[Ethical principles for the design of a clinical trial in oncology]. / Règles éthiques pour la conception d'un essai clinique en oncologie.

Clinical research in the area of cancer is of utmost importance in order to improve patient care, both in terms of overall survival and quality of life. The implementation of clinical trials on medicinal products, now falling under EU Regulation 536/2014, is conditioned on prior scientific authorisation from the French National Agency for the Safety of Medicines and Health Products and a favorable ethical opinion from a Research Ethics Committee (REC). OBJECTIVE: The objective of this work is to report on the main problematic issues identified during the evaluation of oncology dossiers by the REC in order to present the expected elements and thus optimise the evaluation procedures. METHODS: The National Conference of the Research Ethics Committees analysed the questions raised by the REC during their evaluation of clinical trials of oncology drugs submitted to the European information system in 2022. RESULTS: Out of a total of fourteen dossiers, nine were subject to ethical questions on the protocol and all dossiers required modifications to the information documents. DISCUSSION: The heterogeneous quality of the dossiers reminds the need to submit well-argued, methodologically robust protocols with supervised research procedures that are safe for the participants. The drafting of information documents needs to be thoroughly reconsidered in order to present clear, concise, loyal and respectful documents for patients' rights.

Bevacizumab and ranibizumab for neovascular age-related macular degeneration: an updated meta-analysis of randomised clinical trials.

PURPOSE: Neovascular age-related macular degeneration (AMD) is the main cause of central vision loss among individuals aged 50 years or older in developed countries. The aim of this study was to review systematically the effect of bevacizumab compared to ranibizumab in patients with AMD at 1 year. METHODS: A systematic review was performed on Medline, Embase, and the Cochrane Library and Trial registers to October 2013. Eligibility criteria for selecting studies were randomised controlled trials (RCT) comparing bevacizumab with ranibizumab in patients with neovascular AMD. Odds ratio (OR) and mean difference (MD) estimates were synthesized under fixed- and random-effects models. Heterogeneity was assessed using the Q statistic and I(2). RESULTS: Five RCTs were included, representing 2,686 randomised patients. The meta-analysis confirmed the non-inferiority of bevacizumab compared to ranibizumab for change in visual acuity at 1 year (MD 0.57 letters, -1.80 to 0.66, p = 0.37, I(2) = 0 %). Better anatomical results were found for ranibizumab. Bevacizumab was associated with a 34 % increase in the number of patients with at least one serious systemic adverse event (OR 1.34, 1.08 to 1.66, p = 0.01, I(2) = 0 %). CONCLUSIONS: The pooled evidence confirmed that, compared with ranibizumab, bevacizumab was associated with equivalent effects on visual acuity at 1 year and with a higher risk of systemic serious adverse events. The current available data do not show which types of adverse events occur more frequently. In practice, bevacizumab should be used under a risk-management plan until further studies have been carried out to assess accurately the increased risk of systemic adverse events.

ELLIPSE Study: a Phase 1 study evaluating the tolerance of bevacizumab nasal spray in the treatment of epistaxis in hereditary hemorrhagic telangiectasia.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is a dominantly inherited genetic vascular disorder in which epistaxis is the most frequent manifestation, responsible for high morbidity. Management of this symptom has no standard, and local treatments are often aggressive. Their efficacy is variable and has not been proven. Anti-angiogenic drugs, such as bevacizumab, are a new treatment strategy. Its systemic administration in patients with HHT improves liver damage-related symptoms and epistaxis. To limit the systemic adverse effects of bevacizumab and to ease administration, a local administration seems suitable. PRIMARY OBJECTIVE: To evaluate the tolerance of increasing doses of bevacizumab administered as a nasal spray in patients with HHT-related epistaxis. Secondary objectives were to study the bioavailability and efficacy of bevacizumab against epistaxis when given as a nasal spray. METHODOLOGY: Phase 1, randomized, double-blind, placebo-controlled, monocentric study performed sequentially (dose escalation) on 5 groups of 8 patients. Each group was made up of 6 verum and 2 placebos. Five increasing doses of bevacizumab nasal spray (25 mg/mL) were evaluated: 12.5, 25, 50, 75 and 100 mg. RESULTS: A total of 40 patients were included between October 2011 and October 2012. Bevacizumab nasal spray was well tolerated in all patients and the drug was not detected in their serum. No dose limiting toxicity was observed. No efficacy was observed at any dose in this study. CONCLUSION: Based on these results, bevacizumab nasal spray is a safe treatment of epistaxis in HHT. However, a randomized Phase 2 study is needed to determine its efficacy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier #NCT01507480.

A new prognostic clinicopathological classification of pituitary adenomas: a multicentric case-control study of 410 patients with 8 years post-operative follow-up.

Pituitary adenomas are currently classified by histological, immunocytochemical and numerous ultrastructural characteristics lacking unequivocal prognostic correlations. We investigated the prognostic value of a new clinicopathological classification with grades based on invasion and proliferation. This retrospective multicentric case-control study comprised 410 patients who had surgery for a pituitary tumour with long-term follow-up. Using pituitary magnetic resonance imaging for diagnosis of cavernous or sphenoid sinus invasion, immunocytochemistry, markers of the cell cycle (Ki-67, mitoses) and p53, tumours were classified according to size (micro, macro and giant), type (PRL, GH, FSH/LH, ACTH and TSH) and grade (grade 1a: non-invasive, 1b: non-invasive and proliferative, 2a: invasive, 2b: invasive and proliferative, and 3: metastatic). The association between patient status at 8-year follow-up and age, sex, and classification was evaluated by two multivariate analyses assessing disease- or recurrence/progression-free status. At 8 years after surgery, 195 patients were disease-free (controls) and 215 patients were not (cases). In 125 of the cases the tumours had recurred or progressed. Analyses of disease-free and recurrence/progression-free status revealed the significant prognostic value (p < 0.001; p < 0.05) of age, tumour type, and grade across all tumour types and for each tumour type. Invasive and proliferative tumours (grade 2b) had a poor prognosis with an increased probability of tumour persistence or progression of 25- or 12-fold, respectively, as compared to non-invasive tumours (grade 1a). This new, easy to use clinicopathological classification of pituitary endocrine tumours has demonstrated its prognostic worth by strongly predicting the probability of post-operative complete remission or tumour progression and so could help clinicians choose the best post-operative therapy.

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 patient's 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 Gehan's 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.

Abstracting stage in population-based cancer registries: the example of oral cavity and oropharynx cancers.

Population-based cancer registries (PBCRs) are instruments to provide cancer incidence to promote cancer control and etiological research. A setting of mandatory (standard) variables is routinely collected for patient and tumor. One recommended variable is tumor stage, which supplies information on disease status and is an essential prognostic factor. However, it is not considered as necessary information to be collected by the PBCR. There are studies showing the value of stage as a prognostic variable to evaluate survival, socio-economic status, race and ethnics differences. Our aim is to analyze the feasibility of PBCRs in abstracting TNM for oral cavity and oropharynx. These topographies were selected due to the clinical accessibility of stage tumors by visual inspection and palpation. About 23% of the PBCRs who contributed to CI5-IX indicated their collection of TNM stage for all cancer sites. We analyzed 23,935 cases of oral cavity (OCC) and oropharynx cancer (OPC) from 13 PBCRs. Complete TNM stage for OCC was 52.7% for males and 47.6% for females; for OPC, it was 56% in both genders. Incomplete stage on OCC and OPC ranged from 22 to 25%. Missing was about 18-27% (most common in oral cavity). Missing stage was significantly higher in males for OCC aged > or =70 years, OR 1,64 (1.39-1.94). Our results demonstrate that OPC tend to have more stage, when compared with OCC. Even if it can be diagnosed by visual inspection, these results highlight the fact that information on stage can be a reliable indicator of access to healthcare and diagnosis awareness. Our results demonstrate that is feasible for PBCR to collect stage, although improving completeness of this information needs further technical training and international recommendation to adopt TNM stage as a standard variable for the PBCRs.

[Direct medical cost of erythropoiesis-stimulating agents in anaemia treatment of chronic renal failure patient: a literature review]. / Coût médical direct des agents stimulant l'érythropoïèse dans le traitement de l'anémie chez le patient insuffisant rénal chronique: revue de la littérature.

INTRODUCTION: Management of anaemia in chronic renal insufficiency (CRI) represents an important medico-economic challenge because of the great number of patients and the cost of the erythropoiesis-stimulating agent (ESA). The aim of this study was to identify determinants of the costs associated with these treatments in order to choose, with equal efficacy, the most efficient ASE. METHOD: A bibliographic research was realised by Medline database interrogation. RESULTS: Among the direct medical costs, five studies showed that acquisition of epoetine alfa (EA) compared to darbepoetin alfa (DA) was less expensive. Concerning the costs associated with the route of administration, the subcutaneous injection (SC) of epoetine allowed a gain in costs because of the decrease of doses compared to the intravenous (IV) route. The switch from EA in SC to DA in IV, for hemodialysis patients, was associated with a reduction of the number of injections and with a treatment's cost lower by DA than by EA. Costs related to the regimen of administration, notably those related to nursing, medical and pharmaceutical time, were negligible towards those associated to the acquisition of the ASE. Finally, the costs of the therapeutic follow-up and treatment of the adverse effects of the ASE were similar between the EA and the DA. CONCLUSION: The costs associated with the prices of acquisition of the ASE, negotiated by the structure of care, represent the most important part of the direct medical costs.

Oral cavity cancer in developed and in developing countries: population-based incidence.

BACKGROUND: The incidence of oral cavity cancer (OCC) is not well documented because it is rarely described in accord with the anatomic definition but is usually grouped with oropharyngeal subsites. We studied the incidence of OCC in developed and in developing countries. METHODS: The age-standardized and age-specific incidence rates of OCC were calculated for the period 1998-2002, using the topographic definition used by the Union Internationale Contre le Cancer (UICC), based on data from CI5-IX. RESULTS: The highest rates are observed in Pakistan, Brazil, India, and France and were consistent with country-specific risk factors and their prevalence. CONCLUSIONS: In developing countries, people are exposed to a wider range of risk factors, starting at younger ages, and primary prevention measures and policies are needed. Awareness of professionals must be improved to identify people at risk and target them for prevention and to minimize the consequences of OCC.

Alcohol intake and oral cavity cancer risk among men in a prospective study in Kerala, India.

OBJECTIVE: The aim of the study was to evaluate the role of alcohol drinking and patterns of consumption in oral cancer incidence and mortality in a cohort study using data from the Trivandrum Oral Cancer Screening Study, India. METHODS: At baseline, the study participants completed a lifestyle questionnaire including items on frequency and duration of alcohol consumption. They were followed up for oral cancer incidence and mortality. Data from 32 347 subjects, of whom 134 eventually developed oral cancer, were analysed to estimate risk of oral cancer incidence and mortality according to drinking patterns, using a Cox regression model adjusted for age, religion, education, occupation, body mass index (BMI), standard of living index, chewing habits, smoking habits, and vegetable and fruit intake. RESULTS: Current and past drinkers were each associated with significantly increased risk of developing oral cancer. The hazard ratio increased significantly by 49% (95% CI = 1-121%) among current drinkers and 90% (95% CI = 13-218%) among past drinkers. A significant dose-response relationship between intake frequency, duration and oral cancer risk (incidence and mortality) was observed. CONCLUSIONS: As with other lifestyle factors, alcohol intake plays an important role in oral carcinogenesis in this population, and understanding this role is relevant to developing public health policies targeting at-risk population.

Prognostic factors of recurrent respiratory papillomatosis from a registry of 72 patients.

CONCLUSIONS: The database revealed severity factors relating to human papillomavirus (HPV) type and age at diagnosis. While not exhaustive, the database is easy to use and could serve for a European multicentre epidemiological study. OBJECTIVES: To propose a database as a starting point for a national registry and to estimate prognostic factors in recurrent respiratory papillomatosis (RRP). MATERIALS AND METHODS: This was a retrospective study carried out in a tertiary care teaching hospital. From January 2005 to July 2007, epidemiological, clinical and treatment information on patients undergoing endoscopy for RRP in the department was entered in a database. Data were collected on three forms: the first comprised information about disease history before assessment in the department, the second about the disease and its treatment in the department, and the third about evolution after treatment. RESULTS: Data on 72 patients were entered into an RRP database between January 2005 and July 2007. In all, 82% had already been treated for RRP in a different centre; 24 had juvenile-onset (JORRP) and 48 adult-onset (AORRP) papillomatosis. Cidovir injections had been administered to 91% of the patients. Histology found nine cases of dysplasia, one of carcinoma in situ and one of invasive carcinoma. Subglottic and tracheal locations were significantly more frequent in JORRP than in AORRP, as were the maximum Derkay scores and annual numbers of endoscopies. Patients with type 11 HPV had significantly more endoscopies per year than those with type 6.

Microvascular decompression for trigeminal neuralgia: the importance of a noncompressive technique--Kaplan-Meier analysis in a consecutive series of 330 patients.

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 (

Microvascular decompression for primary trigeminal neuralgia: long-term effectiveness and prognostic factors in a series of 362 consecutive patients with clear-cut neurovascular conflicts who underwent pure decompression.

OBJECT: The purpose of this study was to evaluate the long-term efficacy of microvascular decompression (MVD) and to identify the factors affecting outcome in patients treated for primary trigeminal neuralgia (TN). Only the cases with a clear-cut neurovascular conflict (vascular contact and/or compression of the root entry zone of the trigeminal nerve) found at surgery and treated with "pure" MVD (decompression of the root without any additional lesioning or cutting of the adjacent rootlets) were retained. METHODS: The study included 362 patients who were followed up over a period of 1 to 18 years (median follow-up 7.2 years). A Kaplan-Meier survival analysis was generated at 1 and 15 years of follow-up for all of the considered factors. According to Kaplan-Meier analysis, the success rate (defined as pain-free patients without any medication) was 91% at 1 year and estimated to be 73.38% after 15 years of follow-up. RESULTS: None of the following patient-related factors played any significant role in prognosis: sex, patient age at surgery, history of systemic hypertension, duration of neuralgia before surgery, or history of failed trigeminal surgery. Patients with atypical neuralgia (a baseline of permanent pain) had the same outcome as those with a typical (purely spasmodic) presentation. In addition, the side and topography of the trigeminal nerve did not play a role, whereas involvement of all three divisions of the nerve had a negative effect on outcome. Concerning anatomical factors, neither the type of the compressive vessel nor its location along or around the root was found to be significant. However, the severity of compression was important-the more severe the degree of compression, the better the outcome (p = 0.002). The authors also found that presence of focal arachnoiditis had a negative influence on outcome (p = 0.002). CONCLUSIONS: Pure MVD can offer patients affected by a primary TN a 73.38% probability of long-term (15 years) cure of neuralgia. The presence of a clear-cut and marked vascular compression at surgery (and possibly-although not yet reliably--on preoperative magnetic resonance imaging) is the guarantee of a higher than 90% success rate.

Antioxidants to reduce sperm DNA fragmentation: an unexpected adverse effect.

Reactive oxygen species (ROS) have a negative impact on sperm DNA, leading to the formation of oxidative products such as 8-oxo-7,8-dihydroxyguanosine. This compound causes fragmentation and, thus, has a mutagenic effect. Patient treatment with oral antioxidant vitamins is, therefore, standard practice for male infertility, in an attempt to decrease formation of ROS and improve fertility. In this study, the DNA fragmentation index and the degree of sperm decondensation were measured using the sperm chromatin structure assay before and after 90 days treatment with antioxidant vitamins associated with zinc and selenium. Antioxidant treatment led to a decrease in sperm DNA fragmentation (-19.1%, P < 0.0004), suggesting that at least part of the decay was linked to ROS. However, it also led to an unexpected negative effect: an increase in sperm decondensation with the same order of magnitude (+22.8%, P < 0.0009). The opening of interchain disulphide bridges in protamines may explain this aspect, as antioxidant vitamins, especially vitamin C, are able to open the cystin net, thus interfering with paternal gene activity during preimplantation development. This observation might explain the discrepancy observed concerning the role of these antioxidant treatments in improving male fertility.

Silent coronaropathy: usefulness of dobutamine stress echocardiography in ischemic stroke.

BACKGROUND: Several testing options are available to detect asymptomatic coronary artery disease (CAD). Dobutamine stress echocardiography (DSE) has been reported to increase the sensitivity and specificity of stress testing to detect CAD. Most studies concerned patients with known or suspected CAD who have a high pretest probability of disease. We aimed to perform a preliminary evaluation of DSE in atherothrombotic stroke. METHODS: Patients with transient ischemic attack or nondisabling ischemic stroke attributable to an atherothrombotic source were prospectively recruited. Patients with a history of angina pectoris or electrocardiographic signs of previous myocardial infarction were excluded. DSE was considered positive when regional reduction or deterioration of myocardial thickening developed in 1 segment. Coronary angiography was performed in patients with positive DSE. RESULTS: Sixty-four patients were recruited. Analysis of DSE was possible in 60 patients. Overall the test provided clinically useful information in 60/64 patients studied (>90%). DSE was positive in 9 patients (15%). Coronary angiography was performed in 8 patients, high-grade focal lesions were found in 3 patients, and 5 patients showed diffuse atheroma. Univariate logistic regression analysis showed that the main factor predictive of a positive DSE was the presence of an aortic arch atheroma (p = 0.003). Multivariate logistic regression analysis showed that two factors had an independent predictive value of positive DSE: aortic arch atheroma (p = 0.007) and dyslipidemia (p = 0.09). CONCLUSION: DSE may improve prevention of further vascular events in patients with an atherothrombotic source of ischemic stroke. This screening may be of particular benefit to patients with an aortic arch atheroma.

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.