Response-adapted omission of radiotherapy in children and adolescents with early-stage classical Hodgkin lymphoma and an adequate response to vincristine, etoposide, prednisone, and doxorubicin (EuroNet-PHL-C1): a titration study.

BACKGROUND: Children and adolescents with early-stage classical Hodgkin lymphoma have a 5-year event-free survival of 90% or more with vincristine, etoposide, prednisone, and doxorubicin (OEPA) plus radiotherapy, but late complications of treatment affect survival and quality of life. We investigated whether radiotherapy can be omitted in patients with adequate morphological and metabolic responses to OEPA. METHODS: The EuroNet-PHL-C1 trial was designed as a titration study and recruited patients at 186 hospital sites across 16 European countries. Children and adolescents with newly diagnosed stage IA, IB, and IIA classical Hodgkin lymphoma younger than 18 years of age were assigned to treatment group 1 to be treated with two cycles of OEPA (vincristine 1·5 mg/m2 intravenously, capped at 2 mg, on days 1, 8, and 15; etoposide 125 mg/m2 intravenously, on days 1-5; prednisone 60 mg/m2 orally on days 1-15; and doxorubicin 40 mg/m2 intravenously on days 1 and 15). If no adequate response (a partial morphological remission or greater and PET negativity) had been achieved after two cycles of OEPA, involved-field radiotherapy was administered at a total dose of 19·8 Gy (usually in 11 fractions of 1·8 Gy per day). The primary endpoint was event-free survival. The primary objective was maintaining a 5-year event-free survival rate of 90% in patients with an adequate response to OEPA without radiotherapy. We performed intention-to-treat and per-protocol analyses. The trial was registered at ClinicalTrials.gov (NCT00433459) and with EUDRACT, (2006-000995-33) and is completed. FINDINGS: Between Jan 31, 2007, and Jan 30, 2013, 2131 patients were registered and 2102 patients were enrolled onto EuroNet-PHL-C1. Of these 2102 patients, 738 with early-stage disease were allocated to treatment group 1. Median follow-up was 63·3 months (IQR 60·1-69·8). We report on 714 patients assigned to and treated on treatment group 1; the intention-to-treat population comprised 713 patients with 323 (45%) male and 390 (55%) female patients. In 440 of 713 patients in the intention-to-treat group who had an adequate response and did not receive radiotherapy, 5-year event-free survival was 86·5% (95% CI 83·3-89·8), which was less than the 90% target rate. In 273 patients with an inadequate response who received radiotherapy, 5-year event-free survival was 88·6% (95% CI 84·8-92·5), for which the 95% CI included the 90% target rate. The most common grade 3-4 adverse events were neutropenia (in 597 [88%] of 680 patients) and leukopenia (437 [61%] of 712). There were no treatment-related deaths. INTERPRETATION: On the basis of all the evidence, radiotherapy could be omitted in patients with early-stage classical Hodgkin lymphoma and an adequate response to OEPA, but patients with risk factors might need more intensive treatment. FUNDING: Deutsche Krebshilfe, Elternverein für Krebs-und leukämiekranke Kinder, Gießen, Kinderkrebsstiftung Mainz of the Journal Oldtimer Markt, Tour der Hoffnung, Menschen für Kinder, Mitteldeutsche Kinderkrebsforschung, Programme Hospitalier de Recherche Clinique, and Cancer Research UK.

18F-fluorocholine PET/CT detects parathyroid gland hyperplasia as well as adenoma: 401 PET/CTs in one center.

BACKGROUND: During the past decade, 18F-fluorocholine (FCH) PET/CT has been continuously performed at Tenon Hospital (Paris, France) for the detection of hyperfunctioning parathyroid glands (PT). METHODS: A cohort of 401 patients, deliberately referred for HPT since September 2012, has been analyzed. The aim of this real-life retrospective study was to determine the diagnostic utility of FCH in this setting, overall and in subgroups according to the type of hyperparathyroidism (HPT), the context of FCH in the imaging work-up and in the patient's history: initial imaging or persistence or recurrence after previous parathyroidectomy (PTX). The influence of the histologic type of resected PTs, hyperplasia or adenoma, on the preoperatory detection on FCH PET/CT has been studied as well. RESULTS: Four hundred one FCH PET/CTs were included in the cohort, performed in 323 patients with primary HPT (pHPT), including 18 with familial HPT (fHPT), and in 78 patients with secondary renal HPT (rHPT). The overall positivity rate in the 401 FCH PET/CTs was 73%. The PTX rate was twice greater in patients whose FCH PET/CT was positive than negative (73% vs. 35%). Abnormal PT(s) were pathology proven in 214 patients: only hyperplastic gland(s) in 75 cases and at least one adenoma in 136 cases; FCH PET/CT sensitivity was 89% and 92%, respectively. Similarly, there was no significant difference in patient-based sensitivity whether FCH PET/CT was performed as 1st line or later in the imaging work-up, or indicated for initial imaging or for suspicion of persistent or recurrent HPT. Gland-based sensitivity was significantly lower for hyperplasia than for adenoma (72% and 86%, respectively). The lowest gland-based sensitivity value was 65%, observed in case of hyperplasia and when FCH was performed late in the imaging work-up. FCH PET/CT correctly showed multiglandular HPT (MGD) in 36/61 proven cases, 59%. Results of ultrasonography (US) and 99mTc-sestaMIBI (MIBI) imaging were available in 346 and 178 patients, respectively. For both modalities, the corresponding sensitivity values were significantly less than those of FCH PET/CT (e.g., overall gland-based sensitivity 78% for FCH, 45% for US, 30% for MIBI) and MGD was detected in 32% of cases by US and 15% by MIBI. CONCLUSIONS: Although FCH PET/CT has been performed since 2017 as 1st line imaging for HPT at Tenon Hospital (Paris, France), a large majority of patients underwent prior US and/or MIBI in their preoperative work-up. Therefore, a selection bias is very likely, as most patients referred to FCH PET/CT had non-conclusive or discordant results of US and MIBI, explaining the low performance of those modalities in the present cohort compared to published results. Nevertheless, the superiority of FCH PET/CT over US and MIBI in detecting abnormal PTs reported in various comparative studies is definitely confirmed in this larger real-life cohort. The detection with FCH PET/CT of hyperplastic PTs was somewhat lower than that of adenomas but was better than using US or MIBI. The present results lead to recommend FCH PET/CT as the first line imaging modality in HPT when it is widely available or, if less available, at least in HPT with predominance of hyperplasia and/or MGD.

Response-adapted omission of radiotherapy and comparison of consolidation chemotherapy in children and adolescents with intermediate-stage and advanced-stage classical Hodgkin lymphoma (EuroNet-PHL-C1): a titration study with an open-label, embedded, multinational, non-inferiority, randomised controlled trial.

BACKGROUND: Children and adolescents with intermediate-stage and advanced-stage classical Hodgkin lymphoma achieve an event-free survival at 5 years of about 90% after treatment with vincristine, etoposide, prednisone, and doxorubicin (OEPA) followed by cyclophosphamide, vincristine, prednisone, and procarbazine (COPP) and radiotherapy, but long-term treatment effects affect survival and quality of life. We aimed to investigate whether radiotherapy can be omitted in patients with morphological and metabolic adequate response to OEPA and whether modified consolidation chemotherapy reduces gonadotoxicity. METHODS: Our study was designed as a titration study with an open-label, embedded, multinational, non-inferiority, randomised controlled trial, and was carried out at 186 hospital sites across 16 European countries. Children and adolescents with newly diagnosed intermediate-stage (treatment group 2) and advanced-stage (treatment group 3) classical Hodgkin lymphoma who were younger than 18 years and stratified according to risk using Ann Arbor disease stages IIAE, IIB, IIBE, IIIA, IIIAE, IIIB, IIIBE, and all stages IV (A, B, AE, and BE) were included in the study. Patients with early disease (treatment group 1) were excluded from this analysis. All patients were treated with two cycles of OEPA (1·5 mg/m2 vincristine taken intravenously capped at 2 mg, on days 1, 8, and 15; 125 mg/m2 etoposide taken intravenously on days 1-5; 60 mg/m2 prednisone taken orally on days 1-15; and 40 mg/m2 doxorubicin taken intravenously on days 1 and 15). Patients were randomly assigned to two (treatment group 2) or four (treatment group 3) cycles of COPP (500 mg/m2 cyclophosphamide taken intravenously on days 1 and 8; 1·5 mg/m2 vincristine taken intravenously capped at 2 mg, on days 1 and 8; 40 mg/m2 prednisone taken orally on days 1 to 15; and 100 mg/m2 procarbazine taken orally on days 1 to 15) or COPDAC, which was identical to COPP except that 250 mg/m2 dacarbazine administered intravenously on days 1 to 3 replaced procarbazine. The method of randomisation (1:1) was minimisation with stochastic component and was centrally stratified by treatment group, country, trial sites, and sex. The primary endpoint was event-free survival, defined as time from treatment start until the first of the following events: death from any cause, progression or relapse of classical Hodgkin lymphoma, or occurrence of secondary malignancy. The primary objectives were maintaining 90% event-free survival at 5 years in patients with adequate response to OEPA treated without radiotherapy and to exclude a decrease of 8% in event-free survival at 5 years in the embedded COPDAC versus COPP randomisation to show non-inferiority of COPDAC. Efficacy analyses are reported per protocol and safety in the intention-to-treat population. The trial is registered with ClinicalTrials.gov (trial number NCT00433459) and EUDRACT (trial number 2006-000995-33), and is closed to recruitment. FINDINGS: Between Jan 31, 2007, and Jan 30, 2013, 2102 patients were recruited. 737 (35%) of the 2102 recruited patients were in treatment group 1 (early-stage disease) and were not included in our analysis. 1365 (65%) of the 2102 patients were in treatment group 2 (intermediate-stage disease; n=455) and treatment group 3 (advanced-stage disease; n=910). Of these 1365, 1287 (94%) patients (435 [34%] of 1287 in treatment group 2 and 852 [66%] of 1287 in treatment group 3) were included in the titration trial per-protocol analysis. 937 (69%) of 1365 patients were randomly assigned to COPP (n=471) or COPDAC (n=466) in the embedded trial. Median follow-up was 66·5 months (IQR 62·7-71·7). Of 1287 patients in the per-protocol group, 514 (40%) had an adequate response to treatment and were not treated with radiotherapy (215 [49%] of 435 in treatment group 2 and 299 [35%] of 852 in treatment group 3). 773 (60%) of 1287 patients with inadequate response were scheduled for radiotherapy (220 [51%] of 435 in the treatment group 2 and 553 [65%] of 852 in treatment group 3. In patients who responded adequately, event-free survival rates at 5 years were 90·1% (95% CI 87·5-92·7). event-free survival rates at 5 years in 892 patients who were randomly assigned to treatment and analysed per protocol were 89·9% (95% CI 87·1-92·8) for COPP (n=444) versus 86·1% (82·9-89·4) for COPDAC (n=448). The COPDAC minus COPP difference in event-free survival at 5 years was -3·7% (-8·0 to 0·6). The most common grade 3-4 adverse events (intention-to-treat population) were decreased haemoglobin (205 [15%] of 1365 patients during OEPA vs 37 [7%] of 528 treated with COPP vs 20 [2%] of 819 treated with COPDAC), decreased white blood cells (815 [60%] vs 231 [44%] vs 84 [10%]), and decreased neutrophils (1160 [85%] vs 223 [42%] vs 174 [21%]). One patient in treatment group 2 died of sepsis after the first cycle of OEPA; no other treatment-related deaths occurred. INTERPRETATION: Our results show that radiotherapy can be omitted in patients who adequately respond to treatment, when consolidated with COPP or COPDAC. COPDAC might be less effective, but is substantially less gonadotoxic than COPP. A high proportion of patients could therefore be spared radiotherapy, eventually reducing the late effects of treatment. With more refined criteria for response assessment, the number of patients who receive radiotherapy will be further decreased. FUNDING: Deutsche Krebshilfe, Elternverein für Krebs-und leukämiekranke Kinder Gießen, Kinderkrebsstiftung Mainz, Tour der Hoffnung, Menschen für Kinder, Programme Hospitalier de Recherche Clinique, and Cancer Research UK.

Overexpression of IgG2 in patients resembling IgG4-related disease with normal IgG4.

IgG4-Related Disease (IgG4-RD) results from tissue infiltration by IgG4-expressing plasma cells and lymphocytes, leading to fibrosis and organomegaly. Clinical presentation is remarkably variable according to organ involvement, and high IgG4 serum concentration, initially considered a diagnostic hallmark of IgG4-RD, tends to be forgone as an indispensable criterion for its diagnosis; it can indeed be absent in some patients, highlighting the diversity of presentation of this dysimmune condition. Nevertheless, elevation of IgG4 serum concentration in suggestive settings remains an argument in favour of IgG4-RD, and while other IgG subclasses can be elevated, this biological feature lacks any diagnostic value. We retrospectively studied 9 patients (5 females, 4 males, 31-81 years old) for whom a diagnosis of IgG4-RD had been considered, based on clinical, imaging or histological criteria, but appeared to display abnormally high serum IgG2 while IgG4 levels were normal. Increased serum IgG1 in one case and increased IgG3 in another one were also noticed. Immunohistochemical analyses of intracellular immunoglobulins could be performed on tissue lymph node biopsies from 2 patients, which demonstrated strong infiltration with IgG2-expressing plasma cells. Thus, overexpression of IgG2 subclass may highlight cases of dysimmune disorders resembling IgG4-RD, although the disease trigger might be different, notably infectious. We suggest measuring all serum IgG subclass levels in patients with features consistent with IgG4-RD.

Multiple endocrine neoplasia type 1 or 4: detection of hyperfunctioning parathyroid glands with 18F-fluorocholine PET/CT. Illustrative cases and pitfalls.

18F-fluorocholine (FCH) PET/CT is now well established to detect the hyperfunctioning parathyroid glands (HFPTG) in a case of sporadic primary hyperparathyroidism (pHPT), but only limited evidence is available about the utility of FCH PET/CT to detect the HFPTG in patients with multiple endocrine neoplasia (MEN) type 1 or 4. The pHPT in this context frequently consists in a multiglandular disease with small hyperplastic glands rather than adenomas, which is challenging for imaging modalities. The data of patients with MEN1 or MEN4 after parathyroidectomy referred to FCH PET/CT for presurgical localization of HFPTG were retrospectively reviewed, including follow-up after parathyroidectomy, in search for diagnostic performance and for potential pitfalls. In the present cohort, 16 patients referred to FCH PET/CT as part of their initial pHPT work-up were subsequently operated, 44 abnormal parathyroid glands (PT) were resected, of which 32 (73%) had been detected on FCH PET/CT and 2 considered as equivocal foci. Nine patients referred to FCH PET/CT for recurrent pHPT who were subsequently operated, 14 abnormal PT were resected, all had been detected on FCH PET/CT. FCH PET/CT permitted a unilateral approach for PTx in 4 of them. In one patient with MEN4 and pHPT, the HFPTG could not be visualized on FCH PET/CT but was localized by ultrasonography. Several causes of false positive or false negative results, incidental finding and pitfalls are listed and discussed. FCH PET/CT has a positive benefit/risk ratio in the detection of HFPTG in case of MEN1 (the data in MEN4 being currently very limited) with the most effective detection rate of current imaging modalities for HFPTG, few pitfalls, and an adequate impact on patient management compared to sesta MIBI SPECT and ultrasonography.

Feasibility, Safety and Impact of (18F)-FDG PET/CT in patients with pregnancy-associated cancer: experience of the French CALG (Cancer Associé à La Grossesse) network.

BACKGROUND: The incidence of pregnancy-associated cancers has been increasing for decades. (18F)-FDG Positron Emission Tomography (PET)/Computed Tomography (CT) imaging has become a golden standard in the staging of many malignant diseases. The aims of the current study were to evaluate the feasibility, safety and impact of (18F)-FDG PET/CT performed during pregnancy. MATERIAL AND METHODS: A retrospective analysis from the prospective database of the Cancer Associé à La Grossesse (CALG) network (Tenon Hospital, France) including patients who underwent (18F)-FDG PET/CT during their pregnancy between 2015 and 2020. RESULTS: Of the 536 patients for whom advice from the CALG network was requested during the study period, 359 were diagnosed with cancer during pregnancy. Study population was composed of 63 (17.5%) patients who underwent (18F)-FDG PET/CT. Most cancers were diagnosed during the second trimester. Seventy-five percent were diagnosed with breast cancer, mostly locally advanced invasive ductal carcinomas. Median term of pregnancy at PET/CT was 24.8 weeks of gestation. Twelve (19%), 24 (38.1%) and 22 (34.9%) patients underwent the exam during the 1st, 2nd and 3rd trimester, respectively. (18F)-FDG PET/CT resulted in stage modification for 38 (60.3%) of the patients (28 with more extensive lymph node involvement and 10 with metastatic disease) with subsequently/accordingly modified first-line medical treatment. Fifty patients gave birth to healthy newborns. Two patients had a medical termination of pregnancy, five had a medical abortion, one neonatal death occurred in a patient with severe preeclampsia (unrelated to (18F)-FDG PET/CT). The data of 46 children were available at 6 months, 29 at 12 months, and 15 at 24 months. No cases of mental retardation, childhood cancer, or malformation were reported within 2 years. CONCLUSION: (18F)-FDG PET/CT has a major impact on the management of pregnancy-associated cancers and does not appear to cause fetal side effects suggesting that the exam is feasible during pregnancy as maternal benefits outweigh fetal risks.

Patient external dose rate after 177Lu-DOTATATE therapy: factors affecting its decrease and predictive value.

Rationale: Peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE (oxodotreotide) results in external radiation exposure from the patient. In the PREELU observational prospective study, we determined the equivalent dose rate at 1 m of the patient (EDR-1m) for a period following PRRT. The main objective was to predict which patients could be discharged from the hospital at approximately 3 h after the administration of 177Lu-DOTATATE, i.e. at the end of the infusion of amino-acids according to our PRRT protocol. As presenting no undue risk of radiation exposure for the public, those patients could be treated as outpatients or day patients, rather than inpatients. Methods: We sequentially measured EDR-1m facing the sternum and then the pelvis during 50 PRRT in 24 patients with metastatic neuroendocrine tumours, each 30 minutes after ending administration of Lutathera, over at least 180 minutes. Results: 180 minutes after the administration of ca. 7400 MBq of Lutathera, EDR-1m was <40 µSv/h in all cases, and <25 µSv/h in 32 cases (64%). After an overnight hospital stay, EDR-1m was <25 µSv/h in all cases. The EDR-1m value measured facing the sternum was the greatest in about one-fourth of paired measurements. In patients whose creatinine clearance was >96 mL/min/1.73m2, the EDR-1m was most likely (predictive value=90%) to drop below 25 µSv/h within 180 minutes after the administration of Lutathera. In 16 patients who benefited from several PRRT cycles, the creatinine clearance did not decrease significantly from one cycle to the next, probably due to the kidney protection by the amino-acid infusion. The patients whose EDR-1m dropped below 25 µSv/h at 180 minutes during their first PRRT cycle were unlikely (predictive value= 88%) to decease during the following two years. Conclusion: All patients could have been discharged 3 h after administration according to the criterion EDR-1m <40 µSv/h. Using EDR-1m <25 µSv/h as criterion, an extended hospital stay beyond 3 h would have been necessary in around one-third of the PRRT treatments and could be anticipated based on creatinine clearance ≤96 mL/min/1.73m2. EDR-1m <25 µSv/h at 180 min during the first PRRT yielded a strong predictive value on the patient's survival at two years, a finding that should be confirmed in future studies.

Prolonged response to 177Lu-DOTATATE therapy of a bone marrow infiltration in a refractory thymic neuro endocrine tumor.

Thymic neuro endocrine tumor (tNET) are extremely rare malignancies with poor prognosis, requiring investigation of novel therapeutic approaches. 177Lu-DOTATATE is a successful systemic treatment modality in patients with metastatic gastroenteropancreatic but it role in tNET is not yet well established. Here we report a case of a 39-year-old man with refractory bone marrow infiltration of a tNET, treated by 4 cycles of peptide receptor radionuclide therapy (PRRT) with 177Lu DOTATATE. Since the first cycle, clinical symptoms were substantially decreased, without any severe subacute haematological toxicity. Three months after the end of PRRT, both 68Ga-DOTATOC and 18F-FDG PET confirmed a partial response, already suggested by 177Lu-DOTATATE treatment scan with a significant decrease of the bone marrow uptake between the first and fourth cycle. This report highlights that PRRT could be an effective therapeutic option for advanced bone metastatic disease tNET, with the significant benefit of alleviation of bone pain and radiologic response, without severe or irreversible haematotoxicity.

Diagnostic performance and impact on patient management of 68Ga-DOTA-TOC PET/CT for detecting osteomalacia-associated tumours.

PURPOSE: Oncogenic osteomalacia is an endocrine disorder induced by small benign tumours (TIO) producing excessive fibroblast growth factor-23 (FGF23). The only way of curing oncogenic osteomalacia is surgical resection of the culprit TIO, which is extremely difficult to detect using conventional imaging modalities due to its small size and variable location in the body. Since TIO frequently overexpress somatostatin receptors, a clinical utility of SPECT or PET with radiolabelled somatostatin analogues has been reported. Among them, 68Ga-DOTA-TOC has recently been granted a marketing authorization, facilitating its routine application. We report here the results of the first series evaluating the diagnostic performance of 68Ga-DOTA-TOC PET/CT in detecting TIO and its impact on patient management. METHODS: 68Ga-DOTA-TOC PET/CT and clinical and imaging data from 15 patients with clinical and biochemical signs of oncogenic osteomalacia were retrospectively reviewed. The 68Ga-DOTA-TOC PET/CT findings were compared with the results of post-surgical pathology and clinical and biochemical follow-up. RESULTS: 68Ga-DOTA-TOC PET/CT resulted in the detection of one focus suspicious for TIO in nine of 15 patients (60%), and a tumour was surgically removed in eight. Post-operative pathology confirmed a TIO in those eight patients whose symptoms diminished promptly and biochemical anomalies resolved. 68Ga-DOTA-TOC PET/CT sensitivity, specificity and accuracy were 73%, 67% and 71%, respectively. 68Ga-DOTA-TOC PET/CT findings affected patient management in 67% of cases. In particular, 68Ga-DOTA-TOC PET/CT was able to detect the TIO with a negative or a false-positive result of a previous 111In-pentetreotide SPECT/CT in 5/8 patients (63%) or a previous FDG PET/CT in 7/11 patients (64%). No close relationship was found between the positivity of 68Ga-DOTA-TOC PET/CT and the serum level of a biochemical marker. However, a true-positive result of 68Ga-DOTA-TOC PET/CT was obtained in only one patient with a non-elevated serum level of FGF23. CONCLUSION: 68Ga-DOTA-TOC PET/CT is an accurate imaging modality in the detection of TIO; in particular, it is worthwhile after failure of somatostatin receptor SPECT(/CT) or FDG PET/CT.

Vertebral metastases from neuroendocrine tumours: How to avoid false positives on 68Ga-DOTA-TOC PET using CT pattern analysis?

OBJECTIVES: To develop criteria to improve discrimination between vertebral metastases from neuroendocrine tumours (NETs) and benign bone lesions on PET combined with CT using DOTA-D-Phe1-Tyr3-octreotide labelled with gallium-68 (68Ga-DOTA-TOC). METHODS: In 535 NET patients, 68Ga-DOTA-TOC PET/CT examinations were reviewed retrospectively for vertebral CT lesions and/or PET foci. For each vertebral PET abnormality, appearance on CT, biological volume (BV), standardized uptake value (SUVmax) and ratios to those of reference organs were determined. All vertebral abnormalities were characterized as a metastasis, a typical vertebral haemangioma (VH) or other benign lesion. RESULTS: In 79 patients (14.8 %), we found 107 metastases, 34 VHs and 31 other benign lesions in the spine. The optimal cut-off values to differentiate metastases from benign lesions were BV ≥0.72 cm3, SUVmax ≥2, SUVmax ratio to a reference vertebra ≥2.1, to liver ≥0.28 and to spleen ≥0.14. They corresponded to lesion-based 68Ga-DOTA-TOC PET/CT sensitivity of 87 %, 98 %, 97 %, 99 % and 94 %, and specificity of 55 %, 100 %, 90 %, 97 %, 100 %, respectively. CONCLUSIONS: The high sensitivity of 68Ga-DOTA-TOC-PET/CT in detecting NET vertebral metastases was confirmed; this study showed that specificity could be improved by combining CT features and quantifying 68Ga-DOTA-TOC uptake. KEY POINTS: • Bone metastases in neuroendocrine tumours correlate with prognosis. • Benign bone lesions may mimic metastases on 68 Ga-DOTA-TOC PET/CT imaging. • The specific polka-dot CT pattern may be missing in some vertebral haemangiomas. • Lesion atypical for haemangiomas can be better characterized by quantifying 68 Ga-DOTA-TOC uptake.

Paediatric and adolescent Hodgkin lymphoma: information derived from diffuse organ uptake of 18 F-fluorodeoxyglucose on pre-treatment and on interim PET/CT.

PURPOSE: To evaluate, in children with Hodgkin lymphoma (HL), the frequency and intensity of visually diffuse FDG uptake by selected organs at baseline (bPET) and on interim PET/CT (iPET), and to evaluate the relation between FDG uptake, metabolic response and evolution of the disease with treatment. PATIENTS AND METHODS: Thirty children with HL had bPET and then iPET after two cycles of treatment, which were blind-read retrospectively. Excluding sites with focal uptake, diffuse FDG uptake by thymus, bone marrow at iliac crests, liver, spleen, and the spinal cord at the 12th thoracic vertebra (Th12) was evaluated visually using a three-point scoring method and semiquantitatively by measuring SUVmax. Visualisation of activated brown adipose tissue (BAT) was also quoted. Five children had refractory HL. Recurrence-free survival was determined for each patient. Nine patients relapsed; in 21 non-relapsing patients, the median follow-up period was 43 months (range: 28-61). RESULTS: On bPET, the rate of diffuse and intense (visual score = 3) FDG uptake was 48 % in the spleen, 43 % in the spinal cord at Th12, 37 % in bone marrow, 21 % in the thymus and 7 % in BAT. At least one of those sites showed diffuse and intense FDG uptake in 77 % of patients. On iPET, a significant decrease in SUVmax was observed in thymus, iliac crest bone marrow and spleen, but not in spinal cord. In contrast, the FDG uptake by the liver significantly increased. The absence of SUVmax increase in the liver between bPET and iPET was the best criterion to predict a refractory disease (PPV = 55 %, NPV = 100 %). Its area under ROC (AUC) was 0.9 vs. 0.73 for five-point Deauville criteria. For prediction of relapse, two criteria were derived from the evolution of diffuse uptake between bPET and iPET: no increase in liver uptake and an increase > 5 % in spinal cord uptake. As compared with 13 patients who matched none of those criteria, the hazard ratio (HR) for relapse was 2.1 in 13 patients who matched one criterion, and 10.3 in four patients who matched both (Kaplan-Meier analysis p = 0.005). CONCLUSION: Diffuse and intense FDG uptake by organs is frequent in children with HL on bPET. On iPET, it is frequently reduced in all sites except the liver, which may pose problems for visual quotation of the FDG intensity of HL foci. The variation of SUVmax between bPET and iPET permitted us to achieve a prediction of refractory or relapsing HL that was at least as effective as using criteria based on FDG uptake by the HL lesions. The results of this retrospective pilot study need further validation.

Comparison of normocalcemic versus hypercalcemic primary hyperparathyroidism in a hypercalciuric renal stone population.

CONTEXT: Primary hyperparathyroidism (PHPT) is commonly diagnosed in the setting of hypercalcemia, whereas normocalcemic primary hyperparathyroidism (NHPT) may be misdiagnosed. OBJECTIVE: Our objective was to compare hypercalcemic hyperparathyroidism (HPHPT) versus NHPT hypercalciuric renal stone patients. DESIGN AND SETTING: We took advantage of a routine calcium load test performed in hypercalciuric renal stone patients to assess retrospectively among PHPT patients, prevalence and characteristics of NHPT and HPHPT under a calcium restricted diet. RESULTS: Among 1671 hypercalciuric patients included, 91 patients have a final diagnosis of PHPT(post load ionized calcium (iCa)>1.31 mmol/L and PTH>30 pg/ml). Prevalence of NHPT is 40% of all PHPT, however according to total serum calcium 4/35 NHPT and 7/56 HPHPT would have been misclassified in the other group. 18/35 NHPT and 40/56 HPHPT underwent parathyroidectomy. No significant characteristics related to parathyroid weight, stone composition or bone remodeling biomarkers is detected between groups. Whereas iCa is higher in HPHPT in fasting state and after calcium load, we found no difference for calcium diet, 24-hour calciuria, or calcitriol. Of notice, renal calcium excretion (FECa) post load increases by 303% in NHPT but only 176% in HPHPT (p=0.01) likely explained by a lesser PTH decrease (p=0.02). However, a strong negative association (p<0.0001) detected between pooled pre and post load iCa and PTH only in NHPT group suggests a persistent efficient PTH-CaSR control within parathyroid glands in this group. CONCLUSION: Our data show the relevance of dynamic tests to unmask NHPT in hypercalciuric renal stone patients.

Activity of Lutetium-177 Prostate-specific Membrane Antigen and Determinants of Outcomes in Patients with Metastatic Castration-resistant Prostate Cancer Previously Treated with Cabazitaxel: The PACAP Study.

BACKGROUND: Both cabazitaxel and lutetium-177 prostate-specific membrane antigen (Lu-PSMA) improve survival in metastatic castration-resistant prostate cancer (mCRPC) after an androgen receptor pathway inhibitor and docetaxel, but there are limited data regarding Lu-PSMA activity after cabazitaxel. OBJECTIVE: To assess the activity of Lu-PSMA and determinants of outcomes after cabazitaxel in mCRPC. DESIGN, SETTING, AND PARTICIPANTS: A retrospective analysis was conducted of consecutive mCRPC patients from eight European centers treated with Lu-PSMA after cabazitaxel. INTERVENTION: Lu-PSMA every 6-8 wk at a dose of 6-7.6 GBq. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was radiographic progression-free survival (rPFS). The secondary endpoints included time to prostate-specific antigen (PSA) progression (TTPSA), overall survival (OS), PSA decline, objective response rate (ORR), clinical benefit, and safety. RESULTS AND LIMITATIONS: Of 126 patients, 68% had International Society of Urological Pathology (ISUP) grade 4-5 disease, 21% had visceral metastases, and 7% had lymph node disease only. DNA damage repair (DDR) alterations were detected in 11/50 (22%) patients with available testing. Patients received a median number of 3 Lu-PSMA cycles (interquartile range 2-4). With a median follow-up of 12.0 mo, the median rPFS was 4.4 mo (95% confidence interval [CI] 3.2-5.4), TTPSA 3.5 mo (95% CI 3.0-4.6), and OS 8.9 mo (95% CI 6.5-12.7). The ORR was 35%, and 55 patients (44%) experienced a PSA decline of ≥50%. The time to castration resistance of <12 mo was associated with shorter rPFS (p = 0.01). A similar trend was observed for ISUP grade 4-5 (p = 0.08), and baseline positron-emission tomography parameters including PSMA mean standardized uptake value (SUV) and maximum SUV (respectively, p = 0.06 and 0.05). The duration of previous cabazitaxel or DDR status did not impact outcomes. Patients experiencing a PSA decline of ≥ 50% on therapy demonstrated longer rPFS, TTPSA, and OS (all p < 0.0001). Limitations include retrospective data collection and investigator-based rPFS assessment. CONCLUSIONS: Lu-PSMA demonstrated a substantial PSA decline but limited rPFS after cabazitaxel in a real-life setting. Adverse baseline characteristics, baseline positron-emission tomography parameters, and quality of PSA response may help identify patients less likely to benefit from Lu-PSMA. PATIENT SUMMARY: Lutetium-177 prostate-specific membrane antigen (Lu-PSMA) improved outcomes in patients with castration-resistant prostate cancer, but there are limited data about its activity after cabazitaxel, a chemotherapy that is also the standard of care in this setting. We conducted a study across eight European centers and showed substantial responses on Lu-PSMA after cabazitaxel, although activity was short lived in a heavily pretreated population. Our findings prompt for real-life evaluation of Lu-PSMA in earlier settings to define the best therapeutic sequence.

18F-fluorodihydroxyphenylalanine vs other radiopharmaceuticals for imaging neuroendocrine tumours according to their type.

6-Fluoro-((18)F)-L-3,4-dihydroxyphenylalanine (FDOPA) is an amino acid analogue for positron emission tomography (PET) imaging which has been registered since 2006 in several European Union (EU) countries and by several pharmaceutical firms. Neuroendocrine tumour (NET) imaging is part of its registered indications. NET functional imaging is a very competitive niche, competitors of FDOPA being two well-established radiopharmaceuticals for scintigraphy, (123)I-metaiodobenzylguanidine (MIBG) and (111)In-pentetreotide, and even more radiopharmaceuticals for PET, including fluorodeoxyglucose (FDG) and somatostatin analogues. Nevertheless, there is no universal single photon emission computed tomography (SPECT) or PET tracer for NET imaging, at least for the moment. FDOPA, as the other PET tracers, is superior in diagnostic performance in a limited number of precise NET types which are currently medullary thyroid cancer, catecholamine-producing tumours with a low aggressiveness and well-differentiated carcinoid tumours of the midgut, and in cases of congenital hyperinsulinism. This article reports on diagnostic performance and impact on management of FDOPA according to the NET type, emphasising the results of comparative studies with other radiopharmaceuticals. By pooling the results of the published studies with a defined standard of truth, patient-based sensitivity to detect recurrent medullary thyroid cancer was 70 % [95 % confidence interval (CI) 62.1-77.6] for FDOPA vs 44 % (95 % CI 35-53.4) for FDG; patient-based sensitivity to detect phaeochromocytoma/paraganglioma was 94 % (95 % CI 91.4-97.1) for FDOPA vs 69 % (95 % CI 60.2-77.1) for (123)I-MIBG; and patient-based sensitivity to detect midgut NET was 89 % (95 % CI 80.3-95.3) for FDOPA vs 80 % (95 % CI 69.2-88.4) for somatostatin receptor scintigraphy with a larger gap in lesion-based sensitivity (97 vs 49 %). Previously unpublished FDOPA results from our team are reported in some rare NET, such as small cell prostate cancer, or in emerging indications, such as metastatic NET of unknown primary (CUP-NET) or adrenocorticotropic hormone (ACTH) ectopic production. An evidence-based strategy in NET functional imaging is as yet affected by a low number of comparative studies. Then the suggested diagnostic trees, being a consequence of the analysis of present data, could be modified, for some indications, by a wider experience mainly involving face-to-face studies comparing FDOPA and (68)Ga-labelled peptides.

FDG PET/CT in children and adolescents with lymphoma.

The aim of this review is to give an overview of FDG PET/CT applications in children and adolescents with lymphoma. Today, FDG PET is used for tailoring treatment intensity in children with Hodgkin lymphoma within the framework of international treatment optimisation protocols. In contrast, the role of this method in children with Non-Hodgkin lymphoma is not well defined. This paper overviews clinical appearance and metabolic behaviour of the most frequent lymphoma subtypes in childhood. The main focus of the review is to summarise knowledge about the role of FDG PET/CT for initial staging and early response assessment.

The Presence of an Arteria Lusoria Should Be Checked When Reporting 18 F-FCH PET/CT Performed to Localize Hyperfunctioning Parathyroid Glands.

ABSTRACT: Nonrecurrent inferior laryngeal nerve (NRILN) is a rare anatomical variant, which significantly increases the risk of nerve injury during neck surgery, for example, thyroidectomy or parathyroidectomy (PTX). The absence of the brachiocephalic trunk and presence of arteria lusoria (AL) are strong predictors of NRILN in the right neck. FCH PET/CT is now a recognized imaging modality in hyperparathyroidism (HPT). We report 2 patients with primary or renal HPT in whom FCH PET detected right HFPTs and low-dose noncontrast CT evidenced AL. The NRILN was thus preserved during PTX. We recommend searching for AL on FCH PET/CT (even low-dose) in HPT before PTX.

Fully automated radiolabeling of [68Ga]Ga-EMP100 targeting c-MET for PET-CT clinical imaging.

BACKGROUND: c-MET is a transmembrane receptor involved in many biological processes and contributes to cell proliferation and migration during cancer invasion process. Its expression is measured by immunehistochemistry on tissue biopsy in clinic, although this technique has its limitations. PET-CT could allow in vivo mapping of lesions expressing c-MET, providing whole-body detection. A number of radiopharmaceuticals are under development for this purpose but are not yet in routine clinical use. EMP100 is a cyclic oligopeptide bound to a DOTA chelator, with nanomolar affinity for c-MET. The aim of this project was to develop an automated method for radiolabelling the radiopharmaceutical [68Ga]Ga-EMP100. RESULTS: The main results showed an optimal pH range between 3.25 and 3.75 for the complexation reaction and a stabilisation of the temperature at 90 °C, resulting in an almost complete incorporation of gallium-68 after 10 min of heating. In these experiments, 90 µg of EMP-100 peptide were initially used and then lower amounts (30, 50, 75 µg) were explored to determine the minimum required for sufficient synthesis yield. Radiolysis impurities were identified by radio-HPLC and ascorbic acid and ethanol were used to improve the purity of the compound. Three batches of [68Ga]Ga-EMP100 were then prepared according to the optimised parameters and all met the established specifications. Finally, the stability of [68Ga]Ga-EMP100 was assessed at room temperature over 3 h with satisfactory results in terms of appearance, pH, radiochemical purity and sterility. CONCLUSIONS: For the automated synthesis of [68Ga]Ga-EMP100, the parameters of pH, temperature, precursor peptide content and the use of adjuvants for impurity management were efficiently optimised, resulting in the production of three compliant and stable batches according to the principles of good manufacturing practice. [68Ga]Ga-EMP100 was successfully synthesised and is now available for clinical development in PET-CT imaging.