Evelyne Decullier

Systematic Review of the Empirical Evidence of Study Publication Bias and Outcome Reporting Bias

Background The increased use of meta-analysis in systematic reviews of healthcare interventions has highlighted several types of bias that can arise during the completion of a randomised controlled trial. Study publication bias has been recognised as a potential threat to the validity of meta-analysis and can make the readily available evidence unreliable for decision making. Until recently, outcome reporting bias has received less attention. Methodology/Principal Findings We review and summarise the evidence from a series of cohort studies that have assessed study publication bias and outcome reporting bias in randomised controlled trials. Sixteen studies were eligible of which only two followed the cohort all the way through from protocol approval to information regarding publication of outcomes. Eleven of the studies investigated study publication bias and five investigated outcome reporting bias. Three studies have found that statistically significant outcomes had a higher odds of being fully reported compared to non-significant outcomes (range of odds ratios: 2.2 to 4.7). In comparing trial publications to protocols, we found that 40–62% of studies had at least one primary outcome that was changed, introduced, or omitted. We decided not to undertake meta-analysis due to the differences between studies. Conclusions Recent work provides direct empirical evidence for the existence of study publication bias and outcome reporting bias. There is strong evidence of an association between significant results and publication; studies that report positive or significant results are more likely to be published and outcomes that are statistically significant have higher odds of being fully reported. Publications have been found to be inconsistent with their protocols. Researchers need to be aware of the problems of both types of bias and efforts should be concentrated on improving the reporting of trials.

Sirolimus and Secondary Skin-Cancer Prevention in Kidney Transplantation

BACKGROUND Transplant recipients in whom cutaneous squamous-cell carcinomas develop are at high risk for multiple subsequent skin cancers. Whether sirolimus is useful in the prevention of secondary skin cancer has not been assessed. METHODS In this multicenter trial, we randomly assigned transplant recipients who were taking calcineurin inhibitors and had at least one cutaneous squamous-cell carcinoma either to receive sirolimus as a substitute for calcineurin inhibitors (in 64 patients) or to maintain their initial treatment (in 56). The primary end point was survival free of squamous-cell carcinoma at 2 years. Secondary end points included the time until the onset of new squamous-cell carcinomas, occurrence of other skin tumors, graft function, and problems with sirolimus. RESULTS Survival free of cutaneous squamous-cell carcinoma was significantly longer in the sirolimus group than in the calcineurin-inhibitor group. Overall, new squamous-cell carcinomas developed in 14 patients (22%) in the sirolimus group (6 after withdrawal of sirolimus) and in 22 (39%) in the calcineurin-inhibitor group (median time until onset, 15 vs. 7 months; P=0.02), with a relative risk in the sirolimus group of 0.56 (95% confidence interval, 0.32 to 0.98). There were 60 serious adverse events in the sirolimus group, as compared with 14 such events in the calcineurin-inhibitor group (average, 0.938 vs. 0.250). There were twice as many serious adverse events in patients who had been converted to sirolimus with rapid protocols as in those with progressive protocols. In the sirolimus group, 23% of patients discontinued the drug because of adverse events. Graft function remained stable in the two study groups. CONCLUSIONS Switching from calcineurin inhibitors to sirolimus had an antitumoral effect among kidney-transplant recipients with previous squamous-cell carcinoma. These observations may have implications concerning immunosuppressive treatment of patients with cutaneous squamous-cell carcinomas. (Funded by Hospices Civils de Lyon and others; TUMORAPA ClinicalTrials.gov number, NCT00133887.).

Bevacizumab in Patients With Hereditary Hemorrhagic Telangiectasia and Severe Hepatic Vascular Malformations and High Cardiac Output

CONTEXT The only treatment available to restore normal cardiac output in patients with hereditary hemorrhagic telangiectasia (HHT) and cardiac failure is liver transplant. Anti-vascular endothelial growth factor treatments such as bevacizumab may be an effective treatment. OBJECTIVES To test the efficacy of bevacizumab in reducing high cardiac output in severe hepatic forms of HHT and to assess improvement in epistaxis duration and quality of life. DESIGN, SETTING, AND PATIENTS Single-center, phase 2 trial with national recruitment from the French HHT Network. Patients were 18 to 70 years old and had confirmed HHT, severe liver involvement, and a high cardiac index related to HHT. INTERVENTION Bevacizumab, 5 mg per kg, every 14 days for a total of 6 injections. The total duration of the treatment was 2.5 months; patients were followed up for 6 months after the beginning of the treatment. MAIN OUTCOME MEASURE Decrease in cardiac output at 3 months after the first injection, evaluated by echocardiography. RESULTS A total of 25 patients were included between March 2009 and November 2010. Of the 24 patients who had echocardiograms available for reread, there was a response in 20 of 24 patients with normalization of cardiac index (complete response [CR]) in 3 of 24, partial response (PR) in 17 of 24, and no response in 4 cases. Median cardiac index at beginning of the treatment was 5.05 L/min/m(2) (range, 4.1-6.2) and significantly decreased at 3 months after the beginning of the treatment with a median cardiac index of 4.2 L/min/m(2) (range, 2.9-5.2; P < .001). Median cardiac index at 6 months was significantly lower than before treatment (4.1 L/min/m(2); range, 3.0-5.1). Among 23 patients with available data at 6 months, we observed CR in 5 cases, PR in 15 cases, and no response in 3 cases. Mean duration of epistaxis, which was 221 minutes per month (range, 0-947) at inclusion, had significantly decreased at 3 months (134 minutes; range, 0-656) and 6 months (43 minutes; range, 0-310) (P = .008). Quality of life had significantly improved. The most severe adverse events were 2 cases of grade 3 systemic hypertension, which were successfully treated. CONCLUSION In this preliminary study of patients with HHT associated with severe hepatic vascular malformations and high cardiac output, administration of bevacizumab was associated with a decrease in cardiac output and reduced duration and number of episodes of epistaxis. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00843440.

Onco-neural antibodies and tumour type determine survival and neurological symptoms in paraneoplastic neurological syndromes with Hu or CV2/CRMP5 antibodies

Objective: Anti-Hu antibodies (Hu-Ab) and anti-CV2/CRMP5 antibodies (CV2/CRMP5-Ab) have been identified in association with paraneoplastic neurological disorders. However, it is not clear whether these antibodies are associated with specific neurological symptoms or are only markers of anti-cancer immune reaction. Methods: To address this question, 37 patients with CV2/CRMP5-Ab and 324 patients with Hu-Ab were compared. Results: Whereas the age and sex ratio were the same between the two groups, the distribution of neurological symptoms was not. Patients with CV2/CRMP5-Ab presented more frequently cerebellar ataxia, chorea, uveo/retinal symptoms and myasthenic syndrome (Lambert–Eaton myasthenic syndrome LEMS or myasthenia gravis). They also had a better Rankin score. In contrast, dysautonomia, brainstem encephalitis and peripheral neuropathy were more frequent in patients with Hu-Ab. Limbic encephalitis occurred similarly in both groups. Small-cell lung cancer was the most frequently associated tumour in both groups of patients, while malignant thymoma was observed only in patients with CV2/CRMP5-Ab. In particular, patients with CV2/CRMP5-Ab and thymoma developed myasthenic syndrome more frequently, while patients with SCLC developed neuropathies more frequently. Chorea and myasthenic syndrome were only seen in patients with CV2/CRMP5-Ab. The median survival time was significantly longer in patients with CV2/CRMP5-Ab, and this effect was not dependent on the type of tumour. Interpretation: The data demonstrate that in patients with paraneoplastic neurological syndromes, the neurological symptoms and survival vary with both the type of associated onco-neural antibody and the type of tumour.

Ranibizumab versus Bevacizumab for Neovascular Age-related Macular Degeneration: Results from the GEFAL Noninferiority Randomized Trial.

OBJECTIVE To evaluate the relative efficacy and safety profile of bevacizumab versus ranibizumab intravitreal injections for the treatment of neovascular age-related macular degeneration (AMD). DESIGN Multicenter, prospective, noninferiority, double-masked, randomized clinical trial performed in 38 French ophthalmology centers. The noninferiority limit was 5 letters. PARTICIPANTS Patients aged ≥50 years were eligible if they presented with subfoveal neovascular AMD, with best-corrected visual acuity (BVCA) in the study eye of between 20/32 and 20/320 measured on the Early Treatment of Diabetic Retinopathy Study chart and a lesion area of less than 12 optic disc areas (DA). METHODS Patients were randomly assigned to intravitreal administration of bevacizumab (1.25 mg) or ranibizumab (0.50 mg). Hospital pharmacies were responsible for preparing, blinding, and dispensing treatments. Patients were followed for 1 year, with a loading dose of 3 monthly intravitreal injections, followed by an as-needed regimen (1 injection in case of active disease) for the remaining 9 months with monthly follow-up. MAIN OUTCOME MEASURES Mean change in visual acuity at 1 year. RESULTS Between June 2009 and November 2011, 501 patients were randomized. In the per protocol analysis, bevacizumab was noninferior to ranibizumab (bevacizumab minus ranibizumab +1.89 letters; 95% confidence interval [CI], -1.16 to +4.93, P < 0.0001). The intention-to-treat analysis was concordant. The mean number of injections was 6.8 in the bevacizumab group and 6.5 in the ranibizumab group (P = 0.39). Both drugs reduced the central subfield macular thickness, with a mean decrease of 95 μm for bevacizumab and 107 μm for ranibizumab (P = 0.27). There were no significant differences in the presence of subretinal or intraretinal fluid at final evaluation, dye leakage on angiogram, or change in choroidal neovascular area. The proportion of patients with serious adverse events was 12.6% in the bevacizumab group and 12.1% in the ranibizumab group (P = 0.88). The proportion of patients with serious systemic or ocular adverse events was similar in both groups. CONCLUSIONS Bevacizumab was noninferior to ranibizumab for visual acuity at 1 year with similar safety profiles. Ranibizumab tended to have a better anatomic outcome. The results are similar to those of previous head-to-head studies.

Subsequent skin cancers in kidney and heart transplant recipients after the first squamous cell carcinoma.

Background. The increased incidence of skin cancers in transplant patients is well documented; however, few data exist on the risk of subsequent skin tumors in a given patient after the first skin cancer. The aim of this study was to compare the individual rate of subsequent skin cancers in kidney (KTR) and heart transplant recipients (HTR) after the first squamous cell carcinoma (SCC) and to assess risk factors for tumor multiplicity. Methods. In all, 188 patients (121 KTR/67 HTR) were studied for up to 5 years. The cumulative number of SCC, basal cell carcinomas, Bowen’s diseases, premalignant keratoses, and keratoacanthomas was recorded yearly after the first SCC. Results. Overall, 71% of patients developed 757 new skin tumors. At 5 years, 100% of HTR and 88% of KTR had presented new tumors. However, the mean number of all tumors was significantly higher in KTR (3.4 vs. 2.0, 4.8 vs. 2.6, 6.6 vs. 2.9, 8.5 vs. 3.5, and 9.7 vs. 4.6 at 1, 2, 3, 4, and 5 years, respectively). Transplantation before 1984, multiple tumors at first consultation, eye and hair color, and skin type were predictive of multiple tumors. Early minimization of immunosuppression and of sun exposure tended to be associated with a reduced rate of all tumors and of SCC, respectively. Conclusions. Although the proportion of HTR developing new tumors is greater as compared with KTR, the mean number of tumors per patient is higher in KTR. This could be due to a longer immunosuppression in patients younger at transplantation.

Peritoneal carcinomatosis treated with cytoreductive surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for advanced ovarian carcinoma: a French multicentre retrospective cohort study of 566 patients.

BACKGROUND Despite a high response rate to front-line therapy, prognosis of epithelial ovarian carcinoma (EOC) remains poor. Approaches that combine Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) have been developed recently. The purpose of this study was to assess early and long-term survival in patients treated with this strategy. PATIENTS AND METHODS A retrospective cohort multicentric study from French centres was performed. All consecutive patients with advanced and recurrent EOC treated with CRS and HIPEC were included. RESULTS The study included 566 patients from 13 centres who underwent 607 procedures between 1991 and 2010. There were 92 patients with advanced EOC (first-line treatment), and 474 patients with recurrent EOC. A complete cytoreductive surgery was performed in 74.9% of patients. Mortality and grades 3 to 4 morbidity rates were 0.8% and 31.3%, respectively. The median overall survivals were 35.4 months and 45.7 months for advanced and recurrent EOC, respectively. There was no significant difference in overall survival between patients with chemosensitive and with chemoresistant recurrence. Peritoneal Cancer Index (PCI) that evaluated disease extent was the strongest independent prognostic factor for overall and disease-free survival in all groups. CONCLUSION For advanced and recurrent EOC, curative therapeutic approach combining optimal CRS and HIPEC should be considered as it may achieve long-term survival in patients with a severe prognosis disease, even in patients with chemoresistant disease. PCI should be used for patients selection.

Cultured autologous oral mucosal epithelial cell sheet (CAOMECS) transplantation for the treatment of corneal limbal epithelial stem cell deficiency.

PURPOSE Total bilateral corneal limbal epithelial stem cell deficiency (LSCD) cannot be treated with the surgical transplantation of autologous limbus or cultured autologous limbal epithelium. Transplantation of allogenic limbal epithelium is possible but requires immunosuppressive treatments. Cultured autologous oral mucosal epithelial cell sheet (CAOMECS) is a transparent, resistant, viable, and rapidly bioadhesive cell sheet, cultured with the UpCell-Insert technology (CellSeed, Inc., Tokyo, Japan), which allows for grafting onto the patients corneal stroma without suturing. It has therefore been proposed as an alternative treatment for LSCD. METHODS The objectives were to assess the safety and efficacy of CAOMECS, using a prospective Gehans design. Safety was measured in terms of ocular adverse events during the study period, and efficacy was measured using a composite criterion based on epithelial defect, punctate epithelial keratopathy, conjunctival epithelium on the cornea, number of vascular pediculi, and vessel activity. RESULTS CAOMECS was found to be safe and effective. In total, 26 eyes of 25 patients received a graft. Two patients experienced serious adverse events classified as not product related. Twenty-five patients were included in the efficacy analysis, as one patient was lost to follow-up. The treatment was found to be effective in 16 of 25 patients at 360 days after grafting. Of the 23 patients who completed follow-up at 360 days, 22 had no ulcers, and 19 showed a decrease in the severity of the punctate epithelial keratopathy. CONCLUSIONS CAOMECS is a well-tolerated and safe tissue-engineered product. These results suggest its efficacy for reconstructing the ocular surface in patients with total bilateral corneal LSCD.

Micro-vascular decompression for primary Trigeminal Neuralgia (typical or atypical). Long-term effectiveness on pain; prospective study with survival analysis in a consecutive series of 362 patients.

SummaryBackground. Few publications on primary Trigeminal Neuralgia treated by Micro-Vascular Decompression (MVD) report large series, with long-term follow-up, using Kaplan-Meier (K-M) analysis. None was specifically directed to the comparative study of MVD effectiveness on Trigeminal Neuralgia with typical (i.e., with paroxysmal pain only) and atypical features (i.e., with association of a permanent background of pain). Method. The authors report a series of 362 patients having clearcut vascular compression and treated with pure MVD – i.e., without any additional cut or coagulation of the adjacent root fibers. Follow-up was 1 to 18 y (8 y on average, with a median of 7.2 y). Results were considered overall, then separately for patients with typical (237 (65.5%)) and atypical (125 (34.5%)) clinical presentation. Findings. One year after operation, (294 (81.2%) of patients were totally-free – of paroxysmal pain, and also of permanent background pain – and not needing any medication) 13 (3.6%) still had a background of pain but without the need for medication which 55 patients (15.2%), treatment had failed. At latest review (8 y on average) the corresponding rates were 80, 4.9 and 15.1%, respectively. Kaplan-Meier analysis estimated the probability of total cure at 15 y to be 73.4%.There was no difference in the cure rate between patients with typical and atypical features at one year: 81 and 81.16%, respectively. The probability of cure at 15 y was identical for the two clinical presentations. Conclusions. Pure MVD offers patients affected by Trigeminal Neuralgia due to vascular compression a long-lasting cure in three-fourths of the cases. Both typical and atypical presentations respond well to MVD, view in contrast to the classical view that an atypical presentation has an adverse effect on outcome after surgery.

MICROVASCULAR DECOMPRESSION FOR TRIGEMINAL NEURALGIA : THE IMPORTANCE OF A NONCOMPRESSIVE TECHNIQUE-KAPLAN-MEIER ANALYSIS IN A CONSECUTIVE SERIES OF 330 PATIENTS. Commentary

OBJECTIVE Microvascular decompression, although a well-established procedure for treating primary trigeminal neuralgia, still has no standardized protocol. The practical consequences of having the implant keep the conflicting vessels apart, whether or not in contact with the root, is still in debate. The present work was undertaken to answer this question. METHODS Patients were segregated into 2 groups: Group I (260 patients) had a Teflon prosthesis implanted without contact to the root, and Group II (70 patients) had a similar implant with contact to the root. Cure rates in the 2 groups were compared at the latest follow-up (≤15 yr; average, 8.2 yr) using Kaplan-Meier analysis. RESULTS In Group I, the cure rate was 82% (214 of 260 patients), whereas in Group II, the cure rate was 67% (47 of 70 patients) (P = 0.01). Kaplan-Meier analysis of the follow-up period up to 15 years also shows a significant difference (P = 0.05). CONCLUSION These results strongly support the goal of performing the procedure without the implant in contact with the root. This is easier with the superior cerebellar artery, because of its laxity and small number of perforating branches, than with the anteroinferior cerebellar artery, which has perforators to the brainstem and labyrinthine artery arising from its cisternal portion. The significantly better long-term cure rate when the implant is not in contact with the root favors the “pure” decompressive effect of the microvascular decompression procedure, rather than a conduction block mechanism.