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.

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.

Italian Multicenter Study on Accuracy of 18F-FDG PET/CT in Assessing Bone Marrow Involvement in Pediatric Hodgkin Lymphoma.

INTRODUCTION: The present study investigated the utility of fluorine-18 (18F) fluoro-2-deoxy-d-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in assessing bone marrow involvement (BMI) compared with bone marrow biopsy (BMB) in newly diagnosed pediatric Hodgkin lymphoma (HL). PATIENTS AND METHODS: A total of 224 pediatric patients with HL underwent 18F-FDG PET/CT at staging. BMB or follow-up imaging was used as the standard of reference for the evaluation of BMI. RESULTS: 18F-FDG PET/CT was negative for BMI in 193 cases. Of the 193 patients, the findings for 16 were originally reported as doubtful and later interpreted as negative for BMI, with negative findings on follow-up imaging and BMB. At BMB, 1 of the 16 patients (6.25%) had BMI. Of the 193 patients, 192 (99.48%) had negative BMB findings. Thus, the 18F-FDG PET/CT findings were truly negative for 192 patients and falsely negative for 1 patient for BMI. CONCLUSION: 18F-FDG PET/CT showed high diagnostic performance in the evaluation of BMI in pediatric HL. Thus, BMB should be ideally reserved for patients presenting with doubtful 18F-FDG PET/CT findings for BMI.

Yttrium-90 ibritumomab tiuxetan (Zevalin) followed by BEAM (Z-BEAM) conditioning regimen and autologous stem cell transplantation (ASCT) in relapsed or refractory high-risk B-cell non-Hodgkin lymphoma (NHL): a single institution Italian experience.

Chemo-refractory NHL has a very poor outcome; the addiction of RIT to salvage regiment pre ASCT had recently demonstrated promising results.We performed a retrospective sequential study to determine the feasibility of standard Zevalin with BEAM in high-risk relapse/refractory NHL. A matched cohort analysis with a group treated with standard BEAM without Zevalin was performed as secondary endpoint. Between October 2006 and January 2013, 37 NHL patients at high risk for progression or early (< 1 year) or multiple relapses were treated with Z-BEAM and ASCT after R-DHAP or R-ICE as salvage therapy. Clinical characteristics were 19 refractory and 18 early or multiple relapse; 16 patients received 1, and 21 had 2 or more previous rituximab-containing chemotherapy. At the end of treatment, response was CR 22 (59%), PR 10 (27%), PD 4 (11%), and toxic death (TD) 1 (3%). With a median follow up of 61 months, 3-year PFS was 61% and OS 61%. Fifteen patients died, 12 of lymphoma. Comparison with 21 treated with BEAM alone showed a numerical higher 3-yr PFS rate in favor of Z-BEAM but not statistically significant (57 vs 48%). With the limitation of the small sample subgroup analysis, a significant benefit was observed in relapsed patients for PFS (78% Z-BEAM vs 22% BEAM p = 0.016) and OS (83% Z-BEAM vs 22% BEAM p = 0.001). In relapsed/refractory high-risk NHL, Z-BEAM+ASCT is able to achieve a good ORR. Three-year PFS is promising for early relapsed patients but is not satisfactory for those with refractory disease.

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.

Prognostic Role of Pre-Radiation Therapy (18)F-Fluorodeoxyglucose Positron Emission Tomography for Primary Mediastinal B-Cell Lymphomas Treated with R-CHOP or R-CHOP-Like Chemotherapy Plus Radiation.

PURPOSE: To validate, in a monoinstitutional cohort with extended follow-up, that post-rituximab chemotherapy (R-CT) (18)F-fluorodeoxyglucose positron emission tomography ((18)FDG-PET) is a prognostic factor allowing discrimination of primary mediastinal B-cell lymphoma (PMBCL) patients at higher risk for progression after radiation therapy. METHODS AND MATERIALS: We analyzed 51 patients, and (18)FDG-PET scans were re-examined evaluating both the Deauville 5-point scale (D5PS) score and the standardized uptake value (SUV) of residual activity, if present. These parameters were then tested by univariate analysis for a potential correlation with progression-free survival (PFS) as the primary study endpoint. RESULTS: Median follow-up time was 51 months (range, 9-153 months). After R-CT, D5PS score was 1 in 10 (19.6%), 2 in 11 (21.6%), 3 in 7 (13.8%), 4 in 17 (33.3%), and 5 in 6 patients (11.7%). Forty-three out of 51 patients (84.3%) had an SUVmax ≤5, and 8 out of 51 (15.7%) had an SUVmax ≥5. Overall, 6 patients experienced progression or relapse: 1 had a D5PS score 2 (with SUVmax ≤5), and 5 had a D5PS score 5 (and SUVmax ≥5). Patients with a D5PS score 5 showed significantly lower PFS rates versus all other scores (log-rank P<.001), as did patients with SUVmax ≥5 when compared with those with SUVmax ≤5 (log-rank P<.001). CONCLUSIONS: The present study confirmed the prognostic role of (18)FDG-PET after R-CT, with patients with a D5PS score of 5 and/or an SUVmax ≥5 being at high risk of progression/relapse after RT.

Post-ABVD/pre-radiotherapy (18)F-FDG-PET provides additional prognostic information for early-stage Hodgkin lymphoma: a retrospective analysis on 165 patients.

OBJECTIVE: To evaluate the prognostic role of both interim fluorine-18 fludeoxyglucose positron emission tomography (i-(18)F-FDG-PET) and end-of-chemotherapy fluorine-18 fludeoxyglucose positron emission tomography (eoc-(18)F-FDG-PET) in patients with early-stage Hodgkin lymphoma (HL). METHODS: We screened 257 patients with early-stage HL treated with combined modality therapy between March 2003 and July 2011. All were staged using fluorine-18 fludeoxyglucose positron emission tomography ((18)F-FDG-PET) before chemotherapy and after two doxorubicin, bleomycin, vinblastine and dacarbazine cycles (i-(18)F-FDG-PET); 165 patients were also evaluated by (18)F-FDG-PET at the end of chemotherapy (eoc-(18)F-FDG-PET). RESULTS: After revision, 85% of patients were negative for i-(18)F-FDG-PET and 15% were positive. After eoc-(18)F-FDG-PET revision, 23 patients had a positive scan. The median follow-up was 56 months. The 5-year overall survival (OS) and progression-free survival (PFS) for the whole cohort were 97.5% and 95.6%, respectively. For i-(18)F-FDG-PET-negative and i-(18)F-FDG-PET-positive patients, the 5-year PFS rates were 98% and 84%, respectively; for eoc-(18)F-FDG-PET-negative and eoc-(18)F-FDG-PET-positive patients, the 5-year PFS rates were 97% and 78%, respectively. Combining the i-(18)F-FDG-PET and eoc-(18)F-FDG-PET results, the 5-year PFS were 97%, 100% and 82% in negative/negative, positive/negative and positive/positive groups, respectively. The 5-year OS rates were 98% and 83% in eoc-(18)F-FDG-PET-negative and eoc-(18)F-FDG-PET-positive patients, respectively; the 5-year OS was 98%, 100% and 83% in negative/negative, positive/negative and positive/positive groups, respectively. CONCLUSION: This study provides additional information on the prognostic role of i-(18)F-FDG-PET and eoc-(18)F-FDG-PET in early-stage HL. As data are accumulating and the clinical scenario is rapidly evolving, we might need to rethink the use of (18)F-FDG-PET as a prognostic marker for early-stage HL in the near future. ADVANCES IN KNOWLEDGE: This study provides additional information on the prognostic role of i-(18)F-FDG-PET and eoc-(18)F-FDG-PET in early-stage HL. On the basis of the present data, we may suggest to use eoc-(18)F-FDG-PET as a strong prognostic marker, especially for patients with i-(18)F-FDG-PET positivity.

Diagnostic and prognostic value of 18F-FDG PET/CT in comparison with morphological imaging in primary adrenal gland malignancies - a multicenter experience.

OBJECTIVE: To evaluate the diagnostic and prognostic role of fluorine-18 fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) in comparison to morphological imaging such as computed tomography in primary adrenal malignancies. MATERIALS AND METHODS: In this multicenter retrospective study, 68 patients with adrenal malignancy were included. All patients had histologically proven diagnosis of primary adrenal malignancy (adrenocortical carcinoma, malignant pheochromocytoma, neuroblastoma and lymphoma), one whole body (18)F-FDG PET/CT scan and one whole-body contrast enhancement computed tomography (CECT) scan acquired within one month and were followed clinically and by performing morphological tests for at least 12 months. RESULTS: Overall sensitivity, specificity, accuracy, positive and negative predictive values for CECT and (18)F-FDG PET/CT were respectively, 59%, 100%, 65%, 100%, 27% and 75%, 100%, 82%, 100% and 63%. For adrenocortical carcinomas, (18)F-FDG PET/CT showed a better accuracy (93.4%) than CECT (75%). For neuroblastomas (18)F-FDG PET/CT also showed better accuracy (70.4%) than CECT (66.7%). For malignant pheochromocytomas (18)F-FDG PET/CT and CECT showed the same accuracy (90%). For primary adrenal lymphomas, (18)F-FDG PET/CT showed better accuracy (100%) than CECT (74.41%). Kaplan-Mayer curves showed that "histotypes" and "metastases at the last follow-up" were similarly detected for both disease free survival (DFS) and overall survival (OS), while "global 18F-FDG PET/CT" and "presence of metastases at diagnosis" were significant for DFS. Stratifying the sample by the presence or absence of metastases at diagnosis, standardized uptake value (SUVmax) was a significant prognostic factor for DFS when metastases were absent (Wald test=7.035, P=0.008). CONCLUSION: Our multicenter study demonstrated that (18)F-FDG PET/CT better than CECT diagnosed adrenal malignancies achieving also a good prognostic performance. Therefore management algorithms should include (18)F-FDG PET/CT.

Radiation therapy in primary mediastinal B-cell lymphoma with positron emission tomography positivity after rituximab chemotherapy.

PURPOSE: To investigate the role of radiation therapy (RT) in patients affected with primary mediastinal B-cell lymphoma (PMBCL) with residual (18)fluorodeoxyglucose positron emission tomography ((18)FDG-PET)-positive disease after rituximab chemotherapy (R-CT). METHODS AND MATERIALS: Thirty-seven patients treated with R-CT and RT, all with (18)FDG-PET scan at diagnosis and before RT, were included. All (18)FDG-PET scans were reviewed, and responses were classified according to the Deauville 5-point scoring system. Outcomes measures were overall survival (OS) and progression-free survival (PFS), estimated for the whole cohort and for subgroups according to (18)FDG-PET score after R-CT. RESULTS: The median follow-up time was 40.9 months. Three patients were assigned to Deauville score 1 (8.1%), 9 to score 2 (24.3%), 7 to score 3 (19%), 14 to score 4 (37.8%), and 4 to score 5 (10.8%). After RT, all patients with score 3-4 experienced a complete response (CR). Among patients with score 5, 1 was in CR (25%), 2 had persistent positivity (50%), and 1 showed progressive disease (25%). A total of 4 patients experienced progression or relapse: 1 of 33 (3%) with scores 1-4, and 3 of 4 (75%) with score 5. The 3-year OS and PFS of the whole cohort were 89.8% and 88.7%, respectively. OS was significantly different between scores 1-3 and scores 4-5 (100% vs 77% at 3 years, P<.05). Patients with a score of 5 had a significantly worse outcome than did all other patients (OS at 2 years, 33.3% vs 100%). CONCLUSIONS: Approximately 50% of PMBCL patients show residual disease at (18)FDG-PET scan after R-CT. RT is able to convert to CR approximately 85% of these patients, but those with a Deauville score of 5 (10%) appear at high risk of progression and death, and they might be candidates for intensified programs.

Multivariate analysis of brain metabolism reveals chemotherapy effects on prefrontal cerebellar system when related to dorsal attention network.

BACKGROUND: Functional brain changes induced by chemotherapy are still not well characterized. We used a novel approach with a multivariate technique to analyze brain resting state [18 F]FDG-PET in patients with lymphoma, to explore differences on cerebral metabolic glucose rate between chemotherapy-treated and non-treated patients. METHODS: PET/CT scan was performed on 28 patients, with 14 treated with systemic chemotherapy. We used a support vector machine (SVM) classification, extracting the mean metabolism from the metabolic patterns, or networks, that discriminate the two groups. We calculated the correct classifications of the two groups using the mean metabolic values extracted by the networks. RESULTS: The SVM classification analysis gave clear-cut patterns that discriminate the two groups. The first, hypometabolic network in chemotherapy patients, included mostly prefrontal cortex and cerebellar areas (central executive network, CEN, and salience network, SN); the second, which is equal between groups, included mostly parietal areas and the frontal eye field (dorsal attention network, DAN). The correct classification membership to chemotherapy or not chemotherapy-treated patients, using only one network, was of 50% to 68%; however, when all the networks were used together, it reached 80%. CONCLUSIONS: The evidenced networks were related to attention and executive functions, with CEN and SN more specialized in shifting, inhibition and monitoring, DAN in orienting attention. Only using DAN as a reference point, indicating the global frontal functioning before chemotherapy, we could better classify the subjects. The emerging concept consists in the importance of the investigation of brain intrinsic networks and their relations in chemotherapy cognitive induced changes.

Interim positron emission tomography and clinical outcome in patients with early stage Hodgkin lymphoma treated with combined modality therapy.

The aim of the study was to investigate whether interim positron emission tomography (iPET) is prognostic in a cohort of patients with early stage Hodgkin lymphoma (HL) homogeneously treated with 3-4 cycles of ABVD (adriamycin, bleomycin, vinblastine and dacarbazine) followed by 30 Gy involved field radiotherapy. Eighty patients were selected (stage I-IIA HL, availability of iPET, minimum follow-up of 12 months), and after central review, 70 were judged negative (iPET-: 87.5%) and 10 positive (iPET+: 12.5%). The two groups were then analyzed for response, progression-free survival (PFS) and overall survival (OS). Only one out of 70 iPET- patients relapsed, with 69 in continuous complete remission (CCR). All 10 iPET + patients achieved a complete response and maintained persistent CCR at follow-up. The 3-year PFS and OS were, respectively, 97% and 98.4% for iPET- and 100% and 100% for iPET+ (p = 0.63). iPET positivity does not seem to be a significant prognostic factor, and change in therapeutic strategy on the basis of iPET does not appear currently advisable outside clinical trials.

Interim 18-FDG-PET/CT failed to predict the outcome in diffuse large B-cell lymphoma patients treated at the diagnosis with rituximab-CHOP.

Role of interim-PET (I-PET) in diffuse large B-cell Lymphoma (DLBCL) is controversial. To determine predictive value of I-PET on progression-free survival (PFS), we enrolled 88 first-line DLBCL patients treated with 6-8 R-CHOP courses regardless of I-PET. PET/CT were performed at diagnosis, after 2 to 4 courses and at the end of therapy with central reviewing according to visual dichotomous criteria. Results are as follows: I-PET, 72% negative, 28% positive; final-PET (F-PET), 88% negative, 12% positive; clinical complete response 90%. Concordance between clinical response and F-PET negativity was 97% because of 2 false positive. With a median follow-up of 26.2 months, 2-year overall survival and PFS were 91% and 77%, respectively. Two-year PFS for I-PET and F-PET negative versus positive were as follows: I-PET 85% versus 72% (P = .0475); F-PET 83% versus 64% (P < .001). Because of a small number of events, 2 independent bivariate Cox models were tested for PFS. In model 1, F-PET contradicted I-PET (hazard ratio [HR] = 5.03, P = .015 vs 1.27, P = 691); in model 2, F-PET (HR = 4.54) and International propnostic Index score (HR = 5.36, P = .001) remained independent prognostic factors. In conclusion, positive I-PET is not predictive of a worse outcome in DLBCL; larger prospective studies and harmonization of I-PET reading criteria are needed.

Dual MRI-SPECT agent for pH-mapping.

A new dual MRI/SPECT pH-responsive agent where the SPECT active moiety acts as reporter of the concentration making it possible to exploit the responsiveness of the MRI probe.

Lymphoscintigraphic localization of sentinel node in early colorectal cancer: results of a monocentric study.

BACKGROUND AND OBJECTIVES: Evaluation of the feasibility of the sentinel node technique in early colorectal neoplasms and its overall accuracy in predicting nodal metastases. METHODS: Thirty-five patients with colon or rectal lesions or degenerate polyps not radically excised by endoscopy were included. Lymphatic mapping was performed with 99mTc labeled albumin colloid injected submucosally by an endoscopic route the afternoon before the surgical procedure. The day of the intervention, 2.5% patent blue V dye (S.A.L.F: Italy) was injected circumferentially around the tumor. A hand held gamma detecting probe (Scintiprobe m100, Pol-Hi-Tech, Italy) was employed to detect "hot" nodes, in vivo and ex vivo. All sentinel nodes were embedded separately for haematoxylin and eosin staining. No IHC or PCR techniques were employed. RESULTS: Sentinel lymph nodes (SLN) were successfully identified in 35 out of 35 patients. Concordance between SLN and nodal status was observed in 32 out of 35 cases (91.4%); four patients (11.4%) were upstaged. Three skip nodal metastases were observed (false-negative rate: 8.5%). CONCLUSIONS: The sentinel node technique with blue dye and radiotracer seems valuable in early colorectal cancers detected by screening programs: a good organization and a learning curve are needed, as further multicentric studies.

In vivo migration of labeled autologous natural killer cells to liver metastases in patients with colon carcinoma.

BACKGROUND: Besides being the effectors of native anti-tumor cytotoxicity, NK cells participate in T-lymphocyte responses by promoting the maturation of dendritic cells (DC). Adherent NK (A-NK) cells constitute a subset of IL-2-stimulated NK cells which show increased expression of integrins and the ability to adhere to solid surface and to migrate, infiltrate, and destroy cancer. A critical issue in therapy of metastatic disease is the optimization of NK cell migration to tumor tissues and their persistence therein. This study compares localization to liver metastases of autologous A-NK cells administered via the systemic (intravenous, i.v.) versus locoregional (intraarterial, i.a.) routes. PATIENTS AND METHODS: A-NK cells expanded ex-vivo with IL-2 and labeled with (111)In-oxine were injected i.a. in the liver of three colon carcinoma patients. After 30 days, each patient had a new preparation of (111)In-A-NK cells injected i.v. Migration of these cells to various organs was evaluated by SPET and their differential localization to normal and neoplastic liver was demonstrated after i.v. injection of 99mTc-phytate. RESULTS: A-NK cells expressed a donor-dependent CD56+ CD16+ CD3- (NK) or CD56+ CD16+ CD3+ (NKT) phenotype. When injected i.v., these cells localized to the lung before being visible in the spleen and liver. By contrast, localization of i.a. injected A-NK cells was virtually confined to the spleen and liver. Binding of A-NK cells to liver neoplastic tissues was observed only after i.a. injections. CONCLUSION: This unique study design demonstrates that A-NK cells adoptively transferred to the liver via the intraarterial route have preferential access and substantial accumulation to the tumor site.

Impact of axillary nodal metastases on lymphatic mapping and sentinel lymph node identification rate in patients with early stage breast cancer.

PURPOSE: The aim of this study was to define the impact of the presence of axillary nodal metastases on lymphatic mapping and sentinel lymph node (SLN) identification rate in patients with early breast cancer. METHODS: Two hundred and forty-six lymphatic mapping procedures were performed with both labelled nanocolloid and blue dye, followed by SLN biopsy and/or complete axillary dissection. The following parameters were recorded: patient's age, tumour laterality and location, tumour size, tumour histology, tumour stage, tumour grade, lymphovascular invasion, radiotracer injection site (subdermal-peritumoural/peri-areolar), SLN visualisation at lymphoscintigraphy, SLN metastases (presence/absence, size) and other axillary metastases (presence/absence, number). Discriminant analysis was used to analyse the data. RESULTS: SLNs were identified by labelled nanocolloid alone in 94.7% of tumours, by blue dye alone in 93.5% and by the combined technique in 99.2%. Discriminant analysis showed the gamma probe SLN identification rate to be significantly limited by the presence of axillary nodal metastases. In particular, the size of SLN metastases and the number of other axillary metastases were the most important variables in reducing the gamma probe SLN identification rate (p = 0.004 and p = 0.002, respectively). On the other hand, high tumour grade was the only parameter limiting the blue dye SLN identification rate. CONCLUSION: The accuracy of lymphatic mapping with labelled nanocolloid is limited by the presence of axillary nodal metastases, and particularly by the degree of SLN tumoural invasion and the presence and number of other axillary nodal metastases. Neither of these elements seems to interfere with the blue dye identification rate. The combination of the two tracers maximises the SLN identification rate.