Safety and efficacy of low-dose PI3K inhibitor taselisib in adult patients with CLOVES and Klippel-Trenaunay syndrome (KTS): the TOTEM trial, a phase 1/2 multicenter, open-label, single-arm study.

PURPOSE: PIK3CA pathogenic variants in the PIK3CA-related overgrowth spectrum (PROS) activate phosphoinositide 3-kinase signaling, providing a rationale for targeted therapy, but no drug has proven efficacy and safety in this population. Our aim was to establish the six-month tolerability and efficacy of low-dose taselisib, a selective class I PI3K inhibitor, in PROS patients. METHODS: Patients over 16 years with PROS and PIK3CA pathogenic variants were included in a phase IB/IIA multicenter, open-label single-arm trial (six patients at 1 mg/day of taselisib, then 24 at 2 mg/day). The primary outcome was the occurrence of dose limiting toxicity (DLT). Efficacy outcomes were the relative changes after treatment of (1) tissue volume at affected and unaffected sites, both clinically and on imaging; (2) cutaneous vascular outcomes when relevant; (3) biologic parameters; (4) quality of life; and (5) patient-reported outcomes. RESULTS: Among 19 enrolled patients, 2 experienced a DLT (enteritis and pachymeningitis) leading to early trial termination (17 treated, 10 completed the study). No serious adverse reaction occurred in the 1 mg cohort (n = 6). No significant reduction in affected tissue volume was observed (mean -4.2%; p = 0.81; SD 14.01). Thirteen (76.4%) participants reported clinical improvement (pain reduction, chronic bleeding resolution, functional improvement). CONCLUSION: Despite functional improvement, the safety profile of low-dose taselisib precludes its long-term use.

Acute acral eruptions in children during the COVID-19 pandemic: Characteristics of 103 children and their family clusters.

BACKGROUND: A marked increase in frequency of acute acral eruptions (AAE) was observed in children during the COVID-19 pandemic in the spring period. OBJECTIVES: In this observational multicenter study, based on children with AAE, we aimed to assess the proportion of household members possibly infected by SARS-CoV-2. METHODS: We collected data from all children observed with AAE, prospectively from April 7, 2020 to June 22, 2020, and retrospectively since February 28, 2020. The primary outcome was the household infection rate, defined as the proportion of family clusters having at least one member with COVID-19 infection other than the child with AAE ("index child"). The definition of a case was based on characteristic clinical signs and a positive PCR or serology. RESULTS: The study included 103 children in 10 French departments and in Quebec. The median age was 13 years and the interquartile range [8-15], with a female-to-male ratio of 1/1.15. In children with AAE, all PCR tests were negative (n=18), and serology was positive in 2/14 (14.3%) cases. We found no significant anomalies in the lab results. A total of 66 of the 103 families (64.1%) of included children had at least one other infected member apart from the index child. The total number of household members was 292, of whom 119 (40.8%) were considered possibly infected by SARS-CoV-2. No index children or households exhibited severe COVID-19. DISCUSSION: Among the 103 households included, 64.1% had at least one infected member. Neither children with AAE nor their households showed severe COVID-19.

Age-specific characteristics of neutrophilic dermatoses and neutrophilic diseases in children.

BACKGROUND: Our suggested 'modern' concepts of 'neutrophilic dermatoses' (ND) and 'neutrophilic disease' were based on observations in adult patients and have not been studied in paediatric patients. Only a minority of ND occurs in children, and little is known about age-specific characteristics. OBJECTIVES: To describe age-specific characteristics of ND in children and to study whether our suggested 'modern' classification of ND may be applied to children. METHODS: We conducted a retrospective multicentre study in a French cohort of 27 paediatric patients diagnosed with pyoderma gangrenosum (PG) or Sweet's syndrome (SS). RESULTS: Demographics and distribution of typical/atypical forms were similar in patients diagnosed with PG and SS. Atypical ND were more frequent in infants (90%), when compared to young children (60%) and adolescents (33%). Neutrophilic disease was observed in 17/27 patients and was most frequent in infants. Neutrophilic disease of the upper respiratory tract, as well as cardiac neutrophilic disease, was only observed in infants, whereas other locations were similarly found in infants, young children and adolescents. In infants and young children, ND were associated with a large spectrum of general diseases, whereas in adolescents associations were limited to inflammatory bowel disease and Behçet's disease. CONCLUSIONS: Our study describes the concept of ND in paediatric patients and shows that they have some characteristics different from ND occurring in adults. ND occurring in infants can be associated with a large spectrum of general diseases. Occurrence of neutrophilic disease is frequent in children. Thus, ND occurring in young paediatric patients should incite clinicians to schedule complementary explorations in order to search for involvement of other organs and to rule out monogenetic autoinflammatory syndromes.

Biological treatments for paediatric psoriasis : a retrospective observational study on biological drug survival in daily practice in childhood psoriasis.

BACKGROUND: Three biotherapies - etanercept, adalimumab and ustekinumab - are licensed in childhood psoriasis. The few data available on their efficacy and tolerance are mainly derived from industry trials. However, biological drug survival impacts long-term performance in real-life settings. OBJECTIVE: The objective of this study was to evaluate the survival rates of biological therapies in children with psoriasis in real-life conditions. Secondary objectives were to evaluate the factors associated with the choice of the biological therapy and to report severe adverse events. MATERIALS AND METHODS: This study was an observational retrospective study. Data were extracted from the clinical records of 134 children. Kaplan-Meier estimates were used to analyse drug survival overall and in subgroups of plaque psoriasis, bio-naïve and non-naïve patients. RESULTS: We analysed 184 treatment courses: 70 with etanercept, 68 with adalimumab and 46 with ustekinumab. Factors associated with the choice of first-line biological agent were age at initiation (younger for adalimumab, P < 0.0001), age at onset of psoriasis (younger for adalimumab and etanercept, P = 0.03) and baseline Psoriasis Assessment Severity Index and Physician global assessment (both higher for adalimumab, P < 0.001). Drug survival rates were higher for ustekinumab than for adalimumab and etanercept (P < 0.0001) for all treatment and all psoriasis types, plaque-type psoriasis (P = 0.0003), patients naïve for biological agents (P = 0.0007) and non-naïve patients (P = 0.007). We reported eight serious adverse events (SAEs): severe infections (n = 3), significant weight gain (n = 2), psoriasis flare (n = 1) and malaise (n = 1). Biological therapy was discontinued in three children (one with psoriasis flare and two with weight gain). Only the two cases of weight gain resulted in an unfavourable outcome. CONCLUSIONS: Our real-life comparative study found that ustekinumab had the best drug survival outcome. The profile of SAEs in children was comparable to that in adults. These results will assist dermatologists in the decision-making process when choosing treatment options for children with psoriasis in daily practice.

[Clinical and evolutionary characteristics of a child with aquagenic keratoderma: A retrospective study of 12 patients]. / Caractéristiques cliniques et évolutives de la kératodermie aquagénique de l'enfant : étude rétrospective de 12 cas.

INTRODUCTION: Aquagenic keratoderma (AK) is a rare condition characterized by wrinkled and edematous appearance of the skin of the hands occurring within minutes of immersion in water. Other than in a setting of cystic fibrosis, AK has rarely been reported in children, with only 13 clinical cases on record. Many clinicians are unfamiliar with AK and have fears relating to the association with cystic fibrosis The aim of this study is to describe the characteristics and to discuss management of the disease. METHODS: Retrospective, multicentre study, including children aged under 16 years presenting AK. RESULTS: 12 children were included. KA started at a mean age of 9.25 years (range: 20 months to 15 years). Clinical appearance and mode of onset were classical, with the palms being more severely affected than the soles. Pruritus or pain were reported in six cases. The median impact on daily life was 1.5/10. Some of the children underwent investigations: two had a negative sweat test, three had molecular analysis of the gene CFTR: one was negative and two had a heterozygote mutation. The course of the disease was variable: eight stabilizations, two exacerbations, one cure and one improvement. DISCUSSION: This is the first series on childhood KA. Clinical characteristics were similar to those seen in adults. Impact was moderate and the disease course was variable. Systematic medical check-up for cystic fibrosis does not appear warranted in children since to date, cystic fibrosis has not been diagnosed in any patients presenting AK alone. CONCLUSION: AK is rare in children and should not cause erroneous concern, and improvement can occur.

[Psoriatic arthritis in France, from infants to the elderly: Findings from two cross-sectional, multicenter studies]. / Rhumatisme psoriasique en France, du nourrisson à la personne âgée : données de deux études transversales multicentriques.

BACKGROUND: Psoriatic arthritis affects 20-30% of patients with psoriasis. Few epidemiological data are available in France about its prevalence and its association with skin lesions and comorbidities. OBJECTIVES: To assess the epidemiological aspects and the risk factors for psoriatic arthritis in children and adults in France. METHODS: Two cross-sectional studies were conducted in France in children (χ-Psocar, 23 pediatric dermatology centers belonging to the SFDP, 1 year) and adults (Resopsocar, 29 dermatology centers belonging to GEM RESOPSO, 4 months) to study the link between psoriasis and cardiovascular and metabolic comorbidities. RESULTS: Three hundred and thirteen children (males: 47.6%; mean age: 9.4 yrs) and 1,954 adults (males: 56.0%; mean age: 48.5 yrs) with psoriasis were included, with 4.2% of the children and 21.0% of the adults presenting psoriatic arthritis. Prevalence increased with age: 2.2% of children, 14.2% of adolescents, and over 20% after 40 years. It decreased after the age of 70 years (19.4%). Regardless of age, arthritis was not associated with gender. In the children's group, rheumatism was associated with nail involvement (P=0.04) and disease severity (P=0.0004). Adult rheumatism was associated with generalized plaque psoriasis (P=0.002), disease severity (P<0.0001), and obesity (P<0.0001). Localized plaque psoriasis was less often associated with arthritis (P<0.05). CONCLUSIONS: These two cross-sectional studies conducted in 2267 patients in France yielded information on the prevalence of joint involvement from infants to elderly subjects. It is the first study conducted in a single population to provide data for the whole population. Prevalence gradually increases with age, without gender difference, before decreasing in old age. We confirm the association of nail involvement in the first years of life, and of obesity in adults.

Inclusion of Radiation Environment Variability in Total Dose Hardness Assurance Methodology.

Variability of the space radiation environment is investigated with regard to parts categorization for total dose hardness assurance methods. It is shown that it can have a significant impact. A modified approach is developed that uses current environment models more consistently and replaces the radiation design margin concept with one of failure probability during a mission.

[Impact of sex and age on the clinical and epidemiological aspects of childhood psoriasis: Data from a French cross-sectional multicentre study]. / Impact de l'âge et du sexe sur les aspects cliniques et épidémiologiques du psoriasis de l'enfant. Données d'une étude transversale multicentrique française.

BACKGROUND: The prevalence of childhood psoriasis is estimated at between 0.4% and 0.7%. Clinical aspects of the diseases depend on age. The aim of this study was to investigate the clinical aspects of psoriasis according to age and sex. PATIENTS AND METHODS: A cross-sectional, multicentre study of children with psoriasis was performed by investigators belonging to the Research Group of the French Society of Paediatric Dermatology. The study was conducted from April 2012 to March 2013. Inclusion criteria were age less than 18 years and clinical diagnosis of psoriasis. The children were classified into 3 groups by age: infants: <2 years; children: ≥2 years and <13 years; adolescents≥13 years. The information collected included demographic data, clinical, epidemiological, and therapeutic aspects of the psoriasis, as well as analysis of comorbidities. RESULTS: Three hundred and thirteen children were included: 27 (8.6%) infants, 207 (66.1%) children, and 79 (25.2%) adolescents. Plaque psoriasis was the most frequent clinical type of psoriasis seen in children and adolescents (>41%), but it accounted for only 25.9% of psoriasis of infants (P<0.0001). Napkin psoriasis (37.0%) and inverse psoriasis (22.2%) were the most common forms of psoriasis seen in infants and were described significantly more frequently in this group than in the two other groups (P<0.003). Nail involvement was more common in adolescents (37.2%, P=0.03) and children (32.9%) than in infants (14.8%) and affected boys more than girls (43.6% vs 22.0%, P<0.0001). Girls presented scalp psoriasis more frequently (17.7% vs 8.7%, P=0.02). Local vitamin-D treatment and systemic therapies were used more frequently in children and adolescents than in infants. There was no significant difference for treatment use, including for acitretin, according to gender. DISCUSSION: Plaque psoriasis was the most common clinical type of psoriasis in children but affected less than 50% of the children. Age had a significant impact on extra-cutaneous skin disorders and on treatment used, while sex had little incidence. The frequency of comorbidities was not affected by age. CONCLUSION: Childhood psoriasis thus presents specific characteristics dependent on the age of the child. The results of studies exclusively dealing with adults cannot be extrapolated to children.

Psoriasis and obesity in French children: a case-control, multicentre study.

BACKGROUND: Obesity is more common in adults with psoriasis than in the general population, but there is a lack of data available regarding this association in children. OBJECTIVES: To evaluate whether obesity was more common in French children with psoriasis of any clinical type or severity. METHODS: A multicentre case-control study was performed in 23 French dermatology centres. Children without chronic or genetic inflammatory disease were selected as controls and matched for age, sex and dermatology centre. We used three weight cut-off categories to compare the two groups: overweight, overweight with abdominal obesity and overweight with obesity according to the French Health Authority guidelines. RESULTS: A total of 261 children with psoriasis were included. The mean age was 9.8 years, 126 were boys and 135 were girls. Overall, 42.5% of these children had plaque psoriasis and 32.2% had severe psoriasis. There was no difference between the psoriasis and control groups when the frequency of children who were overweight was compared (20·7% in psoriasis group vs. 17·1% in control group; P = 0·18). Overweight with abdominal obesity including obesity (18·4% vs. 10·4%; P = 0·009) and obesity alone (10·0% vs. 3·1%; P = 0·001) were more common in the psoriasis group. CONCLUSIONS: This study shows that being overweight with abdominal obesity and being obese is more common in children with psoriasis than in controls. The risk factors are the same as those that affect the French general population, i.e. female sex and having a parent who was overweight. The severity and clinical type of psoriasis do not affect overweight and obesity.

The BRAAFF checklist: a new dermoscopic algorithm for diagnosing acral melanoma.

BACKGROUND: The parallel ridge pattern (PRP) is considered the dermoscopic hallmark of acral melanoma (AM). However, it was recently shown that approximately one-third of AMs do not display a PRP dermoscopically, rendering their detection more troublesome. OBJECTIVES: To investigate the diagnostic accuracy of dermoscopic criteria for the diagnosis of AM. METHODS: Dermoscopic images of consecutive cases of histopathologically diagnosed AMs and acral naevi with histopathological diagnosis or with at least 1 year of follow-up were evaluated by three independent investigators for the presence of predefined criteria. Crude and adjusted odds ratios and their corresponding 95% confidence intervals were calculated by univariate and multivariate logistic regression, respectively. Receiver operating characteristic curves were used to choose among competing classification schemes. RESULTS: In total 603 lesions (472 naevi and 131 AMs) were included in the study. A scoring system (named BRAAFF) composed of six variables was associated with optimal area under the curve and sensitivity for the diagnosis of AM. This method includes four positive (irregular blotches, ridge pattern, asymmetry of structures and asymmetry of colours) and two negative predictors (furrow pattern and fibrillar pattern). CONCLUSIONS: The BRAAFF checklist significantly improves the diagnostic accuracy of dermoscopy for the diagnosis of AM.

[Progressive pigmented purpuric dermatosis in young children]. / Capillarite purpurique chronique diffuse du petit enfant.

BACKGROUND: Pigmented purpuric dermatosis (or Schamberg's disease) is characterized by chronic macular purpura and capillaritis. It is more common in young adult males and adolescents and is generally localized on the lower limbs. In this article, we report on five young children with generalized Schamberg's disease. PATIENTS AND METHODS: Five children (aged 13 months to 5 years) were included in this retrospective study. Time to consultation delay ranged from 15 days to 1 year. RESULTS: All patients presented asymptomatic generalized macular purpura. Skin biopsies were performed in 4 cases and were characteristic. The results of coagulation tests and complete blood counts were within the normal range in all patients. The clinical course was chronic, with periods of improvement and worsening. No treatment was prescribed. DISCUSSION: Schamberg's disease is uncommon in childhood. Our observations suggest that this diagnosis is not exceptional. Clinical appearance, setting and normal blood count values are sufficient to enable a diagnosis to be made. The clinical course is generally chronic, and as yet no treatments have demonstrated efficacy.

Information-based TMS to mid-lateral prefrontal cortex disrupts action goals during emotional processing.

The ability to respond to emotional events in a context-sensitive and goal-oriented manner is essential for adaptive functioning. In models of behavioral and emotion regulation, the lateral prefrontal cortex (LPFC) is postulated to maintain goal-relevant representations that promote cognitive control, an idea rarely tested with causal inference. Here, we altered mid-LPFC function in healthy individuals using a putatively inhibitory brain stimulation protocol (continuous theta burst; cTBS), followed by fMRI scanning. Participants performed the Affective Go/No-Go task, which requires goal-oriented action during affective processing. We targeted mid-LPFC (vs. a Control site) based on the individualized location of action-goal representations observed during the task. cTBS to mid-LPFC reduced action-goal representations in mid-LPFC and impaired goal-oriented action, particularly during processing of negative emotional cues. During negative-cue processing, cTBS to mid-LPFC reduced functional coupling between mid-LPFC and nodes of the default mode network, including frontopolar cortex-a region thought to modulate LPFC control signals according to internal states. Collectively, these results indicate that mid-LPFC goal-relevant representations play a causal role in governing context-sensitive cognitive control during emotional processing.

Insulin growth factor receptor (IGF-1R) antibody cixutumumab combined with the mTOR inhibitor temsirolimus in patients with metastatic adrenocortical carcinoma.

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancy without an available effective systemic chemotherapy. Insulin growth factor 2 (IGF-2) overexpression leading to the activation of the IGF-1 receptor (IGF-1R)/mammalian target of rapamycin (mTOR) pathway is well described in ACC. Cixutumumab, a fully human IgG1 monoclonal antibody directed at IGF-1R was combined with temsirolimus on the basis of preclinical data. METHODS: Patients received cixutumumab, 3-6 mg kg(-1) intravenously (IV) weekly, and temsirolimus, 25-37.5 mg IV weekly (4-week cycles), with restaging after 8 weeks. RESULTS: Twenty-six patients were enrolled (13 (50%) men); median age, 47 years; median number of prior therapies, 4. Five patients previously received an IGF-1R inhibitor and one, temsirolimus. The most frequent toxicities, at least possibly drug related, were grade 1-2 thrombocytopenia (38%), mucositis (58%), hypercholesterolaemia (31%), hypertriglyceridemia (35%), and hyperglycaemia (31%). In all, 11 of 26 patients (42%) achieved stable disease (SD) >6 months (duration range=6-21 months) with 3 of the 11 having received a prior IGF-1R inhibitor. CONCLUSION: Cixutumumab combined with temsirolimus was well tolerated and >40% of patients achieved prolonged SD.

A phase II randomized trial of induction chemotherapy versus no induction chemotherapy followed by preoperative chemoradiation in patients with esophageal cancer.

BACKGROUND: The contribution of induction chemotherapy (IC) before preoperative chemoradiation for esophageal cancer (EC) is not known. We hypothesized that IC would increase the rate of pathologic complete response (pathCR). METHODS: Trimodality-eligibile patients were randomized to receive no IC (Arm A) or IC (oxaliplatin/FU; Arm B) before oxaliplatin/FU/radiation. Surgery was attempted ∼5-6 weeks after chemoradiation. The pathCR rate, post-surgery 30-day mortality, overall survival (OS), and toxic effects were assessed. Bayesian methods and Fisher's exact test were used. RESULTS: One hundred twenty-six patients were randomized dynamically to balance the two arms for histology, baseline stage, gender, race, and age. Fifty-five patients in Arm A and 54 in Arm B underwent surgery. The median actuarial OS for all patients (54 deaths) was 45.62 months [95% confidence interval (CI), 27.63-NA], with median OS 45.62 months (95% CI 25.56-NA) in Arm A and 43.68 months (95% CI 27.63-NA) in Arm B (P = 0.69). The pathCR rate in Arm A was 13% (7 of 55) and 26% (14 of 54) in Arm B (two-sided Fisher's exact test, P = 0.094). Safety was similar in both arms. CONCLUSIONS: These data suggest that IC produces non-significant increase in the pathCR rate and does not prolong OS. Further development of IC before chemoradiation may not be beneficial. Clinical trial no.: NCT 00525915 (www.clinicaltrials.gov).

A two-dimensional finite element model of intercellular cAMP signaling through gap junction channels.

While cyclic adenosine monophosphate (cAMP) is typically considered an intracellular signal, it has been shown to spread between adjacent cells through connexin-based gap junction channels, promoting gap junctional intercellular communication (GJIC). Gap junction-mediated signaling is critical for the coordinated function of many tissues, and have been linked with cardiovascular disease, neurogenerative disease, and cancers. In particular, it plays a complex role in tumor suppression or promotion. This work introduces a two-dimensional finite element model that can describe intercellular cAMP signaling in the presence of gap junctions on membrane interfaces. The model was utilized to simulate cAMP transfer through one and two gap junction channels on the interface of a cluster of two pulmonary microvascular endothelial cells. The simulation results were found to generally agree with what has been observed in the literature in terms of GJIC. The research outcomes suggest that the proposed model can be employed to evaluate the permeability properties of a gap junction channel if its cAMP volumetric flow rate can be experimentally measured.

Dependence of ß3-adrenergic signaling on the adipokine leptin in cardiac myocytes.

ß3-Adrenergic receptors (ß3ARs) negatively regulate ß-adrenergic signaling via nitric oxide and are dependent on the adipokine leptin for normal expression in adipocytes, thus making ß3AR an attractive candidate for cross-talk with leptin in the heart. Accordingly, we tested the hypothesis that cardiac ß3AR expression and function are dependent on leptin and are severely diminished in leptin-deficient ob/ob mice. Using isolated cardiac myocyte physiology studies, we found that ß3AR function was significantly diminished in ob/ob myocytes and in wild-type myocytes treated with leptin antagonist. This finding was supported by quantitative PCR demonstrating markedly decreased ß3AR mRNA levels in ob/ob mice. Both ß3AR mRNA and function were restored in ob/ob mice after in vivo leptin repletion. We propose that diminished ß3AR signaling may be the critical element to explain the direct effects of leptin on the myocardium and suggest that this work reveals a key feature in the role of leptin in obesity-related cardiac hypertrophy and heart failure.