RESUMEN

Objective: In non-muscle-invasive bladder cancer (NMIBC), local recurrence after transurethral resection of the bladder (TURB) is common. Outcomes vary between urological centres, partly due to the sub-optimal surgical technique and insufficient application of measures recommended in the guidelines. This study evaluated early recurrence rates after primary TURB for NMIBC before and after introducing a standardized treatment protocol. Methods: Medical records of all patients undergoing primary TURB for NMIBC in 2010 at Skåne University Hospital, Malmö, Sweden, were reviewed. A new treatment protocol for NMIBC was defined and introduced in 2013, and results documented during the first year thereafter were compared with those recorded in 2010 prior to the intervention. The primary endpoint was early recurrence at first control cystoscopy. Comparisons were made by Chi-square analysis and Fisher's exact test. Recurrence-free survival (RFS) in the two cohorts was also investigated. Results: TURB was performed on 116 and 159 patients before and after the intervention, respectively. The early recurrence rate decreased from 22% to 9.6% (p = 0.005) at the first control cystoscopy after treatment. Residual/Recurrent tumour at the first control cystoscopy after the primary TURB (i.e. at second-look resection or first control cystoscopy) decreased from 31% to 20% (p = 0.038). The proportion of specimens containing muscle in T1 tumours increased from 55% to 94% (p < 0.001). RFS was improved in the intervention group (HR = 0.65, CI = 0.43-1.0; p = 0.05). Conclusions: Introduction of a standardized protocol and reducing the number of surgeons for primary treatment of NMIBC decreased the early recurrence rate from 22% to 9.6% and lowered the recurrence incidence by 35%.

Asunto(s)

Carcinoma de Células Transicionales/cirugía , Cistoscopía/normas , Recurrencia Local de Neoplasia/prevención & control , Guías de Práctica Clínica como Asunto , Neoplasias de la Vejiga Urinaria/cirugía , Administración Intravesical , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Carcinoma de Células Transicionales/patología , Quimioterapia Adyuvante , Femenino , Humanos , Masculino , Músculo Liso/patología , Invasividad Neoplásica , Recurrencia Local de Neoplasia/epidemiología , Indicadores de Calidad de la Atención de Salud , Calidad de la Atención de Salud , Estudios Retrospectivos , Suecia/epidemiología , Neoplasias de la Vejiga Urinaria/patología

RESUMEN

[This corrects the article DOI: 10.1371/journal.pone.0079573.].

RESUMEN

Taxane based chemotherapy is the standard of care treatment in castration resistant prostate cancer (CRPC). There is convincing evidence that taxane therapy affects androgen receptor (AR) but the exact mechanisms have to be further elucidated. Our studies identified c-jun as a crucial key player which interacts with AR and thus determines the outcome of the taxane therapy given. Docetaxel (Doc) and paclitaxel (Pac) agents showed different effects on LNCaP and LNb4 evidenced by alteration in the protein and mRNA levels of c-jun, AR and PSA. Docetaxel-induced phophorylation of c-jun occurred before JNK phosphorylation which suggests that c-jun phosphorylation is independent of JNK pathways in prostate cancer cells. A xenograft study showed that mice treated with Pac and bicalutamide showed worse outcome supporting our hypothesis that upregulation of c-jun might act as a potent antiapoptotic factor. We observed in our in vitro studies an inverse regulation of PSA- and AR-mRNA levels in Doc treated LNb4 cells. This was also seen for kallikrein 2 (KLK 2) which followed the same pattern. Given the fact that response to taxane therapy is measured by PSA decrease we have to consider that this might not reflect the true activity of AR in CRPC patients.

Asunto(s)

Hidrocarburos Aromáticos con Puentes/farmacología , Hidrocarburos Aromáticos con Puentes/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-jun/metabolismo , Receptores Androgénicos/metabolismo , Taxoides/farmacología , Taxoides/uso terapéutico , Anilidas/uso terapéutico , Animales , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Citometría de Flujo , Humanos , Inmunohistoquímica , Masculino , Ratones , Ratones Desnudos , Nitrilos/uso terapéutico , Unión Proteica , Proteínas Proto-Oncogénicas c-jun/genética , ARN Interferente Pequeño , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores Androgénicos/genética , Compuestos de Tosilo/uso terapéutico

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The aim of this study was to examine the expression of serotonin receptors in patients with breast cancer and to explore their utility as diagnostic and prognostic markers. Immunohistochemical analysis was performed to examine the expression of serotonin (5-HT) receptor subtypes 1A, 1B, 2B and 4 in a tissue microarray containing tumor specimens from 102 patients. Statistical analysis was performed to correlate the expression of these proteins with regard to clinical parameters. We found that all four serotonin receptors (5-HTRs) exhibited different expression patterns in breast cancer specimens. In general strong staining for 5-HTR1A was observed on the membrane of cancer cells but it was detected only in the cytoplasm of non-malignant cells. 5-HTR1B and 5-HTR2B were predominantly expressed in the cytoplasm of breast cancer cells, while 5-HTR4 was exclusively found in the nucleus of malignant and non-malignant cells. Correlation analysis revealed a significant correlation of 5-HTR2B with estrogen receptor-α (ER-α) and 5-HTR4 with ER-α and progesterone (PR). In conclusion, the different expression patterns and subcellular localization of 5-HTRs in breast cancer may reflect their role in breast cancer progression.

Asunto(s)

Biomarcadores de Tumor/análisis , Neoplasias de la Mama/metabolismo , Receptores de Serotonina/biosíntesis , Membrana Celular/metabolismo , Núcleo Celular/metabolismo , Femenino , Humanos , Inmunohistoquímica , Receptores de Serotonina/análisis , Análisis de Matrices Tisulares

RESUMEN

PURPOSE: This study was conducted to examine the effects of 5-HT on extracellular signal-regulated kinase 1/2 (Erk1/2) and Akt pathways in prostate cancer (PC) cells. METHODS: PC cell lines PC-3, Du145, and LNCaP stimulated with 5-HT in the presence of MEK or PI3K inhibitors and 5-HT receptor subtype 1A antagonist were analyzed by Western blotting and immunofluorescence. The proliferation assay BrdU and Boyden chamber were used to determine proliferation and migration, respectively. RESULTS: 5-HT dose-dependently induced rapid activation of Erk1/2 in PC-3 and Du145 cells, whereas in LNCaP cells, Erk1/2 phosphorylation was slow and sustained for up to 18 h. Similarly, 5-HT induced phosphorylation of Akt within 1 hour of stimulation, however, Akt phosphorylation was more pronounced in Du145 cells compared with PC-3 or LNCaP cells. The action of 5-HT was inhibited to varying degrees by inhibitors of MAPK and PI3K as well as by a 5-HT receptor subtype 1A antagonist. In addition to proliferation, 5-HT induced migration of PC-3 and Du145 cells, which were alleviated by the aforementioned inhibitors. The effects of 5-HT on LNCaP cells appeared to be related to neuroendocrine-phenotype acquisition and chromogranin A and neuron specific enolase expression. CONCLUSIONS: This study addresses the role of 5-HT in Erk1/2 and Akt activation in PC cells. The data presented here identify 5-HT receptors as a novel target in castration-resistant PC. Furthermore, our observations are in line with previous studies, which point towards neuroendocrine factors facilitating progression and migration of prostatic cancer cells in an androgen-deficient environment. Nonetheless, additional studies are warranted to corroborate the role of 5-HTR antagonists as a potential target for anticancer therapy.

Asunto(s)

Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serotonina/farmacología , Transducción de Señal/efectos de los fármacos , Western Blotting , Butadienos/farmacología , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Cromonas/farmacología , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Técnica del Anticuerpo Fluorescente , Humanos , Masculino , Proteína Quinasa 1 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 3 Activada por Mitógenos/antagonistas & inhibidores , Morfolinas/farmacología , Sistemas Neurosecretores/patología , Nitrilos/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Fosforilación/efectos de los fármacos , Piperazinas/farmacología , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología , Factores de Tiempo

RESUMEN

Treatment with docetaxel is the standard of care as first line chemotherapy in castration resistant prostate cancer. Due to serious side effects from the commercially available Taxotere formulation, we aimed to develop a safe and effective nanoparticle formulation of docetaxel. Liquid crystal nanoparticles (LCNPs), based on phosphatidyl choline, glycerol dioleate and polysorbate 80 dispersed in excess aqueous solution, were produced by simple procedures as carriers of docetaxel. Their effect on tumor growth in male SCID mice inoculated with PC-3 cells was compared to the effect of Taxotere and empty LCNP vehicle. Immunohistochemistry was performed to evaluate cell proliferation, angiogenesis and apoptosis in tumor tissue. Docetaxel and lipid excipients were dispersed into well-defined LCNP, stable during long-term storage. Mice subjected to LCNP/docetaxel formulation showed a better tumor regression than mice treated with Taxotere, with an indication of better tolerability. Immunohistochemical staining showed a decreased expression of Ki-67 in tumors from LCNP/docetaxel treated animals, especially in the cores of the tumors, suggesting better penetration/absorption compared to Taxotere. A new lipid-based nanoparticle formulation has been developed as carrier for docetaxel. Treatment effects in SCID mice indicate that this may be an interesting alternative to the current marketed formulation product.

Asunto(s)

Antineoplásicos Fitogénicos/uso terapéutico , Nanopartículas , Neoplasias de la Próstata/tratamiento farmacológico , Taxoides/uso terapéutico , Animales , Antineoplásicos Fitogénicos/administración & dosificación , Docetaxel , Humanos , Masculino , Ratones , Ratones SCID , Neoplasias de la Próstata/patología , Taxoides/administración & dosificación , Trasplante Heterólogo

RESUMEN

OBJECTIVE: to determine the performance characteristics of the prostate cancer gene 3 (PCA3) score on the outcome of biopsy relative to different ranges of free-to-total prostate-specific antigen (PSA) ratio (f/tPSA) in men with a previous negative biopsy and a PSA level of 2.5-10 ng/mL, as urine tests like PCA3 are currently under investigation in order to improve prostate cancer diagnosis and to decrease the rate of unnecessary rebiopsies. PATIENTS AND METHODS: data from the previous prospective European multicentre study were reviewed. Only patients with a PSA level of 2.5-10 ng/mL were included in the present study. In all, 301 patients had complete data. The diagnostic accuracy of the PCA3 score for predicting a positive biopsy outcome was studied using sensitivity, specificity, negative and positive predictive values. The PCA3 performance was evaluated relative to three different subgroups of f/tPSA, as follows: >20% (group 1), 10-20% (group 2) and <10% (group 3). RESULTS: the prostate cancer detection rates were 18.8%, 23.9% and 34.8% in groups 1, 2 and 3, respectively. The area under the receiver operating characteristic curve of the PCA3 score, total PSA and f/tPSA was 0.688, 0.553 and 0.571, respectively. The percentage of men with positive biopsies was 30.6%, 37.0% and 44.4% in those with a PCA3 score of >30, vs 10.3%, 15.5% and 28.6% when the PCA3 score was <30, in groups 1, 2 and 3, respectively. The difference was significant only in groups 1 and 2. In men with a f/tPSA of ≤ 10% the difference in detection rates relative to the PCA3 score was not statistically significant regardless of which PCA3 threshold was used. A high PCA3 score was significantly associated with age, clinical T2 stage and positive biopsy (P < 0.001, 0.013 and <0.001, respectively). In bivariate analysis accounting for the PCA3 score and the f/tPSA, a PCA3 score of >30 was a significant independent predictor of positive biopsies (odds ratio 3.01; 95% confidence interval 1.74-5.23; P < 0.001). CONCLUSIONS: PCA3 remained a better predictor of prostate cancer than f/tPSA. In men with a f/tPSA of >10%, the use of the PCA3 score was highly correlated with the risk of having cancer on re-biopsy, and could prevent unnecessary prostate biopsies if the value is low.

Asunto(s)

Antígenos de Neoplasias/orina , Biomarcadores de Tumor/orina , Antígeno Prostático Específico/metabolismo , Próstata/patología , Neoplasias de la Próstata/patología , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Métodos Epidemiológicos , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Próstata/orina

RESUMEN

BACKGROUND: The Prostate CAncer gene 3 (PCA3) assay has shown promise as an aid in prostate cancer (pCA) diagnosis in identifying men with a high probability of a positive (repeat) biopsy. OBJECTIVE: This study evaluated the clinical utility of the PROGENSA PCA3 assay. DESIGN, SETTING, AND PARTICIPANTS: This European prospective, multicentre study enrolled men with one or two negative biopsies scheduled for repeat biopsy. MEASUREMENTS: After digital rectal examination (DRE), first-catch urine was collected to measure PCA3 mRNA concentration and to calculate the PCA3 score. The PCA3 score was compared to biopsy outcome. The diagnostic accuracy of the PCA3 assay was compared to percent of free prostate-specific antigen (%fPSA). RESULTS AND LIMITATIONS: In 463 men, the positive repeat biopsy rate was 28%. The higher the PCA3 score, the greater the probability of a positive repeat biopsy. The PCA3 score (cut-off of 35) had a greater diagnostic accuracy than %fPSA (cut-off of 25%). The PCA3 score was independent of the number of previous biopsies, age, prostate volume, and total prostate-specific antigen (PSA) level. Moreover, the PCA3 score was significantly higher in men with high-grade prostate intraepithelial neoplasia (HGPIN) versus those without HGPIN, clinical stage T2 versus T1, Gleason score >or=7 versus <7, and "significant" versus "indolent" (clinical stage T1c, PSA density [PSAD] <0.15ng/ml, Gleason score in biopsy

Asunto(s)

Antígenos de Neoplasias/orina , Biopsia/métodos , Regulación Neoplásica de la Expresión Génica , Neoplasias de la Próstata/orina , ARN Neoplásico/genética , Anciano , Antígenos de Neoplasias/genética , Europa (Continente) , Estudios de Seguimiento , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias/métodos , Pronóstico , Estudios Prospectivos , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología

RESUMEN

BACKGROUND: Cyclin A1 is a cell cycle regulator that has been implicated in the progression of prostate cancer. Its role in invasion and metastasis of this disease has not been characterized. METHODS: Immunohistochemistry and cDNA microarray analyses were used to assess protein and mRNA expression of cyclin A1 and proteins with roles in metastasis, including vascular endothelial growth factor (VEGF), metalloproteinase 2 (MMP2), and MMP9, in human prostate cancer. Transient transfection and infection with viral vectors expressing cyclin A1 and short hairpin RNA (shRNA) targeting cyclin A1 were used to study the effects of altered cyclin A1 expression in PC3 prostate cancer cells. The BrdU assay, annexin V staining, and invasion chambers were used to examine cyclin A1 effects on proliferation, apoptosis, and invasion, respectively. The role of cyclin A1 and androgen receptor (AR) in transcription of VEGF and MMP2 was assessed by promoter mutation and chromatin immunoprecipitation. The effect of cyclin A1 expression on tumor growth and metastasis was analyzed in a mouse model of metastasis. All statistical tests were two-sided. RESULTS: Cyclin A1 protein and mRNA expression were statistically significantly higher in prostate cancers than in adjacent benign tissues. A statistically significant correlation between expression of cyclin A1 and of MMP2, MMP9, and VEGF was observed in prostate tumors from 482 patients (P values from Spearman rank correlation tests < .001). PC3 cells that overexpressed cyclin A1 showed increased invasiveness, and inhibition of cyclin A1 expression via shRNA expression reduced invasiveness of these cells. Eight of 10 mice (80%) bearing PC3 cells overexpressing cyclin A1 had infiltration of tumor cells in lymph node, liver, and lung, but all 10 mice bearing tumors expressing control vector were free of liver and lung metastases and only one mouse from this group had lymph node metastasis (P values from Fisher exact tests < .001). Cyclin A1, in concert with AR, bound to and increased expression from the VEGF and MMP2 promoters. CONCLUSIONS: Cyclin A1 contributes to prostate cancer invasion by modulating the expression of MMPs and VEGF and by interacting with AR.

Asunto(s)

Biomarcadores de Tumor/metabolismo , Ciclina A/metabolismo , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Anciano , Anciano de 80 o más Años , Animales , Inmunoprecipitación de Cromatina , Ciclina A/genética , Ciclina A1 , Ensayo de Inmunoadsorción Enzimática , Regulación Neoplásica de la Expresión Génica , Humanos , Immunoblotting , Inmunohistoquímica , Masculino , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Metribolona/farmacología , Ratones , Invasividad Neoplásica , Neovascularización Patológica/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Neoplasias de la Próstata/irrigación sanguínea , ARN Mensajero/metabolismo , Receptores Androgénicos/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Regulación hacia Arriba , Factor A de Crecimiento Endotelial Vascular/metabolismo

RESUMEN

OBJECTIVES: Because the term "interstitial cystitis" (IC) has different meanings in different centers and different parts of the world, the European Society for the Study of Interstitial Cystitis (ESSIC) has worked to create a consensus on definitions, diagnosis, and classification in an attempt to overcome the lack of international agreement on various aspects of IC. METHODS: ESSIC has discussed definitions, diagnostic criteria, and disease classification in four meetings and extended e-mail correspondence. RESULTS: It was agreed to name the disease bladder pain syndrome (BPS). BPS would be diagnosed on the basis of chronic pelvic pain, pressure, or discomfort perceived to be related to the urinary bladder accompanied by at least one other urinary symptom such as persistent urge to void or urinary frequency. Confusable diseases as the cause of the symptoms must be excluded. Classification of BPS types might be performed according to findings at cystoscopy with hydrodistention and morphologic findings in bladder biopsies. The presence of other organ symptoms as well as cognitive, behavioral, emotional, and sexual symptoms, should be addressed. CONCLUSIONS: The name IC has become misleading and is replaced by BPS. This name is in line with recent nomenclature recommendations by the European Association of Urology and is based on the axial structure of the International Association for the Study of Pain classification. To facilitate the change of the name, ESSIC agreed to include IC in the overall term (BPS/IC) during this transition period.

Asunto(s)

Cistitis Intersticial/clasificación , Cistitis Intersticial/diagnóstico , Proyectos de Investigación , Sociedades Médicas , Terminología como Asunto , Europa (Continente) , Humanos

RESUMEN

OBJECTIVES: Serum tPSA lacks specificity. The DD3(PCA3) gene is highly specific for prostate cancer and is detectable in prostate cancer cells shed into urine after rectal palpation. A newly developed nucleic acid sequence based amplification assay (uPM3) for detecting DD3(PCA3) RNA in urine samples was evaluated prospectively in patients referred for prostate cancer detection. METHODS: The uPM3 assay simultaneously detects the relative expression of DD3(PCA3) RNA and PSAmRNA as a marker for prostate cells in urine. Urine samples were collected after attentive digital rectal palpation prior to transrectal guided prostate biopsy. Samples were provided as a single void specimen (20-30 ml), stabilized in phosphate buffer and centrifuged. Lysis was performed on cell pellets DD3(PCA3) RNA and PSAmRNA were extracted and amplification was performed using isothermic nucleic acid based amplification (NASBA). The two targets were detected in real-time using specific beacons as probes in a thermostated spectrofluorimeter. Parameters of the amplification curve were defined after a logistic curve fitting routine and a classification tree model was constructed to predict the outcome of patients (i.e. cancer and non-cancer). RESULTS: 201 patients were included in this prospective study. 158/201 analyzed urine samples contained enough prostate cells sufficient for DD3(PCA3) analysis (79% adequacy rate). Prostate cancer was found in 62 (39%) of the evaluable patients. Overall sensitivity, specificity, positive predictive value and negative predictive value for the uPM3 assay at a cut-off 0.5 probability were 82%, 76%, 67% and 87% respectively as compared to 98%, 5%, 40% and 83% respectively for tPSA (at a cutoff of 2.5 ng/ml). In the tPSA categories <4, 4-10 and >10 ng/ml sensitivity was 73%, 84% and 84% and specificity was 61%, 80% and 70%, respectively. The AUC (area under the curve) was 0.87 (CI 0.81-0.92). CONCLUSION: The uPM3 assay showed excellent clinical performances and a specificity far superior to tPSA.

Asunto(s)

Antígenos de Neoplasias/genética , Neoplasias de la Próstata/orina , ARN/orina , Adulto , Anciano , Anciano de 80 o más Años , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos