Development and Validation of Analytical Methods for Radiochemical Purity of 177Lu-PSMA-1.

Prostate Specific Membrane Antigen (PSMA) is a highly relevant target in nuclear medicine due to its overexpression in prostate cancer. The 68Ga/177Lu-PSMA-1 combination is a theranostic agent for the detection and treatment of tumors overexpressing the PSMA target. Specifically, 177Lu-PSMA-1 is used in the treatment of castration-resistant prostate cancer that is ineffective or intolerant to the latest generation of chemotherapy and/or hormone therapy. This radiopharmaceutical is manufactured in a radiopharmaceutical synthesizing unit and must pass a quality control where the radiochemical purity (RCP) is assessed prior to release of the batch. RCP evaluation is performed by high-performance liquid chromatography (HPLC) and thin-layer chromatography (TLC). Since there is no monograph for 177Lu-PSMA-1 in the European Pharmacopoeia, we validate the analytical methods according to the EANM recommendations adapted from ICH Q2. Specificity, linearity, accuracy, precision, intermediate precision, limit of quantification (LOQ) and robustness were described for HPLC and TLC in this study. The results obtained demonstrated the robustness and reliability of the HPLC and TLC analytical methods for the evaluation of the RCP of 177Lu-PSMA-1.

Outcome Prediction at Patient Level Derived from Pre-Treatment 18F-FDG PET Due to Machine Learning in Metastatic Melanoma Treated with Anti-PD1 Treatment.

(1) Background: As outcome of patients with metastatic melanoma treated with anti-PD1 immunotherapy can vary in success, predictors are needed. We aimed to predict at the patients' levels, overall survival (OS) and progression-free survival (PFS) after one year of immunotherapy, based on their pre-treatment 18F-FDG PET; (2) Methods: Fifty-six metastatic melanoma patients-without prior systemic treatment-were retrospectively included. Forty-five 18F-FDG PET-based radiomic features were computed and the top five features associated with the patient's outcome were selected. The analyzed machine learning classifiers were random forest (RF), neural network, naive Bayes, logistic regression and support vector machine. The receiver operating characteristic curve was used to compare model performances, which were validated by cross-validation; (3) Results: The RF model obtained the best performance after validation to predict OS and PFS and presented AUC, sensitivities and specificities (IC95%) of 0.87 ± 0.1, 0.79 ± 0.11 and 0.95 ± 0.06 for OS and 0.9 ± 0.07, 0.88 ± 0.09 and 0.91 ± 0.08 for PFS, respectively. (4) Conclusion: A RF classifier, based on pretreatment 18F-FDG PET radiomic features may be useful for predicting the survival status for melanoma patients, after one year of a first line systemic treatment by immunotherapy.

Does whole-body bone SPECT/CT provide additional diagnostic information over [18F]-FCH PET/CT for the detection of bone metastases in the setting of prostate cancer biochemical recurrence?

BACKGROUND: To assess whether whole-body (WB) bone SPECT/CT provides additional diagnostic information over [18F]-FCH PET/CT for the detection of bone metastases in the setting of prostate cancer biochemical recurrence (PC-BR). METHODS: Patients referred for a PC-BR and whom benefited from a WB bone SPECT/CT and FCH PET/CT were retrospectively included. Tests were classified as positive, equivocal, or negative for bone metastases. A best valuable comparator (BVC) strategy including imaging and follow-up data was used to determine the metastatic status in the absence of systematic histological evaluation. RESULTS: Between January 2011 and November 2017, 115 consecutive patients with a PC-BR were evaluated. According to the BVC, 30 patients had bone metastases and 85 patients did not present with bone lesions. The sensitivity, specificity, positive and negative predictive values were respectively 86.7% [69.3-96.2], 98.8% [93.6-100.0], 96.3% [78.7-99.5], and 95.5% [89.4-98.1] for WB bone SPECT/CT and 93.3% [77.9-99.2], 100.0% [95.8-100.0], 100.0 and 97.7% [91.8-99.4] for FCH PET/CT. There was no significant difference in diagnostic accuracy of bone metastases between WB Bone SPECT/CT (AUC 0.824 [0.74-0.90]) and FCH PET/CT (AUC 0.829 [0.75-0.90], p = 0.41). CONCLUSION: Despite good performances for the diagnosis of bone metastases in PC-BR, WB bone SPECT/CT does not provide additive diagnostic information over concomitant FCH PET/CT.

18F-Choline and 18F-FDG PET/CT in a Patient With Diffuse Large B-Cell Lymphoma and Recurrent Prostate Cancer.

We report herein the case of an 80-year-old man who was referred for a biochemical recurrence of a high-risk prostate cancer. In addition to prostate cancer recurrence, F-choline allowed partial initial staging of an incidental diffuse large B-cell lymphoma which was further confirmed and staged using F-FDG and a biopsy. Two types of metabolic behavior were therefore identified using F-choline and F-FDG which corresponded to 2 different uptake patterns, that is, those of the prostate and lymphoma tumoral cell contingents.

R-CHOP 14 with or without radiotherapy in nonbulky limited-stage diffuse large B-cell lymphoma.

The benefit of radiotherapy (RT) after chemotherapy in limited-stage diffuse large B-cell lymphoma (DLBCL) remains controversial. We conducted a randomized trial in patients with nonbulky limited-stage DLBCL to evaluate the benefit of RT after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Patients were stratified according to the modified International Prognostic Index, including lactate dehydrogenase, Eastern Cooperative Oncology Group performance status, age, and disease stage. The patients received 4 or 6 consecutive cycles of R-CHOP delivered once every 2 weeks, followed or not by RT at 40 Gy delivered 4 weeks after the last R-CHOP cycle. All patients were evaluated by fluorodeoxyglucose-positron emission tomography scans performed at baseline, after 4 cycles of R-CHOP, and at the end of treatment. The primary objective of the trial was event-free survival (EFS) from randomization. The trial randomly assigned 165 patients in the R-CHOP arm and 169 in the R-CHOP plus RT arm. In an intent-to-treat analysis with a median follow-up of 64 months, 5-year EFS was not statistically significantly different between the 2 arms, with 89% ± 2.9% in the R-CHOP arm vs 92% ± 2.4% in the R-CHOP plus RT arm (hazard ratio, 0.61; 95% confidence interval [CI], 0.3-1.2; P = .18). Overall survival was also not different at 92% (95% CI, 89.5%-94.5%) for patients assigned to R-CHOP alone and 96% (95% CI, 94.3%-97.7%) for those assigned to R-CHOP plus RT (P = not significant). R-CHOP alone is not inferior to R-CHOP followed by RT in patients with nonbulky limited-stage DLBCL. This trial was registered at www.clinicaltrials.gov as #NCT00841945.

Survival and prognostic factors after adjuvant 131iodine-labeled lipiodol for hepatocellular carcinoma: a retrospective analysis of 106 patients over 20 years.

OBJECTIVE: Hepatocellular carcinoma (HCC) has high recurrence rate after curative treatment. The aim of the present study was to report our experience with adjuvant use of 131I-lipiodol after curative treatment of HCC in terms of recurrence and survival in a large cohort of patients with a long follow-up. METHODS: All patients treated with 131I-lipiodol after curative treatment of HCC in two French centers from 1991 to 2009 were included in a retrospective cohort study. RESULTS: One hundred and six patients were included. The median (range) follow-up was 6 years (0.3-22). Forty-three patients (41%) had cirrhosis. Recurrence-free survival rates at 1, 2, 5, 10, and 20 years were 73, 57, 40, 30, and 14%, respectively. Cirrhosis was an independent predictive factor of recurrence [RR = 1.18, 95% CI (1.11-3.02), p = 0.019]. Overall, survival rates at 1, 2, 5, 10, and 20 years were 90, 83, 59, 37, and 23%, respectively. Prognostic factors were recurrence [RR = 2.73, 95% CI (1.35-5.54); p = 0.005], age over 60 years (RR = 1.91, 95% CI [1.02-3.61]; p = 0.044), and tumor number over 3 [RR = 3.31, 95% CI (1.25-8.77); p = 0.016]. CONCLUSION: Our results suggest that the effect of 131I-lipiodol after curative treatment of HCC could be related to a beneficial impact on risk factors of early tumor recurrence. This could be evaluated in further studies using modern radioembolization methods.

Consolidation anti-CD22 fractionated radioimmunotherapy with 90Y-epratuzumab tetraxetan following R-CHOP in elderly patients with diffuse large B-cell lymphoma: a prospective, single group, phase 2 trial.

BACKGROUND: Radioimmunotherapy represents a potential option as consolidation after chemoimmunotherapy in patients with diffuse large B-cell lymphoma who are not candidates for transplantation. We aimed to assess activity and toxicity of fractionated radioimmunotherapy using anti-CD22 90Y-epratuzumab tetraxetan as consolidation after front-line induction chemoimmunotherapy in untreated elderly patients with diffuse large B-cell lymphoma. METHODS: We did a prospective, single-group, phase 2 trial at 28 hospitals in France, with patients recruited from 17 hospitals. Eligible patients were aged 60-80 years with bulky stage 2-3 or stage 3-4 CD20-positive diffuse large B-cell lymphoma, previously untreated, and not eligible for transplantation. Patients received six cycles of R-CHOP (rituximab [375 mg/m2], cyclophosphamide [750 mg/m2], doxorubicin [50 mg/m2], and vincristine [1·4 mg/m2, up to 2 mg] all on day 1, and prednisone [40 mg/m2] daily for 5 days), administered every 14 days. 6-8 weeks after R-CHOP, responders received two doses of 15 mCi/m2 (555 MBq/m2) 90Y-epratuzumab tetraxetan administered 1 week apart. The primary endpoint was 2 year event-free survival in all registered eligible patients who received at least 1 day of study treatment; the safety analysis was done in the same population. This trial is registered with ClinicalTrials.gov, number NCT00906841. FINDINGS: Between Oct 22, 2008, and Dec 16, 2010, we recruited 75 patients, of whom four (5%) were excluded after central pathology review; hence, 71 (95%) patients were included in the analysis. All patients started induction treatment; 57 (80%) received radioimmunotherapy. With a median follow-up of 37 months (IQR 30-44), the estimated 2 year event-free survival was 75% (95% CI 63-84). Radioimmunotherapy toxicity consisted of grade 3-4 thrombocytopenia in 48 (84%) of 57 patients and neutropenia in 45 (79%) of 57 patients. One patient developed myelodysplastic syndrome 28 months after receiving radioimmunotherapy and one patient developed acute myeloid leukaemia 5 months after receiving radioimmunotherapy. INTERPRETATION: Fractionated radioimmunotherapy with 90Y-epratuzumab tetraxetan might be appropriate for response consolidation after induction chemotherapy in older patients with advanced diffuse large B-cell lymphoma, but further comparative studies are needed. FUNDING: Immunomedics, Amgen, Canceropôle Grand Ouest, the GOELAMS/LYSA group and the French National Agency for Research (Investissements d'Avenir).

Pulmonary Scintigraphy for the Diagnosis of Acute Pulmonary Embolism: A Survey of Current Practices in Australia, Canada, and France.

UNLABELLED: There are currently no data published regarding the proportion of nuclear medicine centers using SPECT or SPECT/CT rather than planar ventilation/perfusion (V/Q) imaging in patients with suspected acute pulmonary embolism (PE). Furthermore, the reporting criteria used for interpretation of both planar and SPECT V/Q scans are variable and data are lacking regarding which criteria are commonly used in various centers. The aim of this study was to assess current practices regarding the performance and interpretation of lung scintigraphy across 3 different countries. METHODS: A short online survey composed of simple multiple-choice questions was distributed to nuclear medicine departments in Australia, Canada, and France during the period April to December 2014. The survey covered image acquisition, interpretation criteria for SPECT and planar images, and use of pseudoplanar images and radiopharmaceuticals. Information was initially solicited by 2 sets of e-mails, which pointed to the survey internet link. Departments were subsequently contacted by telephone. A single response per department was consolidated. RESULTS: Three hundred thirty-one responses were collected (Australia, 74; Canada, 48; and France, 209). Twenty-eight percent of centers indicated use of V/Q planar imaging alone whereas 72% of centers included some form of SPECT in their acquisition protocol for evaluation of PE, specifically V/Q SPECT in 36%, V/Q SPECT/CT in 29%, Q SPECT/CT in 2%, and both V/Q planar and SPECT in 5%, with a strong variability among countries. The most commonly used criteria for SPECT interpretation were the those of the European Association of Nuclear Medicine (60%). Criteria used for planar interpretation were heterogeneous (European Association of Nuclear Medicine criteria, 35%; Prospective Investigation of Pulmonary Embolism Diagnosis study, 29%; no standardized criteria, 21%). Sixty-three percent of departments used pseudoplanar images in addition to SPECT images. CONCLUSION: In the 3 countries surveyed, SPECT has largely replaced planar imaging for evaluation of PE, with almost half of the SPECT studies incorporating a CT acquisition. Criteria used for interpretation are inconsistent, especially for planar imaging.

The impacts of blended learning design in first year medical studies.

In the first year of medical studies in France, students prepare for a highly selective entrance exam limited by numerus clausus into the second year. We have discontinued live lectures, made maximum use of new information and communication technologies and introduced tutorials in an attempt to make the first year more equitable and to personalise teaching. The reform is based on blended learning with flipped classroom organized into a four-week cycles of different activities. Each cycle corresponds to a learning module. The teachers' and students' opinions were analysed to evaluate the reforms and allow teaching methods to be adapted accordingly. The student profiles at registration and success in the exams following the reform are described. The tutorial's notes are correlated to the final scores at the entrance exam. The keys to success seem to be modified by the reform providing greater equality of opportunity between students. The factors associated to success are baccalaureate highest grades, high School Specialisation (maths, physics or earth and life sciences) and repeating the first year class. The use of blended learning allows us to face the increase of student enrolment, and to facilitate the acceptance of these pedagogical methods for both students and teachers.

Radioiodine therapy in benign thyroid disorders. Evaluation of French nuclear medicine practices.

OBJECTIVES: Radioiodine is currently used routinely in the treatment of hyperthyroidism including Graves' disease (GD), toxic multinodular goitre (TMNG) and toxic solitary nodule (TSN) but no consensus exists on the most appropriate way to prescribe iodine--fixed dose or calculated doses based on the gland size or turnover of (131)I. We carried out the first nationwide French survey assessing the current practices in radioiodine treatment of hyperthyroidism. MATERIAL AND METHODS: A questionnaire was sent to French nuclear medicine hospital units and cancer treatment centres (n=69) about their practices in 2012. RESULTS: Euthyroidism was considered the successful outcome for 33% of respondents, whereas hypothyroidism was the aim in 26% of cases. Fixed activities were the commonest therapeutic approach (60.0% of GD prescribed doses and 72.5% for TMNG and TSN), followed by calculated activities from Marinelli's formula (based on a single uptake value and thyroid volume). The fixed administered dose was chosen from between 1 to 3 levels of standard doses, depending on the patient characteristics. Factors influencing this choice were disease, with a median of 370 MBq for GD and 555 MBq for TSN and TMNG, thyroid volume (59%) and uptake (52%) with (131)I or (99m)Tc. Even physicians using fixed doses performed pretherapeutic thyroid scan (98%). CONCLUSION: This study shows that practices concerning the prescription of (131)I therapeutic doses are heterogeneous. But the current trend in France, as in Europe, is the administration of fixed doses. The study provides the baseline data for exploring the evolution of French clinical practices.

Study of inter- and intra-observer reproducibility in the interpretation of [(18)F]choline PET/CT examinations in patients suffering from biochemically recurrent prostate cancer following curative treatment.

BACKGROUND: The aim of this study was to investigate the reproducibility of intra- and inter-observer interpretation of [(18)F]choline positron emission tomography/computed tomography examinations in patients suffering from biochemically recurrent prostate cancer following curative treatment. METHODS: A total of 60 patients with biochemical recurrence after curative treatment were included in this bicentric study. The interpretations were based on a systematic analysis of several anatomic regions and all the four nuclear medicine physicians used identical result consoles. The examinations were interpreted with no knowledge of the patients' clinical context. Two months later, a second interpretation of all these examinations was performed using the same method, in random order. RESULTS: To evaluate local recurrences, when the prostate is in place, the results showed moderate inter- and intra-observer reproducibility: concordance of all 4 physicians has a Fleiss' kappa coefficient of 0.553 with a confidence interval of (0.425 to 0.693). For patients who had had a prostatectomy, there was excellent concordance for the negative examinations. For the lymphatic basin, inter- and intra-observer reproducibility was excellent with a Fleiss' kappa coefficient of 0.892 with a confidence interval of (0.788 to 0.975). The lymphatic sub-group analysis was also good. For the lymphatic groups in the right or left hemi-pelves, all Fleiss' kappa and Cohen's kappa coefficients are varying from 0.760 to 1 with narrow confidence intervals from (0.536 to 0.984) to (1 to 1) in favour of good/excellent inter-observer reproducibility. To evaluate bone metastasis, inter-observer reproducibility was good with a Fleiss' kappa coefficient of 0.703 and a confidence interval of (0.407 to 0.881). CONCLUSION: Our study is at time the only one on the reproducibility of interpretation of [(18)F]choline positron emission tomography/computed tomography examinations, which is a key examination for the treatment of patients suffering biochemical recurrence of prostate cancer. Interpretation of the [(18)F]choline positron emission tomography/computed tomography examination is not so useful at prostate level in patients not previously treated with prostatectomy but has a great interest on patients treated by prostatectomy. It showed good concordance in the interpretation of sub-diaphragmatic lymphatic recurrences as well as in bone metastasis.

¹8F-FDG PET predicts survival after pretargeted radioimmunotherapy in patients with progressive metastatic medullary thyroid carcinoma.

PURPOSE: PET is a powerful tool for assessing targeted therapy. Since (18)F-FDG shows a potential prognostic value in medullary thyroid carcinoma (MTC), this study evaluated (18)F-FDG PET alone and combined with morphological and biomarker evaluations as a surrogate marker of overall survival (OS) in patients with progressive metastatic MTC treated with pretargeted anti-CEA radioimmunotherapy (pRAIT) in a phase II clinical trial. METHODS: Patients underwent PET associated with morphological imaging (CT and MRI) and biomarker evaluations, before and 3 and 6 months, and then every 6 months, after pRAIT for 36 months. A combined evaluation was performed using anatomic, metabolic and biomarker methods. The prognostic value of the PET response was compared with demographic parameters at inclusion including age, sex, RET mutation, time from initial diagnosis, calcitonin and CEA concentrations and doubling times (DT), SUVmax, location of disease and bone marrow involvement, and with response using RECIST, biomarker concentration variation, impact on DT, and combined methods. RESULTS: Enrolled in the study were 25 men and 17 women with disease progression. The median OS from pRAIT was 3.7 years (0.2 to 6.5 years) and from MTC diagnosis 10.9 years (1.7 to 31.5 years). After pRAIT, PET/CT showed 1 patient with a complete response, 4 with a partial response and 24 with disease stabilization. The combined evaluation showed 20 responses. For OS from pRAIT, univariate analysis showed the prognostic value of biomarker DT (P = 0.011) and SUVmax (P = 0.038) calculated before pRAIT and impact on DT (P = 0.034), RECIST (P = 0.009), PET (P = 0.009), and combined response (P = 0.004) measured after pRAIT. PET had the highest predictive value with the lowest Akaike information criterion (AIC 74.26) as compared to RECIST (AIC 78.06), biomarker variation (AIC 81.94) and impact on DT (AIC 79.22). No benefit was obtained by combining the methods (AIC 78.75). This result was confirmed by the analysis of OS from MTC diagnosis. CONCLUSION: (18)F-FDG PET appeared as the most potent and simplest prognostic method to predict survival in patients with progressive MTC treated with pRAIT. Biomarker DT before pRAIT also appeared as an independent prognostic factor, but no benefit was found by adding morphological and biomarker evaluation to PET assessment.

Adjuvant Intraarterial Lipiodol or ¹³¹I-Lipiodol After Curative Treatment of Hepatocellular Carcinoma: A Prospective Randomized Trial.

UNLABELLED: The prevention of tumor recurrence after curative treatment of hepatocellular carcinoma (HCC) is unresolved. Postoperative intraarterial injection of (131)I-labeled lipiodol has been proposed as adjuvant treatment. The aim of this prospective randomized trial was to evaluate if a single dose of postoperative adjuvant intraarterial (131)I-lipiodol (vs. unlabeled lipiodol) could reduce the rate of intrahepatic recurrence at 2 y. METHODS: Patients who underwent curative treatment for HCC and recovered within 6 wk were randomly assigned to receive a single 2,200-MBq (131)I-lipiodol dose or a single unlabeled lipiodol dose on a 1:1 basis. Recurrence-free and overall survival rates were analyzed. RESULTS: Between June 2005 and February 2009, we included 58 patients (median age of 63 y [range, 23-85 y]): 29 received intraarterial (131)I-lipiodol and 29 received lipiodol adjuvant treatment. At 2 y after treatment, the rate of patients with intrahepatic recurrence was 28% in the (131)I-lipiodol group and 56% in the lipiodol group (P = 0.0449). The Kaplan-Meier analysis confirmed this result, with a 2-y recurrence-free survival in the (131)I-lipiodol and lipiodol groups of 73% and 45%, respectively (P = 0.0259). The 5-y recurrence-free survival rates in the (131)I-lipiodol and lipiodol groups were 40% and 0%, respectively (P = 0.0184). The overall and specific survivals were not significantly different between groups (P = 0.9378 and P = 0.1339, respectively). (131)I-lipiodol had no severe toxic effects. CONCLUSION: After curative treatment of patients with HCC, one 2,200-MBq dose of intraarterial (131)I-lipiodol significantly decreased the rate of intrahepatic recurrence but failed to improve overall or specific survival.

Tandem myeloablative 131I-rituximab radioimmunotherapy and high-dose chemotherapy in refractory/relapsed non-Hodgkin lymphoma patients.

This Phase I/II study investigated myeloablative (131)I-rituximab radioimmunotherapy (RIT) and high-dose chemotherapy supported by one or two autologous stem cell transplantations in heavily pretreated patients with relapsed or refractory B cell non-Hodgkin lymphoma. Myeloablative RIT was safe and feasible when followed by autologous stem cell transplantation with low incidence of secondary late effects and could be a reasonable alternative regimen especially in elderly patients and in patients who have concerns about high-dose chemotherapy. Tandem myeloablative (131)I-rituximab RIT and high-dose chemotherapy supported by two autologous stem cell transplantations was also feasible. However, the toxicity was higher than after myeloablative RIT, therefore it might be recommended to restrict the tandem approach to lymphoma with poor prognosis.

[Towards a pedagogical e-learning approach to improve preparation for medical school curriculum in Grenoble: results over the 10 last years]. / Réforme pédagogique et « e-learning ¼ pour le concours de première année à la faculté de médecine de Grenoble : satisfaction des étudiants et des enseignants.

INTRODUCTION: Before 2005, at Grenoble, the teaching of the first year of medicine satisfied neither the students, nor the teachers anxious to exempt a correctly targeted effective teaching. METHODS: By 2006, the Grenoble-native teaching method was reformed in-depth with the introduction of information and communication technology (ICT) in education. Each sequence was over 4 weeks connecting: self- learning using multi-media resources, questions submitted online, meetings with teaching staff for interactive question-answer sessions in the presence of the teacher,) tutorials animated by older students for Multiple Choice Question (MCQ) training in preparation for the exams. The whole health formation was structured in 12 cycles of this same structured sequence. Since 2010, this method was extended from the faculty of medicine to the faculty of pharmacy and maieutic. Each year, more than 1600 students, 40 teachers and 140 tutors are concerned. The ICT laboratory was responsible for the production of the multi-media support, of the management of the questions online, the collection and the treatment of the evaluations of the lesson by the students. It also took part in the preparation of the MCQ trainings and after each sequence, delivered to students their personal ranking. RESULTS: Staffs between teachers and students are organized for the 12 cycles. The teachers' and students' opinions were analyzed to evaluate the reforms and allow teaching methods to be adapted accordingly. The expressed satisfaction' rate vary from 85% with more than 91% by students and teachers. The intensive use of new information and communication technologies is well accepted, by both sides: teachers and students. After each tutorial, students had their results and their rank, which are linked with the contest result. The mean of the 12 notes obtained during the tutorials is correlated with the note with the contest (R of Spearman=0.75). Student profiles at registration and success in the exams following the reform are described. The keys to success (e.g. social background, high school specialization) seem to be modified by the reform providing greater equality of opportunity between students. CONCLUSION: Since 2006, the teachers have adopted this teaching reform. All the returns from the students but also the staff and the teachers, allowed us to improve teachings quality. This teaching reform modified the profiles and the characteristics of the students received with the contest as well as the nature of the factors of this success.

Phase II trial of anticarcinoembryonic antigen pretargeted radioimmunotherapy in progressive metastatic medullary thyroid carcinoma: biomarker response and survival improvement.

UNLABELLED: The prognosis of medullary thyroid carcinoma (MTC) varies from long- to short-term survival based on such prognostic factors as serum calcitonin and carcinoembryonic antigen (CEA) doubling times (DTs). This prospective phase II multicenter trial evaluated the efficacy and safety of anti-CEA pretargeted radioimmunotherapy (pRAIT) in rapidly progressing metastatic MTC patients and also how serum biomarker DTs correlate with clinical outcome. METHODS: From June 2004 to January 2008, 42 patients were treated with anti-CEA × anti-diethylenetriaminepentaacetic acid (DTPA) bispecific antibody (hMN-14 × m734) (40 mg/m(2)), followed by (131)I-di-DTPA-indium bivalent hapten (1.8 GBq/m(2)) 4-6 d later. RESULTS: The disease control rate (durable stabilization plus objective response) was 76.2%. Grade 3-4 hematologic toxicity was observed in 54.7% of patients and myelodysplastic syndrome in 2, including 1 heavily treated previously. After pRAIT, 21 of 37 assessed patients (56.7%) showed a significant impact on DT (≥100% increase of pre-pRAIT calcitonin or CEA DT or prolonged decrease of the biomarker concentration after pRAIT). Pre-pRAIT DT and post-pRAIT DT were significant independent predictors for overall survival (OS) from pRAIT (pre-pRAIT: hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.24-0.86; P = 0.016; and post-pRAIT: HR, 5.32; 95% CI, 1.63-17.36; P = 0.006) and OS from diagnosis (pre-pRAIT: HR, 0.21; 95% CI, 0.08-0.51; P = 0.001; and post-pRAIT: HR, 6.16; 95% CI, 1.81-20.98; P = 0.004). CONCLUSION: pRAIT showed antitumor activity, with manageable hematologic toxicity in progressive MTC. Increased biomarker DT after treatment correlated with increased OS.

Reduction of renal uptake of 111In-DOTA-labeled and A700-labeled RAFT-RGD during integrin αvß3 targeting using single photon emission computed tomography and optical imaging.

Integrin α(v)ß(3) expression is upregulated during tumor growth and invasion in newly formed endothelial cells in tumor neovasculature and in some tumor cells. A tetrameric RGD-based peptide, regioselectively addressable functionalized template-(cyclo-[RGDfK])4 (RAFT-RGD), specifically targets integrin α(v)ß(3) in vitro and in vivo. When labeled with indium-111, the RAFT-RGD is partially reabsorbed and trapped in the kidneys, limiting its use for further internal targeted radiotherapy and imaging investigations. We studied the effect of Gelofusine on RAFT-RGD renal retention in tumor-bearing mice. Mice were imaged using single photon emission computed tomography and optical imaging 1 and 24 h following tracer injection. Distribution of RAFT-RGD was further investigated by tissue removal and direct counting of the tracer. Kidney sections were analyzed by confocal microscopy. Gelofusine significantly induced a >50% reduction of the renal reabsorption of (111)In-DOTA-RAFT-RGD and A700-RAFT-RGD, without affecting tumor uptake. Injection of Gelofusine significantly reduced the renal retention of labeled RAFT-RGD, while increasing the tumor over healthy tissue ratio. These results will lead to the development of future therapeutic approaches.

18F-FLT and 18F-FDG positron emission tomography for the imaging of advanced well-differentiated gastro-entero-pancreatic endocrine tumours.

PURPOSE: Gastro-entero-pancreatic (GEP) endocrine tumours are a heterogenous group of tumours of variable localization and prognosis. It has been suggested that positron emission tomography (PET) using 2-[18F]fluoro-2-deoxy-D-glucose (18F-FDG) may have a prognostic value and help to identify patients at risk of progression. [18F]fluoro-3'-deoxy-3'-L-fluorothymidine (18F-FLT) has been recently developed as a PET proliferation tracer. At present, there are no studies investigating its role in GEP. The aim of this prospective study was to assess the value of 18F-FLT-PET for the evaluation of GEP. MATERIALS AND METHODS: Ten patients with biopsy-proven locally advanced or metastasized, well-differentiated GEP neuroendocrine tumours were prospectively enrolled and scheduled for 18F-FDG and 18F-FLT-PET. Images were compared with other conventional diagnostic procedures, namely computed tomography, ultrasound, somatostatin receptor scintigraphy and with clinical and diagnostic follow-up. RESULTS: Evaluation criteria were interpreted in terms of assumed presence of tumoral tissue. According to the patient's status, FDG was positive in five out of the seven patients with stable disease and in two out of the three patients with progressive disease. No positive case was identified by 18F-FLT in either the primary or the metastatic tumour site, whatever the status of patients, and this was probably a reflection of the slow proliferation rate of tumours. CONCLUSION: These preliminary data suggest that 18F-FLT-PET is not a suitable tracer for the evaluation of advanced well-differentiated GEP tumours. FDG showed good diagnostic performance but does not help to identify patients at risk of progression.

European French-speaking study from the GEMO group on bone metastases management: a special focus on external beam radiotherapy practice survey.

BACKGROUND AND PURPOSE: This study seeks to perform a survey of patterns of practice among the different physicians involved in the bone metastases management, with special focus on external beam radiotherapy (EBRT). METHODS AND MATERIALS: A questionnaire about bone metastases based on clinical cases and supplemented with general questions, including medical therapies, EBRT and metabolic radiotherapy strategies, surgery, and supportive care approaches, was sent to 4,706 French-speaking physicians in Belgium, France, Luxemburg, and Switzerland. RESULTS: Overall, 644 questionnaires were analyzed. Twenty-eight percent concerned the radiotherapy approach and were judged adequate to respond to the part dedicated to EBRT. Sixty-nine percent of physicians used a total dose irradiation of 30 Gy delivered in ten fractions. A large majority (75%) used two opposed fields prescribed at mid-depth (30%), or with non-equally weighted fields (45%). Seventy percent irradiated also above and below the concerned vertebra. A dosimetry planning treatment was done in 85% and high-energy megavoltage photons were used in 42%. Moreover, 54% physicians used short course radiotherapy in routine. CONCLUSIONS: Radiotherapy remains the mainstay of treatment of bone metastases, but there is substantial heterogeneity in clinical practice. Guidelines and treatment protocols are required to improve the treatment quality.