Michela Cinquini

Speed of updating online evidence based point of care summaries: Prospective cohort analysis

Objective To evaluate the ability of international point of care information summaries to update evidence relevant to medical practice. Design Prospective cohort bibliometric analysis. Setting Top five point of care information summaries (Clinical Evidence, EBMGuidelines, eMedicine, Dynamed, UpToDate) ranked for coverage of medical conditions, editorial quality, and evidence based methodology. Main outcome measures From June 2009 to May 2010 we measured the incidence of research findings relating to potentially eligible newsworthy evidence. As samples, we chose systematic reviews rated as relevant by international research networks (such as, Evidence-Based Medicine, ACP Journal Club, and the Cochrane Collaboration). Every month we assessed whether each sampled review was cited in at least one chapter of the five summaries. The cumulative updating rate was analysed with Kaplan-Meier curves. Results From April to December 2009, 128 reviews were retrieved; 53% (68) from the literature surveillance journals and 47% (60) from the Cochrane Library. At nine months, Dynamed had cited 87% of the sampled reviews, while the other summaries had cited less than 50%. The updating speed of Dynamed clearly led the others. For instance, the hazard ratios for citations in EBM Guidelines and Clinical Evidence versus the top performer were 0.22 (95% confidence interval 0.17 to 0.29) and 0.03 (0.01 to 0.05). Conclusions Point of care information summaries include evidence relevant to practice at different speeds. A qualitative analysis of updating mechanisms is needed to determine whether greater speed corresponds to more appropriate incorporation of new information.

Risk/benefit profile of bevacizumab in metastatic colon cancer: A systematic review and meta-analysis

BACKGROUND Bevacizumab, an anti vascular endothelial growth factor antibody is licensed in several tumours and widely used in colorectal cancer. However, bevacizumab has several adverse effects which may appear unexpectedly and differ according to the tumour. AIMS The aim of this work is to quantify the overall risk of bevacizumab-related side effects in patients affected by advanced colorectal cancer and to compare them with its overall benefit. METHODS We performed a systematic review and meta-analysis investigating bevacizumab in metastatic colorectal cancer. Our primary endpoint was safety and secondary endpoints were overall survival and progression-free survival. The relative risks for side effects were calculated with their 95% confidence interval using the inverse of variance method. For statistically significant relative risks, number needed to harm were calculated. RESULTS We retrieved six out of 17 eligible papers encompassing 3385 patients. Only hypertension (relative risk 2.98 95% confidence interval 2.32-3.84), gastrointestinal perforations (relative risk 5.04 95% confidence interval 1.72-14.79) and bleeding (relative risk 2.07 95% confidence interval 1.19-3.62) were significantly increased. Bevacizumab significantly improved both overall survival (HR 0.80 95% confidence interval 0.71-0.91) and progression-free survival (hazard ratio (HR) 0.62 95% confidence interval 0.52-0.74). Number needed to treat for overall survival is 12, whilst number needed to harms ranges from 2 to 14.286. CONCLUSION These results show that the benefits of the treatment with bevacizumab outweigh the toxicity that may occur: enough to justify its use in advanced colorectal cancer.

Analysis of Gene Expression in Early-Stage Ovarian Cancer

Purpose: Gene expression profile was analyzed in 68 stage I and 15 borderline ovarian cancers to determine if different clinical features of stage I ovarian cancer such as histotype, grade, and survival are related to differential gene expression. Experimental Design: Tumors were obtained directly at surgery and immediately frozen in liquid nitrogen until analysis. Glass arrays containing 16,000 genes were used in a dual-color assay labeling protocol. Results: Unsupervised analysis identified eight major patient partitions, one of which was statistically associated to overall survival, grading, and histotype and another with grading and histotype. Supervised analysis allowed detection of gene profiles clearly associated to histotype or to degree of differentiation. No difference was found between borderline and grade 1 tumors. As to recurrence, a subset of genes able to differentiate relapsers from nonrelapsers was identified. Among these, cyclin E and minichromosome maintenance protein 5 were found particularly relevant, as their expression was inversely correlated to progression-free survival (P = 0.00033 and 0.017, respectively). Conclusions: Specific molecular signatures define different histotypes and prognosis of stage I ovarian cancer. Mucinous and clear cells histotypes can be distinguished from the others regardless of tumor grade. Cyclin E and minichromosome maintenance protein 5, whose expression was found previously to be related to a bad prognosis of advanced ovarian cancer, appear to be potential prognostic markers in stage I ovarian cancer too, independent of other pathologic and clinical variables.

Risk of infections using anti-TNF agents in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis: a systematic review and meta-analysis

ABSTRACT Introduction: Five anti-tumor necrosis factor (anti-TNF) agents have received regulatory approval for use in rheumatology: adalimumab, golimumab, infliximab, certolizumab, and etanercept. Apart from their well-documented therapeutic value, it is still uncertain to what extent they are associated with an increased risk of infectious adverse events. Areas covered: We conducted a systematic review and meta-analysis of published randomized studies to determine the effect of anti-TNF drugs on the occurrence of infectious adverse events (serious infections; tuberculosis; opportunistic infections; any infection). We searched Medline, Embase, and the Cochrane Library up to May 2014 to identify eligible studies in adult patients with rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis that evaluated anti-TNF drugs compared with placebo or no treatment. Expert opinion: Our study encompassed data from 71 randomized controlled trials involving 22,760 participants (range of follow-up: 1–36 months) and seven open label extension studies with 2,236 participants (range of follow-up: 6–48 months). Quantitative synthesis of the available data found statistically significant increases in the occurrence of any infections (20%), serious infections (40%), and tuberculosis (250%) associated with anti-TNF drug use, while the data for opportunistic infections were scarce. The quality of synthesized evidence was judged as moderate. Further evidence from registries and long-term epidemiological studies are needed to better define the relationship between anti-TNF agents and infection complications.

Is there evidence for different effects among EGFR-TKIs? Systematic review and meta-analysis of EGFR tyrosine kinase inhibitors (TKIs) versus chemotherapy as first-line treatment for patients harboring EGFR mutations

Three EGFR tyrosine kinase inhibitors have been compared to standard chemotherapy as up-front treatment in patients with advanced EGFR-positive NSCLC. We performed a systematic review and meta-analysis using indirect comparisons to estimate the risk/benefit associated with each drug. EGFR-TKIs fared better than chemotherapy in terms of PFS. The relative probability of overall response was gefitinib versus erlotinib 0.96 (95% CI 0.69-1.34), gefitinib versus afatinib 0.91 (95% CI 0.67-1.23), erlotinib versus afatinib 0.94 (95% CI 0.65-1.35). Indirect comparisons for safety showed the RR for diarrhea gefitinib versus erlotinib 0.80 (95% CI 0.63-1.01), gefitinib versus afatinib 0.29 (95% CI 0.20-0.41), erlotinib versus afatinib 0.36 (95% CI 0.25-0.54); for rash gefitinib versus erlotinib 1.00 (95% CI 0.82-1.22), gefitinib versus afatinib 0.41(95% CI 0.25-0.65), erlotinib versus afatinib 0.41 (95% CI 0.25-0.66); for hypertransaminasemia gefitinib versus erlotinib 2.29 (95% CI 1.63-3.23). Our analysis showed that all treatments had similar efficacy but they differ for toxicities.

The zinc finger gene ZIC2 has features of an oncogene and its overexpression correlates strongly with the clinical course of epithelial ovarian cancer.

Purpose: Epithelial ovarian tumors (EOT) are among the most lethal of malignancies in women. We have previously identified ZIC2 as expressed at a higher level in samples of a malignant form (MAL) of EOT than in samples of a form with low malignant potential (LMP). We have now investigated the role of ZIC2 in driving tumor growth and its association with clinical outcomes. Experimental Design: ZIC2 expression levels were analyzed in two independent tumor tissue collections of LMP and MAL. In vitro experiments aimed to test the role of ZIC2 as a transforming gene. Cox models were used to correlate ZIC2 expression with clinical endpoints. Results: ZIC2 expression was about 40-fold in terms of mRNA and about 17-fold in terms of protein in MAL (n = 193) versus LMP (n = 39) tumors. ZIC2 mRNA levels were high in MAL cell lines but undetectable in LMP cell lines. Overexpression of ZIC2 was localized to the nucleus. ZIC2 overexpression increases the growth rate and foci formation of NIH3T3 cells and stimulates anchorage-independent colony formation; downregulation of ZIC2 decreases the growth rate of MAL cell lines. Zinc finger domains 1 and 2 are required for transforming activity. In stage I MAL, ZIC2 expression was significantly associated with overall survival in both univariate (P = 0.046) and multivariate model (P = 0.049). Conclusions: ZIC2, a transcription factor related to the sonic hedgehog pathway, is a strong discriminant between MAL and LMP tumors: it may be a major determinant of outcome of EOTs. Clin Cancer Res; 18(16); 4313–24. ©2012 AACR.

Reply to Arterial Stiffness in Patients With Peripheral Arterial Disease

To the Editor: Many thanks to Balta and colleagues for the appreciation of our work “Increased Aortic Stiffness and Related Factors in Patients With Peripheral Arterial Disease” recently published in The Journal of Clinical Hypertension. However, we disagree on some remarks made by the same authors. We did not mention the effects of heart failure and inflammatory disease such as psoriasis on aortic stiffness. Neither of these conditions were included in our analysis because the patients did not present these symptoms at the time of enrollment in the study. In addition, it would be more interesting to conduct a study in patients without atherosclerosis disease, diabetes, or hypertension to clarify the relationship between alcohol intake and aortic stiffness. In the discussion, we mention the lack of relationship between the common risk factors (smoking and diabetes) and aortic pulse wave velocity (aPWV) illustrating the results (in Table 2) on the main determinants of aPWV (age, heart rate, blood pressure) leaving out, however, the lack of relationship between smoking (b=0.56, P=.31), dyslipidemia (b=0.82, P=.08), low-density lipoprotein (b=0.008, P=.19), cerebrovascular disease (b=2.87, P=.12), and aortic stiffness. These results are in agreement with the findings of a recent systematic review of the literature concerning aPWV and cardiovascular risk factors. In particular, Cecelja and Chowienczyk identified several studies with data relating aPWV to age, blood pressure, and a variable number of other cardiovascular risk factors, in which regression models were available. The results from this review demonstrate that only age and blood pressure are consistently related to aPWV. Other risk factors were no longer significant after adjusting for age and blood pressure, suggesting that the impact of traditional risk factors, other than BP, on aPWV is small or insignificant. Furthermore, atherosclerosis risk factors, per se, appear to play a minor role in aortic stiffening as highlighted by McEniery and colleagues. Finally, we report that the regression model could only predict a part of the variability of aPWV (R=11; 8%, P=.01) indicating that markers of inflammation and/or vascular calcification associated with PAD, not currently studied in our paper, may play an important role in aortic stiffness. Arteriosclerosis and atherosclerosis are two processes pathologically distinct and largely driven by different mechanisms.

Increased Aortic Stiffness and Related Factors in Patients With Peripheral Arterial Disease

A number of conditions have been associated with functional changes of large arteries. The aim of this study was to evaluate the factors associated with aortic stiffness in patients with peripheral arterial disease (PAD). The authors studied 86 patients with PAD (ankle‐brachial pressure index [ABPI] ≤0.9) and 86 controls. Aortic stiffness was determined by pulse wave velocity (aPWV) using applanation tonometry. In PAD patients, aPWV was higher compared with controls (11±3 vs 9.8±1.8; P=.002). In multiple regression analysis, aPWV was independently associated with pulse pressure (β=0.05, P=.01) in the PAD patients and with age in the control group (β=0.08, P=.0005). The results of this study confirm an aPWV increase in patients with PAD and emphasize the association between blood pressure and aPWV. Further studies are necessary to assess whether higher aortic stiffening adds prognostic value to ABPI, which is the most powerful prognostic indicator in PAD.

Epidemiologic evidence of slow growing, nonprogressive or regressive breast cancer: A systematic review

The general aim of this systematic review is to mitigate breast cancer (BC) overdiagnosis and overtreatment. The specific aim is to summarize available data on the occurrence and features of indolent invasive or in situ (DCIS) BC, and precisely survival of untreated cases, prevalence of occult cancers found in autopsies, frequency of regressive BC. PubMed, Embase and Cochrane Library were systematically searched up to 3/31/2014. Eligibility criteria were: cohort studies, case‐control studies, uncontrolled case series assessing survival in women with a diagnosis of BC who did not receive treatment compared to treated women; case series of autopsies estimating the prevalence of undiagnosed BC; cohort studies, case‐control studies, uncontrolled case series, case reports assessing the occurrence of spontaneous regression of BC in women with a confirmed histology diagnosis. Untreated BC: 8 cohort studies and 12 case series (3593 BC) were included. In three controlled cohort studies (diagnoses 1978–2006), the 5‐years overall survival was 19–43%. Occult BC: 8 case series (2279 autopsies) were included. The prevalence of invasive BC undiagnosed during lifetime range was 0–1.5%, while for DCIS the range was 0.2–14.7%. Spontaneous regression: 2 cohort studies, 3 case reports, 1 case series included. In the cohort studies the relative risk of regression for screen detected compared with nonscreened BC was estimated as 1.2 and 1.1. It seems plausible that around 10% of invasive BC are not symptomatic during life, and that one fith of BC patients if untreated would be alive after 5 years. Around 1 of 10 screen‐detected BC may regress according two studies.

Aortic augmentation index in patients with peripheral arterial disease.

Aortic augmentation index (AIx) is used to investigate arterial stiffness. The authors tested the hypothesis that patients with peripheral arterial disease (PAD) demonstrate a higher AIx and also evaluated several related factors. In 97 patients with PAD, identified by ankle‐brachial pressure index (ABPI ≤0.9), and 97 controls (ABPI ≥0.91<1.4), AIx (%) was determined using tonometry of the radial artery. There was no significant difference between patients and controls in characteristics of age, sex, height, diastolic blood pressure, mean blood pressure, and heart rate. AIx was higher in patients with PAD (32±9 vs 28±9; P=.001). In multivariate regression analysis, AIx was independently associated with heart rate (β=−0.40, P=.0005). This study showed that AIx increased in patients with PAD and that heart rate is a determinant of AIx. Further studies are necessary to assess the pathophysiological and clinical importance of AIx in patients with PAD.