Malignant peripheral nerve sheath tumors (MPNST) are rare, aggressive soft-tissue sarcomas frequently associated with neurofibromatosis type 1 (NF1). Prognostic factors and optimal treatment strategies remain poorly defined. METHODS:Retrospective cohort study including all MPNST patients managed at Centre Léon Bérard (2000-2025). Overall survival (OS) was estimated using Kaplan-Meier and multivariable Cox models with multiple imputation. Transcriptional heterogeneity was explored via bulk RNA sequencing in a tumor subset. RESULTS:The cohort comprised 206 patients and 219 tumor episodes. Median OS was 53.6 months. NF1-associated tumors had inferior OS compared with sporadic tumors (median OS 26.6 vs 141.0 months, p = 0.012), with a 5-year restricted mean survival time (RMST) reduction of 7.6 months (95% CI -13.8 to -1.2; p = 0.025). Independent predictors of worse OS were higher stage (HR 2.37, p < 0.001), FNCLCC grade (HR 1.79, p < 0.001), NF1 status (HR 1.74, p = 0.006), central location (HR 1.75, p = 0.013) and older age (HR 1.41 per 10 years, p < 0.001); female sex was protective (HR 0.46, p < 0.001). Major biopsy-surgical histologic discordance occurred in 21.3% of cases. Radiotherapy showed context-dependent survival associations, with benefit in grade 3 tumors (HR 0.39, p < 0.001), locally advanced disease (HR 0.32, p = 0.003) and after macroscopically incomplete resections (HR 0.34, p = 0.027). Exploratory transcriptomic analysis identified two NF1-independent expression states defined by Schwann-lineage/immune versus proliferative programs. CONCLUSIONS:Outcomes remain poor, particularly in NF1. Discordance supports centralized expert review. Disease extent and anatomical location are major prognostic drivers. Radiotherapy may be beneficial in selected high-risk contexts. The transcriptomic landscape supports hypothesis-generating biomarker development based on tumor-state biology beyond NF1 status alone.

Percutaneous cryoablation is a promising minimally invasive treatment for unresectable plexiform neurofibromas in adults with neurofibromatosis type 1. In this study, cryoablation reduced tumour size by at least 20% in 71% of treated cases, with most patients reporting improvements in pain and quality of life. The procedure was well tolerated with no severe complications, highlighting its potential as a safe alternative to surgery.

Electromagnetic hyper-sensitivity (EHS) and its causal link with radio-frequencies raise a major question of public health. In the frame of the clinical study DEMETER, 26 adult volunteers self-diagnosed as EHS-positive agreed to reply to a self-assessment questionnaire and to provide a skin biopsy sampling to establish a primary fibroblast cell line. The questionnaire and the biological data revealed, independently, 2 subsets of donors associated each with a low background, highly responsive (LBHR) and a high background, lowly responsive (HBLR) phenotype. A couple of subsets based on questionnaire data and based on the yield of spontaneous DNA double-strand breaks were found to be composed of the same donors at 64% identity. After exposure to X-rays, and application of anti-γH2AX, pATM, and MRE11 immunofluorescence, all the DEMETER fibroblasts (26/26) elicited a delayed radiation-induced ATM nucleoshuttling (RIANS). The use of RIANS biomarkers showed that the 2 phenotypes described above corresponded to DEMETER donors with a high risk of cancer (LBHR) or high risk of accelerated aging (HBLR). By exposing DEMETER cells to H2O2 followed by an antioxidative agent, we confirmed that EHS may be related to the management of DNA strand breaks. A preliminary molecular model of EHS inspired by the RIANS model was proposed.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

This retrospective observational study aimed to determine the effectiveness, safety and patterns of the use of nivolumab in patients with advanced melanoma in real‐world clinical practice in France using data from a Temporary Authorization for Use Program (ATU). Data were collected from patients with unresectable or metastatic melanoma enrolled in a French national database (Réseau pour la Recherche et l'Investigation Clinique sur le Mélanome: Ric‐Mel) and treated with nivolumab during the ATU program (12 September 2014 to 31 August 2015). The primary objectives of the study were to evaluate the effect of patient characteristics on clinical response and overall survival (OS). Among 400 included patients (median age 66 years), the majority (83%) received nivolumab as second‐ or subsequent‐line therapy. The median durations of progression‐free survival and OS were 3.3 and 14.1 months, respectively, and 31.6% of patients achieved an objective response with a median duration of 20.1 months (range: 0‐34.7). The safety profile of nivolumab was manageable and consistent with those of previous clinical trials, with an incidence of grade 3‐5 adverse events of 13.8%. The safety and effectiveness of nivolumab in patients with advanced melanoma in real‐world clinical practice in France were in line with the data reported in the Phase 3 trials CheckMate 066 and 037 of nivolumab in this patient population.

The individual response to ionizing radiation (IR) raises a number of medical, scientific, and societal issues. While the term "radiosensitivity" was used by the pioneers at the beginning of the 20st century to describe only the radiation-induced adverse tissue reactions related to cell death, a confusion emerged in the literature from the 1930s, as "radiosensitivity" was indifferently used to describe the toxic, cancerous, or aging effect of IR. In parallel, the predisposition to radiation-induced adverse tissue reactions (radiosensitivity), notably observed after radiotherapy appears to be caused by different mechanisms than those linked to predisposition to radiation-induced cancer (radiosusceptibility). This review aims to document these differences in order to better estimate the different radiation-induced risks. It reveals that there are very few syndromes associated with the loss of biological functions involved directly in DNA damage recognition and repair as their role is absolutely necessary for cell viability. By contrast, some cytoplasmic proteins whose functions are independent of genome surveillance may also act as phosphorylation substrates of the ATM protein to regulate the molecular response to IR. The role of the ATM protein may help classify the genetic syndromes associated with radiosensitivity and/or radiosusceptibility.

La neurofibromatose de type 1 (NF1) est caractérisée par des neurofibromes cutanés (NF) ou plexiformes (NFP) sous-cutanés/profonds entraînant gêne fonctionnelle, douleurs neurogènes importantes et désordres esthétiques sévères. Le traitement repose sur une chirurgie invasive avec des suites post-opératoires et des cicatrices parfois délabrantes. La cryothérapie percutanée est une technique de thermoablation guidée par imagerie à l'aide d'aiguilles fines. Elle est utilisée dans le traitement des tumeurs des tissus mous. L'objectif de cette étude préliminaire est d'évaluer l'efficacité de cette technique sur la taille tumorale et la douleur. Huit patients NF1, de plus de 18 ans et porteurs d'un NF bénin non résécable ou résécable avec rançon cicatricielle importante, ont été inclus, entre janvier 2020 et avril 2021, dans cette étude rétrospective monocentrique. La cryothérapie est réalisée sous anesthésie générale ou neuroleptanalgésie, avec des aiguilles Ice Sphere* ou Ice Rod* selon la taille et de la forme de la tumeur. L'ablation est réalisée avec le système Visual-ICETM* et la technique de congélation consiste en 2 cycles de 10 min de congélation. La procédure est arrêtée lorsque le contrôle radiologique visualise soit une congélation complète de la tumeur soit l'extension du glaçon près d'une structure à risque (vasculaire, viscérale ou nerveuse). Une évaluation de la douleur à l'aide d'une échelle visuelle analogique (EVA) est réalisée (en pré opératoire, à 6 mois et à la fin de la durée de suivi), et une IRM volumétrique pré- et postopératoire à 3, 6 et 12 mois. La durée moyenne de suivi était de 26,6 semaines. Concernant la douleur, les moyennes d'EVA sont passées de 6,5/10 avant cryothérapie, à 4,65/10 à 6 mois post-cryothérapie puis à 2,6/10 à la date des dernières nouvelles. Le niveau de satisfaction des patients est de 50 % (4/8) très satisfaits, 25 % (2/8) satisfaits et 25% (2/8) neutres. Les volumes tumoraux sur des données préliminaires sont mesurés en moyenne à 559 cc (range 223–1386) avant cryothérapie et à 369 cc (range 90–952) après soit réduction moyenne de 34 %. Aucune complication postopératoire n'a été déplorée. La cryothérapie percutanée est une technique simple, non sanglante qui montre dans ce travail original une efficacité avec diminution significative de la douleur et du volume tumoral pour le traitement des NF/NFP. La cryochirurgie ne laisse pas de cicatrice avec des suites post-opératoires courtes et peu douloureuses permettant une reprise d'activité en 48 h. Ce geste peut être renouvelé si besoin. Le recul de plus de 6 mois pour les premiers patients ne montre pas de reprise évolutive. La seule contre-indication sont les NF/NFP au dépend des gros troncs nerveux en raison du risque de séquelle neurologique. La cryochirurgie pourrait devenir une alternative très intéressante à la chirurgie.

There is no standard of care for unresectable cutaneous squamous cell carcinoma (cSCC). Chemotherapy, alone or combined with radiotherapy, is commonly used mostly as palliative treatment; moreover, its poor safety profile limits its use most of the time, especially in elderly patients. Thus, alternative options are needed. Targeted molecular inhibitors, such as the epidermal growth factor receptor inhibitor cetuximab, seem promising, but data are limited. We retrospectively evaluated clinical outcomes of cetuximab as a single agent in this indication. The primary endpoint was the Disease Control Rate (DCR) at 6 weeks according to RECIST criteria. Secondary endpoints included DCR at 12 weeks, objective response rate (ORR) at 6 and 12 weeks, progression-free-survival (PFS), overall survival (OS), and safety profile. Fifty-eight patients received cetuximab as monotherapy. The median age was 83.2 (range, 47.4 to 96.1). The majority of patients was chemotherapy naïve. The median follow-up was 11.7 months (95% CI: 9.6-30.1). The DCR at 6 and 12 weeks was 87% and 70%, respectively. The ORR was 53% and 42%, respectively, at 6 and 12 weeks. The median PFS and OS were 9.7 months (95% CI: 4.8-43.4) and 17.5 months (95% CI: 9.4-43.1), respectively. Fifty-one patients (88%) experienced toxicity, and 67 adverse events related to cetuximab occurred. Most of them (84%) were grade 1 to 2. Our study shows that cetuximab is safe and efficient for the treatment of patients, even elderly ones, with advanced cSCC. These results indicate that cetuximab is a promising agent to test in new combinations, especially with immune checkpoint inhibitors such as anti-PD-1 agents.

Neurofibromatosis type 1 is a relatively common genetic disease, with a prevalence ranging between 1/3000 and 1/6000 people worldwide. The disease affects multiple systems with cutaneous, neurologic, and orthopedic as major manifestations which lead to significant morbidity or mortality. Indeed, NF1 patients are at an increased risk of malignancy and have a life expectancy about 10-15 years shorter than the general population. The mainstay of management of NF1 is a patient-centered longitudinal care with age-specific monitoring of clinical manifestations, aiming at the early recognition and symptomatic treatment of complications as they occur. Protocole national de diagnostic et de soins (PNDS) are mandatory French clinical practice guidelines for rare diseases required by the French national plan for rare diseases. Their purpose is to provide health care professionals with guidance regarding the optimal diagnostic and therapeutic management of patients affected with a rare disease; and thus, harmonizing their management nationwide. PNDS are usually developed through a critical literature review and a multidisciplinary expert consensus. The purpose of this article is to present the French guidelines on NF1, making them even more available to the international medical community. We further dwelled on the emerging new evidence that might have therapeutic potential or a strong impact on NF1 management in the coming feature. Given the complexity of the disease, the management of children and adults with NF1 entails the full complement healthcare providers and communication among the various specialties.

Background. The recent publication of randomized trials investigating the efficacy of adjuvant therapy and completion lymph node dissection at microscopic stage III melanoma calls for a reappraisal of melanoma management from different angles: indications for sentinel lymph node biopsy, indications for completion lymph node dissection in microscopic -stage disease, and adjuvant therapies. Our objective was to evaluate current practices and to question French onco-dermatologists about any changes they envisaged in their practices in the light of recent publications. Methods. We conducted a national survey among members of the Cutaneous Oncology Group of the French Society of Dermatology in October 2017. Results. Forty French health centers were included, and 53 individual responses were collected. Sentinel lymph node biopsy for melanoma was performed at 75 % of the centers. Before the summer of 2017 and the publication of MSLT-II (proving the absence of any therapeutic benefits for complete lymph node dissection in microscopic stage III melanoma), when a positive sentinel lymph node was diagnosed, immediate completion lymph node dissection was performed at 90 % of the centers. After the publication of MSLT-II, 45 % of the respondents considered stopping this practice. The risk -benefit ratio prompted prescription of nivolumab and of combined dabrafenib + trametinib as adjuvant therapy by respectively 96 % and 79 % of respondents, while the corresponding rates for interferon and ipilimumab were only 21 % and 15 %. Conclusion. Early melanoma management stands on the verge of major changes thanks to the arrival of efficient adjuvant therapies and a decrease in immediate completion lymph node dissections for patients with microscopic stage III is also anticipated. 0 2019 Published by Elsevier Masson SAS.

ImportanceCalcific uremic arteriolopathy (CUA), a rare, potentially fatal, disease with calcium deposits in skin, mostly affects patients with end-stage renal disease who are receiving dialysis. Chemical composition and structure of CUA calcifications have been poorly described. ObjectivesTo describe the localization and morphologic features and determine the precise chemical composition of CUA-related calcium deposits in skin, and identify any mortality-associated factors. Design, Setting, and ParticipantsA retrospective, multicenter cohort study was conducted at 7 French hospitals including consecutive adults diagnosed with CUA between January 1, 2006, and January 1, 2017, confirmed according to Hayashi clinical and histologic criteria. Patients with normal renal function were excluded. For comparison, 5 skin samples from patients with arteriolosclerosis and 5 others from the negative margins of skin-carcinoma resection specimens were also analyzed. Main Outcomes and MeasuresLocalization and morphologic features of the CUA-related cutaneous calcium deposits were assessed with optical microscopy and field-emission-scanning electron microscopy, and the chemical compositions of those deposits were evaluated with mu Fourier transform infrared spectroscopy, Raman spectroscopy, and energy dispersive radiographs. ResultsThirty-six patients (median [range] age, 64 [33-89] years; 26 [72%] female) were included, and 29 cutaneous biopsies were analyzed. Calcific uremic arteriolopathy and arteriolosclerosis skin calcifications were composed of pure calcium-phosphate apatite. Calcific uremic arteriolopathy vascular calcifications were always circumferential, found in small to medium-sized vessels, with interstitial deposits in 22 (76%) of the samples. A thrombosis, most often in noncalcified capillary lumens in the superficial dermis, was seen in 5 samples from patients with CUA. Except for calcium deposits, the vessel structure of patients with CUA appeared normal, unlike thickened arteriolosclerotic vessel walls. Twelve (33%) patients died of CUA. Conclusions and RelevanceCalcific uremic arteriolopathy-related skin calcifications were exclusively composed of pure calcium-phosphate apatite, localized circumferentially in small to medium-sized vessels and often associated with interstitial deposits, suggesting its pathogenesis differs from that of arteriolosclerosis. Although the chemical compositions of CUA and arteriolosclerosis calcifications were similar, the vessels' appearances and deposit localizations differed, suggesting different pathogenetic mechanisms.

e21598 Background: Nivolumab was the first anti-PD1 therapy to receive a European marketed authorization for the treatment of advanced (unresectable or metastatic) melanoma. To collect and evaluate real-life clinical data and use of nivolumab, an observational retrospective study (CA 209-555) was conducted in patients with advanced melanoma treated during the French Temporary Authorization Use (ATU) with 2-years of follow-up (NCT03325257). Methods: Data from 342 patients included in the ATU program by 17 participating French centers were collected via the RIC-Mel database. Demographic characteristics, efficacy and safety of nivolumab (3mg/kg every 2 weeks) were assessed in patients who received at least one dose, between Sept. 2014 and Dec. 2015. Results: Patients were most commonly diagnosed with cutaneous melanoma (70%); the median age was 66 years, 61% were male, 34.5% had BRAF V600 mutations and 84% had ECOG performance status of 0 or 1. The majority of patients (71%) had stage IV M1c (7th AJCC) and approximatively 50% had > 2 metastatic sites. Most patients (82.7%) were pretreated with ≥ 1 line of therapy; and the mean nivolumab treatment duration was 9.7 months. One and 2-year overall survival (OS) rates were 55.7 and 38%, respectively, with a median OS of 14.3 months (95% CI, 12.1-18.6). The overall response rate (ORR) was 32% with a 11.9% complete response rate and a disease control rate of 53%. Of note, subgroup analysis in older patients ( > 75 years) and those with brain metastases showed 39% and 23% ORR, respectively; and 2-year OS rates of 38% and 25%, respectively. The incidence of grade ≥3 adverse events (AE) was 14%, the most frequent being gastrointestinal (3.5%) and pulmonary (3.5%). Discontinuation of nivolumab due to AEs occurred in 8% of patients. Conclusions: Results from this first french real-life analysis confirm efficacy and safety observed with Nivolumab in phase 3 clinical studies in patients with treatment-naive (CA209-066) and pre-treated (CA209-037) advanced melanoma. Moreover, they provide additional information on subgroup populations with high unmet need that are typically excluded from clinical trials, including older patients and those with brain metastases.

In neurofibromatosis-1 (NF1), internal plexiform neurofibromas can be life-threatening following transformation into malignant peripheral nerve sheath tumors, or cause significant morbidity through compression of organs, mainly the spine or nerve roots (Tucker et al., 2005Tucker T. Wolkenstein P. Revuz J. Zeller J. Friedman J.M. Association between benign and malignant peripheral nerve sheath tumors in NF1.Neurology. 2005; 65: 205-211Crossref PubMed Scopus (209) Google Scholar). Multiple or infiltrating tumors are surgically intractable. Thus, medical treatment to shrink such tumors to reduce organ compression or the long-term risk of malignant transformation would be highly valuable in the treatment of NF1. Deregulation of the mTOR pathway contributes to NF1 development (Bhola et al., 2010Bhola P. Banerjee S. Mukherjee J. Balasubramanium A. Arun V. Karim Z. et al.Preclinical in vivo evaluation of rapamycin in human malignant peripheral nerve sheath explant xenograft.Int J Cancer. 2010; 126: 563-571Crossref PubMed Scopus (35) Google Scholar). The inhibition of mTOR by rapamycin potently suppressed the growth of aggressive NF1-associated malignancies in a genetically engineered murine model (Johannessen et al., 2008Johannessen C.M. Johnson B.W. Williams S.M.G. Chan A.W. Reczek E.E. Lynch R.C. et al.TORC1 is essential for NF1-associated malignancies.Curr Biol. 2008; 18: 56-62Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar). These data suggest that rapamycin or its derivatives, such as everolimus, could be a potential therapy for NF1. This proof of concept has been performed in tuberous sclerosis, in which rapamycin and everolimus were able to efficiently treat angiomyolipomas and tubers (Sasongko et al., 2016Sasongko T.H. Ismail N.F.D. Zabidi-Hussin Z. Rapamycin and rapalogs for tuberous sclerosis complex.Cochrane Database Syst Rev. 2016; 7: CD011272PubMed Google Scholar). Therefore, we performed a trial to assess the efficacy of everolimus for surgically intractable and life-threatening internal neurofibromas in NF1 in adulthood. A detailed description of the methods is presented in the Supplementary Materials online. The NFitor trial, a multicenter, open-label, single-arm, non-randomized, single-stage phase 2a study, was conducted at three centers in France from April 2011 to October 2014, in accordance with the Declaration of Helsinki and local laws and regulations, and the protocol was approved by the CPP-Île-de-France IX Institutional Review Board (Paris, France, authorization no. 10-033). All participants gave written and informed consent. The ClinicalTrials.gov registration number is NCT01412892. Adult patients over 18 years old were included if they had NF1 with at least one internal plexiform neurofibroma that was life-threatening or causing significant morbidity and was surgically intractable. All patients received orally administrated everolimus (RAD001, two 5-mg tablets, i.e., 10-mg oral everolimus once daily) for 1 year and were followed for an additional year after the therapy was stopped. The primary end point was a 30% reduction in target lesion volume without an increase in the target volume of four other lesions after 1 year of treatment. Indeed, at baseline, up to five large internal neurofibromas were identified by magnetic resonance imaging per patient for volume measurement during the study. The largest lesion was designated as the target. The secondary efficacy end points were internal plexiform neurofibroma volume at 2 years, disease-related symptoms, such as pain and infirmity, and quality of life. Safety was assessed as the number of serious and/or nonserious adverse effects. With a sample size of 23 patients (single-arm trial with a Fleming single-stage procedure), an observation of at least four successes would lead to the conclusion that the drug warrants further investigation. A total of 23 patients (15 males) were included in the trial (Supplementary Figure S1 online), with a mean age of 31.6 years. Details of the population characteristics at baseline are available in Table 1. Details of the treatment (dosage, total duration, reasons leading to dosage modifications) are available in Supplementary Table S1 online. Overall, 16 of 23 patients received 5 to 10 mg/day everolimus for 1 year. Four patients stopped because of adverse events or serious adverse events, two because of disease progression, and two for personal convenience. No death occurred among the enrolled patients during the trial period. None of the 23 everolimus-treated patients in the intention-to-treat population reached the primary end point, that is, a 30% reduction in target lesion volume without an increase in the target volume of four other lesions after 1 year of treatment. We assessed the volume of the target lesion and the total volume of the internal neurofibromas at baseline (M0), month 12 (M12) (after 1 year of everolimus treatment), and month 24 (M24) (after 1 year of stopping the treatment) for the per-protocol population. There was no significant difference between M0 and M12, M0 and M24, or M12 and M24 for the total volume of the internal neurofibromas (Supplementary Tables S2 and S3 online). There was no difference over time for the visual analog scale–assessed global pain score, and for the global health status from the health-related quality of life scale (Supplementary Table S4 online). A high percentage of patients had at least one treatment-related adverse effect (Supplementary Table S5 online). Severe adverse effects occurred in 11 patients (Table 2).Table 1Study population characteristics (n = 23)CharacteristicsDataMissing DataMales, n (%)15 (65.2)—Age, years, mean ± SD31.6 ± 8.3—Total follow-up, months, mean ± SD (range)19.1 ± 8.7 (2.3–25.9)—Sporadic cases, n (%)16 (69.6)—Café-au-lait spots, n (%)23 (100)—At least six café-au-lait spots, n (%)18 (78.3)1Freckling, n (%)18 (78.3)—Absence of gliomas, n (%)19 (82.6)4Lisch nodules, n (%)8 (34.8)6Distinctive bony lesions , n (%)6 (26.1)—Abbreviation: SD, standard deviation. Open table in a new tab Table 2Serious adverse eventsIdPatAge at Baseline, YearsSexInclusion DateSAE DateType of SAEEnd of Follow-Up10339.25Male04/28/201112/20/2012Cat-scratch disease05/23/201310531.21Female05/12/201106/23/2011Aphtosis with weight loss07/21/201110921.68Male09/15/201101/20/2012Facial folliculitis09/05/201311633.85Male04/12/201210/12/2012Cytolytic hepatitis05/15/201411722.46Male04/19/201210/17/2013Traffic accident06/05/201412025.81Female01/10/201303/05/2013Viral E hepatitis09/09/201320127.62Female10/21/201104/01/2012Epistaxis04/16/201220442.77Male02/29/201201/20/2013Sub-cutaneous infectious09/19/201320530.34Male09/24/201201/14/2013Laryngitis09/04/201430146.43Female12/12/201107/30/2012Uncontrolled major Hypertension10/18/201230246.13Female02/06/201204/11/2012Menorrhagia02/24/2014Abbreviations: IdPat, patient identification number; SAE, serious adverse event. Open table in a new tab Abbreviation: SD, standard deviation. Abbreviations: IdPat, patient identification number; SAE, serious adverse event. In total, everolimus had essentially no effect in shrinking tumors in our trial. Another trial assessed the mTOR inhibitor sirolimus for the treatment of inoperable NF1-associated plexiform internal neurofibromas in a pediatric population (median age in the sirolimus group was 8.2 years old; range 3–17.7 years) (Weiss et al., 2015Weiss B. Widemann B.C. Wolters P. Dombi E. Vinks A. Cantor A. et al.Sirolimus for progressive neurofibromatosis type 1-associated plexiform neurofibromas: a neurofibromatosis Clinical Trials Consortium phase II study.Neuro Oncol. 2015; 17: 596-603Crossref PubMed Scopus (93) Google Scholar). The time to progression (i.e., >20% increase in the sum of the volumes of all index plexiform neurofibromas) was significantly longer for the sirolimus group (15.4 months) than for the placebo group (11.9 months), but sirolimus treatment was not associated with a reduction in plexiform neurofibroma volume. The prevalence of internal plexiform neurofibromas increases during adolescence, whereas the sum of all internal plexiform neurofibromas appears to be stable in adulthood (Sbidian et al., 2012Sbidian E. Hadj-Rabia S. Riccardi V.M. Valeyrie-Allanore L.L. Barbarot S. Chosidow O. et al.Clinical characteristics predicting internal neurofibromas in 357 children with neurofibromatosis-1: results from a cross-selectional study.Orphanet J Rare Dis. 2012; 7: 62Crossref PubMed Scopus (16) Google Scholar). Thus, mTOR inhibitors may be effective during the early development of internal plexiform neurofibromas and not when once established. This study did not confirm the effect on chronic pain that we reported with sirolimus previously (Hua et al., 2014Hua C. Zehou O. Ducassou S. Minard-Colin V. Hamel-Teillac D. Wolkenstein P. et al.Sirolimus improves pain in NF1 patients with severe plexiform neurofibromas.Pediatrics. 2014; 133: e1792-e1797Crossref PubMed Scopus (23) Google Scholar). In conclusion, monotherapy with everolimus should not be considered as a treatment for NF1–related plexiform neurofibromas in adults. Further studies should investigate the potential effect of dual mTOR inhibitors, or the association of mTOR inhibitors with other innovative therapies. Other targeted therapies have been tested, such as imatinib for NF1-associated plexiform neurofibromas, with response rates of approximately 15% (Robertson et al., 2012Robertson K.A. Nalepa G. Yang F.-C. Bowers D.C. Ho C.Y. Hutchins G.D. et al.Imatinib mesylate for plexiform neurofibromas in patients with neurofibromatosis type 1: a phase 2 trial.Lancet Oncol. 2012; 13: 1218-1224Abstract Full Text Full Text PDF PubMed Scopus (160) Google Scholar). The most promising approach currently seems to be the use of MEK inhibitors, as reported in a multicenter phase 1 trial of selumetinib in pediatric NF1 patients with inoperable internal plexiform neurofibromas (Dombi et al., 2016Dombi E. Baldwin A. Marcus L.J. Fisher M.J. Weiss B. Kim A. et al.Activity of selumetinib in neurofibromatosis type 1-related plexiform neurofibromas.N Engl J Med. 2016; 375: 2550-2560Crossref PubMed Scopus (369) Google Scholar). The authors observed tumor volume decreases from baseline of 20% in 17 of 24 (71%) children. These results open the field to new drug associations with targeted therapies or immunotherapies (Haworth et al., 2017Haworth K.B. Arnold M.A. Pierson C.R. Choi K. Yeager N.D. Ratner N. et al.Immune profiling of NF1-associated tumors reveals histologic subtype distinctions and heterogeneity: implications for immunotherapy.Oncotarget. 2017; 8: 82037-82048Crossref PubMed Scopus (29) Google Scholar, Reilly et al., 2017Reilly K.M. Kim A. Blakely J. Ferner R.E. Gutmann D.H. Legius E. et al.Neurofibromatosis type 1-associated MPNST state of the science: outlining a research agenda for the future.J Natl Cancer Inst. 2017; 109Crossref PubMed Scopus (59) Google Scholar). SB received research grants from Pierre Fabre Laboratory and Fondation pour la dermatite atopique, personal fees from Bioderma, Laboratoire La Roche Posay, Sanofi-Genzyme, AbbVie; non-financial support from AbbVie, Novartis, Janssen. OZ received personal fees from Novartis and was investigator for Novartis. PW received fees from Pierre Fabre and was an investigator for Novartis. ES, SF, PB, SB-G, and LV-A state no conflict of interest. We would like to thank Amélie Anota for the statistical analysis of the Global Score Status (Methodology and Quality of Life: Oncology Unit & Quality of Life and Cancer Clinical Research Platform at Besancon, France). We thank the patient Association Neurofibromatose et Von Recklinghausen and Novartis who supported this work. Novartis provided the drug. The trial was designed, and the protocol written, independently by the authors (PW, SBG). Data were collected using case-report forms. The authors (PW, SF, OZ) vouch for the integrity and completeness of the data and the statistician (ES) verified the accuracy of the data analysis and computed all statistical analyses. The principal investigators had unrestricted access to the data after the database was locked; they prepared the manuscript and decided to publish. The trial was approved by the Institutional Review Board (CPP-Île-de-Francee–IX, Paris, France, authorization no. 10–033) and by the French Health Agency (Agence Franҫaise de Sécurité Sanitaire des Produits de Santé, AFSSAPS). This study is registered at ClinicalTrials.gov, NCT01412892. This paper was presented in part at the Journées Dermatologiques de Paris Congress, Paris, 2015. Download .pdf (.18 MB) Help with pdf files Supplementary Materials

e21571 Background: Melanomas of unknown primary (MUP) are considered as metastatic disease. Epidemiologic features of MUP patients have been described in several studies, but never yet from the French national melanoma active file. Methods: Data collected between March 2012 and April 2017 were retrieved from the database of the RIC-Mel (Research and Clinical Investigation on Melanoma) network and have been analyzed. Skin, mucous membranes and eyes of all MUP patients were examined in search of a primitive lesion by a dermatologist. Results: Among the 18,379 patients included, 2.6% (n = 480) were MUP and 24.3% (n = 4,348) were in metastatic diseases (AJCC stage III/IV) with a known primary melanoma (MKP). Epidemiologic analysis showed that MUP and metastatic MKP patients were comparable regarding sex distribution and age at metastatic diagnosis. Regarding mutational statues, BRAF alterations were more often reported in MUP than metastatic MKP patients (47% vs 39%, p = 0.01). Death rate analysis indicates that MUP patients had a most pejorative prognosis as compared to metastatic MKP patients (18% vs 16%, p < 0.001). The MUP patients had also a greater tumor load supported by a more frequent visceral dissemination (41% vs 24% for metastatic MKP patients) (p < 0.001). Conclusions: This first analyze of MUP in the French melanoma active file showed that this subpopulation had a poorer prognosis than metastatic MKP patients. This could be supported by many hypotheses such as the lack of specific cytotoxic T cells development due to a shorter time to develop a melanoma-specific immunity, more BRAF mutations correlated with a most aggressive profile and more visceral metastasis. Furthermore, no statistical difference was founded regarding the age at metastatic diagnosis. Our results supported the need to set up a close monitoring for MUP patients.

F-FDOPA is a well-established tool to explore pheochromocytomas. It tends to replace I-MIBG scan in metastatic pheochromocytomas, multiple endocrine neoplasia type 2-related tumors, succinate dehydrogenase [ubiquinone] iron-sulfur subunit-negative tumors, and succinate dehydrogenase[ZERO WIDTH SPACE]-positive lesions. To our knowledge, no study has characterized physiological and pathological adrenal glands with F-FDOPA from a quantitative point of view. We report the features of different normal and pathological adrenal glands with F-FDOPA. Within our series, only pheochromocytomas present a significantly increased uptake reflecting the high specificity of this tracer. Tumors such as adenomas or myelolipomas present no F-FDOPA significant accumulation. Interestingly, adrenal gland hyperplasia and solitary glands do not demonstrate compensatory uptake.

Introduction Many studies have reported the high performance of 6-fluorine-18-fluorodihydroxyphenilalanine (18F-FDOPA) PET/CT in the diagnosis of pheochromocytomas but nobody seems to have investigated physiological and pathological adrenal glands from a quantitative point of view. The purpose of the present study was to assess the quantitative 18F-FDOPA uptake of normal and pathologic adrenal glands and to establish thresholds to characterize pheochromocytomas. We were especially interested in characterizing the remaining adrenal glands captation after an adrenalectomy. Patients and methods We reviewed 112 18F-FDOPA PET/CT scans taken for different indications. A total of 212 adrenal glands, of which 17 were pheochromocytomas, were analyzed on the basis of their functional and morphological features. The final diagnosis was based on histologic proof when available (six pheochromocytomas) or after synthesis of clinical, biological, morphological, and functional results. Maximum standardized uptake value (SUVmax), mediastinum, and liver ratios in case of pheochromocytomas, adenomas, and solitary adrenal glands were determined and compared with those of healthy glands. Receiver operating characteristic curves were determined and areas under the curve were compared for different cutoffs of each index. Results Pheochromocytomas demonstrated a higher 18F-FDOPA uptake compared with normal adrenal glands (mean SUVmax: 7.5, SD 4.0, range: 3.5–20.0 vs. mean SUVmax: 2.6, SD: 0.8, range: 1.0–6.9) (P<0.0001). An SUVmax threshold of 4.2 has a sensitivity and specificity of 94 and 98%, respectively. The areas under the curve were 0.988, 0.991, and 0.987 for an SUVmax of 4.2, a mediastinum ratio of 3.0, and a liver ratio of 1.7, respectively. A large number of nonsecreting pheochromocytomas were noticed. On the basis of the SUVmax no statistically significant difference was found between secreting (SUVmax: 8.9, SD: 5.3) and nonsecreting pheochromocytomas (SUVmax: 5.1, SD: 0.9) (P=0.141). After unilateral adrenalectomy, solitary glands presented no increased uptake compared with healthy adrenal glands. An unexpected lower captation was also observed (SUVmax: 2.0, P=0.047). Conclusion We confirm the high affinity of 18F-FDOPA for secreting or nonsecreting pheochromocytoma. Indeed within a series of various adrenal glands, only these tumors presented a significant increased uptake compared with normal adrenal glands. Because of a high rate of nonhypersecreting lesions, 18F-FDOPA can act as a surrogate to biological assays. After an adrenalectomy, the remaining glands did not demonstrate compensatory accumulation of 18F-FDOPA. To our knowledge this last point has never been addressed.

BACKGROUND:Management of metastatic melanoma is changing rapidly following the introduction of innovative effective therapies, with consequences for the allocation of healthcare resources. The objective of this study was to assess hospitalisation costs of metastatic melanoma in France from 2011 to 2013 from the perspective of the government payer.METHODS:The population studied corresponded to all adults with metastatic melanoma hospitalised in France between 1st January 2011 and 31st December 2013 who required chemotherapy, immunotherapy or radiotherapy due to tumour progression and unresectable Stage III or Stage IV melanoma. Metastatic melanoma was identified by ICD-10 codes documented in the hospital patient discharge records. For each patient, hospital stays were stratified into a pre- or post- progression health state using proxy variables for the RECIST criteria. All healthcare expenditure documented in the French national hospital claims system database and incurred between the index hospitalisation (or change of progression state) and the end of follow-up were analysed. For the principal analysis, valuation of healthcare resource consumption was performed using official national hospitalisation tariffs. Any expensive therapy administered during the stay was documented from a linked database of expensive drugs (FICHCOMP).RESULTS:Seventy-eight thousand seven hundred fifty hospital stays by 10,337 patients with metastatic melanoma were identified over the three-year study period. Annual per capita costs of hospitalisation were € 5046 in the pre-progression stage and € 19,006 in the post-progression stage. Hospitalisations attributed to adverse drug reactions to chemotherapy or immunotherapy were observed in 27% of patients. Annual per capita costs of these hospitalisations related to adverse drug reactions were € 3762 in the pre-progression stage and € 5523 in the post-progression stage.CONCLUSIONS:Hospitalisation costs related to metastatic melanoma rise substantially as the disease progresses. Treatment strategies which slow down disease progression would be expected to reduce costs of hospitalisation for metastatic melanoma, although they may also entail significant acquisition costs. This will entail organisational changes of resource allocation for the treatment of metastatic melanoma in hospitals.