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[18F]FDG PET/CT and [68Ga]Ga-DOTATATE PET/CT are both used to predict tumor biology in neuroendocrine neoplasms. Although the presence of discordant ([18F]FDG-avid/non–[68Ga]Ga-DOTATATE–avid) disease predicts poor prognosis, the significance of the volume of such discordant disease remains undetermined. The aim of this study is to investigate discordant tumor volume as a potential biomarker in patients with advanced gastroenteropancreatic neuroendocrine neoplasms (GEPNENs). Methods: A multicenter retrospective study in patients with advanced GEPNENs and paired [18F]FDG and [68Ga]Ga-DOTATATE PET/CT no more than 85 d apart was conducted. Patients with discordant disease were identified by the NETPET score, and discordant lesions were contoured with a flat [18F]FDG SUV cutoff of 4. The primary variable of interest was the total discordant volume (TDV), which was the sum of the volumes of discordant lesions. Patients were dichotomized into high- and low-TDV cohorts by the median value. The primary endpoint was overall survival. Results: In total, 44 patients were included (50% men; median age, 60 y), with primary cancers in the pancreas (45%), small bowel (23%), colon (20%), and other (12%). Of the patients, 5% had grade 1 disease, 48% had grade 2 disease, and 48% had grade 3 disease (24% well differentiated, 67% poorly differentiated, 10% unknown within the grade 3 cohort). The overall median survival was 14.1 mo. Overall survival was longer in the low-TDV cohort than in the high-TDV cohort (median volume, 43.7 cm3; survival time, 23.8 mo vs. 9.4 mo; hazard ratio, 0.466 [95% CI, 0.229–0.948]; P 5 0.0221). Patients with no more than 2 discordant intrahepatic lesions survived longer than those with 2 or more lesions (31.8 mo vs. 10.2 mo, respectively; hazard ratio, 0.389 [95% CI, 0.194–0.779]; P 5 0.0049). Conclusion: TDV is a potential prognostic biomarker in GEPNENs and should be investigated in future neuroendocrine neoplasm trials., SCOPUS: ar.j, info:eu-repo/semantics/published

Background: Gastroenteropancreatic neuroendocrine neoplasms (GEPNENs) are heterogeneous in clinical course, biology, and outcomes. The NETPET score predicts survival by scoring uptake on dual [68Ga]DOTATATE and [18F]FDG PET/CT scans. We aimed to validate previous single-centre findings in a multicentre, international study. Methods: Dual scans were assigned a NETPET score of P1 (DOTATATE positive/FDG negative), P2–4 (DOTATATE positive/FDG positive), or P5 (DOTATATE negative/FDG positive). NETPET score, histological grade, age at diagnosis, and presence/absence of extrahepatic disease were compared to overall survival/time to progression on univariate and multivariate analysis. Results: 319 metastatic/unresectable GEPNEN patients were included. The NETPET score was significantly associated with overall survival and time to progression on univariate and multivariate analysis (all p < 0.01). Median overall survival/time to progression was 101.8/25.5 months for P1, 46.5/16.7 months for P2–4, and 11.5/6.6 months for P5. Histological grade correlated with overall survival and time to progression on univariate and multivariate analysis (all p < 0.01), while presence/absence of extrahepatic disease did not. Age at diagnosis correlated with overall survival on univariate and multivariate analysis (p < 0.01). The NETPET score also correlated with histological grade (p < 0.001). Conclusion: This study validates the NETPET score as a prognostic biomarker in metastatic GEPNENs, capturing the complexity of dual PET imaging., SCOPUS: ar.j, info:eu-repo/semantics/published

Trastuzumab remains an important drug in the management of human epidermal growth factor receptor 2 (HER2) overexpressing breast cancer (BC). Several studies reported resistance mechanisms to trastuzumab, including impaired HER2-accessibility caused by mucin 4 (MUC4). Previously, we demonstrated an increase of Zirconium- 89-radiolabeled-trastuzumab (89Zr-Trastuzumab) accumulation when MUC4- overexpressing BC-cells were challenged with the mucolytic drug N-Acetylcysteine (NAC). Hereby, using the same approach we investigated whether tumor exposure to NAC would also enhance trastuzumab-efficacy. Dual SKBr3 (HER2+/MUC4-, sensitive to trastuzumab) and JIMT1 (HER2+/ MUC4+, resistant to trastuzumab) HER2-BC-bearing-xenografts were treated with trastuzumab and NAC. Treatment was monitored by molecular imaging evaluating HER2-accessibility/activity (89Zr-Trastuzumab HER2-immunoPET) and glucose metabolism (18F-FDG-PET/CT), as well as tumor volume and the expression of key proteins. In the MUC4-positive JIMT1-tumors, the NAC-trastuzumab combination resulted in improved tumor-growth control compared to trastuzumab alone; with smaller tumor volume/weight, lower 18F-FDG uptake, lower %Ki67 and pAkt-expression. NAC reduced MUC4-expression, but did not affect HER2-expression or the trastuzumabsensitivity of the MUC4-negative SKBr3-tumors. These findings suggest that improving HER2-accessibility by reducing MUC4- masking with the mucolytic drug NAC, results in a higher anti-tumor effect of trastuzumab. This provides a rationale for the potential benefit of this approach to possibly treat a subset of HER2-positive BC overexpressing MUC4., SCOPUS: ar.j, info:eu-repo/semantics/published

Purpose: To investigate and compare the quantitative accuracy of 90Y imaging across different generation PET/CT scanners, for the purpose of dosimetry after radioembolization with resin microspheres. Methods: A strict experimental and imaging protocol was followed by 47 international sites using the NEMA 2007/IEC 2008 PET body phantom with an 8-to-1 sphere-to-background ratio of 90Y solution. The phantom was imaged over a 7-day period (activity ranging from 0.5 to 3.0 GBq) and all reconstructed data were analysed at a core laboratory for consistent processing. Quantitative accuracy was assessed through measures of total phantom activity, activity concentration in background and hot spheres, misplaced counts in a nonradioactive insert, and background variability. Results: Of the 69 scanners assessed, 37 had both time-of-flight (ToF) and resolution recovery (RR) capability. These current generation scanners from GE, Philips and Siemens could reconstruct background concentration measures to within 10 % of true values over the evaluated range, with greater deviations on the Philips systems at low count rates, and demonstrated typical partial volume effects on hot sphere recovery, which dominated spheres of diameter <20 mm. For spheres >20 mm in diameter, activity concentrations were consistently underestimated by about 20 %. Non-ToF scanners from GE Healthcare and Siemens were capable of producing accurate measures, but with inferior quantitative recovery compared with ToF systems. Conclusion: Current generation ToF scanners can consistently reconstruct 90Y activity concentrations, but they underestimate activity concentrations in small structures (≤37 mm diameter) within a warm background due to partial volume effects and constraints of the reconstruction algorithm. At the highest count rates investigated, measures of background concentration (about 300 kBq/ml) could be estimated on average to within 1 %, 5 % and 2 % for GE Healthcare (, 0, SCOPUS: ar.j, info:eu-repo/semantics/published

Resectability of hepatocellular carcinoma in patients with chronic liver disease is dramatically limited by the need to preserve sufficient remnant liver in order to avoid postoperative liver insufficiency. Preoperative treatments aimed at downsizing the tumor and promoting hypertrophy of the future remnant liver may improve resectability and reduce operative morbidity. Here we report the case of a patient with a large hepatocellular carcinoma arising from chronic liver disease. Preoperative treatment, including tumor downsizing with transarterial radioembolization and induction of future remnant liver hypertrophy with right portal vein embolization, resulted in a 53% reduction in tumor volume and compensatory hypertrophy in the contralateral liver. The patient subsequently underwent extended right hepatectomy with no postoperative signs of liver decompensation. Pathological examination demonstrated a margin-free resection and major tumor response. This new therapeutic sequence, combining efficient tumor targeting and subsequent portal vein embolization, could improve the feasibility and safety of major liver resection for hepatocellular carcinoma in patients with liver injury., SCOPUS: ar.j, info:eu-repo/semantics/published

Binding of trastuzumab to HER2 receptors can be impaired by steric hindrance caused by mucin MUC4. As mucolytic drugs can breakdown disulfide bonds of mucoproteins, we checked if this approach could positively affect zirconium-89-labeled trastuzumab ([(89)Zr]T) binding/uptake., SCOPUS: ar.j, info:eu-repo/semantics/published

Texture indices are of growing interest for tumor characterization in 18F-FDG PET. Yet, on the basis of results published in the literature so far, it is unclear which indices should be used, what they represent, and how they relate to conventional indices such as standardized uptake values (SUVs), metabolic volume (MV), and total lesion glycolysis (TLG). We investigated in detail 31 texture indices, 5 firstorder statistics (histogram indices) derived from the gray-level histogram of the tumor region, and their relationship with SUV, MV, and TLG in 3 different tumor types. Methods: Three patient groups corresponding to 3 cancer types at baseline were studied independently: patients with metastatic colorectal cancer (72 lesions), non- small cell lung cancer (24 lesions), and breast cancer (54 lesions). Thirty-one texture indices were studied in addition to SUVs, MV, and TLG, and 5 indices extracted from histogram analysis were also investigated. The relationships between indices were studied as well as the robustness of the various texture indices with respect to the parameters involved in the calculation method (sampling schemes and tumor volume of interest). Results: Regardless of the patient group, many indices were highly correlated (Pearson correlation coefficient r ≥ 0.80), making it desirable to focus on only a few uncorrelated indices. Three histogram indices were highly correlated with SUVs (r ≥ 0.84). Four texture indices were highly correlated with MV, and none was highly correlated with SUVs (r ≤ 0.55). The resampling formula used to calculate texture indices had a substantial impact, and resampling using at least 32 discrete values should be used for texture indices calculation. The texture indices change as a function of the segmentation method was higher than that of peak and maximum SUVs but less than mean SUV for 5 texture indices and was larger than that of MV for 14 texture indices and for the 5 histogram indices. All these results were extremely c, SCOPUS: ar.j, info:eu-repo/semantics/published

SCOPUS: er.j, info:eu-repo/semantics/published

Intraarterial administration of (90)Y microspheres to the spleen in patients with malignant lymphoma was mentioned once in the literature in 1973. This case study illustrates the potential indication of selective internal radiotherapy in a heavily pretreated patient with highly refractory disease with a marginal zone lymphoma in leukemic phase and symptomatic splenomegaly. We describe the clinical course of disease; the biological and clinical response to the treatment after radioembolization; and simulation and dosimetry by multimodal imaging via single-photon emission computed tomography and computed tomography. The advantages of radioembolization for the management of lymphomatous splenomegaly are discussed., JOURNAL ARTICLE, SCOPUS: ar.j, info:eu-repo/semantics/published

Background The study purpose was to assess the predictive value of 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography (PET)/computerized tomography (CT) metabolic response after a single course of chemotherapy in patients with metastatic colorectal cancer (mCRC). Patients and methods FDG-PET/CT scans were carried out at baseline and on day 14 in 41 patients with unresectable mCRC treated with a biweekly regimen of chemotherapy. Metabolic nonresponse was defined by <15% decrease in FDG uptake in the dominant proportion of the patient's lesions or if a lesion was found metabolically progressive. The PET-based response was correlated with radiological response (primary end point) and patient's outcome (secondary end points). Results RECIST response rate in metabolically responding patients was 43% (10 of 23) compared with 0% (0 of 17) in nonresponding patients (P = 0.002). The metabolic assessment's predictive performance for RECIST response was sensitivity 100% [95% confidence interval (CI) 69% to 100%], specificity 57% (95% CI 37% to 75%), positive predictive value 43% (95% CI 23% to 66%), and negative predictive value 100% (95% CI 80% to 100%). Comparing metabolically responding versus nonresponding patients, the hazard ratio (HR) was 0.28 (95% CI 0.10-0.76) for overall survival and 0.57 (95% CI 0.27-1.21) for progression-free survival. Conclusion The metabolic response measured by FDG-PET/CT after a single course of chemotherapy in mCRC is able to identify patients who will not benefit from the treatment., Journal Article, SCOPUS: ar.j, info:eu-repo/semantics/published

http://www.omicsonline.org/2155-9619/2155-9619-2-113.php, info:eu-repo/semantics/published

In PET-based patient monitoring, metabolic tumor changes occurring between PET scans are most often assessed visually or by measuring only a few parameters (tumor volume or uptake), neglecting most of the image content. We propose and evaluate a parametric imaging (PI) method to assess tumor changes at the voxel level., Journal Article, SCOPUS: ar.j, info:eu-repo/semantics/published

The aim of this retrospective study was to describe the intra-individual heterogeneity of the ¹⁸F-labelled fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) response among lesions in bone-dominant metastatic breast cancer patients treated with systemic therapies., Journal Article, SCOPUS: ar.j, info:eu-repo/semantics/published

Selective internal radiotherapy (SIRT) using Yttrium-90 labeled resin microspheres is increasingly used for the radioembolization of unresectable liver metastases of colorectal cancer (CRC). The treatment can be simulated by scintigraphy with Tc(99m)-labeled macroaggregates of albumin (MAA). The aim of the study was to develop a predictive dosimetric model for SIRT and to validate it by correlating results with the metabolic treatment response. The simulation of the dosimetry was performed by mathematically converting all liver voxel MAA-SPECT uptake values to the absolute Y(90) activity. The voxel values were then converted to a simulated absorbed dose (Gy) using simple MIRD formalism. The metabolic response was defined as the change in total lesion glycolysis (TLG) on FDG-PET. A total of 39 metastatic liver lesions were studied in eight evaluable patients. The mean administered Y(90) activity was 1.69 GBq (range: 1.33-2.04 GBq). The median (95% CI) simulated absorbed dose (Gy) was 29 Gy (1–98 Gy) and 66 Gy(32–159 Gy) in the poor (<50% TLG change) and the good responders (TLG change > 50%),respectively [DOSAGE ERROR CORRECTED].Using a simple cut-off value of 1 for the MAA-tumor-to-normal uptake ratio, a significant metabolic response was predicted with a sensitivity of 89% (17/19), a specificity of 65% (13/20), a positive predictive value of 71% (17/24) and a negative predictive value of 87% (13/15). Integrated multimodality imaging allows prediction of metabolic response post radioembolization using Y(90)-resin microspheres, and should be used for patient selection.

Selective internal radiotherapy (SIRT) using Yttrium-90 labeled resin microspheres is increasingly used for the radioembolization of unresectable liver metastases of colorectal cancer (CRC). The treatment can be simulated by scintigraphy with Tc(99m)-labeled macroaggregates of albumin (MAA). The aim of the study was to develop a predictive dosimetric model for SIRT and to validate it by correlating results with the metabolic treatment response. The simulation of the dosimetry was performed by mathematically converting all liver voxel MAA-SPECT uptake values to the absolute Y(90) activity. The voxel values were then converted to a simulated absorbed dose (Gy) using simple MIRD formalism. The metabolic response was defined as the change in total lesion glycolysis (TLG) on FDG-PET. A total of 39 metastatic liver lesions were studied in eight evaluable patients. The mean administered Y(90) activity was 1.69 GBq (range: 1.33-2.04 GBq). The median change in TLG of the lesions was 48%. The median (95% CI) simulated absorbed dose (Gy) was 20 Gy (1-68 Gy) and 46 Gy (22-110 Gy) in the poor (<50% TLG change) and the good responders (TLG change > 50%), respectively. Using a simple cut-off value of 1 for the MAA-tumor-to-normal uptake ratio, a significant metabolic response was predicted with a sensitivity of 89% (17/19), a specificity of 65% (13/20), a positive predictive value of 71% (17/24) and a negative predictive value of 87% (13/15). Integrated multimodality imaging allows prediction of metabolic response post radioembolization using Y(90)-resin microspheres, and should be used for patient selection., Journal Article, SCOPUS: ar.j, info:eu-repo/semantics/published

Background: Standard evaluation of response to chemotherapy in metastatic CRC is unsatisfactory. Metabolism based imaging using positron emission tomography and fluorodeoxyglucose (FDG-PET) is increasingly used to assess treatment efficacy. Aim: To evaluate the prognostic value of FDG-PET metabolic response to chemotherapy in resectable metastatic CRC. Methods: We reviewed retrospectively 382 patients with metastatic CRC between 7/2002 and 8/2006. Patients curatively operated from CRC metastases treated with preoperative chemotherapy and evaluated by FDG PET at baseline and before surgery were considered eligible for the study. Time to progression (TTP) was defined as the time between surgery and the first proof of recurrence of disease. Total Lesion Glycolysis (TLG) was used as the metabolic parameter. It represents the product of the mean standardised FDG uptake (SUV) of each lesion and its volume. The change of the sum of the TLG of all lesions was calculated. A cut-off of 30% was used to differentiate responders and non- responders. Results: 18 patients (median age 65 yrs) were included. 16 patients were operated from liver mets, and 2 from lung mets. Chemotherapy regimen was FOLFOX 4 in 10 patients, FOLFIRI in 7, and FOLFIRI-bevacizumab in 1 patient. Median number of lesions was 3 (1 to 10) before and 1 after chemotherapy. Median baseline TLG was 115.8 (6.8–841.8). Median post chemo TLG was 12.8 (0–1608.9). The distribution of the metabolic responses was CR 5, PR 9, SD 1, PD 3, with a response rate of 14/18 (78%, 95% CI : 52%-94%). Baseline TLG was not different between responders and non responders (p=0.88). Median follow-up was 422 days: 6 patients died, 15 had recurrent disease. Median TTP was 31 days for non responders, and 197 days for responders (p value not calculated because of the small number of non responding patients). After dichotomization of TLG values using their median as threshold, the post chemo TLG influenced significantly TTP (p=0.001, media