The relationship of embolic particle size to patient outcomes in prostate artery embolisation for benign prostatic hyperplasia: a systematic review and meta-regression.

AIM: To explore the relationship of embolic particle size used in prostate artery embolisation (PAE) to patient outcomes. MATERIALS AND METHODS: A systematic review of PubMed, EMBASE, and the Cochrane database was undertaken to identify all existing studies using PAE for benign prostatic hyperplasia (BPH). Inclusion criteria included prospective studies reporting baseline and 12-month International Prostate Symptom Score (IPSS) and particle size. Exclusion criteria were overlapping studies, commentaries, abstracts, and letters. Data extraction from eligible studies included the size of embolic particle, particle material, and baseline and 12-month values for the following patient outcomes: IPSS, IPSS quality of life, urinary flow rate (Q-max), prostate volume, prostate specific antigen, and post-void residual volume. A meta-regression analysis was then undertaken to examine the relationship of particle size to patient outcome measures. RESULTS: Six studies with a total of 687 patients were identified. Meta-regression analysis demonstrated particle size as a statistically significant (p<0.001) moderator of 12-month IPSS change following PAE. No statistically significant relationships were identified with other patient outcome measures. CONCLUSION: Smaller embolic particle size is associated with a greater reduction in IPSS following PAE.

Phase III randomized study of second line ADI-PEG 20 plus best supportive care versus placebo plus best supportive care in patients with advanced hepatocellular carcinoma.

Background: Arginine depletion is a putative target in hepatocellular carcinoma (HCC). HCC often lacks argininosuccinate synthetase, a citrulline to arginine-repleting enzyme. ADI-PEG 20 is a cloned arginine degrading enzyme-arginine deiminase-conjugated with polyethylene glycol. The goal of this study was to evaluate this agent as a potential novel therapeutic for HCC after first line systemic therapy. Methods and patients: Patients with histologically proven advanced HCC and Child-Pugh up to B7 with prior systemic therapy, were randomized 2 : 1 to ADI-PEG 20 18 mg/m2 versus placebo intramuscular injection weekly. The primary end point was overall survival (OS), with 93% power to detect a 4-5.6 months increase in median OS (one-sided α = 0.025). Secondary end points included progression-free survival, safety, and arginine correlatives. Results: A total of 635 patients were enrolled: median age 61, 82% male, 60% Asian, 52% hepatitis B, 26% hepatitis C, 76% stage IV, 91% Child-Pugh A, 70% progressed on sorafenib and 16% were intolerant. Median OS was 7.8 months for ADI-PEG 20 versus 7.4 for placebo (P = 0.88, HR = 1.02) and median progression-free survival 2.6 months versus 2.6 (P = 0.07, HR = 1.17). Grade 3 fatigue and decreased appetite occurred in <5% of patients. Two patients on ADI-PEG 20 had ≥grade 3 anaphylactic reaction. Death rate within 30 days of end of treatment was 15.2% on ADI-PEG 20 versus 10.4% on placebo, none related to therapy. Post hoc analyses of arginine assessment at 4, 8, 12 and 16 weeks, demonstrated a trend of improved OS for those with more prolonged arginine depletion. Conclusion: ADI-PEG 20 monotherapy did not demonstrate an OS benefit in second line setting for HCC. It was well tolerated. Strategies to enhance prolonged arginine depletion and synergize the effect of ADI-PEG 20 are underway. Clinical Trial number: www.clinicaltrials.gov (NCT 01287585).

Accuracy of mandibular proximal segment position using virtual surgical planning and custom osteosynthesis plates.

The purpose of this study was to determine whether the use of custom osteosynthesis plates increased the accuracy of proximal segment position following bilateral sagittal split osteotomy in a cohort of 30 patients when compared to a control group of 25 patients who had surgery with conventional plates. Surgery was performed by a single surgeon between October 2015 and December 2017. Post-surgical cone beam computed tomography scans were segmented using Mimics Innovation Suite (Materialise NV), and surface-based superimposition was achieved using ProPlan CMF (Materialise NV). However, there was a tendency for the rotational error to be smaller in the custom group than in the control group. The root mean square error in both groups and for all variables fell within clinical parameters of 2 mm and 4°. In conclusion, the results of this study indicate that customized mandibular fixation plates do not necessarily improve the accuracy of the proximal segments post-surgically; however they may be of benefit in individual patients.

Antibody targeting of doxorubicin-loaded liposomes suppresses the growth and metastatic spread of established human lung tumor xenografts in severe combined immunodeficient mice.

Beta1 integrins, expressed on the cell surface of human non-small cell lung carcinomas, are used here as a target for the selective delivery of anti-cancer drug-loaded liposomes. Fab' fragments of a monoclonal antibody specific for human beta1 integrins were conjugated to sterically stabilized liposomes. Confocal microscopy of beta1 integrin-positive lung tumor cells incubated with fluorescently labeled anti-beta1 Fab immunoliposomes revealed a tumor-specific binding and efficient internalization of the liposomes into the tumor cells. The ability of these liposomes to deliver cytotoxic drugs to the tumor and kill these cells was demonstrated in vitro by incubating tumor cells with doxorubicin-loaded anti-beta1 Fab' immunoliposomes. The drug-loaded immunoliposomes were >30-fold more cytotoxic to the tumor cells than drug-loaded liposomes without antibody, nonspecific Fab' control immunoliposomes with drug or immunoliposomes without drug. The therapeutic efficacy of doxorubicin-loaded immunoliposomes was also evaluated in a metastatic human lung tumor xenograft/severe combined immunodeficient (SCID) mouse model. SCID mice that received i.v. injections of human lung tumor cells developed primary tumor nodules in the lung that subsequently metastasized to the liver and adrenal gland. Treatment of SCID mice bearing established lung tumor xenografts with doxorubicin-loaded anti-beta1 Fab immunoliposomes resulted in a significant suppression of tumor growth (monitored periodically by quantifying serum levels of a tumor marker), whereas tumors grew progressively in mice treated with control formulations. In addition to suppressing the growth of the primary lung tumor nodules, the immunoliposomes prevented the metastatic spread of the tumor to the liver and adrenal glands and increased the median survival time of the tumor-bearing mice. We conclude that Fab' immunoliposomes directed to tumor-associated integrins represent a potentially viable approach clinically for the selective delivery of drugs to solid tumors and may be useful in preventing the metastatic spread of lung cancer.

Immunogenicity and pharmacokinetic attributes of poly(ethylene glycol)-grafted immunoliposomes.

Immunoliposomes composed of hydrogenated soy phosphatidylcholine, cholesterol, methoxypoly(ethylene glycol)-distearoyl phosphatidylethanolamine (mPEG-DSPE), and hydrazide-PEG-DSPE (mole ratio, 57:38:3.3:1.7) linked to periodate-oxidized chimerized mouse IgG (C225, anti-human epidermal growth factor receptor) were prepared by an optimized aggregation-free procedure. The antigen-binding activity of the immunoliposomes was well preserved. When injected intravenously into naive rats, the immunoliposomes (approximately 18 IgG per 100 nm liposome) exhibited long circulation times (MRT = 8.5 h, Cl = 0.2 ml/h). Subsequent injections of the immunoliposomes into the same animals resulted in rapid clearance (MRT < or = 0.7 h, Cl > or = 7 ml/h), which was accompanied by a significant increase in anti-C225 specific titers. Upon repeated injection or coinjection with the parent liposomes free C225 consistently exhibited prolonged circulation without any increase in C225-specific antisera, but was cleared quickly when administered into animals that had been pretreated with the immunoliposomes. Screening of the immunoliposome induced antisera against human polyclonal IgG and C225-derived Fab' fragment revealed that the immune response was specifically triggered by the constant human region of C225. These results demonstrate that the preparations of PEG-grafted immunoliposomes are more immunogenic than the free IgG component, which is of profound importance to the antibody-mediated liposomal drug delivery effort.

What are dental non-attenders' preferences for anxiety management techniques? A cross-sectional study based at a dental access centre.

OBJECTIVE: Dental anxiety is a barrier to attendance. Dental non-attenders may seek emergency care and may prefer to receive anxiety management measures for treatment required. Little is known about the preferences of these dental non-attenders for different anxiety management techniques. Understanding such preferences may inform management pathways, improve experiences, alleviate anxieties and encourage a more regular attendance pattern. As such, the aim of this study was to gain a greater understanding of the dental anxiety of patients attending a dental access centre for emergency dental treatment and to ascertain preferences for different anxiety management techniques. DESIGN: Cross-sectional study involving self-completed questionnaires and clinical observation. SETTING: NHS Dental Access Centre, York, UK. SUBJECTS AND METHODS: Two hundred participants not registered with a general dental practitioner, aged 18 years or over, experiencing pain and self-referred were recruited on a consecutive sampling basis. Participants completed a questionnaire eliciting demographic and dental history details, dental anxiety and preferences for dental anxiety management options. MAIN OUTCOME MEASURES: Correlation of the modified dental anxiety scale with preference for different dental anxiety management techniques. RESULTS: No significant predictive factors were found that explained preferring local anaesthetic to sedation, or general anaesthesia for restorations or extractions. Those highly anxious were less likely to consider tell-show-do techniques (p=0.001) or watching explanatory videos (p=0.004) to be helpful for overcoming their anxieties than the low or moderate anxiety groups. CONCLUSIONS: People attending access centres may represent a group who are unwilling to explore non-pharmacological methods to overcome their anxieties. This supports the need for sedation to provide treatment. Future work may include exploring in more depth the thoughts and opinions of this group of patients to improve understanding of their complex dental attitudes. From this, more effective strategies may be developed to encourage regular dental attendance.

Poly(ethylene glycol)-grafted liposomes with oligopeptide or oligosaccharide ligands appended to the termini of the polymer chains.

Novel conjugates tailor-made for inclusion in liposomal formulations, containing distearoylphosphatidylethanolamine (DSPE) as a lipid anchor, heterobifunctional polyethylene glycol (PEG) with a molecular weight of 2000 as a linking moiety, and a biological cell adhesive ligand [YIGSR peptide or Sialyl Lewis(X) oligosaccharide (SLX)], were synthesized. They were characterized by NMR, chromatography, and matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOFMS). Inclusion of either of the ligand-PEG-lipid conjugates (2 mol %) in a lecithin/cholesterol/ methoxy-PEG2000-DSPE (55:40:3 mole ratio) lipid mixture followed by preparation of unilamellar vesicles (100 nm) resulted in positioning of 55% of the YIGSR and 63% of the SLX ligands on the periphery of the outer surface-grafted polymeric "brush", as determined by a combination of specific enzymatic alterations of each ligand and HPLC. Similar densities of ligand-bearing PEG chains were incorporated into liposomes by simply incubating (37 degrees C, 5 h) either one of the ligand-PEG-lipid conjugates with preformed lipid vesicles. This conjugate insertion process was aggregation free. Using enzymatic derivatization-HPLC, it was demonstrated that all the ligands incorporated into lipid membranes by this new approach were positioned exclusively on the outer leaflet of the liposomal bilayers. Since liposomes of this type are intended for in vivo use as long-circulating, ligand-presenting platforms, the insertion approach is preferable because of the more efficient utilization of ligand-PEG-lipid conjugates.