Long non-coding RNAs in cutaneous melanoma : clinical perspectives

Metastatic melanoma of the skin has a high mortality despite the recent introduction of targeted therapy and immunotherapy. Long non-coding RNAs (lncRNAs) are defined as transcripts of more than 200 nucleotides in length that lack protein-coding potential. There is growing evidence that lncRNAs play an important role in gene regulation, including oncogenesis. We present 13 lncRNA genes involved in the pathogenesis of cutaneous melanoma through a variety of pathways and molecular interactions. Some of these lncRNAs are possible biomarkers or therapeutic targets for malignant melanoma

Psoriasis vulgaris exacerbation during treatment with a PD-1 checkpoint inhibitor : case report and literature review

Objective: The incidence of immune-related adverse events is growing as the use of checkpoint inhibitors is exponentially increasing. Cutaneous adverse events are among the most frequent immune-related adverse events. The purpose of this case report and literature review is to highlight psoriasis as a potential adverse event with need for early recognition. Case Report and Literature Review: We describe the case of a 65-year-old woman with psoriasis exacerbation while treated with nivolumab (anti-PD-1) for a stage IV melanoma. She had a history of scalp psoriasis but she presented with psoriatic lesions on both lower and upper limbs. Our patient was treated with topical steroids. So far, 34 other cases with an exacerbation of psoriasis during treatment with anti-PDL-1 or PD-1 therapy have been reported in the literature. A broad range of therapies are described, without any available guidelines for this particular condition. Conclusion: Psoriasis exacerbation is an established side effect of PD-1/PDL-1 checkpoint inhibitors with 35 reported cases. Early recognition and management are challenging as there are no clear guidelines available. A close collaboration between oncologist and dermatologist is mandatory to manage this immune-related adverse event

Candidate RNA biomarkers in biofluids for early diagnosis of ovarian cancer : a systematic review

Ovarian cancer is often diagnosed in an advanced stage and is associated with a high mortality rate. It is assumed that early detection of ovarian cancer could improve patient outcomes. Unfortunately, effective screening methods for early diagnosis of ovarian cancer are still lacking. Extracellular RNAs circulating in human biofluids can reliably be measured and are emerging as potential biomarkers in cancer. In this systematic review, we present 75 RNA biomarkers detectable in human biofluids that have been studied for early diagnosis of ovarian cancer. The majority of these markers are microRNAs identified using RT-qPCR or microarrays in blood-based fluids. A handful of studies used RNA-sequencing and explored alternative fluids, such as urine and ascites. Candidate RNA biomarkers that were more abundant in biofluids of ovarian cancer patients compared to controls in at least two independent studies include miR-21, the miR-200 family, miR-205, miR-10a and miR-346. Amongst the markers confirmed to be lower in at least two studies are miR-122, miR-193a, miR-223, miR-126 and miR-106b. While these biomarkers show promising diagnostic potential, further validation is required before implementation in routine clinical care. Challenges related to biomarker validation and reflections on future perspectives to accelerate progress in this field are discussed

Peritumoral endothelial indoleamine 2,3-dioxygenase expression is an early independent marker of disease relapse in colorectal cancer and is influenced by DNA mismatch repair profile

Targeting immune checkpoint molecules has become a major new strategy in the treatment of several cancers. Indoleamine 2,3-dioxygenase (IDO)-inhibitors are a potential next-generation immunotherapy, currently investigated in multiple phase I-III trials. IDO is an intracellular immunosuppressive enzyme and its expression/ activity has been associated with worse prognosis in several cancers. The aim of this study was to investigate the expression pattern of IDO in colorectal cancer (CRC). In a cohort of 94 CRC patients, primary tumors (PTs) with corresponding tumor-draining lymph nodes (TDLNs, n = 93) and extranodal/distant metastases (n = 27) were retrospectively analyzed by immunohistochemical staining for IDO, CD8 and Foxp3. 45 MSS and 37 MSI-H tumors were selected to compare IDO expression, as these tumors are considered to have different immunogenicity. A highly consistent expression pattern of IDO was observed in the PT, TDLNs and metastases, indicating that immune resistance may be determined very early in the disease course. IDO was expressed both by tumoral cells and host endothelial cells and these expressions were highly correlated (p < 0.001). IDO expression was observed more frequently in the MSI-H subset compared with the MSS subset (43% vs 22% for tumoral expression (p = 0.042) and 38% vs 16% for endothelial expression (p = 0.021)). Endothelial IDO expression was demonstrated to be a negative prognostic marker for recurrence free survival independent of disease stage and DNA mismatch repair (MMR) status (HR 20.67, 95% CI: 3.05-139.94; p = 0.002). These findings indicate that endothelial IDO expression in primary CRC, in addition to the MMR profile, may be helpful in disease stratification.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Performance assessment of total RNA sequencing of human biofluids and extracellular vesicles

RNA profiling has emerged as a powerful tool to investigate the biomarker potential of human biofluids. However, despite enormous interest in extracellular nucleic acids, RNA sequencing methods to quantify the total RNA content outside cells are rare. Here, we evaluate the performance of the SMARTer Stranded Total RNA-Seq method in human platelet-rich plasma, platelet-free plasma, urine, conditioned medium, and extracellular vesicles (EVs) from these biofluids. We found the method to be accurate, precise, compatible with low-input volumes and able to quantify a few thousand genes. We picked up distinct classes of RNA molecules, including mRNA, lncRNA, circRNA, miscRNA and pseudogenes. Notably, the read distribution and gene content drastically differ among biofluids. In conclusion, we are the first to show that the SMARTer method can be used for unbiased unraveling of the complete transcriptome of a wide range of biofluids and their extracellular vesicles

Effect of anti-interleukin drugs in patients with COVID-19 and signs of cytokine release syndrome (COV-AID): a factorial, randomised, controlled trial.

BACKGROUND: Infections with SARS-CoV-2 continue to cause significant morbidity and mortality. Interleukin (IL)-1 and IL-6 blockade have been proposed as therapeutic strategies in COVID-19, but study outcomes have been conflicting. We sought to study whether blockade of the IL-6 or IL-1 pathway shortened the time to clinical improvement in patients with COVID-19, hypoxic respiratory failure, and signs of systemic cytokine release syndrome. METHODS: We did a prospective, multicentre, open-label, randomised, controlled trial, in hospitalised patients with COVID-19, hypoxia, and signs of a cytokine release syndrome across 16 hospitals in Belgium. Eligible patients had a proven diagnosis of COVID-19 with symptoms between 6 and 16 days, a ratio of the partial pressure of oxygen to the fraction of inspired oxygen (PaO(2):FiO(2)) of less than 350 mm Hg on room air or less than 280 mm Hg on supplemental oxygen, and signs of a cytokine release syndrome in their serum (either a single ferritin measurement of more than 2000 μg/L and immediately requiring high flow oxygen or mechanical ventilation, or a ferritin concentration of more than 1000 μg/L, which had been increasing over the previous 24 h, or lymphopenia below 800/mL with two of the following criteria: an increasing ferritin concentration of more than 700 μg/L, an increasing lactate dehydrogenase concentration of more than 300 international units per L, an increasing C-reactive protein concentration of more than 70 mg/L, or an increasing D-dimers concentration of more than 1000 ng/mL). The COV-AID trial has a 2 × 2 factorial design to evaluate IL-1 blockade versus no IL-1 blockade and IL-6 blockade versus no IL-6 blockade. Patients were randomly assigned by means of permuted block randomisation with varying block size and stratification by centre. In a first randomisation, patients were assigned to receive subcutaneous anakinra once daily (100 mg) for 28 days or until discharge, or to receive no IL-1 blockade (1:2). In a second randomisation step, patients were allocated to receive a single dose of siltuximab (11 mg/kg) intravenously, or a single dose of tocilizumab (8 mg/kg) intravenously, or to receive no IL-6 blockade (1:1:1). The primary outcome was the time to clinical improvement, defined as time from randomisation to an increase of at least two points on a 6-category ordinal scale or to discharge from hospital alive. The primary and supportive efficacy endpoints were assessed in the intention-to-treat population. Safety was assessed in the safety population. This study is registered online with ClinicalTrials.gov (NCT04330638) and EudraCT (2020-001500-41) and is complete. FINDINGS: Between April 4, and Dec 6, 2020, 342 patients were randomly assigned to IL-1 blockade (n=112) or no IL-1 blockade (n=230) and simultaneously randomly assigned to IL-6 blockade (n=227; 114 for tocilizumab and 113 for siltuximab) or no IL-6 blockade (n=115). Most patients were male (265 [77%] of 342), median age was 65 years (IQR 54-73), and median Systematic Organ Failure Assessment (SOFA) score at randomisation was 3 (2-4). All 342 patients were included in the primary intention-to-treat analysis. The estimated median time to clinical improvement was 12 days (95% CI 10-16) in the IL-1 blockade group versus 12 days (10-15) in the no IL-1 blockade group (hazard ratio [HR] 0·94 [95% CI 0·73-1·21]). For the IL-6 blockade group, the estimated median time to clinical improvement was 11 days (95% CI 10-16) versus 12 days (11-16) in the no IL-6 blockade group (HR 1·00 [0·78-1·29]). 55 patients died during the study, but no evidence for differences in mortality between treatment groups was found. The incidence of serious adverse events and serious infections was similar across study groups. INTERPRETATION: Drugs targeting IL-1 or IL-6 did not shorten the time to clinical improvement in this sample of patients with COVID-19, hypoxic respiratory failure, low SOFA score, and low baseline mortality risk. FUNDING: Belgian Health Care Knowledge Center and VIB Grand Challenges program