Surgical delivery of drug releasing poly(lactic-co-glycolic acid)/poly(ethylene glycol) paste with in vivo effects against glioblastoma

Introduction

The median survival of patients with glioblastoma multiforme (astrocytoma grade 4) remains less than 18 months despite radical surgery, radiotherapy and systemic chemotherapy. Surgical implantation of chemotherapy eluting wafers into the resection cavity has been shown to improve length of survival but the current licensed therapy has several drawbacks. This paper investigates in vivo efficacy of a novel drug eluting paste in glioblastoma.

Methods

Poly(lactic-co-glycolic acid)/poly(ethylene glycol) (PLGA/PEG) self-sintering paste was loaded with the chemotherapeutic agent etoposide and delivered surgically into partially resected tumours in a flank murine glioblastoma xenograft model.

Results

Surgical delivery of the paste was successful and practical, with no toxicity or surgical morbidity to the animals. The paste was retained in the tumour cavity, and preliminary results suggest a useful antitumour and antiangiogenic effect, particularly at higher doses. Bioluminescent imaging was not affected significantly by the presence of the paste in the tumour.

Conclusions

Chemotherapy loaded PLGA/PEG paste seems to be a promising technology capable of delivering active drugs into partially resected tumours. The preliminary results of this study suggest efficacy with no toxicity and will lead to larger scale efficacy studies in orthotopic glioblastoma models.     

Focal Therapy in Prostate Cancer: International Multidisciplinary Consensus on Trial Design

Background

Focal therapy has been introduced for the treatment of localised prostate cancer (PCa). To provide the necessary data for consistent assessment, all focal therapy trials should be performed according to uniform, systematic pre- and post-treatment evaluation with well-defined end points and strict inclusion and exclusion criteria.

Objective

To obtain consensus on trial design for focal therapy in PCa.

Design, setting, and participants

A four-staged consensus project based on a modified Delphi process was conducted in which 48 experts in focal therapy of PCa participated. According to this formal consensus-building method, participants were asked to fill out an iterative sequence of questionnaires to collect data on trial design. Subsequently, a consensus meeting was held in which 13 panellists discussed acquired data, clarified the results, and defined the conclusions.

Outcome measurements and statistical analysis

A multidisciplinary board from oncologic centres worldwide reached consensus on patient selection, pretreatment assessment, evaluation of outcome, and follow-up.

Results and limitations

Inclusion criteria for candidates in focal therapy trials are patients with prostate-specific antigen <15 ng/ml, clinical stage T1c–T2a, Gleason score 3 + 3 or 3 + 4, life expectancy of >10 yr, and any prostate volume. The optimal biopsy strategy includes transrectal ultrasound-guided biopsies to be taken between 6 mo and 12 mo after treatment. The primary objective should be focal ablation of clinically significant disease with negative biopsies at 12 mo after treatment as the primary end point.

Conclusions

This consensus report provides a standard for designing a feasible focal therapy trial.

Patient summary

A variety of ablative technologies have been introduced and applied in a focal manner for the treatment of prostate cancer (PCa). In this consensus report, an international panel of experts in the field of PCa determined pre- and post-treatment work-up for focal therapy research.     

Skeletal muscle fibrosis and stiffness increase after rotator cuff tendon injury and neuromuscular compromise in a rat model

Rotator cuff tears can cause irreversible changes (e.g., fibrosis) to the structure and function of the injured muscle(s). Fibrosis leads to increased muscle stiffness resulting in increased tension at the rotator cuff repair site. This tension influences repairability and healing potential in the clinical setting. However, the micro‐ and meso‐scale structural and molecular sources of these whole‐muscle mechanical changes are poorly understood. Here, single muscle fiber and fiber bundle passive mechanical testing was performed on rat supraspinatus and infraspinatus muscles with experimentally induced massive rotator cuff tears (Tenotomy) as well as massive tears with chemical denervation (Tenotomy + BTX) at 8 and 16 weeks post‐injury. Titin molecular weight, collagen content, and myosin heavy chain profiles were measured and correlated with mechanical variables. Single fiber stiffness was not different between controls and experimental groups. However, fiber bundle stiffness was significantly increased at 8 weeks in the Tenotomy + BTX group compared to Tenotomy or control groups. Many of the changes were resolved by 16 weeks. Only fiber bundle passive mechanics was weakly correlated with collagen content. These data suggest that tendon injury with concomitant neuromuscular compromise results in extra‐cellular matrix production and increases in stiffness of the muscle, potentially complicating subsequent attempts for surgical repair. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:1111–1116, 2014.     

Type A achievement striving and failure to achieve personal goals

The purpose of the present study was to examine relations involving the Type A behavior pattern, goal-setting behavior, and goal achievement. Type A and B subjects completed two sequential general information tests. On each test, subjects were required to establish a performance goal prior to the test, and after completing the test, subjects were given feedback on their actual performance. On both tests, results confirmed that Type A's, compared to Type B's, set significantly higher performance goals, performed no differently, showed significantly larger discrepancies between performance and goals, were significantly less likely to achieve their performance goal. Furthermore, it was found that Type A's set goals on test 2 that exceeded their test 1 performance to a greater extent than Type B's, but only among subjects who failed to achieve their test 1 goals. No differences were found between Type A's and B's on goal-setting behavior following a success in goal achievement on test 1. Results of the experiment suggest that Type A achievement striving represents a breakdown in achievement-related self-regulation, which may have negative psychological consequences associated with failure to achieve personal goals.     

Receptor occupancy of nonpeptide corticotropin-releasing factor 1 antagonist DMP696: correlation with drug exposure and anxiolytic efficacy

4-(1,3-Dimethoxyprop-2-ylamine)-2,7-dimethyl-8-(2,4-dichlorophenyl)-pyrazolo[1,5-a]-1,3,5-triazine (DMP696) is a highly selective and potent, nonpeptide corticotropin-releasing factor 1 (CRF(1)) antagonist. In this study, we measured in vivo CRF(1) receptor occupancy of DMP696 by using ex vivo ligand binding and quantitative autoradiography and explored the relationship of receptor occupancy with plasma and brain exposure and behavioral efficacy. In vitro affinity (IC(50)) of DMP696 to brain CRF(1) receptors measured using the brain section binding autoradiography in this study is similar to that assessed using homogenized cell membrane assays previously. The ex vivo binding assay was validated by demonstrating that potential underestimation of receptor occupancy with this procedure could be minimized by identifying an appropriate in vitro incubation time (40 min) based upon the dissociation kinetics of DMP696. Orally administrated DMP696 dose dependently occupied CRF(1) receptors in the brain, with ~60% occupancy at 3 mg/kg. In the defensive withdrawal test of anxiety, this dose of DMP696 produced approximately 50% reduction in the exit latency. The time course of plasma and brain drug levels paralleled that of receptor occupancy, with peak exposure at 90 min after dosing. The plasma-free concentration of DMP696 corresponding to 50% CRF(1) receptor occupancy (in vivo IC(50), 1.22 nM) was similar to the in vitro IC(50) (~1.0 nM). Brain concentrations of DMP696 were over 150-fold higher than the plasma-free levels. In conclusion, doses of DMP696 occupying over 50% brain CRF(1) receptors are consistent with doses producing anxiolytic efficacy in the defense withdrawal test of anxiety, and the IC(50) value estimated in vivo based on plasma-free drug concentrations is consistent with the in vitro IC(50) value.     

A two-millimetre free margin from invasive tumour minimises residual disease in breast-conserving surgery

Aims: In breast‐conserving surgery, the width of free margin around a tumour to ensure adequate excision is controversial. The aim of this study was first to evaluate the frequency of residual disease in wider excision specimens in patients who undergo further surgery because of close margins of < 5 mm. Secondly, the ability of demographic and tumour‐related factors to predict the close margins was appraised. Patients and methods: Three‐hundred‐and‐three patients were included in the study. Patients undergoing wider excision were assessed for the presence of residual disease, and this was tested for association with the width of the initial free margin. Various factors were studied for association with close or involved margins by univariate analysis. Results: Fifty‐three per cent of patients were eligible for re‐excision based on the need for a 5‐mm clearance. With a free margin of 2 mm or more from invasive tumour, the probability of finding residual disease was 2.4%. The probability of residual disease was higher for ductal carcinoma in situ (DCIS) and did not decline with increasing the free margin width. Tumour size, lobular cancer type, vascular invasion and nodal involvement were associated with close margins. Conclusions: We suggest that a free margin of 2 mm from invasive tumour is adequate to minimise residual disease, whereas the equivalent free margin for DCIS remains unclear. Patients with large tumours and lobular cancer type should be counselled at the time of first surgery concerning the higher risk of further excision and mastectomy.     

A new noninvasive method to determine central venous pressure

Knowledge of central venous pressure (CVP) is considered valuable in the assessment and treatment of various states of critical illness and injury. OBJECTIVES: We tested a noninvasive means of determining CVP (NICVP), by monitoring forearm volume changes in response to externally applied circumferential pressure to the upper arm veins. METHODS: Sixteen patients who were undergoing CVP monitoring as a part of their care had NICVP determined and compared with CVP. Volume changes were measured in the forearm with mercury-in-silastic strain gauge plethysmography. A pressure cuff is placed in the upper extremity. The cuff is inflated over 5s to a pressure above CVP but below diastolic arterial pressure (40 mmHg). This allows blood into the forearm but prevents venous return. After 45-60 s the cuff is rapidly deflated. NICVP was determined as the cuff pressure noted at the maximum derivative of the forearm volume decrease during deflation. NICVP was then compared to invasively measured CVP taken during the same period. RESULTS: A total of 48 trials (three per subject) were performed on 16 patients. The range of CVP recorded was 0-22 mmHg. The correlation between CVP and NICVP was 0.98 (95% CI: 0.95-0.98) (p<0.001). The bias between methods was 0.26 mmHg with the limits of agreement being 3.4 to -2.89 mmHg. When the average of three trials per patients was analysed the bias stayed at 0.26 mmHg but the limits of agreement improved to 2.54 and -2.03 mmHg. CONCLUSION: NICVP as determined in this study may be a clinically useful substitute for traditional CVP measurement and may offer a valid tool for early diagnosis and treatment of acute states in which knowledge of CVP would be helpful.     

Methods for studying the binding of aluminum by serum protein

We describe methods for studying the binding of Al by protein in serum: ultrafiltration, gel filtration, and immuno-affinity chromatography. For ultrafiltration we used an Amicon YM10 cellophane membrane with a nominal cutoff of 10 000 Da to separate ultrafiltrable and non-ultrafiltrable Al. For gel filtration we used Sephacryl S-300, and for immuno-affinity chromatography we used anti-transferrin coupled to CNBr-activated Sepharose to identify the Al-binding protein. For 30 normal subjects 54% of the total Al in serum was non-ultrafiltrable; for 30 patients with chronic renal failure being treated by hemodialysis 67% was non-ultrafiltrable. In both groups transferrin was identified as the major Al-binding protein in the serum. Results of gel-filtration studies should be interpreted with caution: some gel media adsorb "free" Al, which can be subsequently taken up by transferrin or desferrioxamine passing through the column. We find affinity chromatography to be a specific and reliable method, suitable for use in quantitative studies.     

Motor Vehicle Crash Fatalities among Hispanics in Rural North Carolina

OBJECTIVES: Deaths from motor vehicle crashes (MVCs) have decreased significantly over the past three decades. Unfortunately, few data have been collected regarding death rates for MVCs in minority populations. The purpose of this study was to compare the death rate of whites versus Hispanics for MVCs in a rural environment. METHODS: This study examined one rural county in North Carolina from January 1, 1999, to December 31, 1999. A retrospective cohort study was performed using the North Carolina State Highway Patrol computerized database of MVCs. Data regarding the total number of MVCs, fatalities, alcohol-related deaths, seatbelt usage, and cause of the collision were analyzed for both whites and Hispanics. Census information regarding population in this region also was obtained from the U.S. Bureau of Census. Data were analyzed using a chi-square test, with an alpha value of 0.05 used to establish statistical significance. RESULTS: During the study period, whites were involved in 2,689 MVCs, compared with 158 MVCs for Hispanics. Whites were involved in ten fatal MVCs, compared with seven fatal MVCs involving Hispanics. The percent of fatal MVCs for whites was 0.3%, or 10 deaths per 2,689 MVCs. In contrast, the percent of fatal MVCs for Hispanics was 4.4%, or 7 deaths per 158 MVCs; odds ratio (OR) = 12.4, 95% CI = 4.7 to 33.1. The 2000 Census Report for Pitt County noted a white population of 81,613 and a Hispanic population of 4,216. Based on these population data, the death rate for MVCs per 100,000 population was 12.3 for whites versus 166.0 for Hispanics, OR = 13.6, 95% CI = 5.2 to 35.6. Although the cause for this disparity was not determined, previous studies suggest that alcohol and decreased seatbelt usage are contributing factors. CONCLUSIONS: In this study, the death rates among Hispanics for rural MVCs were significantly higher than for whites. The causes of this disparity are not clear but are important to define. Only by understanding this disparity can we begin to develop appropriate interventions that may prevent these deaths.