Identification of three clinical neurofibromatosis 1 subtypes: Latent class analysis of a series of 1351 patients.

BACKGROUND: Neurofibromatosis 1 (NF1) is one of the most common inherited disorders characterized by mutations in the tumour suppressor gene NF1. Its clinical manifestations are highly variable and unpredictable. A specific NF1 mutation does not predict the severity or complications of the disease. OBJECTIVE: The objective of this study was to build an empirical classification scheme without any a priori hypotheses to identify the underlying NF1 subtypes that best explain the observed heterogeneity. METHODS: We performed latent class analysis (LCA) of 1351 consecutive NF1 patients aged >17 years seen between 2002 and 2014. Data and phenotypic features were collected prospectively on a standardized form. RESULTS: The median age was 36.8 (17-81) years. A three-class model showed the best fit: 706 (52%) belonged to the LC1 'Cutaneous neurofibromas' class having preferentially cutaneous neurofibromas (99%), plexiform neurofibromas (63%) and blue-red macules (29%); 593 (44%) belonged to the LC2 'Subcutaneous neurofibromas' class characterized by the presence of at least 10 subcutaneous neurofibromas (21%) and a familial form (77%) and 52 (4%) belonged to the LC3 'Dysmorphic phenotype' class characterized by dysmorphic features (78%) and learning difficulties (87%). Patients in LC1 had a higher likelihood of developing scoliosis (RR = 1.7, 95% confidence interval (CI) [1.2-2.4]). Patients in LC2 were more likely to be men (RR = 1.4, 95% CI [1.1-1.7]). Patients in LC3 were at higher risk of having an optic pathway glioma (RR = 4.8, 95% CI [1.9-11.8]) and epilepsy (RR = 4.5, 95% CI [1.8-11.6]). CONCLUSION: Our findings invite the performance of a larger cohort study to test whether the various latent classes reflect different underlying genetic modifiers of these phenotypic traits.

Immune checkpoint inhibitor treatment of a first cancer is associated with a decreased incidence of second primary cancer.

BACKGROUND: Second primary cancers (SPCs) are diagnosed in over 5% of patients after a first primary cancer (FPC). We explore here the impact of immune checkpoint inhibitors (ICIs) given for an FPC on the risk of SPC in different age groups, cancer types and treatments. PATIENTS AND METHODS: The files of the 46 829 patients diagnosed with an FPC in the Centre Léon Bérard from 2013 to 2018 were analyzed. Structured data were extracted and electronic patient records were screened using a natural language processing tool, with validation using manual screening of 2818 files of patients. Univariate and multivariate analyses of the incidence of SPC according to patient characteristics and treatment were conducted. RESULTS: Among the 46 829 patients, 1830 (3.9%) had a diagnosis of SPC with a median interval of 11.1 months (range 0-78 months); 18 128 (38.7%) received cytotoxic chemotherapy (CC) and 1163 (2.5%) received ICIs for the treatment of the FPC in this period. SPCs were observed in 7/1163 (0.6%) patients who had received ICIs for their FPC versus 437/16 997 (2.6%) patients receiving CC and no ICIs for the FPC versus 1386/28 669 (4.8%) for patients receiving neither CC nor ICIs for the FPC. This reduction was observed at all ages and for all histotypes analyzed. Treatment with ICIs and/or CC for the FPC are associated with a reduced risk of SPC in multivariate analysis. CONCLUSION: Immunotherapy with ICIs alone and in combination with CC was found to be associated with a reduced incidence of SPC for all ages and cancer types.

Long-term efficacy and safety of sonidegib in patients with advanced basal cell carcinoma: 42-month analysis of the phase II randomized, double-blind BOLT study.

BACKGROUND: Basal cell carcinomas (BCCs) exhibit aberrant activation of the hedgehog pathway. Sonidegib is a hedgehog pathway inhibitor approved for the treatment of locally advanced BCC (laBCC) and metastatic BCC (mBCC) based on primary results of the BOLT study [Basal Cell Carcinoma Outcomes with LDE225 (sonidegib) Treatment]. OBJECTIVES: This is the final 42-month analysis of the BOLT study, evaluating the efficacy and safety of sonidegib. METHODS: Adults with no prior hedgehog pathway inhibitor therapy were randomized in a 1 : 2 ratio to sonidegib 200 mg or 800 mg once daily. Treatment continued for up to 42 months or until disease progression, unacceptable toxicity, death, study termination or withdrawal of consent. The primary efficacy end point was the objective response rate (ORR) by central review, assessed at baseline; weeks 5, 9 and 17; then subsequently every 8 or 12 weeks during years 1 or 2, respectively. Safety end points included adverse event monitoring and reporting. RESULTS: The study enrolled 230 patients, 79 and 151 in the 200-mg and 800-mg groups, respectively, of whom 8% and 3.3% remained on treatment by the 42-month cutoff, respectively. The ORRs by central review were 56% [95% confidence interval (CI) 43-68] for laBCC and 8% (95% CI 0·2-36) for mBCC in the 200-mg group and 46·1% (95% CI 37·2-55·1) for laBCC and 17% (95% CI 5-39) for mBCC in the 800-mg group. No new safety concerns emerged. CONCLUSIONS: Sonidegib demonstrated sustained efficacy and a manageable safety profile. The final BOLT results support sonidegib as a viable treatment option for laBCC and mBCC. What's already known about this topic? Basal cell carcinoma (BCC) is usually treatable with surgery or radiation therapy, but there are limited treatment options for patients with advanced BCC. Sonidegib, a hedgehog pathway inhibitor approved for the treatment of advanced BCC, demonstrated clinically relevant efficacy and manageable safety in prior analyses of the phase II randomized, double-blind BOLT study [Basal Cell Carcinoma Outcomes with LDE225 (sonidegib) Treatment]. What does this study add? This final 42-month analysis of BOLT is the longest follow-up available for a hedgehog pathway inhibitor. Clinically relevant efficacy results were sustained from prior analyses, with objective response rates by central review of the approved 200-mg daily dose of 56% in locally advanced BCC and 8% in metastatic BCC. No new safety concerns were raised. The results confirmed sonidegib as a viable long-term treatment option for patients with advanced BCC.

Long-term efficacy and safety of sonidegib in patients with locally advanced and metastatic basal cell carcinoma: 30-month analysis of the randomized phase 2 BOLT study.

BACKGROUND: Patients with locally advanced basal cell carcinoma (laBCC) or metastatic BCC (mBCC), two difficult-to-treat populations, have had limited treatment options. Sonidegib, a hedgehog pathway inhibitor (HPI), was approved in laBCC based on results from the BOLT trial. OBJECTIVE: To evaluate long-term efficacy and safety of sonidegib in laBCC and mBCC in the BOLT 18- and 30-month analyses. METHODS: BOLT (NCT01327053, ClinicalTrials.gov), a double-blind phase 2 study, enrolled patients from July 2011 until January 2013. Eligible HPI-treatment-naïve patients with laBCC not amenable to curative surgery/radiotherapy or mBCC were randomized 1 : 2 to sonidegib 200 mg (laBCC, n = 66; mBCC, n = 13) or 800 mg (laBCC, n = 128; mBCC, n = 23). Tumour response was assessed per central and investigator review. RESULTS: With 30 months of follow-up, among patients treated with sonidegib 200 mg (approved dose), objective response rates were 56.1% (central) and 71.2% (investigator) in laBCC and 7.7% (central) and 23.1% (investigator) in mBCC. Tumour responses were durable as follows: median duration of response was 26.1 months (central) and 15.7 months (investigator) in laBCC and 24.0 months (central) and 18.1 months (investigator) in mBCC. Five patients with laBCC and three with mBCC in the 200-mg arm died. Median overall survival was not reached in either population; 2-year overall survival rates were 93.2% (laBCC) and 69.3% (mBCC). In laBCC, efficacy was similar regardless of aggressive or non-aggressive histology. Sonidegib 200 mg continued to have a better safety profile than 800 mg, with lower rates of grade 3/4 adverse events (43.0% vs. 64.0%) and adverse events leading to discontinuation (30.4% vs. 40.0%). CONCLUSION: Sonidegib continued to demonstrate long-term efficacy and safety in these populations. These data support the use of sonidegib 200 mg per local treatment guidelines.

[Management of craniofacial type 1 neurofibromatosis]. / Prise en charge des atteintes craniofaciales de la neurofibromatose de type 1.

Type I neurofibromatosis (NF) is the most common autosomal dominant disease. It concerns one in 3000 births, the penetrance is close to 100% and 50% of new cases are de novo mutations (17q11.2 chromosome 17 location). Cranio-maxillofacial region is concerned in 10% of the cases, in different forms: molluscum neurofibroma, plexiform neurofibroma, cranio-orbital neurofibroma, parotido-jugal neurofibroma, cervical neurofibroma. These lesions have different prognosis depending on the craniofacial localization: ocular functional risk, upper airway compressive risk, nerve compression risk, aesthetic and social impact. The maxillofacial surgeon in charge of patients with type I NF should follow the patient from the diagnosis and organize the different surgical times in order to take care about the different issues: vital, functional and aesthetic. We describe the treatment of facial localizations of type 1 NF as it is done at the University Hospital of Lyon and at the Rhône-Alpes-Auvergne neurofibromatosis reference center.

Germline BAP1 mutations predispose also to multiple basal cell carcinomas.

The BRCA1-associated protein 1 (BAP1) gene encodes a nuclear deubiquitin enzyme which acts as a tumour suppressor. Loss of function germline mutations of BAP1 have been associated with an enhanced risk of uveal and cutaneous melanomas, mesothelioma, clear cell renal cancer and atypical cutaneous melanocytic proliferations. In two independent BAP1 families, we noticed an unusual frequency of basal cell carcinomas (BCCs). Indeed, 19 BCCs were diagnosed in four patients, either of superficial (13/19) or nodular (6/19) subtype; they were all located in chronic sun-exposed areas (limbs, head or neck). Immunohistochemistry (IHC) identified in the 19 tumours, complete or partial loss of BAP1 protein nuclear expression, restricted to the BCC nests. A control study was conducted in 22 sporadic BCCs in 22 subjects under 65 without known associated BAP1 tumours: no loss of BAP1 expression was found. Overall, our observations suggest that BCCs are part of the BAP1 cancer syndrome, perhaps in relation with chronic sun exposure and melanocortin 1 receptor (MC1R) variants. In conclusion, cutaneous follow-up of BAP1 carriers should not only aim to detect melanocytic neoplasms but also BCCs.

[Locoregional treatments of brain metastases for patients with metastatic cutaneous melanoma: French national guidelines]. / Traitements locorégionaux de métastase(s) cérébrale(s) chez des patients atteints d'un mélanome cutané métastatique : recommandations nationales françaises.

INTRODUCTION: The management of metastatic cutaneous melanoma is changing, marked by innovative therapies. However, their respective use and place in the therapeutic strategy continue to be debated by healthcare professionals. OBJECTIVE: The French national cancer institute has led a national clinical practice guideline project since 2008. It has carried out a review of these modalities of treatment and established recommendations. METHODS: The clinical practice guidelines development process is based on systematic literature review and critical appraisal by experts. The recommendations are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines are reviewed by independent practitioners in cancer care delivery. RESULTS: This article presents the results of bibliographic search, the conclusions of the literature and the recommendations concerning locoregional treatments of brain metastases for patients with metastatic cutaneous melanoma.

[Management of patients with metastatic cutaneous melanoma: French national guidelines. French National Cancer Institute]. / Prise en charge thérapeutique des patients atteints d'un mélanome cutané métastatique : recommandations nationales françaises. L'Institut national du cancer.

BACKGROUND: Recent years have seen the emergence of new molecules for the treatment of patients with metastatic cutaneous melanoma, with significant benefits in terms of survival and the opening of new therapeutic perspectives. In addition, many techniques are currently being developed for locoregional treatment of metastatic sites. Management of metastatic melanoma is thus fast-changing and is marked by innovative therapeutic approaches. However, the availability of these new treatments has prompted debate among healthcare professionals concerning their use and their place in therapeutic strategy. AIMS: Since 2008, the French National Cancer Institute (INCa) has been leading a project to define and diffuse national clinical practice guidelines. It has performed a review of these treatment methods, which it aims to circulate, and it is seeking to develop recommendations in order to allow nationwide implementation of innovative approaches while promoting good use thereof. METHODS: The clinical practice guidelines development process is based on systematic literature review and critical appraisal by experts within a multidisciplinary working group, with feedback from specialists in cancer care delivery. The recommendations are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines are reviewed by independent practitioners in cancer care delivery. RESULTS: This article presents the national recommendations for first- and second-line systemic treatment and for locoregional treatment of metastatic sites in patients presenting metastatic cutaneous melanoma.

Prognostic factors associated with healing of venous leg ulcers: a multicentre, prospective, cohort study.

BACKGROUND: Some prognostic markers of venous leg ulcer (VLU) healing have been evaluated, mostly in retrospective studies. OBJECTIVES: To identify which clinical characteristics, among those known as possible prognostic factors of VLU healing, and which VLU-associated sociodemographic and psychological factors, are associated with complete healing at week 24 (W24). METHODS: A prospective, multicentre, cohort study was conducted in 22 French dermatology departments between September 2003 and December 2007. The end point was comparison between healed and nonhealed VLUs at W24, for patient clinical and biological characteristics; psychological, cognitive and social assessments; affected leg inclusion characteristics; venous insufficiency treatment and percentage of initial wound area reduction during follow-up. RESULTS: In total, 104 VLUs in 104 patients were included; 94 were analysed. The mean VLU area and duration were 36.8 ± 55.5 cm2 and 24.8 ± 45.7 months, respectively. At W24, 41/94 VLUs were healed. Univariate analysis significantly associated complete healing with superficial venous surgery (P = 0.001), adherence to compression therapy at W4 (P = 0.03) and W24 (P = 0.01), ankle-joint ankylosis (P = 0.01) and mean percentage of VLU area reduction at W4 (P = 0.04). Multivariate analysis retained superficial venous surgery during follow-up [odds ratio (OR) 8.4, 95% confidence interval (CI) 1.9-48.2] and percentage reduction of the VLU area at W4 (OR 1.6, 95% CI 1.0-2.14) as being independently associated with healing. CONCLUSIONS: These results indicate that complete healing of long-standing, large VLUs is independently associated with ablation of the incompetent superficial vein and percentage of wound area reduction after the first 4 weeks of treatment.

Efficacy of a silver lipidocolloid dressing on heavily colonised wounds: a republished RCT.

Nearly all open wounds are contaminated by microorganisms. This generally corresponds to simple bacterial growth, without leading to deleterious effects or compromising the progress of the healing process. In acute wounds, the probability of wound infection increases as the level of contamination does. However, it is more complex for chronic wounds, which are able to contain and tolerate large amounts of bacteria, many times higher than the usual threshold level (>105 bacteria/g of tissue) defining infection in acute wounds,1 without inducing local signs. Nevertheless, many clinical and experimental studies indicate that the probability for chronic wounds to heal properly is limited when the bacterial load exceeds this level of contamination; even when body defences are still able to prevent tissue invasion, bacteria can impair wound healing.

Efficacy and safety of hyaluronic acid in treatment of leg ulcers: a double-blind RCT.

OBJECTIVE: To investigate the efficacy and safety of hyaluronic acid in the local treatment of leg ulcers of venous or mixed aetiology, compared with a neutral vehicle. METHOD: A 60-day double-blind, randomised, multicentre, controlled superiority trial. The primary endpoint was the percentage wound size reduction after 45 days of treatment. Secondary endpoints included pain intensity, rate of complete ulcer healing, and aspect of the wound (percentage of necrotic, fibrinous or granulation tissue) and of the peri-ulcer skin. RESULTS: A total of 101 patients were randomised and analysed in the intention-to-treat (ITT) population (50 in the hyaluronic acid; 51 in the control group). Seventy-five patients were considered in the per protocol (PP) population (38 vs 37, respectively). At day 45, the percentage of ulcer surface reduction was significantly greater in the hyaluronic acid treatment group (39 ± 6%) compared with the neutral vehicle (control) group (5 ± 9%) (p=0.002). A similar result was obtained at day 15, day 30 and day 60. From day 0 to day 45, pain intensity (VA S) decreased by mean 9.8 ± 3.5mm in the hyaluronic acid group, but slightly increased by 0.8 ± 3.2mm in the control group (p=0.029). Burden of pain, as estimated by the area under the curve of daily pain (from day 0 to day 60), was significantly lower in the hyaluronic acid group (121.9 ± 20.7mm2) than in the control group (207.4 ± 32.9mm2; p=0.028). Other secondary endpoints (rate of complete healing, characteristics of the wound and peri-ulcer skin) were not significantly different between the two groups. Treatments were well tolerated and adverse events were comparable between the two groups in terms of their frequency, relationship to treatment and severity. CONCLUSION: Hyaluronic acid cream was significantly more effective than the neutral vehicle in the local treatment of leg ulcers of venous or mixed aetiology, in terms of wound size reduction and reducing the burden of pain, with a good safety profile.

[Usefulness of systematic brain magnetic resonance imaging in children with neurofibromatosis type 1]. / La réalisation systématique de l'imagerie par résonance magnétique cérébrale a-t-elle un intérêt chez l'enfant atteint de neurofibromatose de type 1?

BACKGROUND AND AIM: The aim of this study was to evaluate the usefulness of systematic screening of asymptomatic neurofibromatosis type 1 (NF1) children with magnetic resonance imaging (MRI). PATIENTS AND METHODS: We retrospectively reviewed the MRIs of children diagnosed with NF1 disease according to the National Institutes of Health criteria, who had been followed for at least 1 year by the department of pediatric neurology (Lyon, France). Brain MRI was systematically performed in asymptomatic patients under 6 years of age. RESULTS: One hundred patients with a median follow-up of 3.7 years (range, 1-8.6 years) were reviewed. Brain MRI was performed in a total of 94 children. Nine optic pathway gliomas were detected in symptomatic patients. Six children had symptoms caused by the tumor. Gliomas remained stable in 10 patients; 1 symptomatic glioma in an 8-year-old girl required treatment. Spontaneous regression was seen in 1 patient. CONCLUSION: Our results suggest that MRI screening of asymptomatic children to detect optic pathway gliomas does not improve the therapeutic decision and should not be performed systematically. We suggest further investigation in collaboration with the French NF Network.

An innovative water-soluble biopolymer improves efficacy of ciclopirox nail lacquer in the management of onychomycosis.

BACKGROUND: A new 8% ciclopirox-medicated nail lacquer (P-3051), based on a new technology, revealed superior properties in terms of affinity to keratin, nail permeation, and ease of use. OBJECTIVE: This study aims to assess the efficacy and safety of P-3051 vs. the market 8% ciclopirox nail lacquer. METHODS: This is a multicentre, randomized, three-arm, placebo-controlled, parallel groups, evaluator-blinded study. Overall, 467 patients with onychomycosis of at least one big toenail were randomized to receive P-3051, the reference drug or placebo in a 2 : 2 : 1 ratio for a 48-week treatment by daily application, followed by a 12-week follow-up. RESULTS: The study satisfied its objective by demonstrating that P-3051 was both superior to placebo and non-inferior to reference in the complete cure rate after a 48-week active treatment period. Switching the non-inferiority to superiority hypothesis, the superiority of P-3051 vs. reference was nearly significant at week 48 (confirmed at week 52), and it was significant at week 60 (cure rate for P-3051 is 119% higher than reference; P < 0.05). Altogether, the results on primary endpoint exceed expectations; superiority test was performed also on secondary endpoints to confirm the superiority trend of the study. At the end of follow-up, percentages of patients who achieved the endpoint 'responder' in the P-3051 group were 66% higher than reference (P < 0.05), and those who achieved the endpoint 'decrease of diseased nail' were 40% higher (P < 0.05). CONCLUSION: Ciclopirox 8% hydrolacquer is more active than reference ciclopirox nail lacquer in the treatment of onychomycosis.

[Utility of 18 FDG positon emission tomography in detection of sarcomatous transformation in neurofibromatosis type 1]. / Intérêt de la tomographie par émission de positons au fluorodéoxyglucose 18 dans la détection des neurofibrosarcomes au cours de la neurofibromatose de type 1.

BACKGROUND: The appearance of malignant peripheral nerve sheath tumours (MPNST) marks a critical stage in the course of neurofibromatosis type 1 (NF1). Since the diagnostic criteria are fairly non-specific, histological examination alone can confirm malignancy. We assessed the value of 18 FDG positron emission tomoscintigraphy (PET scan) in screening for such malignant tumours. PATIENTS AND METHODS: Between October 2000 and August 2006, all of our patients with NF1 and suspected MPNST underwent PET scan. Inclusion criteria consisted of clinical signs (increased tumour size or induration, pain) and/or laboratory values. Analysis of PET scan images, based upon determination of tumour/liver binding ratio with a cut-off point of 1.5 times hepatic binding, was used to classify lesions as non-suspect or pathological. In the case of suspect lesions, histological analysis was performed. For non-suspect lesions, patients either underwent monitoring or excision of the lesion where necessary and technically feasible. RESULTS: Thirty-eight patients with 49 tumours were included in the study. In 8 patients, PET scan showed suspect lesions (12 tumours), and histological analysis of these tumours revealed 6 MPNST. In 30 patients (37 tumours) PET scan showed non-suspect binding, and no malignant tumours were demonstrated either on histological examination or after mean follow-up of 33.5 months. PET scan thus demonstrated a sensitivity and negative predictive value of 100%, specificity of 86%, and a positive predictive value of 50%. The ratios of positive and negative probability were respectively 7.14 and 0. DISCUSSION: Our study, to our knowledge the most extensive yet performed, demonstrates the value of PET scan in detecting MPNST, particularly based on its 100% negative predictive value. To date, other than biopsy, no examinations allow diagnosis with any certainty. The literature reports 2 studies analysing the value of PET scan. The first involved 18 NF1 patients with 23 plexiform neurofibromas: of 7 tumours with hyperbinding, 5 were MPNST. The second study concerned 5 NF1 patients with a total of 15 tumours: 7 tumours showed hyperbinding, of which 6 were MPNST. Using the same evaluation criteria, our study yielded comparable results. The negative predictive value of 100% provides a strong argument in favour of a benign tumour. CONCLUSION: Our study confirms the value of PET scan in the detection of NF1 even though false positives require medical-surgical confirmation before any potentially detrimental therapeutic decisions may be made.