Radio-Guided Surgery with a New-Generation ß-Probe for Radiolabeled Somatostatin Analog, in Patients with Small Intestinal Neuroendocrine Tumors.

BACKGROUND: 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. OBJECTIVE: We aimed to assess the sensitivity (SE) and SP of the intraoperative RGS approach using a ß-probe with a per-lesion analysis, while assessing safety and feasibility as secondary objectives. METHODS: 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 ß-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. RESULTS: 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% SE and 86.4% SP. The median absorbed dose for the surgery staff was 30 µSv (range 12-41 µSv). CONCLUSION: This study reports optimal accuracy in detecting lesions of SI-NETs using the intraoperative RGS approach with a novel ß-probe. The method was found to be safe, feasible, and easily reproducible in daily clinical practice, with minimal radiation exposure for the staff. RGS might potentially improve radical resection rates in SI-NETs. CLINICAL TRIALS REGISTRATION: 68Ga-DOTATOC Radio-Guided Surgery with ß-Probe in GEP-NET (RGS GEP-NET) [NCT0544815; https://classic. CLINICALTRIALS: gov/ct2/show/NCT05448157 ].

[18 F]-FDG PET radiomic model as prognostic biomarker in diffuse large B-cell lymphoma.

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.

Dosimetry of 177Lu-PSMA-617 after Mannitol Infusion and Glutamate Tablet Administration: Preliminary Results of EUDRACT/RSO 2016-002732-32 IRST Protocol.

Radio-ligand therapy (RLT) with177Lu-PSMA-617 is a promising option for patients with metastatic castration-resistant prostate-cancer (mCRPC). A prospective phase-II study (EUDRACT/RSO,2016-002732-32) on mCRPC is ongoing at IRST (Meldola, Italy). A total of 9 patients (median age: 68 y, range: 53⁻85) were enrolled for dosimetry evaluation of parotid glands (PGs), kidneys, red marrow (RM) and whole body (WB). Folic polyglutamate tablets were orally administered as PGs protectors and 500 mL of a 10% mannitol solution was intravenously infused to reduce kidney uptake. The whole body planar image (WBI) and blood samples were acquired at different times post infusion (1 h, 16⁻24 h, 36⁻48 h and 120 h). Dose calculation was performed with MIRD formalism (OLINDA/EXM software). The median effective half-life was 33.0 h (range: 25.6⁻60.7) for PGs, 31.4 h (12.2⁻80.6) for kidneys, 8.2 h (2.5⁻14.7) for RM and 40.1 h (31.6⁻79.7) for WB. The median doses were 0.48 mGy/MBq (range: 0.33⁻2.63) for PGs, 0.70 mGy/MBq (0.26⁻1.07) for kidneys, 0.044 mGy/MBq (0.023⁻0.067) for RM and 0.04 mGy/MBq (0.02⁻0.11) for WB. A comparison with previously published dosimetric data was performed and a significant difference was found for PGs while no significant difference was observed for the kidneys. For PGs, the possibility of reducing uptake by administering glutamate tablets during RLT seems feasible while further research is warranted for a more focused evaluation of the reduction in kidney uptake.

Correlation of dose with toxicity and tumour response to 90Y- and 177Lu-PRRT provides the basis for optimization through individualized treatment planning.

PURPOSE: Peptide receptor radionuclide therapy (PRRT) with 90Y-labelled and 177Lu-labelled peptides is an effective strategy for the treatment of metastatic/nonresectable neuroendocrine tumours (NETs). Dosimetry provides important information useful for optimizing PRRT with individualized regimens to reduce toxicity and increase tumour responses. However, this strategy is not applied in routine clinical practice, despite the fact that several dosimetric studies have demonstrated significant dose-effect correlations for normal organ toxicity and tumour response that can better guide therapy planning. The present study reviews the key relationships and the radiobiological models available in the literature with the aim of providing evidence that optimization of PRRT is feasible through the implementation of dosimetry. METHODS: The MEDLINE database was searched combining specific keywords. Original studies published in the English language reporting dose-effect outcomes in patients treated with PRRT were chosen. RESULTS: Nine of 126 studies were selected from PubMed, and a further five were added manually, reporting on 590 patients. The studies were analysed and are discussed in terms of weak and strong elements of correlations. CONCLUSION: Several studies provided evidence of clinical benefit from the implementation of dosimetry in PRRT, indicating the potential contribution of this approach to reducing severe toxicity and/or reducing undertreatment that commonly occurs. Prospective trials, possibly multicentre, with larger numbers of patients undergoing quantitative dosimetry and with standardized methodologies should be carried out to definitively provide robust predictive paradigms to establish effective tailored PRRT.

Role of interim 18F-FDG-PET/CT for the early prediction of clinical outcomes of Non-Small Cell Lung Cancer (NSCLC) during radiotherapy or chemo-radiotherapy. A systematic review.

BACKGROUND: Non-Small Cell Lung Cancer (NSCLC) is characterized by aggressiveness and includes the majority of thorax malignancies. The possibility of early stratification of patients as responsive and non-responsive to radiotherapy with a non-invasive method is extremely appealing. The distribution of the Fluorodeoxyglucose (18F-FDG) in tumours, provided by Positron-Emission-Tomography (PET) images, has been proved to be useful to assess the initial staging of the disease, recurrence, and response to chemotherapy and chemo-radiotherapy (CRT). OBJECTIVES: In the last years, particular efforts have been focused on the possibility of using ad interim 18F-FDG PET (FDGint) to evaluate response already in the course of radiotherapy. However, controversial findings have been reported for various malignancies, although several results would support the use of FDGint for individual therapeutic decisions, at least in some pathologies. The objective of the present review is to assemble comprehensively the literature concerning NSCLC, to evaluate where and whether FDGint may offer predictive potential. METHODS: Several searches were completed on Medline and the Embase database, combining different keywords. Original papers published in the English language from 2005 to 2016 with studies involving FDGint in patients affected by NSCLC and treated with radiation therapy or chemo-radiotherapy only were chosen. RESULTS: Twenty-one studies out of 970 in Pubmed and 1256 in Embase were selected, reporting on 627 patients. CONCLUSION: Certainly, the lack of univocal PET parameters was identified as a major drawback, while standardization would be required for best practice. In any case, all these papers denoted FDGint as promising and a challenging examination for early assessment of outcomes during CRT, sustaining its predictivity in lung cancer.

Therapeutic schemes in 177Lu and 90Y-PRRT: radiobiological considerations.

BACKGROUND: The purpose of this work is to implement a radiobiological model to compare different treatment schedules for Peptide Receptor Radionuclide Therapy (PRRT) with 177Lu and 90Y. The principal radiobiological quantities were studied as a function of radionuclides, fractionation schemes, activity distribution in kidneys and tumor radiosensitivity. METHODS: Clinical data were used to derive representative absorbed doses for several treatment schemes for 177Lu-PRRT and for 90Y-PRRT and considered as input data for the radiobiological model. Both uniform and non-uniform activity distributions were considered for kidneys and cortex; for tumors a possible uptake reduction after each cycle and inter-patient radiosensitivity variability were investigated. Normal-Tissue-Complication-Probability (NTCP) and Tumor-Control-Probability (TCP) were evaluated. RESULTS: Hyper-cycling has a limited advantage in terms of BED reduction on kidneys for 177Lu, while for 90Y the effect is sizable and helps in reducing the NTCP. For all 177Lu-schemes the renal toxicity risk is negligible while for some 90Y-schemes the NTCP is not null. In case of tumor uptake reduction with cycles the treatment efficacy is reduced with a BED loss up to 46%. The TCP decreases when assuming normally-distributed tumor radiosensitivity values. CONCLUSIONS: This paper discusses how the combination of dosimetry and radiobiological modeling may help in exploring the link between the treatment schedule and the potential clinical outcome. The results highlight the capability of model to reproduce the available clinical data and provide useful qualitative information. Further investigation on dose distribution and dose uptake reduction with accurate clinical data is needed to progress in this field.

A PET-Surrogate Signature for the Interrogation of the Metabolic Status of Breast Cancers.

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.

Peptide receptor radionuclide therapy with 177Lu- or 90Y-SSTR peptides in malignant pheochromocytomas (PCCs) and paragangliomas (PGLs): results from a single institutional retrospective analysis.

BACKGROUND: Malignant pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare tumors and available systemic therapies are limited. AIM: 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). METHODS: 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. RESULTS: 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%) had locally advanced and fourteen (47%) had metastatic disease. Twenty-seven (90%) patients had disease progression at baseline. Four (13%) patients were treated with 90Y, sixteen (53%) with 177Lu and ten (33%) with 90Y + 177Lu respectively. The median total cumulative activity from treatment with 90Y- alone was 9.45 GBq (range 5.11-14.02 GBq), from 177Lu- alone was 21.9 GBq (7.55-32.12 GBq) and from the combination treatment was 4.94 GBq from 90Y- and 6.83 GBq from 177Lu- (ranges 1.04-10.1 and 2.66-20.13 GBq, respectively). Seven out of 30 (23%) patients had partial response and 19 (63%) stable disease. Median follow up was 8.9 years (IQR: 2.9-12). The 5-y and 10-y PFS was 68% (95% CI: 48-82) and 53% (95% CI: 33-69), respectively, whereas 5-y and 10-y OS was 75% (95% CI: 54-87) and 59% (95% CI: 38-75), respectively. Grade 3 or 4 acute hematological toxicity occurred in three patients, two with leucopenia and one with thrombocytopenia, respectively. CONCLUSION: PRRT with 177Lu- or 90Y-DOTA-TATE or -TOC is feasible and well tolerated in advanced PGLs and PCCs.

Investigation of 90Y-avidin for prostate cancer brachytherapy: a dosimetric model for a phase I-II clinical study.

PURPOSE: A novel method for prostate irradiation is investigated. Similarly to (125)I or (103)Pd seed brachytherapy, (90)Y-avidin could be injected via the perineum under ultrasound image guidance. This study inspects the theoretical feasibility with a dosimetric model based on Monte Carlo simulation. METHODS: A geometrical model of the prostate, urethra and rectum was designed. The linear-quadratic model was applied to convert (125)I absorbed dose prescription/constraints into (90)Y dose through biological effective dose (BED) calculation. The optimal (90)Y-avidin injection strategy for the present model was obtained. Dose distribution was calculated by Monte Carlo simulation (PENELOPE,GEANT4). Dose volume histograms (DVH) for the prostate, urethra and rectum were compared to typical DVHs of (125)I seed brachytherapy, used routinely in our institute. RESULTS: With (90)Y-avidin, at least 95% of the prostate must receive more than 70 Gy. The absorbed dose to 10% of the urethra (D(10%_urethra)) and the maximum absorbed dose to the rectum (D(max_rectum)) must be lower than 122 Gy. For the present model, the optimum strategy consists in multiple injections of (90)Y-avidin 50 µl drops, for a total volume of 3.1 ml. The minimum activity to deliver the prescribed absorbed dose is 0.7 GBq, which also fully respects urethral and rectal constraints. The resulting dose map has a maximum in the central region with a sharp decrease towards the urethra and the prostate edge. Notably, D(10%_urethra) is 95 Gy and D(max_rectum) is below 2 Gy. Prostate absorbed dose is higher with (90)Y-avidin than (125)I seeds, although the total volume receiving the prescribed absorbed dose is 1-2% lower. Urethral DVH strictly depends on the (90)Y distribution, to be optimized according to prostate shape; in our model, BED(30%_urethra) is 90 Gy with (90)Y-avidin, whereas for patients receiving (125)I seeds it ranges between 150 and 230 Gy. The rectal DVH is always more favourable with (90)Y. CONCLUSION: The methodology is theoretically feasible and can deliver an effective treatment in T1-T2 prostate cancer. Pharmacokinetic and biodistribution studies in prostate cancer patients are needed for validation.

First Live-Experience Session with PET/CT Specimen Imager: A Pilot Analysis in Prostate Cancer and Neuroendocrine Tumor.

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 µSv). CONCLUSIONS: the image acquisition of specimens obtained by patients who received intra-surgery injections 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.

Gene expression profiling and FDG-PET radiomics uncover radiometabolic signatures associated with outcome in DLBCL.

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.

3D dosimetry in patients with early breast cancer undergoing Intraoperative Avidination for Radionuclide Therapy (IART) combined with external beam radiation therapy.

PURPOSE: Intraoperative Avidination for Radionuclide Therapy (IART) is a novel targeted radionuclide therapy recently used in patients with early breast cancer. It is a radionuclide approach with (90)Y-biotin combined with external beam radiotherapy (EBRT) to release a boost of radiation in the tumour bed. Two previous clinical trials using dosimetry based on the calculation of mean absorbed dose values with the hypothesis of uniform activity distribution (MIRD 16 method) assessed the feasibility and safety of IART. In the present retrospective study, a voxel dosimetry analysis was performed to investigate heterogeneity in distribution of the absorbed dose. The aim of this work was to compare dosimetric and radiobiological evaluations derived from average absorbed dose vs. voxel absorbed dose approaches. METHODS: We evaluated 14 patients who were injected with avidin into the tumour bed after conservative surgery and 1 day later received an intravenous injection of 3.7 GBq of (90)Y-biotin (together with 185 MBq (111)In-biotin for imaging). Sequential images were used to estimate the absorbed dose in the target region according to the standard dosimetry method (SDM) and the voxel dosimetry method (VDM). The biologically effective dose (BED) distribution was also evaluated. Dose/volume and BED volume histograms were generated to derive equivalent uniform BED (EUBED) and equivalent uniform dose (EUD) values. RESULTS: No "cold spots" were highlighted by voxel dosimetry. The median absorbed-dose in the target region was 20 Gy (range 15-27 Gy) by SDM, and the median EUD was 20.4 Gy (range 16.5-29.4 Gy) by the VDM; SDM and VDM estimates differed by about 6 %. The EUD/mean voxel absorbed dose ratio was >0.9 in all patients, indicative of acceptable uniformity in the target. The median BED and EUBED values were 21.8 Gy (range 15.9-29.3 Gy) and 22.8 Gy (range 17.3-31.8 Gy), respectively. CONCLUSION: VDM highlighted the absence of significant heterogeneity in absorbed dose in the target. The EUD/mean absorbed dose ratio indicated a biological efficacy comparable to that of uniform distribution of absorbed dose. The VDM is recommended for improving accuracy, taking into account actual activity distribution in the target region. The radiobiological model applied allowed us to compare the effects of IART® with those of EBRT and to match the two irradiation modalities.

Personalized Dosimetry in Targeted Radiation Therapy: A Look to Methods, Tools and Critical Aspects.

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.

Dosimetric Approaches for Radioimmunotherapy of Non-Hodgkin Lymphoma in Myeloablative Setting.

Radioimmunotherapy (RIT) is a safe and active treatment available for non-Hodgkin lymphomas (NHLs). In particular, two monoclonal antibodies raised against CD20, that is Zevalin (90Y-ibritumomab-tiuxetan) and Bexxar (131I-tositumomab) received FDA approval for the treatment of relapsing/refractory indolent or transformed NHLs. RIT is likely the most effective and least toxic anticancer agent in NHLs. However, its use in the clinical setting is still debated and, in case of relapse after optimized rituximab-containing regimens, the efficacy of RIT at standard dosage is suboptimal. Thus, clinical trials were based on the hypothesis that the inclusion of RIT in myeloablative conditioning would allow to obtain improved efficacy and toxicity profiles when compared to myeloablative total-body irradiation and/or high-dose chemotherapy regimens. Standard-activity RIT has a safe toxicity profile, and the utility of pretherapeutic dosimetry in this setting can be disputed. In contrast, dose-escalation clinical protocols require the assessment of radiopharmaceutical biodistribution and dosimetry before the therapeutic injection, as dose constrains for critical organs may be exceeded when RIT is administered at high activities. The aim of the present study was to review and discuss the internal dosimetry protocols that were adopted for non-standard RIT administration in the myeloablative setting before hematopoietic stem cell transplantation in patients with NHLs.

Peptide receptor radionuclide therapy with ¹77Lu-DOTATATE: the IEO phase I-II study.

PURPOSE: Peptide receptor radionuclide therapy (PRRT) is used in tumours expressing type 2 somatostatin receptors (sst(2)), mainly neuroendocrine. The aim of this prospective phase I-II study was to evaluate the toxicity and efficacy of (177)Lu-DOTATATE in multiple cycles. METHODS: Fifty-one consecutive patients with unresectable/metastatic sst(2)-positive tumours, divided into two groups, received escalating activities (3.7-5.18 GBq/cycle, group 1; 5.18-7.4 GBq/cycle, group 2) of (177)Lu-DOTATATE. Cumulative activities ranged from 3.7 to 29.2 GBq (median 26.4 GBq in median 6 cycles, group 1, 21 patients) and 5.55 to 28.9 GBq (median 25.2 GBq in 4 cycles, group 2, 30 patients), based on dosimetry. RESULTS: No major acute or delayed renal or haematological toxicity occurred (one grade 3 leukopenia and thrombocytopenia). Cumulative renal absorbed doses were 8-37 Gy (9-41 Gy bioeffective doses). A median decrease of creatinine clearance of 21.7% 6 months after PRRT, 23.9% after 1 year and 27.6% after 2 years was observed. Higher losses (>20%) occurred in patients with risk factors for renal toxicity, particularly hypertension and diabetes. Cumulative bone marrow doses were <1.5 Gy. Blood elements showed a progressive mild drop during cycles and recovered during follow-up (median 30 months). Thirty-nine patients were progressive at enrolment. Partial and complete responses occurred in 15 of 46 (32.6%) assessable patients. The median time to progression was 36 months. Overall survival was 68% at 36 months. Non-responders and patients with extensive tumour involvement had lower survival. CONCLUSION: (177)Lu-DOTATATE was well tolerated up to 29 GBq cumulative activity (up to 7.4 GBq/cycle). The maximum tolerated dose/cycle was not reached. However, considering the individual bone marrow function and the presence of risk factors for kidney toxicity, it seems safer to divide cumulative activities into lower activity cycles.

A multiple points method for 4D CT image sorting.

PURPOSE: Artifacts affect 4D CT images due to breathing irregularities or incorrect breathing phase identification. The purpose of this study is the reduction of artifacts in sorted 4D CT images. The assumption is that the use of multiple respiratory related signals may reduce uncertainties and increase robustness in breathing phase identification. METHODS: Multiple respiratory related signals were provided by infrared 3D localization of a configuration of markers placed on the thoracoabdominal surface. Multidimensional K-means clustering was used for retrospective 4D CT image sorting, which was based on multiple marker variables, in order to identify clusters representing different breathing phases. The proposed technique was tested on computational simulations, phantom experimental acquisitions, and clinical data coming from two patients. Computational simulations provided a controlled and noise-free condition for testing the clustering technique on regular and irregular breathing signals, including baseline drift, time variant amplitude, time variant frequency, and end-expiration plateau. Specific attention was given to cluster initialization. Phantom experiments involved two moving phantoms fitted with multiple markers. Phantoms underwent 4D CT acquisition while performing controlled rigid motion patterns and featuring end-expiration plateau. Breathing cycle period and plateau duration were controlled by means of weights leaned upon the phantom during repeated 4D CT scans. The implemented sorting technique was applied to clinical 4D CT scans acquired on two patients and results were compared to conventional sorting methods. RESULTS: For computational simulations and phantom studies, the performance of the multidimensional clustering technique was evaluated by measuring the repeatability in identifying the breathing phase among adjacent couch positions and the uniformity in sampling the breathing cycle. When breathing irregularities were present, the clustering technique consistently improved breathing phase identification with respect to conventional sorting methods based on monodimensional signals. In patient studies, a qualitative comparison was performed between corresponding breathing phases of 4D CT images obtained by conventional sorting methods and by the described clustering technique. Artifact reduction was clearly observable on both data set especially in the lower lung region. CONCLUSIONS: The implemented multiple point method demonstrated the ability to reduce artifacts in 4D CT imaging. Further optimization and development are needed to make the most of the availability of multiple respiratory related variables and to extend the method to 4D CT-PET hybrid scan.

First Ex Vivo Results of ß--Radioguided Surgery in Small Intestine Neuroendocrine Tumors with 90Y-DOTATOC.

Background: In neuroendocrine tumor (NET), complete surgery could better the prognosis. Radioguided surgery (RGS) with ß--radioisotopes is a novel approach focused on developing a new probe that, detecting electrons and operating with low background, provides a clearer delineation of the lesions with low radiation exposition for surgeons. As a first step to validate this procedure, ex vivo specimens of tumors expressing somatostatin receptors, as small intestine neuroendocrine tumor (SI-NET), were tested. Materials and Methods: SI-NET presents a high uptake of a beta-emitting radiotracer, 90Y-DOTATOC. Five SI-NET patients were enrolled after performing a 68Ga-DOTATOC positron emission tomography/computed tomography (CT) and a CT enterography; 24 h before surgery, they received 5 mCi of 90Y-DOTATOC. Results: Surgery was performed as routine. Tumors and surrounding tissue were sectioned in different samples and examined ex vivo with the beta-detecting probe. All the tumor samples showed high counts of radioactivity that was up to a factor of 18 times higher than the corresponding cutoff value, with a sensitivity of 96% and a specificity of 100%. Conclusions: These first ex vivo RGS tests showed that this probe can discriminate very effectively between tumor and healthy tissues by the administration of low activities of 90Y-DOTATOC, allowing more precise surgery.

Sentinel node detection by lymphoscintigraphy and sentinel lymph node biopsy in vulvar melanoma.

PURPOSE: Vulvar melanoma is a rare malignant tumour. Its surgical excision is the mainstay of treatment whilst the surgical management of regional lymph nodes remains controversial; on the contrary elective inguinofemoral lymphadenectomy causes considerable morbidity. Lymphoscintigraphy (LS) and sentinel lymph node biopsy (SLNB) are accurate staging procedures of lymph node status in breast cancer and cutaneous melanoma patients. In this retrospective paper we report our experience of LS and SLNB in vulvar melanoma patients. METHODS: Twenty-two consecutive patients with a diagnosis of vulvar melanoma were treated at our institute: patients with clinically positive groin nodes or with previous surgery on the primary tumour were excluded. Twelve were selected for our analysis. All patients underwent sentinel lymph node localization with LS the day before surgery and the surgical procedure of SLNB associated with radical surgery. RESULTS: Six patients had metastatic SLNB and in five of six (83.3%) it was the only positive node. In the other six patients SLNB was negative for metastatic disease. No skip metastases were observed. In SLNB negative patients the mean Breslow thickness was 2.06 mm (range: 0.60-7.10) and only one patient showed a high Breslow thickness (patient 8). In SLNB positive patients the mean Breslow thickness was 4.33 mm (1.8-6.0). CONCLUSION: Our data indicate that, even in vulvar melanoma, the sentinel lymph node pathological status predicts the pathological status of the remaining groin nodes and suggests that elective groin dissection can be spared in cases of a negative SLNB. Breslow thickness (<1 mm) was not predictive of negative nodes.