Effect of sirolimus on malignancy and survival after kidney transplantation: systematic review and meta-analysis of individual patient data.

OBJECTIVE: To examine risk of malignancy and death in patients with kidney transplant who receive the immunosuppressive drug sirolimus. DESIGN: Systematic review and meta-analysis of individual patient data. DATA SOURCES: Medline, Embase, and the Cochrane Central Register of Controlled Trials from inception to March 2013. ELIGIBILITY: Randomized controlled trials comparing immunosuppressive regimens with and without sirolimus in recipients of kidney or combined pancreatic and renal transplant for which the author was willing to provide individual patient level data. Two reviewers independently screened titles/abstracts and full text reports of potentially eligible trials to identify studies for inclusion. All eligible trials reported data on malignancy or survival. RESULTS: The search yielded 2365 unique citations. Patient level data were available from 5876 patients from 21 randomized trials. Sirolimus was associated with a 40% reduction in the risk of malignancy (adjusted hazard ratio 0.60, 95% confidence interval 0.39 to 0.93) and a 56% reduction in the risk of non-melanoma skin cancer (0.44, 0.30 to 0.63) compared with controls. The most pronounced effect was seen in patients who converted to sirolimus from an established immunosuppressive regimen, resulting in a reduction in risk of malignancy (0.34, 0.28 to 0.41), non-melanoma skin cancer (0.32, 0.24 to 0.42), and other cancers (0.52, 0.38 to 0.69). Sirolimus was associated with an increased risk of death (1.43, 1.21 to 1.71) compared with controls. CONCLUSIONS: Sirolimus was associated with a reduction in the risk of malignancy and non-melanoma skin cancer in transplant recipients. The benefit was most pronounced in patients who converted from an established immunosuppressive regimen to sirolimus. Given the risk of mortality, however, the use of this drug does not seem warranted for most patients with kidney transplant. Further research is needed to determine if different populations, such as those at high risk of cancer, might benefit from sirolimus.

The effects of lysine analogs during pelvic surgery: a systematic review and meta-analysis.

Pelvic vasculature is complex and inconsistent while pelvic bones impede access to pelvic organs. These anatomical characteristics render pelvic surgery inherently difficult, and some of these procedures are frequently associated with blood loss that necessitates blood transfusion. The aim of this study was to review the literature on the use of lysine analogs to prevent bleeding and blood transfusion during pelvic surgery. The objective of this study was to assess the safety and efficacy of lysine analogs during pelvic surgery. A systematic literature search was performed using Medline, Cochrane Register of Clinical Trials, Embase, and the reference lists of relevant articles. Randomized controlled trials or observational cohort studies comparing a lysine analog to placebo or standard care were included. Outcomes collected were blood transfusion, blood loss, thromboembolic adverse events (myocardial infarction, stroke, deep vein thrombosis, and pulmonary embolism), nonthromboembolic adverse events, and death. There were no language limitations. Fifty-six articles reported on 68 comparisons between a lysine analog and an inactive comparator, involving a total of 7244 patients published between 1961 and 2013. Thirty-nine studies evaluated urologic procedures, and 21 evaluated gynecologic procedures. Thirty-six studies (60%) were published before 1980. Of the 43 randomized comparisons, only 30 (44%) had a score of 3 or higher on Jadad's 5-point scale of methodological quality. Among randomized trials, lysine analogs reduced the risk of blood transfusion (pooled odds ratio [OR], 0.47; 95% confidence interval [CI], 0.35-0.64) and blood loss (pooled OR, 0.22; 95% CI, 0.18-0.27). There was a small statistically insignificant increased risk of thromboembolic events (pooled OR, 1.07; 95% CI, 0.72-1.59) and no-thrombotic serious adverse events (pooled OR, 1.11; 95% CI, 0.67-1.83). In the 17 randomized trials published since the year 2000, only 6 thrombotic events were reported, 4 of which occurred in the placebo arm. Lysine analogs did not increase risk of death (pooled OR, 0.91; 95% CI, 0.34-2.48). These results are significant as they indicate that lysine analogs significantly reduce blood loss and blood transfusion during pelvic surgery. Although there does not appear to be a large increase in the risk of thromboembolic and nonthrombotic adverse events, more data are required to definitively assess these outcomes. Based on this review, lysine analogs during pelvic surgery seem to reduce bleeding and blood transfusion requirements. Although there does not seem to be a significant risk of adverse effects, larger studies would help clarify risks, if any, associated with lysine analog use.

Effectiveness and safety of thiotepa as conditioning treatment prior to stem cell transplant in patients with central nervous system lymphoma.

BACKGROUND: Thiothepa is a cytostatic agent used in managing solid malignancies, and also as conditioning treatment before hematopoietic stem cell transplantation [HSCT]. This systematic review summarizes evidence on its effectiveness and safety, in patients with central nervous system [CNS] lymphoma. METHODS: We searched 3 databases for clinical studies. When feasible, we performed meta-analyses. RESULTS: We identified 13 eligible studies, none of which with a priori controls. So data synthesis focused on the 226 patients who received thiotepa. Based on pooled estimates, 75.9% of thiotepa-treated patients achieved a complete remission (95% confidence interval [CI] = 67.5-82.8), and 61.7% had a progression-free survival for up to 125 months post-treatment (95% CI = 49.4-72.7). However, 25.5% relapsed, 24.6% experienced infection, and 13.2% experienced neurotoxicity. DISCUSSION: Thiotepa-based conditioning followed by HSCT may be effective in most CNS lymphoma patients, with a manageable toxicity profile. But adequately powered randomized trials are needed to better evaluate and isolate the effects of thiotepa.

Spot urine protein measurements in kidney transplantation: a systematic review of diagnostic accuracy.

BACKGROUND: Quantification of proteinuria (albuminuria) in renal transplant recipients is important for diagnostic and prognostic purposes. Recent guidelines have recommended quantification of proteinuria by spot protein-to-creatinine ratio (PCR) or spot albumin-to-creatinine ratio (ACR). Validity of spot measurements remains unclear in renal transplant recipients. METHODS: Systematic review of adult kidney transplant recipients. Studies that reported the diagnostic accuracy of PCR or ACR as compared with 24-h urine protein or albumin excretion in renal transplant recipients were included. RESULTS: The search identified 8 studies involving 1871 renal transplant recipients. The correlation of the PCR to 24-h protein ranged from 0.772 to 0.998 with a median value of 0.92. PCR sensitivity ranged from 63 to 99 (50% of sensitivities were >90%); PCR specificity varied from 73 to 99 (50% of specificities were >90%). Only one study reported the bias; percent bias ranged from 12 to 21% and accuracy (within 30% of 24 h urine protein) ranged from 47 to 56% depending on the degree of proteinuria. For the ACR, percent bias ranged from 9 to 21%, and the accuracy (within 30%) ranged from 38 to 80%. CONCLUSIONS: The data regarding diagnostic accuracy of PCR and ACR is limited. Only one report studied the absolute measures of agreement (bias and accuracy). We recommend verifying PCR and ACR measurements with a 24-h protein before making any major diagnostic (e.g. biopsy) or therapeutic (e.g. change in immunosuppressive agents) decisions in this population.

Accuracy of cystatin C-based estimates of glomerular filtration rate in kidney transplant recipients: a systematic review.

BACKGROUND: As with creatinine, cystatin C can be incorporated into a formula to estimate the glomerular filtration rate (GFR). The overall performance of cystatin C-based equations in kidney transplantation is unclear with conflicting results between studies. METHODS: Systematic review of adult kidney transplant recipients. Studies that reported mean bias (mean difference between the measured and estimated GFRs) or accuracy of the cystatin C-based GFR estimation equation (e.g. percentage of estimates within 30% of the measured GFR) against the measured GFR using renal or plasma clearance of contrast agents, radioisotopes or inulin were included. RESULTS: The search identified 10 studies that examined 14 different cystatin C-based estimating equations (n = 5 equations evaluated in more than one study). The Le Bricon equation had the best performance with a bias that ranged from -6.4 to +2.8 mL/min/1.73 m(2); 85% (95% CI, 82-88) of estimates were within 30% of the measured GFR. For the other equations, 66-82% of estimates were within 30% of the measured GFR. For the modification of diet in renal disease (MDRD) equation, 68% (95% CI, 65-72) of estimates were within 30% of the measured GFR. CONCLUSIONS: The cystatin C-based Le Bricon equation was the most accurate, and most of the cystatin C-based equations showed improvements in 30% and 50% accuracy compared with the creatinine-based MDRD equation. Cystatin C-based equations may offer an advantage over the MDRD equation in kidney transplant recipients. Estimating equations re-expressed with standardized cystatin C have been developed and their accuracy needs to be tested in the kidney transplant population.

HIV pre-exposure prophylaxis (PrEP)--a quantitative ethics appraisal.

BACKGROUND: There is now strong evidence that preventive oral antiretroviral therapy can moderately reduce likelihood of HIV infection. This concept is called HIV pre-exposure prophylaxis (PrEP). Premature closures of some previous PrEP clinical trials, secondary to ethical concerns, did not stop research. We aimed to appraise the extent of ethics considerations reporting in PrEP study documents. METHODS: We conducted a systematic quantitative ethics appraisal, grounded in PrEP literature and using eight principles proposed by Ezechiel Emanuel. We developed an a priori checklist of 101 evidence-based ethics items. We obtained protocols for eleven of nineteen clinical controlled studies identified. Two reviewers independently appraised study documents against the checklist. Ethics appraisal was synthesized using adjusted percentages of items reported. RESULTS: On average, 58% of the 101 ethics items were mentioned or addressed in documents, with variations noted both across studies and across principles. Considerations pertaining to social value were least reported (43% of checklist items, on average) whereas considerations related to informed consent and favorable risk-benefit ratio were most reported (75% of checklist items, on average). DISCUSSION: Some PrEP studies reportedly address more ethics considerations than others but, overall, ethics considerations reporting could be much improved. While this review does not allow us to comment on the actual execution of HIV PrEP trials, it is a reminder that optimism generated by potentially effective interventions should not overshadow the importance of ethics in research design and development. Improving ethics reporting might improve the perceived value of PrEP research and subsequent data.