Eileen Connolly - Academia.edu (original) (raw)

Papers by Eileen Connolly

Research paper thumbnail of Akt Inhibition Is Associated With Favorable Immune Profile Changes Within the Tumor Microenvironment of Hormone Receptor Positive, HER2 Negative Breast Cancer

Frontiers in Oncology, Jun 16, 2020

Research paper thumbnail of High Dose Radiation Therapy (HDRT) Induces Notch1 Signaling in Endothelial Cells of Tumor Vasculature

International Journal of Radiation Oncology Biology Physics, Sep 1, 2019

Research paper thumbnail of Gradient Index, But Not Energy Index, Correlates With Time to Obliteration of Pediatric Arteriovenous Malformations Following Stereotactic Radiosurgery

International Journal of Radiation Oncology Biology Physics, Oct 1, 2016

using Cox regression was used to assess the association of OS and variables including RT, age, an... more using Cox regression was used to assess the association of OS and variables including RT, age, and year of diagnosis. Results: 1382 patients diagnosed with T-ALL were identified. The median age at diagnosis was 9 years. There was a significant increase in the use of RT with 48.1% of patients between 2003 and 2012 receiving RT compared with 35.4% between 1980 and 2002 (P<0.001). Age at diagnosis and sex were not associated with differential use of radiation. On univariate analysis, RT was associated with an improvement in 5-year OS compared with no RT (81.6% vs. 73.7, P<0.001). OS was also improved for patients between 2003 and 2012 compared with 1980 and 2002 (84.8% vs. 69.0%, P<0.001), and age less than 10 years compared with age 10 years or older (80.6% vs. 73.1%, PZ0.001). On multivariate analysis, RT use (HRZ 0.672, PZ0.002), year of diagnosis between 2003 and 2012 (HRZ 0.464, P<0.001), and age at diagnosis <10 years (HRZ 0.635, P<0.001) all independently predicted for improved OS. In contrast to the majority of pediatric malignancies where RT use is decreasing, utilization of RT for T-ALL has been increasing. RT use is associated with improved OS independent of year of diagnosis and age of the patient. Limitations include the absence of data in the SEER database regarding chemotherapy, RT site, and CNS risk stratification of ALL patients.

Research paper thumbnail of Comparison of effect of rectal volume delineation methods on dose constraint endpoints in the treatment of prostate cancer with intensity-modulated radiation therapy

Journal of Radiation Oncology, May 24, 2013

Research paper thumbnail of Koebner phenomenon: Consideration when choosing fractionation for breast irradiation

Advances in radiation oncology, Apr 1, 2018

Research paper thumbnail of Obesity and survival in the neoadjuvant breast cancer setting: role of tumor subtype in an ethnically diverse population

Breast Cancer Research and Treatment, Sep 25, 2017

Background-Obesity may negatively affect survival in breast cancer (BC), but studies are conflict... more Background-Obesity may negatively affect survival in breast cancer (BC), but studies are conflicting, and associations may vary by tumor subtypes and race/ethnicity groups. Methods-In a retrospective review, we identified 273 women with invasive BC administered Adriamycin/Taxane-based neoadjuvant chemotherapy from 2004-2016 with body mass index (BMI) data at diagnosis. Obesity was defined as BMI ≥30. Associations between obesity and event-free survival (EFS), using STEEP events, and overall survival (OS), using all-cause mortality, were assessed overall and stratified by tumor subtype [[Hormone Receptor Positive (HR +)/HER2-, HER2+, and Triple Negative Breast Cancer (TNBC])] in our diverse population. Results-Median follow-up was 32.6 months (range 5.7-137.8 months). Overall, obesity was associated with worse EFS (HR 1.71, 95% CI 1.03-2.84, p=0.04) and a trend towards worse OS (p=0.13). In HR+/HER2-disease (n=135), there was an interaction between obesity and hormonal therapy with respect to OS but not EFS. In those receiving tamoxifen (n=33), obesity was associated with worse OS (HR 9.27, 95% CI 0.96-89.3, p=0.05). In those receiving an aromatase inhibitor (n=89), there was no association between obesity and OS. In TNBC (n=44), obesity was associated with worse EFS (HR 2.62, 95% CI 1.03-6.66, p=0.04) and a trend towards worse OS (p=0.06). In HER2+ disease (n=94), obesity was associated with a trend towards worse EFS (HR

Research paper thumbnail of High-Dose Radiation Increases Notch1 in Tumor Vasculature

International Journal of Radiation Oncology Biology Physics, Mar 1, 2020

Research paper thumbnail of Targeted Intraoperative Radiotherapy (TARGIT-IORT) for Early-Stage Invasive Breast Cancer: A Single Institution Experience

Frontiers in Oncology

Purpose/ObjectiveWe present our single-institution experience in the management of invasive breas... more Purpose/ObjectiveWe present our single-institution experience in the management of invasive breast cancer with targeted intraoperative radiotherapy (TARGIT-IORT), focusing on patient suitability for IORT determined by the American Society for Radiation Oncology (ASTRO) Accelerated Partial Breast Irradiation (APBI) consensus guidelines.Materials/MethodsWe identified 237 patients treated for biopsy-proven early-stage invasive breast cancer using low energy x-ray TARGIT-IORT at the time of lumpectomy between September 2013 and April 2020 who were prospectively enrolled in an institutional review board (IRB) approved database. We retrospectively reviewed preoperative and postoperative clinicopathologic factors to determine each patient’s ASTRO APBI suitability (suitable, cautionary or unsuitable) according to the 2017 consensus guidelines (CG). Change in suitability group was determined based on final pathology. Kaplan-Meier methods were used to estimate the survival probability and rec...

Research paper thumbnail of Abstract P2-07-09: Characterization of the tumor microenvironment in patients with hormone receptor positive, HER2 negative early breast cancer

Cancer Research, 2022

Background: Patients (pts) with early stage HER2+ breast cancer (HER2+ EBC) are often treated wit... more Background: Patients (pts) with early stage HER2+ breast cancer (HER2+ EBC) are often treated with neoadjuvant chemotherapy (NACT). Recent studies have demonstrated that increased densities of tumor infiltrating lymphocytes (TIL) are associated with increased rates of pathologic complete response (pCR) in HER2+ EBC. However, outside of standard TIL analysis, a more comprehensive description of the tumor microenvironment (TME) and its impact on clinical outcomes in HER+ EBC is not well defined. Using novel methods, we sought to characterize the TME of patients with hormone receptor positive (HR+), HER2+ EBC treated with NACT. In addition to standard H&E based TIL analysis, we utilized quantitative multiplex immunofluorescence (qmIF), spatial analysis and analysis of RNA-based gene signatures to assess for pretreatment TME characteristics associated with pCR to NACT in HER2+/HR+ EBC. Methods: We identified 29 pts with HER2+/HR+ EBC treated with NACT between 2005 and 2015 for which pre...

Research paper thumbnail of Postoperative complications following intraoperative radiotherapy in abdominopelvic malignancy: A single institution analysis of 113 consecutive patients

Journal of surgical oncology, Jan 2, 2017

Intraoperative radiotherapy (IORT) has advantages over external beam radiation therapy (EBRT). Fe... more Intraoperative radiotherapy (IORT) has advantages over external beam radiation therapy (EBRT). Few studies have described side effects associated with its addition. We evaluated our institution's experience with abdominopelvic IORT to assess safety by postoperative complication rates. Prospectively collected IRB-approved database of all patients receiving abdominopelvic IORT (via high dose rate brachytherapy) at Johns Hopkins Hospital between November 2006 and May 2014 was reviewed. Patients were discussed in multidisciplinary conferences. Those selected for IORT were patients for whom curative intent resection was planned for which IORT could improve margin-negative resection and optimize locoregional control. Perioperative complications were classified via Clavien-Dindo scale for postoperative surgical complications. A total of 113 patients were evaluated. Most common diagnosis was sarcoma (50/113, 44%) followed by colorectal cancer (45/113, 40%), most of which were recurrent ...

Research paper thumbnail of Inhibition of Cap-initiation complexes linked to a novel mechanism of eIF4G depletion in acute myocardial ischemia

Cell Death & Differentiation, 2006

Translational control in the rat heart was characterized during acute myocardial ischemia introdu... more Translational control in the rat heart was characterized during acute myocardial ischemia introduced by left coronary artery ligature. Within 10 min of ischemia, eukaryotic (eIF)4E binds to its negative regulator, eIF4E-binding protein-1 (4E-BP1), but the levels of 4E-BP1 are insufficient to disrupt capdependent mRNA initiation complexes. However, by 1 h of ischemia, the abundance of the cap-initiation complex protein eIF4G is reduced by relocalization into TIAR protein complexes, triggering 4E-BP1 sequestration of eIF4E and disruption of cap-dependent mRNA initiation complexes. As the heart begins to fail at 6 h, proteolysis of eIF4G is observed, resulting in its depletion and accompanied by limited destruction of 4E-BP1 and eIF4E. eIF4G proteolysis and modest loss of 4E-BP1 are associated with caspase-3 activation and induction of cardiomyocyte apoptotic and necrotic death. Acute heart ischemia therefore downregulates cap-dependent translation through eIF4E sequestration triggered by eIF4G depletion.

Research paper thumbnail of Accelerated partial breast irradiation using balloon brachytherapy for ductal carcinoma in situ of the breast: A 5-year experience

Brachytherapy, 2009

Medical Image Analysis, Volume 8, Issue 2, Pages 107, April 2009, Authors:Bradley R. Prestidge, M... more Medical Image Analysis, Volume 8, Issue 2, Pages 107, April 2009, Authors:Bradley R. Prestidge, MD, MS; Amir Sadeghi, Ph.D.; Arthur Rosenthal, MD; Kathryn Safford, MD; Romero Pino, Ph.D.; Sylvia Gutierrez-Zubyk, MD. ...

Research paper thumbnail of Patterns of Care in Pediatric Craniopharyngioma: Outcomes Following Definitive Radiotherapy

Anticancer Research, 2019

Background/Aim: Few data are available on the utility of definitive radiation therapy (RT) for pe... more Background/Aim: Few data are available on the utility of definitive radiation therapy (RT) for pediatric craniopharyngioma. This study sought to evaluate practice patterns and patient outcomes using the Surveillance Epidemiology and End Results database from 2004-2014. Materials and Methods: Overall survival (OS) was compared between five treatment groups, definitive radiation therapy (RT), gross total resection (GTR), subtotal resection (STR), STR+RT, and observation/biopsy only, using Kaplan-Meier analysis and log-rank tests. Multivariate Cox proportional hazards modeling determined variables independently associated with OS. Results: A total of 373 patients met the study criteria. GTR and definitive RT conferred superior OS than observation/biopsy (p=0.008 and 0.029), but were equivalent to STR+RT (p=0.350 and 0.200). GTR was associated with a higher OS than STR (p=0.027). On multivariate analysis, STR+RT, GTR, and definitive RT were associated with statistically equivalent OS (p=0.990). Conclusion: Definitive RT for pediatric craniopharyngioma affords similar outcomes to established modalities of therapy such as GTR and STR+RT.

Research paper thumbnail of Predictors of Breast Reconstruction Failure and Morbidity in Patients Undergoing Postmastectomy Radiotherapy in the Era of Neoadjuvant Chemotherapy

International Journal of Radiation Oncology*Biology*Physics, 2019

of testing. We hypothesized that ultra-young patients with breast cancer (<35 years) from a singl... more of testing. We hypothesized that ultra-young patients with breast cancer (<35 years) from a single high-volume academic institution would have high rates of screening and fewer disparities in receipt of genetic testing, and therefore facilitate a prospective study of radiation toxicity among mutation carriers. Materials/Methods: After IRB approval, the medical records of 532 patients ages 35 and younger at time of breast cancer diagnosis between 1990 and 2010 at a single institution were reviewed. Demographic features including race, ethnicity, language, and highest education level were captured, in addition to family history, Ashkenazi Jewish ancestry, receipt of genetic counseling and genetic testing results. Statistical analysis included chi-square and linear-by-linear association tests. Results: The overall rate of genetic testing was 55% (290/532) in this cohort. From 1990 to 1998, the annual rate of testing was roughly stable, with a mean of 42%; then following NCCN guidelines publication in 1999, the testing rate steadily increased to 89-100% by the end of the study period (years 2009 and 2010). Of 199 patients who saw a genetic counselor, 157 (79%) received genetic testing, and an additional 133 patients were tested without seeing a genetic counselor. Fifty-four patients (19%) had germline mutations in BRCA1 (n Z 29), BRCA2 (nZ17) or other (CHEK2Z2, PTENZ2, p53Z2, RAD51CZ1, ATMZ1). Receipt of genetic testing was correlated with higher levels of education (pZ0.00084), race (pZ0.047), Ashkenazi Jewish ancestry (pZ0.024), and diagnosis after implementation of NCCN testing guidelines in 1999 (pZ0.0002). Family history, ethnicity, language, and whether the patient had children were not correlated with receipt of genetic testing. Conclusion: Rates of genetic testing among ultra-young breast cancer patients were high, particularly in response to national guidelines published in 1999, after which it took 10 years to exceed 90% testing rate in this group. Disparities exist in receipt of genetic testing related to patient race and education level, even in the specialized setting, though is likely driven by early time points in this study. Future efforts will involve exploring barriers and facilitators to genetic testing that could be employed outside the tertiary care setting, and studying radiation toxicity among mutation carriers in a large center with over 90% rate of testing in highrisk groups.

Research paper thumbnail of Adaptive Deformable Registration and Fusion for Fractionated Stereotactic Radiosurgery Using a Small Animal Irradiator

International Journal of Radiation Oncology*Biology*Physics, 2018

to a third party software, Velocity TM , for the deformable registration with the planning CT ima... more to a third party software, Velocity TM , for the deformable registration with the planning CT image set. The registration process transformed the plan dose to each CBCT image set and deformed it as the delivered fraction dose for each structure. The accumulated dose for both targets and normal tissues was calculated with the actual deformed dose to CBCT. Results: It is observed that dose distribution for both targets and normal tissues has changed over the course of treatment. The variation of the accumulated dose from the plan dose is organ and patient dependent. The largest variation was up to 150% in minimum dose. Maximum dose and mean dose had less variations in general. The percent variation of minimum, maximum and mean dose is summarized in a table for CTV, GTV and normal tissues. The change in the shape and volume of each structure was also observed by the translational deviation of the DICOM center of a structure more than a centimeter in x, y or z direction for some patients. The weekly breakdown of the variations in accumulated dose and structural volumetric center presents a consistent deformation of some structures over the course of treatment. Conclusion: Conventional fractionation H&N cancer radiotherapy in is a standard protocol. IGRT has been employed to correct the patient positioning by kV orthogonal or CBCT imaging. Considerable variations have been observed in dose distribution over the course of treatment for both targets and normal tissues due to the organ deformation. The results of this study can be used to determine whether or when adaptive therapy is needed throughout the treatment or to calculate any remedy necessary at the end of the course.

Research paper thumbnail of Abscopal Effect in Congenital Fibrosarcoma With Novel EML4-NTRK3 Fusion

International Journal of Radiation Oncology*Biology*Physics, 2016

Results: Expression analysis confirmed overexpression of HDAC enzymes (particularly HDAC1 and HDA... more Results: Expression analysis confirmed overexpression of HDAC enzymes (particularly HDAC1 and HDAC9). UN-KC-6141 cells showed low to absent basal expression of MHC class I alleles, consistent with immune escape. Co-stimulatory and co-inhibitory markers were expressed at low (CD80, CD86, and 4-1BBL) and minimal (PD-L1) levels respectively, while cells showed up-regulation of CD44 and CD133, both associated with CaPan stem cells. Treatment with HDACi resulted in reversal of immune escape, with nearly 100% of cells showing MHC expression (RT alone did not show this effect). The combined regimen (RT plus HDACi) showed the highest up-regulation of immune co-stimulatory markers (CD80, CD86, and 4-1BBL). Moderate PD-L1 expression and apoptotic signaling through Fas/CD95 were also observed in all treatment groups. T cells presented with antigens from the combined treatment group demonstrated enhanced cytotoxicity compared to control and monotherapy groups, indicating improved activation. Conclusion: Our preclinical results support the combination of epigenetic immune priming with ablative radiation to enhance the immunogenicity of pancreatic tumors. This regimen of Immune Priming Ablation (IPA) has the potential to improve clinical outcomes of combination radiation and immunotherapy.

Research paper thumbnail of Obesity and Survival in Women with Invasive Breast Cancer Receiving Neoadjuvant Chemotherapy: Role of Tumor Subtype and Race

International Journal of Radiation Oncology*Biology*Physics, 2017

desquamation. For the 33 curative-intent patients, five-year LRC was 84%, DFS was 52%, and OS was... more desquamation. For the 33 curative-intent patients, five-year LRC was 84%, DFS was 52%, and OS was 64%. The remaining 1187 patients with de novo stage IV disease had significantly worse OS, with a 5-year OS of 33% (PZ0.003). In the curative-intent patients, neither biologic subtype, mediastinal/sternal resection, nor radiation dose was associated with improved LRC, DFS, or OS (P>0.05). Conclusion: For selected patients presenting with breast cancer metastatic to the sternum or mediastinum, curative-intent treatment with chemotherapy, surgery, and radiation offers durable cure and improved survival compared to most patients with de novo stage IV breast cancer. Future updates to the AJCC staging system should consider this finding.

Research paper thumbnail of Risk Factors Associated with Interval Time between Initial Non-Small Cell Lung Cancer (NSCLC) Diagnosis and Development of Brain Metastases

International Journal of Radiation Oncology*Biology*Physics, 2017

The management of glioma has evolved to increasing reliance on molecular characterization over hi... more The management of glioma has evolved to increasing reliance on molecular characterization over histological findings. We aimed to analyze glioma management and molecular findings in the NCI NIH glioma patient cohort spanning the last 22 years in an effort to elucidate the impact of molecular characterization on response to radiation therapy (RT) as well as additional prognostic features as a platform for ongoing molecular and dosimetric analysis. Materials/Methods: 102 patients with a diagnosis of grade II and grade III glioma were evaluated between 1995 and 2017, 95 were included in the analysis following thorough chart review. Kaplan-Meier analysis was performed for the purpose of comparison amongst patient and disease variables molecular characterization (IDH mutation, 1p19q deletion), management trends, overall survival (OS) and progression free survival (PFS). Results: 95 patients median age 37 (10-72) with original diagnosis of 21 astrocytoma, 8 Oligoastrocytoma, 20 Olidodendroglioma, 29 Anaplastic Astrocytoma, 3 Anaplastic Oligoastrocytoma, 12 Anaplastic Oligodendroglioma, 2 anaplastic glioneuronal tumor were analyzed. With a median follow-up of 7.3 years, median OS for WHO Grade 2 and Grade 3 cohorts were 8.6 years and 4.8 years (pZ.02), with median PFS of 6.9 vs 4.5 years (pZ.56). When further stratified by molecular marker subtype, gliomas with 1p/19q co-deletion compared to 1p/19q intact had OS of 7.1 years vs 5.0 (pZ.05) and PFS of 5.7 vs 2.6 (pZ.22). Gliomas with IDH mutation compared to IDH wild type had OS of 5.5 vs 3.6 years (pZ.03) and PFS of 5.3 vs 3.6 years (pZ.78). Comparing patients treated with RT versus no RT by histologically based WHO subtype was not associated with a statistically significant difference in OS (RT 7.1 years vs no RT 6.2 years, pZ.25) with a trend toward worse PFS in the RT group (RT 5.5 years vs no RT 5.9 years, pZ.06). However, when analyzed by molecular subtyping, patients with 1p/19q codeletion and IDH mutated tumors treated with RT had improved OS with 1p/19q co-deleted OS 7.9 years vs 1p/19q intact 4 years, (pZ.04). IDH mutated glioma OS was 6.8 years vs IDH wild type 3.85 years (pZ.01). PFS analyzed by molecular subtype did not demonstrate a significant difference between groups with 1p/ 19q co-deleted PFS 6.5 years vs 1p/19q intact 3.7 years, pZ.98, and IDH mutated PFS 5.5 years vs IDH wild type 3.5 years, (pZ0.62). Conclusion: Previously reported trends were validated in the NCI NIH population. In contrast to histologic WHO grading, molecular characterization was prognostic for OS and predictive for response to RT. The ongoing addition of deep sequencing analysis results to imaging and RT dosimetry characteristics will further define prognostic and predictive factors in the evolving management of this challenging patient population.

Research paper thumbnail of Associations of Lymphovascular Invasion and Clinical Outcomes in Breast Cancer After Neoadjuvant Chemotherapy

International Journal of Radiation Oncology*Biology*Physics, 2016

To report the clinical result of phase II study of whole breast irradiation with simultaneously i... more To report the clinical result of phase II study of whole breast irradiation with simultaneously integrated tumor bed (TB) boost for early stage breast cancer. Materials/Methods: From October 2010 to April 2013, 200 patients with breast cancer who received breast conservative surgery were prospectively enrolled in this WBI-SIB study with inversely intensity modulated radiation therapy. The radiation therapy schema was 45 Gy in 25 fractions to the breast and an additional concurrent 0.6 Gy delivered to the TB. Acute breast skin toxicity was assessed according to the common terminology criteria (CTC) for adverse events version 3.0 based on the highest grade toxicity. Cosmetic results were graded using 4-point scale according to the Harvard criteria by patient's self-assessment. Local control was calculated using the method of Kaplan-Meier. Results: The median age for all patients was 45 year old. The mean breast PTV was 529.2cc and TB PTV was 92.9cc. The ipsilateral lung mean V 20 was 17.2% and mean heart dose was 531cGy for left breast cancer. The acute skin toxicity was Grade 0 in 16 patients (8%), Grade 1 in 126 (63%) and Grade 2 in 58 (29%). Moist desquamation rate was 10.5% for all patients. In multivariate analysis, the predictive factors for grade 2 acute dermatitis were breast PTV (P Z 0.031) and TB PTV (P<0.001). In 185 cases, global breast cosmesis was judged as excellent or good in 87.1% and fair in 12.9%. Median follow-up time was 38 months, 2 patients had inbreast recurrence, and one patient has ipsilateral axillary lymph node and lung metastasis. Local control rate of 3 year was 98.7%. Conclusion: WBI-SIB for early stage breast cancer had good acute skin toxicity profile and cosmetic result in our hospital. The local control rate of 3 years was excellent. The WBI-SIB treatment scheme is feasible in Chinese patients.

Research paper thumbnail of Proteomic modulation in breast tumors after metformin exposure: results from a “window of opportunity” trial

Clinical and Translational Oncology, 2016

Purpose-Reverse Phase Protein Array (RPPA) is a high-throughput antibody-based technique to asses... more Purpose-Reverse Phase Protein Array (RPPA) is a high-throughput antibody-based technique to assess cellular protein activity. The goal of this study was to assess protein marker changes by RPPA in tumor tissue from a pre-surgical metformin trial in women with operable breast cancer (BC). Methods-In an open-label trial, metformin 1500-mg PO daily was administered prior to resection in 35 non-diabetic patients with stage 0-III BC, body mass index ≥25 kg/m 2. For RPPA, formalin-fixed paraffin-embedded (FFPE) samples were probed with 160 antibodies. Paired and two-sample t-tests were performed (p ≤ 0.05).

Research paper thumbnail of Akt Inhibition Is Associated With Favorable Immune Profile Changes Within the Tumor Microenvironment of Hormone Receptor Positive, HER2 Negative Breast Cancer

Frontiers in Oncology, Jun 16, 2020

Research paper thumbnail of High Dose Radiation Therapy (HDRT) Induces Notch1 Signaling in Endothelial Cells of Tumor Vasculature

International Journal of Radiation Oncology Biology Physics, Sep 1, 2019

Research paper thumbnail of Gradient Index, But Not Energy Index, Correlates With Time to Obliteration of Pediatric Arteriovenous Malformations Following Stereotactic Radiosurgery

International Journal of Radiation Oncology Biology Physics, Oct 1, 2016

using Cox regression was used to assess the association of OS and variables including RT, age, an... more using Cox regression was used to assess the association of OS and variables including RT, age, and year of diagnosis. Results: 1382 patients diagnosed with T-ALL were identified. The median age at diagnosis was 9 years. There was a significant increase in the use of RT with 48.1% of patients between 2003 and 2012 receiving RT compared with 35.4% between 1980 and 2002 (P<0.001). Age at diagnosis and sex were not associated with differential use of radiation. On univariate analysis, RT was associated with an improvement in 5-year OS compared with no RT (81.6% vs. 73.7, P<0.001). OS was also improved for patients between 2003 and 2012 compared with 1980 and 2002 (84.8% vs. 69.0%, P<0.001), and age less than 10 years compared with age 10 years or older (80.6% vs. 73.1%, PZ0.001). On multivariate analysis, RT use (HRZ 0.672, PZ0.002), year of diagnosis between 2003 and 2012 (HRZ 0.464, P<0.001), and age at diagnosis <10 years (HRZ 0.635, P<0.001) all independently predicted for improved OS. In contrast to the majority of pediatric malignancies where RT use is decreasing, utilization of RT for T-ALL has been increasing. RT use is associated with improved OS independent of year of diagnosis and age of the patient. Limitations include the absence of data in the SEER database regarding chemotherapy, RT site, and CNS risk stratification of ALL patients.

Research paper thumbnail of Comparison of effect of rectal volume delineation methods on dose constraint endpoints in the treatment of prostate cancer with intensity-modulated radiation therapy

Journal of Radiation Oncology, May 24, 2013

Research paper thumbnail of Koebner phenomenon: Consideration when choosing fractionation for breast irradiation

Advances in radiation oncology, Apr 1, 2018

Research paper thumbnail of Obesity and survival in the neoadjuvant breast cancer setting: role of tumor subtype in an ethnically diverse population

Breast Cancer Research and Treatment, Sep 25, 2017

Background-Obesity may negatively affect survival in breast cancer (BC), but studies are conflict... more Background-Obesity may negatively affect survival in breast cancer (BC), but studies are conflicting, and associations may vary by tumor subtypes and race/ethnicity groups. Methods-In a retrospective review, we identified 273 women with invasive BC administered Adriamycin/Taxane-based neoadjuvant chemotherapy from 2004-2016 with body mass index (BMI) data at diagnosis. Obesity was defined as BMI ≥30. Associations between obesity and event-free survival (EFS), using STEEP events, and overall survival (OS), using all-cause mortality, were assessed overall and stratified by tumor subtype [[Hormone Receptor Positive (HR +)/HER2-, HER2+, and Triple Negative Breast Cancer (TNBC])] in our diverse population. Results-Median follow-up was 32.6 months (range 5.7-137.8 months). Overall, obesity was associated with worse EFS (HR 1.71, 95% CI 1.03-2.84, p=0.04) and a trend towards worse OS (p=0.13). In HR+/HER2-disease (n=135), there was an interaction between obesity and hormonal therapy with respect to OS but not EFS. In those receiving tamoxifen (n=33), obesity was associated with worse OS (HR 9.27, 95% CI 0.96-89.3, p=0.05). In those receiving an aromatase inhibitor (n=89), there was no association between obesity and OS. In TNBC (n=44), obesity was associated with worse EFS (HR 2.62, 95% CI 1.03-6.66, p=0.04) and a trend towards worse OS (p=0.06). In HER2+ disease (n=94), obesity was associated with a trend towards worse EFS (HR

Research paper thumbnail of High-Dose Radiation Increases Notch1 in Tumor Vasculature

International Journal of Radiation Oncology Biology Physics, Mar 1, 2020

Research paper thumbnail of Targeted Intraoperative Radiotherapy (TARGIT-IORT) for Early-Stage Invasive Breast Cancer: A Single Institution Experience

Frontiers in Oncology

Purpose/ObjectiveWe present our single-institution experience in the management of invasive breas... more Purpose/ObjectiveWe present our single-institution experience in the management of invasive breast cancer with targeted intraoperative radiotherapy (TARGIT-IORT), focusing on patient suitability for IORT determined by the American Society for Radiation Oncology (ASTRO) Accelerated Partial Breast Irradiation (APBI) consensus guidelines.Materials/MethodsWe identified 237 patients treated for biopsy-proven early-stage invasive breast cancer using low energy x-ray TARGIT-IORT at the time of lumpectomy between September 2013 and April 2020 who were prospectively enrolled in an institutional review board (IRB) approved database. We retrospectively reviewed preoperative and postoperative clinicopathologic factors to determine each patient’s ASTRO APBI suitability (suitable, cautionary or unsuitable) according to the 2017 consensus guidelines (CG). Change in suitability group was determined based on final pathology. Kaplan-Meier methods were used to estimate the survival probability and rec...

Research paper thumbnail of Abstract P2-07-09: Characterization of the tumor microenvironment in patients with hormone receptor positive, HER2 negative early breast cancer

Cancer Research, 2022

Background: Patients (pts) with early stage HER2+ breast cancer (HER2+ EBC) are often treated wit... more Background: Patients (pts) with early stage HER2+ breast cancer (HER2+ EBC) are often treated with neoadjuvant chemotherapy (NACT). Recent studies have demonstrated that increased densities of tumor infiltrating lymphocytes (TIL) are associated with increased rates of pathologic complete response (pCR) in HER2+ EBC. However, outside of standard TIL analysis, a more comprehensive description of the tumor microenvironment (TME) and its impact on clinical outcomes in HER+ EBC is not well defined. Using novel methods, we sought to characterize the TME of patients with hormone receptor positive (HR+), HER2+ EBC treated with NACT. In addition to standard H&E based TIL analysis, we utilized quantitative multiplex immunofluorescence (qmIF), spatial analysis and analysis of RNA-based gene signatures to assess for pretreatment TME characteristics associated with pCR to NACT in HER2+/HR+ EBC. Methods: We identified 29 pts with HER2+/HR+ EBC treated with NACT between 2005 and 2015 for which pre...

Research paper thumbnail of Postoperative complications following intraoperative radiotherapy in abdominopelvic malignancy: A single institution analysis of 113 consecutive patients

Journal of surgical oncology, Jan 2, 2017

Intraoperative radiotherapy (IORT) has advantages over external beam radiation therapy (EBRT). Fe... more Intraoperative radiotherapy (IORT) has advantages over external beam radiation therapy (EBRT). Few studies have described side effects associated with its addition. We evaluated our institution's experience with abdominopelvic IORT to assess safety by postoperative complication rates. Prospectively collected IRB-approved database of all patients receiving abdominopelvic IORT (via high dose rate brachytherapy) at Johns Hopkins Hospital between November 2006 and May 2014 was reviewed. Patients were discussed in multidisciplinary conferences. Those selected for IORT were patients for whom curative intent resection was planned for which IORT could improve margin-negative resection and optimize locoregional control. Perioperative complications were classified via Clavien-Dindo scale for postoperative surgical complications. A total of 113 patients were evaluated. Most common diagnosis was sarcoma (50/113, 44%) followed by colorectal cancer (45/113, 40%), most of which were recurrent ...

Research paper thumbnail of Inhibition of Cap-initiation complexes linked to a novel mechanism of eIF4G depletion in acute myocardial ischemia

Cell Death & Differentiation, 2006

Translational control in the rat heart was characterized during acute myocardial ischemia introdu... more Translational control in the rat heart was characterized during acute myocardial ischemia introduced by left coronary artery ligature. Within 10 min of ischemia, eukaryotic (eIF)4E binds to its negative regulator, eIF4E-binding protein-1 (4E-BP1), but the levels of 4E-BP1 are insufficient to disrupt capdependent mRNA initiation complexes. However, by 1 h of ischemia, the abundance of the cap-initiation complex protein eIF4G is reduced by relocalization into TIAR protein complexes, triggering 4E-BP1 sequestration of eIF4E and disruption of cap-dependent mRNA initiation complexes. As the heart begins to fail at 6 h, proteolysis of eIF4G is observed, resulting in its depletion and accompanied by limited destruction of 4E-BP1 and eIF4E. eIF4G proteolysis and modest loss of 4E-BP1 are associated with caspase-3 activation and induction of cardiomyocyte apoptotic and necrotic death. Acute heart ischemia therefore downregulates cap-dependent translation through eIF4E sequestration triggered by eIF4G depletion.

Research paper thumbnail of Accelerated partial breast irradiation using balloon brachytherapy for ductal carcinoma in situ of the breast: A 5-year experience

Brachytherapy, 2009

Medical Image Analysis, Volume 8, Issue 2, Pages 107, April 2009, Authors:Bradley R. Prestidge, M... more Medical Image Analysis, Volume 8, Issue 2, Pages 107, April 2009, Authors:Bradley R. Prestidge, MD, MS; Amir Sadeghi, Ph.D.; Arthur Rosenthal, MD; Kathryn Safford, MD; Romero Pino, Ph.D.; Sylvia Gutierrez-Zubyk, MD. ...

Research paper thumbnail of Patterns of Care in Pediatric Craniopharyngioma: Outcomes Following Definitive Radiotherapy

Anticancer Research, 2019

Background/Aim: Few data are available on the utility of definitive radiation therapy (RT) for pe... more Background/Aim: Few data are available on the utility of definitive radiation therapy (RT) for pediatric craniopharyngioma. This study sought to evaluate practice patterns and patient outcomes using the Surveillance Epidemiology and End Results database from 2004-2014. Materials and Methods: Overall survival (OS) was compared between five treatment groups, definitive radiation therapy (RT), gross total resection (GTR), subtotal resection (STR), STR+RT, and observation/biopsy only, using Kaplan-Meier analysis and log-rank tests. Multivariate Cox proportional hazards modeling determined variables independently associated with OS. Results: A total of 373 patients met the study criteria. GTR and definitive RT conferred superior OS than observation/biopsy (p=0.008 and 0.029), but were equivalent to STR+RT (p=0.350 and 0.200). GTR was associated with a higher OS than STR (p=0.027). On multivariate analysis, STR+RT, GTR, and definitive RT were associated with statistically equivalent OS (p=0.990). Conclusion: Definitive RT for pediatric craniopharyngioma affords similar outcomes to established modalities of therapy such as GTR and STR+RT.

Research paper thumbnail of Predictors of Breast Reconstruction Failure and Morbidity in Patients Undergoing Postmastectomy Radiotherapy in the Era of Neoadjuvant Chemotherapy

International Journal of Radiation Oncology*Biology*Physics, 2019

of testing. We hypothesized that ultra-young patients with breast cancer (<35 years) from a singl... more of testing. We hypothesized that ultra-young patients with breast cancer (<35 years) from a single high-volume academic institution would have high rates of screening and fewer disparities in receipt of genetic testing, and therefore facilitate a prospective study of radiation toxicity among mutation carriers. Materials/Methods: After IRB approval, the medical records of 532 patients ages 35 and younger at time of breast cancer diagnosis between 1990 and 2010 at a single institution were reviewed. Demographic features including race, ethnicity, language, and highest education level were captured, in addition to family history, Ashkenazi Jewish ancestry, receipt of genetic counseling and genetic testing results. Statistical analysis included chi-square and linear-by-linear association tests. Results: The overall rate of genetic testing was 55% (290/532) in this cohort. From 1990 to 1998, the annual rate of testing was roughly stable, with a mean of 42%; then following NCCN guidelines publication in 1999, the testing rate steadily increased to 89-100% by the end of the study period (years 2009 and 2010). Of 199 patients who saw a genetic counselor, 157 (79%) received genetic testing, and an additional 133 patients were tested without seeing a genetic counselor. Fifty-four patients (19%) had germline mutations in BRCA1 (n Z 29), BRCA2 (nZ17) or other (CHEK2Z2, PTENZ2, p53Z2, RAD51CZ1, ATMZ1). Receipt of genetic testing was correlated with higher levels of education (pZ0.00084), race (pZ0.047), Ashkenazi Jewish ancestry (pZ0.024), and diagnosis after implementation of NCCN testing guidelines in 1999 (pZ0.0002). Family history, ethnicity, language, and whether the patient had children were not correlated with receipt of genetic testing. Conclusion: Rates of genetic testing among ultra-young breast cancer patients were high, particularly in response to national guidelines published in 1999, after which it took 10 years to exceed 90% testing rate in this group. Disparities exist in receipt of genetic testing related to patient race and education level, even in the specialized setting, though is likely driven by early time points in this study. Future efforts will involve exploring barriers and facilitators to genetic testing that could be employed outside the tertiary care setting, and studying radiation toxicity among mutation carriers in a large center with over 90% rate of testing in highrisk groups.

Research paper thumbnail of Adaptive Deformable Registration and Fusion for Fractionated Stereotactic Radiosurgery Using a Small Animal Irradiator

International Journal of Radiation Oncology*Biology*Physics, 2018

to a third party software, Velocity TM , for the deformable registration with the planning CT ima... more to a third party software, Velocity TM , for the deformable registration with the planning CT image set. The registration process transformed the plan dose to each CBCT image set and deformed it as the delivered fraction dose for each structure. The accumulated dose for both targets and normal tissues was calculated with the actual deformed dose to CBCT. Results: It is observed that dose distribution for both targets and normal tissues has changed over the course of treatment. The variation of the accumulated dose from the plan dose is organ and patient dependent. The largest variation was up to 150% in minimum dose. Maximum dose and mean dose had less variations in general. The percent variation of minimum, maximum and mean dose is summarized in a table for CTV, GTV and normal tissues. The change in the shape and volume of each structure was also observed by the translational deviation of the DICOM center of a structure more than a centimeter in x, y or z direction for some patients. The weekly breakdown of the variations in accumulated dose and structural volumetric center presents a consistent deformation of some structures over the course of treatment. Conclusion: Conventional fractionation H&N cancer radiotherapy in is a standard protocol. IGRT has been employed to correct the patient positioning by kV orthogonal or CBCT imaging. Considerable variations have been observed in dose distribution over the course of treatment for both targets and normal tissues due to the organ deformation. The results of this study can be used to determine whether or when adaptive therapy is needed throughout the treatment or to calculate any remedy necessary at the end of the course.

Research paper thumbnail of Abscopal Effect in Congenital Fibrosarcoma With Novel EML4-NTRK3 Fusion

International Journal of Radiation Oncology*Biology*Physics, 2016

Results: Expression analysis confirmed overexpression of HDAC enzymes (particularly HDAC1 and HDA... more Results: Expression analysis confirmed overexpression of HDAC enzymes (particularly HDAC1 and HDAC9). UN-KC-6141 cells showed low to absent basal expression of MHC class I alleles, consistent with immune escape. Co-stimulatory and co-inhibitory markers were expressed at low (CD80, CD86, and 4-1BBL) and minimal (PD-L1) levels respectively, while cells showed up-regulation of CD44 and CD133, both associated with CaPan stem cells. Treatment with HDACi resulted in reversal of immune escape, with nearly 100% of cells showing MHC expression (RT alone did not show this effect). The combined regimen (RT plus HDACi) showed the highest up-regulation of immune co-stimulatory markers (CD80, CD86, and 4-1BBL). Moderate PD-L1 expression and apoptotic signaling through Fas/CD95 were also observed in all treatment groups. T cells presented with antigens from the combined treatment group demonstrated enhanced cytotoxicity compared to control and monotherapy groups, indicating improved activation. Conclusion: Our preclinical results support the combination of epigenetic immune priming with ablative radiation to enhance the immunogenicity of pancreatic tumors. This regimen of Immune Priming Ablation (IPA) has the potential to improve clinical outcomes of combination radiation and immunotherapy.

Research paper thumbnail of Obesity and Survival in Women with Invasive Breast Cancer Receiving Neoadjuvant Chemotherapy: Role of Tumor Subtype and Race

International Journal of Radiation Oncology*Biology*Physics, 2017

desquamation. For the 33 curative-intent patients, five-year LRC was 84%, DFS was 52%, and OS was... more desquamation. For the 33 curative-intent patients, five-year LRC was 84%, DFS was 52%, and OS was 64%. The remaining 1187 patients with de novo stage IV disease had significantly worse OS, with a 5-year OS of 33% (PZ0.003). In the curative-intent patients, neither biologic subtype, mediastinal/sternal resection, nor radiation dose was associated with improved LRC, DFS, or OS (P>0.05). Conclusion: For selected patients presenting with breast cancer metastatic to the sternum or mediastinum, curative-intent treatment with chemotherapy, surgery, and radiation offers durable cure and improved survival compared to most patients with de novo stage IV breast cancer. Future updates to the AJCC staging system should consider this finding.

Research paper thumbnail of Risk Factors Associated with Interval Time between Initial Non-Small Cell Lung Cancer (NSCLC) Diagnosis and Development of Brain Metastases

International Journal of Radiation Oncology*Biology*Physics, 2017

The management of glioma has evolved to increasing reliance on molecular characterization over hi... more The management of glioma has evolved to increasing reliance on molecular characterization over histological findings. We aimed to analyze glioma management and molecular findings in the NCI NIH glioma patient cohort spanning the last 22 years in an effort to elucidate the impact of molecular characterization on response to radiation therapy (RT) as well as additional prognostic features as a platform for ongoing molecular and dosimetric analysis. Materials/Methods: 102 patients with a diagnosis of grade II and grade III glioma were evaluated between 1995 and 2017, 95 were included in the analysis following thorough chart review. Kaplan-Meier analysis was performed for the purpose of comparison amongst patient and disease variables molecular characterization (IDH mutation, 1p19q deletion), management trends, overall survival (OS) and progression free survival (PFS). Results: 95 patients median age 37 (10-72) with original diagnosis of 21 astrocytoma, 8 Oligoastrocytoma, 20 Olidodendroglioma, 29 Anaplastic Astrocytoma, 3 Anaplastic Oligoastrocytoma, 12 Anaplastic Oligodendroglioma, 2 anaplastic glioneuronal tumor were analyzed. With a median follow-up of 7.3 years, median OS for WHO Grade 2 and Grade 3 cohorts were 8.6 years and 4.8 years (pZ.02), with median PFS of 6.9 vs 4.5 years (pZ.56). When further stratified by molecular marker subtype, gliomas with 1p/19q co-deletion compared to 1p/19q intact had OS of 7.1 years vs 5.0 (pZ.05) and PFS of 5.7 vs 2.6 (pZ.22). Gliomas with IDH mutation compared to IDH wild type had OS of 5.5 vs 3.6 years (pZ.03) and PFS of 5.3 vs 3.6 years (pZ.78). Comparing patients treated with RT versus no RT by histologically based WHO subtype was not associated with a statistically significant difference in OS (RT 7.1 years vs no RT 6.2 years, pZ.25) with a trend toward worse PFS in the RT group (RT 5.5 years vs no RT 5.9 years, pZ.06). However, when analyzed by molecular subtyping, patients with 1p/19q codeletion and IDH mutated tumors treated with RT had improved OS with 1p/19q co-deleted OS 7.9 years vs 1p/19q intact 4 years, (pZ.04). IDH mutated glioma OS was 6.8 years vs IDH wild type 3.85 years (pZ.01). PFS analyzed by molecular subtype did not demonstrate a significant difference between groups with 1p/ 19q co-deleted PFS 6.5 years vs 1p/19q intact 3.7 years, pZ.98, and IDH mutated PFS 5.5 years vs IDH wild type 3.5 years, (pZ0.62). Conclusion: Previously reported trends were validated in the NCI NIH population. In contrast to histologic WHO grading, molecular characterization was prognostic for OS and predictive for response to RT. The ongoing addition of deep sequencing analysis results to imaging and RT dosimetry characteristics will further define prognostic and predictive factors in the evolving management of this challenging patient population.

Research paper thumbnail of Associations of Lymphovascular Invasion and Clinical Outcomes in Breast Cancer After Neoadjuvant Chemotherapy

International Journal of Radiation Oncology*Biology*Physics, 2016

To report the clinical result of phase II study of whole breast irradiation with simultaneously i... more To report the clinical result of phase II study of whole breast irradiation with simultaneously integrated tumor bed (TB) boost for early stage breast cancer. Materials/Methods: From October 2010 to April 2013, 200 patients with breast cancer who received breast conservative surgery were prospectively enrolled in this WBI-SIB study with inversely intensity modulated radiation therapy. The radiation therapy schema was 45 Gy in 25 fractions to the breast and an additional concurrent 0.6 Gy delivered to the TB. Acute breast skin toxicity was assessed according to the common terminology criteria (CTC) for adverse events version 3.0 based on the highest grade toxicity. Cosmetic results were graded using 4-point scale according to the Harvard criteria by patient's self-assessment. Local control was calculated using the method of Kaplan-Meier. Results: The median age for all patients was 45 year old. The mean breast PTV was 529.2cc and TB PTV was 92.9cc. The ipsilateral lung mean V 20 was 17.2% and mean heart dose was 531cGy for left breast cancer. The acute skin toxicity was Grade 0 in 16 patients (8%), Grade 1 in 126 (63%) and Grade 2 in 58 (29%). Moist desquamation rate was 10.5% for all patients. In multivariate analysis, the predictive factors for grade 2 acute dermatitis were breast PTV (P Z 0.031) and TB PTV (P<0.001). In 185 cases, global breast cosmesis was judged as excellent or good in 87.1% and fair in 12.9%. Median follow-up time was 38 months, 2 patients had inbreast recurrence, and one patient has ipsilateral axillary lymph node and lung metastasis. Local control rate of 3 year was 98.7%. Conclusion: WBI-SIB for early stage breast cancer had good acute skin toxicity profile and cosmetic result in our hospital. The local control rate of 3 years was excellent. The WBI-SIB treatment scheme is feasible in Chinese patients.

Research paper thumbnail of Proteomic modulation in breast tumors after metformin exposure: results from a “window of opportunity” trial

Clinical and Translational Oncology, 2016

Purpose-Reverse Phase Protein Array (RPPA) is a high-throughput antibody-based technique to asses... more Purpose-Reverse Phase Protein Array (RPPA) is a high-throughput antibody-based technique to assess cellular protein activity. The goal of this study was to assess protein marker changes by RPPA in tumor tissue from a pre-surgical metformin trial in women with operable breast cancer (BC). Methods-In an open-label trial, metformin 1500-mg PO daily was administered prior to resection in 35 non-diabetic patients with stage 0-III BC, body mass index ≥25 kg/m 2. For RPPA, formalin-fixed paraffin-embedded (FFPE) samples were probed with 160 antibodies. Paired and two-sample t-tests were performed (p ≤ 0.05).