Intraoperative Photoacoustic Imaging of Breast Cancer

Breast cancer is one of the most common cancers to affect women, presenting a lifetime risk of 1 in 8. Treatment of stage 1 and 2 cancers usually involves breast conserving surgery (BCS). The goal of BCS is to remove the entire tumour with a surrounding envelope of healthy tissue, referred to as a negative margin. Unfortunately, up to 50% of surgeries fail to remove the whole tumour. To minimize the risk of cancer recurrence, a second surgery, must therefore be performed. Currently, there is no widely accepted intraoperative tool to significantly mitigate this problem. Employed systems are usually based on imaging, such as x-ray or ultrasonography. Unfortunately, sensitivity and specificity deficits, especially related to breast density, reduce the effectiveness of these methods. Photoacoustic tomography (PAT) is a relatively new imaging modality which uses safe near-infrared laser illumination to generate 3-D images of soft tissues to a depth of up to several cm. We used a custom designed and built intraoperative PAT system, called iPAT, to perform a 100 patient study on freshly excised breast lumpectomy specimens within the surgical setting. The system enabled the evaluation of tumour extent, shape, morphology and position within lumpectomy specimens measuring up to 11 cm in diameter. Scan results were used to compare iPAT-derived tumour size to the gold-standard pathologic examination, and when available, to x-ray, ultrasonography and DCE-MRI. Imaging results were also used to classify specimen margins as close or wide, and positive predictive values (PPV), negative predictive values (NPV), sensitivity and specificity were then calculated to estimate the effectiveness of the iPAT system at predicting lumpectomy margin status. With a close margin prevalence of 35%, the PPV, NPV, sensitivity and specificity of iPAT were found to be 71%, 83%, 69%, and 84%, respectively. Information provided by the iPAT system identified 9 out of the 12 positive specimens, potentially reducing the positive margin rate by 75%. . Contrary to expected photoacoustic contrast mechanisms, iPAT images of hemoglobin distribution correlated poorly with US and X-ray tumour imaging, while hypo-intense regions in lipid-weighted iPAT images were in excellent agreement

Guiding nanoparticle enhanced photothermal therapy for cancer with photoacoustic thermal imaging and diffuse optical tomography

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Objective Assessment and Design Improvement of a Staring, Sparse Transducer Array by the Spatial Crosstalk Matrix for 3D Photoacoustic Tomography.

Accurate reconstruction of 3D photoacoustic (PA) images requires detection of photoacoustic signals from many angles. Several groups have adopted staring ultrasound arrays, but assessment of array performance has been limited. We previously reported on a method to calibrate a 3D PA tomography (PAT) staring array system and analyze system performance using singular value decomposition (SVD). The developed SVD metric, however, was impractical for large system matrices, which are typical of 3D PAT problems. The present study consisted of two main objectives. The first objective aimed to introduce the crosstalk matrix concept to the field of PAT for system design. Figures-of-merit utilized in this study were root mean square error, peak signal-to-noise ratio, mean absolute error, and a three dimensional structural similarity index, which were derived between the normalized spatial crosstalk matrix and the identity matrix. The applicability of this approach for 3D PAT was validated by observing the response of the figures-of-merit in relation to well-understood PAT sampling characteristics (i.e. spatial and temporal sampling rate). The second objective aimed to utilize the figures-of-merit to characterize and improve the performance of a near-spherical staring array design. Transducer arrangement, array radius, and array angular coverage were the design parameters examined. We observed that the performance of a 129-element staring transducer array for 3D PAT could be improved by selection of optimal values of the design parameters. The results suggested that this formulation could be used to objectively characterize 3D PAT system performance and would enable the development of efficient strategies for system design optimization

Potential for photoacoustic imaging of the neonatal brain

Photoacoustic imaging (PAI) has been proposed as a non-invasive technique for imaging neonatal brain injury. Since PAI combines many of the merits of both optical and ultrasound imaging, images with high contrast, high resolution, and a greater penetration depth can be obtained when compared to more traditional optical methods. However, due to the strong attenuation and reflection of photoacoustic pressure waves at the skull bone, PAI of the brain is much more challenging than traditional methods (e.g. near infrared spectroscopy) for optical interrogation of the neonatal brain. To evaluate the potential limits the skull places on 3D PAI of the neonatal brain, we constructed a neonatal skull phantom (1.4-mm thick) with a mixture of epoxy and titanium dioxide powder that provided acoustic insertion loss (1-5MHz) similar to human infant skull bone. The phantom was molded into a realistic infant skull shape by means of a CNCmachined mold that was based upon a 3D CAD model. To evaluate the effect of the skull bone on PAI, a photoacoustic point source was raster scanned within the phantom brain cavity to capture the imaging operator of the 3D PAI system (128 ultrasound transducers in a hemispherical arrangement) with and without the intervening skull phantom. The resultant imaging operators were compared to determine the effect of the skull layer on the PA signals in terms of amplitude loss and time delay. © 2013 Copyright SPIE

A Novel Hybrid Imaging System to Aid in Surgical Decision Making

Background: Breast cancer accounts for 25% of all cancer cases among women. In breast-conserving surgery, a common treatment, the tumour is excised with a healthy tissue margin. However, detection of the margin can be difficult. Current techniques to guide excision are often insufficient, and re-excision can occur up to 25% of the time. Methods: Photoacoustic imaging is a hybrid imaging modality that combines the advantages of optical imaging and ultrasound while using safe non-ionizing light. This project involves the development of a novel imaging system with a new scanner design to overcome common limitations and provide images to aid in surgical decision making. Results: A new imaging system has been developed and tested with imaging phantoms. Discussion & Conclusion: Results obtained with imaging phantoms are promising; high resolution images with good contrast have been shown. Further research using surgical excised tumour specimens will be conducted as a pilot study. Interdisciplinary Reflection: Various imaging methods are combined and applied to medical needs. In addition, this imaging system is incredibly versatile and can be used for many areas of research including animal studies, human studies, and from macroscopic imaging to microscopy

Effects of Direct Renin Inhibition on Myocardial Fibrosis and Cardiac Fibroblast Function

Myocardial fibrosis, a major pathophysiologic substrate of heart failure with preserved ejection fraction (HFPEF), is modulated by multiple pathways including the renin-angiotensin system. Direct renin inhibition is a promising anti-fibrotic therapy since it attenuates the pro-fibrotic effects of renin in addition to that of other effectors of the renin-angiotensin cascade. Here we show that the oral renin inhibitor aliskiren has direct effects on collagen metabolism in cardiac fibroblasts and prevented myocardial collagen deposition in a non-hypertrophic mouse model of myocardial fibrosis. Adult mice were fed hyperhomocysteinemia-inducing diet to induce myocardial fibrosis and treated concomitantly with either vehicle or aliskiren for 12 weeks. Blood pressure and plasma angiotensin II levels were normal in control and hyperhomocysteinemic mice and reduced to levels lower than observed in the control group in the groups treated with aliskiren. Homocysteine-induced myocardial matrix gene expression and fibrosis were also prevented by aliskiren. In vitro studies using adult rat cardiac fibroblasts also showed that aliskiren attenuated the pro-fibrotic pattern of matrix gene and protein expression induced by D,L, homocysteine. Both in vivo and in vitro studies demonstrated that the Akt pathway was activated by homocysteine, and that treatment with aliskiren attenuated Akt activation. In conclusion, aliskiren as mono-therapy has potent and direct effects on myocardial matrix turnover and beneficial effects on diastolic function

Influenza A virus hemagglutinin glycosylation compensates for antibody escape fitness costs

Rapid antigenic evolution enables the persistence of seasonal influenza A and B viruses in human populations despite widespread herd immunity. Understanding viral mechanisms that enable antigenic evolution is critical for designing durable vaccines and therapeutics. Here, we utilize the primerID method of error-correcting viral population sequencing to reveal an unexpected role for hemagglutinin (HA) glycosylation in compensating for fitness defects resulting from escape from anti-HA neutralizing antibodies. Antibody-free propagation following antigenic escape rapidly selected viruses with mutations that modulated receptor binding avidity through the addition of N-linked glycans to the HA globular domain. These findings expand our understanding of the viral mechanisms that maintain fitness during antigenic evolution to include glycan addition, and highlight the immense power of high-definition virus population sequencing to reveal novel viral adaptive mechanisms.Fil: Kosik, Ivan. National Institute of Allergy and Infectious Diseases; Estados UnidosFil: Ince, William L.. National Institute of Allergy and Infectious Diseases; Estados Unidos. National Center For Toxicological Research. Food And Drug Administration; Estados UnidosFil: Gentles, Lauren E.. National Institute of Allergy and Infectious Diseases; Estados UnidosFil: Oler, Andrew J.. National Institute of Allergy and Infectious Diseases; Estados UnidosFil: Kosikova, Martina. National Center For Toxicological Research. Food And Drug Administration; Estados UnidosFil: Angel, Matthew. National Institute of Allergy and Infectious Diseases; Estados UnidosFil: Magadan, Javier Guillermo. National Institute of Allergy and Infectious Diseases; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Xie, Hang. National Center For Toxicological Research. Food And Drug Administration; Estados UnidosFil: Brooke, Christopher B.. University of Illinois at Urbana; Estados UnidosFil: Yewdell, Jonathan W.. National Institute of Allergy and Infectious Diseases; Estados Unido

Peri-operative red blood cell transfusion in neonates and infants: NEonate and Children audiT of Anaesthesia pRactice IN Europe: A prospective European multicentre observational study

BACKGROUND: Little is known about current clinical practice concerning peri-operative red blood cell transfusion in neonates and small infants. Guidelines suggest transfusions based on haemoglobin thresholds ranging from 8.5 to 12 g dl-1, distinguishing between children from birth to day 7 (week 1), from day 8 to day 14 (week 2) or from day 15 (≥week 3) onwards. OBJECTIVE: To observe peri-operative red blood cell transfusion practice according to guidelines in relation to patient outcome. DESIGN: A multicentre observational study. SETTING: The NEonate-Children sTudy of Anaesthesia pRactice IN Europe (NECTARINE) trial recruited patients up to 60 weeks' postmenstrual age undergoing anaesthesia for surgical or diagnostic procedures from 165 centres in 31 European countries between March 2016 and January 2017. PATIENTS: The data included 5609 patients undergoing 6542 procedures. Inclusion criteria was a peri-operative red blood cell transfusion. MAIN OUTCOME MEASURES: The primary endpoint was the haemoglobin level triggering a transfusion for neonates in week 1, week 2 and week 3. Secondary endpoints were transfusion volumes, 'delta haemoglobin' (preprocedure - transfusion-triggering) and 30-day and 90-day morbidity and mortality. RESULTS: Peri-operative red blood cell transfusions were recorded during 447 procedures (6.9%). The median haemoglobin levels triggering a transfusion were 9.6 [IQR 8.7 to 10.9] g dl-1 for neonates in week 1, 9.6 [7.7 to 10.4] g dl-1 in week 2 and 8.0 [7.3 to 9.0] g dl-1 in week 3. The median transfusion volume was 17.1 [11.1 to 26.4] ml kg-1 with a median delta haemoglobin of 1.8 [0.0 to 3.6] g dl-1. Thirty-day morbidity was 47.8% with an overall mortality of 11.3%. CONCLUSIONS: Results indicate lower transfusion-triggering haemoglobin thresholds in clinical practice than suggested by current guidelines. The high morbidity and mortality of this NECTARINE sub-cohort calls for investigative action and evidence-based guidelines addressing peri-operative red blood cell transfusions strategies. TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT02350348

Dementia in Latin America : paving the way towards a regional action plan

Regional challenges faced by Latin American and Caribbean countries (LACs) to fight dementia, such as heterogeneity, diversity, political instabilities, and socioeconomic disparities, can be addressed more effectively grounded in a collaborative setting based on the open exchange of knowledge. In this work, the Latin American and Caribbean Consortium on Dementia (LAC-CD) proposes an agenda for integration to deliver a Knowledge to Action Framework (KtAF). First, we summarize evidence-based strategies (epidemiology, genetics, biomarkers, clinical trials, nonpharmacological interventions, networking and translational research) and align them to current global strategies to translate regional knowledge into actions with transformative power. Then, by characterizing genetic isolates, admixture in populations, environmental factors, and barriers to effective interventions and mapping these to the above challenges, we provide the basic mosaics of knowledge that will pave the way towards a KtAF. We describe strategies supporting the knowledge creation stage that underpins the translational impact of KtAF