A low total metabolic tumor volume independently predicts for a longer time to first treatment in initially observed, low tumor burden follicular lymphoma.

Watchful waiting is an acceptable management strategy for advanced-stage, low tumor burden (LTB) patients with follicular lymphoma (FL). However, the prediction of how long this treatment-free observation period will last remains imperfect. We explored whether total metabolic tumor volume (TMTV) and other positron emission tomography parameters were predictive of time to first treatment (TTFT). We analyzed 97 grade 1-3A advanced-stage LTB FL patients and found that a high TMTV was associated with other tumor burden features at diagnosis. Patients with a TMTV above our established cutoff of 50 mL had a significantly shorter median duration of observation (2.6 vs. 8.8 years; p = 0.001). At 5 years, 77% of patients with a high TMTV and 46% of patients with a low TMTV required treatment. In the multivariable analysis, a high TMTV was the only independent factor predicting TTFT (hazard ratio = 2.09; p = 0.017). Overall, TMTV is a strong predictor of the duration of observation in LTB FL patients. Upon validation of our cutoff in external series and standardization of the methodology, the TMTV could become an additional factor to consider deferring or initiating treatment in otherwise LTB patients.

PET-based radiomics signature can predict durable responses to CAR T-cell therapy in patients with large B-cell lymphoma.

Chimeric antigen receptor (CAR) T-cell therapy is a promising treatment option for relapsed or refractory (R/R) large B-cell lymphoma (LBCL). However, only a subset of patients will present long-term benefit. In this study, we explored the potential of PET-based radiomics to predict treatment outcomes with the aim of improving patient selection for CAR T-cell therapy. We conducted a single-center study including 93 consecutive R/R LBCL patients who received a CAR T-cell infusion from 2018 to 2021, split in training set (73 patients) and test set (20 patients). Radiomics features were extracted from baseline PET scans and clinical benefit was defined based on median progression-free survival (PFS). Cox regression models including the radiomics signature, conventional PET biomarkers and clinical variables were performed for most relevant outcomes. A radiomics signature including 4 PET-based parameters achieved an AUC = 0.73 for predicting clinical benefit in the test set, outperforming the predictive value of conventional PET biomarkers (total metabolic tumor volume [TMTV]: AUC = 0.66 and maximum standardized uptake value [SUVmax]: AUC = 0.59). A high radiomics score was also associated with longer PFS and OS in the multivariable analysis. In conclusion, the PET-based radiomics signature predicted efficacy of CAR T-cell therapy and outperformed conventional PET biomarkers in our cohort of LBCL patients.

A PET-CT score for discriminating malignant from benign pleural effusions.

BACKGROUND AND OBJECTIVES: The results of previous PET-CT studies are contradictory for discriminating malignant from benign pleural effusions. We purpose to develop a PET-CT score for differentiating between benign and malignant effusions. PATIENTS AND METHODS: We conducted a prospective study of consecutive patients with pleural effusions undergoing PET-CT from October 2013 to October 2019 (referral cohort). PET-CT scan features evaluated using the SUV were: linear thickening; nodular thickening; nodules; masses; circumferential thickening; mediastinal and fissural pleural involvement; intrathoracic lymph nodes; pleural loculation; inflammatory consolidation; pleural calcification; cardiomegaly; pericardial effusion; bilateral effusion; lung mass; liver metastasis and other extra-pleural malignancy. The results were validated in an independent prospective cohort from November 2019 to June 2021. RESULTS: One hundred and ninety-nine patients were enrolled in the referral cohort (91 with malignant effusions and 108 benign). The most useful parameters for the development of a PET-CT score were: nodular pleural thickening, pleural nodules with SUV>7.5, lung mass or extra pleural malignancy (10 points each), mammary lymph node with SUV>4.5 (5 points) and cardiomegaly (-1 point). With a cut-off value of >9 points in the referral cohort, the score established the diagnosis of malignant pleural effusion with sensitivity 87.9%, specificity 90.7%, positive predictive value 88.9%, negative predictive value 89.9%, positive likelihood ratio 7.81 and negative likelihood ratio 0.106. These results were validated in an independent prospective cohort of 75 patients. CONCLUSIONS: PET-CT score was shown to provide relevant information for the identification of malignant pleural effusion.

Impact of 18F-FDG-PET/CT on the management of Staphylococcus aureus bacteraemia: a retrospective observational study.

OBJECTIVES: To assess the impact of 18F-FDG-PET/CT on the diagnosis and management of patients with Staphylococcus aureus bacteraemia (SAB). METHODS: Post hoc analysis of a prospective cohort of consecutive adult patients diagnosed with SAB (January 2013-December 2017). Patients who underwent 18F-FDG-PET/CT at the discretion of the attending physician were included. Endpoints were the identification of previously unknown infectious foci and changes in clinical management, defined as changes in the duration or class of antibiotic therapy, a surgical procedure on the source of infection or a change in the decision to remove or retain an implantable device. RESULTS: We included 39 patients (median age: 69 years, IQR:60-79). Fifteen (39%) patients did not have an infectious focus identified before 18F-FDG-PET/CT). Thirty new infectious foci were detected in 22/39 (56%) patients. In 11/15 (73%) patients without an identified focus at least one infectious focus was detected by 18F-FDG-PET/CT. In 22/26 (85%) patients with implantable devices, 18F-FDG-PET/CT confirmed or ruled out infection or detected local complications. Out of 13 device infections, 10 were detected by 18F-FDG-PET/CT (7/10 for the first time). In 19/39 (49%) patients 18F-FDG-PET/CT results led to changes in clinical management (15 changes in antibiotic therapy, 2 device removals, 2 surgical procedures, 1 avoidance of a surgical procedure). CONCLUSIONS: 18F-FDG-PET/CT may be a useful asset in the management of selected SAB cases, allowing the identification of previously undetected infectious foci and optimization of therapy, particularly in patients with endovascular devices. Indication should be made on a case-by-case basis.

Position Statement on the Diagnosis, Treatment, and Response Evaluation to Systemic Therapies of Advanced Neuroendocrine Tumors, With a Special Focus on Radioligand Therapy.

BACKGROUND: The aim of this study was to provide a guidance for the management of neuroendocrine tumors (NETs) in clinical practice. MATERIAL AND METHODS: Nominal group and Delphi techniques were used. A steering committee of 8 experts reviewed the current management of NETs, identified controversies and gaps, critically analyzed the available evidence, and formulated several guiding statements for clinicians. Subsequently, a panel of 26 experts, was selected to test agreement with the statements through 2 Delphi rounds. Items were scored on a 4-point Likert scale from 1 = totally agree to 4 = totally disagree. The agreement was considered if ≥75% of answers pertained to Categories 1 and 2 (consensus with the agreement) or Categories 3 and 4 (consensus with the disagreement). RESULTS: Overall, 132 statements were proposed, which incorporated the following areas: (1) overarching principles; (2) progression and treatment response criteria; (3) advanced gastro-enteric NETs; (4) advanced pancreatic NETs; (5) advanced NETs in other locations; (6) re-treatment with radioligand therapy (RLT); (7) neoadjuvant therapy. After 2 Delphi rounds, only 4 statements lacked a clear consensus. RLT was not only recommended in the sequencing of different NETs but also as neoadjuvant treatment, while several indications for retreatment with RLT were also established. CONCLUSION: This document sought to pull together the experts' attitudes when dealing with different clinical scenarios of patients suffering from NETs, with RLT having a specific role where evidence-based data are limited.

Usefulness of the FDG PET/CT in the management of cystic echinococcosis: A pilot study.

OBJECTIVES: Cystic echinococcosis is a zoonotic disease caused by the cestode Echinococcus granulosus. The activity of the cysts is assessed through the WHO-IWGE standardized classification based on ultrasound features. However, viability of the cysts is not always concordant with the activity assessed by ultrasound. The aim of the present study is to describe the metabolic activity of cysts in patients with cystic echinococcosis through FDG-PET. METHODS: Prospective observational study where adult patients diagnosed of cystic echinococcosis were offered to undergo FDG PET/CT before treatment onset. Demographic, clinical, radiological, and histopathological information was collected from all patients. RESULTS: Sixteen patients were included, 50% were male, and age ranged from 18 to 85 years. Most of the patients had liver involvement, and all patients had CE3, CE4 or CE5 stage of the WHO-IWGE classification. Only one patient (CE5) had an increased 18F-FDG uptake of the cyst in the FDG PET/CT. From the 5 patients who underwent surgical treatment, only one showed signs of viability of the cyst: a patient with CE5 with no increased 18F-FDG uptake of the cyst. CONCLUSION: In our pilot study, we did not find the correlation between the FDG PET/CT imaging and the cystic echinococcosis cyst bioactivity.

Prognostic impact of total metabolic tumor volume in large B-cell lymphoma patients receiving CAR T-cell therapy.

Chimeric antigen receptor (CAR) T-cell therapy provides long-term remissions in patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL). Total metabolic tumor volume (TMTV) assessed by 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET) has a confirmed prognostic value in the setting of chemoimmunotherapy, but its predictive role with CAR T-cell therapy is not fully established. Thirty-five patients with R/R LBCL who received CAR T-cells were included in the study. TMTV and maximum standardized uptake value (SUVmax) were measured at baseline and 1-month after CAR T-cell infusion. Best response included 9 (26%) patients in complete metabolic response (CMR) and 16 (46%) in partial metabolic response (PMR). At a median follow-up of 7.6 months, median PFS and OS were 3.4 and 8.2 months, respectively. A high baseline TMTV (≥ 25 cm3) was associated with a lower PFS (median PFS, 2.3 vs. 8.9 months; HR = 3.44 [95% CI 1.18-10.1], p = 0.02). High baseline TMTV also showed a trend towards shorter OS (HR = 6.3 [95% CI 0.83-47.9], p = 0.08). Baseline SUVmax did not have a significant impact on efficacy endpoints. TMTV and SUVmax values showed no association with adverse events. Metabolic tumor burden parameters measured by 18FDG-PET before CAR T-cell infusion can identify LBCL patients who benefit most from this therapy.

The 18F phantom clinical trials qualification for 18F-FDG-PET scanning adopted by GELTAMO (Grupo Español de Linfomas/Trasplante Autólogo de Médula Ósea). / Cualificación de fantomas 18F para ensayos clínicos con imagen PET/TC-18F-FDG adoptada por GELTAMO (Grupo Español de Linfomas/Trasplante Autólogo de Médula Ósea).

INTRODUCTION AND OBJECTIVES: Since different PET/CT (Positron Emission Tomography/Computed Tomography) scanners give different qualitative readings, a program for clinical trial qualification (CTQ) is mandatory to guarantee a reliable and reproducible use of PET/CT in prospective multi-centre clinical trials. Within this work we will show the results carried out in performing CTQ in Spain. MATERIALS AND METHODS: We set up, under the auspices of Grupo Español de Linfomas/Trasplante Autólogo de Médula Osea (GELTAMO), a CTQ program consisting of the acquisition and analysis of 18F uniformity and image quality phantoms for the reduction of inter-scanner variability (ISV). The ISV was estimated on background activity concentration (BAC) and sphere to background ratio (SBR) and defined as their 95% confidence level. RESULTS: Twenty-six out of 27 (96%) scanners fulfilled the CTQ requirements. The CTQ was fulfilled at the first round in 27% of the cases, while in 38%, 15% and 20%, two, three or more than three iterations, were required, respectively. The mean CTQ time was (1.8 ± 1.4) months (range: 0.3-4.6). The ISV in BAC and SBR were 20.3% and 67.7%. CONCLUSIONS: The CTQ proven to be a reliable tool to reduce ISV. This enabled to set-up clinical trials in which PET/CT was used to evaluate different clinical endpoints.

Cell free circulating tumor DNA in cerebrospinal fluid detects and monitors central nervous system involvement of B-cell lymphomas.

The levels of cell free circulating tumor DNA (ctDNA) in plasma correlated with treatment response and outcome in systemic lymphomas. Notably, in brain tumors, the levels of ctDNA in the cerebrospinal fluid (CSF) are higher than in plasma. Nevertheless, their role in central nervous system (CNS) lymphomas remains elusive. We evaluated the CSF and plasma from 19 patients: 6 restricted CNS lymphomas, 1 systemic and CNS lymphoma, and 12 systemic lymphomas. We performed whole exome sequencing or targeted sequencing to identify somatic mutations of the primary tumor, then variant-specific droplet digital PCR was designed for each mutation. At time of enrolment, we found ctDNA in the CSF of all patients with restricted CNS lymphoma but not in patients with systemic lymphoma without CNS involvement. Conversely, plasma ctDNA was detected in only 2/6 patients with restricted CNS lymphoma with lower variant allele frequencies than CSF ctDNA. Moreover, we detected CSF ctDNA in 1 patient with CNS lymphoma in complete remission and in 1 patient with systemic lymphoma, 3 and 8 months before CNS relapse was confirmed; indicating CSF ctDNA might detect CNS relapse earlier than conventional methods. Finally, in 2 cases with CNS lymphoma, CSF ctDNA was still detected after treatment even though a complete decrease in CSF tumor cells was observed by flow cytometry (FC), indicating CSF ctDNA better detected residual disease than FC. In conclusion, CSF ctDNA can better detect CNS lesions than plasma ctDNA and FC. In addition, CSF ctDNA predicted CNS relapse in CNS and systemic lymphomas.

Mutational Landscape and Tumor Burden Assessed by Cell-free DNA in Diffuse Large B-Cell Lymphoma in a Population-Based Study.

PURPOSE: We analyzed the utility of cell-free DNA (cfDNA) in a prospective population-based cohort to determine the mutational profile, assess tumor burden, and estimate its impact in response rate and outcome in patients with diffuse large B-cell lymphoma (DLBCL). EXPERIMENTAL DESIGN: A total of 100 patients were diagnosed with DLBCL during the study period. Mutational status of 112 genes was studied in cfDNA by targeted next-generation sequencing. Paired formalin-fixed, paraffin-embedded samples and volumetric PET/CT were assessed when available. RESULTS: Appropriate cfDNA to perform the analyses was obtained in 79 of 100 cases. At least one mutation could be detected in 69 of 79 cases (87%). The sensitivity of cfDNA to detect the mutations was 68% (95% confidence interval, 56.2-78.7). The mutational landscape found in cfDNA samples was highly consistent with that shown in the tissue and allowed genetic classification in 43% of the cases. A higher amount of circulating tumor DNA (ctDNA) significantly correlated with clinical parameters related to tumor burden (elevated lactate dehydrogenase and ß2-microglobulin serum levels, advanced stage, and high-risk International Prognostic Index) and total metabolic tumor volume assessed by PET/CT. In patients treated with curative intent, high ctDNA levels (>2.5 log hGE/mL) were associated with lower complete response (65% vs. 96%; P < 0.004), shorter progression-free survival (65% vs. 85%; P = 0.038), and overall survival (73% vs. 100%; P = 0.007) at 2 years, although it did not maintain prognostic value in multivariate analyses. CONCLUSIONS: In a population-based prospective DLBCL series, cfDNA resulted as an alternative source to estimate tumor burden and to determine the tumor mutational profile and genetic classification, which have prognostic implications and may contribute to a future tailored treatment.

Effectiveness of relaxation techniques before diagnostic screening of cancer patients / Efectividad de las técnicas de relajación en oncología antes de realizar pruebas diagnósticas en neuroimagen

Psychophysiological arousal was observed in cancer patients during the application of relaxation techniques prior to a diagnostic scan (PET-CT). The aim of the study is two fold: firstly, it is sought to establish whether such techniques can minimize patient arousal before diagnostic screening begins, and secondly to measure which of them are most effective. The dependent variable is electrodermal activity, recording the attentional level and emotional response, and the independent variable comprises the relaxation techniques used, namely Jacobson, breathing and visualization. The 39 patients were split into experimental groups to whom the relaxation techniques (Jacobson, breathing exercises, and visualization) were applied before they went for the PET-CT. An activity-module procedure was applied to track electrodermal activity during the relaxation sessions, consisting of instructions, time out; wait, task; relaxation and end of the recording session. The control group received no relaxation techniques before the PET-CT. Session-end results show that patients who perform relaxation techniques achieve greater attentional focus using Jacobs on’stechnique(M= .212) and enhanced emotional containment using visualization (M= .206). It is concluded that relaxation techniques minimize the state of activation during the waiting period before a diagnostic scan.

Se registra la activación psicofisiológica en pacientes oncológicos durante la aplicación de técnicas de relajación antes de someterse a una prueba diagnóstica (TEP-TAC). Se plantea un doble objetivo: primero, comprobar si dichas técnicas minimizan el estado de activación de los pacientes antes de realizar pruebas diagnósticas, y en segundo lugar, medir cuáles de estas son más efectivas para relajarse. La variable dependiente es la actividad electrodérmica, registrando el nivel atencional y la respuesta emocional, y la variable independiente son las técnicas de relajación de Jacobson, de respiración y de visualización. Se distribuyen los pacientes (n = 39) en 3 grupos experimentales y se les aplican las técnicas antes de realizar el TEP-TAC: Jacobson, respiración y visualización. Se utiliza un procedimiento para el registro de la actividad electrodérmica durante la relajación por módulos de actividad: instrucciones, tiempo muerto; espera, tarea; relajación, y fin del registro. El grupo control no recibe relajación antes del TEP-TAC. Los resultados indican que los pacientes que realizan relajación consiguen mayor focalización atencional con Jacobson (M = .212) y mayor contención emocional con la visualización (M = .206). Se concluye que las técnicas de relajación minimizan el estado de activación durante el periodo de espera antes de una prueba diagnóstica.

Hypofractionated 3D radiotherapy for inoperable T1-3 N0-1 non-small-cell lung cancer.

OBJECTIVE: This study assessed the toxicity and clinical outcomes of three-dimensional (3D) hypofractionated radiotherapy (HFRT) for medically inoperable T1-3 N0-1 non-small-cell lung cancer (NSCLC). METHODS: 34 patients with inoperable early-stage NSCLC were treated from August 2008 to April 2013. Prior to enrolment, patients were required to be evaluated by an experienced thoracic surgeon to determine the "operability". All received 57 Gy in 19 fractions followed by escalated doses of 3-Gy fractions, up to a total dose of 66 Gy using a 3D conformal technique. Toxicities were measured using the Common Terminology Criteria for Adverse Effects v. 4.0. RESULTS: The median follow-up was 33 months (7-74 months). Toxicity grades ≥3 were not observed. Local control (LC) was 80.4% at 2 years, whereas regional control (RC) was 78%. The overall survival (OS), time to progression (TTP) and time to distant metastasis (TTM) at 2 years were 60%, 59% and 80%, respectively. For patients with T1-2 N0 and a tumour size <45 mm (n = 19), rates of OS, TTP and TTM at 2 years were 71%, 75% and 94%, respectively. LC and RC at 2 years were 85% and 94%, respectively. CONCLUSION: HFRT using 3.0-Gy fractions amounting to a total dose of 66 Gy is the recommended dose. A Phase 2 trial is warranted in order to assess the safety and efficacy of this fractionation scheme. ADVANCES IN KNOWLEDGE: HFRT results in a favourable outcome in early-stage lung cancer without the usual restrictions in tumour size and/or location associated with previous treatment methods. No special equipment is required, therefore permitting its application in any centre.

Lung ventilation-perfusion scintigraphy in children on long-term parenteral nutrition.

PURPOSE: Pulmonary emboli (PE) are one of the major complications associated with total parenteral nutrition (TPN). Ventilation-perfusion scintigraphy (V/Q) remains the most used test for the diagnosis of PE and follow-up of patients on TPN. The aim of our study was to demonstrate the high prevalence of undiagnosed PE in children on TPN. METHODS: The medical and imaging files of 64 patients on TPN who underwent V/Q examinations covering the period of 1986-2004 were reviewed. Children were aged between 3.18 months and 21.6 years. TPN was started at birth (range 0-15 years). All children had a normal chest radiograph and no symptoms at the time of the V/Q scan. A comparative analysis between the prevalence of PE and risk factors (number of days per week with lipophilic content of the TPN, bowel inflammation and thrombophilic factors (protein C and S) was performed. RESULTS: Of the 64 patients, 25 (39%) had an abnormal V/Q scan. A total of 29 PE episodes were diagnosed in all patients. Two children had three episodes of PE. The median age at PE diagnosis was 4.6 years. In 17 patients (68%) diagnosis was achieved on the first V/Q scan performed. PE was bilateral in 56% and unilateral in 44%. PE was the main cause of 2 out 15 recorded deaths. All risk factors were associated with an increase in PE prevalence by statistical analysis. CONCLUSION: PE is underdiagnosed in children on long-term TPN. Lung V/Q scintigraphy is useful in the diagnosis of PE in children with a low pretest probability.

Fluordeoxyglucose-PET study in first-episode schizophrenic patients during the hallucinatory state, after remission and during linguistic-auditory activation.

OBJECTIVES: We tested the hypothesis that endogenous auditory verbal hallucinations (AVH) involve activation of auditory/linguistic association cortices that are usually activated by externally presented speech. METHODS: Nine neuroleptic-naive patients with first-episode schizophrenia (Diagnostic and Statistical Manual for Mental Disorders-IV criteria) with prominent AVH underwent three PET scans using F-fluordeoxyglucose (FDG): (i) shortly after presentation, while experiencing prominent and frequent AVH; (ii) after medication-induced remission (R), using a stable dose of risperidone; (iii) also in remission, during bilateral linguistic auditory activation (LAA) induced by spoken text mimicking the content of the hallucinations experienced while the first PET was performed, using headphones. PET scans were acquired using an Advanced-Nxi Scanner (GE Healthcare). Intrasubject realignment, spatial normalization and statistical analysis of PET images were carried out using statistical parametric mapping. Differences between AVH and R and between LAA and R were statistically evaluated using a voxel-wise paired t-test. A voxel level threshold of P<0.01 was used to determine which regions underwent the most significant changes in F-FDG uptake. RESULTS: During AVH, patients demonstrated a significant activation of the supplementary motor area, anterior cingulum, medial superior frontal area and cerebelum. Activation was also observed in the left superior frontal area, right superior temporal pole and right orbitofrontal region. During LAA, greater FDG uptake was observed in the right and left superior and middle temporal cortices, left hippocampus and parahippocampal regions. CONCLUSION: Our findings show a different pattern of regional cerebral glucose metabolism between AVH and physiological auditory activation. This feature does not support the hypothesis that AVH in acute schizophrenic patients reflects an abnormal activation of auditory-linguistic pathways. However, it does suggest that cortical regions implicated in the generation of inner speech could be involved.

Usefulness of 18-fluorodeoxyglucose positron emission tomography in the evaluation of tumor cardiac thrombus from renal cell carcinoma.

PURPOSE: Retrospectively analysed our experience in Renal Cell carcinoma (RCC) patients studied with 18-Fluorodeoxyglucose Positron Emission Tomography (FDG PET) to rule out the incidence and clinical impact of heart metastases. MATERIAL AND METHODS: In two years, 37 patients with RCC were studied with FDG PET. 10 were studied for initial staging and 27 patients were evaluated for suspected recurrence or re-staging. RESULTS: In two patients (5%), PET scan showed pathological focal uptake in myocardium. On the bases of this finding, MRI was performed visualizing a myocardial mass in both lesions and confirmed by histology in one of them. The hypothesis of prolepses of the tumour by thrombus in RCC patients justified the surgery. CONCLUSION: Whole-body FDG PET in RCC patients could help to diagnose cardiac metastasis, and allows the possibility of therapeutic surgery, due to the thrombus significance of heart involvement.