Organized cervical cancer screening: A randomized controlled trial assessing the effect of sending invitation letters.

OBJECTIVE: To evaluate the effect of implementing two modalities of organized Cervical Cancer Screening (CCS) program on screening uptake after a six-month delay. METHODS: A three-armed cluster randomized control trial was conducted in France between January 8 and July 2, 2021, involving148 510 women aged 40 to 65 and 1070 general practitioners. In the Optimized screening group, an invitation letter was posted to non-adherent women, and general practitioners were sent a list of their non-adherent patients. In the Organized screening group, an invitation letter was posted to non-adherent women. In the Usual care group, no invitation was sent. The endpoint was cervical cancer screening uptake after a six months period a) among all eligible women (primary endpoint); and b) among initially non-adherent women (post-hoc analysis). Statistical analysis was based on a logistic mixed model that compared between-group percentages of adherent women. A hierarchical comparison successively tested differences between the three arms (alpha 5 % risk). RESULTS: Among all 148,510 eligible women, screening uptake was 63.6 % (31,731/49910) in the Optimized screening group vs 61.8 % (30,210/48847) in the Usual care group (OR [IC95 %] = 1.05[0.93; 1.18]). Among the 64,370 initially non-adherent women, screening uptake was 17.9 % (3955/22134) in the Optimized screening group vs 11.6 % (5321/20995) in the Usual care group (OR [IC95 %] = 1.70[1.56;1.86]). There was no significant difference between Optimized and Organized screening groups (17.2 % vs 17.9 %; OR [IC95 %] = 1.02[0.94; 1.11]). CONCLUSIONS: The implementation of an organized screening based on an invitation letter resulted in a modest increase in participation among non-adherent women six months later.

Haemodynamic effect of dexmedetomidine during paediatric kidney transplantation.

BACKGROUND: Dexmedetomidine is increasingly used for its ability to stabilise haemodynamic status during general anaesthesia. However, there is currently no data on paediatric kidney transplant recipients (pKTR). This study investigates the haemodynamic impact of dexmedetomidine administered perioperatively in pKTR. METHODS: From 2019 to 2023, a retrospective study was conducted at Nantes University Hospital involving all pKTR under 18 years of age. The study compared intraoperative haemodynamic parameters between patients administered dexmedetomidine during kidney transplantation (DEX group) and those who did not receive it (no-DEX group). Mean arterial pressure (MAP) and heart rate (HR) were monitored throughout the duration of anaesthesia and compared. Graft function was assessed based on creatinine levels and glomerular filtration rate (GFR) at specific intervals. The perioperative use of fluids and vasoactive drugs, as well as their administration within 24 h post-surgery, were analysed. RESULTS: Thirty-eight patients were enrolled, 10 in the DEX group and 28 in the no-DEX group. Intraoperative HR was similar between the groups; however, MAP was higher in the DEX group (mean difference 9, standard deviation (SD, 1-11) mmHg, p = 0.039). No differences were found regarding the use of fluid and vasoactive drug therapy between groups. GFR at 1 month post-transplantation was significantly elevated in the DEX group (p = 0.009). CONCLUSIONS: pKTR receiving intraoperative dexmedetomidine exhibited higher perioperative MAP compared to those not administered dexmedetomidine. Additionally, the DEX group demonstrated superior graft function at 1 month. The direct impact of dexmedetomidine on immediate postoperative graft function in pTKR warrants further investigation in a prospective multicentre randomised study.

Pa o2 and Mortality in Neonatal Extracorporeal Membrane Oxygenation: Retrospective Analysis of the Extracorporeal Life Support Organization Registry, 2015-2020.

OBJECTIVES: Extracorporeal life support can lead to rapid reversal of hypoxemia but the benefits and harms of different oxygenation targets in severely ill patients are unclear. Our primary objective was to investigate the association between the Pa o2 after extracorporeal membrane oxygenation (ECMO) initiation and mortality in neonates treated for respiratory failure. DESIGN: Retrospective analysis of the Extracorporeal Life Support Organization (ELSO) Registry data, 2015-2020. PATIENTS: Newborns supported by ECMO for respiratory indication were included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Pa o2 24 hours after ECMO initiation (H24 Pa o2 ) was reported. The primary outcome was 28-day mortality. We identified 3533 newborns (median age 1 d [interquartile range (IQR), 1-3]; median weight 3.2 kg [IQR, 2.8-3.6]) from 198 ELSO centers, who were placed on ECMO. By 28 days of life, 731 (20.7%) had died. The median H24 Pa o2 was 85 mm Hg (IQR, 60-142). We found that both hypoxia (Pa o2 < 60 mm Hg) and moderate hyperoxia (Pa o2 201-300 mm Hg) were associated with greater adjusted odds ratio (aOR [95% CI]) of 28-day mortality, respectively: aOR 1.44 (95% CI, 1.08-1.93), p = 0.016, and aOR 1.49 (95% CI, 1.01-2.19), p value equals to 0.045. CONCLUSIONS: Early hypoxia or moderate hyperoxia after ECMO initiation are each associated with greater odds of 28-day mortality among neonates requiring ECMO for respiratory failure.

Early diagnosis of melanoma: a randomized trial assessing the impact of the transmission of photographs taken with a smartphone from the general practitioner to the dermatologist on the time to dermatological consultation.

BACKGROUND: Difficulty obtaining a dermatological consultation is an obstacle to the early diagnosis of melanoma. On the one hand, patients survival depends on the lesion thickness at the time of diagnosis. On the other hand, dermatologists treat many patients with benign lesions. Optimizing patient care pathways is a major concern. The aim of the present study was to assess whether the e-mail transmission of photographs of suspected melanoma lesions between general practitioners (GPs) and dermatologists reduces the time to dermatological consultation for patients whose suspicious skin lesions ultimately require resection. METHODS: We conducted a cluster-randomized controlled study in primary care involving 51 French GPs between April 2017 and August 2019. A total of 250 patients referred to a dermatologist for a suspected melanoma lesion were included GPs were randomized to either the smartphone arm or the usual care arm. In the smartphone arm, the GPs referred patients to the dermatologist by sending 2 photographs of the suspicious lesion using their smartphone. The dermatologist then had to set up an appointment at an appropriate time. In the usual care arm, GPs referred patients to a dermatologist according to their usual practice. The primary outcome was the time to dermatological consultation for patients whose lesion ultimately required resection. RESULTS: 57 GPs volunteered were randomized (27 to the smartphone arm, and 30 to the usual care arm). A total of 125 patients were included in each arm (mean age: 49.8 years; 53% women) and followed 8 months. Twenty-three dermatologists participated in the study. The time to dermatological consultation for patients whose suspicious skin lesion required resection was 56.5 days in the smartphone arm and 63.7 days in the usual care arm (mean adjusted time reduction: -18.5 days, 95% CI [-74.1;23.5], p = .53). CONCLUSIONS: The e-mail transmission of photographs from GPs to dermatologists did not improve the dermatological management of patients whose suspicious skin lesions ultimately required resection. Further research is needed to validate quality criteria that might be useful for tele-expertise in dermatology. TRIAL REGISTRATION: Registered on ClinicalTrials.gov under reference number NCT03137511 (May 2, 2017).

Multicenter prospective observational study of dupilumab-induced ocular events in atopic dermatitis patients.

BACKGROUND: Although ocular adverse events are frequent in AD patients treated with dupilumab, their characterization remains limited due to a lack of prospective studies with a systematic ophthalmological examination. OBJECTIVE: To examine the incidence, characteristics and risk factors of dupilumab-induced ocular adverse events. METHODS: A prospective, multicenter, and real-life study in adult AD patients treated with dupilumab. RESULTS: At baseline, 27 out of 181 patients (14.9%) had conjunctivitis. At week 16 (W16), 25 out of 27 had improved their conjunctivitis and 2 remained stable and 34 out of 181 patients (18.7%) had dupilumab-induced blepharoconjunctivitis: either de novo (n = 32) or worsening of underlying blepharoconjunctivitis (n = 2). Most events (27/34; 79.4%) were moderate. A multivariate analysis showed that head and neck AD (OR = 7.254; 95%CI [1.938-30.07]; p = 0.004), erythroderma (OR = 5.635; 95%CI [1.635-21.50]; p = 0.007) and the presence of dry eye syndrome at baseline (OR = 3.51; 95%CI [3.158-13.90]; p = 0.031) were independent factors associated with dupilumab-induced blepharoconjunctivitis. LIMITATIONS: Our follow-up period was 16 weeks and some late-onset time effects may still occur. CONCLUSION: This study showed that most dupilumab-induced blepharoconjunctivitis cases are de novo. AD severity and conjunctivitis at baseline were not found to be associated risk factors in this study.

Random forest of perfect trees: concept, performance, applications and perspectives.

MOTIVATION: The principle of Breiman's random forest (RF) is to build and assemble complementary classification trees in a way that maximizes their variability. We propose a new type of random forest that disobeys Breiman's principles and involves building trees with no classification errors in very large quantities. We used a new type of decision tree that uses a neuron at each node as well as an in-innovative half Christmas tree structure. With these new RFs, we developed a score, based on a family of ten new statistical information criteria, called Nguyen information criteria (NICs), to evaluate the predictive qualities of features in three dimensions. RESULTS: The first NIC allowed the Akaike information criterion to be minimized more quickly than data obtained with the Gini index when the features were introduced in a logistic regression model. The selected features based on the NICScore showed a slight advantage compared to the support vector machines-recursive feature elimination (SVM-RFE) method. We demonstrate that the inclusion of artificial neurons in tree nodes allows a large number of classifiers in the same node to be taken into account simultaneously and results in perfect trees without classification errors. AVAILABILITY AND IMPLEMENTATION: The methods used to build the perfect trees in this article were implemented in the 'ROP' R package, archived at https://cran.r-project.org/web/packages/ROP/index.html. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Raltegravir 1200 mg once daily as maintenance therapy in virologically suppressed HIV-1 infected adults: QDISS open-label trial.

BACKGROUND: Raltegravir (RAL) has favorable tolerability and safety profile, with few and manageable drug interactions. The use of RAL 1200 mg once daily (qd) for first-line therapy is well established. We assessed efficacy and safety of RAL 1200 mg qd, as part of triple combined antiretroviral therapy (cART), for maintenance strategy. METHODS: The QDISS trial (NCT03195452) was a 48-week multicenter, single-arm, open-label study designed to evaluate the ability of 2 NRTIs + RAL 1200 mg qd to maintain virological suppression in HIV-1 infected subjects on a stable cART with 2 NRTIs and a third agent for at least 6 months. The primary endpoint was the proportion of participants with HIV-1 RNA < 50 copies/mL at week 24, by the FDA snapshot algorithm. RESULTS: Of 100 participants 91% maintained viral suppression (95% CI: 83.6-95.8) at week 24 and 89% (81.2-94.4) at week 48. At week 24, there was one virological failure, without emergence of resistance-associated mutation and 10 participants had discontinued, 4 because of adverse events (AEs). Over 48 weeks, 7 AEs of grade 3-4 were reported, one possibly study-drug related (spontaneous abortion). BMI remained stable regardless of previous therapy or baseline BMI category. Over 48 weeks, total cholesterol (p = 0.023) and LDL-cholesterol (p = 0.009) decreased, lifestyle and ease subscale significantly improved (p = 0.04). The quality of life and Patients Reported Outcomes (PROs) also improved at W12 (p = 0.007). CONCLUSION: RAL 1200 mg qd as part of a maintenance triple therapy showed a high efficacy in virologically suppressed HIV-1 infected subjects, with good safety profile and improved lipid profile and patient reported outcomes. TRIAL REGISTRATION: Clinical trials.gov NCT03195452 and EudraCT 2016-003702-13.

Effectiveness of a multi-faceted intervention to deprescribe proton pump inhibitors in primary care: protocol for a population-based, pragmatic, cluster-randomized controlled trial.

BACKGROUND: Inappropriately using proton pump inhibitors (PPI) is associated with severe adverse drug reactions and may have major consequences on healthcare costs. Deprescribing (the process by which a healthcare professional supervises the withdrawal of an inappropriate medication, to manage polypharmacy and improve outcomes) should be considered when an inappropriate PPI prescription is identified. Deprescribing interventions directed solely to prescribers have limited efficacy and are rarely targeted to patients. The aim of this trial is to assess the efficacy of a multi-faceted intervention with patients and general practitioners (GPs) to deprescribe PPI. METHODS: We will conduct a pragmatic, cluster-randomized, population-based, controlled trial in two regions of Western France. GPs with practices with over 100 patients, and their adult patient to whom over 300 defined daily doses (DDD) of PPIs have been dispensed in the year before baseline will be included. A total of 1300 GPs and 33,000 patients will be cluster-randomized by GPs practices. Three arms will be compared: i) a multi-faceted intervention associating a) a patient education brochure about PPI deprescribing sent directly to patients (the brochure was designed using a mixed-methods study), and b) a personalized letter with the Bruyere's PPI deprescribing algorithm sent to their respective GPs, or ii) a single intervention where only the GPs received the letter and algorithm, or iii) no intervention. The primary outcome will be PPI deprescribing, defined as the proportion of patients achieving at least a 50% decrease in the amount of PPI dispensed to them (DDD/year) at 12 months compared to baseline. Secondary outcomes will include incremental cost-utility ratio (using EQ-5D-5L scale and National Health Insurance's database), acid rebound (using the Gastroesophageal Reflux Disease Impact Scale), and the patients' attitudes towards deprescribing (using the French rPATD). DISCUSSION: Based on previous trials, we anticipate more than 10% "successful PPI deprescribing" in the multi-faceted intervention compared to the single intervention on GPs and the control arm. The study has been funded through a national grant and will be launched in autumn 2020, for early results by the end of 2022. TRIAL REGISTRATION: Clinicaltrials.gov NCT04255823 ; first registered on February 5, 2020.

Local characteristics associated with higher prevalence of ESBL-producing Escherichia coli in community-acquired urinary tract infections: an observational, cross-sectional study.

OBJECTIVES: The prevalence of ESBL-producing Escherichia coli (ESBL-E. coli) in community-acquired urinary tract infections (UTI) has been increasing worldwide since 2000, but with large geographical variations. The aim of this study was to determine whether the ESBL-E. coli rate in urine samples from individuals with community-acquired UTI was associated with the local socio-economic, environmental, agricultural and healthcare characteristics. METHODS: This was a cross-sectional study in western France using data on antibiotic susceptibility of E. coli isolated from urine samples of individuals with community-acquired UTI analysed in non-hospital laboratories from 2015 to 2017. The ESBL-E. coli rate was calculated for each laboratory. Data on socio-economic characteristics, human antibiotic consumption, hospital bed density, animal farming density and percentage of agricultural land and surface water were retrieved at the municipality level and aggregated by study area. Their association with ESBL-E. coli prevalence was quantified using multivariate linear regression models with a backward selection. RESULTS: From 358 291 E. coli isolates from urine samples tested in 92 laboratories, the mean ESBL-E. coli prevalence for the study period was 3.30%. In an adjusted model, the ESBL-E. coli rate was significantly (P < 0.05) and positively associated with the local percentage of people >65 years old, third-generation cephalosporin use (DDD/1000 inhabitants), number of hospital beds/km2, poultry density, pig density and percentage of agricultural land. Lower deprivation was associated with a higher ESBL-E. coli rate. CONCLUSIONS: Several anthropogenic factors (primary care, hospitals and animal farming) are associated with the local ESBL-E. coli rate in community-acquired UTI. These results could contribute to improve risk management, including identification of at-risk patient groups.

Diuretics decrease fluid balance in patients on invasive mechanical ventilation: the randomized-controlled single blind, IRIHS study.

BACKGROUND: Fluid overload has been associated with increased morbidity and mortality in critically ill patients. The goal of this study was to assess the efficacy and safety of a diuretic strategy to overcome positive fluid balance in patients on invasive mechanical ventilation. METHODS: Design: Multicenter, single-blind, randomized-controlled study. Patients were randomized into a diuretic (furosemide) or a control group. Patients were eligible in case of fluid overload defined as in-ICU weight increase ≥ 3%, invasive mechanical ventilation (FiO2 ≤ 60% and PEEP ≤ 10 cm H2O on inclusion) and hemodynamic stabilization. The primary outcome was fluid balance, defined as weight variation from reference weight to successful extubation. The main secondary outcome was the safety of diuretic. RESULTS: 171 patients were randomized. After 5 exclusions, 166 patients were included in the analysis: 77 in the diuretic and 89 in the control group. Fluid balance was 1.4 [- 2.5 to 4.5] kg in the diuretic and 6.4 [0.5-11.2] kg in the control group (p < 0.001). In the multiple imputation analysis, fluid balance was significantly decreased in the diuretic group (mean difference = - 4.8 95% CI [- 7.3 to - 2.5], p < 0.001). Eleven (14%) patients died in the diuretic group and 16 (18%) patients in the control group (p = 0.5). There was a worsening of Acute Kidney Injury in 67 (75.3%) patients of the control group versus 46 (59.7%) patients in the diuretic group (p = 0.03). CONCLUSIONS: In this multicenter randomized-controlled study, protocolized diuretic therapy reduced fluid accumulation in patients receiving mechanical ventilation and was well tolerated with a favorable safety profile. Trial registration NCT02345681, Registered January 26 2015, Prospectively registered, https://clinicaltrials.gov/ct2/show/NCT02345681?term=02345681&draw=2&rank=1 .

Five-year follow-up of patients enrolled in the NEAT 001/ANRS 143 randomized clinical trial: NEAT 001/ANRS 143 LONG TERM study.

BACKGROUND: Few long-term data are available in subjects having initiated ART with an NRTI-sparing regimen. OBJECTIVES: Outcomes of subjects enrolled in the NEAT 001/ANRS 143 randomized clinical trial (comparing ritonavir-boosted darunavir + raltegravir versus ritonavir-boosted darunavir + tenofovir disoproxil fumarate/emtricitabine) were retrospectively collected, through anonymized electronic case report forms, up to 6 years post-enrolment. METHODS: The last NEAT 001 visit (Week 96) was conducted in 745/805 randomized subjects (363/401 ritonavir-boosted darunavir + raltegravir and 382/404 ritonavir-boosted darunavir + tenofovir disoproxil fumarate/emtricitabine). Of these, 430 were enrolled in NEAT 001/ANRS 143 LONG TERM (NLT) study (201 raltegravir, 229 tenofovir disoproxil fumarate/emtricitabine), with a median follow-up of 44.4 months. RESULTS: During NLT follow-up, the proportion of AIDS, non-AIDS events, virological rebound and serious adverse events, discontinuation for virological failure and for adverse events did not differ between groups; discontinuations for virological failure since NEAT 001 inclusion were more frequent in subjects with baseline CD4 <200 cells/mm3 (11.9% versus 5.3%; P = 0.077). At last follow-up, a quarter of subjects (22.2% for ritonavir-boosted darunavir + raltegravir and 29.7% for ritonavir-boosted darunavir + tenofovir disoproxil fumarate/emtricitabine) were still receiving their initial regimen. Integrase inhibitor exposure was not associated with weight gain (P = 0.48), while tenofovir disoproxil fumarate exposure was associated with a trend to higher creatinine increase (P = 0.067). CONCLUSIONS: After a median of 5.6 years, subjects initiating ritonavir-boosted darunavir + raltegravir or ritonavir-boosted darunavir + tenofovir disoproxil fumarate/emtricitabine experienced few serious clinical adverse events. Most discontinuations were for reasons unrelated to adverse events or virological failure.

Blood Predictive Biomarkers for Nivolumab in Advanced Melanoma.

Nivolumab response rate is 40% in metastatic melanoma. Few studies have evaluated pre-treatment biomarkers predictive of response. The aim of this study was to identify potential peripheral blood biomarkers associated with survival in patients with advanced melanoma treated with nivolumab. All advanced melanoma cases treated with anti-programmed cell death protein 1 (anti-PD1) over a 3-year period in the Dermato-Oncology Department, Nantes, France were identified. For each case, 9 potential blood biomarkers were identified. Bivariate and multivariate analyses, adjusted for the American Joint Committee on Cancer (AJCC) classification stage, Eastern Cooperative Oncology Group (ECOG) performance status, lactate dehydrogenase (LDH) level and failure to respond to first-line therapy, were used to test the association between biomarkers and overall survival (primary outcome) or progression-free survival (secondary outcome). Increased monocyte count, leukocyte/lymphocyte ratio and neutrophil/lymphocyte ratio were significantly associated with decreased overall survival after bivariate and multivariate analyses. Increased monocyte count was also significantly associated with decreased progression-free survival. These blood variables are easily measured and could help to predict patient response before the introduction of anti-PD1 therapy.

Use of Smartphones for Early Detection of Melanoma: Systematic Review.

BACKGROUND: The early diagnosis of melanoma is associated with decreased mortality. The smartphone, with its apps and the possibility of sending photographs to a dermatologist, could improve the early diagnosis of melanoma. OBJECTIVE: The aim of our review was to report the evidence on (1) the diagnostic performance of automated smartphone apps and store-and-forward teledermatology via a smartphone in the early detection of melanoma, (2) the impact on the patient's medical-care course, and (3) the feasibility criteria (focusing on the modalities of picture taking, transfer of data, and time to get a reply). METHODS: We conducted a systematic search of PubMed for the period from January 1, 2007 (launch of the first smartphone) to November 1, 2017. RESULTS: The results of the 25 studies included 13 concentrated on store-and-forward teledermatology, and 12 analyzed automated smartphone apps. Store-and-forward teledermatology opens several new perspectives, such as it accelerates the care course (less than 10 days vs 80 days), and the related procedures were assessed in primary care populations. However, the concordance between the conclusion of a teledermatologist and the conclusion of a dermatologist who conducts a face-to-face examination depended on the study (the kappa coefficient range was .20 to .84, median κ=.60). The use of a dermoscope may improve the concordance (the kappa coefficient range was .29 to .87, median κ=.74). Regarding automated smartphone apps, the major concerns are the lack of assessment in clinical practice conditions, the lack of assessment in primary care populations, and their low sensitivity, ranging from 7% to 87% (median 69%). In this literature review, up to 20% of the photographs transmitted were of insufficient quality. The modalities of picture taking and encryption of the data were only partially reported. CONCLUSIONS: The use of store-and-forward teledermatology could improve access to a dermatology consultation by optimizing the care course. Our review confirmed the absence of evidence of the safety and efficacy of automated smartphone medical apps. Further research is required to determine quality criteria, as there was major variability among the studies.

Effect of Physician Notification Regarding Nonadherence to Colorectal Cancer Screening on Patient Participation in Fecal Immunochemical Test Cancer Screening: A Randomized Clinical Trial.

Importance: Increasing participation in fecal screening tests is a major challenge in countries that have implemented colorectal cancer (CRC) screening programs. Objective: To determine whether providing general practitioners (GPs) a list of patients who are nonadherent to CRC screening enhances patient participation in fecal immunochemical testing (FIT). Design, Setting, and Participants: A 3-group, cluster-randomized study was conducted from July 14, 2015, to July 14, 2016, on the west coast of France, with GPs in 801 practices participating and involving adult patients (50-74 years) who were at average risk of CRC and not up-to-date with CRC screening. The final follow-up date was July 14, 2016. Interventions: General practitioners were randomly assigned to 1 of 3 groups: 496 received a list of patients who had not undergone CRC screening (patient-specific reminders group, 10 476 patients), 495 received a letter describing region-specific CRC screening adherence rates (generic reminders group, 10 606 patients), and 455 did not receive any reminders (usual care group, 10 147 patients). Main Outcomes and Measures: The primary end point was patient participation in CRC screening 1 year after the intervention. Results: Among 1482 randomized GPs (mean age, 53.4 years; 576 women [38.9%]), 1446 participated; of the 33 044 patients of these GPs (mean age, 59.7 years; 17 949 women [54.3%]), follow-up at 1 year was available for 31 229 (94.5%). At 1 year, 24.8% (95% CI, 23.4%-26.2%) of patients in the specific reminders group, 21.7% (95% CI, 20.5%-22.8%) in the generic reminders group, and 20.6% (95% CI, 19.3%-21.8%) in the usual care group participated in the FIT screening. The between-group differences were 3.1% (95% CI, 1.3%-5.0%) for the patient-specific reminders group vs the generic reminders group, 4.2% (95% CI, 2.3%-6.2%) for the patient-specific reminders group vs the usual care group, and 1.1% (95% CI, -0.6% to 2.8%) for generic reminders group vs the usual care group. Conclusions and Relevance: Providing French GPs caring for adults at average risk of CRC with a list of their patients who were not up-to-date with their CRC screening resulted in a small but significant increase in patient participation in FIT screening at 1 year compared with patients who received usual care. Providing GPs with generic reminders about regional rates of CRC screening did not increase screening rates compared with usual care. Trial Registration: clinicaltrials.gov Identifier: NCT02515344.

Clinical significance of BRAF mutation status in circulating tumor DNA of metastatic melanoma patients at baseline.

Circulating tumor DNA is a promising non-invasive tool for cancer monitoring. The main objective of our work was to investigate the relationship between mutant BRAF DNA in plasma and clinical response. Thirty-eight stage IV patients with a V600 mutated BRAF melanoma were included prior to any treatment. DNA was extracted from plasma and mutant DNA was detected using the amplification-refractory mutation system method. Before the beginning of any treatment, the corresponding BRAF mutation was detected in 29 of the 38 tested plasma samples (76.3% positive per cent agreement). We observed a strong correlation between the presence of circulating mutated DNA and overall survival (OS; P=.02), and with the number of metastatic sites (P=.01). The presence of circulating mutated DNA was also strongly correlated with serum LDH activity (P<.01) and S100 protein concentration (P<.01). Finally, seven patients presented discordant BRAF status in different tumor sites. In all these patients, the test performed on ctDNA was positive, suggesting that ctDNA analysis might be less sensitive to tumor heterogeneity. Altogether, these results suggest that plasmatic mutant BRAF DNA is a prognostic factor of OS, correlated with tumor burden. In addition, it represents an interesting alternative source of DNA to detect BRAF mutations before treatment.

Dysgeusia and weight loss under treatment with vismodegib: benefit of nutritional management.

PURPOSE: Whereas vismodegib is effective in the treatment of locally advanced/metastatic basal cell carcinoma, dysgeusia and weight loss are common side effects of such treatment. The main objective of this study was to monitor the nutritional status of vismodegib-treated patients. Secondary objective was to assess the incidence of dysgeusia and the benefit of early nutritional management. METHODS: This prospective study included all patients who started vismodegib between October 2011 and May 2013 at Nantes University Hospital. Prior to July 2012, patients treated with vismodegib had not received any specific nutritional management (Historical cohort). Body weight and presence of dysgeusia were recorded monthly. Patients treated after July 2012 (Nutrition cohort) were evaluated by a physician of the Nutrition Support Unit and received dietary counseling at vismodegib initiation. A standardized nutritional management protocol was initiated in case of significant weight loss. RESULTS: Forty-five patients (21 and 24 in the Nutrition and Historical cohort, respectively) were enrolled. In the Nutrition cohort, five patients (24 %) were undernourished at vismodegib initiation, and the 6-month cumulative incidence of dysgeusia was 71 %. Eight patients (38 %) and 13 patients (54 %) had a weight loss greater than 5 % in the Nutrition and Historical cohort, respectively (p = 0.3727). CONCLUSION: The results of this pilot study suggest the benefit of early nutritional screening. The potential benefit of nutritional support in this setting warrants further investigation.

Inclusion of populations at risk of advanced melanoma in an opportunistic targeted screening project involving general practitioners.

OBJECTIVE: The study objective was to measure the rates of inclusion of populations at risk of advanced melanoma in a pilot targeted screening project involving general practitioners. DESIGN: This cross-sectional database study compared the inclusion rates of patients who signed inclusion in a targeted screening project with those of patients who did not, during a period in which both groups of patients consulted investigators. SETTING: Data were extracted from the national healthcare insurance records in western France from 11 April to 30 October 2011. PATIENTS: Patients, older than 18, considered for the data extraction had consulted one of the 78 participating GPs during the study period, and were affiliated with the national healthcare insurance. MAIN OUTCOME MEASURES: Inclusion in the screening was the main outcome measure. Patients at risk of advanced melanoma were characterized by male gender, age over 50, low income, rural residence, farmer, and presence of chronic disease. RESULTS: A total of 57,279 patients consulted GPs during the inclusion period and 2711 (4.73%) were included in the targeted screening. Populations at risk of advanced melanoma were less included: men (OR = 0.67; 95%CI [0.61-0.73]; p < 0.001), older than 50 (OR = 0.67; 95%CI [0.60-0.74]; p < 0.001), low income (OR = 0.65; 95%CI [0.55-0.77]; p < 0.001), farmer (OR = 0.23; 95%CI [0.17-0.30]; p < 0.001) and presence of a chronic disease (OR = 0.87; 95%CI [0.77-0.98]; p < 0.028). CONCLUSION: This study demonstrated inequalities in the inclusion of patients in a melanoma screening. Patients at risk of advanced cancer were screened less often. Further studies should focus on GPs ability to identify and screen these patients. KEY POINTS Advanced melanoma is more frequently diagnosed in men, older patients and socioeconomically disadvantaged populations, which leads to survival inequalities. • Despite the involvement of general practitioners, the implementation of targeted melanoma screening did not avoid inclusion inequalities. • Men, older patients, patients suffering from chronic diseases, and low-income patients were less likely to benefit from screening. • The display of a conventional or an alarmist poster in the waiting room did not statistically reduce these inclusion inequalities.

Patients at elevated risk of melanoma: individual predictors of non-compliance to GP referral for a dermatologist consultation.

OBJECTIVE: The aim of this study is to assess whether patients at elevated risk of melanoma attended a dermatologist consultation after a General Practitioner referral and to determine individual predictors of non-compliance. METHOD: This survey included 1506 high-risk French patients (selected using the Self-Assessment Melanoma Risk Score) referred to a dermatologist between April and October 2011. Compliance was evaluated from January to April 2012, based on attendance at a dermatologist consultation (or scheduling an appointment). Demographic data and factors mapping the Health Belief Model were tested as correlates using a multivariate logistic regression. RESULTS: Compliance with referral was 58.4%. The top seven factors associated with non-compliance were as follows: GP advice to consult was unclear (OR=13.22; [7.66-23.56]); no previous participation in cancer screenings, including smear tests (OR=5.03; [2.23-11.83]) and prostate screening (OR=2.04; [1.06-3.97]); lack of knowledge that melanoma was a type of cancer (OR=1.94; [1.29-2.92]); and reporting no time to make an appointment (OR=2.08; [1.82-2.38]), forgetting to make an appointment (OR=1.26; [1.08-1.46]), long delays in accessing an appointment (OR=1.25; [1.12-1.41]), not being afraid of detecting something abnormal (OR=1.54; [1.35-1.78]), no need to consult a dermatologist to feel secure (OR=1.28; [1.09-1.51]). CONCLUSION: Physicians should be aware of the factors predicting patient compliance with referrals for dermatologist consultations; better General Practitioner counseling might enhance compliance in high-risk populations.

Did the new French pay-for-performance system modify benzodiazepine prescribing practices?

BACKGROUND: French general practitioners (GPs) were enrolled in a new payment system in January 2012. As part of a national agreement with the French National Ministry of Health, GPs were asked to decrease the proportion of patients who continued their benzodiazepine treatment 12 weeks after its initiation and to decrease the proportion of patients older than 65 who were prescribed long half-life benzodiazepines. In return, GPs could expect an extra payment of up to 490 euros per year. This study reports the evolution of the corresponding prescribing practices of French GPs during that period regarding patients who were prescribed a benzodiazepine for the first time. METHODS: The national healthcare system's administrative database was used to report the longitudinal follow-up of two historical cohorts of French patients from the Pays de la Loire area. STUDY PATIENTS: The "2011" and "2012" cohorts included all patients who initiated benzodiazepine regimens from April 1 to June 30 in 2011 and 2012, respectively.The primary outcomes were the proportion of those study patients who continued benzodiazepine treatment after 12 weeks and the proportion of study patients >65 years who were prescribed long half-life benzodiazepines.Analyses were performed using a multi-level regression. RESULTS: In total, 41,436 and 42,042 patients initiated benzodiazepine treatment in 2011 and 2012, respectively. A total of 18.97% of patients continued treatment for more than 12 weeks in 2012, compared with 18.18% in 2011. In all, 27.43% and 28.06% of patients >65 years continued treatment beyond 12 weeks in 2011 and 2012, respectively. The proportion of patients >65 years who were prescribed long half-life benzodiazepines decreased from 53.5% to 48.8% (p < 0.005) due to an increase in short half-life benzodiazepine prescriptions. Patients >65 years who were prescribed short half-life benzodiazepines were more likely to continue treatment after 12 weeks (p < 0.005). CONCLUSIONS: Despite the pay-for-performance strategy, the number of short half-life benzodiazepine prescriptions increased between 2011 and 2012, and the number of long half-life benzodiazepine initiations remained unchanged. Reducing the proportion of long half-life benzodiazepine prescriptions might be counterproductive because prescribing short half-life benzodiazepines was associated with higher rates of continuation beyond the recommended duration.