¿Cómo Intervenir el Proceso de Caries en Personas Mayores? Adaptación del Consenso de ORCA/EFCD/DGZ / How to Intervene the Caries Process in Older Persons? Adaptation of the ORCA/EFCD/DGZ Consensus

Los cambios demográficos y epidemiológicos actuales determinarán un aumento en la prevalencia e incidencia de caries, específicamente lesiones de caries radicular (RCLs, por sus siglas en inglés) en personas mayores, por lo que la necesidad de tratamiento de mayor cobertura y efectividad será también cada vez mayor. Este artículo resume en español la evidencia actual disponible acerca de las recomendaciones clínicas para las intervenciones preventivas, no invasivas, micro o mínimamente invasivas e invasivas para el manejo de la caries dental en personas mayores, con especial énfasis en RCLs. La presente publicación se basa en un taller de consenso, seguido de un proceso de consenso e-Delphi, realizado por un panel de expertos nominados por la Organización Europea para la Investigación en Caries (ORCA), la Federación Europea de Odontología Conservadora (EFCD) y la Federación Alemana de Odontología Conservadora (DGZ). El propósito de este artículo es presentar las principales conclusiones alcanzadas en el consenso de ORCA/EFCD/DGZ para permitir una mejor difusión del conocimiento y la aplicación de estos conceptos en la práctica clínica, orientando la correcta toma de decisiones en el manejo de la enfermedad y RCLs en las personas mayores.

Current demographic and epidemiological changes will condition increased caries prevalence and incidence, specifically root caries lesions (RCLs) in the elderly. There will be a need, therefore, for therapeutic approaches with greater coverage and effectiveness. This article summarizes, in Spanish, the current available evidence leading to clinical recommendations for preventive, non-invasive, micro or minimally invasive and invasive interventions for the management of dental caries in older people, with special emphasis on RCLs. This publication is based on a consensus workshop, followed by an e-Delphi consensus process, conducted by a panel of experts nominated by the European Organization for Caries Research (ORCA), the European Federation of Conservative Dentistry (EFCD) and the German Federation of Conservative Dentistry (DGZ). The purpose of this article is to present the main conclusions reached in the ORCA/EFCD/DGZ consensus to allow a better dissemination of knowledge and the application of these concepts in clinical practice, guiding the correct decision-making for the disease management and the RCLs in the elderly.

Understanding dental caries as a non-communicable and behavioral disease: Management implications.

New paradigms in caries conceptualization have emerged during the last decades, leading to intense debate and discussion on how to approach the disease, both from a preventive and a therapeutic perspective. Among many new ideas, research discoveries and technologies, one major concept can be highlighted that created a deep frontier between the old and the new paradigm in caries conceptualization; the non-communicable nature of the disease, firmly associated with behaviors and lifestyles. This article synthetizes the conceptual construction of dental caries as a non-communicable disease (NCD) based on the current evidence and discusses the appropriate management of the disease in this context. Dental caries has shifted from being considered transmissible and infectious to an ecological and non-communicable disease. Environmental factors such as frequent sugars intake, disrupt the symbiosis of the dental biofilm leading to a dysbiosis, which favors caries lesion initiation and progression. As an NCD, dental caries shares characteristics with other NCDs such as cardiovascular and chronic respiratory diseases, cancer and diabetes, including long duration and slow progression, not being transmissible from person-to-person, being strongly related to modifiable behavioral risk factors, and affecting preferentially disadvantaged populations with a strong inequality gradient. Given the high prevalence of dental caries, and its consequences on people's health and quality of life, a recognizable conceptual view of caries as a NCD is required to target an effective management. Current understanding of dental caries supports prevention through acting on the modifiable risk factors (behaviors) and involves management based on an interdisciplinary approach. Communicating these modern concepts among researchers, clinicians and policymakers is needed to decrease the global high burden of the disease.

Creación de un Currículo de Competencias en Cariología para Estudiantes de Pregrado de Odontología en Chile / Development of a Competency-based Curriculum in Cariology for Undergraduate Dental Students in Chile

RESUMEN: Objetivo: Creación de un currículo de competencias mínimas en Cariología, para la formación de los Cirujano-Dentistas egresados de las escuelas de Odontología de Chile. Metodologías: A partir de una reunión de académicos de las Universidades de Talca y de Chile (año 2011), se elaboró una propuesta de currículo inicial, basado en los dominios propuestos por la Unión Europea (Schulte AG y cols). Durante el año 2016, dicha propuesta fue analizada mediante diálogos digitales y grupos de trabajo, con la participación del 96% de las Escuelas de Odontología existentes en el país, que concluyeron en un documento intermedio. Este documento fue analizado, discutido y perfeccionado durante el Taller para el Desarrollo de un Currículo de Competencias Mínimas en Cariología para las Escuelas de Odontología Chilenas (22/Mayo/2017, Talca, organizado por la Universidad de Talca y la Universidad de Chile) con la asistencia de representantes del 96% de las escuelas dentales chilenas, Ministerio de Salud de Chile, Colegio de Cirujano-Dentistas de Chile y con la asesoría de los profesores de Cariología Dres. Margherita Fontana y Carlos González-Cabezas (Universidad de Michigan, Ann Arbor, EEUU). Cada grupo de trabajo revisó el documento y envió nuevos comentarios, los que fueron incorporados en el documento final por una comisión asesora. Resultados: El documento del Currículo en Cariología se organizó en 5 Dominios: 1. Conocimientos base; 2. Determinación de Riesgo, diagnóstico de caries y detección de lesiones de caries; 3. Toma de decisiones y manejo preventivo no operatorio; 4. Toma de decisiones y manejo operatorio y 5. Cariología basada en la evidencia, en la práctica clínica y de salud pública. Se consensuaron las definiciones operacionales, las competencias principales y las sub-competencias para cada uno de los dominios. Las sub-competencias fueron clasificadas en tres niveles: A: Ser competente en; B: Tener conocimientos sobre y C: Estar familiarizado con. El documento final fue enviado a todos los participantes del taller para su aprobación y difusión en cada una de las instituciones involucradas. Conclusiones: Se logró, por medio de consenso, la construcción del Currículo de Competencias mínimas en Cariología para estudiantes de pregrado de Odontología en las universidades chilenas.

ABSTRACT: Objective: Development of a minimum set of competencies in Cariology that every dentist graduated from a Dental School in Chile must have. Methodology: Starting from a meeting of scholars from the Universities of Talca and Chile (year 2011), an initial proposal for a curriculum was developed, based on the domains proposed by the European Cariology Curriculum (Schulte, et al, 2011). During 2016, this proposal was discussed through online dialogues and working groups, with the participation of 95.2% of the Chilean dental schools, which resulted in an intermediate document. This document was analyzed, discussed and refined during the Workshop for the Development of a Curriculum of Minimum Competencies in Cariology for Chilean Dental Schools (May 22, 2017, Talca, organized by the Universities of Talca and Chile) with the attendance of representatives from 95.2% of the Chilean dental schools, the Chilean Ministry of Health, Chilean College od Dentists and with the assistance of the professors of Cariology Margherita Fontana and Carlos González-Cabezas (University of Michigan, Ann Arbor, USA). Each working group revised the document and provided feedback, which was incorporated in the final document by an advisory committee, elected on the day of the workshop, including the authors of the present article. Results: The Cariology Curriculum was organized in 5 Domains: 1. Basic knowledge; 2. Risk assessment, caries diagnosis and caries lesion detection; 3. Decision-making and non-operative preventive treatment; 4. Decision making and operative treatment; and 5. Evidence-based, clinical and public health practice. Operational definitions, main competencies and sub-competencies for each domain were agreed. Sub-competencies were classified into three levels: A: Be competent in; B: Have knowledge about, and C: Be familiar with. The final document was sent to all the participants of the workshop for dissemination in each of the institutions involved. Conclusions: The development of the Competency-based Curriculum in Cariology for undergraduate dental students at Chilean universities was achieved through consensus.

MRI findings in men on active surveillance for prostate cancer: does dutasteride make MRI visible lesions less conspicuous? Results from a placebo-controlled, randomised clinical trial.

OBJECTIVES: To investigate changes in the Apparent Diffusion Coefficient (ADC) using diffusion-weighted imaging (DWI) in men on active surveillance for prostate cancer taking dutasteride 0.5 mg or placebo. METHODS: We analysed 37 men, randomised to 6 months of daily dutasteride (n = 18) or placebo (n = 19), undergoing 3T multi-parametric Magnetic Resonance Imaging (mpMRI) scans at baseline and 6 months. Images were reviewed blind to treatment allocation and clinical information. Mean ADC of peripheral (PZ) and transition (TZ) zones, and MR-suspicious lesions were compared between groups over 6 months. Conspicuity was defined as the PZ divided by tumour ADC, and its change over 6 months was assessed. RESULTS: A decrease in mean conspicuity in the dutasteride group (but not the controls) was seen over 6 months (1.54 vs 1.38; p = 0.025). Absolute changes in ADC and conspicuity were significantly different between placebo and dutasteride groups at 6 months: (-0.03 vs 0.08, p = 0.033) and (0.11 vs -0.16, p = 0.012), as were percentage changes in the same parameters: (-2.27% vs 8.56% p = 0.048) and (9.25% vs -9.89% p = 0.013). CONCLUSIONS: Dutasteride was associated with increased tumour ADC and reduced conspicuity. A lower threshold for triggering biopsy might be considered in men on dutasteride undergoing mpMRI for prostate cancer. KEY POINTS: • Dutasteride increases ADC and reduces conspicuity in small mpMRI-visible prostate cancers. • Knowledge of dutasteride exposure is important in the interpretation of prostate mpMRI. • A lower threshold for triggering biopsy may be appropriate on dutasteride.

The Effect of Dutasteride on Magnetic Resonance Imaging Defined Prostate Cancer: MAPPED-A Randomized, Placebo Controlled, Double-Blind Clinical Trial.

PURPOSE: Dutasteride, which is licensed for symptomatic benign prostatic hyperplasia, has been associated with a lower progression rate of low risk prostate cancer. We evaluated the effect of dutasteride on prostate cancer volume as assessed by T2-weighted magnetic resonance imaging. MATERIALS AND METHODS: In this randomized, double-blind, placebo controlled trial, men with biopsy proven, low-intermediate risk prostate cancer (up to Gleason 3 + 4 and PSA up to 15 ng/ml) who had visible lesion of 0.2 ml or greater on T2-weighted magnetic resonance imaging sequences were randomized to daily dutasteride 0.5 mg or placebo for 6 months. Lesion volume was assessed at baseline, and 3 and 6 months with image guided biopsy to the lesion at study exit. The primary end point was the percent reduction in lesion volume over 6 months. This trial was registered with the European Clinical Trials register (EudraCT 2009-102405-18). RESULTS: A total of 42 men were recruited between June 2010 and January 2012. In the dutasteride group, the average volumes at baseline and 6 months were 0.55 and 0.38 ml, respectively and the average reduction was 36%. In the placebo group, the average volumes at baseline and 6 months were 0.65 and 0.76 ml, respectively, and the average reduction was -12%. The difference in percent reductions between the groups was 48% (95% CI 27.4-68.3, p <0.0001). The most common adverse event was deterioration in erectile function, which was 25% in men randomized to dutasteride and 16% in men randomized to placebo. CONCLUSIONS: Dutasteride was associated with a significant reduction in prostate cancer volume on T2-weighted magnetic resonance imaging compared to placebo.

Salivary protein characteristics from saliva of carious lesion-free and high caries adults

It has been argued that specific salivary proteins could have a protective effect against caries, but data from the many available studies are rather contradictory. The purpose of this study was to analyze whether there is a relationship between protein concentration, electrophoretic profile and concentration of salivary IgA and the presence or absence of caries in adults. Adults with high caries activity (HC) and without caries lesions (CF), assessed by ICDAS criteria, were asked to provide unstimulated saliva samples. Protein concentration (μg/mL) was determined using the Bradford method. Western blotting was used to detect IgA. Data were compared using Student’s t test at p<0.05. Total protein concentration in CF was higher (50.65±7.5 μg/mL) than in HC individuals (26.80±2.5 μg/mL) (p=0.001). More protein bands were visualized in the gels from CF than the HC group (p=0.001). CF subjects showed higher salivary IgA concentration (11.27±0.5 μg) than HC individuals (1.71±0.2μg) (p=0.001).Salivary composition in high caries experience and cariesfree young adults seems to differ in terms of the type and amount of proteins. Further research is needed to expand these findings.

Se ha descrito que proteínas salivales específicas podrían tener un efecto protector sobre la caries, sin embargo, los datos de los numerosos estudios disponibles son contradictorios. El propósito de este trabajo fue analizar si existe una relación entre la concentración total de proteínas, perfil electroforético y la concentración de IgA salival y la presencia o ausencia de lesiones de caries en adultos. Se obtuvieron muestras de flujo salival no estimulado de adultos con alta actividad de caries (HC) y sin lesiones de caries (CF), evaluados según criterios ICDAS. La concentración total de proteínas (mg / ml) se determinó utilizando el método de Bradford. Para detección de IgA se empleó Western Blot. Los datos se compararon mediante la prueba t student, estableciendo diferencias significativas si p<0,05. La concentración total de proteínas en CF fue mayor (50,65 ± 7,5 mg / ml) que en individuos HC (26,80 ± 2,5 mg / ml) (p=0,001). En los geles, se visualizó un mayor número de bandas de proteínas en CF que en el grupo HC (p=0,001). Los Sujetos CF mostraron mayor concentración de IgA salival (11,27 ± 0,5 μg) que los individuos HC (1,71 ± 0,2 μg) (p=0,001). La composición salival de sujetos adultos jóvenes con alta experiencia y libres de caries, parece ser diferente en función del tipo y la cantidad de proteínas. Se requiere de más investigación para profundizar estos resultados.

Impact of dutasteride on nocturia in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH): a pooled analysis of three phase III studies.

PURPOSE: To assess the impact of dutasteride compared with placebo on nocturia in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia, using pooled data from dutasteride phase III studies. METHODS: Nocturia was assessed using Question 7 of the International Prostate Symptom Score questionnaire. Efficacy measures included: mean change in nocturia at 24 months; proportion of patients with improvement/worsening in nocturia; nocturnal voiding frequency at baseline and study end, overall and by baseline subgroups; and nocturnal voiding frequency <2 at study end in patients with baseline score ≥ 2. RESULTS: In total, 4,321 patients with a mean age of 66 years were evaluated. From month 12 onwards, mean nocturia improvements were significantly superior with dutasteride than with placebo (p ≤ 0.05). Reduction in nocturia was significantly better with dutasteride than with placebo across all baseline subgroups tested (p ≤ 0.05). Also at month 24, dutasteride therapy resulted in a greater proportion of subjects with nocturia improvement compared with placebo (p ≤ 0.05), with the largest treatment group differences in subjects with a baseline nocturia score of 2 or 3. Among patients with significant nocturia at baseline (score ≥ 2), significantly more subjects with dutasteride versus placebo had a score <2 at month 24 (26 vs. 19 %, p < 0.001). CONCLUSIONS: After 24 months of treatment, dutasteride treatment provided significantly greater improvements in nocturia, and less worsening, compared with placebo, primarily in subjects with two or three nocturia episodes per night. Studies specifically designed to assess nocturia are required to prospectively confirm these findings.

Modeling and analysis of Gleason score 8-10 prostate cancers in the REDUCE study.

OBJECTIVE: To explore explanations for the numerical imbalance of biopsy-detected Gleason 8-10 prostate cancers (PCa) diagnosed in years 3-4 in the dutasteride and placebo groups of the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study. METHODS: REDUCE was a 4-year, randomized, double-blind, placebo-controlled trial of dutasteride (0.5 mg/d) vs placebo for PCa risk reduction. We modeled the incidence of Gleason 8-10 cancer and used logistic regression analysis to evaluate the effects of baseline predictors of PCa, as well as post-baseline prostate volume at the time of biopsy, on PCa diagnosis. We compared needle biopsy Gleason scores with corresponding surgery Gleason scores. All statistical tests conducted were 2-sided. RESULTS: Had there been a scheduled biopsy occurring only at year 4, we estimated a similar incidence of Gleason 8-10 PCa in the dutasteride (n = 45) and placebo (n = 46) groups. Two biopsy Gleason 7 cancers in the placebo group (n = 150) were upgraded to Gleason 8-10 cancer on prostatectomy, and no patients in the dutasteride group (n = 111) were upgraded. Logistic regression analysis demonstrated the effect of prostate volume on Gleason 8-10 cancer diagnosis. CONCLUSION: Although modeling of REDUCE data showed a similar incidence of Gleason 8-10 cancer in the dutasteride and placebo groups at year 4, an association between dutasteride and Gleason 8-10 cancer cannot be definitely excluded. It is likely that several biases, notably study design and prostate size at the time of biopsy, contributed to the numerical imbalance in Gleason 8-10 cancers observed between the treatment groups in years 3-4.

Nocturia improvement in the combination of Avodart(®) and tamsulosin (CombAT) study.

PURPOSE: The purpose of the study was to assess the impact of dutasteride plus tamsulosin combination therapy, compared with dutasteride or tamsulosin monotherapy, on nocturia in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia (LUTS/BPH) using data from the 4-year CombAT study. METHODS: Nocturia was assessed using Question 7 of the International Prostate Symptom Score questionnaire. Efficacy measures included as follows: mean change in nocturia at 3-month intervals up to 48 months; proportion of patients with improvement/worsening in nocturia; nocturnal voiding frequency at baseline and study end, overall and by baseline subgroups; and nocturnal voiding frequency <2 at study end in patients with a baseline score ≥ 2. RESULTS: In total, 4,722 patients with a mean age of 66 years were included. Mean nocturia improvements were significantly superior (p ≤ 0.01) with combination therapy than with either monotherapy (adjusted mean change from baseline in IPSS Question 7 score at month 48: combination therapy -0.5, dutasteride -0.4, tamsulosin -0.3). Reduction in nocturia score with combination therapy was significantly (p ≤ 0.01) better than tamsulosin monotherapy across all baseline subgroups tested, except for men with previous 5ARI use. Among those with a baseline IPSS Q7 score ≥ 2, more patients with combination therapy had a score <2 at month 48 (34 %) compared with dutasteride (30 %, p = 0.018) or tamsulosin (26 %, p < 0.0001). CONCLUSIONS: Combination therapy provided greater improvements and less worsening of nocturia compared with both dutasteride and tamsulosin monotherapies. These analyses are the first to show greater improvement with a 5ARI/α-blocker combination versus either agent alone for the management of nocturia in patients with LUTS/BPH.

Burden of Illness in Prostate Cancer Patients with a Low-to-Moderate Risk of Progression: A One-Year, Pan-European Observational Study.

Objective. To assess the impact of low-to-moderate risk prostate cancer on patients' quality of life (QoL) at diagnosis and within the first year of treatment. Subjects and Methods. Men (n = 672) aged 50-75 years with prostate cancer (Gleason score ≤7, PSA ≤20 ng/mL and clinical staging T1c-T2b) were enrolled in five European countries. Patients completed five questionnaires, including EORTC Quality of Life Questionnaire-Prostate Cancer 25 (QLQ-PR25) and EORTC Quality of Life Questionnaire-Cancer 30 (QLQ-C30). Questionnaires were completed at baseline, at 3 months and 12 months after starting treatment. The primary endpoint was the change in QLQ-PR25 urinary symptoms subscale score from baseline to the assessment at 3 months. Results. Mean (SD) age was 65.0 (5.7) years and 400 (66%) men had Gleason score ≤6 prostate cancer. The most frequently used initial treatment was radical prostatectomy (71% of patients). QLQ-PR25 urinary symptoms subscale score was significantly increased at 3 months (P < 0.001), indicating that urinary symptoms worsened after treatment. The score was lower at 12 months than at 3 months, but it was still significantly higher than at baseline (P < 0.001). Hormonal treatment-related symptoms, sexual functioning, and sexual activity scores significantly worsened at 3 and 12 months (all P < 0.001). For the QLQ-C30 questionnaire, global health status/QoL score significantly decreased at month 3 but was not different from baseline by month 12. Scales for physical, role, and social functioning, and fatigue, showed significant deterioration at 3 and 12 months. Conclusions. Low-to-moderate risk prostate cancer may have a substantial effect on patients' QoL within one year following treatment.

Influence of baseline variables on changes in International Prostate Symptom Score after combined therapy with dutasteride plus tamsulosin or either monotherapy in patients with benign prostatic hyperplasia and lower urinary tract symptoms: 4-year results of the CombAT study.

OBJECTIVE: To examine, using post hoc analysis, the influence of baseline variables on changes in international prostate symptom score (IPSS), maximum urinary flow rate (Qmax ) and IPSS quality of life (QoL) in patients with moderate-to-severe lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) treated with either the α-blocker tamsulosin or the dual 5-alpha reductase inhibitor dutasteride, alone or in combination, as part of the 4-year Combination of Avodart and Tamsulosin (CombAT) study. PATIENTS AND METHODS: CombAT was a 4-year, multicentre, randomized, double-blind, parallel-group study in 4844 men ≥50 years of age with a clinical diagnosis of BPH by medical history and physical examination, an IPSS ≥12 points, prostate volume (PV) ≥30 mL, total serum PSA level ≥1.5 ng/mL, and Qmax >5 mL/s and ≤15 mL/s with a minimum voided volume ≥125 mL. Eligible subjects were randomized to receive oral daily tamsulosin, 0.4 mg; dutasteride, 0.5 mg; or a combination of both. Baseline variable subgroups analysed were as follows: PV (30 to <40; 40 to <60; 60 to <80; ≥80 mL), PSA level (1.5 to <2.5; 2.5 to <4; ≥4 ng/mL), age (median: <66, ≥66 years), IPSS (median: <16, ≥16; IPSS thresholds, <20, ≥20), IPSS QoL score (question 8, Q8) (median: <4, ≥4), Qmax (median: <10.4, ≥10.4 mL/s), BPH impact index (BII) (median: <5, ≥5) and body mass index (BMI, median: <26.8, ≥26.8 kg/m(2) ). Within each baseline variable subgroup, changes in IPSS, Qmax and IPSS QoL Q8 from baseline were evaluated using a generalized linear model with effects for baseline IPSS, Qmax or IPSS QoL Q8 and treatment group at each post-baseline assessment up to and including the month 48 visit using a last observation carried forward approach. The treatment comparisons of combination therapy vs dutasteride and combination therapy vs tamsulosin were performed from the general linear model with statistical significance defined as P ≤ 0.01. RESULTS: Combination therapy resulted in a significantly greater improvement from baseline IPSS at 48 months vs tamsulosin monotherapy across all baseline subgroups. The benefit of combination therapy over dutasteride was confined to groups with lower baseline PV (<60 mL) and PSA (<4 ng/mL). In groups with baseline PV ≥60 mL and PSA ≥4 ng/mL, dutasteride and combination therapy show similar improvements in symptoms. Combination therapy resulted in significantly improved Qmax compared with tamsulosin but not dutasteride monotherapy. Qmax improvement appeared to increase with PV and PSA level in combination therapy subjects. The proportion of subjects with an IPSS QoL ≤2 (at least mostly satisfied) at 48 months was significantly higher with combination therapy than with dutasteride for subgroups with PV 40-60 mL and PSA level <4 ng/mL and than with tamsulosin for all PSA subgroups and PV subgroups ≥40 mL. CONCLUSIONS: CombAT data support the use of long-term combination therapy with dutasteride and tamsulosin in patients considered at risk for progression of BPH, as determined by high PV (≥30 mL) and high PSA (≥1.5 ng/mL). Combination therapy, dutasteride monotherapy and tamsulosin monotherapy all improved Qmax , but to different extents (combination therapy > dutasteride >> tamsulosin), suggesting that dutasteride contributes most to the Qmax benefit in combination therapy. Combination therapy provided consistent improvement over tamsulosin in LUTS across all analysed baseline variables at 48 months. Compared with dutasteride, the superiority of combination therapy at 48 months was shown in patients with PV <60 mL or PSA <4 ng/mL.

Predictors of pathological progression among men with localized prostate cancer undergoing active surveillance: a sub-analysis of the REDEEM study.

PURPOSE: We identify risk factors for pathological progression among men on active surveillance in the REDEEM (REduction by Dutasteride of clinical progression Events in Expectant Management trial). MATERIALS AND METHODS: REDEEM was a 3-year, randomized, double-blind study of patients in 65 North American academic centers. Eligible men were 48 to 82 years old, with low risk prostate cancer (T1c-T2a), Gleason score 6 or less, 3 or fewer cores positive, tumor less than 50% of any 1 core, serum prostate specific antigen 11 ng/ml or less, life expectancy greater than 5 years and undergoing active surveillance. Entry biopsies (10 cores or more) were required. The analysis included 276 patients with 1 biopsy or more after the start of study treatment. Patients received dutasteride 0.5 mg per day or placebo for 3 years. Time to pathological progression (volume [4 or more cores positive or 50% or greater of 1 core] or grade progression [Gleason score 7 or greater]) in a post-baseline biopsy (not preceded by therapeutic intervention), and baseline variables were analyzed using a Cox proportional hazard model. RESULTS: In total 94 of 276 patients with a post-baseline biopsy (34.1%) had pathological progression, 54 (19.6%) had volume progression only, 19 (6.9%) had grade progression only and 21 (7.6%) had both types of progression. Older age (HR 1.05, 95% CI 1.01-1.08, p=0.009) and higher prostate specific antigen density (HR 1.06, 95% CI 1.04-1.09, p<0.001) were associated with pathological progression. Post-baseline prostate specific antigen identified grade, but not volume progression in patients treated with placebo and dutasteride. CONCLUSIONS: Older age and higher prostate specific antigen density were independent predictors of pathological progression. Post-baseline measurements as predictors of pathological progression could not be established. Further studies are needed to evaluate the role of dutasteride and establish better markers of pathological progression in active surveillance.

The REDUCE Follow-Up Study: low rate of new prostate cancer diagnoses observed during a 2-year, observational, followup study of men who participated in the REDUCE trial.

PURPOSE: The primary objective of the REDUCE (REduction by DUtasteride of prostate Cancer Events) Follow-Up Study was to collect data on the occurrence of newly diagnosed prostate cancers for 2 years beyond the 4-year REDUCE study. MATERIALS AND METHODS: The 4-year REDUCE study evaluated prostate cancer risk reduction in men taking dutasteride. This 2-year observational study followed men from REDUCE with a clinic visit shortly after study conclusion and with up to 2 annual telephone calls during which patient reported data were collected regarding prostate cancer events, chronic medication use, prostate specific antigen levels and serious adverse events. No study drug was provided and all biopsies during the 2-year followup were performed for cause. The primary objective was to collect data on the occurrence of new biopsy detectable prostate cancers. Secondary end points included assessment of Gleason score and serious adverse events. RESULTS: A total of 2,751 men enrolled in the followup study with numbers similar to those of the REDUCE former treatment groups (placebo and dutasteride). Few new prostate cancers were detected during the 2-year followup period in either former treatment group. A greater number of cancers were detected in the former dutasteride group than in the former placebo group (14 vs 7 cases). No Gleason score 8-10 prostate cancers were detected in either former treatment group based on central pathology review. No new safety issues were identified during the study. CONCLUSIONS: Two years of followup of the REDUCE study cohort demonstrated a low rate of new prostate cancer diagnoses in the former placebo and dutasteride treated groups. No new Gleason 8-10 cancers were detected.

Dutasteride treatment over 2 years delays prostate-specific antigen progression in patients with biochemical failure after radical therapy for prostate cancer: results from the randomised, placebo-controlled Avodart After Radical Therapy for Prostate Cancer Study (ARTS).

BACKGROUND: Rising prostate-specific antigen (PSA) levels after radical therapy are indicative of recurrent or residual prostate cancer (PCa). This biochemical recurrence typically predates clinically detectable metastatic disease by several years. Management of patients with biochemical recurrence is controversial. OBJECTIVE: To assess the effect of dutasteride on progression of PCa in patients with biochemical failure after radical therapy. DESIGN, SETTING, AND PARTICIPANTS: Randomised, double-blind, placebo-controlled trial in 294 men from 64 centres across 9 European countries. INTERVENTION: The 5α-reductase inhibitor, dutasteride. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary end point was time to PSA doubling from start of randomised treatment, analysed by log-rank test stratified by previous therapy and investigative-site cluster. Secondary end points included time to disease progression and the proportion of subjects with disease progression. RESULTS AND LIMITATIONS: Of the 294 subjects randomised (147 in each treatment group), 187 (64%) completed 24 mo of treatment and 107 discontinued treatment prematurely (71 [48%] of the placebo group, 36 [24%] of the dutasteride group). Dutasteride significantly delayed the time to PSA doubling compared with placebo after 24 mo of treatment (p<0.001); the relative risk (RR) reduction was 66.1% (95% confidence interval [CI], 50.35-76.90) for the overall study period. Dutasteride also significantly delayed disease progression (which included PSA- and non-PSA-related outcomes) compared with placebo (p<0.001); the overall RR reduction in favour of dutasteride was 59% (95% CI, 32.53-75.09). The incidence of adverse events (AEs), serious AEs, and AEs leading to study withdrawal were similar between the treatment groups. A limitation was that investigators were not blinded to PSA levels during the study. CONCLUSIONS: Dutasteride delayed the biochemical progression of PCa in patients with biochemical failure after radical therapy for clinically localised disease. The safety and tolerability of dutasteride were generally consistent with previous experience. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov, NCT00558363.

Usefulness of prostate-specific antigen (PSA) rise as a marker of prostate cancer in men treated with dutasteride: lessons from the REDUCE study.

OBJECTIVES: To determine if dutasteride-treated men can be monitored safely and adequately for prostate cancer based on data from the Reduction by Dutasteride in Prostate Cancer Events (REDUCE) study. To analyse whether the use of treatment-specific criteria for repeat biopsy maintains the usefulness of prostate-specific antigen (PSA) level for detecting high grade cancers. PATIENTS AND METHODS: The REDUCE study was a randomized, double-blind, placebo-controlled investigation of whether dutasteride (0.5 mg/day) reduced the risk of biopsy-detectable prostate cancer in men with a previous negative biopsy. The usefulness of PSA was evaluated using biopsy thresholds defined by National Comprehensive Cancer Network guidelines in the placebo group and any rise in PSA from nadir (the lowest PSA level achieved while in the study) in the dutasteride group. The number of cancers detected on biopsy in the absence of increased/suspicious PSA level as well as sensitivity, specificity, positive predictive value and negative predictive value for high grade prostate cancer detection were analysed by treatment group. Prostate cancer pathological characteristics were compared between men who did and did not meet biopsy thresholds. RESULTS: Of 8231 men randomized, 3305 (dutasteride) and 3424 (placebo) underwent at least one prostate biopsy during the study and were included in the analysis. If only men meeting biopsy thresholds underwent biopsy, 25% (47/191) of Gleason 7 and 24% (7/29) of Gleason 8-10 cancers would have been missed in the dutasteride group, and 37% (78/209) of Gleason 7 and 22% (4/18) Gleason 8-10 cancers would have been missed in the placebo group. In both groups, the incidence of Gleason 7 and Gleason 8-10 cancers generally increased with greater rises in PSA. Sensitivity of PSA kinetics was higher and specificity was lower for the detection of Gleason 7-10 cancers in men treated with dutasteride vs placebo. Men with Gleason 7 and Gleason 8-10 cancer meeting biopsy thresholds had greater numbers of positive cores, percent core involvement, and biopsy cancer volume vs men not meeting thresholds. CONCLUSION: Using treatment-specific biopsy thresholds, the present study shows that the ability of PSA kinetics to detect high grade prostate cancer is maintained with dutasteride compared with placebo in men with a previous negative biopsy. The sensitivity of PSA kinetics with dutasteride was similar to (Gleason 8-10) or higher than (Gleason 7-10) the placebo group; however, biopsy decisions based on a single increased PSA measurement from nadir in the dutasteride group resulted in a lower specificity compared with using a comparable biopsy threshold in the placebo group, indicating the importance of confirmation of PSA measurements.

Efecto del extracto atomizado de las hojas de Calophyllum brasiliense ôlagarto caspiõ sobre la glicemia / Effect of the atomized of calophylum brasiliense ôlagarto caspiõ leaves on the glycemia

OBJETIVO: Evaluar el efecto hipoglicemiante del Calophylum brasiliense. MATERIAL Y MÉTODO: Preparamos los extractos atomizado, acuoso, hexánico, diclorometánico, metanólico y etanólico de las hojas de Calophyllum brasiliense. La diabetes experimental fue inducida por administración intraperitoneal de 100 mg/kg de estreptozotocina. El efecto hipoglicemiante de Calophyllum brasiliense fue evaluado en ratas hiperglicémicas, con niveles de glucosa superiores a 300 mg/dLy la dosis usada fue 250, 500, 1000 y 1500 mg/kg, comparándolo con el grupo control negativo que recibió 10 ml de agua destilada vía oral y un grupo control positivo al que se le administró Glibenclamida a la dosis de 10 mg/Kg. Los valores de glucosa fueron determinados a las 1, 2, 3 y 4 horas, después de administrar los extractos y los controles. Finalmente el extracto atomizado fue fraccionado con el fin de caracterizar los principios activos de la planta. RESULTADOS: Observamos efecto hipoglicemiante una hora después de administrados los extractos. El mayor efecto observado con la dosis de 1000 mg/Kg, fue 69.28% superior a la Glibenclamida, duró todo el tiempo del experimento (4 horas), y demostramos la presencia de Calanólidas por Resonancia Magnética Nuclear (RMNH/RMNC). CONCLUSIONES: El extracto atomizado de Calophyllum brasiliense posee un buen efecto hipoglicemiante a la dosis de 1000 mg/Kg (100%), en comparación con Glibenclamida.

OBJETIVE: To evaluate the hypoglycemic effect of Calophylum brasiliense. MATERIALS AND METHOD: We prepared the atomized, aqueous, methanolic, hexanic, dicloromethanic and ethanolic, extracts from the leaves of Calophyllum brasiliense. The experimental diabetes was induced by intraperitoneal administration of 100 mg/kg of streptozotocin. The hypoglycemic effect of Calophyllum brasiliense was evaluated on hyperglycemic rats with levels of glucose higher than 300 mg/dL and the doses used were 250, 500, 1000 and 1500 mg/kg, compared with negative control group that received 10 ml of distilled water by mouth and the positive control group that received 10 mg of Glibenclamide. The blood glucose was determined at 1, 2, 3 and 4 hours after the administration of the extracts and the controls. Finally the atomized extract was fractioned in order to elucidate the active principles of the plant. RESULTS: We observed hypoglycemic effect since one hour after the administration of the extracts, the greatest effect was observed with the dose of 1000 mg/kg, even superior to Glibenclamide. The effect persisted all the time that we did the experiments (4 hours). We demonstrated the presence of calanolides with nuclear magnetic resonance (RMNH / RMNC). CONCLUSIONS: Our results indicate that Calophyllum brasiliense has a good hypoglycemic effect even superior to the Glibenclamide.

Effect of dutasteride on prostate biopsy rates and the diagnosis of prostate cancer in men with lower urinary tract symptoms and enlarged prostates in the Combination of Avodart and Tamsulosin trial.

BACKGROUND: A 23% relative risk reduction (RRR) in prostate cancer (PCa) was shown in men receiving dutasteride in the 4-yr Reduction by Dutasteride of Prostate Cancer Events study, in whom biopsies were protocol dependent. OBJECTIVE: Our aim was to explore PCa risk reduction in men with benign prostatic hyperplasia (BPH) from the Combination of Avodart and Tamsulosin (CombAT) study, in which biopsies were undertaken for cause. DESIGN, SETTING, AND PARTICIPANTS: CombAT was a 4-yr randomized double-blind parallel group study in 4844 men ≥50 yr of age with clinically diagnosed moderate to severe BPH, International Prostate Symptom Score ≥12, prostate volume ≥30 ml, and serum prostate-specific antigen (PSA) 1.5-10 ng/ml. Men underwent annual PSA measurement and digital rectal examination (DRE), and prostate biopsies were performed for cause. INTERVENTION: All patients took tamsulosin 0.4 mg/d, dutasteride 0.5 mg/d, or a combination of both. MEASUREMENTS: The primary end point was incidence of PCa. Secondary end points included postbaseline prostate biopsy rates and Gleason score of cancers. RESULTS AND LIMITATIONS: Dutasteride (alone or in combination with tamsulosin) was associated with a 40% RRR of PCa diagnosis compared with tamsulosin monotherapy (95% confidence interval, 16-57%; p=0.002) and a 40% reduction in the likelihood of biopsy. There were similar reductions in low- and high-grade Gleason score cancers. The biopsy rate in the groups receiving dutasteride trended toward a higher diagnostic yield (combination: 29%, dutasteride: 28%, tamsulosin: 24%). One limitation was the lack of a standardized approach to PCa diagnosis and grading. CONCLUSIONS: Dutasteride, alone or in combination with tamsulosin, significantly reduced the relative risk of PCa diagnosis in men with BPH undergoing annual DRE and PSA screening. Consistent with the increased usefulness of PSA for PCa detection, men receiving dutasteride had a numerically lower biopsy rate and higher yield of PCa on biopsy. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT00090103 (http://www.clinicaltrials.gov/ct2/show/NCT00090103).

The effect of dutasteride on the usefulness of prostate specific antigen for the diagnosis of high grade and clinically relevant prostate cancer in men with a previous negative biopsy: results from the REDUCE study.

PURPOSE: We assessed whether dutasteride enhances the usefulness of total prostate specific antigen for diagnosing clinically significant prostate cancer. MATERIALS AND METHODS: The 4-year REDUCE study evaluated the efficacy and safety of 0.5 mg dutasteride daily for prostate cancer risk reduction in men with a prostate specific antigen of 2.5 to 10.0 ng/ml and a negative prostate biopsy. Specificity, sensitivity, and positive and negative predictive values of prostate specific antigen for the diagnosis of prostate cancer were assessed. RESULTS: Final prostate specific antigen before biopsy and change from month 6 to final prostate specific antigen performed better for the diagnosis of Gleason score 7-10 tumors in men who received dutasteride vs placebo as assessed by the area under the ROC curves (0.700 vs 0.650, p = 0.0491; and 0.699 vs 0.593, p = 0.0001, respectively). Increases in prostate specific antigen were associated with a higher likelihood of biopsy detectable, Gleason score 7-10 and clinically significant (modified Epstein criteria) prostate cancer. Percentage decreases in prostate specific antigen from baseline to month 6 in the dutasteride arm did not predict prostate cancer overall or Gleason score 7-10 cancer. CONCLUSIONS: In men with a previously negative prostate biopsy, prostate specific antigen performed better during the 4-year study as a marker of prostate cancer in men who received dutasteride vs placebo. The degree of prostate specific antigen increase after 6 months was a better indicator of clinically significant cancer in the dutasteride arm than in the placebo arm. Conversely, the initial decrease in prostate specific antigen in men taking dutasteride did not predict the likelihood of prostate cancer.

Treatment costs of prostate cancer in the first year after diagnosis: a short-term cost of illness study for France, Germany, Italy, Spain and the UK.

OBJECTIVE: To calculate the total cost per patient of prostate cancer treatment and the economic cost burden by stage, in the first year after diagnosis, for five European countries. METHODS: Data from the Information Management Systems, Inc. database, survival data, expert opinion, published data and unit costs from various published official sources were used to calculate total costs per patient by stage for each country, from a payer's perspective. Diagnostic costs, first surgery, radio-, chemo- and hormonal therapy costs were included. Costs were aggregated for incident cases. RESULTS: The mean direct costs per patient for initial treatment were euro3698 in Germany, euro3256 in Spain, euro3682 in the UK, euro5226 in Italy and euro5851 in France. The total costs for all diagnosed patients in the first year from diagnosis were (million euro) 116.7 (UK), 244 (Germany), 385 (France), 202 (Italy) and 114.6 (Spain). CONCLUSIONS: The direct initial healthcare cost burden of the most common non-skin-related male cancer, prostate cancer, in France, Germany, Italy, Spain and the UK is considerable. Given the high and increasing prevalence of prostate cancer due to ageing populations in Europe, and the significant cost burden of the disease, national health policy makers should be aware of prostate cancer as a priority disease area.