Efficiency and tolerance of second-line triple BRAF inhibitor/MEK inhibitor/anti-PD1 combined therapy in BRAF mutated melanoma patients with central nervous system metastases occurring during first-line combined targeted therapy: a real-life survey.

Although current systemic therapies significantly improved the outcome of advanced melanoma, the prognosis of patient with central nervous system (CNS) metastases remains poor especially when clinically symptomatic. We aimed to investigate the efficiency of CNS targets and tolerance of second-line combined anti-PD1/dual-targeted anti-BRAF/anti-MEK therapy implemented in patients with CNS progression after initially efficient first-line combined targeted therapy in patients with BRAF-mutated melanoma in a real-life setting. A monocentric retrospective analysis including all such patients treated from January 2017 to January 2022 was conducted in our tertiary referral center. The response of CNS lesions to second-line triple therapy was assessed through monthly clinical and at least quarterly morphological (according to RECIST criteria) evaluation. Tolerance data were also collected. Seventeen patients were included with a mean follow-up of 2.59 (±2.43) months. Only 1 patient displayed a significant clinical and morphological response. No statistically significant difference was observed between patients receiving or not additional local therapy (mainly radiotherapy) as to response achievement. Immunotherapy was permanently discontinued in 1 patient owing to grade 4 toxicity. Mean PFS and OS after CNS progression were 2.59 and 4.12 months, respectively. In this real-life survey, the subsequent addition of anti-PD1 to combined targeted therapy in melanoma patients with upfront CNS metastases did not result in significant response of CNS targets in most BRAF mutated melanoma patients with secondary CNS progression after initially successful first-line combined targeted therapy.

Biologics combined with conventional systemic agents for the treatment of children with severe psoriasis. Real-life data from the BiPe cohorts and a practice survey among French and Italian pediatric dermatologists.

Combined therapies involve the use of multiple drugs to increase efficacy and reduce the toxicity of individual treatments. We evaluated the use of combinations of conventional systemic therapies and biologics in children with psoriasis in daily practice. This two-part study used data from the 170 children in the Franco-Italian BiPe cohorts to evaluate the use, efficacy, and safety of combined conventional systemic-biologic therapies, and from a survey carried out among French and Italian dermatologists to better understand the reasons for using or avoiding these combinations. In total, 33 children (19.4%) from 13 dermatology centers received 48 combined conventional systemic-biologic therapies (cumulative duration: 43.6 years), including three triple combination therapies (acitretin-methotrexate, with a TNF-alpha inhibitor). A total of 14 different combinations were used, most frequently etanercept-acitretin (n = 10), adalimumab-acitretin (n = 7), adalimumab-methotrexate (n = 5), and ustekinumab-methotrexate (n = 5). The combined therapies were started at biologic initiation in 41 cases (85.4%), and after a period of biologic monotherapy in the remaining 7 cases. Mean PGA and PASI scores decreased between baseline and M3 with all the combinations used. Four serious adverse events were reported, all with favorable outcomes. The survey was completed by 61 dermatologists: 39 (63.9%) had previously used or planned to use the combined therapies, most commonly TNF-alpha inhibitors with acitretin or methotrexate. The main reason for using these treatments was to improve the outcome of biologic therapies in cases of partial efficacy or loss of efficacy. Combined therapies have been used frequently in the treatment of childhood psoriasis, in a range of clinical situations and in variable drug combinations, without significant toxicity. Although the use of these combined therapies needs to be clarified in future management guidelines, these combined therapies should be considered for the treatment of children with severe psoriasis, psoriatic arthritis, and recalcitrant disease.

New-onset inflammatory bowel diseases among IL-17 inhibitor-treated patients: results from the case-control MISSIL study.

OBJECTIVES: To describe new-onset IBD (new IBD) in patients treated with IL-17 inhibitors (IL-17i), to assess their incidence and to identify their risk factors in real life. METHODS: A French national registry (MISSIL) aimed to report all cases of new IBD in patients treated with IL-17i from January 2016 to December 2019. Using the estimated number of patients treated by IL-17 in France during the study period, the annual incidence rates of new IBD was reported in IL-17i-treated patients. A case-control study was performed with two controls per new IBD case matched by gender, age and underlying inflammatory disease. RESULTS: Thirty-one cases of new IBD under IL-17i were collected: 27 patients treated for spondyloarthritis and four patients for psoriasis. All were observed with secukinumab (SEK). The median time to onset of new IBD symptoms was 4.0 (1.5-7.5) months. SEK was discontinued in all patients. The evolution was favourable with complete resolution (17/31), improvement (7/31) or stabilization (5/31). Two patients died: one due to a massive myocardial infarction and one due to post-colectomy complications. The incidence of new IBD decreased from 0.69/100 patient-years [PY] (7/1010) in 2016 to 0.08/100 PY (6/7951) in 2019. No previous treatment with etanercept (odds ratio [OR] = 0.33, 95% CI: 0.14-0.80, P = 0.014) and low number of previous biologic therapies (OR = 0.67, 95% CI: 0.47, 0.94, P = 0.021) were significantly associated with new IBD. CONCLUSION: The incidence of new IBD was low and decreased from 2016 to 2019. The outcome was favourable in 24 out of 31 patients, but two patients died.

Benefit/risk Ratio of Low-dose Methotrexate in Cutaneous Lesions of Mycosis Fungoides and Sézary Syndrome.

Low-dose methotrexate is widely used in mycosis fungoides and Sézary syndrome, but few studies have evaluated this treatment. The aim of this study was to evaluate the benefit/risk ratio of this regimen on skin lesions. A retrospective survey of a series of patients treated for mycosis fungoides or Sézary syndrome with low-dose methotrexate and followed for at least one year in a tertiary referral centre was performed. From a total of 48 patients, complete response and partial response were achieved in 10 (21%) and 25 (52%) patients, respectively, with no significant difference in response rates between mycosis fungoides and Sézary syndrome. Of the responders, 20 out of 35 (57%) relapsed after a median time of 11 months. Forty-four of the total of 48 patients discontinued methotrexate, mainly due to primary or secondary failure and/or limiting toxicity (9 patients). Overall, the benefit/risk ratio of low-dose methotrexate in mycosis fungoides and Sézary syndrome appears favorable and this treat-ment remains a valid option in mycosis fungoides/Sézary syndrome. However, its activity is limited in duration and significant toxicity may occur in some patients.

Decision Tree Learning Algorithm for Classifying Knee Injury Status Using Return-to-Activity Criteria.

Anterior cruciate ligament (ACL) injury rates in female adolescents are increasing. Irrespective of treatment options, approximately 1/3 will suffer secondary ACL injuries following their return to activity (RTA). Despite this, there are no evidence-informed RTA guidelines to aid clinicians in deciding when this should occur. The first step towards these guidelines is to identify relevant and feasible measures to assess the functional status of these patients. The purpose of this study was therefore to evaluate tests frequently used to assess functional capacity following surgery using a Reduced Error Pruning Tree (REPT). Thirty-six healthy and forty-two ACLinjured adolescent females performed a series of functional tasks. Motion analysis along with spatiotemporal measures were used to extract thirty clinically relevant variables. The REPT reduced these variables down to two limb symmetry measures (maximum anterior hop and maximum lateral hop), capable of classifying injury status between the healthy and ACL injured participants with a 69% sensitivity, 78% specificity and kappa statistic of 0.464. We, therefore, conclude that the REPT model was able to evaluate functional capacity as it relates to injury status in adolescent females. We also recommend considering these variables when developing RTA assessments and guidelines.Clinical Relevance- Our results indicate that spatiotemporal measures may differentiate ACL-injured and healthy female adolescents with moderate confidence using a REPT. The identified tests may reasonably be added to the clinical evaluation process when evaluating functional capacity and readiness to return to activity.

Hemophagocytic lymphohistiocytosis in advanced melanoma treated with dabrafenib and trametinib combination: two cases.

Hemophagocytic lymphohistiocytosis (HLH) has been only rarely reported in patients with BRAF-mutated advanced melanoma treated with targeted therapies and never with first-line dabrafenib/trametinib combination thus far. Two patients treated with first-line dabrafenib and trametinib combination therapy for metastatic melanoma presented with sudden occurrence of fever, cytopenia, rhabdomyolysis, hepatic cytolysis, hypertriglyceridemia and very high ferritin levels after few weeks of treatment, associated with concomitant epstein-barr virus (EBV) reactivation in one patient. In both cases, drug-induced HLH was primarily considered owing to a high H-score and the absence of other etiology. Patients rapidly improved after treatment discontinuation associated with oral steroids in one patient and did not relapse after subsequent treatment resumption with a concurrent anti-BRAF/anti-MEK combination. In metastatic melanoma HLH may occur either spontaneously in the absence of any treatment as a paraneoplastic condition, related to an intercurrent infection or drug-induced mainly with various immunotherapy or with dabrafenib and trametinib following immunotherapy. However, such observations are scarce and these are the first cases of HLH occurring during first-line treatment with dabrafenib and trametinib in advanced melanoma to our knowledge. Pathomechanisms remain to be elucidated since triggering factors may encompass the treatment itself but also other significant actors including viral reactivation along with the underlying disease. The liability of treatment should be considered in cases of HLH occurring in patients with advanced melanoma successfully treated with a combined targeted therapy. A rechallenge with a concurrent anti-BRAF/anti-MEK can be proposed in this setting.

Delayed diagnosis and inappropriate clinical management of nicorandil-induced oral lesions: A case report.

Oral ulcers have a number of causes, and as a result, their etiology can be difficult to determine. Clinical management can range from simple treatment of the symptoms to extensive surgical excision, as in the case of malignant ulcers. Nicorandil, an antiangina drug, has been identified as a potential trigger for cutaneomucosal ulcers. This article reviews the importance of taking a full medical history when seeking to identify the side effects of treatments. We present the case of a 70-year-old patient with chronic ulceration of the oral mucosa. Determining the cause of ulceration as a side effect of taking nicorandil was delayed because the team that initially managed the patient hypothesized a malignant etiology. As a result, a partial glossectomy was performed for diagnostic and therapeutic purposes. After extensive examination of the patient's medical history and current treatments, nicorandil was identified as the potential trigger. The patient finally recovered after discontinuation of nicorandil.

Tolerance of Douglas Fir Somatic Plantlets to Aluminum Stress: Biological, Cytological, and Mineral Studies.

Aluminum (Al) is well known as a potent inhibitor of plant growth and development. It is notably present in soils in the soluble and bioavailable form Al3+ when the soil pH drops below 5. This situation is frequent, especially in softwood forests when litter decomposition is slow. In the present work, we studied the effects of Al3+ on the growth and development of Douglas fir plantlets. Somatic plantlets, regenerated via somatic embryogenesis, were grown in vitro on media supplemented with different concentrations of aluminum chloride (AlCl3): 0 µM, 200 µM, 500 µM. and 1 mM. We show that a concentration of 500 µM AlCl3 in medium significantly reduced root elongation (-21.8%), as well as stem growth (-14.6%). Also, a 25% reduction in dry mass of the plantlets was observed in presence of a concentration of 200 µM of AlCl3. Histological analysis of root tissues revealed significant damage, especially in conducting vessels. In addition, mineral cation content of plantlets was disturbed under Al exposure. More particularly, the Mg and K contents of needles and the Ca content of stems and needles were significantly reduced in presence of a concentration of 500 µM AlCl3 in the culture medium (-35.6%, -33.5%, -24%, and -34% respectively). However, all these damages appeared at relatively high Al concentrations when compared with other herbaceous species. This study shed light on the ability of Douglas fir in vitro plantlets to cope with the acid-driven toxicity of Al.

Translation and Validation of the Hospital for Special Surgery Pediatric Functional Activity Brief Scale for French Paediatric Populations.

Purpose: Physical activity level is a prognostic variable for patients with injuries. Self-report questionnaires exist to obtain these measures; however, they are not accessible to all populations because of language barriers. Therefore, the purpose of this study was to translate and validate the Hospital for Special Surgery Pediatric Functional Activity Brief Scale (HSS Pedi-FABS) for francophones. Method: We translated the HSS Pedi-FABS using the forward-reverse translation approach and validated it among bilingual adults and an expert panel before administering it to a paediatric population. A repeated-measures crossover design was used: forty-three middle school students, aged 13.1 (SD 0.75) years, were randomly administered either the English or the French questionnaire. Two days later, all participants completed the other version. The translated questionnaire was assessed for its convergent validity (Spearman's r correlation coefficients [rs ]), internal consistency (Cronbach's α), and reliability (standard error of measurement [SEM]). Results: All assessments had a significance level of p < 0.001 with an excellent Spearman's r correlation coefficient between the participants' total scores on the translated questionnaires (rs  = 0.911). The overall scores for the questionnaire and the individual items of the questionnaire revealed excellent internal consistency (α = 0.868) and reliability (SEM = 0.334). Conclusions: The validated and reliable translated questionnaire can be used by researchers and clinicians to assess physical activity levels in French paediatric populations.

Objectif : le niveau d'activité physique est un pronostic variable pour les patients qui présentent des blessures. Il existe des questionnaires d'autoévaluation pour obtenir ces mesures, mais ils ne sont pas accessibles à toutes les populations à cause de la barrière de la langue. La présente étude visait à traduire et à valider le Hospital for Special Surgery Pediatric Functional Activity Brief Scale (HSS Pedi-FABS) pour les francophones. Méthodologie : les chercheurs ont traduit le HSS Pedi-FABS au moyen du processus de rétrotraduction et l'ont validé auprès d'adultes bilingues et d'un groupe d'experts avant de l'utiliser auprès d'une population pédiatrique. Ils ont utilisé une méthodologie transversale par mesures répétées : 43 élèves du début du secondaire de 13,1 ans (ÉT 0,75) ont répondu au hasard au questionnaire anglais ou français. Deux jours plus tard, tous les participants ont rempli l'autre version. Les questionnaires traduits ont été évalués pour leur validité convergente (coefficients de corrélation Rho de Spearman [rs ]), leur cohérence interne (coefficient alpha [α] de Cronbach) et leur fiabilité (erreur type de mesure). Résultats : toutes les évaluations présentaient un seuil de signification de p < 0,001 et un excellent coefficient de corrélation Rho de Spearman entre les scores totaux des participants dans les questionnaires traduits (rs  = 0,911). Les scores totaux du questionnaire et de chacun de ses éléments ont révélé une excellente cohérence interne (α = 0,868) et une excellente fiabilité (erreur type de mesure = 0,334). Conclusion : le questionnaire validé et traduit avec fiabilité peut être utilisé par les chercheurs et les cliniciens pour évaluer les niveaux d'activité physique de populations pédiatriques francophones.

Unexpected features of exponentially growing Tobacco Bright Yellow-2 cell suspension culture in relation to excreted extracellular polysaccharides and cell wall composition.

This article presents a new insight about TBY-2 cells; from extracellular polysaccharides secretion to cell wall composition during cell suspension culture. In the medium of cells taken 2 days after dilution (end of lag phase), a two unit pH decrease from 5.38 to 3.45 was observed and linked to a high uronic acid (UA) amount secretion (47.8%) while, in 4 and 7 day-old spent media, pH increased and UA amounts decreased 35.6 and 42.3% UA, respectively. To attain deeper knowledge of the putative link between extracellular polysaccharide excretion and cell wall composition, we determined cell wall UA and neutral sugar composition of cells from D2 to D12 cultures. While cell walls from D2 and D3 cells contained a large amount of uronic acid (twice as much as the other analysed cell walls), similar amounts of neutral sugar were detected in cells from lag to end of exponential phase cells suggesting an enriched pectin network in young cultures. Indeed, monosaccharide composition analysis leads to an estimated percentage of pectins of 56% for D3 cell wall against 45% D7 cell walls indicating that the cells at the mid-exponential growth phase re-organized their cell wall linked to a decrease in secreted UA that finally led to a stabilization of the spent medium pH to 5.4. In conclusion, TBY-2 cell suspension from lag to stationary phase showed cell wall remodeling that could be of interest in drug interaction and internalization study.

Sporadic Porphyria in a patient with stage II melanoma treated with interferon α.

Porphyria cutanea tarda (PCT) is the most common form of human porphyria, due to reduced activity of uroporphyrinogen decarboxylase (UROD). There are many factors which can trigger PCT such as viral infections, excessive alcohol intake, iron overload, hepatotoxic drugs and hepatic tumours. Drug induced PCT is well documented but PCT induced by interferon α has rarely been described and only in cases of Hepatitis C Virus (HCV) infection or haematological malignancies. Here, we report the first case of de novo PCT induced by adjuvant interferon α (IFNα) therapy in a patient with stage II melanoma.

No Viral Transcripts Associated with Folliculotropic Mycosis Fungoides Using a High Throughput Sequencing Approach.

is missing (Short communication).

Is photodynamic therapy a relevant therapeutic option in refractory benign familial pemphigus (Hailey-Hailey disease)? A series of eight patients.

INTRODUCTION/BACKGROUND: Treatment of benign familial pemphigus or Hailey-Hailey disease (HHD), a rare inherited condition associated with a significant impairment of quality of life, is often challenging and disappointing with frequent relapses and infectious complications. Topical photodynamic therapy (PDT) may offer new perspectives in this difficult setting. MATERIAL AND METHODS: Eight patients with long-lasting HHD lesions refractory to multiple treatments were treated on at least one involved site with PDT using methyl-amino levulinate with a standardized protocol of three sessions of irradiation separated by 3-week intervals. RESULTS: A complete or partial clearing was achieved in all treated areas, and the result was satisfactorily maintained in all cases after a follow-up period ranging from 3 to 36 months. Results were of higher quality in non-inguinal areas. Tolerance was overall acceptable with local pain during and shortly after irradiation being the main limiting factor. DISCUSSION/CONCLUSION: Our series, although limited in size, emphasizes the interest of PDT in this difficult condition even though results may be incomplete. Treatment-related pain can be adequately managed by prior analgesics, cooling with sprayed water and local tumescent anesthesia. Overall, PDT appears as a relevant option in refractory HHD management with a favorable benefit/risk ratio.

High Expression of Fas/CD95 on CD4+ Circulating T Cells: An Exclusion Criterion in the Diagnosis of Mycosis Fungoides?

The aim of this 10-year monocentric prospective study was to determine a cut-off value of Fas/CD95 expression by peripheral blood CD4+ T lymphocytes in discriminating patients with mycosis fungoides from controls with cutaneous benign lymphocytic conditions. CD95 expression in peripheral blood CD4+ T lymphocytes was measured using flow cytometry in 330 patients referred for diagnosis: 104 with mycosis fungoides and 226 with eczema, psoriasis, drug reaction, etc. The sensitivity and specificity of different thresholds of CD95 expression were calculated regarding the final diagnosis of patients with mycosis fungoides or controls. CD95 expression higher than 30% reached a specificity of 91% in ruling out a diagnosis of mycosis fungoides, although overall CD95 expression was not significantly different from that of controls (p = 0.309) and sensitivity was very low (5%). Thus, peripheral CD95 expression higher than 30% could be used among the exclusion criteria in a multicomponent score for mycosis fungoides diagnosis.

Development of monoclonal gammopathy under biotherapy in psoriasis: a French multicenter retrospective study.

BACKGROUND: Biotherapies or targeted therapies are fairly new treatments indicated for moderate to severe psoriasis. The side effects appear to be mainly infectious or cancerous. The role of biotherapies in the development of a pre-cancerous condition, monoclonal gammopathy of undetermined significance (MGUS), has recently been debated in the literature. OBJECTIVES: To evaluate the incidence of MGUS in psoriasis patients treated with biotherapy. MATERIALS AND METHODS: This study was a French multicenter retrospective study carried out through the French multicenter study group RESOPSO. Data on the results of serum protein electrophoreses performed before and within at least six months after the start of the biotherapy were collected. Demographic data, medical history, and psoriasis treatment history were specified. RESULTS: Four hundred and forty three patients were eligible for inclusion. Of these, three presented with monoclonal gammopathy for which the assessment was in favor of MGUS. The average treatment period was 19.7 months. Six patients presented with MGUS prior to the treatment. These patients' immunoglobulin levels remained stable, with an average remission of 24 months. Only psoriatic rheumatism appeared to be statistically linked to MGUS. CONCLUSION: The incidence and frequency of MGUS in psoriasis patients treated with biotherapy do not appear to increase relative to the general population.

Efficacy and Tolerance of Cetuximab Alone or Combined with Chemotherapy in Locally Advanced or Metastatic Cutaneous Squamous Cell Carcinoma: An Open Study of 14 Patients.

BACKGROUND/AIMS: Previous reports highlighted the potential interest of cetuximab alone or in combination with chemotherapy in locally advanced or metastatic cutaneous squamous cell carcinomas (cSCC) care. MATERIAL AND METHODS: To further evaluate the efficiency and safety of cetuximab in advanced cSCC, a single-center retrospective study including all patients treated with cetuximab alone or combined with carboplatin for locally advanced or metastatic cSCC was conducted in a tertiary referral center. The primary end point was the overall response rate (ORR) after 2 cycles of treatment. Secondary end points were best overall disease control rate (DCR), overall survival (OS), best response duration, progression-free survival (PFS), and toxicity profile. RESULTS: Of the 14 enrolled patients, no complete response was obtained after 2 cycles of treatment, but 3 partial responses and 6 stable diseases were observed. ORR and DCR were 21.4 and 64.3%, respectively. Median OS and PFS were 9.25 and 2.65 months, respectively. Median PFS was longer with combined treatment compared with cetuximab monotherapy (9.03 vs. 3.55 months). The safety profile was acceptable with a trend toward a relationship between acne-like rash and longer response (median PFS 5.2 vs. 2.2 months). DISCUSSION/CONCLUSION: In all series including ours, disease control is usually rapidly obtained with cetuximab alone or combined with conventional chemotherapy, although with a minority of partial responses and no complete response. However, this control is of short duration in most cases. The safety profile is acceptable. A randomized phase III trial is warranted to better assess the benefit/risk ratio.

Cutaneous epithelial tumors induced by vemurafenib involve the MAPK and Pi3KCA pathways but not HPV nor HPyV viral infection.

The inhibitors of mutant BRAF that are used to treat metastatic melanoma induce squamoproliferative lesions. We conducted a prospective histopathological and molecular study on 27 skin lesions from 12 patients treated with vemurafenib. Mutation hot spots in HRAS, NRAS, KRAS, BRAF, and Pi3KCA were screened. HPV and HPyV infection status were also determined. The lesions consisted of 19 verrucal papillomas, 1 keratoacanthoma and 7 squamous cell carcinomas. No mutations were found within BRAF and NRAS. KRAS, HRAS, and Pi3KCA oncogenic mutations were found in 10 (83.3%), 7 (58.3%), and 4 (33.3%) patients respectively; however, these mutations were not consistent within all tumors of a given patient. Pi3KCA mutation was always associated with a mutation in HRAS. Finally, no correlation was found between the mutated gene or type of mutation and the type of cutaneous tumor or clinical response to vemurafenib. P16 protein level was not indicative of HPV infection. HPV was detected in only two lesions. Two cases had MCPyV, and one had HPyV7. In conclusion, neither HPV nor HPyV seem to be involved in the development of squamoproliferative lesions induced by verumafenib. By contrast, HRAS and KRAS play a predominant role in the physiopathology of these tumors.