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Simple Summary: Treatment with cyclin-dependent kinase 4/6 inhibitor (CDK4/6i), has demonstrated significantly improved progression-free survival in patients with hormone receptor-positive, HER2-negative, advanced breast cancer, when used in combination with endocrine therapies. However, limited data exists on its cutaneous adverse events (AE). The aim of our retrospective study was to investigate the prevalence, types and management of cutaneous AE during CDK4/6i. 79 adult advanced breast cancer patients affected by 125 skin adverse events during treatment with CDK4/6i were recruited at eleven centers. The most frequent cutaneous reactions were pruritus (49/79 patients), alopecia (25/79), and ec-zematous lesions (24/79). We showed that skin reactions are usually mild in severity, and prompt management may limit the negative impact on patients, facilitating beneficial continuation of oncologic treatment. Background: The introduction of cyclin-dependent kinase inhibitors (CDK4/6i) was a great advance in therapeutics for patients with estrogen receptor+/human epidermal growth factor receptor (HER2) locally advanced and metastatic breast cancer. Despite the increasing use of these agents, their adverse drug-related events have not yet been fully characterized. We describe the spectrum of cutaneous adverse reactions occurring in advanced breast cancer patients treated with cyclin-dependent kinase inhibitors, analyzing types, severity, time to onset, and possible treatment outcomes. Methods: We performed a multicentric retrospective study including patients with advanced breast cancer who developed cutaneous lesions during treatment with CDK4/6i in the period from June 2020 to June 2021. Patients > 18 years were recruited at eleven onco-dermatology units located in Albania (1), Argentina (1), France (1), Greece (3), Italy (3), and Spain (2). We evaluated patients' epidemiological and clinical characteristics, types of cutaneous adverse events, their time to onset, and treatment outcomes. The severity of the skin reactions was assessed using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 score. Results: Seventy-nine patients (median age: 62.3 years; range 39–83 years) were included in the study, and, collectively, we recorded a total of 165 cutaneous adverse events during follow-up visits. The most frequent cutaneous reactions were pruritus (49/79 patients), alopecia (25/79), and eczematous lesions (24/79). Cutaneous toxicities were usually mild in severity (>65%) and occurred after a median of 6.5 months. Only four patients (5%) required treatment discontinuation due to the severity of the skin lesions. The majority of the skin reactions were managed with topical treatments. Conclusions: To the best of our knowledge, we present the largest case series of cutaneous adverse events developing in advanced breast cancer patients treated with CDK4/6i. We showed that cutaneous toxicities are usually mild in severity, and manageable with standard supportive care; however, in selected cases, they can lead to treatment discontinuation with possible implications for patients' clinical outcomes. [ABSTRACT FROM AUTHOR]

Immune-related adverse events (irAEs) remain generally unpredictable, and severe irAEs remain challenging to detect early and manage. Very severe (grade IV–V) irAEs have not been extensively characterised in prospective studies, and their predictive factors remain unknown. The objective of the study was to describe and identify predictive factors of very severe (grade IV–V) irAEs. The French Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie (REISAMIC) registry has prospectively collected all clinically significant irAEs occurring in patients treated with immune checkpoint inhibitors at Gustave Roussy Institute since 2014. This was a single-centre prospective cohort study at the Gustave Roussy Institute cancer centre (Villejuif, France). The participants were all adult patients with a solid or haematological cancer treated with an anti–programmed cell death 1 (PD-1) or an anti–programmed cell death-ligand 1 (PD-L1) and who presented a clinically significant irAE. The main outcomes included the clinical and laboratory characteristics of patients with very severe irAEs, including tumour type, affected organs, time to irAE occurrence, blood cell count and serum biochemistry parameters. Of the 1187 patients prospectively followed in REISAMIC between December 2014 and January 2020, 380 (32.0%) had at least one irAE, and 34 (2.86%) presented with very severe irAEs (grades IV–V). Among the 380 patients with an irAE, the distribution of very severe irAEs (grades IV–V) was 8.95% and death (grade V) was 3.95%. Among the 34 patients with very severe irAEs, 33 were treated with monotherapy of PD-1 or PD-L1 inhibitors, and one patient was treated with a combination of PD-1 and cytotoxic T-lymphocyte–associated protein 4 inhibitors. The median time to occurrence was shorter for very severe irAEs (median [interquartile range]: 41 days [0–634] for grades IV–V; versus 91 days [0–1123] for grades I–III; p = 0.01680). On initiation of immunotherapy, the predictive factors for very severe irAEs were performance status ≥2, elevated neutrophil/lymphocyte ratio and treatment for lung cancer. Very severe (grade IV–V) immunological toxicities occurred earlier than mild severe toxicities. On initiation of immunotherapy, patients with poor performance status, elevated neutrophil/lymphocyte ratio and lung cancer are identified at risk of developing these very severe toxicities. These results could help to develop risk scores to identify patients at risk of developing severe toxicities. • Very severe immune-related adverse events (irAEs) are challenging to detect early and manage. • Very severe irAEs occurred earlier than mild severe irAEs. • The predictive factors for very severe irAEs were performance status ≥ 2 and elevated neutrophil/lymphocyte ratio. • The organ most implicated in irAE death was lung with pneumonitis. [ABSTRACT FROM AUTHOR]

Sarcoid-like granulomatosis (SLG) reaction caused by immunotherapy remains poorly understood. This study aims to investigate the outcome of patients with cancer and SLG associated with immunotherapy. Between April 2016 and June 2020, 434 patients with immunological adverse events were screened from the ImmunoTOX assessment board of Gustave Roussy, an academic cancer centre in France. Among them, 28 patients had SLG associated with immunotherapy (SLG cohort) and 406 patients had other immunological adverse events (control cohort). Clinical characteristics and outcome of patients were compared from SLG and control cohort. The SLG cohort consisted of 28 patients, 14 women and 14 men, with the median (range) age of 56.5 (28.7–75.3) years. Patients in the SLG cohort with sarcoidosis were asymptomatic (only radiographical finding) in 13 (46.4%) cases; otherwise, the most frequent symptoms were dyspnoea in 8 (28.6%) patients and cough in 5 (17.8%) patients. The computerised tomography scan found sarcoidosis localisations in mediastinal or peri-hilar thoracic lymph nodes in 26 (92.9%) patients, and lung parenchymal involvement was found in 14 (50.0%) patients. The radiographic Scadding stages for sarcoidosis classification were distributed in stages 0, I, II, III and IV in 2 patients (7.1%), 13 patients (46.4%), 11 patients (39.3%), 1 patient (3.6%) and 1 patient (3.6%), respectively. Compared with patients with other immunological toxicities (cohort control), patients with sarcoidosis presented most frequently with melanoma (75.0% versus 21.9% of patients; p < 0.001) and more often received combined therapies of anti–programmed cell death 1 plus anti–cytotoxic T-lymphocyte antigen 4 protein (46.4% versus 12.6% of patients; p = 0.002). Patients with sarcoidosis had an improved overall survival (OS); the median OS was not reached in the SLG cohort and 40.4 months in the control cohort, hazard ratio = 0.232 (95% confidence interval: 0.086–0.630) (p = 0.002). Sarcoidosis-like reactions in patients receiving immunotherapy were reported as non-severe immunological reactions in most cases and were correlated with improved OS. SLG should not be misdiagnosed as tumour progression in patients receiving immunotherapy treatment for cancer. • Sarcoidosis associated with immunotherapy correlated with improved overall survival. • Sarcoidosis associated with anticancer immunotherapy was generally of mild severity. • Sarcoidosis seems more related to the combination of anti–programmed cell death 1 plus anti–cytotoxic T-lymphocyte antigen 4 protein. [ABSTRACT FROM AUTHOR]

Purpose: To report the impact of establishing and maintaining a high intracameral pressure (ICP) of 200 mmHg on UT-DSAEK graft preparation using an artificial anterior chamber pressuriser (ACP) control unit (Moria SA, Antony, France). Method: Retrospective laboratory and clinical study. Four paired donor corneas were mounted on an artificial anterior chamber and subjected to 70 mmHg ("low") and 200 mmHg ("high") ICP using an ACP system. The central corneal thinning rate was measured after 5 min using AS-OCT and the endothelial cell viability was analysed using trypan blue and live/dead staining following 70 mmHg and 200 mmHg ICP. Visual outcomes and complications in a clinical case series of nine patients with bullous keratopathy who underwent UT-DSAEK using 200 mmHg ICP during graft preparation are reported. Results: Laboratory outcomes showed 2 ± 1% and 2 ± 2% dead cells following 70 mmHg and 200 mmHg ICP respectively. Percentage viability in the 70 mmHg group (52.94 ± 5.88%) was not found to be significantly different (p = 0.7) compared to the 200 mmHg group (59.14 ± 10.43%). The mean corneal thinning rate after applying 200 mmHg ICP was 27 ± 13 μm/min centrally (7.2%/min). In the clinical case series, two cases were combined with cataract surgery. Re-bubbling rate was 11%. At the last follow-up (259 ± 109 days), graft thickness was 83 ± 22 μm centrally, endothelial cell density was 1175 ± 566 cell/mm2 and the BCVA of 0.08 ± 0.12 logMAR was recorded with no episodes of rejection. Conclusion: ACP control unit for UT-DSAEK graft preparation helps in consistently obtaining UT-DSAEK grafts without compromising endothelial cell viability. [ABSTRACT FROM AUTHOR]