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The surface topography of titanium dental implants has a great influence on osseointegration. In this work, we try to determine the osteoblastic behavior and gene expression of cells with different titanium surfaces and relate them to the physicochemical properties of the surface. For this purpose, we have used commercial titanium discs of grade 3: as-received corresponds to machined titanium without any surface treatment (MA), chemically acid etched (AE), treated via sand blasting with Al2O3 particles (SB) and a sand-blasting treatment with acid etching (SB+AE). The surfaces have been observed using scanning electron microscopy (SEM) and the roughness, wettability and surface energy with dispersive and polar components have been characterized. Osteoblastic cultures were performed with SaOS-2 osteoblastic cells determining cell viability as well as alkaline phosphatase levels for 3 and 21 days, and osteoblastic gene expression was determined. The roughness values of the MA discs was 0.02 μm, which increases to 0.3 μm with acid attack and becomes the maximum for the sand-blasted samples, reaching values of 1.2 μm for SB and SB+AE. The hydrophilic behavior of the MA and AE samples with contact angles of 63° and 65° is superior to that of the rougher samples, being 75° for SB and 82° for SB+AE. In all cases, they show good hydrophilicity. GB and GB+AE surfaces present a higher polar component in the surface energy values, 11.96 and 13.18 mJ/m2, respectively, than AE and MA, 6.64 and 9.79 mJ/m2, respectively. The osteoblastic cell viability values at three days do not show statistically significant differences between the four surfaces. However, the viability of the SB and SB+AE surfaces at 21 days is much higher than that of the AE and MA samples. From the alkaline phosphatase studies, higher values were observed for those treated with sand blasting with and without acid etching compared to the other two surfaces, indicating a greater activity in osteoblastic differentiation. In all cases except in the Osterix (Ostx) —osteoblast-specific transcription factor—a decrease in gene expression is observed in relation to the MA samples (control). The most important increase was observed for the SB+AE condition. A decrease in the gene expression of Osteoprotegerine (OPG), Runt-related transcription factor 2 (Runx2), Receptor Activator of NF-κB Ligand (RANKL) and Alkaline Phosphatase (Alp) genes was observed in the AE surface.

Circulating osteogenic precursor (COP) cells are peripheral blood cells with a capacity for osteogenesis. The objective of our study was to ascertain the percentage of COPs as an early biomarker of osteoporosis and the effect of these cells in response to Denosumab (DmAb) (anti-resorptive) or to Teriparatide (TPDP) (anabolic) as very effective drugs in the treatment of the illness. A first study was conducted on healthy volunteers, with three age ranges, to determine the percentage of COPs and relate it to their anthropometric and biochemical characteristics, followed by a second longitudinal study on patients with osteoporosis, whereby one group of patients was treated with TPTD and another with DmAb. All were analyzed by cytometry for COP percentage in blood, bone turnover markers, and bone mass. Our findings show that COPs are influenced by age and become more prolific in the stages of growth and skeletal maturation. A higher percentage of COPs is found in osteoporotic disease, which could constitute a predictive marker thereof. We also show how treatment with TPTD or DmAb mobilizes circulating osteogenic precursors in the blood. Significant increases in % COPs were observed after 12 months of treatment with Dmb (21.9%) and TPTD (17%). These results can be related to an increase in osteogenesis and, consequently, a better and more efficient repair of bone tissue.

The transcription factor, early growth response-1 (EGR-1), is involved in the regulation of cell differentiation, proliferation, and apoptosis in response to different stimuli. EGR-1 is described to be involved in pancreatic endoderm differentiation, but the regulatory mechanisms controlling its action are not fully elucidated. Our previous investigation reported that exposure of mouse embryonic stem cells (mESCs) to the chemical nitric oxide (NO) donor diethylenetriamine nitric oxide adduct (DETA-NO) induces the expression of early differentiation genes such as pancreatic and duodenal homeobox 1 (Pdx1). We have also evidenced that Pdx1 expression is associated with the release of polycomb repressive complex 2 (PRC2) and P300 from the Pdx1 promoter; these events were accompanied by epigenetic changes to histones and site-specific changes in the DNA methylation. Here, we investigate the role of EGR-1 on Pdx1 regulation in mESCs. This study reveals that EGR-1 plays a negative role in Pdx1 expression and shows that the binding capacity of EGR-1 to the Pdx1 promoter depends on the methylation level of its DNA binding site and its acetylation state. These results suggest that targeting EGR-1 at early differentiation stages might be relevant for directing pluripotent cells into Pdx1-dependent cell lineages., C.S.-A. was a doctoral PFIS fellow of ISCIII (FI11/00301). This study was supported by grants from Consejería de Igualdad, Salud y Políticas Sociales, Junta de Andalucía (PI105/2010, TCMR06/009, and PI-0022) to F.J.B. and F.M.; from Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía (CTS-7127/2011) to F.J.B.; from ISCIII cofunded by Fondos FEDER (RED-TERCEL RD 16-011-0034, along with PICI PICI21/00016 and GVA-COVID19/2021/047 to B.S.); from Servicio Andaluz de Salud (SAS 11245), and from Ministerio de Economía y Competitividad- Secretaría de Estado de Investigación Desarrollo e Innovación (IPT-2011-1615-900000). Along with this, there was support to PAIDI group CTS576, and by the European Regional Development Fund (FEDER) and the Consejería de Economía, Conocimiento, Empresas y Universidades de la Junta de Andalucía, within the framework of the operational program FEDER Andalucía 2014–2020. Specific Objective 1.2.3 “Promotion and generation of frontier knowledge and knowledge oriented to the challenges of society, development of emerging technologies” led the reference research project (UPO-1381598) of J.R.T.

The recent identification of rearrangements of neurotrophic tyrosine receptor kinase (NTRK) genes and the development of specific fusion protein inhibitors, such as larotrectinib and entrectinib, have revolutionised the diagnostic and clinical management of patients presenting with tumours with these alterations. Tumours that harbour NTRK fusions are found in both adults and children; and they are either rare tumours with common NTRK fusions that may be diagnostic, or more prevalent tumours with rare NTRK fusions. To assess currently available evidence on this matter, three key Spanish medical societies (the Spanish Society of Medical Oncology (SEOM), the Spanish Society of Pathological Anatomy (SEAP), and the Spanish Society of Paediatric Haematology and Oncology (SEHOP) have brought together a group of experts to develop a consensus document that includes guidelines on the diagnostic, clinical, and therapeutic aspects of NTRK-fusion tumours. This document also discusses the challenges related to the routine detection of these genetic alterations in a mostly public Health Care System., SEOM, SEAP and SEHOP have received financial support for this project in the form of unrestricted collaboration in the logistics of expert meeting from Bayer and Roche.

Fragility fractures constitute a major public health problem worldwide, causing important high morbidity and mortality rates. The aim was to present the epidemiology of fragility fractures and to assess the imminent risk of a subsequent fracture and mortality. This is a retrospective population-based cohort study (n = 1369) with a fragility fracture. We estimated the incidence rate of index fragility fractures and obtained information on the subsequent fractures and death during a follow-up of up to three years. We assessed the effect of age, sex, and skeletal site of index fracture as independent risk factors of further fractures and mortality. Incidence rate of index fragility fractures was 86.9/10,000 person-years, with highest rates for hip fractures in women aged ≥80 years. The risk of fracture was higher in subjects with a recent fracture (Relative Risk(RR), 1.80, p &lt, 0.01). Higher age was an independent risk factor for further fracture events. Significant excess mortality was found in subjects aged ≥80 years and with a previous hip fracture (hazard ratio, 3.43 and 2.48, respectively). It is the first study in Spain to evaluate the incidence of major osteoporotic fractures, not only of the hip, and the rate of imminent fracture. Our results provide further evidence highlighting the need for early treatment.

A spotlight has been shone on endoglin in recent years due to that fact of its potential to serve as both a reliable disease biomarker and a therapeutic target. Indeed, endoglin has now been assigned many roles in both physiological and pathological processes. From a molecular point of view, endoglin mainly acts as a co-receptor in the canonical TGFβ pathway, but also it may be shed and released from the membrane, giving rise to the soluble form, which also plays important roles in cell signaling. In cancer, in particular, endoglin may contribute to either an oncogenic or a non-oncogenic phenotype depending on the cell context. The fact that endoglin is expressed by neoplastic and non-neoplastic cells within the tumor microenvironment suggests new possibilities for targeted therapies. Here, we aimed to review and discuss the many roles played by endoglin in different tumor types, as well as the strong evidence provided by pre-clinical and clinical studies that supports the therapeutic targeting of endoglin as a novel clinical strategy. H.P. Departamento de Defensa de EE. UU. W81XWH-16-1-0131 Fundación Proyecto Neurofibromatosis. T.G.M.FPU (Ministerio de Ciencia, Innovación y Universidades, Gobierno de España). Retos-Colaboración RTC-2014-2102-1 y PI17-000464 de MINECO-FEDER

© 2020 by the authors., Ewing sarcoma is a highly aggressive round cell mesenchymal neoplasm, most often occurring in children and young adults. At the molecular level, it is characterized by the presence of recurrent chromosomal translocations. In the last years, next-generation technologies have contributed to a more accurate diagnosis and a refined classification. Moreover, the application of these novel technologies has highlighted the relevance of intertumoral and intratumoral molecular heterogeneity and secondary genetic alterations. Furthermore, they have shown evidence that genomic features can change as the tumor disseminates and are influenced by treatment as well. Similarly, next-generation technologies applied to liquid biopsies will significantly impact patient management by allowing the early detection of relapse and monitoring response to treatment. Finally, the use of these novel technologies has provided data of great value in order to discover new druggable pathways. Thus, this review provides concise updates on the latest progress of these breakthrough technologies, underscoring their importance in the generation of key knowledge, prognosis, and potential treatment of Ewing Sarcoma., This work was supported by grants from the Consejería de Salud (Junta de Andalucía, grants No PI-0036-2017 and PI-0040-2017) awarded to JDM and ATA, respectively; by grants from the Asociación Pablo Ugarte, Fundación María García Estrada and FARO niños con cáncer to JDM and EdA. EdA’s laboratory is supported by the AECC project (GCB13-1578), ISCIIIFEDER (PI14/01466, PI17/00464), CIBERONC (CB16/12/00361) and Fundación CRIS Contra el Cáncer. This work was also supported by a Juan de la Cierva Incorporación fellowship (IJC-2018-036767-I) to ATA, and a pre-doctoral fellowship from the VI Plan Propio from the Universidad de Sevilla to JOP.

This article belongs to the Special Issue Biology of Boron Neutron Capture Therapy (BNCT)., [Background]: Boron neutron capture therapy requires a 2 mM 10B concentration in the tumor. The well-known BNCT patient treatment method using boronophenylalanine (BPA) as a boron-carrying agent utilizes [18F]fluoroBPA ([18F]FBPA) as an agent to qualify for treatment. Precisely, [18F]FBPA must have at least a 3:1 tumor to background tissue ratio to qualify the patient for BNCT treatment. Normal, hyperplasia, and cancer thyroids capture iodine and several other large ions, including BF4−, through a sodium-iodine symporter (NIS) expressed on the cell surface in normal conditions. In cancer, NIS is also expressed within the thyroid cell and is not functional., [Methods]: To visualize the thyroids and NIS, we have used a [18F]NaBF4 positron emission tomography (PET) tracer. It was injected into the tail veins of rats. The [18F]NaBF4 PET tracer was produced from NaBF4 by the isotopic exchange of natural 19F with radioactive 18F. Rats were subject to hyperplasia and tumor-inducing treatment. The NIS in thyroids was visualized by immunofluorescence staining. The boron concentration was calculated from Standard Uptake Values (SUV) in the PET/CT images and from the production data. Results: 41 MBq, 0.64 pmol of [18F]NaBF4 PET tracer that contained 0.351 mM, 53 nmol of NaBF4 was injected into the tail vein. After 17 min, the peak activity in the thyroid reached 2.3 MBq/mL (9 SUVmax). The natB concentration in the thyroid with hyperplasia reached 381 nM., [Conclusions]: Such an incorporation would require an additional 110 mg/kg dose of [10B]NaBF4 to reach the necessary 2 mM 10B concentration in the tumor. For future BNCT treatments of thyroid cancer, contrary to the 131I used now, there is no post-treatment radioactive decay, the patient can be immediately discharged from hospital, and there is no six-month moratorium for pregnancy. This method can be used for BNCT treatment compounds of the type R-BFn, where 1, This project was partially funded by the Spanish RTI2018-098117-B-C21 project.

[Objective] To evaluate the incidence of osteoporotic hip fracture in the Macarena Health Area (Seville)., [Setting and participants] This was a prospective observational study that collected all osteoporotic hip fractures that occurred between March 2013 and February 2014 at the Clinical Unit of Traumatology and Orthopaedics. All cases collected during the first 6 months of the study were followed for 1 year after the occurrence of the event., [Outcome measures] We evaluated the incidence of osteoporotic hip fractures in the Macarena Health Area (Seville) from 1 March 2013 to 28 February 2014, and we compared the incidence with that in 2 previous studies carried out with the same methodology in 1994 and 2006. Furthermore, we calculated the morbidity and degree of disability 1 year after the fracture occurred and determined mortality and the associated factors., [Results] The overall incidence was 228 per 100 000 individuals/year (95% CI 204.5 to 251.6), and the incidence was higher in women than in men. In women, the incidence rate decreased in all age groups over time, while in men, the incidence rate increased. The mortality rate 1 year after the episode was 27.2%. The factors associated with overall mortality were a body mass index below 25 kg/m2, renal failure and low plasma proteins., [Conclusions] Our results show a high incidence of osteoporotic hip fracture that is increasing in men, and in men it is associated with a higher mortality than in women. There is room to improve the modifiable factors associated with mortality and the available rehabilitation interventions to reduce the disability associated with these fractures., This study was funded by the Research Project of Consejería de Salud, Junta de Andalucía (Spain) (PIN-0092-2016).

Authors are indebted with Ms Monica Glebocki for extensive editing of the manuscript, Background: Periodontitis, the most prevalent chronic inflammatory disease, has been related to cardiovascular diseases. Autophagy provides a mechanism for the turnover of cellular organelles and proteins through a lysosome-dependent degradation pathway. The aim of this research was to study the role of autophagy in peripheral blood mononuclear cells from patients with periodontitis and gingival fibroblasts treated with a lipopolysaccharide of Porphyromonas gingivalis. Autophagy-dependent mechanisms have been proposed in the pathogenesis of inflammatory disorders and in other diseases related to periodontitis, such as cardiovascular disease and diabetes. Thus it is important to study the role of autophagy in the pathophysiology of periodontitis. Methods: Peripheral blood mononuclear cells from patients with periodontitis (n = 38) and without periodontitis (n = 20) were used to study autophagy. To investigate the mechanism of autophagy, we evaluated the influence of a lipopolysaccharide from P. gingivalis in human gingival fibroblasts, and autophagy was monitored morphologically and biochemically. Autophagosomes were observed by immunofluorescence and electron microscopy. Results: We found increased levels of autophagy gene expression and high levels of mitochondrial reactive oxygen species production in peripheral blood mononuclear cells from patients with periodontitis compared with controls. A significantly positive correlation between both was observed. In human gingival fibroblasts treated with lipopolysaccharide from P. gingivalis, there was an increase of protein and transcript of autophagy-related protein 12 (ATG12) and microtubule-associated protein 1 light chain 3 alpha LC3. A reduction of mitochondrial reactive oxygen species induced a decrease in autophagy whereas inhibition of autophagy in infected cells increased apoptosis, showing the protective role of autophagy. Conclusion: Results from the present study suggest that autophagy is an important and shared mechanism in other conditions related to inflammation or alterations of the immune system, such as periodontitis

By blocking of sodium–iodide symporter (NIS) in thyroid gland with potassium perchlorate administered in drinking water to rats for 18 months, we provoke hyperplasia of thyroid which led to thyroid cancer, but also of hyperplasia (benign tumour) of pituitary gland since the lack of thyroid hormones, as a consequence of NIS blockage, hyper-stimulates pituitary in order to produce more thyrotropin stimulating hormone (TSH), the hormone that stimulates thyroid for hormone secretion. There is evidence that hyperplasia of pituitary is provoked by perchlorate or estradiol benzoate in animal models. NIS is expressed in pituitary at the level of about one-tenth of that in thyroid. [18F]tetrafluoroborate ([18F]TFB), which mimics iodine, is a large mononegative anion that binds specifically to NIS. TFB-SUVmax (maximum Standard Uptake Value in the volume of interest, g/mL) in PET is correlated with NIS expression in thyroid. The view of [18F]TFB CT/PET/MRI study of pituitary gland in a rat is shown in Fig. 1. Maximum SUV is 2.17 on cold colour scale and magenta is a tumour zone. MRI was done nine days after PET/CT. The enlarged pituitary gland (magenta) compared with the outline of a pituitary gland of a control animal (blue) can be seen. The imaging was later confirmed by a necropsy with pituitary tumour. The finding was repeated in five other rats treated in the same way.

Journal Article; Age and sex have been identified as predictors of outcome in malignant melanoma (MM). This aim of this multicentre, cross-sectional study was to analyse the role of age and sex as explanatory variables for the diagnosis of thin MM. A total of 2430 patients with MM were recruited. Cases of in situ-T1 MM were more frequent than T2-T4 MM (56.26% vs. 43.74%). Breslow thickness increased throughout decades of life (analysis of variance (ANOVA) p

Abnormal Wnt signaling and impaired cell–cell adhesion due to abnormal E-cadherin and b-catenin func tion have been implicated in many cancers, but have not been fully explored in nasopharyngeal carcinoma. The aim of this study was to analyze b-Catenin cellular location and E-cadherin expression levels in nasopharyngeal carcinoma. E-cadherin expression levels were also correlated with clinical data and underlying pathology. b-Catenin and E-cadherin expression were examined in 18 nasopharyn geal carcinoma and 7 non-tumoral inflammatory pharynx tissues using immunohistochemical methods. Patient clin ical data were collected, and histological evaluation was performed by hematoxylin/eosin staining. b-catenin was detected in membrane and cytoplasm in all cases of naso pharyngeal carcinoma, regardless of histological type; in non-tumoral tissues, however, b-catenin was observed only in the membrane. As for E-cadherin expression levels, strong staining was observed in most non-tumoral tissues, but staining was only moderate in nasopharyngeal carci noma tissues. E-cadherin expression was associated with b-catenin localization, study group, metastatic disease, and patient outcomes. Reduced levels of E-cadherin protein observed in nasopharyngeal carinoma may play an important role in invasion and metastasis. Cytoplasmic b-catenin in nasopharyngeal carcinoma may impair cell– cell adhesion, promoting invasive behavior and a metastatic tumor phenotype.

It It is widely held that solid cell nests (SCN) of the thyroid are ultimobranchial body remnants. SCNs are composed of main cells and C cells. It has been suggested that main cells might be pluripotent cells contributing to the histogenesis of C cells and follicular cells, as well as to the formation of certain thyroid tumors. The present study sought to analyze the immunohistochemical profile of SCN and to investigate the potential stem cell role of SCN main cells. Tissue sections from ten cases of nodular hyperplasia (non-tumor goiter) with SCNs were retrieved from the files of the Hospital Infanta Luisa (Seville, Spain). Parathormone (PTH), calcitonin (CT), thyroglobulin (TG), thyroid tran scription factor (TTF-1), galectin 3 (GAL3), cytokeratin 19 (CK 19), p63, bcl-2, OCT4, and SALL4 expression were evaluated by immunohistochemistry. Patient clinical data were collected, and tissue sections were stained with hematoxylin–eosin for histological examination. Most cells stained negative for PTH, CT, TG, and TTF-1. Some cells staining positive for TTF-1 and CT required discussion. However, bcl-2, p63, GAL3, and CK 19 protein expression was detected in main cells. OCT4 protein expression was detected in only two cases, and SALL4 expression in none. Positive staining for bcl-2 and p63, and negative staining for PTH, CT, and TG in SCN main cells are both consistent with the widely accepted minimalist definition of stem cells, thus supporting the hypothesis that they may play a stem cell role in the thyroid gland, although further research will be required into stem cell markers. Furthermore, p63 and GAL-3 staining provides a much more sensitive means of detecting SCNs than staining for carcinoembryonic antigen, calcitonin, or other markers; this may help to distinguish SCNs from their mimics.

La realidad aumentada (RA) se configura como una tecnología de gran potencial en la formación universitaria, ofreciendo la posibilidad de combinar la información digital con la física en tiempo real a través de diferentes dispositivos tecnológicos (tablet, smartphones, gafas,…). Nuestro estudio perseguía un doble objetivo: por una parte, conocer el grado de motivación que la utilización de objetos en formato RA despierta en los alumnos de medicina y, por otra, analizar si el género de los alumnos afecta positivamente en el grado de motivación mostrada. Para el análisis de la motivación despertada en los alumnos por la experiencia realizada con los objetos de RA elaborados se utilizó un cuestionario elaborado por Keller (2010), el “Instructional Material Motivational Survey” (IMMS). La muestra del estudio estuvo formada por alumnos de primer curso del Grado de Medicina de la Universidad de Sevilla (España), que cursaban la asignatura de “Anatomía Humana I”. Podemos destacar que la experiencia realizada llamó la atención de los alumnos, y que el material les despertó la curiosidad ayudándoles a mantener la atención y disfrutando, por lo general, con la experiencia realizada a la vez que el contenido del material presentado era relevante para sus intereses. Del estudio podemos sacar las siguientes conclusiones: el instrumento de diagnóstico se presenta como un buen predictor para explicar la motivación, atención, confianza, relevancia y satisfacción que despierta la interacción con los objetos de RA. La RA se presenta como una tecnología de gran utilidad para el aprendizaje de los alumnos de medicina, su incorporación a la enseñanza es fácil y el género de los estudiantes no determina el grado de aceptación que tienen de la RA. The Augmented Reality (AR) is formed as a technology of great potential in the universitary education, offering the possibility of combining the digital information with the real time physics across different technological devices (tablet, smartphones, glasses …). Our study was chasing an objective double, on one hand to know the degree of motivation that the utilization of objects in format AR wakes up in the medical student and for analyzing other one if the kind of the student concerns positively in the degree of showed motivation. For the analysis of the motivation woken up in the student for the experience realized with the objects of elaborated AR a questionnaire was in use elaborated for Keller (2010), the "Instructional Material Motivational Survey" (IMMS). The sample of the study was formed by student of the first year of the Degree of Medicine of the University of Seville (Spain), who were dealing the subject of "Human Anatomy I ". We can emphasize that the realized experience called the attention of the student, and that the material they woke the curiosity up helping them to support the attention and enjoying in general with the experience realized simultaneously that the content of the presented material was relevant for his interests. Of The study we can extract the following conclusions: The instrument of diagnosis appears as a good predictor to explain the motivation, attention, confidence, relevancy and satisfaction that wakes the interaction up with AR's objects. The AR appears as a technology of great utility for the learning of the student of medicine, his incorporation to the education is easy and the gender of the students does not determine the degree of acceptance that they have of the AR.

Introduction: gastrointestinal stromal tumors (GISTs) are spe cific, generally KIT (CD117)-positive, mesenchymal tumors of the digestive tract displaying KIT or PDGFRA gene mutations. Clini cally, they tend to present as solitary tumors of the intestinal wall; more rarely, multiple tumors may occur in one or more organs. Objective: to review the morphological, immunohistochemi cal and molecular features of multiple, non-metastatic forms of GIST. Sources: review of the literature on Medline, and authors’ own experience. Conclusions: multiples GISTs may occur in three different contexts: as spontaneous lesions (in both adults and children); due to familial GIST syndrome (autosomal dominant inheritance); or in association with specific syndromes (e.g. Carney’s triad, Car ney-Stratakis syndrome, type I neurofibromatosis). Outside these contexts, the existence of multiple GISTs is deemed to be the re sult of tumor metastasis, and therefore indicative of advancedstage disease. Clinicians need to be aware of these variants, whose prognosis and treatment differ.

The cell kinetic of prostatic intraepithelial neoplasia (PIN) is poorly understood. Herein we report the kinetic pattern of PIN, both not associated (primary) and associated (secondary) with coexistent invasive carcinoma (PCa). Surgical specimens collected in 20 cases of primary PIN, 20 of secondary PIN and 20 of PCa were studied by MIB-1 immunostaining, in situ end-labeling (ISEL) and DNA histogram analysis, and the cell density in each case was estimated using the formula N = (n pi/4)2. Fifty high-power fields (HPF), or the complete lesion if smaller, were screened in each lesion, and both mean and standard deviation were recorded. Statistical differences were studied by means of Fisher's exact test. ISEL indices were significantly (P < 0.0001) lower in PCa (0.1 +/- 0.3) than in primary PIN (0.5 +/- 0.3), while the MIB-I indices were similar in both conditions (P = 0.56). Statistically significant differences were also detected for both MIB-1 and ISEL indices when secondary PIN (MIB-1 1.9 +/- 0.7, ISEL 3.7 +/- 3.3) was compared with primary PIN (MIB-1 2.5 +/- 2.1, ISEL 0.5 +/- 0.3) and PCa (P < 0.0001). In terms of cellularity, primary PIN (26.3 +/- 7.1) revealed scores significantly lower (P < 0.0001) than those recorded in PCa (39.0 +/- 8.8) and secondary PIN (32.9 +/- 14.3). In conclusion, early prostatic tumor is mainly defined by down-regulated apoptosis rather than by increased proliferation. Secondary PIN displays unique kinetic features suggesting an evolved stage of primary PIN.