Adaptive radiotherapy (up to 74 Gy) or standard radiotherapy (66 Gy) for patients with stage III non-small-cell lung cancer, according to [18F]FDG-PET tumour residual uptake at 42 Gy (RTEP7-IFCT-1402): a multicentre, randomised, controlled phase 2 trial.

BACKGROUND: Thoracic radiation intensification is debated in patients with stage III non-small-cell lung cancer (NSCLC). We aimed to assess the activity and safety of a boost radiotherapy dose up to 74 Gy in a functional sub-volume given according to on-treatment [18F]fluorodeoxyglucose ([18F]FDG)-PET results. METHODS: In this multicentre, randomised, controlled non-comparative phase 2 trial, we recruited patients aged 18 years or older with inoperable stage III NSCLC without EGFR mutation or ALK rearrangement with an Eastern Cooperative Oncology Group performance status of 0-1, and who were affiliated with or a beneficiary of a social benefit system, with evaluable tumour or node lesions, preserved lung function, and who were amenable to curative-intent radiochemotherapy. Patients were randomly allocated using a central interactive web-response system in a non-masked method (1:1; minimisation method used [random factor of 0·8]; stratified by radiotherapy technique [intensity-modulated radiotherapy vs three-dimensional conformal radiotherapy] and by centre at which patients were treated) either to the experimental adaptive radiotherapy group A, in which only patients with positive residual metabolism on [18F]FDG-PET at 42 Gy received a boost radiotherapy (up to 74 Gy in 33 fractions), with all other patients receiving standard radiotherapy dosing (66 Gy in 33 fractions over 6·5 weeks), or to the standard radiotherapy group B (66 Gy in 33 fractions) over 6·5 weeks. All patients received two cycles of induction platinum-based chemotherapy cycles (paclitaxel 175 mg/m2 intravenously once every 3 weeks and carboplatin area under the curve [AUC]=6 once every 3 weeks, or cisplatin 80 mg/m2 intravenously once every 3 weeks and vinorelbine 30 mg/m2 intravenously on day 1 and 60 mg/m2 orally [or 30 mg/m2 intravenously] on day 8 once every 3 weeks). Then they concomitantly received radiochemotherapy with platinum-based chemotherapy (three cycles for 8 weeks, with once per week paclitaxel 40 mg/m2 intravenously and carboplatin AUC=2 or cisplatin 80 mg/m2 intravenously and vinorelbine 20 mg/m2 intravenously on day 1 and 40 mg/m2 orally (or 20 mg/m2 intravenously) on day 8 in 21-day cycles). The primary endpoint was the 15-month local control rate in the eligible patients who received at least one dose of concomitant radiochemotherapy. This RTEP7-IFCT-1402 trial is registered with ClinicalTrials.gov (NCT02473133), and is ongoing. FINDINGS: From Nov 12, 2015, to July 7, 2021, we randomly assigned 158 patients (47 [30%] women and 111 [70%] men) to either the boosted radiotherapy group A (81 [51%]) or to the standard radiotherapy group B (77 [49%)]. In group A, 80 (99%) patients received induction chemotherapy and 68 (84%) received radiochemotherapy, of whom 48 (71%) with residual uptake on [18F]FDG-PET after 42 Gy received a radiotherapy boost. In group B, all 77 patients received induction chemotherapy and 73 (95%) received radiochemotherapy. At the final analysis, the median follow-up for eligible patients who received radiochemotherapy (n=140) was 45·1 months (95% CI 39·3-48·3). The 15-month local control rate was 77·6% (95% CI 67·6-87·6%) in group A and 71·2% (95% CI 60·8-81·6%) in group B. Acute (within 90 days from radiochemotherapy initiation) grade 3-4 adverse events were observed in 20 (29%) of 68 patients in group A and 33 (45%) of 73 patients in group B, including serious adverse events in five (7%) patients in group A and ten (14%) patients in group B. The most common grade 3-4 adverse events were febrile neutropenia (seven [10%] of 68 in group A vs 16 [22%] of 73 in group B), and anaemia (five [7%] vs nine [12%]). In the acute phase, two deaths (3%) occurred in group B (one due to a septic shock related to chemotherapy, and the other due to haemotypsia not related to study treatment), and no deaths occurred in group A. After 90 days, one additional treatment-unrelated death occurred in group A and two deaths events occurred in group B (one radiation pneumonitis and one pneumonia unrelated to treatment). INTERPRETATION: A thoracic radiotherapy boost, based on interim [18F]FDG-PET, led to a meaningful local control rate with no difference in adverse events between the two groups in organs at risk, in contrast with previous attempts at thoracic radiation intensification, warranting a randomised phase 3 evaluation of such [18F]FDG-PET-guided radiotherapy dose adaptation in patients with stage III NSCLC. FUNDING: Programme Hospitalier de Recherche Clinique National 2014.

An extended bore length solid-state digital-BGO PET/CT system: design, preliminary experience, and performance characteristics.

PURPOSE: A solid-state PET/CT system uses bismuth germanium oxide (BGO) scintillating crystals coupled to silicon photomultipliers over an extended 32 cm axial field-of-view (FOV) to provide high spatial resolution and very high sensitivity. Performance characteristics were determined for this digital-BGO system, including NEMA and EARL standards. METHODS: Spatial resolution, scatter fraction (SF), noise equivalent count rate (NECR), sensitivity, count rate accuracy, and image quality (IQ) were evaluated for the digital-BGO system as per NEMA NU 2-2018, at 2 sites of first clinical install. System energy resolution was measured. Bayesian penalized-likelihood reconstruction (BPL) was used for IQ. EARL Standards 2 studies were reconstructed by BPL combined with a contrast-enhancing deep learning algorithm. An Esser PET phantom was evaluated. Three patient examples were obtained with low-dose radiotracer activity: 2 MBq/kg of [18F]FDG ([18F]-2-fluoro-2-deoxy-D-glucose), 2.3 MBq/kg [68Ga]Ga-DOTA-TATE ([dodecane tetra-acetic acid,Tyr3]-octreotate), and 14.5 MBq/kg [82Rb]RbCl ([82Rb]-rubidium-chloride). Total scan times were ≤ 8 min. RESULTS: NEMA sensitivity was 47.6 cps/kBq at the axial center. Spatial resolution at 1 cm from the center axis was ≤4.5 mm (filtered back projection) and ≤3.8 mm (ordered subset expectation maximization). SF was 35.6%, count rate accuracy was 2.16%, and peak NECR was 485.2 kcps at 16.9 kBq/mL. Contrast for IQ was 61.1 to 90.7% (smallest to largest sphere) with background variations from 7.6 to 2.1%, and a "lung" error of 4.7%. The average detector energy resolution was 9.67%. Image quality for patient scans was good. EARL Standards 2 criteria were robustly met and Esser phantom features ≥4.8 mm were resolved at 2 min per bed position. CONCLUSION: A solid-state 32 cm axial FOV digital-BGO PET/CT system provides good spatial and energy resolution, high count rates, and superior NEMA sensitivity in its class, enabling fast clinical acquisitions with low-dose radiotracer activity.

Normal organ dosimetry for thyroid cancer patients treated with radioiodine as part of the multi-centre multi-national Horizon 2020 MEDIRAD project.

PURPOSE: Dosimetry is rarely performed for the treatment of differentiated thyroid cancer patients with Na[131I]I (radioiodine), and information regarding absorbed doses delivered is limited. Collection of dosimetry data in a multi-centre setting requires standardised quantitative imaging and dosimetry. A multi-national, multi-centre clinical study was performed to assess absorbed doses delivered to normal organs for differentiated thyroid cancer patients treated with Na[131I]I. METHODS: Patients were enrolled in four centres and administered fixed activities of 1.1 or 3.7 GBq of Na[131I]I using rhTSH stimulation or under thyroid hormone withdrawal according to local protocols. Patients were imaged using SPECT(/CT) at variable imaging time-points following standardised acquisition and reconstruction protocols. Whole-body retention data were collected. Dosimetry for normal organs was performed at two dosimetry centres and results collated. RESULTS: One hundred and five patients were recruited. Median absorbed doses per unit administered activity of 0.44, 0.14, 0.05 and 0.16 mGy/MBq were determined for the salivary glands of patients treated at centre 1, 2, 3 and 4, respectively. Median whole-body absorbed doses for 1.1 and 3.7 GBq were 0.05 Gy and 0.16 Gy, respectively. Median whole-body absorbed doses per unit administered activity of 0.04, 0.05, 0.04 and 0.04 mGy/MBq were calculated for centre 1, 2, 3 and 4, respectively. CONCLUSIONS: A wide range of normal organ doses were observed for differentiated thyroid cancer patients treated with Na[131I]I, highlighting the necessity for individualised dosimetry. The results show that data may be collated from multiple centres if minimum standards for the acquisition and dosimetry protocols can be achieved.

Phase II study of 131 I-metaiodobenzylguanidine with 5 days of topotecan for refractory or relapsed neuroblastoma: Results of the French study MIITOP.

PURPOSE: We report the results of the French multicentric phase II study MIITOP (NCT00960739), which evaluated tandem infusions of 131 I-metaiodobenzylguanidine (mIBG) and topotecan in children with relapsed/refractory metastatic neuroblastoma (NBL). METHODS: Patients received 131 I-mIBG on day 1, with intravenous topotecan daily on days 1-5. A second activity of 131 I-mIBG was given on day 21 to deliver a whole-body radiation dose of 4 Gy, combined with a second course of topotecan on days 21-25. Peripheral blood stem cells were infused on day 31. RESULTS: Thirty patients were enrolled from November 2008 to June 2015. Median age at diagnosis was 5.5 years (2-20). Twenty-one had very high-risk NBL (VHR-NBL), that is, stage 4 NBL at diagnosis or at relapse, with insufficient response (i.e., less than a partial response of metastases and more than three mIBG spots) after induction chemotherapy; nine had progressive metastatic relapse. Median Curie score at inclusion was 6 (1-26). Median number of prior lines of treatment was 3 (1-7). Objective response rate was 13% (95% confidence interval [CI]: 4-31) for the whole population, 19% for VHR-NBL, and 0% for progressive relapses. Immediate tolerance was good, with nonhematologic toxicity limited to grade-2 nausea/vomiting in eight patients. Two-year event-free survival was 17% (95% CI: 6-32). Among the 16 patients with VHR-NBL who had not received prior myeloablative busulfan-melphalan consolidation, 13 had at least stable disease after MIITOP; 11 subsequently received busulfan-melphalan; four of them were alive (median follow-up: 7 years). CONCLUSION: MIITOP showed acceptable tolerability in this heavily pretreated population and encouraging survival rates in VHR-NBL when followed by busulfan-melphalan.

PET-MRI for evaluation of response to radiochemotherapy in patients with locally advanced cervical cancer.

OBJECTIVE: We aimed to analyze the diagnostic test accuracy of positron emission tomography and a magnetic resonance imaging scan (PET-MRI) fusion in evaluating tumor response after radiochemotherapy in patients with locally advanced cervical cancer. METHODS: Patients treated at two institutes between January 2008 and December 2016 were studied retrospectively. Re-evaluation by positron emission tomography (PET) and magnetic resonance imaging (MRI) was performed in a non-concurrent way 4-8 weeks after treatment. A nuclear medicine doctor and a radiologist (subsequently referred as "radiologists"), both experts in gynecological oncology, re-examined the post-treatment MRI and positron emission tomography-computed tomography (PET-CT) separately, and then performed a fusion of these examinations. In this study we describe this "a posteriori fusion methodology", with two levels, enabling limitation of anatomical shifts. The gold standard was anatomical pathology analysis of the surgical specimen, since all patients underwent surgery following this radiological re-evaluation. The radiologists' degree of certainty in their diagnoses, and the impact of fusion on their diagnostic confidence were assessed by the radiologists, using two Likert judgment scales. They also adjudicated on possible changes of interpretation after the fusion. RESULTS: Thirty-one patients were included. The PET-MRI fusion has a sensitivity of 79% and a specificity of 90%. The positive predictive value (PPV) was 94%, and the negative predictive value (NPV) was 69%. In 45% of cases (n=13), radiologists reported an improvement in their degree of certainty in their diagnosis using a Likert judgment scale, due to inspecting the PET and MRI fused. A change in interpretation of tumor response was observed using a Likert judgment scale in 31% of cases. CONCLUSION: PET-MRI fusion improves the radiologist's own diagnostic confidence in assessing response to concurrent radiochemotherapy in locally advanced cervical cancer. More studies using a latest generation hybrid system will be necessary to further compare to MRI and PET-CT.

Efficacy and safety of 177Lu­DOTATATE in patients with advanced pancreatic neuroendocrine tumours: data from the NETTER-R international, retrospective study.

PURPOSE: NETTER-R aimed to determine the efficacy, safety and tolerability of 177Lu-DOTATATE in patients with progressive, advanced pancreatic neuroendocrine tumours (panNETs) using retrospective real-world data from multiple sites. METHODS: This international study retrospectively included patients with panNETs treated with 177Lu-DOTATATE. The primary endpoint was progression-free survival (PFS) by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Secondary endpoints included overall survival (OS), safety and tumour response. RESULTS: In total, 110 patients with panNETs were studied; 65.5% received a cumulative dose of 177Lu-DOTATATE 29.6 GBq ± 10% (median: 7.4 GBq). In 62 patients with available RECIST v1.1 tumour response, the median PFS was 24.8 months (95% confidence interval [CI]: 17.5-34.5), and the objective response rate was 40.3% (95% CI: 28.1-53.6); all responses were partial. With a median follow up of 24.5 months (range: 2.0-123.4 months) after the first cycle of 177Lu-DOTATATE, the median OS in the full analysis set (n = 110) was 41.4 months (95% CI: 28.6-50.2). PFS (hazard ratio [HR]: 3.672; p = 0.0009) and OS (HR: 3.360; p < 0.0001) were longer in patients who received no chemotherapy prior to 177Lu-DOTATATE than those who did. No treatment-emergent adverse events (TEAEs) led to treatment discontinuation. Grade 3 anaemia, lymphopenia and thrombocytopenia occurred in 0.9%, 5.4% and 0.9% of patients, respectively. No acute leukaemia or myelodysplastic syndrome was reported. Six patients (5.5%) had renal TEAEs. All renal grade ≥ 3 events were transient and did not lead to treatment modification. CONCLUSIONS: These results reinforce the role of 177Lu-DOTATATE for the treatment of patients with advanced, somatostatin receptor-positive panNETs.

Lessons from a multicentre retrospective study of peptide receptor radionuclide therapy combined with lanreotide for neuroendocrine tumours: a need for standardised practice.

PURPOSE: PRELUDE aimed to assess use and effectiveness/safety of lanreotide autogel/depot (LAN) combined with 177Lu-DOTATOC or 177Lu-DOTATATE (LAN-peptide receptor radionuclide therapy [PRRT]) in patients with progressive neuroendocrine tumours (NETs). METHODS: International, non-interventional, retrospective, non-comparative analysis of medical records from patients with progressive metastatic or locally advanced grade 1 or 2 gastroenteropancreatic (GEP)- or lung-NETs. The primary endpoint was progression-free survival (PFS) at end of last LAN-PRRT cycle. Secondary endpoints included PFS at last available follow-up, best overall response, objective response rate (ORR), presence and severity of diarrhoea and flushing, and safety. Post-hoc analyses were conducted to determine pre-treatment tumour growth rate (TGR) cutoffs that best predicted the ORR during treatment. RESULTS: Forty patients were enrolled (GEP-NETs, n = 39; lung-NETs, n = 1). PFS rates were 91.7% at end of last LAN-PRRT cycle and 95.0% at last available follow-up. In the full analysis set, best overall response among patients with GEP-NETs (n = 23) was stable disease (n = 14, 60.9%), partial response (n = 8, 34.8%) and progressive disease (n = 1, 4.3%). The ORR was 27.3% at end of last LAN-PRRT cycle and 36.8% at last available follow-up. Optimal baseline TGR cutoffs for predicting ORR at these time points were 1.18% and 0.33%, respectively. At baseline, 81.0% of patients had diarrhoea or flushing; both remained stable or improved in most cases. No increased adverse drug reactions were reported. CONCLUSION: Despite the major recruitment shortfall for the PRELUDE study, effectiveness data were encouraging in this selected population, highlighting the potential usefulness and feasibility of LAN combined with and after PRRT in patients with GEP-NETs. The study also identified challenges associated with evaluating clinical practice in a rare-disease setting and highlighted the need for standardisation of PRRT procedures. TRIAL REGISTRATION: Trial number: NCT02788578; URL: https://clinicaltrials.gov/ct2/show/NCT02788578.

Impact of liver tumour burden, alkaline phosphatase elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate: an analysis of the NETTER-1 study.

PURPOSE: To assess the impact of baseline liver tumour burden, alkaline phosphatase (ALP) elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate. METHODS: In the phase 3 NETTER-1 trial, patients with advanced, progressive midgut neuroendocrine tumours (NET) were randomised to 177Lu-Dotatate (every 8 weeks, four cycles) plus octreotide long-acting release (LAR) or to octreotide LAR 60 mg. Primary endpoint was progression-free survival (PFS). Analyses of PFS by baseline factors, including liver tumour burden, ALP elevation, and target lesion size, were performed using Kaplan-Meier estimates; hazard ratios (HRs) with corresponding 95% CIs were estimated using Cox regression. RESULTS: Significantly prolonged median PFS occurred with 177Lu-Dotatate versus octreotide LAR 60 mg in patients with low (< 25%), moderate (25-50%), and high (> 50%) liver tumour burden (HR 0.187, 0.216, 0.145), and normal or elevated ALP (HR 0.153, 0.177), and in the presence or absence of a large target lesion (diameter > 30 mm; HR, 0.213, 0.063). Within the 177Lu-Dotatate arm, no significant difference in PFS was observed amongst patients with low/moderate/high liver tumour burden (P = 0.7225) or with normal/elevated baseline ALP (P = 0.3532), but absence of a large target lesion was associated with improved PFS (P = 0.0222). Grade 3 and 4 liver function abnormalities were rare and did not appear to be associated with high baseline liver tumour burden. CONCLUSIONS: 177Lu-Dotatate demonstrated significant prolongation in PFS versus high-dose octreotide LAR in patients with advanced, progressive midgut NET, regardless of baseline liver tumour burden, elevated ALP, or the presence of a large target lesion. Clinicaltrials.gov : NCT01578239, EudraCT: 2011-005049-11.

Chemoradiotherapy for locally advanced cervix cancer without aortic lymph node involvement: can we consider metabolic parameters of pretherapeutic FDG-PET/CT for treatment tailoring?

PURPOSE: Aim of the study was to assess impact of pretherapeutic FDG-PET/CT metabolic parameters on response to chemoradiotherapy (CRT) and survival in locally advanced cervical cancer (LACC) patients without paraaortic lymph node involvement. METHODS: LACC patients treated with CRT without macrometastatic involvement after paraaortic surgical staging were included. All patients had received at least 45 Gy radiotherapy and five cycles of platinum-based chemotherapy. High-risk histologies were excluded. Two senior nuclear physician experts in gynaecologic oncology reviewed all PET/CT exams, and extracted tumor SUVmax, MTV, and TLG (standardized uptake value, metabolic tumor volume, and total lesion glycolysis respectively). Response to CRT was assessed with a pelvic MRI done after 45 Gy. Medical charts were reviewed for clinical, pathology, and survival data. RESULTS: Ninety-three patients were included in the study. The overall survival (OS) rates at 2 and 5 years were 83.0% [95%CI: 72.5-89.8] and 71.2% [57.5-81.2] respectively. The RFS rates at 2 and 5 years were 72.5% [61.5-80.9] and 64.4% [52.3-74.2] respectively. Higher cervical SUVmax and TLG were significantly associated with poor response to CRT. In multivariate analysis, cervical SUVmax was the main predictive factor for OS. CONCLUSION: Cervical tumor SUVmax was demonstrated to be a non-invasive prognostic biomarker for response to treatment and survival in LACC patients without paraaortic involvement. SUVmax and other PET/CT metabolic parameters require further prospective investigation to help tailoring of local treatment.

Evaluation of 2 diuretic 18fluorine-fluorodeoxyglucose positron emission tomography/computed tomography imaging protocols for intrapelvic cancer.

BACKGROUND: 18F-Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) plays an important part in the oncological evaluation of the abdomen and pelvis, but the interpretation and quantification is often hampered by intense physiological urinary activity. We evaluate 2 different diuretic imaging protocols by comparing intensity of urinary activity and we look at the impact of multiple variables on the final urinary activity. METHODS: Comparative analysis of 102 patients (median age: 64) having intrapelvic carcinoma. After full body acquisition, 58 patients were administered 20 mg of furosemide 90 min post injection of FDG (P90). For 44 patients, 20 mg of furosemide was administered 30 min post injection of FDG (P30). Comparisons between groups were performed using the Mann-Whitney Test and χ2. The BMI, creatinine, clearance, age, injected activity, diuretic protocol, gender and glycemia were evaluated with multivariate analysis for their impact on the final urinary activity. RESULTS: Concerning the comparison of the urinary activity we observe a significant difference (P=0.0029) between P90 and P30 for the SUVmax (median 4.3 [range 1.6: 17.7] vs. 6.0 [range 2.9: 15.1]), and for the SUVmean (P<0.001) (median 2.4 [range 1.1; 9.9] vs. 3.8 [range 2.0; 10.1]). For 2 patients of P30, the acquisition was interrupted because the patient needed to void. Multivariate analysis shows that creatinine and creatinine clearance do not have a significant independent impact on the final bladder activity. CONCLUSIONS: By comparing the 2 diuretic imaging protocols, we found a significant lower urinary activity for the P90 protocol and the regression decision tree shows that the P90 protocol is mostly superior. The P30 protocol, which seems to be less well tolerated, is adequate in the group of patients with an injected activity of less than 240 MBq and older than 65 years, if P90 is not feasible. For most patients with injected activity ≥240 MBq or BMI of ≥25 and a glycemia >120 mg/dL, a significant amount of residual urinary activity remains for both protocols.

Nonsurgical giant cell tumour of the tendon sheath or of the diffuse type: are MRI or 18F-FDG PET/CT able to provide an accurate prediction of long-term outcome?

PURPOSE: To investigate whether MRI (RECIST 1.1, WHO criteria and the volumetric approach) or (18)F-FDG PET/CT (PERCIST 1.0) are able to predict long-term outcome in nonsurgical patients with giant cell tumour of the tendon sheath or of the diffuse type (GCT-TS/DT). METHODS: Fifteen "nonsurgical" patients with a histological diagnosis of GCT-TS/DT were divided into two groups: symptomatic patients receiving targeted therapy and asymptomatic untreated patients. All 15 patients were evaluated by MRI of whom 10 were treated, and a subgroup of 7 patients were evaluated by PET/CT of whom 4 were treated. Early evolution was assessed according to MRI and PET/CT scans at baseline and during follow-up. Cohen's kappa coefficient was used to evaluate the degree of agreement between PERCIST 1.0, RECIST 1.1, WHO criteria, volumetric approaches and the reference standard (long-term outcome, delay 505 ± 457 days). The response rate in symptomatic patients with GCT-TS/DT receiving targeted therapy was also assessed in a larger population that included additional patients obtained from a review of the literature. RESULTS: The kappa coefficients for agreement between RECIST/WHO/volumetric criteria and outcome (15 patients) were respectively: 0.35 (p = 0.06), 0.26 (p = 0.17) and 0.26 (p = 0.17). In the PET/CT subgroup (7 patients), PERCIST was in perfect agreement with the late symptomatic evolution (kappa = 1, p < 0.05). In the treated symptomatic group including the additional patients from the literature the response rates to targeted therapies according to late symptomatic assessment, and PERCIST and RECIST criteria were: 65 % (22/34), 77 % (10/13) and 26 % (10/39). CONCLUSION: (18)F-FDG PET/CT with PERCIST is a promising approach to the prediction of the long-term outcome in GCT-TS/DT and may avoid unnecessary treatments, toxicity and costs. On MRI, WHO and volumetric approaches are not more effective than RECIST using the current thresholds.

Evaluation of a blood miRNA/mRNA signature to follow-up Lu-PRRT therapy for G1/G2 intestinal neuroendocrine tumors.

Background: 177Lu-oxodotreotide peptide receptor therapy (LuPRRT) is an efficient treatment for midgut neuroendocrine tumors (NETs) of variable radiological response. Several clinical, biological, and imaging parameters may be used to establish a relative disease prognosis but none is able to predict early efficacy or toxicities. We investigated expression levels for mRNA and miRNA involved in radiosensitivity and tumor progression searching for correlations related to patient outcome during LuPRRT therapy. Methods: Thirty-five patients received LuPRRT for G1/G2 midgut NETs between May 2019 and September 2021. Peripheral blood samples were collected prior to irradiation, before and 48 h after the second and the fourth LuPRRT, and at 6-month follow-up. Multiple regression analyses and Pearson correlations were performed to identify the miRNA/mRNA signature that will best predict response to LuPRRT. Results: Focusing on four mRNAs and three miRNAs, we identified a miRNA/mRNA signature enabling the early identification of responders to LuPRRT with significant reduced miRNA/mRNA expression after the first LuPRRT administration for patients with progressive disease at 1 year (p < 0.001). The relevance of this signature was reinforced by studying its evolution up to 6 months post-LuPRRT. Moreover, nadir absolute lymphocyte count within the first 2 months after the first LuPRRT administration was significantly related to low miRNA/mRNA expression level (p < 0.05) for patients with progressive disease. Conclusion: We present a pilot study exploring a miRNA/mRNA signature that correlates with early hematologic toxicity and therapeutic response 12 months following LuPRRT. This signature will be tested prospectively in a larger series of patients.

Impact of different models based on blood samples and images for bone marrow dosimetry after 177Lu-labeled somatostatin-receptor therapy.

BACKGROUND: Peptide receptor radionuclide therapy with 177Lu-DOTATATE is a recognized option for treating neuroendocrine tumors and has few toxicities, except for the kidneys and bone marrow. The bone marrow dose is generally derived from a SPECT/CT image-based method with four timepoints or from a blood-based method with up to 9 timepoints, but there is still no reference method. This retrospective single-center study on the same cohort of patients compared the calculated bone marrow dose administered with both methods using mono, bi- or tri-exponential models. For the image-based method, the dose was estimated using Planetdose© software. Pearson correlation coefficients were calculated. We also studied the impact of late timepoints for both methods. RESULTS: The bone marrow dose was calculated for 131 treatments with the blood-based method and for 17 with the image-based method. In the former, the median absorbed dose was 15.3, 20.5 and 28.3 mGy/GBq with the mono-, bi- and tri-exponential model, respectively. With the image-based method, the median absorbed dose was 63.9, 41.9 and 60.8 with the mono-, bi- and tri-exponential model, respectively. Blood samples after 24h post-injection did not evidence any change in the absorbed bone marrow dose with the bi-exponential model. On the contrary, the 6-day post-injection timepoint was more informative with the image-based model. CONCLUSION: This study confirms that the estimated bone marrow dose is significantly lower with the blood-based method than with the image-based method. The blood-based method with a bi-exponential model proved particularly useful, without the need for blood samples after 24h post-injection. Nevertheless, this blood-based method is based on an assumption that needs to be more validated. The important difference between the two methods does not allow to determine the optimal one to estimate the true absorbed dose and further studies are necessary to compare with biological effects.

Insertion of synthetic lesions on patient data: a method for evaluating clinical performance differences between PET systems.

BACKGROUND: Performance assessment of positron emission tomography (PET) scanners is crucial to guide clinical practice with efficiency. We have already introduced and experimentally evaluated a simulation method allowing the creation of a controlled ground truth for system performance assessment. In the current study, the goal was to validate the method using patient data and demonstrate its relevance to assess PET performances accuracy in clinical conditions. METHODS: Twenty-four patients were recruited and sorted into two groups according to their body mass index (BMI). They were administered with a single dose of 2 MBq/kg 18F-FDG and scanned using clinical protocols consecutively on two PET systems: the Discovery-IQ (DIQ) and the Discovery-MI (DMI). For each BMI group, sixty synthetic lesions were dispatched in three subgroups and inserted at relevant anatomical locations. Insertion of synthetic lesions (ISL) was performed at the same location into the two consecutive exams. Two nuclear medicine physicians evaluated individually and blindly the images by qualitatively and semi-quantitatively reporting each detected lesion and agreed on a consensus. We assessed the inter-system detection rates of synthetic lesions and compared it to an initial estimate of at least 1.7 more targets detected on the DMI and the detection rates of natural lesions. We determined the inter-reader variability, evaluated according to the inter-observer agreement (IOA). Adequate inter-reader variability was found for IOA above 80%. Differences in standardized uptake value (SUV) metrics were also studied. RESULTS: In the BMI ≤ 25 group, the relative true positive rate (RTPR) for synthetic and natural lesions was 1.79 and 1.83, respectively. In the BMI > 25 group, the RTPR for synthetic and natural lesions was 2.03 and 2.27, respectively. For each BMI group, the detection rate using ISL was consistent to our estimate and with the detection rate measured on natural lesions. IOA above 80% was verified for any scenario. SUV metrics showed a good agreement between synthetic and natural lesions. CONCLUSIONS: ISL proved relevant to evaluate performance differences between PET scanners. Using these synthetically modified clinical images, we can produce a controlled ground truth in a realistic anatomical model and exploit the potential of PET scanner for clinical purposes.

RadioLigand Therapy with [177Lu]Lu-PSMA-617 for Salivary Gland Cancers: Literature Review and First Compassionate Use in France.

Salivary gland cancers are rare tumors comprising a large group of heterogeneous tumors with variable prognosis. Their therapeutic management at a metastatic stage is challenging due to the lack of therapeutic lines and the toxicity of treatments. [177Lu]Lu-PSMA-617 (prostate-specific membrane antigen) is a vectored radioligand therapy (RLT) initially developed to treat castration-resistant metastatic prostate cancer with encouraging results in terms of efficacy and toxicity. Many malignant cells could be treated with [177Lu]Lu-PSMA-617 as long as they express PSMA as a consequence of androgenic pathway activation. RLT may be used when anti-androgen hormonal treatment has failed, particularly in prostate cancer. [177Lu]Lu-PSMA-617 has been proposed in certain salivary gland cancers, though the expression of PSMA is demonstrated by a significant uptake using [68Ga]Ga-PSMA-11 PET scan. This theranostic approach could be a new therapeutic option, warranting prospective investigation in a larger cohort. We review the literature on this subject and offer a clinical illustration of compassionate use in France as a perspective for administering [177Lu]Lu-PSMA-617 in salivary gland cancer.

Functional testicular evaluation using PET/CT with 18F-fluorodeoxyglucose.

PURPOSE: PET/CT using (18)F-FDG is a well-established diagnostic examination in oncology, cardiology and neurology. The clinical significance of nontumoral testicular uptake of FDG is unknown. Functional testicular imaging may have important clinical applications in the diagnosis and prognosis of male infertility. The aim of this study was to determine the andrological value of a FDG PET/CT in analysing testicular function, by correlating the PET/CT data with the sperm parameters. METHODS: Retrospective analysis of FDG PET/CT in 20 consecutive cancer patients without testicular pathology in whom two semen samples had been obtained for analysis before any chemotherapy. FDG PET/CT parameters were the mean standardized uptake value (SUVmean), used for measuring the intensity of uptake, and the functional testicular volume (FV). For statistical analysis, a Spearman's rank correlation test and a Mann-Whitney test were used. RESULTS: Of 20 patients (mean age 22 years), 18 had provided two sperm samples for cryopreservation. Sperm concentration was above 20 × 10(6)/ml in 55% of the patients. The intensity of uptake and the FV were correlated with the total sperm count, the sperm concentration and motility (p < 0.05). The difference in SUVmean between the two testes showed an inverse correlation with sperm concentration (p = 0.036). Normospermic and oligospermic men had significant differences in: (1) mean SUVmean, (2) mean FV, and (3) the difference in intensity of uptake between the testes (p < 0.05). CONCLUSION: This is the first report on the andrological value of FDG PET/CT in analysing nontumoral testicular function. This pilot study showed a significant correlation between intensity of uptake of FDG and testicular FV with the main sperm parameters. PET/CT with FDG could become a useful new tool in assisted reproductive technologies and other andrological or urological applications.

Evaluation of a method based on synthetic data inserted into raw data prior to reconstruction for the assessment of PET scanners.

BACKGROUND: Performance assessment of positron emission tomography (PET) scanners is crucial to guide clinical practice with efficiency. Even though clinical data are the final target, their use to characterize systems response is constrained by the lack of ground truth. Phantom tests overcome this limitation by controlling the object of study, but remain simple and are not representative of patient complexity. The objective of this study is to evaluate the accuracy of a simulation method using synthetic spheres inserted into acquired raw data prior to reconstruction, simulating multiple scenarios in comparison with equivalent physical experiments. METHODS: We defined our experimental framework using the National Electrical Manufacturers Association NU-2 2018 Image Quality standard, but replaced the standard sphere set with more appropriate sizes (4, 5, 6, 8, 10 and 13 mm) better suited to current PET scanner performance. Four experiments, with different spheres-to-background ratios (2:1, 4:1, 6:1 and 8:1), were performed. An additional dataset was acquired with a radioactive background but no activity within the spheres (water only) to establish a baseline. Then, we artificially simulated radioactive spheres to reproduce other experiments using synthetic data inserted into the original sinogram. Images were reconstructed following standard guidelines using ordered subset expectation maximization algorithm along with a Bayesian penalized likelihood algorithm. We first visually compared experimental and simulated images. Afterward, we measured the activity concentration values into the spheres to calculate the mean and maximum recovery coefficients (RCmean and RCmax) which we used in a quantitative analysis. RESULTS: No significant visual differences were identified between experimental and simulated series. Mann-Whitney U tests comparing simulated and experimental distributions showed no statistical differences for both RCmean (P value = 0.611) and RCmax (P value = 0.720). Spearman tests revealed high correlation for RCmean (ρ = 0.974, P value < 0.001) and RCmax (ρ = 0.974, P value < 0.001) between both datasets. From Bland-Altman plots, we highlighted slight shifts in RCmean and RCmax of, respectively, 2.1 ± 16.9% and 3.3 ± 22.3%. CONCLUSIONS: We evaluated the efficiency of our hybrid method in faithfully mimicking practical situations producing satisfactory results compared to equivalent experimental data.

Comparison of Two Types of Amino Acid Solutions on 177Lu-Dotatate Pharmacokinetics and Pharmacodynamics in Patients with Metastatic Gastroenteropancreatic Neuroendocrine Tumors.

BACKGROUND: 177Lu-Dotatate is used in the treatment of somatostatin-receptor-positive inoperable progressive gastroenteropancreatic neuroendocrine tumors. A co-infusion of amino acids (AAs) is administered to prevent renal toxicity. OBJECTIVE: This study aimed to quantify the impact of two types of AA cocktails on the pharmacokinetics and toxicity of 177Lu-Dotatate. METHODS: Four injections of 7400 MBq 177Lu-Dotatate were given per patient with administration of either Primene® 10% (containing a cocktail of 20 AAs with 22g of Lysine and 16.8 g of Arginine) or Lysakare® (containing 25 g of Lysine and 25 g of Arginine). Nine blood samples were collected at each cycle. Radioactivity-time data were analyzed according to a population-based model using NONMEM (version 7.4.1). Renal and hematological toxicity was evaluated after each cycle. RESULTS: 1,678 177Lu-Dotatate plasma concentrations versus time were analyzed from 83 consecutive patients with Primene® (n= 45 pts) or Lysakare® (n= 36 pts). Population pharmacokinetic analysis showed that Primene® significantly increased the elimination rate constant of 177Lu-Dotatate as opposed to Lysakare®. Primene® also significantly lowered Lutathera® plasma exposure (AUC) by 34%, whereas Lysakare® increased AUC by 7%. There was no renal toxicity in either case. Lymphopenia significantly correlated with AUC (p=0.021) with a trend towards higher toxicity with Lysakare®. CONCLUSION: Unlike Primene®, Lysakare® does not increase 177Lu-Dotatate elimination. This difference is associated with a significant impact on AUC. The latter parameter has a high interpatient variability but a low intrapatient variability, which could have important clinical implications for treatment tailoring.

Evaluation of a trainer phantom in the learning phase of sentinel lymph node identification in breast cancer.

BACKGROUND: The concept of a learning phase is difficult to implement in a university setting, as it is unacceptable to subject a patient who requires only lymphadenectomy to axillary dissection for the purpose of training surgeons. We therefore sought to evaluate intraoperative sentinel node detection using a phantom, the Senti-Trainer. Learning phases on the Senti-Trainer and detection rate were assessed in order to determine whether the proficiency of surgeons in training improved with the number of procedures. METHODS: Twenty residents each performed 30 detection procedures of a sentinel node on the silicon phantom. Each resident was evaluated at each procedure, and an observation report was made every five procedures. Evaluation was single-blind as the surgeons did not know the result of the previous detection and were aware of the results only after the thirtieth procedure. RESULTS: The mean detection rate was 75% during the first procedure and reached 95% (or 5% detection errors) at the 30th procedure (p<0.0001; OR=6.33 with a 95% CI=[2.31; 17.33]). Proficiency in sentinel lymph node (SLN) identification also increased with the number of procedures performed. The ability to localize SLN improved during the learning phase with the increasing number of procedures performed. Mean detection time during the 30 procedures was 150 s (range: 115-210 s). CONCLUSIONS: Training on a phantom showed that this is a valuable teaching tool that enables surgeons to become familiar with gamma probes. It cannot replace the clinical training phase, but is an important aid to proficiency in intraoperative detection.