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Background: Women with HR+ breast cancer experience a persistent risk of distant recurrence (DR) even after completion of 5 years of adjuvant endocrine therapy, with more than 50% of DR occurring after 5 years (late DR). The prognostic genomic signatures currently being used in the clinic were not developed or optimized specifically for late DR. We have previously shown that the Breast Cancer Index (BCI) and BCIN+ prognostic models were significantly prognostic for risk of overall (0-10y) and late (5-10y) distant recurrence (DR) in N0 and N1 HR+ patients in the Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial. Here, the prognostic performance of the BCI and BCIN+ models with alternative cut-points optimized for late DR were evaluated in patients from the TEAM trial, who were free from DR for at least 5 years. Methods: BCI testing was performed blinded to clinical outcome. The pre-specified alternative cut-points 4.4 and 1.8 for BCI and BCIN+ models were determined previously from Trans-aTTom and IDEAL studies, respectively (ESMO 2021). Kaplan-Meier analysis and log-rank test were used to evaluate the prognostic significance of BCI/BCIN+ risk groups based on DR. Univariate and multivariate Cox models were used to estimate hazard ratios (HRs) and the associated 95% confidence intervals (CIs). Results: 1285 HR+ N0 (median age 69.2, 54.2% T1, 92.5% G2-3, 21.3% chemotherapy) and 1762 N1 (median age 68.5, 49.7% T1, 80.8% G2-3, 42.6% chemotherapy) patients who remained free from DR at 5 years post randomization were included in the current analysis. For N0 patients, BCI identified 439 (34%) and 846 (66%) patients as low and high-risk with late 10-year DR rates of 3.8% (95% CI: 1.5-6.0%) and 9.1% (95% CI: 6.8-11.4%), respectively (HR: 2.6, 95% CI: 1.4-5.0; p=0.0025). For N1 patients, BCIN+ identified 287 (16%) and 1475 (84%) patients as low and high-risk with late 10-year DR rates of 3.4% (95% CI: 1.2-5.5%) and 12.3% (95% CI: 10.4-14.2%), respectively (HR: 3.5, 95% CI: 1.8-6.9; p< 0.0001). Similar results were observed in the HER2- patients. Notably, BCI/BCIN+ remained a statistically significant prognostic factor in the multivariate analysis after controlling for age, tumor size, grade, treatment. (Table). Conclusions: Compared to the original BCI/BCIN+ models, the optimized BCI and BCIN+ models showed improved prognostic performance for identifying low-risk patients with a very low risk of late DR (< 4%), for both N0 and N1 patients. These results provide further validation of BCI clinical utility as an aid in the decision-making for extended endocrine therapies for HR+ breast cancer, particularly in patients with N1 disease that may be spared extended endocrine treatment. Table Citation Format: John MS Bartlett, Keying Xu, Jenna Wong, Gregory R. Pond, Yi Zhang, Melanie Spears, Ranelle Salunga, Elizabeth Mallon, Karen J. Taylor, Annette Hasenburg, Christos Markopoulos, Luc Dirix, Caroline Seynaeve, Cornelis J.H. van de Velde, Daniel Rea, Catherine A. Schnabel, Kai Treuner, Jane Bayani. Validation of the Breast Cancer Index (BCI) prognostic models optimized for late distant recurrence in postmenopausal women with early-stage HR+ breast cancer in the TEAM trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-11-10.

Purpose: To characterize differences in directives to limit treatments and discontinue invasive mechanical ventilation (IMV) in elderly (65 - 80 years) and very elderly (> 80 years) intensive care unit (ICU) patients. Measurements: We prospectively described new orders to limit treatments, IMV discontinuation strategies [direct extubation, direct tracheostomy, spontaneous breathing trial (SBT), NIV use], and associations between initial failed SBT and outcomes in 142 ICUs from 6 regions (Canada, India, United Kingdom, Europe, Australia/New Zealand, United States). Results: We evaluated 788 (586 elderly; 202 very elderly) patients. Very elderly (vs. elderly) patients had similar withdrawal orders but significantly more withholding orders, especially cardiopulmonary resuscitation and dialysis, after ICU admission [67 (33.2%) vs. 128 (21.9%); p=0.002]. Orders to withhold reintubation were written sooner in very elderly (vs. elderly) patients [4 (2-8) vs. 7 (4-13) days, p=0.02]. Very elderly and elderly patients had similar rates of direct extubation [39 (19.3%) vs. 113 (19.3%)], direct tracheostomy [10 (5.0%) vs. 40 (6.8%)], initial SBT [105 (52.0%) vs. 302 (51.5%)] and initial successful SBT [84 (80.0%) vs. 245 (81.1%)]. Very elderly patients experienced similar outcomes, but had higher hospital mortality. Direct tracheostomy and initial failed SBT were associated with worse outcomes. Regional differences existed in withholding orders at ICU admission and in withholding and withdrawal orders after ICU admission. Conclusions: Very elderly (vs. elderly) patients had more orders to withhold treatments after ICU admission and higher hospital mortality, but similar ICU outcomes and IMV discontinuation. Significant regional differences existed in withholding and withdrawal practices.

Background: Current clinical decision rules to exclude deep vein thrombosis (DVT) are underused partly because of their complexity. A simplified rule that can be easily applied would be more appealing to use in clinical practice. Methods: We used individual patient data from prospective diagnostic studies of patients suspected of DVT to develop a new clinical decision rule. The primary outcome was presence of DVT either at initial testing or during follow-up. DVT was considered safely excluded if the upper 95% confidence interval (CI) of DVT prevalence was

Multiparametric assays for risk stratification are widely used in the management of both node negative and node positive hormone receptor positive invasive breast cancer. Recent data from multiple sources suggests that different tests may provide different risk estimates at the individual patient level. The TEAM pathology study consists of 3284 postmenopausal ER+ve breast cancers treated with endocrine therapy Using genes comprising the following multi-parametric tests OncotypeDx®, Prosigna™ and MammaPrint® signatures were trained to recapitulate true assay results. Patients were then classified into risk groups and survival assessed. Whilst likelihood χ2 ratios suggested limited value for combining tests, Kaplan–Meier and LogRank tests within risk groups suggested combinations of tests provided statistically significant stratification of potential clinical value. Paradoxically whilst Prosigna-trained results stratified Oncotype-trained subgroups across low and intermediate risk categories, only intermediate risk Prosigna-trained cases were further stratified by Oncotype-trained results. Both Oncotype-trained and Prosigna-trained results further stratified MammaPrint-trained low risk cases, and MammaPrint-trained results also stratified Oncotype-trained low and intermediate risk groups but not Prosigna-trained results. Comparisons between existing multiparametric tests are challenging, and evidence on discordance between tests in risk stratification presents further dilemmas. Detailed analysis of the TEAM pathology study suggests a complex inter-relationship between test results in the same patient cohorts which requires careful evaluation regarding test utility. Further prognostic improvement appears both desirable and achievable.

Purpose The in vivo dosimetric monitoring in HDR brachytherapy is important for improving patient safety. However, there are very limited options available for clinical application. In this study, we present a new in vivo dose measurement system with a plastic scintillating detector (PSD) for GYN HDR brachytherapy. Methods An FDA approved PSD system, called OARtrac (AngioDynamics, Latham, NY), was used with various applicators for in vivo dose measurements for GYN patients. An institutional workflow was established for the clinical implementation of the dosimetric system. Action levels were proposed based on the measurement and system uncertainty for measurement deviations. From October 2018 to September 2019, a total of 75 measurements (48 fractions) were acquired from 14 patients who underwent HDR brachytherapy using either a multichannel cylinder, Venezia applicator, or Syed-Neblett template. The PSDs were placed in predetermined catheters/channels. A planning CT was acquired for treatment planning in Oncentra (Elekta, Version-4.5.2) TPS. The PSDs were contoured on the CT images, and the PSD D90% values were used as the expected doses for comparison with the measured doses. Results The mean difference from patient measurements was −0.22% ± 5.98%, with 26% being the largest deviation from the expected value (Syed case). Large deviations were observed when detectors were placed in the area where dose rates were less than 1 cGy/s. Conclusions The establishment of clinical workflow for the in vivo dosimetry for both the intracavitary and interstitial GYN HDR brachytherapy will potentially improve the safety of the patient treatment.

Novel human epidermal growth factor receptor 2 (HER2)-directed antibody-drug conjugates have demonstrated efficacy in HER2-low expressing breast cancers, which are currently defined as those with immunohistochemistry (IHC) scores of 1+ or 2+ with a negative in situ hybridization assay. However, current HER2 testing methods are designed to identify HER2-amplified tumors with high expression levels. The true definition of HER2-low expressing breast cancers remains controversial. Using quantitative molecular analysis of breast cancers based on RNA expression, the dynamic range of HER2 expression exceeds that detected by in situ IHC approaches. Erb-B2 receptor tyrosine kinase 2 (ERBB2) mRNA expression levels across IHC groups using patient samples derived from the Tamoxifen Exemestane Adjuvant Multicenter Trial were investigated. The standardized mean differences in ERBB2 mRNA scores in log base 2 are 0.47 (95% CI, 0.36–0.57), 0.58 (95% CI, 0.26–0.70), and 0.32 (95% CI, −0.12 to 0.75) when comparing IHC 0+ without staining versus IHC 0+ with some staining, IHC 0+ with some staining versus IHC 1+, and IHC 1+ versus IHC 2+/fluorescence in situ hybridization–negative, respectively. The results showed immunohistochemical methods have a comparatively limited dynamic range for measuring HER2 protein expression. The range of expression based on RNA abundance suggests a molecular method defining HER2-low cancers may better serve the treatment decision needs of this group. Indeed, the validity of RNA abundance to identify HER2-low cancers and predict treatment response needs to be further evaluated by prospective clinical trials.

The rapid and sensitive surface-enhanced Raman scattering (SERS) detection of molecular biomarkers from real samples is still a challenge because the intrinsically trace analytes may have a low molecular affinity for metal surfaces. Herein, we develop a smart signal conversion and amplification strategy based on silver-gold-silica core-satellite structure nanoparticles (Ag@Au@SiO

BACKGROUND: This work proposed a joint L1 and total variation (TV) regularized reconstruction method for X-ray fluorescence tomography (XFT), and investigated the performance of this method in quantitative imaging of gold nanoparticles (GNPs). METHODS: We developed a dual-modality XFT/CT imaging system which consisted of a benchtop X-ray source, a translation/rotation stage, a silicon drift detector for X-ray fluorescence (XRF) detection, and a flat panel detector for transmission X-ray detection. A pencil-beam collimator was 3D printed with steel and employed in sample excitation. The sensitivity of the XFT imaging system was determined by imaging water phantoms with multiple inserts containing GNP solutions of various concentrations (0.02–0.16 wt.%). A joint L1 and total variation (TV) regularized algorithm was developed for XFT reconstruction, where the L1 regularization was used to reduce image artifacts and the TV regularization was used to preserve the shape of targets. Nonlinear conjugate gradient (NCG) descent algorithm with backtracking line search was adopted to solve the reconstruction problem. We compared the L1 + TV regularization method with filtered back projection (FBP), maximum likelihood expectation maximization (ML-EM), L1 regularization, and TV regularization methods. Contrast-to-noise ratio (CNR), Dice similarity coefficient (DSC) and localization error (LE) metrics were used to compare the performance of different methods. The CT and XFT imaging doses were also measured using EBT2 radiochromic films. RESULTS: The 3D printed pencil-beam collimator shaped an excitation beam with a 2 mm full width at half maximum at the imaging isocenter. Based on the phantom imaging experiments, the joint L1 and TV regularization method performed better than FBP, ML-EM, L1 regularization and TV regularization methods, with higher localization accuracy (offset 0.99) between the reconstructed and true GNP concentration. The estimated XFT imaging dose is about 41.22 cGy under current setting. CONCLUSIONS: The joint L1 + TV regularized reconstruction algorithm performed better in noise suppression and shape preservation. Using the L1 + TV regularized reconstruction, the XFT system is able to localize GNP targets with submillimeter accuracy and quantify GNP distribution at a concentration of 0.02 wt.% or lower.

The formation of pre-metastatic niche is a key step in the metastatic burden. The pluripotent factor Lin28B is frequently expressed in breast tumors and is particularly upregulated in the triple negative breast cancer subtype. Here, we demonstrate that Lin28B promotes lung metastasis of breast cancer by building an immune-suppressive pre-metastatic niche. Lin28B enables neutrophil recruitment and N2 conversion. The N2 neutrophils are then essential for immune suppression in pre-metastatic lung by PD-L2 up-regulation and a dysregulated cytokine milieu. We also identify that breast cancer-released exosomes with low let-7s are a prerequisite for Lin28B-induced immune suppression. Moreover, Lin28B-induced breast cancer stem cells are the main sources of low-let-7s exosomes. Clinical data further verify that high Lin28B and low let-7s in tumors are both indicators for poor prognosis and lung metastasis in breast cancer patients. Together, these data reveal a mechanism by which Lin28B directs the formation of an immune-suppressive pre-metastatic niche.

Background Recently, it has been found that the gut microbiota may affect the development of lung cancer through the “gut‐lung axis.” To investigate this relationship, we performed this study to determine whether the gut microbiota in non‐small‐cell lung cancer (NSCLC) patients is different from that in healthy adults. Methods Quantitative PCR (qPCR) was used to detect the expression levels of eight gut butyrate‐producing bacteria in healthy adults and NSCLC patients. We enrolled 30 patients with NSCLC and 30 subjects from 100 healthy adults after matching for age and sex. Results Compared to healthy adults, most of the gut butyrate‐producing bacteria in NSCLC patients were significantly decreased; these included Faecalibacterium prausnitzii, Clostridium leptum, Clostridial cluster I, Ruminococcus spp., Clostridial Cluster XIVa, and Roseburia spp. Among the gut butyrate‐producing bacteria, we analyzed Clostridial cluster IV and Eubacterium rectale were not decreased in NSCLC patients. Conclusions We conclude that NSCLC patients had gut butyrate‐producing bacteria dysbiosis. Further studies should be performed to investigate the underlying mechanisms of how these specific bacteria affect lung cancer progression and prognosis.

Objective This cross‐sectional study aimed to investigate the characteristics and epidemiology of hyperuricemia in older adults in China and evaluate possible associations between hyperuricemia and sarcopenia. Methods Three hundred and eighty‐eight study subjects (>60 years old) meeting the inclusion criteria received blood tests and standardized examinations for bone mineral density, muscle mass, muscle strength, and physical performance. Data including demographic and clinical characteristic and comorbidity were also collected. All data were analyzed retrospectively. Results In the study population, higher uric acid levels were significantly correlated with higher muscle mass, grip strength, and bone density, but were unrelated to physical performance. When uric acid levels were separated into quartiles and the population was divided by sex, the correlation of uric acid to muscle mass was retained in some quartiles for both men and women, and the correlation to handgrip was only retained for one quartile for men. The correlation to bone density was retained in women in all analyses. Conclusion In the population as a whole, higher uric acid levels were significantly correlated with higher muscle mass, grip strength, and bone density, but had no relationship to physical performance. Differences between men and women in these relationships need to be studied further.

Purpose Small animal irradiation is crucial to the investigation of radiobiological mechanisms. The paradigm of clinical radiation therapy is trending toward high-precision, stereotactic treatment. However, translating this scheme to small animal irradiation is challenging owing to the lack of high-quality image guidance. To overcome this obstacle, we developed a multimodality image guided precision radiation platform. Methods and Materials The platform consists of 4 modules: x-ray computed tomography (CT), bioluminescence tomography (BLT), fluorescence molecular tomography (FMT), and radiation therapy. CT provides animal anatomy and material density for radiation dose calculation, as well as body contour for BLT and FMT reconstruction. BLT and FMT provide tumor localization to guide radiation beams and molecular activity to evaluate treatment outcome. Furthermore, we developed a Monte Carlo–based treatment planning system (TPS) for 3-dimensional dose calculation, calibrated it using radiochromic films sandwiched in a water-equivalent phantom, and validated it using in vivo dosimeters surgically implanted into euthanized mice (n = 4). Finally, we performed image guided irradiation on mice bearing orthotopic breast and prostate tumors and confirmed radiation delivery using γH2AX histology. Results The Monte Carlo–based TPS was successfully calibrated by benchmarking simulation dose against film measurement. For in vivo dosimetry measured in the euthanized mice, the average difference between the TPS calculated dose and measured dose was 3.86% ± 1.12%. Following the TPS-generated treatment plan, we successfully delivered 20 Gy dose to an animal bearing an orthotopic prostate tumor using 4 BLT-guided radiation beams and 5 Gy dose to an animal bearing an orthotopic breast tumor using a single FMT-guided radiation beam. γH2AX histology presented significantly more DNA damage in irradiated tumors and thus validated the dose delivery accuracy. Conclusions Combined with Monte Carlo TPS, this multimodality CT/BLT/FMT image guided small animal radiation platform can specifically localize tumors, accurately calculate dose distribution, precisely guide radiation delivery, and molecularly evaluate treatment response. It provides an advanced toolset for radiobiology and translational cancer research.

To investigate associations between dietary protein and vitamin intake and physical function status in older adults with sarcopenia. Data of 707 participants with sarcopenia aged > 60 years from the National Health and Nutrition Examination Survey (NHANES) 1999–2004 were analyzed. Body composition, body mass index (BMI), physical function status, demographics, dietary intake (protein and vitamins A, C, E), lifestyle factors and comorbidities were measured, stratified by gender. Dietary levels of carbohydrate, fat and vitamin E differed significantly between genders (P

The image guided small animal arc radiation treatment platform has adopted onboard cone beam computed tomography and bioluminescence tomography (BLT). We used BLT to guide irradiation delivery and quantitatively assess irradiation-induced tumor response.BLT was first validated on a tissue-simulating phantom, where the internal chemiluminescent liquid had a constant volume while its luminescence intensity gradually decayed. Then, in vivo experiments were performed on BALB/c mice orthotopically inoculated with 4T1 breast carcinoma cells expressing luciferase. Animals either received radiation treatment (radiation therapy [RT] group, n = 9) or did not (control group, n = 9). BLT was used to guide delivery of a single-fraction 5-Gy radiation dose to the tumor and to evaluate the treatment response. Terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL) staining was used to evaluate irradiation-induced DNA damage and cell apoptosis.Phantom results showed that BLT not only recovered the constant target volume with2% deviation but also accurately monitored the decay of the chemiluminescent molecules. For the RT group of animals, there was significant reduction in both the BLT-based tumor volume (21% ± 10%, P = .001) and bioluminescence intensity (48% ± 17%, P = .0008). For the control group, a significant increase was detected in the BLT tumor volume (35% ± 12%, P .0001) but not the BLT bioluminescence intensity (P = .4). There was a significant difference in the BLT tumor volume between the RT and control groups 7 days after irradiation (P = .03). Regression analysis suggests a strong correlation between the BLT and cone beam computed tomography tumor volume (RBLT onboard the image guided small animal arc radiation treatment platform can be used to accurately guide irradiation delivery and to quantitatively assess treatment response by simultaneously monitoring tumor volume and cancer cell population.

A number of clinical trials have demonstrated that the use of probiotics has the potential to prevent nosocomial infections. However, the mechanism underlying probiotic-induced anti-infection and sepsis remains to be investigated. In the present study, 200 µl/day of Lactobacillus rhamnosus GG (LGG) or normal saline (control) was orally administrated to 4-week-old C57BL6 mice 4 weeks prior to cecal ligation and puncture (CLP). A number of mice were sacrificed 24 h after CLP, and the remaining mice were used for survival studies. Ileum tissues were collected to evaluate the injury on the intestine. Blood samples were also obtained to investigate the changed metabolic pattern in mice that underwent different treatments using ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS). In the survival studies, the mortality of CLP-induced septic mice pretreated with LGG was significantly lower compared with untreated mice (P=0.029). Ileum mucosal damage was evident in the control septic mice. Based on the data of UPLC-QTOF-MS, phosphatidylcholines were increased and lysophosphatidylcholines (LPCs) that contained polyunsaturated fatty acids were decreased in septic mice, whereas saturated fatty acid LPCs reveal no significant difference between septic and sham mice. In addition, the metabolic profile in the septic mice pretreated with LGG was much closer to that of sham mice compared with control septic mice. The results of the present study suggest that probiotic pre-administration reduces the mortality in septic mice by decreasing ileum mucosal damage, increasing the gut barrier integrity and altering global serum metabolic profiles.

We present a visual notation to support the understanding and reasoning about program edits. The graph-based representation directly supports a number of editing operations beyond those offered by a typical, linear program-edit model and makes obvious otherwise hidden states the code can reach through selectively undoing or redoing changes.

Few randomized clinical trials have evaluated the efficacy of ginseng in patients with type 2 diabetes mellitus (T2DM). The current meta-analysis evaluated the ginseng-induced improvement in glucose control and insulin sensitivity in patients with type-2 diabetes or impaired glucose tolerance.Randomized clinical trials comparing ginseng supplementation versus control, in patients with T2DM or impaired glucose tolerance, were hand-searched from Medline, Cochrane, and Google Scholar databases by 2 independent reviewers using the terms "type 2 diabetes/diabetes/diabetic, impaired glucose tolerance, and ginseng/ginsenoside(s)." The primary outcome analyzed was the change in HbA1c, whereas the secondary outcomes included fasting glucose, postprandial glucose, fasting insulin, postprandial insulin, insulin resistance Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), triglycerides, total cholesterol, low density lipoprotein (LDL), and high density lipoprotein (HDL).Of the 141 studies identified, 8 studies were chosen for the current meta-analysis. The average number of patients, age, and sex distribution among the groups were comparable. Results reveal no significant difference in HbA1c levels between the ginseng supplementation and the control groups (pooled standardized difference in means = -0.148, 95% CI: -0.637 to 0.228, P = 0.355). Ginseng supplementation improved fasting glucose, postprandial insulin, and HOMA-IR levels, though no difference in postprandial glucose or fasting insulin was observed among the groups. Similarly, triglycerides, total cholesterol, and LDL levels showed significant difference between the treatment groups, while no difference in HDL was seen. In addition, ginseng-related therapy was ineffective in decreasing the fasting glucose levels in patients treated with oral hypoglycemic agents or insulin.The present results establish the benefit of ginseng supplementation in improving glucose control and insulin sensitivity in patients with T2DM or impaired glucose intolerance.