Duplex mapping of 2036 primary varicose veins

ObjectiveTo produce a comprehensive anatomical and hemodynamic ultrasound scan mapping of the whole limb in patients with primary varicose veins (VVs).DesignAn analysis of venous duplex scans performed on patients referred for treatment of primary VVs.MethodsA total of 2036 limbs were evaluated, looking for the origin of VVs in the saphenous systems and in the perforating vein (PV) systems, as well as for the presence of non-saphenous reflux.ResultsThe sapheno-femoral junction (SFJ) of the great saphenous vein (GSV) was involved in 1330 limbs (65.3%). We have noted that finding reflux in the groin does not imply that it originates at that point necessarily, as reflux from the pelvis or abdominal wall can also cause primary VVs (SFJ reflux, 41.9% and competent SFJ with reflux from proximal veins, 35.4%). We also noted that analyzing only the presence of reflux in the SFJ of the GSV would miss 10.9% of limbs of reflux in the SFJ of the anterior accessory GSV. In 237 limbs (11.6%), reflux was observed in the popliteal fossa. In the PV system, we distinguished those PVs with retrograde flow that acted as an origin of the VVs, and other PVs that acted as re-entry points. Based on this difference, the location identified as the most frequent origin of VVs in the PV system was the thigh, specifically in the group of PVs of the medial thigh of the femoral canal, with 85 PVs with a total of 238 incompetent PVs identified. Pure non-saphenous reflux was observed in 162 limbs (8%).ConclusionThe assumption that the origin of VVs would be exclusively in the sapheno-femoral or sapheno-popliteal junction, is a mistaken attitude and a comprehensive duplex scan mapping is recommended

Identification of tissue microRNAs predictive of sunitinib activity in patients with metastatic renal cell carcinoma

PURPOSE: To identify tissue microRNAs predictive of sunitinib activity in patients with metastatic renal-cell-carcinoma (MRCC) and to evaluate in vitro their mechanism of action in sunitinib resistance. METHODS: We screened 673 microRNAs using TaqMan Low-density-Arrays (TLDAs) in tumors from MRCC patients with extreme phenotypes of marked efficacy and resistance to sunitinib, selected from an identification cohort (n = 41). The most relevant differentially expressed microRNAs were selected using bioinformatics-based target prediction analysis and quantified by qRT-PCR in tumors from patients presenting similar phenotypes selected from an independent cohort (n = 101). In vitro experiments were conducted to study the role of miR-942 in sunitinib resistance. RESULTS: TLDAs identified 64 microRNAs differentially expressed in the identification cohort. Seven candidates were quantified by qRT-PCR in the independent series. MiR-942 was the most accurate predictor of sunitinib efficacy (p = 0.0074). High expression of miR-942, miR-628-5p, miR-133a, and miR-484 was significantly associated with decreased time to progression and overall survival. These microRNAs were also overexpressed in the sunitinib resistant cell line Caki-2 in comparison with the sensitive cell line. MiR-942 overexpression in Caki-2 up-regulates MMP-9 and VEGF secretion which, in turn, promote HBMEC endothelial migration and sunitinib resistance. CONCLUSIONS: We identified differentially expressed microRNAs in MRCC patients presenting marked sensitivity or resistance to sunitinib. MiR-942 was the best predictor of efficacy. We describe a novel paracrine mechanism through which high miR-942 levels in MRCC cells up-regulates MMP-9 and VEGF secretion to enhance endothelial migration and sunitinib resistance. Our results support further validation of these miRNA in clinical confirmatory studies

First line treatment with rituximab-Hyper-CVAD alternating with rituximab-Methotrexate-Cytarabine and followed by consolidation with 90Y-Ibritumomab-Tiuxetan in patients with mantle cell lymphoma. Results of a phase 2 pilot multicenter trial from the GELT

D. First line treatment with rituximab-Hyper-CVAD alternating with rituximab-Methotrexate-Cytarabine and followed by consolidation with 90Y-Ibritumomab-Tiuxetan in patients with mantle cell lymphoma. Results of a phase 2 pilot multicenter trial from th

Effects of technosols based on organic amendments addition for the recovery of the functionality of degraded quarry soils under semiarid Mediterranean climate: A field study

13 páginas.- 4 figuras.- 2 tablas.- referencias.- Supplementary data to this article can be found online athttps://doi.org/10.1016/j.scitotenv.2021.151572This study aims to evaluate the effects of technosols made with different organic amendments to restore degraded soils in a semiarid limestone quarry. The effects on soil quality, functionality and organic matter dynamics of the technosols amended with waste of gardening, greenhouse horticultural, stabilized sewage sludge and two mixtures of sludge with both vegetable composts were assessed. Several physical and chemical properties, humus fractions, soil respiration and molecular composition was performed after 6 and 18 months. Un-amended soils, and nearby natural undegraded soils served as reference. Amended technosols increased water retention capacity, electrical conductivity, total organic carbon and nitrogen, respect to not amended and natural soils. Humus fraction composition was not altered over time. Un-amended soils, very poor in organic matter, did not show any pyrolyzable compounds or labile soil organic matter by thermogravimetry. In contrast, the pyrochromatograms of natural soils showed lignocellulosic materials, polypeptides and a noticeable presence of alkylic compounds. In technosols with both types vegetable compost, the organic matter structure was more complex, showing compounds from lignin-derived and long-chain alkyl, polysaccharides, chlorophyll isoprenoids and nitrogen. In sludge technosol, a set of sterols was outstanding. The mixtures showed a molecular fingerprint of materials derived from the decomposition of the organic amendments that formed them. These signs of the contribution of different organic matter forms derived from the amendments were also reported by the series exothermic peaks found in the calorimetry. This short-term study indicates a clear effect of the amendments on the recovery of soil organic matter and presumably of its functionality. After the amendments application, microbial activity and soil respiration rates increased rapidly but ceased 18 months later. The molecular composition of the organic matter of the soils amended with plant compost was very similar to that of natural, non-degraded soils in nearby areas.This work was supported by the Spanish Ministry of Economy and Competitiveness (MINECO), and FEDER funds, through the project CGL2017-88734-R (BIORESOC) MINECO/AEI/FEDER, UE and FEDER-Junta de Andalucía Research Projects RESTAGRO (UAL18-RNM-A021-B), MarkFire (PAIDI2020, PY20_01073) and Restoration of Abandoned Agricultural Soils in Semiarid Zones to Improve Productivity and Soil Quality and Enhance Carbon Sequestration (P18-RT-4112). Isabel Miralles is grateful for funding received from the Ramón y Cajal Research Grant (RYC-2016-21191) from the Spanish Ministry of Economy and Competitiveness (MINECO), Raúl Ortega thanks his postdoctoral contract HIPATIA of the University of Almería Research Plan. Layla M. San Emeterio thanks the pre-doctoral FPI fellowship (grant number BES-2017-079811).Peer reviewe

Single nucleotide polymorphism associations with response and toxic effects in patients with advanced renal-cell carcinoma treated with first-line sunitinib: a multicentre, observational, prospective study.

BACKGROUND Sunitinib is a tyrosine kinase inhibitor with proven efficacy in renal-cell carcinoma, but some patients do not respond or need dose reductions due to toxicity. Because there are no validated molecular predictors of response or toxicity to sunitinib, we aimed to identify genetic markers predictive of outcome and toxic effects. METHODS In our observational, prospective study we enrolled previously untreated adults (≥ 18 years) with clear-cell renal-cell carcinoma at 15 institutions in the Spanish Oncology Genitourinary Group in Spain. Patients received sunitinib according to local practice guidelines. We assessed RECIST response, progression-free survival (PFS), overall survival, and toxicity of sunitinib with 16 key polymorphisms in nine genes: VEGFR2 (rs2305948 and rs1870377), VEGFR3 (rs307826, rs448012, and rs307821), PDGFR-α (rs35597368), VEGF-A (rs2010963, rs699947, and rs1570360), IL8 (rs1126647), CYP3A4 (rs2740574), CYP3A5 (rs776746), ABCB1 (rs1045642, rs1128503, and rs2032582), and ABCB2 (rs2231142). We assessed associations with efficacy and toxicity by use of univariable and multivariable analyses (with clinical factors associated with outcomes as covariates). We adjusted for multiplicity using the Bonferroni method; p values of less than 0·0031 before adjustment were deemed to still be significant after adjustment. FINDINGS We enrolled 101 patients between Oct 10, 2007, and Dec 13, 2010. 95 of these patients were included in toxicity analyses and 89 in the efficacy analyses. Two VEGFR3 missense polymorphisms were associated with reduced PFS with sunitinib on multivariable analysis: rs307826 (hazard ratio [HR] per allele 3·57, 1·75-7·30; p(unadjusted)=0·00049, p(adjusted)=0·0079) and rs307821 (3·31, 1·64-6·68; p(unadjusted)=0·00085, p(adjusted)=0·014). The CYP3A5*1 (rs776746) high metabolising allele was associated in a multivariable analysis with an increased risk of dose reductions due to toxicity (HR per allele 3·75, 1·67-8·41; p(unadjusted)=0·0014, p(adjusted)=0·022). No other SNPs were associated with sunitinib response or toxicity. INTERPRETATION Polymorphisms in VEGFR3 and CYP3A5*1 might be able to define a subset of patients with renal-cell carcinoma with decreased sunitinib response and tolerability. If confirmed, these results should promote interventional studies testing alternative therapeutic approaches for patients with such variants. FUNDING Pfizer.This study was supported by an unrestricted educational grant from Pfizer. We thank Enrique Grande for his critical review of the manuscript and worthy comments, M Victoria Bolós for helping with bureaucratic issues, and Julia Llinares for her contribution to data monitoring and collection.S

Deep sequencing reveals microRNAs predictive of antiangiogenic drug response

The majority of metastatic renal cell carcinoma (RCC) patients are treated with tyrosine kinase inhibitors (TKI) in first-line treatment; however, a fraction are refractory to these antiangiogenic drugs. MicroRNAs (miRNAs) are regulatory molecules proven to be accurate biomarkers in cancer. Here, we identified miRNAs predictive of progressive disease under TKI treatment through deep sequencing of 74 metastatic clear cell RCC cases uniformly treated with these drugs. Twenty-nine miRNAs were differentially expressed in the tumors of patients who progressed under TKI therapy (P values from 6 × 10(-9) to 3 × 10(-3)). Among 6 miRNAs selected for validation in an independent series, the most relevant associations corresponded to miR-1307-3p, miR-155-5p, and miR-221-3p (P = 4.6 × 10(-3), 6.5 × 10(-3), and 3.4 × 10(-2), respectively). Furthermore, a 2 miRNA-based classifier discriminated individuals with progressive disease upon TKI treatment (AUC = 0.75, 95% CI, 0.64-0.85; P = 1.3 × 10(-4)) with better predictive value than clinicopathological risk factors commonly used. We also identified miRNAs significantly associated with progression-free survival and overall survival (P = 6.8 × 10(-8) and 7.8 × 10(-7) for top hits, respectively), and 7 overlapped with early progressive disease. In conclusion, this is the first miRNome comprehensive study, to our knowledge, that demonstrates a predictive value of miRNAs for TKI response and provides a new set of relevant markers that can help rationalize metastatic RCC treatment.status: publishe

Deep sequencing reveals microRNAs predictive of antiangiogenic drug response

The majority of metastatic renal cell carcinoma (RCC) patients are treated with tyrosine kinase inhibitors (TKI) in first-line treatment; however, a fraction are refractory to these antiangiogenic drugs. MicroRNAs (miRNAs) are regulatory molecules proven to be accurate biomarkers in cancer. Here, we identified miRNAs predictive of progressive disease under TKI treatment through deep sequencing of 74 metastatic clear cell RCC cases uniformly treated with these drugs. Twenty-nine miRNAs were differentially expressed in the tumors of patients who progressed under TKI therapy (P values from 6 × 10(–9) to 3 × 10(–3)). Among 6 miRNAs selected for validation in an independent series, the most relevant associations corresponded to miR–1307-3p, miR–155-5p, and miR–221-3p (P = 4.6 × 10(–3), 6.5 × 10(–3), and 3.4 × 10(–2), respectively). Furthermore, a 2 miRNA–based classifier discriminated individuals with progressive disease upon TKI treatment (AUC = 0.75, 95% CI, 0.64–0.85; P = 1.3 × 10(–4)) with better predictive value than clinicopathological risk factors commonly used. We also identified miRNAs significantly associated with progression-free survival and overall survival (P = 6.8 × 10(–8) and 7.8 × 10(–7) for top hits, respectively), and 7 overlapped with early progressive disease. In conclusion, this is the first miRNome comprehensive study, to our knowledge, that demonstrates a predictive value of miRNAs for TKI response and provides a new set of relevant markers that can help rationalize metastatic RCC treatment

Identification of tissue microRNAs predictive of sunitinib activity in patients with metastatic renal cell carcinoma

PURPOSE: To identify tissue microRNAs predictive of sunitinib activity in patients with metastatic renal-cell-carcinoma (MRCC) and to evaluate in vitro their mechanism of action in sunitinib resistance. METHODS: We screened 673 microRNAs using TaqMan Low-density-Arrays (TLDAs) in tumors from MRCC patients with extreme phenotypes of marked efficacy and resistance to sunitinib, selected from an identification cohort (n = 41). The most relevant differentially expressed microRNAs were selected using bioinformatics-based target prediction analysis and quantified by qRT-PCR in tumors from patients presenting similar phenotypes selected from an independent cohort (n = 101). In vitro experiments were conducted to study the role of miR-942 in sunitinib resistance. RESULTS: TLDAs identified 64 microRNAs differentially expressed in the identification cohort. Seven candidates were quantified by qRT-PCR in the independent series. MiR-942 was the most accurate predictor of sunitinib efficacy (p = 0.0074). High expression of miR-942, miR-628-5p, miR-133a, and miR-484 was significantly associated with decreased time to progression and overall survival. These microRNAs were also overexpressed in the sunitinib resistant cell line Caki-2 in comparison with the sensitive cell line. MiR-942 overexpression in Caki-2 up-regulates MMP-9 and VEGF secretion which, in turn, promote HBMEC endothelial migration and sunitinib resistance. CONCLUSIONS: We identified differentially expressed microRNAs in MRCC patients presenting marked sensitivity or resistance to sunitinib. MiR-942 was the best predictor of efficacy. We describe a novel paracrine mechanism through which high miR-942 levels in MRCC cells up-regulates MMP-9 and VEGF secretion to enhance endothelial migration and sunitinib resistance. Our results support further validation of these miRNA in clinical confirmatory studies