Biocompatible gold nanoparticles designed to absorb light at wave-lengths of high tissue transparency have been of particular interest for biomedical applications. The ability of such nanoparticles ...to convert absorbed near-infrared light to heat and induce highly localized hyperthermia has been shown to be highly effective for photothermal cancer therapy, resulting in cell death and tumor remission in a multitude of preclinical animal models. Here we report the initial results of a clinical trial in which laser-excited gold-silica nanoshells (GSNs) were used in combination with magnetic resonance–ultrasound fusion imaging to focally ablate low-intermediate-grade tumors within the prostate. The overall goal is to provide highly localized regional control of prostate cancer that also results in greatly reduced patient morbidity and improved functional outcomes. This pilot device study reports feasibility and safety data from 16 cases of patients diagnosed with low- or intermediate-risk localized prostate cancer. After GSN infusion and high-precision laser ablation, patients underwent multiparametric MRI of the prostate at 48 to 72 h, followed by postprocedure mpMRI/ultrasound targeted fusion biopsies at 3 and 12 mo, as well as a standard 12-core systematic biopsy at 12 mo. GSN-mediated focal laser ablation was successfully achieved in 94% (15/16) of patients, with no significant difference in International Prostate Symptom Score or Sexual Health Inventory for Men observed after treatment. This treatment protocol appears to be feasible and safe in men with low- or intermediate-risk localized prostate cancer without serious complications or deleterious changes in genitourinary function.
To evaluate the clinical safety profile for the use of gold nanoshells in patients with human prostate cancer. This follows on the nonclinical safety assessment of the AuroShell particles reported ...previously. Twenty-two patients, with biopsy diagnosed prostate cancer, underwent nanoshell infusion and subsequent radical prostatectomy (RRP). Fifteen of these patients had prostates that were additionally irradiated by a single-fiber laser ablation in each prostate hemisphere prior to RRP. Patients in the study were assessed at 9 time points through 6 months postinfusion. Adverse events were recorded as reported by the patients and from clinical observation. Blood and urine samples were collected at each patient visit and subjected to chemical (16 tests), hematological (23 tests), immunological (3 tests, including total PSA), and urinalysis (8 tests) evaluation. Temperature of the anterior rectal wall at the level of the prostate was measured. The study, recorded 2 adverse events that were judged attributable to the nanoparticle infusion: (1) an allergic reaction resulting in itching, which resolved with intravenous antihistamines, and (2) in a separate patient, a transient burning sensation in the epigastrium. blood/hematology/urinalysis assays indicated no device-related changes. No change in temperature of the anterior rectal wall was recorded in any of the patients. The clinical safety profile of AuroShell particles is excellent, matching nonclinical findings. A recent consensus statement suggested that the published literature does not support a preference for any ablation technique over another.1 Now that clinical safety has been confirmed, treatment efficacy of the combined infusion plus laser ablation in prostate will be evaluated in future studies using imaging modalities directing the laser against identified prostate tumors.
Gold nanoshells (dielectric silica core/gold shell) are a novel class of hybrid metal nanoparticles whose unique optical properties have spawned new applications including more sensitive molecular ...assays and cancer therapy. We report a new photo-physical property of nanoshells (NS) whereby these particles glow brightly when excited by near-infrared light. We characterized the luminescence brightness of NS, comparing to that of gold nanorods (NR) and fluorescent beads (FB). We find that NS are as bright as NR and 140 times brighter than FB. To demonstrate the potential application of this bright two-photon-induced photoluminescence (TPIP) signal for biological imaging, we imaged the 3D distribution of gold nanoshells targeted to murine tumors.
In the SVR trial (Single Ventricle Reconstruction), newborns with hypoplastic left heart syndrome were randomly assigned to receive a modified Blalock-Taussig-Thomas shunt (mBTTS) or a right ...ventricle-to-pulmonary artery shunt (RVPAS) at Norwood operation. Transplant-free survival was superior in the RVPAS group at 1 year, but no longer differed by treatment group at 6 years; both treatment groups had accumulated important morbidities. In the third follow-up of this cohort (SVRIII Long-Term Outcomes of Children With Hypoplastic Left Heart Syndrome and the Impact of Norwood Shunt Type), we measured longitudinal outcomes and their risk factors through 12 years of age.
Annual medical history was collected through record review and telephone interviews. Cardiac magnetic resonance imaging (CMR), echocardiogram, and cycle ergometry cardiopulmonary exercise tests were performed at 10 through 14 years of age among participants with Fontan physiology. Differences in transplant-free survival and complication rates (eg, arrhythmias or protein-losing enteropathy) were identified through 12 years of age. The primary study outcome was right ventricular ejection fraction (RVEF) by CMR, and primary analyses were according to shunt type received. Multivariable linear and Cox regression models were created for RVEF by CMR and post-Fontan transplant-free survival.
Among 549 participants enrolled in SVR, 237 of 313 (76%; 60.7% male) transplant-free survivors (mBTTS, 105 of 147; RVPAS, 129 of 161; both, 3 of 5) participated in SVRIII. RVEF by CMR was similar in the shunt groups (RVPAS, 51±9.6 n=90, and mBTTS, 52±7.4 n=75;
=0.43). The RVPAS and mBTTS groups did not differ in transplant-free survival by 12 years of age (163 of 277 59% versus 144 of 267 54%, respectively;
=0.11), percentage predicted peak Vo
for age and sex (74±18% n=91 versus 72±18% n=84;
=0.71), or percentage predicted work rate for size and sex (65±20% versus 64±19%;
=0.65). The RVPAS versus mBTTS group had a higher cumulative incidence of protein-losing enteropathy (5% versus 2%;
=0.04) and of catheter interventions (14 versus 10 per 100 patient-years;
=0.01), but had similar rates of other complications.
By 12 years after the Norwood operation, shunt type has minimal association with RVEF, peak Vo
, complication rates, and transplant-free survival. RVEF is preserved among the subgroup of survivors who underwent CMR assessment. Low transplant-free survival, poor exercise performance, and accruing morbidities highlight the need for innovative strategies to improve long-term outcomes in patients with hypoplastic left heart syndrome.
URL: https://www.
gov; Unique identifier: NCT0245531.
In this study, high resolution backward-mode photoacoustic microscopy (PAM) is used to noninvasively image progressive extravasation and accumulation of nanoshells within a solid tumor in vivo. PAM ...takes advantage of the strong near-infrared absorption of nanoshells and their extravasation tendency from leaky tumor vasculatures for imaging. Subcutaneous tumors are grown on immunocompetent BALB/c mice. Polyethylene glycol (PEGylated) nanoshells with a peak optical absorption at approximately 800 nm are intravenously administered. With an 800-nm laser source, a prescan prior to nanoshell injection is taken to determine the background that is free of nanoshell accumulation. After injection, the 3-D nanoshell distribution at the tumor foci is monitored by PAM for 6 h. Experimental results show that accumulated nanoshells delineate the tumor position. Nanoshell accumulation is heterogeneous in tumors: more concentrated within the tumor cortex and largely absent from the tumor core. Because nanoshells have been recently demonstrated to enhance thermal therapy of subcutaneous tumors, we anticipate that PAM will be an important aid before, during, and after nanoshell thermal therapy.
We report on a pilot study showing a proof of concept for the passive delivery of nanoshells to an orthotopic tumor where they induce a local, confined therapeutic response distinct from that of ...normal brain resulting in the photothermal ablation of canine transmissible venereal tumor (cTVT) in a canine brain model. cTVT fragments grown in severe combined immunodeficient mice were successfully inoculated in the parietal lobe of immunosuppressed, mixed-breed hound dogs. A single dose of near-IR (NIR)-absorbing, 150-nm nanoshells was infused i.v. and allowed time to passively accumulate in the intracranial tumors, which served as a proxy for an orthotopic brain metastasis. The nanoshells accumulated within the intracranial cTVT, suggesting that its neovasculature represented an interruption of the normal blood-brain barrier. Tumors were thermally ablated by percutaneous, optical fiber-delivered, NIR radiation using a 3.5-W average, 3-minute laser dose at 808 nm that selectively elevated the temperature of tumor tissue to 65.8 +/- 4.1 degrees C. Identical laser doses applied to normal white and gray matter on the contralateral side of the brain yielded sublethal temperatures of 48.6 +/- 1.1 degrees C. The laser dose was designed to minimize thermal damage to normal brain tissue in the absence of nanoshells and compensate for variability in the accumulation of nanoshells in tumor. Postmortem histopathology of treated brain sections showed the effectiveness and selectivity of the nanoshell-assisted thermal ablation.
Background
In the United Network of Organ Sharing (UNOS) allocation scheme prior to October 18, 2018, heart transplant (HTx) candidates with extracorporeal membrane oxygenation (ECMO), temporary ...mechanical circulatory support (MCS), or pulmonary artery (PA) catheter inotropic support all received Status 1A priority. In revised scheme, patients with PA catheter and inotropic support are Status 3 after those on ECMO (Status 1) or temporary MCS (Status 2). We examined the impact of the allocation change on HTx candidates listed Status 1A versus Status 3 at a high‐volume transplant center.
Methods
Between January 2017 and January 2021, 75 patients were listed with a PA catheter and inotropic support prior to the allocation change (Era 1) and 48 were listed after (Era 2). Clinical characteristics and outcomes were compared for these 123 patients.
Results
Heart transplant (HTx) candidates in Era 2 had higher median inotrope doses at listing. There was no significant difference in inpatient wait list days (12 vs. 20 days, P = .15), transition to temporary MCS (33.3% vs. 22.7%, P = .15), or wait list mortality (6.3% vs. 4.0%, P = .68). There was also no significant difference in survival to transplantation (91.7% vs. 94.7%, P = .71). There were no differences in post‐transplant outcomes including 1‐year survival (88.6% vs. 93.0%, P = .38).
Conclusion
At a high‐volume transplant center, the UNOS allocation change did not result in increased wait list time, use of temporary MCS, or mortality on the waitlist or post‐transplant for candidates on inotropic support with continuous hemodynamic monitoring.
•Patients strongly wanted to pursue alternative treatments before starting a statin.•Attitudes about taking statins based on risk differ from scientific recommendations.•52% of patients did not tell ...their prescriber that they might not take the statin.•The existing literature likely underestimates rates of primary nonadherence.
Statin medications reduce cardiovascular events, but many patients never start taking their prescribed statin (primary nonadherence). Limited knowledge exists about the attitudes and beliefs of those with primary nonadherence. In this study, patients with primary nonadherence to statin medications (n = 173) completed a self-administered cross-sectional survey that assessed their attitudes and beliefs related to primary nonadherence and to potential motivators for statin use. Patients were recruited in 2019 from two academic health systems and nationwide internet advertisements. Only 49 of 173 (28.3%) patients with primary nonadherence reported having cardiovascular disease (CVD). Ninety-nine patients (57.2%) never filled their prescription, and 74 (42.8%) filled but never took any statin. Over half failed to initially inform their prescriber they might not take the statin. Patients strongly or somewhat agreed that they desired alternate treatment plans such as diet and/or exercise (n = 134; 77.4%) or natural remedies/dietary supplements (n = 125; 72.3%). Ninety-eight (56.6%) stronglyor somewhat worried about the possibility of statin dependence or addiction. Twenty-seven (15.6%) patients noted that they would not take a statin based solely on CVD risk estimates; 50 (28.9%) selected a CVD risk threshold of >20%; and 23 (13.3%) a threshold of >50% as motivating factors to take statins. Patients with primary nonadherence have attitudes about taking statins based on CVD risk that differ from scientific recommendations, may not tell providers about their hesitation to take statins, and likely prefer alternative initial approaches to cholesterol lowering. Early shared decision-making and assessment of patient attitudes about statins could potentially better align initial approaches for CVD risk reduction.
In this paper, we have designed and fabricated a microfluidic channel to focus biological cells using dielectrophoresis for cytometry applications. The device consists of an elliptic-like channel ...fabricated by isotropic etching of soda lime glass wafers and a subsequent wafer-bonding process. Microelectrodes are patterned on the circumference of the channel to generate ac fringing fields that result in negative dielectrophoretic forces directing cells from all directions to the center of the channel. An analysis using a thin shell model and experiments with microbeads and human leukemia HL60 cells indicate that biological cells can be focused using an ac voltage of an amplitude up to 15 V/sub p-p/ and a frequency below 100 kHz, respectively. This design eliminates the sheath flow and the fluid control system that makes conventional cytometers bulky, complicated, and difficult to operate, and offers the advantages of a portable module that could potentially be integrated with on-chip impedance or optical sensors into a micro total analysis system.
We describe the manipulation of aqueous droplets in an immiscible, low-permittivity suspending medium. Such droplets may serve as carriers for not only air- and water-borne samples, contaminants, ...chemical reagents, viral and gene products, and cells, but also the reagents to process and characterise these samples. We present proofs-of-concept for droplet manipulation through dielectrophoresis by: (1). moving droplets on a two-dimensional array of electrodes, (2). achieving dielectrically-activated droplet injection, (3). fusing and reacting droplets, and (4). conducting a basic biological assay through a combination of these steps. A long-term goal of this research is to provide a platform fluidic processor technology that can form the core of versatile, automated, micro-scale devices to perform chemical and biological assays at or near the point of care, which will increase the availability of modern medicine to people who do not have ready access to modern medical institutions, and decrease the cost and delays associated with that lack of access.
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