NCAPH drives breast cancer progression and identifies a gene signature that predicts luminal a tumour recurrence.

BACKGROUND: Luminal A tumours generally have a favourable prognosis but possess the highest 10-year recurrence risk among breast cancers. Additionally, a quarter of the recurrence cases occur within 5 years post-diagnosis. Identifying such patients is crucial as long-term relapsers could benefit from extended hormone therapy, while early relapsers might require more aggressive treatment. METHODS: We conducted a study to explore non-structural chromosome maintenance condensin I complex subunit H's (NCAPH) role in luminal A breast cancer pathogenesis, both in vitro and in vivo, aiming to identify an intratumoural gene expression signature, with a focus on elevated NCAPH levels, as a potential marker for unfavourable progression. Our analysis included transgenic mouse models overexpressing NCAPH and a genetically diverse mouse cohort generated by backcrossing. A least absolute shrinkage and selection operator (LASSO) multivariate regression analysis was performed on transcripts associated with elevated intratumoural NCAPH levels. RESULTS: We found that NCAPH contributes to adverse luminal A breast cancer progression. The intratumoural gene expression signature associated with elevated NCAPH levels emerged as a potential risk identifier. Transgenic mice overexpressing NCAPH developed breast tumours with extended latency, and in Mouse Mammary Tumor Virus (MMTV)-NCAPHErbB2 double-transgenic mice, luminal tumours showed increased aggressiveness. High intratumoural Ncaph levels correlated with worse breast cancer outcome and subpar chemotherapy response. A 10-gene risk score, termed Gene Signature for Luminal A 10 (GSLA10), was derived from the LASSO analysis, correlating with adverse luminal A breast cancer progression. CONCLUSIONS: The GSLA10 signature outperformed the Oncotype DX signature in discerning tumours with unfavourable outcomes, previously categorised as luminal A by Prediction Analysis of Microarray 50 (PAM50) across three independent human cohorts. This new signature holds promise for identifying luminal A tumour patients with adverse prognosis, aiding in the development of personalised treatment strategies to significantly improve patient outcomes.

NCAPH Drives Breast Cancer Progression and Identifies a Gene Signature that Predicts Luminal A Tumor Recurrence.

Despite their generally favorable prognosis, luminal A tumors paradoxically pose the highest ten-year recurrence risk among breast cancers. From those that relapse, a quarter of them do it within five years after diagnosis. Identifying such patients is crucial, as long-term relapsers could benefit from extended hormone therapy, whereas early relapsers may require aggressive treatment. In this study, we demonstrate that NCAPH plays a role in the pathogenesis of luminal A breast cancer, contributing to its adverse progression in vitro and in vivo. Furthermore, we reveal that a signature of intratumoral gene expression, associated with elevated levels of NCAPH, serves as a potential marker to identify patients facing unfavorable progression of luminal A breast cancer. Indeed, transgenic mice overexpressing NCAPH generated breast tumors with long latency, and in MMTV-NCAPH/ErbB2+ double-transgenic mice, the luminal tumors formed were more aggressive. In addition, high intratumoral levels of Ncaph were associated with worse breast cancer evolution and poor response to chemotherapy in a cohort of genetically heterogeneous transgenic mice generated by backcrossing. In this cohort of mice, we identified a series of transcripts associated with elevated intratumoral levels of NCAPH, which were linked to adverse progression of breast cancer in both mice and humans. Utilizing the Least Absolute Shrinkage and Selection Operator (LASSO) multivariate regression analysis on this series of transcripts, we derived a ten-gene risk score. This score is defined by a gene signature (termed Gene Signature for Luminal A 10 or GSLA10) that correlates with unfavorable progression of luminal A breast cancer. The GSLA10 signature surpassed the Oncotype DX signature in discerning tumors with unfavorable outcomes (previously categorized as Luminal A by PAM50) across three independent human cohorts. This GSLA10 signature aids in identifying patients with Luminal A tumors displaying adverse prognosis, who could potentially benefit from personalized treatment strategies.

Intermediate Molecular Phenotypes to Identify Genetic Markers of Anthracycline-Induced Cardiotoxicity Risk.

Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex trait with a polygenic component that is mainly unidentified. We propose that levels of intermediate molecular phenotypes (IMPs) in the myocardium associated with histopathological damage could explain CDA susceptibility, so variants of genes encoding these IMPs could identify patients susceptible to this complication. Thus, a genetically heterogeneous cohort of mice (n = 165) generated by backcrossing were treated with doxorubicin and docetaxel. We quantified heart fibrosis using an Ariol slide scanner and intramyocardial levels of IMPs using multiplex bead arrays and QPCR. We identified quantitative trait loci linked to IMPs (ipQTLs) and cdaQTLs via linkage analysis. In three cancer patient cohorts, CDA was quantified using echocardiography or Cardiac Magnetic Resonance. CDA behaves as a complex trait in the mouse cohort. IMP levels in the myocardium were associated with CDA. ipQTLs integrated into genetic models with cdaQTLs account for more CDA phenotypic variation than that explained by cda-QTLs alone. Allelic forms of genes encoding IMPs associated with CDA in mice, including AKT1, MAPK14, MAPK8, STAT3, CAS3, and TP53, are genetic determinants of CDA in patients. Two genetic risk scores for pediatric patients (n = 71) and women with breast cancer (n = 420) were generated using machine-learning Least Absolute Shrinkage and Selection Operator (LASSO) regression. Thus, IMPs associated with heart damage identify genetic markers of CDA risk, thereby allowing more personalized patient management.

Intermediate molecular phenotypes to identify genetic markers of anthracycline-induced cardiotoxicity risk.

Cardiotoxicity due to anthracyclines (CDA) affects cancer patients, but we cannot predict who may suffer from this complication. CDA is a complex disease whose polygenic component is mainly unidentified. We propose that levels of intermediate molecular phenotypes in the myocardium associated with histopathological damage could explain CDA susceptibility; so that variants of genes encoding these intermediate molecular phenotypes could identify patients susceptible to this complication. A genetically heterogeneous cohort of mice generated by backcrossing (N = 165) was treated with doxorubicin and docetaxel. Cardiac histopathological damage was measured by fibrosis and cardiomyocyte size by an Ariol slide scanner. We determine intramyocardial levels of intermediate molecular phenotypes of CDA associated with histopathological damage and quantitative trait loci (ipQTLs) linked to them. These ipQTLs seem to contribute to the missing heritability of CDA because they improve the heritability explained by QTL directly linked to CDA (cda-QTLs) through genetic models. Genes encoding these molecular subphenotypes were evaluated as genetic markers of CDA in three cancer patient cohorts (N = 517) whose cardiac damage was quantified by echocardiography or Cardiac Magnetic Resonance. Many SNPs associated with CDA were found using genetic models. LASSO multivariate regression identified two risk score models, one for pediatric cancer patients and the other for women with breast cancer. Molecular intermediate phenotypes associated with heart damage can identify genetic markers of CDA risk, thereby allowing a more personalized patient management. A similar strategy could be applied to identify genetic markers of other complex trait diseases.

Influences of umbilical cord mesenchymal stem cells and their exosomes on tumor cell phenotypes.

Mesenchymal stem cells (MSCs), extensively utilized in contemporary stem cell research, hold significant potential in the treatment of neoplastic diseases. This study aims to investigate the influences of umbilical cord mesenchymal stem cells (UMSCs) and their exosomes (UMSCs-exos) on tumor cell phenotypes. UMSCs and UMSCs-exos, isolated from human umbilical cord tissue, were validated for isolation efficiency and differentiation capacity using flow cytometry, electron microscopy, and cell staining. MDA-MB-231, BGC-823, A549, and LN-229, which are human breast (BC), gastric (GC), lung carcinoma (LC) cells and glioma cells, respectively, were treated with UMSCs and UMSCs-exos. Cell counting kit-8 (CCK-8), cell scratch-wound, and Transwell assays were performed on treated cultures to observe the phenotypic changes induced by UMSCs- and UMSCs-exos-treated cancer cells. The results demonstrated that UMSCs highly express PE-labeled positive surface antigens and exhibit low expression of FITC-labeled negative surface antigens, alongside possessing osteogenic and adipogenic differentiation potentials. Electron microscopy revealed UMSCs-exos to be approximately 30-150 nm in diameter, averaging 126.62±1.64 nm, and displaying increased Tsg101, CD9, and CD63 protein expression. Moreover, MDA-MB-231 and BGC-823 cells exhibited enhanced proliferation, invasion, and migration upon UMSCs and UMSCs-exos treatment. In contrast, A549 cells showed minimal alteration to invasiveness but a marked increase in proliferation and migration capabilities, while LN-229 cells displayed a phenotype indicative of suppressed activity. In conclusion, UMSCs and UMSCs-exos effectively promote the growth of BC and LC cells and inhibit the activity of GC and glioma cells, presenting promising avenues for future neoplastic disease treatments.

Transient Inhibition of the JAK/STAT Pathway Prevents B-ALL Development in Genetically Predisposed Mice.

Preventing development of childhood B-cell acute lymphoblastic leukemia (B-ALL), a disease with devastating effects, is a longstanding and unsolved challenge. Heterozygous germline alterations in the PAX5 gene can lead to B-ALL upon accumulation of secondary mutations affecting the JAK/STAT signaling pathway. Preclinical studies have shown that this malignant transformation occurs only under immune stress such as exposure to infectious pathogens. Here we show in Pax5+/- mice that transient, early-life administration of clinically relevant doses of ruxolitinib, a JAK1/2 inhibitor, significantly mitigates the risk of B-ALL following exposure to infection; 1 of 29 animals treated with ruxolitinib developed B-ALL versus 8 of 34 untreated mice. Ruxolitinib treatment preferentially targeted Pax5+/- versus wild-type B-cell progenitors and exerted unique effects on the Pax5+/- B-cell progenitor transcriptional program. These findings provide the first in vivo evidence for a potential strategy to prevent B-ALL development. SIGNIFICANCE: JAK/STAT inhibition suppresses tumorigenesis in a B-ALL-susceptible mouse model, presenting a novel approach to prevent B-ALL onset.

Sublingual MV140 for Prevention of Recurrent Urinary Tract Infections.

Sublingual MV140 for Prevention of Recurrent UTIThis randomized placebo-controlled trial tested MV140, a sublingual preparation of whole-cell inactivated bacteria, in women with recurrent urinary tract infection (UTI). MV140 administered sublingually for either 3 or 6 months decreased UTI incidence and prevented recurrence for up to 1 year compared with placebo, without serious adverse events.

Impact of whole-cell bacterial immunoprophylaxis in the management of recurrent urinary tract infections in the frail elderly.

PURPOSE: This study aimed to determine the effectiveness of whole-cell bacterial immunotherapy, i.e. MV140 and autovaccines, in reducing the number ofurinary tract infections (UTIs)in frail elderly patients with recurrent UTI (RUTI). METHOD: A prospective cohort observational study was performed including 200 frail elderly subjects suffering RUTI, both females and males, between 2016 and 2018. The effectiveness of autovaccines and the polybacterial formulation MV140 (Uromune®), consisting ofwhole-cell heat-inactivated Escherichia coli25%, Klebsiella pneumoniae25%, Proteus vulgaris25% andEnterococcus faecalis25% were evaluated. Subjects initiated a 3-month sublingually daily course with MV140 or autovaccine, either first treatment or a new course if they had been previously vaccinated prior to inclusion in the study. Number of UTIs and quality of life (QoL, SF-36 score) were measured in the different study groups. RESULTS: The mean age for participants was 82.67 (SD, 7.12) for female and 80.23 (SD, 11.12) for male subjects. In all groups, 12 months following bacterial immunotherapy, the number of UTIs significantly decreased compared to before the treatment with autovaccine or MV140: the rate of reduction ranged between 7- and 40-fold. An increase in QoL scoring was also observed in any study group. When comparing medical interventions, MV140 conferred significantly higher benefit than autovaccines. For previously vaccinated individuals, a new 3-month course with MV140 or autovaccines provided further clinical improvement. CONCLUSIONS: MV140 and autovaccines emerge as valuable immunoprophylaxis for the management of RUTI in the frail elderly, contributing to an improvement in patient's quality of life. Herein, MV140 has shown to confer a higher effectiveness compared to autovaccines, regardless sex or course of treatment.

Relationship between obstetric history and recurrent urinary infections.

Urinary tract infections affect more than 50% of women. 25% derive from recurrent UTI (RUTI). It is not known the relationship between obstetric history and RUTI occurrence. Investigate the relationship between obstetric events and RUTI. Multicenter observational retrospective study. Groups: G.RUTI (n = 294): women with RUTI; G.NON.RUTI (n = 126): women without RUTI (treated and cured of renal cancer). Descriptive statistics, ANOVA analysis of variance (with Scheffe's test for normal samples and Kruskal-Wallis for other distributions), Fisher's exact test, Pearson and Spearman correlation studies, and multivariate analysis multiple regression were used. Mean age 61.04 years (19-92), G.RUTI: 56.77 years SD 4.46 (19-85). G.NON.RUTI: 71 years SD 6.73 (25-92) (p = 0.0001). Obstetric history: Nulliparous G.RUTI: 20 (3.4%) G.NON.RUTI: 90 (71.42%) p 0.0001; Eutocic G.RUTI: 416 (70.74%) G.NON.RUTI: 30 (23.8%) p 0.0001. Dystocic G.RUTI: 58 (9.86%) G.NON.RUTI: 56 (44.44%) p 0.0001. G.RUTI abortion: 102 (17.34%) G.NON.RUTI: 30 (23.8%) p 0.1381. Hysterectomy without adnexectomy G.RUTI: 100 (17%) G.NON.RUTI: 18 (14.28%) p 0.5640. Hysterectomy with adnexectomy G.RUTI: 100 (17%) G.NON.RUTI: 66 (52.28%) p 0.0001. Nulliparity, dystocic delivery, and hysterectomy with adnexectomy are more frequent in women without RUTI, while eutocic births are more associated with RUTI. The most prevalent gynaecological-obstetric history in women with RUTI is eutocic delivery associated with a good health state.

The Second Oncogenic Hit Determines the Cell Fate of ETV6-RUNX1 Positive Leukemia.

ETV6-RUNX1 is almost exclusively associated with childhood B-cell acute lymphoblastic leukemia (B-ALL), but the consequences of ETV6-RUNX1 expression on cell lineage decisions during B-cell leukemogenesis are completely unknown. Clinically silent ETV6-RUNX1 preleukemic clones are frequently found in neonatal cord blood, but few carriers develop B-ALL as a result of secondary genetic alterations. The understanding of the mechanisms underlying the first transforming steps could greatly advance the development of non-toxic prophylactic interventions. Using genetic lineage tracing, we examined the capacity of ETV6-RUNX1 to instruct a malignant phenotype in the hematopoietic lineage by cell-specific Cre-mediated activation of ETV6-RUNX1 from the endogenous Etv6 gene locus. Here we show that, while ETV6-RUNX1 has the propensity to trigger both T- and B-lymphoid malignancies, it is the second hit that determines tumor cell identity. To instigate leukemia, both oncogenic hits must place early in the development of hematopoietic/precursor cells, not in already committed B-cells. Depending on the nature of the second hit, the resulting B-ALLs presented distinct entities that were clearly separable based on their gene expression profiles. Our findings give a novel mechanistic insight into the early steps of ETV6-RUNX1+ B-ALL development and might have major implications for the potential development of ETV6-RUNX1+ B-ALL prevention strategies.

Increased urinary markers of kidney damage in the institutionalized frail elderly due to recurrent urinary tract infections.

OBJECTIVE: To characterize the impact on kidney injury of recurrent urinary tract infections (RUTI) in the frail elderly. METHODS: Prospective observational study in 200 frail elderly subjects for 1 year. Groups: GA (n = 100): subjects without RUTI, GB (n = 100): subjects with RUTI. Variables: age, concomitant diseases, glomerular filtration rate (GFR), urine neutrophil gelatinase-associated lipocalin (NGAL) at the beginning (NGAL-1) and end (NGAL-2) of the study, urine N-acetyl glucosaminidase (NAG) at the beginning (NAG-1) and the end (NAG-2) of the study, urine transforming growth factor-beta 1 (TGFß-1). Descriptive statistics, Mann-Whitney test, Chi-squared test, Fisher's exact test, and multivariate analysis were used. RESULTS: Mean age was 84.33 (65-99) years old, with no difference between GA and GB. Mean NGAL-1 was 1.29 ng/ml (0.04-8). There was lower in GA than in GB. Mean NGAL-2 was 1.41 ng/ml (0.02-9.22). NGAL-2 was lower in GA than in GB. Mean NAG-1 was 0.38 UU.II/ml (0.01-2.63. NAG-1 in GA was lower than in GB. Mean NAG-2 was 0.44 UU.II/ml (0-3.41). NAG-2 was lower in GA compared with GB. Mean TGFß-1 was 23.43 pg/ml (0.02-103.76). TGFß-1 was lower in GA than GB. There were no differences in the presence of secondary diagnoses between GA and GB. NAG-2 and NGAL-1 were the most determining factors of renal function; in GA it was NGAL-2, followed by NAG-1; in GB it was NGAL-1, followed by NAG-2. CONCLUSION: Frail elderly with RUTI have higher urinary levels of renal injury markers, specifically NGAL, NAG, and TGFß-1, chronically in periods between urinary tract infection (UTI). Urinary markers of renal injury, specifically NGAL, NAG, and TGFß-1, identify early deterioration of renal function, compared with serum creatinine, or albuminuria, in frail elderly with recurrent urinary infections.

El signo de Nicoladoni-Branham / The Nicoladoni-Branham sign

No disponible

Inhibition of inflammatory signaling in Pax5 mutant cells mitigates B-cell leukemogenesis.

PAX5 is one of the most frequently mutated genes in B-cell acute lymphoblastic leukemia (B-ALL), and children with inherited preleukemic PAX5 mutations are at a higher risk of developing the disease. Abnormal profiles of inflammatory markers have been detected in neonatal blood spot samples of children who later developed B-ALL. However, how inflammatory signals contribute to B-ALL development is unclear. Here, we demonstrate that Pax5 heterozygosis, in the presence of infections, results in the enhanced production of the inflammatory cytokine interleukin-6 (IL-6), which appears to act in an autocrine fashion to promote leukemia growth. Furthermore, in vivo genetic downregulation of IL-6 in these Pax5 heterozygous mice retards B-cell leukemogenesis, and in vivo pharmacologic inhibition of IL-6 with a neutralizing antibody in Pax5 mutant mice with B-ALL clears leukemic cells. Additionally, this novel IL-6 signaling paradigm identified in mice was also substantiated in humans. Altogether, our studies establish aberrant IL6 expression caused by Pax5 loss as a hallmark of Pax5-dependent B-ALL and the IL6 as a therapeutic vulnerability for B-ALL characterized by PAX5 loss.

The Association between Prostate-Specific Antigen Velocity (PSAV), Value and Acceleration, and of the Free PSA/Total PSA Index or Ratio, with Prostate Conditions.

INTRODUCTION: Prostate-specific antigen velocity (PSAV) is used to monitor men with clinical suspicion of prostate cancer (PCa), with a normal cut-off point of 0.3-0.5 ng/mL/year. The aim of the study is to establish the predictive capacity of PSAV (value and acceleration) and of the free PSA/total PSA index or ratio. METHOD: Prospective multicentre observational study in 2035 men of over 47 years of age. INCLUSION CRITERIA: men who wished to be informed on the health of their prostate. EXCLUSION CRITERIA: men with a previously diagnosed prostate condition. Groups: GA: (n = 518): men with serum PSA equal to or greater than 2.01 ng/mL. GB: (n = 775): men with serum PSA greater than or equal to 0.78 ng/mL and less than 2.01 ng/mL. GC: (n = 742): men with serum PSA less than 0.78 ng/mL. VARIABLES: prostate-specific antigen (PSA); age; body mass index (BMI); PSA velocity (PSAV) (ng/mL per year); free PSA/total PSA index (iPSA); PSAV acceleration (increasing: positive, or decreasing: negative); prostate diagnosis (benign prostatic hyperplasia (BPH), prostatic intraepithelial neoplasia (PIN), or infectious and non-infectious prostatitis and prostatic adenocarcinoma (PCa)); de novo diagnoses of urinary tract diseases or conditions; concomitant treatments, diseases and conditions; final diagnosis of prostate health. RESULTS: Mean age 62.35 years (SD 8.12), median 61 (47-94); age was lowest in GC. Mean BMI was 27.89 kg/m2 (SD 3.96), median 27.58 (18.56-57.13); no differences between groups. Mean PSAV was 0.69, SD 2.16, median 0.13 (0.001-34.46); PSAV was lowest in GC. Mean iPSA was 27.39 u/L (SD 14.25), median 24.29 (3.7-115); iPSA was lowest in GA. PSAV had more positive acceleration in GA and more negative acceleration in GC. There were 1600 (78.62%) cases of normal prostate or BPH, 322 (15.82%) cases of PIN or non-infectious prostatitis, and 113 (5.55%) cases of PCa. There were more cases of BPH in GC and more cases of PIN or prostatitis and cancer in GA (p = 0.00001). De novo diagnoses: 15 cases of urinary incontinence (UI), 16 discomfort/pain in LUT, 112 cases of voiding disorders, 12 urethral strictures, 19 hematuria, 51 cystitis, 3 pyelonephritis, 4 pelvic inflammatory disease; no differences were found between groups. In the multivariate analysis, PSAV and the direction of PSAV acceleration (positive or negative) were the variables which were correlated most strongly with prostate health. iPSA was associated with the presence of prostatitis, PCa, and BPH. Men in GA had more prostatitis, PCa, treatment with alpha blockers, and history of previous smoking. GB had more cases of BPH and more positive acceleration of PSAV. GC had more normal prostates, more BPH, more use of ranitidine, and more PSAV with negative acceleration. CONCLUSIONS: PSAV, direction of PSAV acceleration, and iPSA in PSA cut-off points of 0.78 ng/mL and 2.01 ng/mL in a priori healthy men over 47 predict the probability of benign or malignant pathology of the prostate.

Effects on Health-Related Quality of Life of Biofeedback Physiotherapy of the Pelvic Floor as an Adjunctive Treatment Following Surgical Repair of Cystocele.

OBJECTIVES: to demonstrate the benefits of physiotherapy (PT) with pelvic floor biofeedback (BFB) in improving health-related quality of life when used as a complementary therapy after surgical treatment of cystocele, in cases in which perineal pain or discomfort persists. MATERIALS AND METHODS: prospective observational study in 226 women who received complementary therapy after surgical treatment of cystocele due to persistent perineal discomfort or pain. Groups: GA (n = 78): women treated with 25 mg of oral pregabalin every 12 h plus BFB, consisting of 20 once-weekly therapy sessions, each 20 min long, with perineal pregelled surface electrodes connected to a screen which provides visual feedback; GB (n = 148): women treated with oral pregabalin 25 mg every 12 h without BFB. VARIABLES: age, body mass index (BMI), time since onset of cystocele prior to surgery (TO), SF-36 health-related quality of life survey score, diseases and concomitant health conditions, follow-up time, success, or failure of postsurgical treatment. RESULTS: average age 67.88 years (SD 12.33, 30-88), with no difference between GA and GB. Average body mass index (BMI) 27.08 (SD 0.45, 18.74-46.22), with no difference between GA and GB. Time since onset of cystocele prior to surgery (TO) was 6.61 years (SD 0.6), with no difference between GA and GB. Pretreatment SF-36 score was lower in GA success than GB success. Treatment was successful in 141 (63.20%) women and failed in 82 (36.80%). PT and age were the main predictors of success, and the least important were pretreatment SF-36 and the time elapsed after the intervention. In GA, 63 women (80.80%) showed improvement while 15 (19.20%) did not. Age was the main predictor of treatment success, while the least important was BMI. In GB, 78 women (53.80%) showed improvement while 67 (46.20%) did not improve. The main predictor was time since cystocele onset prior to surgery, while the least important was age. The odds ratio (OR) of improving quality of life for each unit increase in SF-36 was 11.5% (OR = 0.115) in all patients, with no difference between success and failure; in GA it was 23.80% (OR = 0.238), with a difference between success and failure; in GB it was 11.11% (OR = 0.111), with no difference between success and failure. GA and GB success had more history of eutocic delivery. GA success had more rUTI. GB success and GA failure both had more history of UI corrective surgery. The "failure" outcome had a higher number of patients with more than two concomitant pathological conditions. CONCLUSIONS: BFB as an adjunctive treatment improves quality of life in women suffering from persistent discomfort after surgery for cystocele. Young women who meet the criteria for recurrent urinary tract infection or who have a history of eutocic delivery show greater improvement. Body mass index does not influence response to treatment, while the presence of more than two concomitant conditions indicates a poor prognosis for improving quality of life.

Benefits of Physiotherapy on Urinary Incontinence in High-Performance Female Athletes. Meta-Analysis.

Introduction: High performance female athletes may be a risk group for the development of urinary incontinence due to the imbalance of forces between the abdomen and the pelvis. Pelvic floor physiotherapy may be a useful treatment in these patients. Objectives: (1) To identify the scientific evidence for pelvic floor (PF) dysfunctions that are associated with urinary incontinence (UI) in high-performance sportswomen. (2) To determine whether pelvic floor physiotherapy (PT) corrects UI in elite female athletes. Materials and methods: Meta-analysis of published scientific evidence. The articles analyzed were found through the following search terms: (A) pelvic floor dysfunction elite female athletes; (B) urinary incontinence elite female athletes; (C) pelvic floor dysfunction elite female athletes physiotherapy; (D) urinary incontinence elite female athletes physiotherapy. Variables studied: type of study, number of individuals, age, prevalence of urinary incontinence described in the athletes, type of sport, type of UI, aspect investigated in the articles (prevalence, response to treatment, etiopathogenesis, response to PT treatment, concomitant health conditions or diseases. Study groups according to the impact of each sport on the PF: G1: low-impact (noncompetitive sports, golf, swimming, running athletics, throwing athletics); G2: moderate impact (cross-country skiing, field hockey, tennis, badminton, baseball) and G3: high impact (gymnastics, artistic gymnastics, rhythmic gymnastics, ballet, aerobics, jump sports (high, long, triple and pole jump)), judo, soccer, basketball, handball, volleyball). Descriptive analysis, ANOVA and meta-analysis. Results: Mean age 22.69 years (SD 2.70, 18.00-29.49), with no difference between athletes and controls. Average number of athletes for each study was 284.38 (SD 373,867, 1-1263). The most frequent type of study was case-control (39.60%), followed by cross-sectional (30.20%). The type of UI was most often unspecified by the study (47.20%), was stress UI (SUI, 24.50%), or was referred to as general UI (18.90%). Studies on prevalence were more frequent (54.70%), followed by etiopathogenesis (28.30%) and, lastly, on treatment (17.00%). In most cases sportswomen did not have any disease or concomitant pathological condition (77.40%). More general UI was found in G1 (36.40%), SUI in G2 (50%) and unspecified UI in G3 (63.64%). In the meta-analysis, elite athletes were found to suffer more UI than the control women. In elite female athletes, in general, physiotherapy contributed to gain in urinary continence more than in control women (risk ratio 0.81, confidence interval 0.78-0.84)). In elite female athletes, former elite female athletes and in pregnant women who regularly engage in aerobic activity, physiotherapy was successful in delivering superior urinary continence compared to the control group. The risk of UI was the same in athletes and in the control group in volleyball female athletes, elite female athletes, cross-country skiers and runners. Treatment with PT was more effective in control women than in gymnastics, basketball, tennis, field hockey, track, swimming, volleyball, softball, golf, soccer and elite female athletes. Conclusions: There is pelvic floor dysfunction in high-performance athletes associated with athletic activity and urinary incontinence. Eating disorders, constipation, family history of urinary incontinence, history of urinary tract infections and decreased flexibility of the plantar arch are associated with an increased risk of UI in elite female athletes. Pelvic floor physiotherapy as a treatment for urinary incontinence in elite female athletes, former elite female athletes and pregnant athletes who engage in regular aerobic activity leads to a higher continence gain than that obtained by nonathlete women.

An intact gut microbiome protects genetically predisposed mice against leukemia.

The majority of childhood leukemias are precursor B-cell acute lymphoblastic leukemias (pB-ALLs) caused by a combination of prenatal genetic predispositions and oncogenic events occurring after birth. Although genetic predispositions are frequent in children (>1% to 5%), fewer than 1% of genetically predisposed carriers will develop pB-ALL. Although infectious stimuli are believed to play a major role in leukemogenesis, the critical determinants are not well defined. Here, by using murine models of pB-ALL, we show that microbiome disturbances incurred by antibiotic treatment early in life were sufficient to induce leukemia in genetically predisposed mice, even in the absence of infectious stimuli and independent of T cells. By using V4 and full-length 16S ribosomal RNA sequencing of a series of fecal samples, we found that genetic predisposition to pB-ALL (Pax5 heterozygosity or ETV6-RUNX1 fusion) shaped a distinct gut microbiome. Machine learning accurately (96.8%) predicted genetic predisposition using 40 of 3983 amplicon sequence variants as proxies for bacterial species. Transplantation of either wild-type (WT) or Pax5+/- hematopoietic bone marrow cells into WT recipient mice revealed that the microbiome is shaped and determined in a donor genotype-specific manner. Gas chromatography-mass spectrometry (GC-MS) analyses of sera from WT and Pax5+/- mice demonstrated the presence of a genotype-specific distinct metabolomic profile. Taken together, our data indicate that it is a lack of commensal microbiota rather than the presence of specific bacteria that promotes leukemia in genetically predisposed mice. Future large-scale longitudinal studies are required to determine whether targeted microbiome modification in children predisposed to pB-ALL could become a successful prevention strategy.

The American Society of Anesthesiologists Physical Status (ASA-PS) Risk Group Classification Can Be Used to Anticipate Functional Recovery Outcomes after the Surgical Treatment of Female Urinary Incontinence with Transobturator Suburethral Tape.

INTRODUCTION: Stress urinary incontinence (SUI) has an incidence of 15-80% in women. One of the most widely used surgical techniques for treatment is the placement of a suburethral transobturator tape (TOT). Although this technique has a relatively low morbidity rate, it is not exempt from intraoperative or postoperative complications, which can have an impact on functional recovery, understood as the return to routine life prior to the intervention. AIMS: To assess the time for functional recovery in women operated on for SUI by TOT; to identify complications and related factors, according to anaesthetic risk, which condition the time to functional recovery; and proposals for improvements in the prevention of possible complications and in reducing functional recovery time. MATERIALS AND METHODS: A non-concurrent prospective observational multicenter study of 891 women undergoing TOT for stress urinary incontinence since 1 April 2003, who were successful in achieving urinary continence (completely dry). Study groups: GA (n = 443): patients with ASA I risk. GB (n = 306): patients with ASA II risk. GC (n = 142): patients with anaesthetic risk ASA III. Investigated variables: age, body mass index, follow-up time, secondary diagnoses, surgical history, obstetric-gynecological history, toxic habits, and complications derived from surgery: bleeding, pain, infection. Descriptive statistics, Student's t test, Chi2, Fisher, ANOVA, multivariate analysis, significance for p < 0.05. RESULTS: Mean age was 60.10 years (SD13.38), with no difference between groups. Mean body mass index (BMI) was 26.55 kg/m2 (SD 4.51), lowest in GA. GB had more HT (38.6%) than GC (23.23%), more type 2 diabetes (19.83% versus 10.56%), and more respiratory disorders (6.97% versus 2.11%). There were more women with anxiety in GB (19.3%) than in GC (6.33%) (p = 0.0221) and GA (10.51%) (p = 0.0004). There was more hypothyroidism in GB (16.08%) compared to GC (2.11%) and GA (9.07%). There was more history of curettage in GC (11.97%) versus GB (5.63%); and more pelvic surgery in GB (71.31%) and GC (66.9%) compared to GA (32.57%). There were more concomitant treatments with benzodiazepines in GC (27.46%) and GB (28.41%) than in GA (8.86%), and more parapharmacy treatments in GB (17.96%) than in GC (6.33%). Following the operation, 113 patients had some sign or symptom that required medical attention: in GA 48 (10.83%), in GB 49 (16.06%), in GC 16 (13.22%). Mean days until functional recovery in patients with complications: in GA 5.72 (SD2.05); bleeding 3 (SD1), pain 6.40 (SD1.34), and infection 7.33 (SD0.57), with fewer days for bleeding than for pain or infection. GB: 27.96 (SD 28.42), bleeding 3 (SD0), pain 46.69 (SD31.36), infection 10.83 (SD3.90); lowest for patients with bleeding. GC: 9.44 (SD 2.50); for bleeding 7.66 (SD2. 08), pain 10.66 (SD1.15), infection 10 (SD3.46); no differences. Overall, for women with bleeding, the time was 4.16 days (SD1.94); less in GA and GB than in GC. Pain, at 31.33 days (SD 30.70), was the factor that most delayed functional recovery; in GB women, it took longer to return to work due to pain (45.96, SD31.36) compared to GA (6.4, SD 1.34) and GC (10.66, SD1.15). In women with infection, overall mean time was 10.11 days (SD 3.61) with no difference between groups. CONCLUSIONS: Mean time for the return to normal activity in patients who underwent TOT for SUI is 5 days if there are no complications, and 16.91 days if there are any. The ASA-SP risk group classification can be used to anticipate functional outcomes. An ASA-PS risk-based functional recovery forecasting protocol should be adapted, especially ASA II patients who may present with long-term disabling postoperative pain. Preventive management measures are proposed that favour functional recovery.

Profilaxis farmacológica de la tromboembolia venosa en la prostatectomía radical / Pharmacological venous thromboembolism prophylaxis in radical prostatectomy

ANTECEDENTES Y OBJETIVO: El tromboembolismo pulmonar es una de las causas más comunes de muerte no quirúrgica en pacientes sometidos a cirugía urológica abdominopélvica. Desde el inicio de la profilaxis para la enfermedad tromboembólica venosa los episodios de trombosis venosa profunda y tromboembolia pulmonar han descendido considerablemente. Nuestro objetivo es analizar los predictores de la enfermedad tromboembólica, la variabilidad clínica en la utilización de la profilaxis farmacológica para esta enfermedad y los resultados de su aplicación. MATERIAL Y MÉTODOS: Estudio retrospectivo multicéntrico de 610 pacientes intervenidos mediante prostatectomía radical entre diciembre de 2013 y noviembre de 2014 en 7hospitales generales de España, Italia y Portugal. Se clasificó a los pacientes según sus características basales en grupos de riesgo trombótico y grupos de riesgo hemorrágico. Se evaluaron los eventos tromboembólicos venosos que se presentaron en los diferentes grupos. RESULTADOS: La edad media fue de 65,22años (48-78). El índice de masa corporal medio fue de 26,7 y la mediana del riesgo de ASA fue 2. En todos los pacientes se inició la deambulación en las primeras 24h. En el 4,1% se utilizó compresión neumática intermitente y en el 84,6%, profilaxis farmacológica con heparinas de bajo peso molecular. Solo en el 3,4% se utilizó la combinación de profilaxis mecánica con la farmacológica. Se observó disminución de la incidencia de eventos tromboembólicos en los pacientes que recibieron profilaxis farmacológica, con una reducción absoluta del riesgo del 6,8%. No se objetivó aumento del riesgo hemorrágico en los pacientes que recibieron profilaxis tromboembólica. CONCLUSIONES: En este estudio sobre pacientes sometidos a prostatectomía radical no hubo diferencia en las complicaciones hemorrágicas derivadas del uso de profilaxis farmacológica para la enfermedad tromboembólica venosa. La profilaxis farmacológica reduce el riesgo de presentar un evento tromboembólico en pacientes sometidos a prostatectomía radical, si bien este riesgo no se asocia con la técnica de abordaje

BACKGROUND AND AIM: Pulmonary thromboembolism is one of the most common causes of non-surgical death in patients following urological abdominopelvic surgery. Since the beginning of prophylaxis for venous thromboembolic disease, episodes of deep vein thrombosis and pulmonary thromboembolism have decreased. Our objective is to analyse the prognosis factors of thromboembolic disease, the clinical variability in the use of pharmacological prophylaxis and the results of its application. MATERIAL AND METHODS: Retrospective multicentric study of 610 patients undergoing radical prostatectomy between December 2013 and November 2014, in 7general hospitals in Spain, Italy and Portugal. Patients were classified according to their baseline characteristics into thrombotic risk groups and haemorrhagic risk groups. The venous thromboembolic events that occurred in the different groups were analysed. RESULTS: The average age was 65.22years (48-78). The average body mass index was 26.7 and the average ASA risk 2.1. In all patients, early mobilization began in the first 24hours. In 4.1% intermittent pneumatic compression was used and 84.6% received pharmacological prophylaxis with low molecular weight heparins. Only 3.4% used the combination of mechanical prophylaxis with pharmacological prophylaxis. We observed a decrease in the incidence of thromboembolic events in the patients who received pharmacological prophylaxis, with an absolute risk reduction of 6.8%. There was no increase in the risk of haemorrhage in the patients who received pharmacological prophylaxis. CONCLUSIONS: In this study on patients undergoing radical prostatectomy, there was no difference in haemorrhagic complications derived from the use of pharmacological prophylaxis for venous thromboembolic disease. Pharmacological prophylaxis reduces the risk of presenting a thromboembolic event in patients undergoing radical prostatectomy, although this risk is not associated with the approach technique