Maintenance treatment for recurrent ovarian carcinoma – Evidence supporting the efficacy and safety of PARP inhibitors

While recent advances in treatment mean that women with ovarian cancer are living longer, many eventually experience disease relapse highlighting the need for new treatments that can extend progression-free survival (PFS). The PARP inhibitors olaparib, niraparib and rucaparib have been approved by the US Food and Drug Administration and the European Commission and are currently available for the maintenance treatment of patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. Here, we review the efficacy and safety data from the key clinical trials supporting the approvals for these treatments as second-line maintenance therapies, including Study 19, SOLO2/ ENGOT-OV21 (olaparib), NOVA/ENGOT-OV16 (niraparib) and ARIEL3 (rucaparib). Across trials, PFS was improved with PARP inhibitor maintenance treatment versus placebo in patients with a BRCA mutation. However, evidence from some of the trials shows that a wider group of patients can benefit from PARP inhibitor maintenance treatment including those with or without homologous recombination deficient tumours. The safety profile for olaparib, niraparib and rucaparib was generally similar across trials with haematological and gastrointestinal adverse events and fatigue/asthenia being the most common. As evidenced by the significant improvements in PFS and manageable safety profiles in these trials, PARP inhibitors represent a new standard of care for recurrent ovarian cancer following platinum-based chemotherapy and delay the need for further chemotherapy

Supplemental Release Limits for the Directed Reuse of Steel in Road Barriers and Lead in Shielding Products by the Department of Energy

The DOE National Center of Excellence for Metals Recycle (NMR) proposes to define and implement a complex-wide directed reuse strategy for surplus radiologically impacted lead (Pb) and steel as part of the U.S. Department of Energy's commitment to the safe and cost-effective recycle or reuse of excess materials and equipment across the DOE complex. NMR will, under this proposal, act on behalf of the DOE Office of Environmental Management, Office of Technical Program Integration (specifically EM-22), as the Department's clearinghouse for DOE surplus lead, steel and products created from these materials by developing and maintaining a cost-effective commercially-based contaminated lead and steel recycle program. It is NMR's intention, through this directed reuse strategy, to mitigate the adverse environmental and economic consequences of managing surplus lead and steel as a waste within the complex. This approach promotes the safe and cost-effective reuse of scrap metals in support of the Department's goals of resource utilization, energy conservation, pollution prevention and waste minimization. This report discusses recommendations for supplemental radiological release limits for the directed reuse of contaminated lead and steel by the DOE within the nuclear industry. The limits were originally selected from the American National Standards Institute and Health Physics Society standard N13.12 titled ''Surface and Volume Radioactivity Standards for Clearance'' (Health Physics Society, 1999) but were subsequently modified as a result of application-specific issues. Both the health and measurement implications from the adoption and use of the limits for directed reuse scenarios are discussed within this report

Occupational therapy for people with psychotic conditions in community settings: a pilot randomized controlled trial

OBJECTIVES: To investigate the effectiveness of a long established intervention, occupational therapy for people with psychotic conditions, and to inform future research designs. DESIGN: A pilot randomized controlled trial. SETTING: Two community mental health teams in a UK city. PARTICIPANTS: Forty-four adults with schizophrenia or other psychotic conditions, and functional problems. INTERVENTIONS: Twelve months of individualized occupational therapy in community settings, as an adjunct to usual care and compared to treatment as usual. A two to one randomization ratio was used in favour of occupational therapy. OUTCOME MEASURES: Social Functioning Scale, Scale for the Assessment of Negative Symptoms and employment. RESULTS: Both groups' scores on Social Functioning Scale and Scale for the Assessment of Negative Symptoms showed significant improvement over 12 months. The Social Functioning Scale overall mean difference for occupational therapy was 2.33, P=0.020 and for treatment as usual was 6.17, P=0.023. The Scale for the Assessment of Negative Symptoms total mean difference for occupational therapy was -16.25, P<0.001 and for treatment as usual was -17.36, P= 0.011. There were no differences between the two groups on any of the outcome measures. After 12 months the occupational therapy group showed clinically significant improvements that were not apparent in the control group. These were in four subscales of the Social Functioning Scale: relationships, independence performance, independence competence and recreation. Out of 30 people receiving occupational therapy those with a clinical level of negative symptoms reduced from 18 (64%) to 13 (46%), P=0.055. CONCLUSION: This pilot study suggested that individualized occupatio

Can transplanting enhance mobile marine invertebrates in ecologically engineered rock pools?

© 2018 Elsevier Ltd The field of eco-engineering has burgeoned in recent years in response to the proliferation of artificial structures. Adding water-retaining features to seawalls has been successful in increasing biodiversity relative to the surrounding structure. Artificial rock pools may not, however, completely mimic natural rock pools. Here, we compared natural colonisation, through dispersal and recruitment, of intertidal mobile species to water-retaining flowerpots on seawalls with that into rock pools. This represents the more usual ‘passive’ approach to eco-engineering where features are built to enhance biodiversity and are allowed to colonise naturally, as opposed to seeding or transplanting organisms to features. While flowerpots supported some mobile species not found on the seawall, other species common on natural shores did not recruit to flowerpots. Thus, in a second experiment we tested the effectiveness of an ‘active’ approach through transplanting mobile organisms to flowerpots to expedite the colonisation process. For the species examined, however, most individuals did not stay in the flowerpots for more than 24 h after being transplanted. Further understanding of the processes (e.g. dispersal distances, recruitment) influencing colonisation of eco-engineered habitats is needed to effectively inform management of marine infrastructure, particularly for projects targeted at restoration rather than enhancement

Theoretical analysis of the mechanisms of a gender differentiation in the propensity for orthostatic intolerance after spaceflight

<p>Abstract</p> <p>Background</p> <p>A tendency to develop reentry orthostasis after a prolonged exposure to microgravity is a common problem among astronauts. The problem is 5 times more prevalent in female astronauts as compared to their male counterparts. The mechanisms responsible for this gender differentiation are poorly understood despite many detailed and complex investigations directed toward an analysis of the physiologic control systems involved.</p> <p>Methods</p> <p>In this study, a series of computer simulation studies using a mathematical model of cardiovascular functioning were performed to examine the proposed hypothesis that this phenomenon could be explained by basic physical forces acting through the simple common anatomic differences between men and women. In the computer simulations, the circulatory components and hydrostatic gradients of the model were allowed to adapt to the physical constraints of microgravity. After a simulated period of one month, the model was returned to the conditions of earth's gravity and the standard postflight tilt test protocol was performed while the model output depicting the typical vital signs was monitored.</p> <p>Conclusions</p> <p>The analysis demonstrated that a 15% lowering of the longitudinal center of gravity in the anatomic structure of the model was all that was necessary to prevent the physiologic compensatory mechanisms from overcoming the propensity for reentry orthostasis leading to syncope.</p

An Exercise in Reverse Engineering for Safety-Critical Systems: An Experience for the Classroom

Since the Y2K crisis, reverse engineering has become a major area of work in industrial software application development, but lacks emphasis in US academia. This issue is exemplified by the high demand for software systems in new and expanding software application areas, which has resulted in systems being implemented before the requirements and design phases have been completed. Towards the maintenance of such systems, it is necessary to conducted reverse engineering for the derivation of software documentation for requirements and high-level and low-level design. When this scenario exists in the domain of safety-critical system, particularly in the aviation industry, reverse engineering takes on greater value because such software systems have to undergo development regulations and certification restrictions. This work reports on the pedagogical revelations gained from conducting reverse engineering on a software system that was developed and deployed for use in managing the assignment of commercial aircrafts to airport terminal gates. The software system incorporated genetic algorithms solutions and was implemented on a high-speed multi-processor system. The reverse engineering methodology applied was based on the RTCA DO-178C Software Considerations in Airborne Systems and Equipment Certification specification for onboard avionic software systems

The role of bisphosphonates in breast cancer: The present and future role of bisphosphonates in the management of patients with breast cancer

At least 25% of patients with breast cancer develop skeletal metastases, with bone the site of disease producing the greatest morbidity. It is apparent that the bisphosphonates present an important component of the treatment strategy. They are now the treatment of choice in tumour-induced hypercalcaemia, and they can reduce bone pain and skeletal complications such as pathological fractures. In addition, bisphosphonates are being increasingly evaluated in the prevention of bone metastases and to prevent and treat cancer therapy-induced osteoporosis. Ongoing research is aimed at trying to define the optimum route, dose, schedule and type of bisphosphonate

Current management of treatment-induced bone loss in women with breast cancer treated in the United Kingdom

New therapeutic options in breast cancer have improved survival but consequently increase the relevance of late complications. Ovarian suppression/ablation and aromatase inhibitors (AI) in the adjuvant setting have improved outcome, but have clinically important adverse effects on bone health. However, investigation and management of cancer treatment-induced bone loss (CTIBL) is poorly defined with no national guidance. In 2004, a questionnaire was sent to over 500 breast surgeons and oncologists who treat breast cancer within the United Kingdom. The questionnaire evaluated access to bone densitometry and specialist expertise as well as attitudes to investigation of CTIBL and anticipated changes in the use of AI for postmenopausal early breast cancer. A total of 354 completed questionnaires were received, 47 from clinicians not currently treating breast cancer. Of the 307 evaluable questionnaires, 164 (53%) were from breast surgeons, 112 (36%) from clinical oncologists and 31 (10%) from medical oncologists. Although most respondents recognised that CTIBL was the responsibility of the treating breast team, investigations for CTIBL are limited even though most had adequate access to bone densitometry; 98 (32%) had not requested a DXA scan in the last 6 months and 224 (73%) had requested fewer than five scans. In all, 235 (76%) were not routinely investigating patients on AI for bone loss. A total of 277 (90%) felt that their practice would benefit from national guidelines to manage these patients, and the majority (59%) had little or no confidence in interpreting DXA results and advising on treatment. This questionnaire has highlighted clear deficiencies in management of CTIBL in early breast cancer. The development of national guidelines for the management of these patients and educational initiatives for breast teams are urgently required

Off-trial evaluation of bisphosphonates in patients with metastatic breast cancer

BACKGROUND: Bisphosphonate therapy has been readily accepted as standard of care for individuals with bone metastases from breast cancer. In this study we determined whether the proportion of patients experiencing a skeletal related event (SRE) in a clinical practice population was similar to that observed in phase III randomized controlled studies. METHODS: A retrospective chart review was conducted of 110 patients receiving intravenous bisphosphonates for advanced breast cancer. The proportion of patients experiencing at least one SRE after 12 months of therapy was determined. SRE included vertebral or non-vertebral fracture, cord compression, surgery and/or radiotherapy to bone. RESULTS: The proportion of patients who had an SRE was 30% (28 individuals) and the median time to first event was greater than 350 days. Non-vertebral events and radiotherapy were the most frequent type of SRE, while cord compression and hypercalcaemia were rare (1%). Most patients in the study had bone-only disease (58.2%) and most had multiple bone lesions. In the first 12 months the mean duration of exposure to intravenous bisphosphonates was 261 days and most patients remained on treatment until just before death (median 27 days). CONCLUSION: This study suggests that the rate of clinically relevant SREs is substantially lower than the event rate observed in phase III clinical trials. We attribute this lower rate to observational bias. In the clinical trial setting it is possible that over-detection of skeletal events occurs due to the utilisation of regular skeletal survey or radionucleotide bone scan, whereas these procedures are not routine in clinical practice. Phase IV observational studies need to be conducted to determine the true benefits of bisphosphonate therapy in order to implement rationale use of bisphosphonates

Molecular and clinical predictors of improvement in progression-free survival with maintenance PARP inhibitor therapy in women with platinum-sensitive, recurrent ovarian cancer: A meta-analysis

BACKGROUND: The authors performed a meta‐analysis to better quantify the benefit of maintenance poly(ADP‐ribose) polymerase inhibitor (PARPi) therapy to inform practice in platinum‐sensitive, recurrent, high‐grade ovarian cancer for patient subsets with the following characteristics: germline BRCA mutation (gBRCAm), somatic BRCA mutation (sBRCAm), wild‐type BRCA but homologous recombinant‐deficient (HRD), homologous recombinant‐proficient (HRP), and baseline clinical prognostic characteristics. METHODS: Randomized trials comparing a PARPi versus placebo as maintenance treatment were identified from electronic databases. Treatment estimates of progression‐free survival were pooled across trials using the inverse variance weighted method. RESULTS: Four trials included 972 patients who received a PARPi (olaparib, 31%; niraparib, 35%; or rucaparib, 34%) and 530 patients who received placebo. For patients who had germline BRCA1 mutation (gBRCAm1) (N = 471), the hazard ratio (HR) was 0.29 (95% CI, 0.23‐0.37); for those who had germline BRCA2 mutation (gBRCAm2) (N = 236), the HR was 0.26 (95% CI, 0.17‐0.39); and, for those who had sBRCAm (N = 123), the HR was 0.22 (95% CI, 0.12‐0.41). The treatment effect was similar between the gBRCAm and sBRCAm subsets (P = .48). In patients who had wild‐type BRCA HRD tumors (excluding sBRCAm; N = 309), the HR was 0.41 (95% CI, 0.31‐0.56); and, in those who had wild‐type BRCA HRP tumors (N = 346), the HR was 0.64 (95% CI, 0.49‐0.83). The relative treatment effect was greater for the BRCAm versus HRD (P = .03), BRCAm versus HRP (P < .00001), and HRD versus HRP (P < .00001) subsets. There was no difference in benefit based on age, response after recent chemotherapy, and prior bevacizumab. CONCLUSIONS: In platinum‐sensitive, recurrent, high‐grade ovarian cancer, maintenance PARPi improves progression‐free survival for all patient subsets. PARPi therapy has a similar magnitude of benefit for sBRCAm and gBRCAm. Although patients with BRCAm derive the greatest benefit, the absence of a BRCAm or HRD could not be used to exclude patients from maintenance PARPi therapy