Sonidegib in the Treatment of Locally Advanced Basal Cell Carcinoma: a Retrospective Study.

Sonidegib, a hedgehog pathway inhibitor, is indicated for treatment of locally advanced basal cell carcinoma, based on the results of the BOLT study. However, to date, no real-world study of sonidegib has been reported. An observational, retrospective, single-centre study (PaSoS study) was conducted. The primary objective was to evaluate the efficacy of sonidegib for treatment of locally advanced basal cell carcinoma in a real-world setting. Secondary objectives included modalities of use, tolerability, tumour evolution, and management after discontinuation. A total of 21 patients treated with sonidegib were included from March 2018 to January 2021. The median follow-up was 18.7 months and median exposure 7.0 months. Objective response (OR) rate was 81.0% (n = 17) including 6 (29%) patients with a complete response (CR). Disease control rate was 100%. First tumour response was rapid, with a median time of 2.3 months. Nine (43%) patients underwent surgery after sonidegib discontinuation, and no relapse was observed. All the patients experienced at least 1 adverse event (AE). Muscle spasms were the most frequent AE (n = 14; 67%), followed by dysgeusia (n = 8; 38%) and alopecia (n = 12; 57%). The efficacy and safety profile of sonidegib in this first-to-date real-life trial are consistent with prior results. Overall, real-world evidence corroborated sonidegib efficacy and tolerability as a first-line treatment for locally advanced basal cell carcinoma.

Haemorrhagic shock secondary to a diffuse ulcerative enteritis after Ipilimumab and Nivolumab treatment for metastatic melanoma: a case report.

We provide a unique case of haemorrhagic shock complicating a corticosteroid-resistant diffuse ulcerative enteritis in a patient treated with a combination of an anti cytotoxic T-lymphocyte antigen-4 (CTLA4) and an anti programmed cell death protein 1 (PD-1) for metastatic melanoma. Immunotherapy has changed the perspective for the management of patients with metastatic melanoma but are also responsible for digestive complications mainly represented by immunomediated colitis. Digestive bleeding is common in patients with extensive colonic lesions but has never been described in enteritis independent of colitis. The patient with acute intestinal obstruction related ileitis without evidence of stricture on imaging and then had a gastro-intestinal bleed. In the absence of haemorrhagic lesions on upper gastrointestinal endoscopy, colonoscopy and computed tomography (CT) angiography, a surgical exploration with enteroscopy was performed. This revealed an extensive ulcerated jejunoileitis, with active bleeding, within a Meckel's diverticulum. Management included resection of the Meckel diverticulum with a transient double barrel ileostomy. Two infliximab infusions were given due to persistent bleeding. We observed a dramatic improvement after infliximab treatment with complete cessation of bleeding and no further need for transfusions. A complete mucosal healing has been achieved on enteroscopy at 3 months with disappearance of histological inflammatory lesions. This observation suggests that infliximab represents a therapeutic option in severe enteritis and may be as effective as in more moderate immune-mediated enterocolitis.

Successful Treatment of Generalized Eruptive Keratoacanthoma of Grzybowski with Acitretin.

INTRODUCTION: Keratoacanthomas (KA) are common cutaneous skin tumors originating from the hair follicles. Unlike squamous cell carcinoma, KA can regress spontaneously and have a benign evolution. Solitary KA is the most common form but familial multiple KA (Ferguson-Smith type), genetically predisposed KA (such as in xeroderma pigmentosum, or Muir-Torre syndrome), or sporadic multiple eruptive KA (Grzybowski type) have been described. Generalized eruptive KA of Grzybowski (GEKA) is a rare condition (around 40 reported cases). The pathophysiology is still unclear. Human papillomavirus (HPV) has been detected in sporadic KA but the presence of HPV39 has never been reported, to our knowledge, in GEKA. CASE REPORT: GEKA in an 80-year-old woman was successfully treated with acitretin (0.5 mg/kg/day) combined with surgical removal of the largest lesions. Treatment was well tolerated and led to decreased pruritus and tumor regression within 6 months. The presence of HPV39 was detected in a lesion by polymerase chain reaction and Sanger sequencing. No genetic alteration was found, in particular in the genes usually altered in squamous cell carcinoma (including NOTCH1, NOTCH2, CDKN2A, TP53). CONCLUSION: We report a case of GEKA associated with the presence of HPV39 and the successful use of acitretin combined with surgical removal of the larger lesions.

Severe necrotizing myositis associated with long term anti-neoplastic efficacy following nivolumab plus ipilimumab combination therapy.

Immune-related adverse events (irAEs), have been reported under immune checkpoint inhibitors. Nivolumab plus ipilimumab (N + I) demonstrated meaningful improvements in key patient-reported outcomes, in patients with pretreated microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). We report a case of severe necrotizing myositis which occurred in a patient treated with N + I combination for mCRC MSI-H. A 61-year-old woman was diagnosed with mCRC MSI-H and BRAFV600E mutated with synchronous liver, pleural, and lymph nodes metastases. After she failed to respond to standard chemotherapy (two lines with 5-fluorouracil, oxaliplatin, and irinotecan + bevacizumab), she received in a clinical trial (CheckMate 142), nivolumab 3 mg/kg, and ipilumumab 1 mg/kg every 3 weeks [4]. One week after the second infusion, she developed rapidly extending proximal muscles weakness associated with diffuse erythematous rash with grade 2/5 strength on abdominal, dorsal, and proximal limb muscles and impressive muscular edema. The creatine kinase level was at 14827 U/L (0-160 U/L), without any detectable autoantibodies. The electromyogram showed a severe myogenic syndrome, and muscular histological analysis demonstrated extensive muscular necrosis, with scarce lymphocytic infiltrates and pathological expression of class I HLA and C5b9 complement deposits with severe endomysial edema. N-I therapy was discontinued. Intravenous methylprednisolone was initiated for 3 days followed by 1 mg/kg/day orally, combined with intravenous immunoglobulins (2 g/kg/day for 2 days). At 3 years of first infusion of N + I, patient is without any new progressive disease, in partial response on the liver, pleural, and nodes metastasis, with only persistent minor psoas weakness.

Osteopenia and fractures associated with long-term therapy with MEK inhibitors.

Targeted therapies have markedly improved the survival of patients with melanoma. We report the case of two patients with advanced melanoma controlled by long-term MEK inhibitor or combination of BRAF and MEK inhibitors, who developed fractures related to severe osteopenia. A 48-year-old woman was treated by pimasertib after the failure of two lines of chemotherapy, and a 42-year-old man was treated by an association of BRAFi (dabrafenib) and MEKi (trametinib) after the failure of one line of chemotherapy. During follow-up, both complained of buttock pain, revealing primary fractures of the pelvis and lumbar vertebra. In both patients, none had osteoporosis risk factors; DEXA scan revealed osteopenia, and analysis ruled out metastatic bone lesion or secondary osteoporosis. Zoledronic acid, cholecalciferol (vitamin D3), oral calcium, and pain killers were introduced, leading to no further bone event. Numerous pathways are involved in the homeostasis of bone turnover, and the effect of tyrosine kinase inhibitors on those pathways is not well known yet. The absence of usual causes of osteoporosis or metastatic bone lesion and kinetics of symptoms lead us to suggest that MEK inhibitors were responsible for the development of osteoporosis. To the best of our knowledge, this is the first report of fractures associated with osteopenia in patients treated with MEKi. Long-term survival owing to new targeted treatment could be associated with yet underestimated adverse effects such as osteopenia/osteoporosis that could impair patient's quality of life and should be investigated.

Immune checkpoint inhibitor-related myositis and myocarditis in patients with cancer.

OBJECTIVE: To report the clinicopathologic features and outcome of myositis in patients treated with immune checkpoint inhibitors (ICIs) (irMyositis). METHODS: We retrospectively analyzed patients diagnosed with irMyositis in tertiary centers in Paris, France, and Berlin, Germany, from January 2015 to July 2017. The main outcomes were clinical manifestations and muscle histology, which included major histocompatibility complex class I (MHC-I), C5b-9, CD3, CD4, CD8, CD20, CD68, programmed cell death protein 1 (PD-1), programmed cell death 1 ligand 1 (PD-L) 1, and programmed cell death 1 ligand 2 (PD-L2). RESULTS: Ten patients with metastatic cancer were included; median age was 73 (range 56-87) years. Median follow-up duration was 48 (range 16-88) weeks. Six patients developed myositis during nivolumab therapy, 1 patient during pembrolizumab, 1 patient during durvalumab, and 2 patients during combined nivolumab and ipilimumab. Median delay between ICI initiation and myositis onset was 25 (range 5-87) days. Clinical manifestations were dominated by acute or subacute myalgia (8 patients) and limb-girdle (7), axial (7), and oculomotor (7) weakness. Four patients had evidence of myocarditis. In all patients, creatine kinase levels were elevated (median 2,668, range 1,059-16,620 U/L), while anti-acetylcholine receptor and myositis-associated antibodies were negative. Electrodiagnostic studies showed myopathic process without decrement in all patients. Muscle biopsy constantly showed multifocal necrotic myofibers, sarcolemmal MHC-I, and endomysial inflammation, consisting mainly of CD68+ cells expressing PD-L1 and CD8+ cells expressing PD-1. ICI treatment was withdrawn in all patients; 9 patients received immunosuppressive therapy, which consistently led to marked clinical improvement. CONCLUSIONS: irMyositis presents with remarkably homogeneous and unique clinicopathologic features, expanding the nosologic spectrum of inflammatory myopathies in patients with cancer. ICI withdrawal and treatment with corticosteroids improve outcome.

Transient pituitary ACTH-dependent Cushing syndrome caused by an immune checkpoint inhibitor combination.

Immune checkpoint inhibitors have improved survival in numerous advanced malignancies, but are associated with a number of immune-related adverse events, including endocrinopathies. Endogenous Cushing's syndrome (CS) is a rare disorder resulting from exposure to high levels of circulating cortisol. CS can be caused either by adrenal cortex tumors or hyperplasia or by pituitary or extra-pituitary tumors over-secreting ACTH (known as ACTH-dependent CS). We report the first case of transient ACTH-dependent CS, which appeared after combined ipilimumab and nivolumab therapy. Our patient presented typical clinical features of CS after three infusions of combined therapy, high serum and daily urinary free cortisol, and high serum ACTH levels. Pituitary MRI showed an enlargement of the pituitary gland suggesting ACTH secretion of pituitary origin, which was confirmed by inferior petrosal sinus sampling. The pituitary findings were preceded by thyroiditis. The evolution was characterized by spontaneous CS regression and subsequent appearance of severe corticotroph deficiency consistent with destructive hypophysitis. Immunotherapy is a novel cause of CS.

Focal necrotizing myopathy with 'dropped-head syndrome' induced by cobimetinib in metastatic melanoma.

Therapeutic advances derived from targeted therapy and immune checkpoint inhibitors can improve melanoma prognosis. Since 2015, cobimetinib has been approved in combination with vemurafenib in the first-line treatment for BRAF-mutated melanoma. For NRAS-mutated melanomas, MEK inhibition seems to be a therapeutic target, and association with checkpoint inhibitor provides a further therapeutic perspective. Infraclinical creatine phosphokinase (CPK) elevation is an MEK inhibitor side effect. We describe a case of focal necrotizing myopathy with 'dropped-head syndrome' induced by cobimetinib, 1 month after its introduction. The clinical presentation comprised interscapular pain, axial fatigue with cervical hypotonia, CPK elevation, intense fluorine-18-fluorodeoxyglucose uptake in cervical muscles, and necrotizing myopathy was confirmed by muscle biopsy. Cobimetinib was temporarily discontinued, resulting in CPK normalization. Re-evaluation showed partial response, motivating continuation of combination therapy with a reduced dose of cobimetinib (40 mg/day). Because prescription of targeted therapies is likely to increase, this adverse event should be known.

Autoimmune diabetes induced by PD-1 inhibitor-retrospective analysis and pathogenesis: a case report and literature review.

Anti-PD-1 antibody treatment is approved in advanced melanoma and provides median overall survival over 24 months. The main treatment-related side effects are immune-related adverse events, which include rash, pruritus, vitiligo, thyroiditis, diarrhoea, hepatitis and pneumonitis. We report a case of autoimmune diabetes related to nivolumab treatment. A 73-year-old man was treated in second line with nivolumab at 3 mg/kg every two weeks for metastatic melanoma. At 6 weeks of treatment, he displayed diabetic ketoacidosis. Nivolumab was withheld 3.5 weeks and insulin therapy was initiated, enabling a normalization of glycaemia and the disappearance of symptoms. Laboratory investigations demonstrated the presence of islet cell autoantibodies, while C-peptide was undetectable. Retrospective explorations on serum banked at week 0 and 3 months before the start of nivolumab, already showed the presence of autoantibodies, but normal insulin, C-peptide secretion and glycaemia. Partial response was obtained at month 3, and nivolumab was then resumed at the same dose. The clinical context and biological investigations before, at and after nivolumab initiation suggest the autoimmune origin of this diabetes, most likely induced by anti-PD-1 antibody in a predisposed patient. The role of PD-1/PD-L1 binding is well known in the pathogenesis of type 1 diabetes. Therefore, this rare side effect can be expected in a context of anti-PD-1 treatment. Glycaemia should be monitored during PD-1/PD-L1 blockade. The presence of autoantibodies before treatment could identify individuals at risk of developing diabetes, but systematic titration may not be relevant considering the rarity of this side effect.

Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome induced by nivolumab.

INTRODUCTION: A new articular syndrome described as immunrelated side effect of immunotherapy: PD-1 inhibitors have revolutionized the treatment of advanced melanoma but are responsible for immune-related toxicity. We report a case of remitting seronegative symetrical synovitis with pitting edema (RS3PE) syndrome induced by nivolumab. CASE REPORT: A 80 year-old man with stage IV BRAF-wild type and NRAS exon 2-mutated melanoma was treated first line by nivolumab 3mg/kg every 2 weeks. At week 4, before the 3rd infusion, he presented with inflammatory arthralgia, synovitis of proximal interphalangeal, wrist and ankle joints, and edema of both hands and forearms. Laboratory tests showed inflammatory syndrome (CRP = 8.4mg/dL), negative rheumatoid factor, and anti-CCP antibodies. Radiographs did not show any joint erosion but joint ultrasound displayed intra-articular effusion and tenosynovitis. PET/CT performed 6 and 3 months before treatment for melanoma work-up showed an isolated hypermetabolism of the shoulder girdle. The diagnosis of RS3PE was retained. A systemic corticosteroid treatment (0.5mg/kg/d) was initiated; nivolumab was hold during 4 weeks leading to remission of clinical symptoms within 10 days, CRP level normalization and without relapse when nivolumab was resumed. Corticosteroids were progressively tapered and stopped after 9 months. After 5 months, anti-PD1 was definitively stopped because of disease progression. CONCLUSION: With this atypical case, clinicians should remain alert on a whole range of autoimmune diseases susceptible to be induced.