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Purpose: Gastroenteropancreatic -neuroendocrine tumours (GEP-NETs) are commonly treated with surgical resection or long-term therapies for tumour growth control. Lutetium [ 177 Lu]-DOTA-TATE was approved for the treatment of GEP-NETs after the phase III NETTER 1trial demonstrated improved progression free survival, objective response rates and health-related quality of life (HRQoL) compared to high-dose somatostatin analogues. No real-world data exist on prescribing habits and clinically significant endpoints for [ 177 Lu]Lu-DOTA-TATE treatment in Italy. REAL-LU is a multicentre, long-term observational study in patients with unresectable/metastatic GEP-NETs progressing on standard therapies in Italian clinical practice. A pre-specified interim analysis was performed at the end of the enrolment period, data from which are described herein., Methods: Overall duration of REAL-LU will be approximately 48 months, with 12- and 36-month recruitment and follow-up periods, respectively. The primary objective is to evaluate [ 177 Lu]Lu-DOTA-TATE effectiveness in terms of progression-free survival. Secondary objectives include safety, impact on HRQoL, and identification of prognostic factors. This pre-specified interim analysis describes patient profiles, at the end of enrollment, of those prescribed [ 177 Lu]Lu-DOTA-TATE for GEP-NETs in Italy., Results: Among 161 evaluable patients, mean age was 64.7 ± 10.3 years at study entry, 83.8% presented with no clinical signs of disease at physical examination, and most had minor disease symptoms. All patients had metastatic disease, most commonly in the liver (83.9%) with a median of two metastatic sites. In 90.7% of patients, the disease was stage IV, and 68.3% had ≥ 1 target lesion. [ 177 Lu]Lu-DOTA-TATE was prescribed mainly as second-line therapy (61.6%) and following surgery (58.4%). HRQoL assessments revealed high levels of functioning and low levels of symptoms at baseline; 50.0% of patients were symptom-free at study entry., Conclusion: The characteristics of patients who received [177Lu]Lu-DOTA-TATE in Italy are similar to those of the GEP-NET population of NETTER 1 with trial but with a higher proportion of patients with a grade 2 (71%). With regard to the tumor grade profile, our study cohort appears to be closer to that of NETTER-2 study population which included patients with G2 or G3 advanced GEP-NETs (i.e. Ki-67 ≥ 10% and ≤ 55%). Further analysis of effectiveness and safety can be anticipated as REAL-LU data mature., Study Registration: ClinicalTrials.gov, NCT04727723; Study Registration Date: 25 January, 2021; https://clinicaltrials.gov/study/NCT04727723?cond=NCT04727723&rank=1., (© 2024. The Author(s).)

Purpose: High PSMA expression might be correlated with structural characteristics such as growth patterns on histopathology, not recognized by the human eye on MRI images. Deep structural image analysis might be able to detect such differences and therefore predict if a lesion would be PSMA positive. Therefore, we aimed to train a neural network based on PSMA PET/MRI scans to predict increased prostatic PSMA uptake based on the axial T2-weighted sequence alone., Material and Methods: All patients undergoing simultaneous PSMA PET/MRI for PCa staging or biopsy guidance between April 2016 and December 2020 at our institution were selected. To increase the specificity of our model, the prostatic beds on PSMA PET scans were dichotomized in positive and negative regions using an SUV threshold greater than 4 to generate a PSMA PET map. Then, a C-ENet was trained on the T2 images of the training cohort to generate a predictive prostatic PSMA PET map., Results: One hundred and fifty-four PSMA PET/MRI scans were available (133 [ 68 Ga]Ga-PSMA-11 and 21 [ 18 F]PSMA-1007). Significant cancer was present in 127 of them. The whole dataset was divided into a training cohort (n = 124) and a test cohort (n = 30). The C-ENet was able to predict the PSMA PET map with a dice similarity coefficient of 69.5 ± 15.6%., Conclusion: Increased prostatic PSMA uptake on PET might be estimated based on T2 MRI alone. Further investigation with larger cohorts and external validation is needed to assess whether PSMA uptake can be predicted accurately enough to help in the interpretation of mpMRI., (© 2024. The Author(s).)

Neuroendocrine neoplasms (NENs) are rare tumors with diverse clinical behaviors. Large databases like the Surveillance, Epidemiology, and End Results (SEER) program and national NEN registries have provided significant epidemiological knowledge, but they have limitations given the recent advancements in NEN diagnostics and treatments. For instance, newer imaging techniques and therapies have revolutionized NEN management, rendering older data less representative. Additionally, crucial parameters, like the Ki67 index, are missing from many databases. Acknowledging these gaps, the Italian Association for Neuroendocrine Tumors (Itanet) initiated a national multicenter prospective database in 2019, aiming to gather data on newly-diagnosed gastroenteropancreatic neuroendocrine (GEP) NENs. This observational study, coordinated by Itanet, includes patients from 37 Italian centers. The database, which is rigorously maintained and updated, focuses on diverse parameters including age, diagnostic techniques, tumor stage, treatments, and survival metrics. As of October 2023, data from 1,600 patients have been recorded, with an anticipation of reaching 3600 by the end of 2025. This study aims at understanding the epidemiology, clinical attributes, and treatment strategies for GEP-NENs in Italy, and to introduce the Itanet database project. Once comprehensive follow-up data will be acquired, the goal will be to discern predictors of treatment outcomes and disease prognosis. The Itanet database will offer an unparalleled, updated perspective on GEP-NENs, addressing the limitations of older databases and aiding in optimizing patient care. STUDY REGISTRATION: This protocol was registered in clinicaltriasl.gov (NCT04282083)., (© 2024. The Author(s).)

Gastroparesis is a long-term complication of diabetes related to autonomic neuropathy. It is characterized clinically by delayed gastric emptying and upper gastrointestinal symptoms, including early satiety, postprandial fullness, nausea, vomiting, and abdominal pain. Gastric emptying scintigraphy is the gold standard for diagnosis as it reveals delayed gastric emptying. Therapeutic strategies include dietary modifications, improvement of glycemic control, and prokinetic drugs. Case descriptions of diabetic gastroparesis in pediatric ages are very scarce. We report the case of a 16-year-old adolescent with severe presentation of diabetic gastroparesis. She presented with recurrent episodes of nausea, vomiting and abdominal pain which led progressively to reduced oral intake and weight loss. Her past glycemic control had been quite brittle, as demonstrated by several hospitalizations due to diabetic ketoacidosis and recurrent episodes of severe hypoglycemia. After the exclusion of infectious, mechanical, metabolic, and neurological causes of vomiting, a gastric emptying scintigraphy was performed, leading to the diagnosis of gastroparesis. Treatment with metoclopramide was started with progressive relief of symptoms. To improve glycemic control, insulin therapy with an advanced hybrid, closed loop system was successfully started. Pediatricians should consider diabetic gastroparesis in children and adolescents with long-standing, poorly controlled diabetes and appropriate symptomology., Competing Interests: Conflict of interest: None declared., (©Copyright 2024 by Turkish Society for Pediatric Endocrinology and Diabetes / The Journal of Clinical Research in Pediatric Endocrinology published by Galenos Publishing House.)

Background: SMC1A is a subunit of the cohesin complex that participates in many DNA- and chromosome-related biological processes. Previous studies have established that SMC1A is involved in cancer development and in particular, is overexpressed in chromosomally unstable human colorectal cancer (CRC). This study aimed to investigate whether SMC1A could serve as a therapeutic target for CRC., Methods: At first, we studied the effects of either SMC1A overexpression or knockdown in vitro. Next, the outcome of SMC1A knocking down (alone or in combination with bevacizumab, a monoclonal antibody against vascular endothelial growth factor) was analyzed in vivo., Results: We found that SMC1A knockdown affects cell proliferation and reduces the ability to grow in anchorage-independent manner. Next, we demonstrated that the silencing of SMC1A and the combo treatment were effective in increasing overall survival in a xenograft mouse model. Functional analyses indicated that both treatments lead to atypical mitotic figures and gene expression dysregulation. Differentially expressed genes were implicated in several pathways including gene transcription regulation, cellular proliferation, and other transformation-associated processes., Conclusions: These results indicate that SMC1A silencing, in combination with bevacizumab, can represent a promising therapeutic strategy for human CRC., (© 2024. The Author(s).)

Constrictive pericarditis (CP) is a rare condition that can affect the pericardium after every pericardial disease process and has been described even after SARS-CoV-2 infection or vaccine. In CP, the affected pericardium, usually the inner layer, is noncompliant, constraining the heart to a fixed maximum volume and impairing the diastolic function. This leads to several clinical features, that, however, can be pleomorphic. In its difficult diagnostic workup, noninvasive multimodal imaging plays a central role, providing important morphological and functional data, like the enhanced ventricular interdependence and the dissociation between intrathoracic and intracardiac pressures. An early and proper diagnosis is crucial to set an appropriate therapy, changing the prognosis of patients affected by CP. In this review, we cover in detail the main elements of each imaging technique, after a reminder of pathophysiology useful for understanding the diagnostic findings., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Journal of Cardiovascular Echography.)

Background: Understanding how cancer signaling pathways promote an immunosuppressive program which sustains acquired or primary resistance to immune checkpoint blockade (ICB) is a crucial step in improving immunotherapy efficacy. Among the pathways that can affect ICB response is the interferon (IFN) pathway that may be both detrimental and beneficial. The immune sensor retinoic acid-inducible gene I (RIG-I) induces IFN activation and secretion and is activated by actin cytoskeleton disturbance. The actin cytoskeleton regulatory protein hMENA, along with its isoforms, is a key signaling hub in different solid tumors, and recently its role as a regulator of transcription of genes encoding immunomodulatory secretory proteins has been proposed. When hMENA is expressed in tumor cells with low levels of the epithelial specific hMENA 11a isoform, identifies non-small cell lung cancer (NSCLC) patients with poor prognosis. Aim was to identify cancer intrinsic and extrinsic pathways regulated by hMENA 11a downregulation as determinants of ICB response in NSCLC. Here, we present a potential novel mechanism of ICB resistance driven by hMENA 11a downregulation., Methods: Effects of hMENA 11a downregulation were tested by RNA-Seq, ATAC-Seq, flow cytometry and biochemical assays. ICB-treated patient tumor tissues were profiled by Nanostring IO 360 Panel enriched with hMENA custom probes. OAK and POPLAR datasets were used to validate our discovery cohort., Results: Transcriptomic and biochemical analyses demonstrated that the depletion of hMENA 11a induces IFN pathway activation, the production of different inflammatory mediators including IFNβ via RIG-I, sustains the increase of tumor PD-L1 levels and activates a paracrine loop between tumor cells and a unique macrophage subset favoring an epithelial-mesenchymal transition (EMT). Notably, when we translated our results in a clinical setting of NSCLC ICB-treated patients, transcriptomic analysis revealed that low expression of hMENA 11a , high expression of IFN target genes and high macrophage score identify patients resistant to ICB therapy., Conclusions: Collectively, these data establish a new function for the actin cytoskeleton regulator hMENA 11a in modulating cancer cell intrinsic type I IFN signaling and extrinsic mechanisms that promote protumoral macrophages and favor EMT. These data highlight the role of actin cytoskeleton disturbance in activating immune suppressive pathways that may be involved in resistance to ICB in NSCLC., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Internal Bremsstrahlung (IB) is a process accompanying β-decay but neglected in Voxel S-Values (VSVs) calculation. Aims of this work were to calculate, through Monte Carlo (MC) simulation, updated 90 Y-VSVs including IB, and to develop an analytical model to evaluate 90 Y-VSVs for any voxel size of practical interest., Methods: GATE (Geant4 Application for Tomographic Emission) was employed for simulating voxelized geometries of soft tissue, with voxels sides l ranging from 2 to 6 mm, in steps of 0.5 mm. The central voxel was set as a homogeneous source of 90 Y when IB photons are not modelled. For each l, the VSVs were computed for 90 Y decays alone and for 90 Y + IB. The analytical model was then built through fitting procedures of the VSVs including IB contribution., Results: Comparing GATE-VSVs with and without IB, differences between + 25% and + 30% were found for distances from the central voxel larger than the maximum β-range. The analytical model showed an agreement with MC simulations within ± 5% in the central voxel and in the Bremsstrahlung tails, for any l value examined, and relative differences lower than ± 40%, for other distances from the source., Conclusions: The presented 90 Y-VSVs include for the first time the contribution due to IB, thus providing a more accurate set of dosimetric factors for three-dimensional internal dosimetry of 90 Y-labelled radiopharmaceuticals and medical devices. Furthermore, the analytical model constitutes an easy and fast alternative approach for 90 Y-VSVs estimation for non-standard voxel dimensions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Associazione Italiana di Fisica Medica e Sanitaria. Published by Elsevier Ltd. All rights reserved.)

Purpose: In nuclear medicine, Dose Point Kernels (DPKs), representing the energy deposited all around a point isotropic source, are extensively used for dosimetry and are usually obtained by Monte Carlo (MC) simulations. For beta-decaying nuclides, DPK is usually estimated neglecting Internal Bremsstrahlung (IB) emission, a process always accompanying the beta decay and consisting in the emission of photons having a continuous spectral distribution. This work aims to study the significance of IB emission for DPK estimation in the case of 32 P and provide DPK values corrected for the IB photon contribution., Methods: DPK, in terms of the scaled absorbed dose fraction, F(R/X 90 ), was first estimated by GAMOS MC simulation using the standard beta decay spectrum of 32 P, F β (R/X 90 ). Subsequently, an additional source term accounting for IB photons and their spectral distribution was defined and used for a further MC simulation, thus evaluating the contribution of IB emission to DPK values, F β+IB (R/X 90 ). The relative percent difference, δ, between the DPKs obtained by the two approaches, F β+IB vs. F β , was studied as a function of the radial distance, R., Results: As far as the energy deposition is mainly due to the beta particles, IB photons does not significantly contribute to DPK; conversely, for larger R, F β+IB values are higher by 30-40% than F β ., Conclusions: The inclusion of IB emission in the MC simulations for DPK estimations is recommended, as well as the use of the DPK values corrected for IB photons, here provided., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Objectives: To compare the efficacy of low and moderate 131 I activities in low-risk differentiated thyroid carcinoma (DTC) patients requiring postoperative thyroid remnant ablation in a real-world clinical setting., Methods: We retrospectively reviewed the records of 299 low-risk DTC patients (pT1-T2, Nx(0) Mx) who had undergone (near)-total thyroidectomy followed by 131 I therapy, using either low (1.1 GBq) or moderate (2.2 GBq) radioiodine activities. The response to initial treatments was evaluated after 8-12 months, and patient responses were classified according to the 2015 American Thyroid Association guidelines., Results: An excellent response was observed in 274/299 (91.6%) patients, specifically, in 119/139 (85.6%) and 155/160 (96.9%) patients treated with low and moderate 131 I activities, respectively ( p = 0.029). A biochemically indeterminate or incomplete response was observed in seventeen (22.2%) patients treated with low 131 I activities and three (1.8%) patients treated with moderate 131 I activities ( p = 0.001). Finally, five patients showed an incomplete structural response, among which three and two received low and moderate 131 I activities, respectively ( p = 0.654)., Conclusions: When 131 I ablation is indicated, we encourage the use of moderate instead of low activities, in order to reach an excellent response in a significantly larger proportion of patients, including patients with the unexpected persistence of the disease.

Background: In differentiated thyroid cancer (DTC) patients, the response to initial treatments is evaluated 6-12 months after radioiodine therapy (RIT) according to the 2015 American Thyroid Association (2015 ATA) criteria. In selected patients, diagnostic 131-radioiodine whole-body scintigraphy (Dx-WBS) is recommended. We evaluated the diagnostic performance of 123 I-Dx-WBS-SPECT/CT imaging in detecting incomplete structural responses in the early follow-up of DTC patients and, additionally, derived optimized basal-Tg value as a yardstick for scintigraphic imaging. Methods: We reviewed the records of 124 low or intermediate-risk DTC patients with negative anti-thyroglobulin antibody. All patients had undergone (near)-total-thyroidectomy followed by RIT. The response to initial treatments was evaluated 6-12 months after RIT. Results: According to the 2015 ATA criteria, 87, 19 and 18 DTC patients were classified to have excellent response (ER), indeterminate/incomplete biochemical response (BIndR/BIR) or structural incomplete response (SIR), respectively. Among patients with less than ER, 18 had a positive 123 I-Dx-WBS-SPECT/CT. Metastatic disease at 123 I-Dx-WBS-SPECT/CT mainly involved lymph nodes within the central compartment, and corresponding neck ultrasound examinations were negative. The ROC curve analysis was performed to define the best basal-Tg cut-off (i.e., 0.39 ng/mL; AUC = 0.852) able to discriminate patients with and without positive 123 I-Dx-WBS-SPECT/CT, respectively. The overall sensitivity, specificity, accuracy, PPV and NPV were 77.8%, 89.6%, 87.9%, 56.0% and 95.9%, respectively. Basal-Tg cut-off was an independent risk factor for having a positive 123 I-Dx-WBS-SPECT/CT. Conclusion: 123 I-Dx-WBS-SPECT/CT identified lymph node metastases in 14/37 patients with less than ER and a negative neck ultrasound, thus modifying the management of such patients. The diagnostic performance of 123 I-Dx-WBS-SPECT/CT significantly increased in patients with basal-Tg values ≥ 0.39 ng/mL.

Prostate cancer (PCa) is the most frequently diagnosed cancer worldwide and the second most common cause of cancer-related deaths among men. Progress in molecular imaging has magnified its clinical management; however, an unmet clinical need involves the identification of new imaging biomarkers that complement the gold standard of prostate-specific membrane antigen (PSMA) positron emission tomography (PET) in cases of clinically significant PCa that do not express PSMA. Fibroblast activation protein (FAP) is a type II transmembrane serine overexpressed in many solid cancers that can be imaged through quinoline-based PET tracers derived from an FAP inhibitor (FAPi). Preliminary results of FAPi application in PCa (in PSMA-negative lesions, and in comparison with fluorodeoxyglucose-FDG) are now available in the literature. FAP-targeting ligands for PCa are not limited to detection, but could also include therapeutic applications. In this preliminary review, we provide an overview of the clinical applications of FAPi ligands in PCa, summarising the main results and highlighting contemporary strengths and limitations.

Merkel cell carcinoma is a rare, aggressive skin malignancy, also known as neuroendocrine carcinoma of the skin, with high rates of recurrence and distant metastasis. In refractory metastatic Merkel cell carcinoma (mMCC), besides immunotherapy, chemotherapy, and radiation, peptide receptor radionuclide therapy (PRRT) may be a viable option since this type of tumor can express somatostatin receptors. Methods: We performed a comprehensive review of the literature to evaluate the efficacy of PRRT in mMCC patients. Results: Thirty-seven patients with mMCC received PRRT (1-5 cycles) with 177 Lu- or 90 Y-labeled somatostatin analogs (cumulative activity, 1.5-30 GBq). Radiographic response was available for 19 of 28 patients who received PRRT alone. Six (31.6%) of 19 patients showed objective responses, from partial to complete, and no severe adverse events were reported. Conclusion: Our analysis supports the use of PRRT in mMCC with sufficient somatostatin receptor uptake, although the quality of the available evidence is low. Prospective clinical trials are already in development and have started accruing in some parts of the world., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Background/aim: At present, multidisciplinary tumor boards (MDTB) are considered best practice in oncology. However, web-based virtualization of MDTB may increase participation in meetings, the number of cases discussed, and adherence to guidelines, deliver better treatment, and eventually improve outcomes for patients with prostate cancer., Patients and Methods: This is an observational study focused on exploring the structuring process and implementing a multi-institutional virtual MDTB in Sicily, Italy. Other endpoints included the analysis of cooperation between participants, adherence to guidelines, patient outcomes, and patient satisfaction., Results: Overall, 126 patients were referred to the virtual MDTB for a total of 302 cases discussed in an 18-month period. Nearly 45% of cases were referred from general hospitals or tertiary centers, 38% from comprehensive cancer centers, and only 17% from academic ones. Most health professional participants (95%) reported eliminating geographical barriers and consequently reducing costs and saving time as key advantages of virtual meetings over face-to-face ones. Using a specifically designed platform for virtual MDTBs was another excellent point, especially to geolocate clinical trials and time-lapse data storage. The majority of referred patients had stage T 3-4 prostate cancer (79%). Overall, 71% of proposals discussed were approved unchanged, while 19% changed after the virtual MDTB discussion. Debated points were mostly radiologic, surgical, medical, or radiation treatment-related issues. In particular, the prescriptive appropriateness of positron emission tomography with 68Ga-prostatic specific membrane antigen, newer drugs, radiation versus surgical approach, stage T3-4 cases, and adjuvant therapy represented the most debated issues. The proposed diagnostic and/or therapeutic options were controlled for adherence to the guidelines and/or updated scientific evidence. Overall, 98% of approved proposals and changes were in line with the guidelines. Overall, most participants felt virtual MDTB was very useful and case discussions led to a major change of strategy in 19% of cases., Conclusion: Virtual MDTBs are a very useful way to achieve best management of prostate cancer while saving time and fostering cooperation., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: 18 F-FDG PET/CT imaging represents the most important functional imaging method in oncology. European Society of Medical Oncology and the National Comprehensive Cancer Network guidelines defined a crucial role of 18 F-FDG PET/CT imaging for local/locally advanced breast cancer. The application of artificial intelligence on PET images might potentially contributes in the field of precision medicine., Objective: This review aims to summarize the clinical indications and limitations of PET imaging for comprehensive artificial intelligence in relation to breast cancer subtype, hormone receptor status, proliferation rate, and lymphonodal (LN)/distant metastatic spread, based on recent literature., Methods: A literature search of the Pubmed/Scopus/Google Scholar/Cochrane/EMBASE databases was carried out, searching for articles on the use of artificial intelligence and PET in breast tumors. The search was updated from January 2010 to October 2021 and was limited to original articles published in English and about humans. A combination of the search terms "artificial intelligence", "breast cancer", "breast tumor", "PET", "Positron emission tomography", "PET/CT", "PET/MRI", "radiomic"," texture analysis", "machine learning", "deep learning" was used., Results: Twenty-three articles were selected following the PRISMA criteria from 139 records obtained from the Pubmed/Scopus/Google Scholar/Cochrane/EMBASE databases according to our research strategy. The QUADAS of 30 full-text articles assessed reported seven articles that were excluded for not being relevant to population and outcomes and/or for lower level of evidence. The majority of papers were at low risk of bias and applicability. The articles were divided per topic, such as the value of PET in the staging and re-staging of breast cancer patients, including new radiopharmaceuticals and simultaneous PET/MRI., Conclusion: Despite the current role of AI in this field remains still undefined, several applications for PET/CT imaging are under development, with some preliminary interesting results particularly focused on the staging phase that might be clinically translated after further validation studies., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Differentiating between febrile lower urinary tract infection (LUTI) and acute pyelonephritis (APN) is crucial for prompt clinical management. We investigated whether the high mobility group box-1 (HMGB1) could be a useful biomarker in differentiating between LUTI or APN., Methods: We enrolled seventy-four pediatric patients with suspected LUTI/APN, according to the positive or negative renal scintigraphy (DMSA) scan. If the first DMSA findings were abnormal, a second DMSA was performed after six months. Voiding cystourethrography ruled out vesicoureteral reflux (VUR)., Results: Higher serum (s) HMGB1 levels characterized the APN group when compared to LUTI patients (13.3 (11.8-14.3) versus 5.9 (5.2-6.8) ng/mL, p : 0.02), whereas there were no differences according to urine (u) HMGB1 values. sHMGB1 correlated with C-reactive protein (CRP) levels (β = 0.47; p : 0.02). Receiver operating characteristic curves identified the best diagnostic profile for detecting APN. sHMGB1 area under the curve was different from CRP ( p : 0.01) and white blood cells ( p : 0.003). After multivariate analyses, VUR (HR:4.81) and sHMGB1 (HR 1.16; p : 0.006) were independently associated with the risk of renal scarring development., Conclusions: sHMGB1 could represent a marker to differentiate APN from LUTI. Measurement of sHMGB1 could select children for early intervention or long-term follow-up.

Background: Radiomic features are increasingly utilized to evaluate tumor heterogeneity in PET imaging but to date its role has not been investigated for Cho-PET in prostate cancer. The potential application of radiomics features analysis using a machine-learning radiomics algorithm was evaluated to select 18 F-Cho PET/CT imaging features to predict disease progression in PCa., Methods: We retrospectively analyzed high-risk PCa patients who underwent restaging 18 F-Cho PET/CT from November 2013 to May 2018. 18 F-Cho PET/CT studies and related structures containing volumetric segmentations were imported in the "CGITA" toolbox to extract imaging features from each lesion. A Machine-learning model has been adapted using NCA for feature selection, while DA was used as a method for feature classification and performance analysis., Results: One hundred and six imaging features were extracted for 46 lesions for a total of 4876 features analyzed. No significant differences between the training and validating sets in terms of age, sex, PSA values, lesion location and size (P>0.05) were demonstrated by the machine-learning model. Thirteen features were able to discriminate FU disease status after NCA selection. Best performance in DA classification was obtained using the combination of the 13 selected features (sensitivity 74%, specificity 58% and accuracy 66%) compared to the use of all features (sensitivity 40%, specificity 52%, and accuracy 51%). Per-site performance of the 13 selected features in DA classification were as follows: T = sensitivity 63%, specificity 83%, accuracy 71%; N = sensitivity 87%, specificity 91% of and accuracy 90%; bone-M = sensitivity 33%, specificity 77% and accuracy 66%., Conclusions: An artificial intelligence model demonstrated to be feasible and able to select a panel of 18 F-Cho PET/CT features with valuable association with PCa patients' outcome.

Background: We aimed to evaluate the role of circulating miRNAs as a biomarker of the persistence of papillary thyroid cancer (PTC) in patients with an "uninformative" thyroglobulin (Tg) measurement., Methods: We prospectively enrolled 49 consecutive PTC patients with Tg-positive antibodies (TgAb) who had undergone a (near)-total thyroidectomy and 131 I therapy (RIT). The serum thyroid stimulating hormone (TSH), Tg, and TgAb levels were measured before and at 6 and 12 months after RIT, respectively. The serum miRNA (221, 222, 375, 155, and 146b) levels were measured simultaneously., Results: The response to the initial therapy was assessed according to the 2015 ATA criteria. A decrease in 50% or more of serum miRNA over time was observed in 41/49 PTC patients, who showed an excellent response (ER), but six and two patients were classified to have an indeterminate/incomplete biochemical or incomplete structural response to initial therapy., Conclusion: Serum miRNA kinetics emerge as a promising biomarker for the early detection of a persistent disease in PTC patients with uninformative Tg results.

Objective . 177 Lu is one of the most employed isotopes in targeted radionuclide therapies and theranostics, and 3D internal dosimetry for such procedures has great importance. Voxel S-Values (VSVs) approach is widely used for this purpose, but VSVs are available for a limited number of voxel dimensions. The aim of this work is to develop an analytic model for the calculation of 177 Lu-VSVs in any cubic voxelized geometry of practical interest. Approach . Monte Carlo (MC) simulations were implemented with the toolkit GAMOS to evaluate VSVs in voxelized geometries of soft tissue from a source of 177 Lu homogeneously distributed in the central voxel. Nine geometric setups, containing 15 × 15 × 15 cubic voxels of sides l ranging from 2 mm to 6 mm, in steps of 0.5 mm, were considered. For each l , the VSVs computed as a function of the 'normalized radius', R n =  R/l (with R  = distance from the center of the source voxel), were fitted with a parametric function. The dependencies of the parameters as a function of l were then fitted with appropriate functions, in order to implement the model for deducing 177 Lu-VSVs for any l within the aforementioned range. Main results . The MC-derived VSVs were satisfactorily compared with literature data for validation, and the VSVs computed with the analytic model agree with the MC ones within 2% for R n ≤ 2 and within 6% for R n > 2. Significance . The proposed model enables the easy and fast calculation, with a simple spreadsheet, of 177 Lu-VSVs in any cubic voxelized geometry of practical interest, avoiding the necessity of implementing ad-hoc MC simulations to estimate VSVs for specific voxel dimensions not available in literature data., (© 2022 IOP Publishing Ltd.)

The FcγRII (CD32) ligands are IgFc fragments and pentraxins. The existence of additional ligands is unknown. We engineered T cells with human chimeric receptors resulting from the fusion between CD32 extracellular portion and transmembrane CD8α linked to CD28/ζ chain intracellular moiety (CD32-CR). Transduced T cells recognized three breast cancer (BC) and one colon cancer cell line among 15 tested in the absence of targeting antibodies. Sensitive BC cell conjugation with CD32-CR T cells induced CD32 polarization and down-regulation, CD107a release, mutual elimination, and proinflammatory cytokine production unaffected by human IgGs but enhanced by cetuximab. CD32-CR T cells protected immunodeficient mice from subcutaneous growth of MDA-MB-468 BC cells. RNAseq analysis identified a 42 gene fingerprint predicting BC cell sensitivity and favorable outcomes in advanced BC. ICAM1 was a major regulator of CD32-CR T cell-mediated cytotoxicity. CD32-CR T cells may help identify cell surface CD32 ligand(s) and novel prognostically relevant transcriptomic signatures and develop innovative BC treatments., (© 2022 Sconocchia et al.)

The tumor stroma, which comprises stromal cells and non-cellular elements, is a critical component of the tumor microenvironment (TME). The dynamic interactions between the tumor cells and the stroma may promote tumor progression and metastasis and dictate resistance to established cancer therapies. Therefore, novel antitumor approaches should combine anticancer and anti-stroma strategies targeting dysregulated tumor extracellular matrix (ECM). ECM remodeling is a hallmark of solid tumors, leading to extensive biochemical and biomechanical changes, affecting cell signaling and tumor tissue three-dimensional architecture. Increased deposition of fibrillar collagen is the most distinctive alteration of the tumor ECM. Consequently, several anticancer therapeutic strategies have been developed to reduce excessive tumor collagen deposition. Herein, we provide an overview of the current advances and challenges of the main approaches aiming at tumor collagen normalization, which include targeted anticancer drug delivery, promotion of degradation, modulation of structure and biosynthesis of collagen, and targeting cancer-associated fibroblasts, which are the major extracellular matrix producers.

In prostate cancer (PCa), the use of new radiopharmaceuticals has improved the accuracy of diagnosis and staging, refined surveillance strategies, and introduced specific and personalized radioreceptor therapies. Nuclear medicine, therefore, holds great promise for improving the quality of life of PCa patients, through managing and processing a vast amount of molecular imaging data and beyond, using a multi-omics approach and improving patients' risk-stratification for tailored medicine. Artificial intelligence (AI) and radiomics may allow clinicians to improve the overall efficiency and accuracy of using these "big data" in both the diagnostic and theragnostic field: from technical aspects (such as semi-automatization of tumor segmentation, image reconstruction, and interpretation) to clinical outcomes, improving a deeper understanding of the molecular environment of PCa, refining personalized treatment strategies, and increasing the ability to predict the outcome. This systematic review aims to describe the current literature on AI and radiomics applied to molecular imaging of prostate cancer., (© 2022. The Author(s) under exclusive licence to European Society of Radiology.)

Objective. The direct Monte Carlo (MC) simulation of radiation transport exploiting morphological and functional tomographic imaging as input data is considered the gold standard for internal dosimetry in nuclear medicine, and it is increasingly used in studies regarding trans-arterial radio-embolization (TARE). However, artefacts affecting the functional scans, such as reconstruction artefacts and motion blurring, decrease the accuracy in defining the radionuclide distribution in the simulations and consequently lead to errors in absorbed dose estimations. In this study, the relevance of such artefacts in patient-specific three-dimensional MC dosimetry was investigated in three cases of 90 Y TARE. Approach. The pre-therapy 99m Tc MacroAggregate Albumin (Tc-MAA) SPECTs and CTs of patients were used as input for simulations performed with the GEANT4-based toolkit GATE. Several pre-simulation SPECT-masking techniques were implemented, with the aim of zeroing the decay probability in air, in lungs, or in the whole volume outside the liver. Main results. Increments in absorbed dose up to about +40% with respect to the native-SPECT simulations were found in liver-related volumes of interest (VOIs), depending on the masking procedure adopted. Regarding lungs-related VOIs, decrements in absorbed doses in right lung as high as -90% were retrieved. Significance. These results highlight the relevant influence of SPECT artefacts, if not properly treated, on dosimetric outcomes for 90 Y TARE cases. Well-designed SPECT-masking techniques appear to be a promising way to correct for such misestimations., (© 2022 Institute of Physics and Engineering in Medicine.)

Homeodomain-interacting protein kinase 2 (HIPK2) is an evolutionary conserved kinase that has gained attention as a fine tuner of multiple signaling pathways, among which those commonly altered in colorectal cancer. The aim of this study was to evaluate the relationship of HIPK2 expression with progression markers and mutational pattern and gain insights into the contribution of HIPK2 activity in colorectal cancer. We evaluated a retrospective cohort of colorectal cancer samples by IHC for HIPK2 expression and by next-generation sequencing (NGS) for the detection of mutations of cancer associated genes. We show that the percentage of HIPK2-positive cells increases with tumor progression, significantly correlates with tumor-node-metastasis (TNM) staging and associates with a worse outcome. In addition, we observed that high HIPK2 expression significantly associates with KRAS mutations but not with other cancer-related genes. Functional characterization of the link between HIPK2 and KRAS show that activation of the RAS pathway either due to KRAS mutation or via upstream receptor stimulation, increases HIPK2 expression at the protein level. Of note, HIPK2 physically participates in the active RAS complex while HIPK2 depletion impairs ERK phosphorylation and the growth of tumors derived from KRAS mutated colorectal cancer cells. Overall, this study identifies HIPK2 as a prognostic biomarker candidate in patients with colorectal cancer and underscores a previously unknown functional link between HIPK2 and the KRAS signaling pathway., Implications: Our data indicate HIPK2 as a new player in the complex picture of the KRAS signaling network, providing rationales for future clinical studies and new treatment strategies for KRAS mutated colorectal cancer., (©2022 American Association for Cancer Research.)

Objectives: Although expert consensus recommendations suggest 2-3 h as the time interval between bone-seeking radiotracers injection and acquisition, it has been reported that images obtained early after [ 99m Tc]Tc-HMDP administration are sufficient to diagnose cardiac amyloidosis. We evaluated the diagnostic performance of [ 99m Tc]Tc-DPD early phase whole body scan with respect to late phase imaging., Methods: We qualitatively and semiquantitatively reviewed [ 99m Tc]Tc-DPD imaging of 53 patients referred for suspect cardiac amyloidosis. Findings of early and late phase images were compared with SPECT results (considered the standard-of-reference) determining sensitivity and specificity for visual analysis of each phase imaging and for each semiquantitative index., Results: SPECT imaging was negative for cardiac accumulation in 25 patients and positive in 28. Visual analysis of early phase whole body scan had an extremely significant capability to predict SPECT results; nevertheless, complete agreement was not reached. Visual analysis of late phase imaging showed slightly better results. Semiquantitative analysis of early phase images, namely heart to mediastinum ratio, performed better than semiquantitative analysis of late phase images., Conclusion: Visual analysis of [ 99m Tc]Tc-DPD early phase whole body scan is promising in diagnosing cardiac amyloidosis; further studies are needed to confirm our results in different clinical scenarios., Key Points: • Visual analysis of early phase planar imaging using [ 99m Tc]Tc-DPD is accurate to diagnose cardiac amyloidosis and may be satisfactory at least in frail patients with high cardiac burden of amyloid fibrils., (© 2021. The Author(s), under exclusive licence to European Society of Radiology.)

Purpose: To assess and compare clinical outcomes and costs, to the Italian healthcare system, of three therapeutic options approved in the management of adult patients with gastro-enteropancreatic neuroendocrine tumours (GEP-NETs)., Methods: We compared the efficacy, safety, and costs of [177Lu]Lu-DOTA-TATE, everolimus (both originator and generic products), and sunitinib in patients with advanced GEP-NETs (NET G1 and G2) that had progressed following treatment with somatostatin analogs (SSAs). A cost-consequence model was developed and validated by a panel of clinical experts from three NET reference centres in Italy. The clinical outcomes included in the model were median progression-free survival and the incidence of grade 3 or 4 adverse events (AEs), as reported in pivotal clinical trials. The costs for acquisition and administration of each treatment, and of managing AEs, were calculated from the perspective of the Italian national health service. Treatment costs per progression-free month were calculated separately for patients with NETs of pancreatic (PanNETs; all three treatments) and gastrointestinal (GI-NETs; [177Lu]Lu-DOTA-TATE and everolimus only) origin., Results: In patients with PanNETs, total costs per progression-free month were €2989 for [177Lu]Lu-DOTA-TATE, €4975 for originator everolimus, €3472 for generic everolimus, and €5337 for sunitinib. In patients with GI-NETs, total costs per progression-free month were €3189 for [177Lu]Lu-DOTA-TATE, €4990 for originator everolimus, and €3483 for generic everolimus., Conclusions: [177Lu]Lu-DOTA-TATE was associated with lower costs per progression-free month versus relevant treatment options in patients with GI-NETs or PanNETs (NET G1-G2; progressed following SSA treatment), although acquisition and administration costs are higher. These findings provide further economic arguments in the overall context of treatment decision-making., (© 2021. The Author(s).)

Background: Early in-vivo diagnosis of Alzheimer's disease (AD) is crucial for accurate management of patients, in particular, to select subjects with mild cognitive impairment (MCI) that may evolve into AD, and to define other types of MCI non-AD patients. The application of artificial intelligence to functional brain [ 18 F]fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography(CT) aiming to increase diagnostic accuracy in the diagnosis of AD is still undetermined. In this field, we propose a radiomics analysis on advanced imaging segmentation method Statistical Parametric Mapping (SPM)-based completed with a Machine-Learning (ML) application to predict the diagnosis of AD, also by comparing the results with following Amyloid-PET and final clinical diagnosis., Methods: From July 2016 to September 2017, 43 patients underwent PET/CT scans with FDG and Florbetaben brain PET/CT and at least 24 months of clinical/instrumental follow-up. Patients were retrospectively evaluated by a multidisciplinary team (MDT = Neurologist, Psychologist, Radiologist, Nuclear Medicine Physician, Laboratory Clinic) at the G. Giglio Institute in Cefalù, Italy. Starting from the cerebral segmentations applied by SPM on the main cortical macro-areas of each patient, Pyradiomics was used for the feature extraction process; subsequently, an innovative descriptive-inferential mixed sequential approach and a machine learning algorithm (i.e., discriminant analysis) were used to obtain the best diagnostic performance in prediction of amyloid deposition and the final diagnosis of AD., Results: A total of 11 radiomics features significantly predictive of cortical beta-amyloid deposition ( n = 6) and AD ( n = 5) were found. Among them, two higher-order features (original_glcm_Idmn and original_glcm_Id), extracted from the limbic enthorinal cortical area (ROI-1) in the FDG-PET/CT images, predicted the positivity of Amyloid-PET/CT scans with maximum values of sensitivity (SS), specificity (SP), precision (PR) and accuracy (AC) of 84.92%, 75.13%, 73.75%, and 79.56%, respectively. Conversely, for the prediction of the clinical-instrumental final diagnosis of AD, the best performance was obtained by two higher-order features (original_glcm_MCC and original_glcm_Maximum Probability) extracted from ROI-2 (frontal cortex) with a SS, SP, PR and AC of 75.16%, 80.50%, 77.68%, and 78.05%, respectively, and by one higher-order feature (original_glcm_Idmn) extracted from ROI-3 (medial Temporal cortex; SS = 80.88%, SP = 76.85%, PR = 75.63%, AC = 78.76%., Conclusions: The results obtained in this preliminary study support advanced segmentation of cortical areas typically involved in early AD on FDG PET/CT brain images, and radiomics analysis for the identification of specific high-order features to predict Amyloid deposition and final diagnosis of AD.

Aim: In this comprehensive review we present an update on the most relevant studies evaluating the utility of amino acid PET radiotracers for the evaluation of glioma recurrence as compared to magnetic resonance imaging (MRI)., Methods: A literature search extended until June 2020 on the PubMed/MEDLINE literature database was conducted using the terms "high-grade glioma", "glioblastoma", "brain tumors", "positron emission tomography", "PET", "amino acid PET", "[ 11 C]methyl-l-methionine", "[ 18 F]fluoroethyl-tyrosine", "[ 18 F]fluoro-l-dihydroxy-phenylalanine", "MET", "FET", "DOPA", "magnetic resonance imaging", "MRI", "advanced MRI", "magnetic resonance spectroscopy", "perfusion-weighted imaging", "diffusion-weighted imaging", "MRS", "PWI", "DWI", "hybrid PET/MR", "glioma recurrence", "pseudoprogression", "PSP", "treatment-related change", and "radiation necrosis" alone and in combination. Only original articles edited in English and about humans with at least 10 patients were included., Results: Forty-four articles were finally selected. Conventional amino acid PET tracers were demonstrated to be reliable diagnostic techniques in differentiating tumor recurrence thanks to their high uptake from tumor tissue and low background in normal grey matter, giving additional and early information to standard modalities. Among them, MET-PET seems to present the highest diagnostic value but its use is limited to on-site cyclotron facilities. [ 18 F]labelled amino acids, such as FDOPA and FET, were developed to provide a more suitable PET tracer for routine clinical applications, and demonstrated similar diagnostic performance. When compared to the gold standard MRI, amino acid PET provides complementary and comparable information to standard modalities and seems to represent an essential tool in the differentiation between tumor recurrence and other entities such as pseudoprogression, radiation necrosis, and pseudoresponse., Conclusions: Despite the introduction of new advanced imaging techniques, the diagnosis of glioma recurrence remains challenging. In this scenario, the growing knowledge about imaging techniques and analysis, such as the combined PET/MRI and the application of artificial intelligence (AI) and machine learning (ML), could represent promising tools to face this difficult and debated clinical issue.

Purpose: This multicentric study aimed to investigate the main prognostic factors associated with treatment response at 1 year after radioactive iodine therapy (RAIT) and the last disease status in pediatric patients affected by differentiated thyroid carcinoma (DTC)., Materials and Methods: In the period 1990-2020, all consecutive patients ≤ 18 years from six different centers were retrospectively included. Patients were classified as low, intermediate, and high risk for persistence/recurrence. The response to RAIT was evaluated and scored 1 year later according to 2015 ATA guidelines. Moreover, at the last follow-up, the disease status was evaluated and dichotomized as no evidence of disease (NED) or persistent disease., Results: Two hundred and eighty-five patients (197 female, 88 male; mean age 14.4 years) were recruited. All, except nine, underwent near-total thyroidectomy followed by RAIT. One-year after first RAIT, 146/276 (53%) patients had excellent response, 37/276 (14%) indeterminate response, and 91/276 (33%) incomplete response. One-year after RAIT, children with excellent response had significantly lower stimulated thyroglobulin (sTg) compared to not excellent group (median sTg 4.4 ng/ml vs 52.5 ng/ml, p < 0.001). ROC curve showed sTg higher than 27.2 ng/ml as the most accurate to predict 1-year treatment response. After a median follow-up of 133 months, NED was present in 241 cases (87%) while persistent disease in 35 (13%). At multivariate analysis, sTg and 1-year treatment response categories were both significantly associated with the last disease status (p value 0.023 and < 0.001)., Conclusions: In pediatric DTC, sTg is significantly associated with 1-year treatment response and final outcome. However, 1-year response is the principal prognostic factor able to predict pediatric DTCs outcome., (© 2021. The Author(s).)

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 [ 68 Ga]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 [ 68 Ga]DOTATOC PET/CT before complete PRRT with [ 177 Lu]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. [ 68 Ga]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 [ 68 Ga]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&#95;Skewness and HISTO&#95;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&#95;Skewness; HISTO&#95;Kurtosis, and Grading) did not improve the AUC significantly with 0.744. SUV max , 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 [ 177 Lu]DOTATOC PRRT, regardless of the lesion site.

Importance: Data about the optimal timing for the initiation of peptide receptor radionuclide therapy (PRRT) for advanced, well-differentiated enteropancreatic neuroendocrine tumors are lacking., Objective: To evaluate the association of upfront PRRT vs upfront chemotherapy or targeted therapy with progression-free survival (PFS) among patients with advanced enteropancreatic neuroendocrine tumors who experienced disease progression after treatment with somatostatin analogues (SSAs)., Design, Setting, and Participants: This retrospective, multicenter cohort study analyzed the clinical records from 25 Italian oncology centers for patients aged 18 years or older who had unresectable, locally advanced or metastatic, well-differentiated, grades 1 to 3 enteropancreatic neuroendocrine tumors and received either PRRT or chemotherapy or targeted therapy after experiencing disease progression after treatment with SSAs between January 24, 2000, and July 1, 2020. Propensity score matching was done to minimize the selection bias., Exposures: Upfront PRRT or upfront chemotherapy or targeted therapy., Main Outcomes and Measures: The main outcome was the difference in PFS among patients who received upfront PRRT vs among those who received upfront chemotherapy or targeted therapy. A secondary outcome was the difference in overall survival between these groups. Hazard ratios (HRs) were fitted in a multivariable Cox proportional hazards regression model to adjust for relevant factors associated with PFS and were corrected for interaction with these factors., Results: Of 508 evaluated patients (mean ([SD] age, 55.7 [0.5] years; 278 [54.7%] were male), 329 (64.8%) received upfront PRRT and 179 (35.2%) received upfront chemotherapy or targeted therapy. The matched group included 222 patients (124 [55.9%] male; mean [SD] age, 56.1 [0.8] years), with 111 in each treatment group. Median PFS was longer in the PRRT group than in the chemotherapy or targeted therapy group in the unmatched (2.5 years [95% CI, 2.3-3.0 years] vs 0.7 years [95% CI, 0.5-1.0 years]; HR, 0.35 [95% CI, 0.28-0.44; P < .001]) and matched (2.2 years [95% CI, 1.8-2.8 years] vs 0.6 years [95% CI, 0.4-1.0 years]; HR, 0.37 [95% CI, 0.27-0.51; P < .001]) populations. No significant differences were shown in median overall survival between the PRRT and chemotherapy or targeted therapy groups in the unmatched (12.0 years [95% CI, 10.7-14.1 years] vs 11.6 years [95% CI, 9.1-13.4 years]; HR, 0.81 [95% CI, 0.62-1.06; P = .11]) and matched (12.2 years [95% CI, 9.1-14.2 years] vs 11.5 years [95% CI, 9.2-17.9 years]; HR, 0.83 [95% CI, 0.56-1.24; P = .36]) populations. The use of upfront PRRT was independently associated with improved PFS (HR, 0.37; 95% CI, 0.26-0.51; P < .001) in multivariable analysis. After adjustment of values for interaction, upfront PRRT was associated with longer PFS regardless of tumor functional status (functioning: adjusted HR [aHR], 0.39 [95% CI, 0.27-0.57]; nonfunctioning: aHR, 0.29 [95% CI, 0.16-0.56]), grade of 1 to 2 (grade 1: aHR, 0.21 [95% CI, 0.12-0.34]; grade 2: aHR, 0.52 [95% CI, 0.29-0.73]), and site of tumor origin (pancreatic: aHR, 0.41 [95% CI, 0.24-0.61]; intestinal: aHR, 0.19 [95% CI, 0.11-0.43]) (P < .001 for all). Conversely, the advantage was not retained in grade 3 tumors (aHR, 0.31; 95% CI, 0.12-1.37; P = .13) or in tumors with a Ki-67 proliferation index greater than 10% (aHR, 0.73; 95% CI, 0.29-1.43; P = .31)., Conclusions and Relevance: In this cohort study, treatment with upfront PRRT in patients with enteropancreatic neuroendocrine tumors who had experienced disease progression with SSA treatment was associated with significantly improved survival outcomes compared with upfront chemotherapy or targeted therapy. Further research is needed to investigate the correct strategy, timing, and optimal specific sequence of these therapeutic options.

In the recent years, artificial intelligence (AI) applications have gained interest in the field of cardiovascular medical imaging, including positron emission tomography (PET). The use of AI in cardiac PET imaging is to date limited, although first, important results have been shown, overcoming technical issues, improving diagnostic accuracy and providing prognostic information. In this review we aimed to summarize the state-of-the-art regarding AI applications in cardiovascular PET.

Abstract: A 71-year-old woman was operated on for undifferentiated lung adenocarcinoma. Four months after surgery, she developed bone and adrenal metastases. She underwent palliative radiation therapy of left scapula and right iliac bone. Thereafter, she started immune checkpoint inhibitor (ICI) therapy with anti-PD-1 antibodies achieving complete tumor response. Twenty months later, a follow-up 18F-FDG PET/CT confirmed tumor response and revealed high radiotracer accumulation in correspondence of retroperitoneal and subcutaneous fat opacities. The contiguous fasciae were mildly thickened. The temporal relation with ICI therapy together with tumor response and corticosteroids therapy effectiveness led to conclude for ICI-related adverse events., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: This review aimed to summarize the available literature on the clinical application of [ 18 F] FLT PET imaging in primary brain tumours., Methods: A comprehensive search strategy based on Pubmed/Medline, Scopus, Web of Science, Cochrane Library, Google Scholar, and the Embase databases was carried on using the following search string: ('3` Fluorothymidine'/exp OR 'FLT' OR '[81F]-FLT' OR '[ 18 F] Fluorothymidine') AND ('pet'/exp OR 'pet' OR 'positron emission tomography') AND ('glioma'/exp OR 'glioma' OR 'brain tumour'/exp OR 'brain tumour'). The search was updated till March 2021 and only articles in English and studies investigating the clinical applications of [ 18 F] FLT PET and PET/CT in primary brain tumours were considered eligible for inclusion., Results: The literature search ultimately yielded 52 studies included in the systematic review, with main results as follows: a) the uptake of [ 18 F] FLT may guide stereotactic biopsy but does not discriminate between grade II and III glioma. b) [ 18 F] FLT uptake and texture parameters correlate with overall survival (OS) in newly diagnosed gliomas. c) In patients with recurrent glioma, proliferative volume (PV) and tumour-to-normal brain (T/N) uptake ratio are independent predictors of survival. d) Patients demonstrating response to therapy at [ 18 F] FLT PET scan show longer OS compared to non-responders. e) [ 18 F] FLT PET demonstrated good performance in discriminating tumour recurrence from radionecrosis. However, controversial results exist in comparative literature examining the performance of [ 18 F] FLT vs. other radiotracers in the assessment of recurrence., Conclusion: [ 18 F] FLT PET imaging has demonstrated potential benefits for grading, diagnostic and prognostic purposes, despite the small sample size studies due to the relatively low availability of the radiotracer., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Purpose: The aim of this proof-of-concept study is to propose a simplified personalized kidney dosimetry procedure in 177 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., Methods: We conducted a phantom study involving external count-rate measurements in an abdominal phantom setup filled with activity concentrations of 99m Tc, reproducing patient-relevant organ effective half-lives occurring in 177 Lu PRRT. GATE Monte Carlo (MC) simulations of the experiment, using 99m Tc and 177 Lu as sources, were performed. Furthermore, we tested this method via MC on a clinical case of 177 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., 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 99m Tc and 177 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., 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., (Copyright © 2021 Associazione Italiana di Fisica Medica e Sanitaria. Published by Elsevier Ltd. All rights reserved.)

To date, the virtual multidisciplinary tumor boards (vMTBs) are increasingly used to achieve high-quality treatment recommendations across health-care regions, which expands and develops the local MTB team to a regional or national expert network. This review describes the process of lung cancer-specific MTBs and the transition process from face-to-face tumor boards to virtual ones. The review also focuses on the project organization's description, advantages, and disadvantages. Semi-structured interviews identified five major themes for MTBs: current practice, attitudes, enablers, barriers, and benefits for the MTB. MTB teams exhibited positive responses to modeled data feedback. Virtualization reduces time spent for travel, allowing easier and timely patient discussions. This process requires a secure web platform to assure the respect of patients' privacy and presents the same unanswered problems. The implementation of vMTB also permits the implementation of networks especially in areas with geographical barriers facilitating interaction between large referral cancer centers and tertiary or community hospitals as well as easier access to clinical trial opportunities. Studies aimed to improve preparations, structure, and conduct of MTBs, research methods to monitor their performance, teamwork, and outcomes are also outlined in this article. Analysis of literature shows that MTB participants discuss 5-8 cases per meeting and that the use of a vMTB for lung cancer and in particular stage III NSCLC and complex stage IV cases is widely accepted by most health professionals. Despite still-existing gaps, overall vMTB represents a unique opportunity to optimize patient management in a patient-centered approach., (© 2021. The Author(s).)

Background: We aimed to test whether the prognostic value of 18 F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (FDG-PET/CT) in metastatic castration-resistant prostate cancer (mCRPC) extends to the estimation of systemic treatment response duration., Methods: mCRPC patients submitted to FDG-PET/CT in four Italian centers from 2005 to 2020 were retrospectively enrolled. Clinical and biochemical data at the time of imaging were collected, and SUV max of the hottest lesion, total metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were calculated. The correlation between PET- and biochemical-derived parameters with Overall Survival (OS) was analysed. The prediction of treatment response duration was assessed in the subgroup submitted to FDG-PET/CT in the six months preceding Chemotherapy (namely Docetaxel or Cabazitaxel, 24 patients) or Androgen-Receptor Targeted Agents (ARTA, namely Abiraterone or Enzalutamide, 20 patients) administration., Results: We enrolled 114 mCRPC patients followed-up for a median interval lasting 15 months. While at univariate analysis, prostate-specific antigen (PSA), Alkaline Phosphatase (ALP), MTV, and TLG were associated with OS, at the multivariate Cox regression analysis, the sole MTV could independently predict OS (p < 0.0001). In the subgroup submitted to FDG-PET/CT before the systemic treatment initiation, PSA and TLG could also predict treatment response duration independently (p < 0.05). Of note, while PSA could not indicate the best treatment choice, lower TLG was associated with higher success rates for ARTA but had no impact on chemotherapy efficacy., Conclusions: FDG-PET/CT's prognostic value extends to predicting treatment response duration in mCRPC, thus potentially guiding the systemic treatment selection., (© 2021. The Author(s).)

Purpose: The objective of this review was to explore the potential clinical application of unconventional non-amino acid PET radiopharmaceuticals in patients with gliomas., Methods: A comprehensive search strategy was used based on SCOPUS and PubMed databases using the following string: ("perfusion" OR "angiogenesis" OR "hypoxia" OR "neuroinflammation" OR proliferation OR invasiveness) AND ("brain tumor" OR "glioma") AND ("Positron Emission Tomography" OR PET). From all studies published in English, the most relevant articles were selected for this review, evaluating the mostly used PET radiopharmaceuticals in research centers, beyond amino acid radiotracers and 2-[ 18 F]fluoro-2-deoxy-D-glucose ([ 18 F]FDG), for the assessment of different biological features, such as perfusion, angiogenesis, hypoxia, neuroinflammation, cell proliferation, tumor invasiveness, and other biological characteristics in patients with glioma., Results: At present, the use of non-amino acid PET radiopharmaceuticals specifically designed to assess perfusion, angiogenesis, hypoxia, neuroinflammation, cell proliferation, tumor invasiveness, and other biological features in glioma is still limited., Conclusion: The use of investigational PET radiopharmaceuticals should be further explored considering their promising potential and studies specifically designed to validate these preliminary findings are needed. In the clinical scenario, advancements in the development of new PET radiopharmaceuticals and new imaging technologies (e.g., PET/MR and the application of the artificial intelligence to medical images) might contribute to improve the clinical translation of these novel radiotracers in the assessment of gliomas., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Amyloid precursor protein and its derivates represent a central factor in the process of neurodegeneration in Alzheimer's disease (AD). Since mental illnesses share with AD cognitive impairment, amyloid indicators have been used to explore the unknown pathophysiologic mechanisms underlining psychiatric illness. This work aims to compare the role of amyloid markers, together with tau proteins, among various mental disorders evaluating the possible role of altered amyloid metabolism in the onset and in the course of psychiatric diseases, considering the relationship with cognitive impairment in dementia. This review includes articles written in English, published between 1 January 2011 and 31 January 2021, which evaluated amyloid and tau proteins in psychiatric patients. After screening, 31 studies were included in the review. Results suggest that amyloid metabolism is altered in major psychiatric disorders and that it could be a marker of cognitive impairment. Nevertheless, the role of amyloid in mental diseases seems to be related to neurodevelopmental alteration as well as neurodegeneration processes, like in AD. The role of amyloid in the pathogenesis of mental disorders is still unknown. Amyloid should not be only considered as a marker of cognitive impairment in mental illness, but also for altered neurodevelopment.

Endogenous acetaldehyde production from the metabolism of ingested alcohol exposes hematopoietic progenitor cells to increased genotoxic risk. To develop possible therapeutic strategies to prevent or reverse alcohol abuse effects, it would be critical to determine the temporal progression of acute ethanol toxicity on progenitor cell numbers and proliferative status. We followed the variation of the cell proliferation rate in bone marrow and spleen in response to acute ethanol intoxication in the MITO-Luc mouse, in which NF-Y-dependent cell proliferation can be assessed in vivo by non-invasive bioluminescent imaging. One week after ethanol administration, bioluminescent signals in bone marrow and spleen decreased below the level corresponding to physiological proliferation, and they progressively resumed to pre-treatment values in approximately 4 weeks. Boosting acetaldehyde catabolism by administration of an aldehyde dehydrogenase activity activator or administration of polyphenols with antioxidant activity partially restored bone marrow cells' physiological proliferation. These results indicate that in this mouse model, bioluminescent alteration reflects the reduction of the physiological proliferation rate of bone marrow progenitor cells due to the toxic effect of aldehydes generated by alcohol oxidation. In summary, this study presents a novel view of the impact of acute alcohol intake on bone marrow cell proliferation in vivo.

Background: To determine the capability of 99m Tc-DPD scintigraphy to detect early cardiac involvement and predict clinical worsening in transthyretin (TTR) gene mutation patients., Methods: Eleven mutated subjects with normal interventricular septum (IVS) thickness, NT-proBNP level and no cardiac symptoms underwent three seriate 99m Tc-DPD scans (visually and semiquantitatively analyzed), and was followed-up for 5-8-years., Results: Six patients showed no myocardial accumulation in all scans. Increased IVS thickness occurring in one patient 4 years after the last scan was the only abnormal finding in these patients; no cardiac symptoms developed during the follow-up. In three patients, cardiac radiotracer uptake was found at enrollment; other laboratory/instrumental abnormal findings occurred later and cardiac symptoms developed during the follow-up period. Two patients had a negative 99m Tc-DPD scan at enrollment and showed cardiac uptake in the following scans. Increased mean left-ventricular (LV) wall thickness was found 3 years after positive scintigraphy; NT-proBNP increased later in one patient. These patients developed cardiac symptoms during the follow-up period., Conclusions: 99m Tc-DPD scan detects cardiac involvement in subjects with TTR gene mutation earlier than ECG, echocardiography and biochemical markers, occurring some years before the fulfillment of current diagnostic criteria for cardiac amyloidosis. A positive 99m Tc-DPD scan predicts cardiac symptoms onset., (© 2019. American Society of Nuclear Cardiology.)