FDG PET-CT imaging in head and neck paragangliomas: A centre experience.

Head and neck paragangliomas (HNPGLs) are rare tumours with ~ 30% genetic mutations, mainly in succinate dehydrogenase (SDHx) genes. The utility of FDG PET-CT in HNPGLs is questioned by recent developments in novel radiotracers. We therefore performed a retrospective study in a single tertiary referral centre to address the utility of FDG PET/CT in HNPGLs. METHODS: Clinical data on genetic testing and follow-up were collected for patients who had FDG PET-CT scans from 2004 to 2016. Receiver operator characteristic (ROC) analysis was used to compare standardized uptake values (SUVs), metabolic tumour volume (MTV) and total lesion glycolysis (TLG) between lesions in patients who had a clinically related event: event (+) and those who did not: event (-). Similarly, we compared PET parameters between SDHx+ patients and a control group with low probability of mutation. RESULTS: Of 153 HNPGL patients, 73 (29 SDHx+) with 93 FDG-positive lesions were identified: 53.8% of lesions were assessed in a pre-therapeutic setting. In comparison with a reference extracted from clinicoradiological database, FDG PET-CT showed good performance to detect HNPGLs (96.6% accuracy). In this study population, 16 disease progression, 1 recurrence and 1 death were recorded and event (+) patients had lesions with higher SUVmax (p = .03 and p = .02, respectively). Conversely, there were no differences in PET parameters between lesions in SDHx+ patients and controls with low probability of SDHx+ mutations. CONCLUSIONS: FDG PET-CT has clinical utility in HNPGLs, mostly before local treatment. There were no significant differences in PET parameters between SDHx patients and a sporadic HNPGL population. However, regardless of SDHx mutation status, a high SUVmax was associated with more clinical events and prompts to a closer follow-up.

Evaluation of glycodendron and synthetically modified dextran clearing agents for multistep targeting of radioisotopes for molecular imaging and radioimmunotherapy.

A series of N-acetylgalactosamine-dendrons (NAG-dendrons) and dextrans bearing biotin moieties were compared for their ability to complex with and sequester circulating bispecific antitumor antibody streptavidin fusion protein (scFv4-SA) in vivo, to improve tumor-to-normal tissue concentration ratios for multistep targeted (MST) radioimmunotherapy and diagnosis. Specifically, a total of five NAG-dendrons employing a common synthetic scaffold structure containing 4, 8, 16, or 32 carbohydrate residues and a single biotin moiety were prepared (NAGB), and for comparative purposes, a biotinylated-dextran with an average molecular weight of 500 kD was synthesized from amino-dextran (DEXB). One of the NAGB compounds, CA16, has been investigated in humans; our aim was to determine if other NAGB analogues (e.g., CA8 or CA4) were bioequivalent to CA16 and/or better suited as MST reagents. In vivo studies included dynamic positron-emission tomography (PET) imaging of (124)I-labeled-scFv4-SA clearance and dual-label biodistribution studies following MST directed at subcutaneous (s.c.) human colon adenocarcinoma xenografts in mice. The MST protocol consists of three injections: first, a scFv4-SA specific for an antitumor-associated glycoprotein (TAG-72); second, CA16 or other clearing agent; and third, radiolabeled biotin. We observed using PET imaging of the (124)I-labeled-scFv4-SA clearance that the spatial arrangement of ligands conjugated to NAG (i.e., biotin linked with an extended spacer, referred to herein as long-chain (LC)) can impact the binding to the antibody in circulation and subsequent liver uptake of the NAG-antibody complex. Also, NAGB CA32-LC or CA16-LC can be utilized during MST to achieve comparable tumor-to-blood ratios and absolute tumor uptake seen previously with CA16. Finally, DEXB was equally effective as NAGB CA32-LC at lowering scFv4-SA in circulation, but at the expense of reducing absolute tumor uptake of radiolabeled biotin.

Increased [68Ga]Ga-SST uptake in the uncinate pancreatic process in new digital PET/CT machine and potential association with clinical and histologic factors in NET patients.

INTRODUCTION: A physiological increase in the uptake of [68Ga]Ga-labeled somatostatin analogues ([68Ga]Ga-SST) PET tracers has been reported in the uncinate pancreatic process (UP) and might be even higher in latest generation of PET/CT scanners and might be falsely interpreted as NET. We aimed to investigate the uptake of UP in a large population of NET patients who underwent [68Ga]Ga-SST PET/CT with digital SiPM detectors. We also explored potential associations between UP uptake and various clinical, imaging, and pathological factors routinely assessed in NET patients. METHODS: We analyzed all consecutive NET patients from July 2018 to June 2022 in this retrospective, single-center study. All patients underwent a [68Ga]Ga-SST PET/CT scan on a digital SiPM PET/CT scanner. On visual analysis, we distinguished between normal linear and homogenous UP uptake or abnormal if otherwise. We compared SUVmax/mean in patients with normal UP uptake to those with abnormal UP uptake with suspicious NET lesions on contrast-enhanced CT (ce-CT) and according to the site of the primary NET (pancreatic NET vs. other), patient gender (female vs. male) and tumor grade (grade 1-2 vs. 3) using a Mann-Whitney test. We also assessed the correlation between SUVmax/mean values in UP with patients' age, primary NET Ki-67 counting, and its SUVmax/mean, TLA and MTV values. RESULTS: We included 131 NET patients with a total of 34 [68Ga]Ga-DOTATATE PET/CT and 113 [68Ga]Ga-DOTATOC PET/CT scans. An abnormal UP uptake was seen in 32 patients with 65.7% of suspicious NET lesion or extrinsic compression on morphological imaging. Normal UP uptake SUVmax/mean were measured in 115 [68Ga]Ga-SST scans (78.2%) with normal UP uptake and without suspicious lesion on morphological imaging. We found an average SUVmax of 12.3 ± 4.1 for [68Ga]Ga-DOTATATE and 19.8 ± 9.8 g/ml for [68Ga]Ga-DOTATOC, hence higher than those reported in the literature [SUVmax 5 ± 1.6 to 12.6 ± 2.2 g/ml] with significant difference with abnormal UP uptake and between both PET tracers (both p < 0.01). Significant results were a higher UP uptake on [68Ga]Ga-DOTATOC in male patients (p = 0.02) and significant associations between UP uptake on [68Ga]Ga-DOTATOC and SUVmax/mean of the primary tumor (ρ [0.337-0.363]; p [0.01-0.02]). CONCLUSION: We confirmed a higher and very frequent UP uptake in latest SiPM-detector [68Ga]Ga-SST PET/CT with an even higher uptake in patients that had [68Ga]Ga-DOTATOC PET/CT. SUVmean/max were significantly higher in abnormal UP uptake but there were overlaps with UP SUV values for both [68Ga]Ga-SST and a correlation to morphological imaging is crucial. Besides, significant associations between UP uptake and SUVmean/max of the primary NET as well as patients' gender were seen in the larger cohort of [68Ga]Ga-DOTATOC patients suggesting that both physiological and pathological parameters could affect UP uptake.

Immune checkpoint inhibitor-related myositis and myocarditis: diagnostic pitfalls and imaging contribution in a real-world, institutional case series.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are reshaping the prognosis of many cancers, but often cause immune-related adverse events (irAEs). Among neurological irAEs, myositis is the most frequently reported. Our aim is to describe clinical and non-clinical characteristics, treatment and outcome of all irMyositis (skeletal limb-girdle and/or ocular myositis) and irMyocarditis cases in our reference center. METHODS: We retrospectively enrolled all irMyositis/irMyocarditis patients seen between 2018 and 2022. We reviewed demographics, clinical characteristics, biological, neurophysiological, imaging workup, treatment and outcome. RESULTS: We included 14 consecutive patients. The most frequent treatments were pembrolizumab (35%) or ipilimumab-nivolumab combination (35%). Limb-girdle, ocular (non-fluctuating palpebral ptosis and/or diplopia with or without ophthalmoparesis) and cardiac phenotypes were equally distributed, overlapping in 40% of cases. Ocular involvement was frequently misdiagnosed; review of brain MRIs disclosed initially missed signs of skeletal myositis in one patient and ocular myositis in 3. Seven patients had other co-existing irAEs. When performed, myography showed a myogenic pattern. CK was elevated in 8/15 patients, troponin-T in 12/12 and troponin-I in 7/9 tested patients. ICI were discontinued in all cases, with further immunosuppressive treatment in nine patients. In most cases, neurological and cardiological outcome was good at last follow-up. CONCLUSION: Myositis is a potentially severe irAE. Despite its heterogeneous presentation, some highly suggestive clinical symptoms, such as ocular involvement, or radiological signs should raise physicians' attention to avoid misdiagnosis. We thus recommend a multidisciplinary assessment (including complete neuromuscular evaluation) even in case of isolated myocarditis. Our series underlines the importance of an early diagnosis, since suspension of ICI and adequate treatment are usually associated with good functional outcome.

Anatomical Quantitative Volumetric Evaluation of Liver Segments in Hepatocellular Carcinoma Patients Treated with Selective Internal Radiation Therapy: Key Parameters Influencing Untreated Liver Hypertrophy.

Background: Factors affecting morphological changes in the liver following selective internal radiation therapy (SIRT) are unclear, and the available literature focuses on non-anatomical volumetric assessment techniques in a lobar treatment setting. This study aimed to investigate quantitative changes in the liver post-SIRT using an anatomical volumetric approach in hepatocellular carcinoma (HCC) patients with different levels of treatment selectivity and evaluate the parameters affecting those changes. This retrospective, single-institution, IRB-approved study included 88 HCC patients. Whole liver, liver segments, tumor burden, and spleen volumes were quantified on MRI at baseline and 3/6/12 months post-SIRT using a segmentation-based 3D software relying on liver vascular anatomy. Treatment characteristics, longitudinal clinical/laboratory, and imaging data were analyzed. The Student's t-test and Wilcoxon test evaluated volumetric parameters evolution. Spearman correlation was used to assess the association between variables. Uni/multivariate analyses investigated factors influencing untreated liver volume (uLV) increase. Results: Most patients were cirrhotic (92%) men (86%) with Child-Pugh A (84%). Absolute and relative uLV kept increasing at 3/6/12 months post-SIRT vs. baseline (all, p ≤ 0.005) and was maximal during the first 6 months. Absolute uLV increase was greater in Child-Pugh A5/A6 vs. ≥B7 at 3 months (A5, p = 0.004; A6, p = 0.007) and 6 months (A5, p = 0.072; A6, p = 0.031) vs. baseline. When the Child-Pugh class worsened at 3 or 6 months post-SIRT, uLV did not change significantly, whereas it increased at 3/6/12 months vs. baseline (all p ≤ 0.015) when liver function remained stable. The Child-Pugh score was inversely correlated with absolute and relative uLV increase at 3 months (rho = -0.21, p = 0.047; rho = -0.229, p = 0.048). In multivariate analysis, uLV increase was influenced at 3 months by younger age (p = 0.013), administered 90Y activity (p = 0.003), and baseline spleen volume (p = 0.023). At 6 months, uLV increase was impacted by younger age (p = 0.006), whereas treatment with glass microspheres (vs. resin) demonstrated a clear trend towards better hypertrophy (f = 3.833, p = 0.058). The amount (percentage) of treated liver strongly impacted the relative uLV increase at 3/6/12 months (all f ≥ 8.407, p ≤ 0.01). Conclusion: Liver function (preserved baseline and stable post-SIRT) favored uLV hypertrophy. Younger patients, smaller baseline spleen volume, higher administered 90Y activity, and a larger amount of treated liver were associated with a higher degree of untreated liver hypertrophy. These factors should be considered in surgical candidates undergoing neoadjuvant SIRT.

Spatial Distribution of Recurrence and Long-Term Toxicity Following Dose Escalation to the Dominant Intra-Prostatic Nodule for Intermediate-High-Risk Prostate Cancer: Insights from a Phase I/II Study.

Objectives: We investigated spatial patterns between primary and recurrent tumor sites and assessed long-term toxicity after dose escalation stereotactic body radiation therapy (SBRT) to the dominant intra-prostatic nodule (DIN). Materials and methods: In 33 patients with intermediate-high-risk prostate cancer (PCa), doses up to 50 Gy were administered to the DIN. Recurrence sites were determined and compared to the original tumor development sites through multiparametric MRI and 68Ga-labeled prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (68Ga-PSMA-PET/CT) images. Overlap rates, categorized as 75% or higher for full overlap, and 25-74% for partial overlap, were assessed. Long-term toxicity is reported. Results: All patients completed treatment, with only one receiving concomitant androgen deprivation therapy (ADT). Recurrences were diagnosed after a median of 33 months (range: 17-76 months), affecting 13 out of 33 patients (39.4%). Intra-prostatic recurrences occurred in 7 patients (21%), with ≥75% overlap in two, a partial overlap in another two, and no overlap in the remaining three patients. Notably, five patients with intra-prostatic recurrences had synchronous bone and/or lymph node metastases, while six patients had isolated bone or lymph node metastasis without intra-prostatic recurrences. Extended follow-up revealed late grade ≥ 2 GU and GI toxicity in 18% (n = 6) and 6% (n = 2) of the patients. Conclusions: Among patients with intermediate-high-risk PCa undergoing focal dose-escalated SBRT without ADT, DIN recurrences were infrequent. When present, these recurrences were typically located at the original site or adjacent to the initial tumor. Conversely, relapses beyond the DIN and in extra-prostatic (metastatic) sites were prevalent, underscoring the significance of systemic ADT in managing this patient population. Advances in knowledge: Focal dose-escalated prostate SBRT prevented recurrences in the dominant nodule; however, extra-prostatic recurrence sites were frequent.

Imaging assessment of toxicity related to immune checkpoint inhibitors.

In recent years, a wide range of cancer immunotherapies have been developed and have become increasingly important in cancer treatment across multiple oncologic diseases. In particular, immune checkpoint inhibitors (ICIs) offer promising options to improve patient outcomes. However, a major limitation of these treatments consists in the development of immune-related adverse events (irAEs) occurring in potentially any organ system and affecting up to 76% of the patients. The most frequent toxicities involve the skin, gastrointestinal tract, and endocrine system. Although mostly manageable, potentially life-threatening events, particularly due to neuro-, cardiac, and pulmonary toxicity, occur in up to 30% and 55% of the patients treated with ICI-monotherapy or -combination therapy, respectively. Imaging, in particular computed tomography (CT), magnetic resonance imaging (MRI), and 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/computed tomography (18F-FDG-PET/CT), plays an important role in the detection and characterization of these irAEs. In some patients, irAEs can even be detected on imaging before the onset of clinical symptoms. In this context, it is particularly important to distinguish irAEs from true disease progression and specific immunotherapy related response patterns, such as pseudoprogression. In addition, there are irAEs which might be easily confused with other pathologies such as infection or metastasis. However, many imaging findings, such as in immune-related pneumonitis, are nonspecific. Thus, accurate diagnosis may be delayed underling the importance for adequate imaging features characterization in the appropriate clinical setting in order to provide timely and efficient patient management. 18F-FDG-PET/CT and radiomics have demonstrated to reliably detect these toxicities and potentially have predictive value for identifying patients at risk of developing irAEs. The purpose of this article is to provide a review of the main immunotherapy-related toxicities and discuss their characteristics on imaging.

99mTc-macroaggregated albumin SPECT/CT predictive dosimetry and dose-response relationship in uveal melanoma liver metastases treated with first-line selective internal radiation therapy.

First-line selective internal radiation therapy (SIRT) showed promising outcomes in patients with uveal melanoma liver metastases (UMLM). Patient survival depends on liver's disease control. SIRT planning is essential and little is known about dosimetry. We investigated whether 99mTc-MAA-SPECT/CT dosimetry could predict absorbed doses (AD) evaluated on 90Y-PET/CT and assess the dose-response relationship in UMLM patients treated with first-line SIRT. This IRB-approved, single-center, retrospective analysis (prospectively collected cohort) included 12 patients (median age 63y, range 43-82). Patients underwent MRI/CT, 18F-FDG-PET/CT before and 3-6 months post-SIRT, and 90Y-PET/CT immediately post-SIRT. Thirty-two target lesions were included. AD estimates in tumor and non-tumor liver were obtained from 99mTc-MAA-SPECT/CT and post-SIRT 90Y-PET/CT, and assessed with Lin's concordance correlation coefficients (ρc and Cb), Pearson's coefficient correlation (ρ), and Bland-Altman analyses (mean difference ± standard deviation; 95% limits-of-agreement (LOA)). Influence of tumor characteristics and microsphere type on AD was analyzed. Tumor response was assessed according to size-based, enhancement-based and metabolic response criteria. Mean target lesion AD was 349 Gy (range 46-1586 Gy). Concordance between 99mTc-MAA-SPECT/CT and 90Y-PET/CT tumor dosimetry improved upon dose correction for the recovery coefficient (RC) (ρ = 0.725, ρc = 0.703, Cb = 0.969) with good agreement (mean difference: - 4.93 ± 218.3 Gy, 95%LOA: - 432.8-422.9). Without RC correction, concordance was better for resin microspheres (ρ = 0.85, ρc = 0.998, Cb = 0.849) and agreement was very good between predictive 99mTc-MAA-SPECT/CT and 90Y-PET/CT dosimetry (mean difference: - 4.05 ± 55.9 Gy; 95%LOA: - 113.7-105.6). After RC correction, 99mTc-MAA-SPECT/CT dosimetry overestimated AD (- 70.9 ± 158.9 Gy; 95%LOA: - 382.3-240.6). For glass microspheres, concordance markedly improved with RC correction (ρ = 0.790, ρc = 0.713, Cb = 0.903 vs without correction: ρ = 0.395, ρc = 0.244, Cb = 0.617) and 99mTc-MAA-SPECT/CT dosimetry underestimated AD (148.9 ± 267.5 Gy; 95%LOA: - 375.4-673.2). For non-tumor liver, concordance was good between 99mTc-MAA-SPECT/CT and 90Y-PET/CT dosimetry (ρ = 0.942, ρc = 0.852, Cb = 0.904). 99mTc-MAA-SPECT/CT slightly overestimated liver AD for resin (3.4 ± 3.4 Gy) and glass (11.5 ± 13.9 Gy) microspheres. Tumor AD was not correlated with baseline or post-SIRT lesion characteristics and no dose-response threshold could be identified. 99mTc-MAA-SPECT/CT dosimetry provides good estimates of AD to tumor and non-tumor liver in UMLM patients treated with first-line SIRT.

Comparison of integrin αvß3 expression with 68Ga-NODAGA-RGD PET/CT and glucose metabolism with 18F-FDG PET/CT in esophageal or gastroesophageal junction cancers.

BACKGROUND: The primary aims of this study were to compare in patients with esophageal or esophagogastric junction cancers the potential of 68Ga-NODAGA-RGD PET/CT with that of 18F-FDG PET/CT regarding tumoral uptake and distribution, as well as histopathologic examination. METHODS: Ten 68Ga-NODAGA-RGD and ten 18F-FDG PET/CT were performed in nine prospectively included participants (1 woman; aged 58 ± 8.4 y, range 40-69 y). Maximum SUV (SUVmax) and metabolic tumor volumes (MTV) were calculated. The Mann-Whitney U test and Spearman correlation analysis (ρ) were used. RESULTS: 68Ga-NODAGA-RGD PET/CT detected positive uptake in 10 primary sites (8 for primary tumors and 2 for local relapse suspicion), 6 lymph nodes and 3 skeletal sites. 18F-FDG PET/CT detected positive uptake in the same sites but also in 16 additional lymph nodes and 1 adrenal gland. On a lesion-based analysis, SUVmax of 18F-FDG was significantly higher than those of 68Ga-NODAGA-RGD (4.9 [3.7-11.3] vs. 3.2 [2.6-4.2] g/mL, p = 0.014). Only one participant showed a higher SUVmax in an osseous metastasis with 68Ga-NODAGA-RGD as compared to 18F-FDG (6.6 vs. 3.9 g/mL). Correlation analysis showed positive correlation between 18F-FDG and 68Ga-NODAGA-RGD PET parameters (ρ = 0.56, p = 0.012 for SUVmax, ρ = 0.78, p < 0.001 for lesion-to-background ratios and ρ = 0.58, p = 0.024 for MTV). We observed that 18F-FDG uptake was homogenous inside all the confirmed primary sites (n = 9). In contrast, 68Ga-NODAGA-RGD PET showed more heterogenous uptake in 6 out of the 9 confirmed primary sites (67%), seen mostly in the periphery of the tumor in 5 out of the 9 confirmed primary sites (56%), and showed slight extensions into perilesional structures in 5 out of the 9 confirmed primary sites (56%). CONCLUSIONS: In conclusion, 68Ga-NODAGA-RGD has lower potential in the detection of esophageal or esophagogastric junction malignancies compared to 18F-FDG. However, the results suggest that PET imaging of integrin αvß3 expression may provide complementary information and could aid in tumor diversity and delineation. TRIAL REGISTRATION: Trial registration: NCT02666547. Registered January 28, 2016-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02666547 .

Automatic Head and Neck Tumor segmentation and outcome prediction relying on FDG-PET/CT images: Findings from the second edition of the HECKTOR challenge.

By focusing on metabolic and morphological tissue properties respectively, FluoroDeoxyGlucose (FDG)-Positron Emission Tomography (PET) and Computed Tomography (CT) modalities include complementary and synergistic information for cancerous lesion delineation and characterization (e.g. for outcome prediction), in addition to usual clinical variables. This is especially true in Head and Neck Cancer (HNC). The goal of the HEad and neCK TumOR segmentation and outcome prediction (HECKTOR) challenge was to develop and compare modern image analysis methods to best extract and leverage this information automatically. We present here the post-analysis of HECKTOR 2nd edition, at the 24th International Conference on Medical Image Computing and Computer-Assisted Intervention (MICCAI) 2021. The scope of the challenge was substantially expanded compared to the first edition, by providing a larger population (adding patients from a new clinical center) and proposing an additional task to the challengers, namely the prediction of Progression-Free Survival (PFS). To this end, the participants were given access to a training set of 224 cases from 5 different centers, each with a pre-treatment FDG-PET/CT scan and clinical variables. Their methods were subsequently evaluated on a held-out test set of 101 cases from two centers. For the segmentation task (Task 1), the ranking was based on a Borda counting of their ranks according to two metrics: mean Dice Similarity Coefficient (DSC) and median Hausdorff Distance at 95th percentile (HD95). For the PFS prediction task, challengers could use the tumor contours provided by experts (Task 3) or rely on their own (Task 2). The ranking was obtained according to the Concordance index (C-index) calculated on the predicted risk scores. A total of 103 teams registered for the challenge, for a total of 448 submissions and 29 papers. The best method in the segmentation task obtained an average DSC of 0.759, and the best predictions of PFS obtained a C-index of 0.717 (without relying on the provided contours) and 0.698 (using the expert contours). An interesting finding was that best PFS predictions were reached by relying on DL approaches (with or without explicit tumor segmentation, 4 out of the 5 best ranked) compared to standard radiomics methods using handcrafted features extracted from delineated tumors, and by exploiting alternative tumor contours (automated and/or larger volumes encompassing surrounding tissues) rather than relying on the expert contours. This second edition of the challenge confirmed the promising performance of fully automated primary tumor delineation in PET/CT images of HNC patients, although there is still a margin for improvement in some difficult cases. For the first time, the prediction of outcome was also addressed and the best methods reached relatively good performance (C-index above 0.7). Both results constitute another step forward toward large-scale outcome prediction studies in HNC.

Overview of the HECKTOR Challenge at MICCAI 2022: Automatic Head and Neck Tumor Segmentation and Outcome Prediction in PET/CT.

This paper presents an overview of the third edition of the HEad and neCK TumOR segmentation and outcome prediction (HECKTOR) challenge, organized as a satellite event of the 25th International Conference on Medical Image Computing and Computer Assisted Intervention (MICCAI) 2022. The challenge comprises two tasks related to the automatic analysis of FDG-PET/CT images for patients with Head and Neck cancer (H&N), focusing on the oropharynx region. Task 1 is the fully automatic segmentation of H&N primary Gross Tumor Volume (GTVp) and metastatic lymph nodes (GTVn) from FDG-PET/CT images. Task 2 is the fully automatic prediction of Recurrence-Free Survival (RFS) from the same FDG-PET/CT and clinical data. The data were collected from nine centers for a total of 883 cases consisting of FDG-PET/CT images and clinical information, split into 524 training and 359 test cases. The best methods obtained an aggregated Dice Similarity Coefficient (DSCagg) of 0.788 in Task 1, and a Concordance index (C-index) of 0.682 in Task 2.

Lymphopenia during 177Lu-DOTATATE therapy leading to recurrence of tuberculosis: a case report.

We report the case of a 72-year-old woman who presented with tuberculous arthritis during the setting of 177Lu-DOTATATE therapy for a grade-2 neuro-endocrine pancreatic tumor with liver metastases. We hypothesized that this recurrence might have been related to the occurrence of lymphopenia, which is common during PRRT. Indeed, though lymphopenia is frequently dismissed, it could lead to the development of opportunistic diseases and its severity should be examined, especially in case of abnormal clinical symptoms.

Tumor response assessment on imaging following immunotherapy.

In recent years, various systemic immunotherapies have been developed for cancer treatment, such as monoclonal antibodies (mABs) directed against immune checkpoints (immune checkpoint inhibitors, ICIs), oncolytic viruses, cytokines, cancer vaccines, and adoptive cell transfer. While being estimated to be eligible in 38.5% of patients with metastatic solid or hematological tumors, ICIs, in particular, demonstrate durable disease control across many oncologic diseases (e.g., in melanoma, lung, bladder, renal, head, and neck cancers) and overall survival benefits. Due to their unique mechanisms of action based on T-cell activation, response to immunotherapies is characterized by different patterns, such as progression prior to treatment response (pseudoprogression), hyperprogression, and dissociated responses following treatment. Because these features are not encountered in the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), which is the standard for response assessment in oncology, new criteria were defined for immunotherapies. The most important changes in these new morphologic criteria are, firstly, the requirement for confirmatory imaging examinations in case of progression, and secondly, the appearance of new lesions is not necessarily considered a progressive disease. Until today, five morphologic (immune-related response criteria (irRC), immune-related RECIST (irRECIST), immune RECIST (iRECIST), immune-modified RECIST (imRECIST), and intra-tumoral RECIST (itRECIST)) criteria have been developed to accurately assess changes in target lesion sizes, taking into account the specific response patterns after immunotherapy. In addition to morphologic response criteria, 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/computed tomography (18F-FDG-PET/CT) is a promising option for metabolic response assessment and four metabolic criteria are used (PET/CT Criteria for Early Prediction of Response to Immune Checkpoint Inhibitor Therapy (PECRIT), PET Response Evaluation Criteria for Immunotherapy (PERCIMT), immunotherapy-modified PET Response Criteria in Solid Tumors (imPERCIST5), and immune PERCIST (iPERCIST)). Besides, there is evidence that parameters on 18F-FDG-PET/CT, such as the standardized uptake value (SUV)max and several radiotracers, e.g., directed against PD-L1, may be potential imaging biomarkers of response. Moreover, the emerge of human intratumoral immunotherapy (HIT-IT), characterized by the direct injection of immunostimulatory agents into a tumor lesion, has given new importance to imaging assessment. This article reviews the specific imaging patterns of tumor response and progression and available imaging response criteria following immunotherapy.

First communication on the efficacy of combined 177Lutetium-PSMA with immunotherapy outside prostate cancer.

Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy is a validated treatment option for patients with advanced prostate cancer. Although PSMA expression is not limited to prostate tissue, little is known about its relevance to other types of cancer. Here, we present a case report of a patient with uterine leiomyosarcoma that is progressing while on immunotherapy and treated with 177Lu-PSMA radionuclide therapy. We report for the first time that 177Lu-PSMA radionuclide therapy combined with immunotherapy outside of prostate cancer. We did observe post-treatment reduction of tumor growth rate, although we did not notice disease response based on RECIST criteria. We suggest that 177Lu-PSMA treatment especially combined with immunotherapy may be an option for patients with cancer without other therapeutic options. Insights: 177Lu-PSMA radionuclide therapy should be considered for any tumor stained positive for PSMA.

Overview of the RGD-Based PET Agents Use in Patients With Cardiovascular Diseases: A Systematic Review.

Studies using arginine-glycine-aspartate (RGD)-PET agents in cardiovascular diseases have been recently published. The aim of this systematic review was to perform an updated, evidence-based summary about the role of RGD-based PET agents in patients with cardiovascular diseases to better address future research in this setting. Original articles within the field of interest reporting the role of RGD-based PET agents in patients with cardiovascular diseases were eligible for inclusion in this systematic review. A systematic literature search of PubMed/MEDLINE and Cochrane library databases was performed until October 26, 2021. Literature shows an increasing role of RGD-based PET agents in patients with cardiovascular diseases. Overall, two main topics emerged: the infarcted myocardium and atherosclerosis. The existing studies support that αvß3 integrin expression in the infarcted myocardium is well evident in RGD PET/CT scans. RGD-based PET radiotracers accumulate at the site of infarction as early as 3 days and seem to be peaking at 1-3 weeks post myocardial infarction before decreasing, but only 1 study assessed serial changes of myocardial RGD-based PET uptake after ischemic events. RGD-based PET uptake in large vessels showed correlation with CT plaque burden, and increased signal was found in patients with prior cardiovascular events. In human atherosclerotic carotid plaques, increased PET signal was observed in stenotic compared with non-stenotic areas based on MR or CT angiography data. Histopathological analysis found a co-localization between tracer accumulation and areas of αvß3 expression. Promising applications using RGD-based PET agents are emerging, such as prediction of remodeling processes in the infarcted myocardium or detection of active atherosclerosis, with potentially significant clinical impact.

Safety and Efficacy of Ipilimumab plus Nivolumab and Sequential Selective Internal Radiation Therapy in Hepatic and Extrahepatic Metastatic Uveal Melanoma.

To assess the safety and efficacy of ipilimumab plus nivolumab around selective internal radiation therapy (SIRT) in patients with metastatic uveal melanoma (mUM). We present a retrospective, single center study of 32 patients with mUM divided into two groups based on the treatment received between April 2013 and April 2021. The SIRT_IpiNivo cohort was treated with Yttrium-90 microspheres and ipilimumab plus nivolumab before or after the SIRT (n = 18). The SIRT cohort underwent SIRT but did not receive combined immunotherapy with ipilimumab plus nivolumab (n = 14). Twelve patients (66.7%) of the SIRT_IpiNivo arm received SIRT as first-line treatment and six patients (33.3%) received ipilimumab plus nivolumab prior to SIRT. In the SIRT group, seven patients (50.0%) received single-agent immunotherapy. One patient treated with combined immunotherapy 68 months after the SIRT was included in this group. At the start of ipilimumab plus nivolumab, 94.4% (n = 17) presented hepatic metastases and 72.2% (n = 13) had extra liver disease. Eight patients (44.4%) of the SIRT_IpiNivo group experienced grade 3 or 4 immune related adverse events, mainly colitis and hepatitis. Median overall survival from the diagnosis of metastases was 49.6 months (95% confidence interval (CI); 24.1-not available (NA)) in the SIRT_IpiNivo group compared with 13.6 months (95% CI; 11.5-NA) in the SIRT group (log-rank p-value 0.027). The presence of extra liver metastases at the time of SIRT, largest liver lesion more than 8 cm (M1c) and liver tumor volume negatively impacted the survival. This real-world cohort suggests that a sequential treatment of ipilimumab plus nivolumab and SIRT is a well-tolerated therapeutic approach with promising survival rates.

Head and neck tumor segmentation in PET/CT: The HECKTOR challenge.

This paper relates the post-analysis of the first edition of the HEad and neCK TumOR (HECKTOR) challenge. This challenge was held as a satellite event of the 23rd International Conference on Medical Image Computing and Computer-Assisted Intervention (MICCAI) 2020, and was the first of its kind focusing on lesion segmentation in combined FDG-PET and CT image modalities. The challenge's task is the automatic segmentation of the Gross Tumor Volume (GTV) of Head and Neck (H&N) oropharyngeal primary tumors in FDG-PET/CT images. To this end, the participants were given a training set of 201 cases from four different centers and their methods were tested on a held-out set of 53 cases from a fifth center. The methods were ranked according to the Dice Score Coefficient (DSC) averaged across all test cases. An additional inter-observer agreement study was organized to assess the difficulty of the task from a human perspective. 64 teams registered to the challenge, among which 10 provided a paper detailing their approach. The best method obtained an average DSC of 0.7591, showing a large improvement over our proposed baseline method and the inter-observer agreement, associated with DSCs of 0.6610 and 0.61, respectively. The automatic methods proved to successfully leverage the wealth of metabolic and structural properties of combined PET and CT modalities, significantly outperforming human inter-observer agreement level, semi-automatic thresholding based on PET images as well as other single modality-based methods. This promising performance is one step forward towards large-scale radiomics studies in H&N cancer, obviating the need for error-prone and time-consuming manual delineation of GTVs.

Simplified patient-specific renal dosimetry in 177Lu therapy: a proof of concept.

PURPOSE: The aim of this proof-of-concept study is to propose a simplified personalized kidney dosimetry procedure in 177Lu peptide receptor radionuclide therapy (PRRT) for neuroendocrine tumors and metastatic prostate cancer. It relies on a single quantitative SPECT/CT acquisition and multiple radiometric measurements executed with a collimated external probe, properly directed on kidneys. METHODS: We conducted a phantom study involving external count-rate measurements in an abdominal phantom setup filled with activity concentrations of 99mTc, reproducing patient-relevant organ effective half-lives occurring in 177Lu PRRT. GATE Monte Carlo (MC) simulations of the experiment, using 99mTc and 177Lu as sources, were performed. Furthermore, we tested this method via MC on a clinical case of 177Lu-DOTATATE PRRT with SPECT/CT images at three time points (2, 20 and 70 hrs), comparing a simplified kidney dosimetry, employing a single SPECT/CT and probe measurements at three time points, with the complete MC dosimetry. RESULTS: The experimentally estimated kidney half-life with background subtraction applied was compatible within 3% with the expected value. The MC simulations of the phantom study, both with 99mTc and 177Lu, confirmed a similar level of accuracy. Concerning the clinical case, the simplified dosimetric method led to a kidney dose estimation compatible with the complete MC dosimetry within 6%, 12% and 2%, using respectively the SPECT/CT at 2, 20 and 70 hrs. CONCLUSIONS: The proposed simplified procedure provided a satisfactory accuracy and would reduce the imaging required to derive the kidney absorbed dose to a unique quantitative SPECT/CT, with consequent benefits in terms of clinic workflows and patient comfort.

Impact of prophylactic cranial irradiation and hippocampal sparing on 18F-FDG brain metabolism in small cell lung cancer patients.

BACKGROUND AND PURPOSE: Prophylactic cranial irradiation (PCI) in small-cell lung cancer (SCLC) patients improves survival. However, it is also associated with cognitive impairment, although the underlying mechanisms remain poorly understood. Our study aims to evaluate the impact of PCI and potential benefit of hippocampal sparing (HS) on brain metabolism assessed by 18F-Fluoro-Deoxy-Glucose Positron Emission Tomography/Computed Tomography (18F-FDG PET/CT). MATERIALS AND METHODS: We retrospectively included 22 SCLC patients. 50% had hippocampal-sparing (HS) PCI. 18F-FDG PET/CT was performed 144.5 ± 73 days before and 383 ± 451 days after PCI. Brain 18F-FDG PET scans were automatically segmented in 12 regions using Combined-AAL Atlas from MI-Neurology Software (Syngo.Via, Siemens Healthineers). For all atlas regions, we computed SUV Ratio using brainstem as a reference region (SUVR = SUVmean/Brainstem SUVmean) and compared SUVR before and after PCI, using a Wilcoxon test, with a level of significance of p < 0.05. RESULTS: We found significant decreases in 18F-FDG brain metabolism after PCI in the basal ganglia (p = 0.004), central regions (p = 0.001), cingulate cortex (p < 0.001), corpus striata (p = 0.003), frontal cortex (p < 0.001), parietal cortex (p = 0.001), the occipital cortex (p = 0.002), precuneus (p = 0.001), lateral temporal cortex (p = 0.001) and cerebellum (p < 0.001). Conversely, there were no significant changes in the mesial temporal cortex (MTC) which includes the hippocampi (p = 0.089). The subgroup who received standard PCI showed a significant decrease in metabolism of the hippocampi (p = 0.033). Contrastingly, the subgroup of patients who underwent HS-PCI showed no significant variation in metabolism of the hippocampi (p = 0.783). CONCLUSION: PCI induced a diffuse decrease in 18F-FDG brain metabolism. HS-PCI preserves metabolic activity of the hippocampi.

68Ga-DOTATOC PET/CT to detect immune checkpoint inhibitor-related myocarditis.

BACKGROUND: Immune checkpoint inhibitor (ICI)-related myocarditis is a rare but potentially fatal adverse event that can occur following ICI exposure. Early diagnosis and treatment are key to improve patient outcomes. Somatostatin receptor-based positron emission tomography-CT (PET/CT) showed promising results for the assessment of myocardial inflammation, yet information regarding its value for the diagnosis of ICI-related myocarditis, especially at the early stage, is limited. Thus, we investigated the value of 68Ga-DOTA(0)-Phe(1)-Tyr(3)-octreotide (68Ga-DOTATOC) PET/CT for the early detection and diagnosis of ICI-related myocarditis. METHODS: Consecutive patients with clinically suspected ICI-related myocarditis from July 2018 to February 2021 were retrospectively evaluated in this single-center study. All patients underwent imaging for the detection of ICI-related myocarditis using either cardiac magnetic resonance (CMR) imaging or 68Ga-DOTATOC PET/CT. PET/CT images were acquired 90 min after the injection of 2 MBq/kg 68Ga-DOTATOC with pathological myocardial uptake in the left ventricle (LV) suggestive of myocarditis defined using a myocardium-to-background ratio of peak standard uptake value to mean intracavitary LV standard uptake (MBRpeak) value above 1.6. Patients had a full cardiological work-up including ECG, echocardiography, serum cardiac troponin I (cTnI), cardiac troponin T and creatine kinase (CK), CK-MB. Endomyocardial biopsy and inflammatory cytokine markers were also analyzed. The detection rate of ICI-related myocarditis using 68Ga-DOTATOC PET/CT and CMR was assessed. RESULTS: A total of 11 patients had clinically suspected ICI-related myocarditis; 9 underwent 68Ga -DOTATOC PET/CT. All nine (100%) patients with 68Ga-DOTATOC PET/CT presented with pathological myocardial uptake in the LV that was suggestive of myocarditis (MBRpeak of 3.2±0.8, range 2.2-4.4). Eight patients had CMR imaging and 3/8 (38%) patients had lesions evocative of myocarditis. All PET-positive patients were previously treated with a high dose of steroids and intravenous immunoglobulin prior to PET/CT had elevated serum cTnI except for one patient for whom PET/CT was delayed several days. Interestingly, in 5/6 (83%) patients who presented with concomitant myositis, pathological uptake was seen on whole-body 68Ga-DOTATOC PET/CT images in the skeletal muscles, suggesting an additional advantage of this method to assess the full extent of the disease. In contrast, four patients with CMR imaging had negative findings despite having elevated serum cTnI levels (range 20.5-5896.1 ng/mL), thus defining possible myocarditis. Newly identified immune correlates could provide specific biomarkers for the diagnosis of ICI-related myocarditis. Most tested patients (six of seven patients) had serum increases in the inflammatory cytokine interleukin (IL)-6 and in the chemokines CXCL9, CXCL10, and CXCL13, and the mass cytometry phenotypes of immune cell populations in the blood also showed correlations with myocardial inflammation. Four of five patients with myocarditis exhibited a Th1/Th2 imbalance favoring a pronounced inflammatory Th1, Th1/Th17, and Th17 CD4 memory T-cell response. The high proportion of non-classical monocytes and significantly reduced levels of CD31 in four to five patients was also consistent with an inflammatory disease. CONCLUSION: The use of 68Ga-DOTATOC PET/CT along with immune correlates is a highly sensitive method to detect ICI-related myocarditis especially in the early stage of myocardial inflammation, as patients with elevated cTnI may present normal CMR imaging results. 68Ga-DOTATOC PET/CT is also useful for detecting concomitant myositis. These results need to be confirmed in a larger population of patients and validated against a histological gold standard if available.