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This trial compared gefitinib, an inhibitor of the tyrosine kinase of epidermal growth factor (EGFR), with carboplatin plus paclitaxel as initial treatment of pulmonary adenocarcinoma in more than 1200 East Asian patients. The primary end point, progression-free survival, was significantly longer with gefitinib therapy among patients whose tumors carried an EGFR mutation and with carboplatin plus paclitaxel therapy among patients with mutation-negative tumors. In East Asian patients with pulmonary adenocarcinoma, progression-free survival was significantly longer with gefitinib therapy among patients whose tumors carried an EGFR mutation and with carboplatin plus paclitaxel therapy among patients with mutation-negative tumors. Inhibitors of the epidermal growth factor receptor (EGFR) tyrosine kinase have clinical efficacy, as compared with the best supportive care 1 or standard chemotherapy, 2 when given as second-line or third-line therapy for advanced non–small-cell lung cancer. Treatment with EGFR tyrosine kinase inhibitors is most effective in women, patients who have never smoked, patients with pulmonary adenocarcinomas, and patients of Asian origin. In these populations, such treatment is associated with favorable rates of objective responses, progression-free survival, and overall survival. 1 , 3 , 4 These populations also have a relatively high incidence of somatic mutations in the region of the EGFR gene that encodes . . .

Two phase II trials in patients with previously-treated advanced non-small-cell lung cancer suggested that gefitinib was efficacious and less toxic than was chemotherapy. We compared gefitinib with docetaxel in patients with locally advanced or metastatic non-small-cell lung cancer who had been pretreated with platinum-based chemotherapy. We undertook an open-label phase III study with recruitment between March 1, 2004, and Feb 17, 2006, at 149 centres in 24 countries. 1466 patients with pretreated (≥one platinum-based regimen) advanced non-small-cell lung cancer were randomly assigned with dynamic balancing to receive gefitinib (250 mg per day orally; n=733) or docetaxel (75 mg/m 2 intravenously in 1-h infusion every 3 weeks; n=733). The primary objective was to compare overall survival between the groups with co-primary analyses to assess non-inferiority in the overall per-protocol population and superiority in patients with high epidermal growth factor receptor (EGFR)-gene-copy number in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00076388. 1433 patients were analysed per protocol (723 in gefitinib group and 710 in docetaxel group). Non-inferiority of gefitinib compared with docetaxel was confirmed for overall survival (593 vs 576 events; hazard ratio [HR] 1·020, 96% CI 0·905–1·150, meeting the predefined non-inferiority criterion; median survival 7·6 vs 8·0 months). Superiority of gefitinib in patients with high EGFR-gene-copy number (85 vs 89 patients) was not proven (72 vs 71 events; HR 1·09, 95% CI 0·78–1·51; p=0·62; median survival 8·4 vs 7·5 months). In the gefitinib group, the most common adverse events were rash or acne (360 [49%] vs 73 [10%]) and diarrhoea (255 [35%] vs 177 [25%]); whereas in the docetaxel group, neutropenia (35 [5%] vs 514 [74%]), asthenic disorders (182 [25%] vs 334 [47%]), and alopecia (23 [3%] vs 254 [36%]) were most common. INTEREST established non-inferior survival of gefitinib compared with docetaxel, suggesting that gefitinib is a valid treatment for pretreated patients with advanced non-small-cell lung cancer. AstraZeneca.

[...] this analysis would exclude different numbers and types of patients from each group and would not be a balanced randomised comparison. Oral gefitinib indeed has a similar efficacy to intravenous docetaxel, but better tolerability and quality of life. [...] treating with gefitinib first could be advantageous in providing patients with the opportunity for improved tolerability and quality of life without compromising efficacy.

Neuroblastoma is a biologically diverse and clinically challenging tumour. At one end of the clinical spectrum, children with localised, low risk disease, can survive with little or no therapy. Spontaneous resolution of this tumour has been seen and children have survived despite residual macroscopic tumour remaining at the end of therapy. In contrast, the majority of children present with widespread metastatic disease and are rarely curable. Paradoxically this is an aggressive form of disease despite appearing sensitive to both chemotherapy and radiotherapy. The majority of these patients relapse and only 20% survive 2 years. This thesis is concerned only with the management of stage 4 patients and concentrates on 3 main areas. Firstly, the role of control of the primary tumour was considered, in this essentially systemic disease. It was shown that complete surgical resection of the primary reduces local relapse and improves survival. Prognostic factors for stage 4 patients were examined during this analysis and the identification of prognostic subgroups was possible. Secondly a retrospective analysis of all stage 4 patients treated within this centre was completed, to determine the usefulness of external beam radiotherapy in the palliation of advanced disease. The final part of this thesis is experimentally based. Factors that may improve the clinical effectiveness of 131I-meta-iodobenzylguanidine (131I-mIBG) were investigated. This molecule is a targeting agent, which, when administered systemically, is selectively accumulated by tumours of neural crest origin. In clinical practice the individual tumour uptake can be variable and the optimum timing of administration is still undetermined. Initially a new formulation of 131I-mIBG was investigated. This 'no carrier added' (nca) formulation meant that smaller quantities of drug could be administered and tumour specific accumulation increased. Before clinical studies could be contemplated, laboratory investigations had to be completed, to determine if this new preparation behaved similarly to the traditional formulation. The work documented in this thesis confirms this is the case. Another aim of this thesis was to examine biological factors that may modulate specific tumour accumulation of this agent. The effect of pre-dosing neuroblastoma cells in culture, with chemotherapy agents, resulted in a 2-5 fold increase in specific type 1 tumour accumulation. This may be a very significant finding for the future administration of 131I-mIBG in combination therapy regimens. Unfortunately the combination of elevated temperature and 131I-mIBG exposure resulted in decreased tumour accumulation of 131I-mIBG.

Neuroblastoma is a biologically diverse and clinically challenging tumour. At one end of the clinical spectrum, children with localised, low risk disease, can survive with little or no therapy. Spontaneous resolution of this tumour has been seen and children have survived despite residual macroscopic tumour remaining at the end of therapy. In contrast, the majority of children present with widespread metastatic disease and are rarely curable. Paradoxically this is an aggressive form of disease despite appearing sensitive to both chemotherapy and radiotherapy. The majority of these patients relapse and only 20% survive 2 years. This thesis is concerned only with the management of stage 4 patients and concentrates on 3 main areas. Firstly, the role of control of the primary tumour was considered, in this essentially systemic disease. It was shown that complete surgical resection of the primary reduces local relapse and improves survival. Prognostic factors for stage 4 patients were examined during this analysis and the identification of prognostic subgroups was possible. Secondly a retrospective analysis of all stage 4 patients treated within this centre was completed, to determine the usefulness of external beam radiotherapy in the palliation of advanced disease. The final part of this thesis is experimentally based. Factors that may improve the clinical effectiveness of 131I-meta-iodobenzylguanidine (131I-mIBG) were investigated. This molecule is a targeting agent, which, when administered systemically, is selectively accumulated by tumours of neural crest origin. In clinical practice the individual tumour uptake can be variable and the optimum timing of administration is still undetermined. Initially a new formulation of 131I-mIBG was investigated. This 'no carrier added' (nca) formulation meant that smaller quantities of drug could be administered and tumour specific accumulation increased. Before clinical studies could be contemplated, laboratory investigations had to be completed, to determine if this new preparation behaved similarly to the traditional formulation. The work documented in this thesis confirms this is the case. Another aim of this thesis was to examine biological factors that may modulate specific tumour accumulation of this agent. The effect of pre-dosing neuroblastoma cells in culture, with chemotherapy agents, resulted in a 2-5 fold increase in specific type 1 tumour accumulation. This may be a very significant finding for the future administration of 131I-mIBG in combination therapy regimens. Unfortunately the combination of elevated temperature and 131I-mIBG exposure resulted in decreased tumour accumulation of 131I-mIBG.

Guiding the beta-emitting isotope lutetium-177 to prostate cancer lesions with the prostate-specific membrane antigen–targeted radioligand 177 Lu-PSMA-617 plus using standard care was compared with standard care in patients with metastatic castration-resistant prostate cancer. The radioligand therapy prolonged progression-free and overall survival. Adverse effects were more common, but quality of life was maintained.

Background Given the increasing complexity of contemporary clinical practice, there has never been a more important time to provide interprofessional educational (IPE) activities across the learning continuum to develop collaborative practice. From the outset of health professional training, it is crucial that students not only develop their own professional skills but also gain an awareness of the capabilities of other healthcare professionals and how best to work collaboratively. Despite simulation being a common teaching modality in many undergraduate curricula, little is known about the range of interprofessional activities within these settings. Therefore, this study aims to address the following research question: What is known about undergraduate in-person (IP) simulation-based education (SBE)? Methods We conducted a scoping literature review, adhering to the PRISMA-ScR extension guidelines, and used the Arksey and O’Malley framework. Our search covered three electronic databases: Web of Science (WOS), MEDLINE, and Embase. We utilised Covidence systematic review software to assist in screening articles. To support data charting, we developed a data extraction tool and employed both qualitative and quantitative techniques through numerical and thematic analysis to ensure a comprehensive representation of our data. Results A total of 97 studies were included, with most publications originating from the USA, UK, and Australia. Two main themes emerged regarding the impact of IP SBE at an individual level: confidence and role identification. Several themes related to the impact on teams included knowledge of other professional roles/values, communication, and teamwork. The studies identified various barriers and enablers to simulation, particularly logistical barriers and financial challenges associated with complex technologically enabled simulation. Faculty collaboration and resources were reported as primary enablers in facilitating the delivery of simulation activities. Conclusions The impact of IP-SBE on learners and interprofessional teams is predominantly positive, with reported benefits including increased confidence, enhanced role identification, and improved communication and teamwork skills. However, challenges such as logistical barriers and resource constraints highlight the need for collaborative faculty efforts and adequate infrastructure to support IP-SBE implementation. Despite the growing interest in IP-SBE, there remains a notable lack of standardised reporting on simulation design and debriefing processes in both teaching practice and research.

Abstract Context Insulin resistance is common in women with polycystic ovary syndrome (PCOS). Inositol may have insulin sensitizing effects; however, its efficacy in the management of PCOS remains indeterminate. Objective To inform the 2023 international evidence-based guidelines in PCOS, this systematic review and meta-analysis evaluated the efficacy of inositol, alone or in combination with other therapies, in the management of PCOS. Data Sources Medline, PsycInfo, EMBASE, All EBM, and CINAHL from inception until August 2022. Study Selection Thirty trials (n = 2230; 1093 intervention, 1137 control), with 19 pooled in meta-analyses were included. Data Extraction Data were extracted for hormonal, metabolic, lipids, psychological, anthropometric, reproductive outcomes, and adverse effects by 1 reviewer, independently verified by a second. Data Synthesis Thirteen comparisons were assessed, with 3 in meta-analyses. Evidence suggests benefits for myo-inositol or D-chiro-inositol (DCI) for some metabolic measures and potential benefits from DCI for ovulation, but inositol may have no effect on other outcomes. Metformin may improve waist-hip ratio and hirsutism compared to inositol, but there is likely no difference for reproductive outcomes, and the evidence is very uncertain for body mass indexI. Myo-inositol likely causes fewer gastrointestinal adverse events compared with metformin; however, these are typically mild and self-limited. Conclusion The evidence supporting the use of inositol in the management of PCOS is limited and inconclusive. Clinicians and their patients should consider the uncertainty of the evidence together with individual values and preferences when engaging in shared decision-making regarding the use of inositol for PCOS.