A Kinetically Controlled Bioconjugation Method for the Synthesis of Radioimmunoconjugates and the Development of a Domain Mapping MS-Workflow for Its Characterization.

Immunoconjugates exploit the high affinity of monoclonal antibodies for a recognized antigen to selectively deliver a cytotoxic payload, such as drugs or radioactive nuclides, at the site of disease. Despite numerous techniques have been recently developed for site-selective bioconjugations of protein structures, reaction of ε-amine group of lysine residues with electrophilic reactants, such as activated esters (NHS), is the main method reported in the literature as it maintains proteins in their native conformation. Since antibodies hold a high number of lysine residues, a heterogeneous mixture of conjugates will be generated, which can result in decreased target affinity. Here, we report an intradomain regioselective bioconjugation between the monoclonal antibody Trastuzumab and the N-hydroxysuccinimide ester of the chelator 2,2',2″,2‴-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid (DOTA) by a kinetically controlled reaction adding substoichiometric quantities of the activated ester to the mAb working at slightly basic pH. Liquid chromatography-mass spectrometry (LC-MS) analyses were carried out to assess the chelator-antibody ratio (CAR) and the number of chelating moieties linked to the mAb chains. Proteolysis experiments showed four lysine residues mainly involved in bioconjugation (K188 for the light chain and K30, K293, and K417 for the heavy chain), each of which was located in a different domain. Since the displayed intradomain regioselectivity, a domain mapping MS-workflow, based on a selective domain denaturation, was developed to quantify the percentage of chelator linked to each mAb domain. The resulting immunoconjugate mixture showed an average CAR of 0.9. About a third of the heavy chains were found as monoconjugated, whereas conjugation of the chelator in the light chain was negligible. Domain mapping showed the CH3 domain bearing 13% of conjugated DOTA, followed by CH2 and VH respectively bearing 12.5 and 11% of bonded chelator. Bioconjugation was not found in the CH1 domain, whereas for the light chain, only the CL domain was conjugated (6%). Data analysis based on LC-MS quantification of different analytical levels (intact, reduced chains, and domains) provided the immunoconjugate formulation. A mixture of immunoconjugates restricted to 15 species was obtained, and the percentage of each one within the mixture was calculated. In particular, species bearing 1 DOTA with a relative abundance ranging from 4 to 20-fold, in comparison to species bearing 2DOTA, were observed. Pairing of bioconjugation under kinetic control with the developed domain mapping MS-workflow could raise the standard of chemical quality for immunoconjugates obtained with commercially available reactants.

Metabolic delineation of IDH1 wild-type glioblastoma surgical anatomy: how to plan the tumor extent of resection.

PURPOSE: Magnetic resonance imaging (MRI) is the current standard for preoperative planning of glioblastoma (GBM) surgery. However, recent data on the use of 11 C-methionine positron emission tomography (11[C]-MET PET) suggest its role in providing additional information beyond MRI. The purpose of this study is to establish if there is a correlation between anatomical and metabolic data. METHODS: We retrieved all GBM cases treated from 2014 to January 2021. Preoperative MRI (Enhancing Nodule -EN-, FLAIR and Total Tumor Volume -TTV-), PET volumes and histological samples obtained from the different tumor regions were evaluated to analyze potential correlations between anatomical, metabolic and pathological data. RESULTS: 150 patients underwent surgery for GBM and 49 of these were also studied preoperatively with 11[C]-MET PET; PET volume was evaluated in 47 patients. In 33 patients (70.21%) preoperative 11[C]-MET PET volume > preoperative EN volume and in 11 (23.4%) preoperative 11[C]-MET PET volume > preoperative TTV. We found a significant correlation between preoperative TTVs and PET volumes (p = 0.016) as well as between preoperative EN volumes and PET volumes (p = < 0.001). Histologically, 109 samples were evaluated. ENs samples exhibited the conventional GBM morphology while samples from the FLAIR regions showed white matter tissue, with focal to diffuse tumor cells infiltration and areas of reactive astrogliosis. CONCLUSION: We submit that 11[C]-MET PET volume generally overcome EN. The presence of neoplastic cells confirm these metabolic data. It should be considered in the surgical planning to achieve a Supra Total Resection (SupTR).

Acrometastases to the Hand: A Systematic Review.

Background and Objectives: The term acrometastases (AM) refers to secondary lesions sited distally to the elbow and knee, representing 0.1% of all bony metastases. By frequency, pulmonary cancer and gastrointestinal and genitourinary tract neoplasms are the most responsible for the reported AM. Improvements in oncologic patient care favor an increase in the incidence of such rare cases. We performed a systematic review of acrometastases to the hand to provide further insight into the management of these fragile patients. We also present a peculiar case of simultaneous acrometastasis to the ring finger and pathological vertebral fracture. Material and Methods: A literature search according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement was conducted using the PubMed, Google Scholar, and Scopus databases in December 2020 on metastasis to the hand and wrist, from 1986 to 2020. MeSH terms included acrometastasis, carpal metastasis, hand metastasis, finger metastasis, phalangeal metastasis, and wrist metastasis. Results: In total, 215 studies reporting the follow-up of 247 patients were analyzed, with a median age of 62 years (range 10-91 years). Overall, 162 out of 247 patients were males (65.6%) and 85 were females (34.4%). The median reported follow-up was 5 months (range 0.5-39). The median time from primary tumor diagnosis to acrometastasis was 24 months (range 0.7-156). Acrometastases were located at the finger/phalanx (68.4%), carpal (14.2%), metacarpal (14.2%), or other sites (3.2%). The primary tumors were pulmonary in 91 patients (36.8%). The average interval from primary tumor diagnosis to acrometastasis varied according to the primary tumor type from 2 months (in patients with mesenchymal tumors) to 64.0 months (in patients with breast cancer). Conclusions: Acrometastases usually develop in the late stage of oncologic disease and are associated with short life expectancy. Their occurrence can no longer be considered rare; physicians should thus be updated on their surgical management and their impact on prognosis and survival.

A preliminary PET radiomics study of brain metastases using a fully automatic segmentation method.

BACKGROUND: Positron Emission Tomography (PET) is increasingly utilized in radiomics studies for treatment evaluation purposes. Nevertheless, lesion volume identification in PET images is a critical and still challenging step in the process of radiomics, due to the low spatial resolution and high noise level of PET images. Currently, the biological target volume (BTV) is manually contoured by nuclear physicians, with a time expensive and operator-dependent procedure. This study aims to obtain BTVs from cerebral metastases in patients who underwent L-[11C]methionine (11C-MET) PET, using a fully automatic procedure and to use these BTVs to extract radiomics features to stratify between patients who respond to treatment or not. For these purposes, 31 brain metastases, for predictive evaluation, and 25 ones, for follow-up evaluation after treatment, were delineated using the proposed method. Successively, 11C-MET PET studies and related volumetric segmentations were used to extract 108 features to investigate the potential application of radiomics analysis in patients with brain metastases. A novel statistical system has been implemented for feature reduction and selection, while discriminant analysis was used as a method for feature classification. RESULTS: For predictive evaluation, 3 features (asphericity, low-intensity run emphasis, and complexity) were able to discriminate between responder and non-responder patients, after feature reduction and selection. Best performance in patient discrimination was obtained using the combination of the three selected features (sensitivity 81.23%, specificity 73.97%, and accuracy 78.27%) compared to the use of all features. Secondly, for follow-up evaluation, 8 features (SUVmean, SULpeak, SUVmin, SULpeak prod-surface-area, SUVmean prod-sphericity, surface mean SUV 3, SULpeak prod-sphericity, and second angular moment) were selected with optimal performance in discriminant analysis classification (sensitivity 86.28%, specificity 87.75%, and accuracy 86.57%) outperforming the use of all features. CONCLUSIONS: The proposed system is able i) to extract 108 features for each automatically segmented lesion and ii) to select a sub-panel of 11C-MET PET features (3 and 8 in the case of predictive and follow-up evaluation), with valuable association with patient outcome. We believe that our model can be useful to improve treatment response and prognosis evaluation, potentially allowing the personalization of cancer treatment plans.

Prognostic meaning of neutrophil to lymphocyte ratio (NLR) and lymphocyte to monocyte ration (LMR) in newly diagnosed Hodgkin lymphoma patients treated upfront with a PET-2 based strategy.

Recent reports identify NLR (the ratio between absolute neutrophils counts, ANC, and absolute lymphocyte count, ALC), as predictor of progression-free survival (PFS) and overall survival (OS) in cancer patients. We retrospectively tested NLR and LMR (the ratio between absolute lymphocyte and monocyte counts) in newly diagnosed Hodgkin lymphoma (HL) patients treated upfront with a PET-2 risk-adapted strategy. NLR and LMR were calculated using records obtained from the complete blood count (CBC) from 180 newly diagnosed HL patients. PFS was evaluated accordingly to Kaplan-Meier method. Higher NLR was associated to advanced stage, increased absolute counts of neutrophils and reduced count of lymphocytes, and markers of systemic inflammation. After a median follow-up of 68 months, PFS at 60 months was 86.6% versus 70.1%, respectively, in patients with NLR ≥ 6 or NLR < 6. Predictors of PFS at 60 months were PET-2 scan (p < 0.0001), NLR ≥ 6.0 (p = 0.02), LMR < 2 (p = 0.048), and ANC (p = 0.0059) in univariate analysis, but only PET-2 was an independent predictor of PFS in multivariate analysis. Advanced-stage patients (N = 119) were treated according to a PET-2 risk-adapted protocol, with an early switch to BEACOPP regimen in case of PET-2 positivity. Despite this strategy, patients with positive PET-2 still had an inferior outcome, with PFS at 60 months of 84.7% versus 40.1% (negative and positive PET-2 patients, respectively, p < 0.0001). Independent predictors of PFS by multivariate analysis were PET-2 status and to a lesser extend NLR in advanced stage, while LMR maintained its significance in early stage. By focusing on PET-2 negative patients, we found that patients with NLR ≥ 6.0 or LMR < 2 had an inferior outcome compared to patients with both ratios above the cutoff (78.7 versus 91.9 months, p = 0.01). We confirm NLR as predictor of PFS in HL patients independently from stage at diagnosis. Integration of PET-2 scan, NLR and LMR can result in a meaningful prognostic system that needs to be further validated in prospective series including patients treated upfront with PET-2 adapted-risk therapy.

Predictive and Prognostic Value of Early Disease Progression by PET Evaluation in Advanced Non-Small Cell Lung Cancer.

OBJECTIVE: To assess the predictive and prognostic value of progressive metabolic disease (PMD) by the use of early 18Fluorodeoxyglucose positron emission tomography (18FDG-PET) in patients with clinical stage IV non-small cell lung cancer (NSCLC) treated with first-line chemotherapy. METHODS: An 18FDG-PET performed following the first cycle of chemotherapy (PET-1) was compared with a pretreatment 18FDG-PET (PET-0) and a computed tomography (CT) scan after the third cycle (CT-3). The primary endpoint was the positive predictive value (PPV) of PMD. Secondary endpoints included the prognostic value of PMD. RESULTS: Eleven of 38 patients (29%) had a PMD by PET-1, and 15 (39%), including all patients with a PMD, experienced a progressive disease by CT-3. The PPV of PMD was 100% according to both the European Organization for Research and Treatment of Cancer (EORTC) criteria and the PET Response Criteria In Solid Tumors (PERCIST) (p value for both, <0.0001). Patients with a PMD by PET-1 had a median overall survival of 7.0 months versus 14.0 months for those without a PMD (p = 0.04, according to the EORTC criteria). CONCLUSIONS: Early 18FDG-PET assessment deserves further investigation for the identification of NSCLC patients who do not benefit from first-line chemotherapy.

Evaluation of erlotinib treatment response in non-small cell lung cancer using metabolic and anatomic criteria.

BACKGROUND: In this paper the clinical value of PET for early prediction of tumor response to erlotinib in patients with advanced or metastatic non-small cell lung cancer (NSCLC) after failure of at least one prior chemotherapy regimen is evaluated. The aim was to compare the early metabolic treatment response using European Organization for Research and Treatment of Cancer (EORTC) 1999 recommendations and PET Response Criteria in Solid Tumors (PERCIST), and the standard treatment response using Response Evaluation Criteria in Solid Tumors (RECIST). METHODS: Twenty patients with stage IV NSCLC were enrolled prospectively. PET/CT studies were performed before, then 48 hours, and 45 days after the initiation of erlotinib treatment. The lesion with the highest uptake in each patient was evaluated according to EORTC 1999 recommendations, PERCIST and RECIST to assess metabolic and anatomic response. Response classifications were compared statistically using Wilcoxon signed-rank test. Disease-free survival (DFS) and overall survival (OS) were calculated by the Kaplan-Meier Test. RESULTS: At 48 hours, the Kaplan-Meier analysis showed that EORTC proved to be a significant prognostic factor for predicting DFS and OS. At 45 days, there was a significant difference in response evaluation between RECIST and metabolic classifications. RECIST and PERCIST were significant prognostic factors for predicting DFS and OS. EORTC was not able to discriminate responder from non-responder patients. CONCLUSIONS: This study shows that, according to the EORTC protocol, the PET exam is able to provide early identification of patients who benefit from Erlotinib treatment. Used at the end of therapy, PERCIST could be considered an appropriate metabolic evaluation method to discriminate responders from non-responders.

Circulating myeloid-derived suppressor cells correlate with clinical outcome in Hodgkin Lymphoma patients treated up-front with a risk-adapted strategy.

In the attempt to find a peripheral blood biological marker that could mirror the dysregulated microenvironment of Hodgkin Lymphoma (HL), we analysed the amount of myeloid-derived suppressor cells (MDSC), including the three main sub-types (monocytic, granulocytic and CD34 + fraction). The absolute MDSC count was investigated in 60 consecutive newly diagnosed HL patients and correlated with clinical variables at diagnosis and outcome. Patients received standard-of-care chemotherapy with the exception of interim fluorodeoxyglucose positron emission tomography (PET-2)-positive patients, who were switched early to a salvage regimen. All MDSC subsets were increased in HL patients compared to normal subjects (P < 0·0001) and were higher in non-responders. However, a strong prognostic significance was limited to immature (CD34(+) ) MDSC. A cut-off level of 0·0045 × 10(9) /l for CD34(+) MDSC resulted in 89% (95% confidence interval [CI] 52-99%) sensitivity and 92% (95% CI 81-98%) specificity. The positive predictive value to predict progression-free survival was 0·90 for PET-2 and 0·98 for CD34(+) MDSC count; the negative predictive value was 0·57 for PET-2 and 0·73 for CD34(+) MDSC. PFS was significantly shorter in patients with more than 0·0045 × 10(9) CD34(+) MDSC cells/l at diagnosis and/or PET-2 positivity (P < 0·0001). In conclusion, all circulating MDSC subsets are increased in HL; CD34(+) MDSC predict short PFS, similarly to PET-2 but with the advantage of being available at diagnosis.

Baseline IgM Amounts Can Identify Patients with Poor Outcomes: Results from a Real-Life Single-Center Study on Classical Hodgkin Lymphoma.

Hodgkin Lymphoma (HL) is characterized by an inflammatory background in which the reactive myeloid cells may exert an immune-suppressive effect related to the progression of the disease. Immunoglobulin M is the first antibody isotype produced during an immune response, which also plays an immunoregulatory role. Therefore, we investigated if, as a surrogate of defective B cell function, it could have any clinical impact on prognosis. In this retrospective, observational, single-center study, we evaluated 212 newly diagnosed HL patients, including 132 advanced-stage. A 50 mg/dL level of IgM at baseline resulted in 84.1% sensitivity and 45.5% specificity for predicting a complete response in the whole cohort (area under curve (AUC) = 0.62, p = 0.013). In multivariate analysis, baseline IgM ≤ 50 mg/dL and the presence of a large nodal mass (<7 cm) were independent variables able to predict the clinical outcome, while, after two cycles of treatment, IgM ≤ 50 mg/dL at baseline and PET-2 status were independent predictors of PFS. The amount of IgM at diagnosis is a valuable prognostic factor much earlier than PET-2, and it can also provide information for PET-2-negative patients. This can help to identify different HL classes at risk of treatment failure at baseline.

Salvage Radiotherapy PSMA PET/CT-guided in Men With PSA Recurrence.

BACKGROUND/AIM: To evaluate the clinical outcome in men with recurrent prostate cancer (PCa) treated by salvage radiotherapy (sRT) prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT)-guided. PATIENTS AND METHODS: From January 2021 to January 2023, 33 patients who previously underwent definitive/systemic therapy were submitted to sRT PSMA PET/CT-guided for PCa recurrence: 16 (48.5%) on the prostate bed (PB), 12 (36.4%) on the lymph node (LN) and five (15.1%) on the bone. The median PSA value was 3.3 ng/ml (range=0.3-15.5 ng/ml): 0.2-0.5 ng/ml (18.2% cases), 0.51-1 ng/ml (39.4% cases) and >1 ng/ml (42.4% cases). Median 18F PSMA PET/CT standardized uptake value (SUVmax) was evaluated on PB, vs. LN vs. bones PCa recurrences and was equal to 12.5 vs. 19.0 vs. 30.1, respectively. RESULTS: Overall, at a median follow up of 12 months, 23/33 patients (69.7%) had local control without distant progression (PSA and SUVmax evaluation): 14/16 (87.5%) vs. 7/12 (58.3%) vs. 2/5 (40%) underwent sRT on the PB vs. LN vs. bone metastases, respectively. CONCLUSION: PSMA PET/CT allows to perform sRT early in men with PCa recurrence and low PSA values obtaining a complete clinical response in approximately 70% of the cases one year from treatment.

Biodistribution Assessment of a Novel 68Ga-Labeled Radiopharmaceutical in a Cancer Overexpressing CCK2R Mouse Model: Conventional and Radiomics Methods for Analysis.

The aim of the present study consists of the evaluation of the biodistribution of a novel 68Ga-labeled radiopharmaceutical, [68Ga]Ga-NODAGA-Z360, injected into Balb/c nude mice through histopathological analysis on bioptic samples and radiomics analysis of positron emission tomography/computed tomography (PET/CT) images. The 68Ga-labeled radiopharmaceutical was designed to specifically bind to the cholecystokinin receptor (CCK2R). This receptor, naturally present in healthy tissues such as the stomach, is a biomarker for numerous tumors when overexpressed. In this experiment, Balb/c nude mice were xenografted with a human epidermoid carcinoma A431 cell line (A431 WT) and overexpressing CCK2R (A431 CCK2R+), while controls received a wild-type cell line. PET images were processed, segmented after atlas-based co-registration and, consequently, 112 radiomics features were extracted for each investigated organ / tissue. To confirm the histopathology at the tissue level and correlate it with the degree of PET uptake, the studies were supported by digital pathology. As a result of the analyses, the differences in radiomics features in different body districts confirmed the correct targeting of the radiopharmaceutical. In preclinical imaging, the methodology confirms the importance of a decision-support system based on artificial intelligence algorithms for the assessment of radiopharmaceutical biodistribution.

Pancreatic Neuroendocrine Tumor (Pan-NET) Presented by Abdominal Pain: A Case Report and Literature Review.

A pancreatic neuroendocrine tumor (Pan-NET) is a rare neoplasm originating in the neuroendocrine system. Carcinoid syndrome occurs in approximately 19% of patients with functional Pan-NETs, typically when liver metastases occur. In this paper, we describe the case of a patient with a low-grade non-functional Pan-NET, but with a typical clinical presentation of carcinoid syndrome. An 81-year-old male was admitted to our Department of Internal Medicine at Cannizzaro Hospital (Catania, Italy) because of the onset of abdominal pain with nausea, loose stools, and episodic flushing. Firstly, an abdominal contrast-enhanced CT scan showed a small pancreatic hyper-vascular mass; then, a gallium-68 DOTATOC integrated PET/CT revealed an elevated expression of SSTR receptors. Serum chromogranin A and urinary 5-HIAA measurements were negative. We performed an endoscopic ultrasonography (EUS) by a fine-needle biopsy (EUS-FNB), allowing the immunostaining of a small mass (0.8 cm) and the diagnosis of a low-grade (G1) non-functional Pan-NET (NF-Pan-NET). Surgery was waived, while a follow-up strategy was chosen. The early recognition of Pan-NETs, although rare, is necessary to improve the patient's survival. Although helpful to allow for immunostaining, EUS-FNB needs to be warranted in future studies comparing EUS-FNB to EUS-FNA (fine-needle aspiration), which is, to date, reported as the tool of choice to diagnose Pan-NETs.

A Critical Analysis of the Robustness of Radiomics to Variations in Segmentation Methods in 18F-PSMA-1007 PET Images of Patients Affected by Prostate Cancer.

BACKGROUND: Radiomics shows promising results in supporting the clinical decision process, and much effort has been put into its standardization, thus leading to the Imaging Biomarker Standardization Initiative (IBSI), that established how radiomics features should be computed. However, radiomics still lacks standardization and many factors, such as segmentation methods, limit study reproducibility and robustness. AIM: We investigated the impact that three different segmentation methods (manual, thresholding and region growing) have on radiomics features extracted from 18F-PSMA-1007 Positron Emission Tomography (PET) images of 78 patients (43 Low Risk, 35 High Risk). Segmentation was repeated for each patient, thus leading to three datasets of segmentations. Then, feature extraction was performed for each dataset, and 1781 features (107 original, 930 Laplacian of Gaussian (LoG) features, 744 wavelet features) were extracted. Feature robustness and reproducibility were assessed through the intra class correlation coefficient (ICC) to measure agreement between the three segmentation methods. To assess the impact that the three methods had on machine learning models, feature selection was performed through a hybrid descriptive-inferential method, and selected features were given as input to three classifiers, K-Nearest Neighbors (KNN), Support Vector Machines (SVM), Linear Discriminant Analysis (LDA), Random Forest (RF), AdaBoost and Neural Networks (NN), whose performance in discriminating between low-risk and high-risk patients have been validated through 30 times repeated five-fold cross validation. CONCLUSIONS: Our study showed that segmentation methods influence radiomics features and that Shape features were the least reproducible (average ICC: 0.27), while GLCM features the most reproducible. Moreover, feature reproducibility changed depending on segmentation type, resulting in 51.18% of LoG features exhibiting excellent reproducibility (range average ICC: 0.68-0.87) and 47.85% of wavelet features exhibiting poor reproducibility that varied between wavelet sub-bands (range average ICC: 0.34-0.80) and resulted in the LLL band showing the highest average ICC (0.80). Finally, model performance showed that region growing led to the highest accuracy (74.49%), improved sensitivity (84.38%) and AUC (79.20%) in contrast with manual segmentation.

Proton boron capture therapy (PBCT) induces cell death and mitophagy in a heterotopic glioblastoma model.

Despite aggressive therapeutic regimens, glioblastoma (GBM) represents a deadly brain tumor with significant aggressiveness, radioresistance and chemoresistance, leading to dismal prognosis. Hypoxic microenvironment, which characterizes GBM, is associated with reduced therapeutic effectiveness. Moreover, current irradiation approaches are limited by uncertain tumor delineation and severe side effects that comprehensively lead to unsuccessful treatment and to a worsening of the quality of life of GBM patients. Proton beam offers the opportunity of reduced side effects and a depth-dose profile, which, unfortunately, are coupled with low relative biological effectiveness (RBE). The use of radiosensitizing agents, such as boron-containing molecules, enhances proton RBE and increases the effectiveness on proton beam-hit targets. We report a first preclinical evaluation of proton boron capture therapy (PBCT) in a preclinical model of GBM analyzed via µ-positron emission tomography/computed tomography (µPET-CT) assisted live imaging, finding a significant increased therapeutic effectiveness of PBCT versus proton coupled with an increased cell death and mitophagy. Our work supports PBCT and radiosensitizing agents as a scalable strategy to treat GBM exploiting ballistic advances of proton beam and increasing therapeutic effectiveness and quality of life in GBM patients.

Detection Rate of 68Ga-PSMA PET/CT vs. mpMRI Targeted Biopsy for Clinically Significant Prostate Cancer.

BACKGROUND/AIM: To evaluate the diagnostic accuracy of 68Ga-prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) vs. multiparametric magnetic resonance imaging (mpMRI) targeted biopsy (TPBx) in the diagnosis of clinically significant prostate cancer (csPCa: Grade Group ≥2). PATIENTS AND METHODS: From January 2021 to January 2022, 45 patients (median age: 67 years) with negative digital rectal examination underwent transperineal prostate biopsy for abnormal PSA values (median 7.3 ng/ml). Before prostate biopsy, all patients underwent mpMRI and 68Ga-PET/CT examinations, which included mpMRI (PI-RADS version 2 ≥3), and 68Ga-PET/CT index lesions suspicious for cancer (SUVmax ≥5 g/ml) underwent cognitive targeted cores (mpMRI-TPBx and PSMA-TPBx: four cores) combined with extended systematic prostate biopsy (eSPBx: median 18 cores). The procedure was performed transperineally using a tru-cut 18-gauge needle under sedation and antibiotic prophylaxis. RESULTS: PCa was found in 29/45 (64.4%) men; in detail, 22/45 (48.9%) were csPCa. 68Ga-PSMA-TPBx vs. mpMRI-TPBx vs. eSPBx missed one (4.5%) vs. four (18.1%) vs. seven (31.8%) csPCa, respectively; mpMRI-TPBx vs. 68Ga-PSMA-TPBx for csPCa showed a diagnostic accuracy of 73.7 vs. 77.5%. CONCLUSION: 68Ga-PSMA PET/CT TPBx demonstrated good accuracy in the diagnosis of csPCa, which was not inferior to mpMRI-TPBx (77.5 vs. 73.7%), improving the detection rate for cancer in systematic biopsy.

Use of 18F-fluorodeoxyglucose positron emission tomography-computed tomography in patients affected by polymyalgia rheumatica and persistent increase of acute phase reactants.

Polymyalgia rheumatica (PMR) is an inflammatory disease affecting older adults characterized by aching pain and morning stiffness of the shoulder and pelvic girdles. Moreover, PMR can be associated with giant cell arteritis (GCA). Generally, PMR is highly responsive to steroids, reaching complete remission in the majority of cases. However, the possibility of occult diseases, including extra-cranial GCA, should be excluded. 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) is able to detect the presence of peri-/articular or vascular inflammation, which may be both present in PMR, thus representing a useful diagnostic tool, mainly in presence of extra-cranial GCA. We retrospectively evaluated all consecutive patients who received the diagnosis of PMR in our rheumatology clinic, classified according to the 2012 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria, in the period between April 2020 and May 2022. Among this case series, we selected the patients who underwent 18F-FDG-positron emission tomography (PET) because of the persistent increase of acute phase reactants (APR) besides the steroid therapy. Eighty patients were diagnosed with PMR. Nine out of them also presented arthritis of the wrists during the follow-up, whereas none showed signs of cranial GCA at the diagnosis. Seventeen out of eighty subjects (mean age 71.5 ± 7.5 years; M/F 2/15) presented persistent increase of erythrocyte sedimentation rate (mean ESR 44.2 ± 20.8 mm/h) and/or C-reactive protein (mean CRP 25.1 ± 17 mg/l), thus they underwent total body 18F-FDG-PET/CT. Large vessel 18F-FDG uptake indicating an occult GCA was found in 5/17 (29.4%) cases. Twelve out of seventeen (70.6%) patients showed persistence of peri-/articular inflammation, suggesting a scarce control of PMR or the presence of chronic arthritis. Finally, in 2 cases, other inflammatory disorders were found, namely an acute thyroiditis and a hip prosthesis occult infection. 18F-FDG-PET/CT in PMR patients with persistent increase of APR is a useful diagnostic technique in order to detect occult GCA, persistence of active PMR or other misdiagnosed inflammatory diseases.

A New Preclinical Decision Support System Based on PET Radiomics: A Preliminary Study on the Evaluation of an Innovative 64Cu-Labeled Chelator in Mouse Models.

The 64Cu-labeled chelator was analyzed in vivo by positron emission tomography (PET) imaging to evaluate its biodistribution in a murine model at different acquisition times. For this purpose, nine 6-week-old female Balb/C nude strain mice underwent micro-PET imaging at three different time points after 64Cu-labeled chelator injection. Specifically, the mice were divided into group 1 (acquisition 1 h after [64Cu] chelator administration, n = 3 mice), group 2 (acquisition 4 h after [64Cu]chelator administration, n = 3 mice), and group 3 (acquisition 24 h after [64Cu] chelator administration, n = 3 mice). Successively, all PET studies were segmented by means of registration with a standard template space (3D whole-body Digimouse atlas), and 108 radiomics features were extracted from seven organs (namely, heart, bladder, stomach, liver, spleen, kidney, and lung) to investigate possible changes over time in [64Cu]chelator biodistribution. The one-way analysis of variance and post hoc Tukey Honestly Significant Difference test revealed that, while heart, stomach, spleen, kidney, and lung districts showed a very low percentage of radiomics features with significant variations (p-value < 0.05) among the three groups of mice, a large number of features (greater than 60% and 50%, respectively) that varied significantly between groups were observed in bladder and liver, indicating a different in vivo uptake of the 64Cu-labeled chelator over time. The proposed methodology may improve the method of calculating the [64Cu]chelator biodistribution and open the way towards a decision support system in the field of new radiopharmaceuticals used in preclinical imaging trials.

The Role of [68Ga]Ga-DOTA-SSTR PET Radiotracers in Brain Tumors: A Systematic Review of the Literature and Ongoing Clinical Trials.

BACKGROUND: The development of [68Ga]Ga-DOTA-SSTR PET tracers has garnered interest in neuro-oncology, to increase accuracy in diagnostic, radiation planning, and neurotheranostics protocols. We systematically reviewed the literature on the current uses of [68Ga]Ga-DOTA-SSTR PET in brain tumors. METHODS: PubMed, Scopus, Web of Science, and Cochrane were searched in accordance with the PRISMA guidelines to include published studies and ongoing trials utilizing [68Ga]Ga-DOTA-SSTR PET in patients with brain tumors. RESULTS: We included 63 published studies comprising 1030 patients with 1277 lesions, and 4 ongoing trials. [68Ga]Ga-DOTA-SSTR PET was mostly used for diagnostic purposes (62.5%), followed by treatment planning (32.7%), and neurotheranostics (4.8%). Most lesions were meningiomas (93.6%), followed by pituitary adenomas (2.8%), and the DOTATOC tracer (53.2%) was used more frequently than DOTATATE (39.1%) and DOTANOC (5.7%), except for diagnostic purposes (DOTATATE 51.1%). [68Ga]Ga-DOTA-SSTR PET studies were mostly required to confirm the diagnosis of meningiomas (owing to their high SSTR2 expression and tracer uptake) or evaluate their extent of bone invasion, and improve volume contouring for better radiotherapy planning. Some studies reported the uncommon occurrence of SSTR2-positive brain pathology challenging the diagnostic accuracy of [68Ga]Ga-DOTA-SSTR PET for meningiomas. Pre-treatment assessment of tracer uptake rates has been used to confirm patient eligibility (high somatostatin receptor-2 expression) for peptide receptor radionuclide therapy (PRRT) (i.e., neurotheranostics) for recurrent meningiomas and pituitary carcinomas. CONCLUSION: [68Ga]Ga-DOTA-SSTR PET studies may revolutionize the routine neuro-oncology practice, especially in meningiomas, by improving diagnostic accuracy, delineation of radiotherapy targets, and patient eligibility for radionuclide therapies.

Could 68Ga-PSMA PET/CT Evaluation Reduce the Number of Scheduled Prostate Biopsies in Men Enrolled in Active Surveillance Protocols?

Background: To evaluate the accuracy of 68Ga-prostate specific membrane antigen (PSMA) PET/CT in the diagnosis of clinically significant prostate cancer (csPCa) (Grade Group > 2) in men enrolled in Active Surveillance (AS) protocol. Methods: From May 2013 to May 2021, 173 men with very low-risk PCa were enrolled in an AS protocol study. During the follow-up, 38/173 (22%) men were upgraded and 8/173 (4.6%) decided to leave the AS protocol. After four years from confirmatory biopsy (range: 48−52 months), 30/127 (23.6%) consecutive patients were submitted to mpMRI and 68Ga-PSMA PET/CT scan before scheduled repeated biopsy. All the mpMRI (PI-RADS > 3) and 68Ga-PET/TC standardised uptake value (SUVmax) > 5 g/mL index lesions underwent targeted cores (mpMRI-TPBx and PSMA-TPBx) combined with transperineal saturation prostate biopsy (SPBx: median 20 cores). Results: mpMRI and 68Ga-PSMA PET/CT showed 14/30 (46.6%) and 6/30 (20%) lesions suspicious for PCa. In 2/30 (6.6%) men, a csPCa was found; 68Ga-PSMA-TPBx vs. mpMRI-TPBx vs. SPBx diagnosed 1/2 (50%) vs. 1/2 (50%) vs. 2/2 (100%) csPCa, respectively. In detail, mpMRI and 68Ga-PSMA PET/TC demonstrated 13/30 (43.3%) vs. 5/30 (16.7%) false positive and 1 (50%) vs. 1 (50%) false negative results. Conclusion: 68Ga-PSMA PET/CT did not improve the detection for csPCa of SPBx but would have spared 24/30 (80%) scheduled biopsies showing a lower false positive rate in comparison with mpMRI (20% vs. 43.3%) and a negative predictive value of 85.7% vs. 57.1%, respectively.

[68Ga]DOTATOC PET/CT Radiomics to Predict the Response in GEP-NETs Undergoing [177Lu]DOTATOC PRRT: The "Theragnomics" Concept.

Despite impressive results, almost 30% of NET do not respond to PRRT and no well-established criteria are suitable to predict response. Therefore, we assessed the predictive value of radiomics [68Ga]DOTATOC PET/CT images pre-PRRT in metastatic GEP NET. We retrospectively analyzed the predictive value of radiomics in 324 SSTR-2-positive lesions from 38 metastatic GEP-NET patients (nine G1, 27 G2, and two G3) who underwent restaging [68Ga]DOTATOC PET/CT before complete PRRT with [177Lu]DOTATOC. Clinical, laboratory, and radiological follow-up data were collected for at least six months after the last cycle. Through LifeX, we extracted 65 PET features for each lesion. Grading, PRRT number of cycles, and cumulative activity, pre- and post-PRRT CgA values were also considered as additional clinical features. [68Ga]DOTATOC PET/CT follow-up with the same scanner for each patient determined the disease status (progression vs. response in terms of stability/reduction/disappearance) for each lesion. All features (PET and clinical) were also correlated with follow-up data in a per-site analysis (liver, lymph nodes, and bone), and for features significantly associated with response, the Δradiomics for each lesion was assessed on follow-up [68Ga]DOTATOC PET/CT performed until nine months post-PRRT. A statistical system based on the point-biserial correlation and logistic regression analysis was used for the reduction and selection of the features. Discriminant analysis was used, instead, to obtain the predictive model using the k-fold strategy to split data into training and validation sets. From the reduction and selection process, HISTO_Skewness and HISTO_Kurtosis were able to predict response with an area under the receiver operating characteristics curve (AUC ROC), sensitivity, and specificity of 0.745, 80.6%, 67.2% and 0.722, 61.2%, 75.9%, respectively. Moreover, a combination of three features (HISTO_Skewness; HISTO_Kurtosis, and Grading) did not improve the AUC significantly with 0.744. SUVmax, however, could not predict the response to PRRT (p = 0.49, AUC 0.523). The presented preliminary "theragnomics" model proved to be superior to conventional quantitative parameters to predict the response of GEP-NET lesions in patients treated with complete [177Lu]DOTATOC PRRT, regardless of the lesion site.