The Dark Side of Activated Phosphoinositide 3-Kinase-δ Syndrome 2: A Story Rewritten through FDG-PET.

Background: Activated phosphoinositide 3-kinase-δ syndrome 2 (APDS2) is characterized by lymphoproliferation and increased risk of malignancy. FDG-PET/CT may represent a helpful diagnostic tool for differentiating these clinical features and correctly diagnosing inborn errors of immunity (IEI). Case report: We present the case of a female patient diagnosed with Hodgkin's lymphoma at 19 years of age, although atypical imaging aspects emerged: baseline FDG-PET/CT revealed several hot lymph nodes with a symmetrical distribution, and increased tracer uptake in spleen, axial, and appendicular bone marrow. Imaging repeated after chemotherapy and autologous stem cell transplantation showed persistent increased FDG uptake at multiple supradiaphragmatic nodes and in bone marrow. After the diagnosis of APDS2 and rapamycin treatment, FDG-PET/CT confirmed complete metabolic normalization of all sites. Conclusions: In the IEI scenario, FDG-PET/CT plays an effective role in differentiating malignant proliferation and immune dysregulation phenotypes. Atypical patterns at FDG-PET/CT should be interpreted as a red flag for the need of an early immunological evaluation.

Psychometric Properties of the Italian Version of the Short-Form Supportive Care Needs Survey Questionnaire (SCNS-SF34-It): A Multicenter Validation Study.

This study aimed to evaluate psychometric properties of the Italian version of the Short-Form Supportive Care Needs Survey Questionnaire (SCNS-SF34) in a cancer population. A multicenter prospective observational study was carried out in outpatient and inpatient settings. The evaluated psychometric properties were as follows: the five-domain structure, the internal consistency, the convergent validity with the Edmond Symptom Assessment System (ESAS) questionnaire, the discriminant validity and test-retest reliability. A total of 714 patients with different types, stages and treatment settings of cancer were recruited. A total of 56% of participants were women, the median age 59 years (range 18-88). The prevalence of patients reporting at least one unmet need was 78.7%. The factor analysis explained 71.3% of the total variance, confirming the five-domain structure of the original model. Internal consistency was good, with Cronbach's alpha values ranging from 0.87 ("psychosocial need", "patient support and health system", "information") to 0.90 ("sexuality"). The convergent validity of the SCNS-SF34-It with the ESAS scale was low, suggesting that these questionnaires cover different concepts. The SCNS-SF34-It was able to discriminate differences between groups, and the test-retest reliability was good (ICC 0.72-0.84). The SCNS-SF34-It proved to be a reliable instrument for use in clinical practice for evaluating unmet needs in the Italian population of cancer patients. This study was not registered.

European Association of Nuclear Medicine Focus 5: Consensus on Molecular Imaging and Theranostics in Prostate Cancer.

BACKGROUND: In prostate cancer (PCa), questions remain on indications for prostate-specific membrane antigen (PSMA) positron emission tomography (PET) imaging and PSMA radioligand therapy, integration of advanced imaging in nomogram-based decision-making, dosimetry, and development of new theranostic applications. OBJECTIVE: We aimed to critically review developments in molecular hybrid imaging and systemic radioligand therapy, to reach a multidisciplinary consensus on the current state of the art in PCa. DESIGN, SETTING, AND PARTICIPANTS: The results of a systematic literature search informed a two-round Delphi process with a panel of 28 PCa experts in medical or radiation oncology, urology, radiology, medical physics, and nuclear medicine. The results were discussed and ratified in a consensus meeting. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Forty-eight statements were scored on a Likert agreement scale and six as ranking options. Agreement statements were analysed using the RAND appropriateness method. Ranking statements were analysed using weighted summed scores. RESULTS AND LIMITATIONS: After two Delphi rounds, there was consensus on 42/48 (87.5%) of the statements. The expert panel recommends PSMA PET to be used for staging the majority of patients with unfavourable intermediate and high risk, and for restaging of suspected recurrent PCa. There was consensus that oligometastatic disease should be defined as up to five metastases, even using advanced imaging modalities. The group agreed that [177Lu]Lu-PSMA should not be administered only after progression to cabazitaxel and that [223Ra]RaCl2 remains a valid therapeutic option in bone-only metastatic castration-resistant PCa. Uncertainty remains on various topics, including the need for concordant findings on both [18F]FDG and PSMA PET prior to [177Lu]Lu-PSMA therapy. CONCLUSIONS: There was a high proportion of agreement among a panel of experts on the use of molecular imaging and theranostics in PCa. Although consensus statements cannot replace high-certainty evidence, these can aid in the interpretation and dissemination of best practice from centres of excellence to the wider clinical community. PATIENT SUMMARY: There are situations when dealing with prostate cancer (PCa) where both the doctors who diagnose and track the disease development and response to treatment, and those who give treatments are unsure about what the best course of action is. Examples include what methods they should use to obtain images of the cancer and what to do when the cancer has returned or spread. We reviewed published research studies and provided a summary to a panel of experts in imaging and treating PCa. We also used the research summary to develop a questionnaire whereby we asked the experts to state whether or not they agreed with a list of statements. We used these results to provide guidance to other health care professionals on how best to image men with PCa and what treatments to give, when, and in what order, based on the information the images provide.

NTRK rearranged sarcoma of the bone. Role for larotrectinib in the neoadjuvant setting of an ultra-rare tumor: a case report.

BACKGROUND: Neurotrophic tyrosine receptor kinase (NTRK) gene-fusion targeted molecules revolutionized the paradigm of treatment of a limited subgroup of cancers of various histologies. Entrectinib and larotrectinib obtained unprecedented response rates in patients with cancer harboring NTRK rearrangements. This evidence recently led to the agnostic approval of these drugs, and evidence (confirmation) of their activity in a broader disease setting is emerging. Here, we report the case of a patient affected by EML4-NTRK3 rearranged undifferentiated spindle cell bone sarcoma treated with larotrectinib, and we argue (discuss about) the incidence and clinical presentation of NTRK gene-fusion positive bone sarcomas, the potential use of upfront treatment with NTRK inhibitors in neoadjuvant setting, and the role of a multidisciplinary tumor board. Despite the rarity of these rearrangements in patients with primitive bone sarcomas, the therapy with NTRK inhibitors represents a highly effective strategy to be pursued in selected cases even in neoadjuvant settings. The management of these very rare cancers should always be discussed in a multidisciplinary board of reference centers.

New Developments in Myeloma Treatment and Response Assessment.

Recent innovative strategies have dramatically redefined the therapeutic landscape for treating multiple myeloma patients. In particular, the development and application of immunotherapy and high-dose therapy have demonstrated high response rates and have prolonged remission duration. Over the past decade, new morphologic or hybrid imaging techniques have gradually replaced conventional skeletal surveys. PET/CT using 18F-FDG is a powerful imaging tool for the workup at diagnosis and for therapeutic evaluation allowing medullary and extramedullary assessment. The independent negative prognostic value for progression-free and overall survival derived from baseline PET-derived parameters such as the presence of extramedullary disease or paramedullary disease, as well as the number of focal bone lesions and SUVmax, has been reported in several large prospective studies. During therapeutic evaluation, 18F-FDG PET/CT is considered the reference imaging technique because it can be performed much earlier than MRI, which lacks specificity. Persistence of significant abnormal 18F-FDG uptake after therapy is an independent negative prognostic factor, and 18F-FDG PET/CT and medullary flow cytometry are complementary tools for detecting minimal residual disease before maintenance therapy. The definition of a PET metabolic complete response has recently been standardized and the interpretation criteria harmonized. The development of advanced PET analysis and radiomics using machine learning, as well as hybrid imaging with PET/MRI, offers new perspectives for multiple myeloma imaging. Most recently, innovative radiopharmaceuticals such as C-X-C chemokine receptor type 4-targeted small molecules and anti-CD38 radiolabeled antibodies have shown promising results for tumor phenotype imaging and as potential theranostics.

Impact of minimal residual disease standardised assessment by FDG-PET/CT in transplant-eligible patients with newly diagnosed multiple myeloma enrolled in the imaging sub-study of the FORTE trial.

Background: 18F-FDG-PET/CT is the current standard technique to define minimal residual disease (MRD) outside the bone marrow (BM) in multiple myeloma (MM), recently standardised applying the Deauville scores (DS) to focal lesions (FS) and bone marrow uptake (BMS) and defining the complete metabolic response (CMR) as uptake below the liver background (DS <4). Methods: In this analysis, we aimed at confirming the role of CMR, and complementarity with BM multiparameter flow cytometry (MFC) at 10-5, in an independent cohort of newly diagnosed transplant-eligible MM patients previously enrolled in the phase II randomised FORTE trial. 109 of the 474 global patients enrolled in the trial between February 23, 2015, and April 5, 2017, who had paired PET/CT (performed at baseline [B] and preceding maintenance therapy [PM]) and MFC evaluation, were included in this analysis. Findings: At B, 93% of patients had focal lesions within the bones (FS ≥4 in 89%) and 99% increased BM uptake (BMS ≥4 in 61%). At PM, CMR was achieved in 63% of patients, which was a strong predictor for prolonged PFS in univariate analysis at landmark time PM (HR 0.40, P = 0.0065) and in Cox multivariate analysis (HR 0.31, P = 0.0023). Regarding OS, a trend in favour of CMR was present in univariate (HR 0.44, P = 0.094), and Cox multivariate model (HR 0.17, P = 0.0037). Patients achieving both PET/CT CMR and MFC negativity at PM showed significantly extended PFS in univariate (HR 0.45, P = 0.020) and multivariate analysis (HR 0.41, P = 0.015). Interpretation: We herein confirm the applicability and validity of DS criteria to define CMR and its prognostic relevance and complementarity with MFC at the BM level. Funding: Amgen, Celgene/Bristol Myers Squibb, Italian Ministry of Health (RC-2022-2773423).

Prognostic value of integrated morphofunctional imaging methods in inoperable intrahepatic cholangiocarcinoma.

Introduction and aim: Intrahepatic cholangiocarcinoma (iCCA) is a disease characterized by rarity, heterogeneity, and high mortality, where surgical resection is often not possible. Nowadays, due to the recent introduction of new therapeutic options such as trans-arterial radioembolization (TARE), it is increasingly important to define the role of morphofunctional imaging methods for the prognostic stratification of patients affected by iCCA. The aim of the study was to verify the prognostic value of morphofunctional imaging methods at the baseline in patients with inoperable iCCA. Methods: In total, 45 patients with iCCA were sent to our center between January 2016 and March 2021 for being evaluated to be treated with TARE. All of them underwent both [18F]-FDG-PET/CT and contrast-enhanced CT (ceCT) in a single procedure and were included in our study. The inclusion criteria were as follows: a diagnosis of inoperable iCCA; both [18F]-FDG-PET/CT and ceCT scans; and washout from therapy for at least 2 months before baseline [18F]-FDG-PET/CT and ceCT scans. Both clinical and laboratory data and baseline imaging data (ceCT and [18F]-FDG-PET/CT) were collected. In particular, regarding clinical and laboratory data, we collected overall survival (OS), gender, age, prior therapies, liver function indices, and tumor markers. Regarding ceCT, we collected TNM staging, lesion diameter, volume, vascularization, and presence of intravascular necrosis. Regarding [18F]-FDG-PET/CT, we collected TNM staging, Standard-Uptake-Value max (SUVmax), Metabolic-Tumor-Volume (MTV), and Total-Lesion-Glycolysis (TLG=MTV*lesions SUVmean). Philips-Vue-PACS software was used, setting hepatic SUVmean as TLG threshold. Results: A statistically significant correlation was found between some examined parameters at morphofunctional investigations at the baseline and OS. [18F]-FDG-PET/CT parameters statistically correlated with OS were the stage of disease greater than M0 (p = 0.037), major lesion SUVmax (p = 0.010), MTV (p ≤ 0.001), and TLG (p < 0.001). Other parameters at ceCT correlated with OS were the stage of disease greater than T2 (p = 0.038), maximum lesion diameter (p = 0.07), volume of the major lesion (p = 0.016), and total volume of lesions (p = 0. 009). Biochemical parameters correlated with OS were gamma glutamyl transferase (GGT, p = 0.014), alkaline phosphatase (ALP, p = 0.019), carcinoembryonic antigen (CEA, p = 0.004), and carbohydrate antigen 19-9 (CA 19-9, p < 0.001). From the parameters estimated by the multivariate model, we derived a four-variable score for OS combining nodal involvement and SUVmax at [18F]-FDG-PET/CT, GGT, and CA 19-9 levels. Conclusion: Considering our data, performing integrated pre-therapy imaging is critical for the prognostic stratification of patients with iCCA.

68Ga-FAPI PET/CT Interobserver Agreement on Tumor Assessment: An International Multicenter Prospective Study.

68Ga-fibroblast activation protein inhibitors (FAPIs) are promising radiotracers for cancer imaging, with emerging data in the recent years. Nonetheless, the interobserver agreement on 68Ga-FAPI PET/CT study interpretations in cancer patients remains poorly understood. Methods: 68Ga-FAPI PET/CT was performed on 50 patients with various tumor entities (sarcoma [n = 10], colorectal cancer [n = 10], pancreatic adenocarcinoma [n = 10], genitourinary cancer [n = 10], and other types of cancer [n = 10]). Fifteen masked observers reviewed and interpreted the images using a standardized approach for local, local nodal, and metastatic involvement. Observers were grouped by experience as having a low (<30 prior 68Ga-FAPI PET/CT studies; n = 5), intermediate (30-300 studies; n = 5), or high level of experience (>300 studies; n = 5). Two independent readers with a high level of experience and unmasked to clinical information, histopathology, tumor markers, and follow-up imaging (CT/MRI or PET/CT) served as the standard of reference (SOR). Observer groups were compared by overall agreement (percentage of patients matching SOR) and Fleiss κ with mean and corresponding 95% CI. We defined acceptable agreement as a κ value of at least 0.6 (substantial or higher) and acceptable accuracy as at least 80%. Results: Highly experienced observers agreed substantially on all categories (primary tumor: κ = 0.71; 95% CI, 0.71-0.71; local nodal involvement: κ = 0.62; 95% CI, 0.61-0.62; distant metastasis: κ = 0.75; 95% CI, 0.75-0.75), whereas observers with intermediate experience showed substantial agreement on primary tumor (κ = 0.73; 95% CI, 0.73-0.73) and distant metastasis (κ = 0.65; 95% CI, 0.65-0.65) but moderate agreement on local nodal stages (κ = 0.55; 95% CI, 0.55-0.55). Observers with low experience had moderate agreement on all categories (primary tumor: κ = 0.57; 95% CI, 0.57-0.58; local nodal involvement: κ = 0.51; 95% CI, 0.51-0.52; distant metastasis: κ = 0.54; 95% CI, 0.53-0.54). Compared with SOR, the accuracy for readers with high, intermediate, and low experience was 85%, 83%, and 78%, respectively. In summary, only highly experienced readers showed substantial agreement and a diagnostic accuracy of at least 80% in all categories. Conclusion: The interpretation of 68Ga-FAPI PET/CT for cancer imaging had substantial reproducibility and accuracy among highly experienced observers only, especially for local nodal and metastatic assessments. Therefore, for accurate interpretation of different tumor entities and pitfalls, we recommend training or experience with at least 300 representative scans for future clinical readers.

European Association of Nuclear Medicine (EANM) Focus 4 consensus recommendations: molecular imaging and therapy in haematological tumours.

Given the paucity of high-certainty evidence, and differences in opinion on the use of nuclear medicine for hematological malignancies, we embarked on a consensus process involving key experts in this area. We aimed to assess consensus within a panel of experts on issues related to patient eligibility, imaging techniques, staging and response assessment, follow-up, and treatment decision-making, and to provide interim guidance by our expert consensus. We used a three-stage consensus process. First, we systematically reviewed and appraised the quality of existing evidence. Second, we generated a list of 153 statements based on the literature review to be agreed or disagreed with, with an additional statement added after the first round. Third, the 154 statements were scored by a panel of 26 experts purposively sampled from authors of published research on haematological tumours on a 1 (strongly disagree) to 9 (strongly agree) Likert scale in a two-round electronic Delphi review. The RAND and University of California Los Angeles appropriateness method was used for analysis. Between one and 14 systematic reviews were identified on each topic. All were rated as low to moderate quality. After two rounds of voting, there was consensus on 139 (90%) of 154 of the statements. There was consensus on most statements concerning the use of PET in non-Hodgkin and Hodgkin lymphoma. In multiple myeloma, more studies are required to define the optimal sequence for treatment assessment. Furthermore, nuclear medicine physicians and haematologists are awaiting consistent literature to introduce volumetric parameters, artificial intelligence, machine learning, and radiomics into routine practice.

Actionable imaging findings in the daily PET/CT scenario.

Background and aim: The American College of Radiology (ACR) defines "actionable findings" the ones requiring a special communication between radiologists and referring clinicians, suggesting to organize their categorization in a three-degree scale on the basis of the risk for the patient to develop complications. These cases may fall in a grey-zone communication between different care figures with the risk of being underestimated or even not being considered at all. In this paper, our aim is to adapt the ACR categorization to the most frequent actionable findings encountered when reporting PET/CT images in a Nuclear Medicine Department, describing the most frequent and relevant imaging features and presenting the modalities of communication and the related clinical interventions that can be modulated by the prognostic severity of the clinical cases. Materials and methods: We performed a descriptive, observational and critical analysis of the most relevant literature on the topic of "actionable findings", in particular, starting from the reports of the ACR Actionable Reporting Work Group, we categorised and described, in a narrative review, the most relevant "actionable findings" encountered in the Nuclear Medicine PET/CT daily practice. Results: To the best of our knowledge, to date there are no clear indications on this selective PET/CT topic, considering that the current recommendations target mainly radiologists and assume a certain level of radiological expertise. We resumed and classified the main imaging conditions under the term of "actionable findings" according to the corresponding anatomical districts, and we described their most relevant imaging features (independently of PET avidity or not). Furthermore, a different communication timing and strategy was suggested on the basis of the findings' urgency. Conclusion: A systematic categorization of the actionable imaging findings according to their prognostic severity may help the reporting physician to choose how and when to communicate with the referring clinician or to identify cases requiring a prompt clinical evaluation. Effective communication is a critical component of diagnostic imaging: timely receipt of the information is more important than the method of delivery.

Clinical Value of FDG-PET/CT in Multiple Myeloma: An Update.

FDG-PET/CT is a standardized imaging technique that has reached a great importance in the management of patients affected by Multiple Myeloma. It is proved, in fact, that it allows a deep evaluation of therapy efficacy and provides several prognostic indexes both at staging and after therapy. For this reason, it is now recognised as a gold standard for therapy assessment. Beside this, in reacent years FDG-PET/CT contribution to the understanding of Multiple Myeloma has progressively grown. Papers have been published analyzing the prognostic value of active disease volume measurement and standardization issues, the meaning of FDG positive paramedullary and extrameduallary disease, the prognostic impact of FDG positive minimal residual disease, the relation between focal lesions and clonal eterogenity of this disease and the comparison with whole body DWI-MR in terms of detection and therapy assessment. These newer aspects not of clinical impact yet, of FDG-PET/CT in Multiple Myeloma will be presented and discussed in this review.

PET/CT in Non-Hodgkin Lymphoma: An Update.

Non-Hodgkin lymphomas represents a heterogeneous group of lymphoproliferative disorders characterized by different clinical courses, varying from indolent to highly aggressive. 18F-FDG-PET/CT is the current state-of-the-art diagnostic imaging, for the staging, restaging and evaluation of response to treatment in lymphomas with avidity for 18F-FDG, despite it is not routinely recommended for surveillance. PET-based response criteria (using five-point Deauville Score) are nowadays uniformly applied in FDG-avid lymphomas. In this review, a comprehensive overview of the role of 18F-FDG-PET in Non-Hodgkin lymphomas is provided, at each relevant point of patient management, particularly focusing on recent advances on diffuse large B-cell lymphoma and follicular lymphoma, with brief updates also on other histotypes (such as marginal zone, mantle cell, primary mediastinal- B cell lymphoma and T cell lymphoma). PET-derived semiquantitative factors useful for patient stratification and prognostication and emerging radiomics research are also presented.

PSMA PET for the Evaluation of Liver Metastases in Castration-Resistant Prostate Cancer Patients: A Multicenter Retrospective Study.

Background: To evaluate the diagnostic performance of PSMA-PET compared to conventional imaging/liver biopsy in the detection of liver metastases in CRPC patients. Moreover, we evaluated a PSMA-PET/CT-based radiomic model able to identify liver metastases. Methods: Multicenter retrospective study enrolling patients with the following inclusion criteria: (a) proven CRPC patients, (b) PSMA-PET and conventional imaging/liver biopsy performed in a 6 months timeframe, (c) no therapy changes between PSMA-PET and conventional imaging/liver biopsy. PSMA-PET sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy for liver metastases were calculated. After the extraction of radiomic features, a prediction model for liver metastases identification was developed. Results: Sixty CRPC patients were enrolled. Within 6 months before or after PSMA-PET, conventional imaging and liver biopsy identified 24/60 (40%) patients with liver metastases. PSMA-PET sensitivity, specificity, PPV, NPV, and accuracy for liver metastases were 0.58, 0.92, 0.82, 0.77, and 0.78, respectively. Either number of liver metastases and the maximum lesion diameter were significantly associated with the presence of a positive PSMA-PET (p < 0.05). On multivariate regression analysis, the radiomic feature-based model combining sphericity, and the moment of inverse difference (Idm), had an AUC of 0.807 (95% CI:0.686-0.920). Conclusion: For liver metastases assessment, [68Ga]Ga-PSMA-11-PET demonstrated moderate sensitivity while high specificity, PPV, and inter-reader agreement compared to conventional imaging/liver biopsy in CRPC patients.

Spine Infections: The Role of Fluorodeoxyglucose Positron Emission Tomography (FDG PET) in the Context of the Actual Diagnosis Guideline.

Spondylodiscitis is an infectious process that requires numerous health care professionals to be clearly diagnosed and eventually successfully treated. It implies a variety of microbiological agents and conditions; during the diagnostic workup, it is difficult to correctly identify them, and the clinician has to rapidly choose the correct treatment to avoid permanent injuries to the patient. In this context, we conducted a review to better understand the most suitable use of Positron Emission Tomography with 18-Fluoro-deossi-glucose (FDG PET) in a patient suspected of spondylodiscitis, based on current guidelines and literature.. We wanted to review the role of FDG PET in the spondylodiscitis diagnosis and follow up in the context of the current guidelines.

The Role of FDG-PET and Whole-Body MRI in High Grade Bone Sarcomas With Particular Focus on Osteosarcoma.

Sarcoma represents less than 2% of adult malignancies and about 15% to 20% of malignancies in children and adolescents/young adults. This neoplasm accounts for more than 80 different clinico-pathological entities with different clinical behavior; osteosarcoma and ewing sarcoma are the most frequent primary bone tumors. Because of the general poor prognosis, it is important to find out as many prognostic factors as possible to choose the best therapeutical approach and to correctly schedule the follow-up examinations. Third level imaging such as MRI and PET/CT are of utmost importance in the evaluation of sarcoma patients. The spine and bones in general are optimal sites to be evaluated with FDG PET/CT since the physiological background is low. The standardized uptake value (SUV max, a semiquantitave parameter) is used as a surrogate for proliferative cell rate, and the spatial heterogeneity of FDG distribution within the primary mass as a surrogate for malignancy. In several studies SUVmax was a predictive value for overall survival and progression-free survival. Whole-body MRI is a well-established technique for systemic, radiation-free evaluation, which is mostly applied in the oncological field. WB-MRI provides a combination of anatomical and functional sequences and is useful specifically in the evaluation of disease in organs with relatively high background activity such as the brain, liver, kidney, and spinal canal. These technologies provide accurate staging (also useful to drive the biopsy towards the most active foci in large heterogeneous masses), therapy assessment, relapse detection of local recurrence and distance metastasis but also prognostic indexes, in the context of whole body diagnostic procedures. This paper will provide an overview of the role and added value of PET/CT and WB-MRI in bone sarcomas particular focus on osteosarcoma. We also analyzed the role of the PET/CT and MRI for target delineation of radiation therapy and we and we will do an analysis of future prospects as new tracer non FDG.