Distinct functional domains of the epsin-related Ent5p, a cargo adaptor for the SNARE Tlg2p in transport between endosomes and Golgi.

The epsin-related adaptor proteins Ent3p and Ent5p participate in budding of clathrin coated vesicles in transport between trans-Golgi network and endosomes in yeast. Transport of the arginine permease Can1p was analyzed, which recycles between plasma membrane and endosomes and can be targeted to the vacuole for degradation. ent3∆ cells accumulate Can1p-GFP in endosomes. Can1p-GFP is transported faster to the vacuole upon induction of degradation in ent5∆ cells than in wild type cells. The C-terminal domain of Ent5p was sufficient to restore recycling of the secretory SNARE GFP-Snc1p between plasma membrane and TGN in ent3∆ ent5∆ cells. The SNARE Tlg2p was identified as interaction partner of the Ent5p ENTH domain by in vitro binding assays and the interaction site on Ent5p was mapped. Tlg2p functions in transport from early endosomes to the trans-Golgi network and in homotypic fusion of these organelles. Tlg2p is partially shifted to denser fractions in sucrose density gradients of organelles from ent5∆ cells while distribution of Kex2p is unaffected demonstrating that Ent5p acts as cargo adaptor for Tlg2p in vivo. Taken together we show that Ent3p and Ent5p have different roles in transport and function as cargo adaptors for distinct SNAREs.

The value of semiquantitative PET features and end-of-therapy PET in grade 3B follicular lymphoma.

Grade 3B follicular lymphoma (G3BFL) is a rare lymphoma thought to sit on a continuum between low-grade FL and diffuse large B-cell lymphoma (DLBCL). The prognostic impact of quantitative positron emission tomography (PET) metrics such as total metabolic tumour volume (TMTV), total lesion glycolysis (TLG), and maximum standard uptake value (SUVmax) have been extensively analysed in FL and DLBCL, but G3BFL data are lacking. Here, we describe PET outcomes and radiomic characteristics in 46 G3BFL cases uniformly treated with R-CHOP (like) chemotherapy. Central semi-automated PET TMTV, TLG, and SUVmax analyses, using MIM software, were correlated with clinical outcomes and compared with published results in low-grade FL and DLBCL. In G3BFL, the end-of-treatment complete metabolic response was associated with improved progression-free survival (PFS; p = 0.002) and overall survival (OS; p = 0.04). G3BFL median TLG (1455) and SUVmax (16.50) sit between published values for low-grade FL (TLG: 1112, SUVmax: 11.3) and DLBCL (TLG: 3004, SUVmax: 24.35). No association between TMTV (>350 cm3) and survival was seen (PFS: p = 0.24; OS: p = 0.40). High SUVmax (>19.2) and TLG (>2760) both conferred inferior PFS but not OS (PFS: SUVmax p = 0.004; TLG p = 0.05). These data support the routine incorporation of PET radiomics at baseline and treatment response for G3BFL.

Artificial intelligence-based, volumetric assessment of the bone marrow metabolic activity in [18F]FDG PET/CT predicts survival in multiple myeloma.

PURPOSE: Multiple myeloma (MM) is a highly heterogeneous disease with wide variations in patient outcome. [18F]FDG PET/CT can provide prognostic information in MM, but it is hampered by issues regarding standardization of scan interpretation. Our group has recently demonstrated the feasibility of automated, volumetric assessment of bone marrow (BM) metabolic activity on PET/CT using a novel artificial intelligence (AI)-based tool. Accordingly, the aim of the current study is to investigate the prognostic role of whole-body calculations of BM metabolism in patients with newly diagnosed MM using this AI tool. MATERIALS AND METHODS: Forty-four, previously untreated MM patients underwent whole-body [18F]FDG PET/CT. Automated PET/CT image segmentation and volumetric quantification of BM metabolism were based on an initial CT-based segmentation of the skeleton, its transfer to the standardized uptake value (SUV) PET images, subsequent application of different SUV thresholds, and refinement of the resulting regions using postprocessing. In the present analysis, ten different uptake thresholds (AI approaches), based on reference organs or absolute SUV values, were applied for definition of pathological tracer uptake and subsequent calculation of the whole-body metabolic tumor volume (MTV) and total lesion glycolysis (TLG). Correlation analysis was performed between the automated PET values and histopathological results of the BM as well as patients' progression-free survival (PFS) and overall survival (OS). Receiver operating characteristic (ROC) curve analysis was used to investigate the discrimination performance of MTV and TLG for prediction of 2-year PFS. The prognostic performance of the new Italian Myeloma criteria for PET Use (IMPeTUs) was also investigated. RESULTS: Median follow-up [95% CI] of the patient cohort was 110 months [105-123 months]. AI-based BM segmentation and calculation of MTV and TLG were feasible in all patients. A significant, positive, moderate correlation was observed between the automated quantitative whole-body PET/CT parameters, MTV and TLG, and BM plasma cell infiltration for all ten [18F]FDG uptake thresholds. With regard to PFS, univariable analysis for both MTV and TLG predicted patient outcome reasonably well for all AI approaches. Adjusting for cytogenetic abnormalities and BM plasma cell infiltration rate, multivariable analysis also showed prognostic significance for high MTV, which defined pathological [18F]FDG uptake in the BM via the liver. In terms of OS, univariable and multivariable analysis showed that whole-body MTV, again mainly using liver uptake as reference, was significantly associated with shorter survival. In line with these findings, ROC curve analysis showed that MTV and TLG, assessed using liver-based cut-offs, could predict 2-year PFS rates. The application of IMPeTUs showed that the number of focal hypermetabolic BM lesions and extramedullary disease had an adverse effect on PFS. CONCLUSIONS: The AI-based, whole-body calculations of BM metabolism via the parameters MTV and TLG not only correlate with the degree of BM plasma cell infiltration, but also predict patient survival in MM. In particular, the parameter MTV, using the liver uptake as reference for BM segmentation, provides solid prognostic information for disease progression. In addition to highlighting the prognostic significance of automated, global volumetric estimation of metabolic tumor burden, these data open up new perspectives towards solving the complex problem of interpreting PET scans in MM with a simple, fast, and robust method that is not affected by operator-dependent interventions.

Can physiologic colonic [18F]FDG uptake in PET/CT imaging predict response to immunotherapy in metastatic melanoma?

AIM: The development of biomarkers that can reliably and early predict response to immune checkpoint inhibitors (ICIs) is crucial in melanoma. In recent years, the gut microbiome has emerged as an important regulator of immunotherapy response, which may, moreover, serve as a surrogate marker and prognosticator in oncological patients under immunotherapy. Aim of the present study is to investigate if physiologic colonic [18F]FDG uptake in PET/CT before start of ICIs correlates with clinical outcome of metastatic melanoma patients. The relation between [18F]FDG uptake in lymphoid cell-rich organs and long-term patient outcome is also assessed. METHODOLOGY: One hundred nineteen stage IV melanoma patients scheduled for immunotherapy with ipilimumab, applied either as monotherapy or in combination with nivolumab, underwent baseline [18F]FDG PET/CT. PET/CT data analysis consisted of standardized uptake value (SUV), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) calculations in the colon as well as measurements of the colon-to-liver SUV ratios (CLRmean, CLRmax). Visual grading of colon uptake based on a four-point scale was also performed. Moreover, the spleen-to-liver SUV ratios (SLRmean, SLRmax) and the bone marrow-to-liver SUV ratios (BLRmean, BLRmax) were calculated. We also measured serum lipopolysaccharide (LPS) levels as a marker for bacterial translocation and surrogate for mucosal defense homeostasis. The results were correlated with patients' best clinical response, progression-free survival (PFS), and overall survival (OS) as well as clinical signs of colitis. RESULTS: Median follow-up [95%CI] from the beginning of immunotherapy was 64.6 months [61.0-68.6 months]. Best response to treatment was progressive disease (PD) for 60 patients, stable disease (SD) for 37 patients, partial response (PR) for 18 patients, and complete response (CR) for 4 patients. Kaplan-Meier curves demonstrated a trend for longer PFS and OS in patients with lower colonic SUV and CLR values; however, no statistical significance for these parameters as prognostic factors was demonstrated. On the other hand, patients showing disease control as best response to treatment (SD, PR, CR) had significantly lower colonic MTV and TLG than those showing PD. With regard to lymphoid cell-rich organs, significantly lower baseline SLRmax and BLRmax were observed in patients responding with disease control than progression to treatment. Furthermore, patients with lower SLRmax and BLRmax values had a significantly longer OS when dichotomized at their median. In multivariate analysis, PET parameters that were found to significantly adversely correlate with patient survival were colonic MTV for PFS, colonic TLG for PFS, and BLRmax for PFS and OS. CONCLUSIONS: Physiologic colonic [18F]FDG uptake in PET/CT, as assessed by means of SUV, before start of ipilimumab-based treatment does not seem to independently predict patient survival of metastatic melanoma. On the other hand, volumetric PET parameters, such as MTV and TLG, derived from the normal gut may identify patients showing disease control to immunotherapy and significantly correlate with PFS. Moreover, the investigation of glucose metabolism in the spleen and the bone marrow may offer prognostic information.

Application of an artificial intelligence-based tool in [18F]FDG PET/CT for the assessment of bone marrow involvement in multiple myeloma.

PURPOSE: [18F]FDG PET/CT is an imaging modality of high performance in multiple myeloma (MM). Nevertheless, the inter-observer reproducibility in PET/CT scan interpretation may be hampered by the different patterns of bone marrow (BM) infiltration in the disease. Although many approaches have been recently developed to address the issue of standardization, none can yet be considered a standard method in the interpretation of PET/CT. We herein aim to validate a novel three-dimensional deep learning-based tool on PET/CT images for automated assessment of the intensity of BM metabolism in MM patients. MATERIALS AND METHODS: Whole-body [18F]FDG PET/CT scans of 35 consecutive, previously untreated MM patients were studied. All patients were investigated in the context of an open-label, multicenter, randomized, active-controlled, phase 3 trial (GMMG-HD7). Qualitative (visual) analysis classified the PET/CT scans into three groups based on the presence and number of focal [18F]FDG-avid lesions as well as the degree of diffuse [18F]FDG uptake in the BM. The proposed automated method for BM metabolism assessment is based on an initial CT-based segmentation of the skeleton, its transfer to the SUV PET images, the subsequent application of different SUV thresholds, and refinement of the resulting regions using postprocessing. In the present analysis, six different SUV thresholds (Approaches 1-6) were applied for the definition of pathological tracer uptake in the skeleton [Approach 1: liver SUVmedian × 1.1 (axial skeleton), gluteal muscles SUVmedian × 4 (extremities). Approach 2: liver SUVmedian × 1.5 (axial skeleton), gluteal muscles SUVmedian × 4 (extremities). Approach 3: liver SUVmedian × 2 (axial skeleton), gluteal muscles SUVmedian × 4 (extremities). Approach 4: ≥ 2.5. Approach 5: ≥ 2.5 (axial skeleton), ≥ 2.0 (extremities). Approach 6: SUVmax liver]. Using the resulting masks, subsequent calculations of the whole-body metabolic tumor volume (MTV) and total lesion glycolysis (TLG) in each patient were performed. A correlation analysis was performed between the automated PET values and the results of the visual PET/CT analysis as well as the histopathological, cytogenetical, and clinical data of the patients. RESULTS: BM segmentation and calculation of MTV and TLG after the application of the deep learning tool were feasible in all patients. A significant positive correlation (p < 0.05) was observed between the results of the visual analysis of the PET/CT scans for the three patient groups and the MTV and TLG values after the employment of all six [18F]FDG uptake thresholds. In addition, there were significant differences between the three patient groups with regard to their MTV and TLG values for all applied thresholds of pathological tracer uptake. Furthermore, we could demonstrate a significant, moderate, positive correlation of BM plasma cell infiltration and plasma levels of ß2-microglobulin with the automated quantitative PET/CT parameters MTV and TLG after utilization of Approaches 1, 2, 4, and 5. CONCLUSIONS: The automated, volumetric, whole-body PET/CT assessment of the BM metabolic activity in MM is feasible with the herein applied method and correlates with clinically relevant parameters in the disease. This methodology offers a potentially reliable tool in the direction of optimization and standardization of PET/CT interpretation in MM. Based on the present promising findings, the deep learning-based approach will be further evaluated in future prospective studies with larger patient cohorts.

Prognostic value of maximum standard uptake value, metabolic tumour volume, and total lesion glycolysis of 18F-FDG PET/CT in patients with malignant pleural mesothelioma: a systematic review and meta-analysis.

PURPOSE: Present work systematically reviewed relevant literature based on 18F-FDG PET parameters and conducted a meta-analysis to examine the prognostic value of maximal standard uptake value (SUVmax), total lesional glycolysis (TLG), and metabolic tumour volume (MTV) in the prognosis of malignant pleural mesothelioma (MPM). METHODS: The relevant literature published in English were searched on PubMed, Cochrane Library, and EMBASE databases. We also evaluated the significance of SUVmax, TLG, and MTV in prognosis prediction using pooled hazard ratios (HRs). RESULTS: The current study comprised 12 primary studies with a total of 1307 MPM cases. According to our results, the pooled HR (95% confidence interval [CI]) of increased SUVmax for overall survival (OS) was 1.30 (95% CI 1.13-1.49, P = 0.000), whereas the increased TLG was 1.81(95% CI 1.25-2.61, P = 0.089). The increased MTV was not significantly related to OS (1.14 [95% CI 0.87-1.50, P = 0.18]).However, study design-stratified subgroup analysis suggested that differences in OS of retrospective and prospective subgroups were statistically significant, and no significant heterogeneity among different studies was observed. CONCLUSION: Based on the findings from the present work, PET/CT can significantly affect the prognosis prediction in MPM cases. Also, the increased SUVmax and TLG values predict an increased risk of mortality.

Baseline [18F]FDG PET/CT may predict the outcome of newly diagnosed follicular lymphoma in patients managed with initial "watch-and-wait" approach.

OBJECTIVES: To investigate if baseline [18F]FDG PET/CT can predict the outcome of follicular lymphoma (FL) in patients managed with an initial "watch-and-wait" approach. METHODS: Thirty-eight newly diagnosed FL patients who were managed with an initial "watch-and-wait" approach and undergone baseline [18F]FDG PET/CT were retrospectively enrolled. The standard uptake value (SUV), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of FL lesions were measured on PET/CT. Patients were followed up for at least 24 months or until initiation of FL therapy. The endpoint was the time to initiation of lymphoma treatment (TLT). RESULTS: After a median follow-up of 28 months (range 3-94 months), lymphoma treatment was initiated in 21/38 (55.3%) patients (median 15 months, range 3-51 months). Patients with TLT < 24 months showed SUVmax and TLG values significantly higher than those with TLT ≥ 24 months (p < 0.05). Receiver operating characteristic analysis demonstrated cutoff values of SUVmax > 9.5, MTV > 90.62 ml, and TLG > 144.96 SUVbw*ml were optimal for predicting TLT < 24 months. Kaplan-Meier analysis showed SUVmax > 9.5, MTV > 90.62 ml, and TLG > 144.96 SUVbw*ml had statistically significant correlations with shorter TLT (p < 0.01). Lymph node regions ≥ 3 and lymph nodes > 3 cm had almost significance (p < 0.1). In multivariate analysis, SUVmax > 9.5 (HR 3.2 [95% CI 1.1-9.2], p = 0.033) and TLG > 144.96 SUVbw*ml (HR 9.3 [95% CI 1.8-47.7], p = 0.008) were demonstrated to be independent predictive factors for shorter TLT. CONCLUSIONS: Metabolic indices (SUVmax and TLG) of baseline [18F]FDG PET/CT could predict the outcome independently in FL patients under an initial "watch-and-wait" approach. KEY POINTS: • "Watch-and-wait" approach is part of the overall treatment plan in asymptomatic patients with low tumor burden FL. However, the time to initiation of active treatment varies from months to years. • In our retrospective study of 38 patients with FL managed with an initial "watch-and-wait" approach, the SUVmax and TLG were demonstrated to be independent predictive factors for time to initiation of FL treatment. • Baseline [18F]FDG PET/CT may help to better select patients with FL who are most likely to benefit from "watch-and-wait" management.

Utility and limitations of metabolic parameters in head and neck cancer: finding a practical segmentation method.

PURPOSE: Although metabolic tumor volume (MTV) and total lesion glycolysis (TLG) have shown good prognostic value in head and neck cancer (HNC), there are still many issues to resolve before their potential application in standard clinical practice. The purpose of this study was to compare the discrimination ability of two relevant segmentation methods in HNC and to evaluate the potential benefit of adding lymph nodes' metabolism (LNM) to the measurements. METHODS: We retrospectively analyzed a recently published database of 62 patients with HNC treated with chemoradiotherapy. MTV and TLG were measured using an absolute threshold of SUV2.5. Comparison analysis with previously published background-level threshold (BLT) results was done through Concordance index (C-index) in eight prognostic models. RESULTS: BLT obtained better C-index values in five out of the eight models. The addition of LNM improved C-index values in six of the prognostic models. CONCLUSION: We found a potential benefit in adding LNM to the main tumor measurements, as well as in using a BLT for MTV segmentation compared to the most commonly used SUV2.5 threshold. Despite its limitations, this study suggests a practical and simple manner to use these parameters in standard clinical practice, aiming to help elaborate a general consensus.

11C-Methionine PET/CT in Assessment of Multiple Myeloma Patients: Comparison to 18F-FDG PET/CT and Prognostic Value.

Multiple myeloma (MM) is the second most common haematological malignancy and remains incurable despite therapeutic advances. 18F-FDG (FDG) PET/CT is a relevant tool MM for staging and it is the reference imaging technique for treatment evaluation. However, it has limitations, and investigation of other PET tracers is required. Preliminary results with L-methyl-[11C]- methionine (MET), suggest higher sensitivity than 18F-FDG. This study aimed to compare the diagnostic accuracy and prognostic value of 1FDG and MET in MM patients. We prospectively compared FDG and MET PET/CT for assessment of bone disease and extramedullary disease (EMD) in a series of 52 consecutive patients (8 smoldering MM, 18 newly diagnosed MM and 26 relapsed MM patients). Bone marrow (BM) uptake patterns and the detection of focal lesions (FLs) and EMD were compared. Furthermore, FDG PET parameters with known MM prognostic value were explored for both tracers, as well as total lesion MET uptake (TLMU). Median patient age was 61 years (range, 37-83 years), 54% were male, 13% of them were in stage ISS (International Staging System) III, and 31% had high-risk cytogenetics. FDG PET/CT did not detect active disease in 6 patients, while they were shown to be positive by MET PET/CT. Additionally, MET PET/CT identified a higher number of FLs than FDG in more than half of the patients (63%). For prognostication we focussed on the relapsed cohort, due to the low number of progressions in the two other cohorts. Upon using FDG PET/CT in relapsed patients, the presence of more than 3 FLs (HR 4.61, p = 0.056), more than 10 FLs (HR 5.65, p = 0.013), total metabolic tumor volume (TMTV) p50 (HR 4.91, p = 0.049) or TMTV p75 (HR 5.32, p = 0.016) were associated with adverse prognosis. In MET PET/CT analysis, TMTV p50 (HR 4.71, p = 0.056), TMTV p75 (HR 6.27, p = 0.007), TLMU p50 (HR 8.8, p = 0.04) and TLMU p75 (HR 6.3, p = 0.007) adversely affected PFS. This study confirmed the diagnostic and prognostic value of FDG in MM. In addition, it highlights that MET has higher sensitivity than FDG PET/CT for detection of myeloma lesions, including FLs. Moreover, we show, for the first time, the prognostic value of TMTV and TLMU MET PET/CT in the imaging evaluation of MM patients.

[F18] FDG-PET/CT for manual or semiautomated GTV delineation of the primary tumor for radiation therapy planning in patients with esophageal cancer: is it useful?

BACKGROUND: Target volume definition of the primary tumor in esophageal cancer is usually based on computed tomography (CT) supported by endoscopy and/or endoscopic ultrasound and can be difficult given the low soft-tissue contrast of CT resulting in large interobserver variability. We evaluated the value of a dedicated planning [F18] FDG-Positron emission tomography/computer tomography (PET/CT) for harmonization of gross tumor volume (GTV) delineation and the feasibility of semiautomated structures for planning purposes in a large cohort. METHODS: Patients receiving a dedicated planning [F18] FDG-PET/CT (06/2011-03/2016) were included. GTV was delineated on CT and on PET/CT (GTVCT and GTVPET/CT, respectively) by three independent radiation oncologists. Interobserver variability was evaluated by comparison of mean GTV and mean tumor lengths, and via Sørensen-Dice coefficients (DSC) for spatial overlap. Semiautomated volumes were constructed based on PET/CT using fixed standardized uptake values (SUV) thresholds (SUV30, 35, and 40) or background- and metabolically corrected PERCIST-TLG and Schaefer algorithms, and compared to manually delineated volumes. RESULTS: 45 cases were evaluated. Mean GTVCT and GTVPET/CT were 59.2/58.0 ml, 65.4/64.1 ml, and 60.4/59.2 ml for observers A-C. No significant difference between CT- and PET/CT-based delineation was found comparing the mean volumes or lengths. Mean Dice coefficients on CT and PET/CT were 0.79/0.77, 0.81/0.78, and 0.8/0.78 for observer pairs AB, AC, and BC, respectively, with no significant differences. Mean GTV volumes delineated semiautomatically with SUV30/SUV35/SUV40/Schaefer's and PERCIST-TLG threshold were 69.1/23.9/18.8/18.6 and 70.9 ml. The best concordance of a semiautomatically delineated structure with the manually delineated GTVCT/GTVPET/CT was observed for PERCIST-TLG. CONCLUSION: We were not able to show that the integration of PET/CT for GTV delineation of the primary tumor resulted in reduced interobserver variability. The PERCIST-TLG algorithm seemed most promising compared to other thresholds for further evaluation of semiautomated delineation of esophageal cancer.

Value of pretreatment 18F-FDG PET/CT in prognosis and the reflection of tumor burden: a study in pediatric patients with newly diagnosed neuroblastoma.

Fluorine-18 fluorodeoxyglucose (18F-FDG) PET/CT has been commonly used in pediatric patients with newly diagnosed neuroblastoma (NB) for diagnosis. We retrospectively reviewed 40 pediatric patients with newly diagnosed NB who underwent 18F-FDG PET/CT. Clinicopathological factors and metabolic parameters including maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) on PET/CT were evaluated as predictive factors for progression-free survival (PFS) and overall survival (OS) by univariate and multivariate analysis. Spearman rank correlation analyses were used to estimate the correlations between clinical factors and PET findings. The mean follow-up after 18F-FDG-PET/CT was 32.9 months. During the follow-up period 15 (37.5%) patients experienced progression, and 9 (22.5%) died. MTV (P=0.001) and TLG (p=0.004) remained significant predictive factors for tumor progression, along with lactate dehydrogenase (LDH), neuron-specific enolase (NSE) and bone metastasis. Univariate analysis showed that bone metastasis, LDH (>1064 IU/L), NSE (>364.4 ug/L), MTV (>191 cm3) and TLG (>341.41 g) correlated with PFS, and LDH (>1064 IU/L), NSE (>364.4 ug/L) and MTV (>191 cm3) correlated with OS (p<0.05). In multivariate analysis, MTV and bone metastasis were independent prognostic factors for PFS (p=0.001 and 0.023, respectively), and MTV remained the only independent prognostic factor for OS (p= 0.004). We also found that there were correlations between semiquantitative PET/CT parameters and clinical features in NB. Our results suggested that 18F-FDG PET/CT was a useful tool to predictive progression and to reflect tumor burden for patients with NB.

Prognostic Impact of Pretreatment 2-[18F]-FDG PET/CT Parameters in Primary Gastric DLBCL.

Background and Objectives: Primary gastric diffuse large-B cell lymphoma (DLBCL) is an aggressive lymphoma subtype with high 18F-FDG avidity but unclear criteria for 2-[18F]-FDG PET/CT in the evaluation of treatment response and prognostication. Our aim was to investigate whether the pretreatment 2-[18F]-FDG PET/CT variables may predict treatment response (at end of first-line therapy) and prognosis in primary gastric DLBCL. Materials and Methods: we included 57 patients with a diagnosis of primary gastric DLBCL and a baseline 2-[18F]-FDG PET/CT and an end of treatment PET/CT after 6 cycles of R-CHOP chemotherapy. We analyzed PET images qualitatively and semi-quantitatively by deriving the maximum standardized uptake value body weight (SUVbw), the maximum standardized uptake value lean body mass (SUVlbm), the maximum standardized uptake value body surface area (SUVbsa), lesion to liver SUVmax ratio (L-L SUV R), lesion to blood-pool SUVmax ratio (L-BP SUV R), metabolic tumor volume and total lesion glycolysis of gastric lesion (gMTV and gTLG), and total MTV (tMTV) and TLG. Survival curves were plotted according to the Kaplan-Meier analysis. Results: at a median follow up of 80 months, the median PFS and OS were 69 and 80 months. Baseline gMTV, gTLG, tMTV, and TLG were significantly higher in patients with incomplete response (partial response and progression) compared to complete response group. tMTV and TLG were confirmed to be independent prognostic factors both for PFS (p = 0.023 and p = 0.038) and OS (p = 0.038 and p = 0.026); instead, the other metabolic parameters were not related to outcome survival. Conclusions: high tMTV and TLG were significantly correlated with shorter survival (PFS and OS) and may predict incomplete response after therapy.

Usefulness of [18F]fluorodeoxyglucose PET/CT for evaluating the PD-L1 status in nasopharyngeal carcinoma.

PURPOSE: To explore the relationship between [18F]fluorodeoxyglucose (18F-FDG uptake) and PD-L1 expression and determine the usefulness of 18F-FDG PET/CT for evaluating the PD-L1 status in tumour cells (TCs) and tumour-infiltrating immune cells (TIICs) in patients with nasopharyngeal carcinoma (NPC). METHODS: We retrospectively evaluated the records of 84 eligible patients who received an initial histopathological diagnosis of NPC between December 2016 and March 2019. All tissue specimens and PET/CT images were collected prior to treatment. High PD-L1 expression in TCs and TIICs was defined as ≥ 50% of stained cells. RESULTS: There was a significant difference in 18F-FDG uptake according to the PD-L1 status in TCs and TIICs. Univariate analysis showed that PD-L1 expression in TCs was associated with tumour maximum standardized uptake value (SUVmax) (P < 0.001), primary tumour total lesion glycolysis (TLG; P < 0.001), and T stage (P = 0.044), but not with plasma Epstein-Barr virus (EBV) load (P = 0.816), whereas PD-L1 expression in TIICs was related to SUVmax (P = 0.011), TLG (P = 0.001), T stage (P = 0.028), and plasma EBV load (P = 0.003). In multivariate logistic regression, PD-L1 expression in TCs was positively associated with SUVmax (P = 0.003) and TLG (P = 0.001), and in TIICs, negatively associated with SUVmax (P = 0.038) and plasma EBV load (P = 0.025). CONCLUSIONS: 18F-FDG uptake in NPC lesions was positively correlated with PD-L1 expression in TCs and negatively correlated with PD-L1 expression in TIICs. Thus, 18F-FDG PET/CT may be useful for evaluating the PD-L1 status in patients with NPC.

Low metabolic activity in primary gastric adenocarcinoma is associated with resistance to chemoradiation and the presence of signet ring cells.

PURPOSES: Preoperative chemoradiation is a potential treatment option for localized gastric adenocarcinoma (GAC). Currently, the response to chemoradiation cannot be predicted. We analyzed the pretreatment maximum standardized uptake value (SUVmax) and total lesion glycolysis (TLG) on positron emission tomography/computed tomography as potential predictors of the response to chemoradiation. METHODS: We analyzed the SUVmax and TLG data from 59 GAC patients who received preoperative chemoradiation. We used logistic regression models to predict a pathologic complete response (pCR) and Kaplan-Meier curves to determine overall survival among patients with high and low SUVmax or TLG. RESULTS: Twenty-nine patients (49%) had Siewert type III adenocarcinoma and 30 (51%) had tumors located in the lower stomach. Forty-one patients had poorly differentiated GAC, and 26 had signet ring cells. The median SUVmax was 7.3 (0-28.2) and the median TLG was 56.6 (0-1881.5). Patients with signet ring cells had a low pCR rate, as well as a low SUVmax and TLG. In the multivariable logistic regression model, high SUVmax was a predictor of pCR (odds ratio = 11.1, 95% confidence interval = 2.12-50.0, p = 0.004). Overall survival was not associated with the SUVmax (log-rank p = 0.69) or TLG (log-rank p = 0.85) CONCLUSION: A high SUVmax was associated with sensitivity to chemoradiation and pCR in GAC, and signet ring cells seemed to confer resistance.

The relationship between FDG PET/CT-defined metabolic parameters and the histopathological subtype of oesophageal carcinomas.

PURPOSE: 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) combined with computed tomography (CT) scan is accepted as a standard tool in the staging of oesophageal cancer (OC). Histological subtype of tumour is known to be a major determinant of prognosis and metabolic behaviour. In this study, we aimed to evaluate the effect of histological subtypes of OC on standard uptake value (SUVmax), metabolic tumour volume (MTV), and total lesion glycolysis (TLG) obtained by PET/CT, and also to compare this effect with prognosis. MATERIAL AND METHODS: Images and clinical course data of 57 patients who were diagnosed with EC and treated in our hospital between 2009 and 2016 were evaluated in a retrospective manner. PET/CT images were re-analysed in terms of metabolic parameters, and observations were compared with histological subtypes. RESULTS: No significant difference was observed between histological subtypes with SUVmax, overall survival (OS), or progression-free survival (PFS). Thus, MTV was observed to be related with histological subtype; MTV values of adenocancer patients were significantly higher than those of squamous cell cancer patients. CONCLUSIONS: Metabolic tumour volume was related with histological subtype of OC, but clinical staging, TLG, and SUVmax values were not related with histological subtype, which may suggest the use of MTV as a routine parameter for OC and inclusion of MTV observations in prognostic scoring.

Prognostic role of baseline 18F-FDG PET/CT metabolic parameters in Burkitt lymphoma.

PURPOSE: Burkitt's lymphoma (BL) is an aggressive lymphoma subtype with high 18F-FDG avidity at 18F-FDG-PET/CT, but no validated criteria for PET/CT in treatment evaluation or prediction of outcome in BL are available. The aim of our study was to investigate whether the metabolic baseline PET/CT parameters can predict treatment response and prognosis in BL. MATERIALS AND METHODS: We retrospectively enrolled 65 patients who underwent baseline 18F-FDG-PET/CT, interim and end of treatment PET/CT. The PET images were analyzed visually and semi-quantitatively by measuring the maximum standardized uptake value body weight (SUVbw), the maximum standardized uptake value lean body mass (SUVlbm), the maximum standardized uptake value body surface area (SUVbsa), lesion to liver SUVmax ratio (L-L SUV R), lesion to blood-pool SUVmax ratio (L-BP SUV R), total metabolic tumor volume (tMTV) and total lesion glycolysis (TLG). Survival curves were plotted according to the Kaplan-Meier method. RESULTS: At a median follow-up of 40 months, the median PFS and OS were 34 and 39 months. MTV and TLG were significantly higher in patients with partial response compared to complete response group at end of treatment, while no significant differences were found at interim. Other metabolic PET/CT parameters were not related to treatment response. MTV and TLG were demonstrated to be independent prognostic factors for both PFS and OS; instead SUVbw, SUVlbm, SUVbsa, L-L SUV R and L-BP SUV R were not related to outcome survival. CONCLUSIONS: Metabolic tumour features (MTV and TLG) were significantly correlated with response to treatment and long-term outcome.

Metabolic tumor burden on baseline 18F-FDG PET/CT improves risk stratification in pediatric patients with mature B-cell lymphoma.

PURPOSE: In order to better identify patients most at risk of treatment failure and disease progression in pediatric mature B-cell non-Hodgkin lymphoma (B-NHL), the prognostic role of metabolic tumor burden measured on baseline 18F-FDG PET/CT scan, including total metabolic tumor volume (TMTV) and total lesion glycolysis (TLG), was investigated. METHODS: Pretreatment 18F-FDG PET/CT scans from 46 consecutive pediatric patients (median age 7 years; range 2-18 years) with newly diagnosed B-NHL were retrospectively analyzed. Clinicopathological parameters and imaging characteristics, including TMTV, TLG, and bone marrow (BM) involvement detected by PET/CT were compared to predict progression-free survival (PFS) and overall survival (OS). RESULTS: The median follow-up time was 31 months. Areas under the curve of TMTV and TLG to predict events were 0.820 and 0.816, respectively. The 2-year PFS and OS were 29% and 43% in 7 patients with high TLG (> 5797 g) vs. 93% and 96% in those with low TLG (P < 0.001). High TMTV (> 524 cm3) was present in ten patients and predicted a significantly inferior outcome (PFS: 50% vs. 92%, P = 0.001; OS: 60% vs. 96%, P = 0.002). In multivariate analysis, TMTV and TLG outperformed other clinicopathological factors, including serum lactate dehydrogenase and BM involvement on biopsy, and remained the most robust predictors of survival. Furthermore, TLG sub-stratified patients with distinct outcomes efficiently within high- or intermediate-risk groups, with the negative predictive value of 100% and 92% and the positive predictive value of 100% and 50% for high-risk and intermediate-risk patients, respectively. On the other hand, BM involvement identified only by PET demonstrated an inferior prognostic value in comparison with BM biopsy. CONCLUSIONS: Baseline TMTV and TLG are both strong independent prognostic factors for pediatric B-NHL and provide a potential approach to aid in risk sub-stratification, especially in patients with high-risk disease.

Prognostic role of baseline 18 F-FDG PET/CT parameters in MALT lymphoma.

Mucosa-associated lymphoid tissue (MALT) lymphoma is an indolent lymphoma with good prognosis and variable fluorine-18 fluorodeoxyglucose (18 F-FDG) avidity. Many possible prognostic factors have been investigated with controversial results, but the possible prognostic role of 18 F-FDG positron emission tomography/computed tomography (PET/CT) remains unclear. Our aim was to evaluate the prognostic impact of qualitative and semiquantitative baseline PET/CT parameters on outcome of MALT lymphoma. We retrospectively enrolled 161 patients with histologically confirmed MALT lymphoma who underwent 18 F-FDG PET/CT before any treatment. PET images were qualitatively and semiquantitatively analyzed by measuring the maximum standardized uptake value body weight (SUVbw), lean body mass (SUVlbm), body surface area (SUVbsa), metabolic tumor volume (MTV), and total lesion glycolysis (TLG). The Kaplan-Meier method was used to estimate the progression-free survival (PFS) and overall survival (OS) times. Cox regression models were performed to determine the relation between PET/CT features and OS and PFS. Ninety-eight patients had positive 18 F-FDG PET/CT showing 18 F-FDG uptake (mean SUVbw, 10.1; SUVlbm, 7.2; SUVbsa, 2.7; MTV, 88.8; and TLG, 526); the remaining 63 were not 18 F-FDG avid. 18 F-FDG avidity was significantly correlated with tumor size and Ki-67 score. Relapse/progression of disease occurred in 47 patients with an average time of 40.2 months; death occurred in 12 patients with an average of 59 months. At a median follow-up of 62 months, median PFS and OS were 52 and 62 months, respectively. Advanced tumor stage and extragastric site were demonstrated to be independent prognostic factors for PFS, while only tumor stage for OS. Instead, PET/CT parameters were not related to survival, despite positive correlation at univariate analysis between MTV and TLG with PFS and positive PET/CT with PFS and OS. In conclusion, a 61% rate of PET avidity in biopsy-confirmed MALT lymphoma was found, and it was correlated with tumor size and Ki-67 score. Only tumor stage and localization were independently correlated with PFS and OS.

FDG PET-derived parameters as prognostic tool in progressive malignant pleural mesothelioma treated patients.

PURPOSE: The value of FDG PET-derived parameters in predicting overall survival (OS), local relapse-free survival (LRFS) and distant relapse-free survival (DRFS) in treated patients with malignant pleural mesothelioma (MPM) was evaluated. METHODS: This retrospective evaluation included 55 MPM patients treated between March 2006 and February 2015 with FDG PET/CT-guided salvage helical tomotherapy (HTT) after previous surgery plus chemotherapy. Univariate Cox regression analysis was performed to assess the impact of the following FDG PET-derived parameters: biological target volume (BTV), mean and maximum standardized uptake values (SUVmean/max), metabolic tumour volume (MTV) and total lesion glycolysis (TLG), measured using different uptake thresholds (40%, 50% and 60%). Logistic regression was then performed to identify the best FDG PET-derived parameters for selecting patients with poorer survival. RESULTS: The median OS was 9.1 months (range 0.0 - 69.6 months) after the end of HTT; 54/55 patients were dead at the last follow-up. BTV and TLG40, TLG50 and TLG60 were the most significant predictors of OS (p < 0.005). The median OS was 4.8 months in patients with MTV60 >5 cm3 and TLG40 >334.4, compared with 13.8 months and 16.1 months in patients with smaller values, respectively. The median LRFS and DRFS were 6.2 months (range 1.2 - 39.4 months) and 6.5 months (0.0 - 66.4 months), respectively. TLG40, TLG50 and TLG60 were significantly correlated with LRFS (p < 0.015). Median DRFS was 6.4 months in patients with MTV40 >39.6 cm3 and 6.2 months in patients with TLG40 >334.4, compared with 17 months and 18.8 months in patients with smaller values. BTV, TLG40 and MTV40 were also found to be good predictors in patients with poor OS/LRFS/DRFS (median survival times less than the median values). CONCLUSION: FDG PET-derived parameters effectively discriminated patients with a poor prognosis and may be helpful in the selection of MPM patients for salvage HTT.

The role of F-18 FDG PET/CT in evaluating the impact of HIV infection on tumor burden and therapy outcome in patients with Hodgkin lymphoma.

BACKGROUND: To evaluate the impact of HIV infection on tumor burden and therapy outcome following treatment with chemotherapy in patients with Hodgkin lymphoma. METHODS: A total of 136 patients with classical Hodgkin lymphoma were studied (mean age ± SD = 32.31 ± 1.39 years, male = 86, female = 50). Advanced disease (stage III and IV) was present in 64% of patients. HIV infection was present in 57 patients while 79 patients were HIV-negative. Baseline F-18 FDG PET/CT was obtained in all patients. SUVmax, MTV and TLG were determined on the baseline scan to evaluate for tumor burden. All patients completed a standard regimen of adriamycin, bleomycin, vinblastine and dacarbazine (ABVD). After a median period of 8 weeks (range = 6 to 17 weeks), a repeat F-18 FDG PET/CT scan was obtained to evaluate response to therapy using Deauville 5-point scoring system. RESULTS: The HIV-positive and HIV-negative groups were similar with regards to age and disease stage. The groups were heterogeneous with respect to gender (p = 0.029). The SUVmax, MTV and TLG of lesions were not significant different between the two groups. Complete response was seen in 72.8% of the study population. Presence of HIV infection was associated with higher rate of treatment failure with 40.4% of the HIV-positive patients having treatment failure while only 17.7% of the HIV-negative patients had treatment failure (p = 0.0034). HIV infection was a significant predictor of response to chemotherapy. Effects of SUVmax, MTV, TLG and Ann Arbor stage of the disease were not statistically significant as predictors of therapy outcome. In a multiple logistic regression, presence of HIV infection still remained an independent predictor of therapy outcome in the presence of other factors such as SUVmax, MTV, TLG and the Ann Arbor stage of the disease. CONCLUSIONS: HIV infection is not associated with a higher tumor burden in patients with Hodgkin lymphoma. HIV infection is, however, a strong predictor of poor therapy outcome in patients treated with standard regimen of ABVD.