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Protontherapy to maintain local control of head and neck paragangliomas

Purpose:Uveal melanomas (UM) are genetically simple tumors carrying few copy number alterations (CNA) and a low mutation burden, except in rare MBD4-deficient, hypermutated cases. The genomics of uveal melanoma metastatic progression has not been described. We assessed the genetic heterogeneity of primary and metastatic MBD4-proficient and -deficient uveal melanomas.Experimental Design: We prospectively collected 75 metastatic and 16 primary samples from 25 consecutive uveal melanoma patients, and performed whole-exome sequencing.Results:MBD4-proficient uveal melanomas contained stable genomes at the nucleotide level, acquiring few new single nucleotide variants (SNVs; 16 vs. 13 in metastases and primary tumors, respectively), and no new driver mutation. Five CNAs were recurrently acquired in metastases (losses of 1p, 6q, gains of 1q, 8q, and isodisomy 3). In contrast, MBD4-deficient uveal melanomas carried more than 266 SNVs per sample, with high genetic heterogeneity and TP53, SMARCA4, and GNAS new driver mutations. SNVs in MBD4-deficient contexts were exploited to unveil the timeline of oncogenic events, revealing that metastatic clones arose early after tumor onset. Surprisingly, metastases were not enriched in monosomy 3, a previously defined metastatic risk genomic feature. Monosomy 3 was associated with shorter metastatic-free interval compared with disomy 3 rather than higher rate of relapse.Conclusions:MBD4-proficient uveal melanomas are stable at the nucleotide level, without new actionable alterations when metastatic. In contrast, MBD4 deficiency is associated with high genetic heterogeneity and acquisition of new driver mutations. Monosomy 3 is associated with time to relapse rather than rate of relapse, thus opening avenues for a new genetic prognostic classification of uveal melanomas.

Supplementary figure 6 - Comparisons of CCFs between samples including inter- and intra-metastatic comparisons in MBD4pro samples.

Supplementary Table 1: Patients and tumors characteristics

Purpose This study aimed to assess the risk of acute and late radiation-induced toxicity in patients with COVID-19. Material and methods All the patients irradiated in Institut Curie from March to July 2020 were included if the first symptoms related to COVID-19 occurred no more than two months before the start of radiation therapy (RT) or 15 days after the end of RT. Results Twenty-nine patients were included in this analysis. Twenty-five patients had no co-morbidities (86.2%), including morbid obesity. The diagnosis of COVID-19 infection was based on a positive SARS-CoV-2 RNA test for 18 patients (62.1%), a positive serology test for three patients (10.3%), and/or radiologic findings for 12 patients (41.4%). Three patients with symptoms highly suggestive of COVID-19 were included, although they had negative biologic tests and did not have a chest CT scan. Median time from the diagnosis of COVID-19 to the onset of RT was 5.5 days. Modification of RT course due to COVID-19 status was observed in 15 patients, including four for whom RT was definitively stopped. Six patients needed hospitalization for hypoxemic lung disease requiring intensive care. The majority of patients did not experience severe (> grade 2) acute toxicity. After a median follow-up of 6 months (IQR, 1 - 9 months), none of the patients had unusual clinical or radiological late toxicities. Conclusion The observed acute and late toxicities were ultimately similar to those observed in a population not infected with COVID-19. These results do not prompt modification of standard RT protocols for irradiation of COVID-19 patients.

Hodgkin lymphoma (HL) is a highly curable hematological malignancy. Consolidation radiation therapy techniques have made significant progresses to improve organ-at-risk sparing in order to reduce late radiation-induced toxicity. Recent technical breakthroughs notably include intensity modulated proton therapy (IMPT), which has demonstrated a major dosimetric benefit at the cardiac level for mediastinal HL patients. However, its implementation in clinical practice is still challenging, notably due to the limited access to proton therapy facilities. In this context, the purpose of this study was to estimate the benefit of IMPT for HL proton therapy for diverse cardiac adverse events and to propose a general frame for mediastinal HL patient selection strategy for IMPT based on cardiotoxicity reduction, patient clinical factors, and IMPT treatment availability.This retrospective dosimetric study included 30 mediastinal HL patients treated with VMAT. IMPT plans were generated on the initial simulation scans. Dose to the heart, to the left ventricle and to the valves were retrieved to calculate the relative risk (RR) of ischemic heart disease (IHD), congestive heart failure (CHF) and valvular disease (VD). Composite relative risk reduction (cRRR) of late cardiotoxicity, between VMAT and IMPT, were calculated as the weighted mean of relative risk reduction for IHD, CHF and VD, calculated across a wide range of cardiovascular risk factor combinations. The proportion of mediastinal HL patients who could benefit from IMPT was estimated in European countries, based on the country population and on the number of active gantries, to propose country-specific cRRR thresholds for patient selection.Compared with VMAT, IMPT significantly reduced average mean doses to the heart (2.36 Gy vs 0.99 Gy,While a statistically significant clinical benefit is theoretically expected for ischemic heart disease, cardiac heart failure and valvular disease for mediastinal HL patients with IMPT, the overall cardiotoxicity risk reduction is notable only for a minority of patients. In the context of limited IMPT availability, this study proposed a general model-based selection approach for mediastinal HL patient based on calculated cardiotoxicity reduction, taking into consideration patient clinical characteristics and IMPT facility availability.

Radiation therapy (RT) is used for the treatment of sacral chordoma, in combination with surgery or alone for unresected tumours, to improve local control (LC) and potentially overall survival (OS). The purpose of the present study was to evaluate efficacy and toxicity of proton therapy (PT), and/or intensity modulated radiation therapy (IMRT), particularly Tomotherapy, for sacral chordoma treatment.After a median follow-up of 46 months (range, 0-125 months), eight local relapses were observed, and seven patients developed distant metastasis (particularly bone and lung). The 2- and 5- year local relapse rates were 11.4% CI (0.65-22.2%) and 29% (10.5-47.4%), respectively. Over the follow-up period, ten patients died (24.4%). The estimated 2- and 5-year OS rates were 91.4% CI (82.5-100%) and 74.5% (59.4-93.5%), respectively. Fibrosis,RT remains essential to improve local control in sacral chordoma. The combination of proton and photon seems to improve organ at risk sparing, resulting in a decreased rate of reported late toxicities.

Simple Summary Hodgkin lymphoma (HL) is a highly curable disease; proton therapy for mediastinal HL irradiation might theoretically reduce late toxicities compared with classical radiotherapy techniques. However, optimal patient selection for this technique is subject to debate. While implementation at a larger scale of proton therapy for HL may face organizational, political, and societal challenges, new highly effective systematic drugs are being widely evaluated for this disease. Abstract Consolidative radiation therapy for early-stage Hodgkin lymphoma (HL) improves progression-free survival. Unfortunately, first-generation techniques, relying on large irradiation fields, were associated with an increased risk of secondary cancers, and of cardiac and lung toxicity. Fortunately, the use of smaller target volumes combined with technological advances in treatment techniques currently allows efficient organs-at-risk sparing without altering tumoral control. Recently, proton therapy has been evaluated for mediastinal HL treatment due to its potential to significantly reduce the dose to organs-at-risk, such as cardiac substructures. This is expected to limit late radiation-induced toxicity and possibly, second-neoplasm risk, compared with last-generation intensity-modulated radiation therapy. However, the democratization of this new technique faces multiple issues. Determination of which patient may benefit the most from proton therapy is subject to intense debate. The development of new effective systemic chemotherapy and organizational, societal, and political considerations might represent impediments to the larger-scale implementation of HL proton therapy. Based on the current literature, this critical review aims to discuss current challenges and controversies that may impede the larger-scale implementation of mediastinal HL proton therapy.

International audience; Since the development of new radiotherapy techniques that have improved healthy tissue sparing, reirradiation (reRT) has become possible. The selection of patients eligible for reRT is complex given that it can induce severe or even fatal side effects. The first step should therefore be to assess, in the context of multidisciplinary staff meeting, the patient's physical status, the presence of sequelae resulting from the first irradiation and the best treatment option available. ReRT can be performed either curatively or palliatively to treat a cancer-related symptom that is detrimental to the patient's quality of life. The selected techniques for reRT should provide the best protection of healthy tissue. The construction of target volumes and the evaluation of constraints regarding the doses that can be used in this context have not yet been fully codified. These points raised in the literature suggest that randomized studies should be undertaken to answer pending questions.

Highlights • During COVID-19 lockdown, the number of radiotherapy treatments had to be reduced. • Given number of delayed treatments, the post-crisis period should be anticipated. • Data visualization software allowed to predict when peak activity would happen.

Objectives: Iris melanomas represent 2–3% of uveal melanomas; the diffuse variant accounts for approximately 10% of all iris melanomas. Different treatment modalities for diffuse iris melanomas (DIM) have been proposed depending on the local status as well as the age and general condition of the patient. Methods: This study is a single-centre retrospective case series describing the diagnosis, treatments and outcomes of DIM. Treatment consisted of enucleation or proton beam therapy (PT) of the whole anterior segment. Patients who were treated with PT benefitted from limbal stem cell preservation before irradiation. Results: Between 1996 and 2016, a total of 14 patients with DIM presented to our institution and were included in the database. The global survival was 86%. The median follow-up was 4.6 years (range 4 months to 15 years). Only 1 patient (7%) developed metastatic disease of the DIM (gastric location). No patient developed liver metastasis. Seven patients were treated by enucleation and 7 by PT after limbal stem cell preservation. After a conservative attempt, local tumour recurrence occurred in 2 patients at 2 years, requiring enucleation. The cornea was clear after irradiation in all patients. Cataract (n = 6) and glaucoma (n = 4) were the main complications after irradiation. Conclusions: DIM is a very rare tumour. The global survival is excellent. Conservative treatment with PT is an efficient alternative to enucleation and allows good local tumour control. Cataract and glaucoma are the main radiation-related complications, but the corneal status was excellent due to the stem cell harvest prior to radiotherapy.

Purpose: To report a case of locally recurrent spindle-cell iris amelanotic melanoma 16 years after proton-beam therapy. Observations: In 2001, a 45-year-old man presented with an amelanotic iris melanoma, extending from the 5 to 10 o'clock positions on his left eye. High-frequency ultrasonography showed extension of melanoma into the ciliary body. He was initially managed with proton-beam therapy (60 Gy delivered in four fractions over four consecutive days) and underwent ocular and systemic examination at regular intervals over the following years. Local tumor control was achieved, and the patient did not develop metastasis during sixteen consecutive years. In 2017, 16 years after he received proton-beam therapy, the patient developed a focal amelanotic lesion strongly suggestive of a local recurrence of iris melanoma, although it extended from the 1 to 6 o'clock positions. He also presented with treatment-resistant glaucoma with an intraocular pressure (IOP) of 37 mmHg, despite maximal topical IOP-lowering therapy. Since a second irradiation of the anterior segment was contraindicated, the eye was enucleated. Pathological analysis confirmed the diagnosis of iris melanoma and demonstrated iridocorneal angle invasion extending from the initial site to the recurrent tumor location. Conclusions and importance: Regular ophthalmological surveillance for life with gonioscopy and high-frequency ultrasonography is recommended in patients with iris melanoma, due to the possibility of delayed local recurrence more than a decade after the initial treatment. Keywords: Ciliary body, Iris, Melanoma, Radiotherapy, Irido-corneal angle, Proton-beam therapy

International audience; Proton minibeam radiation therapy (pMBRT) is a new approach in proton radiotherapy, by which a significant increase in the therapeutic index has already been demonstrated in RG2 glioma-bearing rats. In the current study we investigated the response of other types of glioma (F98) and performed a comparative evaluation of tumor control effectiveness by pMBRT (with different levels of dose heterogeneity) versus conventional protons. The results of our study showed an equivalent increase in the lifespan for all evaluated groups (conventional proton irradiation and pMBRT) and no significant differences in the histopathological analysis of the tumors or remaining brain tissue. The reduced long-term toxicity observed with pMBRT in previous evaluations at the same dose suggests a possible use of pMBRT to treat glioma with less side effects while ensuring the same tumor control achieved with standard proton therapy.

Radiotherapy (RT) is one of the most frequently used methods for cancer treatment. Despite remarkable advancements in RT techniquesthe treatment of radioresistant tumours (i.e. high-grade gliomas) is not yet satisfactory. Finding novel approaches less damaging for normal tissues is of utmost importance. This would make it possible to increase the dose applied to tumours, resulting in an improvement in the cure rate. Along this line, proton minibeam radiation therapy (pMBRT) is a novel strategy that allows the spatial modulation of the dose, leading to minimal damage to brain structures compared to a high dose (25 Gy in one fraction) of standard proton therapy (PT). The aim of the present study was to evaluate whether pMBRT also preserves important cerebral functions. Comprehensive longitudinal behavioural studies were performed in irradiated (peak dose of 57 Gy in one fraction) and control rats to evaluate the impact of pMBRT on motor function (motor coordination, muscular tonus, and locomotor activity), emotional function (anxiety, fear, motivation, and impulsivity), and cognitive function (learning, memory, temporal processing, and decision making). The evaluations, which were conducted over a period of 10 months, showed no significant motor or emotional dysfunction in pMBRT-irradiated rats compared with control animals. Concerning cognitive functions, similar performance was observed between the groups, although some slight learning delays might be present in some of the tests in the long term after irradiation. This study shows the minimal impact of pMBRT on the normal brain at the functional level.

Objective To evaluate the outcomes of orbital exenteration with temporalis muscle flap repair of the socket and secondary healing of the anterior surface of the flap in ocular, conjunctival, and eyelid malignancies. Design Retrospective single-centre study. Participants Consecutive patients who underwent total exenteration for malignancy with temporal muscle flap repair of the socket between December 2009 and January 2016. Methods We report the outcomes of this surgical technique in terms of healing without fistula formation and time to epithelialization. Results Twenty-nine patients underwent surgery using this technique. Diagnoses consisted of 18 conjunctival melanomas, 2 choroidal melanomas, 6 squamous cell carcinomas, 2 sebaceous cell carcinomas, and 1 basal cell carcinoma. Mean age at surgery was 70.7 years and mean follow-up was 27.4 months. On histological analysis, tumour excision was complete in 25 patients, of whom 3 had an orbital recurrence after exenteration (3 conjunctival melanomas). Four patients had incomplete tumour excision, of whom 3 underwent postoperative orbital radiotherapy with no subsequent orbital recurrences. Complete epithelialization of the socket occurred in mean 7.9 weeks (range 2–16 weeks). Flap necrosis occurred in 1 patient after postoperative radiotherapy (with sino-nasal fistula formation); 2 other patients developed sino-orbital fistulas. Conclusion After orbital exenteration, spontaneous epithelialization of the socket may take up to several months. Use of a temporalis muscle flap can reduce the duration of socket healing postoperatively, even if left to heal by secondary intention. This may facilitate early postoperative radiotherapy when indicated. Aesthetic results are acceptable and local surgical complications are rare.

Proton minibeam radiation therapy (pMBRT) is a novel dose delivery method based on spatial dose fractionation. pMBRT has been shown to be promising in terms of reduced side effects and superior tumour control in high-grade glioma-bearing rats compared to standard irradiation. These findings, together with the recent optimized implementation of pMBRT in a clinical pencil beam scanning system, have triggered reflection on the possible application to patient treatments. In this context, the present study was designed to conduct a first theoretical investigation of the clinical potential of this technique. For this purpose, a dedicated dose engine was developed and used to evaluate two clinically relevant patient treatment plans (high-grade glioma and meningioma). Treatment plans were compared with standard proton therapy plans assessed by means of a commercial treatment planning system (ECLIPSE-Varian Medical systems) and Monte Carlo simulations. A multislit brass collimator consisting of 0.4 mm wide slits separated by a centre-to-centre distance of 4 or 6 mm was placed between the nozzle and the patient to shape the planar minibeams. For each plan, spread-out Bragg peaks and homogeneous dose distributions (±7% dose variations) can be obtained in target volumes. The Peak-to-Valley Dose Ratios (PVDR) were evaluated between 9.2 and 12.8 at a depth of 20 mm for meningioma and glioma, respectively. Dose volume histograms (DVHs) for target volumes and organs at risk were quantitatively compared, resulting in a slightly better target homogeneity with standard PT than with pMBRT plans, but similar DVHs for deep-seated organs-at-risk and lower average dose for shallow organs. The proposed delivery method evaluated in this work opens the way to an effective treatment for radioresistant tumours and will support the design of future clinical research.

Background The long-term survival of germline retinoblastoma patients is decreased due to the risk of second primary tumors (SPTs) that occur years after the diagnosis of retinoblastoma. This risk is related to genetic predisposition and other factors, such as the treatment of retinoblastoma by external beam radiotherapy (EBRT). Procedure We studied the incidence, risk factors, and prognosis of specific craniofacial SPTs developed within the margins of radiation field in a cohort of 209 patients with germline retinoblastoma treated with EBRT at our institution between 1977 and 2010. Clinical characteristics, survival, incidence, and histology of craniofacial SPTs were recorded. Results Fifty-three of the 209 patients developed 60 distinct craniofacial SPTs in irradiated field with a median time from EBRT of 16.9 years (4-35) and a median follow-up of 24.8 years (5.3-40). Osteosarcoma (33.3%) and undifferentiated sarcoma (23.3%) were the more prevalent histological entities. Benign tumors (16.7%) also occurred. The cumulative incidence of craniofacial SPTs reached 32.6% at 35 years after EBRT, and the median survival after diagnosis was five years. In our series, irradiation under 12 months of age, bilateral EBRT, or previous treatment of retinoblastoma with chemotherapy did not significantly increase the risk of craniofacial SPTs. Conclusions This work presents a strong argument to avoid EBRT in the management of retinoblastoma and emphasizes the high risk and poor prognosis of specific craniofacial SPTs. This study also points to the question of the need and benefits of special programs for early detection of craniofacial SPTs in survivors of irradiated germline retinoblastoma.

Up to 50% of uveal melanomas (UM) metastasise to the liver within 10 years of diagnosis, and these almost always prove rapidly fatal. As histopathological growth patterns (HGPs) of liver metastases of the replacement and desmoplastic type, particularly from colon and breast carcinoma, may import valuable biological and prognostic information, we have studied HGP in a series of 41 UM liver metastases originating from 41 patients from the period 2006-2017. Twenty patients underwent enucleation while 21 had radiation therapy. Analysis of UM by array comparative genomic hybridisation revealed: 25 (64%) patients with high risk (monosomy3/8q gain); 13 (33%) intermediate risk (M3/8normal or disomy3/8q gain); and 1 low risk (disomy3/8normal). The principal HGP was replacement in 30 (73%) cases and desmoplastic in 11 (27%) cases. Cases with replacement demonstrated striking vascular co-option/angiotropism. With the development of liver metastasis, only the replacement pattern, largest primary tumour diameter, and R2 (incomplete resection) status predicted diminished overall survival (OS; p < 0.041, p < 0.017, p < 0.047, respectively). On multivariate analysis, only HGP (hazard ratio; HR = 6.51, p = 0.008) and resection status remained significant. The genomic high-risk variable had no prognostic value at this stage of liver metastasis. Chi-square test showed no association of HGP with monosomy 3 or 8q gain. Eighteen of 41 (44%) patients are alive with disease and 23 (56%) patients died with follow-up ranging from 12 to 318 months (mean: 70 months, median: 47 months). In conclusion, we report for the first time the frequency of the replacement and desmoplastic HGPs in liver UM metastases resected from living patients, and their potential important prognostic value for UM patients, as in other solid cancers. These results may potentially be utilised to develop radiological correlates and therapeutic targets for following and treating patients with UM metastases.

PURPOSE: The Sturge–Weber Syndrome (SWS) is a phacomatosis which include facial nevus flammeus, glaucoma, diffuse choroidal hemangioma, and leptomeningeal hemangiomatosis. External beam radiotherapy (EBRT) using photons was used to treat retinal detachment. We investigate the anatomical and functional results in a long-term basis. METHODS: Retrospective review of SWS patients treated by EBRT (20 Gy in 10 fractions) for an exudative diffuse choroidal hemangioma. Visual acuity, B-scan tumor thickness, size of retinal detachment, intra-ocular pressure, and hypotonic treatment were collected before EBRT, 1 year after, and at the latest news. RESULTS: Twenty-five patients (26 eyes) were treated between 2001 and 2014. Retinal detachment including the macula was found among twenty-six eyes before treatment. The average follow-up time was 47 months. The mean tumor thickness was initially 4.5 mm, 2.8 mm at first year, and 2.7 mm at the last visit. The retina was reattached at the last visit for all eyes except two. The visual acuity was stable or better for 20 eyes (p = 0.02). Four patients developed mild cataract during the follow-up. CONCLUSION: EBRT using 20 Gy in 10 fractions is efficient, decreases tumor thickness, reattaches the retina, and stabilizes visual acuity. In the long term, retinal reattachment allows ocular conservation by preventing phthisis bulbi.

To evaluate the efficacy of bevacizumab on reduction of the enucleation rate and control of intraocular pressure (IOP) in neovascular glaucoma (NVG)-complicating proton beam therapy for UM and to identify the determinants of the efficacy of bevacizumab. Retrospective comparative study of patients with rubeosis following proton therapy for uveal melanoma. Patients were divided into two groups: a bevacizumab group and a control group which comprised two subgroups: panretinal photocoagulation (PRP)/cryotherapy and observation subgroups. Bevacizumab was administered by three intravitreal injections at 1-month intervals. A second series of injections was administered when necessary. Data concerning IOP and the secondary enucleation rate were collected and compared between the two groups. Univariate and multivariate analyses were performed to determine predictive factors of response to bevacizumab. A total of 169 patients who developed rubeosis following proton therapy between 2006 and 2016 were included: 44 patients in the bevacizumab group and 125 in the control group (38 in the PRP/cryotherapy subgroup and 87 in the observation subgroup). The two groups presented the same baseline characteristics apart from hypertension, retro-equatorial site, and proximity of the optic disk, which were more frequent in the control group, while initial retinal detachment and larger tumor volume were more frequent in the bevacizumab group. After a mean follow-up of 31 months, IOP was less than 21 mmHg in 54.54% of patients after IVB versus 72.7% before treatment (p = 0.06). Statistical analysis did not reveal any statistically significant reduction of the enucleation rate in the bevacizumab group compared to the observational group, whereas the PRP/cryotherapy group showed better eye retention rate (p = 0.15). No enucleation was performed when IOP was

Simple Summary Hodgkin lymphoma (HL) is a highly curable disease; in this context, the limitation of late adverse events is of prime importance for the patient. Proton therapy for mediastinal HL irradiation theoretically limits secondary cancer excess risk and should reduce late toxicities compared with classical radiation therapy techniques. However, due to the limited clinical experience, strong evidence is still lacking to support proton therapy in HL management despite excellent tolerance. In addition, randomized controlled trials are probably unrealistic in this context. National and international registries may be useful to strengthen support for HL proton therapy. Abstract Consolidative radiation therapy (RT) is of prime importance for early-stage Hodgkin lymphoma (HL) management since it significantly increases progression-free survival (PFS). Nevertheless, first-generation techniques, relying on large irradiation fields, delivered significant radiation doses to critical organs-at-risk (OARs, such as the heart, to the lung or the breasts) when treating mediastinal HL; consequently, secondary cancers, and cardiac and lung toxicity were substantially increased. Fortunately, HL RT has drastically evolved and, nowadays, state-of-the-art RT techniques efficiently spare critical organs-at-risks without altering local control or overall survival. Recently, proton therapy has been evaluated for mediastinal HL treatment, due to its possibility to significantly reduce integral dose to OARs, which is expected to limit second neoplasm risk and reduce late toxicity. Nevertheless, clinical experience for this recent technique is still limited worldwide. Based on current literature, this critical review aims to examine the current practice of proton therapy for mediastinal HL irradiation.

Aims: Orbital extraocular extension of choroidal melanoma is very rare with small melanomas. We report the case of a patient whose small choroidal melanoma was initially overlooked and was revealed by a large extrascleral extension. Methods: A 48-year-old Caucasian woman presented with sudden total visual loss in the right eye. Multicolor imaging of the fundus showed right optic disc edema and an orange and green lesion near the optic disc. The diagnosis of unilateral optic neuritis was made. Magnetic resonance imaging showed an extraocular mass adjacent to the optic nerve; on ultrasound, this mass was acoustically hollow and a small intraocular component was visible. Results: Choroidal melanoma with a large extrascleral extension was diagnosed (T4eN0M0, stage IIIC according to the AJCC 7th TNM classification, 2010). The size of the extraocular nodule was 13 × 5 mm. Treatment consisted of enucleation followed by adjuvant external beam orbital radiotherapy. Tumor analysis showed a mixed cell type melanoma with monosomy 3. The patient developed liver metastasis 10 months after local treatment. Conclusion: Extraocular extension of choroidal melanoma can occur with small lesions. Prognosis is generally poor according to AJCC TNM. This case is a reminder that fundus examination may reveal the nature of the mass in some patients with orbital tumors.

Purpose: Uveal melanomas (UM) are genetically simple tumors carrying few copy number alterations (CNA) and a low mutation burden, except in rare MBD4-deficient, hypermutated cases. The genomics of uveal melanoma metastatic progression has not been described. We assessed the genetic heterogeneity of primary and metastatic MBD4-proficient and -deficient uveal melanomas. Experimental Design: We prospectively collected 75 metastatic and 16 primary samples from 25 consecutive uveal melanoma patients, and performed whole-exome sequencing. Results: MBD4-proficient uveal melanomas contained stable genomes at the nucleotide level, acquiring few new single nucleotide variants (SNVs; 16 vs. 13 in metastases and primary tumors, respectively), and no new driver mutation. Five CNAs were recurrently acquired in metastases (losses of 1p, 6q, gains of 1q, 8q, and isodisomy 3). In contrast, MBD4-deficient uveal melanomas carried more than 266 SNVs per sample, with high genetic heterogeneity and TP53, SMARCA4, and GNAS new driver mutations. SNVs in MBD4-deficient contexts were exploited to unveil the timeline of oncogenic events, revealing that metastatic clones arose early after tumor onset. Surprisingly, metastases were not enriched in monosomy 3, a previously defined metastatic risk genomic feature. Monosomy 3 was associated with shorter metastatic-free interval compared with disomy 3 rather than higher rate of relapse. Conclusions: MBD4-proficient uveal melanomas are stable at the nucleotide level, without new actionable alterations when metastatic. In contrast, MBD4 deficiency is associated with high genetic heterogeneity and acquisition of new driver mutations. Monosomy 3 is associated with time to relapse rather than rate of relapse, thus opening avenues for a new genetic prognostic classification of uveal melanomas.

This study compared the cytogenetic profiles of choroidal melanoma samples retrieved before and after proton beam irradiation. Twenty-four consecutive patients who underwent both fine-needle aspiration biopsy (FNAB) during tantalum clip positioning, and endoresection within three months of irradiation, were retrospectively included. Chromosome alterations were explored by array comparative genomic hybridization. Age at diagnosis was 50 &plusmn, 14 years, tumor thickness was 8.6 &plusmn, 1.7 mm and tumor diameter was 12.4 &plusmn, 2.3 mm. Six FNAB samples were non-contributive (25%), versus one endoresection sample (4%) (p = 0.049). Among 17 cases with paired contributive samples, the profiles of chromosomes 3 and 8 were identical in all cases, except one with partial chromosome 3 loss on the FNAB sample only. Three cases presented additional discordant aberrations on chromosomes other than 3 or 8q. Overall, we identified monosomy 3 in two cases, 8q gain in six cases, and both alterations in three cases. All cases presented GNAQ or GNA11 mutations assessed by a custom next-generation sequencing panel. Among the six cases with non-contributive initial FNAB, three cases presented abnormal 3 or 8q chromosomes detected on the endoresection material. These results demonstrate the higher rentability of endoresection material for cytogenetic analysis compared to FNAB, and provide clinical evidence of tumor heterogeneity in choroidal melanoma.

There is increasing evidence of the survival benefit of treating uveal melanoma in an early stage, however it is important to discuss with the patient the associated risk of visual loss. We investigated visual outcomes for uveal melanomas staged T1 (T1UM) treated by proton beam radiotherapy (PBR) as a function of their distance to fovea-optic disc. This retrospective study included a cohort of 424 patients with T1UM treated with PBR between 1991 and 2010 with at least a 5-year follow-up. Visual acuity (VA) was analyzed for patients with posterior edge of tumor located at &ge, 3 mm (GSup3) or &lt, 3 mm (GInf3) from fovea-optic disc. The mean follow-up duration was 122 months, no tumor recurrence was observed. The mean baseline and final VA were 20/25 and 20/32 for GSup3 (n = 75), and 20/40 and 20/80 for GInf3 (n = 317) respectively. The frequency of a 20/200 or greater visual conservation was 93.2%(CI95%:87.7&ndash, 99.1) and 60.1%(CI95%:54.9&ndash, 65.9) for GSup3 and GInf3 respectively. This difference between groups was statistically significant (p &lt, 0.001). The risk factors for significant VA loss (less than 20/200) were GInf3 location (p &lt, 0.001), tumor touching optic disc (p = 0.04), initial VA inferior to 20/40 (p &lt, 0.001), documented growth (p = 0.002), and age greater than 60 years (p &lt, 0.001). In summary, PBR for T1UM yields excellent tumor control and good long-term visual outcomes for tumors located &ge, 3 mm from fovea-optic disc.

Uveal melanomas (UM) are genetically simple tumors carrying few copy number alterations (CNA) and a low mutation burden, except in rare

Background Retinoblastoma with macroscopic optic nerve (ON) invasion depicted by imaging at diagnosis remains a major problem and carries a poor prognosis. We sought to describe the treatment and outcome of these high-risk patients. Methods Retrospective mono-institutional clinical, radiological, and histological review of patients with uni- or bilateral retinoblastoma with obvious ON invasion, defined by radiological optic nerve enlargement (RONE) depicted by computed tomography scan or magnetic resonance imaging (MRI), was performed. Results Between 1997 and 2014, among the 936 patients with retinoblastoma treated at Institut Curie, 11 had detectable RONE. Retinoblastoma was unilateral in 10 and bilateral in one. Median age at diagnosis was 28 months (range, 11-96). ON enlargement extended to the orbital portion in three patients, to the optic canal in five, to the prechiasmatic portion in two, and to the optic chiasm in one. Nine patients received neoadjuvant chemotherapy and partial response was obtained in all. Enucleation was performed in 10/11 patients-by an anterior approach in three and by anterior and subfrontal approaches in seven. Three patients had a positive ON resection margin (2/3 after primary enucleation). All enucleated patients received adjuvant treatment (conventional chemotherapy: 10, high-dose chemotherapy: seven, radiotherapy: five). Leptomeningeal progression occurred in four patients. Seven are in first complete remission (median follow up: 8 years [3.5-19.4]). Conclusion Neoadjuvant chemotherapy and microscopic complete resection have a pivotal role in the management of retinoblastoma with RONE. MRI is recommended for initial and pre-operative accurate staging. Surgery should be performed by neurosurgeons in case of posterior nerve invasion. Radiotherapy is required in case of incomplete resection.

Purpose: To facilitate the initiation of observational studies on late effects of proton therapy in pediatric patients, we report on current patterns of proton therapy use worldwide in patients aged less than 22 years. Materials & methods: Fifty-four proton centers treating pediatric patients in 2016 in 11 countries were invited to respond to a survey about the number of patients treated during that year by age group, intent of treatment, delivery technique and tumor types. Results: Among the 40 participating centers (participation rate: 74%), a total of 1,860 patients were treated in 2016 (North America: 1205, Europe: 432, Asia: 223). The numbers of patients per center ranged from 1 to 206 (median: 29). Twenty-four percent of the patients were

International audience; In radiation therapy, a renewed interest is emerging for the study of spatially fractionated irradiation. In this article, a few applications using spatial fractionation of the dose will be discussed with a focus on proton minibeam radiation therapy. Examples of calculated dose (1D profiles and 2D dose distributions) and biological evidence obtained so far will be presented for various spatially fractionated techniques GRID, micro- and minibeam radiation therapy. Recent results demonstrating that proton minibeam radiation therapy leads to an increase in normal tissues sparing will be discussed, which opens the door to a dose escalation in the tumour and a possibly efficient treatment of very radioresistant tumours.

International audience; Purpose Proton minibeam radiation therapy (pMBRT) is a novel radiation therapy approach that exploits the synergies of proton therapy with the gain in normal tissue preservation observed upon irradiation with narrow, spatially fractionated, beams. The net gain in normal tissue sparing that has been shown by pMBRT may lead to the efficient treatment of very radioresistant tumors, which are currently mostly treated palliatively. The aim of this study was to perform an evaluation of the tumor effectiveness of proton minibeam radiation therapy for the treatment of RG2 glioma-bearing rats. Methods and Materials Two groups (n = 9) of RG2 glioma-bearing rats were irradiated with either standard proton therapy or with pMBRT, with a dose prescription of 25 Gy in 1 fraction. The animals were followed up for a maximum of 6 months. At the end of the study, histopathological studies were performed to assess both the tumor presence and the possible side effects. Results Tumor control was achieved in the 2 irradiated series, with superior survival in the pMBRT group compared with the standard proton therapy group. Long-term (>170 days) survival rates of 22% and 67% were obtained in the standard proton therapy and pMBRT groups, respectively. No tumor was observed in the histopathological analysis. Although animals with long-term survival in the standard radiation therapy exhibit substantial brain damage, including marked radionecrosis, less severe toxicity was observed in the pMBRT group. Conclusions pMBRT offers a significant increase in the therapeutic index of brain tumors: The majority of the glioma-bearing rats (67%) survived 6 months with less severe side effects.

International audience; Extraordinary normal tissue response to highly spatially fractionated X-ray beams has been explored for over 25 years. More recently, alternative radiation sources have been developed and utilized with the aim to evoke comparable effects. These include protons, which lend themselves well for this endeavour due to their physical depth dose characteristics as well as corresponding variable biological effectiveness. This paper addresses the motivation for using protons to generate spatially fractionated beams and reviews the technological implementations and experimental results to date. This includes simulation and feasibility studies, collimation and beam characteristics, dosimetry and biological considerations as well as the results of in vivo and in vitro studies. Experimental results are emerging indicating an extraordinary normal tissue sparing effect analogous to what has been observed for synchrotron generated X-ray microbeams. The potential for translational research and feasibility of spatially modulated proton beams in clinical settings is discussed

We report an exceptional case of a very late local failure in a 9-year-old boy presenting with a chordoma of the cranio-cervical junction. The child was initially treated with a combination of surgical resection followed by high dose photon-proton radiation therapy. This aggressive therapy allowed a 9-year remission with minimal side-effects. Unfortunately, he subsequently presented with a local failure managed with a second full-dose course of protons. The child died one year later from local bleeding of unclear etiology.

Chondrosarcoma is a rare malignant tumor of the cartilage affecting young adults. Surgery, followed by charged-particle irradiation, is considered the reference standard for the treatment of patients with grade I to II skull base chondrosarcoma. The present study was conducted to assess the effect of the quality of surgery and radiation therapy parameters on local control (LC) and overall survival (OS).From 1996 to 2013, 159 patients (median age 40 years, range 12-83) were treated with either protons alone or a combination of protons and photons. The median total dose delivered was 70.2 Gy (relative biologic effectiveness [RBE]; range 67-71). Debulking and biopsy were performed in 133 and 13 patients, respectively.With a median follow-up of 77 months (range 2-214), 5 tumors relapsed based on the initial gross tumor volume. The 5- and 10-year LC rates were 96.4% and 93.5%, respectively, and the 5- and 10-year OS rates were 94.9% and 87%, respectively. A total of 16 patients died (13 of intercurrent disease, 3 of disease progression). On multivariate analysis, age40 years and primary disease status were independent favorable prognostic factors for progression-free survival and OS, and local tumor control was an independent favorable predictor of OS. In contrast, the extent of surgery, dosimetric parameters, and adjacent organs at risk were not prognostic factors for LC or OS.Systematic high-dose postoperative proton therapy for skull base chondrosarcoma can achieve a high LC rate with a low toxicity profile. Maximal safe surgery, followed by high-dose conformal proton therapy, is therefore recommended.

Purpose To assess the planning, treatment, and follow-up strategies worldwide in dedicated proton therapy ocular programs. Methods and Materials Ten centers from 7 countries completed a questionnaire survey with 109 queries on the eye treatment planning system (TPS), hardware/software equipment, image acquisition/registration, patient positioning, eye surveillance, beam delivery, quality assurance (QA), clinical management, and workflow. Results Worldwide, 28,891 eye patients were treated with protons at the 10 centers as of the end of 2014. Most centers treated a vast number of ocular patients (1729 to 6369). Three centers treated fewer than 200 ocular patients. Most commonly, the centers treated uveal melanoma (UM) and other primary ocular malignancies, benign ocular tumors, conjunctival lesions, choroidal metastases, and retinoblastomas. The UM dose fractionation was generally within a standard range, whereas dosing for other ocular conditions was not standardized. The majority (80%) of centers used in common a specific ocular TPS. Variability existed in imaging registration, with magnetic resonance imaging (MRI) rarely being used in routine planning (20%). Increased patient to full-time equivalent ratios were observed by higher accruing centers ( P =.0161). Generally, ophthalmologists followed up the post–radiation therapy patients, though in 40% of centers radiation oncologists also followed up the patients. Seven centers had a prospective outcomes database. All centers used a cyclotron to accelerate protons with dedicated horizontal beam lines only. QA checks (range, modulation) varied substantially across centers. Conclusions The first worldwide multi-institutional ophthalmic proton therapy survey of the clinical and technical approach shows areas of substantial overlap and areas of progress needed to achieve sustainable and systematic management. Future international efforts include research and development for imaging and planning software upgrades, increased use of MRI, development of clinical protocols, systematic patient-centered data acquisition, and publishing guidelines on QA, staffing, treatment, and follow-up parameters by dedicated ocular programs to ensure the highest level of care for ocular patients.

Background Sentinel lymph-node (LN) biopsy (SLNB) is a valuable tool to assess the regional LN status in Merkel cell carcinoma (MCC). However, its prognostic value is still debated. This study was undertaken to assess SLNB usefulness for MCC management and to determine the impact of SLNB status on disease-free survival (DFS) and overall survival (OS) by comparing SLNB-positive versus -negative patients according to demographic, clinical and treatment characteristics. Patients and methods In this retrospective, multicenter observational study, SLNB was proposed to all patients referred for clinically N0 MCC. Treatment schedule consisted of wide-margin surgical resection of primary MCC followed by adjuvant radiation therapy (aRT) to the primary site and, for SLNB-positive patients, radical LN dissection followed by regional aRT. Univariate and multivariate analyses determined factors associated with DFS and OS. Results Among 87 patients with successful SLNB, 21 (24.1%) were SLNB-positive. Median follow-up for the entire series was 39 months; respective 3-year DFS and OS rates were 73% and 81.4%, respectively. Univariate analysis (all patients) identified SLNB-negativity as being associated with prolonged OS (P = 0.013) and aRT (all sites considered) was associated with longer DFS (P = 0.004) and OS (P = 0.018). Multivariate analysis (all patients) retained SLNB status and aRT (all sites considered) as being associated with improved DFS (P = 0.014 and 0.0008) and OS (P = 0.0020 and 0.0019). Moreover, for SLNB-negative patients, tumor-bed irradiation was also significantly associated with prolonged DFS (P = 0.006) and OS (P = 0.014). Conclusion(s) The present study demonstrates that SLNB-negativity is a strong predictor of longer DFS and OS in stage I and II MCC patients. The similar benefit for aRT on tumor bed observed in this study has to be confirmed by a prospective study. The results advocate for SLNB being considered to all MCC patients.

Purpose Choroidal melanoma is a rare tumour in adults. The mean age at diagnosis is 60, but the tumour can affect women of childbearing age. A negative effect of pregnancy on patients' survival has not been formally excluded to date. The aim of the present study is to evaluate the effect of pregnancy on the prognosis of choroidal melanoma. Methods We conducted a single-centre retrospective study at the Institut Curie on the population of women of childbearing age who were diagnosed with choroidal melanoma between June 1980 and October 2013. We took a particular interest in the prognosis of those who were pregnant at the time of diagnosis and in the prognosis of those who chose to get pregnant after the treatment. Results We found 27 pregnant patients at the time of diagnosis and 13 patients who became pregnant after the treatment. There was no difference in the survival between these two groups of patients and the group of other women of childbearing age diagnosed with choroidal melanoma (p = 0.52). There was also no difference in metastasis-free survival (p = 0.91). Most women were able to carry their pregnancies to term (67% had a term pregnancy, and only 7% had an abortion). For women who were pregnant when they were diagnosed with choroidal melanoma, a conservative treatment was chosen in 85% of cases, and proton beam therapy was the most widely used treatment. Conclusions Survival in women of childbearing age does not appear to be influenced by pregnancy. We show that proton beam therapy can be used to treat women who are pregnant at the time of choroidal melanoma diagnosis.

We report an exceptional case of a very late local failure in a 9-year-old boy presenting with a chordoma of the cranio-cervical junction. The child was initially treated with a combination of surgical resection followed by high dose photon–proton radiation therapy. This aggressive therapy allowed a 9-year remission with minimal side-effects. Unfortunately, he subsequently presented with a local failure managed with a second full-dose course of protons. The child died one year later from local bleeding of unclear etiology.

Purpose To report the efficacy of Hydrosorb® versus control (water based spray) as topical treatment of grade 1–2 radiodermatitis in patients (pts) treated for early stage breast cancer (BC) with normo fractionated radiotherapy (RT). Patients and methods BC pts were randomized to receive either Hydrosorb® (A) or water based spray (B). The primary endpoint was local treatment failure defined as interruption of RT because of skin radiotoxicity or change of local care because of skin alteration. Secondary endpoints were: evaluation of skin colorimetry, pain, quality of life. Results Two-hundred seventy-eight pts were enrolled. There were 186 successfully treated pts. There were 60 "failures" in the Hydrosorb® arm, and 62 in the control arm ( p =0.72), but mostly without interruption of the RT. Twenty-four pts stopped RT for local care. The average absolute reduction of colorimetric levels between day 28 and day 0 was 4 in the Hydrosorb®, and 4.2 in the water spray groups, respectively ( p =0.36). Forty-eight patients in the Hydrosorb® arm had a VAS >2 versus 51 pts in the placebo arm, i.e. 34% and 38%, respectively ( p =0.45). A significant reduction of pain was observed on D 7 and D 21 in the Hydrosorb® arm. Conclusions The present study showed no significant difference between Hydrosorb® and simple water spray in the treatment of acute radio-induced dermatitis even if there was a trend to an improvement in pain at the first weeks after the treatment. Systematic prevention measures and modern breast cancer radiotherapy techniques now allow excellent tolerability, but the place of topical treatment to optimize this tolerability has yet to be defined. It seems that the most important part of the skin care is the prevention of skin reactions using new adapted techniques, as well as strict hygiene.

Optimal treatment for pediatric craniopharyngioma remains controversial. Although conservative surgery followed by radiation is favored, particularly when hypothalamic infiltration. Proton beam therapy (PT) offers further sparing of normal tissues exposure compared to photons. The objectives of this study were; To assess the efficacy of limited surgery followed by PT in children with craniopharyngioma; To evaluate feasibility of dose escalation while maintaining risk-adapted dose constraints to the chiasm. The trial included 33 patients (17 males), median age 9.0 years (2.1–15.5) at diagnosis, 9.6 years (3.3–15.8) at radiation. All patients underwent surgery (1–5, median: 2) with measurable residue. Median interval between diagnosis and PT was 7.2 months (2.5–73.6). Median PTV was 31.1 cm3 (12.7–136). Imaging studies during radiation identified increase in size of cystic components in 11 patients, including 2 who required re-planning. Total median dose was 54.4 CGE (52.2–56.1). Based on dosimetric parameters, 5 patients underwent slight dose escalation. Median dose to the chiasm was 52.7 CGE (51.8–54.4). At a median follow-up of 4.3 years (1.3–7.0) since radiation, 32 patients are alive. 3 patients experienced progression. All patients are on hormone replacement, 25/32 patients have normal vision in at least one eye, 17/32 have restricted fields. 24 patients have normal academic status, 8 patients require special schooling. Median BMI is 24.1 (18.7–36.3), 11 patients are overweight and 9 obese. CONCLUSION: This study supports the use of PT in pediatric craniopharyngioma, although the objective of dose escalation, using passive scattering delivery was not reached, preventing dose effect relationship evaluation.

Background and purpose Skull-base chondrosarcoma (ChSa) is a rare bone tumor and the outcome of patients with this malignancy has been documented only in a limited number of series with a restricted number of patients. Objective This study was conducted to assess the outcome and prognostic factors of a large cohort of ChSa patients treated with radiotherapy in two proton therapy centers. Materials and methods From 1996 to 2015, 251 (male, 43.4%) patients (mean age, 42.0 ± 16.2 years) were treated with protons with (n = 135; 53.8%) or without photons (n = 116; 46.2%). Median delivered dose was 70.2 GyRBE. Failure-free survival (FFS), overall survival (OS) and CTCAE grade ≥3 toxicity free survival (TFS) were calculated using the Kaplan–Meier method. Results After a median follow-up of 88.0 months for surviving patients, local and distant failures were observed in 12 (4.8%) and 4 (1.6%) patients, respectively. Late failures >6 years were observed in 4 (33.3%) patients. The estimated 7-year FFS was 93.1%. Twenty-five (10%) patients died. The estimated 7-year OS was 93.6%. Tumor volume (p = 0.006) and optic pathway compression (p = 0.027) were significantly associated with the risk of treatment failure on univariate analysis. Treatment failure was significantly associated with a higher risk of death (hazard ratio = 126). The estimated 7-year TFS was 84.2%. Conclusions The outcome of skull-base ChSa patients treated with high-dose protons with or without photons is excellent, particularly for patients with small tumors with no optic pathway compression. Treatment failure was however associated with a significantly increased risk of death.

International audience; PURPOSE:Proton minibeam radiation therapy (pMBRT) is an innovative approach that combines the advantages of minibeam radiation therapy with the more precise ballistics of protons to further reduce the side effects of radiation. One of the main challenges of this approach is the generation of very narrow proton pencil beams with an adequate dose-rate to treat patients within a reasonable treatment time (several minutes) in existing clinical facilities. The aim of this study was to demonstrate the feasibility of implementing pMBRT by combining the pencil beam scanning (PBS) technique with the use of multislit collimators. This proof of concept study of pMBRT with a clinical system is intended to guide upcoming biological experiments.METHODS:Monte Carlo simulations (TOPAS v3.1.p2) were used to design a suitable multislit collimator to implement planar pMBRT for conventional pencil beam scanning settings. Dose distributions (depth-dose curves, lateral profiles, Peak-to-Valley Dose Ratio (PVDR) and dose-rates) for different proton beam energies were assessed by means of Monte Carlo simulations and experimental measurements in a water tank using commercial ionization chambers and a new p-type silicon diode, the IBA RAZOR. An analytical intensity-modulated dose calculation algorithm designed to optimize the weight of individual Bragg peaks composing the field was also developed and validated.RESULTS:Proton minibeams were then obtained using a brass multislit collimator with five slits measuring 2 cm × 400 μm in width with a center-to-center distance of 4 mm. The measured and calculated dose distributions (depth-dose curves and lateral profiles) showed a good agreement. Spread-out Bragg peaks (SOBP) and homogeneous dose distributions around the target were obtained by means of intensity modulation of Bragg peaks, while maintaining spatial fractionation at shallow depths. Mean dose-rates of 0.12 and 0.09 Gy/s were obtained for one iso-energy layer and a SOBP conditions in the presence of multislit collimator.CONCLUSIONS:This study demonstrates the feasibility of implementing pMBRT on a PBS system. It also confirms the reliability of RAZOR detector for pMBRT dosimetry. This newly developed experimental methodology will support the design of future preclinical research with pMBRT.

Uveal melanomas are the most frequent primary malignant eye tumor. Enucleation was historically the gold standard. Since then, several studies showed that conservative treatments did not increase the risk of metastasis or survival. Choroidal melanomas are both radioresistant and located close to visual structures (the optic nerve and macula) of the eye, which may be preserved in some settings without compromising tumor control, as this is the first priority. Different types of radiation therapy may be used for such tumors: brachytherapy and charged particles, including proton beam therapy. If visual prognosis is dependent to the local treatment, the vital prognosis is dependent on the metastatic risk, with a risk of liver involvement in 20 to 50% of patients, depending on tumor size and genomics. Median survival after the discovery of liver metastases is about 15 months. The management of these patients is often complex. Systemic therapies (chemotherapy, targeted therapies, immunotherapy, etc.) yield limited response rates and although local treatments of liver metastases are promising, they are only feasible in selected patients. The mission of the MELACHONAT national network is to improve the management of patients regardless of the stage of the disease. The patient association ANPACO is dedicated to help uveal melanoma patients in their health care path and to promote knowledge dissemination within the patient community. The aim of this review is to focus on the local treatments of uveal melanomas as well as the management of their metastatic evolution.

Background: ECCO essential requirements for quality cancer care (ERQCC) are explanations and descriptions of challenges, organisation and actions that are necessary to give high-quality care to patients who have a specific type of cancer. They are written by European experts representing all disciplines involved in cancer care. ERQCC papers give oncology teams, patients, policymakers and managers an overview of the elements needed in any healthcare system to provide high quality of care throughout the patient journey. References are made to clinical guidelines and other resources where appropriate, and the focus is on care in Europe. Melanoma: essential requirements for quality care: • Melanoma, the most-deadly skin cancer, is rising in incidence among fair-skinned people in Europe. Increasing complexity of care for advanced disease in clinical areas such as staging and new therapies requires attention to a number of challenges and inequalities in a diverse patient group.• Care for advanced melanoma must only be carried out in, or in collaboration with, specialist melanoma centres which have both a core multidisciplinary team and an extended team of allied professionals, and which are subject to quality and audit procedures. Access to such units is far from universal in all European countries.• It is essential that, to meet European aspirations for high-quality comprehensive cancer control, healthcare organisations implement the requirements in this paper, paying particular attention to multidisciplinarity and patient-centred pathways from diagnosis to treatment and follow-up, to improve survival and quality of life for patients.Conclusion: Taken together, the information presented in this paper provides a comprehensive description of the essential requirements for establishing a high-quality service for melanoma. The ERQCC expert group is aware that it is not possible to propose a ‘one size fits all’ system for all countries, but urges that access to multidisciplinary teams and specialised treatments is guaranteed to all patients with melanoma., SCOPUS: re.j, info:eu-repo/semantics/published

International audience; Retinoblastoma (Rb) results from biallelic inactivation of the RB1 gene. Hereditary Rb patients i. e germline carriers of a RB1 mutation also have a risk of developing subsequent malignant neoplasms (SMN) such as os-teosarcomas. This SMN risk is maximized by external beam radiotherapy treatments (EBRT), which is why these treatments are now avoided. Nevertheless, EBRT is still a matter of great concern, as EBRT-treated patients are in their adulthood and SMNs remain the major cause of death for patients. To decipher the relationship between RB1 genotype and SMN development in EBRT treated patients, we conducted a retrospective study in a cohort of 160 irradiated hereditary Rbs with fully resolved RB1 mutational status. Median follow-up was 22 years [1-51] and median age of patients was 27 years old [7-53]. Among these 160 Rb patients, 120 did not develop any SMN (75%) and 40 developed SMNs (25%). The age at which EBRT is given (i.e. before or after the age of 12 months) was not correlated to SMN development (p = 0.6). We didn't find any difference in RB1 mutation type between patients with or without SMN, neither could we detect any linkage between mutation type and SMN location, SMN type and age at diagnosis. Interestingly, among 13 carriers of a RB1 low penetrance mutation, 3 of them developed sarcomas, a rare tumor that cannot be attributed to the general population. Our study cannot explain why a RB1 mutation leads or not to a SMN but demonstrated that EBRT patients with a low penetrance mutation remain at risk of SMN and should be cautiously monitored.