Comparison of Digital versus Analog 68Ga-PSMA-11 PET/CT Performance in Hormone-Sensitive Prostate Cancer Patients with Early Biochemical Recurrence or Persistence after Radical Treatment.

The aim of this study was to investigate whether the favorable characteristics of novel digital PET/CT (dPET) scanners compared to analog systems (aPET) could translate into an improved disease localization in prostate cancer (PCa) patients with early biochemical recurrence/persistence (BCR/BCP). A retrospective analysis was conducted on 440 consecutive analog (n = 311) or digital (n = 129) 68Ga-PSMA-11 PET/CT scans performed in hormone-sensitive ADT-free PCa patients with early-BCR/BCP (PSA at PET ≤ 2.0 ng/mL), previously treated with radical intent (radical-prostatectomy/radiotherapy). dPET showed a higher positivity rate compared to aPET (48.8% [63/129] vs. 37.3% [116/311], p = 0.03), despite the slightly lower median PSA value of the dPET cohort (0.33 [IQR: 0.26-0.61] vs. 0.55 [IQR: 0.40-0.85] ng/mL, p < 0.01). dPET detection rate was higher in both PSA ranges 0.2-0.5 ng/mL (39.0% [32/82] vs. 25.2% [34/135], p = 0.03) and 0.5-1.0 ng/mL (63.2% [24/38] vs. 40.8% [53/130], p = 0.02), but not for PSA ≥ 1.0 ng/mL. dPET detected a higher per patient median number of pathologic findings (PSMA-RADS ≥ 3) and multi-metastatic cases (>3 lesions) among N1/M1-positive scans (21.7% [10/46] vs. 8.6% [9/105], p = 0.03). Moreover, the proportion of uncertain findings among pathological lesions was significantly lower for dPET than aPET (24.4% [39/160] vs. 38.5% [60/156], p = 0.008). Overall, 68Ga-PSMA-11 dPET showed a better performance compared to aPET, resulting in a higher scan-positivity rate, a higher number of detected pathological lesions, and a lower rate of uncertain findings.

Machine Learning CT-Based Automatic Nodal Segmentation and PET Semi-Quantification of Intraoperative 68Ga-PSMA-11 PET/CT Images in High-Risk Prostate Cancer: A Pilot Study.

High-resolution intraoperative PET/CT specimen imaging, coupled with prostate-specific membrane antigen (PSMA) molecular targeting, holds great potential for the rapid ex vivo identification of disease localizations in high-risk prostate cancer patients undergoing surgery. However, the accurate analysis of radiotracer uptake would require time-consuming manual volumetric segmentation of 3D images. The aim of this study was to test the feasibility of using machine learning to perform automatic nodal segmentation of intraoperative 68Ga-PSMA-11 PET/CT specimen images. Six (n = 6) lymph-nodal specimens were imaged in the operating room after an e.v. injection of 2.1 MBq/kg of 68Ga-PSMA-11. A machine learning-based approach for automatic lymph-nodal segmentation was developed using only open-source Python libraries (Scikit-learn, SciPy, Scikit-image). The implementation of a k-means clustering algorithm (n = 3 clusters) allowed to identify lymph-nodal structures by leveraging differences in tissue density. Refinement of the segmentation masks was performed using morphological operations and 2D/3D-features filtering. Compared to manual segmentation (ITK-SNAP v4.0.1), the automatic segmentation model showed promising results in terms of weighted average precision (97-99%), recall (68-81%), Dice coefficient (80-88%) and Jaccard index (67-79%). Finally, the ML-based segmentation masks allowed to automatically compute semi-quantitative PET metrics (i.e., SUVmax), thus holding promise for facilitating the semi-quantitative analysis of PET/CT images in the operating room.

Cost-effectiveness analysis of personalised versus standard dosimetry for selective internal radiation therapy with TheraSphere in patients with hepatocellular carcinoma.

Aims: To perform a cost-effectiveness analysis (CEA) comparing personalised dosimetry with standard dosimetry in the context of selective internal radiation therapy (SIRT) with TheraSphere for the management of adult patients with locally advanced hepatocellular carcinoma (HCC) from the Italian Healthcare Service perspective. Materials and methods: A partition survival model was developed to project costs and the quality-adjusted life years (QALYs) over a lifetime horizon. Clinical inputs were retrieved from a published randomised controlled trial. Health resource utilisation inputs were extracted from the questionnaires administered to clinicians in three oncology centres in Italy, respectively. Cost parameters were based on Italian official tariffs. Results: Over a lifetime horizon, the model estimated the average QALYs of 1.292 and 0.578, respectively, for patients undergoing personalised and standard dosimetry approaches. The estimated mean costs per patient were €23,487 and €19,877, respectively. The incremental cost-utility ratio (ICUR) of personalised versus standard dosimetry approaches was €5,056/QALY. Conclusions: Personalised dosimetry may be considered a cost-effective option compared to standard dosimetry for patients undergoing SIRT for HCC in Italy. These findings provide evidence for clinicians and payers on the value of personalised dosimetry as a treatment option for patients with HCC.

The role of PET/CT in thyroid autoimmune diseases.

Autoimmune thyroid diseases (AITD) are a heterogeneous group of disorders. They include, in particular, Graves' disease and Hashimoto's thyroiditis with a wide range of different functional status ranging from subclinical biochemical abnormalities to severe hyperthyroidism or severe hypothyroidism respectively. Furthermore, other conditions more frequently infectious or drug related can cause an immune reaction in the thyroid tissue. In AITDs, positron emission tomography/computed tomography (PET/CT) does not play a primary role for disease diagnosis or management, but accidental findings can occur in both symptomatic and asymptomatic patients, and they should be recognized and well interpreted. A comprehensive literature search of the PubMed databases was conducted to identify papers (systematic review, prospective and retrospective study, case report) evaluating the role of PET/CT in thyroid autoimmune diseases. Thyroid diffuse uptake of 18F-fluoro-2-deoxy-2-d-glucose ([18F]FDG) has been shown to be frequently associated with AITDs, but also with immune-induced thyroid disorders related to SARS-CoV-2 or immunotherapy, while malignant lesions more often have a focal aspect. Other radiopharmaceuticals as [68Ga]-DOTA-peptides, [68Ga]-fibroblast activation protein inhibitors (FAPIs) and [68Ga]-prostate specific membrane antigen ([68Ga]-PSMA) showed similar findings. In conclusion, PET/CT scan in AITDs does not play a primary role in the diagnosis, but the occasional finding of a thyroid uptake must always be described in the report and possibly investigated for a better patient's management.

Impact of radioguided occult lesion localization in the management of cervical recurrences from differentiated thyroid cancer.

BACKGROUND: Surgery is the elective treatment for cervical relapse from differentiated thyroid cancer (DTC) but it is technically challenging, with risk of failure and morbidity. We explored the feasibility and the efficacy of radioguided occult lesion localization (ROLL) with intratumoral 99mTc radiolabeled human albumin macroaggregates ([99mTc]MAA) injection in this setting. METHODS: Fifteen patients who underwent ROLL by ultrasonography (US)-guided intratumoral injection of [99mTc]MAA between December 2013 and October 2016 for DTC recurrence were considered for this study. A hand-held gamma-probe was employed for intrasurgical lesion detection. Mini-invasive ROLL-guided excision for soft tissue recurrence and ROLL-assisted modified radical neck dissection for lymph-node metastases were performed respectively. RESULTS: DTC recurrence was located in loco-regional lymph-nodes (N.=8 patients) and in thyroid bed (N.=7 patients). A total of 27 lesions was identified and injected before surgery. On a total of 124 lesions resected, histology showed 38 DTC metastases. In particular, 26 out of 27 lesions injected with [99mTc]MAA were correctly detected intra-operatively and resected without surgical complications. Ten patients received subsequent radioactive iodine (RAI) treatment to verify the complete recurrence resection. At a median follow-up of 16 months patients were classified in complete response (N.=4), biochemical incomplete response (N.=3), indeterminate response (N.=1) with no evidence of structural disease. The remaining 7 patients were classified as structural incomplete response for cervical persistent disease (N.=2), for cervical recurrence (N.=2) and for both cervical and lung metastases progression (N.=3). CONCLUSIONS: ROLL is a simple and safe procedure in the surgical management of DTC loco-regional relapse.

Imaging medullary thyroid cancer patients with detectable serum markers: state of the art and future perspectives.

PURPOSE: Medullary thyroid carcinoma (MTC) originates from thyroid parafollicular C-cells and represents <5% of all thyroid cancers. Serum Calcitonin (CTn) is considered the most sensitive marker of persistent or recurrent disease and is measured in association to CEA. According to the American Thyroid Association (ATA) guidelines, following initial surgery when CTn level remains below 150 pg/mL, follow-up may rely on repeated serum marker determinations and on neck ultrasonography (US). When CTn level exceeds 150 pg/ml, additional imaging is required. In this review, we provide an overview of available imaging tools to monitor MTC course and propose an effective imaging strategy for MTC patients according to their clinical situation. METHODS: A literature search focusing on available imaging tools to monitor MTC provided the currently available information for this review. Recent evidence-based reports and reviews were considered as priority over older evidence. RESULTS: For MTC patients with detectable CTn levels and disease recurrence, PET/CT imaging with 18F-DOPA or 68Ga-DOTA-peptides present the best sensitivity for lesion detection. 18F FDG PET/CT represents a prognostic tool and is useful in case of aggressive disease. Neck ultrasound, chest CT scan and MRI of the liver and of the axial skeleton represent complementary techniques. Beyond the diagnostic accuracy, the clinical impact of imaging is variable according to different disease settings and tumor marker levels. Finally, other applications of imaging such as response to focal and systemic treatments and new promising PET tracers should be further investigated. CONCLUSION: The role of imaging in MTC patients improved, especially with the use of 18F-DOPA PET/CT that provides high quality diagnostic images. However, the impact on therapeutic management should be further evaluated in the different disease settings and in proper prospective trials.

Predictive factors of a worse response to radioactive Iodine-I131 treatment in hyperthyroidism: outcome analysis in 424 patients. A single centre experience.

PURPOSE: Aim of our study was to search for variables associated with worse outcomes in patients treated with radioactive iodine (RAI) for hyperthyroidism by a dosimetric-based approach. METHODS: Four hundred twenty-four patients with hyperthyroidism related to Toxic Multinodular Goiter (TMG; n = 213), Grave's disease (GD; n = 150) and toxic adenoma (TA; n = 61) treated with RAI between 2000 and 2018 and with at least 12 months follow-up were retrospectively evaluated. Association between outcomes (response vs. no response) at 6 and 12 months and baseline TSH values, anti-thyroid drugs (ATD) duration and posology, RAI absorbed dose and dimensional reduction of target mass at ultrasound was evaluated by Mann-Whitney test. Risk factors for response vs. no-response were analysed by binary logistic regression model. RESULTS: Overall response rate was 78.7 and 83% at 6 and 12 months, respectively. Both at 6 and 12 months higher TSH baseline values (p < 0.001), lower ATD duration (p = 0.004 and p = 0.043), lower ATD posology (p = 0.014 and p = 0.005), and lower dose to target (DT) (327 vs. 373 Gy, p = 0.003) were associated to response. Longer ATD duration and higher ATD posology were independent risk factors for no response at 6 and 12 months in GD and TMG, with no response at 6 months in TA subgroups. CONCLUSIONS: Low TSH levels, longer duration and higher posology of ATD were associated with worse response to RAI. These data confirm that RAI therapy should be considered earlier in patients' management to allow better outcome and avoid ATD toxicity.

The Challenge of Evaluating Response to Peptide Receptor Radionuclide Therapy in Gastroenteropancreatic Neuroendocrine Tumors: The Present and the Future.

The NETTER-1 study has proven peptide receptor radionuclide therapy (PRRT) to be one of the most effective therapeutic options for metastatic neuroendocrine tumors (NETs), improving progression-free survival and overall survival. However, PRRT response assessment is challenging and no consensus on methods and timing has yet been reached among experts in the field. This issue is owed to the suboptimal sensitivity and specificity of clinical biomarkers, limitations of morphological response criteria in slowly growing tumors and necrotic changes after therapy, a lack of standardized parameters and timing of functional imaging and the heterogeneity of PRRT protocols in the literature. The aim of this article is to review the most relevant current approaches for PRRT efficacy prediction and response assessment criteria in order to provide an overview of suitable tools for safe and efficacious PRRT.

Hyperglycemia and 18F-FDG PET/CT, issues and problem solving: a literature review.

Positron emission tomography/computed tomography (PET/CT) is a standard procedure for imaging cancer commonly used in the clinical practice for several diseases, in particular for cancer staging, restaging, treatment monitoring and radiation therapy planning. Despite the availability of many radiotracers, 18F-fluoro-2-deoxy-2-D-glucose ([18F]FDG) is the most used. International PET/CT guidelines propose protocols for patients' correct preparation before [18F]FDG injection, in particular with the regard of diabetic patients and therapy management. Hyperglycemic conditions and oral or insulin medication showed advantages and disadvantages on PET/CT scan accuracy: A correct knowledge of effects of these conditions on glucose metabolism assumes a fundamental role on patients management before [18F]FDG PET/CT scan.

68Ga-Prostate-Specific Membrane Antigen 11 PET/CT Detects Residual Glioblastoma After Radical Surgery in a Patient With Synchronous Recurrent Prostate Cancer: A Case Report.

Prostate-specific membrane antigen (PSMA) is a transmembrane enzyme also known as folate hydrolase 1 highly expressed by prostate cancer (PCa) cells. However, PSMA overexpression by tumor-associated neovasculature of a variety of solid tumors, including glioblastoma (GBM), has also been proven. This clinical case reports about a 67-year-old man with a history of PCa who underwent radical surgery for GBM and performed a Ga-PSMA-11 PET/CT to restage PCa. PET imaging showed PSMA uptake in GBM residual disease after surgery. This finding suggests a possible role of PSMA inhibitors as diagnostic and therapeutic agents in patients affected by GBM.

Major limits of dosimetrically determined activities in advanced differentiated thyroid carcinoma.

The 2013/59 EURATOM directive defines all nuclear medicine applications for therapeutic purpose as a form of radiotherapy and underlines the need of both justification and optimization of these procedures, including radioactive iodine therapy (RAIT) with [131I] for metastatic differentiated thyroid cancer (DTC). In metastatic DTC, optimal activity to be administered to achieve the best response rate with limited toxicity is still a matter of debate and international guidelines do not provide univocal recommendations on the preferable use of empiric versus a dosimetry-based approach in these patients. The purpose of this literature review is to describe the possible limits of dosimetry in RAIT planning according to methodological aspects, tumoral heterogeneity and to report clinical data on the impact on patients' outcome of different approaches. Due to the lack of standardized dosimetry protocols and clinical data assessing the superiority of a dosimetry-based vs an empiric approach in these patients, there is a need of standardisation and prospective, properly conducted studies to validate and to assess the best approach.

68Ga-DOTA-TOC PET/CT of von Hippel-Lindau Disease.

We present a rare case of a 42-year-old man with a long history of von Hippel-Lindau disease that was scanned with Ga-DOTA-TOC PET/CT for suspicion of disease relapse. Ga-DOTA-TOC imaging demonstrated increased DOTA-TOC uptake in pancreas tail and intramedullary and extramedullary spinal hemangioblastomas, only some of which have already been highlighted at MRI examination. This case illustrates the significant role the Ga-labeled somatostatin receptor analogs PET/CT in the management of the von Hippel-Lindau disease.

Interventional locoregional treatment and metabolic response: advantages of using PET/CT in the evaluation of response to treatment.

INTRODUCTION: Interventional oncology locoregional therapies are validated treatment modalities for primary and secondary tumors in liver, lung, kidney and bone. At this time, there is no accordance in the choice of imaging modality to assess treatment response. Morphological imaging and RECIST 1.1 criteria based on size variation are limited by several critical points. On the other hand the role of functional imaging, in particular by [18F]-fluorodeoxyglucose ([18F]-FDG) positron emission tomography (PET), in both staging and response evaluation of locoregional treatments remains unclear because of the heterogeneous nature of available data. The aim of this paper was to summarize the available literature illustrating the state of art of metabolic evaluation of response after locoregional therapies in the three major organs of interest: liver, lung and bone. EVIDENCE ACQUISITION: Medline database was searched for relevant original paper evaluating the role of [18F]-FDG PET in interventional oncology treatment published up to June 2017 excluding case reports. EVIDENCE SYNTHESIS: Finally 41 studies papers evaluating the role of [18F]-FDG PET in both staging and in response evaluation of locoregional treatments focused on liver tumoral lesions (N.=29), on lung lesions (N.=10) and on bone lesions (N.=2) were considered for this review. CONCLUSIONS: PET/CT appears to perform well in the assessment of response to interventional therapies compared to conventional imaging, not only in terms of response evaluation but also as a possible prognostic tool. Nevertheless further prospective, homogenous studies are required to confirm these data, in particular for lung and bone lesions.

Calculation of tumour and normal tissue biological effective dose in 90Y liver radioembolization with different dosimetric methods.

PURPOSE: Radioembolization with 90Y microspheres is an effective treatment for unresectable liver tumours. Two types of microspheres are available: resin (SIR-Spheres®) and glass (Theraspheres®). The aim of this study is to compare biological effective dose (BED) values obtained with three different dosimetric methods. METHODS: 29 HCC patients were included in this study: 15 were treated with resin(mean injected activity 1.5GBq, range 0.8-2.7GBq) and 14 with glass microspheres (2.6GBq, range 1.3-4.1GBq). Average doses to tumours and normal liver tissues were calculated with AAPM, multi-compartmental MIRD and Voxel-based methods and consequently the BED values were obtained. Planar images were used for the AAPM method: 99mTc-MAA SPECT-CT attenuation and scatter corrected images (resin) and 99m Tc-MAA SPECT attenuation corrected (glass) were employed for the other two methods. RESULTS: Regardless of type of microspheres, both for tumours and normal liver tissues, no significant statistical differences were found between MIRD and Voxel for both doses and BED values. Conversely AAPM gave discordant results with respect to the other two methods (Mann-Whitney p-values⩽0.01). For resin spheres the calculated tumour-to-normal tissue ratios on planar images were on average 14 times greater than those obtained on SPECT-CT images, while they were 4 times greater on glass. A linear correlation was observed between MIRD and Voxel BEDs. CONCLUSIONS: The AAPM method appears to be less precise for absorbed dose and BED estimation, while MIRD and voxel based dosimetry are more confident each other.

99mTc-MIBI Imaging in the presurgical characterization of thyroid follicular neoplasms: relationship to multidrug resistance protein expression.

UNLABELLED: Recently, thyroid (99m)Tc-methoxyisobutylisonitrile ((99m)Tc-MIBI) scintiscanning has been proposed in an attempt to preoperatively identify thyroid malignancies, but discrepant results have been reported for oncocytic lesions. The aim of this study was to investigate the usefulness of visual and semiquantitative analyses of (99m)Tc-MIBI scintigraphy for preoperatively characterizing thyroid nodules with indeterminate cytologic diagnoses, segregating in advance nononcocytic variants from those that are oncocytic. This study also aimed to analyze the relationship between (99m)Tc-MIBI images and P-glycoprotein (P-gp)/multidrug resistance-associated protein-1 (MRP1) immunohistochemical expression. METHODS: Fifty-one consecutive patients with cold thyroid nodules cytologically diagnosed as nononcocytic or oncocytic follicular neoplasm were prospectively studied. Visual and semiquantitative (99m)Tc-MIBI scanning was performed and the diagnoses of the lesions were histologically proven by subsequent thyroidectomy. Immunohistochemical evaluation of P-gp and MRP1 was also performed on surgical samples. RESULTS: Visual and semiquantitative (99m)Tc-MIBI scintiscans showed a low specificity in preoperatively discriminating malignant oncocytic lesions. In nononcocytic nodules, the semiquantitative method was more accurate than the visual (94.44% and 77.78%, respectively). P-gp protein expression was negative in all thyroid lesions, whereas apical plasma membrane MRP1 expression was found in 78% of the lesions with a negative (99m)Tc-MIBI retention index, compared with 11% of lesions with a positive retention index, correlating most strongly with a negative (99m)Tc-MIBI RI in those cases with strong MRP1 apical expression. CONCLUSION: Semiquantitative (99m)Tc-MIBI scintigraphy is an adjunctive method to predict preoperatively the malignant behavior of nononcocytic follicular thyroid nodules indeterminate at fine-needle aspiration biopsy, with a potential impact on the definition of their clinical management. Moreover, the good correlation found between immunohistochemical apical expression of MRP1 and the scintigraphic findings supports the (99m)Tc-MIBI results and provides tissue information on the molecular mechanisms responsible for (99m)Tc-MIBI images in thyroid lesions.