Evolution of Diagnoses, Survival, and Costs of Oncological Medical Treatment for Non-Small-Cell Lung Cancer over 20 Years in Osona, Catalonia.

Non-small-cell lung cancer (NSCLC) has experienced several diagnostic and therapeutic changes over the past two decades. However, there are few studies conducted with real-world data regarding the evolution of the cost of these new drugs and the corresponding changes in the survival of these patients. We collected data on patients diagnosed with NSCLC from the tumor registry of the University Hospital of Vic from 2002 to 2021. We analyzed the epidemiological and pathological characteristics of these patients, the diverse oncological treatments administered, and the survival outcomes extending at least 18 months post-diagnosis. We also collected data on pharmacological costs, aligning them with the treatments received by each patient to determine the cost associated with individualized treatments. Our study included 905 patients diagnosed with NSCLC. We observed a dynamic shift in histopathological subtypes from squamous carcinoma in the initial years to adenocarcinoma. Regarding the treatment approach, the use of chemotherapy declined over time, replaced by immunotherapy, while molecular therapy showed relative stability. An increase in survival at 18 months after diagnosis was observed in patients with advanced stages over the most recent years of this study, along with the advent of immunotherapy. Mean treatment costs per patient ranged from EUR 1413.16 to EUR 22,029.87 and reached a peak of EUR 48,283.80 in 2017 after the advent of immunotherapy. This retrospective study, based on real-world data, documents the evolution of pathological characteristics, survival rates, and medical treatment costs for NSCLC over the last two decades. After the introduction of immunotherapy, patients in advanced stages showed an improvement in survival at 18 months, coupled with an increase in treatment costs.

An exhaustive ADDIS principle for online FWER control.

In this paper, we consider online multiple testing with familywise error rate (FWER) control, where the probability of committing at least one type I error will remain under control while testing a possibly infinite sequence of hypotheses over time. Currently, adaptive-discard (ADDIS) procedures seem to be the most promising online procedures with FWER control in terms of power. Now, our main contribution is a uniform improvement of the ADDIS principle and thus of all ADDIS procedures. This means, the methods we propose reject as least as much hypotheses as ADDIS procedures and in some cases even more, while maintaining FWER control. In addition, we show that there is no other FWER controlling procedure that enlarges the event of rejecting any hypothesis. Finally, we apply the new principle to derive uniform improvements of the ADDIS-Spending and ADDIS-Graph.

Regulatory Issues of Platform Trials: Learnings from EU-PEARL.

Although platform trials have many benefits, the complexity of these designs may result not only in increased methodological but also regulatory and ethical challenges. These aspects were addressed as part of the IMI project EU Patient-Centric Clinical Trial Platforms (EU-PEARL). We reviewed the available guidelines on platform trials in the European Union and the United States. This is supported and complemented by feedback received from regulatory interactions with the European Medicines Agency and the US Food and Drug Administration. Throughout the project we collected the needs of all relevant stakeholders including ethics committees, regulators, and health technology assessment bodies through active dialog and dedicated stakeholder workshops. Furthermore, we focused on methodological aspects and where applicable identified the corresponding guidance. Learnings from the guideline review, regulatory interactions, and workshops are provided. Based on these, a master protocol template was developed. Issues that still need harmonization or clarification in guidelines or where further methodological research is needed are also presented. These include questions around clinical trial submissions in Europe, the need for multiplicity control across the whole master protocol, the use of non-concurrent controls, and the impact of different randomization schemes. Master protocols are an efficient and patient-centered clinical trial design that can expedite drug development. However, they can also introduce additional operational and regulatory complexities. It is important to understand the different requirements of stakeholders upfront and address them in the trial. While relevant guidance is increasing, early dialog with relevant stakeholders can help to further support such designs.

Optimal allocation strategies in platform trials with continuous endpoints.

Platform trials are randomized clinical trials that allow simultaneous comparison of multiple interventions, usually against a common control. Arms to test experimental interventions may enter and leave the platform over time. This implies that the number of experimental intervention arms in the trial may change as the trial progresses. Determining optimal allocation rates to allocate patients to the treatment and control arms in platform trials is challenging because the optimal allocation depends on the number of arms in the platform and the latter typically varies over time. In addition, the optimal allocation depends on the analysis strategy used and the optimality criteria considered. In this article, we derive optimal treatment allocation rates for platform trials with shared controls, assuming that a stratified estimation and a testing procedure based on a regression model are used to adjust for time trends. We consider both, analysis using concurrent controls only as well as analysis methods using concurrent and non-concurrent controls and assume that the total sample size is fixed. The objective function to be minimized is the maximum of the variances of the effect estimators. We show that the optimal solution depends on the entry time of the arms in the trial and, in general, does not correspond to the square root of k allocation rule used in classical multi-arm trials. We illustrate the optimal allocation and evaluate the power and type 1 error rate compared to trials using one-to-one and square root of k allocations by means of a case study.

A meta-analysis and real-world cohort study on the sex-related differences in efficacy and safety of immunotherapy for hepatocellular carcinoma.

Background & Aims: Sex-related differences in the immune pathogenesis of hepatocellular carcinoma (HCC), particularly related to oestrogen-dependent secretion of pro-tumourigenic cytokines, are well-known. Whether sex influences the efficacy and safety of immunotherapy is not known. Methods: We performed a restricted maximum likelihood random effects meta-analysis of five phase III trials that evaluated immune checkpoint inhibitors (ICIs) in advanced HCC and reported overall survival (OS) hazard ratios (HRs) stratified by sex to evaluate sex-related differences in OS. In a real-world cohort of 840 patients with HCC from 22 centres included between 2018 and 2023, we directly compared the efficacy and safety of atezolizumab + bevacizumab (A+B) between sexes. Radiological response was reported according to RECIST v1.1. Uni- and multivariable Cox regression analyses were performed for OS and progression-free survival (PFS). Results: In the meta-analysis, immunotherapy was associated with a significant OS benefit only in male (pooled HR 0.79; 95% CI 0.73-0.86) but not in female (pooled HR 0.85; 95% CI 0.70-1.03) patients with HCC. When directly comparing model estimates, no differences in the treatment effect between sexes were observed. Among 840 patients, 677 (81%) were male (mean age 66 ± 11 years), and 163 (19%) were female (mean age 67 ± 12 years). Type and severity of adverse events were similar between the two groups. OS and PFS were comparable between males and females upon uni- and multivariable analyses (aHR for OS and PFS: 0.79, 95% CI 0.59-1.04; 1.02, 95% CI 0.80-1.30, respectively). Objective response rates (24%/22%) and disease control rates (59%/59%) were also similar between sexes. Conclusion: Female phase III trial participants experienced smaller OS benefit following ICI therapy for advanced HCC, while outcomes following A+B treatment were comparable between sexes in a large real-world database. Based on the ambiguous sex-related differences in survival observed here, further investigation of sex-specific clinical and biologic determinants of responsiveness and survival following ICIs are warranted. Impact and implications: While immune checkpoint inhibitors have emerged as standard of care for the treatment of hepatocellular carcinoma, there are conflicting reports on whether the efficacy of cancer immunotherapy differs between females and males. Our study suggests ambiguous sex-related differences in outcomes from immunotherapy in hepatocellular carcinoma. Further investigation of sex-specific clustering in clinicopathologic and immunologic determinants of responsiveness to immune checkpoint inhibitor therapy should be prioritised. Systematic review registration: PROSPERO CRD42023429625.

Attentional Bias Modification Training Based on Virtual Reality and Eye Tracking in Anorexia Nervosa Patients.

Anorexia nervosa (AN) patients exhibit attentional bias (AB) related to the body, which is the tendency to pay greater attention to weight-related body areas compared to non-weight-related ones. This phenomenon has been linked to elevated levels of body dissatisfaction (BD) and may potentially reduce the effectiveness of body exposure therapy. The purpose of this pilot study is to assess the efficacy of a single session of a new body-related AB modification task (ABMT) that combines virtual reality with eye tracking in patients with AN. The goals of the ABMT are to reduce body-related AB by balancing attention between weight and non-weight-related body areas and to reduce BD levels. Twenty-three adolescent patients with AN were embodied in a virtual avatar and immersed in a virtual environment where they completed the ABMT. Body-related AB measures and BD levels were assessed before and after the training. A paired samples t-test showed statistically significant differences between pre-assessment and post-assessment; the complete fixation time on weight-related body parts was reduced and BD levels decreased. The initial evidence of the efficacy of this ABMT has important clinical implications, since AB and BD are considered risk factors for developing and maintaining eating disorder symptomatology among patients with AN.

On the use of non-concurrent controls in platform trials: a scoping review.

BACKGROUND: Platform trials gained popularity during the last few years as they increase flexibility compared to multi-arm trials by allowing new experimental arms entering when the trial already started. Using a shared control group in platform trials increases the trial efficiency compared to separate trials. Because of the later entry of some of the experimental treatment arms, the shared control group includes concurrent and non-concurrent control data. For a given experimental arm, non-concurrent controls refer to patients allocated to the control arm before the arm enters the trial, while concurrent controls refer to control patients that are randomised concurrently to the experimental arm. Using non-concurrent controls can result in bias in the estimate in case of time trends if the appropriate methodology is not used and the assumptions are not met. METHODS: We conducted two reviews on the use of non-concurrent controls in platform trials: one on statistical methodology and one on regulatory guidance. We broadened our searches to the use of external and historical control data. We conducted our review on the statistical methodology in 43 articles identified through a systematic search in PubMed and performed a review on regulatory guidance on the use of non-concurrent controls in 37 guidelines published on the EMA and FDA websites. RESULTS: Only 7/43 of the methodological articles and 4/37 guidelines focused on platform trials. With respect to the statistical methodology, in 28/43 articles, a Bayesian approach was used to incorporate external/non-concurrent controls while 7/43 used a frequentist approach and 8/43 considered both. The majority of the articles considered a method that downweights the non-concurrent control in favour of concurrent control data (34/43), using for instance meta-analytic or propensity score approaches, and 11/43 considered a modelling-based approach, using regression models to incorporate non-concurrent control data. In regulatory guidelines, the use of non-concurrent control data was considered critical but was deemed acceptable for rare diseases in 12/37 guidelines or was accepted in specific indications (12/37). Non-comparability (30/37) and bias (16/37) were raised most often as the general concerns with non-concurrent controls. Indication specific guidelines were found to be most instructive. CONCLUSIONS: Statistical methods for incorporating non-concurrent controls are available in the literature, either by means of methods originally proposed for the incorporation of external controls or non-concurrent controls in platform trials. Methods mainly differ with respect to how the concurrent and non-concurrent data are combined and temporary changes handled. Regulatory guidance for non-concurrent controls in platform trials are currently still limited.

Modification of Body-Related Attentional Bias through Virtual Reality and Eye-Tracking in Healthy Participants: Implications for Anorexia Nervosa Treatments.

Cognitive biases have a significant impact on the etiology and treatment of eating disorders (EDs). These biases, including selective attentional bias (AB) to disliked body parts, may reinforce concerns about body shape, fear of gaining weight and body image disturbances and may contribute to dietary restriction and restraint. Decreasing AB could reduce core symptoms in anorexia nervosa (AN). This study represents a preliminary exploration aiming to assess whether AB towards weight-related (WR) and non-weight-related (NW) body parts could be reduced through an AB modification task in a virtual reality (VR) environment in healthy participants. A total of 54 female participants, aged 22.98 ± 1.89, were recruited. The task consisted of directing the participants' attention towards all body parts equally in a VR setting. Eye-tracking (ET) measurements (complete fixation time [CFT] and number of fixations [NF]) were made before and after the task. The results showed a significant reduction of the AB in the two groups with an initial AB towards WR body parts or towards NW body parts. Participants showed a tendency to more balanced (non-biased) attention after the intervention. This study provides evidence of the usefulness of AB modification tasks in a non-clinical sample.

Disturbances in sodium and chloride homeostasis predict outcome in stable and critically ill patients with cirrhosis.

BACKGROUND: Hyponatremia has prognostic implications in patients with cirrhosis, and thus, has been incorporated in the 2016 MELD-UNOS update. Changes in serum chloride are commonly perceived as 'just' parallel to changes in serum sodium. However, these are less well studied in the context of cirrhosis. AIMS: To investigate whether serum chloride independently predicts outcomes in patients with advanced chronic liver disease (ACLD) and stable clinical course or with critical illness. METHODS: 891 patients with ACLD (defined by hepatic venous pressure gradient [HVPG] ≥6 mm Hg) were followed after HVPG measurement between 2003 and 2020 (ACLD cohort). 181 critically ill patients with cirrhosis admitted to the ICU between 2004 and 2007 were recruited for the ICU cohort. Hypo-/hypernatremia (normal: 136-145 mmol/L) and hypo-/hyperchloremia (normal: 98-107 mmol/L) at baseline were assessed. RESULTS: ACLD cohort: 68% of male patients with a median MELD (adjusted for Na) of 11 (9-17) were included (Child-Pugh-stages-A/B/C: 46%/38%/16%) and followed for a median of 60 months. Lower serum chloride (adjusted average HR per mmol/L: 0.965 [95% confidence interval (95% CI): 0.945-0.986], p = 0.001) showed a significant association with hepatic decompensation/liver-related mortality on multivariable Cox regression analysis adjusted for age, HVPG, albumin and MELD. In line, hypochloremia was significantly associated with hepatic decompensation/liver-related mortality (adjusted average HR: 1.656 [95% CI:1.267-2.163], p < 0.001). ICU cohort: 70% of patients were male, median MELD was 31(22-39) at ICU admission (92% with Child-Pugh-stage-C). After adjusting for hypo-/hypernatremia, MELD, and blood pH, hypochloremia remained independently associated with ICU-mortality (aOR Cl: 3.200 [95%CI: 1.209-8.829], p = 0.021). CONCLUSION: Hypochloremia is associated with increased mortality in clinically stable and critically ill patients with cirrhosis independently of MELD including serum sodium.

An Attentional Bias Modification Task, through Virtual Reality and Eye-Tracking Technologies, to Enhance the Treatment of Anorexia Nervosa.

Mirror exposure therapies (METs) have been shown to be effective in reducing body image disturbances through the habituation process. Virtual reality (VR) combined with eye-tracking techniques can provide innovative solutions to some of METs' limitations reported with patients with anorexia nervosa (AN), especially the negative influence of body-related attentional bias (AB). This pilot study aimed to assess the preliminary efficacy of a new VR-based AB modification task (ABMT) among healthy women and the procedure's user experience. AB levels towards weight- and non-weight-related body parts, using complete fixation time (CFT) and number of fixations (NF), were assessed throughout the ABMT procedure (300 trials). The user experience was evaluated at the end of the procedure. The results showed that VR-based ABMT was effective in reducing AB significantly after 150 trials for both CFT- and NF-based measures, although 225 trials were necessary to get the same result for women with an NF initially more oriented towards weight-related body parts. Overall, the software received a "C-rating" on a scale from "A" (most usable) to "F" (least usable). These results provide evidence of the opportunity to use a VR-based ABMT procedure to reduce AB and improve existing treatments for AN.

Efficacy of a topical formulation containing MIA (Melanoma Inhibitory Activity) - Inhibitory peptides in a case of recalcitrant vitiligo in combination with UV exposure.

INTRODUCTION: Vitiligo is an acquired chronic pigmentation disorder of the skin. Even if the role of the immune system seems to be well established, new pathogenetic hypothesis are rising in these years. It has been recently suggested by the development of an animal model that a protein called Melanoma Inhibitory Activity (MIA) is involved in the pathogenesis of vitiligo. This protein interacts with the adhesion molecules expressed on the melanocytes causing its detachment from extracellular matrix proteins and creating the depigmented macules. A topical preparation based on oligopeptides able to inhibit the actions of the MIA protein has been introduced to the market, claiming activity on vitiligo. PATIENT CONCERNS AND DIAGNOSIS: A patient affected by non-segmental vitiligo for 10 years, recalcitrant to any treatment (such as steroids, immunomodulators, kellin, UVB-NB and UVA) came to our observation. INTERVENTIONS: We used this topical preparation containing the MIA inhibitors peptides in selected areas (face and sides of the trunk) leaving untreated other areas as control (legs and arms). The patient was required to be sun exposed or to have some UVA sessions during the treatment to stimulate the melanocytes replications. OUTCOMES: After 9 months of treatments, he recovered from 50% to 80% of repigmentation only in the treated areas, without any side effects locally or systemically. CONCLUSION: Even if other studies are required to better determine the efficacy of this approach, this first observation about the use of the MIA-inhibitors peptides for the treatment of non-segmental vitiligo indicates that this topical preparation containing the MIA inhibitors peptides could be a very promising option for the cure of this disease.

Adaptive clinical trial designs with blinded selection of binary composite endpoints and sample size reassessment.

For randomized clinical trials where a single, primary, binary endpoint would require unfeasibly large sample sizes, composite endpoints (CEs) are widely chosen as the primary endpoint. Despite being commonly used, CEs entail challenges in designing and interpreting results. Given that the components may be of different relevance and have different effect sizes, the choice of components must be made carefully. Especially, sample size calculations for composite binary endpoints depend not only on the anticipated effect sizes and event probabilities of the composite components but also on the correlation between them. However, information on the correlation between endpoints is usually not reported in the literature which can be an obstacle for designing future sound trials. We consider two-arm randomized controlled trials with a primary composite binary endpoint and an endpoint that consists only of the clinically more important component of the CE. We propose a trial design that allows an adaptive modification of the primary endpoint based on blinded information obtained at an interim analysis. Especially, we consider a decision rule to select between a CE and its most relevant component as primary endpoint. The decision rule chooses the endpoint with the lower estimated required sample size. Additionally, the sample size is reassessed using the estimated event probabilities and correlation, and the expected effect sizes of the composite components. We investigate the statistical power and significance level under the proposed design through simulations. We show that the adaptive design is equally or more powerful than designs without adaptive modification on the primary endpoint. Besides, the targeted power is achieved even if the correlation is misspecified at the planning stage while maintaining the type 1 error. All the computations are implemented in R and illustrated by means of a peritoneal dialysis trial.

On model-based time trend adjustments in platform trials with non-concurrent controls.

BACKGROUND: Platform trials can evaluate the efficacy of several experimental treatments compared to a control. The number of experimental treatments is not fixed, as arms may be added or removed as the trial progresses. Platform trials are more efficient than independent parallel group trials because of using shared control groups. However, for a treatment entering the trial at a later time point, the control group is divided into concurrent controls, consisting of patients randomised to control when that treatment arm is in the platform, and non-concurrent controls, patients randomised before. Using non-concurrent controls in addition to concurrent controls can improve the trial's efficiency by increasing power and reducing the required sample size, but can introduce bias due to time trends. METHODS: We focus on a platform trial with two treatment arms and a common control arm. Assuming that the second treatment arm is added at a later time, we assess the robustness of recently proposed model-based approaches to adjust for time trends when utilizing non-concurrent controls. In particular, we consider approaches where time trends are modeled either as linear in time or as a step function, with steps at time points where treatments enter or leave the platform trial. For trials with continuous or binary outcomes, we investigate the type 1 error rate and power of testing the efficacy of the newly added arm, as well as the bias and root mean squared error of treatment effect estimates under a range of scenarios. In addition to scenarios where time trends are equal across arms, we investigate settings with different time trends or time trends that are not additive in the scale of the model. RESULTS: A step function model, fitted on data from all treatment arms, gives increased power while controlling the type 1 error, as long as the time trends are equal for the different arms and additive on the model scale. This holds even if the shape of the time trend deviates from a step function when patients are allocated to arms by block randomisation. However, if time trends differ between arms or are not additive to treatment effects in the scale of the model, the type 1 error rate may be inflated. CONCLUSIONS: The efficiency gained by using step function models to incorporate non-concurrent controls can outweigh potential risks of biases, especially in settings with small sample sizes. Such biases may arise if the model assumptions of equality and additivity of time trends are not satisfied. However, the specifics of the trial, scientific plausibility of different time trends, and robustness of results should be carefully considered.

Implementing Risk-Sharing Arrangements for Innovative Medicines: The Experience in Catalonia (Spain).

OBJECTIVES: Publications assessing health and economic outcomes of risk-sharing arrangements (RSAs) are limited. Better knowledge of these outcomes would shed light on the pertinence of such arrangements, informing design improvements for the future. The aim of the study is to describe the different types of RSAs implemented in Catalonia and their health and economic outcomes. METHODS: Retrospective descriptive analysis of RSAs implemented from January 2016 to December 2019 in the Catalan Health Service, CatSalut. Individual RSAs were reviewed and categorized according to standard RSA guidelines. Relevant health and economic outcomes pertaining to the RSAs were analyzed using aggregate data recorded in Catalan central registries. RESULTS: A total of 15 RSAs were implemented over the study period (10 of which are still ongoing). A total of 8 consisted of performance-linked reimbursements (PLRs) and 7 of cost-sharing arrangements (CSAs). The arrangements were implemented in the oncohematology (n = 11), rare disease (n = 3), and neurology (n = 1) areas. A total of 951 patients were included in PLR and 73% achieved the target health outcomes. Total medication costs were €9 295 755 of which 11% were refunded to CatSalut. CSAs involved 2066 patients and resulted in overall refunds of €1 349 564 (2.61%) for CatSalut. CONCLUSIONS: Both PLRs and CSAs were used to manage the different uncertainties related to accessing innovative medicines in Catalonia. The data generated provide relevant information to inform decision-making, allowing an adaptation of the initial recommendation for use and access. Additional efforts are required to increase the RSA assessments and their publication.

A class of two-sample nonparametric statistics for binary and time-to-event outcomes.

We propose a class of two-sample statistics for testing the equality of proportions and the equality of survival functions. We build our proposal on a weighted combination of a score test for the difference in proportions and a weighted Kaplan-Meier statistic-based test for the difference of survival functions. The proposed statistics are fully non-parametric and do not rely on the proportional hazards assumption for the survival outcome. We present the asymptotic distribution of these statistics, propose a variance estimator, and show their asymptotic properties under fixed and local alternatives. We discuss different choices of weights including those that control the relative relevance of each outcome and emphasize the type of difference to be detected in the survival outcome. We evaluate the performance of these statistics with small sample sizes through a simulation study and illustrate their use with a randomized phase III cancer vaccine trial. We have implemented the proposed statistics in the R package SurvBin, available on GitHub (https://github.com/MartaBofillRoig/SurvBin).

Pathological response to neoadjuvant therapy with chemotherapy vs chemoradiotherapy in stage III NSCLC-contribution of IASLC recommendations.

BACKGROUND: Neoadjuvant treatment (NT) with chemotherapy (Ch) is a standard option for resectable stage III (N2) NSCLC. Several studies have suggested benefits with the addition of radiotherapy (RT) to NT Ch. The International Association for the Study of Lung Cancer (IASLC) published recommendations for the pathological response (PHR) of NSCLC resection specimens after NT. AIM: To contribute to the IASLC recommendations showing our results of PHR to NT Ch vs NT chemoradiotherapy (ChRT). METHODS: We analyzed 67 consecutive patients with resectable stage III NSCLC with positive mediastinal nodes treated with surgery after NT Ch or NT ChRT between 2013 and 2020. After NT, all patients were evaluated for radiological response (RR) according to Response Evaluation Criteria in Solid Tumours criteria and evaluated for surgery by a specialized group of thoracic surgeons. All histological samples were examined by the same two pathologists. PHR was evaluated by the percentage of viable cells in the tumor and the resected lymph nodes. RESULTS: Forty patients underwent NT ChRT and 27 NT Ch. Fifty-six (83.6%) patients underwent surgery (35 ChRT and 21 Ch). The median time from ChRT to surgery was 6 wk (3-19) and 8 wk (3-21) for Ch patients. We observed significant differences in RR, with disease progression in 2.5% and 14.8% of patients with ChRT and Ch, respectively, and partial response in 62.5% ChRT vs 29.6% Ch (P = 0.025). In PHR we observed ≤ 10% viable cells in the tumor in 19 (54.4%) and 2 cases (9.5%), and in the resected lymph nodes (RLN) 30 (85.7%) and 7 (33.3%) in ChRT and Ch, respectively (P = 0.001). Downstaging was greater in the ChRT compared to the Ch group (80% vs 33.3%; P = 0.002). In the univariate analysis, NT ChRT had a significant impact on partial RR [odds ratio (OR) 12.5; 95% confidence interval (CI): 1.21 - 128.61; P = 0.034], a decreased risk of persistence of cancer cells in the tumor and RLN and an 87.5% increased probability for achieving downstaging (OR 8; 95%CI: 2.34-27.32; P = 0.001). CONCLUSION: We found significant benefits in RR and PHR by adding RT to Ch as NT. A longer follow-up is necessary to assess the impact on clinical outcomes.

Structural brain correlates in major depression, anxiety disorders and post-traumatic stress disorder: A voxel-based morphometry meta-analysis.

The high comorbidity of Major Depressive Disorder (MDD), Anxiety Disorders (ANX), and Posttraumatic Stress Disorder (PTSD) has hindered the study of their structural neural correlates. The authors analyzed specific and common grey matter volume (GMV) characteristics by comparing them with healthy controls (HC). The meta-analysis of voxel-based morphometry (VBM) studies showed unique GMV diminutions for each disorder (p < 0.05, corrected) and less robust smaller GMV across diagnostics (p < 0.01, uncorrected). Pairwise comparison between the disorders showed GMV differences in MDD versus ANX and in ANX versus PTSD. These results endorse the hypothesis that unique clinical features characterizing MDD, ANX, and PTSD are also reflected by disorder specific GMV correlates.

Design of phase III trials with long-term survival outcomes based on short-term binary results.

Pathologic complete response (pCR) is a common primary endpoint for a phase II trial or even accelerated approval of neoadjuvant cancer therapy. If granted, a two-arm confirmatory trial is often required to demonstrate the efficacy with a time-to-event outcome such as overall survival. However, the design of a subsequent phase III trial based on prior information on the pCR effect is not straightforward. Aiming at designing such phase III trials with overall survival as primary endpoint using pCR information from previous trials, we consider a mixture model that incorporates both the survival and the binary endpoints. We propose to base the comparison between arms on the difference of the restricted mean survival times, and show how the effect size and sample size for overall survival rely on the probability of the binary response and the survival distribution by response status, both for each treatment arm. Moreover, we provide the sample size calculation under different scenarios and accompany them with the R package survmixer where all the computations have been implemented. We evaluate our proposal with a simulation study, and illustrate its application through a neoadjuvant breast cancer trial.

Effectiveness and tolerability of a squalane and dimethicone-based treatment for head lice.

Head lice (Pediculus humanus capitis) are worldwide obligate human ectoparasites, with high implications in pediatrics. In Europe, first-line topical neurotoxic insecticidal therapeutic strategies are being replaced by topical physically acting agents as the first-choice treatment. Safety of the active ingredients and high efficacy in a one-time single-dose treatment with a brief treatment application time are key issues for consumer use and effective compliance. The aim of this study was to assess the in vitro efficacy of a newly developed squalane and dimethicone-based pediculicidal formula, against motile head lice and eggs after 2 and 5 min immersion in the product, as well as its skin tolerance and acceptability under dermatological and pediatric expert control in children with atopic skin. The results indicate that at both time points, 100% mortality rate of head lice crawling stages and late-stage eggs was achieved. The formula was well tolerated and suitable for children with atopic skin from 12 months of age. Showing high in vitro efficacy and good skin acceptability, this solution is presented as a new safe alternative therapy for treatment of head lice infestations.