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1.  Application of F-18-Sodium Fluoride (NaF) Dynamic PET-CT (dPET-CT) for Defect Healing: A Comparison of Biomaterials in an Experimental Osteoporotic Rat Model 
The aim of the current study was to measure and compare the effect of various biomaterials for the healing of osteoporotic bone defects in the rat femur using 18F-sodium fluoride dPET-CT.
Osteoporosis was induced by ovariectomy and a calcium-restricted diet. After 3 months, rats were operated on to create a 4-mm wedge-shaped defect in the distal metaphyseal femur. Bone substitution materials of calcium phosphate cement (CPC), composites of collagen and silica, and iron foams with interconnecting pores were inserted. Strontium or bisphosphonate, which are well known for having positive effects in osteoporosis treatment, were added into the materials. Eighteen weeks after osteoporosis induction and 6 weeks following femoral surgery, dPET-CT studies scan were performed with 18F-Sodium Fluoride. Standardized uptake values (SUVs) and a 2-tissue compartmental learning-machine model (K1-k4, vessel density [VB], influx [ki]) were used for quantitative analysis.
k3, reflecting the formation of fluoroapatite, revealed a statistically significant increase at the biomaterial-bone interface due to the Sr release from strontium-modified calcium phosphate cement (SrCPC) compared to CPC, which demonstrated enhanced new bone formation. In addition, k3 as measured in the porous scaffold silica/collagen xerogel (Sc-B30), showed a significant increase based on Wilcoxon rank-sum test (p<0.05) as compared with monolithic silica/collagen xerogel (B30) in the defect region. Furthermore, ki, reflecting the net plasma clearance of tracer to bone mineral measured in the iron foam with coating of the bisphosphonate zoledronic acid (Fe-BP), was enhanced as compared with plain iron foam (Fe) in the defect region.
k3 was the most significant parameter for the characterization of healing processes and revealed the best differentiation between the 2 different biomaterials. PET scanning using 18F-sodium fluoride seems to be a sensitive and useful method for evaluation of bone healing after replacement with these biomaterials.
PMCID: PMC4210358  PMID: 25317537
Aortopulmonary Septal Defect; Biomarkers; Pharmacological; Osteoporosis
2.  Quantitative approaches of dynamic FDG-PET and PET/CT studies (dPET/CT) for the evaluation of oncological patients 
Cancer Imaging  2012;12(1):283-289.
Objectives: The use of dynamic positron emission tomography/computed tomography (dPET/CT) studies with [18F]deoxyglucose (FDG) in oncological patients is limited and primarily confined to research protocols. A more widespread application is, however, desirable, and may help to assess small therapeutic effects early after therapy as well as to differentiate borderline differences between tumour and non-tumour lesions, e.g., lipomas versus low-grade liposarcomas. The aim is to present quantification approaches that can be used for the evaluation of dPET/CT series in combination with parametric imaging and to demonstrate the feasibility with regard to tumour diagnostics and therapy management. Methods: A 60-min data acquisition and short acquisition protocols (20-min dynamic series and a static image 60 min post injection) are discussed. A combination of a modified two-tissue compartment model and non-compartmental approaches from the chaos theory (fractal dimension of the time–activity curves) are presented. Fused PET/CT images as well as regression-based parametric images fused with CT or with PET/standardised uptake value images are demonstrated for the exact placement of volumes of interest. Results: The two-tissue compartmental method results in the calculation of 5 kinetic parameters, the fractional blood volume VB (known also as the distribution volume), and the transport rates k1 to k4. Furthermore, the influx according to Patlak can be calculated from the transport rates. The fractal dimension of the time–activity curves describes the heterogeneity of the tracer distribution. The use of the regression-based parametric images of FDG helps to visualise the transport/perfusion and the transport/phosphorylation-dependent FDG uptake, and adds a new dimension to the existing conventional PET or PET/CT images. Conclusions: More sophisticated quantification methods and dedicated software as well as high computational power and faster acquisition protocols can facilitate the assessment of dPET/CT, and may find use in clinical routine, in particular for the assessment of early therapeutic effects or new treatment protocols in combination with the new generation of PET/CT scanners.
PMCID: PMC3485644  PMID: 23033440
Dynamic PET; oncology; compartment modelling; non-compartment modelling; parametric imaging; feature extraction
3.  Dynamic 18F-fluorodeoxyglucose positron emission tomography/CT in hibernoma: Enhanced tracer uptake mimicking liposarcoma 
World Journal of Radiology  2013;5(12):498-502.
We report on two cases of patients with fat-equivalent masses in computed tomography (CT), referred to our department for dynamic positron emission tomography/CT (dPET/CT) with 18F-fluorodeoxyglucose (18F-FDG) in order to investigate their dignity. Both qualitative and quantitative information, as derived from dPET/CTs, couldn’t exclude a high-grade liposarcoma: Visual evaluation, revealed a large hypermetabolic focus of intense 18F-FDG uptake in each patient (average SUVs 8.3 and 11.3). Regression-based parametric imaging demonstrated an enhanced distribution volume, which correlates to perfusion, and a high phosphorylation rate that correlates to cell viability. Kinetic analysis, based on a two-tissue compartment model demonstrated an enhanced FDG transport k1 and an enhanced phosphorylation rate k3. A non-compartmental approach based on fractal dimension revealed also enhanced values. However, final diagnosis was based on biopsy, which revealed hibernoma, a benign brown fat tumor. Brown adipose contains increased numbers of mitochondria and a high-rate of glucose metabolism. Therefore, they have increased FDG uptake. The evaluation of lipomatous lesions on CT, with high FDG uptake, should include the possibility of hibernoma as a differential diagnosis.
PMCID: PMC3874507  PMID: 24379937
Hibernoma; Dynamic positron emission tomography/CT; 18F-fluorodeoxyglucose; Kinetic Modeling; Parametric imaging
4.  Level of TNF-related apoptosis-inducing-ligand and CXCL8 correlated with 2-[18F]Fluoro-2-deoxy-D-glucose uptake in anti-VEGF treated colon cancers 
The changes and correlations of TRAIL (TNF-related apoptosis-inducing-ligand) and CXCL8 (IL8) prior to treatment and three months following therapy as well as the corresponding Positron emission tomography (PET/CT) (SUVmax: standardized uptake maximum values) results were evaluated.
The measurements were taken before and after treatment for comparison purposes. The study population comprised 29 patients with Metastatic Colorectal cancer (MCRC), undergoing PET/CT scanning prior to treatment.
There were significant changes prior to treatment and three months later for sTRAIL (p=0.0080) and CXCL8 (p=0.0001)values. Generally, sTRAIL values were increasing during therapy, while a decrease was observed for CXCL8. Correlation analysis was applied to the data and revealed significant correlations for the SUVmax in the primary tumor prior to treatment and CXCL8 prior to therapy (p=0.0303). Furthermore, significant correlations were observed for the SUVmax and sTRAIL (p=0.0237) as well as CXCL8 (p=0.0002) three months after treatment initiation. CXCL8 prior to treatment was also correlated with the SUV three months after onset of treatment (p=0.0072). A significant correlation was noted for one combination of two variables, the SUVmax in the metastases and CXCL8 prior to treatment (p=0.0175). These results are supported when we group the SUVmax in the metastases following treatment into two groups with SUVmax <5 and SUVmax >5.
This study provides evidence that proteomics patterns of sTRAIL and CXCL8 predict tumor response und survival in MCRC patients treated with bevacizumab and within a high concordance of FDG-PET/CT findings.
PMCID: PMC3808407  PMID: 24145180
metastatic colorectal cancer (MCRC); CXCL8 (IL8); soluble TRAIL (sTRAIL); anti VEGF antibody (Bevacizumab); F-18-Deoxyglucose positron emission tomography (FDG-PET/CT); proteomics study; (SUVmax: standardized uptake maximum values)
5.  Dynamic PET with 18F-Deoxyglucose (FDG) and quantitative assessment with a two-tissue compartment model reflect the activity of glucose transporters and hexokinases in patients with colorectal tumors 
Dynamic PET (dPET) with 18F-Deoxyglucose (FDG) provides quantitative information about distribution of the tracer in a predefined volume over time. A two-tissue compartment model can be used to obtain quantitative data regarding transport of FDG into and out of the cells, phosphorylation and dephosphorylation rate of intracellular FDG, and fractional blood volume in the target volume, also named vessel density. Aim of the study was the correlation of glucose transporters expression and hexokinases with the corresponding compartment parameters.Patients with colorectal tumors were examined with dynamic PET prior to surgery. Afterwards, tumor samples were obtained during surgery and gene expression was assessed using gene arrays. The dynamic PET data were evaluated to quantify the parameters of a two tissue compartment model for colorectal tumors using a Volume-of-Interest (VOI) technique. A multiple correlation/regression analysis was performed using glucose transporters as independent variables and k1 as the dependent variable. A correlation of r=0.7503 (p=0.03) was obtained for the transporters SLC2A1, SLC2A2, SLC2A4, SLC2A8, SLC2A9, SLC2A10 and k1. The correlation of r=0.7503 refers to an explained variance of data of 56.30 %, therefore more than 50 % of data changes are associated with the gene expression. An analysis of the hexokinases HK1-HK3 and k3 revealed a correlation coefficient of r=0.6093 (p=0.04), which is associated with an explained variance of 37.12 %. Therefore, parameters k1 and k3 reflect gene activity. The results demonstrate that k1 and k3 of the two-tissue compartment model are correlated with glucose transporters and hexokinases.
PMCID: PMC3784805  PMID: 24116350
Dynamic PET; compartment model; glucose transporter; hexokinase
6.  Positron Emission Tomography as a Surrogate Marker for Evaluation of Treatment Response in Patients with Desmoid Tumors under Therapy with Imatinib 
BioMed Research International  2013;2013:389672.
We used 2-deoxy-2-[18F] fluoro-D-glucose (FDG) positron emission tomography (PET) to evaluate patients with desmoid tumors undergoing therapy with imatinib. The study included 22 patients with progressive disease (PD) of a biopsy proven desmoid tumor treated orally with imatinib 800 mg daily. Patients were examined using PET prior to onset of therapy and during treatment. Restaging was performed in parallel using computed tomography (CT) and/or magnetic resonance imaging (MRI). Outcome of 22 evaluable patients was as follows: five patients with partial response (PR); twelve patients with stable disease (SD) accounting for 77% with non-progressive disease; five patients showed PD. A 30% decrease of the mean average standardized uptake value (SUV) of sequential PET examinations could be demonstrated; no patient demonstrated a substantial increase in SUV. Patients with PR/SD were matched to a group of nonprogressive disease and tested versus PD. The initial average SUV and SUVmax seem to be candidates for a response prediction with an approximate P-value of 0.06553 and 0.07785, respectively. This is the first larger series of desmoid patients monitored using PET showing that early SUV changes may help to discriminate responders from nonresponders and, thus, to decide whether imatinib therapy should be continued.
PMCID: PMC3671300  PMID: 23762842
7.  Evaluation of bone remodeling with 18F-fluoride and correlation with the glucose metabolism measured by 18F-FDG in lumbar spine with time in an experimental nude rat model with osteoporosis using dynamic PET-CT 
Rats with osteoporosis were involved by combining ovariectomy (OVX) either with calcium and Vitamin D deficiency diet (Group D), or with glucocorticoid (dexamethasone) treatment (Group C). In the period of 1-12 months, dynamic PET-CT studies were performed in three groups of rats including Group D, Group C and the control Group K (sham-operated). Standardized uptake values (SUVs) were calculated, and a 2-tissue compartmental learning-machine model (calculation of K1-k4, VB and the plasma clearance of tracer to bone mineral (Ki) as well as a non-compartmental model based on the fractal dimension (FD) was used for quantitative analysis of both groups. The evaluation of PET data was performed over the lumbar spine. The correlation analysis revealed a significant linear correlation for certain dPET quantitative parameters and time up to 12 months after induction of osteoporosis. Based on the 18F-Fluoride data, we noted a significant negative correlation for K1 (the fluoride/hydroxyl exchange) in the Group C and a significant positive correlation for k3, SUV (bone metabolism) and FD in the Group K. The evaluation of the 18F-FDG data revealed a significant positive correlation for SUV (glucose metabolism) only in Group C. The correlation between the two tracers revealed significant results between K1 of 18F-Fluoride and SUV of FDG in Group K as well as between FD of 18F-Fluoride and FDG in Group D and C and between k3 of 18F-Fluoride and SUV of FDG in Group C.
PMCID: PMC3601472  PMID: 23526138
dPET-CT; 18F-FDG; 18F-fluoride; osteoporosis
10.  18F-Deoxyglucose (FDG) kinetics evaluated by a non-compartment model based on a linear regression function using a computer based simulation: correlation with the parameters of the two-tissue compartment model 
Parametric imaging with a linear regression function of the tracer activity curve fit is a non-compartmental method, which can be used for the evaluation of dynamic PET (dPET) studies. However, the dependency of the slope of the regression function fit on the 18F-Deoxyglucose (FDG) 2-tissue compartment parameters (vb, k1-k4) is not known yet. This study is focused on the impact of the 2-tissue compartment parameters on the slope of the curve. A data base of 1760 dynamic PET FDG studies with the corresponding 2-tissue compartment model parameter solutions were available and used to calculate synthetic time-activity data based on the 2-tissue compartment model. The input curve was calculated from the median values of the input curves of the 1760 dynamic data sets. Then, sequentially each of the five parameters (vb, k1-k4) of the 2-tissue compartment model was varied from 0.1 to 0.9 and tracer activity curves were calculated (60000 curves/parameter). A linear regression function was fitted to these curves. The comparison of the slope values of the regression function with the corresponding compartment data revealed a primary dependency on k3, which is associated with the intracellular phosphorylation of FDG. The squared correlation coefficient was high with r2=0.9716, which refers to 97 % explained variance of the data. k2 and vb had only a minor impact, while k1 and k4 had no impact on the slope values. The results demonstrate, that k3 has a major impact on the slope values calculated by the linear regression function.
PMCID: PMC3484418  PMID: 23145361
FDG; non-compartment model; parametric imaging
11.  Multimodal hypoxia imaging and intensity modulated radiation therapy for unresectable non-small-cell lung cancer: the HIL trial 
Radiotherapy, preferably combined with chemotherapy, is the treatment standard for locally advanced, unresectable non-small cell lung cancer (NSCLC). The tumor response to different therapy protocols is variable, with hypoxia known to be a major factor that negatively influences treatment effectiveness. Visualisation of tumor hypoxia prior to the use of modern radiation therapy strategies, such as intensity modulated radiation therapy (IMRT), might allow optimized dose applications to the target volume, leading to improvement of therapy outcome. 18 F-fluoromisonidazole dynamic positron emission tomography and computed tomography (18 F-FMISO dPET-CT) and functional magnetic resonance imaging (functional MRI) are attractive options for imaging tumor hypoxia.
The HIL trial is a single centre study combining multimodal hypoxia imaging with 18 F-FMISO dPET-CT and functional MRI, with intensity modulated radiation therapy (IMRT) in patients with inoperable stage III NSCLC. 15 patients will be recruited in the study. All patients undergo initial FDG PET-CT and serial 18 F-FMISO dPET-CT and functional MRI before treatment, at week 5 of radiotherapy and 6 weeks post treatment. Radiation therapy is performed as inversely planned IMRT based on 4D-CT.
Primary objectives of the trial are to characterize the correlation of 18 F-FMISO dPET-CT and functional MRI for tumor hypoxia imaging in NSCLC and evaluate possible effects of radiation therapy on tumor re-oxygenation. Further objectives include the generation of data regarding the prognostic value of 18 F-FMISO dPET-CT and functional MRI for locoregional control, progression free survival and overall survival of NSCLC treated with IMRT, which will form the basis for larger clinical trials focusing on possible interactions between tumor oxygenation and radiotherapy outcome.
Trial registration
The protocol ID is NCT01617980
PMCID: PMC3503648  PMID: 22974533
Hypoxia; Imaging; Radiotherapy; Non-small-cell lung cancer
12.  Correlation of Dynamic PET and Gene Array Data in Patients with Gastrointestinal Stromal Tumors 
The Scientific World Journal  2012;2012:721313.
Introduction. The results obtained with dynamic PET (dPET) were compared to gene expression data obtained in patients with gastrointestinal stromal tumors (GIST). The primary aim was to assess the association of the dPET results and gene expression data. Material and Methods. dPET was performed following the injection of F-18-fluorodeoxyglucose (FDG) in 22 patients with GIST. All patients were examined prior to surgery for staging purpose. Compartment and noncompartment models were used for the quantitative evaluation of the dPET examinations. Gene array data were based on tumor specimen obtained by surgery after the PET examinations. Results. The data analysis revealed significant correlations for the dPET parameters and the expression of zinc finger genes (znf43, znf85, znf91, znf189). Furthermore, the transport of FDG (k1) was associated with VEGF-A. The cell cycle gene cyclin-dependent kinase inhibitor 1C was correlated with the maximum tracer uptake (SUVmax) in the tumors. Conclusions. The data demonstrate a dependency of the tracer kinetics on genes associated with prognosis in GIST. Furthermore, angiogenesis and cell proliferation have an impact on the tracer uptake.
PMCID: PMC3373132  PMID: 22701369
13.  Comparison between 68Ga-bombesin (68Ga-BZH3) and the cRGD tetramer 68Ga-RGD4 studies in an experimental nude rat model with a neuroendocrine pancreatic tumor cell line 
EJNMMI Research  2011;1:34.
Receptor scintigraphy gains more interest for diagnosis and treatment of tumors, in particular for neuroendocrine tumors (NET). We used a pan-Bombesin analog, the peptide DOTA-PEG2-[D-tyr6, β-Ala11, Thi13, Nle14] BN(6-14) amide (BZH3). BZH3 binds to at least three receptor subtypes: the BB1 (Neuromedin B), BB2 (Gastrin-releasing peptide, GRP), and BB3. Imaging of ανβ3 integrin expression playing an important role in angiogenesis and metastasis was accomplished with a 68Ga-RGD tetramer. The purpose of this study was to investigate the kinetics and to compare both tracers in an experimental NET cell line.
This study comprised nine nude rats inoculated with the pancreatic tumor cell line AR42J. Dynamic positron emission tomography (PET) scans using 68Ga-BZH3 and 68Ga-RGD tetramer were performed (68Ga-RGD tetramer: n = 4, 68Ga-BZH3: n = 5). Standardized uptake values (SUVs) were calculated, and a two-tissue compartmental learning-machine model (calculation of K1 - k4 vessel density (VB) and receptor binding potential (RBP)) as well as a non-compartmental model based on the fractal dimension was used for quantitative analysis of both tracers. Multivariate analysis was used to evaluate the kinetic data.
The PET kinetic parameters showed significant differences when individual parameters were compared between groups. Significant differences were found in FD, VB, K1, and RBP (p = 0.0275, 0.05, 0.05, and 0.0275 respectively). The 56- to 60-min SUV for 68Ga-BZH3, with a range of 0.86 to 1.29 (median, 1.19) was higher than the corresponding value for the 68Ga-RGD tetramer, with a range of 0.78 to 1.31 (median, 0.99). Furthermore, FD, VB, K1, and RBP for 68Ga-BZH3 were generally higher than the corresponding values for the 68Ga-RGD tetramer, whereas k3 was slightly higher for 68Ga-RGD tetramer.
As a parameter that reflects receptor binding, the increase of K1 for 68Ga-BZH3 indicated higher expression of bombesin receptors than that of the ανβ3 integrin in neuroendocrine tumors. 68Ga-BZH3 seems better suited for diagnosis of NETs owing to higher global tracer uptake.
PMCID: PMC3292467  PMID: 22214362
68Ga-bombesin; 68Ga-RGD tetramer; PET; kinetic modeling; neuroendocrine tumors
14.  A phase II study evaluating neo-/adjuvant EIA chemotherapy, surgical resection and radiotherapy in high-risk soft tissue sarcoma 
BMC Cancer  2011;11:510.
The role of chemotherapy in high-risk soft tissue sarcoma is controversial. Though many patients undergo initial curative resection, distant metastasis is a frequent event, resulting in 5-year overall survival rates of only 50-60%. Neo-adjuvant and adjuvant chemotherapy (CTX) has been applied to achieve pre-operative cytoreduction, assess chemosensitivity, and to eliminate occult metastasis. Here we report on the results of our non-randomized phase II study on neo-adjuvant treatment for high-risk STS.
Patients with potentially curative high-risk STS (size ≥ 5 cm, deep/extracompartimental localization, tumor grades II-III [FNCLCC]) were included. The protocol comprised 4 cycles of neo-adjuvant chemotherapy (EIA, etoposide 125 mg/m2 iv days 1 and 4, ifosfamide 1500 mg/m2 iv days 1 - 4, doxorubicin 50 mg/m2 day 1, pegfilgrastim 6 mg sc day 5), definitive surgery with intra-operative radiotherapy, adjuvant radiotherapy and 4 adjuvant cycles of EIA.
Between 06/2005 and 03/2010 a total of 50 subjects (male = 33, female = 17, median age 50.1 years) were enrolled. Median follow-up was 30.5 months. The majority of primary tumors were located in the extremities or trunk (92%), 6% originated in the abdomen/retroperitoneum. Response by RECIST criteria to neo-adjuvant CTX was 6% CR (n = 3), 24% PR (n = 12), 62% SD (n = 31) and 8% PD (n = 4). Local recurrence occurred in 3 subjects (6%). Distant metastasis was observed in 12 patients (24%). Overall survival (OS) and disease-free survival (DFS) at 2 years was 83% and 68%, respectively. Multivariate analysis failed to prove influence of resection status or grade of histological necrosis on OS or DFS. Severe toxicities included neutropenic fever (4/50), cardiac toxicity (2/50), and CNS toxicity (4/50) leading to CTX dose reductions in 4 subjects. No cases of secondary leukemias were observed so far.
The current protocol is feasible for achieving local control rates, as well as OS and DFS comparable to previously published data on neo-/adjuvant chemotherapy in this setting. However, the definitive role of chemotherapy remains unclear in the absence of large, randomized trials. Therefore, the current regimen can only be recommended within a clinical study, and a possibly increased risk of secondary leukemias has to be taken into account.
Trial registration NCT01382030, EudraCT 2004-002501-72
PMCID: PMC3248452  PMID: 22152120
15.  The Use of Positron Emission Tomography in Soft Tissue Sarcoma Patients under Therapy with Trabectedin 
Marine Drugs  2009;7(3):331-340.
We used 2-deoxy-2-[18F] fluoro-D-glucose (FDG) positron emission tomography (PET) to evaluate the FDG uptake in patients with advanced and/or metastatic soft tissue sarcoma (STS) undergoing therapy with Ecteinascidin-743 (ET-743, Trabectedin, Yondelis™).
Patients and Methods
The pilot study included nine patients with metastatic STS receiving a minimum of one cycle of treatment with trabectedin. Patients were examined using PET prior to onset of therapy and after completion of one or three cycles of trabectedin. Restaging according to Response Evaluation Criteria in Solid Tumours (RECIST) was performed in parallel using computed tomography (CT) and/or magnetic resonance imaging (MRI) and served for reference.
Clinical outcome of nine evaluable patients was as follows: one patient with partial remission (PR), three patients with stable disease (SD), and five patients with progressive disease (PD). A more than 40% decrease of the standardized uptake value (SUV) of sequential PET examination could be demonstrated for the responding patient (PR), whereas patients with SD or PD showed a stable SUV, but no increase in SUV.
To our knowledge, this is the first small series of patients being treated with trabectedin and monitored using sequential PET imaging demonstrating SUV stabilization in nearly all monitored patients.
PMCID: PMC2763103  PMID: 19841717
fluorodeoxyglucose; positron emission tomography; RECIST; soft tissue sarcoma; trabectedin
16.  The Merendino procedure following preoperative imatinib mesylate for locally advanced gastrointestinal stromal tumor of the esophagogastric junction 
Gastrointestinal stromal tumors (GIST) of the esophagogastric junction might pose a major problem to surgical resection. If locally advanced, extended or multivisceral resection with relevant procedural-specific morbidity and mortality is often necessary.
Case presentation
We report a case of a patient with a locally advanced GIST of the esophagogastric junction who was treated by transhiatal resection of the lower esophagus and gastric cardia with reconstruction by interposition of segment of the jejunum (Merendino procedure). Prior to resection, downsizing of the tumor had successfully been achieved by treatment with imatinib mesylate for six months. Histological proof of GIST by immunohistochemical expression of c-KIT and/or PDGF alpha Receptor is crucial to allow embarking on this treatment strategy.
A multimodal approach for an advanced GIST of the esophagogastric junction with preoperative administration of imatinib mesylate could avoid extended resection. The Merendino procedure might be considered as the reconstruction method of choice after resection of GIST at this location.
PMCID: PMC2323006  PMID: 18394167

Results 1-16 (16)