Impact of background parenchymal enhancement levels on the diagnosis of contrast-enhanced digital mammography in evaluations of breast cancer: comparison with contrast-enhanced breast MRI.

PURPOSE: To compare the diagnostic performances of contrast-enhanced digital mammography (CEDM) and breast MRI in evaluations of breast cancer, with a focus on the impact of background parenchymal enhancement (BPE) levels. METHODS: The present study included women who underwent CEDM and breast MRI to evaluate the disease extent of breast cancer between January 2018 and December 2019. Readers judged BPE levels (minimal-mild or moderate-marked) on CEDM, and were asked to assign findings suggesting malignancy using the following criteria: (1) enhancement other than BPE and (2) BI-RADS 4/5 calcifications without enhancement. On MRI, BI-RADS 3 and BI-RADS 4/5 lesions were evaluated as benign and malignant, respectively. The diagnostic performances of CEDM and MRI were compared separately between women with minimal-mild BPE and those with moderate-marked BPE. RESULTS: Sixty-nine patients comprising 43 postmenopausal and 26 premenopausal women were included in the present study. In total, 195 lesions (94 malignant and 101 benign) were identified. The sensitivity and specificity of CEDM for the diagnosis of all lesions were 90.8 and 91.5% with minimal-mild BPE and 79.3 and 76.2% with moderate-marked BPE, respectively. The sensitivity and specificity of MRI were 90.0% and 71.0% with minimal-mild BPE and 87.5% and 78.1% with moderate-marked BPE, respectively. The accuracy of CEDM was significantly superior to that of MRI in women with minimal-mild BPE on both CEDM and MRI (p = 0.002). Regarding the negative impact of a correct diagnosis on CEDM, the odds ratio of "moderate-marked BPE" was 0.382. CONCLUSION: In patients with minimal-mild BPE, the diagnostic performance of CEDM was superior to that of MRI.

The association between MRI findings and breast cancer subtypes: focused on the combination patterns on diffusion-weighted and T2-weighted images.

PURPOSE: To assess morphology on diffusion-weighted imaging (DWI) and intratumoral signal intensity (SI) on T2-weighted images (T2WI) of breast carcinomas, and to evaluate the association between the combined DWI and T2WI findings and breast cancer subtypes. METHODS: Two hundred and eighty breast cancer patients who underwent breast MRI prior to therapy were included in this retrospective study. All had invasive carcinomas, which were classified into five subtypes: Luminal A-like (n = 149), Luminal B-like (n = 63), Hormone receptor-positive HER2 (n = 31), Hormone receptor-negative HER2 (n = 13), or Triple-negative (TN) (n = 24). Based on the morphology on DWI, the tumors were classified into two patterns: DWI-homogeneous or DWI-heterogeneous. If DWI-heterogeneous, an assessment of intratumoral SI on T2WI was performed: tumors with intratumoral high/low SI on T2WI were classified as Hete-H/Hete-L, respectively. The associations between (1) the morphological patterns on DWI and the five subtypes, and (2) the intratumoral SI patterns on T2WI and the five subtypes in DWI-heterogeneous were evaluated. RESULTS: There was a significant association between (1) the morphological patterns on DWI and the five subtypes (p < 0.0001), and (2) the intratumoral SI patterns on T2WI and the five subtypes in DWI-heterogeneous (p < 0.0001). DWI-homogeneous was dominant in Luminal A-like (67.1%), and Hete-H was dominant in TN type (75%). Hete-H, suggesting the presence of intratumoral necrosis, included high proliferative and/or aggressive subtypes more frequently (80%) than Hete-L, suggesting the presence of fibrotic focus. Fibrotic focus was seen more commonly in the luminal subtypes. CONCLUSION: The combined findings on DWI and T2WI revealed breast carcinomas that were associated with particular subtypes.

Comparison of 3- and 1.5-T dynamic breast MRI for visualization of spiculated masses previously identified using mammography.

OBJECTIVE: The purpose of this article is to determine the effectiveness of MRI for visualizing spiculated breast cancer lesions that were previously identified using mammography and to compare the diagnostic quality of 3- and 1.5-T dynamic MRI by assessing the visualization of spiculation in such lesions. MATERIALS AND METHODS: One hundred twenty MRI studies of breast cancers clearly identified as spiculated masses using mammography (71 MRI studies at 3 T that included both bilateral axial and unilateral sagittal images and 49 MRI studies at 1.5 T that included bilateral axial images only) were independently reviewed by three radiologists. The three different radiologists scored the visualization of the spiculation with respect to 3-T sagittal, 3-T axial, or 1.5-T axial images. RESULTS: The diagnostic quality of sagittal 3-T dynamic MRI studies, as determined by assessing the visualization of spiculation, was significantly better than that of axial 3-T (p = 0.009) and 1.5-T (p = 0.004) studies. For small (< 1 cm) lesions, the diagnostic quality of sagittal 3-T studies determined by assessing the visualization of spiculation was significantly better than that of axial 1.5-T studies (p = 0.029). CONCLUSION: Unilateral sagittal in-plane and through-plane high-spatial-resolution 3-T images can offer particularly higher spatial resolution for improved assessment of spiculation than do axial in-plane high-spatial-resolution images obtained at 1.5 and 3 T.

The role of breast MR imaging in pre-operative determination of invasive disease for ductal carcinoma in situ diagnosed by needle biopsy.

OBJECTIVES: To evaluate whether magnetic resonance (MR) imaging features can predict the presence of occult invasion in cases of biopsy-proven pure ductal carcinoma in situ (DCIS). METHODS: We retrospectively reviewed 92 biopsy-proven pure DCIS in 92 women who underwent MR imaging. The following MR imaging findings were compared between confirmed DCIS and invasive breast cancer (IBC): lesion size, type, morphological and kinetic assessments by ACR BI-RADS MRI, and findings of fat-suppressed T2-weighted (FS-T2W) imaging. RESULTS: Sixty-eight of 92 (74%) were non-mass-like enhancements (NMLE) and 24 were mass lesions on MR imaging. Twenty-one of 68 (31%) NMLE and 13 of 24 (54%) mass lesions were confirmed as IBC. In NMLE lesions, large lesions (P = 0.007) and higher signal intensities (SI) on FS-T2W images (P = 0.032) were significantly associated with IBC. Lesion size remained a significant independent predictor of invasion in multivariate analysis (P = 0.032), and combined with FS-T2W SIs showed slightly higher observer performances (area under the curve, AUC, 0.71) than lesion size alone (AUC 0.68). There were no useful findings that enabled the differentiation of mass-type lesions. CONCLUSIONS: Breast MR imaging is potentially useful to predict the presence of occult invasion in biopsy-proven DCIS with NMLE. KEY POINTS: MR mammography permits more precise lesion assessment including ductal carcinoma in situ A correct diagnosis of occult invasion before treatment is important for clinicians This study showed the potential of MR mammography to diagnose occult invasion Treatment and/or aggressive biopsy can be given with greater confidence MR mammography can lead to more appropriate management of patients.

Incremental value of T2-weighted and diffusion-weighted MRI for prediction of biochemical recurrence after radical prostatectomy in clinically localized prostate cancer.

BACKGROUND: For men with clinically localized prostate cancer and candidates to receive radical prostatectomy (RP) a main concern is a cancer recurrence after treatment. Although previous studies have demonstrated the diagnostic utility of diffusion-weighted imaging (DWI) for prostate cancer, the prognostic value of pretreatment DWI has not been investigated yet. PURPOSE: To investigate the incremental value of MRI-based T staging using DWI and T2-weighted imaging (T2WI) as compared with the clinical parameters in prediction of biochemical recurrence (BCR) after RP for clinically localized prostate cancer. MATERIAL AND METHODS: Sixty MR examinations, obtained before RP between April 2002 and March 2009, were retrospectively reviewed using T2WI alone, DWI alone, or T2WI + DWI for T staging according to the 2002 American Joint Committee on Cancer guidelines. The relationship between MRI stage and BCR was evaluated using Kaplan-Meier survival estimates. Multivariate analysis and receiver operating characteristics (ROC) curve analysis were used to investigate the incremental value over the standard clinical variables in prediction of BCR. RESULTS: As of August 2009, 12 (20%) patients had BCR. Based on T2WI + DWI, both T3a (compared to OC disease) and T2 (compared to T1c) showed significantly higher BCR rates (p=0.047 and 0.025, respectively). Multivariate analysis and area under ROC curve analysis confirmed the additional value of MRI staging to the conventional clinical variables in prediction of BCR. CONCLUSION: The combination of T2WI and DWI on performing pretreatment MRI helped predict BCR after RP in clinically localized prostate cancer.

Metastatic skull tumors: MRI features and a new conventional classification.

Skull metastases are malignant bone tumors which are increasing in incidence. The objectives of this study were to characterize the MR imaging features, locations, and extent of metastatic skull tumors to determine the frequency of the symptomatic disease, and to assess patient outcomes. Between September 2002 and March 2008, 175 patients undergoing routine head MR imaging were found to have metastatic skull tumors. Contrast-enhanced study with fat suppression was used in some cases when required. Classification of metastases was simplified to three yes/no questions: first, with regard to location (either in the calvarium or in the cranial base); second, with regard to distribution within the plane of the cranial bone (either "circumscribed" meaning clearly demarcated and confined to one bone, or "diffuse" and likely to spread across a suture to another bone); and third, with regard to invasion ("intraosseous" in cranial bones only, or "invasive" spreading from the skull, either out into the scalp or inward to the dura and perhaps further in). Primary sites were breast cancer (55%), lung cancer (14%), prostate cancer (6%), malignant lymphoma (5%), and others (20%). The mean time from primary diagnosis to skull metastasis diagnosis was 71 months for cases of breast cancer, 26 months for prostate cancer, 9 months for lung cancer, and 4 months for malignant lymphoma. Calvarial circumscribed intraosseous metastases were found most frequently (27%). The patients were mainly asymptomatic. However, some patients suffered from local pain or cranial nerve palsies that harmed their quality of life. Treatment, mainly for symptomatic cases, was by local or whole-skull irradiation. Metastatic skull tumors are not rare, and most are calvarial circumscribed intraosseous tumors. MR images contribute to understanding their type, location, and multiplicity, and their relationship to the brain, cranial nerves, and dural sinuses. Radiation therapy improved the QOL of patients with neurological symptoms.

Moyamoya patients exhibit higher brain temperatures than normal controls.

The balance between heat production (metabolism) and heat removal (blood flow) helps in keeping the temperature of the brain constant. In patients with moyamoya disease, this balance may be disturbed. The purpose of this study was to assess the thermal pathophysiology of the brain in patients with moyamoya disease. The study included 12 consecutive patients with moyamoya disease and 10 controls. Temperature was measured by image postprocessing of diffusion-weighted images. Our noninvasive thermometry showed that the ventricular temperature of moyamoya disease patients was higher than that of normal controls. The mean temperature difference of 1.1 degrees C between the two groups was significant. Patients with moyamoya disease tend to have elevated ventricular temperatures, which may represent a mismatch between cerebral metabolism and perfusion.

Neoadjuvant chemotherapy for breast cancer: correlation between the baseline MR imaging findings and responses to therapy.

OBJECTIVE: To retrospectively evaluate the magnetic resonance (MR) imaging findings of breast cancer before neoadjuvant chemotherapy (NAC) and to compare findings of chemosensitive breast cancer with those of chemoresistant breast cancer. METHODS: The MR imaging findings before NAC in 120 women undergoing NAC were reviewed. The MR imaging findings were compared with the pathological findings and responses. RESULTS: A complete response (pCR) and marked response were achieved in 12 and 35% of 120 breast cancers in 120 women respectively. Breast cancers with a pCR or marked response were classified as chemosensitive breast cancer. The remaining 64 breast cancers (53%) were classified as chemoresistant breast cancer. Large tumour size, a lesion without mass effect, and very high intratumoural signal intensity on T2-weighted MR images were significantly associated with chemoresistant breast cancer. Lesions with mass effect and washout enhancement pattern were significantly associated with chemosensitive breast cancer. Areas with very high intratumoural signal intensity on T2-weighted images corresponded pathologically to areas of intratumoural necrosis. CONCLUSION: Several MR imaging features of breast cancer before NAC can help predict the efficacy of NAC.

Optimum b value for resolving crossing fibers: a study with standard clinical b value using 1.5-T MR.

INTRODUCTION: We sought to investigate the optimum b value for resolving crossing fiber using high-angular resolution diffusion imaging (HARDI)-based multi-tensor tractography. The study tested the standard b values that are commonly used in the routine clinical setting. METHODS: Ten normal volunteers (five men and five women) with a mean age of 26.3 years (range, 22-32 years) were scanned using a 1.5-T clinical magnetic resonance unit. Single-shot echo-planar imaging was used for diffusion-weighted imaging with a diffusion-sensitizing gradient in 32 orientations. The b values of 700, 1,400, 2,100, and 2,800 s/m(2) were used. Data postprocessing was performed using multi-tensor methods. The depiction of the optic nerves, optic tracts, and decussation of superior cerebellar peduncles were assessed. RESULTS: The depictions of the nerve fibers were independent of the b values tested. CONCLUSION: The depiction of crossing fibers by HARDI-based multi-tensor tractography is not substantially influenced by b values ranging from 700 to 2,800 s/m(2). Thus, the optimum b value within this range may be the lowest one considering the higher signal to noise ratio.

MR tractography: a review of its clinical applications.

Magnetic resonance tractography based on diffusion-tensor imaging was first introduced to the medical imaging community a decade ago. It has been successfully applied to a number of neurological conditions and most commonly used for preoperative planning for brain tumors and vascular malformations. Areas of active research include stroke, and dementia, where it provides valuable information not available through other imaging techniques. This technique was first introduced using the deterministic streamline algorithm and has evolved to use more sophisticated probabilistic approaches. We will review the past, present, and future of tractography, focusing primarily on its clinical applications.

A cluster of microcalcifications: women with high risk for breast cancer versus other women.

BACKGROUND: Abnormal screening mammographic findings are the most common presentation of ductal carcinoma in situ, which usually appears as a cluster of microcalcifications. No report has documented the risk of malignancy between the finding of a cluster of microcalcifications and women with high risk of breast cancer. METHODS: We investigated the morphologic descriptors of a cluster of microcalcifications in women with a high risk for breast cancer and compared the results with the characteristics of a cluster of microcalcifications in other women. A retrospective review was performed for 81 non-palpable clusters of microcalcifications that had stereotactic vacuum-assisted breast biopsy. RESULTS: The frequency of malignancy associated with a cluster of microcalcifications was 27%. The 50% frequency of malignancy with high risk for breast cancer was higher, but not significantly so, than the 24% frequency of 71 cases without high risk for breast cancer (P = 0.125). The frequency of malignancy and ADH of a cluster of microcalcifications with high risk of breast cancer was 70%, significantly higher than the 30% frequency of 71 cases without high risk of breast cancer (P = 0.028). CONCLUSIONS: A cluster of microcalcifications in women with high risk for breast cancer should be considered suspicious and referred for biopsy.

Microperfusion-induced elevation of ADC is suppressed after contrast in breast carcinoma.

PURPOSE: To investigate the effect of gadolinium (Gd)-DTPA on the apparent diffusion coefficient (ADC) of breast carcinoma and to analyze the relationship between pre/postcontrast ADC and the degree of contrast enhancement. MATERIALS AND METHODS: Nineteen histopathologically confirmed breast carcinomas (mean size = 22 mm) were analyzed. Their ADCs before and after contrast administration were measured. The contrast-to-noise ratios (CNRs) of the tumors were measured on fat-suppressed 3D T1-weighted images in precontrast, early, and late postcontrast phases. These results were correlated with the measured ADC values. RESULTS: A significant decrease in the measured ADC was noted after contrast administration (-23%, P = 0.01). Lesions with relatively high ADC before contrast (>1.3 x 10(-3) mm(2)/sec; n = 12) demonstrated a larger degree of ADC reduction (mean 34%) than lesions with low ADC (< or =1.3 x 10(-3) mm(2)/sec; n = 7) (mean 4.5%). When an early postcontrast image was used as a surrogate marker of malignant potential, we found a significant inverse correlation with postcontrast ADC (gamma = -0.57, P = 0.02). CONCLUSION: Postcontrast ADC exhibited lower values than precontrast ADC, which is thought to reflect suppression of the microperfusion-induced effect on diffusion-weighted imaging. Postcontrast ADC may be a better indicator than precontrast ADC to reflect malignant potential of tumors.

Triple-negative breast cancer: correlation between MR imaging and pathologic findings.

PURPOSE: To retrospectively evaluate the magnetic resonance (MR) imaging findings of "triple-negative" breast cancer (ie, cancer that is estrogen receptor [ER] negative, progesterone receptor [PR] negative, and human epidermal growth factor receptor 2 [HER2] negative) and to compare them with those of breast cancers that are ER positive, PR positive, and HER2 negative. MATERIALS AND METHODS: Institutional review board approval and informed consent were obtained. The MR imaging findings in 176 randomly assigned women (mean age, 56 years; range, 29-87 years) with surgically confirmed triple-negative breast cancers (n = 59) or ER-positive/PR-positive/HER2-negative breast cancers (n = 117) were reviewed. MR imaging findings included tumor shape, margin, internal enhancement, and size, as well as intratumoral signal intensity that was stronger than or almost the same as that of water or vessels on T2-weighted MR images. The MR imaging findings were compared with the pathologic findings. RESULTS: High histologic grade (P < .001), unifocal lesion (P = .012), mass lesion type (P < .001), smooth mass margin (P = .001), rim enhancement (P < .001), persistent enhancement pattern (P = .005), and very high intratumoral signal intensity on T2-weighted MR images (P = .002) were significantly associated with triple-negative breast cancer. Very high intratumoral signal intensity on T2-weighted MR images was significantly associated with intratumoral necrosis (P < .001). CONCLUSION: Several MR imaging features might be used for detecting triple-negative breast cancer.

Comparison of FDG PET and MRI for evaluating the tumor extent of breast cancer and the impact of FDG PET on the systemic staging and prognosis of patients who are candidates for breast-conserving therapy.

BACKGROUND: FDG PET has not yet found a role in the clinical evaluation of the tumor extent of breast cancer. FDG PET has been reported to be useful for evaluating the prognoses of breast cancer patients with more accuracy than conventional imaging modalities. The purpose of this study was to compare the accuracy of FDG PET and MRI for the preoperative assessment of the tumor extent of breast cancer, for evaluating the impact of FDG PET on systemic staging, and also for predicting the prognosis of patients who are candidates for breast-conserving therapy. METHODS: The study was a prospective series of 23 breasts with breast cancer that underwent both FDG PET and MRI before surgery. Systemic staging with FDG PET was also performed. The correlation between the results of these examinations and histological findings was thus examined. The maximum standardized uptake value (SUVmax) of the tumors was investigated in association with the patient prognoses. RESULTS: When evaluating the local tumor extent, the accuracy of FDG PET (43.5%) was significantly lower than that of MRI (91%) (P < 0.001). The sensitivity, specificity, and accuracy of FDG PET regarding the nodal status were 60, 94, and 87%, respectively. No patients demonstrated any distant metastasis, whereas FDG PET gave a false positive in one patient. The mean follow-up period was 61 months. The SUVmax value of the worse prognosis patient group was significantly higher than that of the good prognosis patient group (P = 0.032). CONCLUSIONS: FDG PET is not a breast imaging modality for evaluating the local tumor extent, but it is useful for predicting the prognoses of patients who are candidates for breast-conserving therapy.

Segmental enhancement on breast MR images: differential diagnosis and diagnostic strategy.

The histopathological variations of segmental enhancement on breast magnetic resonance imaging (MRI) were investigated, with the aim of identifying imaging characteristic clues to their differential diagnosis. We reviewed 70 breast MRI examinations demonstrating segmental enhancement, classified them based on their histopathology, and assessed their MRI findings as follows: (1) confluent or not confluent, (2) late enhancement pattern, and the absence or presence of (3) clustered ring enhancements and (4) surrounding high signal intensity (SI) on T2-weighted imaging. Thirteen lesions (18.5%) were benign, eight (11.5%) were high risk, 25 (36%) were ductal carcinoma in situ (DCIS) and 24 (34%) were infiltrating mammary carcinomas (IMC). Clustered ring enhancements were demonstrated in 74% of malignancies (high risk, DCIS and IMC) but no benign lesions (P=0.0001). The surrounding high SI on T2-weighted imaging was seen in four of five IMC with marked lymphatic involvement. Clustered ring enhancement was not demonstrated in six of seven IMC of tubular and/or lobular types. Segmental enhancement was seen in not only DCIS but also IMC, high-risk and benign lesions. Clustered ring enhancement and surrounding high SI on T2-weighted imaging were clues to their differential diagnosis and helpful to decide their diagnostic strategy.

Usefulness and limitations of the Japan Mammography Guidelines for the categorization of microcalcifications.

BACKGROUND: The Japan Mammography Guidelines, referred to the American College of Radiology Breast Imaging Reporting and Data System (BI-RADS), are intended to standardize the terminology in mammographic reports and the assessment of findings and to recommend action to be taken. The Japan Mammography Guidelines have explicit guidelines for the categorization of microcalcifications. The purpose of this study was to assess the positive predictive value (PPV) of each categorization of microcalcifications according to the decision table proposed by the Japan Mammography Guidelines according to BI-RADS morphology and distribution parameters and the pathologic outcome. METHODS: A retrospective review was performed of 101 non-palpable screening mammography-detected microcalcification lesions without mass that had stereotactic vacuum-assisted breast biopsy (SVAB). This study was approved by our institutional review board, and informed consent was obtained for all SVAB. We classified microcalcification lesions according to the decision table. Histological findings were reviewed. RESULTS: In calcification morphology, all 32 punctate morphology microcalcifications, regardless of distribution, were benign (100%), whereas 25% (9/36) amorphous morphology microcalcifications, 67% (14/21) pleomorphic morphology microcalcifications and 92% (11/12) linear morphology microcalcifications were malignant. For calcification distribution, 28% (15/55) cluster distribution microcalcifications, 40% (17/43) segmental distribution microcalcifications and 67% (2/3) linear distribution microcalcifications were malignant. Features with high positive PPV showed segmental or linear distribution of linear morphology (100%, respectively), segmental distribution of pleomorphic morphology (100%) and cluster distribution of linear morphology (80%). The PPV for cluster punctate, cluster amorphous, cluster pleomorphic and cluster linear microcalcifications was 0, 21, 50 and 80%, respectively. The PPV for segmental punctate, segmental amorphous, segmental pleomorphic and segmental linear microcalcifications was 0, 27, 100 and 80%, respectively. The PPV for linear amorphous and linear linear microcalcifications was 50 and 100%. CONCLUSIONS: The decision table proposed by the Japan Mammography Guidelines according to BI-RADS morphology and distribution parameters is useful, but continued development of the decision table to improve standardization in mammographic interpretation is needed.

Comparison of magnetic resonance imaging, multidetector row computed tomography, ultrasonography, and mammography for tumor extension of breast cancer.

INTRODUCTION: Breast imaging modalities can assess the tumor extent and adequacy of excision, but there have been no reports comparing magnetic resonance (MR) imaging, multidetector row computed tomography (MDCT), ultrasonography (US) and mammography (MMG) for the tumor extent of breast cancer. We prospectively assessed the accuracy of MR imaging, MDCT, US and MMG for preoperative assessment of the tumor extent of breast cancer. METHODS: Preoperative MR imaging, MDCT, US and MMG were performed for 210 breasts with breast cancer. The MR and MDCT images were independently interpreted by one of two radiologists with knowledge of the clinical and MMG findings. The US was performed with knowledge of the clinical and MMG findings by one of five US technologists. The correlation of the results of these examinations with histological findings was examined. RESULTS: Of the 210 index breast tumors, 210 (100%) could be detected on MR, 208 (99%) were detected on MDCT, 209 (99.5%) were detected on US, and 195 (93%) were detected on MMG. For evaluating local tumor extent, the accuracy of MR imaging (76%) was significantly higher than those of MDCT, US, and MMG (71%, 56%, and 52%, respectively) (P = 0.001, P < 0.0001, and P < 0.0001). MDCT was significantly more accurate than US (P < .0001) or MMG (P < .0001), and US was significantly more accurate than MMG (P = 0.004). MR imaging and US had substantial risk (11% and 17%) of overestimation of the tumor extent. Regarding ductal carcinoma in situ (DCIS), for non-comedo DCIS, the accuracies of MR imaging (89%), MDCT (72%), and US (61%) were significantly higher than the 22% accuracy of MMG (P < 0.0001, P = 0.012, and P = 0.016), but for comedo DCIS, there were no significant differences among the four breast imaging modalities. CONCLUSION: MR imaging was the most accurate breast imaging modality for the tumor exten of breast cancer, although MR imaging had a substantial of risk of overestimation. MR imaging, MDCT and US can complement MMG for the preoperative evaluation of patients who are candidates for breast-conserving surgery.