Early response monitoring in malignant lymphoma using fluorine-18 fluorodeoxyglucose single-photon emission tomography

Metabolic response monitoring early during chemotherapy may have a major impact on clinical management of patients with malignant lymphoma. In two patients with non-Hodgkin's lymphoma fluorine-18 fluorodeoxyglucose (18FDG) single-photon emission tomography (SPET) studies were performed during the first two chemotherapeutic cycles. Persisting uptake predicted treatment failure whereas a sharp reduction of 18FDG uptake was demonstrated in the case of a responsive tumour. Qualitative analysis of conventional 18FDG imaging may thus serve to identify patients with a non-responding tumour. The potential of this technique in the determination of the initial response remains to be established. Imaging with 18FDG and SPET appears promising as a more easily available methodology than 18FDG positron emission tomography.     

Metabolic characterization of breast tumors with positron emission tomography using F-18 fluorodeoxyglucose

PURPOSE: To evaluate the diagnostic value of position emission tomographic (PET) imaging with F-18 fluorodeoxyglucose (FDG) in differentiating between benign and malignant breast tumors. PATIENTS AND METHODS: Fifty-one patients, with suspicious breast lesions newly discovered either by physical examination or by mammography, underwent PET imaging before exploratory surgery. FDG-PET images of the breast were analyzed visually and quantitatively for objective assessment of regional tracer uptake. RESULTS: Primary breast cancer was identified visually with a sensitivity of 68% to 94% and a specificity of 84% to 97% depending on criteria used for image interpretation. Quantitative analysis of FDG uptake in tumors using standardized uptake values (SUV) showed a significant difference between benign (1.4 +/- 0.5) and malignant (3.3 +/- 1.8) breast tumors (P < .01). Receiver operating characteristic (ROC) curve analysis exhibited a sensitivity of 75% and a specificity of 100% at a threshold SUV value of 2.5. Sensitivity increased to 92% with a corresponding specificity of 97% when partial volume correction of FDG uptake was performed based on independent anatomic information. CONCLUSION: PET imaging allowed accurate differentiation between benign and malignant breast tumors providing a high specificity. Sensitivity for detection of small breast cancer ( < 1 cm) was limited due to partial volume effects. Quantitative image analysis combined with partial volume correction may be necessary to exploit fully the diagnostic accuracy. PET imaging may be helpful as a complimentary method in a subgroup of patients with indeterminate results of conventional breast imaging.     

Limbic dysfunction in schizophrenia and mania. A study using 18F-labelled fluorodeoxyglucose and positron emission tomography

BACKGROUND: Diagnostic classes (derived from CATEGO) can be correlated with regional brain metabolism in patients with major psychiatric disorders. METHOD: Seventeen patients with schizophrenia, 15 with mania, 10 with depression and 10 healthy Volunteers were examined with positron emission tomography (PET) and 18F-labelled fluorodeoxyglucose, as a marker for glucose metabolism. The number of possible comparisons of regions of interest was reduced by principal-components analysis, and differences in factor scores were determined between diagnostic groups. RESULTS: Four independent factors, representing distributed brain systems, emerged: an anterior-posterior (1), a left-right temporal (2), a temporofrontal (3), and a mediofrontal (4) system, of which (1), (2) and (3) were abnormal in schizophrenia, (1) and (2) in mania, and (1) in depression. CONCLUSIONS: Abnormal patterns of metabolism could be detected, in decreasing order, in schizophrenia, mania and depression. Some of these abnormalities are likely to be due to medication, but others will be associated with structural or functional abnormalities of the frontolimbic system in the diagnostic groups.     

Comparison of fluorine-18 fluorodeoxyglucose positron emission tomography and technetium-99m methoxyisobutylisonitrile scintimammography in the detection of breast tumours

The aim of this study was to compare, in breast cancer patients, the diagnostic accuracy of positron emission tomography (PET) using fluorine-18 fluorodeoxyglucose (FDG) and scintimammography (SMM) using technetium-99m methoxyisobutylisonitrile (MIBI). A total of 20 patients (40 breasts with 22 lesions) were evaluated serially with MIBI and, on the following day, with FDG. For SMM, planar and single-photon emission tomography imaging in the prone position was performed starting at 10 min following the injection of MIBI (740 MBq). For PET, scans were acquired 45-60 min after the injection of FDG (370 MBq) and attentuation correction was performed following transmission scans. Results from SMM and PET were subsequently compared with the histopathology results. True-positive results were obtained in 12/13 primary breast cancers (mean diameter=29 mm, range 8-53 mm) with both FDG and MIBI. False-negative results were obtained in two local recurrences (diameter <9 mm) with both FDG and MIBI. In benign disease, FDG and MIBI did not localize three fibrocystic lesions, two fibroadenomas and one inflammatory lesion (true-negative), but both localized one fibroadenoma (false-positive). Collectively, the results demonstrate a sensitivity of 92%, and a specificity of 86%, for primary breast cancer regardless of whether FDG or MIBI was used. In contrast to MIBI scintigraphy, FDG PET scored the axillae correctly as either positive (metastatic disease) or negative (no axillary disease) in all 12 patients. The tumour/non-tumour ratio for MIBI was 1.97 (range 1.43-3.1). The mean standard uptake value (SUV) for FDG uptake was 2.57 (range 0.3-6.2). The diagnostic accuracy of SMM was equivalent to that of FDG PET for the detection of primary breast cancer. For the detection of in situ lymph node metastases of the axilla, FDG seems to be more sensitive than 99mTc-MIBI.     

Cerebral blood flow and personality: a positron emission tomography study

OBJECTIVE: To determine current practice patterns of obtaining informed consent for infertility treatment by reproductive endocrinologists and to assess changes in response to reports of an association between ovulation induction and ovarian cancer. METHODS: Board-certified reproductive endocrinologists (n = 575) were surveyed by mail regarding how they informed patients and obtained consent for infertility treatments and how their practices had been influenced by studies suggesting a link between ovulation induction and ovarian cancer. Data were analyzed using chi2 and logistic regression analyses. RESULTS: The return rate was 62.1% (357 of 575 surveys). Most respondents (92%) used discussions with physicians to inform their patients of risks and benefits of all infertility treatments. Additional means, such as audiovisual aids, were used significantly more often for assisted reproductive technologies (including intracytoplasmic sperm injection and use of donated eggs) than for less invasive therapies (31-43% versus 4-11%, P < .001). Most physicians (46-66%) used verbal consent alone for hysterosalpingogram, intrauterine insemination, and ovulation induction. Formal written consent was used significantly more often for the various assisted reproductive technologies than for hysterosalpingogram, intrauterine insemination, or ovulation induction (94-95% versus 26-44%). Although most physicians (70%) did not believe that ovulation induction increases the risk of ovarian cancer, 83% addressed this risk when obtaining consent and 47% reported changing their practices since an association was reported. Common changes included limiting length of treatment and addressing ovarian cancer risk. CONCLUSION: Current practice patterns of obtaining informed consent for various infertility treatments by board-certified reproductive endocrinologists show, as expected, that informed consent is more rigorous for assisted reproductive technologies. Although most surveyed did not believe that ovulation induction increases risk of ovarian cancer, the majority of physicians addressed that risk when obtaining consent and nearly half changed their practices on the basis of a possible association.     

Reproducibility of fluorine-18-6-fluorodopa positron emission tomography in normal human subjects

We calculated the mean energy required to produce an ion pair (W) in methane-, propane- and butane-based tissue-equivalent (TE) gas mixtures from W values in pure constituent gases according to various models for energy partition among gas components. We found an agreement between the experimental and calculated W values in the methane-based TE gas regardless of the model concept. In contrast, only those models which take into account differences in the stopping powers, total ionization cross sections and model constants of gas components give acceptable results for the propane-based TE gas. The calculated W value for high-energy electrons in the isobutane-based TE gas mixture is 25.2 eV for high-energy electrons and 28.0 eV for approximately 5 MeV alpha particles.     

Fluorine-18 fluorodeoxyglucose positron emission tomography in the differential diagnosis of pancreatic carcinoma: a report of 106 cases

The aim of this study was to evaluate fluorine-18 fluorodeoxyglucose positron emission tomography ([18F]FDG PET) as a tool for the differential diagnosis of pancreatic carcinoma while taking into account serum glucose level. A group of 106 patients with unclear pancreatic masses were recruited for the study. PET was performed following intravenous administration of an average of 190 MBq [18F]FDG. Focally increased glucose utilisation was used as the criterion of malignancy. In addition, the "standardised uptake value" (SUV) was determined 45 min after injection. Carcinoma of the pancreas was demonstrated histologically in 74 cases, and chronic pancreatitis in 32 cases. Employing visual evaluation, 63 of the 74 (85%) pancreatic carcinomas were identified by PET. In 27 of the 32 cases (84%) of chronic pancreatitis it was possible to exclude malignancy. False-negative results (n=11) were obtained mostly in patients with raised serum glucose levels (10 out of 11), and false-positives (n=5) in patients with inflammatory processes of the pancreas. Thus PET showed an overall sensitivity of 85%, a specificity of 84%, a negative predictive value of 71%, and a positive predictive value of 93%. In a subgroup of patients with normal serum glucose levels (n=72), the results were 98%, 84%, 96% and 93%, respectively. Quantitative assessment yielded a mean SUV of 6.4+/-3.6 for pancreatic carcinoma as against a value of 3.6+/-1.7 for chronic pancreatitis (P<0.001), without increasing the diagnostic accuracy. This shows PET to be of value in assessing unclear pancreatic masses. The diagnostic accuracy of PET examinations is very dependent on serum glucose levels.     

Controlled prospective study of positron emission tomography using the glucose analogue [18f]fluorodeoxyglucose in the evaluation of pulmonary nodules

BACKGROUND: Positron emission tomography (PET) is a new imaging technique which, by measuring focal metabolic activities, can make a qualitative statement (benign or malignant) about a tumour. PET has been described in many studies to provide a high diagnostic accuracy for the evaluation of pulmonary coin lesions. However, these studies were not always supported by histological confirmation of the results. In a controlled prospective study, it was investigated whether the diagnostic accuracy of PET is sufficiently high to allow omission of diagnostic thoracotomy or thoracoscopy in the case of a negative finding. METHODS: A PET scan was carried out before operation using [18F]fluorodeoxyglucose (FDG) in 50 patients with pulmonary coin lesions (diameter 30 mm or less). All of these lesions were completely removed thoracoscopically or by a formal thoracotomy and were examined histologically. Using the histology results, the diagnostic accuracy of the PET procedure with regard to a benign or malignant diagnosis was evaluated and compared with that of computed tomography (CT). Results From a total of 54 coin lesions (four of the 50 patients had two lesions) there were 31 malignant (19 primary bronchial carcinomas, 12 metastases) and 23 benign diagnoses. With the PET procedure 28 of 31 malignant and 19 of 23 benign lesions were classified correctly (sensitivity 90 per cent, specificity 83 per cent). False negatives included two bronchial carcinomas and one metastasis. CT had a sensitivity of 100 per cent and specificity of 52 per cent. CONCLUSION: FDG PET cannot generally be considered as a replacement for diagnostic thoracoscopy or thoracotomy at the present time. However, by combining FDG PET with radiological follow-up, clinical applications may evolve in patients at low risk for a malignant tumour or at high risk for surgical complications.     

18F]fluorodeoxyglucose uptake in neonatal acute lung injury measured by positron emission tomography

PURPOSE: Our goal was to investigate the role of serial dynamic contrast-enhanced SPGR MRI in the nonsurgical follow-up of patients with temporomandibular joint (TMJ) pain. METHOD: Ten patients (10 joints) with internal derangement of the TMJ were imaged with T1-weighted SE and serial postgadolinium SPGR MR pulse sequences. RESULTS: On T1-weighted images prior to treatment, the disk position was normal in one joint and anteriorly displaced without reduction in nine joints. After treatment, the disk remained normally positioned in one joint, was anteriorly displaced without reduction in eight joints, and was anteriorly displaced with reduction in one joint. The dynamic study after treatment showed a decrease in contrast enhancement of the posterior disk attachment in 7 of 10 joints. These seven patients had resolution or reduction in joint pain. CONCLUSION: These results suggest an association between a decrease in contrast enhancement of the posterior disk attachment and resolution or reduction in joint pain. This association was much stronger than the association between the clinical findings and the anatomy of the disk.     

Introducing fluorine-18 fluoromisonidazole positron emission tomography for the localisation and quantification of pig liver hypoxia

Fluorine-18 labelled fluoromisonidazole ([18F]FMISO) has been shown to accumulate in hypoxic tissue in inverse proportion to tissue oxygenation. In order to evaluate the potential of [18F]FMISO as a possible positron emission tomography (PET) tracer for imaging of liver tissue hypoxia, we measured the [18F]FMISO uptake in 13 domestic pigs using dynamic PET scanning. Hypoxia was induced by segmental arterial hepatic occlusion. During the experimental procedure the fractional concentration of inspired oxygen (FiO2) was set to 0.67 in group A (n=6) and to 0.21 in group B (n=7) animals. Before and after arterial occlusion, the partial pressure of O2 in tissue (TPO2) and the arterial blood flow were determined in normal flow and flow-impaired liver segments. Standardised uptake values [SUV=kBq tissue (in g) / body weight (in kg) x injected dose (in kBq)] for [18F]FMISO were calculated from PET images obtained 3 hours after injection of about 10 MBq/kg body weight [18F]FMISO. Immediately before PET scanning, the mean arterial blood flow was significantly decreased in arterially occluded segments [group A: 0. 41 (0.32-0.52); group B: 0.24 (0.16-0.33) ml min-1 g-1] compared with normal flow segments [group A: 1.05 (0.76-1.46); group B: 1.14 (0.83-1.57) ml min-1 g-1; geometric mean (95% confidence limits); P<0.001 for both groups]. After PET scanning, the TPO2 of occluded segments (group A: 5.1 (4.1-6.4); group B: 3.5 (2.6-4.9) mmHg] was significantly decreased compared with normal flow segments [group A: 26.4 (21.2-33.0); group B: 18.2 (13.3-25.1) mmHg; P<0.001 for both groups]. During the 3-h PET scan, the mean [18F]FMISO SUV determined in occluded segments increased significantly to 3.84 (3.12-4.72) in group A and 5.7 (4.71-6.9) in group B, while the SUV remained unchanged in corresponding normal liver tissue [group A: 1.4 (1.14-1. 71); group B: 1.31 (1.09-1.57); P<0.001 for both groups]. Regardless of ventilation conditions, a significant inverse exponential relationship was found between the TPO2 and the [18F]FMISO SUV (r2=0. 88, P<0.001). Our results suggest that because tracer delivery to hypoxic tissues was maintained by the portal circulation, the [18F]FMISO accumulation in the liver was found to be directly related to the severity of tissue hypoxia. Thus, [18F]FMISO PET allows in vivo quantification of pig liver hypoxia using simple SUV analysis as long as tracer delivery is not critically reduced.     

Evaluation of pancreatic tumors with positron emission tomography and F-18 fluorodeoxyglucose: comparison with CT and US

PURPOSE: To assess the clinical value of positron emission tomography (PET) with fluorine-18-labeled fluorodeoxyglucose (FDG) for identification of pancreatic carcinoma. MATERIALS AND METHODS: Forty-six patients suspected of having a pancreatic neoplasm and who were to undergo surgery prospectively underwent FDG PET, computed tomography (CT), and transabdominal ultrasound (US). Endoscopic US was performed in 40 patients. Images were independently interpreted and compared with the histopathologic findings at surgery (41 patients) or with clinical follow-up findings (five patients). RESULTS: In 33 of 35 patients, foci of pancreatic carcinomas (10-100 mm in diameter) were identified as an increase in FDG uptake, whereas CT, transabdominal US, and endoscopic US depicted the foci in 31, 31, and 28, cases, respectively. Among 11 benign lesions, nine showed no increased FDG uptake (specificity = 82%). Specificities of the other modalities were lower. False-positive findings were obtained in a case of chronic active pancreatitis and in a serous cystadenoma. CONCLUSION: FDG PET, which provides "biochemical" information, is accurate in identifying pancreatic carcinoma and may be a method of choice when imaging equivocal masses detected with other "anatomic" imaging studies.     

Metabolic imaging of malignant pleural mesothelioma with fluorodeoxyglucose positron emission tomography

BACKGROUND: The diagnosis of malignant mesothelioma is a challenging medical problem. CT often cannot differentiate between benign diffuse pleural thickening and malignant mesothelioma, while thoracentesis and CT-guided biopsies are insensitive. We have assessed the value of positron emission tomography (PET) with 2-fluoro-2-deoxy-D-glucose (FDG) in the evaluation of malignant mesothelioma. METHODS: Twenty-eight consecutive patients referred for the evaluation of suspected malignant mesothelioma were evaluated by FDG-PET imaging. Measured attenuation correction was performed in 26 of 28 cases for quantitation with the standardized uptake value (SUV) method. The results of PET imaging were compared with those of video-assisted thoracoscopy or surgical biopsies. RESULTS: Surgical biopsy specimens confirmed the presence of malignant disease in 24 patients and demonstrated benign processes in the remaining four. The uptake of FDG was significantly higher in malignant than in benign lesions (SUV=4.9+/-2.9 and SUV=1.4+/-0.6, respectively; p<0.0001). With a SUV cutoff of 2.0 to differentiate between malignant and benign disease, a sensitivity of 91% and a specificity of 100% could be achieved, although the activity in some epithelial mesotheliomas tended to be close to this threshold. FDG-PET images provided excellent delineation of the active tumor sites. Hypermetabolic lymph node involvement was noted on FDG-PET images in 12 patients, 9 of which appeared normal on CT scans. Histologic examination in six patients confirmed malignant nodal disease in five cases and indicated granulomatous lymphadenitis in one. CONCLUSION: In this highly selected population, FDG-PET imaging was a sensitive method to identify malignant mesothelioma and determine the extent of the disease process.     

Correlation between myocardial blood flow and fasting glucose metabolism in ischemic heart disease. Quantitative assessment by nitrogen-13 ammonia and fluorine-18 fluorodeoxyglucose positron emission tomography

In Poland cutaneous form of anthrax is occurring sporadically. Most of these cases were recognized in the eastern part of the country adjacent to the eastern border (Lomza region and others). The latest literature on epidemiology, diagnosis, prevention and treatment of anthrax is reviewed in order to spread modern views on anthrax and to implement changes in the diagnostic methods of anthrax in Poland.     

Evaluation of fluorodeoxyglucose positron emission tomography in the management of soft-tissue sarcomas

OBJECTIVE: This study aimed to determine whether clinical tests of ocular function and macular appearance independently can help to predict which patients with unilateral neovascular age-related macular degeneration (AMD) will have a choroidal neovascular membrane (CNVM) develop in their fellow eye. DESIGN: The study design was a prospective cohort study. PARTICIPANTS: One hundred twenty-seven patients with unilateral neovascular AMD observed for up to 4.5 years participated. INTERVENTION: Functional measurements included visual acuity, macular visual field, glare recovery time, and foveal electroretinogram amplitude and implicit time. MAIN OUTCOME MEASURE: The age-adjusted proportion of patients having a CNVM develop over follow-up assessed by the Cox proportional hazards model with stepwise selection was measured. RESULTS: On average, 8.8% of patients had a CNVM develop each year. Independent risk factors for the fellow eye were its glare recovery time in minutes (relative risk = 1.30, confidence interval = 1.10-1.54, P = 0.003) and its extent of visible macular abnormalities on a four-point scale (relative risk = 1.62, confidence interval = 1.06-2.59, P = 0.03). Of the fellow eyes that converted, the interval to have a CNVM develop was inversely related to the foveal electroretinogram implicit time. CONCLUSIONS: A slower recovery from glare and more extensive funduscopic changes appear to be independent risk factors for the development of a CNVM in the fellow eyes of patients with unilateral neovascular AMD. A slower foveal electroretinogram implicit time may be a sign of early stage CNVM development, perhaps because of outer retinal ischemia. These results have clinical management implications, particularly for those patients at high risk of having a potentially treatable form of AMD develop.     

Dynamic positron emission tomography with F-18 fluorodeoxyglucose imaging in differentiation of benign from malignant lung/mediastinal lesions

PURPOSE: This study was done to evaluate the diagnostic utility of dynamic positron emission tomography (PET) with F-18 fluorodeoxyglucose (FDG) imaging in patients with suspected malignant pulmonary lesions. We wanted to test the hypothesis that the rate of FDG uptake (FDG influx constant values) would differentiate malignant from benign lung or mediastinal lesions. MATERIALS AND METHODS: We performed segmental dynamic PET imaging studies following administration of FDG in 19 patients with indeterminate pulmonary lesions based on chest radiograph and/or CT scans. Patlak analysis was done to compute Ki (FDG influx constant) values and compared with FDG standardized uptake values (SUVs) and histology. RESULTS: FDG Ki values (mean+/-SD) were significantly greater (p < 0.01) in all 12 malignant lesions (0.029+/-0.02) as compared with 7 benign lesions (0.0024+/-0.0011) with good correlation to the SUV values. Distinct time activity curve patterns were identified in malignant and benign lesions with continued uptake in malignant lesions. CONCLUSION: Dynamic PET-FDG imaging accurately differentiates malignant from benign pulmonary lesions. In certain cases with equivocal findings on visual analysis and SUV values, dynamic imaging may be further helpful in differentiating benign and malignant lesions.     

Cerebral imaging of decompression injury patients with 18-F-2-fluoro-2-deoxyglucose positron emission tomography

Four statistical strategies were used to evaluate whether occurrence of daily stressors increases lower gastrointestinal (GI) symptoms in irritable bowel syndrome (IBS) patients. Across-subject concurrent correlations between weekly stress and symptoms were positive but casually ambiguous and obscured between- and within-subject and occasion relationships. Multiple regressions assessing (weekly and daily) relations showed that prior symptoms predicted subsequent symptoms but that prior and concurrent daily stress had no consistent effects. Idiographic correlations also showed little evidence for a relationship between stress and symptoms. Daily stress did not appear to increase GI symptoms in IBS patients on a general basis. Daily recording methodology, in conjunction with within-subject analytic strategies, is proposed as an innovative approach to examine relations between stress and physical symptomatology.     

Attenuation-corrected 99mTc-tetrofosmin single-photon emission computed tomography in the detection of viable myocardium: comparison with positron emission tomography using 18F-fluorodeoxyglucose

OBJECTIVES: The purpose of this study was to assess the efficacy of attenuation-corrected (AC) technetium-99m (99mTc)-tetrofosmin single-photon emission computed tomography (SPECT) in detecting viable myocardium compared to 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET). BACKGROUND: The role of 99mTc-labeled perfusion tracers in the assessment of myocardial viability remains controversial. Attenuation artifacts affect the diagnostic accuracy of SPECT images. METHODS: Twenty-four patients with coronary artery disease (mean left ventricular ejection fraction 30%) underwent resting 99mTc-tetrofosmin SPECT and FDG PET imaging. Both AC and non-attenuation-corrected (NC) SPECT images were generated. RESULTS: Using a 50% threshold for viability by FDG PET, the percentage of concordant segments of viability between 99mTc-tetrofosmin and FDG on the patient basis increased from 79.8%+/-14.0% (mean+/-SD) on the NC images to 90.8%+/-10.6% on the AC images (p=0.002). The percentage of 99mTc-tetrofosmin defect segments within PET-viable segments, an estimate for the degree of underestimation of viability, decreased from 19.8%+/-15.2% on the NC images to 9.7%+/-12.6% on the AC images (p=0.01). Similar results were obtained when a 60% threshold was used to define viability by FDG PET. When the anterior-lateral and inferior-septal regions were separately analyzed, the effect of attenuation correction was significant only in the inferior-septal region. CONCLUSIONS: The results indicate that AC 99mTc-tetrofosmin SPECT improves the detection of viable myocardium mainly by decreasing the underestimation of viability particularly in the inferior-septal region, although some underestimation/overestimation of viability may still occur even with attenuation correction.     

Short-term and long-term verbal memory: a positron emission tomography study

Short-term and long-term retention of experimentally presented words were compared in a sample of 33 healthy normal volunteers by the [15O]H2O method with positron emission tomography (PET). The design included three conditions. For the long-term condition, subjects thoroughly studied 18 words 1 week before the PET study. For the short-term condition, subjects were shown another set of 18 words 60 sec before imaging, with instructions to remember them. For the baseline condition, subtracted from the two memory conditions, subjects read a third set of words that they had not previously seen in the experiment. Similar regions were activated in both short-term and long-term conditions: large right frontal areas, biparietal areas, and the left cerebellum. In addition, the short-term condition also activated a relatively large region in the left prefrontal region. These complex distributed circuits appear to represent the neural substrates for aspects of memory such as encoding, retrieval, and storage. They indicate that circuitry involved in episodic memory has much larger cortical and cerebellar components than has been emphasized in earlier lesion studies.