Despite the increased use of177Lu in nuclear medicine (NM) over the last 10 years, the knowledge of the actual exposure of the extremities due to manipulation of this pharmaceutical is limited. The purpose of this study is to assess the extremity dose during the preparation and administration of177Lu-labelled radiopharmaceuticals in a wide range of NM practices. Workers in 10 NM centres throughout Europe wore a ring dosimeter on the base of the index finger of the non-dominant hand during preparation and/or administration of177Lu-labelled radiopharmaceuticals. Information on manipulated activity, tasks performed and protection measures was collected to allow sub-analyses. The median ring dose per monitoring interval was 0.16 mSv, with a maximum of 2.27 mSv in one month. The median normalised dose amounted 3.5µSv GBq-1(range 0.5-525). The highest monthly doses were found for workers involved in preparation of the pharmaceutical. The workers performing manual administrations (6.5µSv GBq-1) showed higher normalised ring doses than those using the gravity method (3.5µSv GBq-1) or a syringe pump (1.0µSv GBq-1). Explanations for the wide range of normalised ring doses may be found in the different techniques applied in this study and the differences in minimum reportable doses of the dosimeters. When the data is extrapolated using a fingertip to ring dose ratio of 5, an annual fingertip dose of 1-136 mSv is found, with a median fingertip dose of 10 mSv per year. Extremity exposure during177Lu handling remained well below dose limits. The highest normalised doses occurred during preparation and manual administration. Overall, this investigation shows doses remain low when appropriate radiation protection measures (e.g. shielding and minimising time at short distance) are being applied.

This substudy of the phase III NETTER-1 trial evaluated [177Lu]Lu- DOTATATE (hereafter 177Lu-DOTATATE) for advanced midgut neuroendocrine tumors and aimed to assess dosimetry of a standard 4-cycle protocol and any potential relationship to toxicity. Change in tumor size by absorbed dose was an exploratory endpoint. Methods: Patients with locally advanced or metastatic, well-differentiated, midgut neuroendocrine tumors were enrolled in this substudy between August 2013 and January 2016. Patients were scheduled to receive 4 infusions of 7.4 GBq of 177Lu-DOTATATE for a cumulative injected activity of 29.6 GBq. After a 177Lu-DOTATATE infusion, whole-body planar images (4-6 time points for up to 7 d) and SPECT/CT images (at 24 and/or 48 h) were acquired, and absorbed and time-integrated activity coefficients were calculated to derive dosimetry. Blood and urine samples were used to determine the blood clearance and activity elimination rate. Tumor absorbed dose was derived using a sphere model, interpolating 177Lu dose factors on the basis of each lesion mass. Tumor size was assessed by measuring the longest and perpendicular dimensions on CT at measured time points. Results: Dosimetric assessments were evaluated in 20 patients. Organ dosimetry showed substantial interpatient variability. The predicted mean cumulative absorbed doses to kidneys and bone marrow were 19.4 (SD, 8.7) and 1.0 (SD, 0.8) Gy, respectively. Three patients had kidney doses between 28 and 33 Gy; 2 had grade 1 increased serum creatinine, and 1 showed no evidence of renal toxicity (up to 5 y of follow-up). Hematologic toxicity was primarily mild or moderate (grade 1-2) with no increase over time or association with cumulative absorbed dose. Tumor kinetics in 65 lesions demonstrated stable activity over time. Inter- and intrapatient variability was observed, and the median cumulative absorbed dose was 134 Gy (range, 7-2,218 Gy). Acknowledging the limitations of the imaging methods used and tumor volume assessments, we found no correlation between the best tumor size reduction and the absorbed dose, though most tumors (90%) shrank over the 72-wk study period. Conclusion: The dosimetry data support the findings that the standard treatment regimen with 177Lu-DOTATATE that includes personalized adjustments according to acute toxicity assessments is well tolerated and manageable.

Malignant pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare tumors and available systemic therapies are limited. To explore the role of peptide receptor radionuclide therapy (PRRT) with Yttrium-90 (90Y) and Lutetium-177 (177Lu) peptides in pheochromocytomas (PCCs) and paragangliomas (PGLs). We retrospectively analyzed more than 1500 patients with histologically proven neuroendocrine tumors treated with 177Lu- or 90Y-DOTA-TATE or –TOC between 1999 to 2017 at our Institute. Overall, 30 patients with confirmed malignant PCCs and PGLs matched inclusion/exclusion criteria and were considered eligible for this analysis. Thirty (n = 30) patients were treated: 22 with PGLs and 8 with PCCs (12 M and 18 F, median age 47 [IQR: 35–60 years]). Eighteen patients (n = 18) had head and neck PGLs, 3 patients thoracic PGLs and 1 patient abdominal PGL. Sixteen patients (53

Metabolic alterations in cancers can be exploited for diagnostic, prognostic, and therapeutic purposes. This is exemplified by 18F-fluorodeoxyglucose (FDG)-positron emission tomography (FDG-PET), an imaging tool that relies on enhanced glucose uptake by tumors for diagnosis and staging. By performing transcriptomic analysis of breast cancer (BC) samples from patients stratified by FDG-PET, a 54-gene signature (PETsign) is identified that recapitulates FDG uptake. PETsign is independently prognostic of clinical outcome in luminal BCs, the most common and heterogeneous BC molecular subtype, which requires improved stratification criteria to guide therapeutic decision-making. The prognostic power of PETsign is stable across independent BC cohorts and disease stages including the earliest BC stage, arguing that PETsign is an ab initio metabolic signature. Transcriptomic and metabolomic analysis of BC cells reveals that PETsign predicts enhanced glycolytic dependence and reduced reliance on fatty acid oxidation. Moreover, coamplification of PETsign genes occurs frequently in BC arguing for their causal role in pathogenesis. CXCL8 and EGFR signaling pathways feature strongly in PETsign, and their activation in BC cells causes a shift toward a glycolytic phenotype. Thus, PETsign serves as a molecular surrogate for FDG-PET that could inform clinical management strategies for BC patients.

Radio-guided surgery (RGS) holds promise for improving surgical outcomes in neuroendocrine tumors (NETs). Previous studies showed low specificity (SP) using γ-probes to detect radiation emitted by radio-labeled somatostatin analogs. We aimed to assess the sensitivity (SE) and SP of the intraoperative RGS approach using a β-probe with a per-lesion analysis, while assessing safety and feasibility as secondary objectives. This prospective, single-arm, single-center, phase II trial (NCT05448157) enrolled 20 patients diagnosed with small intestine NETs (SI-NETs) with positive lesions detected at 68Ga-DOTA-TOC positron emission tomography/computed tomography (PET/CT). Patients received an intravenous injection of 1.1 MBq/Kg of 68Ga-DOTA-TOC 10 min prior to surgery. In vivo measurements were conducted using a β-probe. Receiver operating characteristic (ROC) analysis was performed, with the tumor-to-background ratio (TBR) as the independent variable and pathology result (cancer vs. non-cancer) as the dependent variable. The area under the curve (AUC), optimal TBR, and absorbed dose for the surgery staff were reported. The intraoperative RGS approach was feasible in all cases without adverse effects. Of 134 specimens, the AUC was 0.928, with a TBR cut-off of 1.35 yielding 89.3 https://classic.clinicaltrials.gov/ct2/show/NCT05448157 ]

Objective: to evaluate the feasibility of the intra-operative application of a specimen PET/CT imager in a clinical setting. Materials and methods: this is a pilot analysis performed in three patients who received an intra-operative administration of 68Ga-PSMA-11 (n=2) and 68Ga-DOTA-TOC (n=1), respectively. Patients were administrated with PET radiopharmaceuticals to perform radio-guided surgery with a beta-probe detector during radical prostatectomy for prostate cancer (PCa) and salvage lymphadenectomy for recurrent neuroendocrine tumor (NET) of the ileum, respectively. All procedures have been performed within two ongoing clinical trials in our Institute (NCT05596851 and NCT05448157). Pathologic assessment with immunohistochemistry (PSMA-staining and SSA immunoreactivity) was considered as standard of truth. Specimen images were compared with baseline PET/CT images and histopathological analysis. Results: Patients received 1 MBq/Kg of 68Ga-PSMA-11 (PCa) or 1.2 MBq/Kg of 68Ga-DOTA-TOC (NET) prior to surgery. Specimens were collected, positioned in the dedicated specimen container, and scanned to obtain high resolution PET/CT images. In all cases a perfect match was observed between the findings detected by the specimen imager and histopathology. Overall, the PET spatial resolution was sensibly higher for the specimen images compared to the baseline whole-body PET/CT images. Furthermore, the use of the PET/CT specimen imager did not significantly interfere with any procedures, and the overall length of the surgery was not affected using the PET/CT specimen imager. Finally, the radiation exposure of the operating theater staff was lower than 40 µSv per procedure (range 26 – 40 Sv). Conclusion: the image acquisition of specimens obtained by patients who received intra-surgery injection of 68Ga-PSMA-11 and 68Ga-DOTA-TOC was feasible and reliable also in a live-experience session and has been easily adapted to surgery daily-practice. The high sensitivity, together with the evaluation of intra-lesion tumor heterogeneity, were the most relevant results since the data derived from specimen PET/CT imaging matched perfectly with the histopathological analysis.

Emerging evidence indicates that chemoresistance is closely related to altered metabolism in cancer. Here, we hypothesized that distinct metabolic gene expression profiling (GEP) signatures might be correlated with outcome and with specific fluorodeoxyglucose positron emission tomography (FDG-PET) radiomic profiles in diffuse large B-cell lymphoma (DLBCL). We retrospectively analyzed a discovery cohort of 48 consecutive patients with DLBCL treated at our center with standard first-line chemoimmunotherapy by performing targeted GEP (T-GEP)- and FDG-PET radiomic analyses on the same target lesions at baseline. T-GEP-based metabolic profiling identified a 6-gene signature independently associated with outcomes in univariate and multivariate analyses. This signature included genes regulating mitochondrial oxidative metabolism (SCL25A1, PDK4, PDPR) that were upregulated and was inversely associated with genes involved in hypoxia and glycolysis (MAP2K1, HIF1A, GBE1) that were downregulated. These data were validated in 2 large publicly available cohorts. By integrating FDG-PET radiomics and T-GEP, we identified a radiometabolic signature (RadSig) including 4 radiomic features (histo kurtosis, histo energy, shape sphericity, and neighboring gray level dependence matrix contrast), significantly associated with the metabolic GEP-based signature (r = 0.43, P = .0027) and with progression-free survival (P = .028). These results were confirmed using different target lesions, an alternative segmentation method, and were validated in an independent cohort of 64 patients. RadSig retained independent prognostic value in relation to the International Prognostic Index score and metabolic tumor volume (MTV). Integration of RadSig and MTV further refined prognostic stratification. This study provides the proof of principle for the use of FDG-PET radiomics as a tool for noninvasive assessment of cancer metabolism and prognostic stratification in DLBCL.

To evaluate the association between radiomic features (RFs) extracted from 18 F‐FDG PET/CT ( 18 F‐FDG‐PET) with progression‐free survival (PFS) and overall survival (OS) in diffuse large‐B‐cell lymphoma (DLBCL) patients eligible to first‐line chemotherapy. DLBCL patients who underwent 18 F‐FDG‐PET prior to first‐line chemotherapy were retrospectively analyzed. RFs were extracted from the lesion showing the highest uptake. A radiomic score to predict PFS and OS was obtained by multivariable Elastic Net Cox model. Radiomic univariate model, clinical and combined clinical‐radiomic multivariable models to predict PFS and OS were obtained. 112 patients were analyzed. Median follow‐up was 34.7 months (Inter‐Quartile Range (IQR) 11.3–66.3 months) for PFS and 41.1 (IQR 18.4–68.9) for OS. Radiomic score resulted associated with PFS and OS ( p < 0.001), outperforming conventional PET parameters. C‐index (95% CI) for PFS prediction were 0.67 (0.58–0.76), 0.81 (0.75–0.88) and 0.84 (0.77–0.91) for clinical, radiomic and combined clinical‐radiomic model, respectively. C‐index for OS were 0.77 (0.66–0.89), 0.84 (0.76–0.91) and 0.90 (0.81–0.98). In the Kaplan‐Meier analysis (low‐IPI vs. high‐IPI), the radiomic score was significant predictor of PFS ( p < 0.001). The radiomic score was an independent prognostic biomarker of survival in DLBCL patients. The extraction of RFs from baseline 18 F‐FDG‐PET might be proposed in DLBCL to stratify high‐risk versus low‐risk patients of relapse after first‐line therapy, especially in low‐IPI patients.

Radiomic analysis of 18F[FDG] PET/CT images might identify predictive imaging biomarkers, however, the reproducibility of this quantitative approach might depend on the methodology adopted for image analysis. This retrospective study investigates the impact of PET segmentation method and the selection of different target lesions on the radiomic analysis of baseline 18F[FDG] PET/CT images in a population of newly diagnosed diffuse large B-cell lymphoma (DLBCL) patients. The whole tumor burden was segmented on PET images applying six methods: (1) 2.5 standardized uptake value (SUV) threshold; (2) 25% maximum SUV (SUVmax) threshold; (3) 42% SUVmax threshold; (4) 1.3∙liver uptake threshold; (5) intersection among 1, 2, 4; and (6) intersection among 1, 3, 4. For each method, total metabolic tumor volume (TMTV) and whole-body total lesion glycolysis (WTLG) were assessed, and their association with survival outcomes (progression-free survival PFS and overall survival OS) was investigated. Methods 1 and 2 provided stronger associations and were selected for the next steps. Radiomic analysis was then performed on two target lesions for each patient: the one with the highest SUV and the largest one. Fifty-three radiomic features were extracted, and radiomic scores to predict PFS and OS were obtained. Two proportional-hazard regression Cox models for PFS and OS were developed: (1) univariate radiomic models based on radiomic score; and (2) multivariable clinical–radiomic model including radiomic score and clinical/diagnostic parameters (IPI score, SUVmax, TMTV, WTLG, lesion volume). The models were created in the four scenarios obtained by varying the segmentation method and/or the target lesion; the models’ performances were compared (C-index). In all scenarios, the radiomic score was significantly associated with PFS and OS both at univariate and multivariable analysis (p < 0.001), in the latter case in association with the IPI score. When comparing the models’ performances in the four scenarios, the C-indexes agreed within the confidence interval. C-index ranges were 0.79–0.81 and 0.80–0.83 for PFS radiomic and clinical–radiomic models; 0.82–0.87 and 0.83–0.90 for OS radiomic and clinical–radiomic models. In conclusion, the selection of either between two PET segmentation methods and two target lesions for radiomic analysis did not significantly affect the performance of the prognostic models built on radiomic and clinical data of DLBCL patients. These results prompt further investigation of the proposed methodology on a validation dataset.

Targeted radiation therapy (TRT) is a strategy increasingly adopted for the treatment of different types of cancer. The urge for optimization, as stated by the European Council Directive (2013/59/EURATOM), requires the implementation of a personalized dosimetric approach, similar to what already happens in external beam radiation therapy (EBRT). The purpose of this paper is to provide a thorough introduction to the field of personalized dosimetry in TRT, explaining its rationale in the context of optimization and describing the currently available methodologies. After listing the main therapies currently employed, the clinical workflow for the absorbed dose calculation is described, based on works of the most experienced authors in the literature and recent guidelines. Moreover, the widespread software packages for internal dosimetry are presented and critical aspects discussed. Overall, a selection of the most important and recent articles about this topic is provided.