Single-agent anti-PD-1 or combined with ipilimumab in patients with mucosal melanoma: an international, retrospective, cohort study.

BACKGROUND: Mucosal melanoma (MM) is a rare melanoma subtype with distinct biology and poor prognosis. Data on the efficacy of immune checkpoint inhibitors (ICIs) are limited. We determined the efficacy of ICIs in MM, analyzed by primary site and ethnicity/race. PATIENTS AND METHODS: A retrospective cohort study from 25 cancer centers in Australia, Europe, USA and Asia was carried out. Patients with histologically confirmed MM were treated with anti-programmed cell death protein 1 (PD-1) ± ipilimumab. Primary endpoints were response rate (RR), progression-free survival (PFS), overall survival (OS) by primary site (naso-oral, urogenital, anorectal, other), ethnicity/race (Caucasian, Asian, Other) and treatment. Univariate and multivariate Cox proportional hazards model analyses were conducted. RESULTS: In total, 545 patients were included: 331 (63%) Caucasian, 176 (33%) Asian and 20 (4%) Other. Primary sites included 113 (21%) anorectal, 178 (32%) urogenital, 206 (38%) naso-oral and 45 (8%) other. Three hundred and forty-eight (64%) patients received anti-PD-1 and 197 (36%) anti-PD-1/ipilimumab. RR, PFS and OS did not differ by primary site, ethnicity/race or treatment. RR for naso-oral was numerically higher for anti-PD-1/ipilimumab [40%, 95% confidence interval (CI) 29% to 54%] compared with anti-PD-1 (29%, 95% CI 21% to 37%). Thirty-five percent of patients who initially responded progressed. The median duration of response (mDoR) was 26 months (95% CI 18 months-not reached). Factors associated with short PFS were Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥3 (P < 0.01), lactate dehydrogenase (LDH) more than the upper limit of normal (ULN) (P = 0.01), lung metastases (P < 0.01) and ≥1 previous treatments (P < 0.01). Factors associated with short OS were ECOG PS ≥1 (P < 0.01), LDH >ULN (P = 0.03), lung metastases (P < 0.01) and ≥1 previous treatments (P < 0.01). CONCLUSIONS: MM has poor prognosis. Treatment efficacy of anti-PD-1 ± ipilimumab was similar and did not differ by ethnicity/race. Naso-oral primaries had numerically higher response to anti-PD-1/ipilimumab, without difference in survival. The addition of ipilimumab did not show greater benefit over anti-PD-1 for other primary sites. In responders, mDoR was short and acquired resistance was common. Other factors, including site and number of metastases, were associated with survival.

Dorsal rhizotomy in cerebral palsy: How root sectioning is influenced by intraoperative neuromonitoring?

INTRODUCTION AND OBJECTIVE: Dorsal rhizotomy is a controversial procedure for treating spasticity in children with cerebral palsy, particularly regarding the influence of intraoperative neuromonitoring (ION). The objective of this study was to evaluate the influence of ION in adjusting root sectioning compared the preoperative program established by the multidisciplinary team. MATERIAL AND METHODS: Twenty-four consecutive children with spastic diplegia or quadriplegia, operated on between 2017 and 2020 in the University Hospital of Nancy, France, were studied. All underwent the same procedure: Keyhole Intralaminar Dorsal rhizotomy (KIDr) with enlarged multilevel interlaminar openings to access all roots from L2 to S2. The Ventral Root (VR) was stimulated to map radicular myotomes, and the Dorsal Root (DR) to test excitability of the segmental circuitry. Muscle responses were observed independently by the physiotherapist and by EMG-recordings. The study compared final root sectioning per radicular level and per side after ION versus the preoperative program determined by the multidisciplinary team. RESULTS: ION resulted in significant differences in final percentage root sectioning (P<0.05), with a decrease for L2 and L3 and an increase for L5. ION modified the symmetry of sectioning, with 32% instead of 5% in preoperative program. Only 5 children showed change in GMFC score 6 months after surgery. CONCLUSION: The use of ION during dorsal rhizotomy led to important modifications of root sectioning during surgery, which justifies individual control of each root, level by level and side by side, to optimize the therapeutic effect.

Ophthalmological lesions in shaken baby syndrome: A retrospective analysis of 133 consecutive cases (1992-2018).

INTRODUCTION: Shaken Baby Syndrome (SBS) is a non-accidental head trauma in which shaking causes cranio-cerebral lesions. Shaking can lead to ophthalmologic lesions such as retinal hemorrhage (RH). The aim of the present study was to compare our long-term results in to the literature data. PATIENTS AND METHODS: This study was a single-center retrospective descriptive analysis of 133 consecutive SBS cases (1992-2018). Only seniors in ophthalmology were authorized to perform these examinations. We studied type of lesion (retinal, intra-vitreal, papilledema), location (uni- or bi-lateral), and correlation with gender and age. Infants with a traumatic context without suspicion of child abuse were excluded. RESULTS: Mean age at diagnosis was 131days (range, 14days-10months). Boys accounted for 72.2% of the population. The prevalence of ophthalmologic lesions was 70.3%. 94.4% were RH; intra-vitreous hemorrhage (6.7%) and papilledema (11.1%) were less frequent. Lesions were bilateral in 81.1% of cases. Retinal lesions were classified in terms of location. Macular involvement was diagnosed in 8.2% of cases. 18.8% of retinal lesions could not be classified because of lack of precision in the ophthalmology report. The prevalence of ophthalmic lesions was higher for children aged over 6months: 80%. CONCLUSION: This series highlighted a high rate of ophthalmic lesions in SBS, with a high rate of bilateral involvement. RH was the most frequent lesion. RH in a context of subdural hematoma is a strong argument in favor of SBS. The forensic implications are that rigorous ophthalmologic examination by a senior practitioner is mandatory.

Prenatal neurosurgical counseling for conditions affecting the fetal nervous system.

OBJECTIVE: The aim of this study was to share a single center's experience of prenatal neurosurgical counseling and explore pregnant women's experiences with counseling. MATERIAL AND METHODS: This retrospective study analyzed data for 81 women who received prenatal counseling in a single institution (same senior pediatric neurosurgeon) over a 6-year period. Additionally, a retrospective questionnaire study was conducted with 33 women who chose to continue their pregnancy, to assess the strengths and weaknesses of counseling and analyze the reasons for their decision. RESULTS: Spinal dysraphism was the most frequent condition leading to prenatal counseling, followed by conditions affecting the cerebrospinal fluid. 57.6% of the women did not follow the French national recommendations on folic acid supplementation in the periconceptional period, and 38.3% underwent termination of pregnancy (TOP). One-third of the 33 women who answered our questionnaire changed their mind about TOP after counseling, and 50% reported that the information provided influenced their decision. CONCLUSION: Prenatal neurosurgical counseling is nowadays an important part of a pediatric neurosurgeon's practice. It provides specific information to the woman to decide whether to continue the pregnancy. Urological concerns are frequent among the malformations encountered. Hence, we conclude that these women should be offered the possibility of seeing a urologist. Areas for improvement include greater awareness regarding folic acid supplementation and improved psychological care. The advantage for a woman of consulting a neurosurgeon consists in receiving information that is as accurate as possible about the level of disability of the future child and about surgery and follow-up.

Late effects of craniospinal irradiation for medulloblastomas in paediatric patients.

Along with surgery, radiation therapy (RT) remains an essential option to cure patients suffering from medulloblastoma. However, its long-term adverse effects, particularly due to craniospinal irradiation (CSI), which is necessary to eradicate microscopic spread, are a limiting factor. The most frequent sequelae involve neurocognitive and endocrine impairment, which occurs in nearly all patients. Recent progress achieved through genetic and molecular biology offers the possibility to better stratify patients according to risk factors such as age, post-resection tumour residue and metastasis. Thus, new therapeutic studies assess the possibility to reduce radiation dose and/or radiation field size for patients with the most favourable prognosis. New radiotherapy techniques are also used such as Intensity-Modulated Radiotherapy (IMRT), tomotherapy and proton therapy, which aim at reducing the dose delivered to normal tissue. Conventional photon-based therapy has a relatively high exit dose in contrast with proton therapy which causes less damage to surrounding healthy tissue. It is noteworthy that each technique requires a long follow-up in order to prove that late effects could be reduced without compromising survival rates. Dosimetric comparison theoretically suggests that proton therapy may be the superior method for CSI in terms of late effects, but further research is needed to firmly establish this. Whatever the technique used, the great complexity of CSI requires discipline and expertise along with an external quality control online before the first RT session.

Surgical approach to the posterior fossa in children, including anesthetic considerations and complications: The prone and the sitting position. Technical note.

INTRODUCTION: Medulloblastoma (MB) in children is, in most cases, a midline lesion located in the posterior fossa, with a high tendency to invade the fourth ventricle (and sometimes its floor). METHODS: In this technical note, we present both the sitting and the prone position for children with medulloblastoma. These positions will be described together by deliberately deciding not to oppose one against the other. The park bench position, seldom used in pediatric neurosurgery is not described here. The latter procedure can be useful, however, for MB located more laterally or within the cerebellopontine angle. RESULTS: The aim of this technical note is to provide the reader with a step by step procedure (from installation to closure), at least from the author's point of view. A special focus regarding anesthetic considerations is also provided. This anesthesia requires perfect coordination and communication between both the anesthetic and surgical teams. Complications of posterior fossa surgery are mentioned as well. Some of the advantages and disadvantages of each positions are mentioned. CONCLUSION: Only careful installation, respect of certain surgical principles (careful attention of the vermis and dentate nuclei for example), knowledge of anatomy, closure and perioperative monitoring, screening and immediate correction of potentially devastating complications will enable surgeons to obtain the best results from their surgery.

Cerebellar swelling after surgery for medulloblastoma with leptomeningeal dissemination in children. A case based-update.

OBJECT: Despite the improvement in the overall management of medulloblastomas in recent years, certain phenomena and in particular postoperative cerebellar swelling remain an enigma. This rare complication, little described in the literature, is nonetheless life threatening for the patients. CASE REPORTS: We report our experience about two children who developed severe cerebellar swelling with hydrocephalus and upward herniation soon after a gross total resection of a fourth ventricle medulloblastoma by a telo-velar approach. Despite rapid management of ventricular dilation and optimal medical intensive treatment of intracranial hypertension, both children died quickly after the surgery. Pathological examination analyses were in favour of anaplastic/large cell medulloblastoma. DISCUSSION: Diffuse cerebellar swelling with upward herniation may occur postoperatively in young children with anaplastic/large cell medulloblastoma with leptomeningeal spread. In the literature, only 4 cases have been so far described with delayed onset of symptoms. Two children survived with an aggressive management (decompressive surgery and early radio-chemotherapy). CONCLUSION: Cerebellar swelling is an unrecognised and sudden complication of posterior fossa surgery for metastatic anaplastic medulloblastoma with leptomeningeal dissemination in young children. An initial less invasive surgical approach could be considered in such cases, in order to prevent this complication with potentially tragic issue, and which cannot be managed with a CSF shunt alone.

Optic pathway tumor in children: Toward a new classification for neurosurgical use.

OBJECT: Optic pathway tumors (OPT) represent a challenge for pediatric neurosurgeons. Role of surgery is debated due to the high risk of iatrogenic damage, and in lasts decades it lost its importance in favor of chemotherapy. However, in some cases surgery is necessary to make biomolecular and histological diagnosis, to manage intracranial hypertension (IH) and to cooperate with medical therapies in controlling tumor relapse. With the aim to standardize selection of surgical OPT cases, we propose a simple, practical and reproducible classification. METHODS: We retrospectively analyzed data of 38 patients with OPT treated at our institution (1990-2018). After careful analysis of MRI images, we describe a new classification system. Group 1: lesion limited to one or both optic nerve(s). Group 2: chiasmatic lesions extending minimally to hypothalamus. Group 3: hypothalamo-chiasmatic exophitic lesions invading the third ventricle; they can be further divided on the base of concomitant hydrocephalus. Group 4: hypothalamo-chiasmatic lesions extending widely in lateral direction, toward the temporal or the frontal lobes. Patients' data and adopted treatment are reported and analyzed, also depending on this classification. RESULTS: Twenty children were operated on for treatment of OPT during the study period. Permanent clinical impairment was noted in 5 (25%) of operated patients, while visual improvement was noted in 1 patient. OS rate was 100% at 5 years, with a median follow up of 9 years (ranging from 2 to 23). Prevalence of intracranial hypertension and proportion of first-line surgical treatment decision were significantly higher in groups 3-4 compared to groups 1-2 (P<0.001 for both tests). CONCLUSION: Surgery can offer a valuable therapeutic complement for OPT without major risk of iatrogenic damage. Surgery is indispensable in cases presenting with IH, as in groups 3 and 4 lesions. Eligibility of patients to surgery can be based on this new classification system.

The relationship between spontaneous cerebrospinal fluid leak and idiopathic intracranial hypertension.

Surgical treatment of spontaneous cerebrospinal fluid (CSF) leak is now performed by ENT surgeons, endonasal endoscopy being preferred to craniotomy as less invasive. However, it is often the symptom of underlying idiopathic intracranial hypertension, which lies outside the traditional sphere of ENT competence. Surgery is a necessary step, but should not obscure the need to treat the underlying pathology. This treatment is complex, and requires multidisciplinary team-work between otorhinolaryngologist, ophthalmologist, neurologist, neurosurgeon, radiologist, dietician, endocrinologist and psychotherapist. The present update details this multidisciplinary management to which the ENT surgeons must be attentive before and after spontaneous CSF leak repair.

Diffuse infiltrative pontine glioma biopsy in children with neuronavigation, frameless procedure: A single center experience of 10 cases.

INTRODUCTION: This study presented pediatric DIPG 's biopsy with frameless Neuronavigation. PATIENTS AND METHODS: We report our experience about 10 patients who had Diffuse Intrinsic Pontine Glioma between 2014 and 2018. All patients were biopsied with BrainLab Varioguide Neuronavigation®. We always used fusion between specific CT Scan and MRI to selected target, made planning and biopsies. All patients were included in BIOMEDE after scientific and ethic discussions. We always selected a trans-cerebellar trajectory and made same procedure (lot of biopsies at one level). All patients have MRI at J1 to verify site of biopsy and to eliminate complication. RESULTS: The average age was 8.1 years. Symptoms were common with principally headaches and nystagmus. All biopsies were contributive for histopathological diagnosis and establish molecular profile for molecular study. We have no definitive morbidity and procedure duration was 93minutes in average. All MRI didn't showed intracranial complication after procedure and showed great precision of biopsy compared with the selected target. DISCUSSION: We reviewed the literature and compare our results with series of DIPG biopsies using stereotactic frame or robotic assisted frameless. It was a safe, accuracy and easiness procedure. We always have histopathological and molecular result to proceed next step of treatment. This modality is an alternative possibility to biopsy very young patients with low morbidity.

Influence of Natural Polyphenols on Isolated Yeast Dipodascus magnusii Mitochondria.

The effect of stilbene polyphenols (resveratrol and pinosilvin) and flavonoids (dihydromyricetin, epigallocatechin, and dihydroquercetin) on producing the reactive oxygen species (ROS) due to cell respiration using the isolated mitochondria of the fungus Dipodascus (Endomyces) magnusii was studied. It was shown that the inhibition of the ROS generation with stilbenes is related to both the oxygen consumption inhibition and their antioxidant properties. The degree of manifestation of polyphenol antioxidant properties depended on the number of hydroxyl groups in a polyphenol molecule. Of the flavonoids tested, dihydromyricetin was most active in reducing the ROS generation, but its inhibitory effect on oxygen consumption by mitochondria was significantly lower as compared to that of the stilbenes. The data obtained show that the mechanism of reducing the ROS generation with polyphenols is associated with both the respiratory inhibition and their antioxidant properties.

Spinal cord tumors in children: A review of 21 cases treated at the same institution.

INTRODUCTION: Spinal cord tumors in children (SCTC) are rare with a frequent diagnostic delay. Its management is multidisciplinary and challenging due to functional implications. The position of surgery is now better established but the role and timing of chemotherapy (CT) and radiotherapy (RT) still remains under debate. Adverse effects of treatments are important to be taken into account, in the follow-up of these children. The aim of this paper was to present a series of 21 cases of SCTC treated at the same institution, to briefly present clinical features, treatments and outcome, with a special focus on spinal deformities in children with this condition. MATERIAL AND METHODS: Twenty-one consecutive SCTC were referred to our institution from 1990 to 2014. Data regarding age, sex, diagnostic delay, clinical examination, MRI, surgery, pathology, other treatment (CT and RT), orthopedic issues and follow-up of these children were retrospectively recorded. RESULTS: Mean age was 8years (standard deviation: 5.2years) (range: 4 months-17years). Mean diagnosis delay was 5.5 months (standard deviation: 6.5 months) (range: 0 days-18 months). All children (10 girls, 11 boys) were operated on (10 partial removals, 7 subtotal and 4 gross total removals) as first-line treatment. Pathological results showed 12 juvenile pilocytic astrocytomas, 1 grade III astrocytoma, 1 grade IV astrocytoma, 3 oligodendrogliomas, 2 ependymomas, 1 glioblastoma and 1 rhabdoid tumor. Fourteen children (66.7%) received additional treatment: 12 CT and 7 RT. Ten children had postoperative spinal deformities. Mean follow-up (FU) was 71 months (5 months-180 months), with a median FU at 60 months, where 8 tumor progressions and 4 deaths were observed. Overall, survival (at 5years) was 81% and progression free survival (at 5years) was 67%. CONCLUSION: Surgery is the goal standard for SCTC and the only appropriate treatment in cases of a low-grade lesion with stable disease on MR follow-up. Additional treatment must be reserved for high-grade lesions or tumor progression not attainable by a second look surgery. Spinal deformities are a frequent complication. Overall, survival and event free survival primarily depends on the pathology. Studies involving more centers are obligatory with the aim of collecting more cases and drawing more definitive conclusions regarding the management of these tumors.

[Hypofractionated stereotactic radiotherapy for brain metastasis: Benefit of additional whole brain radiotherapy?] / Radiothérapie stéréotaxique hypofractionnée des métastases cérébrales : bénéfice de l'irradiation encéphalique totale ?

PURPOSE: To study overall survival, risk of neurological death, local recurrence and development of new brain metastasis in patients treated for brain oligometastases with hypofractionated stereotactic radiotherapy with CyberKnife®, according to the association or not with an additional whole brain irradiation. PATIENTS AND METHODS: Institutional retrospective study of 102 patients treated for one to three brain metastasis: 76 with exclusive hypofractionated stereotactic radiotherapy and 26 with hypofractionated stereotactic radiotherapy and whole brain irradiation. Objectives were assessed and compared between these two groups according to the Kaplan-Meier method and Cox model. RESULTS: Median follow-up was 18.8 months. There were no difference between exclusive hypofractionated stereotactic radiotherapy and hypofractionated stereotactic radiotherapy with whole brain irradiation for overall survival (respective median 21.5 and 20.1 months), risk of neurological death (respectively 9.2% and 15.4% at one year). At one year: the risk of cerebral progressive disease was greater in the group receiving exclusive hypofractionated stereotactic radiotherapy (respectively 43.4% vs. 26.2%, P=0.043), the risk of local recurrence was 25% versus 17.6% (P=0.28) and the development of new brain metastasis was 23.7% versus 11.5% (P=0.27). After salvage treatments, crude local control was similar in the two groups, respectively 78.6% and 73.5%. Whole brain irradiation has been avoided for 72.4% of patients in the group receving exclusive hypofractionated stereotactic radiotherapy. CONCLUSION: Whole brain irradiation improves local control of brain metastatic disease in addition to hypofractionated stereotactic radiotherapy. Sparing whole brain irradiation for salvage treatments only does not affect overall survival or risk of neurological death in selected patients with favourable prognosis.

IRF6 and SPRY4 Signaling Interact in Periderm Development.

Rare mutations in IRF6 and GRHL3 cause Van der Woude syndrome, an autosomal dominant orofacial clefting disorder. Common variants in IRF6 and GRHL3 also contribute risk for isolated orofacial clefting. Similarly, variants within genes that encode receptor tyrosine kinase (RTK) signaling components, including members of the FGF pathway, EPHA3 and SPRY2, also contribute risk for isolated orofacial clefting. In the mouse, loss of Irf6 or perturbation of Fgf signaling leads to abnormal oral epithelial adhesions and cleft palate. Oral adhesions can result from a disruption of periderm formation. Here, we find that IRF6 and SPRY4 signaling interact in periderm function. We crossed Irf6 heterozygous ( Irf6+/-) mice with transgenic mice that express Spry4 in the basal epithelial layer ( TgKRT14::Spry4). While embryos with either of these mutations can have abnormal oral adhesions, using a new quantitative assay, we observed a nonadditive effect of abnormal oral epithelial adhesions in the most severely affected double mutant embryos ( Irf6+/-;TgKRT14::Spry4). At the molecular level, the sites of abnormal oral adhesions maintained periderm-like cells that express keratin 6, but we observed abnormal expression of GRHL3. Together, these data suggest that Irf6 and RTK signaling interact in regulating periderm differentiation and function, as well as provide a rationale to screen for epistatic interactions between variants in IRF6 and RTK signaling pathway genes in human orofacial clefting populations.

A review of craniofacial and dental findings of the RASopathies.

OBJECTIVES: The RASopathies are a group of syndromes that have in common germline mutations in genes that encode components of the Ras/mitogen-activated protein kinase (MAPK) pathway and have been a focus of study to understand the role of this pathway in development and disease. These syndromes include Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NSML or LEOPARD syndrome), neurofibromatosis type 1 (NF1), Costello syndrome (CS), cardio-facio-cutaneous (CFC) syndrome, neurofibromatosis type 1-like syndrome (NFLS or Legius syndrome) and capillary malformation-arteriovenous malformation syndrome (CM-AVM). These disorders affect multiple systems, including the craniofacial complex. Although the craniofacial features have been well described and can aid in clinical diagnosis, the dental phenotypes have not been analysed in detail for each of the RASopathies. In this review, we summarize the clinical features of the RASopathies, highlighting the reported craniofacial and dental findings. METHODS: Review of the literature. RESULTS: Each of the RASopathies reviewed, caused by mutations in genes that encode different proteins in the Ras pathway, have unique and overlapping craniofacial and dental characteristics. CONCLUSIONS: Careful description of craniofacial and dental features of the RASopathies can provide information for dental clinicians treating these individuals and can also give insight into the role of Ras signalling in craniofacial development.

[Prenatal diagnosis of neural tube defects: Correlation between prenatal and postnatal data]. / Diagnostic prénatal des dysraphismes spinaux : corrélation des données anténatales et postnatales.

OBJECTIVES: Neural tube defects (NTD) are congenital anomalies that can cause significant neurological long-term disabilities. Theses malformations are accessible to prenatal diagnosis and quite recently, to in utero repair for some myelomeningoceles. The aim of this study was to analyse the correlation between prenatal and postnatal examinations. MATERIALS AND METHODS: A descriptive retrospective monocentric study has been conducted between January 2004 and December 2014 in a tertiary care maternity. All patients who benefited a prenatal diagnosis of NTD for their foetus, and for whom postnatal data were available were included. Prenatal and postnatal data, especially type of dysraphism, levels of defect and extent, and associated anomalies were compared. RESULTS: Sixty spinal dysraphisms were diagnosed antenataly. Concerning the type of dysraphism, ultrasound diagnosis was well correlated with postnatal findings (ρ=0.7048). Prenatal level and extent were correlated with postnatal data (respectively ρ=0.539 and ρ=0.562). Vertebral upper level defined by ultrasound agreed with postnatal constatations in 80.8% of cases within one vertebra, and in 84.6% of cases within two vertebras. Concerning indirect signs of spina bifida, prenatal data agreed with postnatal ones for most of them, especially for Arnold Chiari II malformation. CONCLUSION: There is a high correlation between prenatal and postnatal data. Prenatal ultrasound seems to be efficient for description of neural tube defects and to identify foetuses for which the benefit of in utero surgery exists.

Anti-PD-1 therapy in patients with advanced melanoma and preexisting autoimmune disorders or major toxicity with ipilimumab.

Background: Anti-PD-1 antibodies (anti-PD-1) have clinical activity in a number of malignancies. All clinical trials have excluded patients with significant preexisting autoimmune disorders (ADs) and only one has included patients with immune-related adverse events (irAEs) with ipilimumab. We sought to explore the safety and efficacy of anti-PD-1 in such patients. Patients and methods: Patients with advanced melanoma and preexisting ADs and/or major immune-related adverse events (irAEs) with ipilimumab (requiring systemic immunosuppression) that were treated with anti-PD-1 between 1 July 2012 and 30 September 2015 were retrospectively identified. Results: One hundred and nineteen patients from 13 academic tertiary referral centers were treated with anti-PD-1. In patients with preexisting AD (N = 52), the response rate was 33%. 20 (38%) patients had a flare of AD requiring immunosuppression, including 7/13 with rheumatoid arthritis, 3/3 with polymyalgia rheumatica, 2/2 with Sjogren's syndrome, 2/2 with immune thrombocytopaenic purpura and 3/8 with psoriasis. No patients with gastrointestinal (N = 6) or neurological disorders (N = 5) flared. Only 2 (4%) patients discontinued treatment due to flare, but 15 (29%) developed other irAEs and 4 (8%) discontinued treatment. In patients with prior ipilimumab irAEs requiring immunosuppression (N = 67) the response rate was 40%. Two (3%) patients had a recurrence of the same ipilimumab irAEs, but 23 (34%) developed new irAEs (14, 21% grade 3-4) and 8 (12%) discontinued treatment. There were no treatment-related deaths. Conclusions: In melanoma patients with preexisting ADs or major irAEs with ipilimumab, anti-PD-1 induced relatively frequent immune toxicities, but these were often mild, easily managed and did not necessitate discontinuation of therapy, and a significant proportion of patients achieved clinical responses. The results support that anti-PD-1 can be administered safely and can achieve clinical benefit in patients with preexisting ADs or prior major irAEs with ipilimumab.