Tyrosine kinase inhibitors as a first-line treatment in patients with newly diagnosed chronic myeloid leukemia in chronic phase: A mixed-treatment comparison.

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 (MR(4.5) ≤ 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.

A systematic review and meta-analysis of tests to predict wound healing in diabetic foot.

BACKGROUND: This systematic review summarized the evidence on noninvasive screening tests for the prediction of wound healing and the risk of amputation in diabetic foot ulcers. METHODS: We searched MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE, Embase, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, and Scopus from database inception to October 2011. We pooled sensitivity, specificity, and diagnostic odds ratio (DOR) and compared test performance. RESULTS: Thirty-seven studies met the inclusion criteria. Eight tests were used to predict wound healing in this setting, including ankle-brachial index (ABI), ankle peak systolic velocity, transcutaneous oxygen measurement (TcPo2), toe-brachial index, toe systolic blood pressure, microvascular oxygen saturation, skin perfusion pressure, and hyperspectral imaging. For the TcPo2 test, the pooled DOR was 15.81 (95% confidence interval [CI], 3.36-74.45) for wound healing and 4.14 (95% CI, 2.98-5.76) for the risk of amputation. ABI was also predictive but to a lesser degree of the risk of amputations (DOR, 2.89; 95% CI, 1.65-5.05) but not of wound healing (DOR, 1.02; 95% CI, 0.40-2.64). It was not feasible to perform meta-analysis comparing the remaining tests. The overall quality of evidence was limited by the risk of bias and imprecision (wide CIs due to small sample size). CONCLUSIONS: Several tests may predict wound healing in the setting of diabetic foot ulcer; however, most of the available evidence evaluates only TcPo2 and ABI. The overall quality of the evidence is low, and further research is needed to provide higher quality comparative effectiveness evidence.

A systematic review and meta-analysis of glycemic control for the prevention of diabetic foot syndrome.

OBJECTIVE: The objective of this review was to synthesize the available randomized controlled trials (RCTs) estimating the relative efficacy and safety of intensive vs less intensive glycemic control in preventing diabetic foot syndrome. METHODS: We used the umbrella design (systematic review of systematic reviews) to identify eligible RCTs. Two reviewers determined RCT eligibility and extracted descriptive, methodologic, and diabetic foot outcome data. Random-effects meta-analysis was used to pool outcome data across studies, and the I(2) statistic was used to quantify heterogeneity. RESULTS: Nine RCTs enrolling 10,897 patients with type 2 diabetes were included and deemed to be at moderate risk of bias. Compared with less intensive glycemic control, intensive control (hemoglobin A1c, 6%-7.5%) was associated with a significant decrease in risk of amputation (relative risk [RR], 0.65; 95% confidence interval [CI], 0.45-0.94; I(2) = 0%). Intensive control was significantly associated with slower decline in sensory vibration threshold (mean difference, -8.27; 95% CI, -9.75 to -6.79). There was no effect on other neuropathic changes (RR, 0.89; 95% CI, 0.75-1.05; I(2) = 32%) or ischemic changes (RR, 0.92; 95% CI, 0.67-1.26; I(2) = 0%). The quality of evidence is likely moderate. CONCLUSIONS: Compared with less intensive glycemic control therapy, intensive control may decrease the risk of amputation in patients with diabetic foot syndrome. The reported risk reduction is likely overestimated because the trials were open and the decision to proceed with amputation could be influenced by glycemic control.

A systematic review and meta-analysis of débridement methods for chronic diabetic foot ulcers.

BACKGROUND: Several methods of débridement of diabetic foot ulcers are currently used. The relative efficacy of these methods is not well established. METHODS: This systematic review and meta-analysis was conducted to find the best available evidence for the effect of débridement on diabetic foot wound outcomes. We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Web of Science, and Scopus through October 2011 for randomized controlled studies (RCTs) and observational comparative studies. RESULTS: We identified 11 RCTs and three nonrandomized studies reporting on 800 patients. The risk of bias was moderate overall. Meta-analysis of three RCTs showed that autolytic débridement significantly increased the healing rate (relative risk [RR], 1.89; 95% confidence interval [CI] 1.35-2.64). Meta-analysis of four studies (one RCT) showed that larval débridement reduced amputation (RR, 0.43; 95% CI, 0.21-0.88) but did not increase complete healing (RR, 1.27; 95% CI, 0.84-1.91). Surgical débridement was associated with shorter healing time compared with conventional wound care (one RCT). Insufficient evidence was found for comparisons between autolytic and larval débridement (one RCT), between ultrasound-guided and surgical débridement, and between hydrosurgical and surgical débridement. CONCLUSIONS: The available literature supports the efficacy of several débridement methods, including surgical, autolytic, and larval débridement. Comparative effectiveness evidence between these methods and supportive evidence for other methods is of low quality due to methodologic limitations and imprecision. Hence, the choice of débridement method at the present time should be based on the available expertise, patient preferences, the clinical context and cost.

A systematic review and meta-analysis of off-loading methods for diabetic foot ulcers.

BACKGROUND: Increased plantar foot pressure is one of several key factors that lead to diabetic foot ulcers. Multiple methods have been proposed to relieve this pressure and thus enhance wound healing and potentially prevent relapse. We aimed in this systematic review to find the best available evidence for off-loading methods. METHODS: We searched MEDLINE, Embase, Cochrane CENTRAL, Web of Science, and Scopus through October 2011. Pairs of independent reviewers selected studies and extracted data. Predefined outcomes of interest included complete wound healing, time to complete wound healing, amputation, infection, and relapse rates. RESULTS: We identified 19 interventional studies, of which 13 were randomized controlled trials, including data from 1605 patients with diabetic foot ulcers using an off-loading method. The risk of bias in the included studies was moderate. This analysis demonstrated improved wound healing with total contact casting over removable cast walker, therapeutic shoes, and conventional therapy. There was no advantage of irremovable cast walkers over total contact casting. There was improved healing with half-shoe compared with conventional wound care. Therapeutic shoes and insoles reduced relapse rate in comparison with regular footwear. Data were sparse regarding other off-loading methods. CONCLUSIONS: Although based on low-quality evidence (ie, evidence warranting lower certainty), benefits are demonstrated for use of total contact casting and irremovable cast walkers in the treatment of diabetic foot ulcers. Reduced relapse rate is demonstrated with various therapeutic shoes and insoles in comparison with regular footwear.

A systematic review and meta-analysis of adjunctive therapies in diabetic foot ulcers.

BACKGROUND: Multiple adjunctive therapies have been proposed to accelerate wound healing in patients with diabetes and foot ulcers. The aim of this systematic review is to summarize the best available evidence supporting the use of hyperbaric oxygen therapy (HBOT), arterial pump devices, and pharmacologic agents (pentoxifylline, cilostazol, and iloprost) in this setting. METHODS: We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Web of Science, and Scopus through October 2011. Pairs of independent reviewers selected studies and extracted data. Predefined outcomes of interest were complete wound healing and amputation. RESULTS: We identified 18 interventional studies; of which 9 were randomized, enrolling 1526 patients. The risk of bias in the included studies was moderate. In multiple randomized trials, the addition of HBOT to conventional therapy (wound care and offloading) was associated with increased healing rate (Peto odds ratio, 14.25; 95% confidence interval, 7.08-28.68) and reduced major amputation rate (odds ratio, 0.30; 95% confidence interval, 0.10-0.89), compared with conventional therapy alone. In one small trial, arterial pump devices had a favorable effect on complete healing compared with HBOT and in another small trial compared with placebo devices. Neither iloprost nor pentoxifylline had a significant effect on amputation rate compared with conventional therapy. No comparative studies were identified for cilostazol in diabetic foot ulcers. CONCLUSIONS: There is low- to moderate-quality evidence supporting the use of HBOT as an adjunctive therapy to enhance diabetic foot ulcer healing and potentially prevent amputation. However, there are only sparse data regarding the efficacy of arterial pump devices and pharmacologic interventions.

Patient and service user engagement in research: a systematic review and synthesized framework.

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.

Patient engagement in research: a systematic review.

BACKGROUND: A compelling ethical rationale supports patient engagement in healthcare research. It is also assumed that patient engagement will lead to research findings that are more pertinent to patients' concerns and dilemmas. However; it is unclear how to best conduct this process. In this systematic review we aimed to answer 4 key questions: what are the best ways to identify patient representatives? How to engage them in designing and conducting research? What are the observed benefits of patient engagement? What are the harms and barriers of patient engagement? METHODS: We searched MEDLINE, EMBASE, PsycInfo, Cochrane, EBSCO, CINAHL, SCOPUS, Web of Science, Business Search Premier, Academic Search Premier and Google Scholar. Included studies were published in English, of any size or design that described engaging patients or their surrogates in research design. We conducted an environmental scan of the grey literature and consulted with experts and patients. Data were analyzed using a non-quantitative, meta-narrative approach. RESULTS: We included 142 studies that described a spectrum of engagement. In general, engagement was feasible in most settings and most commonly done in the beginning of research (agenda setting and protocol development) and less commonly during the execution and translation of research. We found no comparative analytic studies to recommend a particular method. Patient engagement increased study enrollment rates and aided researchers in securing funding, designing study protocols and choosing relevant outcomes. The most commonly cited challenges were related to logistics (extra time and funding needed for engagement) and to an overarching worry of a tokenistic engagement. CONCLUSIONS: Patient engagement in healthcare research is likely feasible in many settings. However, this engagement comes at a cost and can become tokenistic. Research dedicated to identifying the best methods to achieve engagement is lacking and clearly needed.

Accuracy of urea breath test in Helicobacter pylori infection: meta-analysis.

AIM: To quantitatively summarize and appraise the available evidence of urea breath test (UBT) use to diagnose Helicobacter pylori (H. pylori) infection in patients with dyspepsia and provide pooled diagnostic accuracy measures. METHODS: We searched MEDLINE, EMBASE, Cochrane library and other databases for studies addressing the value of UBT in the diagnosis of H. pylori infection. We included cross-sectional studies that evaluated the diagnostic accuracy of UBT in adult patients with dyspeptic symptoms. Risk of bias was assessed using QUADAS (Quality Assessment of Diagnostic Accuracy Studies)-2 tool. Diagnostic accuracy measures were pooled using the random-effects model. Subgroup analysis was conducted by UBT type (13C vs 14C) and by measurement technique (Infrared spectrometry vs Isotope Ratio Mass Spectrometry). RESULTS: Out of 1380 studies identified, only 23 met the eligibility criteria. Fourteen studies (61%) evaluated 13C UBT and 9 studies (39%) evaluated 14C UBT. There was significant variation in the type of reference standard tests used across studies.Pooled sensitivity was 0.96 (95%CI: 0.95-0.97) andpooled specificity was 0.93 (95%CI: 0.91-0.94). Likelihood ratio for a positive test was 12 and for a negative test was 0.05 with an area under thecurve of 0.985. Meta-analyses were associated with a significant statistical heterogeneity that remained unexplained after subgroup analysis. The included studies had a moderate risk of bias. CONCLUSION: UBT has high diagnostic accuracy for detecting H. pylori infection in patients with dyspepsia. The reliability of diagnostic meta-analytic estimates however is limited by significant heterogeneity.

Open versus endovascular stent graft repair of abdominal aortic aneurysms: do we need more randomized clinical trials?

We performed an analysis to assess the need for conducting additional randomized controlled trials (RCTs) comparing open and endovascular aneurysm repair (EVAR) for abdominal aortic aneurysm (AAA). Trial sequential analysis (TSA) is a statistical methodology that can calculate the required information size of a meta-analysis and assess the risk of random errors similar to interim analysis in a single optimally powered trial. It helps to decide whether we have obtained sufficient evidence or whether further RCTs are required. For short-term mortality reintervention rates, TSA showed firm evidence that there would be no extra benefit in conducting more RCTs to detect the effectiveness of EVAR versus open repair. For long-term mortality, TSA revealed either inconclusive evidence to support or refute endovascular or open repair; so, further RCTs should be performed to investigate long-term, all-cause mortality after AAA repair.

Trastuzumab for Her2/neu-positive metastatic salivary gland carcinoma: Case report and review of the literature.

Salivary gland carcinomas metastasize to distant organs in 20% of salivary gland malignancies. Applying immunohistochemistry (IHC) measures, salivary gland tumors showed a wide range of oncogene markers expression, including the human epidermoid receptor 2 (Her2/neu), which could be targeted with monoclonal antibody. Treating salivary gland tumors, which have Her2/neu over-expression, with trastuzumab was reported in a few case reports. We report a 61-year-old Caucasian male, with a history of salivary gland tumor, who presented after 20 years of complete surgical resection with kidney mass. He was treated as primary renal cell carcinoma, unclassified, with nephrectomy and adjuvant clinical trail where he received placebo. Subsequently, he developed multiple hepatic lesions and retroperitoneal mesenteric lymphadenopathy; CT-guided biopsy revealed adenocarcinoma with Her2/neu, 3+ by IHC. The patient was treated successfully with trastuzumab with near-complete response.

Tumor lysis syndrome: a systematic review of case series and case reports.

Tumor lysis syndrome (TLS) is a clinical condition that is caused by a massive lysis of tumor cells that accumulate very rapidly and disturb hemodynamics. This oncologic emergency requires immediate intervention. Tumor lysis syndrome was first described in the 19th century. Since then, it has become a well-known disease with improved management measures. Tumor lysis syndrome can occur after any type of neoplasm. It is highly associated with rapidly proliferating tumors compared with those that are well demarcated, such as acute lymphoblastic leukemia and high-grade non-Hodgkin lymphoma. Initiation of chemotherapy, radiotherapy, or steroid treatment may trigger TLS, or it may develop spontaneously. The release of massive quantities of intracellular contents may produce hyperkalemia, hyperphosphatemia, secondary hypocalcemia, hyperuricemia, and acute renal failure. Prevention and treatment measures include intravenous hydration, use of allopurinol and rasburicase, management of TLS-associated electrolyte abnormalities, and renal replacement therapy; the use of urine alkalinization remains controversial. In this article, we summarize the findings of case series and case reports published over the past 6 years in an effort to help familiarize clinicians better recognize and manage TLS.

Undergraduate medical students' perceptions, attitudes, and competencies in evidence-based medicine (EBM), and their understanding of EBM reality in Syria.

BACKGROUND: Teaching evidence-based medicine (EBM) should be evaluated and guided by evidence of its own effectiveness. However, no data are available on adoption of EBM by Syrian undergraduate, postgraduate, or practicing physicians. In fact, the teaching of EBM in Syria is not yet a part of undergraduate medical curricula. The authors evaluated education of evidence-based medicine through a two-day intensive training course. METHODS: The authors evaluated education of evidence-based medicine through a two-day intensive training course that took place in 2011. The course included didactic lectures as well as interactive hands-on workshops on all topics of EBM. A comprehensive questionnaire, that included the Berlin questionnaire, was used to inspect medical students' awareness of, attitudes toward, and competencies' in EBM. RESULTS: According to students, problems facing proper EBM practice in Syria were the absence of the following: an EBM teaching module in medical school curriculum (94%), role models among professors and instructors (92%), a librarian (70%), institutional subscription to medical journals (94%), and sufficient IT hardware (58%). After the course, there was a statistically significant increase in medical students' perceived ability to go through steps of EBM, namely: formulating PICO questions (56.9%), searching for evidence (39.8%), appraising the evidence (27.3%), understanding statistics (48%), and applying evidence at point of care (34.1%). However, mean increase in Berlin scores after the course was 2.68, a non-statistically significant increase of 17.86%. CONCLUSION: The road to a better EBM reality in Syria starts with teaching EBM in medical school and developing the proper environment to facilitate transforming current medical education and practice to an evidence-based standard in Syria.

Nephrotic syndrome after treatment of Crohn's disease with mesalamine: Case report and literature review.

Inflammatory bowel disease and its various treatments may affect the kidney in several ways. Recently, case reports have been published documenting the development of nephrotic syndrome after the treatment for inflammatory bowel disease with 5-aminosalicylic acid derivatives. We report a 50-year-old patient who was diagnosed with Crohn's disease and was treated with mesalamine. The patient subsequently developed nephrotic syndrome and a renal biopsy showed minimal change disease. He was treated with losartan and rosuvastatin and showed improvement in his renal function and serum cholesterol level. This is the first reported case in Crohn's disease although there have been six previous case reports of nephrotic syndrome following salicylic acid derivatives for ulcerative colitis.

Tissue plasminogen activator versus heparin for locking dialysis catheters: A systematic review.

BACKGROUND AND OBJECTIVES: Hemodialysis catheters are commonly used when renal replacement therapy is initiated. These catheters have significant complications. Among "locking" solutions used in an attempt to decrease these complications is recombinant tissue plasminogen activator (rt-PA). This systematic review is to determine the efficacy of rt-PA versus heparin, the standard of care. MATERIALS AND METHODS: A systematic review of randomized controlled trials studying rt-PA alone or rt-PA plus heparin versus heparin alone as locking agents for hemodialysis catheters, which included patients needed a temporary hemodialysis catheter for hemodialysis. We identified relevant trials through electronic databases and correspondence with experts. Two investigators independently reviewed potentially eligible trials and extracted data. RESULTS: Three trials met the inclusion criteria. One trial reported an improved catheter malfunctioning in patients using rt-PA plus heparin to lock catheters (20.0%) versus heparin alone (34.8%). Another trial reported higher blood flow rate in hemodialysis catheters in patients who received rt-PA (231.6 ± 12.4 mL/min) compared with those who received heparin (206.9 mL/min). The third trial reported formation and weight of clots which were decreased by half in rt-PA group versus heparin group. CONCLUSIONS: In the few randomized trials that met our inclusion criteria, the use of rt-PA as a locking solution for hemodialysis catheters seems to be associated with fewer adverse events and catheter malfunctioning as compared with heparin. Our systematic review is limited by the few randomized trials addressing our question and the wide variety of outcome measures. Further prospective randomized trials are needed to confirm this conclusion.