Mandatory role of endoplasmic reticulum in preserving NADPH regeneration in starved MDA-MB-231 breast cancer cells.

Cancer growth requires high amount of nicotinamide adenine dinucleotide phosphate (NADPH) to feed the anabolic reactions and preserve the redox balance. NADPH level is largely preserved by the oxidative arm of the pentose phosphate pathway (PPP). Here, we show that prolonged glucose deprivation of triple negative breast cancer MDA-MB-231 cells decreases proliferation rate, promotes hexose funneling to glycolysis hampering the PPP. The impairment in PPP activity and the consequent NADPH depletion are partially counterbalanced by enhancing the malic enzyme-1 catalyzed conversion of glutamine-derived malate to pyruvate. However, the use of these glucose-independent carbons implies the integrity of the two PPPs represented in all eukaryotic cells, i.e., the well-recognized cytosolic PPP, triggered by glucose-6-phosphate dehydrogenase (G6PD) and its reticular counterpart, triggered by hexose-6P-dehydrogenase (H6PD). This evidence configures the reticular PPP as a mandatory player in the regeneration of NADPH reductive power by cancer cells.

Recovery of cardiovascular diagnostic testing in Italy 1 year after coronavirus disease-2019 outbreak compared with other countries in Europe and worldwide: results from the International Atomic Energy Agency INCAPS COVID 2 survey.

Aims: Recovery of cardiovascular diagnostic testing in Italy after the coronavirus disease-2019 (COVID-19) pandemic has not been quantified. The study aims to describe cardiac diagnostic procedure volumes, centres practice and protocols, and staff members' well-being 1 year after COVID-19 outbreak in Italy. Methods and results: A global survey was conducted by the International Atomic Energy Agency to evaluate changes in cardiac diagnostic procedure volumes in April 2021. Evaluated procedures were transoesophageal echocardiogram, coronary computed tomography angiography, coronary artery calcium scanning, nuclear medicine infection studies, invasive coronary angiography, rest and stress transthoracic echocardiogram, cardiac magnetic resonance, single-photon emission computed tomography and positron emission tomography, and stress electrocardiogram. Data were compared with April 2020 and March 2019. Forty-two Italian centres took part in the survey. In April 2020, there was a 72% decrease of median volumes of cardiac diagnostic procedures compared with March 2019. In April 2021, volumes of cardiac diagnostic procedures remained decreased by 3% when compared with March 2019. Stress electrocardiogram, coronary computed tomography angiography, and stress cardiac magnetic resonance volumes increased in April 2021 compared with baseline (29%, 6%, and 16%, respectively). The majority of centres had adopted physical distancing measures (93%), COVID-19 screening through questionnaires (76%), or temperature checks (93%). Twenty-five per cent of physicians at Italian responding sites reported excessive levels of psychological stress. Conclusion: In April 2021, volumes of cardiac diagnostic procedures at Italian responding sites were still recovering. Centres had implemented several adaptations to ensure the provision of care to their patients. Even 1 year after the pandemic, a substantial minority of Italian healthcare providers were still experiencing excessive psychological stress.

The coronavirus disease-2019 pandemic has had an impact on cardiovascular care provision, leading to a decrease in the number of diagnostic procedures performed. As of April 2021, volumes of cardiovascular diagnostic procedures in Italy were still recovering, despite the implementation of several adaptations by healthcare centres to deal with the pandemic.

Progression trajectories from prodromal to overt synucleinopathies: a longitudinal, multicentric brain [18F]FDG-PET study.

The phenoconversion trajectory from idiopathic/isolated Rapid eye movement (REM) sleep behavior disorder (iRBD) towards either Parkinson's Disease (PD) or Dementia with Lewy Bodies (DLB) is currently uncertain. We investigated the capability of baseline brain [18F]FDG-PET in differentiating between iRBD patients eventually phenoconverting to PD or DLB, by deriving the denovoPDRBD-related pattern (denovoPDRBD-RP) from 32 de novo PD patients; and the denovoDLBRBD-RP from 30 de novo DLB patients, both with evidence of RBD at diagnosis. To explore [18F]FDG-PET phenoconversion trajectories prediction power, we applied these two patterns on a group of 115 iRBD patients followed longitudinally. At follow-up (25.6 ± 17.2 months), 42 iRBD patients progressed through overt alpha-synucleinopathy (21 iRBD-PD and 21 iRBD-DLB converters), while 73 patients remained stable at the last follow-up visit (43.2 ± 27.6 months). At survival analysis, both patterns were significantly associated with the phenoconversion trajectories. Brain [18F]FDG-PET is a promising biomarker to study progression trajectories in the alpha-synucleinopathy continuum.

External beam radiotherapy followed by image-guided adaptive brachytherapy in locally advanced cervical cancer: a multicenter retrospective analysis.

PURPOSE: To evaluate oncological outcomes and toxicities in patients with locally advanced cervical cancer (LACC) treated with concurrent chemoradiotherapy followed by image-guided adaptive brachytherapy at two Italian centres. MATERIAL AND METHODS: A retrospective analysis was conducted on 122 patients with LACC treated between 2010 and 2022. Primary endpoints were local control (LC), pelvic control (PC), and nodal control (NC). Secondary endpoints included disease-free survival (DFS), metastasis-free survival (MFS), overall survival (OS), and late toxicity. Correlations between patient characteristics and oncological outcomes were conducted. RESULTS: Brachytherapy planning was CT and MRI-based in 88 (72.1%) and 34 patients (27.9%), respectively. The mean total dose (EQD2) delivered to high-risk clinical target volume was 82 Gy. Overall treatment time was ≤ 50 days and > 50 days in 48 (39.3%) and 74 patients (60.7%), respectively. At a mean follow up of 101 months, 3 and 5-year LC rates were 87% and 85%, respectively. Five-year PC and NC rates were 77% and 85.1%. Five-year DFS and OS were 61% and 65.4%, respectively, with significant correlations between these outcomes and FIGO stage and nodal status at diagnosis. Gastrointestinal, genitourinary and vaginal adverse effects were the most reported late toxicities and 8 (6.5%) grade 3-5 events were observed. 32 patients (26.2%) had vaginal stenosis and it was significantly related to 3D imaging used for brachytherapy planning. CONCLUSIONS: The study confirmed the efficacy and safety of chemoradiotherapy and IGABT for LACC. Full implementation of MRI treatment planning and interstitial techniques could further enhance personalized treatment and outcomes.

PSMA PET-targeted Biopsy for Prostate Cancer Diagnosis: Initial Experience From a Multicenter Cohort.

OBJECTIVE: To describe the initial experience with PSMA-PET/CT-guided biopsy in European referral centres. METHODS: This multicenter observational cohort study was endorsed by the Young Academic Urologist (YAU) Prostate Cancer Group of the EAU and conducted across 6 tertiary-level European centres. PSMA-guided biopsies were carried out in a cognitive/fusion manner for all the recruited patients with or without MRI-guided biopsies and/or standard biopsy (SB). PCa and clinical significant PCa (csPCA) detection rate (DR) at prostate biopsy was assessed. Uni- and multivariable models were employed to identify features related to csPCA. RESULTS: Overall, 72 patients were recruited. The topographic location of the dominant lesion depicted by PSMA PET/CT was significantly associated with the location of csPCa, especially in the biopsy naïve cohort. The DR for PCa and csPCa of PSMA-PET/CT-guided biopsies was significantly higher than SB (0.40 ± 0.43 vs 0.23 ± 0.29, and 0.36 ± 0.44 vs 0.21 ± 0.30, respectively, both P <.05) but did not surpass MRI-guided biopsies (0.40 ± 0.43 vs 0.47 ± 0.44, and 0.36 ± 0.44 vs 0.47 ± 0.34, respectively, both P >.05). PSMA-PET/CT-guided biopsy performed better in the biopsy naïve than in the repeated biopsy setting. A SUVmax cut-off value equal to 4.8 provided the best results for detecting csPCa. CONCLUSION: Our real-world data illustrate the potentialities of PSMA-PET/CT-guided biopsy in diagnosing PCa. Specifically, in biopsy naïve patients with suspicion of high-risk disease, the use of PSMA-PET/CT-targeted biopsy can be considered. Additionally, in the context of repeated biopsies, a PSMA-PET/CT target biopsy might be advisable over the SB.

Metabolic tumor volume assessed by 18F FDG - PET CT scan as a predictive biomarker for immune checkpoint blockers in advanced NSCLC and its biological correlates.

PURPOSE: This study aimed to explore metabolic tumor volume (tMTV) as assessed 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG-PET/CT), and understand its biological meaning in patients with NSCLC exposed to immune checkpoint blockers(ICBs). EXPERIMENTAL DESIGN: In this study, patients with advanced NSCLC and a positive PET scan within 42 days of first line treatment were enrolled in 11 institutions across 4 countries. Total MTV (tMTV) was analyzed, with a 42% SUVmax threshold. Survival was analyzed according to high tMTV (≥ median). Plasma proteomic profile, whole exome, transcriptome and other analysis were performed on monocentric cohorts to explore its biological correlates. RESULTS: Of the 518 patients included, 167 received ICBs, 257 had chemotherapy plus ICBs, and 94 had chemotherapy. Median tMTV was 99 cm3. Median overall survival (OS) for patients with high tMTV treated with ICBs was 11.4 months vs 29.6 months (P<0.0012) for those with low tMTV. In patients receiving chemotherapy-ICB tMTV did not correlate with OS (P=0.099). In patients with PD-L1≥1% and high tMTV, chemotherapy-ICB combination was associated with longer OS compared with ICBs alone (20 vs 11.4 months,p=0.026), while no survival differences observed in low tMTV group. High tMTV correlated (and its detrimental effect seems to be driven by) a specific proteomic profile and increase in genomic instability. CONCLUSION: Our analysis indicates high tTMV is linked to an increase in systemic inflammation, specific cytokines production and chromosomal instability. tTMV may serve as one of the biomarker to select the best upfront strategy in patients with PD-L1 positive advanced NSCLC.

Metabolic and dopaminergic correlates of intellectual enrichment in de-novo Parkinson's disease patients.

BACKGROUND: Cognitive reserve (CR) is an expression of brain resilience in response to damage. Education, occupational experience and leisure activities are thought to increase CR and have beneficial effects on global cognition and cognitive decline in Parkinson's disease (PD). We aimed to disclose brain metabolic and dopaminergic correlates of CR in de-novo PD patients. METHODS: Sixty-two drug-naïve de-novo PD patients underwent [18F]FDG-PET and DAT-SPECT. CR was quantified through the Cognitive-Reserve-Index questionnaire including total-CR and 3 subscores (educational-CR, occupational-CR, leisure-CR). Specific binding ratios (SBRs) and Z-scores in basal ganglia were obtained with 'BasGan-V2'. Z-scores were used as dependent variables in general linear models to assess the interaction between dopaminergic function and CR. Voxel-based correlation between brain metabolism and CR-scores and between SBR and [18F]FDG-PET was evaluated using SPM12 (P<0.05 FWE-corrected at peak and cluster level considered significant). RESULTS: Dopaminergic deficit in the most affected hemisphere (MAH) putamen was significantly less marked in higher CR patients (Z-score -1.7±0.1 highly-educated versus -2.1±0.1 poorly-educated, P<0.02). Total and leisure-related-CR resulted correlated directly with z-scores of the MAH putamen (P<0.018 and P<0.003) and inversely with brain metabolism in both cerebellar hemispheres (P<0.001). MAH-putamen SBR correlated directly with metabolism in occipital and parietal cortex (P<0.003) and inversely in cerebellar hemispheres (P<0.02). CONCLUSIONS: CR proxies demonstrated to correlate directly with dopaminergic function and inversely with metabolism in cerebellar hemispheres in de-novo PD patients. The present multi-modal approach including both metabolic and dopaminergic correlates of CR allowed to identify possible compensation mechanisms, highlighting a potential role of the cerebellum that deserves further investigation.

Composite Prediction Score to Interpret Bone Focal Uptake in Hormone-Sensitive Prostate Cancer Patients Imaged with [18F]PSMA-1007 PET/CT.

Unspecific bone uptake (UBU) related to [18F]PSMA-1007 PET/CT imaging represents a clinical challenge. We aimed to assess whether a combination of clinical, biochemical, and imaging parameters could predict skeletal metastases in patients with [18F]PSMA-1007 bone focal uptake, aiding in result interpretation. Methods: We retrospectively analyzed [18F]PSMA-1007 PET/CT performed in hormone-sensitive prostate cancer (PCa) patients at 3 tertiary-level cancer centers. A fourth center was involved in performing an external validation. For each, a volume of interest was drawn using a threshold method to extract SUVmax, SUVmean, PSMA tumor volume, and total lesion PSMA. The same volume of interest was applied to CT images to calculate the mean Hounsfield units (HUmean) and maximum Hounsfield units. Clinical and laboratory data were collected from electronic medical records. A composite reference standard, including follow-up histopathology, biochemistry, and imaging data, was used to distinguish between PCa bone metastases and UBU. PET readers with less (n = 2) or more (n = 2) experience, masked to the reference standard, were asked to visually rate a subset of focal bone uptake (n = 178) as PCa metastases or not. Results: In total, 448 bone [18F]PSMA-1007 focal uptake specimens were identified in 267 PCa patients. Of the 448 uptake samples, 188 (41.9%) corresponded to PCa metastases. Ongoing androgen deprivation therapy at PET/CT (P < 0.001) with determination of SUVmax (P < 0.001) and HUmean (P < 0.001) independently predicted bone metastases. A composite prediction score, the bone uptake metastatic probability (BUMP) score, achieving an area under the receiver-operating-characteristic curve (AUC) of 0.87, was validated through a 10-fold internal and external validation (n = 89 bone uptake, 51% metastatic; AUC, 0.92). The BUMP score's AUC was significantly higher than that of HUmean (AUC, 0.62) and remained high among lesions with HUmean in the first tertile (AUC, 0.80). A decision-curve analysis showed a higher net benefit with the score. Compared with the visual assessment, the BUMP score provided added value in terms of specificity in less-experienced PET readers (88% vs. 54%, P < 0.001). Conclusion: The BUMP score accurately distinguished UBU from bone metastases in PCa patients with [18F]PSMA-1007 focal bone uptake at PET imaging, offering additional value compared with the simple assessment of the osteoblastic CT correlate. Its use could help clinicians interpret imaging results, particularly those with less experience, potentially reducing the risk of patient overstaging.

Personalised PET imaging in oncology: an umbrella review of meta-analyses to guide the appropriate radiopharmaceutical choice and indication.

PURPOSE: For several years, oncological positron emission tomography (PET) has developed beyond 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG). This umbrella review of meta-analyses aims to provide up-to-date, comprehensive, high-level evidence to support appropriate referral for a specific radiopharmaceutical PET/computed tomography (CT) or PET/magnetic resonance (MR) in the diagnosis and staging of solid cancers other than brain malignancies. METHODS: We performed a systematic literature search on the PubMed/MEDLINE and EMBASE databases for meta-analyses assessing the accuracy of PET/CT and/or PET/MRI with [18F]FDG, somatostatin- receptor-targeting 68Ga-DOTA-peptides, 18F-labelled dihydroxyphenylalanine ([18F]DOPA), prostate-specific membrane antigen (PSMA)-targeted radioligands, and fibroblast activation protein inhibitors (FAPI) in the diagnosis/disease characterisation and staging of solid cancers other than brain tumours. RESULTS: The literature search yielded 449 scientific articles. After screening titles and abstracts and applying inclusion and exclusion criteria, we selected 173 meta-analyses to assess the strength of evidence. One article was selected from references. Sixty-four meta-analyses were finally considered. The current evidence corroborates the role of [18F]FDG as the main player in molecular imaging; PSMA tracers are useful in staging and re-staging prostate cancer; somatostatin-targeting peptides (e.g. [68Ga]Ga- DOTA-TOC and -TATE) or [18F]DOPA are valuable in neuroendocrine tumours (NETs). FAPI has emerged in gastric cancer assessment. According to search and selection criteria, no satisfactory meta-analysis was selected for the diagnosis/detection of oesophageal cancer, the diagnosis/detection and N staging of small cell lung cancer and hepatic cell carcinoma, the diagnosis/detection and M staging of melanoma and Merkel cell carcinoma, cervical, vulvar and penis cancers, the N and M staging of lung and gastroenteropancreatic NET, testicular cancer, and chondrosarcoma, and the M staging of differentiated thyroid, bladder and anal cancers. CONCLUSION: The comprehensive high-level evidence synthesised in the present umbrella review serves as a guiding compass for clinicians and imagers, aiding them in navigating the increasingly intricate seascape of PET examinations.

The LUTADOSE trial: tumour dosimetry after the first administration predicts progression free survival in gastro-entero-pancreatic neuroendocrine tumours (GEP NETs) patients treated with [177Lu]Lu-DOTATATE.

PURPOSE: In Peptide Receptor Radionuclide Therapy (PRRT) with [177Lu]Lu-DOTATATE of gastro-entero-pancreatic neuroendocrine tumours (GEP NETs) a question remains open about the potential benefits of personalised dosimetry. This observational prospective study examines the association of individualized dosimetry with progression free survival (PFS) in G1-G2 GEP NETs patients following the standard [177Lu]Lu-DOTATATE therapeutic regimen. METHODS: The analysis was conducted on 42 patients administered 4 times, and on 165 lesions. Dosimetry was performed after the first and the forth cycle, with two SPECT/CT scans at day 1 and 7 after administration. Global mean Tumour absorbed Dose of each patient (GTD) was calculated after cycle 1 and 4 as the sum of lesion doses weighted by lesion mass, normalized by the global tumour mass. Cumulative GTD_TOT was calculated as the mean between cycle 1 (GTD_1) and 4 (GTD_4) multiplied by 4. Patients were followed-up for median 32.8 (range 18-45.5) months, through blood tests and contrast enhanced CT (ceCT). This study assessed the correlation between global tumour dose (GTD) and PFS longer or shorter than 24 months. After a ROC analysis, we stratified patients according to the best cut-off value for two additional statistical analyses. At last a multivariate analysis was carried out for PFS > / < 24 months. RESULTS: The median follow-up interval was 33 months, ranging from 18 to 45.5 months. The median PFS was 42 months. The progression free survival rate at 20 months was 90.5%. GTD_1 and GTD_TOT were statistically associated with PFS > / < 24 m (p = 0.026 and p = 0.03 respectively). The stratification of patients on GTD_1 lower or higher than the best cut-off value at 10.6 Gy provided significantly different median PFS of 21 months versus non reached, i.e. longer than 45.5 months (p = 0.004), with a hazard ratio of 8.6, (95% C.I.: [2 - 37]). Using GTD_TOT with the best cut-off at 43 Gy, the same PFS values were obtained as after cycle 1 (p = 0.035). At multivariate analysis, a decrease in GTD_1 and, with lower impact, a higher global tumour volume were significantly associated with PFS < 24 months. We calculated the Tumour Control Probability of obtaining PFS > 24 months as a function of GTD_1. DISCUSSION: Several statistical analyses seem to confirm that simple tumour dosimetry with 2 SPECT/CT scans after the first administration allows to predict PFS values after 4 × 7.4 GBq administrations of 177Lu[Lu]-DOTATATE in G1-G2 GEP NETs. This result qualitatively confirms recent findings by a Belgian and a French study. However, dosimetric thresholds are different. This probably comes from different cohort baseline characteristics, since the median PFS in our study (42 m) was longer than in the other studies (28 m and 31 m). CONCLUSION: Tumour dosimetry after the first administration of [177Lu]Lu-DOTATATE offers an important prognostic value in the clinical decision-making process, especially for the future as alternative emitters or administration schedule may become available.

Systemic inflammatory markers and volume of enhancing tissue on post-contrast T1w MRI images in differentiating true tumor progression from pseudoprogression in high-grade glioma.

Background: High-grade glioma (HGG) patients post-radiotherapy often face challenges distinguishing true tumor progression (TTP) from pseudoprogression (PsP). This study evaluates the effectiveness of systemic inflammatory markers and volume of enhancing tissue on post-contrast T1 weighted (T1WCE) MRI images for this differentiation within the first six months after treatment. Material and Methods: We conducted a retrospective analysis on a cohort of HGG patients from 2015 to 2021, categorized per WHO 2016 and 2021 criteria. We analyzed treatment responses using modified RANO criteria and conducted volumetry on T1WCE and T2W/FLAIR images.Blood parameters assessed included neutrophil/lymphocyte ratio (NLR), systemic immune-inflammation index (SII), and systemic inflammation response index (SIRI). We employed Chi-square, Fisher's exact test, and Mann-Whitney U test for statistical analyses, using log-transformed predictors due to multicollinearity. A Cox regression analysis assessed the impact of PsP- and TTP-related factors on overall survival (OS). Results: The cohort consisted of 39 patients, where 16 exhibited PsP and 23 showed TTP. Univariate analysis revealed significantly higher NLR and SII in the TTP group [NLR: 4.1 vs 7.3, p = 0.002; SII 546.5 vs 890.5p = 0.009]. T1WCE volume distinctly differentiated PsP from TTP [2.2 vs 11.7, p < 0.001]. In multivariate regression, significant predictors included NLR and T1WCE volume in the "NLR Model," and T1WCE volume and SII in the "SII Model." The study also found a significantly lower OS rate in TTP patients compared to those with PsP [HR 3.97, CI 1.59 to 9.93, p = 0.003]. Conclusion: Elevated both, SII and NLR, and increased T1WCE volume were effective in differentiating TTP from PsP in HGG patients post-radiotherapy. These results suggest the potential utility of incorporating these markers into clinical practice, though further research is necessary to confirm these findings in larger patient cohorts.

The Glucose-Glutamine Metabolic Interplay in MCF-7 Cells, a Hormone-Sensitive Breast Cancer Model.

BACKGROUND: Selective deprivation of glutamine has been shown to accelerate the generation of reactive oxygen species (ROS) and to impair the activity of a specific pentose phosphate pathway (PPP) located within the endoplasmic reticulum (ER). The consequent oxidative damage suggests that glucose flux through this reticular pathway might contribute to the redox stress of breast cancer cells. We thus evaluated whether this response is reproduced when the glutamine shortage is coupled with the glucose deprivation. METHODS: Cancer growth, metabolic plasticity and redox status were evaluated under saturating conditions and after 48 h starvation (glucose 2.5 mM, glutamine 0.5 mM). The Seahorse technology was used to estimate adenosine triphosphate (ATP)-linked and ATP-independent oxygen consumption rate (OCR) as well as proton efflux rate (PER). 18F-fluoro-deoxy-glucose (FDG) uptake was evaluated through the LigandTracer device. Proliferation rate was estimated by the carboxyfluorescein-diacetate-succinimidyl ester (CFSE) staining, while cell viability by the propidium iodide exclusion assay. RESULTS: Starvation reduced the proliferation rate of MCF-7 cells without affecting their viability. It also decreased lactate release and PER. Overall OCR was left unchanged although ATP-synthase dependent fraction was increased under nutrient shortage. Glutaminolysis inhibition selectively impaired the ATP-independent and the oligomycin-sensitive OCR in control and starved cultures, respectively. The combined nutrient shortage decreased the cytosolic and mitochondrial markers of redox stress. It also left unchanged the expression of the reticular unfolded protein marker GRP78. By contrast, starvation decreased the expression of hexose-6P-dehydrogenase (H6PD) thus decreasing the glucose flux through the ER-PPP as documented by the profound impairment in the uptake rate of FDG. CONCLUSIONS: When combined with glucose deprivation, glutamine shortage does not elicit the expected enhancement of ROS generation in the studied breast cancer cell line. Combined with the decreased activity of ER-PPP, this observation suggests that glutamine interferes with the reticular glucose metabolism to regulate the cell redox balance.

Diverse Imaging Methods May Influence Long-Term Oncologic Outcomes in Oligorecurrent Prostate Cancer Patients Treated with Metastasis-Directed Therapy (the PRECISE-MDT Study).

Metastasis-directed therapy (MDT) has been tested in clinical trials as a treatment option for oligorecurrent prostate cancer (PCa). However, there is an ongoing debate regarding the impact of using different imaging techniques interchangeably for defining lesions and guiding MDT within clinical trials. Methods: We retrospectively identified oligorecurrent PCa patients who had 5 or fewer nodal, bone, or visceral metastases detected by choline or prostate-specific membrane antigen (PSMA) PET/CT and who underwent MDT stereotactic body radiotherapy with or without systemic therapy in 8 tertiary-level cancer centers. Imaging-guided MDT was assessed as progression-free survival (PFS), time to systemic treatment change due to polymetastatic conversion (PFS2), and overall survival predictor. Propensity score matching was performed to account for clinical differences between groups. Results: Of 402 patients, 232 (57.7%) and 170 (42.3%) underwent MDT guided by [18F]fluorocholine and PSMA PET/CT, respectively. After propensity score matching, patients treated with PSMA PET/CT-guided MDT demonstrated longer PFS (hazard ratio [HR], 0.49 [95% CI, 0.36-0.67]; P < 0.0001), PFS2 (HR, 0.42 [95% CI, 0.28-0.63]; P < 0.0001), and overall survival (HR, 0.39 [95% CI, 0.15-0.99]; P < 0.05) than those treated with choline PET/CT-guided MDT. Additionally, we matched patients who underwent [68Ga]Ga-PSMA-11 versus [18F]F-PSMA-1007 PET/CT, observing longer PFS and PFS2 in the former subgroup (PFS: HR, 0.51 [95% CI, 0.26-1.00]; P < 0.05; PFS2: HR, 0.24 [95% CI, 0.09-0.60]; P < 0.05). Conclusion: Diverse imaging methods may influence outcomes in oligorecurrent PCa patients undergoing MDT. However, prospective, head-to-head studies, ideally incorporating a randomized design, are necessary to provide definitive evidence and facilitate the practical application of these findings.

The Homunculus of unspecific bone uptakes associated with PSMA-targeted tracers: a systematic review-based definition.

PURPOSE: Prostate-Specific Membrane Antigen (PSMA)-targeted Positron Emission Tomography (PET) has revolutionised prostate cancer (PCa) diagnosis and treatment, offering superior diagnostic accuracy over traditional methods and enabling theragnostic applications. However, a significant diagnostic challenge has emerged with identifying unspecific bone uptakes (UBUs), which could lead to over-staging and inappropriate treatment decisions if misinterpreted. This systematic review explores the phenomenon of UBUs in PCa patients undergoing PSMA-PET imaging. METHODS: Studies assessing the prevalence, topographical distribution, and potential clinical implications of UBUs were selected according to the Preferred Reporting Items for a Systematic Review and Meta-Analysis (PRISMA) method and evaluated with the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. RESULTS: The percentage of PCa patients with UBUs on PSMA-PET scans ranged from 0 to 71.7%, depending on the radiopharmaceutical used, with [18F]PSMA-1007 showing the highest incidence. The ribs are the primary site of UBUs across all PSMA-targeted radiopharmaceuticals. The spine is the second most frequent UBU site for [68Ga]Ga-PSMA-11, [18F]DCFPyL, [18F]rhPSMA-7, while the pelvic girdle represents the second most frequent site for [18F]PSMA-1007. The average maximum Standardized Uptake Value (SUVmax) of UBUs varied from 3.4 to 7.7 and was generally lower than that of bone metastases. CONCLUSIONS: Our findings underscore the need for heightened awareness and precise interpretation of UBUs to avoid potential over-staging and subsequent inappropriate treatment decisions. Considering the radiopharmaceutical used, PET-derived semiquantitative parameters, the topographical distribution of UBUs, and accurately evaluating the pre-test probability based on clinical and laboratory parameters may aid nuclear medicine physicians in interpreting PSMA-PET findings.

A systematic review and meta-analysis to evaluate the diagnostic accuracy of PSMA PET/CT in the initial staging of prostate cancer.

BACKGROUND: Positron Emission Tomography-Computed Tomography using Prostate-Specific Membrane Antigen (PSMA PET/CT) is notable for its superior sensitivity and specificity in detecting recurrent PCa and is under investigation for its potential in pre-treatment staging. Despite its established efficacy in nodal and metastasis staging in trial setting, its role in primary staging awaits fuller validation due to limited evidence on oncologic outcomes. This systematic review and meta-analysis aims to appraise the diagnostic accuracy of PSMA PET/CT compared to CI for comprehensive PCa staging. METHODS: Medline, Scopus and Web of science databases were searched till March 2023. Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines were followed to identify eligible studies. Primary outcomes were specificity, sensitivity, positive predictive value (PPV) and negative predictive value (NPV) of PSMA PET/CT for local, nodal and metastatic staging in PCa patients. Due to the unavailability of data, a meta-analysis was feasible only for detection of seminal vesicles invasion (SVI) and LNI. RESULTS: A total of 49 studies, comprising 3876 patients, were included. Of these, 6 investigated accuracy of PSMA PET/CT in detection of SVI. Pooled sensitivity, specificity, PPV and NPV were 42.29% (95%CI: 29.85-55.78%), 87.59% (95%CI: 77.10%-93.67%), 93.39% (95%CI: 74.95%-98.52%) and 86.60% (95%CI: 58.83%-96.69%), respectively. Heterogeneity analysis revealed significant variability for PPV and NPV. 18 studies investigated PSMA PET/CT accuracy in detection of LNI. Aggregate sensitivity, specificity, PPV and NPV were 43.63% (95%CI: 34.19-53.56%), 85.55% (95%CI: 75.95%-91.74%), 67.47% (95%CI: 52.42%-79.6%) and 83.61% (95%CI: 79.19%-87.24%). No significant heterogeneity was found between studies. CONCLUSIONS: The present systematic review and meta-analysis highlights PSMA PET-CT effectiveness in detecting SVI and its good accuracy in LNI compared to CI. Nonetheless, it also reveals a lack of high-quality research on its performance in clinical T staging, extraprostatic extension and distant metastasis evaluation, emphasizing the need for further rigorous studies.