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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 p p p Conclusion This study validates the NETPET score as a prognostic biomarker in metastatic GEPNENs, capturing the complexity of dual PET imaging.

(1) Background: The European Association of Urology (EAU) biochemical recurrence (BCR) risk grouping relies on data from historical cohorts that used conventional imaging techniques. In the era of PSMA PET/CT, we compared the patterns of positivity in the two risk groups and provided insight into positivity predictive factors. (2) Methods: Data from 1185 patients who underwent 68Ga-PSMA-11PET/CT for BCR was analyzed, out of which 435 patients treated initially treated by radical prostatectomy were included in the final analysis. (3) Results: A significantly higher rate of positivity in the BCR high-risk group was observed (59% vs. 36%, p < 0.001). BCR low-risk group demonstrated more local (26% vs. 6%, p < 0.001) and oligometastatic (100% vs. 81%, p < 0.001) recurrences. The BCR risk group and PSA level at the time of PSMA PET/CT were independent predictive factors of positivity. (4) Conclusions: This study confirms that the EAU BCR risk groups have different rates of PSMA PET/CT positivity. Even with a lower rate in the BCR low-risk group, oligometastatic disease was 100% in those with distant metastases. Given the presence of discordant positivity and risk classification, integrating PSMA PET/CT positivity predictors into risk calculators for BCR might improve patient classification for subsequent treatment options. Future prospective studies are still needed to validate the above findings and assumptions.

Aim: We aimed to evaluate the role of Positron Emission Tomography (PET) targeting the Prostate-Specific Membrane Antigen (PSMA) for response assessment in metastatic prostate cancer (mPCa) patients treated with taxane-based chemotherapy (docetaxel or cabazitaxel) and its predictive value on patient outcome. Methods: We retrospectively evaluated 37 patients with metastatic hormone-sensitive or castration-resistant prostate cancer (mHSPC or mCRPC) who underwent 68Ga-PSMA-11 PET/CT at baseline and after the last cycle of taxane-based chemotherapy (docetaxel or cabazitaxel) without treatment modification between scans. Biochemical response (BR) was defined as an undetectable or decreased prostate-specific antigen (PSA) by ≥50% compared to baseline. Association between BR and different PET parameters were tested. A cut-off of ≥30% change in PSMA total tumor volume (PSMA-TV) was used to define PSMA responders (PSMA-R) vs PSMA non-responders (PSMA-NR). Correlation between PSMA-PET/CT response and BR was evaluated using the Phi coefficient. Association between PET-response and overall survival (OS) was performed using Cox regression and Kaplan-Meier method. Results: Our cohort was composed of 8 (22%) mHSPC and 29 (78%) mCRPC patients. Twenty-one patients received docetaxel, and 16 received cabazitaxel treatment (median: 6 cycles, interquartile (IQR):5-8). BR was found in 18/37 patients. Using PSMA-TV, PSMA-PET/CT response was concordant with BR in 35/37 patients (Phi=0.89, p

Radionuclide Therapy (RNT) with 177Lu-DOTATATE targeting somatostatin receptors (SSTRs) in neuroendocrine tumours (NET) has been successfully used in routine clinical practice, mainly leading to stable disease. Radiobiology holds promise for RNT improvement but is often extrapolated from external beam radiation therapy (EBRT) studies despite differences in these two radiation-based treatment modalities. In a panel of six human cancer cell lines expressing SSTRs, common radiobiological endpoints (i.e., cell survival, cell cycle, cell death, oxidative stress and DNA damage) were evaluated over time in 177Lu-DOTATATE- and EBRT-treated cells, as well as the radiosensitizing potential of poly (ADP-ribose) polymerase inhibition (PARPi). Our study showed that common radiobiological mechanisms were induced by both 177Lu-DOTATATE and EBRT, but to a different extent and/or with variable kinetics, including in the DNA damage response. A higher radiosensitizing potential of PARPi was observed for EBRT compared to 177Lu-DOTATATE. Our data reinforce the need for dedicated RNT radiobiology studies, in order to derive its maximum therapeutic benefit.

Introduction [177Lu]Lu-DOTATATE is an effective systemic targeted radionuclide therapy for somatostatin receptor (SSTR) positive metastatic or inoperable neuroendocrine tumours (NET). However, for a given injected activity, tumour responses are variable. Our aim was to investigate whether SSTR expression/functionality and known characteristics of intrinsic radiosensitivity, namely proliferation rate, glucose metabolism, cell cycle phase, DNA repair and antioxidant defences were predictors of sensitivity to [177Lu]Lu-DOTATATE in SSTR expressing human cancer cell lines. Methods In six human cancer cell lines and under basal condition, SSTR expression was assessed by qRT-PCR and immunocytochemistry. Its functionality was evaluated by binding/uptake assays with [68Ga]Ga- and [177Lu]Lu-DOTATATE. The radiosensitivity parameters were evaluated as follows: proliferation rate (cell counting), glucose metabolism ([18F]FDG uptake), antioxidant defences (qRT-PCR, colorimetric assay, flow cytometry), DNA repair (qRT-PCR) and cell cycle (flow cytometry). Effect of [177Lu]Lu-DOTATATE on cell viability was assessed 3, 7 and 10 days after 4 h incubation with [177Lu]Lu-DOTATATE using crystal violet. Results Based on cell survival at day 10, cell lines were classified into two groups of sensitivity to [177Lu]Lu-DOTATATE. One group with 20% of survival decrease (−22 to −33%) compared to the untreated control cell lines. The latter had significantly lower total antioxidant capacity, glutathione (GSH) levels and glucose metabolism (p 0.22), combined catalase and GSH peroxidase expression (p = 0.42) and superoxide dismutase (SOD) activity (p = 0.41) were not significantly different between the two groups. Conclusion Antioxidant defences may be major determinants in [177Lu]Lu-DOTATATE radiosensitivity.

Peptide receptor radionuclide therapy with 177Lu-DOTATATE improves the outcome of patients with somatostatin receptor (SSTR)-expressing neuroendocrine tumours. Nevertheless, stable disease has been the main response pattern observed, with some rare complete responses. Lu-177 exerts about two-thirds of its biological effects via the indirect effects of ionizing radiation that generate reactive oxygen species, eventually leading to oxidative damage and cell death. This provides a rationale for targeting the antioxidant defence system in combination with 177Lu-DOTATATE. In the present study, the radiosensitizing potential and the safety of depleting glutathione (GSH) levels using buthionine sulfoximine (BSO) during 177Lu-DOTATATE therapy were assessed in vitro and in vivo using a xenograft mouse model. In vitro, the combination resulted in a synergistic effect in cell lines exhibiting a BSO-mediated GSH decrease. In vivo, BSO neither influenced 177Lu-DOTATATE biodistribution nor induced liver, kidney or bone marrow toxicity. In terms of efficacy, the combination resulted in reduced tumour growth and metabolic activity. Our results showed that disturbing the cell redox balance using a GSH synthesis inhibitor increased 177Lu-DOTATATE efficacy without additional toxicity. Targeting the antioxidant defence system opens new safe treatment combination opportunities with 177Lu-DOTATATE.

Gastroenteropancreatic neuroendocrine neoplasms (GEPNENs) are heterogeneous in clinical course, biology, and outcomes. The NETPET score predicts survival by scoring uptake on dual [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.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).This study validates the NETPET score as a prognostic biomarker in metastatic GEPNENs, capturing the complexity of dual PET imaging.

We present a case of Grade II, well-differentiated rectal neuroendocrine tumor in a 39-year-old patient. Following different sequential treatment modalities, the disease progressed both on metabolic (18F-fluorodeoxyglucose positron emission tomography-computed tomography [18F-FDG PET/CT]) and somatostatin receptor (SSTR)-imaging (68Ga-DOTA-Tyr3-octreotate [68Ga-DOTATATE] PET/CT), and the patient received three cycles of peptide receptor radiotherapy (PRRT). Two years later, upon new progression due to the appearance of metabolically active, 68Ga-DOTATATE PET/CT-negative liver lesions, targeted treatment with everolimus was introduced. Further morphologic and metabolic progression occurred 4 months after everolimus initiation, however, this time liver lesions demonstrated increased SSTR-expression on68Ga-DOTATATE PET/CT. Thus, the patient became eligible for a second PRRT course.

Follicular thyroid cancer (FTC) is a less common form of differentiated thyroid cancer. Liver metastasis of differentiated thyroid cancer frequently occurs in the late onset of the metastatic disease, are often unrescetable and noniodine avid, leading to a poor prognosis. A 69-year-old man with a 14-year history of multi-metastatic follicular thyroid cancer was treated iteratively with 131-Iodine allowing to maintain a stable disease. Upon a recent exponential increase of the thyroglobulin, a peritoneal mass and a voluminous hepatic metastasis were discovered, comorbidities and an insufficient future remnant liver function excluded liver surgical resection. The tumour board proposed a resection of the peritoneal mass followed by selective internal radiation therapy of the liver mass. Due to the already impaired liver function, personalized dosimetry allowed a safe treatment delivering low activity to the nontumoral liver followed by a clinical and imaging response of the liver mass at 3 months. At our knowledge, this is the first case of thyroid liver metastasis treated by selective internal radiation therapy. Keywords: Liver metastasis, Personalized dosimetry, Radioembolization, Thyroid Cancer

Background: The combination of everolimus and an endocrine agent has shown a progression-free survival (PFS) benefit but also significant toxicity in locally advanced and/or metastatic breast cancer (MBC) patients. Disappointingly, all translational research efforts conducted so far on primary/metastatic tissue or baseline ctDNA samples have failed to identify clinically useful biomarkers of benefit with the possible exception of p4EBP1 which requires fresh metastatic biopsies (Bachelot at al, ASCO 2019). Methods: Forty-seven patients were included in the PEARL trial in six Belgian centres. All patients underwent one baseline and one “early” 18FDG-PET/CT on day 14 (blinded to the treating oncologist) after treatment initiation. Eligible patients had prior progression on NSAI and at least one measurable lesion on baseline 18FDG-PET/CT (fulfilling PERCIST). Twenty seven of the 47 patients were treated in a pilot phase aiming to characterize 18FDG-PET/CT metabolic responses 14 and 28 days after treatment initiation. Day 14 18FDG-PET/CT was selected for the second phase in which 20 more patients were included to answer the primary endpoint of the trial, namely the potential of an early FDG-PET/CT to select patients who will not derive a long-term benefit from everolimus-exemestane combination. We considered as “metabolic responders” those patients in whom at least a 25% homogenous decrease in SUVmax was seen in all their target lesions; the so called “consistent” patient-based response, here correlated to PFS. Results: Seventy-four percent of the patients had visceral metastasis, 26% were pretreated with CDK 4/6 inhibitors and 58% with at least one line of chemotherapy (28% ≥ 2 lines) for the treatment of MBC. Metabolic non-response rate on day 14 was 64%. Two patients were considered non-evaluable because they stopped everolimus 3 and 8 days before early 18FDG-PET/CT respectively. The median PFS in non-responding patients was 2.3 months compared to 6 months in those who showed a consistent metabolic response (HR-1.96, 95%CI: 0.98-3.95, p=0.05). We’ll be able to assess whether day 14 ctDNA measurements add predictive value to imaging. Conclusion: Absence of 18FDG-PET/CT metabolic response after 14 days of everolimus-exemestane combination is associated with a low probability to derive benefit from this treatment. The advanced stage of the patients included in this trial (75% visceral metastasis) and their extensive prior treatments can explain the poorer outcome seen with exemestane-everolimus compared to the Bolero2 trial. Citation Format: Andrea Gombos, Martine Piccart-Gebhart, Lieveke Ameye, Peter Vuylsteke, Patrick Neven, Vincent Richard, Francois P Duhoux, Marianne Paesmans, Michail Ignatiadis, Patrick Flamen, Géraldine Gebhart. Pearl or the use of FDG positron emission tomography imaging as an early dynamic biomarker of everolimus efficacy in advanced luminal breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-22.

Background Immunotherapy represents a promising option for treatment of hepatocellular carcinoma (HCC) in cirrhotic patients but its efficacy is currently inconsistent and unpredictable. Locoregional therapies inducing immunogenic cell death, such as transarterial chemoembolization (TACE) or selective internal radiation therapy (SIRT), have the potential to act synergistically with immunotherapy. For the development of new approaches combining locoregional treatments with immunotherapy, a better understanding of the respective effects of TACE and SIRT on recruitment and activation of immune cells in HCC is needed. To address this question, we compared intra-tumor immune infiltrates in resected HCC after preoperative treatment with TACE or SIRT. Methods Data fromr patients undergoing partial hepatectomy for HCC, without preoperative treatment (SURG, n = 32), after preoperative TACE (TACE, n = 16), or preoperative SIRT (n = 12) were analyzed. Clinicopathological factors, tumor-infiltrating lymphocytes (TILs), CD4+ and CD8+ T cells, and granzyme B (GZB) expression in resected HCC, and postoperative overall and progression-free survival were compared between the three groups. Results Clinicopathological and surgical characteristics were similar in the three groups. A significant increase in TILs, CD4+ and CD8+ T cells, and GZB expression was observed in resected HCC in SIRT as compared to TACE and SURG groups. No difference in immune infiltrates was observed between TACE and SURG patients. Within the SIRT group, the dose of irradiation affected the type of immune infiltrate. A significantly higher ratio of CD3+ cells was observed in the peri-tumoral area in patients receiving + cells was observed in patients receiving > 100 Gy. Postoperative outcomes were similar in all groups. Irrespective of the preoperative treatment, the type and extent of immune infiltrates did not influence postoperative survival. Conclusions SIRT significantly promotes recruitment/activation of intra-tumor effector-type immune cells compared to TACE or no preoperative treatment. These results suggest that SIRT is a better candidate than TACE to be combined with immunotherapy for treatment of HCC. Evaluation of the optimal doses for SIRT for producing an immunogenic effect and the type of immunotherapy to be used require further evaluation in prospective studies.

Background While circulating tumour (ct)DNA is an indicator of minimal residual disease and negative prognostic factor in stage II-III colon cancer, no study has ever analysed the value of this biomarker in colon cancer patients treated with neoadjuvant chemotherapy. We sought to fill this gap by using prospectively collected plasma samples from 80 stage III colon cancer patients, receiving one cycle of neoadjuvant FOLFOX followed by surgery +/- adjuvant FOLFOX in the PePiTA trial. Material and Methods Samples were collected at baseline, 2 weeks and surgery. NPY and WIF1 were selected as universal methylation markers for ctDNA, and analysed with ddPCR technology. ROC curves were applied for cut-off points, and outcome measures included 5-year disease-free survival (DFS) and 6-year overall survival (OS). Results After a median follow-up of 52.5 months, baseline circulating-free (cf) DNA was an independent prognostic factor for DFS (HR 3.35, 95% CI: 1.15-9.77, p = .03), and a trend towards a similar association was observed for relative cfDNA changes between baseline and surgery (HR 2.57, 95% CI: 0.94-7.05, p = .07). Among 60 ctDNA assessable patients, 25 (42%) had detectable ctDNA at baseline. While detection of ctDNA at any pre-operative timepoint was not associated with outcome, patients with ctDNA increase (change of the worst trending methylation marker >= 11%, or mean ctDNA change of NPY and WIF1 >= 0%) between baseline and surgery showed a trend towards worse 5-year DFS (HR 3.66, 95% CI: 0.81-16.44, p = .09). Conclusion This is the first study of ctDNA in the neoadjuvant setting of early-stage colon cancer. Results are hypothesis-generating and should be confirmed in larger series.

A 51-year-old male was found with bilateral thyroid nodules on ultrasonography neck imaging. The largest nodule, measuring 23 × 26 × 35 mm, was located in the left lobe and was classified as EU-TIRADS 4. Thyroid function tests were normal, as were serum levels of parathormone, Chromogranin A, carcinoembryonic antigen and calcitonin. The nodule was cold on thyroid scintigraphy. Fine-needle aspiration of the nodule did not demonstrate cellular atypia. High focal uptake was found on both 111In-DTPA-octreotide scintigraphy and 68Ga-DOTATATE PET/CT. Histopathological analysis showed a microfollicular adenoma without malignancy. Immunohistochemical staining did not suggest neuroendocrine neoplasia or C cell hyperplasia. However, high expression of somatostatin receptor 2 (SSTR2) was observed in the microfollicular adenoma compared to the surrounding healthy tissue, with predominant localization in the endothelial cells and at the secretory pole of the thyroid epithelial cells in contact with blood vessels. High focal thyroid uptake on 68Ga-DOTATATE PET/CT can be observed in benign thyroid nodules due to an overexpression of SSTR by endothelial cells. However, incidental focal thyroid uptake on SSTR imaging requires further investigations to rule out thyroid malignancy.

Simple Summary The early treatment of oligometastatic disease (OMD) is a promising therapeutic option for prostate cancer as it has the potential of delaying androgen-deprivation therapy (ADT) and disease progression. Next-generation imaging targeting the prostate-specific membrane antigen (PSMA-PET/CT) is considered the most accurate technique for recurrent prostate cancer. Finding clinico-pathological factors predicting positivity with OMD detection on PSMA-PET/CT, as well as assessing its impact on treatment management, were the main objectives of our study. We selected a homogenous population of ADT-free prostate cancer patients with a PSMA-PET/CT performed at biochemical recurrence (BCR) after radical prostatectomy (RP). OMD was detected in 44% of patients for a total positivity rate of 60%. PSA at the moment of PET, PSAdt, and the absence of previous salvage treatment were factors predicting PSMA-PET/CT positivity with OMD. A change in clinical management occurred in more than half of the patients, mostly to perform metastasis-directed therapy after OMD detection. Abstract Metastasis-directed therapy (MDT) in oligometastatic prostate cancer has the potential of delaying the start of androgen deprivation therapy (ADT) and disease progression. We aimed to analyze the efficacy of PSMA-PET/CT in detecting oligometastatic disease (OMD), to look for predictive factors of OMD, and to evaluate the impact of PSMA-PET/CT findings on clinical management. We retrospectively analyzed a homogeneous population of 196 hormone-sensitive prostate cancer patients (HSPC), considered potential candidates for MDT, with a PSMA-PET/CT performed at biochemical recurrence (BCR) after radical prostatectomy (RP). Multivariable logistic regression analysis was performed based on several clinico-pathological factors. Changes in clinical management before and after PSMA-PET/CT were analyzed. The OMD detection rate was 44% for a total positivity rate of 60%. PSMA-PET/CT positivity was independently related to PSA (OR (95% CI), p) (1.7 (1.3–2.3), p < 0.0001) and PSAdt (0.4 (0.2–0.8), p = 0.013), and OMD detection was independently related to PSA (1.6 (1.2–2.2), p = 0.001) and no previous salvage therapy (0.3 (0.1–0.9), p = 0.038). A treatment change was observed in 58% of patients, mostly to perform MDT after OMD detection (60% of changes). This study showed that PSMA-PET/CT is an excellent imaging technique to detect OMD early in HSPC patients with BCR after RP, changing therapeutic management mostly into MDT.

Biomarkers to identify patients without benefit from adding everolimus to endocrine treatment in metastatic breast cancer (MBC) are needed. We report the results of the Pearl trial conducted in five Belgian centers assessing 18F-FDG-PET/CT non-response (n = 45) and ctDNA detection (n = 46) after 14 days of exemestane-everolimus (EXE-EVE) to identify MBC patients who will not benefit. The metabolic non-response rate was 66.6%. Median PFS in non-responding patients (using as cut-off 25% for SUVmax decrease) was 3.1 months compared to 6.0 months in those showing response (HR: 0.77, 95% CI: 0.40–1.50, p = 0.44). The difference was significant when using a “post-hoc” cut-off of 15% (PFS 2.2 months vs 6.4 months). ctDNA detection at D14 was associated with PFS: 2.1 months vs 5.0 months (HR-2.5, 95% CI: 1.3–5.0, p = 0.012). Detection of ctDNA and/or the absence of 18F-FDG-PET/CT response after 14 days of EXE-EVE identifies patients with a low probability of benefiting from treatment. Independent validation is needed., SCOPUS: ar.j, info:eu-repo/semantics/published

BACKGROUND Early prediction of nonresponse is essential in order to avoid inefficient treatments. PURPOSE To evaluate if parametrical response mapping (PRM)-derived biomarkers could predict early morphological response (EMR) and pathological complete response (pCR) 24-72 hours after initiation of chemotherapy treatment and whether concentric analysis of nonresponding PRM regions could better predict response. STUDY TYPE This was a retrospective analysis of prospectively acquired cohort, nonrandomized, monocentric, diagnostic study. POPULATION Sixty patients were initially recruited, with 39 women participating in the final cohort. FIELD STRENGTH/SEQUENCE A 1.5T scanner was used for MRI examinations. ASSESSMENT Dynamic contrast-enhanced (DCE)-MR images were acquired at baseline (timepoint 1, TP1), 24-72 hours after the first chemotherapy (TP2), and after the end of anthracycline treatment (TP3). PRM was performed after fusion of T1 subtraction images from TP1 and TP2 using an affine registration algorithm. Pixels with an increase of more than 10% of their value (PRMdce+) were corresponding nonresponding regions of the tumor. Patients with a decrease of maximum diameter (%dDmax) between TP1 and TP3 of more than 30% were defined as EMR responders. pCR patients achieved a residual cancer burden score of 0. STATISTICAL TESTS T-test, receiver operating characteristic (ROC) curves, and logistic regression were used for the analysis. RESULTS PRM showed a statistical difference between pCR response groups (P < 0.01) and AUC of 0.88 for the prediction of non-pCR. Logistic regression analysis demonstrated that PRMdce+ and Grade II were significant (P < 0.01) for non-pCR prediction (AUC = 0.94). Peripheral tumor region demonstrated higher performance for the prediction of non-pCR (AUC = 0.85) than intermediate and central zones; however, statistical comparison showed no significant difference. DATA CONCLUSION PRM could be predictive of non-pCR 24-72 hours after initiation of chemotherapy treatment. Moreover, the peripheral region showed increased AUC for non-pCR prediction and increased signal intensity during treatment for non-pCR tumors, information that could be used for optimal tissue sampling. LEVEL OF EVIDENCE 1 Technical Efficacy Stage: 4 J. Magn. Reson. Imaging 2020;51:1403-1411.

Background and Objectives: Selection for surgery in patients with colorectal liver metastases (CRLM) remains inaccurate. We evaluated if CRLM baseline metabolic characteristics, assessed by [18]F-fluorodeoxyglucose-positron emission tomography/computed tomography (18FDG-PET/CT), could predict postoperative outcomes. Methods: In a retrospective series of patients undergoing surgery for CRLM, we defined two groups: the long-term survival (LTS) and early relapse (ER) groups, where the postoperative recurrence-free survivals were ≥5 years or 4.3, defining low- and high-risk mCRS by scores of 0 to 2 and 3 to 6, respectively. Results: From a series of 450 patients operated for CRLM (mean follow-up of 58 months), we included for analysis 23 and 30 patients in the LTS and ER groups, respectively. Clinicopathologic parameters and CRS were similar in the LTS and ER groups. Median SUVmax/SUVmean(liver) ratios were higher in ER vs LTS patients (4.2 and 2.8, P =.008, respectively). mCRS was increased in ER patients (P =.024); 61% of LTS patients had low-risk mCRS and 73% of the ER patients had high-risk mCRS (P =.023). Conclusions: 18FDG-PET/CT characteristics combined with traditional CRS may represent a new tool to improve selection for surgery in patients with CRLM., SCOPUS: ar.j, info:eu-repo/semantics/published

To investigate the association between Prostate-Specific Membrane Antigen (PSMA) expression changes on positron emission tomography–computed tomography (PET/CT) and the response to treatment following the start of enzalutamide or abiraterone in metastatic castration-resistant prostate cancer (mCRPC) patients. All consecutive 68Ga-PSMA-11 PET/CT scans routinely performed at our institution during more than 4 years were retrospectively screened for inclusion. We included mCRPC patients with a baseline PSMA PET/CT performed less than 2 months before the start of either enzalutamide or abiraterone, and a follow-up PSMA PET/CT performed no more than a year after, while still under those novel antiandrogen drugs (NAD). The associated clinical records were reviewed. Patients were considered treatment responders if they presented decreasing PSA levels > 50% or a radiological response based on RECIST 1.1 criteria. PSMA expression changes on the follow-up PET/CT were assessed using per-patient dominant response criteria to classify patients as PSMA-responders (complete disappearance of pathologic PSMA uptake, or a decreased uptake of the majority of lesions) or PSMA-non-responders (new PSMA-expressing lesions, increased uptake of the majority of lesions, or stable PSMA expression of the disease). Descriptive statistics and measures of associations (two-sided Fisher’s exact test and Phi coefficient) were calculated. A total of 11 and 15 patients were included in the enzalutamide and abiraterone groups. Median follow-up was 110 (IQR 76–124) and 87 (IQR 71–242) days, respectively. All treatment responders (3 enzalutamide and 4 abiraterone) were considered PSMA-responders, and all treatment non-responders (8 enzalutamide, 11 abiraterone) were considered PSMA-non-responders. PSMA PET response was thus perfectly associated with conventional response criteria (p = 0.006, Phi = 1 for enzalutamide; p = 0.001, Phi = 1 for abiraterone). In our cohort, no PSMA expression flare phenomenon was detected on follow-up PET/CT scans at a median follow-up of 3 months. However, an early and short-lived flare cannot be excluded. This retrospective study suggests that, after a median follow-up of 3 months under enzalutamide or abiraterone, PSMA expression changes on PET/CT are strongly associated with response to treatment. Prospective studies are needed to better understand PSMA expression dynamics following the start of enzalutamide and abiraterone, along with the role of PSMA PET/CT in response assessment.

Purpose: Reported outcomes of patients with intra-hepatic cholangiocarcinoma (IH-CCA) treated with radioembolization are highly variable, which indicates differences in included patients’ characteristics and/or procedure-related variables. This study aimed to identify patient- and treatment-related variables predictive for radioembolization outcome. Methods: This retrospective multicenter study enrolled 58 patients with unresectable and chemorefractory IH-CCA treated with resin 90Y-microspheres. Clinicopathologic data were collected from patient records. Metabolic parameters of liver tumor(s) and presence of lymph node metastasis were measured on baseline 18F-FDG-PET/CT. 99mTc-MAA tumor to liver uptake ratio (TLRMAA) was computed for each lesion on the SPECT-CT. Activity prescription using body-surface-area (BSA) or more personalized partition-model was recorded. The study endpoint was overall survival (OS) starting from date of radioembolization. Statistical analysis was performed by the log-rank test and multivariate Cox’s proportional hazards model. Results: Median OS (mOS) post-radioembolization of the entire cohort was 10.3 months. Variables associated with significant differences in terms of OS were serum albumin (hazard ratio (HR) = 2.78, 95%CI:1.29–5.98, p = 0.002), total bilirubin (HR = 2.17, 95%CI:1.14–4.12, p = 0.009), aspartate aminotransferase (HR = 2.96, 95%CI:1.50–5.84, p < 0.001), alanine aminotransferase (HR = 2.02, 95%CI:1.05–3.90, p = 0.01) and γ-GT (HR = 2.61, 95%CI:1.31–5.22, p < 0.001). The presence of lymph node metastasis as well as a TLRMAA < 1.9 were associated with shorter mOS: HR = 2.35, 95%CI:1.08–5.11, p = 0.008 and HR = 2.92, 95%CI:1.01–8.44, p = 0.009, respectively. Finally, mOS was significantly shorter in patients treated according to the BSA method compared to the partition-model: mOS of 5.5 vs 14.9 months (HR = 2.52, 95%CI:1.23–5.16, p < 0.001). Multivariate analysis indicated that the only variable that increased outcome prediction above the clinical variables was the activity prescription method with HR of 2.26 (95%CI:1.09–4.70, p = 0.03). The average mean radiation dose to tumors was significantly higher with the partition-model (86Gy) versus BSA (38Gy). Conclusion: Radioembolization efficacy in patients with unresectable recurrent and/or chemorefractory IH-CCA strongly depends on the tumor radiation dose. Personalized activity prescription should be performed., SCOPUS: ar.j, info:eu-repo/semantics/published

The aim of this communication was to assess the efficacy of directed oligometastatic radiotherapy (RT) based on 68Ga-PSMA PET/CT in patients with prostate cancer (PCa) biochemical relapse (BCR) after primary treatment with curative intent., SCOPUS: ar.j, info:eu-repo/semantics/published

Radioembolization of liver metastases of neuroendocrine neoplasms (NEN) has shown promising results; however, the current literature is of limited quality. A large international, multicentre retrospective study was designed to address several shortcomings of the current literature. 244 NEN patients with different NEN grades were included. Primary outcome parameters were radiologic response 3 and 6 months after treatment according to RECIST 1.1 and mRECIST. Secondary outcome parameters included clinical response, clinical and biochemical toxicities. Radioembolization resulted in CR in 2%, PR in 14%, SD in 75% and PD 9% according to RECIST 1.1 and in CR in 8%, PR in 35%, SD in 48% and PD in 9% according to mRECIST. Objective response rates improved over time in 20% and 26% according to RECIST 1.1. and mRECIST, respectively. Most common new grade 3–4 biochemical toxicity was lymphocytopenia (6.7%). No unexpected clinical toxicities occurred. Radioembolization-specific complications occurred in

Purpose of review Targeted radionuclide therapy (TRNT) is characterized by systemic administration of radiolabelled drugs, targeting specific molecular alterations expressed on the tumour cells. Small molecules, labelled with β- or α- emitting radioisotopes, are used to deliver radiation directly to the tumour sites. Pretreatment imaging to visualize whole body biodistribution of the target, using the same drugs labelled with positron or γ-emitting radionuclides, completes the concept of theranostic. This review will briefly summarize the current clinical research findings and applications of TRNT in solid tumours, mostly focusing on neuroendocrine and prostate neoplasms. Recent findings Peptide receptor radionuclide therapy is a major component in the management of gastroentropancreatic neuroendocrine tumours, with favourable safety profile, quality-of-life improvement and survival benefit. On the NETTER-1 study, it proved to be more effective than high-dose long-acting-release octreotide, leading to its regulatory approval. Prostate-specific membrane antigen (PSMA) is an excellent target for TRNT in prostate cancer. 177Lu-PSMA radioligand therapy demonstrated higher response rates in patients with metastatic castration resistant prostate cancer, when compared with second-line chemotherapy. New developments, including targeting of fibroblast activation proteins overexpressed in the tumour stroma, show promising preliminary results in the theranostic setting. Summary Recent research has demonstrated and consolidated the use of TRNT against well established targets in neuroendocrine tumours and prostate cancer. The identification of new promising molecular targets for TRNT, will further expand the theranostic applications of radionuclides in the field of nuclear medicine.

Purpose A multidisciplinary expert panel convened to formulate state-of-the-art recommendations for optimisation of selective internal radiation therapy (SIRT) with yttrium-90 ( 90 Y)-resin microspheres. Methods A steering committee of 23 international experts representing all participating specialties formulated recommendations for SIRT with 90 Y-resin microspheres activity prescription and post-treatment dosimetry, based on literature searches and the responses to a 61-question survey that was completed by 43 leading experts (including the steering committee members). The survey was validated by the steering committee and completed anonymously. In a face-to-face meeting, the results of the survey were presented and discussed. Recommendations were derived and level of agreement defined (strong agreement ≥ 80%, moderate agreement 50%–79%, no agreement ≤ 49%). Results Forty-seven recommendations were established, including guidance such as a multidisciplinary team should define treatment strategy and therapeutic intent (strong agreement); 3D imaging with CT and an angiography with cone-beam-CT, if available, and 99m Tc-MAA SPECT/CT are recommended for extrahepatic/intrahepatic deposition assessment, treatment field definition and calculation of the 90 Y-resin microspheres activity needed (moderate/strong agreement). A personalised approach, using dosimetry (partition model and/or voxel-based) is recommended for activity prescription, when either whole liver or selective, non-ablative or ablative SIRT is planned (strong agreement). A mean absorbed dose to non-tumoural liver of 40 Gy or less is considered safe (strong agreement). A minimum mean target-absorbed dose to tumour of 100–120 Gy is recommended for hepatocellular carcinoma, liver metastatic colorectal cancer and cholangiocarcinoma (moderate/strong agreement). Post-SIRT imaging for treatment verification with 90 Y-PET/CT is recommended (strong agreement). Post-SIRT dosimetry is also recommended (strong agreement). Conclusion Practitioners are encouraged to work towards adoption of these recommendations., info:eu-repo/semantics/published

Predictive factors for adverse events in metastatic colorectal cancer patients treated with regorafenib are currently lacking. In this safety analysis of a prospective phase II clinical trial, we assess the association between several clinical, laboratory, and imaging parameters and the occurrence of adverse events. Our results show that female sex is an independent risk factor for increased toxicity. Background: Regorafenib is a standard treatment for refractory metastatic colorectal cancer (mCRC). In view of the toxicity burden, significant research efforts have been made to increase the therapeutic ratio of this multikinase inhibitor. Predictive factors for treatment-related adverse events (TRAEs), however, are still lacking. Materials and Methods: We assessed the association between a number of baseline clinical, laboratory and imaging parameters and the occurrence of TRAEs in 136 patients who had received regorafenib (160 mg/day, 3-weeks-on/1-week-off) in a prospective phase II clinical trial. Results: Grade >= 2 TRAEs during the first cycle of treatment (84% vs. 60%, P=.002) and grade >= 3 TRAEs throughout the whole treatment (71% vs. 53%, P=.035) occurred more frequently in females, with sex being the only independent predictive factor of early and any-time toxicity (OR 3.4; 95% CI: 1.2-11.1, P=.02 and OR 2.1; 95% CI: 1.0-4.4, P=.045, respectively). Fatigue, anorexia, hypertension, and rash were reported significantly more frequently by females than males (P

Stratification of metastatic colorectal cancer (mCRC) patients is mostly based on clinical and biologic characteristics. This study aimed to validate the prognostic value of 18F-FDG PET/CT-based biomarkers such as baseline whole-body metabolically active tumor volume (WB-MATV) and early metabolic response (mR) in mCRC. Methods: The development cohort included chemorefractory mCRC patients enrolled in 2 prospective Belgian multicenter trials evaluating last-line treatments (multikinase inhibitors). The validation cohort included mCRC patients from an Italian center treated with chemotherapy and bevacizumab as first-line. Baseline WB-MATV was defined as the sum of metabolically active volumes of all target lesions identified on the baseline 18F-FDG PET/CT. Early mR assessment was performed following usual response criteria (response threshold of 30% [PERCIST-30%], response threshold of 15% [PERCIST-15%], European Organization for Research and Treatment of Cancer) and the so-called CONSIST method, which defines response as a decrease of SULmax ≥ 15% for all target lesions. Baseline WB-MATV and early mR assessment were investigated along with usual clinical factors and correlated with overall survival (OS) and progression-free survival (PFS). Results: Clinical factors, baseline WB-MATV, and early mR were evaluable in 192 of 239 and 94 of 125 patients of the development and validation cohorts, respectively. Except for PERCIST-30%, all response methods were equivalent in terms of outcome prediction, and CONSIST was found to be the most accurate. Baseline WB-MATV and early mR using the CONSIST method were independent prognostic parameters after adjustment for clinical factors in the development and validation sets for both OS (hazard ratio [HR] WB-MATV: 1.87 [95% CI, 1.17-2.97], P = 0.005, and HR early mR: 1.79 [95% CI, 1.08-2.95], P = 0.02 for the validation set) and PFS (HR WB-MATV: 1.94 [95% CI, 1.27-2.97], P = 0.002, and HR early mR: 1.69 [95% CI, 1.04-2.73], P = 0.03 for the validation set). Conclusion: Baseline WB-MATV and early mR are strong independent prognostic biomarkers for OS and PFS in mCRC, regardless of treatment received. Therefore, combining these biomarkers improves risk stratification for OS and PFS in mCRC. ispartof: JOURNAL OF NUCLEAR MEDICINE vol:63 issue:4 pages:549-555 ispartof: location:United States status: published

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

Background and Objectives The histological growth pattern (HGP) represents a strong prognostic factor in patients undergoing surgery for colorectal liver metastases (CRLM). We evaluated whether the combination of HGP with clinico-metabolic parameters could improve its prognostic value. Methods In a series of 108 patients undergoing resection of CRLM, the HGP of CRLM was scored according to international guidelines. Baseline clinico-metabolic clinical status was evaluated using a metabolic-Clinical Risk Score (mCRS), combining traditional Memorial Sloan Kettering-CRS parameters with the tumor-to-liver glucose uptake ratio as measured with (18)Fluorodeoxyglucose/positron emission tomography. Results In patients with desmoplastic HGP (DHGP) CRLM (20% of all patients), 5- and 10-years overall survival (OS) and disease free survival (DFS) were 66% and 43% and 37% and 24.5%, as compared with 35% and 21% and 11% and 11% in the non-DHGP group (p = 0.07 and 0.054). Among DHGP patients, those with a low-risk mCRS had improved postoperative outcomes, 5- and 10-years OS and DFS reaching 83.3% and 62.5% and 50% and 33%, as compared with 18% and 0% and 0% and 0% in high-risk mCRS patients (p = 0.007 and 0.003). In contrast, mCRS did not influence postoperative survivals in non-DHGP patients. Conclusions Combining the clinico-metabolic characteristics with the HGP may improve prognostication in patients undergoing surgery for CRLM.