PET radiotracers for whole-body in vivo molecular imaging of prostatic neuroendocrine malignancies.

Prostatic neuroendocrine malignancies represent a spectrum of diseases. Treatment-induced neuroendocrine differentiation (tiNED) in hormonally treated adenocarcinoma has been the subject of a large amount of recent research. However, the identification of neuroendocrine features in treatment-naïve prostatic tumor raises a differential diagnosis between prostatic adenocarcinoma with de novo neuroendocrine differentiation (dNED) versus one of the primary prostatic neuroendocrine tumors (P-NETs) and carcinomas (P-NECs). While [18F]FDG is being used as the main PET radiotracer in oncologic imaging and reflects cellular glucose metabolism, other molecules labeled with positron-emitting isotopes, mainly somatostatin-analogues labeled with 68Ga and prostate-specific membrane antigen (PSMA)-ligands labeled with either 18F or 68Ga, are now routinely used in departments of nuclear medicine and molecular imaging, and may be advantageous in imaging prostatic neuroendocrine malignancies. Still, the selection of the preferred PET radiotracer in such cases might be challenging. In the current review, we summarize and discuss published data on these different entities from clinical, biological, and molecular imaging standpoints. Specifically, we review the roles that [18F]FDG, radiolabeled somatostatin-analogues, and radiolabeled PSMA-ligands play in these entities in order to provide the reader with practical recommendations regarding the preferred PET radiotracers for imaging each entity. In cases of tiNED, we conclude that PSMA expression may be low and that [18F]FDG or radiolabeled somatostatin-analogues should be preferred for imaging. In cases of prostatic adenocarcinoma with dNED, we present data that support the superiority of radiolabeled PSMA-ligands. In cases of primary neuroendocrine malignancies, the use of [18F]FDG for imaging high-grade P-NECs and radiolabeled somatostatin-analogues for imaging well-differentiated P-NETs is recommended. KEY POINTS: • The preferred PET radiotracer for imaging prostatic neuroendocrine malignancies depends on the specific clinical scenario and pathologic data. • When neuroendocrine features result from hormonal therapy for prostate cancer, PET-CT should be performed with [18F]FDG or radiolabeled somatostatin-analogue rather than with radiolabeled PSMA-ligand. • When neuroendocrine features are evident in newly diagnosed prostate cancer, differentiating adenocarcinoma from primary neuroendocrine malignancy is challenging but crucial for selection of PET radiotracer and for clinical management.

Beyond Visual Assessment of Basal Ganglia Uptake: Can Automated Method and Pineal Body Uptake Assessment Improve Identification of Nigrostriatal Dysfunction on 18F-DOPA PET/CT?

The interpretation of 18F-DOPA PET/CT performed for assessing nigrostriatal dysfunction (NSD) is usually based on visual assessment of the uptake in the basal ganglia (VA-BG). In the present study, we evaluate the diagnostic performance of an automated method that assesses BG uptake (AM-BG) and of methods that assess pineal body uptake, and examine whether these methods can enhance the diagnostic performance of VA-BG alone. We retrospectively included 112 scans performed in patients with clinically suspected NSD who also had a subsequent final clinical diagnosis provided by a movement disorder specialist (69 NSD and 43 non-NSD patients). All scans were categorized as positive or negative based on (1) VA-BG, (2) AM-BG, and (3) qualitative and semiquantitative assessment of pineal body uptake. VA-BG, AM-BG, assessment of pineal body 18F-DOPA uptake by VA (uptake > background), by SUVmax (≥0.72), and by pineal to occipital ratio (POR ≥ 1.57) could all significantly differentiate NSD from non-NSD patients (Pv < 0.01 for all five methods). Of these methods, VA-BG provided the highest sensitivity (88.4%) and accuracy (90.2%). Combining VA-BG with AM-BG did not improve diagnostic accuracy. An interpretation algorithm that combines VA-BG with pineal body uptake assessment by POR calculation increased sensitivity to 98.5%, at the expense of decreased specificity. In conclusion, an automated method that assesses 18F-DOPA uptake in the BG and assessment of pineal body 18F-DOPA uptake can significantly separate NSD from non-NSD patients, with apparent inferior diagnostic performance when applied alone compared with VA-BG. When VA-BG categorizes a scan as negative or equivocal, assessment of the 18F-DOPA uptake in the pineal body has the potential to minimize the rate of false negative reports. Further research is essential to validate this approach and to study the pathophysiologic relationship between 18F-DOPA uptake in the pineal body and nigrostriatal dysfunction.

Is There a Role for [18F]FDG PET-CT in Staging MALT Lymphoma?

The role of 18F-fluorodeoxyglucose ([18F]FDG) positron emission tomography-computed tomography (PET-CT) in assessing mucosa-associated lymphoid tissue (MALT) lymphoma is debatable. We retrospectively explored the role of [18F]FDG PET-CT in staging and predicting progression-free-survival (PFS) of patients with newly-diagnosed MALT lymphoma. Sixty-six studies were included. The maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were documented in the "hottest" extranodal and nodal lesions. Extranodal lesions and accompanying nodal disease were detected on PET in 38/66 (57.6%) and 13/66 (19.7%) studies, respectively. Detection rate of extranodal lesions differed significantly between those located in tissues with high/heterogeneous (e.g., stomach) vs low/homogenous (e.g., subcutaneous-tissue, lung) physiologic [18F]FDG-uptake (40.4% vs. 100%, p < 0.01). Nodal lesions had significantly lower SUVmax, MTV and TLG compared with extrandodal lesions in the same patients. Detection and [18F]FDG-avidity of extranodal lesions were higher in patients with advanced, bulky disease and concomitant marrow/nodal involvement. Increased SUVmax of extranodal lesions predicted shorter PFS (HR 1.10, 95% CI 1.01-1.19, p = 0.02). Higher SUVmax and TLG showed trends towards shorter PFS in patients with localized disease. In conclusion, detection rate of extranodal MALT lymphoma lesions located in tissues with low/homogeneous physiologic [18F]FDG-uptake is excellent on [18F]FDG PET-CT. When detected, SUVmax of extranodal lesions may predict PFS.

[18F]FDG PET-CT in patients with DLBCL treated with CAR-T cell therapy: a practical approach of reporting pre- and post-treatment studies.

PURPOSE: The introduction of CD19-specific chimeric antigen receptor T-cell therapy (CAR-T) for treatment of relapsed/refractory diffuse large B cell lymphoma (R/R DLBCL) gives hope to patients with otherwise dismal prognosis. Therapy outcomes, however, depend upon selection of patients and accurate early identification of non-responders. Patients treated with CAR-T usually undergo [18F]FDG PET-CT at time of decision (TD), time of CAR-T transfusion (TT), 1 month (M1), and 3 months (M3) post-therapy. The purpose of the current study was to identify the specific parameters that should be addressed when reporting PET-CT studies in the clinical setting of CAR-T therapy. METHODS: A total of 138 PET-CT scans (30 TD, 42 TT, 44 M1, 22 M3) of 48 patients treated with CAR-T were included. SUVmax, TMTV, and TLG were calculated in all scans. Response was assessed using the Deauville scale and ΔSUVmax method. Overall survival (OS) was the primary endpoint. Median follow-up was 12.8 (IQR 6.4-16.0) months from CAR-T infusion. RESULTS: In a univariate analysis, TD-SUVmax > 17.1 and TT-SUVmax > 12.1 were associated with shorter OS (Pv < 0.05). In a multivariate analysis, three factors were significantly associated with shorter OS: TD-SUVmax > 17.1 (HR 10.3; Pv < 0.01), LDH > 450 U/l (HR 7.7; Pv < 0.01), and ECOG score > 1 (HR 5.5; Pv = 0.04). Data from TD and TT PET-CT scans were not predictive of toxicity. On M1-PET-CT, patients with a Deauville score > 3 had significantly shorter OS (median 7.9 months, versus not reached, Pv < 0.01). ΔSUVmax ≤ 66% on M1-PET-CT predicted shorter OS when M1-SUVmax was compared to TD-SUVmax (Pv = 0.02) but not to TT-SUVmax (Pv = 0.38). CONCLUSION: Pre-treatment SUVmax may guide patient selection for CAR-T therapy. On M1-PET-CT, Deauville score and ΔSUVmax from TD may identify early therapy failure. These parameters are easy to obtain and should be included in the PET-CT report.

A sigh of relief: vaccine-associated hypermetabolic lymphadenopathy following the third COVID-19 vaccine dose is short in duration and uncommonly interferes with the interpretation of [18F]FDG PET-CT studies performed in oncologic patients.

PURPOSE: The incidence of COVID-19 vaccine-associated hypermetabolic lymphadenopathy (VAHL) is high following the administration of the first and second BNT162b2 vaccine doses. The impact of this finding on [18F]FDG PET-CT interpretation and its correlation with the induced humoral immunity have been reported. Assuming the amnestic immune response is different following the third vaccine dose, we aimed to explore the incidence of VAHL over time after the third BNT162b2 dose administration, and its relevance to [18F]FDG PET-CT interpretation in oncologic patients. METHODS: A total of 179 consecutive oncologic patients that underwent [18F]FDG PET-CT after a third BNT162b2 vaccine dose were included. The presence of VAHL was assessed. On VAHL-positive scans, the SUVmax, number, location, and size of the "hot" nodes were recorded. The median time interval between vaccination and imaging was 8 (IQR, 5-14) days. RESULTS: The incidences of all-grade VAHL and grade 3-4 VAHL were 47.5% and 8.9%, respectively. VAHL was identified on 82.5% of studies performed within the first 5 days from vaccination. Grade 3-4 VAHL was observed on 28.1% of studies performed within the first 5 days from vaccination, but was not detected on studies performed more than 5 days from vaccination. Separation between VAHL and malignant lymphadenopathy was not possible in only 2 of the 179 study patients. On a multivariable logistic regression, independent predictors of grade 3-4 VAHL were short time interval between vaccination and imaging (Pv < 0.01), younger age (Pv < 0.01), and lower BMI (Pv = 0.03). CONCLUSION: VAHL is commonly identified on [18F]FDG PET-CT performed within the first 5 days from the third BNT162b2 vaccine dose administration. High-grade VAHL is unlikely to be observed on a scan performed 6 days or longer from vaccination, and is even less likely in older and obese patients.

[STAGING CERVICAL CANCER USING PET-CT AND PET-MRI].

INTRODUCTION: Whole-body Positron Emission Tomography-Computerized Tomography (PET-CT) and pelvic Magnetic Resonance (MR) imaging are included in developed countries in the imaging algorithm of newly diagnosed cervical cancer (CC). In recent years, the novel technology of PET-MR has been introduced in the clinical practice of tumor imaging. We present a patient with newly-diagnosed CC, who was evaluated using whole-body PET-CT and pelvic PET-MR in a single visit in our department. The role of the latter technologies in defining the anatomical, metabolic and functional data for optimal staging of CC is illustrated. We review the advantages and limitations of each of the modalities in staging the primary, nodal and distant disease, discuss the importance of accurate staging for guiding clinical management, and highlight the unique benefit of PET-MR in imaging of CC.

Correlation between BNT162b2 mRNA Covid-19 vaccine-associated hypermetabolic lymphadenopathy and humoral immunity in patients with hematologic malignancy.

PURPOSE: Vaccine-associated hypermetabolic lymphadenopathy (VAHL) is frequently observed on [18F]FDG PET-CT following BNT162b2 administration. Recent data suggest a prominent B cell germinal-center (GC) response elicited by mRNA vaccines in draining lymph nodes. Thus, in this study we aimed to explore the correlation between VAHL and humoral immunity as reflected by post-vaccination serologic testing and by comparing the incidence of VAHL between lymphoma patients treated recently with B cell depleting therapy and those that were not. METHODS: A total of 137 patients with hematologic malignancy that had post-vaccination [18F]FDG PET-CT were included (All-PET group), 86 received both vaccine doses before imaging (PET-2 group). Their VAHL status and grade on imaging were recorded. Among 102 lymphoma patients, 34 (33.3%) were treated during the year prior vaccination with anti-CD20 antibody containing therapy. A subgroup of 54 patients also underwent serologic testing 2-3 weeks after the booster dose, and their anti-spike titers were recorded and graded as well. RESULTS: The overall incidence of VAHL in patients with hematologic malignancy was 31.4%. The 34 lymphoma patients treated during the year prior vaccination with anti-CD20 antibody containing therapy had significantly lower rates of VAHL comparted with all other lymphoma patients (8.8 versus 41.2% in all-PET patients, Pv < 0.01). VAHL rates were 10% in patients with negative serology, 31.3% in patients with low anti-spike titers, and 72.2% in patients with high anti-spike titers. The positive predictive values of VAHL were 90 and 93.3% in all-PET and PET-2 patients, respectively. A positive statistically significant correlation was found between VAHL and serology ranks in All-PET patients (rs = 0.530, Pv < 0.001), and stronger correlation was found in PET-2 patients (rs = 0.642, Pv < 0.001). CONCLUSION: VAHL on [18F]FDG PET-CT of patients with hematologic malignancy may reflect GC B cell proliferation and an effective humoral response elicited by BNT162b2 vaccine.

When Should a Heat-Tolerance Test Be Scheduled After Clinical Recovery From an Exertional Heat Illness?

OBJECTIVE: Researchers have produced a hypothesis of transient heat intolerance (HI) after exertional heat stroke (EHS). Based on this hypothesis, heat-tolerance testing (HTT) has been postponed until weeks 6 to 8 after EHS and other types of exertional heat illness (EHI). We compared the HTT results of participants after either EHS or other EHI who were tested earlier (≤6-week group) versus those who were tested later (>6-week group) to verify the hypothesis. DESIGN: Cohort study. SETTING: Data obtained from records of military athletes who experienced EHS or EHI. PATIENTS OR OTHER PARTICIPANTS: All participants who underwent HTT after EHI or EHS experienced between 2014 and 2018 and for whom complete data regarding the severity of the event (rectal temperature, neurologic symptoms, and laboratory results) and HTT results were available were included. Participants with suspected EHS and those with other EHIs were evaluated separately. MAIN OUTCOME MEASURE(S): The percentages of participants with HI and mean probability of heat tolerance were compared between those tested within 6 weeks of the event and those tested later. RESULTS: A total of 186 participants were included in this study (EHS: 12 in the <6-week group, 9 in the >6-week group; EHI: 94 in the <6-week group, 71 in the >6-week group). In the EHS group, the percentages with HI (33% versus 44%, P = .67) and mean probability of heat tolerance (0.82 versus 0.82, P = .98) did not differ. In the EHI group, participants who were tested after 6 weeks had a greater chance of being diagnosed with HI (38% versus 21.3%, P < .02). CONCLUSIONS: The HTT results were similar between participants with EHS who were tested early (<6 weeks) and those tested late (>6 weeks). Further investigation of heat-tolerance changes in larger cohorts of patients after EHS is required to verify the theory of transient HI.