Pulmonary Metastatic Follicular Thyroid Carcinoma Without Intrathyroidal Primary Thyroid Cancer.

Background/Objective: Follicular thyroid cancer without an intrathyroidal primary cancer is rare. We present a patient with multifocal pulmonary metastatic follicular thyroid cancer without apparent cancer within her thyroid. Case Report: A 44-year-old woman was referred to the thyroid cancer clinic via telemedicine for evaluation of intrapulmonary thyroid tissue. Her past medical history included Roux-en-Y gastric bypass and hysterectomy with bilateral oophorectomy. Six months prior, abdominal computed tomography (CT) showed incidental bilateral lung nodules. Chest CT demonstrated 4 solid left and 1 solid right lung nodules. Lung nodule core biopsy revealed benign thyroid tissue. Thyroid ultrasound showed bilateral subcentimeter anechoic nodules. Chest CT 6 months after initial CT demonstrated stable lung nodules. The levels of thyroid-stimulating hormone, serum thyroglobulin, and thyroglobulin antibody were 1.63 mIU/L (reference range, 0.3-5.5 mIU/L), 40.9 ng/mL (reference range, 0-35 ng/mL), and <1 IU/mL (reference range, <4), respectively. Positron emission tomography/CT showed fluorodeoxyglucose-avid lung lesions measuring 1.5, 1.1, and 2.2 cm and other subcentimeter pulmonary nodules. Repeat lung core biopsy showed thyroid tissue with microfollicular architecture, favoring metastatic follicular carcinoma with neuroblastoma-RAS gene (NRAS) mutation. Total thyroidectomy performed showed multinodular hyperplasia without thyroid cancer. Her postoperative radioiodine scan demonstrated bilateral iodine-avid pulmonary nodules, a serum thyroglobulin level of 179.8 ng/mL, a thyroid-stimulating hormone level of 151.3 mIU/L, and undetectable serum thyroglobulin antibody. She received 261 mCi of radioactive iodine. Fourteen months later, chest CT revealed decreased lung nodules and a serum thyroglobulin level of 0.7 ng/mL. Discussion: Approximately 2 cases of multifocal pulmonary follicular thyroid cancer without a primary source and no other site of metastasis have been reported. Conclusion: Pulmonary follicular thyroid cancer without a primary source and no other site of metastasis is extremely rare.

Enhancing precision: A predictive model for 177Lu-DOTATATE treatment response in neuroendocrine tumors using quantitative 68Ga-DOTATATE PET and clinicopathological biomarkers.

Purpose: This study aims to elucidate the role of quantitative SSTR-PET metrics and clinicopathological biomarkers in the progression-free survival (PFS) and overall survival (OS) of neuroendocrine tumors (NETs) treated with peptide receptor radionuclide therapy (PRRT). Methods: A retrospective analysis including 91 NET patients (M47/F44; age 66 years, range 34-90 years) who completed four cycles of standard 177Lu-DOTATATE was conducted. SSTR-avid tumors were segmented from pretherapy SSTR-PET images using a semiautomatic workflow with the tumors labeled based on the anatomical regions. Multiple image-based features including total and organ-specific tumor volume and SSTR density along with clinicopathological biomarkers including Ki-67, chromogranin A (CgA) and alkaline phosphatase (ALP) were analyzed with respect to the PRRT response. Results: The median OS was 39.4 months (95% CI: 33.1-NA months), while the median PFS was 23.9 months (95% CI: 19.3-32.4 months). Total SSTR-avid tumor volume (HR = 3.6; P = 0.07) and bone tumor volume (HR = 1.5; P = 0.003) were associated with shorter OS. Also, total tumor volume (HR = 4.3; P = 0.01), liver tumor volume (HR = 1.8; P = 0.05) and bone tumor volume (HR = 1.4; P = 0.01) were associated with shorter PFS. Furthermore, the presence of large lesion volume with low SSTR uptake was correlated with worse OS (HR = 1.4; P = 0.03) and PFS (HR = 1.5; P = 0.003). Among the biomarkers, elevated baseline CgA and ALP showed a negative association with both OS (CgA: HR = 4.9; P = 0.003, ALP: HR = 52.6; P = 0.004) and PFS (CgA: HR = 4.2; P = 0.002, ALP: HR = 9.4; P = 0.06). Similarly, number of prior systemic treatments was associated with shorter OS (HR = 1.4; P = 0.003) and PFS (HR = 1.2; P = 0.05). Additionally, tumors originating from the midgut primary site demonstrated longer PFS, compared to the pancreas (HR = 1.6; P = 0.16), and those categorized as unknown primary (HR = 3.0; P = 0.002). Conclusion: Image-based features such as SSTR-avid tumor volume, bone tumor involvement, and the presence of large tumors with low SSTR expression demonstrated significant predictive value for PFS, suggesting potential clinical utility in NETs management. Moreover, elevated CgA and ALP, along with an increased number of prior systemic treatments, emerged as significant factors associated with worse PRRT outcomes.

Feasibility and reliability of measured glomerular filtration rate with [I125]-iothalamate among young adults with mild-to-moderate cerebral palsy.

Objective: Despite the need, measuring glomerular filtration rate (mGFR) is not routinely performed for adults with cerebral palsy (CP), possibly due to unknown feasibility given the secondary complications of CP. This study aimed to assess the feasibility and reliability of mGFR and explore factors associated with eGFR-mGFR discordance among young adults with mild-to-moderate CP. Methods: This single-center, cross-sectional study included 18- to 40-year-olds with CP gross motor function classification system (GMFCS) I-III. The participants were excluded if they were pregnant/lactating, had cognitive impairments, or had contraindications to mGFR. A routine clinical protocol for mGFR and eGFR was used. mGFR feasibility was assessed based on the number of participants who completed testing. mGFR reliability was assessed using the coefficient of variation (CV) across the four 30 min intervals. The association between age, sex, and GMFCS and the percentage of eGFR-mGFR discordance was assessed. Results: Of the 19 participants enrolled, 18 completed the testing [mean age (SD), 29.9 (7.4) years, n = 10 female participants, n = 10/3/5 for GMFCS I/II/III] and most (n = 15) of the participants had an mGFR >90 mL/min; 14 participants (77.8%) had a CV <20%, 2 had a CV between 20 and 25%, and 2 had a CV >50%. eGFR overestimated mGFR by a median (interquartile range) of approximately 17.5% (2-38%); the full range of mis-estimation was -20.5 to 174.3%. Increasing age and GMFCS levels exhibited notable, but weak-to-modest, associations with a larger eGFR-mGFR discordance. Discussion: Obtaining mGFR was feasible and reasonably reliable within this small sample. eGFR overestimated mGFR by a notable amount, which may be associated with patient-level factors.

3-[18F]Fluoro-para-hydroxyphenethylguanidine (3-[18F]pHPG) PET-A Novel Imaging Modality for Paraganglioma.

Context: Functional positron emission tomography (PET) imaging for the characterization of pheochromocytoma and paraganglioma (PCC/PGL) and for detection of metastases in malignant disease, offers valuable clinical insights that can significantly guide patient treatment. Objective: This work aimed to evaluate a novel PET radiotracer, 3-[18F]fluoro-para-hydroxyphenethylguanidine (3-[18F]pHPG), a norepinephrine analogue, for its ability to localize PCC/PGL. Methods: 3-[18F]pHPG PET/CT whole-body scans were performed on 16 patients (8 male:8 female; mean age 47.6 ± 17.6 years; range, 19-74 years) with pathologically confirmed or clinically diagnosed PCC/PGL. After intravenous administration of 304 to 475 MBq (8.2-12.8 mCi) of 3-[18F]pHPG, whole-body PET scans were performed at 90 minutes in all patients. 3-[18F]pHPG PET was interpreted for abnormal findings consistent with primary tumor or metastasis, and biodistribution in normal organs recorded. Standardized uptake value (SUV) measurements were obtained for target lesions and physiological organ distributions. Results: 3-[18F]pHPG PET showed high radiotracer uptake and trapping in primary tumors, and metastatic tumor lesions that included bone, lymph nodes, and other solid organ sites. Physiological biodistribution was universally present in salivary glands (parotid, submandibular, sublingual), thyroid, heart, liver, adrenals, kidneys, and bladder. Comparison [68Ga]DOTATATE PET/CT was available in 10 patients and in all cases showed concordant distribution. Comparison [123I]meta-iodobenzylguanidine [123I]mIBG planar scintigraphy and SPECT/CT scans were available for 4 patients, with 3-[18F]pHPG showing a greater number of metastatic lesions. Conclusion: We found the kinetic profile of 3-[18F]pHPG PET affords high activity retention within benign and metastatic PCC/PGL. Therefore, 3-[18F]pHPG PET imaging provides a novel modality for functional imaging and staging of malignant paraganglioma with advantages of high lesion affinity, whole-body coregistered computed tomography, and rapid same-day imaging.

SPECT/CT Image-Derived Absorbed Dose to Red Marrow Correlates with Hematologic Toxicity in Patients Treated with [177Lu]Lu-DOTATATE.

Hematologic toxicity, although often transient, is the most common limiting adverse effect during somatostatin peptide receptor radionuclide therapy. This study investigated the association between Monte Carlo-derived absorbed dose to the red marrow (RM) and hematologic toxicity in patients being treated for their neuroendocrine tumors. Methods: Twenty patients each receiving 4 treatment cycles of [177Lu]Lu-DOTATATE were included. Multiple-time-point 177Lu SPECT/CT imaging-based RM dosimetry was performed using an artificial intelligence-driven workflow to segment vertebral spongiosa within the field of view (FOV). This workflow was coupled with an in-house macroscale/microscale Monte Carlo code that incorporates a spongiosa microstructure model. Absorbed dose estimates to RM in lumbar and thoracic vertebrae within the FOV, considered as representations of the whole-body RM absorbed dose, were correlated with hematologic toxicity markers at about 8 wk after each cycle and at 3- and 6-mo follow-up after completion of all cycles. Results: The median of absorbed dose to RM in lumbar and thoracic vertebrae within the FOV (D median,vertebrae) ranged from 0.019 to 0.11 Gy/GBq. The median of cumulative absorbed dose across all 4 cycles was 1.3 Gy (range, 0.6-2.5 Gy). Hematologic toxicity was generally mild, with no grade 2 or higher toxicity for platelets, neutrophils, or hemoglobin. However, there was a decline in blood counts over time, with a fractional value relative to baseline at 6 mo of 74%, 97%, 57%, and 97%, for platelets, neutrophils, lymphocytes, and hemoglobin, respectively. Statistically significant correlations were found between a subset of hematologic toxicity markers and RM absorbed doses, both during treatment and at 3- and 6-mo follow-up. This included a correlation between the platelet count relative to baseline at 6-mo follow up: D median,vertebrae (r = -0.64, P = 0.015), D median,lumbar (r = -0.72, P = 0.0038), D median,thoracic (r = -0.58, P = 0.029), and D average,vertebrae (r = -0.66, P = 0.010), where D median,lumbar and D median,thoracic are median absorbed dose to the RM in the lumbar and thoracic vertebrae, respectively, within the FOV and D average,vertebrae is the mass-weighted average absorbed dose of all vertebrae. Conclusion: This study found a significant correlation between image-derived absorbed dose to the RM and hematologic toxicity, including a relative reduction of platelets at 6-mo follow up. These findings indicate that absorbed dose to the RM can potentially be used to understand and manage hematologic toxicity in peptide receptor radionuclide therapy.

Single-Time-Point Imaging for Dosimetry After [177Lu]Lu-DOTATATE: Accuracy of Existing Methods and Novel Data-Driven Models for Reducing Sensitivity to Time-Point Selection.

Estimation of the time-integrated activity (TIA) for dosimetry from imaging at a single time point (STP) facilitates the clinical translation of dosimetry-guided radiopharmaceutical therapy. However, the accuracy of the STP methods for TIA estimation varies on the basis of time-point selection. We constructed patient data-driven regression models to reduce the sensitivity to time-point selection and to compare these new models with commonly used STP methods. Methods: SPECT/CT performed at time period (TP) 1 (3-5 h), TP2 (days 1-2), TP3 (days 3-5), and TP4 (days 6-8) after cycle 1 of [177Lu]Lu-DOTATATE therapy involved 27 patients with 100 segmented tumors and 54 kidneys. Influenced by the previous physics-based STP models of Madsen et al. and Hänscheid et al., we constructed an STP prediction expression, TIA = A(t) × g(t), in a SPECT data-driven way (model 1), in which A(t) is the observed activity at imaging time t, and the curve, g(t), is estimated with a nonparametric generalized additive model by minimizing the normalized mean square error relative to the TIA derived from 4-time-point SPECT (reference TIA). Furthermore, we fit a generalized additive model that incorporates baseline biomarkers as auxiliary data in addition to the single activity measurement (model 2). Leave-one-out cross validation was performed to evaluate STP models using mean absolute error (MAE) and mean square error between the predicted and reference TIA. Results: At days 3-5, all evaluated STP methods performed very well, with an MAE of less than 7% (between-patient SD of <10%) for both kidneys and tumors. At other TPs, the Madsen method and data-driven models 1 and 2 performed reasonably well (MAEs < 17% for kidneys and < 32% for tumors), whereas the error with the Hänscheid method was substantially higher. The proof of concept of adding baseline biomarkers to the prediction model was demonstrated and showed a moderate enhancement at TP1, especially for estimating kidney TIA (MAE ± SD from 15.6% ± 1.3% to 11.8% ± 1.0%). Evaluations on 500 virtual patients using clinically relevant time-activity simulations showed a similar performance. Conclusion: The performance of the Madsen method and proposed data-driven models is less sensitive to TP selection than is the Hänscheid method. At the earliest TP, which is the most practical, the model incorporating baseline biomarkers outperforms other methods that rely only on the single activity measurement.

Effects of ketone supplements on blood ß-hydroxybutyrate, glucose and insulin: A systematic review and three-level meta-analysis.

BACKGROUND: Effects of ketone supplements as well as relevant dose-response relationships and time effects on blood ß-hydroxybutyrate (BHB), glucose and insulin are controversial. OBJECTIVE: This study aimed to summarize the existing evidence and synthesize the results, and demonstrate underlying dose-response relationships as well as sustained time effects. METHODS: Medline, Web of Science, Embase, and Cochrane Central Register of Controlled Trials were searched for relevant randomized crossover/parallel studies published until 25th November 2022. Three-level meta-analysis compared the acute effects of exogenous ketone supplementation and placebo in regulating blood parameters, with Hedge's g used as measure of effect size. Effects of potential moderators were explored through multilevel regression models. Dose-response and time-effect models were established via fractional polynomial regression. RESULTS: The meta-analysis with 327 data points from 30 studies (408 participants) indicated that exogenous ketones led to a significant increase in blood BHB (Hedge's g = 1.4994, 95% CI [1.2648, 1.7340]), reduction in glucose (Hedge's g = -0.3796, 95% CI [-0.4550, -0.3041]), and elevation in insulin of non-athlete healthy population (Hedge's g = 0.1214, 95%CI [0.0582, 0.3011]), as well as insignificant change in insulin of obesity and prediabetes. Nonlinear dose-response relationship between ketone dosage and blood parameter change was observed in some time intervals for BHB (30-60 min; >120 min) and insulin (30-60 min; 90-120 min), with linear relationship observed for glucose (>120 min). Nonlinear associations between time and blood parameter change were found in BHB (>550 mg/kg) and glucose (450-550 mg/kg), with linear relationship observed in BHB (≤250 mg/kg) and insulin (350-550 mg/kg). CONCLUSION: Dose-response relationships and sustained time effects were observed in BHB, glucose and insulin following ketone supplementation. Glucose-lowering effect without increasing insulin load among population of obesity and prediabetes was of remarkable clinical implication. REGISTRY AND REGISTRY NUMBER: PROSPERO (CRD42022360620).

The predictive value of pretherapy [68Ga]Ga-DOTA-TATE PET and biomarkers in [177Lu]Lu-PRRT tumor dosimetry.

PURPOSE: Metastatic neuroendocrine tumors (NETs) overexpressing type 2 somatostatin receptors are the target for peptide receptor radionuclide therapy (PRRT) through the theragnostic pair of 68Ga/177Lu-DOTATATE. The main purpose of this study was to develop machine learning models to predict therapeutic tumor dose using pre therapy 68Ga -PET and clinicopathological biomarkers. METHODS: We retrospectively analyzed 90 segmented metastatic NETs from 25 patients (M14/F11, age 63.7 ± 9.5, range 38-76) treated by 177Lu-DOTATATE at our institute. Patients underwent both pretherapy [68Ga]Ga-DOTA-TATE PET/CT and four timepoints SPECT/CT at ~ 4, 24, 96, and 168 h post-177Lu-DOTATATE infusion. Tumors were segmented by a radiologist on baseline CT or MRI and transferred to co-registered PET/CT and SPECT/CT, and normal organs were segmented by deep learning-based method on CT of the PET and SPECT. The SUV metrics and tumor-to-normal tissue SUV ratios (SUV_TNRs) were calculated from 68Ga -PET at the contour-level. Posttherapy dosimetry was performed based on the co-registration of SPECT/CTs to generate time-integrated-activity, followed by an in-house Monte Carlo-based absorbed dose estimation. The correlation between delivered 177Lu Tumor absorbed dose and PET-derived metrics along with baseline clinicopathological biomarkers (such as Creatinine, Chromogranin A and prior therapies) were evaluated. Multiple interpretable machine-learning algorithms were developed to predict tumor dose using these pretherapy information. Model performance on a nested tenfold cross-validation was evaluated in terms of coefficient of determination (R2), mean-absolute-error (MAE), and mean-relative-absolute-error (MRAE). RESULTS: SUVmean showed a significant correlation (q-value < 0.05) with absorbed dose (Spearman ρ = 0.64), followed by TLSUVmean (SUVmean of total-lesion-burden) and SUVpeak (ρ = 0.45 and 0.41, respectively). The predictive value of PET-SUVmean in estimation of posttherapy absorbed dose was stronger compared to PET-SUVpeak, and SUV_TNRs in terms of univariate analysis (R2 = 0.28 vs. R2 ≤ 0.12). An optimal trivariate random forest model composed of SUVmean, TLSUVmean, and total liver SUVmean (normal and tumoral liver) provided the best performance in tumor dose prediction with R2 = 0.64, MAE = 0.73 Gy/GBq, and MRAE = 0.2. CONCLUSION: Our preliminary results demonstrate the feasibility of using baseline PET images for prediction of absorbed dose prior to 177Lu-PRRT. Machine learning models combining multiple PET-based metrics performed better than using a single SUV value and using other investigated clinicopathological biomarkers. Developing such quantitative models forms the groundwork for the role of 68Ga -PET not only for the implementation of personalized treatment planning but also for patient stratification in the era of precision medicine.

177Lu-DOTATATE Theranostics: Predicting Renal Dosimetry From Pretherapy 68Ga-DOTATATE PET and Clinical Biomarkers.

PURPOSE: Pretreatment predictions of absorbed doses can be especially valuable for patient selection and dosimetry-guided individualization of radiopharmaceutical therapy. Our goal was to build regression models using pretherapy 68Ga-DOTATATE PET uptake data and other baseline clinical factors/biomarkers to predict renal absorbed dose delivered by 177Lu-DOTATATE peptide receptor radionuclide therapy (177Lu-PRRT) for neuroendocrine tumors. We explore the combination of biomarkers and 68Ga PET uptake metrics, hypothesizing that they will improve predictive power over univariable regression. PATIENTS AND METHODS: Pretherapy 68Ga-DOTATATE PET/CTs were analyzed for 25 patients (50 kidneys) who also underwent quantitative 177Lu SPECT/CT imaging at approximately 4, 24, 96, and 168 hours after cycle 1 of 177Lu-PRRT. Kidneys were contoured on the CT of the PET/CT and SPECT/CT using validated deep learning-based tools. Dosimetry was performed by coupling the multi-time point SPECT/CT images with an in-house Monte Carlo code. Pretherapy renal PET SUV metrics, activity concentration per injected activity (Bq/mL/MBq), and other baseline clinical factors/biomarkers were investigated as predictors of the 177Lu SPECT/CT-derived mean absorbed dose per injected activity to the kidneys using univariable and bivariable models. Leave-one-out cross-validation (LOOCV) was used to estimate model performance using root mean squared error and absolute percent error in predicted renal absorbed dose including mean absolute percent error (MAPE) and associated standard deviation (SD). RESULTS: The median therapy-delivered renal dose was 0.5 Gy/GBq (range, 0.2-1.0 Gy/GBq). In LOOCV of univariable models, PET uptake (Bq/mL/MBq) performs best with MAPE of 18.0% (SD = 13.3%), and estimated glomerular filtration rate (eGFR) gives an MAPE of 28.5% (SD = 19.2%). Bivariable regression with both PET uptake and eGFR gives LOOCV MAPE of 17.3% (SD = 11.8%), indicating minimal improvement over univariable models. CONCLUSIONS: Pretherapy 68Ga-DOTATATE PET renal uptake can be used to predict post-177Lu-PRRT SPECT-derived mean absorbed dose to the kidneys with accuracy within 18%, on average. Compared with PET uptake alone, including eGFR in the same model to account for patient-specific kinetics did not improve predictive power. Following further validation of these preliminary findings in an independent cohort, predictions using renal PET uptake can be used in the clinic for patient selection and individualization of treatment before initiating the first cycle of PRRT.

Initial Feasibility and Acute Toxicity Outcomes From a Phase 2 Trial of 18F-Fluorodeoxyglucose Positron Emission Tomography Response-Based De-escalated Definitive Chemoradiotherapy for p16+ Oropharynx Cancer: A Planned Interim Analysis.

PURPOSE: 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET) parameters are prognostic of oncologic outcomes in human papillomavirus-associated oropharyngeal squamous cell carcinoma (OPSCC). We used FDG-PET imaging biomarkers to select patients for de-escalated chemoradiotherapy (CRT), hypothesizing that acute toxicity will be improved with de-escalation. METHODS AND MATERIALS: This is a planned interim initial feasibility and acute toxicity report from a phase 2, prospective, nonrandomized study, which enrolled patients with stage I-II p16+ OPSCC. All patients started definitive CRT to 70 Gy in 35 fractions, and those who met de-escalation criteria on midtreatment FDG-PET at fraction 10 completed treatment at 54 Gy in 27 fractions. We report the acute toxicity and patient-reported outcomes for 59 patients with a minimum follow-up of 3 months. RESULTS: There were no statistically significant differences between baseline patient characteristics in the standard and de-escalated cohorts. There were 28 of 59 (47.5%) patients who met FDG-PET de-escalation criteria and collectively received 20% to 30% less dose to critical organs at risk known to affect toxicity. At 3 months posttreatment, patients who received de-escalated CRT lost significantly less weight (median, 5.8% vs 13.0%; P < .001), had significantly less change from baseline in penetration-aspiration scale score (median, 0 vs 1; P = .018), and had significantly fewer aspiration events on repeat swallow study (8.0% vs 33.3%, P = .037) compared with patients receiving standard CRT. CONCLUSIONS: Approximately half of patients with early-stage p16+ OPSCC are selected for de-escalation of definitive CRT using midtreatment FDG-PET biomarkers, which resulted in significantly improved rates of observed acute toxicity. Further follow-up is ongoing and will be required to determine whether this de-escalation approach preserves the favorable oncologic outcomes for patients with p16+ OPSCC before adoption.

Comparative Effectiveness of Multiple Exercise Interventions in the Treatment of Mental Health Disorders: A Systematic Review and Network Meta-Analysis.

BACKGROUND: The efficacy of exercise interventions in the treatment of mental health disorders is well known, but research is lacking on the most efficient exercise type for specific mental health disorders. OBJECTIVE: The present study aimed to compare and rank the effectiveness of various exercise types in the treatment of mental health disorders. METHODS: The PubMed, Web of Science, PsycINFO, SPORTDiscus, CINAHL databases, and the Cochrane Central Register of Controlled Trials as well as Google Scholar were searched up to December 2021. We performed pairwise and network meta-analyses as well as meta-regression analyses for mental health disorders in general and each type of mental health disorder, with alterations in symptom severity as the primary outcome. RESULTS: A total of 6456 participants from 117 randomized controlled trials were surveyed. The multimodal exercise (71%) had the highest probability of being the most efficient exercise for relieving depressive symptoms. While resistance exercise (60%) was more likely to be the most effective treatment for anxiety disorder, patients with post-traumatic stress disorder (PTSD) benefited more from mind-body exercise (52%). Furthermore, resistance exercise (31%) and multimodal exercise (37%) had more beneficial effects in the treatment of the positive and negative symptoms of schizophrenia, respectively. The length of intervention and exercise frequency independently moderated the effects of mind-body exercise on depressive (coefficient = 0.14, p = .03) and negative schizophrenia (coefficient = 0.96, p = .04) symptoms. CONCLUSION: Multimodal exercise ranked best for treating depressive and negative schizophrenic symptoms, while resistance exercise seemed to be more beneficial for those with anxiety-related and positive schizophrenic symptoms. Mind-body exercise was recommended as the most promising exercise type in the treatment of PTSD. However, the findings should be treated with caution due to potential risk of bias in at least one dimension of assessment and low-to-moderate certainty of evidence. Trial Registration This systematic review was registered in the PROSPERO international prospective register of systematic reviews (CRD42022310237).

Advanced imaging and theranostics in thyroid cancer.

PURPOSE OF REVIEW: Thyroid cancers are endocrine neoplasms with diverse gene expression and behavior, for which constantly evolving anatomic and functional imaging/theranostic agents have an essential role for diagnosis, staging, and treatment. RECENT FINDINGS: To achieve definitive diagnosis, neck ultrasound and associated risk stratification systems, notably Thyroid Imaging Reporting and Data System (TI-RADS), allow improved thyroid nodule characterization and management guidance. Radioactive iodine-131 (RAI) has long played a role in management of differentiated thyroid cancer (DTC), with recent literature emphasizing its effectiveness for intermediate-high risk cancers, exploring use of dosimetry for personalized medicine, and potential for retreatment with RAI following tumor redifferentiation. Iodine-124 positron emission tomography/computed tomography (PET/CT) has promising application for DTC staging and dosimetry. F18-fluorodeoxyglucose (FDG) PET/CT is used for staging of high risk DTC and identification of noniodine-avid disease recurrences, with metabolic uptake consistently portending poor prognosis. Poorly differentiated and anaplastic thyroid cancers are best assessed with anatomic imaging and F18-FDG PET/ CT, though recent studies show a potential theranostic role for Ga68/Lu177-prostate-specific membrane antigen. Medullary thyroid cancers are evaluated with ultrasound, CT, magnetic resonance imaging, and various positron-emitting radiotracers for PET imaging (F18-DOPA, F18-FDG, and recently Ga68-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-octreotate (DOTATATE)); the latter may enable treatment with Lu177-DOTATATE. SUMMARY: Multidisciplinary collaboration is essential to streamline appropriate management, given the wide array of available imaging and new therapies for metabolic and genetically complex cancers.

Differences in tumor-to-normal organ SUV ratios measured with 68 Ga-DOTATATE PET compared with 177 Lu-DOTATATE SPECT in patients with neuroendocrine tumors.

BACKGROUND: Our goal is to quantitatively compare radiotracer biodistributions within tumors and major normal organs on pretherapy 68 Ga-DOTATATE PET to post-therapy 177 Lu-DOTATATE single-photon emission computed tomography (SPECT) in patients receiving peptide receptor radionuclide therapy (PRRT). METHODS: PET/CT at ~ 60 min postinjection of Ga-68 DOTATATE and research 177 Lu-SPECT/CT imaging ~ at 4 h (SPECT1) and ~ 24 h (SPECT2) post-cycle#1 were available. Manual contours of lesions on baseline CT or MRI were applied to co-registered SPECT/CT and PET/CT followed by deep learning-based CT auto-segmentation of organs. Tumor-to-normal organ ratios (TNR) were calculated from standardized uptake values (SUV) mean and SUV peak for tumor, and SUV mean for non-tumoral liver (nliver), spleen and kidney. RESULTS: There were 90 lesons in 24 patients with progressive metastatic neuroendocrine tumor. The correlation between PET and SPECT SUV TNRs were poor/moderate: PET versus SPECT1 R 2 = 0.19, 0.21, 0.29; PET versus SPECT2 R 2 = 0.06, 0.16, 0.33 for TNR nliver ,TNR spleen ,TNR kidney , respectively. Across all patients, the average value of the TNR measured on PET was significantly lower than on SPECT at both time points ( P < 0.001). Using SUV mean for tumor, average TNR values and 95% confidence intervals (CI) were PET: TNR nliver = 3.5 [CI: 3.0-3.9], TNR spleen = 1.3 [CI, 1.2-1.5], TNR kidney = 1.7 [CI: 1.6-1.9]; SPECT1: TNR nliver = 10 [CI: 8.2-11.7], TNR spleen = 2.9 [CI: 2.5-3.4], TNR kidney = 2.8 [CI: 2.3-3.3]; SPECT2: TNR nliver = 16.9 [CI: 14-19.9], TNR spleen = 3.6 [CI: 3-4.2], TNR kidney = 3.6 [CI: 3.0-4.2]. Comparison of PET and SPECT results in a sphere phantom study demonstrated that these differences are not attributed to imaging modality. CONCLUSIONS: Differences in TNR exist for the theranostic pair, with significantly higher SUV TNR on 177 Lu SPECT compared with 68 Ga PET. We postulate this phenomenon is due to temporal differences in DOTATATE uptake and internalization in tumor as compared to normal organs.

A Pipeline for Automated Voxel Dosimetry: Application in Patients with Multi-SPECT/CT Imaging After 177Lu-Peptide Receptor Radionuclide Therapy.

Patient-specific dosimetry in radiopharmaceutical therapy (RPT) is impeded by the lack of tools that are accurate and practical for the clinic. Our aims were to construct and test an integrated voxel-level pipeline that automates key components (organ segmentation, registration, dose-rate estimation, and curve fitting) of the RPT dosimetry process and then to use it to report patient-specific dosimetry in 177Lu-DOTATATE therapy. Methods: An integrated workflow that automates the entire dosimetry process, except tumor segmentation, was constructed. First, convolutional neural networks (CNNs) are used to automatically segment organs on the CT portion of one post-therapy SPECT/CT scan. Second, local contour intensity-based SPECT--SPECT alignment results in volume-of-interest propagation to other time points. Third, dose rate is estimated by explicit Monte Carlo (MC) radiation transport using the fast, Dose Planning Method code. Fourth, the optimal function for dose-rate fitting is automatically selected for each voxel. When reporting mean dose, we apply partial-volume correction, and uncertainty is estimated by an empiric approach of perturbing segmentations. Results: The workflow was used with 4-time-point 177Lu SPECT/CT imaging data from 20 patients with 77 neuroendocrine tumors, segmented by a radiologist. CNN-defined kidneys resulted in high Dice values (0.91-0.94) and only small differences (2%-5%) in mean dose when compared with manual segmentation. Contour intensity-based registration led to visually enhanced alignment, and the voxel-level fitting had high R 2 values. Across patients, dosimetry results were highly variable; for example, the average of the mean absorbed dose (Gy/GBq) was 3.2 (range, 0.2-10.4) for lesions, 0.49 (range, 0.24-1.02) for left kidney, 0.54 (range, 0.31-1.07) for right kidney, and 0.51 (range, 0.27-1.04) for healthy liver. Patient results further demonstrated the high variability in the number of cycles needed to deliver hypothetical threshold absorbed doses of 23 Gy to kidney and 100 Gy to tumor. The uncertainty in mean dose, attributable to variability in segmentation, averaged 6% (range, 3%-17%) for organs and 10% (range, 3%-37%) for lesions. For a typical patient, the time for the entire process was about 25 min (∼2 min manual time) on a desktop computer, including time for CNN organ segmentation, coregistration, MC dosimetry, and voxel curve fitting. Conclusion: A pipeline integrating novel tools that are fast and automated provides the capacity for clinical translation of dosimetry-guided RPT.

68Ga-DOTATATE PET/CT Imaging of Refractory Pituitary Macroadenoma Invading the Orbit.

ABSTRACT: In addition to gastroenteropancreatic neuroendocrine neoplasms, a wide variety of tumors express somatostatin receptors. Somatostatin receptor imaging, heavily utilized in neuroendocrine oncology, may also have utility in the diagnosis of other neoplasms and raises the possibility of potential therapeutic options. We describe the case of a 60-year-old man who underwent 68Ga-DOTATATE PET/CT, demonstrating an avid invasive pituitary macroadenoma. This mass was persistent and refractory despite traditional treatment options. Because of the avidity, 177Lu-DOTATATE therapy was offered, although not ultimately performed, demonstrating a potential treatment for challenging cases utilizing the principles of theranostics.

A Novel Time-Activity Information-Sharing Approach Using Nonlinear Mixed Models for Patient-Specific Dosimetry with Reduced Imaging Time Points: Application in SPECT/CT After 177Lu-DOTATATE.

Multiple-time-point SPECT/CT imaging for dosimetry is burdensome for patients and lacks statistical efficiency. A novel method for joint kidney time-activity estimation based on a statistical mixed model, a prior cohort of patients with complete time-activity data, and only 1 or 2 imaging points for new patients was compared with previously proposed single-time-point methods in virtual and clinical patient data. Methods: Data were available for 10 patients with neuroendocrine tumors treated with 177Lu-DOTATATE and imaged up to 4 times between days 0 and 7 using SPECT/CT. Mixed models using 1 or 2 time points were evaluated retrospectively in the clinical cohort, using the multiple-time-point fit as the reference. Time-activity data for 250 virtual patients were generated using parameter values from the clinical cohort. Mixed models were fit using 1 (∼96 h) and 2 (4 h, ∼96 h) time points for each virtual patient combined with complete data for the other patients in each dataset. Time-integrated activities (TIAs) calculated from mixed model fits and other reduced-time-point methods were compared with known values. Results: All mixed models and single-time-point methods performed well overall, achieving mean bias < 7% in the virtual cohort. Mixed models exhibited lower bias, greater precision, and substantially fewer outliers than did single-time-point methods. For clinical patients, 1- and 2-time-point mixed models resulted in more accurate TIA estimates for 94% (17/18) and 72% (13/18) of kidneys, respectively. In virtual patients, mixed models resulted in more than a 2-fold reduction in the proportion of kidneys with |bias| > 10% (6% vs. 15%). Conclusion: Mixed models based on a historical cohort of patients with complete time-activity data and new patients with only 1 or 2 SPECT/CT scans demonstrate less bias on average and significantly fewer outliers when estimating kidney TIA, compared with popular reduced-time-point methods. Use of mixed models allows for reduction of the imaging burden while maintaining accuracy, which is crucial for clinical implementation of dosimetry-based treatment.

Effect of Propranolol on 18F-Fluorodeoxyglucose Uptake in Brown Adipose Tissue in Children and Young Adults with Neoplastic Diseases.

PURPOSE: To evaluate the effectiveness of propranolol at mitigating FDG uptake in brown adipose tissue (BAT) of pediatric patients with known or suspected malignancies. METHODS: PET/CT scans of 3 cohorts of patients treated from 2005 to 2017 were scored for the presence of FDG uptake by BAT at 7 sites: right or left neck/supraclavicular area, right or left axilla, mediastinum, posterior thorax, and abdomen/pelvis. Uptake was scored as follows: 0, none; 1, mild uptake < liver; 2, moderate uptake = liver; and 3, intense uptake > liver. Group 1 consisted of 323 patients (630 scans) who had no specific preparation to mitigate FDG uptake by BAT. Group 2 consisted of 345 patients (705 scans) who underwent only warming in an uptake room with a fixed temperature at 24 °C. Group 3 consisted of 622 patients (1457 scans) who underwent warming. In group 3, patients 8 years and older, 471 patients (1114 scans), were also pre-medicated with oral propranolol 60 min before injection of FDG. Generalized estimation equation, using the logit link method, was used to model the relationship between the incidence of BAT score > 0, in any site, as a function of age, sex, seasonal effect, and body surface area (BSA). RESULTS: In patients aged 8 years or older, the incidence of BAT uptake was 35-44 % and declined to 15 % with propranolol. BAT was most frequent in the neck (26 %), axilla (18 %), posterior thorax (18 %), mediastinum (14 %), and abdomen/pelvis (8 %); BAT was less common in warm months (p = 0.001). No substantial benefit was shown with pre-injection warming alone. No significant effect was found for age, sex, or BSA separately. When BAT uptake was present, it was usually intense. CONCLUSION: Propranolol preparation minimizes FDG uptake by BAT and should be considered routine for pediatric FDG PET/CT cancer-related protocols in children, adolescents, and young adults.

Salivary and lacrimal dysfunction after radioactive iodine for differentiated thyroid cancer: American Head and Neck Society Endocrine Surgery Section and Salivary Gland Section joint multidisciplinary clinical consensus statement of otolaryngology, ophthalmology, nuclear medicine and endocrinology.

BACKGROUND: Postoperative radioactive iodine (RAI) administration is widely utilized in patients with differentiated thyroid cancer. While beneficial in select patients, it is critical to recognize the potential negative sequelae of this treatment. The prevention, diagnosis, and management of the salivary and lacrimal complications of RAI exposure are addressed in this consensus statement. METHODS: A multidisciplinary panel of experts was convened under the auspices of the American Head and Neck Society Endocrine Surgery and Salivary Gland Sections. Following a comprehensive literature review to assess the current best evidence, this group developed six relevant consensus recommendations. RESULTS: Consensus recommendations on RAI were made in the areas of patient assessment, optimal utilization, complication prevention, and complication management. CONCLUSION: Salivary and lacrimal complications secondary to RAI exposure are common and need to be weighed when considering its use. The recommendations included in this statement provide direction for approaches to minimize and manage these complications.

Synthesis and Evaluation of 11C- and 18F-Labeled SOAT1 Inhibitors as Macrophage Foam Cell Imaging Agents.

PD-132301, an inhibitor of sterol O-acyltransferase 1 (SOAT1; also known as acyl-coenzyme A:cholesterol acyltransferase-1, ACAT1), is under clinical investigation for numerous adrenal disorders. Radiolabeled SOAT1 inhibitors could support drug discovery and help diagnose SOAT1-related disorders, such as atherosclerosis. We synthesized two radiolabeled SOAT1 inhibitors, [11C]PD-132301 and fluorine analogue [18F]1. Rat biodistribution studies were conducted with both agents and, as the most selective tracer, [11C]PD-132301 was advanced to preclinical positron emission tomography studies in (atherosclerotic) ApoE-/- mice. The uptake of [11C]PD-132301 in SOAT1-rich tissue warrants further investigation into the compound as an atherosclerosis and adrenal imaging agent.