Needle Delivery Research Articles

Potent response of QS-21 as a vaccine adjuvant in the skin when delivered with the Nanopatch, resulted in adjuvant dose sparing.

Adjuvants play a key role in boosting immunogenicity of vaccines, particularly for subunit protein vaccines. In this study we investigated the induction of antibody response against trivalent influenza subunit protein antigen and a saponin adjuvant, QS-21. Clinical trials of QS-21 have demonstrated the safety but, also a need of high dose for optimal immunity, which could possibly reduce patient acceptability. Here, we proposed the use of a skin delivery technology – the Nanopatch – to reduce both adjuvant and antigen dose but also retain its immune stimulating effects when compared to the conventional needle and syringe intramuscular (IM) delivery. We have demonstrated that Nanopatch delivery to skin requires only 1/100th of the IM antigen dose to induce equivalent humoral response. QS-21 enhanced humoral response in both skin and muscle route. Additionally, Nanopatch has demonstrated 30-fold adjuvant QS-21 dose sparing while retaining immune stimulating effects compared to IM. QS-21 induced localised, controlled cell death in the skin, suggesting that the danger signals released from dead cells contributed to the enhanced immunogenicity. Taken together, these findings demonstrated the suitability of reduced dose of QS-21 and the antigen using the Nanopatch to enhance humoral responses, and the potential to increase patient acceptability of QS-21 adjuvant.

Does better adherence to GH treatment using jet rather than needle delivery translate into improved growth outcomes?

Does better adherence to GH treatment using jet rather than needle delivery translate into improved growth outcomes?

DDEL-08OVERALL SAFETY AND EFFICACY IN SUBJECTS WITH RECURRENT HGG TREATED ACROSS 2 TOCAGEN STUDIES - PROGNOSTIC FACTORS ASSOCIATED WITH SURVIVAL

High grade glioma (HGG) remains resistant to standard therapies with survival ranging from 7.2-8.1 months. Two Phase 1 clinical studies using a retroviral replicating vector (RRV), Toca 511, in combination with oral Toca FC (extended-release 5-FC) are ongoing to evaluate intracranial delivery of Toca 511 in patients with recurrent HGG. Patients were treated either by administering Toca 511 via intratumoral injection by biopsy needle or convection-enhanced delivery (CED) (NCT01156584), or by injection into the resection cavity wall (NCT01470794). The total safety population included 82 patients. The safety profile was favorable with only 3.7% patients experiencing a treatment related SAE and 1 patient discontinuing treatment due to toxicity (rash). A total of 59 patients who were efficacy evaluable (received Toca 511 and at least one dose of Toca FC) and excluding patients with non-biopsy needle delivery had a mOS of 13.8 months (95% CI 10.8,16.9). Cox-regression was used to examine factors associated with survival outcome. Baseline factors included for univariate analysis were tumor grade (III vs IV), number of recurrences (≤2 vs >2), gender, age (≤55 vs >55), longest diameter of cancerous lesion (continuous), daily dose of Toca FC (≥170 mg/kg vs 80), time between Toca 511 and Toca FC (weeks), and respective study participation (NCT01156568 vs NCT01470794). Of these, tumor grade, number of recurrences, gender and lesion diameter were included for multivariate analysis based on a p value 2 recurrences, the observed median overall survival (mOS) is 14 months (95% CI 11.15, 23.36), comparing favorably to historical benchmarks. 60% and 24.7% of patients were alive after 12 and 24 months, respectively.

SURG-10TRANSCRANIAL TOCA 511 FOLLOWED BY TOCA FC IN SUBJECTS WITH RECURRENT HIGH GRADE GLIOMA (HGG)

Recurrent HGG remains a deadly cancer with survival from 7.2-8.1 months. Viral infection and killing of tumor cells has been demonstrated to stimulate antitumor immune responses pre-clinically. A Phase 1 study using a retroviral replicating vector (RRV), Toca 511, with oral Toca FC (extended-release 5-FC) is nearing completion. In this ongoing study (NCT 01156584) escalating doses of Toca 511 using 2 delivery methods are evaluated for safety and efficacy. Toca FC is administered in monthly cycles starting 4 weeks after injection and doses are escalated. Forty subjects have been treated (38 efficacy evaluable -received Toca 511/Toca FC). Toca 511 to 1.5 x 10^9 TU (3 mL) and Toca FC to 220 mg/kg/day have been safe and well tolerated with no DLTs. Related grade ≥3 adverse events for Toca 511 and Toca FC are infrequent (5.0%, 5.4%) and no subjects have discontinued Toca FC for toxicity. Blood tests show most subjects have no detectable virus - in those that do, clearance of virus occurs. Observed viral RNA signals are below the limit of detection after 2 cycles of Toca FC and viral DNA signal observed 4 weeks after virus injection are below the limit of detection after 3 months in the continuation study. Median survival is 13.8 months (95%CI 7.1, 22.2) using biopsy needle (N = 21); 10.6 months (95%CI 4.3, 13.1) with CED and real-time MRI-guidance (N = 17, p = 0.0276). In multivariate analysis biopsy needle delivery, tumor grade and number of recurrences are significant. Landmark survival is 45% OS12 and 10.5% OS24. Independent radiology review reveals a 3% PR rate (1/35) with clinical benefit rate (PR + SD) of 46%. This study confirms the feasibility and safety of transcranial delivery of RRV without resection. Survival compares favorably to historical data. Additional cohorts will use biopsy needle or intravenous delivery with higher doses of Toca FC.

DDEL-06PRELIMINARY SAFETY OF TOCA 511, A RETROVIRAL REPLICATING VECTOR, IN PATIENTS WITH RECURRENT HIGH GRADE GLIOMA ACROSS THREE SEPARATE PHASE 1 STUDIES

High grade glioma (HGG) remains resistant to standard therapies with survival ranging from 7.2-8.1 months. Two Phase 1 clinical studies using a retroviral replicating vector (RRV), Toca 511, in combination with oral Toca FC (extended-release 5-FC) are ongoing to evaluate intracranial delivery of Toca 511 in patients with recurrent HGG. Patients were treated either by administering Toca 511 via intratumoral injection by biopsy needle or convection-enhanced delivery (CED) (NCT01156584), or by injection into the resection cavity wall (NCT01470794). The total safety population included 82 patients. The safety profile was favorable with only 3.7% patients experiencing a treatment related SAE and 1 patient discontinuing treatment due to toxicity (rash). A total of 59 patients who were efficacy evaluable (received Toca 511 and at least one dose of Toca FC) and excluding patients with non-biopsy needle delivery had a mOS of 13.8 months (95% CI 10.8,16.9). Cox-regression was used to examine factors associated with survival outcome. Baseline factors included for univariate analysis were tumor grade (III vs IV), number of recurrences (≤2 vs >2), gender, age (≤55 vs >55), longest diameter of cancerous lesion (continuous), daily dose of Toca FC (≥170 mg/kg vs 80), time between Toca 511 and Toca FC (weeks), and respective study participation (NCT01156584 vs NCT01470794). Of these, tumor grade, number of recurrences, gender and lesion diameter were included for multivariate analysis based on a p value >0.2 in the univariate analysis. Based on the multivariate analysis, the only statistically significant positive prognostic factor was the category of number of recurrences. Excluding patients with >2 recurrences, the observed median overall survival (mOS) is 14 months (95% CI 11.15, 23.36), comparing favorably to historical benchmarks. 60% and 24.7% of patients were alive after 12 and 24 months, respectively.

Cardiac AAV9 Gene Delivery Strategies in Adult Canines: Assessment by Long-term Serial SPECT Imaging of Sodium Iodide Symporter Expression

Heart failure is a leading cause of morbidity and mortality, and cardiac gene delivery has the potential to provide novel therapeutic approaches. Adeno-associated virus serotype 9 (AAV9) transduces the rodent heart efficiently, but cardiotropism, immune tolerance, and optimal delivery strategies in large animals are unclear. In this study, an AAV9 vector encoding canine sodium iodide symporter (NIS) was administered to adult immunocompetent dogs via epicardial injection, coronary infusion without and with cardiac recirculation, or endocardial injection via a novel catheter with curved needle and both end- and side-holes. As NIS mediates cellular uptake of clinical radioisotopes, expression was tracked by single-photon emission computerized tomography (SPECT) imaging in addition to Western blot and immunohistochemistry. Direct epicardial or endocardial injection resulted in strong cardiac expression, whereas expression after intracoronary infusion or cardiac recirculation was undetectable. A threshold myocardial injection dose that provides robust nonimmunogenic expression was identified. The extent of transmural myocardial expression was greater with the novel catheter versus straight end-hole needle delivery. Furthermore, the authors demonstrate that cardiac NIS reporter gene expression and duration can be quantified using serial noninvasive SPECT imaging up to 1 year after vector administration. These data are relevant to efforts to develop cardiac gene delivery as heart failure therapy.

Magnetic resonance imaging-targeted, 3D transrectal ultrasound-guided fusion biopsy for prostate cancer: Quantifying the impact of needle delivery error on diagnosis.

Magnetic resonance imaging (MRI)-targeted, 3D transrectal ultrasound (TRUS)-guided "fusion" prostate biopsy intends to reduce the ∼23% false negative rate of clinical two-dimensional TRUS-guided sextant biopsy. Although it has been reported to double the positive yield, MRI-targeted biopsies continue to yield false negatives. Therefore, the authors propose to investigate how biopsy system needle delivery error affects the probability of sampling each tumor, by accounting for uncertainties due to guidance system error, image registration error, and irregular tumor shapes. T2-weighted, dynamic contrast-enhanced T1-weighted, and diffusion-weighted prostate MRI and 3D TRUS images were obtained from 49 patients. A radiologist and radiology resident contoured 81 suspicious regions, yielding 3D tumor surfaces that were registered to the 3D TRUS images using an iterative closest point prostate surface-based method to yield 3D binary images of the suspicious regions in the TRUS context. The probabilityP of obtaining a sample of tumor tissue in one biopsy core was calculated by integrating a 3D Gaussian distribution over each suspicious region domain. Next, the authors performed an exhaustive search to determine the maximum root mean squared error (RMSE, in mm) of a biopsy system that gives P ≥ 95% for each tumor sample, and then repeated this procedure for equal-volume spheres corresponding to each tumor sample. Finally, the authors investigated the effect of probe-axis-direction error on measured tumor burden by studying the relationship between the error and estimated percentage of core involvement. Given a 3.5 mm RMSE for contemporary fusion biopsy systems,P ≥ 95% for 21 out of 81 tumors. The authors determined that for a biopsy system with 3.5 mm RMSE, one cannot expect to sample tumors of approximately 1 cm(3) or smaller with 95% probability with only one biopsy core. The predicted maximum RMSE giving P ≥ 95% for each tumor was consistently greater when using spherical tumor shapes as opposed to no shape assumption. However, an assumption of spherical tumor shape for RMSE = 3.5 mm led to a mean overestimation of tumor sampling probabilities of 3%, implying that assuming spherical tumor shape may be reasonable for many prostate tumors. The authors also determined that a biopsy system would need to have a RMS needle delivery error of no more than 1.6 mm in order to sample 95% of tumors with one core. The authors' experiments also indicated that the effect of axial-direction error on the measured tumor burden was mitigated by the 18 mm core length at 3.5 mm RMSE. For biopsy systems with RMSE ≥ 3.5 mm, more than one biopsy core must be taken from the majority of tumors to achieveP ≥ 95%. These observations support the authors' perspective that some tumors of clinically significant sizes may require more than one biopsy attempt in order to be sampled during the first biopsy session. This motivates the authors' ongoing development of an approach to optimize biopsy plans with the aim of achieving a desired probability of obtaining a sample from each tumor, while minimizing the number of biopsies. Optimized planning of within-tumor targets for MRI-3D TRUS fusion biopsy could support earlier diagnosis of prostate cancer while it remains localized to the gland and curable.

Abstracts fromThe 32nd AnnualNational Neurotrauma SymposiumJune 29–July 2, 2014San Francisco, California

Abstracts fromThe 32^nd AnnualNational Neurotrauma SymposiumJune 29–July 2, 2014San Francisco, California

Mo1423 Preliminary Data From the First Italian Experience With a New Universal Needle Delivery System for EUS-Guided FNA: a Randomized Clinical Trial Comparing the 25G and 22G Needle in the EUS-FNA of Solid Lesions

Mo1423 Preliminary Data From the First Italian Experience With a New Universal Needle Delivery System for EUS-Guided FNA: a Randomized Clinical Trial Comparing the 25G and 22G Needle in the EUS-FNA of Solid Lesions

Treatment planning for prostate focal laser ablation in the face of needle placement uncertainty

To study the effect of needle placement uncertainty on the expected probability of achieving complete focal target destruction in focal laser ablation (FLA) of prostate cancer. Using a simplified model of prostate cancer focal target, and focal laser ablation region shapes, Monte Carlo simulations of needle placement error were performed to estimate the probability of completely ablating a region of target tissue. Graphs of the probability of complete focal target ablation are presented over clinically relevant ranges of focal target sizes and shapes, ablation region sizes, and levels of needle placement uncertainty. In addition, a table is provided for estimating the maximum target size that is treatable. The results predict that targets whose length is at least 5 mm smaller than the diameter of each ablation region can be confidently ablated using, at most, four laser fibers if the standard deviation in each component of needle placement error is less than 3 mm. However, targets larger than this (i.e., near to or exceeding the diameter of each ablation region) require more careful planning. This process is facilitated by using the table provided. The probability of completely ablating a focal target using FLA is sensitive to the level of needle placement uncertainty, especially as the target length approaches and becomes greater than the diameter of ablated tissue that each individual laser fiber can achieve. The results of this work can be used to help determine individual patient eligibility for prostate FLA, to guide the planning of prostate FLA, and to quantify the clinical benefit of using advanced systems for accurate needle delivery for this treatment modality.

Optimized delivery system achieves enhanced endomyocardial stem cell retention.

Regenerative cell-based therapies are associated with limited myocardial retention of delivered stem cells. The objective of this study is to develop an endocardial delivery system for enhanced cell retention. Stem cell retention was simulated in silico using 1- and 3-dimensional models of tissue distortion and compliance associated with delivery. Needle designs, predicted to be optimal, were accordingly engineered using nitinol, a nickel and titanium alloy displaying shape memory and superelasticity. Biocompatibility was tested with human mesenchymal stem cells. Experimental validation was performed with species-matched cells directly delivered into Langendorff-perfused porcine hearts or administered percutaneously into the endocardium of infarcted pigs. Cell retention was quantified by flow cytometry and real-time quantitative polymerase chain reaction methodology. Models, computing optimal distribution of distortion calibrated to favor tissue compliance, predicted that a 75°-curved needle featuring small-to-large graded side holes would ensure the highest cell retention profile. In isolated hearts, the nitinol curved needle catheter (C-Cath) design ensured 3-fold superior stem cell retention compared with a standard needle. In the setting of chronic infarction, percutaneous delivery of stem cells with C-Cath yielded a 37.7±7.1% versus 10.0±2.8% retention achieved with a traditional needle without effect on biocompatibility or safety. Modeling-guided development of a nitinol-based curved needle delivery system with incremental side holes achieved enhanced myocardial stem cell retention.

Dry-coated live viral vector vaccines delivered by nanopatch microprojections retain long-term thermostability and induce transgene-specific T cell responses in mice.

The disadvantages of needle-based immunisation motivate the development of simple, low cost, needle-free alternatives. Vaccine delivery to cutaneous environments rich in specialised antigen-presenting cells using microprojection patches has practical and immunological advantages over conventional needle delivery. Additionally, stable coating of vaccine onto microprojections removes logistical obstacles presented by the strict requirement for cold-chain storage and distribution of liquid vaccine, or lyophilised vaccine plus diluent. These attributes make these technologies particularly suitable for delivery of vaccines against diseases such as malaria, which exerts its worst effects in countries with poorly-resourced healthcare systems. Live viral vectors including adenoviruses and poxviruses encoding exogenous antigens have shown significant clinical promise as vaccines, due to their ability to generate high numbers of antigen-specific T cells. Here, the simian adenovirus serotype 63 and the poxvirus modified vaccinia Ankara – two vectors under evaluation for the delivery of malaria antigens to humans – were formulated for coating onto Nanopatch microprojections and applied to murine skin. Co-formulation with the stabilising disaccharides trehalose and sucrose protected virions during the dry-coating process. Transgene-specific CD8+ T cell responses following Nanopatch delivery of both vectors were similar to intradermal injection controls after a single immunisation (despite a much lower delivered dose), though MVA boosting of pre-primed responses with Nanopatch was found to be less effective than the ID route. Importantly, disaccharide-stabilised ChAd63 could be stored for 10 weeks at 37°C with less than 1 log10 loss of viability, and retained single-dose immunogenicity after storage. These data support the further development of microprojection patches for the deployment of live vaccines in hot climates.

Industry Update: the Latest Developments in Therapeutic Delivery

The present industry update covers the period 1 April–30 April 2013, with information sourced from company press releases, regulatory and patent agencies as well as the scientific literature. Next to the publication of a number of industry reports (MarketsandMarkets) on drug-delivery technology, companies and market projections, a number of original manuscripts from the nanotechnology field and its applicability for drug delivery, such as the use of silica-based nanoparticle and self-propelled ‘microrockets’, were received. Progress on patient-friendly delivery methods, such as the ever evolving improved needle(free) delivery (Entrega, BD Medical), inhaled formulations for Parkinson’s disease treatment (Citiats, Northeastern University), inner ear for tinnitus (Auris Medical) and eye for dry eye syndrome (Novaliq), as well as the use of biologics, not as the active ingredient but the delivery vehicle itself (Ambrx antibodies and C4BP protein), demonstrate the never ending creativity to enhance drug treatments with superior delivery technology.

Percutaneous Image-guided Delivery for the Transplantation of Mesenchymal Stem Cells in the Setting of Degenerated Intervertebral Discs

PurposeThe delivery of mesenchymal stem cells (MSCs) to their site of action has remained a technical hurdle for clinical researchers in the expanding field of stem cell–based therapy. The purpose of this study was to test the feasibility of percutaneous image-guided needle delivery of bone marrow–derived human MSCs (hMSCs) to degenerated intervertebral discs (IVDs) in a preclinical model and to assess the containment of these cells within the IVDs. Materials and MethodsDegeneration was induced in the lumbar IVDs of four 28–35-kg female pigs. Approximately 100,000 iodine-124 2′-fluoro-2′-deoxy-1β-D-arabinofuranosyl-5-iodouracil–labeled hMSCs were delivered under fluoroscopic guidance to one of the affected discs in each of the animals. The remaining levels served as internal controls. The animals were imaged by computed tomography (CT) and positron emission tomography (PET) immediately after delivery and 3 days after the procedure. Fifteen days after transplantation, immunohistochemical staining was performed on harvested discs to confirm the presence of delivered hMSCs. ResultsAfter refinement of the technique, PET-CT images on the day of cell transplantation showed initial deposition of the delivered radiolabeled MSCs to the IVD. An additional PET-CT study obtained 3 days later confirmed persistence and containment of activity in the IVD. Findings of histologic evaluation for the presence of human Alu sequences were positive in the treated discs and negative in the controls. ConclusionsImage-guided needle delivery of MSCs for treatment of degenerated IVDs is feasible as demonstrated in this preclinical model. Trials of this minimally invasive technique in humans are warranted.

Nanoencapsulation of Insulin into Zirconium Phosphate for Oral Delivery Applications

The encapsulation of insulin into different kinds of materials for noninvasive delivery is an important field of study because of the many drawbacks of painful needle and syringe delivery such as physiological stress, infection, and local hypertrophy, among others (Khafagy, E.-S.; et al. Adv. Drug Delivery Rev. 2007, 59 (15), 1521-1546). A stable, robust, nontoxic, and viable noninvasive carrier for insulin delivery is needed. We present a new approach for protein nanoencapsulation using layered zirconium phosphate (ZrP) nanoparticles produced without any preintercalator present. The use of ZrP without preintercalators produces a highly pure material, without any kinds of contaminants, such as the preintercalator, which can be noxious. Cytotoxicity cell viability in vitro experiments for the ZrP nanoparticles show that ZrP is not toxic, or harmful, in a biological environment, as previously reported for rats (Zhu, Z. Y.; et al. Mater. Sci. Forum 2009, 620-622, 307-310). Contrary to previous preintercalator-based methods, we show that insulin can be nanoencapsulated in ZrP if a highly hydrate phase of ZrP with an interlayer distance of 10.3 Å (10.3 Å-ZrP or θ-ZrP) is used as a precursor. The intercalation of insulin into ZrP produced a new insulin-intercalated ZrP phase with about a 27 A interlayer distance, as determined by X-ray powder diffraction, demonstrating a successful nanoencapsulation of the hormone. The in vitro release profile of the hormone after the intercalation was determined and circular dichroism was used to study the hormone stability upon intercalation and release. The insulin remains stable in the layered material, at room temperature, for a considerable amount of time, improving the shell life of the peptidic hormone. This type of material represents a strong candidate to developing a noninvasive insulin carrier for the treatment of diabetes mellitus.

Comparison of the Antimicrobial Efficacy of Irrigation Using the EndoVac to Endodontic Needle Delivery

Introduction The purpose of this investigation was to compare the antimicrobial efficacy of root canal irrigation with the EndoVac (Discus Dental, Culver City, CA) to endodontic needle irrigation in the apical 5 mm of root canals infected with Enterococcus faecalis. Methods Bilaterally matched, extracted human teeth were sterilized and inoculated with E. faecalis. Specimens in the EndoVac group were irrigated using the EndoVac system, whereas those in the needle group were irrigated with a 30-G side-vented needle. After chemomechanical preparation, the apical 5 mm of the roots were removed, frozen in liquid nitrogen, and pulverized to expose E. faecalis in dentinal tubules or other morphologic irregularities. The number of colony forming units (cfus) of E. faecalis per mg dentin was determined. Results The EndoVac Group had a mean of 31.6 cfu/mg, whereas the needle group had a mean of 157 cfu/mg. This represents a bacterial reduction of 99.7% in group A and 98.8% in group B when compared with positive controls. Conclusion Although there were fewer cfu/mg when using the EndoVac, there was not a statistically significant difference between the EndoVac and needle groups.

Ethanol Ablation of Hepatocellular Carcinoma Up to 5.0 cm by Using a Multipronged Injection Needle with High-Dose Strategy

To investigate whether ethanol ablation by using a multipronged needle delivery system (multipronged ethanol ablation) could eradicate hepatocellular carcinoma (HCC) up to 5.0 cm in diameter with a single-session high-dose strategy. The hospital ethics committee approved the prospective study, and each patient provided written informed consent. One hundred forty-one patients (125 men, 16 women; mean age, 53 years; range, 27-76 years) with 164 primary or recurrent HCC ranging from 1.3 to 5.0 cm in diameter (mean, 2.9 cm +/- 0.9) were treated with high-dose multipronged ethanol ablation. Patients were unsuitable for surgery, declined surgery and radiofrequency ablation, or had tumors located at unfavorable sites. Primary technique effectiveness (PTE) (complete ablation within two sessions), local tumor progression (LTP), and complications after the treatment were observed. Twenty risk factors of local effectiveness and complications were analyzed by means of univariate and multivariate analysis. Mean number of treatment sessions was 1.1. The mean volume of ethanol per tumor was 31 mL (range, 8-68 mL). PTE was achieved in 134 (95%) of 141 patients and was significantly associated with tumor pattern (capsulated vs noncapsulated, P = .018). After a mean follow-up period of 25 months, LTP was observed in 16 (12%) of 134 patients, and in nine (56%) patients, LTP occurred in tumors 3.1-5.0 cm in diameter. Alanine aminotransferase level (P = .023) was the independent risk factor for LTP. Three (2%) of 141 patients had major complications. Multipronged ethanol ablation with a high-dose strategy can be used to treat HCC up to 5.0 cm in diameter effectively and safely, often in a single session.

A Novel Approach to Drug Delivery for Hepatities C Virus (HCV) for High Immune Responses

Hepatities C Virus (HCV) is a significant health problem worldwide due to the lack of effective vaccines. HCV plasmid DNA (pDNA) vaccine represents a promising means to induce a Th1-biased cell-mediated response which tends to be associated with HCV clearance. However, the immune responses induced by naked pDNA vaccine in large animals as well as in humans are usually too weak to show sufficient protection against new infections. Therefore, it is interesting to look for new ways to deliver HCV pDNA vaccine. In this research, carbon nanotube (CNT) is used as a carrier to deliver the pDNA vaccine of HCV to induce high immune responses, because CNT has some excellent properties such as high strength and good biocompatibility. One of the key approaches to make this idea work is to treat CNT so that it can bind with HCV pDNA with good stability. An approach called 1, 3-dipolar cycloaddition of azomethine ylides was modified. We analyzed the complex of f-CNTs combined with pDNA vaccines expressing HCV E2 protein by using Enzyme-linked immunospot (ELISPOT) or Enzyme-linked immunosorbent assay (ELISA) assay in vitro. The result showed that the CNT approach can induce stronger protective immune responses than the needle delivery of naked pDNA vaccine. We have also found an optimal way to treat CNT in light of the highest immune response in the same testing environment. The success of this research will warrant testing HCV vaccine in large animal models and human clinical trials.

Single Center Experience with Third-Generation Cryosurgery for Management of Organ-Confined Prostate Cancer: Critical Evaluation of Short-Term Outcomes, Complications, and Patient Quality of Life

Technical refinements such as improved ultrasonographic localization and the routine use of urethral warmers and small-gauge needle delivery systems have renewed interest in cryosurgical treatment as a minimally invasive option for selected patients with localized prostate cancer. Only three reports of quality of life (QoL) in prostate cryoablation exist, and none report on patients treated with third-generation cryoablative technology. We critically examine our initial series of consecutive patients at a single institution undergoing primary third-generation cryosurgical treatment of localized prostate cancer with respect to treatment outcome, morbidity profile, and QoL parameters. To our knowledge, this is the first QoL report on third-generation cryoablation of the prostate. We retrospectively review the records of 89 consecutive patients with median followup of 11 months (1-32) who have undergone third-generation cryosurgical ablation of the prostate as primary treatment for localized prostate cancer with intention to cure. Patients were risk stratified according to preprocedural parameters of prostate-specific antigen (PSA), clinical stage, and Gleason score. PSA trends were recorded and treatment effectiveness was observed using different definitions of biochemical failure. Charts were reviewed for postprocedure complications. Quality of life was measured prospectively using the University of California, Los Angeles, Prostate Cancer Index as well as American Urological Association symptom scores. We compare a percent of baseline score (%BS) for various domains between our series of patients treated with primary cryoablation with a series of patients undergoing brachytherapy for localized prostate cancer. Treatment success was defined by achievement of a PSA nadir of < or =0.1 ng/mL and by biochemical disease-free survival (BDFS) assessed with both a PSA threshold of < or =0.4 ng/dL over time and the American Society for Therapeutic Radiology and Oncology (ASTRO) definition of three consecutive rises in PSA. According to risk stratification, 86%, 81.5%, and 78% of low-, intermediate-, and high-risk patients, respectively, achieved a PSA nadir of < or =0.1 ng/mL. Overall, at 12 months follow-up, 94% of patients achieved BDFS using ASTRO criteria while 70% achieved BDFS using a PSA threshold of < or =0.4 ng/mL. With risk stratification, 74%, 70%, and 60% of low-, intermediate-, and high-risk patients, respectively, achieved BDFS defined by PSA threshold of < or =0.4 ng/mL. Complications were rare. The response rate for Health Related Quality of Life (HRQoL) questionnaires was 71% for cryoablation patients and 51% for brachytherapy patients. At 12 months follow-up, patients undergoing cryoablation on average achieved urinary and bowel domain scores comparable to baseline, but sexual domains remained well below baseline. When compared with a brachytherapy series with better baseline sexual function (P = 0.04) and urinary function (P = 0.03), cryotherapy patients experienced more negative impact on sexual function steadily for up to 12 months (P = 0.02). Urinary function was similar between the groups until 18 months, at which time cryoablation patients fared better (P = 0.01); this was sustained up to 24 months (P = 0.04). Treatment success with cryosurgery varies with definition; however, our results are comparable to other series with regard to short-term cancer control. Complication rates in this series of third-generation cryosurgical patients are low. QoL characteristics of third-generation cryoablation are similar to those described in second-generation cryoablation series. Compared with brachytherapy, cryotherapy results in less irritative and obstructive voiding symptoms in the early post-treatment period and may improve urinary function up to 24 months after treatment. In a small group of older patients with baseline erectile dysfunction undergoing cryoablation, sexual function returns to 20% of its baseline value with up to 12 months follow-up.

Use of Nanocarriers for Transdermal Vaccine Delivery

Transdermal delivery is a safe, noninvasive method of administering vaccines directly onto bare skin, offering several potential advantages over traditional needle delivery. This technology is limited by the relative inefficiency of transport of large-molecular-weight vaccine antigens across intact skin. Recent evidence has shown that this barrier can be overcome by properly structured nanosized particles (nanocarriers). The specialized assembly of each type of nanocarrier gives each unique properties and different interactions within the stratum corneum. The use of nanocarriers for vaccine delivery is a platform technology, applicable to delivery of a variety of existing and potential vaccines.