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Ultrafast dynamic contrast-enhanced (UF-DCE) MRI is a new approach to capture kinetic information in the very early post-contrast period with high temporal resolution while keeping reasonable spatial resolution. The detailed timing and shape of the upslope in the time-intensity curve are analyzed. New kinetic parameters obtained from UF-DCE MRI are useful in differentiating malignant from benign lesions and in evaluating prognostic markers of the breast cancers. Clinically, UF-DCE MRI contributes in identifying hypervascular lesions when the background parenchymal enhancement (BPE) is marked on conventional dynamic MRI. This review starts with the technical aspect of accelerated acquisition. Practical aspects of UF-DCE MRI include identification of target hypervascular lesions from marked BPE and diagnosis of malignant and benign lesions based on new kinetic parameters derived from UF-DCE MRI: maximum slope (MS), time to enhance (TTE), bolus arrival time (BAT), time interval between arterial and venous visualization (AVI), and empirical mathematical model (EMM). The parameters derived from UF-DCE MRI are compared in terms of their diagnostic performance and association with prognostic markers. Pitfalls of UF-DCE MRI in the clinical situation are also covered. Since UF-DCE MRI is an evolving technique, future prospects of UF-DCE MRI are discussed in detail by citing recent evidence. The topic covers prediction of treatment response, multiparametric approach using DWI-derived parameters, evaluation of tumor-related vessels, and application of artificial intelligence for UF-DCE MRI. Along with comprehensive literature review, illustrative clinical cases are used to understand the value of UF-DCE MRI.

Diffusion kurtosis imaging (DKI) is a diffusion-weighted imaging method that describes non-Gaussian signal behavior using a relatively simple mathematical model. A parameter, kurtosis K, describes the deviation of the diffusion signal decay from a Gaussian pattern. The deviation reflects the complexity of the tissue microstructure affecting water diffusion. Several studies have investigated the diagnostic performance of DKI in distinguishing malignant from benign breast lesions. DKI has been reported to correlate with subtypes and with several molecular and other factors related to the treatment and prognosis of breast cancer. Some technical considerations remain to be resolved for the clinical application of DKI in the breast. Advances in knowledge: DKI, which increases the sensitivity to complex tissue microstructure compared to standard DWI, has been applied in the breast, allowing to increase clinical performance in distinguishing malignant from benign lesions and in predicting prognosis or treatment response in breast cancer.

To evaluate the diagnostic performance of a non-contrast magnetic resonance imaging (MRI) protocol combining high-resolution diffusion-weighted images (HR-DWI) using readout-segmented echo planar imaging, T1-weighted imaging (T1WI), and T2-weighted imaging (T2WI), using our modified Breast Imaging-Reporting and Data System (modified BI-RADS).Two experienced radiologists, blinded to the final pathological diagnosis, categorized a total of 108 breast lesions (61 malignant and 47 benign) acquired with the above protocol using the modified BI-RADS with a diagnostic decision tree. The decision tree included subcategories of category 4, as in mammography (categories 2, 3, 4A, 4B, 4C, and 5). These results were compared with the pathological diagnoses.The area under the ROC curve (AUC) was 0.89 (95% confidence interval [CI]: 0.82-0.96) for reader 1, and 0.89 (95% CI: 0.83-0.95) for reader 2 (p = 0.90). When categories 4C and above were classified as malignant, the sensitivity, specificity, and accuracy were 82.0%, 89.4%, and 85.2%, for reader 1; and 73.8%, 93.6%, and 82.4% for reader 2, respectively.Our results suggest that using HR-DWI, T1WI/T2WI analyzed with a modified BI-RADS and a decision tree showed promising diagnostic performance in breast lesions, and is worthy of further study.

To investigate whether intravoxel incoherent motion (IVIM) and/or non-Gaussian diffusion parameters are associated with distant disease-free survival (DDFS) in patients with invasive breast cancer.From May 2013 to March 2015, 101 patients (mean age 60.0, range 28-88) with invasive breast cancer were evaluated prospectively. IVIM parameters (flowing blood volume fraction [fThe median observation period was 80 months (range, 35-92 months). Among the 101 patients, 12 (11.9%) developed distant metastasis, with a median time to metastasis of 79 months (range, 10-92 months). Kaplan-Meier analysis showed that DDFS was significantly shorter in patients with K0.98 than in those with K ≤ 0.98 (P = 0.04). Cox regression analysis showed a marginal statistical association between K and distant metastasis-free survival (P = 0.05).Non-Gaussian diffusion may be associated with prognosis in invasive breast cancer. A higher K may be a marker to help identify patients at an elevated risk of distant metastasis, which could guide subsequent treatment.

We sought to investigate the performance of high resolution (HR) diffusion-weighted imaging (DWI) using readout-segmented echo-planar imaging (rs-EPI), compared with high-resolution contrast-enhanced MRI (HR CE-MRI) in terms of morphological accuracy, on the basis of the Breast Imaging and Reporting and Data System (BI-RADS) MRI descriptors and lesion size.This retrospective study included the image data of 94 patients with surgically confirmed malignant breast lesions who had undergone high resolution diffusion-weighted imaging (HR-DWI) and HR CE-MRI. Two radiologists blinded to the final diagnosis independently identified the lesions on HR-DWI, described the morphology of the lesions according to BI-RADS descriptors, and measured lesion size. HR CE-MRI was subsequently evaluated using the same procedure. The inter-method agreement of the morphology was assessed using kappa statistics. Correlation on size was also assessed.Reader A detected 79 mass lesions and 37 non-mass lesions on HR-DWI and HR CE-MRI. Reader B detected 81 mass lesions and 33 non-mass lesions on HR-DWI and HR CE-MRI. Very high agreement (kappa = 0.81-0.89, p .05) was observed in the shape and margin assessment of mass lesions, where agreement on internal enhancement/signals was moderate to substantial (kappa = 0.43-0.61, p .05). Disagreement was mostly seen in the evaluation of rim enhancement. High agreement was observed for non-mass lesion distribution (kappa = 0.76-0.84, p .05), and agreement on internal enhancement/signals was moderate to fair (kappa = 0.34-0.49, p .05). Agreement among heterogeneous, clumped, and clustered-ring patterns was variable. Size assessment showed very strong correlation both in mass (Spearman's rho = 0.90-0.96, p .0001) and non-mass lesions (Spearman's rho = 0.86, p .0001).The findings in morphology and lesion extent showed high agreement between HR-DWI and HR CE-MRI for malignant breast lesions. These results imply the potential of applying HR-DWI for evaluation of malignant breast lesions using BI-RADS MRI.

[Purpose]Category 4 in BI-RADS for magnetic resonance imaging (MRI) has a wide range of probabilities of malignancy, extending from > 2 to 0%, ≤ 2%), 4 (> 2%, 2%, ≤ 10%), 4B (> 10%, ≤ 50%) and 4C (> 50%

PURPOSE: We aimed to investigate the performance of high resolution-diffusion-weighted imaging (HR-DWI) using readout-segmented echo-planar imaging in visualizing malignant breast lesions and evaluating their extent, using pathology as a reference. METHODS: This retrospective study included patients who underwent HR-DWI with surgically confirmed malignant breast lesions. Two radiologists blinded to the final diagnosis evaluated HR-DWI independently and identified the lesions, measuring their maximum diameters. Another radiologist confirmed if those lesions were identical to the pathology. The maximum diameters of the lesions between HR-DWI and pathology were compared, and their correlations were calculated using Spearman's correlation coefficient. Apparent diffusion coefficient (ADC) values of the lesions were measured. RESULTS: Ninety-five mass/64 non-mass lesions were pathologically confirmed in 104 females. Both radiologists detected the same 93 mass lesions (97.9%). Spearman's correlation coefficient for mass lesions were 0.89 and 0.90 (P < 0.0001 and 0001) for the two radiologists, respectively. The size differences within 10 mm were 90.3% (84/93) and 94.6% (88/93) respectively. One radiologist detected 35 non-mass lesions (54.7%) and another radiologist detected 32 non-mass lesions (50.0%), of which 28 lesions were confirmed as identical. Spearman's correlation coefficient for non-mass lesions were 0.59 and 0.22 (P = 0.0002 and 0.22), respectively. The mean ADC value of mass lesions and non-mass lesions were 0.80 and 0.89 × 10-3 mm2/s, respectively. CONCLUSION: Using HR-DWI, malignant mass lesions were depicted with excellent agreement with the pathological evaluation. Approximately half of the non-mass lesions could not be identified, suggesting a current limitation of HR-DWI.

BACKGROUND: In metastatic breast cancer, Overall Response Rate (ORR) for checkpoint inhibitor monotherapy has been limited. Since Radiation Therapy (RT) stimulates anti-cancer immune responses, we evaluated safety and efficacy of a combinatorial therapy of RT with Nivolumab (a Programmed cell death protein 1 (PD-1) inhibitor) on HER2-negative metastatic breast cancer patients in a multicenter and non-randomized phase Ib/II study. PATIENTS AND METHODS: Patients with HER2-negative breast cancer, measurable metastasis (RECIST1.1) and at least one bone metastasis requiring radiation therapy were enrolled. The patients were divided into two cohorts, A and B. Cohort A constitutes estrogen and/or progesterone receptor-positive breast cancer patients that had 1 or 2 lines of endocrine therapy for the metastatic disease. Cohort B constitutes triple negative breast cancer patients that had two or more lines of chemotherapy for metastatic disease and anthracycline and taxane treatment for any disease setting. Single fraction RT of 8 Gy was delivered on day 0. Patients received 3 mg/kg Nivolumab intravenously every 2 weeks from day 1 until the disease progressed. Combined use of endocrine therapy of the physician’s choice was allowed in Cohort A. Primary endpoints were safety and ORR (RECIST1.1) in phase Ib and phase II, respectively. Secondary endpoints were Duration of Response (DOR), Disease Control Rate (DCR) and Progression-Free Survival (PFS). For translational research, we integrated time series multi-omics data that are correlated with Tumor Immune Microenvironment (TIME) to identify novel drug sensitivity-associated signatures using machine learning method. The multi-omics data included data from RNAseq, DNAseq, mass cytometry (CyTOF), multiple cytokines, human leukocyte antigen, radiomics, drug concentrations, tuberculin reaction using Peripheral Blood Mononuclear Cells (PBMCs), serum, plasma, imaging and Formalin-Fixed Paraffin-Embedded (FFPE) samples. RESULTS: 31 patients were enrolled from Jan 2017 to Nov 2018 and 29 patients (18 in Cohort A and 11 in Cohort B) were included in the full analysis set. While seven patients in Cohort A had received 1 or 2 lines of chemotherapy earlier for the metastatic disease, eight patients in Cohort B received three or more lines of chemotherapy. Dose limiting toxicities were not observed in phase Ib. In Cohort A, the ORR was 11.1% (90% with a Confidence Interval (CI) of 3.7-28.6). The best overall responses were: Partial Response (PR) in 2 patients (11.1%), Stable Disease (SD) in 11 patients (61.1%) and Progressive Disease (PD) in 5 patients (27.8%). In Cohort B, ORR was 0% as none of the patients responded to the treatment. The best overall responses were: SD in 4 patients (36.4%), PD in 6 patients (54.5%) and one patient (9.1%) was not evaluated (NE). While the DCR for Cohorts A and B were 72.2% (90% CI: 52.9-85.8) and 36.4% (90% CI: 17.5-60.6), respectively, the median PFS were 4 months (95% CI: 2.1-5.5 months) and 2 months (95% CI: 1.2-4.0 months), respectively. Common toxicities were mild; including 3 patients in Cohort A (16.7%) and 2 patients in Cohort B (18.2%) that experienced grade 3 or 4 toxicity. There were no deaths due to adverse effects. Furthermore, our integrated analysis identified novel candidates for drug sensitivity-associated signatures. CONCLUSIONS: The combination of RT and Nivolumab had a manageable safety profile and demonstrated clinically significant disease control outside the RT fields. Periodic abscopal response data and multi-omics data are also presented. (UMIN: UMIN000026046; ClinicalTrials.gov: NCT03430479). Citation Format: Masahiro Takada, Michio Yoshimura, Kosuke Kawaguchi, Takeshi Kotake, Ryuji Uozumi, Masako Kataoka, Takahiko Koyama, Hironori Kato, Hiroshi Yoshibayashi, Hirofumi Suwa, Wakako Tsuji, Hiroyasu Yamashiro, Tatsuki Kataoka, Hiroshi Ishiguro, Reitaro Tokumasu, Maya Honda, Rikiya Yamashita, Atsushi Yonezawa, Yuki Himoto, Natsuko Onishi, Laxmi Parida, Satoshi Morita, Masakazu Toi. A multicenter phase Ib/II study for evaluating safety and efficacy of Nivolumab in combination with radiation therapy in patients with HER2-negative metastatic breast cancer (KBCRN-B-002 trial) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-09-07.

BACKGROUND: Advances in imuuno-oncology (IO), i.e., a programmed cell death protein 1 (PD-1) inhibitors are revolutionizing cancer treatment by offering hope for a cure. However, the benefit of IO agents in metastatic breast cancer (MBC) is still limited. For immunotherapy to be successful, it is essential to understand the tumor immune contexture. Tumor immune microenvironment (TIME) alterations, such as increased effector-cell composition, inflamed immune cells, and the activated effector immune cells create conditions that enhance immunotherapy in MBC. The abscopal effect induced by Radiation therapy (RT) is known as a modulator of TIME. Then, abscopal effect is considered to be a systemic anti-tumor immune response. In this study, we integrated time series multi-omics data to identify alteration of the TIME signatures with RT combined with N\nivolumab, a PD-1 inhibitor, using a machine learning method. PATIENTS AND METHODS: This study was conducted as a translational research of the KBCRN-B-002 trial, which is a multicenter phase Ib/II study for evaluating the safety and efficacy of nivolumab in combination with RT in patients with HER2-negative MBC (Takada M et al. will make presentation the main results of the study. (UMIN: UMIN000026046; ClinicalTrials.gov: NCT03430479)). Twenty-nine patients were included in the translational analysis set. The multi-omics data included data from RNAseq, DNAseq, mass cytometry (CyTOF), multiple cytokines, human leukocyte antigen, radiomics, drug concentrations, tuberculin reaction using peripheral blood mononuclear cells (PBMCs), serum, plasma, imaging, and Formalin-Fixed Paraffin-Embedded (FFPE) samples. We collected time series data, which included data for the baseline, two weeks after starting therapy, four weeks after starting therapy, and the timing of progressive disease. For the integrated analysis, a unique machine learning method was developed. RESULTS: Our integrated analysis identified the alteration of the tumor immune microenvironment signatures using nivolumab combined with RT for MBC. These results included the signature of the immune cell composition, effector immune cells, and immune suppressor cells, via single-cell analysis using CyTOF. The types of analysis are given in the table. CONCLUSIONS: We identified candidates for TIME signatures for actionable hallmarks of RT combined with IO agent by our machine learning method. Type of AnalysisSampleTime PointBaseline2 Weeks4 WeeksProgressive DiseaseRNAseqFFPE✓RNAseqPBMCs✓✓✓✓DNAseqFFPE✓CyTOFPBMCs✓✓✓✓CytokinesSerum✓✓✓✓Nivolumab ConcentrationSerum✓✓✓✓TILsFFPE✓HLAPBMCs✓Tuberculin ReactionSkin✓ Citation Format: Kosuke Kawaguchi, Masahiro Takada, Takeshi Kotake, Michio Yoshimura, Ryuji Uozumi, Masako Kataoka, Takahiko Koyama, Reitaro Tokumasu, Maya Honda, Rikiya Yamashita, Atsushi Yonezawa, Yuki Himoto, Natsuko Onishi, Hironori Kato, Hiroshi Yoshibayashi, Hirofumi Suwa, Wakako Tsuji, Hiroyasu Yamashiro, Tatsuki Kataoka, Hiroshi Ishiguro, Laxmi Parida, Satoshi Morita, Masakazu Toi. Alteration of the tumor immune microenvironment signatures by nivolumab combined with radiation therapy for patients with metastatic breast cancer (Translational Research of the KBCRN-B-002 trial) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-10-33.

Introduction The aim of this study was to investigate the variation of apparent diffusion coefficient (ADC) values with diffusion time according to breast tumor type and prognostic biomarkers expression. Materials and methods A total of 201 patients with known or suspected breast tumors were prospectively enrolled in this study, and 132 breast tumors (86 malignant and 46 benign) were analyzed. Diffusion-weighted imaging scans with 2 diffusion times were acquired on a clinical 3-T magnetic resonance imaging scanner using oscillating and pulsed diffusion-encoding gradients (effective diffusion times, 4.7 and 96.6 milliseconds) and b values of 0 and 700 s/mm2. Diagnostic performances to differentiate malignant and benign breast tumors for ADC values at short and long diffusion times (ADCshort and ADClong), ΔADC (the rate of change in ADC values with diffusion time), ADC0-1000 (ADC value from a standard protocol), and standard reading including dynamic contrast-enhanced magnetic resonance imaging (BI-RADS) were investigated. The correlations of ADCshort, ADClong, and ΔADC values with hormone receptor expression and breast cancer subtypes were also analyzed. Results The ADC values were lower, and ΔADC was higher in malignant tumors compared with benign tumors. The specificity of ADC values at all diffusion times and ΔADC values for differentiating malignant and benign breast tumors was superior to that of BI-RADS (87.0%-95.7% vs 73.9%), whereas the sensitivity was inferior (87.2%-90.7% vs 100%). Lower ADCshort and ADC0-1000 in ER-positive compared with ER-negative cancers (false discovery rate [FDR]-adjusted P = 0.037 and 0.018, respectively) and lower ADCshort, ADClong, and ADC0-1000 in progesterone receptor-positive compared with progesterone receptor-negative cancers (FDR-adjusted P = 0.037, 0.036, and 0.018, respectively) were found. Ki-67-positive cancers had larger ΔADCs than Ki-67-negative cancers (FDR-adjusted P = 0.018). Conclusions The ADC values vary with different diffusion time and vary in correlation with molecular biomarkers, especially Ki-67. Those results suggest that the diffusion time, which should be reported, might be a useful parameter to consider for breast cancer management.

This study aimed to evaluate the predictions of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for prognosis of triple-negative breast cancer (TNBC), especially with residual disease (RD) after preoperative chemotherapy. This retrospective analysis included 74 TNBC patients who received preoperative chemotherapy. DCE-MRI findings from three timepoints were examined: at diagnosis (MRIpre), at midpoint (MRImid) and after chemotherapy (MRIpost). These findings included cancer lesion size, washout index (WI) as a kinetic parameter using the difference in signal intensity between early and delayed phases, and time-signal intensity curve types. Distant disease-free survival was analysed using the log-rank test to compare RD group with and without a fast-washout curve. The diagnostic performance of DCE-MRI findings, including positive predictive value (PPV) for pathological responses, was also calculated. RD without fast washout curve was a significantly better prognostic factor, both at MRImid and MRIpost (hazard ratio = 0.092, 0.098, p mid was 76.7% by the cut-off point at negative WI value or lesion size = 0, and 66.7% at lesion size = 0. WI and curve types derived from DCE-MRI at the midpoint of preoperative chemotherapy can help not only assess tumour response but also predict prognosis.

Purpose Background parenchymal enhancement (BPE) often affects interpretation of dynamic contrast-enhanced (DCE) MRI. There is limited evidence that reduced BPE is a feature of ultrafast DCE (UF-DCE) MRI. We aimed to evaluate the effect of BPE levels on lesion detectability on UF-DCE MRI in comparison with conventional DCE MRI. Method MRIs of 70 patients with histologically proven breast lesions were retrospectively evaluated. The total number of analyzed lesions was 84 (56 malignant and 28 benign). Using 3 T MRI, 20 phases of UF-DCE MRI based on the three-dimensional gradient-echo VIBE sequence combined with a compressed sensing reconstruction were acquired followed by conventional DCE MRI. Three maximum intensity projection (MIP) images were generated from the 12th phase, the 20th phase of UF-DCE MRI and the initial phase of conventional DCE MRI. Two radiologists independently evaluated the degree of BPE and lesion detectability of the three MIP images for each breast with histologically confirmed lesions. The degree of BPE was scored on a four-point scale and lesion detectability (conspicuity and confidence levels) was scored on a three-point scale. Data were analyzed using the Wilcoxon signed-rank test with Bonferroni correction. Results BPE was lower on UF-DCE MRI than on conventional DCE MRI. Lesion detectability was higher on UF-DCE MRI among patients with higher BPE on conventional DCE MRI or premenopausal women. Conclusions Images with lower BPE can be achieved using UF-DCE MRI and may be advantageous when assessing breast lesions among patients with higher BPE or premenopausal women.

Purpose To evaluate the diagnostic performance of a multiparametric approach to breast lesions including apparent diffusion coefficient (ADC) from diffusion-weighted images (DWI), maximum slope (MS) from ultrafast dynamic contrast enhanced (UF-DCE) MRI, lesion size, and patient's age. Materials and methods In total, 96 lesions (73 malignant, 23 benign) were evaluated. UF-DCE MRI was acquired using a prototype 3D-gradient-echo volumetric interpolated breath-hold examination (VIBE) with compressed sensing. Images were obtained up to 1 min after gadolinium injection. MS was calculated as the percentage relative enhancement/s. An ADC map was automatically generated from DWI at b = 0 and b = 1000 s/mm2. MS and ADC values were measured by two radiologists independently. Interrater agreement was evaluated using intraclass correlation coefficients. Univariate and multivariate logistic regression analyses were performed using MS, ADC, lesion size, and the patient's age. The parameters of the prediction model were generated from the results of the multivariate logistic regression analysis. Area under the curve (AUC) was used to compare diagnostic performance of the prediction model and each parameter. Results Interrater agreements on MS and ADC were excellent (ICC 0.99 and 0.88, respectively). MS, ADC, and patient's age remained as significant parameters after univariate and multivariate logistic regression analysis. The prediction model using these significant parameters yielded an AUC of 0.90, significantly higher than that of MS (AUC 0.74, p = 0.01). The AUCs of ADC, MS, patient's age were 0.87, 0.74 and 0.73, respectively. Conclusions A multiparametric model using ADC from DWI, MS from UF-DCE MRI, and patient's age showed excellent diagnostic performance, with greater contribution of ADC. Combining DWI and UF-DCE MRI might reduce scanning time while preserving diagnostic performance.

Diffusion-weighted imaging (DWI) is increasingly being incorporated into routine breast MRI protocols in many institutions worldwide, and there are abundant breast DWI indications ranging from lesion detection and distinguishing malignant from benign tumors to assessing prognostic biomarkers of breast cancer and predicting treatment response. DWI has the potential to serve as a noncontrast MR screening method. Beyond apparent diffusion coefficient (ADC) mapping, which is a commonly used quantitative DWI measure, advanced DWI models such as intravoxel incoherent motion (IVIM), non-Gaussian diffusion MRI, and diffusion tensor imaging (DTI) are extensively exploited in this field, allowing the characterization of tissue perfusion and architecture and improving diagnostic accuracy without the use of contrast agents. This review will give a summary of the clinical literature along with future directions. Level of Evidence: 5 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2020;52:70-90.

BACKGROUND Ultrafast dynamic contrast-enhanced (UF-DCE) breast MRI is considered a promising method of accelerated breast MRI. However, the value of new kinetic parameters derived from UF-DCE need clinical evaluation. PURPOSE To evaluate the diagnostic performance of the maximum slope (MS), time to enhancement (TTE), and time interval between arterial and venous visualization (AVI) derived from UF-DCE MRI using compressed sensing (CS). STUDY TYPE Retrospective. POPULATION Seventy-five patients with histologically proven breast lesions. The total number of analyzed lesions was 90 (61 malignant and 29 benign). FIELD STRENGTH/SEQUENCE 3T MRI with UF-DCE MRI based on the 3D gradient-echo volumetric interpolated breath-hold examination (VIBE) sequence using incoherent k-space sampling combined with a CS reconstruction followed by conventional DCE MRI. ASSESSMENT The diagnostic performance of the MS, TTE, AVI, and conventional kinetic analysis was analyzed and compared with histology. STATISTICAL TESTS Wilcoxon rank sum test, receiver operating characteristic analysis. RESULTS The MS was larger and the TTE and AVI were smaller for malignant lesions compared with benign lesions: MS: 29.3%/s and 18.4%/s (P

This paper reports on a pilot project that explored the potential of linguistic inquiry in a high school English as a Second Language (ESL) class. In class meetings across the school year, students worked collaboratively to investigate noun phrase pluralization, language acquisition, writing systems, and translation in their own and other languages. Classroom observations and students’ oral and written work provide evidence that: • Examining the structures of the spoken and written languages represented in the ESL classroom captures students’ interest and engages them in critical inquiry about the nature of linguistic knowledge and their beliefs about language. • The cross-linguistic analysis of students’ home languages validates their languages in the school context, defining them as a rich resource worthy of study, rather than as a hindrance to education. These findings are of particular significance in this time of English-only education in the United States, when students’ home languages are often rejected in schools.

Aims We examined the effect of a prostacyclin (PGI 2 ) analog iloprost on histamine-induced acid secretion and investigated how endogenous PGI 2 mediated the decreased secretory response in the damaged stomach after exposure to taurocholate (TC). Main methods Male C57BL/6 mice, both wild-type (WT) and IP receptor knockout (IP-KO) animals, were used after 18 h of fasting. Under urethane anesthesia, the abdomen was incised, and an acute fistula was provided in the stomach. Key findings Acid secretion in WT and IP-KO mice was similarly and dose-dependently increased by histamine. Iloprost decreased the histamine-stimulated secretion in WT but not IP-KO mice. The inhibitory effect of iloprost in WT mice was totally abrogated by the prior administration of CYN154806, a selective somatostatin SST2 receptor antagonist. On the other hand, the acid secretion in WT mice was decreased after exposure of the stomach to 20 mM TC for 20 min, with an increase in mucosal PGI 2 content, but the decrease was significantly less marked in IP-KO mice. The decreased acid response to TC in WT mice was totally prevented by the prior administration of CYN154806 as well as indomethacin. Somatostatin contents in the stomach were reduced after the administration of iloprost or the mucosal exposure to TC, while the blood levels increased. Significance Somatostatin/SST2 receptors are involved in the decreased acid response of the damaged stomach, in addition to PGI 2 /IP receptors. It is assumed that PGI 2 releases somatostatin from D cells, which in turn decreases acid secretion via the activation of SST2 receptors.

Is there a role for linguistic inquiry in a class of high school English Language Learners? Based on a year-long pilot project initiated by a Greater Boston high school teacher, we present evidence: (1) that examining the spoken and written languages represented in the classroom captures students’ interest and engages them in critical inquiry about the nature of linguistic knowledge and about their beliefs about language; (2) that the analysis of students’ home languages validates these languages in the school context, defining them as a rich resource worthy of study, rather than as a hindrance to education.

Background/Aim: Muscarinic acetylcholine receptors exist in five subtypes (M1~M5), and they are widely expressed in various tissues to mediate diverse autonomic functions, including gastric secretion. Although the acid response to acetylcholine is considered to be mainly mediated by the activation of M3-receptors, we recently found that carbachol (CCh)-induced acid secretion was markedly decreased in M4 knockout (KO) mice. In the present study, we demonstrated, using M1~M5 KO mice, the importance of M4 receptors in the cholinergic stimulation of acid secretion and investigated how the secretion is modulated by the activation of M4 receptors. Methods: C57BL/6J mice (12-20 wks old) of wild-type (WT) and M1~M5 KO were used. Under urethane anesthesia, the abdomen was incised, and an acute fistula prepared with a polyethylene tube was provided in the stomach through a pylorus. Then, the stomach was instilled with saline (0.4 ml) through the fistula, and the solution was changed every 20 min. CCh (30 μg/kg) was given SC as a single injection. Atropine (0.3 mg/kg) or CYN154806 [somatostatin-2 receptor (SST2R) antagonist: 0.1-3mg/kg] was given SC 20 min before CCh. Expressions of D cells and M4 receptors was examined immunohistochemically by double staining with anti-somatostatin and anti-M4 receptor antibodies. Results: CCh caused an increase of acid secretion in WT mice, and the effect was completely inhibited by prior administration of atropine. The stimulatory effect of CCh was similarly observed in the animals lacking M1, M2 or M5 receptors but significantly decreased in M3 or M4 KOmice, as compared toWT; especially, the response was all but completely abolished in M4 KO mice. CYN154806, the SST2R antagonist, dose-dependently and significantly reversed the decreased acid response to CCh in M4 but not M3 KO mice. Somatostatin inhibited the secretion of acid under basal and CCh-stimulated conditions. The immunohistochemical study showed the localization of M4 receptors on D cells in the stomach. It was also found that serum somatostatin levels in M4 KO mice were higher than WT mice under basal conditions and that the somatostatin levels in WT mice were decreased in response to CCh. Conclusion: These results suggest that under cholinergic stimulation the secretion of acid is mediated by the activation of both M3 and M4 receptors but does not involve other muscarinic receptor subtypes, and the activation of M4 receptors inhibits the release of somatostatin from D cells and minimizes the acid inhibitory effect of somatostatin through SST2 receptors, resulting in enhancement of the acid response mediated by M3 receptors on parietal cells.

The research reported here focuses on grade 7 (12‐year‐old) students’ epistomological views prior to and after exposure to a teaching unit especially developed to introduce the constructivist view of science. A clinical interview was used to assess students’ understanding about the nature of scientific knowledge and inquiry. Students’ initial epistemological stance is that scientific knowledge is a passively acquired, faithful copy of the world, and that scientific inquiry is limited solely to observing rather than constructing explanations about nature. We found that it is possible to move students beyond this initial view.