Erlotinib or gefitinib for the treatment of relapsed platinum pretreated non-small cell lung cancer and ovarian cancer: a systematic review

BACKGROUND: Platinum-based chemotherapy is the standard of care for ovarian cancer and non-small cell lung cancer (NSCLC). However, resistance to platinum agents invariably develops. Targeted therapies, such as tyrosine kinase inhibitors (TKIs), have great potential here as they exert their anti-tumour effect via alternative mechanisms to platinum-based drugs and as such may remain unaffected by emergent resistance to platinum. METHODS: A systematic review was conducted to investigate whether two EGFR-TKIs, erlotinib and gefitinib, have efficacy in the platinum-resistance setting. Preclinical studies of platinum-resistant cancer cell lines, which had been subsequently treated with EGFR-TKIs, were sought to establish proof-of-concept. Clinical trials reporting administration of EGFR-TKIs to ovarian cancer and NSCLC patients relapsed after therapy with platinum drugs were investigated to determine sensitivity of these cohorts to EGFR-TKI treatment. The role of EGFR mutation, copy number and protein expression on response to EGFR-TKIs after failure of platinum chemotherapy were also investigated. RESULTS: Preclinical models of platinum-resistant cancer were found which display a spectrum of cross-resistance profiles to EGFR-TKIs. Sensitivity to EGFR-TKIs is dependent on the activation of the EGFR pathway or EGFR interacting proteins such as HER-2. EGFR-TKIs show favourable response rates in platinum-pretreated NSCLC, 11.14% and 15.25% for 150mg/day erlotinib and 250mg/day gefitinib, respectively. These response rates significantly improve in patients of Asian descent (28.3% and 29.17%, respectively) and patients with EGFR activation mutations (41.6% and 63.89%, respectively) or increased copy number (33.3% and 45.45%, respectively). Gefitinib significantly outperformed erlotinib and should therefore be the EGFR-TKI of choice in platinum-pretreated relapsed NSCLC. In contrast, response rates are very poor to both erlotinib and gefitinib in platinum pretreated ovarian cancer, 0-5.9% and they should not be used in this cohort of patients. Preclinical models demonstrate that, while cross resistance can occur between platinums and EGFR-TKIs, there is not a generalised cross-resistance phenotype. Erlotinib and gefitinib are suitable for the treatment of platinum-pretreated NSCLC, particularly in patients with EGFR mutations or increases in copy number. Unfortunately, the high rates of EGFR protein overexpression in ovarian cancer are not translating to a clinically useful therapeutic target for EGFR-TKIs; EGFR mutations are rare in ovarian cancer. Newer TKIs may improve response rates in these cohorts and future clinical trials need to collect tumour biopsies from all patients to ensure the success of personalised chemotherapy

The effects of problem-oriented policing on crime and disorder

Problem-oriented Policing (POP) was first introduced by Herman Goldstein in 1979. The approach was one of a series of responses to a crisis in effectiveness and legitimacy in policing that emerged in the 1970s and 1980s. Goldstein argued that police were not being effective in preventing and controlling crime because they had become too focused on the “means” of policing and had neglected the “goals” of preventing and controlling crime and other community problems. Goldstein argued that the unit of analysis in policing must become the “problem” rather than calls or crime incidents as was the case during that period. POP has had tremendous impact on American policing, and is now one of the most widely implemented policing strategies in the US. To synthesize the extant problem-oriented policing evaluation literature and assess the effects of problem-oriented policing on crime and disorder Eligible studies had to meet three criteria: (1) the SARA model was used for a problemoriented policing intervention; (2) a comparison group was included; (3) at least one crime or disorder outcome was reported with sufficient data to generate an effect size. The unit of analysis could be people or places. Several strategies were used to perform an exhaustive search for literature fitting the eligibility criteria. First, a keyword search was performed on an array of online abstract databases. Second, we reviewed the bibliographies of past reviews of problem-oriented policing. Third, we performed forward searches for works that have cited seminal problem-oriented policing studies. Fourth, we performed hand searches of leading journals in the field. Fifth, we searched the publications of several research and professional agencies. Sixth, after finishing the above searches we e-mailed the list of studies meeting our eligibility criteria to leading policing scholars knowledgeable in the area of problem-oriented policing to ensure we had not missed any relevant studies. For our ten eligible studies, we provide both a narrative review of effectiveness and a meta-analysis. For the meta-analysis, we coded all primary outcomes of the eligible studies and we report the mean effect size (for studies with more than one primary outcome, we averaged effects to create a mean), the largest effect, and the smallest effect. Because of the heterogeneity of our studies, we used a random effects model. Based on our meta-analysis, overall problem-oriented policing has a modest but statistically significant impact on reducing crime and disorder. Our results are consistent when examining both experimental and quasi-experimental studies. Conclusions: We conclude that problem-oriented policing is effective in reducing crime and disorder, although the effect is fairly modest. We urge caution in interpreting these results because of the small number of methodologically rigorous studies on POP and the diversity of problems and responses used in our eligible studies

Colored school children in New York /

Mode of access: Internet

A validation study of the Dutch version of the quality of life - Cancer survivor (QOL-CS) questionnaire in a group of prostate cancer survivors [Dataset]

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Discovering protein-protein interaction stabilisers by native mass spectrometry

Native mass spectrometry raw data. Native mass spectra acquired on Q-Exactive HF mass spectromete