Predictive Factors of Non-Response to Vismodegib in Locally Advanced Basal-Cell Carcinoma.

BACKGROUND: Vismodegib has shown clinical efficacy in the management of locally advanced basal cell carcinomas (laBCC). However, non-response to vismodegib is observed in 2-13.5% of patients in clinical studies. The purpose of this study was to identify factors associated with non-response to vismodegib in patients with laBCC. METHODS: We carried out a retrospective multicenter study, including patients with laBCC treated with vismodegib, from July 2011 to May 2019. Response to treatment was assessed according to the RECIST 1.1 criteria. Patients were categorized as responders with a complete response or a partial response or non-responders with a stable disease or a progressive disease according to what has been observed during follow-up. Patient demographics, tumor profile, and treatment modalities were compared in responders and non-responders. RESULTS: Eighty-three patients with laBCC were included in the study. Twenty-five (30.1%) were non-responders to vismodegib. History of treatment with radiotherapy, presence of muscle involvement and intermittent treatment with vismodegib were significantly associated with a non-response (p < 0.001, p = 0.025, p < 0.001). Bone involvement (p = 0.2) and morpheaform IaBCC subtype (p = 0.056) were more frequent in non-responders without reaching statistical significance. CONCLUSION: In this study, non-response of laBCC to vismodegib therapy was associated with muscle involvement. Previous radiotherapy and intermittent use of vismodegib have been identified as causes favoring non-response to vismodegib. Due to the low numbers of patients included in the study, it is difficult to draw firm conclusions. Further studies are needed to confirm these data.

Generalized lymphedema associated with neurologic signs (GLANS) syndrome: a new entity?

BACKGROUND: Primary lymphedema in children, especially generalized disease with facial involvement, is rare. OBJECTIVE: We sought to report 3 childhood cases of lymphedema with associated neurologic findings and to provide a pathophysiologic explanation for this association. METHODS: Clinical observations, electroencephalography, and neuroimaging studies were evaluated. Microcomparative genomic hybridization was performed in 1 case. RESULTS: The 3 children had primary lymphedema of all 4 limbs and the face. This was confirmed by lymphoscintigraphy, which showed hypoplasia of vessels and hypofixation of lymph nodes. They had nonspecific neurologic disorders and electroencephalography abnormalities, without intellectual deficit. Neuroimaging revealed normal findings. Microcomparative genomic hybridization in 1 patient revealed no cytogenetic anomaly. The outcome was fatal in 1 case with development of visceral lymphedema and coma. LIMITATIONS: Genetic studies were performed in only 1 case. CONCLUSION: These observations suggest that neurologic assessment and electroencephalography are indicated for patients with lymphedema of the limbs and face to identify this syndrome.

Transfer of mesenchymal stem cell mitochondria to CD4+ T cells contributes to repress Th1 differentiation by downregulating T-bet expression.

BACKGROUND: Mesenchymal stem/stromal cells (MSCs) are multipotent cells with strong tissue repair and immunomodulatory properties. Due to their ability to repress pathogenic immune responses, and in particular T cell responses, they show therapeutic potential for the treatment of autoimmune diseases, organ rejection and graft versus host disease. MSCs have the remarkable ability to export their own mitochondria to neighboring cells in response to injury and inflammation. However, whether mitochondrial transfer occurs and has any role in the repression of CD4+ Th1 responses is unknown. METHODS AND RESULTS: In this report we have utilized CD4+ T cells from HNT TCR transgenic mice that develop Th1-like responses upon antigenic stimulation in vitro and in vivo. Allogeneic bone marrow-derived MSCs reduced the diabetogenic potential of HNT CD4+ T cells in vivo in a transgenic mouse model of disease. In co-culture experiments, we have shown that MSCs were able to reduce HNT CD4+ T cell expansion, expression of key effector markers and production of the effector cytokine IFNγ after activation. This was associated with the ability of CD4+ T cells to acquire mitochondria from MSCs as evidenced by FACS and confocal microscopy. Remarkably, transfer of isolated MSC mitochondria to CD4+ T cells resulted in decreased T cell proliferation and IFNγ production. These effects were additive with those of prostaglandin E2 secreted by MSCs. Finally, we demonstrated that both co-culture with MSCs and transfer of isolated MSC mitochondria prevent the upregulation of T-bet, the master Th1 transcription factor, on activated CD4+ T cells. CONCLUSION: The present study demonstrates that transfer of MSC mitochondria to activated CD4+ T cells results in the suppression of Th1 responses in part by downregulating T-bet expression. Furthermore, our studies suggest that MSC mitochondrial transfer might represent a general mechanism of MSC-dependent immunosuppression.

g-NK cells from umbilical cord blood are phenotypically and functionally different than g-NK cells from peripheral blood.

FcRγ-deficient natural killer (NK) cells, designated as g-NK cells, exhibit enhanced antibody-dependent cellular cytotoxicity (ADCC) capacity and increased IFN-γ and TNF-α production, rendering them promising for antiviral and antitumor responses. g-NK cells from peripheral blood (PB) are often associated with prior human cytomegalovirus (HCMV) infection. However, the prevalence, phenotype, and function of g-NK cells in umbilical cord blood (UCB-g-NK) remain unclear. Here, we demonstrate significant phenotypical differences between UCB-g-NK and PB-g-NK cells. Unlike PB-g-NK cells, UCB-g-NK cells did not show heightened cytokine production upon CD16 engagement, in contrast to the conventional NK (c-NK) cell counterparts. Interestingly, following in vitro activation, UCB-g-NK cells also exhibited elevated levels of IFN-γ production, particularly when co-cultured with HCMV and plasma from g-NK+ adults. Furthermore, g-NK+ plasma from PB even facilitated the in vitro expansion of UCB-g-NK cells. These findings underscore the phenotypic and functional heterogeneity of g-NK cells based on their origin and demonstrate that components within g-NK+ plasma may directly contribute to the acquisition of an adult phenotype by the "immature" UCB-g-NK cells.

Salivary metabolome indicates a shift in tyrosine metabolism in patients with burning mouth syndrome: a prospective case-control study.

ABSTRACT: The pathophysiology of primary burning mouth syndrome (BMS) remains controversial. Targeted analyses or "omics" approach of saliva provide diagnostic or pathophysiological biomarkers. This pilot study's primary objective was to explore the pathophysiology of BMS through a comparative analysis of the salivary metabolome among 26 BMS female cases and 25 age- and sex-matched control subjects. Secondary objectives included comparative analyses of inflammatory cytokines, neuroinflammatory markers, and steroid hormones among cases and control subjects, and among BMS patients according to their clinical characteristics. Salivary metabolome, neuroinflammatory markers, cytokines, and steroids were, respectively, analysed by liquid chromatography coupled with mass spectrometry, ELISA and protease activity assay, and multiparametric Luminex method. Among the 166 detected metabolites, univariate analysis did not find any discriminant metabolite between groups. Supervised multivariate analysis divided patients into 2 groups with an accuracy of 60% but did not allow significant discrimination (permutation test, P = 0.35). Among the metabolites contributing to the model, 3 belonging to the tyrosine pathway ( l -dopa, l -tyrosine, and tyramine) were involved in the discrimination between cases and control subjects, and among BMS patients according to their levels of pain. Among the detectable molecules, levels of cytokines, steroid hormones, and neuroinflammatory markers did not differ between cases and control subjects and were not associated with characteristics of BMS patients. These results do not support the involvement of steroid hormones, inflammatory cytokines, or inflammatory neurogenic mediators in the pathophysiology of pain in BMS, whereas the observed shift in tyrosine metabolism may indicate an adaptative response to chronic pain or an impaired dopaminergic transmission.

"Plasma cell gingivitis" encompasses multiple entities: a retrospective series of 37 cases.

BACKGROUND: Plasma cell gingivitis is defined as gingival inflammation comprised of plasma cell infiltrates. This diagnostic criterion is non-specific and underlying mechanisms remain unknown. OBJECTIVES: We performed a multidisciplinary clinico-pathological review of cases previously identified as "gingivitis with plasma cell infiltrates", with assessment of putative contributing factors and critical appraisal of the final diagnosis. MATERIALS & METHODS: Cases previously identified as "gingivitis with plasma cell infiltrates" between 2000 and 2020 were included from archives from the GEMUB group, a French multidisciplinary network of physicians with expertise on oral mucosa. RESULTS: Among the 37 included cases, multidisciplinary clinico-pathological review allowed differential diagnosis in seven cases (oral lichen planus n=4, plasma cell granuloma n=1, plasmacytoma n=1, and mucous membrane pemphigoid n=1). The remaining cases were classified as "reactive plasma cell gingivitis" (induced by drugs, trauma/irritation or periodontal disease) (n=18) or "idiopathic plasma cell gingivitis" when no contributing factors were identified (n=12). Clinico-pathological characteristics did not differ significantly between "reactive" and "idiopathic" cases, preventing us from identifying specific features of "idiopathic" plasma cell gingivitis. CONCLUSION: "Plasma cell gingivitis" is a polymorphous, non-specific entity with various aetiologies, of which the diagnosis requires multidisciplinary anatomo-clinical correlation for exclusion of secondary causes of plasma cell infiltration. Although our study was limited by its retrospective design, most cases of "plasma cell gingivitis" appeared to be associated with an underlying cause. We propose a diagnostic algorithm to properly investigate such cases.

Absence of inferior labial and lingual frenula in Ehlers-Danlos syndrome: a minor diagnostic criterion in French patients.

BACKGROUND: Ehlers-Danlos syndrome (EDS) is a heterogenous group of diseases that can be potentially life threatening in the vascular form. The diagnosis is mainly based on a clinical score including many items that demonstrate skin, mucosa, joint, and vessel involvement. The score is particularly helpful in hypermobile and classical forms but can be normal in the vascular type. The absence of the lingual and inferior labial frenula was reported to be a useful diagnostic tool in a series of 12 patients with classical and hypermobile EDS. However, two further reports have contested the value of this sign. OBJECTIVE: To determine the diagnostic value of the absence of inferior labial or lingual frenula in EDS. METHODS: Patients with EDS were prospectively recruited from November 2006 to April 2007 in a French tertiary center. Each patient was examined to check for the presence or absence of the oral frenula and matched with two controls seen from February to May 2007. RESULTS: Forty-three patients (ratio female/male of 2.07 : 1, mean age 31 years, range 4-63 years), 4 with classical EDS, 19 with hypermobile EDS, and 20 with vascular-type EDS, were included and matched with 86 controls. The sensitivity of the absence of the inferior labial frenulum was 42% (95% CI 27, 58) and for the lingual frenulum was 53.5% (95% CI 38, 69). The specificity was 99% (95% CI 94, 100) and 98% (95% CI 92, 100), respectively. In the vascular group, 13 of 20 patients were affected (sensitivity = 65% [95% CI 41, 85]; specificity = 97% [95% CI 87, 100]; odds ratio = 72 [95% CI 8, 645]). Inter-observer agreement was excellent (kappa value 0.91). CONCLUSION: The absence of the inferior labial frenulum or lingual frenulum is a specific sign of EDS that can be easily checked by a physician. It can be helpful in the early diagnosis of the disease, including the vascular type, in affected families. It can also be helpful to distinguish between joint hypermobility syndrome and the hypermobile type of EDS in patients with joint hypermobility.

Combined effects of glycerol and petrolatum in an emollient cream: A randomized, double-blind, crossover study in healthy volunteers with dry skin.

BACKGROUND: The stratum corneum plays an important protective physiological role in providing a barrier to preventing skin desiccation and penetration of external agents. Emollients are used commonly to improve barrier function and skin hydration. AIMS: The primary objective of this study was to evaluate the effect of an emollient, V0034CR cream, and its active ingredients, to restore the cutaneous barrier. Secondary objectives included assessment of the moisturizing activity of each product and tolerance. The study was not designed to evaluate therapeutic benefit. METHODS: In this randomized, double-blind, 4-arm crossover, clinical pharmacology study, the full emollient V0034CR, its vehicle formulation alone, or with glycerol, or petrolatum, was applied to the forearms of healthy volunteers (n = 51) with dry skin (Kligman score of 2 or 3). Cutaneous permeability by Trans Epidermal Water Loss (TEWL) and skin moisture content by corneometry were serially measured for 12 hours following application. An analysis of variance with repeated measures was performed on the evolution of TEWL and corneometry. RESULTS: V0034CR emollient significantly reduced mean TEWL compared to vehicle (P = .0018) and vehicle + glycerol (P = .0001) and significantly increased mean corneometry scores compared to vehicle (P < .0001) and vehicle + petrolatum (P < .0001). CONCLUSIONS: The emollient V0034CR presented combined effects, with the petrolatum component improving skin barrier function, with a reduction in TEWL, and the glycerol component improving skin hydration.

Immunostaining with antibodies to desmoglein provides the diagnosis of drug-induced pemphigus and allows prediction of outcome.

No tool is available to diagnose drug-induced pemphigus (DIP) and to predict its outcome after the withdrawal of the culprit drugs. This retrospective pemphigus case series study compared cutaneous/mucosal immunostaining of a monoclonal antibody directed toward desmogleins 1 and 3 (32-2B) in 37 patients with DIP and 56 patients with idiopathic pemphigus. There was a significant difference between the groups in terms of pruritus, superficial form, mucosal involvement, and circulating antibodies. 32-2B staining disclosed a patchy pattern in 47 (84%) of idiopathic pemphigus cases and in 11 (30%) of DIP cases (P<.0001). A normal pattern, used as a diagnostic test for DIP, had 70.3% sensitivity (95% confidence interval [CI], 53.0-84.1), 83.9% specificity (95% CI, 71.7-92.4), a 32.7% positive predictive value, and a 97.9% negative predictive value. Of 17 patients with DIP with a normal pattern of 32-2B, 14 recovered, whereas only 2 of 9 patients with DIP with a patchy pattern recovered (P<.005).32-2B immunolabeling is useful for diagnosing DIP and is an indicator of a good prognosis.

One-step surgical removal of cutaneous melanoma with surgical margins based on preoperative ultrasound measurement of the thickness of the melanoma.

BACKGROUND: Surgical margins of melanoma vary from 5 mm to 1 or 2 cm depending on histology thickness (Breslow). This approach usually requires two surgical steps: excisional biopsy and further re-excision according to histology thickness. A previous systematic review showed that measuring melanoma thickness with high-resolution ultrasound imaging equipment correlates well with histological measurement of melanoma thickness. Therefore, we routinely determined tumour sonographic thickness in order to perform surgery as a single step. OBJECTIVES: To determine the proportion of patients who receive one-step surgery with adequate margins based on sonographic measurement of melanoma thickness and identify the reasons for differences between these two measurements. MATERIALS AND METHODS: A retrospective series of patients with melanoma, in which thickness was measured by ultrasound (20 MHz) from April 2007 to December 2015 prior to surgery. RESULTS: Ninety-nine melanomas were treated, of which 78 were removed in a single step with surgical margins based on sonometric thickness measurements; 71 of these (91%, 95% CI: 82-96) did not require re-excision, five had excessive margins, and two had insufficient margins. The correlation between the histometric and sonometric measurements was good; r=0.88. Significant absolute difference between sonometric and histometric measurements was associated with thickness, ulceration, and size of tumours, based on bivariate analysis. Thickness remained the only significant factor based on multivariate analysis. CONCLUSION: Measuring the thickness of melanoma with high-resolution ultrasound imaging equipment makes it possible to remove the melanoma in a single step with adequate margins in at least 82% of the cases in routine care.

A comparison of oral and topical corticosteroids in patients with bullous pemphigoid.

BACKGROUND: Bullous pemphigoid is the most common autoimmune blistering skin disease of the elderly. Because elderly people have low tolerance for standard regimens of oral corticosteroids, we studied whether highly potent topical corticosteroids could decrease mortality while controlling disease. METHODS: A total of 341 patients with bullous pemphigoid were enrolled in a randomized, multicenter trial and stratified according to the severity of their disease (moderate or extensive). Patients were randomly assigned to receive either topical clobetasol propionate cream (40 g per day) or oral prednisone (0.5 mg per kilogram of body weight per day for those with moderate disease and 1 mg per kilogram per day for those with extensive disease). The primary end point was overall survival. RESULTS: Among the 188 patients with extensive bullous pemphigoid, topical corticosteroids were superior to oral prednisone (P=0.02). The one-year survival rate was 76 percent in the topical-corticosteroid group and 58 percent in the oral-prednisone group. Disease was controlled at three weeks in 92 of the 93 patients in the topical-corticosteroid group (99 percent) and 86 of the 95 patients in the oral-prednisone group (91 percent, P=0.02). Severe complications occurred in 27 of the 93 patients in the topical-corticosteroid group (29 percent) and in 51 of the 95 patients in the oral-prednisone group (54 percent, P=0.006). Among the 153 patients with moderate bullous pemphigoid, there were no significant differences between the topical-corticosteroid group and the oral-prednisone group in terms of overall survival, the rate of control at three weeks, or the incidence of severe complications. CONCLUSIONS: Topical corticosteroid therapy is effective for both moderate and severe bullous pemphigoid and is superior to oral corticosteroid therapy for extensive disease.

Neurological disorders in patients with bullous pemphigoid.

BACKGROUND: Unexpected cases of bullous pemphigoid (BP) have been reported in adult patients with various neurological disorders suggesting a possible relationship between these diseases. OBJECTIVES: (1) To determine the prevalence and types of neurological disorders in patients with BP, (2) to assess patients' functional impairment, and (3) to compare the clinical and biological findings as well as prognosis of BP patients presenting with or without neurological disorders. METHODS: BP patients with neurological disorders were selected in a series of 341 consecutive BP patients treated in 20 French Dermatology Departments. Functional impairment was prospectively assessed using the Karnofsky score which is a measure of patients' general condition. RESULTS: At least one neurological disorder was present in 123 of the 341 BP patients (36%). They primarily consisted of dementia (n = 68; 20%; 95% CI: 16-25%), cerebral stroke (n = 52; 15%; 95% CI: 4-19%), and/or Parkinson's disease or parkinsonism (n = 32; 9%; 95% CI: 7-13%). BP patients with neurological disease were older than patients without neurological disease (83.8 +/- 7.5 years vs. 79.3 +/- 10.3 years, p < 10(-4)). They also had a lower Karnofsky score (47 +/- 19% vs. 74 +/- 20%, p < 10(-4)). One-year overall survival rates of the two groups were 50.8% (95% CI: 41.8-59.7) and 78.7% (95% CI: 73.0-84.2), respectively (p < 10(-4)). In contrast, the number of bullae and main biological features at baseline were not different between the two groups of patients. CONCLUSION: This study demonstrated a high frequency of neurological disorders, particularly dementia, in BP patients. Most of these patients had a severe functional impairment and a poor prognosis.

High-frequency ultrasound imaging for cutaneous neurofibroma in patients with neurofibromatosis type I.

Neurofibromas (NFs) are benign tumours arising from a nerve sheath, which are present in nearly all patients with neurofibromatosis type 1 (NF1). High-frequency ultrasound (HFU) systems, using frequencies over 20 MHz, were developed to improve visualization of skin tumours by means of increased resolution. To describe NFs by using HFU in patients with NF1. Anonymized HFU (25-MHz) images of NFs were randomized. Initially, two dermatologist investigators, with experience in HFU imaging of the skin, together described the ultrasound images and established eight criteria for NFs. The same task was then repeated by two other dermatologists, also with experience in HFU imaging of the skin, independently, to establish inter-observer agreement. A total of 108 NFs in 29 patients were included. Superficial and subcutaneous NFs were hypoechoic with a round to spindle shape. Plexiform NFs were ill-defined, consisting of multiple hypoechoic linear zones. Good to excellent inter-observer agreement was found for six of the eight criteria (k>0.6). This is the first series describing HFU skin imaging of NFs in patients with NF1. Lateral extension that may correspond to involvement of an adjacent nerve seems to be specific to NFs.

[Aphthous ulcers and oral ulcerations]. / Aphtes et ulcérations buccales.

Aphthous ulcers are painful ulcerations located on the mucous membrane, generally in the mouth, less often in the genital area. Three clinical forms of aphthous ulcers have been described: minor aphthous ulcers, herpetiform aphthous ulcers and major aphthous ulcers. Many other conditions presenting with oral bullous or vesiculous lesions orulcerations and erosions can be mistaken for aphthous ulcers. Currently, treatment of aphthous ulcers is palliative and symptomatic. Topical treatments (topical anesthetics, topical steroids and sucralfate) are the first line therapy. Recurrent aphthous stomatitis (RAS) is defined by the recurrence of oral aphthous ulcers at least 4 times per year. RAS is often idiopathic but can be associated with gastro-intestinal diseases (i.e. celiac disease, inflammatory bowel diseases), nutritional deficiencies (iron, folates...), immune disorders (HIV infection, neutropenia) and rare syndromes. Behçet's disease is a chronic, inflammatory, disease whose main clinical feature is recurrent bipolar aphthosis. Colchicine associated with topical treatments constitutes a suitable treatment of most RAS. Thalidomide is the most effective treatment of RAS but its use is limited by frequent adverse effects. Oral ulcers can be related to a wide range of conditions that constitute the differential diagnoses of aphthous ulcers. Oral ulcers are classified into three main groups: acute ulcers with abrupt onset and short duration, recurrent ulcers (mainly due to postherpetic erythema multiforme) and chronic ulcers (with slow onset and insidious progression). Acute oral ulcers are due to trauma, bacterial infections (including acute necrotizing ulcerative gingivitis), deep fungal infection, gastro-intestinal (namely inflammatory bowel disease) or systemic diseases. Chronic oral ulcers may be drug-induced, or due to benign or malignant tumors. Every oral solitary chronic ulcer should be biopsied to rule out squamous cell carcinoma. A solitary palatal ulcer can be related with necrotizing sialometaplasia.

Treatment of early-stage mycosis fungoides with twice-weekly applications of mechlorethamine and topical corticosteroids: a prospective study.

OBJECTIVE: To determine if a therapeutic regimen of twice-weekly applications of mechlorethamine hydrochloride and betamethasone dipropionate cream is effective in the treatment of early-stage mycosis fungoides while increasing cutaneous tolerance. DESIGN: Prospective nonrandomized study conducted from November 1999 to November 2002. SETTING: Eleven university or hospital dermatology departments in France. PATIENTS: Sixty-four consecutive patients with newly diagnosed early-stage mycosis fungoides (stage IA, n = 33; stage IB, n = 26; stage IIA, n = 5). INTERVENTIONS: Patients were treated with twice-weekly applications of a 0.02% aqueous solution of mechlorethamine followed by an application of betamethasone cream during a 6-month period. MAIN OUTCOME MEASURES: The primary end point was the rate of complete response during the treatment. Secondary end points were mean delay to achieve complete response, rate of severe cutaneous reactions of intolerance, and rate of relapse after achieving complete response. RESULTS: Thirty-seven patients (58%) had a complete response after a mean +/- SD treatment duration of 3.6 +/- 2.5 months: 20 (61%) of 33 patients with stage IA disease, 15 (58%) of 26 patients with stage IB disease, and 2 (40%) of 5 patients with stage IIA disease. Eighteen patients (28%) developed severe cutaneous reactions of intolerance that necessitated treatment discontinuation. Relapse was observed in 17 patients (46%) after a mean +/- SD time of 7.7 +/- 6.5 months. CONCLUSIONS: A regimen of twice-weekly applications of mechlorethamine and betamethasone cream is an effective treatment for early-stage mycosis fungoides. The decreased frequency of applications provides an advantage to the patient by being easy to use with limited adverse effects.

Effect of sonication parameters on transdermal delivery of insulin to hairless rats.

Application of low-frequency ultrasound has been shown to enhance transdermal drug transport of large molecules such as insulin. In this study, we investigated the dependence of ultrasound-induced transdermal delivery of insulin on ultrasound parameters. Insulin was delivered in vivo to hairless rats using 20 kHz ultrasound applied over a range of ultrasound intensity, application time and pulse length. Change in blood glucose levels of the animals was monitored to assess insulin transport. The results showed a threshold below which no detectable changes in blood glucose level was observed for each ultrasound parameter. Moreover, our findings indicated that sonophoretic enhancement is dependent on energy dose and length of ultrasound pulse that is consistent with a cavitation-based mechanism. The more significant effect of lowering glycemia was obtained with application of less than 15 min ultrasound and was similar to subcutaneous injection of 0.5 U of insulin. Pretreatment of hairless rat skin with ultrasound followed by application of insulin resulted in no significant modification in blood glucose level, indicating that transdermal transport of insulin mainly occurred during sonication. Sonophoresis may therefore potentially be applied for non-invasive and painless delivery of insulin in the treatment of insulin-dependent diabetes.