18F-FDG-Based Radiomics and Machine Learning: Useful Help for Aortic Prosthetic Valve Infective Endocarditis Diagnosis?

BACKGROUND: Fluorine-18 fluorodeoxyglucose (18F-FDG)-positron emission tomography (PET)/computed tomography (CT) results in better sensitivity for prosthetic valve endocarditis (PVE) diagnosis, but visual image analysis results in relatively weak specificity and significant interobserver variability. OBJECTIVES: The primary objective of this study was to evaluate the performance of a radiomics and machine learning-based analysis of 18F-FDG PET/CT (PET-ML) as a major criterion for the European Society of Cardiology score using machine learning as a major imaging criterion (ESC-ML) in PVE diagnosis. The secondary objective was to assess performance of PET-ML as a standalone examination. METHODS: All 18F-FDG-PET/CT scans performed for suspected aortic PVE at a single center from 2015 to 2021 were retrospectively included. The gold standard was expert consensus after at least 3 months' follow-up. The machine learning (ML) method consisted of manually segmenting each prosthetic valve, extracting 31 radiomics features from the segmented region, and training a ridge logistic regressor to predict PVE. Training and hyperparameter tuning were done with a cross-validation approach, followed by an evaluation on an independent test database. RESULTS: A total of 108 patients were included, regardless of myocardial uptake, and were divided into training (n = 68) and test (n = 40) cohorts. Considering the latter, PET-ML findings were positive for 13 of 22 definite PVE cases and 3 of 18 rejected PVE cases (59% sensitivity, 83% specificity), thus leading to an ESC-ML sensitivity of 72% and a specificity of 83%. CONCLUSIONS: The use of ML for analyzing 18F-FDG-PET/CT images in PVE diagnosis was feasible and beneficial, particularly when ML was included in the ESC 2015 criteria. Despite some limitations and the need for future developments, this approach seems promising to optimize the role of 18F-FDG PET/CT in PVE diagnosis.

18F-FDG PET/CT-Based Prognostic Survival Model After Surgery for Head and Neck Cancer.

The aims of this multicenter study were to identify clinical and preoperative PET/CT parameters predicting overall survival (OS) and distant metastasis-free survival (DMFS) in a cohort of head and neck squamous cell carcinoma patients treated with surgery, to generate a prognostic model of OS and DMFS, and to validate this prognostic model with an independent cohort. Methods: A total of 382 consecutive patients with head and neck squamous cell carcinoma, divided into training (n = 318) and validation (n = 64) cohorts, were retrospectively included. The following PET/CT parameters were analyzed: clinical parameters, SUVmax, SUVmean, metabolic tumor volume (MTV), total lesion glycolysis, and distance parameters for the primary tumor and lymph nodes defined by 2 segmentation methods (relative SUVmax threshold and absolute SUV threshold). Cox analyses were performed for OS and DMFS in the training cohort. The concordance index (c-index) was used to identify highly prognostic parameters. These prognostic parameters were externally tested in the validation cohort. Results: In multivariable analysis, the significant parameters for OS were T stage and nodal MTV, with a c-index of 0.64 (P < 0.001). For DMFS, the significant parameters were T stage, nodal MTV, and maximal tumor-node distance, with a c-index of 0.76 (P < 0.001). These combinations of parameters were externally validated, with c-indices of 0.63 (P < 0.001) and 0.71 (P < 0.001) for OS and DMFS, respectively. Conclusion: The nodal MTV associated with the maximal tumor-node distance was significantly correlated with the risk of DMFS. Moreover, this parameter, in addition to clinical parameters, was associated with a higher risk of death. These prognostic factors may be used to tailor individualized treatment.

Bone Scintigraphy After a Negative Radiological Skeletal Survey Improves the Detection Rate of Inflicted Skeletal Injury in Children.

Background: Timely diagnosis of child physical abuse is of paramount importance. The added value of bone scintigraphy (BS) after a negative radiological skeletal survey (RSS) in children with suspected physical abuse has never been evaluated. Objective: The objective of this study was to assess the extent to which BS could improve the detection rate of skeletal injury in children with suspected physical abuse with an initial negative RSS. Methods: We used discharge codes to retrospectively identify children evaluated for suspected physical abuse in a university hospital (Nantes, France). We included all consecutive children younger than 3 years old who underwent both RSS and BS, with an interval of ≤96 h between tests, from 2013 to 2019. BS and RSS results were interpreted independently during the study period. We specifically analyzed BS results for children with a negative RSS to assess the value of BS as an add-on test. Results: Among the 268 children ≤3 years old with suspected physical abuse who underwent RSS, 140 (52%) also underwent BS within 96 h and were included in the analysis. The median age was 6 months old (interquartile range: 3-8). The detection rate of ≥1 skeletal injury with RSS alone was 49% (n = 69/140, 95% CI: 41-58%) vs. 58% (n = 81/140, 50-66%) with RSS followed by add-on BS, for an absolute increase in the detection rate of 9% points (95% CI: 4-14%). The number of children with a negative RSS who would need to undergo BS to detect one additional child with ≥1 skeletal injury was 6 (95% CI: 4-11). Conclusion: In young children with suspected physical abuse with a negative RSS, add-on BS would allow for a clinically significant improvement in the detection rate of skeletal injuries for a limited number of BS procedures required. Prospective multicenter studies are needed to confirm these findings.

Hindgut Ciliate Composition of Thoroughbred Mares in Kentucky, USA, and Binary Fission in Polymorphella ampulla.

Species composition and distribution of hindgut ciliates were investigated in the feces of 20 thoroughbred mares in Kentucky, USA. Thirty-three species and six morphotypes belonging to 21 genera were identified. The average density of hindgut ciliates in mares was 13.5 ± 13.7 × 104 cells ml-1, whereas mean number of ciliate species per host was 14.4 ± 5.3. Bundleia nana, B. elongata, B. piriformis, Blepharoconus hemiciliatus, Holophryoides ovalis, H. macrotricha, Blepharoprosthium polytrichum, Prorodonopsis coli, Paraisotrichopsis composita, Blepharocorys microcorys, and Ochoterenaia appendiculata were the first identified species in horses inhabited in USA. Scanning electron microscopic images of Holophryoides macrotricha, Paraisotrichopsis composita, Cycloposthium dentiferum m. corrugatum, C. edentatum m. edentatum, C. edentatum m. scutigerum, Tetratoxum parvum m. parvum, T. parvum m. sulcatum, T. excavatum m. excavatum, Allantosoma intestinale, and Arcosoma brevicorniger were studied. Binary fission in Polymorphella ampulla was also studied.

Interim PET Analysis in First-Line Therapy of Multiple Myeloma: Prognostic Value of ΔSUVmax in the FDG-Avid Patients of the IMAJEM Study.

Purpose: To assess the prognostic value of interim 18F-fluorodeoxyglucose (FDG)-PET analysis using decrease in maximum standardized uptake value (SUVmax) versus visual analysis in patients with multiple myeloma.Patients and Methods: We evaluated the prognostic value of FDG-PET after three cycles of lenalidomide, bortezomib, and dexamethasone (RVD) in patients with FDG-avid multiple myeloma included in the French prospective multicenter IMAJEM study. All images were centrally reviewed and interpreted using visual criteria and maximal standardized uptake value reduction (ΔSUVmax). Known prognostic factors, such as the revised International Staging System and biochemical response after three cycles of chemotherapy, were also evaluated.Results: In the multivariate analysis, only ΔSUVmax [P < 0.001, HR = 5.56; 95% confidence interval (CI), 1.96-15.81] and biochemical response after three cycles of RVD (P = 0.025, HR = 0.29; 95% CI, 0.1-0.85) appeared as independent prognostic factors, with a more discriminative HR for ΔSUVmax. ΔSUVmax analysis (>-25% vs. ≤-25%) identified patients with improved median progression-free survival (22.6 months and not reached, respectively).Conclusions: ΔSUVmax appears to be a powerful tool for the prediction of long-term outcome in patients with FDG-avid multiple myeloma. Other prospective studies are needed to further validate this prognostic biomarker. Clin Cancer Res; 24(21); 5219-24. ©2018 AACR.

Radioimmunotherapy for Treatment of Acute Leukemia.

Acute leukemias are characterized by accumulation of immature cells (blasts) and reduced production of healthy hematopoietic elements. According to the lineage origin, two major leukemias can be distinguished: acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL). Although the survival rate for pediatric ALL is close to 90%, half of the young adults with AML or ALL and approximately 90% of older patients with AML or ALL still die of their disease, raising the need for innovative therapeutic approaches. As almost all leukemic blasts express specific surface antigens, targeted immunotherapy appears to be particularly promising. However, published results of immunotherapy alone are generally modest. Radioimmunotherapy (RIT) brings additional therapeutic mechanisms using radiolabeled monoclonal antibodies (mAbs) directed to tumor antigens, thus adding radiobiological cytotoxicity to immunologic cytotoxicity. Because of the high radiosensitivity of tumor cells and the diffuse widespread nature of the disease, making it rapidly accessible to circulating radiolabeled mAbs, acute leukemias represent relevant indications for RIT. With the development of recombinant and humanized mAbs, innovative radionuclides, and more efficient radiolabeling and pretargeting techniques, RIT has significantly improved over the last 10 years. Different approaches of α and ß RIT targeting CD22, CD33, CD45, or CD66 antigens have already been evaluated or are currently being developed in the treatment of acute leukemia. This review summarizes the preclinical and clinical studies demonstrating the potential of RIT in treatment of AML and ALL.

(90)Y-labelled anti-CD22 epratuzumab tetraxetan in adults with refractory or relapsed CD22-positive B-cell acute lymphoblastic leukaemia: a phase 1 dose-escalation study.

BACKGROUND: Prognosis of patients with relapsed or refractory acute lymphoblastic leukaemia is poor and new treatments are needed. We aimed to assess the feasibility, tolerability, dosimetry, and efficacy of yttrium-90-labelled anti-CD22 epratuzumab tetraxetan ((90)Y-DOTA-epratuzumab) radioimmunotherapy in refractory or relapsed CD22-positive B-cell acute lymphoblastic leukaemia in a standard 3 + 3 phase 1 study. METHODS: Adults (≥18 years) with relapsed or refractory B-cell acute lymphoblastic leukaemia (with CD22 expression on at least 70% of blast cells) were enrolled at six centres in France. Patients received one cycle of (90)Y-DOTA-epratuzumab on days 1 and 8 (give or take 2 days) successively at one of four dose levels: 2·5 mCi/m(2) (92·5 MBq/m(2); level 1), 5·0 mCi/m(2) (185 MBq/m(2); level 2), 7·5 mCi/m(2) (277·5 MBq/m(2); level 3), and 10·0 mCi/m(2) (370 MBq/m(2); level 4). The primary objective was to identify the maximum tolerated dose of (90)Y-DOTA-epratuzumab. We assessed safety during infusions and regularly after radioimmunotherapy over a 6-month period. Analyses included only patients who received radioimmunotherapy. The trial is closed to inclusion and is registered at ClinicalTrials.gov, NCT01354457. FINDINGS: Between Aug 25, 2011, and June 11, 2014, 17 patients (median age 62 years; range 27-77) were treated (five at level 1, three at level 2, three at level 3, and six at level 4). Radioimmunotherapy infusion was overall well tolerated. One dose-limiting toxic effect (aplasia lasting 8 weeks) occurred at level 4, but the maximum tolerated dose was not reached. The most common grade 3-4 adverse events were pancytopenia (one patient at level 2, one at level 3, and six at level 4) and infections (three at level 1, one at level 2, and five at level 4). INTERPRETATION: (90)Y-DOTA-epratuzumab radioimmunotherapy is well tolerated. We recommend the dose of 2 × 10·0 mCi/m(2) 1 week apart per cycle for phase 2 studies. FUNDING: Immunomedics and Direction de la Recherche Clinique of Nantes.

Radioimmunoconjugates for the treatment of cancer.

Radioimmunotherapy (RIT) has been developed for more than 30 years. Two products targeting the CD20 antigen are approved in the treatment of non-Hodgkin B-cell lymphoma (NHBL): iodine 131-tositumomab and yttrium 90-ibritumomab tiuxetan. RIT can be integrated in clinical practice for the treatment of patients with relapsed or refractory follicular lymphoma (FL) or as consolidation after induction chemotherapy. High-dose treatment, RIT in first-line treatment, fractionated RIT, and use of new humanized monoclonal antibodies (MAbs), in particular targeting CD22, showed promising results in NHBL. In other hemopathies, such as multiple myeloma, efficacy has been demonstrated in preclinical studies. In solid tumors, more resistant to radiation and less accessible to large molecules such as MAbs, clinical efficacy remains limited. However, pretargeting methods have shown clinical efficacy. Finally, new beta emitters such as lutetium 177, with better physical properties will further improve the safety of RIT and alpha emitters, such as bismuth 213 or astatine 211, offer the theoretical possibility to eradicate the last microscopic clusters of tumor cells, in the consolidation setting. Personalized treatments, based on quantitative positron emission tomography (PET), pre-therapeutic imaging, and dosimetry procedures, also could be applied to adapt injected activity to each patient.

Prognostic Value and Clinical Impact of (18)FDG-PET in the Management of Children with Burkitt Lymphoma after Induction Chemotherapy.

OBJECTIVE: Burkitt lymphoma (BL) is a rare and aggressive form of B-cell lymphoma that is curable using intensive chemotherapy. Obtaining a complete response (CR) at the end of induction chemotherapy is a major prognostic factor. This study retrospectively evaluates the potential impact of (18)FDG-PET in the management of children with BL after induction chemotherapy, and the prognostic performance of the Deauville criteria. METHODS: Nineteen children with BL treated according to the French LMB2001 protocol between 2005 and 2012 were included. (18)FDG-PET and conventional imaging (CI) were performed after induction chemotherapy to confirm CR. (18)FDG-PET was interpreted according to Deauville criteria with follow-up and/or histology as the gold standard. RESULTS: (18)FDG-PET was negative in 15 cases, in agreement with CI in 9/15 cases. The six discordant cases confirmed to be negative by histology, were considered as true negative for (18)FDG-PET. Negative predictive value (NPV) of CI and (18)FDG-PET were 73 and 93%, respectively. The 5-year progression-free survival (PFS) was significantly higher in patients with negative (18)FDG-PET than those with positive (18)FDG-PET (p = 0.011). CONCLUSION: (18)FDG-PET interpreted using Deauville criteria can help confirm CR at the end of induction chemotherapy, with a prognostic impact on 5-year PFS. Its high NPV could limit the use of residual mass biopsy. Given the small size of our population, these results need to be confirmed by future prospective studies on a larger population.

BCR-ABL1 molecular remission after 90Y-epratuzumab tetraxetan radioimmunotherapy in CD22+ Ph+ B-ALL: proof of principle.

Although targeted therapies are used increasingly in hematologic malignancies, we are unaware of any prior studies of radioimmunotherapy (RAIT) in B-acute lymphoblastic leukemia (ALL), even though this radiosensitive tumor expresses CD22, potentially a good target for this approach. Here, we report a patient with Philadelphia chromosome-positive B-ALL in third relapse who received RAIT with (90) yttrium ((90) Y)-labeled anti-CD22 epratuzumab tetraxetan. Seven weeks after initiating therapy, the patient achieved a BCR-ABL1 molecular remission documented by RT-qPCR, which is now continuing at 6 months while awaiting an allogeneic hematopoietic stem cell transplant. (90) Y-Epratuzumab tetraxetan may be a promising therapeutic option for CD22(+) B-ALL patients.

Radioimmunotherapy of B-Cell Non-Hodgkin's Lymphoma.

This manuscript reviews current advances in the use of radioimmunotherapy (RIT) for the treatment of B-cell non-Hodgkin's lymphoma (NHL). RIT has been in use for more than 20 years and has progressed significantly with the discovery of new molecular targets, the development of new stable chelates, the humanization of monoclonal antibodies (MAbs), and the use of pretargeting techniques. Today, two products targeting the CD20 antigen are approved: (131)I-tositumomab (Bexxar(®)), and (90)Y-ibritumomab tiuxetan (Zevalin(®)). (131)I-tositumomab is available in the United States, and (90)Y-ibritumumab tiuxetan in Europe, the United States, Asia, and Africa. RIT can be integrated in clinical practice using non-ablative activities for treatment of patients with relapsed or refractory follicular lymphoma (FL) or as consolidation after induction chemotherapy in front-line treatment in FL patients. Despite the lack of phase III studies to clearly define the efficacy of RIT in the management of B lymphoma in the era of rituximab-based therapy, RIT efficacy in NHL has been demonstrated. In relapsing refractory FL and transformed NHL, RIT as a monotherapy induces around 30% complete response with a possibility of durable remissions. RIT consolidation after induction therapy significantly improves the quality of the response. Dose-limiting toxicity of RIT is hematological, depending on bone marrow involvement and prior treatment. Non-hematological toxicity is generally low. Different studies have been published assessing innovative protocols of RIT or new indications, in particular treatment in patients with aggressive lymphomas. High-dose treatment, RIT as consolidation after different therapeutic induction modalities, RIT in first-line treatment or fractionated RIT showed promising results. New MAbs, in particular humanized MAbs, or combinations of naked and radiolabeled MAbs, also appear promising. Personalized dosimetry protocols should be developed to determine injected activity.

Intra-arterial injection of 131I-labeled Lipiodol for advanced hepatocellular carcinoma: a 7 years' experience.

BACKGROUND: Internal irradiation with iodine-131 (I)-labeled Lipiodol is one of the currently available forms of palliative therapy for patients with advanced hepatocellular carcinoma (HCC). Despite a cumulative experience of more than 10 years with this treatment, only a few studies have reported on its efficacy and safety. OBJECTIVE: The aim of this study was to retrospectively evaluate the efficacy of intra-arterial I-labeled Lipiodol injection for treatment against advanced HCC. MATERIALS AND METHODS: Fifty patients (47 men and three women; mean age 64 years) given an intra-arterial injection of I-Lipiodol (5 ml of 2.2 GBq Lipiodol labeled with I; number of mean sessions per patient, 1.3; range 1-4) were retrospectively compared with 36 patients (31 men and five women; mean age 64 years) who were given only medical support. Portal vein thrombosis was present in 86 and 100% of patients, respectively. Efficacy was determined on the basis of overall survival as the endpoint using the Kaplan-Meier method. Tumor response was evaluated with computed tomography according to Response Evaluation Criteria In Solid Tumors (RECIST 1.1) and European Association for the Study of the Liver (EASL) criteria. RESULTS: For patients treated with I-Lipiodol, median survival was 32 weeks, compared with 8 weeks for the untreated group (P=0.007). Survival at 6 months and at 1 and 2 years was 65, 35, and 22%, respectively, for patients treated with I-Lipiodol compared with 28, 8, and 0% for the untreated group. At 1 month, more than 80% of patients were responders (complete response, partial response, and stable disease) on the basis of the RECIST and EASL criteria, and at 6 months 39% were responders. No radiotoxic effect was observed, especially with respect to interstitial pneumonia. No significant difference was observed between survival and α-fetoprotein levels, Barcelona Clinic Liver Cancer clinical score, and portal vein thrombosis. CONCLUSION: Intra-arterial injection of I-Lipiodol is safe and provides significant survival benefit in terms of overall survival for patients with advanced HCC.

Assessment of acquisition protocols for routine imaging of Y-90 using PET/CT.

BACKGROUND: Despite the early theoretical prediction of the 0+-0+ transition of 90Zr, 90Y-PET underwent only recently a growing interest for the development of imaging radioembolization of liver tumors. The aim of this work was to determine the minimum detectable activity (MDA) of 90Y by PET imaging and the impact of time-of-flight (TOF) reconstruction on detectability and quantitative accuracy according to the lesion size. METHODS: The study was conducted using a Siemens Biograph® mCT with a 22 cm large axial field of view. An IEC torso-shaped phantom containing five coplanar spheres was uniformly filled to achieve sphere-to-background ratios of 40:1. The phantom was imaged nine times in 14 days over 30 min. Sinograms were reconstructed with and without TOF information. A contrast-to-noise ratio (CNR) index was calculated using the Rose criterion, taking partial volume effects into account. The impact of reconstruction parameters on quantification accuracy, detectability, and spatial localization of the signal was investigated. Finally, six patients with hepatocellular carcinoma and four patients included in different 90Y-based radioimmunotherapy protocols were enrolled for the evaluation of the imaging parameters in a clinical situation. RESULTS: The highest CNR was achieved with one iteration for both TOF and non-TOF reconstructions. The MDA, however, was found to be lower with TOF than with non-TOF reconstruction. There was no gain by adding TOF information in terms of CNR for concentrations higher than 2 to 3 MBq mL-1, except for infra-centimetric lesions. Recovered activity was highly underestimated when a single iteration or non-TOF reconstruction was used (10% to 150% less depending on the lesion size). The MDA was estimated at 1 MBq mL-1 for a TOF reconstruction and infra-centimetric lesions. Images from patients treated with microspheres were clinically relevant, unlike those of patients who received systemic injections of 90Y. CONCLUSIONS: Only one iteration and TOF were necessary to achieve an MDA around 1 MBq mL-1 and the most accurate localization of lesions. For precise quantification, at least three iterations gave the best performance, using TOF reconstruction and keeping an MDA of roughly 1 MBq mL-1. One and three iterations were mandatory to prevent false positive results for quantitative analysis of clinical data. TRIAL REGISTRATION: http://IDRCB 2011-A00043-38 P101103.

¹8F-FDG-PET/CT in initial staging and assessment of early response to chemotherapy of pediatric rhabdomyosarcomas.

PURPOSE: The objective of this retrospective study was to compare positron emission tomography/computed tomography using fluorine-18-fluorodeoxyglucose (18F-FDG-PET/CT) and conventional imaging modalities (CIM) in initial staging and early assessment of response to chemotherapy in children and young adults treated for rhabdomyosarcoma (RMS). PATIENTS AND METHODS: At initial staging, 23 patients (9 months to 21 years) with histologically proven RMS underwent 18F-FDG-PET/CT in addition to CIM (MRI of the primary site, whole-body CT, and bone scintigraphy). After three courses of chemotherapy, 13 patients underwent 18F-FDG-PET/CT in addition to CIM. RECIST criteria and visual analysis of 18F-FDG uptake were used for assessment of response. The standard of reference was determined by an interdisciplinary tumor board on the basis of imaging material, histopathology, and follow-up data (median = 5 years). RESULTS: 18F-FDG-PET/CT sensitivity was superior to that of CIM for determination of lymph node involvement (100 vs. 75%) and detection of metastases (100 vs. 66%). 18F-FDG-PET/CT results changed therapeutic management in 13% of cases. After three courses of chemotherapy 18F-FDG-PET/CT was able to detect 92% of objective responses compared with 84% by CIM. The rate of complete response was 69% with 18F-FDG-PET/CT compared with 8% with CIM. CONCLUSION: This study confirms that 18F-FDG-PET/CT reveals important additional information at initial staging of pediatric RMS, which suggests a superior prognostic value of 18F-FDG-PET/CT in early response to chemotherapy assessment.