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At least 1,567 records · Page 87

Computer aided detection of surgical retained foreign object for prevention

Purpose: Surgical retained foreign objects (RFOs) have significant morbidity and mortality. They are associated with approximately $1.5 × 10{sup 9} annually in preventable medical costs. The detection accuracy of radiographs for RFOs is a mediocre 59%. The authors address the RFO problem with two complementary technologies: a three-dimensional (3D) gossypiboma micro tag, the μTag that improves the visibility of RFOs on radiographs, and a computer aided detection (CAD) system that detects the μTag. It is desirable for the CAD system to operate in a high specificity mode in the operating room (OR) and function as a first reader for the surgeon. This allows for fast point of care results and seamless workflow integration. The CAD system can also operate in a high sensitivity mode as a second reader for the radiologist to ensure the highest possible detection accuracy. Methods: The 3D geometry of the μTag produces a similar two dimensional (2D) depiction on radiographs regardless of its orientation in the human body and ensures accurate detection by a radiologist and the CAD. The authors created a data set of 1800 cadaver images with the 3D μTag and other common man-made surgical objects positioned randomly. A total of 1061 cadaver images contained a single μTag and the remaining 739 were without μTag. A radiologist marked the location of the μTag using an in-house developed graphical user interface. The data set was partitioned into three independent subsets: a training set, a validation set, and a test set, consisting of 540, 560, and 700 images, respectively. A CAD system with modules that included preprocessing μTag enhancement, labeling, segmentation, feature analysis, classification, and detection was developed. The CAD system was developed using the training and the validation sets. Results: On the training set, the CAD achieved 81.5% sensitivity with 0.014 false positives (FPs) per image in a high specificity mode for the surgeons in the OR and 96.1% sensitivity with 0.81 FPs per image in a high sensitivity mode for the radiologists. On the independent test set, the CAD achieved 79.5% sensitivity with 0.003 FPs per image in a high specificity mode for the surgeons and 90.2% sensitivity with 0.23 FPs per image in a high sensitivity mode for the radiologists. Conclusions: To the best of the authors’ knowledge, this is the first time a 3D μTag is used to produce a recognizable, substantially similar 2D projection on radiographs regardless of orientation in space. It is the first time a CAD system is used to search for man-made objects over anatomic background. The CAD system for the μTags achieved reasonable performance in both the high specificity and the high sensitivity modes.

60 APPLIED LIFE SCIENCES↗

WE-B-207-00: CT Lung Cancer Screening Part 1

The US National Lung Screening Trial (NLST) was a multi-center randomized, controlled trial comparing a low-dose CT (LDCT) to posterior-anterior (PA) chest x-ray (CXR) in screening older, current and former heavy smokers for early detection of lung cancer. Recruitment was launched in September 2002 and ended in April 2004 when 53,454 participants had been randomized at 33 screening sites in equal proportions. Funded by the National Cancer Institute this trial demonstrated that LDCT screening reduced lung cancer mortality. The US Preventive Services Task Force (USPSTF) cited NLST findings and conclusions in its deliberations and analysis of lung cancer screening. Under the 2010 Patient Protection and Affordable Care Act, the USPSTF favorable recommendation regarding lung cancer CT screening assisted in obtaining third-party payers coverage for screening. The objective of this session is to provide an introduction to the NLST and the trial findings, in addition to a comprehensive review of the dosimetry investigations and assessments completed using individual NLST participant CT and CXR examinations. Session presentations will review and discuss the findings of two independent assessments, a CXR assessment and the findings of a CT investigation calculating individual organ dosimetry values. The CXR assessment reviewed a total of 73,733 chest x-ray exams that were performed on 92 chest imaging systems of which 66,157 participant examinations were used. The CT organ dosimetry investigation collected scan parameters from 23,773 CT examinations; a subset of the 75,133 CT examinations performed using 97 multi-detector CT scanners. Organ dose conversion coefficients were calculated using a Monte Carlo code. An experimentally-validated CT scanner simulation was coupled with 193 adult hybrid computational phantoms representing the height and weight of the current U.S. population. The dose to selected organs was calculated using the organ dose library and the abstracted scan parameters. This session will review the results and summarize the individualized doses to major organs and the mean effective dose and CTDIvol estimate for 66,157 PA chest and 23,773 CT examinations respectively, using size-dependent computational phantoms coupled with Monte Carlo calculations. Learning Objectives: Review and summarize relevant NLST findings and conclusions. Understand the scope and scale of the NLST specific to participant dosimetry. Provide a comprehensive review of NLST participant dosimetry assessments. Summarize the results of an investigation providing individualized organ dose estimates for NLST participant cohorts.

60 APPLIED LIFE SCIENCES↗

WE-B-207-01: CT Lung Cancer Screening and the Medical Physicist: Background, Findings and Participant Dosimetry Summary of the National Lung Screening Trial (NLST)

The US National Lung Screening Trial (NLST) was a multi-center randomized, controlled trial comparing a low-dose CT (LDCT) to posterior-anterior (PA) chest x-ray (CXR) in screening older, current and former heavy smokers for early detection of lung cancer. Recruitment was launched in September 2002 and ended in April 2004 when 53,454 participants had been randomized at 33 screening sites in equal proportions. Funded by the National Cancer Institute this trial demonstrated that LDCT screening reduced lung cancer mortality. The US Preventive Services Task Force (USPSTF) cited NLST findings and conclusions in its deliberations and analysis of lung cancer screening. Under the 2010 Patient Protection and Affordable Care Act, the USPSTF favorable recommendation regarding lung cancer CT screening assisted in obtaining third-party payers coverage for screening. The objective of this session is to provide an introduction to the NLST and the trial findings, in addition to a comprehensive review of the dosimetry investigations and assessments completed using individual NLST participant CT and CXR examinations. Session presentations will review and discuss the findings of two independent assessments, a CXR assessment and the findings of a CT investigation calculating individual organ dosimetry values. The CXR assessment reviewed a total of 73,733 chest x-ray exams that were performed on 92 chest imaging systems of which 66,157 participant examinations were used. The CT organ dosimetry investigation collected scan parameters from 23,773 CT examinations; a subset of the 75,133 CT examinations performed using 97 multi-detector CT scanners. Organ dose conversion coefficients were calculated using a Monte Carlo code. An experimentally-validated CT scanner simulation was coupled with 193 adult hybrid computational phantoms representing the height and weight of the current U.S. population. The dose to selected organs was calculated using the organ dose library and the abstracted scan parameters. This session will review the results and summarize the individualized doses to major organs and the mean effective dose and CTDIvol estimate for 66,157 PA chest and 23,773 CT examinations respectively, using size-dependent computational phantoms coupled with Monte Carlo calculations. Learning Objectives: Review and summarize relevant NLST findings and conclusions. Understand the scope and scale of the NLST specific to participant dosimetry. Provide a comprehensive review of NLST participant dosimetry assessments. Summarize the results of an investigation providing individualized organ dose estimates for NLST participant cohorts.

60 APPLIED LIFE SCIENCES↗

WE-B-207-02: CT Lung Cancer Screening and the Medical Physicist: A Dosimetry Summary of CT Participants in the National Lung Cancer Screening Trial (NLST)

The US National Lung Screening Trial (NLST) was a multi-center randomized, controlled trial comparing a low-dose CT (LDCT) to posterior-anterior (PA) chest x-ray (CXR) in screening older, current and former heavy smokers for early detection of lung cancer. Recruitment was launched in September 2002 and ended in April 2004 when 53,454 participants had been randomized at 33 screening sites in equal proportions. Funded by the National Cancer Institute this trial demonstrated that LDCT screening reduced lung cancer mortality. The US Preventive Services Task Force (USPSTF) cited NLST findings and conclusions in its deliberations and analysis of lung cancer screening. Under the 2010 Patient Protection and Affordable Care Act, the USPSTF favorable recommendation regarding lung cancer CT screening assisted in obtaining third-party payers coverage for screening. The objective of this session is to provide an introduction to the NLST and the trial findings, in addition to a comprehensive review of the dosimetry investigations and assessments completed using individual NLST participant CT and CXR examinations. Session presentations will review and discuss the findings of two independent assessments, a CXR assessment and the findings of a CT investigation calculating individual organ dosimetry values. The CXR assessment reviewed a total of 73,733 chest x-ray exams that were performed on 92 chest imaging systems of which 66,157 participant examinations were used. The CT organ dosimetry investigation collected scan parameters from 23,773 CT examinations; a subset of the 75,133 CT examinations performed using 97 multi-detector CT scanners. Organ dose conversion coefficients were calculated using a Monte Carlo code. An experimentally-validated CT scanner simulation was coupled with 193 adult hybrid computational phantoms representing the height and weight of the current U.S. population. The dose to selected organs was calculated using the organ dose library and the abstracted scan parameters. This session will review the results and summarize the individualized doses to major organs and the mean effective dose and CTDIvol estimate for 66,157 PA chest and 23,773 CT examinations respectively, using size-dependent computational phantoms coupled with Monte Carlo calculations. Learning Objectives: Review and summarize relevant NLST findings and conclusions. Understand the scope and scale of the NLST specific to participant dosimetry. Provide a comprehensive review of NLST participant dosimetry assessments. Summarize the results of an investigation providing individualized organ dose estimates for NLST participant cohorts.

60 APPLIED LIFE SCIENCES↗

SU-F-T-471: Simulated External Beam Delivery Errors Detection with a Large Area Ion Chamber Transmission Detector

Purpose: The Integral Quality Monitor (IQM), developed by iRT Systems GmbH (Koblenz, Germany) is a large-area, linac-mounted ion chamber used to monitor photon fluence during patient treatment. Our previous work evaluated the change of the ion chamber’s response to deviations from static 1×1 cm2 and 10×10 cm2 photon beams and other characteristics integral to use in external beam detection. The aim of this work is to simulate two external beam radiation delivery errors, quantify the detection of simulated errors and evaluate the reduction in patient harm resulting from detection. Methods: Two well documented radiation oncology delivery errors were selected for simulation. The first error was recreated by modifying a wedged whole breast treatment, removing the physical wedge and calculating the planned dose with Pinnacle TPS (Philips Radiation Oncology Systems, Fitchburg, WI). The second error was recreated by modifying a static-gantry IMRT pharyngeal tonsil plan to be delivered in 3 unmodulated fractions. A radiation oncologist evaluated the dose for simulated errors and predicted morbidity and mortality commiserate with the original reported toxicity, indicating that reported errors were approximately simulated. The ion chamber signal of unmodified treatments was compared to the simulated error signal and evaluated in Pinnacle TPS again with radiation oncologist prediction of simulated patient harm. Results: Previous work established that transmission detector system measurements are stable within 0.5% standard deviation (SD). Errors causing signal change greater than 20 SD (10%) were considered detected. The whole breast and pharyngeal tonsil IMRT simulated error increased signal by 215% and 969%, respectively, indicating error detection after the first fraction and IMRT segment, respectively. Conclusion: The transmission detector system demonstrated utility in detecting clinically significant errors and reducing patient toxicity/harm in simulated external beam delivery. Future work will evaluate detection of other smaller magnitude delivery errors.

60 APPLIED LIFE SCIENCES↗

SU-G-TeP3-07: On the Development of Mechano-Biological Assessment of Leukemia Cells Using Optical Tweezers

Purpose: Patients with BCR-ABL (Ph +ve) acute lymphoblastic leukemia are at very high risk of relapse and mortality. In line with the NIH mission to understand the physical and biological processes, we seek to report mechano-biological method to assessment and distinguish treated/untreated leukemia cells. Methods: BCR-ABL leukemia cell populations and silica microspheres were trapped in a 100x magnification optical trapping system (λ=660 nm, 70 mW). Light refracted through the trapped sample was collected in the back focal plane by a quadrant detector to measure the positions of individual cells. The sample was driven at a known frequency and amplitude with a flexure translation stage, and the target’s response was recorded. The measured response was calibrated using the known driving parameters, and information about cell movements due to mechano-biological effects was extracted. Two leukemia cell populations were tested: a control group and a group treated with 2 Gy. Results: The mechano-biological movements of 10 microspheres, control cells, and treated cells were tracked over a ∼30 minute window at 1 minute intervals. The microsphere population did not see significant change in mechano-biological movements over the testing interval and remained constant. The control cell population saw a two-fold rise in activity that peaked around 1200 seconds, then dropped off sharply. The treated cell population saw a two-fold rise in activity that peaked at 400 seconds, and dropped off slowly. Conclusion: The investigated technique allows for direct measurement the movements of a trapped object due to mechano-biological effects such as thermal and extracellular motion. When testing microspheres, the mechano-biological activity remained constant over time due to the lack of biological factors. In both the control and treated cell populations, the mechano-biological activity was increased, possibly due to mitochondrial activation. This extra activity decreased over time, possibly due to cellular damage from trapping radiation.

46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗

TU-H-CAMPUS-TeP2-02: FLASH Irradiation Improves the Therapeutic Index Following GI Tract Irradiation

Purpose: To investigate and characterize the radiobiological effectiveness of very high dose rate radiotherapy (FLASH) compared to conventional irradiation in an in vivo model. Methods: The gastrointestinal (GI) tract of C57BL/6 mice were irradiated with doses ranging between 10 and 18 Gy using a custom stereotactic jig. A Varian Clinac 21EX was modified to allow dose rates ranging from 0.05 to 240 Gy/s at the position of the mirror. With the gantry at 180 degrees, the jig holding the individual animals was placed above the mirror to take advantage of the reduced source to target distance. Mice were irradiated with 20MeV electrons. Following irradiation, the mice were monitored twice daily for morbidity and daily for weight changes. Results: Mice irradiated with FLASH irradiation had lower weight loss compared to the mice receiving conventional irradiation. Following FLASH irradiation, a maximum weight loss of ∼20% was observed at day 6 with subsequent recovery, while following conventional irradiation, higher weight losses was observed with fewer instances of recovery. Concerning survival, all mice in the conventionally irradiated groups had a 100% mortality in the range of 15.5–18 Gy, while the mice irradiated with FLASH irradiation had a 100% survival in the same range. Conclusion: These results have demonstrated proof of principle that FLASH irradiations have a dramatic impact on the overall survival of mice following GI tract irradiations. If the increase in the therapeutic window can be validated and understood, this would revolutionize the field of radiation oncology and lead to increased cure rates with reduced side effects following treatment, resulting in increased quality of life for cancer survivors. Funding: DoD, Award#:W81XWH-14-1-0014, Weston Havens Foundation, Bio-X (Stanford University), the Office of the Dean of the Medical School, the Office of the Provost (Stanford University), and the Swedish Childhood Cancer Foundation; BL and PM are founders of TibaRay,Inc.; BL and PM have received research grants from Varian and RaySearch Laboratory.

60 APPLIED LIFE SCIENCES↗

WE-FG-207A-00: Advances in Dedicated Breast CT

Mammography-based screening has been a valuable imaging tool for the early detection of non-palpable lesions and has contributed to significant reduction in breast cancer associated mortality. However, the breast imaging community recognizes that mammography is not ideal, and in particular is inferior for women with dense breasts. Also, the 2-D projection of a 3-D organ results in tissue superposition contributing to false-positives. The sensitivity of mammography is breast-density dependent. Its sensitivity, especially in dense breasts, is low due to overlapping tissue and the fact that normal breast tissue, benign lesions and breast cancers all have similar “densities”, making lesion detection more difficult. We ideally need 3-D imaging for imaging the 3-D breast. MRI is 3-D, whole breast ultrasound is 3-D, digital breast tomosynthesis is called 3-D but is really “pseudo 3-D” due to poor resolution along the depth-direction. Also, and importantly, we need to be able to administer intravenous contrast agents for optimal imaging, similar to other organ systems in the body. Dedicated breast CT allows for 3-D imaging of the uncompressed breast. In current designs, the patient is positioned prone on the table and the breast is pendant through an aperture and the scan takes approximately 10 seconds [O’Connell et al., AJR 195: 496–509, 2010]. Almost on the heels of the invention of CT itself, work began on the development of dedicated breast CT. These early breast CT systems were used in clinical trials and the results from comparative performance evaluation of breast CT and mammography for 1625 subjects were reported in 1980 [Chang et al., Cancer 46: 939–46, 1980]. However, the technological limitations at that time stymied clinical translation for decades. Subsequent to the landmark article in 2001 [Boone et al., Radiology 221: 657–67, 2001] that demonstrated the potential feasibility in terms of radiation dose, multiple research groups are actively investigating dedicated breast CT. The development of large-area flat-panel detectors with field-of-view sufficient to image the entire breast in each projection enabled development of flat-panel cone-beam breast CT. More recently, the availability of complimentary metal-oxide semiconductor (CMOS) detectors with lower system noise and finer pixel pitch, combined with the development of x-ray tubes with focal spot dimensions similar to mammography systems, has shown improved spatial resolution and could improve visualization of microcalcifications. These technological developments promise clinical translation of low-dose cone-beam breast CT. Dedicated photon-counting breast CT (pcBCT) systems represent a novel detector design, which provide high spatial resolution (∼ 100µm) and low mean glandular dose (MGD). The CdTe-based direct conversion detector technology was previously evaluated and confirmed by simulations and basic experiments on laboratory setups [Kalender et al., Eur Radiol 22: 1–8, 2012]. Measurements of dose, technical image quality parameters, and surgical specimens on a pcBCT scanner have been completed. Comparative evaluation of surgical specimens showed that pcBCT outperformed mammography and digital breast tomosynthesis with respect to 3D spatial resolution, detectability of calcifications, and soft tissue delineation. Major barriers to widespread clinical use of BCT relate to radiation dose, imaging of microcalcifications, and adequate coverage of breast tissue near the chest wall. Adequate chest wall coverage is also technically challenging but recent progress in x-ray tube, detector and table design now enables full breast coverage in the majority of patients. At this time, BCT has been deemed to be suitable for diagnostic imaging but not yet for screening. The mean glandular dose (MGD) from BCT has been reported to be between 5.7 to 27.8 mGy, and this range is comparable to, and within the range of, the MGD of 2.6 to 31.6 mGy in diagnostic mammography. In diagnostic studies, the median MGD from BCT and mammography were 12.6 and 11.1 mGy, respectively [Vedantham et al., Phys Med Biol. 58: 7921–36, 2013]. Moreover, in diagnostic imaging of the breast the location of the lesion is known and therefore characterization and not detection is by far the primary consideration. The role of bCT is particularly compelling for diagnostic imaging of the breast because it may replace in part the multiple mammographic views of the breast under vigorous compression. Other non-screening potential applications of bCT include the assessment of response to neoadjuvant therapy [Vedantham et al., J Clin Imaging Sci 4, 64, 2014] and pre-surgical evaluation. Learning Objectives: To understand the metrics used to evaluate screening and diagnostic imaging To understand the benefits and limitations of current clinical modalities To understand how breast CT can improve over current clinical modalities To note the early attempts to translate breast CT to the clinic in 1970s-1990s To understand the recent developments in low-dose cone-beam breast CT To understand the recent developments in photon-counting breast CT To understand the radiation dose, clinical translation, and recent developments in diagnostic imaging with breast CT Supported in part by NIH grants R21 CA134128, R01 CA128906 and R01 CA195512. The contents are solely the responsibility of the authors and do not reflect the official views of the NIH or the NCI.; S. Vedantham, Funding sources: Supported in part by NIH/NCI grants R01 CA128906 and R01 CA195512. The contents are solely the responsibility of the authors and do not reflect the official views of the NIH/NCI. Disclosures: Research collaboration with Koning Corporation, West Henrietta, NY. Conflicts of Interest: J. Boone, This research was supported in part by NIH grant R01CA181081; W. Kalender, WK is founder and CEO of CT Imaging GmbH Erlangen, Germany.; A. Karellas, NIH R21 CA134128, R01 CA128906, and R01 CA195512 and Research collaboration with Koning Corporation.

60 APPLIED LIFE SCIENCES↗

WE-FG-207A-01: Introduction to Dedicated Breast CT - Early Studies

Mammography-based screening has been a valuable imaging tool for the early detection of non-palpable lesions and has contributed to significant reduction in breast cancer associated mortality. However, the breast imaging community recognizes that mammography is not ideal, and in particular is inferior for women with dense breasts. Also, the 2-D projection of a 3-D organ results in tissue superposition contributing to false-positives. The sensitivity of mammography is breast-density dependent. Its sensitivity, especially in dense breasts, is low due to overlapping tissue and the fact that normal breast tissue, benign lesions and breast cancers all have similar “densities”, making lesion detection more difficult. We ideally need 3-D imaging for imaging the 3-D breast. MRI is 3-D, whole breast ultrasound is 3-D, digital breast tomosynthesis is called 3-D but is really “pseudo 3-D” due to poor resolution along the depth-direction. Also, and importantly, we need to be able to administer intravenous contrast agents for optimal imaging, similar to other organ systems in the body. Dedicated breast CT allows for 3-D imaging of the uncompressed breast. In current designs, the patient is positioned prone on the table and the breast is pendant through an aperture and the scan takes approximately 10 seconds [O’Connell et al., AJR 195: 496–509, 2010]. Almost on the heels of the invention of CT itself, work began on the development of dedicated breast CT. These early breast CT systems were used in clinical trials and the results from comparative performance evaluation of breast CT and mammography for 1625 subjects were reported in 1980 [Chang et al., Cancer 46: 939–46, 1980]. However, the technological limitations at that time stymied clinical translation for decades. Subsequent to the landmark article in 2001 [Boone et al., Radiology 221: 657–67, 2001] that demonstrated the potential feasibility in terms of radiation dose, multiple research groups are actively investigating dedicated breast CT. The development of large-area flat-panel detectors with field-of-view sufficient to image the entire breast in each projection enabled development of flat-panel cone-beam breast CT. More recently, the availability of complimentary metal-oxide semiconductor (CMOS) detectors with lower system noise and finer pixel pitch, combined with the development of x-ray tubes with focal spot dimensions similar to mammography systems, has shown improved spatial resolution and could improve visualization of microcalcifications. These technological developments promise clinical translation of low-dose cone-beam breast CT. Dedicated photon-counting breast CT (pcBCT) systems represent a novel detector design, which provide high spatial resolution (∼ 100µm) and low mean glandular dose (MGD). The CdTe-based direct conversion detector technology was previously evaluated and confirmed by simulations and basic experiments on laboratory setups [Kalender et al., Eur Radiol 22: 1–8, 2012]. Measurements of dose, technical image quality parameters, and surgical specimens on a pcBCT scanner have been completed. Comparative evaluation of surgical specimens showed that pcBCT outperformed mammography and digital breast tomosynthesis with respect to 3D spatial resolution, detectability of calcifications, and soft tissue delineation. Major barriers to widespread clinical use of BCT relate to radiation dose, imaging of microcalcifications, and adequate coverage of breast tissue near the chest wall. Adequate chest wall coverage is also technically challenging but recent progress in x-ray tube, detector and table design now enables full breast coverage in the majority of patients. At this time, BCT has been deemed to be suitable for diagnostic imaging but not yet for screening. The mean glandular dose (MGD) from BCT has been reported to be between 5.7 to 27.8 mGy, and this range is comparable to, and within the range of, the MGD of 2.6 to 31.6 mGy in diagnostic mammography. In diagnostic studies, the median MGD from BCT and mammography were 12.6 and 11.1 mGy, respectively [Vedantham et al., Phys Med Biol. 58: 7921–36, 2013]. Moreover, in diagnostic imaging of the breast the location of the lesion is known and therefore characterization and not detection is by far the primary consideration. The role of bCT is particularly compelling for diagnostic imaging of the breast because it may replace in part the multiple mammographic views of the breast under vigorous compression. Other non-screening potential applications of bCT include the assessment of response to neoadjuvant therapy [Vedantham et al., J Clin Imaging Sci 4, 64, 2014] and pre-surgical evaluation. Learning Objectives: To understand the metrics used to evaluate screening and diagnostic imaging To understand the benefits and limitations of current clinical modalities To understand how breast CT can improve over current clinical modalities To note the early attempts to translate breast CT to the clinic in 1970s-1990s To understand the recent developments in low-dose cone-beam breast CT To understand the recent developments in photon-counting breast CT To understand the radiation dose, clinical translation, and recent developments in diagnostic imaging with breast CT Supported in part by NIH grants R21 CA134128, R01 CA128906 and R01 CA195512. The contents are solely the responsibility of the authors and do not reflect the official views of the NIH or the NCI.; S. Vedantham, Funding sources: Supported in part by NIH/NCI grants R01 CA128906 and R01 CA195512. The contents are solely the responsibility of the authors and do not reflect the official views of the NIH/NCI. Disclosures: Research collaboration with Koning Corporation, West Henrietta, NY. Conflicts of Interest: J. Boone, This research was supported in part by NIH grant R01CA181081; W. Kalender, WK is founder and CEO of CT Imaging GmbH Erlangen, Germany.; A. Karellas, NIH R21 CA134128, R01 CA128906, and R01 CA195512 and Research collaboration with Koning Corporation.

60 APPLIED LIFE SCIENCES↗

WE-FG-207A-02: Why We Need Breast CT? - Clinical Perspective

Mammography-based screening has been a valuable imaging tool for the early detection of non-palpable lesions and has contributed to significant reduction in breast cancer associated mortality. However, the breast imaging community recognizes that mammography is not ideal, and in particular is inferior for women with dense breasts. Also, the 2-D projection of a 3-D organ results in tissue superposition contributing to false-positives. The sensitivity of mammography is breast-density dependent. Its sensitivity, especially in dense breasts, is low due to overlapping tissue and the fact that normal breast tissue, benign lesions and breast cancers all have similar “densities”, making lesion detection more difficult. We ideally need 3-D imaging for imaging the 3-D breast. MRI is 3-D, whole breast ultrasound is 3-D, digital breast tomosynthesis is called 3-D but is really “pseudo 3-D” due to poor resolution along the depth-direction. Also, and importantly, we need to be able to administer intravenous contrast agents for optimal imaging, similar to other organ systems in the body. Dedicated breast CT allows for 3-D imaging of the uncompressed breast. In current designs, the patient is positioned prone on the table and the breast is pendant through an aperture and the scan takes approximately 10 seconds [O’Connell et al., AJR 195: 496–509, 2010]. Almost on the heels of the invention of CT itself, work began on the development of dedicated breast CT. These early breast CT systems were used in clinical trials and the results from comparative performance evaluation of breast CT and mammography for 1625 subjects were reported in 1980 [Chang et al., Cancer 46: 939–46, 1980]. However, the technological limitations at that time stymied clinical translation for decades. Subsequent to the landmark article in 2001 [Boone et al., Radiology 221: 657–67, 2001] that demonstrated the potential feasibility in terms of radiation dose, multiple research groups are actively investigating dedicated breast CT. The development of large-area flat-panel detectors with field-of-view sufficient to image the entire breast in each projection enabled development of flat-panel cone-beam breast CT. More recently, the availability of complimentary metal-oxide semiconductor (CMOS) detectors with lower system noise and finer pixel pitch, combined with the development of x-ray tubes with focal spot dimensions similar to mammography systems, has shown improved spatial resolution and could improve visualization of microcalcifications. These technological developments promise clinical translation of low-dose cone-beam breast CT. Dedicated photon-counting breast CT (pcBCT) systems represent a novel detector design, which provide high spatial resolution (∼ 100µm) and low mean glandular dose (MGD). The CdTe-based direct conversion detector technology was previously evaluated and confirmed by simulations and basic experiments on laboratory setups [Kalender et al., Eur Radiol 22: 1–8, 2012]. Measurements of dose, technical image quality parameters, and surgical specimens on a pcBCT scanner have been completed. Comparative evaluation of surgical specimens showed that pcBCT outperformed mammography and digital breast tomosynthesis with respect to 3D spatial resolution, detectability of calcifications, and soft tissue delineation. Major barriers to widespread clinical use of BCT relate to radiation dose, imaging of microcalcifications, and adequate coverage of breast tissue near the chest wall. Adequate chest wall coverage is also technically challenging but recent progress in x-ray tube, detector and table design now enables full breast coverage in the majority of patients. At this time, BCT has been deemed to be suitable for diagnostic imaging but not yet for screening. The mean glandular dose (MGD) from BCT has been reported to be between 5.7 to 27.8 mGy, and this range is comparable to, and within the range of, the MGD of 2.6 to 31.6 mGy in diagnostic mammography. In diagnostic studies, the median MGD from BCT and mammography were 12.6 and 11.1 mGy, respectively [Vedantham et al., Phys Med Biol. 58: 7921–36, 2013]. Moreover, in diagnostic imaging of the breast the location of the lesion is known and therefore characterization and not detection is by far the primary consideration. The role of bCT is particularly compelling for diagnostic imaging of the breast because it may replace in part the multiple mammographic views of the breast under vigorous compression. Other non-screening potential applications of bCT include the assessment of response to neoadjuvant therapy [Vedantham et al., J Clin Imaging Sci 4, 64, 2014] and pre-surgical evaluation. Learning Objectives: To understand the metrics used to evaluate screening and diagnostic imaging To understand the benefits and limitations of current clinical modalities To understand how breast CT can improve over current clinical modalities To note the early attempts to translate breast CT to the clinic in 1970s-1990s To understand the recent developments in low-dose cone-beam breast CT To understand the recent developments in photon-counting breast CT To understand the radiation dose, clinical translation, and recent developments in diagnostic imaging with breast CT Supported in part by NIH grants R21 CA134128, R01 CA128906 and R01 CA195512. The contents are solely the responsibility of the authors and do not reflect the official views of the NIH or the NCI.; S. Vedantham, Funding sources: Supported in part by NIH/NCI grants R01 CA128906 and R01 CA195512. The contents are solely the responsibility of the authors and do not reflect the official views of the NIH/NCI. Disclosures: Research collaboration with Koning Corporation, West Henrietta, NY. Conflicts of Interest: J. Boone, This research was supported in part by NIH grant R01CA181081; W. Kalender, WK is founder and CEO of CT Imaging GmbH Erlangen, Germany.; A. Karellas, NIH R21 CA134128, R01 CA128906, and R01 CA195512 and Research collaboration with Koning Corporation.

60 APPLIED LIFE SCIENCES↗

WE-FG-207A-03: Low-Dose Cone-Beam Breast CT: Physics and Technology Development

Mammography-based screening has been a valuable imaging tool for the early detection of non-palpable lesions and has contributed to significant reduction in breast cancer associated mortality. However, the breast imaging community recognizes that mammography is not ideal, and in particular is inferior for women with dense breasts. Also, the 2-D projection of a 3-D organ results in tissue superposition contributing to false-positives. The sensitivity of mammography is breast-density dependent. Its sensitivity, especially in dense breasts, is low due to overlapping tissue and the fact that normal breast tissue, benign lesions and breast cancers all have similar “densities”, making lesion detection more difficult. We ideally need 3-D imaging for imaging the 3-D breast. MRI is 3-D, whole breast ultrasound is 3-D, digital breast tomosynthesis is called 3-D but is really “pseudo 3-D” due to poor resolution along the depth-direction. Also, and importantly, we need to be able to administer intravenous contrast agents for optimal imaging, similar to other organ systems in the body. Dedicated breast CT allows for 3-D imaging of the uncompressed breast. In current designs, the patient is positioned prone on the table and the breast is pendant through an aperture and the scan takes approximately 10 seconds [O’Connell et al., AJR 195: 496–509, 2010]. Almost on the heels of the invention of CT itself, work began on the development of dedicated breast CT. These early breast CT systems were used in clinical trials and the results from comparative performance evaluation of breast CT and mammography for 1625 subjects were reported in 1980 [Chang et al., Cancer 46: 939–46, 1980]. However, the technological limitations at that time stymied clinical translation for decades. Subsequent to the landmark article in 2001 [Boone et al., Radiology 221: 657–67, 2001] that demonstrated the potential feasibility in terms of radiation dose, multiple research groups are actively investigating dedicated breast CT. The development of large-area flat-panel detectors with field-of-view sufficient to image the entire breast in each projection enabled development of flat-panel cone-beam breast CT. More recently, the availability of complimentary metal-oxide semiconductor (CMOS) detectors with lower system noise and finer pixel pitch, combined with the development of x-ray tubes with focal spot dimensions similar to mammography systems, has shown improved spatial resolution and could improve visualization of microcalcifications. These technological developments promise clinical translation of low-dose cone-beam breast CT. Dedicated photon-counting breast CT (pcBCT) systems represent a novel detector design, which provide high spatial resolution (∼ 100µm) and low mean glandular dose (MGD). The CdTe-based direct conversion detector technology was previously evaluated and confirmed by simulations and basic experiments on laboratory setups [Kalender et al., Eur Radiol 22: 1–8, 2012]. Measurements of dose, technical image quality parameters, and surgical specimens on a pcBCT scanner have been completed. Comparative evaluation of surgical specimens showed that pcBCT outperformed mammography and digital breast tomosynthesis with respect to 3D spatial resolution, detectability of calcifications, and soft tissue delineation. Major barriers to widespread clinical use of BCT relate to radiation dose, imaging of microcalcifications, and adequate coverage of breast tissue near the chest wall. Adequate chest wall coverage is also technically challenging but recent progress in x-ray tube, detector and table design now enables full breast coverage in the majority of patients. At this time, BCT has been deemed to be suitable for diagnostic imaging but not yet for screening. The mean glandular dose (MGD) from BCT has been reported to be between 5.7 to 27.8 mGy, and this range is comparable to, and within the range of, the MGD of 2.6 to 31.6 mGy in diagnostic mammography. In diagnostic studies, the median MGD from BCT and mammography were 12.6 and 11.1 mGy, respectively [Vedantham et al., Phys Med Biol. 58: 7921–36, 2013]. Moreover, in diagnostic imaging of the breast the location of the lesion is known and therefore characterization and not detection is by far the primary consideration. The role of bCT is particularly compelling for diagnostic imaging of the breast because it may replace in part the multiple mammographic views of the breast under vigorous compression. Other non-screening potential applications of bCT include the assessment of response to neoadjuvant therapy [Vedantham et al., J Clin Imaging Sci 4, 64, 2014] and pre-surgical evaluation. Learning Objectives: To understand the metrics used to evaluate screening and diagnostic imaging To understand the benefits and limitations of current clinical modalities To understand how breast CT can improve over current clinical modalities To note the early attempts to translate breast CT to the clinic in 1970s-1990s To understand the recent developments in low-dose cone-beam breast CT To understand the recent developments in photon-counting breast CT To understand the radiation dose, clinical translation, and recent developments in diagnostic imaging with breast CT Supported in part by NIH grants R21 CA134128, R01 CA128906 and R01 CA195512. The contents are solely the responsibility of the authors and do not reflect the official views of the NIH or the NCI.; S. Vedantham, Funding sources: Supported in part by NIH/NCI grants R01 CA128906 and R01 CA195512. The contents are solely the responsibility of the authors and do not reflect the official views of the NIH/NCI. Disclosures: Research collaboration with Koning Corporation, West Henrietta, NY. Conflicts of Interest: J. Boone, This research was supported in part by NIH grant R01CA181081; W. Kalender, WK is founder and CEO of CT Imaging GmbH Erlangen, Germany.; A. Karellas, NIH R21 CA134128, R01 CA128906, and R01 CA195512 and Research collaboration with Koning Corporation.

60 APPLIED LIFE SCIENCES↗

WE-FG-207A-04: Performance Characteristics of Photon-Counting Breast CT

Mammography-based screening has been a valuable imaging tool for the early detection of non-palpable lesions and has contributed to significant reduction in breast cancer associated mortality. However, the breast imaging community recognizes that mammography is not ideal, and in particular is inferior for women with dense breasts. Also, the 2-D projection of a 3-D organ results in tissue superposition contributing to false-positives. The sensitivity of mammography is breast-density dependent. Its sensitivity, especially in dense breasts, is low due to overlapping tissue and the fact that normal breast tissue, benign lesions and breast cancers all have similar “densities”, making lesion detection more difficult. We ideally need 3-D imaging for imaging the 3-D breast. MRI is 3-D, whole breast ultrasound is 3-D, digital breast tomosynthesis is called 3-D but is really “pseudo 3-D” due to poor resolution along the depth-direction. Also, and importantly, we need to be able to administer intravenous contrast agents for optimal imaging, similar to other organ systems in the body. Dedicated breast CT allows for 3-D imaging of the uncompressed breast. In current designs, the patient is positioned prone on the table and the breast is pendant through an aperture and the scan takes approximately 10 seconds [O’Connell et al., AJR 195: 496–509, 2010]. Almost on the heels of the invention of CT itself, work began on the development of dedicated breast CT. These early breast CT systems were used in clinical trials and the results from comparative performance evaluation of breast CT and mammography for 1625 subjects were reported in 1980 [Chang et al., Cancer 46: 939–46, 1980]. However, the technological limitations at that time stymied clinical translation for decades. Subsequent to the landmark article in 2001 [Boone et al., Radiology 221: 657–67, 2001] that demonstrated the potential feasibility in terms of radiation dose, multiple research groups are actively investigating dedicated breast CT. The development of large-area flat-panel detectors with field-of-view sufficient to image the entire breast in each projection enabled development of flat-panel cone-beam breast CT. More recently, the availability of complimentary metal-oxide semiconductor (CMOS) detectors with lower system noise and finer pixel pitch, combined with the development of x-ray tubes with focal spot dimensions similar to mammography systems, has shown improved spatial resolution and could improve visualization of microcalcifications. These technological developments promise clinical translation of low-dose cone-beam breast CT. Dedicated photon-counting breast CT (pcBCT) systems represent a novel detector design, which provide high spatial resolution (∼ 100µm) and low mean glandular dose (MGD). The CdTe-based direct conversion detector technology was previously evaluated and confirmed by simulations and basic experiments on laboratory setups [Kalender et al., Eur Radiol 22: 1–8, 2012]. Measurements of dose, technical image quality parameters, and surgical specimens on a pcBCT scanner have been completed. Comparative evaluation of surgical specimens showed that pcBCT outperformed mammography and digital breast tomosynthesis with respect to 3D spatial resolution, detectability of calcifications, and soft tissue delineation. Major barriers to widespread clinical use of BCT relate to radiation dose, imaging of microcalcifications, and adequate coverage of breast tissue near the chest wall. Adequate chest wall coverage is also technically challenging but recent progress in x-ray tube, detector and table design now enables full breast coverage in the majority of patients. At this time, BCT has been deemed to be suitable for diagnostic imaging but not yet for screening. The mean glandular dose (MGD) from BCT has been reported to be between 5.7 to 27.8 mGy, and this range is comparable to, and within the range of, the MGD of 2.6 to 31.6 mGy in diagnostic mammography. In diagnostic studies, the median MGD from BCT and mammography were 12.6 and 11.1 mGy, respectively [Vedantham et al., Phys Med Biol. 58: 7921–36, 2013]. Moreover, in diagnostic imaging of the breast the location of the lesion is known and therefore characterization and not detection is by far the primary consideration. The role of bCT is particularly compelling for diagnostic imaging of the breast because it may replace in part the multiple mammographic views of the breast under vigorous compression. Other non-screening potential applications of bCT include the assessment of response to neoadjuvant therapy [Vedantham et al., J Clin Imaging Sci 4, 64, 2014] and pre-surgical evaluation. Learning Objectives: To understand the metrics used to evaluate screening and diagnostic imaging To understand the benefits and limitations of current clinical modalities To understand how breast CT can improve over current clinical modalities To note the early attempts to translate breast CT to the clinic in 1970s-1990s To understand the recent developments in low-dose cone-beam breast CT To understand the recent developments in photon-counting breast CT To understand the radiation dose, clinical translation, and recent developments in diagnostic imaging with breast CT Supported in part by NIH grants R21 CA134128, R01 CA128906 and R01 CA195512. The contents are solely the responsibility of the authors and do not reflect the official views of the NIH or the NCI.; S. Vedantham, Funding sources: Supported in part by NIH/NCI grants R01 CA128906 and R01 CA195512. The contents are solely the responsibility of the authors and do not reflect the official views of the NIH/NCI. Disclosures: Research collaboration with Koning Corporation, West Henrietta, NY. Conflicts of Interest: J. Boone, This research was supported in part by NIH grant R01CA181081; W. Kalender, WK is founder and CEO of CT Imaging GmbH Erlangen, Germany.; A. Karellas, NIH R21 CA134128, R01 CA128906, and R01 CA195512 and Research collaboration with Koning Corporation.

60 APPLIED LIFE SCIENCES↗

WE-FG-207A-05: Dedicated Breast CT as a Diagnostic Imaging Tool: Physics and Clinical Feasibility

Mammography-based screening has been a valuable imaging tool for the early detection of non-palpable lesions and has contributed to significant reduction in breast cancer associated mortality. However, the breast imaging community recognizes that mammography is not ideal, and in particular is inferior for women with dense breasts. Also, the 2-D projection of a 3-D organ results in tissue superposition contributing to false-positives. The sensitivity of mammography is breast-density dependent. Its sensitivity, especially in dense breasts, is low due to overlapping tissue and the fact that normal breast tissue, benign lesions and breast cancers all have similar “densities”, making lesion detection more difficult. We ideally need 3-D imaging for imaging the 3-D breast. MRI is 3-D, whole breast ultrasound is 3-D, digital breast tomosynthesis is called 3-D but is really “pseudo 3-D” due to poor resolution along the depth-direction. Also, and importantly, we need to be able to administer intravenous contrast agents for optimal imaging, similar to other organ systems in the body. Dedicated breast CT allows for 3-D imaging of the uncompressed breast. In current designs, the patient is positioned prone on the table and the breast is pendant through an aperture and the scan takes approximately 10 seconds [O’Connell et al., AJR 195: 496–509, 2010]. Almost on the heels of the invention of CT itself, work began on the development of dedicated breast CT. These early breast CT systems were used in clinical trials and the results from comparative performance evaluation of breast CT and mammography for 1625 subjects were reported in 1980 [Chang et al., Cancer 46: 939–46, 1980]. However, the technological limitations at that time stymied clinical translation for decades. Subsequent to the landmark article in 2001 [Boone et al., Radiology 221: 657–67, 2001] that demonstrated the potential feasibility in terms of radiation dose, multiple research groups are actively investigating dedicated breast CT. The development of large-area flat-panel detectors with field-of-view sufficient to image the entire breast in each projection enabled development of flat-panel cone-beam breast CT. More recently, the availability of complimentary metal-oxide semiconductor (CMOS) detectors with lower system noise and finer pixel pitch, combined with the development of x-ray tubes with focal spot dimensions similar to mammography systems, has shown improved spatial resolution and could improve visualization of microcalcifications. These technological developments promise clinical translation of low-dose cone-beam breast CT. Dedicated photon-counting breast CT (pcBCT) systems represent a novel detector design, which provide high spatial resolution (∼ 100µm) and low mean glandular dose (MGD). The CdTe-based direct conversion detector technology was previously evaluated and confirmed by simulations and basic experiments on laboratory setups [Kalender et al., Eur Radiol 22: 1–8, 2012]. Measurements of dose, technical image quality parameters, and surgical specimens on a pcBCT scanner have been completed. Comparative evaluation of surgical specimens showed that pcBCT outperformed mammography and digital breast tomosynthesis with respect to 3D spatial resolution, detectability of calcifications, and soft tissue delineation. Major barriers to widespread clinical use of BCT relate to radiation dose, imaging of microcalcifications, and adequate coverage of breast tissue near the chest wall. Adequate chest wall coverage is also technically challenging but recent progress in x-ray tube, detector and table design now enables full breast coverage in the majority of patients. At this time, BCT has been deemed to be suitable for diagnostic imaging but not yet for screening. The mean glandular dose (MGD) from BCT has been reported to be between 5.7 to 27.8 mGy, and this range is comparable to, and within the range of, the MGD of 2.6 to 31.6 mGy in diagnostic mammography. In diagnostic studies, the median MGD from BCT and mammography were 12.6 and 11.1 mGy, respectively [Vedantham et al., Phys Med Biol. 58: 7921–36, 2013]. Moreover, in diagnostic imaging of the breast the location of the lesion is known and therefore characterization and not detection is by far the primary consideration. The role of bCT is particularly compelling for diagnostic imaging of the breast because it may replace in part the multiple mammographic views of the breast under vigorous compression. Other non-screening potential applications of bCT include the assessment of response to neoadjuvant therapy [Vedantham et al., J Clin Imaging Sci 4, 64, 2014] and pre-surgical evaluation. Learning Objectives: To understand the metrics used to evaluate screening and diagnostic imaging To understand the benefits and limitations of current clinical modalities To understand how breast CT can improve over current clinical modalities To note the early attempts to translate breast CT to the clinic in 1970s-1990s To understand the recent developments in low-dose cone-beam breast CT To understand the recent developments in photon-counting breast CT To understand the radiation dose, clinical translation, and recent developments in diagnostic imaging with breast CT Supported in part by NIH grants R21 CA134128, R01 CA128906 and R01 CA195512. The contents are solely the responsibility of the authors and do not reflect the official views of the NIH or the NCI.; S. Vedantham, Funding sources: Supported in part by NIH/NCI grants R01 CA128906 and R01 CA195512. The contents are solely the responsibility of the authors and do not reflect the official views of the NIH/NCI. Disclosures: Research collaboration with Koning Corporation, West Henrietta, NY. Conflicts of Interest: J. Boone, This research was supported in part by NIH grant R01CA181081; W. Kalender, WK is founder and CEO of CT Imaging GmbH Erlangen, Germany.; A. Karellas, NIH R21 CA134128, R01 CA128906, and R01 CA195512 and Research collaboration with Koning Corporation.

60 APPLIED LIFE SCIENCES↗

Mechanisms of murine cerebral malaria: Multimodal imaging of altered cerebral metabolism and protein oxidation at hemorrhage sites

Using a multimodal biospectroscopic approach, we settle several long-standing controversies over the molecular mechanisms that lead to brain damage in cerebral malaria, which is a major health concern in developing countries because of high levels of mortality and permanent brain damage. Our results provide the first conclusive evidence that important components of the pathology of cerebral malaria include peroxidative stress and protein oxidation within cerebellar gray matter, which are colocalized with elevated nonheme iron at the site of microhemorrhage. Such information could not be obtained previously from routine imaging methods, such as electron microscopy, fluorescence, and optical microscopy in combination with immunocytochemistry, or from bulk assays, where the level of spatial information is restricted to the minimum size of tissue that can be dissected. We describe the novel combination of chemical probe–free, multimodal imaging to quantify molecular markers of disturbed energy metabolism and peroxidative stress, which were used to provide new insights into understanding the pathogenesis of cerebral malaria. In addition to these mechanistic insights, the approach described acts as a template for the future use of multimodal biospectroscopy for understanding the molecular processes involved in a range of clinically important acute and chronic (neurodegenerative) brain diseases to improve treatment strategies.

60 APPLIED LIFE SCIENCES↗

Basin-scale biogeography of marine phytoplankton reflects cellular-scale optimization of metabolism and physiology

Extensive microdiversity within Prochlorococcus, the most abundant marine cyanobacterium, occurs at scales from a single droplet of seawater to ocean basins. To interpret the structuring role of variations in genetic potential, as well as metabolic and physiological acclimation, we developed a mechanistic constraint-based modeling framework that incorporates the full suite of genes, proteins, metabolic reactions, pigments, and biochemical compositions of 69 sequenced isolates spanning the Prochlorococcus pangenome. Optimizing each strain to the local, observed physical and chemical environment along an Atlantic Ocean transect, we predicted variations in strain-specific patterns of growth rate, metabolic configuration, and physiological state, defining subtle niche subspaces directly attributable to differences in their encoded metabolic potential. Predicted growth rates covaried with observed ecotype abundances, affirming their significance as a measure of fitness and inferring a nonlinear density dependence of mortality. Our study demonstrates the potential to interpret global-scale ecosystem organization in terms of cellular-scale processes.

59 BASIC BIOLOGICAL SCIENCES↗

Estimating economic damage from climate change in the United States

Estimates of climate change damage are central to the design of climate policies. Here, we develop a flexible architecture for computing damages that integrates climate science, econometric analyses, and process models. We use this approach to construct spatially explicit, probabilistic, and empirically derived estimates of economic damage in the United States from climate change. The combined value of market and nonmarket damage across analyzed sectors—agriculture, crime, coastal storms, energy, human mortality, and labor—increases quadratically in global mean temperature, costing roughly 1.2% of gross domestic product per +1°C on average. Importantly, risk is distributed unequally across locations, generating a large transfer of value northward and westward that increases economic inequality. By the late 21st century, the poorest third of counties are projected to experience damages between 2 and 20% of county income (90% chance) under business-as-usual emissions (Representative Concentration Pathway 8.5).

Hsiang, Solomon (ORCID:0000000220740829)↗

Pervasive shifts in forest dynamics in a changing world

Forest dynamics arise from the interplay of environmental drivers and disturbances with the demographic processes of recruitment, growth, and mortality, subsequently driving biomass and species composition. However, forest disturbances and subsequent recovery are shifting with global changes in climate and land use, altering these dynamics. Changes in environmental drivers, land use, and disturbance regimes are forcing forests toward younger, shorter stands. Rising carbon dioxide, acclimation, adaptation, and migration can influence these impacts. Recent developments in Earth system models support increasingly realistic simulations of vegetation dynamics. In parallel, emerging remote sensing datasets promise qualitatively new and more abundant data on the underlying processes and consequences for vegetation structure. In combination, these advances hold promise for improving the scientific understanding of changes in vegetation demographics and disturbances.

54 ENVIRONMENTAL SCIENCES↗

Vaccination before or after SARS-CoV-2 infection leads to robust humoral response and antibodies that effectively neutralize variants

Current coronavirus disease 2019 (COVID-19) vaccines effectively reduce overall morbidity and mortality and are vitally important to controlling the pandemic. Individuals who previously recovered from COVID-19 have enhanced immune responses after vaccination (hybrid immunity) compared with their naïve-vaccinated peers; however, the effects of post-vaccination breakthrough infections on humoral immune response remain to be determined. Here, we measure neutralizing antibody responses from 104 vaccinated individuals, including those with breakthrough infections, hybrid immunity, and no infection history. We find that human immune sera after breakthrough infection and vaccination after natural infection broadly neutralize SARS-CoV-2 (severe acute respiratory coronavirus 2) variants to a similar degree. Although age negatively correlates with antibody response after vaccination alone, no correlation with age was found in breakthrough or hybrid immune groups. Together, our data suggest that the additional antigen exposure from natural infection substantially boosts the quantity, quality, and breadth of humoral immune response regardless of whether it occurs before or after vaccination.

60 APPLIED LIFE SCIENCES↗