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PURPOSE: To evaluate the outcomes of adding arthroscopy to osteosynthesis of distal radius fractures (DRF) with volar locking plate (VLP), by Patient-Rated Wrist Evaluation (PRWE) 1 year after surgery. METHODS: In total, 186 functionally independent adult patients who met the inclusion criteria (DRF and a clinical decision for surgery with a VLP) were randomized to arthroscopic assistance or not. Primary outcome was PRWE questionnaire results 1 year after surgery. For the main variable, PRWE, we obtained the minimal clinically important difference based on a distribution-based method. Secondary outcomes included Disabilities of the Arm, Shoulder and Hand and 12-Item Short Form Health Survey questionnaires, range of motion, strength, radiographic measures, and presence of joint step-offs by computed tomography. Data were collected preoperatively and at +1 and +4 weeks, +3 and +6 months, and +1 year after surgery. Complications were recorded throughout the study. RESULTS: In total, 180 patients (mean age: 59.0 ± 14.9 years; 76% women) were analyzed by modified intention to treat. A total of 82% of the fractures were intra-articular (AO type C). No significant difference between arthroscopic (AG) and control (CG) groups in median PRWE was found at +1 year (median AG: 5.0, median CG: 7.5, difference in medians 2.5; 95% confidence interval [CI] -2.0, 7.0, P = .328). The proportion of patients who exceeded the minimal clinically important difference of 12.81 points in the AG and CG was 86.4% vs 85.1%, P = .819, respectively. Percentage of associated injuries and step-offs reduction maneuvers was greater with arthroscopy (mean differences: 17.1 95% CI -0.1, 26.1, P < .001) and 17.4 (95% CI 5.0, 29.7, P = .007). The difference in percentage of residual joint step-offs at the postsurgical computed tomography in radioulnar, radioscaphoid, and radiolunate joints was not significant (P = .990, P = .538, and P = .063). Complications were similar between groups (16.9% vs 20.9%, P = .842). CONCLUSIONS: Adjuvant arthroscopy did not significantly improve PRWE score +1 year after surgery for DRF with VLP, although the statistical power of the study is below the initially estimated to detect the expected difference. LEVEL OF EVIDENCE: Level I, randomized controlled trial.

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Objectives: Cryoglobulins (CGs) are serum proteins that undergo a reverse cold-induced precipitation in vitro. The CGs are a well-known cause of analytical interferences in several laboratory tests, leading to spurious results. With this in view, we present a case of a patient initially misdiagnosed due to CGs interference in Hepatitis C Virus (HCV) serology. Case presentation: We report a case of a woman of advanced age affected by acute renal failure that required urgent haemodialysis. In the absence of infections and other causes of CGs production, a diagnosis of acute renal failure secondary to essential cryoglobulinemia was established. However, an unexpected positive HCV viral load was encountered. At this point, a false-seronegative HCV infection conditioned to CGs interference in vitro was suspected, confirmed by repeating serology in pre-warmed serum. Finally, the patient was correctly diagnosed with HCV-secondary cryoglobulinemia. Conclusions: As shown in the case, the presence of CGs in blood may represent a challenge for the correct interpretation of several laboratory tests. The identification of CGs and the pre-treatment of serum are decisive to avoid spurious results and reach a genuine diagnosis.

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Angiogenesis process contributes to the pathogenesis of B-cell chronic lymphocytic leukemia (B-CLL) being the levels of VEGFA and bFGF higher in patients than in healthy controls. Our aim was to evaluate the implication of angiogenesis factors genetic variants in the predisposition to B-CLL and their association with clinical factors and survival. We performed a population-based case-control study in 224 Spanish B-CLL patients and 476 healthy randomly selected controls to evaluate susceptibility to developing B-CLL. Six polymorphisms were evaluated: rs1109324, rs1547651, rs3025039 (+936 C>T), rs833052 of the VEGFA gene, rs1449683 (c.233C>T) of the bFGF gene and (-710 C>T) of the VEGFR1 gene. The association between clinical parameters and patient outcome was analyzed. Carriers of the CT/TT variants of rs3025039 showed a significant protective effect against developing B-CLL. The CT/TT variants of rs1449683 show a tendency towards the development of the disease and the same variants associated significantly with higher genetic risk and with reduced disease free survival. Moreover, the association persisted in the early-stage disease subgroup. Our study provides evidence of the protective effect of the T/- rs3025039 VEGFA variant against B-CLL development and the association of CT/TT variants of the rs1449683 bFGF gene with genetic risk and an adverse survival.

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The mechanisms of chemotherapy resistance in triple negative breast cancer remain unclear, and so, new molecules which might mediate this resistance could optimize treatment response. Here we analyzed the involvement of the miRNA-449 family in the response to doxorubicin. The cell viability, cell-cycle phases, and the expression of in silico target genes and proteins of sensitive/resistant triple negative breast cancer cell lines were evaluated in response to doxorubicin treatment and after gain/loss of miRNAs-449 function achieved by transient transfection. Triple negative breast cancer patients were selected for ex vivo experiments and to evaluate gene and miRNAs expression changes after treatment, as well as survival analysis by Kaplan-Meier. Doxorubicin treatment upregulated miRNAs-449 and DNA-damage responder factors E2F1 and E2F3 in triple negative breast cancer sensitive breast cancer cells, while expression remained unaltered in resistant ones. In vitro overexpression of miRNAs-449 sensitized cells to the treatment and significantly reduced the resistance to doxorubicin. These changes showed also a strong effect on cell cycle regulation. Finally, elevated levels of miRNA-449a associated significantly with better survival in chemotherapy-treated triple negative breast cancer patients. These results reveal for the first time the involvement of the miRNA-449 family in doxorubicin resistance and their predictive and prognostic value in triple negative breast cancer patients.

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A subset of HER2+ breast cancer patients manifest clinical resistance to trastuzumab. Recently, miR-26a and miR-30b have been identified as trastuzumab response regulators, and their target gene CCNE2 seems to play an important role in resistance to trastuzumab therapy. Cell viability was evaluated in trastuzumab treated HER2+ BT474 wt (sensitive), BT474r (acquired resistance), HCC1954 (innate resistance), and MDA-MB-231 (HER2-) cell lines, and the expression of miR-26a, miR-30b, and their target genes was measured. BT474 wt cell viability decreased by 60% and miR-26a and miR-30b were significantly overexpressed (~3-fold, p = 0.003 and p = 0.002, respectively) after trastuzumab treatment, but no differences were observed in resistant and control cell lines. Overexpression of miR-30b sensitized BT474r cells to trastuzumab (p = 0.01) and CCNE2, was significantly overexpressed after trastuzumab treatment in BT474r cells (p = 0.032), but no significant changes were observed in sensitive cell line. When CCNE2 was silenced BT474r cell sensitivity to trastuzumab increased (p = 0.03). Thus, the molecular mechanism of trastuzumab action in BT474 cell line may be regulated by miR-26a and miR-30b and CCNE2 overexpression might play an important role in acquired trastuzumab resistance in HER2+ breast cancer given that resistance was diminished when CCNE2 was silenced.

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The tumour-suppressor gene TP53 has been associated with the angiogenic pathway by a TP53 response element sequence of the VEGFR1 promoter. Within that sequence, the polymorphism -710 C/T VEGFR1, which confers variable transcriptional activation by TP53, has been identified. Our group found an association between this polymorphism and breast cancer (BC) risk. We decided to investigate a possible epistatic interaction between this polymorphism and others located at gene TP53. We chose four polymorphisms (Ex4 + 119G > C, IVS4-91A > G, IVS6 + 62A > G and IVS7 + 92T > G) to analyse out of a total of 461 controls and 453 BC patients in a Spanish population. The two-locus combined analysis of TP53 and -710 C/T VEGFR1 polymorphisms was performed with the multifactor dimension reduction approach. Kaplan-Meier disease-free survival curves were calculated using the SPSS package. Carriers of at least one Pro allele of the Ex4 + 119G > C TP53 polymorphism presented a significant BC risk [OR = 1.34, (95 % CI 1.03-1.75), p value = 0.029]. The epistatic gene-gene analysis showed that the best two-locus model was the combination between Ex4 + 119G > C TP53 and -710 C/T VEGFR1 showing OR of 1.44 (95 % CI 1.10-1.88, p value = 0.0083). Moreover, the Pro/Pro genotypes of Ex4 + 119G > C were associated with poor disease-free survival (p value = 0.013). We conclude that the Ex4 + 119G > C TP53 polymorphism is an independent, low penetrance marker of BC risk in this population. In addition, our findings suggest that the combination of Ex4 + 119G > C TP53 and -710 C/T VEGFR1 genotypes confers a higher risk to develop BC. Also, a possible association of the Ex4 + 119G > C TP53 genotype with decreased disease-free survival in these patients is proposed.

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Vascular endothelial growth factor (VEGF) is a potent regulator of angiogenesis and thereby involved in the development and progression of solid tumours. The association between polymorphisms of angiogenesis pathway genes and risk of breast cancer (BC) has been widely studied, but the results are not conclusive. This information is especially limited in Spanish women, so we decided to conduct a case-control study. Here, we selected four commonly studied polymorphisms in VEGF, rs3025039 (known as +936 C/T), rs1109324, rs154765 and rs833052, one polymorphism at the promoter of the VEGFR1 (-710 C/T) and another in the FGF2, rs1449683, gene to explore their association with BC susceptibility. Genotyping was performed by TaqMan SNP assays and polymerase chain reaction-restriction fragment length polymorphis (PCR-RFLP) on 453 patients and 461 controls in a population from Valencia (Spain). We observed that women carriers of +936 CT + TT VEGF genotypes have a protective effect concerning this disease (p = 0.014; OR 0.67, 95% CI 0.48-0.92) in the global group of patients. The haplotype TGAC of VEGF (rs3025039, rs1109324, rs154764 and rs833052) shows a reduction of the risk to develop BC (p = 3e-04; OR 0.48, 95% CI 0.32-0.72). Furthermore, we found that carriers of -710 CT + TT VEGFR1 genotypes have also a protective effect (p = 0.039; OR 0.55, 95% CI 0.31-0.98). When we stratified by groups of ages these associations were maintained. Our data report for the first time the association of the polymorphism -710 C/T VEGFR1 with BC. Additional experiments focused on VEGF-A, VEGFR1 and sVEGFR1 gene expression demonstrated that carriers of T allele at -710 C/T VEGFR1 genotype have higher levels of sVEGFR1/VEGF-A than the C/C genotype carriers. This was consistent with the hypothesis that this polymorphism may act as low penetrance risk factor. The data provided suggest that +936 C/T VEGF and -710 C/T VEGFR1 genotypes are likely important genetic markers of susceptibility to BC.

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BACKGROUND: Molecular analysis of minimal residual disease is only applicable in acute myeloblastic leukemia (AML) patients with genetic markers (20-30%). This study analyzes the feasibility of the real-time quantitative polymerase chain reaction (RQ-PCR) assay to detect mutant nucleophosmin (NPM1) during follow-up in AML patients. Moreover, we compare the NPM1 results with those of WT1 expression to MRD assessment. METHODS: The study includes 97 samples from 24 AML patients with type A NPM1 mutation at diagnosis. MRD was evaluated simultaneous by RQ-PCR assay to detect NPM1-mutated and WT1 expression. RESULTS: The expression levels of WT1 and NPM1 in 93 paired samples showed a strong positive correlation (r=0.81; p<0.0001). However, the kinetics of disappearance were different, WT1 decreased rapidly after induction but maintained these residual levels after treatment in patients in complete remission, whereas NPM1 experienced a mild reduction after induction but was undetectable in long survivor patients. CONCLUSIONS: This study shows the feasibility of the RQ-PCR assay to monitor MRD in AML patients carrying NPM1 mutations and its advantage over RQ-PCR assay for WT1. Owing to NPM1-mutated is specific of leukemic cells and shows higher levels at presentation.

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BACKGROUND AND OBJECTIVES: The Wilms' tumor (WT1) gene is overexpressed in patients with most forms of acute leukemia. Several studies have reported the usefulness of quantitative assessment of WT1 expression as a molecular marker of minimal residual disease. However, the biological significance and the prognostic impact of WT1 overexpression in acute myeloid leukemia (AML) is still uncertain. DESIGN AND METHODS: We analyzed the prognostic relevance of WT1 expression in a cohort of 77 adult patients with AML, using a real-time quantitative reverse-transcription polymerase chain reaction approach. RESULTS: WT1 expression was significantly higher in AML patients than in normal controls (p = 0.0001). The normalized levels of WT1 with respect to the control gene for beta-glucuronidase (GUS) in AML samples showed a median WT1/GUS ratio of 0.93 (range 0-25). We classified the patients into two groups according to this ratio. Forty patients (52%) showed a WT1/GUS ratio 1. A ratio > 1, although significantly associated with FLT3 mutations, was the strongest independent prognostic factor for disease-free survival (p = 0.004), relapse risk (p = 0.005) and cumulative incidence risk (p = 0.01). This adverse prognostic value was more evident in patients aged 60 years and younger. INTERPRETATION AND CONCLUSIONS: The WT1/GUS ratio is an independent prognostic factor for predicting relapse in patients with AML and it could be included as part of the initial evaluation to establish more defined risk groups.

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