Early response monitoring during [177Lu]Lu-PSMA I&T therapy with quantitated SPECT/CT predicts overall survival of mCRPC patients: subgroup analysis of a Swiss-wide prospective registry study.

PURPOSE: To assess early tumor response with quantitated SPECT/CT and to correlate it with clinical outcome in metastatic castration-resistant prostate cancer (mCRPC) patients treated with 177Lutetium-PSMA I&T therapy. METHODS: Single-center, observational study, part of the prospective Swiss national cancer registry study investigating the safety and efficacy of [177Lu]Lu-PSMA I&T (EKNZ: 2021-01271) in mCRPC patients treated with at least two cycles of [177Lu]Lu-PSMA I&T 6-weekly. After the first and second cycle quantitated SPECT/CT (Symbia Intevo, Siemens) was acquired 48 h after injection (three fields of view from head to thigh, 5 s/frame) and reconstructed using xQuant® (48i, 1 s, 10-mm Gauss). Image analysis: The PSMA-positive total tumor volumes (TTV) were semi-automatically delineated using a SUV threshold of 3 with MIMencore® (version 7.1.3, Medical Image Merge Software Inc.). Changes in TTV, highest tumor SUVmax, and total tumor SUVmean between cycles 1 and 2 were calculated and grouped into a) stable or decrease and b) increase. Serum PSA levels were assessed at each therapy cycle and at follow-up until progression or death. Changes in TTV, PSA, SUVmax, and SUVmean were correlated with PSA-progression-free survival (PSA-PFS) and the overall survival (OS) using the Kaplan-Meier methodology (log-rank test). RESULTS: Between 07/2020 and 04/2022, 111 patients were screened and 73 finally included in the data analysis. The median follow-up was 8.9 months (range 1.4-26.6 months). Stable or decreased TTV at cycle 2 was associated with longer OS (hazard ratio (HR) 0.28, 95% confidence interval (CI) 0.09-0.86, p < 0.01). Similar, stable, or decreased PSA was associated with longer OS (HR 0.21; CI 0.07-0.62, p < 0.01) and PSA-PFS (HR 0.34; 95% CI 0.16-0.72, p < 0.01). Combining TTV and PSA will result in an augmented prognostic value for OS (HR 0.09; CI 0.01-0.63; p < 0.01) and for PSA-PFS (HR 0.11; CI 0.02-0.68; p < 0.01). A reduction of SUVmax or SUVmean was not prognostically relevant, neither for OS (p 0.88 and 0.7) nor for PSA-PFS (p 0.73 and 0.62, respectively). CONCLUSION: Six weeks after initiating [177Lu]Lu-PSMA I&T, TTV and serum PSA appear to be good prognosticators for OS. Combined together, TTV + PSA change demonstrates augmented prognostic value and can better predict PSA-PFS. Larger studies using TTV change prospectively as an early-response biomarker are warranted for implementing management change towards a more personalized clinical practice.

Effect of high-dose glucocorticoid treatment on human brown adipose tissue activity: a randomised, double-blinded, placebo-controlled cross-over trial in healthy men.

BACKGROUND: Glucocorticoids (GCs) are widely applied anti-inflammatory drugs that are associated with adverse metabolic effects including insulin resistance and weight gain. Previous research indicates that GCs may negatively impact brown adipose tissue (BAT) activity in rodents and humans. METHODS: We performed a randomised, double-blinded cross-over trial in 16 healthy men (clinicaltrials.govNCT03269747). Participants received 40 mg of prednisone per day for one week or placebo. After a washout period of four weeks, participants crossed-over to the other treatment arm. Primary endpoint was the increase in resting energy expenditure (EE) in response to a mild-cold stimulus (cold-induced thermogenesis, CIT). Secondary outcomes comprised mean 18F-FDG uptake into supraclavicular BAT (SUVmean) as determined by FDG-PET/CT, volume of the BAT depot as well as fat content determined by MRI. The plasma metabolome and the transcriptome of supraclavicular BAT and of skeletal muscle biopsies after each treatment period were analysed. FINDINGS: Sixteen participants were recruited to the trial and completed it successfully per protocol. After prednisone treatment resting EE was higher both during warm and cold conditions. However, CIT was similar, 153 kcal/24 h (95% CI 40-266 kcal/24 h) after placebo and 186 kcal/24 h (95% CI 94-277 kcal/24 h, p = 0.38) after prednisone. SUVmean of BAT after cold exposure was not significantly affected by prednisone (3.36 g/ml, 95% CI 2.69-4.02 g/ml, vs 3.07 g/ml, 95% CI 2.52-3.62 g/ml, p = 0.28). Results of plasma metabolomics and BAT transcriptomics corroborated these findings. RNA sequencing of muscle biopsies revealed higher expression of genes involved in calcium cycling. No serious adverse events were reported and adverse events were evenly distributed between the two treatments. INTERPRETATION: Prednisone increased EE in healthy men possibly by altering skeletal muscle calcium cycling. Cold-induced BAT activity was not affected by GC treatment, which indicates that the unfavourable metabolic effects of GCs are independent from thermogenic adipocytes. FUNDING: Grants from Swiss National Science Foundation (PZ00P3_167823), Bangerter-Rhyner Foundation and from Nora van der Meeuwen-Häfliger Foundation to MJB. A fellowship-grant from the Swiss National Science Foundation (SNF211053) to WS. Grants from German Research Foundation (project number: 314061271-TRR 205) and Else Kröner-Fresenius (grant support 2012_A103 and 2015_A228) to MR.

3D-Quantitated Single Photon Emission Computed Tomography/Computed Tomography: Impact on intended Management Compared to Lung Perfusion Scan in Marginal Candidates for Pulmonary Resection.

OBJECTIVES: Based on previous studies, single-photon emission computed tomography/computed tomography (SPECT/CT) has been proven more accurate and reproducible than planar lung perfusion scintigraphy to assess lobar perfusion. However, the impact of 3D-quantitated SPECT/CT on intended management in functionally marginal candidates for pulmonary resection is unknown. The evaluation of this impact was the main aim of this study. METHODS: Consecutive candidates for lung resection underwent preoperative evaluation according to ERS/ESTS Algorithm and underwent preoperative lung perfusion imaging. The lobar contribution to the total lung perfusion was estimated using established planar scintigraphic methods and 3-dimensional quantitative SPECT/CT method (CT Pulmo3D and xSPECT-Quant, Siemens). The difference in estimated lobar perfusion with resulting changes in predicted postoperative (ppo) lung function and extent of lung resection were analyzed to reveal possible changes in operability. In-hospital outcome was assessed. RESULTS: One hundred twenty patients (46 females) were enrolled. The mean age (±SD) of patients was 68 ± 9 years, target lesions were in upper lobes in 57.7% and in lower lobes in 33.5%. The median FEV1 (forced expiratory volume in 1 second) was 70.5% (IQR 52-84) and median DLCO (diffusion capacity of lung for carbon monoxide) was 56.6% [47.1-67.4]. The planar posterior oblique method, compared to 3D-quantitated SPECT/CT, underestimated the perfusion of upper lobes by a median difference of 5% (right [2-9], left [2.5-8]; P = <.0001), while it overestimated the perfusion of lower lobes (left by 4% [2-7], right by 6% [2-9]; P = <.0001). In contrast to planar scintigraphy-based evaluation, 4 patients (3.3%), all with upper lobe lesions, were classified as inoperable when 3D-quantitated SPECT/CT was used for calculation of the ppo lung function. CONCLUSIONS: In selected patients with upper lobe lesions, 3D-quantitated SPECT/CT would have changed the treatment strategy from operable to inoperable. Importantly, postoperative mortality in this particular subgroup was disproportionally high. 3D-quantitated SPECT/CT shall be further evaluated as it might improve preoperative risk stratification in functionally marginal candidates.

Cell-Free DNA Genomic Profiling and Its Clinical Implementation in Advanced Prostate Cancer.

Most men with prostate cancer (PCa), despite potentially curable localized disease at initial diagnosis, progress to metastatic disease. Despite numerous treatment options, choosing the optimal treatment for individual patients remains challenging. Biomarkers guiding treatment sequences in an advanced setting are lacking. To estimate the diagnostic potential of liquid biopsies in guiding personalized treatment of PCa, we evaluated the utility of a custom-targeted next-generation sequencing (NGS) panel based on the AmpliSeq HD Technology. Ultra-deep sequencing on plasma circulating free DNA (cfDNA) samples of 40 metastatic castration-resistant PCa (mCRPC) and 28 metastatic hormone-naive PCa (mCSPC) was performed. CfDNA somatic mutations were detected in 48/68 (71%) patients. Of those 68 patients, 42 had matched tumor and cfDNA samples. In 21/42 (50%) patients, mutations from the primary tumor tissue were detected in the plasma cfDNA. In 7/42 (17%) patients, mutations found in the primary tumor were not detected in the cfDNA. Mutations from primary tumors were detected in all tested mCRPC patients (17/17), but only in 4/11 with mCSPC. AR amplifications were detected in 12/39 (31%) mCRPC patients. These results indicate that our targeted NGS approach has high sensitivity and specificity for detecting clinically relevant mutations in PCa.

Role of 18F-FDG PET/CT in the postoperative follow-up in patients with stage I-III NSCLC: A retrospective single-institution study.

BACKGROUND: The optimal surveillance strategy in patients with resected non-small cell lung cancer (NSCLC) is unknown. Early detection of recurrences by follow-up imaging might improve survival and whole-body 18F-FDG-PET/CT might be the optimal imaging modality given its high accuracy in preoperative staging. MATERIAL AND METHODS: Data from a single-center cohort of 205 patients with resected stage I-III NSCLC and FDG-PET/CT surveillance was retrospectively collected. Patients had preoperative FDG-positive tumors and FDG-PET/CT at 6, 12, 24 months, chest CT at 18 months. Thereafter, annual chest CT was performed for stage I-II, annual FDG-PET/CT for stage III. RESULTS: With a median follow-up of 26.3 months (range, 4.1-60.6), the rate for recurrence and secondary primary lung cancer (SPLC) was 22 % and 8 %, respectively. Associated symptoms were present in 48 % (recurrence) and 18 % (SPLC) of patients. Overall, 83 % of recurrences, and 65 % of SPLC were detected on FDG-PET/CT. 82 % of recurrences were detected in one of the first two follow-up PET/CT scans. Second curatively intended treatment (SCIT) was possible in 37 % of patients with recurrence and 100 % with SPLC. The 2-year recurrence-free survival rate after SCIT for recurrence was 53 % [95 %CI; 31-91 %]. Non-malignant FDG-positive findings occurred in 25 % of patients (71 % possible infections). CONCLUSION: In our cohort of patients, more than 80% of all recurrences were identified in one of the three FDG-PET/CTs performed as part of our imaging protocol during the first two years after resection. Nearly all patients with non-distant recurrence qualified for a SCIT. Further studies are needed to identify patients who might benefit from an even more intensive surveillance strategy.

Prognostic value of baseline metabolic tumor volume in children and adolescents with intermediate-risk Hodgkin lymphoma treated with chemo-radiation therapy: FDG-PET parameter analysis in a subgroup from COG AHOD0031.

BACKGROUND: Positron emission tomography (PET)-based measures of baseline total-body tumor burden may improve risk stratification in intermediate-risk Hodgkin lymphoma (HL). MATERIALS AND METHODS: Evaluable patients were identified from a cohort treated homogeneously with the same combined modality regimen on the Children's Oncology Group AHOD0031 study. Eligible patients had high-quality baseline PET scans. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were each measured based on 15 thresholds for every patient. Univariate and multivariable Cox regression and Kaplan-Meier survival analyses assessed for an association of MTV and TLG with event-free survival (EFS). RESULTS: From the AHOD0031 cohort (n = 1712), 86 patients were identified who (i) were treated with four cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone, cyclophosphamide (ABVE-PC) chemotherapy followed by involved field radiotherapy, and (ii) had a baseline PET scan that was amenable to quantitative analysis. Based on univariate Cox regression analysis, six PET-derived parameters were significantly associated with EFS. For each of these, Kaplan-Meier analyses and the log-rank test were used to compare patients with highest tumor burden (i.e., highest 15%) to the remainder of the cohort. EFS was significantly associated with all six PET parameters (all p < .029). In a multivariable model controlling for important covariates including disease bulk and response to chemotherapy, MTV2BP was significantly associated with EFS (p = .012). CONCLUSION: Multiple baseline PET-derived volumetric parameters were associated with EFS. MTV2BP was highly associated with EFS when controlling for disease bulk and response to chemotherapy. Incorporation of baseline MTV into risk-based treatment algorithms may improve outcomes in intermediate-risk HL.

Comparison of [18F]FDG PET/CT with magnetic resonance imaging for the assessment of human brown adipose tissue activity.

BACKGROUND: Brown adipose tissue (BAT) is a thermogenic tissue which can generate heat in response to mild cold exposure. As it constitutes a promising target in the fight against obesity, we need reliable techniques to quantify its activity in response to therapeutic interventions. The current standard for the quantification of BAT activity is [18F]FDG PET/CT. Various sequences in magnetic resonance imaging (MRI), including those measuring its relative fat content (fat fraction), have been proposed and evaluated in small proof-of-principle studies, showing diverging results. Here, we systematically compare the predictive value of adipose tissue fat fraction measured by MRI to the results of [18F]FDG PET/CT. METHODS: We analyzed the diagnostic reliability of MRI measured fat fraction (FF) for the estimation of human BAT activity in two cohorts of healthy volunteers participating in two prospective clinical trials (NCT03189511, NCT03269747). In both cohorts, BAT activity was stimulated by mild cold exposure. In cohort 1, we performed [18F]FDG PET/MRI; in cohort 2, we used [18F]FDG PET/CT followed by MRI. Fat fraction was determined by 2-point Dixon and 6-point Dixon measurement, respectively. Fat fraction values were compared to SUVmean in the corresponding tissue depot by simple linear regression. RESULTS: In total, 33 male participants with a mean age of 23.9 years and a mean BMI of 22.8 kg/m2 were recruited. In 32 participants, active BAT was visible. On an intra-individual level, FF was significantly lower in high-SUV areas compared to low-SUV areas (cohort 1: p < 0.0001 and cohort 2: p = 0.0002). The FF of the supraclavicular adipose tissue depot was inversely related to its metabolic activity (SUVmean) in both cohorts (cohort 1: R2 = 0.18, p = 0.09 and cohort 2: R2 = 0.42, p = 0.009). CONCLUSION: MRI FF explains only about 40% of the variation in BAT glucose uptake. Thus, it can currently not be used to substitute [18F] FDG PET-based imaging for quantification of BAT activity. TRIAL REGISTRATION: ClinicalTrials.gov. NCT03189511 , registered on June 17, 2017, actual study start date was on May 31, 2017, retrospectively registered. NCT03269747 , registered on September 01, 2017.

Simplified dual time point FDG-PET/computed tomography for determining dignity of pancreatic lesions.

BACKGROUND: Predicting the dignity of pancreatic lesions is still a diagnostic challenge. The differentiation between benign changes in chronic pancreatitis from pancreatic cancer remains difficult. Therefore, the aim of this study was to evaluate whether early dual time point kinetics of pancreatic lesions in 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) may be helpful to differentiate pancreatic lesions. METHODS: We prospectively analyzed 64 patients (pancreatic cancer n = 45 and chronic pancreatitis n = 19) scheduled for dual time point FDG-PET/computed tomography scan for pancreatic lesions from 2005 to 2014. Studies were performed 60 and 90 minutes after application of F-FDG. Histological samples were collected for all patients, either by resection or by biopsy. Semiquantitative analysis was performed using the minimum, the maximum, and the average standardized uptake value (SUV) from the two different sets of images. To increase sensitivity and specificity, a formula addressing the weighting of standardized uptake values was created. RESULTS: With a sensitivity of 82.6%, specificity of 77.8%, accuracy of 79.7%, positive predictive value of 90.5%, and negative predictive value of 63.6% SUVmax@time1 > 3.45 was the most reliable single quantitative parameter for malignancy of the pancreatic lesions. Weighting of standardized uptake values produced a formula that showed an even better profile. CONCLUSIONS: In patients with suspicious pancreatic lesions, the simplified dual time point FDG-PET/computed tomography may represent a valuable diagnostic tool in characterizing pancreatic lesions.

Validation of different PSMA-PET/CT-based contouring techniques for intraprostatic tumor definition using histopathology as standard of reference.

PURPOSE: Accurate definition of the intraprostatic gross tumor volume (GTV) is crucial for diagnostic and therapeutic approaches in patients with primary prostate cancer (PCa). The optimal methodology for contouring of GTV using Prostate specific membrane antigen positron emission tomography (PSMA-PET) information has not yet been defined. METHODS AND MATERIALS: PCa patients who underwent a [68Ga]PSMA-11-PET/CT followed by radical prostatectomy were prospectively enrolled (n = 20). Six observer teams with different levels of experience and using different PET image scaling techniques performed manual contouring of GTV. Additionally, semi-automatic segmentation of GTVs was performed using SUVmax thresholds of 20-50%. Coregistered histopathological gross tumor volume (GTV-Histo) served as reference. Inter-observer agreement was assessed by calculating the Dice similarity coefficient (DSC). RESULTS: Most contouring methods provided high sensitivity and specificity. For manual delineation, scaling the PET images from SUVmin-max: 0-5 resulted in high sensitivity (>86%). The highest specificity (100%) was obtained by scaling the PET images from SUVmin-max: 0-SUVmax. High interobserver agreement (median DSC 0.8) was observed when using the same PET image scaling technique (PET images SUVmin-max: 0-5). For semi-automatic segmentation, a low SUVmax threshold of 20% optimized sensitivity (SUVmax threshold 20%, 100% sensitivity, 32% of prostatic volume), whereas a higher threshold optimized specificity (SUVmax threshold 40%-50%, 100% specificity). CONCLUSIONS: Contouring of regions with high tracer-uptake resulted in very high specificities and should be used for biopsy guidance. Both manual and semi-automatic approaches using validated SUV scaling (SUVmin-max: 0-5) or thresholding (20%) may provide high sensitivity, and should be considered for PSMA-PET-based focal therapy approaches.

Quantitative PET/CT in clinical practice: assessing the agreement of PET tumor indices using different clinical reading platforms.

OBJECTIVE: The aim of this study was to determine whether various fluorine-18-fluorodeoxyglucose PET/CT-derived parameters used in oncology vary significantly depending on the interpretation software systems used in clinical practice for multiple human solid tumors. PATIENTS AND METHODS: A total of 120 fluorine-18-fluorodeoxyglucose PET/CT studies carried out in patients with pancreatic, lung, colorectal, and head and neck cancers were evaluated retrospectively on two different vendor software platforms including Mirada and MIMVista. Regions of interest were placed on the liver to determine the liver mean standardized uptake value at lean body mass (SUL) and on each tumor to determine the SULmax, SULpeak. Total lesion glycolysis (TLG) and metabolic tumor volume (MTV) were determined using fixed thresholds of 50% of SULmax and SULpeak. Inter-reader, intersystem intraclass correlations, systematic bias, and variability reflected by the 95% limits of agreement, and precision were determined. RESULTS: There was excellent inter-reader reliability between the readers and the two software systems, with intraclass correlations more than 0.9 for all PET metrics, with P values less than 0.0001. The bias and SD on Bland-Altman analysis between the two software platforms for tumor SULmax, SULpeak, Max50MTV, and Peak50MTV, respectively, for Reader 1 were -1.52±2.24, 0.80±3.67, -0.80±13.01, and -4.49±20.6. For Reader 2, the biases were -1.62±1.95, 0.18±3.60, -0.27±4.64, and -3.13±8.30. The precision between the two systems was better for SULmax and SULpeak, with less variance observed, than for volume-based metrics such as Max50MTV and Peak50MTV or TLG. CONCLUSION: Excellent correlation has been found between two tested software reading platforms for all PET-derived metrics in a dual-reader analysis. Overall, the SULmax and SULpeak values had less bias and better precision compared with the MTV and TLG.

Prediction of Response to Immune Checkpoint Inhibitor Therapy Using Early-Time-Point 18F-FDG PET/CT Imaging in Patients with Advanced Melanoma.

The purpose of this study was to evaluate 18F-FDG PET/CT scanning as an early predictor of response to immune checkpoint inhibitors (ICIs) in patients with advanced melanoma. Methods: Twenty patients with advanced melanoma receiving ICI prospectively underwent 18F-FDG PET/CT at 3 scan intervals: before treatment initiation (SCAN-1), at days 21-28 (SCAN-2), and at 4 mo (SCAN-3). This study was approved by the institutional review board, and informed consent was received from all patients who were enrolled between April 2012 and December 2013. Tumor response at each posttreatment time point was assessed according to RECIST 1.1, immune-related response criteria, PERCIST (PERCIST 1.0), and European Organization for Research and Treatment of Cancer (EORTC) criteria. Performance characteristics of each metric to predict best overall response (BOR) at ≥ 4 mo were assessed. Results: Twenty evaluable patients were treated with ipilimumab (n = 16), BMS-936559 (n = 3), or nivolumab (n = 1). BOR at ≥ 4 mo included complete response (n = 2), partial response (n = 2), stable disease (n = 1), and progressive disease (n = 15). Response evaluations at SCAN-2 using RECIST 1.1, immune-related response criteria, PERCIST, and EORTC criteria demonstrated accuracies of 75%, 70%, 70%, and 65%, respectively, to predict BOR at ≥ 4 mo. Interestingly, the optimal PERCIST and EORTC threshold values at SCAN-2 to predict BOR were >15.5% and >14.7%, respectively. By combining anatomic and functional imaging data collected at SCAN-2, we developed criteria to predict eventual response to ICI with 100% sensitivity, 93% specificity, and 95% accuracy. Conclusion: Combining functional and anatomic imaging parameters from 18F-FDG PET/CT scans performed early in ICI appears predictive for eventual response in patients with advanced melanoma. These findings require validation in larger cohorts.

(68)Ga-HBED-CC-PSMA PET/CT Versus Histopathology in Primary Localized Prostate Cancer: A Voxel-Wise Comparison.

PURPOSE: We performed a voxel-wise comparison of (68)Ga-HBED-CC-PSMA PET/CT with prostate histopathology to evaluate the performance of (68)Ga-HBED-CC-PSMA for the detection and delineation of primary prostate cancer (PCa). METHODOLOGY: Nine patients with histopathological proven primary PCa underwent (68)Ga-HBED-CC-PSMA PET/CT followed by radical prostatectomy. Resected prostates were scanned by ex-vivo CT in a special localizer and histopathologically prepared. Histopathological information was matched to ex-vivo CT. PCa volume (PCa-histo) and non-PCa tissue in the prostate (NPCa-histo) were processed to obtain a PCa-model, which was adjusted to PET-resolution (histo-PET). Each histo-PET was coregistered to in-vivo PSMA-PET/CT data. RESULTS: Analysis of spatial overlap between histo-PET and PSMA PET revealed highly significant correlations (p < 10(-5)) in nine patients and moderate to high coefficients of determination (R²) from 42 to 82 % with an average of 60 ± 14 % in eight patients (in one patient R(2) = 7 %). Mean SUVmean in PCa-histo and NPCa-histo was 5.6 ± 6.1 and 3.3 ± 2.5 (p = 0.012). Voxel-wise receiver-operating characteristic (ROC) analyses comparing the prediction by PSMA-PET with the non-smoothed tumor distribution from histopathology yielded an average area under the curve of 0.83 ± 0.12. Absolute and relative SUV (normalized to SUVmax) thresholds for achieving at least 90 % sensitivity were 3.19 ± 3.35 and 0.28 ± 0.09, respectively. CONCLUSIONS: Voxel-wise analyses revealed good correlations of (68)Ga-HBED-CC-PSMA PET/CT and histopathology in eight out of nine patients. Thus, PSMA-PET allows a reliable detection and delineation of PCa as basis for PET-guided focal therapies.

Use of standardized uptake value thresholding for target volume delineation in pediatric Hodgkin lymphoma.

PURPOSE: A limitation of [(18)F] 2-fluoro-2-deoxy-d-glucose positron emission tomography (FDGPET) in radiation planning for Hodgkin lymphoma (HL) is significant variability in delineation of tumor volume. One approach to reduce variability is to apply automatic or semiautomatic segmentation methods such as thresholding based on a percent tumor maximum standardized uptake value (SUVmax). Here, we apply various tumor SUVmax thresholds and examine their effects in involved field radiation therapy (IFRT) and involved site radiation therapy (ISRT) target volumes. METHODS AND MATERIALS: PET/computed tomography data sets were reviewed for 16 pediatric and young adult patients treated with IFRT. The following percent tumor SUVmax thresholds were applied to the prechemotherapy PET: 15%, 20%, 25%, 30%, 35%, and 40%. Clinical target volumes for IFRT and ISRT plans were manually generated based on these threshold volumes (CTVPET) and compared with clinical target volumes generated using the standard qualitative visual method (CTVQVM). Treatment plans were generated, doses to normal structures were compared, and the optimum threshold, defined as the CTVPET that corresponded to the percent overlap closest to 100% when compared with the CTVQVM, was determined. RESULTS: On average, there was a 7.6-fold increase in PET volume between 40% and 15% SUVmax. When the 6 SUVmax thresholds were applied in the design of target volumes for IFRT, 2 of 16 patients had a change in treatment volume. There was a 2.4-fold increase in ISRT CTVs generated based on the 15% and 40% SUVmax, which translated into a clinically significant decrease in dose to normal structures when the ISRT plans that were generated using the 15% SUVmax volumes were compared with the 40% SUVmax. In most patients, the optimum threshold was SUVmax 15%. CONCLUSIONS: Accurate target volume delineation with [(18)F] 2-fluoro-2-deoxy-d-glucose PET in HL is challenging and may require more precise and reproducible segmentation methods as we move toward more conformal therapies.

Impact of 4D-(18)FDG-PET/CT imaging on target volume delineation in SBRT patients with central versus peripheral lung tumors. Multi-reader comparative study.

PURPOSE: Evaluation of the effect of co-registered 4D-(18)FDG-PET/CT for SBRT target delineation in patients with central versus peripheral lung tumors. METHODS: Analysis of internal target volume (ITV) delineation of central and peripheral lung lesions in 21 SBRT-patients. Manual delineation was performed by 4 observers in 2 contouring phases: on respiratory gated 4DCT with diagnostic 3DPET available aside (CT-ITV) and on co-registered 4DPET/CT (PET/CT-ITV). Comparative analysis of volumes and inter-reader agreement. RESULTS: 11 cases of peripheral and 10 central lesions were evaluated. In peripheral lesions, average CT-ITV was 6.2 cm(3) and PET/CT-ITV 8.6 cm(3), resembling a mean change in hypothetical radius of 2 mm. For both CT-ITVs and PET/CT-ITVs inter reader agreement was good and unchanged (0.733 and 0.716; p=0.58). All PET/CT-ITVs stayed within the PTVs derived from CT-ITVs. In central lesions, average CT-ITVs were 42.1 cm(3), PET/CT-ITVs 44.2 cm(3), without significant overall volume changes. Inter-reader agreement improved significantly (0.665 and 0.750; p<0.05). 2/10 PET/CT-ITVs exceeded the PTVs derived from CT-ITVs by >1 ml in average for all observers. CONCLUSION: The addition of co-registered 4DPET data to 4DCT based target volume delineation for SBRT of centrally located lung tumors increases the inter-observer agreement and may help to avoid geographic misses.

Prognostic Value of FDG PET/CT-Derived Parameters in Pancreatic Adenocarcinoma at Initial PET/CT Staging.

OBJECTIVE: The purpose of this study is to evaluate the performance of PET-derived parameters as prognostic markers for overall survival (OS) and progression-free survival (PFS) outcome in patients with pancreatic adenocarcinoma. MATERIALS AND METHODS: We conducted a retrospective study of 106 patients (62 men and 44 women) with histologically proven pancreatic adenocarcinoma who underwent initial staging FDG PET/CT before treatment. Peak standardized uptake value (SUV), maximum SUV (SUVmax), metabolic tumor volume, and tumor glycolytic activity of the primary pancreatic tumor were measured. Two segmentation methods were performed to obtain the metabolic tumor volume and tumor glycolytic activity for all tumors: a gradient-based segmentation model (metabolic tumor volume and tumor glycolytic activity by gradient edge detection) and a fixed-threshold model with a threshold of 50% of the lesion's SUVmax and peak SUV. Univariate and multivariate Cox regression models were developed including clinical and imaging parameters for OS and PFS. RESULTS: Multivariate Cox regression analysis showed a statistically significant association between PFS and age, SUVmax, peak SUV, and tumor glycolytic activity by gradient edge detection. There was a statistically significant difference in PFS for patients with values above and below the median cutoff points for SUVmax (hazard ratio [HR], 1.12; p < 0.01), peak SUV (HR, 1.25; p < 0.02), and tumor glycolytic activity measured by gradient edge detection (HR, 1.00; p < 0.02) of the primary tumor. However, multivariate Cox regression analysis showed a statistically significant association only between tumor glycolytic activity by gradient edge detection and OS (p = 0.04), and there was a statistically significant difference in OS between patients with values above and below the median cutoff point for the tumor glycolytic activity by gradient edge detection of the primary tumor (HR, 1.42; p = 0.05). CONCLUSION: Age, SUVmax, peak SUV, and total lesion glycolysis (i.e., tumor glycolytic activity) of the primary tumor are associated with PFS, and tumor glycolytic activity is associated with OS in patients with pancreatic adenocarcinoma.

18F-FDG PET/CT qualitative and quantitative evaluation in neurofibromatosis type 1 patients for detection of malignant transformation: comparison of early to delayed imaging with and without liver activity normalization.

UNLABELLED: (18)F-FDG PET/CT has shown increased accuracy, compared with morphologic imaging, in differentiating malignant peripheral nerve sheath tumors (MPNSTs) from benign neurofibromas (BNFs) in patients with neurofibromatosis type 1 (NF1). Delayed (18)F-FDG PET imaging typically enhances malignant tumor to background. Our goal was to compare the effectiveness of early (1-h) and delayed (4-h) (18)F-FDG PET/CT imaging in differentiating MPNSTs from BNFs in patients with NF1, with and without liver activity normalization. METHODS: NF1 patients presenting new symptoms or enlarging lesions were clinically evaluated with early and delayed (18)F-FDG PET/CT imaging. SULmax (maximum standardized uptake value derived for lean body) and SULmax/liver (lesion uptake adjusted to mean liver activity) were obtained for all sites identified with abnormal metabolic activity. Qualitative and quantitative evaluations, including receiver-operating-characteristic (ROC) comparison of early and delayed imaging sessions, were performed. Histopathology and clinical follow-up (1-9 y) were considered as a gold standard. RESULTS: Forty-one NF1 patients with early and delayed (18)F-FDG PET/CT scans were identified, and 93 lesions were retrospectively analyzed, representing 24 MPNSTs (all histologically confirmed) and 69 BNFs (26 histologically confirmed). Qualitative evaluation on early imaging showed sensitivity, specificity, positive predictive value, and negative predictive value for separating MPNSTs from BNFs of 91%, 84%, 67%, and 96% versus 91%, 81%, 63%, and 96%, respectively, on 4-h delayed imaging. The mean SULmax was significantly higher for MPNSTs than BNFs on both early scans (6.5 vs. 2.0, P < 0.01) and delayed imaging (8.3 vs. 2.3, P < 0.02). However, SULmax overlap between benign and malignant lesions persisted even after normalization to mean liver activity. ROC-derived best SULmax cutoffs were 3.2 on early (area under the curve, 0.973) and 4.1 on delayed scans (area under the curve, 0.978). ROC analysis for SULmax/liver improved test specificity (94% vs. 87%, P < 0.05) on early and (93% vs. 88%, P < 0.05) on delayed imaging. CONCLUSION: Qualitative interpretation of (18)F-FDG PET/CT discriminates MPNSTs from BNFs in NF1 patients with similar accuracy on both early and delayed imaging. Quantitative data showed better sensitivity on delayed acquisition and best test specificity with lesion SULmax normalization to liver activity, more so than with delayed imaging at 4 h.

Two-time-point FDG PET/CT: liver SULmean repeatability.

OBJECTIVE. The purpose of this study was to evaluate the repeatability of liver mean standardized uptake value normalized to lean body mass (SULmean) in the same patients at different time points within the right lobe of the liver at (18)F-FDG PET/CT, in a clinical setting. MATERIALS AND METHODS. Two PET/CT studies performed on two different dates from each of 130 patients who had normal livers according to structural imaging were included in this reader study. The mean (± SD) length of time between the studies was 235 ± 192 days. SULmean was measured with a 30-mm diameter spherical volume of interest (VOI) placed within the right lobe of the liver (above, below, and at the level of the main portal vein) by two expert readers. ANOVA, intraclass correlation coefficient (ICC), and Bland-Altman analysis were performed. RESULTS. The ICC for the first and second set of studies varied between 0.487 and 0.535 for reader 1 and between 0.472 and 0.545 for reader 2. The mean percentage variation for SULmean between the two time scans for the VOIs placed above, below, and at the level of the main portal vein were 3.55% ± 23.19%, 4.65% ± 23.87%, and 4.30% ± 23.03%, respectively, for reader 1 and 4.49% ± 23.23%, 4.33% ± 23.74%, and 4.48% ± 23.01%, respectively, for reader 2. Using 95% CI, the reference range for intrapatient variations between the studies in liver SULmean was -0.5 to 0.60. CONCLUSION. There is only fair repeatability of liver SULmean measured between two time points in the same patient in a clinical setting. Scan-to-scan intrapatient variation in absolute liver SULmean was -0.5 to 0.60.

Liver standardized uptake value corrected for lean body mass at FDG PET/CT: effect of FDG uptake time.

OBJECTIVE: The objective of this study is to establish the magnitude change and interreader reliability of the liver standardized uptake value corrected for lean body mass (SULmean) in dual-time-point imaging at 1 and 2 hours and 1 and 4 hours. PATIENTS AND METHODS: Early and delayed FDG PET/CT scans were included for 28 patients (13 men and 15 women) who had normal liver by CT or ultrasound. The average uptake time between the early and delayed scans were 55 minutes (range, 44-69 minutes) for pancreatic adenocarcinoma patients (n = 19) and 184 minutes (range, 140-197 minutes) for neurofibromatosis patients (n = 9). A 30-mm-diameter spherical volume of interest was placed within the right lobe of the liver above, below, and at the level of the main portal vein by 2 independent readers. Correlation coefficients, analysis of variance, intraclass correlation coefficient, and Bland-Altman analysis were performed. RESULTS: The mean liver SULmean was between 1.39 and 1.42 and between 1.28 and 1.3 in early and delayed images, respectively (P = 0.001). There is time-dependent reduction in the mean liver SULmean at 2-hour (7%-8%) and 4-hour uptake time (15%-21%) compared with 1-hour uptake time. The correlation coefficient between delayed uptake time and liver SULmean reduction is 0.39 to 0.41 at the upper aspect of the liver. The intraclass correlation coefficient for 2 readers varied between 0.997 and 0.998 and between 0.995 and 0.999 in early and delayed images, respectively (P = 0.001). CONCLUSIONS: There is time-dependent reduction of mean liver SULmean, about 7% to 8% within the clinically relevant FDG uptake time, in the same patient with excellent interreader agreement in early and delayed images within the right lobe of the liver. Therefore, liver SULmean could represent a useful reference parameter in quantitative analysis of dual-phase FDG PET/CT in malignancy or atypical infection/inflammatory disease. Furthermore, it may be suitable as a normalization factor in currently available formulae quantifying therapy response on PET imaging.

FDG volumetric parameters and survival outcomes after definitive chemoradiotherapy in patients with recurrent head and neck squamous cell carcinoma.

OBJECTIVE: The purpose of this study was to establish the predictive value of (18)F-FDG parameters for overall survival in biopsy-proven recurrent head and neck squamous cell cancer (HNSCC) patients after definitive chemoradiotherapy. MATERIALS AND METHODS: We conducted a retrospective study including 34 patients with HNSCC who had biopsy-proven recurrence between April 2004 and March 2012 and underwent FDG PET/CT at our institution at the time of recurrence. Maximum standardized uptake value (SUVmax), peak SUV (SUVpeak), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were measured. The primary outcome measure was overall survival. ROC analysis, univariate and multivariate Cox regression models, and Kaplan-Meir survival curves were performed. RESULTS: In univariate analyses, human papillomavirus (HPV) status (p = 0.04), primary site recurrence of MTV (p = 0.03), metastasis of MTV (p = 0.02), metastasis of TLG (p = 0.02), total MTV (p = 0.002), and total TLG (p = 0.04) were significantly associated with overall survival outcome. Total MTV remained as significant independent prognostic factor when adjusted for all other covariates except for primary site recurrence SUVmax and SUVpeak and lymph node SUVmax and SUVpeak. There was a significant difference in time to survival between patients with total MTV above and below the 50th percentile (Mantel-Cox log-rank test, p = 0.05 and Gehan-Breslow-Wilcoxon test, p = 0.03) and the optimum threshold of 16.8 mL (Mantel-Cox log-rank test, p = 0.01 and Gehan-Breslow-Wilcoxon test, p = 0.01; hazard ratio [HR], 0.25). CONCLUSION: FDG PET/CT-based total MTV and clinical HPV status may be significant prognostic markers for overall survival of patients with recurrent HNSCC after definitive chemoradiotherapy.

Evolving role of FDG PET/CT in multiple myeloma imaging and management.

OBJECTIVE: Multiple myeloma is the most common cause of primary malignancy in bones. Radiography has been the imaging reference standard for decades. However, the growing use of CT, MRI, and PET technology has led to earlier diagnosis of multiple myeloma, more accurate therapy assessment, and better prediction of patient outcome. This article is focused on the evolving role of (18)F-FDG PET/CT in multiple myeloma diagnosis, therapy assessment, and prognosis. CONCLUSION: FDG PET/CT is a valuable imaging modality in diagnosis, therapy assessment, and prognosis of multiple myeloma.