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Introduction: The International Hidradenitis Suppurativa Severity Score System (IHS4) is a validated tool that measures inflammatory lesions, including draining tunnels, in hidradenitis suppurativa (HS)., Objective: To evaluate secukinumab efficacy using IHS4 in patients with moderate to severe HS., Methods: Data from the SUNSHINE and SUNRISE trials, which assessed subcutaneous secukinumab 300 mg every 2 (SECQ2W) and 4 (SECQ4W) weeks in adults with moderate to severe HS, were analyzed. Assessments included changes from baseline in IHS4 and severity classification up to Week 52; IHS4-55, IHS4-75, IHS4-90 responses (55%, 75% and 90% reduction in IHS4) and concordance between IHS4-55 and HS clinical response (HiSCR), at Weeks 16 and 52., Results: In total, 1084 patients (SECQ2W = 361; SECQ4W = 360; placebo = 363) were analyzed. At Week 16, SECQ2W and SECQ4W demonstrated a numerically higher reduction in IHS4 from baseline versus placebo (adjusted mean [95% CI]: -10.80 [-12.30 to -9.30] and -9.46 [-10.96 to -7.96] vs. -4.92 [-6.43 to -3.41]); the reduction was maintained until Week 52 in both dose regimens. A greater proportion of patients achieved IHS4-55 with SECQ2W (43.4%) and SECQ4W (39.5%) versus placebo (31.5%) at Week 16, with further improvement at Week 52. Similar trends were observed for IHS4-75 and IHS4-90 responses. While no patients had mild disease based on IHS4 (80.7% had severe and 19.3% had moderate HS) at baseline, a greater proportion of patients were categorized as having mild disease at Week 16 in the SECQ2W (25.9%) and SECQ4W (24.0%) groups versus placebo (16.4%); this trend continued up to Week 52 in both dose regimens. Strong concordance (>85%) was observed between IHS4-55 and HiSCR., Conclusions: Both SECQ2W and SECQ4W demonstrated efficacy in improving treatment response as measured by IHS4 and reducing disease severity versus placebo at Week 16 and these improvements were sustained through Week 52. These findings support that the dynamic and dichotomous IHS4 can efficiently detect treatment response changes in clinical trial settings., (© 2024 The Author(s). Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Background: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease associated with a substantial disease burden. Secukinumab has previously been reported to have sustained efficacy with a favourable safety profile in patients with moderate-to-severe HS. It is unknown whether prior biologic exposure affects the efficacy and safety of secukinumab., Objectives: To investigate the efficacy and safety of secukinumab in patients with moderate-to-severe HS based on prior exposure to -biologics., Methods: This was an analysis of the SUNSHINE and SUNRISE phase III trials of secukinumab in patients with moderate-to-severe HS. Patients were randomized at baseline to receive secukinumab every 2 (SECQ2W) or 4 weeks (SECQ4W), or placebo for 16 weeks. After week 16, patients on the SECQ2W and SECQ4W schedules remained on the same treatment regimen, while patients randomized to placebo were switched to either SECQ2W or SECQ4W up to week 52. Assessments based on prior exposure to biologics included Hidradenitis Suppurativa Clinical Response (HiSCR), abscess and inflammatory nodule (AN) count, flare rates, HS-related pain [numerical rating scale 30 (NRS30)], 55% reduction in the International Hidradenitis Suppurativa Severity Score System (IHS4-55), Dermatology Life Quality Index, EuroQol-5D and safety., Results: Overall, 1084 patients were randomized in the SUNSHINE and SUNRISE trials and included in this analysis; 255 (23.5%) were biologic-experienced [SECQ2W (n = 80); SECQ4W (n = 81); placebo (n = 94)] and 829 (76.5%) were biologic-naïve [SECQ2W (n = 281); SECQ4W (n = 279); placebo (n = 269)]. At week 16, responses were more efficacious for secukinumab than for placebo with regard to HiSCR in patients who were biologic-experienced {SECQ2W 37.0% [odds ratio (OR) 1.60, 95% confidence interval (CI) 0.83-3.08]; SECQ4W 38.8% [OR 1.67, 95% CI 0.86-3.22]; placebo 27.3%} and biologic-naïve [SECQ2W 45.6% (OR 1.64, 95% CI 1.15-2.33); SECQ4W 45.4% (OR 1.61, 95% CI 1.13-2.29); placebo 34.2%]. Similar results were observed for AN count, NRS30 and IHS4-55. The higher response seen at week 16 with secukinumab was sustained, with a trend toward improvement over time, through to week 52 in both subgroups. Additional efficacy was observed for quality-of-life assessments, and no differences in safety between subgroups were observed., Conclusions: Regardless of prior biologic exposure, secukinumab was efficacious in improving the signs and symptoms of HS. This finding positions secukinumab as the first option in patients who are biologic-naïve, as well as in patients who have previously been treated with other biologic therapy, based on individual patient needs., Competing Interests: Conflicts of interest C.C.Z. reports consultancy/advisory boards disease-­relevant honoraria from Boehringer Ingelheim, Incyte, InflaRx, Janssen, Novartis, Regeneron, Sanofi, UCB and Viatris; has received speaker fees from Almirall, Novartis and UCB; is President of the European Hidradenitis Suppurativa Foundation (EHSF) e.V., coordinator of the ALLOCATE Skin Group of the ERN-Skin, chair of the Acne/Rosacea/Hidradenitis Suppurativa Task Force group of the European Academy of Dermatology and Venerology (EADV), and Editor of EADV News. He is co-copyright holder of the International Hidradenitis Suppurativa Severity Score System (IHS4) on behalf of the EHSF e.V. His institution has received disease-relevant grants from Boehringer Ingelheim, InflaRx, Novartis and UCB for his participation as a clinical investigator. T.P. has received consulting fees from AbbVie, Almirall, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Galderma, Incyte, Janssen, LEO Pharma, Novartis, Pfizer, Sanofi Genzyme, Sun Pharma, UCB and Vyne. D.P. reports consultancy, investigator, advisory board or data safety monitoring board honoraria from Bickel Biotechnology, Biofrontera, BMS, Dermira, LEO Pharma, US Novartis Pharmaceuticals, Pfizer, Regeneron and Sanofi. D.P.’s institution has received grants/research funding for the role of investigator from Almirall, Amgen, AOBiome, Asana Biosciences, Bickel Biotechnology, Celgene, Dermira, Eli Lilly, LEO Pharma, Menlo Therapeutics, Novartis Pharmaceuticals, Novo Nordisk, Ortho Dermatologics, Pfizer and Regeneron. M.B.W. is an employee of and stockholder in Novartis Ireland Ltd. A.O. has been principal investigator in clinical trials sponsored by AbbVie, Alfasigma, Almirall, Amgen, Difa Cooper, Celgene, Eli Lilly, Galderma, Janssen, Laboratori Farmacologici Milanesi, LEO Pharma, Novartis, Pfizer, Pierre Fabre, Regeneron, Sanofi, UCB Pharma and Boehringer Ingelheim. A.O.’s institution has received disease-relevant grants from AbbVie, Alfasigma, Almirall, Amgen, Difa Cooper, Celgene, Eli Lilly, Galderma, Janssen, Laboratori Farmacologici Milanesi, LEO Pharma, Novartis, Pfizer, Pierre Fabre, Regeneron, Sanofi, UCB Pharma and Boehringer Ingelheim. A.O. has received speaker fees from AbbVie, UCB, LEO Pharma, Novartis, Pfizer and Eli Lilly. M.S.A. has been the principal investigator for clinical trials funded by Novartis, Arcutis Biotherapeutics, Galderma Laboratories, Eli Lilly, AbbVie, Pfizer, Concert Pharmaceuticals, Dermira, UCB, Incyte, Boehringer Ingelheim, Amgen, Evelo Sciences, LEO Pharma, Bristol Myers Squibb, Dice Therapeutics, Kiniksa Pharmaceuticals, Zai Lab, Sanofi and Bausch Health; and has been on advisory boards for Amgen, AbbVie, Sanofi, Novartis, Incyte, Boehringer Ingelheim, UCB, Arcutis, Bristol Myers Squibb and Bausch Health. X.L. is an employee of Novartis Pharma Co., Ltd. China. L.U., A.L.M., I.A. and I.L. are employees and stockholders of Novartis Pharma AG, Switzerland. S.R. is an employee and stockholder of Novartis Pharmaceuticals Corp., USA. P.M.-B. has received honoraria for acting as a consultant and/or as a speaker for Regeneron, Pfizer, Eli Lilly, AbbVie, Janssen, Novartis, LEO Pharma, Almirall, Sanofi, Viatris, L’Oréal, Organon, Cantabria Labs, Evelo Biosciences and CSL; and has been principal investigator in clinical trials supported by Pfizer, Biogen, Janssen, Amgen, AbbVie, Sanofi, and Novartis., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Competing Interests: Conflicts of interest Xiaoling Wei is an employee of Novartis. Anna Passera, Elisa Muscianisi, Lorenz Uhlmann, Li Chen, Santiago G Moreno, Ruvie Martin, Marc Vandemeulebroecke, Deborah Keefe, Shoba Ravichandran, Magdalena B. Wozniak are employees of Novartis and hold company stock.

Purpose: Patients with resected localized clear-cell renal cell carcinoma (ccRCC) remain at variable risk of recurrence. Incorporation of biomarkers may refine risk prediction and inform adjuvant treatment decisions. We explored the role of tumor genomics in this setting, leveraging the largest cohort to date of localized ccRCC tissues subjected to targeted gene sequencing., Experimental Design: The somatic mutation status of 12 genes was determined in 943 ccRCC cases from a multinational cohort of patients, and associations to outcomes were examined in a Discovery (n = 469) and Validation (n = 474) framework., Results: Tumors containing a von-Hippel Lindau (VHL) mutation alone were associated with significantly improved outcomes in comparison with tumors containing a VHL plus additional mutations. Within the Discovery cohort, those with VHL+0, VHL+1, VHL+2, and VHL+≥3 tumors had disease-free survival (DFS) rates of 90.8%, 80.1%, 68.2%, and 50.7% respectively, at 5 years. This trend was replicated in the Validation cohort. Notably, these genomically defined groups were independent of tumor mutational burden. Amongst patients eligible for adjuvant therapy, those with a VHL+0 tumor (29%) had a 5-year DFS rate of 79.3% and could, therefore, potentially be spared further treatment. Conversely, patients with VHL+2 and VHL+≥3 tumors (32%) had equivalent DFS rates of 45.6% and 35.3%, respectively, and should be prioritized for adjuvant therapy., Conclusions: Genomic characterization of ccRCC identified biologically distinct groups of patients with divergent relapse rates. These groups account for the ∼80% of cases with VHL mutations and could be used to personalize adjuvant treatment discussions with patients as well as inform future adjuvant trial design., (©2023 The Authors; Published by the American Association for Cancer Research.)

Background: Few therapeutic options are available for patients with moderate-to-severe hidradenitis suppurativa. We aimed to assess the efficacy of secukinumab in patients with moderate-to-severe hidradenitis suppurativa in two randomised trials., Methods: SUNSHINE and SUNRISE were identical, multicentre, randomised, placebo-controlled, double-blind phase 3 trials done in 219 primary sites in 40 countries. Patients aged 18 years old or older with the capacity to provide written informed consent and with moderate-to-severe hidradenitis suppurativa (defined as a total of ≥5 inflammatory lesions affecting ≥2 distinct anatomical areas) for at least 1 year were eligible for inclusion. Included patients also agreed to daily use of topical over-the-counter antiseptics on the areas affected by hidradenitis suppurativa lesions while on study treatment. Patients were excluded if they had 20 or more fistulae at baseline, had ongoing active conditions requiring treatment with prohibited medication (eg, systemic biological immunomodulating treatment, live vaccines, or other investigational treatments), or met other exclusion criteria. In both trials, patients were randomly assigned (1:1:1) by means of interactive response technology to receive subcutaneous secukinumab 300 mg every 2 weeks, subcutaneous secukinumab 300 mg every 4 weeks, or subcutaneous placebo all via a 2 mL prefilled syringe in a double-dummy method as per treatment assignment. The primary endpoint was the proportion of patients with a hidradenitis suppurativa clinical response, defined as a decrease in abscess and inflammatory nodule count by 50% or more with no increase in the number of abscesses or in the number of draining fistulae compared with baseline, at week 16, assessed in the overall population. Hidradenitis suppurativa clinical response was calculated based on the number of abscesses, inflammatory nodules, draining fistulae, total fistulae, and other lesions in the hidradenitis suppurativa affected areas. Safety was assessed by evaluating the presence of adverse events and serious adverse events according to common terminology criteria for adverse events, which were coded using Medical Dictionary for Regulatory Activities terminology. Both the SUNSHINE, NCT03713619, and SUNRISE, NCT03713632, trials are registered with ClinicalTrials.gov., Findings: Between Jan 31, 2019, and June 7, 2021, 676 patients were screened for inclusion in the SUNSHINE trial, of whom 541 (80%; 304 [56%] women and 237 [44%] men; mean age 36·1 years [SD 11·7]) were included in the analysis (181 [33%] in the secukinumab every 2 weeks group, 180 [33%] in the secukinumab every 4 weeks group, and 180 [33%] in the placebo group). Between the same recruitment dates, 687 patients were screened for inclusion in the SUNRISE trial, of whom 543 (79%; 306 [56%] women and 237 [44%] men; mean age 36·3 [11·4] years) were included in the analysis (180 [33%] in the secukinumab every 2 weeks group, 180 [33%] in the secukinumab every 4 weeks group, and 183 [34%] in the placebo group). In the SUNSHINE trial, significantly more patients in the secukinumab every 2 weeks group had a hidradenitis suppurativa clinical response (rounded average number of patients with response in 100 imputations, 81·5 [45%] of 181 patients) compared with the placebo group (60·7 [34%] of 180 patients; odds ratio 1·8 [95% CI 1·1-2·7]; p=0·0070). However, there was no significant difference between the number of patients in the secukinumab every 4 weeks group (75·2 [42%] of 180 patients) and the placebo group (1·5 [1·0-2·3]; p=0·042). Compared with the placebo group (57·1 [31%] of 183 patients), significantly more patients in the secukinumab every 2 weeks group (76·2 [42%] of 180 patients; 1·6 [1·1-2·6]; p=0·015) and the secukinumab every 4 weeks group (83·1 [46%] of 180 patients; 1·9 [1·2-3·0]; p=0·0022) had a hidradenitis suppurativa clinical response in the SUNRISE trial. Patient responses were sustained up to the end of the trials at week 52. The most common adverse event by preferred term up to week 16 was headache in both the SUNSHINE (17 [9%] patients in the secukinumab every 2 weeks group, 20 [11%] in the secukinumab every 4 weeks group, and 14 [8%] in the placebo group) and SUNRISE (21 [12%] patients in the secukinumab every 2 weeks group, 17 [9%] in the secukinumab every 4 weeks group, and 15 [8%] in the placebo group) trials. No study-related deaths were reported up to week 16. The safety profile of secukinumab in both trials was consistent with that previously reported, with no new or unexpected safety findings detected., Interpretation: When given every 2 weeks, secukinumab was clinically effective at rapidly improving signs and symptoms of hidradenitis suppurativa with a favourable safety profile and with sustained response up to 52 weeks of treatment., Funding: Novartis Pharma., Competing Interests: Declaration of interests ABK reports grants from AbbVie, Anapyts Bio, Aristea, Bristol Myers Squibb, ChemoCentryx, Eli Lilly, Incyte, Janssen, Moonlake, Novartis, Pfizer, UCB, and Sonoma Bio and fellowship funding from AbbVie and Janssen paid to her institution; royalties from BIDMC; consulting fees from AbbVie, Alumis, Bayer, Bristol Myers Squibb, Boehringer-Ingelheim, Eli Lilly, FIDE, Novartis, Moonlake, Janssen, Pfizer, Priovant, Sonoma Bio, Sanofi, Target RWE, UCB, and Ventyx; stock in Ventyx; serving on advisory boards for Target RWE; serving as an advisory council member to the National Institute of Health Director; and serves on the board of directors of Almirall. GBEJ reports grants from AbbVie, Boehringer-Ingelheim, CSL Behring, Regeneron, InflaRx, Novartis, LEO Foundation, and UCB, paid to their institution, and honoraria for advisory board meetings from Coloplast, Union Therapeutics, Toosonix, Boehringer-Ingelheim, Kymera, Sanofi, Viela Bio, ChemoCentryx, LEO Pharma, Afyx, Incyte, InflaRx, Janssen Cilag, Novartis, and UCB. AA reports consulting fees from AbbVie, Boehringer-Ingelheim, InflaRx, and UCB, paid to their institution, and consulting fees from Novartis, AbbVie, and Boehringer-Ingelheim. ZR reports consulting fees and honoraria from AbbVie, Amgen, Janssen-Cilag, Novartis, UCB, Sanofi; consulting fees from Celltrion; personal fees for attending meetings or for travel from AbbVie, Janssen-Cilag, Novartis, UCB, and Sanofi; and payment for expert testimony from AbbVie, Amgen, Celltrion, Janssen-Cilag, Novartis, and UCB. ABG reports research and educational grants from AnaptysBio, Janssen, Novartis, Ortho Dermatologics, Sun Pharma, BMS, and UCB Pharma, paid to their institution; consulting fees from Amgen, AnaptysBio, Avotres Therapeutics, Boehringer-Ingelheim, Bristol Myers Squibb, Dermavant, Eli Lilly, Janssen, Novartis, Pfizer, Sanofi, Sun Pharma, UCB Pharma, and DiCE Therapeutics; honoraria as an advisory board member, or non-promotional speaker from Amgen, AnaptysBio, Avotres Therapeutics, Boehringer-Ingelheim, Bristol Myers Squibb, Dermavant, Eli Lilly, Janssen, Novartis, Pfizer, Sanofi, Sun Pharma, and UCB Pharma; is a president of International Dermatology Outcome Measures; and holds stock options in XBiotech, for work on a rheumatoid arthritis project. FGB reports consulting fees from AbbVie, Novartis, and UCB; honoraria and support for attending meetings or travel from AbbVie, Janssen Cilag, Novartis, and UCB; and served on a Data Safety Monitoring Board or Advisory Board for AbbVie, Boehringer-Ingelheim, Janssen Cilag, Novartis, UCB, Incyte, and Moonlake. CP reports consulting fees from Almirall, AbbVie, Amgen, BMS, Boehringer-Ingelheim, Celgene, GSK, Janssen, LEO Pharma, Eli Lilly, Merck, Novartis, Pfizer, Sanofi, and UCB and served on a Data Safety Monitoring Board or Advisory Board for IQVIA. EJGB reports grants from Horizon 2020 ImmunoSep and RISKinCOVID, Horizon Health EPIC-CROWN-2, Sobi, bioMérieux, MSD, Abbott, Novartis, UCB, and AbbVie, paid to their institution, and consulting fees from Sobi, Pfizer, Abbott, ThermoFisher, and Menarini. APV reports consulting fees from Janssen-Cilag; payment or honoraria from AbbVie, Almirall, BMS, Janssen-Cilag, Leo Pharma, Eli Lilly, MSD, Novartis, and UCB; and support for attending meetings or travel from Janssen-Cilag and UCB. AS reports consulting fees from Regeneron, Novartis, and AbbVie, paid to their institution; payment or honoraria from AbbVie, Novartis, Regeneron, Sanofi; support for attending meetings or travel from AbbVie, Janssen-Cilag, Novartis, and Sanofi; and fees for participation on a Data Safety Monitoring Board or Advisory Board from AbbVie, Novartis, and Sanofi. FR reports grants from ALK-Abelló, Allergopharma, Blueprint Medicines, Mylan, Novartis, and ThermoFisher; served on a Data Safety Monitoring Board or Advisory Board for ALK-Abelló, Boehringer-Ingelheim, Blueprint Medicines, Leo Pharma, and UCB; and is an active member of the German Association of Allergy and Clinical Immunology. AR and his institution received grants from AbbVie, Alvotech, Amgen, AnaptysBio, Argenx, Biothera, Bristol Myers Squibb, Celgene, Celltrion, Dermira, Galderma, Inflarx, Janssen, Kiniksa, Kymab, Leo Pharma, Novartis, Pfizer, Trevi Therapeutics, and UCB; payment or honoraria from Chema Rzeszow, Eli Lilly, Leo Pharma, Novartis, Sandoz, and Takeda; and served on a Data Safety Monitoring Board or Advisory Board for AbbVie, Galderma, Sandoz, and Sanofi Aventis. IL reports payment or honoraria from Novartis and support for attending meetings or travel from Sanofi. TP reporfts grants from Almirall, Incyte, and Pfizer, paid to their institution, and consulting fees from AbbVie, Almirall, Bristol Myers Squibb, Eli Lilly, Galderma, Incyte, Janssen, LEO Pharma, Novartis, and UCB. AM reports consulting fees from AbbVie, Boehringer-Ingelheim, Jansen, Eli Lilly, Novartis, Novo Nordisk, Sandoz, and UCB; payment for expert testimony or honoraria from AbbVie, Boehringer-Ingelheim, Jansen, Eli Lilly, Novartis, Novo Nordisk, Sandoz, and UCB; and support for attending meetings or travel from AbbVie, Novartis, Jansen, and UCB. PM-B reports consulting fees from AbbVie, Almirall, Eli Lilly, Janssen, LEO Pharma, Novartis, Pfizer, and Sanofi; payment or honoraria from AbbVie, Almirall, Janssen, LEO Pharma, Eli Lilly, Novartis, Organon, Pfizer, Sanofi, and Viatris; support for attending meetings or travel from AbbVie, Almirall, Janssen, LEO Pharma, Eli Lilly, Novartis, and Sanofi; and served on a Data Safety Monitoring Board or Advisory Board for AbbVie, Janssen, LEO Pharma, Eli Lilly, Novartis, Pfizer, and Sanofi. GK reports consulting fees from Bayer; payment or honoraria from AbbVie, Abbott, Actelion Pharmaceuticals, Amgen, Basilea Pharmaceutica, Biogen IDEC, Boehringer-Ingelheim, Bristol Myers Squibb, Celgene, Hexal, Janssen-Cilag, LEO Pharma, Eli Lilly, MSD, Mylan, Novartis, Parexel, Pfizer, and UCB; support for attending meetings or travel from AbbVie, Abbott, Amgen, Basilea Pharmaceutica, Celgene, Janssen-Cilag, LEO Pharma, MSD, Novartis, Pfizer, Sanofi, and UCB; and served on a Data Safety Monitoring Board or Advisory Board for AbbVie, Abbott, Amgen, Basilea, Bayer, Boehringer-Ingelheim, Bristol Myers Squibb, Celgene, Janssen-Cilag, LEO Pharma, Eli Lilly, Novartis, and UCB. P-AB reports consulting fees from Novartis, AbbVie, Pfizer, and UCB pharma; payment or honoraria from Novartis and AbbVie; support for attending meetings or travel from Novartis; and served on a Data Safety Monitoring Board or Advisory Board for Novartis. MBW, ALM, XW, LU, AP, DK, RM, CF, LC, MV, SR, and EM are employees of Novartis and hold company stock. RS is Director and Founder of Samson Medical, has participated in pharmaceutical advisory boards for Eli Lilly and Company, Pfizer, and Leo Pharmaceutical, has participated in speaker bureaus for AbbVie, Novartis, and Pfizer, and has acted as a principal investigator in clinical trials for AbbVie, Aerotech, Akesobio, Amgen, Arcutis, Arena, Ascend AstraZeneca, Bayer, Biotherapeutics Boehringer-Ingelheim, Bristol-Myer Squibb, Celgene, Coherus BioSciences, Connect, Demira, Eli Lilly, Galderma, GlaxoSmithKline, F Hoffman–La Roche, Janssen, MedImmune, Merck, Merck Sharpe & Dohme, Novartis, Oncobiologics, Pfizer, Principia, Regeneron, Roche, Reistone Biopharma, Samson Clinical, Sanofi-Genzyme, Sun Pharma UCB, Valeant, and Zai Labs. RS is President of the Australasian Hair and Wool Research Society, and Vice President of the International Society of Dermatology and The International Academy of Dermatology. LPR declares no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Circulating miRNAs have shown great promises as noninvasive diagnostic and predictive biomarkers in several solid tumors. While the miRNA profiles of renal tumors have been extensively explored, knowledge of their circulating counterparts is limited. Our study aimed to provide a large-scale genome-wide profiling of plasma circulating miRNA in clear-cell renal cell carcinoma (ccRCC). Plasma samples from 94 ccRCC cases and 100 controls were screened for 754 circulating micro-RNAs (miRNA) by TaqMan arrays. Analyses including known risk factors for renal cancer-namely, age, sex, hypertension, obesity, diabetes, tobacco smoking and alcohol consumption-highlighted that circulating miRNA profiles were tightly correlated with the stage of the disease. Advanced tumors, characterized as stage III and IV, were associated with specific miRNA signatures that significantly differ from both controls and earlier stage ccRCC cases. Molecular pathway enrichment analyses of their gene targets showed high similarities with alterations observed in renal tumors. Plasma circulating levels of miR-150 were significantly associated with RCC-specific survival and could marginally improve the predictive accuracy of clinical parameters in our series, including age at diagnosis, sex and conventional staging. In summary, our results suggest that circulating miRNAs may provide insights into renal cell carcinoma progression., (© 2017 UICC.)

Previous genome-wide association studies (GWAS) have identified six risk loci for renal cell carcinoma (RCC). We conducted a meta-analysis of two new scans of 5,198 cases and 7,331 controls together with four existing scans, totalling 10,784 cases and 20,406 controls of European ancestry. Twenty-four loci were tested in an additional 3,182 cases and 6,301 controls. We confirm the six known RCC risk loci and identify seven new loci at 1p32.3 (rs4381241, P=3.1 × 10 -10 ), 3p22.1 (rs67311347, P=2.5 × 10 -8 ), 3q26.2 (rs10936602, P=8.8 × 10 -9 ), 8p21.3 (rs2241261, P=5.8 × 10 -9 ), 10q24.33-q25.1 (rs11813268, P=3.9 × 10 -8 ), 11q22.3 (rs74911261, P=2.1 × 10 -10 ) and 14q24.2 (rs4903064, P=2.2 × 10 -24 ). Expression quantitative trait analyses suggest plausible candidate genes at these regions that may contribute to RCC susceptibility.

The utility of KRAS mutations in plasma circulating cell-free DNA (cfDNA) samples as non-invasive biomarkers for the detection of pancreatic cancer has never been evaluated in a large case-control series. We applied a KRAS amplicon-based deep sequencing strategy combined with analytical pipeline specifically designed for the detection of low-abundance mutations to screen plasma samples of 437 pancreatic cancer cases, 141 chronic pancreatitis subjects, and 394 healthy controls. We detected mutations in 21.1% (N=92) of cases, of whom 82 (89.1%) carried at least one mutation at hotspot codons 12, 13 or 61, with mutant allelic fractions from 0.08% to 79%. Advanced stages were associated with an increased proportion of detection, with KRAS cfDNA mutations detected in 10.3%, 17,5% and 33.3% of cases with local, regional and systemic stages, respectively. We also detected KRAS cfDNA mutations in 3.7% (N=14) of healthy controls and in 4.3% (N=6) of subjects with chronic pancreatitis, but at significantly lower allelic fractions than in cases. Combining cfDNA KRAS mutations and CA19-9 plasma levels on a limited set of case-control samples did not improve the overall performance of the biomarkers as compared to CA19-9 alone. Whether the limited sensitivity and specificity observed in our series of KRAS mutations in plasma cfDNA as biomarkers for pancreatic cancer detection are attributable to methodological limitations or to the biology of cfDNA should be further assessed in large case-control series.

Epidemiologic studies have reported that moderate alcohol consumption is inversely associated with the risk of renal cancer. However, there is no information available on the associations in renal cancer subsites. From 1992 through to 2010, 477,325 men and women in the European Prospective Investigation into Cancer and Nutrition cohort were followed for incident renal cancers (n = 931). Baseline and lifetime alcohol consumption was assessed by country-specific, validated dietary questionnaires. Information on past alcohol consumption was collected by lifestyle questionnaires. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated from Cox proportional hazard models. In multivariate analysis, total alcohol consumption at baseline was inversely associated with renal cancer; the HR and 95% CI for the increasing categories of total alcohol consumption at recruitment versus the light drinkers category were 0.78 (0.62-0.99), 0.82 (0.64-1.04), 0.70 (0.55-0.90), 0.91 (0.63-1.30), respectively, (ptrend  = 0.001). A similar relationship was observed for average lifetime alcohol consumption and for all renal cancer subsites combined or for renal parenchyma subsite. The trend was not observed in hypertensive individuals and not significant in smokers. In conclusion, moderate alcohol consumption was associated with a decreased risk of renal cancer., (© 2015 UICC.)

Context: Marked unexplained national variations in incidence rates of kidney cancer have been observed for decades in Europe., Objective: To investigate geographic variations at the regional level and identify European regions with high incidence rates of kidney cancer., Evidence Acquisition: Regional- and national-level incidence data were extracted from the Cancer Incidence in Five Continents databases, local cancer registry databases, and local published reports. World population age-standardised rates (ASRs) were calculated for the periods 2003-2007 and 1988-1992. Rates by period and sex were compared using map visualisation., Evidence Synthesis: During 2003-2007, the highest ASR was found in the Plzen region, Czech Republic (31.4/100,000 person-years in men). Other regions of the Czech Republic had ASRs of 18.6-27.5/100,000 in men, with a tendency for higher rates in regions south of Prague. Surrounding regions, including eastern Germany and regions of Slovakia and Austria, had medium-to-high incidence rates (13.0-16.8/100,000 in men). Three other areas in Europe showed higher incidence rates in men compared with the rest of the continent: Lithuania, Estonia, Latvia, and Belarus (15.0-17.6/100,000); Iceland (13.5/100,000), and northern Italy (up to 16.0/100,000). Similar regional differences were observed among women, with rates approximately half of those observed in men in the same region. In general, these regional geographic variations remained stable over the periods 1988-1992 and 2003-2007, although higher incidence rates were detected in the Baltic countries in 2003-2007., Conclusions: Several European regions show particularly high rates of kidney cancer incidence. Large variations were observed within countries covered by national health-care systems, implying that overdetection is not the major factor., Patient Summary: We present regional geographic variations in kidney cancer incidence rates in Europe. We highlight several regions with high incidence rates where further studies should be conducted for cancer control and prevention., (Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Detection of lung cancer at an early stage by sensitive screening tests could be an important strategy to improving prognosis. Our objective was to identify a panel of circulating microRNAs in plasma that will contribute to early detection of lung cancer., Material and Methods: Plasma samples from 100 early stage (I to IIIA) non-small-cell lung cancer (NSCLC) patients and 100 non-cancer controls were screened for 754 circulating microRNAs via qRT-PCR, using TaqMan MicroRNA Arrays. Logistic regression with a lasso penalty was used to select a panel of microRNAs that discriminate between cases and controls. Internal validation of model discrimination was conducted by calculating the bootstrap optimism-corrected AUC for the selected model., Results: We identified a panel of 24 microRNAs with optimum classification performance. The combination of these 24 microRNAs alone could discriminate lung cancer cases from non-cancer controls with an AUC of 0.92 (95% CI: 0.87-0.95). This classification improved to an AUC of 0.94 (95% CI: 0.90-0.97) following addition of sex, age and smoking status to the model. Internal validation of the model suggests that the discriminatory power of the panel will be high when applied to independent samples with a corrected AUC of 0.78 for the 24-miRNA panel alone., Conclusion: Our 24-microRNA predictor improves lung cancer prediction beyond that of known risk factors.

Genetic variants located within the 12p13.33/RAD52 locus have been associated with lung squamous cell carcinoma (LUSC). Here, within 5,947 UADT cancers and 7,789 controls from 9 different studies, we found rs10849605, a common intronic variant in RAD52, to be also associated with upper aerodigestive tract (UADT) squamous cell carcinoma cases (OR = 1.09, 95% CI: 1.04-1.15, p = 6x10(-4)). We additionally identified rs10849605 as a RAD52 cis-eQTL inUADT(p = 1x10(-3)) and LUSC (p = 9x10(-4)) tumours, with the UADT/LUSC risk allele correlated with increased RAD52 expression levels. The 12p13.33 locus, encompassing rs10849605/RAD52, was identified as a significant somatic focal copy number amplification in UADT(n = 374, q-value = 0.075) and LUSC (n = 464, q-value = 0.007) tumors and correlated with higher RAD52 tumor expression levels (p = 6x10(-48) and p = 3x10(-29) in UADT and LUSC, respectively). In combination, these results implicate increased RAD52 expression in both genetic susceptibility and tumorigenesis of UADT and LUSC tumors.

The incidence of renal cell carcinoma (RCC) is increasing worldwide, and its prevalence is particularly high in some parts of Central Europe. Here we undertake whole-genome and transcriptome sequencing of clear cell RCC (ccRCC), the most common form of the disease, in patients from four different European countries with contrasting disease incidence to explore the underlying genomic architecture of RCC. Our findings support previous reports on frequent aberrations in the epigenetic machinery and PI3K/mTOR signalling, and uncover novel pathways and genes affected by recurrent mutations and abnormal transcriptome patterns including focal adhesion, components of extracellular matrix (ECM) and genes encoding FAT cadherins. Furthermore, a large majority of patients from Romania have an unexpected high frequency of A:T>T:A transversions, consistent with exposure to aristolochic acid (AA). These results show that the processes underlying ccRCC tumorigenesis may vary in different populations and suggest that AA may be an important ccRCC carcinogen in Romania, a finding with major public health implications.

Purpose: Findings from epidemiological studies examining physical activity in relation to pancreatic cancer risk have suggested decreased risks for physical activity; however, the results are inconsistent., Methods: The association between occupational and leisure-time physical activity and risk of pancreatic cancer was examined among 826 pancreatic cancer cases and 930 age-, sex- and center-matched controls from a large multicenter central European study in Czech Republic and Slovakia recruited between 2004 and 2012. Data on physical activity including type and dose (frequency, intensity, and duration) were examined using multivariable-adjusted logistic regression models., Results: Occupational physical activity was not significantly associated with risk of pancreatic cancer [odds ratio (OR) 0.90, 95 % confidence interval (CI) 0.71-1.15]. A 35 % decrease in risk of pancreatic cancer was observed for regular leisure-time physical activity (OR 0.65, 95 % CI 0.52-0.87). The risk estimates were significant for low and moderate intensity of activity with the strongest protective effect among individuals who exercised during more than 40 weeks per year. The results for cumulated leisure-time physical activity assessed 1 year prior to diagnosis achieved the same level of risk reduction. In addition, stronger risk estimates for leisure-time physical activity were observed among women (men: OR 0.74, 95 % CI 0.54-1.01; women: OR 0.53, 95 % CI 0.37-0.75). The findings for female participants were stronger for intensity and frequency of leisure-time physical activity, in particular for light and moderate activity (OR 0.43, 95 % CI 0.25-0.75; and OR 0.57, 95 % CI 0.37-0.88, respectively)., Conclusion: These results provide evidence for a decreased risk of pancreatic cancer associated with regular leisure-time physical activity.

The quality of tissue samples and extracted mRNA is a major source of variability in tumor transcriptome analysis using genome-wide expression microarrays. During and immediately after surgical tumor resection, tissues are exposed to metabolic, biochemical and physical stresses characterized as "warm ischemia". Current practice advocates cryopreservation of biosamples within 30 minutes of resection, but this recommendation has not been systematically validated by measurements of mRNA decay over time. Using Illumina HumanHT-12 v3 Expression BeadChips, providing a genome-wide coverage of over 24,000 genes, we have analyzed gene expression variation in samples of 3 hepatocellular carcinomas (HCC) and 3 lung carcinomas (LC) cryopreserved at times up to 2 hours after resection. RNA Integrity Numbers (RIN) revealed no significant deterioration of mRNA up to 2 hours after resection. Genome-wide transcriptome analysis detected non-significant gene expression variations of -3.5%/hr (95% CI: -7.0%/hr to 0.1%/hr; p = 0.054). In LC, no consistent gene expression pattern was detected in relation with warm ischemia. In HCC, a signature of 6 up-regulated genes (CYP2E1, IGLL1, CABYR, CLDN2, NQO1, SCL13A5) and 6 down-regulated genes (MT1G, MT1H, MT1E, MT1F, HABP2, SPINK1) was identified (FDR <0.05). Overall, our observations support current recommendation of time to cryopreservation of up to 30 minutes and emphasize the need for identifying tissue-specific genes deregulated following resection to avoid misinterpreting expression changes induced by warm ischemia as pathologically significant changes.

Peripheral T-cell lymphomas are very aggressive hematologic malignancies for which there is no targeted therapy. New, rational approaches are necessary to improve the very poor outcome in these patients. Phosphatidylinositol-3-kinase is one of the most important pathways in cell survival and proliferation. We hypothesized that phosphatidylinositol-3-kinase inhibitors could be rationally selected drugs for treating peripheral T-cell lymphomas. Several phosphatidylinositol-3-kinase isoforms were inhibited genetically (using small interfering RNA) and pharmacologically (with CAL-101 and GDC-0941 compounds) in a panel of six peripheral and cutaneous T-cell lymphoma cell lines. Cell viability was measured by intracellular ATP content; apoptosis and cell cycle changes were checked by flow cytometry. Pharmacodynamic biomarkers were assessed by western blot. The PIK3CD gene, which encodes the δ isoform of phosphatidylinositol-3-kinase, was overexpressed in cell lines and primary samples, and correlated with survival pathways. However, neither genetic nor specific pharmacological inhibition of phosphatidylinositol-3-kinase δ affected cell survival. In contrast, the pan-phosphatidylinositol-3-kinase inhibitor GDC-0941 arrested all T-cell lymphoma cell lines in the G1 phase and induced apoptosis in a subset of them. We identified phospho-GSK3β and phospho-p70S6K as potential biomarkers of phosphatidylinositol-3-kinase inhibitors. Interestingly, an increase in ERK phosphorylation was observed in some GDC -0941-treated T-cell lymphoma cell lines, suggesting the presence of a combination of phosphatidylinositol-3-kinase and MEK inhibitors. A highly synergistic effect was found between the two inhibitors, with the combination enhancing cell cycle arrest at G0/G1 in all T-cell lymphoma cell lines, and reducing cell viability in primary tumor T cells ex vivo. These results suggest that the combined treatment of pan-phosphatidylinositol-3-kinase + MEK inhibitors could be more effective than single phosphatidylinositol-3-kinase inhibitor treatment, and therefore, that this combination could be of therapeutic value for treating peripheral and cutaneous T-cell lymphomas.

Gene expression microarray and next generation sequencing efforts on conventional, clear cell renal cell carcinoma (ccRCC) have been mostly performed in North American and Western European populations, while the highest incidence rates are found in Central/Eastern Europe. We conducted whole-genome expression profiling on 101 pairs of ccRCC tumours and adjacent non-tumour renal tissue from Czech patients recruited within the "K2 Study", using the Illumina HumanHT-12 v4 Expression BeadChips to explore the molecular variations underlying the biological and clinical heterogeneity of this cancer. Differential expression analysis identified 1650 significant probes (fold change ≥2 and false discovery rate <0.05) mapping to 630 up- and 720 down-regulated unique genes. We performed similar statistical analysis on the RNA sequencing data of 65 ccRCC cases from the Cancer Genome Atlas (TCGA) project and identified 60% (402) of the downregulated and 74% (469) of the upregulated genes found in the K2 series. The biological characterization of the significantly deregulated genes demonstrated involvement of downregulated genes in metabolic and catabolic processes, excretion, oxidation reduction, ion transport and response to chemical stimulus, while simultaneously upregulated genes were associated with immune and inflammatory responses, response to hypoxia, stress, wounding, vasculature development and cell activation. Furthermore, genome-wide DNA methylation analysis of 317 TCGA ccRCC/adjacent non-tumour renal tissue pairs indicated that deregulation of approximately 7% of genes could be explained by epigenetic changes. Finally, survival analysis conducted on 89 K2 and 464 TCGA cases identified 8 genes associated with differential prognostic outcomes. In conclusion, a large proportion of ccRCC molecular characteristics were common to the two populations and several may have clinical implications when validated further through large clinical cohorts.

Background: Vorinostat (suberoylanilide hydroxamic acid, SAHA), an inhibitor of class I and II histone deacetylases, has been approved for the treatment of cutaneous T-cell lymphoma. In spite of emerging information on the effect of vorinostat in many types of cancer, little is yet known about this drug's mechanism of action, which is essential for its proper use in combination therapy. We investigated alterations in gene expression profile over time in cutaneous T-cell lymphoma cells treated with vorinostat. Subsequently, we evaluated inhibitors of PI3K, PIM and HSP90 as potential combination agents in the treatment of cutaneous T-cell lymphoma., Design and Methods: The genes significantly up- or down-regulated by vorinostat over different time periods (2-fold change, false discovery rate corrected P value<0.05) were selected using the short-time series expression miner. Cell viability was assessed in vitro in cutaneous T-cell lymphoma cells through measuring intracellular ATP content. Drug interactions were analyzed by the combination index method with CalcuSyn software., Results: The functional analysis suggests that vorinostat modifies signaling of T-cell receptor, MAPK, and JAK-STAT pathways. The phosphorylation studies of ZAP70 (Tyr319, Tyr493) and its downstream target AKT (Ser473) revealed that vorinostat inhibits phosphorylation of these kinases. With regards to effects on cutaneous T-cell lymphoma cells, combining vorinostat with PI3K inhibitors resulted in synergy while cytotoxic antagonism was observed when vorinostat was combined with HSP90 inhibitor., Conclusions: These results demonstrate the potential targets of vorinostat, underlining the importance of T-cell receptor signaling inhibition following vorinostat treatment. Additionally, we showed that combination therapies involving histone deacetylase inhibitors and inhibitors of PI3K are potentially efficacious for the treatment of cutaneous T-cell lymphoma.

Primary cutaneous anaplastic large-cell lymphoma (C-ALCL) and cutaneous peripheral T-cell lymphoma not otherwise specified (C-PTL-NOS) are cutaneous T-cell lymphomas with distinct clinical behaviors. Whereas C-ALCL has a favorable prognosis with frequent spontaneous disease regression, C-PTL-NOS runs a more aggressive course. The molecular pathogenesis of these cutaneous T-cell lymphoma types has not yet been studied in detail. In this issue, van Kester et al. report new imbalances that could contribute to our understanding of the differences between these two lymphoma types.

Background: Interferon (IFN)-alpha is widely used in the treatment of mycosis fungoides (MF) and when used in combination with photochemotherapy (psoralen plus ultraviolet A, PUVA) both improved response and duration of complete remission have been reported. However, in spite of encouraging results of the initial studies, currently there is no information available on specific prognostic factors enabling prediction of patients' resistance to PUVA +/- IFN-alpha treatment., Objectives: To identify factors responsible for resistance to PUVA +/- IFN-alpha treatment in MF patients., Patients/methods: The gene expression profiling of pretreatment samples from 29 patients diagnosed as IA, IB or IIA stage of MF enrolled in a randomized PUVA vs. PUVA + IFN-alpha clinical trial was analysed using cDNA microarrays. A Cox model (SAM) and gene set enrichment analysis (GSEA) were used for identification of genes and biologically significant pathways related to resistance to treatment., Results: Genes involved in NF-kappaB signalling, T-cell receptor (TCR) signalling, cytokine signalling and proliferation were differentially expressed between responders and nonresponders. Interestingly, expression of markers representative of those pathways was found not only in the tumoral cells, but also in specific subpopulations of macrophages, dendritic cells and other non-neoplastic cell types constituting the tumour microenvironment, likely involved in the promotion of survival and proliferation of cutaneous T-cell lymphoma., Conclusions: Gene expression changes in both the tumour and the tumour microenvironment are an important determinant of treatment outcome in early-stage MF patients. Some proinflammatory factors such as NF-kappaB, inflammatory cytokines and their receptors in addition to TCR-associated molecules could be promising targets for MF treatment.