De-escalating axillary management after neoadjuvant chemotherapy in breast cancer: The ratio of positive sentinel lymph nodes matters.

BACKGROUND: De-escalation of axillary surgery in breast cancer (BC) patients diminishes sequelae without compromising cancer outcomes. Surgical management of the axilla is challenging after neoadjuvant treatment. We aimed to identify the factors associated with residual axillary disease amenable to lymphadenectomy in patients with positive sentinel lymph node biopsy (SLNB). METHODS: We conducted a retrospective observational study in Hospital 12 de Octubre (Spain). We included BC patients with positive SLNB who underwent axillary dissection after neoadjuvant chemotherapy. Univariate and multivariate logistic regression models were performed to identify independent predictors of residual axillary disease. We estimated the ratio of positive nodes in SLNB and assessed the diagnostic validity of this ratio in relation to residual axillary disease. RESULTS: We included 103 patients in the study. Residual axillary disease was identified in 54 patients (52.4%). Clinically node positive status at diagnosis (OR = 18.3, 95%CI: 4.0-83.6) and a ratio of positive nodes in SLNB ≥0.5 (OR = 6.5, 95%CI 41.7-23.7) were associated with residual axillary disease. The sensitivity and negative predictive value of a ratio of positive nodes in SLNB ≥0.5 were 87% (95%CI 75.1%-94.6%) and 75% (95%CI 55.1%-89.3%), respectively. CONCLUSIONS: In our study, for patients with positive SLNB after neoadjuvant chemotherapy, stage N+ at diagnosis and a ratio of positive nodes in SLNB ≥0.5 were independent risk factors of positive residual axillary disease. This ratio is a feasible measure with a good diagnostic validity for residual axillary disease and could be used as a guiding factor in the surgical management of these patients.

Single nucleotide polymorphisms in ADAM17, IL23R and SLCO1C1 genes protect against infliximab failure in adults with Crohn's disease.

BACKGROUND: To predict primary failure of infliximab (IFX) therapy in Crohn's disease (CD) and to identify patients who maintain long-term effectiveness to IFX is currently not feasible. Some genetic variations are proposed as potential biomarkers. AIM: We assessed a set of single nucleotide polymorphisms (SNPs) in genes related to the IFX mechanism of action and the presence of HLA-DQA1 * 05 allele on the primary response and long-term durability in CD patients. METHODS: A multi-centre cross-sectional study of IFX-exposed adult patients with CD was undertaken. Treatment persistence and time to failure were co-primary endpoints. DNA from the 131 patients was genotyped. Association between SNPs and clinical variables with IFX persistence was assessed. RESULTS: Failure to IFX was documented in 65 (49.6%) out of 131 patients. IFX persistence was associated either with carrying the TT genotype in ADAM17 rs10929587 (ORa=0.2; 95%CI=0.1-0.8; p = 0.021), or the CC genotype in SLCO1C1 rs3794271 (ORa=0.2; 95%CI=0.1-0.7; p = 0.008), according to multivariate logistic regression. In contrast, previous bowel resection increased the risk of IFX failure (ORa=2.8; 95%CI=1.1-7.3; p = 0.025). Cox regression analysis confirmed these findings and also identified IL23R rs10489629-TT (HRa 0.41; 95%CI=0.22-0.75; p = 0.004) and concomitant immunosuppressants (HRa 0.46; 95%CI=0.27-0.77; p = 0.003) as protection from IFX failure. However, no association between HLA-DQA1 * 05 allele and persistence of IFX therapy was found, with similar failure rates among carriers and non-carriers (52.8% vs. 47.4%, respectively; p = 0.544). CONCLUSIONS: SNPs rs10929587-TT in ADAM17, rs10489629-TT in IL23R and rs3794271-CC in SLCO1C1, together with no previous bowel surgery and concomitant immunosuppression, were identified as protection from failure to IFX.

Clinical landscape of LAG-3-targeted therapy.

Lymphocyte-activated gene 3 (LAG-3) is a cell surface inhibitory receptor and a key regulator of immune homeostasis with multiple biological activities related to T-cell functions. LAG-3 is considered a next-generation immune checkpoint of clinical importance, right next to programmed cell death protein 1 (PD-1) and cytotoxic T-cell lymphocyte antigen-4 (CTLA-4). Indeed, it is the third inhibitory receptor to be exploited in human anticancer immunotherapies. Several LAG-3-antagonistic immunotherapies are being evaluated at various stages of preclinical and clinical development. In addition, combination therapies blocking LAG-3 together with other immune checkpoints are also being evaluated at preclinical and clinical levels. Indeed, the co-blockade of LAG-3 with PD-1 is demonstrating encouraging results. A new generation of bispecific PD-1/LAG-3-blocking agents have also shown strong capacities to specifically target PD-1+ LAG-3+ highly dysfunctional T cells and enhance their proliferation and effector activities. Here we identify and classify preclinical and clinical trials conducted involving LAG-3 as a target through an extensive bibliographic research. The current understanding of LAG-3 clinical applications is summarized, and most of the publically available data up to date regarding LAG-3-targeted therapy preclinical and clinical research and development are reviewed and discussed.

Efficacy and safety of onabotulinumtoxin A injection in male patients with detrusor overactivity after stress urinary incontinence surgery.

INTRODUCTION AND OBJECTIVE: The use of onabotulinumtoxin A (BoNT-A) injection in male patients with detrusor overactivity (DO) after stress urinary incontinence (SUI) surgery has been scarcely described. Our aim was to assess results of this treatment in this specific population. MATERIALS AND METHODS: Retrospective analysis of men with previous SUI surgery who had been treated with a first injection of 100 U BoNT-A because of DO since 2010 in our department. Treatment response was assessed with the Treatment Benefit Scale: 1) greatly improved; 2) improved; 3) not changed; 4) worsened after treatment (Treatment Benefit Scale 1 or 2: treatment response). Complications were classified according to the Clavien-Dindo classification. Treatment continuation was considered present if, at the last visit, patients had received a BoNT-A injection within the preceding 12 months. Pre- and post-treatment urodynamic variables were compared. RESULTS: Eighteen patients were included, median age 71.1 (59.1-83.5) years. Twelve (66.7%) patients reported response to treatment. Two (11.1%) complications were detected: urinary retention requiring clean intermittent catheterization (Clavien-Dindo 2). No complications related to previous SUI surgery were detected. Fifteen (83.3%) patients had a follow-up >12 months (median follow-up 57 [15-89] months) and all of them had discontinued treatment at the end of follow-up. Urodynamic studies showed significant improvement in terms of DO and bladder compliance. CONCLUSION: Although most men with DO after SUI surgery respond to intradetrusor BoNT-A injection, all of them discontinue treatment due to personal reasons. It is a safe procedure, with urinary retention requiring clean intermittent catheterization being the most frequent complication.

Efficacy and safety of onabotulinumtoxin A injection in male patients with detrusor overactivity after stress urinary incontinence surgery. / Eficacia y seguridad de la inyección de onabotulinumtoxin A en pacientes varones con hiperactividad del detrusor tras la cirugía para incontinencia urinaria de esfuerzo.

INTRODUCTION AND OBJECTIVE: The use of onabotulinumtoxin A (BoNT-A) injection in male patients with detrusor overactivity (DO) after stress urinary incontinence (SUI) surgery has been scarcely described. Our aim was to assess results of this treatment in this specific population. MATERIALS AND METHODS: Retrospective analysis of men with previous SUI surgery who had been treated with a first injection of 100U BoNT-A because of DO since 2010 in our department. Treatment response was assessed with the Treatment Benefit Scale: 1) greatly improved; 2) improved; 3) not changed; 4) worsened after treatment (Treatment Benefit Scale 1 or 2: treatment response). Complications were classified according to the Clavien-Dindo classification. Treatment continuation was considered present if, at the last visit, patients had received a BoNT-A injection within the preceding 12 months. Pre- and post-treatment urodynamic variables were compared. RESULTS: Eighteen patients were included, median age 71.1 (59.1-83.5) years. Twelve (66.7%) patients reported response to treatment. Two (11.1%) complications were detected: urinary retention requiring clean intermittent catheterization (Clavien-Dindo 2). No complications related to previous SUI surgery were detected. Fifteen (83.3%) patients had a follow-up>12 months (median follow-up 57 [15-89] months) and all of them had discontinued treatment at the end of follow-up. Urodynamic studies showed significant improvement in terms of DO and bladder compliance. CONCLUSION: Although most men with DO after SUI surgery respond to intradetrusor BoNT-A injection, all of them discontinue treatment due to personal reasons. It is a safe procedure, with urinary retention requiring clean intermittent catheterization being the most frequent complication.

Úlcera duodenal benigna con penetración en cabeza de páncreas, con obstrucción de la vía biliar / Benign duodenal ulcer penetrating into pancreas, with obstruction of common bile duct

Resumen Objetivo: Reportamos un caso clínico con presentación atípica de una úlcera duodenal benigna que simula el cuadro clínico y radiológico de una neoplasia de páncreas. Materiales y Método: Presentamos el caso de un varón de 83 años que debuta con un cuadro clínico de astenia e ictericia mucocutánea. En estudio de imagen se identifica una masa en cabeza pancreática. En estudio endoscópico se observa úlcera duodenal benigna penetrada a cabeza de páncreas que condiciona obstrucción de vía biliar. Discusión y Conclusiones: El manejo de estos pacientes suele ser quirúrgico porque desarrollan un deterioro asociado a sepsis o perforación. Si la situación clínica lo permite se puede intentar un tratamiento conservador. En nuestro caso el paciente precisó un mes de hospitalización con antibioticoterapia intravenosa de amplio espectro, reposo alimentario, nutrición parenteral y tratamiento con inhibidores de la bomba de protones (IBP) para la resolución del cuadro. La penetración o fistulización a la cabeza del páncreas es una complicación grave e infrecuente de la enfermedad ulcerosa péptica. Su manejo puede ser conservador en casos seleccionados donde no exista perforación de la úlcera a la cavidad peritoneal, ni exista deterioro séptico ni hemodinámico.

Aim: To report an atypical presentation of a benign duodenal ulcer that simulates pancreatic neoplasia. Materials and Method: A case of a 83 years old male patient with astenia and jaundice due to a benign duodenal ulcer penetrating into the pancreas with obstruction of common bile duct. Imagining study identified a pancreatic head mass. The patient required one month admission, receiving broad-spectrum antibiotics, parenteral nutrition and intravenous proton pump inhibitors. Discussion and Conclusion: Due to frequent complications associated to this condition, such as haemodynamic failure, sepsis or free peritoneal perforation, surgery is the main treatment. However, in mild cases, as in our patient, conservative management can be considered. Penetration or fistulization to the head of the pancreas is a rare and serious complication of peptic ulcer disease. Its management can be conservative in selected cases where there is no perforation of the ulcer into the peritoneal cavity, nor septic or hemodynamic deterioration.

Does Rapid Drug Desensitization to Chemotherapy Affect Survival Outcomes?

BACKGROUND AND OBJECTIVE: Hypersensitivity reactions to oxaliplatin may affect prognosis by jeopardizing the timely completion of scheduled treatment sessions or by forcing reactive patients into unexpected changes in therapy. Rapid drug desensitization (RDD) enables these patients to receive their first-choice treatments safely. However, the possible effects of RDD on the efficacy of oxaliplatin have never been studied. Objective: The objective of this study was to evaluate the effect of RDD on survival rates in oxaliplatin-hypersensitive patients. METHODS: We performed a 7-year retrospective study to compare survival between oxaliplatin-hypersensitive cases (patients receiving oxaliplatin by RDD) and nonallergic controls (patients receiving standard oxaliplatin infusions). The primary endpoint of this study was overall survival (OS) in cases and controls (Kaplan-Meier method with log-rank test comparisons). RESULTS: OS was 23.7 months (95%CI, 15.3-30.9) for the 67 cases who underwent 337 RDDs, while for controls (n=143), OS was 34.5 months (95%CI, 21.7-55.5). There were no significant differences between the groups (HR, 1.42; 95%CI, 0.93-2.17; P =.104). CONCLUSIONS: Survival outcomes of oxaliplatin-hypersensitive patients who received oxaliplatin via RDD did not differ significantly from those of control patients who received oxaliplatin via standard administration. Receiving oxaliplatin by means of RDD might be an effective therapeutic alternative for oxaliplatin-hypersensitive patients.

Improvement in the identification and quantification of UV filters and additives in sunscreen cosmetic creams by gas chromatography/mass spectrometry through three-way calibration techniques.

The simultaneous determination of 2,6-di-tert-butyl-4-methyl-phenol (BHT), benzophenone (BP), benzophenone-3 (BP3) and diisobutyl phthalate (DiBP) in seven sunscreen creams was carried out by gas chromatography/mass spectrometry (GC/MS) using DiBP-d4 as internal standard. The content of BP3, which is a UV filter, must not exceed 6% (w/w) in cosmetic products according to Regulation (EU) 2017/238 and the use of DiBP in cosmetic products shall be prohibited according to Regulation (EC) No 1223/2009. The conclusions obtained with the univariate standard methodology in the identification of the analytes contained in the creams were wrong. However, a calibration based on PARAFAC or PARAFAC2 decompositions, where the samples of the prediction set were projected on the model obtained previously with the calibration set, enabled the unequivocal identification and quantification of the analytes even in the presence of interferents not considered in the calibration model. The PARAFAC2 decomposition was used to overcome the shifts in the retention time of BP and BP3. These three-way calibration techniques are needed to avoid false negative results. The method had not proportional or constant bias. The presence of BHT was detected in the seven sunscreen creams analysed at an amount of 6.48 10-2%, 8.53 10-2%, 1.70 10-4%, 1.11 10-4%, 2.51 10-3%, 3.20 10-5% and 6.35 10-3%. The concentrations of DiBP found in four creams were 3.49 10-2%, 3.19 10-2%, 3.26 10-2% and 2.51 10-2%. On the other hand, BP was only detected in two of the cosmetic creams analysed at an amount of 7.84 10-3% and 1.04 10-2%. In addition, BP3 was detected in six of the creams at an amount of 4.73%, 3.49%, 4.94 10-3%, 1.98 10-3%, 6.62 10-1% and 1.73%. Therefore, none of the cosmetic creams contained BP3 in an amount higher than 6%.

The behaviour of Tenax as food simulant in the migration of polymer additives from food contact materials by means of gas chromatography/mass spectrometry and PARAFAC.

The migration of benzophenone (BP), an antioxidant (2,6-di-tert-butyl-4-methyl-phenol (BHT)) and three plasticizers (diisobutyl phthalate (DiBP), bis(2-ethylhexyl) adipate (DEHA) and diisononyl phthalate (DiNP)) from different food contact materials into Tenax as food simulant was studied. The packaging materials analysed were: polyethylene (PE) and polyvinyl chloride (PVC) cling-films, paper bread bag, brown paper popcorn bag intended to be heated in a microwave oven and polypropylene (PP) coffee capsules. The analysis was carried out using PARAFAC and PARAFAC2 decompositions and gas chromatography/mass spectrometry (GC/MS), being DiBP-d4 the internal standard. Tenax has been used as food simulant for specific migration of dry foodstuffs according to Commission Regulation (EU) 10/2011. PARAFAC and PARAFAC2 decompositions enabled the unequivocal identification and quantification of all the analytes despite some of the m/z ratios of the coeluting interferents were shared with the analytes. Otherwise, the presence of the analytes could not have been ensured according to the EU legislation in force. BHT, DiBP and DEHA were contained in the Tenax blanks in some of the analyses. The amount of BP and DiBP migrated from the PVC film was 83.53 µg L-1 and 31.30 µg L-1, respectively; whereas 71.62 µg L-1 of BP and 27.45 µg L-1 of DiBP migrated from the PP coffee capsules. None of the analytes were detected above the capability of detection in the non-spiked migration samples of the rest of the food contact materials analysed. The efficiency of Tenax as an adequate food simulant has also been studied through the values of its adsorption capability which were different depending on the analytes and the materials. In the spiked migration samples, these values ranged from 25.33% to 99.37%.

Effect of the cleaning procedure of Tenax on its reuse in the determination of plasticizers after migration by gas chromatography/mass spectrometry.

This paper presents the simultaneous determination of a UV stabilizer (benzophenone (BP)) together with four plasticizers (butylated hydroxytoluene (BHT), diisobutyl phthalate (DiBP), bis(2-ethylhexyl) adipate (DEHA) and diisononyl phthalate (DiNP)) in Tenax by gas chromatography/mass spectrometry and PARAFAC, using DiBP-d4 as internal standard. Regulation (EU) No. 10/2011 establishes Tenax as food simulant E for testing specific migration from plastics into dry foodstuffs. This simulant must be cleaned before its use to eliminate impurities. Tenax is expensive, so its reuse would save costs. A two-way ANOVA was used to study some parameters affecting the cleaning and the extraction of Tenax. The most adequate conditions were chosen taking the values of the coefficient of variation and the average recovery rates of spiked Tenax samples into account. A study to determine if some analytes remain in Tenax when it is reused and the effect that the cleaning procedure may have in the adsorption capability of Tenax was proposed. This study led to the conclusion that Tenax could not be reused in this multiresidue determination. All the analytes were unequivocally identified in all the stages of this work and trueness was verified at a 95% confidence level in all cases. A calibration based on PARAFAC provided the following values of capability of detection (CCß): 2.28 µg L-1 for BHT, 10.57 µg L-1 for BP, 7.87 µg L-1 for DiBP, 3.04 µg L-1 for DEHA and 124.8 µg L-1 for DiNP, with the probabilities of false positive and false negative fixed at 0.05. The migration of the analytes from a printed paper sample into Tenax was also studied. The presence of BHT in the food simulant was confirmed and the amount released of this analyte from the paper was 2.56 µg L-1.

PCA3 as a second-line biomarker in a prospective controlled randomized opportunistic prostate cancer screening programme. / PCA3 como biomarcador de segunda línea en un programa de screening oportunista prospectivo, aleatorizado y controlado.

OBJECTIVES: PCA3 performance as a single second line biomarker is compared to the European Randomised Study of Screening for Prostate Cancer risk calculator model 3 (ERSPC RC-3) in an opportunistic screening in prostate cancer (PCa). MATERIAL AND METHODS: 5,199 men, aged 40-75y, underwent prostate-specific antigen (PSA) screening and digital rectal examination (DRE). Men with a normal DRE and PSA ≥3ng/ml had a PCA3 test done. All men with PCA3 ≥35 underwent an initial biopsy (IBx) -12 cores-. Men with PCA3 <35 were randomized 1:1 to either IBx or observation. We compared them to those obtained with ERSPC RC-3. RESULTS: PCA3 test was performed on 838 men (16.1%). In PCA3(+) and PCA3(-) groups, global PCa detection rates were 40.9% and 14.7% with a median follow-up (FU) of 21.7 months (P<.001). In the PCA3(+) arm (n=301, 35.9%), PCa was identified in 115 men at IBx (38.2%). In the randomized arm, 256 underwent IBx and PCa was found in 46 (18.0%) (P<.001). The biopsy-sparing potential would have been 64.1% as opposed to 76.6% if we had used ERSPC RC-3. However, the estimated false negative cases for HGPCa would have been reduced by 37.1% (89 to 56 patients). Moreover, if we had applied PCA3-35 to avoid IBx, 14.7% PCa and 9.1% of clinical significant PCa patients would not have been diagnosed during this FU. CONCLUSIONS: When PCA3-35 is used as a second-line biomarker when PSA ≥3ng/ml and DRE is normal, IBx could be avoided in 12.5% less than if ERSPC RC-3 is used and would reduce the false negative cases by 36.2%. At a FU of 21.7 months, this dual protocol would miss 9.1% of clinically significant PCa, so strict FU is mandatory with established biopsy criteria based on PSA and DRE in cases with PCA3 <35.

Dealing with the ubiquity of phthalates in the laboratory when determining plasticizers by gas chromatography/mass spectrometry and PARAFAC.

Determining plasticizers and other additives migrated from plastic materials becomes a hard task when these substances are already present in the laboratory environment. This work dealt with this drawback in the multiresidue determination of four plasticizers (2,6-di-tert-butyl-4-methyl-phenol (BHT), diisobutyl phthalate (DiBP), bis(2-ethylhexyl) adipate (DEHA) and diisononyl phthalate (DiNP)) and a UV stabilizer (benzophenone (BP)) by gas chromatography/mass spectrometry (GC/MS) using DiBP-d4 as internal standard. The ubiquity of DiBP by a non-constant leaching process in the laboratory was detected, which could not guarantee the achievement of a trustworthy quantification. To handle this, the assessment of the level of DiBP in solvent blanks having fixed the probabilities of false non-compliance (α) and false compliance (ß) at 0.01 was performed. On the other hand, another special case was that of DiNP, in whose chromatogram finger peaks appear because of an array of possible C9 isomers. PARAFAC, used for the identification and quantification of all the substances, is a useful chemometric tool that enabled a more reliable determination of this analyte since no peak areas were considered but chromatographic and spectral loadings. Since phthalates may migrate from rubber latex items, an evaluation of the existence of matrix effects on the determination of the five analytes was conducted prior to an extraction with hexane from a dummy for infants. As matrix effects were present, the quantification of the compounds under study was performed following the standard addition method using PARAFAC sample loadings as response variable. As a result, the presence of BHT was confirmed, being its concentration equal to 37.87µgL(-1). Calibrations based on PARAFAC yielded the following values for the decision limit (CCα): 1.16µgL(-1) for BHT, 1.34µgL(-1) for BP, 1.84µgL(-1) for DEHA and 51.42µgL(-1) for DiNP(for α=0.05 and two replicates).

[Update on the diagnosis of PCa in urine. The current role of urine markers]. / Actualización en el diagnóstico del CaP en orina. Papel actual de los marcadores urinarios.

Prostate cancer (PCa) is still a main health issue, in fact it is responsible for 10% of cancer deaths across Europe. The morphology of the prostate gland makes urine an ideal sample, non invasive, for determination both diagnostic and prognostic biomarkers. We use urinary PCA3 levels to indicate a prostate biopsy, and it is the only urinary biomarkers in PCa with FDA approval for clinical use. Many other biomarkers based on the expression of specific genes of PCa are being studied and validated, for instance the fusion gene TMPRSS2-ERG with a commercial kit available, while another approach is to test the expression of a panel of genes. An emerging focus of research, which deserves attention, is miRNAs. Other newer approaches such as epigenetics, proteomics and metabolomics also would be very useful in the future for the development and validation of new biomarkers. In this paper we review the state of the art in the field of urinary biomarkers in PCa.

Standard addition method based on four-way PARAFAC decomposition to solve the matrix interferences in the determination of carbamate pesticides in lettuce using excitation-emission fluorescence data.

The simultaneous determination of two carbamate pesticides (carbaryl and carbendazim) and of the degradation product of carbaryl (1-naphthol) in iceberg lettuce was achieved by means of PARAFAC decomposition and excitation-emission fluorescence matrices. A standard addition method for a calibration based on four-way data was applied using different dilutions of the extract from iceberg lettuce as a fourth way that provided the enough variation of the matrix to carry out the four-way analysis. A high fluorescent overlapping existed between the three analytes and the fluorophores of the matrix. The identification of two fluorescent matrix constituents through the four-way model enabled to know the matrix contribution in each dilution of the extract. This contribution was subtracted from the previous signals and a subsequent three-way analysis was carried out with the tensors corresponding to each dilution. The PARAFAC decomposition of these resulting tensors showed a CORCONDIA index equal to 99%. For the identification of the analytes, the correlation between the PARAFAC spectral loadings and the reference spectra has been used. The trueness of the method, in the concentration range studied, was guaranteed because there was neither constant nor proportional bias according to the appropriate hypothesis tests. The best recovery percentages were obtained with the data from the most diluted extract, being the results: 127.6% for carbaryl, 125.55% for carbendazim and 87.6% for 1-naphthol. When the solvent calibration was performed, the decision limit (CCα) and the capability of detection (CCß) values, in x0=0, were 2.21 and 4.38 µg L(-1) for carbaryl, 4.87 and 9.64 µg L(-1) for carbendazim; and 3.22 and 6.38 µg L(-1) for 1-naphthol, respectively, for probabilities of false positive and false negative fixed at 0.05. However, these values were 5.30 and 10.49 µg L(-1) for carbaryl, 18.05 and 35.73 µg L(-1) for carbendazim; and 1.92 and 3.79 µg L(-1) for 1-naphthol, respectively, when the matrix-matched calibration using the most diluted extract was carried out in the recovery study.

External validation of FXYD3 and KRT20 as predictive biomarkers for the presence of micrometastasis in muscle invasive bladder cancer lymph nodes.

INTRODUCTION: Recent studies have proposed that FXYD3 and KRT20 mRNA quantified by quantitative reverse transcription polymerase chain reaction (qRT-PCR) in paraffin could be biomarkers to detect lymph nodes with micrometastases that avoid detection by conventional analysis with hematoxylin-eosin (HE). A validation study was conducted on the lymph nodes of patients who underwent radical cystectomy. OBJECTIVE: To classify the adenopathic state of a sample of patients who underwent cystectomy, based on the lymph node expression of FXYD3 and KRT20. The secondary objective was to assess whether there is a differential oncologic evolution for the patients, depending on the lymph node expression of these proteins. MATERIAL AND METHOD: The study included lymph nodes from 64 patients who underwent cystectomy for infiltrating bladder tumor: The model was developed using metastatic lymph nodes from 15 patients and lymph nodes from 4 patients with no known tumor. Genetic expression was measured using real-time qRT-PCR. We calculated (using qRT-PCR) the median expression of FXYD3 and KRT20 mRNA in the lymph node tissue. We then analyzed the receiver operating characteristic (ROC) curves, according to the function y=0.1400+0.250FXYD3-2.532. The cutoff was established using an ROC curve. The formula was applied to the remaining lymph node tissue, based on the previously established cutoff. The sample was classified into 4 subgroups: HE- qRT-PCR-, HE- qRT-PCR+, HE+ qRT-PCR+ y HE+, qRT-PCR-. A descriptive, comparative analysis was performed, as well as a metastatic progression-free survival analysis, calculating the Kaplan and Meyer curves for the 3 established subgroups. The test results were considered statistically significant at P<.05. RESULTS: Using qRT-PCR, we verified that there were differences in the median expression of FXYD3 (P=.05) and KRT20 (P=.009) between the lymph node tissues of patients with benign prostate hyperplasia and those of patients with lymph node metastasis. A cutoff was assigned to 0.377. The sample was classified as follows: 37.5% of the patients were pN0 by HE and pN0 by qRT-PCR (-HE -qRT-PCR), 39.1% were pN0 by HE but metastatic by qRT-PCR (-HE +qRT-PCR), and 15 patients (23.4%) were metastatic by both techniques (+HE +qRT-PCR). The Kaplan and Meyer curves showed poorer metastatic progression-free survival for the patients who were +HE and +qRT-PCR than for the other subgroups, with no significant differences between -HE +qRT-PCR and -HE -qRT-PCR. CONCLUSIONS: According to our results, 39.1% of the patients with infiltrating vesical tumors overexpressed the FXYD3 and KRT20 biomarkers and were N0 by HE. We observed no differential clinical behavior among the patients who underwent cystectomy according to their expression of FXYD3 and KRT20 when they were N0 by HE.

Advanced hair damage model from ultra-violet radiation in the presence of copper.

OBJECTIVE: Damage to hair from UV exposure has been well reported in the literature and is known to be a highly complex process involving initiation via absorption of UV light followed by formation and propagation of reactive oxygen species (ROS). The objective of this work was to understand these mechanisms, explain the role of copper in accelerating the formation of ROS and identify strategies to reduce the hair damage caused by these reactive species. METHODS: The location of copper in hair was measured by Transmission electron microscopy-(TEM) X-ray energy dispersive spectroscopy (XEDS) and levels measured by ICP-OES. Protein changes were measured as total protein loss via the Lowry assay, and MALDI ToF was used to identify the biomarker protein fragments. TBARS assay was used to measure lipid peroxide formation. Sensory methods and dry combing friction were used to measure hair damage due to copper and UV exposure and to demonstrate the efficacy of N,N' ethylenediamine disuccinic acid (EDDS) and histidine chelants to reduce this damage. RESULTS: In this work, a biomarker protein fragment formed during UV exposure is identified using mass spectrometry. This fragment originates from the calcium-binding protein S100A3. Also shown is the accelerated formation of this peptide fragment in hair containing low levels of copper absorbed from hair during washing with tap water containing copper ions. Transmission electron microscopy (TEM) X-ray energy dispersive spectroscopy (XEDS) studies indicate copper is located in the sulphur-poor endo-cuticle region, a region where the S100A3 protein is concentrated. A mechanism for formation of this peptide fragment is proposed in addition to the possible role of lipids in UV oxidation. A shampoo and conditioner containing chelants (EDDS in shampoo and histidine in conditioner) is shown to reduce copper uptake from tap water and reduce protein loss and formation of S100A3 protein fragment. In addition, the long-term consequences of UV oxidation and additional damage induced by copper are illustrated in a four-month wear study where hair was treated with a consumer relevant protocol of hair colouring treatments, UV exposure and regular shampoo and conditioning. CONCLUSIONS: The role of copper in accelerating UV damage to hair has been demonstrated as well as the ability of chelants such as EDDS and histidine in shampoo and conditioner products to reduce this damage.

Identification and quantification of carbamate pesticides in dried lime tree flowers by means of excitation-emission molecular fluorescence and parallel factor analysis when quenching effect exists.

A non-separative, fast and inexpensive spectrofluorimetric method based on the second order calibration of excitation-emission fluorescence matrices (EEMs) was proposed for the determination of carbaryl, carbendazim and 1-naphthol in dried lime tree flowers. The trilinearity property of three-way data was used to handle the intrinsic fluorescence of lime flowers and the difference in the fluorescence intensity of each analyte. It also made possible to identify unequivocally each analyte. Trilinearity of the data tensor guarantees the uniqueness of the solution obtained through parallel factor analysis (PARAFAC), so the factors of the decomposition match up with the analytes. In addition, an experimental procedure was proposed to identify, with three-way data, the quenching effect produced by the fluorophores of the lime flowers. This procedure also enabled the selection of the adequate dilution of the lime flowers extract to minimize the quenching effect so the three analytes can be quantified. Finally, the analytes were determined using the standard addition method for a calibration whose standards were chosen with a D-optimal design. The three analytes were unequivocally identified by the correlation between the pure spectra and the PARAFAC excitation and emission spectral loadings. The trueness was established by the accuracy line "calculated concentration versus added concentration" in all cases. Better decision limit values (CCα), in x0=0 with the probability of false positive fixed at 0.05, were obtained for the calibration performed in pure solvent: 2.97 µg L(-1) for 1-naphthol, 3.74 µg L(-1) for carbaryl and 23.25 µg L(-1) for carbendazim. The CCα values for the second calibration carried out in matrix were 1.61, 4.34 and 51.75 µg L(-1) respectively; while the values obtained considering only the pure samples as calibration set were: 2.65, 8.61 and 28.7 µg L(-1), respectively.

Optimizing prostate cancer screening; prospective randomized controlled study of the role of PSA and PCA3 testing in a sequential manner in an opportunistic screening program.

OBJECTIVES: To reduce unnecessary biopsies (Bx) in an opportunistic screening programme of prostate cancer. MATERIAL AND METHODS: We perform a prospective evaluation of PCA3 as a second line biomarker in an opportunistic screening for prostate cancer (PCa). From September-2010 until September-2012, 2,366 men, aged 40-74 years and with >10 years life expectancy, were initially screened with PSA/digital rectal examination (DRE). Men with previous Bx or with recent urine infections were excluded. Men with abnormal DRE and/or PSA >3 ng/ml were submitted for PCA3. All men with PCA3 ≥ 35 underwent an initial biopsy (IBx) -12cores-. Men with PCA3 < 35 were randomized 1:1 to either IBx or observation. Re-biopsy(16-18 cores) criteria were PSA increase >.5 ng/ml at 4-6 months or PSAv > .75 ng/ml/year. RESULTS: With median follow-up (FU) of 10.1 months, PCA3 was performed in 321/2366 men (13.57%), 289 at first visit and 32 during FU. All 110 PCA3+ men (34.3%) were biopsied and PCa was identified in 43 men in IBx (39.1%). In the randomized arm, 110 were observed and 101 underwent biopsy, finding 12 PCa (11.9%), showing a statistically significant reduction of PCa detection rate in this cohort (P<.001). Global PCa detection rates were 40.9% and 9.5% for the PCA3+ and PCA3- branches, respectively (P<.001). Area under the curve for PSA and PCA3 were .601 and .74, respectively. This is an ongoing prospective study limited by its short follow-up period and still limited enrolment. CONCLUSIONS: PCA3 as a second line biomarker within an opportunistic dual screening protocol, can potentially avoid 65.7% and 50.1% biopsies at first round and at median FU of 10.1 months, respectively, just missing around 3.2% of high grade PCa.

Causalidad, derechos humanos y justicia social en la Comisión de Determinantes Sociales en Salud / Causation, human rights and cocial justice in the Commission of Social Determinants of Health

Se presenta la reseña crítica del artículo de Venkatapuram, Bell y Marmot, titulado: ''El derecho a las suturas: epidemiología social, derechos humanos y justicia social'', el cual presenta los planteamientos de la Comisión de Determinantes Sociales de la Salud-CDSS, acerca de las relaciones causales entre las condiciones de vida y los resultados en salud, apelando a la justicia social y a la consideración de tales determinantes como parte de los derechos humanos. Se aportan elementos para su análisis crítico respecto de la apuesta por la causalidad y acerca de su concepción sobre justicia social y los determinantes de la enfermedad como violación a los derechos humanos. Se señalan puntos para el debate y se concluye con una invitación a tomar parte en el mismo.

It presents a critical review of the article Venkatapuram, Bell and Marmot, entitled: ''The right to sutures: social epidemiology, human rights and social justice,'' which presents the proposals of the Commission on Social Determinants of Health-CDSS, about causal relationships between living conditions and health outcomes, appealing to social justice and consideration of such determinants as part of human rights. Provides elements for critical analysis of causality and committed about their conception of social justice and determinants of disease as a human rights violation. Points are identified for discussion and concludes with an invitation to take part in it.