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PURPOSE The prognosis of patients with early-stage unfavorable Hodgkin lymphoma remains unsatisfactory. We assessed the efficacy and safety of brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (BV-AVD) in previously untreated, early-stage unfavorable Hodgkin lymphoma (ClinicalTrials.gov identifier: NCT02292979 ). METHODS BREACH is a multicenter, randomized, open-label, phase II trial. Eligible patients were age 18-60 years with ≥ 1 unfavorable EORTC/LYSA criterion. Patients were randomly assigned (2:1) to four cycles of BV-AVD or standard doxorubicin, bleomycin, vincristine, and dacarbazine (ABVD), followed by 30 Gy involved node radiotherapy. The primary end point was the positron emission tomography (PET) response rate after two cycles by expert independent review using the Deauville score. The study was designed to test if the PET-negative rate after two cycles of BV-AVD was superior to 75%. We hypothesized a 10% increase in the PET-negative rate after two cycles of BV-AVD. RESULTS Between March 2015 and October 2016, 170 patients were enrolled. After two cycles, the primary end point of the study was met: 93 (82.3%; 90% CI, 75.3 to 88.0) of 113 patients in the BV-AVD arm were PET-negative (Deauville score 1-3) compared with 43 (75.4%; 90% CI, 64.3% to 84.5%) of 57 in the ABVD arm. The 2-year progression-free survival (PFS) was 97.3% (95% CI, 91.9 to 99.1) and 92.6% (95% CI, 81.4% to 97.2%) in the BV-AVD and ABVD arms, respectively. High total metabolic tumor volume was associated with a significantly shorter PFS (hazard ratio, 17.9; 95% CI, 2.2 to 145.5; P < .001). For patients with high total metabolic tumor volume, the 2-year PFS rate was 90.9% (95% CI, 74.4 to 97.0) and 70.7% (95% CI, 39.4% to 87.9%) in the BV-AVD and ABVD arms, respectively. CONCLUSION BV-AVD demonstrated an improvement in the PET-negative rate compared with ABVD after two cycles.

Purpose: Primary objective was to compare the per-patient detection rates (DR) of [18F]DCFPyL versus [18F]fluoromethylcholine positron emission tomography/computed tomography (PET/CT), in patients with first prostate cancer (PCa) biochemical recurrence (BCR). Secondary endpoints included safety and impact on patient management (PM). Methods: This was a prospective, open label, cross-over, comparative study with randomized treatment administration of [18F]DCFPyL (investigational medicinal product) or [18F]fluoromethylcholine (comparator). Men with rising prostate-specific antigen (PSA) after initial curative therapy were enrolled. [18F]DCFPyL and [18F]fluoromethylcholine PET/CTs were performed within a maximum time interval of 12 days. DR was defined as the percentage of positive PET/CT scans identified by 3 central imaging readers. PM was assessed by comparing the proposed pre-PET/CT treatment with the local treatment", defined after considering both PET/CTs. Results: A total of 205 patients with first BCR after radical prostatectomy (73%; median PSA = 0.46 ng/ml [CI 0.16;27.0]) or radiation therapy (27%; median PSA = 4.23 ng/ml [CI 1.4;98.6]) underwent [18F]DCFPyL- and/or [18F]fluoromethylcholine -PET/CTs, between July and December 2020, at 22 European sites. 201 patients completed the study. The per-patient DR was significantly higher for [18F]DCFPyL- compared to [18F]fluoromethylcholine -PET/CTs (58% (117/201 patients) vs. 40% (81/201 patients), p < 0.0001). DR increased with higher PSA values for both tracers (PSA ≤ 0.5 ng/ml: 26/74 (35%) vs. 22/74 (30%); PSA 0.5 to ≤ 1.0 ng/ml: 17/31 (55%) vs. 10/31 (32%); PSA 1.01 to < 2.0 ng/ml: 13/19 (68%) vs. 6/19 (32%);PSA > 2.0: 50/57 (88%) vs. 39/57 (68%) for [18F]DCFPyL- and [18F]fluoromethylcholine -PET/CT, respectively). [18F]DCFPyL PET/CT had an impact on PM in 44% (90/204) of patients versus 29% (58/202) for [18F]fluoromethylcholine. Overall, no drug-related nor serious adverse events were observed. Conclusions: The primary endpoint of this study was achieved, confirming a significantly higher detection rate for [18F]DCFPyL compared to [18F]fluoromethylcholine, in men with first BCR of PCa, across a wide PSA range. [18F]DCFPyL was safe and well tolerated.

PURPOSE: This prospective, nonrandomized, interventional phase 1-2 study investigated the individualization of elective node irradiation in clinically N0 head and neck squamous cell carcinoma by sentinel lymph node (SLN) mapping with single-photon emission computed tomography/computed tomography (SPECT/CT) and its impact on tumor control and radiation-related toxicity. METHODS AND MATERIALS: Forty-four patients with clinically N0 head and neck squamous cell carcinoma treated with definitive (chemo-)radiation therapy were imaged with SPECT/CT after 99mTc nanocolloid injection around the tumor. The neck levels containing up to the 4 hottest SLNs were selected for prophylactic irradiation. A comparative virtual planning was performed with the selection of neck levels based on the current international guidelines. Regional control was monitored as a function of the selected volume. Dosimetric data for the organs at risk were compared between the plans. Normal tissue complication probability (NTCP) rates were derived for xerostomia, dysphagia, and hypothyroidism to predict the clinical benefit and correlated to quality-of-life (QoL) assessments at 6 months. RESULTS: Sixteen percent of patients presented unpredicted lymphatic drainage, and 48% drained unilaterally. The nodal clinical target volume based on lymphoscintigraphy was smaller than the nodal clinical target volume based on international guidelines by a factor of 2 (P < .0001). After a median follow-up of 46 months, only 1 patient experienced a regional relapse in a nonirradiated area. Significant median dose reductions to organs at risk were observed, particularly to contralateral salivary glands in patients with unilateral drainage (14.6-28.1 Gy) and to the thyroid gland in all patients (22.4-48.9 Gy). Median NTCP reductions were observed for xerostomia (0.3% to 13.7%), dysphagia (1.7% to 10.8%), and hypothyroidism (14.0% to 36.1%). QoL at 6 months was improved, particularly in patients irradiated unilaterally. CONCLUSIONS: Neck SLN mapping with SPECT/CT individualizes and reduces the elective nodal target volumes without compromising the regional control. The NTCP rates were reduced and favorable QoL were observed in all patients, particularly in the case of unilateral irradiation.

Background: Haemolytic anaemia secondary to cancer is a rare and potentially fatal cancer complication belonging to the Thrombotic Microangiopathies (TMAs), which include the better known Thrombotic Thrombocytopenic Purpura (TTP) and Haemolytic-Uremic Syndrome (HUS). Making the diagnosis is important, as there is generally no response to classic TMA treatment, including plasma therapy, plasmapheresis, and rituximab. Yet, in current practice, diagnosis is often made late. Survival can be improved by administering chemotherapy early. Few cases have been described in the literature, and no other cases of TMA secondary to breast cancer with proof of response to a targeted treatment, such as everolimus combined with exemestane, have been reported. Case Presentation: A 76-year-old Caucasian woman with metastatic breast cancer was treated with aromatase inhibitors but presented with tumour progression and deterioration of her general condition. An evaluation revealed haemolytic anaemia with thrombocytopenia in combination with organ damage (brain and heart). She did not respond to classic TMA treatment, but to an antitumour treatment of exemestane combined with everolimus. Conclusion: This case demonstrates the need for and efficacy of a specific treatment for TMA secondary to cancer, as well as the efficacy of everolimus and exemestane in the management of TMA associated with progressive breast cancer

Antibody-labeled gold nanoparticles represent a promising novel tool regarding cancer imaging and therapy. Nevertheless, the characterization of biodistribution of such immunonanocarriers has been poorly documented. In this study, the biodistribution of (89)Zr-labeled cetuximab before and after the coupling reaction to gold nanoparticles (AuNPs) was compared and the quantitative imaging performance of (89)Zr immuno-PET was evaluated. Cetuximab was functionalized with the desferal moiety and labeled with (89)Zr ((89)Zr-Df-Bz-NCS-cetuximab). AuNPs with a mean diameter of 5 nm were synthesized according a new method developed in the laboratory, and conjugated to (89)Zr-Df-Bz-NCS-cetuximab using carbodiimide chemistry (AuNPs-PPAA-cetuximab-(89)Zr). The two tracers were injected in A431 xenograft-bearing mice. Tumor and liver uptakes were assessed at different times after injection using quantitative PET imaging. The in vivo specificity of the binding was investigated using a saturating dose of unlabeled cetuximab. Radiolabeled cetuximab was conjugated to AuNPs with a coupling reaction yield >75%. All conjugates were stable in vitro and to a lesser extent in plasma. In vivo distribution studies revealed no significant difference in tumor uptake for cetuximab conjugated to nanoparticles up to 72 h after injection, compared with unconjugated cetuximab. Immuno-PET studies showed that AuNPs-PPAA-cetuximab-(89)Zr provided high tumor-to-background ratio. The liver uptake of AuNPs-PPAA-cetuximab-(89)Zr was higher, compared with (89)Zr-Df-Bz-NCS-cetuximab. In vivo blocking experiments demonstrated selective tumor targeting after coupling reaction. This study showed that the conjugation of AuNPs to cetuximab did not affect its tumor accumulation and that the efficacy of EGFR-targeted nanoparticles was unaltered. The (89)Zr-labeled cetuximab-targeted gold nanoparticles could be a valuable tool for theranostic purposes.

IF 2.755; International audience; Two hundred and ten nuclear medicine physicians, radiologists, and hematologists from 26 countries attended the 6th International Workshop on Positron Emission Tomography (PET) in Lymphoma and Myeloma held in Menton, France, in September 2016. The meeting was under the auspices of the European Lymphoma Institute (ELI), the European Association of Nuclear Medicine (EANM) the Lymphoma Study Association (LYSA), the Italian Foundation on Lymphoma (FIL) and the Carnot Institute for Lymphoma (CALYM). Forty scientific posters were presented. For the first time, specialists in the field of multiple myeloma (MM) were involved in the expert session. The aim was to establish from the experience of Italian and French studies new guidelines of FDG-PET/CT reporting for myeloma staging and restaging. The meeting dedicated an entire session to MM imaging followed by a session on the role of PET in Peripheral T cell Lymphoma. An entire session addressed the issues of Deauville scale particularly for end treatment assessment and the challenging consequences of immunomodulatory treatments on PET reporting. A specific session presented the potential role of baseline metabolic tumor measurement to predict outcome and identify different risk categories and the main results obtained in different lymphoma entities were described. Whether it could replace clinical staging has been extensively discussed. The more recent results obtained in the H10 trial have been presented and compared to the published data in early stage Hodgkin lymphoma. Finally, the ongoing studies using PET for guiding therapeutic strategies have been reported by the various lymphoma cooperative groups that participated to the meeting.

The last fifty years have seen remarkable progress in the prevention, detection and treatment of cancer. However, the current methods for cancer management including radiation, surgery and chemotherapy suffer from many disappointments, such as non-specific suppression of proliferating cancer cells, non-specific systemic distribution, inadequate drug concentration at the target site, developpment of resistance, and a limited ability to monitor the response to therapy. The concept of the “magic bullet”, proposed by Paul Ehrlich more than 100 years ago, postulated that the ideal drug should selectively target and destroy the cause of disease. Therefore, due to their high specificity, the monoclonal antibodies have shown a great promise in the treatment of cancer. However, the effectiveness of antibodies against cancer, and specifically against solid tumours, which are harder to treat, might be improved. In this context, antibodies are being administered in combination with other therapeutic strategies, such as chemotherapy or radiation, or developed as targeted vehicles by attaching toxins or radionuclides. An extension of these approaches is the study of antibody-modified nanomaterials, and particularly antibody-functionalized gold nanoparticles, which use gold nanoparticles as therapeutic agents and antibodies as targeting ligands, offering a promise of selectively conducting the nanoparticles to tumour cells, and thus a focused targeting thanks to the antibody selectivity. These gold nanoparticles may be used for photothermal therapy, as sensitizers in radiation therapy, and offer more flexibility of design in providing platforms for binding of several therapeutic agents in a single structure for effective improvement of cancer therapy. The general goal of this thesis was to explore the efficiency of targeting cancer cells by using antibodies directed against EGFR, or anti-CD105 antibodies directed against endoglin after their conjugation to gold nanoparticles. It is a proof of concept, where these immunonanoconjugates were evaluated as an imaging tool with the hope of operating them in future therapies and even in theranostic purposes. The approach of conjugating bioactive anticancer molecules, such as antibodies, to nanoparticles has some limitations, notably the risk of losing the antibody specificity for the target after the conjugation reaction. Thus, the assessment of target recognition properties and comparative biodistribution studies of antibodies before and after conjugation to gold nanopaticles were performed. In order to trace these immunonanoconjugates in vivo, the antibodies were firstly radiolabelled before nanoparticle conjugation. For conjugation reaction to gold nanoparticles, we chose two types of monoclonal antibodies directed against EGFR or endoglin (CD105). In this work, our efforts focused on the development of a tool that could be used as an imaging probe in a first step. The first specific aim consisted in the assessment of the effect of nanoparticle conjugation on the antibody biodistribution and on the antibody specificity for its target. Regarding antibody recognition properties, we studied the binding properties of these immunanoconjugates in vitro and in vivo through blocking experiments, and we tried to explain the reasons of the possible loss of antibody immunoreactivity through structural characterization of these conjugates. Another aspect that was treated in this work consisted in justifying the choice of the radiolabel for tracking these immunoconjugates in vivo. We initially directly radiolabelled the antibodies with radioiodine, a common and easy procedure used in laboratory. The unexpected tumour uptake profile of iodinated anti-CD105 antibodies, compared with the known kinetics of most intact antibodies, led us to reconsider the choice of the radiolabel. We studied the biological distribution of anti-CD105 antibodies in mice bearing tumours (two tumour models), and we compared the pharmacokinetic profile of iodinated anti-CD105 antibodies and that of 89Zr-labelled anti-CD105 antibodies, as validated tracers, in order to highlight the limitations of the direct anti-CD105 antibody radioiodination on stable antibody tracking. Besides the validation of these immunonanoconjugates as tracers suitable for cancer imaging, we have high expectations of investigating their therapeutic potential. As highly potent and selective drugs are still lacking, we hope that these assemblies, as novel agents for cancer management, will provide an effective strategy to improve cancer therapy through combining the targeting properties of antibodies and the additional therapeutic properties of gold nanoparticles. (BIFA - Sciences biomédicales et pharmaceutiques) -- UCL, 2014