Browsing by Subject "Medicine"
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Item Open Access A Deep Learning Model for V50%, V60%, and V66.7% Prediction in LINAC-based Treatment Planning of Single-Iso-Multiple-Targets (SIMT) Stereotactic Radiosurgery (SRS)(2023) Khazaieli, MercedehBrain metastases are a common complication of many types of cancer, including lung, breast, and melanoma. Approximately 30-40% of patients develop brain metastases that originate from primary systemic tumors during the course of cancer treatment. One treatment method is a LINAC-based single-isocenter multiple-target (SIMT) stereotactic radiosurgery (SRS). High plan quality has been one of the important goals in radiotherapy treatment planning. Generation of a high quality SRS treatment plan, particularly a SIMT plan, usually requires planners’ extensive planning experience, multiple runs of planning and trial-and-error, and frequent communication among planners, physicians and other radiation oncology team members. In clinical practice with potentially limited resources, SIMT SRS planning could be time-consuming and may have large variations in plan dosimetric quality. Therefore, an estimation of achievable dosimetric outcome can help reduce plan quality variation and improve planning efficiency. Assuming 20Gy in a single fraction of treatment, the volume of normal brain tissue receiving 10Gy (V50%), 12Gy (V60%), and 13Gy (V66.7%) are known predictors of brain tissue toxicity, or radionecrosis. We developed deep learning networks for the prediction of V50%, V60%, and V66.7% based on each patient’s target delineation. A prediction of achievable V10Gy, V12Gy, and V13Gy (assuming 20Gy x 1fx) can assist physicians in the determination of fractionation schemes (i.e., single fx vs. multiple fx). Such predictions can be used as guidelines for planners to generate a SIMT plan more rapidly with reduced dosimetric variability. A key technical innovation of this work is the spherical projection design: by projecting target distribution on a spherical surface, the target distribution in 3D is collapsed to a polar-azimuthal angular distribution map. This transformation enables a dimensional reduction for deep learning input without losing volumetric information. Our results indicate promising potential but there is a need for further work to improve the accuracy of our predictions.
Item Open Access A Deep-Learning Method of Automatic VMAT Planning via MLC Dynamic Sequence Prediction (AVP-DSP) Using 3D Dose Prediction: A Feasibility Study of Prostate Radiotherapy Application(2020) Ni, YiminIntroduction: VMAT treatment planning requires time-consuming DVH-based inverse optimization process, which impedes its application in time-sensitive situations. This work aims to develop a deep-learning based algorithm, Automatic VMAT Planning via MLC Dynamic Sequence Prediction (AVP-DSP), for rapid prostate VMAT treatment planning.
Methods: AVP-DSP utilizes a series of 2D projections of a patient’s dose prediction and contour structures to generate a single 360º dynamic MLC sequence in a VMAT plan. The backbone of AVP-DSP is a novel U-net implementation which has a 4-resolution-step analysis path and a 4-resolution-step synthesis path. AVP-DSP was developed based on 131 previous prostate patients who received simultaneously-integrated-boost (SIB) treatment (58.8Gy/70Gy to PTV58.8/PTV70 in 28fx). All patients were planned by a 360º single-arc VMAT technique using an in-house intelligent planning tool in a commercial treatment planning system (TPS). 120 plans were used in AVP-DSP training/validation, and 11 plans were used as independent tests. Key dosimetric metrics achieved by AVP-DSP were compared against the ones planned by the commercial TPS.
Results: After dose normalization (PTV70 V70Gy=95%), all 11 AVP-DSP test plans met institutional clinic guidelines of dose distribution outside PTV. Bladder (V70Gy=6.8±3.6cc, V40Gy=19.4±9.2%) and rectum (V70Gy=2.8±1.8cc, V40Gy=26.3±5.9%) results in AVP-DSP plans were comparable with the commercial TPS plan results (bladder V70Gy=4.1±2.0cc, V40Gy=17.7±8.9%; rectum V70Gy=1.4±0.7cc, V40Gy=24.0±5.0%). 3D max dose results in AVP-DSP plans(D1cc=118.9±4.1%) were higher than the commercial TPS plans results(D1cc=106.7±0.8%). On average, AVP-DSP used 30 seconds for a plan generation in contrast to the current clinical practice (>20 minutes).
Conclusion: Results suggest that AVP-DSP can generate a prostate VMAT plan with clinically-acceptable dosimetric quality. With its high efficiency, AVP-DSP may hold great potentials of real-time planning application after further validation.
Item Open Access A Feasibility Study of Noninvasive Intracranial Pressure Monitoring for Adults After Traumatic Brain Injury in Uganda(2022) Petitt, ZoeyIntroduction: Traumatic brain injury (TBI) accounts for the majority of Uganda’s neurosurgical disease burden, but invasive intracranial pressure (ICP) monitoring is infrequently used. Noninvasive monitoring through tools like pupillometry could change the care of TBI patients in such a setting. Given the novelty of noninvasive monitoring in Uganda, this study sought to assess the feasibility of pupillometry for noninvasive ICP monitoring for TBI patients. Methods: Healthcare workers in Kampala, Uganda received education on pupillometry, practiced using the device on healthy volunteers, and completed interviews focused on pupillometry and its potential implementation. Qualitative analysis of the interviews assessed pupillometry acceptability and feasibility. Quantitative analysis assessed learning time, time to obtain a measurement, and accuracy of measurements during training. Results: Twenty-two providers completed the study. Participants described how pupillometry would add value to the care of patients with TBI during examination, delivering interventions, and monitoring. Reported concerns included the cost, understanding, and maintenance needs of the pupillometer. Participants also discussed potential challenges with using pupillometry, including limited accessibility and availability as well as challenges with documentation. They suggested offering continued education and providing technical support as strategies to support successful implementation. During training, average time to learn was 13.6 minutes (IQR 3.8) and average time to obtain a measurement was 51.1 seconds (IQR 14.2). Paired t tests to evaluate accuracy after training showed no statistically significant difference in the comparison measurements. Conclusion: Pupillometry would be feasible to use for noninvasive ICP monitoring for TBI patients in Uganda, as long as concerns about the device could be addressed and implementation barriers overcome.
Item Open Access A High-Tech Solution for the Low Resource Setting: A Tool to Support Decision Making for Patients with Traumatic Brain Injury(2019) Elahi, CyrusBackground. The confluence of a capacity-exceeding disease burden and persistent resource shortages have resulted in traumatic brain injury’s (TBI) devastating impact in low and middle income countries (LMIC). Lifesaving care for TBI depends on accurate and timely decision making within the hospital. As result of technology and highly skilled provider shortages, treatment delays are common in low resource settings. This reality demands a low cost, scalable and accurate alternative to support decision making. Decision support tools leveraging the accuracy of modern prognostic modeling techniques represents one possible solution. This thesis is a collation of research dedicated to the advancement of TBI decision support technology in low resource settings. Methods. The study location included three national and referral hospitals in Uganda and Tanzania. We performed a survival analysis, externally validated existing TBI prognostic models, developed our own prognostic model, and performed a feasibility study for TBI decision support tools in an LMIC. Results. The survival analysis revealed a greater surgical benefit for mild and moderate head injuries compared to severe injuries. However, severe injury patients experienced a higher surgery rate than mild and moderate injuries. We developed a prognostic model using machine learning with a good level of accuracy. This model outperformed existing TBI models in regards to discrimination but not calibration. Our feasibility study captured the need for improved prognostication of TBI patients in the hospital. Conclusions. This pioneering work has provided a foundation for further investigation and implementation of TBI decision support technologies in low resource settings.
Item Embargo A Mixed-Method Approach to Assessing the Need and Capacity for Epilepsy Surgery in a National Referral Hospital in Uganda(2024) Antwi, PrinceAbstract
Background: An estimated 80% of patients with epilepsy reside in LMICs, where surgical options for treating medication refractory epilepsy (MRE) may not be readily available. This study assesses the need for an epilepsy surgery program in Uganda and evaluates the current capacity for implementing such a program at the nation’s largest hospital, the Mulago National Referral Hospital (MNRH).
Methods: Medical records of 183 adult patients receiving care for epilepsy at the Bosa Psychiatric Clinic between January and April 2021 were retrospectively reviewed to determine patterns of medical management of epilepsy. 13 clinicians across Psychiatry, Neurology, and Neurosurgery were interviewed; these interviews were analyzed thematically to address the subjects of need and capacity for epilepsy surgery at MNRH. 41 patients and 63 caregivers were surveyed on their perceptions and attitudes toward surgery as a potential treatment for epilepsy.
Results: Nearly half (49%) of patients receiving care at the Bosa Clinic had been treated on two or more anti-epileptic drugs (AEDs) over the course of their disease, with Carbamazepine, Sodium Valproate, and Phenytoin being the most commonly prescribed medications. Only few patients had records of prior brain imaging (8.2%) and EEG (21%) in their medical charts, and no patient had prior referral for surgical evaluation. The interviewed clinicians noted that there is a need for an epilepsy surgery program to augment the current medical practice. They identified infrastructure, cost, further specialized training, and public perception as factors to address in implementing a sustainable epilepsy surgery program locally. 53.3% of patients and 58.5% of caregivers would consider epilepsy surgery only after they had tried 5 or more AEDs without resolution of seizures, citing complications and cost as deterrents.
Conclusions: Both clinical records and clinician interviews demonstrated a need for a surgical option for treating idiopathic epilepsy among Ugandans with medication refractory epilepsy. Investigative modalities such as EEG, CT, and MRI are locally accessible for preliminary evaluation of surgical candidacy. A future pilot program could serve as a platform for training personnel to sustain an epilepsy surgery program at MNRH, and patients and caregivers would subscribe to surgical treatment if a local program is affordable and has a low complication rate.
Item Embargo A Prospective Observational Study of Inpatient Myocardial Infarction Care in Northern Tanzania(2024) Gedion, KalipaBackground: The uptake of evidence-based secondary preventative therapy among patients with myocardial infarction (MI) patients is low in northern Tanzania, and short-term mortality is high. The aim of this study was to describe current patterns of inpatient and discharge care among hospitalized patients with MI to identify opportunities for improvement.
Methods: Adult patients (18 years old) participants with acute MI were consecutively enrolled in the emergency department of a tertiary care hospital in Moshi, Tanzania, from February 2022 through January 2023. A standardized questionnaire collecing demographic and health data was administered to participants at enrollment. During hospitalization, research assistants administered a standardized questionnaire to participants on a daily basis to collect information about symptom progression and counselling received. Information about inpatient testing and treatment were obtained directly from electronic medical records. At time of discharge, a discharge survey was administered to participants to collect information about discharge counseling and post-discharge plans for appointments and medications. Discharge prescriptions were collected directly from the medical record. Thirty days after enrollment, a follow-up survey was administered via telephone to participants to assess symptom status, medication use, and appointment attendance.
Results: Of the 73 participants with MI, 21 (29%) died during their initial hospitalization. During the hospital stay: 39 (53%) participants received aspirin, 29 (40%) received clopidogrel, 28 (38%) received dual antiplatelet therapy, 25 (34%) received a beta-blocker, and 36 (49%) received a statin. Fourty-three (59%) participants reported being informed of their diagnosis during their hospitalization, and 21 (29%) reported receiving dietary counselling. Of 9 participants who reported ongoing tobacco use, 2 (22%) reported receiving smoking cessation counseling. Of the 52 participants who survived to hospital discharge, 36 (69%) were given a follow-up appointment, 18 (35%) were prescribed aspirin, 23 (44%) were prescribed clopidogrel, 14 (27%) were prescribed dual antiplatelet therapy, 15 (29%) were prescribed a beta-blocker, and 21 (40%) were prescribed a statin. Four (5%) participants died between discharge and follow-up, resulting in an overall thirty-day mortality rate of 34%. Of the 48 participants surviving to 30 days, 14 (29%) were rehospitalized, 35 (73%) reported ongoing chest pain or dyspnea, 2 (4%) reported taking aspirin, and 4 (8%) reported taking clopidogrel.
Conclusions: There are multiple opportunities to improve uptake of evidence-based MI care during the inpatient and discharge phases of care. Further study is needed to address barriers to enhance the quality of MI care and reduce MI-associated mortality.
Item Open Access A Systems Thinking, Community-Based Exploration of Health Equity and Agency: Women’s Migraine as a Paradigmatic Case(2017) Befus, DeannaBackground. Creating health equity—“the attainment of the highest level of health for all people”— is a core tenet of public health (American Public Health Association, 2015; United States Department of Health and Human Services, 2011, p. 1). Achieving health equity requires the identification and amelioration of patterns of systemic disadvantage and the elimination of health disparities (Gostin & Powers, 2006; United States Department of Health and Human Services, 2011). To do this, health researchers must address social determinants of health (SDOH) and of equity. I have selected women with migraine as a paradigmatic case for this exploration of health equity and agency.
Migraine is a common and debilitating neurobiological disorder without a cure (Goadsby, 2012). It affects almost three times as many women as men, and disproportionately disables women occupying low social locations, that is, occupying a low position on the social hierarchy (Burch, Loder, Loder, & Smitherman, 2015b; Stewart, Roy, & Lipton, 2013). A dearth of effective and affordable treatment options has rendered non-pharmacological self-management a crucial part of living with migraine, yet clinical treatment guidelines consistently emphasize pharmacological intervention (Becker et al., 2015; Diamond et al., 2007; Raphael, 2012). Much of migraine research is epidemiological (Burch et al., 2015b; Buse et al., 2013; Lipton, Serrano, Holland, et al., 2013). The resulting gap in knowledge around the experiences and needs of women navigating the complexities of life with migraine is especially pronounced for those who are less likely or able to access systems that document and treat the condition.
Objective and Methods. The overall purpose of this dissertation is to develop knowledge on the effects of social and structural determinants on the experiences of women living with migraine, with attention to their strategies and priorities for self-management through a systems thinking lens. To do this in the context of this dissertation, I first explore the benefits of critical systems approaches for health equity research (Chapter 2), followed by a description of the development and use of two systems thinking tools for data collection in community focus groups of women with migraine (Chapter 3). Our study team used the system support map tool (SSM) to identify and describe migraine triggers and features, self-management strategies, and the needs and outcomes associated with self-management (Chapter 4). The connection circle (CC) tool explored the relationships between triggers and features, self-management strategies, and outcomes (Chapter 5).
We conducted seven focus groups with 19 women with migraine from diverse social locations and analyzed the data using qualitative content analysis, dimensional analysis, and measures of complexity. We examined variation by social location in the data from both tools.
Findings. The tools we developed allowed us to feasibly and effectively collect rich and nuanced data from community-based women with migraine. One of the tools—the CC— may be more effective when coupled with problem solving techniques when used with women in low social locations (Chapter 3).
The SSM data underscored the distinctions in migraine experience by social location (Chapter 4). While women from all social locations identified stress as a top migraine trigger, descriptions and definitions of stress varied. Women in low social locations were more likely to engage in isolating and avoidant self-management activities, and women in higher social locations were more likely to use proactive, complementary, and integrative approaches. Women in low social locations had lower expectations for self-management and were more interested in pain management than women in higher social locations, who were more interested in self-improvement.
The CC data revealed that ‘conceptualization of complexity,’ or the way and degree to which participants contemplated dynamic interrelationships, was a key dimension in understanding how women in diverse social locations identified relationships between different aspects of their migraine experiences. There were clear differences in the conceptualizations of and capacities for complexity by social location. Women in high social locations demonstrated greater depth, breadth, and structure of this key dimension than women in low social locations.
Discussion and Conclusions. As a non-fatal, but highly disabling, condition with limited and costly treatment options, migraine provides an excellent paradigmatic case for exploring health equity. Ability to have a high quality of life with migraine may be deeply entwined with one’s social location. Therefore, to improve the experiences of the group most affected by migraine—women in low social locations—we cannot limit our research and treatment to the biological and behavioral. We need to think in terms of the social and structural. Creating equitable outcomes, wherein everyone has an equal opportunity for a fulfilling and healthy life, requires that we intervene on multiple levels, engage with affected women, and explicitly commit to addressing social and structural determinants of health AND equity.
Item Unknown Advanced Applications of 3D Dosimetry and 3D Printing in Radiation Therapy(2016) Miles, DevinAs complex radiotherapy techniques become more readily-practiced, comprehensive 3D dosimetry is a growing necessity for advanced quality assurance. However, clinical implementation has been impeded by a wide variety of factors, including the expense of dedicated optical dosimeter readout tools, high operational costs, and the overall difficulty of use. To address these issues, a novel dry-tank optical CT scanner was designed for PRESAGE 3D dosimeter readout, relying on 3D printed components and omitting costly parts from preceding optical scanners. This work details the design, prototyping, and basic commissioning of the Duke Integrated-lens Optical Scanner (DIOS).
The convex scanning geometry was designed in ScanSim, an in-house Monte Carlo optical ray-tracing simulation. ScanSim parameters were used to build a 3D rendering of a convex ‘solid tank’ for optical-CT, which is capable of collimating a point light source into telecentric geometry without significant quantities of refractive-index matched fluid. The model was 3D printed, processed, and converted into a negative mold via rubber casting to produce a transparent polyurethane scanning tank. The DIOS was assembled with the solid tank, a 3W red LED light source, a computer-controlled rotation stage, and a 12-bit CCD camera. Initial optical phantom studies show negligible spatial inaccuracies in 2D projection images and 3D tomographic reconstructions. A PRESAGE 3D dose measurement for a 4-field box treatment plan from Eclipse shows 95% of voxels passing gamma analysis at 3%/3mm criteria. Gamma analysis between tomographic images of the same dosimeter in the DIOS and DLOS systems show 93.1% agreement at 5%/1mm criteria. From this initial study, the DIOS has demonstrated promise as an economically-viable optical-CT scanner. However, further improvements will be necessary to fully develop this system into an accurate and reliable tool for advanced QA.
Pre-clinical animal studies are used as a conventional means of translational research, as a midpoint between in-vitro cell studies and clinical implementation. However, modern small animal radiotherapy platforms are primitive in comparison with conventional linear accelerators. This work also investigates a series of 3D printed tools to expand the treatment capabilities of the X-RAD 225Cx orthovoltage irradiator, and applies them to a feasibility study of hippocampal avoidance in rodent whole-brain radiotherapy.
As an alternative material to lead, a novel 3D-printable tungsten-composite ABS plastic, GMASS, was tested to create precisely-shaped blocks. Film studies show virtually all primary radiation at 225 kVp can be attenuated by GMASS blocks of 0.5cm thickness. A state-of-the-art software, BlockGen, was used to create custom hippocampus-shaped blocks from medical image data, for any possible axial treatment field arrangement. A custom 3D printed bite block was developed to immobilize and position a supine rat for optimal hippocampal conformity. An immobilized rat CT with digitally-inserted blocks was imported into the SmART-Plan Monte-Carlo simulation software to determine the optimal beam arrangement. Protocols with 4 and 7 equally-spaced fields were considered as viable treatment options, featuring improved hippocampal conformity and whole-brain coverage when compared to prior lateral-opposed protocols. Custom rodent-morphic PRESAGE dosimeters were developed to accurately reflect these treatment scenarios, and a 3D dosimetry study was performed to confirm the SmART-Plan simulations. Measured doses indicate significant hippocampal sparing and moderate whole-brain coverage.
Item Open Access Aerobic Training-Induced Host Changes Alter Breast Cancer Cell Phenotypes and Tumor Progression(2015) Glass, OliverA growing number of studies have investigated the role of exercise both during and after a breast cancer diagnosis. Observational data suggests that regular endurance exercise is associated with a 20-50% reduction in cancer-specific mortality in women diagnosed with early stage breast cancer, compared to inactive women; however it is unclear whether there is a differential association across breast cancer subtypes. As a pre-requisite to guide future large phase II/III clinical trials, there is a critical need to confirm the biological plausibility of the exercise association in breast cancer patients as well as elucidate the underlying mechanisms of action via utilization of preclinical models.
In the present study we investigated the systemic effects of prescribed aerobic training in cancer patients and the direct impact on breast cancer cell subtype phenotypes. In order to test the in vivo significance, we interrogated aerobic training effects on breast cancer progression and tumor biology using syngeneic breast cancer mouse models.
Our results suggest that aerobic training may alter the host availability of pro-inflammatory and growth factor cytokines in patients with solid tumors. Modulation of systemic effectors in breast cancer patients compared to controls causes a differential phenotypic response on breast cancer cell subtypes. In vivo, aerobic training has a differential response on breast tumor progression compared to controls that is mediated by Hif1-α and metabolic reprogramming of breast cancer cells.
Item Open Access An Agonist CD27 Antibody for Brain Tumor Immunotherapy(2017) Riccione, KatherineGlioblastoma (GBM) is a uniformly lethal cancer with an overall survival of less than 15 months. Aggressive standard of care therapies fail to eradicate these tumors and are non-specific, resulting in incapacitating toxicities. In contrast to such therapies, by virtue of exploiting the inherent specificity and vigilance of the immune system, immunotherapy provides an exquisitely precise approach for safe and effective tumor treatment. Specifically, peptide vaccines offer a promising strategy for inducing potent cytotoxic glioma-specific immune responses. However, they are limited by various mechanisms of glioma-mediated immunosuppression, including low/dysfunctional antigen-presentation, an increased fraction of regulatory T cells, T cell inhibitory pathways, and cytokine dysregulation. Such challenges can be overcome by the combined use of immunomodulatory adjuvants to improve the setting in which T cells recognize and respond to glioma antigens. To this end, a clinically-relevant high-affinity human anti-human CD27 immunomodulatory antibody (αhCD27) that induces potent antitumor T cell responses through engagement of the CD27 T cell costimulatory pathway was recently developed. This antibody is efficacious as a monotherapy in preclinical tumor models and has given rise to significant clinical responses in early phase trials. Given the preliminary success of monotherapy αhCD27 in inducing endogenous antitumor immunity, the overall goal of this dissertation research was to develop a peptide vaccine platform that employs αhCD27 as a vaccine adjuvant for its translation as a novel brain tumor immunotherapeutic.
Chapter 1 provides an overview of brain tumor immunotherapy, including the evolution of the field to date, various genres of treatment modalities, and ongoing progress and challenges. Chapter 2 discusses the approach of T cell immunomodulation, an emerging field in cancer treatment, including the clinical development of various FDA-approved antibodies and their relevance to brain tumors, synergy with current brain tumor standard of care, and emerging immunomodulatory targets. Chapter 3 provides the rationale for targeting the CD27 costimulatory molecule in particular and includes preliminary data that serves as the basis for the preclinical development of αhCD27 as an immunotherapy for brain tumors. Chapter 4 shows the systematic approach for optimizing αhCD27 as a vaccine adjuvant in a murine model of intracranial melanoma alongside a vaccine targeting a model tumor antigen. Lastly, Chapter 5 explores the use of αhCD27 to combat tumor-mediated immunosuppression, an important aspect of its adjuvant activity and the basis for two upcoming phase I clinical trials for malignant glioma.
This dissertation comprises original research as well as figures and illustrations from previously published material used to exemplify distinct concepts in immunotherapy for cancer. These published examples were reproduced with permission in accordance with journal and publisher policies described in the Appendix.
In summary, this work 1) identifies costimulatory T cell immunomodulation as a promising strategy for brain tumor immunotherapy, 2) explores and optimizes the potential for an agonist CD27 to enhance the tumor immune response when combined with a vaccine, 3) has opened up a new line of investigation into the role of CD27 in tumor-mediated immunosuppression, and 4) provides future prospects of utilizing an agonist CD27 antibody as a vaccine adjuvant for the treatment of brain tumors. Together, these studies hold great promise to improve the clinical outlook for brain tumor patients.
Item Open Access An Aperture-Preserved Approach to Adaptive Radiotherapy of Prostate Cancer Using IMRT and VMAT(2018) Pappafotis, RyanOver the course of a patient’s radiotherapy treatment, there are often changes of internal anatomy relative to the planning CT scan. Because patients are typically treated with a treatment plan created based on one planning CT, dose is likely deposited in healthy tissue locations not targeted by the initial treatment plan, thus leading to less dose given in the target region. To combat this problem, adaptive radiation therapy (ART) was introduced where a new treatment plan is created based on the anatomy of the patient imaged on the treatment day. However, ART often cannot be feasibly routinely applied due to the involved time-intensive workflow required for implementation. For patients treated with VMAT and IMRT, part of this workflow is delivery quality assurance (QA) to verify the accuracy of radiation fields. This study introduces a new approach to remove the need for delivery QA for adapted plans in an attempt to shorten the ART clinical workflow. The implemented approach is a partial re-optimization of the initial plan maintaining the segment shapes from the original plan and minimum monitor unit (MU) constraints. Dose will be delivered through aperture shapes that have already passed QA protocol before the patient’s initial treatment, eliminating the DQA step from the ART workflow.
CT images from 20 prostate cancer patients were retrospectively chosen for this study. Each of these patients had 5 CT-on-rails (CTOR) images taken, one from each week of their treatment, in addition to their original planning CT. Partially re-optimized VMAT and IMRT plans were created for all 100 images and compared to dosimetry directly calculated onto the treatment CT from the original plan. Goals for treatment adaption included regaining coverage lost on the treatment day CT as well as sparing organs at risk. Dosimetric benefits of this adaption method could be seen in many treatment plans.
Successful ART plans, with significant change of anatomy between initial plan and ART plans, were delivered and measured on treatment machine. They show similar DQA quality as original plans, demonstrating that partial re-optimization can be performed and delivered to a patient without the need for delivery QA. With the shortened workflow of this technique, adaptive therapy may become a viable option for patients that typically may not qualify for a full adapted plan.
Item Open Access An Investigation in Quantitative Accuracy in Preablation I-131 Scans: 7-pinhole system compared with single-pinhole system.(2018) Yu, TingtingPurpose: Early detection and prevention of differentiated thyroid cancer using thyroidectomy and ablation therapy can reduce disease persistence and recurrence. A preablation I-131 scan performed between the thyroidectomy and ablation therapy may improve patient management. Although I-123 would involve less radiation dose, I-131 is widely available, and its long half-life enables imaging 24-72 hours after injection, which is crucial for dosimetry and which enhances visibility of distant metastasis. Typically, 2-10 mCi I-131 is administered. To avoid stunning effects, 2 mCi is suggested. However, with 2 mCi, images are noisy. Compared with standard single pinhole SPECT systems, 7-pinhole systems may provide greater geometric efficiency when using smaller pinhole diameter and thereby reduce noise. Due to the size of 7-pinhole systems, collision constraints may, however, increase the pinhole radius of rotation (ROR), thereby reducing efficiency. Herein we assess the competing effects of more pinholes and larger ROR to determine whether 7 pinholes could meaningfully improve efficiency, at a comparable or better spatial resolution.
Methods: Radiotracer distributions and attenuation were computer simulated using modified XCAT phantom. Single-pinhole and 7-pinhole trajectories were developed to provide minimal RORs while avoiding collision with the patient. Reconstructed images were computer simulated, modeling attenuation, spatial resolution, and Poisson noise. Single-pinhole and 7-pinhole were compared for a range of lesion sizes and activity concentrations. Comparison metrics included lesion conspicuity, uniformity, and contrast; and image quality in terms of noise, contrast recovery and RMSE. Gamma camera sensitivity and spatial resolution were also assessed.
Results: In this study, seven-pinhole configurations were compared to a clinically typical single-pinhole system. In the low-count study, it was found that the seven-pinhole system with 4-5 mm pinhole diameter could outperform the benchmark single-pinhole system. In the high-count study, it was found that seven-pinhole system with 3 mm pinhole diameter could outperform the benchmark single-pinhole system. However, ROR increases are great enough to substantially decrease the benefit of seven pinholes, for the pinhole configuration considered here.
Conclusion: Seven pinhole maybe suitable for preablation scan because high sensitivity allows better detect the lesion with low activity concentration and smaller pinhole diameter allows better resolve the metastasis.
Item Embargo Antibacterial Utilization for Febrile Illnesses and Laboratory-confirmed Bloodstream Infections in Northern Tanzania(2023) Moorthy, Ganga S.Antibacterial management of febrile patients in low-resource settings is challenging and adherence to treatment guidelines is variable. We describe antibacterial use in febrile patients, use of effective therapy for laboratory-confirmed bloodstream infections, and adherence to published guidelines for common febrile illnesses among patients enrolled in prospective hospital-based fever surveillance studies in Moshi, Tanzania.
We compared data from two hospital-based prospective cohort studies, Cohort 1 (2011–2014) and Cohort 2 (2016–2019), that enrolled febrile infants, children, and adults. A study team member administered a standardized questionnaire, performed a physical examination, and collected blood cultures on all participants. Ceftriaxone, ciprofloxacin, amoxicillin-clavulanate, or azithromycin were categorized as broad-spectrum antibacterials based on published frameworks and local antimicrobial availability. Participants with laboratory-confirmed bloodstream infections were categorized as receiving effective or ineffective antibacterials based on culture and susceptibility data. Antimicrobials prescribed for preliminary or final diagnosis of pneumonia, urinary tract infection, or presumed sepsis were compared with syndrome-specific recommendations from the World Health Organization (WHO) and the Tanzania Standard Treatment Guidelines. We used descriptive statistics and logistic regression to describe factors associated with antibacterial use.
We analyzed data from 2175 participants. The median age of participants in Cohort 1 was 29 (IQR: 5-41) and 22 in Cohort 2 (IQR: 2-45). Among all participants, 50% were female. There were 430 (42.0%) and 501 (45.1%) participants who reported use of antibacterials prior to admission in Cohort 1 and Cohort 2, respectively. There were 989 (91.4%) participants who received antibacterials during admission for febrile illness in Cohort 1 versus 1060 (93.6%) in Cohort 2 (p < 0.001); 548 (52.5%) in Cohort 1 and 682 (60.2%) in Cohort 2 (p < 0.001) received broad-spectrum therapy. Inpatient use of ceftriaxone, metronidazole, and ampicillin increased between the two cohorts (ceftriaxone p = < 0.001; metronidazole p = 0.02; ampicillin p = < 0.001). Laboratory-confirmed bacteremia was found in 38 (3.6%) participants in Cohort 1 and 47 (4.2%) participants in Cohort 2. Complete data to determine appropriateness of antibacterial prescription were available for 81 (95.3%) of 85 participants and 52 (63.0%) participants were prescribed effective therapy. Guideline-consistent therapy for pneumonia, urinary tract infection, and sepsis increased over time.
Receipt of antibacterials prior to and after hospital admission were high and use of broad-spectrum medications was common. A large proportion of participants with culture-confirmed bloodstream infections were treated with ineffective antibacterials but consistency of antibacterial prescribing with WHO and Tanzanian treatment guidelines improved over time. Our results highlight the need for improved diagnostics for febrile illness, data on local antimicrobial resistance patterns, institution-specific clinical guidelines, and provider education to improve prescribing practices and rational use of antimicrobials in Tanzania.
Item Open Access Antibody-Redirected T-Cell Immunotherapy for Brain Tumors(2014) Choi, Bryan DaehahnThe most common primary malignant brain tumor, glioblastoma, is uniformly fatal. Current therapy provides only incremental benefits in survival and is often incapacitating owing to limits defined by nonspecific toxicity. By contrast, immunotherapy offers a particularly promising approach, and has the theoretical potential to target and eliminate malignant cells with unprecedented specificity. The goal of this dissertation is to apply recombinant technologies to develop a new immune-based therapy for patients with malignant glioma. This work will span the design, production, and preclinical testing of a novel bispecific antibody designed to redirect T cells against a tumor-specific mutant of the epidermal growth factor receptor, EGFRvIII.
Chapters 1 and 2 will provide an overview of broad topics in antitumor immunotherapy and immune biology, with special focus on concepts as they relate to tumors of the central nervous system. In addition, the history and current state of bispecific antibodies, particularly those of the bispecific T-cell engager (BiTE) subclass, as well as their potential role in the treatment of malignant disease, will be considered in detail. Data presented in Chapter 3 will describe our approach to generating novel bispecific tandem single-chain antibody reagents, while experiments in Chapter 4 will demonstrate the capacity of one of these molecules, an EGFRvIII-specific BiTE, to achieve antitumor efficacy both in vitro and in vivo using murine models of glioma. Addressing a major barrier to the translation of immune therapies for cancer, chapter 5 will establish a potential role for BiTEs in overcoming cell-mediated immune suppression associated with malignant disease. Lastly, Chapter 6 and 7 will report on emerging areas of study, including the use of syngeneic, transgenic murine systems, and strategies by which BiTEs may be propelled rapidly into early phase clinical trials.
In summary, separating BiTEs from other available immunotherapeutic approaches, our work in this field suggests that BiTEs are (1) highly-specific molecules that greatly reduce the risk of toxicity, (2) have the ability to penetrate the blood-brain barrier and accumulate in intracerebral tumors, and (3) may potentially overcome multiple mechanisms of immunosuppression present in patients with glioblastoma. Together, these studies have the potential to improve the clinical management of patients with glioblastoma through the generation of a novel therapeutic.
Item Open Access Application of TG-218 to SRS and SBRT Pre-Treatment Patient Specific QA(2020) Xia, YuqingAbstract
Purpose: Updated recommendations for pre-treatment QA of patient-specific intensity modulated radiation therapy (IMRT) and Volumetric modulated arc therapy (VMAT) quality assurance (QA) were recently published by the AAPM task group TG-218. While the traditionally most common QA analysis is to use a Gamma index with dose & spatial analysis criteria of 3% & 3mm, respectively, TG-218 recommends a tighter spatial tolerance of 2mm for standard IMRT QA, and that even tighter tolerances should be considered for stereotactic radiosurgery (SRS) and stereotactic body radiotherapy (SBRT). Our purpose is to report our experience with applying the TG-218 recommendations to a large clinical SRS and SBRT program. In addition, a new SRS technique was recently developed at Duke, called Conformal Arc Informed Volumetric Modulated Arc Therapy (CAVMAT), which is designed to be less sensitive to configuration and delivery errors. We measured the agreement of CAVMAT for pre-treatment QA and compared it to the current standard (VMAT) to evaluate whether CAVMAT is more robust to delivery errors than VMAT.
Methods: We re-analyzed the pre-treatment QA with respect to the TG-218 recommendations. For Portal Dosimetry (Varian Medical Systems, Palo Alto, CA), this included IMRT brain (n=25) and SBRT / hypofractionated image guided radiotherapy (HIGRT) cases that utilize flattened photon beams (n=18). For Delta4 (ScandiDos, Madison, WI) this included single target SRS (n=24), multiple target SRS (n=25), SBRT cases using VMAT (n=74), and SBRT cases using IMRT with FFF photons (n=23). For ArcCHECK (Sun Nuclear, Melbourne, FL)), we take 25 single target VMAT SRS cases and 25 multiple target VMAT SRS cases. For SRS MapCHECK(Sun Nuclear, Melboume, FL), we analyze 10 multiple target VMAT SRS cases with 16 targets. A Gamma analysis was performed with 6 spatial/dose criteria combinations: 3%/3mm, 3%/2mm, 3%/1mm, 2%/1mm, 4%/1mm, 5%/1mm. We then calculated the TG-218 action limit and tolerance limit per plan type and compared to the “universal” TG-218 action limit of 90% having a Gamma <1.
To compare CAVMAT and VMAT, log file analysis and pre-treatment QA was performed for 10 patients with 20 plans (10 VMAT, 10 CAVMAT) with 46 targets in total. 10 VMAT plans were re-planned using CAVMAT, and the dosimetric effect due to treatment delivery errors was quantified for V6Gy, V12Gy, and V16Gy of healthy brain along with the maximum, average and minimum doses of each target. Gamma analysis of VMAT and CAVMAT plans was performed using Delta4 and SRS MapCHECK with 3% / 1mm, 2% / 1mm, 1% / 1mm criteria to assess the agreement during patient specific quality assurance.
Result: For Portal Dosimetry QA of IMRT brain and SBRT/HIGRT using a 3%/1mm criteria, the TG-218 action limit was 99.68, and 90.14, respectively; with 3.68% and 3.68% of cases failing the universal 90% criteria. For Delta4 QA of single target SRS, multiple target SRS, and SBRT IMRT with FFF using a 3%/1mm criteria, the TG-218 action limit was 93.64, 97.12, and 92.01, respectively; with 0%, 0%, and 0% of cases failing the universal 90% criteria. For Delta4 QA of SBRT VMAT using a 4%/1mm criteria, the TG-218 action limit was 94.47, with 100% passing. For ArcCHECK QA of single target and multiple target SRS VMAT using a 3%/2mm criteria, the TG-218 action limit was 98.06 and 96.59 respectively, with 100% passing. For SRS MapCHECK QA of multiple target SRS VMAT cases using 3%1mm criteria, the TG-218 action limit was 99.24 with 100% passing.
The average increase in V6Gy, V12Gy, V16Gy due to treatment delivery errors as quantified using the trajectory logfile was 0.94 ± 1.43, 0.90 ± 1.38%, and 1.23 ± 1.54% respectively for VMAT, and 0.035 ± 0.14%, 0.14 ± 0.18%, and 0.28 ± 0.24% for CAVMAT. The average change to target maximum, average, and minimum dose due to delivery errors was 0.53 ± 0.46%, 0.52 ± 0.46%, and 0.53 ± 0.56%, for VMAT, and 0.16 0.18%, 0.11 0.08%, and 0.03 0.24% for CAVMAT. There was no significant difference in magnitude of MLC discrepancies during delivery for VMAT and CAVMAT. For Gamma analysis with strict 1% / 1mm criteria, the average passing rate of VMAT gamma analysis is 94.53 ± 4.42%, while that of CAVMAT is 99.28 ± 1.74%.
Conclusion: For most QA devices, spatial tolerance of pre-treatment QA for SRS/SBRT can be tightened to 1mm while still maintaining an in-control QA process. The gamma criteria to 3%/1mm for all SRS cases and SBRT with IMRT and transitioning to a 4%1mm criteria for SBRT with VMAT have a spatial tolerance that is appropriate for the radiotherapy technique while not resulting in an excessive false positive failure rate. The CAVMAT treatment planning technique resulted in superior gamma analysis passing rate for each gamma analysis criteria.
Item Open Access Assessment of Current Cervical Cancer Screening Practice and Responses to a Novel Screening Device, Transvaginal Digital Colposcopy, Among Gynecologists in Hyderabad, India(2015) Gorthala, SisiraBackground: India has the highest burden of cervical cancer mortality, globally, with 67,477 deaths in 2012. A novel device, the transvaginal digital colposcope (TVDC), or a small handheld colposcope, could potentially improve quality of care and address barriers to cervical cancer screening, by reducing patient discomfort and aiding practitioners in screening. Studies which validate India-WHO guidelines for cervical cancer screening report wide ranges of sensitivity and specificity for techniques currently used in low-resource settings, all of which are contingent on numerous factors from patient awareness to receptivity to user training, suggesting that the context is paramount to improving cervical cancer detection. To that end, assessment of the healthcare and physician environment in terms of practice and reaction to the new device is essential prior to device implementation in order to anticipate benefits or negative consequences of device use.
Methods: A survey was developed to explore experiences, practice, and approaches to cervical cancer screening based on a new technology, and administered to 15 gynecologists in various clinical settings in Hyderabad, India. First, participants answered questions about past and current practices for cervical cancer screening, diagnosis, and treatment procedures. Next, physicians assessed images from a clinical trial involving imaging of cervix by the TVDC and with standard colposcopy. To check physician interpretation of images from the clinical trial, biopsy or histologic confirmation was used for positive results, while colposcopy was used as the reference standard for negative results.
Results: Colposcopy and magnification for visualization of the cervix were preferred by all physicians, in spite of low frequency of in-house use or referrals for the procedure. Accuracy among physicians interpreting TVDC images ranged from 25%-100%, while accuracy with colposcopy images ranged from 38%-100%. Sensitivity for TVDC images and corresponding colposcopy images was 72% and 91% respectively, while specificity was 54% and 38% respectively. Physicians were more likely to report suspicion for cancer in positive cases with a false negative rate with TVDC images and corresponding colposcopy images at 19% and 0%. Images with the new device were either considered comparable to or were preferred to colposcopy images, but disagreement in interpretation between TVDC and colposcopy for the same patient ranged from 13%-63%.
Conclusion: This study shows how observation-based cervical cancer screening or diagnostic techniques, without preceding, adjunct screening or diagnostic tests, may have low specificity in disease detection. However, a new technology TVDC may be appropriate for this type of setting. Further research into patient attitudes, physician motivation, physician experience with colposcopy and clinical decision-making is required prior to implementation if gains in reduction of cervical cancer incidence and deaths are to be realized.
Item Open Access Assessment of Two Diabetes Point-of-Care Analyzers Measuring Hemoglobin A1c in the Peruvian Amazon(2016) Saxton, Anthony TylerAims: Measurement of glycated hemoglobin (HbA1c) is an important indicator of glucose control over time. Point-of-care (POC) devices allow for rapid and convenient measurement of HbA1c, greatly facilitating diabetes care. We assessed two POC analyzers in the Peruvian Amazon where laboratory-based HbA1c testing is not available.
Methods: Venous blood samples were collected from 203 individuals from six different Amazonian communities with a wide range of HbA1c, 4.4-9.0% (25-75 mmol/mol). The results of the Afinion AS100 and the DCA Vantage POC analyzers were compared to a central laboratory using the Premier Hb9210 high-performance liquid chromatography (HPLC) method. Imprecision was assessed by performing 14 successive tests of a single blood sample.
Results: The correlation coefficient r for POC and HPLC results was 0.92 for the Afinion and 0.93 for the DCA Vantage. The Afinion generated higher HbA1c results than the HPLC (mean difference = +0.56% [+6 mmol/mol]; p < 0.001), as did the DCA Vantage (mean difference = +0.32% [4 mmol/mol]). The bias observed between POC and HPLC did not vary by HbA1c level for the DCA Vantage (p = 0.190), but it did for the Afinion (p < 0.001). Imprecision results were: CV = 1.75% for the Afinion, CV = 4.01% for the DCA Vantage. Sensitivity was 100% for both devices, specificity was 48.3% for the Afinion and 85.1% for the DCA Vantage, positive predictive value (PPV) was 14.4% for the Afinion and 34.9% for the DCA Vantage, and negative predictive value (NPV) for both devices was 100%. The area under the receiver operating characteristic (ROC) curve was 0.966 for the Afinion and 0.982 for the DCA Vantage. Agreement between HPLC and POC in classifying diabetes and prediabetes status was slight for the Afinion (Kappa = 0.12) and significantly different (McNemar’s statistic = 89; p < 0.001), and moderate for the DCA Vantage (Kappa = 0.45) and significantly different (McNemar’s statistic = 28; p < 0.001).
Conclusions: Despite significant variation of HbA1c results between the Afinion and DCA Vantage analyzers compared to HPLC, we conclude that both analyzers should be considered in health clinics in the Peruvian Amazon for therapeutic adjustments if healthcare workers are aware of the differences relative to testing in a clinical laboratory. However, imprecision and bias were not low enough to recommend either device for screening purposes, and the local prevalence of anemia and malaria may interfere with diagnostic determinations for a substantial portion of the population.
Item Open Access Attending To Race: Exploring How Faculty, Trainees And Medical Students Operationalize Race In Medicine(2022) Narayanasamy, ShantiBackground. Race-based medicine assumes that genetic or biological differences account for the observed health differences among races. Race-based medicine has been shown to result in poor patient outcomes. Nevertheless, this practice continues due to a lack of clarity about the role of race in clinical medicine and research. This study aims to describe the use of race in medicine among physicians and medical students.Methods. This study employed a mixed methods design consisting of 1) a quantitative online survey, and 2) qualitative semi-structured interviews. The study population were medical students, residents, fellows and clinical faculty (M.D, D.O, Ph.D) from a large academic medical center in the southern U.S. A novel survey instrument was developed for this study, to cover the key domains we studied. Results. Of the 1,372 total survey responses, the final sample consisted of 1,016 completed responses (536 faculty, 267 trainees, and 213 students). 91.5% of students, 84.3% of trainees, and 83% of faculty believe the best measure of race is self-report. Students were less likely to use race as a proxy for these variables compared to faculty and trainees. Conclusions. In this exploratory study we found that there are significant differences between students, and faculty/trainees in the use of race in medicine.
Item Open Access Barriers and Facilitators to Emergency Care: Acute Injury in the Kilimanjaro Region(2023) Frankiewicz, Parker LBackground: Trauma and injury present a significant global burden – one that is only exacerbated in low- and middle-income settings like Tanzania. We aimed to describe the landscape of emergency care and financial catastrophe in the Kilimanjaro region by leveraging the Three Delays Model.
Methods: This was a cross-sectional study using an ongoing traumatic injury registry as well as separate financial questionnaires collected by researchers from the Duke Global Health Institute at Duke University in collaboration with the Kilimanjaro Christian Medical Centre (KCMC) in Moshi, Tanzania from December 2022 until February 2023.
Results: The majority of the acute injury population that presented to the KCMC emergency department underwent some form of financial catastrophe due to the out-of-pocket (OOP) costs incurred due to their medical needs (catastrophic health expenditure (CHE): 66.1%; impoverishment: 85.5%). The households of those who experienced a financial catastrophe tended to include a greater number of dependents (CHE, 22% and impoverishment, 21% with ≥6 dependents) and a lower average monthly adult-equivalent income (CHE: 76,923 TZS; impoverishment: 96,774 TZS). Individuals who underwent a financial catastrophe also experienced a greater number of facility transfers as well as more transfers with later surgery. At the end of an individual’s hospital stay, those who experienced financial catastrophe incurred substantially more medical expenses. Those who experienced a CHE had OOP costs that were 3.4 times higher than those without; those who were impoverished had OOP costs that were 1.96 times higher than those who did not.
Conclusions: Delay 1 (decision to seek care) and Delay 2 (reaching appropriate care facility) could be significant factors for those who will later experience some form of financial catastrophe. Further research is needed to better assess potential impacts on patient health outcomes and develop targeted intervention strategies for those most at-risk.
Item Open Access Barriers to Implementing Antimicrobial Stewardship Programs in Three Low- and Middle-income Country Tertiary Care Settings: Findings from a Multi-site Qualitative Study(2021) Rolfe, Jr, Robert JosephBackground: Antimicrobial resistance has been named as one of the top ten threats to public health in the world. Hospital-based antimicrobial stewardship programs (ASPs) can help reduce antimicrobial resistance. The purpose of this study was to determine perceived barriers to the development and implementation of ASPs in tertiary care centers in three low- and middle-income countries (LMICs). Methods: Interviews were conducted with 45 physicians at tertiary care hospitals in Sri Lanka (n=22), Kenya (12), and Tanzania (11). Interviews assessed knowledge of antimicrobial resistance and ASPs, current antimicrobial prescribing practices, access to diagnostics that inform antimicrobial use, receptiveness to ASPs, and perceived barriers to implementing ASPs. Two independent reviewers coded the interviews using principles of applied thematic analysis, and comparisons of themes were made across the three sites. Results: Barriers to improving antimicrobial prescribing included prohibitively expensive antimicrobials, limited antimicrobial availability, resistance to changing current practices regarding antimicrobial prescribing, and limited diagnostic capabilities. The most frequent of these barriers in all three locations was limited drug availability. Many physicians in all three sites had not heard of ASPs before the interviews. Improved education was a suggested component of ASPs at all three sites. The creation of guidelines was also recommended, without prompting, by interviewees at all three sites. Although most participants felt microbiological results were helpful in tailoring antibiotic courses, some expressed distrust of laboratory culture results. Biomarkers like erythrocyte sedimentation rate and c-reactive protein were not felt to be specific enough to guide antimicrobial therapy. Despite limited or no prior knowledge of ASPs, most interviewees were receptive to implementing protocols that would include documentation and consultation with ASPs regarding antimicrobial prescribing. Conclusions: Our study highlighted several important barriers to implementing ASPs that were shared between three tertiary care centers in LMICs. Improving drug availability, enhancing availability of and trust in microbiologic data, creating local guidelines, and providing education to physicians regarding antimicrobial prescribing are important steps that could be taken by ASPs in these facilities.