Efficacy and safety of radium-223 dichloride in patients with castration-resistant prostate cancer and symptomatic bone metastases, with or without previous docetaxel use: A prespecified subgroup analysis from the randomised, double-blind, phase 3 ALSYMPCA trial

Background: Primary results from the phase 3 ALSYMPCA trial showed that radium-223 dichloride (radium-223), a targeted α-emitter, improved overall survival compared with placebo and was well tolerated in patients with castration-resistant prostate cancer and symptomatic bone metastases. We did a prespecified subgroup analysis from ALSYMPCA to assess the effect of previous docetaxel use on the efficacy and safety of radium-223. 

Methods: In the phase 3, randomised, double-blind ALSYMPCA trial, patients with symptomatic castration-resistant prostate cancer, at least two symptomatic bone metastases, no known visceral metastases, and who were receiving best standard of care were randomly assigned (2:1) via an interactive voice response system to receive six injections of radium-223 (50 kBq/kg intravenously) or matching placebo, with one injection given every 4 weeks. Patients had either received previous docetaxel treatment or were unsuitable for or declined docetaxel; previous docetaxel use (yes or no) was a trial stratification factor. We investigated the effect of previous docetaxel use on radium-223 treatment for the primary endpoint of overall survival, the main secondary efficacy endpoints, and safety. Efficacy analyses were done for the intention-to-treat population; safety analyses were done for the safety population. The trial has been completed and is registered with ClinicalTrials.gov, number NCT00699751. 

Findings: Randomisation took place between June 12, 2008, and Feb 1, 2011. 526 (57%) of 921 randomly assigned patients had received previous docetaxel treatment (352 in the radium-223 group and 174 in the placebo group) and 395 (43%) had not (262 in the radium-223 group and 133 in the placebo group). Radium-223 prolonged median overall survival compared with placebo, irrespective of previous docetaxel use (previous docetaxel use, hazard ratio [HR] 0·70, 95% CI 0·56-0·88; p=0·002; no previous docetaxel use, HR 0·69, 0·52-0·92; p=0·01). The benefit of radium-223 compared with placebo was seen in both docetaxel subgroups for most main secondary efficacy endpoints; risk for time to time to first symptomatic skeletal event was reduced with radium-223 versus placebo in patients with previous docetaxel use, but the difference was not significant in those with no previous docetaxel use. 322 (62%) of 518 patients previously treated with docetaxel had grade 3-4 adverse events, compared with 205 (54%) of 383 patients without docetaxel. Patients who had previously been treated with docetaxel had a higher incidence of grade 3-4 thrombocytopenia with radium-223 than with placebo (31 [9%] of 347 patients vs five [3%] of 171 patients), whereas the incidence was similar between treatment groups among patients with no previous docetaxel use (seven [3%] of 253 patients vs one [1%] of 130 patients). The incidences of grade 3-4 anaemia and neutropenia were similar between the radium-223 and placebo groups within both docetaxel subgroups. 

Interpretation: Radium-223 is effective and well tolerated in patients with castration-resistant prostate cancer and symptomatic bone metastases, irrespective of previous docetaxel use. 

Funding: Algeta ASA and Bayer HealthCare Pharmaceuticals.

Efficacy and safety of peri-prostatic local anaesthetic injection in tram-rectal biopsy of the prostrate:A prospective randomised study

Objective: To assess the efficacy and safety of periprostatic lignocaine injection in trans-rectal ultrasound (TRUS) -guided biopsy of the prostate gland.

Methods: Ninety- six men (mean age 65 years, range 47-74) undergoing TRUS biopsy were randomised into the local anaesthetic (LA) or placebo group. Six to twelve biopsy cores were taken, the majority being 10 cores. Patients were asked to fill in the expected pain score on a visual analogue scale (VAS) prior to the procedure. They also completed the actual pain experienced on VAS after the biopsy. The incidence of complications was documented.

Results: The age, mean prostate specific antigen (PSA) were comparable in both groups. The expected pain score was also comparable (5.2 +/- 1.6 in LA, 5.0 +/- 1.4 in Placebo). In the LA group, the mean actual pain score was 3.0 +/- 1.8 and in the placebo group it was 6.5 +/- 2.2 (P = 0.0001). When patients were asked whether they would undergo the procedure again in the same way, 100% of the LA group and only 64% of the placebo group responded 'yes'(P=0.002 using Fisher's test). The complication rates were not significantly different between the two groups.

Conclusion: Peri-prostatic injection of local anaesthetic is safe and reduces discomfort significantly, and should be routinely offered to patients.

Cadaveric fascia lata pubovaginal slings:early results on safety, efficacy and patient satisfaction

Objective To prospectively evaluate and quantify the efficacy of cadaveric fascia lata (CFL) as an allograft material in pubovaginal sling placement to treat stress urinary incontinence (SUI).

Patients and methods Thirty-one women with SUI (25 type II and six type III; mean age 63 years, range 40-75) had a CFL pubovaginal sling placed transvaginally. The operative time, blood loss, surgical complications and mean hospital stay were all documented. Before and at 4 months and 1 year after surgery each patient completed a 3-day voiding diary and validated voiding questionnaires (functional inquiry into voiding habits, Urogenital Distress Inventory and Incontinence Impact Questionnaire, including visual analogue scales).

Results The mean (range) operative time was 71 (50-120) min, blood loss 78.7 (20-250) mL and hospital stay 1.2 (1-2) days; there were no surgical complications. Over the mean follow-up of 13.5 months, complete resolution of SUI was reported by 29 (93%) patients. Overactive bladder symptoms were present in 23 (74%) patients before surgery, 21 (68%) at 4 months and two (6%) at 1 year; 80% of patients with low (<15 cmH (2) O) voiding pressures before surgery required self-catheterization afterward, as did 36% at 4 months, but only one (3%) at 1 year. Twenty-four (77%) patients needed to adopt specific postures to facilitate voiding. After surgery there was a significant reduction in daytime frequency, leakage episodes and pad use (P <0.05). The severity of leak and storage symptoms was also significantly less (P <0.002), whilst the severity of obstructive symptoms remained unchanged. Mean subjective levels of improvement were 69% at 4 months and 85% at 1 year, with corresponding objective satisfaction levels of 61% and 69%, respectively. At 1 year, approximate to 80% of the patients said they would undergo the procedure again and/or recommend it to a friend.

Conclusion Placing a pubovaginal sling of CFL allograft is a highly effective, safe surgical approach for resolving SUI, with a short operative time and rapid recovery. Storage symptoms are significantly improved, and subjective improvement and satisfaction rates are high.

Artificial urinary sphincter implantation in the irradiated patient:safety, efficacy and satisfaction

Objective To compare the long-term outcome of artificial urinary sphincter (AUS) implantation in patients after prostatectomy, with and with no history of previous irradiation.

Patients and methods The study included 98 men (mean age 68 years) with urinary incontinence after prostatectomy for prostate cancer (85 radical, 13 transurethral resection) who had an AUS implanted. Twenty-two of the patients had received adjuvant external beam irradiation before AUS implantation. Over a mean (range) follow-up of 46 (5-118) months, the complication and surgical revision rates were recorded and compared between irradiated and unirradiated patients. The two groups were also compared for the resolution of incontinence and satisfaction, assessed using a questionnaire.

Results Overall, surgical revision was equally common in irradiated (36%) and unirradiated (24%) patients. After activating the AUS, urethral atrophy, infection and erosion requiring surgical revision were more common in irradiated patients (41% vs 11%; P <0.05); 70% of patients reported a significant improvement in continence, regardless of previous irradiation. Patient satisfaction remained high, with >80% of patients stating that they would undergo surgery again and/or recommend it to others, despite previous Irradiation and/or the need for surgical revision.

Conclusions Despite higher complication and surgical revision rates in patients who have an AUS implanted and have a history of previous Irradiation, the long-term continence and patient satisfaction appear not to be adversely affected.

Precision Teaching in IV Fluid Prescribing and Patient Safety

OBJECTIVES: Precision Teaching (PT) has been shown to be an effective intervention to assess teaching method effectiveness and evaluate learning outcomes. SAFMEDS (Say All Fast Minute Every Day Shuffled) are a practice/assessment procedure within the PT framework to assist learning and fluency. We explored the effects of a brief intervention with PT, to impart high frequency performance in safe intravenous fluid prescription in a group of final year undergraduate medical students.
METHODS: 133 final year undergraduate medical students completed a multiple choice question (MCQ) test on safe IV fluid prescription at the beginning and end of the study. The control group (n= 76) of students were taught using a current standardized teaching method. Students allocated to the intervention arm of the study were additionally instructed on PT and the use of SAFMEDS. The study group (n = 57) received 50 SAFMEDS cards containing information on the principles of IV fluid prescription scenarios. These students were trained/tested twice per day for 1 minute.
RESULTS: Interim analysis showed that the study group displayed an improvement in fluency and accuracy as the study progressed. There was a statistically significant improvement in MCQ performance for the PT group compared with the control group between the beginning and end of the study (35% vs 15%).
CONCLUSION: These results suggest PT employing SAFMEDS is an effective method for improving fluency, accuracy and patient safety in intravenous fluid prescribing amongst undergraduate medical students.

Metacognition in Patient Safety

OBJECTIVES: To determine if cognitive reflection has a positive influence on clinical decision making in undergraduate medical students. METHODS: 153 final year undergraduate medical students completed a 3 hour interactive Safe Thinking Workshop on nontechnical skills and patient safety, incorporating an introduction to metacognitive concepts. All students underwent augmented Cognitive Reflective Testing during the workshop. Students then inspected and interpreted a set of arterial blood gas results relating to a patient with acute respiratory distress, then answered a short questionnaire addressing biochemical diagnosis, clinical diagnosis and effective management. A separate question was embedded in the questionnaire to determine if astute students could determine the severity of the illness. The study group (n = 78) completed the questionnaire immediately after the Safe Thinking Workshop, whilst the control group (n = 75) completed the questionnaire prior to the Workshop.RESULTS: The mean total score for study students was 80.51%, with a mean total score of 57.9% for the control group (t-test; p<0.05). Correct classification of illness severity was observed in 13.2% of study students, compared with 4.1% of control students (p<0.05). CONCLUSION: These results suggest that clinical decision making and recognition of illness severity can be enhanced by specific teaching in nontechnical skills, metacognitiion and cognitive reflection.

Changes in quality and safety attributes throughout long term storage of tomato juice processed by high pressure.

Tomato is the second most widely grown vegetable crop across the globe and it is one of widely cultivated crops in Sri Lanka. However, tomato industry in Sri Lanka facing a problem of high postharvest loss (54%) during the glut coupled with heavy revenue loss to the country by importing processed products. The aim of this work is to develop shelf-stable tomato product with maximum quality characteristics using high pressure processing (HPP). Tomato juice with altered and unaltered pH was processed using HPP at 600 MPa for 1 min after blanching (90 oC/2 min). As a control tomato juice was subjected to thermal processing (TP) at 95 oC /20 min. Processed samples were stored under 20oC and 28oC for 9 month period and analysed for total viable count (TVC) and instrumental colour (L, a, b) value at 0,1,2 3, and 4 week and 2, 3, 6 and 9 months interval. The raw juice sample had initial 6.69 log10 CFU/ml and both TP and HPP caused a more than 4.69 log10 reduction in the TVC of juice and microbial numbers remained low throughout the storage period even at 3 months after storage irrespective of the storage temperature. Both TP and HPP treated samples had the redness ⤘a value’ of 14.44-17.15 just after processing and showed non-significant reduction with storage in all the treatments after 3 months. The storage study results and discussed in relation to the end goal and compared with the literature.

One-Year Safety of Olodaterol Once Daily via Respimat® in Patients with GOLD 2-4 Chronic Obstructive Pulmonary Disease: Results of a Pre-Specified Pooled Analysis

The novel long-acting β2-agonist olodaterol demonstrated an acceptable safety profile in short-term phase II clinical studies. This analysis of four randomized, double-blind, placebo-controlled, parallel-group, phase III studies (1222.11, NCT00782210; 1222.12, NCT00782509; 1222.13, NCT00793624; 1222.14, NCT00796653) evaluated the long-term safety of olodaterol once daily (QD) in a large cohort of patients with moderate to very severe (Global initiative for chronic Obstructive Lung Disease 2-4) chronic obstructive pulmonary disease (COPD). The studies compared olodaterol (5 or 10 μg) QD via Respimat®, formoterol 12 μg twice daily (BID) via Aerolizer® (1222.13 and 1222.14), and placebo for 48 weeks. Patients continued receiving background maintenance therapy, with ∼60% receiving concomitant cardiovascular therapy and 25% having a history of concomitant cardiac disease. Pre-specified analyses of pooled data assessed the adverse events (AEs) and serious AEs in the whole population, and in subgroups with cardiac disease, along with in-depth electrocardiogram and Holter monitoring. In total, 3104 patients were included in the safety analysis: 876 received olodaterol 5 μg, 883 received olodaterol 10 μg, 885 received placebos, and 460 received formoterol 12 μg BID. Overall incidence of on-treatment AEs (71.2%), serious AEs (16.1%), and deaths (1.7%) were balanced across treatment groups. Respiratory and cardiovascular AEs, including major adverse cardiac events, were reported at similar frequencies in placebo and active treatment groups. The safety profiles of both olodaterol 5 μg (marketed and registered dose) and 10 μg QD delivered via Respimat® are comparable to placebo and formoterol BID in this population, with no safety signals identified.

A review of the global pesticide legislation and the scale of challenge in reaching the global harmonization of food safety standards

Pesticide use is important in agriculture to protect crops and improve productivity. However, they have the potential to cause adverse human health or environmental effects, dependent on exposure levels. This review examines existing pesticide legislation worldwide, focusing on the level of harmonisation, and impacts of differing legislation on food safety and trade. Pesticide legislation varies greatly worldwide as countries have different requirements guidelines and legal limits for plant protection. Developed nations have more stringent regulations than developing countries, which lack the resources and expertise to adequately implement and enforce legislation. Global differences in pesticide legislation act as a technical barrier to trade. International parties such as the European Union (EU), Codex Alimentarius Commission (Codex), and North American Free Trade Agreement (NAFTA) have attempted to harmonise pesticide legislation by providing maximum residue limits (MRLs), but globally these limits remain variable. Globally harmonised pesticide standards would serve to increase productivity, profits and trade, and enhance the ability to protect public health and the environment.