Predictive factors for the outcome of radioiodine therapy in patients with benign thyroid diseases.

PURPOSE: Radioiodine therapy (RIT) of benign thyroid diseases is an established therapy. This study aimed to identify factors predictive for outcome in patients with non-toxic goiter (NTG), unifocal (UFA), multifocal (MUFA) or diffuse autonomy (DISA) and Graves' disease (GD). METHODS: Retrospective analysis of 205 patients with benign thyroid disease (54 NTG, 46 MUFA, 24 DISA, 26 UFA, 55 GD) who underwent RIT. Follow up time was 12 months for determining treatment outcome. RESULTS: The type of disease was predictive for volume reduction after 12 months (NTS 66%, DISA 67%, MUFA 58%, UFA 51%, GD 71%, p<0.001) and post-treatment hypothyroidism (NTS 48%, DISA 33%, MUFA 15%, UFA 15%, p=0.006). Initial volume, intra-therapeutic uptake and intra-therapeutic half-life were independent prognostic factors for volume reduction 12 months after RIT. In patients with NTG, UFA, MUFA, DISA post-treatment hypothyroidism was significantly correlated with extent of volume reduction 12 months after RIT, achieved dose, higher pre-therapeutic TSH values and younger age. Two different strategies for pre-therapeutic dosimetry used in MUFA showed no differences regarding the therapeutic outcome. In GD, effective half-life, initial volume and Graves' ophthalmopathy were predictive for treatment failure. CONCLUSION: Reduction of thyroid volume and the percentage of hypothyroid patients one year after RIT was primarily dependent on the type of disease. In MUFA and DISA we could identify volume reduction after 3 months as a reliable predictor for hypothyroidism while in patients with GD a short intra-therapeutic half-life, a large pre-therapeutic volume and active Graves' ophtalmopathy were relevant predictors for treatment failure suggesting an intensified follow-up scheme in these patients.

Benefit of Static FET PET in Pretreated Pediatric Brain Tumor Patients with Equivocal Conventional MRI Results.

BACKGROUND: MRI has shortcomings in differentiation between tumor tissue and post-therapeutic changes in pretreated brain tumor patients. PATIENTS: We assessed 22 static FET-PET/CT-scans of 17 pediatric patients (median age 12 years, range 2-16 years, ependymoma n=4, medulloblastoma n=4, low-grade glioma n=6, high-grade glioma n=3, germ cell tumor n=1, choroid plexus tumor n=1, median follow-up: 112 months) with multimodal treatment. METHOD: FET-PET/CT-scans were analyzed visually by 3 independent nuclear medicine physicians. Additionally quantitative FET-Uptake for each lesion was determined by calculating standardized uptake values (SUVmaxT/SUVmeanB, SUVmeanT/SUVmeanB). Histology or clinical follow-up served as reference. RESULTS: Static FET-PET/CT reliably distinguished between tumor tissue and post-therapeutic changes in 16 out of 17 patients. It identified correctly vital tumor tissue in 13 patients and post-therapeutic changes in 3 patients. SUV-based analyses were less sensitive than visual analyses. Except from a choroid plexus carcinoma, all tumor entities showed increased FET-uptake. DISCUSSION: Our study comprises a limited number of patients but results corroborate the ability of FET to detect different brain tumor entities in pediatric patients and discriminate between residual/recurrent tumor and post-therapeutic changes. CONCLUSIONS: We observed a clear benefit from additional static FET-PET/CT-scans when conventional MRI identified equivocal lesions in pretreated pediatric brain tumor patients. These results warrant prospective studies that should include dynamic scans.

Point Spread Function Reconstruction for Integrated 18F-FET PET/MRI in Patients With Glioma: Does It Affect SUVs and Respective Tumor-to-Background Ratios?

PURPOSE: Semiquantitative F-FET PET assessment using the tumor's SUV or tumor-to-background ratios (TBRs) can separate gliomas from peritumoral tissue or progression from pseudoprogression. This study investigated if point spread function (PSF) reconstruction of F-FET PET data affects SUV-based dignity assessment. MATERIALS AND METHODS: This study is a retrospective analysis of 87 glioma patients (female, 36; male, 51; age, 48 [13-81] years) undergoing F-FET PET/MRI for staging (n = 17) or restaging (n = 70). PET was reconstructed using ordered-subset expectation maximization with and without PSF. Lesions were delineated with semiautomated background-adapted thresholding relative to SUVmax; background was delineated contralaterally. Comparative measurements with a National Electrical Manufacturers Association International Electrotechnical Commission PET body phantom (sphere-to-background ratios, 8:1 and 4:1) were performed. RESULTS: PSF showed significantly higher tumor SUVmax (median difference, +0.1; interquartile range, 0.04-0.18), SUVmean (+0.05; 0.03-0.08), TBRmax|mean (+0.1; 0.04-0.2), and TBRmean|mean (+0.06; 0.03-0.09) than non-PSF (P < 0.001). Background SUVmean was unaffected. In patients and phantom, differences between PSF and non-PSF increased with TBR and decreased with lesion's PET volume. Differences only exceeded 0.2 SUV for SUVmax or 0.1 SUV for SUVmean if TBR was greater than 3 and lesion's PET volume was less than 10 mL (d = 27 mm). Dignity assessment by PSF and non-PSF was concordant in all patients examined for staging (cutoff, TBRmean|mean > 1.6; positive, 14; negative, 3) and restaging (cutoff, TBRmax|mean > 2.0; positive, 67; negative, 3). CONCLUSIONS: PSF increased tumor SUVmax and SUVmean compared with non-PSF F-FET PET/MRI data, especially in small lesions with high TBR (>3). However, dignity assessment using established TBR cutoffs was not affected.

Pretherapeutic FDG-PET total metabolic tumor volume predicts response to induction therapy in pediatric Hodgkin's lymphoma.

BACKGROUND: Standardized treatment in pediatric patients with Hodgkin's lymphoma (HL) follows risk stratification by tumor stage, erythrocyte sedimentation rate and tumor bulk. We aimed to identify quantitative parameters from pretherapeutic FDG-PET to assist prediction of response to induction chemotherapy. METHODS: Retrospective analysis in 50 children with HL (f:18; m:32; median age, 14.8 [4-18] a) consecutively treated according to EuroNet-PHL-C1 (n = 42) or -C2 treatment protocol (n = 8). Total metabolic tumor volume (MTV) in pretherapeutic FDG-PET was defined using a semi-automated, background-adapted threshold. Metabolic (SUVmax, SUVmean, SUVpeak, total lesion glycolysis [MTV*SUVmean]) and heterogeneity parameters (asphericity [ASP], entropy, contrast, local homogeneity, energy, and cumulative SUV-volume histograms) were derived. Early response assessment (ERA) was performed after 2 cycles of induction chemotherapy according to treatment protocol and verified by reference rating. Prediction of inadequate response (IR) in ERA was based on ROC analysis separated by stage I/II (1 and 26 patients) and stage III/IV disease (7 and 16 patients) or treatment group/level (TG/TL) 1 to 3. RESULTS: IR was seen in 28/50 patients (TG/TL 1, 6/12 patients; TG/TL 2, 10/17; TG/TL 3, 12/21). Among all PET parameters, MTV best predicted IR; ASP was the best heterogeneity parameter. AUC of MTV was 0.84 (95%-confidence interval, 0.69-0.99) in stage I/II and 0.86 (0.7-1.0) in stage III/IV. In patients of TG/TL 1, AUC of MTV was 0.92 (0.74-1.0); in TG/TL 2 0.71 (0.44-0.99), and in TG/TL 3 0.85 (0.69-1.0). Patients with high vs. low MTV had IR in 86 vs. 0% in TG/TL 1, 80 vs. 29% in TG/TL 2, and 90 vs. 27% in TG/TL 3 (cut-off, > 80 ml, > 160 ml, > 410 ml). CONCLUSIONS: In this explorative study, high total MTV best predicted inadequate response to induction therapy in pediatric HL of all pretherapeutic FDG-PET parameters - in both low and high stages as well as the 3 different TG/TL. TRIAL REGISTRATION: Ethics committee number: EA2/151/16 (retrospectively registered).

I-123-MIBG scintigraphy in patients with neuroblastoma.

AIM: According to German guidelines, I-123-MIBG scintigraphy in neuroblastoma (NB) is preferably performed as early (about 4 h p.i.) and late (24 h p.i.) planar imaging and single- photon emission computed tomography (SPECT) or SPECT/CT 24 h p.i. This study evaluated if the work-up could be reduced to a single timepoint. METHODS: Retrospective analysis of 37 examinations in 26 patients (f:8; m:18; age, 0.5-23.5a) with NB (initial, 15; restaging, 22). All 74 (early + late) pairs of ventral/dorsal planar whole-body images were reviewed by 3 independent readers in random order blinded to clinical data (1, certainly physiological; 2, likely physiological; 3, likely malignant; 4, certainly malignant). CT/MRI or SPECT served as standard of reference if planar images were equivocal. RESULTS: Two-hundred malignant lesions were rated (1-23 lesions per examination). The lesions' mean score was higher at late vs. early imaging for all readers (3.6 vs. 3.4, 3.7 vs. 3.2, 3.5 vs. 3.2; each p < 0.01). Fifty-one lesions (25.5 %) were considerably underrated at early vs. late imaging (score difference ≥2) by any reader (29/153 skeletal lesions, 12/28 primary tumors [PT], 10/18 abdominal lymph nodes [LN]). Early image did not detect any lesion in 6 patients with PT only. In contrast, 9 lesions (4.5 %) were underrated by late vs. early imaging: 5 skeletal lesions (pelvis, 2; femoral shaft, 3), 1 PT, 3 LN, and 0/1 liver lesions. Tumor spread was underestimated thereby at late vs. early imaging in 1 patient (LN) but SPECT was correct. CONCLUSION: The early planar image provided no relevant information over the late image in any patient and may only be performed after weighting of risks (stress) and benefits - especially if SPECT or SPECT/CT is routinely performed. Vice versa, early planar image alone does not suffice.

Software-assisted dosimetry in peptide receptor radionuclide therapy with 177Lutetium-DOTATATE for various imaging scenarios.

In peptide receptor radionuclide therapy (PRRT) of patients with neuroendocrine neoplasias (NENs), intratherapeutic dosimetry is mandatory for organs at risk (e.g. kidneys) and tumours. We evaluated commercial dosimetry software (Dosimetry Toolkit) using varying imaging scenarios, based on planar and/or tomographic data, regarding the differences in calculated organ/tumour doses and the use for clinical routines. A total of 16 consecutive patients with NENs treated by PRRT with 177Lu-DOTATATE were retrospectively analysed. Single-photon emission computed tomography (SPECT)/low-dose computed tomography (CT) of the thorax and abdomen and whole body (WB) scintigraphy were acquired up to 7 days p.i. (at a maximum of five imaging time points). Different dosimetric scenarios were evaluated: (1) a multi-SPECT-CT scenario using SPECT/CT only; (2) a planar scenario using WB scintigraphy only; and (3) a hybrid scenario using WB scintigraphy in combination with a single SPECT/low-dose CT. Absorbed doses for the kidneys, liver, spleen, lungs, bladder wall and tumours were calculated and compared for the three different scenarios. The mean absorbed dose for the kidneys estimated by the multi-SPECT-CT, the planar and the hybrid scenario was 0.5 ± 0.2 Sv GBq-1, 0.8 ± 0.4 Sv GBq-1 and 0.6 ± 0.3 Sv GBq-1, respectively. The absorbed dose for the residual organs was estimated higher by the planar scenario compared to the multi-SPECT-CT or hybrid scenario. The mean absorbed tumour doses were 2.6 ± 1.5 Gy GBq-1 for the multi-SPECT-CT, 3.1 ± 2.2 Gy GBq-1 for the hybrid scenario and 5.3 ± 6.3 Gy GBq-1 for the planar scenario. SPECT-based dosimetry methods determined significantly lower kidney doses than the WB scintigraphy-based method. Dosimetry based completely on SPECT data is time-consuming and tedious. Approaches combining SPECT/CT and WB scintigraphy have the potential to ensure compromise between accuracy and user-friendliness.

Individualized risk assessment in neuroblastoma: does the tumoral metabolic activity on 123I-MIBG SPECT predict the outcome?

PURPOSE: Risk-adapted treatment in children with neuroblastoma (NB) is based on clinical and genetic factors. This study evaluated the metabolic tumour volume (MTV) and its asphericity (ASP) in pretherapeutic 123I-MIBG SPECT for individualized image-based prediction of outcome. METHODS: This retrospective study included 23 children (11 girls, 12 boys; median age 1.8 years, range 0.3-6.8 years) with newly diagnosed NB consecutively examined with pretherapeutic 123I-MIBG SPECT. Primary tumour MTV and ASP were defined using semiautomatic thresholds. Cox regression analysis, receiver operating characteristic analysis (cut-off determination) and Kaplan-Meier analysis with the log-rank test for event-free survival (EFS) were performed for ASP, MTV, laboratory parameters (including urinary homovanillic acid-to-creatinine ratio, HVA/C), and clinical (age, stage) and genetic factors. Predictive accuracy of the optimal multifactorial model was determined in terms of Harrell's C and likelihood ratio χ 2. RESULTS: Median follow-up was 36 months (range 7-107 months; eight patients showed disease progression/relapse, four patients died). The only significant predictors of EFS in the univariate Cox regression analysis were ASP (p = 0.029; hazard ratio, HR, 1.032 for a one unit increase), MTV (p = 0.038; HR 1.012) and MYCN amplification status (p = 0.047; HR 4.67). The mean EFS in patients with high ASP (>32.0%) and low ASP were 21 and 88 months, respectively (p = 0.013), and in those with high MTV (>46.7 ml) and low MTV were 22 and 87 months, respectively (p = 0.023). A combined risk model of either high ASP and high HVA/C or high MTV and high HVA/C best predicted EFS. CONCLUSIONS: In this exploratory study, pretherapeutic image-derived and laboratory markers of tumoral metabolic activity in NB (ASP, MTV, urinary HVA/C) allowed the identification of children with a high and low risk of progression/relapse under current therapy.

Imaging of Tumor Metabolism Using Positron Emission Tomography (PET).

Molecular imaging employing PET/CT enables in vivo visualization, characterization, and measurement of biologic processes in tumors at a molecular and cellular level. Using specific metabolic tracers, information about the integrated function of multiple transporters and enzymes involved in tumor metabolic pathways can be depicted, and the tracers can be directly applied as biomarkers of tumor biology. In this review, we discuss the role of F-18-fluorodeoxyglucose (FDG) as an in vivo glycolytic marker which reflects alterations of glucose metabolism in cancer cells. This functional molecular imaging technique offers a complementary approach to anatomic imaging such as computed tomography (CT) and magnetic resonance imaging (MRI) and has found widespread application as a diagnostic modality in oncology to monitor tumor biology, optimize the therapeutic management, and guide patient care. Moreover, emerging methods for PET imaging of further biologic processes relevant to cancer are reviewed, with a focus on tumor hypoxia and aberrant tumor perfusion. Hypoxic tumors are associated with poor disease control and increased resistance to cytotoxic and radiation treatment. In vivo imaging of hypoxia, perfusion, and mismatch of metabolism and perfusion has the potential to identify specific features of tumor microenvironment associated with poor treatment outcome and, thus, contribute to personalized treatment approaches.

Increased evidence for the prognostic value of primary tumor asphericity in pretherapeutic FDG PET for risk stratification in patients with head and neck cancer.

PURPOSE: In a previous study, we demonstrated the first evidence that the asphericity (ASP) of pretherapeutic FDG uptake in the primary tumor provides independent prognostic information in patients with head and neck cancer. The aim of this work was to confirm these results in an independent patient group examined at a different site. METHODS: FDG-PET/CT was performed in 37 patients. The primary tumor was delineated by an automatic algorithm based on adaptive thresholding. For the resulting ROIs, the metabolically active part of the tumor (MTV), SUVmax, SUVmean, total lesion glycolysis (TLG) and ASP were computed. Univariate Cox regression with respect to progression free survival (PFS) and overall survival (OS) was performed. For survival analysis, patients were divided in groups of high and low risk according to the parameter cut-offs defined in our previous work. In a second step, the cut-offs were adjusted to the present data. Univariate and multivariate Cox regression was performed for the pooled data consisting of the current and the previously described patient group (N = 68). In multivariate Cox regression, clinically relevant parameters were included. RESULTS: Univariate Cox regression using the previously published cut-off values revealed TLG (hazard ratio (HR) = 3) and ASP (HR = 3) as significant predictors for PFS. For OS MTV (HR = 2.7) and ASP (HR = 5.9) were significant predictors. Using the adjusted cutoffs MTV (HR = 2.9/3.3), TLG (HR = 3.1/3.3) and ASP (HR = 3.1/5.9) were prognostic for PFS/OS. In the pooled data, multivariate Cox regression revealed a significant prognostic value with respect to PFS/OS for MTV (HR = 2.3/2.1), SUVmax (HR = 2.1/2.5), TLG (HR = 3.5/3.6), and ASP (HR = 3.4/4.4). CONCLUSIONS: Our results confirm the independent prognostic value of ASP of the pretherapeutic FDG uptake in the primary tumor in patients with head and neck cancer. Moreover, these results demonstrate that ASP can be determined unambiguously across different sites.

Asphericity of pretherapeutic tumour FDG uptake provides independent prognostic value in head-and-neck cancer.

OBJECTIVE: To propose a novel measure, namely the 'asphericity' (ASP), of spatial irregularity of FDG uptake in the primary tumour as a prognostic marker in head-and-neck cancer. METHODS: PET/CT was performed in 52 patients (first presentation, n = 36; recurrence, n = 16). The primary tumour was segmented based on thresholding at the volume-reproducible intensity threshold after subtraction of the local background. ASP was used to characterise the deviation of the tumour's shape from sphere symmetry. Tumour stage, tumour localisation, lymph node metastases, distant metastases, SUVmax, SUVmean, metabolic tumour volume (MTV) and total lesion glycolysis (TLG) were also considered. The association of overall (OAS) and progression-free survival (PFS) with these parameters was analysed. RESULTS: Cox regression revealed high SUVmax [hazard ratio (HR) = 4.4/7.4], MTV (HR = 4.6/5.7), TLG (HR = 4.8/8.9) and ASP (HR = 7.8/7.4) as significant predictors with respect to PFS/OAS in case of first tumour manifestation. The combination of high MTV and ASP showed very high HRs of 22.7 for PFS and 13.2 for OAS. In case of recurrence, MTV (HR = 3.7) and the combination of MTV/ASP (HR = 4.2) were significant predictors of PFS. CONCLUSIONS: ASP of pretherapeutic FDG uptake in the primary tumour improves the prediction of tumour progression in head-and-neck cancer at first tumour presentation. KEY POINTS: Asphericity (ASP) characterises the spatial heterogeneity of FDG uptake in tumours. ASP is a promising prognostic parameter in head-and-neck cancer. ASP is useful for identification of high-risk patients with head-and-neck cancer.

Inverse dynamic analysis of the lower extremities during nordic walking, walking, and running.

Compared with walking (W), Nordic walking (NW) exhibits greater cardiopulmonary and cardiovascular benefits. Some authors conjecture that compared with W or running (R), NW imposes smaller mechanical loads on the musculoskeletal system. The purpose of the current study was to quantify any differences in joint loading of the lower extremities among NW, W, and R. Fifteen experienced adults participated. Kinematic and force measurements were combined using an inverse dynamics approach to yield joint moments. The results showed no biomechanical benefit of NW. Instead, NW involved greater knee joint loading just after heel strike compared with W. This was due to the longer steps and the higher sole angle during the first part of the stance phase. The sagittal and frontal plane moments were smaller for NW compared with R, but in the transverse plane, the ankle moments were greater in NW than in W or R. Based on these results, NW is not recommended as an exercise for persons who seek to reduce biomechanical loading of the lower extremities.