Publications by authors named "Michael J Naughton"

42 Publications

Phase I Study of Docetaxel and Temsirolimus in Refractory Solid Tumors.

Am J Clin Oncol 2021 09;44(9):443-448

Division of Hematology/Oncology, Medical University of South Carolina, Hollings Cancer Center, Charleston, SC.

Introduction: The mammalian target of rapamycin (mTOR) is a downstream mediator in the phosphatidylinositol 3-kinase/Akt signaling pathway, and plays a central role in cell proliferation, growth, differentiation, migration, and survival. Temsirolimus (CCI-779), a selective inhibitor of the mTOR, is an ester analog of rapamycin (sirolimus) with improved aqueous solubility and pharmacokinetic (PK) properties. Preclinical studies have confirmed additive and synergistic antitumor activity in cancer cell lines (breast, prostate cancer) with combinations of taxanes and mTOR inhibitors. We conducted a phase I open-label, dose-escalation study to determine the maximal tolerated dose (MTD) of docetaxel in combination with temsirolimus in patients with refractory solid tumors.

Patients And Methods: Eligible patients had a diagnosis of a refractory solid malignancy, measurable disease, and adequate organ function. Patients were sequentially enrolled in 4 dose level intravenous combinations of docetaxel and temsirolimus. Temsirolimus was administered weekly with docetaxel administered every 3 weeks. Laboratory data for tumor markers and radiologic imaging were conducted prestudy and then after every 2 cycles of the treatment. Radiologic response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Blood samples for PK and pharmacodynamic analysis were planned to be drawn at MTD. Apart from the traditional 3+3 design, we also implemented Bayesian Optimal Interval design which uses isotonic regression method to select MTD. We proceeded with isotonic regression analysis by using 20% dose-limiting toxicity (DLT) rate as target.

Results: Twenty-six patients were treated in this study in 4 cohorts and dose levels. Fourteen males and 12 females were enrolled with a median age of 50 years (range of 27 to 72 y) and median Eastern Cooperative Oncology Group performance score of 1. Tumor histologies included pancreas (6), colon (5), rectum (3), gallbladder (2), non-small cell lung (2), endometrium (1), neuroendocrine (1), esophagus (1), stomach (1), pharynx (1), small intestine (1), and duodenum (1). Stable disease was observed in 2/4 (50%), 3/7 (43%), 4/10 (40%), and 3/5 (60%) patients in cohorts 1, 2, 3, and 4, respectively. Dose escalation in cohorts 2, 3, and 4 was complicated by DLTs such as grade 4 neutropenia and grade 3 diarrhea and an inability for patients to tolerate treatments during and beyond cycle 1 without dose reductions. Therefore, we could not determine an MTD or recommended phase II dose using the traditional 3+3 study analysis. Blood samples for PK and pharmacodynamic analysis were not collected since MTD was not determined. By using 20% DLT rate closest to the target, isotonic regression analysis showed identical estimated DLT rates in dose -1 (docetaxel 50 mg/m2 and temsirolimus 15 mg/m2) and dose level 1 (docetaxel 60mg/m2 and temsirolimus 15 mg/m2).

Conclusions: Dose escalation of docetaxel and temsirolimus was limited by severe myelosuppressive toxicity in this phase I study. Most of the DLTs occurred after cycle 1 of therapy hence, we were unable to determine MTD or collect blood samples for PK and pharmacodynamic analysis. Our trial did not meet its objectives due to significant DLTs with this chemotherapy combination. Although our novel use of Bayesian Optimal Interval design using isotonic regression method to select MTD showed identical estimated DLT rates in dose levels 1 and -1, clinically our patients were not able to complete 2 cycles of this regimen without dose reductions due to myelosuppressive toxicity in either of these dose levels, and hence, escaped clinical validity. This combination regimen should not be studied further at the dose levels and schedules tested in our study.
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http://dx.doi.org/10.1097/COC.0000000000000852DOI Listing
September 2021

Light- and Melanin Nanoparticle-Induced Cytotoxicity in Metastatic Cancer Cells.

Pharmaceutics 2021 Jun 26;13(7). Epub 2021 Jun 26.

Department of Physics, Boston College, Chestnut Hill, MA 02467, USA.

Melanin nanoparticles are known to be biologically benign to human cells for a wide range of concentrations in a high glucose culture nutrition. Here, we show cytotoxic behavior at high nanoparticle and low glucose concentrations, as well as at low nanoparticle concentration under exposure to (nonionizing) visible radiation. To study these effects in detail, we developed highly monodispersed melanin nanoparticles (both uncoated and glucose-coated). In order to study the effect of significant cellular uptake of these nanoparticles, we employed three cancer cell lines: VM-M3, A375 (derived from melanoma), and HeLa, all known to exhibit strong macrophagic character, i.e., strong nanoparticle uptake through phagocytic ingestion. Our main observations are: (i) metastatic VM-M3 cancer cells massively ingest melanin nanoparticles (mNPs); (ii) the observed ingestion is enhanced by coating mNPs with glucose; (iii) after a certain level of mNP ingestion, the metastatic cancer cells studied here are observed to die-glucose coating appears to slow that process; (iv) cells that accumulate mNPs are much more susceptible to killing by laser illumination than cells that do not accumulate mNPs; and (v) non-metastatic VM-NM1 cancer cells also studied in this work do not ingest the mNPs, and remain unaffected after receiving identical optical energy levels and doses. Results of this study could lead to the development of a therapy for control of metastatic stages of cancer.
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http://dx.doi.org/10.3390/pharmaceutics13070965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8309021PMC
June 2021

Association of PET-based estradiol-challenge test for breast cancer progesterone receptors with response to endocrine therapy.

Nat Commun 2021 02 2;12(1):733. Epub 2021 Feb 2.

Alvin J. Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA.

Estrogen receptor (ER) testing of breast cancer imperfectly predicts response to endocrine therapy (ET). We hypothesize that a brief estradiol challenge will increase tumor progesterone receptor (PgR) levels only in tumors with functional ER. In this prospective, phase 2, single-center, single-arm trial (NCT02455453), we report the association of response to ET with change in tumor uptake of the progestin analog, 21-[F]fluorofuranylnorprogesterone (FFNP), before and after a one-day estradiol challenge. In 43 postmenopausal women with advanced ER+ breast cancer, we show a post-challenge increase in tumor FFNP uptake only in 28 subjects with clinical benefit from ET (responders), but not in 15 without clinical benefit (nonresponders) (p < 0.0001), indicating 100% sensitivity and specificity. We further show significantly longer survival (p < 0.0001) in the responding subjects. Our results demonstrate that change in tumor FFNP uptake after estradiol challenge is highly predictive of response to ET in women with ER+ breast cancer.
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http://dx.doi.org/10.1038/s41467-020-20814-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854611PMC
February 2021

Optical confinement in the nanocoax: coupling to the fundamental TEM-like mode.

Opt Express 2020 Oct;28(21):32152-32164

The nanoscale coaxial cable (nanocoax) has demonstrated optical confinement in the visible and the near infrared. We report on a novel nanofabrication process which yields optically addressable, sub-µm diameter, and high aspect ratio metal-insulator-metal nanocoaxes made by atomic layer deposition of Pt and AlO. We observe sub-diffraction-limited optical transmission via the fundamental, TEM-like mode by excitation with a radially polarized optical vortex beam. Our experimental results are based on interrogation with a polarimetric imager. Finite element method numerical simulations support these results, and their uniaxial symmetry was exploited to model taper geometries with both an electrically large volume, (15λ), and a nanoscopic exit aperture, (λ/200).
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http://dx.doi.org/10.1364/OE.402723DOI Listing
October 2020

Extraordinary optical transmission in nano-bridged plasmonic arrays mimicking a stable weakly-connected percolation threshold.

Opt Express 2020 Oct;28(21):31425-31435

Ultrasensitive sensors of various physical properties can be based on percolation systems, e.g., insulating media filled with nearly touching conducting particles. Such a system at its percolation threshold featuring the critical particle concentration, changes drastically its response (electrical conduction, light transmission, etc.) when subjected to an external stimulus. Due to the critical nature of this threshold, a given state at the threshold is typically very unstable. However, stability can be restored without significantly sacrificing the structure sensitivity by forming weak connections between the conducting particles. In this work, we employed nano-bridged nanosphere lithography to produce such a weakly connected percolation system. It consists of two coupled quasi-Babinet complementary arrays, one with weakly connected, and the other with disconnected metallic islands. We demonstrate via experiment and simulation that the physics of this plasmonic system is non-trivial, and leads to the extraordinary optical transmission at narrowly defined peaks sensitive to system parameters, with surface plasmons mediating this process. Thus, our system is a potential candidate for percolation effect based sensor applications. Promising detection schemes could be based on these effects.
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http://dx.doi.org/10.1364/OE.403034DOI Listing
October 2020

Nano-bridged nanosphere lithography.

Nanotechnology 2020 Mar 3;31(24):245302. Epub 2020 Mar 3.

International Academy of Optoelectronics at Zhaoqing, South China Normal University, Zhaoqing, 526238 Guangdong, People's Republic of China.

We develop nano-bridged nanosphere lithography (NB-NSL), a modification to the widely used conventional nanosphere lithography (NSL). Nano-bridges between polystyrene (PS) spheres of a pristine NSL template are controllably formed in a two-step process: (i) spin-coating of a dilute styrene solution on top of the template, followed by (ii) oxygen plasma etching of the template. We show that the nanobridge dimensions can be precisely tuned by controlling the pre-processing conditions and the plasma etching time. The resulting lithography templates feature control over the shape and size of the apertures, which determine the morphology of the final nano-island arrays after material deposition and template removal. The unique advantage of NB-NSL is that PS particle templates based on a single PS particle diameter can be utilized for the fabrication of a variation of nano-island shapes and sizes, whereas conventional NSL yields only bowtie-shaped nano-islands, with their size being predetermined by the PS particle diameter of the template.
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http://dx.doi.org/10.1088/1361-6528/ab7c4cDOI Listing
March 2020

Facile fabrication and formation mechanism of aluminum nanowire arrays.

Nanotechnology 2020 Feb 8;31(9):095301. Epub 2019 Nov 8.

Anodized alumina membranes (AAMs) have proven effective at making vertically-oriented and well-ordered metal nanowire arrays, which are useful in plasmonics and electrochemistry. Here, we produced Al nanowires via directed AAM pore nucleation: a patterned oxide mask on a flat Al surface directed where pores did and did not form, the pores acting to oxidize Al around the sites without pores. This left Al nanowires embedded in the AAM, and produced freestanding Al nanowires after etching the AAM. The nanowire tops had two distinct contours, smooth bowls and flat rough surfaces-suggesting that nanowires with bowl tops result from slow pore development relative to pattern-nucleated pores, not pore blockage as prior literature suggests. The observed low porosity of ∼2%, as opposed to the more typical 10%, suggests pore nucleation in the electrolyte employed may need greater local variations in electric field or pH, possibly explaining the electrolyte's peculiar ability to make Al nanowires. Finally, a soft nano-imprint lithography process was developed here to pattern the mask without damaging the stamp, avoiding a stamp degradation problem in previous work that utilized hard nano-imprint lithography.
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http://dx.doi.org/10.1088/1361-6528/ab55beDOI Listing
February 2020

Artificial Mushroom Sponge Structure for Highly Efficient and Inexpensive Cold-Water Steam Generation.

Glob Chall 2018 Dec 15;2(12):1800035. Epub 2018 Oct 15.

Institute for Advanced Materials South China Academy of Advanced Optoelectronics and Guangdong Provincial Key Laboratory of Quantum Engineering and Quantum Materials South China Normal University Guangzhou 510006 P. R. China.

A bioinspired structure of an artificial mushroom, made of the common polyvinyl alcohol sponge coated with charcoal, is fabricated, with high efficiency in generating cold water steam of ≈73% under 1 sun illumination, due to very high light absorption, efficient water supply, and low heat loss. In addition, the structure is very inexpensive, and thus ideal for applications in portable cold (boil-free) steam generators for water purification and desalination.
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http://dx.doi.org/10.1002/gch2.201800035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6607233PMC
December 2018

Predictors of Locoregional Recurrence After Failure to Achieve Pathologic Complete Response to Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer.

J Natl Compr Canc Netw 2019 04;17(4):348-356

aDepartment of Radiation Oncology, Washington University School of Medicine, Saint Louis, Missouri.

Background: This study evaluated factors predictive of locoregional recurrence (LRR) in women with triple-negative breast cancer (TNBC) treated with neoadjuvant chemotherapy who do not experience pathologic complete response (pCR).

Methods: This is a single-institution retrospective review of women with TNBC treated with neoadjuvant chemotherapy, surgery, and radiation therapy in 2000 through 2013. LRR was estimated between patients with and without pCR using the Kaplan-Meier method. Patient-, tumor-, and treatment-specific factors in patients without pCR were analyzed using the Cox proportional hazards method to evaluate factors predictive of LRR. Log-rank statistics were then used to compare LRR among these risk factors.

Results: A total of 153 patients with a median follow-up of 48.6 months were included. The 4-year overall survival and LRR were 70% and 15%, respectively, and the 4-year LRR in patients with pCR was 0% versus 22.0% in those without (P<.001). In patients without pCR, lymphovascular space invasion (LVSI; hazard ratio, 3.92; 95% CI, 1.64-9.38; P=.002) and extranodal extension (ENE; hazard ratio, 3.32; 95% CI, 1.35-8.15; P=.009) were significant predictors of LRR in multivariable analysis. In these patients, the 4-year LRR with LVSI was 39.8% versus 15.0% without (P<.001). Similarly, the 4-year LRR was 48.1% with ENE versus 16.1% without (P=.002). In patients without pCR, the presence of both LVSI and ENE were associated with an even further increased risk of LRR compared with patients with either LVSI or ENE alone and those with neither LVSI nor ENE in the residual tumor (P<.001).

Conclusions: In patients without pCR, the presence of LVSI and ENE increases the risk of LRR in TNBC. The risk of LRR is compounded when both LVSI and ENE are present in the same patient. Future clinical trials are warranted to lower the risk of LRR in these high-risk patients.
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http://dx.doi.org/10.6004/jnccn.2018.7103DOI Listing
April 2019

Treatment response as predictor for brain metastasis in triple negative breast cancer: A score-based model.

Breast J 2019 05 28;25(3):363-372. Epub 2019 Mar 28.

Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri.

Background: Triple negative breast cancer (TNBC) has worse prognosis than other subtypes of breast cancer, and many patients develop brain metastasis (BM). We developed a simple predictive model to stratify the risk of BM in TNBC patients receiving neo-adjuvant chemotherapy (NAC), surgery, and radiation therapy (RT).

Methods: Patients with TNBC who received NAC, surgery, and RT were included. Cox proportional hazards method was used to evaluate factors associated with BM. Significant factors predictive for BM on multivariate analysis (MVA) were used to develop a risk score. Patients were divided into three risk groups: low, intermediate, and high. A receiver operating characteristic (ROC) curve was drawn to evaluate the value of the risk group in predicting BM. This predictive model was externally validated.

Results: A total of 160 patients were included. The median follow-up was 47.4 months. The median age at diagnosis was 49.9 years. The 2-year freedom from BM was 90.5%. Persistent lymph node positivity, HR 8.75 (1.76-43.52, P = 0.01), and lack of downstaging, HR 3.46 (1.03-11.62, P = 0.04), were significant predictors for BM. The 2-year rate of BM was 0%, 10.7%, and 30.3% (P < 0.001) in patients belonging to low-, intermediate-, and high-risk groups, respectively. Area under the ROC curve was 0.81 (P < 0.001). This model was externally validated (C-index = 0.79).

Conclusions: Lack of downstaging and persistent lymph node positivity after NAC are associated with development of BM in TNBC. This model can be used by the clinicians to stratify patients into the three risk groups to identify those at increased risk of developing BM and potentially impact surveillance strategies.
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http://dx.doi.org/10.1111/tbj.13230DOI Listing
May 2019

On-Chip Electrochemical Detection of Cholera Using a Polypyrrole-Functionalized Dendritic Gold Sensor.

ACS Sens 2019 03 28;4(3):654-659. Epub 2019 Feb 28.

Rapid diagnosis of an infectious disease outbreak in the field is critical for limiting the escalation of an outbreak into an epidemic. Devices suited to point-of-care (POC) diagnosis of cholera must not only demonstrate clinical laboratory levels of sensitivity and specificity but do so in a portable and low-cost manner, with a simplistic readout. We report work toward an on-chip electrochemical immunosensor for the detection of cholera toxin subunit B (CTX), based on a dendritic gold architecture biofunctionalized via poly(2-cyanoethyl)pyrrole (PCEPy). The dendritic electrode has an ∼18× greater surface area than a planar gold counterpart, per electrochemical measurements, allowing for a higher level of detection sensitivity. A layer of PCEPy polymer generated on the dendritic surface facilitated the performance of an electrochemical enzyme-linked immunosorbant assay (ELISA) for CTX on-chip, which demonstrated a detection limit of 1 ng mL, per a signal-to-noise ratio of 2.6. This was more sensitive than detection using a simple planar gold electrode (100 ng mL) and also matched the diagnostic standard optical ELISA, but on a miniaturized platform with electrical readout. The ability to meet POC demands makes biofunctionalized gold dendrites a promising architecture for on-chip detection of cholera.
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http://dx.doi.org/10.1021/acssensors.8b01484DOI Listing
March 2019

Emerging Perspectives on mTOR Inhibitor-Associated Pneumonitis in Breast Cancer.

Oncologist 2018 06 27;23(6):660-669. Epub 2018 Feb 27.

The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Substantial improvements in the early detection and treatment of breast cancer have led to improvements in survival, but breast cancer remains a significant cause of morbidity and mortality in women. In 2012, the mammalian target of rapamycin (mTOR) inhibitor everolimus was approved by the U.S. Food and Drug Administration for the treatment of advanced breast cancer in patients resistant to endocrine therapy. Although everolimus is generally well tolerated, mTOR inhibitor-associated pneumonitis is one of the most common adverse drug events leading to treatment discontinuation. To date, the underlying pathophysiology of this toxicity is unclear, and this uncertainty may hinder the optimization of management strategies. However, experiences from breast cancer and renal cell carcinoma clinical trials indicate that mTOR inhibitor-associated pneumonitis can be effectively managed by early detection, accurate diagnosis, and prompt intervention that generally involves everolimus dose reductions, interruptions, or discontinuation. Management can be achieved by a multidisciplinary approach that involves the collaborative efforts of nurses, oncologists, radiologists, infectious disease specialists, pulmonologists, clinical pharmacists, and pathologists. Comprehensive education must be provided to all health care professionals involved in managing patients receiving everolimus therapy. Although general recommendations on the management of mTOR inhibitor-associated pneumonitis have been published, there is a lack of consensus on the optimal management of this potentially serious complication. This article provides an overview of mTOR inhibitor-associated pneumonitis, with a focus on the detection, accurate diagnosis, and optimal management of this class-related complication of mTOR inhibitor therapy.

Implications For Practice: This article summarizes the pathogenesis, clinical presentation, incidence, detection, and optimal management of everolimus-related noninfectious pneumonitis in breast cancer. In particular, this article provides a detailed overview of the important aspects of the detection, accurate diagnosis, and appropriate management of mammalian target of rapamycin inhibitor-associated pneumonitis. In addition, this article emphasizes that effective management of this adverse drug event in patients with breast cancer will require a multidisciplinary approach and collaboration among various health care professionals.
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http://dx.doi.org/10.1634/theoncologist.2017-0343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6067931PMC
June 2018

Evaluation of [Zr]trastuzumab-PET/CT in differentiating HER2-positive from HER2-negative breast cancer.

Breast Cancer Res Treat 2018 Jun 13;169(3):523-530. Epub 2018 Feb 13.

Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA.

Purpose: To evaluate whether tumor uptake of [Zr]trastuzumab can distinguish HER2-positive from HER2-negative breast cancer.

Methods: Women with HER2-positive (n = 34) and HER2-negative (n = 16) breast cancer underwent PET/CT 5 ± 2 days following [Zr]trastuzumab administration. HER2 status was determined based on immunohistochemistry and/or fluorescence in situ hybridization of primary or metastatic/recurrent tumor. Tumor [Zr]trastuzumab uptake was assessed qualitatively and semiquantitatively as maximum standardized uptake value (SUV), and correlated with HER2 status. Additionally, intrapatient heterogeneity of [Zr]trastuzumab uptake was evaluated.

Results: On a per-patient basis, [Zr]trastuzumab-PET/CT was positive in 30/34 (88.2%) HER2-positive and negative in 15/16 (93.7%) HER2-negative patients. Considering all lesions, the SUV was not significantly different in patients with HER2-positive versus HER2-negative disease (p = 0.06). The same was true of when only hepatic lesions were evaluated (p = 0.42). However, after excluding hepatic lesions, tumor SUV was significantly higher in HER2-positive compared to HER2-negative patients (p = 0.003). A cutoff SUV of 3.2, determined by ROC analysis, demonstrated positive-predictive value of 83.3% (95% CI 65.3%, 94.4%), sensitivity of 75.8% (57.7%, 88.9%), negative-predictive value of 50% (24.7%, 75.3%), and specificity of 61.5% (95% 31.6%, 86.1%) for differentiating HER2-positive from HER2-negative lesions. There was intrapatient heterogeneity of [Zr]trastuzumab uptake in 20% of patients with multiple lesions.

Conclusions: [Zr]trastuzumab has the potential to characterize the HER2 status of the complete tumor burden in patients with breast cancer, thus obviating repeat or multiple tissue sampling to assess intrapatient heterogeneity of HER2 status.
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http://dx.doi.org/10.1007/s10549-018-4696-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5955803PMC
June 2018

Long-term outcomes of APBI via multicatheter interstitial HDR brachytherapy: Results of a prospective single-institutional registry.

Brachytherapy 2018 Jan - Feb;17(1):171-180. Epub 2017 Oct 28.

Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, MO. Electronic address:

Purpose: Long-term outcome reports of accelerated partial-breast irradiation (APBI) are limited. Here, we report the 10-year outcomes of APBI delivered using multicatheter interstitial implant (ISI) brachytherapy.

Methods And Materials: Patients with early-stage breast cancer treated with APBI via ISI brachytherapy were enrolled in a prospective registry. Selection criteria included age ≥40 years, ductal carcinoma in situ or invasive tumor ≤3 cm, negative margins (≥2 mm), and negative axillary nodes. 34 Gy in 10 twice-daily fractions was administered to 2 cm of breast tissue surrounding the surgical bed. Toxicity and cosmetic outcomes were collected prospectively.

Results: A total of 175 patients were included. The median followup time was 10.0 years. Ten-year ipsilateral breast tumor control, regional control, freedom from distant metastasis, breast cancer-specific survival, and overall survival were 92.1%, 96.9%, 97.4%, 97.1%, and 81.2%, respectively. High-grade disease was correlated with increase in the rate of ipsilateral breast tumor recurrence. Grade 1 or 2 skin toxicity was present in 44 patients, and Grade 3 skin toxicity was present in only 1 patient. There were no Grade 4 or higher toxicities observed. Thirty-seven patients developed fat necrosis. Dose Homogeneity Index of ≤0.85 and integrated reference air-kerma of >3400 cGycm/h correlated with higher rates of fat necrosis. There were 115 (66%), 51 (29%), 8 (5%), and 0 (0%) patients having excellent, good, fair, and poor cosmetic outcomes, respectively.

Conclusions: APBI using ISI brachytherapy offers excellent clinical outcomes in appropriately selected patients with excellent cosmetic outcomes and low rates of toxicities such as symptomatic fat necrosis.
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http://dx.doi.org/10.1016/j.brachy.2017.09.009DOI Listing
July 2018

Health Care, Business, and Ethics: The Goods We Hold in Common.

Health Prog 2016 Nov-Dec;97(6):21-5

The common good is one of those terms that most of us think we understand until we start talking about it. Our conversations too often become platitudinous and moralistic, feeling more and more abstract and vague. As one health care executive said to me, “How would I know if the common good bit me?"
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August 2018

Wireless communication system via nanoscale plasmonic antennas.

Sci Rep 2016 08 24;6:31710. Epub 2016 Aug 24.

Department of Physics, Boston College, 140 Commonwealth Ave. Chestnut Hill, Massachusetts 02467, USA.

Present on-chip optical communication technology uses near-infrared light, but visible wavelengths would allow system miniaturization and higher energy confinement. Towards this end, we report a nanoscale wireless communication system that operates at visible wavelengths via in-plane information transmission. Here, plasmonic antenna radiation mediates a three-step conversion process (surface plasmon → photon → surface plasmon) with in-plane efficiency (plasmon → plasmon) of 38% for antenna separation 4λ0 (with λ0 the free-space excitation wavelength). Information transmission is demonstrated at bandwidths in the Hz and MHz ranges. This work opens the possibility of optical conveyance of information using plasmonic antennas for on-chip communication technology.
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http://dx.doi.org/10.1038/srep31710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4995427PMC
August 2016

Shielded Coaxial Optrode Arrays for Neurophysiology.

Front Neurosci 2016 9;10:252. Epub 2016 Jun 9.

Department of Physics, Boston College Chestnut Hill, MA, USA.

Recent progress in the study of the brain has been greatly facilitated by the development of new tools capable of minimally-invasive, robust coupling to neuronal assemblies. Two prominent examples are the microelectrode array (MEA), which enables electrical signals from large numbers of neurons to be detected and spatiotemporally correlated, and optogenetics, which enables the electrical activity of cells to be controlled with light. In the former case, high spatial density is desirable but, as electrode arrays evolve toward higher density and thus smaller pitch, electrical crosstalk increases. In the latter, finer control over light input is desirable, to enable improved studies of neuroelectronic pathways emanating from specific cell stimulation. Here, we introduce a coaxial electrode architecture that is uniquely suited to address these issues, as it can simultaneously be utilized as an optical waveguide and a shielded electrode in dense arrays. Using optogenetically-transfected cells on a coaxial MEA, we demonstrate the utility of the architecture by recording cellular currents evoked from optical stimulation. We also show the capability for network recording by radiating an area of seven individually-addressed coaxial electrode regions with cultured cells covering a section of the extent.
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http://dx.doi.org/10.3389/fnins.2016.00252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4899445PMC
July 2016

Aluminum Nanowire Arrays via Directed Assembly.

Nano Lett 2015 Nov 30;15(11):7294-9. Epub 2015 Oct 30.

Department of Physics, Boston College , 140 Commonwealth Avenue, Chestnut Hill, Massachusetts 02467, United States.

Freestanding and vertically-oriented metal nanowire arrays have potential utility in a number of applications, but presently lack a route to fabrication. Template-based techniques, such as electrodeposition into lithographically defined nanopore arrays, have produced well-ordered nanowire arrays with a maximum pitch of about 2 μm; such nanowires, however, tend to cluster due to local attractive forces. Here, we modify this template fabrication method to produce well-ordered, vertically-oriented, freestanding Al nanowire arrays, etched from an underlying Al substrate, with highly tunable pitch. In addition, optical measurements demonstrated that the nanowires support the propagation of surface plasmon polaritons.
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http://dx.doi.org/10.1021/acs.nanolett.5b02408DOI Listing
November 2015

Effect of weight loss on bone health in overweight/obese postmenopausal breast cancer survivors.

Breast Cancer Res Treat 2015 Aug 15;152(3):637-43. Epub 2015 Jul 15.

Division of Public Health Sciences, and Siteman Cancer Center, Department of Surgery, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8100, Saint Louis, MO, USA,

Current guidelines recommend weight loss in obese cancer survivors. Weight loss, however, has adverse effects on bone health in obese individuals without cancer but this has not been evaluated in breast cancer survivors. We investigated the associations of intentional weight loss with bone mineral density (BMD) and bone turn-over markers in overweight/obese postmenopausal breast cancer survivors. Participants were overweight/obese breast cancer survivors (N = 81) with stage I, II or IIIA disease enrolled in the St. Louis site of a multi-site Exercise and Nutrition to Enhance Recovery and Good health for You (ENERGY) study; a randomized-controlled clinical trial designed to achieve a sustained ≥7 % loss in body weight at 2 years. Weight loss was achieved through dietary modification with the addition of physical activity. Generalized estimating equations were used to assess differences in mean values between follow-up and baseline. Mean weight decreased by 3 and 2.3 % between baseline and 6-month follow-up, and 12-month follow-up, respectively. There were decreases in osteocalcin (10.6 %, p value < 0.001), PINP (14.5 %, p value < 0.001), NTx (19.2 % p value < 0.001), and RANK (48.5 %, p value < 0.001), but not BALP and CTX-1 levels between baseline and 12-month follow-up. No significant changes occurred in mean T-scores, pelvis and lumbar spine BMD between baseline and 12-month follow-up. A 2.3 % weight loss over 12 months among overweight/obese women with early-stage breast cancer does not appear to have deleterious effect on bone health, and might even have beneficial effect. These findings warrant confirmation, particularly among breast cancer survivors with a larger magnitude of weight loss.
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http://dx.doi.org/10.1007/s10549-015-3496-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521978PMC
August 2015

A nanocoaxial-based electrochemical sensor for the detection of cholera toxin.

Biosens Bioelectron 2015 Dec 2;74:406-10. Epub 2015 Jul 2.

Department of Biology, Boston College, Chestnut Hill, MA 02467, United States. Electronic address:

Sensitive, real-time detection of biomarkers is of critical importance for rapid and accurate diagnosis of disease for point of care (POC) technologies. Current methods do not allow for POC applications due to several limitations, including sophisticated instrumentation, high reagent consumption, limited multiplexing capability, and cost. Here, we report a nanocoaxial-based electrochemical sensor for the detection of bacterial toxins using an electrochemical enzyme-linked immunosorbent assay (ELISA) and differential pulse voltammetry (DPV) or square wave voltametry (SWV). The device architecture is composed of vertically-oriented, nanoscale coaxial electrodes in array format (~10(6) coaxes per square millimeter). The coax cores and outer shields serve as integrated working and counter electrodes, respectively, exhibiting a nanoscale separation gap corresponding to ~100 nm. Proof-of-concept was demonstrated for the detection of cholera toxin (CT). The linear dynamic range of detection was 10 ng/ml-1 µg/ml, and the limit of detection (LOD) was found to be 2 ng/ml. This level of sensitivity is comparable to the standard optical ELISA used widely in clinical applications, which exhibited a linear dynamic range of 10 ng/ml-1 µg/ml and a LOD of 1 ng/ml. In addition to matching the detection profile of the standard ELISA, the nanocoaxial array provides a simple electrochemical readout and a miniaturized platform with multiplexing capabilities for the simultaneous detection of multiple biomarkers, giving the nanocoax a desirable advantage over the standard method towards POC applications.
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http://dx.doi.org/10.1016/j.bios.2015.06.069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4549174PMC
December 2015

Randomized Trial of Oral Cyclophosphamide and Veliparib in High-Grade Serous Ovarian, Primary Peritoneal, or Fallopian Tube Cancers, or BRCA-Mutant Ovarian Cancer.

Clin Cancer Res 2015 Apr 14;21(7):1574-82. Epub 2015 Jan 14.

National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

Purpose: Veliparib, a PARP inhibitor, demonstrated clinical activity in combination with oral cyclophosphamide in patients with BRCA-mutant solid tumors in a phase I trial. To define the relative contribution of PARP inhibition to the observed clinical activity, we conducted a randomized phase II trial to determine the response rate of veliparib in combination with cyclophosphamide compared with cyclophosphamide alone in patients with pretreated BRCA-mutant ovarian cancer or in patients with pretreated primary peritoneal, fallopian tube, or high-grade serous ovarian cancers (HGSOC).

Experimental Design: Adult patients were randomized to receive cyclophosphamide alone (50 mg orally once daily) or with veliparib (60 mg orally once daily) in 21-day cycles. Crossover to the combination was allowed at disease progression.

Results: Seventy-five patients were enrolled and 72 were evaluable for response; 38 received cyclophosphamide alone and 37 the combination as their initial treatment regimen. Treatment was well tolerated. One complete response was observed in each arm, with three partial responses (PR) in the combination arm and six PRs in the cyclophosphamide alone arm. Genetic sequence and expression analyses were performed for 211 genes involved in DNA repair; none of the detected genetic alterations were significantly associated with treatment benefit.

Conclusion: This is the first trial that evaluated single-agent, low-dose cyclophosphamide in HGSOC, peritoneal, fallopian tube, and BRCA-mutant ovarian cancers. It was well tolerated and clinical activity was observed; the addition of veliparib at 60 mg daily did not improve either the response rate or the median progression-free survival.
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http://dx.doi.org/10.1158/1078-0432.CCR-14-2565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4383665PMC
April 2015

Structured metal thin film as an asymmetric color filter: the forward and reverse plasmonic halos.

Sci Rep 2014 Dec 1;4:7267. Epub 2014 Dec 1.

Department of Physics, Boston College, Chestnut Hill, MA, 02467, USA.

We observe asymmetric color filtering under unpolarized incidence in a structured metallic (Ag) film, where the center of an optically thick circular Ag disk surrounded by a step gap appears dark when observed from one side, and bright from the other. The latter situation corresponds to abnormally high optical transmission through the optically thick film. We explain this by a three-step process: coupling of photons to surface plasmon polaritons (SPPs), wave interference of SPPs forming resonant cavity modes, and out-coupling from SPPs to photons. Full wave electromagnetic simulations based on the finite element method support our findings. These results may have potential applications in areas such as optical color filtering and biosensing via dielectric detection within the step gap plasmonic cavity.
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http://dx.doi.org/10.1038/srep07267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248275PMC
December 2014

Leakage radiation microscope for observation of non-transparent samples.

Opt Express 2014 Sep;22(19):22895-904

We describe a leakage radiation microscope technique that can be used to extend the leakage radiation microscopy to optically non-transparent samples. In particular, two experiments are presented, first to demonstrate that acquired images with our configuration correspond to the leakage radiation phenomenon and second, to show possible applications by directly imaging a plasmonic structure that previously could only be imaged with a near-field scanning optical microscope. It is shown that the measured surface plasmon wavelength and propagation length agree with theoretically-calculated values. This configuration opens the possibility to study important effects where samples are optically non-transparent, as in plasmonic cavities and single hole plasmonic excitation, without the use of time-consuming near-field scanning optical microscopy.
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http://dx.doi.org/10.1364/OE.22.022895DOI Listing
September 2014

Nanocoaxes for optical and electronic devices.

Analyst 2015 Jan;140(1):39-58

Department of Physics, Boston College, Chestnut Hill, Massachusetts 02467, USA.

The evolution of micro/nanoelectronics technology, including the shrinking of devices and integrated circuit components, has included the miniaturization of linear and coaxial structures to micro/nanoscale dimensions. This reduction in the size of coaxial structures may offer advantages to existing technologies and benefit the exploration and development of new technologies. The reduction in the size of coaxial structures has been realized with various permutations between metals, semiconductors and dielectrics for the core, shield, and annulus. This review will focus on fabrication schemes of arrays of metal - nonmetal - metal nanocoax structures using non-template and template methods, followed by possible applications. The performance and scientific advantages associated with nanocoax-based optical devices including waveguides, negative refractive index materials, light emitting diodes, and photovoltaics are presented. In addition, benefits and challenges that accrue from the application of novel nanocoax structures in energy storage, electronic and sensing devices are summarized.
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http://dx.doi.org/10.1039/c4an01447bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4250387PMC
January 2015

Near-field observation of light propagation in nanocoax waveguides.

Opt Express 2014 Jun;22(12):14148-54

We report the observation of propagating modes of visible and near infrared light in nanoscale coaxial (metal-dielectric-metal) structures, using near-field scanning optical microscopy. Together with numerical calculations, we show that the propagated modes have different nature depending on the excitation wavelength, i.e., plasmonic TE11 and TE21 modes in the near infrared and photonic TE31, TE41 and TM11 modes in the visible. Far field transmission out of the nanocoaxes is dominated by the superposition of Fabry-Perot cavity modes resonating in the structures, consistent with theory. Such coaxial optical waveguides may be useful for future nanoscale photonic systems.
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http://dx.doi.org/10.1364/OE.22.014148DOI Listing
June 2014

A randomized phase II trial investigating the effect of platelet function inhibition on circulating tumor cells in patients with metastatic breast cancer.

Clin Breast Cancer 2013 Dec;13(6):409-15

Department of Medicine, Division of Oncology, Washington University School of Medicine in St. Louis, St. Louis, MO.

Background: Blockade of platelet activation and aggregation can inhibit metastasis in preclinical models and is associated with cancer prevention. To test whether disruption of platelet function with clopidogrel and aspirin would decrease the number of circulating tumor cells (CTCs) in patients with metastatic breast cancer, a randomized phase II study was performed.

Methods: Patients with metastatic breast cancer who were not currently receiving cytotoxic chemotherapy were eligible. Patients were randomized to receive either clopidogrel and aspirin or to a control group receiving no treatment. Phlebotomy was performed at baseline, at 2 and 4 weeks, and monthly thereafter to obtain specimens to assess CTC, platelet aggregation, and thrombin activity. The primary end point was the proportion of patients with detectable CTCs at 1 month.

Results: Forty-eight patients were enrolled and 42 were evaluable at 1 month. Baseline CTC numbers were ≥ 5 in 13% and ≥ 1 in 65% of patients. Despite adequate platelet function inhibition in the treatment group, the proportion of patients with detectable CTCs was similar between the clopidogrel/aspirin and control groups at baseline (P = .21) and 4 weeks (P = .75), showing no treatment effect. Measured endogenous thrombin potential did not correlate with CTC number. No bleeding-related serious adverse events (SAEs) occurred.

Conclusion: The baseline CTC numbers were lower than expected, decreasing the ability to detect an impact of platelet inhibition on CTCs. Clopidogrel and aspirin were well tolerated. Future studies evaluating the potential therapeutic role of antiplatelet therapy in breast cancer remain of interest, and they may be informed by these results.
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http://dx.doi.org/10.1016/j.clbc.2013.08.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3949605PMC
December 2013

Nanocoax-based electrochemical sensor.

Anal Chem 2013 Nov 21;85(21):10040-4. Epub 2013 Oct 21.

Department of Physics, ‡Department of Biology, §Integrated Sciences Cleanroom Facility, Boston College , Chestnut Hill, Massachusetts 02467, United States.

We have used a facile polymer imprint process to fabricate a three-dimensional electrochemical nanosensor, the sensitivity of which is two decades higher than that of planar controls. The device is composed of an array of vertically oriented nanoscale coaxial electrodes, with the coax cores and shields serving as integrated working and counter electrodes, respectively, each with a nanoscale separation gap (coax annulus width). Arrays of ~10(6) devices per square millimeter were prepared with different gaps, with smaller gaps yielding higher sensitivity. A coax-based sensor with a 100 nm gap was found to have sensitivity 90 times greater than that of a planar sensor control, which had conventional millimeter-scale electrode gap spacing. We suggest that this enhancement is due to the combination of rapid diffusion of molecules between the closely spaced electrodes and the large number of nanoscale electrochemical cells operating in parallel, both of which enhance current per unit surface area compared to planar or other nanostructured devices.
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http://dx.doi.org/10.1021/ac402441xDOI Listing
November 2013

Plasmonic halos--optical surface plasmon drumhead modes.

Nano Lett 2013 Feb 9;13(2):519-23. Epub 2013 Jan 9.

Department of Physics, Boston College, 140 Commonwealth Avenue, Chestnut Hill, Massachusetts 02467, USA.

We present the observation and systematic study of a novel optical phenomenon, a "plasmonic halo", wherein surface plasmons optically excited on circular silver microcavities form confined drumhead modes that, under resonant conditions, emanate colorful far-field radiation from their perimeter boundaries. We demonstrate both experimentally and theoretically that such circular microcavities integrated with perimeter step gaps can generate surface plasmon cavity modes which modulate optical transmission/emission through/from the device, yielding the plasmonic halo effect. Via the tuning of geometric and/or material parameters, optical properties of this device can be manipulated in the visible range, leading to potential applications in biomedical plasmonics and discrete optical filtering, among others.
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http://dx.doi.org/10.1021/nl303955xDOI Listing
February 2013

A phase II study of UCN-01 in combination with irinotecan in patients with metastatic triple negative breast cancer.

Breast Cancer Res Treat 2013 Jan 15;137(2):483-92. Epub 2012 Dec 15.

Section of Breast Oncology, Division of Oncology, Department of Medicine, Washington University School of Medicine, Campus Box 8056, 660 South Euclid Avenue, St. Louis, MO 63110, USA.

Mutations in TP53 lead to a defective G1 checkpoint and the dependence on checkpoint kinase 1 (Chk1) for G2 or S phase arrest in response to DNA damage. In preclinical studies, Chk1 inhibition resulted in enhanced cytotoxicity of several chemotherapeutic agents. The high frequency of TP53 mutations in triple negative breast cancer (TNBC: negative for estrogen receptor, progesterone receptor, and HER2) make Chk1 an attractive therapeutic target. UCN-01, a non-selective Chk1 inhibitor, combined with irinotecan demonstrated activity in advanced TNBC in our Phase I study. The goal of this trial was to further evaluate this treatment in women with TNBC. Patients with metastatic TNBC previously treated with anthracyclines and taxanes received irinotecan (100-125 mg/m(2) IV days 1, 8, 15, 22) and UCN-01 (70 mg/m(2) IV day 2, 35 mg/m(2) day 23 and subsequent doses) every 42-day cycle. Peripheral blood mononuclear cells (PBMC) and tumor specimens were collected. Twenty five patients were enrolled. The overall response (complete response (CR) + partial response (PR)) rate was 4 %. The clinical benefit rate (CR + PR + stable disease ≥6 months) was 12 %. Since UCN-01 inhibits PDK1, phosphorylated ribosomal protein S6 (pS6) in PBMC was assessed. Although reduced 24 h post UCN-01, pS6 levels rose to baseline by day 8, indicating loss of UCN-01 bioavailability. Immunostains of γH2AX and pChk1(S296) on serial tumor biopsies from four patients demonstrated an induction of DNA damage and Chk1 activation following irinotecan. However, Chk1 inhibition by UCN-01 was not observed in all tumors. Most tumors were basal-like (69 %), and carried mutations in TP53 (53 %). Median overall survival in patients with TP53 mutant tumors was poor compared to wild type (5.5 vs. 20.3 months, p = 0.004). This regimen had limited activity in TNBC. Inconsistent Chk1 inhibition was likely due to the pharmacokinetics of UCN-01. TP53 mutations were associated with a poor prognosis in metastatic TNBC.
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http://dx.doi.org/10.1007/s10549-012-2378-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3539064PMC
January 2013
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