score at diagnosis. Results: Among the 977 participants, the mean (standard deviation) age was 35.3 (3.9) years. At diagnosis, 17.2% of the patients had at least one severe endocrine symptom. During 3512 person-years of follow-up, the high symptom group had a worse RFS than the low-symptom group [HR = 2.05; 95% confidence interval (CI) = 1.19-3.54]. In particular, hot flashes (HR = 5.59; 95% CI = 1.96-15.93) and breast sensitivity (HR = 1.82; 95% CI = 1.00-3.32) were associated with reduced RFS. Conclusion: Close monitoring of pretreatment endocrine symptoms may be important in patients diagnosed with breast cancer at a young age.

Longitudinal multi-omics study of palbociclib resistance in HR-positive/HER2-negative metastatic breast cancer.

BACKGROUND: Cyclin-dependent kinase 4/6 inhibitor (CDK4/6) therapy plus endocrine therapy (ET) is an effective treatment for patients with hormone receptor-positive/human epidermal receptor 2-negative metastatic breast cancer (HR+/HER2- MBC); however, resistance is common and poorly understood. A comprehensive genomic and transcriptomic analysis of pretreatment and post-treatment tumors from patients receiving palbociclib plus ET was performed to delineate molecular mechanisms of drug resistance. METHODS: Tissue was collected from 89 patients with HR+/HER2- MBC, including those with recurrent and/or metastatic disease, receiving palbociclib plus an aromatase inhibitor or fulvestrant at Samsung Medical Center and Seoul National University Hospital from 2017 to 2020. Tumor biopsy and blood samples obtained at pretreatment, on-treatment (6 weeks and/or 12 weeks), and post-progression underwent RNA sequencing and whole-exome sequencing. Cox regression analysis was performed to identify the clinical and genomic variables associated with progression-free survival. RESULTS: Novel markers associated with poor prognosis, including genomic scar features caused by homologous repair deficiency (HRD), estrogen response signatures, and four prognostic clusters with distinct molecular features were identified. Tumors with TP53 mutations co-occurring with a unique HRD-high cluster responded poorly to palbociclib plus ET. Comparisons of paired pre- and post-treatment samples revealed that tumors became enriched in APOBEC mutation signatures, and many switched to aggressive molecular subtypes with estrogen-independent characteristics. We identified frequent genomic alterations upon disease progression in RB1, ESR1, PTEN, and KMT2C. CONCLUSIONS: We identified novel molecular features associated with poor prognosis and molecular mechanisms that could be targeted to overcome resistance to CKD4/6 plus ET. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03401359. The trial was posted on 18 January 2018 and registered prospectively.

Haplotype-specific insertion-deletion variations for allele-specific targeting in Huntington's disease.

Huntington's disease (HD) is a dominantly inherited neurodegenerative disease caused by an expanded CAG repeat in huntingtin (HTT). Given an important role for HTT in development and significant neurodegeneration at the time of clinical manifestation in HD, early treatment of allele-specific drugs represents a promising strategy. The feasibility of an allele-specific antisense oligonucleotide (ASO) targeting single-nucleotide polymorphisms (SNPs) has been demonstrated in models of HD. Here, we constructed a map of haplotype-specific insertion-deletion variations (indels) to develop alternative mutant-HTT-specific strategies. We mapped indels annotated in the 1000 Genomes Project data on common HTT haplotypes, revealing candidate indels for mutant-specific HTT targeting. Subsequent sequencing of an HD family confirmed candidate sites and revealed additional allele-specific indels. Interestingly, the most common normal HTT haplotype carries indels of big allele length differences at many sites, further uncovering promising haplotype-specific targets. When patient-derived cells carrying the most common HTT diplotype were treated with ASOs targeting the mutant alleles of candidate indels (rs772629195 or rs72239206), complete mutant specificity was observed. In summary, our map of haplotype-specific indels permits the identification of allele-specific targets in HD subjects, potentially contributing to the development of safe HTT-lowering therapeutics that are suitable for early treatment in HD.

PAM-altering SNP-based allele-specific CRISPR-Cas9 therapeutic strategies for Huntington's disease.

Huntington's disease (HD) is caused by an expanded CAG repeat in huntingtin (HTT). Since HD is dominant and loss of HTT leads to neurological abnormalities, safe therapeutic strategies require selective inactivation of mutant HTT. Previously, we proposed a concept of CRISPR-Cas9 using mutant-specific PAM sites generated by SNPs to selectively inactivate mutant HTT. Aiming at revealing suitable targets for clinical development, we analyzed the largest HD genotype dataset to identify target PAM-altering SNPs (PAS) and subsequently evaluated their allele specificities. The gRNAs based on the PAM sites generated by rs2857935, rs16843804, and rs16843836 showed high levels of allele specificity in patient-derived cells. Simultaneous use of two gRNAs based on rs2857935-rs16843804 or rs2857935-rs16843836 produced selective genomic deletions in mutant HTT and prevented the transcription of mutant HTT mRNA without impacting the expression of normal counterpart or re-integration of the excised fragment elsewhere in the genome. RNA-seq and off-target analysis confirmed high levels of allele specificity and the lack of recurrent off-targeting. Approximately 60% of HD subjects are eligible for mutant-specific CRISPR-Cas9 strategies of targeting one of these three PAS in conjunction with one non-allele-specific site, supporting high applicability of PAS-based allele-specific CRISPR approaches in the HD patient population.

Efficacy of preoxygenation with end-tidal oxygen when using different oxygen concentrations in patients undergoing general surgery: a single-center retrospective observational study.

BACKGROUND: Preoxygenation is a simple but very important procedure for preventing arterial desaturation. A higher fraction of inspired oxygen (FiO2) increases atelectasis and 80% oxygen results in significantly less atelectasis than 100% oxygen. We investigated whether there was a difference in the duration of adequate preoxygenation when using 100% and 80% oxygen. The proportion of patients for whom >3 min was required to achieve adequate preoxygenation was also investigated. METHODS: The VitalDB database of patients underwent general surgery between February 1, 2021 and November 12, 2021 was reviewed. The time between the start of preoxygenation and the point where a 10% difference between FiO2 and end-tidal oxygen (EtO2) was defined as the preoxygenation time. The patients were classified into 100% and 80% groups according to the oxygen concentration. Propensity score matching (PSM) was performed to control for potential confounding factors. RESULTS: Only 330 of the 1,377 patients had sufficient data for analysis: 179 in the 80% group and 151 in the 100% group. After PSM, 143 patients in each group were analyzed. The median preoxygenation time was 143 s [interquartile range (IQR): 120.5-181.5 s] and 144 s (IQR: 109.75-186.25 s) in the 80% and 100% groups, respectively [P=0.605; median difference =-1 s; 95% confidence interval (CI): -13 to 10]. Of the patients, 27% required >3 min for adequate preoxygenation. CONCLUSIONS: No difference in preoxygenation time was found between the 80% and 100% groups. For some patients, breathing for 3 min is not sufficient for adequate preoxygenation. EtO2 monitoring aids evaluation of whether preoxygenation was adequate.

Allele-specific silencing of the gain-of-function mutation in Huntington's disease using CRISPR/Cas9.

Dominant gain-of-function mechanisms in Huntington's disease (HD) suggest that selective silencing of mutant HTT produces robust therapeutic benefits. Here, capitalizing on exonic protospacer adjacent motif-altering (PAM-altering) SNP (PAS), we developed an allele-specific CRISPR/Cas9 strategy to permanently inactivate mutant HTT through nonsense-mediated decay (NMD). Comprehensive sequence/haplotype analysis identified SNP-generated NGG PAM sites on exons of common HTT haplotypes in HD subjects, revealing a clinically relevant PAS-based mutant-specific CRISPR/Cas9 strategy. Alternative allele of rs363099 (29th exon) eliminates the NGG PAM site on the most frequent normal HTT haplotype in HD, permitting mutant-specific CRISPR/Cas9 therapeutics in a predicted ~20% of HD subjects with European ancestry. Our rs363099-based CRISPR/Cas9 showed perfect allele specificity and good targeting efficiencies in patient-derived cells. Dramatically reduced mutant HTT mRNA and complete loss of mutant protein suggest that our allele-specific CRISPR/Cas9 strategy inactivates mutant HTT through NMD. In addition, GUIDE-Seq analysis and subsequent validation experiments support high levels of on-target gene specificity. Our data demonstrate a significant target population, complete mutant specificity, decent targeting efficiency in patient-derived cells, and minimal off-target effects on protein-coding genes, proving the concept of PAS-based allele-specific NMD-CRISPR/Cas9 and supporting its therapeutic potential in HD.

Long-Term Breast Cancer Outcomes of Pregnancy-Associated Breast Cancer (PABC) in a Prospective Cohort.

Background: Given that peak age of breast cancer (BC) is younger in Asians than in Western populations, relatively higher prevalence of pregnancy-associated breast cancer (PABC) has been reported. This study aimed to analyze the characteristics and clinical outcomes of PABC in Korea. Methods: We defined PABC as BC diagnosed during pregnancy or in the first postpartum year. We compared the clinicopathological characteristics and BC outcomes between patients with PABC and non-PABC patients in the prospective YBC cohort from Samsung Medical Center. Results: In total, 1492 patients were initially enrolled, and 1364 patients were included, of which 93 had PABC (6.8%). The median age of patients with PABC was 34 years. Hormone receptor expression was lower (64.6% vs 74.6%) and frequency of HER2 overexpression was higher (26.9% vs 17.6%) in patients with PABC than in non-PABC patients. The 5-year overall survival (OS) rates were 83.2% and 93.4% in patients with PABC and non-PABC patients, respectively (p < 0.001). The 5-year disease-free survival (DFS) rates were 72.2% and 83.8% in PABC and non-PABC patients. Conclusion: Compared to non-PABC patients, patients with PABC had poorer OS and DFS in this prospective cohort. Exploratory biomarker analysis for PABC is warranted.

The Role of Chemotherapy in Patients With HER2-Negative Isolated Locoregional Recurrence of Breast Cancer: A Multicenter Retrospective Cohort Study.

Background: The role of chemotherapy for isolated locoregional recurrence (iLRR) of breast cancer has not been firmly established after local therapies. Methods: We performed a multicenter, retrospective analysis to evaluate the clinical implications of chemotherapy in breast cancer patients with HER2-negative iLRR. Results: Of a total of 277 patients, 146 (52.7%) received chemotherapy for iLRR. Median follow-up duration was 56.1 months. Eighty-six (31.0%) patients had luminal B-like and 100 (36.1%) had TNBC iLRR. There was a trend of longer disease free survival (DFS) in the chemotherapy group (4-year DFS: 70.4 vs. 59.5%, HR = 0.68, 95% CI 0.45-1.02, log-rank p = 0.059). When adjusted with clinically relevant factors, DFS was significantly prolonged with chemotherapy (adjusted HR = 0.61, 95% CI 0.40-0.94, p = 0.023). Subgroup analyses for DFS showed patients with disease free interval (DFI) <5 years or prior chemotherapy had a benefit from chemotherapy (adjusted HR = 0.57, p = 0.018; adjusted HR = 0.51, p = 0.005, respectively). Regarding the molecular subtypes, a longer DFS with chemotherapy was observed both in luminal B-like (4-year DFS: 77.8 vs. 55.0%, HR = 0.51, 95% CI 0.27-0.99, log-rank p = 0.048) and in TNBC patients (4-year DFS: 61.9 vs. 42.8%, HR = 0.49, 95% CI 0.24-1.02, log-rank p = 0.056), but not in luminal A-like. Conclusions: The chemotherapy for iLRR of breast cancer should be individualized for each patient, considering DFI, prior chemotherapy, and molecular subtypes.

Part-time shoulder use operational impact on the safety performance of interstate 476.

OBJECTIVE: With every change in a roadway to improve the network operational performance, the roadway safety behavior is impacted. Part-time shoulder use (PTSU) is one strategy that significantly impacts the operational performance of a roadway for several hours each workday. This study evaluates the impact of PTSU on safety behavior and the possibility of crash prevention. METHOD: Current predictive safety measures do not account for the part-time dimensional changes of PTSU effectively. Using Vissim-based microsimulation trajectory data in the Surrogate Safety Assessment Model (SSAM) program, developed by the Federal Highway Administration, this study gauged the safety disposition of Interstate 476 (I-476) in southeast Pennsylvania (PA). The two key safety evaluation factors include the number of conflicts and the time-to-collision (TTC) of each conflict. The number of conflicts represents unsafe scenarios that could become crashes if neither possibly impacted vehicles adjusts their route. TTC is the minimum time for the conflict to become a crash if either vehicle's route was not adjusted to avoid the collision. Both factors were averaged across six 20-min periods during the 2-h commuting period simulated. RESULTS: Due to the improved operational performance, the TTC values for the PTSU scenarios decreased, reducing safety; however, the number of conflicts occurring reduced significantly, counterbalancing the reduced safety from the TTC reduction. CONCLUSIONS: PTSU has great operational improvement effects which create a faster-moving transportation network. The higher speeds caused by the enhanced operations increases the risk of a crash during unsafe situations, but the number of unsafe situations occurring will significantly reduce. The reduced number of unsafe situations indicates an increased probability of crash avoidance but does not indicate a definitive reduction in crashes.

Clinical Characteristics and Exploratory Genomic Analyses of Germline BRCA1 or BRCA2 Mutations in Breast Cancer.

gBRCA1/2 mutations increase the incidence of breast cancer by interrupting the homologous recombination repair (HRR) pathway. Although gBRCA1 and gBRCA2 breast cancer have similar clinical profiles, different molecular characteristics have been observed. In this study, we conducted comprehensive genomic analyses and compared gBRCA1/2 breast cancer. Sanger sequencing to identify gBRCA1/2 mutations was conducted in 2,720 patients, and gBRCA1 (n = 128) and gBRCA2 (n = 126) mutations were analyzed. Within this population, deep target sequencing and matched whole-transcriptome sequencing (WTS) results were available for 46 and 34 patients, respectively. An internal database of patients with breast cancer with wild-type gBRCA was used to compile a target sequencing (n = 195) and WTS (n = 137) reference dataset. Three specific mutation sites, p.Y130X (n = 14) and p.1210Afs (n = 13) in gBRCA1 and p.R294X (n = 22) in gBRCA2, were comparably frequent. IHC subtyping determined that the incidence of triple-negative breast cancer was higher among those with a gBRCA1 mutation (71.9%), and estrogen receptor-positive breast cancer was dominant in those with a gBRCA2 mutation (76.2%). gBRCA1/2 mutations were mutually exclusive with PIK3CA somatic mutations (P < 0.05), and gBRCA1 frequently cooccurred with TP53 somatic mutations (P < 0.05). The median tumor mutation burden was 6.53 per megabase (MB) in gBRCA1 and 6.44 per MB in gBRCA2. The expression of AR, ESR1, and PGR was significantly upregulated with gBRCA2 mutation compared with gBRCA1 mutation. gBRCA1 and gBRCA2 breast cancer have similar clinical characteristics, but they have different molecular subtypes, coaltered somatic mutations, and gene expression patterns. IMPLICATIONS: Even though gBRCA1 and gBRCA2 mutations both alter HRR pathways, our results suggest that they generate different molecular characteristics and different mechanisms of carcinogenesis.

Chemotherapy induces dynamic immune responses in breast cancers that impact treatment outcome.

To elucidate the effects of neoadjuvant chemotherapy (NAC), we conduct whole transcriptome profiling coupled with histopathology analyses of a longitudinal breast cancer cohort of 146 patients including 110 pairs of serial tumor biopsies collected before treatment, after the first cycle of treatment and at the time of surgery. Here, we show that cytotoxic chemotherapies induce dynamic changes in the tumor immune microenvironment that vary by subtype and pathologic response. Just one cycle of treatment induces an immune stimulatory microenvironment harboring more tumor infiltrating lymphocytes (TILs) and up-regulation of inflammatory signatures predictive of response to anti-PD1 therapies while residual tumors are immune suppressed at end-of-treatment compared to the baseline. Increases in TILs and CD8+ T cell proportions in response to NAC are independently associated with pathologic complete response. Further, on-treatment immune response is more predictive of treatment outcome than immune features in paired baseline samples although these are strongly correlated.