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1.  Breast Implant–associated Anaplastic Large Cell Lymphoma: Updated Results from a Structured Expert Consultation Process 
Despite increased cases published on breast implant–associated anaplastic large cell lymphoma (BIA-ALCL), important clinical issues remain unanswered. We conducted a second structured expert consultation process to rate statements related to the diagnosis, management, and surveillance of this disease, based on their interpretation of published evidence.
A multidisciplinary panel of 12 experts was selected based on nominations from national specialty societies, academic department heads, and recognized researchers in the United States.
Panelists agreed that (1) this disease should be called “BIA-ALCL”; (2) late seromas occurring >1 year after breast implantation should be evaluated via ultrasound, and if a seroma is present, the fluid should be aspirated and sent for culture, cytology, flow cytometry, and cell block to an experienced hematopathologist; (3) surgical removal of the affected implant and capsule (as completely as possible) should occur, which is sufficient to eradicate capsule-confined BIA-ALCL; (4) surveillance should consist of clinical follow-up at least every 6 months for at least 5 years and breast ultrasound yearly for at least 2 years; and (5) BIA-ALCL is generally a biologically indolent disease with a good prognosis, unless it extends beyond the capsule and/or presents as a mass. They firmly disagreed with statements that chemotherapy and radiation therapy should be given to all patients with BIA-ALCL.
Our assessment yielded consistent results on a number of key, incompletely addressed issues regarding BIA-ALCL, but additional research is needed to support these statement ratings and enhance our understanding of the biology, treatment, and outcomes associated with this disease.
PMCID: PMC4323400
2.  A Brief Account of Nanoparticle Contrast Agents for Photoacoustic Imaging 
Photoacoustic imaging (PAI) is a hybrid, nonionizing modality offering excellent spatial resolution, deep penetration, and high soft tissue contrast. In PAI, signal is generated based on the absorption of laser-generated optical energy by endogenous tissues or exogenous contrast agents leading to acoustic emissions detected by an ultrasound transducer. Research in this area over the years has shown that PAI has the ability to provide both physiological and molecular imaging, which can be viewed alone or used in a hybrid modality fashion to extend the anatomic and hemodynamic sensitivities of clinical ultrasound. PAI may be performed using inherent contrast afforded by light absorbing molecules such as hemoglobin, myoglobin, and melanin or exogenous small molecule contrast agent such as near infrared dyes and porphyrins. However, this review summarizes the potential of exogenous nanoparticle-based agents for PAI applications including contrast based on gold particles, carbon nanotubes, and encapsulated copper compounds.
PMCID: PMC4067981  PMID: 23983210
Photoacoustic imaging; gold nanoparticle; copper nanoparticle; carbon nanoparticle; NIR dyes; porphyrins; fibrin; angiogenesis; melanoma; sentinel lymphnode; thrombus
3.  Sustained Visual Acuity Loss in the Comparison of Age-Related Macular Degeneration Treatments Trials 
JAMA ophthalmology  2014;132(8):915-921.
Although anti–vascular endothelial growth factor treatment of neovascular age-related macular degeneration (AMD) results in improved vision overall, loss of substantial vision can occur. Understanding the processes that lead to loss of vision may lead to preventive strategies.
To determine the incidence, characteristics, causes, and baseline predictors of sustained visual acuity loss after 2 years of treatment with ranibizumab or bevacizumab for neovascular AMD.
A cohort study within a randomized clinical trial of participants in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT).
Participants were randomly assigned to treatment with ranibizumab or bevacizumab and to 2 years of monthly or as needed injections or monthly injections for 1 year and as needed injections the following year.
Sustained visual acuity loss, defined as loss of 15 or more letters from baseline at weeks 88 and 104.
Among 1030 participants, 61 eyes (5.9%) developed sustained visual acuity loss in 2 years. Within this group, visual acuity decreased gradually over time, with a mean decrease of 2, 19, and 33 letters from baseline at 4 weeks, 1 year, and 2 years, respectively. At 2 years, eyes with sustained visual acuity loss had more scarring (60.0% vs 41.4%, P = .007), more geographic atrophy (GA) (31.6% vs 20.7%, P = .004), larger lesions (16 vs 8 mm2, P < .001), and higher proportions of intraretinal fluid (82.5% vs 51.0%, P < .001), subretinal hyperreflective material (84.5% vs 44.2%, P < .001), retinal thinning (43.3% vs 23.0%, P < .001), and thickening (20.0% vs 12.1%, P < .001). Likely causes of sustained visual acuity loss included foveal scarring (44.3%), pigmentary abnormalities (27.9%), and foveal GA (11.5%). Baseline factors independently associated with a higher incidence of sustained visual acuity loss were the presence of nonfoveal GA (odds ratio [OR], 2.86; 95% CI, 1.35–6.08; P = .006), larger area of choroidal neovascularization (OR for a >4-disc area vs ≤1-disc area, 3.91; 95% CI, 1.70–9.03; P = .007), and bevacizumab treatment (OR, 1.83; 95% CI, 1.07–3.14; P = .03).
Sustained visual acuity loss was relatively rare in CATT. The development of foveal scar, pigmentary abnormalities, or GA contributed to most of the sustained visual acuity loss. Risk was 3% higher among eyes treated with bevacizumab. Treatment that targeted the prevention of scarring or GA may improve vision outcomes.
TRIAL REGISTRATION Identifier: NCT00593450
PMCID: PMC4151260  PMID: 24875610
4.  Optobiology: Optical control of biological processes via protein engineering 
Biochemical Society transactions  2013;41(5):1183-1188.
Enabling optical control over biological processes is a defining goal of the new field of optogenetics. Control of membrane voltage by natural rhodopsin-family ion channels has found widespread acceptance in neuroscience, due to the fact that these natural proteins control membrane voltage without further engineering. In contrast, optical control of intracellular biological processes has been a fragmented effort, with various laboratories engineering light-responsive properties into proteins in different manners. Here, we review the various systems that have been developed for controlling protein functions with light based on vertebrate rhodopsins, plant photoregulatory proteins, and, most recently, the photoswitchable fluorescent protein Dronpa. By allowing biology to be controlled with spatiotemporal specificity and tunable dynamics, light-controllable proteins will find applications in the understanding of cellular and organismal biology and in synthetic biology.
PMCID: PMC4076147  PMID: 24059506
optogenetics; LOV domain; cryptochrome; phytochrome; UVR8; fluorescent protein
5.  Anti-Angiogenesis Therapy in the Vx2 Rabbit Cancer Model with a Lipase-cleavable Sn 2 Taxane Phospholipid Prodrug using αvβ3-Targeted Theranostic Nanoparticles 
Theranostics  2014;4(6):565-578.
In nanomedicine, the hydrophobic nature of paclitaxel has favored its incorporation into many nanoparticle formulations for anti-cancer chemotherapy. At lower doses taxanes are reported to elicit anti-angiogenic responses. In the present study, the facile synthesis, development and characterization of a new lipase-labile docetaxel prodrug is reported and shown to be an effective anti-angiogenic agent in vitro and in vivo. The Sn 2 phosphatidylcholine prodrug was stably incorporated into the lipid membrane of αvβ3-integrin targeted perfluorocarbon (PFC) nanoparticles (αvβ3-Dxtl-PD NP) and did not appreciably release during dissolution against PBS buffer or plasma over three days. Overnight exposure of αvβ3-Dxtl-PD NP to plasma spiked with phospholipase enzyme failed to liberate the taxane from the membrane until the nanoparticle integrity was compromised with alcohol. The bioactivity and efficacy of αvβ3-Dxtl-PD NP in endothelial cell culture was as effective as Taxol® or free docetaxel in methanol at equimolar doses over 96 hours. The anti-angiogenesis effectiveness of αvβ3-Dxtl-PD NP was demonstrated in the Vx2 rabbit model using MR imaging of angiogenesis with the same αvβ3-PFC nanoparticle platform. Nontargeted Dxtl-PD NP had a similar MR anti-angiogenesis response as the integrin-targeted agent, but microscopically measured decreases in tumor cell proliferation and increased apoptosis were detected only for the targeted drug. Equivalent dosages of Abraxane® given over the same treatment schedule had no effect on angiogenesis when compared to control rabbits receiving saline only. These data demonstrate that αvβ3-Dxtl-PD NP can reduce MR detectable angiogenesis and slow tumor progression in the Vx2 model, whereas equivalent systemic treatment with free taxane had no benefit.
PMCID: PMC3982128  PMID: 24723979
lipase-labile docetaxel prodrug; perfluorocarbon; nanoparticles
6.  Synthesis and characterization of membrane stable bis(arylimino)isoindole dyes and their potential application in nano-biotechnology 
Tetrahedron letters  2012;53(32):4134-4137.
A synthetic methodology of preparing novel membrane stable, responsive dyes is revealed in this manuscript. 1,3-bis(arylimino)isoindole dyes were synthesized and their properties to undergo intramolecular hydrogen bonding was studied with fluorescence spectroscopy in varying solvent polarities. Based on the functional moieties, compound that is capable of hydrogen donor and acceptor interactions produces predominant photoexcitation in comparison to the responsive dyes that lack these functionalities. These dyes, by the virtue of the presence of long chain acyl groups could be incorporated stably within the phospholipids membrane of core-shell nanoparticles. Nanoparticle was ‘cracked’ to release the dye from a hydrophobic to a hydrophilic environment, A significant change in florescence intensity was then observed, indicating the direct change in effect of intramolecular hydrogen bonding based on solvent polarity changes. This unique study provided implications of many further applications towards nanomedicine and nano-biotechnology.
PMCID: PMC3398693  PMID: 22822276
Fluorescence dye; Bis(imino)isoindole; Responsive dyes; Membrane stable; Nano-biotechnology
7.  Antiangiogenic nanotherapy with lipase-labile Sn-2 fumagillin prodrug 
Nanomedicine (London, England)  2012;7(10):1507-1519.
The chemical instability of antiangiogenic fumagillin, combined with its poor retention during intravascular transit, requires an innovative solution for clinical translation. We hypothesized that an Sn-2 lipase-labile fumagillin prodrug in combination with a contact-facilitated drug delivery mechanism, could be used to address these problems.
αvβ3-targeted and nontargeted nanoparticles with and without fumagillin in the prodrug or native forms were evaluated in vitro and in vivo in the Matrigel™ (BD Biosciences, CA, USA) plug model of angiogenesis in mice.
In vitro experiments demonstrated that the new fumagillin prodrug decreased viability at least as efficacious as the parent compound, on an equimolar basis. In the Matrigel mouse angiogenesis model, αvβ3-fumagillin prodrug decreased angiogenesis as measured by MRI (3T), while the neovasculature was unaffected with the control nanoparticles.
The present approach resolved the previously intractable problems of drug instability and premature release in transit to target sites.
PMCID: PMC3498609  PMID: 22709347
angiogenesis; fumagillin; nanomedicine; nanoparticle; prodrug; therapy
8.  Sensitive Biological Detection with a Soluble and Stable Polymeric Paramagnetic Nano Cluster 
Journal of the American Chemical Society  2012;134(25):10377-10380.
We describe the design, synthesis and biological characterization of manganese oxocluster-based “single molecule magnets (SMMs)”. We demonstrate that polymeric micellar nanoparticles can serve as a carrier and help to stabilize delicate SMM molecules from breaking down easily and thus prevent their property loss. Concentrating thousands of Mn-clusters per micelle provided a high ionic and per-particle relaxivity allowing sensitive MR imaging in vivo. This reports one of the earliest examples of in vivo imaging of a rationally designed polymeric micelles that features SMM.
PMCID: PMC3397310  PMID: 22693958
10.  Influence of Patient Preferences on the Cost-Effectiveness of Screening for Lynch Syndrome 
Journal of Oncology Practice  2012;8(3 Suppl):e24s-e30s.
This cost-utility analysis reports on the effect of quality of life on the value of screening all new patients with colorectal cancer for Lynch syndrome.
Patients and relatives have varying preferences for genetic testing and interventions related to hereditary cancer syndromes. We examined how the impact of these services on quality of life (QoL) affects the cost-effectiveness of screening for Lynch syndrome among probands newly diagnosed with colorectal cancer and their relatives.
We constructed a state-transition model comparing screening strategies (clinical criteria, prediction algorithms, tumor testing, and upfront germline testing) with no screening to identify Lynch syndrome. The model incorporated individuals' health state utilities after screening, germline testing, and risk-reducing surgeries, with utilities persisting for 12 months in the base case. Outcomes consisted of quality-adjusted life-years (QALYs), costs, and cost per QALY gained. Sensitivity analyses assessed how the duration and magnitude of changes in QoL influenced results.
Multiple screening strategies yielded gains in QALYs at acceptable costs compared with no screening. The preferred strategy—immunohistochemistry of tumors followed by BRAF mutation testing (IHC/BRAF)—cost $59,700 per QALY gained in the base case. The duration and magnitude of decreases in QoL after decisions related to germline testing and surgeries were key determinants of the cost-effectiveness of screening. IHC/BRAF cost > $100,000 per QALY gained when decrements to QoL persisted for 21 months.
Screening for Lynch syndrome in the population is likely to yield long-term gains in life expectancy that outweigh any short-term decreases in QoL, at acceptable costs. Counseling for individuals should aim to mitigate potential negative impact of genetic testing and risk-reducing interventions on QoL.
PMCID: PMC3348599  PMID: 22942831
11.  Use of Colony-Stimulating Factors With Chemotherapy: Opportunities for Cost Savings and Improved Outcomes 
Myeloid colony-stimulating factors (CSFs) decrease the risk of febrile neutropenia (FN) from high-risk chemotherapy regimens administered to patients at 20% or greater risk of FN, but little is known about their use in clinical practice. We evaluated CSF use in a multiregional population-based cohort of lung and colorectal cancer patients (N = 1849). Only 17% (95% confidence interval [CI] = 8% to 26%) patients treated with high-risk chemotherapy regimens received CSFs, compared with 18% (95% CI = 16% to 20%) and 10% (95% CI = 8% to 12%) of patients treated with intermediate- (10%–20% risk of FN) and low-risk (<10% risk of FN) chemotherapy regimens, respectively. Using a generalized estimating equation model, we found that enrollment in a health maintenance organization (HMO) was strongly associated with a lower adjusted odds of discretionary CSF use, compared with non-HMO patients (odds ratio = 0.44, 95% CI = 0.32 to 0.60, P < .001). All statistical tests were two-sided. Overall, 96% (95% CI = 93% to 98%) of CSFs were administered in scenarios where CSF therapy is not recommended by evidence-based guidelines. This finding suggests that policies to decrease CSF use in patients at lower or intermediate risk of FN may yield substantial cost savings without compromising patient outcomes.
PMCID: PMC3119647  PMID: 21670423
12.  Two Mechanistic Pathways for Thienopyridine-Associated Thrombotic Thrombocytopenic Purpura 
We sought to describe clinical and laboratory findings for a large cohort of patients with thienopyridine-associated thrombotic thrombocytopenic purpura (TTP).
The thienopyridine derivatives, ticlopidine and clopidogrel, are the 2 most common drugs associated with TTP in databases maintained by the U.S. Food and Drug Administration (FDA).
Clinical reports of TTP associated with clopidogrel and ticlopidine were identified from medical records, published case reports, and FDA case reports (n = 128). Duration of thienopyridine exposure, clinical and laboratory findings, and survival were recorded. ADAMTS13 activity (n = 39) and inhibitor (n = 30) were measured for a subset of individuals.
Compared with clopidogrel-associated TTP cases (n = 35), ticlopidine-associated TTP cases (n = 93) were more likely to have received more than 2 weeks of drug (90% vs. 26%), to be severely thrombocytopenic (84% vs. 60%), and to have normal renal function (72% vs. 45%) (p < 0.01 for each). Compared with TTP patients with ADAMTS13 activity >15% (n = 13), TTP patients with severely deficient ADAMTS13 activity (n = 26) were more likely to have received ticlopidine (92.3% vs. 46.2%, p < 0.003). Among patients who developed TTP >2 weeks after thienopyridine, therapeutic plasma exchange (TPE) increased likelihood of survival (84% vs. 38%, p < 0.05). Among patients who developed TTP within 2 weeks of starting thienopyridines, survival was 77% with TPE and 78% without.
Thrombotic thrombocytopenic purpura is a rare complication of thienopyridine treatment. This drug toxicity appears to occur by 2 different mechanistic pathways, characterized primarily by time of onset before versus after 2 weeks of thienopyridine administration. If TTP occurs after 2 weeks of ticlopidine or clopidogrel therapy, therapeutic plasma exchange must be promptly instituted to enhance likelihood of survival.
PMCID: PMC3167088  PMID: 17868804
13.  Physician Survey of the Effect of the 21-Gene Recurrence Score Assay Results on Treatment Recommendations for Patients With Lymph Node–Positive, Estrogen Receptor–Positive Breast Cancer 
Journal of Oncology Practice  2011;7(2):94-99.
This physician survey looks at the effect of the 21-gene recurrence score assay results on adjuvant treatment recommendations for patients with lymph node–positive, estrogen receptor–positive breast cancer.
To survey the effect of the 21-gene recurrence score (RS) assay results on adjuvant treatment recommendations for patients with lymph node–positive (N+), estrogen receptor–positive (ER+) breast cancer.
Medical oncologists who ordered the 21-gene RS assay were invited to complete a survey regarding their most recent patient with N+/ER+ breast cancer. We obtained responses from 160 (16%) of the 1,017 medical oncologists.
Most of the respondents were in community (71%) versus academic (25%) settings and had practiced for a median of 11 years. T1, T2, or T3 disease was reported in 62%, 35%, and 3% of patients, respectively. One, two, three, or ≥ 4 nodes were reported in 69%, 18%, 6%, and 3% of patients, respectively. Eighty-six percent of the oncologists made treatment recommendations before obtaining the RS; 51% changed their recommendations after receiving the RS. In 33%, treatment intensity decreased from chemotherapy plus hormonal therapy to hormonal therapy alone. In 9%, treatment intensity increased from hormonal therapy alone to chemotherapy plus hormonal therapy. In 8%, treatment recommendations changed in a way that did not fit the definition of either increased or decreased intensity.
In this survey of physician practice, the RS result was used to guide adjuvant treatment decision making in N+/ER+ breast cancer more often in patients with tumors less than 5 cm in size and one to three positive lymph nodes than in patients with larger tumors and four or more positive nodes and yielded an overall reduction in recommendations for chemotherapy.
PMCID: PMC3051869  PMID: 21731516
14.  HIV-related Pneumocystis carinii Pneumonia in Older Patients Hospitalized in the Early HAART Era 
To determine whether older age continues to influence patterns of care and in-hospital mortality for hospitalized persons with HIV-related Pneumocustis carinii pneumonia (PCP), as determined in our prior study from the 1980s.
Retrospective chart review.
Patients (1,861) with HIV-related PCP at 78 hospitals in 8 cities from 1995 to 1997.
Medical record notation of possible HIV infection; alveolar-arterial oxygen gradient; CD4 lymphocyte count; presence or absence of wasting; timely use of anti-PCP medications; in-hospital mortality.
Compared to younger patients, patients ≥50 years of age were less likely to have HIV mentioned in their progress notes (70% vs 82%, P < .001), have mild or moderately severe PCP cases at admission (89% vs 96%, P < .002), receive anti-PCP medications within the first 2 days of hospitalization (86% vs 93%, P <.002), and survive hospitalization (82% vs 90%, P < .003). However, age was not a significant predicator of mortality after adjustment for severity of PCP and timeliness of therapy.
While inpatient PCP mortality has improved by 50% in the past decade, 2-fold age-related mortality differences persist. As in the 1980s, these differences are associated with lower rates of recognition of HIV, increased severity of illenss at admission, and delays in initiation of PCP-specific treatments among older individuals—factors suggestive of delayed recognition of HIV infection, pneumonia, and PCP, respectively. Continued vigilance for the possibility of HIV and HIV-related PCP among persons ≥50 years of age who present with new pulmonary symptoms should be encouraged.
PMCID: PMC1495267  PMID: 11556938
HIV; Pneumocystis carinii pneumonia; age; quality of care; outcomes

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