PRRT: identikit of the perfect patient.

Peptide receptor radionuclide therapy (PRRT) has been strengthened since the publication of NETTER-1. Nevertheless, the correct positioning in the therapeutic algorithm is debated, and no optimal sequence has yet been standardized. Possible criteria to predict the response to PRRT in neuroendocrine tumors (NET) have been proposed. The aim of this review is to define the perfect identity of the eligible patient who can mostly benefit from this therapy. Possible predictive criteria which have been analysed were: primary tumor site, grading, tumor burden, FDG PET and 68Ga-PET uptake. Primary tumor site and 68Ga-PET uptake do not play a pivotal role in predicting the response, while tumor burden, FDG PET uptake and grading seem to represent predictive/prognostic factors for response to PRRT. The heterogeneity in trial designs, patient populations, type of radionuclides, previous therapies and measurement of outcomes, inevitably limits the strength of our conclusions, therefore care must be taken in applying these results to clinical practice. In conclusion, the perfect patient, selected by 68Ga-PET uptake, will likely have a relatively limited liver tumor burden, a ki67 index <20% and will respond to PRRT irrespective to primary tumor. Nevertheless, we have mostly prognostic than predictive factors to predict the efficacy of PRRT in individual patients, while a promising tool could be the NETest. However, to date, the identikit of the perfect patient for PRRT is a puzzle without some pieces and still we cannot disregard a multidisciplinary discussion of the individual case to select the patients who will mostly benefit from PRRT.

Impact of the SARS-CoV2 pandemic dissemination on the management of neuroendocrine neoplasia in Italy: a report from the Italian Association for Neuroendocrine Tumors (Itanet).

INTRODUCTION: The organization of the healthcare system has significantly changed after the recent COVID-19 outbreak, with a negative impact on the management of oncological patients. The present survey reports data collected by the Italian Association for Neuroendocrine Tumors on the management of patients with neuroendocrine neoplasia (NEN) during the pandemic dissemination. METHODS: A survey with 57 questions was sent to NEN-dedicated Italian centers regarding the management of patients in the period March 9, 2020, to May 9, 2020 RESULTS: The main modification in the centers' activity consisted of decreases in newly diagnosed NEN patients (- 76.8%), decreases in performed surgical procedures (- 58%), delays to starting peptide receptor radionuclide therapy (45.5%), postponed/canceled follow-up examinations (26%), and canceled multidisciplinary teams' activity (20.8%). A low proportion of centers (< 10%) reported having to withdraw systemic anti-tumor medical treatment due to concerns about the pandemic situation, whereas PRRT was withdrawn from no patients. CONCLUSION: Although the COVID-19 outbreak induced the centers to reduce some important activities in the management of NEN patients, the Italian network was able to provide continuity in care without withdrawing anti-tumor treatment for the majority of patients.

Adaptive behavioural coping strategies as reaction to COVID-19 social distancing in Italy.

OBJECTIVE: Social distancing, as experienced by the Italian population during the COVID-19 outbreak, generated the long-term activation of stress-response in individuals. This has been a crucial opportunity to study the coping strategies that people put in place to adapt their lives and habits to such a unique condition. For this reason, we have investigated both emotion-focused and problem-oriented coping strategies among the Italian population by relating them to other structural factors, such as social, economic and cultural conditions. MATERIALS AND METHODS: More than 140,000 online interviews were collected in Italy from March 22 to April 2, 2020. This large dataset was used to carry out multivariate statistical data analysis with the aim of creating behavioral profiles, starting from coping parameters and other information. This technique has produced an association, showing a good level of statistical significance, between coping strategies and reactions to social distancing, due to the health emergency, during the data collection phase. RESULTS: Two coping indicators - problem-oriented and focused on positive emotions coping strategies - were selected as objective variables in a "decision tree" modelling. The results have shown a link between individual factors (i.e., atmosphere at home) and educational and social factors (i.e., compliance with restrictions during the health emergency). CONCLUSIONS: The reduction of social interaction had quite a significant impact on people's behavior; furthermore, coping strategies have played a crucial role in facing this stressor. For both the selected coping indicators, the best predictor was the atmosphere perceived at home. Moreover, the respondents' previous experiences have played a relevant role in the acceptance of new rules imposed by the government. This information can be useful in planning future social policies, both at national and international level, during such peculiar times.

CT protocol optimisation in PET/CT: a systematic review.

PURPOSE: Currently, no consistent guidelines for CT scans used within PET/CT examinations are available. This systematic review provides an up-to-date overview of studies to answer the following questions: What are the specific CT protocols used in PET/CT? What are the possible purposes of requiring a CT study within a PET/CT scan? Is the CT protocol obtained from a dosimetric optimisation study? MATERIALS AND METHOD: PubMed/MEDLINE, Cochrane Library, Embase and Scopus were systematically searched for relevant studies in accordance with the PRISMA statement. The literature search was conducted from January 2007 until June 2019. Data derived from studies were standardized in order to reduce possible biases, and they were divided into clinically homogeneous subgroups (adult, child or phantom). Subsequently, we divided the CT protocol intents into 3 types (anatomic localization only, attenuation correction only and diagnostic purpose). A narrative approach was used to summarise datasets and to investigate their heterogeneity (due to medical prescription methodology) and their combination in multiseries CT protocols. When weighted computed tomography dose index (CTDIw) was available, we calculated the volumetric computed tomography dose index (CTDIvol) using the pitch value to make the results uniform. Eventually, the correlation between protocol intents and CTDIvol values was obtained using a Kruskal-Wallis one-way ANOVA statistical test. RESULT: Starting from a total of 1440 retrieved records, twenty-four studies were eligible for inclusion in addition to two large multicentric works that we used to compare the results. We analyzed 87 CT protocols. There was a considerable range of variation in the acquisition parameters: tube current-time product revealed to have the most variable range, which was 10-300 mAs for adults and 10-80 mAs for paediatric patients. Seventy percent of datasets presented scans acquired with tube current modulation, 9% used fixed tube current and in 21% of them, this information was not available. Dependence between mean CTDIvol values and protocol intent was statistically significant (p = 0.002). As expected, in diagnostic protocols, there was a statistically significant difference between CTDIvol values of with and without contrast acquisitions (11.68 mGy vs 7.99 mGy, p = 0.009). In 13 out of 87 studies, the optimisation aim was not reported; in 2 papers, a clinical protocol was used; and in 11 works, a dose optimisation protocol was applied. CONCLUSIONS: According to this review, the dose optimisation in PET/CT exams depends heavily on the correct implementation of the CT protocol. In addition to this, considering the latest technology advances (i.e. iterative algorithms development), we suggest a periodic quality control audit to stay updated on new clinical utility modalities and to achieve a shared standardisation of clinical protocols. In conclusion, this study pointed out the necessity to better identify the specific CT protocol use within PET/CT scans, taking into account the continuous development of new technologies.

Radiomic Profiling of Head and Neck Cancer: 18F-FDG PET Texture Analysis as Predictor of Patient Survival.

Background and Purpose: The accurate prediction of prognosis and pattern of failure is crucial for optimizing treatment strategies for patients with cancer, and early evidence suggests that image texture analysis has great potential in predicting outcome both in terms of local control and treatment toxicity. The aim of this study was to assess the value of pretreatment 18F-FDG PET texture analysis for the prediction of treatment failure in primary head and neck squamous cell carcinoma (HNSCC) treated with concurrent chemoradiation therapy. Methods: We performed a retrospective analysis of 90 patients diagnosed with primary HNSCC treated between January 2010 and June 2017 with concurrent chemo-radiotherapy. All patients underwent 18F-FDG PET/CT before treatment. 18F-FDG PET/CT texture features of the whole primary tumor were measured using an open-source texture analysis package. Least absolute shrinkage and selection operator (LASSO) was employed to select the features that are associated the most with clinical outcome, as progression-free survival and overall survival. We performed a univariate and multivariate analysis between all the relevant texture parameters and local failure, adjusting for age, sex, smoking, primary tumor site, and primary tumor stage. Harrell c-index was employed to score the predictive power of the multivariate cox regression models. Results: Twenty patients (22.2%) developed local failure, whereas the remaining 70 (77.8%) achieved durable local control. Multivariate analysis revealed that one feature, defined as low-intensity long-run emphasis (LILRE), was a significant predictor of outcome regardless of clinical variables (hazard ratio < 0.001, P=0.001).The multivariate model based on imaging biomarkers resulted superior in predicting local failure with a c-index of 0.76 against 0.65 of the model based on clinical variables alone. Conclusion: LILRE, evaluated on pretreatment 18F-FDG PET/CT, is associated with higher local failure in patients with HNSCC treated with chemoradiotherapy. Using texture analysis in addition to clinical variables may be useful in predicting local control.

Real-life management and outcome of thyroid carcinoma-related bone metastases: results from a nationwide multicenter experience.

PURPOSE AND PATIENTS: The M.O.S.CA.TI. (Metastases of the Skeleton from CArcinoma of the ThyroId) is a multicenter, retrospective study investigating the real-life outcome and management of bone metastases (BM) in 143 patients (63 M, 80 F; median age 64 years, range 11-87) with differentiated thyroid carcinoma (DTC). RESULTS: Radio-active iodine (RAI) treatment was performed in 131 patients (91.6%), surgical approach and/or external radiotherapy in 68 patients (47.6%), and anti-resorptive bone-active drugs in 32 patients (22.4%; in 31 zoledronate and in one denosumab). At the start of treatment, 24 patients (75.0%) receiving anti-resorptive bone-active drugs had at least one clinical skeletal-related event (SRE) (p < 0.001). One or more clinical SREs (pathological fractures and/or malignant hypercalcemia and/or spinal cord compression) developed in 53 patients (37.1%). Development of SREs was significantly associated with metachronous BM (hazard ratio (HR) 2.04; p = 0.04), localization of BM to cervical spine (HR 3.89; p = 0.01), and lack of avid RAI uptake (HR 2.66; p = 0.02). Thirty-nine patients (27.3%) died in correlation with development of SREs (HR 6.97; p = 0.006) and localization of BM to the hip (HR 3.86; p = 0.02). Moreover, overall mortality was significantly decreased by RAI therapy (HR 0.10; p = 0.02), whereas no significant effects were induced by bone-active drugs (p = 0.36), external radiotherapy (p = 0.54), and surgery (p = 0.43) of BM. CONCLUSIONS: SREs are very frequent in BM from DTC and they impact patient survival. In the real life, the use of bone-active drugs is currently limited to zoledronate in patients with pre-existing SREs. In this clinical setting, RAI therapy, but not zoledronate, decreased mortality.

Spectroscopy analysis of phenolic and sugar patterns in a food grade chestnut tannin.

Tannin of chestnut (Castanea sativa Mill.) wood, commonly used in winemaking was characterised with a spectroscopy qualitative approach that revealed its phenolic composition: several vibrational diagnostic bands assigned using the Attenuated Total Reflectance-Infrared Spectroscopy, and fragmentation patterns obtained using the Laser-Desorption-Ionization Time-of-Flight technique evidenced polygalloylglucose, e.g. castalagin/vescalagin-like structures as the most representative molecules, together with sugar moieties. The implication of these findings on winemaking application and the potential influence of the chemical structure on the sensory properties of wine are discussed.

Somatostatin receptor positron emission tomography/computed tomography imaging in Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is an uncommon aggressive primary cutaneous carcinoma with neuroendocrine differentiation. However, literature data about the use of somatostatin receptor positron emission tomography/computed tomography (PET/CT) imaging in MCC are limited and its role is not clearly stated. OBJECTIVE: To investigate the role of PET/CT using somatostatin analogues radiolabelled with gallium-68 in patients with MCC. METHODS: All patients affected by MCC who performed a somatostatin receptor PET/CT imaging from October 2007 to May 2014 were retrospectively analysed. The diagnostic performances of PET/CT were evaluated on a patient-based analysis and compared to final diagnosis (histology = 3 or clinical/radiological follow-up = 20). RESULTS: We evaluated 23 consecutive MCC patients [18 men; median age 71 years (range 47-87)]. Primary tumour was located in ear (1/23), cheek (3/23), arm (2/23), hand (1/23), back (1/23), anal canal (1/23), gluteus (4/23), thigh (3/23) and popliteal fossa (1/23). In 6/23 patients, the site of primary tumour was unknown. PET/CT was performed to detect primary tumour site (4/23) or to stage (8/23) or re-stage (11/23) patients. PET/CT resulted positive in 14/23 patients and according to the final diagnosis was defined true positive, true negative, false positive (FP) and false negative in 11/23, 8/23, 3/23 and 1/23 cases respectively. FP PET/CT results were due to unspecific liver uptake, post-surgical inflammation and pancreatic neuroendocrine tumour. PET/CT was unable to detect primary tumour site in all patients with unknown primary MCC. Sensitivity, specificity and diagnostic accuracy of PET/CT were 92%, 73% and 83% respectively. CONCLUSIONS: In our experience, somatostatin receptor PET/CT imaging resulted useful in patients with MCC and presented high diagnostic performances with a significant impact in disease management although in patients with unknown primary MCC, it was unable to identify the primary tumour site.

18F-FDG PET/CT focal, but not osteolytic, lesions predict the progression of smoldering myeloma to active disease.

Identification of patient sub-groups with smoldering multiple myeloma (SMM) at high risk of progression to active disease (MM) is an important goal. 18F-FDG PET/CT (positron emission tomography (PET) integrated with computed tomography (PET/CT) using glucose labelled with the positron-emitting radionuclide (18)F) allows for assessing early skeletal involvement. Identification of osteolytic lesions by this technique has recently been incorporated into the updated International Myeloma Working Group criteria for MM diagnosis. However, no data are available regarding the impact of focal lesions (FLs) without underlying osteolysis on time to progression (TTP) to MM. We hence prospectively studied a cohort of 120 SMM patients with PET/CT. PET/CT was positive in 16% of patients (1 FL: 8, 2 FLs: 3, >3 FLs: 6, diffuse bone marrow involvement: 2). With a median follow-up of 2.2 years, 38% of patients progressed to MM, in a median time of 4 years, including 21% with skeletal involvement. The risk of progression of those with positive PET/CT was 3.00 (95% confidence interval 1.58-5.69, P=0.001), with a median TTP of 1.1 versus 4.5 years for PET/CT-negative patients. The probability of progression within 2 years was 58% for positive versus 33% for negative patients. In conclusion, PET/CT positivity significantly increased the risk of progression of SMM to MM. PET/CT could become a new tool to define high-risk SMM.

Applications of PET imaging with radiolabelled choline (11C/18F-choline).

The use of radiopharmaceuticals is the distinguishing characteristics of nuclear medicine. Among the panel of available radiopharmaceuticals in many PET centers around the world, choline is well represented, being widely used to image prostate cancer. Carbon-11 labelled choline can only be produced in centres with a cyclotron available, but the 18F-labelled radiopharmaceutical is distributed and licensed in several countries in Europe. Besides prostate cancer, other possible uses of choline are related to its ability to indirectly evaluate the cell proliferation as a measure of the synthesis of lipids required for cell membrane. In particular, the radiopharmaceutical can be successfully used in those districts where 18F-FDG has a high uptake, like the brain. Moreover, slow growing tumors, not always taking up 18F-FDG, like hepatocellular carcinoma, can also be imaged. We will evaluate possibly uses of this molecule in patients affected by prostate cancer, brain tumors and hepatocellular carcinoma.

Combined imaging approach to diagnose a meningioma in a patient with prostate and lung cancers / Uso combinado de técnicas de imagen para el diagnóstico de meningioma en un paciente con cáncer de próstata y de pulmón

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Quantitative comparison between the commercial software STRATOS(®) by Philips and a homemade software for voxel-dosimetry in radiopeptide therapy.

BACKGROUND: Targeted radionuclide therapy is a rapidly growing modality. A few commercial treatment planning systems are entering the market. However, some in-house systems are currently developed for a more flexible and customized dosimetry calculation at voxel-level. For this purpose, we developed a novel software, VoxelMed, and performed a comparison with the software STRATOS. METHODS: The validation of both of them was undertaken using radioactive phantoms with different volume inserts. A cohort of 10 patients was also studied after a therapeutic administration of (177)Lu-labelled radiopeptides. The activity, number of disintegrations, absorbed dose and dose-volume histogram (DVH) were calculated for the phantoms and the kidneys in patients, which were the main critical organs at risk in this study. RESULTS: In phantoms the absorbed doses computed with VoxelMed and STRATOS agree within 5%. In patients at the voxel-level the absorbed dose to kidneys (VoxelMed: mean 0.66 Gy/GBq) showed a limited difference of 5%, but with a remarkable range (-40%, +60%) between the two software packages. Voxel-dosimetry allows to estimate the dose non-homogeneities in volumes, which may be evaluated through DVHs. CONCLUSION: This study demonstrates that a fully 3D voxel-dosimetry with multiple SPECT images is feasible by using home-made or commercial software package and absorbed dose results obtained are similar. The main difference between the studied tools was observed in the activity integration method (effective vs physical half-time to time activity curve tail). We believe that an effective half-time integration method produces a more accurate approximation of clinical uptake and resultant dosimetry.

The prognostic role of post-induction FDG-PET in patients with follicular lymphoma: a subset analysis from the FOLL05 trial of the Fondazione Italiana Linfomi (FIL).

BACKGROUND: [18F]fluorodeoxyglucose-positron emission tomography (PET) is emerging as a strong diagnostic and prognostic tool in follicular lymphoma (FL) patients. PATIENTS AND METHODS: In a subset analysis of the FOLL05 trial (NCT00774826), we investigated the prognostic role of post-induction PET (PI-PET) scan. Patients were eligible to this study if they had a PI-PET scan carried out within 3 months from the end of induction immunochemotherapy. Progression-free survival (PFS) was the primary study end point. RESULTS: A total of 202 patients were eligible and analysed for this study. The median age was 55 years (range 33-75). Overall, PI-PET was defined as positive in 49 (24%) patients. Conventional response assessment with CT scan was substantially modified by PET: 15% (22/145) of patients considered as having a complete response (CR) after CT were considered as having partial response (PR) after PI-PET and 53% (30/57) patients considered as having a PR after CT were considered as a CR after PI-PET. With a median follow-up of 34 months, the 3-year PFS was 66% and 35%, respectively, for patients with negative and positive PI-PET (P<0.001). At multivariate analysis, PI-PET (hazard ratio 2.57, 95% confidence interval 1.52-4.34, P<0.001) was independent of conventional response, FLIPI and treatment arm. Also, the prognostic role of PI-PET was maintained within each FLIPI risk group. CONCLUSIONS: In FL patients, PI-PET substantially modifies response assessment and is strongly predictive for the risk of progression. PET should be considered in further updates of response criteria.

Kidney dosimetry in ¹77Lu and 9°Y peptide receptor radionuclide therapy: influence of image timing, time-activity integration method, and risk factors.

Kidney dosimetry in (177)Lu and (90)Y PRRT requires 3 to 6 whole-body/SPECT scans to extrapolate the peptide kinetics, and it is considered time and resource consuming. We investigated the most adequate timing for imaging and time-activity interpolating curve, as well as the performance of a simplified dosimetry, by means of just 1-2 scans. Finally the influence of risk factors and of the peptide (DOTATOC versus DOTATATE) is considered. 28 patients treated at first cycle with (177)Lu DOTATATE and 30 with (177)Lu DOTATOC underwent SPECT scans at 2 and 6 hours, 1, 2, and 3 days after the radiopharmaceutical injection. Dose was calculated with our simplified method, as well as the ones most used in the clinic, that is, trapezoids, monoexponential, and biexponential functions. The same was done skipping the 6 h and the 3 d points. We found that data should be collected until 100 h for (177)Lu therapy and 70 h for (90)Y therapy, otherwise the dose calculation is strongly influenced by the curve interpolating the data and should be carefully chosen. Risk factors (hypertension, diabetes) cause a rather statistically significant 20% increase in dose (t-test, P < 0.10), with DOTATATE affecting an increase of 25% compared to DOTATOC (t-test, P < 0.05).

The use of FDG-PET in the initial staging of 142 patients with follicular lymphoma: a retrospective study from the FOLL05 randomized trial of the Fondazione Italiana Linfomi.

BACKGROUND: The role of [¹8F] fluorodeoxyglucose (FDG)-positron emission tomography (PET) in follicular lymphoma (FL) staging is not yet determined. PATIENTS AND METHODS: The aim of the present study was to investigate the role of PET in the initial staging of FL patients enrolled in the FOLL05-phase-III trial that compared first-line regimens (R-CVP, R-CHOP and R-FM). Patients should have undergone conventional staging and have available PET baseline to be included. RESULTS: A total of 142 patients were analysed. PET identified a higher number of nodal areas in 32% (46 of 142) of patients and more extranodal (EN) sites than computed tomography (CT) scan. Also, the Follicular Lymphoma International Prognostic Index (FLIPI) score increased in 18% (26 of 142) and decreased in 6% (9 of 142) of patients. Overall, the impact of PET on modifying the stage was highest in patients with limited stage. Actually, 62% (15 of 24) of cases with limited disease were upstaged with PET. CONCLUSIONS: The inclusion of PET among staging procedures makes the evaluation of patients with FL more accurate and has the potential to modify therapy decision and prognosis in a moderate proportion of patients. Further prospective clinical trials on FL should incorporate PET at different moments, and the therapeutic criteria to start therapy should be re-visited in the views of this new tool.

PET/CT Imaging in Oncology: Exceptions That Prove the Rule.

(18)F-FDG PET/CT is a diagnostic three-dimensional non-invasive device, routinely employed in neurology, cardiology, and oncology, and which contributes to patient care giving functional informations about glucose metabolism. In particular, staging, restaging, follow-up and response to treatment of tumors are the most common applications in oncologic field. Many neoplasms show increased glucose metabolism and consequent (18)F-FDG uptake. Nevertheless, some relative differentiated cancers, such as clear cell carcinoma of the kidney and bronchioloalveolar adenocarcinoma, show tipically faintly/no uptake resulting in a consequent negative PET/CT scan. This case report represents an extreme case in which three relative well-differentiated cancer forms, all characterized by low glucose metabolism, affect the same patient at the same time while (18)F-FDG PET/CT scan is negative.

Pulmonary artery involvement in Takayasu arteritis. PET/CT versus CT angiography.

OBJECTIVES: To report a patient with Takayasu arteritis in whom 18F-Fluorodeoxyglucose (FDG) positron emission tomography (PET)/computerised tomography (CT) failed to demonstrate pulmonary artery involvement. METHODS: A patient with Takayasu arteritis underwent PET/CT and CT angiography before and one year after immunosuppressive treatment. RESULTS: Before treatment, PET/CT showed increased FDG uptake in the aortic arch and epiaortic arteries; pulmonary arteries were not visualised. Follow-up PET/CT one year later demonstrated resolution of abnormal vascular FDG uptake. CT angiography of the chest/abdomen prior to treatment revealed circumferential thickening of the ascending aorta, aortic arch, supra-aortic branches, and left inferior intralobar pulmonary artery with normal lumen diameter (27 mm). After therapy, CT angiography revealed decreased aortic wall thickening with complete resolution of intralobar wall thickening. However, the lumen of the central pulmonary artery was increased (32 mm). CONCLUSIONS: PET/CT is very sensitive in depicting active vasculitis, but cannot visualise the pulmonary arteries, presumably because their diameter is below the power of detection of PET/CT. CT angiography or magnetic resonance angiography is required to evaluate pulmonary artery abnormalities.