Epigenetic regulation of H3K27me3 in laying hens with fatty liver hemorrhagic syndrome induced by high-energy and low-protein diets.

BACKGROUND: Fatty liver hemorrhagic syndrome (FLHS) in the modern poultry industry is primarily caused by nutrition. Despite encouraging progress on FLHS, the mechanism through which nutrition influences susceptibility to FLHS is still lacking in terms of epigenetics. RESULTS: In this study, we analyzed the genome-wide patterns of trimethylated lysine residue 27 of histone H3 (H3K27me3) enrichment by chromatin immunoprecipitation-sequencing (ChIP-seq), and examined its association with transcriptomes in healthy and FLHS hens. The study results indicated that H3K27me3 levels were increased in the FLHS hens on a genome-wide scale. Additionally, H3K27me3 was found to occupy the entire gene and the distant intergenic region, which may function as silencer-like regulatory elements. The analysis of transcription factor (TF) motifs in hypermethylated peaks has demonstrated that 23 TFs are involved in the regulation of liver metabolism and development. Transcriptomic analysis indicated that differentially expressed genes (DEGs) were enriched in fatty acid metabolism, amino acid, and carbohydrate metabolism. The hub gene identified from PPI network is fatty acid synthase (FASN). Combined ChIP-seq and transcriptome analysis revealed that the increased H3K27me3 and down-regulated genes have significant enrichment in the ECM-receptor interaction, tight junction, cell adhesion molecules, adherens junction, and TGF-beta signaling pathways. CONCLUSIONS: Overall, the trimethylation modification of H3K27 has been shown to have significant regulatory function in FLHS, mediating the expression of crucial genes associated with the ECM-receptor interaction pathway. This highlights the epigenetic mechanisms of H3K27me3 and provides insights into exploring core regulatory targets and nutritional regulation strategies in FLHS.

Results of a Phase Ib Study Investigating Durvalumab in Combination with Eribulin in Patients with HER2-Negative Metastatic Breast Cancer and Recurrent Ovarian Cancer.

INTRODUCTION: The release of tumor-associated antigens with cytotoxic chemotherapy treatment may enhance the response to immune checkpoint blockade. Eribulin is a microtubule inhibitor with proven overall survival (OS) benefit in metastatic breast cancer (MBC), which may also enhance intratumoral vascular remodeling. Durvalumab, a humanized monoclonal antibody, targets the programmed cell death ligand-1 (PD-L1) receptor. This study sought to determine the maximum tolerated dose and recommended phase II dose (RP2D) of eribulin in combination with durvalumab, as well as the safety and preliminary antitumor activity of the combination in patients with previously treated HER2-negative (HER2-) MBC and recurrent ovarian cancer (ROC). METHODS: Cohorts of 3-6 patients with HER2- MBC and ROC were treated in a modified 3+3 design. Eligible patients received escalating doses of eribulin (1.1 mg/m2 or 1.4 mg/m2 IV on day 1 and day 8) with durvalumab (1.12 g IV on day 1) in 21-day cycles until dose-limiting toxicity (DLT), intolerable adverse events (AEs), disease progression, or other reasons for withdrawal. PRIMARY ENDPOINT: the rate of DLTs during cycles 1 and 2 of therapy. Secondary endpoints: AE rate, objective response rate (ORR), progression-free survival (PFS), and OS. RESULTS: Nine patients with a median of 4 prior therapies for advanced disease were treated: 5 patients with HER2- MBC (1 with triple-negative disease and 4 with hormone-positive disease) and 4 patients with ROC. The RP2D of eribulin was 1.4 mg/m2 in combination with durvalumab. There were no DLTs experienced during the first two cycles of therapy. The most common treatment-related AEs (>50%) were fatigue, neutropenia, decreased white blood cell count, anemia, AST and alkaline phosphatase elevation, hyperglycemia, and nausea; most were grade 1 or 2. There was one immune-related AE of grade 3 (hepatitis) after 5 cycles of treatment, for which patient came off study. Two other patients discontinued study drug related to toxicity (neutropenia [n = 1], hepatic toxicity [n = 1]). ORR was 55%, and 4 additional patients experienced stable disease. All MBC patients exhibited a response to therapy. Median PFS was 6.2 months. Median OS was 15.0 months. CONCLUSION: The combination of eribulin at a dose of 1.4 mg/m2 with standard dose durvalumab had a favorable AE profile in patients with previously treated HER2- MBC and ROC. The early antitumor activity observed in all MBC patients enrolled in the study suggests that further investigation of this combination is warranted.

Resveratrol prevents cognitive deficits induced by sleep deprivation via modulating sirtuin 1 associated pathways in the hippocampus.

Accumulating evidence confirms that sleep insufficiency is a high risk factor for cognitive impairment, which involves inflammation and synaptic dysfunction. Resveratrol, an agonist of the Sirt1, has demonstrated anti-inflammation and neuroprotective effects in models of Alzheimer's disease, Parkinson's disease, and schizophrenia. However, the beneficial effects of resveratrol on sleep deprivation-induced cognitive deficits and its underlying molecular mechanisms are unclear. In the present study, thirty-two male C57BL/6 J mice were randomly divided into a Control+DMSO group, Control+Resveratrol group, SD+DMSO group, and SD+Resveratrol group. The mice in the SD+Resveratrol group underwent 5 days of sleep deprivation after pretreatment with resveratrol (50 mg/kg) for 2 weeks, while the mice in the SD+DMSO group only underwent sleep deprivation. After sleep deprivation, we evaluated spatial learning and memory function using the Morris water maze test. We used general molecular biology techniques to detect changes in levels of pro-inflammatory cytokines and Sirt1/miR-134 pathway-related synaptic plasticity proteins. We found that resveratrol significantly reversed sleep deprivation-induced learning and memory impairment, elevated interleukin-1ß, interleukin-6, and tumor necrosis factor-α levels, and decreased brain-derived neurotrophic factor, tyrosine kinase receptor B, postsynaptic density protein-95, and synaptophysin levels by activating the Sirt1/miR-134 pathway. In conclusion, resveratrol is a promising agent for preventing sleep deprivation-induced cognitive dysfunction by reducing pro-inflammatory cytokines and improving synaptic function via the Sirt1/miR-134 pathway.

Food emulsifier based on the interaction of casein and butyrylated dextrin for improving stability and emulsifying properties.

Green hydrophobically modified butyrylated dextrin (BD) was used to modulate casein (CN). The CN/BD complex nanoparticles were formed at different CN-to-BD mass ratios based on a pH-driven technology. The interaction force, stability, and emulsifying properties of complex nanoparticles were investigated. The nanoparticles had a negative charge and a small particle size (160.03, 152.6, 155.9, 206.13, and 231.67 nm) as well as excellent thermal stability and environmental stability (pH 4.5, 5.5, 6.6, 7.5, 8.5, and 9.5; ionic strength, 50, 100, 200, and 500 mM). Transmission electron microscopy demonstrated the successful preparation of complex nanoparticles and their spherical shape. Fourier transform infrared spectroscopy, fluorescence spectroscopy, and dissociation analysis results showed that the main driving forces of formed CN/BD nanoparticles were hydrogen bonding and hydrophobic interaction. Furthermore, the CN/BD nanoparticles (CN/BD mass ratio, 1:1; weight/weight) exhibited the lowest creaming index, and optical microscopy showed that it has the most evenly dispersed droplets after 7 d of storage, which indicates that the CN/BD nanoparticles had excellent emulsifying properties. Butyrylated dextrin forms complex nanoparticles with CN through hydrogen bonding and hydrophobic interaction to endow CN with superior properties. The results showed that it is possible to use pH-driven technology to form protein-polysaccharide complex nanoparticles, which provides some information on the development of novel food emulsifiers based on protein-polysaccharide nanoparticles. The study provided significant information on the improvement of CN properties and the development of emulsions based on CN.

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OBJECTIVES: To investigate the association between childhood trauma and game addiction in adolescents, as well as the mediating effect of self-control. METHODS: A cross-sectional study was conducted using cluster random sampling. The participants were 2 664 adolescents from a senior high school in Henan Province. The research tools included a demographic data questionnaire, Childhood Trauma Questionnaire-Short Form, Self-Control Scale, and Game Addiction Scale for Adolescents. The Bootstrap method was used to test the parallel mediating effect, with the five dimensions of self-control as mediators. RESULTS: The prevalence of game addiction among the adolescents was 17.68% (471/2 664). There was a positive correlation between childhood trauma and game addiction scores (P<0.01), and a negative correlation between childhood trauma scores and each dimension of self-control (P<0.01). Moreover, all five dimensions of self-control were negatively correlated with game addiction scores (P<0.01) and acted as parallel mediators between childhood trauma and game addiction. The mediating effects of restraint from entertainment (accounting for 15.6% of the total effect) and resistance to temptation (accounting for 10.6% of the total effect) were stronger. CONCLUSIONS: Childhood trauma may increase the risk of game addiction by impairing adolescents' self-control abilities. The reduction of childhood trauma can cultivate self-control in adolescents and prevent the occurrence of game addiction.

AMPK-autophagy-mediated inhibition of microRNA-30a-5p alleviates morphine tolerance via SOCS3-dependent neuroinflammation suppression.

BACKGROUND: The development of morphine tolerance is a clinical challenge for managing severe pain. Studies have shown that neuroinflammation is a critical aspect for the development of analgesic tolerance. We found that AMPK-autophagy activation could suppress neuroinflammation and improve morphine tolerance via the upregulation of suppressor of cytokine signaling 3 (SOCS3) by inhibiting the processing and maturation of microRNA-30a-5p. METHODS: CD-1 mice were utilized for the tail-flick test to evaluate morphine tolerance. The microglial cell line BV-2 was utilized to investigate the mechanism of AMPK-autophagy-mediated posttranscriptional regulation of SOCS3. Proinflammatory cytokines were measured by western blotting and real-time PCR. The levels of SOCS3 and miRNA-processing enzymes were evaluated by western blotting, real-time PCR and immunofluorescence staining. RESULTS: Based on experimental verification, miRNA-30a-5p could negatively regulate SOCS3. The AMPK activators AICAR, resveratrol and metformin downregulated miRNA-30a-5p. We found that AMPK activators specifically inhibited the processing and maturation of miRNA-30a-5p in microglia by degrading DICER and AGO2 via autophagy. Furthermore, a miRNA-30a-5p inhibitor significantly improved morphine tolerance via upregulation of SCOS3 in mice. It markedly increased the level of SOCS3 in the spinal cord of mice and subsequently inhibited morphine-induced phosphorylation of NF-κB p65. In addition, a miRNA-30a-5p inhibitor decreased the levels of IL-1ß and TNF-α caused by morphine in microglia. CONCLUSION: AMPK-autophagy activation suppresses neuroinflammation and improves morphine tolerance via the upregulation of SOCS3 by inhibiting miRNA-30a-5p.

Racial Disparities in Time to Treatment Persist in the Setting of a Comprehensive Breast Center.

BACKGROUND: Racial disparities in breast cancer care have been linked to treatment delays. We explored whether receiving care at a comprehensive breast center could mitigate disparities in time to treatment. METHODS: Retrospective chart review identified breast cancer patients who underwent surgery from 2012 to 2018 at a comprehensive breast center. Time-to-treatment intervals were compared among self-identified racial and ethnic groups by negative binomial regression models. RESULTS: Overall, 2094 women met the inclusion criteria: 1242 (59%) White, 262 (13%) Black, 302 (14%) Hispanic, 105 (5%) Asian, and 183 (9%) other race or ethnicity. Black and Hispanic patients more often had Medicaid insurance, higher American Society of Anesthesiologists (ASA) scores, advanced-stage breast cancer, mastectomy, and additional imaging after breast center presentation (p < 0.05). After controlling for other variables, racial or ethnic minority groups had consistently longer intervals to treatment, with Black women experiencing the greatest disparity (incidence rate ratio 1.42). Time from initial comprehensive breast center visit to treatment was also significantly shorter in White patients versus non-White patients (p < 0.0001). Black race, Medicaid insurance/being uninsured, older age, earlier stage, higher ASA score, undergoing mastectomy, having reconstruction, and requiring additional pretreatment work-up were associated with a longer time from initial visit at the comprehensive breast center to treatment on multivariable analysis (p < 0.05). CONCLUSION: Racial or ethnic minority groups have significant delays in treatment even when receiving care at a comprehensive breast center. Influential factors include insurance delays and necessity of additional pretreatment work-up. Specific policies are needed to address system barriers in treatment access.

Mastectomy or Margin Re-excision? A Nomogram for Close/Positive Margins After Lumpectomy for DCIS.

BACKGROUND: Anatomic extent of ductal carcinoma in situ (DCIS) may be uncertain in spite of clinical, pathologic, and imaging data. Consequently close/positive margins are common with lumpectomy for DCIS and often lead to a challenge in deciding whether to perform a re-excision or mastectomy. PATIENTS AND METHODS: From a single health system, we identified cases of lumpectomy for DCIS with close/positive margins who underwent re-excision for the purpose of constructing a nomogram. In total, 289 patients were available for analysis. The patients were randomly divided into two sets allocating 70% to the modeling and 30% to the validation set. A multivariable logistic regression model was used to estimate the probability of overall positive margin status using multiple clinicopathologic predictors. Nomogram validation included internal tenfold cross-validation, internal bootstrap validation, and external validation for which a concordance index was calculated to assess the external validity. RESULTS: Significant predictors of persistent positive margins from regression modeling included necrosis at diagnosis (non-comedo or comedo); DCIS not associated with calcifications on core biopsy; high-grade DCIS; progesterone receptor positivity; and number of positive margins at initial surgery. When subjected to internal validation, the nomogram achieved an uncorrected concordance index of 0.7332, a tenfold cross-validation concordance index of 0.6795, and a bootstrap-corrected concordance index of 0.6881. External validation yielded an estimated concordance index of 0.7095. CONCLUSION: Using clinical and pathologic variables from initial diagnosis and surgery for DCIS, this nomogram predicts persistent positive margins with margin re-excision, and may be a valuable tool in surgical decision-making.

Impact of Screening Mammography on Treatment in Young Women Diagnosed with Breast Cancer.

BACKGROUND: There is little data exploring the impact of screening mammography on subsequent treatment in the 40-49-year age group with breast cancer. We sought to assess the association between frequency of mammography in young women and extent of surgery and chemotherapy required. METHODS: An IRB-approved retrospective review was performed of patients diagnosed with breast cancer between ages 40 and 49 years from 1 January 2010 to 19 November 2018 within a single health system. Patients were grouped based on last screening 1-24 months prior to diagnosis (1-24 group), > 25 months prior to diagnosis (> 25 group), never screened, and > 25+ never screened (combination group). Multivariate logistic regression models were used to assess for associations between screening intervals and tumor and nodal stage, chemotherapy use, and extent of surgery. RESULTS: Of 869 patients included for analysis, 20% were never screened, 60% screened 1-24 months, and 19% screened > 25 months prior to diagnosis. Compared with the 1-24 months group, the never-screened group, > 25 months group, and combined group were more likely to receive chemotherapy. The never-screened and combined groups were more likely to undergo mastectomy and/or axillary lymph node dissection. Of patients undergoing upfront surgery, the > 25 months and combined groups were more likely to receive adjuvant chemotherapy, while the never-screened and combined groups were more likely to have nodal disease. CONCLUSION: Our findings support the initiation of screening mammography at age 40 years to reduce the risk of aggressive treatments for newly diagnosed breast cancers in this group.

Dietary phytoestrogen intake and lung cancer risk: an analysis of the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial.

Phytoestrogens (PEs) have estrogen-like activity and were found to lower incidences of several hormone-dependent cancers. Emerging evidence suggests that estrogen may play a role in lung cancer carcinogenesis. We aim to evaluate dietary PE intake and lung cancer risk using data from the Prostate, Lung, Colorectal and Ovarian cancer screening trial. A total of 1706 lung cancer cases were identified. The association between lung cancer risk and PE intake (in quartiles) was calculated using the Cox proportional hazard models adjusting for potential confounders. Stratified analyses by smoking status, sex and histology were also performed. The highest quartile of total PE intake was associated with a reduced risk of lung cancer compared with the lowest quartile [hazard ratio (HR) = 0.85, 95% confidence interval (CI): 0.73-0.99 for >1030 µg/day versus <290 µg/day] (P trend = 0.56). Similar patterns were observed among ever smokers (HR = 0.84, 95% CI: 0.71-0.98), non-small cell histology (HR = 0.84, 95% CI: 0.72-0.99), male (HR = 0.84, 95% CI: 0.69-1.03) and female (HR = 0.80, 95% CI: 0.64-0.99 for 510-1030 µg/day, HR = 0.84, 95% CI: 0.67-1.06 for >1030 µg/day versus <290 µg/day) subjects with no significant linear trend observed. Despite a lower consumption compared with the Asian population, increased PE intake still appears to decrease lung cancer risk in a Caucasian-dominant population. Future studies are needed to replicate these results in independent cohorts and shed a light on the potential mechanism of the protective effect of PEs on lung carcinogenesis and the interaction between PEs, smoking and endogenous estrogens.

LINC01315 silencing inhibits the aggressive phenotypes of colorectal carcinoma by sponging miR-205-3p.

Long non-coding RNAs (lncRNAs) are important regulatory factors in the progression of cancers. In this study, we investigated the molecular mechanism of long intergenic non-coding 01315 (LINC01315) in inhibiting the aggressive characteristics of colorectal carcinoma (CRC) cells. We proved that LINC01315 was significantly upregulated in CRC. Knockdown of LINC01315 decreased CRC cell growth and invasion in vitro. Bioinformatics analysis and a luciferase reporter experiment showed direct binding between LINC01315 and miR-205-3p. Furthermore, LINC01315 positively modulated protein kinase AMP-activated catalytic subunit α 1 (PRKAA1) expression by serving as a "sponge" for miR-205-3p. Moreover, LINC01315 regulated the growth and invasive phenotypes of CRC cells by sponging miR-205-3p. Downregulation of LINC01315 remarkedly impaired the tumorigenicity of CRC cells in vivo in a transplanted tumour model. Altogether, our results demonstrated that downregulation of LINC01315 suppresses CRC progression by sponging miR-205-3p.

Trends in neoadjuvant chemotherapy versus surgery-first in stage I HER2-positive breast cancer patients in the National Cancer DataBase (NCDB).

BACKGROUND: Neoadjuvant chemotherapy (NAC) is the standard of care for locally advanced HER2 + breast cancer (BC). Optimal sequencing of treatment (NAC vs. surgery first) is less clear cut in stage I (T1N0) HER2 + BC, where information from surgical pathology could impact adjuvant treatment decisions. Utilizing the NCDB, we evaluated the trend of NAC use compared to upfront surgery in patients with small HER2 + BC. METHODS: We identified NCDB female patients diagnosed with T1 N0 HER2 + BC from 2010 through 2015. Prevalence ratios (PR) using multivariable robust Poisson regression models were calculated to measure the association between baseline characteristics and the receipt of NAC. Analysis of trends over time was denoted by annual percent change (APC) of NAC versus surgery upfront. RESULTS: Of the 14,949 that received chemotherapy and anti-HER2 therapy during the study period, overall 1281 (8.6%) received NAC and 13,668 (91.4%) received adjuvant treatment. Patients receiving NAC increased annually from 4.2% in 2010 to 17.3% in 2015, with the most rapid increase occurring between years 2013 (8.5%) and 2014 (14.2%). The greatest increase was seen in patients with cT1c tumors with an APC of 37.8% over the study period (95% CI 29.0, 47.3%, p < 0.01), although a significant trend was likewise seen in patients with cT1a (APC = 26.1%,95% CI 1.59, 56.6%), and cT1b (APC = 27.4%, 95% CI 18.0, 37.7%) tumors. Predictors of neoadjuvant therapy receipt were age younger than 50 (PR = 1.69, 95% CI 1.52, 1.89), Mountain/Pacific area (PR = 1.24, 95% CI 1.05, 1.46), and estrogen receptor negativity (ER- PR + : PR = 2.01, 95% CI 1.51, 2.68; ER- PR- : PR = 1.49, 95% CI 1.32, 1.69). CONCLUSIONS: Neoadjuvant therapy for T1 N0 HER2 + BC increased over the study period and was mostly due increased use in clinical T1c tumors. This may be consistent with secular change in Pertuzumab treatment following FDA approval in 2013.

Adherence to NCCN Guidelines for Genetic Testing in Breast Cancer Patients: Who Are We Missing?

BACKGROUND: Genetic predisposition accounts for 5-10% of all breast cancers (BC) diagnosed. NCCN guidelines help providers identify appropriate candidates for counseling and testing. Concerns about underutilization of genetic testing have spurred interest in broader peri-diagnostic testing. We evaluated surgeon adherence to NCCN guidelines and studied patterns of testing in newly diagnosed BC patients. METHODS: A total of 397 patients were identified with newly diagnosed BC treated at our institution between 2016 and 2017 with no prior genetic testing. Eligibility for genetic testing based on NCCN criteria, referral, and patient compliance were recorded. RESULTS: In total, 212 of 397 (53%) met NCCN testing criteria. Fifty-nine of 212 (28%) patients went untested despite meeting one or more criteria. Fourteen of 59 (24%) of these were referred but did not comply. Most common criteria for meeting eligibility for testing both in the overall cohort and among missed patients were family history-based. Age > 45 years old and non-Ashkenazi Jewish descent were predictive of missed referral (p < 0.01). We identified pathogenic mutations in 16 of 153 (10%) patients who did undergo testing (11 (7%) BRCA1 or 2 and 5 (3%) with other predisposition gene mutations) or 16 of 397 (4%) among the overall group. CONCLUSIONS: Our data highlight the underutilization of genetic testing. Even in the setting of a full-service breast center with readily available genetic counseling, there is a substantial miss rate for identifying eligible patients, related to assessment of family history, patient age, and ethnicity, as well as patient compliance. Broader peri-diagnostic testing should be considered, and higher compliance rates with patients referred should be sought.

Prognostic Factors and Survival Outcomes among Patients with Breast Cancer and Brain Metastases at Diagnosis: A National Cancer Database Analysis.

INTRODUCTION: The aim of this study was to assess for clinicopathologic and socioeconomic features that predict improved survival for patients with advanced breast cancer with synchronous brain metastases at diagnosis. METHODS: We utilized the National Cancer Database (NCDB) to identify all patients with brain metastases present at diagnosis, with adequate information on receptor status (ER, PR, Her2), clinical T stage of cT1-4, clinical M1, with 3,943 patients available for analysis. The association between brain metastases patterns and patient/disease variables was examined by robust Poisson regression model. Cox proportional hazards model was used to quantify the associations between overall survival (OS) and these variables. RESULTS: In univariable analysis, OS was significantly associated with the number of sites of metastases (p < 0.0001). Patients with 2 or more additional extracranial sites of metastases had significantly worse OS (median 8.8 months, 95% confidence interval [CI] 7.8, 9.9) than patients with brain metastases only (median OS 10.6 months, 95% CI 9.4, 12.9) or brain metastases plus one other extracranial site of metastases (median OS 13.1 months, 95% CI 11.8, 14.4). Risk factors which predicted poor prognosis included triple-negative disease, high comorbidity score, poorly differentiated tumors, invasive lobular histology, multi-organ involvement of metastases, and government or lack of insurance. Factors which improve survival include younger age and Hispanic race. DISCUSSION/CONCLUSION: Using a large NCDB, we identified various factors associated with prognosis for patients with brain metastases at the time of breast cancer diagnosis. Insurance status and related socioeconomic challenges provide potential areas for improvement in care for these patients. This information may help stratify patients into prognostic categories at the time of diagnosis to improve treatment plans.

Secondary Invasive Breast Events among Patients with Hormone-Positive Breast Cancer and High-Risk Oncotype DX Recurrence Scores 26-30 and ≥31.

BACKGROUND: The Oncotype DX Recurrence Score (ODx RS) is the most widely adopted genomic assay used to guide treatment for patients with early-stage, hormone-positive (HR+) breast cancer (BC), with higher scores predicting greater risk of recurrence and benefit from chemotherapy. Patients with ODx RS >25 typically recieve adjuvant chemotherapy; however, data regarding efficacy of chemotherapy for reducing recurrence in this population have been mixed. OBJECTIVES: This study aimed to evaluate outcomes of patients with early-stage HR+ BC with high-risk ODx RS (26-30 and ≥31) in order to assess treatment patterns and outcomes. We hypothesized that the benefit of chemotherapy in these groups may be minimal and that select patients may forgo chemotherapy in favor of more aggressive endocrine therapy and ovarian suppression. METHODS: We performed a retrospective analysis of 515 patients with early-stage, HR+ BC with high-risk ODx RS 26-30 and ≥31 treated between 2006 and 2018. Patients were stratified by RS: low-risk (≤10), intermediate-risk (11-25), and high-risk (≥26). The Kaplan-Meier method was used to estimate the time to secondary invasive breast events (SIBE) or distributions overall and among different RS groups with the log rank test used to compare distributions between groups. RESULTS: Rates of chemotherapy administration were 7% among the low-risk group, 18% among the intermediate-risk group, and 83% among high-risk patients with 41 SIBE (8%) reported. When stratified by ODx RS, 5-year rates of SIBE were 4%, 6%, and 16% for low-risk, intermediate-risk, and high-risk RS, respectively. Among the 27 lymph node (LN)-negative patients with ODx RS 26-30, 74% received chemotherapy. The 5-year rate of SIBE was 25% among patients who received chemotherapy and 33% among those who did not (p = 0.5489). Among the 23 LN-negative patients with ODx RS ≥31, 91% of patients received chemotherapy. The 5-year rate of SIBE was 0% both with and without chemotherapy. CONCLUSIONS: There was no statistically significant difference in SIBE for patients with high-risk ODx RS based on chemotherapy treatment. More aggressive endocrine therapy with ovarian suppression has become an alternative to chemotherapy among patients with intermediate-risk ODx RS (16-25). This approach may be useful among patients with high-risk ODx RS, with additional studies needed in this patient population.

Use of neoadjuvant versus adjuvant chemotherapy for hormone receptor-positive breast cancer: a National Cancer Database (NCDB) study.

INTRODUCTION: Neoadjuvant chemotherapy (NAC) is a well-established therapeutic option for patients with locally advanced disease often allowing downstaging and facilitation of breast conserving therapy. With evolution of better targeted treatment regimens and awareness of improved outcomes for significant responders, use of NAC has expanded particularly for triple negative and HER2-positive (HER2+) breast cancer. In this study, we explore utility of neoadjuvant chemotherapy for hormone receptor-positive HER2-negative (HR+ HER2-) patients. METHODS: Patients with HR+ HER2- breast cancer treated with chemotherapy before or after surgery were identified from 2010 to 2015 in the NCDB. Multivariable regression models adjusted for covariates were used to determine associations within these groups. RESULTS: Among 134,574 patients (clinical stage 2A, 64%; 2B, 21%; 3, 15%), 105,324 (78%) had adjuvant chemotherapy (AC) and 29,250 (22%) received NAC. Use of NAC increased over time (2010-2015; 13.2-19.4% and PR = 1.34 for 2015; p < 0.0001). Patients were more likely to receive NAC with cT3, cT4, and cN+ disease. Patients less likely to receive NAC were age ≥ 50, lobular carcinoma, increased Charlson-Deyo score, and government insurance. Complete response (pCR) was noted in 8.3% of NAC patients. Axillary downstaging occurred in 21% of patients, and predictors included age < 50 years, black race, poorly differentiated grade, invasive ductal histology, and either ER or PR negativity. CONCLUSIONS: NAC use among HR+ HER2- breast cancer patients has expanded over time and offers downstaging of disease for some patients, with pCR seen in only a small subset, but downstaging of the axilla in 21%. Further analysis is warranted to determine the subgroup of patients with HR+ HER2- disease who benefit from this approach.

Diabetes and Metformin Association with Recurrence Score in a Large Oncotype Database of Breast Cancer Patients.

BACKGROUND: The Oncotype DX® (ODX) is a genomic assay that provides clinicians with a prediction of benefit of chemotherapy in node-negative, tamoxifen-treated breast cancer. However, the relationship between ODX recurrence score (RS) and diabetes, a common comorbidity in breast cancer patients, has been inadequately described in the literature. Specifically, the association of diabetes treatment with metformin and RS is inconclusive, with different studies reporting conflicting results. Because diabetes has been associated with higher RS, it has been suggested that management of diabetes with metformin in breast cancer patients may be associated with a lower RS. OBJECTIVES: We studied a large cohort of early-stage, hormone-positive breast cancer patients to determine if there is an association between RS and metformin treatment. METHODS: In this study, we retrospectively examined the medical records of 514 early-stage, hormone-positive breast cancer patients who had oncotype testing performed between 2007 and 2017. Number (%) or median were used to describe the patients' characteristics between groups and were compared by the Kruskal-Wallis test at a significance level of 5%. RESULTS: Of this cohort, 67 (13%) had a diabetes diagnosis at the time of breast cancer diagnosis, including both diabetes mellitus and pre-diabetes. The median RS for non-diabetic patients was 16 and the median RS for diabetic patients was 15. This difference was not significant, nor was there a statistical difference in RS between diabetic patients taking metformin (median RS = 15) and diabetic patients not taking metformin (median RS = 15). These results held true even when controlling for BMI. CONCLUSIONS: We conclude that neither diabetes diagnosis nor metformin use is associated with a difference in oncotype RS in this population of diabetic patients.

BRCA Mutation Association with Recurrence Score and Discordance in a Large Oncotype Database.

BACKGROUND: The Oncotype DX Breast Cancer Assay is a 21-gene assay used to predict the likelihood of distant recurrence and the benefit of chemotherapy in patients with node-negative, tamoxifen-treated breast cancer. Prior studies demonstrated 7-19% discordance, or a difference between the recurrence score (RS) and tumor grade (TG) in breast cancer patients. BRCA mutated tumors (BRCA+) have been shown to be associated with higher RS as compared to BRCA-negative patients (BRCA-). OBJECTIVES: We developed a large Oncotype RS database to determine if the BRCA mutation status is associated with discordance. METHODS: We identified 723 patients (32 [4%] mutation-positive and 691 [96%] mutation-negative patients) with early-stage, hormone-positive breast cancer treated between 2006 and 2018, with tumor characteristics available for analysis. Discordance was defined as one- or two-step difference between RS (low, intermediate, high risk) and TG (well [WD], moderately [MD], and poorly [PD] differentiated). Mutation positive was defined as BRCA1 deleterious mutation, BRCA2 deleterious mutation, BRCA mutation of unknown type, BRCA variant of undetermined significance (VUS) or other mutation (classified as other VUS). Number (%) or median were used to describe patient characteristics between groups and were compared by the Kruskal-Wallis test at a significance level of 5%. RESULTS: Among these patients, there were 32 (4% of total) who were identified as mutation-positive. Of those patients, 16% had a documented deleterious mutation in BRCA1, 22% in BRCA2, 6% had a BRCA mutation of unknown type (either 1 or 2), 25% were BRCA VUS, and 31% other VUS (most commonly CHEK2 and ATM). The median RS was 23.5 in patients with deleterious BRCA mutations (1, 2 or unknown) versus 16 in patients in the BRCA-negative database, which was statistically significant (p < 0.01). One- and two-step discordance was present in 46 and 8%, respectively, of patients with deleterious BRCA mutations versus 53 and 11%, respectively, in the BRCA-negative database. CONCLUSIONS: Patients with deleterious BRCA mutations demonstrated no difference in rates of discordance as compared to BRCA-negative patients. We further demonstrated that patients with BRCA-positive tumors display higher RS than patients with BRCA-negative tumors.

The application of metagenomic next-generation sequencing in diagnosing Chlamydia psittaci pneumonia: a report of five cases.

BACKGROUND: Chlamydia psittaci pneumonia is a zoonotic infectious disease caused by Chlamydia psittaci. Diagnostic tools, including culture, serologic test and PCR-based methods, are available but prone to false negative results. CASE PRESENTATION: This report included five cases of Chlamydia psittaci pneumonia. Symptoms and signs common to all 5 cases included fever, coughing, generalized muscle ache, and most notably, inflammatory infiltration of the lungs upon chest CT and X-ray. Metagenomic next-generation sequencing (mNGS) revealed the presence of Chlamydia psittaci in biopsy lung tissue in 3 cases and bronchoalveolar lavage fluid in the remaining 2 cases. Three patients responded to doxycycline plus moxifloxacin; two patients responded to moxifloxacin alone. CONCLUSIONS: mNGS could be used to diagnose Chlamydia psittaci pneumonia.

Practice Changing Potential of TAILORx: A Retrospective Review of the National Cancer Data Base from 2010 to 2015.

BACKGROUND: Uncertainty regarding chemotherapy benefit among breast cancer patients with intermediate Oncotype Dx® recurrence scores (RS; 11-25) led to the TAILORx study. We evaluated chemotherapy use in patients with intermediate RS to determine practice change potential based on the TAILORx results. METHODS: National Cancer Data Base patients with hormone receptor-positive/human epidermal growth factor receptor 2 (HER2)-negative, N0 breast cancer were identified and were divided into three groups: Group A, ≤ 50 years of age (RS 11-15); Group B, ≤ 50 years of age (RS 16-25); and Group C, > 50 years of age (RS 11-25). Demographic and clinical factors were compared using Chi square tests and Poisson regression models to determine predictors of chemotherapy receipt. RESULTS: Overall, 37,087 patients met the inclusion criteria, with 6.3% in Group A and 11.7% in Group C having received chemotherapy that may have been avoided based on TAILORx. The majority of Group B (64.7%) did not receive chemotherapy, whereas TAILORx showed potential benefit from treatment. Chemotherapy use decreased over time for all intermediate RS patients. T2 tumors, high grade, and treatment before 2012 increased the likelihood of chemotherapy receipt among both groups. Younger patients with the lower intermediate RS (Group A) were more likely to receive chemotherapy if they had treatment at community or comprehensive centers, whereas moderate grade was also a significant factor to receive chemotherapy in Group B. Significant factors in older patients (Group C) were Black race, estrogen receptor-positive/progesterone receptor-negative, and moderate/high grade. CONCLUSIONS: The most potential impact of TAILORx findings on practice change is for patients ≤ 50 years of age with RS of 16-25 who did not receive chemotherapy but may benefit. These findings may serve as a baseline for future analysis of practice patterns related to TAILORx.