Diagnostic CT-Enabled Planning (DART): Results of a Randomized Trial in Palliative Radiation Therapy.

PURPOSE: Using diagnostic computed tomography (dCT) scans instead of CT simulation (CTsim) scans can increase departmental efficiency and reduce patient burden. The goal of the DART trial was to assess the efficacy and acceptability of dCT-based planning workflows with a focus on patient experiences, plan deliverability and adequacy of target coverage, and workflows. METHODS AND MATERIALS: Patients undergoing same-day CTsim and treatment for palliative radiation therapy to thoracic, abdominopelvic, or proximal limb targets with a recent dCT (within 28 days) in a reproducible position were eligible. After stratifying by target type (bone or soft tissue vs. visceral), participants were randomized (1:2 ratio) between CTsim-based (CTsim arm) vs. dCT-based planning (dCT arm). The primary endpoint was time in center (TIC), defined as total time spent in the cancer center on first day of treatment, from first radiation department appointment to first fraction completion. Secondary endpoints included plan deliverability, adequacy of target coverage, and stakeholder acceptability. RESULTS: Thirty-three patients (42 treatment sites) were enrolled between June 2022 and April 2023. The median age was 72 (interquartile range [IQR]: 67-78), 73% were male, and the most common primary cancers were lung (33%), prostate (24%), and breast (12%). The most common dose and fractionations were 8 Gy in 1 and 20 Gy in 5 fractions (50% and 43% of plans, respectively). TIC was 4.7 ± 1.1 hours (mean ± SD) in the CTsim arm vs. 0.41 ± 0.14 hours in the dCT arm (P < .001). All dCT plans were deliverable. All plans in both arms were rated as "acceptable" (80% CTsim; 81% dCT) or "acceptable with minor deviation" (20% CTsim; 19% dCT). Patient perception of acceptability was similar in both arms with the exception of time burden, which was rated as "acceptable" by 50% in the CTsim arm vs. 90% in the dCT arm (P = .025). CONCLUSION: dCT-based radiation planning substantially reduced TIC without detriment in plan deliverability or quality and had a tangible impact on patient experience with reduced patient-reported time burden.

A power Doppler ultrasound method for improving intraoperative tip localization for visually obstructed needles in interstitial prostate brachytherapy.

PURPOSE: High-dose-rate (HDR) interstitial brachytherapy (BT) is a common treatment technique for localized intermediate to high-risk prostate cancer. Transrectal ultrasound (US) imaging is typically used for guiding needle insertion, including localization of the needle tip which is critical for treatment planning. However, image artifacts can limit needle tip visibility in standard brightness (B)-mode US, potentially leading to dose delivery that deviates from the planned dose. To improve intraoperative tip visualization in visually obstructed needles, we propose a power Doppler (PD) US method which utilizes a novel wireless mechanical oscillator, validated in phantom experiments and clinical HDR-BT cases as part of a feasibility clinical trial. METHODS: Our wireless oscillator contains a DC motor housed in a 3D printed case and is powered by rechargeable battery allowing the device to be operated by one person with no additional equipment required in the operating room. The oscillator end-piece features a cylindrical shape designed for BT applications to fit on top of the commonly used cylindrical needle mandrins. Phantom validation was completed using tissue-equivalent agar phantoms with the clinical US system and both plastic and metal needles. Our PD method was tested using a needle implant pattern matching a standard HDR-BT procedure as well as an implant pattern designed to maximize needle shadowing artifacts. Needle tip localization accuracy was assessed using the clinical method based on ideal reference needles as well as a comparison to computed tomography (CT) as a gold standard. Clinical validation was completed in five patients who underwent standard HDR-BT as part of a feasibility clinical trial. Needle tips positions were identified using B-mode US and PD US with perturbation from our wireless oscillator. RESULTS: Absolute mean ± standard deviation tip error for B-mode alone, PD alone, and B-mode combined with PD was respectively: 0.3 ± 0.3 mm, 0.6 ± 0.5 mm, and 0.4 ± 0.2 mm for the mock HDR-BT needle implant; 0.8 ± 1.7 mm, 0.4 ± 0.6 mm, and 0.3 ± 0.5 mm for the explicit shadowing implant with plastic needles; and 0.5 ± 0.2 mm, 0.5 ± 0.3 mm, and 0.6 ± 0.2 mm for the explicit shadowing implant with metal needles. The total mean absolute tip error for all five patients in the feasibility clinical trial was 0.9 ± 0.7 mm using B-mode US alone and 0.8 ± 0.5 mm when including PD US, with increased benefit observed for needles classified as visually obstructed. CONCLUSIONS: Our proposed PD needle tip localization method is easy to implement and requires no modifications or additions to the standard clinical equipment or workflow. We have demonstrated decreased tip localization error and variation for visually obstructed needles in both phantom and clinical cases, including providing the ability to visualize needles previously not visible using B-mode US alone. This method has the potential to improve needle visualization in challenging cases without burdening the clinical workflow, potentially improving treatment accuracy in HDR-BT and more broadly in any minimally invasive needle-based procedure.

White matter integrity is associated with gait impairment and falls in mild cognitive impairment. Results from the gait and brain study.

BACKGROUND: Mild Cognitive Impairment (MCI) is an intermediate state between normal cognition and dementia that is associated with twice the risk of falls. It is unknown whether white matter integrity (WMI) is associated with increased risk of falls in MCI. The purpose of this study was to evaluate if early changes in WMI were associated with gait impairment and falls. METHODS: Forty-three participants with MCI from the Gait and Brain Study underwent standardized assessment of cognition, gait performance under single and dual-task conditions (walking while talking), and WMI using 3 Tesla diffusion tensor imaging (DTI). Macro-structural imaging characteristics (white and grey matter morphology) as well as microstructural WMI parameters were examined for associations with falls and gait performance. Significantly associated WM tracts were then used to test the interplay between WMI and history of falls, after adjusting for other important covariates. RESULTS: Multiple WM tracts (corpus callosum, forceps minor, and the left inferior fronto-occipital fasciculus) were significantly associated with history of falls and lower dual-task gait performance. A multivariable regression model showed that fall history was associated with the radial diffusivity in the forceps minor, even after adjusting for education, sex, BMI, MMSE scores, comorbidities, gait velocity and WMH volume as covariates. CONCLUSIONS: Multiple WM tracts that are known to be involved in executive and visuospatial functions were preferentially affected in MCI individuals with history of falls. Our preliminary findings support the notion that WMI in key brain regions may increase risk of falls in older adults with MCI.

Detection of Active Caspase-3 in Mouse Models of Stroke and Alzheimer's Disease with a Novel Dual Positron Emission Tomography/Fluorescent Tracer [68Ga]Ga-TC3-OGDOTA.

Apoptosis is a feature of stroke and Alzheimer's disease (AD), yet there is no accepted method to detect or follow apoptosis in the brain in vivo. We developed a bifunctional tracer [68Ga]Ga-TC3-OGDOTA containing a cell-penetrating peptide separated from fluorescent Oregon Green and 68Ga-bound labels by the caspase-3 recognition peptide DEVD. We hypothesized that this design would allow [68Ga]Ga-TC3-OGDOTA to accumulate in apoptotic cells. In vitro, Ga-TC3-OGDOTA labeled apoptotic neurons following exposure to camptothecin, oxygen-glucose deprivation, and ß-amyloid oligomers. In vivo, PET showed accumulation of [68Ga]Ga-TC3-OGDOTA in the brain of mouse models of stroke or AD. Optical clearing revealed colocalization of [68Ga]Ga-TC3-OGDOTA and cleaved caspase-3 in brain cells. In stroke, [68Ga]Ga-TC3-OGDOTA accumulated in neurons in the penumbra area, whereas in AD mice [68Ga]Ga-TC3-OGDOTA was found in single cells in the forebrain and diffusely around amyloid plaques. In summary, this bifunctional tracer is selectively associated with apoptotic cells in vitro and in vivo in brain disease models and represents a novel tool for apoptosis detection that can be used in neurodegenerative diseases.

Is the Importance of Heart Dose Overstated in the Treatment of Non-Small Cell Lung Cancer? A Systematic Review of the Literature.

PURPOSE: Some recent studies have suggested a relationship between cardiac dose and mortality in non-small cell lung cancer (NSCLC), but others have reported conflicting data. The goal of this study was to conduct a systematic review and meta-analysis to provide an evidence-based estimate of the relationship between cardiac dose and mortality in these patients. METHODS AND MATERIALS: A systematic review of MEDLINE (PubMed) and Embase databases (inception to January 2018) was performed according to PRISMA guidelines. Studies that evaluated cardiac dosimetric factors in patients with NSCLC and included outcomes of cardiac events, cardiac mortality, and/or overall survival were identified. RESULTS: From 5614 patients across 22 studies, a total of 214 cardiac dosimetric parameters (94 unique) were assessed as possible predictors of cardiac toxicity or death. Assessed predictors included general (eg, mean heart dose [MHD]), threshold-based (eg, heart V5), and anatomic-based (eg, atria, ventricles) dosimetric factors. The most commonly analyzed parameters were MHD, heart V5, and V30. Most studies did not make corrections for multiplicity of testing. For overall survival, V5 was found to be significant on multivariable analysis (MVA) in 1 of 11 studies and V30 in 2 of 12 studies; MHD was not significant in any of 8 studies. For cardiac events, V5 was found to be significant on multivariable analysis in 1 of 2 studies, V30 in 1 of 3 studies, and MHD in 2 of 4 studies. A meta-analysis of the data could not be performed because most negative studies did not report effect estimates. CONCLUSIONS: Consistent heart dose-volume parameters associated with overall survival of patients with NSCLC were not identified. Multiplicity of testing is a major issue and likely inflates the overall risk of type I errors in the literature. Future studies should specify predictors a priori, correct for multiplicity of testing, and report effect estimates for nonsignificant variables.

An Aspartyl Cathepsin Targeted PET Agent: Application in an Alzheimer's Disease Mouse Model.

BACKGROUND: Early detection of Alzheimer's disease (AD) pathology is a serious challenge for both diagnosis and clinical trials. The aspartyl protease, Cathepsin D (CatD), is overexpressed in AD and could be a biomarker of disease. We have previously designed a unique contrast agent (CA) for dual-optical and magnetic resonance imaging of the activity of the CatD class of enzymes. OBJECTIVE: To compare the uptake and retention of a novel, more sensitive, and clinically-translatable 68Ga PET tracer targeting CatD activity in 5XFAD mice and non-Tg littermates. METHODS: The targeted CA consisted of an HIV-1 Tat cell penetrating peptide (CPP) conjugated to a specialized cleavage sequence targeting aspartyl cathepsins and a DOTA conjugate chelating 68Ga. PET images were acquired using a Siemens Inveon preclinical microPET in female Tg AD mice and non-Tg age matched female littermates (n = 5-8) following intravenous CA administration at 2, 6, and 9 months of age. Additionally, 18F fluorodeoxyglucose (FDG) PET imaging was performed at 10 months to measure glucose uptake. RESULTS: The Tg mice showed significantly higher relative uptake rate of the targeting CA in the forebrain relative to hindbrain at all ages compared to controls, consistent with histology. In contrast, no differences were seen in CA uptake in other organs. Additionally, the Tg mice did not show any differences in relative uptake of FDG at 10 months of age in the forebrain relative to the hindbrain compared to age matched non-Tg controls. CONCLUSIONS: Elevated aspartryl cathepsin activity was detected in vivo in the 5XFAD mouse model of AD using a novel targeted PET contrast agent.

Prolonged In Vivo Retention of a Cathepsin D Targeted Optical Contrast Agent in a Mouse Model of Alzheimer's Disease.

BACKGROUND: Cathepsin D (CatD) is a lysosomal protease that is elevated early in Alzheimer's disease (AD). We have previously developed a Targeted contrast agent (CA) to detect CatD activity in vivo, consisting of a magnetic resonance imaging/fluorescent moiety linked to a cell penetrating peptide (CPP) by means of a CatD cleavage site and have demonstrated its uptake in the brain of an AD mouse model. OBJECTIVE: The purpose of this study was to characterize the in vivo retention of a near infra-red fluorescent dye labeled version of this CA. METHODS: Six adult C57Bl/6 wild-type mice and six adult 5XFAD transgenic AD mice were studied using a small animal imaging system at five and twelve months of age using our novel Targeted CA, or two different control CAs; a Non-Targeted (lacking the CatD cleavage site) and a Non-Penetrating (lacking the CPP). Following intravenous CA administration, the optical signal was recorded within the brain and uptake and washout curves were measured and fitted to a one-phase exponential decay curve. RESULTS: In all wild-type and 5XFAD mice, the washout of the Targeted CA that included a CPP domain was significantly slower than the washout of the Non-Penetrating and Non-Targeted CA. Furthermore, the washout of the CatD Targeted CA was significantly slower in the 5XFAD mice compared to the age matched wild-type controls (p <  0.05) at 5 and 12 months of age. Control CAs showed no differences in washout. CONCLUSIONS: The prolonged retention of the CatD targeted CA in 5XFAD mice suggests this agent may be useful for AD detection.

Labelling dendritic cells with SPIO has implications for their subsequent in vivo migration as assessed with cellular MRI.

An optimized non-invasive imaging modality capable of tracking and quantifying in vivo DC migration in patients would provide clinicians with valuable information regarding therapeutic DC-based vaccine outcomes. Superparamagnetic iron oxide (SPIO) nanoparticles were used to label bone marrow-derived DC. In vivo DC migration was tracked and quantified non-invasively using cellular magnetic resonance imaging (MRI) in a mouse model. Labelling DC with SPIO reflects the kinetics of DC migration in vivo but appears to reduce overall DC migration, in part due to nanoparticle size. Magnetic separation of SPIO-labelled (SPIO(+)) DC from unlabelled (SPIO(-)) DC prior to injection improves SPIO(+) DC migration to the lymph node. Corresponding MR image data better correlate with the presence of DC in vivo; an improved immunological response is also seen. Cellular MRI is a viable, non-invasive imaging tool that can routinely track DC migration in vivo. Consideration should be given to optimizing MRI contrast agent-labelling of clinical-grade DC in order to accurately correlate DC fate to immunological outcomes in patients.

Surface dose measurement for helical tomotherapy.

PURPOSE: To compare the surface dose measurements made by different dosimeters for the helical tomotherapy (HT) plan in the case of the target close to the surface. METHODS: Surface dose measurements in different points for the HT plan to deliver 2 Gy to the planning target volume (PTV) at 5 mm below the surface of the cylindrical phantom were performed by radiochromic films, single use metal oxide semiconductor field-effect transistor (MOSFET) dosimeters, silicon IVD QED diode, and optically stimulated luminescence (OSL) dosimeters. RESULTS: The measured doses by all dosimeters were within 12 +/- 8% difference of each other. CONCLUSIONS: Radiochromic films, EBT, and EBT2, provide high spatial resolution, although it is difficult to get accurate measurements of dose. Both the OSL and QED measured similar dose to that of the MOSFET detectors. The QED dosimeter is promising as a reusable on-line wireless dosimeter, while the OSL dosimeters are easier to use, require minimum setup time and are very precise.

Semiquantitation of mouse dendritic cell migration in vivo using cellular MRI.

Despite recent therapeutic advances, including the introduction of novel cytostatic drugs and therapeutic antibodies, many cancer patients will experience recurrent or metastatic disease. Current treatment options, particularly for those patients with metastatic breast, prostate, or skin cancers, are complex and have limited curative potential. Recent clinical trials, however, have shown that cell-based therapeutic vaccines may be used to generate broad-based, antitumor immune responses. Dendritic cells (DC) have proved to be the most efficacious cellular component for therapeutic vaccines, serving as both the adjuvant and antigen delivery vehicle. At present it is not possible to noninvasively determine the fate of DC-based vaccines after their administration to human subjects. In this study, we demonstrate that in vitro-generated mouse DC can be readily labeled with superparamagnetic iron oxide nanoparticles, Feridex, without altering cell morphology, or their phenotypic and functional maturation. Feridex-labeling enables the detection of DC in vivo after their migration to draining lymph nodes using a 1.5 T clinical magnetic resonance scanner. In addition, we report a semiquantitative approach for analysis of magnetic resonance images and show that the Feridex-induced signal void volume, and fractional signal loss, correlates with the delivery and migration of small numbers of in vitro-generated DC. These findings, together with ongoing preclinical studies, are key to gaining information critical for improving the efficacy of therapeutic vaccines for the treatment cancer, and potentially, chronic infectious diseases.

Cellular magnetic resonance imaging: in vivo imaging of melanoma cells in lymph nodes of mice.

Metastasis is responsible for most deaths due to malignant melanoma. The clinical significance of micrometastases in the lymph is a hotly debated topic, but an improved understanding of the lymphatic spread of cancer remains important for improving cancer survival. Cellular magnetic resonance imaging (MRI) is a newly emerging field of imaging research that is expected to have a large impact on cancer research. In this study, we demonstrate the cellular MRI technology required to reliably image the lymphatic system in mice and to detect iron-labeled metastatic melanoma cells within the mouse lymph nodes. Melanoma cells were implanted directly into the inguinal lymph nodes in mice, and micro-MRI was performed using a customized 1.5-T clinical MRI system. We show cell detection of as few as 100 iron-labeled cells within the lymph node, with injections of larger cell numbers producing increasingly obvious regions of signal void. In addition, we show that cellular MRI allows monitoring of the fate of these cells over time as they develop into intranodal tumors. This technology will allow noninvasive investigations of cellular events in cancer metastasis within an entire animal and will facilitate progress in understanding the mechanisms of metastasis within the lymphatic system.

Imaging islets labeled with magnetic nanoparticles at 1.5 Tesla.

We have developed a magnetic resonance imaging (MRI) technique for imaging Feridex (superparamagnetic iron oxide [SPIO])-labeled islets of Langerhans using a standard clinical 1.5-Tesla (T) scanner and employing steady-state acquisition imaging sequence (3DFIESTA). Both porcine and rat islets were labeled with SPIO by a transfection technique using a combination of poly-l-lysine and electroporation. Electron microscopy demonstrated presence of SPIO particles within the individual islet cells, including beta-cells and particles trapped between cell membranes. Our labeling method produced a transfection rate of 860 pg to 3.4 ng iron per islet, dependent on the size of the islet. The labeling procedure did not disrupt either the function or viability of the islets. In vitro 3DFIESTA magnetic resonance images of single-labeled islets corresponded with their optical images. In vivo T2*-weighted scan using 1.5 T detected as few as 200 SPIO-labeled islets transplanted under rat kidney capsule, which correlated with immunohistochemistry of the transplant for insulin and iron. Ex vivo 3DFIESTA images of kidneys containing 200, 800 or 2,000 SPIO-labeled islet isografts showed good correlation between signal loss and increasing numbers of islets. These data provide evidence that islets can be labeled with SPIO and imaged using clinically available 1.5- T MRI.

In vivo MRI of cancer cell fate at the single-cell level in a mouse model of breast cancer metastasis to the brain.

Metastasis (the spread of cancer from a primary tumor to secondary organs) is responsible for most cancer deaths. The ability to follow the fate of a population of tumor cells over time in an experimental animal would provide a powerful new way to monitor the metastatic process. Here we describe a magnetic resonance imaging (MRI) technique that permits the tracking of breast cancer cells in a mouse model of brain metastasis at the single-cell level. Cancer cells that were injected into the left ventricle of the mouse heart and then delivered to the brain were detectable on MR images. This allowed the visualization of the initial delivery and distribution of cells, as well as the growth of tumors from a subset of these cells within the whole intact brain volume. The ability to follow the metastatic process from the single-cell stage through metastatic growth, and to quantify and monitor the presence of solitary undivided cells will facilitate progress in understanding the mechanisms of brain metastasis and tumor dormancy, and the development of therapeutics to treat this disease.