Lutetium [177Lu]-DOTA-TATE in gastroenteropancreatic-neuroendocrine tumours: rationale, design and baseline characteristics of the Italian prospective observational (REAL-LU) study.

PURPOSE: Gastroenteropancreatic -neuroendocrine tumours (GEP-NETs) are commonly treated with surgical resection or long-term therapies for tumour growth control. Lutetium [177Lu]-DOTA-TATE was approved for the treatment of GEP-NETs after the phase III NETTER 1trial demonstrated improved progression free survival, objective response rates and health-related quality of life (HRQoL) compared to high-dose somatostatin analogues. No real-world data exist on prescribing habits and clinically significant endpoints for [177Lu]Lu-DOTA-TATE treatment in Italy. REAL-LU is a multicentre, long-term observational study in patients with unresectable/metastatic GEP-NETs progressing on standard therapies in Italian clinical practice. A pre-specified interim analysis was performed at the end of the enrolment period, data from which are described herein. METHODS: Overall duration of REAL-LU will be approximately 48 months, with 12- and 36-month recruitment and follow-up periods, respectively. The primary objective is to evaluate [177Lu]Lu-DOTA-TATE effectiveness in terms of progression-free survival. Secondary objectives include safety, impact on HRQoL, and identification of prognostic factors. This pre-specified interim analysis describes patient profiles, at the end of enrollment, of those prescribed [177Lu]Lu-DOTA-TATE for GEP-NETs in Italy. RESULTS: Among 161 evaluable patients, mean age was 64.7 ± 10.3 years at study entry, 83.8% presented with no clinical signs of disease at physical examination, and most had minor disease symptoms. All patients had metastatic disease, most commonly in the liver (83.9%) with a median of two metastatic sites. In 90.7% of patients, the disease was stage IV, and 68.3% had ≥ 1 target lesion. [177Lu]Lu-DOTA-TATE was prescribed mainly as second-line therapy (61.6%) and following surgery (58.4%). HRQoL assessments revealed high levels of functioning and low levels of symptoms at baseline; 50.0% of patients were symptom-free at study entry. CONCLUSION: The characteristics of patients who received [177Lu]Lu-DOTA-TATE in Italy are similar to those of the GEP-NET population of NETTER 1 with trial but with a higher proportion of patients with a grade 2 (71%). With regard to the tumor grade profile, our study cohort appears to be closer to that of NETTER-2 study population which included patients with G2 or G3 advanced GEP-NETs (i.e. Ki-67 ≥ 10% and ≤ 55%). Further analysis of effectiveness and safety can be anticipated as REAL-LU data mature. STUDY REGISTRATION: ClinicalTrials.gov, NCT04727723; Study Registration Date: 25 January, 2021; https://clinicaltrials.gov/study/NCT04727723?cond=NCT04727723&rank=1.

Impact of patient's habitus on image quality and quantitative metrics in 18F-FDG PET/CT images.

PURPOSE: To study how the quantitative parameters of 18F-FDG PET imaging change with the emission scan duration (ESD) and the body-mass-index (BMI) in phantom and patients on a time-of-flight (TOF)-PET/CT system. METHODS: The image-quality phantom with (b-NEMA-IQ, BMI = 29.2 kg/m2) and without (NEMA-IEC, BMI = 21.4 kg/m2) a 'belt' of water-bags was filled with 18F-FDG activities to obtain nominal standardized uptake values (SUV) of 19, 8 and 5. Patients with BMI ≤ 25 kg/m2 (L-BMI) and BMI > 25 kg/m2 (H-BMI) were enrolled in this study. Phantom and patients underwent list-mode PET acquisition at 120 s/bed-position. Images reconstructed with clinical protocol and different ESD (120, 90, 75, 60, 45, 30 s) were analysed for comparison of maximum SUV (SUVmax), maximum standardized uptake value lean-body-mass corrected (SULmax) and noise. RESULTS: 79 oncologic patients (45 L-BMI, 44 H-BMI) were analysed. From 90 s to 30 s, an increasing variation of SUVmax and SULmax with respect to the reference 120 s time was observed, from 18% to 60% and from 16% to 37% for phantom and patients, respectively. SUVmax values were significantly higher (+50%) in b-NEMA-IQ than NEMA-IQ phantom and in H-BMI (+33%) than L-BMI patients. No significant difference was found in SULmax for the two BMI categories in both phantom and patients. CV values decreased when increasing ESD, being higher in H-BMI patients (0.13-0.25) and b-NEMA-IQ phantom (0.15-0.28) than in L-BMI patients (0.11-0.21) and NEMA-IQ phantom (0.11-0.20). CONCLUSIONS: Reduction of ESD may severely impact on the variations of SUVmax and SULmax in 18F-FDG PET/CT imaging. This study confirms recommendations of using SUL for lesion uptake quantification, being unaffected by BMI variation.

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.

Prevalence of interstitial pneumonia suggestive of COVID-19 at 18F-FDG PET/CT in oncological asymptomatic patients in a high prevalence country during pandemic period: a national multi-centric retrospective study.

PURPOSE: To assess the presence and pattern of incidental interstitial lung alterations suspicious of COVID-19 on fluorine-18-fluorodeoxyglucose positron emission tomography (PET)/computed tomography (CT) ([18F]FDG PET/CT) in asymptomatic oncological patients during the period of active COVID-19 in a country with high prevalence of the virus. METHODS: This is a multi-center retrospective observational study involving 59 Italian centers. We retrospectively reviewed the prevalence of interstitial pneumonia detected during the COVID period (between March 16 and 27, 2020) and compared to a pre-COVID period (January-February 2020) and a control time (in 2019). The diagnosis of interstitial pneumonia was done considering lung alterations of CT of PET. RESULTS: Overall, [18F]FDG PET/CT was performed on 4008 patients in the COVID period, 19,267 in the pre-COVID period, and 5513 in the control period. The rate of interstitial pneumonia suspicious for COVID-19 was significantly higher during the COVID period (7.1%) compared with that found in the pre-COVID (5.35%) and control periods (5.15%) (p < 0.001). Instead, no significant difference among pre-COVID and control periods was present. The prevalence of interstitial pneumonia detected at PET/CT was directly associated with geographic virus diffusion, with the higher rate in Northern Italy. Among 284 interstitial pneumonia detected during COVID period, 169 (59%) were FDG-avid (average SUVmax of 4.1). CONCLUSIONS: A significant increase of interstitial pneumonia incidentally detected with [18F]FDG PET/CT has been demonstrated during the COVID-19 pandemic. A majority of interstitial pneumonia were FDG-avid. Our results underlined the importance of paying attention to incidental CT findings of pneumonia detected at PET/CT, and these reports might help to recognize early COVID-19 cases guiding the subsequent management.

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.

Downstaging unresectable hepatocellular carcinoma by radioembolization using 90-yttrium resin microspheres: a single center experience.

BACKGROUND: Only one third of patients with hepatocellular carcinoma can benefit from curative treatments at the time of first diagnosis. Tumor downstaging by radioembolization may enable initially unresectable hepatocellular carcinoma (HCC) to be treated with surgery lengthening survival. METHODS: From June 2011 through June 2014, all patients with a first diagnosis of unresectable HCC with intrahepatic portal vein thrombosis were treated in our center with radioembolization using 90-yttrium resin microspheres. A 3-year enrollment period and a 5-year follow-up were planned to adequately investigate survivals. RESULTS: Twenty-four patients were enrolled, five were downstaged to surgery, eight did not reach downstaging but achieved partial response or stable disease, and eleven showed HCC progression despite radioembolization. High tumor absorbed radiation doses (454 vs. 248 and 138 Gy, P=0.005) and low serum AFP levels (53 vs. 1,447 and 4,603 ng/mL, P=0.05) were the variables significantly associated with successful downstaging. Mean and median survivals were 54, 30 and 11 months and 70, 24 and 11 months in the three groups respectively. No severe side effects were registered. CONCLUSIONS: In our center, about 20% of patients with locally advanced unresectable hepatocellular carcinoma were successfully downstaged to surgery after radioembolization. This strategy increases survival and is associated with an excellent safety profile.

Performance evaluation of a new time of flight PET/CT scanner: Results of a multicenter study.

PURPOSE: The aim of this multicenter study was to evaluate the performance of the upgraded version of the Ingenuity TF PET/CT scanner, according to the NEMA NU-2 2012 standards. METHODS: Spatial resolution, sensitivity, count rate response, scatter fraction, image quality and accuracy were evaluated on three Ingenuity TF scanners installed in Italian hospitals. Furthermore, energy and timing resolution were measured. A detailed image quality phantom analysis was performed to evaluate the effect of different clinical reconstruction parameters, including the application of PSF correction. RESULTS: Results show an average spatial resolution of 4.7 mm and an average absolute system sensitivity of 7.9 cps/kBq. The average maximum NECR was 119.83 kcps at 20.67 kBq/ml, while the maximum true event rate was 322.62 kcps at the concentration of 24.51 kBq/ml. The average maximum bias below NECR peak was 12.58%. All the results of NEMA tests were in agreement with the values declared by the manufacturer. The estimated average energy and timing resolution were 10.83% and 536.2 ps, respectively. Image quality phantom analysis obtained with different reconstruction settings showed that PSF correction was the parameter that affected mainly on contrast recovery coefficient, while the iteration number and amplitude of Gaussian filter had no significant effect. Of relevance, the application of PSF correction never led to recovery coefficient values higher than 100% and to Gibbs or edge artifacts. CONCLUSIONS: The new Ingenuity TF model shows physical performance similar to other scanners of the latest generation for all standard NEMA NU2-2012 measurements.

PET-CT post therapy dosimetry in radioembolization with resin 90Y microspheres: Comparison with pre-treatment SPECT-CT 99mTc-MAA results.

Resin microspheres radioembolization is an effective treatment for liver tumors when the surgical option is not feasible. Doses delivered to tumor and normal liver can be assess in the pre-therapy phase by means of a 99mTc-MAA SPECT-CT simulation and after the treatment with 90Y PET-CT acquisition. The optimal therapeutic 90Y activity is determined on 99mTc-MAA SPECT-CT dose results in order to avoid healthy parenchyma toxicity and to effectively irradiate the tumor. The assumption of identical radiopharmaceutical distribution between simulation and verification is still under debate and literature data showed controversial results. In this study 10 HCC patient's dosimetry performed on 99mTc SPECT-CT and 90Y PET-CT were compared. Patients were selected when a good agreement between the pre and post-therapy distribution was observed in order to investigate the intrinsic dosimetric variations between the two imaging modalities. Mean doses (MIRD and Voxel approaches) showed a good correlation (Pearson's coefficient r > 0.90) both for tumor and normal liver. Dose Volume Histogram curves were compared with a good agreement particularly for normal liver (D50). Goal doses were achieved for 90% of patients. Bland-Altman analysis indicates lower variations for healthy parenchyma than for tumor (1.96 SD equal to 9.1 Gy and 68 Gy respectively) confirming the robustness of the dose-toxicity approach. PET-CT dosimetry well correlates with SPECT-CT doses (under assumption of same catheter position and 90Y activity). Better agreement was showed for 7/10 and 8/10 patients for T and NL respectively, confirming dosimetry as effective tool to optimize and individualize the treatment.

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.

Multicenter Semiquantitative Evaluation of (123)I-FP-CIT Brain SPECT.

AIMS: The aims of this study were: (1) to cross-compare data from semiquantitative, software-assisted, and phantom-corrected evaluations of (123)I-ioflupane [(123)I]N-ω-fluoropropyl-2ß-carbomethoxy-3ß-{4-iodophenyl}nortropane FP-CIT brain single-photon emission computed tomography (SPECT) acquired in three centers; (2) to assess the accuracy of semiquantitative evaluation; and (3) to identify the threshold with the best accuracy, sensitivity, and specificity in patients with suspected Parkinsonian Syndrome. MATERIAL AND METHODS: Two-hundred-twenty patients, acquired in three centers, were included. All of them underwent (123)I-FP-CIT brain SPECT. All examinations were analyzed with the freely available software, BasGan, and semiquantitative data were used to predict disease. Analysis was based on the values from the most deteriorated putamen and caudate, normalized for age, and corrected by anthropomorphic phantom data. Receiver operating characteristic (ROC) analysis was performed and areas under the curve (AUC) were estimated. RESULTS: Analysis showed high AUCs (.880, .866, .920, and .882 for each center and multicenter setting). Best thresholds were 1.53 and 1.56 for putamen and caudate, respectively. Thresholds of putamen data showed sensitivity and specificity of 86% and 89%, respectively, in the multicenter setting. Neither sensibility nor specificity showed significant differences among centers. CONCLUSION: A unique, accurate threshold for all centers, with high sensitivity and specificity was identified. Semiquantitative assessment of (123)I-FP-CIT brain SPECT among different centers resulted reliable, accurate, and potentially useful in clinical trials.

Impact of pregnancy on prognosis of differentiated thyroid cancer: clinical and molecular features.

OBJECTIVE: Differentiated thyroid cancer (DTC) commonly occurs in women of child-bearing age and represents the second most frequent tumor diagnosed during pregnancy only behind breast cancer. It is possible that associated physiological changes could favor tumor development and growth. However, few data are available about the outcome of DTC related to pregnancy, leading to conflicting results. METHODS: Among the study population, 340 patients with DTC <45 years old were retrospectively studied. Patients were divided into three groups according to the time of tumor diagnosis in respect of pregnancy. Group 1, diagnosis of DTC at least 2 years after delivery; group 2, diagnosis during pregnancy or within the second year after delivery; and group 3, nulliparous patients at the time of diagnosis. We evaluated clinical outcome and immunohistochemical expression of estrogen receptor α (ERα), ERß, progesterone receptor, and aromatase. We also analyzed the gene expression of NIS (SLC5A5) and the prevalence of BRAF(V600E) mutations. RESULTS: Persistence/recurrence of disease was significantly higher in group 2 patients than control groups (P=0.023). No significant differences were observed in other clinical parameters. Furthermore, no differences among the groups were recorded about ER pattern, NIS expression, and BRAF mutations. CONCLUSIONS: Persistence/recurrence of DTC is significantly higher in pregnant patients, suggesting that pregnancy could really exert a negative prognostic role in patients with DTC. The underlying mechanisms are not yet clarified and further studies are required. Our results suggest that a more careful follow-up is needed when diagnosis of DTC occurs during pregnancy or shortly after.

Papillary thyroid carcinoma presenting as a solitary soft tissue arm metastasis in an elderly hyperthyroid patient. Case report and review of the literature.

A case of papillary thyroid carcinoma (PTC) presenting as a solitary metastasis in the right arm muscle is described in an elderly hyperthyroid male patient. A 2-cm nodule in the right bycipites muscle was found to be a papillary carcinoma of thyroid origin and a primary, 3.5-cm tumor was subsequently found in the left lobe of a hyperfunctioning gland due to toxic goiter. Both tumors were well differentiated PTC, follicular variant. No high grade features, nor extrathyroidal spread, nor regional lymph node metastases were found, but histology evidenced intrathyroidal vascular invasion. After radical surgery and radioiodine therapy, the patient is currently disease-free 4 years after diagnosis. This is the third reported case of PTC manifesting as a single soft tissue metastasis and the first associated with hyperthyroidism. Hematogenous spread of differentiated PTC is rare, although less unusual in PTC follicular variant. Histological vascular invasion, hypervascularity and increased blood flow in the hyperfunctioning thyroid gland might have facilitated the dissemination of malignant tumor cells through the bloodstream. Literature data indicate that PTC in elderly patients is increasing and is often clinically aggressive. Radical surgical and radiometabolic treatments are required also in this age group to improve clinical outcome.

Characterization of the ideal candidate for knee radiosynoviorthesis treatment in patients with rheumatoid arthritis.

OBJECTIVES: (1). To identify the main parameters that positively influence the outcome of knee radiosynoviorthesis (RSO) in patients with rheumatoid arthritis (RA) and (2). to determine the ideal candidate for this procedure. METHODS: We considered 80 knees (in 57 patients) that had undergone follow-up for at least 5 years and/or prosthesis implantation after RSO treatment. The parameters evaluated included age, gender, oligo-articular or polyarticular involvement, disease progression, radiological joint damage (Larsen scale), instability and/or axial deviation, body mass index (BMI), and psychological motivation for prosthesis implantation. RESULTS: Knee Larsen stage IV, presence of instability-axial deviation, disease progression, psychological motivation to the surgical replacement and BMI higher than the 85th percentile were associated with a negative outcome for RSO (prosthesis implantation). CONCLUSIONS: The ideal candidate for the RSO treatment is a patient with a low Larsen stage, no instability and/or axial deviation and a BMI below the 85th percentile. A patient's psychological motivation for the treatment should be evaluated before the RSO procedure.

Thyroid cytology and risk of thyroid cancer: differences among indeterminate specimens.

OBJECTIVE: To assess the potential for stratification of indeterminate cytologic findings on fine-needle aspiration (FNA) of thyroid nodules in an effort to improve therapeutic strategies. METHODS: We attempted to determine the malignant risk associated with various indeterminate FNA cytologic patterns by correlation of specimens with the final histologic diagnosis. For this analysis, we identified 294 computerized medical records of surgically treated thyroid nodules during a 5-year period at our institution with the corresponding FNA cytology reports available. RESULTS: Of the 294 surgical cases, 162 with a positive or indeterminate cytologic report were selected, reviewed, and classified. Of 52 patients with positive cytologic findings on FNA, 51 (98%) had a final histologic report of a malignant thyroid nodule. Of 110 patients with indeterminate specimens, 30 (27%) had a final histologic diagnosis of thyroid carcinoma. The presence of nuclear atypia was predictive of thyroid carcinoma in 75% of patients, a Hürthle cell cytologic pattern was associated with a malignant thyroid nodule in 33%, and a hypercellular smear was suggestive of malignant involvement in 26% of cases. The lowest rate of malignant potential was associated with cytologic microfollicular and scant colloid alone subtype (6%). CONCLUSION: The results of this study show that indeterminate thyroid cytologic specimens can be subdivided into groups with different malignant risks. A microfollicular cytologic pattern in the absence of a hypercellular smear or nuclear atypia does not support a recommendation of surgical treatment. A malignant cytologic diagnosis has a high positive predictive value for detection of thyroid cancer.

Fine-needle aspiration biopsy of the thyroid: comparison between thyroid palpation and ultrasonography.

OBJECTIVE: To describe our experience with fine-needle aspiration biopsy (FNAB) of the thyroid and compare our results with direct palpation versus ultrasound scanning (USS) in an area of endemic goiter in Italy. METHODS: We considered all patients submitted to ultrasound-guided FNAB of thyroid nodules during a 10-month period at our outpatient clinic and analyzed the following: (1) clinical data (number of nodules and identification of the nodule for FNAB); (2) USS data (number of nodules and identification of the nodule for FNAB on the basis of hypoechoic pattern + blurred perinodal halo + microcalcifications or intranodal color Doppler signal indicative of blood flow); (3) cytologic specimens, categorized as suspicious, malignant, negative, or nondiagnostic; and (4) histologic final report of the cytologically positive nodules. RESULTS: The study group consisted of 348 female and 72 male patients who underwent FNAB of the thyroid at our institution. Among the 140 patients with no palpable thyroid nodules, USS showed that 106 had a single nodule and 34 had multinodular goiters. Among the 182 patients with a single palpable thyroid nodule, USS revealed that 138 had a single nodule, 42 had a multinodular goiter, and 2 had lobe enlargement without detectable nodules. All 98 patients with multinodular palpable goiter had a similar pattern on USS. Of the 420 cytologic specimens, 46(11.0%) were positive for thyroid cancer, 313 (74.5%)were negative, and 61 (14.5%) were nondiagnostic. Histologic malignant growth was confirmed in 27 cytologically positive nodules. Of these histologically malignant nodules, 12 (45%) were nonpalpable, 9 (33%) were single palpable nodules, and 6 (22%) were from a nodule with a suspicious ultrasound pattern within a multinodular goiter. CONCLUSION: Manually guided FNAB is not feasible in nonpalpable nodules and not accurate in a multinodular goiter. Both situations are clinical challenges, and USS should be performed for accurate FNAB under these circumstances. Because 52% of histologically malignant nodules in our study were found only with the aid of ultrasound-guided FNAB, this procedure should be used where multinodular goiter is endemic. Our overall rate of nondiagnostic specimens was comparable to that reported in the literature.