Anne-Ségolène Cottereau

Molecular Profile and FDG-PET/CT Total Metabolic Tumor Volume Improve Risk Classification at Diagnosis for Patients with Diffuse Large B-Cell Lymphoma

Purpose: The prognostic impact of total metabolic tumor volume (TMTV) measured on pretreatment 18F-FDG PET/CT and its added value to molecular characteristics was investigated in patients with diffuse large B-cell lymphoma (DLBCL). Experimental Design: For 81 newly diagnosed patients with DLBCL treated with rituximab and CHOP/CHOP-like regimen, TMTV was computed using the 41% SUVmax thresholding method. According to the gene expression profile, determined using DASL (cDNA-mediated Annealing, Selection, Ligation and extension) technology, a subset of 57 patients was classified in germinal center B (GCB) or activated B-cell (ABC) subtypes and MYC or BCL2 overexpressed. Results: Median follow-up was 64 months. Five-year progression-free survival (PFS) and overall survival (OS) were 60% and 63% in the whole population. Median pretherapy TMTV was 320 cm3 (25th–75th percentiles 106–668 cm3). With a 300 cm3 cutoff, patients with high TMTV (n = 43) had a 5-year PFS and OS of 43% and 46% compared with 76% and 78% for patients with a low TMTV (P = 0.0023, P = 0.0047). ABC status, MYC, or BCL2 overexpression and both overexpression (“dual expressor,” DE) were significantly associated with a worse PFS and OS. TMTV combined with molecular data allowed a significant better risk substratification of ABC/GCB patients, on PFS and OS. High TMTV individualized in molecular-low-risk patients a group with a poor outcome (MYC, PFS=51%, OS=55% BCL2, PFS=49%, OS=49% or DE PFS=50%, OS=50%) and a group with a good outcome (MYC, PFS=93%, OS=93% BCL2, PFS=86%, OS=86%, or DE PFS=81%, OS=81%). Conclusions: The combination of molecular and imaging characteristics at diagnosis could lead to a more accurate selection of patients, to increase tailor therapy. Clin Cancer Res; 22(15); 3801–9. ©2016 AACR.

Prognostic value of baseline total metabolic tumor volume (TMTV0) measured on FDG-PET/CT in patients with peripheral T-cell lymphoma (PTCL)

BACKGROUND Most peripheral T-cell lymphoma (PTCL) patients have a poor outcome and the identification of prognostic factors at diagnosis is needed. PATIENTS AND METHODS The prognostic impact of total metabolic tumor volume (TMTV0), measured on baseline [(18)F]2-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography, was evaluated in a retrospective study including 108 PTCL patients (27 PTCL not otherwise specified, 43 angioimmunoblastic T-cell lymphomas and 38 anaplastic large-cell lymphomas). All received anthracycline-based chemotherapy. TMTV0 was computed with the 41% maximum standardized uptake value threshold method and an optimal cut-off point for binary outcomes was determined and compared with others prognostic factors. RESULTS With a median follow-up of 23 months, 2-year progression-free survival (PFS) was 49% and 2-year overall survival (OS) was 67%. High TMTV0 was significantly associated with a worse prognosis. At 2 years, PFS was 26% in patients with a high TMTV0 (>230 cm(3), n = 53) versus 71% for those with a low TMTV0, [P < 0.0001, hazard ratio (HR) = 4], whereas OS was 50% versus 80%, respectively, (P = 0.0005, HR = 3.1). In multivariate analysis, TMTV0 was the only significant independent parameter for both PFS and OS. TMTV0, combined with PIT, discriminated even better than TMTV0 alone, patients with an adverse outcome (TMTV0 >230 cm(3) and PIT >1, n = 33,) from those with good prognosis (TMTV0 ≤230 cm(3) and PIT ≤1, n = 40): 19% versus 73% 2-year PFS (P < 0.0001) and 43% versus 81% 2-year OS, respectively (P = 0.0002). Thirty-one patients (other TMTV0-PIT combinations) had an intermediate outcome, 50% 2-year PFS and 68% 2-year OS. CONCLUSION TMTV0 appears as an independent predictor of PTCL outcome. Combined with PIT, it could identify different risk categories at diagnosis and warrants further validation as a prognostic marker.

Baseline Total Metabolic Tumor Volume measured with fixed or different adaptive thresholding methods equally predicts outcome in Peripheral T cell lymphoma.

The purpose of this study was to compare in a large series of peripheral T cell lymphoma, as a model of diffuse disease, the prognostic value of baseline total metabolic tumor volume (TMTV) measured on 18F-FDG PET/CT with adaptive thresholding methods with TMTV measured with a fixed 41% SUVmax threshold method. Methods: One hundred six patients with peripheral T cell lymphoma, staged with PET/CT, were enrolled from 5 Lymphoma Study Association centers. In this series, TMTV computed with the 41% SUVmax threshold is a strong predictor of outcome. On a dedicated workstation, we measured the TMTV with 4 adaptive thresholding methods based on characteristic image parameters: Daisne (Da) modified, based on signal-to-background ratio; Nestle (Ns), based on tumor and background intensities; Fit, including a 3-dimensional geometric model based on spatial resolution (Fit); and Black (Bl), based on mean SUVmax. The TMTV values obtained with each adaptive method were compared with those obtained with the 41% SUVmax method. Their respective prognostic impacts on outcome prediction were compared using receiver-operating-characteristic (ROC) curve analysis and Kaplan–Meier survival curves. Results: The median value of TMTV41%, TMTVDa, TMTVNs, TMTVFit, and TMTVBl were, respectively, 231 cm3 (range, 5–3,824), 175 cm3 (range, 8–3,510), 198 cm3 (range, 3–3,934), 175 cm3 (range, 8–3,512), and 333 cm3 (range, 3–5,113). The intraclass correlation coefficients were excellent, from 0.972 to 0.988, for TMTVDa, TMTVFit, and TMTVNs, and less good for TMTVBl (0.856). The mean differences obtained from the Bland–Altman plots were 48.5, 47.2, 19.5, and −253.3 cm3, respectively. Except for Black, there was no significant difference within the methods between the ROC curves (P > 0.4) for progression-free survival and overall survival. Survival curves with the ROC optimal cutoff for each method separated the same groups of low-risk (volume ≤ cutoff) from high-risk patients (volume > cutoff), with similar 2-y progression-free survival (range, 66%–72% vs. 26%–29%; hazard ratio, 3.7–4.1) and 2-y overall survival (79%–83% vs. 50%–53%; hazard ratio, 3.0–3.5). Conclusion: The prognostic value of TMTV remained quite similar whatever the methods, adaptive or 41% SUVmax, supporting its use as a strong prognosticator in lymphoma. However, for implementation of TMTV in clinical trials 1 single method easily applicable in a multicentric PET review must be selected and kept all along the trial.

Early Phase 99 Tc-HMDP Scintigraphy for the Diagnosis and Typing of Cardiac Amyloidosis

Although bisphosphonate scintigraphy has emerged as a valuable modality for cardiac amyloidosis (CA) diagnosis and typing with transthyretin CA showing strong cardiac uptake [(1)][1], the procedure in its current form is time consuming and may be regarded as inadequate especially in frail patients.

Brain FDG-PET metabolic abnormalities in patients with long-lasting macrophagic myofasciitis

The aim of this study was to characterize brain metabolic abnormalities in patients with macrophagic myofascitis (MMF) and the relationship with cognitive dysfunction through the use of PET with 18F-FDG. Methods: 18F-FDG PET brain imaging and a comprehensive battery of neuropsychological tests were performed in 100 consecutive MMF patients (age [mean ± SD], 45.9 ± 12 y; 74% women). Images were analyzed with statistical parametric mapping (SPM12). Through the use of analysis of covariance, all 18F-FDG PET brain images of MMF patients were compared with those of a reference population of 44 healthy subjects similar in age (45.4 ± 16 y; P = 0.87) and sex (73% women; P = 0.88). The neuropsychological assessment identified 4 categories of patients: those with no significant cognitive impairment (n = 42), those with frontal subcortical (FSC) dysfunction (n = 29), those with Papez circuit dysfunction (n = 22), and those with callosal disconnection (n = 7). Results: In comparison with healthy subjects, the whole population of patients with MMF exhibited a spatial pattern of cerebral glucose hypometabolism (P < 0.001) involving the occipital lobes, temporal lobes, limbic system, cerebellum, and frontoparietal cortices, as shown by analysis of covariance. The subgroup of patients with FSC dysfunction exhibited a larger extent of involved areas (35,223 voxels vs. 13,680 voxels in the subgroup with Papez circuit dysfunction and 5,453 voxels in patients without cognitive impairment). Nonsignificant results were obtained for the last subgroup because of its small population size. Conclusion: Our study identified a peculiar spatial pattern of cerebral glucose hypometabolism that was most marked in MMF patients with FSC dysfunction. Further studies are needed to determine whether this pattern could represent a diagnostic biomarker of MMF in patients with chronic fatigue syndrome and cognitive dysfunction.

Predictive Value of PET Response Combined with Baseline Metabolic Tumor Volume in Peripheral T-Cell Lymphoma Patients

Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of aggressive non-Hodgkin lymphomas with poor outcomes on current therapy. We investigated whether response assessed with PET/CT combined with baseline total metabolic tumor volume (TMTV) could detect early relapse or refractory disease. Methods: From 7 European centers, 140 patients with nodal PTCL who underwent baseline PET/CT were selected. Forty-three had interim PET (iPET) performed after 2 cycles (iPET2), 95 had iPET performed after 3 or 4 cycles (iPET3/4), and 96 had end-of-treatment PET (eotPET). Baseline TMTV was computed with a 41% SUVmax threshold, and PET response was reported using the Deauville 5-point scale. Results: With a median of 43 mo of follow-up, the 2-y progression-free survival (PFS) and overall survival (OS) were 51% and 67%, respectively. iPET2-positive patients (Deauville score ≥ 4) had a significantly worse outcome than iPET2-negative patients (P < 0.0001, hazard ratio of 6.8 for PFS; P < 0.0001, hazard ratio of 6.6 for OS). The value of iPET3/4 was also confirmed for PFS (P < 0.0001) and OS (P < 0.0001). The 2-y PFS and OS for iPET3/4-positive (n = 28) and iPET3/4-negative (n = 67) patients were 16% and 32% versus 75% and 85%, respectively. The eotPET results also reflected patient outcome. A model combining TMTV and iPET3/4 stratified the population into distinct risk groups (TMTV ≤ 230 cm3 and iPET3/4-negative [2-y PFS/OS, 79%/85%]; TMTV > 230 cm3 and iPET3/4-negative [59%/84%]; TMTV ≤ 230 cm3 and iPET3/4-positive [42%/50%]; TMTV > 230 cm3 and iPET3/4-positive [0%/18%]). Conclusion: iPET response is predictive of outcome and allows early detection of high-risk PTCL patients. Combining iPET with TMTV improves risk stratification in individual patients.

Molecular Profile and FDG-PET Metabolic Volume at Staging in DLBCL—Response

We thank Adams and colleagues for their interest in our research (1) on the prognostic value of baseline total metabolic tumor volume (TMTV) combined with molecular data in patients with diffuse large B-cell lymphoma (DLBCL). They give us the opportunity to discuss TMTV and clinical prognostic

Interim PET in lymphoma: from Deauville to Peking criteria. On the road, again…

The first set of criteria for PET response assessment in lymphoma proposed by an international committee (International Harmonized Project, IHP criteria) was published in 2007 [1]. The tumor residual uptake observed after treatment was compared visually to a reference background, which was according to the size of the residual lesion, the mediastinal blood pool or the surrounding background. However, these criteria were set only for end-of-treatment PET despite that interim PET (iPET) performed after the first cycles of chemotherapy began to be proposed by several groups as a good tool for early-adapted treatment strategy. In addition, some studies pointed out that several patients classified as PET-positive had a favorable outcome, especially in DLBCL. Moreover, interpretation discrepancies were observed among readers. Consequently, new criteria were proposed to report both interim and end-of-treatment PET, and first published in Leukemia & Lymphoma in 2009 [2]: Deauville criteria was a five-point scale system scoring visually the tumor residual uptake according to different level of regional background taken as a reference. A positive iPET was defined as tumor residual uptake moderately or markedly higher than the liver i.e. Score 4 or 5. Setting a comparison of the tumor residual uptake with a well-defined, recognizable organ i.e. the liver, instead of the mediastinal blood pool, especially when the residual uptake is in a bulky mediastinal mass, improved the inter-observer agreement and also reduced the number of instances of false-positive scans. This five-PS scale became the new standard for PET/CT response assessment in the updated recommendations presented at the 12th International Conference on Malignant Lymphoma and published in 2014 [3]. These criteria were expanded to apply to all FDG-avid histologies, applicable for both interim and end-of-treatment PET. They specified reading the PET on a SUV scale and defined the Score 5 as two to three times the liver SUVmax [3] instead of ‘markedly’. This was needed to improve consistency of PET interpretation but introduced a quantitative analysis of SUV differences, only specified for Score 5. No SUVmax cutoff has to be chosen to discriminate Score 4 and Score 3, and additionally there remain some borderline cases not easily and reproducibly gradable with a SUV scale. This raises some difficulties in interpreting potential PET positivity and opens the road to quantitative assessment. Quantification of the response at interim after two and four cycles of chemotherapy with a DSUVmax approach based of the reduction of SUVmax from baseline, first proposed in 2007 in DLBCL, was shown more reproducible between readers and more robust than Deauville criteria by further decreasing the number of false-positive studies [4]. However, two prospective trials applying this criterion have reported conflicting results. The PETAL study including 600 patients with DLBCL demonstrated that PET after two cycles of immunochemotherapy reported with the DSUVmax approach with a cutoff of 66% of reduction was highly predictive of outcome [5]. By contrast, the SAKK study which included 138 patients treated by R-CHOP on a 14-day cycle could not demonstrate at 2 years any impact of DSUV on EFS [6]. This result could potentially be explained by the presence in the SAKK study of a large percentage of low-risk patients as well as to the chemotherapy regimen used. Indeed, in a retrospective study comparing the study in 114 patients with DLBCL, Deauville criteria with the DSUVmax approach has been shown that the prognostic impact of DSUVmax was lower in low-risk patients or in patients treated by dose-dense– dose-intense immunochemotherapy which could induce an inflammatory reaction

Whole-Body Diffusion-weighted MR Imaging of Iron Deposits in Hodgkin, Follicular, and Diffuse Large B-Cell Lymphoma

Purpose To analyze the frequency and distribution of low-signal-intensity regions (LSIRs) in lymphoma lesions and to compare these to fluorodeoxyglucose (FDG) uptake and biologic markers of inflammation. Materials and Methods The authors analyzed 61 untreated patients with a bulky lymphoma (at least one tumor mass ≥7 cm in diameter). When a LSIR within tumor lesions was detected on diffusion-weighted images obtained with a b value of 50 sec/mm2, a T2-weighted gradient-echo (GRE) sequence was performed and calcifications were searched for with computed tomography (CT). In two patients, Perls staining was performed on tissue samples from the LSIR. LSIRs were compared with biologic inflammatory parameters and baseline FDG positon emission tomography (PET)/CT parameters (maximum standardized uptake value [SUVmax], total metabolic tumor volume [TMTV]). Results LSIRs were detected in 22 patients and corresponded to signal void on GRE images; one LSIR was due to calcifications, and three LSIRS were due to a recent biopsy. In 18 patients, LSIRs appeared to be related to focal iron deposits; this was proven with Perls staining in two patients. The LSIRs presumed to be due to iron deposits were found mostly in patients with aggressive lymphoma (nine of 26 patients with Hodgkin lymphoma and eight of 20 patients with diffuse large B-cell lymphoma vs one of 15 patients with follicular lymphoma; P = .047) and with advanced stage disease (15 of 18 patients). LSIRS were observed in spleen (n = 14), liver (n = 3), and nodal (n = 8) lesions and corresponded to foci FDG uptake, with mean SUVmax of 9.8, 6.7, and 16.2, respectively. These patients had significantly higher serum levels of C-reactive protein, α1-globulin, and α2-globulin and more frequently had microcytic anemia than those without such deposits (P = .0072, P = .003, P = .0068, and P < .0001, respectively). They also had a significantly higher TMTV (P = .0055) and higher levels of spleen involvement (P < .0001). Conclusion LSIRs due to focal iron deposits are detected in lymphoma lesions and are associated with a more pronounced biologic inflammatory syndrome.

Integrative PET: a new concept for outcome prediction in lymphoma

Integrative FDG-PET in lymphoma is a new concept which can be defined as a method of prognostic imaging: PET imaging data are combined with data from other fields (clinical, biological, molecular) or other imaging techniques to get a better risk stratification of the patients. New treatments have drastically improved the outcomes in the most frequent lymphoma subtypes such as Hodgkin Lymphoma (HL) and Diffuse large B cell lymphoma (DLBCL) of follicular lymphoma (FL); however, a small percentage of patients is at high risk of treatment failure or relapses and cannot be selected accurately by the classic prognostic factors. Treatment of lymphoma is now a delicate balance between the risk of under treatment and over treatment. Therapy should be tailored to maintain or improve the cure rate in patient with high risk factors and to reduce the toxicity of drugs or radiations in low-risk patient. New prognosticators are under investigation in lymphoma before treatment or after the first few cycles of chemotherapy (interim evaluation). Before treatment, molecular biomarkers characterizing the tumour genetic status can be obtained from the biopsied materials and have been evaluated as ‘‘a priori’’ prognostic factors. Similarly, baseline imaging could identify groups of treatment-resistant patients with a risk of poor outcome. By contrast, interim imaging early predicts treatment outcome and constitutes a chemosensitivity appraisal of the tumour in a specific patient. Both approaches are complementary. In this regard, interim FDG-PET (iPET) has been proposed for early risk stratification in lymphoma and the first results published ten years ago were enthusiastic. However in advanced stage HL, more recent data have reported that the 5-year PFS of iPET is 23 % in PET positive patients and less than 90 % in PET negative when the Deauville criteria are used for PET reporting. The NPV (85–90 %) and PPV (70–75 %) do not reach the values which were reported initially. The issue is further complex in DLBCL since in a large prospective series that has included more than 800 patients and used the DSUVmax for iPET reporting, the 2-year TTF was 47 % in PET positive patients and 79 % in the PET negative group. More recently, quantitative baseline PET has been proposed as an alternative to iPET for outcome prediction in an effort to obtain prognostic information at staging without doing another PET scan. Quantitative PET requires a strict adherence to international guidelines for FDG-PET in oncology but the major clues are biological (incorrect timing of the acquisition) or due to human errors (versatile use of different acquisition or reconstruction parameters, incorrect reporting of injected activity and erroneous localization of the involved sites). Indeed, in many countries, the equipments are strictly controlled by manufacturers and health agencies. The prognostic value of different derived metrics (metabolic tumour volume, SUV max and Total Lesion Glycolysis, TLG) has been assessed in HL, DLBCL and recently in primary mediastinal B cell lymphoma (PMBCL) and peripheral T cell lymphoma (PTCL). Although MTV and TLG were identified as interesting prognostic factors, they do not allow a sufficient categorization of patients to change treatment only on this approach. Integrative PET might overcome these difficulties. One of the simplest examples is combination of a quantitative parameter with a clinical index. In a retrospective study & Michel Meignan michel.meignan@aphp.fr; michel.meignan@hmn.aphp.fr