Firwana, Belal

Tyrosine kinase inhibitors (TKI) are the initial treatment for majority of newly diagnosed patients with chronic myelogenous leukemia (CML) in chronic phase (CP) and are associated with marked improvement in hematological, cytogenetic, molecular response and survival rates compared with other therapies. In this review, we summarize the evidence of TKI efficacy for patients with newly diagnosed CP‐CML. Six trials at low risk of bias evaluating TKIs as an initial treatment in adults with newly diagnosed CP‐CML and enrolling 2,456 patients were included. Follow‐up times ranged from a median of 3 months to 5 years. Direct comparison showed statistically higher rates of major molecular response (MMR ≤ 0.1%IS) achievement with second‐generation TKIs at 12 months which was sustained throughout treatment period. Bayesian mixed‐treatment comparison (MTC) analysis demonstrated superiority of both nilotinib and dasatinib over imatinib in terms of efficacy. Nilotinib was associated with higher deeper molecular responses (MR4.5 ≤ 0.0032%IS) at 60 months than dasatinib but no difference in MMR. The differences between nilotinib and dasatinib are likely clinically trivial. Among TKIs, nilotinib was found to have the best survival profile. Both nilotinib and dasatinib are associated with significantly better MMR compared to imatinib that is sustained over 60 months. This analysis shows that new‐generation TKIs are not only showing faster response but also maintaining a more potent one through longer follow‐up period. It is important to note out that MTC is not a substitute for well‐conducted RCTs investigating direct comparisons.

Background Motor vehicle accidents associated with commercial driving are an important cause of occupational death and impact public safety. Objectives We summarise the evidence regarding the type, prevalence and impact of medical conditions discovered during health assessment of commercial drivers. Evidence review We conducted a systematic review of multiple electronic databases and made a manual search for relevant studies that enrolled commercial drivers in any country and reported the outcomes of health assessment carried out in the context of commercial driving through November 2012. Data were extracted by a pair of independent reviewers and synthesised using a metanarrative approach. Results We identified 32 studies of moderate methodological quality enrolling 151 644 commercial drivers (98% men). The prevalence of multiple health conditions was high (sleep disorders 19%, diabetes 33%, hypertension 23% and obesity 45%). Some conditions, such as sleep disorders and obesity, were linked to increased risk of crashes. Evidence on several other highly relevant medical conditions was lacking. Cost-effectiveness data were sparse. Conclusions Several medical conditions are highly prevalent in commercial drivers and can be associated with increased risk of crashes, thus providing a rationale for health assessment of commercial drivers.

Abstract Background There is growing attention towards increasing patient and service user engagement ( PSUE ) in biomedical and health services research. Existing variations in language and design inhibit reporting and indexing, which are crucial to comparative effectiveness in determining best practices. Objective This paper utilizes a systematic review and environmental scan to derive an evidence‐based framework for PSUE . Design A metanarrative systematic review and environmental scan/manual search using scientific databases and other search engines, along with feedback from a patient advisory group ( PAG ). Eligible sources English‐language studies, commentaries, grey literature and other sources (including systematic and non‐systematic reviews) pertaining to patient and public involvement in biomedical and health services research. Data extracted Study description (e.g. participant demographics, research setting) and design, if applicable; frameworks, conceptualizations or planning schemes for PSUE ‐related endeavours; and methods for PSUE initiation and gathering patients'/service users' input or contributions. Results Overall, 202 sources were included and met eligibility criteria; 41 of these presented some framework or conceptualization of PSUE . Sources were synthesized into a two‐part framework for PSUE: (i) integral PSUE components include patient and service user initiation, reciprocal relationships, colearning and re‐assessment and feedback, (ii) sources describe PSUE at several research stages, within three larger phases: preparatory, execution and translational. Discussion and Conclusions Efforts at developing a solid evidence base on PSUE are limited by the non‐standard and non‐empirical nature of much of the literature. Our proposed two‐part framework provides a standard structure and language for reporting and indexing to support comparative effectiveness and optimize PSUE .

AbstractAimsPioglitazone, a thiazolidinedione, was approved for treatment of Type 2 diabetes. However, several observational studies suggest an association of pioglitazone with an increased risk of bladder cancer in patients with diabetes. Therefore, we sought to perform a systematic review and meta‐analysis to evaluate the magnitude of this association and the quality of the supporting evidence.MethodsElectronic databases were queried to identify controlled studies of pioglitazone that measured the risk of bladder cancer.ResultsSix studies involving 215 142 patients using pioglitazone were included, with a median period of follow‐up of 44 months. The hazard of developing bladder cancer was significantly higher in patients using pioglitazone (hazard ratio 1.23; 95% CI 1.09–1.39; I2 = 0%) compared with control groups. The risk of bias was moderate across the six studies. Considering an incidence rate of 20.8 per 100 000 person years, the number needed to harm was five additional cases of bladder cancer per 100 000 person years.ConclusionsPatients treated with pioglitazone have a slight increased risk of bladder cancer compared to general population. Patient involvement and weighing treatment benefits versus risks should be discussed with patient toward shared decision. Patients with type 2 diabetes with risk factors, such as family history, smoking, or exposure to certain forms of chemotherapy may need to consider other anti‐hyperglycemic agents. Also, pioglitazone should be discontinued in type 2 diabetes patients with newly diagnosed bladder cancer.

Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem-cell disorders, characterized phenotypically by the abnormal accumulation of mature-appearing myeloid cells. Polycythemia vera, essential thrombocythemia, primary myelofibrosis (also known as ‘ BCR-ABL1-negative’ MPNs), and chronic myeloid leukemia (CML) are the primary types of MPNs. After the discovery of the BCR-ABL1 fusion protein in CML, several oncogenic tyrosine kinases have been identified in ‘ BCR-ABL1-negative’ MPNs, most importantly, JAK2V617F mutation. The similarity in the clinical characteristics of the BCR-ABL1-negative MPN patients along with the prevalence of the Janus kinase mutation in this patient population provided a strong rationale for the development of a new class of pharmacologic inhibitors that target this pathway. The first of its class, ruxolitinib, has now been approved by the food and drug administration (FDA) for the management of patients with intermediate- to high-risk myelofibrosis. Ruxolitinib provides significant and sustained improvements in spleen related and constitutional symptoms secondary to the disease. Although noncurative, ruxolitinib represents a milestone in the treatment of myelofibrosis patients. Other types of JAK2 inhibitors are being tested in various clinical trials at this point and may provide better efficacy data and safety profile than its predecessor. In this article, we comprehensively reviewed and summarized the available preclinical and clinical trials pertaining to JAK inhibitors.