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-[ <sup>18</sup> F]fluoro-D-glucose positron emission tomography/computed tomography ( <sup>18</sup> F-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 <sup>18</sup> F-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 <sup>177</sup> Lu-PSMA radionuclide therapy. We report for the first time that <sup>177</sup> Lu-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 <sup>177</sup> Lu-PSMA treatment especially combined with immunotherapy may be an option for patients with cancer without other therapeutic options. Insights: <sup>177</sup> Lu-PSMA radionuclide therapy should be considered for any tumor stained positive for PSMA

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

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. 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. 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. 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

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-[ <sup>18</sup> F]fluoro-D-glucose positron emission tomography/computed tomography ( <sup>18</sup> F-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. <sup>18</sup> F-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

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

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 <sup>18</sup> F-Fluoro-Deoxy-Glucose Positron Emission Tomography/Computed Tomography ( <sup>18</sup> F-FDG PET/CT). We retrospectively included 22 SCLC patients. 50% had hippocampal-sparing (HS) PCI. <sup>18</sup> F-FDG PET/CT was performed 144.5 ± 73 days before and 383 ± 451 days after PCI. Brain <sup>18</sup> F-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. We found significant decreases in <sup>18</sup> F-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). PCI induced a diffuse decrease in <sup>18</sup> F-FDG brain metabolism. HS-PCI preserves metabolic activity of the hippocampi

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 <sup>177</sup> Lu-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

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

The aim of this proof-of-concept study is to propose a simplified personalized kidney dosimetry procedure in <sup>177</sup> Lu 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. We conducted a phantom study involving external count-rate measurements in an abdominal phantom setup filled with activity concentrations of <sup>99m</sup> Tc, reproducing patient-relevant organ effective half-lives occurring in <sup>177</sup> Lu PRRT. GATE Monte Carlo (MC) simulations of the experiment, using <sup>99m</sup> Tc and <sup>177</sup> Lu as sources, were performed. Furthermore, we tested this method via MC on a clinical case of <sup>177</sup> Lu-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. 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 <sup>99m</sup> Tc and <sup>177</sup> Lu, 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. 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