PET assessment of acute gastrointestinal graft versus host disease.

Acute gastrointestinal graft versus host disease (GI-GVHD) is a common complication following allogeneic haematopoietic cell transplantation (HCT), and is characterised by severe morbidity, frequent treatment-refractoriness, and high mortality. Early, accurate identification of GI-GVHD could allow for therapeutic interventions to ameliorate its severity, improve response rates and survival; however, standard endoscopic biopsy is inadequately informative in terms of diagnostic sensitivity or outcome prediction. In an era where rapid technological and laboratory advances have dramatically expanded our understanding of GI-GVHD biology and potential therapeutic targets, there is substantial scope for novel investigations that can precisely guide GI-GVHD management. In particular, the combination of tissue-based biomarker assessment (plasma cytokines, faecal microbiome) and molecular imaging by positron emission tomography (PET) offers the potential for non-invasive, real-time in vivo assessment of donor:recipient immune activity within the GI tract for GI-GVHD prediction or diagnosis. In this article, we review the evidence regarding GI-GVHD diagnosis, and examine the potential roles and translational opportunities posed by these novel diagnostic tools, with a focus on the evolving role of PET.

The value of 18 F-FDG PET/CT quantitative indexes in the diagnosis of nondestructive posttransplant lymphoproliferative disorders after pediatric liver transplantation.

BACKGROUND: Posttransplant lymphoproliferative disease (PTLD) is a serious complication after pediatric liver transplantation (pLT), which may lead to death. 18 F-FDG PET/CT is rarely considered in PTLD after pLT and lacks clear diagnostic guidelines, especially in the differential diagnosis of nondestructive PTLD. The aim of this study was to find a quantifiable 18 F-FDG PET/CT index to identify nondestructive PTLD after pLT. METHODS: This retrospective study collected the data of patients who underwent pLT, postoperative lymph node biopsy, and 18 F-FDG PET/CT at Tianjin First Central Hospital from January 2014 to December 2021. Quantitative indexes were established using lymph node morphology and the maximum standardized uptake value (SUVmax). RESULTS: A total of 83 patients met the inclusion criteria and were included in this retrospective study. To distinguish between PTLD-negative cases and nondestructive PTLD cases, according to the receiver operating characteristic curve, (the shortest diameter of the lymph node at the biopsy site [SDL]/the longest diameter of the lymph node at the biopsy site [LDL])*(SUVmax at the biopsy site [SUVmaxBio]/SUVmax of the tonsils [SUVmaxTon]) had the maximum area under the curve (0.923; 95% confidence interval: 0.834-1.000), and the cutoff value was 0.264 according to the maximum value of Youden's index. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 93.6%, 94.7%, 97.8%, 85.7%, and 93.9%, respectively. CONCLUSIONS: (SDL/LDL)*(SUVmaxBio/SUVmaxTon) has good sensitivity, specificity, positive predictive and negative predictive values, and accuracy, and can be used as a good quantitative index for the diagnosis of nondestructive PTLD.

Real-world effectiveness of preemptive therapy (PET) for cytomegalovirus (CMV) disease prevention in CMV high-risk donor seropositive/recipient seronegative (D+R-) liver transplant recipients (LTxR).

BACKGROUND: Despite superiority of preemptive therapy (PET) compared to universal prophylaxis for prevention of cytomegalovirus (CMV) disease in the CAPSIL randomized trial among CMV D+R- liver transplant recipients (LTxRs), real-world effectiveness may be lower because of logistical concerns about feasibility of PET. METHODS: We retrospectively assessed PET as standard clinical care at a single transplant center among 50 consecutive adult CMV D+R- LTxRs undergoing a first liver transplant between 4/4/2019 and 5/18/2021 and compared outcomes and adherence to those randomized to PET in the CAPSIL study (N = 100). The primary outcome was CMV disease and secondary outcomes were biopsy-confirmed acute allograft rejection, retransplant, invasive fungal infections, and death, all assessed by 1-year post-transplant. Exploratory outcomes included virologic parameters and measures of adherence to protocol-specified CMV qPCR monitoring. RESULTS: Baseline characteristics were similar between groups. The cumulative incidence of CMV disease at 1-year post-transplant was 4/50 (8%) versus 9/100 (9%) in the real-world and CAPSIL cohorts, respectively, p = 1.0. The rate of breakthrough CMV disease during the 100-day PET period was low (2/50 [4%]) and similar to the PET cohort from the CAPSIL study (3/100 [3%]).  All secondary and exploratory outcomes were not significantly different between the real-world and CAPSIL PET cohorts. CONCLUSIONS: In this first reported study of real-world PET, the feasibility and effectiveness for CMV disease prevention and for other clinical outcomes in CMV D+R- LTxRs were similar to those reported with PET in a clinical trial. Additional studies to confirm feasibility and generalizability in other settings are warranted.

First-in-Humans Evaluation of Safety and Dosimetry of 64Cu-LLP2A for PET Imaging.

There remains an unmet need for molecularly targeted imaging agents for multiple myeloma (MM). The integrin very late antigen 4 (VLA4), is differentially expressed in malignant MM cells and in pathogenic inflammatory microenvironmental cells. [64Cu]Cu-CB-TE1A1P-LLP2A (64Cu-LLP2A) is a VLA4-targeted, high-affinity radiopharmaceutical with promising utility for managing patients diagnosed with MM. Here, we evaluated the safety and human radiation dosimetry of 64Cu-LLP2A for potential use in MM patients. Methods: A single-dose [natCu]Cu-LLP2A (Cu-LLP2A) tolerability and toxicity study was performed on CD-1 (Hsd:ICR) male and female mice. 64Cu-LLP2A was synthesized in accordance with good-manufacturing-practice-compliant procedures. Three MM patients and six healthy participants underwent 64Cu-LLP2A-PET/CT or PET/MRI at up to 3 time points to help determine tracer biodistribution, pharmacokinetics, and radiation dosimetry. Time-activity curves were plotted for each participant. Mean organ-absorbed doses and effective doses were calculated using the OLINDA software. Tracer bioactivity was evaluated via cell-binding assays, and metabolites from human blood samples were analyzed with analytic radio-high-performance liquid chromatography. When feasible, VLA4 expression was evaluated in the biopsy tissues using 14-color flow cytometry. Results: A 150-fold mass excess of the desired imaging dose was tolerated well in male and female CD-1 mice (no observed adverse effect level). Time-activity curves from human imaging data showed rapid tracer clearance from blood via the kidneys and bladder. The effective dose of 64Cu-LLP2A in humans was 0.036 ± 0.006 mSv/MBq, and the spleen had the highest organ uptake, 0.142 ± 0.034 mSv/MBq. Among all tissues, the red marrow demonstrated the highest residence time. Image quality analysis supports an early imaging time (4-5 h after injection of the radiotracer) as optimal. Cell studies showed statistically significant blocking for the tracer produced for all human studies (82.42% ± 13.47%). Blood metabolism studies confirmed a stable product peak (>90%) up to 1 h after injection of the radiopharmaceutical. No clinical or laboratory adverse events related to 64Cu-LLP2A were observed in the human participants. Conclusion: 64Cu-LLP2A exhibited a favorable dosimetry and safety profile for use in humans.

Human biodistribution and radiation dosimetry of the demyelination tracer [18F]3F4AP.

PURPOSE: [18F]3F4AP is a novel PET radiotracer that targets voltage-gated potassium (K+) channels and has shown promise for imaging demyelinated lesions in animal models of neurological diseases. This study aimed to evaluate the biodistribution, safety, and radiation dosimetry of [18F]3F4AP in healthy human volunteers. METHODS: Four healthy volunteers (2 females) underwent a 4-h dynamic PET scan from the cranial vertex to mid-thigh using multiple bed positions after administration of 368 ± 17.9 MBq (9.94 ± 0.48 mCi) of [18F]3F4AP. Volumes of interest for relevant organs were manually drawn guided by the CT, and PET images and time-activity curves (TACs) were extracted. Radiation dosimetry was estimated from the integrated TACs using OLINDA software. Safety assessments included measuring vital signs immediately before and after the scan, monitoring for adverse events, and obtaining a comprehensive metabolic panel and electrocardiogram within 30 days before and after the scan. RESULTS: [18F]3F4AP distributed throughout the body with the highest levels of activity in the kidneys, urinary bladder, stomach, liver, spleen, and brain and with low accumulation in muscle and fat. The tracer cleared quickly from circulation and from most organs. The clearance of the tracer was noticeably faster than previously reported in nonhuman primates (NHPs). The average effective dose (ED) across all subjects was 12.1 ± 2.2 µSv/MBq, which is lower than the estimated ED from the NHP studies (21.6 ± 0.6 µSv/MBq) as well as the ED of other fluorine-18 radiotracers such as [18F]FDG (~ 20 µSv/MBq). No differences in ED between males and females were observed. No substantial changes in safety assessments or adverse events were recorded. CONCLUSION: The biodistribution and radiation dosimetry of [18F]3F4AP in humans are reported for the first time. The average total ED across four subjects was lower than most 18F-labeled PET tracers. The tracer and study procedures were well tolerated, and no adverse events occurred.

Fetal Dose from PET and CT in Pregnant Patients.

When pregnancy is discovered during or after a diagnostic examination, the physician or the patient may request an estimate of the radiation dose received by the fetus as per guidelines and standard operating procedures. This study provided the imaging community with dose estimates to the fetus from PET/CT with protocols that are adapted to University of Michigan low-dose protocols for patients known to be pregnant. Methods: There were 9 patients analyzed with data for the first, second, and third trimesters, the availability of which is quite rare. These images were used to calculate the size-specific dose estimate (SSDE) from the CT scan portion and the SUV and 18F-FDG uptake dose from the PET scan portion using the MIRD formulation. The fetal dose estimates were tested for correlation with each of the following independent measures: gestational age, fetal volume, average water-equivalent diameter of the patient along the length of the fetus, SSDE, SUV, and percentage of dose from 18F-FDG. Stepwise multiple linear regression analysis was performed to assess the partial correlation of each variable. To our knowledge, this was the first study to determine fetal doses from CT and PET images. Results: Fetal self-doses from 18F for the first, second, and third trimesters were 2.18 mGy (single data point), 0.74-1.82 mGy, and 0.017-0.0017 mGy, respectively. The combined SSDE and fetal self-dose ranged from 1.2 to 8.2 mGy. These types of images from pregnant patients are rare. Conclusion: Our data indicate that the fetal radiation exposure from 18F-FDG PET and CT performed, when medically necessary, on pregnant women with cancer is low. All efforts should be made to minimize fetal radiation exposure by modifying the protocol.

A first-in-human study of [68Ga]Ga-CDI: a positron emitting radiopharmaceutical for imaging tumour cell death.

PURPOSE: This study assesses human biodistribution, radiation dosimetry, safety and tumour uptake of cell death indicator labelled with 68Ga ([68Ga]Ga-CDI), a novel radiopharmaceutical that can image multiple forms of cell death. METHODS: Five participants with at least one extracranial site of solid malignancy > 2 cm and no active cancer treatment in the 8 weeks prior to the study were enrolled. Participants were administered 205 ± 4.1 MBq (range, 200-211 MBq) of [68Ga]Ga-CDI and 8 serial PET scans acquired: the first commencing immediately and the last 3 h later. Participants were monitored for clinical, laboratory and electrocardiographic side effects and adverse events. Urine and blood radioactivity was measured. Spherical volumes of interest were drawn over tumour, blood pool and organs to determine biodistribution and calculate dosimetry. In one participant, tumour specimens were analysed for cell death using terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) staining. RESULTS: [68Ga]Ga-CDI is safe and well-tolerated with no side effects or adverse events. [68Ga]Ga-CDI is renally excreted, demonstrates low levels of physiologic uptake in the other organs and has excellent imaging characteristics. The mean effective dose was 2.17E - 02 ± 4.61E - 03 mSv/MBq. It images constitutive tumour cell death and correlates with tumour cell death on histology. CONCLUSION: [68Ga]Ga-CDI is a novel cell death imaging radiopharmaceutical that is safe, has low radiation dosimetry and excellent biodistribution and imaging characteristics. It has potential advantages over previously investigated radiopharmaceuticals for imaging of cell death and has progressed to a proof-of-concept trial. TRIAL REGISTRATION: ACTRN12621000641897 (28/5/2021, retrospectively registered).

3D Segmentation Guided Style-Based Generative Adversarial Networks for PET Synthesis.

Potential radioactive hazards in full-dose positron emission tomography (PET) imaging remain a concern, whereas the quality of low-dose images is never desirable for clinical use. So it is of great interest to translate low-dose PET images into full-dose. Previous studies based on deep learning methods usually directly extract hierarchical features for reconstruction. We notice that the importance of each feature is different and they should be weighted dissimilarly so that tiny information can be captured by the neural network. Furthermore, the synthesis on some regions of interest is important in some applications. Here we propose a novel segmentation guided style-based generative adversarial network (SGSGAN) for PET synthesis. (1) We put forward a style-based generator employing style modulation, which specifically controls the hierarchical features in the translation process, to generate images with more realistic textures. (2) We adopt a task-driven strategy that couples a segmentation task with a generative adversarial network (GAN) framework to improve the translation performance. Extensive experiments show the superiority of our overall framework in PET synthesis, especially on those regions of interest.

Infective Endocarditis: New Challenges in a Classic Disease.

Infective endocarditis is a relatively rare, but deadly infection, with an overall mortality of around 20% in most series. Clinical manifestations have evolved in response to significant epidemiological shifts in industrialized nations, with a move toward a nosocomial or health-care-related pattern, in older patients, with more episodes associated with prostheses and/or intravascular electronic devices and a predominance of staphylococcal and enterococcal etiology.Diagnosis is often challenging and is based on the conjunction of clinical, microbiological, and imaging information, with notable progress in recent years in the accuracy of echocardiographic data, coupled with the recent emergence of other useful imaging techniques such as cardiac computed tomography (CT) and nuclear medicine tools, particularly 18F-fluorodeoxyglucose positron emission/CT.The choice of an appropriate treatment for each specific case is complex, both in terms of the selection of the appropriate agent and doses and durations of therapy as well as the possibility of using combined bactericidal antibiotic regimens in the initial phase and finalizing treatment at home in patients with good evolution with outpatient oral or parenteral antimicrobial therapies programs. A relevant proportion of patients will also require valve surgery during the active phase of treatment, the timing of which is extremely difficult to define. For all the above, the management of infective endocarditis requires a close collaboration of multidisciplinary endocarditis teams.

Diagnostic performance of 18 F-FDG-PET/CT in inflammation of unknown origin: A clinical series of 317 patients.

BACKGROUND: Inflammation of unknown origin (IUO) is a challenging situation in internal medicine. OBJECTIVES: To describe the final diagnoses in IUO and assess the helpfulness of 18 F-fluorodesoxyglucose positron emission tomography with computerized tomography (18 F-FDG-PET/CT) in the diagnosis strategy. RESULTS: A total of 317 IUO patients with 18 F-FDG-PET/CT were enrolled. A diagnosis was reached in 228 patients: noninfectious inflammatory diseases (NIID) (37.5%), infectious diseases (18.6%), malignancies (7.9%), and non-systemic-inflammatory miscellaneous diseases (7.9%). The two leading causes of NIID were polymyalgia rheumatica and giant cell arteritis. 18 F-FDG-PET/CT results were classified as true positive in 49.8% of patients and contributory in 75.1% of overall IUO patients (after the complete investigation set and a prolonged follow-up). In multivariate analysis, only C-reactive protein minimum level (≥50 mg/L) was associated with the contributory status of 18 F-FDG-PET/CT. CONCLUSION: Within the wide spectrum of IUO underlying diseases, 18 F-FDG-PET/CT is helpful to make a diagnosis and to eliminate inflammatory diseases. Obese patients constitute a specific group needing further studies.

Early stopping in clinical PET studies: How to reduce expense and exposure.

Clinical positron emission tomography (PET) research is costly and entails exposing participants to radioactivity. Researchers should therefore aim to include just the number of subjects needed to fulfill the purpose of the study. In this tutorial we show how to apply sequential Bayes Factor testing in order to stop the recruitment of subjects in a clinical PET study as soon as enough data have been collected to make a conclusion. By using simulations, we demonstrate that it is possible to stop a study early, while keeping the number of erroneous conclusions low. We then apply sequential Bayes Factor testing to a real PET data set and show that it is possible to obtain support in favor of an effect while simultaneously reducing the sample size with 30%. Using this procedure allows researchers to reduce expense and radioactivity exposure for a range of effect sizes relevant for PET research.

Surveillance in Patients With Diffuse Large B Cell Lymphoma.

With improvement in the cure rates for diffuse large B cell lymphoma, the question of surveillance imaging in patients who achieve complete remission after the initial therapy has become relevant. Some of the clinical practice guidelines recommend surveillance scanning. However, several studies have reported no benefit in overall survival with scans. Moreover, studies have highlighted an increased risk for developing secondary malignancies because of exposure to ionizing radiation from the scans. Different international societies have contrasting guidelines for the role of surveillance computerized tomography scans in patients who achieve complete remission after first-line therapy. Any benefit of surveillance imaging must be balanced by the costs, risk of radiation exposure, and lack of survival benefit. The PubMed platform was searched using relevant keywords for English-language articles with no date restrictions. Search terms were cross-referenced with review articles, and additional articles were identified by manually searching reference lists. Results were reviewed by the authors and selected for inclusion based on relevance. We present a review of this current data available for surveillance imaging in patients with diffuse large B cell lymphoma.

Radiation Exposure in Pediatric Sarcoma Patients Receiving Initial Curative Chemotherapy.

The objective of our study is to estimate the radiation exposure to pediatric patients with sarcoma getting required (or highly recommended) ionizing radiation scans during initial chemotherapy and to determine how often distant progressive disease was discovered. Data from the last 25 years from the Children's Oncology Group open phase III protocols were reviewed for the most common pediatric sarcomas: osteosarcoma, Ewing's sarcoma, and rhabdomyosarcoma. The number of required/recommended ionizing radiation scans, including chest radiographs, chest computed tomography, positron emission tomography scans, and bone scans during induction, consolidation, and maintenance chemotherapy, were recorded and the total radiation dose per patient was calculated. In addition, the number of patients who were removed from protocol during chemotherapy because of new or distant progressive disease was documented. In our analysis of 5845 patients, the average pediatric patient with sarcoma on protocol was exposed to an ionizing radiation dose of 37.1 mGy, equivalent to the lifetime dose of nuclear power plant workers, whereas the progression of disease was detected at most in 5.4% of the patients. Our study is meant to inform pediatric oncologists more precisely of the actual risks and benefits of mandated surveillance scans during chemotherapy in patients with sarcoma.

The Role of Generative Adversarial Networks in Radiation Reduction and Artifact Correction in Medical Imaging.

Adversarial networks were developed to complete powerful image-processing tasks on the basis of example images provided to train the networks. These networks are relatively new in the field of deep learning and have proved to have unique strengths that can potentially benefit radiology. Specifically, adversarial networks have the potential to decrease radiation exposure to patients through minimizing repeat imaging due to artifact, decreasing acquisition time, and generating higher quality images from low-dose or no-dose studies. The authors provide an overview of a specific type of adversarial network called a "generalized adversarial network" and review its uses in current medical imaging research.

The Risk of Developing Secondary Central Nervous System Tumors After Diagnostic Irradiation From Computed Tomography in Pediatrics: A Literature Review.

BACKGROUND: Advanced diagnostic imaging has provided tremendous benefits; however, increased use of ionizing radiation modalities such as cranial computed tomography (CT) may be associated with an increased risk of developing central nervous system tumors. METHODS: A literature review identified studies published for more than the last 50 years from 1968 to 2018 that explored the association between head CT scans and developing central nervous system tumors in pediatrics. We reviewed seven studies that described and analyzed the risk of brain tumors. RESULTS: A positive correlation between exposure to CT scans and developing central nervous system tumors was evident in all cohorts. The strength of the association varied across the studies. Exclusion of patients with predisposing factors to central nervous system tumors was examined in four studies with a decreased risk to develop central nervous system tumors noted in three studies. Two studies reported nonsignificant reduction in the excess relative risk per milliGray of brain dose after adjusting for predisposing factors, whereas the reduction was significant in one study. The frequency of CT exposure was proportional to the risk of developing tumors in two studies although not significantly maintained in two other studies. Gender had no significant effect on the central nervous system tumor risk. The calendar year at the time of imaging showed decreasing risk in those exposed to CT in more recent years compared with prior decades. CONCLUSIONS: Prospective epidemiologic studies are needed to examine the precise carcinogenic effect of exposure to ionizing radiation and help tailor further preventive measures.

OCCUPATIONAL RADIATION DOSE TO NUCLEAR MEDICINE STAFF DUE TO TC99M, F18-FDG PET AND THERAPEUTIC I-131 BASED EXAMINATIONS.

The aim was to track the exposure to radiation workers in six nuclear medicine examinations. A number of 180 patients were recruited and external exposure was measured. Patients had undergone cardiac stress and rest, bone scan, I-131 therapy, Gallium-67 and FDG PET/CT imaging. The average dose received due to cardiac stress and rest were 20.4 ± 5.0 and 16.0 ± 3.8 µSv per patient, respectively, whereas for bone scan, Ga-67, FDG and I-131 therapy, the average dose was 6.1 ± 2.5, 6.0 ± 1.4, 11.1 ± 2.2 and 4.1 ± 2.6 µSv per patient. The patient-to-staff dose coefficients were on average 0.051 ± 0.009, 0.042 ± 0.010, 0.034 ± 0.016, 0.039 ± 0.021, 0.052 ± 0.012, 0.094 ± 0.021 µSv m2/MBq h for stress, rest, bone, I-131, Ga-67 and FDG reported post-administration, respectively. Patient injection and setup for imaging represent a high percentage of the total dose received by staff. The information revealed is able to revise local measures, safety standards, and could help further in dose optimization and minimal exposure to occupationally exposed worker in nuclear medicine laboratories.

Intensive Imaging Surveillance of Survivors of Breast Cancer May Increase Risk of Radiation-induced Malignancy.

BACKGROUND: Current clinical guidelines recommend mammography as the only imaging method for surveillance in asymptomatic survivors of early breast cancer (EBC). However, non-recommended tests are commonly used. We estimated the imaging radiation-induced malignancies (IRIM) risks in survivors of EBC undergoing different imaging surveillance models. MATERIALS AND METHODS: We built 5 theoretical models of imaging surveillance, from annual mammography only (model 1) to increasingly imaging-intensive approaches, including computed tomography (CT) scan, positron emission tomography-CT, bone scan, and multigated acquisition scan (models 2 through 5). Using the National Cancer Institute's Radiation Risk Assessment Tool, we compared the excess lifetime attributable cancer risk (LAR) for hypothetical survivors of EBC starting surveillance at the ages of 30, 60, or 75 years and ending at 81 years. RESULTS: For all age groups analyzed, there is a statistically significant increase in LAR when comparing model 1 with more intensive models. As an example, in a patient beginning surveillance at the age of 60 years, there is a 28.5-fold increase in the IRIM risk when comparing mammography only versus a schedule with mammography plus CT scan of chest-abdomen and bone scan. We found no differences when comparing models 2 through 5. LAR is higher when surveillance starts at a younger age, although the age effect was only statistically significant in model 1. CONCLUSION: Non-recommended imaging during EBC surveillance can be associated with a significant increase in LAR. In addition to the lack of survival benefit, additional tests may have significant IRIM risks and should be avoided.