Structural modifications toward improved lead-203/lead-212 peptide-based image-guided alpha-particle radiopharmaceutical therapies for neuroendocrine tumors.

PURPOSE: The lead-203 (203Pb)/lead-212 (212Pb) elementally identical radionuclide pair has gained significant interest in the field of image-guided targeted alpha-particle therapy for cancer. Emerging evidence suggests that 212Pb-labeled peptide-based radiopharmaceuticals targeting somatostatin receptor subtype 2 (SSTR2) may provide improved effectiveness compared to beta-particle-based therapies for neuroendocrine tumors (NETs). This study aims to improve the performance of SSTR2-targeted radionuclide imaging and therapy through structural modifications to Tyr3-octreotide (TOC)-based radiopharmaceuticals. METHODS: New SSTR2-targeted peptides were designed and synthesized with the goal of optimizing the incorporation of Pb isotopes through the use of a modified cyclization technique; the introduction of a Pb-specific chelator (PSC); and the insertion of polyethylene glycol (PEG) linkers. The binding affinity of the peptides and the cellular uptake of 203Pb-labeled peptides were evaluated using pancreatic AR42J (SSTR2+) tumor cells and the biodistribution and imaging of the 203Pb-labeled peptides were assessed in an AR42J tumor xenograft mouse model. A lead peptide was identified (i.e., PSC-PEG2-TOC), which was then further evaluated for efficacy in 212Pb therapy studies. RESULTS: The lead radiopeptide drug conjugate (RPDC) - [203Pb]Pb-PSC-PEG2-TOC - significantly improved the tumor-targeting properties, including receptor binding and tumor accumulation and retention as compared to [203Pb]Pb-DOTA0-Tyr3-octreotide (DOTATOC). Additionally, the modified RPDC exhibited faster renal clearance than the DOTATOC counterpart. These advantageous characteristics of [212Pb]Pb-PSC-PEG2-TOC resulted in a dose-dependent therapeutic effect with minimal signs of toxicity in the AR42J xenograft model. Fractionated administrations of 3.7 MBq [212Pb]Pb-PSC-PEG2-TOC over three doses further improved anti-tumor effectiveness, resulting in 80% survival (70% complete response) over 120 days in the mouse model. CONCLUSION: Structural modifications to chelator and linker compositions improved tumor targeting and pharmacokinetics (PK) of 203/212Pb peptide-based radiopharmaceuticals for NET theranostics. These findings suggest that PSC-PEG2-TOC is a promising candidate for Pb-based targeted radionuclide therapy for NETs and other types of cancers that express SSTR2.

Auranofin Inhibition of Thioredoxin Reductase Sensitizes Lung Neuroendocrine Tumor Cells (NETs) and Small Cell Lung Cancer (SCLC) Cells to Sorafenib as well as Inhibiting SCLC Xenograft Growth.

Thioredoxin Reductase (TrxR) is a key enzyme in hydroperoxide detoxification through peroxiredoxin enzymes and in thiol-mediated redox regulation of cell signaling. Because cancer cells produce increased steady-state levels of reactive oxygen species (ROS; i.e., superoxide and hydrogen peroxide), TrxR is currently being targeted in clinical trials using the anti-rheumatic drug, auranofin (AF). AF treatment decreased TrxR activity and clonogenic survival in small cell lung cancer (SCLC) cell lines (DMS273 and DMS53) as well as the lung atypical (neuroendocrine tumor) NET cell line H727. AF treatment also significantly sensitized DMS273 and H727 cell lines in vitro to sorafenib, a multi-kinase inhibitor that was shown to decrease intracellular glutathione. The pharmacokinetic and pharmacodynamic properties of AF treatment in a mouse SCLC xenograft model was examined to maximize inhibition of TrxR activity without causing toxicity. AF was administered intraperitoneally at 2 mg/kg or 4 mg/kg (IP) once (QD) or twice daily (BID) for 1 to 5 days in mice with DMS273 xenografts. Plasma levels of AF were 10-20 µM (determined by mass spectrometry of gold) and the optimal inhibition of TrxR (50 %) was obtained at 4 mg/kg once daily, with no effect on glutathione peroxidase 1 activity. When this daily AF treatment was extended for 14 days a significant prolongation of median survival from 19 to 23 days (p=0.04, N=30 controls, 28 AF) was observed without causing changes in animal bodyweight, CBCs, bone marrow toxicity, blood urea nitrogen, or creatinine. These results show that AF is an effective inhibitor of TrxR both in vitro and in vivo in SCLC, capable of sensitizing NETs and SCLC to sorafenib, and supports the hypothesis that AF could be used as an adjuvant therapy with agents known to induce disruptions in thiol metabolism to enhance therapeutic efficacy.

Chemokine Receptor CXCR4 Radioligand Targeted Therapy Using 177Lutetium-pentixather for Pulmonary Neuroendocrine Cancers.

Intermediate to high-grade lung neuroendocrine tumors (NETs; i.e., atypical carcinoid tumors) and neuroendocrine carcinomas (NECs) are currently difficult to cure. These tumors were found to express the CXCR4 G-protein coupled receptor that can be targeted with radioligands. PCR and flow cytometric analysis of lung NET and NEC cell lines using an anti-CXCR4 antibody demonstrated that all cell lines tested expressed CXCR4. PET/CT imaging with 68Galium-pentixafor in mouse xenografts of NETs and NECs verified tumor targeting that was blocked by a CXCR4 agonist. Clonogenic survival analysis demonstrated a more than additive enhancement of killing when 1 µM auranofin (a thioredoxin reductase inhibitor) was used as a radiosensitizer in combination with 177Lu-pentixather (10 µCi). DMS273 small cell lung cancer xenografts in female nude mice treated with 25 µCi/g 177Lu-pentixather induced inhibition of tumor growth and resulted in an increase in overall survival without causing unacceptable normal tissue toxicities. Immunohistochemical staining of 95 retrospective human samples (containing 90 small cell lung carcinomas) demonstrated 84% CXCR4 positivity. In a multivariable analysis of this cohort that included age, gender, stage, primary site, SSTR2 status, and CXCR4 status, Cox regression models determined that only distant metastasis at presentation (P < 0.01) and a CXCR4 H-score >30 (P = 0.04) were significantly associated with reduced survival. Prospective clinical testing of patient tumors identified CXCR4-positivity in 76% of 21 NECs, 67% of 15 lung NETs (including 8 of 10 atypical carcinoids), and 0% of 25 non-lung NETs (including 5 NETS G3s). These data support the hypothesis that CXCR4-targeted theranostics can be utilized effectively for select NETs and NECs.

PET/CT Imaging in Treatment Planning and Surveillance of Sinonasal Neoplasms.

Sinonasal cancers are uncommon malignancies with a generally unfavorable prognosis, often presenting at an advanced stage. Their high rate of recurrence supports close imaging surveillance and the utilization of functional imaging techniques. Whole-body 18F-FDG PET/CT has very high sensitivity for the diagnosis of sinonasal malignancies and can also be used as a "metabolic biopsy" in the characterization of some of the more common subgroups of these tumors, though due to overlap in uptake, histological confirmation is still needed. For certain tumor types, radiotracers, such as 11C-choline, and radiolabeled somatostatin analogs, including 68Ga-DOTATATE/DOTATOC, have proven useful in treatment planning and surveillance. Although serial scans for posttreatment surveillance allow the detection of subclinical lesions, the optimal schedule and efficacy in terms of survival are yet to be determined. Pitfalls of 18F-FDG, such as post-surgical and post-radiotherapy crusting and inflammation, may cause false-positive hypermetabolism in the absence of relapse.

The Impact of Radiopharmaceutical Therapy on Renal Function.

Radiopharmaceuticals used for cancer therapy are highly selective, designed to kill malignant cells and spare healthy tissues. Side effect rates are generally less than other treatments, but it is still the utmost concern to minimize normal organ toxicity and maximize radiation dose to the target lesions in applying radiopharmaceutical therapies (RPTs). Most commonly affected normal organs include bone marrow, kidneys and liver. The impact of RPTs to renal function is generally considered low. Peptide receptor radionuclide therapy (PRRT) using somatostatin radiopharmaceuticals, particularly 90Y-DOTATOC, has the potential to induce nephrotoxicity. This is because PRRT radiopharmaceuticals are primarily cleared thorough glomerular filtration and reabsorption/retainment of them at the renal proximal tubules exposes kidneys to additional radiation. Amino acid co-infusion is the standard regimen for competitive inhibition of tubular reabsorption of PRRT radiopharmaceuticals to mitigate nephrotoxicity. Other measures to protect renal function include hydration, use of plasma expander or radioprotectant, personalized renal dosimetry to limit renal radiation dose and close monitoring of renal function. Limited data suggest alpha emitter PRRT radiopharmaceuticals have less impact on kidney function compared to beta emitter PRRT, but more studies are needed for long term renal toxicity. 131I-MIBG is primarily excreted unchanged thorough the kidneys but renal absorbed dose is low and potential toxicities to the bone marrow and lungs are the most significant clinical concerns. Other RPTs that are not mainly cleared through kidneys such as 223Ra or radioimmunotherapy have no concern for kidney toxicity.

Potential for Increasing Uptake of Radiolabeled 68Ga-DOTATOC and 123I-MIBG in Patients with Midgut Neuroendocrine Tumors Using a Histone Deacetylase Inhibitor Vorinostat.

Background: Histone deacetylase (HDAC) inhibitors have been shown in preclinical studies to upregulate norepinephrine transporters in neuroblastoma and pheochromocytoma, and somatostatin receptors in pulmonary carcinoid, small cell lung cancer, and pancreatic neuroendocrine malignancies. This pilot imaging study in humans focuses on midgut neuroendocrine carcinoma metastatic to the liver, evaluating the effect of pretreatment with the HDAC inhibitor vorinostat on uptake of 123I-MIBG and 68Ga-DOTATOC. Materials and Methods: Multiple midgut neuroendocrine liver metastases in clinically stable subjects were imaged with 123I-MIBG and 68Ga-DOTATOC before and after a 4-d course of vorinostat. Scans were performed with strict attention to detail and timed about 1 month apart occurring just before monthly long-acting octreotide administrations. Uptake changes in tumor and normal liver parenchyma were assessed on positron emission computed tomography (PET/CT) with standardized uptake values and on single photon emission computed tomography (SPECT) with qualitative ratio images. Results: The experimental units were metastatic liver lesions within patients (n = 50). There was no significant difference in administered activity or uptake time between pairs of scans for either radiotracer. Statistically significant increase in maximum standardized uptake values (SUVmax) averaged over all lesions was noted on the 68Ga-DOTATOC PET scans (+11%, p < 0.01). SUVmax in normal liver showed no significant change (p = 0.12). There was no qualitative change in uptake of 123I-MIBG after vorinostat. Conclusions: In this pilot imaging study in patients with midgut neuroendocrine liver metastases, a short course of the HDAC inhibitor vorinostat induced a statistically significant increase in SUVmax on 68Ga-DOTATOC PET/computed tomography (CT) imaging in some hepatic neuroendocrine tumor metastases. There was no significant effect of vorinostat on tumor uptake of 123I-MIBG on SPECT/CT imaging. Given the pilot nature of this trial, the findings merit further investigation with a more rigorous protocol evaluating longer pretreatment and different dosages of vorinostat or other HDAC inhibitors, as well as effects on the therapeutic capability of 177Lu- or 90Y-somatostatin analogs.

Multiparametric magnetic resonance imaging and positron emission tomography findings in neurodegenerative diseases: Current status and future directions.

Neurodegenerative diseases (NDDs) are characterized by progressive neuronal loss, leading to dementia and movement disorders. NDDs broadly include Alzheimer's disease, frontotemporal lobar degeneration, parkinsonian syndromes, and prion diseases. There is an ever-increasing prevalence of mild cognitive impairment and dementia, with an accompanying immense economic impact, prompting efforts aimed at early identification and effective interventions. Neuroimaging is an essential tool for the early diagnosis of NDDs in both clinical and research settings. Structural, functional, and metabolic imaging modalities, including magnetic resonance imaging (MRI) and positron emission tomography (PET), are widely available. They show encouraging results for diagnosis, monitoring, and treatment response evaluation. The current review focuses on the complementary role of various imaging modalities in relation to NDDs, the qualitative and quantitative utility of newer MRI techniques, novel radiopharmaceuticals, and integrated PET/MRI in the setting of NDDs.

Addition of 131I-MIBG to PRRT (90Y-DOTATOC) for Personalized Treatment of Selected Patients with Neuroendocrine Tumors.

Peptide receptor radionuclide therapy (PRRT) is an effective treatment for metastatic neuroendocrine tumors. Delivering a sufficient tumor radiation dose remains challenging because of critical-organ dose limitations. Adding 131I-metaiodobenzylguanidine (131I-MIBG) to PRRT may be advantageous in this regard. Methods: A phase 1 clinical trial was initiated for patients with nonoperable progressive neuroendocrine tumors using a combination of 90Y-DOTATOC plus 131I-MIBG. Treatment cohorts were defined by radiation dose limits to the kidneys and the bone marrow. Subject-specific dosimetry was used to determine the administered activity levels. Results: The first cohort treated subjects to a dose limit of 1,900 cGy to the kidneys and 150 cGy to the marrow. No dose-limiting toxicities were observed. Tumor dosimetry estimates demonstrated an expected dose increase of 34%-83% using combination therapy as opposed to 90Y-DOTATOC PRRT alone. Conclusion: These findings demonstrate the feasibility of using organ dose for a phase 1 escalation design and suggest the safety of using 90Y-DOTATOC and 131I-MIBG.

A Framework for Patient-Centered Pathways of Care for Radiopharmaceutical Therapy: An ASTRO Consensus Document.

Radiopharmaceutical therapy (RPT) is an area of projected growth and importance with several agents in clinical use, new agents in late-phase clinical trials, and many others under testing and development. This article proposes a framework for developing pathways of care that can be broadly applied to all RPTs, representing the current status of RPT. It suggests foundational elements for many pathways of care for patients with cancer and concludes with areas in active development and the future horizon for RPT treatment centers. Developing a framework for patient-centered pathways of care is a critical step in establishing RPT as standard therapy for patients with a diverse spectrum of cancers. This expected increase in RPT treatment options will affect a much larger population of patients with complex cancer. It will also require enhanced coordination and collaboration among appropriately qualified personnel with diverse expertise in image acquisition, image interpretation, quantitative imaging, dosimetry calculation, radiation quality assurance and safety as well as oncology care and RPT-induced sequelae and response assessment. The essential role of this evolving RPT care team within multidisciplinary oncology care is a cornerstone of this framework for a patient-centered pathway of care for RPT. Given the status of current RPT practice and the horizon for future applications, this patient-centered pathway of care guidance is timely and should help inform future clinical RPT practice paradigms. A task force was recruited from the Theranostic Working Group of the American Society for Radiation Oncology (ASTRO) in May 2019 with equal representation from the nuclear medicine community. The task force expanded on a framework that was originally conceived by the Working Group for patient-centered care. This framework was developed to incorporate the strengths of both radiation oncologists and nuclear medicine physicians. The manuscript was then developed by the task force and posted on the ASTRO website for a 6-week public comment period ending in July 2020. Comments were adjudicated, and the draft was sent to external organizations for potential endorsement. This document was sent to the ASTRO Board of Directors in October 2020 for approval.

Radiopharmaceuticals for Neuroendocrine Tumors.

Neuroendocrine tumors (NETs) are a heterogeneous group of tumors that originate in endocrine tissues throughout the body. Peptide receptor radionuclide therapy (PRRT) has emerged as a promising therapeutic option for patients with locally advanced and/or metastatic disease refractory to standard of care treatment. The landmark international phase III NETTER-1 trial led to the approval of 177Lu-DOTATATE (Lutathera) in the treatment of somatostatin receptor-positive gastroenteropancreatic NETs. Similarly, data from the multicenter, phase II Study IB12B led to the approval of meta-[131I]Iodo-Benzyl-Guanidine (I31I-MIBG) for treatment of iobenguane scan-positive, unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma. With the clinical approval of these novel radiopharmaceuticals for managing select patients with NETs, additional studies are needed to refine patient selection, predict and assess therapy response, and optimize radiopharmaceutical delivery and clinical outcomes.

Polyazamacrocycle Ligands Facilitate 89Zr Radiochemistry and Yield 89Zr Complexes with Remarkable Stability.

Over the last three decades, the chemistry of zirconium has facilitated antibody development and the clinical management of disease in the precision medicine era. Scientists have harnessed its reactivity, coordination chemistry, and nuclear chemistry to develop antibody-based radiopharmaceuticals incorporating zirconium-89 (89Zr: t1/2 = 78.4 h, ß+: 22.8%, Eß+max = 901 keV; EC: 77%, Eγ = 909 keV) to improve disease detection, identify patients for individualized therapeutic interventions. and monitor their response to those interventions. However, release of the 89Zr4+ ion from the radiopharmaceutical remains a concern, since it may confound the interpretation of clinical imaging data, negatively affect dosimetric calculations, and hinder treatment planning. In this report, we relate our novel observations involving the use of polyazamacrocycles as zirconium-89 chelators. We describe the synthesis and complete characterization of zirconium 2,2',2″,2‴-(1,4,7,10-tetraazacyclotridecane-1,4,7,10-tetrayl)tetraacetic acid (Zr-TRITA), zirconium 3,6,9,15-Tetraazabicyclo[9.3.1] pentadeca-1(15),11,13-triene-3,6,9-triacetic acid (Zr-PCTA), and zirconium 2,2',2″-(1,4,7-triazacyclononane-1,4,7-triyl)triacetic acid (Zr-NOTA). In addition, we elucidate the solid-state structure of each complex using single-crystal X-ray diffraction analysis. Finally, we found that [89Zr]Zr-PCTA and [89Zr]Zr-NOTA demonstrate excellent stability in vitro and in vivo and provide a rationale for these observations. These innovative findings have the potential to guide the development of safer and more robust immuno-PET agents to improve precision medicine applications.

Prospective Analysis of the Impact of 68Ga-DOTATOC Positron Emission Tomography-Computerized Axial Tomography on Management of Pancreatic and Small Bowel Neuroendocrine Tumors.

OBJECTIVES: A prospective clinical trial evaluated the effect of Ga-DOTATOC positron emission tomography-computerized axial tomography (PET-CT) on change in management of patients with lung, pancreatic, and small bowel neuroendocrine tumors. The primary eligibility criterion was a histologically proven tumor with positive somatostatin receptor subtype 2A immunohistochemistry. The primary and secondary end points were change in patient management and safety. METHODS: Referring physicians completed questionnaires pre- and post-Ga-DOTATOC PET-CT, stating current and planned patient management, respectively, with tumor board adjudication of final management decisions. Change in management was categorized as follows: no change; minor change (additional imaging, supportive care); or major change (octreotide/lanreotide therapy, tumor biopsy, surgery, peptide receptor radiotherapy, chemotherapy, biological therapy, liver embolization). RESULTS: A major change in management was recommended for 54 (47.37%) of 114 subjects and a minor change for 6 (5.26%) of 114 subjects, with no change for 54 (47.37%) of 114 subjects. Grade 1 adverse events were observed in 26 of 114 subjects (nausea, headache, back pain, diarrhea); one grade 2 (petechiae) and one grade 3 (abdominal pain) adverse event were observed. No grade 2 or 3 adverse events were related to study drug and none required intervention. CONCLUSIONS: Imaging with Ga-DOTATOC PET-CT has a significant impact on management of patients with neuroendocrine tumors.

Potential False-Positive Meckel's Scan Caused by Umbilical Ornamentation.

An 18-year-old woman presented to the emergency department for bloody stools. A CT scan of the abdomen ruled out intussusception. Meckel's scan was ordered to rule for Meckel's diverticulum before upper endoscopy and colonoscopy. After proper pretreatment with H2 blocker, Tc-pertechnetate Meckel's scan was performed. Dynamic planar imaging revealed a focus of gradual increase in uptake in midabdomen suggestive of Meckel's diverticulum. A SPECT/CT was done to localize the focus of uptake. Surprisingly, the focus of uptake localized to the periumbilical region on SPECT/CT images. The cause of uptake could be due to local inflammation from umbilical ornamentation.

The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Medical Management of Pancreatic Neuroendocrine Tumors.

This article is the result of the North American Neuroendocrine Tumor Society consensus conference on the medical management of pancreatic neuroendocrine tumors from July 19 to 20, 2018. The guidelines panel consisted of medical oncologists, pathologists, gastroenterologists, endocrinologists, and radiologists. The panel reviewed a series of questions regarding the medical management of patients with pancreatic neuroendocrine tumors as well as questions regarding surveillance after resection. The available literature was reviewed for each of the question and panel members voted on controversial topics, and the recommendations were included in a document circulated to all panel members for a final approval.

Association of gallbladder hyperkinesia with acalculous chronic cholecystitis: A case-control study.

BACKGROUND: This is the first case-control study investigating an association between gallbladder hyperkinesia and symptomatic acalculous chronic cholecystitis. METHODS: This retrospective study in a single academic center compared resolution of biliary pain in adults with gallbladder hyperkinesia, defined as a hepatobiliary iminodiacetic acid scan ejection fraction ≥80%, undergoing cholecystectomy (study group) with those treated medically without cholecystectomy (control group). Of 1,477 hepatobiliary iminodiacetic acid scans done between 2013 and 2018, a total of 296 adults without gallstones had an ejection fraction ≥80%, of whom 46 patients met predetermined eligibility criteria. Demographic data, hepatobiliary iminodiacetic acid scan ejection fraction, chronicity of pain, and resolution of pain were compared between groups. RESULTS: Demographics (mean ± standard deviation) in the control group (n = 25) and in the study group (n = 21) were, respectively, age 40 y ± 16 y and 39 y ± 14 y, body mass index 28.9 ± 5.2 and 29.1 ± 7.1 kg/m2, with 15 (60%) and 18 (86%) females in each. Resolution of pain after cholecystectomy occurred in 18 of 21 patients (86%); however, pain persisted in 20 of 25 patients (80%) treated medically after mean follow-up of 36 ± 28 months (range 10-120 months) (P < .01). Pain resolution with cholecystectomy was independent of demographic variables, hepatobiliary iminodiacetic acid scan ejection fraction, and chronicity of pain. The odds of pain resolution was 19.7 times greater with cholecystectomy than without (odds ratio, 19.7; 95% confidence interval, 4.34, 89.43; P < .01), and remained robust even with the odds adjusted for each covariate. Gallbladder histopathology confirmed chronic cholecystitis in all 21 cholecystectomy specimens. CONCLUSION: Symptomatic gallbladder hyperkinesia could be a new indication for cholecystectomy in adults.

Comparison of T1Rho MRI, Glucose Metabolism, and Amyloid Burden Across the Cognitive Spectrum: A Pilot Study.

OBJECTIVE: The pathological cascades associated with the development of Alzheimer's disease (AD) have a common element: acidosis. T1rho MRI is a pH-sensitive measure, with higher values associated with greater neuropathological burden. The authors investigated the relationship between T1rho imaging and AD-associated pathologies as determined by available diagnostic imaging techniques. METHODS: Twenty-seven participants (men, N=13, women, N=14; ages 55-90) across the cognitive spectrum (healthy control subjects [HCs] with normal cognition, N=17; participants with mild cognitive impairment [MCI], N=7; participants with mild AD, N=3) underwent neuropsychological testing, MRI (T1-weighted and T1rho [spin-lattice relaxation time in the rotating frame]), and positron emission tomography imaging ([11C]Pittsburg compound B for amyloid burden [N=26] and [18F]fluorodeoxyglucose for cerebral glucose metabolism [N=12]). The relationships between global T1rho values and neuropsychological, demographic, and imaging measures were explored. RESULTS: Global mean and median T1rho were positively associated with age. After controlling for age, higher global T1rho was associated with poorer cognitive function, poorer memory function (immediate and delayed memory scores), higher amyloid burden, and more abnormal cerebral glucose metabolism. Regional T1rho values, when controlling for age, significantly differed between HCs and participants with MCI or AD in select frontal, cingulate, and parietal regions. CONCLUSIONS: Higher T1rho values were associated with greater cognitive impairment and pathological burden. T1rho, a biomarker that varies according to a feature common to each cascade rather than one that is unique to a particular pathology, has the potential to serve as a metric of neuropathology, theoretically providing a measure for assessing pathological status and for monitoring the neurodegeneration trajectory.

Nuclear Imaging of Neuroendocrine Tumors.

Consensus guidelines acknowledge the role of gallium Ga-68 (68Ga) 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic (DOTA) somatostatin receptor (SSTR) positron emission tomography/computed tomography (PET/CT) in management of neuroendocrine tumor (NET) patients. 68Ga-DOTA-SSTR PET/CT demonstrates superior performance to conventional imaging in initial detection, staging, detection of recurrent tumor, and detection of unknown primary in known metastatic disease. 68Ga-DOTA-SSTR PET/CT is low yield for NET detection in the setting of symptoms or elevated biomarkers when conventional imaging is negative, but may still guide management. The role of 68Ga-DOTA-SSTR PET/CT is not established in monitoring response to systemic therapy but may identify progression through detection of new metastases.

Regional Myocardial Remodeling Characteristics Correlates With Cardiac Events in Sarcoidosis.

BACKGROUND: The poor prognosis of cardiac sarcoidosis (CS) underscores the need for risk stratification. PURPOSE: To investigate the prognostic significance of ventricular/myocardial remodeling features in sarcoidosis. STUDY TYPE: Retrospective. POPULATION: In all, 132 biopsy-proven sarcoidosis patients imaged from 2008 to 2018. The primary endpoint was a composite of cardiac mortality, new onset arrhythmias, hospitalization for heart failure, and device implantation. FIELD STRENGTH/SEQUENCE: No field strength or sequence restrictions. ASSESSMENT: Global and regional ventricular/myocardial remodeling features were assessed by standard volumetric measurements and automated function imaging postprocessing analysis. STATISTICAL TESTS: Student's t-test or Mann-Whitney test (chi2 test or Fisher's exact test for categorical variables) were used for comparisons. Cox-proportional hazards regression model, univariate /multivariate analyses, and receiver operating characteristic were performed to relate clinical/lab data, imaging parameters to the endpoints. RESULTS: Over a median follow-up of 40.7 (interquartile range 18.8-60.5) months, 41 (31.1%) patients developed adverse cardiac events. Abnormal left ventricular (LV) geometric remodeling alterations (measured by LV mass index and relative wall thickness) occurred 3.66-fold more frequently in patients with endpoints than patients without. The ratio of patients with endpoints increased as ventricular remodeling phenotype progressed. In patients with endpoints, regional myocardial wall thickness (RMWT) was significantly (P = 0.022) increased in six clustered LV segments located in the middle interventricular septum and basal/middle anterolateral walls. In all of the abnormal ventricular remodeling stages, patients with endpoints constantly had higher mean RMWT than those without. Among clinical, electrocardiographic, and imaging parameters, LV mass index (hazard ratio [HR] 1.010 95% confidence interval [CI] 1.002-1.018, P = 0.017) and mean RMWT (HR 3.482 95% CI 1.679-7.223, P = 0.001) were independently associated with endpoints. Sarcoidosis patients without this RMWT distribution pattern were significantly (P < 0.001) more likely to be free of the occurrence of subsequent cardiac events. DATA CONCLUSION: Regional myocardial remodeling characteristics are associated with subsequent adverse cardiac events in sarcoidosis. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY STAGE: 2 J. Magn. Reson. Imaging 2020;52:499-509.