Clinical Focus

  • Diagnostic Radiology

Academic Appointments

  • Clinical Assistant Professor, Radiology

Professional Education

  • Fellowship: UCSF Dept of Radiology (2018) CA
  • Board Certification: American Board of Radiology, Diagnostic Radiology (2018)
  • Residency: University of Chicago Medical Center Radiology Residency (2017) IL
  • Residency: Weill Cornell Medicine Radiology Residency Program (2015) NY
  • Internship: Maimonides Medical Center Internal Medicine Residency (2013) NY
  • Medical Education: Albert Einstein College of Medicine (2012) NY

All Publications

  • SCOUT® Localization Using MRI Guidance: Initial Experience. Journal of breast imaging Dashevsky, B. Z., Yan, P., Liang, T., Daniel, B. L. 2024


    The Food and Drug Administration approved the MRI-compatible wireless SCOUT localization system in April 2022. The purpose of this study was to evaluate feasibility of SCOUT localization under MRI guidance. We present our initial experience adopting MRI-guided SCOUT localization and compare it to MRI-guided wire localization.Electronic medical records and imaging were retrospectively reviewed for all patients who underwent MRI-guided SCOUT or wire localization at our institution between October 2022 and July 2023. Statistical analysis was performed using 2-sample proportion and Wilcoxon rank-sum tests.There were 14 MRI-guided SCOUT and 23 MRI-guided wire localization cases during the study period. All SCOUTs were placed without complication and were considered to be in adequate proximity to the target. There was no significant difference in complication rate (P = .25) or days lapsed from MRI-detected abnormality to surgery (P = .82) between SCOUT and wire cases. SCOUT was placed at time of biopsy for 71% (10/14) of cases. 57% (8/14) of SCOUT cases were used for breast conservation surgery (BCS) compared to 100% (23/23) of wire cases (P <.01), with all 6 SCOUTs not used for BCS placed at time of biopsy.MRI-guided SCOUT localization is feasible and offers an alternative to MRI-guided wire localization, with no SCOUT complications reported. SCOUT placement at time of biopsy obviates the need for an additional procedure, but predicting appropriateness is challenging, with 60% (6/10) of SCOUTs placed at time of MRI-guided biopsy not used for subsequent localization surgery.

    View details for DOI 10.1093/jbi/wbae025

    View details for PubMedID 38837068

  • SCOUT Radar Localization at Time of Breast Biopsy. Journal of breast imaging Dashevsky, B. Z., Muneer, M. S., Hao, M., Liang, T., Wapnir, I. L., Poplack, S. P. 2024


    OBJECTIVE: Evaluate surgical utilization of SCOUT reflectors placed at breast biopsy.METHODS: Consent was waived for this retrospective IRB-approved, HIPAA-compliant study. Breast biopsy examinations that reported the term "SCOUT" between January 2021 and June 2022 were identified using an institutional search engine. Cases were included if a SCOUT reflector was placed at time of breast biopsy and excluded if lesion pathology was already known. Analysis was performed at the lesion level. A multivariate-regression analysis evaluated 6 variables with potential impact on SCOUT utilization.RESULTS: One hundred twenty-one lesions in 112 patients met inclusion criteria. Biopsy yielded 93% (113/121) malignant, 3% (4/121) elevated risk, 2% (2/121) benign-discordant, and 2% (2/121) benign-concordant results. Two cases lost to follow-up were excluded. SCOUT reflectors were utilized for lumpectomy (58%, 69/119 lesions) and excisional biopsy (6%, 7/119 lesions). SCOUTs were not utilized due to mastectomy (23%, 27/119), subsequent wire localization (2%, 2/119), and nonsurgical cases (12%, 14/119). Reflector placement utilization was 52% higher for findings less than 3.5cm in size (P <.001), 33% higher in patients without prior treated breast cancer (P =.012), and 19% higher in patients with no suspicious ipsilateral lymph node (P =.048).CONCLUSION: SCOUT reflector placement at time of biopsy was utilized for surgery 64% (76/119) of the time, although most (98%, 119/121) biopsies were malignant, elevated risk, or benign-discordant. Factors increasing reflector utilization include smaller lesion size, no suspicious ipsilateral lymph node, and no prior treated breast cancer.

    View details for DOI 10.1093/jbi/wbae024

    View details for PubMedID 38776638

  • Breast Hemangiomas: Imaging Features With Histopathology Correlation. Journal of breast imaging Dhami, A., Hao, M., Waheed, U., Dashevsky, B. Z., Bean, G. R. 2024


    Breast hemangiomas are rare benign vascular lesions. In a previously performed review of approximately 10,000 breast surgical pathology results, roughly 0.15% (15/~10,000) were hemangiomas. Hemangiomas are more frequent in women and have a documented age distribution of 1.5 to 82 years. They are most often subcutaneous or subdermal and anterior to the anterior mammary fascia but may rarely be seen in the pectoralis muscles or chest wall. On imaging, breast hemangiomas typically present as oval or round masses, often measuring less than 2.5cm, with circumscribed or mostly circumscribed, focally microlobulated margins, equal or high density on mammography, and variable echogenicity on US. Calcifications, including phleboliths, can be seen. Color Doppler US often shows hypovascularity or avascularity. MRI appearance can vary, although hemangiomas are generally T2 hyperintense and T1 hypointense with variable enhancement. Pathologic findings vary by subtype, which include perilobular, capillary, cavernous, and venous hemangiomas. If core biopsy pathology results are benign, without atypia, and concordant with imaging and clinical findings, surgical excision is not routinely indicated. Because of histopathologic overlap with well-differentiated or low-grade angiosarcomas, surgical excision may be necessary for definitive diagnosis. Findings that are more common with angiosarcomas include size greater than 2cm, hypervascularity on Doppler US, irregular shape, and invasive growth pattern.

    View details for DOI 10.1093/jbi/wbae011

    View details for PubMedID 38557759

  • Rare Cancer on the Rise: An Educational Review of Breast Implant-associated Anaplastic Large Cell Lymphoma. Journal of breast imaging Mitry, M. A., Sogani, J., Sutton, E. J., Kumar, P., Horwitz, S., Elmi, A., Patel, S. N., Gallagher, K., Dashevsky, B. Z., Mango, V. 2020; 2 (4): 398-407


    Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare but increasingly important diagnosis as the incidence of breast implant placement, both elective and reconstructive, continues to rise. When detected and treated early, this indolent disease carries an excellent prognosis. However, because the clinical presentation is often nonspecific, it is crucial for radiologists to accurately identify the imaging findings associated with BIA-ALCL to facilitate a timely diagnosis. This article will provide radiologists with an overview of the diagnosis, imaging findings, and management of BIA-ALCL.

    View details for DOI 10.1093/jbi/wbaa041

    View details for PubMedID 38424964

  • A machine learning model that classifies breast cancer pathologic complete response on MRI post-neoadjuvant chemotherapy. Breast cancer research : BCR Sutton, E. J., Onishi, N., Fehr, D. A., Dashevsky, B. Z., Sadinski, M., Pinker, K., Martinez, D. F., Brogi, E., Braunstein, L., Razavi, P., El-Tamer, M., Sacchini, V., Deasy, J. O., Morris, E. A., Veeraraghavan, H. 2020; 22 (1): 57


    For breast cancer patients undergoing neoadjuvant chemotherapy (NAC), pathologic complete response (pCR; no invasive or in situ) cannot be assessed non-invasively so all patients undergo surgery. The aim of our study was to develop and validate a radiomics classifier that classifies breast cancer pCR post-NAC on MRI prior to surgery.This retrospective study included women treated with NAC for breast cancer from 2014 to 2016 with (1) pre- and post-NAC breast MRI and (2) post-NAC surgical pathology report assessing response. Automated radiomics analysis of pre- and post-NAC breast MRI involved image segmentation, radiomics feature extraction, feature pre-filtering, and classifier building through recursive feature elimination random forest (RFE-RF) machine learning. The RFE-RF classifier was trained with nested five-fold cross-validation using (a) radiomics only (model 1) and (b) radiomics and molecular subtype (model 2). Class imbalance was addressed using the synthetic minority oversampling technique.Two hundred seventy-three women with 278 invasive breast cancers were included; the training set consisted of 222 cancers (61 pCR, 161 no-pCR; mean age 51.8 years, SD 11.8), and the independent test set consisted of 56 cancers (13 pCR, 43 no-pCR; mean age 51.3 years, SD 11.8). There was no significant difference in pCR or molecular subtype between the training and test sets. Model 1 achieved a cross-validation AUROC of 0.72 (95% CI 0.64, 0.79) and a similarly accurate (P = 0.1) AUROC of 0.83 (95% CI 0.71, 0.94) in both the training and test sets. Model 2 achieved a cross-validation AUROC of 0.80 (95% CI 0.72, 0.87) and a similar (P = 0.9) AUROC of 0.78 (95% CI 0.62, 0.94) in both the training and test sets.This study validated a radiomics classifier combining radiomics with molecular subtypes that accurately classifies pCR on MRI post-NAC.

    View details for DOI 10.1186/s13058-020-01291-w

    View details for PubMedID 32466777

    View details for PubMedCentralID PMC7254668

  • Incidence of benign and malignant peri-implant fluid collections and masses on magnetic resonance imaging in women with silicone implants. Cancer medicine Sutton, E. J., Dashevsky, B. Z., Watson, E. J., Tyagi, N., Bernard-Davila, B., Martinez, D., Dogan, A., Horwitz, S. M., Cordeiro, P. G., Morris, E. A. 2020; 9 (10): 3261-3267


    To assess the incidence of benign and malignant peri-implant fluid collections and/or masses on magnetic resonance imaging (MRI) in women with silicone implants who are being screened for silent implant rupture.The institutional review board approved this HIPAA-compliant retrospective study and waived informed consent. Women who underwent silicone implant oncoplastic and/or cosmetic surgery and postoperative implant-protocol MRI from 2000 to 2014 were included. Peri-implant fluid collections and/or masses were measured volumetrically. A benign peri-implant fluid collection and/or mass was pathologically proven or defined as showing 2 years of imaging and/or clinical stability. A malignant peri-implant fluid collection was pathologically proven. Incidence of peri-implant fluid collections and/or masses and positive predictive value (PPV) were calculated on a per-patient level using proportions and exact 95% confidence intervals (CIs). Fisher's exact test was used in the analysis to test statistical significance pre-defined as P-value < 0.05.A total of 1070 women with silicone implants were included (mean age, 50.7 years; range, 40.4-53.8). Median time between reconstructive surgery and first MRI was 88.9 months (range, 0.8-1363.3). Eighteen women (1.7%) had a peri-implant fluid collection and/or mass: 15/18 (83.3%) had adequate follow-up; and only 1/15 was malignant implant associated anaplastic large cell lymphoma, with a PPV of 6.7% (95% CI: 0.003-0.0005). The median peri-implant fluid collection size was 89 mL (range, 18-450 mL).Peri-implant fluid collections and/or masses identified at silicone implant protocol breast MR imaging are rarely seen 24 months after reconstructive surgery. Image-guided fine-needle aspiration with flow cytometry may be warranted to evaluate for implant-associated lymphoma.

    View details for DOI 10.1002/cam4.2189

    View details for PubMedID 31568670

    View details for PubMedCentralID PMC7221432

  • Differentiation between subcentimeter carcinomas and benign lesions using kinetic parameters derived from ultrafast dynamic contrast-enhanced breast MRI. European radiology Onishi, N., Sadinski, M., Gibbs, P., Gallagher, K. M., Hughes, M. C., Ko, E. S., Dashevsky, B. Z., Shanbhag, D. D., Fung, M. M., Hunt, T. M., Martinez, D. F., Shukla-Dave, A., Morris, E. A., Sutton, E. J. 2020; 30 (2): 756-766


    This study aims to evaluate ultrafast DCE-MRI-derived kinetic parameters that reflect contrast agent inflow effects in differentiating between subcentimeter BI-RADS 4-5 breast carcinomas and benign lesions.We retrospectively reviewed consecutive 3-T MRI performed from February to October 2017, during which ultrafast DCE-MRI was performed as part of a hybrid clinical protocol with conventional DCE-MRI. In total, 301 female patients with 369 biopsy-proven breast lesions were included. Ultrafast DCE-MRI was acquired continuously over approximately 60 s (temporal resolution, 2.7-7.1 s/phase) starting simultaneously with the start of contrast injection. Four ultrafast DCE-MRI-derived kinetic parameters (maximum slope [MS], contrast enhancement ratio [CER], bolus arrival time [BAT], and initial area under gadolinium contrast agent concentration [IAUGC]) and one conventional DCE-MRI-derived kinetic parameter (signal enhancement ratio [SER]) were calculated for each lesion. Wilcoxon rank sum test or Fisher's exact test was performed to compare kinetic parameters, volume, diameter, age, and BI-RADS morphological descriptors between subcentimeter carcinomas and benign lesions. Univariate/multivariate logistic regression analyses were performed to determine predictive parameters for subcentimeter carcinomas.In total, 125 lesions (26 carcinomas and 99 benign lesions) were identified as BI-RADS 4-5 subcentimeter lesions. Subcentimeter carcinomas demonstrated significantly larger MS and SER and shorter BAT than benign lesions (p = 0.0117, 0.0046, and 0.0102, respectively). MS, BAT, and age were determined as significantly predictive for subcentimeter carcinoma (p = 0.0208, 0.0023, and < 0.0001, respectively).Ultrafast DCE-MRI-derived kinetic parameters may be useful in differentiating subcentimeter BI-RADS 4 and 5 carcinomas from benign lesions.• Ultrafast DCE-MRI can generate kinetic parameters, effectively differentiating breast carcinomas from benign lesions. • Subcentimeter carcinomas demonstrated significantly larger maximum slope and shorter bolus arrival time than benign lesions. • Maximum slope and bolus arrival time contribute to better management of suspicious subcentimeter breast lesions.

    View details for DOI 10.1007/s00330-019-06392-5

    View details for PubMedID 31468162

    View details for PubMedCentralID PMC7570436

  • Preventive Care: How Mammography Utilization Changes as Women Age. Journal of the American College of Radiology : JACR Yuan, C., Kulkarni, K., Dashevsky, B. Z. 2020; 17 (2): 238-247


    To evaluate the impact of comorbid conditions and age on mammography use.We used data from the 2011 to 2015 Medical Expenditure Panel Survey, which contained records for 40,752 women over the age of 40. Use was defined as a mammogram within the previous 1 or 2 years, analyzed separately. A logit model was employed to evaluate associations between use and comorbidities and age. Statistical significance was defined by a P < .05 by two-sided test.Of the 36,575 women in our study sample, 45.9%, 43.6%, 3.9%, and 5.7% reported a history of hypertension (HTN), hyperlipidemia (HLD), prior heart attack (MI), and prior stroke, respectively. Among women without a comorbid condition, there was 47.3% annual mammography use. HTN and HLD were associated with increased use (2.5 and 6.8 percentage points [pp], P< .01). In comparison, prior MI was associated with decreased annual use (-8.2 pp, P < .01). Prior stroke was not significantly associated with annual mammography (-1.5 pp, P = .42). Results were similar for biennial use. The age trend in use showed that the age with maximum screening use was approximately 60 years.Mammography use was higher in patients with HTN and HLD and lower in patients with prior MI and stroke, which may reflect differences in comorbidity-related general health care use. Use increased until it peaked around age 60. An understanding of how mammography use naturally evolves as people age may help better target specific populations and improve overall use of preventive care.

    View details for DOI 10.1016/j.jacr.2019.09.008

    View details for PubMedID 31628897

  • Utility and Outcomes of Imaging Evaluation for Palpable Lumps in the Postmastectomy Patient. AJR. American journal of roentgenology Dashevsky, B. Z., Hayward, J. H., Woodard, G. A., Joe, B. N., Lee, A. Y. 2019; 213 (2): 464-472


    OBJECTIVE. The objective of our study was to assess the utility of targeted breast ultrasound and mammography in evaluating palpable lumps in the mastectomy bed. MATERIALS AND METHODS. This retrospective study identified postmastectomy patients who presented for initial imaging evaluation of palpable lumps between January 2009 and December 2015. Clinical, imaging, and pathology results were reviewed. Surgical reconstruction type and percutaneous sampling data were collected. Patients were excluded if they had known malignancy at imaging presentation, if the palpable lump was not at the mastectomy site, or if there was less than 1 year clinical or imaging follow-up in the absence of biopsy. Each palpable site was assigned as a case, and analyses were performed at the case level. RESULTS. Among the 101 patients with a history of prophylactic or therapeutic mastectomy who presented during the study period, 118 palpable cases met the inclusion criteria. All 118 cases were evaluated with ultrasound and 43 with mammography. Among the 75 cases evaluated with ultrasound alone, nine cancers were detected. Among the 43 cases evaluated with both ultrasound and mammography, three cancers were sonographically detected, of which two were mammographically visible and one was mammographically occult. There were two false-negative ultrasound cases; both underwent sampling because of the level of clinical suspicion. In total, 14 palpable lumps in 12 patients were malignant, and 104 palpable lumps in 89 patients were nonmalignant. Targeted ultrasound yielded a negative predictive value (NPV) of 97% and a positive predictive value 2 of 27%. CONCLUSION. Our data suggest that targeted breast ultrasound, with its high NPV, should be the initial imaging test of choice for palpable lumps after mastectomy. Mammography yielded no additional cancers but was helpful in confirming benign diagnoses. The two false-negative ultrasound cases support palpation-guided sampling for imaging-occult and clinically suspicious palpable lumps.

    View details for DOI 10.2214/AJR.18.20550

    View details for PubMedID 31039027

  • Teaching Medical Students Optimal Consulting Skills: The Challenge of Generating Better Referring Physicians. Cureus Phillips, A. W., Potter, T., Dashevsky, B. Z., Masse, N., Greenberg, B., Straus, C. M. 2019; 11 (7): e5172


    Rationale and objectives We sought to incorporate a new teaching module into the traditional medical student radiology clerkship, to improve the necessary skills for future referring physicians. Materials and methods A new required and graded module was introduced in 2014 into the radiology clerkship in year three of medical school: the Mystery Case. Each student was provided a unique and undifferentiated case from a dedicated teaching file containing de-identified images and requisition data. Students were expected to complete three serial tasks over one week: 1) prepare a voice recognition-derived, structured radiological report utilizing appropriate and relevant vocabulary; 2) discuss pertinent additional clinical information; and 3) discuss appropriate follow-up imaging, in addition to information on how to best prepare patients for these potential patient exams (e.g., with or without contrast, bowel preparation, and length of study). Students were provided written examples and dedicated class instruction with interactive discussions covering specific cases and associated related cases through random pairing with radiology resident and attending mentors. At the close of the week, students gave brief oral presentations of their cases and submitted the tasks for a written evaluation. Upon completion of the clerkship, the students completed a Likert-type six-item survey to evaluate the perceived improvement in select skills. Results The survey was completed by 82% (54/66) of the enrolled students, with 85% finding the Mystery Case an effective use of time. Medical students perceived an improved awareness of the patient care process (77%), awareness of the medical imaging resources available (89%), ability to understand a radiology report (74%), and ability to advise patients (69%). Conclusion Introduction of the Mystery Case as a graded exercise in the medical school radiology clerkship was perceived by students as effective use of time, with an improvement in the skills essential for future referring physicians.

    View details for DOI 10.7759/cureus.5172

    View details for PubMedID 31528521

    View details for PubMedCentralID PMC6743658

  • Breast implant-associated anaplastic large cell lymphoma: Clinical and imaging findings at a large US cancer center. The breast journal Dashevsky, B. Z., Gallagher, K. M., Grabenstetter, A., Cordeiro, P. G., Dogan, A., Morris, E. A., Horwitz, S. M., Sutton, E. J. 2019; 25 (1): 69-74


    Evaluate the clinical presentation and imaging findings of breast implant-associated anaplastic large cell lymphoma (BIA ALCL) at a large US cancer center.HIPAA-compliant IRB approved retrospective study, for which informed consent was waived. The Hospital Information System was screened for women who underwent implant reconstruction and were diagnosed with BIA ALCL between 2010 and 2016. Two radiologists reviewed images in consensus. Clinical and imaging characteristics were summarized using means and ranges for continuous variables and percentages for categorical variables.Patient cohort included 11 women with BIA ALCL (mean age at diagnosis = 54 years, range: 35-77), including women with (9/11) and without (2/11) history of breast cancer. Mean time from breast implant placement to diagnosis was 10 years (range: 6-14). BIA ALCL was identified in patients with saline (4/11) and silicone (5/11) implants. Implants were textured in 7/11 (63%) and unknown in 4/11 (36%) cases. All patients presented with a peri-implant seroma, (9/11 documented on imaging). Two of 11 patients had a mass within this seroma. Ten of 11 patients (91%) presented with symptoms.Saline and silicone breast implants may predispose patients to a rare lymphoma subtype, BIA ALCL, which presents on imaging as a peri-implant fluid collection ± mass.

    View details for DOI 10.1111/tbj.13161

    View details for PubMedID 30521149

  • Lymph node wire localization post-chemotherapy: Towards improving the false negative sentinel lymph node biopsy rate in breast cancer patients. Clinical imaging Dashevsky, B. Z., Altman, A., Abe, H., Jaskowiak, N., Bao, J., Schacht, D. V., Sheth, D., Kulkarni, K. 2018; 48: 69-73


    To evaluate whether the disease status of the pre-neoadjuvant chemotherapy (NAC) core biopsied lymph node (preNACBxLN) in patients with node positive breast cancer corresponds to nodal status of all surgically retrieved lymph nodes (LNs) post-NAC and whether wire localization of this LN is feasible.HIPPA compliant IRB approved retrospective study including breast cancer patients (a.) with preNACBxLN confirmed metastases, (b.) who received NAC, and (c.) underwent wire localization of the preNACBxLN. Electronic medical records were reviewed. Fisher's exact test was used to compare differences in residual disease post-NAC among breast cancer subtypes.28 women with node positive breast cancer underwent ultrasound guided wire localization of the preNACBxLN, without complication. There was no evidence of residual nodal disease for 16 patients, with mean 4.4 (median 4) LNs resected. 12 patients had residual nodal metastases, with mean 9.2 (median 7) LNs resected and mean 2.3 (median 2) LNs with tumor involvement. 11 patients had metastases detected within the localized LN. One patient had micrometastasis in a sentinel LN, despite no residual disease in the preNACBxLN. Patients with luminal A/B breast cancer more often had residual nodal metastases (86%) at pathology, as compared to patients with HER2+ (20%) and Triple Negative breast cancer (50%), though not quite achieving statistical significance (p=0.055).Ultrasound guided wire localization of the preNACBxLN is feasible and may improve detection of residual tumor in patients post-NAC.

    View details for DOI 10.1016/j.clinimag.2017.10.003

    View details for PubMedID 29035756

  • Appearance Constrained Semi-Automatic Segmentation from DCE-MRI is Reproducible and Feasible for Breast Cancer Radiomics: A Feasibility Study. Scientific reports Veeraraghavan, H., Dashevsky, B. Z., Onishi, N., Sadinski, M., Morris, E., Deasy, J. O., Sutton, E. J. 2018; 8 (1): 4838


    We present a segmentation approach that combines GrowCut (GC) with cancer-specific multi-parametric Gaussian Mixture Model (GCGMM) to produce accurate and reproducible segmentations. We evaluated GCGMM using a retrospectively collected 75 invasive ductal carcinoma with ERPR+ HER2- (n = 15), triple negative (TN) (n = 9), and ER-HER2+ (n = 57) cancers with variable presentation (mass and non-mass enhancement) and background parenchymal enhancement (mild and marked). Expert delineated manual contours were used to assess the segmentation performance using Dice coefficient (DSC), mean surface distance (mSD), Hausdorff distance, and volume ratio (VR). GCGMM segmentations were significantly more accurate than GrowCut (GC) and fuzzy c-means clustering (FCM). GCGMM's segmentations and the texture features computed from those segmentations were the most reproducible compared with manual delineations and other analyzed segmentation methods. Finally, random forest (RF) classifier trained with leave-one-out cross-validation using features extracted from GCGMM segmentation resulted in the best accuracy for ER-HER2+ vs. ERPR+/TN (GCGMM 0.95, expert 0.95, GC 0.90, FCM 0.92) and for ERPR + HER2- vs. TN (GCGMM 0.92, expert 0.91, GC 0.77, FCM 0.83).

    View details for DOI 10.1038/s41598-018-22980-9

    View details for PubMedID 29556054

    View details for PubMedCentralID PMC5859113

  • MRI features predictive of negative surgical margins in patients with HER2 overexpressing breast cancer undergoing breast conservation. Scientific reports Dashevsky, B. Z., Oh, J. H., Apte, A. P., Bernard-Davila, B., Morris, E. A., Deasy, J. O., Sutton, E. J. 2018; 8 (1): 315


    Here we develop a tool to predict resectability of HER2+ breast cancer at breast conservation surgery (BCS) utilizing features identified on preoperative breast MRI. We identified patients with HER2+ breast cancer who obtained pre-operative breast MRI and underwent BCS between 2002-2013. From the contoured tumor on pre-operative MRI, shape, histogram, and co-occurrence and size zone matrix texture features were extracted. In univariate analysis, Spearman's correlation coefficient (Rs) was used to assess the correlation between each image feature and an endpoint (surgical re-excision). For multivariate modeling, we employed a support vector machine (SVM) method in a manner of leave-one-out cross-validation (LOOCV). Of 109 patients with HER2+breast cancer who underwent BCS, 39% underwent surgical re-excision. 62% had residual cancer at re-excision. In univariate analysis, solidity (Rs = -0.32, p = 0.009) and extent (Rs = -0.29, p = 0.019) were significantly associated with re-excision. Skewness in post-contrast 1, 2, and 3 (Rs = 0.25, p = 0.045; Rs = 0.30, p = 0.015; Rs = 0.28, p = 0.026) and kurtosis in post-contrast 1 (Rs = 0.26, p = 0.035) were also statistically significant. LOOCV-based SVM test achieved 74.4% specificity and 71.4% sensitivity when 21 features were used. Thus, tumor texture, histogram and morphological MRI features may assist surgical planning, encouraging wide margins or mastectomy in patients who may otherwise go on to re-excision.

    View details for DOI 10.1038/s41598-017-18758-0

    View details for PubMedID 29321645

    View details for PubMedCentralID PMC5762896

  • Multicenter Research Studies in Radiology. Academic radiology Dashevsky, B. Z., Bercu, Z. L., Bhosale, P. R., Burton, K. R., Chatterjee, A. R., Frigini, L. A., Heacock, L., Herskovits, E. H., Lee, J. T., Subhas, N., Wasnik, A. P., Gyftopoulos, S. 2018; 25 (1): 18-25


    Here we review the current state of multicenter radiology research (MRR), and utilize a survey of experienced researchers to identify common advantages, barriers, and resources to guide future investigators.The Association of University Radiologists established a Radiology Research Alliance task force, Multi-center Research Studies in Radiology, composed of 12 society members to review MRR. A REDCap survey was designed to gain more insight from experienced researchers. Recipients were authors identified from a PubMed database search, utilizing search terms "multicenter" or "multisite" and "radiology." The survey included investigator background information, reasons why, barriers to, and resources that investigators found helpful in conducting or participating in MRR.The survey was completed by 23 of 80 recipients (29%), the majority (76%) of whom served as a primary investigator on at least one MRR project. Respondents reported meeting collaborators at national or international (74%) and society (39%) meetings. The most common perceived advantages of MRR were increased sample size (100%) and improved generalizability (91%). External funding was considered the most significant barrier to MRR, reported by 26% of respondents. Institutional funding, setting up a central picture archiving and communication system, and setting up a central database were considered a significant barrier by 30%, 22%, and 22% of respondents, respectively. Resources for overcoming barriers included motivated staff (74%), strong leadership (70%), regular conference calls (57%), and at least one face-to-face meeting (57%).Barriers to MRR include funding and establishing a central database and a picture archiving and communication system. Upon embarking on an MRR project, forming a motivated team who meets and speaks regularly is essential.

    View details for DOI 10.1016/j.acra.2017.05.019

    View details for PubMedID 28927579

  • Whole body metabolic tumor volume is a prognostic marker in patients with newly diagnosed stage 3B non-small cell lung cancer, confirmed with external validation. European journal of hybrid imaging Dashevsky, B. Z., Zhang, C., Yan, L., Yuan, C., Xiong, L., Liu, Y., Liu, H., Kong, F. S., Pu, Y. 2017; 1 (1): 8


    TNM Stage 3B encompasses a wide range of primary tumor and nodal metastatic tumor burden. This study aimed to evaluate the prognostic value of quantitative FDG PET/CT parameters in patients with newly diagnosed Stage 3B Non-Small Cell Lung Cancer (NSCLC).Institutional review board approved retrospective study identified patients diagnosed with Stage 3B NSCLC (8th edition TNM classification) on baseline FDG PET/CT at two medical centers (Medical centers A and B), between Feb 2004 and Dec 2014. Patients were excluded if they had prior NSCLC treatment or recent diagnosis of a second primary cancer. Quantitative FDG PET/CT parameters including whole body metabolic tumor volume (MTVwb), total lesion glycolysis (TLGwb), and maximum standardized uptake value (SUVmaxwb) were measured from baseline PET/CT using Edge method with Mimvista software. The primary endpoint was overall survival (OS). Cox proportional hazard regression and Kaplan-Meier overall survival analyses were used to test for an association between OS and quantitative FDG PET/CT parameters. The distributions of MTVwb, TLGwb, SUVmaxwb were skewed, so a natural logarithm transformation was applied and the transformed variables [(ln(MTVwb), ln(TLGwb), and ln(SUVmaxwb)] were used in the analysis.The training set included 110 patients from center A with Stage 3B NSCLC. 78.2% of patients expired during follow-up. Median OS was 14 months. 1-year, 2-year, and 5-year OS was 56.5%, 34.6% and 13.9%, respectively. Univariate Cox regression analysis showed no significant difference in OS on the basis of age, gender, histology, ln(TLGwb), or ln(SUVmaxwb). ln(MTVwb) was positively associated with OS [hazard ratio (HR) of 1.23, p = 0.037]. This association persisted on multivariate Cox regression analysis (HR 1.28, p = 0.043), with adjustments for age, gender, treatment and tumor histology. External validation with 44 patients from center B confirmed increasing MTVwb was associated significantly worse OS. An MTVwb cut-off point of 85.6 mL significantly stratified Stage 3B NSCLC patient prognosis.MTVwb is a prognostic marker for OS in patients with Stage 3B NSCLC, independent of age, gender, treatment, and tumor histology.

    View details for DOI 10.1186/s41824-017-0013-z

    View details for PubMedID 29782599

    View details for PubMedCentralID PMC5954780

  • Incidental focal uptake in the breast and axilla on FDG PET: Clinical considerations and differential diagnosis. Clinical imaging Magee, A. L., Dashevsky, B. Z., Jahangir, K., Kulkarni, K. 2017; 45: 96-104


    Incidental focal FDG uptake in the breast or axilla on PET/CT performed for evaluation of extra-mammary primary disease presents a diagnostic challenge. Radiologists must consider a broad differential diagnosis, assess clinical history, and judiciously employ other imaging modalities such as mammography, ultrasound and MRI in the pursuit of findings which help narrow the differential diagnosis. Tissue sampling may be reserved for nondiagnostic imaging scenarios.

    View details for DOI 10.1016/j.clinimag.2017.06.001

    View details for PubMedID 28645096

  • Breast cancer molecular subtype classifier that incorporates MRI features. Journal of magnetic resonance imaging : JMRI Sutton, E. J., Dashevsky, B. Z., Oh, J. H., Veeraraghavan, H., Apte, A. P., Thakur, S. B., Morris, E. A., Deasy, J. O. 2016; 44 (1): 122-9


    To use features extracted from magnetic resonance (MR) images and a machine-learning method to assist in differentiating breast cancer molecular subtypes.This retrospective Health Insurance Portability and Accountability Act (HIPAA)-compliant study received Institutional Review Board (IRB) approval. We identified 178 breast cancer patients between 2006-2011 with: 1) ERPR + (n = 95, 53.4%), ERPR-/HER2 + (n = 35, 19.6%), or triple negative (TN, n = 48, 27.0%) invasive ductal carcinoma (IDC), and 2) preoperative breast MRI at 1.5T or 3.0T. Shape, texture, and histogram-based features were extracted from each tumor contoured on pre- and three postcontrast MR images using in-house software. Clinical and pathologic features were also collected. Machine-learning-based (support vector machines) models were used to identify significant imaging features and to build models that predict IDC subtype. Leave-one-out cross-validation (LOOCV) was used to avoid model overfitting. Statistical significance was determined using the Kruskal-Wallis test.Each support vector machine fit in the LOOCV process generated a model with varying features. Eleven out of the top 20 ranked features were significantly different between IDC subtypes with P < 0.05. When the top nine pathologic and imaging features were incorporated, the predictive model distinguished IDC subtypes with an overall accuracy on LOOCV of 83.4%. The combined pathologic and imaging model's accuracy for each subtype was 89.2% (ERPR+), 63.6% (ERPR-/HER2+), and 82.5% (TN). When only the top nine imaging features were incorporated, the predictive model distinguished IDC subtypes with an overall accuracy on LOOCV of 71.2%. The combined pathologic and imaging model's accuracy for each subtype was 69.9% (ERPR+), 62.9% (ERPR-/HER2+), and 81.0% (TN).We developed a machine-learning-based predictive model using features extracted from MRI that can distinguish IDC subtypes with significant predictive power. J. Magn. Reson. Imaging 2016;44:122-129.

    View details for DOI 10.1002/jmri.25119

    View details for PubMedID 26756416

    View details for PubMedCentralID PMC5532744

  • The Potential of High Resolution Magnetic Resonance Microscopy in the Pathologic Analysis of Resected Breast and Lymph Tissue. Scientific reports Dashevsky, B. Z., D'Alfonso, T., Sutton, E. J., Giambrone, A., Aronowitz, E., Morris, E. A., Juluru, K., Ballon, D. J. 2015; 5: 17435


    Pathologic evaluation of breast specimens requires a fixation and staining procedure of at least 12 hours duration, delaying diagnosis and post-operative planning. Here we introduce an MRI technique with a custom-designed radiofrequency resonator for imaging breast and lymph tissue with sufficient spatial resolution and speed to guide pathologic interpretation and offer value in clinical decision making. In this study, we demonstrate the ability to image breast and lymphatic tissue using 7.0 Tesla MRI, achieving a spatial resolution of 59 × 59 × 94 μm(3) with a signal-to-noise ratio of 15-20, in an imaging time of 56 to 70 minutes. These are the first MR images to reveal characteristic pathologic features of both benign and malignant breast and lymph tissue, some of which were discernible by blinded pathologists who had no prior training in high resolution MRI interpretation.

    View details for DOI 10.1038/srep17435

    View details for PubMedID 26639673

    View details for PubMedCentralID PMC4671009

  • Breast cancer subtype intertumor heterogeneity: MRI-based features predict results of a genomic assay. Journal of magnetic resonance imaging : JMRI Sutton, E. J., Oh, J. H., Dashevsky, B. Z., Veeraraghavan, H., Apte, A. P., Thakur, S. B., Deasy, J. O., Morris, E. A. 2015; 42 (5): 1398-406


    To investigate the association between a validated, gene-expression-based, aggressiveness assay, Oncotype Dx RS, and morphological and texture-based image features extracted from magnetic resonance imaging (MRI).This retrospective study received Internal Review Board approval and need for informed consent was waived. Between 2006-2012, we identified breast cancer patients with: 1) ER+, PR+, and HER2- invasive ductal carcinoma (IDC); 2) preoperative breast MRI; and 3) Oncotype Dx RS test results. Extracted features included morphological, histogram, and gray-scale correlation matrix (GLCM)-based texture features computed from tumors contoured on pre- and three postcontrast MR images. Linear regression analysis was performed to investigate the association between Oncotype Dx RS and different clinical, pathologic, and imaging features. P < 0.05 was considered statistically significant.Ninety-five patients with IDC were included with a median Oncotype Dx RS of 16 (range: 0-45). Using stepwise multiple linear regression modeling, two MR-derived image features, kurtosis in the first and third postcontrast images and histologic nuclear grade, were found to be significantly correlated with the Oncotype Dx RS with P = 0.0056, 0.0005, and 0.0105, respectively. The overall model resulted in statistically significant correlation with Oncotype Dx RS with an R-squared value of 0.23 (adjusted R-squared = 0.20; P = 0.0002) and a Spearman's rank correlation coefficient of 0.49 (P < 0.0001).A model for IDC using imaging and pathology information correlates with Oncotype Dx RS scores, suggesting that image-based features could also predict the likelihood of recurrence and magnitude of chemotherapy benefit.

    View details for DOI 10.1002/jmri.24890

    View details for PubMedID 25850931

    View details for PubMedCentralID PMC4784421

  • Comparison of 18F-FDG PET/CT for Systemic Staging of Newly Diagnosed Invasive Lobular Carcinoma Versus Invasive Ductal Carcinoma. Journal of nuclear medicine : official publication, Society of Nuclear Medicine Hogan, M. P., Goldman, D. A., Dashevsky, B., Riedl, C. C., Gönen, M., Osborne, J. R., Jochelson, M., Hudis, C., Morrow, M., Ulaner, G. A. 2015; 56 (11): 1674-80


    Although guidelines such as those of the National Comprehensive Cancer Network consider (18)F-FDG PET/CT for systemic staging of newly diagnosed stage III breast cancer patients, factors in addition to stage may influence the utility of PET/CT. Because invasive lobular carcinoma (ILC) is less conspicuous than invasive ductal carcinoma (IDC) on (18)F-FDG PET, we hypothesized that tumor histology may be one such factor. We evaluated PET/CT systemic staging of patients newly diagnosed with ILC compared with IDC.In this Institutional Review Board-approved retrospective study, our Hospital Information System was screened for ILC patients who underwent PET/CT in 2006-2013 before systemic or radiation therapy. Initial stage was determined from examination, mammography, ultrasound, MR, or surgery. PET/CT was performed to identify unsuspected distant metastases. A sequential cohort of stage III IDC patients was evaluated for comparison. Upstaging rates were compared using the Pearson χ(2) test.The study criteria were fulfilled by 146 ILC patients. PET/CT revealed unsuspected distant metastases in 12 (8%): 0 of 8 with initial stage I, 2 of 50 (4%) stage II, and 10 of 88 (11%) stage III. Upstaging to IV by PET/CT was confirmed by biopsy in all cases. Three of 12 upstaged patients were upstaged only by the CT component of the PET/CT, as the metastases were not (18)F-FDG-avid. In the comparison stage III IDC cohort, 22% (20/89) of patients were upstaged to IV by PET/CT. All 20 demonstrated (18)F-FDG-avid metastases. The relative risk of PET/CT revealing unsuspected distant metastases in stage III IDC patients was 1.98 times (95% confidence interval, 0.98-3.98) that of stage III ILC patients (P = 0.049). For (18)F-FDG-avid metastases, the relative risk of PET/CT revealing unsuspected (18)F-FDG-avid distant metastases in stage III IDC patients was 2.82 times (95% confidence interval, 1.26-6.34) that of stage III ILC patients (P = 0.007).(18)F-FDG PET/CT was more likely to reveal unsuspected distant metastases in stage III IDC patients than in stage III ILC patients. In addition, some ILC patients were upstaged by non-(18)F-FDG-avid lesions visible only on the CT images. Overall, the impact of PET/CT on systemic staging may be lower for ILC patients than for IDC patients.

    View details for DOI 10.2967/jnumed.115.161455

    View details for PubMedID 26294295

    View details for PubMedCentralID PMC4869690

  • Appearance of untreated bone metastases from breast cancer on FDG PET/CT: importance of histologic subtype. European journal of nuclear medicine and molecular imaging Dashevsky, B. Z., Goldman, D. A., Parsons, M., Gönen, M., Corben, A. D., Jochelson, M. S., Hudis, C. A., Morrow, M., Ulaner, G. A. 2015; 42 (11): 1666-1673


    To determine if the histology of a breast malignancy influences the appearance of untreated osseous metastases on FDG PET/CT.This retrospective study was performed under IRB waiver. Our Hospital Information System was screened for breast cancer patients who presented with osseous metastases, who underwent FDG PET/CT prior to systemic therapy or radiotherapy from 2009 to 2012. Patients with invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), or mixed ductal/lobular (MDL) histology were included. Patients with a history of other malignancies were excluded. PET/CT was evaluated, blinded to histology, to classify osseous metastases on a per-patient basis as sclerotic, lytic, mixed lytic/sclerotic, or occult on CT, and to record SUVmax for osseous metastases on PET.Following screening, 95 patients who met the inclusion criteria (74 IDC, 13 ILC, and 8 MDL) were included. ILC osseous metastases were more commonly sclerotic and demonstrated lower SUVmax than IDC metastases. In all IDC and MDL patients with osseous metastases, at least one was FDG-avid. For ILC, all patients with lytic or mixed osseous metastases demonstrated at least one FDG-avid metastasis; however, in only three of seven patients were sclerotic osseous metastases apparent on FDG PET.The histologic subtype of breast cancer affects the appearance of untreated osseous metastases on FDG PET/CT. In particular, non-FDG-avid sclerotic osseous metastases were more common in patients with ILC than in patients with IDC. Breast cancer histology should be considered when interpreting non-FDG-avid sclerotic osseous lesions on PET/CT, which may be more suspicious for metastases (rather than benign lesions) in patients with ILC.

    View details for DOI 10.1007/s00259-015-3080-z

    View details for PubMedID 25971426

    View details for PubMedCentralID PMC4558334

  • Radiology Teaching Files: an Assessment of Their Role and Desired Features Based on a National Survey. Journal of digital imaging Dashevsky, B., Gorovoy, M., Weadock, W. J., Juluru, K. 2015; 28 (4): 389-98


    A radiology teaching file (TF) is a system containing a collection of cases with teaching value. Given the wide variety of TF solutions available, we conducted a national survey to better understand the need for TFs, TF features desired by users and their current implementation. A 28-question survey was created which explored TF implementation, utilization, and preferences among respondents. The survey was emailed to residents and faculty throughout the USA, with a request for program coordinators to forward the survey to their departments. The survey was completed by 396 respondents from 115 different institutions. These respondents included 60% residents, 21% attendings (non-program directors), 12% program directors, 5% fellows, and 1% medical students. TFs were assigned to one of three categories: personal TFs, shared in-house TFs, and public TFs. Seventy-six percent of respondents kept a personal TF using a variety of media, and 67% used a shared in-house TF. Of the public TFs used, the most popular were those requiring paid subscriptions. The features respondents valued most provided efficient querying of cases, simulated basic PACS functionality, enabled self-directed learning, and facilitated case submissions. There is a trend toward utilizing electronic media for TFs. The media utilized should be understood and reviewed to ensure PHI is properly secured. Contemporary users demand a high degree of functionality from TF solutions, and use both in-house and commercial products to meet their needs.

    View details for DOI 10.1007/s10278-014-9755-3

    View details for PubMedID 25582529

    View details for PubMedCentralID PMC4501957

  • Breast cancer in women in their thirties (2007-2013): a retrospective review. Breast disease Arleo, E. K., Reichman, M., Dashevsky, B. Z., Babagbemi, K., Drotman, M. 2015; 35 (2): 87-93


    Due to an increasing number of breast cancer diagnoses in younger women anecdotally noted at our institution, we conceived of this study %was to retrospectively review the records of women diagnosed with breast cancer under the age of 40 for potentially alterable versus unalterable risk factors in their history. Between 2007 and 2013, there were 52 patients less than 40 years of age with breast cancer at our institution: 79% (41/52) presented with a clinical abnormality (palpable mass, nipple discharge or inversion) and 21% (11/52) were asymptomatic but diagnosed on early screening mammograms. Seventy-five percent (39/52) of the cancers had an invasive component and 87% (45/52) were intermediate to high grade. Sixty percent (31/52) of subjects had stage 0 or I disease, but 40% (21/52) had later stage disease (stage II or greater). The vast majority of the cancers were ER+ (82%) and PR+ (78%). Fifty-six percent (28/50; 2 unknown) of the subjects had a documented history of hormonal contraception. Fifty-three percent (27/51; 1 unknown) of had no family history of breast cancer whatsoever, and 80% (41/51) had no family history of breast cancer in a first degree relative. Six were positive for BRCA 1, 2, or a variant (6/52 = 12%).

    View details for DOI 10.3233/BD-150400

    View details for PubMedID 25835055

  • Screening mammography for women in their 40s: a retrospective study of the potential impact of the U.S. Preventive Service Task Force's 2009 breast cancer screening recommendations. AJR. American journal of roentgenology Arleo, E. K., Dashevsky, B. Z., Reichman, M., Babagbemi, K., Drotman, M., Rosenblatt, R. 2013; 201 (6): 1401-6


    The objective of our study was to review screening mammography examinations performed at our institution from 2007 through 2010 with the primary endpoint of determining the incidence of breast cancer and associated histologic and prognostic features in women in their 40s.Patients who presented for screening mammography who ultimately (i.e., after additional imaging, including diagnostic mammographic views and ultrasound) received a BI-RADS assessment of a category 4 or 5 for a suspicious abnormality were followed retrospectively through completion of care and were analyzed with respect to pathology results after biopsy, treatment, and family history.During the study period, 43,351 screening mammography examinations were performed; 1227 biopsies were recommended on the basis of those studies and yielded 205 breast cancers (cancer detection rate of 4.7 per 1000 screening examinations). These screening examinations included 14,528 (33.5%) screening examinations of patients in their 40s; 413 biopsies were recommended and yielded 39 breast cancers (39/205 = 19%) (cancer detection rate of 2.7 per 1000 screening examinations). More than 50% (21/39) of the cancers in women in their 40s were invasive. Only 8% (3/39) of the women in their 40s with screening-detected breast cancer had a first-degree relative with breast cancer.From 2007 through 2010, patients in their 40s accounted for one third of the population undergoing screening mammography and for nearly 20% of the screening-detected breast cancers--more than half of which were invasive. This information should be a useful contribution to counseling women in this age group when discussing whether or not to pursue regular screening mammography.

    View details for DOI 10.2214/AJR.12.10390

    View details for PubMedID 24261383

  • A case of primary breast angiosarcoma. Radiology case reports Dashevsky, B. Z., Charnoff-Katz, K., Shin, S. J., Babagbemi, K., Rosenblatt, R. 2013; 8 (3): 741


    Angiosarcoma of the breast is a rare malignancy that may be easily misdiagnosed. Of the two forms, the more common form presents in patients (typically postmenopausal0 with a history of breast cancer, secondary to irradiation or chronic lymphedema. In contrast, the rarer form, primary angiosarcoma, arises sporadically in premenopausal women who present with palpable masses. Primary angiosarcoma accounts for 1 in 2,500 cases (0.04%) of breast cancer (1). The described patient presented with primary breast angiosarcoma. Ultrasound, mammography, and magnetic resonance imaging findings are presented.

    View details for DOI 10.2484/rcr.v8i3.741

    View details for PubMedID 27330634

    View details for PubMedCentralID PMC4900109

  • Adjacent mutations in the gating loop of Kir6.2 produce neonatal diabetes and hyperinsulinism. EMBO molecular medicine Shimomura, K., Flanagan, S. E., Zadek, B., Lethby, M., Zubcevic, L., Girard, C. A., Petz, O., Mannikko, R., Kapoor, R. R., Hussain, K., Skae, M., Clayton, P., Hattersley, A., Ellard, S., Ashcroft, F. M. 2009; 1 (3): 166-77


    K(ATP) channels regulate insulin secretion from pancreatic beta-cells. Loss- and gain-of-function mutations in the genes encoding the Kir6.2 and SUR1 subunits of this channel cause hyperinsulinism of infancy and neonatal diabetes, respectively. We report two novel mutations in the gating loop of Kir6.2 which cause neonatal diabetes with developmental delay (T293N) and hyperinsulinism (T294M). These mutations increase (T293N) or decrease (T294M) whole-cell K(ATP) currents, accounting for the different clinical phenotypes. The T293N mutation increases the intrinsic channel open probability (Po((0))), thereby indirectly decreasing channel inhibition by ATP and increasing whole-cell currents. T294M channels exhibit a dramatically reduced Po((0)) in the homozygous but not in the pseudo-heterozygous state. Unlike wild-type channels, hetT294M channels were activated by MgADP in the absence but not in the presence of MgATP; however, they are activated by MgGDP in both the absence and presence of MgGTP. These mutations demonstrate the importance of the gating loop of Kir channels in regulating Po((0)) and further suggest that Mg-nucleotide interaction with SUR1 may reduce ATP inhibition at Kir6.2.

    View details for DOI 10.1002/emmm.200900018

    View details for PubMedID 20049716

    View details for PubMedCentralID PMC3378123

  • A Kir6.2 mutation causing severe functional effects in vitro produces neonatal diabetes without the expected neurological complications DIABETOLOGIA Tammaro, P., Flanagan, S. E., Zadek, B., Srinivasan, S., Woodhead, H., Hameed, S., Klimes, I., Hattersley, A. T., Ellard, S., Ashcroft, F. M. 2008; 51 (5): 802-810


    Heterozygous activating mutations in the pancreatic ATP-sensitive K+ channel cause permanent neonatal diabetes mellitus (PNDM). This results from a decrease in the ability of ATP to close the channel, which thereby suppresses insulin secretion. PNDM mutations that cause a severe reduction in ATP inhibition may produce additional symptoms such as developmental delay and epilepsy. We identified a heterozygous mutation (L164P) in the pore-forming (Kir6.2) subunit of the channel in three unrelated patients and examined its functional effects.The patients (currently aged 2, 8 and 20 years) developed diabetes shortly after birth. The two younger patients attempted transfer to sulfonylurea therapy but were unsuccessful (up to 1.1 mg kg(-1) day(-1)). They remain insulin dependent. None of the patients displayed neurological symptoms. Functional properties of wild-type and mutant channels were examined by electrophysiology in Xenopus oocytes.Heterozygous (het) and homozygous L164P K(ATP) channels showed a marked reduction in channel inhibition by ATP. Consistent with its predicted location within the pore, L164P enhanced the channel open state, which explains the reduction in ATP sensitivity. HetL164P currents exhibited greatly increased whole-cell currents that were unaffected by sulfonylureas. This explains the inability of sulfonylureas to ameliorate the diabetes of affected patients.Our results provide the first demonstration that mutations such as L164P, which produce a severe reduction in ATP sensitivity, do not inevitably cause developmental delay or neurological problems. However, the neonatal diabetes of these patients is unresponsive to sulfonylurea therapy. Functional analysis of PNDM mutations can predict the sulfonylurea response.

    View details for DOI 10.1007/s00125-008-0923-1

    View details for Web of Science ID 000254750400015

    View details for PubMedID 18335204

    View details for PubMedCentralID PMC2292422

  • Direct visualization of KirBac3.1 potassium channel gating by atomic force microscopy. Journal of molecular biology Jarosławski, S., Zadek, B., Ashcroft, F., Vénien-Bryan, C., Scheuring, S. 2007; 374 (2): 500-5


    KirBac3.1 belongs to a family of transmembrane potassium (K(+)) channels that permit the selective flow of K-ions across biological membranes and thereby regulate cell excitability. They are crucial for a wide range of biological processes and mutations in their genes cause multiple human diseases. Opening and closing (gating) of Kir channels may occur spontaneously but is modulated by numerous intracellular ligands that bind to the channel itself. These include lipids (such as PIP(2)), G-proteins, nucleotides (such as ATP) and ions (e.g. H(+), Mg(2+), Ca(2+)). We have used high-resolution atomic force microscopy (AFM) to examine KirBac3.1 in two different configurations. AFM imaging of the cytoplasmic surface of KirBac3.1 embedded in a lipid bilayer has allowed visualization of the tetrameric assembly of the ligand-binding domain. In the absence of Mg(2+), the four subunits appeared as four protrusions surrounding a central depression corresponding to the cytoplasmic pore. They did not display 4-fold symmetry, but formed a dimer-of-dimers with 2-fold symmetry. Upon addition of Mg(2+), a marked rearrangement of the intracellular ligand-binding domains was observed: the four protrusions condensed into a single protrusion per tetramer, and there was an accompanying increase in protrusion height. The central cavity within the four intracellular domains also disappeared on addition of Mg(2+), indicating constriction of the cytoplasmic pore. These structural changes are likely transduced to the transmembrane helices, which gate the K(+) channel. This is the first time AFM has been used as an interactive tool to study K(+) channels. It has enabled us to directly measure the conformational changes in the protein surface produced by ligand binding.

    View details for DOI 10.1016/j.jmb.2007.09.043

    View details for PubMedID 17936299

  • Calcium-dependent gating of MthK, a prokaryotic potassium channel. The Journal of general physiology Zadek, B., Nimigean, C. M. 2006; 127 (6): 673-85


    MthK is a calcium-gated, inwardly rectifying, prokaryotic potassium channel. Although little functional information is available for MthK, its high-resolution structure is used as a model for eukaryotic Ca(2+)-dependent potassium channels. Here we characterize in detail the main gating characteristics of MthK at the single-channel level with special focus on the mechanism of Ca(2+) activation. MthK has two distinct gating modes: slow gating affected mainly by Ca(2+) and fast gating affected by voltage. Millimolar Ca(2+) increases MthK open probability over 100-fold by mainly increasing the frequency of channel opening while leaving the opening durations unchanged. The Ca(2+) dose-response curve displays an unusually high Hill coefficient (n = approximately 8), suggesting strong coupling between Ca(2+) binding and channel opening. Depolarization affects both the fast gate by dramatically reducing the fast flickers, and to a lesser extent, the slow gate, by increasing MthK open probability. We were able to capture the mechanistic features of MthK with a modified MWC model.

    View details for DOI 10.1085/jgp.200609534

    View details for PubMedID 16735753

    View details for PubMedCentralID PMC2151542

  • 3-D structural and functional characterization of the purified KATP channel complex Kir6.2-SUR1. The EMBO journal Mikhailov, M. V., Campbell, J. D., de Wet, H., Shimomura, K., Zadek, B., Collins, R. F., Sansom, M. S., Ford, R. C., Ashcroft, F. M. 2005; 24 (23): 4166-75


    ATP-sensitive potassium (K(ATP)) channels conduct potassium ions across cell membranes and thereby couple cellular energy metabolism to membrane electrical activity. Here, we report the heterologous expression and purification of a functionally active K(ATP) channel complex composed of pore-forming Kir6.2 and regulatory SUR1 subunits, and determination of its structure at 18 A resolution by single-particle electron microscopy. The purified channel shows ATP-ase activity similar to that of ATP-binding cassette proteins related to SUR1, and supports Rb(+) fluxes when reconstituted into liposomes. It has a compact structure, with four SUR1 subunits embracing a central Kir6.2 tetramer in both transmembrane and cytosolic domains. A cleft between adjacent SUR1s provides a route by which ATP may access its binding site on Kir6.2. The nucleotide-binding domains of adjacent SUR1 appear to interact, and form a large docking platform for cytosolic proteins. The structure, in combination with molecular modelling, suggests how SUR1 interacts with Kir6.2.

    View details for DOI 10.1038/sj.emboj.7600877

    View details for PubMedID 16308567

    View details for PubMedCentralID PMC1356316