Scanning Time Points Research Articles

Outcomes of Management of Progressive Radiosurgery-Treated Brain Metastasis With Resection Followed by Pathology-Informed Management: A Retrospective Study

BACKGROUND AND OBJECTIVES: In patients treated with stereotactic radiosurgery (SRS) for brain metastases, follow-up imaging demonstrating progression may result from treatment effect/radionecrosis (RN) or tumor progression. We report long-term outcomes for a cohort of patients who demonstrated radiological progression on serial imaging after initial radiation and who underwent resection, at which point histology informed further management. METHODS: A retrospective chart review identified 76 patients with an associated 82 brain lesions between 2009 and 2022, that were initially treated with SRS, and then demonstrated suspicious imaging developing through at least 2 scan time points with either pathologic confirmation of tumor or RN. RESULTS: Of the 82 lesions, 55 lesions (67.1%) were found to be tumor and were treated with repeat radiation and 27 (32.9%) were found to have pathologically confirmed RN and conservatively managed. 14/27 lesions ultimately found to be radionecrotic required steroids preoperatively due to neurological symptoms. None of these lesions required further intervention with median postsurgery follow-up of 24.4 months (range 1-104 months). There were 55 instances (in 51 patients) of confirmed recurrent/progressive tumor who we treated with repeat aggressive radiation with either Cs-131 brachytherapy (12 [21.8%]) or SRS (43 [78.2%]). Among patients treated with reirradiation, the median follow-up to local failure was 15.2 months (95% CI 7.3-26.6 months). The 2-year local control rate was 79.5% (95% CI 68.3%-92.5%). CONCLUSION: These results support resection of radiosurgery-treated lesions with progression continuing through serial imaging, and this pathology-informed management results in excellent control of both RN and tumor progression after radiosurgery.

Individual lymph node position variation for rectal cancer patients treated with long course chemoradiotherapy

Background and purposeDelivery of high precision radiotherapy lymph node boosts requires detailed information on the interfraction positional variation of individual lymph nodes. In this study we characterized interfraction positional shifts of suspected malignant lymph nodes for rectal cancer patients receiving long course radiotherapy. Furthermore, we investigated parameters which could affect the magnitude of the position variation. Materials and MethodsFourteen patients from a prospective clinical imaging study with a total of 61 suspected malignant lymph nodes in the mesorectum, presacral, and lateral regions, were included. The primary gross tumor volume (GTVp) and all suspected malignant lymph nodes were delineated on six magnetic resonance imaging scans per patient. Positional variation was calculated as systematic and random errors, based on shifts of center-of-mass, and estimated relative to either bony structures or the GTVp using a hierarchical linear mixed model. ResultsDepending on location and direction, systematic and random variations (relative to bony structures) were within 0.6–2.8 mm and 0.6–2.9 mm, respectively. Systematic and random variations increased when evaluating position relative to GTVp (median increase of 0.6 mm and 0.5 mm, respectively). Correlations with scan time-point and relative bladder volume were found in some directions. ConclusionsUsing linear mixed modeling, we estimated systematic and random positional variation for suspected malignant lymph nodes in rectal cancer patients treated with long course radiotherapy. Statistically significant correlations of the magnitude of the lymph node shifts were found related to scan time-point and relative bladder volume.

Oligomeric amyloid-β targeted contrast agent for MRI evaluation of Alzheimer's disease mouse models.

Oligomeric amyloid beta (oAβ) is a toxic factor that acts in the early stage of Alzheimer's disease (AD) and may initiate the pathologic cascade. Therefore, detecting oAβ has a crucial role in the early diagnosis, monitoring, and treatment of AD. The purpose of this study was to evaluate MRI signal changes in different mouse models and the time-dependent signal changes using our novel gadolinium (Gd)-dodecane tetraacetic acid (DOTA)- ob5 aptamer contrast agent. We developed an MRI contrast agent by conjugating Gd-DOTA-DNA aptamer called ob5 to evaluate its ability to detect oAβ deposits in the brain using MRI. A total of 10 control mice, 9 3xTg AD mice, and 11 APP/PS/Tau AD mice were included in this study, with the age of each model being 16 or 36 weeks. A T1-weighted image was acquired at the time points before (0min) and after injection of the contrast agent at 5, 10, 15, 20, and 25min. The analyses were performed to compare MRI signal differences among the three groups and the time-dependent signal differences in different mouse models. Both 3xTg AD and APP/PS/Tau AD mouse models had higher signal enhancement than control mice at all scan-time points after injection of our contrast media, especially in bilateral hippocampal areas. In particular, all Tg AD mouse models aged 16 weeks showed a higher contrast enhancement than those aged 36 weeks. For 3xTg AD and APP/PS/Tau AD groups, the signal enhancement was significantly different among the five time points (0min, 5min, 10min, 15min, 20min, and 25min) in multiple ROI areas, typically in the bilateral hippocampus, left thalamus, and left amygdala. The findings of this study suggest that the expression of the contrast agent in different AD models demonstrates its translational flexibility across different species. The signal enhancement peaked around 15-20min after injection of the contrast agent. Therefore, our novel contrast agent targeting oAβ has the potential ability to diagnose early AD and monitor the progression of AD.

Alzheimer's disease prevention: Apolipoprotein e4 moderates the effect of physical activity on brain beta-amyloid deposition in healthy older adults

ObjectivesTo investigate if higher baseline physical activity levels are associated with less β-amyloid burden and whether the ApoE4 genotype moderates this association cross-sectionally and longitudinally. DesignProspective cohort study. Methods204 cognitively normal older adults (74.5 ± 6.6 years; 26 % ApoE4-carrier) were analyzed. Baseline physical activity was measured using the Minnesota Physical Activity Questionnaire. Brain β-amyloid burden was measured with positron emission tomography using 11C-labeled Pittsburgh compound. A subsample of 128 participants underwent longitudinal positron emission tomography (2.0 ± 0.9 scans over 5 ± 3 years). Statistical analysis was run according to physical activity (high/low group) and the ApoE4 genotype (carrier/noncarrier). ResultsThe ApoE4 genotype moderated the relationship between physical activity and β-amyloid, such that low physical activity had a greater impact on β-amyloid deposition in ApoE4-carriers than noncarriers. This ApoE4 × physical activity effect on brain β-amyloid deposition was also observed when all available β-amyloid scan timepoints were included in the model. β-amyloid deposition increased over time (p < 0.001), and ApoE4-carriers had disproportionately greater β-amyloid accumulation than ApoE4-noncarriers. The lower physical activity group had marginally greater β-amyloid accumulation than the higher physical activity group (p = 0.099), but there was no significant ApoE4 effect on β-amyloid accumulation. ConclusionsLow physical activity in combination with the ApoE4-carrier genotype is associated with increased β-amyloid burden, suggesting that ApoE4 moderates the effect of physical activity on β-amyloid load. However, this effect was insufficient for baseline physical activity to modulate the change in β-amyloid accumulation over time.

First-in-human study of PSMA-targeting agent, [18F]AlF-P16-093: dosimetry and initial evaluation in prostate cancer patients.

This is a first-in-human study to evaluate the radiation dosimetry of a new prostate-specific membrane antigen (PSMA)-targeted radiopharmaceutical, [18F]AlF-P16-093, and also initial investigation of its ability to detect PSMA-positive tumors using PET scans in a cohort of prostate cancer (PCa) patients. The [18F]AlF-P16-093 was automatically synthesized with a GE TRACERlab. A total of 23 patients with histopathologically proven PCa were prospectively enrolled. Dosimetry and biodistribution study investigations were carried out on a subset of six (6) PCa patients, involving multiple time-point scanning. The mean absorbed doses were estimated with PMOD and OLINDA software. [18F]AlF-P16-093 was successfully synthesized, and radiochemical purity was > 95%, and average labeling yield was 36.5 ± 8.3% (decay correction, n = 12). The highest tracer uptake was observed in the kidneys, spleen, and liver, contributing to an effective dose of 16.8 ± 1.3 μSv/MBq, which was ~ 30% lower than that of [68Ga]Ga-P16-093. All subjects tolerated the PET examination well, and no reportable side-effects were observed. The PSMA-positive tumors displayed rapid uptake, and they were all detectable within 10 min, and no additional lesions were observed in the following multi-time points scanning. Each patient had at least one detectable tumor lesion, and a total of 356 tumor lesions were observed, including intraprostatic, lymph node metastases, bone metastases, and other soft tissue metastases. We report herein a streamlined method for high yield synthesis of [18F]AlF-P16-093. Preliminary study in PCa patients has demonstrated its safety and acceptable radiation dosimetry. The initial diagnostic study indicated that [18F]AlF-P16-093 PET/CT is efficacious and potentially useful for a widespread application in the diagnosis of PCa patients.

Multi-parameter cardiac magnetic resonance imaging detects anthracycline-induced cardiotoxicity in rabbits model

BackgroundCardiac magnetic resonance (CMR) quantitative T1 and T2 mapping offers a non-invasive means to evaluate early cardiotoxicity changes. This study aimed to pinpoint the earliest CMR indicators of myocardial injury in Anthracycline-induced cardiotoxicity (AIC) and to elucidate the connections between these CMR indicators and associated pathological indicators. MethodsA total of 34 rabbits were administered doxorubicin at a dosage of 1 mg/kg/weekly. The study incorporated six 3T CMR scan time points: baseline, and at intervals of four, six, eight, twelve, and sixteen weeks. Cine, T1 and T2 mapping sequences assessed the left ventricular ejection fraction (LVEF), native T1, extracellular volume fraction (ECV), and T2 values. Following each time point, three rabbits were sacrificed for histological analysis involving Hematoxylin and eosin (H&E), Masson, TUNEL, and microvascular density (MVD) stains. Spearman correlations and linear mixed model analysis served in the statistical analysis. ResultsDiverse degrees of alternation were recorded in LVEF, native T1, T2, and ECV over time. LVEF declined to 49.0 ± 2.6 % at 12 weeks from the baseline of 53.4 ± 3.2 %, p < 0.001. Native T1 values increase from the baseline (1396.5 ± 79.2 ms) until 8 weeks (1498.8 ± 95.4 ms, p < 0.001). T2 values increased from the baseline (36.6 ± 3.3 ms) within 4 weeks of initiation (37.5 ± 3.4, p = 0.02) and remained elevated through 16 weeks (42.8 ± 0.3, p < 0.01). ECV was elevated at 8 weeks (33.9 ± 3.8 %, p = 0.005) compared to the baseline (30.2 ± 2.5 %). By week 12, myocardial edema and increased CVF were apparent (p = 0.04 and = 0.001, respectively). The area under ROC curve for positive CMR presence and the gold standards were 0.87 (T2-ROC, 4 weeks) and 0.92 (LVEF&BNP-ROC, 12 weeks). ConclusionT1 and T2 mapping are effective tools for cardiotoxicity detection and monitoring. The prolongation of T2 value emerged as the most consistent and early-onset indicator.

Outcomes of Brain Metastases with Suspicious Imaging Undergoing Resection to Evaluate for Radionecrosis vs. Tumor Progression

In patients treated with stereotactic radiosurgery (SRS) for brain metastases, radiographic changes on surveillance imaging may result from treatment effect/radionecrosis (RN) or tumor progression. Distinguishing between these processes is critical to appropriate management. We report long-term outcomes for a cohort of patients who demonstrated radiographic progression on serial imaging after initial radiation and ultimately underwent resection to inform further management. A retrospective chart review identified 76 patients with an associated 82 brain lesions between 2009 and 2022 that were initially treated with SRS, then demonstrated suspicious imaging changes developing through at least two scan time points that led to pathologic confirmation of either tumor or RN. We report clinical outcomes and details of further treatments. Of the 82 lesions, 55 (67.1%) were found to be pathologically-confirmed viable tumor and were treated with repeat radiation and 27 (32.9%) were found to be strictly RN and conservatively managed. Over half of the lesions (14/27) ultimately found to be radionecrotic required use of steroids pre-operatively due to neurologic symptoms. Among the 27 that were found to be RN, the most common histology was melanoma (33.3%, n = 9). The most common dose fractionation regimen was 20 Gy in 1 fx (n = 11, 40.7%; range: 16-20 Gy x 1Fx), and the median BED (10) was 50.4 Gy (IQR 41.6 - 50 Gy). None of these lesions required further intervention with median post-surgery follow up of 24.4 months (range 1-104 months). There were 55 instances (in 51 patients) of pathologically-confirmed recurrent/progressive tumor who were consequently treated with repeat radiation with either Cs-131 brachytherapy (12 (21.8%)) or SRS (43 (78.2%)). The most common histology was NSCLC (37.2%, n = 19). The most common fractionation for repeat irradiation with SRS was 8 Gy x 3 fx (n = 15, 27.3%), followed by 5 Gy x 5 fx (n = 10, 18.2%), and 4 Gy x 5 fx (n = 8, 14.6%). Four individuals each had two lesions that were re-irradiated for local recurrence. Among patients treated with re-irradiation, the median follow-up to local failure was 15.2 months (95% CI 7.3-26.6 months). Radionecrosis was confirmed on pathology in 4/55 (7.2%) of lesions. The median follow-up from date of SRS2 to local failure was 14.1 months (95% CI 7.6-24.3 months). The 2-yr local control rate was 74.8% (95% CI 61.7-90.7%). We recommend cautious monitoring of possible progression after radiosurgery, with consideration of resection for continuous progression, as a significant proportion of radiographic progression are ultimately pure RN. Management determined by pathology (observation for RN; additional radiation for confirmed tumor) leads to excellent control.

Theranostic Surrogacy of [123I]NaI for Differentiated Thyroid Cancer Radionuclide Therapy.

Precise dosimetry has gained interest for interpreting the response assessments of novel therapeutic radiopharmaceuticals, as well as for improving conventional radiotherapies such as the "one dose fits all" approach. Although radioiodine as same-element isotope theranostic pairs has been used for differentiated thyroid cancer (DTC), there are insufficient studies on the determination of its dosing regimen for personalized medicine and on extrapolating strategies for companion diagnostic radiopharmaceuticals. In this study, DTC xenograft mouse models were generated after validating iodine uptakes via sodium iodine symporter proteins (NIS) through in vitro assays, and theranostic surrogacy of companion radiopharmaceuticals was investigated in terms of single photon emission computed tomography (SPECT) imaging and voxel-level dosimetry. Following a Monte Carlo simulation, the hypothetical energy deposition/dose distribution images were produced as [123I]NaI SPECT scans with the use of 131I ion source simulation, and dose rate curves were used to estimate absorbed dose. For the tumor, a peak concentration of 96.49 ± 11.66% ID/g occurred 2.91 ± 0.42 h after [123I]NaI injection, and absorbed dose for 131I therapy was estimated as 0.0344 ± 0.0088 Gy/MBq. The absorbed dose in target/off-target tissues was estimated by considering subject-specific heterogeneous tissue compositions and activity distributions. Furthermore, a novel approach was proposed for simplifying voxel-level dosimetry and suggested for determining the minimal/optimal scan time points of surrogates for pretherapeutic dosimetry. When two scan time points were set to Tmax and 26 h and the group mean half-lives were applied to the dose rate curves, the most accurate absorbed dose estimates were determined [-22.96, 2.21%]. This study provided an experimental basis to evaluate dose distribution and is expected hopefully to improve the challenging dosimetry process for clinical use.

Harnessing olaparib, palbociclib, and endocrine therapy: A phase I/II trial of olaparib, palbociclib and fulvestrant in patients with BRCA mutation-associated, hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (HOPE).

TPS1126 Background: Hormone receptor-positive (HR+) metastatic breast cancer (MBC) in patients (pts) with germline or somatic BRCA1 or BRCA2 (g/s BRCA1/2) mutations has dual drivers: hormone receptor signaling and homologous recombination deficiency. The PALOMA-3 trial showed superiority of fulvestrant (F) with palbociclib (P) compared to F alone. The OlympiAD trial showed the poly-ADP ribose polymerase inhibitor (PARPi) olaparib (O) to be superior to chemotherapy in BRCA1/2-associated MBC. However, treatment resistance inevitably develops; targeting dual therapeutic drivers concurrently may delay or circumvent resistance. O and P have overlapping hematologic toxicity and the safety of combined O, P and F is unknown. The tolerability of O + P is particularly relevant given the emergence of potentially less myelosuppressive PARPi. Methods: HOPE (NCT03685331) is a phase I/II trial to evaluate safety and efficacy of O, P and F in pts with g/s BRCA1/2-associated, HR+ MBC. Eligible pts have an ECOG performance status 0-1, measurable/evaluable breast cancer, any/no prior endocrine therapy, and 0-2 lines of chemotherapy for MBC. Prior platinum is allowed for curative intent if completed at least 12 months prior to MBC diagnosis, or for MBC if no progression during therapy. Prior PARPi and CDK4/6i are permitted on phase I, and are permitted during phase II if there was no progression on them. Treatment (28-day cycles) consists of: O orally twice daily continuously; F 500mg intramuscularly on day 1 of each cycle plus load; and P orally once daily on days 1-21. Phase I begins with a 28-day safety run-in of O and F alone. O and P doses are based on dose level (DL): DL 0 (starting level), O 300mg, P 75mg; DL 1, O 300mg, P 100mg; DL 2, O 300mg, P 125mg; DL-1, O 250mg, P 75mg and DL-2, O 200mg, P 75mg. For phase II, O and P will be dosed at MTD. Pts have tissue collection at baseline and peripheral blood cfDNA analysis at baseline, at progression, and at all scan timepoints (every 3 cycles). Phase I primary endpoint is MTD. A 3+3 dose escalation design is used with a 30% rate of dose limiting toxicity (DLT) deemed acceptable, and 6 patients treated at a dose for it to be declared MTD. A minimum of 2 and a maximum of 18 patients will be enrolled on the phase I. Phase II primary endpoint is PFS using Kaplan-Meier methods and secondary efficacy endpoints are objective response rate and 24-week clinical benefit rate. Phase II will evaluate 54 subjects to provide 80% power to detect an increase in PFS from 7 months with O monotherapy to 10 months. Exploratory objectives include examination of baseline tissue for PARPi predictive biomarkers and measures of tumor immunogenicity as well as serial serum evaluation for reversion mutations. Enrollment is ongoing. Clinical trial information: NCT03685331 .

18F-FDG gallbladder uptake: observation from a total-body PET/CT scanner

BackgroundTotal-body positron emission tomography/computed tomography (PET/CT) scanners are characterized by higher signal collection efficiency and greater spatial resolution compared to conventional scanners, allowing for delayed imaging and improved image quality. These advantages may also lead to better detection of physiological processes that diagnostic imaging professionals should be aware of. The gallbladder (GB) is not usually visualized as an 18F-2-fluorodeoxyglucose (18F-FDG)-avid structure in routine clinical PET/CT studies; however, with the total-body PET/CT, we have been increasingly visualizing GB activity without it being involved in an inflammatory or neoplastic process. The aim of this study was to report visualization rates and characteristics of GB 18F-FDG uptake observed in both healthy and oncological subjects scanned on a total-body PET/CT system.Materials and methodsScans from 73 participants (48 healthy and 25 with newly diagnosed lymphoma) who underwent 18F-FDG total-body PET/CT were retrospectively reviewed. Subjects were scanned at multiple timepoints up to 3 h post-injection. Gallbladder 18F-FDG activity was graded using liver uptake as a reference, and the pattern was qualified as present in the wall, lumen, or both. Participants’ characteristics, such as age, sex, body-mass index, blood glucose, and other clinical parameters, were collected to assess for any significant correlation with GB 18F-FDG uptake.ResultsAll 73 subjects showed GB uptake at one or more imaging timepoints. An increase in uptake intensity overtime was observed up until the 180-min scan, and the visualization rate of GB 18F-FDG uptake was 100% in the 120- and 180-min post-injection scans. GB wall uptake was detected in a significant number of patients (44/73, 60%), especially at early timepoint scans, whereas luminal activity was detected in 71/73 (97%) subjects, especially at later timepoint scans. No significant correlation was found between GB uptake intensity/pattern and subjects’ characteristics.ConclusionThe consistent observation of GB 18F-FDG uptake recorded in this study in healthy participants and subjects with a new oncological diagnosis indicates that this is a normal physiologic finding rather than representing an exception.

Dynamic chest computed tomography change analysis and prediction of length of stay for delta variant COVID-19 patients

OBJECTIVE: As hospital admission rate is high during the COVID-19 pandemic, hospital length of stay (LOS) is a key indicator of medical resource allocation. This study aimed to elucidate specific dynamic longitudinal computed tomography (CT) imaging changes for patients with COVID-19 over in-hospital and predict individual LOS of COVID-19 patients with Delta variant of SARS-CoV-2 using the machine learning method. MATERIALS AND METHODS: This retrospective study recruited 448 COVID-19 patients with a total of 1761 CT scans from July 14, 2021 to August 20, 2021 with an averaged hospital LOS of 22.5 ± 7.0 days. Imaging features were extracted from each CT scan, including CT morphological characteristics and artificial intelligence (AI) extracted features. Clinical features were obtained from each patient's initial admission. The infection distribution in lung fields and progression pattern tendency was analyzed. Then, to construct a model to predict patient LOS, each CT scan was considered as an independent sample to predict the LOS from the current CT scan time point to hospital discharge combining with the patients' corresponding clinical features. The 1761 follow-up CT data were randomly split into training set and testing set with a ratio of 7:3 at patient-level. A total of 85 most related clinical and imaging features selected by Least Absolute Shrinkage and Selection Operator were used to construct LOS prediction model. RESULTS: Infection-related features were obtained, such as the percentage of the infected region of lung, ground-glass opacity (GGO), consolidation and crazy-paving pattern, and air bronchograms. Their longitudinal changes show that the progression changes significantly in the earlier stages (0–3 days to 4–6 days), and then, changes tend to be statistically subtle, except for the intensity range between (−470 and −70) HU which exhibits a significant increase followed by a continuous significant decrease. Furthermore, the bilateral lower lobes, especially the right lower lobe, present more severe. Compared with other models, combining the clinical, imaging reading, and AI features to build the LOS prediction model achieved the highest R 2 of 0.854 and 0.463, Pearson correlation coefficient of 0.939 and 0.696, and lowest mean absolute error of 2.405 and 4.426, and mean squared error of 9.176 and 34.728 on the training and testing set. CONCLUSION: The most obvious progression changes were significantly in the earlier stages (0–3 days to 4–6 days) and the bilateral lower lobes, especially the right lower lobe. GGO, consolidation, and crazy-paving pattern and air bronchograms are the most main CT findings according to the longitudinal changes of infection-related features with LOS (day). The LOS prediction model of combining clinical, imaging reading, and AI features achieved optimum performance.

P2.03-01 Initial Biodistribution Data of ImmunoPET A Phase 0/1 Study Characterising PD-L1 with 89 Zr-Durvalumab (MEDI4736) PET/CT

ImmunoPET is a multicentre, single arm, phase 0-1 study investigating the use of 89Zr-durvalumab PET/CT to interrogate the expression of PD-L1 in patients with NSCLC. We present the initial biodistribution data, which is being used to establish the safety and scan timepoints for a multicentre study in Stage III patients.

Longitudinal detection of new MS lesions using deep learning.

The detection of new multiple sclerosis (MS) lesions is an important marker of the evolution of the disease. The applicability of learning-based methods could automate this task efficiently. However, the lack of annotated longitudinal data with new-appearing lesions is a limiting factor for the training of robust and generalizing models. In this study, we describe a deep-learning-based pipeline addressing the challenging task of detecting and segmenting new MS lesions. First, we propose to use transfer-learning from a model trained on a segmentation task using single time-points. Therefore, we exploit knowledge from an easier task and for which more annotated datasets are available. Second, we propose a data synthesis strategy to generate realistic longitudinal time-points with new lesions using single time-point scans. In this way, we pretrain our detection model on large synthetic annotated datasets. Finally, we use a data-augmentation technique designed to simulate data diversity in MRI. By doing that, we increase the size of the available small annotated longitudinal datasets. Our ablation study showed that each contribution lead to an enhancement of the segmentation accuracy. Using the proposed pipeline, we obtained the best score for the segmentation and the detection of new MS lesions in the MSSEG2 MICCAI challenge.

Mastoid Growth and the Configuration of Cochlear Implant Electrode Lead.

To study the changes in the coiled configuration of electrode excess lead in the mastoid cavity in the cochlear implant recipients over time. Post-operative CT scans at two different appointments of fourteen patients with cochlear implants (CI) were retrospectively analyzed using a DICOM viewer software (3D-slicer). Mastoid thickness (MT) was measured in the oblique coronal plane from the round window (RW) entrance to the mastoid edge and inter-cochlear distance (ICD) was measured in the axial plane at the fundus level between two ears. 3D segmentation of the entire inner ear of both sides and coiled electrode excess lead was performed to visually compare the changes in coiled configuration between the two CT scan time points. MT and ICD increased logarithmically with the patient's age, as has been measured from both the 1st and the 2nd CT scans and a weak linear correlation between MT and ICD was observed. Growth in MT and ICT measured between the time of 1st and 2nd CT scans showed a strong linear correlation. In eight cases, changes in the electrode excess lead have been observed in the 2nd CT scan, either a change in the coiling configuration of electrode excess lead or shifted laterally toward the mastoid edge. The ICD growth between the 1st and the 2nd CT scans was >2mm in only seven cases and all of them were children. All other six cases had no observed changes in the coiled electrode lead. In addition, the mastoid growth between the 1st and the 2nd CT scan was >2.5mm in only 4 cases. Coiled configuration of electrode excess lead could change when the MT and ICD increased over time.

T2 relaxation time for the early prediction of treatment response to chemoradiation in locally advanced rectal cancer

ObjectivesPoor responders to chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC) can still have a good prognosis if the treatment strategy is changed in time. However, no reliable predictor of early-treatment response has been identified. The purpose of this study was to investigate the role of T2 relaxation time in magnetic resonance imaging (MRI) for the early prediction of a pathological response to CRT in LARC.MethodsA total of 123 MRIs were performed on 41 LARC patients immediately before, during, and after CRT. The corresponding tumor volume, T2 relaxation time, and apparent diffusion coefficient (ADC) values at different scan time points were obtained. The Mann–Whitney U test was used to compare the T2 relaxation time between pathological good responders (GR) and non-good responders (non-GR). The area under the curve (AUC) value was used to quantify the diagnostic ability of each parameter in predicting tumor response to CRT.ResultsTwenty-one (51%) and 20 (49%) were GRs and non-GRs, respectively. T2 relaxation time showed an excellent intraclass correlation coefficient (ICC) of > 0.85 at three-time points. It was significantly lower in the GR group than in the non-GR group during and after CRT. The early T2 decrease had a high AUC of 0.91 in differentiating non-GRs and GRs, similar to 0.90 of the T2 value after CRT.ConclusionsT2 relaxation time may help predict treatment response to CRT for LARC earlier, rather than having to wait until the end of CRT, thereby alleviating the physical burden for patients with no good response.

Is a single late SPECT/CT based kidney 177Lu-dosimetry superior to hybrid dosimetry with sequential multiple time-point whole-body planar scans in combination with an early SPECT/CT?

PurposeThe aim is to assess the impact of different imaging-protocols on image-based kidney dosimetry in 177Lu labelled peptide receptor radiotherapies. MethodsKidney data of five [177Lu]Lu-OPS201 injected pigs and a 3D printed phantom were used for comparing the absorbed doses and time-integrated activity coefficients calculated based on the following imaging-protocols: A-) multiple time-point SPECT/CTs, B-) multiple time-point planar scans in combination with one SPECT/CT, C-) single time-point SPECT/CT. In addition, the influence of late scan time-points on kidney dosimetry was investigated by sequentially eliminating scan data at > 100 h from the pig/phantom datasets for imaging-protocols A and B. ResultsCompared to imaging-protocol A, absorbed doses based on imaging-protocols B and C (scans at > 24 h post-injection) were always lower (differences > 34%). The best agreement in absorbed dose was achieved by imaging-protocol C at ∼ 100 h post-injection (difference: 4%). Regarding the phantom/pig experiments, eliminating scan data at > 100 h post-injection increased the time-integrated activity coefficients calculated based on imaging-protocols A and B by up to 83%. ConclusionWhile imaging-protocol A is accurate if scans at >∼100 h are included, it is time-consuming. In addition to being time-consuming, imaging-protocol B shows high differences associated with organ-count overlay, a lack of accuracy concerning the geometric mean based 2D attenuation correction, and 2D background subtraction due to the inhomogeneous and time-varying background contributions. Our findings indicate that dosimetry based on imaging-protocol C, if appropriately performed, provides similar kidney absorbed doses compared to imaging-protocol A, while only a single scan time-point is necessary.

Validation of deep learning-based nonspecific estimates for amyloid burden quantification with longitudinal data

PurposeTo validate our previously proposed method of quantifying amyloid-beta (Aβ) load using nonspecific (NS) estimates generated with convolutional neural networks (CNNs) using [18F]Florbetapir scans from longitudinal and multicenter ADNI data. Methods188 paired MR (T1-weighted and T2-weighted) and PET images were downloaded from the ADNI3 dataset, of which 49 subjects had 2 time-point scans. 40 Aβ- subjects with low specific uptake were selected for training. Multimodal ScaleNet (SN) and monomodal HighRes3DNet (HRN), using either T1-weighted or T2-weighted MR images as inputs) were trained to map structural MR to NS-PET images. The optimized SN and HRN networks were used to estimate the NS for all scans and then subtracted from SUVr images to determine the specific amyloid load (SAβL) images. The association of SAβL with various cognitive and functional test scores was evaluated using Spearman analysis, as well as the differences in SAβL with cognitive test scores for 49 subjects with 2 time-point scans and sensitivity analysis. ResultsSAβL derived from both SN and HRN showed higher association with memory-related cognitive test scores compared to SUVr. However, for longitudinal scans, only SAβL estimated from multimodal SN consistently performed better than SUVr for all memory-related cognitive test scores. ConclusionsOur proposed method of quantifying Aβ load using NS estimated from CNN correlated better than SUVr with cognitive decline for both static and longitudinal data, and was able to estimate NS of [18F]Florbetapir. We suggest employing multimodal networks with both T1-weighted and T2-weighted MR images for better NS estimation.

18F]Fluorothymidine(FLT)-PET imaging of thymidine kinase 1 pharmacodynamics in non-small cell lung cancer treated with pemetrexed.

3070 Background: Imaging of tumor proliferation has been studied with FLT-PET in various tumor types including NSCLC. Pemetrexed inhibits thymidylate synthase(TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide formyltransferase (GARFT). TS inhibition upregulates the thymidine salvage pathway including relocalisation of ENT1 to membrane and TK1 activation as a transient “flare” response. We hypothesise that this can be detected as an increase in FLT tumoral uptake that subsequently decreases with reduced proliferation. This study was conducted to assess FLT uptake as an early pharmacodynamics(PD) marker of pemetrexed response. Methods: This was an open-label imaging study in 21 patients with Stage 3/4 NSCLC treated with pemetrexed and platinum-based chemotherapy. Patients underwent FLT PET/CT scan at baseline and 4h after administration of pemetrexed. Platinum component of treatment was administered on the day after second FLT scan for cycle 1. Plasma for TK1 activity expression were collected before each scan time point and analysed by ELISA. Percentage change in standardized uptake value (%ΔSUV) was calculated as [SUV(PET2) – SUV(PET1)]/ SUV(PET1)*100. Treatment response calculated by RECIST 1. 1 and survival data were collected. Results: 17 patients had evaluable PET/CT scans for pemetrexed response. Median percentage difference for SUVmean and SUVmax in tumour lesions increased by 3% and 10.3% respectively. 5 patients showed homogeneous FLT flare at 4h after pemetrexed, 2 patients had decrease, 10 patients had heterogeneous FLT response (regardless of platinum doublet). There was no significant correlation between plasma TK1 activity and FLT flare. At 9 weeks, 4 patients had partial response, 9 stable disease and 4 progressive disease. Baseline and weighted average ΔSUVmax were not associated with survival. The 5 patients with FLT flare in all lesions showed a median OS of 31 months, unlike the group with heterogenous or decrease uptake(15 months). FLT uptake in bone marrow and small bowel significantly increased at 4h (t test p = 0.004, p = 0.004, respectively) indicating increased thymidine salvage activity. Early FLT uptake was not predictive for tumour RECIST response or OS. In multivariable cox regression analysis, pre-treatment TK1 activity, adjusted for performance status, smoking history and age, independently affected survival in this group (p = 0.011). Conclusions: Early FLT flare at 4h was seen in NSCLC post pemetrexed administration indicating activation of thymidine salvage pathway. Median overall survival of patients with an FLT flare response was more than twice longer than patients with mixed or no response. However, the small sample size lacked power to show statistical significance in the OS comparison. Further studies should evaluate this and the relationship to other prognostic variables in a larger cohort of patients. Clinical trial information: NCRI UK badge 9249.

Longitudinal [18F]GE-180 PET Imaging Facilitates In Vivo Monitoring of TSPO Expression in the GL261 Glioblastoma Mouse Model.

The 18 kDa translocator protein (TSPO) is increasingly recognized as an interesting target for the imaging of glioblastoma (GBM). Here, we investigated TSPO PET imaging and autoradiography in the frequently used GL261 glioblastoma mouse model and aimed to generate insights into the temporal evolution of TSPO radioligand uptake in glioblastoma in a preclinical setting. We performed a longitudinal [18F]GE-180 PET imaging study from day 4 to 14 post inoculation in the orthotopic syngeneic GL261 GBM mouse model (n = 21 GBM mice, n = 3 sham mice). Contrast-enhanced computed tomography (CT) was performed at the day of the final PET scan (±1 day). [18F]GE-180 autoradiography was performed on day 7, 11 and 14 (ex vivo: n = 13 GBM mice, n = 1 sham mouse; in vitro: n = 21 GBM mice; n = 2 sham mice). Brain sections were also used for hematoxylin and eosin (H&E) staining and TSPO immunohistochemistry. [18F]GE-180 uptake in PET was elevated at the site of inoculation in GBM mice as compared to sham mice at day 11 and later (at day 14, TBRmax +27% compared to sham mice, p = 0.001). In GBM mice, [18F]GE-180 uptake continuously increased over time, e.g., at day 11, mean TBRmax +16% compared to day 4, p = 0.011. [18F]GE-180 uptake as depicted by PET was in all mice co-localized with contrast-enhancement in CT and tissue-based findings. [18F]GE-180 ex vivo and in vitro autoradiography showed highly congruent tracer distribution (r = 0.99, n = 13, p < 0.001). In conclusion, [18F]GE-180 PET imaging facilitates non-invasive in vivo monitoring of TSPO expression in the GL261 GBM mouse model. [18F]GE-180 in vitro autoradiography is a convenient surrogate for ex vivo autoradiography, allowing for straightforward identification of suitable models and scan time-points on previously generated tissue sections.

Abstract OT2-18-01: Harnessing olaparib, palbociclib, and endocrine therapy (HOPE): Phase I/II trial of olaparib, palbociclib and fulvestrant in patients with BRCA1/2-associated, hormone receptor-positive, HER2-negative metastatic breast cancer

Abstract Background: Hormone receptor-positive (HR+) metastatic breast cancer (MBC) that occurs in the context of a germline or somatic BRCA1 or BRCA2 (BRCA1/2) mutation has dual drivers: hormone receptor signaling and homologous recombination deficiency. The PALOMA-3 trial studied the selective estrogen receptor downregulator fulvestrant and the CDK4 and CDK6 inhibitor (CDK4/6i) palbociclib in patients with HR+ MBC. Compared with fulvestrant and placebo, combination fulvestrant and palbociclib demonstrated significant and clinically meaningful improvements in progression-free survival (PFS) and overall survival. The OlympiAD trial examined patients with HER2-negative MBC and a germline BRCA1/2 mutation who were treated with the poly(ADP-ribose) polymerase inhibitor (PARPi) olaparib or non-platinum chemotherapy. Olaparib resulted in improved PFS, double the response rate, and a lower risk of disease progression or death compared to chemotherapy. Despite these remarkable therapeutic advances, resistance to treatment inevitably develops and contributes to mortality in patients with MBC. Targeting dual therapeutic drivers concurrently may delay or circumvent resistance; however, olaparib and palbociclib have overlapping hematologic toxicity and the safety of combined olaparib, palbociclib and fulvestrant has not been determined. Methods: HOPE (NCT03685331) is a phase I/II clinical trial to evaluate the safety and efficacy of olaparib, palbociclib and fulvestrant in patients with HR+ MBC and a pathogenic or likely pathogenic germline or somatic variant in BRCA1/2. Eligible patients are biological males, postmenopausal females, or premenopausal females on ovarian suppression who have an ECOG performance status 0-1, measureable/evaluable breast cancer, any/no prior endocrine therapy, and 0-2 prior lines of chemotherapy for MBC. Prior platinum chemotherapy is allowed for curative intent treatment if completed at least 12 months prior to diagnosis of metastatic disease, or for MBC if there was no progression during therapy. Prior PARPi and prior CDK4/6i are permitted without restriction during phase I, and are permitted during phase II provided there was no progression on these therapies. Treatment (28-day cycles) consists of: olaparib 300mg by mouth twice daily continuously; fulvestrant 500mg intramuscularly on day 1 of each cycle and day 15 of the first cycle; and oral palbociclib once daily on days 1-21. For phase I, palbociclib dose is based on dosing cohort. Dose Levels (DL) are: DL 0 (starting level), 75mg; DL 1, 100mg; DL 2, 125mg. Phase I treatment begins with a 28-day safety run-in of fulvestrant and olaparib alone. For phase II, palbociclib will be dosed at MTD. Subjects will have archival tissue collection or fresh biopsy at baseline as well as research blood samples for cfDNA analysis at baseline, at progression, and at all scan timepoints (every 3 cycles). The phase I primary endpoint is determination of MTD. A 3+3 dose escalation design will be utilized with a 30% rate of dose limiting toxicity (DLT) deemed acceptable, and 6 patients treated at a dose for it to be declared MTD. This schema yields a minimum of 2 and a maximum of 18 patients on the phase I. For the phase II trial, the primary endpoint is PFS estimated using Kaplan-Meier methods and secondary efficacy endpoints are objective response rate and 24-week clinical benefit rate. The phase II trial will evaluate 54 subjects to provide 80% power to detect an increase in PFS from 7 months with olaparib monotherapy to 10 months. Exploratory objectives include examination of baseline tissue for PARPi predictive biomarkers and measures of tumor immunogenicity as well as serial serum evaluation for reversion mutations. Enrollment has begun. Citation Format: Alexandra Torres, Carey Kokkonen, Mary Oladeji, Kurt D'Andrea, Rosemarie Mick, Vivek Narayan, Michael Mallamaci, Gayle Ewing, Hayley Knollman, Nadine M. Tung, Mark Robson, Katherine L. Nathanson, Susan Domchek, Payal D. Shah. Harnessing olaparib, palbociclib, and endocrine therapy (HOPE): Phase I/II trial of olaparib, palbociclib and fulvestrant in patients with BRCA1/2-associated, hormone receptor-positive, HER2-negative metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-18-01.