Age-dependent ventilator-induced lung injury: Mathematical modeling, experimental data, and statistical analysis.

A variety of pulmonary insults can prompt the need for life-saving mechanical ventilation; however, misuse, prolonged use, or an excessive inflammatory response, can result in ventilator-induced lung injury. Past research has observed an increased instance of respiratory distress in older patients and differences in the inflammatory response. To address this, we performed high pressure ventilation on young (2-3 months) and old (20-25 months) mice for 2 hours and collected data for macrophage phenotypes and lung tissue integrity. Large differences in macrophage activation at baseline and airspace enlargement after ventilation were observed in the old mice. The experimental data was used to determine plausible trajectories for a mathematical model of the inflammatory response to lung injury which includes variables for the innate inflammatory cells and mediators, epithelial cells in varying states, and repair mediators. Classification methods were used to identify influential parameters separating the parameter sets associated with the young or old data and separating the response to ventilation, which was measured by changes in the epithelial state variables. Classification methods ranked parameters involved in repair and damage to the epithelial cells and those associated with classically activated macrophages to be influential. Sensitivity results were used to determine candidate in-silico interventions and these interventions were most impact for transients associated with the old data, specifically those with poorer lung health prior to ventilation. Model results identified dynamics involved in M1 macrophages as a focus for further research, potentially driving the age-dependent differences in all macrophage phenotypes. The model also supported the pro-inflammatory response as a potential indicator of age-dependent differences in response to ventilation. This mathematical model can serve as a baseline model for incorporating other pulmonary injuries.

The Association of QRS Duration with Risk of Adverse Outcomes in Sex- and Race- Based Subgroups: The Dallas Heart Study.

Introduction: We explored sex and race differences in the prognostic implications of QRS prolongation among healthy adults. Methods: Participants from the Dallas Heart Study (DHS) free of cardiovascular (CV) disease who underwent ECG testing and cMRI evaluation were included. Multivariable linear regression was used to examine the cross-sectional association of QRS duration with left ventricular (LV) mass, LV ejection fraction (LVEF), and LV end diastolic volume (LVEDV). Association of QRS duration with risk of MACE was evaluated using Cox models. Interaction testing was performed between QRS duration and sex/race respectively for each outcome of interest. QRS duration was log transformed. Results: The study included 2,785 participants. Longer QRS duration was associated with higher LV mass, lower LVEF, and higher LVEDV, independent of CV risk factors ([ß: 0.21, P<0.001], [ß: - 0.13, P<0.001], [ß: 0.22, P<0.001] respectively). Men with longer QRS duration were more likely to have higher LV mass and higher LVEDV compared to women (P-int=0.012, P-int=0.01, respectively). Black participants with longer QRS duration were more likely to have higher LV mass as compared to White participants (P-int<0.001). In Cox analysis, QRS prolongation was associated with higher risk of MACE in women (HR = 6.66 [95% CI: 2.32, 19.1]) but not men. This association was attenuated after adjustment for CV risk factors, with a trend toward significance (HR = 2.45 [95% CI: 0.94, 6.39]). Longer QRS duration was not associated with risk of MACE in Black or White participants in the adjusted models. No interaction between sex/race and QRS duration for risk of MACE was observed. Discussion: In healthy adults, QRS duration is differentially associated with abnormalities in LV structure and function. These findings inform the use of QRS duration in identifying subgroups at risk for CV disease, and caution against using QRS duration cut offs uniformly for clinical decision making. What is known?: QRS prolongation in healthy adults is associated with higher risk of death, cardiovascular disease, and left ventricular hypertrophy. What the study adds?: QRS prolongation may reflect a higher degree of underlying LV hypertrophy in Blacks compared to Whites. Longer QRS interval may reflect higher risk of adverse cardiac events, driven by prevalent cardiovascular risk factors. Graphic Abstract: Risk of underlying left ventricular hypertrophy in demographic groups based on QRS prolongation.

Subterranean Survivorship and Seasonal Emergence of Laricobius spp. (Coleoptera: Derodontidae), Biological Control Agents for the Hemlock Woolly Adelgid.

Following the adventive arrival, subsequent spread, and ensuing impact of Adelges tsugae Annand (Hemiptera: Adelgidae), the hemlock woolly adelgid (HWA) in the eastern United States, a robust initiative was launched with the goal of decreasing ecosystem impacts from the loss of eastern hemlock (Pinales: Pinaceae). This initiative includes the use of biological control agents, including Laricobius spp. (Insecta: Coleoptera). Laboratory production of these agents is limited by subterranean mortality and early emergence. Therefore, the subterranean survivorship and timing of emergence of a mixture of Laricobius spp. was investigated. PVC traps internally lined with a sticky card and covered with a mesh screen were inserted into the soil to measure the percent emergence of adults based on the number of larvae placed within. The number of emerged adults in the field and laboratory-reared larval treatments was adjusted based on emergence numbers in the control and used as the response variable. Independent variables included in the final model were: treatment (field-collected vs. laboratory-reared), organic layer depth (cm), soil pH, and April-to-December mean soil moisture. No differences were found in survivorship between field-collected and laboratory-reared treatments. As pH and organic layer increased survivorship decreased, significantly. Although the majority of emergence occurred in the fall, emergence also occurred in spring and summer. The occurrence of spring and summer emergence and low survivorship (17.1 ± 0.4%) in the field across all treatments suggests that these are characteristics of Laricobius spp. field biology in their introduced range and not artifacts of the laboratory rearing process.

Subsewershed SARS-CoV-2 Wastewater Surveillance and COVID-19 Epidemiology Using Building-Specific Occupancy and Case Data.

To evaluate the use of wastewater-based surveillance and epidemiology to monitor and predict SARS-CoV-2 virus trends, over the 2020-2021 academic year we collected wastewater samples twice weekly from 17 manholes across Virginia Tech's main campus. We used data from external door swipe card readers and student isolation/quarantine status to estimate building-specific occupancy and COVID-19 case counts at a daily resolution. After analyzing 673 wastewater samples using reverse transcription quantitative polymerase chain reaction (RT-qPCR), we reanalyzed 329 samples from isolation and nonisolation dormitories and the campus sewage outflow using reverse transcription digital droplet polymerase chain reaction (RT-ddPCR). Population-adjusted viral copy means from isolation dormitory wastewater were 48% and 66% higher than unadjusted viral copy means for N and E genes (1846/100 mL to 2733/100 mL/100 people and 2312/100 mL to 3828/100 mL/100 people, respectively; n = 46). Prespecified analyses with random-effects Poisson regression and dormitory/cluster-robust standard errors showed that the detection of N and E genes were associated with increases of 85% and 99% in the likelihood of COVID-19 cases 8 days later (incident-rate ratio (IRR) = 1.845, p = 0.013 and IRR = 1.994, p = 0.007, respectively; n = 215), and one-log increases in swipe card normalized viral copies (copies/100 mL/100 people) for N and E were associated with increases of 21% and 27% in the likelihood of observing COVID-19 cases 8 days following sample collection (IRR = 1.206, p < 0.001, n = 211 for N; IRR = 1.265, p < 0.001, n = 211 for E). One-log increases in swipe normalized copies were also associated with 40% and 43% increases in the likelihood of observing COVID-19 cases 5 days after sample collection (IRR = 1.403, p = 0.002, n = 212 for N; IRR = 1.426, p < 0.001, n = 212 for E). Our findings highlight the use of building-specific occupancy data and add to the evidence for the potential of wastewater-based epidemiology to predict COVID-19 trends at subsewershed scales.

Advanced heart failure patients supported with ambulatory inotropic therapy: What defines success of therapy?

OBJECTIVE: The objective of this study was to describe the profiles and outcomes of a cohort of advanced heart failure patients on ambulatory inotropic therapy (AIT). BACKGROUND: With the growing burden of patients with end-stage heart failure, AIT is an increasingly common short or long-term option, for use as bridge to heart transplant (BTT), bridge to ventricular assist device (BTVAD), bridge to decision regarding advanced therapies (BTD) or as palliative care. AIT may be preferred by some patients and physicians to facilitate hospital discharge. However, counseling patients on risks and benefits is critically important in the modern era of defibrillators, durable mechanical support and palliative care. METHODS: We retrospectively studied a cohort of 241 patients on AIT. End points included transplant, VAD implantation, weaning of inotropes, or death. The primary outcomes were survival on AIT and ability to reach intended goal if planned as BTT or BTVAD. We also evaluated recurrent heart failure hospitalizations, incidence of ventricular arrhythmias (VT/VF) and indwelling line infections. Unintended consequences of AIT, such reaching unintended end point (e.g. VAD implantation in BTT patient) or worse than expected outcome after LVAD or HT, were recorded. RESULTS: Mean age of the cohort was 60.7 ± 13.2 years, 71% male, with Class III-IV heart failure (56% non-ischemic). Average ejection fraction was 19.4 ± 10.2%, pre-AIT cardiac index was 1.5 ± 0.4 L/min/m2 and 24% had prior ventricular arrhythmias. Overall on-AIT 1-year survival was 83%. Hospitalizations occurred in 51.9% (125) of patients a total of 174 times for worsening heart failure, line complication or ventricular arrhythmia. In the BTT cohort, only 42% were transplanted by the end of follow-up, with a 14.8% risk of death or delisting for clinical deterioration. For the patients who were transplanted, 1-year post HT survival was 96.7%. In the BTVAD cohort, 1-year survival after LVAD was 90%, but with 61.7% of patients undergoing LVAD as INTERMACS 1-2. In the palliative care cohort, only 24.5% of patients had a formal palliative care consult prior to AIT. CONCLUSIONS: AIT is a strategy to discharge advanced heart failure patients from the hospital. It may be useful as bridge to transplant or ventricular assist device, but may be limited by complications such as hospitalizations, infections, and ventricular arrhythmias. Of particular note, it appears more challenging to bridge to transplant on AIT in the new allocation system. It is important to clarify the goals of AIT therapy upfront and continue to counsel patients on risks and benefits of the therapy itself and potential unintended consequences. Formalized, multi-disciplinary care planning is essential to clearly define individualized patient, as well as programmatic goals of AIT.

Cardiac Resynchronization Therapy Response Assessment with Electromechanical Activation Mapping within 24 Hours of Device Implantation: A Pilot Study.

BACKGROUND: Cardiac resynchronization therapy (CRT) response assessment relies on the QRS complex narrowing criterion. Yet one third of patients do not improve despite narrowed QRS after implantation. Electromechanical wave imaging (EWI) is a quantitative echocardiography-based technique capable of noninvasively mapping cardiac electromechanical activation in three dimensions. The aim of this exploratory study was to investigate the EWI technique, sensitive to ventricular dyssynchrony, for informing CRT response on the day of implantation. METHODS: Forty-four patients with heart failure with left bundle branch block or right ventricular (RV) paced rhythm and decreased left ventricular ejection fraction (LVEF; mean, 25.3 ± 9.6%) underwent EWI without and with CRT within 24 hours of device implantation. Of those, 16 were also scanned while in left ventricular (LV) pacing. Improvement in LVEF at 3-, 6-, or 9-month follow-up defined (1) super-responders (ΔLVEF ≥ 20%), (2) responders (10% ≤ ΔLVEF < 20%), and (3) nonresponders (ΔLVEF ≤ 5%). Three-dimensionally rendered electromechanical maps were obtained under RV, LV, and biventricular CRT pacing conditions. Mean RV free wall and LV lateral wall activation times were computed. The percentage of resynchronized myocardium was measured by quantifying the percentage of the left ventricle activated within 120 msec of QRS onset. Correlations between percentage of resynchronized myocardium and type of CRT response were assessed. RESULTS: LV lateral wall activation time was significantly different (P ≤ .05) among all three pacing conditions in the 16 patients: LV lateral wall activation time with CRT in biventricular pacing (73.1 ± 17.6 msec) was lower compared with LV pacing (89.5 ± 21.5 msec) and RV pacing (120.3 ± 17.8 msec). Retrospective analysis showed that the percentage of resynchronized myocardium with CRT was a reliable response predictor within 24 hours of implantation for significantly (P ≤ .05) identifying super-responders (n = 7; 97.7 ± 1.9%) from nonresponders (n = 17; 89.9 ± 9.9%). CONCLUSION: Electromechanical activation mapping constitutes a valuable three-dimensional visualization tool within 24 hours of implantation and could potentially aid in the timely assessment of CRT response rates, including during implantation for adjustment of lead placement and pacing outcomes.

Monitoring Canine Myocardial Infarction Formation and Recovery via Transthoracic Cardiac Strain Imaging.

Myocardial elastography (ME) is an ultrasound-based strain imaging method that aims to determine the degree of ischemia or infarction as a result of the change in the elastic properties of the myocardium. A survival canine model (n = 11) was employed to investigate the ability of ME to image myocardial infarction formation and recovery. Infarcts were generated by ligation of the left anterior descending coronary artery. Canines were survived and imaged for 4 days (n = 7) or 4 weeks (n = 4), allowing sufficient time for recovery via collateral perfusion. A radial strain-based metric, percentage of healthy myocardium by strain (PHMε), was developed as a marker for healthy myocardial tissue. PHMε was strongly linearly correlated with actual infarct size as determined by gross pathology (R2 = 0.80). Mean PHMε was reduced 1-3 days post-infarction (p < 0.05) at the papillary and apical short-axis levels; full infarct recovery was achieved by day 28, with mean PHMε returning to baseline levels. ME was capable of diagnosing individual myocardial segments as non-infarcted or infarcted with high sensitivity (82%), specificity (92%) and precision (85%) (area under the receiver operating characteristic curve = 0.90). The study therefore strengthens the ME premise that it can detect and assess myocardial infarction progression and recovery in vivo and could thus provide an important role in both disease diagnosis and treatment assesssment.

Catheter Ablation Lesion Visualization With Intracardiac Strain Imaging in Canines and Humans.

Catheter ablation is a common treatment for arrhythmia, but can fail if lesion lines are noncontiguous. Identification of gaps and nontransmural lesions can reduce the likelihood of treatment failure and recurrent arrhythmia. Intracardiac myocardial elastography (IME) is a strain imaging technique that provides visualization of the lesion line. Estimation of lesion size and gap resolution were evaluated in an open-chest canine model ( n = 3 ), and clinical feasibility was investigated in patients undergoing ablation to treat typical cavotricuspid isthmus (CTI) atrial flutter ( n = 5 ). A lesion line consisting of three lesions and two gaps was generated on the canine left ventricle via epicardial ablation. One lesion was generated in one canine right ventricle. Average lesion and gap areas were measured with high agreement (33 ± 14 and 30 ± 15 mm2, respectively) when compared against gross pathology (34 ± 19 and 26 ± 11 mm2, respectively). Gaps as small as 11 mm2 (3.6 mm on epicardial surface) were identifiable. Absolute error and relative error in estimated lesion area were 9.3 ± 8.4 mm2 and 31% ± 34%; error in estimated gap area was 11 ± 9.0 mm2 and 40% ± 29%. Flutter patients were imaged throughout the procedure. Strain was shown to be capable of differentiating between baseline and after ablation completion as confirmed by conduction block. In all patients, strain decreased in the CTI after ablation (mean paired difference of -17% ± 11%, ). IME could potentially become a useful ablation monitoring tool in health facilities.

Noninvasive localization of cardiac arrhythmias using electromechanical wave imaging.

Cardiac arrhythmias are a major cause of morbidity and mortality worldwide. The 12-lead electrocardiogram (ECG) is the current noninvasive clinical tool used to diagnose and localize cardiac arrhythmias. However, it has limited accuracy and is subject to operator bias. Here, we present electromechanical wave imaging (EWI), a high-frame rate ultrasound technique that can noninvasively map with high accuracy the electromechanical activation of atrial and ventricular arrhythmias in adult patients. This study evaluates the accuracy of EWI for localization of various arrhythmias in all four chambers of the heart before catheter ablation. Fifty-five patients with an accessory pathway (AP) with Wolff-Parkinson-White (WPW) syndrome, premature ventricular complexes (PVCs), atrial tachycardia (AT), or atrial flutter (AFL) underwent transthoracic EWI and 12-lead ECG. Three-dimensional (3D) rendered EWI isochrones and 12-lead ECG predictions by six electrophysiologists were applied to a standardized segmented cardiac model and subsequently compared to the region of successful ablation on 3D electroanatomical maps generated by invasive catheter mapping. There was significant interobserver variability among 12-lead ECG reads by expert electrophysiologists. EWI correctly predicted 96% of arrhythmia locations as compared with 71% for 12-lead ECG analyses [unadjusted for arrhythmia type: odds ratio (OR), 11.8; 95% confidence interval (CI), 2.2 to 63.2; P = 0.004; adjusted for arrhythmia type: OR, 12.1; 95% CI, 2.3 to 63.2; P = 0.003]. This double-blinded clinical study demonstrates that EWI can localize atrial and ventricular arrhythmias including WPW, PVC, AT, and AFL. EWI when used with ECG may allow for improved treatment for patients with arrhythmias.

4D cardiac electromechanical activation imaging.

Cardiac abnormalities, a major cause of morbidity and mortality, affect millions of people worldwide. Despite the urgent clinical need for early diagnosis, there is currently no noninvasive technique that can infer to the electrical function of the whole heart in 3D and thereby localize abnormalities at the point of care. Here we present a new method for noninvasive 4D mapping of the cardiac electromechanical activity in a single heartbeat for heart disease characterization such as arrhythmia and infarction. Our novel technique captures the 3D activation wave of the heart in vivo using high volume-rate (500 volumes per second) ultrasound with a 32 × 32 matrix array. Electromechanical activation maps are first presented in a normal and infarcted cardiac model in silico and in canine heart during pacing and re-entrant ventricular tachycardia in vivo. Noninvasive 4D electromechanical activation mapping in a healthy volunteer and a heart failure patient are also determined. The technique described herein allows for direct, simultaneous and noninvasive visualization of electromechanical activation in 3D, which provides complementary information on myocardial viability and/or abnormality to clinical imaging.

Localization of Accessory Pathways in Pediatric Patients With Wolff-Parkinson-White Syndrome Using 3D-Rendered Electromechanical Wave Imaging.

OBJECTIVES: This study sought to demonstrate the feasibility of electromechanical wave imaging (EWI) for localization of accessory pathways (AP) prior to catheter ablation in a pediatric population. BACKGROUND: Prediction of AP locations in patients with Wolff-Parkinson-White syndrome is currently based on analysis of 12-lead electrocardiography (ECG). In the pediatric population, specific algorithms have been developed to aid in localization, but these can be unreliable. EWI is a noninvasive imaging modality relying on a high frame rate ultrasound sequence capable of visualizing cardiac electromechanical activation. METHODS: Pediatric patients with ventricular pre-excitation presenting for catheter ablation were imaged with EWI immediately prior to the start of the procedure. Two clinical pediatric electrophysiologists predicted the location of the AP based on ECG. Both EWI and ECG predictions were blinded to the results of catheter ablation. EWI and ECG localizations were subsequently compared with the site of successful ablation. RESULTS: Fifteen patients were imaged with EWI. One patient was excluded for poor echocardiographic windows and the inability to image the entire ventricular myocardium. EWI correctly predicted the location of the AP in all 14 patients. ECG analysis correctly predicted 11 of 14 (78.6%) of the AP locations. CONCLUSIONS: EWI was shown to be capable of consistently localizing accessory pathways. EWI predicted the site of successful ablation more frequently than analysis of 12-lead ECG. EWI isochrones also provide anatomical visualization of ventricular pre-excitation. These findings suggest that EWI can predict AP locations, and EWI may have the potential to better inform clinical electrophysiologists prior to catheter ablation procedures.

Catheter Ablation for Atrial Tachycardia in Adults With Congenital Heart Disease: Electrophysiological Predictors of Acute Procedural Success and Post-Procedure Atrial Tachycardia Recurrence.

OBJECTIVES: This study sought to determine the electrophysiological predictors of acute procedural success and of post-ablation recurrence of atrial tachyarrhythmias (ATs) in our adult congenital heart disease (ACHD) population undergoing catheter ablation for treatment of AT. BACKGROUND: Catheter ablation is frequently performed to treat persistent AT in ACHD. The predictors of post-ablation AT recurrence have not been well studied in the ACHD population. METHODS: The authors performed a retrospective study of all catheter ablations for treatment of AT performed in ACHD patients between December 1, 2005, and July 20, 2017, at Columbia University Medical Center. Pre-specified clinical and procedural data of interest and the time from ablation to recurrence were determined by chart and procedure report review. RESULTS: A total of 140 patients (mean age: 45 years) underwent catheter ablation for 182 AT. Of the AT, 179 (93%) were intra-atrial macro-re-entrant tachycardia, and 12 (7%) had a focal origin. The presence of a single mechanism was a predictor of acute procedural success that could be achieved in 89% of the patients. At a median of 49.9 months, 62 patients (44%) had recurrent AT. Time to recurrence was significantly shorter (12.5 months) for recurrent AT in 13 of the 20 patients with previous Fontan procedure. By multivariable analysis, acute procedural success was a positive predictor and prior surgical maze procedure was a negative predictor of AT-free survival. Of the 62 patients with recurrent AT, 42 (68%) had a second catheter ablation procedure, and in 22 of these, the AT mechanism was different than previously observed. CONCLUSIONS: Catheter ablation for AT in ACHD patients is an effective method of arrhythmia control. More than 1 AT mechanism per patient is common. Acute procedural success is a predictor of freedom from AT recurrence. The majority of patients achieve multiple arrhythmia-free years.

3D-rendered Electromechanical Wave Imaging for Localization of Accessory Pathways in Wolff-Parkinson-White Minors.

Arrhythmia localization prior to catheter ablation is critical for clinical decision making and treatment planning. The current standard lies in 12-lead electrocardiogram (ECG) interpretation, but this method is non-specific and anatomically limited. Accurate localization requires intracardiac catheter mapping prior to ablation. Electromechanical Wave Imaging (EWI) is a high frame-rate ultrasound modality capable of non-invasively mapping the electromechanical activation in all cardiac chambers in vivo. In this study, we evaluate 3D-rendered EWI as a technique for consistently localizing the accessory pathway (AP) in Wolff-Parkinson-White (WPW) pediatric patients. A 2000 Hz EWI diverging sequence was used to transthoracically image 13 patients with evidence of ECG pre-excitation, immediately prior to catheter ablation and after successful ablation whenever possible. 3D-rendered activation maps were generated by co-registering and interpolating the 4 resulting multi-2D isochrones. A blinded electrophysiologist predicted the AP location on 12-lead ECG prior to ablation. Double-blinded EWI isochrones and clinician assessments were compared to the successful ablation site as confirmed by intracardiac mapping using a segmented template of the heart with 19 ventricular regions. 3D-rendered EWI was shown capable of consistently localizing AP in all the WPW cases. Clinical ECG interpretation correctly predicted the origin with an accuracy of 53.8%, respectively 84.6% when considering predictions in immediately adjacent segments correct. Our method was also capable of assessing the difference in activation pattern from before to after successful ablation on the same patient. These findings indicate that EWI could inform current diagnosis and expedite treatment planning of WPW ablation procedures.

Single institution validation of a modified graded prognostic assessment of patients with breast cancer brain metastases.

AIM: The number of breast cancer brain metastases is a prognostic clinical variable in the modified graded prognostic assessment (GPA) Index for breast cancer. PATIENTS & METHODS: We retrospectively gathered data from 127 breast cancer patients who underwent radiation therapy for brain metastasis. Patients were stratified by both breast GPA and modified breast GPA scores, and survival was determined using the Kaplan-Meier curves and Cox proportional hazards model. RESULTS & CONCLUSION: The Kaplan-Meier curve for patients under the breast GPA classification were not significant, but were significant under the modified breast GPA classification. The inclusion of number of brain metastases into the modified breast GPA index improved prognosis, thus validating the use of the modified breast GPA in prognosticating patient outcome.

Design, Modeling and Synthesis of 1,2,3-Triazole-Linked Nucleoside-Amino Acid Conjugates as Potential Antibacterial Agents.

Copper-catalyzed azide-alkyne cycloadditions (CuAAC or click chemistry) are convenient methods to easily couple various pharmacophores or bioactive molecules. A new series of 1,2,3-triazole-linked nucleoside-amino acid conjugates have been designed and synthesized in 57-76% yields using CuAAC. The azido group was introduced on the 5'-position of uridine or the acyclic analogue using the tosyl-azide exchange method and alkylated serine or proparylglycine was the alkyne. Modeling studies of the conjugates in the active site of LpxC indicate they have promise as antibacterial agents.

Breast cancer subtype and stage are prognostic of time from breast cancer diagnosis to brain metastasis development.

Breast cancer brain metastasis (BCBM) is associated with high morbidity and mortality. Patients with breast cancer risk factors associated with rapid development of BCBM could potentially benefit from early brain metastasis screening. We retrospectively reviewed all BCBM patients treated with brain radiotherapy at our institution from 1997 to 2015. Interval time to BCBM was defined as date of pathologic breast cancer diagnosis to date of radiographic evidence of brain metastasis. Patients were stratified by breast cancer molecular subtype and stage at diagnosis. Kaplan Meier analysis was conducted on time to development of BCBM. Breast cancer risk factors were correlated with time to BCBM on Cox proportion hazard analysis. The study cohort comprised 121 BCBM patients, with median interval time to BCBM of 46 months. Times to BCBM for Her2+/2HR+, Her2+, Her2-/HR+, and triple-negative (TNBC) subtypes were 70, 44, 42, and 28 months respectively (p = 0.002). Time to BCBM for stages I, II, III, and IV were 70, 54, 29, and 24 months, respectively (p = 0.000). BCBM patients were further stratified by both molecular subtype (TNBC vs. non-TNBC) and stage (I, II vs. III, IV). Median times to BCBM for non-TNBC/stage I-II, TNBC/stage I-II, non-TNBC stage III-IV, and TNBC/stage III-IV were 68, 47, 29, and 6 months respectively (p = 0.000). Subtype and stage were associated with shorter time to BCBM on multivariate analysis. Subtype and initial stage are independently correlated with decreased time to development of BCBM. Patients with advanced high stage and triple negative breast cancer develop brain metastases significantly earlier.

Hypofractionated radiation therapy versus standard fractionated radiation therapy with concurrent temozolomide in elderly patients with newly diagnosed glioblastoma.

PURPOSE: Adjuvant hypofractionated radiation therapy (HRT) for elderly patients with newly diagnosed glioblastoma (GBM) is a reasonable option compared with standard fractionation radiation therapy (SFRT). Outcomes in patients receiving HRT in the presence of temozolomide (TMZ) compared with SFRT with TMZ are unclear. We examined HRT for GBM with TMZ in comparison to SFRT with TMZ. METHODS AND MATERIALS: We conducted a retrospective analysis of patients ≥60 years of age with newly diagnosed GBM who received SFRT or HRT from 1994 to 2014 in the postoperative setting. Inclusion criteria included SFRT (60 Gy/30 fractions or 59.4 Gy/33 fractions) versus HRT (40 Gy/15 fractions). RESULTS: In this cohort, 158 patients were treated with SFRT versus 26 with HRT. Median survival in patients receiving SFRT compared with HRT was 430 and 475 days (P = .550), respectively. Ninety-five percent of the SFRT patients received TMZ versus 100% of those treated with HRT. Patients receiving HRT were older (median, 72 vs 66 years). All HRT patients were treated with the intensity modulated radiation therapy (IMRT) technique versus SFRT, in which 57% had IMRT. Multivariate Cox regression showed decreased overall survival (OS) associated with patient age >70 (hazard ratio [HR], 1.84), lower Karnofsky performance status (HR, 5.25), biopsy versus surgical resection (HR, 4.18), radiation therapy planning technique 3- or 2-dimensional planning versus IMRT (HR, 1.91; HR, 3.40, respectively). Analysis restricted to patients receiving IMRT-based planning showed no difference in OS between HRT and SFRT. For patients receiving TMZ, there was no survival difference between those treated with HRT and those treated with SFRT. CONCLUSIONS: Elderly GBM patients receiving HRT and those receiving SFRT had similar OS. Subset analysis patients receiving concurrent TMZ showed no difference in OS between the HRT and SFRT groups.

A Modern Radiotherapy Series of Survival in Hispanic Patients with Glioblastoma.

BACKGROUND: Studies have shown racial differences in cancer outcomes. We investigate whether survival differences existed in Hispanic patients with glioblastoma (GBM) compared with other ethnicities from our modern radiotherapy series, because no study to date has focused on outcomes in this group after radiation therapy. METHODS: We retrospectively evaluated 428 patients diagnosed with GBM from 1996 to 2014 at our institution, divided into 4 groups based on self-report: white, black, Hispanic, and Asian/Indian. The primary outcome was overall survival. We analyzed differences in prognostic factors among the whole cohort compared with the Hispanic cohort alone. RESULTS: Baseline characteristics of the 4 racial groups were comparable. With a median follow-up of 387 days, no survival differences were seen by Kaplan-Meier analysis. Median overall survival for Hispanic patients was 355 days versus 450 days for the entire cohort. Factors significant for patient outcomes in the entire cohort differed slightly from those specific to Hispanic patients. Low Karnofsky Performance Status was significant on multivariate analysis in the whole population, but not in Hispanic patients. Extent of resection, recursive partitioning analysis class, and radiation therapy total dose were significant on multivariate analysis in both the whole population and Hispanic patients. CONCLUSIONS: We found that Hispanic patients with GBM had no difference in survival compared with other ethnicities in our cohort. Differences exist in factors associated with outcomes on single and multivariate analysis for Hispanic patients with GBM compared with the entire cohort. Additional studies focusing on Hispanic patients will aid in more personalized treatment approaches in this group.

Breast cancer subtype as a predictor for outcomes and control in the setting of brain metastases treated with stereotactic radiosurgery.

We investigated effects of breast cancer subtype on overall survival (OS), local and distant control, and time from initial diagnosis to brain metastases (BM). We also investigated advances in graded prognostic assessment (GPA) scores. A cohort of 72 patients treated for BM from breast cancer with Gamma Knife stereotactic radiosurgery at our institution from 2000 to 2014 had subtyping available and were used for this study. Median follow up for OS was 12 months and for control was 6 months. OS for luminal, HER2, and triple negative subtypes were 26, 20, and 22 months. OS when stratified by Sperduto et al. (J Clin Oncol 30(4):419-425, 2012) and Subbiah et al. (J Clin Oncol 33(20):2239-2245, 2015) GPAs were similar (p = 0.087 and p = 0.063). KPS and treatment modality were significant for OS (p = 0.002; p = 0.034). On univariate analysis, triple negative subtype and >3 BM were trending and significant for decreased OS (p = 0.084; p = 0.047). On multivariable analysis HER2, triple negative, and >3 BM were significant for OS (p = 0.022; p = 0.040; p = 0.009). Subtype was significant for response on a per lesion basis (p = 0.007). Subtype was trending towards significance when analyzing time from initial diagnosis to BM treatment (p = 0.064). Breast cancer subtype is an important prognostic factor when stratifying breast cancer patients with BM. The addition of number of BM to the GPA is a useful addition and should be further investigated. Subtype has an effect on lesion response, and also on rate of development BM after initial diagnosis.

Elevated CO2 increases constitutive phenolics and trichomes, but decreases inducibility of phenolics in Brassica rapa (Brassicaceae).

Increasing global atmospheric CO2 has been shown to affect important plant traits, including constitutive levels of defensive compounds. However, little is known about the effects of elevated CO2 on the inducibility of chemical defenses or on plant mechanical defenses. We grew Brassica rapa (oilseed rape) under ambient and elevated CO2 to determine the effects of elevated CO2 on constitutive levels and inducibility of carbon-based phenolic compounds, and on constitutive trichome densities. Trichome density increased by 57% under elevated CO2. Constitutive levels of simple, complex, and total phenolics also increased under elevated CO2, but inducibility of each decreased. Induction of simple phenolics occurred only under ambient CO2. Although induction of complex and total phenolics occurred under both ambient and elevated CO2, the damage-induced increases were 64% and 75% smaller, respectively, under elevated CO2. Constitutive phenolic levels were positively correlated with leaf C:N ratio, and inducibility was positively correlated with leaf N and negatively correlated with leaf C:N ratio, as would be expected if inducibility were constrained by nitrogen availability under elevated CO2. We conclude that B. rapa is likely to exhibit higher constitutive levels of both chemical and mechanical defenses in the future, but is also likely to be less able to respond to herbivore damage by inducing phenolic defenses. To our knowledge, this is only the second study to report a negative effect of elevated CO2 on the inducibility of any plant defense.