Intravoxel Incoherent Motion and Quantitative Non-Gaussian Diffusion MR Imaging: Evaluation of the Diagnostic and Prognostic Value of Several Markers of Malignant and Benign Breast Lesions.

Purpose To investigate the performance of integrated approaches that combined intravoxel incoherent motion (IVIM) and non-Gaussian diffusion parameters compared with the Breast Imaging and Reporting Data System (BI-RADS) to establish multiparameter thresholds scores or probabilities by using Bayesian analysis to distinguish malignant from benign breast lesions and their correlation with molecular prognostic factors. Materials and Methods Between May 2013 and March 2015, 411 patients were prospectively enrolled and 199 patients (allocated to training [n = 99] and validation [n = 100] sets) were included in this study. IVIM parameters (flowing blood volume fraction [fIVIM] and pseudodiffusion coefficient [D*]) and non-Gaussian diffusion parameters (theoretical apparent diffusion coefficient [ADC] at b value of 0 sec/mm2 [ADC0] and kurtosis [K]) by using IVIM and kurtosis models were estimated from diffusion-weighted image series (16 b values up to 2500 sec/mm2), as well as a synthetic ADC (sADC) calculated by using b values of 200 and 1500 (sADC200-1500) and a standard ADC calculated by using b values of 0 and 800 sec/mm2 (ADC0-800). The performance of two diagnostic approaches (combined parameter thresholds and Bayesian analysis) combining IVIM and diffusion parameters was evaluated and compared with BI-RADS performance. The Mann-Whitney U test and a nonparametric multiple comparison test were used to compare their performance to determine benignity or malignancy and as molecular prognostic biomarkers and subtypes of breast cancer. Results Significant differences were found between malignant and benign breast lesions for IVIM and non-Gaussian diffusion parameters (ADC0, K, fIVIM, fIVIM · D*, sADC200-1500, and ADC0-800; P < .05). Sensitivity and specificity for the validation set by radiologists A and B were as follows: sensitivity, 94.7% and 89.5%, and specificity, 75.0% and 79.2% for sADC200-1500, respectively; sensitivity, 94.7% and 96.1%, and specificity, 75.0% and 66.7%, for the combined thresholds approach, respectively; sensitivity, 92.1% and 92.1%, and specificity, 83.3% and 66.7%, for Bayesian analysis, respectively; and sensitivity and specificity, 100% and 79.2%, for BI-RADS, respectively. The significant difference in values of sADC200-1500 in progesterone receptor status (P = .002) was noted. sADC200-1500 was significantly different between histologic subtypes (P = .006). Conclusion Approaches that combined various IVIM and non-Gaussian diffusion MR imaging parameters may provide BI-RADS-equivalent scores almost comparable to BI-RADS categories without the use of contrast agents. Non-Gaussian diffusion parameters also differed by biologic prognostic factors. © RSNA, 2017 Online supplemental material is available for this article.

Apparent diffusion coefficient as a potential surrogate marker for Ki-67 index in mucinous breast carcinoma.

PURPOSE: To examine the association between apparent diffusion coefficient (ADC), cellularity, and Ki-67 index in mucinous breast carcinoma (MBC) compared with invasive carcinoma of no special type (NST). ADC's ability to identify lesions with highly proliferating MBC was also examined. MATERIALS AND METHODS: Pathologically confirmed MBCs (mucinous group, n = 18) and NSTs (control group, n = 18) were retrospectively analyzed. ADC was calculated from signal intensity of diffusion-weighted imaging at b values of 0 and 1000 sec/mm(2) . The Ki-67 index and cellularity were histopathologically evaluated. The mucinous group was classified into high Ki-67 mucinous group (Ki-67 index ≥14%, highly proliferating) and low Ki-67 mucinous group. RESULTS: In the mucinous group, minimum ADC (ADCmin) showed an inverse correlation with cellularity (r = -0.802, P < 0.0001) and Ki-67 index (r = -0.825, P < 0.0001). In the control group, ADCmin showed inverse correlation with cellularity (r = -0.537 P = 0.022), but no correlation with Ki-67 index (r = 0.035, P = 0.892). ADCmin of high Ki-67 mucinous group was significantly lower than that of low Ki-67 mucinous group (P = 0.005). CONCLUSION: This study demonstrates an inverse correlation between ADC and Ki-67 index in MBC and the ability of ADC to identify highly proliferating MBC. Considering that ADC can evaluate whole lesions noninvasively, ADC may be a promising noninvasive surrogate marker for Ki-67 index in the risk stratification of MBC.

Giant cell arteritis with myeloperoxidase anti-neutrophil cytoplasmic antibody seropositivity in a patient with systemic sclerosis.

To the best of our knowledge, systemic sclerosis with overlapping characteristics of both microscopic polyangiitis and giant cell arteritis (i.e. microscopic polyangiitis involving the superficial temporal artery or giant cell arteritis with myeloperoxidase anti-neutrophil cytoplasmic antibody seropositivity) has not been reported previously. An 82-year-old woman with diffuse cutaneous systemic sclerosis experienced dyspnoea on exertion and fever. No signs of infection were observed on computed tomography. Her fever persisted despite antibiotic treatment for occult bacterial infection and secondary Clostridioides difficile-associated diarrhoea. Microscopic polyangiitis was suspected because of myeloperoxidase anti-neutrophil cytoplasmic antibody seropositivity, and giant cell arteritis was suspected as a differential diagnosis due to swelling of the superficial temporal artery. Arterial biopsy revealed inflammatory cell infiltration with granuloma formation. Based on the presence of granulomatous inflammation in the superficial temporal artery, we concluded that giant cell arteritis with myeloperoxidase anti-neutrophil cytoplasmic antibody seropositivity occurred as a complication. After glucocorticoid therapy, her fever and dyspnoea on exertion improved with a gradual decline in the serum myeloperoxidase anti-neutrophil cytoplasmic antibody levels. It is possible that vasculitis occurs as a complication in patients with systemic sclerosis in cases where the fever persists and cannot be explained by systemic sclerosis itself, infectious disease, or malignancy. Clinicians must be careful not to prematurely diagnose microscopic polyangiitis based on myeloperoxidase anti-neutrophil cytoplasmic antibody seropositivity or giant cell arteritis based on the swelling of the superficial temporal artery. Careful evaluation of the presence of granulomatous inflammation in an arterial biopsy specimen is essential to differentiate between microscopic polyangiitis and giant cell arteritis.

A heterozygous splicing variant IVS9-7A > T in intron 9 of the MAPT gene in a patient with right-temporal variant frontotemporal dementia with atypical 4 repeat tauopathy.

Right temporal variant frontotemporal dementia, also called right-predominant semantic dementia, often has an unclear position within the framework of the updated diagnostic criteria for behavioral variant frontotemporal dementia or primary progressive aphasia. Recent studies have suggested that this population may be clinically, neuropathologically, and genetically distinct from those with behavioral variant frontotemporal dementia or left-predominant typical semantic variant primary progressive aphasia. Here we describe a Japanese case of right temporal variant frontotemporal dementia with novel heterozygous MAPT mutation Adenine to Thymidine in intervening sequence (IVS) 9 at position -7 from 3' splicing site of intron 9/exon 10 boundary (MAPT IVS9-7A > T). Postmortem neuropathological analysis revealed a predominant accumulation of 4 repeat tau, especially in the temporal lobe, amygdala, and substantia nigra, but lacked astrocytic plaques or tufted astrocytes. Immunoelectron microscopy of the tau filaments extracted from the brain revealed a ribbon-like structure. Moreover, a cellular MAPT splicing assay confirmed that this novel variant promoted the inclusion of exon 10, resulting in the predominant production of 4 repeat tau. These data strongly suggest that the MAPT IVS9-7 A > T variant found in our case is a novel mutation that stimulates the inclusion of exon 10 through alternative splicing of MAPT transcript and causes predominant 4 repeat tauopathy which clinically presents as right temporal variant frontotemporal dementia.

The added value of non-contrast 3-Tesla MRI for the pre-operative localization of hyperparathyroidism.

OBJECTIVE: We investigated the efficacy of non-contrast 3-Tesla MR imaging added to the combination of sestamibi with99mTc (MIBI) scintigraphy and Ultrasonography (US) for the pre-operative localization of Primary Hyperparathyroidism (PHPT) lesions. METHODS: A total of 34 parathyroid glands, including nine normal glands, were examined with MIBI, US, and non-contrast 3-Tesla MRI. MRI was performed with the acquisition of T1- and T2-weighted images and fat-suppressed T2-weighted images. We calculated the sensitivities of MIBI, US, and the 'additional' MRI, with knowledge of the former two modalities' results. RESULTS: For the diagnosis of PHPT lesions, the sensitivity values of MIBI, US, and additional MRI were 88.0% (22/25), 84.0% (21/25), and 92.0% (23/25), respectively. Normal glands were not visualized with any modality (0/9). One lesion was detected neither with US nor MRI, but only with MIBI, with the limitation that MIBI represented no more than laterality. The two glands not identified in MRI were 4 mm and 6 mm in their size, which are within the range of normal gland's size. Two lesions were not detected with US or MIBI but were visualized with the additional MRI, which indicated that the MRI contributed an 8.0% (2/25) improvement of sensitivity, compared from that of US. Fat-suppressed T2-weighted images were useful in the identification of parathyroid lesions, as these images helped to differentiate between the lesion and the adjacent tissue. CONCLUSION: Additional non-contrast 3-Tesla MRI was a useful adjunctive tool for localization of PHPT, which improved the sensitivity of the pre-operative localization of PHPT lesions. Fat-suppressed T2-weighted images contributed to their identification. LEVEL VI: Evidence from a single descriptive or qualitative study.

Diagnostic performance of maximum slope: A kinetic parameter obtained from ultrafast dynamic contrast-enhanced magnetic resonance imaging of the breast using k-space weighted image contrast (KWIC).

PURPOSE: To compare the diagnostic performance of the kinetic parameter maximum slope (MS) in breast lesions obtained by ultrafast dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) of the contrast wash-in period with that of the washout index (WI) derived from standard DCE MRI and that of the Breast Imaging Reporting and Data System (BI-RADS) category. MATERIALS AND METHODS: In total, 138 contrast enhanced lesions (90 malignant, 48 benign) were evaluated. Ultrafast DCE MRI images were acquired using a k-space-weighted image contrast (KWIC), obtained 0-1 min after gadolinium injection (3.75 s/frame; 16 frames) and followed by standard DCE MRI (60 s/frame, 3 frames). MS was calculated for the KWIC time series as percentage relative enhancement per second (%/s). As a semi-quantitative parameter for the standard DCE MRI time series, WI was evaluated using the change in signal intensity between early and delayed phases. The diagnostic performance (malignant/benign differentiation) of MS, WI, and BI-RADS category was compared by ROC analysis using the area under the curve (AUC). RESULTS: The AUC of MS was as good as that of WI (0.81 vs. 0.79, respectively; P = 0.81), yet inferior to the BI-RADS category (0.81 vs. 0.96, respectively; <0.001). MS tended to have higher sensitivity (91.1% [82/90]) compared with WI (87.8% [79/90]) with same specificity (62.5% [30/48]). CONCLUSIONS: MS obtained by ultrafast DCE MRI of the breast is a promising kinetic parameter in the differential diagnosis of malignant and benign breast lesions with decreased scanning time.

The Value of Lesion Size as an Adjunct to the BI-RADS-MRI 2013 Descriptors in the Diagnosis of Solitary Breast Masses.

PURPOSE: This study aimed to evaluate the MRI findings of breast solitary masses in diagnostic procedures to decide the appropriate category based on American College of Radiology (ACR) BI-RADS-MRI 2013, with the focus on lesion size. METHODS: A retrospective review of 2,603 consecutive breast MRI reports identified 250 pathologically-proven solitary breast masses. Dynamic-contrast enhanced images and diffusion-weighted images were performed on a 3.0/1.5 Tesla Scanner with a 16/4 channel dedicated breast coil. MRI findings were re-evaluated according to ACR BI-RADS-MRI 2013. BI-RADS-MRI descriptors, lesion size and minimum apparent diffusion coefficient (ADC) value were statistically analyzed using univariate/multivariate logistic regression analysis and receiver operator characteristic (ROC) analysis. Based on the results, a diagnostic decision tree was constructed. RESULTS: Of the 250 lesions, 152 (61%) were malignant and 98 (39%) were benign. In univariate logistic regression analysis, most of the BI-RADS descriptors, lesion size, and ADC value were significant. Lesion size and ADC value were binarized with optimal cut-off values of 12 mm and 1.1 × 10-3 mm2/s, respectively. Multivariate logistic regression analysis showed that lesion size (≥12 mm or not), margin (circumscribed or not), kinetics (washout or not) and internal enhancement characteristics (IEC) (rim enhancement present or absent) significantly contributed to the diagnosis (P < 0.05). Using these four significant parameters, a decision tree was constructed to categorize lesions into detailed assessment categories/subcategories (Category 4A, 4B, 4C and 5). CONCLUSION: Lesion size is an independent contributor in diagnosing solitary breast masses. Adding the information of lesion size to BI-RADS-MRI 2013 descriptors will allow more detailed categorizations.

Intravoxel incoherent motion (IVIM) and non-Gaussian diffusion MRI of the lactating breast.

PURPOSE: To investigate the effect of breastfeeding on IVIM and non-Gaussian diffusion MRI in the breast. MATERIALS AND METHODS: An IRB approved prospective study enrolled seventeen volunteers (12 in lactation and 5 with post-weaning, range 31-43 years; mean 35.4 years). IVIM (fIVIM and D*) and non-Gaussian diffusion (ADC0 and K) parameters using 16 b values, plus synthetic apparent diffusion coefficients (sADCs) from 2 key b values (b = 200 and 1500 s/mm2) were calculated using regions of interest. ADC0 maps of the whole breast were generated and their contrast patterns were evaluated by two independent readers using retroareolar and segmental semi-quantitative scores. To compare the diffusion and IVIM parameters, Wilcoxon signed rank tests were used between pre- and post-breastfeeding and Mann-Whitney tests were used between post-weaning and pre- or post-breastfeeding. RESULTS: ADC0 and sADC values significantly decreased post-breastfeeding (1.90 vs. 1.72 × 10-3 mm2/s, P < 0.001 and 1.39 vs. 1.25 × 10-3 mm2/s, P < 0.001) while K values significantly increased (0.33 vs. 0.44, P < 0.05). fIVIM values significantly increased after breastfeeding (1.97 vs. 2.97%, P < 0.01). No significant difference was found in D* values. There was significant heterogeneity in ADC0 maps post-breastfeeding, both in retroareolar and segmental scores (P < 0.0001 and =0.0001). CONCLUSION: IVIM and non-Gaussian diffusion parameters significantly changed between pre- and post-breastfeeding status, and care needs to be taken in interpreting diffusion-weighted imaging (DWI) data in lactating breasts.

Variability of non-Gaussian diffusion MRI and intravoxel incoherent motion (IVIM) measurements in the breast.

We prospectively examined the variability of non-Gaussian diffusion magnetic resonance imaging (MRI) and intravoxel incoherent motion (IVIM) measurements with different numbers of b-values and excitations in normal breast tissue and breast lesions. Thirteen volunteers and fourteen patients with breast lesions (seven malignant, eight benign; one patient had bilateral lesions) were recruited in this prospective study (approved by the Internal Review Board). Diffusion-weighted MRI was performed with 16 b-values (0-2500 s/mm2 with one number of excitations [NEX]) and five b-values (0-2500 s/mm2, 3 NEX), using a 3T breast MRI. Intravoxel incoherent motion (flowing blood volume fraction [fIVIM] and pseudodiffusion coefficient [D*]) and non-Gaussian diffusion (theoretical apparent diffusion coefficient [ADC] at b value of 0 sec/mm2 [ADC0] and kurtosis [K]) parameters were estimated from IVIM and Kurtosis models using 16 b-values, and synthetic apparent diffusion coefficient (sADC) values were obtained from two key b-values. The variabilities between and within subjects and between different diffusion acquisition methods were estimated. There were no statistical differences in ADC0, K, or sADC values between the different b-values or NEX. A good agreement of diffusion parameters was observed between 16 b-values (one NEX), five b-values (one NEX), and five b-values (three NEX) in normal breast tissue or breast lesions. Insufficient agreement was observed for IVIM parameters. There were no statistical differences in the non-Gaussian diffusion MRI estimated values obtained from a different number of b-values or excitations in normal breast tissue or breast lesions. These data suggest that a limited MRI protocol using a few b-values might be relevant in a clinical setting for the estimation of non-Gaussian diffusion MRI parameters in normal breast tissue and breast lesions.

A pilot study to determine the diagnostic criteria of spiculated masses for BI-RADS MRI category 5: when to perform re-biopsy after discordant pathologic result?

BACKGROUND: This study aimed to investigate (1) the MRI and clinical findings useful to differentiate malignant from benign spiculated masses and (2) the diagnostic criteria of spiculated masses for BI-RADS MRI category 5, for which any non-malignant biopsy result is considered discordant and a re-biopsy is recommended. MATERIALS AND METHODS: Spiculated breast masses, depicted by 3.0/1.5-T contrast-enhanced MRI between June 2008 and March 2014, were retrospectively analyzed. Patient's age, lesion size, minimum/average apparent diffusion coefficient values (ADCmin/ADCave), and BI-RADS descriptors were compared between malignant and benign lesions. Based on these results, we assessed criteria to define category 5 spiculated masses with a ≥95 % probability of malignancy and evaluated their diagnostic performance. RESULTS: A total of 140 lesions (Malignant group, n = 131; Benign group, n = 9) were analyzed. Patient's age, lesion size, ADCmin and ADCave showed significant differences between the two groups, while none of the BI-RADS descriptors, including kinetic curve assessment, showed any significant difference in frequency. Multivariate logistic regression analysis demonstrated that patient's age and lesion size were the significant predictive factors of malignancy. Of all the assessed criteria for category 5 spiculated masses, "age >50 years or size >9 mm, or both" were selected as the best criteria to minimize the possibility of unnecessary re-biopsies and inappropriate follow-up for malignancies. CONCLUSIONS: Patient's age and lesion size are useful to differentiate malignant from benign spiculated breast masses. In cases with non-malignant biopsy results, spiculated masses with "age >50 years or size >9 mm, or both" are more likely malignant.

The added value of non-contrast 3-Tesla MRI for the pre-operative localization of hyperparathyroidism

Abstract Objective: We investigated the efficacy of non-contrast 3-Tesla MR imaging added to the combination of sestamibi with99mTc (MIBI) scintigraphy and Ultrasonography (US) for the pre-operative localization of Primary Hyperparathyroidism (PHPT) lesions. Methods: A total of 34 parathyroid glands, including nine normal glands, were examined with MIBI, US, and non-contrast 3-Tesla MRI. MRI was performed with the acquisition of T1- and T2-weighted images and fat-suppressed T2-weighted images. We calculated the sensitivities of MIBI, US, and the ‛additional' MRI, with knowledge of the former two modalities' results. Results: For the diagnosis of PHPT lesions, the sensitivity values of MIBI, US, and additional MRI were 88.0% (22/25), 84.0% (21/25), and 92.0% (23/25), respectively. Normal glands were not visualized with any modality (0/9). One lesion was detected neither with US nor MRI, but only with MIBI, with the limitation that MIBI represented no more than laterality. The two glands not identified in MRI were 4 mm and 6 mm in their size, which are within the range of normal gland's size. Two lesions were not detected with US or MIBI but were visualized with the additional MRI, which indicated that the MRI contributed an 8.0% (2/25) improvement of sensitivity, compared from that of US. Fat-suppressed T2-weighted images were useful in the identification of parathyroid lesions, as these images helped to differentiate between the lesion and the adjacent tissue. Conclusion: Additional non-contrast 3-Tesla MRI was a useful adjunctive tool for localization of PHPT, which improved the sensitivity of the pre-operative localization of PHPT lesions. Fatsuppressed T2-weighted images contributed to their identification. Level VI: Evidence from a single descriptive or qualitative study.

Mutations in the essential Escherichia coli gene, yqgF, and their effects on transcription.

The Escherichia coli yqgF gene is highly conserved across a broad spectrum of bacterial genomes. The gene was first identified as being essential for cell growth during screening for targets for broad-spectrum antibiotics. YqgF is structurally similar to RuvC, a Holliday junction resolvase, but its function has not been established. This study describes the isolation of a temperature-sensitive yqgF mutant, the growth of which was inhibited by rho or nusA multicopy plasmids, indicating that YqgF is involved in transcription. Rho is a global transcription termination factor that acts at Rho-dependent terminator sites, which exist not only at the ends of genes but also within genes. The transcription of genes possessing intragenic, or upstream, Rho-dependent terminators was reduced in temperature-sensitive yqgF mutants. This transcription inhibition was sensitive to the Rho inhibitor, bicyclomycin. In addition, the transcription of mutant tnaA genes defective for upstream Rho-dependent termination was not significantly affected by the yqgF mutation. Taken together, these results suggest that YqgF is involved in anti-termination at Rho-dependent terminators in vivo.