Challenges and Opportunities in Toxicology

Challenges and Opportunities in Medical Imaging

Linda Ding, PhD

Shirin Sioshansi, MD

Hesham Malik, MD

Elisa Franquet-Elia, MD

Lacey McIntosh, DO, MPH

Evan Ruppell, DO

Robert Licho, MD

Young Kim, MD

Alan Goldstein, MD

Kriti Mittal, MD

Ming-Jin Wang, MD

Patan Gultawatvichai, MD

Savant Mehta, MD

Kimberly Foley, NP

Sean Wilson, MD

Maryann L Bishop-Jodoin, MEd

Thomas J FitzGerald, MD

Abstract

Yttrium-90 (Y-90) therapy has become an important component to the care of patients with primary hepatic malignancies and lesions that have metastasized to the liver. Therapy is administered through an intra-arterial procedure after an interventional procedure is performed using an albumin labeled product to ensure therapy will be delivered to the target volume of interest with minimal migration from the target of choice. In the past, dose to target has been measured by activity delivered and qualitative deposition of dose on metabolic imaging post application. Imaging tools such as single positron emission computer tomography (SPECT) and digital positron emission tomography have given us insight into quantitative dose to volumetric tumor target and dose to normal tissue. Recent validation of computational software has provided voxel-based dosimetry similar to applied processes established in radiation oncology planning systems. This development presents an opportunity to create dose volume analysis similar to teletherapy and brachytherapy dose delivery for Y-90 therapy. In this case report, we review Y-90 dosimetry on a patient with dual diagnosis of a locally advanced high-risk adenocarcinoma of the prostate which required treatment to the para-aortic lymph nodes located in the same axial plane with renal parenchyma. Although not clinically anticipated, hepatocellular carcinoma was serendipitously discovered at the time of staging for prostate cancer. Treatment dosimetry of the hepatocellular carcinoma is reviewed in retrospect with voxel-based commercial software. Same day SPECT study suggested dose localized to the liver, however voxel planning software confirmed unintentional dose to additional structures including the right kidney and uninvolved liver which influenced radiation therapy treatment planning for prostate carcinoma. With modern available tools, post therapy dosimetry for Y-90 can be performed in a manner similar to volumetric dosimetry used in radiation oncology and provide valuable dose volume analysis of dose delivered to target and additional tissue.

F Yang, MD

G Bowden, MD

S Patel, MD

S Ghosh, PhD

J Yun, PhD

K Aronyk, MD

J Amanie, MD

B Warkentin, PhD

M Larocque, PhD

A Heikal, PhD

LS Rowe, MD

BM Wheatley, MD PhD

A Fairchild, MD

Abstract

Background. Frameless fixation with a thermoplastic mask is an alternative to traditional frame-based immobilization for Gamma-Knife stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (FSRT). However, interruptions during beam-on time can significantly prolong treatment delivery, impacting patient experience and unit workflow.

Aim. We investigated clinical and technical predictors of treatment interruptions, and the phases of treatment during which interruptions are most likely to occur.

Methods. Patients undergoing frameless Gamma Knife SRS or FSRT in 2020 were retrospectively reviewed. Clinical parameters were extracted from electronic medical records. Dosimetric and treatment interruption data were obtained from Gamma Knife treatment reports. Univariate and multivariate analyses analyzed technical and clinical predictors of treatment interruptions.

Results. Our cohort included 84 patients receiving 141 fractions encompassing 255 lesions. 49/84 (58.3%) were female, 79/84 (94.0%) had brain metastases, 49/84 (58.3%) were taking dexamethasone and 30/84 (35.7%) used analgesics. 89/106 (84.0%) courses were single fractions. Mean planned beam-on time was 37.1 minutes (range 7.1-118.8 min) versus a total bed time of 64.9 minutes (range 15-252min) per fraction. 64.5% (91/141) of fractions were interrupted at least once; 12/141 fractions were paused 20 times or more, with a maximum 54 pauses. The mean number of pauses per quartile decreased the further the patient proceeded in beam-on time, and patients receiving first lifetime cranial radiation paused more often than during subsequent fractions. At least one pause occurred in 100% of fractions with a planned beam-on time exceeding 60 minutes. Planned beam-on time, number of gating events and high-definition motion management alarms significantly correlated with total number of pauses on multivariate analysis (all p<0.0001); these three factors, along with prep time and number of operator-initiated pauses, predicted total time on the Gamma Knife couch (all p<0.0001). Clinical factors, medication use, and prior SRS/FSRT were not predictive of pauses.

Conclusions. Planned beam-on time, number of gating events and high-definition motion management alarms significantly predicted likelihood of interruptions during frameless Gamma Knife SRS/FSRT. These factors should be considered in selection of immobilization method, especially if exceeding 60 minutes.

Tianchi Ren, MD

Ilona Lavender, BRADMedImag

Dee Nandurkar, A. Prof., FRANZCR

Steuart Rorke, FRCPA

Ronnie Ptasznik, A. Prof., FRANZCR

Abstract

Objective:To assess efficacy of bedside cytology assessment of thyroid fine needle aspirate samples performed by junior medical staff compared to cytologists.

Methods: Retrospective analysis was performed of 1490 thyroid fine needle aspirates. Samples were divided into three groups: cellular adequacy assessment performed by cytologists, interns, and no onsite adequacy assessment (blind). A 45-minute training session was provided to medical interns with the aim of identifying whether adequate cellular material was demonstrated, as defined by the Bethesda criteria. The primary outcome was the rate of nondiagnostic samples, and the secondary outcome was the number of fine needle aspirate passes required to reach sample adequacy.

Results: The incidence of non-diagnostic samples for the cytologist, blind, and intern groups were 6.90%, 17.1% and 14.0% respectively (p<0.001). There was no statistically significant difference in non-diagnostic rate between the blind and intern groups. Significantly more aspirates required more than two passes in the cytologist group (74.8%) and blind (94.7%) compared to the intern group (58.7%, p<0.001).

Conclusions: On-site adequacy assessment performed by cytopathologists is the gold standard for minimising non-diagnostic thyroid FNAs, however, medical staff with minimal anatomical pathology experience can be trained to perform on-site adequacy assessment and improve outcomes with the implementation of a simple targeted training program.

Richard Grondin

Ofelia M. Littrell

Yi Ai

Peter Huettl

Francois Pomerleau

Jorge E. Quintero

Don M. Gash

Zhiming Zhang

Greg A. Gerhardt

Abstract

Glial cell line-derived neurotrophic factor (GDNF) remains a promising disease modifying therapeutic agent for the dopamine-containing neurons that are affected in Parkinson’s disease and recent clinical findings show renewed promise for its use in patients with Parkinson’s disease. However, translating this approach from research laboratories to the clinic has been met with obstacles, including insufficient brain biodistribution, immunogenicity, and poor stability of unglycosylated wildtype GDNF produced from bacteria. We have previously reported that continuous infusion of a novel glycosylated mammalian variant of GDNF (GDNFv) has increased biodistribution compared to wildtype GDNF along with increased dopamine turnover in the non-human primate brain. Here, we extend these findings by comparing continuous versus pulsatile intrastriatal infusion of GDNFv in intact rhesus macaques. Intermittent, pulsatile delivery paradigms were explored to possibly enhance drug distribution in the brain while decreasing the total amount of drug and infusion volume needed to achieve target activation. Vehicle or GDNFv was directly administered into the putamen via a pump and catheter system using a constant flow rate or using pulsatile profiles of two patterns: pulsatile infusion of 24-hour duration or 48-hour duration. Study endpoints involved comparisons of brain biodistribution, retrograde transport to nigral neurons and dopamine turnover. Each catheter was placed in or near the center of the putamen as confirmed by post-operative magnetic resonance imaging. Our results support that continuous and pulsatile administration of GDNFv was well tolerated in all animals. In addition, pulsatile delivery of GDNFv demonstrated favorable physiological activity of potential therapeutic value with biodistribution, retrograde transport to nigral cells and significant dopamine turnover modulation comparable or better than that achieved with continuous flow delivery. More importantly, the animals administered GDNFv via pulsatile protocols only received half the total drug amount and half the infused volume used in the continuously-infused animals, while still attaining a similar efficacy in increasing dopamine turnover. These data suggest that pulsatile delivery of trophic factors, such as GDNFv, may be a viable disease altering strategy for patients with Parkinson’s disease by offering a means to reduce the drug amount needed to improve dopamine function while limiting potential therapeutic barriers.

J. Douglas Bremner, MD

Marina Piccinelli, PhD

Ernest V. Garcia, PhD

Valeria M. Moncayo, MD

Lisa Elon, M.S., M.P.H

Jonathon A. Nye, PhD

C. David Cooke, M.S.E.E

Brianna P. Washington, MD

Rebeca Alvarado Ortega, BS

Shivang R. Desai, MD

Alexis K. Okoh, MD

Brian Cheung, MD

Britt O. Soyebo, BS

Lucy H. Shallenberger, MPH

Paolo Raggi, MD

Amit J. Shah, MD

Obada Daaboul, MD

Mohamed Nour Jajeh, MD

Carrie Ziegler, BS

Emily G. Driggers, BS

Nancy Murrah, RN

Carlo N. De Cecco, MD

Marly van Assen, PhD

Robert T. Krafty, PhD

Arshed A. Quyyumi, MD

Viola Vaccarino, MD, PhD

Abstract

Objective: Coronary heart disease is a leading cause of death and disability. Although psychological stress has been identified as an important potential contributor, mechanisms by which stress increases risk of heart disease and mortality are not fully understood. The purpose of this study was to assess mechanisms by which stress acts through the brain and heart to confer increased CHD risk.

Methods: Coronary Heart Disease patients (N=10) underwent cardiac imaging with [Tc-99m] sestamibi single photon emission tomography at rest and during a public speaking mental stress task. Patients returned for a second day and underwent positron emission tomography imaging of the brain, heart, bone marrow, aorta (indicating inflammation) and subcutaneous adipose tissue, after injection of [18F]2-fluoro-2-deoxyglucose for assessment of glucose uptake followed mental stress. Patients with (N=4) and without (N=6) mental stress-induced myocardial ischemia were compared for glucose uptake in brain, heart, adipose tissue and aorta with mental stress.

Results: Patients with mental stress-induced ischemia showed a pattern of increased uptake in the heart, medial prefrontal cortex, and adipose tissue with stress. In the heart disease group as a whole, activity increase with stress in the medial prefrontal brain and amygdala correlated with stress-induced increases in spleen (r=0.69, p=0.038; and r=0.69, p=0.04 respectfully). Stress-induced frontal lobe increased uptake correlated with stress-induced aorta uptake (r=0.71, p=0.016). Activity in insula and medial prefrontal cortex was correlated with post-stress activity in bone marrow and adipose tissue. Activity in other brain areas not implicated in stress did not show similar correlations. Increases in medial prefrontal activity with stress correlated with increased cardiac glucose uptake with stress, suggestive of myocardial ischemia (r=0.85, p=0.004). Conclusions: These findings suggest a link between brain response to stress in key areas mediating emotion and peripheral organs involved in inflammation and hematopoietic activity, as well as myocardial ischemia, in Coronary Heart Disease patients.

Farshid GheisariReza Vali
 

Abstract

Hepatocellular Carcinoma (HCC) is a growing global health burden with high incidence and mortality rates. Despite advances in surgical techniques and perioperative care, outcomes after surgical treatment have not improved over the past three decades. Molecular imaging is an emerging field that enables researchers to study diseases at the molecular and cellular levels, enabling the detection of elevated serum α-fetoprotein (AFP) and abnormal expressions of various HCC-specific and nonspecific cell surface antigens and intracellular targets. Molecular imaging techniques detect liver lesions at the molecular and cellular level, allowing early detection and accurate staging of HCC. Positron emission tomography (PET) imaging offers greater sensitivity and specificity, while hepatobiliary-specific radiotracers with SPECT imaging provide insights into benign and malignant lesion differentiation. Radiomics and artificial intelligence are vital in deciphering molecular imaging data, with machine learning algorithms boosting diagnostic gains and predicting treatment response. Theranostics, a state-of-the-art application, provides diagnostic and therapeutic leverage following a single imaging agent. By understanding tumor biology in real time, radiopharmaceuticals can be transformed into personalized radiotherapies, enabling clinicians to make science-driven decisions throughout the illness. Future directions include developing novel radiotracers and integrating AI into clinical decision-making. Collaboration between academic researchers, clinicians, and industry colleagues is crucial to converting exciting advances into improved clinical outcomes for HCC patients.

Maria Greenwald, MD, FACR & JoAnn Ball, MSN, RN, ANP

Abstract

Objectives: Increasing levels of atherosclerosis correlate with increasing degrees of hearing loss. We hypothesized that arterial inflammation observed on FDG-PET/CT scans correlates with audiogram test results and that Major Adverse Cardiovascular Events occur in subjects with severe hearing loss (>40 dB).

Methods: A FDG-PET/CT imaging prospective study was performed in an NIH trial including 115 rheumatoid arthritis subjects over age 50 without a history of cardiovascular disease, and 22 subjects were selected for concurrent audiograms. All were evaluated by 18-fluorodeoxyglucose positron emission tomography computed tomography scans and audiogram tests, at baseline and 6 months. In our institution, 320 similar RA subjects were identified over age 50 with no prior cardiovascular disease and chart review completed for 10 years to evaluate MACE occurrence. Audiograms were available for the 320 retrospective patients.

Results: In the imaging study, at baseline there was a strong correlation between arterial inflammation on FDG-PET/CT and hearing test results (p<0.002). Hearing loss over 30 decibels was strongly associated with high levels of inflammation on FDG-PET/CT imaging. In the larger 320 retrospective group, there were 11 MACE (3.4%) in the 10 years period which occurred in subjects with even greater hearing loss (average measurement was over 50 dB).

Conclusion: Atherosclerosis was identified through FDG-PET/CT imaging studies and hearing tests. All MACE occurred in patients with significant hearing loss. Testing comprised a unique population with systemic inflammation from RA. If confirmed in larger studies in the general population, audiograms might provide a cost- effective substitute for FDG-PET/CT imaging and provide potentially an improved individual patient cardiovascular risk assessment. Audiograms may infer cardiovascular

Yahia M Lodi

Adam Bowen

Aria Soltani

Irfan Khan

H Polavarapu

Anas Hourani

Abstract

Background: Despite the advancement in acute ischemic stroke with large vessel occlusion (LVO), golden time is lost in assessment lengthy neurological examination and redundantly in the Emergency department, often after emergency medical service prehospital stroke scale evaluation indicating possible LVO. A simple acute ischemic stroke scale (AISS) of the cortical representations of the anterior circulation can rapidly predict LVO, saving precious time to initiate early intravenous tissue plasminogen activator and endovascular mechanical thrombectomy. We proposed an ASIS in the emergency department called Gaze Weakness Neglect Speech (GWNS) to evaluate its feasibility and predictability for the detection of LVO in anterior circulation in the emergency department. Additionally, to evaluate if time can be gained that has been lost in obtaining National Institute of Health stroke Scale (NIHSS) and computed tomographic angiography (CTA), avoiding unnecessary radiation.

Methods: This is a prospective observational study. An institutional review board permission was obtained, and patient enrollment started in January 2020 and ended in January 2021. Consecutive patients from January 2020 to September 2021 were selected from the database. The GWNS stroke scale was used by stroke and vascular neurologist during the emergency triage. The GWNS stroke scale scores range from 0 to 4 (1 for positive 0 for negative). The GWNS stroke scale assesses gaze deviation or gaze preference (G), presence of any weakness (W), neglect/disregard (N), and any speech impairment (S). Demographic data, CTA/cerebral angiographic data, and scores from NIHSS were also collected. The collected data was analyzed by a biostatistician to determine the association between the GWNS scale score and LVO.

Results: In our study,109 qualifying patients were selected. Fifty-eight patients had GWNS stroke scale score of 3 or 4, with 57 having confirmed LVO and 1 presenting after a seizure.  The GWNS stroke score ≥3 (0.86) correlated with LVO better than NIHSS (0.67), regardless of hemisphere side involvement. The GWNS stroke scale score of ≥3 also was effective in detection of proximal and distal blood vessels occlusion in the anterior circulation (Internal carotid artery, middle cerebral artery and its branches).  A GWNS stroke scale score of ≥3 with presence of gaze was the most predictive for LVO (0.9) followed by neglect/disregards (0.8). The time to obtain GWNS stroke scale was 1.5 minutes (range 1-3) and time to obtain/interpretation CTA was 41.3 +/- 7.4 minutes after emergency department arrival (range: 29-51 minutes).

Conclusions: Our Gaze Weakness Neglect Speech stroke scale can be performed rapidly in the emergency department and is highly predictive of LVO in the internal carotid artery, middle cerebral artery and middle cerebral branches. A GWNS stroke scale score of ≥3 is highly predictive of LVO, especially when gaze or neglect is present. Patients can potentially bypass CTA or advanced imaging in future studies, saving precious time and millions of brain cells for better outcome.

Hans Van der Wall, MB, BS, PhD, D Med Sc, FRACP

Robert Breit, MB.BS, FRACS, FAOrthA

Leticia Burton, BAppSc (MRS), PhD, NMT, MComm

Clayton Frater, Dip/NMT, BHealthMngt, PhD, MANZSNM

Warwick J Bruce, MB.BS, FRACS, FICS, FAOrthA

Abstract

Exercise for good health and as a prerequisite for most sporting endeavours is both an aspirational and necessary requirement at a time when obesity plagues much of the well-developed world. It has led to great advances in the science of exercise and a medical specialty devoted to sporting injuries. Epidemiology of sporting injury is crucial in this process in order to prevent injury and to focus attention on dangerous practices in some sports. The bone scan was historically considered a mainstay for the diagnosis of sporting injuries involving stress fractures, acute fractures and some soft tissue injuries. However, the role of scintigraphy has been supplanted by magnetic resonance imaging (MRI) in many of these settings, largely due to its high contrast resolution for soft tissues, spatial resolution of the relevant anatomy and the absence of radiation exposure. Nevertheless, there remains a valuable contribution from scintigraphy with the development of single photon emission computed tomography (SPECT) co-located with x-ray computed tomography (CT) in the same instrument. The place of scintigraphy in the evaluation of sporting injuries needs to be critically evaluated against the competing modalities of CT, MRI and high-resolution ultrasound. It is no longer appropriate or critically acceptable to examine scintigraphy in isolation from the other available imaging modalities.

Daishi Shimada

Masafumi Seki

Abstract

Different viral infections show characteristic imaging findings based on their particular pathophysiology. SARS-COV-2 shows characteristically high transmissibility and virulence, and it can evade the human immune system. COVID-19 patients frequently develop severe illness involving cytokine storm leading to acute respiratory distress syndrome (ARDS), as well as alveolar flood and severe vascular damage resulting in sepsis and organ damage. These basically develop from bilateral ground-glass infiltrations that are also found in the adult viral pneumonias, such as measles, respiratory syncytial virus, human metapneumovirus, and cytomegalovirus pneumonias. Secondary bacterial pneumonia due to co-infection with bacteria is a major issue in viral pneumonia, especially in influenza pneumonia, but patients with adult viral pneumonias are very different from bacterial pneumonia patients, and they are usually young, produce less sputum, and sometimes show characteristic skin lesions, including rash and vesicular lesions. Accurate diagnosis of the specific pathogen of viral pneumonia is important to perform the appropriate treatment and prevent infection, and it can recently be performed by multiplex PCR.

Covid-19 In Children: A Single Centered Study

Rajendra Nerli

Sonali Bijjargi

Shridhar C. Ghagane

Swapnil A. Pattanshetti

Shadab Rangrez

Shreyas Rai

Abstract

Introduction: There is limited data available on the epidemiological features, clinical manifestations, and transmission patterns in children with COVID-19, although there has been widespread information available regarding COVID-19 in adults. The objective of our study was to report our experience in the management of children admitted with COVID-19 to our hospital.

Materials & Methods: We retrospectively reviewed the in-patient records of all children  18 years of age admitted to our COVID-19 facility during the period March 2020 till May 2021. Detailed information including demographic data, travel and contact history, living conditions and overcrowding, symptoms, and presence of co-morbid conditions were noted. The clinical symptoms, physical findings, laboratory readings and imaging data were similarly noted and analysed.

Results: During the study period a total of 67 children (30 males and 37 females) with a mean age of 11.88 4.35 years were admitted to the COVID-19 facility. The presenting symptoms were fever (71.64%), skin rashes (14.93%), breathlessness (7.46%), cough (31.34%), cold (2.99%), headache (8.96%), sore throat (25.37%), loose motions (26.87%) and vomiting (8.96%). The RT-PCR was positive in 60 (89.55%) children. Sixty-one (91.045%) children recovered over a period of 10-14 days and were discharged.  Six (8.955%) children died due to multisystem failure. When compared to the children who recovered, the children who died had a significantly raised serum ferritin, IL 6, C reactive proteins, D-Dimer levels, and Sr LDH.

Conclusions: COVID-19 has been affecting children, more so in the second wave, with increased hospitalizations and mortality.

Ilham Zaidi

Jagadeeswari Vardha

Abdul khayum

Sahifa Anjum

Shikhar Chaudhary

Aditi Bakshi

Jasmeen Kaur Gill

Jaiprakash Gurav

Abstract

Tuberculosis (TB) along with pulmonary co-infections in patients became a grave concern to public health complicating the disease diagnosis, treatment, and prognosis. It became a challenge to healthcare professionals urging to develop new diagnostic tools and treatment regimens. This paper reviews the complex interplay and management strategies for Tuberculosis patients with co-infections. It encompasses antimicrobial therapy tailored to particular pathogens, including their susceptibility profiles to antibiotics, and understanding the potential implications of drug interactions with anti- Tuberculosis medications. In cases of co-infection between Tuberculosis and Human Immuno-Deficiency Virus (HIV), a particular focus is placed on the significance of synergistic methods and treatment duration.

Moreover, immunomodulatory drugs, immunotherapies, cellular treatments, adjunct therapies, and immunomodulatory agents that are customised to the patient’s immunological status and co-infecting pathogens emerge as a crucial component. Mitigating the transmission of pulmonary co-infections requires the implementation of infection control measures in both healthcare settings and communities. A strong barrier against the spread of tuberculosis and related illnesses is formed by administrative, engineering, and personal protective measures combined with screening, education, isolation, and contact tracking.

Prospective approaches underscore the necessity for enhanced diagnostic instruments, promoting cutting-edge technologies including molecular diagnostics, immunological tests, radiological imaging, biosensors, and point-of-care diagnostics. Comprehensive management is emphasised through multidisciplinary care comprising pulmonologists, infectious disease experts, microbiologists, and immunologists. Priorities for research include combination medications, new therapeutic approaches, personalised medicine, and developing diagnostic techniques to improve knowledge of and treatments for pulmonary co-infections.

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