A European, prospective, observational study of enzalutamide in patients with metastatic castration-resistant prostate cancer: PREMISE.

In randomized clinical trials, the androgen-receptor inhibitor enzalutamide has demonstrated efficacy and safety in metastatic castration-resistant prostate cancer (mCRPC). This study captured efficacy, safety and patient-reported outcomes (PROs) of enzalutamide in mCRPC patients in a real-world European setting. PREMISE (NCT0249574) was a European, long-term, prospective, observational study in mCRPC patients prescribed enzalutamide as part of standard clinical practice. Patients were categorized based on prior docetaxel and/or abiraterone use. The primary endpoint was time to treatment failure (TTF), defined as time from enzalutamide initiation to permanent treatment discontinuation for any reason. Secondary endpoints included prostate-specific antigen (PSA) response, time to PSA progression, time to disease progression and safety. PROs included EuroQol 5-Dimension, 5-Level questionnaire, Functional Assessment of Cancer Therapy-Prostate and Brief Pain Inventory-Short Form. Overall, 1732 men were enrolled. Median TTF with enzalutamide was 12.9 months in the chemotherapy- and abiraterone-naïve cohort (Cohort 1) and 8.4 months in the postchemotherapy and abiraterone-naïve cohort (Cohort 2). Clinical outcomes based on secondary endpoints also varied between cohorts. Cohorts 1 and 2 showed small improvements in health-related quality of life and pain status. The proportions of patients reporting treatment-emergent adverse events (TEAEs) were 51.0% and 62.2% in Cohorts 1 and 2, respectively; enzalutamide-related TEAEs were similar in both cohorts. The most frequent TEAE across cohorts was fatigue. These data from unselected mCRPC patients in European, real-world, clinical-practice settings confirmed the benefits of enzalutamide previously shown in clinical trial outcomes, with safety results consistent with enzalutamide's known safety profile.

The dioxin receptor has tumor suppressor activity in melanoma growth and metastasis.

Melanoma is a highly metastatic and malignant skin cancer having poor rates of patient survival. Since the incidence of melanoma is steadily increasing in the population, finding prognostic and therapeutic targets are crucial tasks in cancer. The dioxin receptor (AhR) is required for xenobiotic-induced toxicity and carcinogenesis and for cell physiology and organ homeostasis. Yet, the mechanisms by which AhR affects tumor growth and dissemination are largely uncharacterized. We report here that AhR contributes to the tumor-stroma interaction, blocking melanoma growth and metastasis when expressed in the tumor cell but supporting melanoma when expressed in the stroma. B16F10 cells engineered to lack AhR (small hairpin RNA for AhR) exacerbated melanoma primary tumorigenesis and lung metastasis when injected in AhR+/+ recipient mice but not when injected in AhR- /- mice or when co-injected with AhR-/- fibroblasts in an AhR+/+ stroma. Contrary, B16F10 cells expressing a constitutively active AhR had reduced tumorigenicity and invasiveness in either AhR genetic background. The tumor suppressor role of AhR in melanoma cells correlated with reduced migration and invasion, with lower numbers of cancer stem-like cells and with altered levels of ß1-integrin and caveolin1. Human melanoma cell lines with highest AHR expression also had lowest migration and invasion. Moreover, AHR expression was reduced in human melanomas with respect to nevi lesions. We conclude that AhR knockdown in melanoma cells requires stromal AhR for maximal tumor progression and metastasis. Thus, AhR can be a molecular marker in melanoma and its activity in both tumor and stromal compartments should be considered.

[Cystic tubulopapillary adenoma with apocrine differentiation and BRAF V600E mutation. A case report and review of the literature]. / Adenoma tubulopapilar quístico con diferenciación apocrina: descripción de un caso con mutación de BRAF V600E y revisión de la literatura.

Syringocystadenoma papilliferum (SCAP), tubular adenoma (TA) and hydrocystoma (HC) are benign adnexal tumors. Recently it has been suggested that these lesions belong to the same morphological spectrum: Tubulopapillary cystic adenoma with apocrine differentiation (TPCAa). BRAF and K-Ras (KRAS) mutations have been described in SCAP and TA, but not in HC. Moreover, verrucous epithelial proliferations have been observed in TPCAa. We present a case of TPCAa with BRAF V600E mutation and BRAF VE1 immunohistochemical expression in the SCAP, AT, HC and verrucous hyperplasia components.

[Cost-effectiveness model of a fixed dose combination of solifenacin and tamsulosin for the treatment of LUTS associated with BPH with inadequate response to monotherapy.] / Modelo de coste­efectividad de la combinación a dosis fijas de solifenacina y tamsulosina en el tratamiento de los STUI asociados a HBP con respuesta inadecuada a la monoterapia.

OBJECTIVE: To compare the cost-effectiveness of fixed dose combination of solifenacin 6 mg and tamsulosin 0.4 mg in a controlled absorption system (TOCAS) with free dose combination of tolterodine plus tamsulosin, when used for the treatment of patients with moderate to severe lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) who do not respond adequately to monotherapy. The analysis was conducted from the perspective of the Spanish National Health System. METHODS: A Markov model was developed in Excel, with 1-year time horizon. The transition probabilities of the model were obtained from the NEPTUNE clinical trial and published literature. Unit costs were obtained from Spanish sources. The use of healthcare resources was validated by Spanish clinical experts. Both deterministic and probabilistic analyses were performed to determine the key drivers of the model. RESULTS: Treatment with fixed dose combination of solifenacin plus TOCAS was found to be dominant, as it resulted in lower annual costs (€ 1,349 vs. € 1,619) and greater quality-adjusted life years (QALY) gained per patient (0.8406 vs. 0.8386) when compared with free dose combination of tolterodine plus tamsulosin. According to the probabilistic analyses, the probability of the fixed dose combination treatment being cost-effective at a willingness to pay threshold of € 20,000 or 30,000 would be 100%. CONCLUSIONS: This analysis suggests that fixed dose combination of solifenacin plus TOCAS represents a cost-effective choice for the treatment of patients with moderate to severe LUTS/BHP, compared to free dose combination of tolterodine plus tamsulosin.

[TFEB-amplified renal cell carcinoma. A case report and review of the literature]. / Carcinoma de células renales asociado a amplificación del gen TFEB. Presentación de un caso y revisión de la literatura.

Renal carcinomas associated with translocation of transcription factors of the MiT/TFE family include, according to the latest World Health Organization classification, carcinomas with Xp11 translocation that involve the TFE3 gene and those with translocation t(6;11)(p21;q12) that affect the TFEB gene. Each one of these sub-types have well-defined clinicopathological and molecular characteristics. Currently, progress in molecular techniques has led to the description of neoplasms with molecular changes in these same genes but with alterations different to translocation. Thus, recently, cases have been published of TFEB-amplified renal carcinomas with prognoses that vary from cases associated with translocation and could therefore represent a new entity. We present a case of TFEB-amplified renal carcinoma with a full description of the clinicopathological characteristics and an updated revision of these neoplasms.

[Cost effectiveness of Mirabegron and antimuscarinic drugs in patients with hiperactive bladder.] / Coste-efectividad de mirabegrón y los antimuscarínicos en pacientes con vejiga hiperactiva.

OBJECTIVE: To evaluate the costeffectivenessof mirabegron in comparison to theantimuscarinic drugs tolterodine, solifenacin andfesoterodine, in the treatment of urgency, increasedmicturition frequency and urinary incontinence in patientswith overactive bladder (OAB). MATERIAL AND METHODS: A Markov model in Excel,with a time horizon of 5 years was developed fromthe National Health System and societal perspective.Clinical effectiveness was estimated from a clinical trial(SCORPIO) and a network meta-analysis. Unit costswere obtained from Spanish sources. The effectivenessof the treatments was measured as quality adjusted lifeyears(QALY). Deterministic and probabilistic sensitivityanalyses were performed. RESULTS: For the 5-year time horizon, the incrementalcost per patient with mirabegron 50 mg versustolterodine was € 195.52 and € 157.42, from theNational Health System (NHS) and societal perspectivesrespectively, with a gain of 0.0127 QALY withmirabegron. Consequently, the cost of gaining a QALYwith mirabegron versus tolterodine was 15,432 € and12,425 € respectively. The probability that mirabegronwould be cost-effective at a willingness to pay thresholdof € 30,000 was: 70% (NHS) and 71% (society)versus tolterodine; 94% (NHS and society) versussolifenacin 5 mg; 84% (NHS) and 84.5% (society)versus solifenacin 10 mg; 96% (NHS and society)versus fesoterodine 4 mg; 98% (NHS) and 99% (society)versus fesoterodine 8 mg. The highest probability thatmirabegron would be cost-effective at a willingness topay threshold of € 20.000 and € 25.000 per QALYgained, is obtained versus fesoterodine 4 mg and 8 mgfrom both NHS and society perspectives. CONCLUSIONS: The treatment of patients with OABwith mirabegron 50 mg is likely to be cost-effectivecompared to treatment with antimuscarinics.

OBJETIVO: Evaluar el coste-efectividad de mirabegrón frente a los fármacos antimuscarínicos tolterodina, solifenacina y fesoterodina, en el tratamiento sintomático de la urgencia, el aumento de la frecuencia miccional y la incontinencia de urgencia en los pacientescon vejiga hiperactiva (VH).MÉTODOS: Modelo de Markov en Excel, con un horizonte temporal de 5 años, desde la perspectiva del Sistema Nacional de Salud y de la sociedad. La efectividad clínica se obtuvo de un ensayo clínico frente a tolterodina y de un metaanálisis. Los costes unitarios se obtuvieron de fuentes españolas. La efectividad de los tratamientos se midió como años de vida ajustados por calidad de vida (AVAC). Se realizaron análisis de sensibilidad determinísticos y probabilísticos. RESULTADOS: Para el horizonte temporal de 5 años, el coste incremental por paciente con mirabegrón 50 mg frente a tolterodina es de 195,52 € y 157,42 €, desde las perspectivas del Sistema Nacional de Salud (SNS) y social, respectivamente, con una ganancia de 0,0127 AVAC con mirabegrón. El coste de ganar un AVAC con mirabegrón frente a tolterodina sería de 15.432 € y de 12.425 €, respectivamente. La probabilidad de que mirabegrón sea coste-efectivo frente a tolterodina, sería del 70% y del 71%, respectivamente. Para el SNS, la probabilidad de coste-efectividad de mirabegrón frente a solifenacina 5 y 10 mg sería del 84% y del 84,5%, respectivamente y en comparación con fesoterodina 4 y 8 mg sería del 96% y 98%, respectivamente. CONCLUSIONES: El tratamiento de los pacientes con VH con mirabegrón 50 mg es probablemente coste- efectivo en comparación con el tratamiento con antimuscarínicos.

[From tumour to tumour: Metastasis of invasive ductal breast carcinoma to chromophobe renal cell carcinoma]. / Tumor a tumor: metástasis de carcinoma ductal infiltrante de mama sobre carcinoma de células cromófobas de riñón.

The coexistence of two or more tumours in the same patient is unusual, but even rarer is the metastasis of one tumour to another. Most reports are based on evidence from autopsies; very few refer to surgical specimens. The most common primary tumour is pulmonary carcinoma and most frequent metastatic tumour is renal clear cell carcinoma. We present the case of a 54 year-old female with a past history of infiltrating ductal carcinoma of the breast with metastases in lung, lymph nodes and bone. Three months previously to her referral to us, she had developed a renal mass and underwent nephrectomy. Histopathology revealed a renal chromophobe cell carcinoma with intratumoral breast cancer metastasis. We describe the histopathological, immunohistochemical and molecular features and review the recent literature.

Cost effectiveness of rivaroxaban versus enoxaparin for prevention of post-surgical venous thromboembolism from a U.S. payer's perspective.

BACKGROUND: Major orthopaedic surgery, such as total hip replacement (THR) and total knee replacement (TKR), is associated with an increased risk of venous thromboembolism (VTE). OBJECTIVE: Clinical trials have demonstrated the efficacy of rivaroxaban, a once-daily, orally administered Factor Xa inhibitor, for the prevention of VTE in patients undergoing THR or TKR. This analysis evaluated the cost effectiveness of rivaroxaban compared with enoxaparin, from a U.S. payer's perspective. METHODS: A decision-analytic model was developed to compare the costs and outcomes associated with rivaroxaban and enoxaparin for the prevention of VTE. The model replicated short-term clinical outcomes from the phase III RECORD trials. RECORD1 and RECORD2 compared rivaroxaban 10 mg daily (qd), given for 35 days, with enoxaparin 40 mg qd, given for 35 days or 10 to 14 days, respectively, in patients undergoing THR. RECORD3 compared 10 mg of rivaroxaban qd for 10 to 14 days versus 40 mg of enoxaparin qd for 10 to 14 days in patients undergoing TKR. The decision-analytic model also included data on long-term complications and sequelae as captured in observational studies and databases. It also included direct year 2010 medical costs over 1-year and 5-year time horizons. A series of sensitivity analyses were performed to determine the impact of different factors on the results of the model. Results of the cost-effectiveness analysis were reported in terms of symptomatic VTE events avoided. RESULTS: Rivaroxaban was associated with cost savings of $US 511.93 per patient and prevented an average of 0.0145 symptomatic VTE events per patient in the THR population, compared with enoxaparin. For a TKR population, 10 to 14 days of rivaroxaban prophylaxis was associated with cost savings of $US 465.74 and prevented an average 0.0193 symptomatic VTE events per patient. Sensitivity analysis suggested that the results of the model were robust, with cost savings ranging from $US 133.96-629.57 in the THR population and $US 293.01-848.68 in the TKR population, depending on the variables used. Sensitivity analysis also suggested that the economic profile of rivaroxaban is improved when the time horizon of the model is extended from 1 year to 5 years. A probabilistic sensitivity analysis confirmed the findings of baseline results, showing that rivaroxaban was less costly and more effective in all model simulations for both populations. CONCLUSIONS: This decision-analytic model analysis, from the U.S. payer's perspective, concluded that rivaroxaban may be cost saving in both the THR and the TKR populations, when compared with enoxaparin in the U.S.

Cost analysis: treatment of chemotherapy-induced anemia with erythropoiesis-stimulating agents in five European countries.

OBJECTIVE: Cost-analysis comparing darbepoetin-alfa (DARB), epoetin-alfa (EPO-A), and epoetin-beta (EPO-B) for treatment of chemotherapy-induced anemia in Belgium concluded that costs for DARB-treated patients were significantly lower than costs for EPO-A- or EPO-B-treated patients. The objective of the present study was to extend the Belgian analysis to Austria, France, Italy, Portugal, and Spain, estimating differences in costs between erythropoiesis-stimulating agents (ESAs) in each country. METHODS: Differences in epidemiology and treatment patterns between countries were adjusted using data from Eurostat, national cancer registries, IMS sales data, and reimbursement and treatment guidelines. Belgian unit costs were replaced with country-specific costs. Costs were analyzed using a mixed-effects model stratifying for propensity score quintiles. RESULTS: All populations were comparable to the Belgian population in terms of age, gender, ESA, and blood transfusions use. After adjusting for country-specific chemotherapy use and cancer incidence, total management costs per patient (Euro, 2010) were 19-26% (France, Spain) lower with DARB compared with EPO-A (p < 0.0001) and 20-36% (Portugal, Austria) compared with EPO-B (p < 0.01). Anemia-related costs with DARB were between 12% (Portugal; p = 0.0235) and 38% (Italy; p < 0.0001) lower compared with EPO-A (p < 0.01; all remaining countries), and between 13% (Austria; p = 0.064) and 19% (Portugal; p = 0.0028) lower compared with EPO-B (p < 0.05; all remaining countries except Italy; p = 0.0935). LIMITATIONS: Not all differences could be accounted for by a lack of country-specific data; however, the potential under- and over-estimation of costs should be similar for all three ESAs. CONCLUSIONS: These findings are in line with the Belgian analysis. In all countries, total and anemia-related costs were lowest in patients receiving DARB vs EPO-A or EPO-B. This study demonstrates the feasibility of adapting real-life country-specific data to other settings, adjusting for differences in patients' characteristics and treatment strategies. These findings should be valuable in healthcare decision-making in oncology patients treated in each of the countries studied.

Cost and outcomes associated with rivaroxaban vs enoxaparin for the prevention of postsurgical venous thromboembolism from a US payer's perspective.

OBJECTIVE: The objective of this analysis was the evaluation of the outcomes and costs associated with rivaroxaban and enoxaparin for the prevention of postsurgical venous thromboembolism (VTE) in patients undergoing total hip replacement (THR) and total knee replacement (TKR) from the US payer perspective. METHODS: VTE event rates have been reported in three Phase III clinical trials that compared rivaroxaban and enoxaparin for VTE prevention after orthopedic surgery during the prophylaxis (≤35 days for THR patients and 10-14 days for TKR patients) and post-prophylaxis periods (≤90 days following surgery). These data were used in this decision-analytic model to estimate and compare health outcomes and costs associated with rivaroxaban and enoxaparin. The base-case analysis considered the number and costs of symptomatic VTE events during the prophylaxis period only. A 90-day horizon was considered in the sensitivity analysis. RESULTS: Following THR, when extended durations of prophylaxis (35 days) were compared, rivaroxaban was associated with lower costs than enoxaparin, with total saving costs of $695/patient. When an extended duration of rivaroxaban prophylaxis (35 days) was compared with a short duration (10-14 days) of enoxaparin prophylaxis, rivaroxaban was estimated to prevent 9.9 additional symptomatic VTE events per 1000 patients, while saving $244/patient (rate/1000 patients). In the TKR population, short duration of rivaroxaban prophylaxis was estimated to prevent 13.1 additional symptomatic VTE events per 1000 patients. It was also less costly than short duration enoxaparin prophylaxis, with a saving of $411/patient (rate/1000 patients). LIMITATIONS: Only statistically significant differences were captured in the base-case economic analysis, and, therefore, differences in pulmonary embolism (PE) and bleeding events were not captured. CONCLUSIONS: In this model, rivaroxaban reduced total treatment payer costs vs enoxaparin for the prevention of VTE in THR or TKR patients.

Fitting a xenobiotic receptor into cell homeostasis: how the dioxin receptor interacts with TGFbeta signaling.

As our knowledge on the mechanisms that control cell function increases, more complex signaling pathways and quite intricate cross-talks among regulatory proteins are discovered. Establishing accurate interactions between cellular networks is essential for a healthy cell and different alterations in signaling are known to underline human disease. Transforming growth factor beta (TGFbeta) is an extracellular cytokine that regulates such critical cellular responses as proliferation, apoptosis, differentiation, angiogenesis and migration, and it is assumed that the latency-associated protein LTBP-1 plays a relevant role in TGFbeta targeting and activation in the extracellular matrix (ECM). The dioxin receptor (AhR) is a unique intracellular protein long studied because of its critical role in xenobiotic-induced toxicity and carcinogenesis. Yet, a large set of studies performed in cellular systems and in vivo animal models have suggested important xenobiotic-independent functions for AhR in cell proliferation, differentiation and migration and in tissue homeostasis. Remarkably, AhR activity converges with TGFbeta-dependent signaling through LTBP-1 since cells lacking AhR expression have phenotypic alterations that can be explained, at least in part, by the coordinated regulation of both proteins. Here, we will discuss the existence of functional interactions between AhR and TGFbeta signaling. We will focus on regulatory and functional aspects by analyzing how AhR status determines TGFbeta activity and by proposing a mechanism through which LTBP-1, a novel AhR target gene, mediates such effects. We will integrate ECM proteases in the AhR-LTBP-1-TGFbeta axis and suggest a model that could help explain some in vivo phenotypes associated to AhR deficiency.

Recruitment of CREB1 and histone deacetylase 2 (HDAC2) to the mouse Ltbp-1 promoter regulates its constitutive expression in a dioxin receptor-dependent manner.

Latent TGFbeta-binding protein 1 (LTBP-1) is a key regulator of TGFbeta targeting and activation in the extracellular matrix. LTBP-1 is recognized as a major docking molecule to localize, and possibly to activate, TGFbeta in the extracellular matrix. Despite this relevant function, the molecular mechanisms regulating Ltbp-1 transcription remain largely unknown. Previous results from our laboratory revealed that mouse embryonic fibroblasts (MEF) lacking dioxin receptor (AhR) had increased Ltbp-1 mRNA expression and elevated TGFbeta activity, suggesting that AhR repressed Ltbp-1 transcription. Here, we have cloned the mouse Ltbp-1 gene promoter and analysed its mechanism of transcriptional repression by AhR. Reporter gene assays, AhR over-expression and site-directed mutagenesis showed that basal Ltbp-1 transcription is AhR-dependent. Chromatin immunoprecipitation (ChIP) and RNA interference (RNAi) revealed that AhR regulates Ltbp-1 transcription by a mechanism involving recruitment of co-activators such as CREB1 and co-repressors such as HDAC2 to the Ltbp-1 promoter. In AhR-expressing (AhR+/+) MEF cells, the recruitment of HDAC1, 2 and 4 correlated with decreased K8H4 acetylation and impaired binding of pCREB(Ser133) to the Ltbp-1 promoter, likely maintaining a constitutive repressed state. AhR-/- MEF cells had the opposite pattern of HDACs and pCREB1(Ser133) binding to Ltbp-1 promoter, and therefore, over-expressed Ltbp-1 mRNA. In agreement, siRNA for HDAC2 increased Ltbp-1 expression and K8H4 acetylation in AhR+/+ but not in AhR-/- MEF cells. We suggest that HDAC2 binding keeps Ltbp-1 promoter repressed in AhR+/+ MEF cells, whereas in AhR-null MEF cells the absence of HDAC2 and the binding of pCREB(Ser133) allow Ltbp-1 transcription. Thus, epigenetics can contribute to constitutive Ltbp-1 repression by a mechanism requiring AhR activity.

LTBP-1 blockade in dioxin receptor-null mouse embryo fibroblasts decreases TGF-beta activity: Role of extracellular proteases plasmin and elastase.

In mouse embryonic fibroblasts (MEF) lacking dioxin receptor (AhR), high levels of latent transforming growth factor-beta (TGF-beta)-binding protein-1 (LTBP-1) correlated with increased TGF-beta1 activity, an observation suggesting that LTBP-1 could contribute to maintain TGF-beta1 levels. Here, using small interfering RNAs (siRNA), we have first analyzed if LTBP-1 expression affected TGF-beta1 activity in MEF cells. We have then determined how LTBP-1 levels could alter the activity of extracellular proteases known to activate TGF-beta1, and finally, whether protease inhibition could reduce TGF-beta1 activation. LTBP-1 inhibition by siRNA in AhR-/- MEF decreased the amount of active TGF-beta1 and reduced plasminogen activators (PA)/plasmin and elastase activities and thrombospondin-1 (TSP-1) expression, without significantly affecting their mRNA levels. On the contrary, LTBP-1 siRNA restored matrix metalloproteinase-2 (MMP-2) activity in AhR-/- MEF. Interestingly, whereas a TGF-beta1 neutralizing antibody mimicked many of the LTBP-1 siRNA effects on extracellular proteases, addition of recombinant TGF-beta1 protein increased proteases activity over basal levels in AhR-/- MEF. These proteases contributed to TGF-beta activation since their specific inhibitors reduced active TGF-beta levels in these cells. These results suggest that LTBP-1 contributes to TGF-beta1 activation in MEF, possibly by influencing the activities of PA/plasmin, elastase, TSP-1, and MMP-2. TGF-beta1, on the other hand, could be also involved in maintaining the activity of these extracellular proteases. Thus, LTBP-1 appears to play a role in TGF-beta1 activation through a process involving extracellular protease activities, which, in turn, could be affected by TGF-beta1 levels.