BackgroundMicroRNA expression is altered in cancer cells, and microRNAs could serve as diagnostic/prognostic biomarker for cancer patients. Our study was designed to analyze circulating serum microRNAs in patients with renal cell carcinoma (RCC).Methodology/Principal FindingsWe first explored microRNA expression profiles in tissue and serum using TaqMan Low Density Arrays in each six malignant and benign samples: Although 109 microRNAs were circulating at higher levels in cancer patients' serum, we identified only 36 microRNAs with up-regulation in RCC tissue and serum of RCC patients. Seven candidate microRNAs were selected for verification based on the finding of up-regulation in serum and tissue of RCC patients: miR-7-1*, miR-93, miR-106b*, miR-210, miR-320b, miR-1233 and miR-1290 levels in serum of healthy controls (n = 30) and RCC (n = 33) patients were determined using quantitative real-time PCR (TaqMan MicroRNA Assays). miR-1233 was increased in RCC patients, and thus validated in a multicentre cohort of 84 RCC patients and 93 healthy controls using quantitative real-time PCR (sensitivity 77.4%, specificity 37.6%, AUC 0.588). We also studied 13 samples of patients with angiomyolipoma or oncocytoma, whose serum miR-1233 levels were similar to RCC patients. Circulating microRNAs were not correlated with clinical-pathological parameters.Conclusions/SignificanceMicroRNA levels are distinctly increased in cancer patients, although only a small subset of circulating microRNAs has a tumor-specific origin. We identify circulating miR-1233 as a potential biomarker for RCC patients. Larger-scaled studies are warranted to fully explore the role of circulating microRNAs in RCC.
Adjuvant treatment of melanoma patients with immune-checkpoint inhibition (ICI) and targeted therapy (TT) significantly improved recurrence-free survival. This study investigates the real-world situation of 904 patients from 13 German skin cancer centers with an indication for adjuvant treatment since the approval of adjuvant ICI and TT. From adjusted log-binomial regression models, we estimated relative risks for associations between various influence factors and treatment decisions (adjuvant therapy yes/no, TT vs. ICI in BRAF mutant patients). Of these patients, 76.9% (95% CI 74–80) opted for a systemic adjuvant treatment. The probability of starting an adjuvant treatment was 26% lower in patients >65 years (RR 0.74, 95% CI 68–80). The most common reasons against adjuvant treatment given by patients were age (29.4%, 95% CI 24–38), and fear of adverse events (21.1%, 95% CI 16–28) and impaired quality of life (11.9%, 95% CI 7–16). Of all BRAF-mutated patients who opted for adjuvant treatment, 52.9% (95% CI 47–59) decided for ICI. Treatment decision for TT or ICI was barely associated with age, gender and tumor stage, but with comorbidities and affiliated center. Shortly after their approval, adjuvant treatments have been well accepted by physicians and patients. Age plays a decisive role in the decision for adjuvant treatment, while pre-existing autoimmune disease and regional differences influence the choice between TT or ICI.
9570 Background: Clinical trials demonstrated a significantly improved recurrence-free survival (RFS) of melanoma patients treated adjuvantly with immune checkpoint inhibition (ICI) and targeted therapy (TT). As data from controlled trials are based on selected populations, we investigated melanoma patients with high risk of recurrence who opted for ICI, TT, or no adjuvant treatment (NoTx) under real-world conditions. Methods: In a prior analysis of this multicenter, retrospective cohort study, patients with resected melanoma stage III-IV between 06/2018 and 09/2019 were analyzed for adjuvant therapy choice (Lodde et al., Cancers 2021). In this follow-up study, the treatment course of ICI- and TT-treated patients as well as recurrence characteristics, subsequent management and outcomes also including NoTx patients were examined. Results: 814 patients were included (72 stage IIIA, 266 IIIB, 383 IIIC, 24 IIID, 69 IV; 309 BRAF mut); 533 patients received ICI (66%), 114 TT (14%, 36.9% of all BRAF mutated patients), 167 patients had opted for NoTx (21%). Median treatment duration was 10.2 and 11.7 months for ICI and TT, respectively. ICI was discontinued prematurely in 51% (273/533) and TT in 44% (50/114) of patients. The main reason for discontinuation was progressive disease (PD) in ICI patients (58%, 158/273) and adverse events in TT patients (60%, 33/50). At a median follow-up (FU) of 24.6 months for ICI, 25.3 months for TT, and 21.8 months for NoTx, 48% of ICI (255/533), 35% of TT (40/114), and 45% of NoTx (75/167) patients had developed a recurrence mostly at distant sites (ICI 62%, TT 63%, NoTx 64%). In patients with recurrence, median time from start of adjuvant treatment to 1st recurrence was 6.1 months in ICI and 17.6 months in TT. Median RFS was 32.0 months for ICI (95% CI 25.7-38.3), not reached for TT, and 22.3 months for NoTx (95% CI 15.2-29.4). Among BRAF mut patients with stage III, risk of recurrence was higher for ICI than TT (hazard ratio adjusted for age, sex and tumor stage, 2.31; 95% CI 1.56-3.43). Subsequent systemic treatment for the 1st recurrence was given in 76% (192/253) of ICI, 83% (33/40) of TT, and 53% (40/75) of NoTx patients. Among patients who received the 1st subsequent systemic treatment for metastatic disease, PD was the best response in 67% (82/123) for ICI, 55% (11/20) for TT, and 50% (16/32) for NoTX. Conclusions: After 2 years of FU, recurrences were mostly at distant sites in all groups. ICI had higher discontinuation rates and more and earlier recurrences than TT. BRAF mut melanoma patients treated with ICI had a significantly higher risk of relapse than TT-treated patients. Response to subsequent systemic treatment was low for both ICI and TT.
IntroductionCheckpoint-Inhibition (CPI) with PD-1- and PD-L1-inhibitors is a well-established therapy for advanced stage melanoma patients. CPI mainly acts via T-lymphocytes. However, recent literature suggests also a role for B cells modulating its efficacy and tolerability of CPI.Case ReportWe report a 48-year-old female patient with metastatic melanoma affecting brain, lung, skin and lymph nodes. A preexisting granulomatosis with polyangiitis was treated with rituximab over five years prior to the diagnosis of melanoma, resulting in a complete depletion of B cells both in peripheral blood as well as the tumor tissue. In the absence of the mutation of the proto-oncogene b-raf, treatment with the PD-1 inhibitor nivolumab was initiated. This therapy was well tolerated and resulted in a deep partial response, which is ongoing for 14+ months. Flow cytometric analysis of peripheral blood mononuclear cells revealed 15% IL-10 producing and 14% CD24 and CD38 double positive regulatory B cells.ConclusionThe exceptional clinical response to nivolumab monotherapy in our patient with depleted B cells sheds a new light on the relevance of B cells in the modulation of immune responses to melanoma. Obviously, B cells were not required for the efficacy of CPI in our patient. Moreover, the depletion of regulatory B cells may have improved efficacy of CPI.
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