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Objective: To review the available literature and identify factors associated with successful outcomes after varicocele repair (VR) in the setting of non-obstructive azoospermia (NOA). Methods: The PubMed and EMBASE databases were searched for relevant articles. Primary outcomes were return of spontaneous spermatogenesis, sperm retrieval rates (SRRs), and unassisted and assisted pregnancy rates. Histopathological subtypes, when available, were used for subgroup analysis. Results: A total of 16 articles were finally included. The average sample size was 43 and average duration of follow-up was 10.5 months. The average rate of primary spermatogenesis after VR was 27.3%. The average SRR, across five studies in men with NOA undergoing microscopic testicular sperm extraction status after varicocelectomy, was 48.9% vs 32.1% for the untreated cohort groups, and the average spontaneous pregnancy rate was 5.24%. Histopathology subtype was a significant contributing factor when analysed. Conclusion: Varicocele repair should be considered in men with NOA, as it may allow some patients to avoid assisted reproductive technologies and improves success rates when utilised.
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OBJECTIVE: To compare racial differences in male fertility history and treatment. DESIGN: Retrospective review of prospectively collected data. SETTING: North American reproductive urology centers. PATIENT(S): Males undergoing urologist fertility evaluation. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Demographic and reproductive Andrology Research Consortium data. RESULT(S): The racial breakdown of 6,462 men was: 51% White, 20% Asian/Indo-Canadian/Indo-American, 6% Black, 1% Indian/Native, <1% Native Hawaiian/Other Pacific Islander, and 21% "Other". White males sought evaluation sooner (3.5 ± 4.7 vs. 3.8 ± 4.2 years), had older partners (33.3 ± 4.9 vs. 32.9 ± 5.2 years), and more had undergone vasectomy (8.4% vs. 2.9%) vs. all other races. Black males were older (38.0 ± 8.1 vs. 36.5 ± 7.4 years), sought fertility evaluation later (4.8 ± 5.1 vs. 3.6 ± 4.4 years), fewer had undergone vasectomy (3.3% vs. 5.9%), and fewer had partners who underwent intrauterine insemination (8.2% vs. 12.6%) compared with all other races. Asian/Indo-Canadian/Indo-American patients were younger (36.1 ± 7.2 vs. 36.7 ± 7.6 years), fewer had undergone vasectomy (1.2% vs. 6.9%), and more had partners who underwent intrauterine insemination (14.2% vs. 11.9%). Indian/Native males sought evaluation later (5.1 ± 6.8 vs. 3.6 ± 4.4 years) and more had undergone vasectomy (13.4% vs. 5.7%). CONCLUSION(S): Racial differences exist for males undergoing fertility evaluation by a reproductive urologist. Better understanding of these differences in history in conjunction with societal and biologic factors can guide personalized care, as well as help to better understand and address disparities in access to fertility evaluation and treatment.
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Fertilidad , Conocimientos, Actitudes y Práctica en Salud/etnología , Disparidades en el Estado de Salud , Disparidades en Atención de Salud/etnología , Infertilidad Masculina/etnología , Infertilidad Masculina/terapia , Aceptación de la Atención de Salud/etnología , Técnicas Reproductivas Asistidas/tendencias , Adulto , Índice de Masa Corporal , Estudios Transversales , Femenino , Encuestas de Atención de la Salud , Humanos , Infertilidad Masculina/diagnóstico , Infertilidad Masculina/fisiopatología , Estilo de Vida/etnología , Masculino , Edad Materna , América del Norte/epidemiología , Edad Paterna , Factores Raciales , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , VasectomíaRESUMEN
It is widely accepted that oxidative stress plays an important role in the pathophysiology of male infertility and that antioxidants could have a significant role in the treatment of male infertility. The main objectives of this study are: 1) to systematically review the current evidence for the utility of antioxidants in the treatment of male infertility; and 2) propose evidence-based clinical guidelines for the use of antioxidants in the treatment of male infertility. A systematic review of the available clinical evidence was performed, with articles published on Scopus being manually screened. Data extracted included the type of antioxidant used, the clinical conditions under investigation, the evaluation of semen parameters and reproductive outcomes. The adherence to the Cambridge Quality Checklist, Cochrane Risk of Bias for randomized controlled trials (RCTs), CONSORT guidelines and JADAD score were analyzed for each included study. Further, we provided a Strength Weakness Opportunity Threat (SWOT) analysis to analyze the current and future value of antioxidants in male infertility. Of the 1,978 articles identified, 97 articles were included in the study. Of these, 52 (53.6%) were uncontrolled (open label), 12 (12.4%) unblinded RCTs, and 33 (34.0%) blinded RCTs, whereas 44 (45.4%) articles tested individual antioxidants, 31 (32.0%) a combination of several products in variable dosages, and 22 (22.6%) registered antioxidant products. Based on the published evidence, we 1) critically examined the necessity of additional double-blind, randomized, placebo-controlled trials, and 2) proposed updated evidence-based clinical guidelines for antioxidant therapy in male infertility. The current systematic review on antioxidants and male infertility clearly shows that antioxidant supplementation improves semen parameters. In addition, it provides the indications for antioxidant treatment in specific clinical conditions, including varicocele, unexplained and idiopathic male infertility, as well as in cases of altered semen quality.
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The effects of reactive oxygen species on male fertility are governed by the oxidative paradox, defined by a delicate balance between oxidative stress and antioxidant capacity. When regulated appropriately, reactive oxygen species ensure effective function; however, when uninhibited, they represent key players in male factor infertility. Mechanisms responsible for this include oxidative destruction of sperm lipid membranes, damage to gamete DNA both by gene mutation and by direct breakdown of the DNA backbone, mitochondrial dysfunction and apoptotic cell death. Utilizing various male pathologies as case studies, we see ways in which oxidative stress has the potential to impact fertility in a negative way. Varicocele, erectile dysfunction, testicular cancer and even idiopathic male infertility highlight common mechanistic pathways, as well as subtle variations in the ways reactive oxygen species can operate. Oxidative biomarkers have emerged to better study male infertility, predict reproductive success and modify assisted reproductive technologies to minimize oxidative stress.
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Infertilidad Masculina , Neoplasias Testiculares , Varicocele , Antioxidantes/metabolismo , Humanos , Infertilidad Masculina/metabolismo , Masculino , Estrés Oxidativo , Especies Reactivas de Oxígeno/metabolismo , Espermatozoides/metabolismo , Neoplasias Testiculares/metabolismo , Varicocele/metabolismoRESUMEN
OBJECTIVE: To identify factors and stress coping mechanisms associated with burnout within the field of urology. METHODS: A survey study was completed using the abbreviated Maslach Burnout Inventory to evaluate emotional exhaustion, depersonalization, and low personal achievement. Demographic information, training status, practice setting, work hours, and mechanisms used to cope with stress were evaluated. Participants were also asked to comment on contributors to burnout in an open-ended question. Univariate analysis and multivariate regression identified factors associated with measures of burnout. RESULTS: A total of 476 survey responses from 377 practicing urologists and 99 residents/fellows were included. Burnout was identified in 49.6% of all participants. Burnout through high emotional exhaustion was seen in 40.7%, high depersonalization in 30.7%, and low personal achievement in 18.3%. Trainees exhibited higher levels of depersonalization and lower levels of personal achievement. Higher levels of emotional exhaustion were identified in urologists in the middle of their careers and those in private practice. Urologists identified documentation, insurance and reimbursement, government regulations, medical practice expectations, and patient expectations as stressors contributing to burnout. Exercising and socializing were consistently associated with lower measures of burnout whereas stress eating and alcohol use were associated with higher measures of burnout on multivariate analysis. CONCLUSION: Burnout in urology was associated with trainee status, years in practice, and practice setting. Exercising and socializing were protective against burnout whereas stress eating and alcohol consumption were associated with higher rates of burnout.
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Adaptación Psicológica , Agotamiento Profesional/psicología , Internado y Residencia , Estrés Psicológico/psicología , Urólogos/psicología , Urología , Logro , Adulto , Anciano , Consumo de Bebidas Alcohólicas , Agotamiento Profesional/epidemiología , Agotamiento Profesional/etiología , Agotamiento Profesional/prevención & control , Despersonalización/epidemiología , Despersonalización/psicología , Ingestión de Alimentos/psicología , Ejercicio Físico/psicología , Femenino , Humanos , Internado y Residencia/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Motivación , Administración de la Práctica Médica , Práctica Privada , Análisis de Regresión , Participación Social/psicología , Estrés Psicológico/epidemiología , Estrés Psicológico/etiología , Estrés Psicológico/prevención & control , Encuestas y Cuestionarios , Urólogos/estadística & datos numéricos , Urología/estadística & datos numéricos , Adulto JovenRESUMEN
OBJECTIVE: To determine if there has been a change in empirical medical therapy (EMT) practices since a 2010 American Urological Association survey reported that 25% of urologists treated infertile men who were pursuing a pregnancy with testosterone (T). DESIGN: Survey-based cohort study of AUA members. SETTING: Practice patterns were evaluated of urologists in academic and nonacademic hospital centers. PATIENTS: Practice patterns were evaluated in the treatment of men with idiopathic infertility. INTERVENTIONSS: None. MAIN OUTCOME MEASURES: Subgroup analysis by means of univariate analysis between means (Fisher exact test) and descriptive proportions was used to compare male infertility fellowship-trained urologists (RUs) to general urologists (non-RUs). RESULTS: A total of 191 urologists responded (4.7%). Excluding trainees, 164 responses (85.9%) were analyzed: 134 (82.3%) were from non-RUs and 29 from (17.7%) RUs. Over all, 65.9% treated male infertility with a combination of EMT and surgery (93.1% of RU vs. 60.4% of non-RUs). The most common medications used by RUs were clomiphene (100%), anastrozole (85.7%), and hCG/LH (82.1%). Non-RUs used these less frequently. Overall, 24.4% of the urologists reported that they would use T to treat male infertility: 14.4% (n = 4) of RUs and 24.4% (n = 30) of non-RUs. CONCLUSIONS: A total of 65.9% of urologists would treat male infertility with the use of EMT and surgery. The most common EMTs were clomiphene, anastrozole, and hCG/LH. Of concern, 24.4% of urologists considered T to treat male infertility, a medication with known contraceptive potential. This is unchanged from the 2010 survey, and confirms the need for reproductive medicine guidelines that include the topic of EMT use in infertile men.
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OBJECTIVE: To characterize the referral patterns and characteristics of men presenting for infertility evaluation using data obtained from the Andrology Research Consortium. DESIGN: Standardized male infertility questionnaire. SETTING: Male infertility centers. PATIENT(S): Men presenting for fertility evaluation. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Demographic, infertility history, and referral data. RESULT(S): The questionnaires were completed by 4,287 men, with a mean male age of 40 years ± 7.4 years and female partners age of 37 years ± 4.9 years. Most were Caucasian (54%) with other races being less commonly represented (Asian 18.6%, and African American 5.5%). The majority (59.7%) were referred by a reproductive gynecologist, 19.4% were referred by their primary care physician, 4.2% were self-referred, and 621 (14.5%) were referred by "other." Before the male infertility investigation, 12.1% of couples had undergone intrauterine insemination, and 4.9% of couples had undergone in vitro fertilization (up to six cycles). Among the male participants, 0.9% reported using finasteride (5α-reductase inhibitor) at a dose used for androgenic alopecia, and 1.6% reported exogenous testosterone use. CONCLUSION(S): This broad North American patient survey shows that reproductive gynecologists are the de facto gateway for most male infertility referrals, with most men being assessed in the male infertility service being referred by reproductive endocrinologists. Some of the couples with apparent male factor infertility are treated with assisted reproductive technologies before a male factor investigation. The survey also identified potentially reversible causes for the male infertility including lifestyle factors such as testosterone and 5α-reductase inhibitor use.
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Endocrinólogos , Infertilidad Masculina/terapia , Derivación y Consulta , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Técnicas Reproductivas Asistidas , Encuestas y CuestionariosRESUMEN
OBJECTIVES: To review the literature and provide an updated summary on the role of reactive oxygen species (ROS) in male infertility. METHODS: A review of PubMed, Cochrane review, and Web of Science databases for full-text English-language articles published between 1943 and 2017 was performed, focusing on the aetiology of ROS, physiological role of ROS on spermatic function, pathological role of ROS in infertility, evaluation of ROS, and role of antioxidants in oxidative stress. RESULTS: ROS play a role in spermatic function and fertilisation. The literature describes both a physiological and a pathological role of ROS in fertility. A delicate balance between ROS necessary for physiological activity and antioxidants to protect from cellular oxidative injury is essential for fertility. CONCLUSION: Although elevated levels of ROS are implicated as a cause of infertility, there is no consensus on selecting patients to test for ROS, which test to perform, or if treatment for ROS can have a positive impact on infertility rates and pregnancy.
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A 42-year-old female with remote history of intrauterine device (IUD) placement presented with gross hematuria, urinary urgency, and dyspareunia. Cystoscopy showed an encrusted, free-floating intravesical foreign body consistent with a heavily calcified IUD. It was removed endoscopically using holmium laser cystolitholapaxy. The patient remained symptom free postoperatively. While most intravesical IUDs are thought to be the result of migration after several months, this patient became pregnant within 4 weeks after initial insertion. Therefore this may represent a case either of early intravesical migration or of accidental IUD placement into the bladder at the time of initial insertion.
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Cistoscopía/métodos , Remoción de Dispositivos/métodos , Dispositivos Intrauterinos/efectos adversos , Litotripsia por Láser , Adulto , Femenino , Humanos , Láseres de Estado Sólido , Litotripsia por Láser/instrumentación , Litotripsia por Láser/métodos , Embarazo , Embarazo Ectópico/diagnóstico , Embarazo Ectópico/etiología , Embarazo Ectópico/cirugía , Resultado del Tratamiento , Vejiga Urinaria/diagnóstico por imagen , Vejiga Urinaria/patología , Vejiga Urinaria/cirugía , Trastornos Urinarios/diagnóstico , Trastornos Urinarios/etiologíaRESUMEN
OBJECTIVES: The study examined the effect the life-long vegetarian diet on male fertility and focused on vegetarians living in the Loma Linda blue zone, a demographic area known for life longevity. The objective was to compare sperm characteristics of vegetarian with non-vegetarian males. STUDY DESIGN: The cross-sectional observational study was based on semen analyses of 474 males from 2009 to 2013. Patients categorized themselves as either life-long lacto-ovo vegetarians (N=26; vegetable diet with dairy and egg products), vegans (N=5; strictly vegetables with no animal products) or non-vegetarians (N=443; no diet restrictions). Sperm quality was assessed using a computer-aided sperm analyzer and strict morphology and chromatin integrity were manually evaluated. RESULTS: Lacto-ovo vegetarians had lower sperm concentration (50.7±7.4M/mL versus non-vegetarians 69.6±3.2M/mL, mean±S.E.M.). Total motility was lower in the lacto-ovo and vegan groups (33.2±3.8% and 51.8±13.4% respectively) versus non-vegetarians (58.2±1.0%). Vegans had lowest hyperactive motility (0.8±0.7% versus lacto-ovo 5.2±1.2 and non-vegetarians 4.8±0.3%). Sperm strict morphologies were similar for the 3 groups. There were no differences in rapid progression and chromatin integrity. CONCLUSIONS: The study showed that the vegetables-based food intake decreased sperm quality. In particular, a reduction in sperm quality in male factor patients would be clinically significant and would require review. Furthermore, inadequate sperm hyperactivation in vegans suggested compromised membrane calcium selective channels. However, the study results are cautiously interpreted and more corroborative studies are needed.
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Dieta Vegana/efectos adversos , Dieta Vegetariana/efectos adversos , Dieta/efectos adversos , Infertilidad Masculina/etiología , Espermatogénesis , Espermatozoides/patología , Adulto , Instituciones de Atención Ambulatoria , California , Estudios de Casos y Controles , Forma de la Célula , Tamaño de la Célula , Ensamble y Desensamble de Cromatina , Estudios Transversales , Composición Familiar , Femenino , Humanos , Infertilidad Femenina , Infertilidad Masculina/patología , Infertilidad Masculina/prevención & control , Masculino , Persona de Mediana Edad , Autoinforme , Análisis de Semen , Espermatozoides/citologíaRESUMEN
Reactive oxygen species (ROS) are an integral component of sperm developmental physiology, capacitation, and function. Elevated ROS levels, from processes such as infection or inflammation, can be associated with aberrations of sperm development, function, and fertilizing capacity. We review the impact of ROS on sperm physiology, its place in infertility evaluation, the implications for reproductive outcomes, and antioxidant therapy. Our systematic review of PubMed literature from the last 3 decades focuses on the physiology and etiology of ROS and oxidative stress (OS), evaluation of ROS, and antioxidants. ROS is normally produced physiologically and is used to maintain cellular processes such as sperm maturation, capacitation, and sperm-oocyte interaction. When ROS production exceeds the buffering capacity of antioxidants, OS occurs and can have a negative impact on sperm and fertility. ROS and antioxidant capacity testing can potentially add additional prognostic information to standard laboratory testing for the infertile male, although its role as standard part of an evaluation has yet to be determined. Elevated ROS levels have been implicated with abnormal semen parameters and male infertility, but the impact of ROS on fertilization rates and pregnancy is controversial. This is partly because of the lack of consensus on what type of patients may be suitable for ROS testing and assay standardization. Routine ROS testing for the infertile male is not currently recommended.
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Antioxidantes/fisiología , Infertilidad Masculina/fisiopatología , Especies Reactivas de Oxígeno/farmacología , Espermatozoides/fisiología , Antioxidantes/farmacología , Humanos , Masculino , Espermatozoides/efectos de los fármacosAsunto(s)
Epididimitis/metabolismo , Proteínas/metabolismo , Espermatozoides/metabolismo , Humanos , MasculinoRESUMEN
Nutraceuticals are food products that that can provide medical or health benefits by preventing or treating disease processes. The high costs associated with assisted reproductive techniques for male infertility have led consumers to find less expensive alternatives for potential treatment. Nutraceuticals are widely available and have many antioxidant properties. This articles reviews the current English literature regarding readily available nutraceuticals and their potential effects on male infertility and potential side effects with excess intake.
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Suplementos Dietéticos , Fertilidad/fisiología , Infertilidad Masculina/terapia , Antioxidantes/metabolismo , Humanos , Masculino , Estrés Oxidativo/fisiologíaRESUMEN
Men with 47,XYY syndrome present with varying physical attributes and degrees of infertility. A retrospective chart review was performed on a male infertility and genetic anomaly database. Three patients with 47,XYY were found. Each presented with > 2 years of infertility. All were tall with elevated body mass indices. Scrotal findings ranged from normal to atrophic testicles. Semen analyses demonstrated oligospermia and varying endocrine profiles. Because of the diverse phenotype and potential lack of symptoms, identification and diagnosis of men with 47,XYY syndrome may be difficult. We recommend careful screening of 47,XYY patients and referral to primary physicians for long-term follow-up for increased incidence of health-related comorbidities.
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PURPOSE: We determined empirical medical therapy practice patterns for idiopathic infertility. MATERIALS AND METHODS: We performed a survey of 7,745 practicing American Urological Association members from July to November 2010. Respondents were questioned on empirical medical therapy use, patient evaluation and selection, and preferred medications. RESULTS: A total of 387 urologists (5%) participated in the survey, of whom 16% had infertility fellowship training, two-thirds used empirical medical therapy and 78% treated with empirical medical therapy and surgery. Laboratory values important for identifying ideal candidates include sperm concentration, serum follicle-stimulating hormone and serum testosterone. The most common medications used were clomiphene citrate, human chorionic gonadotropin and anastrozole. Of respondents 25% would treat infertile males with testosterone while the patient actively pursued pregnancy. Overall 60.5% of respondents would treat with empirical therapy for 3 to 6 months. Of fellowship trained and general urologist respondents 70% and 47%, respectively, counseled patients that empirical medical therapy has unknown effects on pregnancy and sperm count. CONCLUSIONS: Empirical medical therapy is used by two-thirds of survey respondents for idiopathic male infertility. There is no clear, universal pattern to the evaluation or identification of the ideal patient for such therapy among those surveyed. There is no consensus on the optimal medication and considerable ambiguity exists as to perceived effects on fertility. Of concern is that 25% of respondents use exogenous testosterone, a medication known for its contraceptive potential, for male infertility treatment. These findings confirm the need for additional studies to establish recommendations on the empirical use of medical therapy in the setting of male infertility.
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Infertilidad Masculina/tratamiento farmacológico , Pautas de la Práctica en Medicina/estadística & datos numéricos , Urología/métodos , Humanos , Masculino , Selección de Paciente , Estadísticas no Paramétricas , Encuestas y Cuestionarios , Estados Unidos , Urología/educaciónRESUMEN
Many over-the-counter (OTC) vitamins and supplements have been used to improve male fertility. The purpose of this study is to review the effects of these OTC supplements on male fertility. A Pub Med and Medline review of the randomized controlled studies utilizing OTC vitamins and supplements readily available in the United States over the last 3 decades was performed. Many studies demonstrate the positive effects of OTC supplementation on semen parameters and pregnancy outcomes. Conversely, many studies also demonstrate a lack of improvement and potential complications with supplementation. Confounding factors include lack of standard dosing regimens, duration of treatment, and control for dietary intake. No standard exists for which OTC supplement and vitamin studies have been conducted or the medications dosed. Definitive conclusions as to their true effects on male subfertility and dosing regimen could not be identified.
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Suplementos Dietéticos , Infertilidad Masculina/tratamiento farmacológico , Medicamentos sin Prescripción/uso terapéutico , Antioxidantes/administración & dosificación , Antioxidantes/uso terapéutico , Glutatión/administración & dosificación , Glutatión/uso terapéutico , Humanos , Masculino , Medicamentos sin Prescripción/administración & dosificación , Estrés Oxidativo/efectos de los fármacos , Ensayos Clínicos Controlados Aleatorios como Asunto , Semen/efectos de los fármacos , Análisis de Semen , Resultado del Tratamiento , Vitaminas/administración & dosificación , Vitaminas/uso terapéuticoRESUMEN
OBJECTIVES: To compare the postoperative complications and survival metrics after multiple renal arteries (MRA) and single renal artery (SRA) laparoscopically procured living donor kidney transplantation (LLDKT). MRA are the most frequently encountered anatomic variation during kidney transplantation. The long-term outcomes of LLDKT with MRA are not well characterized. METHODS: A retrospective review of our institution's LLDKT database was performed. All surgeries were performed at a single tertiary care academic center between June 1999 and September 2008. Patients were divided into 2 cohorts (MRA vs SRA), and analysis was limited to patients with at least 1-year follow-up. RESULTS: Of 584 LLDKTs, 510 had at least 1-year follow-up (median: 36 months). A total of 393 grafts had an SRA, whereas 117 (23%) had MRA. When complications were stratified by the Clavien classification system, no differences were noted between groups (P = .5). Furthermore, rates of vascular (P = .2) and urological (P = .9) complications were similar between groups. There was, however, a higher incidence of slow graft function in the MRA group (P = .01), despite similar rates of delayed graft function (P = .9) and acute rejection (P = .4). Furthermore, allograft survival was similar between both groups with 76% of MRA and 81% of SRA grafts functioning at 5 years (P = .49). Patient overall survival was likewise similar between groups with 88% of MRA and 86% of SRA recipients surviving at 5 years (P = .76). CONCLUSIONS: Despite a higher incidence slow graft function, MRA in LLDKT does not adversely affect long-term allograft and patient overall survival.
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Trasplante de Riñón/métodos , Laparoscopía , Arteria Renal/anomalías , Femenino , Humanos , Donadores Vivos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
PURPOSE: Wilms' tumor is the most common renal tumor in children. Outcomes have improved dramatically over the past few decades, but important treatment questions remain. These include the role of molecular biologic markers in stratifying patients for therapy or targeting tumors for treatment. We present a summary of these advances and outline the current treatment of Wilm's tumor. MATERIALS AND METHODS: The medical literature and results of all cooperative group studies reporting treatment of children with Wilms' tumor were reviewed. RESULTS: Overall survival exceeds 90% for most patients with nephroblastoma. However, outcomes for patients with rhabdoid tumors and diffuse anaplasia remain poor. The role of renal sparing surgery in patients with bilateral tumors is clear, but for children with unilateral tumors it continues to be defined. CONCLUSIONS: Current protocols conducted by pediatric oncology groups are beginning to incorporate biologic features to stratify patients for therapy. Treatment strategies continue to focus on limiting late effects of treatment while maintaining an excellent survival. New therapies are needed to treat the high-risk patients who continue to have high relapse and mortality rates.