Neoadjuvant-adjuvant pertuzumab in HER2-positive early breast cancer: final analysis of the randomized phase III PEONY trial.

The randomized, multicenter, double-blind, placebo-controlled, phase III PEONY trial (NCT02586025) demonstrated significantly improved total pathologic complete response (primary endpoint) with dual HER2 blockade in HER2-positive early/locally advanced breast cancer, as previously reported. Here, we present the final, long-term efficacy (secondary endpoints: event-free survival, disease-free survival, overall survival) and safety analysis (62.9 months' median follow-up). Patients (female; n = 329; randomized 2:1) received neoadjuvant pertuzumab/placebo with trastuzumab and docetaxel, followed by adjuvant 5-fluorouracil, epirubicin, and cyclophosphamide, then pertuzumab/placebo with trastuzumab until disease recurrence or unacceptable toxicity, for up to 1 year. Five-year event-free survival estimates are 84.8% with pertuzumab and 73.7% with placebo (hazard ratio 0.53; 95% confidence interval 0.32-0.89); 5-year disease-free survival rates are 86.0% and 75.0%, respectively (hazard ratio 0.52; 95% confidence interval 0.30-0.88). Safety data are consistent with the known pertuzumab safety profile and generally comparable between arms, except for diarrhea. Limitations include the lack of ado-trastuzumab emtansine as an option for patients with residual disease and the descriptive nature of the secondary, long-term efficacy endpoints. PEONY confirms the positive benefit:risk ratio of neoadjuvant/adjuvant pertuzumab, trastuzumab, and docetaxel treatment in this patient population.

Association of artificial intelligence-powered and manual quantification of programmed death-ligand 1 (PD-L1) expression with outcomes in patients treated with nivolumab ± ipilimumab.

Assessment of programmed death ligand 1 (PD-L1) expression by immunohistochemistry (IHC) has emerged as an important predictive biomarker across multiple tumor types. However, manual quantitation of PD-L1 positivity can be difficult and leads to substantial inter-observer variability. Although the development of artificial intelligence (AI) algorithms may mitigate some of the challenges associated with manual assessment and improve the accuracy of PD-L1 expression scoring, use of AI-based approaches to oncology biomarker scoring and drug development has been sparse, primarily due to the lack of large-scale clinical validation studies across multiple cohorts and tumor types. We developed AI-powered algorithms to evaluate PD-L1 expression on tumor cells by IHC and compared it with manual IHC scoring in urothelial carcinoma, non-small cell lung cancer, melanoma, and squamous cell carcinoma of the head and neck (prospectively determined during the phase II and III CheckMate clinical trials). 1,746 slides were retrospectively analyzed, the largest investigation of digital pathology algorithms on clinical trial datasets performed to date. AI-powered quantification of PD-L1 expression on tumor cells identified more PD-L1-positive samples compared with manual scoring at cutoffs of ≥1% and ≥5% in most tumor types. Additionally, similar improvements in response and survival were observed in patients identified as PD-L1-positive compared with PD-L1-negative using both AI-powered and manual methods, while improved associations with survival were observed in patients with certain tumor types identified as PD-L1-positive using AI-powered scoring only. Our study demonstrates the potential for implementation of digital pathology-based methods in future clinical practice to identify more patients who would benefit from treatment with immuno-oncology therapy compared with current guidelines using manual assessment.

Snoring severity is associated with carotid vascular remodeling in young adults with overweight and obesity.

BACKGROUND: Snoring is often used as a surrogate measure for obstructive sleep apnea (OSA), a sleep disorder associated with cardiovascular disease (CVD) risk. Whether snoring is linked to CVD independent of OSA remains unclear. We aimed to explore the snoring and subclinical CVD association in adults with and without OSA. METHODS: We conducted a cross-sectional study in 122 overweight/obese participants (24% male; mean age 40.1 years) attending the 24-month follow-up visit of a lifestyle intervention. Using home-based objective measures of sleep-disordered breathing, we stratified participants into 3 snoring/OSA categories using the snoring index (SI), a measure of snoring vibration, and oxygen desaturation index (ODI): (1) OSA (ODI ≥ 5), (2) non-OSA heavy snorer (ODI <5, above-median SI), and (3) non-OSA low snorer (ODI <5, below-median SI). Vascular measures including pulse wave velocity ([PWV]; carotid-femoral [cf], femoral-ankle [fa], brachial-ankle [ba]), carotid intima-media thickness (IMT), and carotid interadventitial diameter (IAD) were compared across snoring/OSA categories. Linear regressions assessed the association between snoring and subclinical CVD independent of traditional CVD risk factors. RESULTS: Compared to non-OSA low snorers, common carotid IMT and IAD were higher in non-OSA heavy snorers, and faPWV, IMT, and IAD were higher among those with OSA. The difference between non-OSA heavy snorers and low snorers persisted after adjusting for age, race, sex, blood pressure, body mass index, lipids, and insulin resistance (P < .05 for IMT and IAD). CONCLUSIONS: In overweight/obese young to middle-aged adults, objectively measured snoring was related to vascular remodeling in those without OSA. Snoring may contribute to CVD risk but warrants further examination in larger prospective cohorts.

The Association of MUC16 Mutation with Tumor Mutation Burden and Its Prognostic Implications in Cutaneous Melanoma.

BACKGROUND: MUC16 is a mucin marker that is frequently mutated in melanoma, but whether MUC16 mutations could be useful as a surrogate biomarker for tumor mutation burden (TMB) remains unclear. METHODS: This study rigorously evaluates the MUC16 mutation as a clinical biomarker in cutaneous melanoma by utilizing genomic and clinical data from patient samples from The Cancer Genome Atlas (TCGA) and two independent validation cohorts. We further extended the analysis to studies with patients treated with immunotherapies. RESULTS: Analysis results showed that samples with MUC16 mutations had a higher TMB than the samples of wild-type, with strong statistical significance (P < 0.001) in all melanoma cohorts tested. Associations between MUC16 mutations and TMB remained statistically significant after adjusting for potential confounding factors in the TCGA cohort [OR, 9.28 (95% confidence interval (CI), 5.18-17.39); P < 0.001], Moffitt cohort [OR, 31.95 (95% CI, 8.71-163.90); P < 0.001], and Yale cohort [OR, 8.09 (95% CI, 3.12-23.79); P < 0.01]. MUC16 mutations were also found to be associated with overall survival in the TCGA [HR, 0.62; (95% CI, 0.45-0.85); P < 0.01] and Moffitt cohorts [HR, 0.49 (95% CI, 0.28-0.87); P = 0.014]. Strikingly, MUC16 is the only top frequently mutated gene for which prognostic significance was observed. MUC16 mutations were also found valuable in predicting anti-CTLA-4 and anti-PD-1 therapy responses. CONCLUSIONS: MUC16 mutation appears to be a useful predictive marker of global TMB and patient survival in melanoma. IMPACT: This is, to the best of our knowledge, the first systematic evaluation of MUC16 mutation as a clinical biomarker and a predictive biomarker for immunotherapy in melanoma.

Cardiovascular Disease Risk Factor Burden During the Menopause Transition and Late Midlife Subclinical Vascular Disease: Does Race/Ethnicity Matter?

Background The extent to which cardiovascular disease (CVD) risk factors across the menopause explain racial/ethnic differences in subclinical vascular disease in late midlife women is not well documented and was explored in a multi-ethnic cohort. Methods and Results Participants (n=1357; mean age 60 years) free of clinical CVD from the Study of Women's Health Across the Nation had common carotid artery intima-media thickness, interadventitial diameter, and carotid plaque presence assessed by ultrasonography on average 13.7 years after baseline visit. Early to late midlife time-averaged cumulative burden of traditional CVD risk factors calculated using serial measures from baseline to the ultrasound visit were generally less favorable in black and Hispanic women compared with white and Chinese women, including education and smoking status and time-averaged cumulative blood pressure, high-density lipoprotein cholesterol, and fasting insulin. Independent of these risk factors, BMI, and medications, common carotid artery intima-media thickness was thicker in black women, interadventitial diameter was wider in Chinese women, yet plaque presence was lower in black and Hispanic women compared with white women. CVD risk factor associations with subclinical vascular measures did not vary by race/ethnicity except for high-density lipoprotein cholesterol on common carotid artery intima-media thickness; an inverse association between high-density lipoprotein cholesterol and common carotid artery intima-media thickness was observed in Chinese and Hispanic but not in white or black women. Conclusions Race/ethnicity did not particularly moderate the association between traditional CVD risk factors measured across the menopause transition and late midlife subclinical vascular disease. Unmeasured socioeconomic, cultural, and nontraditional biological risk factors likely play a role in racial/ethnic differences in vascular health and merit further exploration.

Residential Exposure to PM2.5 and Ozone and Progression of Subclinical Atherosclerosis Among Women Transitioning Through Menopause: The Study of Women's Health Across the Nation.

Objective: This article aims to examine the association between long-term ambient air pollution and progression of subclinical atherosclerosis with 2-year follow-up among midlife women from the Study of Women's Health Across the Nation (SWAN). Materials and Methods: Carotid duplex ultrasonography was performed in participants from a SWAN ancillary study carried out at the Pittsburgh and Chicago sites. Mean and maximum carotid intima-media thickness (CIMT) and plaque burden were assessed throughout the common, bulb, and internal carotid artery. The yearly mean exposure to PM2.5 (particulate matter) and ozone was generated based on monitors within 20 km of the participants' home. The effect of air pollutants during follow-up on progression of CIMT was estimated using linear mixed-effects models, and the effect on progression of plaque presence and plaque index, a measure of extent of plaque, was evaluated using logistic regression. Results: This study included 417 (257 White and 160 Black) women with a mean age of 51 years at baseline. A 1 µg/m3 higher yearly mean exposure to PM2.5 during follow-up was associated with a 4.28 (95% confidence interval [CI]: 0.02-8.54) µm/year increase in maximum CIMT, after adjusting for socioeconomic and traditional cardiovascular disease (CVD) risk factors. Exposure to PM2.5 contributed to a 30% (95% CI: 3%-65%) higher odds of plaque index progression adjusting for socioeconomic factors only. Conclusions: PM2.5 independently contributed to progression of subclinical atherosclerosis, among women transitioning through menopause, a time of increasing CVD risk. Yet no significant associations between ozone and subclinical atherosclerosis were observed.

Five-year exposure to PM2.5 and ozone and subclinical atherosclerosis in late midlife women: The Study of Women's Health Across the Nation.

INTRODUCTION: Effects of more than one-year exposure to air pollution on atherosclerosis is seldom studied. This paper aims to examine the association between five-year exposure to particulate matter ≤2.5 µm (PM2.5), ozone (O3) and atherosclerosis observed about seven years later in late midlife women. MATERIAL AND METHODS: This study was conducted among 1188 women of the Study of Women's Health Across the Nation (SWAN) from five sites, Detroit, MI; Oakland, CA; Pittsburgh, PA; Chicago, IL; and Newark, NJ, with available data on both air pollutant exposure and carotid ultrasound scans. Five-year mean annualized exposure levels of two air pollutants, PM2.5 and ozone (O3), were collected during 5 SWAN visits (1999-2005) from monitors 20 km within the participant's residential address. Linear regression models were used to estimate the association of prior five-year mean annualized exposure to PM2.5 and O3 with common carotid intima-media thickness (cIMT) and inter-adventitial diameter (IAD) examined approximately seven years later (2009-2013). Logistic and multinomial logistic regressions were applied to assess the associations of air pollutants with plaque presence and plaque index, respectively. RESULTS: At time of carotid ultrasound scan, women were on average 59.6 (±2.7) years old and a majority was postmenopausal (88.4%). The women were White (48.4%), Black (31.2%), Chinese (13.3%) and Hispanic (7.1%). A 1 µg/m3 higher 5-year mean annualized exposure to PM2.5 was associated with an 8.0 µm (95% CI: 1.0-15.1) greater maximum cIMT at a later mid-life, adjusting for cardiovascular disease risk factors; but was only related to IAD after adjusting for site. No association was found between either pollutant and plaque presence or plaque index. CONCLUSIONS: Long-term exposure to PM2.5 may contribute to elevated risk of atherosclerosis in the post-menopausal period.

Using spatio-temporal modeling for exposure assessment in an investigation of fine particulate air pollution and cardiovascular mortality.

BACKGROUND: U.S. urban air quality has improved dramatically over the past decades. We evaluated acute effects of fine particulate matter (PM2.5) on cardiovascular (CVD) mortality among residents of Allegheny County in SW Pennsylvania (1999-2011) using spatio-temporal modeling of air pollutants (AP) to reduce misclassification error in exposure assessment. METHODS: Spatio-temporal kriging of daily PM2.5 and ozone (O3) was used to produce daily exposure estimates at the residence ZIP code. Time-stratified case-crossover analysis was conducted to examine short-term effects of PM2.5 on CVD mortality, adjusting for O3 and apparent mean temperature. We studied both single and distributed lags for days 0-5. All CVD mortality and subcategories of ischemic heart disease (IHD), acute myocardial infarction, cerebrovascular disease, peripheral vascular disease (PVD), heart failure and cardiac arrhythmia were examined. RESULTS: A total of 62,135 deaths were identified. We found significant associations of PM2.5 with IHD and PVD mortality at lag day 5: (2.1% (95% CI, 0.2-4.1%) and (7.6%, 95% CI, 0.05-15.7%) per 10µg/m3 increase of PM2.5 in single lag models and for IHD in distributed lag models. There were no statistically significant associations with PM2.5 for any of the other outcomes. CONCLUSIONS: The application of finer scale geographically resolved AP exposures made it possible to study acute effects of PM2.5 on CVD mortality in a large metropolitan area. Our study results demonstrated the continued presence of a dose response relationship of increased risk of CVD mortality within this lower range of PM2.5 exposure.

Revisiting Nonresidential Environmental Exposures and Childhood Lead Poisoning in the US: Findings from Kansas, 2000-2005.

Although blood lead levels (BLLs) in US children have dramatically declined over the past 40 years, there remain pockets of children living in areas with elevated BLLs. While some increases (≥ 10 µg/dL) may be associated with legacy lead paint, ambient air lead may be contributing to the problem. A deidentified dataset of information on over 60,000 Kansas children under 3 years of age who were tested for BLL was provided through the Kansas Environmental Public Health Tracking Network for the period 2000-2005. Using ArcGIS, we calculated distance (in miles) from a lead-emitting industry referred to as a toxic release inventory (TRI) site. The USEPA TRI database tracks the management of certain toxic chemicals that may pose a threat to human health. US facilities in different industry sectors must report annually amount of substances like lead into the environment including their exact location. Distance from a TRI site was inversely related to BLL after controlling for area-level poverty and pre-1950 housing. The results of our evaluation indicate there is a significant relationship between proximity to lead industry and childhood BLLs. Proximity to sources of lead emissions should be evaluated as a possible factor when identifying children for targeted BLL testing.

Chest modeling and personalized surgical planning for pectus excavatum.

Pectus excavatum is among the most common major congenital anomalies of the chest wall whose correction can be performed via minimally invasive Nuss technique that places a pectus bar to elevate the sternum anteriorly. However, the size and bending of the pectus bar are manually modeled intraoperatively by trial-and-error. The procedure requires intense pain management in the months following surgery. In response, we are developing a novel distraction device for incremental and personalized PE correction with minimal risk and pain, akin to orthodontic treatment using dental braces. To design the device, we propose in this study a personalized surgical planning framework for PE correction from clinical noncontrast CT. First, we segment the ribs and sternum via kernel graph cuts. Then costal cartilages, which have very low contrast in noncontrast CT, are modeled as 3D anatomical curves using the cosine series representation and estimated using a statistical shape model. The size and shape of the correction device are estimated through model fitting. Finally, the corrected/post-surgical chest is simulated in relation to the estimated shape of correction device. The root mean square mesh distance between the estimated cartilages and ground truth on 30 noncontrast CT scans was 1.28 +/- 0.81 mm. Our method found that the average deformation of the sterna and cartilages with the simulation of PE correction was 49.71 +/- 10.11 mm.